The Organic Chemistry of Drug Synthesis, Volumes 1 to 4

The Organic Chemistry of Drug Synthesis Volume 1 DANIEL LEDNICER Chemical Research Mead Johnson & Co. Evansville, Indiana LESTER A . MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas

with a Glossary by Philip F. vonVoigtlander The Upjohn Company

A WILEY-INTERSCIENCE PUBLICATION

JOHN WILEY & SONS New York • Chichester • Brisbane • Toronto

Copyright © 1977 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library

of Congress

Cataloging

in Publication

Lednicer, Daniel, 1929The organic chemistry of drug synthesis. "A Wiley-Interscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421.L423 615M91 ISBN 0-471-52141-8

76-28387

Printed in the United States of America 10 9

Data:

To Beryle and Betty whose steadfastness made that which follows become real

The three princes of Serendip, Balakrama, Vijayo, and Rajahsigha, as they traveled "...were always making discoveries, by accident and sagacity, of things they were not in quest of...n*

^Horace Walpole, in a letter of January 28, 1754, as quoted in "The Three Princes of Serendip," by E. J. Hodges, Atheneum, N.Y., 1!K)4 vii

Preface

There exists today an abundance of excellent texts covering the various aspects of organic chemistry. The student of medicinal chemistry can choose among any of a number of first-rate expositions of that field. The reader who is primarily interested in the synthesis of some particular class of medicinal agents, however, will often find that he must consult either the original literature or some specialized review article. The same quandary faces the student who wishes to become acquainted with the biologic activity characteristic of some class of organic compounds. There thus seemed to be a place for a book that would cover specifically the chemical manipulations involved in the synthesis of medicinal agents. A book then was intended that would supplement both the available medicinal and organic chemistry texts. Comprehensive coverage of both the preparation and biologic activity of all organic compounds reported in the literature to show such activity would lead to a truly enormous treatise. In order to keep this book within bounds, we deliberately restricted our coverage to medicinal agents that have been assigned generic names. This means that at some time during the development of a drug, the sponsoring laboratory has felt the agent to have sufficient promise to apply to the USAN Council or its equivalent ;ibroad for the granting of such a name. By far, the majority of t he compounds in this volume denoted by generic names are marketed as drugs; some compounds, however, have either gotten only us far as clinical trial and failed, or are as yet in early preimirketing stages. We have not excluded the former since these .ire often closely related to drugs in clinical practice and thus serve as further illustration of molecular manipulation. We have further kept the book fairly current insofar as drugs available for sale in the United States are concerned. The informed reader will note that this book is not nearly as current when it comes to drugs available only outside this country—our own version of ix

the drug lag. In order to sustain the chemical focus of the book, we departed in organization from the traditional texts in medicinal chemistry. The current volume is organized by structural classes rather than in terms of pharmacologic activities. This seems to allow for more natural treatment of the chemistry of many classes of compounds, such as the phenothiazines which form the nucleus for more than a single class of drugs. This framework has admittedly led to some seemingly arbitrary classifications. The sulfonamides, for example, are all regarded as derivatives of paminobenzenesulfonamide even though this is sometimes the smallest moiety in a given sulfa drug; should these be classed as sulfonamides or as a derivative of the appropriate heterocycle? In this case at least, since the biologic activity is well known to be associated with the sulfonamide portion—the pharmacophoric group—the compounds are kept together. Occasionally the material itself demanded a departure from a purely structural approach. The line of reasoning that leads from morphine to the 4-phenylpiperidines is so clear—if unhistoric—as to demand exposition in an integral chapter. The chronologically oriented chapter on the development of the local anesthetics is included specifically to give the reader some appreciation of one of the first approaches to drug development. We hope it is clear from the outset that the syntheses outlined in this book represent only those published in the literature. In many cases this can be assumed to bear little relation to the processes used in actually producing the drugs on commercial scale. The latter are usually developed after it is certain the drug will be actually marketed. As in the case of all largescale organic syntheses, they are changed from the bench-scale preparations in order to take into account such factors as economics and safety. Details of these are not usually readily available. Again in the interest of conciseness, the discussion of the pharmacology of the various drugs was cut to the bone. The activity is usually indicated by only a short general phrase. Comparisons among closely related analogs as to differences in efficacy or side effects are usually avoided. Such discussion more properly belongs in a specialized text on clinical pharmacology. Since we do not presume that the reader is acquainted with biologic or medical terms, a glossary of the more common terms used in the book has been included following the last chapter. This glossary is intended more to provide simple definitions than in-depth pharmacologic discussion. We urge the reader interested in further study of such entries to consult any of the excellent reference works in medicinal chemistry, such as Burger's "Medicinal

Chemistry" or Rushig and Ehrhard's "Arzneimittel." This book assumes a good working knowledge of the more common organic reactions and a rudimentary knowledge of biology. We hope it will be of interest to all organic chemists curious about therapeutic agents, how these were developed, the synthetic operations used in their preparation, and the types of structures that have proven useful as drugs. We hope further that this long look at what has gone before may provide food for thought not only to the practicing medicinal chemist but also to the organic chemist engaged in research in pure synthetic chemistry. Finally, we would like to express our most sincere appreciation to Ms. Carolyn Jarchow of The Upjohn Company. Among the press of daily responsibilities she not only found time for typing this manuscript, but provided the mass of structural drawings .is well. Daniel Lednicer Lester A. Mitscher October 1975

Kalamazoo, Michigan Lawrence, Kansas

Contents

PAGE Chapter 1.

Introduction

1

Chapter 2.

A Case Study in Molecular Manipulation: The Local Anesthetics 1. Esters of Aminobenzoic Acids and Alkanolamines a. Derivatives of Ethanolamine b. Modification of the Basic Ester Side Chain 2. Amides and Anilides 3. Miscellaneous Structures References

12 14 18 21

Chapter 3.

Monocyclic Alicyclic Compounds 1. Prostaglandins 2. Miscellaneous Alicyclic Compounds References

23 23 35 38

Chapter 4.

Benzyl and Benzhydryl Derivatives 1. Agents Based on Benzyl and Benzhydryl Amines and Alcohols a. Compounds Related to Benzhydrol b. Compounds Related to Benzylamine c. Compounds Related to Benzhydrylamine References

40

Chapter 5.

Phenethyl and Phenylpropylamines References

62 83

Chapter 6.

Arylacetic and Arylpropionic Acids xiii

85

4 9 9

40 40 50 58 60

PAGE References

98

Chapter 7.

Arylethylenes and Their Reduction Products References

100 106

Chapter 8.

Monocyclic Aromatic Compounds 1. Benzoic Acids 2. Anthranillic Acids 3. Anilines 4. Derivatives of Phenols 5. Derivatives of Arylsulfonic Acids a. Sulfanilamides b. Bissulfonamidobenzenes c. Sulfonamidobenzoic Acids d. Sulfonylureas e. Diarylsulfones References

108 108 110 111 115 120 120 132 134 136 139 141

Chapter 9.

Polycyclic Aromatic Compounds 1. Indenes a. Indenes with Basic Substituents b. Indandiones 2. Dihydronaphthalenes 3. Dibenzocycloheptenes and Dibenzocycloheptadienes 4. Colchicine References

145 145 145 147 148

Chapter 10. Steroids 1. Commercial Preparation of Estrogens, Androgens, and Progestins 2. Aromatic A-Ring Steroids 3. 19-Norsteroids a. 19-Norprogestins b. 19-Norsteroids by Total Synthesis c. 19-Norandrogens 4. Steroids Related to Testosterone 5. Steroids Related to Progesterone 6. The Oral Contraceptives 7. Cortisone and Related Antiinflammatory Steroids 8. Miscellaneous Steroids References xiv

149 152 154 155 156 160 163 163 166 169 172 178 186 188 206 207

PAGE Chapter 11. Tetracyclines References

212 216

Chapter 12. Acyclic Compounds References

218 225

Chapter 13.

Five-Membered Heterocycles 1. Derivatives of Pyrrolidine 2. Nitrofurans 3. Oxazolidinediones and an Isoxazole 4. Pyrazolonones and Pyrazolodiones 5. Imidazoles 6. Imidazolines 7. Hydantoins 8. Miscellaneous Five-Membered Heterocycles References

226 226 228 232 234 238 241 245 247 250

Chapter 14.

Six-Membered Heterocycles 1. Pyridines 2. Derivatives of Piperidine 3. Morpholines 4. Pyrimidines 5. Barbituric Acid Derivatives 6. Pyrazines and Piperazines 7. Miscellaneous Monocyclic Hetexocycles References

253 253 256 260 261 267 277 280 283

Chapter 15.

Derivatives of Morphine, Morphinan, and Benzomorphan; 4-Phenylpiperidines 1. Morphine 2. Morphinans 3. Benzomorphans 4. 4-Phenylpiperidines References

286 287 292 296 298 310

Five-Membered Heterocycles Fused to One Benzene Ring 1. Benzofurans 2. Indoles 3. Indole Alkaloids 4. Isoindoles 5. Indazoles 6. Benzoxazoles 7. Benzimidazoles

313 313 317 319 321 323 323 324

Chapter 16.

PAGE 8. Benzothiazoles References Chapter 17.

326 328

Six-Membered Heterocycles Fused to One Benzene Ring 1. Coumarins and Chromones 2. Quinolines 3. Isoquinolines 4. Six-Membered Rings Containing Two Hetero Atoms Fused to One Benzene Ring 5. 1,2,4-Benzothiadiazines and Their Reduction Products References

330 330 337 347 351 355 360

Chapter 18.

Benzodiazepmes References

363 371

Chapter 19.

Phenothiazines References

372 391

Chapter 20.

Additional Heterocycles Fused to Two Benzene Rings 1. Dibenzopyrans 2. Acridines 3. Thioxanthenes 4. Dibenzazepines a. Dihydrodibenzazepines b. Dibenzazepines 5. Dibenzoxepins 6. Dibenzodiazepines 7. Dibenzothiazepines References

393 393 396 397 401 401 403 404 404 405 406

Chapter 21.

3-Lactam Antibiotics 1. Penicillins 2. Cephalosporins References

40? 40£ 416 420

Chapter 22.

Miscellaneous Fused Heterocycles 1. Purines References

423 423 431

Cross Index of Drugs

433 xvi

PAGE Glossary

448

Index

457

xvii

THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS

CHAPTER 1

Introduction

Medicinal chemistry, like truth, defies ready definition. The practicing organic chemist as a rule knows operationally what is, or more often what is not, medicinal chemistry. He would be hnrd pressed, however, to set down on paper a rigorous definit ion of that discipline. Organic chemistry and medicinal chemistry share a venerable iommon history. Many of the founders of organic chemistry had .in intense interest not only in molecules from nature but also in the effects of synthetic compounds on living systems. One ured mention in this connection only Emil Fischer1s work in carbohydrates and proteins and Paul Ehrlich's pioneering work on i licmotherapy, With the development of a series of efficacious synthetic medicinal agents, a body of lore evolved concerning !he molecular modifications that would most likely lead to biologically active molecules. Almost of necessity, then, this specialized knowledge engendered the discipline that came to be known as medicinal chemistry. The operational manipulations were still those or organic chemistry, as indeed were the moleinles being modified; the emphasis of the work was subtly ilmnged, however, from that of classic organic chemistry. The overriding goal became the creation of molecules that would niter some process in a living system. Tangentially, then, we fipproach an organic chemist's working definition of medicinal ihemistry: The use of synthetic organic chemistry to create molecules that will alter in a useful way some disease process in a living system. The use of drugs to treat disease antedates modern science hy a good many millenia. Every culture sooner or later developed U s own pharmacopeia. These compendia of natural products and 1

Introduction

extracts were interesting collections of many substances, most of which were at best useless, but include a residue of drugs with indisputable biologic activity. Opium, hashish, cocaine, and caffeine all derive from these ancient sources. It was natural therefore that medicinal chemistry at its birth concentrated on medicinal agents related to natural products. Despite some early successes, this area remained essentially quiescent until the development of more sophisticated synthetic methods made the preparation of more complex molecules feasible. A second broad source for biologically active molecules came out of the biochemical investigation on hormonal substances. This work led to the isolation of such substances as thyroxin, epinephrine, the steroids, and most recently the prostaglandins. Synthetic work that took the structure of epinephrine as its starting point resulted in the development of a host of drugs useful as, respectively, central nervous system stimulants, antiappetite agents, and blood-pressure-lowering compounds. The original indication for the preparation of steroid drugs seemed to be for use in replacement therapy for cases of insufficiency. A combination of clever synthetic work and serendipitous biology led to a drug that bids fair to revolutionize the sexual ethic in Western society—the Pill. Analogous manipulation of the cortisone molecule has yielded a series of extremely potent antiinflammatory agents. More recently this process has been repeated with the prostaglandins. In this case, the introduction of the first prostaglandin into medical practice—as an abortifacient agent—came within a mere dozen years of the identification of these elusive and unstable hormonal agents. The third, and to date, perhaps the most important source of new structures for drugs, comes from the synthetic efforts of the medicinal chemist combined with the various biologic screens operated by his colleague, the pharmacologist. Prompted either by some pet structural theory or some dimly perceived structural features present in biologically active compounds described in the literature, medicinal chemists have frequently prepared structurally novel compounds. More often than not, the results of testing these merely added to the world's enormous mass of negative data. Sometimes, however, these compounds turned out to have biologic activity, although not necessarily that which was intended. Such a finding th^n started the arduous and exciting search for the structural features that optimize activity at the expense of side effects. (It can be stated baldly that the drug without side effects has yet to be devised.) If all went well-which it does for only about one in five thousand compounds synthesized—the compound eventually reached the marketplace as a drug with a generic name.

Introduction

Since this is a profit-oriented world, research programs are sometimes started in order to prepare a variation on a competitor's drug. Although at first sight it is an activity to be viewed askance, this endeavor has often met with unexpectedly fruitful results. Small variations on the phenothiazine antihistamines-iprompted perhaps by motivation such as the above—led to the first drugs available for treatment of schizophrenia. Modification of the central heterocyclic ring then gave a series of drugs effective for the treatment of depression—the tricyclic antidepressants. For the past few years, however, there has been a hiatus in the pace of discovery of novel medicinal agents. It has been postulated by some that the field has now slowed down due to the limitations of the almost strictly empirical approach that has been applied to date to drug development. It is possible, too, that the higher standards of efficacy and safety that a new drug must meet today, combined with the enormously increased costs of clinical trials, have acted to keep all but the most promising new drugs off the market. No discussion of drug development is complete without mention of the serious efforts being applied towards rational drug development. The availability of sophisticated new methods has made it possible to describe the structure of biologically active compounds in such detail as to include the molecular orbital structure. New recognition of the effect of such physical properties as lipid-water distribution on biologic activity has come from the work of Hansch. Ready access to computers has Led to many studies on the correlation of these physical properties and biologic activity. Since this field is so young, it has yet to make its mark on drug development. In sum, then, the sources for the inspiration that have led to the development of drugs have been many and varied. In all of these, however, the process involved synthetic organic chemistry at some important early stage. This book explores the chemistry that has actually been used to prepare the organic compounds that eventually became drugs. Since this is done from the viewpoint of organic chemistry, the book—except for the first historical chapter—is organized on a structural rather than a pharmacologic framework. This book is intended as a supplement rather than a substitute for the current texts in medicinal chemistry. The reader is thus urged to consult the latter when he finds the admittedly cursory discussions of biologic activity to be found below inadequate.

CHAPTER 2

A Case Study in Molecular Manipulation: The Local Anesthetics

Man!s use of drugs predates by at least several millenia the development of any systematic study of therapeutics or pharmacology. The inquisitive nature of Homo sapiens led him to ingest will-nilly various plants found in his environment. Those which produced either pleasant or apparently therapeutic effects were incorporated into his culture. Those which produced toxic effects were relegated to use in hunting or warfare or in satisfying his other notable characteristic-belligerence. Thus, various parts of the world have seen the use of such plant products as opium, hashish, cocaine, and alcohol as part of the ritual of life. To this day, new alkaloids with effects on the central nervous system are being discovered as a result of their use by Amazonian tribes. The growth of the exact sciences in the nineteenth century led to chemical and pharmacologic investigation of these various plant products. This work usually involved isolation and attempts at structural determination of the active principles from the extracts. Since many of these organic compounds have fairly complex structures and the extant methods of structure determination were limited by imperfections in organic theory as well as by the lack of spectroscopic methods, these were often not correctly identified for many years. The partial structures that were obtained did, however, suggest that the active compounds were not easily attainable by total synthesis, given the methods then available. Initial efforts at the preparation of synthetic versions of the active compounds at that time usually consisted in the preparation of structural fragments that embodied various known features of the natural product. This process of stripping down the molecule had the advantage not

Local Anesthetics

only of defining that part of the molecule necessary for biologic activity but also provided molecules ammenable to commercial preparation by total synthesis. One should hasten to add that this approach was only successful in certain instances. The line of research that led from the isolation of cocaine to the development of the local anesthetics is perhaps a classic example of the molecular dissection approach to medicinal chemistry. It had been known from the time of the Conquistadores that the Incas of the Andean Altoplano chewed the leaves of the coca bush (Erythroxylon coca) in order to combat fatigue and deaden the pangs of hunger. Wohler discovered the local deadening of pain produced by dilute solution of the alkaloid, cocaine, obtained from extracts of the leaves;1 the first rational recorded use of the extracts in medicine was as a local anesthetic for opthalmic surgery. It was early determined that hydrolysis of cocaine affords benzoic acid, methanol, and a nonsaponifiable fragment dubbed ecgonine (2).2 Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready thermal decarboxylation to tropinone (4) ,3""5 The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently.6""8 Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine.9 Reduction, esterification with methanol followed by benzoylation then affords cocaine.

Local Anesthetics

Although the gross structure was known by the turn of the century, the stereochemistry was not fully elucidated until some fifty years later. In essence, the relative steric position of the acid and hydroxyl functions was established by acyl migration from oxygen to nitrogen and back. Thus, Curtius reaction on benzoylecgonine (6) affords amine, 7, in which the new amine group can be assumed to have the same stereochemistry as the precursor, carboxyl. That this is cis to the acyl group can be inferred from the finding that treatment of 7 with base gives the amide (8); this reverts to the ester with acid.10 CH3-

CH3-

Degradation of cocaine by means of cyanogen bromide leads to the well-known demethylation-N-cyanation reaction. Hydrolysis of the N-cyano function affords the carbamate (10). Treatment of that carbamate with sodium methoxide leads to formation of the cyclic acyl urea (11), demonstrating the cis relation of the carboxyl group and the nitrogen bridge in cocaine. 11 ' 12 Finally, correlation of ecgoninic acid (12), an oxidation product of ecgonine with L-glutamic acid, showed the absolute configuration of cocaine to be 2(R)-carbomethoxy-3(S)-benzoyloxy-l(R)tropane. The bulk of the work on analogs of cocaine was aimed at compounds that would maximize the local anesthetic component of the biologic activity of that.compound. Although pain is essential to alert sentient organisms to injury, there are situations in which this reaction can be inconvenient and deleterious. One need bring to mind only the many forms of minor surgery in which the procedure is made more convenient for both the physician and patient by the fact that the area under attack has been treated so as to cease transmission of the pain signal. Although the

Local Anesthetics

CO 2 CH 3 OCOC 6 H 5 !0C 6H5

11

CO2H

12

molecular mode of action of this class of drugs is as yet unclear, it is known that these agents in some way specifically bind to a component in nerve axons so as to interrupt nervous conduction. The fact that these drugs are usually administered subcutaneously or topically means that their locus of action tends to be restricted to the vicinity of the site of administration. Several local anesthetics show some vasoconstrictor action; this serves to inhibit diffusion from the injection site and further localize the affected area. Local anesthetics are sometimes injected directly into the lower section of the spine so as to block sensation in areas below the injection. This technique, known as spinal anesthesia or "saddle block," was at one time used extensively in childbirth. Reduction of tropanone affords the alcohol epitropanol (13), epimeric with the alcohol obtained on hydrolysis of atropine. The finding that the benzoyl ester, tropacocaine (14), possessed local anesthetic activity showed that the carbomethoxy group was not required for activity.14

CH 3 1

CH3-N

OH 13

Local Anesthetics The bicyclic tropane ring o f cocaine o f course presented serious synthetic difficulties. In o n e attempt to find an a p propriate substitute for this structural u n i t , a piperidine w a s prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia a f fords the piperidone, 17. Isophorone (15) m a y well b e an intermediate in this p r o c e s s ; conjugate addition o f ammonia would then give the aminoketone, 16. Further aldol reaction followed b y ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then b y reaction with benzoyl chloride gives the ester, 19. Ethanolysis o f the nitrile (20) affords alpha-eucaine (21),15 an effective, albeit somewhat toxic, local anesthetic. Condensation o f t h e intermediate, 16, with acetaldehyde rather than acetone gives the piperidone containing one less methyl group (22). Reduction o f the ketone with sodium amalgam CH3

CH3


CH3

CH 2 CH 3

H 0 15

II 0 16

17, R=H 18, R=CH 3

CH,

1 CH3 1 CH3

CH^

cu

HO

CN 19

CH 3

24

CHJ3 ^ TT | CH3

2Or R=N 21, R=(=0), OC 2 H 5

Local Anesthetics

affords largely the equatorial alcohol (23). Esterification by means of benzoyl chloride gives beta-eucaine (24),16>17 an effective local anesthetic. The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simplification of the structure of local anesthetics but resulted finally in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine.

1.

ESTERS OF AMINOBENZOIC ACIDS AND ALKANOLAMINES

a.

Derivatives of Ethanolamine

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important i lasses of local anesthetics. It was found that the simple ethyl «".ter of p-aminobenzoic acid, benzocaine (25),18 showed activity .i1. a local anesthetic. It is of interest to note that this drug, i irst introduced in 1903, is still in use today. Once the struchire of cocaine was established, the presence of an alkanolamine moiety in cocaine prompted medicinal chemists to prepare esters <>l aminobenzoic acids with acyclic alkanolamines. Formula 26 i^presents the putative relationship of the target substances with cocaine. 0

M // CH3CH2OC-V 25

26

Preparation of the prototype in this series, procaine (31),19 '.l.irts with the oxidation of p-nitrotoluene (27) to the corresponding benzoic acid (28) . This is then converted to the acid •hloride (29); reaction of the halide with diethylaminoethanol Milords the so-called basic ester (30). Reduction by any of a -.pries of standard methods (e.g., iron and mineral acid, catalytic reduction) affords procaine (31).19 The ready acceptance of procaine in the clinic as a local

10

Local Anesthetics

27

28, R=0H 29r R=C1

30

\

O

-CO 2 CH 2 CH 2 N

anesthetic led to the preparation of an enormous number of analogs based on this relatively simple structure. The chemistry involved in this work tends to be relatively simple by todayfs standards and is passed over quickly. It was soon found that the esterification reaction could be performed directly on an appropriate derivative of the aminobenzoic acid itself. Thus, ester interchange of an ester of p-aminobenzoic acid (32) with diethylaminoethanol leads to the desired basic ester. (The reaction is driven to completion by removal of the liberated lower alcohol by distillation.) In an alternate approach, the sodium salt of the acid (32a) is alkylated to the ester by means of 2chlorotriethylamine. Compounds containing alkoxy groups tend to be prepared from the hydroxylated nitrobenzoic acids. Thus, for example, alkylation of 33 with propyl bromide in the presence of sodium carbonate affords the ester-ether, 34. Hydrolysis of the ester followed by esterification of the acid chloride by means of diethylaminoethanol gives the intermediate, 35. Reduction of the nitro group gives propoxycaine (36).20 Reductive alkylation of the w,2V-dimethyl analog of procaine (37) with butyraldehyde affords the corresponding iv-butyl analog, tetracaine (38).21 Table 1 lists some additional simple analogs of procaine attainable by variations of the methods outlined above. Paraethoxycaine is of particular note in that it demonstrates that ,

r> IT / *-' 2 5

+

32

32a

ClCH2CH2N

/Vminoalkyl Benzoates

11

OH

OCH 2 CH 2 CH 3

OCH 2 CH 2 CH 3

CoH,

33

34, 35,

CH

CO2CH2CH2N

S

R=CH 2 CH 2 CH 3 R=CH 2 CH 2 N-C 2 H 5

36

3 CH3(CH2)3NH-r

CH3

VcO 2 CH 2 CH 2 lT X

CH3

37

38

not only do these compounds exhibit low order of positional specilicity for activity, but functional groups may even be inter»hnnged at will (e.g., ethoxy for amino). l.ihle 1 -COCH 2 CH 2 N Y

X

X

Y

Z

Generic Name

Reference

OH

H

NH2

Hydroxyprocaine

22

01

H

NH2

Chloroprocaine

23

H

O(CH 2 ) 3 CH3

NH2

Ambucaine

24

NH2

H

Me tabutoxycaine

25

II

NH2

O(CH 2 ) 2 CH 3

Propa1acaine

26

II

H

OC2H5

Paraethoxycaine

27

I 2 ) 3 CH3

12

Local Anesthetics

b.

Modification of the Basic Ester Side Chain

The structure of the side chain carrying the aliphatic basic nitrogen atom shows the same lack of structural demand for biologic activity as does the exact nature of the substitution pattern in the aromatic ring. Thus, acylation of 3(2V,lv-dibutylamino)propanol (39) with pnitrobenzoyl chloride affords the intermediate, 40. Reduction of the nitro group gives butacaine (41),28 an agent equipotent as cocaine as a topical anesthetic. . 1 /(CH2)3CH3 7~C0CH2CH2CH2N X (CH 2 ) 3 CH 3

(CH3CH2CH2CH2 )2NCH2CH2CH2OH 39

40, R=0 41, R=H Incorporation of extensive branching in the side chain similarly does not decrease pharmacologic activity. Reductive alky lation of aminoalcohol, 42, with isobutyraldehyde affords the amine, 43, Acylation of the amine with benzoyl chloride probably goes initially to the amide (44). The acid catalysis used in the reaction leads to an N to 0 acyl migration to afford iso~ bucaine (45).29 NH 2 HOCH 2 OCH 3 CH3 42

|

HOCH2C-NCH2CH CH3

HOCH 2 ONCH 2 CH CH3

43

0

CH3

N

CH3

^-COCH2CNHCH2CH I V CH3 45

In an analogous sequence, reductive alkylation of aminoalcohol, 46, with cyclohexanone affords the secondary amine (47). Acylation with benzoyl chloride affords hexylcaine (48)30 in a reaction that may again involve acyl migration. Inclusion of the basic side chain nitrogen atom in a hetero-

Aminoalkyl Benzoates

13

cyclic ring is apparently consistent with activity. Condensation of a-picoline with formaldehyde affords the alcohol, 49. Treatment of this with sodium' in alcohol leads to reduction of the aromatic ring and formation of the corresponding piperidine (50). Acylation with the acid chloride from anthranilic acid followed by exposure to acid affords piridocaine (51).31

CH 3 I HOCHCH2NH2

>

46

CH 3 I HOCHCH2NH

O

47 0 CH, -C-OCHCH2NH

NX

48 Benzoylation of 3-chloropropan-l-ol affords the haloester, 52. Condensation of this intermediate with the reduction product of a-picoline (53) affords the local anesthetic, piperocaine (54).32

3^N^

HOCH C 2H 2 49 CO2CH2CH2

if

o y<>OCH2CH2CH2Cl 52

+

51

CH3^N 53

14

Local Anesthetics

0 H Yc0CH2CH2CH2N

\ X

54 In a variation of the scheme above, alkylation o£ p-hydroxybenzoic acid with cyclohexyl iodide affords the cyclohexyl ether, 55. (Under alkaline reaction conditions, the ester formed concurrently does not survive the reaction.) Acylation of the acid chloride obtained from 55 with the preformed side chain (56) gives eyelomethycaine (57),33

Q

HO(CH2)3N CH 56

57

2.

AMIDES AND ANILIDES

The common thread in the local anesthetics discussed thus far has been the presence of an aromatic acid connected to an aliphatic side chain by an ester linkage. It is well known in medicinal chemistry that such ester functions are readily cleaved by a large group of enzymes (esterases) ubiquitously present in the body. In the hope of increasing the half-life of the local anesthetics, an amide bond was used as replacement for the ester. There was obtained an agent, procainamide (58), that indeed still showed local anesthetic activity. In addition, however, this drug proved to have a direct depressant effect on the cardiac ventricular muscle. As such, the drug found use in the clinic as an agent for the treatment of cardiac arrhythmias. It should be noted that it has since been largely supplanted by the anilides discussed below. Research aimed at the preparation of antipyretic agents re-

15

Amides and Anilides

0 II ^ -CNHCH2CH2N C2H5 58 lated to quinine adventitiously led to the preparation of an ex~ (raordinarily potent albeit rather toxic local anesthetic. Acy~ lation of isatin (59) affords 60. Treatment of the product (60) with sodium hydroxide affords the substituted quinolone, 62. The t ransformation may be rationalized by assuming the first step to involve cleavage of the lactam bond to afford an intermediate •.uch as 61. Aldol condensation of the ketone carbonyl with the .imide methyl group leads to the observed product (62). Such rearrangements are known as Pfitzinger reactions. Treatment with phosphorus pentachloride serves both to form the acid chloride .mil to introduce the nuclear halogen (63) (via the enol form of 1 lie quinolone). Condensation of the acid chloride with N9N-dlrthyl ethylenediamine gives the corresponding amide (64). Displacement of the ring halogen with the sodium salt from n-butanol completes the synthesis of dibucaine (65) .3U CO2H

62

;<), R = H no, R=COCH3

H / CONCH2CH2N

COCl

H CONCH2CH2N "CoH 2n5

N

O(CH2)3CH3 65

64

Continued synthetic work in the general area of anesthetic inn 1 iles revealed the interesting fact that the amide function can Im reversed. That is, compounds were at least equally effective in which the amide nitrogen was attached to the aromatic ring ^ml the carbonyl group was part of the side chain.

16

Local Anesthetics

Preparation of the first of these anilides begins with the acylation of 2,6-xylidine with chloroacetyl chloride to give chloroamide (64). Displacement of the halogen by means of diethylamine affords lidocaine (65).35 Use of pyrrolidine as the nucleophile in the last step affords pyrrocaine (66).36 The amide functionality in lidocaine as well as the steric hindrance caused by the presence of two ortho groups render this agent unusually resistant to degradation by enzymatic hydrolysis. This, in conjunction with its rapid onset of action, has led to widespread use of this drug for the establishment of nerve blocks prior to surgery. It should be added that lidocaine is finding increasing use as an antiarrhythmic agent, probably as a consequence of its depressant effect on the ventricular cardiac muscle.

+

ClCOCHoCl

NHCOCH2N N

C 22HH 5

NHCOCHoCl 65 64

CH // v NHCOCH

•0

66 In this small subseries, too, the basic nitrogen atom can be included in a ring. Condensation of pyridine-2-carboxylic acid with ethyl chloroformate in the presence of base affords the mixed anhydride (67), an activated form of the acid equivalent in some ways to an acid chloride. Reaction of this anhydride with 2,6-xylidine gives the corresponding amide. Alkylation of the pyridine nitrogen with methyl iodide affords the pyridinium salt (69). Catalytic hydrogenation of this salt leads to reduction of the heterocyclic ring (which has lost some aromatic character by the presence of the charged nitrogen). There is thus obtained

17

Amides and Anilides

mepivacaine (71).37 In much the same vein, alkylation of the intermediate, 68, with butyl iodide (to 70) followed by catalytic reduction leads to bupivacaine (72).38

O

0 II C 2 H 5 OOOC II 0

HO.

67

68

(CH 2 ) 3 CH 3 72 69, R=CH3 70, R=(CH 2 ) 3 CH 3 Acylation of ortho-toluidine with 2-bromopropiony1 bromide .i ("fords the haloamide (73). Displacement of the halogen by m<»ans of butylamine affords prilocaine (74),39 0 II NHCCHCH 3 I Br 73

CH 3 II0

NHCCHNH(CH 2 ) 3 CH 3 CH 3 74

Replacement of one of the aromatic methyl groups in lido(Mine by a carboxylic ester proves consistent with pharmacologic iifLivity. The product, tolycaine (76) , 4 0 is obtained from the Miithranilic ester, 75, by the same two-step scheme as the protoIype drug. * C o H c;

>NHCCH2N

18

Local Anesthetics

3.

MISCELLANEOUS STRUCTURES

As shown above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77); alkylation of this with iV-(3-chloropropyl)morpholine affords pramoxine (78).hl O(CH2 )3CH3

O(CH2 )3CH3

OCH 2 CH 2 CH 2 N

77

0

78

One of the more complex local anthetics in fact comprises a basic ether of a bicyclic heterocyclic molecule. Condensation of 1-nitropentane with acid aldehyde, 79, affords the phthalide, 81, no doubt via the hydroxy acid, 80. Reduction of the nitro group via catalytic hydrogenation leads to the amine (82).U2 Treatment of that amine with sodium hydroxide leads to ring opening of the lactone ring to the intermediary amino acid, 83. This cyclizes spontaneously to the lactam so that the product isolated from the reaction mixture is in fact the isoquinoline derivative (84). Dehydration by means of strong acid affords the isocarbrostyril (85).43 Phosphorus oxychloride converts the oxygen function to the corresponding chloride (85) via the enol form. Displacement of halogen with the sodium salt from 2-dimethylaminoethanol affords dimethisoquin (87) .hl* Carbamates in some ways incorporate features of both esters and amides in the same function. Reaction of the piperidine bearing the diol side chain (88) with phenyl isocyanate affords the Ms-carbamate. This product, diperodon (89)9 A 4 > 4 5 has found some use as a local anestnetic.

XO2H CH3(CH2)3CHNO2 79

80

CH3(CH2)3CHNO2

CH3(CH2)3CHNH2

19

Miscellaneous Structures

(CH2)3CH3

(CH2 )3CH3 84

85

83

I OCH2CH2N (CH2)3CH3 86

HOCH2CHCH2N OH 88

X

\-NHC-OCH2CHCH2N 0 I -NC=O 89

The low structural specificity in the local anesthetic seIICS is perhaps best illustrated by phenacaine (91), a local ano'.thetic that lacks not only the traditional ester or amide funcf urn but the basic aliphatic nitrogen as well. First prepared at t ho turn of the century, a more recent synthesis starts by conilonsation of p-ethoxyaniline with ethyl orthoacetate to afford !he imino ether (90). Reaction of that intermediate with a secUIKI mole of the aniline results in a net displacement of ethanol, probably by an addition-elimination scheme. There is thus obl,lined the amidine, 91, phenacaine.1*6 The story outlined above illustrates well the course frequently taken in drug development. Although the lead for the InrnL anesthetics came from a naturally occurring compound, the in|uence is much the same when the initial active compound is uninvered by some random screening process. Initial synthetic work usually tends to concentrate on some analytic process aimed f*t defining the portions of the lead molecule necessary for biolnj.»ic activity. Further effort often ensues in order to minimize IIHIIO side effect, reduce toxicity, or provide better oral activity. The further analogs thus provided often lead to a rede-

20

Local Anesthetics

/OC 2 H 5 >-NH,

C2H5O

90

91 finition of the minimal active structure. Once the structure of some new drug is made public, commercial considerations enter. Much work is then devoted by companies other than that which did the original work in order to develop some analog that will gain them a proprietary position in that field. Although often excoriated by the consumer minded, this so-called molecular manipulation has in fact often resulted in significant advances in therapy. At least several instances are noted later in this book in which the drug of choice was in fact produced some time after the lead compound had appeared, by workers at a rival concern. The low structural requirements for local anesthetic activity do not maintain in all classes of drugs. Structural requirements for biologic activity in fact follow a full continuum from those cases in which addition of a single carbon atom serves to abolish activity to the case of the local anesthetics that tolerate quite drastic alterations. This observation perhaps arises out of the mechanism by which drugs exert their biologic effects. A substantial number of medicinal agents owe their action to more or less direct interaction with specific biopolymers known as receptors. Many of these receptors normally serve as targets for molecules produced for natural functioning of the organism. Drugs thus act either by substituting for the natural hormone or by competing with it for receptor sites (agonist or antagonist activity). Thus, the activities of such drugs that include the steroids and prostaglandins tend to exhibit great sensitivity to structural changes. At the other end of the continuum there exist drugs that act by some as yet undefined general mechanisms. Much work is currently devoted to study of the fine physiochemical structure of medicinal agents in this class. Considerable progress has

Miscellaneous Structures

21

been achieved towards a better understanding of the effects of biologic activity of such factors as water-lipid partition coefficients, molecular orbital relationships, and tertiary structure. It is thus not inconceivable that a set of compounds that bears little similarity to the eye of the organic chemist are in fact quite similar when redefined in the appropriate physical chemical terms.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. M. IS. 1(>. 17. IK. \\). .'<). .'I. .V. :s. M. .",. .'(». .'/. -•H.

F. Wohler, Ann., 121, 372 (1862). W. Lossen, Ann., 133, 351 (1865). R. Willstatter and W. Muller, Chem. Ber., 31, 1202 (1898). C. Liebermann, Chem. Ber., 23, 2518 (1890). R. Willstatter and A. Bode, Chem. Ber., 34, 519 (1901). R. Willstatter, Chem. Ber., 31, 1534 (1898). G. Merling, Chem. Ber., 24, 3108 (1891). R. Willstatter, Chem. Ber., 29, 393 (1896). R. Willstatter and A. Bode, Chem. Ber., 34, 1457 (1901). G. Fodor, Nature, 170, 278 (1952). K. Hess, A. Eichel, and C. Uibrig, Chem. Ber., 50, 351 (1917). G. Fodor, 0. Kovacs, and I. Weisz, Nature, 174, 141 (1954). E. Hardegger and H. Oh, Helv. Chim. Acta, 38, 312 (1955). H. A. D. Jowett and F. L. Pyman, J. Chem. Soc, 95, 1020 (1909). C. Harries, Ann., 328, 322 (1903). G. Meiling, Chem. Ber., 6, 173 (1896). H. King, J. Chem. Soc, 125, 41 (1924). H. Salkowski, Chem. Ber., 28, 1917 (1895). A. Einhorn and E. Uhlfelder, Ann., 371, 125 (1909). R. 0. Clinton and S. Claskowski, U. S. Patent 2,689,248 (1954). 0. Eisler, U. S. Patent 1,889,645 (1932). W. Grimme and H. Schmitz, Chem. Ber., 84, 734 (1917). H. C. Marks and M. I. Rubin, U. S. Patent 2,460,139 (1949). J. Buchi, E. Stunzi, M. Flurg, R. Hirt, P. Labhart, and L. Ragaz, Helv. Chim. Acta, 34, 1002 (1951). Anon., British Patent 728,527 (1955). R. D. Clinton, U. J. Salvador, S. C. Laskowski, and M. W. Ison, J. Amer. Chem. Soc, 74, 592 (1952). W. G. Christiansen and S. E. Harris, U. S. Patent 2,404,691 (1946). W. B. Burnett, R. L. Jenkens, C. H. Peet, E. E. Dreger, and R. Adams, J. Amer. Chem. Soc, 59, 2248 (1937).

22

29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.

Local Anesthetics

J. R. Reasenberg and S. D. Goldberg, J. Amer. Chem. Soc, 67, 933 (1945). A. C. Cope and E. M. Hancock, J. Amer. Chem. Soc, 66, 1453 (1944). L. A. Walter and R. J. Fosbinder, J. Amer. Chem. Soc, 61, 1713 (1939). S. M. McElvain, U. S. Patent 1,784,903 (1930). S. M. McElvain and T. P. Carney, J. Amer. Chem. Soc, 68, 2592 (1946). K. Miescher, Helv. Chim. Acta, 15, 163 (1932). N. F. Lofgren and B. J. Lundquist, U. S. Patent 2,441,498 (1948). N. Lofgren, C. Tegner, and B. Takman, Acta Chem. Scand., 11, 1724 (1957). H. Rinderknecht, Helv. Chim. Acta, 42, 1324 (1959). Anon., British Patent 869,978 (1959). N. Lofgren and C. Tegner, Acta Chem. Scand., 14, 486 (1960). R. Hiltmann, F. Mietzsch, and W. Wirth, U. S. Patent 2,291,077 (1960). J. W. Wilson, C. L. Zirkle, E. L. Anderson, J. J. Stehle, and G. E. Ullyott, J. Org. Chem., 16, 792 (1951). J. W. Wilson and E. L. Anderson, J, Org. Chem., 16, 800 (1951). J. W. Wilson, N. D. Dawson, W. Brooks, and G. E. Ullyott, J. Amer. Chem. Soc, 71, 937 (1949). T. H. Rider, J. Amer. Chem. Soc, 52, 2115 (1930). M. S. Raasch and W. R. Brode, J. Amer. Chem. Soc, 64, 1112 (1942). R. H. DeWolfe, J. Org. Chem., 27, 490 (1962).

CHAPTER 3

Monocyclic Alicyclic Compounds

As the preceding section correctly suggests, aromatic rings abound in compounds that show biologic activity. The reasons for this are many; the role of the pi electrons in some form of charge transfer complex ranks among the more important. There .ire few monocyclic alicyclic compounds known that are used as medicinal agents. The relatively few older agents in this class tend to be analogs of aromatic compounds in which that ring has been reduced and perhaps contracted as well. The fact that these retain ac(Lvity suggests that the ring plays a largely steric role in the biologic activity in these agents. This past decade, however, has seen the elucidation of a potent class of biologically active compounds that have in common .1 cyclopentane ring. It is to these, the prostaglandins, that we .'iddress ourselves first.

1.

PROSTAGLANDINS

The previous chapter traced the evolution of a biologically act ive compound isolated from plant material—cocaine—into an extensive series of drugs by chemical dissection of that molecule. Another frequently applied approach to drug development depends on (he identification and study of the organic compounds that regulate most of the functions of mammalian organisms: the hormones, ncurotransmitters, and humoral factors. Although many of these factors are high-molecular-weight polypeptides, a significant number of these substances are relatively simple organic compounds of molecular weight below 600, and therefore accessible by synthesis using common laboratory methods. In the usual course of events, the existence of a humoral factor is first inferred from some pharmacologic observation. Isolation of the active 23

24

Monocyclic Alicyclic Compounds

principle is often accomplished with the aid of some bioassay that involves the original pharmacology such as, for example, the contraction of an excised muscle strip in an organ bath. Put simply, in this way, during the isolation process, the fraction to be kept is distinguished from those to be discarded. Structure determination follows the isolation of the regulating factor as a pure compound; once a time-consuming process, the advent of modern instrumental methods has greatly shortened the time of this last step. The sensitivity of the newer methods has further drastically reduced the sample size required for structural assignment. The quantities of hormones available from mammalian sources tend to be on the diminutive side. A thorough study of the pharmacology of a newly isolated humoral substance usually relies on the availability of significant quantities of that compound; the ingenuity of the synthetic organic chemist has usually stepped in to fill this demand by preparation of the agent in question by either partial or total synthesis. The further pharmacology thus made possible often has a feedback effect on the direction of synthetic programs. Thus, the data from animal testing may suggest the need for a less readily metabolized analog, an antagonist, a compound that shows a split among the several activities of the prototype, or perhaps simply one that is active by mouth. All these reasons have, in fact, served as goals for such analog programs. The chemical scheme of organization of this volume leads us to postpone the discussion of the best-known example of this approach, the steroids, to a later chapter. Instead, the development of the most recent class of drugs to be developed from mammalian leads is discussed first. The observation that human seminal fluid contains a humoral principle that causes both smooth muscle contraction and vasoconstriction was made independently by Goldblatt and von Euler in the mid-1950s. The latter was able to show that this principle was a lipid-soluble substance different from any of the other substances known at the time; the name prostaglandins was given these substances after their putative source, the prostate gland. (Subsequent work showed that much higher levels of these compounds can be obtained from the seminal vesicles; vesiculoglandin might thus have been a more appropriate and euphonious name.) The ready degradation of these substances and the lack of many of today1s techniques for effecting separation of complex mixtures thwarted further development of the lead at that time. The observation lay dormant until the 1950s when Bergstrom and his colleagues in Sweden, in some elegant work, were able to isolate two of the prostaglandins in pure form (PGEl5 PGFxa). Spectral methods for structure determination, too, had made giant

Prostaglandins

25

strides in the intervening two decades. The structural assignment of the prostaglandins did not lag far behind their isolation. *

OH

OH

PGEj. and PGFxa were in fact only the first of an impressive series of prostaglandins found to occur in various tissues in I he animal kingdom. It was in fact determined quite early that these compounds are by no means restricted to the accessory sex glands or for that matter to males; prostaglandins have been detected in trace quantities in a host of tissues in mammals of both sexes. The nomenclature of the naturally occurring compounds and certain derivatives followed the usage of the Swedish workers. The prefix is followed by a letter designating the state of oxidation of the cyclopentane ring: A denotes the conmgated enone, obtained by direct dehydration; B represents the <*uone in which the double bond has migrated to the more highly substituted position; E denotes the hydroxy ketone; F denotes the diol. (PG-C, D, G, and H have been described as well but are beyond the scope of this chapter.) The numeral subscript refers to the number of double bonds in the side chain: 1 is always a /rans-olefin at 13,14; 2 contains a cis double bond at 5,6 in addition to that of a PG X , while a PG3 contains the first two as well as a third olefin (cis) at 17,18. Like many natural products that contain chiral centers, prostaglandins occur in op(ically active form; the absolute configuration has been determined to be as depicted above. The convention has been adopted that a denotes a substituent below the plane of the ring and 3 nbove. The letter a in PGFia thus refers to the configuration of the alcohol group at 9. Structures of PGA2 and PGB3 are shown by way of illustration. More highly substituted prosta~ y, Inndins obtained by total synthesis are named as derivatives of the parent hydrocarbon, prostanoic acid (5); the a and 3 notation is again used to denote stereochemistry. The extreme potency of the prostaglandins in a variety of pluirmacologic test systems was apparent even in the absence of Hood sources of supply of these compounds. Although ubiquitous

26

Monocyclic Alicyclic Compounds

'.OoH

CO2H

OH PGA,

17

19

in the animal kingdom, they occur in concentrations too low to make their isolation by extraction an attractive proposition. It was soon found that the biologic precursors of prostaglandms are the essential fatty acids. This finding was in fact applied in obtaining the first supplies of prostaglandins from sources other than extraction of tissue.2 Thus, for example, mixture of PGEX and PGFia is obtained from in vitro enzymic conversion of 8,11, 14-eicosatrienoic acid (6) by sheep seminal vessicles. There is good evidence that the cyclization occurs by direct attack of molecular oxygen via an internal peroxide such as 6a.

CO2H

PGE,

6a Further pharmacologic investigation made possible by these sources of prostaglandins identified many areas in which the drugs might have useful activity. These, to name only a few, in-

Prostaglandins

27

eluded interruption of pregnancy and treatment of hypertension, ulcers, and possibly asthma. At the same time, two of the key problems of this class of agents were uncovered: the very rapid metabolism of prostaglandins and the associated low oral activity as well as the complex set of biologic activities displayed by each of the naturally occurring compounds. Practical syntheses were therefore needed in order both to prepare materials for further study in sizeable quantity and also to permit the preparation of analogs in order to overcome the shortcomings of the natural products. Work towards the solution of this problem constituted one of the intensive areas of synthetic organic chemistry in the past decade. Many very elegant total synthesis have been developed for both the prostaglandins and their analogs. The limitation of space confines our attention to only three of these with apologies to the chemists whose work has been omitted; the reader is referred to a recent review for a summary of alternate routes.3 The intense activity in this field—it has been estimated that as many as a thousand analogs have been prepared to datepromises a number of drugs in the near future. At this writing, two prostaglandins are available for use by the clinician. Both these compounds, dinoprost (7, PGF2a) and dinoprostone (8, PGE 2 ), are used for the termination of pregnancy in the second trimester.

CO2H

/ ^ Y

N

'

v

CO2H

HO

The gross molecular structure of the prostaglandins presents two problems at first sight. The first of these is the presence of the five-membered ring; although a veritable host of reactions are at hand for the construction of cyclohexanes, the menu for cyclopentanes is relatively limited. The problem of stereochemistry is superimposed on this. Neglecting for the moment the geometry of the double bonds, the four chiral centers mean the gross structure 8 has 16 isomers; 7 has 32 isomers. In one of their solutions to the problem, Corey and his coworkers solved the first problem by starting with a preconstructed cyclopentane; the stereochemistry was steered by deriving the oxygen atoms from a rigid bicyclic molecule. Alkylation of

28

Monocyclic Alicyclic Compounds

the anion of cyclopentadiene with chloromethyl ether affords diene, 10. Special precautions must be taken in this reaction to avoid the thermal and base-catalyzed migration of the double bonds to the more stable position adjacent the alkyl group. Diels-Alder addition of the latent ketene, 2-chloroacrylonitrile, gives the adduct, 11, as a mixture of isomers. Treatment of this with base presumably first gives the cyanohydrin; this hydrolyzes to the intermediate, 12, under the reaction conditions. In an alternate approach, 10 is condensed with 2-chloroacryloyl chloride to give 13. This compound is then treated with sodium azide to give first the acid azide. This rearranges to the isocyanate, 15, on heating. This last hydrolyzes to 12 under very mild conditions.4

o-

CH 2 OCH 3

10

COC1 OCH,

0CH3 | CH2-K

^ NCO 15

Oxidation of the ketone, 12, under Bayer-Villiger conditions (peracid) rearranges the carbonyl group to the corresponding lactone without affecting the isolated double bond (16). Saponification of the lactone gives the hydroxy acid, 17. When this last is treated with an iodine:iodide mixture in base, there is obtained the iodolactone, 18. It should be noted that this reaction is of necessity both regio- and stereospecific; addition to the other face of the ring is sterically prohibited, while addition to the other side of the double bond would afford a more strained ring system. Acetylation followed by reductive removal of iodine with tributyltin hydride gives the key intermediate,

Prostaglandins

29

19. This molecule now carries both oxygens of future prostaglandin as well as the anchors for the side chains, all in the proper relative configuration. In subsequent work, hydroxyacid, 17, was resolved into its optical isomers; that corresponding to the configuration of natural prostaglandins was carried through the scheme below to give optically active 19 and eventually chiral PGs.5

CH3OCH2 _

^ 16

12

ti OAc -OAcC H O 0C H 3 19

17

CH3OCH

18

The methyl ether in 19 is then cleaved by treatment with boron tribromide; oxidation of the primary alcohol thus obtained (20) with a pyridine:chromium trioxide complex known as Collins reagent affords aldehyde, 21. This is condensed without prior purification with the ylide obtained from the phosphonate, 22. There is thus obtained the intermediate, 23, which now incorporates one of the requisite side chains two hydrogen atoms removed from the natural configuration. In the original work, the side chain ketone at 15 was reduced with zinc borohydride to give mixtures of a and (3 alcohols.6 In a later modification, 23 is deacetylated and condensed with biphenylisocyanate. Reduction of the ketourethane is accomplished with the extremely bulk alkylborane, 26. The bulk of the large substituent at 11 in combination with the steric demands of the reagent ensure the formation of a large preponderance of the desired 15a hydroxyl compound. Removal of the urethane (lithium hydroxide) followed by reclosure of the lactone with ethyl chloroformate gives 25.7 Reaction of 25 with dihydropyran serves to protect the hydroxyls by converting these to the tetrahydropyranyl ethers (THP). Reduction of the lactone thus protected with diisobutyl

30

Monocyclic Alicyclic Compounds

22

19 Y^CHjOH

V cCHO

OAc

OAc 20

QAC

21

P \

- * C55Hl l rt

26

OH

OH 25

0-C-NHC6H,,C6H5 ° 24

aluminum hydride at -78° affords the corresponding lactol(27). Condensation of the lactol with the ylide from phosphonium salt, 29, proceeds, presumably via the small amount of hydroxyaldehyde in equilibrium with the lactol, to yield the intermediate, 25. The Wittig reaction must be carried out under "salt-free" conditions in order to insure the cis geometry of the double bond at 5,6. Removal of the protecting groups affords dinoprost (7). Careful oxidation of 28 prior to removal of the protecting groups leads dinoprostone (8).e>7 This synthetic scheme is well suited to the preparation of other prostaglandins or for that matter analogs. The use of a suitably unsaturated ylide for the reaction with 21 leads eventually to PGE3 and PGF 3 a. 8 Since the key intermediate, 21, contains the bulk of the functionality that distinguishes prostaglandins, analogs can, in principle at least, be readily prepared by using variously modified ylides at the synthetic branching points, 21 and 27. The synthetic route to the prostaglandins developed by Kelly and his colleagues at Upjohn similarly depends on a rigid polycyclic framework for establishment of the stereochemistry. The synthesis differs significantly from that above in that a rearrangement step is used to attain the stage comparable to 23. Epoxidation of norbornene was found some time prior to this work not to stop at the monoepoxide step. Instead, this intermediate goes on to rearrange to the bicyclic aldehyde, 31.9 Ketalization of the aldehyde with neopentyl glycol (32) followed by reaction with dichloroketene gives the 2+2 cycloadduct, 33. The halogen is then removed by reduction with zinc

Prostaglandins

31

CO2H

25

CO2H

(C6H5)3P(CH2)4CO2 29

OH

HO

OH

30

CHO

31 In ammonium chloride. Reaction of the cyclobutanone, which of course occurs in both the R and S forms, with 1-ephedrine (35) affords the oxazolidone, 36, as a pair of diastereomers (Rl and SI). The higher melting of these is then separated by crystallization; chromatography of this isomer over silica affords directly optically active 37 of the same absolute configuration as the target molecule.10 Bayer-Villiger oxidation followed by de~ ketalization affords lactone aldehyde, 38. This is then reacted in a Wittig condensation with the ylide from hexyltriphenylphosphonium bromide to give 39. Opening of the cyclopropyl ring by the cyclopropylcarbinylhomoallyl arrangement, a scheme developed earlier for prosta-

32

Monocyclic Alicyclic Compounds

31

32

'— CIIO

39

OH

glandin synthesis,11 is one of the key steps in the present route as well. A generalized mechanistic scheme for this reaction, well known in simpler systems, is depicted above (A to D ) . Regio- and stereoselectivity are maintained by the demands of orbital overlap. Epoxidation of the olefin, 36, affords 40. Solvolysis of the latter in dry formic acid gives a mixture of the desired product, 42 (both a and 3 hydroxyl at 15), as well as a mixture of the glycols (41). Solvolytic recycling of the mixture in the same medium affords eventually about a 45% yield of the product,

Prostaglandins

33

43,12 identical to intermediate 25 in the synthesis discussed earlier. It should be noted that this synthesis, too, is well suited for the preparation of analogs, since it presents a synthetic branch point at 38 in addition to that which occurs later. Intermediate 43, when subjected to the required further steps, gives dinoprostone, or alternately, dinoprost.

OH 42

Drugs of particularly complex structure are often prepared commercially by partial synthesis from some abundant, structurally related, natural product obtained from plants. The majority of steroid drugs are in fact prepared in just this way. Prostaglandins are unique in that no prostanoid compounds have yet been found in plants, a perhaps surprising finding in view of the wide distribution of essential fatty acids in plant materials. The unexpected source of starting material for partial synthesis of these agents was the sea. The isolation of 15(R)-PGA2 and its ncetate (44) from the lowly sea whip, 13 Plexura homomalla, one of the so-called soft corals, made an approach to prostaglandins from natural products possible. In a process developed by the group at Upjohn, acetate 44 is first treated with basic hydrogen peroxide. These conditions, known to be selective for epoxidation of the double bonds of enones, afford the epoxide, 45, as well as some of the 3 isomer. Reductive opening of the oxirane with aluminum amalgam leads to the hydroxyketone (46); regiospecificity is probably attained by the greater reactivity of the bond a to the ketone towards heterolysis. This compound is then converted to its trimethylsilyl <*lher; reduction of the ketone by means of sodium borohydride followed by hydrolysis of the acetate triol gives 47 accompanied by a small amount of the 93 isomer. Oxidation of 41 with 2,3(\ ichlorodicyanoquinone interestingly proceeds selectively at the .illylic alcohol at 15 to give the corresponding side chain ketone, 48. Reduction of the ketone—as the Ms-trimethylsilyl et hcr-affords largely the 15a hydroxy compound (7) . In effect then, this sequence (47-±7) serves as a means of inverting the

Monocyclic Alicyclic Compounds

34

configuration at 15 from that found in the sea to that required for dinoprost (7).

CO 2 CH 3 CO 2 CH 3

CO 2 CH 3 CO 2 CH 3

CO 2 CH 3 CO 2 CH 3

OH 50

CO 2 CH 3

OH

48

51

CO 2 H

HO

OH

Prostaglandins

35

In a variation on this scheme, the 15 acetate is first saponified and the resulting alcohol converted to the methanesulfonate (49). Solvolysis in acetone results in what in essence is an SNX displacement and thus affords a 1:1 mixture of 15a and 153 isomers. The former is isolated to afford the desired product with the mammalian configuration at 15 (50). Application of the epoxidation scheme mentioned above (44 to 46) leads to dinoprostone (8). Subsequent further investigation of the coral divulged the interesting fact that colonies from some locations yield the analog of 44 in which the configuration at 15 is exclusively (S). 1 5 This natural product is simply the acetate of 50. Conversion of this to dinoprostone devolves on hydration of the double bond at 10,11. Hydrolysis by means of esterases present in the coral effects both deacetylation and removal of the methyl ester. The latter is restored by mild means with methyl iodide on the salt of the acid. The resulting hydroxyester (50) is then epoxidized (51, basic hydrogen peroxide) and reduced (aluminum amalgam) to give 5. 16

2.

MISCELLANEOUS ALICYCLIC COMPOUNDS

The simplification of the local anesthetic pharmacophore of cocaine to an aryl substituted ester of ethanolamine has been described previously. Atropine (52) is a structurally closely related natural product whose main biologic action depends on inhibition of the parasympathetic nervous system. Among its many other actions, the compound exerts useful spasmolytic effects. It was therefore of some interest to so modify the molecule as to maximize this particular activity at the expense of the side effects. In much the same vein as the work on cocaine, the structural requirements for the desired activity had at one time been whittled down to embrace in essence an a-substituted phenylacetic acid ester of ethanolamine (53). I-CH

53

36

Monocyclic Alicyclic Compounds

A further simplification of the requirements for activity came from the preparation of two spasmolytic agents that completely lack the aromatic ring. Thus, double alkylation of phenylacetonitrile (54) with 1,5-dibromopentane leads to the corresponding cyclohexane (55). This intermediate is then saponified and the resulting acid (56) esterified with iv,iv-diethylethanolamine. Catalytic reduction of the aromatic ring affords dicyclonine (51).17

CO 2 H

56

55

CO 2 CH 2 CH 2 N^

57

An interesting variation of this theme starts with the achlorination of dicyclohexylketone (58). Treatment of the halogenated intermediate with base leads to the acid, 60, by the Favorski rearrangement. Esterification of the acid with 2(1pyrolidino)ethanol yields dihexyrevine (61)-18 Both this agent and its earlier congener are recommended for use in GI spasms.

CfO

C0 2 H

58, 59, X=C1

6O

CO 2 CH 2 CH

61

O

Miscellaneous Alicyclic Compounds

37

Amphetamine (62) is an agent closely related to the biogenic amines involved in various processes of the central nervous system. As such it is a drug with a multitude of activities; its main clinical use is as a central stimulant. This very activity, in fact, stands in the way of exploitation of the drug's activity as a local vasoconstricting agent, and thus constriction of mucous membranes. Preparation of the fully saturated analog (64) by catalytic reduction of methamphetamine (63) affords a compound that retains the desired activity with some reduction in side effect.19 The product, propylhexedrine (64), is used as a nasal decongestant.

-CH2CHNH2

O-

-CH2CHNHCH3

CHq

CH2CHNHCH3

CH 3

62

63

CH,

64

Further indication that the carbocyclic ring in this series serves a largely steric function comes from the finding that a five-membered ring analog, cyclopentamine (69), is also biologically active. Condensation of cyclopentanone with cyanoacetic acid in a modified Knoevnagel reaction followed by decarboxylation affords the unsatured nitrile, 65. Reduction of the double bond and subsequent reaction of the product (66) with methylmagnesium halide leads to the methyl ketone, 67. This affords the desired product (69) on reductive amination with methylamine.20

CN

CH2CN

CHCN • CO 2 H

66 65

NCH 3

NHCH3 |

\ - C H 2 C H - CHo

69

I

\-CH2

68

CH 3

O

0 II CH2C-CH3

67

Monocyclic Alicyclic Compounds

38

Although chemically related to the above cycloalkylamines, pentethylcyclanone (71) is stated to have antitussive activity. The compound is prepared rather simply by alkylation of the anion (7Oa) of the self-condensation product of cyclopentanone (70) with N-(2-chloroethyl)-morpholine.2 *

LJ\

LJ

\

CH2CH2N 70

7Oa

0

71

The hypnotic activity of ethanol is too well known to need comment. It is an interesting sidelight that this is a property shared with a number of other alcohols of relatively low molecular weight. Activity in fact increases with lipid solubility. This is probably due to better absorption and, with branching on the carbinol carbon, perhaps decreased metabolic destruction. Conversion of a hypnotic alcohol to its carbamate often serves to impart sedative properties to the agent. Thus, reaction of the product of ethynylation of cyclohexanone (72) with phosgene followed by ammonia gives the sedative-hypnotic, meparfynol (74)22; reaction with allophanyl chloride gives directly the sedativehypnotic, clocental (25).23 HC-C

OH

72

HC=C

OCOCl

73

HC=C

OCONHo

74

0 0 II I! OCNHCNH 2

0 75

REFERENCES 1.

S. Abrahamsson, S. Bergstrom, and B. Samuelsson, Proc. Chem.

Soc, 1962, 332.

References

2.

3.

4. 5. 6. 7. 8.

9. 10. 11.

12. L3. 14. 15. 16. 17. 18. 19. M). J\. .'2. »>3.

39

(a) E. G. Daniels and J. E. Pike, "Prostaglandin Symposium of the Worcester Foundation for Expt. Biol.," P. W. Ramwell and J. E. Shaw (Eds.), Interscience, N. Y. (1963); (b) D. A. van Dorp, R. K. Beerthuis, D. H. Nutgren, and H. VonKeman, Nature, Lond., 203, 839 (1964). U. Axen, J. E. Pike, and W. P. Schneider, Total Synthesis of Prostaglandins, Synthesis, Vol. 1, J. W. ApSimon (Ed.), Wiley, N. Y., 1973. E. J. Corey, T. Ravindranathan, and S. Terashima, J. Amer. Chem. Soc, 93, 4326 (1971). E. J. Corey, T. K. Schaaf, W. Huber, V. Koelliker, and N. M. Weinshenker, J. Amer. Chem. Soc, 92, 397 (1970). E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, J. Amer. Chem. Soc. r 91, 5675 (1969). E. J. Corey, K. Becker, and R. V. Varma, J. Amer. Chem. Soc., 94, 8616 (1972). E. J. Corey, H. Shirahama, H. Yamamoto, S. Terashima, A. Venkateswarlo, and T. K. Schaaf, J. Amer. Chem. Soc, 93, 1491 (1971). J. Meinwald, S. S. Labana, and M. S. Chade, J. Amer. Chem. Soc, 85, 582 (1963). R. C. Kelly and V. Van Rheenen, Tetrahedron Lett., 1709 (1973). G. Just, Ch. Simonovitch, F. H. Lincoln, W. P. Schneider, U. Axen, G. B. Spero, and J. E. Pike, J. Amer. Chem. Soc, 91, 5364 (1969). R. C. Kelly, V. VanRheenen, I. Schletter, and M, D, Pillai, J. Amer. Chem. Soc, 95, 2746 (1973). A. J. Weinheimer and R. L. Spraggins, Tetrahedron Lett., 5185 (1969). G. L. Bundy, F. H. Lincoln, N. A. Nelson, J. E. Pike, and W. P. Schneider, Ann. N. Y. Acad. Sci., 180, 76 (1971). W. P. Schneider, R. D. Hamton, and L. E. Rhuland, J. Amer. Chem. Soc, 94, 2122 (1972). G. L. Bundy, W. P. Schneider, F. H. Lincoln, and J. E. Pike, J. Amer. Chem. Soc, 94, 2124 (1972). C. H. Tilford, M. G. VanCampen, and R. S. Shelton, J. Amer. Chem. Soc, 69, 3902 (1947). M. Kopp and B. Tchoubar, Bull. Soc Chim. France, 84 (1952). B. L. Zemitz, E. B. Macks, and M. L. Moore, J. Amer. Chem. Soc, 69, 1117 (1947). E. Rohrman, U. S. Patent 2,520,015 (1950). H. Veberwasser, German Patent 1,059,901 (1959). K. Junkmann and H. Pfeiffer, U. S. Patent 2,816,910 (1957). W. Grimene and H. Emde, German Patent 959,485 (1957).

CHAPTER 4

Benzyl and Benzhydryl Derivatives

The previous chapter pointed up the relative paucity of useful medicinal agents to be found among simple monocyclic alicyclic compounds. Current intensive research on the prostaglandins may, of course, change that in the future. It is well known, however, that the chances of finding a biologically active molecule increase dramatically with the incorporation into the structure of one or more aromatic or heteroaromatic rings. This common observation has been ascribed to many of the known properties of these rings, such as their rigid planarity, the ability of the pi cloud to enter into charge-transfer complexes, or the polarizability of the same cloud, to name only a few. Much effort is currently devoted to theoretical studies bearing on these points. As will be seen, the arylaliphatic compounds represent one of the larger structural classes of drugs; these compounds show therapeutic activity in a widely divergent series of pathologic states. Discovery of activity in this series has tended to be largely empirical. The description of a novel active structure usually heralded the preparation of a flood of analogs, by the originator in order to improve the therapeutic ratio and by his competitor in order to gain some proprietary patent position. Some of the more imaginative analog programs were sometimes rewarded by the finding of novel structures with unanticipated biologic activities.

1.

AGENTS BASED ON BENZYL AND BENZHYDRYL AMINES AND ALCOHOLS

a.

Compounds Related to Benzhydrol

Many of the more debilitating symptoms of allergic states such as rashes, rhinitis, and runny eyes, are thought to be due to hist40

Arylmethylamines and Alcohols

41

amine released as the end product of a lengthy chain of biochemical reactions that begins with the interaction of the allergen with some antibody. Although this process is known in some detail, attempts to intervene therapeutically in a rational manner have not thus far been successful. It has been known for some time, however, that a fairly large class of organic compounds would alleviate many of the symptoms of allergic reactions. Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. The prototype of the antihistamines based on benzhydrol, diphenhydramine (3), is familiar to many today under the trade name Benadryl®. Light-induced bromination of diphenylmethane affords benzhydryl bromide (2). This is then allowed to react with dimethylaminoethanol to give the desired ether.* Although no mechanistic studies have been reported, it is not unlikely that the bromine undergoes SNx solvolysis in the reaction medium; the carbonium ion then simply picks up the alcohol. It might be noted in passing that the theophyline salt of 4 is familiar to many travelers as a motion sickness remedy under the trade name Dram amine®. Several analogs bearing different substituents on the aromatic rings are accessible by essentially the same route. The appropriate benzhydrol (4) is first prepared by reaction of an

CHBr

>

^

CHO'CH2CH2N


42

Benzyl and Benzhydryl Derivatives

used largely as an antihistamine, as is the p~bromo analog, bromodiphenhydramine (6b).3 The o-tolyl compound, orphenadrine (6c) S exhibits diminished antihistaminic properties at the expense of antispasmodic activity. It has found some use in control of the symptoms of Parkinson's disease. We shall meet this type of activity, referred to for simplicity as antiparkinson activity, again.

CHO CHOCH2CH2N

CHR MgBr

4, 5a, 5b, 5c,

R-OH R=C1; X=p-OCH3 R=Cl; X=p-Br R=Cl; X=o~CH3

6a, X=p-OCH3 6b, X=p-Br 6c, X=o-CH3

Sd, R=C1; X=p-Cl Oxygen to nitrogen spacing apparently is not too critical for retention of activity. Thus, inclusion of the nitrogen atom in either a five- or six-membered ring affords active compounds. Alkylation of benzhydryl bromide (2) with 4-hydroxy-l-methylpiperidine affords the potent antihistamine, diphenylpyraline (7).5 Similarly, alkylation of the p-chloro benzhydryl halide (5d) with 3-hydroxy-l-methylpyrrodiline gives pyroxamine (8).

CHO-/

N- CH,

5d

8 Inclusion of a second nitrogen atom in the side chain seemingly increases the spasmolytic effect of the benzhydrol derivatives. Alkylation of the benzdryl chloride (9) with the sodium

43

Arylmethylamines and Alcohols

salt obtained from w-(2-hydroxyethyl)-piperazine affords the basic ether (10). Alkylation of this intermediate with a-chloro-oxylene gives chlorbenzoxamine (II).6

Cl CHCl

Cl +

NaOCH2CH2N

NH

CHOCH2CH2N

NH

10

Cl CHOCH2CH2N

yN-CH2

II

CH 11

When the additional nitrogen atom is included in one of the aromatic rings, on the other hand, there is obtained a compound with antihistaminic properties. Reaction of the Grignard reagent from 4-chlorobromobenzene with pyridine-2-aldehyde gives the benzhydrol analog (12). The alcohol is then converted to its sodium salt by means of sodium, and this salt is alkylated with 2V-(2-chloroethyl)dimethylamine. Carbinoxamine (13) is thus obtained.7 > 8

CHO :HOH

12

OCH2CH2N

13

The oxygen atom in these molecules can in many cases be dispensed with as well; substitution of sulfur for nitrogen affords a molecule whose salient biologic properties are those of a sedative and tranquilizer. Friedel-Crafts acylation of the nbutyl ether of thiophenol with benzoyl chloride gives the corresponding benzophenone. Reduction of the ketone (15) followed by

44

Benzyl and Benzhydryl Derivatives

treatment with thionyl chloride affords the benzhydryl chloride (16). Displacement of the halogen with thiourea gives, by reaction of the last at its most nucleophilic center, the isothiouronium salt, 17. Hydrolysis of the salt leads to the sulfur analog of a benzhydrol (18). Alkylation of the sodium salt of this last with N~(2-chloroethyl)dimethylamine affords oaptodiamine (19).9 The substitution of the lone proton on the benzhydryl carbon by a methyl group again affords compounds with antihistamine activity. Reaction of an appropriate acetophenone (21) with phenylmagnesium bromide affords the desired tertiary alcohols (22).

o CH 2 CH 2 CH 2 CH 3 CHX n-BuS

n-Bu 14

15, X=OH 16, X»Cl

17

:SCH2CH2N

"CH,

CHSH

n-BuS 19

18

Alkylation of these as their sodium salts with the ubiquitous N(2-chloroethyl)dimethylamine affords the desired antihistamines. There are thus obtained, respectively, mephenhydramine (23a),10 chlorphenoxamine (23b),11 and mebrophenhydramine (23c).12 Alkylation of the tertiary alcohol, 22b, with the pyrrolidine derivative, 24, affords meclastine (25).l3 In much the same vein, reaction of 2~acetylpyridine with phenylmagnesium bromide gives the tertiary alcohol, 27. Alkylation in the usual way leads to the potent antihistamine, doxylamine (28).lh Performance of an imaginary 1,2-shift on the benzhydrol antihistamines, that is, attachment of the side chain directly to the benzhydryl carbon while leaving the hydroxyl group intact, affords a series of molecules with markedly altered biologic activities. As a class, these agents tend to be devoid of antihistaminic activity, while they retain some of the sedative and antiparkinson

45

Ary line thy lamines and Alcohols

activity. It should be noted that these agents are of only minor importance in drug therapy today.

CH3 OCH 2 CH 2 N

CH3 21a., X=H 21b, X=C1 21c, X=Br

22a, X=H 22b, X=C1 22c, X=Br

23a, X=H 23b, X=C1 23c, X=Br

I CH 2 CH 2 Cl I CH 3

24

OH

26

27

OCH2CI12N

28

The prototype, diphenidol (3O), is used as an antiemetic This agent is obtained in one step from the reaction of the Grignard reagent of halide, 29, with benzophenone.15 The lower homolog, 32, is effective chiefly as a muscle relaxant and antiparkinson agent. Conjugate addition of piperidine to ethyl acrylate gives the amino ester (31). Condensation of this with phenylmagnesium bromide affords pirindol (32) ,1S? Introduction of branching in the side chain is apparently consistent with retention of the antiparkinson activity. Bromination of propiophenone gives the brominated ketone, 33. Dis-

46

Benzyl and Benzhydryl Derivatives

C1CII2CH2CH2N

o

\

CH 2 CH 2 CH 2 N

29 30

2=lICHCO C 2H 25 O* C

C 2 n 5 0 2 CCH 2 CII 2 31 32

placement of halogen with piperidine leads to the aminoketone (34). Condensation of the last with phenylmagnesium bromide affords the spasmolytic agent, diphepanol (35).17

Br I COCHCH^ 33

OCHClIj

O 34

O H 35

Condensation of the anion obtained on reaction of acetonitrile with sodium amide, with o-chlorobenzophenone (36), affords the hydroxynitrile, 37. Catalytic reduction leads to the corresponding amino alcohol (note that the benzhydryl alcohol is not hydrogenolyzed). Reductive alkylation with formaldehyde and hydrogen in the presence of Raney nickel gives the antitussive agent, chlorphedianol (39).x8 Cyclization of the side chain onto the nitrogen atom leads to compounds with sedative and tranquilizing activity. The lack of structural specificity, that is, the fact that both positional isomers (41,43) show the same activity, is notable. Thus, condensation of the Grignard reagent from 2-bromopyridine with benzophenone affords the tertiary carbinol, 40. Catalytic reduction

Arylmethylamines and Alcohols

47

in acetic acid leads to selective hydrogenation of the heterocyclic ring and formation of azacyclonol (41).19 The analogous sequence using an organometallic derived from 4-bromopyridine gives pipradol (43).20 Substitution of an alicyclic ring for one of the aromatic rings in the amino alcohols such as 32 or 39 produces a series of useful antispasmodic agents that have found some use in the treatment of the symptoms of Parkinson's disease. Mannich reaction of acetophenone with formaldehyde and piperidine affords the aminoketone, 44a. Reaction of the ketone with cyclohexylmagnesium

+

9

CH2CN CH2CN

36

37

38, 39,

R=H R=CH3

bromide leads to trihexyphenidil (45)21; alternately, condensation with the Grignard reagent from cyclopentyl bromide affords cycrimine (46),22 Reaction of the aminoketone, 44a, with the (•rignard reagent from the bicyclic halide, 47 (from addition of hydrogen bromide to norbornadiene), affords biperidin (48),23 In much the same vein, the Mannich product from acetophenone with formaldehyde and pyrrolidine (44b) affords procyclidine (49) on reaction with cyclohexylmagnesium bromide. In an interesting variation, the ketone is first reacted with phenylmagnesium bromide. Catalytic hydrogenation of the carbinol (So) thus obtained i\'in be stopped after the reduction of only one aromatic ring.24

Benzyl and Benzhydryl Derivatives

48

OH

(C6H5)2C=O

0 II -OCH3

-OH

40

41

42

43

0

O

-CCH2CH2N 44a

O H CH C 2H 2 O

045

Arylmethylamines and Alcohols

49

44a

OH :H2CH2N

\

O

CH 2 CH 2

47 48

46

CCH 2 CH 44b

50

49

Relatively small modifications of the structures of the above spasmolytic agents produce a dramatic change in biologic act ivity. Incorporation of a methylene between the aromatic ring and the quaternary center, methylation of the side chain, and finally esterification of the alcohol yields propoxyphene. This ngent, under the trade name of Darvon® (now available as a generic drug), has been in very wide use as an analgesic agent for the t reatment of mild pain. Mannich reaction of propiophenone with formaldehyde and dimethylamine affords the corresponding aminoketone (51). Reaction of the ketone with benzylmagnesium bromide

50

Benzyl and Benzhydryl Derivatives

gives the amino alcohol (52). It is of note that this intermediate fails to show analgesic activity in animal assays. Esterification of the alcohol by means of propionic anhydride affords the propionate (53) *25 The presence of two chiral centers in this molecule means, of course, that the compound will exist as two racemic pairs. The biologic activity has been found to be associated with the a isomer. Resolution of that isomer into its optical antipodes showed the d isomer to be the active analgesic; this is now denoted as propoxyphene (d,53). The 1 isomer is almost devoid of analgesic activity; the compound does, however, show useful antitussive activity and is named levopropoxyphene (1,53).26

51

b.

Compounds Related to Benzylamine

Further illustration for the lack of structural specificity required for antihistaminic activity comes from the finding that ethylenediamines carrying both a benzylamine and an additional aromatic substituent on one of the nitrogens afford a series of useful therapeutic agents. Alkylation of benzylaniline with N(2-chlorethyl)dimethylamine affords phenbenzamine (54).27 Treatment of the secondary amine with iV-(2-chloroethyl)pyrrolidine affords the antihistamine, histapyrrodine (55).2& As in the case of the benzhydryl ethers, inclusion of the

Arylmethylamines and Alcohols

51

CH2CH2N

CH2CH2N

7

55

54

nitrogen atom in a ring is consistent with activity. Thus, condensation of N-methyl-4~piperidone with aniline yields the corresponding Shiff base. Reduction followed by alkylation of the secondary amine (57) with benzyl chloride by means of sodium amide affords bamipine (58).29

56

57

58

Substitution of a 2-pyridyl residue for the phenyl attached directly to nitrogen affords a series of potent antihistamines. Preparation of these compounds, too, is accomplished by a series of alkylation reactions. It is further probable that the order of the reaction can be readily interchanged. Thus, alkylation of 2-aminopyridine with the chloroethyldimethylamine side chain leads to the diamine, 59. Alkylation with benzyl chloride af~ 1ords tripelenamine (60); reaction with p-methoxybenzyl chloride loads to pyrilamine (61).30 In a variation on this approach, p-chlorobenzaldehyde is I irst condensed with 2-aminopyridine. Reduction of the resulting Shiff base (62) affords the corresponding secondary amine. Alkyl.it ion with the usual side chain affords the antihistamine, chlorpiframine (64).31

52

r

Benzyl and Benzhydryl Derivatives

y-NCH2CH2NX CHo

a

NHCH2CH2N

NCH2CH2N CH2

59 60

OCH* 61

62

63

N-CH2CH2N I CH,

64

Aromatic rings containing more than one hetero atom also yield active antihistamines. Alkylation of 2-aminopyrimidine (65) with p~methoxybenzyl chloride gives the corresponding secondary amine (66). Alkylation with the usual chloroamine affords thonzylamine (67).32 Application of the same sequence to 2-aminothiazole (68) affords zolamine (70). The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72),33 The correspond-

53

Arylmethylamines and Alcohols

-NH2

-»

f~\mCH2-f~\-OC}l3

-^ <^" V N -CH 2 -<^> •OCH3

CH2C1 65

CH2CH2N

66

CH3 67

OCH3 C

VNH2

—>

\\

\

V0CH3

-OCH,

CH2CH2N

68

CH3

70 ing agent containing the cyclic side chain is obtained by alkylation on the secondary amine, 57, with the same halide; methaphencycline (73)3h is thus obtained. Interestingly, replacement of both benzene rings of the prototype molecule (54) by heterocyclic rings is not only consistent with activity, but yields two of the more potent antihistamines. tCHq

NHCH2CH2N

71

-NCH2CH2N

CH 72

VNH-/

N-CH3

57 73

54

Benzyl and Benzhydryl Derivatives

Resorting to alkylation chemistry again, 2-aminopyridine is condensed with the usual side chain halide to give diamine, 74. Alkylation of this with 2-chloromethylthiophene gives methapyrilene (75).35 Reaction with 2-chloromethyl~5-chlorothiophene affords the potent antihistamine chlorothen (76).35

A/ -O N V .«• ex n^N Q C H NC -H2 S^— « N^NHCH C N 1T 2H 2 -^ ^ I /^n3 CH 2 CH 2 N 75

N

CH

3

N-CH 2 I /^H 3 CH 2 CH 2 N

76

Appropriately substituted benzylamines have provided a number of drugs useful in the treatment of high blood pressure. The fact that pharmacologic studies have shown these agents to act by very different mechanisms makes it likely that the benzylamine nucleus plays at best a small role in the biologic action of these compounds. Rather, these compounds are thought to owe their activity to the particular functionality (pharmacophoric group). The observation that a similar group often has the same activity when attached to a quite different amine bears out this suspicion. Thus, alkylation of benzylmethylamine with propargyl bromide affords pargyline (77).36 This drug, developed initially as an antidepressant, acting by monamine oxidase inhibition (MAO inhibition, see aromatic hydrazines for fuller discussion), was found to lower blood pressure in hypertensive individuals by some as yet undefined mechanism.

CH2C=CH 77 Blood pressure is under the control of the autonomic (sometimes called the involuntary or reflex) nervous system. That is, the pressure is adjusted automatically in response to signals from various baroreceptors. Control of abnormally high pressure can, at least in theory, be achieved by interfering with the chain of transmission of the neural signals that lead to elevation of pressure. Initial success in control of hypertension was met with the ganglionic blocking agents which in effect in-

Arylmethy1amines and Alcohols

55

terrupted all neuronal signals. Since many other bodily functions are under autonomic control, this mode of therapy had a significant number of side effects. The next development, the peripheral sympathetic blocking agents, acts further down the chain of control and thus shows more specificity for blood pressure response. Many of the sympathetic responses are mediated at the last stage by reaction of a neurotransmitter amine such as norepinephrine (see below) with a receptor site on the tissue that is to give the response. Sophisticated pharmacologic study has led to the classification of these as a and 3 sympathetic receptors (the details are beyond the scope of this book). Drugs are now available whose effects can be explained by the assumption of blockade of either a or p receptors. The goal of work in this field is, of course, to find drugs that will block specifically either a or 3 receptors in only the cardiovascular system. Quaternization of o-bromo-2V,z\f-dimethy lben zy lamine with the p-toluene-sulfonate of ethanol affords bretylium tosylate (78),37 an antihypertensive agent acting by peripheral sympathetic blockade. The guanidine function has proven particularly useful in providing antihypertensives that act by peripheral sympathetic blockade. Several such compounds that contain a quite different hydrocarbon moiety are met later (guanadrel, guanethidine, guancycline, debrisoquin) . Reaction of benzylamine with methyl isothiocyanate gives the corresponding thiourea (79). Methylation affords the product of alkylation at the most nucleophilic center, the thioenol ether (80) . Displacement of the thiomethyl group by methylamine (probably by an addition elimination process) affords bethanidine (81).3B Reaction of dibenzylamine with ethylene oxide affords the <jjnino alcohol, 82. Treatment of that product with thionyl chloride gives the a-sympathetic blocking agent, dibenamine (83),39 Condensation of phenol with propylene chlorohydrin (84) gives the jlcohol, 85. Reaction with thionyl chloride affords the chloride (86). Use of the halide to alkylate ethanolamine affords the secondary amine (87). Alkylation of this last with benzyl chloride (88) followed by conversion of the hydroxyl to chloride by means of thionyl chloride completes the preparation of phenoxybenzamine (89) .i*° This agent, too, is an antihypertensive drug that owes its action to blockade of the a-sympathetic receptors. The block.ide induced by these drugs is of unusually long duration (the 3~ haloamine function is known to be a good alkylating agent for many polypeptides). This very long duration of action and a ceri ain lack of specificity for the cardiovascular system has diminished the usefulness of these agents. The more familiar method of inducing surgical anesthethesia

56

Benzyl and Benzhydryl Derivatives

SCH3 ,CH2NHO=NCH3

.CHoNHCNHCH-.

80

79 /NHCH, NHC

81 OH I

0CH2CHCH3

O

84 85, X=OH 86, X=C1

/)CH2CHCH3 IINCH2CH2OH 87

iCH2CHCH3

NCH 2 CH 2 X CH 2 88, X=OH 89, X-Cl

82, X=OH 83, X=C1

is by the administration of low molecular compounds such as ether or chloroform by inhalation. Such anesthesia can, however, also be achieved by parenteral administration of a quite different set of agents. Two of these can be regarded as derivatives of benzylamine. Reaction of cyclohexanone with piperidine hydrochloride and potassium cyanide affords the aminonitrile, 90; this intermediate is, at least formally, the analog of a cyanohydrine with piperidine taking the place of water in the reaction sequence. Phencyclidine**1 (91) can be obtained by reaction of that amino-

57

Ary line thy lamines and Alcohols

nitrile with phenylmagnesium bromide. Although the overall sequence suggests displacement of cyanide ion, there is some evidence from related systems to suggest that the actual reaction pathway involves preionization of 90 to the ternary imine (92), followed by addition of the organometallic reagent.

CN

O

O£> 90

91

92

Preparation of the oxygenated analog, ketamine, proceeds by a quite different route. Addition of cyclopentylmagnesium bromide to o-chlorobenzonitrile gives the ketone, 93. Bromination of the ketone affords 94. Reaction of that intermediate with aqueous methylamine affords the imino alcohol (95) obtained by hydrolysis of the halogen and transformation of the ketone to the imine (though not necessarily in that order). Thermolysis of the imine hydrochloride leads one of the cyclopentane bonds to undergo a 1,2 shift to the adjacent unsaturated center and thus ring enlargement. Loss of a proton with ketonization gives the parenteral general anesthetic agent ketamine (96).h2

93

58

Benzyl and Benzhydryl Derivatives

c.

Compounds Related to Benzhydrylamine

As previously shown, derivatives of benzhydrol have provided a large number of useful antihistaminic agents. Continued delving into the structural requirement for activity revealed that the oxygen atom could, in fact, be replaced by nitrogen. It is of note that the nitrogen atom remote from the benzhydryl carbon is included in a piperazine ring in these drugs. Much of this chemistry is rendered possible by the various techniques that have been developed for placing differing substitution on the two nitrogen atoms. Piperazine can, for example, be monoacetylated (a); alkylation of the remaining nitrogen followed by deacylation allows a different alkyl group to be placed at the remaining heteroatom. Reaction of benzhydryl chloride with N-methylpiperazine (b) gives cyclizine (97)h3; analogous reaction with p-chlorobenzhy-

dryl chloride (5d) affords chlorocyclizine

(98),h3 HN

NCOR

(a) \ NCH3 97, X=H 98, X=C1

(b)

Acylation of the monosubstituted piperazine, 99 (obtainable by the protection-deprotection scheme outlined above), with cinnamoyl chloride gives the corresponding amide (100). Reduction of the carbonyl by means of lithium aluminum hydride affords cinnarizine (101),hk

100

101

Alkylation of the p-chloro analog (102) of the monosubstituted piperazine with m-methylbenzyl chloride (103) yields the

Benzhydrylamine-Related Compounds

59

antihistamine meclizine (1O5)1*5; reaction of 1O2 with p-tertiarybutylbenzyl chloride (104) gives buclizine (106).45 Alkylation of the terminal nitrogen with hydrophilic side chains derived from polyethylene glycols affords compounds in which the sedative properties inherent in antihistamines are accentuated. Thus, alkylation of 102 with the chloro derivative of diethylene glycol (107) affords the sedative hydroxyzine (108)h6; in the same vein, alkylation with the de] ivative of triethylene glycol (109) gives hydrochlorobenzethylamine (110).h7

Q CHN

NCH2-<

CH3 )-C-CH3

X

CH3 106

102 \ CHN

NCH2CH2OCH2CH2OH

CHN

108

110

CH2C1

1O3

NCH2 CH2 OCH2 CH2 OCH2 CH2 OH

CH2C1 104

107, n=l 109, n=2

Benzyl and Benzhydryl Derivatives

60 REFERENCES

G. Rieveschl, Jr., U. S. Patent 2,421,714 (1947). H. Morren, U. S. Patent 2,668,856 (1954). G. Rieveschl, Jr., U. S. Patent 2,257,963 (1950). A. F. Harms and W. T. Nauta, J. Med. Chem., 2, 57 (1960). L. H. Knox and R. Kapp, U. S. Patent 2,479,843 (1949). H. G. Morren, R. Denayer, R. Linz, H. Strubbe, and S. Trolin, Ind. Chim. Belg., 22, 429 (1957). C. H. Tilford and R. S. Shelton, U. S. Patent 2,606,195 (1952). 8. A. P. Swain, U. S. Patent 2,800,485 (1957). 9. 0. H. Hubner and P. V. Petersen, U. S. Patent 2,830,088 (1958). 10. M. Protiva and J. Jilek, Chem. Listy, 43, 257 (1949). 11. H. Arnold, N. Brock, E. Kuhas, and D. Lorenz, Arzneimittel Forsch., 4, 189 (1954). 12. L. Novak and M. Protiva, Coll. Czech. Chem. Commun. , 24, 3966 (1959). 13. Anon., British Patent 942,152 (1963). 14. N. Sperber, D. Papa, E. Schwenk, and M. Sherlock, J. Amer. Chem. Soc, 71, 887 (1949). 15. K. Miescher and A. Marxer, U. S. Patent 2,411,664 (1946). 16. D. W. Adamson, British Patent 624,118 (1949). 17. L. Stein and E. Lindner, U. S. Patent 2,827,460 (1958). 18. R. Lorenz and H. Henecka, U. S. Patent 3,031,377 (1962). 19. C. H. Tilford, R. S. Shelton, and M. G. VanCampen, J. Amer. Chem. Soc, 70, 4001 (1948). 20. E. L. Schumann, M. G. VanCampen, and R. C. Pogge, U. S. Patent 2,804,422 (1957). 21. J. J. Denton, W. B. Neier, and V. A. Lawson, J. Amer. Chem. Soc, 71, 2053 (1949). 22. J. J. Denton, H. P. Schedl, V. A. Lawson, and W. B. Neier, J. Amer. Chem. Soc, 72, 3795 (1950). 23. W. Klavehn, U. S. Patent 2,789,110 (1957). 24. D. W. Adamson, P. A. Barrett, and S. Wilkinson, J. Chem. Soc , 52 (1951). 25. R. A. Pohland and H. R. Sullivan, J. Amer. Chem. Soc, 75, 4458 (1953). 26. R. A. Pohland and H. R. Sullivan, J. Amer. Chem. Soc, 77, 3400 (1955). 27. L. P. Kyrides and F. B. Zienty, U. S. Patent 2,634,293 (1953) . 28. H. Hopff and C. S. Schuster, U. S. Patent 2,623,880 (1952). 29. R. Kallischnigg, U. S. Patent 2,683,714 (1954). 30. C. P. Huttrer, C. Djerassi, W. L. Beears, R. L. Mayer, and

References

61

C. R. Scholz, J, Amer. Chem, Soc9f 68, 1999 Q-946) , R. F. Phillips and E. M. Cates, U. S. Patent 2,607,778 (1952). 32. H. L. Friedman and A, V. Tolstouhov, U, S, Patent 2,465,865 (1949). 33. F. Leonard and U. V. Solmssen, J. Amer. Chem, Soctf 70, 2066 (1948). 34. A. Stoll and J. P. Bourguin, U. S. Patent 2,717,251 C.1955) , 35. R. C. Clapp, J, H, Clark, J. R, Vaughan, J, P, English, and G. W. Anderson, J, Amer. Chem, $oc, 69, 1549 (1947), 36. W. B. Martin, U. S. Patent 3,155,584 Q-964)t 37. F. C. Copp and D, Stephenson, U, S. Patent 3,038,0Q4 Q.962). 38. E. Walton and G, K, Ruffe11, British Patent 973,882 Q964), 39. E. Rabald and H. Dimroth, German Patent 824,208 (1951). 40. J. F. Kerwin and G. E. Ullyott, U. S. Patent 2,599,000 (1952). 41. E. F. Godefroi, V. H. Maddox, H. Woods, and R. F. Parcell, U. S. Patent 3,097,136 (1963). 42. C. L. Stevens, I. L. Keundt, M. E. Munk, and M. D. Pillai, J. Org. Chem., 3Of 2967 (1965). 43. R. Baltzly, R. DuBrevil, W. S. Ide, and E. B. Lorz, j . Org. Chem., 14, 775 (1949). 44. P. A. J. Janssen, U. S. Patent 2,882,271 (1959). 45. H. Morren, U. S. Patent 2,709,169 (1955). 46. H. Morren, U. S. Patent 2,899,436 (1959). 47. H. Morren, British Patent 817,231 (1959). 31.

CHAPTER 5

Phenethyl and Phenylpropylamines

By the turn of the century the theory of chemical mediation of physiologic responses had gained some currency. There ensued in some laboratories an intense search for endogenous chemical modifiers of bodily responses; The first such agent to be isolated from mammalian tissue was the ubiquitous hormone, epinephrine—at that time known as adrenaline. This compound has played an important role in pharmacology as well as in medicinal chemistry. In the former, a study of this molecule has gone far towards elucidating the operation of the sympathetic nervous system. At the same time, chemistry based on the phenethylamine portion of epinephrine has served as a prototype for subsequent researches built around the theme of modifying an endogenous hormone in order both to modulate its biologic effects and to provide hormone antagonists. Current work on blockers of the |3 receptors in the sympathetic nervous system in order to provide drugs for treatment of diseases of the cardiovascular system suggests that the final word in this story remains to be written. Breathing, heart action, control of blood pressure, glandular secretions, and related involuntary actions aimed at maintaining the organism are all under control of the autonomic nervous system which consists of the sympathetic (adrenergic) and parasympathetic (cholinergic) components. Signals that originate in the brain terminate at neurosecretory cells that release on neural stimulation a small amount of a specific hormone. In the case of the cholinergic system, this agent is acetylcholine. Of more direct concern, stimulation of a nerve in the adrenergic system results in release of norepinephrine. This amine, released at the appropriate site, interacts with a receptor on the target tissue; this interaction brings about the observed physiologic response (e.g., contraction of an involuntary muscle). This chain of action has been recently further detailed: norepinephrine is thought to stimulate the enzyme adenyl cyclase which in turn 62

63

Phenethyl and Phenylpropylamines

causes formation of 3',5!-cyclic adenyl phosphate (3f,5f cAMP). This last may be the true intracellular messenger molecule. Epinephrine itself does find some use in clinical medicine. The drug is used in order to increase blood pressure in cases of circulatory collapse, and to relax the bronchial muscle in acute asthma and in anaphylactic reactions. These activities follow directly from the agentfs physiologic role. The biogenetic precursor of epinephrine, norepinephrine, has activity in its own right as a mediator of sympathetic nerve action. (An apocryphal story has it that the term nor is derived from a label seen on a bottle of a key primary amine in a laboratory in Germany: N ohne R). This agent, too, is used to increase blood pressure. Friedel-Crafts acylation of catechol with chloroacetyl chloride gives the a-haloacetophenone (2). Displacement of halogen by methylamine (3) followed by catalytic reduction gives the amino alcohol (4). Resolution as the tartrate salt affords the (-) isomer, epinephrine (4). Substitution of ammonia as the base in this sequence gives norepinephrine. Isolation of the (-) isomer affords levarterenol (5).1 Reaction of the same halide with isopropylamine followed by reduction leads to isoproterenol (6). This agent, used as the racemate, is employed largely for its effect in relieving bronchial spasms in asthmatics. It might be noted in passing that isoproterenol occupies an important role in pharmacology in the classification of sympathetic receptors. Removal of one of the aromatic hydroxyl groups gives an agent similar to epinephrine in its effects but with longer dura-

CH*

Lion of action. The largest use of this drug, however, depends on its vasoconstricting action; phenylephrine is used extensively as a nasal decongestant due to its ability to constrict the blood vessels in mucous tissue on local application. In one published

64

Phenethyl and Phenylpropylamines

synthesis, the benzyl ether of m-hydroxybenzaldehyde is subjected to Reformatski reaction with ethyl bromacetate to give the hydroxyester (8). Treatment with hydrazine leads to the hydrazide (9). This last is then rearranged to the intermediate isocyanate by means of nitrous acid; intramolecular addition of the hydroxyl group gives the oxazolidone (11). The presence of an acyl group on nitrogen avoids some of the difficulties often encountered in attempts to monomethylate amines. In this case, the reaction is accomplished by means of sodium hydride and methyl iodide. Treatment with strong acid cleaves both the heterocycle, which is in effect a cyclic carbonate, and the benzyl ether. Phenylephrine (13)2 is thus obtained. The isomer of isoproterenol in which both aromatic hydroxyl groups are situated meta to the side chain also exhibits bronchiodilating activity. Oxidation of 3,5-dimethoxyacetophenone by means of selenium dioxide affords the glyoxal derivative (15). Treatment of the aldehyde with isopropylamine in the presence of

6H5CH2O

Vj^C

C 6H 5 CH 2 0 '

2 COR

C 6H 5 CH 2 0 "

8, R=-OC2H5 9, R=NHNH2

^CHCH2NHCH3 OH 13

CfiH5CH2O

10

C6H5CH2O

hydrogen and Raney nickel leads to the amino alcohol (16). (The sequence probably proceeds by first addition of the amine to the aldehyde. Reduction of either the carbinolamine or the Shiff base derived therefrom gives an aminoketone; reduction of the ketone will afford the amino alcohol.) Removal of the ethereal methyl groups by means of hydrogen bromide gives metaproterenol (17 ).3 Condensation of the substituted phenethyl bromide, 18, with piperazine can be stopped at the monosubstituted amine (19). Reaction of this amine with propiophenone and formaldehyde in a Mannich reaction affords eprazinone (20),h an antitussive agent. Substitution of an aromatic heterocycle directly onto the

65

Phenethyl and Phenylpropylamines

CH3O

CH3O

CH3O

CH3O 15

14

OC2H5 -CHCHoBr

18

16, R=CH3 17, R=H

OC2H5 -CIICIKN

19

nitrogen of these amino alcohols markedly changes the activity of these compounds. Thus, the compound substituted by a 2-pyridyl group, phenyramidol (21), finds use largely as a muscle relaxant. This agent is obtained by reaction of the anion from 2-aminopyridine with styrene oxide.5

CHCHo 21 Replacement of the aromatic hydroxyl groups in isopreterenol by chlorine again causes a marked shift in biologic activity. This agent, dichloroisoproterenol (25), was found to be an antagonist rather than agonist towards the 3-sympathetic receptors. Although this first of a long series of so-called 3 blockers had limited practical utility, it pointed the way to the development of drugs with many applications in the control of some of the romplications of heart disease such as arythmia, angina, and Intely possibly hypertension. It is thought that these agents .ict by antagonizing the effects of endogenous epinephrine by competing with the latter for receptor sites. Preparation of the prototype starts with the radical side 1 hain bromination of dichloroacetophenone to give the bromoketone (J3). The carbonyl group is then reduced by means of sodium hurohydride; displacement of halogen by means of isopropylamine

66

Phenethyl and Phenylpropylamines

affords dichloroisoproterenol (25).6 Starting with 2-acetylnaphthalene, an analogous scheme affords pronethanol (27), while the methanesulfonyl derivative of p-aminoacetophenone (28) leads to the 3-blocker soltalol (29).

Cl-

0 I! CCHX

CHa CIICH2NHCH

Cl 22, X=H 23, X=Br

24

25 3HCII2NHCH

2b

VcOCII3

CH3 CH,

27 CH, I CHC1I2NHCII

CH3SO2NH

• CH,

28

29

Alkylation on the carbon atom remote from the aromatic ring affords a further series of useful medicinal agents. Although these are by an large no longer frank sympathetic agonists, they retain sufficient properties of the parent compounds to find use as central nervous system stimulants, bronchiodilators, and when appropriately modified, appetite-suppressing agents. The first of these compounds, interestingly, derives from ancient Chinese folk medicine. For millenia, the stems of various species of Ephedra had been in use in China as mild stimulants. Investigation of the plant revealed the active compound to be the alkaloid, ephedrine (31), whose structure proved to be remarkably close to that of epinephrine (absolute configuration shown). In an interesting synthesis7 of this agent, benzaldehyde is first fermented with glucose and yeast. There results the addition of acetate in a reaction similar to an acyloin condensation. As in almost all enzymatically catalyzed reactions, the newly formed chiral center is introduced stereospecifically—as it happens, in the desired sense. Reductive amination is then employed to introduce the nitrogen atom. If we assume for the moment that the Shiff base

Phenethyl and Phenylpropylamines

67

is an intermediate in this reaction, this molecule can be depicted as in either A or B. It should be noted that each of these contains an interaction between the hydroxyl and another mediumsized group. In the case of A, however, this interaction is mitigated by the possibility of chelation. The stereochemistry of ephedrine (31) is in fact that obtained by reduction of A.

CH->

COCH, 30

31

Mannich condensation of the primary amine corresponding to ephedrine (32) with formaldehyde and m-methoxyacetophenone yields oxyfedrine (33)B; this agent retains the vasodilating activity of ephedrine and is in fact denoted a coronary vasodilating agent.

0 CH 3 II I CCH2CH2NHCHCH-

OH 7

H2NCHCH- ' CH-i

OH

CH 3 O 32

33

Addition of a hydroxyl group to the aromatic ring of ephedrine as well as changing the substitution on nitrogen leads to a compound whose main activity is to raise blood pressure. Thus, formation of the Shiff base of the zn-hydroxy analog of 30 with benzylamine (34), followed by catalytic reduction, yields metar,uninol (35). When optically active hydroxyketone is employed in

68

Phenethyl and Phenylpropylamines

the synthesis, steric induction again obtains; the drug is thus obtained directly as the (-) isomer.

34

35

The homolog of epinephrine in this series is a potent vasoconstrictor. Reaction of 3,4-dimethoxypropiophenone with butyl nitrite leads to nitrosation at the a position (36). Stepwise reduction of the nitrosoketone leads to the amino alcohol (37). Removal of the methyl ether affords racemic 38. Resolution of this last followed by separation of the (-) isomer gives levonordefrine (38).9

CH3 CH3O

0 II CCH 2CH 3

CH3O-

OH I CHCH-CH3 NH?

RO RO

CH3O 36

37, R=H 38, R=CH 3

A closely related compound bearing oxygen substitution at the 2 and 5 positions shows activity as a 3-sympathetic blocking agent. Acylation of the dimethyl ether of hydroquinone with propionic anhydride gives the ketone 39. This is then brominated to 40. Displacement by halogen by tertiary butylamine (41) followed by reduction of the carbonyl group gives the amino alcohol. It is of note that the product, butoxamine (42) t is obtained exclusively as its erythro isomer.10 OCH

OCH CCH-CH3

OCH30H CHCHCH3 NHC(CH3)3

NHC(CH3 )3 OCH, 39, X=H 40, X=Br

OCHo 41

OCH, 42

69

Phenethyl and Phenylpropylamines

Incorporation of a hydroxyl group at the para position of ephedrine in addition to alkylation of nitrogen with a somewhat more complex side chain gives a drug whose main action is that of a peripheral vasodilator. Reductive amination of phenoxyacetone (43) (obtained from sodium phenoxide and chloroacetone) with ammonia and hydrogen affords amine, 44. Syntheses of the remaining fragment starts with the benzylation of p-hydroxypropiophenone (45). Bromination of the product gives 47. Displacement of halogen by amine, 44, leads to the aminoketone, 48. The benzyl group is then removed by hydrogenolysis (note that the carbonyl is apparently untouched by this reaction). Reduction of the carbonyl group by means of sodium borohydride affords isoxsuprine (50).X1 The analog, 51, in which the ether oxygen is replaced by methylene3 has much the same activity as 50. This compound, nylidrin (51), is obtainable by reduction of the Shiff base from p-hydroxyephedrine and 4-phenyl-2-butanone.

CCH2CH3 —>C6H5CH2O-C

>C-CHCH3 -?-> C6H5CH2

CCHNHCHCH2OH

CH 3 CH 3 45

MI2

0 II -OCH2OCH3

I

~OCH2CHCH3

49

44

43

OH

CH 3 -CHCH-NHCHCH2CH2OH

CH 3

51

V

CH3

>CHCHNHCHCH2(M/ CH3 50

Omission of the side chain hydroxyl group from molecules based on epinephrine or ephedrine does not abolish the sympathomimetic activity of the resulting compounds. Many of these agents exert a considerable stimulant action on the central nervous system. As such, drugs in this class have been widely used-and

70

Phenethyl and Phenylpropylamines

abused—as agents to combat fatigue and drowsiness. These are the classical "pep pills." Many of these drugs, in addition, show decided activity in suppressing appetite. Much work has gone into structural modifications aimed at splitting the central nervous system stimulant activity from the antiappetite effect. This action, referred to an anorexic activity, is highly desirable in drugs aimed at combatting obesity. The prototype, amphetamine (52), is obtained by reductive amination of phenylacetone by means of ammonia and hydrogen.12 Isolation of the (+) isomer by resolution gives dextroamphetamine, a somewhat more potent stimulant than the racemate. NH2 -CH2CHCH3 51

52

NHCH3 I -CHoCHCHU

53

Reduction of phenylacetone in the presence of methylamine rather than ammonia gives methamphetamine (53), an agent similar in action to the primary amine. Alkylation of 53 with benzyl chloride affords the analog, benzphetamine (54).12 Incorporation of a metatrifluoromethyl group often has a potentiating effect on the activity of drugs acting on the central nervous system. The preparation of the amphetamine analog bearing this substituent begins with formation of the oxime of m~trifluoromethylphenylacetone (56). Catalytic reduction of that oxime gives the corresponding primary amine, 57. Acylation of the amine with acetic anhydride (58), followed by metal hydride reduction, affords fenfluramine (58),14 Extension of the alkyl group on the carbon bearing the amine changes the pharmacologic profile. Reductive amination of 1phenylbutanone-2 (60) with pyrrolidine in formic acid gives prolitane (61),15 a central nervous system stimulant agent with antidepressant properties. Incorporation of a phenolic hydroxyl group greatly attenu-

Phenethyl and Phenylpropylamines

71

NHR CF3 56

^^

CH2CHCH3

57, R=H 58, R=COCH3 NHC 2 H 5

CF3

CH2CHCH3

59

Q

0

II CH 2 C CH 2 CH 2

I CH 2 CHCH 2 CH 2 CH2

61

60

ates the CNS activity in the amphetamine series; there is obtained instead an agent that finds use in conjunction with atropine in opthalmology as a drug for dilating the pupil of the eye (midriatic). Condensation of anisaldehyde with nitroethane gives the nitrostyrene (62). Treatment with hydrogen chloride in the presence of iron hydrolyzes this enol nitro compound to the corresponding phenyl acetone (63). This last is then converted to the primary amine (64) by way of the oxime. Removal of the ethereal methyl group with strong acid gives hydroxyamphetamine (65),16

CHO

/CH3 CH=C

NH2 CH2CHCH3

OCH, 62

64, R=CH3 65, R=H

Primary amines are often rapidly inactivited in vitro by one of several pathways for metabolic degration. One of the more

72

Phenethyl and Phenylpropylamines

important of these—oxidative deamination—begins by oxidation of the amine to the corresponding Shiff base. Amphetamine derivatives bearing alkyl groups of the a position should therefore have longer duration of action by virtue of the lack of hydrogen at the oxidizable position. The synthesis reported for one such agent starts with the Friedel-Crafts acylation of benzene with isobutyryl chloride to give ketone (66). Alkylation of the anion of this ketone with benzyl chloride gives 67. Nonenolizable ketones are known to cleave on treatment with strong base. Thus, exposure of 67 to sodium amide gives the scision product, amide 68. Hoffmann degradation of the amide (68) by means of sodium hypochlorite gives phentermine (69),16 an agent used to control obesity by suppression of appetite. Methylation of the primary amine via its benzal derivative (70) affords mephentermine (71),16 Reaction of the methylated compound with chloroacetyl chloride yields the halogenated amide, 72. Use of this compound to effect a double alkylation on ethanolamine affords oxoethazine (73),17 This apparently small change alters the activity of the end product to that of a local anesthetic.

0 CH3 II I // H2NC-OCH2~( CH3 66

67

CH 3

CH 3 I C 6 H 5 CH=N-CCH 2

CH 3 NHOCH 2 I CH 3

68

CH 3

71

69

70

CH 3

72

N-OCH2CH 2 C-N I NCCH NCH C/ 2 2 CH CHa CH 2 0 I CH2OH

73

73

Phenethyl and Phenylpropylamines

The p-chloro analog of phentermine has much the same activity as the parent compound, with perhaps a somewhat decreased activity on the central nervous system. Alkylation of p-chlorobenzyl chloride with the carbanion obtained from treatment of 2nitropropane with strong base affords the compound containing the required carbon skeleton (74). Catalytic reduction of the nitro group yields chlorphentermine (75),18 CH 3 O2N-CH CH 3

C1CH

•-C1

74

75

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79).19

-CH=CH2

N 2 CHCO 2 C 2 H 5

NCO

76, R=C2H5 77, R=H

78

uiNHo

79

Phenethyl and Phenylpropylamines

74

A somewhat more complex application of this notion is represented by the CNS stimulant fencamfine (83). Diels-Alder addition of cyclopentadiene and nitrostyrene affords the norbornene derivative, 80. Catalytic hydrogenation reduces both the remaining double bond and the nitro group (81).20 Condensation with acetaldehyde gives the corresponding imine (82); a second reduction step completes the synthesis of fencamfine (83).21

In the discussion of benzylamines, we have met medicinal agents that owe their activity to some particular functionality almost without reference to the structure of the rest of the molecule. The hydrazine group is one such function in that it frequently confers monamine oxidase-inhibiting activity to molecules containing that group. Such agents frequently find use as antidepressants. Thus, reduction of the hydrazone of phenylacetaldehyde (84) affords the antidepressant phenelzine (85). Similar treatment of the derivative of phenylacetone (86) gives pheniprazine (87).22 r 2

NM-I2 84, R=H 86, R=CH 3

>CH 2 CHR "~

NHNH 2 85, R=H 87, R=CH 3

Phenethyl and Phenylpropylamines

75

Yet another example of a so-called pharmacophoric group is the biguanide functionality, a grouping associated with oral antidiabetic activity (see the section on sulfonylureas for a fuller discussion of this activity). Condensation of 2-phenethylamine with dicyanamide affords directly the orally active hypoglycemic

agent phenformin

(88),23

/~~\-CH2CH2NH2

+

N=CNC

> C

X

YcH2CH2NCNHC

The structural constraints of the present chapter have sufficient breadth to allow inclusion of an antibiotic whose basic structural element is the phenethylamine moiety. The biologic activity, it need hardly be said, has little in common with the foregoing drugs. Chloramphenicol, the first of the broad-spectrum antibiotics, was initially isolated from cultures of various Streptomyces strains. Structural determination revealed the drug to be one of the simpler molecules among the antibiotics. This very simplicity made the agent amenable to preparation by total synthesis both in the laboratory and on commercial scale. The first published synthesis of chloramphenicol211 establishes the carbon skeleton and the bulk of the functionality in the very first step. Thus, base-catalyzed condensation of benzaldehyde with nitroethanol affords the aldol product (89) as a mixture of stereoisomers. Catalytic reduction of the total mixture gives the .iminodiol, 90. At this point the threo isomer is separated and resolved into the optical isomers; the (-) isomer is then elaborated further. Acylation by means of dichloroacetyl chloride followed by treatment with base to remove o-acylated products -iffords the amide (91). Acetylation by means of acetic anhydride protects the hydroxyl groups towards the conditions of the next step as their acetates (92). The array of functionality present i ii this molecule is surprisingly stable to strong acid; nitration proceeds in a straightforward manner to afford the compound containing the nitro group in the para position. Treatment of this intermediate (93) with base removes the ester acetate groups to .ifford finally chloramphenicol (94). The apparently loose structural requirements for antihistaminic agents have already been alluded to. Thus, active compounds .ire obtained almost regardless of the nature of the atom that connects the side chain with the benzhydryl moiety. In fact, a inrthylene group, too, can also serve as the bridging group. Re.iction of the aminoester, 95 (obtained by Michael addition of

76

Phenethyl and Phenylpropylamines

NO 2 -CHO

CH 2 CH 2 OH

OCOCH3 02N-<

^CHCHCH 2 OCOCH 3

NHCOCHCl 2

NHCOCHC1 2

93

0,N-

OCOCH

-CHCHCH 2 OCOCH 3

92

OH I CHCHCH 2 OH NHCOCHCla 91

-CHCHCHoOH NHCOCHClo

94

piperidine to ethyl acrylate), with an excess of phenylmagnesium bromide gives the aminocarbinol, 96. Hydrogenolysis of the bis benzylic hydroxyl group affords the antihistamine fenpiprane (97).25

C 2 H 5 O 2 CCH 2 CH 2

O

CHCH2CH

•O

95 97

Substitution of an amphetamine-like moiety on the nitrogen atom of this molecule markedly alters biologic activity; the product, prenylamine (102), exhibits coronary vasodilator activity. Knoevnagel condensation of benzaldehyde with malononitrile gives the unsaturated cyanoester (98). The second phenyl group is introduced by means of conjugate addition of phenylmagnesium bromide (99). Hydrolysis followed by decarboxylation affords the nitrile (100). Reduction of the nitrile to the corresponding amine (101) followed by alkylation with 2-chloro-l-phenylpropane yields prenylamine (102).26 Substitution of a pyridyl ring for one of the benzene rings

Phenethyl and Phenylpropylamines

11

of these agents gives compounds with somewhat enhanced activity, as in the case of the oxygen- and nitrogen-bridged antihistamines. Starting materials for the preparation of these agents are the same diarylcarbinols used to prepare the hetero-bridged compounds. These (103) are first converted to the respective chlorides (104) by treatment with thionyl chloride. Catalytic reduction gives

CH-CH X CO2C2H5

S

CO2C2H5

CH-CH2CN

98

100

I CH3 CHCH2CH2NHCH2CH2

CHCH2CH2NH2

102

101

t lie diarylmethanes (105). The protons on the methylene group of these compounds are sufficiently acidic to be removed by strong bnses such as sodium amide or butyl lithium. Alkylation of the resulting carbanion with N~(2-chloroethyl)dimethylamine affords, respectively, pheniramine (106),27 chlorpheniramine (107),27 or hrompheniramine (1O8). Resolution of the two halogenated antihistamines revealed that the antihistaminic activity was associated with the (+) isomer; these are denoted dexchlorpheniramine (ilO7) and dexbrompheniramine (+108).

CHY

in/, X=H,Cl,Br Y=OH liul, X=H,Cl,Br Y=C1

CHCH2CH2N

105, X=H,Cl,Br

106, X=H 107, X=C1 108, X=Br

78

Phenethyl and Phenylpropylamines

The presence of unsaturation in the side chain is also compatible with antihistaminic activity. Mannich condensation of p-chloroacetophenone with formaldehyde and pyrollidine affords the amino ketone, 109. Reaction with an organometallic reagent from 2-bromopyridine gives 110. Dehydration leads to triprolidine (111).28

X-/' NVCCH2CH2

109, X=C1

O

C=CHCH2

O

111

no

112, X=H

V

C=CHCH2N

113

I

114

Reaction of the Mannich product (112) from acetophenone itself with the Grignard reagent from p-chlorobcnzyl chloride gives the carbinol, 113. Dehydration in this case gives the antihistamine pyrrobutamine (114),29 It is not immediately clear why dehydration does not occur in the other sense so as to afford the energetically more favored stilbene. As a class, analgesics tend to be built around portions of the morphine molecule that, as a minimum, incorporate a piperidine ring. The detailed discussion of the chemistry and biologic activity of these compounds is therefore incorporated in that particular section of this volume. Biologic activity, however, cannot be always neatly categorized; there exists a series of narcotic analgesics whose structure and chemistry more nearly fit those of the phenylpropylamines than those of the morphine analogs. The curious reader is asked to skip to that section for a fuller discussion of the rationale for what follows. Suffice it to say for the present that extensive dissection of the morphine molecule evolved the so-called morphine rule. This holds that the structural elements necessary for analgesic activity are

Phenethyl and Phenylpropylamines

79

represented by the partial structure below.

The first of the analgesic agents to incorporate the structural elements of this rule in an acyclic compound, methadone (119) , was developed in Germany during the Second World War. Details as to structure and synthesis were available to the outside world immediately following the end of hostilities only in the form of intelligence reports. Repetition of the putative synthesis revealed that ambiguity existed as to the structure of the final product. The key step, alkylation of the anion obtained from diphenylacetonitrile with zv-(2-chloropropyl)-dimethylamine, in fact affords a pair of isomeric amines. One of these can be Imagined to arise by straightforward displacement of halogen by the carbanion (115). The isomeric amine is thought to arise by internal cyclization of the haloamine to the aziridinium salt (117) prior to alkylation. Attack on this charged species by the carbanion at the center most susceptible to nucleophilic displacement will afford the isomeric amine (116). Reaction of the abnormal alkylation product (116) with ethylmagnesium bromide affords, .ifter hydrolysis of the intermediate imine, the compound that turned out to be methadone (119).30 Similar treatment of the expected alkylation product gives isomethadone (118).30 Synthesis of the intermediate aminonitrile for methadone by A re"giospecific route served to confirm the structure. AlkylatLon of diphenylacetonitrile with l-chloro-2-propanol affords the .ilcohol, 120, free of isomeric products (although it is possible here, too, to imagine cyclization of the halide prior to alkylation). The hydroxyl is then converted to the bromide (121) by

CHCN +

Pi I /Ui 3 CHCIIoN CH3

3

—>

I PT-I | | /^H3 NC-C-CHCHoN 3

JL V^

115

+

1 PU | | ^Ui3 NC-C-CH2CHN I

3

Phenethyl and Phenylpropylamines

80

u CH, ^ CH-CH2

0 CH3 l| I I / CH3CH2C-C-CH-CH2N

CH3 fH CII3CII2C-C-CH2CHN S CH o

CH3 CH3 117 118

119

means of phosphorus tribromide. Displacement of halogen by means of dimethylamine completes the synthesis of an amine identical to 116.31>32 in much the same vein, displacement of halogen on 121 with morpholine gives the amine, 122. Elaboration of the nitrile to the ketone affords the analgesic, phenadoxone (123),33 This same scheme, starting with displacement of halogen by piperidine, gives dipipanone (125).3A Omission of the side chain methyl group also leads to an active analgesic, the potency of which is somewhat less than half that of the parent. Alkylation of the familiar nitrile with N(2-chloroethyl)dimethylamine gives the amine, 126, Reaction with

Br ! NC-CCH 2 CHCH 3

OH i

NC-CCH 2 CHCH 3

116

12O

CH3CH2C-CCH2CHN CH3

r

0

NC-CCH2CHN>

CH 3 CH 2 C-CCH 2 CH-N CH 3

X

CH 3 123

122, X=0 124, X=CH2

125

Phenethyl and Phenylpropylamines

81

ethyl Grignard reagent leads to normethadone (127) S

CH3CH2C-CCH2CH2N

NCCCH2CH2N

CH3

'CH,

127

126

Modification of the ketonic side chain is also consistent with retention of analgesic activity. Thus, reduction of methadone with lithium aluminum hydride affords the alcohol, 128 (apparently as a single diastereomer). Acetylation gives acetylmethadol (129),36 Hydrolysis of the nitrile in 130 (obtained by an alkylation analogous to that used to prepare 126) affords the acid, 131. Esterification with ethanol affords the analgesic agent, norpipanone (132).35

CH3 CH3CH2CH-C-CH2CHN

119

CH3

129

128

O

N( -CCH2CH2

130

0 1O ! C H C 3 CH C C C -CH C ^ 3H 2H 2R

HO 02CCH C 2H 2 O

131

o CH O CHC 20 52C 2H 2 fl

132

82

Phenethyl and Phenylpropylamines

Replacement of the ketone by an amide leads to increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloroamine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135),37 Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone.

NC-C-CHCH2N

CH 3 133

0 -» HO2C-CCHCH2N

0

NC-C-CHCH2N

JcH3

0

CH3

134

135

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2~dimethylamino~lchloropropane gives isoaminile (137).38 It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity.

CH3

r CH 3 N

CH

NC-CCH2CHN

-CH2CN 136

137

Phenethyl and Phenylpropylamines

83

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. It). 17. 18. 19. JO. .'I. JZ.

,'*>. M. *•!>.

H. Loewe, Arzneimittel Forsch., 4, 586 (1954). E. D. Bergman and M. Sulzbacher, J. Org. Chem., 16, 84 (1951). Anon. Belgian Patent 611,502 (1961). M. Constantin, J. F. Pognat, and G. Streichenbrecher, Arnzeimittel Forsch., 24, 1793 (1974). A. P. Gray, D. E. Heitmeier, and E. E. Spinner, j . Amer. Chem. Soc., 81, 4351 (1959). J. Mills, U. S. Patent 2,938,921 (1960). G. P. Menshikov and M. M. Rubenstein, J. Gen. Chem. u. S. S. R., 13, 801 (1943). K. Thiele, U. S. Patent 3,225,095 (1965). W. H. Hartung, J. C. Munch, E. Miller, and F. Crossley, J. Amer. Chem. Soc, 53, 4149 (1939). Anon. Netherlands Patent Application 6,407,885 (1963). H. D. Moed and J. VanDijk, Rec. Trav. Chim. Pays Bas, 75, 1215 (1956). W. H. Hartung and J. C. Munch, J. Amer. Chem. Soc, 53, 1875 (1931). R. V. Heinzelman and B. D. Aspergren, U. S. Patent 2,789,138 (1957). L. Bereyi, P. Hugon, J. C. LeDouarec, and H. Schmitt, French Patent M1658 (1963). E. Seeger and A. Kottler, German Patent 1,093,799 (1960). L. L. Abell, W. R. Bruce, and J. Seifter, U. S. Patent 2,590,079 (1952). J. Seifter, R. S. Hanslick, and M. E. Freed, U. S. Patent 2,780,646 (1957). G. G. Bachman, H. B. Haas, and G. 0. Platau, J. Amer. Chem. Soc, 76, 3972 (1954). A. Burger and W. L. Yost, J. Amer. Chem. Soc, 70, 2198 (1948), G. I. Poos, J. Kleis, R. R. Wittekind, and J. Roseneau, J. Org. Chem., 26, 4898 (1961). J. Thesing, G. Seitz, R. Hotory, and S. Sommer, German Patent 1,110,159 (1961). J. H. Biel, A. E. Drukker, T. F. Mitchell, E. P. Sprengler, P. A. Nunfer, A. C. Conway, and A. Horita, J. Amer. Chem. Soc, 81, 2805 (1959). S. L. Shapiro, V. A. Parrino, and L. Freedman, J. Amer. Chem. Soc, 81, 2220 (1959). J. Controulis, M. C. Rebstock, and H. M. Crooks., Jr., J. Amer. Chem. Soc, 71, 2463 (1949). A. W. Ruddy and J. S. Buckley, J. Amer. Chem. Soc, 72, 718

84

26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

Phenethyl and Phenylpropylamines

(1950) . G. Erhart, Arch. Pharm., 295, 196 (1962). N. Sperber and D. Papa, U. S. Patent 2,567,245 (1951). D. W. Adamson, P. A. Barrett, J. W. Billinghurst, and T. S. G. Jones, j . Chem. Soc., 312 (1958). J. Mills, U. S. Patent 2,655,509 (1953). E. M. Schultz, C. M. Robb, and J. M. Sprague, J. Amer. Chem. Soc, 69, 188 (1947). E. M. Schultz, C. M. Robb, and J. M. Sprague, J. Amer. Chem. Soc, 69, 2454 (1947). N. R. Easton, J. H. Gardner, and J. R. Stevens, J. Amer. Chem. Soc., 69, 2941 (1947). M. Bockmuhl and G. Erhart, Ann., 561, 52 (1948). P. Ofner and E. Walton, J. Chem. Soc., 2158 (1950). D. J. Dupre, J. Elks, B. A. Hems, K. N. Speyer, and R. M. Evans, J. Chem. Soc, 500 (1949). M. E. Speeter, W. M. Byrd, L. C* Cheney, and S. S. Binkley, J. Amer. Chem. Soc, 71, 57 (1949). P. A. J. Janssen, J. Amer. Chem. Soc, 78, 3862 (1956). W. Stuhmer and S. Funke, U. S. Patent 2,934,557 (I960).

CHAPTER 6

Arylacetic and Arylpropionic Acids

Organic compounds that share some feature of structure or functionality often exhibit similar biologic effects. Thus, although (he arylalkylamines differ in pharmacologic profile, their effects t end to be those which are mediated via the autonomic or central nervous system. The arylacetic and arylpropionic acids by contrast show no such common targets. It is of note in this conneclion that, unlike the corresponding amines, these acids find few structural counterparts among endogenous mammalian hormones. As every sufferer of a toothache knows, inflammation and pain often go together. Specific drugs are available to treat each of iliese; the steroid antiinflammatory agents will deal very specifically with inflammation, while the narcotic analgesics will go far towards obviating pain. There is often, however, an understandable reluctance to rely on such potent drugs for treatment of trivial, though annoying, inflammation and pain. One of the oldest drugs in the modern armamentarium, aspirin, interestingly enough, is effective in the treatment of both inflammation and minor pain (in the words of the immortal ads: minor aches, neuKilgia, and neuritis). A recently discovered use of this drug ironically pointed out one of its major shortcomings. Aspirin i :m be used with some effect for the treatment of the pain and inflammation attendant to arthritis. Its low potency, however, necessitates its administration in gram quantities. Many individuals unfortunately find that their stomachs are intolerant of such large quantities of aspirin. While the steroids are quite effective for treatment of arthritis, clinicians usually prefer In reserve these drugs for more serious cases because of the potential side effects. An interesting sidelight is the observa(ion that most of the known antiinflammatory drugs, steroids or not, show a tendency to exacerbate existing stomach ulcers and perhaps even precipitate these. There exists, therefore, a real pi nee in medicine for a more potent aspirin-like compound with 85

86

Arylacetic and Arylpropionic Acids

reduced side effects. Acetylation of isopropylbenzene gives the corresponding acetophenone (2). Wilgerodt oxidation of the ketone leads to the corresponding acetic acid, ibufenac (3),% an. antiinflammatory agent with somewhat greater potency than aspirin. In one of several processes for the preparation of the methylated analog (5), the acetophenone is converted to its cyanohydrin (4). Heating with hydrogen iodide and red phosphorus reduces the benzylic hydroxyl while simultaneously effecting hydrolysis of the nitrile. There is thus obtained ibuprofen (5),* an agent with about twice the potency of the prototype (3).

COCH3

CH-C

>

CH-C

X

VCH2CO2H

VC-CH3

w

Friedel-Crafts acylation of biphenyl with acetyl chloride gives the ketone (6). Rearrangement to the acetic acid is again achieved by means of the Wilgerodt reaction. Esterification followed by alkylation of the anion obtained by treatment of the ester (7) with strong base with ethyl iodide affords the alkylated intermediate (8). Saponification gives the analgesic namoxyrate (9). An analogous scheme applied to the 3-fluorobiphenyl derivative (10) affords first the acetic ester (11). In order to circumvent the complications often involved in achieving monoalkylation of such compounds, the ester is first converted to the malonate (12) by means of sodium ethoxide and ethyl carbonate. Alkylation of 12 can, in fact, afford only the monoethyl compound (13). Acid hydrolysis of the esters with concomitant decarboxylation gives the potent antiinflammatory agent, flubiprofen (14).2 In a similar scheme, acylation of 2-methoxynaphthalene gives ketone, 15. This is then converted to the acetic acid by the Wilgerodt reaction. Esterification, alkylation of the carbanion (sodium hydride; methyl iodide), and finally saponification affords naproxen (17).3 The intense current effort on nonsteroid antiinflammatory agents and acrylacetic acids in particular make

Arylacetic and Arylpropionic Acids

87

CH 2 CH 3 CH 2 CO 2 C 2 H 5

-CHCO2R

7, X=H 11, X=F

6, X=H 10, X=F

8, X==C2H5 9, X=H

12

it probable that the above are but the forerunners of an extensive series of clinical agents. CH 3 COCH, CH 3 O'

*. CH 2 CO 2 CH 3 CH3O

15

CHCOoH CH3O

16

17

A compound closely related to naproxen has radically different pharmacologic properties; methallenestri1 (23) is in fact a •synthetic estrogen. At the time clinicians first started to foresee a use for compounds with estrogenic effects, naturally occurring compounds such as estrone or estradiol were all but unavail,-ihle in any quantity. Many groups thus undertook a systematic search for simplified structures that would possess the desired hormonal property. One such approach was based on the known estrogenic activity of doisynolic acid (18)> a degradation product from alkali fusion of estrone.'* Condensation of the substit uted propionaphthone (19) with the brominated isobutyrate ester (2O) in a Reformatski reaction gives a hydroxyester (21) whose carbon skeleton mimics that of the degradation product. Saponification followed by dehydration gives the unsaturated acid (22). llydrogenation completes the synthesis of methallenestril (23).5 Attachment of a group containing a basic nitrogen atom to I he phenylacetic acid side chain affords a drug that has found use as a mild stimulant. (Careful examination of the structure

Arylacetic and Arylpropionic Acids

88

'CH2CH3 CH3 C-CO2C2H5 / \ CH3 Br 19 20

CH3 CH3-C-CO2H

CHq

CH-CH,

23

22

18

will reveal a structural fragment related to amphetamine.) This drug, methyl phenidate, has gained some fame under the trade name of Ritalin® for its paradoxical use as a means for controlling hyperkinetic children. Alkylation of the carbanion obtained from phenylacetonitrile with 2-chloropyridine gives the diarylacetonitrile (24). Treatment with sulfuric acid gives partial hydrolysis to the amide (25). Reflux in methanol affords the corresponding ester (26). Catalytic hydrogenation over platinum results in reduction of the heterocyclic ring to afford methyl phenidate (27).6

CHCN

24

CHCOR

25, R=NH2 26, R=OCH3

Incorporation of the benzylic carbon of phenylacetic acid into a cyclohexane ring affords an agent whose activity is closely related to that of the narcotic analgesics. This activity is particularly noteworthy for the fact that this structure repre-

Arylacetic and Arylpropionic Acids

89

sents a departure from the "morphine rule" cited earlier. Formation of the dimethylamine enamine from crotonaldehyde affords the basically substituted butadiene (28). Diels-Alder condensation with the unsaturated ester (29) gives a pair of isomeric 1:1 adducts in the ratio of 3:1. The predominant product (30) is that which results from that transition state that involves the fewest steric interactions (A). [The transition state to form the minor isomer (B) involves interaction of the relatively bulky phenyl and dimethylamino group, while the same intermediate towards the major product involves the smaller carbethoxy group in the same interaction.] The major product, tilidine (30),7 is an analgesic effective against severe pain.

C6H5

CH3CH=CHCH0

CO2CH3

30

':ir2=CH-CH=CH-N

, CH-, 'CH,

28

CO 2 CH 3

31

The natural product, atropine (32), can be regarded as a inj'.hly substituted ester of phenylacetic acid and an amino alcohol. Although the agent is used clinically, chiefly as a midrifitic agent, the molecule possesses a host of other biologic activities. The drug has antispasmodic, bronchiodilating, and anti*uu*retory activity. Atropine thus provided an attractive starting point for efforts to synthesize agents that would show some nf the above actions. In fact, esters of amino alcohols and 2,2-disubstituted pltoiiylacetic acids show useful antitussive activity; the mechanism of action may include bronchiodilation. Double alkylation of the anion of phenylacetonitrile with 1,4-dibromobutane gives flio eyelopentane-substituted derivative (33). Saponification

90

Arylacetic and Arylpropionic Acids

32 followed by treatment with thionyl chloride affords the acid chloride (35). Condensation with diethylaminoethanol gives caramiphene (36) . 8 Displacement of one of the halogens of 3,3~dichloroethyl ether by means of the sodium salt from 34 gives the haloester (37). The action of dimethylamine on this intermediate affords carbetapentane (39) . 9 Alkylation of phenylacetonitrile with an excess of ethyl iodide gives the substituted nitrile (39). A sequence similar to that used in going from 34 to 38 gives the antitussive, oxeladine (40).10

COCH 2 CH 2 OCH 2 CH 2 X

COCH 2 CH 2 N C2II5

37, X-Cl

36

_CH 2 CN

COX

33

34, X=0H 35, x-Cl

0

OCN \ CH2 CH2 CH3 CH3

p -u

C-COCH2 CH2 OCH2 CH 2 N ^2n5

CH 2 CH 3 CH 3 40

39

Arylacetic and Arylpropionic Acids

91

Esters of diphenylacetic acids with derivatives of ethanolamine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydrofuran (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46).xl

CHO

X

42

cr

NH

43

C2H5 45

44

CoHe

CHCO 2 CH 2 CH 2 N

47

CHCO

,O

46

The presence of an additional alkyl group on the benzylic r.'irbon is consistent with antispasmodic activity in this series. Alkylation of ethyl diphenyl acetate by means of sodium amide and methyl iodide followed by saponification gives the acid, 49. listerification with diethylaminoethanol affords aprophen (So) ,12 The second aromatic ring can, interestingly, be replaced by ii cycloalkyl group. Thus, treatment of diethyl phenylmalonate with 1,2-dibromocyclopentane in the presence of strong base iif Fords the cyclopentenyl derivative (52). [The fact that the olefin ends up in the relatively unfavored position suggests that I he initial step in this reaction may be elimination of hydrogen

Arylacetic and Arylpropionic Acids

92

/CH3 CHCO2C2H5

CO2H

/C2H5 CO2CH2CH2N 50

48

bromide to give the allylic halide (53); this last would suffer displacement to lead to the observed olefin.] Hydrolysis of the ester groups with concomitant decarboxylation gives the phenylacetic acid (54). Esterification of the acid with 2-(w-pyrrolidino)ethanol via its acid chloride affords the antispasmodic agent cyclopyrazolate (55).13

CO 2 C 2 H 5

s CO 2 C 2 H 5 -CH

CHC09H

51 52

Br Br

a" 53

55

Treatment of the sodium salt of phenylacetic acid with isopropylmagnesium bromide affords the so-called Ivanov reagent, a formally doubly charged species whose anionic moiety is often formulated as 56. This dianion undergoes aldol condensation with cyclopentanone to give the corresponding hydroxyacid (57). Alkylation of the salt of the acid with N-(2-chloroethyl)dimethylamine gives cyclopentolate (58).1U This agent has atropine-like activity with the midriatic component predominating. A rather more complex amino alcohol side chain is accessible by a variation of the Mannich reaction. Taking advantage of the acidic proton in acetylenes, propargyl acetate (61) is condensed with formaldehyde and dimethylamine to give the acetylated amino

Arylacetic and Arylpropionic Acids

93

CHCO 2 H OH

CHCO 2 CH 2 CH 2 N

56 57

CH3CO2CII2CrCH

61

58

CH 3 CO 2 CH 2 CHCCH 2 N

62

alcohol (62). Ester interchange of this with the product from partial hydrogenation of benzilic acid (59), gives the antispasmodic agent, oxybutynin (60).15 Incorporation of a hydroxyl group directly onto the benzylic carbon of the diphenylacetic acid again changes the pharmacologic profile of the compound; although the drug retains the anticholinergic activity of atropine, its main use has been in the treatment of anxiety and tension. Oxidation of benzoin (63) with potassium bromate leads to benzilic acid (64) by the well-known rearrangement of the intermediate, benzil. Esterification by means of diethylaminoethanol affords benactizine (65).16

0 OH

63

OH I / CCO2CH2CH2N

65

Peripheral vascular disease, often one of the sequelia of atherosclerosis, is characterized by markedly decreased circula-

94

Arylacetic and Arylpropionic Acids

tion in the extremities. The course of the disease is frequently punctuated by acute episodes in which the blood vessels undergo spastic closure. One of the few nonnitrogen-containing phenylacetic acid derivatives to show antispasmodic activity has found some use in the treatment of this disease. The drug, cyclandelate (67),17 is obtained by esterification of mandelic acid (66) with 3,5,5~trimethylcyclohexanol.

66 The placement of a nitrogen atom directly on the benzilic carbon atom is apparently consistent with antispasmodic activity. Esterification of 2(iv-piperidyl)ethanol by means of chloroacyl chloride (68) gives the basic ester (69). Displacement of the remaining halogen by piperidine gives dipiproverin (70) ,ia

O

CH-COCl ' ., Cl

68

~>

r >CHCO2CH2CH2N \ ~ / •_ \ Cl

69

J /

> r X\-CHCO2CH2CH2N \ \,rr / I \ f

o

70

Antispasmodic activity, interestingly, is maintained even in the face of the deletion of the ethanolamine ester side chain. Reaction of anisaldehyde with potassium cyanide and dibutylamine hydrochloride affords the corresponding a-aminonitrile (72) (a functionality analogous to a cyanohydrin). Treatment with sulfuric acid hydrolyzes the nitrile to the amide to yield ambucetamide (73),19

71

CN / \ / CONH2 z(CH2 )3CH3 —> CH3O-T >CH ,(CH2)3CH3 NN V-=-/ ^ N (CH2)3CH3 ^(CH2)3CH3 72 73

Arylacetic and Arylpropionic Acids

95

The activity of acylureas as hypnotic and anticonvulsant agents is dealt with in some detail later. This is again one of the cases in which the functionality rather than structure determines pharmacologic activity. Thus, acylation of urea with phenylacetyl chloride gives the anticonvulsant agent, phenacemide (74).20

0 -CH2COC1

+

H2NCONH2

— >

('

N

0

VCH2CNHCNH2

74 It will be recalled that both epinephrine and norepinephrine are pressor agents, that is, they cause an increase in blood pressure. It would therefore be expected that antagonists to these endogenous pressor amines might have a useful effect on hypertension. One approach to this problem consists in the preparation of compounds that interfere with biosynthesis of these amines by the administration of false substrates^ that would be unable to go through the final steps of biogenesis. A crucial step in the biosynthetic scheme for formation of norepinephrine consists in the decarboxylation of DOPA (dihydroxyphenylalanine, 75) to dopamine (76). (Side chain hydroxylation completes the scheme.) Substitution at the carbon adjacent the carboxyl group should hinder this reaction. Reaction of the substituted phenylacetone (77) with ammonium chloride and potassium cyanide affords the corresponding a-aminonitrile (78), The L isomer is then separated from the racemate by means of the camphorsulfonic acid salt. (The unwanted D isomer can then be subjected to basic hydrolysis to give back starting ketone that can be then recycled.) Treatment of the L isomer with concentrated sulfuric acid at the same time effects hydrolysis of the nitrile to the acid and cleavage of the remaining methyl ether. There is thus obtained methyldopa (79).21 While this drug has in fact found considerable use as an antihypertensive agent, there is evidence to indicate that the mechanism of action may be considerably more Involved than a simple block of pressor amine synthesis. The thyroid gland, located in the base of the neck, exerts a key role on growth and metabolism. In contrast with that of some of the other endocrine glands, this control is effected through a pair of relatively simple molecules, thyroxine, and its close congener, triiodothyronine. Cases of thyroid deficiency (hypothyroidism) are common enough to warrant the production

96

Arylacetic and Arylpropionic Acids

NH2

NC NH2 CH 2 OCH 3

HO

CH2C-CO2H

—> 77

78

CH 3 79

NH 2 CH2CHCO2H

75

CH 2 CH 2 NH 2

76

of these hormones commercially. In contrast to the steroid hormones, thyroxine and its analogs have few, if any, applications beyond replacement therapy. Since the structure of the hormone is constant among most mammals, crude extracts of thyroid glands from slaughterhouses constitute an important form of drug for treatment of deficiencies. The pure hormones are used in medicine as well; these in turn are obtained both by total synthesis and purification of extracts from animal sources. One published synthesis starts by the formation of the benzenesulfonate of phenol, 77. This compound, it should be noted, is particularly suited for nucleophilic aromatic substitution, since the benzenesulfonate is activated by the ortho nitro, as well as the para carbonyl group. In fact, treatment of 77 with the anion from the monomethyl ether of hydroquinone gives the di~ phenyl ether (79) . Azlactones such as 80 have proven of great utility in synthesis, since the parent amino acid is cyclized into a form that masks both the amino and carboxyl groups. The reactivity of the methylene group is enhanced by the adjacent imine. Condensation of the aldehyde group of 79 with 8O by means of sodium acetate and acetic anhydride affords 81. When the condensation product is exposed to sodium methoxide, this reagent attacks the carbonyl group of the azlactone; the ring is thus opened to form the ester enamide (82). Reduction of this product with Raney nickel selectively reduces the aromatic nitro group to the corresponding amine (83). This amine is then transformed to an iodo group by diazotization and treatment of the diazonium salt with iodine-sodium iodide. Catalytic hydrogenation over

Arylacetic and Arylpropionic Acids

97

platinum reduces the enamine double bond; hydrolysis of this ester-amide gives the amino acid (86). The aromatic methyl ether in the remote ring is then cleaved by means of hydroiodic acid (80) to afford the key diodo intermediate (87). The L form of this amino acid is isolated by optical resolution for further elaboration to the thyroid hormones. In the course of synthetic work on the thyroid hormones, a series of specialized reactions have been developed for the direct introduction of iodine ortho to phenolic groups. Thus, treatment of the diiodo compound with either the sodium salt of N-iodo-p-toluenesulfonamide or a mixture of iodine and sodium iodide in aqueous dimethylamine affords L-triiodothyronine,22 which goes by the generic name of liothyronine (88). This compound, interestingly, is more active as av thyroid hormone than thyroxine itself. Treatment of intermediate (87) with an excess of one of the iodinating reagents gives levothyroxine (89).2Z Preparation of the diiodo derivative from the D form of the intermediate, 87, gives dextrothyroxine, a compound with much reduced thyroid activity that has been used for the treatment of elevated cholesterol levels.

CHO OoN 77

CH 3 O NHCOCH3

82, X-NO2 83, X=NH2 84, X=I

81

98

Arylacetic and Arylpropionic Acids

CH 3 O

87 85, R'=COCH 3 ; R M =CH 3 86, R f =R"=H

I 0

\

/-CH2CHCO2H

88, X=H 89, X=I

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

J. S. Nicholson and S. S. Adams, U. S. Patent 3,228,831 (1966). S. S. Adams, J. Bernard, J. S. Nicholson, and A. B. Blancafort, U. S. Patent 3,755,427 (1973). I. T. Harrison, B. Lewis, P. Nelson, W. Rooks, A. Roszkowski, A. Tomalonis, and J. H. Fried, J. Med. Chem., 13, 203 (1970). K. Miescher, Helv. Chim. Acta, 27, 1727 (1944). A. Horeau and J. Jacques, Compt. Rend., 224, 862 (1947). L. Panizzon, Helv. Chim. Acta, 27, 1748 (1944). G. Satzinger, Ann., 728, 64 (1962). H. Martin and F. Hafliger, U. S. Patent 2,404,588 (1946). Anon., British Patent 753,799 (1956). V. Petrow, 0. Stephenson, and A. M. Wild, U. S. Patent 2,885,404 (1959). J. H. Biel, H. L. Friedman, H. A. Leiser, and E. P. Sprengler, J. Amer. Chem. Soc., 74, 1485 (1952). H. E. Zaugg and B. W. Horrom, J. Amer. Chem. Soc, 72, 3004

Arylacetic and Arylpropionic Acids

13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

99

(1950). H. G. Kolloff, J. H. Hunter, E. H. Woodruff, and R. B. Moffett, J. Amer. Chem. Soc, 70, 3862 (1948). G. R. Treves, U. S. Patent 2,554,511 (1951). Anon., British Patent 940,540 (1963). F. F. Blicke and C. E. Maxwell, J. Amer. Chem. Soc, 64, 428 (1942). N. Brock, E. Kuhas, and D. Lorenz, Arzneimittel Forsch., 2, 165 (1952). H. Najer, P. Chabrier, and R. Guidicelli, Bull. Soc. Chim. (Fr.), 335 (1958). P. A. J. Janssen, J. Amer. Chem. Soc., 76, 6192 (1959). M. A. Spielman, A. 0. Geiszler, and W. J. Close, J. Amer. Chem. Soc, 70, 4189 (1948). D. Reinhold, R. A. Firestone, W. A. Gaines, J. Chemerda, and M. Sletzinger, J. Org. Chem., 33, 1209 (1968). H. Nahm and W. Siedel, Chem. Ber., 96, 1 (1963).

CHAPTER 7

Arylethylenes and Their Reduction Products

The isolation of the estrogens, the so-called female sex hormones, occasioned intensive work on the endocrine activity of this series of endogenous compounds. This was hampered in no small way by the minute quantities in which these hormones occur in nature as well as by the lack of sources of these agents other than isolation from mammals. However, enough data was accumulated to indicate that such agents had great potential for the treatment of the various dysfunctions that result from deficient levels of estrogens. Initial attempts to prepare these compounds by total synthesis were hindered by the fact that the structure of the estrogens had been only partly solved. It was known, however, that steroids consisted of a tetracyclic nucleus, and in the estrogens such as, for example, estrone (1), one of these rings was present as an aromatic phenol. The demonstration that the phenathrene derivative, 2,2 showed estrogenic activity in experimental animals encouraged further departures from the vaguely realized steroid nucleus in the search for estrogenic agents. The great variety of structures that have by now been shown to exhibit estrogenic activity2 leads to the suspicion that the estrogen receptor may be unusually nonspecific compared to receptors for other steroid hormones.

100

101

Arylethylenes

One of the first of the synthetic estrogens devoid of the steroid nucleus, diethylstilbestrol (7), is still fairly widely used today. Although initially employed for cases of estrogen deficiency, the drug has found utility in such diverse uses as in the fattening of cattle and the recently approved indication as a "morning-after'1 contraceptive. The initial synthesis for this agent involves first the alkylation of desoxyanisoin (3) with ethyl iodide by means of strong base (4). Reaction of the product with ethyMagnesium bromide gives the corresponding alcohol (5). Dehydration under acidic conditions affords largely the trans olefin (6) accompanied by a minor amount of the cis isomer. Cleavage of the methyl ether groups in the trans isomer to the phenol completes the synthesis of diethylstilbestrol (7).3 It is of note that the molecule can be coiled so as to assume the shape of a steroid. (The aromatic rings assume the functions of the terminal rings, while each of the ethyl groups provides bulk corresponding to the remaining alicyclic rings.)

,o

0 II CH2C

CH 2 CH 3 I Oil

CH2CH3

CH-C

,CH-C / - . sm-c — n H3 C1I3O V j ^

>

CH 3 O^

cn 3

CH2CIl;

CII2CH3

ICHoCH X

X

OR

CH

CHX (II 3 O

\

^

8, X=H 9, X=C1

,

a

Cl \ ocn-

6, R-=CH3 7, R=H

Gil 2CH 3 C-CII CIl 3

An interesting alternate synthesis for this agent starts with the chlorination of the benzylic carbon of 8 by means of N~ thiorosuccinimide. Treatment of the chloro compound (9) with sodium amide in liquid ammonia serves to remove remaining proton cm that carbon. This carbanion (10) then performs an alkylation M\iction on unreacted starting chloride. The product of this nlkylation (11) still contains a fairly acidic benzylic proton;

Arylethylenes

102

removal of this proton leads to beta elimination of hydrogen chloride and formation of the stilbestrol intermediate in a single step (6) .* Catalytic reduction of diethylstilbestrol proceeds stereospecifically (see Newman projections below) to afford the meso isomer, hexestrol (12).5 This synthetic estrogen is said to produce fewer side effects than the parent molecule. The meso form is more potent than the DL isomer. An alternate synthesis of this drug involves the cobaltous chloride-catalyzed coupling of the Grignard reagent from 13 with the analogous benzilic chloro compound (9). Demethylation of the product (14) gives hexestrol.6 The higher melting point of the meso form allows its separation from the DL by-product formed in this reaction by recrystallization. CH 2 CH 3 I Br-CH OCH,

13

12, R=H 14, R-0CH3

CH 3 CH 2

CH 3 CH 2

CH2CH3

CH2CH3 12

Self-condensation of the substituted propiophenone, 15, by the pinacol reaction proceeds to give the glycol, 16, as the meso isomer. (If it is assumed that the transition state for this reaction resembles product, this stereoselectivity can be rationalized on the grounds of steric interaction; compare A, which leads to the observed product, with B.) Dehydration under very specialized conditions (acetyl chloride, acetic anhydride) affords the bisstyrene-type diene (17) . Removal of the acyl groups by means of base affords the synthetic estrogen, dien-

Arylethylenes

estrol (18).

103

7

CH 2 CH 3

CH 3 CO 2

CO

O

o o CH3CHOOH

CH 3 CO 2

I OH CH 2 CH 3

OR

CH I! C-C

c-c

16

1

RO

•I

CH

CH,

17, R=CH3CO 18, R=H

AcO

.OAc KJ

CH,

, O2CCH3

it o Cj H o

Clio Clio

AcO

AcO

Insertion of an additional carbon atom between the two aromatic rings, interestingly, does not diminish estrogenic activity. Aldol condensation of anisaldehyde with p-methoxybutyrophenone (19) gives the substituted chalcone (20). A second ethyl group is then introduced into the molecule by conjugate addition of othylmagnesium bromide (21). Reaction of the saturated ketone with methylmagnesium bromide leads to the carbinol (22) . Dehydration followed by catalytic reduction completes construction of the carbon skeleton. Cleavage of the aromatic ether groups by means of hydrogen bromide affords the synthetic estrogen, benzrstrol (24).Q

CH 2 CH 2 CH 3 CHO T>CH3 OCH,

19

20

Arylethylenes

104

CH2CH3

CHoO

CH2CH3

OCH3

CUUO-

OCH3

22

CH 2 CH 3

RO

o

CH-CH-CH

I

OR

CH oCH•

23, R CH3 24, R-H The observation that one of the ethyl groups in stilbestrol can be replaced by an aromatic ring and the other by halogen with full retention of biologic activity illustrates the structural latitude in this series of drugs. Reaction of 4,4'-dimethoxybenzophenone (25) (obtained by Friedel-Crafts acylation of anisole by p-methoxybenzoylchloride) with the Grignard reagent from p-methoxybenzyl chloride affords the alcohol (26). Acid-catalyzed dehydration gives the corresponding ethylene (27) . Chlorination of the vinyl carbon by either chlorine in carbon tetrachloride or N-chlorosuccinimide affords the estrogen, chlortrianisene (28) ,9 Alkylation of one of the phenolic groups of the triarylethylene synthetic estrogens with an alkyl group terminating in basic nitrogen causes a fundamental change in biologic activity. First, the intrinsic activity of the compound is markedly reduced. Unlike the pure estrogens, which show increasing biologic responses with increasing doses, the resulting agents, called impeded estrogens, show a low maximal response regardless of dose. More important is the finding that these agents will antagonize many of the effects of concurrently administered pure estrogens. Agents of this class are therefore sometimes called estrogen antagonists. At one time estrogen antagonists seemed to hold much promise as contraceptive agents, since these compounds are remarkably effective in inhibiting pregnancy in the laboratory rat. Further in-

Arylethylenes

105

CH3q

CH3O

c=o CH3O

CH3O 25

CH3O" 28

vestigation showed that this effect was not manifested in higher species since these, unlike the rat, are not exquisitely sensitive to estrogen levels for conception. The first of these ngents, ironically, has found use as a drug for treatment of infertility. Ovulation is triggered in women by a series of hormones secreted by the pituitary gland. The estrogen antagonists nre known to suppress this secretion. Once administration of the drug is stopped, the gland rebounds with the outpouring of very large amounts of pituitary hormones, triggering ovulation. Alkylation of 4-hydroxybenzophenone by means of base with 2rhlorotriethylamine affords the so-called basic ether (29). In a sequence analogous to the preparation of 28, the ketone is first reacted with benzylmagnesium chloride (30). Dehydration (31) and chlorination complete the synthesis of clomiphene (32).10 It is of note that the commercial product is in fact a mixture of the two geometrical isomers. These have been separated and seem to differ in some degree in their endocrine properties. Substitution of thiophene rings for the benzene rings and a slight modification in the carbon skeleton leads to a marked nIteration in pharmacologic activity. The agents obtained by these modifications are apparently devoid of endocrine activity; instead, the compounds possess analgesic activity. Possibly as 11 result of some side effects, their use is restricted to veterin.iry practice. Michael addition of dimethylamine to ethyl crot Diiate gives the aminoester (33). Condensation with the lithium rrngent from 2-bromothiophene leads to addition of two equivalents of the organometalic (34). Dehydration yields dimethyl-

Arylethylenes

106

HO

NCH2CH2O CoH q

CoH

31, X=H 32, X=C1 thiambutene (35).1X The same scheme s t a r t i n g with the d i e t h y l amine adduct ^36,) affords the analog, die thy It hi ambu tene (38). 1]

CH3 R2NCHCH2CO2C2H5

33, R=CH3 36, R=C2H5

OH CH33 »

34, R=CH3 37, R=C9H

35, R=CH3 38, R=C2H5

REFERENCES 1. 2. 3.

J . W. Cook, E. C. Dodds, and C. L. Hewett, Nature, 131, 56 (1933). See, for example, D. Lednicer in Contraception; The Chemical Control of Fertility, (D. Lednicer, Ed.)> Marcel Dekker, N. Y., 1969, p . 197. E. C. Dodds, L. Goldberg, W. Lawson, and R. Robinson, Nature, 142, 34 (1938).

Arylethylenes

4.

107

M. S. Kharasch and M. Kleinman, J. Amer. Chem. Soc, 65, 11 (1943). 5. N. R. Campbell, E. C. Dodds, and W. Lawson, Nature, 142, 1121 (1938). 6. M. S. Kharasch and M. Kleinman, J. Amer, Chem. Soc, 65, 491 (1943). 7. E. C. Dodds, L. Goldberg, W. Lawson, and R. Robinson, Proc. Roy. Soc. (Lond.) B127, 148 (1939). 8. A. H. Stuart, A. J. Shukis, R. C. Tallman, C. McCann, and G. R. Treves, J. Amer. Chem. Soc, 68, 729 (1946). 9. R. S. Shelton and M. G. VanCampen, U. S. Patent 2,430,891 (1947). 10. R. E. Allen, F. Palapoli, and E. L. Schumann, U. S. Patent 2,914,563 (1959). 11. D. W. Adamson, J. Chem. Soc, 885 (1950).

CHAPTER 8

Monocyclic Aromatic Compounds

Although medicinal agents discussed in previous chapters often contained benzene rings, these were usually at some remove from the pharmacologically significant functionality. In a number of those agents, furthermore, the aromatic ring provided only steric bulk, as evidenced by the fact that in at least some cases reduction of the ring still provided active molecules. The compounds in the present section carry the functionality directly on the benzene ring. There is good evidence that the aromatic character of this ring plays an important role in their drug action. 1.

BENZOIC ACIDS

The introduction of the salicylates into therapy begins with the identification more than a century and a half ago of the substance in the bark of willow trees (Salix sp.), the glycoside salicin, 2, which was responsible for the antipyretic action of extracts known since antiquity. Degradation by chemical and enzymatic means of 2 gave glucose and salicyl alcohol (2). Further work on this natural product showed that salicylic acid (3), prepared by oxidation of the alcohol, had analgesic, antipyretic, and antiinflammatory activity in its own right. Salicylic acid itself, however, proved too irritating to mucous membranes to be used as such. Its acetyl ester, prepared by any of the standard ways, overcomes the irritation sufficiently for the drug to be used orally. This, of course, is now familiar to all as aspirin (4) . One of the first prodrugs, aspirin, is cleaved to the active agent, salcylic acid, in the liver as well as various other tissues. Despite the advent of numerous newer agents for the alleviation of the pain and inflammation characteristic of inflammatory diseases, aspirin remains the most widely used drug for this 108

109

Benzoic Acids

purpose. The safety of aspirin and the fact that it is available without prescription also makes it one of the most widely used drugs for self-medication. It has been estimated that some 35 tons are consumed daily in the United States alone. CH20H O(C 6 H X 1 O 5 )

CH20H

CO2H OCOCHU

CONHo

The popularity of aspirin has led to the preparation of a host of relatively simple derivatives in the hope of finding a drug that would be either superior in action or better tolerated. Halicylamide (5)y for example, is sometimes prescribed for patLents allergic to aspirin. It should be noted, however, that this agent is not as active as the parent compound as an antiinflammatory or analgesic agent. This may be related to the fact I hat salicylamide does not undergo conversion to salicylic acid in the body. Substitution of an amino group into the molecule affords an nj>ent with antibacterial activity. Although seldom used alone, para-aminosalicylic acid (PAS, 7) has been employed as an adjunct to streptomycin and isoniazid in treatment of tuberculosis. (There is evidence the drug acts as an antimetabolite for the para-aminobenzoic acid required for bacterial metabolism.) One of the more recent of the many preparations for this drug involves carboxylation of meta-aminophenol (6) by means of ammonium t.irbonate under high pressure.1

CO2H HoN

110

Monocyclic Aromatic Compounds

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxybenzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimethobenzamide (II).2

CHO

CHO

CH2NHj

OCH2CH2N

,cn

OCH2CH2N

CH

CH3 10

0 NCH 2 CH 2 O-(

X

)-CH 2 NHC

CH-. CH3O

0CH 11

2.

ANTHRANILLIC ACIDS

The relatively low potency of aspirin in overcoming the symptoms of inflammatory diseases has led to a continuing search for new antiinflammatory agents. Although many more potent agents have been introduced to clinical practice, most of these elicit some side effects that limit their use. Derivatives of N-aryl anthranillic acids have provided a series of quite effective antiinflammatory drugs, the so-called fenamic acids. Ullman condensation of m-trifluoromethylaniline (13) with oiodobenzoic acid in the presence of copper-bronze affords flufenamic acid (14).3 An analogous reaction of o-chlorobenzoic acid with 2,3-dimethylaniline (15) gives mefenamic acid (16) ;** meclofenamic acid (18) is obtained b y Ullman condensation employing 2,6-dichloro-3-methylaniline (17).

Anthranillic Acids

111

H9N

12a, R'=I 12b, R'=Cl

3.

13, X=Y=H;Z=CF3 15, X=H;Y=Z=CH3 17, X-Y=Cl;Z=CH3

14, X=Y=H;Z=CF3 16, X=H;Y=Z=CH3 18, X=Y=Cl;Z=CH3

ANILINES

Although aniline was found to possess peripheral analgesic activity more than a century ago, its use in medicine was precluded by the toxic manifestations produced by that compound. Metabolic oxidation of this amine gives largely phenylhydroxylamine (19). This compound, which is known to convert hemoglobin to the form that is incapable of binding oxygen, methemoglobin, is thought to be responsible for the toxicity of aniline. Paradoxically, another product of metabolic hydroxylation, p-aminophenol, again shows analgesic activity; this compound, too, however, shows too narrow a therapeutic ratio for use as a drug. Formation of derivatives of aniline that circumvent hydroxylation on nitrogen has provided a number of useful peripheral analgesics. Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21, An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p~ hydroxyacetophenone.5 The duration of action of acetaminophen is limited by the formation of water-soluble derivatives of the phenol (glucuronide •ind sulfate) that are then excreted via the kidney. Protection of the phenol as an ether inhibits such inactivation without diminishing biologic activity. Acetylation of p-ethoxyaniline6 .iffords the widely used peripheral analgesic, phenacetin (25). This drug is quite frequently found in headache remedies in combination with aspirin and caffeine (APC®, PAC®). Although the .miline derivatives show analgetic potency comparable to aspirin, they apparently have no effect on inflammation. Physostigmine (36) is actually a complex fused heterocycle rather than a simple derivative of aniline. The drug is men-

112

Monocyclic Aromatic Compounds

NHCOCH3

X=C-CH3

OH 22, X=0 23, X=NNH2

NHOH

NHCOCH q

19

20

M1COCH3

tioned at this particular point because analysis of the structure eventually led to a simple aniline derivative with much the same activity as the natural product. The alkaloid was first isolated from the ordeal bean (Physostigma venenosum) of West Africa (so named by its use by witch doctors in a trial process analogous to the trial by fire used in other cultures). Pharmacologic investigation showed the drug to be of value in the treatment of glaucoma by reducing intraocular pressure when applied topically to the eye. One of the more recent total syntheses of this compound starts by aldol condensation of the substituted acetophenone, 26, with ethyl cyanoacetate (27). Conjugate addition of hydrogen cyanide to the product followed by hydrolysis and decarboxylation of the resulting acid affords the dinitrile, 28b. Catalytic reduction of the nitrile affords diamine, 29; this is converted to the bis-IV-methyl derivative by the Decker monoalkylation procedure (30). Treatment of that intermediate with hydrogen iodide effects removal of the phenolic methyl ether groups to yield hydroquinone, 31. Oxidation of 31 with potassium ferricyanide possibly involves first formation of the benzoquinone (32); Shiff base formation with the amine would then give 33. Aromatization of that intermediate would then afford the iminium salt, 34; addition of the second amine to this leads to the observed reaction product, 35.

113

Anilines

Reaction of the phenol with methyl isocyanate then gives physostigmine (36).7 The relative inaccessibility of physostigmine led to molecular dissection studies to define the parts of the molecule necessary for activity. A surprisingly simple derivative of m-hydroxyaniline, neostigmine (40), proved to have the same activity as the complex heterocyclic molecule. In addition, this drug has found use as a cholinsterase inhibitor in pathologic conditions such as myasthenia gravis, marked by insufficient muscle tone. Reaction of m-dimethylaminophenol (37) witn phosgene affords tne carbamoyl chloride, 38. Treatment with dimethylamine gives the CH 3

CH 3 I

C=0

CH 3 Q

rn

r

IT

* \J\J2\* 2

5

C=C

CH3O

OCHq 26

28a, R=CO2 28b, R=H

27

CH 3 CH3 O ^ ^ s ^ ^ CH- CH2 CH2 NHR X CH 2 NHR

29, R=H 30, R=CH3

I CH3

HO

CH-CH2CH2NHCH3 NHCHo 31

I

Monoeyelie Aromatic Compounds

114

CH3 T3JHCH3

NHCH2 0 NHCH3

32

33

I CH3

T

I

klCH, CH3 CH3

CH3

35, R=H 36, R=COMCH3

34

corresponding carbamate (39). Quaternization with bromomethane affords neostigmine (40).8

N-CH3Br

37

38, R=C1

40

The great diversity of forms characteristic of the life cycle of the causative agent of malaria—the plasmodia-h&s led to the development of a series of chemically distant drugs for combating the organism at different stages. During an intense effort aimed at the development of antimalaria drugs in the 1940s, it was found that sulfonamides containing a pyrimidine ring had some activity against plasmodia at an early stage in the life cycle. The analog program on pyrimidines included some open-chain versions of this heterocycle as well. These last, the biguanides, were found to be quite active in their own right. (It was subsequently established that these compounds undergo oxidative cyclization to dihydropyrimidines in the body to give the actual antimalarial—see cycloguanyl).

Anilines

115

Alkylation of isopropylamine with cyanogen bromide affords the intermediate, 41. Condensation of this with p-chlorophenylguanidine (42, obtainable, for example by reaction of the aniline with S-methylthiourea) affords directly chlorguanide or paludrine (42). 9 J 1 0 The same sequence starting with m-chloroaniline leads to the biguanide, 44; chlorination in acetic acid gives chlorproguanil (45)911 a compound with a somewhat longer duration of action.

CH3\

CH3\ CHNHCN

CHNlIo + BrCN

// Cl- ff

NH NH II « / -NHCNHCNHCH

A. NX

43

41

42

NIIC / N\

r

W Cl

4.

NH m M It s

VNHCNHCNHCH

NH NH -NI1CNHCNHCH

CH

3

X

CH3

44

Cl 45

DERIVATIVES OF PHENOLS

The low structural specificity of the antihistamines has already been noted. It is perhaps not too surprising, therefore, to find that attachment of the basic side chain directly onto one of the .iromatic rings affords active compounds. In an unusual reaction reminiscent of the Claisen rearrangement, benzyl chloride affords the substituted phenol, 46, on heating with phenol itself. Alkyl.ition of 46 with 2-dimethylaminoethyl chloride gives phenyltoloxamine (47).12 Alkylation of that same intermediate (46) with 1bromo-2-chloropropane, leads to 48. Use of that halide to alkyl.ite piperidine gives the antihistamine, pirexyl (49),13 The basic ether of a rather more complex phenol, interestingly, exhibits a-sympathetic blocking rather than antihistaminic activity. Nitrosation of the phenol derived from p-cymene (50) Hives the expected nitroso derivative (51). Reduction (52) followed by acylation gives the acetamide, 53. Alkylation of the phenol with 2-dimethylaminoethyl chloride gives the corresponding basic ether (54). Hydrolysis of the amide gives the free

Monocyclic Aromatic Compounds

116

CH, C 6 H 5 OH

+

/CH 3 OCH 2 CH 2 N 'CH, 47

C 6 H 5 CH 2 C1 OH 46

CH 2

.^N/JHJ V

OCH2CHC1 I CH3

u

OCH2CHN

\

CH 3 49

48 amine (55); this aniline is then converted to the phenol (56) via the diazonium salt. Acylation of that product affords moxysylyt (57).lh ,CH CH3 CH-

OH 50

CH

CH

-CH3 OH 51, X=NO 52, X=NH2 53, X=NHCOCH3

CH3 I CH-CH3 OCH2CH2N

H RN CH3-'

54, R= 55, R=H

RO.

CH3 I CH-CH3 • ^ 3

CH

OCH2CH2N

N

CH3

56, X=H 57, X=COCH3

Derivatives of Phenols

117

The guanidine function, when attached to an appropriate lipophilic function, often yields compounds that exhibit antihypertensive activity by means of their peripheral sympathetic blocking effects. Attachment of an aromatic ring via a phenolic ether seems to fulfill these structural requirements. Alkylation of 2,6-dichlorophenol with bromochloroethane leads to the intermediate, 58, Alkylation of hydrazine with that halide gives 59, Reaction of the hydrazine with S-methylthiourea affords the guanidine, guanoclor (60).1S

^OCH2CH2NHNHCr Cl 58, R=C1 59, R=NHNH2

60

As noted previously (see Chapter 5 ) , modification of the substitution pattern on the aromatic ring and on nitrogen compounds related to epinephrine affords medicinal agents that show P-sympathetic blocking activity. Such agents have an important place in the treatment of many of the manifestations of diseases of the cardiovascular system such as, for example, arrhythmias, angina, and even hypertension. Interposition of oxygen between the propanolamine side chain and the aromatic ring has proven fully compatible with this activity. Reaction of epichlorohydrin with I-naphthol affords the glycidic ether (61). Opening of the oxirane ring with isopropylamine gives racemic propranolol (62),16>17 the only 3-blocker available for sale in the United States. It is of note that the / isomer is some 60 to 80 times more potent than its epimer. An analogous sequence on the allyl ether of catechol (63) leads to oxyprenolol (64); in the same vein, ortho-allylphenol (65) affords alprenolol (66).19

?H 0CH2CHCH2

0CH2CHCH2NHCH X

61

62

CH 3

118

Monocyclic Aromatic Compounds

OCH 2 CH=CH 2

,OCH2CH=CH2 OCH2CHCH2NHCH CHa

OH 64

63

CH2CH=CH2 II ^ CH3 "OCH2CHCH2NHCH

CH2CH=CH2

3

OH 66

65

Terminally O-arylated glycerols and their derivatives have yielded a number of useful skeletal muscle relaxants that possess some sedative properties. Thus, alkylation of o~cresol with 1chloropropan-2,3-diol affords mephenesin (67). Treatment of the glycol with phosgene selectively forms the terminal carbamoyl chloride; reaction of that with ammonia gives mephenesin carbamate (68) ,19 An analogous scheme starting with catechol monomethyl ether (69) gives the sedative often included in cough syrups, guaiaphenesin (70);19 conversion to the carbamate affords methocarbamol (71) . 2 0 Application of the three-step sequence to p-chlorophenol affords chlorphenesin carbamate (72).21 0 II •OCH2CHCH2OCNH2 OH

C1CH 2 CHCH 2 OH k

OH

69, R=OCH3

OCH 2 CHCH 2 OH I OH

67, R=CH3 70, R=OCH3

68, R=CH3 71, R=OCH3

0 II -OCH2CHCH2OC1SIH2 OH 72

Derivatives of Phenols

119

Reaction of the glycol, 70, affords an oxazolidinone rather than the expected carbamate (71) on fusion with urea. It has been postulated that the urea is in fact the first product formed. This compound then undergoes 0 to N migration with loss of carbon dioxide; reaction of the amino alcohol with the isocyanic acid known to result from thermal decomposition of urea affords the observed product, mephenoxolone (74)22; this compound shows activity quite similar to that of the carbamate. An analogous reaction on the glyceryl ether, 75, affords metaxalone (76),22

3

68

0H I OCH2CHCH2NH2

NH OCH2XCHCH2 74

73

Cl

OCH2CHCH2OH I OH 75

76

Epidemiologic studies have established a firm association between elevated blood lipids and atherosclerosis. Although the normalization of such elevated lipids would seem a desirable goal, there is as yet no evidence to show whether this has any effect on the course of the disease. One of the more effective agents available for lowering elevated triglyceride levels is a compound that more closely resembles a plant hormone than a medicinal agent. The drug may be prepared, albeit in low yield, by straightforward alkylation of phenol with ethyl isobutyrate. A more interesting method involves reaction of the phenol with chloroform and acetone to afford the acid, 77a. Esterification with ethanol gives clofibrate (77b).23 A fuller discussion of diuretic compounds will be found later in this section. Suffice to say that the majority of these

120

Monocyclic Aromatic Compounds

CH 3 CHC1.

OC-CO2R

Cl

(CH3 )2C0

CH 3 77 a, R=H 77b, R=C 2 H 5 agents contain one or more sulfonamide groups. Ethacrynic acid (81) thus stands by itself structurally as a diuretic. Alkylation of 2,3-dichlorophenol by means of ethyl bromoacetate followed by saponification of the product gives the acid, 78. Acylation with butyryl chloride leads to the corresponding ketone (79). Mannich reaction to the carbonyl group with formaldehyde and dimethylamine leads to amine, 8O. Elimination of dimethylamine by means of base affords ethacrynic acid (81) .2h 0

Cl

CH 3 CH 2 CH 2 C OCH 2 CO 2 H 78

79

0

9

Cl

CH 3 CH 2C—C

CH3CH2CIIC

CH 2

CH 2

CH,

CH,

81 80

5.

DERIVATIVES OF ARYLSULFONIC ACIDS

a.

Su1fanilami de s

Rather early in the evolution of bacteriology it was noted that these single-celled organisms readily stain with organic dye molecules. An elaborate classification scheme can in fact be de-

Derivatives of Arylsulfonic Acids

121

vised for bacteria based on their behavior to various dyes. Some effort, most notably on the part of Paul Ehrlich, was devoted to finding dyes that would bind to bacteria without affecting mammalian cells. It was hoped that in this way a dye could be devised that was toxic to the microbe without affecting the mammalian host—in effect an antibiotic. This concept seemed to have finally borne fruit some forty years after the initial work with the introduction of the dye protonsil (82) as an effective antibacterial agent.25 Careful metabolic work on this drug by a group of French workers showed that the agent was in fact cleaved to sulfanilamide (83) and the amine, 84, in vivo. Testing of the two fragments revealed that the activity of the drug resided entirely in the sulfanilamide fragment. That compound in fact showed full activity when administered alone in vitro or in vivo.26

//

S O

N H

9

2

N H

2

—

>

H

2

\\

N - <

V

.

S

O

2

N

H

83

82

2

+

YT

H

XT

2

N

/ '

-

\

X

\

ATTT

/ ~ N H

2

84

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-aminobenzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction; that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid; instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Is thus without effect on these higher organisms.

H O C H ^

0

8

7

8

6

122

Monocyclic Aromatic Compounds

Y

/ A H

HO2C-//

V

VNCH24N A ^ N

~~> acid

85 Both the dramatic effectiveness and shortcomings of this first antibiotic spurred the preparation of more than 5000 analogs. Although great improvements were eventually realized, the class as a whole suffers from a relatively narrow antibacterial spectrum, comparatively low potency, and rapid development of resistant organisms. An unexpected bonus from the clinical trials carried out on new experimental sulfa drugs was the development of entirely new classes of drugs. In essence, each of these followed from discovery of an apparent side effect by acute clinical observation. Thus, the finding that the sulfonyl urea analogs resulted in lowered blood sugar led to the oral antidiabetic agents. In this way, there were also discovered structural modifications that endowed this class of compounds with diuretic activity and uricosuric activity. A later section in the book details how the findings from the sulfonamide derivatives were developed and elaborated into molecules that bear little resemblance to the humble progenitor, sulfanilamide. Besides the shortcomings noted above, some of the early sulfa drugs were poorly soluble in water. Since the drugs are excreted largely unchanged in the urine, crystals of the compounds sometimes formed in the kidneys and urine with attendant discomfort and tissue damage. Considerable attention was therefore devoted to preparation of agents with better solubility characteristics. The drugs are available by one of two fairly straightforward routes. Chlorosulfonation of acetanilide gives the corresponding sulfonyl chloride (88); reaction with the appropriate amine gives the intermediate, 89. Hydrolysis in either acid or base leads to the sulfanilamide (90).

so,ci

*

H K '

>SO2NHR'

89, R=COCH3 90, R=H

Derivatives of Arylsulfonic Acids

123

In the alternate approach, the amide formation is performed on para-nitrobenzenesulfonyl chloride (91). Reduction by either chemical or catalytic methods affords directly the desired product (90) .

O2N-V

-SO2NHR

>SO 2 Cl 91

H2N-\

92

7~SO2NHR 90

Since the chemistry involved in the synthesis of these agents is self-evident, they are listed without comment in Table 1 below. The preparation of selected more complex basic residues is detailed in the section that follows. Table 1.

Derivatives of Sulfafanilamide

SO2NHR

Compound Number

Generic Name

R

90

Sulfanilamide

H

93

Sulfacetamide

-COCH3

94

Sulfaproxylene

0 II C

/ — \

J

96

27 S

VoCH x

X=J 95

Reference

Sulfacarbamide

-CNH2

Sulfathiourea

~CNH2 II S

CH

3

28

CH3 29

il 0

30

NH 97

Sulfaguanidine

--ONH2

31

124

Monocyclic Aromatic Compounds

Table 1, continued

98

Sulfisoxazole

\

//

VJII3

^

yjii3

cwCH3 99

200

Sulfamoxole

\\

•• NT -^^PTJ

33

Sulfaphenazole

V

N //

201

Sulfasomizole

102

Sulfathiazole

103

Sulfapyridine

^ N>^

104

Sulfachloropyridazine

^^ iN^T

35

D o o

Cl 105

39

Sulfamethoxypyridazine OCH 3

106

Sulfadiazine

2O7

Sulfamerazine

o Y^^^i

31

3

Derivatives of Arylsulfonic Acids

125

Table 1, continued

108

109

Sulfadimidine

"Tf^^T

CH3

41

Y CH3 Sulfaisodimidine CH3

110

111

Glymidine

^

O C H2 C H2 OCH,

Sulfameter 0

O C H3 112 Sulfadimethoxine v^N^OCH3 O C H3 113 Sulformethoxine yN^ I CH O 3 O C H3 114 Sulfalene 115

Sulfamethizole

y

S

V

CH

3

^8

N—N 116

Sulfaethidole

117

Glyprothiazole

^SxCH 2 CH 3 N—N S

C

^

49

^

45 46

126

Monocyclic Aromatic Compounds Table 1, continued CH3 i -CH3

Glybuthiazole

118

50

N — N CH3

Claisen condensation of propionitrile with ethyl acetate in the presence of sodium ethoxide gives the cyanobutanone, 119. This presumably forms oxime, 120, on reaction with hydroxylamine; that intermediate is not isolated as it cyclizes spontaneously to the isoxazole, 121. Acylation of the isoxazole with the sulfonyl chloride, 88, affords sulfisoxazole (98) after removal of the acetyl group.

CH3C=0 CH3 119

CH3-C=NOH 1

CH3~

CH3

CH3-

CN

98

NH2 121

120

The aminothiazole, 123, required for preparation of sulfathiazole (102), one of the older sulfonamides still in use, is available directly from the reaction of 1,2-dichloroethoxyethane with thiourea. The intermediate, 122, is not observed, as elimination of ethanol is spontaneous under the reaction conditions.

Cl Cl S 1 1 II CH2CH-OC2H5 -f H2NCM2

102 N^OCo 122

123

Acylation of thiosemicarbazide with propionyl chloride, interestingly, does not stop at the acylated product (124). Instead, this intermediate cyclizes to the thiadiazole, 125, under the reaction conditions. Hydrolysis then affords the heterocyclic amine, 126. Acylation by 88 followed by removal 6f the acetyl group affords sulfaethidole (116); variation of the acid chloride used in the preparation of the heterocycle leads to 117 and 118. The heterocyclic moiety of a sulfonamide need not be pre-

Derivatives of Arylsulfonic Acids

127

0 II

CH 3 CH 2 CC1

H 2 N-C

NH 2 NH 2x CH 3 CH 2 C-N-C XCH 2 CH 3 0 « H *

124

CH 2 CH 3

125, 126,

R=COCH2CH3 R=H

formed before attachment of the sulfonamide fragment. In an interesting variation on the above sequence, the semicarbazide of acetaldehyde (127) is acylated with the sulfonyl chloride, 88. Oxidation of the intermediate leads the semicarbazone to cyclize to a thiadiazole (129). Deacetylation affords the sulfamethizole (115) .

127

128 \

>-S0o

129, R=CH3CO 115, R=H It may be speculated that one spur to the synthesis of the numerous pyrimidine-substituted sulfonamides was the known efficacy of sulfaguanidine; an aminopyrimidine does, of course, confnin a good part of the guanidine functionality. One of the classical preparations of 2-aminopyrimidine starts with the condensation of guanidine with formylacetic ester (130) to give the pyrimidone, 131 (shown as the keto tautomer). Reaction with phosphorus oxychloride converts the oxygen to chlorine (132) via

128

Monocyclic Aromatic Compounds

the enol. Catalytic hydrogenation affords the desired amine (133). This is then taken on to sulfadiazine (106) in the usual way.

H2N-C

CO 2 C 2 H 5 1 CH2 CHO

Hisr^,

130

131

0

132, 133,

R=Cl R=H

CO 2 C 2 H 5 CH2 C=0 CH,

107

134

135

/CH3 0=C H 2 N-C

CH2

108

CH3

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, 135; acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). \ A somewhat different approach is used to prepare the compounds containing the amine at the 4 position. Condensation of the amidine from acetonitrile (138) with the enol ether from formylacetonitrile (137) leads to the requisite pyrimidine (139).

Derivatives of Arylsulfonic Acids

129

Since the ring nitrogen at 3 is now comparable in reactivity to the amine at 4, acylation with one equivalent of 88 gives a mixture of products. The desired product, sulfaisodimidine (1O9), can be obtained by acylation with an excess of the sulfonyl chloride (140) followed by alkaline hydrolysis. The rate of saponification of the sulfonamide group attached to the ring nitrogen is sufficiently greater to cause it to be lost selectively.

!l CH CN

+

2 HN

)-CH > C H 33

~>

' NSO2Ar

137

138 140, A r = p - C H 3 C N H C 6 H 4 II 0

Inclusion of oxygen on the pyrimidine ring has been found empirically to increase the effective serum half-lives. Villsmeier reaction on the dimethylacetal of methoxyacetaldehyde (141) with phosgene and dimethylformamide affords the acrolein derivative, 142. Condensation of this with guanidine gives the pyrimidine, 143, (The enamine can be viewed as a latent aldehydethe dimethylamino group is probably lost in the course of an addition elimination reaction with one of the guanidine groups.) This pyrimidine serves as starting material for sulfameter (111).

CH3OCH2CH

-V

N

141

N

CH3OC

CH3

CHO

142

143

The preparation of sulfadimethoxine (112) takes advantage of (he observation that inclusion of electron-releasing substituents on a pyrimidine ring activates halogen attached to the ring towards nucleophilic aromatic substitution. Preparation of the required starting material begins by conversion of barbituric acid (144) to the trihalide (145) by means of phosphorus oxychloride. Treatment with two equivalents of sodium methoxide effects tl isplacement of only two of the halogens (146). Reaction of that intermediate with the sodium salt from sulfanilamide (93) effects replacement of the remaining chlorine to give sulfadimethoxine (112).

130

Monocyclic Aromatic Compounds

H 144

OCH v

OCH

146 A somewhat more circuitous route is required to prepare sulfonamide-containing pyrimidines unsubstituted at 2. Thus, acylation of the 2-thiomethyl pyrimidine, 147> with the sulfonyl chloride, 88, affords 148. Removal of sulfur by means of Raney nickel (149) followed by deacetylation gives sulformethoxine (113) . SCH 3 SCH 3 OCH3 OCH 3 148

147 N' RNHG

N VSONH^ Y^ OCH3 2 OCH 3 /

14 9, R=COCH 3 11 3, R=H

Derivatives of Arylsulfonic Acids

131

Preparation of the substituted piperazine required for sulfalene (114) starts with bromination of 2-aminopiperazine to give the dihalide (150). Displacement of halogen by sodium methoxide proceeds regioselectively at the more reactive 3 position to give 151. Hydrogenolysis over palladium on charcoal gives the desired intermediate (152).

1

II

NH2

114

152

151

150

OCH3

Similar selectivity in displacement reactions is shown by 3,6-dichloropyridazine (153) (available by halogenation of the product from maleic anhydride and hydrazine). Thus, reaction of the dihalide with the sodium salt from sulfanilamide (93) affords sulfachloropyridazine (104). Reaction of this last with sodium methoxide under somewhat more drastic conditions results in displacement of the remaining chlorine to give sulfamethoxypyridazine (105) . NUN

cl-/' V c i 153

104

OCH, 105 Acylation of a sulfonamide on the amide nitrogen serves to remove the sometimes objectionable taste of these drugs. Reaction of intermediate, 154, with acetic anhydride followed by reduction of the nitro group affords acetyl methoxyprazine (156).51 The last, which has much the same biologic action as the parent compound, is used for oral administration in syrups. Sterilization of the G.I. tract either in preparation for surgery or treatment of intestinal infection requires administrat ion of an antibiotic in a form such that it will not be absorbed

132

Monocyclic Aromatic Compounds

to

CH3O

so2

\

CH3C=O 155, R=0

254

156, R=H prior to the desired site of action. Acylation of the amine nitrogen of a sulfa antibiotic with a dibasic acid affords compounds that are not absorbed systemically following oral administration. Reaction of sulfathiazole with succinic anhydride under rigorously controlled conditions affords directly succinyl sulfathiazole (157)52; a similar reaction with phthalic anhydride gives

phthaloyl sulfathiazole

(158),53

O=CCH2CH2CO2H 157

158

b.

Bissulfonamidobenzenes

Among one of the more unusual side effects noticed as the use of the sulfonamides became widespread was the increased urine output of many patients treated with these drugs. The fact that the urine was unusually alkaline led to the suspicion, later ^onfirmed by independent means, that these agents were responsible for partial inhibition of the enzyme carbonic anhydrase. Inhibition of this enzyme causes increased excretion of sodium and bicarbonate ions as well as water, in effect bringing about diure-

Derivatives of Arylsulfonic Acids

133

sis. While the use of diuretics had long been recognized as a valuable tool for the treatment of many diseases involving water retention, relatively few effective agents were available prior to the development of the compounds based on the sulfonamides. These serendipitous observations led to an intensive effort to maximize the effect of these agents on carbonic anhydrase. It was soon found that among the simpler compounds, the best activity is obtained by inclusion of two sulfonamide groups disposed meta to each other on the aromatic ring. Treatment of chlorobenzene with chlorosulfonic acid under forcing conditions affords the bis sulfonyl chloride, 159. Ammonolysis of this intermediate gives chlorphenamide (160). A similar sequence on metachloroaniline leads to chloraminophenamide (162).54 Dihalogenated aromatics are apparently sufficiently inert towards the bischlorosulfonation reaction; thus a more elaborate sequence is required for preparation of such analogs. Reaction of orthochlorophenol. with chlorosulfonic acid affords intermediate (163); ammonolysis gives the sulfonamide (164). In an unusual reaction, treatment of the phenol with phosphorus trichloride then replaces the hydroxyl group by chlorine to afford dichlorophenamide (165),55 S09Cl Cl SO2NH

R=H

> NH2

159, R=H 161, R=NH2

Cl

OH 1 SO2R I J SO2R

163t , R=C1 164,, R=NH2

160, R=H 162, R=NH2

Cl Cl

SO2NH2 r SO2NH2 165

Chlorosulfonation of chlorobenzene under milder conditions jiffords the product of monosubstitution (166) ; reaction with

134

Monoeyelie Aromatic Compounds

ammonia then gives the sulfonamide (167). Chlorosulfonation of that sulfonamide then affords an intermediate (168) suitable for preparation of diuretics containing differing substituents on nitrogen. Thus, reduction of the cyclic cyanohydrin, 169, affords the amine, 170; formylation by ester interchange with methyl formate (171) followed by reduction with lithium aluminum hydride gives the N-methylated derivative (172) . Acylation of the last by the sulfonyl chloride, 168? gives the diuretic mefruside (173).56

168 166, R=Cl 167, R==NH2

CH3 r-v N-CH/^CT

173

RHNCH2

CN 169

c.

170, R-H 171, R=CHO 172, R=CH3 Sulfonamidobenzoic Acids

Diuretic activity can be retained in the face of replacement of one of the sulfonamide groups by a carboxylic acid or amide. Reaction of the dichlorobenzoic acid, 174, with chlorsulfonic acid gives the sulfonyl chloride, 175; this is then converted to the amide (176). Reaction of that compound with furfurylamine leads to nucleophilic aromatic displacement of the highly1activated chlorine at the 2 position. There is thus obtained the very potent diuretic furosemide (177),57 Nitrosation of 2,6-dimethylpiperidine gives the correspond-

Derivatives of Arylsulfonic Acid

CO2H

174

135

CO2H

SO2R 175, R=C1 176, R=NH2

ing N~nitroso compound (178); reduction leads to the hydrazine derivative, 179. Reaction of that intermediate with the acid chloride, 180 (available from the chlorosulfonation product of p-chlorobenzoic acid), gives the diuretic clopamide (181).5e

ON H q 1RC 178, R = N O 179, R =N H2

CH

C .OC1 SO N 2H 2 180

181

When penicillin was first introduced, clinicians were plagued by the extremely rapid excretion in the urine of this then extremely scarce drug. It was hoped that some other acidic compound administered along with the antibiotic might be excreted by the kidneys competitively with the drug and thus slow its loss via urine. A search for such an agent turned to a sulfonamide acid of known low toxicity, probenecid (183). In fact, administration of this compound, which has no significant antibacterial nctivity in its own right, along with penicillin significantly prolonged blood levels of the antibiotic. In the course of these studies it was also noted, however, that probenecid promoted excretion of uric acid. The ready availability of long-acting penicillin derivatives has long since obviated the need for prohenecid as an adjunct. The drug has since found a place in the treatment of gout. The drug can be prepared in a straightforward manner by reaction of sulfonyl chloride, 182, with di-n-propylamine fol-

136

Monocyclic Aromatic Compounds

lowed by hydrolysis of the nitrile to a carboxylic acid.59

>-SO,Cl

>

HO2C-('

/ CH2 CH 2 CH 3 ySO 2 N k CH2CH2CH3 183

182

d.

Sulfonylureas

Diabetes is a disorder of carbohydrate metabolism traceable to deficiencies in the production of insulin by the pancreas. Prior to the discovery of insulin by Banting and Best in the 1930s, the lifespan of a young diabetic was limited indeed. The finding that those diabetics whose disease began early in life could be maintained on insulin from animal sources was dramatic. A goodly number of diabetics do not manifest the disease until well into their forties. Such patients may be controlled for some time by diet or by insulin. The finding that some of the sulfonamide antibiotics could lower blood sugar in some individuals (hypoglycemia) led to the development of an additional method for treatment of the hyperglycemia of adult-onset diabetes. (It should be noted that the drug is without effect on individuals lacking capacity to produce insulin—the youthful diabetics). Systematic modification of the sulfanilamide molecule in order to maximize the hypoglycemic activity led to the observation that the sulfonamide is best replaced by a sulfonylurea function. Modification on both the aromatic ring and the substituent on the terminal nitrogen modulates the activity of the products . Sulfonylureas are accessible by the many methods that have been developed for the preparation of simpler ureas. For example, treatment of p-toluenesulfonamide (184) with butyl isocyanate (185) affords tolbutamide (186).60 Reaction of the sodium salt of p-chlorosulfonamide with

+ 184

OCNCH2CH2CH2CH, 185

Derivatives of Arylsulfonic Acid

137

186 ethyl chlorocarbonate gives the carbamate, 188. Reaction of that intermediate with n-propylamine gives chlorpropamide (189).61 SO2NH2

sO 2 NHCO 2 C 2 H 5

187

188 0

/T~\ SO NHCNHCH CH CH 2

2

2

3

189 Treatment of piperidine with nitrous acid affords the Nnitroso derivative (190); reduction gives the corresponding hydrazine (191). Condensation of this intermediate with the carbamate (192) obtained from p-toluenesulfonamide leads to the oral hypoglycemic agent tolazemlde (193).62 In a similar vein, reaction of the hydrazine obtained by the same sequence from azepine (194) with the carbamate, 188, gives azepinamide (195),62

-SO2NHCO2C2n5 190, R=NO 191f R=NH2

H2N-N

194

192

188

193

SO2NHCNHN 195

In another approach to the required functionality, the sodium salt of acetyl sulfanilamide (196) is condensed with butyl

138

Monocyclic Aromatic Compounds

isothiocyanate (197) to afford the thiourea, 198. Reaction with nitrous acid serves to convert the thiourea to a urea (199). Hydrolysis of acetyl group with aqueous base affords carbutemide (200).63 An analogous sequence starting with the meta-substituted sulfanilamide (200) affords l-butyl-3-rnetanylurea (202) . 6 4

SO2NH2

CHoCONH

196

+

SCN(CH2)3CH3

/

—>

X I!

\

I CH

198, R=COCH 3 ; X=S 199, R=COCH3; X=0 200, R=H: X=0

197

0 N

SO 2 NH 2

^SO 2 NHCNHCII 2 CH 2 CH 2 CH 3

CH.CO:

201

202

Inclusion of a para acetyl group requires a somewhat different approach to the preparation of these compounds. Reaction of the diazonium salt from p-aminoacetophenone with sulfur dioxide affords the sulfonyl chloride, 203; this is then converted to the sulfonamide, 204. Elaboration via the carbamate with cyclohexylamine affords acetohexamide (205),65

SO2R 203, R=Cl 204, R=NH2 0 II /—\ SO2NHCNH-/ \ 205 It is of note that hypoglycemic activity is maintained even when the aromatic ring is fused onto a carbocyclic ring. Chlorsulfonation of hydrindan gives chloride, 206. Reaction of the sulfonamide (207) obtained from that intermediate with cyclohexyl isocyanate leads to glyhexamide (2O8).66

Derivatives of Arylsulfonic Acid

139

0 SO2R

SO2NHCNH

206, R=C1 207, R=NH2

O

2O8

Finally, attachment of a rather complex side chain to the para position of the benzene ring on the sulfonamide leads to the very potent, long-acting oral antidiabetic agent, glyburide (215).67 Preparation of this compound starts with the chlorosulfonation of the acetamide of 3-phenethylamine (209). The resulting sulfonyl chloride (210) is then converted to the sulfonamide (211) and deacylated (212) . Reaction with the salicylic acid derivative, 213, in the presence of carbodiimide affords the amide, 214. Condensation of that with cyclohexylisocyanate affords glyburide (215).68

R1NHCtt2CH2-T

CH 3 CONHCH 2 CH 2

VsO2R2

210, R11:=CH3CO; R22=Cl 211, RX=CH3C0; R =NH2 212, R =H; R2=NH2

2O9

213

OCH 3

215

e.

214

Diarylsulfones

Compounds closely related to the sulfonamide antibiotics proved to be the first drugs effective against Mycobacterium leprae, the causative agent of the disease known since antiquity, leprosy. These drugs are at least partly responsible for the decline of those horror spots, the leper colonies. Synthesis of the first of the antileprosy drugs, dapsone (219), starts with aromatic nucleophilic substitution of the

140

Monocyclic Aromatic Compounds

sodium salt of the sulfinic acid, 216, on p-chloronitrobenzene to afford the sulfone (217). Reduction of the nitro group (218) followed by deacetylation gives dapsone (219). The low solubility of this drug in water makes it unsuitable for administration by injection. Reaction of dapsone with the sodium bisulfite adduct of formaldehyde gives the water-soluble prodrug sulfoxone (220).69 Reaction of the diamine, 219, with the sodium bisulfite adduct from glucose gives the solubilized derivative glucosufone (221),70

NHCOCH,

NHCOCH,

SO2Na 216

217, R=0 218, R=H

219

S03Na HNCH(CHOH)4CII2OH

HNCH2OSO2Na

HN-CH(CH20H)4CH0H

HNCH2OSO2Na

I

S03Na 221

220

Derivatives of Arylsulfonic Acid

141

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226); hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227).7X

222

H2N-<' >S02-^ >NH2 227

223

224, R=H 225, R=COCH3

<

I 02N~(' >S02< >NHCOCH, 226

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11.

J. T. Sheehan, J. Amer. Chem. Soc, 70, 1665 (1943). M. W. Goldberg, U. S. Patent 2,879,293 (1959). J. H. Wilkinson and I. L. Finar, J. Chem. Soc, 32 (1948). C. V. Winder, J. Wax, L. Scotti, R. A. Scherrer, E. M. Jones, and F. W. Short, J. Pharmacol. Exp. Ther., 138, 405 (1962). D. E. Pearson, K. N. Carter, and C. M. Greer, J. Amer. Chem. Soc, 75, 5905 (1953). C. M. Baker and J. R. Campbell, U. S. Patent 2,887,513 (1959). J. Harley-Mason and A. H. Jackson, J. Chem. Soc, 3651 (1954). K. Kawara, Japanese Patent 3,071 (1951). F. H. S. Curd and F. L. Rose, J. Chem. Soc, 729 (1946). A. D. Ainsley, F. H. S. Curd, and F. L. Rose, J. Chem. Soc, 98 (1949). A. F. Crowther, F. H. S. Hurd, and F. L. Rose, J. Chem. Soc,

142

12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

Monocyclic Aromatic Compounds

1780 (1951). L. C. Cheney, R. R. Smith, and S. B. Binkley, J. Amer. Chem. Soc, 71, 60 (1949). Anon., British Patent 914,008 (1962); Chem. Abst., 58, 523c (1963). A. Buzas, J. Teste, and J. Frossard, Bull. Soc. Chim. Fr., 839 (1959). Anon., Belgian Patent 629,613 (1963); Chem. Abst., 60, 14,437d (1963). R. Howe and R. G. Shanks, Nature, 210, 1336 (1966). A. F. Crowther and L. H. Smith, J. Med. Chem., 11, 1009 (1968). A. Brandstrom, N. Carrodi, U. Junggren, and T. E. Jonsson, Acta Pharm. Suecica, 3, 303 (1966). H. L. Yale, E. J. Pribyl, W. Braker, F. H. Bergeim, and W. A. Lott, J. Amer. Chem. Soc, 72, 3710 (1950). R. S. Murphy, U. S. Patent 2,770,649 (1956). H. E. Parker, U. S. Patent 3,214,336 (1965). C. D. Lunsford, R. P. Mays, J. A. Ridiman, Jr., and R. S. Murphey, J. Amer. Chem. Soc, 82, 1166 (1900). H. Gilman and G. R. Wilder, J. Amer. Chem. Soc, 77, 6644 (1955). E. M. Schultz, E. S. Cragoe, Jr., J. B. Bricking, W. A. Bolhofer, and J. M. Sprague, J. Med. Chem., 5, 660 (1962). G. Domagk, Deut. Med. Wochenschr., 61, 250 (1935). J. Trefouel, J. Fourneau, F. Nitti, and D. Bovet, Compt. Rend. Soc Biol., 120, 756 (1935). M. L. Crossley, E. H. Northey, and M. E. Hultquist, J. Amer. Chem. Soc, 61, 2950 (1939). H. Gysin, U. S. Patent 2,503,820 (1950). P. S. Winnek, G. W. Anderson, H. W. Marson, H. E. Faith, and R. 0. Roblin, Jr., J. Amer. Chem. Soc, 64, 1682 (1942). L. C. Leitch, B. E. Baker, and L. Brickman, Can. J. Res., 23B, 139 (1945). R. 0. Roblin, Jr., J. H. Williams, P. S. Winnek, and J. P. English, J. Amer. Chem. Soc, 62, 2002 (1940). H. M. Wuest and M. Hoffer, U. S. Patent 2,430,094 (1947). W. Loop, E. Luhrs, and P. Hauschildt, U. S. Patent 2,809,966 (1957). P. Schmidt and J. Druey, Helv. Chim. Acta, 41, 306 (1958). A. Adams and R. Slack, J. Chem. Soc, 3070 (1959). R. J. Fossbinder and L. A. Walter, J. Amer. Chem. So$., 61, 2032 (1939). • R. Winterbottom, J. Amer. Chem. Soc, 62, 160 (1940). M. M. Lester and J. P. English, U. S. Patent 2,790,798 (1957).

References

39. 40. 41. 42. 43.

44.

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

143

J. H. Clark, U. S. Patent 2,712,012 (1955). H. J. Backer and A. B. Grevenstuk, Rec. Trav. Chim. Pays Bas, 61, 291 (1942). W. T. Caldwell, E. C. Kornfeld, and C. K. Donnell, J. Amer. Chem. Soc, 63, 2188 (1941). W. Loop and E. Luhrs, Ann., 580, 225 (1953). K. Gutsche, A. Harwart, H. Horstmann, H. Priewe, G. Raspe, E. Schraufstatter, S. Wirtz, and U. Worffel, Arzneimittel Forsch., 14, 373 (1964). H. Horstmann, T. Knott, W. Scholtan, E. Schraufstatter, A. Walter, and U. Worffel, Arzneimittel Forsch., 11, 682 (1961). R. G. Shepherd, W. E. Taft, and H. M. Krazinski, J. Org. Chem., 26, 2764 (1961). Anon., Belg. Patent 618,639 (1962); Chem. Abs., 59, 7,540c (1963). B. Camerino and G. Palamidessi, U. S. Patent 3,098,069 (1963). 0. Hubner, U. S. Patent 2,447,702 (1948). H. Wojahn and H. Wuckel, Arch. Pharm., 284, 53 (1951). Anon., Brit. Patent 828,963 (1960); Chem. Abs., 54, 12,5OOi (1960). B. Camarino and G. Palamidessi, Gazz. Chim. Ital., 90, 1815 (1960). M. L. Moore and C. S. Miller, J. Amer. Chem. Soc, 64, 1572 (1942). M. L. Moore, U. S. Patent 2,324,013 (1943). F. C. Novella and J. M. Sprague, J. Amer. Chem. Soc., 79, 2028 (1957). E. M. Schultz, U. S. Patent 2,835,702 (1958). H. Horstmann, H. Wollweber, and K. Meng, Arzneimittel Forsch., 17, 653 (1967). K. Sturm, W. Siedel, and R. Weyer, German Patent 1,122,541 (1962). E. Jucker and A. Lindenmann, Helv. Chim. Acta, 45, 2316 (1962). C. S. Miller, U. S. Patent 2,608,507 (1952). H. Ruschig, W. Avmuller, G. Korger, H. Wagner, and J. Scholtz, U. S. Patent 2,968,158 (1961). F. J. Marshall and M. V. Sigal, J. Org. Chem., 23, 927 (1958). J. B. Wright and R. E. Willette, J. Med. Chem., 5, 815 (1962). E. Haack, U. S. Patent 2,907,692 (1959). E. Haack, Arzneimittel Forsch., 8, 444 (1958). F. J. Marshall, M. V. Sigal, H. R. Sullivan, C. Cesnik, and

144

Monocyclic Aromatic Compounds

M. A. Root, J. Med. Chem., 6, 60 (1963). H. Hoehn and H. Breur, U. S. Patent 3,097,242 (1963). W. Avmuller, A. Bander, R. Heerdt, K. Muth, P. Pfaff, F. H. Schmidt, H. Weber, and R. Weyer, Arzneimittel Forsch., 16, 640 (1966). 68. R. S. P. Hsi, J. Labeled Comp.r 9, 91 (1973). 69. H. Bauer, J. Amer. Chem. Soc, 61, 617 (1939). 70. Anon., Swiss Patent 234,108 (1944); Chem. Abstr., 43, 4297a (1949). 71. L. L. Bambas, J. Amer. Chem. Soc, 67, 671 (1945). 66. 67.

CHAPTER 9

Polycyclic Aromatic Compounds

1.

INDENES

a.

Indenes with Basic Substituents

The low order of structural specificity required for classical antihistaminic activity was noted earlier. It has been found possible to substitute an indene nucleus for one of the two aromatic rings that most of these agents possess. The basic side chain may be present as either dimethylaminoethy1 or itself cycLized to provide an additional fused ring. Alkylation of 1-indanone with 2-dimethylaminoethyl chloride affords the substituted ketone (1). Condensation with the Lithium reagent obtained from 2-ethylpyridine affords the alcohol (2). Dehydration under acidic conditions gives dimethylpyrindene (3).x Mannich reaction of methylamine and formaldehyde with two equivalents of acetophenone leads to the unusual double condensation product, 4. Treatment of this diketone with base leads to the intramolecular aldol product (5). The symmetrical nature of 4 allows but one product. Strong acid serves to both cyclize the carbonyl group into the aromatic ring and to dehydrate the tertiary alcohol (although not necessarily in that order); there is thus obtained the diene, 6. Conditions for the catalytic hydrogenation of this product can be so arranged as to give the product of 1,4 addition of hydrogen, the indene, pyrindamine (7).

CH2CH2N X

CH3

145

Polycyclic Aromatic Compounds

146

HO

CH I CH CH2CH2N

CH3 CH2CH2N

XH2CH2\ C=O N-CH3

-CH,

\

N-CH,

Indenes

b.

147 Indandiones

Anticoagulant therapy was developed with the adventitious discovery of dicoumarol (8). A fuller discussion of the rationale for the use of such compounds is found in the chapter on Five-Membered Heterocycles Fused to One Benzene Ring. The reader!s attention is directed, however, at the fact that dicoumarol is a polycarbonyl compound containing a very acidic hydrogen. A series of similarly acidic 1,3-indandiones have been found to constitute an additional class of anticoagulant agents.

Condensation of an appropriately substituted phenylacetic acid with phthalic anhydride in the presence of sodium acetate leads to aldol-like reaction of the methylene group on the acid with the carbonyl on the anhydride. Dehydration followed by decarboxylation of the intermediate affords the methylenephthalides (12). Treatment of the phthalides with base affords directly the indandiones, probably via an intermediate formally derived from the keto-acid anion (13). The first agent of this class to be introduced was phenindandione (14)3; this was followed by anisindandione (15)h and chlorindandione (16).s Replacement of the phenyl group at the 2 position by diphenylacetyl affords an anticoagulant with long duration of action and improved therapeutic ratio. Condensation of dimethyl phthalate with 1,1-diphenylacetone (17) in the presence of base affords phenindandione (18).6

9, R=H 10, R=OCH3 11, R=Cl

13

148

Polycyclic Aromatic Compounds

14, R=H 15, R=OCH3 16, R=Cl

18

2.

DIHYDRONAPHTHALENES

As noted previously, triarylethylenes substituted by a basic group, such as clomiphene, exhibit estrogen antagonist activity. Formal cyclization of that molecule to a more steroid-like, rigid conformation enhances potency in this series. Wittig condensation of the ylide from the phosphonium salt, 19y with the hydroxymethylene ketone, 20, affords the product, 21, as a mixture of isomers. Catalytic hydrogenation leads to 22. Treatment of that intermediate with aluminum chloride leads to selective demethylation of that ether para to the carbonyl group (23). Cyclization by means of tosic acid gives the dihydro* naphthalene nucleus (24). Alkylation of the phenol with iv-(2chloroethyl)pyrrolidine affords nafoxidine (25) . 7 OCH 3

19

20

149

Dihydronaphthalenes

OCH3

21

22, R=CH3 23, R=H

CH3O 25

3.

24

DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTADIENES

Almost anyone who has at some time in his life met some reverses is familiar with depression. In the normal course of events, changing circumstances will soon lead to the replacement of this state of mind by a more pleasant one. There exist, however, a set of pathologic states in which depression feeds on itself in a destructive cycle. Individuals affected with this syndrome— whether precipitated by outside events or not—eventually find it most difficult to function. The advent of antidepressant drugs, first the MAO inhibitors and more recently the tricyclic antidepressants, have made this syndrome amenable to treatment. The intent in the preparation of the first of these drugs was possibly the synthesis of analogs of the phenothiazine tranquilizer drugs (A). It is a well-known rule of thumb in medicinal chemistry that biologic activity can often be maintained when sulfur is replaced by an ethylene group—saturated or unsaturated—and weakly basic nitrogen by carbon (B). Careful pharmatologic evaluation of the compounds produced by this rationale revealed them to have utility as antidepressants rather than t ranquilizers.

Polycyclic Aromatic Compounds

150

12 a

26

29a

CH 2 N 29

28

CHCH 2 CH 2 N 31, R=H 32, R=CH 3 Preparation of the key intermediate to this series begins by reduction of the methylene phthalide, 12a, with hydriodic acid and red phosphorus. Cyclization of the acid (26) thus obtained affords the tricyclic ketone, 27. Reaction with the Grignard reagent from 3-dimethylamino-2-methylpropyl chloride affords the

Dibenzocycloheptenes

151

alcohol, 28. Dehydration of the carbinol gives butriptyline (29).8 The scheme used above for attaching the side chain is not applicable to secondary amines since such compounds would not form organometallics. In an ingenious synthesis, the ketone, 27, is first condensed with cyclopropyl-magnesium bromide (29a). Solvolysis in hydrogen bromide goes to the allylic halide, 30, via the cyclopropylcarbinyl cation (see Prostaglandins for a fuller exposition of this reaction). Displacement of the allylic halogen by means of methylamine gives nortriptylene (31)9; reaction with dimethylamine, on the other hand, gives amytriptylene (32) . An alternate scheme for preparation of the last drug involves first bromination of the methylene group on 33 (obtainable by several methods from 27). A displacement reaction of the Grignard reagent prepared from 34 on 2-dimethylaminoethyl chloride affords again amytriptylene (32).10

32 CHBr

34

33

To anticipate briefly, shortening the length of the side chain in the phenothiazines from three to two carbon atoms changes the activity of the products from neuroleptics to antihistaminic ngents. A rather similar effect is seen in the tricyclic antidepressants. Reaction of ketone, 27, with the Grignard reagent from 4-chloro-l-methylpipyridine (35) affords the tertiary alcohol, 36. Dehydration gives the antihistamine, cyproheptadine (37).11

27

-CH3 35

36

37

Polycyclic Aromatic Compounds

152

Introduction of an additional double bond into the tricyclic nucleus, on the other hand, is consistent with antidepressant activity. Alkylation of the potassium salt, obtained on treatment of hydrocarbon, 38, with ammonia, with the chlorocarbamate, 39, affords the intermediate, 40. Basic hydrolysis leads to protriptylene (41),12 . CO 2 C qSS. 5 ClCH2CH2CH2N

X

39

CHi

CH 2 CH 2 CH 2 N

38

40, R=CO 2 C 2 H 5 41, R=H

4.

COLCHICINE

The active principle of the autumn crocus (Colchicum autumnale), colchicine (48), is one of the very few drugs that have remained in reputable medical use since ancient times. This drug was the only useful treatment available for the excruciating pain associated with crystallization of uric acid in the joints characteristic of gout until the advent of allopurinol. Although the precise mechanism by which colchicine gives this dramatic relief remains undefined, the antimitotic activity of this agent is thought to play a role in its effect. Due to the difficulty of preparation, few analogs of colchicine exist; it is structurally a one-drug class. Preparation of the molecule by total synthesis is rendered unusually difficult by the presence of the two fused seven-membered rings, one of which is a tropolone. The most recent of several total syntheses of this molecule is noteworthy for building this very system in a single step. 13 The synthesis starts with the oxidative phenol coupling reaction on the diphenolic compound, 42. This reaction, carried out in the presence of an iron chloride:DMF complex proceeds by first forming a radical para to the free phenol on the more highly oxygenated ring; addition of this to the para position of the remaining phenolic ring affords, after appropriate adjustment of electrons, the spirodienone, 43. Treatment with diazomethane converts the phenol to the ether; reduction by means of sodium borohydride affords the alcohol, 44, as a mixture of epimers. Methyleneation by means of the Simmons-Smith reaction (methylene iodide:zinc-copper couple)

Colchicine

153

converts the olefinic bond to a cyclopropane (45). Oxidation by means of Jones reagent gives the ketone, 46. CH3O CH3O

CH3O CH3O

CH3O CH3O

"OCH,

CH3O

OCH3

OCHo

CH3O

CH3O. >—X

CH-,0

CH 3 O

CH3O' CH

CH 3 O

OCH3 0 49

47, X=H 48, X=Br

OCl', 45, X=<

[

OH

46, X=O

CH3O.

\

VNIICOCH3

(

CH j

50

The key step in this sequence, achieved by exposure of 46 to a mixture of sulfuric acid and acetic anhydride, involves opening of the cyclopropane ring by migration of a sigma bond from the quaternary center to one terminus of the former cyclopropane. This complex rearrangement, rather reminiscent of the tl ienone-phenol reaction, serves to both build the proper carbon skeleton and to provide ring C in the proper oxidation state. The synthesis concludes by the route pioneered by Eschenmoser.lh Bromination of 47 proceeds at the position a to the tropolone ring to give 48. Displacement of halogen by ammonia followed by base hydrolysis of the tropolone methyl ether gives trimethylrolchicinic acid. Acetylation of the amine followed by reesteri-

154

Polycyclic Aromatic Compounds

fication of the tropolone yields colchicine (50).

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

C. F. Huebner, E. Donoghue, P. Wenk, E. Sury, and J. A. Nelson, J. Amer. Chem. Soc, 82, 2077 (1960). J. T. Plati and W. Wenner, U. S. Patent 2,470,108 (1947). C. S. Jacques, E. Gordona, and E. Lipp, Can. Med. Assoc. J., 62, 465 (1950). A. Horeau and J. Jacques, Bull. Soc. Chim. France, 53 (1948). H. G. Kreg, Pharmazie, 13, 619 (1958). D. G. Thomas, U. S. Patent 2,672,483 (1954). D. Lednicer, D. E. Emmert, S. C. Lyster, and G. W. Duncan, J. Med. Chem., 12, 881 (1969). S. 0. Winthrop, M. A. Davis, G. S. Myers, J. G. Gavin, R. Thomas, and R. Barber, J. Org. Chem., 27, 230 (1962). R. D. Hoffsommer, D. Taub, and N. L. Wendler, J. Org. Chem., 27, 4134 (1962). R. D. Hoffsommer, D. Taub, and N. L. Wendler, J. Med. Chem., 8, 555 (1965). E. L. Engelhardt, U. S. Patent 3,014,911 (1961). M. Tischler, J. M. Chemerda, and J. Kollonowitsch, Belgian Patent 634,448 (1964); Chem. Abst., 61, 4295a (1964). E. Kotani, F. Miyazaki, and S. Tobinaga, Chem. Commun., 300 (1974). J. Schreiber, W. Leimgruber, M. Pesaro, P. Schudel, T. Threfall, and A. Eschenmoser, Helv. Chim. Acta, 44, 540 (1961).

CHAPTER 10

Steroids

The development of this class of tetracyclic alicyclic compounds into several classes of therapeutically useful drugs represents one of the most vivid illustrations of the serendipitous nature of medicinal chemistry. Each series of steroid drugs, the estrogens, the androgens, the progestins, and finally the corticoids, were first discovered during investigations of mammalian endocrine systems. The infinitesimal amounts of these agents present in mammalian tissues hampered the initial endocrinologic work; it was obvious that material would have to be obtained from some source other than isolation from animal glands in order to define the mode of action of the compounds. The potent biologic effects of these compounds, as well as the structural complexity of those for which a structure had been assigned, acted as a spur to synthetic chemists. The initial work consisted largely of partial syntheses from steroids from some other, more abundant natural source. With time, each of the natural steroids has been prepared by total synthesis. With the few exceptions noted below, the total syntheses, although often elegant, have not proved commercially competitive with partial synthesis. Once the steroid hormones became available to endocrinologists in sizeable quantities, the pharmacology of the agents was investigated in greater detail. It was found that these drugs had unanticipated uses far beyond mere replacement therapy. Thus the corticoids, the steroids of the adrenal cortex, were to be of great value in the relief of inflammation; the androgens elaborated by the male testes were found to have anabolic effects. Finally, an appropriate combination of progestin and estrogen was found to inhibit ovulation in the female, leading eventually to the development of the oral contraceptive, the Pill. The steroids, as found in mammalian systems, are seldom useful as drugs due to a fairly general lack of oral activity. Most of the agents exert other actions in addition to the desired one. 155

156

Steroids

one. An androgen, for example, continues to have masculinizing properties even though it is in use as an anabolic agent. These reasons, as well as the search for patentable entities, led to intensive efforts on both the synthesis and pharmacology of modified steroids. The goal of oral activity has been handily met; the split between the desired pharmacologic activity and the intrinsic endocrine activity has at best been only partly achieved.

1.

COMMERCIAL PREPARATION OF ESTROGENS, ANDROGENS, AND PROGESTINS

The steroids as a class represent a structurally complex problem for the synthetic chemist. Even a relatively simple compound such as estrone possesses three ring fusions, two of which can lead to isomers and four chiral centers (identified below by * ) . Only one of the sixteen possible isomers possesses the desired activity in satisfactory potency.

estrone Although all the main classes of steroids have now been attained by total synthesis, most drugs are in fact, as noted above, prepared by partial synthesis from natural products that contain the steroid nucleus. The bulk of the world's supply of steroid starting material is derived by differing chemical routes from only two species of plants: the Mexican yam, a species of Dioscorea, and the humble soybean. The advantage of using plants rather than valuable domestic animals as raw material is fairly obvious. Cr» a process developed by the chemists at Syntex,1 the yam is first processed to afford the sapogenin diosgenin (1). This material, which contains the requisite tetracyclic nucleus in the correct stereochemical array, contains six superfluous carbon atoms in the side chain. Treatment of diosgenin with hot acetic anhydride in the presence of a catalyst such as p-toluenesulfonic acid leads to a reaction reminiscent of the formation of enol

Commercial Preparation

157

AcO

ethers from ketals. In this case the net result of the transformation is the opening of the spiran ring to a dihydrofuran (2); the hydroxyl at 3 is acetylated under these reaction conditions.2 Oxidation of (2) with chromium trioxide effects the desired scission of the side chain with formation of the desired 20 ketone. Treatment of this ester of a (3~ketoalcohol with acetic anhydride leads to elimination of that ester grouping; there is obtained an intermediate with functionality suitable for subsequent modification, 16-dehydropregnenolone (4). Catalytic reduction goes as expected, preferentially at the conjugated double bond, to afford pregnenolone acetate (5). When progesterone (6) is the target molecule, the acetate is first removed by saponification; oxidation with an aluminum alcoholate (Oppenauer reaction), leads initially to the unconjugated 3-keto~5~ene compound. The basic reaction conditions serve to shift the double bond into conjugation. Progesterone is a key intermediate in the manufacture of cortical steroids. The various intermediates listed above are currently turned out in tonnage quantity. A progesterone precursor, 16-dehydropregenolone acetate, serves as a starting material to the androgens as well. In an ingenious scheme 4 is first converted to its oxime; treatment of (8) under the conditions of the Beckmann rearrangement leads to migration of the unsaturated center to nitrogen, with consequent formation of the acylated eneamine (9). Hydrolysis affords presumably first the eneamine (10); this unstable entity further

Steroids

158

suffers hydrolysis to give, finally, dehydroepiandrosterone acetate (11). Removal of the acetate by saponification followed by Openauer oxidation leads to the conjugated 3-enone (12). There is thus obtained androstenedione (12).3>l*

-NOH

AcO

AcO

AcO

The nonsapponifiable fraction from the very abundant oil from soybeans is known to be rich in a mixture of steroids bearing a ten carbon atom side chain at the 17 position. The chemists at Upjohn developed an efficient and economical route for exploitation of this natural product as a source of progesterone.s>6 Only stigmasterol (13), of the many steroids present in the crude extract, bears unsaturation in the side chain; it is therefore the only component of the mixture suitable for further processing. Following its separation by an ingenious leaching process, this compound is subjected to the conditions of the Openauer oxidation to afford stigmastadienone (14). Ozonization of this compound affects only the most electron-rich double bond, that in the side chain; workup affords the ketoaldehyde (15) which is but one carbon atom removed from the goal. This aldehyde is then converted selectively to the 22-eneamine (16). Oxidation of this last under a variety of conditions (ozonization, photo-oxygenation) affords progesterone (17). The structurally simplest steroids, the aromatic A ring estrogens, have ironically proven most difficultly accessible because this aromatic ring is not found in any of the plant sterols available in commercial quantities. The main task of partial synthesis from naturally occurring material thus becomes

Commercial Preparation

159

CHO

17

the excision of the angular methyl group at the A-B ring junction. In one of the earlier routes, androstenedione was first reduced to androsterone (18). (Introduction of hydrogen on the alpha side, the side below the plane of the molecule, is determined by attachment of the catalyst to the least-hindered side of the molecule.) Treatment of the ketone with bromine in acetic acid leads to formation of the 2,4-dibromide.19 (There is good evidence that bromination affords first the 2-bromosteroids; this then brominates again to give the 2,2-dibromo compound; the final product is obtained after a series of rearrangements.) Treatment of the dibromide with hot collidine leads to dehydrobromination and formation of the 1,4-dienone (21). Estrone (25) is obtained in modest yield when that last compound is passed through a column at 600°C in the presence of mineral oil.7 In an alternate approach, the dienone is subjected to allylic bromination with iv-bromosuccinimide. The bromo compound (22) thus produced gives triene 23 on treatment with collidine. Pyrolysis in mineral oil leads to loss of the methyl group; catalytic hydrogenation reduces the 6 double bond to afford estrone.8 The better yield obtained on pyrolysis of the triene apparently compensates for the additional steps in this sequence. In the most interesting and recent modification, the dienone is first converted to its propylene ketal (20). Aromatization is accomplished by treatment of this intermediate with the radical anion obtained from lithium and diphenyl in refluxing tetrahydrofuran. Since the methyl group in this case leaves as methyl lithium, diphenylmethane is included

160

Steroids

in the reaction mixture to quench this by-product in order to prevent its reaction with starting material.9 Workup of the reaction mixture under acidic conditions results in hydrolysis of the ketal at 17; estrone is then obtained directly in a quite respectable yield.

12

18

24

frH

19

25

2. AROMATIC A-RING STEROIDS The female of mammalian species secretes a series of steroid hormones characterized by an aromatic A ring and the lack of a side chain at the 17 position. These compounds serve as regulators in the reproductive processes of the species. The name (estrogens) comes from the fact that in some lower animals the elaboration of this type of compound is directly involved with the phe-

Aromatic A-Ring Steroids

161

nomenon of heat estrus. In humans, these hormones are involved not only in the menstrual cycle, but also in such diverse processes as implantation in the uterus of fertilized ova and calcium metabolism. Estrogen deficiency has an adverse effect on general health; the psychic manifestations of menopause, for example, are at least partly traceable to the rapidly changing estrogen titers characteristic of that time of life. Although estrone and estradiol (26) have both been isolated from human urine, it has recently been shown that it is the latter that is the active compound that binds to the so-called estrogen receptor protein.10 Reduction of estrone with any of a large number of reducing agents (for example, any of the complex metal hydrides) leads cleanly to estradiol. This high degree of stereoselectivity to afford the product of attack at the alpha side of the molecule is characteristic of many reactions of steroids. This tendency is particularly marked at the 17 position; attack at the alpha side meets only hydrogen interactions but approach from the opposite side is hindered by the adjacent 18 methyl group. Although both estrone and estradiol are available for replacement therapy, they suffer the disadvantage of poor activity on oral administration and short duration of action even when administered parenterally, because of ready metabolic disposition. In order to overcome these deficiencies, there was developed a series of esters of estradiol with long-chain fatty acids. These esters are oil-soluble and correspondingly water-insoluble compounds. They are usually administered intramuscularly by injection. Since they are not soluble in water they form a so-called depot that remains at or near the site of injection. As the esters slowly hydrolyze by exposure to body fluids, the relatively water-soluble estrone is released and finds its way into the bloodstream. In this way the patient is provided with a reasonably constant lowlevel dose of the hormone. The esters are prepared by first treating estradiol with the appropriate acid chloride. The resulting diester, 27, is then subjected to mild acid or basic hydrolysis; in this way, the phenolic ester group is removed selectively. It has been established that both the 17 hydroxy androgens nnd estrogens, when administered orally, are quickly converted 1O water-soluble inactive metabolites by intestinal bacteria, usually by reactions at the 17 position. It is this inactivation process that is largely responsible for the low-order oral potency observed with these agents. Incorporation of an additional carbon atom at the 17 position should serve to make the now tertiary ;ilcohol less susceptible to metabolic attack and thus potentially confer oral activity to these derivatives.

162

Steroids

OCOR

25

O2CR

compound 27a 28a 28b

R CII2CH3 CH 2 CH 2 CH 2 CH 3

CH2CH

•O

generic name cstradiol diproplonato cstradiol valcrate

estradiol cypionatc

28c

estradiol bonzoate

28d

estradiol hexahydrobonzoate

Reaction of estrone with a metal acetylide affords 17aethynyl-173-hydroxy-estradiol (ethynylestradiol, 3Oa; E E ) . 1 2 This compound is equipotent with estradiol by subcutaneous administration, but it is 15 to 20 times as active when administered orally. Ethynylation of the methyl ether of estradiol analogously affords rnestranol (30b).13 It should be noted that the same factors apply in these reactions as in previously discussed reductions at 17; almost the sole products of these reactions are those which result from attack of reagent from the least hindered a side of the steroid. Ethynylestradiol and mestranol are of special commercial significance since the majority of the oral contraceptives now on sale incorporate one or the other of the compounds as the estrogenic component.

Aromatic A-Ring Steroids

29a, R=H 29b, R=CH3

3.

19-NORSTEROIDS

a.

19-Norprogestins

163

3Oa, R=H, ethynylestradiol 3Ob, R=CH3 , mestranol

Progesterone (17) possesses poor activity when administered by mouth. This fact was particularly frustrating since it was known as early as the late 1930s that this compound effectively inhibited ovulation in rabbits when administered subcutaneously. The development of an orally effective progestin thus seemed to hold out the promise of the long looked for oral contraceptive. In the following decade two compounds were indeed reported to show oral progestational activity. The first of these, ethisterone (31), was not suitable for use since it elicited androgenic responses as well; the second compound^ product of a long and involved degradation of the difficultly attainable natural product strophanthidin, was formulated at the time as 19~nor~ progesterone (32),16 (This product has since been shown to be isomeric with progesterone at both C-14 and C-17). Both these leads served to spur further synthetic efforts in this area.

31 The elaboration of a method for the reduction of aromatic rings to the corresponding dihydrobenzenes under controlled conditions by A. J. Birch opened a convenient route to compounds related to the putative norprogesterone. This reaction, now known as the Birch reduction,17 is typified by the treatment of

164

Steroids

the monomethyl ether of estradiol with a solution of lithium metal in liquid ammonia in the presence of an alcohol as a proton source. Initial reaction consists in 1,4 metalation of the most electron-deficient positions of the aromatic ring—in the case of an estrogen, the 1 and 4-positions. Reaction of the intermediate with the proton source leads to the dihydrobenzene; a special virtue of this sequence in steroids is the fact that the double bond at 2 in effect becomes an enol ether moiety. Treatment of that product (34) with weak acid, for example, oxalic acid, leads to hydrolysis of the enol ether, producing 3,y-unconjugated ketone 35. Hydrolysis under more strenuous conditions (mineral acids) results in migration of the double bond as well to yield 19-nortestosterone (36, nandrolone).1B

CH3O

CH3O 33

34

36

35

Oppenauer oxidation of the enol ether (34) affords the corresponding 17 ketone (37) (the enol ether is stable to the basic oxidation conditions). This ketone affords the corresponding 17a-ethynyl compound on reaction with metal acetylides. Hydrolysis of the enol ether under mild conditions leads directly to ethynodrel (39),19 an orally active progestin. This is the progestational component of the first oral contraceptive to be offered for sale. Treatment of the ethynyl enol ether with strong acid leads to yet another oral progestin employed as a contraceptive, norethindrone (40).20 In practice these and all other socalled combination contraceptives are mixtures of 1-2% mestranol

19-Norsteroids

165

or ethynylestradiol and an oral progestin (see Table 1 in Section f). It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced estradiol methyl ether in early batches of 37. This, when subjected to oxidation and ethynylation, would of course lead to mestranol. In any event, the need for the presence of estrogen in the mixture is now well established experimentally.

34

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p~toluenesulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41).21 This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42),22 the progestational component of Riglovic®. Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product; since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,17p-diol affords ethynodiol diacetate, one of the most potent oral progestins (44),23 In another approach to analogs, nortestosterone is first ronverted to the thioketal by treatment with ethylene dithiol in the presence of boron trifluoride. (The mild conditions of this reaction compared to those usually employed in preparing the oxygen ketals probably accounts for the double bond remaining at 4,5.) Treatment of this derivative with sodium in liquid ammonia

166

Steroids

affords the 3-desoxy analog (46). Oxidation by means of Jones reagent followed by ethynylation of the 17 ketone leads to the orally active progestin, lynestrol (48).24 OCOCH3 OCOCH3 ,.CHCH

OH

48

b.

47

19-Norsteroids by Total Synthesis

Steroids not readily accessible by modification of plant starting materials, for example, those possessing unusual substituents at the angular positions, are made available by total synthesis.

19-Norsteroids

167

It is probable, too, that intensive-process research development on the reactions involved in these syntheses may have made these routes commercially competitive with partial syntheses based on plant sterols. In the first of these sequences, often called the TorgovSmith synthesis, the initial step consists in condensation of a 2-alkyl-cyclopentane-l,3-dione with the allyl alcohol obtained from 6-methoxy-l-tetralone and vinylmagnesium chloride. Although this reaction at first sight resembles a classic SN-[ displacement, the reaction is actually carried out with only a trace of base. It is not at all unlikely that the extremely acidic dione causes the allyl alcohol to lose hydroxide and form the allyl cation; this then reacts with the anion of the dione. Cyclization of the condensation product under acid conditions affords, where the starting material was 2-methylcyclopentanedione, the complete carbon skeleton of the 19-norsteroids; when 2-ethylcyclopentane~ 1,3-dione is used instead, an intermediate to a commercial progestin is obtained. Catalytic reduction of the 14 double bond proceeds at the a side due to the presence of the bulky angular group at 13. This step has the additional important consequence of establishing the important trans C/D ring juncture. There is evidence to suggest that this is the thermodynamically unfavored configuration. Reduction of the ketone proceeds as expected for such steroids to give the 3~alcohol. Birch reduction of the remaining superfluous double bond at 8 proceeds to establish the trans B/C ring juncture. Although this happens to be the thermodynamically favored product, an argument based on kinetics will predict the same product. There has thus been produced the 18 methyl homolog of estrone methyl ether as a racemate. This compound, when subjected to the same series of transformations used to prepare norethindrone, affords racemic norgestrel (54).2S It is of note that although the synthesis has involved the formation of no fewer than 6 chiral centers, only two of the 64 possible isomers are formed. Extension of the conjugation of the 3 ketone in the 19 norprogestins has been found to increase significantly the potency of these agents. A total synthesis has been evolved for preparing one of these agents that was first obtained by partial synthesis.26 This consists in adding each of the steroid rings sequentially starting at D. Reaction of the unsaturated ketone, r >59 with 2-methylcyclopentane-1,2-dione in a Robinson annelation (conjugate addition followed by aldol cyclization) affords the C/D fragment, 56. This is then saponified and resolved into its optical isomers. Reduction of the S isomer proceeds at the a face opposite the angular methyl group, as in the steroids, to establish in one step the stereochemistry at 8 and 13. The 17

168

Steroids

HO

C=CH2

CH3O

ketone is then converted to the 173 benzoate in several steps and the keto acid cyclized to the enol lactone, 58. Reaction of 58 with the Grignard reagent from halide, 59, affords after deketalization the diketone, 60. (This last presumably proceeds by addition of the Grignard to the lactone carbonyl, followed by opening to a 1,5-diketone and then cyclization.) Treatment of the tricyclic diketone, 60, with pyrrolidine affords the tetracyclic steroid skeleton as the enamine, 61. Exposure of this last to weak acid results in hydrolysis of the enamine to the ketone (62) without subsequent migration of the double bonds. This is then converted to triene, 63, with dichlorodicyanoquinone. (An alternate procedure consists in forming the 11 hydroxy~4,9-diene by oxidation of the diene with molecular oxygen in the presence of triethylamine followed by reduction of the intermediate hydroperoxide; dehydration of the alcohol affords the triene.) The triene is then oxidized to the 3,17-diketone. This compound regioselectively forms a cyanohydrin at 17; the 3 ketone is then protected as its oxime. The cyanohydrin is removed with mild base and the resulting ketone ethynylated at 17. Removal of the oxime affords chiral norgestatriene (66).27

OB 2

CH 3 O 2

OBz

19-Norsteroids

169

OBz

CN

OBz

OH ,» CECH

HON" 64

c.

HON 65

19-Norandrogens

The integrity of the reproductive system as well as that of the male accessory sex organs of mammalian species is supported by a series of steroid hormones secreted largely in the testes, known collectively as the androgens. These compounds are C-19 steroids, mid, like the estrogens, lack a side chain at C17; the series is Iypified by testosterone (67). As with the other sex hormones, the first clinical use of nndrogens was for support therapy in individuals deficient in the (endogenous hormone. The discovery that androgens exert an anabolic effect greatly extended the indications for their use.

170

Steroids

67 These agents promised utility by prompting a decreased excretion of nitrogenous metabolites by causing an increase in protein synthesis in various pathologic conditions marked by wastage of muscle tissue. Before such use could be undertaken, the problems of the low order of oral activity and ready metabolism and excretion of the natural androgens had to be overcome. Additionally, since use as anabolic agents would not necessarily be restricted to males, means had to be found to overcome the androgenic or masculinizing effect of these agents. Oral activity and metabolism were first tackled by the preparation of oil-soluble esters as detailed in Section b. The goal of oral activity was first met not in the 19-nor series but in the compounds possessing the 10 methyl group of natural products. Androgens containing the 17a-alkyl grouping are active on oral administration for much the same reason the corresponding estrogens show activity by that route—inhibition of transformation at 17 in the gut. It was found early that the same sort of argument applied to the 19-nor compounds. Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69).20 (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol; treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71).13 Condensation of the lynestrol intermediate (47) with ethylmagnesium bromide affords the oral androgen ethylestrenol (72).2A Animal experiments on the various drugs above have all shown increased anabolic effects relative to androgenicity. In the case of androgens as with estrogens there is occasionally need for treatment of patients with chronic sustained doses of these drugs. Resort is made to esters of the androgen with long-chain fatty acids in order to provide oil-soluble agents;

19-Norsteroids

171

CH 3 O

CH 2 CH 3

CH3O

CH3O 30b

47

these are then used as solutions in oil to provide a depot of drug. For example, treatment of 19-nortestosterone with decanoic anhydride and pyridine affords nandrolone decanoate (74a).28 Acylation of 73 with phenylpropionyl chloride yields nandrolone phenpropionate (74b).29 OCR11

73, R!=H 75, Rf=CH3

74a, 74br 76a, 76b,

R'=H, Rrr=(CH2)8CH3 R'=H, RM=CH2CH2C6H5 R'=CH33 RBl=CH2CH3 Rr=CH3, Rtf= /CH2)8CH3

76c, Rf=CH3,

•O

Steroids

172 4.

STEROIDS RELATED TO TESTOSTERONE

Oil-soluble derivatives of testosterone itself predate those of its 19-nor congener; these agents too are used to administer depot injections so as to provide in effect long-term blood levels of drug. Thus, acylation of testosterone with propionyl chloride in the presence of pyridine yields testosterone propionate (76a)30; acylation by means of decanoic anhydride yields testosterone decanoate (76b).31 Finally, reaction of 75 with 3cyclopentylpropionyl chloride affords testosterone cypionate (76c),32 This last undergoes hydrolysis unusually slowly because of the presence of two substituents at the 6 position (see Newman's Rule of 6 ) . 3 3 Reaction of dehydroepiandrosterone with an excess of methylmagnesium bromide affords the 17a-methyl compound; again the aforementioned steric effects lead to high stereoselectivity. Oppenauer oxidation of the resultant intermediate (77a) proceeds with a shift of the double bond into conjugation to yield methyltestosterone (78a).34 When the initial condensation is carried out with the Grignard reagent from allyl bromide instead, this sequence yields allylestrenol (78b).36 Perhaps most startling is the fact that the product obtained from the use of a metal acetylide in this synthesis, ethisterone (78c), shows little, if any androgenic potency. Instead, the compound is an orally effective progestin.

11 77 a, R=CH3 77b, R=C=CH

78a, R=CH3 78b, R=CH2CH=CH2 78c, R=C=

Steroids Related to Testosterone

173

These agents, as well as those discussed below, have all been used at one time as orally active anabolic-androgenic agents. Dehydrogenation of methyl-testosterone by means of chloranil extends the conjugation to afford the 4,6-diene-3-one system of 79. This compound in turn undergoes 1,6 conjugate addition of methylmagnesium bromide in the presence of cuprous chloride to afford largely the 6a-methyl product (80), known as bolasterone.37 Dehydrogenation with selenium dioxide, on the other hand, affords the cross-conjugated diene, methandrostenolone (81).38 Hydroxylation of the double bond of methyltestosterone by means of osmium tetroxide and hydrogen peroxide affords the 4,5 diol. This undergoes beta elimination on treatment with base to yield oxymestrone (83).39

Catalytic reduction of dehydroepiandrosterone goes as expected largely from the unhindered side of the molecule to nfford a trans A/B ring fusion, 84. Reaction with methyl Grignard reagent followed by oxidation of the intermediate yields andro,'jtanolone (86) .h0 (There is some evidence that the corresponding tlLhydrotestosterone lacking the 17 methyl group may in fact be the physiologic androgen.) Formylation of 86 with ethyl formate mid base gives oxymetholone (87).hl Catalytic reduction of the -uialogous hydroxmethylene compound from dihydrotestosterone propi onate gives first the 23-methyl product. Treatment with base leads this to isomerize to the thermodynamically favored equatorial 2a-methyl compound, dromostanolone propionate (88).hl The iormyl ketone (87) undergoes a reaction typical of this functional .irray on treatment with hydrazine, leading to formation of the

Steroids

174

anabolic steroidal pyrazole (89), stanazole.1*2 Bromination of 86 with a single equivalent of bromine under carefully buffered conditions permits the isolation of the monobromide (9O). Dehydrohalogenation with lithium chloride in DMF affords the enone (91) >h3 an important intermediate to compounds discussed below.

HO"

HO 84

H

85

91

H

90

0 OCCH2CH3 CH*

HOC]

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92).44 Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate; the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone (94),k5 a potent anabolic agent. The 17-desmethyl analog of 91— obtainable by the same route as 91—like many other conjugated ketones, reacts with diazomethane, possibly by a 1,3-dipolar addition reaction, to form the pyrazole (96), This, on treatment with silica gel, followed by acetylation of the product, affords

Steroids Related to Testosterone

175

methenolone acetate (97).46 It should be noted that the product in this case is the vinyl methyl group rather than the cyclopropane often observed on decomposition of pyrazoles not adjacent to a ketone.

CH

OH • HO

H

,^[>NCH3

93

OH

OAc

,cfP

£6P S H

97

98 99

Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms.47 The chemistry of fluoxymestrone is more typical of that of

176

Steroids

the corticoids we meet below than it is of the androgens. This potent androgenic anabolic agent was in fact developed in parallel with the corticoids. The present discussion, however, allows an examination of some of this chemistry unencumbered by the excess functionality of the corticoids. Although several routes to this agent have been published, we only consider the most direct. One of the stumbling blocks in the early work on the synthesis of corticoids was the introduction of the 11-3-hydroxy group necessary for activity. Because of its remoteness from existing functionality, there were few ways in which this could be introduced chemically. The signal discovery of the microbiologic conversion of progesterone to ll~a~hydroxy progesterone by Peterson and Murray at Upjohn48 made such compounds readily accessible. Analogous microbiologic oxidation of androstenedione (12) affords the ll~a-hydroxy derivative, 100. Oxidation with chromium trioxide yields adrenosterone (101). (This compound can also be obtained directly from cortisone by scision of the dihydroxyacetone side chain with sodium bismuthate.) Treatment with a limited amount of pyrrolidine under carefully controlled conditions leads to selective eneamine formation at the least hindered ketone—at 3 (102). (The 11 ketone is highly hindered and will not form an eneamine using any of the common methods.) Reaction with methylmagnesium bromide followed by removal of the eneamine yields the familiar 17a-methyl 173~hydroxy derivative (lO3)~^\ote again the resistance of the extremely hindered 11 ketone to addition reactions. The ketone at 3 is then again converted to its eneamine. Treatment of this intermediate with lithium aluminum hydride, followed by hydrolysis of the eneamine, gives the dihydroxyketone (104). The secondary alcohol at 11 is next selectively converted to the toluenesulfonate ester; this last affords the 9(11) olefin (105) on treatment with base. When 105 is subjected to iV-bromoacetamide in water—in effect, hypobromous acid—the 9a-bromo, 11(3-hydroxy compound (106) is obtained. It is presumed that the initial bromonium ion is formed on the lesshindered side; diaxial opening with hydroxide at 11 will lead to the observed product. Treatment with base leads to displacement of bromine by the alkoxide ion and consequent formation of the 9,11 epoxide (109). This scheme then is a strategem allowing specific synthesis of the alternate epoxide than would be obtained on direct treatment of 105 with a peracid. Ring opening of the oxirane with hydrogen fluoride affords the key 9a-fluro-llphydroxy function in 1O8 and completes the synthesis of fiuoxymestrone,1*9 an anabolic-androgenic agent. The inclusion of a 6a-methyl group is known to potentiate the effect of progestins. Dimethisterone represents an applica-

Steroids Related to Testosterone

177

107

105

no

108

f ion of this modification to the ethisterone molecule. Oxidation of 109—obtained by acetylation of 772?-with perphthalic acid jffords largely the a-epoxide 110, by reason of the approach of lhe bulky reagent from the unhindered side of the molecule. Re.ietion of this oxide with methyl Grignard reagent proceeds by the well-known diaxial opening of oxiranes with nucleophiles to •ifford the 63-methyl 5a-hydroxy compound (111); the acetate is lost during this transformation by reaction with excess Grignard reagent. The resulting triol is then allowed to react with an

178

Steroids

excess of dihydropyran in order to mask the hydroxyls as their tetrahydropyranyl ether. The acetylene is converted to its anion with sodium amide and alkylated with methyl iodide to afford the propyne side chain. Treatment with dilute acid to remove the tetrahydropyranyl ether groups followed by oxidation with chromium trioxide:pyridine complex converts the secondary alcohol at 3 to the corresponding ketone (113). This 3-hydroxyketone undergoes dehydration to the conjugated ketone when subjected to strong acid. The previously isolated methyl group at 6 now occupies an epimerizable position by virtue of its vinylogous relation to the ketone. The methyl group in fact isomerizes to the more stable equatorial 6a position, to afford dimethistexone (114).50?51 This agent, like its prototype, is an orally effective progestin. ™C=CH

AcO

AcO . i C—C ~ CH 3

CH3

5.

114

HO CH 3

113

HO CH,

112

STEROIDS RELATED TO PROGESTERONE

The lack of oral activity of progesterone proper has already been mentioned. Even after the orally active 19-nor agents, which showed progestational activity, had been elaborated, the search continued for an orally active compound that contained the full pregnane nucleus (115). At the time such a compound would have had the economic advantage of sidestepping the then burdensome ring A aromatization reactions. The fir§t indication that such a goal was attainable came from the observation that 17a-methylprogesterone (116) was more potent than progesterone itself as a progestin.52 A systematic investigation of substituents at 17 revealed that although the 17a-hydroxyl analog is only weakly active, the corresponding 17aacetoxy compound is in fact a relatively active progestin.

Steroids Related to Progesterone

179

MCH3

115

116

Epoxidation of one of the early intermediates from the diosgenin route, pregnenolone (4), with alkaline hydrogen peroxide selectively affords, as this reagent usually does, the product of attack at the conjugated ketone (117).53 Diaxial opening of the oxirane with hydrogen bromide proceeds both regio- and stereospecifically to the bromohydrin (118). Catalytic reduction of this last in the presence of ammonium acetate removes the halogen while leaving the unsaturation at 5,6 unaffected. The 17a-hydroxypregnenolone (119) thus obtained is formylated at 3 under relatively mild conditions; this formate is then treated with acetic anhydride in the presence of p-TSA to afford the 3-formate- 17 -acetate (120) . Oppenauer oxidation of the formateacetate leads directly to hydroxyprogesterone acetate (121) , 5A In a modification of this scheme, hydroxypregnenolone is first acetylated under mild conditions to the 3-acetate and then under forcing conditions with caproic anhydride to give the acetatecaproate (122). Ester interchange with methanol removes the acetate at 3; Oppenauer oxidation affords hydroxyprogesterone

caproate

(124) ,55

Introduction of a substituent at the 6 position serves, as we have seen in the case of dimethisterone, to increase markedly the potency of progestins. In the first of these efforts, ncetoxyprogesterone, an agent known to have oral activity, was the molecule so modified. Treatment of hydroxyprogesterone (125)—obtained by Oppenauer oxidation of 17a-hydroxypregnenolone (119)—with an excess of ethylene glycol leads to the bis ketal, 7 26. The shift of the double bond to 5,6 is characteristic of the />~keto-4-ene chromophore. The olefin gives a mixture of the antid 3-epoxides when subjected to peracid, with the former predominating. Treatment of the a-oxide with methyl Grignard reagent leads to the familiar diaxial opening and thus the product 128. Deketalization reveals the (3-ketoalcohol grouping at positions 3 and 5 in 129. This readily dehydrates to 130 on treatment with base. The methyl group equilibrates to the I liermodynamically more stable equatorial 6a position on exposure to acid. Acetylation under forcing conditions affords 132,

Steroids

180

medroxyprogesterone acetate.55 Dehydrogenation of this compound with chloranil affords 133, megesterol acetate.56 Both these agents are potent orally active progestins.

bO H Br 117

118

120

119

OAc IICO, 121

O i:COC (H2 C 4) H 3 123

124

122

119 125

130

127

H O CH3 128

Steroids Related to Progesterone

CH3

181

CH3 133

132

131

Replacement of the 6 methyl of 133 by a chlorine atom proves to be compatible with biologic activity. Epoxidation of diene, 134-obtained from hydroxyprogesterone acetate by chloranil dehydrogenation—with a bulky peracid gives the 6,7a~oxide, 135. Ring opening with hydrochloric acid in aqueous dioxane affords the intermediate chlorohydrin 136; this is not isolated, since it dehydrates to chlormadinone acetate (137) under the reaction conditions.57 This last agent, incidentally, has undergone extensive clinical trial as a contraceptive in its own right without added progestin. Reports from these trials were said to be encouraging. The high potency of the compound permitted the use of low doses, hence the sobriquet, "minipill."

121

134

0

135

''OH 137

136

182

Steroids

6-Methyl-16-dehydropregnenolone, the key intermediate to the preparation of both melengesterol acetate and medrogestone, is not readily prepared from any of the intermediates described thus far. Petrov and his collaborators have devised several interesting schemes that go back to diosgenin (1) as the starting point. These schemes perform the necessary modifications in rings A and B with the sapogenin side chain still in place. In essence this approach employs this side chain as a protecting group for the future 16-dehydro-20-ketone function. In one of these routes, diosgenin (1) is first converted to the 3-toluenesulfonate. Solvolysis of this homoallylic alcohol derivative (138) affords the 3,5-cyclosteroid, 140, via the cyclopropyl carbinyl ion, 139. (This general reaction was probably first found in the steroids and bore the name of "i-steroid rearrangement.") Oxidation of the product by means of the chromium trioxide-pyridinc complex affords ketone, 141. Reaction of this with methyl magnesium iodide affords two isomeric carbinols with the a-isomer predominating. Solvolysis in the presence of a nucleophile such as acetic acid reverses the eyelopropylcarbinyl transformation to afford homoalylic acetate, 143. Removal of the sapogenin side chain much as in the case of J leads to the desired product, 144.5B

140

138

AcO AcO 143

Steroids Related to Progesterone

183

Substitution at the 16 position was found to lead to further potentiation of progestational activity. Reaction of 144 with diazomethane at the conjugated double bond at 16 gives first the pyrazole, 145. This heterocycle affords the 16 methyl enone on pyrolysis [analogous to the reaction observed at the 1 position cited earlier (95-97)]. Selective epoxidation of the conjugated double bond to the 16,17a-epoxide over that at 5,6 is achieved by oxidation with basic hydrogen peroxide. Opening of this tetrasubstituted oxirane ring in acid proceeds with loss of a proton from the 3 position (16 methyl) to afford the desired 16-methylene~17a-hydroxy-20-ketone functionality in the D ring. Oppenhauer oxidation of the saponified product gives 1*9; this is then dehydrogenated to the 4,6-diene with chloranil. Acetylation under forcing conditions completes the synthesis of melengesterol acetate (151),59

144

1 50, R=H 151 f R=COCH3 The oral activity of 17a-methyl progesterone (116) has already been alluded to. This agent, which may well owe this property to the inhibition of metabolism in a manner analogous to the gonadal steroids, is not sufficiently potent in its own right to constitute a useful drug. Incorporation of known potentiating modifications yields the commercially available oral progestin medrogestone (154). Reduction of the conjugated 16, 17 double bond of 6-methyl-16-dehydropregnenolone acetate by means of lithium in liquid ammonia leads initially to the 17 enolate ion, 152; this is alkylated in situ with methyl iodide. The now-familiar steric control asserts itself to afford the 17a-

184

Steroids

methyl compound, 153. The acetate group is lost as a side reaction. In an interesting modification on the usual scheme, 153 is treated with aluminum isopropoxide and a ketone (Oppenauer conditions) as well as chloranil in a single reaction; the 4,6 diene, 154 (medrogesterone), is obtained directly from this step.60

144

154 It should be noted that the stereochemistry of the B/C and C/D junctions has remained inviolate in all the modifications discussed to date. It was in fact assumed that changing either of these was a quick path to loss of activity. Just such a modification, however, led to a progestin with a unique pharmacologic profile. Allylic bromination of pregnenolone acetate with dibromodimethylhydantoin affords the 7-bromo compound (155) of undefined stereochemistry. Dehydrobromination by means of collidine followed by saponification affords the 5,7 endocyclic cis,cis-diene, 156. This compound contains the same chromophore as ergosterol, a steroid used as a vitamin D precursor. The latter displays a complex series of photochemical reactions; among the known products is lumisterol, in which the stereochemistry at both C 9 and Cio is inverted. Indeed, irradiation of 156 proceeds to give just such a product (158). This reaction can be rationalized by

Steroids Related to Progesterone

185

assuming first a light-induced ring opening to an intermediate such as the triene, 157; such a species would be predicted to ring close in conrotatory fashion with the formation of the observed stereochemistry. Oppenauer oxidation of the product goes in the usual fashion, although one double bond remains out of conjugation (159), Treatment with acid gives the fully conjugated diene of dydrogesterone (160).61 It is a common property of progestins that they will inhibit ovulation when combined with estrogens. Dydrogesterone has no effect on ovulation either by itself or in combination with estrogens. Some progestins, particularly those which possess the full progesterone skeleton, will induce masculinizing changes in the female offspring of treated female animals. Dydrogesterone differs in this respect, too, since no such effects are observed after its administration.

AcO

Ac

155

159

16O

158

156

157

186

Steroids

6.

THE ORAL CONTRACEPTIVES

The original rationale for the use of progestins as oral contraceptives—besides the animal experiments previously alluded toresided in the fact that females do not ovulate during pregnancya time in which there are known to exist high levels of circulating blood progesterone. It was therefore intended to mimic the hormonal state of pregnancy by administration of exogenous progestational agents; as we have already seen, it was found empirically that an estrogen was needed to combine with the progestin in order to achieve full efficacy. In a normal menstrual cycle, the lining of the uterus undergoes a series of morphologic changes, whether ovulation occurs or not, characterized by proliferation of the blood vessels and tissues of the walls. The phenomenon of menstruation represents the periodic sluffing of this buildup in the absence of conception. It was thus thought inadvisable to maintain a woman in a continued amenstrual state. The almost universal practice has been adopted of administering the contraceptive for a time that roughly corresponds to the greater part of the menstrual cycle—20-21 days. Discontinuance of drug at this point for a period of 4-5 days leads to the sluffing of the uterine wall and the bleeding characteristic of menses. Table 1 below lists some of the combination (estrogen plus progestin) oral contraceptives that have been available commercially. Table 1.

Combination Oral Contraceptives

Trade Named

Progestin

mg a

Estrogen

mg a .05

Anovlar

norethindrone acetate

4.0

EE*

Enovid-E

norethinodrel

2,5

MEC

0.1

Lyndiol

lynestrol

5.0

ME

0.15

Norinyl

morethindrone

1.0

EE

0.05

Ovral

norgestrel

0.5

EE

0.05

Ovulen

ethynodiol diacetate

1.0

ME

0.1

Planor

norgestrienone

2.0

ME

0.1

0.0 medroxyprogesterone acetate 10.0

EE

0.05

Provest

The Oral Contraceptives

187

Table 1, continued Riglovis

Riglovis

0.5

EE

0.05

Volidan

melengesterol acetate

4.0

EE

0.05

Mg in daily dose. EE, ethinyl estradiol. Registered trademarks,

ME, mestranol.

Advances in reproductive physiology as well as empirical observations suggested that the progestational component of the Pill need not be administered for the full 21 days. In analogy to the normal menstrual cycle it was considered that the progestin need be included for only the last few days. Such a regimen would have the advantage of reducing exposure to the progestational component of these drugs. This expectation was borne out in practice. The so-called sequential contraceptives consist of a series of 15 doses of estrogen alone; these are followed by five dosages of the estrogen-progestin combination. In practice this regime has been well tolerated, although it may be fractionally less efficacious than the more traditional contraceptives. Some of the commercially available sequential contraceptives are listed below in Table 2. Table 2.

Sequential Oral Contraceptives

Trade Namea

Progestin

mg

Estrogen

mg

C-Quens

chlormadinone acetate

2.0

ME

0.08

Norquens

norethindrone

2.0

ME

0.08

Oraeon

dimethisterone

25.0

EE

0.10

Ortho-Novum

norethindrone

2.0

ME

0.08

Registered trademark. In addition, several progestins have been used in the absence of estrogens for purposes of contraception. It is clear that they owe their efficacy, which is not as high as that of the combination or sequential treatments, to some mechanism other than inhibition of ovulation. These are not yet represented by marketed entities for that indication. Several progestins have been formulated for administration

188

Steroids

as depot injections; the low water solubility of these compounds allows the agent to be deposited intramuscularly in a microcrystalline form. Slow dissolution provides a chronic blood level of the compound. At least one of these agents, medroxyprogesterone acetate (Depo Provera®), has shown promise in the clinic as an injectable contraceptive of relatively long duration. Its mechanism of action is probably a combination of inhibition of ovulation and some other effect on the reproductive process.

7.

CORTISONE AND RELATED ANTIINFLAMMATORY STEROIDS

It was known as early as 1927 that the adrenal glands of mammalian species secrete a series of substances essential to the survival of the individual. The hormonal nature of these secretions was suggested by the observation that extracts of the adrenal gland and more specifically of the outer portion of that organ (cortex) would ensure survival of animals whose adrenals had been excised. By 1943 no fewer than 28 steroids had been isolated from adrenal cortical extracts. These compounds were found to be involved in the regulation of such diverse and basic processes as electrolyte balance, carbohydrate metabolism, and resistance to trauma, to name only a few. Again, as in the case of the other steroid hormones, the quantities of these compounds isolable from animal sources was barely sufficient for structural characterization. Complete biologic characterization therefore depended on material made available by synthesis. Approaches to these compounds by classical steroid chemistry were greatly hampered by the finding that one of the principal cortical steroids, cortisone (161), possessed oxygen substitution at the 11 position. There was at the time no obvious way for functionalizing C X 1 by chemical means; at this writing, in fact, this is still not readily accomplished.9A As we saw earlier, plant materials provided an efficient starting point for the steroids discussed previously; unfortunately, the corresponding C-ring oxygenated plant sterols are not available in comparable supply. Instead, early syntheses fell back on a starting material from animal sources; cholic acid (162), one of the bile acids, possessing oxygenation at C 1 2 . This material available in tonnage quantities from ox bile from slaughterhouses, was used as starting material for the synthesis of the initial quantities of cortisone.62 Briefly, this partial synthesis devolves conceptually on three basic operations: degradation of the bile acid side chain to the required dihydroxyacetone moiety, transposition of oxygen from C 1 2 to C l l 3 and finally generation of the 3-keto-4-ene system from the 3,7 diol. Once cortisone was

Cortisone and Related Steroids

189

found to have important therapeutic uses, this process (which will not be detailed here; see reference 63 for a detailed discussion) was considerably modified and the process developed to a point of quite high efficiency. There is reason to believe, however, that the bile acid route was finally supplanted by the route that included microbiologic oxidation.

HO

161

162

The availability of cortisone in sizeable quantities made it possible for Kendall and Hench at the Mayo Clinic to follow up on their clinical observation that patients suffering from rheumatoid arthritis showed symptomatic relief in the presence of high endogenous cortisone levels. Indeed, they were soon able to describe the dramatic relief afforded arthritics by treatment with pharmacologic doses of cortisone. As this drug came into use for this, as well as for treatment of other inflammation, side effects were found that were perhaps a manifestation of the important physiologic role of this class of steroids. There were seen, for example, disturbances in electrolyte balance and glucose metabolism as well as more bizarre effects, such as the development at high chronic doses of the so-called moon face and dowagers hump. An intense effort was mounted on the part of most large pharmaceutical companies to prepare analogs that would emphasize the antiinflammatory activity without increasing the side effects due to hormonal potency. It cannot be disputed that dramatic increases in potency over cortisone were finally achieved; it is equally clear that the purely antiinflammatory corticoid has yet to be found. It had been known for some time from studies of biosynthesis that corticoids rise physiologically from progesterone by hydroxylation at both C n and in the side chain. In fact, perfusion of steroids with the preformed side chain through isolated beef adrenal glands effects just that reaction. Reasoning that microorganisms might well possess some enzyme system analogous to that which carries out that hydroxylation, a group at Upjohn undertook a systematic search to screen for such activity. They were

190

Steroids

rewarded by the observation that the soil organisms, Rhizopus arrhizus or nigricans, effected conversion of progesterone to lla-hydroxyprogesterone in 50% yield. This conversion became the keystone in a synthesis of cortisone from progesterone—and thus from stigmasterol and eventually soybean sterols. Large-scale commercial production of modified corticoids starts with just that microbiologic oxidation of progesterone to yield lla-hydroxyprogesterone (163). Oxidation of the alcohol leads to the trione, 164. In the first step for conversion of the progesterone side chain to that of cortisone, the compound is condensed with ethyl oxalate. Selectivity is achieved due to the great steric hindrance about C 1 2 and the increased reactivity of the methyl ketone at C2i over the corresponding 2 position. (Formation of an enolate at the latter would decrease the nucleophilicity of that position by distributing the charge over the conjugated system.) Formation of enolate 165 serves to activate the 21 position selectively towards halogenation. In an essentially one-pot reaction, the sodium salt of the enolate is first treated with two equivalents of bromine. The crude bromo compound obtained from this reaction (166) is then treated with a metal alkoxide. The dibromoketone undergoes the characteristic Favorsky reaction as well as dehydrohalogenation to yield the unsaturated ester, 167. The ketone at 3 is then protected as either its ketal or enamine. Reduction with lithium aluminum hydride simultaneously reduces the ester to the alcohol and the ketone at 11 to the lip-alcohol; acetylation followed by removal of the protecting group affords compound 169, two oxygens removed from the goal. Osmium tetroxide is well known to oxidize olefins to the corresponding diols. This reagent in the presence of hydrogen peroxide carries this oxidation one step further in the case of allylic acetates such as those present in 169 and oxidizes the secondary alcohol to a ketone.6* Thus, reaction of 169 with either the above reagent or phenyliodosoacetate in the presence of osmium tetroxide affords directly hydrocortisone acetate (17Oa),85 an important drug in its own right and starting material for other antiinflammatory agents. Several products of relatively lower importance are derived from 170a. Saponification of the acetate at 21 gives hydrocortisone (170b). Oxidation of the 11 alcohol yields cortisone acetate (171a); cortisone (171b) is obtained when this last is saponified. As is apparent at a glance, cortisone is an intricate molecule with a wealth of functionality. Steroid transformations in the corticoid series require serious strategic planning in order to provide the appropriate protecting groups and to introduce substituents in the proper order. It is therefore easy in a discussion of this chemistry to get lost in a welter of detail.

191

Cortisone and Related Steroids

H0

17

",,

168 AcOCH2 \ 0 ^>w I J**^

169

166

167

HO

,~OR ho

170a, R=Ac 170b, R=H

171a, R=Ac 171b, R=H

For this reason in this section we depart from our practice of discussing each synthesis in detail. Certain standard operations, for example, introduction of 9-fluoro substituents, are referred to as though they were a single reaction; only the salient points of the syntheses are dwelt on. Examination of some of these syntheses strongly suggests that these were aimed at preparing compounds for biologic assay. It is more than likely that the commercial preparations have only the final product in common with the published route. One of the first indications that the antiinflammatory potency of the corticoids could be increased was the observation that incorporation of a 9a-fluoro group in hydrocortisone resulted in a tenfold increase in activity. Treatment of hydrocortisone acetate (170a) with phosphorus oxychloride in pyridine yields the corresponding olefin, 172. This, on being subjected to the reaction sequence depicted in the transformation of 104 to 108 (addition of HOBr, closure to the epoxide and ring opening with HF),

Steroids

192 affords fludrocortisone acetate (173)/ OAc

HO 170a

173

172

Incubation of cortisone with Corynebacterium simplex results in dehydrogenation of the bond at 1,2 and the isolation of the corresponding 1,4-diene, prednisone (174); hydrocortisone affords prednisolone (175a) when subjected to this microbiologic transformation.67 Both these agents as well as the ester, prednisolone acetate (175b), were found to show increased potency over the parent compounds; there is also a suggestion that other hormonal activities may be decreased. The subsequent finding that modifications in corticoids that lead to increased potency are often additive in effect led to inclusion of this feature in most later clinical agents.

HO

174

175a, R=H 175b, R=COCH3

Both the above potentiating modifications were next included in a single molecule. Catalytic reduction of 173 affords the corresponding 5a-derivative. This is then taken on to the 2,4dibromo compound (see the transformation of 12 to 21 -For discussion); dehydrohalogenation gives the 1,4 diene, 9<x-fluoroprednisolone acetate (176) 9 6 9 > 7 0 a potent antiinflammatory agent. We have already seen that incorporation of a 6 methyl group into progestins increases the biologic activity of these mole-

193

Cortisone and Related Steroids

OAc

173

175

174

HO

176 cules (see 112, 132, and 133); the analogous modification of corticoids has a similar effect on potency. Condensation of cortisone (171b) with formaldehyde converts the dihydroxyacetone moiety of the steroids to a double internal acetal, referred to as the bismethylenedioxy group, a common protecting group for the corticoid side chain (see inset). Ketalization of the steroid thus protected shifts the double bond to the 5 position. Treatment of 178 with peracid affords a mixture of the two epoxides. This mixture is then rearranged to ketone, 180, by treatment with formic acid. This last gives the methyl carbinol, 181, with methyl Grignard reagent (the 11 ketone is too hindered to undergo Grignard addition under all but the most forcing conditions). Dehydration of the tertiary alcohol followed by reduction with lithium aluminum hydride leads to the ketal, 182; it should be noted that the double bond of 178 has in effect been restored. Indeed, deketalization of 182 leads to the conjugated ketone containing now an additional methyl group at the 6a position. The additional double bond at the 1 position is introduced in this case by treatment with selenium dioxide. Removal of the protecting group with acetic acid affords methylprednisolone (185),71»72 a widely used corticoid. The corresponding 63-fluoro steroid also exhibits potent

Steroids

194

CH3 185

195

Cortisone and Related Steroids

antiinflammatory activity. Rather than carrying the dihydroxyacetone side chain through the synthesis in a protected form, the route to the fluoro compound intercepts an intermediate towards formation of that side chain; the cortical side chain in this case is carried along in latent form. Epoxidation of the isolated double bond of 168a (obtained by reduction of the ketone of 168) affords in this case largely the a-epoxide. Opening of the oxirane with hydrogen fluoride gives fluorohydrin, 187, stereospecificity and regiospecificity depending on diaxial opening of the ring. The acrylic acid side chain is next elaborated to the dihydroxyacetone in the same manner as the transformation of 168 to 170a. Deketalization of 188 leads to the 3-hydroxyketone, 189; this readily dehydrates to 190 with base. Dehydrogenation to the 1,4-diene by means of selenium dioxide followed by equilibration of the fluorine to the more stable 6a position completes the synthesis of fluprednisolone acetate (191).73 CH 3 O 2 C

CH 3 O 2 C

CH 3 O 2 C

HO

188

191

Important pathways for biologic deactivation of cortical steroids in humans involve reduction of the ketone at 21 and scision of the entire side chain at C 1 7 . Substitution at Ci 6 , it

196

Steroids

was hoped, would interfere with this degradation by providing steric hindrance to the degradative enzymes. One of the early applications of this strategem involved the preparation of 26(3methyIprednisone (199). Condensation of the enone, 192, an intermediate from the synthesis of cortisone by the bile acid route, with diazomethane followed by pyrolysis of the intermediate pyrazole gives the 16-methyl enone (193) (see transformation of 95 to 97 and 144 to 146 for discussion of this reaction). Catalytic reduction results in addition of hydrogen from the less-hindered side and formation of the 163-methyl intermediate (194). The progesterone side chain in this case is elaborated to the dihydroxyacetone by the so-called Gallagher chemistry. In this, the ketone at 20 is first converted to the enol acetate (195); epoxidation affords an oxirane that is essentially a masked derivative of a ketal at C2o. Hydrolytic opening of the epoxide can be viewed, at least formally, as leading first to the alcohol at 17 and a hemiketal at 20; final product is the hydroxyketone, 196. Bromination, because of the great hindrance about the ketone at C u , proceeds exclusively at the methyl ketone. Displacement of the halogen with acetate completes the side chain (198). Saponification followed by oxidation with zv-bromosuccinide surprisingly goes exclusively at C 3 to give the ketone. Introduction of the double bonds at 1 and 4 (in this case by the bromination debromination sequence) leads to the potent corticoid, 16$-methyl prednisone (199) . 7 S 7 5

AcO 192

193

194

OAc

AcO1

AcO 197

AcON 196

195

197

Cortisone and Related Steroids

198

199

In another scheme to block metabolism of the cortical side chain, the steroid is equipped with a methylene substituent at 16. Thus, 16-dehydropregnenolone acetate (4) is first converted to the corresponding 16 methyl derivative by the diazomethane addition-pyrolysis scheme alluded to above. This is then taken on to 16-methylene-17a-hydroxy progesterone (201) by a route analogous to that outlined earlier (transformation of 144 to 148) for the corresponding 6 methyl analog. Bromination of the methyl group at 21 followed by displacement of the halogen with acetate completes the preparation of the side chain (202). This scheme differs from others we have seen in the late introduction of the oxygen at 11. Thus, incubation of 202 with a Curvularia affords in this case the llp-hydroxy compound (203). Oxidation of that alcohol followed by saponification and finally introduction of the 1,2 double bond—by a second microbiologic step—yields prednylene (2O4).76

201

OAc

202

198

Steroids

.OAc

203

204

Incorporation of some of the traditional potentiating groups into the 16-methyl corticoids leads to a series of exceedingly active compounds. Ketalization of the 16p-methylprednisone intermediate, 196, followed by reduction with sodium in alcohol affords the product of thermodynamic control at 11, the equatorial llahydroxy derivative (metal hydride reduction usually gives 113 alcohols). This compound is then deketalized; the methyl ketone at 21 is brominated and the halogen displaced with acetate ion to afford the compound containing the requisite side chain (206). Oxidation with iV-bromoacetamide selectively leads to the 3-ketone; this is then converted to the 1,4-diene by the bromination-dehydrobromination scheme (208). The 11-hydroxyl group is then converted to the tosylate; treatment with base affords the 9,11 olefin (209). This last is converted to the 9a-fluoro-113-hydroxy grouping by the now-familiar scheme (105 to 108) to afford, after saponification, betamethasone (210).77 The substituents we have seen thus far have all shown stereoselective demands—only one isomer of a given set is compatible OAc 196

HO'1 205

207

206

*

r- OAc

HO

210

209

208

Cortisone and Related Steroids

199

with biologic activity. The 16 position represents an exception to this rule. The agents isomeric at 16 to the above are fully as active as the 163 compounds. Condensation of the intermediate 192 with methyl Grignard reagent leads (by conjugate addition from the least-hindered side) to the free alcohol analog of 194, epimeric at 16, that is, the 16a-isomer. This compound is then converted to cortisone analog 212, lacking the double bond in the A ring, by a sequence identical to that described above for the 163 compound (194 to 199). That double bond is introduced by a modification of the bromination dehydrohalogenation procedure using a single equivalent of bromine (213),78 Protection of the ketone at 3 followed by reduction gives the 11-hydroxy intermediate. This last is dehydrated to the 9,11 olefin and transformed to the 9,11 fluorohydrin in the usual way. The second double bond in ring A in this case is introduced by means of selenium dioxide; saponification completes the synthesis of dexamethasone (216).79>

216

215

214

The potentiation of activity due to the 16a-methyl group also proved additive with that which had been observed earlier on incorporation of the 6a-fluoro substituent. Reaction of 16dehydropregnenolone with methyl Grignard reagent proceeds as with the more complex substrate to give, in this case, 16a-methylpreg~ nenolone, 217. Reacetylation followed by epoxidation gives the 5a,6a-epoxide. Opening of the oxirane ring with hydrogen fluoride followed by acetylation gives intermediate, 218. This is then subjected to the side-chain elaboration reaction discussed earlier (transformation of 194 to 198) to give triacetate, 219. Selective saponification at 3 followed by oxidation gives an

200

Steroids

intermediate 3-hydroxyketone; this, on treatment with base, goes to the conjugated ketone 220 with simultaneous epimerization of fluorine to 6a. In the original work, the 113-hydroxy function of 221 was introduced by perfusion of 220 through isolated beef adrenals; this is presumably not the commercial route. Selenium dioxide oxidation serves to introduce the 1,2 double bond; paramethasone (222)81 is thus obtained. OAc MCH,

AcO

AcO 217

AcO

z F

AcO

218

AcO

219

HO

220

224

223

Dehydration of 221 affords the corresponding 9,11 olefin, 223. When this compound is subjected to the series of reactions for introduction of the 9,11 fluorohydrin, there is obtained the antiinflammatory steroid flumethasone (224),82 As might be expected from the incorporation of a group in almost every position known to increase potency 224 is an extremely active agent. Incorporation of a hydroxyl group at the 16 position has been fully as fruitful of active corticoids as the corresponding methyl derivatives. In this case, however, only the 16a-isomers seem to have reached the stage of the clinic. The key to entry

201

Cortisone and Related Steroids

into this series is a clever dehydration reaction that eliminates water in the same reaction from both 11 and 17. 8 3 Ketalization of hydrocortisone acetate (170a) affords the ketal, 225. Treatment of this compound with thionyl chloride in pyridine at -5°C affords intermediate, 226. Deketalization leads to the true starting material of this series (227). Oxidation of this compound with either osmium tetroxide or potassium premanganate in acetone selectively attacks only the 16,17 double bond and that from the a side, presumably for steric reasons. Thus, in one step, the substituent at 17 is restored and the new one at 16 introduced. Acetylation under mild conditions leads to 228. The 9a-fiuoro-113-alcohol is then introduced by the customary scheme. The 1,2 double bond is introduced by means of selenium dioxide; saponification completes the synthesis of triamcinolone (230). Reaction of this 16,17 diol with acetone forms the ketal, 231; this last is the widely used antiinflammatory steroid triamcinolone acetonide (231).84 ,-OAc -OAc

231

The potentiation obtained with 6a-fluoro group was found to be additive to that of the 16 hydroxy group, just as in the case of the corresponding methyl compounds. The synthesis of these agents relies on introduction of the corresponding hydroxyl group

202

Steroids

at a relatively late stage. As in the case of some of the other 6a-fluoro compounds, one must wonder whether the method used for introducing this function (perfusion through beef adrenals) is in fact that used for commercial production. Hydroxylation of the 21 acetoxy derivative of 16~dehydropregnenolone f232,)-obtainable from the parent compound in a few steps85—affords the 16a,17aglycol; this is protected for subsequent reactions as its acetonide (223). Epoxidation gives mainly the 5a,6a-oxide. This is then transformed to the 63-fluoro enone by the customary reaction sequence (see transformation of 186 to 190). The acetonide is removed during the course of this sequence to afford 235. The above-mentioned biotransformation serves to introduce the 11 oxygen of 236. Fludroxycor tide (237) is obtained from the latter by dehydrogenation at 1,2 and then conversion to its acetonide.86 Alternately, 236 is subjected first to the procedures leading to introduction of the 9a-fluoro grouping (238). Introduction of the 1,2 double bond followed by acetonide formation yields flucinolone acetonide (239).87

235

239

Cortisone and Related Steroids

203

The early structure-activity correlations in the corticoids suggested that the functionality present in cortisone or dihydrocortisone was a minimum for biologic activity; that is, analogs in which any of the keto or hydroxyl groups were deleted tended to be inactive. We saw earlier that, in the case of both the progestins and the androgens, a similar rule apparently fell down for the 3-desoxy compounds, at least one example in each class showing sufficient activity to be marketed as a drug. There are similar exceptions to the rule in the corticoid series: steroids that lack some apparently crucial structural feature, yet sufficiently active to be used as drugs. It is of note that the examples shown below are used mainly as topical antiinflammatory agents. Dehydration of prednisolone acetate (175b) yields the corresponding 9,11 olefin. As a variation on the chemistry we have seen previously, this olefin is allowed to react with chlorine in the presence of lithium chloride. If this addition is assumed to proceed by the customary mechanism, the first intermediate should be the 9a,lla-chloronium ion. Axial attack by chloride anion from the lip position will lead to the observed stereochemistry of the product dichlorisone (240),88

v

-OAc

Cl

. (I I_J 175b 239

240

The oxygen atom at 21 is similarly an expendable group. Reaction of 241 (obtained from 185 by the usual procedure for introduction of the 9a-fluoro group) with methanesulfonyl chloride affords the 21 mesylate (242a). Replacement of the leaving group at 21 with iodine by means of potassium iodide in acetone followed by reduction of the halogen with zinc in acetic acid leads to fluorometholone (243) . " Deletion of the 17a-hydroxy group similarly leads to an effective topical antiinflammatory agent. Treatment of 16a~ methylpregnenolone (244) (obtained by conjugate addition of an organometallie to pregnenolone) sequentially with bromine and acetate ion affords the 21 acetate, 245 (see, for example, the transformation of 196 to 198). In an interesting variation on the method for the introduction of a fluorine atom at 6, the

204

Steroids

185

241

241a, R=OSO2CH3 242b, R=I

HO

CH, 243 intermediate is first treated with HF in the presence of w-bromoacetamide; this in effect results in the addition of BrF, presumably, as judged by the stereochemistry of the product, initiated by formation of the a-bromonium ion. Oxidation of the hydroxyl at 3, followed by elimination of the halogen 3 to the ketone, isomerization of fluorine to the equatorial 6a configuration, and finally saponification lead to 247. Incubation of this with a Curvularla introduces the llp-hydroxy group. Fermentation of 248 with C simplex serves to dehydrogenate the 1,2 bond. There is thus obtained fluocortolone (249).90 Examination of the dates on the references to this chapter will quickly reveal that publications on the corticoids, as indeed all other steroids, reached a steep maximum in the late 1950s to about 1960. After that, publication dropped off to a comparative trickle. It should be kept in mind when examining

Cortisone and Related Steroids

205

245

244

246

HO

|lf.CH3

249

HO,

248

247

these dates that they represent a skewed sample in that the only publications cited are those which led finally to either drugs or agents that almost made the market. Work on steroids did not cease quite as abruptly as the bibliography suggests. The apparent peaking of research in this area is an interesting phenomenon that deserves some comment. To begin with, it is true that within each of the classes of steroids discussed drugs had been found that met most of the demands of the practicing clinician. However, none of these entities was free from some troublesome side effects in some fraction of the patients. Under normal circumstances this might well have led to continuing work at some lower level of activity. Two reasons can be invoked for the decreased effort in this field. In the first place the very large number of analogs tested—this chapter of course barely skims the surface of these—served to convince a number of influential pharmacologists that the splits between the various activities that were being so strenuously sought were probably not achievable. Thus, no pure anabolic androgen, for example, was ever uncovered. Excellent splits achieved in experimental animals had a way of diminishing during clinical trials. A factor at least as important as those above is the passage

206

Steroids

of the Drug Amendments of 1962. The increasing difficulty and expense of placing a drug on the market made manufacturers chary of developing drug that did not have promise of impressive sales figures. Entering a market such as the corticoids with an agent that might not be readily distinguishable pharmacologically from existing entries was clearly too expensive to contemplate seriously. This state of affairs has its silver lining in the fact that much "me-too11 research went by the boards. On the other hand, the true utility of many pharmacologic agents has only been discovered during the course of clinical trials, often for the wrong indication. The high cost of developing a drug for the submission of an NDA and the current trend on the part of the FDA in the United States greatly decreases the chances of such serendipitous discoveries.

8.

MISCELLANEOUS STEROIDS

Although the era of intensive steroid research saw many efforts to develop compounds with activities other than those catalogued, this work met with scant success. One such line of research did, however, bear fruit. It was known for some time that even after the corticoids had been separated from crude extracts of the adrenal cortex, the remaining material, the so-called "amorphous fraction" still possessed considerable mineralocorticoid activity. Aldosterone (250), one of the last steroids to be isolated from this fraction, proved to be the active principle. This compound proved to be an extremely potent agent for the retention of salt, and thus water, in body fluids. An antagonist would be expected to act as a diuretic in those edematous states caused by excess sodium retention. Although aldosterone has been prepared by both total 91 and partial92 synthesis, the complexity of the molecule discouraged attempts to prepare antagonists based directly on the parent compound. The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt; carbonation with C0 2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cyclized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist.93

Miscellaneous Steroids

207

250

77b

252

251

254

253

255

REFERENCES 1.

2.

3. 4.

R. E. Marker, R. B. Wagner, P. R. Ulshafer, E. L. Wittbecker, D. P. J. Goldsmith, and C. H. Ruof, J. Amer. Chem. Soc, 69, 2167 (1947). For a modification of this step, see A. F. B. Cameron, R. M. Evans, J. C. Hamlet, J. S. Hunt, P. G. Jones, and A. G. Long, J. Chem. Soc, 2807 (1955). F. H. Tendick and E. J. Lawson, U. S. Patent 2,335,616 (1943). G. Rosenkranz, 0. Mancera, F. Sondheimer, and C. Djerassi, J. Org. Chem., 21, 520 (1956).

208

References

5. F. W. Heyl and M. E. Herr, J. Amer. Chem. Soc, 72, 2617 (1950). 6. G. Slomp, Jr., and J. L. Johnson, J. Amer, Chem* Socr, 80, 915 (1953). 7. E. B. Hershberg, M. Rubin, and E. Schwenk, J. Org. Chem., 15, 292 (1950). 8. S. Kaufmann, J. Pataki, G. Rosenkranz, J, Romo, and C. Djerassi, J. Amer. Chem. Soc, 72, 4531 (1950). 9. H. L. Dryden, Jr., G. M. Webber, and J. Weiczovek, J. Amer* Chem. Soc, 86, 742 (1964). 10. E. V. Jensen and H. I. Jacobson, Rec Progr. Hormone Res., 18, 387 (1962). 11. See, for example, A. C. Ott, U. S. Patent 2,611,773 (1952). 12. H. H. Inhofen, W. Logeman, W. Hohlweb, and A. Serini, Chem. Ber., 71, 1024 (1938). 13. F. B. Colton, L. N. Nysted, B, Riegel, and A, L. Raymond, J. Amer. Chem. Soc, 79, 1123 (1957). 14. A. W. Makepeace, G. L. Weinstein, and M. H. Friedman, Amer. J. Physiol., 119, 512 (1937). 15. H. H. Inhoffen, W. Logemann, W. Holway, and Af Serini, Chem. Ber., 71, 1024 (1938). 16. W. M. Allen and M. Ehrenstein, Science, 100, 251 (1944). 17. A. J. Birch, Quart. Rev., 4, 69 (1950), 18. A. L. Wilds and N. A. Nelson, J. Amer. Chem. Soc, 75, 5366 (1953). 19. F. B. Colton, U, S. Patent 2,655,518 (1952). 20. C. Djerassi, L. Miramontes, G. Rosenkranz, and F. Sondheimer, J. Amer, Chem. Soc, 76, 4092 (1954). 21. J. Iriarte, C. Djerassi, and H. J. Ringold, j. Amer. Chem. Soc, 81, 436 (1959) . 22. A. Ercoli and R. Gardi, J. Amer. Chem. Soc, 82, 746 (1960). 23. P. D. Klimstra and F. B. Colton, Steroids, 10, 411 (1967). 24. M. S. DeWinter, C. M. Siegmann, and C. A. Szpilfogel, Chem. Ind., 905 (1959). 25. G. H. Douglas, J. M. H. Graves, D. Hartley, Gf A, Hughes, B. J. McLaghlin, J. B. Siddall, and H, Smith, J. Chem. Soc, 5072 (1963). 26. R. Joly, J. Warnant, J. Jolly, and J. Mathieu, Comp. Rend., 258, 5669 (1964). 27. L. Velluz, G. Nomine, R. Bucourt, and J. Mahieu, Comp. Rend., 257, 569 (1963). 28. E. D. DeWyt, 0. Overbeek, and G. A. Overbeek, U. S. Patent 2,998,423 (1961). 29. R. A. Donia and A. C. Ott, U. S. Patent 2,868,809 (1960). 30. Anon., Swiss Patent 206,119 (1939). 31. K. Junkmann, J. Kahol, and H. Richter, U. S. Patent 2,840,508

References

32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44. 45. 46. 47. 48.

49. 50. 51. 52. 53. 54. 55.

209

(1958). A. C. Ott, M. H. Kuizinga, S. C. Lyster, and J. L. Johnson, N. Y. IUPAC Congress, Abstracts of Papers, p. 294 (1951). M. S. Newman, J. Amer. Chem. Soc., 72, 4783 (1950). L. Ruzicka, M. W. Goldberg, and H. R. Rosenberg, Helv. Chim. Acta, 18, 1487 (1935). H. H. Inhoffen, W. Logemann, W. Holweg, and A. Serini, chem. Ber., 71, 1024 (1938). H. H. Inhoffen and W. Logemann, German Patent 882,398 (1953). J. A. Campbell and J. C. Babcock, J. Amer. Chem. Soc, 81, 4069 (1959). C. Megstre, H. Frey, W. Vosser, and A. Wottstein, Helv. Chim. Acta, 39, 734 (1956). B. Camerino, M. B. Patelli, and G. Sala, U. A. Patent 3,060,201 (1962). L. Ruzicka, M. W. Goldberg, H. R. Rosenberg, Helv. Chim. Acta, 18, 1487 (1935). H. J. Ringold, E. Batres, 0. Halpern, and E. Necoechea, J. Amer. Chem. Soc, 81, 427 (1959). R. 0. Clinton, A. J. Manson, F. W. Stonner, A. L. Beyler, G. 0. Potts, and A. Arnold, J. Amer. Chem. Soc, 81, 1513 (1959). R. E. Counsell, P. D. Klimstra, and F. B. Colton, J. Org. Chem., 27, 248 (1962). R. Wiechert, German Patent 1,152,100 (1963). R. Pappo and C. J. Jung, Tetrahedron Lett., 365 (1962). R. Wiechert and E. Kaspar, Chem. Ber., 93, 1710 (I960). J. M. Kramer, K. Bruckner, K. Irmscher, and K. H. Bork, Chem. Ber., 96, 2803 (1963). D. H. Peterson, H. C. Murray, S. H. Eppstein, L. M. Reinecke, A. Weintraub, P. D. Meister, and H. M. Leigh, J. Amer. Chem. Soc, 74, 5933 (1952). M. E. Herr, J. A. Hogg, and R. H. Levin, J. Amer. Chem. Soc, 78, 501 (1956). M. Ackroyd, W. J. Adams, B. Ellis, V. Petrow, and I. A. Stuart Webb, J. Chem. Soc, 4049 (1957). S. P. Barton, D. Burn, G. Cooley, B. Ellis, and V. Petrow, J. Chem. Soc, 1957 (1959). H. Heusser, C. R. Engel, P. T. Herzig, and P. A. Plattner, Helv. Chim. Acta, 33, 2229 (1950). P. L. Julian, E. W. Meyer, W. J. Karpel, and I. R. Waller, J. Amer. Chem. Soc, 72, 5145 (1950). H. J. Ringold, B. L5ken, G. Rosenkranz, and F. Sondheimer, J. Amer. Chem. Soc, 78, 816 (1956). J. C. Babcock, E. S. Gutsell, M. E. Herr, J. A. Hogg, J. C. Stucki, L. E. Barnes, and W. E. Dulin, J. Amer. Chem. Soc,

210

56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

66. 67.

68.

69. 70.

71. 72.

73. 74.

75. 76.

References

80, 2904 (1958). H. J. Ringold, J. P. Ruelas, E. Batres, and C. Djerassi, J. Amer. Chem. Soc., 81, 3712 (1959). K. Bruckner, B. Hampel, and V. Johnson, Chem. Ber., 94, 1225 (1961). D. Burn, B. Ellis, V. Petrow, I. A. Stuart Webb, and D. M. Williamson, J. Chem. Soc, 4092 (1957). D. N. Kirk, V. Petrow, and D. M. Williamson, J. Chem. Soc, 2821 (1961). R. Deghenghi, C. Revesz, and R. Gaudry, J. Med. Chem., 6, 301 (1963). M. P. Rappoldt and P. Westerhoff, Rec Trav. Chim. Pays Bas, 80, 43 (1961). L. H. Sarett, J. Biol. Chem., 162, 601 (1946). L. F. Fieser and M. Fieser, "Steroids," p. 651, Reinhold, N. Y. (1959). K. Miescher and J. Schmidlin, Helv. Chim. Acta, 33, 1840 (1950). J. A. Hogg, P. F. Beal, A. H. Nathan, F. H. Lincoln, W. P. Schneider, B. J. Magerlein, A. R. Hanze, and R. W. Jackson, J. Amer. Chem. Soc, 77, 4436 (1955). J. Fried and E. F. Sabo, J. Amer. Chem. Soc , 76, 1455 (1954). A. Nobile, W. Charney, P. L. Perlman, H. L. Herzog, C. C. Payne, M. E. Tully, M. A. Jernik, and E. B. Hershberg, J. Amer. Chem. Soc, 77, 4184 (1955). H. L. Herzog, C. C. Payne, M. A. Jernik, D. Gould, E. L. Shapiro, E. P. Oliveto, and E. B. Hershberg, J. Amer. Chem. Soc, 77, 4781 (1955). R. F. Hirschmann, R. Miller, R. E. Beyler, L. H. Sarrett, and M. Tischler, J. Amer. Chem. Soc, 77, 3166 (1955). J. Fried, K. Florey, E. F. Sabo, J. E. Herz, A. R. Restivo, A. Borman, and F. M. Singer, J. Amer. Chem. Soc, 77, 4181 (1955). J. H. Fried, G. E. Arth, and L. H. Sarett, J. Amer. Chem. Soc, 81, 1235 (1959). For an alternate synthesis, see G. B. Spero, J. L. Thompson, B. J. Magerlein, A. R. Hanze, H. C. Murray, 0. K. Sebek, and J. A. Hogg, J. Amer. Chem. Soc, 78, 6213 (1956). J. A. Hogg and G. B. Spero, U. S. Patent 2,841,600 (1958). E. P. Olivetto, P. Rausser, A. L. Nussbaum, W. Gerbert, E. B. Hershberg, S* Tolksdorf, M. Eisler, P. L. Perlman, and M. M. Pechet, J. Amer. Chem. Soc, 80, 4428 (1958). D. Taub, R. D. Hoffsomer, H. L. Slates, and N. L. Wendler, J. Amer. Chem. Soc, 80, 4435 (1958). H. J. Mannhardt, F. V. vWerder, K. H. Bork, H. Metz, and

References

211

K. Bruckner, Tetrahedron Lett., 16, 21 (1960). 77. E. P. Olivetto, P. Rausser, H. L. Herzog, E. B. Hershberg, S. Tolksdorf, M. Eisler, P. L. Perlman, and M. M. Pechet, J. Amer. Chem. Soc, 80, 6687 (1958). 78. G. E. Arth, D. B. R. Johnston, J. Fried, W. Spooner, D. Hoff, and L. H. Sarett, J. Amer. Chem. Soc, 80, 3160 (1958). 79. G. E. Arth, D. B. R. Johnston, D. R. Hoff, L. H. Sarrett, R. H. Silber, H. C. Stoerk, and C. A. Winter, J. Amer. Chem. Soc, 80, 3161 (1958). 80. For an alternate route, see E. P. Olivetto, P. Rausser, A. L. Nussbaum, W. Gerbert, E. B. Hershberg, S. Tolksdorf, M. Eisler, P. L. Perlman, and M. M. Pechet, J. Amer. Chem. Soc, 80, 4430 (1958). 81. J. A. Edwards, H. J. Ringold, and C. Djerassi, J. Amer. Chem. Soc, 82, 2318 (1960). 82. J. A. Edwards, H. J. Ring^id, and C. Djerassi, J. Amer. Chem. Soc, 81, 3156 (1959). 83. W. S. Allen and S. Bernstein, J. Amer. Chem. Soc, 77, 1028 (1955). 84. S. Bernstein, R. H. Lenhard, W. S. Allen, M. Heller, R. Littel, S. M. Stollar, L. I. Feldman, and R. H. Blank, J. Amer. Chem. Soc, 81, 1689 (1959). 85. P. L. Julian, E. W. Meyer, W. J. Karpel, and I. R. Waller, J. Amer. Chem. Soc, 72, 5145 (1956). 86. J. S. Mills, A. Bowers, C. Casas-Campillo, C. Djerassi, and H. J. Ringold, J. Amer. Chem. Soc, 81, 1264 (1959). 87. J. S. Mills, A. Bowers, C. Djerassi, and H. J. Ringold, J. Amer. Chem. Soc, 82, 3399 (1960). 88. C. H. Robinson, L. Finckenor, E. P. Olivetto, and D. Gould, J. Amer. Chem. Soc, 81, 2191 (1959). 89. F. H. Lincoln, Jr., W. P. Schneider, and G. B. Spero, U. S. Patent 2,867,638 (1959). 90. A. Domenico, H. Gibbian, U. Kerb, K. Kieslich, M. Kramer, F. Newman, and G. Raspe, Arzneimittel Forsch., 15, 46 (1965). 91. W. S. Johnson, J. C. Collins, R. Pappo, and M. B. Rubin, J. Amer. Chem. Soc, 80, 2585 (1958). 92. D. H. R. Barton and J. M. Beaton, J. Amer. Chem. Soc, 83, 4083 (1961). 93. J. A. Cella and R. C. Tweit, J. Org. Chem., 24, 1109 (1959). 94. For a very recent method for introduction of this functionality by chemical methods, see R. Breslow, J. Amer. Chem. Soc, 96, 6792 (1974).

CHAPTER 11

Tetracyclines

The tetracyclines are valuable orally active broad-spectrum antibiotics prepared by isolation from the fermentation liquors of various strains of Streptomyces or by chemical transformation of fermentation-derived substances. The basic ring system and numbering pattern is as follows:

The first three of these agents to be discovered, tetracycline (I),1 chlortetracycline (2),2 and oxytetracycline (3),3 are subject to two major modes of degradation under conditions occurring during their isolation, purification, formulation, and administration. These are dehydration and epimerization. Each of these reactions leads to inactivation of the antibiotic; thus, considerable effort has been expended in attempts to prevent or minimize these reactions. The dehydration reaction leads by an E 2 process to 8 and is promoted by the tertiary, benzylic nature of the OH group at C 6 and its antiperiplanar trans relationship to the H atom at C 5 a . Furthermore, one of the cannonical forms of the enolizable 3dicarbonyl system present at C 1 X and C 1 2 has a double bond in the C ring. Thus, dehydration leads to aromatization of the C ring, and this factor must provide some of the driving force for the reaction. Work on mutant cultures provided the first practical, although partial, solution to the dehydration phenomenon. A mutant strain whose parent produced chlortetracycline (2) was 212

Tetracyclines

RQH

213

CH3,

OH

JH ^s *1 H L S r ^ OH OH 0 0

1

CONH

C0NH2 OH

OH

0

4, R F C I , Rf=OH

1, R=R'=H R=C1, R '=H 1 3r R=H, R =OH

5, R=Rf=H 6, R=N0 2 , Rf=H 7, R=NMe2, RT=H

found to produce a new antibiotic, 6-demethyIchlortetracycline (4) .** This strain was ultimately shown to lack a necessary enzyme for the incorporation of methionine-derived carbon into the antibiotic at the C 6 position. Having a secondary rather than a tertiary OH at C 6 , this agent is much more stable to dehydration in aqueous acidic solutions than its progenitor. It also has some pharmacodynamic advantages because of its enhanced lipophilicity and was soon introduced into clinical use. This led to a considerable exploration of the chemistry of the tetracyclines with the object of improving still further their pharmacodynamic and therapeutic properties. CH

CONH2

CONH OH

OH

0

0

A practical process had earlier been developed for the transformation of chlortetracycline (2) into tetracycline (1) by catalytic hydrogenolysis of the aromatic chloro group.5 Application of the reaction under suitable conditions to demethyIchlortetra-

214

Tetracyclines

cycline (4) was found to hydrogenolyze both the chlorine and the benzylic hydroxyl group.6 The product, 6-demethyl-6-deoxytetra~ cycline (5), is the simplest reported tetracycline with essentially intact antibiotic properties. Its structure defines the minimum known structural requirements for bioactivity in this series. Although the agent has not seen clinical use in the United States, it is an exceptionally valuable chemical intermediate. In contrast to antibiotics 1-4, it is sufficiently acid stable to be recovered unchanged from solutions in concentrated sulfuric acid. This allows for a wider range of electrophilic reactions than was previously possible. The most successful application of such reactions led to the preparation of 7-dimethylamino-6-demethyl-6-deoxytetracycline (minocycline) (7).

ci

OH

NMe

C0NH2

6, R=N02, R'=H 11, R=H, R'=N02

Nitration of 5 by a mixture of KN03 and concentrated H 2 SO A produces a mixture of the 7- (6) and 9-nitro-6-demethyl~6-deoxytetracyclines (11). The former (6) is reductively methylated by catalytic hydrogenation in the presence of formaldehyde to give minocycline (7).7 This substance has broadened antibacterial activity compared to demethylchlortetracycline (4), especially against Gram-negative organisms resistant to the other tetracyclines by R-factor-mediated mechanisms. In addition, lower daily doses are required because of its relatively low excretion rate. Similar transformations have not as yet been successfully applied to the tetracyclines bearing a hydroxy group at C 5 , and no mutant culture has been reported that biosynthesizes a 6deoxy-5-oxytetracycline. However, other means have been found to avoid 5a,6-dehydration in this subfamily. Treatment of 3 with N-

Tetracyclines

215

chlorosuccinimide, or other sources of positive halogen, in anhydrous acidic media results in good yields of the lla-chloro derivative (12), in which enolization of the carbonyl group at C n is not possible, and part of the driving force for the aromatization reaction is removed. When dehydrating agents such as anhydrous HF are used, 12 dehydrates exocyclically to give 13. Careful reduction removes the blocking halo group while leaving the exocyclic double bond intact to give 6-methylene-5-oxytetracycline (14), an antibiotic in clinical use.8 Treatment of 14 with hydrogen and a catalyst converts it to a mixture of epimeric 6-deoxy-5-oxytetracyclines {15 and 16), each of which is active as an antibiotic. The more active isomer has the natural tetracycline configuration of the methyl group at C 6 and is in clinical use as a-6-deoxyoxytetracycline (IS).9 This highly lipophilic tetracycline is the first ffone-a-day" tetracycline (when used to treat mild infections). OH

NMe 2

CH 2 OH

NMe 2

CONH 2

CH 2

Oil

NMe2

OH

0

0

CONH 2 OH

Oil 'R'!

NMe i

C0NII2 OH

OH

0

15, R=H, R'=CH 3 16, R=CH 3 , R'=H

The second major mode of degradation of this class of antibiotics is epimerization. The dimethylamino function at C4 is axial and subject to a 1,3-diaxial nonbonded interaction with the Ci2a-0H group (which is also axial). Being a to the resonancestabilized 3-tricarbonyl system in ring A, the dimethylamino function can relieve this strain by epimerization. This reaction, which occurs most rapidly in aqueous solutions of pH 3-5, results in an equilibrium mixture consisting of nearly equal amounts of the two epimers. All clinically significant tetracyclines have this property to a greater or lesser extent. Unfortunately, the 4-epitetracyclines are essentially inactive as antibiotics and, in addition, 4-epianhydrotetracycline (9), formed by dehydration

216

Tetracyclines

of 4-epitetracycline (1O), or by the epimerization of anhydrotetracycline (8), has been shown to be toxic. Those tetracyclines which cannot dehydrate (such as 7 and 15) should be free from this kind of toxicity. No chemical technique has yet emerged that prevents epimerization at Ch while preserving bioactivity. This is clearly a worthwhile objective for further work. Since the tetracyclines are not soluble enough for convenient administration in parenteral solutions, derivatives have been sought that have enhanced water solubility. A variety of "prodrugs/' of which the pyrrolidinomethyl analog of tetracycline (17) is representative, have been prepared by a Mannich-type reaction to fill this need.10 This derivative is much more water soluble than the other tetracyclines and is used clinically. It is quite unstable at physiologic pH values and reverts rapidly to tetracycline after administration. Amides are not usually nucleophillic enough to participate in a Mannich reaction; however, the A-ring (3-tricarbonyl system of tetracyclines is unusual in several respects. For example, this group has a pKa of about 3, making it as acidic as many carboxyllic acids. Thus, at the pH of the Mannich reaction, this part of the molecule supports a negative charge and can react with the intermediate methylene imine of pyrrolidine. Attachment of the new group to the nitrogen atom rather than to C 2 or to one of the oxygens allows the system to retain its resonance stabilization (rolitetracycline). NMe2

HO £H3 CH2O

»

D

REFERENCES J. H. Boothe, J. Morton, J. P. Petisi, G. R. Wilkinson, and J. H. Williams, J. Amer. Chem. Soc, 75, 4621 (1953); L. H. Conover, W. T. Moreland, A. R. English, C. R. Stephens, and F. J. Pilgrim, J. Amer. Chem. Soc, 75, 4622 (1953); P. P. Minieri, M. C. Firman, A. G. Mistretta, A. Abbey, C. E. Bricker, N. E. Rigler, and H. Sokol, Antibiot. Ann., 81 (1953-4).

Tetracyclines

2.

3.

4. 5. 6. 7.

8.

9.

10.

217

R. W. Broschard, A. C. Dornbush, S. Gordon, B. L. Hutchings, A. R. Kohler, G. Krupka, S. Kushner, D. V. Lefemine, and C. Pidacks, Science, 109, 199 (1949); B. M. Duggar, Ann. N. Y. Acad. Sci., 51, 111 (1948). A. C. Finlay, G. L. Hobby, S. Y. P'an, P. P. Regna, J. B. Routien, D.-B. Seeley, G. M. Shull, B. A. Sobin, I. A. Solomons, J. W. Vinson, and J. H. Kane, Science, 111, 85 (1950); P. P. Regna, T: A. Solomons, K. Murai, A. E. Timreck, K. J. Brunings, and W. A. Lazier, J. Amer. Chem. Soc., 73, 4211 (1951). J. R. D. McCormick, N. 0. Sjolander, U. Hirsch, E. R. Jensen, and A. P. Doerschuk, J. Amer. Chem. Soc, 79, 4561 (1957). L. H. Conover, W. T. Moreland, A. R. English, C. R. Stephens, and F. J. Pilgrim, J. Amer. Chem. Soc, 75, 4622 (1953). J. R. D. McCormick, E. R. Jensen, P. A. Miller, and A. P. Doerschuk, J. Amer. Chem. Soc, 82, 3381 (1960). M. J. Martel, Jr. and J. H. Boothe, J. Med. Chem., 10, 44 (1967); R. F. Church, R. E. Schaub, and M. J. Weiss, J. Org. Chem., 36, 723 (1971). R. K. Blackwood, J. J. Beereboom, H. H. Rennhard, M. Schach von Wittenau, and C. R. Stephens, J. Amer. Chem. Soc, 85, 3943 (1963). C. R. Stephens, J. J. Beereboom, H. H. Rennhard, P. N. Gordon, K. Murai, R. K. Blackwood, and M. Schach von Wittenau, J. Amer. Chem. Soc, 85, 2643 (1963). W. Seidel, A. Soder, and F. Linder, Munchen Med. Wochenschrift, 17, 661 (1958); W. J. Gottstein, W. F. Minor, and L. C. Cheney, J. Amer. Chem. Soc, 81, 1198 (1959).

CHAPTER 12

Acyclic Compounds

It has become almost an article of faith among both pharmacologists and medicinal chemists that drugs (and for that matter, hormones) owe their action to interaction with some receptors. Much evidence has accumulated to indicate that such receptors consist of specific sites on polypeptide molecules. As such, the receptor site is in all probability a highly organized location with specifically located complexation sites and stereochemistry. It would therefore follow that the best fit to such a receptor could be accomplished by a molecule with correspondingly high organization. Deliberate arrangement of the spacing of functionality is most simply accomplished efficiently by the use of some cyclic nucleus as the foundation for potential medicinal agents. Empirically at least, the vast majority of drugs used in clinical practice incorporate at least one ring. However, there are several exceptions to this rule. We have noted drugs that seem to owe their action to some specific functionality rather than to the carbon skeleton to which they are attached. Many of these agents have counterparts in the acyclic series. A very few agents occur only as acyclic molecules. Derivatives of 1,2 and 1,3 glycols have found extensive use as drugs to relieve mild anxiety. Many of these, in addition, have some activity as muscle-relaxing agents and are used for relief of muscle spasms. The prototype in this series, meprobamate (4), gained some renown in the folklore of the 1950s under the trade name of Miltown®. Reduction of malonic ester, 1, by means of lithium aluminum hydride affords the corresponding glycol (2). (An alternate route to this intermediate goes through formylation of aldehyde, 5, with formaldehyde.) Reaction of the glycol with phosgene affords the intermediate, 3; this gives meprobamate (4)1 on treatment with ammonia. A similar sequence using the malonic ester, 6, as starting material affords the tranquilizer, mebutamate (7) ,2 It has proven poslsible to prepare 218

Acyclic Compounds

219

derivatives bearing different substitution on the two hydroxyl groups in this series. Thus, reaction of the glycol, 2, with dimethyl carbonate affords the cyclic carbonate, 8, in an exchange reaction. Ring opening of this compound by means of isopropylamine proceeds regiospecifically to give the monocarbamate, 9. An exchange reaction of 9 at the remaining hydroxyl group with the carbamate of ethanol affords carisoprodol (10).3 0 II

CHOCX

CH3 CH2OH R CO2C2H5 1, R=CII2CH2CII3 6, R=CHCH2CH3 CH3 \ 0 II CH3L,C CH3CH2CH C112OCMI2 CH3 0

CII3CH2CH2 CH2OH

CH3CH2CH2

CH2OCX II 0

X=C1 X=NH2

cn3

CII2ON

X < CI13CH2CH2 CU2O/

CH 3

CH2OCNHCH

X CHC C H O 3H 2H 2 C 2H

CH3 CHO V CH3CH2CH2 H

>

CH3

CH3CH2CH2

0 II /• CH2OCNHCH

CH3

CH2OCNH2 0 10

Although the following derivatives of 1,2-glycols do in fact contain an aromatic ring, they are presented here because they are so closely related in structure and activity to their acyclic counterparts. Hydrolysis of the cyanohydrin (12) of p-chloroacetophenone with concentrated sulfuric acid affords the hydroxy amide (13). This amide is first hydrolyzed to the acid (14) and then esterified. Reaction of the ester (15) with methylmagnesium iodide gives phenaglycodol (16)^ a minor tranquilizer with some activity as an anticonvulsant agent for petit mal epileptic seizures . Reaction of the glycol (17) from hydroxylation of styrene with ethyl chloroformate affords the carbonate ester, 18. Treatment of this last with ammonia at elevated temperature gives the sedative, styramate (19).5 A similar sequence on the ethyl ana-

220

A c y c l i c Compounds

COCH,

11

13, R=NH2 14, R=0H 15, R=OC2H5

12

OH OH I / -OC-CH3 \ CH3 CH3 16

log, 20 (obtainable by metal hydride reduction of the homolog of 14), gives hydroxyphenamate (21).5

OH I CHCHoOH 17

CHCH2OCOC2Hc

CHCH2OCNH2 19

18 0 OCH2OCNH2 J CH 2 CH 3

20

21

Replacement of the carbamate function by an amide seems to be compatible with meprobamate-like activity in a compound formally derived from a 1,2-glycol. Oxidation of the commercially available aldehyde, 22, under controlled conditions affords the corresponding acid (23) . This is then converted to its amide (24) via the acid chloride. Epoxidation by means of perphthalic acid affords oxanamide (25).6 Acylureas (A) are among the oldest known sedative-hypnotic

Acyclic Compounds

221

/CR2CH3 CH3CH2CH2CH=C X

> CHO

QH CH3CH2CH2CH=C/ ^C. II

0

22 23, R=OH 24, R=NH2

i /°\ ,CH 2 CH 3 CH3CH2CH2CH-C

0 25 drugs. Similar in action to the better-known barbiturates (B), these agents may owe their action to the fact that they incorporate in open form a good portion of the functionality of the barbituric acids:

Rl

ft •

H A

B

Bromination of the substituted butyric acid, 26, by the HellVolhardt-Zelinsky procedure affords the a-halo acid bromide (27). Reaction of this with urea affords directly bromisovalum (28). An analogous sequence on acid, 29 (obtained by decarboxylative hydrolysis of the malonic ester), leads to carbromal (30). Dehydrohalogenation of 30 by means of silver oxide affords the corresponding olefin, ectylurea (31) , 7 itself a sedative-hypnotic. The activity of compounds incorporating the biguanide function as oral antidiabetic agents has been alluded to previously. A very simple alkyl side chain in fact can serve as the carbon moiety of such drugs. Buformin (32),8 obtained by reaction of

222

A c y c l i c Compounds

CH3CHCH2CO2H CH3

Br I CH 3 CHCHCOBr I CH 3

Br 0 1 II CH3CH-CHC]NIHCNH2 I 11 CH3 0

27

28

26

CHCOoH CH3CH2/ 29

Br 0 CH3CH2V| \\ CCNHCNH2 CH3CH/ I

CH 3 CH

30

butylamine and dicyanamide, has found t r e a t m e n t of a d u l t - o n s e t diabetes.

CH3CH2CH2CH2NH2

C-CNHCNH 2

NH II NCNC-NH 2

31

use

as

an

agent

for

the

MI NH CH3CH2CH2CH2NIiCNllCNH2

32

Control of tuberculosis, long one of the scourges of mankind, began with the introduction of effective antibacterial agents. Thus, this disease was treated initially with some small measure of success with various sulfa drugs; the advent of the antibiotic, streptomycin, provided a major advance in antitubercular therapy, as did the subsequent discovery of isoniazid and its analogs. One of the most recent drugs effective against tuberculosis, ethambutol (35), stands out not only for its lack of structural features common to other antituberculars but also by the fact that it is one of the few acyclic medicinal agents with no cyclic counterpart. (By a stretch of the imagination the amino alcohols in this agent may be said to bear some relation to the corresponding functions in the aminoglycoside antibiotics.) Reduction of the ethyl ester of racemic alanine homolog, 33, by means of lithium aluminum hydride affords the amino alcohol (34). The (+) isomer is then separated by means of optical resolution. This resolved base is used to effect a double alkylation reaction on

Acyclic Compounds

223

ethylene dichloride. It is of note that the product, ethambutol (36),9 contains both chiral centers in the (+) form. The meso isomer (+,-) is some 16 times less active, while the levo isomer (-,-) is all but inactive. C0 2 C 2 H 5 CH3CH2CHNH2

CH20H —>

CH20H

CH3CH2<*S«*NH2

>

(CH3CH2 *C *NHCH2--) 2

H

H

33 34

35

Disulfiram, an agent whose structure is more inorganic than organic, constitutes yet another medicinal agent with no cyclic counterpart. This compound, which was actually first patented as an accelerating agent for the vulanization of rubber, has at various times been used to combat chronic alcoholism. The mode of action depends on the simple fact that ingestion of alcohol causes violent sickness in patients treated chronically with disulfiram. Treatment of diethylamine with carbon disulfide and sodium hydroxide affords the salt, 36. Oxidation of this with sodium hypochlorite gives the corresponding disulfide, disulfiram (37).10 q C

2

H

5

\

,| NOSNa

C

2

H

/ 5

36

C2H5 \ >

C

Q

||

|)

/ C

2

H

5

^C

2

H

5

N-C-S-S-CN C2^

/ 5

37

Organometallie compounds occupy a venerable place in medicinal chemistry. Paul Ehrlich devoted the better part of his efforts to the search for "the magic bullet" in the late nineteenth century. That is, he was seeking an agent that would destroy microbes without harming the host. He scored success in this quest by the discovery of the antisyphilitic agent, salvarsan (38). As the field of medicinal chemistry advanced, and more specific and potent drugs became available, organometallic agents have tended to diminish in importance. Salvarsan, for example, has long since been supplanted by antibiotics. In the area of diuretics, too, the initial drugs were organometallics, in this case organomercurial compounds. Most of these have long since been replaced by sulfonamides and thiazides. As a general rule, however, the newer diuretic agents tend to cause excretion of not

224

Acyclic Compounds

only water and sodium ion, which is desirable, but other ions such as potassium and sometimes urea. Loss of these sometimes causes metabolic disturbances. The fact that the mercurial diuretics lead to an almost ideal diuresis in which ions are excreted in concentration mirroring their presence in serum has led to small-scale continued use of these drugs. Condensation of allyl isocyanate with succinimide affords the cyclic diacylurea 39. Acid hydrolysis leads to ring opening of the succinimide (40). Oxymercuration of the terminal olefin bond with mercuric acetate in methanol solution affords the diuretic meralluride (41).ll 0 O=C=NCH2CH=CII2

—>

|

0 0

i. ^-CNHCH2CH=CH2

-»

i HO2CC112C1I2C

4O

0 0 0CH3 li II ) H02CCH2CH2CNHCNIICH2CHCH2Hg0H 58

The cyclized analog of meralluride is prepared by a similar synthesis. Thus, condensation of camphoric acid (42) (obtained by oxidation of camphor) with ammonia gives the bicyclic succinimide (44). Reaction with allyl isocyanate followed by ring opening and then reaction with mercuric acetate affords the mercury derivative (45) as the acetate rather than the hydroxide as above. Reaction with sodium chloride converts that acetate to the halide (46). Displacement on mercury with the disodium salt of thioglycollic acid affords the diuretic mercaptomerine (47).12

CO2H /TAco2H

42

43

CNHCNHCH2CH=CH2 o o 44

Acyclic Compounds

CO2H

CO2H

OCH3 CNHCNHCH2CHCH2HgSCH2CO2Na

II 0

225

II 0 47

OCH3 I ONHCNHCH2CHCH2

1! 0

I! 0

I HgX

45, X=OCOCH3 46, X=C1

REFERENCES 1.

B. J. Ludwig and E. C. Piech, J. Amer. Chem. Soc, 73, 5779 (1951). 2. F. M. Berger and B. J. Ludwig, U. S. Patent 2,878,280 (1959). 3. F. M. Berger and B. J. Ludwig, U. S. Patent 2,937,119 (I960). 4. J. Mills, U. S. Patent 3,812,363 (1957). 5. R. H. Sifferd and L. D. Braitberg, U. S. Patent 3,066,164 (1962). 6. K. W. Wheeler, J. G. VanCampen, and R. S. Shelton, J. Org. Chem., 25, 1021 (1960). 7. D. E. Fancher, U. S. Patent 2,931,832 (1960). 8. S. L Shapiro, V. A. Parino, and L. Freedman, J. Amer. Chem. Soc. 81, 3728 (1959). 9. R. G Wilkinson, M. B. Cantrall, and R. G. Shepherd, J. Med. Chem 5, 835 (1962). 10. G. C Bailey, U. S. Patent 1,796,977 (1931). 11. D. E Pearson and M. V. Sigal, J. Org. Chem., 15, 1055 (1955). Wendt and W. F. Bruce, J. Org. Chem., 23, 1448 (1958). 12. G. W

CHAPTER 13

Five-Membered Heterocycles

1.

DERIVATIVES OF PYRROLIDINE

Derivatives of pyrrolidine containing the ring in its fully reduced form are discussed in earlier sections of this book. To recapitulate, compounds containing this moiety seldom show activities that differ greatly in kind from the corresponding openchain tertiary amine. Oxidation of the ring to a pyrrolidone or succinimide endows the derivatives with CNS activity. Double alkylation on ethylamine by l,4-dibromo-2-hydroxybutane affords the hydroxypyrrolidine, 1. Treatment with thionyl chloride gives the corresponding chloro compound (2). Alkylation of the carbanion of diphenylacetonitrile with 2 gives the aminonitrile, 3. Acid hydrolysis of the nitrile yields the acid (4). This last undergoes rearrangement to the pyrrolidone (7) on treatment with thionyl chloride. This reaction may be rationalized by assuming that the acid chloride (5) first forms in the normal fashion; internal acylation would then lead to the strained bicyclie"quaternary salt, 6. Attack by the chloride ion on the ethylene bridge carbon adjacent to the positive nitrogen affords the observed product (7). Displacement of the halogen with morpholine affords doxapram (8),1 an agent used as a respiratory stimulant, particularly in patients with postanesthetic respiratory depression. Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9, Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllic acid. Lactamization with methylamine gives phensuximide (12).2 226

Derivatives of Pyrrolidine

227

CN N-C2H5 1, X-OH 2, X=C1

4, R=OH 5, R=C1

C6H5 Cl N-C2H5

CH=C

N

CO2C2H5

l| C C N -/H X

10

CO2C2H5

CH-CH2 I I HO2C CO2H 11

I CH3 COC 2H 25 13

14

12

228

Five-Membered Heterocycles

Use of acetophenone rather than benzaldehyde in the Knoevnagel condensation reaction affords the unsaturated ester, 13. Elaboration of this to the succinimide by a scheme analogous to that above leads to the anticonvulsant agent methsuximide (14).2 Although actually a compound known for quite some time, the aliphatic analog, ethosuximide, was in fact introduced after the above agents. This compound can be attained by first subjecting the condensation product, 15, to the succinic acid synthesis used above. Cyclization by means of ammonia gives ethosuximide (17).3

CH3 C 2 H 5 N ^ f / CN C =

% H 3

CH3 ~ *

C2H5/C-CH2 CO2H CO2H

CzH

—>

X H

15 16

17

2 . NITROFURANS Derivatives of 2-nitrofurans are known to possess both bacteriostatic and bacteriocidal properties. That is, the agents will halt and to some degree reverse multiplication of bacteria responsible for infections. In contrast to the antibiotic agents, derivatives of nitrofuran are used largely for topical infections. It should be noted, however, that the word topical is used here in the embriologic sense. Suitable derivatives have found use for treatment of both urinary and digestive tract infections. Considerable ingenuity has been used to design derivatives of nitrofuran so that they will reach some specific site such as the urinary tract following oral administration. The first drugs in this class to be introduced into clinical practice are simple derivatives of 5-nitrofurfural (18). Thus, the oxime is known as nitrofuroxime (19), while the semicarbazone is called nitrofurazone (20). In order to maintain better control over the distribution and metabolism of these antibacterial agents, increasingly complex side chains and rings have been grafted onto the hydrazone. Thus, in one such example, hydroxyethylhydrazine (21) is first converted to the carbamate (22). Condensation with 18 yields nidroxyzone (23).4 Cyclization of 21 by means of diethyl carbonate gives the corresponding aminooxazolidone (24). This compound is then condensed with benzaldehyde to Shiff base (25). An exchange reac-

Nitrofurans

229

r\

x

19

18

C\

02W

\O

X

CH=NNHCNH2

20

CONH2 HOCH2CH2NHNH2 ~~> HOCH2CH2NNH2 21

If \ —>

0

/CONH2

2 N ^ ° ^CH=NN^

22

2J

tion of this last with the oxime, 19, affords furazolidone (26).'"

jr N-<x 0

24

25

,>-CH=N-N \

0 /

26

In a scheme intended to produce a more highly substituted oxazolidone, epichlorohydrin is condensed with morpholine in the presence of strong base to give the aminoepoxide, 27.6 Ring opening of the oxirane by means of hydrazine gives the hydroxyhydrazine (28). Ring closure with diethyl carbonate leads to the substituted oxazolidone (29). Condensation with 18 affords furaltadone (30).7 In much the same vein, treatment of the hydroxyhydrazine, 31 (obtained by ring opening of the thiomethyl epoxide with hydrazine), with diethyl carbonate gives the oxazolidone, 32. Condensation with the ubiquitous 18 leads to nitrofuratel (33),8

230

Five-Membered Heterocycles

0

A HoN-N

CH 2 NHNH 2 CHOH CH 2 -CHCH 2 N

0

CH 2 N

0

0

CH 2 N

0

27 29

28

0

A CH=NN

0

ScH9N

0

30

0

A

CH 2 NHNH 2 CH-OH I CH 2SCH 3

H 2 NN

0 C112SCH3 32

31

02N

^ (T

CII-NN

0 CH o SCH q

33

Reaction of hyrlro£en cyanide with the a~hydrazinoester, 34, leads to the carbamate (35). Cyclization by means of strong acid affords the corresponding aminohydantoin (36).9 Condensation with 15 affords nitrofurantoin (37).10 Treatment of the heterocycle, 38 (obtained from ethylenediamine and carbon disulfide), with nitrous acid affords the Nnitroso compound, 39. Reduction with zinc leads to the corre-

Nitrofurans

231

H2NN H 2 NNCH 2 CO 2 C 2 H 5

H

>

NCH 2 CO 2 C 2 H 5

>

B

^f

34

0 J

y

HN N-

0

V 35

0 36

i // —

V, CH=N-N > 0

11

37

sponding amine (40). This affords, on condensation with 18, the antibacterial agent thiofuradene (41).]

V

NH

S

39, R=N0 40, R=NH2

It will of course have been noted that all the above nitrofurans that contain a second heterocyclic ring are linked to that moiety by what is essentially a hydrazone function. Attachment of the second heterocycle by means of a carbon-carbon bond is apparently consistent with biologic activity. Treatment of the thiosemicarbazone of acetaldehyde (42) with acetyl chloride leads that compound to cyclize to the thiadiazole (perhaps by way of the enol form, 43). Condensation of the active methyl group on that heterocycle (44) with the aldehyde in 18 by means of strong base gives the olefin, 44. Removal of the acetyl group by saponification gives nifurprazine (46),13

232

Five-Membered Heterocycles

S H CH3CH=NNHCNH2

NN // W CH3CH /C

N~~N k

s'

42 43

44

NHR 45, R=COCH3 46, R=H

3.

OXAZOLIDINEDIONES AND AN ISOXAZOLE

As we have seen previously, succinimides containing a quaternary carbon form the basis for a series of anticonvulsant drugs. In the course of research in this series, it was found that the inclusion of additional hetero atoms in the ring was quite compatible with anticonvulsive activity. We consider here the oxazolidinediones; a discussion of the hydantoins is found later in this section. One of the standard methods for construction of the basic heterocyclic ring was elaborated not long after the turn of the century. Thus, condensation of ethyl lactate with guanidine leads to the imine of the desired ring system (47), possibly by a reaction scheme such as that outlined below. Hydrolysis affords the oxazolidinedione (48),1U Methylation in the presence of base gives 49. Treatment of 49 with a strong base such as sodium ethoxide serves to remove the last proton on the heterocyclic ring. Alkylation of the resulting carbanion with allyl bromide affords aloxidone (5O)15; methyl sulfate on the carbanion gives trimethadione (51),16 while ethyl sulfate yields paramethadione (52).17 Hydrazides of isonicotinic acid have been used as antidepressant agents by virtue of their monoamine oxidase-inhibiting activity; the pyridine ring has been shown to be replaceable by an

Oxazolidinediones and an Isoxazole

/OH CH3CH N CO2CH2

H2NX

233

0-

C=NH

CH 3 -CH

C=NH

CH

i

NH

3

V

47

i N-CH* 48

CH2=CHCH2

CHs \_rf_( 52

51

50

isoxazole nucleus. The properly functionalized ring system (54) is obtained by condensation of the diketone ester, 53 (itself a product of condensation of acetone and diethyl oxalate in the presence of base) with hydroxylamine. This ester is then converted to the hydrazide (55) via the acid and acid chloride. Condensation with benzaldehyde affords the corresponding Shiff base (56). Catalytic reduction of that intermediate affords the MAO inhibitor isocarboxazine (57),18

CH 3C-CH2 0

CH3.

CH OC02C2H5 CO2C2H5

0 53

54

55

234

Five-Membered Heterocycles

CH

57

4.

56

PYRAZOLONONES AND PYRAZOLODIONES

One of the first synthetic organic compounds to find use as an important drug was, in fact, a heterocycle. First prepared in 1887, antipyrine, as its name implies, was first used as an agent to reduce fever. One may conjecture that its analgesic and antiinf lammatory properties were uncovered in the course of subsequent clinical application. The pharmacologic spectrum of both classes of heterocyclic compounds is very similar to that of aspirin and some other nonsteroidal antiinflammatory agents. Some of the later agents do show better activity against arthritis than does aspirin, although it should be added that side effects still present a problem in these structural classes. Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60); reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62).19 Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63).20 Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64; displacement of the halogen with dimethylamine leads to aminopropylon (65).21 Antipyretics that carry an alkyl substituent on the remaining carbon atom rather than nitrogen are accessible by condensation of phenylhydrazine with substituted acetoacetates. Thus, reaction of the acetoacetate, 66, with phenylhydrazine followed by N-methylation leads to propylphenazone (67).22 An analogous reaction on the (3-ketoester, 68, affords mofebutazone (69).23 Substitution of a second benzene ring onto the nitrogen atoms of the pyrazoles and incorporation of a second carbonyl group leads to a small series of drugs that have proven quite

Pyrazolonones and Pyrazolodiones

235

0 II C2H5O2CCH2CCH3

CH3

CH3 N-CH3

M MMo

59

58 CH, CHM

H2N

CH3

CH3

ON

CH 3

CH, N-CH 3

62

£T

0 II CH 3

61 0 , II i CH3-CHCMv v CH 3

60 CH3CH-CMv

^CH3

Cl

N-CH3

CCCH3

N

-CH^

65

64

63

^

CH3 CH 3 — CH

CH 3

0 II C2H5O2CCHCCH3

CH3

R

66,

NH

R=CH X

67 68,

CH

3

R=(CH2)3CH3

69

236

Five-Membered Heterocycles

effective in the treatment of the pain associated with rheumatoid arthritis. The side effects of these agents, particularly their propensity to cause gastric irritation, has limited their use to some extent. The prototype for this class, phenylbutazone (7O)9Zi* is obtained in straightforward manner by condensation of diethyl n-butylmalonate with hydrazobenzene in the presence of base; in effect, this represents the formation of the heterocyclic system by simple lactamization.

CO 2

CH3 (CH2 )3CH \J\J 2 *~> o

c

HN > HN

CH3 (CH2

Drugs are seldom excreted in the same form as they are administered. Since such compounds are essentially chemicals foreign to the body, they are processed chemically by the body's detoxification system so as to render them more easily excretable. One of the more common chemical changes observed on aromatic rings consists in hydroxylation to a phenol. Since metabolism is by no means synonymous with inactivation, it sometimes happens that metabolism affords a derivative more active than the drug that was in fact administered. (It might be added that cases have actually been recorded in which the administered agent is intrinsically inactive before some metabolically induced chemical reaction.) Careful study of the metabolic fate of phenylbutazone revealed that in this case there was an agent produced that was more active than the original drug. This agent is now available as a drug in its own right. Condensation of the protected aminophenol, 71, with nitrobenzene affords the corresponding azo compound (72); reduction gives the hydrazobenzene (73). Condensation of this with diethyl butylmalonate gives the heterocycle (74). Removal of the benzyl group by hydrogenolysis gives oxyphenbutazone (75),25

H2N-

-OCH2C6H5

-OCH2C6H5 71

72

73

237

Pyrazolonones and Pyrazolodiones

74, R=CH2C6H5 75, R=H Incorporation of a carbonyl group into the alkyl side chain also proved compatible with biologic activity. The key intermediate (76) is obtainable by Michael addition of the anion from diethyl malonate to methylvinyl ketone followed by ketalization with ethylene glycol. Condensation of 76 with hydrazobenzene leads to the pyrazolodione; hydrolysis of the ketal group affords ketasone (78).26

0 0 \ / C H 3 C •* C H 2 C H 2

2

CO 2 C 2 H 5

76

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-

Five-Membered Heterocycles

238

alent of hydrogen peroxide affords sulfinpyrazone (82) .''

OCO2C2H5 -SCH2CH2Cl 79

5.

SCH 2CH2 81

IMIDAZOLES

The use of nitrofurans and their derivatives as antibacterial agents has been touched upon above. Nitro derivatives of another relatively simple five-membered heterocycle (imidazole) have an important place in the clinic as arntitrichomonal agents. While infections due to trichomonas, a protozoan, are seldom life threatening, they can cause serious; physical discomfort. Agents to combat such infections are therefore in some demand. One of the simpler agents, azomycin (87), interestingly, was first isolated from the culture broth from ai Streptomyces strain. Structure determination established this compound to be one of the rare, naturally occurring nitro compounds. Total synthesis of this agent begins with the condensation of cyanamide with the aminoacetal, 83. Treatment of the intermediate (84) with acid unmasks the aldehyde group; condensation of that function with the primary amino groups affords 2-aminoimidazole (85),28 Diazotization of the amino group in 85 followed by displacement of the diazonium salt (86) by means of sodium nitrite in the presence of

copper affords azomycin

(87) ,29

Synthetic work in the imidazole series is complicated by the ready tautomeric equilibrium that can be set up among the double bond isomers (A, B). Thus, even if a reaction designed to afford the 5 isomer (A) is accomplished regiospecifically, tautomerization of the product affords either the 4 isomer (B) or a mixture of the two. (This tautomerism is, of course, no problem in azomycin because of the symmetry of that molecule.) Thus, nitration of 2-methylimidazole (88) affords a mixture

Imidazoles

239

0CH3

/OCH3

CH-OCH3

C

CH2NH2

N

m

CH2

C^ H

83 84

85

NOo H 57

of the 4- and 5-nitro isomers (89,90). It is possible, however, to take advantage of the above mobile equilibrium in such a way as to lead the mixture to predominantly a single alkylation product (a process reminiscent of the C versus 0 alkylation problem in carbocyclic chemistry). It has been found empirically that

240

Five-Membered Heterocycles

alkylation of the mixture (89,90) in nonpolar solvents favors formation of the product from the 5-nitro isomer. Conversely, alkylation of the preformed anion in solvents such as DMF favor the 4-nitro product. Alkylation of the 5(4)-nitro compound with methyl sulfate in nonpolar solvents affords dimetridazole (91),30 an antitrichomonal agent used in veterinary practice. Alkylation with chlorohydrin leads to metronidazole (92),31 a drug that has found widespread use in the treatment of vaginal trichomoniasis. Finally, alkylation by means of N-(2-chloroethyl)morpholine affords nitrimidazine (93) .

88

y

89

90

I 2

3

N

JL utl

2

3

CH2CH2OH 3

91

92

O

2

N N C H 3 I CH 2 CH 2 N 93

Hyperthyroidism, that is, the overproduction of thyroid hormones, is usually treated by surgical removal of the thyroid gland. Before such a procedure is undertaken, the hyperthyroidism is usually first brought under control by treatment with socalled antithyroid agents. Condensation of the aminoacetal, 83, with methylisocyanate affords the substituted thiourea, 94. Treatment with acid leads to cyclization of the masked aldehyde with the amino group to afford the antithyroid agent methimazole (95). An alternate route consists in reaction of the methylated acetal (96) with thiocyanic acid.32 Reaction of the product with ethyl chloroformate leads to the S-acylated product (97). This undergoes S to N migration with concomitant tautomerization in the presence of a slight excess of ethyl chloroformate. There is thus obtained carbimazole (98).33 The presence of an enolizable thioamide linkage in all other known antithyroid agents led to the speculation that 98 may have to undergo metabolic deacylation in order

Imidazoles

241

to express its activity. OCH3 l CH-OCH3

t CH-0CH3 I CH2NHCH3

/' V v \ N /* S 1 CO 2 C 2 H 5

96 98

6.

IMIDAZOLINRS

The biologic effects of the imidazolines are reminiscent of those of the biogenic amines such as epinephrine and norepinephrine. Although these heterocyclic agents bear almost no structural similarity to the endogenous substances, they show marked effects on the vessels of the circulatory system. The exact effect is highly sensitive to the structure of the side chain. Several of these agents are effective as local vasoconstrictors; these are used extensively as nasal decongestants. Those agents which act as adrenergic blocking agents have been used experimentally in the treatment of hypertension. One such compound, clonidine, is an effective hypertensive agent in man. Condensation of the iminoether (99), obtained by methanolysis of phenylacetonitrile, with ethylendiamine affords tolazoline (loo),33 This drug shows the behavior of an adrenergic blocking agent and has been used in the treatment of peripheral vascular disease due to its vasodilating effect. An analogous reaction on iminoether, 101, yields naphazoline (102).33 This drug paradoxically acts as a topical vasoconstricting agent; it is therefore used extensively as a nasal decongestant. Preparation of the analog of 102 containing a saturated ring

Five-Membered Heterocycles

242

NH 99

100

101

102

starts with conversion of the carboxylic acid, 103, to the corresponding amide (104); this is then dehydrated to the nitrile (105). Reaction of the nitrile with ethylenediamine affords tetrahydrozoline (106),3A a drug used as a nasal decongestant.

COR

103, R=OH 104, R=NH2

105

106

Inclusion of additional alkyl groups on the aromatic ring leads to decongestants with longer duration of action. Thus, reaction of the arylacetonitrile, 109, obtainable from hydrocarbon, 107, by chloromethylation (108), followed by displacement of the halogen by means of cyanide ion with ethylenediamine, leads to xylometazoline (111).35 The analogous reaction of the oxygenated derivative, 110, affords oxymetazoline (112).36 Employment of the imidazoline fragment as one of the basic nitrogen atoms in the ethylenediamine antihistamine structure leads to a molecule in which the cardiovascular effects have been supplanted by antihistaminic activity. Alkylation of benzylaniline (113) with the halogenated imidazoline, 114, affords antazoline (115) y37 a drug used as an antihistamine. Shortening one of the side chains on the aromatic nitrogen and inclusion of a phenol function markedly changes the biologic activity; this product, phentolamine (118), shows a-adrenergic blocking action superior

Imidazolines

243

(CH3)3C-C

(CH3)3C

107

>CH 2 X

108, X=C1;Y=H 109, X=CN;Y=H 110, X=CN;Y=OH

(CH3)3C

111, Y=H 112, Y=OH to tolazoline. The agent can be prepared by alkylation of the aminophenol, 116, by the halide, 114. An interesting alternate synthesis consists in first using 116 as the amine component in the condensation with hydrogen cyanide and formaldehyde to give the a-aminonitrile derivative of formaldehyde (117). Condensation of 117 with ethylene diamine gives phentolamine (118).38 Replacement of the methylene group at the 2 position of the imidazoline ring by nitrogen results in compounds whose main action is that of a hypotensive agent. Although these act to some degree as suppressors of the sympathetic nervous system, the mechanism by which they reduce high blood pressure is thought to lie elsewhere. It is of note that the additional nitrogen in effect builds a guanidine-like function into the molecule. Reaction of ethylenediamine with carbon disulfide gives the heterocycle, 119; methylation proceeds on the nucleophilic sulfur to afford the imidazoline, 120. Condensation of that intermediate with the aromatic amine, 121 (obtained by reduction of one of the two nitration products of tetralin) leads to apparent displacement of methylmercaptan (122) . There is evidence to indicate that reactions of this type in fact involve an addition-elimination sequence. There is thus obtained tramazollne (122)." An analogous sequence on 2,6-dichloroaniline (123) affords clonidine (124) .

244

Five-Membered Heterocycles

NH I CH2

NH-CH2 CH2

ClCR2^!

114

•0

125

213

CH,

CH 3s

NH

+

NCH«

224

OH

OH

118 116 \

CH3 NCH2~CN

OH 227

CH 3 S

229a

229Jb

220

Imidazolines

245

122 121

120

124

7.

HYDANTOINS

The discovery of the hypnotic activity of the barbiturates led to an intensive examination of related heterocyclic systems in the search for agents with a better pharmacologic ratio. Although the hydantoin ring is smaller by one atom than that of the barbiturates, these two heterocycles do share the cyclic acylurea functionality. As shown previously, this functional array leads to hypnotic activity even when present in acyclic form. Although barbiturates had found some use in resolving the convulsions resulting from grand mal epileptic seizures, their hypnotic activity severely restricted their general use. The hydantoins, interestingly, show increased anticonvulsant activity at the expense of the hypnotic effect. One of the earliest preparations of this ring system starts with displacement of the hydroxyl of benzaldehyde cyanohydrin (125) by urea. Treatment of the product (126) with hydrochloric acid leads to addition of the remaining urea nitrogen to the nitrile. There is thus obtained, after hydrolysis of the imine (127), the hydantoin (128). Alkylation by means of ethyl iodide affords ethotoin (129).40 A more direct route to this ring system consists in the treatment of a ketone with an aqueous solution of potassium cya-

Five-Membered Heterocycles

246

125 126

127, X=NH 128, X=0

129 nide and ammonium carbonate to afford the hydantoin directly. Thus, acetophenone affords the hydantoin, 132. The reaction can be rationalized by assuming that the first step consists in formation of the a-aminonitrile (132); addition of ammonia to the nitrile will then give the amino-amidine, 131, The remaining carbonyl group is then provided by either the carbonate ion or the carbon dioxide, with which it is in equilibrium. Methylation of the product affords mephenytoin (133). In a similar fashion, benzophenone leads to diphenylhydantoin (134) , A1 while |3-tetralone gives the spirocyclic hydantoin tetratoin (135),h2

130 132, R=H 133, R=CH 3

Imidazolines

247

135

8.

MISCELLANEOUS FIVE-MEMBERED HETEROCYCLES

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bromination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138); this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140).*3

N NHCOCHo

Br

136

139

138

C9N

s

^ NHCOCH3

140

248

Five-Membered Heterocycles

A thiazole derivative that incorporates a fragment of the amphetamine molecule shows some CNS stimulant activity; more specifically, the compound antagonizes the depression caused by overdoses of barbiturates and narcotics. Reaction of benzaldehyde with sodium cyanide and benzenesulfonyl chloride gives the toluenesulfonyl ester of the cyanohydrin (141). Reaction of this with thiourea leads directly to aminophenazole (143) .^^ It is probable the reaction proceeds by displacement of the tosylate by the thiourea sulfur to give 142; addition of the amino group to the nitrile followed by tautomerization affords the observed product.

143 142 Acylation of benzamidoxime (144) with chloropropionyl chloride gives the O-acylated derivative (145). Reaction of that intermediate with diethylamine serves first to cyclize the molecule to the 1,2,4-oxadiazole heterocycle; subsequent displacement of the halogen on the side chain gives oxolamine (146) y1*5 a drug with antitussive and spasmolytic activity.

/NH 2

,m2 N-OCCH2CH2C1 II 0

144

145

CoH 2n5

Miscellaneous Five-Membered Heterocycles

249

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cyclization of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148) ,1*5 Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer, 149, rather than the fully conjugated isomer. There is thus obtained imolamine (15O) ,1*6

ONHCONH2 II NOH 147

150 One of the side effects noted in the clinical use of the sulfonamide antibacterial agents was a diuretic effect caused by inhibition of the enzyme carbonic anhydrase. Attempts to capitalize on this side effect so as to obtain agents with greatly enhanced diuretic activity first met success when a heterocyclic ring was substituted for the benzene ring of the sulfonamide. Treatment of the hydrazine derivative, 151, with phosgene leads to the 1,3,4-thiadizole, 152.47 (Phosgene possibly acylates one of the ami no groups and thus converts this to a leaving group subsequent to attack by the sulfur on the remaining thioamide.) Acylation of the amine gives the amide, 153, Oxidation of the thiol by means of aqueous chlorine goes directly to the sulfonyl chloride (154). Finally, amonolysis of the halide with ammonia affords acetazolamide (155) .hB The same scheme starting with the butyramide (156) yields butazolamide (157),49 In a further development on this theme, the thiol, 153, is first alkylated to the corresponding benzyl ether (158) . Treatment with sodium methoxide removes the proton on the amide nitrogen to afford the ambient anion (159). This undergoes alkylation with methyl bromide on the ring nitrogen; thus it locks amide into the imine form (160). Chlorolysis serves both to oxidize the sulfur to the sulfone stage and to cleave the benzyl ether linkage; there is thus obtained the sulfonyl chloride, 161.

250

Five-Membered Heterocycles

Amonolysis affords the diuretic agent me tha zolami de (162).'-

HH

N-N Jl

H,N 151

SH

152

153, R=CH3 156, R=CH2CH2CH3

CH 3 CN'X S ^^SCHzCr H

159

158

SO2C1 154

CH3 N~

NSCH2C6H5

CH3CN ^ \ g

RCNH ^ s ^ SO2NH2

0

160

161, X=C1 162, X=NH2

155, R=CH3 157, R=CH2CH2CH3

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

C. D. Luns, A. D. Cale, J. W. Ward, B. V. Franko, and H. Jenkins, J. Med. Chem., 7, 302 (1964). C. A. Miller and L. M. Long, J. Amer. Chem. Soc, 73, 4895 (1951). S. S. G. Sircar, J. Chem. Soc, 600 (1927). W. B. Stillman and A. B. Scott, U. S. Patent 2,416,634 (1947). G. Gever and C. J. O'Keefe, U. S. Patent 2,927,110 (1960). 0. Eisleb, U. S. Patent 1,790,042 (1931). G. Gever, U. S. Patent 2,802,002 (1957). Anon., Belgian Patent 635,608 (1963). W. Treibe and E. Hoffa, Chem. Ber., 31, 162 (1898). K. J. Hayes, U. S. Patent 2,610,181 (1952).

References

11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

251

J. G. Michels, U. S. Patent 2,290,074 (1960). J. Goerdler, J. Ohm, and 0. Tegtmeyer, Chem. Ber., 89, 1534 (1956). Anon., Belgian Patent 630,163 (1963). W. Trabe and R. Aschar, Chem. Ber., 46, 2077 (1913). J. S. H. Davies and W. Hook, British Patent 632,423 (1949). M. A. Spielman, J. Amer. Chem. Soc, 66, 1244 (1944). M. A. Spielman, U. S. Patent 2,575,693 (1951). T. S. Gardner, E. Wenis, and J. Lee, J. Med. Chem., 2, 133 (1960). E. Skita and W. Stummer, German Patent 930,328 (1955). A. Pongrantz and K. L. Zirm, Monatsh., 88, 330 (1957). Anon., Japanese Patent 8770 (1958). Y. Sawa, J. Pharm. Soc Japan, 57, 953 (1937). J. Buchi, J. Amman, R. Lieberherr, and E. Eichenberger, Helv. Chim. Acta, 36, 75 (1953). H. Stenzl, U. S. Patent 2,562,830 (1951). R. Pfister and F. Hafliger, Helv. Chim. Acta, 40, 395 (1957). R. Deuss, R. Pfister, and F. Hafliger, U. S. Patent 2,910,481 (1959). R. Pfister and F. Hafliger, Helv. Chim. Acta, 44, 232 (1961). G. C. Lancini, E. Lazari, and R. Pallanza, Farm. Ed. Sci ., 21, 278 (1966). G. C. Lancini and E. Lazari, Experientia, 21, 83 (1965). V. K. Bhagwat and F. L. Pyman, J. Chem. Soc, 127, 1832 (1928). R. M. Jacob, G. L. Regnies, and C. Crisan, U. S. Patent 2,994,061 (1960). R. G. Jones, E. C. Kornfeld, K. C. McLaughlin, and R. C. Anderson, J. Amer. Chem. Soc, 71, 4000 (1949). A. Sohn, U. S. Patent 2,161,938 (1939). M. E. Synerholm, L. H. Jules, and M. Sayhun, U. S. Patent 2,731,471 (1956). A. Hueni, U. S. Patent 2,868,802 (1959). W. Frushtorfer and H. Mueler-Calgan, German Patent 1,117,588 (1961). K. Miescher and W. Klaver, U. S. Patent 2,449,241 (1943). K. Miescher, A. Marxer, and E. Urech, U. S. Patent 2,503,509 (1950). A. Berg, German Patent 1,191,381 (1963). A. Pinner, Chem. Ber., 21, 2320 (1888). H. R. Henze, U. S. Patent 2,409,754 (1946). L. H. Jules, J. A. Faust, and M. Sayhun, U. S. Patent 2,716,648 (1955). C. D. Hurd and H. L. Wehrmeister, J. Amer. Chem. Soc, 71, 4007 (1949).

252

Five-Membered Heterocycles

44.

R. M. Dodson and H. W. Turner, j . Amer. Chem. Soc, 73, 4517 (1951). G. Ponzio, Gazz. Chim. Ital., 62, 859 (1932). M. D. Aron-Samuel and J. J. Sterne, French Patent M2033 (1963). P. C. Guha, J. Amer. Chem. Soc, 44, 1502 (1922). R. 0. Roblin and J. W. Clapp, J. Amer. Chem. Soc, 72, 4890 (1950). J. R. Vaughan, J. A. Eichler, and G. W. Anderson, J. Org. Chem., 21, 700 (1956). R. W. Young, K. H. Wood, J. A. Eichler, J. R. Vaughan, and G. W. Robinson, J. Amer. Chem. Soc, 78, 4649 (1956).

45. 46. 47. 48. 49. 50.

CHAPTER 14

Six-Membered Heterocycles

1. PYRIDINES Nicotinic acid (2), the oxidation product of the coal tar chemical, 3-picoline, has shown activity in man in lowering elevated cholesterol levels. This property has led to some use of this drug for the treatment of the hyperlipidemias associated with atherosclerosis. It is of interest that the drug, in addition, has a remarkable effect in alleviating the symptoms of pellagra, a vitamin B-deficiency disease. Administration of nicotinic acid is sometimes limited by the facial flushing observed on ingestion of the drug, a phenomenon associated with vasodilation. Nicotinyl alcohol (3), obtained by reduction of 2 with lithium aluminum hydride, capitalizes on this effect; this drug is used as a peripheral vasodilator.

D CH

3

/^

Conversion of the carboxylic acid to the diethyl amide interestingly leads to an agent that exhibits the properties of a respiratory stimulant. One synthesis of this agent starts with the preparation of the mixed anhydride of nicotinic and benzenesulfonic acid (4). An exchange reaction between the anhydride and diethyl benzenesulfonamide affords nikethemide (5).x Although the advent of the antibiotics revolutionized the treatment of bacterial infections, tuberculosis has proven unusually resistant to chemotherapeutic attack. Although many antibiotics are effective to some extent in arresting the progress of 253

254

Six-Membered Heterocycles

0

o

CN

COSO2C6H5

C22H 5

this disease, none is uniformly successful. It had been observed that nicotinamide showed some effect on the tubercule bacillus in vitro. A systematic investigation of related pyridine derivatives led to the discovery of one of the most successful antitubercular agents, isoniazide (7). This hydrazide can be obtained in a straightforward manner by treatment of methyl isonicotinate (6) with hydrazine. Extensive clinical use of this agent showed the drug to possess a wholly unanticipated antidepressant effect in addition to its antibacterial action. This action, later attributed to inhibition of the enzyme monoamine oxidase, led to intensive efforts on the preparation of hydrazides in many heterocyclic series in order to obtain antidepressant agents.

C0 2 CH 3

CONHNHn

CONHNHCHa CH

CONHNHCH0CH0

CONHN=C

CH3

11

oCH,

CONHNHCH

10

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9).2 Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (II),3 on heating with benzylamine.

Pyridines

255

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloropyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19).u CO 2 C 2 H 5

fH

°H

c

"*

CO 2 C 2 H 5

+

—>

CH2 ycs

°

C 2 H 5 ^NA 0

C2H5

fi

H2N \> 12

13

14

? CN

*

CX

CO 2 C 2 H 5

|l 2M 5

/ 2

18

IN

16, X=C 2 H 5 O 17, X=NH

U5H5

^1N^

\jL

1S

H5^N^ 19

In an unusual variant on the Chichibabin reaction, treatment of 3~hydroxypyridine with sodium amide at 200° affords 2,6-diaminopyridine (21). Coupling of the product with benzenediazonium chloride gives phenazopyridine (22).5 This drug is used as an analgesic for the urinary tract in conjunction with antibacterial agents for treatment of urinary infections. Replacement of one of the benzene rings by pyridine in the fenamic acid-type analgesics leads to an agent with full pharmacologic activity. Treatment of the N-oxide of nicotinic acid with phosphorus trichloride followed by hydrolysis of the acid

256

Six-Membered Heterocycles

chloride gives the 2-chlorinated analog (24).6 Nucleophilic aromatic substitution on the halide by m-trifluoromethylaniline affords nifluminic acid (25).7

O

OH

2O

21

22

CO2H

0

24 23

Vinylpyridine (26) exhibits many of the properties of a Michael acceptor. Thus, this molecule will undergo conjugate addition of methoxide ion. There is thus obtained methyridine (27),8 an antinematodal agent used in veterinary practice.

II

*N^CH 2 C H 2 O C H 3 26

2.

27

DERIVATIVES OF PIPERIDINE

The continuing search for molecules that possess the sedativehypnotic properties of the barbiturates but show a better pharmacologic ratio has, as shown above, taken many directions. To name only two variants, the ring has been contracted and even opened entirely; in each case some activity of the parent was retained. Although at one time the acylurea functional array was thought necessary for activity, the work below shows that even

Derivatives of Piperidine

257

this requirement is not ironclad. This lack of structural specificity is in many ways reminiscent of the wide structural latitude that has proven compatible with antihistaminic activity. Conjugate addition of the carbanion from 2-phenylbutyronitrile (28) to methyl acrylate gives the condensation product 29. Saponification affords the corresponding acid (30). Further hydrolysis of the product in acetic acid affords the glutarimide (the formal product of cyclization of the amide with the acid), glutethemide (31).9 Nitration of the butyronitrile gives the pderivative (32). This, when subjected to the same series of transformation as 28, gives the glutarimide, 33. Catalytic reduction of the nitro group affords aminoglutethemide (34).10 Both these agents have found use as sedative-hypnotic agents.

29r 30,

R=CH 3 R=H

31

I OoN

32

33

34

Attachment of a basic amino group to the side chain leads to a compound with antiparkinsonian activity. Alkylation of the carbanion from phenylacetonitrile with 2-chlorotriethylamine affords the product, 36. Conjugate addition of the anion from this to acrylonitrile gives the glutarodinitrile (37). Partial hydrolysis of this in a mixture of sulfuric and acetic acid leads to phenglutarimide (38)•11 The glutarimide best known to the lay public, thalidomide (4o), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated

258

Six-Membered Heterocycles

CH2CH2N

CH2CH2N C o H t;

C-CN CH2CH2CN

CH2CN 36

35

H5C/

NCH2CH2O C\ ( NH

temperature leads directly to thalidomide (40).]

CH2CH2CO2H N-CH CO2H 39

40

Displacement of the geminal substitution to the 4-position of the glutarimide ring interestingly leads to a drug that antagonizes the effects of the barbiturates. As such, the agent is used in the treatment of barbiturate intoxication. The original synthesis involves first the condensation of ethyl methyl ketone with two equivalents cyanoacetamide. The product can be rationalized by assuming first an aldol condensation of the ketone and active methylene compound followed by dehydration to give 41. Conjugate addition of a second molecule of cyanoacetamide would afford 42. Addition of one of the amide amines to the nitrile would then afford the iminonitrile (43). The observed product (44) can be rationalized by assuming the loss of the carboxamide group under strongly basic conditions. Decarboxylative hydrolysis of 44 leads to bemigride (45),13 The wide structural latitude permitted for hypnotic activity is made particularly clear by the observation that the two carbonyl groups in the piperidine ring need not be disposed to form

Derivatives of Piperidine

CH 3

C2

259

CH3^

^C2H5

CH3

if 0

C2H5

NC Y ^ T ~^C C I III NH2 N

0

41 NC

CONH2

CONHo

CH 3

L> 2 n 5

CH3

CH,

Co

NC N

O N

0

H

H 44

43

45

a glutarimide. Methyprylon (51), an effective sedative-hypnotic, actually contains isolated lactam and ketone functions. Formylation of ethyl diethylacetoacetate (46) by means of ethyl formate and strong base affords the derivative, 47. Reaction of this intermediate with ammonia gives the corresponding enamine (48); this cyclizes to the unsaturated lactam on heating (49). Reaction of 49 with formaldehyde in the presence of sodium sulfite proceeds at the activated position a to the ketone carbonyl. Catalytic reduction of the product (50) results first in hydrogenolysis of the allyl alcohol; reduction of the olefinic double bond gives methyprylon (51) ,lt* The association of a specific pharmacologic activity with certain functionality was remarked on earlier. The guanidino group, for example, often yields compounds that show hypotensive activity because of peripheral sympathetic blockade (see, for example, bethanidine). Attachment of a piperidine group to the side chain proves compatible with retention of this activity. 0 II

C5H5 C2H5

x

C2H5 0

COCH3

CO2C2H5

C2H5

C9H ^

C2H5O2C 46 47

Ij CHOH

C2H5O2C

CH II CH NHo

48

260

Six-Membered Heterocycles

0 C

CH3 C

" ~

2H 5 1

0 li

H

" o v H

51

50

3-T

NH - >

^ 3 ^

52

NCH2CN

CH20H

~-> C H 3 - ^

53 CH3-C

« 49 NCH2CH2NH2

—>

54 NCH2CH2NHC

55 Alkylation of the tetrahydropyridine, 52 (obtained by reaction of a suitable protected derivative of 4-piperidone followed by dehydration and deprotection), with chloroacetonitrile affords 53, Reduction of the cyano group gives the diamine (54)„ Reaction of this intermediate with the S-methyl ether of thiourea affords guancycline (55).x5

3.

MORPHOLINES

Although the morpholine ring is often used as a modified version of a tertiary nitrogen, the ring system finds only rare use as a nucleus for medicinal agents. Both compounds below, in fact, may be regarded as more properly related to cyclized forms of hydroxyphenethylamines. Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58). Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59),16 In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61. (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetrazine (62),17 Both these agents show activity related to the parent acyclic molecule; that is, the agents are CNS stimulants

Morpholines

261

and as such are used as appetite suppressants. It has been demonstrated, incidentally, that the phenyl and methyl ring substituents both occupy the equatorial positions, leading to the formulation of these compounds as the trans isomers.18

XH-OH 0 CH 3

NHCCH2OCC6H5 0

56, R=H 60, R=CH3

57 CH-OH CHN

OH / CH2 ycn2

N H

CH.

58

I H .^^C 1 ' -H OH CH2 I I CH3 N IH3 C 61 4.

62

PYRIMIDINES

The finding that 2,4-diaminopyrimidines inhibit the growth of microorganisms by interfering with their utilization of folic acid led to an intensive search for antiinfective agents in this class of heterocyclic compounds. This work led to the develop-

Six-Membered Heterocycles

262

ment of at least two successful antimalarial agents. Condensation of phenylacetonitrile with ethyl propionate in the presence of sodium ethoxide gives the cyanoketone (63). Treatment with diazomethane affords the methyl enol ether of that compound (64). Condensation with guanidine affords pyrimethamine (65).19 (The reaction may well involve reaction of an amino group at the enol ether by an addition-elimination scheme followed by addition of the remaining amino group on guanidine to the nitrile.)

CN

II H5C2

OCH3

64

H 5 C 2 ^ N " ^ NH2 65 Bishomologation of benzaldehyde, 66 (for example, by reduction to the alcohol, conversion to the halide, and then malonic ester synthesis), affords the hydrocinamic acid, 67. Formylation with ethyl formate and base gives the hydroxymethylene derivative, 68. Condensation of that intermediate with guanidine gives the pyrimidine, 69, by a scheme similar to that above. The hydroxyl group is then converted to the amine by successive treatment with phosphorus oxychloride (70) and ammonia. There is thus obtained the antimalarial agent, trimethoprim (71). A shorter route to the same agent consists in first condensing the benzaldehyde with 3-ethoxypropionitrile to afford the cinamonitrile (72) . Reaction with guanidine gives 71 directly.20 The reaction probably involves displacement of the allylic ethoxy group in 72 by guanidine followed by addition to the nitrile; the double bond then shifts into the pyrimidine ring. A change in the substitution pattern on the pyrimidine ring as well as conversion of one of the ring nitrogen atoms to its iv-oxide affords an agent with markedly altered biologic activity. This drug, minoxidil (74), is an extremely effective hypotensive agent acting by means of vasodilitation. (It is of interest that

263

Pyrimidines

CH3O CH3O-C VcH2CH2CO2C2H5 CH3O

CH3O-V >CHO CH3O

CH.O , CO2C2H5 CHOH

CH3O

66

CH3O

CH3O

v

CH3O

CH2OC2H5 CH3O

CH3O

NH, 72

CH3O--C CH3O

71 69, X=OH 7 0 , X=C1

the agent was actually discovered by way of the desoxy analog; although this compound shows some hypotensive activity in its own right, biochemical work revealed the fact that this undergoes Noxide formation in vivo to afford 74.) Condensation of ethyl cyanoacetate with guanidine in the presence of sodium ethoxide affords the starting pyrimidine (71). Reaction with phosphorus oxychloride then serves to replace the hydroxyl group by chlorine (72). Treatment of that intermediate with metachloroperbenzoic acid results in specific oxidation of the nitrogen at the 1 position (73). Displacement of the halogen with piperidine affords minoxidil (74).21 / C=N CH2 ^ CO2C2H5

+

H2NX C=NH H2N7

11 T OH 71

Cl 72

0 N

O 74

Cl 73

264

Six-Membered Heterocycles

Coccidia are protozoans that can wreak havoc in a flock of poultry by the infection known as coccidiosis. Agents that control this disease—coccidiostats—are in view of the world1s heavy dependence on poultry as a source of protein, of great economic significance. One of the more important drugs for treatment of this disease incorporates the pyrimidine nucleus. Condensation of ethoxymethylenemalononitrile with acetamidine affords the substituted pyrimidine, 75. This reaction may well involve conjugate addition of the amidine nitrogen to the malononitrile followed by loss of ethoxide; addition of the remaining amidine nitrogen to one of the nitriles will then lead to the pyrimidine. Reduction of the nitrile gives the corresponding aminomethyl compound (76). Exhaustive methylation of the amine (77) followed by displacement of the activated quaternary nitrogen by bromide ion affords the key intermediate (78),22 Displacement of the halogen by a~picoline gives amprolium (79) . 2 3

HNN

HC NC

CN

I

NC

CCH 3

H

CH*

N ^

yOC2H5

H?N

H 2 NCH 2

NH 2

76

75

CH3

NCH 2

ZCH a

Br

NH2 79 77, Z = N ( C H 3 ) 3 78, Z=Br

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (8O) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.2** Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolata of the unsymmetrically esterified malonate, 81, with butyryl chlo-

Pyrimidines

265

ride. Treatment of the product (82) with mild acid leads to loss of the tertiary butyl ester as isobutylene. The resulting acid quickly decarboxylates to afford 83. Condensation of that product with thiourea affords propylthiouracil (84),25 sometimes known simply as PTU. s H2NCNH2

?H

S CH3 ^ ^ ^ o

'I

CH 3 ^ ^ ^ OH 80b

80a

Cll3' CM2 CO2C2H5

CO2C(CII3)3

H ' CO2C(CH3)3 > CH3CH2CH2CCH X

CO2C2H5

01? / CO H 2

r

1

CH 3 CH 2 CH 2 CCH x

L

CO2C2H5J

82

81

X CH 3 CH 2 CH 2

S ^^ ^x^^OII

° < —

CH 3 Cn 2 CH 2 CCH 2 CO 2 C 2 H 5 83

84

Inclusion of iodine in the thiouracyl molecule similarly proves compatible with antithyroid activity. Alkylation of thiouracyl proper (85) with benzyl chloride affords the thioether, 86. Treatment of this with elemental iodine affords the nuclearly substituted iodo derivative (87). Removal of the benzyl ether by reduction leads to iodothiouracil (88),26 Alkyl uracyls have been known for some time to act as diuretic agents in experimental animals. The toxicity of these agents precluded their use in the clinic. Appropriate modification of the molecule did, however, yield diuretic agents with application in man. Reaction of allylamine with ethyl isocyanate affords the urea, 89 (the same product can of course be obtained from the same reagents with reversed functionality). Condensation with ethyl cyanoacetate affords aminotetradine (90).27 In

266

Six-Membered Heterocycles

SR

SCH 2 C 6 H 5

SH

un

OH

^^ '0H

"Y"

I 87

88

85, R=H 86, R=CH 2 C 6 H 5 much the same vein, amisotetradine (91)27 is obtained by cyclization of the urea obtained from methallylamine and methylisocyanate The latter agent has largely replaced 90 in the clinic because of a lower incidence of side effects. OH 1

CH3CH2N" ''' NCH2GH::=CH2 CH3CH2NHCNHCH2CH=CH2 II 0 89

> H2 90 OH

H2N 91 Although many medicinal agents incorporate the imidazoline ring, the homologous tetrahydropyrimidine moiety has found little use in medicinal chemistry. The exception is a pair of closely related antihelmintic agents used in veterinary practice. Knoevenagel-type condensation of thiophene-2-carboxaldehyde with cyanoacetic acid gives the corresponding unsaturated nitrile (92). This is then methanolyzed in the presence of strong acid to afford the imino-ether, 93. Condensation with N-methylpropylene-1,3diamine proceeds probably by addition-elimination of each amino group in turn with the imino ether. There is thus obtained pyrantel (92),28 The analog, morantel (94),29 is obtained by the same sequence using 3-methylthiophene-2-carboxaldehyde.

Pyrimidines

267

R I=CHC S

92

OCH3

QO

R=H,CH3

/

>

CH, 94, R=H 95, R=CH3

5.

BARBITURIC ACID DERIVATIVES

Derivatives of barbituric acid constitute one of the more venerable families of medicinal agents; the first member of the series, barbital (96), has been in continuous use since 1903. This class of sedative hypnotics is also one of the most widely used, and it should be added, abused series of drugs. Although the agents are generally quite effective in inducing sedation and sleep, all barbiturates share, to a greater or lesser degree, a similar set of disadvantages. To begin with, barbiturates tend to have a relatively low pharmacologic ratio; news reports of suicide by means of barbiturates are not at all uncommon. Sustained use of barbiturates is known to lead to addiction in certain individuals. Finally, use of barbiturates as sleeping agents frequently leads to the so-called hangover on awakening. Unlike the more traditional hangover from alcohol, this syndrome often consists of a dulling of awareness for a considerable time. The large number of these analogs available for purchase attests to the great effort that has gone into attempts to circumvent the limitations of this series of drugs. The final step in the synthesis of all barbiturates consists in either condensation of a suitably substituted malonic or cyanoacetic ester with urea by means of sodium ethoxide (scheme a) or

268

Six-Membered Heterocycles

analogous condensation of such an ester with guanidine followed by hydrolysis of the inline thus produced (scheme b ) . The chemistry of this class of agents devolves on the preparation of the required disubstituted esters. The reader will recognize that methods for the preparation of the bulk of the intermediates are fairly obvious. The synthesis of the majority of these drugs is therefore not considered in detail; the products are listed in Table 1 below. The preparations of some of the less-obvious malonic esters are, however, found below. Table 1.

Derivatives of Barbituric Acid 0 R2

No.

Generic Name

R1

R2

96

barbital

CH2CH3

CH 2 CH 3

97

butethal

CH 2CH 3

-(CH2 )3CH3

98

hexethal

CH 2 CH 3

-(CH 2 ) 5 CH 3

99

probarbital

CH 2 CH 3

100

butabarbital

CH 2 CH 3

101

pentobarbital

CH 2 CH 3

CH3 -CHCH2CH2CH3

102

amobarbital

CH 2 C H 3

•* CH CH2CH2CH

103

phenobarbital

- C H 2 CH 3

104

aprobarbital

CH 2 CH=CH 2

105

butalbital

CH 2 C H = C H 2

CH 3 -CHCH 2 CH 3

CH

CH,

Duration of Action

269

Barbituric Acid Derivatives

Table 1, continued

105

secobarbital

CH2CH=CH2

GHCiH 2 CiH. 2 C»H 3

106

allobarbital

CH2CH=CH2

piT

107

cyclopal

CH 2 CH=CH 2

108

butylallonal

-CH 2 CH=CH 2

/rrr

nn

o U r l 2 v ~ ~ v»lri 2 B r

109

methohexital

CH 2 CH=CH 2

- C H C = C C H C H

110

butylvinal

-CH=CH2

g H C H

HI

vinbarbital

-C=CHCH 2 CH 3 CH3

CH 2 CH3

112

cyclobarbital

•o

CH 2 CH3

113

heptabarbital

O

114

carbubarbital

- (CH2 )3CH3

Long acting (more than 6 h r ) .

2

C H

3

3

2

C H

3

CH 2 CH 3 0 CH 2 CH 2 OCNH 2

Intermediate (3-6 h r ) .

Short acting (less than 3 h r ) . At least one of the protons on the nitrogens flanked by the two carbonyl groups is in fact quite acidic; many of the barbiturates are actually used as their sodium salts, particularly when these drugs are formulated for use by injection. The reader is referred to more specialized texts for this specific information. The duration of action of a barbiturate following administration has an important bearing on its clinical use. The longacting compounds tend to be used as sleeping pills, while the short-acting drugs are used in surgery in conjunction with an inhalation anesthetic.

270

Six-Membered Heterocycles

R\

/ CO 2 C 2 H 5

c=-o

2

R '

0 A NA o

CO 2 C 2 H 5 (CN)

CO 2 C 2 H 5 C/ R 2/ V CO 2 C 2 H 5 (CN) k

H2NV +

R

C-NH

H2N

H

Y

scheme a

scheme b

H

The malonic ester required for synthesis of cyclopal (107)29 can be obtained by alkylation of diethyl allylmalonate (115) with 1,2-dibromocyclopentane in the presence of excess base. It is probable that the reaction proceeds by elimination of hydrogen bromide from the dihalide as the first step. The resulting allilic halide (116) would be the most reactive electrophile in the reaction mixture and thus would quickly alkylate the anion of the malonate to afford 117.

^ CO2C2H5 CH2=CHCH2C^ ^C02C2H5 115

(

/:O 2 C 2 H 5 CH2=CHCH2CH

O"Br -> f

V

CO2C2H5 Br 116

CH2=CHCH2^ /CO2C2H5

117 Condensation of the organometallic reagent obtained by reaction of 1-butyne and ethylmagnesium bromide with acetaldehyde affords the carbinol, 118. Treatment with phosphorus tribromide gives the corresponding propargyl halide (119). Alkylation of diethyl malonate with this reagent, followed then by alkylation with allyl bromide, gives the starting material (120) for metho-

Barbituric Acid Derivatives

hexital

271

(109).30

CH3CH2C~CMgBr

•f

CH3CH2C=CCHCH3

H

X 118, X=OH 119, X=Br

CH3CH=CH2 CO 2C2H5 X 2C2H5 CH3-CrC-CH CO CH3 120 Treatment of an ethylidene malonic ester such as (a) with strong bases results in loss of a proton from the allylic position to produce the ambident ion (b). Alkylation of such carbanions usually occurs at the carbon bearing the carbonyl groups, resulting in the establishment of a quaternary center and deconjugation of the double bond (c).

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, 121, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124), Hydrolysis affords vinbarbital (111),31>32 Application of this scheme to condensation products of cycloalkanones affords the cycloalkenyl-substituted barbiturates. Thus, the condensation product of cyclohexanone and ethyl cyanoacetate (125) affords the intermediate (126) for the synthesis of cyclobarbital (112)33 on alkylation with ethyl bromide. The condensation product of cycloheptanone (127) affords the starting

Six-Membered Heterocyclf

272

CH3 v / CN C 2 H 5 CH 2

C 2 H 5 CH 2 / ^ C0 2 C 2 H 5 122

121

CH3

CN

C2H5 CH

C0 2 C 2 H 5 C2 H 5 C H

C 2H 5

CH; 123

H 124 material (128) for heptabarbital

(113). ~

,CN CO 2 C 2 H 5 125

C2H5 126

CN CO 2 C 2 H 5

The parent compound in this series, that is, the agent substituted by a vinyl group, is obtained by direct vinylation. Reaction of the monosubstituted barbiturate, 129, with ethylene at elevated temperature and pressure in the presence of a zinc catalyst affords butylvinal (110).35 Alkylation of the anion from diethyl butylmalonate with

Barbituric Acid Derivatives

273

o

___ ...9 NH

.

ti 3

CH3CH2CH -Y ^NH

H

H 13

129

°

with ethylene oxide affords the malonate containing an hydroxyethyl side chain (131). This is then converted to the barbiturate (132) in the usual way. Treatment of the product (132) first with phosgene and then ammonia affords the carbamate carbubarbltal (114).36

HOCH2CH2

CO2C2H5

CH 3 CH 2 CH 2 CH 2

CO2C2n5

X

CH3 (CH2 ) 3 || HOCH2CH2 V^^^j^

-*

n 0 131

132

CH 3 (CH 2 ) 3 H2NCOCH2CH2 0

0

114 Condensation of disubstituted malonic ester with iv-methyl urea yields the corresponding barbituric acids bearing a methyl group on nitrogen. (The plane of symmetry that bisects these molecules, of course, makes both nitrogens identical.) Carbethoxylation of ethylphenylacetate (sodium hydride and ethyl chloroformate) affords diethyl phenylmalonate (133). Alkylation with ethyl bromide gives 134. Condensation of this with iv-methyl urea in the presence of base gives mephobarbital (135).37 In much the same way, reaction of the ester, 136, with iv-methyl urea affords hexobarbital (137).38 In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the O-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140),39

Six-Membered Heterocycles

274

CO2C2H5

CO 2 C 2 H 5

CO 2 C 2 H 5 133

N-CH,

135

a CH3 136 137

C,H 2n5v

COC1

CoH,

COC1

HNV C-OCH3

138 C2H5

139

140

Replacement of the oxygen on the carbonyl group at the 2 position by sulfur affords a series of sedative-hypnotic agents that tend to show both faster onset and shorter duration of action than their oxygenated counterparts. These compounds are obtained in a manner quite analogous to the oxygenated analogs, that is, by condensation of the appropriate malonic ester with thiourea in the presence of a strong base. Thus, reaction of 141 with thiourea gives thiopental (142) .t*° (The sodium salt of the latter is sometimes known as sodium pentothal, the "truth serum" known to all lovers of whodunits.) In a similar vein, 143 affords thiam-

Barbituric Acid Derivatives

275

ylal (144),l*° and the ester, 145, leads to thialbarbital (146) .kl It is of note that although the drug can be prepared by the above route, reaction of barbital (96) with phosphorus pentasulfide constitutes an alternate route to thiobarbital (147) ,1*2

R1

CO 2 C 2 H 5

X R2

|^

+

H2NCNH2

CO 2 C 2 H 5

141, R1:=C2H5 R2=CHCH2CH2CH3

142, R1=C2H5 R2=CHCH2CH2CH3

CH3 1

143, R =CH2CH=CH2 R —

CH3 1

144, R -CH2CH=CH2

CH3 145, R ^ C H ^ C H a

CH3 1

146, R =CH2CHrCH2

R2=

C9H -:

II

C9H

147 A somewhat more complex side chain is incorporated by alkylation of the carbanion of the substituted cyanoacetate, 148, with 2-chloroethylmethyl sulfide. Condensation of the resulting cyanoester (149) with thiourea followed by hydrolysis of the resulting imine (150) affords methitural (151) ,1*2 Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. **3 This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double internal alkylation of ethyl

276

Six-Membered Heterocycles

CH3CH2CH2CHCH 148 CH 3 +

CH3

CH3CH2CH2CH

x

CH3CH2CH2CH X — > CH3SCH2CH2 CH3SCH2CH2
C1CH2CH2SCH3

CN

149 150, X=NH 151, X=0 malonate with 155 affords the substituted cyclopentane, 156, of unspecified stereochemistry. Reaction of the ester with thiourea in the presence of strong base gives spirothiobarbital (157) ,l*h 0

CH3

ii 1

CH3CCHCHCC2H5

| d

>

0

CH3

I?

i

X

CH 3 II

CH3CCH2CHCC2H5

>

CH3CHCH2CHCHC2H5

0

X

CO2 C2 H 5

152

154, X-OH 155f X-Br

CO 2 C 2 H 5 C2H5 157

156

The close structural resemblance between the sedative-hypnotic and anticonvulsant agents was mentioned earlier. It is interesting that the two activities can be related in at least one case by a simple chemical transformation. Thus, reductive desulfurization of the thiobarbituric acid, 158, affords primi-

Barbituric Acid Derivatives

277

done (159),45 a drug used in the treatment of grand mal epilepsy.

159

158

6.

PYRAZINES AND PIPERAZINES

Pyridine and the ring system containing an additional nitrogen atom at the 4 position-pyrazine—are to some extent interchangeable as nuclei for antitubercular carboxamides. Preparation of the requisite acid starts by condensation of phenylenediamine with glyoxal to afford quinoxalin (160). Oxidation of this molecule interestingly proceeds at the carbocyclic aromatic ring to afford the heterocyclic dicarboxylic acid (161). Decarboxylation followed by esterification gives 162. Ammonolysis of the ester affords pyrazineamide (163).A6 Mannich reaction on that amide with formaldehyde and morpholine yields morphazineamide (164).47 CHO

H2N

CHO

H2N

(Y 160

162

161

0 IIH

v

\ 164

OlH

CONH2

/ 163

Carboxylic acid, 161, also serves as starting material for a substituted pyrazine that has proven to be an important diuretic agent. As the first step in the synthesis the acid is converted to the corresponding amide (165). Treatment with a single equivalent of hypobromous acid effects Hoffmann rearrangement of only one of the amide groups. Ethanolysis of the intermediate carbamate leads directly to the amino ester (166). Exposure of the

278

Six-Membered Heterocycles

ester to sulfuryl chloride affords the dichloro derivative (167). Ammonolysis of that dihalide proceeds to afford the product of displacement of that halogen activated by the para carboxyl group (168). Heating that intermediate with a salt of guanidine results in the formation of an amide of that base. There is thus obtained amiloride (169).*8

161 165

166

0 Cl

w

NH

CNHCNH2 NHo 169

168

The piperazine ring, like both the pyrrolidine and piperidine heterocycles, is often used in drugs in place of some acyclic tertiary amine. Since no unique properties of the piperazine ring seem to be involved in the biologic activity of those agents, the discussion of those compounds has been relegated to the broader drug classes within which they occur. A small number of piperazines,do, however, defy this rough classification. Reaction of A7-methylpiperazine with phosgene affords the carbamoyl chloride (170). Treatment of this intermediate with diethylamine affords the antiparasitic agent diethyl carha.ma.zlne (171).k» Treatment of a mixture of ortho anisidine and bis(2-hydroxyethyl)amine with hydrogen chloride affords the aryl-substituted piperazine, 171. (The first step in this reaction probably consists in conversion of at least one hydroxyl group to the chloride; this then serves to alkylate the aromatic amine.) Alkyla-

Pyrazines and Piperazines

279

0

CH.N

NH

CH,N

\ || / NCN

NC0C1

171

170

tion of the secondary nitrogen with 4-chloro-p-fluorobutyrophenone (obtained by acylation of fluorobenzene with 4-chlorobutyryl chloride) gives the atarctic agent fluanisone (172).50

HOCH2CH2V

NH

N

NH

HOCH 2 CH 2 OCH 3

OCH-,

171

0 \

II NCH 2 CH 2 CH 2 C

OCHa

172 Alkylation of the monocarbamate of piperazine with the halide, 173, affords 174 after removal of the protecting group by saponification. Alkylation of the amine with the chloroamide, 175 (obtained from amine, 176, and chloroacetyl chloride) gives the local anesthetic lidoflazine (177).51

EtO2CN

NH

O

C1CH2CH2CH2CH

173

HN

N-CH2CH2CH2CH

174

Six-Membered Heterocycles

280

I CH3 (

>NHCCH2«N

NCH 2 CH 2 CH 2 CH

CHo 177

176

7.

MISCELLANEOUS MONOCYCLIC HETEROCYCLES

Condensation of p-chlorobenzaldehyde with 3-mercaptopropionic acid in the presence of ammonium carbonate leads to the thiazinone, 179. The reaction very probably proceeds by the intermediacy of the carbonyl addition product, 178; lactamization completes formation of the observed product. Oxidation of 179 to the sulfone by means of potassium permanganate in acetic acid gives chlormezanone (180),52 a minor tranquilizer with musclerelaxant properties.

NH2 Cl-

-CH S 178

HSCH 2 CH 2 CO 2 H

/ CO2H 2^ H2 179

cU' 180

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug.

Miscellaneous Monocyclic Heterocycires

281

Reaction of p-chloroaniline with dicyanamide affords the biguanide, 182. This is condensed immediately with acetone to form the aminal cydoguanil (183),53 The compound is usually used as a salt with pamoic acid (184). HO2C

OH

HO

CO2H

NH NHCNHCNHCH

NH

CH,

181

Cl +

NH It

NCNHC

NH,

H H 2 N"

NH

182

Cl

Cl

^ N

NH II NH

V

P 1

J55

I C

H2N

NH

Cyclization of the intermediate, 182, by means of ethyl orthoformate takes a quite different course. The nitrogen on the aromatic ring in this case becomes one of the exocyclic groups to afford the chorazanil (185) 95U a compound that shows diuretic activity. Pentylenetetrazol (188) is a drug with profound stimulatory activity on the central nervous system. As such, the agent was at one time used in shock therapy for treatment of mental disease. Although it has since been supplanted by safer methods, the agents still occupy an important role in various experimental animal models in pharmacology. Addition of hydrazine to the imino ether (186) obtained from caprolactam affords 187. Treat-

282

Six-Membered Heterocycles

ment of that hydrazine with nitrous acid affords pentylenetetrazol (188),55 probably via the azide.

$>

/

N

^

N

^-^ ™2

OCH3

(

N

\ ^ N

156 Guanidines with substituents of appropriate lipophilicity have proven quite useful in treatment of hypertension due to their activity as peripheral sympathetic blocking agents. One of the more important drugs in this category is guanethidine (191). Alkylation of the saturated azocine with chloroacetonitrile affords the intermediate, 189. Catalytic reduction of the nitrile gives the diamine (190). Condensation of that with the S-methyl ether of thiourea affords guanethidine (191).S6

C

NH

(

NCH2CN

189 NCH2CH2NH2

/ '

190

X

NCH2CH2NHC" S ' NH9 191

The lack of structural specificity within the sympathetic blocking agents is particularly well illustrated by a drug that is based on a heterocycle in only the loosest sense. Ketalization of cyclohexanone with l-chloro-2,3~propanediol affords 192. Displacement of halogen by means of the sodium salt of phthalimide leads to the intermediate, 193; removal of the phthaloyl protecting group by treatment with hydrazine leads to the primary amine (194). This amine gives the hypotensive agent guanadrel (195) 957 on reaction with the S-methyl ether of thiourea. Like all other hypotensive agents containing the guanidine function, this agent acts by blockade of the sympathetic nervous system.

Miscellaneous Monocyclic Heterocycles

283

CH2C1 HOCH2CHCH2C1 OH 193 192

NH It CH 2 NHC-NH 2

CHo

o

195

o

194

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

P. Oxley, M. W. Partridge, T. D. Robinson, and W. F. Short, J. Chem. Soc, 763 (1946). H. H. Fox and T. Gibbas, J. Org. Chem., 18, 994 (1953). B. M. Bloom and R. E. Carnham, U. S. Patent 3,040,061 (1962). D. Libermann, N. Rist, F. Grumbach, S. Cals, M. Moyeux, and A. Rouaix, Bull. Soc Chim. Fr., 687 (1958). R. N. Shreve, W. M. Swaney, and E. H. Riechers, J. Amer. Chem. Soc, 65, 2241 (1943). E. C. Taylor and A. J. Crovetti, J. Org. Chem., 19, 1633 (1954). C. Hoffmann and A. Faure, Bull. Soc. Chim. Fr., 2316 (1966). N. Greenlagh and P. Arnall, U. S. Patent 3,233,710 (1965). E. Tagmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta, 35, 1541 (1952). K. Hoffmann and E. Urech, U. S. Patent 2,848,455 (1958). E. Tagmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta, 35, 1235 (1952). Anon., British Patent 788,821 (1957). F. B. Thole and J. F. Thorpe, J. Chem. Soc, 99, 422 (1911). 0. Schnider, H. Frick, and A-. H. Lutz, Experientia, 10, 135 (1954). Anon., French Patent M3016 (1965).

284

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

Six-Membered Heterocycles

F. H. Clarke, J. Org. Chem., 27, 3251 (1962). W. G. Otto, Angew. Chem., 68, 181 (1956). D. Dvornik and G. Schilling, J. Med. Chem., 8, 466 (1965). P. B. Russell and G. H. Hitchings, J. Amer. Chem. Soc, 73, 3763 (1951). P. Stenbuck and H. M. Hood, U. S. Patent 3,049,544 (1962). W. C. Anthony and J. J. Ursprung, U. S. Patent 3,461,461 (1969). R. Grewe, Z. Physiol. Chem., 242, 89 (1936). L. H. Sarett, et al., J, Amer. Chem. Soc, 82, 2994 (1960). H. I. Wheeler and D. F. McFarland, Amer. Chem. J., 42, 105 (1909). G. W. Anderson, I. F. Halverstadt, W. H. Miller, and R. 0. Roblin, J. Amer. Chem. Soc, 67, 2197 (1945). H. Barrett, I. Goodman, and K. Dittmer, J. Amer. Chem. Soc, 70, 1753 (1948). V. Papesh and E. F. Schroeder, U. S. Patent 2,729,669 (1956). Anon., Belgian Patent 658,987 (1965). R. Chaux and C. Dufraise, U. S. Patent 1,869,666 (1931). W. J. Doran, U. S. Patent 2,872,448 (1959). A. C. Cope and E. M. Hancock, J. Amer. Chem. Soc, 60, 2644 (1938). A. C. Cope and E. M. Hancock, J. Amer. Chem. Soc, 61, 776 (1939). Z. Eckstein, Przemysl Chem., 9, 390 (1953). W. Taub, U. S. Patent 2,501,551 (1950). M. Seefelder, Chem. Abstr., 56, 9927i (1962). Anon., French Patent M1059 (1962). L. Taub and W. Kropp, German Patent 537,366 (1929). W. Kropp and L. Taub, U. S. Patent 1,947,944 (1934). J. A. Snyder and K. P. Link, J. Amer. Chem. Soc, 75, 1831 (1953). G. H. Donnison, U. S. Patent 2,876,225 (1959). E. H. Vollwiller and D. L. Tabern, U, S. Patent 2,153,730 (1939). 0. Zima and F. VonWerder, U. S. Patent 2,561,689 (1951). M. A. Youtz and P. P. Perkins, J. Amer. Chem. Soc, 51, 3511 (1929). W. J. Doran and E. M. VanHeyningen, U. S. Patent 2,561,689 (1951). J. Y. Bogue and H. C. Carrington, Brit. J. Pharmacol., 8, 230 (1953). S. Kushner, H. Dallian, J. L. Sanjuro, F. L. Bach, S. R. Safir, V. K. Smith, and J. H. Williams, J. Amer. Chem. Soc, 74, 3617 (1952). E. Felder and U, Tiepolo, German Patent 1,129,492 (1962).

References

48. 49.

50. 51. 52. 53. 54. 55. 56. 57.

285

E. J. Cragoe, Belgian Patent 639,386 (1964). S. Kushner, L. M. Brancone, R. I. Hewitt, W. L. McEwen, Y. Subbarow, H. W. Steward, R. J. Turner, and J. J. Denton, J. Org. Chem., 13, 144 (1948). P. A. J. Janssen, U. S. Patent 2,997,472 (1961). P. A. J. Janssen, Netherland Application 6,507,312 (1965). A. R. Surrey, W. G. Webb, and R. M. Gesler, J. Amer. Chem. Soc, SO, 3469 (1958). E. J. Modest, J. Org. Chem., 2, 1 (1956). 0. Clauder and G. Bulsu, Magy. Kern. Foly., 57, 68 (1951). R. Stolle, Chem. Ber., 63, 1032 (1930). R. A. Maxwell, R. P. Mulland, and A. J. Plummer, Experientia, 15, 267 (1959). R. Hardie and J. E, Aaron, U. S. Patent 3,547,951.

CHAPTER 15

Derivatives of Morphine, Morphinan, and Benzomorphan 4-Phenylpiperidines

The sensation of pain is at one and the same time the salvation and bane of all sentient living organisms. In teleologic terms, the function of pain is to alert the organism to the fact that something is amiss in its relation to the environment. Put more simply, pain is an alert signal to injury or malfunction of some organ system. On the other hand, the signal does not terminate once the injury has been noted. Rather, pain often persists past the point at which the causal stimulus has been removed. Pain, too, can often be so intense as to greatly impair normal functions. The relief of pain has therefore figured prominently in many mythologies as one of mankind's aspirations. Opium, the crude dried sap of the immature fruit of the poppy, Papaver somniferum, had some folkloric use as a means of inducing euphoria. The beginning of the nineteenth century saw an increasing interest in systematic study of plant materials that seemed to possess pharmacologic activity. It was in the course of one of these studies that the major alkaloid contained in opium, morphine (1), was isolated and identified. Recognition of its analgesic properties followed the isolation. Although the mechanism of action of this drug and its host of congeners are not known in any detail to this day, their mode of action is usually classed as narcotic. Most of the drugs in this class tend to show very similar pharmacologic response; in cases of dependence the compounds can often be substituted for each other. It is generally accepted that the narcotic analgesics do not in fact interfere with the pain as such; rather, these compounds change the perception of the pain. In other words, the patient may come to regard pain with detachment. This very mechanism may be responsible for one of the major drawbacks of the narcotic 286

Derivatives of Morphine

287

analgesics as a class; since not all pain is physical, there are always a sizeable number of individuals who like nothing better than to gain a sense of detachment from their psychic pain. The euphoriant properties exhibited by some of the narcotics, of course, aggravate this problem. Thus, the prone individual will develop psychic dependence to these drugs. The phenomenon of physical dependence adds an ominous note to this cycle of addiction. As an individual keeps ingesting these drugs, he develops tolerance, that is, he needs ever larger amounts to achieve the desired effect. In addition, the addict develops a true physiologic need for the narcotic. Sudden cessation of drug administration leads to severe physical illness. There has therefore been a major effort of some duration to develop analgesics without this addiction potential.

1.

MORPHINE

Although morphine has been prepared by total synthesis,1 the complexity of the molecule makes such an approach unattractive on a commercial scale. The drug in fact is obtained by fractionation of opium obtained from the poppy; morphine in turn is used as starting material for various derivatives. If it were not for the importance of these drugs in the clinic, some progress might have been made in eradication of the plant. Initial synthetic work was aimed at decreasing side effects such as addiction potential and respiratory depression, as well as at increasing potency and oral activity. Methylation of the phenolic group at 3 affords codeine (2), a weaker analgesic than morphine, which has been used as an antitussive agent. The homolog, ethylmorphine (3),x obtained by alkylation of morphine with ethyl sulfate, shows somewhat greater potency than codeine; its chief use has been in ophthalmology. Alkylation of 1 with N(2chloroethyl)morpholine yields pholcodeine (4). Continuing in the

288

Derivatives of Morphine

vein of simple modification, acetylation of morphine leads to the diacetyl compound heroin (5). This drug, much favored by addicts for its potent euphoriant action on intravenous injection, has been outlawed in the United States for a good many years. Acetylation of codeine (2) by means of acetic anhydride affords thebacon (6).3 CH*

CH3CO2

0

O2CCH3

2, R»CH3 3 r R113 CH 2 CH 3 r 4r R=CH2CH2N .0

CH,

CH3O'

OCOCH,

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) .** Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9),5 an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. When morphine is subjected to a similar reduction-oxidation sequence (1-+1O), there is obtained hydromorphone (10).6 An invariant feature in the molecules discussed thus far has been the presence of a methyl group on nitrogen. Replacement of this group by allyl produces a drug with a markedly different pharmacologic profile. Nalorphine (13), while possessing some analgesic effect in its own right, is used mainly as narcotic antagonist. That is, the agent will prevent many of the side effects of morphine or its congeners such as respiratory depres-

289

Morphine

.CHo

1, R=H 2, R=CH3

7, R=CH3 8, R=H

9, R=CH3 10, R=H

sion, euphoria, nausea, and drowsiness, particularly in cases of narcotic overdoses. It is of interest that the narcotic antagonists may in fact precipitate withdrawal symptoms on administration to addicts. Pure antagonists devoid of significant analgesic activity have a rather limited role in the practice of medicine. It should be noted, however, that a mixture of a pure antagonist, naloxone, and an analgesic, methadone, has recently been proposed for use in humans. In theory the antagonist will tend to block the euphoria or "rush" on intravenous administration sought by the addict, without interfering with the analgesic effect. Some of the more recent narcotic antagonists may find use beyond the treatment of overdosage because they show some analgesic activity in their own right. These antagonist-analgesics promise agents with reduced abuse and addiction potential in part because of the low euphoriant effect. As might be inferred from the close structural similarity of agonists and antagonists, there is good biochemical evidence that the latter may act by competing for receptor sites with true agonists. The prototype of this series is synthesized by first reacting morphine with cyanogen bromide. This reagent in effect serves to replace the methyl group by cyano. Hydrolysis of the intermediate (11) affords desmethylmorphine (12). Alkylation of the last with allyl bromide affords nalorphine (13).7 As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16).8 Catalytic reduction

290

Derivatives of Morphine

CN

11

12 CH2CH=CH2

13 affords oxycodone (17), a relatively potent analgesic. Removal of the aromatic methyl group by means of hydrobromic acid leads to oxymorphone (18),9 an analgesic about ten times as potent as morphine in man, but with high addiction potential.

OCH,

15

16

18

The 14-hydroxy analog of nalorphine constitutes one of the

291

Morphine

most potent pure narcotic antagonists available. The synthesis of this agent begins with the acetylation of oxymorphone by means of acetic anhydride to afford the 3,6-diacetate (19). Treatment with cyanogen bromide followed by hydrolysis gives the corresponding desmethyl compound (20). Removal of the acetate groups by hydrolysis followed by alkylation of the secondary amine with bromide affords naloxone (21) ,10 .CH,

H

18 AcO

AcO 19 /CH 2 CH=CH 2

21 Displacement at carbon by Grignard reagents has been not infrequently observed in allylic systems possessing a good leaving group. One need only bring to mind the coupling by-products observed during the formation of Grignard reagents from allylic or benzylic halides. Thus, treatment of dihydrothebaine (22), obtained by catalytic reduction of thebaine, with methylmagnesium iodide results in displacement of the allylic oxygen at 5 with consequent cleavage of the furan ring. The fact that the leaving group in this case is a phenoxide ion no doubt favors this reaction course. Hydrolysis of the enol ether during the workup affords the intermediate methylated ketone (26).X1 Subsequent work revealed that the same product could be obtained more conveniently by analogous reaction on the enol acetate from hydrocodone (23).12 In order to reform the furan ring, the ketone is first brominated to afford a dibromoketone formulated as 27. Treatment of this with base results first in formation of the phenoxide ion at 4. Displacement of the halogen at 5 affords the recyclized product, 28. The remaining superfluous halogen is

Derivatives of Morphine

292

removed by catalytic reduction (29). Removal of the methyl group at 3 by one of the usual methods affords methyldihydromorphlnone (30).1X»12 This agent is a very potent narcotic analgesic, notable particularly for its good oral activity.

CH3O

CH3O 22, R=OCH3 23, R=OAc

OH CH3 0 26

CHi

CITq

CH3O 28, X ir 29, X fl

2.

27

MORPHINANS

Research towards modulation of the pharmacologic profile of narcotic analgesics and their antagonists for quite some time consisted in modification performed on the natural product such as outlined above. This of necessity precluded deep-seated chemical changes that might profoundly alter the pharmacologic properties. The discovery that many highly simplified molecules that possessed some of the structural features of morphine still showed analgesic activity opened the door to just such chemical manipulations. Although a great many structurally diverse drugs resulted from these researches, the salient problem of the narcotics, addiction liability, seems to go hand in hand with activity in all but a few of these agents. (It should be noted that the following discussion is cast on the lines of progressive structural simplification; no attempt is made to present chronology.) The researches of Grewe and Mondon opened the way to the

Morphinans

293

preparation of the morphinans-nnorphine analogs lacking the furan ring—by total synthesis.13 Modified Knoevnagel condensation of carbethoxycyclohexanone with ethyl cyanoacetate gives the unsaturated cyanoester, 31, Saponification followed by decarboxylation gives the corresponding dicarboxylic acid; migration of the double bond is a consequence of the mechanism of decarboxylation. Reaction with ammonium carbonate affords the corresponding cyclic imide. This dihydroxypyridine (33) is but a tautomer of the initial product. Treatment with phosphorus oxychloride leads to the dihalo compound (34), which affords the tetrahydroisoquinoline, 35, on reduction. Reaction with methyl iodide gives the methiodide (36). Since this ring system now carried a positive charge, there is present in the ring what is in effect a ternary imminium function, a group known to add organometallic reagents. Thus, exposure of the salt to benzylmagnesium chloride affords the adduct (37). Catalytic reduction in the presence of acid results in selective removal of that double bond which is in effect part of an enamine. Treatment of the olefin thus obtained (38) with phosphoric acid leads to Friedel-Crafts-type cyclization into the aromatic ring and formation of the unsubstituted morphinan (39). Although cyclization at the alternate terminal of the double bond is possible in theory, the known preference for six-membered ring formation in this reaction assures regioselectivity. In an extension of this work, Schnider and his colleagues condensed the salt (36) with the Grignard reagent from p-methoxybenzyl chloride. The product (40), on reduction (41) and cyclization, affords the methoxylated morphinan (41). Removal of the methyl ether affords the narcotic analgesic racemorphan (43).1A As an alternate route to functionalized morphinans, the intermediate, 38, is first nitrated, the group entering para to the methylene bridge (44). Reduction of the nitro to the aniline (45) followed then by diazotization and replacement by hydroxyl gives intermediate, 46. Cyclization as above again gives racemorphan . 1 u Resolution of racemorphan via the tartrate salt affords a very potent analgesic. The (-) isomer, [{~)43],15 is a narcotic analgesic showing six to eight times the potency of morphine in man. The methyl ether of the epimer [(+)42], dextromorphan, on the other hand, shows little if any analgesic activity; this compound, however, is quite effective in suppressing the cough reflex. As such it is used extensively in cough remedies. Demethylation of the acetyl derivative (47) of levorphanol affords desmethyl compound, 48. Hydrolytic removal of the acetate (49) followed by alkylation with allyl bromide affords the narcotic antagonist levallorphan (50),15 an agent with properties

294

Derivatives of Morphine

a:

,/^CO2H

•CO2^ 2 5

CXcOH CO 2 C 2 H 5 32

i CH2

OCr36

37

1

33, X=OH 34, X=Cl 35, X=H

CH3 CIl2

N-CH3

•=.

38 38

39

quite similar to nalorphine (13). Alternately, alkylation of 49 with 2-phenethyl bromide gives the antagonist phenomorphan (51); in a similar manner alkylation by means of phenacyl bromide affords the antagonist 1evophenacylmorphan (52).16

Morphinans

295

OCH.

CH 9 N-CH3

36

CH3O 30 41

42, 43,

R=CH3 R=H

38

44, 45,

X=NO 2 X-MI2

48,

R=Ac

49,

R=H NCH2R

50

r

R=CH=CH2

51,

R=CH2C6H5

52,

R=COC6H5

296

Derivatives of Morphine

The narcotic antagonists in the morphinan series are more readily available by an alternate synthesis that avoids the demethylation step. Reaction of cyclohexanone with ethyl cyanoacetate affords the condensation product (53). Hydrolysis followed by decarboxylation leads to the unconjugation unsaturated nitrile (54). This is then reduced to the corresponding amine (55) by means of lithium aluminum hydride. Formation of the amide with p-methoxyphenylacetyl chloride gives the intermediate, 56. Treatment with phosphorus oxychloride brings about condensation of the amide—as its enolate—with the isolated cyclohexane double bond, and thus cyclization. The resulting imine double bond is then selectively reduced to afford the isoquinoline derivative (57).X7 Demethylation followed by resolution yields a key intermediate to compounds 50-52, N-alkylation with an appropriate side chain affords 58; cyclization in a manner analogous to that used to prepare levorphanol (43) gives the desired product.18

CO2C2H5 a

-

&

~

53

e

n

54

-

>

o 55

a

I 50-52

3.

BENZOMORPHANS

In a continuation of the theme of simplification of the morphine ring, it was found that one of the carbocyclic rings (that which contained the allyl alcohol in morphine proper) can be dispensed with as well, to give compounds that show the full activity of the natural prototype. These agents, the benzomorphans, are of

297

Benzomorphans

unusual clinical significance, since one of these compounds, pentazocine (67), seems to show greatly diminished addiction potential when compared to the classic narcotic analgesics. Pharmacologic research in this series pointed up the importance of narcotic antagonist activity in the search for nonaddictive analgesics. It is now considered that analgesics with low addiction potential may well come from those agents which show varying mixtures of agonist and antagonist activity in test animals. It is clear that the search for pure analgesics among compounds bearing some of the structural features of the narcotics have more often than not led to highly addictive agents. The prototype, benzomorphan (63), can be obtained by a variation of the morphinan synthesis. Thus, reaction of the Grignard reagent from p-methoxybenzyl chloride with the lutidine methiodide (59) affords the benzylated dihydropyridine 60. (The addition to the most highly hindered position is rather puzzling.) Reduction of the enamine double bond leads to the tetrahydropyridine (61). Cyclization by means of acid leads directly into the benzomorphan ring system (62). Demethylation of the aromatic ether affords the phenol, 63.19 Although this last compound is in fact a relatively potent analgesic, it is not available commercially as a drug. CH 3

»+ r

CH 2 MgCl

CH 3 O

CH

CH3

CH 3

61

59

CH3 CH3O

OCH,

63

62

61

The key to clinical agents in this series, the secondary amine, 65, is obtained by a sequence analogous to that used to obtain desmethymorphine. Thus, the phenol (63) is first acetylated (64), and then demethylated by treatment with cyanogen bromide; hydrolysis gives the desired aminophenol (65). Alkylation

298

Derivatives of Morphine

with 2-phenethyl bromide affords the potent analgesic agent, phenazocine (66) , 2 0 a compound used briefly in the clinic. Alkylation by means of 3,3-dimethylallyl chloride yields pentazocine (67),21 the analgesic alluded to above. Finally, alkylation with cyclopropylmethyl bromide gives cyclazocine (68),22 a potent narcotic antagonist that has shown analgesic activity in man. This last would be an analgesic agent of choice but for its halucinogenic propensity.

63

AcO 64

CH-, 65 66,

R=CH2CH2C6H5

/CH 3 67, R=CH2CH=C 68, R=C

4.

4-PHENYLPIPERIDINES

More radical dissection of the morphine molecule was in progress concurrently with the work above. The chemistry of the series of analgesics that rely on an acyclic skeleton, the compounds related to methadone, is discussed earlier. Suffice it to say that this series of agents, with the possible exception of propoxyphene, seem to share abuse and addiction potential with their polycyclic counterparts. Examination of the morphine molecule reveals the presence of a 4-phenylpiperidine fragment within the molecule (A). It was

4-Phenylpiperidines

299

presumably this line of reasoning that led to yet another extensive series of synthetic analgesics. The great diversity of structural types that have exhibited analgesic activity has led medicinal chemists to seek the thread common to these various molecules. The so-called "morphine rule" represents one formulation of the elements shared by the large majority of analgesics. Briefly, activity seems to require an aromatic ring (a) attached to a quaternary center (b) and a tertiary nitrogen atom (c) removed at a distance of two carbon atoms from (a). Like most such generalizations, this rule has its exceptions; fentanyl (141), for example, does not fit the rule very well.

The prototype for the phenylpiperidine analgesics (meperidine, also known as pethidine, 75) was discovered by Eisleb in Germany on the very eve of World War II. The consequent blackout on international scientific communications led to work on these molecules being pursued in parallel in both warring camps; it goes without saying that analgesics are at a premium in time of war. The dislocation in Germany following the war meant that the majority of publications on these molecules originated outside Germany. One of the early syntheses of meperidine (75) starts with the double alkylation of phenylacetonitrile with the bischloroethyl amine, 72.23 The highly lachrimatory nature of this material led to the development of an alternate synthesis for the intermediate piperidine (73). Alkylation of phenylacetonitrile with two moles of 2-chloroethylvinyl ether leads to the intermediate (69). This is then hydrolyzed without prior isolation to the diol, 70. Treatment with thionyl chloride affords the corresponding dichloro compound (71). This last is then used to effect a bis alkylation on methylamine, in effect forming the piperidine (73) by cyclization at the opposite end from the original scheme. Saponification to the acid (74) followed by esterification with ethanol affords the widely used analgesic meperidine (75)2i*; substitution of isopropanol for ethanol in the esterification affords properidine (76).24

300

Derivatives of Morphine

C1CH2CH2 N-CH3

N-CH3

CH2CN C1CH2CH2 72

CH 2 CH 2 OR

CH 2 CH 2 C1

C-CN - / \ CH 2 CH 2 OR

CH 2 CH 2 Cl

N-CH-,

69, R=CH=CH2 70, R=H

\ N-CH, CO 2 CH CHi 76 Much work has been carried out in this series on changing the substitution on nitrogen in the hopes of producing compounds with some degree of narcotic antagonist activity in analogy to the agents more closely related to morphine While that goal has not been met, such substitution has afforded agents with enhanced potency relative to meperidine. The key intermediate, normeperidine (81), is obtained by a scheme closely akin to that used for the parent molecule. Thus, alkylation of phenylacetonitrile with the tosyl analog of the bischloroethyl amine (78) leads to the substituted piperidine (79). Basic hydrolysis serves to convert the nitrile to the acid (80). Treatment of this last with sulfuric acid in ethanol serves both to esterify the acid and to remove the toluenesulfonyl group to yield the secondary amine (81).25 Alkylation of that amine with p-(2-chloroethyl)aniline affords anileridine (82),26 an analgesic similar to the parent compound but somewhat more potent. In similar fashion alkylation by means of N-(2-chloroethyl)morpholine gives morpheridine (83),27 while the use of 2-(chloroethyl)-ethanol yields carbethi*

4-Phenylpiperidines

301

dine (84).28 Use of halide, 87 (obtained by reaction of furfuryl alcohol with ethylene oxide, followed by formation of the chloride from the condensation product (86), in this reaction affords

the analgesic furethidine

(85),29

C1CH2CH2\

-CH2CN

NTs

NTs

ClCH2CH2'

NTs

78 Ts-SOo-i

QiOCH 25 82, U = C NH, 83, R C -H C N 2H 2 0

H OpN COC 2H 25 81

84, R=CH2CH2OCH2CH2OH

8b, R^CH

CIUOH

CH2OCH2CH2OH 86

[f

\\

CH2OCH2CH2C1 87

Condensation of normeperidine (81) with 3-chloropropan-l-ol affords the compound possessing the alcohol side chain (88). The hydroxyl is then converted to chlorine by means of thionyl chloride (89); displacement of the halogen by aniline yields piminodine (90).30 Condensation of the secondary amine, 81, with styrene oxide affords the alcohol, 91; removal of the benzyllic hydroxyl group by hydrogenolysis leads to pheneridine (92).31

Derivatives of Morphine

302

Conjugate addition of norpethidine (81) to benzoylethylene gives the ketone, 93. Reduction of the carbonyl group to the alcohol affords the potent analgesic phenoperidine (94),32

N-CH2CH2C6H5

-CH2CH2CH2R «~ 81 CO2C2H5

CO2C2H5

C02CH3

91

92

88, R=0H 89, R-=C1

Q

NCH2CU2CH2NHC6H5 G CO2C2II5 90

opNCH C C H 2H 2C 5 CO C H 225 93

A not uncommon side effect observed with morphine and some of the other narcotic analgesics is constipation due to decreased motility of the gastrointestinal tract. It proved possible to so modify pethidine as to retain the side effect at the expense of analgesic activity. Relief of diarrhea, it will be realized, is a far from trivial indication. Alkylation of the anion from diphenylacetonitrile (95) with ethylene dibromide gives the intermediate, 96.33 Alkylation of normeperidine (81) with that halide affords diphenoxylate (97),34 an antidiarrheal agent.

CHCN

BrCH2CH2Brv

96 95

C H 6\5 N C -H C H C -N 2 2C CH 65 97

In an effort to more closely mimic the aromatic substitution pattern found in morphine (see A) the pethidine analog containing the zi7-hydroxy group was prepared as well. Thus, in a synthesis analogous to that used to prepare the parent compound, double alkylation of m-methoxyphenylacetonitrile with the chloroamine,

4-Phenylpiperidines

303

72y affords the piperidine (98) . Treatment with hydrogen bromide effects both demethylation of the phenolic ether and hydrolysis of the nitrile (99); esterification with ethanol affords bemidone (100).35 Alternately, reaction of the nitrile of 98 with ethylmagnesium bromide gives, on acidic workup, the ketone (101); demethylation affords ketobemidone (102),36 Both these agents are effective analgesics.

"

V

C 3

' CN

"°

98

t H O CO C C 2H 2H 100 3

CH

3°

N-CH, CH3O

COCH2C1I3 101

i HO' COC C 2[:H 3 102

Ring expansion of the nitrogen-containing ring has proven compatible with retention of analgesic activity. Phenylacetonitrile is again the starting material. Alkylation with one equivalent of N-(2-chloroethyl)dimethylamine gives the aminonitrile (103); alkylation of this with bromochloropropane yields the molecule containing the requisite carbon atoms (104). Simply heating the free base leads to cyclization by means of formation of the internal quaternary salt (105); pyrolysis of that salt at 225°C results in elimination of one of the methyl groups, possibly by displacement on carbon by the chloride gegenion. Saponification of the product (106) followed by esterification with ethanol gives ethoheptazine (107),37 an orally effective analgesic used largely in the treatment of mild pain. Exploratory research on structure activity relationships in the meperidine series revealed the interesting fact that the oxygen atom and carbonyl group of this molecule could often be interchanged. That is, the so-called "reversed meperidine" (C) still exhibits analgesic activity in experimental animals. (Note that, except for the interchange, the rest of the molecule is unchanged.) An analog of the above "reversed" pethidine, alphaprodine (114), has found application as an analgesic in the clinic. Michael addition of methylamine to methyl methacrylate (108)

304

Derivatives of Morphine

CN • CH, CHCH2CH2N 103

105

N-CH,

N-CH3

N-CH, 0CCH2CH3 II 0

gives the amino ester, 109. Addition of ethyl acrylate in a second conjugate addition leads to the diester (110). Treatment of this last with base affords via Dieckmann cyclization, the carbomethoxy piperidone (111). The direction of cyclization is probably controlled by formation of the enolate obtained by removal pf the most acidic proton (i.e., that on the tertiary carbon atom). Hydrolysis of the ester followed by decarboxylation gives the piperidone (112). It is highly likely that the methyl group in this ketone occupies the equatorial position. Reaction with phenylmagnesium bromide gives the corresponding tertiary alcohol, 113, which affords alphaprodine (114)3S on acylation with propionic anhydride. Stereochemical assignment by x-ray crystallography showed that the phenyl and methyl groups bear a trans relation.39 It is of note that this isomer is that which would be produced from attack of the organometallic reagent on 112 from the less-hindered side.

4-Phenylpiperidines

nrr r, CH2=C~CO2CH3 CH3

>

305

CH3NHCH2CHCO2CH3 CHq

CH3 I /CH2CHC02CH3 > CH3N N CH2CH2CO2C2H5

109

no

1O8

CH3 ,—< CH3N Vo 113

U2

CH3 / JL-CO 2 CH 3

<

CH3N

Vo 111

114 The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117); acylation with propionic anhydride gives the analgesic agent prolidine (118),h0 Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the

306

109

Derivatives of Morphine

•—>

CH3 /CH2CH-CO2CH3 CH3N X

CH2CO2C2H5 115

/^Y°H3 -—> CH3N 1

—*>

\^A) 116 117, R=H R=CCH2CH3

ketone o£ 4-piperidone to produce several major tranqulizers that bear only the slightest relation to meperidine. The circle was finally closed with the finding that one of the agents developed by this route—fentanyl (141)—is an extremely potent analgesic agent in man. It would almost seem that informed chemical manipulation in the hands of chemists well versed in medicinal agents on some molecule of known activity more often than not produces compounds with biologic activity in some related areas. The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl~4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-l,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) .U1 The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chlorobutyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus, 122a gives the important antipsychotic agent haloperidol (124a) J*2 Similar reaction on 122b leads to trifluoperidol (124b) >k3 while 122c gives chlofluperidol (124c). In a departure from the prototype molecule, the benzylpiperidone is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone (128). The synthesis of the tranquilizer, spiropiperone (130),hM is completed by removal of the benzyl group by hydrogenolysis (129), followed by alkylation with the butyrophenone side chain

4-Phenylpiperidines

(123)

307

. Scheme 1

HOCH 2 : NH 2

CH20

HOCH2NHCH2OH

;z±

a

CH2

~±

HOCH2NHCH c

b

H

H HO - ^

N

CH, CH 3 **^ C 6 H 5

?

o CH3>
P C6H5

119

CH

CHo

CfiH,

CH3

119a, 119b, 119c,

X-C1,Y=H X=H,Y=CF, X=Cl,Y=CF 3

120a, 120b, 120c,

X--Cl,Y~~H X=H,Y-CF3 X-Cl,Y CF3

121a, 121b, 121c,

X=Cl,/=-H X=H,Y=CF3 X-Cl,v-C^3

0

0\\

-C-CH 2 CH 2 CH 2 N

124a, 124b, 124c,

X=C1,Y=H X=H,Y=CF3 X=C1,X=CF3

X

122a, X- C1,Y 1 I 2 2 J b , X=H,Y-CP 3 122c, X=-C1,Y=-CF3

308

Derivatives of Morphine

0 li C 6 H 5 CH 2 N

o I C6H5

225 126

127

129 130

In another essay in heterocyclic chemistry, the ketoester, 131 (an intermediate in the preparation of 125), is allowed to react with o-phenylene diamine. While the transformations involved in formation of the isolated product (132) can be rationalized (decarbomethoxylation, enamine formation, and finally cyclization to a benzimidazolone, possibly with the carbon derived from the decarboxylation), the order of these reactions is far from clear. Catalytic reduction, interestingly, selectively cleaves the benzyl group. It is possible that the bulky substituent on the enamine protects this usually readily reducible function. Alkylation by means of the familiar side chain completes the synthesis of droperidol (134).us This tranquilizer finds important use in conjunction with the analgetic fentanyl (141) in preanesthetic sedation. Aminonitrile formation on 125 with potassium cyanide and piperidine hydrochloride affords the derivative, 235. Hydrolysis as above gives the corresponding amide (136). Debenzylation is accomplished by catalytic reduction. Alkylation of the secondary amine with the side chain (96) used in the preparation of diphenoxylate affords pirintramide (138) he This compound, interestingly enough, is an analgetic agent, although still one that follows the morphine rule, albeit in the side chain. Finally, this general approach produced one of the most potent analgesics known, a compound that paradoxically does not fit the morphine rule at first sight. While details of the preparation are not readily available, in theory at least, treatment

4-Phenylpiperidines

309

CO2C2H5 NH

C 6 H 5 CH 2 N"""YO

131 132

HN

>N

NH

134 of piperidone, 139 , with aniline would be expected to give the

125

C6H5CH2N

C 6 H 5 CH 2 N

O

136

135

C0NH2

o 138

IV

corresponding Shiff base (140). Reduction then would afford the diamine (141). Acylation with propionic anhydride would afford fentanyl (142), an analgetic that shows some 50 times the potency of morphine in man.

310

Derivatives of Morphine

°o

C H 2 C H 2 C 5H 5

139

140 — C H 2 CH 2 C ^H 5

141

— C H 2 C H 2 C (jH 5

REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

(a) M. Gates and M. Tschudi, J. Amer. Chem. Soc, 78, 1380 (1956). (b) D. Elad and D. Ginsburg, J. Amer. Chem. Soc, 76, 312 (1954). P. Chabrier, P. R. L. Ciuclicelly, and C. H. Genot, U. S. Patent 2,619,485 (1952). L. Small, S. G. Turnbull, and H. M. Fitch, J. Org. Chem., 3, 204 (1939). II. Wieland and E. Koralek, Ann., 433, 269 (1923). K. Pfister and M. Tishler, U. S. Patent 2,715,626 (1955). H. Rapoport, R. Nauman, E. R. Bissell, and R. M. Bouner, J. Org. Chem., 15, 1103 (1956). J. Wei j land and A. E. Erickson, J. Amer. Chem. Soc, 69, 869 (1942). M. Freund and E. Speyer, J. Prakt. Chem., 94, 135 (1916). U. Weiss, J. Amer. Chem. Soc, 77, 5891 (1955). M. J. Lowenstein, British Patent 955,493 (1964). L. Small and H. M. Fitch, J. Amer. Chem. Soc, 58, 1457 (1936). L. Small, S. G. Turnbull, and H. M. Fitch, J. Org. Chem., 3, 204 (1939). A. Grewe and A. Mondon, Chem. Ber., 81, 279 (1948).

References

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

311

0. Schider and A. Gussner, Helv. Chim. Acta, 32, 821 (1949). 0. Schider and A. Gussner, Helv. Chim. Actar 34, 2211 (1951). A. Grussner, J. Hellerbach, and 0. Schider, Helv. Chim. Acta, 40, 1232 (1957). 0. Schider and J. Hellerbach, Helv. Chim. Acta, 33, 1437 (1950). J. Hellerbach, A. Gussner, and 0. Schnider, Helv. Chim. Acta, 39, 429 (1956). E. L. May and J. H. Ager, J. Org. Chem., 24, 1432 (1959). E. L. May and N. B, Eddy, J. Org. Chem., 24, 295 (1959). S. Archer, N. F. Albertson, L. S. Harris, A. K. Pierson, and J. G. Bird, J. Med. Chem., 7, 123 (19641. S. Archer, Belgian Patent 611,000 (19621. 0. Eisleb, Chem. Ber., 74, 1433 (1941). A. L. Morrisson and H. Rinderknecht, J. Chem. Soc, 1469 (1950). R. H. Thorp and E. Walton, J. Chem. Soc, 559 (1948). J. Weijlard, P. Dorahovats, A. P. Sullivan, G. Purdue, F. K. Heath, and K. Pfister, J. Amer. Chem. Soc, 78, 2342 (1956). R. J. Anderson, P. M. Frearson, and E. S. Stern, J. Chem. Soc, 4088 (1956). H. Morren, U. S. Patent 2,858,316 (1958). P. M. Frearson, D. G. Hardy, and E. S. Stern, J. Chem. Soc, 2103 (1960). B. Elpern, P. Carabateas, A. E. Soria, L. N. Gardner, and L. Grumbach, J. Amer. Chem. Soc, 81, 3784 (1959). T. D. Perine and N. B. Eddy, J. Org. Chem., 21, 125 (1956). P. A. J. Janssen and N. B. Eddy, J. Med. Chem., 2, 31 (1960). D. J. Dupre, J. Elks, B. Attems, K. N. Speyer, and R. M. Evans, J. Chem. Soc, 500 (1949). P. A. J. Janssen, A. H. Jagenau, and J. Huygens, J. Med. Chem., 1, 299 (1959). A. L. Morrison and II. Rinderknecht, J. Chem. Soc, 1469 (1950). A. W. D. Aridon and A. L. Morison, J. Chem. Soc, 1471 (1950). J. Diamond, W. F. Bruce, and F. T. Tyson, J. Org. Chem., 22, 399 (1957). A. Ziering, A. Motchane, and J. Lee, J, Org. Chem., 22, 1521 (1957). F. R. Ahmed, W. H. Barnes, and G. Kartha, Chem. Ind., 485 (1959). J. F. Caralla, J. Daroll, M. J. Dean, C. S. Franklin, D. M. Temple, J. Wax, and C. V. Winder, J. Med. Chem., 4, 1 (1961). C. S. Schmiddle and R. C. Mansfield, J. Amer. Chem. Soc, 78, 1702 (1956).

312

Derivatives of Morphine

42.

P. A. J. Janssen, C. VanDeWesteringhe, A. H. M. Jageneau, P. J. A. Demoen, B. F. K. Hermans, G. H. P. VanDaele, K. H. L. Schellekens, C. A. M. VanDerEycken, and C. J. E. Niemegeer, J. Med. Chem., 1, 281 (1959). P. A. J. Janssen, British Patent 895,309 (1962). P. A. J. Janssen, U. S. Patent 3,125,578 (1964). P. A. J. Janssen, Belgian Patent 626,307 (1963). P. A. J. Janssen, Belgian Patent 606,856 (1961).

43. 44. 45. 46.

CHAPTER 16

Five-Membered Heterocycles Fused to One Benzene Ring

1.

BENZOFURANS

The spasmolytic agents described previously have in common substitution by basic nitrogen. Recently there has been developed a series of antispasmodic drugs that have as a common structural feature an oxygen-containing heterocyclic ring fused to a benzene ring. Two of the more important drugs, khelin and chromoglycic acid, possess six-membered heterocyclic rings and are discussed in the next section. The five-membered counterpart of these agents, benziodarone (4), has found use as a coronary vasodilator.

!H 2 C H 3

C H 2 CH 3

2, R=CH3 3, R=H

313

314

Five-Membered Benzoheterocycles

Reaction of the potassium salt of salicylaldehyde with chloroacetone affords first the corresponding phenolic ether; aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. FriedelCrafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). Iodination of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4).1 Research on novel fungal secondary metabolites resulted in the isolation of an interesting spiran, griseofulvin (15), from fermentation beers of the mold Penicillium griseofulvum. This compound was eventually found to have activity against a series of pathogenic fungi rather than bacteria. Diseases such as ringworm of the body, scalp, feet, and nails constitute a group of fungal infections limited to the outer cutaneous layers known as superficial mycoses. These infections are unusually tenacious and even successful cures are often quickly followed by reinfection. Griseofulvin owes much of its effectiveness to the fact that the drug binds to the keratin cells which will eventually differentiate to form skin, hair, and so forth. These cells consequently become resistant to infection by the fungus. This mode of action also means that therapy is very slow; weeks to months are required for complete cure. Although griseofulvin is probably still prepared commercially by extraction from fermentation beers, numerous total syntheses of the drug have been reported. In the first of these,2 the key step in the synthetic sequence involves an oxidative phenol coupling reaction patterned after the biosynthesis of the natural product. Preparation of the moiety that is to become the aromatic ring starts by methylation of phloroglucinol (5) with methanolic hydrogen chloride to give the dimethyl ether (6). Treatment of that intermediate with sulfuryl chloride introduces the chlorine atom needed in the final product (7). Synthesis of the remaining half of the molecule starts with the formation of the monomethyl ether (9) from orcinol (8). The carbon atom that is to serve as the bridge is introduced as an aldehyde by formylation with zinc cyanide and hydrochloric acid (10). The phenol is then protected as the acetate. Successive oxidation and treatment with thionyl chloride affords the protected acid chloride (11). Acylation of the free phenol group in 7 by means of 21 affords the ester, 22. The ester is then rearranged by an ortho-Fries reaction (catalyzed by either titanium

Benzofurans

315

OCH,

OR OH

OH Cl 7

5, R=H 6, R=CH3

OCH 3 OCH 3 OCOCH,

Cl 12

0CH

RO

OH

CH3O

/

OR CH3O ^

(

x-c

CI13

13

10 r X=II;R=-H 11, X=C1;R=COCH3

8, R=H 9, R=CH3

3

0CH3 CH3O

OCH , l

OH T^> !^ OH

Cl

CH3

CH,

^

30 , C^

CH3O

0 OCH j

00CH 14 3

Cl

Cl 25

tetrachloride or ultraviolet irradiation) to give the hydroxybenzophenone, 13, which contains, in their proper arrangement, all the carbon atoms of the final product. Treatment with alkaline ferricyanide produces the diradical (presumably on the phenol oxygen and the carbon bearing the carbonyl group); coupling leads to

316

Five-Membered Benzoheterocycles

the spiro compound, dehydrogriseofulvin (14). Catalytic hydrogenation produces predominantly d,1-griseofulvin (15), as the other diastereoisomeric pair is apparently not favored under the conditions used. The second synthesis follows an entirely different synthetic plan—one dependent upon a double-Michael reaction to establish the spiran junction. Chlorophenol, 7, is reacted with chloroacetylchloride to give coumaranone, 16. This is treated with methoxyethynyl propenyl ketone (17) (itself prepared by 1,2-

CH3O.C5

7

16

15

"

addition of lithium ethoxyacetylene to crotonaldehyde followed by manganese dioxide oxidation of the doubly activated secondary carbinol function) in the presence of K tert-butoxide catalyst. The ensuing double-Michael reaction is surprisingly stereospecific; the enantiomeric diastereoisomers representing d,l~griseofulvin (15) predominate. Although well known to most chemists as an acid-base indicator, phenolphthalein (19) in fact has a venerable history as a laxative. (An apocryphal tale has it that it was at one time added to some rather expensive white wines in order to foil counterfeiters of that product; that is, only the authentic product would turn red on addition of caustic. One may imagine that the medicinal use was thus discovered inadvertently to the discomfort of many a tastevin.) The biologic effect of this compound is irritation of the bowel of sufficient intensity to start the peristalsis that leads eventually to evacuation. The low toxicity of the drug as well as its otherwise innocuous nature has led to its extensive over-the-counter use as a laxative. Reaction of phthalic anhydride with phenol in the presence of any one of a number of acid catalysts affords phenolphthalein (19); as an example, the reaction can be catalyzed by a mixture of zinc chloride and thionyl chloride. ** The acid base indicating properties depends on the opening of the phthalide to quinone, 20, above pH 9. Under some circumstances the drug is excreted as the highly colored quinoid form. The resulting red feces and/or urine can alarm the unprepared.

Benzofurans

317

OH

18

19 20

2.

INDOLES

The presence of the indole moiety in many biologically active alkaloids has long held out the promise that simpler compounds built around this nucleus would provide useful drugs. Although a great many such compounds have in fact shown biological activity, relatively few of these agents have found clinical use. It is perhaps of note in this connection that the indole nucleus does not confer on molecules any unique set of biological properties; activities of indole seem to depend more on the nature of the substituents. Etryptamine (23) is a tryptamine derivative which has been used as an antidepressant. Its synthesis involves the condensation of indole-3-carboxaldehyde (21) with the active methylene group of 1-nitropropane to form the inner nitronium salt of the substituted nitrovinyl indole (22). This then is readily reduced to etryptamine (23),5

CHO !H 2CH 3 21

22 CH-NH2 CH 2 CH 3 23

318

Five-Membered Benzoheterocycles

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the RogersCorson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3dimethy1aminopropyl chloride. There is thus obtained iprindol (25).e

,CH, CH2CH2CH2N 24 25 The pharmacologic activity of indomethacin (28) has occasioned much interest because it is one of the most potent of the nonsteroidal antiinflammatory agents. Its reported synthesis starts by conversion of 2-methyl~5-methoxyindoleacetic acid (26) to its tert-butyl ester (27) by means of dicyclohexylcarbodiimide and tert-butanol in the presence of zinc chloride. With the carboxyl group thus protected, the amine function of 27 is acylated with p-chlorobenzoyl chloride. The tert-butyl ester protecting group is then removed pyrrolytically to give indomethacin (28). Although such esters are usually removed by treatment with acid, the instability of N-acyl indoles toward acid and base hydrolysis requires pyrrolytic scision. CH2C02H

26

CH2CO2-CMe3 CH 3 q

CH2CO2H

27 28

319

Indoles

Fischer indole condensation of Ni-benzylphenyl-hydrazine and 1methyl-4-piperidone under the usual acid conditions affords melohydroline (29),8 an indole used as an antihistaminic agent.

0=/

N-CH3

NNH

3.

INDOLE ALKALOIDS

Reserpine (30) is the most important of the related alkaloids found in extracts of the Indian Snakeroot, Rawaulfia serpentina. This root, which had been in use in folkloric medicine in the foothills of the Himalayas, was prescribed for treatment of ills ranging from snakebite through insomnia to insanity. Such diverse claims for natural product mixtures frequently turn out to be groundless when examined by the procedures of modern pharmacology. However, a sufficient number of these have provided leads for new drugs; therefore they cannot be lightly dismissed. In the case of reserpine, authentic reports on the pharmacology of the extracts were published in journals accessible to western scientists in 1949. By 1954 the alkaloid reserpine had been isolated and purified; its value as a medicinal agent was established soon after. This development was followed by the chemical structure determination. Initially, reserpine was used for the treatment of both hypertension and psychoses. The latter indication nearly coincided with the discovery of the tranquilizer chlorpromazine. It is of note that the two drugs ushered in the new era of psychopharmacology. The advent of a host of synthetic antipsychotic agents has diminished the importance of reserpine for this indication. The agent is still frequently prescribed in the treatment of hypertension, as are its closely related congener, rescinnamine (31), and the semisynthetic compound syrosingopine (32). The preparation of reserpine by an ingenious and elegant total synthesis was completed astonishingly soon after completion of the structure determination.9 The great demand for this drug coupled with shortage of material from natural sources because of overharvesting and embargoes led the group at Roussel-UCLAF to effect improvements on the Woodward synthesis.10'11 For a time,

320

Five-Membered Benzoheterocycles

at least, the synthetic material was competitive with reserpine obtained by extraction of the snake root. Omission of the methoxyl group on the aromatic ring of the parent alkaloid affords deserpidine (40), a drug that closely mimics the activity of reserpine itself. Total synthetic preparation of this agent has the important advantage of using tryptamine rather than the difficultly accessible 6-methoxy analog as starting material. A Czech group developed a total synthesis for deserpidine starting with the key intermediate in the Woodward synthesis (33) . 9 Reaction of that compound with zinc and acetic acid simultaneously effects elimination of the cyclic bromoether to the unsaturated ketone and reductively cleaves the lactone initially fused to the carbonyl group. In a single stage there is thus established both the substitution and stereochemistry of substituents for the future E ring. Acetylation gives the intermediate, 34. Hydroxylation of the double bond with a trace of osmium tetroxide in the presence of potassium perchlorate leads to the glycol, 35. Treatment of that compound with periodic acid first cleaves the glycol to the corresponding dialdehyde. The aldehyde adjacent the carbonyl group is cleaved again with loss of one carbon atom under the reaction conditions. Esterification of the crude product then affords the highly functional!zed cyclohexane, 36. Condensation of the aldehyde of 36 with the amine group of tryptamine serves to join ring E with the fragment that will form the remaining rings (37). Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the S~ lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the

OMe

OMe 30, R=OMe,X=-,R'=OMe 31, R=OMe,X=CH=CH,R'=OMe 32, R=OMe,X=- 5 R'=C0 2 Et

321

Indole Alkaloids

MeO 2 C

OMe

OMe

CO2 Me

II |

MeO 2 C

0

MeO 2 C ' ^ f "OCOMf 6 Me 17

40,

"wrong" stereochemistry at C3, affording nearly inactive isodeserpidine (39). Formation of the iminoperchlorate salt followed by reduction with zinc-perchloric acid, however, leads to a mixture sufficiently rich in the natural stereoisomer that fractional crystallization gives satisfactory yields of d,1-deserpidine (40). This is then resolved by crystallization of the d-camphor-sulfonic acid salt to complete the synthesis.

4.

ISOINDOLES

Chlorexolone (46) was apparently synthesized in following up the structural lead represented by chlorothiazide. It was felt, correctly, that significant alterations in pharmacologic profile would follow changes in the heterocyclic ring rather than the ring bearing the sulfonamide group. Chlorexolone was the best of a series of analogs prepared by this rationale.

322

Five-Membered Benzoheterocycles

ci NH

41

Cl

CL

02N

C1O 2 S

rx?o

H 2 NO 2 S

46

45

44

Imine exchange of 4-chlorophthalimide (41) with cyclohexylamine gives intermediate, 42. Reduction by heating with tin and a mixture of hydrochloric-acetic acids leads to the 2-oxoisoindole system (43). Nitration by means of potassium nitrate in sulfuric acid mixture follows normal directing influences to give 44. The nitro group can then be transformed to a chlorosulfonyl function (45) by successively reducing with stannic chloride, diazotizing the resulting amine with nitrous acid, and then performing a Sandmeyer reaction with sulfur dioxide and cuprous chloride in acetic acid. Treatment with liquid ammonia gives chlorexolone (46),13 a diuretic agent used in treatment of hypertension. Chlorthalidone (49) is another thiazide-like diuretic agent that formally contains an isoindole ring. Transformation of the amine in benzophenone, 47, to a sulfonamide group by essentially the same process as was outlined for chlorexolone (46) affords intermediate 48. This product cyclizes to the desired pseudoacid 1-ketoisoindole (49) on successive treatments with thionyl 0

CO2H

0

CO2H

47

49

Isoindoles

323

chloride and ammonia in aqueous ethanol.14 Pseudoacids of this general type are well known in organic chemistry; such acid-base interactions of orthocarboxybenzophenones (50-51) have been studied in some detail.

51

50, X=O,S or Nil

,CH3

CO2C1I3 Nil I CH2

—r N'

OCH2CH2CHjN I

if

'CH3

JNH

i Cll ,

ni

52

5 .

INDAZOLES

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader's prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethy1aminopropyl chloride. There is thus obtained benzydamine (54),15 a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties.

6.

BENZOXAZOLES

The antispasmodic agent, chlorzoxazone (56),16 is obtained by cyclization of the o-hydroxybenzformamide (55), a general method

324

Five-Membered Benzoheterocycles

for preparation of this ring system.

Cl

55

7.

T 56

BENZIMIDAZOLES

Benzimidazoles are generally synthesized from ortho-diamino-ben~ zenes and carboxylic acid derivatives. The antihistaminic agent, clemizole (60), for example, can be prepared by first reacting ortho-diaminobenzene (57) with chloroacetic acid to form 2-chloromethylbenzimidazole (58). Displacement of the halogen with pyro-

57

lidine leads to 59; this is then converted to clemizole (6O)17 by reacting its silver salt with p-chlorobenzylchloride. Although chlormidazole (62) 1 8 is structurally very similar, it is used as a spasmolytic and antifungal agent. It is prepared from 2-methylbenzimidazole (61) by treatment with sodium amide followed by pchlorobenzyl chloride. As shown previously, most strong analgesics incorporate some portion of the morphine molecule; put another way, these agents

Benzimidazoles

325

I

'

^ CH 3

H

61

tend to conform to the morphine rule. Analgesics are known that deviate from these structural requirements. Paradoxically, these drugs, such as, for example, fentanyl, are often far mqre potent than morphine itself as analgesics. A pair of closely related benzimidazoles similarly show analgesic activity far in excess of the natural prototype; at the same time these drugs also show far higher addictive liability than morphine. Nucleophilic aromatic substitution of 2-diethylaminoethylamine on 2,4-dinitrochlorobenzene affords the corresponding amine; reduction with ammonium sulfide selectively converts the nitro group adjacent to the amine to the aniline (64). Condensation of that ortho diamine with the iminoether (65) from p-chlorophenylacetonitrile affords clonitazine (66a).19 Condensation with the iminoether containing the para ethoxy group (65b) leads to etonitazine (66b).19

63 64

x-r

65a, 65b,

Vcn

2

66a, 66b,

X=C1 X=OC 2 H 5

/OC2H5 c^ Nil

X=C1 X=OC 2 H 5

Changing the substitution pattern on the benzimidazole greatly alters the biologic activity. Thus, inclusion of a thiazole ring affords thiabendazole (70), a drug used for the treatment of helminthiasis.

326

Five-Membered Benzoheterocycles

CN NH

67

70

Intermediate arylamidine, 68, is prepared by the aluminum chloride-catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (67) . Amidine, 68, is then converted to its N~ chloro analog (69) by means of sodium hypochlorite. On base treatment, this apparently undergoes a nitrene insertion reaction to produce thiabendazole (70).20

8.

BENZOTHIAZOLES

The sulfonamide group has been used successfully to confer diuretic activity to both aromatic and simple heterocyclic compounds. It is therefore not unexpected to find a similar effect in a heterocycle fused to a benzene ring. Reaction of the substituted benzothiazole, 71, with sodium hypochlorite in a mixture of sodium hydroxide and ammonia affords the sulfenamide, 72, probably by the intermediacy of the sulfenyl chloride.

1*^

N

^jy^ S ^ SH

>

EtOT^J^^S ^ $NH2

71

73

327

Benzothiazoles

In the key step, oxidation with permanganate in acetone leads from the sulfenamide to the sulfonamide. There is thus obtained ethoxysolamide (73).21 The antifungal agent, dianithazole (76),22 is prepared by cleaving the ether function of 2-dimethylamino-6-ethoxybenzothiazole (74) with aluminum chloride in chlorobenzene and then alkylating the sodium salt of the resulting phenol (75) with 2diethylaminoethyl chloride. A dicarbocyanine dye, dithiazinine (79),23 is used as a broad-spectrum anthelmentic agent, although, interestingly, it seems to have been prepared initially for use in photographic emulsions. It is made by heating 2~methylbenzothiazole ethiodide (77) with the malondialdehyde equivalent, 3(ethylmercapto)~acro~ lein diethylacetal (78) in the presence of pyridine. There apparently ensues a sequence of addition-elimination reactions; quenching the reaction mixture with potassium iodide solution results in separation of green crystals of dithiazanine iodide (79).

74

75 NMe2

NCH2CH2 CoH 2n5

76

77

79

328

Five-Membered Benzoheterocycles

REFERENCES 1. 2.

N. P. Buu Hoi and C. Beaudet, U. S. Patent 3,021,042 (1971). D. Taub, C. H. Kuo, H. L. Slates, and N. L. Wendler, Tetrahedron, 12, 1 (1963). 3. G. Stork and M. Tomasz, J. Amer. Chem. Soc, 86, All (1964). 4. H. R. Beaudet, U. S. Patent 2,527,939 (1950). 5. R. V. Heinzelman, W. C. Anthony, D. A. Little, and J. Szmuszkovicz, J. Org. Chem., 25, 1548 (1960). 6. L. M. Rice, E. Hertz, and M. E. Freed, J. Med. Chem., 7, 313 (1964). 7. T. Y. Shen, R. L. Ellis, T. B. Windholz, A. R. Matzuk, A. Rosegay, S. Lucas, B. E. Witzel, C. H. Stammer, A. N. Wilson, F. W. Holly, J. D. Willet, L. H. Sarett, W. J. Holtz, E. A. Rislay, G. W. Nuss, and C. A. Winter, J. Amer. Chem. Soc, 85, 488 (1963). 8. U. Horlein, Chem. Ber., 87, 463 (1954). 9. R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, and R. W. Kierstead, J. Amer. Chem. Soc, 78, 2023; 2657 (1956); Tetrahedron, 2, 1 (1958). 10. L. Velluz, G. Muller, R. Joly, G. Nomine, A. Allais, J. Warnant, R. Bucort, and J. Jolly, Bull. Soc Chim. Fr., 145 (1958). 11. L. Velluz, G. Muller, R. Joly, G. Nomine, J. Mathieu, A. Allais, J. Warnant, J. Vails, R. Bucort, and J. Jolly, Bull. Soc Chim. Fr., 673 (1958). 12. E. Adlerova, L. Blaha, M. Borovicka, I. Ernest, J. 0. Jilek, B. Kakac, L. Novak, M. Rajsner, and M. Protiva, Coll. Czech. Chem. Commun., 25, 221 (1960); L. Blaha, J. Weichet, J. Zvacek, S. Smolik, and B. Kakac, Coll. Czech. Chem. Commun., 25, 237 (1960). 13. E. V. Cornish, G. E. Lee, and W. R. Wragg, Nature, 197, 1296 (1963). 14. W. Graf, E. Girod, E. Schmid, and W. G. Stoll, Helv. Chim. Acta, 42, 1085 (1959). 15. Anon., French Patent 1,382,855 (1964). Chem. Abstr., 62, 13,155a (1965). 16. D. F. Marsh, U. S. Patent 2,895,877 (1950). 17. D. Jerchee, H. Fischer, and M. Kracht, Ann., 575, 173 (1952). 18. S. Herring, H. Keller, and H. M. Muckier, U. S. Patent 2,876,233 (1959). 19. A. Hunger, J. Kebrle, A. Rossi, and K. Hoffman, Experientia, 13, 400 (1957). 20. V. J. Grenda, R. E. Jones, G. Gae, and M. Sletzinger, J. Org. Chem., 30, 259 (1965). 21. Anon., British Patent 795,194 (1958); Chem. Abstr., 52,

References

22. 23.

329

20,212a (1958). N. Steiger and 0. Keller, U. S. Patent 2,578,757 (1951). J. Kendall and H. D. Edwards, U. S. Patent 2,412,815 (1946).

CHAPTER 17

Six-Membered Heterocycles Fused to One Benzene Ring

1.

COUMARINS AND CHROMONES

Clotting of blood is the body's first line of defense against injuries that compromise the integrity of the vasculature. The process of clotting, or coagulation, in essence consists in the polymerization and cross linking of a soluble serum protein, prothrombin, to a hard insoluble polypeptide known as fibrin. Situations do obtain in which it is desirable to retard or even suspend the clotting mechanism. Major surgery is often accompanied by a state known as hypercoagulability; coagulation occurs even within apparently sound vessels to form clots that can block the blood supply to vital organs. Diseases of the circulation such as thrombosis and phlebitis can be controlled by lowering the coaguability of blood. Although still subject to some controversy, anticoagulant therapy has been used in the treatment of stroke. The development of anticoagulant drugs owed its start to an investigation of a disease of cattle characterized by massive hemorrhages. An epidimiologic study revealed that the disease was in fact caused by a factor in the animal's diet; specifically, the affected cattle had fed on spoiled sweet clover. Isolation of the active compound led to its identification as the hydroxycoumarin derivative, 3. The degradative structural assignment was then confirmed by total synthesis. Acylation of methyl salicylate with acetic anhydride affords the intermediate, 1. Strong base forms the carbanion on the acetyl methyl group; this then adds to the carbonyl group of the adjacent ester. Elimination of methanol affords the coumarin (2). Condensation of that product with formaldehyde leads to the addition of two molecules of the heterocycle to the aldehyde in a well-known reaction of enols. 330

Coumarins and Chromones

331

There is thus obtained bishydroxycoumarin (3).x Subsequent pharmacologic and clinical work revealed this compound to be an effective anticoagulant drug in humans. It is of note that none of the synthetic anticoagulants shows in vitro activity. Rather, these compounds owe their effect to inhibition of synthesis by the liver of one of the co-factors necessary for coagulation.

OH

Further work in this area showed that only one of the coumarin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 49 with diethyl carbonate affords 4hydroxycoumarin (2). The reaction may involve the 3-ketoester (5); cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative; cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin: Wisconsin Alumni Research Foundation, WARF) (7).2 The same reaction with p-nitrobenzalacetone (8) affords acenocoumarole (9).3 It might be mentioned in passing that one of the largest uses of warfarin is in fact as a rat poison; animals that ingest the drug in large amounts simply bleed to death. A change in the pK of the molecule by elimination of the acidic enol function and inclusion of basic nitrogen leads to a marked change in biologic activity. That agent, chromonar (13),4 shows activity as a coronary vasodilator. Alkylation of ethyl acetoacetate with 2-chlorotriethylamine affords the substituted ketoester (10). Condensation with resorcinol in the presence of sulfuric acid affords directly the substituted coumarin (11). The first step in the sequence may involve Friedel-Crafts-type condensation of resorcinol with the enolate of 10 to afford the unsaturated ester, 11. Alkylation of the free phenol on 12 by means of ethyl bromoacetate affords chromonar (13) .**

332

Six-Membered Benzoheterocycles

CCH 2 CO 2 C 2 H 5

CH 3 CCH=CH-/

6, X=H 8, X=NO2

^0^0 7, 9,

>X

X=H X=N0 2

0

CH3

il

CH 3 CCHCO 2 C 2 H 5

10

11 \ CHo

0 I! C2H5OCCH2O

CH2CH2N ^2H5

<~-

0 13

12

The psoralens are a family of naturally occurring furocoumarins widely distributed in nature. The crude plant products have a long folkloric history as agents that promote the development of suntans. These products are distinguished from the cosmetic tanning agents in that they are orally active. These drugs have clinical utility in allowing extremely fair-skinned individuals to develop tolerance to sunshine. Preparation of one of the natural products starts with Friedel-Crafts acylation of pyrocatechol with chloroacetic acid by means of phosphorus oxychloride (14). Treatment of the result-

Coumarins and Chromones

333

ing haloketone with sodium ethoxide leads to cyclization with the adjacent phenol (15). Catalytic hydrogenation serves to reduce the carbonyl to a methylene group (16). Condensation of the product with malic acid in sulfuric acid serves to build the coumarin ring in a single step (18). The initial step in this sequence may involve decarboxylation to malonic acid-aldehyde; reaction of the enolate of that product with the aromatic ring would afford an intermediate such as 17, Cyclization with the phenolic hydroxyl followed by decarboxylation would then give 18.) Etherification of the remaining phenol is accomplished by means of diazomethane (19). Dehydrogenation with palladium on carbon in diphenyl ether completes the synthesis of methoxsalen (2O).5

C1CH C1CII2CO2H

18, R=H 19, R=CH 3

17

The synthesis of the psoralen containing a methyl rather than methoxy group on the aromatic ring starts with construction of the coumarin ring. Knoevenagel-like condensation of malonic acid with the substituted salicylaldehyde, 21, affords initially

334

Six-Membered Benzoheterocycles

the unsaturated acid (22). This is then cyclized to the coumarin (23) without prior purification. Decarboxylation completes preparation of the coumarin ring (24). Alkylation of the phenol by means of allyl bromide gives the allyl ether (25). This is converted to the C-allyl compound (26) by the thermal Claisen rearrangement; acetylation with acetic anhydride affords 27. Bromination followed by saponification of the acetate leads to the dibromophenol (28). Solvolysis of this compound in base leads to displacement of halogen by phenoxide to give the dihydrofuran (29). Elimination of the remaining bromine presumably first gives the exocyclic methylene compound. This presumed intermediate is in fact not observed. The overall product from the last reaction is the fully conjugated isomer trioxsalen (30).6

CO2H

< \ ^ CH=C COoH

OH

CH3

CH 3

22

21

23

CH=CH2

C1K

CH 3 25

26, R=H 27, R=COCH3

BrCH, HO RrCH,

RrCH 2 -I 0

"0

CH3 28

29

One of the few nonnitrogenous compounds to show spasmolytic activity is a rather simple chromone. Acylation of the phenolic ketone, 31, with the half ester-half acid chloride from oxalic

Coumarins and Chromones

335

acid presumably first gives the C-acylated derivative {32, shown as the enol). This cyclizes to the chromone under the reaction conditions (33). An alternate path of course involves O-acyclation followed by aldol cyclization. Saponification (34) followed by decarboxylation affords methylchromone (35).7

0 I! CCH 2CH 3

31

33,

R=CO 2 C 2 H 5

34, 35,

R-CO 2 H R=H

Khellin is a natural product closely related to the psoralens in which a chromone ring has been substituted for the coumarin. The plant material has been used since ancient times as a folk remedy; modern pharmacologic work has confirmed the bronchiodilating and antispasmodic activity of khellin. The synthesis outlined below, it should be noted, is selected from a half-dozen or so reported within the last quarter century. Acylation of the hydroquinone derivative, 35, affords the only possible product, acetophenone, 36. The less-hindered phenol is then preferentially converted to its allyl ether (37) and the remaining phenolic function converted to the p-toluenesulfonyl ester (38). In an operation similar to one employed in psoralen synthesis above, the ether is then heated so as to bring about the electrocyclic rearrangement to the C-allylated phenol (39). Ozonization of the double bond gives the corresponding phenylacetaldehyde (40). This is then cyclized without prior isolation to the furan and the tosylate removed by saponification (41). This is an interesting reminder that a benzofuran is formally a cyclized form of an o-hydroxyphenylacetaldehyde. Condensation of 41 with ethyl acetate at the acetyl methyl group affords the corresponding acetoacetate (42). Cyclization of this last product affords khellin (43).8

Six-Membered Benzoheterocycles

336

OCH3

0CH3 A v C0CH3 (1 1 OCH3

35

OCH3 COCH3 OCH3 41

42

OCH3 COCH3 CH2=CHC<

o^^jy^ OR ^

37, R=H 38, R=p-SO2C6H4CH3

36

OCH3

OCII3 CO^3 OSO2C6H4CH3 OCH3 40

CH2-CHCH2 OCH3 39

43

Perhaps one of the most effective agents currently available for the treatment of the bronchial spasms attendant to asthma is a synthetic agent that incorporates the chromone moiety. Alkylation of the dihydroxyacetophenone, 44, with epichlorohydrin results in condensation of two molecules of the phenol with the latent glycerol (45). Reaction of the intermediate with ethyl oxalate affords the chromone ester, 46. Saponification leads to the bronchiodilator cromoglycic acid (47). The agent is usually administered by oral insufflation as its extremely insoluble disodium salt.

Coumarins and Chromones

337

COCH, \ CH2CHCH2C1

-OCH2CHCH2OI OH 45

44 RO2C

CO2R

0

0CH2CHCH2 OH

5

46, R=C 2 H 5 47, R=H

2.

QUINOLINES

One of the world's most widespread diseases is malaria. Although virtually completely eradicated in the United States, almost onethird of the world's population is exposed to the ravages of this disease. Malaria in man is caused by several species of protozoan parasites known as plasmnodia. The organism has an extremely complex life cycle requiring dwelling times in both a mosquito and a vertebrate for multiplication. TI e multiplicity of forms through which the parasite progresses in these hosts means differences in drug sensitivity at various stages in the life cycle of a plasmodium. This in part explains the wide structural variations found among antimalarial agents, since different drugs are effective against plasmodia at different times in their life cycle. It is of note that antibiotics are of limited value in the treatment of malaria. The oldest effective drug for the treatment of this disease is indisputably quinine. Although the antipyretic activity of cinchona bark was known to the Incas, it remained for the Jesuit missionaries to uncover its antimalarial properties in the early seventeenth century. The advance of organic chemistry led to the isolation and identification of the alkaloid, quinine, as the active compound at the turn of this century. The emerging clinical importance of this drug led up to the establishment of cinchona plantations in the Dutch East Indies. This very circum-

338

Six-Membered Benzoheterocycles

stance brought on major efforts towards the development of synthetic antimalarial agents with each World War. In the first such conflict, Germany was cut off from its supplies of quinine and sought eagerly for some synthetic substitute. This effort continued into the 1920s and was eventually rewarded with clinically useful antimalarial drugs. The Second World War saw the United States deeply involved in a war in a fertile breeding ground for malaria—the jungles of the South Pacific—and the Japanese in control of the quinine plantations. A major program was mounted in this country that resulted in the preparation of numerous effective antimalarial agents. The war in Vietnam was fought in malaria country. Although synthetic drugs were by now readily available, they had lost some part of their efficacy due to the development of resistant strains of plasmodia. Considerable interest was again devoted to the development of novel antimalarial drugs. At the same time a new effort was launched for the development of commercially feasible routes for the total synthesis of the oldest of these drugs, quinine. Woodward achieved his first signal success of a lifetime devoted to the preparation of increasingly complex natural products by total synthesis by the successful preparation of quinine.' Despite its elegance, this synthesis did not provide a commercially viable alternative to isolation of the drug from chincona bark. A rather short synthesis for this drug from readily available starting materials has been only recently developed by the group at Hoffmann-LaRoche. (The economics of this synthesis are, however, not known.) The first step consists in carbethoxylation of the anion obtained from 2-ethyl-3-methylpyridine and lithium diisopropyl amide by means of dimethyl carbonate (49). Catalytic reduction of the ester affords the piperidine (50) in which the two side chains are fixed in the cis configuration. Treatment of the piperidine with sodium hypochlorite yields the corresponding N-chloro derivative (51). Photolysis of that active halogen intermediate in the presence of acid leads to the Leffler-Freytag rearrangement, that is, the 1,5-transfer of halogen, and in effect terminal chlorination of the ethyl side chain (52). (This reaction, probably free radical in nature, is thought to involve a five-membered ring transition state, hence the observed regiospecificity.) The secondary amine is then acylated. Dehydrogenation of 52 by means of tertiary butoxide in DMSO provides the vinyl side chain crucial to quinine (53). Esterification gives the intermediate (54) needed for addition of the quinoline moiety.10 (An alternate scheme for the preparation of this intermediate was devised by the same group as well.11) Assembly of the carbon atoms of the natural product is completed by acylation of the lithio derivative obtained from the

Quinolines

339

49 CH 2 CH 3 CH 2 CO 2 C 2 H 5 50, R=H 51, R=C1

COC 6 H 5

CH=CH2 CH2CO2R 53, R=H 54, R=C2H5

I l"^ CH2CH2C1 CH 2 CO 2 C 2 H 5 52

quinoline, 55, with 54 to afford the ketone (56). The carbonyl group is then reduced by means of a metal hydride and the base deacylated (58). Resolution of this base into its optical isomers affords the starting material of proper configuration for completion of the synthesis. Thus, cyclization of the base by SN2 displacement of the hydroxyl group by nitrogen gives the quinuclidine-containing structure 59. Oxygenation of the carbanion of 59 unfortunately proves to be sterically nonselective; there are obtained in equal amounts quinine (60) and quinidine (61),12 Although separation of these diastereomers adds a step, this is one of the interesting cases in which the by-product is an important drug in its own right. Although it has some activity as an antimalarial agent, quinidine is one of the more effective drugs available for the treatment of cardiac arrythmias. A variation on the Wittig reaction provides an interesting alternate method for construction of the desoxy compound (59). In work carried out in Taylor!s laboratory, it was found that reaction of the chloroquinoline, 62, with excess methylenetri-

340

Six-Membered Benzoheterocycles

CH2=CH JCH. CH2

CH2 0

OH

CH30

56

55

57, R=COC6H5 58, R=H

CH=CH2 HO CH3q

CH3Os

61

60

59

phenylphosphorane affords the ylide, 63. (The first equivalent of ylide presumably displaces the halogen on the heterocycle to give the methyl-phosphonium salt, now attached to the 4 position by a C-C bond; this then reacts with a second mole of methylene ylide to form the less basic 63.) Condensation of 63 with the aldehyde, 64 (obtained by a variation of the scheme used to prepare 54), yields the olefin (65). Treatment of that olefin with base serves to first hydrolyze the acetyl group; the basic nitrogen then adds conjugatively to the reactive vinyl quinoline double bond to form the quinuclidine ring and thus, 59. The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and aminoacridines afforded a series of synthetic compounds that exhibited antimalarial activity.14 The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials: the 4-amino-7-chloroquinolines and the 8-amino-6-methoxyquinolines. These will be consi-

341

Quinolines

dered without regard to chronology.

NCOCH3

CH=P(C6H5)3 CH3O

CH3o

CH3O ^

65

63

62

H 03 C H = C H 2C ifC O C H 3 64 CH2CHO

59

Preparation of the key intermediate for the chloroquinoline series starts with Shiff base formation of metachloroaniline with ethyl oxaloacetate (66). Heating of the intermediate leads to cyclization into the aromatic ring and consequent formation of the quinoline ring (67). Saponification of the ester to the acid (68) followed by decarboxylation gives the 4~hydroxy quinoline (69). The hydroxyl group is then replaced by chlorine by means of phosphorus oxychloride (70). Displacement of the reactive halogen at the 4 position by means of the aliphatic diamine, 71, yields the synthetic antimalarial agent chloroquine (72) , 1 5 «" CO2C 2H 5 CH

CH2CO2C2H5

CO 2 C 2 H 5

Cl 66

67, R=C2H5 68, R=H

Six-Membered Benzoheterocycles

342

CH 3 CH3

HNCHCHoCHoCH.N

i

H 2 NCHCH ? CH ? CF 2 N

Cl' 71 69, X^OH 70, X-Cl

72

One scheme for preparation of the diamine side chain consists in first reducing the carbonyl group of the haloketone, 73. Displacement of the halogen with diethylamine gives the amino alcohol (74). Treatment of that intermediate with thionyl bromide serves to replace the hydroxyl by bromine (75). The synthesis is completed by displacement of the bromine with ammonia.16 0 II CH3CCH2CH2CH2C1

OH I • CH 3 CHCH 2 CH 2 CH 2 N ^2n5

73

74 I

CH 3 CHCH 2 CH 2 CH 2 N 75, X=Br 76, X=NH2 A variation on this theme consists in first displacement of the chlorine in 73 with ethylaminoethanol. Reductive amination of the ketone by means of ammonia in the presence of hydrogen gives the hydroxylated diamine (77) . Use of this intermediate to effect displacement of the halogen at the 4 position of 70 affords hydroxychloroquine (78).17 Inclusion of the carbon atoms of an aromatic ring in the side chain sequence is apparently quite consistent with antimalarial activity. Thus, reaction of p-acetamidophenol with formaldehyde and diethylamine affords the Mannich product, 79. This is then converted to the diamine (80) by saponification. Alkylation with the chloroquinoline, 70, affords amidoquine (81),1& The same sequence starting with the Mannich product in which pyrrolidine has been used as the amine (82) gives amopyroquine (83). Deletion of the basic nitrogen atom remote from the quinoline ring serves to abolish antimalarial activity. Thus, glaphenine

343

Quinolines

73

H-HN V

CH 2 CH 2 OH

il

NH2

/

• C o H e;

CH3CHCH2CH2CH2N

CH3CCH2CH2CH2N CH2CH2OH 76

CH2CH2OH 77

CH 3 HNCHCH2CH2CH2N

78

, CII2N

NHCOCH*

NHR

81

79, R=COCH3 80, R=H

83

(85)19 exhibits antiinflammatory activity. It should be noted that this agent in essence is a fenamic acid in which quinoline replaces one of the benzene rings of the prototype. The compound is prepared by condensation of the glycerol ester of anthranilic

344

Six-Membered Benzoheterocycles

acid with the chloroquinoline, 70.

CO2CH2CHCH2OH OH I CO2CH2CHCH2OH

70

H9N

85 84

Finally, the quinoline ring can be methylated at the 3 position with retention of biologic activity. The starting quinoline is prepared by the same scheme as that used for the desmethyl compound by substituting the methylated oxosuccinate ester, 86, in the sequence. The initial quinoline carboxylate (87) is taken on to the dichloro compound (88) by the standard reactions. Condensation with the ubiquitous diamine (76) affords sontoquine (89).20

+

CHCH3 I

c=o CO 2 C 2 H 5 86

87, X=OH,Y=CO2C2H5 88, X=C1,Y=H CH3 n f C 2oH I 5 HN-CHCH2CH2CH2N

89 The key intermediate for the preparation of the 8-aminoquinoline antimalarial agents is obtained by condensation of the substituted aniline, 90, with "dynamite-grade" glycerol in concentrated sulfuric acid. (The reaction may well follow some scheme such as that depicted below.) The nitroquinoline obtained from

Quinolines

345

this reaction (91) is reduced to the amine (92) as needed, since that base is an unstable compound. Alkylation with haloamine (75) affords pamaquine (93).16 (This compound was, in fact, developed in Germany in the 1930s; since the process then used for preparation of the side chain gave a pair of regioisomers, the drug at that time was usually sold as a mixture.)

OH [0HC-CH 2 CH 2 0H] — > OHC-CH=CH 2

[H0CH 2 CHCH 2 0H]

cn3o

C113O N

NIU

CI1CII2C1I?C]I2N

C1C1ICH 2C1I2CH pNlC • Gil j

CHCII2CII2CII2NIICH 9'J

Modification of the synthesis of the side chain by reaction of 73 with isopropyl amine rather than diethylamine gives eventually the haloamine, 94. Alkylation of the aminoquinoline (92)

346

Six-Membered Benzoheterocycles

with this halide gives isopentaquine (95),21 Reductive amination of dihydropyran (which may be regarded as the dehydration product of the cyclic acetal of 5-hydroxy~ pentanal) in the presence of isopropylamine and a trace of acid affords the aminoalcohol, 96. Treatment of this compound with thionyl chloride affords the haloamine, 97. Alkylation of the quinoline, 92, with this halide yields pentaquine (98).22

O

XCH2CH2CH2CH2CH2NHCH

96, X=OH 97, X=C1

CH2CH2CH2CH2CH2NHCH

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with 100 affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102).23 The quinoline nucleus has also provided the basis for an effective poultry coccidiostat. Hydrogenation of the bisisobutyryl ether of 3,4-dihydroxynitrobenzene (103) affords the corresponding aniline (104). Reaction of this compound with ethoxymethylene malonate leads to an addition elimination reaction in which the amine in effect displaces the ethoxy group (105). Cyclization of the ester group onto the highly activated aromatic ring is accomplished by heating in Dowtherm. There is thus obtained buquinolate (106).2A

347

Quinolines

CH

,O

CH 3 CHCH 2 CH 2 CH 2 N

CH 3 CHCH 2 CH 2 CH 2 Br I Br

Br

100

99

I

CH3O.

CHCH 2 CH 2 CH 2 N

CHCII2CH2CH2NH2 I CH 3

CH 3

103

102

(CH3 )'2CHCH2O. (CH3 )2CHCII2O

NR2

—>

fCH3 )2CHCH2O

C2H5O2C 11 I

CO2C22HH5 CH

(CH3 )2CHCH2O

lOlf R^O 104, R=H

OH (CH 3 ) 2 CHCH 2 O N (CH3 ) 2 CHCH 2 O

3.

ISOQUINOLINES

Papaverine (107) is among the host of minor alkaloids that have been isolated from opium. The compound is distinct in its biologic activity from many of the other opium constituents in that it does not exhibit any analgesic activity. Instead, papaverine acts as a nonspecific spasmolytic agent. As such, it has found

348

Six-Membered Benzoheterocycles

considerable use in the treatment of spasms of the vascular, gastrointestinal, and bronchial tracts. Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine.

CH3o CH3O

OCH, 107

OCH,

CII3O

108

The initial synthesis of papaverine is due to Pictet, and fittingly enough involved as its key step the name reaction. Acylation of veratrylamine (109) with dimethoxyphenylacetylchloride affords the amide (110). Cyclization by means of phosphorus oxychloride constitutes the same reaction and affords the dihydroisoquinoline (111). Dehydrogenation by means of a noble metal catalyst affords papaverine (107).

109 107

OCH,

OCH

no

OCH,

111

Isoquinolines

349

A variant on this structure, dioxyline9 has much the same activity as the natural product but shows a better therapeutic ratio. Reduction of the oxime (113) from 3,4-dimethoxyphenyl~ acetone (112) affords the veratrylamine homolog bearing a methyl group on the amine carbon atom (114). Acylation of this with 4ethoxy-3-methoxyphenyl acetyl chloride gives the corresponding amide (115). Cyclization by means of phosphorus oxychloride followed by dehydrogenation over palladium yields dioxyline (116).26

CH3

CHaO^rv T

CH

2

CH

3

CH3OV/T\.CH2 CH3 71 -CH-

J14

I CH

112, X=0 113, X=NOH

115

1J6

V OCH

0CH

3

Reduction of the heterocyclic ring and extension of the side chain bearing the phenyl ring affords a compound with analgesic and antitussive activity. Cyclization of the acetamide of veratrylamine gives the dihydroisoquinoline, 117. Treatment of this compound with acetic anhydride leads to N-acylation with a concomitant shift of the double bond to the exocyclic position (118). Acid hydrolysis of that intermediate opens the heterocyclic ring to afford the acetophenone (119). Aldol condensation of the ketone with p-chlorobenzaldehyde gives the corresponding chalcone (120). Treatment with strong acid serves to deacylate the amide to the amine (121); this condenses to the cyclic Shiff base under the reaction conditions to give a new dihydroisoquinoline (122). Catalytic reduction of both the double bonds followed by methylation of the resulting secondary amine (123) by means of methyl iodide yields methopholine (124).27 Tetrahydroisoquinolines, in which nitrogen occupies a bridge-

350

Six-Membered Benzoheterocycles

CH3O CH3O

CH3O 117

^

|

I N CH2

118

CH3O NICOCH3 CH 119

CH=CII-/~"\cl

CH2CH2122 12 3, R=H 124, R=CH3

120, R=COCH3 121, R=H

head position to yet another ring, exhibit tranquilizing activity qualitatively similar to that of reserpine. Acylation of veratrylamine with the 2-carbethoxyacetyl chloride gives the amide, 125. Cyclization in the usual way leads to the dihydroisoquinoline (126). Catalytic reduction affords the tetrahydro derivative (127). Mannich reaction of the secondary amine with formaldehyde and diethyl isopropylmalonate affords the corresponding Nalkylated compound (128). Successive hydrolysis and decarboxylation of the diacid and then reesterification affords the diester, 129. The last ring is then closed by Dieckmann cyclization; decarboxylative hydrolysis of that intermediate affords the ataractic tetrabenazine (130).28 A similar scheme involving reaction of the intermediate, 127, with diethyl malonate proper affords the ketoester, 131, following the cyclization step. Reaction of the ester with diethylamine gives the amide, 132. Catalytic reduction leads to the alcohol (133); acetylation completes the synthesis of the tranquilizer benzquinamide (134),29 As we have had occasion to note more than a few times previously, the guanidine function forms the basis of a family of hypotensive agents active by reason of their activity as blockers of the peripheral sympathetic system. Condensation of tetrahydro is oquino line with the S-methyl ether of thiourea affords the antihypertensive drug debrisoquin (135),30

Isoquinolines

351

CH3O

CH3

CH,

CH3O CH2CO2C2H5

CH2 I CO2C2I15

CO2C2H5

125

127 CH 3

CH3O

-C112C~CO2C2H5 CO2C2H5

CH3O

CH3O CO2C2H5 129

CH3OV

CH3O.

CH3O

CH3O

COR

131,

R=OC2H5

132,

R-N(C

2

H

133, 5

)

2

134,

R=H R=COCH3

NH N-C"

135

4.

SIX-MEMBERED RINGS CONTAINING TWO HETERO ATOMS FUSED TO ONE BENZENE RING

A miscellany of medicinal agents are based on heterocyclic systems that contain two hetero atoms. Unlike their counterparts unfused to an aromatic ring, these drugs do not show any unifying biologic activity. It is therefore likely that in most cases the

Six-Membered Benzoheterocycles

352

nucleus simply acts as a carrier for the pharmacophoric groups. Reaction of pyrocatechol with epichlorohydrin in the presence of base affords the benzodioxan derivative, 136. (The reaction may well involve initial displacement of halogen by phenoxide followed by opening of the oxirane by the anion from the second phenolic group.) Treatment of the alcohol with thionyl chloride gives the corresponding chloro compound (137).31 Displacement of halogen by means of diethylamine affords piperoxan (138) ,32 a compound with a-sympathetic blocking activity. Esterification of 136 with p-toluenesulfonyl chloride leads to the tosylate (139). Displacement of the ester with guanidine affords guanoxane (140).33 This drug, not surprisingly, shows peripheral sympathetic blocking activity and is therefore used in control of hypertension.

136, X=OH 137, X=C1 139, X=SO2C6H4CH3

I r C o H t;

s

J 1 C2H, 138

140

The phthalazine ring system has yielded a pair of quite effective antihypertensive agents. Both these drugs are believed to act as vasodilators; they would owe much of their effectiveness to the consequent decrease in resistance to blood flow in the periphery. Condensation of the half-aldehyde corresponding

Six-Membered Rings

353

to phthalic acid (141) with hydrazine affords the internal hydrazone-hydrazide (142). Reaction of that intermediate with phosphorus oxychloride gives the chloro compound (143), probably by the intermediacy of the enol. Displacement of halogen with hydrazine yields hydralazine (144) .3l*

CO2H CHO 141

142 NHNH,

$44

143

In much the same vein, reaction of the heterocycle, 145 (obtainable from phthalic acid and hydrazine), with phosphorus oxychloride gives the dichloride, 146. Double displacement of halogen by means of hydrazine leads to dihydralazine (147) .3U

NHNH, 145

146

147

The lack of structural specificity among sedative-hypnotic drugs has been alluded to before. It is perhaps not too surprising that quinazolones, too, show this activity. The prototype, methaqualone (149), is obtained in a single step from the condensation of the^anthranilamide, 148, with o-toluidine.35 (The reaction may well involve first formation of the bisamide; cyclization will then give the quinazolone ring system.) Condensation

354

Six-Membered Benzoheterocycles

of the same starting amide with o-chloroaniline yields mequoqualone (150).36

R ^ i

NHCOCH3 N-OCHo H 11 3

148

149, R--CH3 150, R=Cl Sulfonamide groups are often associated with diuretic activity, as shown in the section devoted to that functionality; the section immediately following deals with heterocyclic variants of this function. It is of interest in connection with the present discussion that the sulfonamide grouping affords a diuretic agent when substituted onto a properly constituted quinazolone. Chlorosulfonation of the substituted acetanilide, 151, followed by ammonolysis of the intermediate sulfonyl chloride (152) serves to introduce the sulfonamide function (153). Oxidation of the methyl group gives the corresponding anthranilamide (154); the acetyl group is then removed by hydrolysis (155). Fusion of the amino acid with propionamide leads directly to the quinazoline ring system (156). (One scheme for formation of the product involves formation of a diacylated amide.) Catalytic reduction then gives quinethazone (157),37

ci

iNHCOCH3

XX

^ ^ Y NHCOCH3

Y

RO 2 S^ \

CH3

151

^

CH3

Cl

^ NHR CO2H

H.NO.S

152, R=C1 153,

1 5 4 , R=COCH3 155, R=H i

H

0

H

*

ci ^ ^ N ^

0 CH2CH3 C1 1 H2NO2S-

H2NO2S " b

7 156

^;

2

x

NH II 0

^CCH2CH3

1,2,4-Benzothiadiazines

5.

355

1,2,4-BENZOTHIADIAZINES AND THEIR REDUCTION PRODUCTS

The development of the so-called thiazide diuretics represents perhaps the most fruitful application of the theory of rigid analogs to medicinal chemistry. At the inception of this work, there were available to clinicians the bissulfonamide carbonic anhydrase inhibitors. Although these descendants of the antibacterial sulfonamides were effective drugs, their use was limited by, among other reasons, their low potency. One route chosen in an effort aimed at improving these drugs consisted in the interposition of an additional atom between the adjacent nitrogen atoms in a drug such as chlorophenamide (158) to form a heterocyclic ring. This new ring is in effect a rigid analog, since one of the nitrogen atoms of one of the amides is now fixed in space.

R Cl.^r ^

NH2 SO2NH2

H2NO2S'^/' S

^R 2

158 The efficacy of these diuretics led to their extensive use in the clinic, particularly in treatment of hypertension. In theory at least, reduction of the blood volume by diuresis should lead to a lowering of pressure (PV=RT). This expectation was in fact met in actual practice. Recent research does, however, seem to indicate that the thiazides have an antihypertensive effect beyond that explainable by a simple lowering of blood volume. Preparation of the first compound in this series, chlorothiazide (162), starts with the high-temperature chlorosulfonation of m-chloroaniline. Ammonolysis of the resulting bissulfonyl chloride (159) leads to the corresponding bissulfonamide '160). Acetylation of the amine gives the amide (161). Formation of the heterocycle is achieved by a reaction analogous to the formation of the quinazolone ring system {161 may be viewed simplistically as the sulfur analog of an anthralic acid diamide). Thus, treatment of 161 with anthranillic acid leads to the benzothiadiazine ring system and consequently to chlorothiazide (162),38 The analogous scheme starting with zn-trifluoromethylaniline affords flumethazide (163).3 9 Replacement of the sulfonamide group at the 7 position by chlorine markedly diminishes the diuretic effect in this series. One such compound, diazoxide (169), exhibits instead potent anti-

356

Six-Membered Benzoheterocycles

159, R=C1 160, R=NH2

163

162 hypertensive activity. It is likely that this drug exerts its blood pressure-lowering activity by means of vasodilitation. Preparation starts with the aromatic nucleophilic displacement of one of the halogens of 164 by the anion from benzylthiol. (It is not clear why displacement occurs at the ortho position in preference to the less-hindered para chlorine.) Debenzylation with concomitant oxidation is achieved with aqueous chlorine. Reaction of the resulting sulfonyl chloride (166) with ammonia gives the corresponding sulfonamide (167). Reduction of the nitro group to the amine (168) followed by insertion of the 3 carbon by means of ethyl orthoacetate affords diazoxide (169).h0

164

165

1,2,4-Benzothiadiazines

357

166, R=cl 167, R=NH2

169

168

Analogs of 162 and 163 in which the heterocyclic ring is fully reduced show a marked increase in potency over the prototypes as well as a more favorable pharmacologic ratio. In practice, however, such compounds are not prepared by reduction of their unsaturated counterparts. Instead, cyclization of the orthoaminosulfonamide is performed with a carbonyl component in a lower oxidation state (e.g., aldehydes rather than acids). In the formal sense at least the products are quite analogous to aminal derivatives of aldehydes. The aromatic component is usually 160. An alternate preparation of the trifluoromethyl analog starts with nucleophilic displacement on 170 by sodium sulfide.' Chlorolysis and aminolysis of the product (171) yields the corresponding sulfonamide (173). Reduction of the nitro group followed by reaction with chlorosulfonic acid leads then to the sulfonyl chloride (174). This is then converted to the bissulfonamide by treatment with ammonia. Table 1 lists the plethora of diuretic agents that have been prepared by the basic reaction scheme for forming the heterocyclic ring (A-B).

358

Six-Membered Benzoheterocycles

NH,

171

170

172, R=C1 2 73, R=NH2

| + H2NO2S " k < ^ - A SNH2 O

Table 1.

SO2NH NH2

RO2

S-

O=C-R

—-> H2NO2S

174, R=C1 175, R=NH2

I I \>^

S

3,4-Dihydro~2H-l,2,4-benzothiadiazines H

XX Compd.NoY . R Generci NameRefrence 4 1 H C l 176 hydrochloro 4 2 H C F 177 hydrofluam 3 178 4 2 C H 2 C H $ 5 C F bendroflum 3 179 4 3 C H ethithiazide C l 2 5 180 4 3 thiabutazide C l o n 2 \->n v \ u / 3 )<£ 181Cl CH/ | cyclopenthi 44 NH

2

182

Cl

Ctt2~^~~—\

y

cyclothiazide

44

1,2,4-Benzothiadiazines

359

Table 1, continued

183 184

Cl Cl

CHCl2 CH2SCH2CH=CH2

185

Cl

CH2SCH2CF3

trichlometh

de

45

althizlde

46

epithiazide

47

Preparation of the aldehyde required for the synthesis of cyclothiazide (182) starts by carbonation of the Grignard reagent obtained from the Diels-Alder adduct (186) from allyl bromide and cyclopentadiene.49 The resulting acid (187) is then converted to the aldehyde (189) by reduction of the corresponding diethyl amide (188) with a metal hydride.

186

187, R=OH 188, R=N(C 2 H 5 ) 2

CH2CHO 189 In the preparation of the thiazides containing more highly functionalized side chains (183-185)9 an acetal of the aldehyde is usually used rather than the free carbonyl compound. Thus, trichlornethiazide (183) is prepared by reaction of 160 with the dimethyl acetal from dichloroacetaldehyde. In a similar vein, alkylation of the acetalthiol, 190, with allyl bromide affords 191, This yields altizide (184) on condensation with 160. Alkylation of 19O with 2,2,2-trifluoroethyl iodide gives 192. This leads to epithiazide (185) on condensation with 160. Methylation of nitrogen at the 2 position also proves to be consistent with diuretic activity. Condensation of 160 with urea affords the heterocycle, 193. Treatment of this compound with methyl iodide and base effects alkylation on the more acidic ring nitrogen (194). Basic hydrolysis then gives the N-methylated aminosulfonamide (195). Condensation of this with chloroacetalde-

360

Six-Membered Benzoheterocycles

hyde leads to methyclothiazide (196)h&m, condensation with the acetal, 192, affords polythiazide (197),47 HSCH2CH (0CH3 ) 2 190

191

192

—e>

SO2NHCH3

II2NSO 193

195

194

n. N^ CH2C1

CH2SCH2CF3

297

196

REFERENCES 1. M. A. Stahman, C. F. Huebner, and K. P. Link, J. Biol. Chem., 138, 513 (1941). 2. M. I. Kawa, M. A. Stahmann, and K. P. Link, J. Amer. Chem, Soc, 66, 902 (1944). 3. W. Stoll and F. Litvan, U. S. Patent 2,648,682 (1953). 4. R. E. Nitz and E. Potzch, Arzneimittel Forsch., 13, 243 (1963). 5. C. Lagercrants, Acta Chem. Scand., 10, 647 (1956). 6. K. D. Kaufman, J. Org. Chem., 26, 117 (1961). 7. M. Clerc-Bory, H. Pacheco, and C. Mentzer, Bull. Soc. Chim. FT., 1083 (1955). 8. R. Aneja, S. K. Mukerjee, and T. S. Seshadri, Chem. Ber., 97$ 297 (1960). 9. R. B. Woodward and W. E. Doering, J. Amer. Chem. Soc., 67, 860 (1945).

References

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

361

M. Uskokovic, C. Reese, H. L. Lee, G. Grethe, and J. Gulzwiller, J. Amer. Chem. Soc, 93, 5902 (1971). M. Uskokovic, J. Gutzwiller, and T. Henderson, J. Amer. Chem. Soc, 92, 203 (1970). J. Gutzwiller and M. Uskokovic, J. Amer. Chem. Soc, 92, 204 (1970). E. C. Taylor and S. F. Martin, J. Amer. Chem. Soc, 94, 6218 (1972). W. Schulemann, F. Schonhofer, and A. Wingler, German Patent 486,079 (1930). A. R. Surrey and H. F. Hammer, J. Amer. Chem. Soc, 68, 113 (1946). R. C. Elderfield, et al., J. Amer. Chem. Soc, 68, 1579 (1946). A. R. Surrey and H. F. Hammer, J. Amer. Chem. Soc, 72, 1814 (1950). J. H. Burckhalter, F. H. Tendrick, E. M. Jones, W. F. Holcomb, and A. L. Rawling, J. Amer. Chem. Soc, 70, 1363 (1948). Anon., Belgian Patent 636,381 (1964). E. A. Steck, L. L. Hallock, and A. J. Holland, J. Amer. Chem. Soc, 68, 380 (1946). R. C. Elderfield, et al., J. Amer. Chem. Soc, 68, 1524 (1946). N. L. Drake, J. VanHook, J. A. Garman, R. Hayer, R. Johnson, S. Melamea, and R. M. Peck, J. Amer. Chem. Soc, 68, 1529 (1946). R. C. Elderfield, H. E. Mertel, R. T. Mitch, I. M. Wempen, and E. Werble, J. Amer. Chem. Soc, 77, 4816 (1955). J. Watson, U. S. Patent 3,267,106 (1966). A. Pictet and M. Finklestein, Chem. Ber., 42, 1979 (1909). E. R. Shepard, U. S. Patent 2,728,769 (1958). A. Brossi, H. Besendorf, B. Pellmont, M. Walter, and 0. Schnider, Helv. Chim. Acta, 43, 1459 (1960). A. Brossi, H. Lindlar, M. Walter, and 0. Schnider, Helv. Chim. Acta, 41, 119 (1958). J. R. Tretter, U. S. Patent 3,053,845 (1962). W. Wenner, Belgian Patent 629,007 (1963). A. Grun, U. S. Patent 2,366,102 (1944). E. Fourneau, U. S. Patent 2,056,046 (1936). A. M. Monro, Chem. Ind., 1806 (1964). J. Druey and B. H. Ringler, Helv. Chim. Acta., 34, 195 (1951). I. K. Kacker and S. H. Zanner, J. Indian Chem. Soc, 28, 344 (1951). G. B. Jackman, V. Petrow, and 0. Stephenson, J. Pharm.

362

37. 38. 39. 40.

41. 42. 43.

44. 45. 46. 47. 48.

Six-Membered Benzoheterocycles

Pharmacol., 28, 344 (1960). E. Cohen, B. Karberg, and J. R. Vaughan, J. Amer. Chem. Soc, 82, 2731 (1968). F. C. Novello and J. M. Sprague, J. Amer. Chem. Soc, 79, 2028 (1957). H. L. Yale, K. Losee, and J. Bernstein, J. Amer. Chem. Soc, 82, 2042 (1960). A. A. Rubin, F. E. Roth, M. W. Winburg, J. G. Topliss, M. H. Sherlock, N. Sperber, and J. Black, Science, 133, 2067 (1961). G. DeStevens, L. H. Werner, A. Halamandavis, and S. Ricca, Experientia, 14, 463 (1950). C. T. Hodvege, R. Babel, and L. C. Cheney, J. Amer. Chem. Soc, 81, 4807 (1959). J. G. Topliss, M. H. Sherlock, F. H. Clark, M. C. Daly, B. W. Pettersen, J. Lipski, and N. Sperber, J. Org. Chem., 26, 3842 (1961). C. W. Whitehead, J. J. Traverso, H. R. Sullivan, and F. J. Marshall, J. Org. Chem., 26, 2814 (1961). G. DeStevens, L. H. Werner, W. E. Barrett, and A. H. Renzi, Experientia, 16, 113 (I960). J. M. McMannus, British Patent 902,658 (1962). J. M. McMannus, U. S. Patent 3,009,911 (1961). W. J. Close, L. R. Swett, L. E. Brady, J. H. Short, and M. Vernstein, J. Amer. Chem. Soc, 82, 1132 (1960).

CHAPTER 18

Benzodiazepines

Each era of medicinal chemistry has been marked by intensive concentration on some structural type in a large number of laboratories. One need only look back in this book to the tables of sulfonamides, barbiturates, and thiazide diuretics, noting the small time span covered by the references to each list. The benzodiazepines have provided such a focus for the past decade. The pace of life in the highly developed industrial nations leads many to become anxious and depressed in view of the high demands placed on them by their peers and society at large. The success ethic and the high price of failure contribute in no small way to this malaise. There thus seemed to exist a need for some anxiolytic agent that would enable the individual to continue functioning in spite of his angst. Such an agent should be without the frank sedation of the barbiturates or the side effects of the major tranquilizers. To anticipate, the benzodiazepines seem to fulfill exactly this role. This, in fact, accounts both for their enormous sales and the efforts of so many pharmaceutical companies to enter this market. This class of medicinal agents was uncovered quite adventitiously in a chemical study, although due credit must be given for the acute pharmacologic studies that uncovered this novel type of activity. The original objective of the synthetic work was the preparation of basic derivatives of the 3,1,4-benzoxadiazepine system (2) for animal testing. The basic ring system had been reported previously in the literature as the dehydration products of 2~ acylaminobenzophenone oximes (1). Repetition of the work quickly cast doubt on the earlier structural assignment. Both the chemistry of the products and their spectral data suggested that the products were in fact quinazoline-3-oxides (3). A preparation of authentic 3a was then undertaken. Reaction of p-chloroaniline with benzoyl chloride in the presence of zinc 363

364

Benzodiazepines

3a, R=CH2Cl chloride initially affords a dimer of the orthoacylation product (5). Hydrolysis gives the orthoaminobenzophenone (6). Reaction with hydroxylamine converts the ketone to the oxime (7); acylation of the aniline by means of chloroacetyl chloride affords the desired intermediate, 8. Cyclodehydration by means of hydrogen chloride then gives the quinoxaline N-oxide (9).

,NH2

9, A=C1 10, A=NHCH3 Displacement of the activated halogen in 9 led to a series of compounds with marked anxiolytic activity in laboratory animals. It soon became apparent that fate had intervened a second time in the chemistry of this series: the compounds were not simple products of displacement of halogen (10) but new hetero-

Benzodiazepines

365

cycles from a ring expansion reaction. The rearrangement is visualized as involving first addition of methylamine to the amidine-like function on the quinoxaline ring (the electron withdrawing effect of the N-oxide group may favor this process). Ring opening will then lead to intermediate, 12. Internal displacement of halogen by the oxime nitrogen affords the benzodiazepine, 13.x This compound, chlordiazepoxide, is better known by its trademark, Librium®. Both this drug and its successors are widely used as minor tranquilizers and muscle relaxants. Several of the more recent drugs of this class show somewhat differing profiles, with some agents exhibiting marked hypnotic activity.

OUC1

JSfHCHa 11

12

13

Neither the oxide nor the amidine function are in fact required for activity. Treatment of the oxime, 7, with chloroacetyl chloride in the presence of sodium hydroxide proceeds directly to the benzodiazepine ring system (14)(the hydroxyl ion presumably fulfills a role analogous to methylamine in the above rearrangement). Reduction of the N-oxide function of 14 leads to diazepam (15),1

14

15

366

Benzodiazepines

Careful study of the metabolic disposition of these compounds led to the realization that active metabolites were quickly formed following administration; it was even suggested that the "real" active agent might be one of these. One of the metabolites, oxazepam (18), was soon prepared and in fact proved to have anxiolytic activity. This drug, too, has found wide acceptance. Treatment of diazepam intermediate 14 with acetic acid results in a reaction analogous to the well-known Polonovski rearrangement (perhaps via 16) to give ester 17. Treatment with an equivalent of base gives oxazepam (18).2 This minor tranquilizer is more potent than diazepam, which is in turn more active than chlordiazepoxide.

OCOCH3

16

17

18 A more recent derivative with activities typical of the class is nitrazepam (21). Reaction of 2-amino-5-nitrobenzophenone (19) with bromoacetylbromide affords the amide, 20. Ring closure in liquid ammonia gives nitrazepam (21).3 More simply, diazepinone, 22, can be nitrated directly at the more reactive C 7 position with potassium nitrate in sulfuric acid. Inclusion of fluorine on the pendant aromatic ring and the basic side chain seems to emphasize the anticonvulsant and hypnotic effects of this class of drugs. Thus alkylation of the benzodiazepinone, 24 (prepared from the corresponding substituted aminobenzophenone), with 2-chlorotriethylamine via its sodium salt affords fluazepam.1* The orthochloro analog of oxazepam is in fact prepared by a

Benzodiazepines

367

CH2Br

19

20

21

22

H ,0 Cl

C=O

23

24

25

368

Benzodiazepines

somewhat more circuitous route than the prototype. Condensation of the aminobenzophenone, 26, with diethyl aminomalonate leads directly to the benzodiazpine containing a carbethoxy group at the 3 position (27). Bromination proceed > at the carbon atom activated by two carbonyl groups (28). Solvolysis of the halogen in methanol leads to the corresponding methyl ether (29). Saponification of the ester followed by decarboxylation of the ketoacid affords the methyl ether of the desired product (30). Cleavage of the ether by means of boron tribromide gives lorazepam (31),5'6

+

•CO 2 C 2 H 5 HoNCH 'CO 2 C 2 H 5

~_N CO 2 C 2 H 5

28, X=Br 29, X=OC1I3

Op IT.

Cl

/yy

OR

"•6 10, R CH 11, R 11

The benzodiazepine ring system is also accessible by some of the more traditional methods for forming benzoheterocycles, such as, for example, cyclodehydration reactions. Reaction of 2benzoylaziridine (33) with the aniline, 32, results in ring opening of the aziridine to produce the amide, 34. This undergoes cyclization into the aromatic ring on heating with either polyphosphoric acid or polyphosphoric acid ethyl ester. There is thus obtained medazepam (35).7>e Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thioamide (37). Condensation of this intermediate with acetyl hydrazide affords triazolam )37).9 The same agent can be prepared by reaction of the amidine, 38> 1 0 with acetylhydrazide.11 The N-methylated analog of intermediate, 15, contains a

369

Benzodiazepines

CH 3 I NH

32

N

\

•=-N

35

0 It CH3CNHNH2

36, X=S 38, X=NH

Cl

c

Cl

37

reactive imine function at the 4-5 position (39). This imine in fact readily adds diketene (an acetoacetate equivalent) to afford ketazolam (40).12 In an alternate approach to the preparation of compounds containing the additional ring, haloamide, 4113 (obtained from the aminobenzophenone and bromoacetylbromide) is alkylated with ethanolamine to afford 42. Treatment of the amino alcohol in acetic acid affords the carbonyl addition product, 43, at the same time

370

Benzodiazepines

resulting in the formation of two rings. The product, cloxazepam (43) ,xt* is an active anxiolytic agent.

CH2

40

39

CHoBr

41, X=C1 44, X=H

42

43

OH I CH 2 CH

46 In much the same manner, alkylation of the deschloro intermediate (44) with 2-hydroxypropylamine, followed by cyclization of the resulting amino alcohol (45) affords oxazolapam (46).

Benzodiazepines

371

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13.

14.

15.

L. H. Sternbach and E. Reeder, J. Org. Chem., 26, 4936 (1961). S. C. Bell and S. J. Childress, J. Org. Chem., 27, 1691 (1962). L. H. Sternbach, R. I. Fryer, 0. Keller, W. Metlesics, G. Sachs, and N. Steiger, J. Med. Chem., 6, 261 (1963). L. H. Sternbach, G. A. Archer, J. V. Early, R. I. Fryer, E. Reeder, N. Wasyliw, L. D. Randall, and R. Banziger, J. Med. Chem., 8, 815 (1965). S. C. Bell, R. J. McCaully, C. Gochman, S. C. Childress, and M. I. Gluckman, J. Med. Chem., 11, 457 (1968). S. C. Bell and S. C. Childress, J. Org. Chem., 33, 216 (1968). K. H. Wllnsch, H. Dettmann, and S. Schbnberg, Chem. Ber., 102, 3891 (1969). G. F. Field, L. H. Sternbach, and W. J. Szally, U. S. Patent 3,624,073 (1971). J. B. Hester, C. G. Chidester, D. J. Duchamp, F. A. MacKellar, and J. Slomp, Tetrahedron Lett., 3665 (1971). G. A. Archer and L. H. Sternbach, J. Org. Chem., 29, 231 (1964). R. Nakajima, C. Hattori, and Y. Nagawa, Jap. J. Pharmacol., 21, 489 (1971). J. Szmuszkovicz, C. G. Chidester, D. J. Duchamp, F. A. MacKellar, and G. Slomp, Tetrahedron Lett., 3665 (1971). L. H. Sternbach, R. I. Fryer, W. Metlesics, E. Reeder, G. Sach, G. Saucy, and A. Stempel, J. Org. Chem., 27, 3788 (1962). T. Miyadera, A. Terada, M. Fukunaga, Y. Kawano, T. Kamioka, C. Tamura, H. Takagi, and R. Tachikawa, J. Med. Chem., 14, 520 (1971). T. L. Lemke and A. R. Hanze, J. Heterocycl. Chem., 8, 125 (1971).

CHAPTER 19

Phenothiazines

Compounds containing the benzhydryl grouping are prominent among the antihistamines; they are represented in this class by both derivatives of benzhydrol and benzhydrylamines. It will be recalled further that the latter usually incorporate some version of an ethylenediamine side chain. It was therefore logical that synthetic work on these agents turn to derivatives in which one of the nitrogens of the side chain replaced the benzhydryl carbon. This line of work, in fact, met with initial success when an additional heteroatom was included to bridge the two aromatic ring. The phenothiazines, in which the additional bridge is represented by sulfur, have in fact proven a particularly fertile ground for the development of compounds with varying pharmacologic activities. As we see below, simple two-carbon side chains generally afford antihistamines; several of these had sufficient sedative effects to be proposed for treatment of Parkinsonfs disease. Inclusion of a methyl group on the side chain adjacent the nitrogen remote from the ring led to potent antihistamines, many of which possess sedative activities. The most dramatic changes in pharmacologic activity involved extension of the side chain so as to separate the nitrogens by three carbon atoms. The initial biologic observations suggested that these compounds had increased sedative activity and diminished antihistamine potency. It remained for an astute pharmacologist to discover that an entirely new biologic activity was displayed by these compounds. That is, these agents were uniquely useful in treatment of various neuroses and psychoses. Administration of chlorpromazine, although not curative, made previously hopelessly ill patients amenable to treatment. The effects of the availability of these drugs on therapy of mental illness have been no less than revolutionary. Synthetic work subsequent to the discovery of the first of the so-called neuroleptic phenothiazines has produced a series of drugs with subtly differing 372

Phenothiazines

373

biologic profiles; we consider the synthesis of these agents at the expense of the pharmacology. Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with N-(chloroethyl)diethylamine affords diethazine (l) , a compound that exhibits both antihistaminic and antiParkinsonian activity.1 Substitution of N-(2chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2),2 an antihistamine of moderate potency.

As noted above, methylation of the side chain leads to an increase in antihistaminic potency. Alkylation of phenothiazine with the halide 3 using sodium amide as a base leads to promethazine (4).l Interestingly, an attempt to prepare the isomeric side chain, as in 6, by use of the secondary chloride 5, again results in formation of the promethazine.1 As in the case of the problem concerning the structure of methadon, this finding has been attributed to intervention of the internal alkylation product (7) in the course of reaction.3 Alkylation of phenothiazine with the N,N-diethyl analog of 3 by means of methylmagnesium iodide leads to ethopropazine (8).4 This compound, which is of course the methyl analog of 3, has also found some use in the treatment of Parkinsonianism.

374

Phenothiazines

CH3CH3 ClCH 2 CHN-CH 3s

CH3 +^CH3 / \ CH3CH — CH2 7

Extensive work on the effects of substitution on the aromatic rings of the phenothiazines on both antihistamine and neuroleptic activity seems to have shown fairly clearly that maximum changes are obtained by inclusion of a substituent at the 2 position. Methopromazine (13) represents an antihistamine bearing such a substituent. Aromatic nucleophilic substitution on o-chloro~ nitrobenzene by means of a salt of the thiophenol, 10, affords the corresponding sulfide (11). Reduction of the nitro group followed by cyclization of the resulting amine leads to the substituted phenothiazine, 12. Alkylation of the latter at the 10 position with the aminohalide, 3, by means of sodium amide in xylene gives the desired product (13).3 In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 15. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine, Alkylation with the familiar halide (3) affords dimethothiazine (18),6 Electrophilic aromatic substitution affords yet another route to ring-substituted phenothiazines. Conversion of the parent phenothiazine to the propionamide (via the magnesium salt) serves both as a protecting group for the amine and as a means of allowing the para-directing effect of the sulfide to prevail. Acylation with propionyl chloride and aluminum chloride thus affords, after saponification of the amide, the ketone (2O). This is then treated with phosgene to give 21, and this last esterified with the aminoalcohol (a) to yield the corresponding urethane (22) .

375

Phenothiazines

10

OCH 3 CH2CHN CH,

12 13

,CHq SO2N

OoN ^CH,

14

15 X CH 3

*Br 26

i 02N

k

CH 2 CH<^ CH3 18

CH

3

V

CH,

3

17

376

Phenothiazines

In an interesting reaction, pyrrolysis of the urethane leads to extrusion of carbon dioxide and formation of 23, propiomazine.7 Although this agent contains the ethylenediamine side chain, its main use is as a sedative.

20 19

I C0C1

21 CH3 HOCH2CHN \|/ (a)

(

.COCH2CH3 CH 3

23

22

The most prominent pharmacologic activity exhibited by phenothiazines bearing the 1,3-propyldiamine side chain is, of course, that of a neuroleptic agent. Treatment of psychoses and severe neuroses constitutes the largest single use of these so-called

377

Phenothiazines

major tranquilizers. In addition, however, many of these drugs have useful activity as sedatives and antiemetics. It should be noted that one of the more potent 1,2 diamines, promethazlne, is occasionally used for these indications as well. Extensive synthetic work has been devoted to attempts to isolate these various activities with the result that specific phenothiazine drugs vary greatly in their clinical profile. Discussion of these profiles is beyond the scope of this book; compounds that are indicated for use other than neuroleptics are, however, identified. The parent drug of this series, promazine (24), was prepared originally as an antihistamine. Following the identification of the more potent chloro analog as an antipsychotic, it too came into use for that indication. The drug is prepared by straightforward alkylation of phenothiazine with N-(3-chloropropyl)dimethylamine by means of sodium hydride in xylene.8

CH 2 CH 2 CH 2 N 24

25

i 26

<

•

I

if

^ CH3 CH2CHCH 2N N 1 CH 3 CH3 29

V

1

1 CH2CHCH2OR 1 CH3 27, 28,

R=H R=OSO2CH3

Phenothiazines

378

Alkylation of phenothiazine with the homologous N-(3-chloro2-methylpropyl)dimethylamine leads to trimeprazine (29). An interesting alternate synthesis to this agent begins with the Michael addition of phenothiazine to methacrylonitrile. Alcoholysis of the nitrile gives the ester (26). The carbonyl group is then reduced by means of lithium aluminum hydride and the resulting alcohol (27) converted to the corresponding mesylate. Displacement with dimethylamine gives trimeprazine (29),5 a major tranquilizer that retains some antihistaminic properties. Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with N-(3~chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33),9 Sulfuration of the methoxy analog of 30 similarly gives a mixture of the desired 2-substituted phenothiazine (35) and byproduct (36). Alkylation of 35 as above affords methoxypromazine (37J.9

30, R=C1 34, R=OCH3

31, R=C1 35, R=OCH3

,CH, CH 2 CH 2 CH 2 N CH* 33, R=C1 37, R=OCH3

32, R=C1 36, R=OCH3

379

Phenothiazines

Alkylation of the parent compound (30) with 2V~(3-chloropropyl)diethylamine rather than the lower homolog affords chlorproethazine (43) . This same compound is available by an alternate route that bypasses the sulfuration reaction. Aromatic nucleophylic substitution on 2,4-dichloronitrobenzene (38) with 2-bromothiophenoxide (39) affords the sulfide (40). Reduction of the nitro group followed by alkylation of the resulting amine (41) with N-(3-chloropropyl)diethylamine gives the intermediate, 42, This is then cyclized by heating in dimethylformamide to give the desired product (43).10

Br

39

40

\

41

Br

NH I s CH 2 CH 2 CH 2 N

CH 2 CH 2 CH 2 N CoH 2n5 43

42

An intermediate used in the preparation of the antihistamine, propiomazine, serves as starting material for a 2-substituted major tranquilizer as well. Thus, reaction of the phosgene

380

Phenothiazines

adduct (21) with amino alcohol 44 affords the carbamate (45). in the case of the two-carbon side chain, pyrrolysis of this urethane leads, after loss of carbon dioxide, to propiomazine (46).11

HOCH2CH2CH2 2i

2

2

44

As

-CH3

2

CO 2 CH 2 CH 2 CH 2 N 45

CH 2 CH 2 CH 2 N 46

It has often been observed in medicinal chemistry that, in those series in which substitution of halogen on an aromatic ring results in increased potency, a yet greater increase can be achieved by inclusion of the trifluoromethyl group. The phenothiazines have proved to be such a series. The requisite starting material can be obtained by the sulfuration reaction of the substituted diphenylamine, 53, with the usual mixture of isomers resulting.13 The Smiles rearrangement offers a regioselective, albeit longer, route to this compound. Displacement on the nitrobenzene, 47, by means of the thiophenoxide from 48 yields the corresponding sulfide. Treatment with base presumably generates an anion on the formamide nitrogen; this negatively charged species then adds to the aromatic ring at the carbon bearing the sulfur (50) . Ring opening results in the loss of the better leaving group to give the thiophenoxide, 51, This last then again undergoes an addition-elimination reaction (52) to give finally the desired product (54) (the strongly basic conditions lead to hydrolysis of the amide). 12 Alkylation of that phenothiazine with zv-(3-chloropropyl)dimethylamine affords the very potent major tranquilizer triflupromazine (55).13 Incorporation of a second nitrogen atom in the side chain, particularly when that atom is part of a piperazine ring, was found to give a series of major tranquilizers similar in biologic activity to chlorpromazine, but of much increased potency. Alky-

381

Phenothiazines

50

CH2CH2CII2N^JJ3 54

55

lation of the lithium salt of phenothiazine by means of 3bromo-1-propanol toluenesulfonate affords the intermediate containing the bromopropyl side chain (63). Condensation of this with the monocarbethoxy derivative of piperazine gives the urethane (64). Reduction of the last by means of lithium aluminum hydride yields perazine (62) *1U In an analogous approach, 2chlorophenothiazine (31) is first alkylated by means of 3~bromo1-chloropropane to afford the compound containing the chloropropyl side chain (58). Alkylation of 4-methylpiperazine with that halide affords prochlorperazine (60),15 In much the same manner, the trifluromethyl analog (54) is first converted to the chloropropyl compound (59), and this then used to alkylate 4-methylpiperazine; the product obtained in this case is triflupromazine (61).16 The synthesis of butaperazine (66) involves yet another variation on this theme. Thus, alkylation of the substituted phenothiazine (56) (obtained by a reaction sequence similar to that used to prepare 26) with the complete preformed side chain (65) (obtainable from 3-bromo-l-chloropropane and methylpiperazine) affords the desired product in a single step.17

382

Phenothiazines

CH2CH2CH2Cl

v 31, X=Cl \ 54, X=CF3 \ 56, X=COCH2CH2CH3

58, X=Cl 59, X=CF3

60, X=C1 61, x=CF3 62

t

C O C C H C H H _ coo axi 2 2 —-y C H C H Br2 CH | — / V (2 N 2C 2H CH C I2N 1 H C -3l C C n H N 222 \o ^—

/

63

66

65

C1CH2CI12CH2N

64

N-CH3

Preparation of the phenothiazine containing a sulfur substituent at the 2 position involves a modification of the schemes reviewed thus far. In essence, the initial step depends on activation of aromatic chlorine towards nucleophilic aromatic substitution by a group that can be easily removed later; a carboxyl group is found to fulfill this need. Thus, treatment of o-chlorobenzoic acid with the substituted aniline (68) affords the corresponding anthranilic acid (69). Decarboxylation removes the activating group. Heating of diphenylamine (70) thus produced with sulfur and iodine gives the desired phenothiazine 71 as well as some of the 4-ethylthio isomer.18 Alkylation of the former (71) with the side chain, 65, affords thiethylperazine (72),19 Replacement of the methyl group of the piperazine-substituted phenothiazines by some more polar group such as hydroxyethyl fragment leads to a further small increase in potency. It should be noted at this point that all phenothiazines manifest a series of side effects. The given set of these varies, however, with the side chains. The availability of the great variety of such structural variations makes it more likely that some drug will b@ found that a given individual will tolerate. Key to this series is hydroxyethylpiperazine. This intermediate is attainable from the monocarbamate of piperazine

Phenothiazines

383

CoH 2n5

67

70

i CoH R

CH 2 CH 2 CH 2 N

N-CH3

71

72 by several routes such as, for example, with ethylene oxide followed by hydrolysis of the urethane. Alkylation of the piperazine derivative with the chloropropyl derivative, 58, affords perphenazine (75)20; the trifluoromethyl derivative, 59, gives fluphenazine (76).21 The 2-acetyl compound (73), prepared in a manner analogous to 56, gives acetophenazine (77),22 and finally use of 74 (obtained by alkylation of 20 with bromochloropropane) in the alkylation reaction gives carphenazine (78).23 Acetylation of perphenazine with acetic anhydride yields thiopropazate (79). " Alkylation of phenothiazine with l~chloro-2-methyl-3bromopropane affords the methylated analog (80) of the intermediate above. Use of this halide to alkylate the piperazine

384

Phenothiazines

C2H5OC-N

NH

>

C2H5OCN

—>

HM^NCH 2 CH 2 CH

I f — \ CH2CH2CH2N NCH2CH2OH

CH2CH2GH2Cl 58, 59, 73, 74,

N~CH2CH2OH

75, 76, 77, 78,

X=C1 X=CF3 X=CE3CO X=CH3CH2CO

1

X-Cl X=CF3 X=CH3CO X=CH3CH2CO

V CH2CH2CH2N

N~CH2CH2CAc

79 derivative,

81,

affords

the tranquilizer

I HN

S H

H N I CH 2 CHCH 2 Cl CH 3 80

dixyrazine

(82),25

\ NCH2CH2OCH2CH2OH 81

Phenothiazines

385

I r~\ IH-CH2N CH2C N(CH2CH2O)2H CH 3

82

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 (itself attainable by alkylation of methylbenzimidazole with a dihalide)• Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86) . 2 6

0 C2H5O2CN

NH

+

C1CH2CII2N

0 N~CH3

> C2H5O2CN

NCH2CH2N'

83

_N-CH3

84

I 0 « CH 2 CH 2 CH N

N(fCH2CH2N

HN

NCH2CH2N

NCH3

NCH3 85

86

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58),27 Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 (prepared by a route

Phenothiazines

386

analogous to that used to obtain 71). Oxidation of the product with peracid followed by saponification gives the sulfone (91). This is then converted to the chloropropyl derivative (92). Treatment with the piperidine (87) affords metopimazine (93) . 2 8

H"NT>CONH V 2

58

CH2CH2CH2N

87

>-CONH2

55

C T T l I COCH 3 90

89

91

a:o O

C1I2CH2CH2N 93

>CONH2

SO2CH3 I CH2C112CH2C1

92

That this is not a general observation is indicated by the fact that piperactizine (95), in which carbon again replaced nitrogen, obtained by alkylation of amino alcohol, 94, with the halide (73) is used mainly as a major tranquilizer.

/—\ 73

+

HN

VCH 2 CH 2 OH

94

CH C C N CH C O 2H 2H 2 V 2H 2H 95

Phenothiazines

387

Rigid analogs have met with some success in medicinal chemistry. In brief, it is first assumed that some particular steric orientation of a given grouping within a molecule is required to give the best possible interaction with the hypothetical receptor site. A loose floppy side chain, of course, has the best chance of assuming the required orientation. That very process, however, must pay the cost of an entropy factor. If, on the other hand, the group is locked into the proper configuration beforehand, an energetically more favorable situation, and hopefully greater potency, will result. The most common way of achieving such rigidity is the inclusion of the group in question into a ring system. It should, however, be added that, during the synthetic work involved in drug development, rigid analogs have been known more than once to lock a group into a configuration that gives no fit whatever with the receptors (i.e., inactive compounds) . It will be at once appreciated that the propyl side chain interposed between the two nitrogens in the prototype phenothiazines constitutes a rather flexible arrangement with a large number of possible conformations. One approach towards restricting the degree of freedom of the side chain incorporates the aliphatic nitrogen in a piperidine, with that heterocycle attached to the phenothiazine by a methylene bridge. Construction of the piperidine starts with a double Michael condensation of ethyl acrylate on methylamine. Dieckmann cyclization of the resulting diester (96) gives the piperidine (97). Catalytic reduction over Raney nickel gives the corresponding hydroxymethyl compound (98) (possibly by hydrogenolysis of the intermediate (3-hydroxy ester), which is then converted to the bromo compound (99). Alkylation of phenothiazine with that halide affords the relatively potent major tranquilizer pecazine (100),29 The ring-contracted analog of 100, methdilazine (106), interestingly enough shows only very weak activity as a tranquilizer; instead, that agent constitutes an important antihistamine. Preparation of the side chain in this case starts with the condensation of N-methylpyrrolidone (101) with ethyl oxalate. The condensation product is then reduced catalytically to remove the double bond and interrupt the conjugated system. Subsequent reduction with lithium aluminum hydride serves to reduce the lactam to the amine and the ester to the corresponding alcohol (103). Cleavage of the diol with sodium periodate to the aldehyde followed by catalytic reduction yield the carbinol (104). This last is then converted to the chloride (105) with thionyl chloride.30 Alkylation of phenothiazine with the cyclic side chain affords methdilazine (106).3 x The 2-piperidinoethyl side chain leads to some very potent

388

Phenothiaz ines

CH3NH

+

CH2=CHCO2C2H5

— >

CH3N

CH2CH2CO2C2H5 96 I yCO2CH3 CH3N

\=0

97 CH 2 **•

•-CII3

98, X=0H 99r X=Br

200

Oil I ^OCO^IIr,

01! I CH 2 X

N

I

CH ,

CH3 101

CH 3 103

J02

104 , 105 ,

2

206

- ^

N-CH3

X=OH X=C1

Phenothiazines

389

major tranquilizers that are said to be unusually free of the side effects characteristic of the phenothiazines. Preparation of the side chain in this case involves first conversion of 2picoline (107) to the homologated alcohol, 108, by treatment of the lithium salt of the former with formaldehyde. Reaction with methyl iodide followed by catalytic reduction of the pyridinium salt (109) affords the piperidine (110). This is then converted to the chloro compound (111).32 Alkylation of the methylthiosubstituted phenothiazine with this side chain affords mesoridazine (115).19 Alternately, the N-acylated derivative of the substituted phenothiazine (112) is oxidized to the corresponding sulfoxide by means of periodic acid. Saponification (113) followed by alkylation with the above side chain affords thloridazine (114).1"

N

CIl3

N V

+1?' SCH2CII2OII

' CH2CH2OH

CH3

^ *CH2CH2X CH3

107

JlOf X=GH 111, X=C1

90

1 CIl, CIl ,

SOCK 3

CIl 3 115 The use of urethanes of phenothiazines involving the heterocyclic nitrogen (22, 45) as a means of attaching the side chain is discussed above. Although these intermediates apparently do not possess antipsychotic activity, two compounds of this general class, endowed with somewhat more complex appendages, do exhibit

Phenothiazines

390

antispasmodic activity. Both these compounds have found some use as antitussive agents. Alkylation of the condensation product of diethylaminoethanol and ethylene oxide (117) with the carbamoyl chloride from phosgene and phenothiazine (116) affords dimethoxanate (119).33 Analogous reaction of the pyrrolidyl alcohol

(118) yields pipazethate

(120),3U

117 HOCH2CH2OCH2CH 125

116

o

.COCH2CH2OCH2CH2R 0

120f R=N

J

Substitution of an additional nitrogen atom onto the threecarbon side chain also serves to suppress tranquilizing activity at the expense of antispasmodic activity. Reaction of phenothiazine with epichlorohydrin by means of sodium hydride gives the epoxide 121. It should be noted that, even if initial attack in this reaction is on the epoxide, the alkoxide ion that would result from this nucleophilic addition can readily displace the adjacent chlorine to give the observed product. Opening of the oxirane with dimethylamine proceeds at the terminal position to afford the amino alcohol, 122. The amino alcohol is then converted to the halide (123). A displacement reaction with dimethylamine gives aminopromazine (124),35

Phenothiazines

391

o /\ C1CH2CHCH2 CH2CHCH2 0 121

CH2CHCH2N CI13 CH3 124

CH3 123

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

P. Charpentier, Compt. Rend., 225, 306 (1947). W. B. Reid, J. B. Wright, H. G. Kolloff, and J. H. Hunter, J. Amer. Chem. Soc, 70, 3100 (1948). E. M. Schultz, C. M. Robb, and J. M. Sprague, J, Amer. Chem. Soc, 69, 188 (1947). S. S. Berg and J. N. Ashley, U. S. Patent 2,607,773 (1952). R. M. Jacob and J. G. Robert, U. S. Patent 2,837,518 (1958). Authors unknown, British Patent 814,512 (1959). J. Schmitt, A. Halot, P. Comoy, M. Susquet, R. Fallard, and J. Boitard, Bull. Soc. Chim. France, 1474 (1957). P. Charpentier, U. S. Patent 2,159,886 (1950). P. Charpentier, P. Gailliot, R. Jacob, J. Gaudechon, and P. Buisson, Compt. Rend., 235, 59 (1952). P. J. C. Buisson and P. Gailliot, U. S. Patent 2,769,002 (1956). J. Schmitt, J. Boitard, P. Comoy, A. Hallot, and M. Susquet, Bull. Soc. Chim. France, 938 (1957). A. Roe and W. F. Little, J. Org. Chem., 20, 1577 (1955). H. L. Yale, F. Sowinsky, and J. Bernstein, J. Amer. Chem. Soc, 79, 4375 (1957). 0. Hromotka, G. Stehlik, and F. Sauter, Monatsh., 91, 107

392

15. 16. 17. 18.

19.

20. 21. 22. 23. 24.

25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

Phenothiazines

(1960). R. J. Herclois, U. S. Patent 2,902,484 (1959). P. N. Craig, E. A. Nodiff, J. J. Lafferty, and G. E. Ullyot, J. Org. Chem., 22, 709 (1957). U. Hoerlein, K. H. Risse, and W. Wirth, German Patent 1,120,451 (1956). J. P. Bourquin, G. Schwarb, G. Gamboni, R. Fischer, L. Ruesch, S. G. Uldimann, U. Theuss, E. Schenke, and J. Renz, Helv. Chim. Acta, 41, 1061 (1958). J. P. Bourquin, G. Schwarb, G. Gamboni, R. Rischer, L. Ruesch, S. G. Uldimann, U. Theuss, E. Schenke, and J. Renz, Helv. Chim. Acta, 41, 1072 (1958). M. H. Sherlock and N. Sperber, U. S. Patent 2,860,138 (1958). H. L. Yale and F. Sowinski, J. Amer. Chem. Soc, 82, 2039 (1960). M. H. Sherlock and N. Sperber, U. S. Patent 2,985,659 (1961). R. F. Tislow, W. F. Bruce, and J. A. Page, U. S. Patent 3,023,146 (1962). E. L. Anderson, G. B. Bellizona, P. N. Craig, G. E. Jaffe, K. P. Janeway, C. Kaizer, B. M. Lester, E. J, Nikawitz, A. M. Parloff, H. E. Reiff, and C. Zirkle, Arzneimittel Forsch., 12, 937 (1962). H. G. Moren, British Patent 861,420 (1961). Author unknown, Belgian Patent 668,927 (1965). J. W. Cusic and H. W. Sause, U. S. Patent 2,957,870 (1960). R. M. Jacob and J. G. Robert, German Patent 1,092,476 (1959), W. A. Schuler, U. S. Patent 2,784,185 (1957). L. W. Marsch and R. Peterson, Arzneimittel Forsch., 9, 715 (1959). R. F. Feldkamp and Y. H. Wu, U. S. Patent 2,945,855 (1960). T. R. Narton, R. A. Seibert, A. A. Benson, and F. W. Bergstrom, J. Amer. Chem. Soc, 68, 1573 (1946). C. vonSeeman, U. S. Patent 2,778,824 (1957). R. M. Jacob, R. Herlclois, R. Vaupre, and M. Messer, Compt. Rend., 243, 1637 (1956).

CHAPTER 2 0

Additional Heterocycles Fused to Two Benzene Rings

1.

DIBENZOPYRANS

A great many organic quaternary bases can inhibit the action of acetyl choline in organ systems activated by that neurotransmitter and thus possess anticholinergic-antispasmodic activity. One such agent is methantheline bromide (4), used in the treatment of peptic ulcer and as an antispasmodic agent in intestinal disorders. Its synthesis involves Friedel-Crafts cyclization of oC02H

CC , -CH3 (CH )

A

C0 2 (CH 2 ) 2 N4CH 3

CH, C0 2 (CH2 )2N-C2H5 CoH e

phenoxybenzoic acid (1) followed by hydrogenolysis with sodium and alcohol of the xanthone carbonyl group to form dibenzopyran, 2. Formation of the requisite acid (3) is accomplished by car393

394

Additional Heterocycles

bonation of the lithium salt obtained by ionization of the acidic proton on 2 by treatment with butyl lithium. Esterification is accomplished by heating the sodium salt of 3 with 2-diethylaminoethyl chloride. Quaternization with methyl bromide gives methantheline bromide (4).x The closely related analog, propantheline bromide (5), is rather more potent than 4. Cannabis is essentially the dried resinous mixture obtained from the leaves and flowering tops of varieties of the Indian hemp plant, Cannabis sativa, a hardy weed that grows in large areas of the inhabited world. This preparation has long been used in many lands as an inhaled sedative and, in the proper surroundings and mental conditions, as a psychotropic agent. Marihuana, tea, Mary Jane, pot, bhang, ganja, Acapulco gold, and grass are but a few of the colorful nicknames for various grades of cannabis. It is thought that the properties of cannabis are largely attributable to the presence of A1-tetrahydrocannabinol (8). The content of 8 in cannabis is quite variable, depending not only on the variety of plant and the conditions of its cultivation but also, since A1-THC is unstable to acid and heat, the methods used for harvesting, processing, storage, and administration. There is, of course, no quality control for this street drug. Because of these objective factors and the substantial subjective component regarding its effects, a raging controversy surrounds this drug; the danger, efficacy, and potential value in clinical medicine are all hotly disputed. The availability of pure A1-THC for carefully controlled pharmacologic and toxicologic studies has begun to sort out fact from fancy. Total chemical syntheses have been very useful in this regard and largely depend on carefully controlled acidcatalyzed condensation of selected monoterpenes with olivetol (7)* For example, citral (6) and olivetol cyclize to A^THC (8) in about 12% yield when condensed in ethanol containing 0.0005 N hydrogen chloride. This process gives somewhat better yields when 1% boron trifluoride is used as the catalyst. Since isomerization to virtually inactive A6-THC takes place readily in acid or upon heating, the cyclizations must be carefully controlled. The mechanism of the cyclization reaction is not certain, but thi scheme shown below (9) may illustrate the process. Because citral (6) is optically inactive, the AL-THC so produced is also racemic. The subsequent synthesis /*~6 of optically active A1THC from an optically active monoterpene, for example, verbenol (10), is especially noteworthy. Treatment of 10 with boron trifluoride in the presence of olivetol (7) leads to optically active A6~THC (12), possibly via 11. Double-bond isomerization is then accomplished by addition of hydrogen chloride catalyzed by zinc chloride. Treatment of the resulting halide (13) with

Dibenzopyrans

395

Me

CHO

potassium tertiary amylate leads to elimination of hydrogen chloride from the 1,2 position, thus affording 8 in good yield.7

OH

Me HO Me

Me

OH

Me

10

12

13

Additional Heterocycles

396 2.

ACRIDINES

Malaria and the development of synthetic antimalarial drugs are discussed in some detail in the section covering quinolines. The organization of this book unfortunately sometimes distorts the chronology involved in drug development. A series of acridine antimalarial compounds were in fact developed almost simultaneously with the quinolines. One of these, quinacrine (18), was used extensively in World War II under the trade name of Atabrine®. Nucleophilic aromatic displacement of the ortho halogen in 14 by para-anisidine affords the aminobenzoic acid, 16. Cyclization of this intermediate by means of phosphorus oxychloride affords initially the acridone; the presence of excess reagent serves to convert the carbonyl group to the halide (17), Displacement of that halogen by l-diethylamino-4-aminopentane yields quinacrine (18).8

OCH

14

15

CO2H

OCH,

16

OCEU

17

HN-CHCH2CH2CH2N

18

Acridines

397

An acridine with a radically different substitution pattern, interestingly, still exhibits antimalarial activity. Condensation of acetone with diphenylamine in the presence of strong acid affords the partly reduced acridine, 20. Alkylation with 3chloro-dimethylaminopropane (via the sodium salt of 20) affords dimethacrine (21).9

19

20 CH

21

3.

THIOXANTHENES

Lucanthone is one of the few orally effective drugs available for treatment of the dread tropical disease schistosomiasis, an infestation of blood flukes of the genus Schistosoma. This drug is paradoxically much better tolerated by children than adults; the relatively high incidence of side effects in the latter means that the agent is used mainly in treating the young. One route to this drug starts with the acid-catalyzed condensation of thiosalicylic acid (22) with p-chlorotoluene (23).t0 There is obtained a difficultly separable mixture of isomeric thioxanthones (24,25). Resort is therefore made to the differing reactivities of the halogen in these isomers towards nucleophilic aromatic displacement. The chlorine in 25 is activated by the ortho carbonyl group, while that in 24 should be relatively inert to this reaction. Heating the mixture of isomeric thioxanthones in the presence of 2-diethylaminoethylamine thus leads to an easily separable mixture of lucanthone (26) and recovered 24. Subsequent syntheses were reported that avoid the isomer problem. One of these starts with conversion of p-chlorotoluene to the sulfonyl chloride (27) by reaction with chlorosulfonic acid.

Additional Heterocycles

398

22

0

24

Cl

25

NHCH2CH2N

26

Reduction with zinc dust in aqueous sulfuric acid gives 2-methyl4-aminothiophenol (28)„ Condensation with 2-chlorobenzoic acid (Ullmann reaction) leads to 29, which can close to but one thioxanthone (25) on treatment with sulfuric acid. Although this procedure is longer than the original, the yields are good and the sequence is regioselective.11 It was subsequently discovered that lucanthone is metabolized in the body in part to hycanthone (30), a compound with enhanced schistomacidal activity. The relatively high biologic activity of lucanthone in experimental animals compared to man was subsequently attributed to the inefficient hydroxylating system present in man for this biochemical conversion.12 Microbiologic oxidation of lucanthone by fermentation with the fungus Aspergillus scelorotium affords hycanthone.13

399

Thioxanthenes

29 23

27

28

NHCH2CH2

The efficacy of the phenothiazines for the treatment of various psychoses led to extensive synthetic programs aimed at modulation of the biologic spectrum of these molecules. As seen elsewhere, much of this work has centered on changes of the nature of the atoms that constitute the center ring. Thus, for example, it has proven possible to replace the nitrogen atom of the phenothiazine by carbon while maintaining neuroleptic activity. Ullmann condensation of the sodium salt of p-chlorothiophenol (31) with 2-iodobenzoic (32) acid gives 33, Cyclization by means of sulfuric acid affords the thioxanthone, 34. Reaction with the Grignard reagent from 3-dimethylaminopropyl chloride affords the tertiary carbinol (35). Dehydration by means of acetic anhydride affords chlorprothixene as a mixture of geometric isomers, 36,xh (Subsequent work showed the Z isomer—chlorine and amine on the same side—to be the more potent compound.) Chlorprothixene is said to cause less sedation than the phenothiazines. Appropriate modification of the last few steps affords clopenthixol (37).15 It is of note that this compound approaches the potency of one of the most active phenothiazines, perphenazine, an agent that has a very similar side chain.

400

Additional Heterocycles

cl 31

32

CIHO

CH 2 CH 2 CH 2 N CH3

NCH2 CH2

35 36

NCH2CII2Oll 37 Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above; Grignard condensation followed by dehydration gives thiothixine (42).16 Reduction of the exocyclic double bond generally decreases neuroleptic activity in this series. Some of these compounds, however, show other activities. Methixene (44), for example, is used as an antispasmodic agent. It is prepared by alkylation of the sodium salt of thioxanthene (43) with iV-methyl-3-chloromethylpiperidine.17 (CH 3 ) 2 NO 2 S

,-COoH

38

39

40

Thioxanthenes

401

"SO2N(CH3)2

"SO2N(CH3)2 CHCH2CH2N(CH3)2 42

41

43

4.

DIBENZAZEPINES

a.

Dihydrodibenzazepines

Although these compounds, too, are structurally closely related to the phenothiazin.es with which they may be considered isosteric, their main activity tends to be as antidepressant agents. The dibenzazepines do themselves enjoy a considerable vogue in the treatment of endogenous depression. Together with the dibenzocycloheptadiene derivatives, they are often referred to collectively as the tricyclic antidepressants. Although this basic ring system has been known since 1899, its pharmacology is of much more recent origin. The synthesis of imipramine (50)18 is typical of the chemistry of this series. 2-Chloromethylnitrobenzene (45) self-condenses to styrene (46) under alkaline conditions (see, for example, stilbestrol). The nitro groups are then reduced to give diamine, 47. Reaction with sodium in amyl alcohol serves to reduce the double bond (48). Strong heating results in cyclization to 10,ll-dihydro-5H-dibenz[b,f]azepine (49), the parent nucleus for the series. Imipramine (50) is prepared from 49 by forming the sodium salt on nitrogen with sodium amide and alkylating this with 3-dimethylaminopropyl chloride. Metabolic disposition of imipramine involves, among other processes, N-

402

Additional Heterocycles

48

CH2CH2CH2N

N

R

51, R=CO2C2H5 5 2 BL~Y\ demethylation. This metabolic transformation product, desipramine (52), is an antidepressant agent in its own right. It is thought by some to be the authentic active agent on administration of imipramine. It may be synthesized chemically from 50 by heating the compound with ethylchlorocarbonate to give the urethane (51); saponification gives the secondary amine.19 This technique for monodealkylation of a tertiary amine has largely supplanted the classic von Braun reaction. The synthetic scheme used to obtain 49 is, of course, not suitable for compounds containing substituents on only one aromatic ring. An interesting ring enlargement has been used to obtain starting materials for such substituted dibenzazepines. Displacement of the benzhydryl chlorine in 53 by cyanide affords the corresponding nitrile (54); hydrolysis to the acid (55) followed by metal hydride reduction gives the primary alcohol (56). Treatment with phosphorus pentoxide leads to dehydration with phenyl migration to afford the ring-enlarged product (57). Catalytic reduction of the stilbene double bond affords the desired halogenated starting material. This dihydrodibenzazepine (58) is then N-alkylated by means of 3-dimethylaminopropyl chloride to give chloripramine (59).20

Dibenzazepines

403

CH20H

53, X=C1 54, X=CN 55, X=C02H

57

56

CH2CH2CH2N

cxxx 58

59

b.

Dibenzazepines

The fully unsaturated tricyclic compounds are also used clinically as antidepressants. Carbamazepine (62),21 for example, is prepared from 10,ll-dihydro-5#-dibenz[b,f]azepine (49) by N~ acetylation followed by bromination with iv~bromosuccinimide to give 60. Dehydrohalogenation by heating in collidine introduces the double bond. Saponification with potassium hydroxide in ethanol leads to dibenz[b,f]azepine (61), the parent substance for the fully unsaturated analogs. Treatment of the secondary

H 60

61

CH 2 CH 2 CH 2 OR CH 2 CH 2 CH 2 N

63, R=H 64/ R=p-S02C6H4CH3

65

NCH2CH2OH

404

Additional Heterocycles

amine (61) with phosgene followed by heating of the carbamoyl chloride thus obtained with ammonia affords carbamazepine (62).2 * Alkylation of the sodium salt of 61 with 3-chloropropan-l-ol followed by reaction of the intermediate (63) with tosyl chloride gives the tosylate, 64. Displacement by 1-(2-hydroxyethyl)piperazine gives opipramol (65) .2Z

5.

DIBENZOXEPINS

One of the two carbon atoms of the ethylene bridge of the antidepressants may be replaced by oxygen. Attachment of the side chain via the olefinic linkage found in amytriptyline affords antidepressants with a biologic profile similar to the carbocyclic prototype. Cyclization of 2-benzyloxybenzoic acid (66) by means of polyphosphoric acid affords the dibenzoxepinone, 67. Condensation with the Grignard reagent from 3-dimethylaminopropyl chloride, followed by dehydration of the alcohol thus produced affords doxepin (68),23 presumably as a mixture of geometrical isomers. In an alternate synthesis of the intermediate ketone, the benzylic halide, 69, is used to alkylate sodium phenoxide. Cyclization of the acid (70) obtained on hydrolysis of the ester by means of trifluoroacetic anhydride again gives 67.2k

,CH, CH2CH2N 68

CH2Br

6.

coo 70

DIBENZODIAZEPINES

Fusion of an additional aromatic ring onto the diazepine ring

Dibenzodiazepines

405

system markedly alters the activity of the resulting compound; this imaginary transformation serves to convert an anxiolytic into an antidepressant agent. Nucleophilic aromatic substitution of the anthranilic acid derivatives, 72, on ortho-bromanitrobenzene affords the diphenylamine, 73. The ester is then saponified and the nitro group reduced to the amine (74). Cyclization of the resulting amino acid by heat affords the lactam (75). Alkylation on the amide nitrogen with 2-dimethylaminoethyl chloride by means of sodium amide affords dibenzepine

(76),25

X

72

7.

CO2R

73, X=N02; R^CH 74, X=NH2; R=H

75

DIBENZOTHIAZEPINES

An interesting additional example of the interchangeability of the bridging atoms in the neuroleptic series comes from the finding that the biologic activity of the phenothiazines is maintained in a compound that contains an extra atom on the nitrogen

;-CH. > 77 78

406

Additional Heterocycles

bridge. Acylation of the amine, 77, by means of the carbamoyl chloride obtained by treatment of iv-methylpiperazine with phosgene gives the unsymmetrical urea, 78. Cyclization with phosphorus oxychloride in DMF leads to the major tranquilizer dothiapine (79).26

REFERENCES 1.

J. W. Cusic and R. A. Robinson, J. Org. Chem., 16, 1921 (1951). 2. E. C. Taylor, K. Leonard, and Y. Shro, J. Amer. Chem. Soc, 88, 367 (1966). 3. R. Mechoulam, P. Braun, and Y. Gaoni, J. Amer. Chem, Soc, 94, 6159 (1972). 4. R. K. Radzan and G. R. Handrick, J. Amer. Chem. Soc, 92, 6061 (1970). 5. T. Petrzilka, W. Haefliger, and C. Sikemeier, Helv. Chim. Acta, 52, 1102 (1969). 6. T. Y. Jen, G. A. Hughes, and H. Smith, J. Amer. Chem. Soc, 89, 4551 (1967). 7. T. Petrzilka and C. Sikemeyer, Helv. Chim. Acta, 50, 2111 (1967). 8. F. Mietzsch and H. Mauss, U. S. Patent 2,113,357 (1938); Chem. Abstr., 32, 4287 (1938). 9. T. Holm, British Patent 933,875 (1963); Chem. Abstr., 60, 510a (1964). 10. H. Mauss, Chem. Ber., 81, 19 (1948). 11. S. Archer and C. M. Suter, J. Amer. Chem. Soc, 74, 4296 (1952). 12. D. A. Berberian, E. W. Dennis, M. Freele, D. Rosi, T. R. Lewis, R. Lorenz, and S. Archer, J. Med. Chem., 12, 607 (1969). 13. D. Rosi, G. Peruzzotti, E. W. Dennis, D. A. Berberian, H. Freele, and S. Archer, J. Med. Chem., 10, 867 (1967).

References

14.

407

J. M. Sprague and E. L. Englehardt, U. S. Patent 2,951,082 (1960). 15. P. V. Petersen, N. 0. Lassen, and T. 0. Holm, U. S. Patent 3,149,103 (1964). 16. B. M. Bloom and J. F. Muren, Belgian Patent 647,066 (1964); Chem. Abstr., 63, 11 512a (1965). 17. J. Schmutz, U. S. Patent 2,905,590 (1959). 18. W. Schindler and F. Hafliger, Helv. Chim. Acta, 37, 472 (1954). 19. Anon., Belgian Patent 614,616 (1962); Chem. Abstr., 58, 11338c (1963). 20. P. N. Craig, B. M. Lester, A. J. Suggiomo, C. Kaiser, and C. M. Zirkle, J. Org. Chem., 26, 135 (1961). 21. W. Schindler, U. S. Patent 2,948,718 (I960). 22. W. Schindler, French Patent M2O9 (1961); Chem. Abstr., 58, 3442f (1963). 23. K. Stach and F. Bickelhaupt, Montash, 93, 896 (1962). 24. B. M. Bloom and J. R. Tretter, Belgian Patent 641,498 (1968); Chem. Abstr., 64, 719c (1966). 25. F. Hunziker, H. Lauener, and J. Schmutz, Arzneimittel Forsch., 13, 324 (1963). 26. Anon., French Patent CAM51 (1964); Chem. Abstr., 61, 8328h (1964).

CHAPTER 21

/3-Lactam Antibiotics

1.

PENICILLINS

It is well known even to segments of the general public that the penicillin story began with the adventitious discovery of the lysis of pathogenic Staphylococcus aureus by Penicillium notatum in Sir Alexander Fleming's laboratory in 1929. The initial work led to extensive and ultimately successful chemical studies that were greatly facilitated by an international cooperative effort which included participation of industrial and governmental laboratories in the United States. During this technology-sharing and transfer phase, it was learned that the natural penicillins (those produced by fermentation on complex natural media) were mixtures of closely related compounds and that the product composition could be profoundly affected by the presence of certain compounds in the growth media. Addition of phenylacetic acid to the fermentation led to predominance of benzylpenicillin, known also as penicillin G. Long after the antibiotic was an established clinical success the structure of penicillin G was determined to be 2. The strain in the fused thiazolidine~3~lactam system results in enormously more pronounced hydrolytic susceptibility of the 3-lactam bond than is characteristic of amides in general and nonstrained 3-lactams in particular. This structural feature hindered early progress in working with these compounds and must be borne uppermost in mind in any consideration of the chemistry of these substances. The 3-lactam antibiotics are cell-wall inhibitors toward susceptible bacteria. To survive in a hostile environment with ionic strengths often quite different from the interior of the cell, bacteria have evolved a rigid, quite complex cell wall. This wall, which has no counterpart in mammals, does differ somewhat among different species of bacteria. Differences in chemical composition lead to variations in their reactions to various 408

Penicillins

409

staining procedures. The terms, gram-negative and gram-positive, which are often used to denote differences in sensitivities to various classes of antibiotics, merely denote reaction or lack thereof to the gram stain procedure. The cell walls of bacteria, which consist of cross-linked peptidoglycans, are elaborated by a specialized series of enzymes. Interference with this process insults the integrity of the protective coating and thus leads eventually to the death of the organism. It has been established that one of the final steps in the cell wall-forming sequence is a cross-linking reaction between peptide chains that gives the polymer three-dimensional character. It is generally accepted that the penicillins and cephalosporins bear a topographical resemblance to the natural substrate for a transamidase essential to this biochemical sequence and that they irreversibly inhibit the enzyme by acylation of the active site. The lack of a counterpart to this process in mammals obviates toxic reactions from this inhibitory process. The penicillins isolated from the beers resulting from fermentation of the molds, Penicillium notatum and Penicillium chrysogenum, were in fact complex mixtures of closely related compounds—a rather common occurrence in antibiotic research. The active compounds proved to be amides of 6-aminopenicillanic acid (2, 6-APA) with differing acyl groups attached to the amine of the 3-lactam ring. 6-APA possesses weak but definite antibacterial properties, and its structure represents the minimum structural requirements for the characteristic bioactivity of the penicillins. The incorporation of an acyl side chain, particularly one containing an aryl residue, increases potency by 50 to 200-fold. Thus 6-APA (2) is the penicillin pharmacophore, and the amide function serves to modulate the kind and intensity of antimicrobial activity. All the clinically useful analogs that have reached the marketplace have flowed from this basic fact or have resulted from the adventitious discovery of analogous substances from natural sources. Penicillin G has a fairly narrow antibacterial spectrum. In particular, fungi and many gram-negative bacteria are rela-

410

3-Lactam Antibiotics

tively insensitive to this agent. A number of strains of bacteria that were once sensitive to penicillins elaborate enzymes, known collectively as penicillinases, that hydrolyze the 3-lactam bond to produce the microbiologically inactive penicilloic acids. Such organisms are resistant to the drug. In addition to this enzymatic destruction, benzyl penicillin hydrolyzes readily in water at all but neutral pH. This leads to storage problems and, because the acid milleau of the stomach and the alkaline conditions extant in the duodenum are too extreme for the antibiotics, leads to substantial loss of drug on oral administration. This requires injection for the treatment of severe infections. Finally, a significant percentage of patients are allergic to the penicillins and cephalosporins. These defects have spurred attempts to prepare analogs. The techniques used have been: (1) natural fermentation (in which the penicillin-producing fungus is allowed to grow on a variety of complex natural nutrients from which it selects acids for incorporation into the side chain), (2) biosynthetic production (in which the fermentation medium is deliberately supplemented with unnatural precursors from which the fungus selects components for the synthesis of "unnatural" penicillins), (3) semisynthetic production (in which 6-aminopenicillanic acid (2) is obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically with 6-APA to form penicillins with new side chains) and (4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods). Following the realization that the presence of phenylacetic acid in the fermentation led to a simplification of the mixture of penicillins produced by the fungus due to preferential uptake of this acid and its incorporation into benzylpenicillin (4), a wide variety of other acids were added to the growing culture. Inclusion of the appropriate acids in the culture medium thus afforded, respectively, phenoxymethylpenicillin (5, penicillin V), phenethicillin (6),2>3 propicillin (7), and phenbencillin (8). These modifications served to increase stability of the lactam bond towards hydrolysis and thus conferred some degree of oral activity. The nature of the penicillin derivatives accessible by this "feeding" route was severely limited by the fact that the acylating enzyme of the Penicillium molds would accept only those carboxylic acids which bore at least some resemblance to its natural substrates. A breakthrough in this field was achieved by the finding that rigid exclusion of all possible side-chain substrate! from the culture medium afforded 6-APA as the main fermentation

Penicillins

411

6,

. CH2CH3 >OCH-

7,

R= C

8,

R= r Vocn-

product.'* It was subsequently found that certain Gram-negative bacteria and some fungi elaborated amidase enzymes that would selectively remove the acyl groups from penicillins produced by natural fermentation, thus again yielding 6-APA.3""8 The availability of this nucleus permitted free reign on the part of the medicinal chemist in the design of side chains to be included in the penicillin antibiotics. It is of note that 6-APA is today classed as a bulk chemical. The proper design of the side chains thus accessible has served not only to overcome many of the shortcomings of the early penicillins, such as acid lability, lack of oral activity, and ready destruction by bacterial penicillinase enzymes, but has provided antibiotics with broadened antibacterial spectra. Although the last step in the preparation of a semisynthetic penicillin may appear to be a straightforward acylation of 6APA, the wealth of functionality and reactivity of the 3-lactam requires highly specialized conditions for achieving this transformation. Attachment of an aromatic or heterocyclic ring directly to

412

3-Lactam Antibiotics

to the amide carbonyl affords antibiotics with increased resistance to bacterial penicillinases. Thus, acylation of 6-APA with 2,6-dimethoxybenzoic acid (9) affords methicillin (10).9 The isomeric lactam, 12, which lacks one of the ortho substituents, interestingly lacks this resistance. 1 0 OCH 3

CO2H

CH3O

6-APA

0 2O

OCH3 ,' C 0 2 H CH3O

11

CH3O / ^ V O C H 3 [I '^ ^ CNH

CH, 3

0 CO 2 H

'COoB

12 Acylation of 6-APA by the naphthoic acid, 13, again affords an agent with considerable steric hindrance about the amide function. There is thus obtained the antibiotic nafcillin (14).1X >12 a compound with good resistance to penicillinases. Sterically hindered derivatives of isoxazole carboxylic acids have yielded a goodly number of antibiotics. Chlorination of the oxime of the appropriately substituted benzaldehydes (15) leads to the intermediates, (16). Condensation of the chloro oximes with ethyl acetoacetate in base gives the esters (17) of the desired isoxazole carboxylic acids. Alternately, the esters

413

Penicillins

may be obtained directly by reaction of the aroylated acetoacetates (19) with hydroxylamine. Condensation of the free acids (18) with 6-APA affords, respectively, oxaclllin (20),13 cloxacillin (21),14 dicloxacillin (22),15 and floxacillin (23).

CH=NOH 16

CHCCH3 'C°2C2H5 19

17, R=C2H5 18, R=H

S

CH

20, 21, 22, 23,

'CO2H

X=Y=H X=H; Y=C1 X-Y=C1 X-Cl; Y=F

It was observed in some of the early research on penicillin that drugs acylated by amino acids had somewhat greater oral activity than those compounds with neutral side chains. Addition of an amino group to benzyl-penicillin, interestingly, also leads to antibiotics with a broadened antibacterial spectrum. One synthesis of this agent begins by protection of the amino group of phenylglycine (24) as its carbobenzyloxy derivative (25). The intermediate is then converted to the mixed carbonic anhydride (26) by means of ethyl chloroformate. Condensation with 6-APA affords the amide (27). Catalytic hydrogenation removes the protecting group to afford ampicillin (28),16 An alternate route to ampicillin not only circumvents the need for 6-APA but also has the advantage of providing a prodrug form of ampicillin as well as the parent compound. Reaction of benzylpenicillin (4) with the acid protecting group, 29, gives the formol ester, 30. Reaction of the product with phosphorus pentachloride leads to the corresponding imino chloride (31).

414

3-Lactam Antibiotics

CHCO2H 24 25, R=H 26, R=COC2H5 0

NCH3

II ] | T 0 QJ—N 27, 25,

1 'CO2H

R=CO 2 CH 2 C 6 H 5 R=H

Successive treatment with propanol and then acid serves in effect to hydrolyze the amide linkage. (Note particularly that this sequence is selective for the exocyclic amide over the azetidone.) Reaction of the protected 6-APA derivative (32) with the acid chloride from 24 affords the pivaloylmethylenedioxy derivative, pivampicillin (33).17»18 This last is a drug in its own right, presumably undergoing hydrolysis to ampicillin (28) after administration. The same transformation can be carried out in vitro by mild acid treatment. Latentiation of ampicillin can also be achieved by tying up the proximate amino and amide functions as an acetone aminal. Inclusion of acetone in the reaction mixture allows 6-APA to be condensed directly with the acid chloride from 24. There is thus obtained directly the prodrug hetacillin (34).19a Although this compound has little antibiotic activity in its own right, it hydrolyzes to ampicillin in the body. The p-hydroxy derivative amoxycillin (35)19l° shows somewhat better oral activity. A similar sequence using formaldehyde gives metampicillin (36).20 Replacement of the primary amine in ampicillin by a carboxylic acid group significantly changes the biologic spectrum of the product. There is obtained the antibiotic carbencillin (37),** an agent with significant activity against the Gram-negative Pseudomonas genus. The compound is attainable by chemistry simi-

Penicillins

415

0 C 6H 5C-S

Cl . S yCH 3 , S >V C ,H 5C=N y ! I CH3 0 . CH3 0 0 rJ— N i, ll 0^— N '', II "CO2CH2OCC(CH3 )3 "CO mr — 30 31 0 I C1CH2OCC(CH3)3 29 "V 1 S yCH* ! _/ ""I f pCH3 0 <1~ 2 I I ^CO2CH2OCC(CH3)3 'tO2CH2OCC(CH3)3 33

CH3 6-APA

+ R^

j VCHCOCI

—^

/ v. j R-^ yen

\

C^-3 ^S N^ ! I CH 3

NS C 0°" 34, 35,

"''COot R=H R=OH

HN —C 0

N

7 ~ r s i ^ VCH3 V

^

CO2H

36

lar to that above, using a suitably half-protected ester of phenylmalonic acid.

3-Lactam Antibiotics

416

6-APA

+

r

X

CO2R VCH

X

CO2H l

CO2H ''CO2H 37

2.

CEPHALOSPORINS

The existence of fungi that produce antibiotics when present in milieus replete with pathogenic organism makes good teleologic sense; this is, after all, the first line of defense for the fungus against its neighbors. The observation that such antibioticproducing fungi do in fact occur in soils and other environments rich in bacteria initiated a worldwide examination of soils, sewage sludges, and related offal for new antibiotics. This program, which has met with some signal successes, continues to this day. It might be added that one of the most troublesome aspects of such programs consists in the constant rediscovery of known antibiotics; the profligacy of nature is apparently not limitless. Considerable interest was generated by the finding that a Penicillium from Sardinian sewage outfall elbatorated a mixture of antibiotics, cephalosporin C, effective against Gram negative bacteria. Structural elucidation of one component, penicillin N, showed the compound to have many features in common with penicillin (38).11 Indeed, the agent is related formally to the earlier antibiotic by cleaving the carbon sulfur bond and then recyclizing onto one of the geminal methyl groups. (A transformation akin to this has in fact been achieved in the laboratory.) The low potency of cephalosporin C soon made it clear that the natural product itself was unsuitable as a clinical antibiotic. The structure would have to be modified in the laboratory to give a more potent semisynthetic analog. Despite much research, no method has yet been found to culture cephalosporin C in such a way as to afford the bare nucleus. This intermediate, 7-ACA (42), is to an analog program in this series what 6-APA is to any penicillin program. Fortunately, several ingenious schemes were elaborated for regioselective cleavage of the side-chain amide. Treatment of cephalosporin with nitrosyl chloride presumably first nitrosates the primary amine on the adipyl side chain; this then goes in the usual way

417

Cephalosporins

to the diazonium salt (40). Displacement of this excellent leaving group by oxygen from the enol form of the amide gives the iminopyran (41). The latter undergoes facile hydrolysis with dilute acid to give 7-ACA (42),22

HO2CV

V

H

CH(CH2)3CN

N

|/Sv

NH 2

2 OCOCH 3

CO2H 38

HO2C /CH, CH CH2 I ! NH CH2 I I NO C 0 NH-R 39

HO2CV

CH I N2+

CH2 I CH2 i

HO

^NH-R

40

HO2C J

O'

CO2H 42

CO2H

The alternate schemes that have been developed for achieving removal of the side chain similarly depend on intramolecular interaction of some derivative of the amine with the amide oxygen to afford some easily hydrolyzed intermediate at an oxidation stage analogous to 41.23 Acylation of 7-ACA with 2~thienylacetylchloride gives the amide cephalothin (43). Displacement of the allylic acetyl group by pyridine affords the corresponding pyridinium salt cephaloridine (44).2S Both these compounds constitute useful injectable antibiotics with some activity against bacteria resistant to penicillin by reason of penicillinase production. In an interesting analogy to the penicillin series, acylation of 7-ACA with the phenylglycine moiety affords a compound with oral activity. Thus, phenylglycine is first protected as the carbo tertiary butyloxy derivative (45). Reaction of this with isobutyloxy chloroformate affords the mixed anhydride (46). Condensation of that with 7-ACA gives the intermediate, 47Treatment with either trifluoroacetic or formic acid provides the free amine cephaloglycin (48).26 The allylic acetoxy group is apparently not necessary for antibiotic activity. Hydrogenolysis of that group in 48 affords cephalexin (49),27 a drug with enhanced oral activity.

418

3-Lactam Antibiotics

0* CO2H 42

43

0 II NHCOC(CH3)3 r

7-CHCOR " CH 2 OCOCH 3 CO 2 H 45, R=H 46, R=OCOCH(CII 3 ) 2

The total syntheses of penicillin28 and cephalosporin29 represent elegant tours de force that demonstrated once again the power of synthetic organic chemistry. These syntheses, however, had little effect on the course of drug development in the respective fields, since they failed to provide access to analogs that could not be prepared by modification of either the side chains or, as in the case of more recent work, modification of 6-APA and 7-ACA themselves. In order to have an impact on drug development, a total synthesis must provide means for preparing

Cephalosporins

419

analogs not accessible from natural product starting materials; cases in point are the Torgov synthesis for steroids, which allowed preparation of the 19-ethyl analogs, or the various prostaglandin routes that allow inclusion of "unnatural" substituents. Very recently total syntheses have been developed for the cephalosporins that allow replacement of the sulfur in the sixmembered ring by oxygen and carbon. The synthesis starts by elaboration of a small unit that will provide the bridgehead nitrogen, the carboxyl group, and a phosphonate unit that will close the six-membered ring by intramolecular ylide condensation. Thus, the amino group of phosphonate, 50, is first protected as the Shiff base by reaction with benzaldehyde (51). Acylation of the lithium derivative with benzyl chlorocarbonate introduces the future carboxyl group as its benzyl ester (52). Removal of the benzyl group gives back the free amine (53) . Reaction of that amine with ethyl thionoformate affords the corresponding formamide derivative of the amine (54). Alkylation of that formamide goes on sulfur to give the enol thioformate (55). This functionality, which represents the eventual ring fusion, is now set up to act as the acceptor in a 2+2 cycloaddition reaction. Thus, exposure of 55 to the ketene obtained in situ from 2~azidoacetyl chloride and triethylamine affords the desired azetidone (56).

H2N-CH2P(OC2H5)2

o

o V

0

-*

H N3 ^ JMSCHJ O o J- N P(oc2i ls>2 " ni

i C6H5CH-NCH2P(OC2H5>a — C6H5CH=NCHP(OC2H5>2 CO2CH2C6H5 5?

CH-SCH3 N PO(OC2I cir 1

<"

u RN1ICH2P(OC2MO 1 2C1I2C6H5 CO R-=CH S

420

H T 0

3-Lactam Antibiotics

H H X N

o NU CH 'NO*C-CH2OCOCH3 — S CH-PO(OC 2H5 )2 1 CO2CH2C(H5 57

H H

co2cn2C(,m

59, Cl S , t rdni

U / ^ UH H / >C1I2CM :

r~\ ,,H H ( \-Cll2CN4__ 5 / \ Ss ' ol_

N

1 0 - N ^ CH2OCOCH3 CO2H

CH 3

js

S

CH2OCOCII3

CO2II 62

C 0211 hi

Reaction of the thiomethyl group with chlorine then converts that functionality to the corresponding S-chloronium salt as a mixture of diastereomers (isomers at both carbon and sulfur). Solvolysis of the salt in the monoacetate of dihydroxyacetone in the presence of silver oxide and silver fluoroborate effects net displacement of sulfur by oxygen. The remaining atoms of the six-membered ring are thus incorporated at one fell swoop, albeit with loss of stereochemistry (57). Treatment of that intermediate with sodium hydride forms the ylide on the carbon adjacent to the phosphonate; this condenses with the carbonyl group on the pendant ether side chain to afford the oxacephalosporin nucleus (58). Hydrogenolysis of the intermediate simultaneously removes the benzyl ester and reduces the azide to the primary amine (59,60). Acylation of the cis isomer (59) with 2-thienylacetic acid affords +rl-oxacephalothin (60),30 Taking into account that the product is racemic, the agent is essentially equipotent with cephalothin (43) itself. Appropriate modification of the synthesis from 56 onward followed by the same type of intramolecular ylide reaction affords +^l~carbacephalothin (61),31 a compound with very similar antibacterial activity.

REFERENCES 0. K. Behrens, J. Corse, J. P. Edwards, L. Garrison, R. G. Sones, Q. F. Soper, F. R. VanAbeele, and C. W. Whitehead, J. Biol. Chem., 175, 793 (1948).

References

2.

3. 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

18.

19.

20. 21. 22.

421

Y. G. Perron, W. F. Minor, C. T. Holdrege, W. J. Gottstein, J. C. Godfrey, L. B. Crast, R. B. Babel, and L. C. Cheney, J. Amer. Chem. Soc., 82, 3934 (1960). K. W. Glombitza, Ann., 673, 166 (1964). F. R. Batchelor, F. P. Doyle, J. H. C. Nayler, and G. N. Rolinson, Nature, 175, 793 (1948). K. Kaufmann and K. Bauer, Naturwissenschaften, 47, 474 (1960). G. N. Rolinson, F. R. Batchelor, D. Butterworth, J. CameronWood, M. Cole, G. C. Eustace, M. V. Hart, M. Richards, and E. B. Chain, Nature, 187, 236 (1960). C. A. Claridge, A. Gourevitch, and J. Lein, Nature, 187, 237 (1960). H. T. Huang, A. R. English, T. A. Seto, G. M. Shull, and B. A. Sobin, J. Amer. Chem. Soc, 82, 3790 (1960). F. P. Doyle, K. Hardy, J. H. C. Nayler, M. J. Soulal, E. R. Stove, and H. R. J. Waddington, J. Chem. Soc, 1453 (1962). K. E. Price, Advan. Appl. Microbiol., 11, 17 (1969). S. B. Rosenman and G. II. Warren, Antimicrob. Agents Chemother., 611 (1961). E. G. Brain, F. P. Doyle, M. D. Mehta, D. Miller, J. H. C. Nayler, and E. R. Stove, J. Chem. Soc, 491 (1963). F. P. Doyle, A. A. W. Long, J. H. C. Nayler, and E. R. Stove, Nature, 192, 1183 (1961). F. P. Doyle, J. C. Hanson, A. A. W. Long, J. H. C. Nayler, and E. R. Stove, J. Chem. Soc, 5838 (1963). Ch. Gloxhuber, H. A. Offe, E. Rauenbusch, W. Scholtan, and J. Schmid, Arzneimittel Forsch., 15, 322 (1965). F. P. Doyle, G. R. Fosker, J. H. C. Nayler, and H. Smith, J. Chem. Soc, 1440 (1962). W. vonDaehne, E. Frederiksen, E. Gundersen, F. Lund, P. Morch, H. J. Petersen, K. Roholt, L. Tybring, and E. Ferrero, Abstr. 5th Int. Congr. Chemother. (Vienna), 201 (1967). W. vonDaehne, E. Frederiksen, E. Gundersen, F. Lund, P. Morch, H. J. Petersen, K. Roholt, L. Tybring, and W. 0. Gotfredsen, J. Med. Chem., 13, 607 (1970). (a) G. A. Hardcastle, Jr., D. A. Johnson, C. A. Panetta, A. I. Scott, and S. A. Sutherland, J. Org. Chem., 31, 897 (1966). (b) A. A. W. Long, J. H. C. Nayler, H. Smith, T. Taylor, and N. Ward, J. Chem. Soc, Ser. C, 1920 (1971). E. Ferrero, Abstr. 5th Int. Congr. Chemother. (Vienna), 201 (1967). P. Acred, D. M. Brown, E. T. Knudsen, G. N. Robinson, and R. Sutherland, Nature, 215, 25 (1967). R. B. Morin, B. G. Jackson, E. H. Flynn, and R. W. Roeske, J. Amer. Chem. Soc, 84, 3400 (1962).

422

3-Lactam Antibiotics

23.

B. Fechtig, H. Peter, H. Bickel, and E. Vischer, Helv. Chim. Acta, 51, 1108 (1968). R. R. Chauvette, E. H. Flynn, B. G. Jackson, E. R. Lavagino, R. B. Morin, R. A. Mueller, R. P. Pioch, R. W. Roeske, C. W. Ryan, J. L. Spencer, and E. M. VanHeyningen, J. Amer. Chem. Soc, 84, 3401 (1962). J. L. Spencer, F. Y. Siu, E. H. Flynn, B. G. Jackson, M. V. Sigal, H. M. Higgins, R. R. Chauvette, S. L. Andrews, and D. E. Bloch, Antimicrob. Ag. Chemother., 573 (1966). J. L. Spencer, E. H. Flynn, R. W. Roeske, F. Y. Siu, and R. R. Chauvette, J. Med. Chem., 9, 746 (1966). C. W. Ryan, R. L. Simon, and E. M. VanHeynigen, J. Med. Chem., 12, 310 (1969). J. C. Sheehan and K. R. Henery-Logan, J. Amer. Chem. Soc, 79, 1262 (1957); 81, 3089 (1959). R. B. Woodward, K. Henster, J. Gosteli, P. Naegeli, W. Oppolzer, R. Ramage, S. Raganathan, and H. Vorburggen, J. Amer. Chem. Soc, 88, 852 (1966). L. D. Cama and B. G, Christensen, J. Amer. Chem. Soc, 96, 7582 (1974). R. N. Guthikonda, L. D. Cama, and B. G. Christensen, J. Amer. Chem. Soc, 96, 7585 (1974).

24.

25. 26. 27. 28. 29. 30. 31.

CHAPTER 22

Miscellaneous Fused Heterocycles

1.

PURINES

It would not be too far fetched to state that life on this planet is totally dependent on two compounds based on the purine nucleus. Two of the bases crucial to the function of DNA and RNA—guanine and adenine—are in fact substituted purines. It is thus paradoxical that the lead for the development of medicinal agents based on this nucleus actually came from observations of the biologic activity of plant alkaloids containing that heterocyclic system, rather than from basic biochemistry. Xanthines such as caffeine (1), theophylline (aminophylline) (2), and theobromine (3) are a class of alkaloids that occur in numerous plants. The CNS stimulant activity of aqueous infusions containing these compounds has been recognized since antiquity. This has, of course, led to widespread consumption of such wellknown beverages as coffee (Coffea arabica), tea (Thea sinesis), mate, and cola beverages (in part Cola acuminata). The annual consumption of caffeine in the United States alone has been estimated to be in excess of a billion kilos. The pure compounds have found some use in the clinic as CNS stimulants. In addition, caffeine is widely used in conjunction with aspirin in various headache remedies. There is some evidence to suggest that these drugs may owe their activity to inhibition of the enzyme that is responsible for hydrolysis of 3f,5f-cyclic AMP (itself a guanine derivative) and thus prolong the action of cyclic AMP. The Traube synthesis represents but one of the many preparations that have been developed for purines. Transesterification of ethyl carboxamidoacetate with methyl urea affords the diamide (4). Treatment with base leads this to cyclize to the pyrimidone (5). Nitrosation on carbon (6) followed by reduction of the nitroso group gives the diamine, 7. Condensation with formic 423

Miscellaneous Fused Heterocycles

424

o

R"

I R1 Z,

R=R'=R"=CH3

2,

R=Rf=CH3;R"=H

3,

R=H;R(=R"=CH3

acid introduces the remaining carbon of the purine nucleus (8). Monomethylation of that compound affords theobromine (3); dimethylation gives caffeine (1). The same sequence using 1,3dimethylurea as one starting material in this sequence leads to theophyline (2).

0=C

H

0 il

NH

CH2 CONH2

0 II C2H5O»CN

NH2

0=C

\ NHCIi 3

C0MI2

V

CH3

0 CH3

1

CH2CO2H •

0 ^ CH3 8, 2,

C H

3

X

0

CH3 i CH2CH2NHCH

11

CH2

N

N I CH3

I CH3

R=H R=CH3

CHoCtUCl

I CH3

CH, 11

10

6,

X=N0

7,

X=NH2

Purines

425

Substitution of somewhat more complex side chains on the imidazole nitrogen of the purines leads to CNS stimulant drugs that have also been used as vasodilators and antispasmodic agents. Thus, alkylation of theophyline (2) with ethyl bromoacetate followed by saponification of the product gives acephylline (9).x Alkylation with l~bromo-2-chloroethane gives the 2-chloroethyl derivative (10). Reaction of that intermediate with amphetamine yields fenethylline (II).2

0

13

CH2CH2X

14, X=OH 15, X=C1

i 0

CH2CH2N 1

N

CH 2 CH 2 OH

16 Substitution of more complex acids for formic acid in the last step of the purine synthesis will afford intermediates substituted on the imidazole carbon atom. Thus, condensation of diaminouracyl, 12, with phenylacetic acid gives the benzylated

426

Miscellaneous Fused Heterocycles

purine, 13. Alkylation with 2-chloroethanol (14) followed by treatment with thionyl chloride affords the intermediate, 15. Use of that intermediate to alkylate iv-(2-hydroxyethyl) ethylamine affords the stimulant bamiphylline (16).3 Rational drug design is the ultimate goal of medicinal chemistry. By this is understood the design of medicinal agents on the basis of knowledge of the intimate biochemistry of the disease process. Allopurinol represents one of the first successes towards this long-term goal. The duration of action of the oncolyltic agent, 6~mercaptopurine, is limited by its facile oxidation to inactive 6-thiouric acid by the enzyme xanthine oxidate. The search for agents that would prolong drug action turned to analogs that contained an extra nitrogen atom~pyrazolo(3,4-d)pyrimidines—in the hopes that these would act as false substrates for the inactivating enzyme (antimetabolites). One such compound, allopurinol (20), proved effective in both laboratory animals and man in inhibiting oxidation of 6-mercaptopurine. In the course of the trial it was noted that the drug caused a decrease in excretion of uric acid. Subsequent administration to patients suffering from gout showed that this well-tolerated drug provided a useful alternative to colchicine for treatment of this disease. As an inhibitor of xanthine oxidase, allopurinol also markedly decreases oxidation of both hypoxanthine and xanthine itself to the sole source of uric acid (19) in man. This metabolic block thus removes the source of uric acid that in gout causes the painful crystalline deposits in the joints. It is of interest that allopurinol itself is oxidized to the somewhat less effective drug, oxypurinol (21), by xanthine oxidase.

xanthine oxidase

17

xanthine oxidase

18

19

OH

OH xanthine oxidase

HO

20

21

Purines

427

Condensation of hydrazine with ethoxymethylenemalononitrile (22) gives 3-amino-4-cyanopyrazole (23). Hydrolysis with sulfuric acid leads to the amide, 24; heating with formamide inserts NC. ^ - \ ^

NC

TT

NH NC

H 22

2

N^" 23

H2N 24 the last carbon atom to afford allopurinol (20) S An alternate process starts by reaction of ethyl 2-ethoxymethylene cyanoacetate (25) and hydrazine in an addition-elimination reaction to give 3-carbethoxy-4-aminopyrazole (26). Heating with formamide again results in allopurinol. C2H5O2C

25

26

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention.5 Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the cyclized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31).6 Substitution of additional basic groups onto a closely related nucleus affords a compound with muscle relaxant activity with some activity in the treatment of angina. Reaction of the

428

Miscellaneous Fused Heterocycles

H2N H9N

NHo

NH2 29

28

27a

u HoN

NH NH2 272)

30

31

pyrimidopyrimidine, 32, with a mixture of phosphorus oxychloride and phosphorus pentachloride gives the tetrachloro derivative, 33. The halogens at the peri positions (4,8) are more reactive to substitution than the remaining pair, which are in effect at 2 positions of pyrimidines. Thus, reaction with piperidine at ambient temperature gives the diamine, 34, Subsequent reaction with bis-2-hydroxyethylamine under more strenuous conditions gives dipyridamole (35).7

32, X=OH 33, X=C1

34

HOCH2CH2V^

M

35

N

Miscellaneous Heterocycles

429

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria; as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2amino-6-methylpyridine (36) proceeds directly to the naphthyridine (38); the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. JV-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). C2H5O2C + C2H5OCH=C CHq

"CO2C2H5

CH.

//CO2C2H5

u NXH

H 36 37

C02H

C0 2 C 2 H 3

39 A benzene ring in a medicinal agent can often be replaced by a pyridine ring with full retention of biologic activity. Some of the more effective antihistamines are in fact products of just such a replacement. Application of this interchange to the phenothiazines affords compounds similar in activity to the parent drugs. The azaphenothiazine nucleus can be prepared by methods quite analogous to those used for the parent ring system. Thus, condensation of 2-chloropyridine with aniline affords the substituted pyridine, 40; fusion with sulfur in the presence of iodine gives 41.9»10 An alternate preparation begins with the aromatic nucleophilic displacement of orthoaminothiophenol (43) on the substituted pyridine, 42, to give the intermediate, 44; this is then acylated with acetic anhydride (45). Treatment with base leads to the azaphenothiazine, 46, via the Smiles rearrangement 11 (see section on phenothiazines for a fuller exposition). Hydrolysis of the acyl group gives again 41. Alkylation of 41

430

Miscellaneous Fused Heterocycles

with 3-dimethylaminopropyl chloride gives the tranquilizer, prothipendyl (47)10; reaction of 41 with 2-dimethylaminopropyl chloride leads to isothipendyl (48) , 1 2 As may be inferred from the fact that the latter has in effect an ethylenediamine side chain, its main activity is as an antihistamine.

41

40

I

CH o CH o CH 2 44, 45,

47, X=N

R=H R=COCH3

49, X=C1

42 CH 2 CH 2 CH 2 N

NCH 2 CH 2 OH

50

Alkylation of the intermediate, 41, with l-bromo-3-chloroethane affords 49; the use of this to alkylate N-(2-hydroxyethyl) piperazine affords oxypendyl (50),13 a neuroleptic with good antiemetic and antivertigo properties. An imidothiazole has proved to be quite active as a broadspectrum antihelmintic agent. Alkylation of 2-aminothiazoline (51)

Miscellaneous Heterocycles

431

with phenacyl bromide, interestingly, proceeds on the ring nitrogen to afford the imino derivative, 52; acylation of that intermediate gives 53. Treatment with sodium borohydride then effects reduction of the keto group (54). Thionyl chloride results in cyclodehydration of that alcohol into the heterocyclic ring to give tetramisole (55).lh

NH2

NR

1

° II CCH2Br

51

r

° v \\

J

>

//

Jl

|t CCH2N

52, 53,

R=H R^COCH 3

OH

COCH 3 I N „

XX

N J

55

54

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

M. Milletti and F. Virgilli, Chemica (Milan), 6, 394 (1951), E. Kohlstaedt and K. II. Klinger, German Patent 1,123,392 (1962); Chem. Abstr., 57, 5,933e (1962). Anon., Belgian Patent 602,888 (1964); Chem. Abstr., 56, 5,981c (1962). R. K. Robins, J. Amer. Chem. Soc, 78, 784 (1956). P. Schmidt and J. Druey, Helv. Chim. Acta, 39, 986 (1956). I. J. Pachter, J. Org. Chem., 28, 1191 (1963). F. G. Fischer, J. Roch, and A. Kottler, U. S. Patent 3,031,450 (1962). G. Y. Lesher, E. J. Froelich, M. D. Gruett, J. H. Bailey, and R. P. Brundage, J. Med. Chem., 5, 1063 (1962). A. vonSchlichtegroll, Arzneimittel Forsch., 7, 237 (1957). A. vonSchlichtegroll, Arzneimittel Forsch., 8, 489 (1958). H. L. Yale and F. Sowinsky, J. Amer. Chem. Soc, 80, 1651 (1958).

432

12. 13. 14.

Miscellaneous Fused Heterocycles

Anon., French Patent 1,173,134 (1958). W. A. Schuler and H. Klebe, Ann., 653, 172 (1962). A. H. M. Raeymaekers, F. T. N. Allewijn, J. Vanderberk, P. J. A. Demoen, T. T. Van Offenwert, and P. A. J. Janssen, J. Med. Chem., 9, 545 (1966).

Cross Index of Drugs

Adrenergic Agents Amphetamine Benzamphetamine Dextroamphetamine Ephedrine &-Epinephrine Isoproterenol

Levonordefrine Mephentermine Metaraminol Methamphetamine &-Norepinephrine Phenylephrine

Levarterenol a Adrenergic Blocking Agents Piperoxan 3 Adrenergic Blocking Agents Alprenolol Butoxamine Dichloroisoproterenol Moxysylyt

Oxyprenolol Propranolol Pronethalol Sotalol

Adrenocortical Steroids Aldosterone Betamethasone Cortisone Cortisone Acetate Flumethasone Fluocortolone Fluorometholone

Hydrocortisone Hydrocortisone Acetate Paramethasone Prednisolone Prednisone Triamcinolone

433

Cross Index of Drugs

434 Aldosterone Antagonist Spironolactone Anabolic Steroids Bolasterone Ethylestrenol Fluoxymesterone Metenolone Acetate Methandrostenolone Nandrolone Nandrolone Decanoate Nandrolone Phenpropionate

Norethandro1 one Normethandrolone Oxandrolone Oxymestrone Oxymetholone Stanazole Tiomesterone

Analgesics Acetaminophen Acetanilide Acetylmethado1 Alphaprodine Aminopropylon Aminopyrine Anileridine Antipyrine Aspirin Bemidone Benzomorphan Benzydamine Carbetidine Clonitazene Codeine Cyclazocine Dextromoramide Diethylthiambutene Dimethylthiambutene Dipipanone Ethoheptazine Ethylmorphine Etonitazene Fentanyl Flufenamic Acid Furethidine Heroin Ibufenac Ibuprofen

Isomethadone Isopyrine Ketasone Ketobemidone Levorphanol Meclofenamic Acid Mefenamic Acid Meperidine Methadone Methopholine Methyl Dihydromorphinone Morpheridine Morphine Nalorphine Naloxone Namoxyrate Nifenazone Nifluminic Acid Normethadone Norpipanone Oxycodone Oxymorphone Oxyphenbutazone Pentazocine Pethidine Phenacetin Phenadoxone Phenazocine Phenazopyridine

Cross Index of Drugs

435

Analgesics (cont.) Pheneridine Phenoperidine Phenylbutazone Phenramidol Pholcodine Piminodine Pirinitramide Prolidine

Properidine Propoxyphene Racemoramide Racemorphan Salicylamide Thebacon Tilidine

Androgens Androstanolone Dromostanolone Propionate Ethylestrenol Fluoxymestrone Mesteralone

Methyltestosterone Testosterone Testosterone Cypionate Testosterone Decanoate Testosterone Propionate

Anorexic Agents Amphetamine Benzphetamine Chlorphentermine Dextroamphetamine

Mephentermine Methamphetamine Phendimetrazine Phenmetrazine Phentermine

Fenfluramine Antialcoholic Disulfiram Antiallergic Steroids Betamethasone Cortisone Dexamethasone Antiarrhythmic Agents Lidocaine Procainamide

Dichlorisone Triamcinolone Triamcinolone Acetonide

Quinidine

Antiasthmatics Chromoglycic Acid Epinephrine

Isoproterenol Khellin

Cross Index of Drugs

436 Antiasthmatics (cont.) Metaproterenol

Nifurprazine

Anticholinergic Agents Atropine Benactizine

Dihexyverine Methantheline Bromide Propantheline Bromide

Dicyclomine Anticoagulants Acenocoumaro1 Anisindione Bi shydroxycoumarin Clorindione Anticonvulsants Aloxidone Diphenylhydantoin Ethosuximide Ethotoin Mephenitoin Methsuximide

Dicoumarol Diphenadione Phenindione Warfarin

Paramethadione Phenacemide Phensuximide Primidone Tetratoin Trimethadione

Antidepressants Amytryptylene Butryptylene Carbamazepine Chloripramine Desipramine Dibenzepin Doxepin Etryptamine Imipramine

Iproniazide Isocarboxazine Methylphenidate Nialamide Nortryptylene Opipramol Phenelzine Pheniprazine Protriptylene Trany1cypromine

Iprindol Antidiarrheal Diphenoxylate Antiemetics Metopimazine Diphenidol

437

Cross Index of Drugs

Antiemetics (cont.) Oxypendyl Pipamazine

Trimethobenzamide

Antigout Agents Allopurinol Colchicine Oxypurinol

Probenecid Sulfinpyrazone

Antihistaminics Antazoline Bamipine Bromodiphenhydramine Brompheniramine Buclizine Chlorocyclizine Chlorothen Chlorpheniramine Chlorphenoxamine Chlorpyramine Cinnarizine Clemizole Cyclizine Cyproheptadine Dexbrompheniramine Dexchlorpheniramine Diethazine Dimethothiazine Dimethylpyrindene Diphenhydramine Diphenylpyraline Doxylamine Fenpiprane Histapyrrodine Isothipendyl Mebhydroline Mebrophenhydramine

Meclastine Meclizine Medrylamine Mephenhydramine Methaphencyc1ine Methaphenylene Methapyrilene Methdilazine Methopromazine Phenbenzamine Pheniramine Phenyltoloxamine Pirexyl Promazine Promethazine Propiomazine Pyrathiazine Pyrilamine Pyrindamine Pyroxamine Pyrrobutamine Thonzylamine Trimeprazine Tripelenamine Triprolidine Zolamine

Antihypertensives Bethandine Bretylium Tosylate Chlorexolone

Clonidine Debrisoquine Deserpidine

438

Cross Index of Drugs

Antihypertensives (cont.) Diazoxide Dibenamine Dihydralazine Guanacline Guanadrel Guanethidine Guanochlor Guanoxan Hydralazine Methyldopa

Minoxidil Pargyline Phenoxybenzamine Phentolamine Rescinnamine Reserpine Syrosingopine Tolazoline Tramazoline

Antiinflammatory Steroids Betamethasone Cortisone Flucinolone Acetonide Fludrocortisone Acetate Fludroxycort ide Flumethasone Fluocortolone Fluorometholone 9a~Fluoroprednisolone Acetate

Fluprednisolone Acetate Hydrocortisone Acetate Methylprednisolone Methylprednisone 163-Methylprednisone Prednylidene Triamcinolone Triamcinolone Acetonide

Antimalarials Amidoquine Amopyroquine Atabrine® Chloroguanide Chloroquine Chloroguanil Cycloguanil Dimethacrine Hydroxych1oroquine Isopentaquine

Paludrine Pamaquine Pentaquine Primaquine Proguanil Pyrimethamine Quinacrine Quinine Sontoquine Trimethoprim

Antimicrobial Agents - Antibiotics Acetyl Methoxyprazine Aminitrazole Amoxycillin Ampicillin Azomycin Benzylpenicillin

Carbenicillin Cephalexin Cephaloglycin Cephaloridin Cephalothin Chloramphenicol

439

Cross Index of Drugs

Antimicrobial Agents - Antibiotics (cont.) Chlormidazole Chlortetracycline Cloxacillin Dapsone Demethylchlortetracycline a~6-Deoxytetracycline Dianithazole Dicloxacillin Dimetridazole Ethambutol Ethionamide Flucloxacillin Furaltadone Furazolidone Glucosulfone Glybuthiazole Glymidine Glyprothiazole Griseofulvin Hetacillin INH Isoniazide Metampicillin Methicillin 6~Methylene-5-oxytetracycline Metronidazole Minoeyeline Morphazineamide Nafcillin Nalidixic Acid Nidroxyzone Nitrafuratel Nitrimidazine Nitrofurantoin Nitrofurazone Nitrofuroxime Oxacillin Oxytetracycline Para-Aminosalicylic Acid

Phenethicillin Phenoxymethylpenicillin Phthaloyl Sulfathiazole Pivampicillin Prontosil Propicillin Pyrazineamide Pyrrolidinomethyltetracycline Salvarsan Streptomycin Succinyl Sulfathiazole Sulfacarbamide Sulfacetamide Sulfachlorpyridazine Sulfadiazine Sulfadimethoxine Sulfadimidine Sulfaethidole Sulfaguanidine Sulfaisodimidine Sulfalene Sulfamerazine Sulfameter Sulfamethizole Sulfamethoxypyridazine Sulfamoxole Sulfanilamide Sulfaphenazole Sulfaproxylene Sulfapyridine Sulfasomizole Sulfathiazole Sulfathiourea Sulfisoxazole Sulformethoxine Sulfoxone Tetracycline Thiazosulfone Thiofuradine

Phenbencillin Antimotionsickness Agents Diphenhydramine Dramamine®

440

Cross Index of Drugs

Antiparasitics Diethyl Carbamazine Dithiazanine Hycanthone

Lucanthone Thiabendazole

Antiparkinsonism Agents Biperiden Cycrimine Diethazine Diphepanol Ethopropazine

Orphenadrine Phenglutarimide Procyclidine Trihexyphenidyl

Antispasmodic Agents Acephylline Adiphenine Ambucetamide Aminopromaz ine Aprophen Atropine Chlorbenzoxamine Chlormidazole Chlorzoxazone Cyclandelate Cyclopyrazate Dicylomine

Dihexyverine Dioxyline Dipiproverine Fenethylline Khellin Methantheline Bromide Methixen Oxolamine Oxybutynin Papaverine Piperidolate Propantheline Bromide

Antithyroid Agents Carbimazole Methimazole Methylthiouraci1

PTU Propylthiouracil Iodothiouracil

Antitussives Caramiphen Carbetapentane Chlorphendianol Codeine Dextromorphan Dimethoxanate Eprazinone Guaiaphenesin

Hydrocodone Isoaminile Levopropoxyphene Methopholine Oxeladin Oxolamine Pentethyleyelanone Pipazethate

441

Cross Index of Drugs

Ataraxic Agent Fluanisone Barbiturate Antagonist Bemegride CNS Stimulants Acephylline Aminophenazole Aminophylline Bamiphylline Caffeine Fencamfamine

Methylphenidate Pentylenetetrazole Phendimetrazine Phenmetrazine Prolintane Theobromine Theophylline

Fenethylline Cholinergic Agents Physostigmine Neostigmine Cholesteropenic Agents Clofibrate Dextrothyronine

Nicotinic Acid

Coccidiostats Amprolium

Buquinolate

Coronary Vasodilators Benziodarone Chromonar

Oxyfedrine Prenylamine

Imolamine Diuretics Acetazolamide Altizide Amiloride Aminotetradine Amisotetradine Bendroflumethiazide Butazolamide

Caffeine Chloraminophenamide Chlorazanil Chlorexolone Chlorothiazide Chlorphenamide Chlorthalidone

Cross Index of Drugs

442

Diuretics (cont.) Clopamide Cyclopentathiazide Cyclothiazide Dichlorophenamide Epithiazide Ethacrynic Acid Ethiazide Ethoxysolamide Flumethazide Furosemide Hydrochlorothiazide Hydroflumethiazide

Meralluride Mercaptomerine Merfruside Methazolamide Methyclothiazide Polythiazide Probenecid Quinethazone Thiabutazide Triamterene Trichlormethiazide

Estrogens Benzestrol Chlorotranisene Dienestrol Diethylstilbesterol Estradiol Estradiol Benzoate Estradiol^ Cypionate Estradiol Dipropionate

Estradiol Hexahydrobenzoate Estradiol Valerate Estrone Ethynylestradiol Hexestrol Mestranol Methallenestril

Estrogen Antagonists Clomiphene

Nafoxidine

Glucocorticoids Bethamethasone Cortisone

Hydrocortisone Acetate Prednisolone Prednisone

Hydrocortisone Laxative Phenolphthalein Local Anesthetics Ambucaine Benzocaine Bupiracaine Butacaine

Chloroprocaine Cocaine Cyclomethycaine Dibucaine

Cross Index of Drugs

443

Local Anesthetics (cont.) Dimethisoquine Diperodon a-Eucaine 3~Eucaine Hexylcaine Hydroxyprocaine Imolamine Isobucaine Lidocaine Lidoflazine Mepiracaine Met abut oxyc aine Oxoethazine Paraethoxycaine

Phenacaine Piperocaine Piridocaine Pramoxine Prilocaine Procainamide Procaine Proparacaine Propoxycaine Pyrrocaine Tetracaine Tolycaine Tropacocaine

MAO Inhibitors Iproniazide Isocarboxazine

Nialamide Tranylcypromine

Midriatics Atropine Cyclopentolate

Hydroxyamphetamine

Miotics Neostigmine

Physostigmine

Mineralcorticoid Aldosterone Muscle Relaxants Carisoprodol Chlordiazepoxide Chlormezanone Chlorphenesin Carbamate Dipyridamole Mephenesin

Mephenesin Carbamate Mephenoxolone Meprobamate Metaxolone Methocarbamol Phenyramidol

Cross Index of Drugs

444

Narcotic Antagonists Anileridine Cyclazocine Levallorphan Levophenacylmorphan

Meperidine Nalorphine Pethidine Phenomorphan

Narcotics Bemidone Codeine Dextromoramide Dihydrocodeine Dipipanone Ethylmorphine Heroin Hydrocodone Hydromorphone Isomethadone Levorphanol Methadone

Methyldihydromorphinone Morphine Naloxone Normethadone Oxycodone Oxymorphone Pentazocine Phenadoxone Pholcodine Piminodine Racemorphan Thebacon

Nasal Decongestion Agents Cyclopentamine Naphazoline Oxymetazoline Phenylephrine

Propylhexedrine Tetrahydrozoline Xylometazoline

Non-Steroidal Antiinflammatory Agents Aminopyrine Antipyrine Aspirin Benzydamine Flubiprofen Glaphenine Ibufenac Ibuprofen Indomethacin

Isopyrine Ketasone Mofebutazone Naproxen Nifenazone Oxyphenbutazone Phenylbutazone Propylphenazone Salicylamine

Oral Contraceptives Chlormadionone Acetate Dimethisterone Ethynodiol Diacetate

Lynestrol Medroxyprogesterone Acetate Megestrol Acetate

Cross Index of Drugs

445

Oral Contraceptives (cont.) Melengestrol Acetate Norethindrone Norethindrone Acetate Norethinodrel

Norgestatrienone Norgestrel Riglovis®

Oral Hypoglycemics Acetohexamide Azepinamide Buformin 1-Butyl-3-metanylurea Carbutemide

Glyburide Glyhexamide Phenformin Tolazemide Tolbutamide

Chlorpropamide Parenteral Anesthetics Phencyclidine Ketamine Peripheral Vasodilators Acephylline Cyclandelate Dihydralazine Fenethylline Hydralazine Progestational Hormones Allylestrenol Chlormadionone Acetate Dimethisterone Dydrogesterone Ethisterone Ethynodiol Diacetate Ethynodrel Hydroxyprogesterone Acetate Hydroxyprogesterone Caproate

Isoxsuprine Minoxidil Nicotinyl Alcohol Nylidrin Tolazoline

Lynestrol Medrogestone Medroxyprogesterone Acetate Megestrol Acetate Melengestrol Acetate Norethindrone Pregnenolone Acetate Progesterone

Respiratory Stimulants Doxapram

Nikethemide

446

Cross Index of Drugs

Sedatives - Hypnotics Allobarbital Aminoglutethemide Amobarbital Aprobarbital Barbital Bromisovalum Butabarbital Butalbital Butethal Butylallonal Butylvinal Carbromal Carbubarbital Clocental Cyclobarbital Cyclopal Ectylurea Glutethemide Heptabarbital Hexethal

Hydrochlorbenzethylamine Mecloqualone Meparfynol Methaqualone Methitural Methohexital Methyprylon Pentobarbital Phenobarbital Probarbital Propiomazine Secobarbital Sodium Pentothal Spirothiobarbital Thalidomide Thialbarbital Thiamylal Thiobarbital Thiopental Vinbarbital

Sedatives - Tranquilizers Acetophenazine Azacyclonol Benzquinamide Bromisovalum Butaperazine Captodiamine Carisoprodol Carphenazine Chlofluperidol Chlordiazepoxide Chlorimpiphenine Chlormezanone Chlorproethazine Chlorpromazine Chlorprothixene Clopenthixal Clothiapine Cloxazepam Diazepam Dixyrazine Droperidol

Fluazepam Fluphenazine Haloperidol Hydroxyphenamat e Hydroxyzine Ketazolam Lorazepam Mebutamate Medazepam Meprobamate Mesoridazine Methoxypromazine Nitrazepam Oxanamide Oxazepam Oxazolapam Oxypendyl Pecazine Perazine Perphenazine Phenaglycodol

Cross Index of Drugs

447

Sedatives - Tranquilizers (cont.) Piperactizine Pipradol Prochlorperazine Promazine Promethazine Propionylpromazine Prothipendyl Spiropiperone

A1-Tetrahydrocannabinol Thiethylperazine Thiopropazate Thiordiazine Thiothixine Triazolam Trifluoperidol Triflupromazine Trimeprazine

Styramate Termination of Pregnancy Agents Dinoprostone Dinoprost Thyroid Hormones Levothyroxine Liothyronine

Thyroxine Triiodothyronine

Vermifuges - Antihelmintics Methyridine Morantel Vitamin Nicotininc Acid

Pyrantel Tetramisole

Glossary

Addiction potential. The ability of a compound to elicit compulsive self-administration. Adrenergic. Relating to epinephrine (adrenaline) or norepinephrine (noradrenaline). Commonly used to describe neurons that utilize norepinephrine as a neurotransmitter and the drugs that interact with these neurons. Adrenergic blocking agent. A drug that blocks the effects of epinephrine and/or norepinephrine. Agonist. A compound that elicits a biologic response by mimicking an endogenous substance. Anabolic activity. The ability of a drug to promote the synthesis of tissue constituents. Analgetic (analgesic). An agent that causes the loss of response to pain without affecting the general level of consciousness. Anaphylactic shock. A systemic hypersensitivity response resulting in dramatic decrease in blood pressure. Androgenic activity. Ability to promote the development of male secondary sex characteristics. Anesthetic, general. A compound that, when given systemically, causes a reversible loss of consciousness sufficient to allow surgical procedures. Anesthetic, local. A compound that blocks conduction of nerve impulses, thus rendering insensible the area to which it is 448

Glossary

449

applied. Anorexic, A substance that decreases appetite. Antagonist. A drug that blocks the biologic effects of an endogenous substance or exogenously applied drug. Anticholinergic. A drug that blocks the effects of the neurotransmitter, acetylcholine. Anticoagulant. An agent that interferes with the ability of the blood to clot. Anticonvulsant. A compound that depresses the central nervous system, thus decreasing frequency and severity of uncontrolled bursts of neuronal activity. Antidepressant. A drug that elevates the mood of individuals suffering from pathologic sadness, Antiemetic. A compound that blocks the vomition reflex. Antihelmintic (Anthelmintic). An agent that is useful in the control of parasitic worms. Antihistamine. Compound that, by occupying the histamine receptors, antagonizes the effects of histamine. Antihyper tensive. An agent that lowers blood pressure. Antiinflammatory. A drug that attenuates the swelling and pain induced by tissue damage. Antimetabolite. A compound that, by competitive blockade of the necessary enzymes, blocks metabolism. Antinematodal. An anthelmintic effective against round worms (nematodes). Antiparasitic. A general term for compounds that kill protozoan or metazoan infective organisms. Antiparkinsoniam. A drug useful in the treatment of the tremors and rigidity associated with Parkinsonfs disease. Antipsychotic. A drug that is useful in decreasing the thought

450

Glossary-

disorders of schizophrenia. izer or neuroleptic.

Also referred to as major tranquil-

Antipyretic. An agent that normalizes an elevated body temperature. Antisecretory. An agent that decreases the secretion of digestive juices in the stomach. Antispasmodic. A general term for any one of several types of drugs that block contraction of the gut. Antithyroid agent. An agent that decreases the synthesis and/or release of thyroid hormones. Antitrichomonal. An antiparasitic effective against the protozoan trichomonads. Antitussive. A drug that blocks the cough reflex. Anxiety. Mental apprehension frequently accompanied by somatic signs such as increased heart rate, palpations, and increased muscle tension. Anxiolytic. A drug that decreases the mental symptoms and somatic signs of anxiety. Asthma.

Difficulty breathing due to constriction of the bronchi.

Atherosclerosis. Hardening of the arteries. obstructive plaques in the arteries.

The formation of

Autonomic nervous system. The portion of the nervous system outside of the brain and spinal cord that is responsible for monitoring and controlling the digestive system, cardiovascular system, and other organs that are not under direct conscious control. Baroreceptor. Specialized pressure-sensitive tissue located in carotid arteries. Nerve impulses proportional to arterial blood pressure are conducted from this tissue to the brain which in turn exerts control over the blood pressure. Biogenic amines. A general term usually used to describe endogenous amine-containing compounds such as dopamine, 5-hydroxytryptamine, and norepinephrine that function as neurotransmitters.

Glossary

451

Bronchial spasm. Contraction of the smooth muscle of the air passages of the lungs resulting in difficult breathing. Bronchiodilator. An agent that relaxes the smooth muscle of the air passages of the lungs. Cardiac arrhythmia. An irregularity of the heart beat. CNS (Central Nervous System).

The brain and the spinal cord.

CNS stimulant. A drug that counteracts fatigue and somnolence. Cholinergic. An agent that mimics acetylcholine. Also refers to neurons that utilize acetylcholine as a neurotransmitter. Coccidiosis. Infestation with coccidia, an intestinal parasite. Coronary vasodilator. A drug that enhances blood flow through the blood vessels of the heart. Diabetes mellitus. A defect in carbohydrate metabolism leading to the appearance of sugar in the urine. Diuretic. A drug that increases the volume of urine formed. Endogenous depression. A serious melancholic state unrelated to the individual's external environment. Epilepsy, grand mal. A disorder resulting in occasional loss of consciousness and violent uncontrolled contraction of the muscles. Epilepsy, petit mal. Similar to grand mal except that muscle manifestations are either absent or confined to occasional jerks. Epinephrine (adrenaline). A biogenic amine released from the adrenal medulla, particularly in moments of stress. Estrogenic activity. Ability to mimic the female hormone by promoting the development of female secondary sex characteristics and modulating the estrus cycle. Febrile. Displaying an elevated body temperature. Ganglionic blocking agent. A drug that blocks neurotransmission at the nicotinic receptors of the sympathetic ganglia, thus blocking vascular reflexes.

452

Glossary

G.I. (gastrointestinal). Refers to the digestive system. Glaucoma. Increased intraocular pressure. Gram negative. Bacteria that fail to retain Gram stain. This group includes the genera Salmonella, Pseudmonas, Pasteurella, Escherichia, and Brucella. Gram positive. Bacteria that retain Gram stain. This group includes the genera Streptococcus, Staphylococus, Diplococcus, and Clostridium. Helmintheasis. Infestation with parasitic worms. Histamine. A diamine found in plant and animal tissues. involved in inflammatory responses.

It is

Hormone. A substance produced by a gland and transported by the blood stream to another part of the body where it produces an effect. Humoral factor. A general term referring to biologically active substances found in the body fluids. Hydrophilicity. Water soluble. Hyperlipidemia. Elevated lipid levels in the blood. Hypertension. Elevated blood pressure. Hypoglycemic agent. A drug that lowers glucose concentrations in the blood. Hypnotic. A drug that induces sleep. Lipophilicity. Soluble in fat or organic solvents. Major tranquilizer. A drug useful in the control of schizophrenia. Also referred to as neuroleptic or antipsychotic. Minor tranquilizer. A drug useful in the control of anxiety. Also referred to as anxiolytic. Myocardial infarction. Blockage of the blood flow to a portion of the heart muscle leading to tissue damage.

Glossary

453

MAO (monoamine oxidase) inhibitor. An agent that blocks one of the enzymes that deaminates amines. Muscle relaxant. A compound that, by either central or peripheral actions, decreases muscle tension. Mutant culture. Genetically altered growth of microorganisms. Narcotic analgesic. A drug that alleviates pain by interacting with the morphine receptor. Narcotic antagonist. A drug that selectively blocks the actions of morphine-like compounds. Neuroleptic. A drug useful in the control of schizophrenia. Also referred to as an antipsychotic or major tranquilizer. Neurosis. A general term for mild emotional disorders often associated with anxiety. Neurotransmitter. A substance that is released from one neuron as a result of depolarization and in turn alters the excitability of adjacent neurons. Norepinephrine. An endogenous catecholamine that functions as a neurotransmitter. Parasympathetic nervous system. That portion of the autonomic nervous system that utilizes acetylcholine as the neurotransmitter at the neuro-effector junctions. Parkinson1s disease. A degenerative neurologic condition manifested by tremor and muscular rigidity. Peripheral sympathetic blocking agent. A drug that disrupts the transmission of nerve impulses to sympathetically innervated structures. Peripheral vascular disease. An insufficiency of blood flow to the extremities. Peripheral vasodilitation. Increase in diameter of the vessels in the extremities leading to an enhancement of blood flow. Pituitary. The primary endocrine gland that controls many of the endocrine tissues of the body. The pituitary is in turn con-

454

Glossary

trolled by feedback from those structures and inputs from the brain. Pharmacophore. The portion of the drug molecule that is responsible for the biologic activity of the drug. Prodrug. A precursor that, after administration and subsequent transformation in the body, forms the active drug. Progestational activity. Effects elicited by progestins, principally a cessation of ovulation and other genital changes related to pregnancy. Prostate gland. One of the male exocrine glands responsible for secreting seminal fluid. Pulmonary embolism. A blood clot trapped in the blood vessels of the lungs. Psychoses. Major thought disorders involving distorted perception and hallucinations. Psychotropic. Affecting the brain in such a way as to alter behavior. Receptor. A macromolecule with which a drug or endogenous substance interacts to produce its effect. Respiratory depression. A decrease in the frequency and/or depth of breathing. Respiratory stimulant. An agent that enhances the frequency and/ or depth of respiration. Schistosome. A genus of blood flukes common to tropical areas. Schistosomiasis. Infestation with schistosomes. Sedative. A drug that decreases responsiveness of the central nervous system. Sedative-hypnotic. A drug that decreases responsiveness of the central nervous system to the point of promoting sleep. Seminal vesicle. An organ in which a portion of the seminal fluid is retained.

Glossary

455

Spasmolytic. A drug that inhibits the contraction of intestinal smooth muscle. Skeletal muscle relaxant. A drug that decreases the tone of volunt ary mus c1e s. Stroke. A general term commonly used to denote a sudden paralysis resulting from a cerebral hemorrhage. a-Sympathetic blocking agent. A drug that binds to, but does not stimulate, adrenergic receptors of the a-type. ^-Sympathetic blocking agent. A drug that binds to, but does not stimulate, adrenergic receptors of the |3-type. Sympathetic nervous system. That portion of the autonomic nervous system that utilizes norepinephrine as a neurotransmitter at its neuroeffector junctions. Sympathomimetic. A drug that produces effects similar to stimulating the sympathetic nervous system, that is, increased blood pressure, dilated bronchi, and mydriasis. Teratogenic. An agent that alters the normal development of the fetus. Therapeutic index. Ratio between the median lethal dose (LD50) and the median effective dose (ED50) of a drug. Thrombophlebitis. Inflammation of the veins involving the formation of blood clots. Thymoleptic. A mood-elevating drug. Thyroid gland. An endocrine gland that secretes thyroxin and triiodothyronine, hormones that modulate the rate of cellular metabolism. Uricosuric. An agent that enhances the excretion of uric acid. Vasoconstrictor. A drug that causes a contraction of the vascular smooth muscle, thus increasing the resistance to blood flow.

Index

Acenocoumarole, 331 Acephylline, 425 Acetaminophen, 111 Acetanilide, 111 Acetazolamide9 249 Acetohexamide, 138 Acetophenazine, 383 Acetyl methoxyprazine, 131 Acetylcholine, as neurotransmitter, 62 Acetylmethadol, 81 Aches, minor, 85 Acylureas, as hypnotics, 95, 220, 245 Addiction to barbiturates, 267 to narcotics, 287 Addiction potential, 287, 289, 292 Adenine, 423 Adenyl cyclase, 62 Adiphenine, 91 Adrenal gland extracts, 188 Adrenaline, see epinephrine a-Adrenergic blocking action, 242 Adrenergic blocking agents, 241 Adrenergic nervous system, 62 Adrenosterone, 176 Agonists, 20 Aldosterone, 206 Allergen, 41

Allobarbital, 269 Allopurinol, 152, 426, 427 Allylestrenol, 172 Aloxidone, 232 Alpha eucaine, 8 Alphaprodine, 303, 304, 305 Alprenolol, 117 Althizide, 359 Ambucaine, 11 Ambucetamide, 94 Amidoquine, 342 Amiloride, 278 Aminitrazole, 247 7-Aminocephalosporanic acid (7-ACA), 416, 417 Aminoglutethemide, 257 l~Aminohydantoin, 230 2~Aminoimidazole, 238 a-Aminonitrile, 94, 95, 243, 246, 306, 307, 427 displacement by organometallies, 57 N-Aminooxazolidone, 228 6-Aminopenicillanic acid (6APA), 409, 410 Aminophenazole, 248 p-Aminophenol, 111 Aminophylline, see theophylline Aminopromazine, 390 Aminopropylon, 234 2-Aminopyrimidine synthesis, 127, 128

457

Index

458

Aminopyrine, 234 Aminotetradine, 265 2-Aminothiazole, 247 2-Aminothiazole synthesis, 126 Amisotetradine, 266 Amobarbital, 268 Amopyroquine, 342 Amoxycillin, 414 Amphetamine, 37, 70 Ampicillin, 413 Amprolium, 264 Amytriptylene, 141, 404 Anabolic effects, 169 Androgens, discovery, 155 Androstanolone, 173 Androstenedione, 158, 176 Anesthesia, parenteral, 56 Angst, 363 Anileridine, 300 Aniline, metabolism, 111 Anisindandione, 147 Anovlar®, 186 Antagonists, 20, 65 Antazoline, 242 Antibodies, 41 Antidepressants, tricyclic, 149, 401 Antimitotic activity, 152 Antipyrine, 234 APC®, 111 Aprobarbital, 268 Aprophen, 91 Aromatic nucleophilic substitution, 325, 256, 374, 379, 396, 397, 405 see also nucleophilic aromatic substitution Arthritis, rheumatoid, 189 4-Aryl-4-hydroxypiperidines, 306, 307 Aspirin, 85, 108, 109, 234 Atabrine®, 396 Atropine, 35, 71, 89, 93 interrelation with cocaine, 5 Autonomic nervous system, divisions, 62

Azacyclonol, 47 Azaphenothiazine, 429 Azepinamide, 137 Azetidone, synthesis, 419 Aziridinium salt, 79 Azlactone, 96 Azomyciriy 238

Bacterial cell walls, inhibitors, 408, 409 Bamiphylline, 426 Bamipine, 51 Barbital, 267, 268 Barbiturates, listing, 268, 269 Baroreceptors, 54 Bayer-Villiger lactone synthesis, 28, 31 Beckmann rearrangement, 157 Bemidone, 305 Bemigride, 258 Benactizine, 93 Benadryl®, 41 Bendroflumethiazide, 358 Benzamphetamine, 70 Benzestrol, 103 Benziodarone, 313, 314 Benzocaine, 9 1,4-Benzodioxans, 352 Benzquinamide, 350 Benzydamine, 323 Benzylpenicillin, 408, 409, 410 Bergstrom, Sune, 24 Beta eucaine, 9 Betamethosone, 198 Bethanidine, 55 Bhang, 394 Biguanide function, in hypoglycemics, 75, 221 Bile acids, steroids from, 188 Biperidin, 47 Birch, Arthur J., 163 Birch reduction, 163, 167, 170 Bishydroxycoumarin, 331 Bismethylenedioxy group, 193 Blocking agents, of 3-sympathetic receptors, 65, 117

Index

Blood, clotting, 330 Blood flukes, 397 Bolasterone, 173 Bromo tribromide, in ether cleavage, 29 Bretylium tosylate, 55 Bromisovalum, 221 Bromodiphenhydramine, 4 2 Brompheniramine, 77 Buclizine, 59 Buformin, 221 Bupivacaine, 17 Buquinolate, 346 Butabarbital, 268 Butacaine, 12 Butalbital, 268 Butaperazine, 381 Butazolamide, 249 Butethal, 268 Butoxamine, 68 Butriptyline, 151 Butylallonal, 269 l-Butyl-3-metanyl urea, 138 Butylvinal, 269, 272 Caffeine, 111, 423, 424 Cannabis sativa, 394 Captodiamine, AA Caramiphene, 90 Carbacephalothin, 420 Carbamazepine, 403, 404 Carbencillin, 414 Carbetapentane, 90 Carbethidine, 300 Carbimazole, 240 Carbinoxamine, 43 Carbonic anhydrase inhibition by sulfonamides, 132 inhibitor, 249 involvement in diuresis, 133 Carboxylation, of phenols, 109 Carbromal, 221 Carbubarbital, 269, 273 Carbutemide, 138 Cardiac arrhythmias, 14

459

Cardiovascular system, sympathetic regulation, 55 Cari soprodiol, 219 Carphenazine, 383 Cephalexln, All Cephaloglycin, All Cephaloridine, All Cephalothin, All, 420 Cephalosporin C, All Chlofluoperidol, 306 Chloraminophenamide, 133 Chioramphenicol, 75 Chlorazanil, 281 Chlorbenzoxamine, 43 Chlorcyclizine, 58 Chlordiazepoxide, 365 Chlorexolone, 321 Chlorguanide, 115 Chlorimipiphenine, 385 Chlorindandione, 147 Chloripramine, 402 Chlormadinone acetate, 181, 187 Chlormidazole, 324 Chloromethylation, 242 Chloroprocaine, 11 Chloroquine, 341 Chlorosulfonation, 122, 133, 134, 135, 139, 354, 355, 357, 397, 400 Chlorothen, 54 Chlorothiazide, 321, 355 Chlorphedianol, 46 Chlorphenamide, 133, 355 Chlorphenesin carbamate, 118 Chlorpheniramine, 11 Chlorphenoxamine, 44 Chlorphentermine, 73 Chlorproethazine, 379 Chlorproguanil, 115 Chlorpromazine, 319, 378 Chlorpropamide, 137 Chiorprothixene, 399 Chlorpyramine, 51 Chlortetracycline, 212, 213 Chlorthalidone, 322

460 Chlortrianisene, 104 Chlorzoxazone, 323 Cholic acid, 188 Cholinergic nervous system, 62 Cholinesterase, inhibitor, 113 Chromoglycic acid, 313, 336 Chromonar, 331 Cinchona bark, 337 Cinnarizine, 58 Claisen condensation, 126 Claisen rearrangement, 115, 334 Clemizole, 324 Clocental, 38 Clofibrate, 119 Clomiphene, 105, 148 Clonidine, 241, 243 Clonitazine, 325 Clopamide, 135 C2 open thixol, 399 Clothiapine, 406 Cloxacillin, 413 Cloxazepam, 370 Cocaine in primitive cultures, 2, 4 structure determination, 5-7 usage by Incas, 5 Codeine, 287, 288 Colchicine, 152, 426 Collins reagent, 29 Conjugate addition, 45, 75, 76, 112, 173, 174, 175, 199, 203, 206, 226, 237, 254, 255, 257, 258, 302, 303, 316, 331, 378, 387 Contraceptive, morning after, 101 Corals, as source of prostanoids, 33 Corey, Elias J., 27 Cortical steroids, discovery, 155 Cortisone, 188, 190 Cortisone acetate, 190 C-Quens®, 187 Curtius rearrangement, 6, 73 Cyclandelate, 94 Cyclazocine, 298

Index

3!,5!-Cyclic adenyl phosphate (3!,5'-cAMP), 63, 423 Cyclization Friedel Crafts, 293, 297 via ylide, 420 Cyclizine, 58 Cycloaddition (2+2), 32, 419 Cyclobarbital, 269, 271 Cyclodehydration, 149, 150, 167, 320, 348, 349, 350, 368, 393, 396, 399, 404, 406, 431 Cycloguanil, 281 Cyclomethycaine, 14 Cyclopal, 269, 270 Cyclopentamine, 37 Cyclopenthiazide, 358 Cyclopentolate, 92 Cyclopropylcarbynyl-homoallyl rearrangement, 31, 151, 182 Cyclopyrazolate, 92 3,5-Cyclosteroid, 182 Cyclothiazide, 358 Cycrimine, 47 Cyproheptadine, 151 Dapsone, 139, 140 Darvon®, 49 Deamination, metabolic, 72 Debrisoquin, 350 Dehydration, with DDQ, 168 Dehydroepiandrosterone, 158 Dehydrogenation with chloranil, 183, 184, 206 microbiological, 187, 192, 204 with selenium dioxide, 193, 195, 199, 200, 201 16~Dehydropregnenolone, 157 6~Demethyl-6-deoxytetracycline, 214 N-Demethylation, by cyanogen bromide, 291 6-Demethyltetracycline, 213 a-6-Deoxytetracycline, 215

Index

461

Depo-Provera®, 188 Dimethothiazlne, 374 Depot, drug administration, 161, Dimethoxanate, 390 Dimethylpyrindene, 145 171, 172 Dimethylthiambutene, 106 Deserpidine, 320, 321 Dimetridazole, 240 Desimipramine, 402 Dinoprost, 27, 33, 34 De smethylmorphine, 289 Dinoprostone, 27, 30, 33, 35 Desulfurization, 130, 166 Dioscorea, see Mexican yam Dexamethosone, 199 Diosgenin, 156, 182 Dexbrompheniramine, 11 Dioxyline, 349 Dexchlorpheniramine, 11 Diphenhydramine, 41 Dextroamphetamine, 70 Diphenidoly 45 Dextromoramide, 82 Diphenoxylate, 302 Dextromorphan, 293 Diphenylhydantoin, 246 Dextrothyroxine, 92 Diphepanol, 46 Diabetes, 136 Dipipanone, 80 Dianithazole, 327 Dipiproverin, 94 Diazepam, 365, 366 Dipyridamole, 428 Diazoxide, 355 Displacement, bromine by nitro, Dibenamine, 55 Dibenzepine, 405 247 Dibucaine, 15 Disulfiram, 223 Dicarbocyanine dye, 327 Dithiazinine, 327 Dichlorisone, 203 Dixyrazine, 384 Dichloroisoproteronol, 65, 66 DNA, 423 Dichlorophenamide, 133 Doisynolic acid, 87 Dicloxacillin, 413 DOPA (dihydroxyphenylalanine), Di co umarol, 147 95 Dicyclonlne, 36 Dopamine, 95 Dieckmann condensation, 305, 306, Doxepin, 404 Doxylamine, 44 350, 387 Diels-Alder condensation, 28, 74, Dramamine®, 41 Dromostanolone proprionate, 89 173 Dienestrol, 102, 103 Droperidol, 308 Diethyl carbamazine, 278 Drug metabolism, 38 Diethylstilbestrol, 101 Dydrogesterone, 185 Diethylthiambutene, 106 Dihexyrevine, 36 Ecgonine, 5 Dihydralazine, 353 Ectylurea, 221 Dihydrocodeine, 288 Dihydropteroic acid, in bacterial Ehrlich, Paul, 1, 121, 223 Eisleb, Otto, 281 metabolism, 121 Eneamine, as protecting group, Diketene, addition to imines, 176 369 Enol nitro hydrolysis, 71 Dimethacrine, 397 Enovid E®, 186 Dimethisoquin, 18 Ephedra, source of ephedrine, Dimethisterone, 176, 178, 187

Index

462

66 Ephedrine, 66 Epinephrine, 95, 241 clinical usage, 63 as neurotransmitter, 62 synthesis, 63 Epithiazide, 359 Eprazinone, 64 Ergosterol, 184 Erytriptamine, 317 Essential fatty acids, 26 Esterases, in drug deactivation, 14 Estradiol, 161 Estradiol benzoate, 162 Estradiol cypionate, 162 Estradiol dipropionate, 162 Estradiol hexahydrobenzoatef 162 Estradiol valerate, 162 Estrogenic activity, 100 Estrogens, 100, 160 antagonists, 104 discovery, 155 impeded, 104 Estrone, 156, 161 synthesis from androstenes, 159 Ethacrinic acid, 120 Ethambutol, 222 Ether cleavage, 314, 368 Ethionamide, 255 Ethisterone, 163, 172 Ethithiazide, 358 Ethoheptazine, 303 Ethopropazine, 373 Ethosuximide, 228 Ethotoin, 245 Ethoxysolamide, 327 Ethylestrenol, 170 Ethylmorphine, 287 Ethynodiol diacetate, 165, 186 Ethynodrel, 164 Ethynylestradiol, 162 Etonitazine, 325 False substrate, mode of action

of sulfas, 121 Favorsky rearrangement, 36, 190 Fencamfine, 74 Fenethylline, 425 Fenfluramine, 70 Fentanyl, 299, 306, 308, 309 Fibrin, 330 Fischer, Emil, 1 Fleming, Sir Alexander, 408 Floxacillin, 413 Fluanisone, 279 Fluazepam, 366 Flubiprofen, 86 Flucinolone acetonide, 202 Fludrocortisone acetate, 192 Fludroxycortide, 202 Flufenamic acid, 110 Flumethasone, 200 Flumethazide, 355 Fluorine, potentiating effect, 191 p-Fluorobutyrophenones, 306, 307 Fluorocortolone, 204 Fluorohydrin, 195, 199, 200, 201, 202 synthesis, 176 Fluorornetholone, 203 9ct~Fluoroprednisolone acetate, 192

Fluoxymestrone, 175, 176 Fluphenazine, 383 Folic acid, in bacterial metabolism, 121 Food and Drug Administration (U. S.), 206 Friedel-Crafts acylation, 314, 331, 332, 335, 374 Fries rearrangement, 314 Furaltadone, 229 Furazolidone, 229 Furethidine, 301 Furosemide, 134 Ganglionic blockade, 54 Ganja, 394 Glaphenine, 342

Index

Glutarimides, synthesis, 257 Glutethemide, 257 Glyburide, 139 Glybuthiazole, 126 Glycosulfone, 140 Glyhexamide, 138 Glymidine, 125 Glyprothiazole, 125 Gold, Acapulco, 394 Grewe, A., 292 Grignard coupling reaction, 102, 291 Griseofulvin, 314, 315 Guaiaphenesin, 118 Guanadrel, 400 Guancycline, 260 Guanethidine, 282 Guanidines, as hypotensives, 117 Guanine, 423 Guanoclor, 117 Guanoxone, 352 Haloperidol, 306 Halucinogenic effects, 298 Hansch, Corwin, 3 Hashish, 2, 4, 394 Heptabarbital, 269, 272 Heroin, 288 Hetacillin, 414 Hexestrol, 102 Hexethal, 268 Hexobarbital, 273 Hexylcaine, 12 Histamine, 41 Histapyrrodine, 50 Hoffmann rearrangement, 72, 277 Hormones isolation and characterization, 24 pituitary, 105 Hycanthone, 398 Hydralazine, 353 Hydrazine cleavage, metabolic, 121 Hydrazine function, in MAO inhibitors, 74

463

Hydrochlorobezethylamine, 59 Hydrochlorothiazide, 358 Hydrocodone, 288, 291 Hydrocortisone, 190 Hydrocortisone acetate, 190 Hydroflumethazide, 358 Hydromorphone, 288 Hydroxyamphetamine, 71 Hydroxychloroquine, 342 Hydroxylation with adrenal slices, 189, 200, 202, 204 metabolic, 111, 236, 398 microbiological, 176, 190, 197, 398 Hydroxyphenamate, 220 Hydroxyprocaine, 11 11-Hydroxyprogesterone, 176, 190 Hydroxyprogesterone acetate, 179 Hydroxyprogesterone caproate, 179 Hydroxyzine, 59 Hypercoagulability, blood, 330 Hyperkinetic children, 88 Hyperthyroidism, 240 Hypoglycemia, 136 Hypothyroidism, 95 Ibufenac, 86 Ibuprofen, 86 Imidazothiazole, 430 Imipramine, 401 Imolamine, 249 Indole synthesis, Fisher, 318, 319 Indomethacin, 318 Insulin, in diabetes, 136 Iodination of phenols, 97, 314 Iodothiouracyl, 265 Iprindol, 318 Iproniazid, 254 Isoaminile, 82 Isobucaine, 12 Isocarboxazine, 233

Index

464

Isodeserpidine, 321 Isomethadone, 79 Isoniazide, 254 Isopentaquine, 346 Isoproteronol, 63 Isopyrine, 234 Isosteric equivalence, 77, 149 benzene and thiophene, 52 carbon and nitrogen, 399 Isothiouronium salts, as source of thiols, 44 Isothipendyl, 430 Isoxazole synthesis, 126 Isoxsuprine, 69 Ivanov reagent, 92, 93 Janssen, P. A. J., 305 Ketamine, 57 Ketasone, 237 Ketazolam, 369 Ketobemidone, 303 Khelin, 313, 335 Knoevenagel condensation, 37, 76, 293, 296, 333 Leffler Freytag reaction, 338 Leprosy, 139 Levallorphan, 293 Levarteronol, 63 Levolorphanol, 296 Levonordefrine, 68 Levophenacylmorphan, 294 Levopropoxyphene, 50 Levorphanol, 293 Levothyroxine, 97 Librium®, 365 Lidocaine, 16 Lidoflazine, 279 Liothyronine, 97 Lipid-water partition, 3, 21 Lipophilicity, 213 Lorazepam, 368 Lucanthone, 397 Lumisterol, 184 Lyndiol®, 186

Lynestrol, 166, 186 Magic bullet, 223 Malonic esters, synthesis, 270273 Mannich condensation, 13, 47, 49, 64, 78, 92, 120, 145, 216, 277, 342, 350 MAO, see monoamine oxidase Marihuana, 394 Mary Jane, 394 Mebrohydroline, 319 Mebrophenhydramine, 44 Mebutamate, 218 Meclastine, 44 Meclizine, 59 Meclofenamic acid, 110 Medazepam, 368 Medrogestoiie, 182, 183

Medroxyprogesterone acetate, 180, 186, 188 Medrylamine, 41 Mefenamic acid, 110 Mefruside, 134 Megesterol acetate, 180 Melengesterol acetate, 182, 183, 187 Menstrual cycle, endocrinology, 161 Meparfynol, 38 Meperidine, 299, 300, 303, 306 reversed, 303 Mephenesin, 118 Mephenesin carbamate, 118 Mephenhydramine, 44 Mephenoxolone, 119 Mephentermine, 72 Mephenytoin, 246 Mephobarbital, 273 Mepivacaine, 17 Meprobamate, 218 Mequoqualone, 354 Meralluride, 224 Mercaptomerine, 224 Mesoridazine, 389 Mesterolone, 174

Index Mestranol, 162, 165 Metabolic activation, 263, 366, 398, 401 Metabolic inactivation, 111, 161, 212, 426 Metabolic inhibitor, 426 Metabutoxycaine, 11 Metampiclllin, 414 Metaproteronol, 64 Metaxolone, 119 Methadone, 79, 81, 289, 298 Methallenestril, 87 Methamphetamine, 37, 70 Methandrostenolone, 173 Methantheline bromide, 393, 394 Methaphencycline, 53 Methaphenylene, 52 Methaprylon, 259 Methapyrilene, 54 Methaqualone, 353 Metharbital, 273 Methazolamide, 250 Methidilazine, 387 Methenolone acetate, 175 Methicillin, 412 Methimazole, 240 Methitural, 275 Methixene, 400 Me thocarbamol, 118 Methohexital, 269, 271 Methopholine, 349 Methopromazine, 374 Methoxsalen, 333 Methoxypromazine, 378 Methsuximide, 228 Methyl phenidate, 88 Methyclothiazide, 342 Methylchromone, 335 Methyldihydromorphinone, 292 Methyldopa, 95 Methylenation, 152 6-Methylene-5-oxytetracycline, 215 Methylprednisolone, 193 163-Methy2prednisolone, 196 17-Methylprogesterone, 178

465

Methyltestosterone, 172 Methylthiouracyl, 264 Methyridine, 265 Metopimazine, 386 Metronidazole, 240 Mexican yam, as source of steroids, 156 Midriatic, 71 Migration, S to N, 240 Miltown®, 218 Minipill contraceptive, 181 Minocycline, 214 Minoxidil, 262 Mofebutazone, 234 Molecular dissection, 9 Molecular manipulation, 20 Monoamine oxidase, 73 inhibition, 54 inhibitors, 149, 232, 254 Morantel, 266 Morphazineamide, 277 Morpheridiney 300 Morphine, 286, 287, 289, 300, 302 biogenesis, 348 Morphine rule, 78, 89, 299, 308, 325 Motion sickness, 41 Moxsylyt, 116 Mycobacterium leprae, 139 Nafcillin, 412 Nafoxidine, 148 Nalidixic acid, 429 Nalorphine, 288, 289 Naloxone, 289, 291 Namoxyrate, 86 Nandrolone, 164 Nandrolone decanoate, 171 Nandrolone phenpropionate, 171 Naphazoline, 241 1,8-Naphthyridine, 429 Naproxen, 86, 87 Narcotic antagonist, 288 Narcotics, 286££. Neostigmine, 114

466

Nerve axons, 7 Nerve blocks, 16 Nervous conduction, 7 Neuralgia, 85 Neuritis, 85 Neurosecretory cells, 62 Neuroses, 372 Neurotransmitters, in regulation of blood pressure, 55 Nialamide, 254 Nicotinic acid, 253 Nicotinyl alcohol, 253 Nidroxyzone, 228 Nifenazone, 234 Nifluminic acid, 256 Nifurprazine, 231 Nikethemide, 253 Nitrazepam, 366 Nitrimidazine, 240 Nitrofurantoin, 230 Nitrofuratel, 229 Nitrofurazone, 228 5-Nitrofurfural, 228 Nitrofuroxime, 228 Nitrosation on carbon, 234, 423 of ketones, 68 on nitrogen, 323 Nor, derivation of term, 63 Noradrenaline, see norepinephrine Norephedrine, 260 Norepinephrine, 95 as neurotransmitter, 62 synthesis, 63 Norethandrolone, 170 Norethindrone, 164, 186, 187 Norethindrone acetate, 165, 186 Norethinodrel, 186 Norgestatriene, 168 Norgestatrienone, 186 Norgestrel, 167, 186 Norinyl®, 186 Normeperidine, 300, 301 Normethadone, 81 Normethandrolone, 170 Norpipanone, 81

Index

19-Norprogesterone, 163 Nortiptylene, 151 Nucleophilic aromatic substitution, 96, 134, 139, 380, 382, 429 see also aromatic nucleophilic substitution Nylidrin, 69 Olivetol, 394 Opium, 2, 4, 286, 287 Oppenauer oxidation, 157, 158, 164, 172, 179, 183, 184, 185, 206, 288 Oraeon®, 187 Oral contraceptives, 162 listing, 186, 187 Ordeal bean, as source of physostigmine, 111 Orphenadrine, 42 Ortho-Novun&, 187 Ovral®, 186 Ovulation, 105 inhibition, 163, 186 Ovulen®, 186 fpxacephalothin, 420 Oxacillin, 413 1,2,4-Oxadiazole, 248, 249 Oxanamide, 220 Oxandrolone, 174 Oxasteroid, 174 Oxazepam, 366 Oxazinone, spiro-, 306 Oxazolapam, 370 Oxazolidones, 229 from glycols, 119 Oxeladine, 90 Oxidation metabolic, 111, 263 Wilgerodt, 86 Oxidative phenol coupling, 112, 152, 314, 348 Oxiranes, diaxial opening, 177 Oxoethazine, 72 Oxolamine, 248

Index

Oxybutynin, 93 Oxycodone, 290 Oxymercuration, 224 Oxymestrone, 173 Oxymetazoline, 242 Oxymetholone, 173 Oxymorphone, 290, 291 Oxypendyl, 430 Oxyphenbutazone, 236 Oxyprenolol, 117 Oxypurinol, 426 Oxytetracycline, 212 Ozonization, preparative, 158 PAC®, 111 Paludrine, 115 Pamaquine, 345 Papaverine, 347, 348 Para-aminobenzoic acid, in bacterial metabolism, 109, 121 Para-aminosalicylic acid, 109 Paraethoxycaine, 10, 11 Paramethadione, 232 Paramethasone, 200 Parasympathetic nervous system, 35, 62 Pargylene, 54 PAS, 109 Pecazine, 387 Pellagra, 253 Penicillin G, see Benzylpenicillin Penicillin N, see cephalosporin C Penicillin V, 410 Penicillinases, 410 Pentaquine, 346 Pentazocine, 297, 298 Pentethylcyclanone, 38 Pentobarbital, 268 Pentylenetetrazole, 281, 282 Pep pills, 70 Perazine, 381 Peripheral vascular disease, 93 Perphenazine, 383 Pethidine, see meperidine

467

Pfitzinger reaction, 15 Pharmacophoric group, definition, 54 Phenacaine, 19 Phenacemide, 95 Phenacetin, 111 Phenadoxone, 80 Phenaglycodol, 219 Phenazocine, 298 Phenazopyridine, 255 Phenbencillin, 410 Phenbenzamine, 50 Phencyclidine, 56 Phendimetrazine, 260 Phenelzine, 74 Pheneridine, 301 Phenethicillin, 410 Phenformin, 75 Phenindandione, 147 Pheniprane, 76 Pheniprazine, 74 Pheniramine, 11 Phenmetrazine, 260 Phenobarbital, 268 Phenol coupling, oxidative, see oxidative phenol coupling Phenolphthalein, 316 Phenomorphan, 294 Phenoperidine, 302 Phenoxybenzamine, 55 Phenoxymethylpenicillin, 410 Phensuximide, 226 Phentermine, 72, 73 Phentolamine, 242, 243 Phenylbutazone, 236 Phenylephrine, 63, 64 Phenylglutarimide, 257 Phenyltoloxamine, 115 Phenyramidol, 65 Phlebitis, 330 Pholcodeine, 287 Photolytic inversion of configuration, 185 Phthalazines, 352 Phthaloyl sulfathiazole, 132 Physical dependence, to nar-

468

cotics, 287 Physostigmine, 111, 113 Pill, the, 2, 155 Piminodine, 301 Pinacol reaction, 102 Pipamazine, 385 Pipazethate, 390 Piperactizine, 386 Piperidolate, 91 Piperocaine, 13 Piperoxan, 352 Pipradol, 47 Pirexyl, 115 Piridocaine, 13 Pirindol, 45 Pirinitramide, 308 Pituitary, 105 Pivampicillin, 414 Planor®, 186 Plasmodia, 114, 337 Polonovski reaction, 366 Polythiazide, 360 Pot, 394 Pramoxine, 18 Prednisolone, 192 Prednisolone acetate, 192 Prednisone, 192 Prednylene, 197 Pregnenolone acetate, 157 Prenylamine, 76 Prilocaine, 17 Primaquine, 346 Primidone, 276 Probarbital, 268 Probenecid, 135 Procainamide, 14 Procaine, 9 Prochlorperazine, 381 Procyclidine, 47 Prodrug, 108, 140, 216, 413, 414 Progesterone, 157, 158 Progestins, discovery, 155 Proguanil, 280 Prolidine, 305 Prolitane, 70 Promazine, 377

Index Promethazine, 373, 377 Prone thanol, 66 Propantheline bromide, 394 Proparacaine, 11 Properidine, 299 Propicillin, 410 Propiomazine, 376, 379 Propionylpromazine, 380 Propoxycaine, 10 Propoxyphene, 48, 50, 298 Propranolol, 117 Propylhexedrine, 37 PropyIphenazone, 234 Propylthiouracyl, 265 Prostaglandins, 25, 26 Prothipendyl, 430 Prothrombin, 330 Protonsil, 121 Protriptylene, 152 Provest®, 186 Pseudoesters, 323 Psoralens, 332 Psychoses, 372, 376 PTU, see propylthiouracyl Pyrantel, 266 Pyrathiazine, 373 Pyrazineamide, 277 Pyridones, synthesis, 255 Pyrilamine, 51 Pyrimethamine, 262 Pyrindamine, 145 Pyroxamine, 42 Pyrrobutamine, 78 Pyrrocaine, 16 Pyrrolidones, by rearrangement, 226 Quinacrine, 396 Quinazoline-3-oxides, rearrangement, 363 Quinazolones, 353, 354 Quinethazone, 354 Quinidine, 339 Quinine, 337, 338, 339 Racemoramide, 82

Index Racemorphan, 293 Rat poison, 331 Rearrangement aminomethylfuran to hydroxypiperidine, 91 aminomethylphthalide to isoquinolone, 18 Beckmann, 157 benzilic acid, 93 Claisen, 115 Curtius, 6, 73 cyclopropylcarbynyl-homoallyl, 31, 151, 182 Favorsky, 36, 190 Fries, 314 Hoffmann, 72, 277 0 to N acyl migration, 6 of quinazolone-3-oxides, 363 Schmidt, 111 Smiles, 380, 429 S to N migration, 240 Receptors, 20 a- and 3-adrenergic, 55 3-adrenergic, 62, 65 estrogen, 100, 161 interaction with drugs, 218 for neurotransmitter amines, 55 opiate, 289 Reductive alkylation, 10, 12, 37, 46, 51, 64, 66, 69, 70, 214, 234, 342, 346 Reformatski reaction, 64, 87 Regulating factors, see hormones Rescinamine, 319 Reserpine, 319, 320, 350 Respiratory depression, with narcotics, 287 Reversed analogs, 15, 303 Rheumatoid arthritis, 236 Rigid analogs, 387 Riglovis®, 165, 187 Ritalin®, 88 RNA, 423 Robinson annelation, 167 Rolitetracycline, 216

469

Roussel-Uclaf synthesis, steroids, 168 S-chloronium salt solvolysis, 420 Saddle block, 7 Salicin, 108 Salicyl alcohol, 108 S'al icy1 amide, 109 Salicylic acid, 108 Salvarsan, 223 Sandmeyer reaction for bromides, 374 for iodides, 96 for nitro groups, 238 for phenols, 116 for sulfonyl chlorides, 138, 322 Schmidt rearrangement, 111 Secobarbital, 269 Selenium dioxide, oxidation of methylketones, 64 see also dehydrogenation Self condensation of benzyl halides, 101 Seminal fluid, source of prostaglandins, 24 Sleeping pills, over the counter, 41 Smiles rearrangement, 380, 429 Soltalol, 66 Sontoquine, 344 Soybeans, as source of steroids, 156, 158 Spinal anesthesia, 7 Spironolactone, 206 Spiropiperone, 306 Spirothiobarbital, 276 Stanazole, 11A Stigmasterol, 158 Stilbestrol, see diethylstilbestrol Styramate, 219 Succinimides, 226 Succinyl sulfathiazole, 132

470

Sulfa drugs, listing, 123-126 Sulfacarbamide, 123 Sulfacetamide, 123 Sulfachloropyridazine, 124, 131 Sulfadiazine, 124 Sulfadiazene, 128 Sulfadimethoxine, 125, 129 Sulfadimidine, 125, 128 Sulfaethidole, 125, 126 Sulfaguanidijie, 123 Sulfaisodimidine, 125, 129 Sulfalene, 125 Sulfamerazine, 124, 128 Sulfameter, 125, 129 Sulfamethizole, 125, 126 Sulfamethoxypyridazine, 124, 131 Sulfamoxole, 124 Sulfanilamide, 121, 123 Sulfaphenazole, 124 Sulfaproxylene, 123 Sulfapyridine, 124 Sulfasomizole, 124 Sulfathiazole, 124, 126 Sulfathiourea, 123 Sulfinpyrazone, 238 Sulfisoxazole, 124 Sulfonyl chlorides, by chlorolysis of sulfides, 249 Sulformethoxine, 125, 130 Sulfoxone, 140 Sulfuration reaction, 373, 378, 380, 382, 429 Sympathetic blocking agents, 259, 282 Sympathetic nervous system control by norepinephrine, 62 peripheral blockers, 55 in regulation of blood pressure, 54 Sympathomimetic activity, 69 Syrosingopine, 319 Teratogenic effects, 257 Testosterone cypionate, 172 Testosterone decanoate, 172 Testosterone propionate,\ 172

Index

Tetrabenazine, 350 Tetracaine, 10 Tetracycline, 212, 213 A'-Tetrahydrocannabinol, 394 Tetrahydropyrimidines, synthesis, 266 Tetrahydrozoline, 242 Tetramisole, 431 Tetratoin, 246 Tetrazole, synthesis, 281 Tilidine, 89 Tiomestrone, 175 Thalidomide, 257 Thebacon, 288 Thebaine, 289, 291 Theobromine, 423, 424 Theophylline, 423, 424, 425 Thiabendazole, 325, 326 Thiabutazide, 358 1,3,4-Thiadiazole, 231, 249 Thiadiazole synthesis, 126, 127 Thialbarbital, 275 Thiamylal, 21A Thiazide diuretics, listing, 358 1,3-Thiazinone, synthesis, 280 Thiazosulfone, 141 Thiethylperazine, 382 Thiobarbital, 275 Thiofuradene, 231 Thiopental, 21A Thiopropazate, 383 Thioridazine, 389 Thiothixene, 400 Thonzylamine, 52 Thrombosis, 397 Thyroid gland, 95 Thyroxine, 95, 97 Tolazamide, 137 Tolazoline, 241 Tolbutamide, 136 Tolycaine, 17 Torgov-Smith synthesis, 167 Tramazoline, 243 Tranylcypromine, 73

Index

Traube purine synthesis, 423 Triamcinolone, 201 Triamcinolone acetonide, 201 Triamterine, 427 Triazines, synthesis, 280 Triazolam, 368 Trichlomethiazide, 359 Trichomonas, 238 Tricyclic antidepressants, 149 Trifluoperidol, 306 Trifluoromethyl group, potentiation of biologic activity, 380 Triflupromazine, 380, 381 Trihexyphenidil, 47 Triiodothyronine, 95 Trimeprazine, 378 Trirnethadione, 232 Trimethobenzamide, 110 Trimethoprim, 262 Trioxsalen, 334 Tripelenamine, 51 Triprolidine, 78 Tropinone, 5 Tropocaine, 7 Truth serum, 274 Ullman condensation, 110, 398, 399 Upjohn, prostaglandin synthesis, 30 Uracyls, 265 Urethanes, decarbonylation, 376, 380 Vasoconstriction, 241 Vasodilator, peripheral, 253 Vessiculoglandin, 24 Villsmeyer reaction, 129 Vinbarbital, 269, 271 Volidan®, 187 von Euler, 24 Warfarin, 331 Water lipid partition, 3, 21 Wittig condensation, 148, 339 Wohler, Friedrich, 5

471 Woodward, Robert B., 319, 338 Xanthines, 423, 424 Xylometazoline, 242 Zolamine, 52

The Organic Chemistry of Drug Synthesis VOLUME 2

DANIEL LEDNICER Mead Johnson and Company Evansville, Indiana

LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas

A WILEY-INTERSCIENCE PUBLICATION

JOHN WILEY AND SONS, New York • Chichester • Brisbane • Toronto

Copyright © 1980 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: Lednicer, Daniel, 1929The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421 .L423 615M 91 ISBN 0-471-04392-3

76-28387

Printed in the United States of America 10

9 8 7 6 5 4 3 2 1

It is our pleasure again to dedicate a book to our helpmeets: Beryle and Betty.

"Has it ever occurred to you that medicinal chemists are just like compulsive gamblers: the next compound will be the real winner."

R. L. Clark at the 16th National Medicinal Chemistry Symposium, June, 1978.

vii

Preface The reception accorded "Organic Chemistry of Drug Synthesis11 seems to us to indicate widespread interest in the organic chemistry involved in the search for new pharmaceutical agents. We are only too aware of the fact that the book deals with a limited segment of the field; the earlier volume cannot be considered either comprehensive or completely up to date. Because the earlier book did, however, lay the groundwork for many of the structural classes or organic compounds that have proven useful in the clinic, it forms a natural base for a series that will, in fact, be comprehensive and up to date. This second volume fills some of the gaps left by the earlier work and describes developments in the field up to the end of 1976. More specifically, we have included literature and patent preparations for

IX

those compounds granted a USAN* generic name prior to and including 1976 that did not appear in Volume I. In assembling the first volume, we faced an apparently staggering mass of material.

It seemed

at the time that attempts to be inclusive would lead to an undigestible compendium.

In order to keep the

reader's interest, we chose instead to be selective about material to be included. first

volume

deals

Specifically, the

predominantly

with

compounds actually used in the clinic.

organic It is, of

course, well known that many compounds die in various stages of clinical

trials, either from lack of

effect, lack of superiority over existing drugs, or the

presence

of

disqualifying

side

effects.

Particularly since 1962, sponsoring companies have become much more demanding in the standards to be met by a drug before undertaking the cost involved in the clinical work leading to an NDA.

For that

reason, this period has seen a large increase in the number of compounds that have been granted generic names but have failed to achieve clinical use.

Many

such failed analogues were omitted from the previous volume.

Since we now intend to make the series

comprehensive, and since those analogues do have heuristic value, we have chosen to violate chronology and include them in the present volume. thus goes beyond simple updating. * United States Adopted Name New Drug Application

x

Volume 2

The organization of the material by chemical classes used earlier has been retained since it provided a convenient method for lending coherence to the subject matter. However, changes in emphasis of research in medicinal chemistry have led us to change the organization of the individual chapters. The small amount of new work devoted to some structural types (e.g., phenothiazines) that formed large units in the earlier book failed to provide sufficient material to constitute a chapter here; what material was available has simply been included under some broader new heading. As was the case previously, syntheses have been taken back to commonly available starting materials as far as possible. An exception to this rule will be found in the section on steroids. Many of the compounds described are corticoids, that are the products of intricate multistep syntheses. In the earlier volume, we described the preparation of some quite highly elaborated corticoids using plant sterols as starting materials. Many of these corticoids are used for preparation of compounds in this volume. Since there seems little point in simply reiterating those sections, a starting material is judged to be readily available if its preparation is described in the first volume. The reference will be to that book rather than to the original literature. We have endeavored, too, to approach biological activity in the same fashion as we did earlier. The first time some therapeutic indication occurs will be the occasion for a concise simplified discussion xi

of the disease state and the rationale for the specific method of drug therapy. Biological activities are noted for each generic compound at the same time as its preparation. It will be emphasized again that the activities quoted are those given by the authors; this book is not intended as a critical text in pharmacology. "Organic Chemistry of Drug Synthesis, Volume 2" is addressed to the same audience as was Volume 1: graduate students in medicinal and organic chemistry, as well as practitioners in the two fields. This book also assumes that the reader will have a good understanding of synthetic organic chemistry and at least a rudimentary knowledge of biology. Finally, we express our sincere appreciation to several individuals who contributed time and talent to this project. Ms. Carolyn Kelly patiently typed the many versions of the manuscript, including the final camera-ready copy, in the midst of the press of her daily responsibilities. Sheila Newland drew the structural formulae, and John Swayze read the entire manuscript and made several useful suggestions to help clarify the text and reduce the number of typos. Ken McCracken and Peggy Williams were extremely helpful in guiding us through the intricacies of the IBM "Office System 6".

Daniel Lednicer Lester A. Mitscher

Evansville, Indiana Lawrence, Kansas January, 1980 xii

Contents Chapter 1.

Chapter 2.

Monocyclic and Acyclic Aliphatic Compounds 1. Cyclopentanes a. Prostaglandins b. Other Cyclopentanoids 2. Cyclohexanes a. Cyclohexane and Cyclohexene Carboxylic Acids b• Cyclohexylamines c. Miscellaneous 3. Adamantanes 4. Noncyclic Aliphatics References

8 12 17 18 20 23

Derivatives of Benzyl and Benzhydryl Alcohols and Amines 1, Derivatives of Benzylamine 2. Benzhydrylamine Derivatives 3. Benzhydrol Derivatives References

26 27 30 31 34

Xlll

1 1 1 7 8

Chapter 3.

Chapter 4.

Chapter 5.

Phenylethyl and Phenylpropylamines 1. Phenylethyl and Phenylpropyl amines a. Those With a Free ArOH Group b. Those Agents With an Acylated or Alkylated ArOH Group 2. l-Phenyl-2-Aminopropanediols 3. Phenylethylamines 4. Phenylpropylamines References Arylalkanoic Acids and Their Derivatives 1. Antiinflammatory Arylacetic Acids 2. Diaryl and Arylalkyl Acetic Acids: Anticholinergic Agents 3. Miscellaneous Arylalkanoic Acids References Monocyclic Aromatic Compounds 1. Derivatives of Benzoic Acid a. Acids b. Anthranilic Acid and Derivatives c. Amides 2. Derivatives of Aniline 3. Derivatives of Phenol a. Basic Ethers b. Phenoxyacetic Acids c. Ethers of 1-Aminopropane2,3-diol 4. Arylsulfones and Sulfonamides a. Sulfones b. Sulfonamides 5. Functionalized Benzene Derivatives a. Alkyl Analogues b. Miscellaneous Derivatives References xiv

36 36 36 44 45 47 55 59 63 63 71 78 82 85 85 85 88 92 95 98 98 101 105 111 111 112 119 119 126 127

Chapter 6.

Steroids 1. Estranes 2. Androstanes 3. Pregnanes a. 11-Desoxy Derivatives b. 11-Oxygenated Pregnanes References

Chapter 7.

Polycyclic Aromatic and Hydroaromatic Compounds 1. Indanes and Indenes 2. Naphthalenes 3. Fluorenes 4• Anthracenes 5. Dibenzocycloheptanes and Dibenzycycloheptenes 6. Tetracyclines References

Chapter 8.

Chapter 9,

135 136 153 164 164 176 200 207 208 211 217 219 221 226 228

Five-Membered Heterocycles 1. Derivatives of Pyrrole 2. Derivatives of Furan 3. Derivatives of Imidazole 4. Derivatives of Pyrazole 5. Derivatives of Oxazole and Isoxazole 6. Derivatives of Thiazole 7. Miscellaneous Five-Membered Heterocycles References

270 273

Six-Membered Heterocycles 1. Pyridines 2. Piperidines 3. Piperazines and Pyrazines 4. Pyrimidines 5. Miscellaneous Structures References

278 278 284 298 302 304 308

Chapter 10. Morphinoids 1. Compounds Derived from Morphine 2. Morphinans 3. Benzomorphans xv

232 233 238 242 261 262 267

314 315 323 325

Chapter 11.

Chapter 12,

4• Phenylpiperidines References

328 337

Five-Membered Heterocycles Fused to One Benzene Ring 1. Indoles 2• Reduced Indoles 3. Indazoles 4. Benzimidazoles 5. Miscellaneous References

340 340 348 350 352 354 358

Six-Membered Heterocycles Fused to One Benzene Ring 1. Quinolines 2. Isoquinolines 3• Quinazolines 4. Cinnolines and Quinoxalines 5. Miscellaneous Benzoheterocycles References

361 362 373 379 387 390 396

Chapter 13.

Benzodiazepines References

Chapter 14.

Heterocycles Fused to Two Benzene Rings 1. Central Rings Containing One Heteroatom 2• Benzoheterocycloheptadienes 3. Derivatives of Dibenzolactams 4. Other Dibenzoheterocycles References

410 420 424 430 432

Chapter 15,

p-Lactam Antibiotics 1. Penicillins 2. Cephalosporins 3. Cephamycins References

435 437 439 442 443

Chapter 16,

Miscellaneous Fused Heterocycles 1. Compounds with Two Fused Rings 2. Compounds with Three or More Fused Rings

445 446

xvi

401 407 409

451

3.

Punnes and Related Heterocycles 4. Polyaza Fused Heterocycles 5. Ergolines References

463 469 475 480

Indexes

483

Cross Index of Drugs

485

Index

501

Errata for VOLUME 1 of ORGANIC CHEMISTRY OF DRUG SYNTHESIS

513

xvii

Monocyclic and Acyclic Aliphatic Compounds 1.

CYCLOPENTANES

a.

Prostaglandins

When realistic quantities of the natural prostaglandins became available, their extreme potency and wide-ranging biological activities were discovered and visions of therapeutic application in the regulation of fertility, control of ulcers, blood pressure, bronchial asthma, and many other conditions led to a torrent of chemical and biological studies which currently measures about four papers daily, and at least one a week dealing with synthesis alone. Initial chemical emphasis lay in developing efficient syntheses of the natural substances to solve the supply problem.

Presently, the emphasis has shifted

to preparation of analogues which are intended to be less expensive, more selective in their action, and longer lasting.

The five drug candidates in this 1

2

Aliphatic Compounds

section are significant representatives of the hundreds of such analogues available. The naturally occurring prostaglandins, E-,, E 2 and A-. , have potent antisecretory activity when given parenterally and have been suggested for use in treatment of gastric ulcers.

Unfortunately,

these natural compounds have relatively poor oral activity and rapid metabolism makes their action short-lived.

Molecular manipulation proved that an

oxygen atom at C-,-. was not necessary for bioactivity but these compounds also lacked the desired oral activity. This problem was solved by a study of the metabolizing enzymes and by borrowing an artifice from steroid chemistry (viz-methyl testosterone, Volume I ) . The most rapid metabolic deactivating reaction is oxidation to the bioinert C.,,- oxo prostaglandins.

Converting the latter to a tertiary

methyl carbinol led to the desired orally active gastric antisecretory agents. Starting with 2-carbomethoxycyclopentanone (1), t-BuOK catalyzed alkylation of methyl u)-bromoheptanoate gave diester 2 which was then hydrolyzed and decarboxylated.

The conjugated double bond was then

introduced by a bromination-dehydrobromination sequence to give versatile prostaglandin synthon 3. Esterification to 4 was followed by conjugate addition of sodio nitromethane to give 5.

Nitroketone 5 was

converted to the sodium salt of the corresponding nitronic acid with sodium in methanol and this was hydrolyzed with icecold dilute H 2 S 0 4 to ketoaldehyde 6.

This sequence is the Nef reaction.

Wittig

Aliphatic Compounds

reaction of this sodio dimethyl-2-ketoheptyl phosphon1 2 ate gave 7. ' Ester hydrolysis to 8 followed by careful reaction with methyl magnesium bromide produced the orally active bronchiodilator, doxaprost (9),

Doxaprost, at least as originally prepared,

is conformationally undefined at C-,^ and is probably a mixture of R and S isomers.

O

,CO2CH3

CO 2 CH 3 CH 2 ) 6 CO 2 R

__ /M—(CH 2 ) 6 CO 2 CH 3

(2)

.(CH 2 ) 6 CO 2 CH 3

{S)

R = CH2NO2

(6)

R = CHO

(30 R = H (£) R = CH3

(CH 2 ) 6 CO 2 R

(7_) R= CH 3 , R» = 0 (_8) R = H, R1 = 0 (fil) R = H, R' = CH 3 , OH

Enzymic studies demonstrated that the 15dehydrogenase was also inhibited by saturation of the C-jo double bond and deprostil (12) embodies this chemical feature as well. 3 Catalytic hydrogenation of 7 produced 10 which was hydrolyzed to 11 and reacted with methyl magnesium bromide in ether. As above, careful control of conditions allowed the organometallic reagent to add selectively to the

4

Aliphatic Compounds

less hindered side chain carbonyl to produce the orally active potent gastric antisecretory agent, deprostil (12).

Interestingly, studies with resolved

12 showed that the unnatural epimer at C-, ^ was more potent. ,(CH2)6CO2R i (CH 2 )4CH 3

(l_0) R = CH 3 , R' = 0 (IV) R = H, R1 = 0 (1J0 R = H, R» = CH3, OH Introduction of an allene function in place of an olefinic double bond is not commonly employed by medicinal chemists, although such derivatives are occasionally used as progestational steroids.

It is

interesting, therefore, that the presence of this synthetic feature is consistent with typical prosta4 glandin biopotency. In this case, the well-known Corey-lactol synthon, 13, was reacted with dilithio pent-4-yn-l-ol to give acetylenic carbinol 14 which was protected by esterification with acetyl chloride to give 15. Treatment of 15 with LiMe^Cu led to allene 16.

The mechanism of this curious reaction

is not clear.

Possibly the reagent forms an organo-

metallic derivative of the acetylene moiety with expulsion of the acetate group and double bond migration as a consequence.

When this sequence was

applied in earlier papers to terminal acetylenes (e.g., J. Am. Chem. Soc. , 91, 3289 (1969)), terminal

Aliphatic Comnounds

OR :

Othp Othp

othp

Othp

(13)

(11)

R=H

(15)

R = COCH 3

OH (CH 2 ) 3 OCOCH 3

X

.(CH 2 ) 4 CH 3

OH

OH

Othp

Othp

(17) (16)

methylation accompanied allene formation and loss of the acetoxy group. Careful alkaline hydrolysis of allene 16 preferentially cleaved the terminal primary ester.

The resulting alcohol was then oxidized to

the carboxylic acid with Jones1 reagent. Saponification under more strenuous conditions removed the remaining acetate group and acid treatment removed the thp ethers.

Xhere is thus obtained prostalene

(17), which has been described as a bronchodilator and hypotensive agent. Animal husbandry requires the careful selection and management of breeding stock and a prize stud is an economically valuable asset.

The expensive

service fee makes it very important that the female be in estrus at the time of mating.

In order to

6

Aliphatic Compounds

optimize the breeding process, two prostaglandin analogues have recently been marketed which are potent luteolytic agents used to regularize or synchronize estrus in horses.

The inclusion of an

aryloxy residue in place of the last three carbons of the aliphatic moiety at the methyl terminus of the prostaglandins greatly increases activity and apparently decreases metabolic deactivation. The synthesis begins with 18, a well-known prostaglandin synthon first developed by Corey, This is condensed with the appropriate phosphonate ylide reagents (19 or 20) which are themselves prepared by reaction of the appropriate ester or acid chloride of an aryloxyacetic acid with the anion of the dimethyl methylphosphonate.

The result-

ing trans-eneone (21 or 22) is reduced with zinc borohydride, the ]D-phenylphenylester serving to give preferential reduction to the 15a~ols.

The ester is

then hydrolyzed with K^CO^/MeOH and the two alcoholic functions are protected as the tetrahydropyranyl ethers.

Reduction with diisobutylaluminum hydride

at -78°C produces lactols 23 and 24 and their C 1 5 epimers.

Reaction with the Wittig reagent from 5-

triphenylphosphonopentanoic acid and acid catalyzed removal of the protecting groups followed by chromatography gives fluprostenol (25) and cloprostenol (26),

respectively. These compounds are several

hundred times more potent by injection than prostaglandin F^

as luteolytic agents, although striking

species differences are observed.

Aliphatic Compounds

00000

(19) R = (CH 3 O) 2 PO, R« = C F 3 (10) R= (CH,O)?PO, R' = Cl (21) R = CF7

(12) R = cr

OH O

6

OH

6thp ^ R= CF3

(.25) R=

(24) R= Cl

b.

(26) R» Cl

Other Cyclopentanoids

Clinical success with the monoamine oxidase inhibitor and amphetamine analogue tranxjlcypromine (27) led to an exploration of the effect of ring size on activity.

It was found that an interesting dissociation

of properties could be achieved and the best of the series, cypenamine (30), is an antidepressant without significant MAO inhibitory activity.

One of the

Q

more convenient syntheses

makes use of the finding

that hydroxylamine-O-sulfonic acid is soluble in diglyme and therefore is suitable for conversion of organoboranes from hindered and unhindered olefins into the corresponding amines,

1-Phenylcyclopentene

Aliphatic

Compounds

(29) R= B

-~

\

(30) R = NH 2

(28) is hydroborated to 29 in the usual way with borohydride and BF 3 .

Addition of H 2 NOSO 3 H followed

by acid hydrolysis completes the synthesis of cxjpenamine (30) with excellent regio and stereospecificity. The reaction sequence is a net cis anti-Markownikoff addition of the elements of NH~ to 28. 2.

CYCLOHEXANES

a,

Cyclohexane and Cyclohexene Carboxylic

Acids This subgroup is classified strictly for chemical convenience because their pharmacological properties are unrelated to one another. Clotting of blood is, of course, one of the more significant ways in which the body protects itself from excessive blood loss after injury. After the healing takes place, the clot, which is a three-dimensional polypeptide, is broken down by proteolytic enzymes such as fibrinolysin or plasmin. In some pathological states, fibrinolysis is hyperactive and inhibitors have a hemostatic value. Plasmin does not occur in free form but is generated as needed from an inactive precursor, plasminogen.

The active of plasminogen to plasmin

is a proteolytic event and can be inhibited by ID-

Aliphatic Compounds

9

aminocarboxylic acids having a structural or spatial resemblance to lysine.

One such agent is p-amino-

methylbenzoic acid (33) and its reduction product tranexamic acid (34).

First p-cyanotoluene (31) is

oxidized to the carboxylic acid (32) with CrO^; then reduction of the nitrile group with Raney cobalt in the presence of liquid ammonia produces p-aminomethylbenzoic acid (33).

Reduction of the aromatic ring of

CH2NH2

CH 2 NH 2

(31) R = CH 3

C31) R = CO 2 H 33 with a platinum catalyst produces mainly the cis isomer.

Upon heating under nitrogen at 315-325°,

isomerization occurs to the trains-analogue (34) which possesses all of the hemostatic activity. Many substances other than estrone possess estrogenic activity and some of these bear only little formal resemblance to the natural hormone. Many years ago, doisynolic acid (39), a steroid degradation product, was shown to have such activity. Over the years many simple compounds have been synthesized following the idea of molecular dissection. One of these is fenestrel (38).

Hageman's

ester (35) is alkylated to 36 by t-BuOK and ethylbromide.

The regioselectivity observed is generally

Aliphatic

10

Compounds

C2H5 .CH,

CO2C2H5

CO2H

(.35) R = H (16) R= C2H5

(38)

(37)

CH3

^JLco2i

JOU

CH3 (40)

(4JJ

R = CN

(43)

(4_2_) R = CO2H

(39)

regarded to be a consequence of the greater reactivity of the enolate at C~ over the other possible enolates (at C. and C L ) . The double bond is reduced with hydrogen and a palladium catalyst and saponification produces 37 of unspecified stereochemistry. Treatment with phenyl magnesium bromide followed by dehydration with tosic acid in acetic acid leads to the estrogen, fenestrel (38).

Presumably, the

double bond remains tri- rather than tetrasubstituted in this case because of the steric interactions this latter case would engender between the ethyl and phenyl groups.

The stereochemistry of fenestrel is

complex so formula 38 implies no stereochemical meaning.

Aliphatic Compounds

11

A smooth muscle relaxant apparently of the antimuscarinic type whose actions, therefore, are somewhat reminiscent of atropine, is isomylamine (43),

Its synthesis begins with the sodamide

catalyzed alkylation of cyclohexyl nitrile (40) with l-bromo-3-methylbutane and the resulting nitrile (41) is hydrolyzed to the acid (42) with HBr in acetic acid. Alkylation of the sodium salt of this acid using p-chloroethyldiethylamine leads to the desired 43. Coughing is a useful physiologic device utilized to clear the respiratory tract of foreign substances and excessive secretions.

Coughing, however, does

not always serve a useful purpose but can rob the patient of sleep.

A number of agents are available

to suppress this.

Many of these are narcotic and

have an undesirable abuse potential. One of the agents available which is claimed to be nonnarcotic 12 is amicibone (45), The synthesis involves base-catalyzed alkylation of benzyl cyclohexanecarboxylate (44) with p-hexamethyleneiminoethyl chloride

a reaction which may go through an

aziridinium intermediate.

0CH2OCO

(4.)

12

Aliphatic Compounds

b.

Cyclohexylamines

Although substantial strides have been made toward the chemotherapeutic control of cancer, much remains to be accomplished with respect to broadening of activity spectrum, decreasing host toxicity, increasing remission time, etc., of the various chemotherapeutic agents available.

Lacking an all-encompassing

rationale upon which to build a drug design program, many potentially useful leads have emerged from directed screening efforts.

The nitrosoureas carmust-

ine (BCNU, 48), lomustine (CCNU, 58) and semustine (MeCCNU, 56) are cases in point belonging to the group of cytotoxic alkylating agents. Cell multiplication requires the rapid synthesis of functional DNA.

Those cells which are dividing

most rapidly, for example, cancer cells, are particularly sensitive to agents which disrupt this process.

The alkylating agents alkylate the purine

and pyrimidine bases and so convert them to unnatural compounds.

This has the consequence of stopping DNA

synthesis and/or inhibiting transcription of the genetic code from DNA.

Normal host cells generally

spend time in a resting stage where they are less damaged by these cytotoxic agents.

Tumor cells, by

contrast, are almost always in an active phase of the cell cycle.

Following up a lead discovered at

the Cancer Chemotherapy National Service Center, it was ultimately shown that unsymmetrical N-nitrosoureas are quite potent alkylating agents and several are now in clinical trial.

Aliphatic Compounds

13

BCNU is synthesized 13 '14 by treating phosgene with ethyleneimine without the addition of a base to take up the HC1 liberated. Reaction of the intermediate urea (46) in situ with hydrogen chloride serves to open the aziridine rings to afford sxjmbis-2-chlorethylurea (47). This is nitrosated with sodium nitrite in formic acid to give BCNU (48).

NH

+ COCI2—••-

N -&- N

^(Cl(CH 2 l2 N )2 c

•• CICH2CH2NCONHCH2CH2CI

(46)

(47)

(4g)

On standing in water under various conditions, two main modes of degradation occur and these are rationalized as follows. The nonnitrosated nitrogen of 49 supplies electrons for an intromolecular displacement of Cl to give intermediate imino ether 50 which collapses to isocyanate 51 and highly reactive 52 which latter fragments, ejecting nitrogen and capturing OH to produce acetaldehyde, after enolization. In the second mode, a cyclic fragmentation process (53) leads to isocyanate 51 and N-hydroxy-2-chloroethylazine (54) which undergoes fragmentation, losing nitrogen and capturing OH (to give 2-chloroethanol) or NH 3 (to give 2-chloroethylamine). As 2-chloroethylamine is a known source of aziridine, this substance has potential alkylating activity. Also, ejection

Aliphatic Compounds

14

N=0 -HC1

fH 2 O

RN=C=0 + CH2=CHN=N0H HO^ 7 I

(49) (50)

H (52)

CH 3 CHO + N2 +

H20

H~VOH Cl

-*» C1CH2CH2N=NOH + (51)

J

(53)

[54)

C1CH2CH2B

N2 + H 2 0

B=OH; NH2

of nitrogen from 52 to 54 leads to electron deficient species which react with nucleophiles. cyanate (51) also adds nucleophiles.

The iso-

Thus, it is

not certain at this stage which of these is the most responsible agent for the bioactivity or whether the antitumor properties are a blend of these.

Aliphatic Compounds

15

The reader has noted that unsymmetrical ureas can nitrosate on either nitrogen and that these decomposition modes enable one to assign structure to the products.

This, in fact, also has preparative

significance and both lomustine (CCNU, 58) and its methyl analogue semustine (MeCCNU, 56) are made in 14 this way. In the semustine synthesis, BCNU (48) is decomposed in the presence of two equivalents of trans-4-methylcyclohexylamine to give an 84% yield of unsymmetrical urea 55—probably

via the trapping

of intermediate isocyanate 51 (R = CELCH^Cl). Nitrosation with NaNO^/HCO^H produces semustine (56) contaminated with some of the alternate nitroso analogue.

Use of cyclohexylamine in this reaction

sequence leads to lomustine (58) instead.

There is

some evidence to suggest that in vivo 4-hydroxylation to 59 may be of great importance in the activity of lomustine*

(5_5) R = CH3 (52) R = H

(_56) R = CH 3 (5J0 R = H ( 5j)) R = OH

A more complex cyclohexylamine, tiletamine (65), is a useful anesthetic in that injection leads to loss of consciousness without an untoward decrease in blood pressure or heart rate and without undue respiratory depression.

Its synthesis

begins with

16

Aliphatic Compounds

ok) (6JD) R= H (61) R = Br

(62)

:NH 2 C 2 H 5

£

(63a)

C6_3b)

1NHC2H5

HC2H5

(65) (64)

bromination of a-thienylcyclopentylketone (60) to give 61.

Reaction with ethylamine appears to involve

carbonyl addition to 62 followed by epoxy formation (63ab) and then rearrangement to ethylimine 64 after proton loss.

It is, of course, apparent that bromide

61 could not undergo a Favorskii rearrangement. Thermolysis of 64 results in a ring expansion and formation of tiletamine (65).

The close structural

relationship between tiletamine and ketamine probably not coincidental.

is

Aliphatic Compounds

c.

17

Miscellaneous

The molecular dissection embodied in the morphine rule (66) has served as a useful empirical guide for the synthesis of analgesic agents even though a number of significant agents fit the rule poorly. Briefly, the morphine rule suggests that substances containing an aromatic ring attached to a quaternary carbon which is in turn separated from a tertiary amine by two carbons might be active. One such is 17 tramadol (69)* It is synthesized by reacting the Grignard reagent prepared from m-methoxybromobenzene (67) with 2-dimethylaminomethylenecyclohexanone (68), itself obtained by Mannich reaction on cyclohexanone, to give tramadol (69).

The isomers are

separated by fractional crystallization of the HC1 salts. CH 2 N(CH 3 ) ;

| / Ar-C-C-C-N

I

{

CH2N(CH3)2

\

(68)

A closely related analgesic which does not fit into the morphine rule is nexeridine (73)* In this 18 case, 2-phenylcyclohexanone (70) is reacted with the lithium salt of N,N-dimethylpropionamide (71) to give tertiary alcohol 72*

Reduction of the latter

with lithium aluminum hydride gives nexeridine (73)*

Aliphatic Compounds

18

CH3CHL1C \

NMe. CHCH3

(71) CN(CH3)2 (70)

(77) X = 0

3•

ADAMANTANES

The adamantane moiety is of medicinal chemical interest because of its inertness, compactness relative to lipid solubilizing character, and symmetry.

Considerable interest, therefore, was en-

gendered by the finding that amantadine (78) was active for the chemoprophy1axis of influenza A in man.

There are not many useful chemotherapeutic

agents available for the treatment of communicable viral infections, so this finding led to considerable molecular manipulation. The recent abrupt end of the National Influenza Immunization program of 1976 prompted a new look at the nonvaccine means for prophylaxis or treatment of respiratory tract infections due to influenza A, especially in that the well-known antigenic shift or drift of the virus obviates usefulness of the vaccine but not amantadine. 19 The synthesis begins with the halogenation of adamantane (74) with bromine to give 76 or chlorine and A1C1 3 to give 75.

The four bridgehead positions

Aliphatic Compounds

19

are identical and surprisingly reactive.

Reaction

NHR (24-) R = H (7_5) R = Cl (76) R = Br

(77) R = COCH 3 (78) R = H

of 76 with acetonitrile in sulfuric acid leads through an apparent S1SL reaction to amide 77 which is hydrolyzed by base to give amantadine (78).

A

similar antiviral agent, rimantadine (83), is also useful for treatment of respiratory diseases due to 20 type A influenza virus. It is synthesized from

-CH (80)

(79)

CHCH3 NH 2 (8_1) X = 0 (8 2) X = NOH

(83)

20

Aliphatic Compounds

adamantyl bromide (76) by AlBr 3 catalyzed addition of vinylbromide to give 79 which is then dehydrohalogenated by heating with KOH to give acetylene 80.

Hydration to methyl ketone 81 is achieved by

HgO-catalyzed reaction with sulfuric acid.

After

oxime formation (82) lithium aluminum hydride reduction leads to rimantidine (83). The high lipophilicity of adamantyl moieties suggests that drugs containing them might pass into tissues of high lipid content or cross the bloodbrain barrier.

Indeed carman.ta.dine (85) is active

against the spasms associated with Parkinson's 21 disease. Amantadine (78) reacts with methyl 2,4dibromobutyrate to give ester 84 which can be hydrolyzed with aqueous barium hydroxide to complete the synthesis of carmantidine (85).

CO2R

(78)

(£4) R - CH3 (85) R = H

4.

NONCYCLIC ALIPHATICS

Many of the biguanides have oral hypoglycemic activity, and metformin (87) is such an antidiabetic agent.

Cyanamide has a highly reactive nitrile

function because of the electropositive NH 2 group

Aliphatic Compounds

21

attached and at pH 8-9 self-adds to form "dicyanamide" (86, for which cyanoguanidine would be a better 22 name). Fusion with dimethylamine leads efficiently to metformin (87) by addition to the nitrile function. 23 Metformin is closely related to buformin. The discovery and clinical acceptance of meprobamate, and the relative chemical accessibility of this group of compounds has led to intensive exploration of 1,3-biscarbamates. It was found that

2

NH 2 CN

»»

NCNHCNH 2

wm

(CH 3 ) 2 NCNHCNH ?

(86)

substitution of one of the NH hydrogens by an alkyl group changed the emphasis of the biological response from muscle relaxant and anticonvulsant to centrally acting muscle relaxant whose action differs somewhat from meprobamate.

Carisoprodol was the best member

of one of these series and lorbamate (92) is its cyclopropyl analogue. The chief synthetic problem to be overcome was the differentiation of the two primary alcohol groups of 89, readily accessible by lithium aluminum hydride reduction of the appropriate 24 di-substituted malonate (88). This was solved by an ester exchange reaction with diethylcarbonate to give 90 which produced carbamate 91 on reaction with

22

Aliphatic Compounds

cyclopropylamine.

Ester exchange of 91 with ethyl

carbamate led efficiently to lorbamate (92), a useful muscle relaxant•

CH3

U

CO2CH3

X /

3v

/">'»"

Y

""

~X

N / CH 3 (CH 2 )2 C89_)

\ CO2CH3 (88_)

\

/

J^

c /

\

CH3(CH2)2

CH2OH

"°

CH 3 (CH 2 ) 2 CH

2°H — CH3 CH

^1 CH 2 OCONH<'

CH3

"v

/V

3

CH2OCONH<^J \

/

^ C . ~ / CH3(CH2)2 •3V / J Z

\ CH2OCONH

(91)

Relatively simple variants of this basic scheme 25 led to the minor lor tranquilizers nisobamate (93) and 26 tybamate (94). CH 3

CH 2 OCONH 2

CH 2 OCONH 2

CH3

C / H

\ / \ CH 2 CONHCH(CH 3 )2

/

CH.fCH^f (93)

\

CH2OCONH(CH2)3CH3

Aliphatic Compounds

23

REFERENCES 1. J. F. Bagli and T. Bogri, Tetrahedron Lett., 3815 (1972); for a photochemically-based alternate synthesis, see J. F. Bagli and T. Bogri, J. Org. Chem. , 37, 2132 (1972). 2. M. Baumgarth, J. Hartin, K. Irmscher, J. Kraemer, D. Orth, H. E. Radunz and H. J, Schliep, Ger. Patent 2,305,437 (1974); W. Lippmann, Prostaglandins, 7, 1 (1974). 3. J. F. Bagli, T. Bogri and S. N. Sehgal, Tetrahedron Lett. , 3329 (1973). 4. P. Crabbe and H. Carpio, J. Chem. Soc., Chem. Commun. , 904 (1972). 5. E. J. Corey, N. M. Weinshenker, T. F. Schaaf and W. Huber, J. Am. Chem. Soc., 91, 5675 (1969). 6. D. Binder, J. Bowler, E. D. Brown, N. S. Crossley, J. Hutton, M. Senior, L. Slater, P. Wilkinson and N. C. A. Wright, Prostaglandins, 6, 87 (1974). 7\ W. R. McGrath and W. L. Kuhn, Arch. Int. Pharmacodyn. Ther. , 172, 405 (1968). 8. M. W. Rathke, N. Inoue, K. R. Varma and H. C. Brown, J. Am. Chem. Soc., 88, 2870 (1966). 9. M. Levine and R. Sedlecky, J. Org. Chem., 24, 115 (1959,); Anon., Spanish Patent 358,367 (1970). 10. A. Mebane, U. S. Patent 3,344,147 (1967); A. H. Nathan and J. A. Hogg, J. Am. Chem. Soc., 78, 6163 (1956).

24 11.

12. 13. 14.

15.

16. 17. 18. 19.

20.

Aliphatic Compounds C. H. Tilford, L. A. Doerle, M. G. VanCampen, Jr., and R. S. Shelton, J". Am. Chem. Soc. , 71, 1705 (1949). A. Frank, A. Kraushaar, H. Margreiter and R. Schunk, Austrian Patent 237,593 (1964). H. Bestian, Ann. Chem., 566, 210 (1950). T. P. Johnson, G. S. McCaleb and J. A. Montgomery, J. Med. Chem., 6, 669 (1963); T. P. Johnson, G. S. McCaleb, P. S. Opliger and J. A. Montgomery, Ibid., 9, 892 (1966). Anon., Netherlands Patent 6,603,587 (1966); C. L. Stevens, A. B. Ash, A. Thuillier, J. H. Amin, A. Balys, W. E. Dennis, J. P. Dickerson, R. P. Galinski, H. T. Hanson, M. D. Pillai and J. W. Stoddard, J. Org. Chem., 31, 2593 (1966). D. Lednicer and L. Mitscher, Organic Chemistry of Drug Synthesis, 1, 59 (1977). Anon., British Patent 997,399 (1965); Chem. Abstr. , 63: 9871f (1965). B. V. Shetty and T. L. Thomas, Ger. Patent 2,509,053 (1975). K. Gerzon, E. V. Krumkalus, R. L. Brindle, F. J. Marshall and M. A. Root, J. Med. Chem. , 6, 760 (1963); H. Stetter, J. Mayer, M. Schwarz and K. Wulff, Chem. Ber. , 93, 226 (1970). P. E. Aldrich, E. C. Hermann, W. E. Meier, M. Paulshock, W. W. Prichard, J. A. Snyder and J. C. Watts, J. Med. Chem., 14, 535 (1971); H. Stetter and P. Goebel, Chem. Ber., 95, 1039 (1962).

Aliphatic Compounds

21. 22. 23. 24. 25.

25

E. H. Gold, U. S. Patent 3,917,840; Chem. Abstr. , 84: 59221k (1976). S. L. Shapiro, V. A. Parrino and L. Freedman, J. Am. Chem. Soc. , 81, 3728 (1959). D. Lednicer and L. Mitscher, Organic Chemistry of Drug Synthesis, 1, 221 (1977). B. L. Ludwig, L. S. Powell and F. M. Berger, J. Med. Chem., 12, 462 (1969). F. M. Berger and B. L. Ludwig, U. S. Patent 2,937,119 (1960); G. Schneider, M. Halmos, P. Meszaros and O. Kovaks, Monatsh., 94, 426 (1963).

Derivatives of Benzyl and Benzhydryl Alcohols and Amines As will become apparent in a perusal of this book, organic molecules owe their biological activity to a variety of structural features.

Sometimes a set of

activities is associated with the structural backbone of a molecule.

For example, most prostanoids share

certain biological properties despite some changes in functionality; the same will be noted later for steroids.

Some biological activities are associated

with a specific arrangement of structural subunits; e. g. , p-adrenergic blocking agents tend to be derivatives of aryloxypropanolamines.

Some activities are

quite directly associated with a specific functionality; no better example of this exists than the host of guanidine-containing sympathetic blocking agents. 26

Sometimes, however, no such discernable

Benzyl and Benzhydryl Derivatives

27

relationship can be detected between activity and structure.

Such classes are often marked by widely

divergent activities.

Derivatives of benzyl- and

benzhydrylamines and alcohols fall into this latter category. 1.

Derivatives of Benzylamine

In the course of some work aimed at delineation of the structure-activity relationships of the antidepressant monoamine oxidase (MAO) inhibiting drug pargyline (1), it was noted that activity was consistent with quite wide modification of the substitution on nitrogen.

One of the best drugs to emerge

from this study is encyprate (4). Hydrogenation of the Shiff base from benzaldehyde and cyclopropylamine (2) gave the secondary amine (3).

Treatment of this

with ethyl chloroformate afforded the MAO inhibitor

encxjprate

(4). 1 ' 2

(1)

(2)

CH2NH-<]

^ ^ ^ C H

~~"

^ ^

2

C-OC2H5 0

(3)

f4)

A derivative of benzylhydrazine, procarbazine (8), exhibits antineoplastic activity.

In an inter-

esting insertion-type sequence, reaction of the ptoluamide (5) with ethyl azodicarboxylate leads directly to the substituted hydrazine (£)•

It is

not unlikely that the first mole of the diazo compound

Benzyl and Benzhydryl Derivatives

28

oxidizes the benzylic methyl group to an anion or radical anion; addition of that to a second mole of diazo compound would give the observed product (6). Methylation by means of sodium hydride and methyl iodide proceeded at the less hindered amide to give (7),

Acid hydrolysis of the carbethoxy groups leads

finally to (8). 3

CH 3 C 2 H5O 2 CN=NCO 2 C 2 H 5

C CH 3

CHNHC CO2C2H5

(S)

™5 C CH3

C CHNHC

2N-NCO2C2H5

L

CD

CO 2 C 2 H 5 C7)

An important feature of the antibiotic chloramphenicol (9) is the presence of the dichloroacetamide function. Inclusion of this amide in a simpler molecule, teclozan (15), leads to a compound with antiamebic activity.

Whether this is cause and

effect or fortuitous is unclear.

The synthesis

begins with alkylation of the alkoxide derived from ethanolamine (10) with ethyl iodide to give the aminoether (11).

Reaction of a,af-dibromo-p-xylene

(12) with 2-nitropropane in the presence of base leads to dialdehyde (13). The reaction probably proceeds by O-alkylation on the nitropropyl anion

Benzyl and Benzhydryl Derivatives

29

followed by bond reorganization and subsequent hydrolysis of the resulting enol ether.

Reductive

alkylation of the dialdehyde with aminoether (11) gives diamine (14).

Acylation by means of dichloro-

acetyl chloride affords teclozan (15). The presence of the dichloroacetamide grouping is apparently not an absolute requirement for antiOH 02N —
\ - CHCHCH2OH

H2NCH2CH2OH—

NHCOCHCI2

en) CH3 -~fl \-CH2Br + C HN NO2 CH CH3

** O=C-^^V-C=

C2H5OCH2CH2HNCH2-V 2-V

yy~CH ~ 2 NHCH 2 CH 2 OC 2 H 5

Ci5) amebic activity. In one pertinent example, reductive alkylation of dialdehyde (16) with n-hexylamine affords 17a and Eschweiler-Clark methylation of 17a by heating with formaldehyde in formic acid then leads to the antiamebic drug symetine (17b).

30

Benzyl and Benzhydryl Derivatives

CH3(CH2)5

O-^ \-CH2NR CCH2)5CH3

(16)

2.

Benzhydrylamine Derivatives

Attachment of piperazine nitrogen directly to a benzhydryl carbon leads to a pair of compounds which show vasodilator activity, and which should be useful in disease states marked by impaired blood circulation.

Reaction of piperonyl chloride (18)

with a mixture of piperazine and piperazine dihydrochloride leads to the monoalkylation product (19), (It may be supposed that the mixture of free base and salt equilibrates to the monobasic salt, thus making the second amine less nucleophilic.)

Alkyl-

ation of 19 by means of benzhydryl chloride then affords the coronary vasodilator medibazine (20).

(11)

C!9)

(20)

Benzyl and Benzhydryl Derivatives

31

In an analogous sequence, condensation of piperazine with 4,4f-difluorobenzhydryl chloride gives the monoalkylation product (22).

Reaction of •7

22 with cinnamyl bromide affords flunarizine (23). Flunarizine is also a coronary vasodilator.

XX

:HCI

(22)

3.

(2 3)

Benzyhydrol Derivatives

Cyprolidol (26), a highly modified benzhydrol derivative, is reported to exhibit antidepressant activity; it is of note that this agent bears little structural relation to either the MAO inhibitors or tricyclic antidepressants.

N

Addition of the carbene from

y~CH=CH2 + N2CHCO2C2H5

•-

N v

/

\ /—CO2C2H5

32

Benzyl and Benzhydryl Derivatives

decomposition of ethyl diazoacetate to 4-vinylpyridine gives the cyclopropane (25) (stereochemistry unspecified).

Condensation of the ester with phenylo

magnesium bromide affords cyprolidol (26). Basic ethers of benzhydrols are among some of the better known antihistaminic compounds.

The

earlier volume describes well over a dozen of these drugs.

However, research in the area of allergy has

recently shifted away from compounds which antagonize the action of histamine to drugs that intervene in earlier stages of the allergic reaction.

The basic

ethers are therefore represented here by but a few entries.

In the preparation of rotoxamine (28),

reaction of pyridine~2-carboxaldehyde with the Grignard reagent formed from p-bromochlorobenzene gives the carbinol (27); alkylation with N,N-dimethylchloroethylamine and optical resolution gives rotox9 amine (28), the levorotatory form of carbinoxamine. A slightly more complex scheme is required for preparation of an antihistaminic agent bearing a secondary amine, e.g., tofenacin (32).

In the

synthesis of tofenacin, alkylation of the benzhydrol (29) with ethyl bromoacetate affords the alkoxy ester (30); saponification followed by conversion to the methylamide gives (31), which is reduced with lithium aluminum hydride to complete the synthesis of 32. 1 0 Antihistaminic properties are well known to be preserved even when nitrogen is included in a ring-, such as in clemastine (36).

Synthesis of 36 is

begun by reaction of 4-chlorobenzophenone (33) with

Benzyl and Benzhydryl Derivatives

33

Cl

(27)

(28)

,CH3 ,CHOH

(29)

.CHOCH2CR

PHOCH2CH2NHCH3

(3J0) R = OC2H5 C_31) R = NHCH3

Ltt OCH2CH 2

CH, (36)

methyl magnesium bromide to give the carbinol (34). Alkylation of 34 with the chloroethyl pyrrolidine (35) then yields clemastine (36). Arrhythmias, that is, disturbances in the regular timed beating of the heart, often result in life-threatening situations, since the pumping efficiency of the heart is directly related to its rhythmic synchronous contractions. Much activity has thus been expended in searching for drugs which abolish irregularities of the beat without compromising other aspects of cardiac function.

One apparently

34

Benzyl

and Benzhydryl

(38)

(37)

Ar. Ar

Ar

Derivatives

Ar •Ar

Ar

OH

Ar Ar Ar

k

Ar

'e J

quite complex compound which exhibits such activity is, in fact, the product of a relatively simple reaction: condensation of cyclopentadiene with bis(2-pyridyl)ketone (37) in the presence of base affords directly pyrinoline (38).12 The condensation can be rationalized by a scheme such as that shown.

1.

2.

REFERENCES B. W. Horrom and W. B. Martin, U. S. Patent 3,088,226 (1963); Chem. Abstr. , 59: 9888e (1963). L. R. Swett, W. B. Martin, J. D. Taylor, G. M. Everett, A. A. Wykes and Y. C. Gladish, Ann. N.

Benzyl and Benzhydryl Derivatives

35

Y. Acad. Sci., 107, 891 (1963). 3. Anon., Belgian Patent 618,638 (1962); Chem. Abstr. , 59: 6313c (1963). 4. A. R. Surrey and J. R. Mayer, J. Ned. Chem., 3, 409 (1961). 5. K. Gerzon and E. R. Shepard, U. S. Patent 2,759,977 (1956); Chem. Abstr., 51: 3664a (1956). 6. Anon., Belgian Patent 616,371; Chem. Abstr., 60: 1767e (1964). 7. P. A. J. Janssen, Ger. Offen. , 1,929,330 (1972). 8. Anon., Belgian Patent 649,145 (1964); Chem. Abstr., 64: 8151c (1966). 9. A. O. Swain, U. S. Patent 2,800,485 (1957). 10. Anon., Belgian Patent 628,167 (1964); Chem. Abstr., 60: 11942h (1964). 11. Anon., British Patent 942,152 (1963); Chem. Abstr., 60: 9250g (1963). 12. Anon., British Patent 1,009,012 (1965); Chem. Abstr., 64: 3503g (1966).

Phenylethyl and Phenylpropylamines 1.

PHENYLETHYL AND PHENYLPROPYLAMINES

a.

Those With a Free ArOH Group

The autonomic nervous system controls tissues and organs whose functions are largely automatic, i.e., not requiring conscious effort for activation. Norepinephrine is the accepted neurotransmitter at the nerve endings and the motor endplate in the sympathetic branch of the autonomic nervous system. Administration of norepinephrine (1) mimics the effect of stimulation of these nerves, causing responses such as vasoconstriction, increased heart rate, relaxation of the ileum, contraction of the uterus in pregnant animals, and relaxation of the lung and bronchial muscles.

Synthetic substances

eliciting some of these responses are called sympathomimetic agents, and a wide variety are known.

More

recently, adrenergic agents (another synonym for 36

Phenylethyl and Phenylpropylamines

37

sympathomimetic agents) have been functionally divided into those acting at a-receptors—

those

mainly associated with excitatory processes such as vasoconstriction--and at p-receptors—those mainly associated with inhibitory processes such as vasodilatation.

Pharmacological agents which block each

of these receptor groups (antagonists) are predominantly used in classifying the drugs.

A finer

subdivision of the p-receptors into p.--which are involved in certain heart muscle and intestinal smooth muscle responses—and p~—which are involved in certain other smooth muscles such as bronchi, uterus and blood vessels--has been found extremely useful.

Isoproterenol (2) is the archetypal p-

agonist, having strong activity against both p., and P 2 receptors.

Generally, the R-configuration at the

benzylic carbon is required for maximal potency amongst the agonists and antagonists of this type.

CH 2 NH 2

H-4-0H

CH2NHCH(CH3);

H-4-OH

One can infer correctly from the foregoing that increased bulk on the nitrogen generally increases selectivity toward the p-receptors.

Further, a

Phenylethyl and Phenylpropylamines

38

catechol ring or a system electronically equivalent to it is needed for optimum activity, especially at the p-receptors, while alkyl branching in the ethanolamine side chain generally decreases potency. The chemistry of most of the drugs in this family is quite simple, accounting in part for the very large number of analogues which have been made. The foundation for the chemistry in this series was laid long ago by Stolz

in his classic synthesis of

the ophthalmic agent adrenalone (3) in which he reacted catechol with chloroacetyl chloride and then displaced the reactive chlorine atom with methylamine to complete the synthesis.

Borohydride reduction

would have given epinephrine (adrenaline). This process, or simple variants of it, is used to prepare many drugs.

For example, one method for

the synthesis of fenoterol (6), a bronchodi1ator, starts with sidechain bromination of m-diacetoxy-

CH2C6H5 AcO.

OH

(6)

Phenylethyl and Phenylpropylamines

39

acetophenone (4) and then displacement of halogen by l-(£-methoxyphenyl)-2~N-benzylaminopropane to give 2 5. Hydrogenation removes the benzyl group, whose function was to prevent overalkylation. Next, HBr cleaves the ether and ester groups, and either catalytic or hydride reduction completes the synthesis of 6. Separation of diastereoisomers was achieved by fractional crystallization. Analogous methods are used to prepare the 3 ophthalmic agent deterenol (7); the bronchodilators clorprenaline (8)

and isoetharine (9);

dilators bamethan (10)

the vaso-

and ifenprodil (11);

and

Q

the smooth muscle relaxant ritodrine (12). Cl

OH

OH

6"!

NH(CH2)3CH2

C2H5 OH (9)

(8)

OX) xrt

OH

(11)

Direct alkylation of the appropriate arylethanolamine is, of course, widely used as, for example, in treatment of ephedrine (13a) with ethyl iodide to give the adrenergic agent, etafedrine Q

(13b),

or with cinnamyl chloride to give the muscle

relaxant, cinnamedrine (14).

Likewise, alkylation

40

Phenylethyl and Phenylpropylamines

of p-hydroxyphenethylamine with 2-chloropyrimidine gives fengripol (15), also a muscle relaxant* The Mannich reaction can also be used to add an alkyl group in the condensation of A-norephedrine (16) with formaldehyde and m-methoxyacetophenone to 12 give oxyfedrine (17), a coronary vasodilator.

OH

R

ere

OH f ^ V C 6 H S

OH

(13a) R = H

OH

(16)

OH

(ly)

°

A departure from the catechol pattern of the natural neurotransmitters was achieved following application of the fact that arylsulfonamido hydrogens are nearly as acidic as phenolic OH groups. Nitration of j>-benzyl oxy ace tophenone gave 18 which was reduced to 19 with Raney nickel and hydrazine, and in turn reacted with mesyl chloride to give sulfonamide 20* Methanesulfonate 20 was then transformed to soterenol (21), a clinically useful bronchodilator, in the

Phenylethyl and Phenylpropylainines

usual way.

41

The analogue mesuprine

(22) was made

by a slight variation in this scheme. blockers sotalol (23) and metalol (24) essentially the same fashion.

The p14

are made in

These agents (23 and

24) owe their activity to their capacity to occupy p-adrenergic receptors without triggering the normal

NHSO 2 CH 3 (18) R= 0? — (19) R = H 2 (20) R- H,SO 2 CH 3

NHSO 2 CH 3

(21) '—

(22) l J -

OH I CH 3 SO 2 NH" ^ ^

CH 3 SO 2 NH

CH3 "^ NHSO 2 CH 3

(23)

(M)

physiological response.

CIS)

The resemblance of 23 and

24 to the normal agonist helps them serve as antagonists.

Greater coverage of p-blockers will be

found in Chapter 5. Amidephrine

(25), an adrenergic agent very

closely related to metalol, finds use as a bronchodilator.

Carbuterol

(27), another bronchodilator,

is made by reacting 3-amino-4-benzyloxyacetophenone with phosgene to give isocyanate 26.

Subsequent

42

Phenylethyl and Phenylpropylamines

treatment of 26 with ammonia produces a urea derivative, which is converted to carbuterol by the familiar bromination, amine displacement and reduction sequence.

OH CHCH2NHCH(CH3)2

,COCH3

OCN C6H5CH2O

HO NHCONH2 (27)

C16)

OH ,CHCH2NHC(CH3)3

HO CH2SO2CH3 (28)

It is evident that some leeway is available in the substituents tolerable in the m-position.

The

bronchodilator sulfonterol (28) is descended from this observation.

Chloromethylanisole (29) is

reacted with methylmercaptan to give 30, and the newly introduced group is oxidized to the methylsulfonyl moiety of 31 with hydrogen peroxide.

Ether

cleavage, acetylation and Fries rearrangement of the phenolic acetate produces 32, which is next brominated with pyrrolidinone hydrobromide tribromide and then oxidized to the glyoxal (33) with dimethyl sulfoxide.

OCH 3

COCHO

CH 2 SO 2 CH 3

CH2SO2CH3

RCH2 CH3O(29) R = Cl (3£) R = SCH 3 (3JL) R * S O 2 C H 3

HO

(32)

(3 3)

0 CH II %/ -7 ArCCH-O-S

(33a)

Phenylethyl and Phenylpropylamines

43

The last reaction perhaps involves an intermediate such as 33a which expells a proton and dimethyl sulfide.

Formation of the Schiff's base with t-

butylamine, reduction with sodium borohydride and hydrogenolysis of the benzyl ether produces sulfonterol (28)*

Despite the fact that the methylene

hydrogen of sulfonterol must be much less acidic than of the corresponding urea proton on carbuterol or the sulfonamide proton on soterenol, good bioactivity is retained. That even further leeway is possible is shown by the utility of the saligenin analogue albuterol (36) as a bronchodilator.

One of the several

syntheses starts by Fries rearrangement of aspirin followed by esterification to 34 which is then brominated and reacted with benzyl t-butylamine to give 35.

Hydride reduction reduces both carbonyls,

and hydrogenolysis of the benzyl group completes the synthesis. Presumably, chelation, believed to be significant in the molecular mode of action of the catecholamines, can still take place with albuterol. CH 2 C 6 H 5 ,COCH3 »• HO' ^

H0

CO 2 CH 3 (34)

C35) OH

(36)

Phenylethyl and Phenylpropylamines

44

b.

Those Agents With An Acylated or Alkylated ArOH Group

Once again we come upon a chemical classification that has no pharmacological significance.

The three

drugs in this small group cause widely different biological responses. Reaction of the Grignard reagent prepared from m-trifluoromethylbromobenzene (37) with methyl1,2-dibromoethylether leads to alkoxy bromide 38, which is then reacted with methylamine to give the 18 anorexic agent fludorex (39).

OCH3

OCOC6Hc

,CHCH2R

(38.) R = Br (3£) R = NHCH3

(40)

OCH3

CHCH2R

(41) R Br (42) R N NH

(43) R = 0 ( 1 1 ) R = H,

The gastric anticholinergic agent, elucaine (40), is synthesized by reaction of styrene oxide. with diethylamine, followed by esterification with 19 benzoyl chloride. In a similar fashion, eprozmol

Phenylethyl and Phenylpropylamines

45

(44), a bronchodilator, is synthesized by adding the elements of CH 3 OBr to styrene, by reaction with t-butylhypobromite in methanol, to give 41. This is next reacted with piperazine to give 42.

A Mannich

reaction with formaldehyde and acetophenone leads to ketone 43, and reduction with borohydride completes 20 the synthesis of eprozinol. 2.

l-PHENYL-2-AMINOPROPANEDIOLS

Chloramphenicol was the first orally active, broadspectrum antibiotic to be used in the clinic, and remains the only antibiotic which is marketed in totally synthetic form.

Its initial popularity was

dampened, and its utilization plummeted when it was found that some patients developed an irreversible aplastic anemia from use of the drug*

Of the hundreds

of analogues synthesized, none are significantly more potent or certain to be safer than chloramphenicol itself.

Two analogues have been given

generic names and fall into this chemical classification.

It was found early in the game that

activity was retained with p-substituents, and that electron withdrawing substituents were best. The synthesis of thiamphenicol 21 (50) begins with pthiomethy1acetophenone (45), which is brominated and then reacted with hexamethylenetetramine to give 46, which is in turn converted to amide 47 by reaction with dichloroacetyl chloride.

Reaction with formal-

dehyde and bicarbonate introduces the hydroxymethyl function of 48, and subsequent Meerwein-PondorffVerley reduction with aluminum isopropoxide gives

46

Phenylethyl and Phenyipropylamxnes

49. T h e p - S C H 3 function w a s oxidized to t h e m e t h y l sulfonyl group o f racemic thiamphenicol (50) w i t h peracetic acid. T h e drug h a s b e e n resolved b y saponification o f 49, treatment with a n optically active acid, reamidation and oxidation. Closely related cetophenicol (52) is synthesized from t h e p-cyano analogue 51 b y reaction w i t h methyl lithium followed by amide exchange to give 52.

L

COCH2R u (45)

ss^CH2OH

1 )f t CH3S

r

OH

OH

NHCOCHCI? R

- ^ (^0) R = CH3SO2 (52) R = CH3CO

NHCOCHC12

R (IE) R= H, OH

R = NH2 C£Z) iR= NHCOCHCI2 OH

22

-

A J NC

OH

NHCOCH3

Phenylethyl and Phenylpropylamines

3.

47

PHENYLETHYLAMINES

Phenylethylamines lacking the p-hydroxy group of norepinephrine (1) and related neurotransmitters are much more lipophilic.

They exert a much more pro-

nounced central—as opposed to peripheral—sympathomimetic effect. direct.

Their action is, however, not

It is generally accepted that these agents

function at least in part by liberating endogenous catecholamines from storage sites.

These, then,

exert their characteristic actions.

It will be

recalled that amphetamine is used clinically for appetite suppression, as an euphoriant-antidepressant, as a nasal decongestant, to improve psychomotor performance, to treat drug depression, in treating children with minimal brain dysfunction (hyperkinesis) and so on.

Insomnia, anxiety and, especial-

ly with large doses, occasionally psychotomimetic activity are undesirable side effects.

Removal of

side effects or greater selectivity of action is, as usual, the objective of molecular manipulation in this drug class. Amphetamine (53) is the prototype drug in this group. One significant objective of molecular manipulation in this group is to retain the appetite depressant activity without significant central stimulation.

This is as yet unrealized. Some of the

drugs prepared with this purpose in mind are discussed in this section.

Reductive alkylation of the nitrogen

atom of amphetamine with p-chloropropionaldehyde 23 produces the anorexic agent mefenorex (54). The

48

Phenylethyl and Phenylpropylamines

Schiff's base of amphetamine with chloral, amphecloral (55), is a single molecule combination of a stimulant 24 -anorexic and a sedative. Presumably, in vivo hydrolysis releases the sedative, chloral, to combat the excitant action of amphetamine with the intended retention of the anorexic action.

CH3 H-C-NHCH2CH2CH2C1

H-C-NH2

(53)

(54)

(55)

The psychotropic (stimulant) action of amphetaminil (57) may be intrinsic or due to in vivo hydrolysis of the a-aminonitrile function—akin to a cyanohydrin—to liberate amphetamine itself.

It is

synthesized by forming the Schiff's base of amphetamine with benzaldehyde to give 56, and then nucleophilic attack on the latter with cyanide anion to 25 form amphetaminil (57). CH3

H~C~~NHCHC6H5 CH2 CN

(56)

(57)

The alkyl terminus of the side chain need not be methyl for retention of activity.

Aletamine (59)

Phenylethyl and Phenylpropylamines

49

is such an agent. It is prepared by the Hofmann rearrangement of a-allyl-p-phenylpropionamide (58).

CH2CH=CH2

CH2CH=CH2

H-C-CONH2 CH,

(58.)

(59)

The action of monoamine oxidase in terminating the bioactivity of primary amines in this class is inhibited by their conversion to secondary amines, which are not substrates for this enzyme.

Greater

selectivity of action, for reasons that are obscure, is often seen when a trimethoxyphenyl moiety is present in the drug.

Such considerations may have

played a role in the design of trimoxamine (66), an 27 antihypertensive agent. The synthesis starts with trimethoxybenzyl chloride (60), which is alkylated with the anion from ethyl allylacetoacetate and NaH to give 61, which is cleaved to ester 62 with sodium ethoxide via a retro-Claisen reaction. Saponification to acid 63 is followed by conversion to a mixed anhydride by means of ethyl chlorocarbonate. ment with ammonia gives amide 64.

Treat-

Hoffman rearrange-

ment with NaOBr gives 65, which is converted to the secondary amine 66 by reaction with ethyl chlorocarbonate, followed by lithium aluminum hydride reduction.

50

Phenylethyl and Phenylpropylamines CH2CH=CH2 R-C-CO2C2H5 CH2C1

f2

CH 3 C)y()CH3 0CH

OCH3 CH2CH=CH2

l

3

fU "T" —>

R

3

H

~

CHCOR

OCH3 _ R = OH (64) R = NH 2

3

(66) R = CH3

Drugs most often react with biopolymers called receptors in order to exert their pharmacological effects and the receptors are optically asymmetric and should therefore require a most favorable configuration and conformation for maximal activity. Thus, there has been much interest in preparation of rigid analogues both for their utility in mapping receptors and because it was felt that an intrinsically correct fit would maximize intrinsic potency. One drug designed with these considerations in mind is rolicyprine (68), an antidepressant. This drug is most probably a latentiated form (prodrug) of the free amine, tranylcypromine (67)* Restriction of the primary amino group into a rigid ring system decreases its conformational possibilities enormously.

Phenylethyl and Phenylpropylamines

51

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug.

One of the clever elements of the rolicyprine

synthesis itself is the reaction of d,l-trantflcxjpromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution.

Addition of dicyclohexylcarbodiimide

activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicrjprine (68). Dopamine (69) is a well-known neurotransmitter which interacts with many receptors in the central

a H 0

(67)

(68)

CH 2 CH 2 NHCO

(71) (69) R = H R=CO 2 H

Phenylethyl and Phenylpropylamines

52

nervous system. In Parkinsonism, a fine tremor and muscular rigidity is present which finds its biochemical basis in low levels of dopamine in certain regions of the CNS.

Administration of dopamine

itself is insufficient to overcome this defect, as it cannot efficiently penetrate the blood-brain barrier. Before the discovery that the corresponding amino acid, DOPA (70), which efficiently entered the brain, was converted enzymatically to dopamine, and thereby constituted effective therapy, various means were employed to attempt such central delivery.

One

of these used the lipophilicity of adamantoyl analogues.

Dopamine was reacted with the acid

chloride of adamantane-1-carboxylic acid to give 29 dopamantine (71), an anti-Parkinsonian agent. A relatively old compound, p-chlorophenxjlalanine (74), is able to penetrate the blood-brain barrier into the CNS and serves as a serotonin inhibitor. Interestingly, it increases copulatory behavior in

CH2CHCO2H .R

(JH-CHCOCH3

(75)

(76)

Phenylethyl and Phenylpropylamines

53

experimental animals, as does testosterone, and has achieved some notoriety on this ground.

One of the

syntheses begins by diazotization of p-chloroaniline (72), followed by Meerwein reaction with cuprous bromide and acrylic acid to give 2-bromopchlorohydrocinnamic acid (73); which is then reacted with 30 ammonia to give p-chlorophenzjlalanine (74). Dobutamine (76), on the other hand, is a dopamine derivative which does not act centrally, but is of interest because of its coronary vasodilator properties.

Such drugs are potentially of value in

treatment of angina pectoralis. Further, it is now undergoing extensive clinical trials as an inotropic agent for use in heart failure.

Its synthesis is

effected by Raney nickel catalyzed reduction of methyl p-methoxyvinylphenylketone (75) to its dihydro analog followed by reductive alkylation with p(3,4-dimethoxyphenyl)ethylamine.

The ether groups

are cleaved with HBr to complete the synthesis of 76.31

NHC 2 H 5

54

Phenylethyl and Phenylpropylamines

Mebeverine (81), a smooth muscle relaxant, is prepared, i.a., by reacting sodium 3,4-dimethoxybenzoate (77) with 1,4-dichlorobutane to form chloroester 78 which is in turn transformed to the corresponding iodide (79) on heating with Nal in methylethyl ketone.

Alkylation of 2-ethylamino-3-p-methoxy-

phenylpropane (#0) with 79 leads to mebeverine (81).32 Mixidine (84), an amidine related to dopamine (84), has coronary vasodilator properties.

It is

prepared by reaction of p-(3,4-dimethoxy)phenethylamine (82) with the ethylimino derivative of Nmethyl-2-pyrrolidone (83) in an apparent additionelimination sequence.

CH3O r\r
(83)

b.

CM)

Miscellaneous

Xxjlamidine (87) is an amidine which serves as a serotonin inhibitor.

This agent is prepared by

alkylation of m-methoxyphenol with a-chloropropionitrile, KI and potassium carbonate in methylethyl ketone to give 85, which is in turn reduced with

Phenylethyl and Phenylpropylamines

55

lithium aluminum hydride to give the primary amine 86.

When 86 is treated with m-tolylacetonitrile in

the presence of anhydrous HC1, the synthesis is 34 completed. Alternately, one can react primary amine 86 with m-tolylacetamidine under acid catalysis to produce xxjlamidine.

fH3 ?CH

( 8_5) R = CN (8(5) R = CH 2 NH2

4.

(<87j

PHENYLPROPYLAMINE S

The drugs of this group also have widely different pharmacological properties, indicating the general absence of a common pharmacophoric moiety in the group. Alverine (88) is an anticholinergic agent prepared by reductive alkylation of ethylamine with 35 two equivalents of phenylpropionaldehyde. Alkylation of cyclohexylidinephenylacetonitrile (89) with 2-chloroethyldimethylamine, using NaH as base, gives nitrile 90.

Note that the product

results from alkylation of the enolate which results in a double bond shift.

This product (90) is trans-

formed to unsaturated amine 91 on heating with HC1.

56

Phenylethyl and Phenylpropylamines

Catalytic hydrogenation of the double bond then produces gamfexine (92), an antidepressant. C2H5 ,(CH 2 ) 3 N(CH 2 ) 3

(88)

,CH 2 CHNHC(CH 3 ) 3

(94) (93)

Reductive amination of methyl 2,2-diphenylethyl ketone (93) with t~butylamine in formic acid leads 37 to terodiline (94), a coronary vasodilator. The relationship between serum cholesterol levels and cardiovascular disease remains suggestive, despite intensive research into the subject.

In any

case, agents which can lower serum cholesterol levels are of therapeutic interest. Beloxamide (98),

Phenylethyl and Phenylpropylamines

57

an N-benzyloxyacetamido derivative, is such an hypocholesterolemic agent.

It is synthesized by alkyl-

ating N-carbethoxyhydroxylamine with benzyl bromide, using sodium ethoxide.

The resulting carbamoyl

ester (95) is alkylated again, this time with 3phenylpropyl bromide and sodium ethoxide to give 96, which is then cleaved to the alkylated O-benzylhydroxylamine derivative 97*

Reaction with acetyl 38 chloride completes the synthesis of beloxamide.

(96) R = CO2C2HS (£7) R = H

CCH 2 )3NOCH 2 Y^N COCH3 I ^ J J

roo%

A propoxxjphene-lik.e analgesic which obeys the empirical morphine rule is pyrroliphene (101)*

A

Mannich reaction involving pyrrolidine, formaldehyde and propiophenone gave amino ketone 99, which was converted to tertiary carbinol 100 by reaction with benzyl magnesium chloride; reaction with acetyl

O (102) (101) R = COCH3

58

Phenylethyl and Phenylpropylamines

chloride completed the synthesis. that pyrroliphene

34

It is gratifying

(101) retained the desired bio-

activity as its synthesis was apparently impelled by the observation that the initial target compounds (e.g., 102) were not very stable chemically, A somewhat related analgesic, noracymethadol (108), is an active metabolite of acetylmethadol.

CH3CHCH2N" (103)

CHCH2N

\ CH C H 2 6 5

CH 2 C 6 H 5 (105)

(107)

(106)

OCOCH3 CHC 2 H 5 CH2CHNHCH3

CH 3 -CH-CH 2

Cl*

N © CH7

CH 2 C 6 H 5

CH 2 C 6 H 5 (109)

(108)

© Cl 9 CH3CH2CH=NCH3

(110)

Phenylethyl and Phenylpropylamines

59

It can be synthesized from methyl benzyl 2-chloropropylamine (103) by sodium amide induced alkylation of 2,2-diphenylacetonitrile to give a mixture of amines 104, 105 and 106.

Amines 105 and 106 are the

expected products of nucleophilic attack on the presumed intermediate asymmetric aziridinium 109* Amine 104 can be rationalized by assuming dehydrohalogenation and rearrangement of the resulting enamine to the charged iminium ion (110) which would rapidly add the nucleophile to give the observed product.

In any event, treatment of nitrile 106

with ethyl magnesium bromide, followed by hydrolysis, produced intermediate ketone 107*

This was reduced

to the secondary carbinol with lithium aluminum hydride and acetylated before catalytic debenzylation 40 of the amine using palladium on carbon catalyst. Given the nature of the initial alkylation reaction, it is doubtful that this is a practical synthesis. REFERENCES 1.

F. Stolz, Cham* Ber. , 37, 4149 (1904).

2.

Anon., Belgian Patent 640,433 (1967); Chem. AJbstr. , 62: 16124e (1964).

3.

R. J. Adamski, P. E. Hartje, S. Namajiri, L. J. Spears and E. H. Yen, Synthesis, 2, 478 (1970); J. R. Corrigan, J. Am. Chem. Soc. , 67, 1894 (1945).

4.

J. F. Nash, U. S. Patent 2,887,509

(1959).

5.

M. Bochmuehl, G. Ehrhart and L. Stein, German Patent 638,650 (1936); Chem. Abstr. , 31: 3209 4 (1937).

60 6. 7. 8. 9. 10. 11.

12. 13.

14. 15.

16. 17.

Phenylethyl and Phenylpropylamines J. R. Corrigan, M. Langerman and M. L. Moore, J. Am. Chem. Soc., 67, 1894 (1945). C. Carron, A. Jullien and B. Bucher, Arzneimittelforsch., 21, 1992 (1971). P. Claassen, U. S. Patent 3,410,944 (1965); Chem. Abstr. , 63: 17965n (1965). T. Ueda, S. Toyoshima, K. Takahashi and M. Muraoka, Chem. Pharm. Bull., 3, 465 (1955). L. H. Welsh and G. L. Keenan, J. Amer. Pharm. Assn., Sci. Ed., 30, 123 (1941). A. P. Gray and D. E. Heitmeier, U. S. Patent 3,274,190 (1966); Chem. Abstr., 66: Pl8725u (1967). K. Thiele, Belgian Patent 630,296 (1963); Chem. Abstr., 61: 1800f (1964). A. A. Larsen, W. A. Gould, H. R. Roth, W. T. Comer, R. H. Uloth, K. W. Dungan and P. M. Lish, J. Ned. Chem., 10, 462 (1967). R. H. Uloth, J. R. Kirk, W. A. Gould and A. A. Larsen, J. Ned. Chem., 9, 88 (1966). C. Kaiser, D. F. Colella, M. S. Schwartz, E. Garvey and J. R. Wardell, Jr., J. Med. Chem., 17, 49 (1974). C. Kaiser, M. S. Schwartz, D. F. Colella and J. R. Wardell, Jr., J. Med. Chem., 18, t>14t (1975). D. T. Collin, D. Hartley, D. Jack, L. H. C. Lunts, J. C. Press, A. C. Ritchie and P. Toon, J. Med. Chem., 13, 674 (1970); Y. Kawamatsu, H. Asagawa, E. Imamiya and H. Hirano, Japanese Patent 74 70,939 (1974).

Phenylethyl and Phenylpropylamines

18. 19. 20. 21.

22.

23.

24. 25. 26. 27.

28.

61

M. Sahyun, Netherlands Patent 6,608,794 (1966); Chem. Abstr., 67: 64023a (1967). S. L. Shapiro, H. Soloway, E. Chodos and L. Freedman, J. Am. Chem* Soc. , 81, 203 (1959). H. E. Saunders, British Patent 1,188,505 (1970); Chem. Abstr., 72: 90466v (1970). R. A. Cutler, R. J. Stenger and C. M. Suter, J. Am. Chem. Soc, 74, 5475 (1952); C. M. Suter, S. Shalit and R. A. Cutler, J. Am. Chem. Soc, 75, 4330 (1953). M. Von Strandtmann, J. Shavel, Jr., and G. Bobowski, Belgian Patent 638,755 (1964); Chem. Abstr., 62: 11740bc (1965). EL Beschke, K. H. Klingler, A. von Schlictegroll and W. A. Schaler, German Patent 1,210,873 (1966); Chem. Abstr., 64: 19486c (1966). C. Cavallito, U. S. Patent 2,923,661 (1960); Chem. Abstr., 54: 9846c (1966). J. Klosa, German Patent 1,112,987 (1959); Chem. Abstr., 56: 3409d (1962). D. D. Micucci, U. S. Patent 3,210,424 (1965); Chem. Abstr., 63: 17897f (1965). F. J. McCarty, P. D. Rosenstock, J. P. Palolini, D. D. Micucci, L. Ashton, W. W. Bennetts and F. P. Palopoli, J. Med. Chem., 11, 534 (1968); F. P. Palopoli, D. D. Micucci and P. D. Rosenstock, U. S. Patent 3,440,274 (1969); Chem. Abstr., 75: 140487n (1971). J. H. Biel, U. S. Patent 3,192,229 (1965); Chem. Abstr., 66: 104,804u (1967).

62 29.

30.

31. 32.

33. 34. 35. 36.

37. 38.

39. 40.

Phenylethyl and Phenylpropylamines H. P. Faro and S. Symchowicz, German Patent 2,254,566 (1973); Chem. Abstr., 79: 104963 (1973). J. H. Burckhalter and V. C. Stephens, J. Am. Chem. Soc. , 73, 56 (1961); G. H. Cleland, J. Org. Chem., 26, 3362 (1961). R. Tuttle and J. Mills, German Patent 2,317,710 (1973); Chem. Abstr., 80; 14721z (1974). Anon., Belgian Patent 609,490 (1962); T. Kralt, H. O. Moes, A. Lindner and W. J. Asma, German Patent 1,126,889 (1962); Chem. Abstr., 59: 517b (1963). G. I. Poos, French Patent 1,576,111 (1969); Chem. Abstr., 72: 132,Slip (1970). Anon., Netherlands Patent 6,508,754 (1966); Chem. Abstr., 65: 2181e (1962). W. Steuhmer and E. A. Elbraechter, Arch. Pharm., 287, 139 (1954). M. D. Aceto, L. S. Harris, A. M. Lands and E. J. Alexander, U. S. Patent 3,328,249 (1967); Chem. Abstr., 67: 99834t (1967). Anon., British Patent 923,942 (1963). B. J. Ludwig, F. Duersch, M. Auerbach, K. Tomeczek and F. M. Berger, J. Med. Chem. , 10, 556 (1967). A. Pohland and H. R. Sullivan, J. Am. Chem. Soc, 75, 4458 (1953). A. Pohland, U. S. Patent 3,021,360 (1962); Chem. Abstr., 56: 3568c (1962).

Arylalkanoic Acids and Their Derivatives 1.

ANTIINFLAMMATORY ARYLACETIC ACIDS

Inflammation is an intimate part of every organism*s apparatus for dealing with injuries imposed by the environment.

Under normal circumstances, the complex

sequence of events characterizing inflammation ceases soon after the environmental challenge stops. Not infrequently, however, the inflammatory process, once started, continues despite the fact that the original triggering event has passed.

The incident

swelling and pain is familiar to all.

Treatment of

chronic or persistant inflammation has gone through some clearly recognizable cycles.

From about the

turn of the century, the standard drug therapy for treatment of this syndrome has consisted of aspirin or another of the simpler aromatics, such as antipyrine and acetaminophen.

The layman chooses

these materials for self-administration.

Use of 63

64

Arylalkanoic Acids

these drugs for severe conditions is, however, limited by their relatively low activity—particularly in treatment of the inflammation due to arthritis—and the incidence of side effects when used at higher doses.

The discovery of the antiinflammatory activity

of cortisone and related corticosteroids quickly led to common prescription of these potent drugs for a wide variety of inflammatory conditions.

This

widespread use uncovered the host of endocrine effects the corticoids elicit upon chronic administration.

This phenomenon required the more selective

use of these compounds. Quite recently, a series of arylacetic acid derivatives has come into clinical use as potent antiinflammatory agents. In general, these compounds show profiles of activity quite similar to aspirin, and though as a rule they are more active and are less likely to cause or exacerbate gastric ulcers. Many of these compounds have been shown to be effective in the treatment of arthritis.

Since they

apparently work by a mechanism different from that of the corticosteroids and are structurally unrelated, they have no corresponding endocrine effects. An interesting example of this class of nonsteroidal antiinflammatory agents is ketoprofen (5). It is synthesized by reaction of the diazonium salt from amine 1 with potassium ethyl xanthate, followed by alkaline hydrolysis to afford thiophenol 2. Reaction of the sodium salt of 2 with 2-iodobenzoic acid results in formation of the corresponding bisarylsulfide via nucleophilic aromatic substitution.

Arylalkanoic Acids

65

Friedel-Crafts cyclization of the dibasic acid gives thiaxanthone 4. Note that the symmetry of this intermediate assures formation of a single product. Desulfurization by means of Raney nickel leads, finally, to the antiinflammatory agent, ketoprofen (5).1

^s^^,CHCC>2H

H2Kja

^^

XHCO7H

CO?H ^ ^

XHCO7H

- j c r —oucr

CD

A

CD

/

(3)

CH3 t^>f^\r^^CHC02H

,CHCO2H

(5)

(4)

Quite a different route is employed to prepare heterocyclic analogues of 5.

For example, acylation

of thiophene with p-fluorobenzoyl chloride (6) affords ketone 7.

Nucleophilic aromatic substitution

with the enolate from diethyl methylmalonate gives / •

the diester 8.

Saponification, followed by decar2 3 boxylation, gives suprofen (9). ' A similar sequence starting with the more highly substituted acid chloride (10) affords cliprofen

(13).2'3

Structure-activity studies in the phenylacetic acid antiinflammatory series have shown that inclusion of a methyl group on the benzylic carbon usually leads to maximal activity. It is of note that this

Arylalkanoic Acids

66

o

C1C

3 (6) X = H (113) X = Cl

(11) X= Cl

CH3CH \ CO2C2H5

^H 3

O-i

CO2C2H5

CHCO 2 H

CO2C2H5

CH,

X (S) X = H

(5) X = H (13) X = Cl

(12) X= Cl

group can be replaced, in at least one case, by chlorine.

Acylation of phenylcyclohexane with ethyl

oxalyl chloride affords the glyoxylic ester 14. Chlorination proceeds met a to the carbonyl group to 4 give 15* Reduction of the keto moiety gives the corresponding mandelate 16, which reacts in turn with thionyl chloride to replace the hydroxyl group by chlorine to give 17; ester hydrolysis affords fenclorac

(18).5

In a similar vein, the keto bridge in 5 can be replaced by oxygen with retention of activity. Reduction of acetophenone derivative 19 by means of sodium borohydride leads to the corresponding alcohol (20).

Reaction with phosphorus tribromide gives 21.

Displacement of the halide with cyanide gives

Arylalkanoic Acids

67

Q-Q-i

-CCO2C2H5

C14)

CCO2C2H5 Cl

w

x= H

°

(17) X = Cl Cl CHCO 2 H Cl

CIS) substituted acetonitrile 22, whose saponification affords the antiinflammatory acid, fenoprofen (23).

II -

-

(11)

-U' |

0' CO2H (22)

-

S

CHCH3 i (2J)) X = OH (21) X= Br

Arylalkanoic Acids

68

Alclofenac (26)

represents one of the more

extreme simplifications in this class of antiinflammatory agents. The general method for preparaQ

tion of related compounds

starts with acylation of

ochlorophenol to give 24. Alkylation of the phenolic group of 24 with allyl bromide affords the corresponding ether (25).

Willgerodt reaction on the

acetophenone results in transposition of the side chain and oxidation to the acid to give alclofenac

(26).

:H2=CHCH2O—^ HO

y—cCOCH,

Cl (25)

(24)

CH 2 =CHCH 2 O~/

\~CH 2 CO 2 H

Cl (16)

Inclusion of basic nitrogen in the £-position is also compatible with antiinflammatory activity in this series. affords 28.

Nitration of phenylacetic acid (27) Methyl iodide alkylation of the enolate

prepared from 28 using two equivalents of sodium hydride gives 29. intermediate (28a).

This appears to involve an Ivanov Catalytic reduction of the

Arylalkanoic Acids

69

nitro group leads to the corresponding aniline (30)• Acetylation to 31, followed by reaction with chlorine, serves to introduce the desired aryl halogen atom. Removal of the acetyl group, followed by cycloalkylation of the primary aniline (33) with Q

l,4-dibromo-2-butene affords pirprofen (34).

CH C 3 0 7 N-/""\-C CHC07H L \ /

CH3

|T^N /~\-

CH3 RNH~/~V-CHCO / V C 2 2H -•

•

^ ^ ^ 9H3 RNH~/ VcHCO2H

Cl (32.) R = COCH3 R= H

2

OoN—^

(50) R = H (31) R = COCH3

V_CH=C

\=r v (28a)

Anthranilic acid derivatives, such as flufenamic acid (35), constitute another effective series of non-steroidal antiinflammatory agents.

Homologation

Arylalkanoic Acids

70

of "the acid function in that series would of course lead to the arylacetic acid series*

It is of note

that one such hybrid compound, diclofenac (40), does in fact exhibit antiinflammatory activity.

In an

interesting synthesis, the diphenylamine 36 is first condensed with oxalyl chloride to give the oxanilic acid chloride 37*

Friedel-Crafts cyclization under

quite mild conditions gives the isatin 38.

Reduction

of the keto group by means of the Wolff-Kishner reaction gives lactam 39, whose hydrolysis affords diclofenac

(40)

(40).10

Arylalkanoic Acids

2.

71

DIARYL AND ARYLALKYL ACETIC ACIDS: ANTICHOLINERGIC AGENTS

Acetylcholine is the neurotransmitter amine of the parasympathetic autonomic nervous system.

A host of

bodily responses, such as gastric secretion, intestinal motility, and constriction of the bronchi, depend on cholinergic transmission.

Quite some time

ago it was discovered that responses due to activation of the cholinergic system can be antagnoized by atropine (41).

Experience with this natural product

foreshadowed the shortcomings of most subsequent anticholinergic drugs.

That is, these agents, as a

class, show little selectivity for a given organ system.

They tend to ablate all responses mediated

by the parasympathetic nervous system.

This lack of

selectivity leads to a set of side effects, such as dryness of the mouth, blurred vision, and CNS effects, which are quite predictable as extensions of the pharmacology.

As has been detailed elsewhere,

numerous SAR studies have reduced the requirements for anticholinergic activity to an ester of a benzilic acid with an alcohol related to ethanolamine; esters of cyclic aminoalcohols tend to be more active than the acyclic counterparts. Clinical trials of some of the more potent tertiary amines revealed these to exhibit marked psychotomimetic activity.

Much subsequent work

thus dealt with the quaternary salts which do not reach the central nervous system. Many of the uses of anticholinergic drugs involve "topical" application (e.g., interior of the stomach, intestine or bronchi);

72

Arylalkanoic Acids

the drugs could thus in principle show a clinically useful effect without first being absorbed parenterally. In addition, quaternization, while greatly inhibiting absorption, should assure that the drug will not cross the blood-brain barrier. Preparation of the quaternary anticholinergic agent benziIonium bromide (47) is begun by conjugate addition of ethylamine to methylaerylate, giving aminoester 42. Alkylation of 42 with methyl bromoacetate leads to diester 43, which is transformed into pyrrolidone 44 by Dieckmann cyclization, followed by decarboxylation.

Reduction of 44 by lithium

aluminum hydride leads to the corresponding aminoalcohol (45)*

Transesterification of alcohol 45

with methyl benzilate leads to 46.

Benzilonium

bromide (47) is obtained by alkylation of ester 46 12 with ethyl bromide* In a similar sequence, reaction of ketoester 52 with 2-thienylmagnesium bromide gives a modest yield of the benzilic ester 53.

Transesterification of

this with aminoalcohol 51, prepared analogously to 45 by starting with methylamine, gives, after quaternization with methyl bromide, heteronium bromide

(54).12 Similarly, lactam formation of diethyl glutamate (55) leads to ethyl pyroglutamate (56).

Reduction

by means of lithium aluminum hydride gives the aminoalcohol 57, which is then N-methylated to give 58.

Treatment with thionyl chloride leads to the

chloroamine 59 and displacement of halogen (possibly via an aziridinium intermediate) with sodium benzilate

CH3N

1 O C C IH (41) CH2OH O H

R=C H 2= 5 (C 484)2.) R

RNH 2 + CH2=CHCO2CH3

6

^RNHCH2CH2CO2CH3

RNCH 2 CO 2 CH 3 \H2CH2CO2CH3

I

R (44) R = C 2 H 5

C?2" H5

(49)R=CH3

(51) R= CH3 OH

-O

C

1

Br H5C2

0

a'

OH

0

CCO 2 CH 3

(52)

(47)

(53)

O-Oc

3^ CH 3

Br'

CH 3

(54)

73

74

Arylalkanoic Acids

affords poldine (60).13

Alkylation of 60 with

dimethyl sulfate gives poldine methylsulfate (61), in which the two-carbon bridge between quaternary N and 0 is preserved by placing a methylene in the position of the pyrrolidine nucleus.

C2H5O2CCHCH2CH2CO2C2H5

L2

- ^ ^ Q c^n^°

" (55)

"" H O C H ^ N ^

2

i I (AD

(16)

R=H

(58_) R = C H 3

C1CH 2

^

I

CH3 CH3SO4

0

(59) C61)

Benzilate esters of piperidinols, as well as those of acyclic aminoalcohols, show similar anticholinergic activity. For example, ester interchange between methyl benzilate and N-methyl-4-piperidinol, followed by quaternization of the resulting ester with methyl bromide, gives parapenzolate bromide 14 (62). In analogous fashion, ester interchange between methyl benzilate and N~ethyl-N-n-propylethanolamine yields benapryzine (63).

Arylalkanoic Acids

C—CO—/

75

N@

r

(/

y-C— COCH2CH2NCH2CH2CH3

CH3

(62)

(63)

Biological activity in this series shows considerable tolerance for modification in the ester moiety as well.

Esters in which one of the aromatic

rings is fully reduced still show good anticholinergic activity.

One such agent, propenzolate (66), is

prepared by displacement of halogen from N-methyl3-chloropiperidine (64) by the sodium salt of acid 65. 1 6

O H (65)0

(66)

In yet a further variation on this scheme, the basic center in the molecule can be present as an

76

Arylalkanoic Acids

amidine.

In the synthesis of oxx/phencz/climine (69),

reaction of chloroacetonitrile with methanol and hydrogen chloride leads to the corresponding iminoether 67.

Condensation of 67 with N-methyl propyle-

nediamine gives the corresponding tetrahydropyrimidine (68).

Displacement of the halogen with the

sodium salt of 65 affords oxxjphencxjclimine (69).

C1CH2CN

m* CICH2C (67) (68)

Omission of the hydroxyl group and one of the cyclic hydrocarbons from the acid moiety is apparently not inconsistent with biological activity.

Thus,

the ester from 2-phenylbutyryl chloride and diethylaminoethoxyethanol, butamirate (71), shows antispasmodic activity.

In analogous fashion, reaction

of the acid chloride from 72 with N-methyl-4piperidinol, followed by quaternization, gives pentapiperium methylsulfate (73).

18

Apparently, minor chemical modifications of the benzilcarboxylic acid containing molecules led to a compound which shows surprising analgesic activity. Condensation of N-methylphenethylamine 74 with

Arylalkanoic Acids

CH 3 CH 2 CHCOC1

77

CH 3 CH 2 CHCO2CH 2 CH2OCH2CH2NC2H5 C2H5

(II) CH3

CH 3 CH 3 CH 2 CHCHCO 2 H

N© CH3SO4t CH3

CH 3 CH 2 CHCHCO 2 '

(73)

(ID

ethylene oxide gives aminoalcohol 75; which is then CH T

{

CH3NHCH2CH2 (74)

XCH 2 CH 2 NCH 2 CH 2 X = OH

-o

(7_6) X = Cl

CH 3 CH 3 NHCH 2 CH2NCH 2 CH 2

I C1CCNCH2CH2NCH2CH2'

(21)

P I CH 3

(79)

Arylalkanoic Acids

78

converted to the halide (76) by means of thionyl chloride.

Reaction with methylamine leads to the

key diamine 77* Acylation of the diamine with chlorodiphenylacetyl chloride (to 78), followed by displacement of the benzylic halogen by sodium ethoxide, affords the analgesic agent carbiphene

(79).19 3.

MISCELLANEOUS ARYLALKANOIC ACIDS

It has been known for some time that thyroxine, and related compounds such as liothyronine (88) are effective in lowering serum cholesterol.

The normal

metabolic activity of this class of thyroid active compounds has precluded their use as hypocholesterolemic agents. r

I CH3O-^

° 2 N CM) R= H

\~0H

(82)

(8.1) R = p-CH 3 C 6 H 4 SO 2

^

CH3O~^

\ ~ 0 — /

\ ~ CH2CO2C2H5

(8jn R = N 0 2 (8J-) R = NH 2

CH7

CH3O

R

•-p(85_) R' = C2H5 (86) R' = H

(88)

•CH2CO2R'

Arylalkanoic Acids

79

A program aimed at preparation of analogues of thyroxine which would maximize their effect on lipids resulted in the preparation of thyromedan (87).

This agent, interestingly, proves also to

have good thyromimetic activity.

In the synthesis

of 87, reaction of the substituted phenylacetate 80 with tosyl chloride leads to the corresponding tosylate (81).

Reaction of that intermediate with

the salt from phenol 82 results in aromatic nucleophilic displacement of the highly activated tosylate to afford the diphenyl ether 83.

The nitro groups

are then reduced catalytically to give diamine 84. Diazotization, followed by Sandmeyer reaction with sodium iodide, affords the desired triiodo intermediate 85.

Saponification affords the acid (86),

and reaction of the sodium salt of the acid with 20 2-chlorotriethylamine gives thgromedan (87). A highly-substituted phenylacetic acid derivative shows activity as a shortacting narcotic and as an injectable general anesthetic.

This

agent, propanidid (90), is obtained by alkylation of 21 phenol 89 with N,N-diethylchloroacetamide.

OCH3 CH3CH2CH2OCCH2 —(/ V-OCH2CNC2H5 \==/ \ C89)

(90)

Clofibrate (91) has been in clinical use for several years as a serum triglyceride lowering agent.

This drug is an important hypocholesteremic

80

Arylalkanoic Acids

agent also, blocking cholesterol biosynthesis. Appearance of this agent on the market occasioned intensive work in many laboratories aimed at discovering additional compounds with this activity.

A

distantly related analogue, halofenate (98), was, in fact, found to be effective.

In addition, however,

clinical trials revealed this analogue to have marked concomitant uricosuric activity; that is, the drug promotes excretion of uric acid. In order to synthesize halofenate, acid 92 is first converted to the acid chloride by means of thionyl chloride; bromination affords the or-halo derivative 93.

This

is then allowed to react with methanol to give the corresponding methyl ester (94).

Displacement of

bromine with the anion from meta-trifluoromethylphenol leads to ester 95.

The ester is then hydrolyzed and

CH 3 Cl-/""VoCCO 2 C 2 H 5 CH 3 (91)

(£8)

(92)

/ /

(95) R = OCH3 (96) R = OH (97) R= Cl

(21) R-Cl (94) R = OCH3

Arylalkanoic Acids

81

the product (96) is converted to the acid chloride (97).

Acylation of N-acetylethanolamine with 97

yields halofenate

(98).22

A disubstituted butyramide, disopyramide, distantly related to some acyclic narcotics interestingly shows good antiarrhythmic activity.

Alkyl-

ation of the anion from phenylacetonitrile with 2bromopyridine yields 99.

Alkylation of the anion

from the latter with N,N-diisopropyl-2-chloroethylamine leads to the amine 100.

Hydration of the 23

nitrile in sulfuric acid affords disopyramide (101).

Br

CH2CN

CHCN

* CT U

.

NCH2CH2CCONH2

(CH3)2CH/

(101)

I

-•

(99)

NCH2CH2CCN

(CH3)2CH/

(100)

Finally, reaction of the half acid chloride of malonate 102 with N^-diethylethylenediamine gives 24 the muscle relaxant fenalamide (103).

82

Arylalkanoic Acids

C2H5 c H 2 /C2H5 CONHCH2CH2N X N C2H5 CO2C2H5

£OC1 CO2C2H5

(103)

REFERENCES 1.

D. Farge, M. N. Messer and C. Moutonnier, U. S. Patent 3,641,127 (1972); Chem. Abstr. , 68: 524 (1968).

2.

P. A. J. Janssen, G. H. P. Van Daele and J. M, Boey, German Patent 2,353,375 (1974).

3.

P. G. H. Van Daele, J. M. Boey, V. K. Sipido, M. F. L. De Bruyn and P. A. J. Janssen, Arzneimittelforsch., 25, 1495 (1975).

4.

D. Julius and N. J. Santora, U. S. Patent 3,321,267 (1971).

5.

D. Julius and N. J. Santora, German Patent 2,122,273

(1972).

6.

M. S. Winston, U. S. Patent 3,600,437 (1971).

7.

N. P. BuuHoi, G. Lambelin and C. Gillet, South African Patent 68 05,495 (1969); Chem. Abstr., 71: 101,554e (1971).

8.

G. Gariraghi, S. Banfi, U. Cornelli, M. Pinza and G. Pifferi, II Farmaco, Ed. Sci., 32, 286

(1977).

Arylalkanoic Acids 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

22. 23.

83

R. W. J. Carney and G. DeStevens, German Patent 2,012,237 (1970). A. Sallman and R. Pfister, German Patent 1,815,802 (1969). R. W. Brimbelcombe, Advances in Drug Research, 7, 165 (1973). W. Ryan and C. Ainsworth, J. Org. Chem., 27, 2901 (1962). F. F. Blicke and C.J. Lu, J. Am. Chem* Soc. , 77, 29 (1955). J. Klosa and G. Delmar, J. Prakt. Chem., 16, 71 (1962). M. D. Mehta and J. G. Bainbridge, U. S. Patent 3,746,743 (1973). J. H. Biel, U. S. Patent 2,995,492 (1957). J. A. Faust, A. Mori and M. Sanyun, J. Am. Chem. Soc. , 81, 2214 (1959). H. Martin and E. Habicht, U. S. Patent 2,987,517 (1961). J. Krapcho and C. F. Turk, J. Med. Chem., 6, 547 (1963). B. Blank, F. R. Pfeiffer, C. M. Greenberg and J. F. Kerwin, J. Med. Chem., 6, 560 (1963). R. Hiltmann, H. Wollweber, F. Hoffmeister and W. Wirth, German Patent 1,134,981 (1962); Chem. Abstr. , 58: 4480f (1963). W. A. Bolhofer, U. S. Patent 3,517,050 (1970). J. W. Cusic and H. W. Sause, U. S. Patent 3,225,054 (1965).

84 24.

Arylalkanoic Acids P. Galimberti, V. Gerosa and M. Melandri, U. S. Patent 3,025,317 (1962); Chem. Abstr., 56: 550c (1962).

Monocyclic Aromatic Compounds The benzene ring per se does not impart any particular pharmacological response to a drug.

It is widely

held that its planarity, its ability to bind to tissue receptors by Van der Waals and charge transfer mechanisms, and, particularly, its ability to serve as a conductor of electrons within a substance serve as modulators, enhancing or diminishing the intensity of response to a molecule that is otherwise inherently bioactive. 1. a.

DERIVATIVES OF BENZOIC ACID Acids

Salicylic acid analogues are often active as nonsteroidal antiinflammatory agents because they interfere with biosynthesis of prostaglandins. Diflunisal (3) appears to be such an agent. It is synthesized from the nitrobiphenyl 1 by catalytic reduction to 85

Monocyclic Aromatic Compounds

86

NO2

'OH

(1)

(1)

.CO2H

CO 2 H

NH2 (4)

(3)

the aniline, diazotization, and heating in aqueous acid to give phenol 2.

This is carboxylated using

K^COo and carbon dioxide to give diflunisal. Alternatively, the corresponding anthranilic acid derivative 4 is diazotized, then hydroxylated by heating in dilute sulfuric acid to give diflunisal. CO 2 H

,CO2H

O2N Cl

SO2NH2

(5)

H2N

(6)

CH 3 (CH 2 ) 3 HN

CO 2 H

;0 SO 2 NH 2

(7)

SO2NH2

Monocyclic Aromatic Compounds

87

Many benzenesulfonamides have diuretic properties, particularly those having two such functions situated meta to one another. To some extent a carboxyl group can serve in place of one of the sulfonamido groups. Bumetanide (8) is such a substance. Chlorosulfonation of p-chlorobenzoic acid leads to 5, which is nitrated, and then converted to sulfonamide 6 with ammonia. The chloro group of 6 is now highly activated toward nucleophilic aromatic substitution, facilitating reaction with phenoxide. Subsequent catalytic reduction in the presence of LiOH produces amino acid 7. Next, treatment with butanol and sulfuric acid not only forms the butyl ester but monoalkylates the amino function. Saponification of the ester group leads to bumetanide (8), a diuretic agent possessing 40-fold greater activity in healthy adults than furosemide. TiJbric acid (10), interestingly, has the mcarboxysulfonamido functionality but its activity is expressed, instead, as suppression of serum triglyceride levels. In its reported preparation, chlorosulfonic acid treatment converts 2-chlorobenzoic acid to chlorosulfonate 9, which readily forms the hypolipidemic agent tibric acid (10) on reaction with 3,5-dimethylpiperidine. 4

(£)

(10)

Monocyelic Aromatic Compounds

88

b.

Anthranilic Acid and Derivatives

N-Aryl anthranilic acids are frequently found to have antiinflammatory activity and have been studied extensively to maximize potency and decrease side effects (gastric irritation, ulcers, etc.)*

These

compounds are often synthesized by reacting an orthohalobenzoate salt with a suitably substituted aniline. This procedure failed, perhaps because of steric hindrance, in attempting to synthesize meclofenamic acid (16).

The successful synthesis begins by

(16) (15)

CM) treating 2-methyl-4~hydroxy acetophenone (11) with NaOCl, which both ortho-chlorinates adjacent to the phenolic OH and effects a haloform reaction. Decarboxylation leads to the chlorinated meta cresol 12.

When

12 is converted to its sodium salt with NaH in DMF

Monocyclic Aromatic Compounds

89

and then treated with 2,4-dichloroquinazoline (13), two molecules of the phenol react with the heterocycle to give the nucleophilic aromatic substitution product 14.

When heated, 14 undergoes an 0 to N-aryl rearrange-

ment (Chapman Rearrangement) to give 15. Upon saponification, carbon dioxide and 2,5-dichloro-3-methylaniline are lost and meclofenamic acid (16) results.

Reaction

of sodium meclofenamate with ethylchloromethyl ether in acetone gives etoclofene (17), which is also active as an antiinflammatory agent.

Etoclofene

reportedly causes less gastrointestinal irritation than meclofenamic acid to which it is presumably converted after passage through the stomach.

XC (20) —

(IS) R = H

(i£) R= C6H5 One of the mainstays in the treatment of tuberculosis is paraaminosaliciflic acid (PAS)* however, a pleasant drug to take.

It is not,

Phengl amino-

salicxjlate (20) was synthesized from 4-nitrosalicylic acid (18) by esterification of its acid chloride with phenol to give 19, which is converted to the desired product (20) by reduction with Raney nickel catalyst.

7

Phengl aminosalicx/late was intended to be more acceptable to patients than PAS. Unquestionably, the most frequently used analgesic is aspirin.

The reader will recall that aspirin is

90

Monocyclic Aromatic Compounds

regarded as a latentiated form o f salicylic acid and is intended t o minimize as far as possible t h e irritation o f t h e gastrointestinal tract that salicylic acid would otherwise cause* Salsalate (24) represents another approach to this problem i n w h i c h selfesterification h a s b e e n used to serve t h e same purpose. D i r e c t self-condensation is difficult to control, although l o w temperature treatment o f salicylic acid w i t h PC1.~ does work. A more stepwise procedure involves t h e condensation o f benzyl salicylate (21) w i t h t h e acid chloride o f salicylate benzyl ether 22 to produce protected dimer 23. Catalytic h y d r o genolysis removes t h e benzyl groups and completes t h e preparation o f salsalate (24).

(22)

OH

(23)

Esterification of certain aromatic acids with p-aminoethanol and propanol derivatives frequently results in molecules that show local anesthetic

Monocyclic Aromatic Compounds

91

activity; and some of these derivatives also have an antiarrythmic action on the heart. such an agent.

Amoproxan (27) is

It can be synthesized by reacting

epichlorohydrin with 3-methylbutanol and BF~ to give epoxide 25.

This, then, is reacted with morpholine

to give alcohol 26, which is then reacted with 3,4,5trimethoxybenzoyl chloride to complete the synthesis of amoproxan (27). CH

3\

/w\ CH(CH2)2OCH2CH—CH2

VI1J

•»

CH3

\ CH(CH2)2OCH2CHCH2N

6

CH 3 (15)

(2,6)

CH3O,

CH

| C= °

X

CH(CH2)2OCH2CHCH2N CH3 (27)

Risocaine (28) manages to retain local anesthetic activity even without having a "basic ester" moiety. Its synthesis follows classic lines involving esterification of p-nitrobenzoic acid with thionyl chloride followed by reaction with propanol, and then catalytic reduction to complete the scheme.

92

M o n o c y c l i c A r o m a t i c Compounds

,CO2CH2CH2CH3 CH3O 6CH3 (2 9)

(28)

CH3 CH3 CH3 0 CO(CH2)3N(CH2)2N(CH2)3OC

CH3 ^ OCH3

(3£) OCH3 Vasodilators may be of value in the treatment of conditions resulting from insufficient blood flow through tissues.

One such agent incorporating a bis-

basic ester moiety is prepared by reacting 3,4,5-trimethoxybenzoyl chloride with 3-chloropropanol to give 29, and condensing two molar equivalents of this with N,N!-dimethylethanediamine to give hexobendine (30). c.

Amides

As one would anticipate, the time honored SchottenBaumann reaction and its variants are the key steps in putting this group of substances together.

Their

intrinsic interest to the medicinal chemist depends upon their pharmacological properties and, in some cases, preparation of some of the less common benzoic acid analogues. Anticholinergic agents play a role in management of ulcers by decreasing the secretion of gastric acid

Monocyclic Aromatic Compounds

93

mediated by the neurohormone acetyl choline.

Prog~

lumide (32) is synthesized from the benzoyl amide of glutamic anhydride derivative 31 by reaction of the 12 more activated carbonyl with dipropyl a m m e .

CON | VCH2)2CH3 H (32)

The diuretic clopamide (35) is synthesized from p-chlorobenzoic acid (33) by chlorosulfonation and subsequent ammonia treatment to give 34.

This is

converted to its acid chloride with thionyl chloride and reacted with the desired hydrazine derivative

(itself prepared by lithium aluminum hydride reduction of N-nitroso-2,6-dime"thyl piperidine) in a Schotten-Baumann reaction to give clopamide. 13

The

15 related diuretics diapamide (36),14 xipamide (37),

Monocyclic Aromatic Compounds

94

and alipamide (38)

are made by simple variants on

this scheme. CH3O,

0

CH 3 O OCH3

CH3O, NHCH 2 CN(C 2 H 5 ) 2 0

CH3O

HO OCH3

OCH3 (40)

(39)

8 CH3O

CH 3 CO

Cl

-a. SO2NH2 (42)

(44)

(43)

The sedatives trimetozine (39),17 and tricetamide (40),18

the CNS stimulants ethamivan (41),19 and 20 sulpiride (42), the antihelmintic agents niclosamide 21 22 23 (43), clioxanide (44), and bromoxanide (45), the coccidiostat alkomide (46), and the antiarrhyth25 mic agent capobenic acid (47) are all made from the corresponding benzoic acids in obvious ways.

ci

CH3

°YY^

0 . 3 0 ^ OCH3 C(CH 3 ) 3

(£6)

(47)

Monocyclic Aromatic Compounds

2.

95

DERIVATIVES OF ANILINE

The clinical success of hindered acetanilide derivatives, such as lidocaine, of course, resulted in the synthesis of many analogues.

Branching in the acid

moiety is consistent with activity as demonstrated by the local anesthetic properties of etidocaine (48) and a formally cyclized analogue, dexivacaine (49). 27 Etidocaine is prepared from 2,6-dimethylaniline by sequential reactions with 2-bromobutyryl chloride and ethylpropylamine.

The preparation of dexivacaine

follows the same pattern.

However, in this case,

resolution by crystallization of its quinic acid salt was carried out, whereupon it was found that the Senantiomer was the longer acting.

N0 2

NHCCHNC2H5

0 l

IHCOCH3

CCH3)3CO(50)

Acetanilide is a well-established analgesic agent.

It is perhaps not suprising then that butacetin

(51) has such activity; however, it appears to have been synthesized while searching for antitubercular agents.

The synthesis proceeds from 4-fluoronitro-

benzene (50) via a nucleophilic aromatic displacement reaction with potassium tert-butoxide, followed by 28 Raney nickel reduction and acetylation.

96

Monocyclic Aromatic Compounds

A molecular dissection of the alkaloid vasicine (52) ultimately resulted in the expectorant and 29 mucolytic agent bromhexine (54). The synthesis starts with displacement of halogen on 2-nitrobenzylbromide (53) by N-methyl eye1ohexylamine, followed by Raney nickel and hydrazine reduction of the nitro group.

Bromination in acetic acid then affords

bromhexine. N0 2

*"O Serotonin (55) is a putative neurotransmitter, especially in the central nervous system, and has a number of peripheral effects as well.

There have

been numerous attempts to associate disturbances in serotonin catabolism and anabolism with mental disease, and antagonists have been prepared as an aid to investigation of these theories and as potential therapeutic agents.

BAS (56) is one such inhibitor

and its structural similarity to 55 makes it understandable that it should be such.

On the other hand,

cinanserin (58) is 157 times more potent as a serotonin inhibitor than 56, and its structural relationship to either 55 or 56 is much less obvious.

This under-

scores one of the more frustrating features of deliberate drug design—that the best analogues occasionally differ strikingly in structure from the lead molecule so that success requires an unsatisfying amount of semirandom molecular manipulation and a very close liason with the pharmacologist into whose hands the drugs are placed for evaluation.

In any

M o n o c y c l i c A r o m a t i c Compounds

97

HO. NH2

H (55)

"

X

J

X

I

T

"

"

CH2C6H5 (56)

NH? NMe2

SH HNCOCH=CHC6H5 (57)

(58)

event, cinanserin is synthesized from 2-aminothiobenzene (57) by S-alkylation using N,N-dimethyl-3chloropropylamine and NaOCEL, followed by reaction with cinnamoyl chloride to give 58. 30 O2C2H5 NCOCl

NCSCH2CH2N(C2H5)2

(59)

CH2CH2N(CH3)2

(60)

Phencarbamide (60)

V

(61.)

is a structural analogue of

acetylcholine which acts as an anticholinergic agent, possibly by serving as a false agonist.

It is made

by reacting N,N-diphenylcarbamoyl chloride (59) with 2-mercapto-N,N-diethylethamine.

98

Monocyclic Aromatic Compounds

Flubanilate (61) has central nervous stimulating activity and is synthesized conveniently from N(2~dimethylamino)ethyl-3-trifluoromethylaniline by 32 reaction with ethylchlorocarbonate. A number of aminobenzophenone derivatives possess nonsteroidal antiinflammatory activity. is diflumidone (63).

Illustrative

Its synthesis involves treatment

of 3-aminobenzophenone (62) with difluoromethanesulfonic anhydride in the presence of triethylamme.

H2

^K. A .

(62)

^s.

33

NHSO2CHF2

(63)

CO 2 C 2 H 5 NSO2CF3

(64)

The closely related antiinflammatory agent triflumidate (64) can be prepared by abstracting the now acidic NH proton of the trifluoromethyl analogue of 63 with sodium hydroxide and reacting the resulting anion with ethyl chlorocarbonate to give 64* 34 3.

DERIVATIVES OF PHENOL

a.

Basic Ethers

The chemical fragment, OCCN=, occurs very frequently in drugs, perhaps deriving some inspiration from

Monocyclic Aromatic Compounds

99

acetyl choline. T h e fact that drugs containing this unit do n o t possess some common pharmacological property suggests that t h e function is involved in transport rather than b e i n g a pharmacophore. Several agents containing this moiety are described in this section,

CH3O

Boxidine

j

^

(69) h a s hypolipidemic p r o p e r t i e s .

^

RQ

(67) R=CH3 (68) R= H i . — I \ (£2.) R=CH2CH2-N>3

(6

—

(66) —

It was synthesized from p-iodoanisole (65) by coppercatalyzed coupling with p-trifluoromethyliodobenzene (66) to give the expected statistical mixture from which unsymmetrical product 67 could be separated. Ether cleavage with HBr and HOAc gave 68; this was then alkylated with the aziridinium ion derived from N-(2-chloroethyl)pyrrolidine, using NaH as base, to complete the synthesis of boxidine (69). The quaternary ammonium salt 73, thenium closzjlate, is an anthelmintic agent.

Many substances

of this general type are effective by interfering with nervous conduction, and thereby muscle tone, of intestinal worms.

This allows their expulsion, not

always in the dead state.

The synthesis

proceeds

from 2-thienylamine (70) by monoalkylation with 2phenoxyethyl bromide (71) to give secondary amine 72.

100

Monocyclic Aromatic Compounds

This is converted by methyl iodide to the quaternary salt which is converted to the p-chlorobenzene sulfonate salt (73) for pharmacological purposes.

(10)

(11)

(13) When l,2~dichloropropane is reacted with o-benzylphenoxide ion (74), halide 75 results, which is then converted to the antitussive agent benproperine (76) 37 on treatment with piperidine.

OCH2CHCH3

CZ1) Guanethidine (77) was the first of a series of antihypertensive agents which act by interfering with adrenergic transmission.

It was subsequently found

that simple substitution of the guanidine function onto a nucleus with appropriate lipophilicity almost invariably affords such sympathetic inhibitors.

Monocyclic Aromatic Compounds

101

NH

NH .O(CH2)3NHCNH2

H2NH2

(77)

(78)

(79)

O(CH 2 ) 2 NHNH-CNH 2

.O(CH 2 ) 2 R

NH 'Cl (8j))

R = Br

(82)

(8J_) R = NHNH2

Thus, for example, guanidine analogues guanoxyfen (79) and guanochlor (82) also possess antihypertensive activity. Guanoxyfen is synthesized

by base-

catalyzed condensation of phenol with chloroacetonitrile, followed by hydride reduction to amine 78. The guanido function is introduced by reaction with S-methylthiourea to give guanoxyfen (79).

When 2-

(2,6-dichlorophenoxy)ethyl bromide (80) is reacted with hydrazine to give 81, and this is reacted with S-methylthiourea, guanochlor (82) results. b.

Phenoxyacetic Acids

The clinical success of clofibrate has naturally led to the synthesis of numerous analogues intended for use as hypocholesterolemic agents.

One of these,

clofenpyride (84), is synthesized readily from pohlorophenoxy-2,2-dimethylacetic acid (83) by conversion to the acid chloride and reaction with 3-hydroxymethylpyridine.

40

Substitution of a single aromatic

10 2

cr

Monocyclic Aromatic Compounds

^

ci" (£3)

(iB4)

ring in the place of the gem-dimethyl groups of 84 is compatible with activity.

Interestingly, the resulting

molecule, halofenate (90) is also reported to show uricosuric activity.

Conversion of p^-chlorophenyl-

acetic acid (85) to its acid chloride (86) activates the benzylic methylene group to bromination with molecular bromine, and the resulting mixed dihalide (87) is reacted with methanol to give ester 88, Nucleophilic halide displacement with the sodium salt of m-trifluoromethylphenol gives intermediate 89, which is saponified with KOH, converted to the acid

^lxj^ ^ C (£5) CF3

.XX IH C F? ^ 0 ' C • C Q R ' C H C 20eI JR^ v "" -^ rM R= =H ,, R '' = C ll (8 (((£££876))) R R B r R = C = Br, R » - 0CH-

N > 2H C O C H 3 Xn C"l ^" (9£)

Monocyclic Aromatic Compounds

103

chloride with thionyl chloride, and then esterified 41 with N-acetylethanolamine to give halofenate (90). Insertion of a second aryl ether oxygen function is also consistent with hypocholesterolemic activity. Burger et aJL. have published an early and apparently 42 general synthesis of such compounds. In the specific case of lifibrate (92), bis-(4~chlorophenoxy) acetic acid (91) is converted to the acid chloride with thionyl chloride, and then reacted with N-methyl piperidine-4-ol to give the desired basic ester 92. C1

ci

C1

g XX \C H C H O C O H 2 — fH 2 m*.0 ]"

(91)

C92)

A seemingly simple variation on these structures results in central stimulant activity instead. £-Methoxyphenyloxyacetic acid (93) is reacted with N,N-diethylethanolamine via the acid chloride to give 43 mefexamide (94).

8 ,OCH2CO2H CH3O (93)

(£4)

The diuretic properties of ethacrxjnic acid (95) were at one time attributed to its role as a Michael

104 acceptor.

Monocyclic Aromatic Compounds

The enone was believed to react with SH

groups on enzymes in the kidney.

This interesting

view was weakened by the discovery that some related molecules which do not possess this structural feature CH.v

^

^OCH2CO2H

CH2

Cl Cl (95)

.OCH3

.OCH, s

C0C1 Cl

C£Z) .OCH2CO2H

Cl Cl (98)

still possess marked diuretic activity.

An analogue

of ethacrijnic acid is synthesized by condensing 2,3dichloromethoxybenzene (96) with the acid chloride of thiophene a-carboxylic acid to give 97.

Ether cleavage

with A1C1-, followed by sodium salt formation, etherification with ethyl chloroacetate, and then saponifi-

c a t i o n g i v e s ticrx/nafen

(98). 44

Monocyclic Aromatic Compounds

10 5

c. Ethers of l-Aminopropane-2,3-diol There has been enormous interest recently in the pharmacological properties of selective p-adrenergic blocking agents following the clinical success of propranolol. That the many pharmacological responses elicited by norepinephrine and epinephrine in various tissues are the consequence of macromolecular receptor substances of slightly different specificities has been known for some time. Such differences are often most conveniently demonstrated through use of selective inhibitors, and functional classifications of such receptors are usually made on that basis. Ahlquist devised a system of receptor classification based largely upon whether excitatory or inhibitory responses followed administration of adrenergic agents. 45 The a-receptor was associated generally with excitatory responses (vasoconstriction, uterine and nictating membrane stimulation) while the p-receptor was associated with inhibitory responses (vasodilation, inhibition of uterine muscle). While the physiological responses following p-receptor stimulation are many, those most prominent are those on the cardiovascular system and on the smooth muscles of the bronchial tree. Subsequently, a lack of faithful parallelism between the cardiac and bronchial effects led Lands et al. to propose a further subdivision of the p-receptors into p.,, which stimulates cardiac muscle and lipolysis, and p^, which relaxes bronchioles and influences the vasculature and shows metabolic effects. Epinephrine (99)

Monocyclic Aromatic Compounds

106

is an archetypal adrenergic agent stimulating a, p., and p~ receptors. OH

on NHCH 3

HO'

(100)

ci

OH

Cl (99)

(101)

T

Oil CH(CII3)2

CH3CONH' (102)

( 103)

(10 3 a

Oil

HO

NHCHMC2

(104)

(]_0_5)

Some specific antagonists of interest in classifying receptors are tolazoline (100, a-receptor antagonist), dichloroisoproterenol

(101, p-receptor

antagonist), practolol (102, p.receptor antagonist), and bunitrolol (103, p^receptor antagonist). described compound 103a

Recently

departs from the previous

structural norm and possesses strong p^receptor blocking selectivity.

These classifications are

rendered somewhat difficult because few of these agents are completely selective and may have additional pharmacological properties, such as varying degrees of intrinsic sympathomimetic agonist action.

Monocyclic Aromatic Compounds

107

Isoproterenol (104) is an important agent for classification because of its selective p-receptor agonist activity.

It is of special interest that its chrono-

tropic (increase in heart rate) and inotropic (increase in force of contraction) effects exceed that of epinephrine; it is also used in the management of mild to moderate asthma due to its bronchodilating effect, resulting in increased vital capacity of the lungs• It is in this context that propranolol (105) and its myriad analogues need to be judged.

Administration

of 105 leads to a decrease in heart rate, cardiac contractile force and myocardial oxygen consumption. These drugs often have some intrinsic adrenergic sympathomimetic activity which leads, i.a., to an increase in airway resistance of little consequence to most patients but of potential danger to asthmatics. Another factor of interest is a direct action on cell membranes, affecting their responsiveness to electrical stimulation and, in isolated atria, decreasing spontaneous frequency, maximal driving frequency, contractility and increasing the electrical threshold. In contrast to the p-blocking action, these "local anesthetic" actions are nonstereospecific.

Whether

these local anesthetic actions are important in antiarrhythmic action is being debated. The therapeutic use of these agents is in control of cardiac arrhythmias, angina pectoris, and in essential and renovascular hypertension.

The various

ancillary activities lead to side effects and much

108

Monocyclic Aromatic Compounds

effort has been expended to refine out these extraneous responses.

It is not universally agreed whether

some intrinsic sympathetic activity (I.S.A.) is desirable or not and, if so, how much a drug should have.

CH20SO2-/A-CH3 >

=/

I

I X CH O CH3 2
2V \ /

X CH< 2r ^ (107) CH3COHN'X^^

CH9 (108)

OH OCH2CHCH2NHCH(CH3)? (HI)

The means used to prepare these agents can be illustrated by the following examples. (109)

Practolol

gives less clinical bronchoconstriction in

some patients than propranolol because its receptor action is more selective.

Serious occasional toxicity

not related to p-blockade has led to its withdrawal from clinical use.

A synthesis is available which

relates the absolute configuration of the more potent

Monocyclic Aromatic Compounds

optical isomer to (+)-lactic acid.

109

The glycerol

derivative 106 is available from D-mannitol and retains the optical activity as the two primary alcohol functions are differentially protected. Displacement with sodium p-acetaraidophenoxide gives 107 which is deblocked with dilute acid, selectively reacts at the primary alcohol function with one molar equivalent of tosyl chloride and pyridine, then treated with NaOH in dimethylsulfoxide to yield epoxide 108.

Epoxide opening with isopropylamine

leads to optically active practolol (109), showing that the ]L-compounds are related to R-(-)-epinephrine. The synthesis of oxprenolol (111) follows a 49 similar course. Epoxide 110, readily synthesized by reaction of the sodium salt of pyrocatechol monoallylether with epichlorohydrin, is reacted either with isopropylamine or with HC1 (to form the intermediate halohydrin) followed by isopropylamine.

OCH2CHCH2NHCH(CH3)V2 (112)

(113)

OH CH2CHCH2NHCH(CH3)2 (114)

(115)

Metoprolol (112),50 acebutolol (113),51 atenolol 52 23 (114), and moprolol (115) are all closely related

Monocyclic Aromatic Compounds

110

and made by this basic route or simple variations of it* .CN

OH

OH 0

CHCH 2 NHC(CH 3 )3

OCH 2 CHCH 2 NHC(CH3)3 C2H5 (116)

(117)

OH

OH

H22CF OCH CHCH2NHC(CH3)3

CH2CHCH2NHC(CH3)3

(118)

(119)

OH

OH OCH2CHCH2NHC(CH 3 )3 (120)

(121)

Replacement of isopropylamine by tert-butyl amino often results in an increase in potency.

This

substitution is used in the p-blockers bunitrolol (116), 5 4 bufuralol (117),5S

bunolol (118),5 6 nadolol

(119), 5 7 and phenbutalol (120).5B

Tazolol

(121)59

whose structure is similar, is not a good p-blocker, 59 possessing substantial ISA. Substitution of groups other than :L-propyl or t-butyl on nitrogen also leads to active compounds. Primary amine 122 is reacted with p-(p-chloroethoxy)benzamide (123) to give the p-blocker, tolamolol

(124).6 0

Monocyclic Aromatic Compounds

,CH3

111

r

.CONH2

OCH2CHCH2NH2 C1(CH 2 )2O (123)

,CH3

XT ^.

OH 'OCH2CHCH2NHCH2CH2O

CONH 2

(124)

4. ARYLSULFONES AND SULFONAMIDES a. Sulfones Until the development of the antibacterial sulfones, Hanson's Disease (leprosy) remained a potentially horrible affliction, treated with largely ineffective ancient remedies. The antibacterial sulfonamides do not do well against this disease and, interestingly, the sulfones which are effective, are not very useful

(125)

(126)

(127)

112

Monocyclic Aromatic Compounds

against most other bacterial infections. (125) is such an agent.

Dapsone

It is somewhat inconvenient

to administer to patients because of its rather low water solubility.

In the search for more easily

administered drugs, 125 was reacted with bromoacetic acid to give acediasulfone (126) which can be administered as a water soluble salt. Acedapsone (127), which is conveniently prepared by acetylation of dapsone, was intended to be a prodrug.

Leprous patients toeing treated with

dapsone were observed to have a lower incidence of malaria and acedapsone was made to capitalize on this observation.

It, indeed, has both antileprotic and

antimalarial activity. b.

Sulfonamides

Because of bacterial resistance and unacceptable side effects in some patients, the antibacterial sulfonamides no longer enjoy the clinical vogue they once had.

Still, their cheapness, undeniable efficacy in

susceptible infections, and the hope of overcoming their deficiencies leads to a continuing interest despite thousands having been synthesized to date. Some of the more significant agents not included in Volume I of this work follow. Generally, N-. -acylsulfonamides are less effective than those having a single N.-aryl group.

One such

acyl analogue, sulfabenzamide (130) is prepared simply from sulfanilamide (128) by bisbenzamide formation (to 129) using benzoyl chloride and pyridine, followed by partial saponification.

Monocyclic Aromatic Compounds

jx

113

*NHCOC6H5 C6H5COHN

(128)

W

NHCOCH XX " (130) 65

llLl

The classic syntheses of the antibacterial sulfonamides involve reaction of the appropriate arylamine with an acid addition salt of p-aminobenzenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride followed by reduction.

Chemical interest

largely resides in preparation of the corresponding arylamines.

For the synthesis of sulfacytine (134),

N-ethyl uracil (131) was converted to its thioamide (132) by reaction with phosphorous pentasulfide.

The

newly introduced sulfur is then displaced with ammonia in methanol to give 133.

(151) X = 0 X= S

the synthesis of 134.

Standard reactions complete

(134)

64

Reaction of cyanoacetone

(135) with phenylhydrazine gives the corresponding pyrrazole (136), which is then converted to sulfazamet (137) in the usual way.

An antibacterial agent

promoted for use in ulcerative colitis is made by

114

Monocyclic Aromatic Compounds

diazotization of sulfapyridine (138) and coupling of the diazonium salt (139) with salicylic acid to give sulfasalazine (140). 6 6 H2N NCCH2COCH3

»»

(•111)

(136)

(HZ) Mafenide (142) was synthesized in part to see whether the p-amino group of the classical sulfonamides had to be attached directly to the ring for efficacy as an antibacterial agent. yes.

The answer is apparently

Reduction of p-cyanobenzenesulfonamide (141)

produces mafenide, which is not a clinically useful antibacterial agent.

(Mi) R = NH2 (M9) R . N 2 e

V

*NH2

(141) R= CN (142) R = CH2NH2

Monocyclic Aromatic Compounds

115

Coccidiosis is an economically significant respiratory disease of fowl.

During the course of

studies directed toward antimalarial agents, sulfanitran (143) was prepared and found to be a coccidiostat. It is prepared conveniently by reaction of p-acetoamidobenzenesulfonyl chloride with p-nitroaniline in acetic acid.

CH3CONH "N0 2 (143)

CH 2 NH 2

^ (145)

"

(146)

Benzenesulfonamides having two substituents on N-, usually have poor antibacterial potency. the case with azabon (146).

Such is

This central stimulant

is prepared in the usual fashion from 3-azabicyclo[2.2.2]nonane (145), which is itself prepared by pyrolysis of aliphatic diamine 144*

116

Monocyclic Aromatic Compounds

A > S°2S ° 2N " 2 (147) (148.)

C1

°* SO2NH2 (150)

Ambuside (149), a diuretic, is prepared from cyclic urea derivative 147 by allylation of the more acidic NH group with allyl bromide by means of NaH, followed by hydrolytic ring opening to give 2-allylsulfamyl-5-chloro-4-sulfamylaniline (148).

This is

in turn treated in acid with 2-ketopropionaldehyde dimethylacetal to give the Schiff base ambuside 70 (149). The enolanil form (150) of ambuside shows some similarity to the open form of some of the cyclic thiazide diuretics (151) which have been speculated to be the active form of these molecules. c.

Sulfonylureas

Linear descendants of the antimicrobial sulfonamides, the orally active sulfonylureas continue to be of interest as alternatives to insulin injections in patients with adult-onset diabetes.

Tolpyrramide

(153) is synthesized from unsymmetrical O-methylurea

Monocyclic Aromatic Compounds

117

derivative 152 and tosyl chloride, followed by mild 71 acid treatment to cleave the O-methyl group. OCH 3

CH 3 (152)

(153)

Glyparamide (155) is made by displacement of the best leaving group of unsymmetrical urea 154 with 72 sodio p-chlorobenzenesulfonamide. Gliborrmride (159) is an endo-endo derivative made from camphor-

(154)

n«;«r» (115)

N(CH3)2

3-carboxamide (156) by borohydride reduction (exo approach) (to 157), followed by a Hoffman reaction to carbamate 158, followed by displacement with sodio73 tosylamide to give gliborrmride, Glyoctamide (160) 74 is the tosylamide of cyclooctylurea. Glipizide (163) is synthesized from 5-methylpyrazine-2-carboxylic acid (161) and 4-(2-aminoethyl)benzene sulfonamide to give sulfonamide 162, which forms glipizide (163) on reaction with cyclohexylisocyanate and base in 75 acetone.

OH

C0NH7 (156)

NHCO2CH3

(157) (158)

NHCONHSO2

(159)

CH3

XX C H (161)

CH3

CH3

(165)

CH3OCH2CH2O (164)

118

Monocyclic Aromatic Compounds

119

Though glxjmidine (164) does not contain a sulfonylurea moiety, this function is probably fulfilled by the aminopyrimidine nucleus, which can be considered to be the cyclized equivalent. It is formed simply by reaction of the corresponding alkoxyaminopyrimidine with benzene sulfonyl chloride, 5.

FUNCTIONALIZED BENZENE DERIVATIVES

a.

Alkyl Analogues

Parkinson's Disease has been fairly convincingly demonstrated to be the manifestation of a deficit of brain dopamine. Administration of this biogenic amine is ineffective in alleviating the symptoms of this disease since the drug fails to cross the blood-brain barrier.

Some success has been achieved by

administering the amino acid precursor of dopamine: dihydroxyphenylalanine (DOPA).

Though this last

substance does penetrate the brain, its activity is limited by prior degradation-starting with decarboxylation in the periphery. A compound which would inhibit the enzyme which catalyzes this first step, DOPA decarboxylase, should permit more efficient utilization of DOPA.

A compound very closely related

structurally to the substrate for the enzyme fulfills this function.

Carbidopa 168 was designed for this

purpose. Carbidopa!s synthesis begins with a modified Strecker reaction using hydrazine and potassium cyanide on arylacetone 165 to give 166.

This is then

hydrolyzed with cold HC1 to give carboxamide 167.

12 0

Monocyclic Aromatic Compounds

OCH

R =CN (167) R = CONH 2

More vigorous hydrolysis with 48% HBr cleaves the amide bond and the arylether group to produce carbidopa (168)*

There is some evidence that carbidopa has

some anti-Parkinsonian activity in its own right.

If

this is confirmed, then its mode of action will be different from that for which the drug was designed and prepared. Another aminoacid-like drug is the antineoplastic agent melphalan (173).

Tumor cells spend less time

in resting phases than normal cells so at any given time, they are more likely to be metabolically active than most normal host cells.

The rationale behind

incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a greater safety margin by fooling tumor cells into taking up the toxin preferentially.

p-Nitrophenyl~

alanine (169) was converted to its phthalimide analogue by heating with phthalic anhydride, and this was converted to its ethyl ester (170).

Catalytic

reduction produced the aniline (171). Heating in acid with ethylene oxide led to 172, which was converted to the bischloride with phosphorous oxychloride, and the protecting groups were removed by heating in 78 hydrochloric acid to give melphalan (173).

Monocyclic Aromatic Compounds

121

CO2H

(169) (170) R = 0 (171) R = H 2 (172) R = CH2CH2OH

02

en*' "

C1CH 2 CH 2

X ^

NH2

(173)

Baclofen (176), a muscle relaxant and hypnotic, is synthesized from ethyl p-chlorocinnamate (174) via the Triton B catalyzed Michael addition of nitromethane (to 175) followed by Raney nickel reduction and saponification. Baclofen is formally a GABA 79 (gamma-aminobutyric acid) analogue. CH 2 NO 2

(174)

(175)

Q_76}

Reaction of p~chlorobenzylmagnesium chloride with the Mannich product from 2-butanone (177) produces the antitussive agent, clobutinol (178).

80

The tranquilizer cintriamide (179) is prepared most

122

Monocyclic Aromatic Compounds

conveniently by a simple Shotten-Baumann reaction of 81 the acid chloride. For reasons that are not very clear, the 1,2,3-trimethoxybenzene moiety is frequently associated with CNS activity. NH 2

CH3COCHCH 2 N(CH3)2

i II / ^Ss^Jt HO

^

cH-rcr J

CH3

OCH-3

Very reactive nitrogen mustards and aziridinecontaining molecules are usually too toxic for general therapeutic use, but find use in neoplastic disease. Benzodepa (182) is such an agent.

Treatment of ethyl

carbamate with phosphorous pentachloride leads to cyanate 180 which readily adds benzyl alcohol to produce carbamate 181.

ii H2NCOC2H5

Displacement of the active

8 • »»

ci2PN=C=O

(180)

„ ,i *• CI2PNHCOCH2C5H5

•*»

(ill)

(182)

chlorines with ethyleneimine leads to the very reactive benzodepa (182).

It was previously known that

carbamates and bisaziridininylphosphinyl agents had antitumor properties, so it was natural to combine both moieties in a single molecule to see if synergism would develop.

Monocyclic Aromatic Compounds

123

As noted above, guanido-containing drugs often exhibit antihypertensive activity. Interposition of an additional nitrogen atom is consistent with activity. There is some evidence to suggest that these hydrazines owe their activity to a mechanism different from the guanidines. One such derivative was originally synthesized to be a herbicide.83 Hydrazone formation

H2NNHC=NH

NHR (183)

*

J CH3

(ill) R = H (185) R = OH

between 2,6-dichlorobenzaldehyde and hydrazinyl guanidine 183 leads efficiently to guanabenz (184). The closely related analogue guanoxabenz (185) is prepared in the analogous fashion using the hydrazinyloxyguanidine derivative prepared by reacting thiomethylimine 186 with hydroxylamine and then with 2,684 dichlorobenzaldehyde. A group of arylalkylketones containing a basic substituent in the side chain shows CNS activities. Roletamide (190) is a hypnotic agent. It is prepared from 3,4,5-trimethoxybenzaldehyde (187) by addition of sodium acetylide (to give 188), followed by Jones oxidation of ethynylaryIketone 189. Michael addition 85 of pyrrolidine-3-ene leads to roletamide (190).

124

Monocyclic Aromatic Compounds

OCH 3

OCH 3

0CH3

(187)

C1£O) (188) X = H, OH (189) X = 0

Reaction of m-chlorobenzonitrile with ethyl Grignard reagent produces ethylaryIketone 191. Bromination in methylene chloride followed by displacement of the a-bromoketone moiety with t-butylamine leads to the antidepressant agent bupropion (192). While the closely related central stimulant pyrovalerone (193) can also be made simply by reacting the requisite a-haloaralkylketone with pyrrolidine, a 0 II CCH2CH3

NHC(CH3)3 CH3 ci

(19,1)

(192)

(!£!) more interesting synthesis goes through quaternary amine 194 which undergoes a Stevens rearrangement on treatment with base to provide intermediate 195, 87 which is hydrogenated to px/rovalerone*

This mecha-

nistic interpretation is supported by studies with unsymmetrical olefins wherein it is seen that the double bond migrates on conversion of 194 to 195.

Monocyclic Aromatic Compounds

125

(194)

Conversion of a ketone to a highly substituted imine interestingly leads to a compound which shows analgesic activity, anidoxime (197)*

Phenyl 2-di-

ethylaminoethyl ketone is converted to its oxime (196) in the usual way, and this is converted to anidoxime by reaction with p-methoxyphenylisocyanate. NOH

^OCNH

II

(197)

An arylamidine found subsequently to have antiarrythmic activity was actually synthesized in the hope of producing a hypoglycemic agent.

Iminochloride

198 is prepared from the corresponding benzamide and the chlorine i§ displaced with n-amylpiperidine to produce bucainide (199).

89

To posit a similarity to (CH 2 ) 5 CH 3

o

Cl NCH 2 CH(CH 3 ) 2 (198)

(199)

Monocyclic Aromatic Compounds

126

the well-established antiarrythmic benzamide procainamide and its congeners is perhaps not too fanciful. While some arylaliphatic acids are established as antiinflammatory agents, it is interesting to note that some arylketones share this activity.

Fenbufen

(200) is prepared simply by a Friedel-Crafts acylation 90 of biphenyl with succinic anhydride. The same reaction using cyclohexylbenzene leads to 201. 0

II

CCH2CH2CO2H CCH 2 CH 2 CO2H

(201) R = H (200)

(20 2) R = Cl

Chlorination enhances activity and is accomplished by treatment of 201 with chlorine in methylene chloride catalyzed by aluminum chloride.

The nonsteroidal

anti inflammatory agent Jbucloxic acid (202) results. b.

91

Miscellaneous Derivatives

Reaction of 2,6-ditertiarybutyl-4-thiolphenol with acetone leads to the dithioketal probucol (203) which 92 has hypolipidemic activity. C(CH3)3

C(CH3)2

(CH 3 ) 3 C (203)

Monocyclic Aromatic Compounds

127

Some tumors are estrogen-dependent and the use of an antiestrogen has therapeutic value. One such antineoplastic agent appears to be patterned after clomiphene. Complex aryl ketone 204 is treated with phenyl magnesium chloride and the resulting tertiary

pCH 2 CH 2 N(CH 3 )2

CH 2 CH 2 N(CH 3 )2

C'H

"°

CH3

(204) (205)

carbinol is dehydrated. The resulting isomers are separated to give tamoxifen (205). Structural assignment amongst the isomers is performed by pmr measurements.93

REFERENCES 1.

2.

3. 4.

W. Ruyle, L. H. Sarett and A. Matzuk, French Patent 1,522,570 (1968); Chem. Abstr., 71: P30241U (1969). W. Ruyle, L. H. Sarett and A. Matzuk, South African Patent 67 01,021 (1968); Chem. Abstr., 70: P106,209k (1969). P. W. Feet, J. Ned. Chem., 14, 432 (1971). G. F. Holland, German Patent 2,145,686 (1972); Chem. Abstr., 77: P48046m (1972).

128 5.

Monocyclic Aromatic Compounds

P. F. Juby, T. W. Huidyma and M. Brown, J. Med. Chem., 11, 111 (1968). 6. G. B. Fregnan, A. Subissi and A. L. Torsello, II Farmaco, Ed. Sci., 30, 353 (1975); A. Salimbeni, E. Manghisi and M. J. Magistretti, II Farmaco, Ed. Sci., 30, 276 (1975). 7. S. A. Friere, U. S. Patent 2,604,488 (1952): Chem. Abstr., 48; 12,807d (1954). 8. C. Cavallito and J. S. Buck, J. Am. Chem. Soc., 65, 2140 (1943). 9. R. Y. Mauvernay, N. Busch, J. Simond and J. Moleyre, U. S. Patent 3,781,432 (1970); Chem. Abstr., 74: 141,861w (1971). 10. J. Buchit, K. H. Hetterich and X. Pereira, Arzneimittel forschung, 18, 1 (1968). 11. O. Kraupp and K. Schloegl, Austrian Patent 231,432 (1964); Chem. Abstr., 60; 15786g (1964). 12. Anonymous, Netherlands Patent 6,510,006 (1966); Chem. Abstr., 65; 3793b (1966). 13. E. Jucker and A. Lindenmann, Helv. Chem. Acta, 45, 2316 (1962). 14. M. L. Hoefle, German Patent 1,158,927 (1963); Chem. Abstr., 60; 10,608a (1964). 15. Anonymous, Netherlands Patent 6,607,680 (1966); Chem. Abstr., 67: 21,706h (1967). 16. H. A. DeWald and M. L. Hoefle, U. S. Patent 3,043,874 (1962); Chem. Abstr., 57: 16,503h (1962). 17. G. R. Pettit, M. F. Baumann and K. H. Rangammal, J. Med. Chem., 5, 800 (1962).

Monocyclic Aromatic Compounds 18. 19. 20. 21.

22. 23. 24.

25. 26.

27.

28. 29. 30.

129

M. E. Kuehne and B. F. Lambert, J. Am. Chem. Soc, 81, 4278 (1959). K. Kratzl and E. Krasnicka, Monatsh. Chemie, 83, 18 (1952). Anonymous, Netherlands Patent 6,500,326 (1965); Chem. Abstr. , 64: 3#486h (1966). B. Duhm, W. Maul, H. Medenwald, K. Patzschke and L. A. Wagner, Z. Naturwissenschaften, 16b, 509 (1961). Anonymous, Netherlands Patent 6,604,303 (1966); Chem. Abstr., 66: 55,247d (1967). W. H. Meek, German Patent 2,347,615 (1975); Chem. Abstr., 83: 58,480m (1975). D. B. Cosulich, D. R. Seeger, M. J. Fahrenbach, K. H. Collins, B. Roth, M. E. Hultquist and J. M. Smith, Jr., J. Am. Chem. Soc, 75, 4675 (1953). A. Garzia, German Patent 2,034,192 (1971); Chem. Abstr., 75: 5513c (1971). H. J. F. Adams, G. H. Kronberg and B. H. Takman, German Patent 2,162,744 (1972); Chem. Abstr., 77: 101,244c (1972). B. F. Tullar, Acta Chem. 8cand. , 11, 1183 (1957); J. Med. Chem., 14, 891 (1971); Acta Pharm. Sueica, 8, 361 (1971). K. Bowden and P. N. Green, J. Chem. Soc, 1795 (1954). J. Keck, Ann., 662, 171 (1963). J. Krapcho, B. Rubin, A. M. Drungis, E. R. Spitzmiller, C. F. Turk, J. Williams, B. N. Craver and J. Fried, J. Med. Chem. , 6, 219

130

31. 32. 33.

34.

35. 36. 37. 38.

39.

40. 41. 42.

Monocyclic Aromatic Compounds (1963). A. Laurent and J. Vilmer, Ann. Pharm. Fr. , 29, 569 (1971). Anon., Netherlands Patent 6,405,529 (1964); Chem. Abstr. , 62: 10,368g (1965). J. K. Harrington and J. E. Robertson, German Patent 1,917,821 (1969); Chem. Abstr., 73: 14,477e (1970). J. K. Harrington, J. E. Robertson, D. C. Kvain, R. R. Hamilton, K. T. McGurran, R. J. Trancik, K. F. Swingle, G. G. I. Moore and J. F. Gerster, J. Med. Chem., 13, 137 (1970). Anon., Netherlands Patent 6,516,582 (1966); Chem. Abstr., 65: 16,901f (1966). F. C. Copp, British Patent 864,885 (1961); Chem. Abstr., 55: 24,792a (1961). Anon., British Patent 914,008 (1962); Chem. Abstr., 58: 12,523a (1963). D. I. Barron, P. M. G. Bavin, G. J. Durant, I. L. Natoff, R. G. W. Spickett and D. K. Vallance, J. Med. Chem., 6, 705 (1963). G. J. Durant, G. M. Smith, R. G. W. Spickett and S. H. B. Wright, J. Med. Chem., 9, 22 (1966); Anon., Belgian Patent 629,613 (1963); Chem. Abstr., 60: 14,437d (1964). Anon., Netherlands Patent 6,610,738 (1968); Chem. Abstr., 68: 39,487t (1968). W. A. Bulhofer, South African Patent 67 05,870 (1967); Chem. Abstr., 71: 101,563g (1969). A. Burger, D. G. Markees, W. R. Nes and W. L. Yost, J. Am. Chem. Soc., 71, 3307 (1949).

Monocyclic Aromatic Compounds 43.

131

G. Thuillier, P. Rumpf and B. Saville, Bull. Soc. Chim. Fr. , 1786 (1960). 44. J. J. Godfroid and J. E. Thuillier, German Patent 2,048,372 (1971); Chem. Abstr., 75: 93,435s (1971). 45. R. P. Ahlquist, Am. J. Physiol. , 153, 586 (1948). 46. A. M. Lands, A. Arnold, J. P. McAuliff, F. P. Luduena and T. G. Brown, Jr., Nature, 214, 597 (1967). 46a. G. Leclerc, A. Mann, C. Wermuth, N. Bieth and J. Schwartz, J. Med. Chem., 20, 1657 (1977). 47. J. C. Danilewicz and J. E. G. Kemp, J. Med. Chem. , 16, 168 (1973). 48. M. Dukes and L. H. Smith, J. Med. Chem., 14, 326 (1971). 49. Anon., Belgian Patent 669,402 (1966); Chem. Abstr., 65: 5402d (1966). 50. A. E. Brandstrom, P. A. E. Carlsson, S. A. I. Carlsson, H. R. Corrodi, L. Ek and B. A. H. Ablad, German Patent 2,106,209 (1971); Chem. Abstr., 76: 10,427c (1972). 51. K. R. H. Wooldridge and B. Berkeley, South African Patent 68 08,345 (1969); Chem. Abstr., 72: 78724V (1970). 52. A. M. Barrett, R. Hull, D. J. LeCount, C. J. Squire and J. Carter, German Patent 2,007,751 (1970); Chem. Abstr., 73: 120,318p (1970). 53. G. Crocl, Arzneimittelforsch., 20, 1074 (1970). 54. H. Koeppe, K. Zeile and A. Engelhardt, South African Patent 68 03,783 (1968); Chem. Abstr., 71: 21,878y (1969).

132

55. 56. 57.

58.

59.

60. 61. 62. 63. 64. 65.

66. 67. 68. 69.

Monocyclic Aromatic Compounds

Anon., Netherlands Patent 6,606,441 (1966); Chem. Abstr. , 67: 21,808t (1967). E. J. Merrill, J. Pharm. Sci., 60, 1589 (1971). F. P. Hauck, C. M. Cimarusti and V. L. Narayanan, German Patent 2,258,995 (1973); Chem. Abstr., 79: 53,096y (1973). H. Ruschig, K. Schmitt, H. Lessenich and G. Haertfelder, South African Patent 68 07,915 (1969); Chem. Abstr., 72: 90,054j (1970). J. A. Edwards, B. Berkoz, G. S. Lewis, 0. Helpern, J. H. Fried, A. M. Strosberg, L. ML Miller, S. Urich, F. Liu and A. P. Roszkowski, J. Ned. Chem. , 17, 200 (1974). J. Augstein, D. A. Cox, A. L. Ham, P. R. Leeming and M. Snarey, J. Med. Chem., 16, 1245 (1973). E. L. Jackson, J. Am. Chem. Soc. , 70, 680 (1948). E. F. Elslager, Z. B. Gavrilis, A. A. Phillips and D. F. Worth, J. Med. Chem., 12, 357 (1969), C. Siebenmann and R. J. Schnitzer, J. Am. Chem. Soc., 65, 2126 (1943). L. Doub, U. Krolls, J. M. Vandenbelt and M. W. Fisher, J. Med. Chem., 13, 242 (1970). G. B. Crippa and M. Guarnari, Gazz. Chim. Ital. , 85, 199 (1955): J. Seydel and E. Kruger-Thiemer, Arzneimittelforsch. , 14, 1294 (1964). A. Korkuczanski, Prezemsx/1 Chem., 37, 162 (1958). E. Muller, J. M. Sprague, L. W. Kissinger and L. F. McBurney, J. Am. Chem. Soc, 62, 2099 (1940). R. G. Shepherd, J. Org. Chem., 12, 275 (1947). A. W. Pircio and C. S. Krementz, U. S. Patent

Monocyclic Aromatic Compounds

70. 71. 72.

73.

74. 75.

76.

77. 78.

79.

80.

133

3,351,528 (1967); Chem. Abstr. , 68: P38,496v (1968). J. E. Robertson, D. A. Dusterhoft and T. F. Mitchell, Jr., J". Med. Chem., 8, 90 (1965). E. Walton, British Patent 872,102 (1961); Chem. Abstr., 57: P785g (1962). G. F. Holland and W. M. McLamore, U. S. Patent 3,033,902 (1962); Chem. Abstr., 57: Pll,109f (1962). K. Hohenlohe-Oehringen, Monatsh. Chem., 101, 610 (1970); H. Breitschnider, K. Hohenlohe-Oehringen and K. Grassmeyr, ibid., 100, 2133 (1969). Anon., French Patent 1,558,886 (1969); Chem. Abstr., 72: P43,231e (1970). V. B. Ambrogi and W. Logemann, German Patent 2,012,138 (1970); Chem. Abstr., 73: 120,674b (1970). K. Gutsche, A. Harwart, H. Horstmann, H. Priewe, G. Raspe, E. Schraufstatter, S. Wirtz and U. Worfel, Arzneimittelforsch., 14, 373 (1964). M. Sletzinger, J. M. Chemerda and F. W. Bollinger, J. Med. Chem., 6, 101 (1963). F. Bergel, V. C. E. Burnop and J. A. Stock, J. Chem. Soc. , 1223 (1955); F. A. Bergel and J. A. Stock, ibid., 2409 (1954). F. Uchimaru, M. Sato, E. Kosasayama, M. Shimizu and H. Takashi, Japanese Patent 70 16,692 (1970); Chem. Abstr., 73: 77,617w (1970). Anon., British Patent 898,010 (1962); Chem. Abstr., 57: 12381i (1962).

134 81. 82. 83. 84.

85.

86. 87. 88.

89.

90.

91.

92.

93.

Monocyclic Aromatic Compounds R. B. Moffett, J. Ned. Chem. , 7, 319 (1964). Z. B. Papanastassiou and T. J. Bardos, J. Ned. Chem. , 5, 1000 (1962). J. Yates and E. Haddock, British Patent 1,019,120 (1964); Chem. Abstr. , 64: PC11132h (1966). W. J. Houlihan and R. E. Manning, German Patent 1,902,449 (1969); Chem. Abstr. , 71: P123963q (1969). S. Safir and R. P. Williams, Belgian Patent 670,495 (1966); Chem. Abstr., 65: PC13615C (1966). D. A. Yeowell, German Patent 2,064,934 (1971); Chem. Abstr., 76: P33965r (1972). W. Heffe, Helv. Chim. Acta, 47, 1289 (1964). M. J. Karten and M. L. Kantor, German Patent 1,805,716 (1969); Chem. Abstr., 71: 980916g (1969). J. R. Shroff and V, Bandurco, U. S. Patent 3,793,322 (1974); Chem* Abstr., 80: P96018n (1974). A. S. Tomcufcic, R. G. Child and A. E. Sloboda, German Patent 2,147,111 (1972); Chem. Abstr., 76: P158368e (1972). F. Krausz, H. Demarne, J. Vaillant, M. Brunaud and J. Navarro, Arzneimittelforsch. , 24, 1360 (1974). M. B. Neuworth, R. J. Laufer, J. W. Barnhart, J. A. Sefranka and D. D. Mclntosh, J. Med. Chem., 13, 722 (1970). D. J. Collins, J. J. Hobbs and C. W. Emmens, J. Ned. Chem., 14, 952 (1971).

6

Steroids Early interest in steroid chemistry centered about cholesterol, the bile acids, and the cardiotonic glycosides, but a dramatic expansion took place in the 1930s with the discovery of steroidal sex hormones and the adrenal cortical hormones.

As each

of the major steroid structures was elucidated, efforts were bent toward developing synthetic methods for their preparation. The impetus for this work was variously to provide amounts of compound sufficient for more detailed pharmacology and clinical application, to prepare orally active analogues, to prepare substances of intrinsic non-hormonal pharmacological activity, and, in some cases, to provide compounds that would antagonize the action of endogenous hormones. The large number of entries outlined in this chapter might mislead the casual reader into assuming that these represent a correspondingly large number 135

136

Steroids

of drugs in actual clinical use. This is in fact not so:

the majority of commercial steroid drugs are to

be found in the first volume of this work.

The

medicinal chemistry and pharmacology of synthetic steroids was a field of intensive concentration for the better part of two decades; numerous compounds were thus produced which showed enough clinical promise to be assigned a generic name, but for one reason or another, most failed to find a place on the drugstore shelf.

The fact that so many of these

compounds do have generic names indicates that they have interesting activity in various animal assays, and have shown sufficient clinical promise to merit inclusion in this work. The numbering system and normal stereochemistry of the steroids of interest to this chapter are as follows:

This stereochemical pattern is taken for granted in the following structures with only departures being detailed. 1.

ESTRANES

The prototype for the estrane series is the female sex hormone estradiol

(1).

Estrogens have important

Steroids

137

applications as replacement therapy for hormonedeficient states found in menopausal and postmenopausal women for the treatment of menstrual irregularities, failure of ovarian development, and in treatment of prostatic carcinoma, etc-

These

compounds also constitute an essential ingredient for the oral contraceptives.

It is important to recall

that when the synthetic work was done, the Pill was as yet untainted by any shadow and was regarded as an unmitigated boon.

There seemed, in fact, to be good

reasons for developing new estrogens of greater potency and specificity.

It is only fairly recently

that there have been serious questions raised about the safety of long-term treatment with exogenous estrogenic compounds, resulting in a lessening commercial interest in these agents.

.8

Q -OH

H0

RO'

(I) (

-^

(3) R = H (£) R = COCH3

Reaction of estrone (2) with an excess of the lithium reagent from 3-iodofuran gives intermediate diol 3.

!rhe stereochemical assignment follows from

the well-known propensity of steroids for attack from the less-hindered backside (of) of the molecule. Acylation of 3 with acetic anhydride then affords the estrogen estrofurate (4)*

Steroids

138

One of the routes for metabolism of the natural estrogens involves oxidation at the 16-position.

The

resulting compounds (estriols) show paradoxical endocrine activities in animal models.

Thus, although

these metabolites show estrogenic activity in their own right, they can to some extent block the action of concurrently administered estradiol.

The unnatural

estriol analogue epimestrol (8) shows this kind of activity. One of the routes to epimestrol begins with acylation of estradiol with benzoyl chloride to give the dibenzoate 5* Pyrolysis of the ester leads to formation of the 16,17-olefin. Hydroxylation by means of osmium tetroxide affords the cis-diol 7 due to the intermediacy of the cyclic osmate ester (6a); attack of the reagents from the a side insures formation of 2 the 16,17a-diol. Saponification is followed by alkylation of the phenolic hydroxyl group with dimethyl sulfate in the presence of base to afford

3 epimestrol (8).

.O2CC6H5 U) C6H5CO2

C6H5CO2 (6)

(5) .OH

'OH RO

(6a)

( 8J

R = CH 3

Steroids

139

Replacement of a ring carbon by a heteroatom, such as nitrogen, has proven a fruitful modification in many classes of medicinal agents.

The resulting

analogues often possess the same qualitative activity as the parent compound.

Although this strategy has

been applied extensively to the steroids, it has not met with overwhelming success.

Two cases of substi-

tution by N in which interesting activity was obtained both contain the heteroatom at the 8-position.

Such

derivatives are most conveniently prepared by total synthesis.

For example, condensation of the substi-

tuted phenethylamine 9 with 2-cyclopentanonepropionic acid (10) affords directly the bicyclic lactam 12, as a mixture of isomeric eneamides.

Though the precise

order of the steps is not clear, the reaction can be rationalized as proceeding via enamine 11; enamide formation will then give the observed products. Catalytic reduction affords the lactam with the expected cis ring junction (13)* Cyclization by means of phosphorus oxychloride then gives the tetracyclic quaternary salt (14).

Treatment with hydrobromic

acid serves both to cleave the methyl ether and to replace the counterion by bromide. obtained quinodinium bromide (15).

There is thus This compound

interestingly exhibits antiarrhythmic rather than hormonal activity, possibly in part because of lack of D-ring functionality required for estrogen receptor activation.

140

Steroids

:fco

NH2

(9)

(10) (11)

(U)

(13)

Br© CH3O

(14)

(15)

The scheme used to prepare the direct 8-azaanalogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence.

Acylation of the phenethylamine 9 with

acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17* Reaction of the heterocycle with 2-methylcyclopentane1,3-dione in the presence of pyridine leads directly to tetracyclic intermediate 20.

The first step in

this transformation probably consists in formation of the olefin 18 by elimination of dimethylamine. Michael addition of the anion from the cyclopentane-

Steroids

141

dione gives a transient intermediate such as 19. Reaction of the enamine nitrogen with one of the carbonyl groups leads to the corresponding cyclized dieneamine 20. Catalytic reduction leads to stereoselective introduction of hydrogen at both C-9 and

NCCH 3 ) 2 (9)

CH 2 =CHCOC1 CH3O

CH3O' (16)

"x5° CH3O

(19)

(18.)

CH7O (20)

CH3O (22)

142

Steroids

C-14 from the a face.

It should be noted that except

for the methyl group at C-13, 20 is quite flat; it is not unreasonable to assume that adsorption to the catalyst will take place at the face opposite that substituent, thus leading to the observed stereochemistry.

The product is, of course, racemic.

Reaction of 20 with lithium acetylide completes the synthesis of estrazinol (22).

It is of note that,

in contrast to 15, this compound shows activity as an estrogen. Reduction of the aromatic A ring of the estratrienes and appropriate substitution at the 1 7 — position leads to compounds that show either androgenic or progestational activity. These 19-nor steroids tend to have much better oral activity than their 19-methylated counterparts.

Orally active

androgens have found some use both in replacement therapy for androgen deficiency and as agents which will reverse protein loss in various pathological wasting diseases (as anabolic agents). Some controversial use is also found in increasing the body mass of professional athletes.

By far the largest clinical

application for the orally active progestins is as a component part of oral contraceptives. 7 Reduction of 19-nortestosterone (23) with sodium borohydride leads to a mixture of isomers consisting largely of the 3p-alcohol (24); the lack of stereospecificity can be traced back to the relative remoteness of that 3-position from chiral centers which could direct the incoming reagent.

Acylation

of diol 24 with acetic anhydride in the presence of

Steroids

143

sodium acetate affords the anabolic agent bolandiol diacetate (25).8

(23)

(16) A fairly common strategy for converting a drug to an agent which is excreted more slowly and may be longer acting pharmacologically consists of the preparation of a very lipophilic derivative.

This is

then administered by subcutaneous or intramuscular injection in an oil solution.

The drug or its hydro-

lysis product then slowly leaches out of that oily depot to provide long-lasting levels in the blood. Reaction of 19-nortestosterone with adamantoyl chloride affords the longacting anabolic agent bolmantalate 9 (26)* There is some evidence to suggest that this ester is not a prodrug, but has hormonal activity in its own right. The presence of a 7a-methyl group has been found to potentiate anabolic activity.

Acetylation of 19-

nortestosterone affords the corresponding 17-acetate

Steroids

144 (27).

Treatment of this compound with chloranil

results in dehydrogenation at C-6,7 and thus formation of the 4,6~diene-3~one moiety.

Reaction of 28 with

methyl Grignard reagent in the presence of cuprous bromide leads to conjugate (1,6) addition from the bottom face of the molecule with concomitant loss of the ester function from C-17 to give the 7a-methyl derivative (29).

Oxidation of the alcohol at C-17

then affords diketone 30.

Condensation of that

product with pyrrolidine leads, because of the highly hindered nature of the ketone at C-17, to selective formation of the 3-enamine (31).

Addition of methylmagnesium

bromide followed by hydrolysis of the enamine function gives mibolerone (32).

This last has, interestingly,

recently been introduced as a canine oral contraceptive .

OCOCH7

OCOCH3 (23)

(28)

(27)

.. s^\—^

(31) (30) R= 0

Steroids

145

The formal replacement of the methyl group at C17 by ethynyl leads, in the 19-nor series, from compounds which show androgenic activity to agents active as progestins.

The prototype for this series, and in

fact the compound used most widely in oral contraceptives, is norethindrone

(33). It is of note that

the analogue missing the ketone at C-3 retains this activity.

Condensation of ethane dithiol with 19-

nor-testosterone affords the corresponding thioketal (34). Desulfurization with sodium in liquid ammonia affords 35. Oxidation affords the 17-ketone; reaction with lithium acetylide gives the progestin cingestol (37). 11 A similar scheme on the isomeric deconjugated ketone 38 (obtained by hydrolyzing the enol ether product from the Birch reduction of estradiol methyl 12 ether under mild conditions) gives tigestol (39).

BCH

(37)

^L_/

1

OH

t^A—i

XJCr - oy^"" (38)

(39)

Steroids

146

An unusual variation on this theme involves a compound containing both extended conjugation involving the bond connecting rings AC and a haloacetylene moiety.

Reaction of ketone 40_

with the anion

obtained by treatment of cis 1,2-dichloroethylene with methyl lithium affords chloroacetylene 41.

This

reagent can be generated either by formation of the organometallic agent by abstraction of a proton followed by loss of hydrogen chloride from the adduct or, more likely, by elimination of HC1 from the ethylene followed by formation of the lithium reagent from the resulting acetylene.

Hydrolysis of the enol

ether under mild conditions (acetic acid) affords the unconjugated ketone 42.

Treatment of that compound

in pyridine with bromine leads to the potent oral 14 progestin ethx/nerone (44). This last reaction can be rationalized by assuming that the first step consists of addition of bromine to the double bond at C-5,10 (43); double dehydrohalogenation will give the observed product.

It is interesting to observe that

44 does not enolize to give an aromatic A ring. OH .•CSiCCJ

CH3O"

CH3O (40)

(44)

(42)

Steroids

147

The potentiation observed in the 19-nor androgens by inclusion of a C-7 methyl group is observed even in the presence of the 17-ethynyl function.

Dehydro-

genation of testosterone propionate (45) by means of chloranil gives the corresponding 4,6-diene (46). Conjugate addition of methyl magnesium bromide leads to the 7a-methyl derivative 47 along with the 7pepimer. Treatment of the major product with DDQ leads in this case to the cross-conjugated 1,4-diene.

It

is likely that the direction of this second dehydrogenation is mandated by the presence of the methyl group at C-7; this group may hinder the approach of reagent to the center which would lead to the alternate diene.

The intermediate is then saponified and

alcohol at C-17 oxidized (48).

Elimination of the

angular methyl group at C-19 with consequent aromatization is achieved by treatment of the diene with lithium in the presence of diphenyl; obtained 7 a-methyl estrone (49).

there is thus Methylation of

the phenolic hydroxyl group followed by reduction of the 17-ketone gives 50.

Birch reduction affords the

corresponding 2,5(10)-diene (51).

The hydroxyl at 17

is then oxidized by means of cyclohexanone and aluminum isopropoxide (Oppenauer oxidation) to give back the 17-ketone (52).

Addition of lithium acetylide

proceeds to give the 17a-ethynyl derivative (53). Hydrolysis of the enol ether under mild conditions leads to the unconjugated ketone.

There is thus 17 obtained the anabolic agent tibolone (54).

OCOC 2 H 5 OCOC 2 H 5

C46) OCOC 2 H 5

(50)

CH 3 O

^^

^"^

CH3O'

'CH3

OH (53)

(54)

148

Steroids

149

Inclusion of a methyl group at the difficultly accessible 11-position also proves compatible with oral progestational activity in the 19-nor series. Preparation of an agent incorporating this feature starts with the 1,4-diene (55), corresponding to 18 adrenosterone. Due to the sterically hindered nature of the carbonyl at C-ll and the low reactivity of that at C-3, ketalization proceeds selectively at C-17 (56); reduction of the 11-keto group by means of lithium tri-t-butoxyaluminum hydride gives intermediate 57*

Aromatization by means of the lithium radical 19 a m on from diphenyl gives intermediate 58 *

Methylation of the phenol (59) followed by oxidation of the alcoholic hydroxyl at C-ll affords 60* Addition of methyl Grignard reagent to that carbonyl group serves to introduce the 11-methyl group (61)*

It is

of note that the corresponding reaction in the 19methylated (androstrane) series proceeds with extreme reluctance.

Deketalization gives the corresponding

17-ketone and acid catalyzed dehydration, followed by catalytic reduction of the olefin (62), gives the intermediate containing the lip-methyl group (63). That molecule is then subjected to the standard carbonyl reduction, Birch reaction, oxidation, ethynylation and, finally, hydrolysis sequence (see 50 to 53).

Hydrolysis of the enol ether under more

strenuous conditions than was employed with 53 gives the conjugated ketone 65*

The carbonyl group is then

reduced to afford the corresponding 3p-alcohol (66)* Exhaustive acetylation affords the potent oral progestin methxjnodiol diacetate (67)*

HCL

(55)

C56)

R= 0

HO

CH

(58)

6

cii3(r

CH 3 O

(59)

61)

(60)

,OH R =^ R = o"

OH CH

CwCH

Cll

CSCH

CH3O' CH3O (613)

(6_4)

OCOCH3 CH

CH3CO2"

(67)

1 5 0

CSCH

•C 3BCH

(66)

151

Steroids

Elaboration of a commercially viable route for total synthesis of 19-nor steroids led to the introduction of the totally synthetic product norgestrel (71) as the progestational component of an oral contraceptive.

As was observed in the "natural" 19-

nor- compounds, reduction of the 17-ethynyl group to 17ethyl affords compounds with androgenic/anabolic activity. Oppenauer oxidation of the total synthesis 22 intermediate 68 leads to the corresponding ketone. Reaction with ethylmagnesium bromide gives the expected condensation product.

It is of note that

reaction is much slower than in the 13-methyl series. Hydrolysis with strong acid affords norbolethone 21 (70). The same compound can be obtained by selective reduction of the ethynyl moiety of norgestrel (71).

.• CH 2 CH 3

CH3O' (70)

(69)

(68)

OCOCH,

HON

dg"-^-x& (72)

(11)

152

Steroids

In much the same vein, acetylation of optically active d-norgestrel by means of acetic anhydride and tosic acid gives the 17-acetate (72).

Reaction with

hydroxylamine hydrochloride in pyridine affords the orally active progestin dexnorgestrel acetime (73).

23

The prevalence of 17-ethynyl carbinols among the orally active 19-nor progestins can lead to the impression that this is a necessary group for activity. The good potency shown by a compound that possesses the 17-hydroxy 17-acetyl moiety more characteristic of the 19-methyl progestins indicates that the structureactivity relationship is not quite that narrow. One such compound, gestonorone caproate (85) is prepared by oxidation of 16-hydropregnenolone (74) the conjugated ketone 75.

to afford

This is then converted to

the aromatic A-ring phenol 77 by the standard dehydrogenation-aromatization scheme (see 47 to 49). Epoxidation of the double bond at O 1 6 by alkaline peroxide gives the 16a,17a-oxide 78.

Methylation of

the phenol affords the corresponding ether (79). Trans-diaxial opening of the oxide bxj means of hydrogen bromide gives the bromohydrin 80; halogen is then removed reductively by means of zinc in acetic acid (81).

The carbonyl group at C-20 is next protected

against the reductive conditions of the subsequent step by conversion to its ethylene ketal (82). Birch reduction leads in the usual way to the enol ether (83). Treatment with strong acid serves to remove both the 20-ketal and the enol ether at C-3, leading to conjugated ketone 84. Treatment of this last intermediate with caproic anhydride and tosic acid affords

Steroids

153

gestonorone caproate (85).25

The caproate function

not only contributes lipophilicity but, presumably, Newman-type hinderence to saponification.

(76) (75)

(77)

(84) R = H CH3O (8^) R= C(CH 2 ) 4 CH 3

2.

ANDROSTANES

Additional unsaturation at C-1,2 is well known to potentiate the action of both androgens and corticoids, The former tend, however, to show poor oral activity in the absence of an alkyl group at the 17-position. Thus, they tend to be used mainly as injectable agents.

As mentioned above, esterification with a

fatty chain leads to agents with long duration of action. Thus, esterification of 86

with the acid

chloride from undec-10-enoic acid gives the injectable anabolic agent boldenone 10-undecylenate (87). 27

An

154

Steroids

enol ether, interestingly, can serve a similar pharmacological purpose.

Thus, acetal interchange of

86 with the diethyl acetal from cyclopentanone gives 88; pyrolysis leads to elimination of ethanol and 28 formation of quinbolone (89)* OCO(CH2)8CH=CH2

(82.)

>o

|

C2H5O

(86.) (88)

Neoplasms involving gonadal tissues are often dependent on sex hormones for growth.

Depriving the

cancerous growth of hormonal stimulation frequently slows its development. The past few years have seen considerable application of hormone antagonists as antineoplastic agents for treatment of such hormonedependent cancers.

Bolasterone (91) is known to be a

potent anabolic/androgenic agent; its 7p-isomer, calusterone, has found some use in the treatment of cancer. As originally prepared, conjugate addition of methylmagnesium bromide to diene 90 affords a mixture of 91 and 92 with the former predominating. Calusterone (92) was separated by chromatography and 29 fractional crystallization.

Steroids

155

OH

UH

OH •CH3

"CH 3

(ii) Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent.

Mannich condensation of the fully saturated

androstane derivative 93 with formaldehyde and dimethyl amine gives aminoketone 94.

A/B-trans steroids

normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95.

It is not at all unlikely

that the reaction proceeds via the 2-methylene intermediate.

The observed stereochemistry is no doubt

attributable to the fact that the product represents the more stable equatorial isomer.

The initial

product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96).

Dehydrohalogenation

by means of lithium carbonate in DMF affords stenJbolone 30 acetate (97). This product is readily separable from a number of by-products by the fact that it forms a water-soluble bisulfite adduct.

156

Steroids

OCOCH-r

OCOCH3 CH3.

A

H C9S)

<M)

OCOCH3

OCOCH3 Br

(96)

Contraction of the B-ring of the orally active androgen 17-methyltestosterone, interestingly, leads to a compound with antiandrogenic activity.

The

general method for preparation of such ring contracted analogues was first developed using cholesterol acetate (98) as a model.

Oxidation by means of

chromium trioxide affords keto acid £9 as the principal product; this is then converted to the enol lactone 100 by means of acetic anhydride.

Pyrolysis of that

enol lactone at 200°C gives the ring contracted 31 condensation product 101. The analogous 17-ketone 102 is used as starting material for the antiandrogen. Reaction with an excess of methylmagnesium bromide affords the 17~methylcarbinol 103; Oppenauer oxidation 32 affords benorterone (104).

Steroids

CH3CO2

CH3CO2

157

(21)

(100)

CH3CO2'

CH3CO2

(101)

..CH,

(104)

Fusion of a heterocyclic ring onto the A-ring of ethynyltestosterone leads to a compound with hormone antagonistic activity.

Such agents find some use in

those cases where either the given hormone is present in excessive amounts by malfunction of the particular endocrine gland or where it is desirable to suppress hormonal stimulation of some end organ.

Condensation

of 17-ethynyl testosterone (105) with ethyl formate in the presence of sodium methoxide gives the corresponding 2-hydroxymethylene derivative (106).

Reaction

of that intermediate with hydroxylamine leads to the 33 pituitary suppressant agent danazol (107).

Steroids

158

OH

OH •CSECH

. ..CSSCH

HO'

(105) (106J

(107)

A somewhat related sequence leads to trilostane (111), a compound that inhibits the adrenal gland; more specifically the agent blocks some of the metabolic responses elicited by the adrenal hormone ACTH in experimental animals.

Reaction of the hydroxy-

methylene derivative 108, obtained from testosterone, with hydroxylamine gives the corresponding isoxazole (109).

Oxidation of the C~4,5 double bond by means

OH OH HO'

(108)

(HE)

NC.

(111)

*-o"

1110)

Steroids

159

of mCPBA proceeds from the less hindered side to give the of-epoxide. Treatment of the intermediate 110 with sodium methoxide leads to scission of the heterocycle and formation of the corresponding cyanoketone 111. It is of interest that the epoxide is apparently inert to these conditions; the nitrile is of course readily epimerized, and thus assumes the more stable of (equatorial) conformation. There is thus obtained 34 trilostane. The ring opening can be rationalized by assuming first formation of the anion 112; electrocyclic rearrangement as shown gives the enolate anion of 111. Fusion of a heterocyclic ring onto the A-ring of a molecule which shows mainly progestational activity leads to an antiinflammatory agent; this finding does not seem to have been followed up to any extent. Condensation of 17-ethynyl testosterone (113) with ethyl formate in the presence of base gives the corresponding 2-hydroxymethyl derivative (114). Reaction of that with p-fluorophenylhydrazine affords 35 the antiinflammatory pyrazolone nivazol (115).

(113)

(114)

Steroids

160

The antineoplastic agent testolactone (121) appears to be obtained commercially by microbiological transformation of either testosterone or progesterone* The compound can be obtained synthetically, albeit in low yield, starting from dehydroepiandrosterone (116a)*

Addition of bromine serves to protect the

double bond as the dibromide (117)* Oxidation with peracetic acid gives the Baeyer-Villiger product 118* The unsaturation at 5,6 is then restored by treatment of the dibromide with sodium iodide (119),

This is

oxidized to the conjugated ketone 120 under Oppenauer conditions,

(A real source of confusion exists in

the fact that 120 bears the trivial chemical name testolactone while the same generic name is used to denote 121* )

Previous work, particularly on cortical

steroids, had shown that inclusion of additional unsaturation in the A ring at 1,2 leads to a significant increase in potency.

Selenium dioxide is a

fairly specific reagent for achieving this transformation, and such treatment of 120 affords testolactone (121). 3 6

(116a) R = H (116b) R • CH3CO

(121)

(117)

(120)

(119)

Steroids

161

It has been known for many years that elevated levels of serum cholesterol are associated with atherosclerosis, although the cause-effect relationship remains unproven.

A rather straightforward thera-

peutic regimen intended for prevention or arrest of the progress of this disease involves lowering levels of serum cholesterol in the high-risk population. Since a good part of the physiological cholesterol load is provided by endogenous synthesis, agents that inhibit this process should lower cholesterol levels in the serum as an adjunct to dietary precautions, although a compensatory increase in endogenous synthesis can combat this artifice.

One approach to

this therapeutic goal consists in providing false substrates for enzyme systems involved in cholesterol biosynthesis. Substitution of heteroatoms for carbon has served to provide such enzyme antagonists in other fields.

The strategy in the case at hand calls

for a cholesterol analogue containing nitrogen in the side chain.

Shiff base formation between dehydroepi-

androsterone acetate (116b) and 3-dimethylaminopropylamine affords imine 122.

Reduction (lithium aluminum

hydride) proceeds to give predominantly the p-amine (123).

Further' methylation by means of formic acid

and formaldehyde (Eschweiler-Clark reaction) leads to 37 azacosterol (124). Though the compound does lower serum cholesterol in experimental animals it is not used clinically in man.

The drug, not unexpectedly,

severely limits cholesterol availability in avian epecies. Since egg formation in birds is dependent on an abundant supply of cholesterol, azacosterol is, in

162

Steroids

fact, an effective avian chemosterilant.

A glance at

the formula of cholesterol (124a) clearly shows the bioisosterism used in the design of 124.

N(CH2)3NCH3)2 (116b)

•"* (S^^L^Y^^

mm

(122)

(124) R = CH 3

(124a)

The crude toxin curare, used by South American Indians to lend authority to their blow gun darts, proved, because of its neuromuscular blocking activity, to be of interest to surgeons. Structural analysis of the mixture led to the erroneous conclusion that the active agents possessed a pair of quaternary nitrogen atoms with definite spacing because of the rigid molecular framework.

Following the rationale based

on this belief led to a number of curarelike synthetic agents in which the spacing is provided by aliphatic chains; it is readily apparent that the rigid network provided by a steroid would provide more accurate location of the charged centers.

The synthesis of

one of these starts with conversion of 125 (probably

Steroids

163

obtained by dehydration of the corresponding 3hydroxy compound) to the enol acetate (126)*

Epoxi-

dation proceeds as expected from the a side to give the bis epoxide (127).

Both regio- and stereochemistry

of the subsequent reaction with piperidine are dictated by the diaxial opening propensity of oxiranes; the hemiacetal-like function left at C-17 spontaneously reverts to the ketone to give 128.

Reduction of that

ketone proceeds in the usual manner to afford 129. Acetylation of the hydroxyl groups (130), followed by quaterization with methyl bromide gives pancuronium (13I).38

bromide

OCOCH 3

H

H (125)

(127) (126)

o

o HO* (128)

(129) R = H (130) R = COCH3 COCH3

164

Steroids

3.

PREGNANES

a.

11-Desoxy Derivatives

Progesterone, 132, is, of course, the prototype pregnane. This natural steroid plays an important role in females in the intricate endocrine chain of events involved in reproduction.

In essence, pro-

gesterone is one of the steroid hormones directly involved in the timing of ovulation.

Very high

levels of progesterone are present in early pregnancy, elaborated biosynthetically by a structure on the ovary (the corpus luteum), and this inhibits ovulation in the gravid female to prevent a superimposed pregnancy.

It is this observation that gave initial

direction to the development of the oral contraceptives.

As with the estrogens, much of the work

described below was carried out before a shadow fell on this class of drugs.

In addition, there was some

evidence from human trials that a potent progestin could provide contraceptive activity in the absence of added estrogen.

Although the efficacy wa^ somewhat

lower than for the combination Pill, the treatment avoided the use of the suspect estrogenic component. The finding that many potent progestins cause tumerous lesions in the beagle on long-term administration effectively laid this class of drugs to rest as far as large-scale usage is concerned.

It can be argued

quite reasonably that this effect is restricted to the beagle, but expert opinion is divided and use has subsided. As described earlier, oral activity can be achieved in the progestins by either removing the 19-

165

Steroids

methyl group or inclusion of an acyloxy group at: the 17-position.

It is of interest that removal of the

oxygen function at C-3 is compatible with biological activity in both series (see 37, 39, this Chapter). Thus, the 3-desoxy analogue of medroxx/progesterone acetate shows very similar activity to the parent substance.

.39 Reaction of medroxyprogesterone (133Y

with ethanedithiol gives the corresponding thioketal (134),

Desulfurization by means of Raney nickel

leads to the 3-desoxy steroid (135).

Treatment with

acetic acid in the presence of trifluoroacetic anhydride completes the synthesis of angesterone acetate

(136)^° CH, •OH

CH,

(132)

CH 3

(136) (135)

Chlormadinone acetate (137), 41 is an extremely potent orally active progestin.

Treatment of this

compound with basic sodium borohydride serves to reduce the ketone at C-3 to the corresponding 3carbinol (138; the regioselectivity is presumably due

166

Steroids

to the more hindered environment about the 20-ketone). Acetylation affords clogestone (139).

Further

dehydrogenation of the A ring of chlormadinone by means of selenium dioxide affords delmadinone acetate

(140). 4 3

•OCOCH-z

•OCOCHx

(138) R = H (139) R = COCH 3

Fusion of a cyclopropyl ring onto the 1,2position of chlormadinone gives a compound which, interestingly, shows mainly antiandrogenic activity. Preparation of cyproterone acetate (146) starts by reaction of triene 141 (obtainable from 17-acetoxy~ 44 progesterone by sequential dehydrogenations at C5,6 and O l , 2 ) with diazomethane affords the pyrazoline (142).

Pyrolysis leads to the cyclopropyl derivative 45 (143) by loss of nitrogen. Oxidation by means of perbenzoic acid gives the C-6,7 epoxide (144). Regioselectivity in this reaction is probably due to conjugate addition of peracid from the a side followed by electron backflow and ejection of benzoate as shown in 143a.

Reaction of that intermediate with

hydrogen chloride serves to open both the oxirane and cyclopropyl rings.

The intermediate chlorohydrin is

not observed as it undergoes spontaneous dehydration

Steroids

to 145.

167

Treatment of the chloromethyl derivative

with collidine serves to reform the cyclopropyl ring; the reaction very probably goes by internal alkylation of the anion generated by the base at the 2-position. There is thus obtained cyproterone acetate (146).

0C0CH3

(143) (141) (142)

OCOCH^

OCOCH3

CH2C1

OCOCH3

(145)

(144)

(143)

(143a)

Inclusion of an additional fused cyclopropane ring at C-16,17 gives a compound in which progestational activity is said to predominate.

Sapon-

ification of the acetate in 143 gives the corresponding 17-alcohol (147).

Heating in refluxing quinoline

results in dehydration with formation of the 16,17-olefin (148).

Reaction with diazomethane gives

168

Steroids

the pyrazoline (149), which on heating in acid affords the biscyclopropyl derivative (150).

This compound

is then taken on to the 6-chloro analogue by a sequence identical to that used to prepare 146.

There is thus 47 48 obtained the progestin gestaclone (151). '

(ISO)

Substitution by a methyl group at the 16-position is known to have a marked potentiating effect in the corticosteroid series.

Combination of such a group

with the unsaturated 6~chloro group in the progesterone series affords an extremely potent progestin.

One

route for preparation of the starting material for this drug consists in first introducing the 17hydroxyl.

Thus, the ketone at C-17 in the progesterone

derivative 152 (obtainable from the corresponding pregnenolone 165) is converted to the enol acetate (153).

The next step in this so-called Gallagher

chemistry consists in conversion of the enol double bond to the epoxide to give 154.

Hydrolytic ring

opening gives initially the hydroxy hemiacetal acetate; this quickly goes on to the hydroxy ketone (155).

OCOCHT

.CH3

(165)

•-•CH3 CH3CO2

CH3CO2

(152)

(153) •OCOCH7 •CH7

CH3CO2" (155)

CH3CO2'

(154)

(158) X = H (159) X = Br

(156) R = CH3CO (157) R = H

•OH ••CH-

1^ R = H (163) R= COCH7

(161) v = 0

(164) 169

170

Steroids

After protection of the C-20 keto group as the dioxolane (156), the 3-acetyl group is saponified and the resulting alcohol (157) is oxidized to the ketone (158).

Bromination (159) followed by dehydro-

bromination introduces the required 4-ene-3-one functionality (160); removal of the ketal would then afford the required starting material (161).

Heating

of 161 in the presence of chloranil then introduces the desired unsaturation at C-6,7.

A sequence iden-

tical to that used to prepare 146 (epoxidation; hydrogen chloride) is then used to introduce the 6chlorine atom

and the progestin clomegestone acetate

(164) results. The analogue of 164 lacking unsaturation at C-6 and oxygen at O 1 7 unexpectedly shows antiestrogenic rather than progestational activity. Pregnenolone 49 analogue 165 is starting material for this analogue as well.

Chlorination of the double bond by means of

chlorine in pyridine affords the dihalo derivative 166.

The stereochemistry is best rationalized by

assuming chloronium ion formation on the less-hindered a-side followed by diaxial opening of that ring by chloride ion.

Oxidation of the alcohol (167) affords

the 3-keto derivative (168), and reaction of that with sodium acetate leads to dehydrochlorination, yielding the enone (169). Exposure of that intermediate to mild acid isomerizes the halogen substituent to the more stable equatorial 6a-position and produces

dometherone (170).

Steroids

171

•••CH3.

•••CH, RO'

CH3CO2 (165)

(166) R = CH3CO (167) R = H

•CH3

•CH3

Yet another observation that carries over from the corticoids to progestins is the potentiation observed by formation of acetonides from the 16,17glycols.

It is of note in this case that the parent

glycol itself fails to show activity in the standard progestational assay.

Treatment of the progesterone

derivative 172 (available by oxidation of 16-dehydropregnenolone (171) with potassium permanganate) with acetone affords the 16,17-cyclic acetal algestone 52 acetonide (173); in the same vein, reaction with 53 acetophenone yields algestone acetophenide (174). Although formation of the latter involves the creation of a new chiral center, only one isomer is in fact isolated from the reaction.

Since acetal formation

is accomplished under thermodynamic conditions, the more stable isomer involving the least steric crowding

Steroids

172 should prevail.

It has been proposed that the config-

uration of 174 is that which carries the aromatic ring oriented away from the steroid molecule (174a). Earlier work had shown that the presence of the 17hydroxyl substituent is crucial for oral activity in the 21-carbon progestin series; progesterone itself

shows poor activity on oral administration.

This key

group can be replaced by halogen with retention of oral activity.

Bromination of pregnenolone acetate

(175a) in acetic acid gives the tetrabromide 175b. Treatment with sodium iodide leads to both elimination of the 5,6-dibromide grouping and displacement of the a-keto halide at C-21 by iodine; there is obtained dihalide 176.

Reduction of the haloketone with 54

bisulfite gives the methylketone 177;

the selec-

tivity is probably due to both the greater reactivity of iodine and the greater steric accessibility of

Steroids

173

that group. Saponification to 178 followed by treatment with peracid gives the 5,6-oxide 179.

Diaxial ring

opening of the oxirane with HF leads to the transfluorohydrin ISO.

Oxidation of the hydroxyl at C-3

by means of Jones reagent then affords hydroxyketone 181.

Treatment of this last with acid serves both to

generate the enone, by dehydration of the tertiary carbinol, and to invert the fluoro group at C-6 to the more stable equatorial, 6a-configuration. is thus obtained haloprogesterone

There

(182).

•CH3CO2'

CH 3 CO 2

(176) R = Ac; X = I

(175a)

(177) R = Ac ; X = H (175b)

(178) R = H; X = H

(179)

F (180) X (182)

Aldosterone (183) is one of the key steroid hormones involved in regulation of the body's mineral and fluid balance. Excess levels of this steroid quickly lead to marked retention of sodium chloride, water and, often as a consequence, hypertension. aldosterone antagonist spironolactone (184)

The

has

proven of great clinical value in blocking the effects

Steroids

174

of hyperaldosteronism.

In addition, the drug has

proven an effective diuretic and antihypertensive agent even in those cases where no gross excesses of aldosterone can be demonstrated. It is of note that the immediate chemical precursor of spironolac tone (184), diene 185 was in fact found to be one of the active metabolites of that drug in the body.

The

diene, canrenone (185) now constitutes a drug in its own right.

Both this and the following aldosterone

antagonists are also available in the form of the potassium salt of the ring-opened hydroxy acid; in this case, potassium canrenoate (186).

OH C*CH2CH2CO2K

(187)

(18b)

Cyclopropanation of the 4,6-diene function proceeds selectively at the 5,6-double bond.

Thus,

reaction of 185 with the ylide from trimethyl sulfonium iodide and sodium hydride, in DMSO, affords predominantly the a-cyclopropyl compound (187) accompanied

Steroids

175

by traces of the $-isomer.

The lactone constitutes 57

the diuretic-antihypertensive prorenone;

the ring-

opened salt is known as potassium prorenoate. Introduction of a carbomethoxy moiety at C-7 should afford a nonreversible counterpart of 184.

To

effect this, addition of cyanide to the extended conjugated system in 185 leads to addition of two moles of the nucleophile; there is obtained the unusual bicyclic intermediate 190.

The reaction may

be rationalized by assuming that addition occurs initially at the terminus of the system to give 188 as expected.

This, however, under the reaction

conditions chosen, undergoes addition of the second mole of cyanide which, of necessity, goes through anion 189; reaction of the negative charge at C-4 with the nitrile at C-7 would lead to the observed product (190).

This can only happen following p-

addition of cyanide.

Hydrolysis of the imine function

proceeds to give diketone 191.

A conformational

drawing (191a) shows that the molecule is by no means as strained as the planar projection would suggest. Reaction of 191 with methoxide reverses the formation of the additional ring.

The reaction sequence probably

starts by addition of methoxide to the carbonyl group (192); collapse of the alkoxide anion gives the intermediate anion 193, which neutralizes itself by facile elimination of the excellent leaving group, cyanide. There is thus finally obtained mexrenone 58 (194); the salt is known as potassium mexrenoate.

Steroids

176

( IBS)

(188)

( 1 <) " )

b.

11-Oxygenated Pregnanes

The story of the discovery of the utility of cortisone as an antiinflammatory agent has been told often enough 59 In brief, cortisone

not to need full repetition here.

is one of the more important hormonal steroids elaborated by the adrenal cortex; this steroid is intimately involved in the regulation of a host of biological processes such as, for example, regulation of glucose utilization and mineral balance.

Administration of

doses far in excess of those required for hormonal

Steroids

177

action were found to alleviate the symptoms of a multitude of conditions marked by inflammation.

When

used for this purpose, the normal hormonal effects are undesirable.

These side effects are, however,

seen to be natural extensions of the hormonal action. Immediately following this discovery, an enormous effort was mounted in the laboratories of the pharmaceutical industry aimed at separation of the antiinflammatory activity of these molecules from their hormonal activities.

The most visible outcome of

this work was a tremendous increase in the milligram potency achieved by various structural modifications. Drugs were produced that, in addition, had changed hormonal spectra; some such steroids had more pronounced effects on glucose metabolism ("glucocorticoids"), whereas others were more effective in changing mineral balance ("mineralocorticoids"). Despite this, no steroid truly devoid of hormonal activity rewarded these efforts.

The full realization

of the clinical deficiencies of the corticoids, coupled with the increasing availability of nonsteroidal antiinflammatory agents, has led to a great decrease in routine use of these drugs in medical practice. It is for that primary reason that the compounds discussed next failed to have greater medical and economic impact.

It is of note that this

work represented an unparalleled effort on the part of medicinal chemists, both as to the complexity of the molecules involved and the length of the synthetic schemes utilized.

In some ways this foreshadowed the

current prostaglandin programs, both in the goal

178

Steroids

(splitting of activities) and in chemical sophistication (in fact, the same names often appear as authors in the late steroid papers and early prostaglandin publications). As has been mentioned, preparation of esters of the C-17 hydroxyl group of selected progestins affords compounds with prolonged action.

Similar chemical

treatment of a corticoid would almost certainly lead to an ester of the sterically more accessible primary alcohol at C-21.

In an interesting method for

achieving esterification of the more hindered and less reactive tertiary 17-hydroxyl, prednisolone (195)

is converted to a mixture of the diasteromeric

cyclic ortho esters (196) by ester interchange with trimethyl ortho-pentanoate. Acid-catalyzed dioxolane ring opening proceeds by protonation of the more OCH 3

-OCO(CH2)3CH3

(197)

Steroids

179

sterically accessible oxygen attached to the 21position.

There is thus obtained prednival

(197).

It is of interest that 197 rearranges to the 21-ester on heating, representing an 0-to-0 acyl migration* It was found quite early in the steroid effort that inclusion of several groups, which singly potentiated activity had an additive effect; for example, a cortisone derivative that included both the unsaturation at C-1,2 and a methyl group at C-6 would be more potent than the derivative that possessed either group alone.

Much of the chemical strategy thus

devolved on designing routes which would permit the inclusion of combinations of potentiating groups. Dehydration of cortisone (198) affords the diene 199. This is then converted to ketal 200.

The selec-

tivity is due to hindrance about both the 11- and 20-carbonyl groups.

The shift of the double bond to

the 5,6-position is characteristic of that particular enone.

Treatment of protected diene 200 with osmium

tetroxide results in selective oxidation of the conjugated double bond at C-16,17 to afford the cis~ diol (201). Reduction of the ketone at C-ll (202) followed by hydrolysis of the ketal function gives the intermediate 203.

a

Selenium dioxide has been

found empirically to dehydrogenate such 3-keto-4-ene steroids to the corresponding 1,4-dienes.

(See, for

example, 120z121 and 137-140.) Thus in the case at hand, reaction of 203 with selenium dioxide gives the diene 204.

Reaction of the cis-diol function with

acetone forms the cyclic acetal and, thus, the corticoid desonide

(205).

Steroids

180

•

(207)

An analogous sequence starting with 6p-fluoro~ cortisone (206),

but omitting the selenium dioxide

dehydrogenation, affords flurandrenolide

(207).

Microbiological oxidation has proven of enormous value in steroid chemistry, often affording selective means of functionalizing remote and chemically inactivated positions. It will bear mentioning that the 11-oxygen for all commercially available corticoids is in fact introduced by such a reaction carried out on plant scale.

Preparation of the 1-dehydro analogue

of 207 involves biooxidation to introduce the 16-hydroxyl.

Incubation of 6a-fluoroprednisolone

Steroids

181

/TO

(208)

with Streptomgces roseochromogenes effects

a-hydroxylation at the 16-position (209).

Reaction

with acetone affords the corticoid flunisolide

65

(210).

The 6-chloro-6-dehydro moiety apparently has a similar potentiating effect on corticoids as it does on progestins. One scheme for preparing the requisite starting 6-chloro compound begins with the opening of oxide 211 with hydrogen chloride to give halohydrin 212.

Reduction of the 21-ester function by means of

lithium aluminum hydride, followed by acetylation, gives 213.

Transformation of the 17,20-olefin to the

requisite hydroxyketone grouping is achieved by a combination of osmium tetroxide and N-morpholine oxideperoxide (NMOP) treatments.

The reaction sequence

presumably starts by hydroxylation of the olefin via the osmate ester; the secondary alcohol at C-20 is then further oxidized to the ketone by the NMOP-

The

latter also served to reoxidize the osmium reagent from the dioxide to the tetroxide, allowing that expensive and toxic reagent to be used in catalytic quantities,

Deketalization (215) followed by acid

Steroids

182

CO2CH3

CH2OAC

HO

(211)

(2J_7) R = Ac (218)

R=H

catalyzed dehydration affords the conjugated ketone (216).

The remaining unsaturation at C-l arid C-6

is then introduced either by sequential treatment with selenium dioxide and chloranil or under special conditions with chloranil alone. Saponification of the acetate affords the corticoid cloprednol

(218)/66

Although oxygenation at O i l seems to be required for activity in the corticoid series, the presence of that function is not incompatible with progestational f\ "7

activity.

Thus, perhaps surprisingly in view of

some corticoids discussed below, mere lack of the hydroxyl group at C-21 seems, in at least one case,

Steroids

183

to give a compound which exhibits progestational activity.

Microbiological oxidation of diketone

epoxide 219 by means of Rhizopus nigricans affords the corresponding lla-hydroxy derivative

(220).

Dehydration of this via the mesylate (221) gives the 9,11-olefin (222). Ring opening of the oxirane moiety by means of hydrogen iodide gives the halohydrin 223. Treatment with zinc in acid serves to remove the halogen reductively (224)} the 17-hydroxy group is then acetylated by means of acetic anhydride in the presence of tosic acid to give 225.

The llp-hydroxy-

9a-halo function is associated with most potent corticoids; the manner of introduction used in this case well illustrates the relatively standard sequence used to incorporate this function.

Addition of the

elements of HOBr to the double bond is usually accomplished by N-bromosuccinimide in aqueous base. Both regio- and stereospecificity are no doubt guided by the initial formation of the 9or ,lla-bromonium ion, followed by nucleophilic diaxial opening to give 226. Treatment of the bromohydrin with base leads to the formation of the p-oxide (227) by intramolecular displacement of halogen by the neighboring alkoxide ion. Addition of hydrogen fluoride to the oxide proceeds with diaxial opening to afford the 9a-fluorollp-hydroxy functional array. In the case at hand there is formed the progestin flurogestone acetate (228).

This drug has been in use for controlling

the estrus cycle in domestic animals under the name Equamate®.

Steroids

184

(220)

R=H

(221)

R= CH 5 SO 2 H

(223)

R = II, X = T

(224)

R = H , X = 11

(225)

R = Ac, X = I

...OAc

(228)

The presence of an additional carbon atom on the dihydroxyacetone side chain is quite compatible with. anti inflammatory activity. Oxidation of 9(Y-fluopred"70 nisolone (229) by means of cupric acetate affords the corresponding 21-aldehyde (230).

Addition of

diazomethane to the aldehyde serves to lengthen the side chain as the epoxide 231•

Opening of the oxirane

ring with hydrogen bromide occurs regioselectively to give the 22-bromo derivative (232).

Heating of the

bromohydrin leads to loss of hydrogen bromide with formation of the alpha diketone (233) (this reaction

185

Steroids

can be rationalized as loss of HBr to give the enol followed by ketonization).

Reduction of the side

chain diketo alcohol by means of yeast proceeds both regio and stereospecifically to give the derivative containing the 21a-hydroxyl group (234).

Acetylation

under mild conditions then affords the antiinflammatory steroid fluperolone acetate

(235). 71

CHO HO •OH

no • -OH

(231)

(229)

f 254 ) R = (235) R =

(230)

(233)

(232)

The potentiating effect of the 16-hydroxyl group in the corticoid series has been mentioned previously. The acetonide of such a steroid, triamcinolone (237), is in fact one of the more widely used corticosteroids. The nature of the group used to form a ketal apparently has only relatively minor influence on biological Reaction of the 16,17-glycol 23612 with 73 3-butanone yields amcinafal (238); in the same vein activity.

condensation with acetophenone leads to amcinafide

Steroids

186

(239).

73

The ketal stereochemistry is not specified.

Unsaturation in the A ring has been usually assumed to be necessary for biological activity; the reader will have noted the high prevalence of 1,4-dienes. It is interesting therefore to note that the analogue possessing a fully saturated A ring is apparently quite active in its own right.

Thus, catalytic

reduction of 237 affords the corticoid drocinonide

(240).74 HO

(236)

(239)

CH 3 ~- R

(240)

(238_) R-= c 2 H 5 , R' = CM 3

It is of interest that there exists a considerable amount of flexibility as to the substituent at O 2 1 in the acetonide series.

For example, 72

formation of the acetonide from 241 mediate 242.

affords inter-

Reaction with methanesulfonyl chloride

gives the corresponding mesylate (243). Displacement

Steroids

187

of the ester with lithium chloride in DMF gives the 75 corticoid halcinonide (244).

HO

(241)

(244)

(242) R = H (243) R = SO2CH3

The C-21 substituent can in fact be dispensed with entirely. Perhaps because descinolone acetonide (254) predates 244 by better than a decade, the synthetic sequence reported for its preparation is quite complex.

Although descinolone (253) could in

principle be prepared in a few steps from some currently available starting materials, such as 241, the original synthesis is presented for its heuristic Value, Epoxyketone 245 is readily available from 16dehydropregnenolone via several steps, including a crucial microbiological lla-hydroxylation. of 245 gives the 9,11-olefin 246.

Dehydration

The alcohol at

C-21 is then converted to the mesylate (247), and this is reduced to give the methyl ketone (248). The olefin is then converted to the 9a-fluoro-llp-hydroxy array (250) by the standard sequence [addition of HOBr, closure to the oxirane (249), opening with H F ] . Note that the reactivity of the epoxides in 249 is

HO.

(245)

(246)

R = OH

(247)

R= OSO2CH3

(248)

R = H

(249)

HO

(254)

•OAc

(255)

CHO :H2CH2CI

188

(257)

Steroids

189

sufficiently different so that reaction occurs regioselectively at C-9,11.

The remaining major trans-

formation is the establishment of the 16a,17a-glycol function; this cannot be readily achieved from 250 since this would demand the cis-opening of an oxirane. Deoxygenation of the epoxide with chromous chloride gives back the 16,17-olefin (251).

In effect the

epoxide has been used in this sequence as a protecting group for an olefin. Hydroxylation with osmium tetroxide gives the desired glycol (252); microbiological dehydrogenation (using Nocardia corallina) serves to introduce the double bond at C-l (253). Reaction with acetone finally affords descinolone 7 f\

acetonide (254),

an antiinflammatory agent.

Although the Vilsmeier reaction is known best in aromatic systems, aliphatic olefins also undergo formylation.

Synthesis of formocortal (257) involves

such a step.

Formation of the monoketal of 255

involves the 3-ketone function with the familiar concomitant shift of the double bond to C-5,6. Reaction of 256 with phosphorous oxychloride and DMF involves first formylation at the 6-position; opening of the ketal to the enol ether by the HC1 produced in the Vilsmeier reaction would afford a hydroxyethyl side chain at C-3.

This is no doubt converted to a

chloroethyl group by excess oxychloride. There is thus obtained the antiinflammatory agent formocortal

(257) J1 As is the case with other classes of steroids, inclusion of nitrogen atoms into corticoids has met with only limited pharmacological success.

Compounds

190

Steroids

containing a pyrazole ring fused onto the A ring have, however, shown sufficient activity to merit generic names.

Synthesis of the requisite inter-

mediate for its incorporation starts with the protection of the dihydroxyacetone side chain.

Reaction of

258 with formaldehyde gives the internal double acetal 259.

(This bismethylenedioxyether-protected

(259a) function is known as BMD for short.)

Dehydro-

genation by means of chloroanil proceeds in the usual way to give the 4,6-diene (260).

Formylation with

ethyl formate and sodium hydride leads to 261.

HO •CH7

CH 3 (260) R = H 2 (261) R = CHOH

HO

(263) R = H (259a)

(262)

(264) R= COCH3

Condensation with phenylhydrazine results in phenylpyrazole 262.

The regiospecificity results from

intermediate phenylhydrazone formation of the more

Steroids

191

reactive aldehyde function.

The sequence is completed

by deprotection of the cortical side chain by acid hydrolysis (263), followed by acetylation of the 21-hydroxy group.

There is thus obtained the corticoid 7A

cortivazol (264). Inclusion of halogen, particularly fluorine, at either the C-6 or O 9 positions in the cortisone molecule is well known to increase potency.

Combina-

tion of these potentiating groups in the same molecule in general leads to an additive influence on potency. The synthesis of one such compound, difluprednate (271), starts with a scheme analogous to that used to prepare 197.

The C-17,21 diol 265 is first converted

to the cyclic ortho-ester (266) by means of methyl ortho-butyrate.

Cautious hydrolysis affords the

17-butyrate ester (267).

Exhaustive acetylation

leads to reaction not only at C-21, but formation of the enol acetate at C-3 as well (268). Reaction of that intermediate with perchloryl fluoride (FCIO^) leads to halogenation at the terminus of the electronrich diene system.

Work-up gives a mixture of the

epimeric 6-fluoro compounds; equilibration in acid provides the more stable equatorial 6or-isomer (269). The 9,11-diene is then taken on to the 9a-fluoro-llphydroxy function by the standard reaction sequence (270). Dehydrogei>ation by means of DDQ completes the 79 synthesis of difluprednate (271). Omission of the 17-hydroxyl group in the 6,9dihalo compounds apparently does not lead to loss of biological activity. Dehydration of the 6<x-fluoro-1780 desoxy intermediate 272 by means of NBS in pyridine

192

Steroids

•OH

••OCOC3H7

X

3

$ (267)

(266)

(265)

OCOCH3 •OCOC3H7

A cO"

(2_70)

F (269)

(268)

leads to the 9,11-olefin (273). This is then converted to the halohydrin by the standard sequence.

Micro-

biological dehydrogenation of the A ring leads to the 1,4-diene.

There is thus obtained the antiinflammatory

steroid diflucortolone (275).

81

Although the most common substituent found at the C-9 position in the commercially available corticoids is fluorine, the initial observation of the

Steroids

193

HO

F (272)

(274)

(273)

F (275)

potentiating effect of halogen was in fact made with chlorine at that spot.

It is thus of interest to

note that one of the more recent 17-desoxy-6,9-dihalo cortocoids contains chlorine at C-9.

Starting material 82 for that compound is 16-methyl steroid 276. In

distinct contrast to previous work, the desired halohydrin is introduced in a convenient single step rather than by the usual three-step sequence „

Thus,

reaction of the olefin with tertiary butyl hypochlorite in the presence of perchloric acid affords directly the 9a-chloro~llp-hydroxy function and, thus, clocortolone (277), an antiinflammatory agent. It is not unlikely that the actual reagent is HOCl; attack on the 9,11-olefin by Cl

would occur from the

less hindered side to give the 9a,lla~chloronium intermediate.

Attack of OH to give diaxial ring

opening would lead to the observed halohydrin.

194

Steroids

OCOCH,

••'CH3

F (276)

OCOCH3

F (277)

The scheme required to prepare the potent trifluoro corticoid cormethasone acetate (292) illustrates the synthetic complexities involved in some of this work.

Sequential acetylation of the pregnenolone

derivative 278 with first acetic anhydride in pyridine and then acetic anhydride in the presence of tosic acid affords diacetate 279*

Reaction of that inter-

mediate with nitrosyl fluoride results initially in addition of the reagent to the 5,6-olefin moiety to afford the fluoro oxime; reaction with a second mole of reagent at nitrogen gives the nitroimine derivative 280; passage over alumina serves to hydrolyze the imine function to the corresponding 6-ketone (281).

CHz

•OCOCH3

•OCOCH3 •-CH3

HO CH3CO2 (278)

CH 3 CO 2 (279)

•OCOCH3 •••CH 7

CH3CO2"

(285)

(282)

R = COCH3, X = H

(283)

R = H, X = H

(284)

R= H, X = Br

F

F

(±£6)

R - COCII3

(289)

R = II

(287)

R -

(290)

R = COCH3

OCOCH7 HO

1 9 5

196

Steroids

Sulfur tetrafluoride in hydrogen fluoride has been developed as a selective and general reagent for converting ketones to the corresponding difluoromethylene groups. Application of that reaction to 281 gives the desired 6,6-difluoro derivative 282.

The

less-hindered acetate at C-3 is then hydrolyzed selectively (to 283); bromination in dioxane leads to the 21~bromo derivative 284. the 3-ketone (285)*

Jones oxidation gives

Reaction of that compound with

silver acetate serves to displace the bromine by acetate, to introduce the enone function by elimination of hydrogen fluoride, and to hydrolyze the 17-acetate.

There is thus obtained 286.

Sapon-

ification of the remaining 21-acetate gives the desired intermediate 287.

Successive microbiological

oxidation with Curvularia lunata and Arthrobacter simplex serves to introduce respectively the llphydroxyl (288) and 1-olefin functions (289). Reacetylation (290) followed by dehydration gives the required 9,11-olefin (291).

This is converted to the

9,11-fluorohydrin by the standard sequence to afford 83 finally cormethasone acetate (292). The recurring theme in work on corticoids discussed thus far

with the exception of the 17-desoxy

compounds consisted in the introduction of additional functions to the basic cortisone molecule.

Some

further success in producing biologically active molecules has been achieved by substituting unnatural functions for those present in the protoype molecule. Thus the hydroxyl groups at both O i l and C-21 can be replaced by halogen with retention of activity.

en ro 1ot-o

u o C-J CO O CO

i PH|

197

198

Steroids

Reaction of the olefin (294), corresponding to fludro84 cortide (293), with chlorine affords directly flu85 cloronide (295). The stereochemistry can, as in the case of 277, be rationalized by invoking the intermediacy of the 9a, llor-chloronium ion.

Reaction of

294 with methanesulfonyl chloride affords the corresponding mesylate (296); displacement of the ester by means of lithium chloride affords the 21-chloro intermediate (297).

Addition of chlorine to the

9,11-double bond gives triclonide (298).

ft ft

A similar

sequence on the tosylate (299), leading through the intermediate fluoride (300), gives the antiinflam87 matory agent tralonide (301). Antiinflammatory activity also persists in the absence of oxygen at either C-17 or C-21.

In this

case, unlike those in which those positions are occupied by halogen, the possibility exists that these are in fact prodrugs.

That is, the compounds

may have no intrinsic biological activity but need to be hydroxylated to the active entities in vivo. The synthetic sequence starts by formation of the bisketal 303 from lla-acetoxy progesterone (302).

Epoxidation

affords predominantly the 5a,6a-oxide (304).

Reaction

with methylmagnesium bromide both opens the oxiran and cleaves the ester (305).

Successive treatment

with aqueous acid and base serves to hydrolyze the ketal groups and dehydrate the resulting p-hydroxyketone (306).

The a,p-unsaturated function provides

a means for epimerization of the 6p-methyl group to 6of. There now remains the task of inverting the configuration at O i l as well.

Oxidation proceeds in

CH3CO2

(302)

(303)

0'*

(304)

HO

CH3 (307)

(306)

HO

(308) (509)

X= 0 /OH X= '••H

(310)

1 9 9

200

Steroids

straightforward manner to give the 11-ketone (307); the highly hindered nature of the llketone permits selective ketal formation at C-3 and O 2 0 (308)* Reduction by means of lithium aluminum hydride (309), followed by hydrolysis of the ketal groups affords antiinflammatory steroid medrysone (310).88 The analogue containing additional unsaturation at C-l, endrysone (311), can presumably be obtained from 310 by any one of the standard dehydrogenation schemes.

REFERENCES 1. 2.

Y. Lefebvre, U. S. Patent 3,428,627 (1969). V. Prelog, L. Ruzicka and P. Wieland, Helv. Chim. Acta, 27, 250 (1944). 3. J. De Visser, Dutch Patent 95,275 (1960). 4. R. E. Brown, D. M. Lustgarten, R. J. Stanaback, M. W. Osborne and R. I. Meltzer, J. Med. Chem. , 7, 232 (1964). 5. R. Clarkson, J. Chem. Soc., 4900 (1965). 6. Anon., Belgian Patent 647,699 (1964). 7. See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 164 (1975). 8. F. B. Colton, U. S. Patent 2,843,608 (1958). 9. R. T. Rapala, Belgian Patent 666,469 (1966); Chem. Abstr., 65: 5506h (1966). 10. J. C. Babcock and J. A. Campbell, Belgian Patent 610,385 (1962); Chem. Abstr., 57: 13834 (1962). 11. M. S. de Winter, C. M. Siegmann and S. A.

Steroids

12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

22. 23. 24.

201

Szpilfogel, Chem. Ind. , 905 (1959). Anon., British Patent 841,411 (1960). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 165 (1975) J. Fried and T. S. Bry, U. S. Patent 3,096,353 (1963). H. L. Dryden, Jr., G. N. Webber and J. Wieczorek, J. Am. Chem. Soc., 86, 742 (1964). P. Wieland and G. Anner, Helv. Chim. Acta. , 50, 289 (1967). Anon., Dutch Patent 6,406,797 (1965); Chem. Abstr. , 64: 12759b (1966). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 177 (1975). J. S. Baran, J. Ned. Chem., 10, 1188 (1967). J. S. Baran, H. D. Lennon, S. E. Mares and E. F. Nutting, Experientia, 26, 762 (1970). H. Smith, G. A. Hughes, G. H. Douglas, G. R. Wendt, G. C. Buzby, Jr., R. A. Edren, J. Fisher, T. Foell, G. Gadstry, D. Hartley, D. Herst, A. B. A. Jansen, K. Ledig, B. J. McLoughlin, J. McMenamin, T. W. Pattison, P. C. Phillips, R. Rees, J. Siddall, J. Sinda, L. L. Smith, J. Tokolics and D. H. P. Watson, J. Chem. Soc, 4472 (1964). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 168 (1975). Anon., British Patent 1,123,104 (1968); Chem. Abstr., 70: 4410b (1969). D. Lednicer and L. A. Mitscher, Organic

202

25. 26. 27. 28. 29. 30.

31. 32. 33.

34. 35. 36.

Steroids

Chemistry of Drug Synthesis, Vol. I, p. 157 (1975). A. Popper, K. Prezewowsky, R. Wiechert, H. Gibian and G. Raspe, Arzneimittelforsh., 19, 352 (1969). C. Meystre, H. Frey, W. Voserand and A. Wettstein, Helv. Chim. Acta, 39, 734 (1956). Anon., Belgian Patent 623,277 (1963). A. Ercoli, R. Gardi and R. Vitali, Chem. Ind., 1284 (1962). J. C. Babcock and J. A. Campbell, U. S. Patent 3,341,557 (1967). R. E. Counsell, P. D. Klimstra and F. B. Colton, J. Org. Chem., 27, 248 (1962); R. Mauli, J. H. Rin^old and C. Djerassi, J. Am. Chem. Soc., 82, 5494 (1960). F. Sorm and H. Dykova, Coll. Czech. Chem. Commun. , 13, 407 (1946). J. Joska, J. Fakjos and F. Sorm, Chem. Ind., 1665 (1958). A. J. Manson, F.W. Stonner, H. C. Neumann, R. G. Christiansen, R. L. Clarke, J. H. Ackerman, D. F. Page, J. W. Dean, D. K. Phillips, G. 0. Potts,, A. Arnold, A. L. Beyler and R. O. Clinton, J. Med. Chem. , 6, 1 (1963). H. C. Neumann, G. 0. Potts, W. T. Ryan and F. W. Stonner, J. Med. Chem., 13, 948 (1970). F. W. Stoner, S. African Patent 68 04,986 (1969); Chem. J. M. Nascimento and M. H. Venda, Rev. Port. Farm., 13, 472 (1963); Chem. Abstr. , 61: 3163a (1964).

Steroids

37. 38. 39.

40. 41.

42. 43. 44.

45. 46. 47. 48. 49.

50.

203

R. E. Counsel1, P. D. Klimstra and R. E. Ranney, J. Med. Chem. , 5, 1224 (1962). W. R. Buckett, C. L. Hewett and D. S. Savage, Chim. Ther. , 2, 186 (1967). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 181 (1975). Anon., Belgian Patent 624,370 (1963); Chem. Abstr., 60: 10764g (1964). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 181 (1975). Anon., Belgian Patent 646,957 (1964). H. J. Ringold, E. Batres, A. Bowers, J. Edwards and J. Zderic, J. Am. Chem. Soc., 81, 3485 (1959) See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 179 (1975). R. Wiechert, E. Kaspar and M. Schenck, German Patent 1,072,991 (1960). R. Wiechert, U. S. Patent 3,234,093 (1966). Anon., British Patent 1,095,958 (1967); Chem. Abstr., 69: 27645a (1968). H. Gries' and J. Hader, German Patent 1,286,039 (1969); Chem. Abstr., 70: 88115v (1969). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 200 (1975). Anon., Belgian Patent 621,981 (1963).

204 51.

Steroids

R. T. Rapala and M. J. Murray, Jr., J. Med. Chem., 5, 1049 (1962). 52. G. Cooley, B. Ellis, F. Hartly and V. Petrow, J. Chem. Soc., 4373 (1955). 53. J. Fried, E. F. Sabo, P. Grabowich, L. J. Lerner, W. W. Kessler, D. M. Brennan and A. Borman, Chem. Ind. , 465 (1961). 54. P. L. Julian and W. J. Karpel, J. Am. Chem. Soc. , 72, 362 (1950). 55. J. S. Mills, 0. Candiani and C. Djerassi, J. Org. Chem. , 25, 1056 (1960). 56. See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 207 (1975). 57. Anon., Belgian Patent 730,163 (1969). 58. R. M. Weier and L. M. Hoffman, J. Ned. Chem., 18, 817 (1975). 59. See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 192 (1975). 60. R. Gardi, R. Vitali and A. Ercoli, Tet. Lett. 448 (1961). 61a. W. S. Allen and S. Bernstein, J. Am. Chem. Soc, 78, 1909 (1956). 61b. S. Bernstein, R. H. Lenhard, W. S. Allen, M. Heller, R. Littell, S. M. Stolar, K. I. Feldman and R. H. Blank, J. Am. Chem. Soc., 81, 1689 (1959). 62. S. Bernstein, R. Littell, J. J. Brown and I. Ringler, J. Am. Chem. Soc, 81, 4573 (1959).

Steroids 63.

64.

65. 66. 67.

68. 69. 70.

71.

72.

73.

74. 75.

205

J. A. Hogg and G. B. Spero, U. S. Patent 2,841,600 (1958); Organic Chemistry of Drug Synthesis, Vol. I, p. 195 (1975). H. J. Ringold, J. A. Zderic, C. Djerassi and A. Bowers, German Patent 1,131,213 (1962); Chem. Abstr. , 58: 10281c (1963). Anon., British Patent 933,867 (1963). Anon., French Patent 1,271,981 (1962); Chem. Abstr., 58: 11448a (1963). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 180 (1975). R. M. Dodson and C. Bergstrom, U. S. Patent 2,705,711 (1955); Chem. Abstr., 50: 5045f (1956). C. Bergstrom, R. T. Nicholson, R. L. Elton and R. M. Dodson, J. Am. Chem. Soc., 81, 4432 (1959). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 193 (1975). E. J. Agnello, S. K. Figdor, G. M. K. Hughes, H. W. Ordway, R. Pinson, Jr., B. M. Bloom and G. D. Laubach, J. Org. Chem., 28, 1531 (1963). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 201 (1975). J. Fried, A. Borman, W. B. Kessler, P. Grabowich and E. F. Sabo, J. Am. Chem. Soc, 80, 2339 (1958). J. Fried, U. S. Patent 3,053,836 (1962). L. T. Difazio and M. A. Augustine, German Patent 2,355,710 (1974); Chem. Abstr., 81: 91807e (1974)

206 76. 77.

78.

79. 80.

81. 82. 83. 84.

85.

87. 88.

Steroids S. Bernstein, J. J. Brown, L. I. Friedman and N. E. Rigler, J. Am. Chem. Soc. , 81, 4956 (1959). G. Baldratti, B. Camerino, A. Consonni, F. Facciano, F. Mancini, U. Pallini, B. Pateli, R. Sciaky, G. K. Suchowsky and F. Tani, Experientia, 22, 468 (1966). H. J. Fried, H. Mrozik, G. E. Arth, T. S. Bry, N. G. Steinberg, M. Tishler, R. Hirschmann and S. L. Steelman, J. Am. Chem. Soc, 85, 236 (1963). A. Ercoli and R. Gardi, S. African Patent 68 03,686 (1968). For preparation of the corresponding 16-methyl analogue, see D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 205 (1975). J. A. Campbell, J. C. Babcock and J. A. Hogg, U. S. Patent 2,876,219 (1959). E. Kaspar and R. Phillippson, U. S. Patent 3,729,495 (1973). R. M. Scribner, U. S. Patent 3,767,684 (1973). See D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 202 (1975). A.Bowers, U. S. Patent 3,201,391 (1965). 86. J. H. Fried, German Patent 1,917,082 (1969); Chem. Abstr. , 72: 67206b (1970). J. H. Fried, S. African Patent 68 00,282 (1968); Chem. Abstr., 70: 58146p (1969). G. B. Spero and J. L. Thompson, U. S. Patent 2,968,655 (1961).

Polycyclic Aromatic and Hydroaromatic Compounds The ring systems covered in this chapter provide the molecular framework upon which the necessary functionality for a diverse range of pharmacologically active agents are assembled.

Intrinsic agonist activity is

rarely, if ever, attributable to the ring system itself among this class, but often replacement or "simplification" by omission of rings leads to a serious decrease in activity.

This is generally

considered to be due to a considerable alteration in lipid/water solubility ratio, a deleterious alteration in the spatial arrangement of the functions necessary to fire the receptor, a change in the pK such that altered intracellular concentrations are achieved, or some such factor.

This lack of intrinsic pharmaco-

phoric action is demonstrated clearly by the indanes in the first section.

Of the six substances covered,

each has a different main pharmacological action! 207

20 8

Polycyclic Aromatic Compounds

1. INDANES AND INDENES Of a series of indanylthiocarbamates, tolindate (2) had significant antifungal properties. It is prepared simply from 5-indanyl thionochloroformate (1) by reaction with N-methyl-m-toluidine. It presumably joins the fairly large family of organic compounds having sulfur divalently bound to carbon which are useful topical agents for dermatophytes.

OCXJL • When indan-2-one (3) forms a Schiff's base with aniline and this is reduced with sodium borohydride, the aminoindane 4 is found. The acidic hydrogen is removed with sodium hydride and this is in turn reacted with 3-diethylaminopropyl chloride to complete the synthesis of aprindine (5), an antiarrythmic 2 agent. (CH2)3N(C2H5)2

O> (3)

NC6H5 (i)

CD

When 1-phenylindene (6) is treated successively with n-butyl lithium and dimethyl p-chloroethylamine, indriline (7), a central stimulant, is formed along with inactive isomer 8, both presumably arising via reaction with the intermediate aziridinium ion.

Polycyclic Aromatic Compounds

209

NMe ? (CH 2 ) 2 N(CH 3 ) 2

(6) (8)

Reaction of p-fluorobenzyl chloride with the anion of diethylmethylmalonate ester followed by saponification and decarboxylation leads to acid 9. Polyphosphoric acid cyclization leads to indanone 10. A Reformatsky reaction with zinc amalgam and bromoacetic ester leads to carbinol 11 which is then

HO

CH 2 CO 2 CH 3

(ID

(9)

•CH 7

(12)

C13)

dehydrated with tosic acid to indene 12.

The active

methylene group of 12 is condensed with p-thiomethylbenzaldehyde, using sodium methoxide as catalyst, and then saponified to give Z-isomer 13 which is in turn

210

Polycyclic Aromatic Comoounds

oxidized with sodium metaperiodate to sulfoxide 14, the antiinflammatory agent sulindac. 4 Phenyl indandiones With an acidic hydrogen often interfere with clot formation.

When electron with-

drawing groups are present in the ^-position, acidity is increased and activity goes up.

The opposite effect

is seen with electron-donating substituents.

Synthe-

sized in the usual way, the anticoagulant bromindione (15) results from sodium acetate-catalyzed condensation of phthalic anhydride and p-a-bromophenylacetic acid. 0 0 0 (15)

An analgesic compound that does not completely embody the essential structural features of the classical morphine rule is dimefadane (19).

Friedel-

Crafts alkylation of benzene with cinnamic acid using a Lewis acid catalyst gives p,p-diphenylacetic acid (16), which is cyclized to indanone 17.

Heating with

ammonium formate (Leuckart reaction) produces indanylamine 18 in a more efficient manner than does hydrogenation of the oxime.

Heating with formalde-

hydeformic acid (Eschweiler-Clark reaction) then produces dimefadane (19),

an analgesic with about

the same potency as codeine but without much of the

Polycyclic Aromatic Compounds

211

untoward gastrointestinal side effects of the natural product.

(17)

(18) R = H (19) R = CH,

(16)

2.

NAPHTHALENES

An analogue of tolindate (2) which has had greater success as an antifungal drug is tolnaftate (20). The synthesis follows the usual path, condensing p-naphthol with C1 9 CS and then reacting the resulting 7 chlorothioformate with N-methyl-m-toluidine. It will be recalled that certain local anesthetic amides, such as procainamide and lidocaine, are active antiarrythmic agents.

Annelation of a

second aromatic ring is consistent with bioactivity. Bunaftine (21) is such an agent, prepared simply from reaction of the acid chloride of 1-naphthoic acid and p-dimethylaminoethylbutylamine.

CH>CH 2 CHCH 2 NCH(CH 3 ) 2

(CH2)2N(C2H5)2

CHT

(2 0)

(21)

(21)

cr

Polycyclic Aromatic Compounds

212

Interestingly, when propranolol is quaternized with methyl chloride, it loses its p-blocker activity and becomes the antiarrythmic agent pranolium chloride

(22).8 A number of amidines have anthelmintic activity. Bunamidine (25), indicated for treatment of human pinworm infestations, is prepared from a-naphthylhexylether (23) by Friedel-Crafts type reaction with cyanogen bromide and aluminum chloride to give nitrile (24).

This, then, is reacted with the magnesium

bromide salt of di-n-propylamine leading to the naph9 thamidine structure (25). -

CH 2 X

O(CH 2 ) 5 CH 3

O(CH2) 5CH3

(2_3) R - H

(26) X = Cl (22) X = ONH2

C2_5)

(24) R = CN

Muscle relaxant activity is found in the aminoxymethylnaphthalene structure of nafomine (27).

The

synthesis proceeds from l-chloromethyl-2-methylnaphthalene (26), which is reacted with N-carbethoxyhydroxylamine and base.

In this way, the basic

nitrogen is protected as the carbamate.

Loss of the

carbethoxy group either during reaction or on workup affords nafomine

(27).10

Polycyclic Aromatic Compounds

213

Certain ethanolamine analogues are active as CNS stimulants if they can be transported across the blood-brain barrier.

One technique for bringing this

about is to esterify them.

One agent designed for

this purpose, but which is more interesting as a vasodilator, is nafronyl (29)*

The acid component

is synthesized by condensing furfuryl chloride and methyl malonate followed by catalytic reduction, alkylation with 1-chloromethylnaphthalene and saponi12 fication/decarboxylation to give 28_. Esterification with N,N~diethylethanolamine produces nafronyl (29).

oMe

Ov

(.29)

A number of products in which one of the naphthalene rings has been reduced have interesting pharmacological properties.

Reaction of tetralone 30_

with dimethylamine under TiCl^ catalysis produces the corresponding enamine (31).

Reaction with formic

acid at room temperature effects reduction of the

Polycyclic Aromatic Compounds

214

eneamine double bond to product the tranguilizer and anti-Parkinsonian agent, lometraline (32). ci

Cl

OCH3 (30)

Branched aryloxyacetic acids often have hypochloesterolemic activity.

When tetralol 33 is reacted

with phenol in a Friedel-Crafts reaction, a-tetralin derivative 34 is formed. a-bromoisobutyrate

This is reacted with ethyl

and saponified to produce the

hypolipidemic agent, nafenopin

(35).

OC(CH 3 ) 2 CO 2 H

OH

(13) (34)

(35)

As noted above, phenylethanolamines are usually p-adrenergic agonists, whereas phenylpropanolamines show antagonist activity.

A small series of phenyl-

ethanolamine blockers is, however, known.

When the

haloatom of u>-bromo-5,6,7,8-tetrahydro-2-acetonaphthone (36) is displaced with isopropylamine and the

Polycyclic Aromatic Compounds

215

carbonyl group is reduced catalytically, the adrenergic blocking agent bunitridine (37) is produced.

lf

OH

ccr*"— oa (37)

(36)

A number of tetralins with the appropriate side chains have p-adrenergic blocking activity.

Presum-

ably, the tetralin ring provides greater lipid solubility than the corresponding benzenes.

Bunolol (41)

is synthesized from phenolic tetralone (38) by sequential reaction with 2,3-dihydroxypropyl chloride (to 39),

tosyl chloride (to 40), and t-butylamine to give

bunolol.

Restoration of a considerable amount of

the water solubility of this small group of drugs is accomplised by incorporating a glycol moiety in the reduced ring.

When 5,8-dihydronaphtho1 (42) is

acetylated and then hydroxylated via the Woodward OH OCH 2 CHCH 2 X

(38_)

(12)

x=

(£0) (40) X X == OSO 2 C 6 H 4 CH 3 (£1) X = NHC(CH 3 ) 3

216

Polycyclic Aromatic Compounds

modification of the Prevost process (silver acetate and iodine), glycol 43 is formed.

The rest of the

molecule is constructed in the usual way involving the sequence: saponification to the phenol, alkylation with epichlorohydrin, and displacement with t-butylamine to produce nadolol (44), a p-adrenergic blocking agent.

j

OCOCH-

OCH2CHCH2NHC(CH3)

(±2)

(43)

H0

' C£4)

Despite the best efforts of the World Health Organization, malaria remains a widespread tropical disease with substantial mortality.

Of the many

structural types explored in attempts to find prophylactic and chemotherapeutic agents, some have been naphthoquinones.

During World War II, a large number

of such quinones with aliphatic side chains were investigated. Several were active in ducks but not in man, and the reason for this difference was traced to man's ability to inactivate these materials by hydroxylation.

To counter this, some agents with

relatively very large hydrocarbon sidechains were made.

For example, acylation of cyclohexanone enamine

45 with dihydrocinnamoyl chloride produced 46, which underwent ring-opening diketone cleavage with base to give acid 47* Wolff-Kishner reduction and hydrogenation

Polycyclic Aromatic Compounds

217

(45)

a

"(CH2)8CO2H

C48)

(49)

over a platinum catalyst produced saturated acid 48 that was converted to the acid chloride with SOC1 2 and then to the acyl peroxide (49) with H^O^ and pyridine.

Heating 49 in acetic acid along with 2-

hydroxynaphthoquinone resulted in radical formation and alkylation to produce the antimalarial agent, 1 ft menoctone (50). 3.

FLUORENES

Many nonsteroidal antiinflammatory agents are acids and are believed to act by inhibiting prostaglandin synthesis.

The synthesis of one such agent, cicloprofen

(53), is illustrative. When fluorene 51 is acylated by ethyl oxalylchloride and A1C1 3 , ketoester 52 results.

Reaction with methyl Grignard reagent, acid

dehydration of the tertiary carbinol, and catalytic reduction of the resulting terminal olefinic linkage produces the antiinflammatory agent, cicloprofen

Polycyclic Aromatic Compounds

218

(53).

19

Elements of the structure of ibuprofen and

its congeners are clearly visible in cicloprofen.

(51

(53)

(52)

A number of amines are also nonsteroidal antiinflammatory agents.

One such agent was uncovered

while searching for estrogenic substances. 9-Fluorenone (54) undergoes Grignard addition and dehydration with p-bromobenzylmagnesium bromide to give 55*

Displacement of halogen with CuCN gives

nitrile 56, which can be converted to the amidine in the usual way. Reaction with ethanol under acidcatalyzed anhydrous conditions leads to iminoether 57 which undergoes displacement with liquid ammonia to 20 give the antiinflammatory age(nt, paranyline (58).

o (54) (58)

(5_5) X = Br (_56) X = CN

NH

(57) X = C

\OC

2H5

One substance intended to be an antiinflammatory agent has achieved much greater prominence because it

Polycyclic Aromatic Compounds

219

is an interferon inducer and is therefore protective against viral infections. This drug is tilorone 21 (63). In its synthesis, fluorene (51) is sulfonated and converted to its potassium salt (59)*

This is

oxidized with KMnO. to the fluorenone (60).

Upon KOH

fusion, nucleophilic substitution to the bis-phenol occurs, accompanied by ring cleavage, to give 61. Friedel-Crafts cyclization (ZnCl^) restores the fluorenone system (62).

Ether formation with p-

bromotriethylamine (probably via the aziridinium) produces tilorone (63).

c^X-jO^Ok (59) X = H 2

(61)

(6£) X = 0

4.

ANTHRACENES

Anthracenes are planar by virtue of the necessity of maintaining aromaticity.

When the central ring is

reduced, an overall "butterfly" conformation is achieved.

For reasons that are not yet understood at

the molecular level, this conformation is often associated with central antidepressant activity. The methylene group of anthrone 64 is acidic by virtue of doubly vinylic activation by the carbonyl group.

Thus, treatment with methyl iodide and base

leads to the 9,9-dimethyl derivative 65.

Grignard

reaction with 6-dimethylaminopropyl magnesium chloride

Polycyclic Aromatic Compounds

220

gives tertiary carbinol 66 and subsequent acid dehydration produces melitracen (67), an antidepressant.22 CH

HO

CH

3^^H3

(CH2)3N(CH )

Vl

(67)

The same nonpolar conformation can be achieved by conversion to bicyclic structures.

1,4-Cyclo-

addition of ethylene to anthracene-9-carboxylic acid gives acid 68.

Successive conversion to the N-

methylamide, via the acid chloride, followed by reduction with lithium aluminum hydride produced benzoctamine (69), a sedative and muscle relaxant.

(68)

23

(69)

Lengthening the side chain produces the antidepressant maprotiline (73), which has a topological relationship to the clinically useful tricyclic antidepressants.

The requisite acid is constructed by

conjugate addition of the carbanion of anthrone (64) to acrylonitrile, followed by hydrolysis to give 70. Reduction of the carbonyl group with zinc and ammonia gives anthracene 71 by dehydration of the intermediate

Polycvclic Aromatic Compounds

221

alcohol function.

Diels-Alder reaction with ethylene 23 gives 72, which is converted to maprotiline (73) by the same three-step sequence as used for benzoctamine.

(CH2)2CO2H (70)

(13) 5.

DIBENZOCYCLOHEPTANES AND DIBENZOCYCLOHEPTENES

Drugs in this structural class have effected a revolution in the treatment of severely depressed patients such that deinstitutionalization is a feasible public policy.

The compounds often show other CNS activities

which depend on the length of the side chain.

One-

carbon chains generally lead to anticonvulsant activity; amines separated from the nucleus by three carbons usually donvey antidepressant activity. Selected examples possess significant anticholinergic activity. Reaction of chlorodibenzocycloheptatriene 74 with butyl lithium, followed by carbonation produces acid 75, which is converted by ammonia, via the acid chloride, to citenamide (76), an anticonvulsant. The partially saturated analogue 77 is prepared

Polycyclic Aromatic Compounds

222

essentially the same way from chlorodibenzocycloheptadiene and is cyrheptamide, also an anticonvul25 sant. In the dihydro series the two benzene rings are not only out of plane, but also helical with respect to one another.

cox (7_5j X = OH (76.) X = N H 2

(77)

Base-catalyzed condensation between phenylacetic acid and phthalic acid produces enol lactone 78, which is reduced to benzoate 79 with HI and phosphorous.

Friedel-Crafts cyclization by polyphosphoric

acid followed by reduction produces alcohol 80.

This

alcohol forms ethers exceedingly easily, probably via the carbonium ion.

Treatment with N-methyl-4—

piperidinol in the presence 6f acid leads to the antidepressant hepzidine (81).

OR (78)

(79)

(8_0) R = H (8T) R = — (

NCH 3

Polycyclic Aromatic Compounds

223

Inclusion of an acetylenic linkage as part of the side chain is apparently consistent with antidepressant activity. Reaction of propargyl magnesium bromide with dibenzocycloheptadieneone leads to carbinol 82.

A Mannich reaction with formaldehyde

and dimethylamine leads to 83 which, upon dehydration with SOC1 9 and pyridine, was transformed into 27 intriptyline (84), an antidepressant.

HO

Rigidity can be achieved with retention of the overall molecular conformation by use of a cyclopropyl ring in place of the olefinic bond bridging the two benzenes.

Treatment of dibenzocyclohepta-

trieneone with dichlorocarbene generated from dichloroacetic ester and sodium ethoxide gives addition product 85.

Reaction with cyclopropyl Grignard

reagent gives carbinol 86 from which the gem-dihaloatoms are removed by lithium and t-butanol to give 87*

Reaction of the latter with HC1 generates

chloride 88 via the intermediate cation (87a). Chloride displacement with methylamine completes the 28 synthesis of antidepressant octriptyline (89). Incorporation of the side chain amino group into a ring leads to tranquilizers.

This is of special

interest in that the amino group is now separated

Polycyclic Aromatic Compounds

224

Cl

H

Cl

H

(85)

(88.) X - Cl (89) X = NHCH,

from the tricyclic ring system by a smaller distance than is common to the other agents discussed.

Reaction

of amine 90 with 6-lactone 91 gives hydroxyamide 92. Cyclodehydration proceeds apparently through the expected Bischler-Napieralski intermediate 93 which cyclizes further to imine 94*

Reduction with sodium

borohydride or hydrogenation with platinum catalyst produces the undesired a is isomer.

On the other

hand, zinc and acetic acid reduction leads to the thermodynamically stable trans product, the minor tranquilizer taclamine (95)/29

The apparent confor-

mation of taclamine is 96. An alternate means of forming 96 arises from reaction of imine 97 with methylvinylketone in a variant of the Robinson annulation reaction.

This

u=o

225

Polycyclic Aromatic Compounds

226

can proceed in two directions, but 98 is the major product.

Formation of the dithiolane derivative with

(CH 2 SH) 2 and BF 3 followed by Raney nickel desulfurization also leads to taclamine.

The availability of

ketone 98 makes it possible to prepare more highly functionalized derivatives. Addition, for example, of t-butyl lithium leads to tranquilizer butaclamol (99). 30 The large alkyl group is equatorial.

(98)

6.

TETRACYCLINES

Still among the most frequently prescribed drugs, the antibiotic tetracyclines have decreased in popularity recently due to development of bacterial resistance in the clinic.

The search for improved agents goes

on. When oxytetracycline (100) is reacted with N-chlorosuccinimide in dimethoxyethane, the active methine group at C-..

reacts and, apparently, there

is formed a hemiketal bond between the C,-OH and the o

C 12 -ketogroup (101).

Dehydration with anhydrous HF

of the tertiary, benzylic C^-OH group takes an exocyclic course, partially because aromatization to

Polycyclic Aromatic Compounds

CH-

OH

OH

N(CH_) 9

:

:

227

32

COWL

'CON! I,

(102)

the naphthalene system is forbidden by the presence of the blocking C-,-. -chlorine atom.

The product is

sufficiently stable to allow electrophilic aromatic substitution.

Reaction with N-chlorosuccinimide in

liquid HF results in formation of the 7,lla-dichloro6-methylene analogue (102),

When the latter is

subjected to chemical reduction (with sodium bisulfite, for example), the labile C,, -Cl atom is removed and meclocycline

(103) is formed.

This broad spectrum

antibiotic is about six times more potent in vitro against Klebsiella pneumoniae than methacycline itself. 31

228

Polycyclic Aromatic Compounds

Nitro derivative 104 is an undesired side product m the synthesis of minocycline.32 Upon catalytic reduction it is converted to the corresponding aniline, amicycline (104). This substance is slightly less than half as active in vitro against Staphx/lococcus aureus than chlortetracycline (100), but is nearly twice as active as its C 7 isomer.33,34

'CONIL

(104) X = 0 f 105) X = II

REFERENCES 1.

B. Elpern and J. B. Youlus, U. S. Patent 3,509,200 (1970); Chew. Abstr. , 73: 14,546b (1970). 2. P. Vanhoff and P. Clarebout, German Patent 2,060,721 (1971); Chem. Abstr., 75: 76,463x (1971). 3. A. Kandel and P. M. Lish, Belgian Patent 667,739 (1966); Chem. Abstr., 65: 8,844c (1966). 4. T. Y. Shen, B. E. Witzel, H. Jones, B. O. Linn and R. B. Greenwald, German Patent 2,039,426 (1971); Chem. Abstr., 74: 141,379x (1971). 5. G. Cavallini, E. Milla, E. Grumelli and F. Ravenna, II Farmaco, Ed. Sci., 10, 710 (1955).

Polycyclic Aromatic Compounds

6.

7. 8. 9. 10.

11. 12. 13. 14. 15. 16. 17. 18.

19.

229

J. A. Barltrop, R. M. Achison, P. G. Philpott, K. E. MacPhee and J* S. Hunt, J. Chem. Soc., 2928 (1956). T. Noguchi, Y. Hashimoto, K. Miyazaki and A. Kaji, Yakugaku Zasshi, 88, 335 (1968). M. Giannini, P. Boni, M. Fedi and G. Bonacchi, II Farmaco, Ed. Sci., 28, 429 (1973). B. R. Luchesi, German Patent 2,333,965 (1974); Chem. Abstr., 80: 95,610n (1974). M. Harfenist, R. B. Burrows, R. Baltzly, E. Pederson, G. R. Hunt, S. Gurbaxani, J. E. D. Keeling and 0. 0. Standen, J. Med. Chem., 14, 97 (1971). W. R. McGrath and E. M. Roberts, Belgian Patent 654,632 (1965); Chem. Abstr. , 65: 669c (1966). E. Szarvasi, L. Neuvy and L. Fontaine, Compt. Rend. , 260, 920 (1965). E. Szarvasi and L. Neuvy, Bull. Soc. Chim. Fr. , 1343 (1962). R. Sarges, German Patent 2,018,135 (1970); Chem. Abstr., 74: 22,601b (1971). Anon., Dutch Patent 6,413,268 (1965); Chem. Abstr., 63: 13,178c (1965). Anon., French Patent 1,390,056 (1965); Chem. Abstr., 62: 16,162d (1965). E. J. Merrill, J. Pharm. Sci., 60, 1589 (1971). F. P. Hauck, C. M. Cimarusti and V. L. Narayanan, German Patent 2,258,995 (1973); Chem. Abstr., 79: 53,096y (1973). L. F. Fieser, J. P. Schirmer, S. Archer, R. R.

230

Polycyclic Aromatic Compounds

Lorenz and P. Pfaffenbach, J. Med. Chem. , 10, 513 (1967). 20.

E. Stiller, P. A. Diassi, D. Gerschutz, D. Meikle, J. Moetz, P. A. Principe and S. D. Levine, J. Med. Chem., 15, 1029 (1972).

21.

R. E. Allen, E. L. Schumann, W. C. Day and M. G. Van Campen Jr., J. Am. Chem. Soc. , 80, 591 (1958).

22.

E. R. Andrews, R. W. Fleming, J. M. Grisar, J. C. Kihm, D. L. Wenstrup and G. D. Mayer, J". Med. Chem. , 17, 882 (1974).

23.

T. Holm, Acta Chem. Scand., 17, 2437 (1963).

24.

M. Wilhelm and P. Schmidt, Helv. Chim. Acta, 52, 1385 (1969).

25.

M. A. Davis, S. O. Winthrop, R. A. Thomas, F. Herr, M.P. Charest and R. Gaudry, J. Med. Chem., 7, 88 (1964).

26.

M. A. Davis, S. 0. Winthrop, J. Stewart, F. A. Sunahara and F. Herr, J. Med. Chem. , 6, 251 (1963).

27.

C. Van der Stelt, A. F, Harms and W. T. Nauta, J. Med. Chem., 4, 335 (1961).

28.

J. F. Cavalla and A. C. White, British Patent 1,406,481 (1975); Chem. Abstr. , 84: 4,744c (1976).

29.

W. E. Coyne and J. W. Cusic, J. Med. Chem., 17, 72 (1974).

30.

F. T. Bruderlein, L. G. Humber and K. Pelz, Can J. Chem., 52, 2119 (1974).

31.

F. T. Bruderlein, L. G. Humber and K. Voith, J. Med. Chem., 18, 185 (1975).

Polycyclic Aromatic Compounds

32.

33. 34. 35.

231

R. K. Blackwood, J. J. Beereboom, H. H. Rennhard, M. Schach von Wittenau and C. R. Stephens, J. Am. Chem. Soc., 83, 2773 (1961). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 215 (1977). J. H. Boothe, J. J. Hlavka, J. P. Petisi and J. L. Spencer, J. Am. Chem. Soc, 82, 1253 (1960). J. Petisi, J. L. Spencer, J. J. Hlavka and J. H. Boothe, J. Ned. Chem., 5, 538 (1962).

8

Five-Membered Heterocycles Heterocyclic compounds occupy a central position among those molecules that make life possible.

In

support, one need only mention the molecular basis of continuation of a given species, i.e., the heterocyclic purines and pyrimidines that form the building blocks of DNA and RNA.

This realization, along with

some early adventitious successes with heterocyclic drugs and the frequency with which the active principles of the important vegetable drugs of antiquity turned out to be heterocycles have led the medicinal chemist to devote a good deal of attention to this class of compounds as a source of potential therapeutic agents.

Perhaps as a result of this, somewhat

over half the organic drugs to have been assigned generic names are heterocyclic molecules.

It does

not, however, follow that all biologically active molecules that contain a heterocyclic moiety owe 232

Five-Membered Heterocycles

233

their activity to that fragment.

As will be seen

below, some classes of heterocycles do share a common biological response; in those cases it is of course a fair assumption that the heterocycle is a significant part of the pharmacophore.

Cases are equally frequent,

however, where it is apparent that the ring contributes little of a specific nature to the activity.

A

relatively neutral heterocyclic ring can often be substituted for a benzene ring with little qualitative effect on biological activity.

For example, medicinal

chemists often substitute a thiophene ring for a benzene ring in a drug.

This practice is the venerable

device of biological isosterism. 1.

DERIVATIVES OF PYRROLE

Molecules whose sole heterocyclic moiety consists of a pyrrolidine ring are dealt with elsewhere in this book.

There is a wealth of evidence to indicate that

N-alkylpyrrolidine is usually a surrogate for a tertiary amine. The large class of antiinflammatory phenylacetic acids are treated at some length in Chapter 4.

A

number of these agents consist of acetic or propionic acids substituted'by an aroyl group.

It is of interest

that the central benzene ring of these molecules can be replaced by pyrrole with retention of activity. For example, Mannich reaction of N-methylpyrrole affords the corresponding dimethylaminomethy1 derivative (2) and treatment with methyl iodide affords the quaternary salt (3).

Displacement of the quaternary

amine by means of cyanide leads to the substituted

234

Five-Membered Heterocycles

acetonitrile 4,

Friedel-Crafts acylation of that

intermediate with the acid chloride from p-toluic acid gives a mixture of the 4-aryl ketone and the desired ketone 5.

Hydrolysis with sodium hydroxide

completes the synthesis of the antiinflammatory agent tolmetin (6).2

9 (I)

C2)

(3)

CH 3

W

(5)

"

IH

(6)

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case.

Condensation of p-

chloroaniline with hexane-2,5-dione (or its dimethoxytetrahydrofuran equivalent) affords pyrrole 7*

The

acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9); the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac

/77X

Five-Membered H e t e r o c y c l e s \ /

\ /

235

ci

Cl

A change in both the substitution pattern and the oxidation state of the heterocyclic ring leads to a compound that exhibits antidepressant activity. This agent, cotinine (13), is found in nature as a product from the autoxidation of nicotine (12) (note the anagram).

The compound can also be obtained in

decidedly modest yield by oxidation of nicotine with 4 hydrogen peroxide.

(13)

Five-Membered Heterocycles

236

A more highly substituted pyrrolidone, doxapram, shows activity as a respiratory stimulant.

Prepara-

tion of this agent involves an interesting rearrangement, which in effect results in a ring exchange reaction,

Alkylation of the anion from diphenylaceto-

nitrile with the chloropyrrolidine 14 affords 15. Hydrolysis of the nitrile function leads to the

CN

CO2H I C2H5

C2"5 (14)

(15) (16)

C2H5

OJD

,CH2CH2CT

expected acid 16.

rCU2CH2N

Treatment of 16 with thionyl chlor-

ide presumably gives first the acid chloride 17; internal acylation would then lead to the bicyclic

Five-Membered Heterocycles

quaternary ammonium salt 18.

237

Attack on the two-carbon

bridge by the gegenion would afford the observed chloroethyl pyrrolidone 19.

(Regioselectivity may be

due to the hindered environment about the one carbon bridge.)

Displacement of chlorine by morpholine

completes the synthesis of doxapram (20). The discovery of the sedative/hynoptic activity of derivatives of barbituric acid has led to very extensive dissections of that molecule.

One outcome

of this work is the realization that acylurea and acylamide derivatives often exhibit CNS depressant activity.

A fair number of such molecules have been

prepared that contain a succinimide or glutarimide pharmacophore.

For example, Michael addition of

cyanide to the stereochemically undefined cinnamate 21 affords intermediate 22.

Acid hydrolysis leads

directly to the tranquilizer fenimide (23).

Although

the stereochemistry of this compound is not specified, the fact that the ethyl group resides on an enolizable center makes it probable that this is in fact the thermodynamically more stable isomer.

C2H5

"

"

'

f

'-H-

~

^

-^

CH = CH

/ CH 3 (21)

\ CO

2C2H5 (12)

(23)

C2H5

238

Five-Membered Heterocycles

2.

DERIVATIVES OF FURAN

Many carbonyl derivatives of 5-nitrofurfural exhibit bacteriostatic activity.

For example, the oxime,

nifuroxime, has found some clinical use in the treatment of infections of the gastrointestinal and urinary tract.

An impressive amount of work has been devoted

to such derivatives in attempts to alter both their distribution and pharmacodynamics by modification of the substituents on the imine nitrogen. was detailed in the earlier volume.

Much of this

By way of addi-

tional examples, reaction of 5-nitrofurfural (24) with N-(2-hydroxyethyl)hydroxylamine gives the anti7 microbial agent nitrofuratrone (25), probably the only nitrone to have been assigned a generic name. In a similar vein condensation with 2-ethylsemicarbazide leads to the semicarbazone nitfursemizone Q

(26),

an antiprotozoal agent for use in poultry.

0 2 N' " ° ' "CH=NCH 2 CH 2 OH

02N

0

CHO

O2^ ^ ° " "CH=NNCNH 2 C2H5

f2_5)

(2±)

(26.)

N-Aminoimidazolinones have found extensive use as synthons for such nitrofurans.

Reaction of an

appropriate 1,2-diamine (27, 31) with urea gives the desired heterocycle (28, 32).

Nitrosation with

Five-Membered Heterocycles

2 39

nitrous acid, followed by reduction of the intermediate (29, 33) with zinc, gives the desired hydrazine (30, 34).

Condensation of 30 with 24 affords nifurdazil

(35).

In a modification of the usual scheme, conden-

sation of 34 with furfuraldehyde gives the hydrazone 36.

Nitration of that intermediate affords nifurimide 10

(37).

i (IT) (n)

R 1 =CH 2 CH2OII R2 =11 R'=H,

R 2 = CII3

(.28)

S

R1 = CH2CII2OH R2 = H

(32.) R ' = H ,

0

(29.) R' = CH2CM2OH R2 = H

R2 = CH3

(.33)

R'=ll,

R2 = CH3

(50)

R'=CI1 2 CH 2 OH R2 = H

{^~)

R. s | l f

R2

=CH

A NN

(M) X = H (37) X = N0 2

c,,2CM,on N

C35)

It is of interest that antibacterial activity can be retained even when the imine carbon-nitrogen bond is replaced by a carbon to carbon double bond. Base-catalyzed condensation of 5-nitrofurfuraldehyde (24) with 2,6-dimethylpyridine (38) affords olefin 39.

Treatment of this compound with hydrogen peroxide

gives the corresponding N-oxide (40).

Heating of

240

Five-Membered Heterocycles

that intermediate in acetic anhydride leads to acetoxylation of the 2-methyl group by the Polonovski reaction. Hydrolysis of the ester group affords nifurpirinol

(42).11

CH3

(38)

(4JJ R = COCH3 (4_2_) R = H

(39)

(£0)

Taking the spacer ethylene moiety o u t and attaching a heterocyclic ring directly to the nitrofuran ring also results in an active antimicrobial agent* Condensation of bromoketone 43 (obtainable b y halogenation of the corresponding acetylnitrofuran) with thiourea gives the aminothiazole 44. Although the detailed mechanism of this well known method for forming thiazoles is still under discussion, the reaction at least formally represents conversion o f the ketone to an imine and displacement o f the halogen by sulfur. Next, the primary amine is nitrosated

Five-Membered Heterocycles

241

(45), and this intermediate is reduced to the hydrazine (46).

Acylation of the more basic terminal

nitrogen with formic acid completes the synthesis of 12 the antimicrobial agent nifurthiazole (47).

NINHCHO (£4) R = H (£5) R = N02 (£6) R = Nil 2

(42)

Interposition of a phenyl ring between the furan and the nitro group radically changes the biological activity; product from this formal replacement is in fact a centrally acting muscle relaxant.

In order to

prepare the target lead, reaction of the diazonium salt (49) from p-nitroaniline (48) with furfural using cupric chloride as catalyst affords the coupling product 50.

In a convergent synthesis, glycine

derivative 51 is converted to the urea 52.

Acid-

catalyzed cyclization leads to aminohydantoin 53. Semicarbazone formation from aldehyde 50 with hydrazine 13

derivative 53 affords dantrolene (54).

242

02N

Five-Membered Heterocycles

f \-NX -AV*

(49) X = N ®

{ }

~ / ) *-02NV ~~-< H= r-// y—^ ° JP-l|0 C (54) HN N H C H C O C H * " ^ ^ N ^ "' *""''' J> 2 2 225 (53

3,

DERIVATIVES OF IMIDAZOLE

In its various oxidation states, the imidazole nucleus has proven to be an unusually fertile source of medicinal agents,

Nitroimidazoles are very often

associated with antimicrobial activity, whereas imidazolines are often present in drugs acting as adrenergic agents.

These considerations suggest, as

a working hypothesis, that these particular imidazole derivatives are integral parts of the respective pharmacophores.

Five-Membered Heterocycles

24 3

While nitrofurans are often prepared as antibacterial agents, nitroimidazole forms the basis for an extensive class of agents used in the treatment of infections by the protozoans. Unlike bacterial infections, protozoal infections are seldom life-threatening.

The physical discomfort occasioned

by such infections is, however, of sufficient importance to provide a useful therapeutic place for antiprotozoal agents.

A particularly common set of

such conditions are parasitic infections of the genitalia caused by Trichomonas vaginalis.

These

disorders are called trichomoniasis. One of the problems complicating the chemistry of the imidazoles needed for preparing these agents is their structural ambiguity.

Imidazoles undergo a

facile tautomeric equilibrium involving a shift of the proton on nitrogen so that it is sometimes difficult to assign unambiguous structures to unsymmetrically substituted derivatives.

Most drugs containing

this ring system are alkylated on one of the ring nitrogens, which locks the molecule into a single tautomeric form and removes the source of ambiguity. The ambident character of imidazoles requires care in selecting those conditions that will lead to alkylation on the desired nitrogen atom. By way of illustration, nitration of 2-isopropylimidazole (55) affords the 4- or 5-nitro derivative (56, 57). isomer 58.

Alkylation with methyl iodide affords The same reaction carried out with di-

methyl sulfate under neutral or acidic conditions provides the isomer methylated at the alternate

244

Five-Mexnbered Heterocycles

nitrogen atom.

There is thus obtained the anti14 protozoal agent ipronidazole (59).

CH 3

CH

3

CSS)

(57)

(59)

In a similar vein, alkylation of 4-(5)-nitroimidazole with N-(2-chloroethyl)morpholine affords a mixture of N-alkylated imidazoles (61 and 62).

The

compound containing the adjacent ring substituents (61) is the antitrichomonal agent nimorazole.

Five-Membered Heterocycles

24 5

/ C CH2CH2 2N

I CH2CH2N (60)

>

0 f

(6T)

Acetylation of the hydroxymethyl imidazole 63 affords the corresponding ester (64), nitration (65) followed by hydrolysis gives intermediate 66, and reaction of this alcohol with potassium cyanate in hydrogen fluoride gives the carbamate ronidazole

(67).16

8 ^H L 3 R =H (63) " ( — 6

5

I CH, R= COCH-

) -;

R

.

02

N

II

CH 2 OCNH 2

ICHT

H

Treatment of 2-methyl-4-(5)-nitroimidazole at reduced temperatures with N-benzoylaziridine in the presence of boron trifluoride etherate leads regiospecifically to the N-alkylated derivative (69). Hydrolysis of the amide function affords the primary amine 70.

Acylation of this with methylchlorothio-

formate affords the antiprotozoal thioncarbamate, 17 carnidazole (71). The same sequence, starting with the C-2 ethyl analogue (72) affords sulnidazole

(75).17

\ 0

24 6

Five-.Membered Heterocycles

CH2CH2NHCOC6H5 ("6J0 R=CH3 f Z2) R=C2H5

f^9) R = CII3 (7_3-) R=C2H5

^ ^ m 2' 2 (-70) f~}

R = CH R= Q

*

CH2CH2NHCOCH3 » (71) R = CH ^ R = C2H5

Hydroxymethylation (formaldehyde) of nitroimidazole 76 affords 77, which is oxidized to aldehyde 78. To prepare the other fragment for this convergent synthesis, reaction of epichlorohydrin with morpholine leads to the aminoepoxide 79, which is reacted with hydrazine to afford 80* Reaction of this substituted hydrazine with dimethyl carbonate affords oxazolinone 81 by sequential ester interchange reactions. Condensation of 81 with aldehyde 78 affords the antitrichomonal agent moxnidazole (82). 18 Nitroimidazoles substituted by an aromatic ring at the 2-position are also active as antitrichomonal agents. Reaction of p-fluorobenzonitrile (83) with saturated ethanolic hydrogen chloride affords iminoether 84. Condensation of that intermediate with the dimethyl acetal from 2-aminoacetaldehyde gives the imidazole #5. Nitration of that heterocycle with nitric acid in acetic anhydride gives 86. Alkylation with ethylene chlorohydrin, presumably under neutral conditions, completes the synthesis of the antitrichomonal, flunidazole (87). 19

0

CJ

ffi

a: CJ ;

o

o

CJ CJ > 5 -

0 *CJ

u T—t

CJ

247

248

Five-Membered Heterocycles

(83)

^ ^

OC 2 H 5

(84)

H2NCH2CH(OCH3)2

| CH 2 CH 2 OH (86)

CiZ.)

Imidazoles devoid of the nitro group no longer show useful antiprotozoal activity, however, several

XCH?C—(( L

x

\—Cl f

Cl (81) X - H (89) X = Br

„. ».

/^N KI

\\

JT~\

M r , I J I o f ,—//

\

•* r1

/ ^ i t r H ru __jF~~\ N

^

J^CH2CH-^

/ Cl

cf

C90)

Cl.

y—

(91,)

_

.Cl

IT

Cl.

(93)

^

SI

Five-Membered Heterocycles

24 9

such compounds have proven to be efficacious as antifungal agents.

Alkylation of imidazole with

bromoketone 89 prepared from 2,4-dichloroacetophenone (89) affords the displacement product 90*

Reduction

of the carbonyl group with sodium borohydride gives the corresponding alcohol 91.

Alkylation of the

alkoxide from that alcohol with 4-chlorobenzyl chloride

20

leads to econazole (92) ; alkylation with 2,4-di,420 chlorobenzyl chloride gives miconazole (93). Ethonam (99), an imidazole derivative with a very different substitution pattern, is also reported to possess antifungal activity.

To prepare it,

alkylation of aminotetralin 94 with methylchloroacetate gives the glycine derivative 95.

Heating

with formic acid then affords the amide 96; this compound is then reacted with ethyl formate to yield hydroxymethylene ester 97.

Reaction with isothio-

cyanic acid gives the imidazole-2-thiol 98.

OHC NH2

NRCH2CO2C2H5

[940

CO2C2H5

(99)

(The

CHOH II

250

Five-Membered Heterocycles

sequence may involve first hydrolysis of the formamido group, followed by addition of the amine to isothiocyanic acid; cyclization of the thiourea nitrogen with the formyl function would complete formation of the heterocycle.) Desulfurization by means of Raney 21 nickel finishes the synthesis of ethonam (99). Not a hormone in the true sense of the word, histamine (100) does act as a potent mediator, leading to a host of biological responses.

Many of the

symptoms attributed to allergies owe their manifestations to exaggerated reaction to endogenous histamine released in response to an external stimulus• Secretion of gastric acid is another process under the control of histamine.

It was hypothesized quite some

time ago that pathological conditions traceable to excess histamine secretion or exaggerated sensitivity to that base could be treated by compounds that antagonized the response to histamine by competition for its receptor sites.

The benzhydryl type anti-

histaminic compounds for the treatment of allergic diseases represent such competitive inhibitors. It was noted, however, that a subset of responses known to be triggered by histamine failed to be blocked by the classical antihistaminic drugs.

This,

as well as further sophisticated pharmacological work, led to the classification of histamine receptors as EL and EL.

To simplify grossly, the EL receptor

controls the responses familiar to every hayfever sufferer; these effects can be alleviated readily by classicial antihistamines.

The latter interestingly

bear little or no structural similarity to histamine

Five-Membered Heterocycles

itself.

251

The EL receptor on the other hand controls

secretion of acid in the stomach; classicial antihistamines have no effect on histamine-induced gastric acid secretion.

Excess gastric acid secretion is

believed by many to be intimately involved in the etiology of ulcers and exacerbation of preexisting ulcers; thus, compounds that can act as selective antagonists to the EL receptor are of considerable potential therapeutic significance. The EL antagonists were developed serendipitously in the course of random screening.

On the other

hand, development of the H~ antagonists started from the premise that one of the best ways to produce an antagonist is to investigate compounds that bear some structural elements of the native agonists.

Pre-

cedence for this came from comparison of the structure of p-adrenergic agonists and their blockers.

Systema-

tic modification of the histamine molecule achieved its first success toward the preparation of an HL 22 antagonist with burimamide (107). Esterification of diamino acid 101 leads to 102.

Reduction with sodium

amalgam serves to convert the ester to a carbinol (103), and treatment of that aminoalcohol with ammonium isothiocyanate affords the imidazothione 105, probably by the intermediacy of thiourea 104.

(Strict

accounting of oxidation states seems to demand oxidation of the carbinol to an aldehyde in the course of this reaction.)

Reduction of the thione with iron

powder in acid probably proceeds via the enol form to 23 afford the desired imidazole (106). Condensation

Five-Membered Heterocycles

252

with methyl isothiocyanate completes the synthesis of burimamide (107)*

CH2CH2NH2

CH2CH2NH2

N N (100) HOCH2CH(CH2)4NH2

NH (101) R = H (102) R = C2H5

NH 2

n s

(103)

(104)

fCH2) 4NIICNIICH3

(CH 2 ) 4 NH 2

I-CNH ; 10 7j

(106)

(CH 2 ) 4 NH 2

n s (105)

Further exploration of the histamine molecule revealed that addition of a methyl group to the 4-position led to an agonist with appreciably increased selectivity 24 for the H 2 receptor. Application of that principle to the prototype antagonist, as well as bioisosteric replacement of one of the side chain methylene groups 25 by sulfur, affords metiamide (111). Reduction of the imidazole carboxylic ester 108 gives the corresponding carbinol (109).

Reaction of that with 2-

mercaptoethylamine, as its hydrochloride, leads to intermediate 110.

In the strongly acid medium, the

Five-Membered Heterocycles

253

amine is completely protonated; this allows the thiol to express its nucleophilicity without competition and the acid also activates the alcoholic function toward displacement. Finally, condensation of the amine with methyl isothiocyanate gives metiamide (111).

Side effects observed in some of the clinical

trials with this agent were attributed to the presence of the thiourea function in the molecule.

A system-

atic search for a functional group isoelectronic with thioureas revealed that cyanoguanides were biologically equivalent, and this substitution avoided the side effects of the former.

In one of the schemes

for preparing the desired product, primary amine 110 is reacted with complex nitrile 112* CH3

-CO2C2H5

N

CH3

V

X

.CH2OH

•CH 2 SCH 2 CH 2 NH 2

3

H N

N

(110)

(109)

(108)

The resulting

/J NHCH3

NCN IIII CH 2 SCH 2 CH 2 NHCNH CH 3

CH

CH3SC

MCN

NN

I CH

(112)

(113)

3

(HI)

addition-elimination sequence affords the highly successful agent for the treatment of ulcers, cimetidine

(113).25

254

Five-Membered Heterocycles

Imidazole provides the nucleus for the antineoplastic agent dacarbazine (116).

Diazotization of

the commercially available aminoamide 114 with nitrous acid gives diazonium salt 115. Reaction of this salt with dimethylamine under anhydrous conditions leads to dacarbazine (116).

The diaryl indole, indoxole (117, see Chapter 11) represents a unique nonsteroidal antiinflammatory agent in that it lacks the labile acidic proton usually found in this class of drugs. Commercialization of indoxole was precluded by its marked photosensitizing side effect.

Subsequent work from another

laboratory showed that biological activity was retained when the indole nucleus was replaced by imidazole.

Condensation of 4,4f-dimethoxybenzil with

ammonium acetate and the ethyl hemiacetal of trifluoroacetaldehyde affords the aniinflammatory agent 27 flumizole (120) in a single step. The reaction can be rationalized by assuming either initial formation of a carbinolamine followed by condensation with one of the aryl carbonyls, or, alternately, by formation of an imine with one of the carbonyls followed by attack on the hemiacetal.

Repetition of the process

and tautomerization will lead to the imidazole ring.

Five-Membered H e t e r o c y c l e s

255

(117) ,OCH3 OH CF3CH^ (119) OCH3

t)CH3 (120) (118)

The pharmacology of both the endogenous amines and drugs that act on the sympathetic nervous system can be best explained by assuming that responses are mediated by two different types of receptors.

The

existence of a- and p-adrenergic receptors has by now received considerable experimental backing.

(It

might be added as an aside that there is considerable evidence that these two classes of receptors can be further subdivided into p. and p~ and possibly or. and a 2 receptors.)

It is an interesting fact that with

few exceptions, drugs that act on the p-adrenergic system all possess some chemical elements of the endogenous agonist epinephrine. In contrast to this, there are no such structural constraints on a-adrenergic agonists or antagonists. Some of the most active a-sympathomimetic agents in fact contain an imidazoline moiety as part of the pharmacophore.

The appropriate ring system can be

256

Five-Membered Heterocycles

formed by a variety of methods.

One of the more

common involves condensation of a compound containing a carbon atom at the acid oxidation level (nitrile, imino ether) with ethylenediamine.

Thus, reaction of

the benzothiophenoacetonitrile derivative 121 with ethylenediamine gives the adrenergic a-agonist metizo28 line (122). As expected the a-adrenergic activity of 122 is expressed as vasoconstriction.

The compound

is used topically as a nasal decongestant, acting on the mucosal vasculature. In a similar vein, condensation of carboxylic acid 123 with ethylenediamine leads to domazoline (124).29

,CH2CS£N

(

(121)

CH3—^

^

^> CH3

CH2CO2H OCH3

0CH

3

(123)

Interposition of an oxygen atom between the aromatic ring and the imidazoline-bearing side chain leads to a compound reported to show antidepressant activity.

Its preparation begins with alkylation of

phenol 125 with chloroacetonitrile to afford intermediate 126.

Condensation of that nitrile with the

Five-Membered Heterocycles

257

mono~p-toluenesulfonamide from ethylenediamine affords 30 the antidepressant imidazoline, fenmetozole (127)*

NH2(CH2)2NHSO2-

ci

y=ss

Cl

(125)

'

Cl.

(126)

(127)

Preparation of a rather more complex imidazoline drug starts with the alkylation of the carbanion from p-chlorophenylacetonitrile (128) with 2-bromopyridine. Reaction of the product (129) with ethylenediamine serves to form the imidazoline ring (130).

Air

oxidation then affords the tertiary carbinol by attack at the highly activated, multiply benzylic carbon. dazadrol

There is thus obtained the antidepressant (131).31

CH2CN

CHCN

-C

HO-C

(131)

258

Five-Membered Heterocycles

Replacement of hydrogen by fluorine in biologically active compounds often leads to marked increases in potency.

Although much work has gone into incor-

poration of fluorine in various drug series, compounds in which all the protons are replaced by that halogen atom are rare.

One such relatively simple molecule

in which only the active hydrogens remain shows sedative activity. Condensation of the imine from hexafluoroacetone (132) with sodium cyanide leads to a trimer which incorporates the cyanide (135)* The sequence can be rationalized by assuming, as the first step, addition of cyanide to the imine function to form an aminonitrile (133)*

Reaction of the amine

function with a second molecule of imine leads to the aminal 134*

Cyclization, followed by reaction of the

newly formed imine function with a third molecule of 133, gives the observed product as its sodium salt (135).

Acidification (136), followed by hydrolytic

CP3

CN

V=NH

NH

CF 3

(132)

(Hi)

(133) CHi

CF3

NH

NH2

CNH-j

CF 3

CF-

CF, HN"

(137)

CF,

(136)

Five-Membered Heterocycles

259

removal of the exocyclic aminal in strong acid, affords the sedative midaflur (137). 3 2 CNS activity apparently is retained when the heterocycle is changed to an imidazolidinoneAlkylation of the anion from the imidazolidinone 138 with dimethylaminoethyl chloride affords imidoline 33 (139), a compound with tranquilizer activity. 0 •N

/CH3 NCH 2 CH 2 N

CH3 CI

Cl

(139)

(138)

The imidazole ring system provides the nucleus for two diuretic agents with structures unusual for that activity.

Reaction of the N-cyanoaniline 140

(obtainable from the aniline (139) and cyanogen bromide) with N-methylchloroacetamide leads to the heterocycle 142*

The sequence can be rationalized by

NHR

x = R = H

(140) X = H, R= CN X - Cl, R = H (144) X= Cl, R = CN

(141) X = H (145) X = Cl

(146) x = Cl

Five-Membered Heterocycles

260

assuming N-alkylation of the aniline as the first step (141).

Cyclization of that hypothetical inter-

mediate gives azolimine (142).

The same sequence

starting with p-chloroaniline (143) affords (146).34

clazolimine

Formal interchange of the carbonyl and imino groups and replacement of the methyl group by acetonitrile interestingly affords a compound with antiinflammatory and presumably no diuretic activity. Reaction of p-chlorophenylisocyanate (147, obtained from 143 and phosgene) with iminodiacetonitrile (148) gives the expected urea 149.

Simple heating of that

intermediate leads to condensation of the aniline with a nitrile group and formation of nimazone (150).35'36

it is of interest that this agent is

distantly related to the arylacetic acid antiinflammatory agent by a formal hydrolytic step. —NCH 2 CN

NCH2CN

NCO CH2CN HN

~

I CH2CN

Hydantoins are well-known anticonvulsant agents and as such have found extensive use in the treatment of epilepsy.

Replacement of one of the carbonyl

groups by thiocarbonyl is consistent with anticonvulsant activity.

Thus, condensation of the ethyl ester

Five-Membered Heterocycles

261

of leucine (151) with allyl isothiocyanate gives the thiourea 152*

Cyclization of that intermediate (153).31

affords albutoin

CHCH 2 CHCO 2 C 2 H 5

O\S 6

^

I NH2

CHCH2CHCO2C2H5

CH3

/

I NHCNHCH?CH=CH?

I

S

N

NCH 2 CH=CH 2

n s (153)

4.

DERIVATIVES OF PYRAZOLE

Pyrazolones rank among some of the more venerable nonsteroidal antiinflammatory agents.

The activity

of antipyrine (154) was discovered not too long after that of aspirin.

The preparation of a plethora of

analogues of that compound, all bearing additional substitution at the 4-position, was described in some detail in the earlier volume. The pyrazolone ring is apparently sufficiently nucleophilic to undergo Mannich reaction.

Thus,

condensation of antipyrine with formaldehyde and the substituted morpholine 155 affords directly the 38 antiinflammatory agent morazone (156). It is of interest that 155 has biological activity in its own right; this amphetamine derivative, phenmetrazine,

Five-Membered Heterocycles

262

not surprisingly, shows CNS stimulant and appetite. . 39 suppressing activity.

0

NH CH 2 O

(155) (154)

CH3

\

NaSO3CH2/

CH 3

(157)

CH, .j/^N^

° ¥

CH

3

(158)

Many of the modifications of the pyrazolone antiinflammatory agents are intended to increase the limited hydrophilicity of the parent molecules. Reaction of aminopyrine (157) with formaldehyde and sodium hydrogen sulfite affords dipx/rone (158),

The

first step can be rationalized as an Eschweiler-Clark type N-methylation reaction, with bisulfite acting as the reducing agent.

The resulting mono N-methyl

analogue of 157 then apparently forms the sulfite adduct of the carbinolamine of formaldehyde. 5.

DERIVATIVES OF OXA2OLE AND ISOXAZOLE

As has been noted previously, the benzene ring of the phenylalkanoic acid antiinflammatory agents can be

Five-Membered Heterocycles

263

replaced by a variety of other aryl groups.

However,

each of these subclasses does seem to have its own specific SAR.

In those cases where the aryl group is

phenyl, optimal activity is obtained with a 2-arylated propionic acid; acetic acids are suitable for other classes•

In the case at hand a terminally substituted

propionic acid was chosen for further development. Acylation of aminoketone 159 with the half acid chloride-ethyl ester of succinic acid affords the amide 160. Cyclization by means of phosphorous oxychloride serves to form the oxazole ring.

Sapon-

ification of the ester gives the antiinflammatory 40 agent oxaprozin (162).

—NH 9

TC—CH2CH2CO2C2HE

(159)

(162)

(161)

Amphetamine and its derivatives have been much used—and abused—as weight-reducing agents.

As a

consequence of the CNS-stimulating activity shown by

Five-Membered Heterocycles

264

these agents, they are fairly efficient in suppressing symptoms of hunger.

Much ingenuity has been exercised

towards incorporating the phenylethylamine moiety in various molecules, in attempts to dissociate the anorexic activity of amphetamine from its other effects on the CNS.

Never completely successful,

this work has led to some molecules that look quite unlike the lead compound.

In one study, reduction of

the cyanohydrin from benzaldehyde (163) with lithium aluminum hydride affords the corresponding aminoalcohol 164.

Reaction of this intermediate with

cyanogen bromide in the presence of sodium acetate leads initially to the N-cyano intermediate 165. Acetate is a sufficiently strong base to catalyze the cyclization of the hydroxyl group onto the nitrile. The initially formed iminooxazolidine then rearranges to the more stable aminooxazoline (167) which is OH

OH

£ ff \

CHCN

=-O-I

—f

V-CH CH

CHCH 2 NH 2

(163) X = H (168) X = Cl (173) X = CF 3

(164) X = H (169) X = Cl (174) X = CF 3

(167) X = H (172) X = Cl (177) X = CF 3

O OH U

(i6_5) X = H (170) X = Cl (^75) X = CF 3

(166) X = H (171) X = Cl

(176) x = cr 3

Five-Membered Heterocycles

known as aminorex (167).

41

265 The same sequence starting

from the cyanohydrins of p-chlorobenzaldehyde and p-trifluoromethylbenzaldehyde affords, respectively, clominorex (172)4"1 and fluminorex

(177).41

Formal oxidation of the methylene group in aminorex and dialkylation of the amine affords a compound with antidepressant activity.

This activity

is also not totally unexpected in a compound related, although very distantly, to amphetamine.

Condensation

of the alkoxide obtained from treatment of ethyl mandelate (178) with N,N-dimethylcyanamide can be envisioned to form initially the adduct 179.

Cycli-

zation of the anion onto the ester group then serves to form the oxazolinone ring.

There is thus obtained

the antidepressant thozalinone (180).

CHCO 2 C 2 H 5 OH (178) CH3

CH,

(180)

(179)

Phenx/lephrine (181) is a well-known a-sympathomimetic agent. As a consequence of this activity, the drug is used extensively for those conditions requiring a vasoconstricting agent.

Modification of the func-

tionality so as to include the aliphatic oxygen and basic nitrogen in an oxazolidine ring is compatible with this biological activity.

Condensation of

266

Five-Membered Heterocycles

norphenylephrine (182) with cycloheptanone results in formation of the cyclic carbinolamine derivative ciclafrine

(183).43 OH CHCH 2 NHR

HO (181) R = C (182) R = H

Hydrazides of isonicotinic acid, isoniazid for example, were among the first compounds to be used as antidepressant drugs.

It is generally accepted that

these agents owe their action to increased brain levels of neurotransmitter amines by inhibition of the enzyme monoamine oxidase (MAO),

The pyridine

ring present in these molecules can, interestingly, be replaced by an isoxazole moiety.

Thus, inter-

change of the isoxazole ester 184 with benzylhydrazine affords directly the MAO-inhibiting antidepressant 44 isocarboxazid (186).

CO2C2H5

Oil)

„,

0*1)

CONHNHCH2

(186)

Five-Membered Heterocycles

6.

26 7

DERIVATIVES OF THIAZOLE

The intensive research on p-adrenergic blocking agents has been discussed in some detail in Chapter 5.

As noted there, interposition of an oxymethylene

moiety between the aromatic ring and the aminoalcohol side chain of sympathomimetic agents is often compatible with antagonist activity.

More recently it has

been found that replacement of the aromatic ring in sympathomimetic amines or their antagonists by a heterocycle often gives active compounds (see also timololf below).

In the preparation of one example,

displacement of halogen on 2-bromothiazole (187) by means of the alkoxide from glycerol acetonide (188) affords the ether 189.

Hydrolysis of the acetonide

leads to the glycol 190* Reaction with an equivalent of methanesulfonyl chloride gives the mesylate (191). (Although the terminal mesylate predominates, some secondary ester is probably formed as well; this is CH

3\/CH3

CH3 CH3 HOCH2!HJH2

—

f\ ^

? ? 0CH?CHCH9 l

—

l/-°CH2CHCH2OR (190) R= H

(189)

" C H ^ (Mi)

||^/-OCH2CHCH2 CH3

(192)

26 8

Five-Membered Heterocycles

not separated since it serves just as well for the subsequent reaction.) Exposure of the hydroxymesylate to sodium methoxide results in formation of the epoxide by internal displacement (192). Opening of the oxirane by means of isopropylamine affords finally tazolol (193). This compound, unexpectedly, does not show the properties of a classical p-adrenergic blocking agent; tazolol retains sufficient intrinsic sympathomimetic activity to be described as a cardiotonic agent. As noted above, nitrofurans and nitroimidazoles have proven useful moieties for the preparation of antibacterial and antiprotozoal agents. It is thus of note that nitrothiazoles have also been used successfully in the preparation of antiparasitic agents. Condensation of 6-nitro-2-aminothiazole (194, available from nitration of aminothiazole) with ethylisocyanate yields the antiprotozoal agent nithiazole (195). In a similar vein, condensation IT" O2N

N

(194)

/T"~ ^ NH2

O2N

N

NHCNHC2H4 (195)

NH

(197)

Five-Membered Heterocycles

269

of 194 with 2-chloroethylisocyanat:e leads to the chloroethylurea 196.

Treatment with base serves to

form the pendant imidazolinone ring.

There is thus

obtained the antischistosomal compound niridazole

(197)." The thiazole ring has been found to be an occasional surrogate for a phenyl ring in certain antiinflammatory agents.

Note that the side chain is

restricted to a simple acetic acid in this series. Reaction of p-chloro-2-mercaptoacetophenone (198) with ethyl cyanoacetate in the presence of base affords thiazole 200. The reaction may involve an adduct such as the iminothioether 199 as an intermediate.

Saponification of the ester moiety of 200

then gives the antiinflammatory agent fenclozic acid

(201).48

Cl—ff

\ Nrsrrr

?i HN

CCH2SH

l H C

2 ~S

/ \ CH7CO2C2H5 I l 1$

C2iE)

Cl (200) R= C2H5 (201) R = H

Five-Membered Heterocvcles

270

A distantly related acid with a more highly functionalized ring shows choleretic rather than antiinflammatory activity.

That is, the compound is

useful in those conditions in which the flow of bile is to be increased.

Construction of the thiazolone

ring is accomplished by a method analogous to that used above to build the thiazole ring.

Thus, conden-

sation of ethyl mercaptoacetate with ethyl cyanoacetate leads to the thiazolinone (203); an intermediate such as 202, involving addition of mercaptide to the nitrile function, can be reasonably invoked. Methylation of 203 with methyl sulfate proceeds on nitrogen with the concomitant shift of the double bond to give 204.

Bromination of the active methylene

(205) followed by displacement of halogen by piperidine 49 affords the choleretic piprozolin (206)* NCCH 2 CO 2 C 2 H 5

HSCH 2 CO 2 C 2 H 5

C C2H2O2CC-

L

"C

5

J

N

C 2 H 5 O 2 CCH 2

(203)

C202)

CH3 CII3

(204) C2051

(20b)

7.

MISCELLANEOUS FIVE-MEMBERED HETEROCYCLES

Acylation with 3-chloropropionyl chloride of the

T>

Five-Membered Heterocycles

271

amidoxime 207 from 2-ethylphenylacetonitrile gives the corresponding N-acylated derivative 208.

This

cyclizes to the oxadizole (209) on heating. Displacement of chlorine with diethylamine affords the muscle relaxant-analgesic agent proxazole (210).

\NHCCH 2 CH 2 C1 » (208)

o+a CH22 CH CH 33

CH 2 CH 2 N^ C2H5

C210J Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents.

For example,

the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle.

It is thus of note that the

1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade.

In its preparation, reaction

of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212.

272

Five-Membered Heterocycles OH C1

II H2NCCN +

S 2 C1 2

»»

v

ym ZT^

C1

>.

^OCH2CHCH2C1

^

(221) (212)

r

OCH 2 CHCH 2 NHC(CH 3 ) 3

(2_i_s)

r

cl

OCH 2 CHCH 2 NHCCCH 3 ) 3

(Hi)

Condensation of that intermediate with epichlorohydrin in the presence of a catalytic amount of piperidine affords the chlorohydrin 213, admixed with some epoxide.

Reaction with tertiary butylamine completes

construction of the propanolamine side chain. Displacement of the remaining halogen atom of 214 with morpholine under more strenuous conditions affords timolol

(215).52

A somewhat different scheme is used to gain entry to the alternate symmetrical 1,3,4-thiadiazole ring system.

Reaction of thiosemicarbazide with

isovaleric acid affords the ring system (217) in one step.

The reaction may be rationalized by positing

acylation to intermediate 216 as the first step. Sulfonylation of the amino group of 217 with pmethoxybenzenesulfonyl chloride affords the oral hypoglycemic agent isoJbuzole (218).

Careful

examination of the structure will reveal elements of

273

Five-Membered Heterocycles

CH3

S II H2NNHCNH2

\ CHCH2CO2H

CH (216)

—N

CH-a

CH7 N

CIICIl2 l

S

NIIS

\

°2

NH-;

CHCHf

en

CH (217)

(218)

the sulfonylurea functionality often associated with that activity.

REFERENCES 1.

W. Herz and J. L. Rogers, J. Am* Chem. Soc., 73, 4921 (1951). 2. J. R. Carson, D. N. McKinstry and S. Wong, J. Med. Chem., 14, 646 (1971). 3. G. Lambelin, J. Roba, C. Gillet and N. P. BuuHoi, German Patent 2,261,965 (1973); Chem. Abstr. , 79: 78604a (1973). 4. W. G. Frankenburg and A. A. Vaitekunas, J. Am. Chem. Soc, 79, 149 (1957). 5. C. D. Lunsford, A. D. Cale, Jr., J. W. Ward, B.

274

Five-Member eel Heterocycles

V. Franko and H. Jenkins, J. Med. Chem. , 7, 302 (1964). 6. C. L. Miller and R. A. Hall, U. S. Patent 3,183,245 (1965). 7. Anon., British Patent 1,106,007 (1968); Chem. Abstr., 68: 86809e (1968). 8. C. A. Johnson, U. S. Patent 3,253,987 (1966); Chem. Abstr., 65: 4332c (1966). 9. F. F. Ebetino, British Patent 1,016,840 (1966); Chem. Abstr., 64: 11215c (1966). 10. J. G. Michels, U. S. Patent 2,927,110 (1960). 11. A. Fujita, M. Nakata, S. Minami and H. Takamatsu, Yakugaku Zasshi, 86, 1014 (1966). 12. W. R. Sherman and D. E. Dickson, J. Org. Chem., 27, 1351 (1962). 13. H. R. Snyder, Jr., C. S. Davis, R. K. Bickerton and R. P. Halliday, J. Med. Chem., 10, 807 (1967), 14. K. Butler, H. L. Howes, J. E. Lynch and D. K. Pirie, J. Med. Chem., 10, 891 (1967). 15. P. N. Giraldi, V. Mariotti, G. Namini, G. P. Tosolini, E. Dradi, W. Logemann, I. de Carnevi and G. Monti, Arzneimittelforsch. , 20, 52 (1970). 16. Anon., Netherlands Patent 6,609,552 (1967); Chem. Abstr., 67: 54123u (1967). 17. J. Heeres, J. H. Mostmans and R. Maes, German Patent 2,429,755 (1975); Chem. Abstr., 82: 156309m (1975). 18. C. Rufer, H.J. Kessler and E. Schroder, J. Med. Chem. , 14, 94 (1971). 19. Arton., Netherlands Patent 6,413,814 (1965); Chem. Abstr., 63: 18097b (1965).

Five-Membered Heterocycles

20. 21.

22.

23. 24.

25.

26. 27. 28. 29. 30. 31. 32.

275

E. F. Godefroi, J. Heeres, J. Van Cutsem and P. A. J. Janssen, J. Med. Chem. , 12, 784 (1969). E. F. Godefroi, J. Van Cutsem, C. A. M. Van Der Eycken and P. A. J. Janssen, J. Med. Chem., 10, 1160 (1967). J. W. Black, W. A. M. Duncan, C. J. Durant, C. R. Ganellin and E. M. Parsons, Nature, 236, 385 (1972). S. Akabori and T. Kaneko, J. Chem. S o c , Japan, 53, 207 (1932); Chem. Abstr., 27: 293 (1933). G. J. Durant, J. C. Emmett, C. R. Ganellin, A. M. Roe and R. A. Slater, J. Med. Chem. , 19, 923 (1976). G. J. Durant, J. C. Emmett, C. R. Ganellin, P. D. Miles, M. E. Parsons, H. D. Prain and G. R. White, J. Med. Chem., 20, 901 (1977). Y. F. Shealy, C. A. Krauth and J. A. Montgomery, J. Org. Chem., 27, 2150 (1962). J. G. Lombardino, German Patent 2,155,558 (1972); Chem. Abstr., 77: 101607 (1972). Anon., French Patent M1614 (1963); Chem. Abstr., 58: 12574e (1964). Anon., French Patent 1,353,049 (1964); Chem. Abstr., 61: 4146c (1964). M. Julia, Bull. Soc. Chim. Fr. , 1365 (1956). L. A. Walter, German Patent 1,905,353 (1969); Chem. Abstr., 72: 317904 (1970). W. J. Middleton and W. J. Krespan, J. Org. Chem., 35, 1480 (1970).

276

33.

34.

35.

36. 37.

38. 39. 40. 41.

42. 43. 44. 45.

Five-Membered Heterocycles

W. B. Wright, Jr., and H. J. Brabander, Belgian Patent 623,942 (1962); Chem. Abstr., 60: 14513e (1964). J. W. Hanifin, Jr., R. Z. Gussin and E. Cohen, German Patent 2,251,354 (1973); Chem. Abstr., 79: 187l7e (1973). F. K. Kirchner and A. W. Zalay, U. S. Patent 3,429,911 (1969); Chem. Abstr., 70: 96783b (1969). J. Perronnet and J.P. Demonte, Bull. Soc. Chim. Fr. , 1168 (1970). S. Oba, Y. Koseki and K. Fukawa, J. Soc. Sci. Phot. Japan, 13, 33 (1951); Chem. Abstr., 46: 3885e (1952). O. Hengen, H. Siemer and A. Doppstadt, Arzneimittelforsch., 8, 421 (1958). F. H. Clarke, J. Org. Chem., 27, 3251 (1962). Anon., French Patent 2,001,036 (1969); Chem. Abstr., 72: 66930w (1970). G. I. Poos, J. R. Carson, J. D. Rosenau, A. P. Roszkowski, N. M. Kelley and J. McGowin, J\ Med. Chem., 6, 266 (1963). R- A. Hardy, C. F. Howell and C. Q. Quinones, U. S. Patent 3,037,990 (1962)G. Satzinger and M. Herrmann, German Patent 2,336,746 (1975); Chem. Abstr., 83: 10047 (1975). T. S. Gardner, E. Wenis and J. Lee, J. Med. Chem., 2, 133 (1970). A. P. Roszkowski, A. M. Strosberg, L. M. Miller, J. A. Edwards, B. Berkoz, G. S. Lewis, O. Halpern and J. H. Fried, Experientia, 28, 1336 (1972).

Five-Membered Heterocycles 46.

47.

48. 49. 50. 51. 52.

53.

277

R. C. O'Neill, A. J. Basso and K. Pfister, U. S. Patent 2,755,285 (1956); Chem. Abstr., 51: 2873a (1957). C. R. Lambert, M. Wilhelm, H. Striebel, F. Kradolfer and P. Schmidt, Experientia, 20, 452 (1964). Anon., Netherlands Patent 6,614,130 (1967); Chem. Abstr., 68: 68976g (1968). G. Satzinger, Ann., 665, 150 (1963). Anon., British Patent 924,608 (1963); Chem. Abstr., 59: 6415h (1963). L. M. Weinstock, P. Davis, B. Handelsman and R. Tull, Tetrahedron Lett., 1263 (1966). B. K. Wasson, W. K. Gibson, R. S. Stuart, H. W. R. Williams and C. H. Yates, J. Med. Chem., 15, 651 (1972). F. L. Chubb and J. Nissenbaum, Can. J. Chem., 37, 1121 (1959).

Six-Membered Ring Heterocycles The six-membered ring heterocycles are of exceptional importance in the context of willingly self administered organic substances. One need only mention glucose and nicotine to make this point. The biological acceptability, within reasonable limits, of these materials is paralleled by the availability of a substantial number of drugs. Substitution of a pyridine ring for a benzene ring often is compatible with retention of biological activity and occasionally this moiety is an essential part of the pharmacophore. Such substitution of =N for CH= is an example of the common medicinal chemical strategy known as bioisosterism. 1. PYRIDINES The aliphatic hydrogens of a-picoline (1) are relatively acidic, so that treatment with phenyl lithium 278

Six-Membered Heterocycles

279

produces the carbanion which can add to chloral, forming 2.

Acid hydrolysis leads to unsaturated acid

3, which is sequentially reduced to acid 4, Fischer-

CH 2 CH 2 COX (1)

(2)

(J)

"

(4) X = OH (5.) X = OCH 3 (6.) X = NH 2

H2CH2NHR

C02H

(ii)

(8,) R = CH

esterified to 5 and transamidated to 6.

Hofmann

rearrangement with NaOBr followed by methanol gives carbamate 7, which is hydrolyzed to 8 and monomethylated.

This fairly lengthy process affords the

vasodilator, betahistine (9). As the result of a screening program examining microbial fermentation products for pharmacological activity (other than antibiotic activity), fusaric acid (10) was isolated from Fusarium oxysporum following the discovery that extracts were potent inhibitors of dopamine p-hydroxylase, and thus interfered with the biosynthesis in vivo of the pressor neurohormone, norepinephrine.

To refine this lead,

amidation of 10 via the acid chloride was carried out

280

Six-Membered Heterocycles

to give the antihypertensive analogue bupicomide

(ID.2 Reaction of ethyl picolinate (12) with dimsyl sodium (from dimethylsulfoxide and sodium hydride) 3 produces oxisuran (13), an antineoplastic agent.

eN x C — O C 2H 25 cxCH2SCHJ I\ til)

H0CH

(13)

(H) An adrenergic p^-receptor agonist related conceptually to salbutamol (14) can be made by substituting a pyridine ring for the benzene.

In this case syn-

thesis starts by hydroxymethylation and formation of the o-benzylether of 3-hydroxypyridine (15) to give 16.

Manganese dioxide perferentially oxidizes the

sterically more accessible primary alcohol group to the aldehyde, and subsequent aldol condensation with nitromethane produces nitrocarbinol 17*

Catalytic

reduction with Raney nickel gives amine 18 which reacts in turn with t-butyl bromide to give amine 19. Hydrogenolysis of the protecting benzyl moiety finishes the synthesis of the bronchodilator, pirbuterol

(20).4 Substantial interest in the pharmacological properties of the nonsteroidal antiinflammatory agents related to mefenamic and flufenamic acid led to examination of a series of aminopyridines instead

Six-Membered Heterocycles

(15)

2 81

(16)

OH (17) X = 0 (1_8) X = H

RO HOCHf^N^C OH

(J_9) R= CH 2 C 6 H 5 (20) R = H

of anthranilates-

Thermal displacement of the halo-

gen of 2-chloronicotinate derivatives (21) with the requisite anilines (22 or 23) led to antiinflammatory agents flunixin (24)

and clonixin (25),

respect-

ively.

a:* (I?) R =CF3 (23) R =Cl

^ ^ ""R ( l i ) R =CF3 R =Cl

The glyceryl ester of clonixin, clonixeril (28), is also an antiinflammatory agent.

It was prepared

2 82

Six-Membered Heterocycles

via a somewhat roundabout method.

Clonixin

(25) was

reacted with chloroacetonitrile and triethylamine to give 26*

Heating 26 with potassium carbonate and

glycerol acetonide displaced the activating group to produce ester 27 which was deblocked in acetic acid to produce

clonixeril.

cw

(2 5)

rr " OC

m> ^ N ^ ^ N H

I

0 0 CH{ Y H ,

Interestingly, a substance somewhat closely related to flunixin, triflocin (30), is a diuretic rather than an antiinflammatory agent.

It can be

prepared by nucleophilic aromatic displacement on 4chloronicotinic acid (29) with m-trifluoromethylaniline. The topical antifungal agent ciclopirox (32) was formed from 2-pyrone 31 by an azaphilone reaction 9 with hydroxylamine. This may be viewed at least formally as an ester (lactone)-amide exchange to an intermediate oximinoester, which ring-closes via an addition-elimination sequence to expel the original lactone ring oxygen in favor of the hydroxylamine nitrogen.

Lactones which readily convert to lactams

in this manner are known as azaphilones.

Six-Membered

Heterocycles

283

CO2H

.X

X07H

U (30.)

(31)

A 1,4-dihydropyridine having coronary vasodilatory activity and, therefore, intended for relief of the intense chest pains of angina pectoris is nifedipine (34).

Using a portion of the classical Hantzsch

pyridine synthesis, condensation of two moles of

CHO C2H5O2C

NHi (33)

CO2C2H5

2 84

Six-Membered Heterocycles

ethyl acetoacetate and one each of ammonia and 2~nitrobenzaldehyde (collectively 33) leads to nifedipine. In the classical Hantzsch process, an oxidative step is needed to produce the pyridine ring system. 2. PIPERIDINES Perhaps following up the rigid analogue concept, an epinephrine analogue with a cyclized side chain is the p^agonist/bronchodilator, rimiterol (38)* Reaction of 3,4-dimethoxybenzaldehyde (35) with 2-pyridyl lithium gives carbinol 36. Oxidation with permanganate and ether cleavage with HBr produces catechol 37. Hydrogenation with a palladium catalyst in acid medium leads to rimiterol by reduction of both the pyridine ring and the ketone function.

OH HO, CH3O

_ 0

HO

(15)

(36)

y HO

y

L

X (38)

)

(37.)

Six-Membered Heterocycles

285

Propiophenone (39) does not easily form ketals directly.

A solution for this difficulty involves

conversion to the gezn-dichloride (40) with PCl 5 and solvolysis to the ketal (41) using sodium methoxide. Acid-catalyzed ketal exchange with piperidine glycol 42 leads to the parenteral anesthetic, etoxadrol

(43).12

Repetition of the same steps starting with

benzophenone led to dioxadrol (44), which is described as an antidepressant agent.

OH CH2OV/C2HS J y C H O (39) X = 0 (iO) X = Cl 2 (41) X= (OCH33))2

(42)

kj

CHO 2 r-'NN^-CHO

(43)

(44)

In the course of an investigation aimed at refining hypotensive leads, 4-benzylpyridine (45) was reduced with a platinum catalyst in acidic medium to the corresponding piperidine, and this was alkylated with dimethylaminoethyl chloride to give 46.

This

,CH 2 CH 2 N(CH 3 ) 2

CH2 (45)

(46)

286

Six-Membered Heterocycles

product, pimetine, is primarily of interest as a hypolipidemic agent. Possibly patterned after the clinically useful p-fluorobutyrophenone haloperidol, lenperone (49) too is a potentially useful tranquilizer.

The synthesis

proceeds from ketone 47 by alkylation with halide 48 14 followed by deketalization.

|| /

o

Y., V

.*. CICH2CH2CH2C

(418)

0

(49)

The reader will recall that many sulfonylurea derivatives are oral hypoglycemic agents and therefore useful oral antidiabetic drugs in adult-onset diabetes. (54).

One more complex than most is gliamilide

Piperidine derivative 50, prepared by reduction

of the corresponding pyridine, undergoes amide exchange to 51 on heating in pyridine with sulfamide (H^NSO^NEU)« Reaction with hydrazine and HC1 removes the phthaloyl protecting group, and acylation of the liberated amino function with 2-methoxynicotinyl chloride gave sulfonylurea 52.

When this was reacted with the

Six-Membered Heterocycles

287

-a:

CH2CH2x

CNH(CH 2 ) 2

(50)R«H (51) R= SO 2 NH 2

(

NSO 2 NH 2

° —

C

OCH3 CNH(CH 2 ) 2

(53) —

/NSNHCNHCH2

(54)

bicyclic endo-diphenyl urea 53, amide exchange took place with expulsion of the better leaving group this case, diphenylamine. gliamilide

in

There was thus obtained

1S

(54).

CH 3 (55)

A number of years ago, pentamethylpiperidine 55 was found to be a rather potent, though not very specific, ganglionic blocking agent.

This finding

was of particular interest, as it was at that time believed that a quaternary ammonium function was a

288

Six-Membered Heterocycles

minimal structural feature for such drugs.

In re-

fining 55 as a lead, triacetone amine (56, synthesized from acetone, ammonia and calcium chloride) was reduced with sodium borohydride and N-alkylated to give 57.

Cyanoethylation with acrylonitrile (with

the aid of sodium t-butoxide) led to nitrile 58. Reduction with lithium aluminum hydride produced the primary amine and Eschweiler-Clark methylation (CH^O and HC0 o H) completed the synthesis of pemerid (59), 16 an antitussive agent. This activity is incidentally unrelated to ganglionic blockade. 0 CH CH

3j

OH

LCH 3

3

H

CH

3 CH3

(56) (57) OCH2CH2CN

Yet another (see lenperone) butyrophenone related to haloperidol is pipamperone (64).

N-benzyl-4-

piperidone (60) has a venerable history as starting material for both central analgesics and CNS drugs. This synthon has been used by the Janssen group as a building block for numerous such drugs.

Reaction of

Six-Membered Heterocycles

289

60 with KCN and piperidine HC1, leads to the aminonitrile (61).

The reaction probably represents

cyanation of the intermediate imine.

Hydrolysis with

hot 90% sulfuric acid hydrates the nitrile to the carboxamide (62) and catalytic reduction deblocks the amine to give 63.

Alkylation with p-fluorophenyl-3-

chloropropyl ketone using a catalytic amount of KI 17 completes the synthesis.

NCH 2 C 6 H5

(60)

CONH2

I

C0NH2

(62) R = C H 2 C 6 H 5 (63.) R - H

(64)

An interesting reaction ensues when the intermediate synthetic precursor (65) to synthon 60 is heated with phenylenediamine.

The reaction can be

rationalized as involving initial enamine-imine formation (66), followed by intramolecular attack on the ester carbonyl groups resulting in carbamate formation (67), which carbamate undergoes intramolecular transamidation to give urea 68.

Other scenarios can be

proposed and defended, but the net result is formation

Six-Membered Heterocycles

290

NH,

,CO2C2H5

NH?

:NH2 7N. \1 '

N

^»»

^NH '0 OC 2 H 5

CH 2 C 6 H 5

C 6 H 5 CH 2

(68)

(70)

of complex urea derivative 68, which readily undergoes catalytic reduction to 69, a versatile intermediate for the preparation of a variety of potential drugs. For example, alkylation with the requisite haloperidol 18 fragment led to the tranquilizer, benperidol (70). Minor variants led to the tranquilizers oxiperomide (71),19

pimozide (72),20

and clopimozide (73),21 22 the analgesic, benztriamide (74).

and

Another fruitful investigation was based upon the cyanohydrin of ketone 60.

This substance (75)

undergoes hydride reduction to the corresponding aminoalcohol, which forms cyclic carbamate 76 on

291

Six-Membered Heterocycles

0

Q-\

OCH 2 CH 2 N

Oi

CHCH 2 CH 2 CH 2 N

NH

(71)

:HCH 2 CH 2 CII 2 N

NH

(72)

\—NrN :iI 2 CH 2 N

(73)

A

\

NNCO2C2H5

Cl (74)

heating with diethylcarbonate.

Hydrogenolysis of the

N-benzyl group and alkylation of the liberated amino group with phenethyl chloride gives fenspiride (77), 23 an blocking bronchodi1ator. C 6 H 5 CH 2 N

C6H5CH2N \

V /

I CH2NH

(76)

(75)

C 6 H 5 CH 2 CH 2 N ^

^

CH 2 NH

(II) Imidazolone analogues are available, for example, starting with piperidone 60 and reacting this with KCN and aniline followed by hydration to amide 78 in

292

Six-Membered Heterocycles

90% sulfuric acid.

Heating 78 with formamide results

in the desired imidazolone formation (79). Catalytic hydrogenolysis (80) and suitable alkylation of this

r~ym2 C6H5CH2N A

(7 9) R= CH2C6Hs

CM) R =H

secondary amine gives the tranquilizer, spiriline 24 (81). (82)

The closely related tranquilizers fluspiriline and fluspiperone (83) are made in the same

general way.

H

CHCH C C N VS ^"XX. ^CCH C C H 2H 2H 2^ 2H 2C 2) M

6

When piperidone 60 is condensed with phenylacetonitrile, using sodium methoxide, 84 results. Catalytic reduction unexpectedly is nonselective, not only reducing the olefinic linkage, but also removing

Six-Membered Heterocycles

the benzyl protecting group.

29 3

The product (85) has to

be rebenzylated to 86 before cyanoethylation to 87 can be carried out.

Hydrolysis of 87 with strong

acid stopped at the glutarimide stage with the production of benzetimide (88), an orally active anticholinergic agent. CN

(84) —

C8S)R-H (86J R = C H 2 C 6 H 5

CN :H9CIIOCN

/ C6H5CII2N

NH '0 C6HS b

5

(88)

The action of phenyl Grignard reagent on piperidone 60 followed by dehydration and deblocking leads to intermediate ^ 9 . When this is reacted with complex halide 90, fenpipalone (91), an antiinflammatory 27 agent, results. The requisite halide (90) is made by treatment of hydroxy pyrrolidine 94 with phosgene. The reaction may proceed via N-acylation to 93 which would undergo ring opening as shown with chloride ion to give 92, which would then cyclize as indicated to give 90.

Such dealkylation of tertiary amines by

acyl halides is a well-established reaction.

An

294

Six-Membered Heterocycles

alternate and perhaps equally credible intermediate in this particular case would be bicyclo carbamate 95, which would be formed whether either 0- or N-acylation were the first event.

00 • (89)

CICH2CH2

t>

Q-HQ.CH2C,,2

CIU

(90)

(91)

(J

OH

CH3

CICHoCIUCH 2

[

CH,

Cii)

Cl (94)

A number of substituted p-aminoacetates inhibit the enzyme cholinesterase. The main function of this enzyme is to hydrolyze acetyl choline and thereby terminate the action of that substrate as a neurotransmitter. Such inhibition is functionally equivalent to the administration of exogenous acetylcholine. Direct administration of the neurotransmitter substance itself is not a useful therapeutic procedure due to rapid drug destruction and unacceptable side

Six-Membered Heterocycles

295

CO 2 CH 3

CH2CO2C2H5 (98) (96)

OCOCH, (99)

effects.

(100)

Aceclidine (100) was synthesized based upon

these considerations.

When glycine analogue 96 is

catalytically reduced, cis-diester 97 is produced. Dieckmann condensation and saponification-decarboxy28 lation then leads to bicyclopiperidone 98. 29 Borohydride reduction gives alcohol 99. Acetylation completes the synthesis of aceclidine (100), a cholinergic agent. Glutarimides may be regarded as oxidized piperidines, and many drugs containing this moiety are sedatives and anticonvulsants. A spiro derivative, alonimid (105) is such a sedative-hypnotic agent.

It

can be prepared by K t-butoxide catalyzed biscyanoethylation of phenylacetonitrile, leading to 101. Alkaline hydrolysis produces tricarboxylic acid 102 which is smoothly converted to the glutaric acid anhydride (103) with acetic anhydride. Friedel-Crafts

296

Six-Membered Heterocycles

cyclization leads to the 6-membered ring, with concomitant anhydride reorganization to give 104* The CH 2 CH 2 R %

CH 2 CH 2 R

(101) R = CN (102) R = CO 2 H

(103)

(104) X = 0 (105) X - NH

azaphilone character of 104 is taken advantage of as reaction with ammonia produces the desired spiroimide 31 105: Interest in compounds of this generic type has cooled considerably in the wake of the thalidomide tragedy* Homophthalimides have an active methylene group, and this property is retained by the octahydroisoquinoline derivative 106.

Base-catalyzed benzylidine

condensation with benzaldehyde gives tesimide (107), an antiinflammatory agent*

32

The imine proton may be

sufficiently acidic for this drug to be classed among the acidic nonsteroidal antiinflammatory agents. As a means of introducing both rigidity and asymmetry for receptor discrimination, bicycloimides are potentially interesting pharmacological tools*

Six-Membered Heterocycles

297

(106)

(107)

One such agent is prepared by NBS and peroxide bromination of ethyl 4-chlorophenylacetate (108) to give 109.

This is converted by sodium hydride to the

benzylic carbene, which is inserted into the double bond of ethyl acrylate to give cis-cyclopropane 110. Partial saponification cleaves the less hindered ester moiety to give 111.

This is next converted to

the alkoxyimide (112) on reaction with diethyl carbonate and diammonium phosphate.

Stronger base (NaOEt)

effects displacement to the imide (113), cyproximide, which has tranquilizing properties.

(10 8) X = H (109) X = Br

(110) R = OC 2 H 5 (111) R = OH (112) R = NHCOC 2 H 5

33

(113)

298

Six-Membered Heterocycles

3.

PIPERAZINES AND PYRAZINES

The classical synthetic method for constructing 2-aminopyrazines is illustrated by the synthesis of ampxjzine (117), a CNS stimulant. Condensation of aminomalonamide and glyoxal leads to pyrazine 114. Hydrolysis to the acid and decarboxylation gives 2-hydroxypyrazine (115).

Reaction with PCl^ produces

chloride 116, and heating with dimethylamine completes the synthesis of

117.34

N(CH 3 ) 2 CHO

"""•

'

(115) X - OH (116) X = Cl

(ill)

Methyl groups are introduced into the aromatic rings of pyrazines by varying the starting materials. For example, use of biacetyl and alanylamide produces trimethyl hydroxypyrazine 118. Chlorination and thermal displacement with dimethyl amine gives triampxjzine (119), an anticholinergic agent intended to inhibit gastric secretion to control some kinds of 35

peptic ulcer.

N

OH

CH (118)

(119)

Six-Membered Heterocycles

299

It has been discovered that direct chlorination of pyrazines can be accomplished and this has also been used to make candidate drugs.

For example, when

2-methylpyrazine (120) is heated with chlorine in carbon tetrachloride, a mixture of the 3-chloro (121) and the 6-chloro derivatives result.

After separation,

121 is heated with piperidine to give modaline (122), an antidepressant.

(120) R = H (121) R = Cl

(122)

When piperazine (123) is reacted with two molar equivalents of 3-bromoacetyl chloride, the antineo37 plastic agent pipobroman (124) results. This material is probably an alkylating agent. Exchange of the leaving groups by mesylate moieties is compatible with bioactivity.

This has been accomplished by

reaction of 124 with silver methanesulfonate to give piposulfan (125)% also an antineoplastic agent.

B/-\8 »• N

BrCH2CH2CN NCCH2CH2Br \——/

fi^ii CH3SO3CH2CH2CN «>• \

NCCH2CH2OSO2CH3 /

H (123)

(12£)

(125)

300

Six-Membered Heterocycles Azaperone (128) is yet another of the tran-

quilizers related to haloperidol.

Nucleophilic

aromatic displacement of 2-chloropyridine by piperazine leads to amine 126 which is then alkylated in turn by 4-chloro-p-fluorobuterophenone

(127) to give

azaperone (128), which is said to be active by topical 39 administration.

C1CH2CH2CH2CO

(X (126)

Alkylation of l-(2-pyrimidyl)piperazine

(129)

with 3-chloro-l-cyanopropane gives nitrile 130, which is reduced with LAH and then acylated with spiroglutaric anhydride 131 to synthesize the tranquilizer

40 buspi rone (132).

a

k^NH (130)

Six-Membered Heterocycles

301

Alkylation of piperazine with the amide formed by reaction of chloroacetyl chloride with pyrrolidine gives amide 133.

Acylation with 3,4,5-trimethoxy-

cinnamoyl chloride completes the synthesis of the peripheral vasodilator, cinepazide

(Ill)

(134).

° (131)

To round o u t this group of drugs in which the piperazine ring appears to serve primarily as a basic spacer unit, or a conformationally restricted ethylenediamine unit, reaction of N-phenylpiperazine (135) with acrylonitrile produces nitrile 136. Conversion

(135)

of the nitrile moiety to a tetrazole ring via a 1,3-dipolar addition process by sodium azide under ammonium chloride catalysis produces zolterine (137), an antihypertensive by virtue of its antiadrenergic/ 42 The tetrazole moiety is an

vasodilator activity.

302

Six-Membered Heterocycles

isoelectronic replacement for a carboxylic acid moeity in a number of drugs. 4.

PYRIMIDINES

Two antibacterial agents related structurally to trimethoprim (138) are diaveridine (141) and ormetoprim (146)*

Diaveridine has been synthesized 43 in

by a minor variant of the trimethoprim route

which veratric aldehyde (139) is sequentially condensed with p-ethoxypropionitrile (to 140) and then guanidine 44 to give 141. Ormetoprim may be made analogously or

yH2 C

H

3

V

T

Y

C H 3

\

° w

c

"

2

'

CH3O ^^^^ OCH3 (138) NII2

CH3(T ^ * ^

OC2H5

-

c , ,

3 0

X r

(140)

(1_4JJ by benzylic bromination (NBS and peroxide) of acetylpyrimidine 142 to give 143, which alkylates 3,4-dimethoxytoluene to give substituted thymine 144 when treated with mercuric chloride in nitrobenzene. The amino groups are restored in the classic fashion by conversion of 144 to chloride 145 with POClg, and

Six-Membered Heterocycles

303

45 then displacement with ammonia to yield 146. Ormetoprim (146) is a coccidiostat as well as an antibacterial agent.

NHCOCH

(1£2) X = H (143) X = Br

(j_44 } x = 0 H

CJ_46)

(]4S) x = c]

Following the success of px/rantel (147) as an anthelmentic

a search was undertaken for an analogue

that would have activity against adult whipworms as well.

This effort was successful with the synthesis

of tetrahydropyrimidine 150, the anthelminitic, 47 oxantel. The C-methyl group of 149 is sufficiently activated that heating together with 3-hydroxybenzaldehyde (148) in the presence of ethyl formate as a water scavenger produces oxantel directly.

CH,

CH 3 (148)

Oil)

(149)

(150)

3 04

Six-Membered Heterocycles

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (151, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with chloromethylmethyl ether to produce eterobarb (152).

(151)

(152)

5. MISCELLANEOUS STRUCTURES As befits their chemical heterogenecity, the miscellaneous group of drugs in this section belong to a wide range of pharmacological classes as well. A pyridazine has found use as an antihypertensive agent. When levulinic acid is reacted with hydrazine, 153 results. This is aromatized to pyridazine 154 when reacted with bromine in acetic acid. One presumes a spontaneous dehydrobromination

Six-Membered Heterocycles

30 5

converts the intermediate to 154.

Oxidation to the

acid (155) is accomplished with potassium dichromate, and this is esterified to 156 under Fischer conditions. Conversion to chloro derivative 157 (with POCl^) is followed by displacement with hydrazine to give 158. The synthesis of blood pressure-lowering hgdracarbazine 49 (159) is then completed by aminolysis with ammonia*

H0

/ 0} ' (154) R = CH 3 (155) R = CO2H (156) R = CO 2 C 2 H 5 *

CO2C2H5

^ H2NNH—^

(157) X = Cl CX 58) X = NHNH2

^ \ V"C0NH2

(159)

The triazinedione, triazuril (163) is active as a poultry coccidiostat.

Diazonium salt 160, prepared

from the appropriate aniline, is coupled with the active methylene group of N-carbethoxycyanoacetamide to give 161.

Hydrolysis of the cyano group is accom-

panied by cyclization, and the resulting acid (162) is decarboxylated to triazuril (163) on heating, A morpholine derivative is active as a muscle relaxant.

To prepare it, reaction of arylphenethanol-

amine derivative 164 with sodium hydride and ethyl

306

Six-Membered Heterocycles

(165). 51

c h l b r o a c e t a t e l e a d s t o flumetrctmide

CH7

CH3 (160)

C2H5O2C (161)

0=/

N—^

: 162)

^—s—-v

y—ci

(163)

•CHOH CH 2 NH 2 (164)

(165)

:x

The carbonyl group of compounds related to 165 can be removed with retention of significant pharmacological activity.

This can, of course, be done by 52 lithium aluminum hydride reduction or by, in at least one significant case, reaction of aryloxy-

epoxide 166 with 2-aminoethylbisulfate to give the antidepressant agent, viloxazine

(167).

The sultam, sulthiame (170), shows anticonvulsant activity. p-Aminobenzenesulfonamide can be alkylated by m-chlorobutylsulfonyl chloride (168) in

307

Six-Membered Heterocycles

o=s=o

(167)

base via presumed intermediate 169, which spontaneously cyclizes to give sulthiame (170). 54

SO2NH2 SO 2 NH 2

SO 2 NH 2

C1(CH2)4SO2C1 (168)

(169)

(170)

Reaction of 2,6-dimethylaniline with thiophosgene produces isothiocyanate 171. When the latter is treated with 3-aminopropanol, thiourea 172 is formed, and this, when treated with hot concentrated hydrochloric acid, cyclizes to xx/lazine (173), an analgetic and muscle relaxant. A great many quaternary amines are active anticholinergic agents. One such parasympathetic blocking

Six-Membered Heterocycles

308

agent is made easily by reacting hyoscyamine with 4butoxybenzylbromide to produce butropium bromide (174).56

N •H C N C H . H ( ) O 3 H 2 I ~0 S (172;

+ C12CS

CH3 "CH7 (173)

(171)

(174) oco—cu REFERENCES

1. 2.

3.

4.

L. A. Walter, W. H. Hunt and R, J. Fosbinder, J. Am. Chem. Soc. , 63, 2771 (1941). K- Shimizu, R. Ushijima and K. Sugiura, German Patent 2,217,084 (1972); Chem. Abstr., 78: 29778f (1973), G, C. Morrison and J- Shavel, Jr., German Patent 1,955,682 (1970); Chem. Abstr., 73: 35225m (1970). W. E. Barth, German Patent 2,204,195 (1972); Chem. Abstr., 77: 151968n (1972).

Six-Membered Heterocycles 5. 6. 7.

8. 9.

10. 11. 12. 13. 14.

15. 16.

309

M. H. Sherlock, U. S. Patent 3,839,344 (1974); Chem. Abstr., 82: 16705n (1975). Anon., Dutch Patent 6,603,357 (1967); Chem. Abstr., 68: 59439g (1968). M. H. Sherlock, South African Patent 68 02185 (1968); Chem. Abstr., 70: 96640c (1969); Swiss Patent 534,129 (1973); Chem. Abstr., 79: 18582g (1973). D. Evans, K. S. Hallwood, C. H. Cashin and EL Jackson, J. Med. Chem., 10, 428 (1967). W. Dittmar, E. Druckrey and H. Urbach, J. Med. Chem., 17, 753 (1974); W. Dittmar and G. Lohaus, Arzneimittelforschung 23, 670 (1973); German Patent 2,214,608 (1973); Chem. Abstr., 79: 146419w (1973). F. Bossert and W. Vater, South African Patent 68 01482 (1968); Chem. Abstr., 70: 96641d (1969). G. H. Sankey and K. D. E. Whiting, J. Heterocycl. Chem., 9, 1049 (1972). W. R. Hardie, J. Hidalgo and I. F. Halvorstadt, J. Med. Chem., 9, 127 (1966). A. P. Gray, W. L. Archer, E. R. Spinner and C. J. Cavallito, J". Am. Chem. Soc. , 79, 3805 (1957). J. W. Ward and C. A. Leonard, French Patent 2,227,868 (1974); Chem. Abstr., 82: 170720v (1975). R. Sarges, J. Med. Chem., 19, 695 (1976). W. B. Lutz, S. Lazarus and R. I. Meltzer, J. Org. Chem., 27, 1695 (1962); N. P. Sanzari and J. F. Emele, U. S. Patent 3,755,586 (1973); Chem. Abstr., 80: 19550c (1974).

310 17.

18. 19. 20.

21.

22. 23. 24. 25. 26.

27.

28. 29.

Six-Membered Heterocycles C. Van der Westeringh, P. Van Daele, B. Hermans, C. Van der Eycken, J. Boey and P. A, J. Janssen, J. Med. Chem., 7, 619 (1964)* Anon., Belgian Patent 626,307 (1963); Chem. Abstr., 60: 10690c (1964). P. A. J. Janssen, U. S. Patent, 3,225,052 (1965); Chem. Abstr., 64: 8194b (1966). P. A. J. Janssen, W. Soudijn, I. Van Wijngaarden and A. Dreese, Arzneimittelforschung, 18, 282 (1968). P. A. J. Janssen, C. J. E. Niemegeers, K. H. L. Schellekens, F. M. Lenaerts and A. Wanquier, Arzneimittelforschung, 25, 1287 (1975). Anon., Belgian Patent 633,495 (1963); Chem. Abstr., 61: 1871c (1964). Anon., Dutch Patent 6,504,602 (1965); Chem. Abstr., 64: 12679d (1966). Anon., Belgian Patent 633,914 (1963); Chem. Abstr., 60: 15882d (1964). P. A. J. Janssen, U. S. Patent 3,238,216 (1966); Chem. Abstr., 65: 8924d (1966). B. Hermans, P. Van Daele, C. Van der Westeringh, C. Van der Eycken, J. Boly, J. Dockx and P. A. J. Janssen, J. Med. Chem., 11, 191 (1968). C. D. Lunsford and W. J. Welstead, South African Patent 67 03,192 (1968); Chem. Abstr., 70: 96,785d (1969). E. E. Mikhlina and M. V. Rubtsov, Zhur. Obschei Khim, 30, 163 (1960). L. H. Sternbach and S. Kaiser, J. Am. Chem. Soc., 74, 2215 (1952).

Six-Membered Heterocycles 30. 31. 32.

33.

34.

35. 36.

37. 38.

39. 40.

41.

311

C. A. Grob, A. Kaiser and E. Renk, Helv. Chim. Acta, 40, 2170 (1957). G. N. Walker, U. S. Patent 3,379,731 (1968); Chem. Abstr., 69: 96497r (1968). H. Zinnes, J. Shavel, Jr., N. A. Lindo and G. Di Pasquale, U. S. Patent 2,634,415 (1972); Chem. Abstr., 76: 72421e (1972). E. N. Greenblatt and S. R. Safir, U. S. Patent 3,344,026 (1967); Chem. Abstr., 68: 29443m (1968). G. W. H. Cheeseman, J. Chem. Soc., 242 (1960); F. H. Muehlmann and A. R. Day, J. Am. Chem. Soc, 78, 242 (1956). Anon., British Patent 1,031,915 (1966); Chem. Abstr., 65: 5471g (1966). W. B. Lutz, S. Lazarus, S. Klutchko and R. I. Meltzer, J. Org. Chem., 29, 415 (1964); M. Gainer, M. Kokorudz and W. A. Langdon, ibid., 26, 2360 (1961). S. Groszkowski, Roczniki Chem., 38, 229 (1964). B. Horrom and J. A. Carbon, German Patent 1,177,162 (1964); Chem. Abstr., 61: 13329a (1964). W. Sondijn and I. Van Wijngaarden, J. Labeled Compounds, 4, 159 (1968). H. C. Ferguson, Y.H. Wu, J. W. Rayburn, L. E. Allen and J. W. Kissel, J. Med. Chem., 15, 477 (1972). C. Fauran and M. Turin, Chim. Ther. , 4, 290 (1969).

312 42. 43. 44. 45. 46.

47. 48. 49. 50. 51.

52.

53. 54. 55.

Six-Membered Heterocycles W. G. Stryker and S. Hayao, Belgian Patent 661,396 (1965); Chem. Abstr., 63: 18114e (1965). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 263 (1977). P. Steinbuck, R. Baltzly and H. M. Hood, J. Org. Chem., 28, 1983 (1963). Anon., Netherlands Application 6,514,743 (1966); Chem. Abstr., 65: 10598c (1966). Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 266267, Formula 94, (1977). J. W. McFarland and H. L. Howes, Jr., J. Med. Chem. , 15, 365 (191(2). C. M. Samour, J. F. Reinhard and J. A. Vida, J. Med. Chem., 14, 187 (1971). D. Libermann and A. Rouaix, Bull. Soc. Chim. Fr. , 1793 (1959). M. W. Miller, German Patent 2,149,645 (1972); Chem. Abstr., 77: 164712Z (1972). W. F. Gannon and G. I. Poos, U. S. Patent 3,308,121 (1967); Chem. Abstr., 67: 32693c (1967). K. B. Mallion, R. W. Turner and A. H. Todd, British Patent 1,138,405 (1969); Chem. Abstr., 70: 96804j (1969). S. A. Lee, British Patent 1,260,886 (1972); Chem. Abstr., 76: 99684e (1972). B. Helferich and R. Behnisch, U. S. Patent 2,916,489 (1959). 0. Behner, H. Henecka, F. Hoffmeister, H. Kreiskott, W. Meiser, H. W. Schubert and W.

Six-Membered Heterocycles

56.

Wirth, Belgian Patent 634,552 (1964); Chem. Abstr. , 61: 4369b (1964). S. Tanaka and K. Hashimoto, German Patent 1,950,378 (1970); CAem« Abstr. , 73: 98,819d (1970).

313

10

Compounds Related to Morphine The development of the first effective analgesic drug, opium, was almost certainly adventitious, and occurred in prehistoric times. The use of the dried exudate from slitting the immature capsule of the opium poppy, Papaver somniferum, as an analgesic, sedative and euphoriant, has a long folkloric history. Isolation of the principal active component morphine (1) as a pure crystalline compound represented one of the early landmarks in organic chemistry.

314

Morphinoids

315

The history of this class of analgesics might have stopped there were it not for the manifold ancillary activities shown by that molecule.

Although

still one of the most widely used agents for treatment of severe pain, morphine is a drug that must be used with caution.

Side effects include respiratory

depression, induction of constipation, and sometimes marked sedation.

The one property that most severely

limits use of this drug is its propensity to induce physical dependence in patients subjected to more than casual exposure. 1.

Compounds Derived from Morphine

Attempts to modify the molecule so as to maximize analgesic activity at the expense of side effects date back almost a full century.

It is ironic that

heroin (diacetyl morphine) was in fact prepared in the course of one such program.

Although early

efforts concentrated on modification of the natural product, the growth of synthetic organic chemistry has led more recently to the preparation of molecules that represent much more deep seated changes in structure.

The concept of molecular dissection has

been used widely in the design of such lead compounds. Some of the more recent molecules inspired by morphine do in fact show promise of providing analgesia with significantly reduced side effects so that compounds are now available that show a much reduced tendency to induce physical dependence, i.e., addiction liability. It has long been a puzzle to medicinal chemists

316

Morphinoids

why a natural product that has no evolutionary association with Homo sapiens should show such profound biological activity.

The puzzle was, if anything,

intensified by reports of the occurrence of receptors for morphine and related opioids in mammalian brains. Receptors for various endogenous hormones and other chemical transmitters have been recognized for some time; it was, however, unexpected to find a specific receptor for an exogenous chemical that plays no known role in the normal biochemical functioning of a mammal * The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended.

Ultimately, a pair of pentapeptides that

bound quite tightly to opiate receptors were isolated from mammalian brains.

These peptides, called

enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems.

They do

in fact show analgesic activity when injected directly into the brain.

It is thought that lack of activity

by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes.

HTyr-Gly-Gly-Phe-MetOH met-enkephalin

[Q HTyr-Gly-Gly-Phe-LeuOH leu-enkephalin (3)

Morphinoids

317

Fragments of the peptide hormone p-lipotropin have been found to show similar binding to opiate receptors.

These molecules, the endorphins, show

profound CNS activity in experimental animals.

It is

of interest that one of these, p-endorphin, incorporates in its chain the exact sequence of amino acids that constitutes methionine enkaphalin. Although these findings are too recent to have had an impact on the design of analgesics, it has already been noted that when properly folded, molecular models of the enkaphalins show a good topographical correspondence with molecules such as morphine. Unless this topographic relationship is fortuitous, this has the most profound future implications for the rational design of analgesic drugs. Morphine and related opiates are known to suppress the cough reflex; these compounds have thus been used extensively in antitussive preparations.

Since this

activity is not directly related to the analgesic potency, the ideal agent is one that has much reduced analgesic activity and thus, presumably, lower addiction potential.

The weak analgesic codeine (4) is

H 2 NOCH 2 CO 2 H

OH

CH3O"

(4)

(6)

CH3

(5)

CH 3 O

OCH 2 CO 2 H

318

Morphinoids

still used in many such preparations, and a variety of analogues have been prepared as substitutes. example, condensation of dihydrocodeinone

For

(5) (avail-

able in several steps from 4) with hydroxylamine derivative 6 affords the antitussive agent codoxime (7).2 Replacement of the N-methyl group of morphine by an allyl moiety leads to a narcotic antagonist.

That

is, the resulting drug, nalorphine, not only shows little analgesic activity but will in fact block most of the actions of morphine. Presumably, it binds to the opiate receptor but has little intrinsic agonist activity.

Incorporation of a new hydroxyl group at

the 14-position in morphine has been found empirically to potentiate greatly the activity of morphine. Combination of these two modifications in a single drug gives a very potent narcotic antagonist, naloxone (8).

It is possible, by suitable modification of

various structural features in narcotic analgesic molecules, to devise compounds, which show both agonist and antagonist activities; it has been found both in experimental animals and in man that such mixed agonists-antagonists afford analgesics with much reduced addiction liability.

The work that

follows apparently was aimed at building agonist activity into the naloxone structure. The starting material for these 14-hydroxy compounds is the opium alkaloid thebaine (9).

Although

present in only small amounts in the alkaloid fraction from Papaver somniferum, it constitutes the major component (as much as 26% of the dried latex) from a

Morphinoids

319

related poppy, Papaver bracteatum.3 Reaction of 9 with hydrogen peroxide leads to intermediate 11. The oxidation may be visualized as a 1,4-oxidation process of the diene system to afford an intermediate such as 10. Successive reduction of the double bond (12) and 4 demethylation affords oxgmorphone (13). This molecule is then protected as the diacetate; N-demethylation followed by saponification affords the key intermediate 14.5 Alkylation of the secondary amine in 14 with l-bromo-3-methyl-2-butene leads to the mixed analgesic agonist-antagonist nalmexone (15). In a somewhat more elaborate scheme, the carbonyl group in 14 is first protected as its cyclic ethylene ketal (16). Alkylation with cyclopropylcarbonyl chloride affords the O,N-diacylated product (17); treatment with lithium aluminum hydride results in reductive cleavage of the O-acyl group and reduction of the amide carbonyl to a methylene group (19). Hydrolysis of the acetal then affords the mixed analgesic/antagonist naltrexone (21). Acylation of 14 with cyclobutylcarbonyl chloride followed by the same series of transformations as above leads to intermediate 22. Reduction of the carbonyl group in that molecule with sodium borohydride gives the analgesic agonist/antagonist nalbuphine (23). An indication that the SAR of the narcotic antagonists was more complex than had been anticipated came from the observation of the tremendous increase in milligram potency obtained by fusing an additional bicyclic ring onto the basic morphine structure. The

OCH-7

CH3O

(ii) COR

(IS)

CH 2 R

(23) (20)

320

Morphinoids

321

resulting molecule, etorphine (26) shows three orders of magnitude greater potency than morphine; this could be interpreted as a better or tighter fit to the receptor.

Synthesis of this molecule also takes

advantage of the diene function found in thebaine. Thus, Diels-Alder condensation of 9 with methyl vinyl ketone affords the bicyclic adduct 24.

The new ring

is formed by approach of the dienophile from the face containing the nitrogen bridge, since this is in fact the least hindered side of the molecule (9a).

Reaction

of the side chain ketone with propylmagnesium bromide then leads to intermediate 25; demethylation of the phenolic ether affords etorphine (26).

8

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action.

To accomplish this,

reduction of 2£ followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27.

The N-methyl group is then removed by the classic

von Braun procedure.

Thus, reaction with cyanogen

bromide leads to the N-cyano derivative (28); hydrolysis affords the secondary amine 29^. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide JO.

Reduction with

lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9

CH3—N •COCHT

CH3O O ' CH 3

(24)

(9a)

CCCH3J3

CH-rO

(2_5) R = CH3 C16) R = H

(2_7)

:CCH3)3

CH3O

CH3O (_2_8) R = CN

C3_0) y = CO

(_2_9) R = H

(11) y

(32)

322

= CH

2

Morphinoids 2.

323

Morphinans

In the course of earlier work it had been ascertained that the furan oxygen of morphine was not essential to analgesic activity.

This observation

led to the preparation of a considerable number of quite potent deoxy analogues of morphine, since these compounds were relatively easily accessible by totally synthetic routes.

Combination of this deoxy nucleus

(called morphinan) with the tertiary hydroxyl found in molecules such as naloxone has led to quite potent analgesics; appropriate modification of the substituent on nitrogen then has led to mixed agonistsantagonists.

These compounds, too, show much reduced

addiction liability.

For example, alkylation of the

anion from tetralone 53 with 1,4-dibromobutane gives the spiro ketone 34.

Condensation of the carbonyl

group with the anion obtained on treatment of acetonitrile with butyl lithium leads to the carbinol 35; the cyano group is then reduced to the primary amine (36) by means of lithium aluminum hydride.

Treatment

of 36 with acid leads to the corresponding tertiary benzylic carbonium ion; this undergoes Wagner-Meerwein rearrangement and proton loss to give the phenanthrene derivative 37, a key intermediate in this series. Several schemes have been developed for proceeding from this point; however, some relatively direct routes suffer from lack of regiospecificity. For example, internal cyclization of epoxide 38 affords both the desired ring system (45) and its isomer 12 (39). In one regiospecific route, amine 37 is

CH 3 O

CH 3 O

CH3O

HO'

(li)

(33)

CN (35)

CH-zO

CH3O

HO' (36)

NH-,

RNH (38)

(37)

.Br —R

H

CH 3 O'

CII3O'

CH 3 O'

(39)

(4\)

R =H

(41)

R = COCI3

(40)

CIUO'

(45)

(4_V)

R = COCI- 3

(4±)

R=H

(40a)

'N—CH CII3O1

C£6)

y = CO,

CiZ)

y

=

CH2

n = 1 , n = 1

(4_8^) y = CO, n = 0 (4_9)

324

y = CH2,

n = 0

i (51)

n = 1 n = 0

Morphinoids

325

treated with bromine to afford the bicyclic bromoamine 40.

The reaction can be rationalized by

assuming initial bromonium ion formation on the underside of the molecule; opening of the ring by the amine will lead to the observed product as its hydrobromide salt.

Reaction of 40 with sodium bicarbonate

results in the rearrangement to the desired skeleton. The inorganic base is not in this case the reagent; rather, it is likely that once 40 is present as the free base, it undergoes the internal displacement via the aziridinium ion.

Following protection of the

amine as the trifluoroacetamide (42), the double bond is oxidized to give mainly the p-epoxide (43). Hydrolysis of the amide linkage (44) followed by treatment with lithium aluminum hydride affords the desired aminoalcohol 45.

Both the regio and stereo-

chemistry of this last reaction follow from the diaxial opening of oxiranes*

Acylation of this

intermediate with cyclobutyicarbonyl chloride gives the corresponding amide (46).

Reduction of the amide

(47) followed by O-demethylation affords butorphanol 13 (50). The same sequence on 45 starting with cyclo14 propyl carbonyl chloride leads to oxilorphan (51). 3.

Benzomorphans

Further dissection of the morphine molecule showed that potent analgesics could be obtained even when one of the carbocyclic rings was omitted.

One such

compound, pentazocine (52), has found considerable use as an analgesic in the clinic.

There is consider-

able evidence to indicate this drug has much less

—R

CH3 CH3

HO CH3

(52J

C

H,

R = CH 2 CH=C

\ (53) R = CH2—<

CH, CH3

(54)

Lh,

— CH3 •CH3 CH3

U1

(57) ( 56)

N-y—<] •NR CH

CH 7 CH

3

(_5_8) R = CN (59)

326

CH,

R =H

M

= co

C6J.)

R = CH?

3

3

Morphinoids

327

addiction potential than does morphine.

The

corresponding cyclopropylmethyl analogue cyclazocine (53), perhaps as a consequence of its greater balance of antagonist activity, has proven to be quite hallucinogenic. Omission of the phenolic group from cyclazocine results in a molecule which retains analgesic activity. In a classical application of the Grewe synthesis, the methylated pyridinium salt 54 is condensed with benzylmagnesium bromide. dihydropyridine 55*

There is thus obtained the

Treatment of that intermediate

with sodium borohydride results in reduction of the iminium function to afford the tetrahydro derivative 56.

Cyclization of 56 on treatment with acid leads

to the desired benzomorphan nucleus. The cis compound (57) is separated from the mixture of isomers and demethylated by the cyanogen bromide procedure (58, 59). Acylation with cyclopropylcarbonyl chloride (to 60) followed by reduction of the resulting amide 14

yields volazocine (61).

Oxidation of the benzylic methylene group in cyclazocine to a ketone is also consistent with analgesic activity.

Acetylation of benzomorphan 62

affords the diacetate 63.

Selective hydrolysis of

the phenolic acetate (64) followed by methylation of the thus uncovered phenol affords intermediate 65. The remaining acetate is then hydrolyzed (66). Oxidation of that compound with chromium trioxide in sulfuric acid leads cleanly to the desired ketone (67). Treatment with hydrobromic acid serves to demethylate the phenolic ether function (68).

Direct

Morphinoids

328

alkylation of the secondary amine with cyclopropylmethyl bromide gives ketazocine (69).

(62)

(6J5) R = COCH3

(66)

(6£) R = H (65.)

R =

CH

3

•N— CH 2 —<]

CH,

RO

HO'

CH7

CH,

CH, (62) R = CH 3

(69)

(68) R = H

4. Phenylpiperidines Extensive molecular dissection of the morphine molecule over the past several decades led to a host of molecules which showed narcotic analgesic activity even though they possessed but faint suggestion of the structural features present in morphine itself. Thus, both cyclic molecules such as meperidine (70) and alphaprodine (71), and acyclic compounds such as methadone (72) were found to be effective analgesics. Common features of these compounds were formalized by the Beckett-Casy rule, which states as minimal required structural features: (a) an aromatic ring attached to

Morphinoids

329

(b) a quaternary center, and finally (c) the presence of nitrogen at a distance equivalent to two carbon atoms from the quaternary center (73).

Although

sufficient exceptions have recently been found to suggest that this is an oversimplification, it is of historical importance because of its guiding influence on analgesic research over a considerable span of time.

CH3 CH3 CCH2CN

NCH, C2H5CO

\

C 2 H 5 OC

CH,

CH7 (70)

(71) (72)

CH2CHCCN

CO2R (73)

(7_4)

R=C2H5

(75)

R =H

It will be recalled that a common side effect of morphine is the induction of constipation.

This

property of the drug has often been exploited in the design of preparations used to control diarrhea.

O

330

-

H

3

Morphinoids

331

There has also been some work devoted to the preparation of a compound that would show greater selectivity toward activity on the gut and away from activity 17 over the CNS. Diphenoxglate (74) has been used extensively in humans for just this purpose; although the drug shows some selectivity, it is far from free of narcotic effects.

(The curious will note the

compound follows the Beckett rule both in the piperidine and side chain moieties.)

Treatment of 74

with potassium tertiary butoxide in DMSO results in 18 saponification to the free acid difenoxin (75). Certain esters have often been employed in attempts to confer organ selectivity to molecules possessing carboxyl functions. Thus, for example, treatment of piperidinecarboxylic acid 76 with Nhydroxysuccinimide and DCC affords the ester 77.

In

a convergent synthesis, the anion from diphenylacetonitrile (78) is alkylated with dibromoethane to afford the bromide 79.

Alkylation of the piperidine

derivative 77 with that halide 79 gives the antidiarrheal agent difenoximide (80).

The same sequence

starting with the phenoxyethyl ester 81 gives fetoxylate (82). Derivatives of 4-phenyl-4-hydroxypiperidine, which may be formally regarded as reversed meperidines, have yielded a series of potent antipsychotic drugs such as haloperidol (83) and bromoperidol (84). Retention of carbon at the 4-position interestingly leads to a molecule with quite different activity. The starting material for this molecule could be synthesized by first preparing the amide (86) from

332

Morphinoids

the benzyl (85) derivative of meperidine.

Reduction

of the amide would then afford the primary amine (87). Acetylation (88) followed by removal of the benzyl group would afford the key intermediate (89) • Alkylation with 4-chloro-p-fluorophenylbutyrophenone 21 affords aceperone (90). This compound exhibits vasodilator and antihypertensive activity.

ii R = F

(8£) R = O C 2 H 5

(84) R = Br

/ H 2 NCH 2

(S6) R = NH 2

CH 3 COHNCH 2

(87)

(88,) R- C 6 H 5 CH 2 (89) R = H

NCH 2 CH 2 CH ; CH 3 CHNCH 2

(£0) Alkylation of diphenylpiperidinols with bis(j>fluorophenyl)butyl side chains has also led to antipsychotic compounds.

For example, reductive cycliza-

tion of the acylation product (92) from fluorobenzene

X O

r U

333

334

Morphinoids

and succinic anhydride gives the corresponding butyrolactone 92.

Treatment with fluorobenzene in the

presence of a Friedel-Crafts catalyst leads to the diarylated acid 93.

The carboxyl group is then

reduced to the corresponding carbinol 94 by means of lithium aluminum hydride, and this is converted to the chloro compound 95 with thionyl chloride. Alkylation of piperidine 96 with that halide gives 22 the neuroleptic compound penfluridol (97). The use of phenylpiperidinols rather than the meperidine-related piperidines as the basic component in antidiarrheal compounds results in retention of activity.

The fact that the base is not directly

related to a narcotic presumably leads to greater selectivity of action on the gut.

Ring scission of

butyrolactone 98 (obtainable by alkylation of a dipheny1acetate ester with ethylene oxide) with hydrogen bromide gives the bromo acid 99.

This is

then converted to the dimethylamide by successive treatment with thionyl chloride and dimethylamine. The initial product from this reaction (100) is not observed as it undergoes spontaneous internal displacement to the cyclic imino ether salt 101.

Treatment

of 101 with amine 102 proceeds at the activated ether 23 carbon to give fluperamide (103); the same reaction with amine 103 affords the antidiarrheal agent 23 loperamide (105). Incorporation of additional basic centers into the phenylpiperidinol nucleus leads to a molecule that shows local anesthetic rather than CNS activity. Condensation of the protected piperidone 106 with

II

II

X

X


to

o

o

t—i

335

Morphinoids

336

phenylmagnesium bromide affords the desired piperidinol (107).

Alkylation of the carbinol by means of

2-chlorotriethylamine gives the corresponding basic ether (108)*

Hydrolysis of the carbamate protecting

group (109), followed by alkylation of the resulting secondary amine with N-(chloroethyl)aniline affords 24 the local anesthetic, diamocaine (110).

C 2 H 5 OC C106) (107) (108)

£2% NHCH 2 CH 2 N

_ N /-AI>CH 2 CH 2 N

CH 2 CH 2 N

HN

\

\

C2H5

(110)

C2H5

(109)

The piperidines discussed thus far contained a single polar substituent on the heterocyclic ring. Except for the last entry, the compounds all showed activity on the CNS or closely related systems.

It

is thus somewhat surprising to find that simple addition of an aroyl group leads to a compound that shows antiinflammatory activity.

The seemingly

complex molecule can in fact be obtained in two steps 25 from simple starting materials. Thus, Mannich reaction of p-fluoroacetophenone with paraformaldehyde and methylamine affords condensation product 111. Treatment with aqueous base leads to cyclization by

Morphinoids

337

internal aldol condensation. There is thus obtained the nonsteroidal antiinflammatory agent flazalone

(U2).26

REFERENCES 1.

2. 3. 4. 5.

6.

J. Hughes, T. W. Smith, H. W. Kosterlitz, L. A. Fothergill, B. A. Morgan and H. R. Morris, Nature, 258, 577 (1975). J. Fishman, U. S. Patent 3,152,042 (1964); Chem. Abstr., 61: 16111f (1964). N. Sharghi and L. Lalezari, Nature, 213, 1244 (1967). U. Weiss, J. Am. Chem. Soc., 77, 5891 (1955). For more detailed discussion, see D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 290 (1975). Anon., French Patent, M6358 (1968); Chem. Abstr., 74: 141,577h (1971).

338 7.

Morphinoids

H. Blumberg, I. J. Pachter and 2. Matossian, U. S. Patent 3,332,950 (1967); Chem. Abstr., 67: 100301 (1967). 8. K. W. Bently and D. G. Hardy, Proc. Chem. Soc., 220 (1963). 9. K. W. Bentley, British Patent 1,136,214 (1968); Chem. Abstr., 70: 78218b (1969). 10. D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 292 (1975). 11. I. Monkovic, H. Wong, B. Belleau, I. J. Pachter and Y. G. Perron, Can. J. Chem., 53, 2515 (1975). 12. I. Monkovic and T. T. Conway, U. S. Patent 3,775,414 (1973); Chem. Abstr., 80: 37349 (1974). 13. I. Monkovic, H. Wong, A. W. Pircio, Y. G. Perron, I. J. Pachter and B. Belleau, Can. J. Chem., 53, 3094 (1975). 14. N. F. Albertson, U. S. Patent 3,382,249 (1968); Chem. Abstr., 69: 96509w (1968). 15. R. Grewe and A. Mondon, Chem. Ber. , 81, 279 (1948). 16. W. F. Michne and N. F. Albertson, J. Med. Chem., 15, 1278 (1972). 17. D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 302 (1975). 18. W. Soudyn and I. Van Wijngaarden, German Patent 1,953,342 (1970); Chem. Abstr., 73, 38571g (1970). 19. E. M. S. Kreider, German Patent 2,161,865 (1972); Chem. Abstr., 17: 139818f (1972). 20. P. A. J. Janssen, German Patent, 1,807,691 (1969); Chem. Abstr., 71: 81194g (1969).

Morphinoids 21. 22. 23.

24. 25. 26.

339

P. A. J. Janssen, Belgian Patent 606,849 (1961); Chem. Abstr., 56: 12861i (1962). Anon., French Patent 2,161,007 (1973); Chem. Abstr., 79: 146,415s (1973). R. A. Stokbroekx, J. Vandenbenk, A. H. M. T. Van Heertum, G. 1VL L. W. Van Laar, M. J. M. C. Van der Aa, W. F. M. Van Beren and P. A. J. Janssen, J. Med. Chem., 16, 782 (1973). B. Hermans, H. Verhoeven and P. A. J. Janssen, J. Med. Chem., 13, 835 (1970). J. T. Plati and W. Wenner, U. S. Patent 2,489,669 (1949); Chem. Abstr., 44, 2555f (1950). L. Levy and D. A. McLure, U. S. Patent 3,408,445 (1968); Chem. Abstr., 70: 47302 (1969).

11

Five-Membered Heterocycles Fused to One Benzene Ring 1. INDOLES The classic and most convenient synthesis of the indole moiety is that of Emil Fischer. Recent examples of its use for drug synthesis includes one preparation of the nonsteroidal antiinflammatory agent, indoxole (2). Reaction of ketone I with phenylhydrazine in acetic acid leads directly to indoxole (2). Alternately, anisoin (3) can be reacted

OCHr

340

Fused Five-Membered Heterocycles

341

with aniline by heating in concentrated HC1, proceeding presumably through direct displacement of OH by aniline followed by cyclodehydration to 2*

A credible

but more involved mechanism can also be written starting with Schifffs base formation. A somewhat more complex example of the Fischer indole synthesis is provided by the tranquilizer, 2 milipertine (8). It can be prepared by reaction acti of

C H 3 O CH3O

x x

CH3COCH2CH2NQ,—Q

- 27

(7)

(8)

l-chlorobutan-3-one (4) with l-(2-methoxyphenyl) piperazine (5), which leads to asymmetrical ketone 6, Reaction of 6 with 3,4-dimethoxyphenylhydrazine leads to complex hydrazone 7 which, on treatment with strong acid, rearranges to milipertine (8)*

The

course of the last reaction reveals one of the classic

342

Fused Five-Membered Heterocycles

features of the Fischer synthesis-cyclization onto the more substituted side of the ketone.

Another

tranquilizer, alpertine (9), has a rather similar structure to 8.

OCH 2 CHCH 2 C1

OH

(10)

(11)

OCH 2 CHCH 2 NHCH(CH 3 ) 2

I OH

(J_2)

Interest in the psychotropic features of the mushroom substance, psilocyrbine, led to an exploration of the chemistry of 4-hydroxyindole (10).

The avail-

ability of this substance provided a suitable starting point for the synthesis of pindolol (12), a p-adrenergic 3

blocking agent.

Reaction of 10 with epichlorohydrin

and NaOH led to ether 11 whose halo atom was readily displaced by isopropylamine to complete the synthesis of 12. One of the more convenient methods of adding a twocarbon side chain to the electron-rich 3-position 4 of indoles is the Speeter-Anthony reaction,

illu-

strated in the synthesis of the antiadrenergic agent, solypertine (15).

In this case, the reaction between

5,6-methylenedioxyindole and oxalyl chloride gives ketoacid chloride 13.

The sequence then proceeds by

amide formation (14) with amine 5.

Reduction with

Fused Five-Membered Heterocycles

343

XJ3 —(

"O

(13.)

(14)

OCH3

n 51

I

v...^^

w.3

I

(Jjo)

lithium aluminum hydride reduces both carbonyls to give solypertine (15) whose structural relationship to milipertine

(S) is obvious.

Another related drug

is oxxjpertine (16), an anti depress ant made by essentially the same route as illustrated for solxjpertine. Combining the nucleophilicity of the indole 3position just illustrated and the well-known tendency of C-2 and C-4 vinyl pyridines to add nucleophiles, a convenient synthesis of the tranquilizer benzindopx/rine (19) was devised.

Reaction of N-benzylindole (17)

with 4-vinylpyridine (18) in acetic acid produced 19 directly. Tryptamine and serotonin are naturally occurring indole ethylamino compounds with pronounced pharmaco-

344

Fused Five-Membered Heterocycles

logical activities. They have served as the inspiration for synthesis of numerous analogues. One such study involved alkylation of 4-benzamidopyridine (21)

X)

CH 2 CH 2 '

CHo

(17)

with 2-(3-indolyl)ethylbromide (20) to give quaternary salt 22; this intermediate was in turn hydrogenated with a Raney nickel catalyst to give indoramin (23), which is antihypertensive, apparently because of its 7 a-adrenergic blocking activity. CH 2 CH 2 Br

jjT\

_

6 e/ H

NHCO

(21) H 2 CH 2 N

(23)

-O

(12)

.NHCO

Fused Five-Membered Heterocycles

34 5

Because of the resonance stabilization possible in its deprotonated form, the 5-tetrazolyl moiety is actually nearly as acidic (pKa ca. 6 ) as many carboxylic acids. This has led to its inclusion in many drug series as a carboxyl surrogate. Apparently related in concept to indomethacin (26a), intrazole (26) is a nonsteroidal antiinflammatory agent which also inhibits platelet aggregation, and therefore is of potential value in keeping the contents of the

CH2CN

(26)

vascular bed free-flowing in certain pathological conditions.

The synthesis begins with 2-(3-indolyl)-

acetonitrile (24) which is transformed to the tetrazoyl derivative (25) by 1,3-dipolar reaction with sodium azide.

The acidic indole NH hydrogen is abstracted

when 25 is treated with two equivalents of sodium

Fused Five-Membered Heterocycles

346

hydride and the salt, when acylated with a single equivalent of 4-chlorobenzoyl chloride, is smoothly transformed to intrazole.

Note that acylation

occurs preferentially at the more nucleophilic (indole) anion. When the indole 3-position is already substituted, electrophilic reagents attack the 2-position instead often through a 3,3-spiro intermediate.

For example,

when 2-(3-indolyl)ethylmercaptan (27) reacts with methyl acetoacetate, the thia-p-carboline analogue 31 results.

It seems plausible that the reaction involves

initial hemithioketal formation (28), followed by electron release by the indole nitrogen and hydroxide

,CH 2 CH 2 S

:H2CH2SH

[

(27)

(28)

H 3 CH 2 CO 2 CH 3

(29)

CH 2 CO 2 R CH 2 CO 2 CH 3 (30)

H CH 3 (33)

CH 2 CON(CH 3 ) 2

(32) R = CH 3 (32) R = H

CH, (34) R = H (35) R = C 2

Fused Five-Membered Heterocycles

displacement to give 29.

347

Compound 29 has interrupted

aromaticity, and a Wagner-Meerwein type rearrangement would led to carbonium ion 30, which would eject a proton to restore indole resonance (31). case, 31 is the product.

In any

Saponification to the free

acid (32 is followed by dimethylamide formation (33), mediated by carboxyl activation via mixed anhydride reaction with ethyl chlorocarbonate. Lithium aluminum hydride reduction to the tertiary amine (34) is followed by base-mediated N-alkylation with ethyl bromide to produce tandamine (35), an antidepressant that inhibits the uptake of norepinephrine into 9 storage granules. Yohimbine (36) is a well-known and reasonably available alkaloid from Corgnanthe x/ohimbe, inter alia.

For this reason, and partly because of its

intrinsic pharmacological activity (including reputed aphrodisiac activity), chemists have frequently studied its properties.

Oppenauer oxidation is

usually attended by saponification and decarboxylation in this series, and yohimbone (37) is the product. Wolf-Kischner reduction to x/ohimbane (38), followed by sodium hydride mediated alkylation, leads to the analgesic agent, mimbane (39).

CH3O2C OH (_36)

(3*0 R = H 3£) R = C H 3

348

Fused Five-Membered Heterocycles

2.

REDUCED INDOLES

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines*

When diphenylamine reacts with chloro-

propionyl chloride, amide 40 results; this in turn readily cyclizes to oxindole 41•

Sodium hydride

followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion); partial demethylation is accomplished by refluxing with ethylchlorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin. Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity.

C1CHCH,

(£0)

fS^|

CH 3 [-CH2CH2NHCH3

(£2)

til)

Fused Five-Membered Heterocycles

349

Hydrazides also containing a metasulfonamide function are known to exhibit diuretic activity. Substitution of an N-aminodihydroindole for the hydrazine is consistent with this activity. Preparation of one such agent is carried out by reaction of 2-methyl~N-aminoindoline

(44) with 3-sulfamoyl-4-

chlorobenzoyl chloride (45), leading to the diuretic 12 indapamide (46).

SO ,N 2H 2 cu, Ox • ' tl N H (44) 2 C4>j) SO 'oNHo (46)

A more highly oxidized indole relative is isatin (47).

The ketonic carbonyl group is nonenolizable

and has interesting properties.

In strong acid it

OCOCH,

•OCOCH (47)

(48)

(49)

350

Fused Five-Membered Heterocycles

becomes protonated, and the oxygen can be replaced by electron-rich moieties.

Almost 100 years ago such a

condensation with phenol was discovered to lead to 48. Acetylation led to oxyphenisatin (49) which has carthartic properties. It is also clearly anticipated that the ketonic moiety will form normal carbonyl derivatives.

When

isatin (47) is treated with sodium hydride and methyl iodide, the acidic hydrogen is alkylated to produce 50.

Then, reaction of the ketone carbonyl with thio-

semicarbazine leads to methisazone (51).

At the

time of its discovery, methisazone was one of a very few antiviral leads showing activity in whole animal tests, and led to an extensive exploration of the properties of analogues.

CH

3

£n 3

(SO)

3.

INDAZOLES

The compounds of medicinal interest in this group so far have all been nonsteroidal antiinflammatory agents or analgesics. (55).

The prototype is benzxjdamine

An interesting alternate synthesis of this

substance starts by sequential reaction of

Fused Five-Membered Heterocycles

351

N-benzylaniline with phosgene, and then with sodium azide to produce carbonyl azide 52.

On heating,

nitrogen is evolved and a separable mixture of nitrene insertion product 53 and the desired ketoindazole 54 results.

The latter reaction appears to be a Curtius-

type rearrangement to produce an N-isocyanate (54a), which then cyclizes. Alkylation of the enol of 54

(52) 54a)

f5,}

o/"

C1I2C6H5

OCIC 2)a2N ,i.li:( O C H C 2H 20 S (_5) (Sb)

with sodium methoxide and 3-dimethylaminopropyl chloride gives benzxjdamine.

Alternatively, use of

chloroacetamide in the alkylation step followed by acid hydrolysis produces bendazac (56) instead. Bendazac, an acetic acid derivative, more closely resembles the classical nonsteroidal antiinflammatory agents. Reduction of the benzene ring is also compatible with activity in this group. 2-thiocarbamoylcyclohexanone

Reaction of N-methyl(57) with methyl hydrazine

Fused Five-Membered Heterocycles

352

produces the analgesic agent, tetrydamine (59), probably with the intermediacy of alkylhydrazone 58.18

NHCH3 HCH3

(57)

4.

—CH,

(59)

(58)

BENZIMIDAZOLES

The control of worm infestations of domestic animals (horse, sheep, cattle, pigs) and humans is an important therapeutic objective for which thiabendazole (60) serves as the prototype of numerous benzimidazole 19 A widely used synthesis of this

derivatives.

system is illustrated by the preparation of oxibenda-

20 First, 4-hydroxyacetamide is alkylated

zole (62).

by use of KOH and n-propyl bromide, and the product is nitrated to give 61.

The latter compound is

NHCOCH,

xc

NHCOCH,

CH 3 (CH 2 ) (60)

(61)

hydrolyzed, reduced to the phenylenediamine with SnCl 2 , converted to the 2-aminobenzimidazole system

Fused Five-Membered Heterocycles

353

by S-methylthiourea and subsequently acylated by methylchloroformate to produce 62.

Lobendazole

•NHCO 2 CH 3

(61)

H

<M) •NHCO 2 CH 3

(64) 91

(63),

x

0*?

albendazole (64), 24

mebendazole (66),

9*3

oxfendazole (65), 24

and eyelobendazole

(67)

are all

made by fairly obvious variants on this basic scheme. Cambendazole (69), best of 300 antihelmintic agents in an extensive study, is made by nitration of thiabendazole (60) to 68, followed by catalytic 25 reduction and acylation with isopropyl chloroformate. H

H •N

•NHco2cH3

r

"i

1

1

11 1 J

v—NHCO2CH3

n

N

(66)

(£§.)

(CH 3 ) 2 CHOCNH (67)

(68)

(69)

354

Fused Five-Membered Heterocycles

Flubendazole (70) belongs in this chemical class and is synthesized by similar methods but its bioactivity is expressed as an antiprotozoal agent. At least in one case, a seemingly minor variation in the overall structure, change to the benzimidazolinone system, considerably alters the nature of

CH 2 CH 2 CH 2 N(CH 3 ) 2

R

=H

(7_2) R= CCH2)3Br

the bioactivity exhibited. Treatment of 4-chloro-Nphenylbenzimidazolinone (71) with t-BuOK and 3bromopropylchloride leads to halide 72, which itself undergoes halogen displacement on heating with dimethylamine to produce the antidepressant, clodazon

(73).26 5.

MISCELLANEOUS

The pharmacological properties of khellin (74) have inspired a continuing interest in analogues.

Change

of the pyrone ring to a benzofuran ring results in a uricosoric agent, benzbromarone (78). In its preparation, Friedel-Crafts acylation of 2-ethylbenzofuran (75) with 4-methoxybenzoyl chloride leads to ketone 76, which undergoes ether cleavage to phenol 77 on

Fused Five-Membered Heterocycles

355

heating with pyridine hydrochloride; subsequent bromination produces benzbromarone (78).27 CH3O

C

2H5

(75)

CH-rO

(_76) R = CH 3 (7_7) R = H

(74) OH

"VY" I (79) (78)

Another khellin-inspired benzofuran is the cardiotonic and vasodilating agent, benfurodil (84)/28 The reported synthesis begins by Reformatsky reaction between zinc, 4~methoxyacetophenone and ethyl bromoacetate to give 79.

The alcoholic function is dehy-

drated with tosic acid, NBS leads to the allylic bromide (80a) via the Wohl-Ziegler procedure, and then SN^ displacement with NaOAc produces acetoxyketone 80b*

Treatment with HC1 then closes the butenolide

ring to give 81.

A Fries rearrangement, followed by

demethylation, acetylation, and then ether formation with bromoacetone gives 82, which condenses to form the furan ring on base treatment; then sodium borohydride reduction produces alcohol 83.

The synthesis

Fused Five-Membered Heterocycles

356

of benfurodil (84) is concluded by reaction with succinic anhydride and pyridine.

EtO 2 C

OCH,

'OCH2COCH3

(8(0) X = H

(82)

(81)

(80a) X = Br (80b) X = 0C0CH 7

,OCOCH2CH2CO2H

(84) (83)

Probably inspired by ibuprofen and its analogues, the nonsteroidal antiinflammatory agent benoxaprofen

HO.

HO,

,CN

.CN

,CO2Et

H2N CH, (8^) X = NH 2

(90)

(88^) X = 0

(8j6) X = N2

(8_9) X = H 2

(8_7) X = OH

Cl

,CO2H

CH,

Fused Five-Membered Heterocycles

357

(91) is synthesized by starting with substituted 29 aniline 85. A Sandmeyer-type sequence of diazotization (86) and acid hydrolysis leads to phenol 87, which undergoes nitration (88) and reduction to give aminophenol 89.

Hydrolysis of the nitrile and

esterification produces ester 90, which is converted to benoxaprofen (91) by acylation with 4-chlorobenzoyl chloride, followed by cyclization and then by saponification of the ethyl ester. A catecholamine potentiator that apparently operates by inhibition of norepinephrine reuptake and that also inhibits gastric secretion is talopram (94).

Its specific synthesis is hard to locate, but

a general approach to this class of substance is 30 available in the literature. A suitable sequence would start from geaz-dimethylphthalide 92 by reaction with phenyl Grignard reagent, followed by perchloric

CH 2 CH 2 CH 2 NHCH3

CH 3 .

"CH 3

^

CH 3

^

CH 3

(94)

acid dehydration of the tertiary carbinol to give oxonium ion 93*

Reaction of 93 with 3-dimethylamino-

propyl magnesium chloride would lead to the tertiary

358

Fused Five-Membered Heterocycles

amino analogue of 94. Demethylation would be accomplished by refluxing with ethyl chlorocarbonate, and the synthesis of talopram could be concluded by hydrolysis of the intermediate carbamate. REFERENCES 1.

2. 3. 4. 5.

6. 7.

8. 9.

J. Szmuszkovicz, E. M. Glenn, R. V. Heinzleman, J. B. Hester, Jr., and G. A. Youngdale, J. Ned. Chem., 9, 527 (1966). S. C. Laskowski, French Patent 1,551,082 (1968); Chem. AJbstr. , 72: 43,733v (1970). Anon., Netherlands Application 6,601,040 (1966); Chem. Abstr., 66: 18,669x (1967). M. E. Speeter and W. C. Anthony, J. Am. Chem. Soc., 76, 6209 (1954). S. Archer, D. W. Wylie, L. S. Harris, T. R. Lewis, J. S. Schulenberg, M. R. Bell, R. K. Kulling and A. Arnold, J. Am. Chem. Soc. , 84, 1306 (1962). A. P. Gray and W. L. Archer, J. Am. Chem. Soc, 79, 3554 (1957). J. L. Archibald and J. L. Jackson, South African Application 6803204 (1969); Chem. Abstr., 72: 121,363r (1970). P. F. Juby and T. W. Huidyma, J. Med. Chem., 12, 396 (1969). D. A. Demerson, German Patent 2,301,525 (1975); Chem. Abstr., 85: 103,883z (1976); W. Lippmann and T. A. Pugsley, Biochem. Pharmacol. , 25, 1179 (1976).

Fused Five-Membered Heterocycles

10.

11. 12.

13. 14. 15. 16.

17. 18. 19.

20. 21. 22.

359

J. Shavel, Jr., and M. Von Strandtmann, French Patent 1,405,326 (1965); Chem. Abstr. , 63: 13,342a (1965). A. Canas-Rodriguez and P. R. Leeming, J. Med. Chem., 15, 762 (1972). L. Beregi, P. Hugon and M. Laubie, French Patent 2,003,311 (1969); Chem. Abstr. , 72: 100,500t (1970). A. Baeyer and M. J. Lazarus, Ber. , 18, 2641 (1885). D. J. Bauer and P. W. Sadler, Brit. J. Pharmacol., 15, 101 (1960). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 323 (1977). G. Palazzo, G. Corsi, L. Baiocchi and B. Silvesterini, J. Med. Chem., 9, 38 (1966); L. Baiocchi, G. Corsi and G. Palazzo, Ann. Chim. (Roma), 55, 116 (1965). G. Palazzo, U. S. Patent 3,470,194 (1969); Chem. Abstr., 72: 110,697n (1970). G. Massaroli, L. Del Corona and G. Signorelli, Boll. Chim. Farm., 108, 706 (1969). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 326 (1977). Anon., British Patent 1,123,317 (1968); Chem. Abstr., 69: 722k (1968). P. P. Actor and J. F. Pagano, Belgian Patent 66,795 (1966); Chem. Abstr., 65: 5307g (1966). R. J. Gyurik and V. J. Theodorides, U. S. Patent 3,915,986 (1975); Chem. Abstr., 84: 31,074r

360

23.

24.

25.

26. 27. 28.

29.

30.

Fused Five-Membered Heterocycles (1976). E. P. Averkin, C. C. Beard, C. C. Dvorak, J. A. Edwards, J. H. Fried, J. G. Killian, R. A. Schlitz, T. P. Kistnerf J. H. Druoge, E. T. Lyons, M. L. Sharp and R. M. Corwin, J. Med. Chem. , 18, 1164 (1975). J. L. H. Van Gelder, A. H. M. Raeymaekers and L. F. C. Roevens, German Patent 2,029,637 (1971); Chem. Abstr. , 74: 100,047s (1971). D. R. Hoff, M. H. Fisher, R. J. Bochis, A. Lusi, F. Waksmunski, J. R. Egerton, J. J. Yakstis, A. C. Cuckler and W. C. Campbell, Experientia, 26, 550 (1970). Anon., Belgian Patent 659,364 (1965); Chem. Abstr. , 64: 2,093d (1966). N. P. BuuHoi, E. Basagni, R. Royer and C. Routier, J. Chem. Soc., 625 (1957). J. Schmidt, M. Susquet, G. Callet, J. Le Meur and P. Comoy, Bull. Soc. Chim. France, 74 (1967); J. Schmidt, M. Susquet, P. Comoy, J. Bottard, G. Callot, T. Clim and J. Le Meur, ibid., 953 (1966). D. W. Dunwell, D. Evans, T. A. Hicks, C. H. Cashin and A. Kitchen, J. Ned. Chem. , 18, 53 (1975). F. J. McEvoy, R. F. Church, E. N. Greenblatt and G. R. Allen, Jr., J. Med. Chem., 15, 1111 (1972).

12

Six-Membered Heterocycles Fused to One Benzene Ring The prevalence of heterocyclic rings among drugs and biochemical agents of mammalian origin can lead to the erroneous assumption that the presence of such rings in drugs means that this moiety of necessity constitutes part of the pharmacophore.

As was noted

in the case of the monocyclic heterocycles, these ring systems, in fact, often merely serve the function of a generalized aromatic system.

The SAR of such

molecules frequently demonstrates that the heterocyclic ring can be replaced by some other moiety with comparable electron distribution and lipophilicity without loss of biological activity.

Sometimes,

however, a given heterocyclic system does constitute part of the pharmacophore.

Replacement of the parti-

cular ring system in such cases leads to loss of the desired biological activity.

Recognition of pharmaco-

phoric functions is today still largely an empirical 361

362

Fused Six-Membered Heterocycles

art, although susceptible to experimental inquiry. It is expected that art will more closely approach science with the emergence of a deeper understanding of the mechanisms of action of drugs on the molecular level, and the increasing frequency with which receptors are now being isolated and studied. 1.

QUINOLINES

The quinoline antimalarial agents constitute one of the earliest examples of pharmacophoric heterocyclic systems.

It was recognized in the 1930's that chloro-

quinolineamines bearing an additional amino group in the side chain were often endowed with activity against the plasmodia that cause malaria.

Further

exploration of these molecules led to an agent with antiamebic activity. Mannich condensation of quinolol 1 with paraformaldehyde and N,N-diethylpropylenediamine affords the antiamebic agent, clamoxxjquin (3).

OH r2H5 I / l 5 ^N^w A ^CH2NHCH2CII2CH2N f^ f f ^ f \

C2HS / + CH2O + H2NCH2CH2CH2N

\2H5

(1)

"

U ^ ci

( }

-

(I) The structures of drugs that have proven clinically useful for treatment of hypertension tend to fall into discrete classes according to their mode of action.

It is thus usually a safe assumption that a

drug containing a guanidine function will show the

Fused Six-Membered Heterocycles

363

properties of a peripheral sympathetic blocking agent; also, phenoxypropanolamines and some phenylethanolamines will be effective by virtue of their p-adrenergic blocking activity. Experimental agents on the other hand tend to show much greater structural diversity; by the same token, it is more difficult to relate mode of action to structure in these cases. It is thus of note that a rather simple aminoquinoline shows hypotensive activity. The synthesis of this aminoquinoline starts with one of the standard sequences for preparation of 4hydroxyquinolines, i.-^-, with the formation of the Shiff base (5) from the appropriately substituted aniline and diethyl oxaloacetate.

Thermal cycliza-

tion gives the quinolone (6); this then spontaneously tautomerizes to the enol form (7).

Saponification

followed by decarboxylation gives the desired quinolol (8).

Treatment of 8 with phosphorus oxychloride

leads to replacement of the hydroxyl group by chlorine (9).

Displacement of halogen by ammonia leads to

the corresponding amine, probably by an additionelimination mechanism. amquinsin (10),

There is thus obtained

a hypotensive agent.

Formation of

the Shiff base of amquinsin with veratraldehyde gives leniquinsin (11),

possibly a prodrug.

A related and relatively simple quinoline derivative has been reported to exhibit antidepressant activity.

Its preparation merely involves displace-

ment of halogen in 12 with piperazine to afford quipazine (13).

LO

a o u PC

364

X Oi

CJ O4

o

u -u.

Fused Six-Membered Heterocycles

365

Derivatives of phenylethanolamine substituted by a phenolic hydroxyl on the para position have been known for some time to exhibit p-adrenergic agonist activity.

As a consequence of this property, the

compounds have proven useful as bronchodilators for the treatment of asthma (see Chapter 3 ) . Since such sympathomimetic drugs tend to have undesired activity on the cardiovascular system in addition to the desired activity on the bronchii, considerable work has been devoted to the preparation of compounds that would show selectivity for the adrenergic receptors O 2 ) that predominate in the lung.

Attachment of the

side chain to a heterocyclic aromatic phenol has been one avenue that has shown promise for achieving this selectivity. Halogenation of the acetyl compound 14 affords the corresponding chloroketone (15).

(Compound 14 is

obtainable by acylation of the quinolol.

The pyridine

ring is, of course, deactivated in the acidic conditions of the reaction.)

Displacement of halogen by

means of isopropylamine leads to the aminoketone

0H

ICHCH NHCH/3

COCH2NHCH v

7

CH,

OH (14_) X = H (15) X = Cl

OH (16)

CH

^

i

OH (U)

\CH3

366

Fused Six-Membered Heterocycles

(16),

Reduction of the carbonyl group by means of

sodium borohydride goes in a straightforward manner 7 to give the aminoalcohol, quinterenol (17)* It is a reasonable assumption that the heterocyclic system in this case simply serves as a surrogate benzene ring. Modern methods for raising poultry tend to concentrate large numbers of birds in a very small space.

Although economically very attractive, the

resulting dense population is an ideal setting for the extremely fast spread of avian epidemics, particularly those respiratory infections spread by droppings. The single-celled parasitic coccidia pose a particular threat to poultry flocks under these conditions. Considerable work has thus been devoted to the development of poultry coccidiostats.

The rapidity with

which these parasites develop resistance to chemotherapeutic agents serves as impetus for the development of a constant flow of drugs with new structures. The "quinates" constitute the prototype for the quinoline poultry coccidiostats; many such agents can be prepared using the following general synthetic schemes.

For example, alkylation of catechol with

isopropyl bromide affords ether 18. affords derivative 19.

Nitration perforce

Catalytic reduction of the

nitro group followed by condensation of the resulting aniline (20) with dimethyl ethoxymethylene malonate (21) affords the anil 22.

The reaction is most

reasonably rationalized by assuming a conjugate addition-elimination sequence.

Heating of the last

intermediate in Dowtherm affords the coccidiostat

T Y

367

368

Fused Six-Membered Heterocycles Q

proquinolate (23).

The same sequence using cyclo-

propylmethyl bromide as alkylating agent for catechol and, later, diethylmethoxymethylenemalonate affords ctjproquinate (28). The synthesis may be varied by reversing the alkylation and nitration steps.

Thus for example,

intermediate 25 can be obtained by alkylation of nitrocatechol 29.

The difference in reactivity of

the two phenolic groups in 29 (meta and para to an electron withdrawing group, respectively) may be used to prepare derivatives carrying different alkyl groups on each of the catechol oxygens. Alkylation of 29 with decyl bromide gives ether 30; reaction of the remaining phenolic function with ethyl iodide then gives 31. This intermediate then is converted to decoquinate (34)

when subjected to the rest of the

synthetic sequence.

(36)

°2CH3 3 C37)

Fused Six-Membered Heterocycles

369

Replacement of one of the ethereal oxygen atoms by a methylene group is compatible with anticoccidial activity.

For example, condensation of substituted

aniline 35 with dimethyl ethoxymethylenemalonate affords aminoacrylate 36.

Thermal cyclization in

diphenyl ether gives nequinate (37). Replacement of the remaining ether oxygen by basic nitrogen leads to a compound that shows antimalarial activity.

Nitration of aniline derivative

38 leads to substitution para to the alkyl group. (Protonation of the amine under the reaction conditions leads to deactivation of the position para to that group relative to that para to alkyl.

The position

meta to the protonated amine is less deactivated.)

f2"5 (18)

(i£)

(40)

C2H

I

OH

C4_2)

5 L

(41)

370

Fused Six-Membered Heterocycles

Reduction of the newly introduced nitro moiety affords aniline 40.

This is then subjected to the familiar

condensation-cyclization sequence to give antimalarial 12 amquinate (42)* Alkylation on nitrogen in this class leads to compounds with antibacterial activity, apparently due to inhibition of DNA gyrase. Condensation of aniline derivative 43 with diethyl ethoxymethylenemalonate, followed by cyclization of the resulting intermediate affords the quinoline 44.

Alkylation with ethyl

iodide by means of sodium hydride in DMF gives the corresponding N-ethyl compound. (Deprotonation of 44 leads to an ambident anion; alkylation at nitrogen may be favored by the greater nucleophilicity and steric accessibility of that atom.)

Saponification 13 of the ester affords oxolinic acid (46). This compound interestingly again illustrates the interchangeability of aromatic rings; the prototype antibacterial agent, nalidixic acid (47),

contains a

OH nn_r_H ,0

(43) ~

| C2H5

(44)

(£S)

(£1)

(46)

371

Fused Six-Membered Heterocycles

1,8-naphthyridine ring system and can be considered an azaquinolone. Reduction of either ring of quinolines greatly alters biological activity.

Although the agent in

which the carbocyclic ring is reduced can be considered a substituted pyridine, it is included here because it is prepared by using chemistry more akin to that of quinolines.

Condensation of the cyclo-

hexanedione derivative 48 with the malondialdehyde enol ether 49 leads directly to the tetrahydroquinoline 51*

The sequence can be envisaged as involving

first an addition-elimination reaction to afford, after double bond migration, intermediate 50; aldol cyclization will then afford the observed product.

OHC

CH 3

.CH,

II CHOC 2 H 5 (49)

(48)

(50)

(51)

ccr (52) (54)

(53)

Reduction of the carbonyl group by Wolff-Kishner reaction gives intermediate 52*

Treatment of that

compound with butyl lithium gives the corresponding

372

Fused Six-Membered Heterocycles

metalated derivative (53); reaction of 53 with tri~ methylsilyl isothiocyanate affords the corresponding thioamide. There is thus obtained the gastric antisecretory agent tiquinamide (54).

This synthetic

sequence is of special interest in that direct chemical reduction of quinolines usually results in reduction of the heterocyclic ring. Reduction of the heterocyclic ring and incorporation of a nitro function affords a compound with antischistosomal activity, oxamniquine (60).

Its

synthesis begins with chlorination of 2,6-dimethylquinoline, which proceeds regiospecifically on the methyl group adjacent to the ring nitrogen (56).

CSS)

h

CS6)

H

CH2NHCH

•«

j

-

4

/NSv/s.,,^.

^ CH3

Fused Six-Membered Heterocycles

373

Displacement of halogen by isopropylamine gives intermediate 57*

High pressure catalytic hydro*

genation leads to reduction of the heterocyclic ring (58), and nitration proceeds para to the NH group (59). Microbiological oxidation of the methyl group in that last intermediate using Aspergillus sclero17 torium affords oxamniquine (60). 2.

ISOQUINOLINES

As has been noted elsewhere, blockers of a-adrenergic receptors often bear little structural resemblance to the phenylethanolamines which are the endogenous agonists.

A relatively simple tetrahydroisoquinoline

derivative in fact shows hypotensive activity by virtue of its a-adrenergic blocking properties. Alkylation of tetrahydroisoquinoline itself with bromochloropropane gives intermediate 62*

Displacement

of the halogen with sodium ethylmercaptide gives thioether 63*

Oxidation of sulfur by means of per-

acetic acid is stopped at the sulfoxide stage to 18

afford esproquin (64)*

(61)

C^2) R = Cl

(64)

(6j$) R = S C 2 H 5

The use of p-adrenergic agonists as bronchodilators is discussed in some detail in Chapter 3.

374

Fused Six-JVtembered Heterocycles

As mentioned there, requirements for activity include the phenylethanolamine side chain and a phenolic hydroxyl group or its equivalent disposed para to the side chain.

It is of note that the side chain hydroxyl

can be omitted from molecules that contain the full catechol substitution of epinephrine with retention of good activity. One such compound, trimethoquinol (71), which in addition contains the side chain sterically constrained by cyclization to a tetrahydroisoquinoline has proven to be a clinically useful bronchodilator.

Condensation of trimethoxy-

benzaldehyde with ethyl chloroacetate under Darzens conditions gives the glycidic ester 66; this is then converted to the sodium salt (67)*

This salt is then

treated with dopamine (69) under conditions which will cause decarboxylation and rearrangement of 67 to the corresponding aldehyde (68).

The reaction condi-

tions are coincidentally the same as those of the Pictet-Spengler synthesis.

Thus, the intermediate

aldehyde reacts with the amine to form carbinolamine 70 or the corresponding imine.

This then cyclizes to 19 the tetrahydroisoquinoline, trimethoquinol (71)* Interestingly, only the 1-J3 isomer is an active bronchodilator. Guanidines attached to a group of appropriate lipophilicity have proven to be useful antihypertensive agents, active by virtue of their peripheral sympathetic blocking activity.

Debrisoquine (72) is

in fact used clinically for that indication.

The

7-bromo analogue (76) also shows antihypertensive

Fused Six-Membered Heterocycles

375

CH 2 CHO

OCH T OCH, (68)

(6j6) R - CH2CH3 CiZ)

R

•

N a

:H2CH2NH2

(69)

OCH,

OCH7

(71) (70)

activity, and can be prepared as follows.

Diazotiza-

tion of the aminodihydroisoquinoline 73, followed by conversion of the diazonium salt to the bromide by heating in the presence of HBr, affords intermediate 74.

Reduction of the imine function

with sodium borohydride gives the saturated heterocycle 75.

Condensation of this secondary amine with 21 S-methylthiourea affords guanisoquin (76).

376

F u s e d Six-Membered

Heterocycles

JOO l J

(H)

CIS)

-

^m CH2SC NH2 N

..AsJ^Nv NH

2

N H

2

Z

(72) C76)

Formation of blood clots is a process necessary for maintenance of the integrity of the circulatory system.

Any break in the system results in clotting

to seal off the potential leakage.

The final step in

the process involves stabilization of the clot by a protein called fibrin.

A number of pathological

conditions result in the formation of clots within the circulatory system in the absence of injury. Such clots—also known as emboli—present a serious hazard by their potential for blocking circulation of blood to vital organs.

The considerable research

devoted to agents that will lyse the fibrin in clots has led to the development of the clinically useful agent, urokinase.

This drug is a fibrinolytic protein-

aceous enzyme isolated from human urine.

The diffi-

culty involved in isolation of significant amounts and the antigenicity of urokinase and a related

Fused Six-Membered Heterocycles

377

microbial product, streptokinase, has led to the search for simple molecules that will accomplish the same end.

A tetrahydroisoquinoline derivative (80)

has shown this activity in animal test systems.

Its

formation involves classical isoguinoline chemistry, and begins with acylation of two molar equivalents of phenethylamine 77 with adipic acid to afford the diamide 78.

Ring closure of the amide by means of

phosphorus oxychloride gives the usual BischlerNapieralski product 79—although butylene chain.

with an intervening

Reduction of the imine by means of

sodium borohydride affords the fibrinolytic agent, oo

bisobrin (80).

CH3I CH2CH2NH2

^ ^

^

^CH2CH2HNC(CH2)4CNHCH2CH2

(77)

,OCH7

CH2CH2CH2CH2 CH3O' (11)

Products of Bischler-Napieralski cyclizations discussed thus far have been reduced in order to afford the desired biologically active compounds. Occasionally, the products obtained directly from the

378

Fused Six-Membered Heterocycles

cyclization have biological activity in their own right.

In one example, acylation of 2-phenethylamine

with p-chlorophenoxyacetyl chloride affords the amide 83; then, cyclization by means of phosphorus pentoxide 23 gives the antiviral agent famotine (84). The same sequence starting with the p-methoxy acid chloride 85 23

gives memo tine (87), an antiviral agent.

C1CCH2O—^

—

(£2) X =Cl (£5) X =OCH3

NH

CM)

(8£) X = Cl (8T) X = OCH3

x = C1

0CH CM) XX =0CH 3

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group.

A series of

experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system.

As an

example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzothiazines below).

Toward this end, reaction of

Fused Six-Membered Heterocycles

379

homophthalic acid with ammonia affords the imide 89; triethylamine catalyzed condensation of that intermediate with p-chlorophenylisocyanate affords the corresponding amide. There is thus obtained the antiinflammatory agent tesicam (90). 24 0

,CO2H

'NH

(88)

CM)

_NH_Q_C1 (£0)

3. QUINA20LINES Quinazolines containing an electron-rich carbocyclic ring have been associated with smooth muscle relaxant activity. The mechanism of action (phosphodiesterase inhibition, a- adrenergic blockade) and organ selectivity (bronchi, vascular smooth muscle) vary greatly with substitution on the heterocyclic ring. Nitration of 3,4-dimethoxypropiophenone (91) affords the nitro derivative 92, and catalytic reduction leads to the aminoketone (93). This is then converted to the corresponding formamide by means of formic-acetic anhydride. Treatment with ammonia completes construction of the quinazoline ring. There is thus obtained the bronchodilator-cardiotonic 25 agent, quazodine (95). In a similar vein, condensation of the substituted anthranilamide 96 with trimethyl orthoformate affords directly the quinazolone 98. Reaction with phosphorus

Fused Six-Membered Heterocycles

380

H

2LH3

CH 2 CH 3

(91)

(£3)

CH 2 CH 3

(91)

oxychloride converts the carbonyl to the enol chloride (99).

Displacement of halogen with monosubstituted

CH

CH (99)

s

C0CH 7 R

o HN

N

(100) R= CH(CH 3 ) 2 (101) R = HOC(CH 3 ) 2

(102) R= CH(CH 3 ) 2 (103) R = HOC(CH 3 ) 2

Fused Six-Membered Heterocycles

381

piperazine 100 gives the bronchodilator piquizil 0Pi

(102)) the same reaction with piperazine 101 leads 27 to another bronchodilator hoquizil (103). A similar scheme is used to construct a quinazoline containing halogen at both positions 2 and 4. The differences in reactivity of these halides make available compounds bearing two different amine substituents.

Nitration of aldehyde 104, followed by

oxidation affords the acid 106.

The acid is then

converted to the primary amide (107), and the nitro group is reduced catalytically to the corresponding

CH3O.

(104)

(109)

(110)

(Ill)

YVJ

CH 2 CH=CH 2 N ;H2

(113)

(112) (114)

Fused Six-Membered Heterocycles

382 amine (108).

Condensation with urea completes con-

struction of the heterocyclic ring (109); this is converted to the desired dichloride by reaction with phosphorus oxychloride (110).

Reaction with ammonia

in THF at room temperature serves to replace the more reactive chlorine by a primary amine (111).

Displace-

ment of the remaining halogen is achieved with piperazine under more strenuous conditions (112). Alkylation of the piperazine nitrogen with ally! bromide affords the antihypertensive agent quinazocin

(113).27

Acylation at the same position gives the

recently commercialized antihypertensive agent prazosin

(114).2& The same scheme starting with 3,4,5-trimethoxybenzaldehyde (115) affords initially dichloroquinazoline 116.

Reaction of this intermediate with

ammonia leads to replacement of the amine at the 2-position (117).

Displacement of the remaining

chlorine with piperazine carbamate 101 affords the 29 antihypertensive agent trimazocin (118). OCH

(116) X = Cl (117) X = NH 2

The extensive series of antibacterial agents consisting of derivatives of 5-nitrofurfural has been discussed in Chapter 8.

It is of interest that a

Fused Six-Membered Heterocycles

383

derivative of nitrofuran in which the carbonyl is at the acid oxidation stage and incorporated into a guinazoline also shows antibacterial activity; this agent, nifurquinazol

(124), is prepared as follows.

Treatment of the amide from 5-nitrofuroic acid with phosphorus oxychloride leads to the corresponding nitrile (120)*

This intermediate is then converted

to the iminoether (121) with ethanolic hydrogen chloride.

Condensation with anthranilic acid in the

presence of sodium methoxide gives the quinazolone 122*

The amide function is then converted to the

iminochloride with phosphorus oxychloride (123). Replacement of halogen by means of diethanolamine 31 affords nifurquinazol (124).

(U9)

(120)

(121)

HO 2 C H2N'

HOCH 2 CH 2

CH 2 CH ? OH

(124)

(123)

(H2)

Benzothiadiazines containing halogen and a sulfonamido group on the carbocyclic ring (125) form a large class of diuretic agents often referred to as

38 4

Fused Six-Membered Heterocycles

the thiazides; the ring sulfone group can b e replaced by carbonyl with retention o f significant biological activity.

32

More recently, it has been found that

diuretic activity is retained when one of the ring nitrogen atoms carries an aryl group.

Toward this

end, the starting aniline 127 is first acetylated (128) by means of acetic anhydride to protect the primary amine in subsequent steps.

Reaction with

chlorosulfonic acid leads to sulfonyl chloride 129; this is converted to the sulfonamide by reaction with ammonia (130). Oxidation of the methyl group by means of permanganate cleanly gives the acid 131; the acetyl group is then removed by hydrolysis. Treatment of the resulting anthranilic acid (132) with phosgene then leads to the isatoic anhydride 133*

Reaction of

that anhydride with ortho-toluidine results in acylation of that aniline by the anthranilic acid (134); tying up the anthranilic acid up as the anhydride serves to both activate the carbonyl towards amide formation and to protect the amine towards self condensation.

The carbamic acid presumably formed as

an intermediate decarboxylates.

Treatment of the

anthranilamide 134 with acetic anhydride affords directly quinazolone 135. (The sequence may be rationalized by assuming acetylation of the aniline as the first step; formation of an imine between the carbonyl and amide nitrogen gives the observed product.) Reduction of the imine function with sodium borohydride in the presence of aluminum chloride gives 33 the diuretic agent metolazone (136).

385

Fused Six-Membered Heterocycles

NHC0CH3 H NSOx

2 2

x

x

(125) X = S02 (126) X = CO

(127) R = H (128) R = COCH3

(129) y = Cl (130) y = NH2

H NN_.O

XO

H2NSO2

(134) H N O2 2S

H2NSO2"

H N O2 2S R= =H C O C H 3 ((113321)) R

H N O2 2S (136)

(135)

The majority of nonsteroidal antiinflammatory agents contain some function which supplies an acidic proton, be this a carboxyl group or a highly activated enol system,

A guinazolone devoid of such potential

enolizable protons forms an interesting exception to this generalization*

(It is tempting in such cases

to speculate that the compound may exert its biological activity by some mechanism distinct from the rest of the class.)

Alkylation of aminobenzophenone

137 with isopropyl iodide gives the corresponding N-alkylated amine (138)*

Treatment of that interme-

diate with urethane in the presence of zinc chloride serves to form the quinazolone ring.

The reaction

may be rationalized by assuming acylation of the

Fused Six-Membered Heterocycles

386

amine as the first step to form urea 139*

Intra-

molecular imine formation then affords the observed 34 antiinflammatory product, proquazone (140).

(139)

(14 0)

(138) R = CH

A more highly oxidized derivative of quinazoline forms the heterocyclic moiety of a compound with CNS activity.

Condensation of the aminopropylpiperazine

141 with isatoic anhydride gives the anthranilamide 142*

Reaction of that amide with phosgene gives

directly the heterocyclic ring.

(The reaction may

proceed by initial formation of the carbamoyl chloride; Cl CNHCH 2 CH 2 CH 2 N

\=/ ^•^^

^s.

NH9 (142)

(141)

,CH 2 CH 2 CH 2 N

(143)

N

Fused Six-Membered Heterocycles

3 87

this may then either acylate the amide or alternatively decompose to an isocyanate.

This last could then add

the amide nitrogen.)

The product of this sequence is 35 the sedative: tranquilizer eloperidone (143)* 4.

CINNOLINES AND QUINOXALINES

Replacement of a methine in oxolinic acid (46) by nitrogen is apparently consistent with retention of antibacterial activity. One approach begins with reduction of nitroacetophenone 144 to afford the corresponding aminoketone (145).

Treatment of this

intermediate with nitrous acid leads to the diazonium salt; the diazonium group condenses with the ketone methylene group (as its enol form) to lead to the cyclized product, cinnoline 147. Bromination proceeds at the position adjacent the enol grouping (148); 0"

OH

L --CH3

COC

"NX

(144) X = 0 2 (145) X = H 2 (146) X =S

(147)

(148)

0 L

II

!l

0

(ill)

(110)

(149)

388

Fused Six-Membered Heterocycles

then displacement by means of cuprous cyanide (149) followed by alkylation on nitrogen affords cyanoketone 150* Hydrolysis of the nitrile function then gives cinoxacin (151),

an antibacterial agent.

The pyrazole derivative phenylbutazone (152) has found extensive clinical use as an antiinflammatory agent.

(The acidic proton here is generated by a

p-dicarbonyl system.)

Incorporation of salient

portions of the molecule in a condensed heterocycle yields a compound, cintazone (160), which also exhibits antiinflammatory activity.

The synthesis of 160

starts with Grignard addition of methylmagnesium bromide to ortho-aminobenzophenone (253), affording carbinol 154; dehydration gives the corresponding olefin (155).

The cirmoline ring is then constructed

by a sequence similar to that used above.

Thus

treatment of the amine with nitrous acid gives the diazonium salt; treatment with mild base (ammonium hydroxide) causes the salt to close to the cinnoline (157)*

Catalytic reduction in acetic acid affords

initially the product (158) of 1,4-addition of hydrogen; this product is in tautomeric equilibrium with cyclic hydrazine 159*

Condensation of 159 with diethyl

amylmalonate leads to formation of the pyrazolodione ring.

There is thus obtained cintazone (160)* Oxidation of 2,3-dimethylquinoxaline (from

phenylenediamine and diacetyl) with either peracids or hydrogen peroxide in acetic acid gives the 1,438 dioxide (162)* Treatment of this bis-N-oxide with selenium dioxide leads to oxidation of one of the methyl groups to the methyl carbinol and formation of

(H2

(152)

(154)

(153)

(155)

(157)

(158)

(156)

!

(160)

(159)

G X - OCX? — OOC (161)

0 (163)

(162)

,CH-NNHCO2CH3 CH, (164)

(165) 389

390

Fused Six-Membered Heterocycles

39 mediquox (163), an agent used "to treat respiratory infections of poultry. Reaction of 162 with selenium dioxide under more strenuous conditions proceeds to the aldehyde stage (164).

Condensation of the carbonyl group with methyl carbazate affords carbadox (165). 40 The biological activity of cctrbadox is similar to that of mediquox. 5.

MISCELLANEOUS BENZOHETEROCYCLES

Partial reduction of lactone 166 (using for example diisobutylaluminum hydride in the cold) affords lactol 167.

Condensation with nitromethane leads to

the corresponding alkylated tetrahydrobenzopyran 170. The sequence probably starts by aldol reaction of the hydroxylactone form of the lactol (168) with nitromethane to give the vinyl nitro intermediate 169;

(166)

(167) (168)

,CH2NO2

:H2NH2

CHNO9

6 (171)

(170)

(169)

Fused Six-Membered Heterocycles

391

intramolecular conjugate addition of the alcohol will then give the observed product.

Since this last step

is in principle reversible, the reaction is expected to yield predominantly the thermodynamically favored bisequatorial cis isomer.

Catalytic reduction of the

nitro group then gives the primary amine anorectic 41 agent fenisorex (171). Condensation of 2,4-dihydroxypropiophenone

(172)

with benzoyl chloride and sodium benzoate goes to afford chromone 174, probably via ester 173.

This

procedure is known as the Kostanecki-Robinson reaction. Methylation (175) of the remaining phenolic function by means of dimethyl sulfate, followed by reaction

'XT™ (172)

(IZJJ R = H

(173)

(175) R = Cfu

(176)

with formaldehyde and hydrogen chloride gives the chloromethyl intermediate 176.

Displacement of

chlorine with dimethylamine then affords the respira42

tory stimulant dimefline

(177).

Fused Six-Membered Heterocycles

392

Modification of the substitution pattern on the same chromone gives a compound with smooth muscle relaxant activity, flavoxate (184).

The synthesis of

this flavone ester is initiated with methylation of the hydroxypropiophenone 177 to 178 followed by reduction of the nitro group to yield aniline 179. The amine is then used to introduce a nitrile by diazotization followed by treatment of the diazonium salt with cuprous cyanide (180); the methyl ether is then cleaved by means of aluminum chloride. Treatment of the phenolic ketone 181 with benzoyl chloride and sodium benzoate serves to build up the chromone ring (182).

The nitrile is next hydrolyzed to the acid

with sulfuric acid.

Esterification of the carboxyl

a s — i t s acid chloride—with N-(2-hydroxyethyl)piperidine affords flavoxate (184).

/

NCH2CH2O2C

(184)

(183)

Reaction of salicylamide 185 (obtainable from a suitable activated derivative of salicylic acid and N,N-diethylethylenediamine) with ethyl chloroformate

Fused Six-Membered Heterocycles

39 3

in the cold followed b y heating affords the benzoxazinedione 187.

44

It is likely that the transformation

proceeds via carbonate 186; the product, letimide (187), is reported to show analgesic activity.

,OCO2C2H5

CNHCH 2 CH 2 N 0

C2H5 (187) (186)

Among the heterocyclic systems that have been used to provide a backbone for acidic, nonsteroidal antiinflammatory agents are benzo-l,2-thiazine dioxides, such as 193*195*

Entry to the ring system is

gained by an interesting ringenlarging rearrangement. The necessary intermediate for the expansion reaction is prepared by alkylation of saccharin (188) with ethyl bromoacetate to afford the ester 189.

Treatment

of that with sodium methoxide results in formation of the anion adjacent to the carbonyl; bond reorganization gives the net result (190) of a ring enlargement. The driving force for the reaction may well reside in the fact that the anion of the product is a weaker base than that of starting material.

Sodium hydroxide

mediated alkylation of the product (190) with methyl iodide might occur at any one of three sites (0, N or C) due to the multidentate nature of the anion; interestingly, the reaction proceeds to give only the N-methylated product (192).

Amide formation from

Fused Six-Membered Heterocycles

394

192 by interchange with 2-aminothiazole affords the antiinflammatory agent sudoxicam (193);

the same

reaction using 2-aminopyridine gives pyroxicam (194). 46 Formation of the amide from 192 and 3-amino5-methyl47 isoxazole leads to isoxicam (195).

ICII2CO2CII3

(188)

s 02

( 190)

(192)

°2 (194)

(193)

(195)

As noted above, a convenient pathway to cinnolines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond.

The analogous reaction

with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198.

Reaction of isatoic anhydride with N-

aminomorpholine affords the hydrazide 196; then, treatment with nitrous acid yields initially the diazonium salt (197).

Under the reaction conditions

Fused Six-Membered Heterocycles

395

this cyclizes to the triazine 198, the analgesic 48 agent molinazone. This must be one of the f e w — i f not the only—compound containing a linear array of four nitrogens ever to be tried in the clinic. • NH 2 NUN

0 0 (,97)

(198)

Changing the substitution pattern on the carbocyclic ring of the benzothiadiazine diuretics is well known to have a marked effect on the qualitative biological activity.

Thus, the direct analogue of

the diuretic chlorothiazide

(199) in which chlorine

replaces one sulfonamide group, diazoxide (200), shows negligible diuretic activity; instead the compound is a potent antihypertensive vasodilator. The same pattern of activity is maintained in a closely related analogue.

Condensation of amino-

sulfonamide 201 with aldehyde 202 affords the saturated heterocyclic system (203); oxidation with silver nitrate leads to the antihypertensive agent pazoxide (204).49

396

Fused Six-Membered Heterocycles

c

(202)

T

( r 9 9 ) R ' = C l ; R 2 = SO 2 NH 2 ; R 3 = H

(201)

(200) R ! = H ; R2 = C1; R 3 = CH 3

02 (2_04)

REFERENCES 1.

For a fuller discussion, see D* Lednicer and L* A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p- 341 (1975). 2. J. H. Burckhalter, W. S. Brinigar and P. E. Thompson, J. Org. Chem., 26, 4070 (1961). 3. A. R. Surrey and H. F. Hammer, J. Am* Chem* Soc, 68, 113 (1946). 4. F. F. Ebetino and G. C. Wright, French Patent 1,388,756 (1965); Chem. Abstr. , 63: 589c (1965). 5. A. Winterstein, U. S. Patent 3,272,806 (1966); Chem. Abstr., 65: 18567 (1966). 6. R. Rodriguez, German Patent 2,006,638 (1970); Chem. Abstr., 73: 98987g (1970).

Fused Six-Membered Heterocycles

7. 8. 9.

10.

11. 12.

13. 14. 15. 16. 17. 18. 19. 20.

39 7

Anon., Netherlands Patent, 6,601,980 (1966); Chem. Abstr., 66: 115616k (1967). E. J. Watson, Jr., Belgian Patent 640,906 (1964); Chem. Abstr., 63: 2962 (1965). R. H. Mizzoni, F. Goble, J. Szanto, D. C. Maplesden, J. E. Brown, J. Boxer and G. De Stevens, Experientia, 24, 1188 (1968). J. J. Ball, M. Davis, J. N. Hodgson, J. M. S. Lucas, E. W. Parnell, B. W. Sharp and D. Warburton, Chem. Ind., 56 (1970). Anon., Netherland Application 6,602,994 (1966); Chem. Abstr., 68: 68899j (1968). R. L. Clark, A. A. Patchett, E. F. Rogers, U. S. Patent 3,377,352 (1968); Chem. Abstr., 71: 38821X (1969). D. Kaminsky and R. I. Meltzer, J. Med. Chem., 11, 160 (1968). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 492 (1975). A. C. W. Curran, J. Chem. Soc., Perkin Trans. I, 975 (1976). A. C. W. Curran and R. G. Shepherd, J. Chem. Soc, Perkin Trans. I, 983 (1976). H. C. Richards, South African Patent 6803,636 (1968); Chem. Abstr., 71: 30369k (1969). A. P. Gray and R. H. Shiley, J. Med. Chem., 16, 859 (1973). E. Yamato, M. Hirakura and S. Sugasawa, Tetrahedron Suppl. , 8, 129 (1966). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 351 (1975).

398

Fused Six-Membered Heterocycles

21.

R. C. Koch, Belgian Patent 635,308 (1964); Chem. Abstr., 61: 11978g (1964). J. L. Fliedner, Jr., J. M. Schor, M. J. Myers and I. J. Pachter, J. Med. Cham., 14, 580 (1971). Anon., Netherlands Application 6,516,328 (1966); Chem. Abstr., 65: 15351b (1966). S. B. Kadin, South African Patent 68 03,465 (1968); Chem. Abstr., 70: 115025z (1969). J. L. Minielli and H. C. Scarborough, French Patent M3207 (1965); Chem. Abstr., 63: 13287 (1965). T. H. Cronin and H.J. E. Hess, South African Patent 67 06512 (1968); Chem. Abstr., 70: 68419 (1969). Anon., British Patent 1,156,973 (1969); Chem. Abstr., 71: 91519f (1969). T. H. Althuis and H.J. Hess, J. Med. Chem., 20, 146 (1977). H.J. Hess, German Offen., 2,120,495 (1971); Chem. Abstr., 76: 1270l2e (1972). W. R. Sherman and A. von Esh, J. Med. Chem., 8, 25 (1965). H. A. Burch, J. Med. Chem., 9, 408 (1966). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, 354-360 (1975). B. V. Shetty, L. A. Campanella, T. L. Thomas, M. Fedorchuk, T. A. Davidson, L. Michelson, H. Volz, S. E. Zimmerman, E. J. Belair and A. P. Truant, J. Med. Chem., 13, 886 (1970). H. Ott and M. Denzer, German Patent 1,805,501 (1969); Chem. Abstr., 71: 30502 (1969).

22. 23. 24. 25.

26.

27. 28. 29. 30. 31. 32. 33.

34.

Fused Six-Membered Heterocycles 35.

36. 37. 38. 39. 40. 41.

42. 43. 44.

45. 46. 47.

399

S. Hayao, H. J. Havera, W. G. Strycker, T. J. Leipzig, R. A. Kulp and H. E. Hartzler, J. Med. Chem., 8, 807 (1965). W. A. White, German Patent 2,065,719 (1975); Chem. Abstr. , 83: 58860k (1975). F. Schatz ami T. Wagner-Jauregg, Helv. Chim. Acta, 51, 1919 (1968). J. K. Landguist and G. J. Stacey, J. Chem. Soc., 2822 (1953). J. D. Johnston, U. S. Patent 3,344,022 (1967); Chem. Abstr. , 67: 111452b (1967). J. D. Johnston, Belgian Patent 669,353 (1965); Chem. Abstr., 65: 7196e (1966). M. W. Klohs, F. J. Petracek, J. W. Bolger and N. Sugisaka, South African Patent 72 00,748 (1973); Chem. Abstr., 79: 126310a (1973). P. da Re, L. Verlicchi and I. Setnikar, Arznei~ mittelforsch., 10, 800 (1960). P. Da Re, L. Verlicchi and I. Setnikar, J. Med. Chem., 2, 263 (1960). H. J. Havera and S. Hayao, South African Patent 67 07,712 (1968); Chem. AJbstr. , 70: 87821k (1969). J. G. Lombardino, E. H. Wiseman and W. M. McLamore, J. Med. Chem., 14, 1171 (1971). J. G. Lombardino and E. H. Wiseman, J. Med. Chem. , 15, 849 (1972). H. Zinnes, M. Schwartz and J. Shavel, Jr., German Patent 2,208,351 (1972); Chem. Abstr., 77: 164722c (1972).

4 00

Fused Six-Membered Heterocycles

48.

EL Herlinger, S. Petersen, E. Tietze, F. Hoffmeister and W. Wirth, German Patent 1,121,055 (1962); Chem. Abstr., 56: 15523e (1962). J. G. Topliss and A. J. Wohl, Swiss Patent 558,376 (1975); Chem. Abstr., 82: 156390f (1975).

49.

13

Benzodiazepines That the benzodiazepines continue to be prominent on the list of the 200 most frequently prescribed drugs in the United States is both a commentary on the nature of our contemporary society and a measure of their acceptance as anxiolytic and tranguilizing substances.

Intensively competitive research into

new analogues continues and this chapter chronicles some of the more prominent members of this group not detailed in the original volume. The original entries into this class, such as chlordiazepoxxde

(1), were N-oxides.

Treatment of

the N-acetate (2) of chlordiazepoxide with aqueous acid served to hydrolyze the acylenamine function to liberate the keto analogue (3) which has been identified in excreta as an active metabolite of 1; this 2 minor tranquilizer has been named demoxepam.

401

Benzodiazepines

402

CII3CO,

NHCH-?

(2)

(3)

It will perhaps be recalled from the earlier volume that such N-oxides are prone to undergo the Polonovski rearrangement when treated with acetic anhydride, and that this was illustrated by the formation of oxazepam.

It is not surprising that

the N-methyl analogue (4) also undergoes this process, and hydrolysis of the resulting acetate gives temazepam (5).

Care must be exercised with the

conditions, or the inactive rearrangement product 6 results.

(5)

(6)

The lactam moiety in benzodiazepines is active toward nucleophiles and numerous analogues have been made by exploiting this fact.

For example, heating

demoxepam (3) with N-cyclopropylmethylamine leads to amidine formation, the minor tranguilizer cyprazepam

403

Benzodiazepines

(7).

On the other hand, treatment of diazepam (8) NHCH?—<J

(7)

(8.) (9)

with phosphorus pentasulfide produces the corresponding thionamide, sulazepam (9), also a minor tranquili2er.

The thionamide moiety is even more NHOCH 2 CH=CH 2

(10)

(ID

prone to aminolytic amidine formation than the lactam itself.

Reaction of thionamide 10 with O-allyl-

hydroxylamine gave the oximinoether 11, uldazepam. 6 An attempt to reduce metabolic N-dealkylation resulted in the preparation of fletazepam (16), whose activity is expressed as a muscle relaxant*

Direct

N-alkylation of the amide NH group at a late stage in the synthesis with trifluoroethy1 iodide and NaH went

Benzodiazepines

404

in poor yield, so the desired alkyl group was introduced at an earlier stage.

Alkyation of 4~chloro-

aniline by the tridhloromesyl ester of trifluoroethanol (12) produced secondary aniline 13.

This

underwent alkylation by aziridine to produce diamine 14.

Acylation with 2-fluorobenzoyl chloride produced

CH 2 CF 3

jcr

CH?

NH CF3CH2OSO2CCI3 Cl

^ ^

(12)

Cl

H9N

(13) (14)

CH 2 CF 3

the desired secondary amide which underwent BischlerNapieralski cyclodehydration with POClg and P2°5 give 15.

to

The lactam moiety was introduced by ruthenium

tetroxide oxidation to give fletazepam (16). Interestingly, the deoxy analogue minus the fluorine atom, prepared by a similar route, tranquilizer.

is also a minor

Benzodiazepines

405

A rather interesting synthesis of the basic ring system based upon oxidative scission of indole precursors was used to prepare prazepam (24), a muscle Q

relaxant.

Starting with indole 17, N-alkylation to

IS was accomplished with cyclopropylmethyl bromide and NaH.

The ester was converted to the amide (21)

by the usual sequence and then reduced to primary amine 22 using lithium aluminum hydride.

CO2Et

|

COX

CH2—<

(17)

(II) (19) (20) (21)

X = OC2H5 X = OH X = Cl X = NH2

(21)

(24)

(25)

406

Benzodiazepines

Oxidation with chromium trioxide in acetic acid cleaved the indole ring to produce intermediate 23 which cyclodehydrated to give prazepam (24). Nitration of benzodiazepines takes place at the electron rich C 7 position, and this was used to prepare flunitrazepam (25), a potent hypnotic agent.

9

It is interesting to note that some l,5~benzodiazepines such as 29 also possess CNS depressant activity.

Treatment of substituted diphenylamine 26

with methyl malonyl chloride and reduction with Raney nickel led to orthophenylenediamine analogue 27. Sodium alkoxide treatment led to lactam formation (28), and alkylation in the usual way with NaH and methyl iodide produced clobazam (29).

(

~}

(27)

(28) R - H (29) R - C H 3

On the other hand, MnO 2 oxidation of lactam 30 or arylation of secondary lactam 32 with bromobenzene using Cu powder and potassium acetate both led to anxiolytic triflubazam (31).

Benzodiazepines

407

(30) (31)

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, p. 365, 1977, L. H. Sternbach and E. Reeder, J. Org. Chem. , 26, 4936 (1961). S. C. Bell and S. J. childress, J. Org. Chem., 27, 1691 (1962). H. M. Wuest, U. S. Patent 3,138,586 (1964); Chem. Abstr. , 61: 7,032f (1964). G. A. Archer and L. H. Sternbach, J. Org. Chem., 29, 231 (1964). J. B. Hester, Jr., German Patent 2,005,176 (1970); Chem. Abstr., 73: 99,001t (1970). M. Steinman, J. G. Topliss, R. Alekel, Y.S. Wong and E. E. York, J. Med. Chem., 16, 1354 (1973). S. Inaba, T. Hirohashi and H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969). L. H. Sternbach, R. I. Fryer, O. Keller, W. Metlesics, G. Sach and N. Steiger, J. Med.

408

10. 11.

Benzodiazepines Chem., 6, 261 (1963). K.H. Weber, A. Bauer and K.H. Hauptmann, Ann., 756, 128 (1972). K.H. Weber, H. Merz and K. Ziele, German Patent 1,934,607 (1970); Chem, Abstr., 72: 100,771g (1970); and K.-H. Weber, K. Minck, A. Bauer and H. Merz, German Patent 2,006,601 (1971); Chem. Abstr., 76: 3918k (1972).

14

Heterocycles Fused to Two Benzene Rings Pharmacological agents based on dibenzo heterocyclic compounds had their inception in the formal cycli2ation by inclusion of a hetero bridging atom of the two benzene rings characteristic of diphenylamine and benzhydryl antihistamines.

As detailed in the earlier

volume, this approach led to the development of the first of the antipsychotic agents, chlorpromazine. Further modification of the central ring led to compounds that showed antidepressant rather than tranquilizing activity.

It might be noted in passing

that it was eventually discovered that the central ring in antidepressants need not be heterocyclic at all; some of the more widely used antidepressant drugs are in fact derivatives of dibenzocycloheptadiene. Further modification of the dibenzoheterocycles has not yielded agents with markedly different activities. The compounds discussed below, with few exceptions, 409

410

Heterocycles Fused to Two Benzene Rings

exhibit either antihistaminic or central nervous system activity* 1.

CENTRAL RING CONTAINING ONE HETEROATOM

Reaction of 2-bromobenzoic acid (1) with chlorosulfonic acid proceeds to afford the sulfonyl chloride 2; treatment with dimethylamine leads to the corresponding sulfonamide (3).

Condensation of bromoacid 3 with

the anion from thiophenol in the presence of copper powder results in displacement of halogen by sulfur (4). Friedel-Crafts cyclization of that sulfide by means of sulfuric acid gives the desired thioxanthone (5)/ which is then reduced to the thioxanthene (6). Treatment of that intermediate with butyl lithium serves to form the anion at the methylene group; the corresponding acyl derivative 7 is obtained by condensation of the anion with methyl acetate.

Mannich

reaction on the ketone with formaldehyde and N-methylpiperazine yields the amino ketone (8). The carbonyl group is then reduced with sodium borohydride. Dehydration by means of phosphorus oxychloride in pyridine gives the major tranquilizer thiothixene (10)*

As might be expected, this last reaction

gives a mixture of isomers; the more active Z isomer is separated from the mixture by fractional crystallization. The presence of a rather more complex substituent on the remote piperafcine nitrogen atom is consistent with tranquilizing activity.

The preparation of one

such agent, 16, begins with reaction of thioxanthone 11 (obtained by a sequence analogous to that used to

Heterocycles Fused to Two Benzene Rings

411

•S> "3\

C ' O-,H (2 ) R = C 1

(i)

NO->S *

(4)

NO?S

NOoS

0^ T'lUCIUN

C5 ) X = 0 fd)

T'3

CH7 •SO 2 N— CH 3

X=H

T.

CH 3

CHC:II2CII2N

OH

NCM

\

/ CIO)

prepare 5) with the Grignard reagent from 3-(tertiaryamyloxy)propyl bromide to afford alcohol 12.

Treatment

with hydrogen bromide serves to dehydrate the carbinolf remove the protecting group from the terminal alcohol,

412

Heterocycles Fused to Two Benzene Rings

and finally to convert that alcohol to the corresponding bromide (13). Although this would be expected as a mixture of isomers, the sharp melting point of the product suggests it may be homogenous. This halide is then used to alkylate the monocarbamate from piperazine, yielding 14. Saponification of the carbamate affords the secondary amine 15* Michael condensation of that base with N-methylacrylamide gives the neuroleptic agent, clothixamide (16).

HO'

(11)

'CH 2 CH 2 CH 2 OCC 2 H 5 | ru

CHCH 2 CH 2 Br

til)

1 CHCH 2 CH 2 N

NCH 2 CH 2 CONHCH 3

CHCH 2 CH 2 N

NR

(14) R = CO.

CIS) R = H '

Reduction of the exocylic double bond and inclusion of the side chain nitrogen in a piperidine ring leads to a compound (19) which exhibits skeletal muscle relaxant activity. Its one step synthesis begins with reaction of thioxanthene (17) with phenyl sodium

Heterocycles Fused to Two Benzene Rings

413

to afford the anion at the methylene group of the heterocycle; then, condensation of that anion with piperidine derivative 18 gives directly methixene (19).3

~X) CHr

CH,

„„

Lucanthone (20) constitutes one of the first effective antischistosomal agents.

Biological invest-

igation of this agent showed that the active species in man is in fact the hydroxylated metabolic product hgcanthone (21)*

The published synthesis for the

latter involves microbial oxidation as the last 4 step.

Additional hydroxylated derivatives of lucan-

thone have been investigated.

One of these, beean-

thone (26), made as part of an investigation of antitumor agents, shows activity against schistosomes comparable to that of hx/canthone. Ullmann reaction of the salt of thiophenol 22 with 2-chlorobenzoic acid in the presence of copper gives the sulfide 23. Ring closure by means of sulfuric acid gives the corresponding thioxanthone (24).

Nucleophilic

aromatic substitution of the chlorine atom in 24 with aminoalcohol 25 gives becanthone (26) directly.

Heterocycles Fused to Two Benzene Rings

414

M 2 NCI. 2 CM 2

,

H

2 COH

NCH 2 CII 2 NH c2ns

The thioxanthene tranguilizers described above may be regarded as phenothiazine analogues in which a methine group acts as surrogate for nitrogen; that is, the side chain is attached to sp^ carbon instead of nitrogen.

It is thus of some interest that further,

rather drastic, modification of the central ring still gives a compound with tranquilizing activity. In the case of clomacran (30), the side chain is again attached to carbon, albeit tetrahedral rather than trigonal carbon.

In addition, the sulfur atom

present in both phenothiazines and thioxanthenes is replaced by a secondary amine.

This might be inter-

preted to mean that the nature of the bridge between the benzene rings is not crucial for biological activity.

The preparation of 30 begins with reaction

of acridone 27 with the Grignard reagent from 3-chloroN,N-dimethylpropylamine to afford tertiary carbinol 28; dehydration by means of acid or simply heat gives the corresponding olefin (29).

Catalytic reduction

completes the synthesis of the tranquilizer, clomacran

(30).6

H e t e r o c y c l e s F u s e d t o Two B e n z e n e

Rings

Cl

415

'Cl

o CH 2 CH 2 N—CH 3

(27) (28)

Cl CH 2 CH 2 CH 2 N—C

'Cl CH 2 CH 2 CH 2 N—-CH 3 (30)

3

CM?

Nuclei for tricyclic antidepressants and tranquilizers almost invariably contain the three rings fused in linear array.

It is thus interesting to

note that an angular arrangement of these rings, such

NH CH 2 CH 2 CH 2 N \ (31)

'CH,

(32)

as in fantridone (32), is consistent with antidepressant -activity.

Alkylation of the anion obtained

by treatment of phenathridone (31) with sodium hydride

416

Heterocycles Fused to Two Benzene Rings

and 3-chloro-N,N-dimethylpropylamine affords fantridone (32) directly. 7 Almost every major structural class discussed to date has featured at least one nonsteroidal antiinflammatory carboxylic acid.

It is thus perhaps not

surprising to find a dibenzoheterocycle serving as the nucleus for one of these agents, furobufen (34). Straightforward Friedel-Crafts acylation of dibenzofuran (33) with succinic anhydride affords a mixture of 2- and 3-acylated products, with the latter predominating.

The mixture is esterified with methanol,

and the methyl ester of the 3-isomer is separated by fractional crystallization.

Hydrolysis back to the

8

acid affords pure 34.

CH 2 C

Replacement of sulfur in the phenothiazines by two methylene groups also results in compounds that retain antipsychotic activity; two examples are carpipramine (41) and clocapramine (44). Although one might describe this as yet another example of the bioisosteric equivalence of sulfur and ethylene, the observed broad latitude in the nature of the tricyclic system in tranquilizers suggests caution in drawing such a conclusion.

In a convergent synthesis of 41,

reaction of N-benzyl-4-piperidone (35) with potassium cyanide and piperidine hydrochloride gives the corresponding a-aminonitrile (36).

Hydrolysis of the

nitrile by means of 90% sulfuric acid gives the amide

Heterocycles Fused to Two Benzene Rings

417

37; hydrogenolysis of the benzyl protecting group then affords the secondary amine 38*

Alkylation of

dibenzazepine 39 with l-bromo-3-chloropropane gives intermediate 40*

Use of that material to alkylate

piperidine 38 affords finally carpipr&mine (41). The same sequence starting with halogen substituted dibenzazepine 42 leads to the tranquilizer clocapra-

mine (44).10

(35)

(3b)

(37)

ooa, (39) x = H

I (4_0) X « H (43)

CONH, " N \ A r~\

vy f

X - Cl

CM)

ooa

o
CH 2 CH 2 CH 2 N^ (41_) X = H (44) X - C l

Heterocycles Fused to Two Benzene Rings

418

Many tricyclic tranquilizers and antidepressants exhibit some measure of anticholinergic activity. It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50).

Reaction of anthra-

quinone (45) with the Grignard reagent from 3-chloroN,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46.

This is then converted to

oxime 47 in a straightforward manner.

Treatment of

that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of

NOH CH, HO

CH

2(:ii2CII2N \

(45)

CHCH 2 CH 2 N \

CH. (49)

(48)

CH,

Heterocycles Fused to Two Benzene Rings

419

the tertiary carbinol and Beckmann rearrangement of the oxime to afford the enelactam 48; the stereochemistry of the product(s) (E/Z) is not specified. The lactam is then reduced to amine 49 with lithium aluminum hydride, and the resulting amine is methylated to obtain elantrine (50)* Replacement of the ring nitrogen in 50 by oxygen yields a molecule that can now again be characterized as a tranguilizer, although one that shows some degree of anticholinergic activity. Synthesis of this agent, pinoxepin (55), begins with the reaction of 1,3-dibromopropane with triphenylphosphine to give the bromoalkylphosphonium salt 51.

Displacement of the

remaining bromine by piperazine then leads to the

BrCH2CH2CH2Br +(C6H513P

•» Br0 (C6H5)3PC]l2Cll2CH2Br

»» Br9 (C0H5)3P%2CII2CH2N Nh

(53)

NCH 2 CH 2 OH

H

CH2CH2NNH (54)

functional phosphonium salt 52. The latter is then converted to the corresponding ylide by means of

420

Heterocycles Fused to Two Benzene Rings

butyl lithium, and the resulting reactive intermediate is condensed with ketone 53.

The product (54) in

this Case consists largely (4:1) of the Z_ isomer. The stereoselectivity may involve complexation of the betaine intermediate with the heterocyclic oxygen. Condensation of the terminal secondary amine with 12 ethylene oxide affords pinoxepin (55). 2.

BENZOHETEROCYCLOHEPTADIENES

Both this and the previous volume are of course organized on the basis of structural classes.

Occasion-

ally, a series of medicinal agents defies attempts at neat classification by such a scheme. The compounds that follow could only be called dibenzoheterocycles by performing the imaginary operation of moving the hetero atom from the flanking to the central ring of the molecule.

The chemistry and biological activity

of those molecules does seem to argue for their inclusion at this juncture. The first of these compounds, pizotyline (65), shows activity much akin to related tricyclic depres13 sants such as imipramine (56). One of several schemes for preparation of the key tricyclic intermediate 63 starts by reaction of 2-chloromethylthiophene 57 with triethyl phosphite.

The net trans-

formation (Arbu2ov reaction) probably starts with formation of phosphonium salt 58; displacement of one of the ethyoxy groups by chloride at carbon then leads to loss of ethyl chloride and formation of the observed phosphonate 59.

Reaction of the ylide

or

9 C 2«5

e U

U

OCoHc O C2H5

(57.) (58)

or(59\) CHO

"CO2H (60)

CH2CH2

HO 2 C

(63)

(62) (61)

CH 3

(64)

0C H 7

CH2CH2CH2N \

CH 3

(56)

(65)

4 2 1

422

Heterocycles Fused to Two Benzene Rings

obtained from the last intermediate with hemi phthalaldehyde (60) gives the diarylethylene 61.

Reduction

of the double bond (62), followed by Friedel-Crafts cyclization by means of polyphosphoric acid affords the requisite ketone 63* This compound is then condensed with the Grignard reagent from l-methyl-4chloropiperidine, and the resulting carbinol (64) is dehydrated. There is thus obtained the antidepressant 14 agent pizotyline (65). Replacement of the thienyl grouping in 65 by pyridyl affords azatadin (75), a compound in which antihistaminic rather than antidepressant activity predominates.

(It is of interest that the equivalent

interchange in the acyclic series affords a pair of compounds each of which is an antihistamine.)

The

synthesis of the tricyclic system in this case starts by acylation of the anion from phenylacetonitrile with ethyl nicotinate to give cyanoketone 66*

Hydro-

lysis of the nitrile followed by decarboxylation of the resulting keto-acid gives ketone 67; reduction then leads to the diarylethane 68.

Functionality is

then introduced into the pyridine ring by the elegant method introduced by Taylor.

Thus, treatment of 68

with peracid gives N-oxide 69; reaction of that with phosphorus trichloride leads to the corresponding 2chloropyridine (70) with simultaneous loss of the oxide.

Displacement of halogen with cyanide followed

by hydrolysis of the resulting nitrile (71) gives the carboxylic acid (72).

Cyclization by means of poly-

phosphoric acid yields the key tricyclic intermediate 73. The ketone is then condensed with the Grignard

NC

(166) X = H (76) X = Cl

(11)

X=H

(83)

X = Cl

(6_7_) X = H; R = 0 f6jO X = H; R = H2 (77) X = Cl; R = 0

(.72)

X=H

(82)

X = C1

X = Cl

X X X X

= H; y = Cl = II; y = CN = y = Cl = Cl; y =CN

oCH,

Cii)

Cl

Cl

CHCOR

X=H

(79)

(7_0) (7JJ (8_0) (81)

CH2CO2C2H5

ci

(6_9)

N-CH3 CHCH2N \ CH7

N ' CH2CH2N—-CHI CH 7

3

(815) R = OH (87) R==N(CH3)2 423

42 4

Heterocycles Fused to Two Benzene Rings

reagent from N-methyl-4-chloropiperidine to afford the carbinol 74. Finally, dehydration of this last intermediate affords the antihistamine azatadine (75).16 A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83.

Condensation of

that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84.

This product is then in turn dehyd-

rated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethylamide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride; catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This This compound also exhibits antihistaminic activity. 3.

DERIVATIVES OF DIBENZOLACTAMS

A recurring theme in the present chapter has been the association of CNS activity with dibenzoheterocycles that bear a basic chain pendant from the central ring.

As we have seen, considerable latitude exists

as to the constitution of the central ring.

The

earlier volume in this series described the preparation of the antidepressant dibenzepin (90), in which the 17 basic function is attached to a lactam nitrogen. It has been found subsequent to this that attachment of the basic center in the guise of a piperazine ring

Heterocycles Fused to Two Benzene Rings

42 5

as an amidine derivative again affords a series of compounds with activity on the CNS. Preparation of the simplest of these examples (95) starts with hydrogenolysis of o-aminobenzoylbenzoic acid (91) with zinc (activated by copper) in ammonia.

Thermal cyclization of the resulting di18 phenylmethane (92) gives the desired lactam (93). Treatment of that intermediate with phosphorus oxychloride in the presence of N,N-dimethylaniline leads to iminochloride 94.

Aminolysis with N-methyl-

piperazine affords the hypnotic agent perlapine

(95).1* Replacement of the bridge methylene group in 95 by a secondary amine is consistent with CNS activity, although the compound in this case (99) is described as a sedative agent.

The synthetic approach used in

this case relies on cyclization of an intermediate in which the piperazine ring is already in place.

Thus,

reaction of the acid chloride from 96 (available by Ullmann reaction of anthranilic acid on 2,5-dichloronitrobenzene) with N-methylpiperazine gives the corresponding amide (97).

The nitro group is then

reduced to yield aniline 98.

Intramolecular dehydra20 tion then affords the amidine, clozapine (99). Replacement of the methylene group in 95 by oxygen results in yet another subtle qualitative change in CNS activity.

The products of this replace-

ment, such as 104 and 111, are characterized as anxiolytic agents.

In the synthesis of 104 we find

yet a different approach to the amidine function, beginning with reaction of 2-chloronitrobenzene with

JUH

CO2H

CO2H

NH 'CH,

0

(92)

(91)

/ 0

H

(93)

3

Clh

/CH2CH2N \

H3

Cl

N' CH3 (9_5)

(90)

(94)

CO2H Cl

[0

H (96)

2

C—N

Cl

L

N

H (£7) (98)

R= 0 R =H

(99)

426

NCH, /

Heterocycles Fused to Two Benzene Rings

427

the anion from p-chlorophenol to afford the product of aromatic nucleophilic displacement (100); then, reduction of the nitro group affords the corresponding aniline (101)* Treatment of that amine with phosgene in the presence of excess triethylamine converts the aniline to the isocyanate (102). Condensation of that intermediate with N-methylpiperazine affords urea 103.

Bishler-Napieralski type cyclization

of the urea into the adjacent ring is accomplished with phosphorus oxychloride. There is thus obtained loxapine

(104).21

(100) R = 0 (101) R = H (103)

r? Cl

C104)

428

Heterocycles Fused to Two Benzene Rings

Another approach to this ring system leaves the formation of the oxygen bridge to the end.

This

scheme starts by reaction of the dichlorobenzoic acid 105 with carbonyldiimidazole (106) to afford the reactive intermediate 107*

Condensation with o-amino-

phenol gives the amide 108, which is then converted to the iminochloride with phosphorus pentachloride. Condensation of 109 with piperazine apparently stops cleanly at monomer 110.

Intramolecular Ullmann

condensation in the presence of copper powder leads to formation of the dibenzoxazepin ring, and thus 22 amoxapine (111).

Ci (106)

C

yy (107)

C Cl

fill)

(n0)

Heterocycles Fused to Two Benzene Rings

429

Finally, replacement of the methylene bridge by a sulfur bridge leads to compounds such as 117 and 123 which are major tranquilizers.

Thus, Ullmann

condensation of thiosaiicylic acid 112 with orthochloronitrobenzene affords thioether 113; the nitro group is then reduced to the aniline (114).

Cycliza-

tion as above leads to the lactam 115, which is then converted to the iminochloride derivative (116). Condensation with N-methylpiperazine affords clothiapine

(117).21

Exactly the same sequence with the methyl

substituted thiosaiicylic acid derivative 118 leads to metiapine

(123).21 CO2H

h (112) X = Cl (118) X = CH 3

(113) (114) (119) (120)

X - Cl; R = 0 X = Cl; R = H X = CH 3 ; R = 0 X = CH 3 ; R = H

= Cl (121) X = CH 3

Cl

(116) X = Cl (122) X = CH 3 (117) X = Cl (123) X = CH 3

430

Heterocycles Fused to Two Benzene Rings

4.

OTHER DIBENZOHETEROCYCLES

Historically, research in industrial medicinal chemistry has occurred in waves.

The discovery of

some novel structure with unique biological activity has often occasioned intensive work in numerous laboratories on the preparation and evaluation of analogues.

Each such wave recedes when it is realized

that further modification of the molecule is reaching the point of diminishing returns.

At this juncture,

the structure is often represented in the clinic by several commercialized drugs; it is judged unlikely that further work will produce a patentably novel compound that could make significant inroads on the market for drugs already available. Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class.

The

earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class.

Instead, the ring system is

used as the aromatic nucleus for a nonsteroidal antiinflammatory agent.

Preparation of 130 starts

with formylation of the rather complex aniline 123* Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement.

The sequence begins with

formation of the anion on the amide nitrogen; addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126.

Rearomatization

Heterocycles Fused to Two Benzene Rings

431

affords thiophenoxide 127; this then attacks the adjacent ring and the resulting negative charge on the ring carbon adjacent to nitrogen is then discharged by expulsion of the nitro group as the nitrite anion.

The formyl group on what is essentially a

diphenylamine is sufficiently labile so that it too comes off under the reaction conditions*

There is

thus obtained the phenothiazine carboxylic ester 129. Saponification of the ester completes the synthesis of the veterinary antiinflammatory agent flutiazin

(130).23

CO 2 CH 3 -O 2 CH 3 C126) (125]

C0 9 R'

(129) R1 = CH 3 (130) R' = H

(128)

Heterocycles Fused to Two Benzene Rings

432

The association between abnormally high levels of serum lipids and atherosclerosis has been discussed earlier.

One of the earliest and still most widely

used drugs for normalizing lipid levels and thus presumably treating atherosclerosis is the phenoxyester clofibrate (131).

The wealth of analogues in this

series has demonstrated that lipid lowering activity is retained when a second chlorophenoxy group is substituted onto the beta carbon of the acid moiety. More recently it was found that the two aromatic rings can be linked to form an eight-membered heterocycle.

In one example, treatment of potassium di-

chloroacetate with the dipotassium salt of bisphenol 132 affords the dibenzoxacin 133 directly, after acidification.

Esterification with methanol gives

the hypolipidemic agent treloxinate

ci—(/

y—OCCO2C:2M5

O 'K

(134).

Cl

f1 3 1 )

Cll2

(J_33") R = II

f 132)

REFERENCES 1.

B. M. Bloom and J . F. Muren, B e l g i a n P a t e n t 647,066 (1964); Chem. Abstr., 6 3 ; 11,512a (1965),

Heterocycles Fused to Two Benzene Rings 2. 3. 4. 5. 6. 7.

8.

9. 10.

11. 12. 13. 14. 15.

433

J. M. Grisar, U. S. Patent 3,196,150 (1965); Chem. Abstr., 63: 18,116f (1965). J, Schmutz, U. S. Patent 2,905,590; Chem. Abstr., 54: 5,699n (1959). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 399, 1977. E. J. Blanz, Jr., and F. A. French, J". Med. Chem., 6, 185 (1963). C. L. Zirkle, U. S. Patent 3,131,190 (1964); Chem. Abstr., 61: 4,326a (1964). J. W. James and R. E. Rodway, British Patent 1,135,947 (1968); Chem. Abstr., 70: 87,603r (1969). G. Schilling and T. A. Dobson, German Patent 2,314,869 (1974); Chem. Abstr., 81: 25,527n (1974). P. A. J. Janssen, U. S. Patent 3,041,344 (1962); Chem. Abstr., 59: 6,417b (1963). M. Nakanishi, C. Tashiro, T. Munakata, K. Araki, T. Tsumagari and H. Imamura, J. Med. Chem., 13, 644 (1970). Anon., Belgian Patent 652,938 (1965); Chem. Abstr., 64: 19,575h (1966). Anon., Netherland Appl. 6,411,861 (1965); Chem. Abstr., 63: 16,366a (1965). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 401404, 1977. J.M. Bastian, A. Ebnother, E. Jucker, E. Rissi and A. P. Stoll, Helv. Chim. Acta, 49, 214 (1966). E. C. Taylor, Jr., and A. J. Crovetti, J. Org. Chem. ,19, 1633 (1954).

434

Heterocycles Fused to Two Benzene Rings

16.

F. J. Villani, U. S. Patent 3,366,635 (1968); Chem. Abstr. ,69: 10,372m (1968). D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. I, p. 405, 1977. D. D. Emrick and W. E. Truce, J. Org. Chem., 26, 1239 (1961). F. Hunziker, F. Kunzle and J. Schmutz, Helv. Chim. Acta, 49, 1433 (1966). F. Hunziker, E. Fischer and J. Schmutz, Helv. Chim. Acta, 50, 1588 (1967). J. Schmutz, F. Kunzle, F. Hunziker and R. Gauch, Helv. Chim. Acta, 50, 245 (1967). C. F. Howell, R. A. Hardy and N. Q. Quinones, French Patent 1,508,536 (1968); Chem. Abstr., 70: 57,923c (1969). B. M. Sutton, U. S. Patent 3,471,482 (1969); Chem. Abstr., 72: 21,701f (1970). J. M. Grisar, R. A. Parker, T. Kariya, T. Blohm, R. W. Fleming, V. Petrow, D. L. Wenstrup and R. G. Johnson, J. Med. Chem., 15, 1273 (1972).

17. 18. 19. 20. 21. 22.

23. 24.

15

i3-Lactam Antibiotics Despite the enormous effort already expended during the past three decades, the p-lactam antibiotic field remains one of the most hotly competitive in the whole field of medicinal chemistry, with new entities constantly being produced to address one or more the clinical deficiencies perceived in existing drugs. Recently, some new basic skeletons have been encountered in fermentation screening programs, and this has given the field yet another burst of activity. Cefoxitin (31) is the first fruit of this effort. Whether the nocardicins, clavulanic acid, thienamycins, etc., will reach the marketplace is not yet clear. Meanwhile, intensive work is still being done among the older ring systems.

435

.OH

CH2OR •CO2H

C0 9 H

R=H R=

J)H II 0

H2N

Clavulanic Acids

NOH

HO 2 C

R=

CH,

OH ^

H

H

NOH CO 2 H HO 2 C, R=

H 2 N*

R = H,

NH2 HO2C

Thienamycins

R=

R=

NOH Nocardicins

436

R = COCH3

3-Lactam Antibiotics

1.

437

PENICILLINS

The new entries in this section are the result of manipulation of polar amide side chains to broaden the antimicrobial spectrum of the penicillins. Carbenicillin (1) is used in the clinic primarily because of its low toxicity and its utility in treating urinary tract infections due to susceptible Pseudomonas species.

Its low potency, low oral activity, and

susceptibility to bacterial p-lactamases make it vulnerable to replacement by agents without these deficits. (4).

One contender in this race is ticarcillin

Its origin depended on the well-known fact (to

medicinal chemists) that a divalent sulfur is often roughly equivalent to a vinyl group.

One synthesis

began by making the monobenzyl ester (2) of (3thienyl)malonic acid, converting this to the acid chloride with SOC1~, and condensing it with 6-aminopenicillanic (6APA) acid to give 3.

Hydrogenolysis

(Pd/C) completed the synthesis of ticarcillin (4).

CO2H (2) (V

Ampicillin

(3) R = CH 2 C 6 H 5 (£) R = H

(5) remains the penicillin of choice

for many infections because of its oral activity and good potency against Gram-negative bacteria.

A

number of prodrugs have been examined in attempts to

3-Lactam Antibiotics

438

improve upon its pharmacodynamic characteristics, and one of these is talampicillin (8). One synthesis involved protecting the primary amino group of ampicillin (5) as the enamine with ethyl acetoacetate (6). This was then esterified by reaction with 3foromophthalide (7), and the enamine was carefully hydrolyzed with dilute HC1 in acetonitrile to produce talampicillin (8)*

0

rr "

CH.

:O?H (S)

O2H Br

(6)

(7) NH? H H CO 2 H

(9) (8)

In an attempt to form orally active penicillins unrelated to ampicillin, use was made of the fact that certain spiro a*-amino acids, such as 9, are well absorbed orally and transported like normal amino acids. Reaction of cyclohexanone with ammonium carbonate and KCN under the conditions of the BuchererBergs reaction led to hydantoin 10. On acid hydrolysis, a-amino acid 11 resulted. Treatment with phosgene

3-Lactam Antibiotics

439

both protected the amino group and activated the carboxyl group toward amide formation (as 12) and reaction with 6-aminopenicillanic acid gave cyclacillin (13).

Interestingly, this artifice

(12)

NH 2 H H H

3 CO2H (13)

seems to have worked, since cyclacillin is more active in vivo than its in vitro spectrum suggests would be likely. 2.

CEPHALOSPORINS

The oral activity and clinical acceptance of cephalexin (14) has led to the appearance of a spate of similar 4 molecules. Cefadroxx/1 (16) is an example. The design of this drug would seem to have derived from the success of amoxTjcillin. The synthesis of cefadroxx/1 was accomplished by N-acylation of 7-aminodesacetylcephalosporanic acid (7 ADCA) after blocking the carboxy group with (CH 3 O) 2 CH 3 SiCl (to 15).

The

440

8-Lactam Antibiotics

blocking group was removed by solvolysis with butanol to give cefadroxyl (16).

CO2SiMe(OCH3)2

(I6.)

Noting that 1,4-cyclohexadiene rings are nearly as planar as benzene rings but of greatly different reactivity, a cephalosporin was synthesized with such a moiety.

Birch reduction of D-a-phenylglycine (17)

led to diene 18.

This was N-protected using t-

butoxycarbonyl azide and activated for amide formation via the mixed anhydride method using isobutylchloroformate to give 19.

Mixed anhydride 19 reacted

readily with 2-aminodesacetoxycephalosporanic acid to give, after deblocking, cephradine (20).

CO2C(CH3)3 CH3 (19)

CIO)

VJW/

"

CO2H

3-Lactam Antibiotics

441

A more traditional cephalosporin analogue is cephapirin (22). It was made by reacting 7-aminocephalosporanic acid with bromoacetyl chloride to give amide 21•

The halo group was displaced by 4-thiopyridine

to give 22, cephapirin. One of the few successful analogues in the plactam series with an aliphatic side chain is cephacetrile (23).

It was made by reacting 7-amino-

cephalosporanic acid with cyanoacetyl chloride in the presence of tributylamine.

H

NCCH 2 o

"

MC

:' S

j x ^

c l l 2 0 A C

\ Q

C0?ll

H

2N

S J

Y C0 7 H (25)

Modifications of the substituent at C~ are conveniently accomplished using sulfur nucleophiles to displace the acetoxy moiety which is present in the fermentation products. an agent.

Cefamandole (26) is such

Reaction of 7-aminocephalosporanic acid

with thiotetrazole 24 gave displacement product 25,

CO 2 H

442

g-Lactam Antibiotics

which was subsequently reacted with dichloroacetyl mandelate to put on the side chain. Deblocking 8 during workup produced cefamandole (26), Reaction of sodio 7-aminocephalosporanic acid with 1-(1H)-tetrazoylacetic acid gave intermediate 27*

Reaction of this last with 2-mercapto-5-methyl-

1,3,4-thiadiazole led to the widely used parenteral cephalosporin, cefazolin (28). H H H NCH

XT

NS^^^N

CO 2 H

(28)

3.

CH

3

CEPHAMYCINS

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Btreptomgces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamgcin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials•

Of the various ways

of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30.

The imino ether moiety solvolyzes more readily

than the p-lactam to produce 7-aminocephamycinic

3-Lactam Antibiotics

443

acid, which was acylated in the usual way to produce cefoxitin (31) with broad spectrum activity and excellent resistance to bacterial degradation. OCH OCH,

CO2Ii (2_9at) X = N H 2 (2_9b) X = N 2+

(30)

ocn3

H :

CO ? H

REFERENCES

3.

Anon., Belgian Patent 646,991 (1964); Chem. Abstr. , 63: 13,269£ (1965). I. Isaka, K. Nakano, T. Kashiwagi, A. Koda, H. Horiguchi, H. Matsui, K. Takahashi and M. Murakami, Chem. and Pharm. Bull., 24, 102 (1976); J. P. Clayton, M. Cole, S. W. Elson, H. Ferres, J. C. Hanson, L* W. Mizen and R. Sutherland, J. Med. Chem., 19, 1385 (1976). H. E. Alburn, D. E. Clark, H. Fletcher and N. H. Grant, Antimicrob. Agts. Chemother. , 586 (1967). T. Ishimaru and Y. Kodama, German Patent

444

5,

6* 7. 8. 9. 10.

6-Lactam Antibiotics 2,163,514 (1973); Chem. Abstr., 79: 78,8262 (1973). J. E. Dolfini, H. E. Applegate, G. Bach, H. Basch, J. Bernstein, J. Schwartz and F. L. Wiesenborn, J. Med. Chem., 14, 117 (1971). L. B. Crast, Jr., R. G, Graham and L. C. Cheney, J. Med. Chem., 16, 1413 (1973). Anon., Netherlands Patent 6,600,586 (1966); Chem. Abstr., 65: 20,131h (1966). J. R. Guarini, U. S. Patent, 3,903,278 (1976). K. Kariyone, H. Harada, M. Kurita and T. Takano, J. Antibiotics, 23, 131 (1970). L. D. Cama, W. J. Leanza, T. R. Beattie and B. G. Christensen, J. Am. Chem. Soc., 94, 1408 (1972); S. Karady, S. H. Pines, L. M. Weinstock, F. E. Roberts, G. S. Brenner, A. M. Hoinowski, T. Y. Cheng and M. Sletzinger, ibid., 94, 1410 (1972).

16

Miscellaneous Fused Heterocycles As may be apparent now, compounds in a given structural class are often associated with good biological activity.

This means that on the operational level,

a good many examples of those structures will be available that have been assigned generic names.

In

terms of this book, those compounds will merit a chapter or even a section. Thus, for example, although p-lactams represent a relatively narrow structural descriptor, activity in this class is sufficiently promising so that a full chapter is needed to fully cover those compounds.

There does, however, exist a

sizeable group of compounds that are not so readily categorized, since relatively few examples of each type have been assigned generic names.

The medicinal

agents discussed below are miscellaneous in that there is no readily apparent unifying thread in terms

445

446

Miscellaneous Fused Heterocycles

of either structure or biological activity by which to group them, other than in a miscellaneous way. 1.

Compounds with Two Fused Rings

Discovery in medicinal chemistry is intimately dependent on available animal test systems.

Except for

certain infectious diseases, it is rare to find a preexisting animal model for the human disease for which drugs are being sought.

For example, animals

do not develop atherosclerosis spontaneously.

As a

result, pharmacologists exercise great ingenuity in devising animal test systems intended to be relevant to diseases.

Such assays, particularly in the area

of agents acting on the CNS, are often quite indirect in that the connection to the human disease may be somewhat circuitous. Those tests are usually validated as far as possible with test results from drugs known to be active in the human.

There thus exists the

distinct possibility that an animal test will preordain the discovery of compounds that act by a closely similar mechanism, and thus have the same side effects, as those already on the market. This is perhaps best illustrated in the field of the centrally acting analgesics.

The animal tests in this area

have proven very reliable in detecting compounds that show analgesic activity in man; at the same time, all drugs discovered by these assays have at least some of the side effects of the prototype, morphine, to a greater or lesser degree.

For this reason, thera-

peutic breakthroughs are relatively rare and celebrated events.

Miscellaneous Fused Heterocycles

447

The discovery of an analgesic that acts by a presumably nonopiate pathway, in fact, resulted from a clinical trial of the compound in question, nefopam (4), in man.

It might be noted that this trial was

designed to study the drug as a muscle relaxant.

It

should also be noted that nefopam fails to show activity in many of the tests used to detect compounds with central analgesic activity. At the present time, there does not seem to exist any solution to that conundrum, short of the clearly unacceptable alternative of using man as the test animal.

The huge

expense and the bureaucratic requirements needed before embarking on a clinical trial in the late 1970 ! s serve to make this kind of discovery less common and inclines the field more and more to modest advances in modulating potency or side effects.

Does

the old saw, "drugs are discovered in the clinic," still have relevance?

Time will tell.

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride; treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). Although most nonsteroidal antiinflammatory agents depend on the presence of an acidic proton for activity, examples of nonacidic drugs are scattered among the various structural classes. A furanopyrrole,

Miscellaneous Fused Heterocycles

448

:H2NH (1)

CH,

octazamide (11), represents yet another structure that has been found to act as a peripheral analgesic/ antiinflammatory agent.

Hydrolysis of substituted

furan 5 gives the corresponding diol (6), which is then reduced catalytically to afford the tetrahydrofuran 7*

Both the method of reduction and the subse-

quent cyclization suggest that the product has the cis configuration. Reaction of 7 with tosyl chloride leads to ditosylate 8; use of that intermediate to bisalkylate benzylamine affords the bicyclic heterocyclic system (9).

Debenzylation (10) followed by

acylation of the resulting secondary amine with benzoyl chloride affords finally octazamide (11).

Miscellaneous Fused Heterocycles

ROCH

449

ROCH

ROCH, (5) R = CH3O (6) R = H

ROCH. (9)

(I) R = P-CH3C6H4SO2

H

G3

One of the first pharmacological classes to be studied by medicinal chemists was local anesthetics. Many of the guiding principles which are used to this day, for example, molecular dissection, side chain substitution and inversion, and the like, were first developed in the course of those early researches. The most tangible fruit of that work was the development of a host of local anesthetic drugs; since there is a limited demand for such agents, the field lay quiescent for a good many years.

The adventitious

discovery that the local anesthetic agent lidocaine (12) showed antiarrhythmic activity in man has lent impetus to renewed interest in local anesthetics for new application.

In particular, compounds are being

sought which escape the main shortcoming of lidocaine; that drug is active for clinical purposes by intravenous administration only.

450

Miscellaneous Fused Heterocycles

Preparation of one of these newer local anesthetic/antiarrhythmic agents, rodocaine (19), starts with the synthesis of an octahydropyrindene.

Conjugate

addition of the enolate from cyclopentanone to acrylonitrile gives the cyanoketone 13.

The carbonyl group

is then protected as its ethylene ketal (14), and the nitrile is reduced to the corresponding primary amine (15).

Deketalization in dilute acid affords a

transient aminoketone, which spontaneously cyclizes to the imine 16.

Dissolving metal reduction (sodium 3 in ethanol) affords the trans-fused bicyclo 17. (Catalytic reduction of 16 affords the cis isomer.

Lp

C H

2 5\

CH

3

QLCIL

CH2CH2CN

qo CII2CU2CH2NH2 C17)

0

(16)

(is)

V-^v

CNH"-y

y

It is unexpected that the presumably thermodynamically controlled metal in alcohol reduction gives the

Miscellaneous Fused Heterocycles

451

trans compounds; the cis isomer is usually the more stable in the analogous all-carbon hydrindane system.) The amide portion of the molecule (18) is assembled by acylation of 2,6-dimethylaniline with 3-chloropropionyl chloride*

Alkylation of 17 with chloroamide

18 affords rodocaine (19). 2.

Compounds with Three or More Fused Rings

Preparation of rigid analogues of medicinal agents sometimes leads to compounds with greatly increased activity.

Briefly, the success of a rigid analogue

depends on locking a previously freely rotating side chain or flexible molecule into a conformation that will give a better fit with some putative receptor. Application of this principle to the tricyclic antidepressants does indeed afford a compound, mianserin (26), which retains the activity of the parent molecule.

Preparation of 26 begins with acylation of

the benzylaniline 20 (available from the benzophenone) with chloroacetyl chloride to give amide 21 •

Treatment

with a mixture of phosphorus oxychloride and polyphosphoric acid leads to cyclodehydration of the amide to the corresponding tricyclic intermediate 22.

Displace-

ment of the now allylic chloride by means of methylamine gives the amine 23; this is then reduced to the diamine 24 with sodium borohydride.

Construc-

tion of the last ring is accomplished by formation of the cyclic diamide (25) from 24 by ester interchange with diethyl oxalate.

Reduction of this a-diamide

with diborane proceeds with no apparent difficulty to

452

Miscellaneous Fused Heterocycles

the diamine, the antidepressant compound mianserin

(26).5

S

(20)

C H X 2= XN C l ((2232)).X = H C H

I

—

CH2C1 (21)

000 N''

\

s\ CH

CH 3

3

(24)

(25)

Application of the same type of reasoning to an anxiolytic benzodiazepine results in a rigid analogue, clazolam (35), which also retains the activity of the parent molecule, diazepam.

It should be noted that

in this case it is a benzene ring rather than a side chain that is conformationally restricted.

Conden-

sation of isatoic anhydride 27 with 2-phenethylamine (28) results in net acylation of the aliphatic amine. The anhydride is in essence both an activated carboxyl derivative and a means of protecting the aniline nitrogen against self-condensation reactions.

The

secondary amine in 29 is then converted to the tosylamide to protect it during subsequent steps.

Treatment

of the amide 30 with phosphorus pentoxide results in

Miscellaneous Fused Heterocycles

453

a Bischler-Napieralski cyclization to the dihydroisoquinoline 31.

The protecting group is then removed

by hydrolysis in strong acid (32), and the double bond is reduced catalytically.

Alkylation of the

diamine 33 with ethyl bromoacetate proceeds as expected at the more basic aliphatic amine to give the glycinate 34.

Base-catalyzed ring closure of the aminoester

serves to close the diazepine ring; there is thus obtained the anxiolytic agent cla.zola.rn (35).

NSO 2 C 6 H 4 CH 3 H 2 NCH 2 CH 2

a

(28) (27)

(31) (2£) R = H (30) R = £

•NHCH2CO2C2H5

(33) R = H

Miscellaneous Fused Heterocycles

454

When the pharmacophoric group in a rigid compound is fused in some position remote from that in the nonrigid compounds, it is likely that the agent is active by some different biological mechanism. Thus, although naranol (40) is formally related to the tricyclic compounds, the basic center is in a quite different position from that in the majority of tricyclic CNS agents. Synthesis of 40 is begun by Mannich reaction of 2-naphthol with formaldehyde and dimethylamine to afford the adduct 37. Reaction of this aminophenol with the substituted piperidone 38 affords the tetracyclic product 40 in a single step.

CIO) (41)

Miscellaneous Fused Heterocycles

455

This seemingly complex transformation can be rationalized by assuming, as the first step, formation of an enolate of ketone 38*

Displacement of dimethyl-

amine on 37 by the enolate will give the phenolketone 39*

Although both regioisomers of the enolate may in

fact be formed, the observed product is from reaction of the less hindered enol.

(An alternate sequence

involves loss of dimethylamine from 37 to give quinonemethide 41; conjugate addition of the same enolate will give 39. )

Simple internal hemiketal 7

formation gives the product 40, naranol,

of unspeci-

fied stereochemistry. Although most available CNS agents are quite effective, they are not without side effects.

There

is, thus, some impetus for a search for novel structures in the hope that these will be better than available drugs.

During this search a derivative of

a partly reduced indole, molindone (48), has been reported to have sedative and tranquil is; ing activity. Condensation of oximinoketone 42 (from nitrosation of 3-pentanone), with cyclohexane-l,3-dione in the presence of zinc and acetic acid leads directly to the indole derivative 47*

The transformation may be

rationalized by assuming as the first step, reduction of 42 to the corresponding a-aminoketone.

Conjugate

addition of the amine to 43 followed by elimination of hydroxide (as water) would give ene-aminoketone 44*

This may be assumed to be in tautomeric equili-

brium with intermediate 45* Aldol condensation of the side chain carbonyl group with the doubly activated ring methylene would then result in cyclization to

Miscellaneous Fused Heterocycles

456

pyrrole 46; simple tautomeric transformation would then give the observed product.

Mannich reaction of

47 with formaldehyde and morpholine gives the 8 tranquilizer molindone (48).

(13)

(£2)

(48)

(£7)

(46)

Tricyclic antihistamines as a rule carry aliphatic nitrogen as a substituent on a side chain attached to the central ring; the side chain nitrogen may be part of a heteroaromatic ring.

Conjugate addition of p-

chloroaniline (49) to the substituted vinylpyridine 50 gives the alkylated aniline 51.

Treatment of that

intermediate with nitrous acid leads to N-nitroso intermediate 52 which is then reduced to the hydrazine (53).

Reaction of 53 with N-methyl-4-piperidone

Miscellaneous Fused Heterocycles

457

under the conditions of the Fischer indole synthesis affords dor&stine (54),9 an antihistamine*

"XX • NH2

cH2=ci-r CH2CH2

C49)

(50) (51)

CA

CH2CH2

CII,

CH2CH.

(.52) X = 0 (54)

(53) X = H

Azanator (59) represents a more classical antihistaminic structure, since the more basic nitrogen in this case occurs in the side chain. Preparation

a ; , , -

o

(55)

q

p .(5;'

(59)

(58)

458

Miscellaneous Fused Heterocycles

of this compound starts with aromatic nucleophilic displacement on pyridine 55 (see Chapter 14) with phenoxide anion.

Friedel-Crafts ring closure of the

product (56) by means of polyphosphoric acid leads to the azaxanthone 57.

This is then converted to the

final product by condensation with the Grignard reagent from N-methyl-4-chloropiperidine (58), followed by dehydration to yield 59. As noted previously, a wide variety of aromatic systems serve as nuclei for arylacetic acid antiinflammatory agents.

It is thus to be expected that

fused heterocycles can also serve the same function. Synthesis of one such agent (64) begins with condensation of indole-3-ethanol (60) with ethyl 3-oxocaproate (61) in the presence of tosic acid, leading directly to the pyranoindole 63.

The reaction may be

rationalized by assuming formation of hemiketal 62, as the first step.

Cyclization of the carbonium ion

2 H (60)

CH 3 CH 2 CH 2 CCH 2 CO 2 C2H5 (61)

CH

CH 3 CH 2 CH 2

2CO2C2H5

(62)

CH 3 CH 2 CH^ "*CH2CO2H

^

J k HJA^ .0 CH 2 CO 2 C 2 H 5

Miscellaneous Fused Heterocycles

459

(from loss of hydroxyl) into the nucleophilic indole 2-position will give the observed product (63). Saponification of the ester gives the antiinflammatory agent prodolic acid (64). A closely related compound, pirandamine (72), bearing a basic rather than an acidic side chain and having a methylene in place of the indole nitrogen, OH ,011

CH 2 CH 2 OH

•CH2CO2C2H5 (66)

(67)

(65)

CH

2 \

r

OH CH,

'CH2CQ2c:2n5

(68)

(69)

/ CH 7

C H

3

CH 2 CH 2 N

CH 2 CR

CH. (70)

R = OH

(7JJ

R = N(CH3)2

(72)

460

Miscellaneous Fused Heterocycles

interestingly exhibits antidepressant activity. Basically, the same synthetic scheme is used for the preparation of this analogue as for compound 64 above.

Condensation of 1-indanone (65) with ethyl

bromoacetate and zinc affords Reformatski product 66; then, reduction with lithium aluminum hydride gives diol 67.

Dehydration with sulfuric acid gives the

indene ethanol 68.

Acid catalyzed condensation of 68

with ethyl acetoacetate then gives the fused tetrahydropyran derivative 69, no doubt by a scheme quite analogous to that above.

The ester is then saponified

to the corresponding acid (70), which is then converted to the dimethylamide (71)*

Reduction with

lithium aluminum hydride completes the synthesis of 12 the antidepressant agent pirandamine (72). Antidepressant activity is retained in tandamine (80), an analogue in which the indole ring is restored, the basic side chain is retained, and the oxygen heterocycle is replaced by the corresponding sulfurcontaining ring.

Acetylation of indole ethanol 60

affords the corresponding acetate 73; the indole nitrogen is then alkylated by means of ethyl iodide and sodium hydride (74).

Conversion of the side

chain oxygen to sulfur is accomplished by first treating the alcohol (from hydrolysis of the acetate (75) with phosphorus tribromide to give 76; displacement of halogen with thiosulfate anion then affords the covalent thiosulfate (77).

In a departure

from the synthetic scheme used above, the basic side chain is introduced directly.

Thus, reaction of

thiosulfate 77 with amidoketone 78 in the presence of

Miscellaneous Fused Heterocycles

:H2OCOCH3

461

H 2 CH 2 NHCHO CH 2 CH 2 NHCHO

(7_3) R = H

(79)

(7_5) R = OH

(74.) R = C 2 H 5

(7jj) R = Br (77) R » SSO 2 Na

»sc 2

::H 2 CII 2 NHCH 2

en

boron trifluoride leads directly to the fused heterocycle (79).

Reduction of the formamide by means of

lithium aluminum hydride then affords monomethyl derivative 80; N-methylation of that intermediate completes the synthesis of the antidepressant agent tandamine

(81).13'14

A rather complex fused isoindoline (87) has been found to show good anorectic activity.

This substance

differs from other anorectic agents by not being a |3-phenethylamine analogue.

Preparation of this

compound starts by reaction of a substituted benzoylbenzoic acid (82) with ethylene diamine.

The product

(84) can be rationalized as being the aminal from the initially obtained monoamide 83.

This is then sub-

jected to reduction with lithium aluminum hydride

Miscellaneous Fused Heterocycles

462

and—without isolation—air oxidation.

Reduction

probably proceeds to the mixed aminal/carbinolamine 85; such a product would be expected to be in equilibrium with the alternate aminal 86*

The latter would

be expected to predominate due to the greater stability of aldehyde aminals over the corresponding ketone derivatives.

Air oxidation of the tetrahydroimidazole

to the imidazoline will then remove 86 from the equilibrium.

There is thus obtained the anorectic

agent mazindol (87)*

(84.) (82)

(83)

Miscellaneous Fused Heterocycles

3.

463

Purines and Related Heterocycles

Considerable research has been devoted to preparation of modified purines in the expectation that such compounds could act as antagonists to, or possibly false substrates for, those involved in normal metabolic processes.

It is surprising to note the

relatively small number of such compounds that have found clinical use.

SCN

H

)

(89)

N0 2

(91)

H2l

(92)

464

Miscellaneous Fused Heterocycles

Thioguanine is one of the most familiar of the medicinal purine analogues.

This compound acts as a

false guanine and has found a role as an antineoplastic agent by reason of its resulting activity as a metabolic inhibitor.

The compound is obtained most

simply by displacement of halogen from 6-chloroguanine (88) with thiocyanate anion.

Hydrolysis of the

product (89) yields thioguanine (90). In much the same vein, displacement of chlorine from 88 with the sodium salt of imididazolethiol 91 affords the antineoplastic agent thiampirine (92). The same reaction starting with purine 93 gives the

18 immunosupressant agent azathioprine (94). Contraction and relaxation of smooth muscle is known to be mediated by way of the cyclic nucleotides. In brief, increase in intracellular levels of cyclic adenosine monophosphate (cAMP) leads to relaxation of smooth muscle.

In the normal course of events, cAMP

is hydrolyzed to its inactive form by the enzyme phosphodiesterase (PDE).

Drugs that inhibit the

action of that enzyme—PDE inhibitors—will tend to promote smooth muscle relaxation. One such drug, theophylline (95) has found extensive use in treatment of asthma based on its ability to relax bronchial smooth muscle.

A search for more lipophilic analogues

of theophylline led to a compound, the hexyl analogue 96 of theobromine, which seemed to have greater selectivity for vascular smooth muscle.

Further

biological investigation revealed that the active agent was in fact the metabolite 101 resulting from w~l-oxidation of the aliphatic side chain.

Miscellaneous Fused Heterocycles

465

Preparation of the requisite side chain starts by alkylation of ethyl acetoacetate with 1,3-dibromopentane; the initially formed bromoketone (shown as the enol 97) undergoes O-alkylation under the reaction conditions to give the dihydropyran 98*

Reaction of

that masked hydroxy ketone derivative with hydrogen

CH.

CH 3 (CH 2 ) 5 N

CH3 (95)

CO9C9 3-V^

CII3CCH2CO2C2II5 + BrCII2CH2CH2Br

•oc

CH

OH CH2 CIl^Br

(98)

(97)

i

(101)

UN

CH3CCII2CH2CH2CH2Br CT^N -

CH,

(100)

bromide affords the requisite bromoketone (99); reaction conditions are apparently sufficient to

Miscellaneous Fused Heterocycles

466

insure decarbethoxylation of the ketoester intermediate. Alkylation of theobromine (100) with 99 affords the 18 vasodilator, pentoxift/lline (101).

,CH,N

(i£3)

(104)

NH 2

occl (105) NH9 NHCHO

NH

NH CH 2 CHCHCO 2 H

I

CH 2 CHCH 2 CO 2 H

OH OH

OH (OH

(109) (108) (107) R = H

Pharmacognosy, the study of plant products with medicinal properties, has contributed many structural leads to drug development.

Although findings have in

recent years been less frequent this discipline

Miscellaneous Fused Heterocycles

467

continues to uncover unusual structure-activity combinations.

In one example, methanol extracts of

the Japanese mushroom Lentinus edodes Sing, were found to have hypolipidemic activity.

The active

compound eritadenine (109) proved to be a purine alkylated with an oxidized sugar fragment; its synthesis can be accomplished as follows.

Ring opening

of the protected lactone (102), derived from erythrose, with sodium phthalimide gives the acid 103; hydrazinolysis then leads to the amino acid 104* Displacement of chlorine in pyrimidine 105 by the amine function on 104 serves to attach the future imidazole nitrogen and the sugar-derived side chain 106.

The

nitro group is then reduced by catalytic hydrogenation (107), the resulting primary amine is the most basic, and is selectively formylated with formic acid. These strongly acidic conditions serve to remove the acetonide protecting group as well (108).

Treatment with

sodium hydroxide then serves to close the imidazole 19 ring, forming eritadenine (109). The several compounds below (115, 120, 121) are related to purines only in that they contain some three nitrogen atoms formally distributed among an indene nucleus.

Despite the varied structures, all

three analogues share activity mediated through the CNS.

In one of the classical methods for construction

of a pyrimidine ring, synthesis of 115 begins with condensation of the substituted cyanoacetate 110 with acetamidine to give the corresponding pyrimidone (111), shown as the enol.

Treatment with acid probably

results initially in hydrolysis of the acetal function

468

Miscellaneous Fused Heterocycles

to give the transient aminoaldehyde 112.

This then

cyclizes to the corresponding imine under the reaction conditions, and this interemdiate tautomerizes to the observed pyrrolopyrimidine 113.

Reaction with phos-

phorus oxychloride serves to replace the hydroxyl group by chlorine (114). Displacement of halogen with 20 benzylamine gives the muscle relaxant rolodine (115).

OH

...L^ C H 2 C H ( O C 2 H 5>2

C2HSO2CN CHCH 2 CH(OC 2 H 5 ) 2

(110) CH 3 C NH

2

CH AA r ; fllS)

Condensation of aminopyrazole 116 with ethoxymethylene malonic ester gives the product of additionelimination (117), which is then cyclized to the piperidone by heating in diphenyl ether.

The product

tautomerizes spontaneously to the hydroxypyridine 118.

The hydroxyl group is then converted to the

chloro derivative by means of phosphorus oxychloride (119).

Displacement of halogen by n-butylamine gives

Miscellaneous Fused Heterocycles

469

the antidepressant compound cartazolate

(120). 21

Replacement of halogen by the basic nitrogen of acetone hydrazone affords the antidepressant etazolate (121).2X

<<2»S

V2"S

(:2IISO.2(:N C

2n5°2c:>

(: H

2 5°2C

(110)

C:O2C:2H5

C2H5O2C OH ("118)

C2H5O2C

NHCH 2 CH 2 CH 2 CH 5 (121)

4.

Polyaza Fused Heterocycles

As noted earlier (see Chapter 12), considerable latitude exists in the nalidixic acid type antibacterial agents as to the exact nature of the two heterocyclic rings.

The minimum requirement for

activity seems to reside in a fused enaminoketone carboxylate function.

(Even so, an additional nitrogen

atom may be interposed in that function, viz. cinoxacin.)

Consistent with this, it is interesting

that inclusion of an additional nitrogen atom in the pyridino ring also gives a molecule (127) that shows

470

Miscellaneous Fused Heterocycles

antibacterial activity.

Synthesis of this agent

begins with successive displacement reactions on 2,6-dichloropyrimidine (122) with pyrrolidine and then ammonia, leading to the diaminopyrimidine 123* The rest of the synthesis follows the usual pattern. Condensation of 123 with ethoxymethylenemalonate gives the substituted malonate 124.

Thermal cycli2a-

tion serves to form the fused pyridone ring (125); saponification of the ester with base then gives the corresponding acid (126). Alkylation of the pyridone nitrogen with diethyl sulfate completes the synthesis 22 of piromidic acid (127).

CJCX,

(122) (123)

co 2 c 2 n 5 AM

(124)

C2H5 (125) R = C 2 H 5 (126) R = H (127)

Replacement of methine by nitrogen, i.e., replacement of a phenyl moiety by pyridine, is consistent with biological activity in quite a few structural-

Miscellaneous Fused Heterocycles

471

biological classes (see Chapter 9 ) . This retention of activity in the face of an interchange of aromatic rings is well illustrated in the case of the acyclic and tricyclic antihistamines.

It is of note that the

same interchange in at least one tricyclic antidepressant drug (dibenzepin, see Chapter 14), affords

r\?R}

(129)

CH*CHCH7 CH3

CH3

(111) (133) an analogue that retains the CNS profile of the parent compound*

Another centrally acting tricyclic agent

bearing a pyridino moiety (132) is prepared as follows.

Condensation of pheny1enediamine (128) with

2-chloronicotinic acid (129) leads directly to the tricyclic lactam 130.

Although the reaction obviously

includes amide formation and nucleophilic aromatic displacement of chlorine, the order of these steps is

4 72

Miscellaneous Fused Heterocycles

not known. Alkylation of the anion obtained from treatment of 130 with the chloroethylamine 131 affords 23 the antidepressant compound propizepine

(132)*

The

last step in this sequence is less straightforward than it might seem.

There is considerable evidence

that such alkylations often proceed by way of the aziridinium ion (133).

It will be appreciated that

attack of the anion at the secondary or tertiary carbon of the aziridinium ring will lead to different 24 products. Extensive investigation of this problem has established that the product from attack at secondary carbon usually predominates. This is, of course, the same compound that would be formed by direct displacement of halogen without involvement of the aziridnium intermediate 133. Two rather broad structural classes account for the large majority of drugs that have proven useful in the clinic for treating depression.

Each of these

has associated with it some clearly recognized side effects: the monoamine oxidase inhibitors, most commonly derivatives of hydrazine, tend to have undesirable effects on blood pressure; the tricyclic compounds on the other hand may cause undesirable changes in the heart.

Considerable effort has thus

been expended toward the development of antidepressants that fall outside those structural classes.

An

unstated assumption in this work is the belief that very different structures will be associated with a novel mechanism of action and a different set of ancillary activities.

One such compound, trazodone

473

Miscellaneous Fused Heterocycles

shown clinically useful antidepressant activity without the typical side effects of the classical drugs. In a convergent synthesis, reaction of 2-chloropyridine with semicarbazide in the presence of a catalytic amount of acid affords the fused triazole 135.

The reaction may be

rationalized by assuming addition of semicarbazide to the protonated atom of chloropyridine to give intermediate 134.

(Although semicarbazide is a stronger

base, protonation of that compound does not lead to any reaction.)

Elimination of hydrogen chloride Cl

cr"

HoNNH \

C=0

H2N

(135) (134)

r~\

HN

v-Q

C:ICH 7 CH 7 CH 7 N 2 2

N—(/

Cl (136)

y>

Cl (137)

NCH2CH2CH2N

N Cl

(138)

474

Miscellaneous Fused Heterocycles

restores aromaticity, and leads to attack by the pyridine nitrogen on the semicarbazide carbonyl. This or the reverse order will give the observed product (135).

Alkylation of piperazine 136 with 1-

bromo-3-chloropropane gives the piperazine derivative 137; use of that intermediate to alkylate heterocycle 135 affords the antidepressant agent trazodone (138)*

25

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 1 2 ) , which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype.

In the synthesis of 146, reaction of

the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141).

Cyclization of the ortho

nitrourea function by means of sodium hydroxide leads to the N-oxide (142); this last reaction represents

(139)

(5 (140) R = Cl (141) R = NH 2

(HA) X = OH (ill) X = Cl

(144)

Miscellaneous Fused Heterocycles

475

one of a series of transformations in which nitro and nitroso groups reveal electrophilic character akin to carbonyl groups.

Reaction of 142 with phosphorous

oxychloride serves to convert the hydroxyl group to chloride (143), which is then displaced with dimethyl27 amine to give the key intermediate 144. Catalytic reduction then converts the azoxide function to the corresponding cyclic hydrazine derivative (145). Finally, condensation with diethyl n-propylmalonate 28 affords the antiinflammatory agent, apazone (146). 5.

Ergolines

Ergotism, popularly known at the time as "St. Anthony's Fire," was one of the dread epidemic diseases of the Middle Ages. Its victims suffered gangrenous degeneration, madness, and death. Scientific investigation eventually revealed that this disease was due to ingestion of foods prepared from rye which was infected with a fungus, Claviceps purpurea.

These infected

foods were more likely to be ingested in times of famine, so prevention of ergotism in modern times is a simple matter.

Chemical investigation of Claviceps

purpurea revealed mycotoxins that were amides of lysergic acid (147), involving a series of unusual internally cyclized tripeptides. Some of these natural products—and drugs made from them—are known collectively as the ergot alkaloids, and have found use in medicine.

Ergonovine,

for example, is a selective stimulant for contraction of uterine muscle and is used in conjunction with labor and delivery.

A mixture of hydrogenated ergot

alkaloids—reduced at the 9,10-position—has

found

476

Miscellaneous Fused Heterocycles

use as a cerebral vasodilator by reason of its aadrenergic blocking activity. Lysergic acid itself has been used as starting material for a small series of drugs.

This natural

product was until quite recently difficultly accessible because Claviceps molds could only be cultivated on growing grains and grasses.

Once harvested, the

mixture of ergot alkaloids needed to be subjected to alkaline hydrolysis to yield the free acid.

The

search for a more efficient method of production led to the finding of a related mold, Claviceps paspali, which can be grown in submerged culture in fermentation tanks; this method of culture is additionally advantageous, as it affords the acid directly, 28 thus bypassing the hydrolysis step. The discovery of the potent hallucinogen LSD-25 (148), (or in street parlance, "acid"), represents one of the classics in serendipity.

In the course of

an analogue program on lysergic acid derivatives in the Sandoz laboratories in Switzerland, Hoffman had occasion to prepare the simple diethylamide derivative. On his way home from work that day, he saw the city of Basle in an entirely new light.

The fantastic

potency of the compound had led him to ingest sufficient drug as dust to experience the hallucinogenic effect.

Recognizing the probable cause of his "trip,"

he verified the effect by deliberately taking a second dose.

This is one of those interesting cases

where animal pharmacology and toxicology came after the human trial.

Miscellaneous Fused Heterocycles

477

A number of hallucinogens, including LSD-25, enjoyed considerable vogue in the counterculture of the late nineteen sixties.

Since there exists no

legitimate source for the drug (it has no recognized clinical use), underground laboratories no doubt broadened their repertoire from acetylation of morphine (to produce heroin) to include amide formation from lysergic acid. (The reaction goes particularly well in dimethylformamide; for some years a major manufacturer of this solvent showed this reaction in its advertisements to illustrate the versatility of their products!)

Lysergic acid has been prepared by total 29 synthesis by a group at Lilly ; rumor has it that

some of the illicit LSD was racemic, and thus a product of underground total synthesis. If so, this reflects a considerable and unexpected degree of expertise! Migraine is a particularly virulent form of headache of which that suffered by the majority of mankind is but a pale reflection; the common remedies, such as aspirin, are all but useless against these attacks.

Although the exact etiology of migraine is

not known, an attack does involve at one stage dilation of the cerebral vasculature.

The skull is a

bony case that cannot accommodate volume expansion of any magnitude.

Methxjsergide (152), a lysergic acid

derivative, which acts as a cerebral vasoconstrictor, has proven of use in treatment of migraine.

Alkyl-

ation of methyl lysergate (149) with methyl iodide, by means of the anion formed with potassium amide, gives the N-methylated product (150).

This is then

Miscellaneous Fused Heterocycles

478

saponified (to 151) and converted to the amide with 2-amino-l-butanol. me thgsergi de (152).

There is thus obtained 30

H C2 ?H S

CO 2 H

CON

CH,

(147)

CO 2 CH 3

(148) CH 2 OH

CO7R

CONHCHCH 2 CH 3

(149) (152)

Cl51} R= H

A different substitution pattern leads to 157, a molecule that exhibits peripheral a-adrenergic blocking activity. activity.

This is manifested as vasodilating

Photochemical addition of methanol to the

9,10-double bond of acid 15J affords the methyl ether 31 with the trans ring fusion (153). Reduction of the corresponding ethyl ester (154) with lithium aluminum hydride then gives the carbinol 155.

Esterification

of that alcohol with substituted nicotinic acid 156, 32 gives the vasodilator nicergoline (157).

Miscellaneous Fused Heterocycles

479

(151)

(153) R = H (157)

(154) R = C 2 H 5

Yet different elaboration of the same molecule affords a compound (162) that acts as an inhibitor to the pituitary peptide hormone prolactin, the factor responsible for supporting lactation. As such the drug has found use in suppressing lactation and in the treatment of prolactin-dependent breast tumors. In the synthesis of 162, catalytic hydrogenation of lysergic acid proceeds from the less hindered side of the molecule to afford the derivative with the trans 30 ring junction (158). As above, reduction of the methyl ester (159) gives the corresponding carbinol. This is then converted to the methane sulfonate (160), and that function is displaced with cyanide ion to afford the acetonitrile derivative 161. CH 2 OSOC:II 3

("I G O )

(161)

X = II

( 1 b2) X - C1

480

Miscellaneous Fused Heterocycles

Chlorination with N-chlorosuccinimide at the activated indole 2-position gives the corresponding chloro derivative, the prolactin inhibitor legotrile (162).

REFERENCES 1.

Anon., Netherlands Application 6,606,390 (1967); Chem. Abstr. , 66: 55535 (1967). 2. A. D. Miller, U. S. Patent 3,975,532 (1976); Chem. Abstr. , 85: 177393m (1976). 3. T. Henshall and E. W. Parnell, J. Chem. Soc., 661 (1962). 4. H. Hermans, K. F. Hubert, G. A. Knaeps and J. J. M. Willems, U. S. Patent 3,679,686 (1972); Chem. Abstr., 78: 43295 (1972). 5. W. J. Van Der Burg, I. L. Bouta, J. De Lobelle, C. Ramon and B. V. Vargaftig, J. Med. Chem. , 13, 35 (1970). 6. H. Otto, British Patent 1,113,754 (1969); Chem. Abstr., 70: 78031 (1969). 7. M. Von Strandtmann, M. P. Cohen and J. Shavel, U. S. Patent 3,549,641 (1970); Chem. Abstr., 75: 91297 (1971). 8. Anon., Belgian Patent 670,798 (1966); Chem. Abstr., 65: 7148 (1966). 9. L. Berger and A. J. Coraz, U. S. Patent 3,409,628 (1968); Chem. Abstr., 71: 38939 (1969), 10. F. J. Villani, T. A. Mann, A. E. Wefer, J. Harmon, L. L. Carca, M. J. Landon, W. Spivak, D.

Miscellaneous Fused Heterocycles

11. 12. 13. 14. 15.

16.

17. 18. 19. 20. 21. 22. 23.

481

Vashi# S. Tuzzi, G. Danks, M. del Prado and R. Lutz, J. Med. Chem. , 18, 1 (1975). C. A. Demerson, L. G. Humber, T. A. Dobson and R. R. Martel, J. Med. Chem., 18, 189 (1975). I. Jirkovsky, L. G. Humber and R. Noureldin, Eur. J. Med. Chem., 11, 571 (1976). I. Jirkovsky, L. G. Humber and R. Noureldin, J. Eeterocyclic Chem., 12, 937 (1975). I. Jirkovsky, L. G. Humber, K. Voitw and M. P. Charest, Arzneimittelforsch., 27, 1642 (1977). P. Aeberli, P. Eden, J. H. Gogerty, W. J. Houlihan and P. Penberthy, J. Med. Chem., 18, 111 (1975). G. H. Hitchings, G. B. Elison and L. E. Mackay, U. S. Patent 3,019,224 (1962); Chem. Abstr. , 58: 3443a (1963). G. H. Hitchings and G. B. Elison, U. S. Patent 3,056,785 (1962); Chem. Abstr., 58: 5701 (1963). W. Mohler and A. Soder, Arzneimittelforsch. , 21, 1159 (1971). T. Kamiya, Y. Saito, M. Hashimoto and H. Seki, Tetrahedron Lett., 4729 (1969). R. A. West and L. Beauchamp, J. Org. Chem., 26, 3809 (1961). H. Hoehn and T. Deuzel, German Patent 2,123,318 (1971); Chem. Abstr., 76: 59619 (1971). S. Minami, T. Shono and J. Matsumoto, Chem. Pharm. Bull., 19, 1426 (1971). C. Hoffmann and A. Faure, Bull. Soc. Chim. Fr. , 2316 (1966).

482 24.

25. 26. 27. 28.

29.

30. 31. 32.

33.

Miscellaneous Fused Heterocycles See for example, D. Lednicer and L. A. Mitscher, Organic Chemistry of Drug Synthesis, Vol. 1, p. 79, 374 (1975). G. Palazzo and B. Silverstrini, U. S. Patent 3,381,009 (1968); Chem. Abstr., 69: 52144 (1968). F. J. Wolf, R. M. Wilson, K. Pfister and M. Tischler, J. Amer. Chem. Soc, 76, 4611 (1954). G. Mixich, Helv. Chim. Acta, 51, 532 (1968). A. Stoll and A. Hoffmann, "Chemistry of the Alkaloids," S. W. Pelletier, ed., Von Nostrand, Reinhold and Company, New York, New York, 1970, pp. 267-300. E. D. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann, R. G. Jones and R. B. Woodward, J. Amer. Chem. Soc, 76, 5226 (1954); E. C. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann, D. E. Morrison, R. G. Jones and R. B. Woodward, J. Amer. Chem. Soc, 78, 3087 (1956). Anon., British Patent 811,964 (1959); Chem. Abstr., 53: 18969 (1959). W. Barbieri, L. Bernardi, G. Bosiosi and A. Temperilli, Tetrahedron, 25, 2401 (1969). G. Acari, L. Bernard!, G. Bosiosio, S. Coda, G. B. Freguan and A. H. Glaser, Experientia, 28, 819 (1972). J. A. Kornfeld and N. J. Bach, German Patent 2,335,750 (1974); Chem, Abstr., 80: 146400 (1974).

Indexes

Cross Index of Drugs Adrenal Suppressant Trilostane Adrenergic Agents Adrenalone Amidephrine Clorprenaline Deterenol Domazoline

Esproquin Etafedrine Metizoline Soterenol

a-Adrenergic Blocking Agents Fenspiride p-Adrenergic Blocking Agents Acebutolol Atenolol Bufuralol Bunitridine Bunitrolol Bunolol Metalol

Metoprolol Moprolol Nadolol Oxprenolol Phenbutalol Pindolol Practolol 485

486

Cross Index of Drugs

p-Adrenergic Blocking Agents (cont.) Sotalol Tazolol Timolol

Tiprenolol Tolamolol

Aldosterone Antagonists Canrenoate Canrenone, Potassium

Mexrenoate, Potassium Prorenoate, Potassium

Anabolic Steroids Bolandiol Diacetate Bolasterone Boldenone Bolmantalate Mibolerone

Norbolethone Quinbolone Stenbolone Acetate Tibolone

Analgesics Anidoxime Anileridine Anilopam Benzydamine Buprenorphine Butacetin Butorphanol Carbiphene Clonixeril Clonixin Dimefadane Dipyrone Etorphine Ketazocine Letimide Methopholine Mimbane

Molinazone Nalbuphine Nalmexone Naltrexone Nefopam Nexeridine Noracymethadol Octazamide Oxilorphan Proxazole Pyrroliphene Salsalate Tetrydamine Tramadol Volazocine Xylazine

Anesthetics Etoxadrol Propanidid

Tiletamine

Cross Index of Drugs

487

Anorexic Agents Aminorex Amphecloral Clominorex Fenisorex

Fludorex Fluminorex Mazindol Mefenorex

Anterior Pituitary Activator Epimestrol Anterior Pituitary Suppressant Danazol Antiadrenal Trilostane Antiadrenergics Solypertine

Zolterine

Antiamebics Bialamicol Clamoxyquin

Symetine Teclozan

Anti androgens Benorterone Cyproterone Acetate

Delmadinone Acetate

Antianginals Flunarizine

Nifedipine

Antiarrhythmic Agents Amoproxan Aprindine Bucainide Bunaftine Capobenic Acid Disopyramide

Pirolazamide Pranolium Chloride Pyrinoline Quindonium Bromide Rodocaine

Cross Index of Drugs

488 Antibacterials Acedapsone Acediasulfone Acetosulfone Sodium Biphenamine Carbadox Cinoxacin Diaveridine Mafenide Mequidox Nifuratrone Nifurdazil Nifurimide Nifuroxime Nifurpirinol

Nifurquinazol Nifurthiazole Ni tro furatrone Ormetoprim Oxolinic Acid Phenyl Aminosalicylate Piromidic Acid Racephenicol Sulfabenzamide Sulfacytine Sulfanitran Sulfasalazine Sulfazamet Thiamphenicol

Antibiotics Amicycline Cefadroxil Cefamandole Cefazolin Cefoxitin Cephacetrile Cephapirin Cephradine Cetophenicol Clavulanic Acid Cyclacillin

Democycline Meclocycline Methacycline Nitrocycline Nocarcidins Sancycline Talampicillin Thienamycin Thiphencillin Ticarcillin

Anticholinergic Agents Alverine Benapryzine Benzetimide BenziIonium Bromide Butropium Dexetimide Domazoline Elantrine Elucaine Glycopyrrolate Heteronium Bromide

Oxybutynin Oxyphencyc1imine Parapenzolate Bromide Pentapiperium Methylsulfate Phencarbamide Poldine Methylsulfate Proglumide Propenzolate Thiphenamil Tofenacin Triampyzine

Cross Index of Drugs

489

Anticoagulant Bromindione Anticonvulsants Albutoin Atolide Citenamide Cyheptamide

Eterobarb Sulthiame Tiletamine

Anti dep re s s ants Aletamine Amedalin Amoxapine Bupropion Butacetin Cartazolate Clodazon Cotinine Cypenamine Cyprolidol Cyproximide Daledalin Dazadrol Dibenzepin Dioxadrol Encyprate Fantridone Fenmetozole Gamfexine Guanoxyfen

Intriptyline Isocarboxazid Ketipramine Maprotiline Melitracin Mianserin Modaline Octriptyline Oxypertine Pirandamine Pizotyline Propizepine Quipazine Rolicyprine Sulpiride Tandamine Thiazesim Thozalinone Trazodone Viloxazine

Hepzidine Antiemetics Metopimazine Antiestrogens Clometherone Delmadinone Acetate

Trimethobenzamide

Tamoxifen

490

Cross Index of Drugs Antifungals

Biphenamine Ciclopirox Econazole Ethonam

Miconazole Tolindate Tolnaftate

Antihelmintics Albendazole Bromoxanide Bunamidine Cambedazole Clioxanide Cyclobendazole Flubendazole Lobendazole

Mebendazole Niclosamide Nitramisole Nitrodan Oxante1 Oxfendazole Oxibendazole Thenium Closylate

Antihistaminics Azanator Azatadine Clemastine Closiramine

Dorastine Mianserin Rotoxamine Terfenadine

Antihypertensives Aceperone Alipamide Amquinsin Bupicomide Chlorothiazide Clopamide Diapamide Guanabenz Guanisoquin Guanochlor Guanoxabenz Guanoxyfen

Hydracarbazine Indoramine Leniquinsin Methyldopa Metolazone Mexrenone Pazoxide Prazocin Quinazocin Trimoxamine Trimazocin

Antiinflammatory Steroids Amcinafal Amcinafide Cormethasone Acetate Cortivazol

Desonide Di fluprednate Drocinonide Endrysone

Cross Index of Drugs

491

Antiinflammatory Steroids (cont.) Flunisolide Halcinonide Nivazol

Tralonide Triclonide

Antimalarials Amquinate

Menoctone

Antimigrane Methysergide Antineoplastics Azathioprine Azatepa BCNU Benzodepa Calusterone CCNU Dacarbazine Lomustine MeCCNU Melphalan

Oxisuran Pipobroman Piposulfan Procarbazine Semustine Tamoxifen Testolactone Thiampirine Thioguanine

Antiparkinsonism Agents Carbidopa Carmantadine

Dopamantine Lometraline

Antiperistaltics Alkofanone Difenoximide Difenoxin

Fetoxylate Fluperamide Loperamide

Antiprotozoals Carnidazole Flubendazole Flunidazole Ipronidazole Moxnidazole Nifursemizone

Nimorazole Nithiazole Oxamniquine Ronidazole Sulnidazole

Cross Index of Drugs

492 Antipyretics Benzydamine Dipyrone

Indoxole

Antipsychotics Carpipramine

Clocapramine

Antischistosomals Becanthone Niridazole

Oxamniquine Teroxalene

Antispasmodic Agents Butamirate

Carmantadine

Antitrichomonals Nimorazole Antitussives Amicibone Benproperine

Clobutinol Codoxime Pemerid

Butamirate Antivirals Amantadine Famotine

Methisazone Rimantadine Tilorone

Memotine Avian Chemosterilant Azacosterol Bronchodi1ators Albuterol* Carbuterol* Clorprenaline* Doxaprost Eprozinol Fenoterol*

Fenspiride Hoquizil Isoetharine* Piquizil Pirbuterol* Prostalene

Cross Index of Drugs

493

Bronchodilators (cont.) Quazodine Quinterenol* Rimiterol* Soterenol* *adrenergic

Sulfonterol* Suloxifen Trimethoquinol*

CNS Stimulants Amphetaminil Ampyzine Azabon Di fluanine

Flubanilate Indriline Mefexamide Pyrovalerone

Ethamivan

Trazodone

Canine Contraceptive Mibolerone Cardiotonics Benfurodi1

Dobutamine

Catecholamine Potentiator Talopram Cathartics Bisoxatin Acetate

Oxyphenisatin Acetate

Choleretic Piprozolin Cholinergic Agent Aceclidine Coccidiostats Alkomide Cyproquinate Decoquinate Nequinate

Proquinolate Sulfanitran Triazuril

Cross Index of Drugs

494 Coronary Vasodilators Dobutamine Flunarizine Medibazine Mixidine

Nifedipine Oxprenolol Oxyfedrine Terodiline

Corticoids Cloprednol Drocinonide

Flunisolide Halcinonide

Cough Suppressant Amicibone Diuretics Alipamide Ambuside Azolimine Bumetanide Chlorothiazide Clazolimine Clopamide Clorexalone Diapamide

Furosemide Indapamide Metalazone Methalthiazide Prorenone Ticrynafen Triflocin Xipramide

Estrogens Epimestrol Estrazinol Estrofurate

Fenestrol Nylestriol

Estrus Regulators Cloprostenol Fluprostenol Expectorant Bromhexine Fibrinolytic Bisobrin

Prostalene

Cross Index of Drugs

495

Gastric Antisecretory Cimetidine Deprostil

Metiamide Tiquinamide

Glucocorticoids Clocortolone Acetate Cortivazol Descinolone Acetonide Diflucortolone Flucloronide Fluperolone Acetate

Flurandrenolide Formocortal Medrysone Nivazol Prednival

Hemostatics Aminomethylbenzoic Acid

Tranexamic Acid

Hypoglycemic Isobuzole Hypolipidemics Beloxamide Boxidine Clofenpyride Eritadenine Halofenate Lifibrate

Nafenopin Pimetine Probucol Tibric Acid Treloxinate

Hypotensives Amquinsin Prorenone Immunosuppressant Azathioprine Interferon Inducer Tilerone

Prostalene

49 6

Cross Index of Drugs Local Anesthetics

Amoproxan Biphenamine Diamocaine Dexivacaine

Etidocaine Risocaine Rodocaine

Luteolytic Agents Cloprostenol

Fluprostenol

Mucolytic Bromhexine Muscle Relaxants Baclofen Benzoctamine Cinnamedrine Dantro1ene Fenalamide Fenyripol Fetoxylate Flavoxate Fletazepam Flumetramide Isomylamine Lorbamate

Mebeverine Mesuprine Metaxalone Na fomine Pancuronium Bromide Prazepam Proxazole Ritodrine Rolodine Methixine Xylazine

Narcotic Antagonists Nalbuphine Nalmexone

Naltrexone

Narcotics Anileridine Buprenorphine Butorphanol

Etorphine Oxilorphan

Non-Steroidal Antiinflammatory Agents Alclofenac Apazone Bendazac

Benoxaprofen Benzydamine Cicloprofen

Cross Index of Drugs

497

Non-Steroidal Antiinflammatory Agents (cont.) Cintazone Cliprofen Clonixeril Clonixin Clopirac Diclofenac Diflumidone Diflunisal Etoclofene Fenamole Fenbufen Fenclorac Fenclozic Acid Fenoprofen Fenoterol Fenpipalone Flazolone Flufenamic Acid Flumizole Flunisolide Flunixin Flutiazin Furobufen

Indoxole Intrazole Isoxicam Ketoprofen Meclofenamic Acid Nimazone Oxaprozin Paranyline Pirprofen Prodolic Acid Proquazone Proxazole Pyroxicam Salsalate Sudoxicam Sulindac Suprofen Tesicam Tesimide Tetrydamine Tolmetin Triflumidate

Oral Hypoglycemics Gliamilide Glibornuride Glipizide Glydanile

Glyoctamide Glyparamide Metformin Tolpyrramide

Glymidine Pituitary Suppressant Danazol Progestins Algestone Acetonide Algestone Acetophenide Angesterone Acetate Cingestol Clogestone Clomegestone Acetate

Delmadinone Acetate Dexnorgestrel Acetime Ethynerone Flurogestone Acetate Gestaclone Gestonorone

498

Cross Index of Drugs

Progestins (cont.) Haloprogesterone Medrogestone Methynodiol Diacetate

Norgestomet Tigestol

Prolactin Inhibitor Lergotrile Respiratory Stimulants Dime f1ine

Doxapram

Sedatives Benzoctamine Clozapine Midaflur Alonimid Flunitrazepam Nisobamate

Nisobamate Tricetamide Trimetozine Perlapine Roletamide

Sedatives - Tranquilizers Acepromazine Alpertine Azaperone Benperidol Benzindopyrine Bromperidol Buspirone Butaclamol Butaperazine Carpipramine Cinperene Cintriamide Clazolam Clobazam Clocapramine Clomacran Cloperidone Clopimozide Clothiapine Clothixamide Cyclophenazine

Cyprazepam Cyproximide Demoxepam Etazolate Fenimide Fletazepam Fluspiperone Fluspiriline Halazepam Hydroxyphenamate Imidoline Lenperone Lometraline Loxapine Metiapine Milipertine Molindone Naranol Nisobamate Oxiperomide Penfluridol

Cross Index of Drugs

499

Sedatives - Tranquilizers (cont*) Pimozide Pinoxepin Pipamperone Pipotiazine Prazepam Spirilene Sulazepam

Taclamine Temazepam Thiothixene Triflubazam Tybamate Uldazepam

Serotonin Inhibitors Chlorophenylalanine Cinanserin

Fonazine Mianserin Xylamidine

Fenclonine Thyromimetic Thyromedan Uricosurics Halofenate Benzobromarone Vasoconstrictors Methysergide Ciclafrine Vasodilators Aceperone Bamethan Benfurodil Betahistine Cinepazide Flunarizine Hexobendine Ifenprodil

Isoxsuprine Mesuprine Nafronyl Nicergoline Oxprenolol Pentoxifylline Pindolol Zolterine

Index Acebutolol, 109 Aceclidine, 295 Acedapsone, 112 Aceperone, 332 Acetaminophen, 63 Acetanilide, 97 Acetylcholine, 71, 93, 97, 294 Acetylenes, hydration, 20 "Acid", 476 Additive effects of substituents, 179 Adrenalin, 38 Adrenalone, 38 Adrenergic agents, 36, 37 Adrenergic agonists, SAR, 37, 38, 251 Adrenergic antagonists, 105-109 p-Adrenergic antagonists, actions, 107 Adrenergic transmission, 100 Adrenergic transmitters, SAR, 106

Albendazole, 353 Albuterol, 43 Albutoin, 261 Alclofenac, 68 Aldosterone, 173 Aletamine, 48 Algestone acetonide, 171 Algestone acetophenide, 171 Alipamide, 94 Alonimid, 295 Alpertine, 342 Alphaprodine, 328 Alverine, 55 Amantadine, 18 Ambuside, 116 Amcinafal, 185 Amcinafide, 185 Amedalin, 348 Amicibone, 11 Amicycline, 228 Amidephrine, 41 Aminals, 258, 462 p-Aminobenzoic acid, 9 7-Aminocephalosporanic acid (7ACA), 441 501

502 7-Aminodesacetylcephalosporanic acid (7ADCA), 439 a-Aminonitrile, 289 Aminooxazoline synthesis, 264 6-Aminopenicillanic acid (6APA), 437 Aminopyrine, 262 Aminorex, 265 Amiquinsin, 363 Amoproxan, 91 Amoxapine, 428 Amphecloral, 48 Amphetamine, 47 Amphetaminil, 48 Ampicillin, 437, 438 Ampyzine, 298 Amquinate, 370 Anagram, 235 Anesthetic, injectable, 15 Angesterone acetate, 165 Anidoxime, 125 Antagonists, p-adrenergic, 41 to histamine, 251 Anticholinergic activity, 71, 221 Antidepressant, 31 Antidepressant activity, 7 Antipyrine, 63, 261 Antisecretory, gastric, 3, 4 Antisecretory activity, 2 Antitussive, 11 Antiulcer activity, 2 Apazone, 475 Aphrodisiac, reputed, 347 Appetite depressants, 47 Aprindine, 208 Arbuzov reaction, 420 Aromatization, by loss of methyl group, 147, 149 Arrhythmias, cardiac, 33 Aspirin, 63, 89 Atenolol, 109

Index

Atropine, 71 Autonomic nervous system, 36 Azabon, 115 Azacosterol, 161 Azanator, 457 Azaperone, 300 Azaphilone, 282, 296 Azatadine, 424 Azathioprine, 464 Aziridinium ion, 11, 208, 219, 325, 472 regiochemistry, 59 Aziridinium salt, 72 Azolimine, 260 Baclofen, 121 Bamethan, 39 BAS, 96 BCNU, 12 Becanthone, 413 Beckett-Casey rule, 328 BeIoxamide, 56 Benapryzine, 74 Bendazac, 351 Benfurodil, 355, 356 Benorterone, 156 Benoxaprofen, 356 Benperidol, 290 Benproperine, 100 Benzbromarone, 354 Benzetimide, 293 Benzilate esters, 74 Benzilonium bromide, 72 Benzindopyrine, 343 Benzoctaffiine, 220 Benzodepa, 122 Benzothiadiazines, 383 Benztriamide, 290 Benzydamine, 350 Betahistine, 279 Bioisosterism (see also biological isosterism), 278 Biological isosterism, 233 Birch reduction, 145, 147,

Index

152, 440 1,3-Riscarbamates, 21 Bischler-Napieralski cyclodehydration, 140, 377, 404, 427, 453 reaction, 224 Bismethylenedioxy protecting group, 190 p-Blockers, 41 Blood-brain barrier, 52, 213 Bolandiol diacetate, 143 Bolasterone, 154 Boldenone 10-undecylenate, 153 Bolmantalate, 143 Boxidine, 99 Breakthroughs, therapeutic, 446 Bromindione, 210 Bromperidol, 331 Bromhexine, 96 Bromoxanide, 94 Bronchodilator, 3, 5, 38, 45, 108 Bucainide, 125 Bucloxic acid, 126 Buformin, 21 Bufuralol, 110 Bumetanide, 87 Bunaftine, 211 Bunamidine, 212 Bunitridine, 215 Bunitrolol, 106, 110 Bunolol, 110, 215 Bupicomide, 280 Buprenorphine, 321 Bupropion, 124 Burimamide, 251 Buspirone, 300 Butacetin, 95 Butamirate, 76 Butaclamol, 226 Butorphanol, 325 Butropium bromide, 308

503 Calusterone, 154 Cambendazole, 353 c-AMP, 464 Canrenone, 174 Carpipramine, 416 Capobenic acid, 94 Car&acfox, 390 Carbencillin, 437 Carbidopa, 119 Carbinoxamine, 32 Carbiphene, 78 Carboxylation of phenols, 86 Carbuterol, 41 Cardiotonic agent, 53 Carisoprodol, 21 Carmantadine, 20 Carmustine, 12 Carnidazole, 245 Cartazoiate, 469 CCM7, 12 Cefadroxil, 440 Cefamandole, 441 Cefazolin, 442 Cefoxitin, 435, 443 Cephalexin, 439 Cephamycin C, 442 Cephradine, 440 Cephapirin, 441 Cetophenicol, 46 Chloramphenicol, 28, 45 Chlordiazepoxide, 401 Chiormadinone acetate, 165 p-Chlorophenylalanine, 52 Chlorothiazide, 395 Chlorpromazine, 409 Cholinergic transmission, 71 Cholinesterase, 294 Chromone synthesis, 391 Ciclafrine, 266 Ciclopirox, 282 Cicloprofen, 217 Cimetidine, 253 Cinanserin, 96 Cinepazide, 301

504 Cingestol, 145 Cinnamedrine, 3 9 Cinnoline synthesis, 387, 394 Cinoxacin, 388 Cintazone, 388, 474 Cintriamide, 121 Citenamide, 221 Clamoxyquin, 362 Clavulanic acid, 435 Clazolam, 452, 453 Clazolimine, 260 Clemastine, 32 Clioxanide, 94 Cliprofen, 65 Clobazam, 406 Clobutinol, 121 Clocapramine, 416 Clocortoloiie, 193 Clodazon, 354 Clofenpyri de, 101 Clofibrate, 79, 101, 432 Clogestone, 166 Clomacran, 414 Clomegestone acetate, 170 Clometherone, 170 Clomifene, 127 Clominorex, 265 Clonixeril, 281 Clonixin, 281 Clopamide, 93 Cloperidone, 387 Clopimozide, 300 Clopirac, 235 Cloprednol, 182 Cloprostenol, 6 Clorprenaline, 39 Closiramine, 424 Clothiapine, 429 Clothixamide, 412 Cocteine, 317 Codoxime, 318 Conjugate addition, 2, 72, 123, 140, 144, 147, 154, 175, 220, 237, 343, 412, 450, 455, 456

Index

Corey lactol, 4 Cormethasone acetate, 194 Cormethasone acetate, 196 Cortisone, 176, 179 Cortivazol, 191 Cotinine, 235 Curare, 162 Cyclacillin, 439 Cyclazocine, 327 Cyclic adenosine monophosphate, see cAMP Cyclobendazole, 353 Cyclopropanation, 32, 166, 168, 174. 223, 297 Cyheptamide, 222 Cypenamine, 7 Cyprazepam, 402 Cyprolidol, 31 Cyproquinate, 368 Cyproterone acetate, 166 Cyproximide, 293 Dacarbazine, 254 Daledalin, 348 Z)anazol, 157 Dantrolene, 242 Dapsone, 112 Darzens condensation, 374 Dazadrol, 257 Debrisoquin, 374 Decoquinate, 368 Dehydrogenation, with chloranil, 144, 147, 170, 182, 190 with DDQ, 147, 191 microbiological, 189, 192, 196 with selenium dioxide, 160, 166, 179 Demoxepam, 401 Deprostil, 3 Descinolone, 187 Descinolone acetonide,

187, 189 Desonide, 179 Deternol, 39

Index

Dexivacaine, 95 Dexnorgestrel acetime, 152 Diabetes, 116 Diamocaine, 336 Diapamide, 93 Diaveridine, 302 Diazepam, 452 Diazoxide, 395 Dibenzepin, 424, 471 Dichloroisoproterenol, 106 Diclofenac, 70 Dicyanamide, 21 Dieckmann cyclization, 72 Difenoximide, 331 Difenoxin, 331 Diflucortolone, 192 Diflumidone, 98 Diflunisal, 85, 86 Difluoromethylene groups, from ketones, 196 Difluprednate, 191 Dihydrocodeinone, 318 Dihydropyridine synthesis, 283 Dihydroxyphenylalanine, see DOPA Dimefadane, 210 Dimefline, 391 Dioxadrol, 285 Diphenoxylate, 331 1,3-Dipolar addition, 301 Dipyrone, 262 Disopxjramide, 81

DNA, 12 Dobutamine, 53 Doisynolic acid, 9 Domazoline, 256

DOPA, 52, 119 Dopamantine, 52 Dopamine, 51 Dorastine, 457 Doxapram, 236, 237 Doxaprost, 3 Drocinonide, 186

JFconazoIe, 249

505 Elantrine, 418 Elucaine, 44 £tocifprate, 27 Endorphins, 317 Endrysone, 200 Enkephalins, 316 Ephedrine, 39 Epimestrol, 13 Epinephrine, 38, 105 Eprozinol, 44 Ergonovine, 475 Ergotism, 475 Eritadenine, 467 Eschweiler-Clark methylation, 29, 162, 210, 28* Esproquin, 373 Estradiol, 136 Estrazinol, 142 Estriols, 138 Estrofurate, 137 Estrogenic activity, 9 Estrogens, 137 Estrone, 137 Estrus synchronization, 6, 183 Etafedrine, 39 Etazolate, 469 Eterobarb, 304 Ethacrynic acid, 103 Ethamivan, 94 Ethonam, 249 Ethynerone, 146 Etidocaine, 95 Etoclofene, 89 Etorphine, 321 Etoxadrol, 285 False substrates, 161 Famotine, 37 Fantridone, 421 Fenalamide, 81 Fenbufen, 126 Fenclorac, 66 Fenclozic acid, 269 Fenestrel, 9 Fenimide, 237

Index

506 Fenisorex, 391 Fenmetozole, 257 Fenoprofen, 67 Fenpipalone, 293 Fenoterol, 38 Fenspi ride, 291 Fengripol, 40 Fetoxylate, 331 Fibrinolysis, 8 Fire, St, Anthony's, 475 Fischer indole synthesis, 340, 457 Flavoxate, 392 Flazalone, 337 Fletazepam, 403 Flubanilate, 98 Flubendazole, 354 Flucloronide, 198 Fludorex, 44 Flufenamic acid, 69 Fludrocortide, 198 Flumetramide, 306 Fluminorex, 265 Flumizole, 254 Flunarizine, 31 Flunidazole, 246 Flunisolide, 181 Flunitrazepam, 406 Flunixin, 281 Fi uperamide, 334 Fluperolone acetate, 185 Fluprostenol, 6 J\Z urandreno lide, 180 Flurogestone acetate, 183 Fluspiperone, 292 Fluspirilene, 292 Flutiazin, 431 Food and Drug Administration, 447 Formocortal, 189 Friedel-Crafts cyanation, 212 Furobufen, 416 Furosemide, 87 Fusaric acid, 279

Gamfexine, 56 Ganglion blocking agent, 287 Gestaclone, 169 Gestonorone caproate, 152 Gliamilide, 286 Glibornuride, 117 Glipizide, 117 Glucocorticoids, 177 Glyoctamide, 117 Glyoxals, from methylketones, 42 Glyparamide, 117 Grewe synthesis, 327 Gua/iaJbenz, 123 Guanethidine, 100 Guanisoquin, 375 Guanochlor, 101 Guanoxajbenz, 123 Guanoxyfen, 101 Halcinonide, 187 Halofenate, 80, 102 Haloform reaction, 88 Haloprogesterone, 173 Hepzidine, 222 Heroin, 315 Heteronium bromide, 72 Heterosteroids, 139-142 Hexobendine, 92 Histamine, antagoni s ts, 250 H-. and EL receptors, 251 in ulcer formation, 251 Hoquizil, 381 Hycanthone, 413 Hydantoin synthesis, 261 Hydracarbazine, 305 Hydroxylamine-o-sulfonic acid, 7 Hydroxylation, osmium tetroxide, 138 Hypoglycemics, oral, 2 0 Hypotensive agent, 5 Ibuprofen, 218, 356

Index

Ifenprodil, 39 Imidazole, synthesis, 246, 249, 254 tautomerism, 243 Imidazoline synthesis, 256 Imidazolinone synthesis, 260 Imidazolone synthesis, 291 Imidoline, 259 Imipramine, 420 Indapamide, 349 Indazole synthesis, 350 Indoles, as starting material for benzodiazepines, 405 Indomethacin, 345 Indoramin, 344 Indoxole, 254, 340 Inflammation, 63 Influenza A, 18 Inhibition, of cholinesterase, 294 of DNA gyrase, 370 of DNA synthesis, 12 of dopamine phydroxylase, 279 of MAO, 266 of monoamine oxidase, 7, 27 of phosphodiesterases, 379, 464 of prolactin, 479 of sympathetic transmission, 100 Insertion reaction, 27 Interferon, inducer, 219 Intrazole, 345 Intriptyline, 223 Ipronidazole, 244 Isobuzole, 272 Isocarboxazid, 266 Isoetharine, 9 Isolectronic groups, 253 Isomglamine, 11 Isoniazid, 266 Isoproterenol, 37, 107

507 Isoxicam, 394 Ivanov salt, 68 Ketamine, 16 Ketazocine, 328 Ketoprofen, 64 p-Lactamases, 442 Leniquinsin, 363 Lenperone, 286 Leprosy, 111 Lergotrile, 480 Letimide, 393 Leucine enkephalin, 317 Lidocaine, 95, 449 Lifibrate, 103 p-Lipotropin, 317 Lithium dimethyl cuprate, 4 Lobendazole, 353 Lometraline, 214 Lomustine, 12, 15 Loperamide, 334 Lorbamate, 21 Loxapine, 427 LSD-25, 476 Lucanthone, 413 Luteolytic activity, 6 Lysergic acid, 475 Mafenide, 114 Mannich reaction, 17, 40, 45, 57, 155, 223, 233, 234, 261, 336, 362, 410, 454, 456 MAO, see monoamine oxidase Maprotiline, 220, 221 Mazindol, 462 Mebendazole, 353 Mebeverine, 54 MeCCNU, 12 Meclocycline, 227 Meclofenamic acid, 88 Medibazine, 30 Mediquox, 390 Medroxyprogesterone

508 acetate, 165 Medrysone, 200 Mefenamic acid, 280 Mefenorex, 47 Mefexamide, 103 Melitracin, 220 Melphalan, 120 Memotine, 378 ^enoctone, 217 Meperidines, 328 reversed, 331 Meprobamate, 21 Mesuprine, 41 Metabolic activation, 464 Metabolism, of steroids, 138 Metalol, 41 Metformin, 20 Methacycline, 227 Methadone, 328 Methionine enkephalin, 317 Methisazone, 350 Methixene, 413 17-Methyltestosterone, 156 Methynodiol diacetate, 149 Methysergide, 477 Metiamide, 252 Metiapine, 429 Metizoline, 256 Metolazone, 384 Metoprolol, 109 ^exenone, 175 Mianserin, 451 Mibolerone, 144 Miconazole, 249 Midaflur, 259 Migraine, 477 Milipertine, 341 Mimbane, 347 Mineralocorticoids, 177 Minocycline, 228 Mixed agonists-antagonists, 318 Mixidine, 54 Modaline, 299 Molecular dissection, 9,

Index

17, 96, 237, 315, 325, 449 Molinazone, 395 Molindone, 455 Monoamine oxidase, 7, 49 Moprolol, 109 Morazone, 261 Morphine, 314 Morphine rule, 17, 328 Moxnidazole, 246 Nadolol, 110 Nafenopin, 214 Nafomine, 212 Nafronyl, 213 Nalbuphine, 319 Nalidixic acid, 370, 469 Nalmexone, 319 Nalorphine, 318 tfaloxone, 318, 323 Naltrexone, 319 Naranol, 454 Nef reaction, 2 Nefopam, 447 Nequinate, 369 Nexeridine, 17 Nicergoline, 478 Niclosamide, 94 Nifedipine, 283 Nifuratrone, 238 Nifurdazil, 239 Nifurimide, 239 iVifuroxime, 238 Nifurpirinol, 240 Nifurquinazol, 383 Nifursemizone, 238 Nifurthiazole, 241 Nimazone, 260 Nimorazole, 244 Niridazole, 269 Nisobamate, 22 Nithiazole, 268 Nitronic acid, 2 tfivazol, 159 Nocardicins, 435 Noracymethadol, 58

Index

Norbolethone, 151 Norepinephrine, biological effects, 38 Norethindrone, 145 Norgestrel, 151 19-Nortestosterone, 142 Nucleophilic aromatic substitution, 64, 65, 79, 89, 95, 281, 282, 406, 410, 413, 425 Octazamide, 448 Octriptyline, 223 Opium, 314 Organoboranes, amination, 7 Ormetoprim, 302 Oxamniquine, 372 Oxantel, 303 Oxaprozin, 263 Oxazepam, 402 Oxazole synthesis, 263 Oxazolinone synthesis, 246, 265 Oxfendazole, 353 Oxibendazole, 352 Oxidation, metabolic, 464 microbiological, 160, 180, 183, 196, 373 by nitroalkanes, 28 with ruthenium tetroxide, 404 Oxilorphan, 325 Oxiperomide, 290 Oxisuran, 280 Oxolinic acid, 370, 387 Oxprenolol, 109 Oxyfedrine, 40

Oxy222orphone, 319 Oxypertine, 343 Oxyphencyclimine, 75 Oxyphenisatin, 350 Oxytetracycline, 226 Pancuronium bromide, 163

509 Papaver bracteatum, 319 Papaver somniferum, 314, 318 Paraaminosalicylic acid, 89 Paranyline, 218 Parapenzolate bromide, 75 Parasympathetic nervous system, 71 Pargyline, 27 Parkinson's disease, 52, 119 Pazoxide, 395 Pemerid, 288 Penfluridol, 334 Pentapiperium methylsulfate, 76 Pentazocine, 325 Pentoxifyl1ine, 466 Perhydropyrindene synthesis, 450 Perlapine, 425 Pharmacophore, 233, 237, 242, 255, 278, 361 Pharmacognosy, 466 Phenbutalol, 110 Phencarbamide, 97 Phenmetrazine, 261 Phenyl aminosalicylate, 89 Phenyljbutazone, 388, 474 Phenylephrine, 265 Phenylpiperidinols, 334 Physical dependence, 314 Pill, the, 137, 164 for canines, 144 Pimetine, 286 Pimozide, 290 Pindolol, 342 Pinoxepin, 419 Pipamperone, 288 Pipobroman, 299 Piposulfan, 299 Piprozolin, 270 Piquizil, 381 Pirandamine, 459

510 Pirbuterol, 280 Piromidic acid, 470 Pirprofen, 69 Pizotyline, 420 Poldine, 74 Poldine methylsulfate, 74 Polonovski reaction, 240, 402 Potassium canrenoate, 174 Potassium mexrenoate, 175 Potassium prorenoate, 175 Poultry, epidemics in, 366 Practolol, 106, 108 Pranolium chloride, 212 Prazepam, 405 Prazosin, 382 Prednisolone, 178 Prednival, 179 Probucol, 126 Procarbazine, 27 Prodolic acid, 459 Prodrug, 48, 50, 89, 198, 363 Progesterone, 164 Proglumide, 93 Propanidid, 79 Propenzolate, 75 Propizepine, 472 Propoxyphene, 5 7 Propranolol, 105, 107, 212 Proquazone, 386 Proquinolate, 368 Prorenone, 175 Prostalene, 5 Proxazole, 271 Purine synthesis, 467 Psilocybine, 342 Psychotomimetic activity, 71 Pifrantel, 303 Pyrazine synthesis, 298 Pyridazine synthesis, 304 Pyrimidine synthesis, 302, 467 Pyrinoline, 34 Pyrovalerone, 124

Index

Pyroxicam, 394 Pyrro1iphene, 5 7 Quazodine, 379 Quinate coccidiostats, 366-370 Quinazosin, 382 Quinbolone, 154 Quindonium bromide, 139 Quinolone synthesis, 363 Quinoxaline synthesis, 388 Quinterenol, 366 Reaction, time honored, 92 Rearrangement, Beckmann, 419 of benzisothiazoles, 393 Chapman, 89 cyclopropylcarbinyl, 223 Fries, 42, 43, 355 glycidic ester, 374 Hofmann, 49, 117, 279 isoxazole to cyanoketone, 159 lactone-amide, 282 ring exchange, 236 Smiles, 430 Stevens, 124 Wagner-Meerwein, 323, 347 Receptors, a-, 105 a-adrenergic, 37 P-, 105 p-adrenergic, 37 as drug targets, 50 for opioids, 316 Reductive alkylation, 47, 55 Reformatsky reaction, 209, 355, 424, 460 Retro-Claisen reaction, 49 Rigid analogues, 50, 223, 284, 296, 451 Rimantadine, 19 Rimiterol, 278

Index

Risocaine, 91 Ritodrine, 39 Ritter reaction, 19 Robinson annulation, 224 Rodocaine, 450 Rolet amide, 103 Rolicyprine, 50 Rolodine, 468 Ronidazole, 245 Rotoxamine, 32 Salbutamol, 280 Salsalate, 90 Sapiens, homo, 316 Semustine, 12, 15 Serotonin, 96, 343 Serum cholesterol, 56, 78, 161 Slow release drugs, 143 Solypertine, 342 Sotalol, 41 Soterenol, 40 Spirilene, 292 Spironolactone, 172 Stenbolone acetate, 155 Strecker reaction, 119 Streptokinase, 377 Sudoxicam, 394 Sulazepam, 403 Sulfabenzamide, 112 Sulfacytine, 113 SuIfanil amide, 112 Sulfanitran, 115 Sulfapyridine, 114 Sulfasalazine, 114 Sulfazamet, 113 Sulfonamide diuretics, SAR, 87 Sulfonterol, 42, 43 Sulindac, 210 Sulnidazole, 245 Sulpiride, 94 Sulthiame, 306 Suprofen, 65 Symetine, 29 Sympathetic blocker, 363

511 Sympathetic nervous system, 36 Sympathomimetic, 47 agents, 36, 365 a- agents, 255 Facia/Bine, 224 Talampicillin, 438 Talopram, 357 Tamoxifen, 127 Tandamine, 347, 460 Tazolol, 110, 268 feciozan, 28 re222azepa7», 402 Terodiline, 56 fesicaia, 379 Tesimide, 296 Testolactone, 160 Tetrahydropyrimidine synthesis, 303 Tetrahydroquinoline synthesis, 371 Tetrazole synthesis, 301, 345 Tetrydamine, 352 Thalidomide, 296 Thebaine, 318 Thenium closylate, 99 Theobromine, 456 Theophylline, 464 Thiabendazole, 352, 353 1,2,5-Thiadiazole synthesis, 271 1,3,4-Thiadiazole synthesis, 272 Thiamphenicol, 45 Thiampirine, 464 Thiazole synthesis, 240, 269 Thiazolinone synthesis, 270 Thienamycin, 435 Thioguanine, 464 Thiothixene, 412 Thioxanthone synthesis, 400

Index

512 Thozalinone, 265 Thyromedan, 7 9 Thyroxine, 78 Tibolone, 147 Tibric acid, 87 Ticarcillin, 437 Ticrynafen, 104 Tienilic acid, see ticryanfen Tigestol, 145 Tiletamine, 15, 16 Filorone, 219 Timolol, 272 Tiquinamide, 372 Tofenacin, 32 Tolamolol, 110 Tolazoline, 106 Tolindate, 208 folmetin, 234 Tolnaftate, 211 Tolpyrramide, 116 Torgov-Smith synthesis, 140 Tralonide, 198 Tramalol, 17 rranexa222ic acid, 9 Tranylcypromine , 7 , 5 0 Trazodone, 472 2*reloxinate, 432 Triacetone amine, 288 Triamcinolone, 185 Triampyzine, 298 Triazinedione synthesis, 305 Triaznril, 305 Tricetamide, 94 rriclonide, 198 Triflocin, 282 Triflubazam, 406 Triflumidate, 98 ^rilostane, 158, 159 Trimazosin, 382 Trimethoprim, 302 Trimethoquinol, 374 Trimetozine, 94 Trimoxamine, 49 Trip, 476

Tryptamine, 343 Tybamate, 22 Ulcerogenic potential, 64 Ullman reaction, 413, 425, 428, 429 Urokinase, 376 Vasodilator, 30 Viloxazifle, 306 Vilsmeir reaction, 189 Volazociiie, 327 von Braun demethylation, 321 Whipworm, 303 Willgerodt reaction, 68 Wittig condensation, 3, 6 Wittig reaction, 420 Woodward hydroxylation, 215 Xipamide, 93 Xylamidine, 54 Xylazine, 307 Yohimbine, 347 Zolterine, 301

Errata for Volume One In a work of this magnitude it is an unfortunate fact of life that errors will creep in.

We are

grateful to our friends and students who have enabled us to compare their lists with ours.

Fortunately,

the majority are typos and other grammatical mistakes that are embarassing but do not obscure the meaning nor the veracity of what we were conveying.

These

have been corrected in subsequent printings of the work and are not reproduced here.

Those mistakes that

are less obvious and/or which we feel might mislead those not familiar with the particular subject matter involved are listed here.

The interested reader can

annotate volume 1 accordingly.

Every effort has

been made to ensure that the number of mistakes that creep into volume 2 have been held to a minimum.

It

is hoped that the authors have the reader's understanding if not forebearance for those which remain. 513

514

Errata

Page 6 8 8 11 16 16 16 16 17 17 18 32 33 33 33 34 36 36 36 38 42 47 47 54

Line

Old Entry

New Entry

13 trop ane. tropane." Hydrogenation Cyanohydrin reaction ester, 19. ester, 20. (X and Y for ambucaine are reversed.) (64a) (64) (65a) (65) 64a Formula 64 65a Formula 65 (CH 2 ) 2 Formula 74 propylamine butylamine 6 (88) via (85) via 21 ,39, ,36, 6 42, 43, 1 42, 43, 5 47 41 29 (7) 14 2 (8). (8), 14 8 dicyclonime dicyclomine 7 dihexyrevine dihexyverine 13 clocental (75) last clocental (25) -1-methylpyrro-1-methylpyrrolidine 14 diline pipradol azacyclonol 2 azacyclonol pipradol 4 Formula 76 19 9 11 Tab. 3 4

515

Errata

66 66 67 68 70 70 70 70 72 74 78

2 4

15 23 26 17 7 3

78 86 86

2 15

86

16

86 86

23

pronethanol soltalol Formula 6 Formulas 37 and 38 Formula 51 (54). 1 2 (58) phenylbutanone-2 oxoethazine fencamfine p-chloroacetophenone Formulae 109, 110, 111 isopropylbenzene alkylation of base with ethyl iodide affords monoethyl Formulas 1-5

pronethalol sotalol (remove "6") (numbers are reversed) (remove "51") (54). 1 3 (59) phenylp entanone-2 oxoethazaine fencamfamine p-methylacetophenone (P-CH3) i s obutylbenz ene alkylation with ethyl iodide of base affords monomethyl CH,-CHCH O —V

k >"

90 90 90 91

5 6

dimethylamine diethylamine carbetapentane (39) (38) Formula 38 38, X=N(C 2 H 5 ) 2 Formula 44 _4

516 92 93 96 96 96 96 97 97 97 97 97 100 102 111 111 111 115 116 117 119 120

Errata 6 11 10 13 15 19 4

cyclopyrazolate cyclopyrazate benactizine benactyzine phenol, 77. phenol, 77a. of 77 of 78a ether (79). ether (79a). of 79 of 79a (80) to afford to afford Formula 77 77a Formula 78 78a Formula 79 79a (Unnumbered formula should be 80) 15 ,2,2 ,2,1 (Formula 7 is superfluous and should be removed.) Formula 16 X=Z=CH3; Y=H 17 of 21 of 20 18 hydrazone (24) hydrazone (23) 9 10 5 (42). ' (43). 9 ' 1 0 2 moxysylyte moxisylyte last (66). * (66). ± o Formulas 76 and 75 (convert Cl to CEL) C1 Formula 81 * 'C1 OCH2CO2H

123 136 137 137

4 3 7

(Compound 94 should be spelled sulfaproxyline.) 1930s 1920s piperidine azepine tolazemide tolazamide

517

Errata Formulas 190, 191, 193

137

carbutemide l-butyl-3-metanylurea thiazosulfone Formula 29

carbutamide l-butyl-3-metanilylurea thiazolsulfone

amytriptylene methylpipyridine tylene Formulas 45/46

amitriptyline "Xi3 methylpiperidine tyline

172

Formula 78b

(Replace angular Me group by H but leave formulae 78a and 78c alone.)

173

Formula 80

138 138

3 5

141 150

151 151 152 153

174 175

17 23 6

7

eneone (91) Formula 92

eneone (95) (Also remove arrow from 91.) OH

518 176 180 183

Errata 39

(107),

(109), Formula 124 Formula 145

f186 193

196 21 196-7 198 199 200

norethinodrel Formulas 174 and 175 N-bromosuccinide Formulae 192-198 Formulae 205-207 Formulae 211-212 Formula 219

norethynodrel (Renumber to 174a and 175c) N-bromosuccinimide

203 213

Formula 240 Formulae 1-3

OH instead of OAc

213

Formulas 9 and 10

219

Formulas 3 and 4

225

Formula 47

Tab-

vf

OCH I CONHCH2CH

Errata

519

224 231

last

(Unnumbered formula is 41.) gives nifurprazine gives the thiadiazole (46).13 Add formula

232

analogue (46) of 46aa

nifurprazine (46a).

N N JT\ = O N-^O>^CH=CH-^ \ 2

233 233

8

isocarboxazine Formula 50

NH.

isocarboxazid (Reverse the methyl and allyl groups.)

234

18

reduction affords

234 235 235

19

(61), Formula 68

reduction and methyl ation affords (61a). CH 3 (CH 2 ) 3 CH(CO 2 C 2 H 5 )

Formula 61

R

2^

CH

3

./=(,

241

Formula 95

242

Formula 101

61, R^H 61a, R=CI

CH,

VcHfC0CH \ NH Formula 102

242

246

4

246

2

246

last

(132);

(130);

acetophenone

p rop i ophenone

tetratoin

tetrantoin

520

246 247 249 257 257 260 263 263 263 263 264

Errata Formulae 130-133 C2H5-C 10 aminitrazole aminitrozole 27 ambient ambident 9 glutethemide glutethimide 12 aminogluthemide aminoglutethimide 6 guancycline guanacline 6 (71). (71a). 8 (72). (72a). (Renumber formulas 71 and 72 "to 71a and 72a.) (An arrow should connect formulas 73 and 74.) H Formula \

J E2N Formulas 75-79

264

266

8 12 15

266

1

265

last

269

1

105

270

6

262

2

entry 110 allilic phenylacetonitrile

265 265

269

262 272

CH 2 CH 2 CH 3

uracyl uracycls (92). 28 (94), 29 amisotetradine aminotetradine

Formulas 63-65 Formula 124

uracil uracils (94). 28 (95), 29 amisometradine aminometridine 105a CH3CHCH2CH2CH3 allylic p-chlorophenylacetonitrile (add a p-chloro group) H 5 C 2 NH

521

Errata 278 279 281

287 295 301 301 301

19

171. Formula 171 Formula 182

last (4). Formula 30 1 furfuryl Formulae 82-85 Formulae 85-87

305 308 315

7 20

316 318 319 320 320

15 last 5 13 17

320 321 322

7

171a. 171a. NH {—NHCNH. <4>." 40 (also remove +) tetrahydrofurfuryl -CO2C2H5

prolidine pirintramide Formula 14

prodilidine piritramide

predominate scision Rawaulfia fused to potassium perchlorate Formulas 30-32 synthesis. Formulas 47-49

predominate. . . 7 scision. Rauwolfia fused a to potassium chlorate

synthesis.12

^

522

Errata

325 325

13 14

327

3

333

last

334

clonitazme etonitazine

clonitazene etonitazene

ethoxysolamide

ethoxazolamide

salicylaldehyde

acetophenone

Formulae 21*30 should have a CEL group instead of

335 336

13

336

8 9

336

^ 30 is

1

,35, Formula 35

,35a, 35a

CH 3

the bronchodi1ator

the antiasthmatic

its extremely

its disodium

insoluble disodium 337

Formulas 46 and 47

-CHOH-

338

23

cincona

cinchona

340

10

59.

59.13

Formula 76

76a

343 346

15

,101.

,103.

346

19

(103) affords

(101) affords

348

13

same

name

352

8

diethylamine

piperidine

352

355 355 356

Formula 138

29 30

5

anthralic anthranillic Formula 163

anthranilic acetic anhydride N

H

523

Errata 358

Formula 182

358

ethiazide

359

1

359

7

Compound 179 trichlomethiazide cyclopentadiene. 49

359

2

althizide

althiazide

359 365

16

altizide "the ox£.me

the N-methyl analogue

13

trichlormethiazide 44 cyclopentadiene. althiazide of the oxime

365 366

7

368

22 25

368

370 373 376

1 28

379 380

1

386

6

389

8

389

8 10

389

Formula 14 of diazepam

N-CH 3

amide (37).

amide (36).

The N-methylated analoa of inter-

Intermediate 15

of desmethyldiazepam

contains

medi ate, 15, contains cloxazepam cloxazolam of 3, of 1, Formula 22

(30) Formulas should all as the side chain. piperactizine of the methylthiosubstituted phenothiazine with (115). 19

(31) have CH 2 CH(CH 3 )N(CH 3 ) 2 piper acetaz ine of substituted phenothiazine 113 with (114). 19

524

389 389

Errata

14

(114) Formulae 112, 113

(115) -SCH 3

and 115 390

5

pyrrolidyl

piperazinyl

390

9

at the expense of

in favor of

390

Formulas 118 and 120

390

Formulas 117 and

-N(CH3)2

119 394

5

394

34

400

7

401

propanthecatalyst.

pronanthecatalyst.

thiothixine

thiothixene

Formula 42 —N

N—CH3

10

amytripty1ine

405 405

10

(The unnumbered formula should be 76) dibenzepine dibenzepin

410

32

4, a

410

36

phenbencillin

4, 1 a phenbenicillin

414

21

carbencillin

carbenicillin

414

17

amoxycillin (35)

amoxycillin (28a)

404

NHR

414

Formula 27,

414

Formula 28, R=X=H

€*

414 417 426

Z

O

amitriptyline

O

X -JT*%- CH-l

Formula 28a, R=H, X=OH 11 10

4

43.

43.

oncolyltic

oncolytic

525

Errata 426

12

oxidate

429

9

(39).

oxidase 8 (39)/

430

2

(47); 10

(47); 11

Changes To Be Made In The Index: Althiazide

Ethoxzolamide

Aminitrozole

Etonitazene

Aminoglutethimide

Fencamfamine

Aminometradine

Flumethiazide

Amisometradine

Glutethimide

Amitriptyline, 151, 404

Guanacline

Benactyzine

Gaunochlor

Benzphetamine

Guanoxan

Betamethasone

Hydro flumethi az i de

Biperiden

Iodothiouracil

Butallonal

Isocarboxazid

l-Butyl-3-metanilyl urea

Isoproterenol

Caramiphen

Levarterinol

Carbenicillin

Levalorphanol

Carbetidine

Mebhydroline

Carbutamide

Mephenoxalone

Carisoprodol

Metaproterenol

Chlorimpiphenine

Metaxalone

Chloropyramine

Methaphenilene

Chlorotrianisene

Methdilazine

Cromoglycic acid

Methyclothiazide, 360

Clonitazene

Methylthiouracil

Cloxazolam

Methyridine, 256

526

Errata

Cyclopyrazate

Moxisylyte

Debrisoquine

Nikethamide

Desipramine

Norethynodrel

Dexamethasone

Nortriptyline

Dicyclomine

Oxoethazaine

Dihexyverine

Paraethoxycaine

Dimetacrine

Pargyline

Dipiproverine

Phenbenicillin

Dithiazanine

Pholcodine

Etriptamine

Piperacetazine

Ethacrynic acid

Piritramide

Ethiazide

Prodilidine

Prolintane Pronethalol Propylthiouracil Prontosil Protripty1ine PTU, see propylthiouracil Rescinnamine Sotalol (delete Sulfadiazene, 128) Sulfaproxy1ine Tetrantoin Thiomestrone Thiazolsulfone Trichlormethiazide Trifluperidol Trihexyphenidyl Tripelennamine Uracils

THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS VOLUME 3

DANIEL LEDNICER Analytical Bio-Chemistry Laboratories, Inc. Columbia, Missouri

LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas

A WILEY-INTERSCIENCE PUBLICATION

JOHN WILEY AND SONS New York

•

Chlchester

•

Brisbane

*

Toronto

•

Singapore

Copyright © 1984 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging In Publication Data: (Revised for volume 3) Lednicer, Daniel, 1929The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." Includes bibliographical references and index. 1. Chemistry, Pharmaceutical. 2. Drugs. 3. Chemistry, Organic—Synthesis. I. Mitscher, Lester A., joint author. II. Title. [DNLM 1. Chemistry, Organic. 2. Chemistry, Pharmaceutical. 3. Drugs—Chemical synthesis. QV 744 L473o 1977] RS403.L38

615M9

76-28387

ISBN 0-471-09250-9 (v. 3) Printed in the United States of America 10

9 0 7 6 5 4 3 2 1

With great pleasure we dedicate this book, too, to our wives, Beryle and Betty.

The great tragedy of Science is the slaying of a beautiful hypothesis by an ugly fact.

Thomas H. Huxley, "Biogenesis and Abiogenisis"

Preface Ihe first volume in this series represented the launching of a trial balloon on the part of the authors. In the first place, wo were not entirely convinced that contemporary medicinal (hemistry could in fact be organized coherently on the basis of organic chemistry. If, however, one granted that this might be done, we were not at all certain that the exercise would engage Ihe interest of others. That book's reception seemed to give nri affirmative answer to each of these questions. The second volume was prepared largely to fill gaps in the coverage and to bring developments in all fields up to a common date - 1976. In the process of preparing those volumes, we formed the habit of scrutenizing the literature for new nonproprietary names as mi indication of new chemical entities in or about to be in the « linic. It soon became apparent that the decreased number of drugs being granted regulatory approval was not matched by a decrease in the number of agents being given new generic Mrtmes, The flow of potential new drugs seemed fairly constant over the years. (For the benefit of the statistician, assignment of new USAN names is about 60 per year.) It was thus ix

x

PREFACE

obvious that the subject matter first addressed in Volume 1 was increasing at a fairly constant and impressive rate. Once we had provided the background data up to 1976, it seemed logical to keep the series current by adding discussion of newer agents. Reports of drugs for new indications as well as the occurrence of brand-new structural types as drugs made it particularly important to update the existing volumes. The five-year cycle for preparation of new volumes represents a compromise between timeliness and comprehensiveness. A shorter period would date earlier entries. This volume thus covers compounds reported up to 1982. As has been the practice in the earlier volumes, the only criterion for including a new therapeutic agent is its having been assigned a United States nonproprietary name (USAN), a so-called generic name. Since the focus of this text is chemistry, we have avoided in the main critical comments on pharmacology. The pharmacological activity or therapeutic utility described for the agents covered is that which was claimed when the USAN name was assigned. The changes in chapter titles as well as changes in their relative sizes in going from volume to volume constitute an interesting guide to directions of research in medicinal chemistry. The first two volumes, for example, contained extensive details on steroid drugs. This section has shrunk to about a third of its former size in this book. The section on 3-lactam antibiotics, on the other hand, has undergone steady growth from volume to volume: not only have the number of entries multiplied but the syntheses have become more complex.

PREFACE

xi

This book, like its predecessors, is addressed to students
Daniel Lednicer I «*ster A. Mitscher

Dublin, Ohio Lawrence, Kansas January, 1984

Contents Chapter 1.

Alicyclic and Cyclic Compounds 1. Cyclopentanes a. Prostaglandins b. Retenoids c. Miscellaneous References

1 1 1 11 13 16

Chapter 2,

Phenethyl and Phenoxypropanolamines 1. Phenylethanolamines References

19 20 34

Chapter 3.

Arylaliphatic Compounds 1. Arylacetic Acid Derivatives 2. Anilines, Benzyl Amines, and Analogues 3. Diarylmethane Analogues 4. Stilbene Analogues References Monocyclic Aromatic Agents 1. Aniline Derivatives 2. Benzoic Acid Derivatives 3. Benzenesulfonic Acid Derivatives References

37 37 45 47 50 52 55 55 58 61 63

Chapter 4.

Chapter 5.

Polycyclic Aromatic Compounds 1, Indanones

65 65 xi i i

CONTENTS

XIV

2. Naphthalenes 3. Tricyclic Compounds: Anthracene, Phenanthrene, and Dibenzocycloheptene References

68 72 78

Chapter 6.

Steroids 1. Estranes 2. Androstanes 3. Pregnanes 4. Miscellaneous Steroids References

81 82 87 90 99 107

Chapter 7.

Compounds Related to Morphine 1. Bridged Polycyclic Compounds 2. Piperidines 3. Miscellaneous Compounds References

109 111 116 121 124

Chapter 8.

Fi\ /e-Membered Heterocycles 1 . Pyrroles and Pyrrolidines 2. Furans 3 . Imidazoles 4 . Triazoles 5. Pyrazolines 6 . Isoxazoles 7. Tetrazoles 8 . Miscellaneous

References

127 127 129 131 137 137 138 139 139 141

Six-Membered Heterocycles 1 , Pyri dines 2. Pyridazines 3 . Pyrimidines 4. Miscellaneous Heterocycles References

145 145 151 152 157 162

Chapter 10. Five-Membered Heterocycles Fused to Benzene 1. Indoles 2. Benzimidazoles 3. Benzothiazoles References

165 165 172 178 179

Chapter 11. Benzofused Six-Membered Heterocycles 1. Quinoline Derivatives 2. Isoquinoline Derivatives

183 183 186

Chapter 9.

CONTENTS

xv

3. Benzopyran Derivatives 4. Benzodioxane Derivatives 5. Benzoxazolinone Derivatives 6. Quinazolinone Derivatives 7. Phthalazines 8. Benzodiazapines and Related Substances 9. Miscellaneous References

188 191 191 192 195 195 198 199

Chapter 12.

Beta Lactams 1. Penicillins 2* Cephalosporins References

203 203 209 221

Chapter 13.

Miscellaneous Fused Heterocycles References

225 250

C r o s s I n d e x of D r u g s Cumulative Index, Vols. Index

1-3

253 261 279

THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS VOLUME 3

1 Alicyclic and Cyclic Compounds 1. CYCLOPENTANES a. Prostaglandins. Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prostaglandin E l 9 F 2 , A 2 , etc*)* with their powerful associated activities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the noncyclic leucotrienes, including the slow releasing substance of anaphylaxis, have been discovered. The activity these substances show in shock and asthma, for example, has excited considerable additional interest. Each of these discoveries has opened new physiological and therapeutic possibilites for exploitation. The newer compounds in particular are chemically and biologically short lived and are present in vanishingly small quantities so that much chemical effort has been expended

2

ALICYCLIC AND CYCLIC COMPOUNDS

on finding more efficient means of preparing them, on enhancing their stability, and on finding means of achieving greater tissue specificity. In addition to its other properties, interest in the potential use of the vasodilative properties of prostaglandin Ei, alprostadil (4^), has led to several conceptually different syntheses.1**5 For this purpose, the classic Corey process 1 has to be modified by reversing the order of addition of the side chains to allow for convenient removal of the unwanted double bond in the upper side chain. For example, Corey lactone jL_ is protected with dihydropyran (acid catalysis), reduced to the lactol with diisobutyaluminum hydride, and then subjected to the usual Wittig reaction to give intermediate 2^. This is esterified with diazomethane, acetylated, and then catalytically hydrogenated to give intermediate 3^ in which all of the oxygen atoms are differentiated. Further transformation to alprostadil (£) follows the well-trodden path of sequential Collins oxidation, Horner-Emmons olefination, zinc borohydride reduction, deetherification with aqueous acetic acid, separ-

r

2

.6o

6thp

(I)

-

(2)

0 ,.(CH?

Oil

Oil (4)

.

othp

(31

ALICYCLIC AND CYCLIC COMPOUNDS ation

of

the

resulting

3

C-15

epimers,

dihydropyranylation,

saponification of the ester groups, Jones oxidation (to duce the C-9 keto group), and f i n a l l y ,

intro-

deetherification.

The classic method f o r

controlling

stereochemistry

perform reactions on c y c l i c

substrates.

A rather

nonetheless e f f i c i e n t

example in the prostaglandin

b i c y c l i c structures for t h i s purpose.

2

Bisacetic

homologation. cyclic ation

and maleic

intermediate (H2/Raney

careful

Ni;

6^

followed

locks

the

Esterification,

Cr(0Ac) 2 )»

esterification

sulfonyl

anhydride

Bromolactonization

(CH 2 N 2 h

f i e l d uses reaction of

by

side-chain

molecule

reductive

base opening

to but

acid d e r i v a -

t i v e j) is available in f i v e steps from Diels-Alder trans-piperylene

is

lengthy

of

as

bi-

dehalogen-

the

lactone,

and dehydration with methane-

chloride gives 1_. The net result

is movement of the

double bond of b_. Treatment of 7 with NaH gives a f o r t u n a t e l y unidirectional

Dieckmann

ring closure;

a l k y l a t i o n with methyl

w-iodoheptanoate introduces the r e q u i s i t e saturated sidechain; l i t h i u m i o d i d e - c o l l i d i n e treatment

saponifies the ester during

the course of which the extra carboxy group is l o s t ; the sidechain methyl

ester

linkage

the future keto group is glycol

is

restored with diazomethane and

protected by reaction with

and acid to give intermediate j3.

manganate oxidation

cleaves

the

double

Next, bond

ethylene

periodate-per-

and

leads

to a

methyl ketone whereupon the r e q u i s i t e trans-stereochemistry established. Villiger

Diazomethane

oxidation

esterification

introduces

followed

by

Ihe dioxolane moiety at the

C-9

of

prevents

3-elimination

Bayer-

the future C - l l a hydroxyl

protected as the acetate.

the

acetoxyl

group of

is

group future

9_.

In

order to shorten the three-carbon sidechain, methoxide removes the acetyl

group so that J>BuOK can close the

NaH catalyzed condensation with methyl

lactone

formate produces

ring. inter-

4

ALICYCLIC AND CYCLIC COMPOUNDS

mediate 22.• Ozonization removes one carbon atom and acetic anhydride is used to form enolacetate _n_, which intermediate is now ready for excision of another carbon, Periodate-permanganate oxidation followed by ethylenediamine hydrolysis proproduces the needed aldehyde linkage, and the remainder of the synthesis is rather straightforward. Horner-Emmons condensation produces ketone VZ_ which is sequentially protected with trimethylsilyl chloride, and reduced with sodium borohydride, the isomers separated, and then the blocking groups are removed by base and then acid treatment to give alprostadil(4). cn 2 co 2 cn^

(CII2)6CO2CII3

(4)

(11)

(12)

ALICYCLIC AND CYCLIC COMPOUNDS

H02CCII?CO(C1I0)7C02H OHCCON-^*C{jIl5 Oil

Otlip f 13 )

(14)

A conveniently short synthesis of alprostadii begins with a mixed aldol assembly of the requisite cyclopentenone 13. 3 This product is then oxidatively cleaved with periodate-permanganate and the alcohol moiety is protected as the tetrahydropyranyl ether U 4 ) • Aqueous chromous sulfate satisfactorily reduces the olefinic linkage and the trans stereoisomer JJ5 predominates after work-up. The remainder of the synthesis of 4^ involves the usual steps, through _16_ to ^, with the exception that thexyl tetrahydrolimonyllithium borohydride is used to reduce the C-15 keto moiety so as to produce preferentially the desired C-15S stereochemistry.

V^Nx^^y'^'ll2'4ul3

C1I0 Othp (15)

on

(17)

(18)

"

6

ALICYCLIC AND CYCLIC COMPOUNDS Consonant with the present interest in chiral synthesis,

two

additional

utilized

a

contributions

combined

can be cited.

microbiological

Sih et^ ai .**

and organic

chemical

sequence in which key chirality establishing steps include the conversion of Y1_ to chiral, but unstable, l&_ by enzymic reduction using the fungus Diplodascus uninucleatus.

Lower side-

chain synthon 20^ was prepared by reduction of achiral 19 with Pencillium decumbens.

on (20)

Stork and Takahashi5 took D-glyceraldehyde synthon _21_ from the chiral

pool and condensed i t

with methyl

lithium diisopropylamide as catalyst action, leading to _22_.

oleate,

using

for the mixed aldol

re-

The olefinic linkage is a latent form

of the future carboxyl group.

Protection of the diastereoiso-

meric mixture's hydroxyl by a methoxymethy1eneoxo ether (MEMO) group

and sequential

acid treatments

lead to

3-lactone ^ 3 .

This is tosylated, reduced to the lactol with d i b a l , and converted to the cyanohydrin (24).

Ethyl vinyl ether is used to

cover the hydroxyl groups and then sodium hexamethyldisi 1azane treatment is used to express the nucleophilicity of the cyanohydrin ether, an umpohlung reagent for aldehydes that Stork has introduced. rivative

25.

This internal displacement gives cyclopentane dePeriodate-permanganate

oxidation

cleaves

the

ALICYCLIC AND CYCLIC COMPOUNDS

7

olefinic linkage, the ether groups are removed by dilute acid,

un

3' ^OH

(21)

(22)

^

T II 2 OCH OH (24)

2

(23)

C1I

2 V:O2C1I3

h Z

3

(25)

(26)

and diazomethane leads to the ester. The other protecting groups are removed to give chiral j26^ which was already well known in its racemic form as a prostaglandin synthon. A significant deactivating metabolic transformation of natural prostaglandins is enzymic oxidation of the C-15 hydroxyl to the corresponding ketone. This is prevented, with retention of activity, by methylation to give the C-15 tertiary carbinol series. This molecular feature is readily introduced at the stage of the Corey lactone (27.) by reaction with methyl Grignard reagent or trimethylaluminum. The resulting mixture of tertiary carbinols (_28) is transformed to oxytocic carbaprost (29) by standard transformations, including separation of diastereoisomers, so that the final product is the C-15 (1R) analogue. This diastereoisomer is reputedly freer of typical prostaglandin side effects than the C-15 (_S) isomer.6 Carbaprost can be converted to the metabolically stable

ALICYCLIC AND CYCLIC COMPOUNDS

A cn3 -on (29)

2 4 3

?" (27)

on

(28)

prostaglandin E analogue, a r b a p r o s t i l

( 3 1 ) , which exerts

secretory

in the stomach

oral

selective 30,

and c y t o p r o t e c t i v e

administration

silanization

which undergoes

blocking

to

activity

and so promotes ulcer

following At

-4b°C,

of the methyl ester of carbaprost

Collins

produce

healing.

anti-

oxidation

arbaprosti 1

and acid 6

(_31_)«

The

gives

catalyzed

stereochemical

c o n f i g u r a t i o n of the drug was confirmed by x-ray a n a l y s i s . branched

alcoholic

moiety

can also

de-

be introduced

by

The

suitable

m o d i f i c a t i o n s in the Horner-Emmons r e a c t i o n . 7

,{ai2)3co2cn^ (29)

"

' c3 CuO (30)

Another device for i n h i b i t i n g transformation by lung prostaglandin-15-dehydrogenase branching at C-16.

is

introduction

of

gem-dimethyl

This stratagem was not s u f f i c i e n t , however,

to provide simultaneously the necessary chemical s t a b i l i t y

to

allow intravaginal administration in medicated devices for the purpose of inducing labor or abortion.

I t was found that this

could be accomplished by replacement of the C-9 carbonyl group by a methylene (a carbon bioisostere) and that the

resulting

ALICYCLIC AND CYCLIC COMPOUNDS agent, meteneprost gastrointestinal injection utilizes

of

( 3 3 ) , gave a lower incidence of side

effects

carbaprost

(29)

the s u l f u r y l i d e

dimethylprostaglandin (32).

fination

on

E2

The r e s u l t i n g reduction

as compared w i t h methyl

ester.

with

(32a).

methyl

This

ester

intramuscular The

synthesis8

reacts w i t h

aluminum

(32a)

16,16-

bis-(trimethylsilyl)

3-hydroxysulfoximine amalgam

produces the u t e r i n e stimulant meteneprost

(32)

undesirable

prepared from JVS-dimethyl - 5 - p h e n y l -

sulfoxime and methyl Grignard ester

9

9

undergoes and

ole-

deblocking

(33).

(33)

Among the other metabolic transformations that result in loss of prostaglandin activity is w-chain oxidative degradation. A commonly employed device for countering this is to use an aromatic ring to terminate the chain in place of the usual aliphatic tail. Further, it is known in medicinal chemistry that a methanesulfonimide moiety has nearly the same pK a as a carboxylic acid and occasionally is biologically acceptable as well as a bioisostere. These features are combined in the uterine stimulant, sulprostone (39). Gratifyingly these changes also result in both enhanced tissue selectivity toward the uterus and lack of dehydration by the prostaglandin-15-dehydrogenase. The synthesis follows closely along normal prostaglandin

10

ALICYCLIC AND CYCLIC COMPOUNDS

lines with the variations being highlighted here. Processed Corey lactone 34 undergoes Horner-Emmons trans olefination with ylide 3^ to introduce the necessary features of the desired u>side chain (_36). After several standard steps, intermediate^ undergoes Wittig cis-olefination with reagent ^ and further standard prostaglandin transformations produce sulprostone (39). 1 0

(MeO)7ZPOCHl 9COC LII70

OCO00 (34) Oil

OCO00 (30)

Cfi 2 ) - C O N I I S O

Othp

othp (37)

on (38)

?

on (39)

Thromboxane A 2 , formed in blood platelets, is a vasoconstrictor with platelet aggregating action wheras prostacyclin, epoprostenol (43), formed in the lining cells of the blood vessels, is a vasodilator that inhibits platelet aggregation. Their biosynthesis from arachadonic acid via the prostaglandin cascade is normally in balance so that they together exert a sort of yin-yang balancing relationship fine tuning vascular homeostasis. The importance of this can hardly be overestimated. Thrombosis causes considerable morbidity and mortality in advanced nations through heart attacks, stroke, pulmonary

ALICYCLIC AND CYCLIC COMPOUNDS

11

embolism, thrombophlebitis, undesirable clotting associated with implanted medical devices, and the like. Impairment of vascular prostacyclin synthesis can well result in pathological hypertension and excess tendency toward forming blood clots. Administering exogenous prostacyclin, epoprostenol (43), shows promise in combating these problems even though the drug is not active if given orally and is both chemically and metabolically unstable so that continuous infusion would seem to be needed lor normal maintenence therapy. The drug is conveniently synthesized from prostaglandin I2 a methyl ester (_40), which undergoes oxybromination in the presence of potassium triiodide to give 41. Treatment with DBN

2 ) 3 CO 2 CM 3

011

OH (40)

OH

; X "

OH (41

»

( 4 2 ) R - CII, (43) R = II

(diazabicyclo[4.3.0]non-5-ene) gives dehydrohalogenation to enol ether j42. Careful alkaline hydrolysis gives the sodium salt of epoprostenol ( 4 ^ ) - U The free acid is extremely unstable, presumably due to the expected acid lability of enol ethers. Much chemical attention is currently devoted to finding chemically stable analogues of 43; Volume 4 will surely have much to say about this. b. Retenoids Ihe discovery that some retinoids posess prophylactic a c t i v i t y against carcinogenesis in epithelial tissues 1 2 has reawakened

12

ALICYCLIC AND CYCLIC COMPOUNDS

interest

in these terpene d e r i v a t i v e s ,

particularly

in

13-cis-

r e t i n o i c acid ( i s o t r e t i n o i n , 48) which is r e l a t i v e l y potent and nontoxic.

I s o t r e t i n o i n also has k e r a t o l y t i c

i n the treatment

of

severe acne.

activity

The synthesis

13 1Lf

*

of

value

i s com-

p l i c a t e d by ready i s o m e r i z a t i o n , and some early confusion existed in the l i t e r a t u r e regarding the i d e n t i t y of some intermediates.

The natural

terpene

3-ionone

(44)

Reformatsky reaction with zinc and ethyl resulting

product

is

reduced

to

the

is

bromoacetate and the allylic

l i t h i u m aluminum hydride and then oxidized to idene)acetaldehyde

(4J5).

This

is

3-methylglutaconic

anhydride to give 46^

subjected to a alcohol

with

trans~(g-ionyl-

condensed in pyridine Careful

with

saponifica-

t i o n gives mainly diacid _47^ which, on heating with copper and q u i n o l i n e , decarboxylates to i s o t r e t i n o i n (48) .

(44)

(47) R = co ,| (48) R = II

(45)

13

>llf

(46)

(4 9) R = II ( i>0) R ~- C:H2C1 (5J J R = CII 2 1»0 3

The keratolytic analogue motretinide (53) is effective in treating acne and the excess epithelial growth characteristic

Al ICYCLIC AND CYCLIC COMPOUNDS

13

of p s o r i a s i s , demonstrating t h a t (ompatible w i t h

activity.

an aromatic terminal

The s y n t h e s i s

15

reflated o r a l l y a c t i v e a n t i p s o r i a t i c / a n t i t u m o r C>2).

These

synthetic

than the natural

compounds

materials.

is

agent,

etrinitate

safety

I ormaldehyde)

to

S0_ followed

i initate (52).

by conversion

margin

synthesized

- \ 3 , 5 - t r i m e t h y l a n i s o l e by sequential c h l o r o m e t h y l a t i o n with t r i p h e n y l p h o s p h i n e .

is

passes through the

have a wider

Etrinitate

ring

to

16

from

(HC1 and

the y 1 id

(51)

W i t t i g o l e f i n a t i o n then leads to e t -

E t r i n i t a t e may then be s a p o n i f i e d , a c t i v a t e d by

MCI3 t o the acid c h l o r i d e , and then reacted w i t h ethylamine t o • live m o t r e t i n i d e

(53).

Cll^

(ill,

CIU

(53)

The retinoids share with certain steroid hormones the disI inction of belonging to the few classes of substances capable DI powerful positive influence on cell growth and differentiai ion. c. Miscellaneous In building their characteristic cell walls, bacteria utilize 1) alanine which they must manufacture enzymatically by epimeri/dtion of the common protein constituent, J_~alanine, taken up in their diet. Because mammals have neither a cell wall nor an apparent need for _D-alanine, this process is an attractive i.iryet for chemotherapists. Thus there has been developed a

14

ALICYCLIC AND CYCLIC COMPOUNDS

group of mechanism-based i n h i b i t o r s principle

utilized

in their

design

of alanine i s that

racemase.

The

the enzyme would

convert an unnatural substrate of high a f f i n i t y

into a reactive

Michael acceptor which would then react with the enzyme t o form a covalent

bond and i n a c t i v a t e

the enzyme.

Being unable t o

biosynthesize an essential element of the c e l l w a l l , the organism so affected would not be able to grow or repair damage. was

hypothesized

would eliminate (54)

that

a strategically

readily

positioned

in the intermediate

t o provide the necessary

reactive

halo

pyridoxal

species.

It atom

complex

A deuterium

atom at the a-carbon is used to adjust the rate of the process ^CO-jH

FCII2?>
f54)

(55)

(56)

so that the necessary reactions occur at what is judged to be the best a

^

ove

possible

(jjl

t 0

!?!D ^

pace.

The process

o r t ie

ru

*

^

is shown

9 fludalanine

schematically

( 5 6 ) . In p r a c t i c e ,

the drug is combined with the 2,4-pentanedione enamine of eyeloserine.

The combination

i s synergistic

as cycloserine i n -

h i b i t s the same enzyme, but by a d i f f e r e n t mechanism.

FCHU CO jC j \ i r

T

^ U ^ L M U

Jo

w

"

Q

II

*"

I'^n ^ I J U «jj i

^-

ruii^Vj

I NH2 (57)

(58)

(59)

ALICYCLIC AND CYCLIC COMPOUNDS

15

One of the syntheses of fludalanine begins with base promoted condensation of ethyl fluoroacetate and ethyl oxalate to give b]_* This is then converted by hydrolytic processes to the insoluble hydrated lithium salt of fluoropyruvate (58)« This last is reductively aminated by reduction with sodium borodeuteride and the resulting racemate is resolved to give D-fludalanine (!59).17 There is a putative relationship between the pattern of certain 1ipids in the bloodstream and pending cardiovascular accidents. As a consequence, it has become a therapeutic objective to reduce the deposition of cholesterol esters in the inner layers of the arterial wall. One attempts through diet or the use of prophylactic drug treatments to reduce the amount of yery low density lipoproteins without interfering with high density lipoproteins in the blood. The latter are believed to be beneficial for they transport otherwise rather water insoluble cholesterol. Clofibrate, one of the main hypocholesterolemic drugs, has been shown to have unfortunate side effects in some patients so alternatives have been sought. Gemcadiol (62) is one of the possible replacements. This compound may be synthesized by alkylating two molar equivalents of the cyclohexylamine imine of isopropanal (j5rO) with 1,6-dibromohexane under the influence of lithium diisopropylamide. The resulting dialdehyde (61) is reduced to gemcadiol (62) with sodium boroCH. Cll.

(60)

(61) R = CHO (62) R = CH 2 OH (63) R = CO 2 H

16 hydride.18 converted t o

ALICYCLIC AND CYCLIC COMPOUNDS There is evidence t h a t diacid

agent at the c e l l u l a r

(63>) which

is

gemcadiol believed

is to

metabolically be the

active

level.

REFERENCES 1. T. J. Schaff and E. J. Corey, J_. Org_. Chern., 3]_9 2921 (1972). 2. H. L. Slates, Z. S. Zelawski, D. Taub and N. L. Wendler, Tetrahedron, 30, 819 (1974). 3. M. Miyano and M. A. Stealey, J_. Org. Chem., 40, 1748 (1975). 4. C. J. Sin, R. G. Salomon, P. Price, R. Sood and G. Peruzzotti, J_. Am. Chem. S o c , 97_, 857 (1975); C. J. Sin, J. B. Heather, R. Sood, P. Price, G. Peruzzotti, L. F. Hsu Lee, and S. S. Lee, ibid., 865. 5. G. Stork and T. Takahashi, J[. Am. Chem. S o c , _99_, 1275 (1977). 6. E. W. Yankee, U. Axen, and G. L. Bundy, jj. Am. Chem. Soc., 96s 5865 (1974). 7. E. W. Yankee and G. L. Bundy, JL Am. Chem. S o c , _94, 3651 (1972); G. Bundy, F. Lincoln, N. Nelson, J. Pike, and W. Schneider, Anru _N._Y. Ac ad. Sci., _76» 180 (1971). 8. F. A. Kimball, G. L. Bundy, A. Robert, and J. R. Weeks, Prostagiandins, J 7 , 657 (1979). 9. C. R. Johnson, J. R. Shanklin, and R. A. Kirchoff, ^. Am. Chem. S o c , %_, 6462 (1973). 10. T. K. Schaff, J. S. Bindra, J. F. Eggler, J. J. Plattner, J. A. Nelson, M. R. Johnson, J. W. Constantine, H.-J. Hess, and W. Elger, J_. Med. Chem., 24_, 1353 (1981). 11. R. A. Johnson, F. H. Lincoln, E. G. Nidy, W. P. Schneider, J. L. Thompson, and U. Axen, J_. Am. Chem. S o c , 100, 7690 (1978).

ALICYCLIC AND CYCLIC COMPOUNDS

17

12. D. L. Newton, W. R. Henderson, and M. B. Sporn, Cancer Res., 40, 3413 (1980). 13. C. D. Robeson, J. D. Cawley, L. Weister, M. H. Stern, C. C. Eddinger, and A. J. Chechak, £. Am. Chern. S o c , 77, 41111 (1955). 14. A. H. Lewin, M. G. Whaley, S. R. Parker, F. I. Carroll, and C. G. Moreland, J_. 0r£. Chern., 47_, 1799 (1982). 15. W. Bollag, R. Rueegg, and G. Ryser, Swiss Patent 616,134 (1980); Chem. Abstr., 93, 71312J (1980). 16. W. Bollag, R. Rueegg, and G. Ryser, Swiss Patent 616,135 (1980); Chem. Abstr., 93_, 71314m (1980). 17. U.-H. Dolling, A. W. Douglas, E. J. J. Grabowski, E. F. Schoenewaldt, P. Sohar, and M. Sletzinger, J_. Org. Chem., 43, 1634 (1978). 18. G. Moersch and P. L. Creger, U.S. Patent 3,929,897 (1975); Chem. Abstr., 85, 32426q (1976).

2 Phenethyl and Phenoxypropanolamines The phenylethanolamine derivatives epinephrine (1) and norepinephrine (2) are intimately associated with the sympathetic nervous system. These two neurotransmitter hor-

(1) R = CH 3 (2) R = H (3) R =

(4)

mones control many of the responses of this branch of the involuntary, autonomic nervous system. Many of the familiar responses of the "fight or flight" syndrome such as vasoconstriction, increase in heart rate, and the like are mediated by these molecules. The profound biological effects elicited by these molecules have spurred an enormous amount of synthetic medicinal chemistry a better understanding of the 19

20

PHENETHYL AND PHENOXYPROPANOLAMINES

action of the compounds at the molecular level and aimed also at producing new drugs. The availability of analogues of the natural substances interestingly led to the elucidation of many new pharmacological concepts. In spite of the fact that they differ only by an N-methyl group, the actions of epinephrine and norepinephrine are not quite the same. The former tends to elicit a largely inhibiting effect on most responses whereas the latter in general has a permissive action. These trends were accentuated in the close analogues isoproterenoi (_3) and phenyiephrine (JO. The pharmacology that lead to the division of the sympathetic nervous system into the a- and 3-adrenergic branches was put on firmer footing by the availability of these two agents. It may be mentioned in passing that isoproterenoi is an essentially pure 3-adrenergic agonist whereas phenylephrine acts largely on the a-adrenergic system. The search for new drugs in this series has concentrated quite closely on their action on the lungs, the heart and the vasculature. Medicinal chemists have thus sought sympathomimetic agents that would act exclusively as bronchodilating agents or as pure cardiostimulant drugs. The adventitious discovery that molecules which antagonize the action of $-sympathomimetic agents - the 3-blockers - lower blood pressure has led to a corresponding effort in this field. 1.

PHENYLETHANOLAMINES

As noted above, 3-adrenergic agonists such as epinephrine t y p i c a l l y cause

relaxation

of

smooth muscle.

This

agent

PHENETHYL AND PHENOXYPROPANOLAMINES

21

would thus in theory be useful as a bronchodilator for treatment of asthma; epinephrine itself, however, is too poorly absorbed orally and too rapidly metabolized to be used in therapy. A large number of analogues have been prepared over the years in attempts to overcome these shortcomings. The initial strategy consisted in replacing the methyl group on nitrogen with an alkyl group more resistant to metabolic N-dealkylation. Isoproterenoi {3) is thus one of the standbys as a drug for treatment of asthma. The tertiary butyl analogue, coiteroi (9) is similarly resistant to metabolic inactivation. (It might be noted that there is some evidence that these more lipophilic alkyl groups, besides providing resistance to inactivation, also result in higher intrinsic activity by providing a better drug receptor interaction.) This drug can in principle be prepared by the scheme typical for phenylethanolamines. Thus acylation of catechol by means of Friedel-Crafts reaction with acetyl chloride affords the ketone 6; this is then halogenated to give intermediate ]_. Displacement of bromine by means of tertiary butyl amine gives the aminoketone J3. Reduction of the carbonyl group by catalytic hydrogenation affords colteroi (9).

(5)

(6) X = II (7) X = Br

CHCH2NHC (CH3) 3

(8)

22

PHENETHYL AND PHENOXYPROPANOLAMINES

Absorption of organic compounds from the gastrointestinal tract is a highly complex process which involves at one one stage passage through a lipid membrane. Drugs that are highly hydrophilic thus tend to be absorbed yery inefficiently by reason of their preferential partition into aqueous media. One strategy to overcome this unfavorable distribution consists in preparing a derivative that is more hydrophobic and which will revert to the parent drug on exposure to metabolizing enzymes after absorption. Such derivatives, often called prodrugs, have been investigated at some length in order to improve the absorption characteristics of the very hydrophilic catecholamines. Acylation of aminoketone £ with the acid chloride from p-toluic acid affords the corresponding ester UCO; catalytic hydrogenation leads to the bronchodilator bitolerol Ul)*. An analogous scheme starting from the N-methyl ketone (JL2) and pivaloyl chloride gives aminoalcohol (14). This compound is then resolved to isolate the levorotatory isomer^. There is thus obtained the drug dipivefrin. 0 2 II R CO

0

0

(8) R 1 = t - B u

(10) R1 = t - B u ;

R 2 = p-CH 3 C 6 II 4

(12) R 1 = CII 3

(13) R 1 = CII 3 ; R 2 = t - B u

(11) R 1 = t - B u ;

R 2 = p-CH

(14) R 1 = CH 3 ; R 2 = t - B u

PHENETHYL AND PHENOXYPROPANOLAMINES

23

A variant on this theme contains mixed acyl groups. In the absence of a specific reference it may be speculated that the synthesis starts with the diacetyl derivative (15). Controlled hydrolysis would probably give the monoacetate U 6 ) since the ester para to the ketone should be activated by that carbonyl function. Acylation with anisoyl chloride followed by reduction would then afford nisobuterol (18).

.CCH 2 NHC(CH 3 ) 3

05)

0 0 CH 3 CO v^ e ^ccii 2 Nnc(ai 3 ) 3

(16)

O cn3c

(17)X = 0 (18) X = II, OH

Catecholamines are also intimately involved in cardiac function, with ^-sympathetic agonists having a generally stimulant action on the heart. Some effort has thus been devoted to the synthesis of agents that would act selectively on the heart. (Very roughly speaking, 3 -adrenergic receptor agonists tend to act on the heart while $ --adrenergic receptor agonists act on the lungs; much the same holds true for antagonists; see below.) Preparation of the cardiotonic agent butopamine (23) starts with reductive ami nation of ketone Jjh Acylation of the resulting amide (_20) with hydroxyacid 2A_ affords the corresponding amine (22_). Treatment with lithium aluminum hydride serves both to reduce the amide and remove the acetyl protecting groups. There is thus obtained 3 butopamine .

24

PHENETHYL AND PHENOXYPROPANOLAMINES

(19)

)-V^ yui y-ClL CIU Clt N IC CH^ CH-Y y-(X:GI_3 NUJC 2cn 2cn \ / Z 2 i CI O iH\^~"^ / r> (22)

(20)

(21)

*- IK)-V ^ yy-O[ i 2CcI-V ^ V y-C 2 ao(3l 2,aiNH GL, \ / L IQ\ * ZO•il \ /

Drugs that block the action of a-adrenergic activation effectively lower blood pressure by opposing the vasoconstricting effects of norepinephrine. Drawbacks of these agents, which include acceleration of heart rate, orthostatic hypotension and fluid retention, were at one time considered to be due to the extension of the pharmacology of a-blockers. Incorporation of 3-blocking activity into the molecule should oppose these effects. This strategy seemed particularly promising in view of the fact that 3-adrenergic blockers were adventitiously found lower blood pressure in their own right. The first such combined a- and 3-blocker, labetoiol has confirmed this strategy and proved to be a clinically useful antihypertensive agent. The drugs in this class share the phenylethanolamine moiety and a catechol surrogate in which the 3-hydroxyl is replaced by some other function that contains relatively acidic protons.

PHENETHYL AND PHENOXYPROPANOLAMINES

25

Synthesis of the prototype4 begins with Friedel Crafts acetylation of salicylamide (24). Bromination of the ketone (25) followed by displacement with amine ZJ_ gives the corresponding aminoketone (28). Catalytic hydrogenation to the aminoalcohol completes the synthesis of labetolol (24). The presence of two chiral centers at remote positions leads to the two diastereomers being obtained in essentially equal amounts.

Q II

H29NC !| 0 (24)

ILNC 2 II 0 (25) X = II (26) X = Br

11~ N IL 11.LJ IT U U -*v V=/

y

Q Q] / ^ II I 3 ILNC 2

(27)

II 0

(28)

° (30) NCii c n 2 c n 2 - v

V~ o X

H2NC 0

O-^

H2NC °

(31) X = 0 (32) X = II, CHI

(29)

In much the same vein, alkylation of bromoketone (26) with amine [30) (obtained by reductive ami nation of the corresponding ketone) affords aminoketone (21). Catalytic reduction leads to medroxaiol (32) , The methyl group on a sulfoxide interestingly proves sufficiently acidic to substitute for phenolic hydroxyl. The preparation of this combined a- and 3-blocker, suifinalol6, begins by protection of the phenolic hydroxyl as its benzoate ester (34). Bromination (35) followed by

26

PHENETHYL AND PHENOXYPROPANOLAMINES

condensation with amine j36^ gives the aminoketone (37). Successive catalytic reduction and saponification affords the aminoalcohol (j$8h Oxidation of the sulfide to he sulfoxide with a reagent such as metaperiodate gives suifinaioi (39). This last step introduces a third chiral center because trigonal sulfur exists in antipodal forms. The number of diastereomers is thus increased to eight. cciipc

(33)

(34) X = H (35) X = Br

ai

3° \ 7~CH2CH2CHNH2

W

\

/

OT1 N

2

(36)

(38) Y -- (39) Y = 0 A phenylethanolamine in which the nitrogen is alkylated by a long chain alphatic group departs in activity from the prototypes. This agent, suloctidil (43) is described as a peripheral vasodilator endowed with platelet antiaggregatory activity. As with the more classical compounds, preparation proceeds through bromination of the substituted propiophenone (40) and displacement of halogen with octylamine. Reduction, in this case by means of sodium borohydride affords suloctidil (43) 7 . 0 \-CCHX CH3 (40) X = H (41) X = Br

2CHS-^

** (ffl3)2C

W

CH3 (42) Y = 0 (43) Y = H, OH

PHENETHYL AND PHENOXYPROPANOLAMINES

27

Pharmacological theory would predict that 3-adrenergic blockers should oppose the vasodilating action of epinephrine and, in consequence, increase blood pressure. It was found, however, that these drugs in fact actually decrease blood pressure in hypertensive individuals, by some as yet undefined mechanism. The fact that this class of drugs tends to be very well tolerated has led to enormous emphasis on the synthesis of novel 3-blockers. The observation that early analogues tended to exacerbate asthma by their blockade of endogenous 3-agonists has led to the search for compounds that show a preference for 3-adrenergic sites. With some important exceptions, drugs in this class are conceptually related to the phenylethanolamines by the interposition of an oxymethylene group between the aromatic ring and the benzyl alcohol.

A 0 3

ArC)(;iI2ClICl2

?'

+• ArOT^CHCI^N R ll

ArOQLCH - U L Q

(44)

Compounds are prepared by a fairly standard sequence which consists of condensation of an appropriate phenol with epichlorohydrin in the presence of base. Attack of phenoxide can proceed by means of displacement of chlorine to give epoxide (45) directly. Alternatively, opening of the epoxide leads to anion 44; this last, then, displaces halogen on the adjacent carbon to lead to the same epoxide. Reaction of the epoxide with the appropriate amine then completes the synthesis.

28

PHENETHYL AND PHENOXYPROPANOLAMINES Application of this scheme to o-cyclopentyl phenol, _o-

cyclohexylphenol penbutoiol

and m~cresol 8

(47) , exapralol

thus leads to (48)

9

respectively,

and bevantolol

(49)

10

.

The phenoxypanolamine t i p r o p i d i l (52) interestingly exhibits much the same biological a c t i v i t y as i t s phenylethanolamine parent s u l o c t i d i l (53).

0 (47)

O(48) cx:ii3 a i3 c NIi -^ y- o cn2 a o i2 N (50)

(49)

H0yC O ,aiC NH aiQ -IaLCH INO Ia(IL ,-)3aL (w K Im\S Y --/O IC L INH C U I, ,1 7)L O ,.^ IL I \-V / IyO 3CL LCL L-L LHC I, 1(C (51) (53) The phenol (55) required for preparation of diacetolol ^£^

can be otained

p-acetamidophenol. (5])^

by Friedel-Crafts

acetylation

of

The starting material (58) for pamatolol

can be derived from p-hydroxyphenylacetonitrile (56)

by reduction to the amine (ET7) followed by treatment with ethyl chloroformate.

Bucindoiol

3-blockers

to

designed

(52) is one of the newer

incorporate

non-adrenergically

mediated vasodilating a c t i v i t y in the same molecule as the adrenergic blocker.

Preparation

of the amine (61) for this

PHENETHYL AND PHENOXYPROPANOLAMINES

29

agent starts by displacement of the dimethyl ami no group in grandne (!59J by the anion from 2-nitropropane. Reduction of the nitro group leads to the requisite intermediate13.

CS . 2)

8 ^ ^

8 (55)

Synthesis of primidolol (65)^ can be carried out by a convergent scheme. One branch consists in application of the usual scheme to o-cresol (J52); ring opening of the intermediate oxirane with ammonia leads to the primary amine (63). The side chain fragment (64) can be prepared by alkylation of pyrimidone (63) with ethylene dibromide to afford J54. Alkylation of aminoalcohol 6^ with halide 64^ affords primidolol. ^ (56)

H2 NCH2 CH2 -jf (57)

V

OH

^ (58)

30

PHENETHYL AND PHEN0XYPROPANOLAMINES

(59)

OH

(60)

*

- / \->0CH2ClOl2NH2 (62)

O*(S=:^M\ (63)

(61)

\ • ^ V-OCII9aOI?NlCH?CH? N )=O

^ o^~\aii2ai2Br (64)

It is by now well accepted that most drugs, particularly those whose structures bear some relation to endogenous agonists owe their effects to interaction with biopolymer receptors. Since the latter are constructed from chiral subunits (amino acids, sugars, etc.), it should not be surprising to note that drugs too show stereoselectivity in their activity. That is, one antipode is almost invariably more potent than the other. In the case of the adrenergic agonists and antagonists, activity is generally associated with the R_ isomer. Though the drugs are, as a rule, used as racemates, occasional entities consist of single enantiomers. Sereospecific synthesis is, of course, preferred to resolution since it does not entail discarding half the product at the end of the scheme. Prenalterol (73) interestingly exhibits adrenergic agonist activity in spite of an interposed oxymethylene group. The stereospecific synthesis devised for this 15 molecule relies on the fact that the side chain is very

PHENETHYL AND PHENOXYPROPANOLAMINES

31

similar in oxidation state to that of a sugar. Condensation of the monobenzyl ether of phenol ^6_ with the epoxide derived from JD-glucofuranose 057) affords the glycosylated derivative 058)• Hydrolytic removal of the protecting groups followed by cleavage of the sugar with periodate gives aldehyde 69. This is in turn reduced to the glycol by means of sodium borohydride and the terminal alcohol is converted to the mesylate (7JJ. Displacement of that group with isopropylamine (72) followed by hydrogenolytic removal of the 0-benzyl ether affords the 3 - selective adrenergic agonist prenalteroi (73).

-fO (66)

OH

^.0

Oil

(67)

OHCQOi 2 o -ff

\ - cx:iI 2 C 6 H 5

>- Rocn 2 aiai 2 o - ^

(69)

CCH3)2CHNHai2CICH2O -(/

(68)

y-oai2c6H5

(70) R = II (71) R = QSO2CH3

J~ CR

(72) R = CH (73) R = H

Formal cyclization of the hydroxyl and amine functions to form a morpholine interestingly changes biological act-

32

PHENETHYL AND PHENOXYPROPANOLAMINES

ivity markedly; the resulting compound shows CNS activity as an antidepressant rather than as an adrenegic agent. Reaction of epoxide (7^) with the mesylate from ethanolamine leads to viloxazine (76) in a single step . It is likely that reaction is initiated by opening of the oxirane by the ami no group. Internal displacement of the leaving group by the resulting alkoxide forms the morpholine ring.

A

2 ociucn a i.i

\ _ y

i

0

00-

(74)

(7b)

\ / •n 2 e n 'OC2H5

i al

2

NU

(7 5)

The widely used tricyclic antidepressant drugs such as imipramine and ami triptypti line have in common a series of side effects that limit their safety. There has thus occasioned a wide search for agents that differ in structure and act by some other mechanism. Nisoxetine and fluoxetine are two nontricyclic compounds which have shown promising early results as antidepressants. Mannich reaction on acetophenone leads to the corresponding aminoketone (78). Reduction of the carbonyl group (_79) followed by replacement of the hydroxyl by chlorine gives intermediate 80. Displacement of chlorine with the alkoxide from the monomethyl ether of catechol gives the corresponding aryl

PHENETHYL AND PHENOXYPROPANOLAMINES

33

ether (jUJ. The amine is then dealkylated to the monomethyl derivative by the von Braun sequence (cyanogen bromide followed by base) to give nisoxetine (82). Displacement on (80) with the monotrifluoromethyl ether from hydroquinone followed by demethylation leads to fluoxetine (84) .

CH2CH2N(CH3)2

(77)

(78) V V-CHCH-, CHO N(CH,)o V=/

i

2

2

3 2

(81) R1 « OQi3; R2 = I (83) R1 » l\'r R2 = OCF3

»

w

|

X (79) X = OH (80) X = Cl *~ y ^CHCHOCILNH CIL \=/

i

2

2

(82) R1 = OCH3; R2 = H (84) R1 = H; R2 = OCI3'

3

34

PHENETHYL AND PHENOXYPROPANOLAMINES REFERENCES

1.

M. Minatoya B, F. Tullar and W. D. Conway, U.S. Patent 3,904,671; Chem. Abstr. 814, 16943e (1976), 2. A. Hussain and J. E. Truelove, German Offen. 2,343,657; Chem. Abstr. jBO, 145839s (1974). 3. J. Mills, K. K. Schmiegel and R. R. Tuttle, Eur. Patent Appl. 7,205 (1980); Chem. Abstr. 93, 94972 (1980). 4. L. H. C. Lunts and D. T. Collin, German Offen. 2,032,642; Chem. Abstr. 75, 5520c (1971). 5. J. T. Suh and T. M. Bare, U.S. Patent 3,883,560; Chem. Abstr. 83, 78914J (1975). 6. Anon. British Patent 1,544,872; Chem. Abstr. 92, 163686s (1980). 7. G. Lambelin, J. Roba, and C. Gi1 let, German Offen. 2,344,404; Chem. Abstr. 83, 97820 (1975). 8. G. Haertfelder, H. Lessenich and K. Schmitt, Arzneim. Forsch. 22, 930 (1972). 9. M. Carissimi, P. Gentili, E. Grumelli, E. Milla, G. Picciola and F. Ravenna, Arzneim. Forsch. 26, 506 (1976). 10. M. Ikezaki, K, Irie, T. Nagao, and K. Yamashita, Japanese Patent 77, 00234; Chem. Abstr. 86, 1894767 (1977). 11. K. R. H. Wooldridge and B. Berkley, South African Patent 68 03,130; Chem. Abstr. 70, 114824 (1969). 12. A. E. Brandstrom, P. A. E. Carlsson, H. R. Corrodi, L. Ek and B. A. H. Ablad, U.S. Patent 3,928,601; Chem. Abstr. 85, 5355J (1976).

PHENETHYL AND PHENOXYPROPANOLAMINES

35

13. W. E. Kreighbaum, W. L. Matier, R. D. Dennis, J. L. Minielli, D. Deitchman, J. L. Perhach, Jr. and W. T. Comer, £• Med. Chem., 23, 285 (1980). 14. J. Augstein, D. A. Cox and A. L. Ham., German Offen. 2,238,504 (1973). Chem. Abstr. jte, 136325e (1973). 15. K. A. Jaeggi, H. Schroeter, and F. Ostermayer, German Offen. 2,503,968; Chem. Abstr. 84, 5322 (1976). 16. S. A. Lee, British Patent 1,260,886; Chem. Abstr. 7<5, 99684e (1972). 17. B. B. Molloy and K. K. Schmiegel, German Offen. 2,500,110; Chem. Abstr. 83, 192809d (1975).

3 Arylaliphatic Compounds The aromatic portion of the molecules discussed in this chapter is frequently, if not always, an essential contributor to the intensity of their pharmacological action. It is, however, usually the aliphatic portion that determines the nature of l.hat action. Thus it is a common observation in the practice of medicinal chemistry that optimization of potency in these drug classes requires careful attention to the correct spatial orientation of the functional groups, their overall electronic densities, and the contribution that they make to the molecule's solubility in biological fluids. These factors are most conveniently adjusted by altering the substituents on the aromatic ring. 1. ARYLACETIC ACID DERIVATIVES [he potent antiinflammatory action exerted by many arylacetic ricid derivatives has led to the continued exploration of this class. It is apparent from a consideration of the structures of compounds that have become prominent that considerable structural latitude is possible without loss of activity. The synthesis of fendofenac (J5), a nonsteroidal antiinflammatory agent (NSAI), starts with condensation of o-chloro37

ARYLALIPHATIC COMPOUNDS

38 acetophenone (1) and 2,4-dichlorophenol ditions

(Cu/NaOH).

The unsymmetrical

j e c t e d t o the Wi11gerodt-Kindler

(2)

under Ullmann con-

diarylether

(_3) i s sub-

reaction to give thioamide _4,

This l a s t i s saponified t o produce fenclofenac (J5) • l

* :o' (1)

C O L C I Cl N \/0 (4)

(2)

(8J

A structure more distantly related to these is amfenac (10). Like most of the others, amfenac, frequently used after tooth extraction, is an antiinflammatory agent by virtue o) 2 c 2 n

(11) R = (12) R = COCH, (13) R = CCl=ai.

(15)

ArC= CCH

ArCH=C =

HO

AKYLALIPHATIC COMPOUNDS of i n h i b i t i o n staglandin (7)

39

of the cyclooxygenase enzyme e s s e n t i a l

biosynthesis.

formation

between

The synthesis

phenylacetone

(f>) by warming in a c e t i c a c i d . in a Fischer

indole

begins with

and

pro-

hydrazone

1-aminoindolin-2-one

Treatment with HCl/EtOH r e s u l t s

rearrangement

produces unsymmetrical

for

to

produce

<8.

Ozonolysis

d i a r y l k e t o n e 9_ which i s converted t o an

intermediate i n d o l i n - 2 - o n e

by cleavage of the ester

and acet-

amide moieties w i t h HC1 and then lactam h y d r o l y s i s w i t h NaOH t o <jive amfenac (10) , 2 A closet

member of t h i s

little

group, r e v e l a t i o n of whose

roal nature requires metabolic t r a n s f o r m a t i o n linkage

to

synthesis phenyl

an a c e t i c begins

by

acid

moiety,

Friedel-Crafts

is

of an a c e t y l e n i c

fluretofen

acylation

of

(JLJJ w i t h acetic acid t o give ketone JL2!.

PCI 5/POCl 3

then

produces

Dohydrohalogenation acetylene,

with

fluretofen

the strong

(14).

(14).

The

2-fluorobiHeating with

a-chlorostyrene

analogue

13. the

base

(NaNH2)

produces

Metabolic

studies

reveal

b y c o n v e r s i o n t o the a r y l a c e t i c acid analogue JL_5.

facile

This is an

active antiinflammatory agent when administered d i r e c t l y and so is believed t o account f o r the a c t i v i t y of f l u r e t o f e n .

A like-

ly pathway f o r t h i s

oxygen-

transformation

involves

terminal

2(

t

Cl (17)

a

N

(18)

(19)

(20)

40

ARYLALIPHATIC COMPOUNDS

a t i o n of the a c e t y l e n i c moiety, which product would then t a u t o merize

to

the

ketene.

Spontaneous

would complete the sequence.

hydration

of

the

latter

3

Phenylacetamides have a v a r i e t y of pharmacological

actions

depending upon the nature of the amine-derived component. Guanfacine central

(17),

a-adrenergic

only once d a i l y

an a n t i h y p e r t e n s i v e receptor a g o n i s t ,

and r e p o r t e d l y

requires

by ester-amide

exchange

acetate (_16) using g u a n i d i n e . Use of ^

n

a

a large,

1idocaine

arrhythmic Schiff's

local

of

methyl

is

than

prepared

2,6-dichlorophenyl

nitrogenous

(20).

component

type

Synthesis

results

cardiac

anti-

begins with

the

base (JL8) derived by reaction of p - c h l o r o - a n i l ine and

borohydride

followed

by

acylation

produces amide _19. . S e l e c t i v e alkylation

with

of l o r c a i n i d e

isopropyl

confining,

with

hydrolysis bromide

phenylacetyl with

completes

chloride

HBr followed the

by

synthesis

(2(3). 5

The s t r u c t u r a l of

administration

Guanfacine

anesthetic

lorcainide

as a

4

lipophilic

like,

drug,

acting

has fewer CNS s i d e e f f e c t s

the somewhat r e l a t e d drug, c l o n i d i n e . readily

agent

requirements for such a c t i v i t y are not very

as can be seen in

lorcainide

with

oxiramide

part (21).

by comparing the

structure

Antiarrhythmic

oxiramide

(21) i s made by a s t r a i g h t f o r w a r d ester-amide exchange reaction

CCLCJIr +

ii2NQi2ai2ai2ai2N

(21)

ARYLALIPHATIC COMPOUNDS

41

i n v o l v i n g ethyl 2-phenoxyphenylacetate and 4 - c i s - ( 2 , 6 ~ d i m e t h y l -

piperidino)butylamine. 6 Introducing yet more structural complexity into the amine component leads to the antiarrhythmic agent disobutamide (24). Disobutamide is structurally related to disopyramide (2b)7 but is faster and longer acting.

The synthesis of 2A_ begins with

sodamide induced alkylation of 2-chlorophenylacetonitrile /'-dii sopropyl ami noethy 1 chloride to give 22. mediated

alkylation,

this

(.hloride, gives n i t r i l e ^ .

time

with

A second sodamide

2-(l-piperidino)ethyl

Subsequent sulfuric acid hydration

completes the synthesis of disobutamide (24). 8

Cl ^QLCN

o

(22)

o 2(4)

(23)

(25) c

CU — CO- QLCIL N 1 1 1

(26) X = Oil (27) X = H

(28)

C0J1

(29)

with

(30) X = 0; R = H (31) X = H 2 ; R = CH2CH2C1

(32)

42

ARYLALIPHATIC COMPOUNDS

The

treacheries

inherent

in

naive

attempts

at

pattern

r e c o g n i t i o n are i l l u s t r a t e d by the f i n d i n g t h a t ester 2^8, known as

cetiedil»

sen reduction

i s said t o be a peripheral of

benzylic hydroxyl of

the

resulting

Grignard

product

vasodilator.

2i6 removes the

group and e s t e r i f i c a t i o n acid

{Z7J

with

Clemmensuperfluous

of the sodium

salt

2~(l-cycloheptylamino)ethyl

(28).9

c h l o r i d e produces c e t i e d i l

(34)

An intresting biphenyl derivative u t i l i z i n g a bioisosteric replacement for a carboxyl nufenoxole (34).

group is the antidiarrheal

agent,

To get around addictive and analgesic side

effects associated with the classical morphine based antidiarrheal agents, a different class of drug was sought. has few analgesic, anticholinergic,

or central

Nufenoxole

effects.

Re-

duction with a ruthenium catalyst

(to prevent hydrogenolysis)

converts

cyclohexane

£-aminobenzoic

acid

to

derivative _29^

Internal J^-acetylation of the cis isomer followed by heating gives bicyclic lactam 3Q_. Hydride reduction to the isoquineuclidine and alkylation gives 2-azabicyclo[2.2.2]octane synthon 31.

This is used to alkylate diphenylacetonitrile to give 32.

Cycloadditioh of sodium azide (ammonium chloride and DMF) gives the normal carboxyl bioisosteric tetrazolyl

analogue 2 1 *

The

synthesis of antidiarrheal nufenoxole is completed by heating

ARYLALIPHATIC

43

COMPOUNDS

©> 8 RC-N=N-CCH~

C \NSN

©

(35)

N—N // \\

(37)

(36)

C0C1 on I (39)

(38)

(40)

with acetic anhydride to give the 2-methyl-l,3,4~oxadiazol-5-yl analogue. 1 0 ' 1 1 believed to

The

mechanism

of

involve J^-acetylation

this

rearrangement

{3$) with subsequent

is ring

opening to the diazoalkane (3^6) which loses nitrogen to give carbene ^7., which cyclizes to the oxadiazole ( 3 8 ) . 1 2

I

CN (41)

Cl

(48)

(46) X = NII 2

(42) X = OH ( 4 3 ) X = Cl

( 4 7 ) X = OH

5 ?H, (44) X = N2HC (45) X • NH n

O

A phenylacetonitrile anthelmintic patented

agent useful

synthesis

derivative, against

involves

a

closantel

sheep l i v e r

(41) 9 flukes.

Schotten-Baumann

is an Its

amidation

44

ARYLALIPHATIC COMPOUNDS

between

acid

closantel

chloride

(41.).

A cinnamoylamide, convulsant

_39_ and

complex

aniline

4^

to

give

is a l o n g - a c t i n g

anti-

13

similar

cinromide

in

its

but is less h e p a t o t o x i c .

(44),

clinical

effects

to

phenacetamide

The synthesis involves the

straight-

forward amidation of acid _4£ v i a the intermediate acid c h l o r i d e (SOC12) A l *

^

appears t h a t the drug is mainly deethylated vr^

v i v o t o give a c t i v e amide 45. 11+

(49) R = 11 (50) R = C(ai3)2(X)2II

2,2-Disubstituted

(51) R - Br (52) R * C(C11^)2CO2II

aryloxyacetic

acid derivatives

related

to clofibrate have been intensively studied in an attempt to get around the side effects of the l a t t e r drug. Ciprofibrate th

an

(48),

a more potent

1ipid-lowering

agent

c l o f i b r a t e , is prepared from Simmons-Smith product $6_ by

Sandmeyer replacement of the ami no group by a hydroxyl via the diazonium s a l t .

Phenol j47^ undergoes the Reimer-Thiemann l i k e

process common to these agents upon alkaline treatment

with

acetone and chloroform to complete the synthesis of c i p r o f i b rate ( 4 8 ) . 1 5 Further

indication

that

substantial

bulk

tolerance

is

available in the para position is given by the l i p i d lowering agent

bezafibrate

(50).

The £-chlorobenzamide

of

tyramine

(49) undergoes a Williamson ether synthesis with ethyl 2-bromo-

ARYLALIPHATIC COMPOUNDS

45

/-methylpropionate to complete the s y n t h e s i s .

The ester

is hydrolyzed in the a l k a l i n e reaction medium. Apparently a s u b s t a n t i a l the aromatic

spacer is also allowable

r i n g and the carboxy group.

between

Gemfibrozil

(52), a

h y p o t r i g l y c e r i d e m i c agent which decreases the i n f l u x of into the l i v e r ,

is a c l o f i b r a t e homologue.

It

group

16

steroid

is made r e a d i l y

by l i t h i u m diisopropylami de-promoted a l k y l a t i o n of sodium i s o propionate w i t h a l k y l bromide 51 . 1 7 A rather d i s t a n t l y carbonyl

moiety

r e l a t e d analogue

as a b i o i s o s t e r i c

incorporating a 3 - d i -

replacement

for

a carboxyl,

a r i l done ( 5 5 ) , blocks the uncoating of p o l i o v i r u s simplex v i r u s

type I and thus

the early stages of v i r u s would

require

careful

inhibits

replication.

timing

as

it

infection

and herpes

of c e l l s

Thus e f f e c t i v e does

A l k y l a t i o n of phenol j>3_ w i t h 1,6-dibromohexane

with

and

therapy

amantidine.

gives

haloether 0

HOA^

CISO^^CJ

(53)

ai,o-^^ci

(54)

on

(55) N11CII3

CN

J *>4.

I^

(56)

(57)

Finkelstein reaction with sodium iodide is followed by

acylation of heptane-3,5-dione to complete the synthesis

of

arildone

2. ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an antiarrhythmic agent is meobentine (57). Its patented synthesis starts with £-hydroxyphenylnitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to 56. Alkylation of _S-methyl-_NJV-dimethylthiourea with 5^ completes the synthesis of meobentine (57). 1 9

46

ARYLALIPHATIC COMPOUNDS

/CI13 NCH2 CHCH2 OCH2CW

G

„

r \ i >v,NQI2QI QL OCH2 Cll

(58)

Bepridil

(59)

(59) blocks the slow calcium channel and serves

as an antianginal agent and a vasodilator. alcohol 5>8_ (derived from epichlorohydrin)

In i t s synthesis, is converted to the

corresponding chloride with thionyl chloride and displaced with the sodium salt of N-benzylaniline to give bepridil (59) 2 0

Nx

C60)

cai2)6ai3

(61)

A number of quaternary amines are effective at modulating nerve transmissions. relatively

They often have the disadvantage of being

nonselective and so possess numerous

sideeffects.

This contrasts with the advantage that they do not cross the blood-brain barrier and so have no central sideeffects.

Clo-

f i l i u m phosphate (63) is such an antiarrhythmic agent.

I t is

synthesized from ester ^

by saponification followed by Clem-

mensen reduction and amide formation (oxalyl chloride followed by n-heptylamine) to give 6K ary amine ^ .

Diborane reduction gives second-

Reaction with acetyl chloride followed by anoth-

er diborane reduction gives the t e r t i a r y amine.

F i n a l l y , re-

action with ethyl bromide and ion exchange with phosphate complete the synthesis of c l o f i l i u m phosphate ( 6 3 ) . 2 1

ARYLALIPHATIC COMPOUNDS

47

(CH 2 ) 4 NH(CH 2 ) 6 CH 3

(62)

(63)

Another quaternary a n t i a r r h y t h m i c ate

(65).

It

rn-methoxybenzyl

is

synthesized

chloride

simply

agent by

is emilium t o s y l quaternization

(_64) w i t h dimethylethylamine

of

followed

by ion exchange. 2 2

,CH 2 NC^Ilj-

fO4)

(65)

(6b)

3. DIARYLMETHANE ANALOGUES Prenylamine (66) was long used in the treatment of angina pectoris, in which condition it was believed to act by inhibiting the uptake and storage of catecholamines in heart tissue. Droprenilami ne (69), an analogue in which the phenyl ring is reduced, acts as a coronary vasodilator. One of several syntheses involves simple reductive alkylation of 1,1-diphenylpropylamine (ji7_) with cyclohexylacetone (68) ,23 Drobuline (71) is a somewhat related cardiac-directed drug with antiarrhythmic action. Since both enantiomers have the

ARYLALIPHATIC COMPOUNDS

48

same a c t i v i t y , i t is l i k e l y that i t s pharmacological action i s due to a local a n e s t h e t i c - l i k e a c t i o n .

I t is synthesized by

sodium amide mediated a l k y l a t i o n of diphenylmethane with a l l y l bromide to give TQ. Epoxidation with im-chloroperbenzoic

acid

followed by opening of the oxirane ring at the least hindered carbon by isopropylamine completes the s y n t h e s i s . l h

(67)

"3

(71)

(70)

A slightly more complex antiarrhythmic agent is pirmentol (74). I t is synthesized from 4-chloropropiophenone (72) by keto group protection as the dioxolane (with ethylene glycol and acid) followed by sodium iodide-mediated alkylation with cis 2,6-dimethylpiperidine to give 7^. Deblocking with acid followed by addition of 2-1ithiopyridine completes the synthesis of pi rmentol (74)%25

0 (72)

(73)

(74)

ARYLALIPHATIC COMPOUNDS

49

For many years a f t e r

activity

of

the discovery

phenothiazine,

almost

centered about rigid analogues.

of the

all

antidepressant

synthetic

activity

Recently attention has been

paid to less r i g i d molecules in part because of the finding that zimelidine inhibition

(77)

is

an antidepressant

of the central

showing

selective

uptake of 5-hydroxytryptamine and

that i t

possesses less anticholinergic a c t i v i t y than amitrip-

tylene.

One of a number of syntheses starts with £-bromoaceto-

phenone and a Mannich reaction (formaldehyde and dimethylamine) to give aminoketone 75_, Reaction with 3 - l i t h i o - p y r i d i n e gives tertiary carbinol 76.*

Dehydration with sulfuric acid gives a

mixture of !_ and £ forms of which the Z. analogue is the more active.26

(75)

Pridefine depressant. agent.

(80)

(76)

is a somewhat structurally

related a n t i -

I t is a centrally active neurotransmitter blocking

I t blocks norepinephrine in the hypothalamus but does

not affect dopamine or 5-hydroxytryptamine.

Its synthesis be-

gins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78.* in

the

Lithium

presence of

ethylamine

aluminum hydride

of pridefine ( 8 0 ) .

27

gives

reduction

Heating

N-ethylsuccinimide

completes

the

79.

synthesis

50

ARYLALIPHATIC COMPOUNDS

6

co?n

0

(78)

(79)

(80)

4. STILBENE ANALOGUES Cells from tissues associated with primary and secondary sexual characteristics are under particular endocrine control. Sex hormones determinethe growth, differentiation, and proliferation of such cells. When a tumor develops in such tissues, it is sometimes hormone dependent and the use of antihormones removes the impetus for the tumor's headlong growth. Many nonsteroidal compounds have estrogenic activity; diethylstilbestirol (81) may be taken as an example. Certain more bulky an-

(81)

(83)

(82)

(84)

OCH 3

(85)

CFLO

ARYLALIPHATIC COMPOUNDS

51

alogues are antagonists at the estrogenic receptor level and exert a second order anti-tumor response. Nitromifene (85) is such an agent. A Grignard reaction of arylether 82 and ketone 83 leads to tertiary carbinol 84. Tosic acid dehydration leads to a mixture of 1_ and E_ stilbenes which constitute the antiestrogen, nitromifene (85), 2 8 Another example is tamoxifen (89). Its synthesis begins with Grignard addition of reagent ^6 to aryl ketone J37_ giving carbinol 8<3. Dehydration leads to the readily separable 1_ and E_ analogues of _89_. Interestingly, in rats the 1_ form is an antiestrogen whereas the £ form is estrogenic. Metabolism involves £-hydroxylation and this metabolite (_90) is more potent than tamoxifen itself. In fact, metabolite 9^ may be the active form of tamoxifen (89). 2 9

MgBr (86)

(87)

(89) X = II (90) X = OH

f88)

52

1.

2.

3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

ARYLALIPHATIC COMPOUNDS REFERENCES D. C. Atkinson, K. E. Godfrey, B. J. Jordan, E. C. Leach, B. Meek, J. D. Nichols, and J. F. Saville, J_. Pharm. Pharmacol,, 26, 357 (1974). W. J. Welstead, Jr., H. W. Moran, H. F. Stauffer, L. B. Turnbull, and L. F. Sancillo, J_. Me^. Chem., 22_, 1074 (1979). W. B. Lacefield and W. S. Marshall, U.S. Patent 3,928,604; H. R. Sullivan, P. Roffey, and R. E. McMahon, Drug Metab. Disposn., I, 76 (1979). J. B. Bream, H. Lauener, C. W. Picard, G. Scholtysik, and T. G. White, Arzneim. Forsch., _25, 1477 (1975). H. K. F. Hermans and S. Sanczuk, U.S. Patent 4,197,303 (1975); Chem. Abstr., _93, 132380d (1980). Anon., Netherlands Patent, 6,605,452 (1962); Chem. Abstr., 6£, 104914e (1967). D. Lednicer and L. A. Mitscher, The Organic Chemistry erf Drug Synthesis, Vol. 2, Wiley, New York, 1980, p. 81. P. K. Youan, R. L. Novotney, C. M. Woo, K. A. Prodan, and F. M. Herschenson, J_. Med. Chem., ,23, 1102 (1980). M. Robba and Y. LeGuen, Eu£. J_. Med_. Chem., 2,, 120 (1967). G. W. Adelstein, C. H. Yen, E. Z. Dajani, and R. G. Biandi, J_. Med^. Chem., J^, 1221 (1976). W. Schneider and R. Dillman, Chem. Ber., 96, 2377 (1963). R. Huisgen, J. Sauer, H. J. Sturm, and J. H. Markgraf, Chem. Ber., 9[3, 2106 (1960). M. A. C. Janssen and V. K. Sipido, German Offen., 2,610,837 (1976); Chem. Abstr., 86, 55186w (1977). E. M. Grivsky, German Offen., 2,535,599 (1976); Chem. Abstr., 84, 164492x (1976). D. K. Phillips, German Offen., 2,343,606 (1974); Chem.

ARYLALIPHATIC COMPOUNDS

16.

17. 18.

19. 20.

?l. ?Z. P3. ?^. ?5. ?6.

71.

53

Abstr, 80, 133048v (1974). E. C. Witte, K. Stach, M. Thiel, F. Schmidt, and H. Stork, German Offen., 2,149,070 (1973); Chem. Abstr., 79_, 18434k (1973). P. L. Creger, G. W. Moersch, and W. A. Neuklis, Proc. R_. Soc. Med., 69, 3 (1976). G. D. Diana, U. J. Salvador, E. S. Zalay, P. M. Carabateas, G. L. Williams, J. C. Collins, and F. Pancic, J_. Med_. Chem., 20, 757 (1977). R. A. Maxwell and E. Walton, German Offen., 2,030,693 (1971); Chem. Abstr., 74., 87660q (1971). R. Y. Mauvernay, N. Busch, J. Simond, A. Monteil, and J. Moleyre, German Offen., 2,310,918 (1973); Chem. Abstr., 79i, 136777X (1973). B. B. Molloy and M. I. Steinberg, Eur. Pat. Appl., 2,604 (1979). R. A. Maxwell and F. C. Copp, German Offen., 2,030,692 (1971); Chem. Abstr., 7±9 76156d (1971). M. Carissimi, F. Ravenna, and G. Picciola, German Offen., 2,521,113 (1976); Chem. Abstr., 34, 164388t (1976). P. J. Murphy, T. L. Williams, J. K. Smallwood, G. Bellamy, and B. B. Molloy, Life Sci., 23>, 301 (1978). R. W. Fleming, German Offen., 2,806,654 (1978); Chem. Abstr., 89, 197346J (1978). B. Carnmalm, T. De Paulis, T. Hogberg, L. Johansson, M.-L. Persson, S.-O. Thorburg, and B. Ulff, Acta Chem. Scand. &_9 ^ , 91 (1982); J.-E. Backvall, R. E. Nordberg, J.-E. Nystrom, T. Hogberg, and B. Ulff, cL Org. Chem., 46, 3479 (1981). S. Ohki, N. Ozawa, Y. Yabe, and H. Matsuda, Chem. Pharm. Bull, 24, 1362 (1976).

54 28.

ARYLALIPHATIC COMPOUNDS

D. J. Collins, J. J. Hobbs, and C. W. Emmens, J^ Med. Chem., 14, 952 (1971). 29. D. W. Robertson and J. A. Katzenellenbogen, J^. Org. Chem., 47, 2386 (1982).

4 Monocyclic Aromatic Agents Fhffi pharmacological

response e l i c i t e d

by monocyclic

aromatic

dgents is a function of the number and spatial arrangement of l.he functional

groups attached to the aromatic ring; this

is

true of a great many drugs. 1. ANILINE DERIVATIVES Many l o c a l heart

anesthetics

muscle

treatment

of

when

have a s e l e c t i v e

given

cardiac

depressant

systemically.

arrhythmias,

This

is

action

on

useful

in

and a l i d o c a i n e - l i k e

with t h i s kind of action is t o c a i n i d e

drug

1

(2).

+ C) LCI I Hr CO Bi-

((12)) X X= =B NrI2 (3)

Part of the reason for ortho substitution in such compounds is to decrease metabolic transformation by enzymic 55

56

MONOCYCLIC AROMATIC AGENTS

amide cleavage. concept.

Encainide

I t s published

catalyzed

condensation

(b)

i s another

synthesis

embodiment

involves

of a - p i c o l i n e

with

acetic

of

this

anhydride-

2-nitrobenzaldehyde

t o give 2 -

J^-Methylation followed by c a t a l y t i c

reduction gives

piperidine

4-.

acylation

The

jD-methoxybenzoyl

synthesis

chloride

to

concludes give

by

antiarrhythmic

with

encainide

When the side chain involves an unsymmetrical urea moiety, muscle relaxant ami dine

(6)

activity

exerts

its

is often seen. activity

One such agent, 1 i d -

as an a n t i p e r i s t a l t i c

I t s synthesis involves the s t r a i g h t f o r w a r d

agent.

reaction of 2 , 6 - d i -

methylphenylisocyanate and JN-methylguanidine. 3

CM, I ^

CM, [ '

"O — A cyclized

•••O — (7)

version,

xilobam

(8) (8),

is

synthesized

from

J^-methyl pyrrol idone by conversion to the imine (_7_) by sequential

reaction

anhydrous

with

ammonia.

triethyloxonium When this

phenylisocyanate, the centrally (8) is formed.1*

is

tetrafluoroborate reacted with

and then

2,6-dimethyl-

acting muscle relaxant xilobam

MONOCYCLIC AROMATIC AGENTS

57

NCO II, N

A number agents.

of

muscle

relaxants

are

useful

anthelmintic

They cause the parasites to relax their attachment to

the gut wall so that they can be eliminated. is carbantel (9>).

One such agent

Its synthesis follows the classic pattern of

reaction of 4-chlorophenylisocyanate with jr-amylamidine. 5 To prepare another such analogue, N-methylation of N,N~ Hicarbomethoxythiourea gives 2£, which i t s e l f

reacts with com-

plex aniline analogue JJ^ to give the veterinary agent felsantel

(12).

(JO)

anthelmintic

6

(1L)

A simple aniline derivative acts as a prostatic antiandro<|on.

Its synthesis involves simple acylation of disubstituted

•iniline 13 with isobutyryl chloride to give flutamide (14). 7

(12)

A phenylguanidine analogue is readily prepared by f i r s t reacting 2-imino-_N-methylpyrrol idine with phenyl isothiocyanate I o give synthon JJ5.

This is next _S-methylated with methyl i o -

dide to give J ^ which i t s e l f , on reaction with pyrrolidine, is

58

MONOCYCLIC AROMATIC AGENTS

3

(13) , R = [[ ( 1 4 ) , R = COCUMc2

I CM,

(J 5)

CH

:

( 1 6 ) , S = SCII^ ( 1 7 ) , X = N(CH2)4

converted to the antidiabetic agent pirogliride (17). Finally, in demonstration of the pharmacological versatility of this chemical subclass, ethyl lodoxamide (20) shows antiallergic properties. It shows a biological relationship with disodium chromoglycate by inhibiting the release of medi-ators of the allergic response initiated by allergens. It can be synthesized by chemical reduction of dinitrobenzene analogue IS_ to the m~diamino analogue JJh This, then, is acylated with ethyl oxalyl chloride to complete the synthesis of ethyl lodoxamide (20) # 9

CJ (18), X (19), X

2. BENZOIC ACID DERIVATIVES It has been documented in an earlier volume that appropriately substituted molecules with two strongly electron withdrawing substituents meta to one another in a benzene ring often possess diuretic properties and, even though the prototypes usually have two substituted sulfonamide moieties so disposed, other groups can replace at least one of them. An example of this is piretanide (24), where one such group is a carboxyl

MONOCYCLIC AROMATIC AGENTS moiety.10

The

59

published

stituted

benzoate ^ l .

catalyst

and

succinic

anhydride.

1 0

synthesis

which

converted

to

is

starts

with

reduced with

succinimide

highly

sub-

a Raney

Z3_ by

nickel

reaction

with

II,NO,S ,0 NO,

(21)

( 22) , X = 0 (23) , X = II,

Reduction t o

(24)

the corresponding ^ - s u b s t i t u t e d

pyrrolidine

takes place w i t h sodium borohydride/boron t r i f l u o r i d e . ification arri_de_

completes the synthesis of the d i u r e t i c

(23)

Sapon-

agent pi r e t -

u

(Z±).

Because

of

resonance

stabilization

of

the

anion, a t e t -

razolyl moiety is often employed s u c c e s s f u l l y as a b i o i s o s t e r i c replacement

for

is

by azosemide

provided

a carboxy group.

prepared by phosphorus ponding benzamide.

(27).

oxychloride

An example i n t h i s Benzonitrile dehydration

Next, a n u c l e o p h i l i c

cludes w i t h

the 1 , 3 - d i p o l a r

addition

of

analogue of

aromatic

reaction of the f l u o r i n e atom leads to ^ £ .

subclass 2b_ i s

the c o r r e s displacement

The synthesis con-

azide

t o the

nitrile

f u n c t i o n t o produce the d i u r e t i c azosemide ( 2 7 ) . 1 2

(25)

Reversal

(26)

of the amide moiety of local

(27)

anesthetics is

60

M0N0CYCLIC AROMATIC AGENTS

consistent with retention of a c t i v i t y . antiarrhythmic It

is

agents.

synthesized

Flecainide

from

mediated e t h e r i f i c a t i o n carefully, appropriate

ester

2,5-dihydroxybenzoic

acid

by

with 2 , 2 , 2 - t r i f l u o r o e t h a n o l .

28_ r e s u l t s .

pyridine

So too with the derived

(30) i s such a substance.

Amide ester

amine analogues

I f done

exchange with the

leads t o 29_.

reduction of the more e l e c t r o n - d e f i c i e n t in the formation of f l e c a i n i d e

base-

aromatic

Catalytic

ring

results

(30).13

(28)

A lipid lowering agent of potential sterolemia

is cetaben

(31).

value in hyperchole-

It is synthesized

facilely by

monoalkylation of ethyl £~aminobenzoate with hexadecyl and then saponification.

bromide

14

Benzamide 32_9 known as benti romide, is a chymotrypsin substrate of value as a diagnostic acid for assessment of pancreatic function.

It is synthesized

by amide formation

between

CII3(CH2)15N1I (31)

ethyl

£~aminobenzoate

morpholine

and ethyl

and j^-benzoyl-tyrosine chlorocarbonate

resulting L-amide (32) is selectively

for

using

N-methyl-

activation.

The

hydrolyzed by sequential

MONOCYCLIC AROMATIC AGENTS use of dimsyl (33). 1 5

61

sodium and dilute acid to give benti romide

CONI COJI (33),

3.

R =H

BENZENESULFONIC ACID DERIVATIVES

As has been discussed previously, substituted £-alkylbenzenesulfonylureas

often possess the property

of

releasing bound

i n s u l i n , thus sparing the requirement for insulin injections "in adult-onset

diabetes.

A pyrimidine moiety,

interestingly,

can serve as a surrogate for the urea function. Gliflumide

(37),

one such

4-isobutyl-2-chloro~pyrimidine

agent,

is

synthesized

(34) by nucleophilic

from

displace-

ment using jp-sulfonamidobenzeneacetic acid (350 to give sulfonamide _3(^.

Reaction, via the corresponding acid chloride, with

S.-l-amino-l-(2-methoxy-5-fluorophenyl )ethane completes the synthesis of the antidiabetic agent gliflumide (37), 1 7

(34)

(.35)

(36)

62

MONOCYCLIC AROMATIC AGENTS

(37)

A related agent, glicetanile sodiurn (42), variant of this process. chlorosulfonic with

Methyl phenylacetate is reacted with

acid to give 3S_9 which i t s e l f

aminopyrimidine

is made by a

derivative _3!9. to

give

readily

reacts

sulfonamide

4£.

Saponification to acid 4^L is followed by conversion to the acid chloride and amide formation with 5-chloro~2-methoxyaniline to complete the synthesis of the hypoglycemic agent

glicetanile

(42).18

f38)

(39)

(40), R = CH. (.41), R = II

(42)

Perhaps analogue

surprisingly,

called

tosifen

the

p-methyl

(45), which

is

benzenesulfonylurea structurally

rather

close to the oral hypoglycemic agents, is an antianginal agent

MONOCYCLIC AROMATIC AGENTS

63

instead. Its synthesis involves ester-amide displacement of carbamate A3_ with jv-2-ami nophenyl propane (44) to give 45.

H,2

(43)

Several

(44)

obvious

variants

(45)

exist.

Tolbutamide,

the

prototypic

drug, has some a n t i a r r h y t h m i c a c t i v i t y by an unknown mechanism. 1 his side e f f e c t which

itself

sugar.

has become the p r i n c i p a l

does

not

in

turn

action with t o s i f e n ,

significantly

lower

blood

19

REFERENCES I.

R.

N. Boys, B. R. Duce, E. R. Smith, and E. W. Byrnes,

German

Offen.

DE2,235,745

(1973);

Chem.

Abstr.,

]8_9

140411V (1973). ?.

H. C. Ferguson and W. D. Kendrick, 3_. MecL Chem., jj6_, 1015 (1973).

1.

G. H. Douglas, J . Diamond, W. U Alioto,

S t u d t , G. N. M i r , R.

K. Anyang, B. J . Burns, J . Cias,

P. R.

L.

Darkes,

S. A. Dodson, S. O'Connor, N. J . Santora, C. T. T s u e i , J . J.

Zulipsky,

and H. K.

Zimmerman, Arzneim. F o r s c h . , 28,

1435 (1978). 4.

C.

R.

Rasmussen, J .

F.

Gardocki,

J.

N.

Plampin,

J.

N.

Twardzik, B. E. Reynolds, A, J . M o l i n a r i , N. Schwartz, W. W.

Bennetts,

B.

E.

Price,

and

J.

Marakowski, j j .

Med.

Chem., 2 ^ , 10 (1978). •».

G.

D.

Diana,

French

Patent

A b s t r . , 72, 78, 7352 (1970).

FR2,003,438

(1969);

Chem.

64

MONOCYCLIC AROMATIC AGENTS

6.

H. Koelling, H. Thomas, A. Widdig, and H. Wollwever, German Offen. DE2,423,679 (1975); Chem. Abstr., 84, 73949k (1976). J. W. Baker, G. L. Bachman, I. Schumacher, D. P. Roman, and A. L. Tharp, J. Med_. Chem., 10, 93 (1967). C. R. Rasmussen, German Offen. DE2,711,757 (1977); Chem. Abstr., 88, 37603s (1978). J. B. Wright, C. M. Hall, and H. G. Johnson, _J- M e d » Chem., n_9 930 (1978). D. Lednicer and L. A. Mitscher, The Organic Chemist ry of_ Drug Synthesis, Vol. 2, Wiley, New York, 1980, p. 87. W. Merkel, J.. Med. Chem., _U, 399 (1976). A. Popelak, A. Lerch, K. Stach, E. Roesch, and K. Hardebeck, German Offen. DEI,815,922 (1970); Chem. Abstr., 23, 45519z (1970). E. H. Banitt, W. R. Bronn, W. E. Coyne, and J. R, Schmid, J. Med_. Chem., 20, 821 (1977). J. D. Albright, S. A. Schaffer, and R. G. Shepherd, J_. Pharm. Sci., 68, 936 (1979). P. L. DeBenneville and N. H. Greenberger, German Offen. DE2,156,835 (1972); Chem. Abstr., 7J_9 114888r (1972). D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977, p. 136. C. Rufer, Ji. Med^ Chem., J7, 708 (1974). K. Gutsche, E. Schroeder, C. Rufer, 0. Loge, and F. Bahlmann, Arzneim. Forsch., 24, 1028 (1974). L. Zitowitz, L. A. Walter, and A. J. Wohl, German Offen. DE2,042,230 (1971); Chem. Abstr., 75, 5532h (1971).

7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19.

5 Polycyclic Aromatic Compounds It will have been noted that important structural moieties are sometimes associated with characteristic biological responses (prostanoids, phenylethanolamines, for example). Just as often, however, such structural features show commonality only in the mind of the organic chemist. As will be readily evident from the very diverse biological activities displayed by drugs built on polycyclic aromatic nucleii, this classification is chemical rather than pharmacological. The nucleus does, however, sometimes contribute to activity by providing a means by which pharmacophoric groups can be located in their required spatial orientation; sometimes too, particularly in the case of the monofunctional compounds, the polycyclic aromatic moiety probably contributes to the partition coefficient so as to lead to efficient transport of the drug to the site of action. 1.INDAN0NES A rather reported

simple derivative of 1-indanone to

particularly

possess noteworthy

analgesic

itself

activity.

has been This

in that this agent, drindene

is (3)9 65

66

POLYCYCLIC AROMATIC COMPOUNDS

departs markedly from the structural pattern of either centrally acting or peripheral analgesics. Condensation of 1-indanone (I) with ethyl chloroformate in the presence of alkoxide gives the corresponding hydroxymethylene derivative 2. Reaction with ammonium acetate leads to the corresponding enamine 3, probably by addition of ammonium ion to the terminus of the enone followed by elimination of hydroxide.

en

(2i ()

0

(3i

NaO , C ^

O(:ii)aicii7o Oil (4)

The discovery of disodium cromogiycate (4) afforded for the first time an agent that was active against allergies by opposing one of the very first events in the allergic reaction; that is, the release of the various substances (mediators) that cause the characteristic symptomology of an allergic attack. The fact that this agent is active only by the inhalation route led to an extensive search for a compound that would show the same activity when administered orally. The various candidates have as a rule been built around some flat polycyclic nucleus and have contained an acidic proton (carboxylate, tetrazole, etc.). One of the simplest of these is built on an indane nucleus. Base catalyzed condensation of phthalic ester 5_ with ethyl acetate affords indanedione 6_ (shown in the enol form). Nitration by means of fuming nitric acid leads the mediator

POLYCYCLIC AROMATIC COMPOUNDS

67

release inhibitor nivimedone (J) The triply activated proton shows acidity in the range of carboxylic acids.

. . .

.

3

$

o (5)

o

(6)

(7)

V V 7., \

/

oc!i2co2n

""2/A C1 C1 (8)

7

c:n 3 °

(9)

(10)

Further investigation on the chemistry of the \/ery potent diuretic drug ethacrinic acid (8) led to a compound that retained the high potency of the parent with reduced propensity for causing side effects, such as loss of body potassium and retention of uric acid. Friedel-Crafts acylation of dichloroanisole 9_ with phenylacetyl chloride gives ketone 10. This is then reacted in a variant of the Mannich reaction which involves the aminal from dimethyl-

>C6H5 CH2 (12)

cn2N(cn3)2

Cl

Cl

Cl

Cl

~

" (1.3)

Cl M

3

(14)

3

(15)

'

(16) R (17) R

Cl

68

PCJLYCYCLIC AROMATIC COMPOUNDS

amine and formaldehyde. The reaction may be rationalized as leading i n i t i a l l y to the adduct JA_; loss of dimethyl amine leads to the enone _12. Cyclization by means of sulfuric acid affords the indanone (J^K This last is in turn al~ kylated on carbon (14) and O-demethylated under acidic conditions. The phenol (W) thus obtained is then alkylated on oxygen by means of ethyl bromoacetate. Saponification of the ester affords indacrinone (17) . 2.NAPHTHALENES As noted e a r l i e r , most c l a s s i c a l antidepressant agents consist

of

propylamine

compounds.

derivatives

of

tricyclic

The antidepressant molecule tametraline

aromatic i s thus

notable in that i t is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4phenyl-1-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenylbutyric acid) with methylamine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20).

(18)

(20)

(21)

POLYCYCLIC AROMATIC COMPOUNDS Topical

fungal

69

infections

usually

1 ike dermal and subdermal

tissues.

lipophilicity

be

antifungal

would

activity

thus

Drugs with

expected

agent

lipophilicity,

to

show

by reason of preferential

to the l i p i d - r i c h site of action. antifungal

involve the

tolnaftate

affords

increased enhanced

distribution

A modification of the

(29),

toicielate

lipid-

which

(28).

increases

its

One approach to

construction of the required bridged tetrahydronaphthoi (25) involves Diels-Alder condensation of a benzyne.

Thus re-

action of dihalo anisole 22_ with magnesium in the presence of cyclopentadiene leads directly to the adduct 2A. l i k e l y that 22_ i n i t i a l l y

I t is

forms a Grignard-like reagent at

the iodo group; this then collapses to magnesium halide and benzyne 23; 1,4 addition to cyclopentadiene leads to the observed product.

Preparation of the requisite phenol j ! £ is

completed by catalytic hydrogenation (25) followed by 0-demethylation .

Reaction of the sodium salt of the phenol

with thiophosgene leads to intermediate 27j condensation of N~methyl-m-toluidine gives t o l c i c l a t e (28).

Br (22)

f 23)

(24)

(2 5) R = CH, (26) R = II

II

C27)

(28)

(29)

™

POLYCYCLIC AROMATIC COMPOUNDS Research carried

mid-1960s

indicated

on i n that

several

laboratories

triarylethylenes

that

in the

carry

an

ethoxyethylamine substituent on one of the rings show yery

promising a n t i f e r t i l i t y activity. I t was quickly found that such agents owe their activity in the particular test system used to their ability to antagonize the effects of endogenous estrogens. One of the more potent agents synthesized in this period was nafoxidine (30), This agent's a n t i f e r t i l i t y activity turned out to be restricted to rodents due to a peculiarity of the reproductive endocrinology of this species. Further clinical testing of compounds in this class revealed that certain estrogen antagonists were remarkably effective in the treatment of breast tumors, particularly those that can be demonstrated to be estrogen dependent. One such agent, tamoxifen, is currently used clinically for that indication. More recent work in this series demonstrated that a carbonyl group can be interposed between the side-chaincarrying aromatic ring and the ethylene function with f u l l retention of activity. Claisen condensation of benzoate 31 with 2-tetralone affords the fr-diketone 32. Reaction of this with p~anisylmagnesium bromide interestingly proceeds preferentially at the ring carbonyl atom. (The thermodynamically favored enol carries the carbonyl at that position.) Spontaneous dehydration leads to the enone 33_. The methoxy group on the ring substituted by the carbonyl group is rendered more reactive by the ketone at the para position thus demethylation with an equivalent of sodium ethylthiol leads to phenol 34. Alkylation with 2-chloroethylpyrrolidine affords the antiestrogenic agent trioxifene (35). 7

POLYCYCLIC AROMATIC COMPOUNDS

71

c

(33)

(34)

another

properties,

(32)

(31)

(30)

Yet

&

that

compound

that

does not f i t

(35)

exhibits

antidepressant

the classical

rather simple substituted amidine.

mold, is a

Reaction of amide 36_

with triethyloxoniurn fluoroborate (Meerwein reagent) affords the corresponding imino ether 37.

Exposure of this

inter-

mediate to methyl amine leads to napactidine (38),^

0 II

CIUCNHCH

CH ? C N

(36)

(37)

(38)

Antifungal activity has been described for an equally straightforward

derivative

of 1-naphthylmethylamine.

This

72

POLYCYCLIC AROMATIC COMPOUNDS

agent, naftidine (40) is obtained by alkylation of amine 39_ with cinnamyl bromide.

(39)

(40)

Excessive activity of the enzyme aldose reductase sometimes accompanies diabetes. The net result is often accumulation of reduced sugars such as galactose in the lens of the eye and ensuing cataract formation* AT res ta t i n (43), an aldose reductase inhibitor, is one of the f i r s t agents found that holds promise of preventing diabetes-induced cataracts. The compound, actually used as i t s sodium salt, is prepared in straightforward manner by imide formation between 1,8-naphthalic anhydride (41) and glycine. CH 2 CO 2 R

(41)

3. TRICYCLIC COMPOUNDS: ANTHRACENE, PHENANTHRENE AND DIBENZOCYCLOHEPTENE The discovery of the activity of the phenothiazines such as chiorpromazine (44) against schizophrenia pointed the way to drug therapy of diseases of the mind. The intensive

POLYCYCLIC AROMATIC COMPOUNDS

73

research on the chemistry and pharmacology of those heterocycles is detailed at some length in the first Volume of this series. Those earlier investigations, it should be noted, centered mainly on modification of the side chain and substitution of the aromatic ring. Subsequent research revealed that considerable latitude exists as to the structural requirements of the central ring. For example, clomacran (45) shows the same antipsychotic activity as its phenothiazine counterpart U4_). It is thus interesting to note that the fully carbocyclic analogue fluotracen (54) also exhibits CNS activity. This particular agent in fact shows a combination of antipsychotic and antidepressant activity. (In connection with the last it may be of some relevance that the compound may be viewed as a ringcontracted analogue of the tricyclic antidepressants.) Reaction of substituted nitrile 46^with phenylmagnesium bromide gives, after hydrolysis, the benzophenone ¥K Reaction of the ketone with the ylide from trimethylsulfoxonium iodide leads to the epoxide 48. Reductive ring opening of the oxirane by means of phosphorus and hydriodic acid completes conversion of the carbonyl to the homologous methyl group (49). Replacement of bromine by a nitrile group is accomplished by treatment of _4S^ with cuprous cyanide. Reaction of the product with the Grignard reagent from 3-methoxybromopropane affords the inline j>l_9 which now contains all the required carbon atoms. Treatment of this intermediate with hybrobromic acid achieves both FriedelCrafts-like ring closure and conversion of the terminal methoxy group to a bromide (52). The latter transformation

74

POLYCYCLIC AROMATIC COMPOUNDS

may

proceed

either

by

direct

SN2

displacement

of

the

protonated methoxy group by bromide or by p r i o r cleavage of the ether to an alcohol followed by the more conventional transformation* dimethyl amine (53).

Displacement completes

of

the

construction

terminal

bromine by

of

side

the

chain

Catalytic reduction proceeds in the usual fashion t o

give the 9,10-dihydro d e r i v a t i v e , f l u o t r a c e n . * 1 specifically

stated,

(Though not

the method of synthesis would suggest

t h a t these groups bear a c i s r e l a t i o n s h i p . )

(45)

(4 4")

(47)

(46)

(49)

(48)

(50)

CH CU CH OCII 2 2 2 3 (51)

CH 2 CII 2 CH 2 Br (52)

(53)

(54)

POLYCYCLIC AROMATIC COMPOUNDS

75

There is much evidence to suggest that one of mankind's dreaded afflictions, cancer, is not one but a loosely related series of diseases. This diversity has acted as a significant bar to the elucidation of the mechanisms underlying the uncontrolled cell division that characterizes tumor growth. Though some progress has been made toward rational design of antitumor agents, a significant portion of the drug discovery process still relies on random screening. It is thus that one of the screens sponsored by the National Cancer Institute (US) discovered the antitumor activity of a deep blue compound which had been originally synthesized as a dye for use in ball point pen ink. Preparation of this compound, ametantrone (58) starts by reaction of leucoquinizarin (55) with diamine ^ to give the bisimine 57. Air oxidation of the intermediate restores the anthraquinone oxidation state. There is thus obtained ametantrone (J58J . A similar sequence starting with the leuco base of tetrahydroxyanthraquinone J59^ affords the yery potent antitumor agent mitoxantrone (61). iR 1OH 0

R 0 NHCH2CH 2OCH2CI1?NH2 •+- n2Ncn2cn2ocn2ci!2Nn2

T T 0 (56) R on II (55) R =OH (59) R = R 0 NHCH2CI2OCH2CI2NH2

0 T n ^T) CHOCH CH NH 2 2 2 2 2 R 0 NHCHH OH (57) R = (60) R»

76

POLYCYCLIC AROMATIC COMPOUNDS

Large-scale treatment of a host of lower organisms with biocides seems to lead almost inevitably to strains of that organism that become resistant to the effects of that agent. We thus have bacteria that no longer succumb to given antibiotics, and insects that seemingly thrive on formerly lethal insecticides. The evolution of strains of plasmodia resistant to standard antimalarial agents, coupled with the US involvement in Vietnam, a hotbed for malaria, led to a renewed search for novel antimalarial agents. Halofantrine (70) is representative of the latest generation of these compounds. The preparation of this phenanthrene starts with the aldol condensation of substituted benzaldehyde J52_ with phenylacetic acid derivative J53_ to give the cinnamic acid 64. Chemical reduction of the nitro group leads to aniline 65, This is then cyclized to the phenanthrene by the classical Pschorr synthesis (nitrous acid followed by strong acid). Though many methods have been proposed for direct reduction of carboxylic acids to aldehydes, these have usually been found less than satisfactory in practice. A more satisfactory method of achieving the transformation consists in reducing the acid to the carbinol (6>7J and then oxidizing that back to the aldehyde (68); the present sequence employs lead tetraacetate for the last step. Reformatski condensation of 68_ with JML-di(ji-butyl )bromoacetamide and zinc affords amidoalcohol j>9. This is reduced to the ami no alcohol by means of diborane to give halofantrine ( 7 0 ) . ^

POLYCYCLIC AROMATIC COMPOUNDS

11

(63)

(6 2)

OH 0 I II • CH(;il 2 CN(nC 4 Ilq)

(69)

on o i II .CHCH 2 CH 2 CN(nC 4 II 9 )

(70)

An analogue of amitriptyline which contains an additional double bond in the central seven membered ring shows much the same activity as the prototype. Treatment of dibenzocycloheptanone 71_ with N-bromosuccinimide followed by triethylamine serves to introduce the additional double bond by the bromination-dehydrohalogenation sequence. Reaction of the carbonyl group with the Grignard reagent from 3chloropropyl-N,N-dimethyl amine serves to introduce the side chain (j[3). Acid catalyzed dehydration affords the antidepressant compound cyclobenzaprine (74).

78

POLYCYCLIC AROMATIC COMPOUNDS

o (72)

HO

CH 2 CH 2 CH 2 N(CH,) (73)

CMCH-CH7N(CH,) 2 (74)

REFERENCES 1. P. D. Hammen and G. M. Milne, German Offen., 2,360,096; Chem. Abstr., 81, 105093 (1974). 2. D. R. Buckle, N. J. Morgan, J. W. Ross, H. Smith, and B. A. Spicer, J_. Med. Chem., JL6, 1334 (1973). 3. S. J. DeSolm, D. W. Woltersdorf, E. J. Cragoe, L. S. Waton and G. M. Fanelli, J. toed. Chem. ^ , , 4 3 7 (1978). 4. S. Reinhard, J_. Org. Chem., 40, 1216 (1975). 5. H. Tanida, R. Muneyuki and T. Tsuji, Bui 1. Chem. Soc. Jap., 37, 40 (1964). 6. P. Melloni, M. Rafaela, V. Vecchietti, W. Logemann, S. Caste!lino, G. Monti, and I, DeCarneri, Eur. OL Med. Chem., 9, 26 (1964). 7. C. D. Jones, T. Suarez, E. H. Massey, L. J. Black and F. C. Tinsley, JL Med. Chem. 22, 962 (1979). 8. J. R. McCarthy, U.S. Patent 3,903,163; Chem. Abstr. 83> 192933 (1975).

POLYCYCLIC AROMATIC COMPOUNDS

9.

B.

Daniel,

German Offen,

79

2,716,943;

Chem. A b s t r .

88,

62215 (1978). 10. S. Kazinrir,

N. Simard-Duquesne and D. M. Dvornik,

U.S.

Patent 3,821,383; Chem. A b s t r . SU 176158 (1974). 1 1 . P. N. Craig and C. L. Z i r k l e , French Patent, Chem. Abstr. JU 12. R. K.

1,523,230;

101609 (1969).

Y. Zeecheng and C. C. Cheng, d_. Med. Chem., 2 1 ,

291 (1978). 13. K. C. Murdock, R. G. C h i l d , P. F. Fabio, R. B. Angier, R. E, Wallace, F. E. Durr, and R. V. C i t a v e l l a , £ . Med. Chem., 22, 1024 (1979). 14. W.

T.

Colwell,

V.

Brown,

P.

Christie,

J.

Lange,

C.

Reece, Y. Yamamoto and D. W. Henry, J . Med. Chem, 15, 771 (1972). 15. S. 0. Winthrop, M. A. Davis, G. S. Myers, J . G. Gavin, R. Thomas and R. Barber, J . Org. Chem., 27, 230 (1962).

6 Steroids The steroid nucleus provides the backbone for both the hormones that regulate sexual function and reproduction and those involved in regulation of mineral and carbohydrate balance. The former comprise the estrogens, androgens, and progestins; cortisone, hydrocortisone, and aldosterone are the more important entities in the second category. Synthetic work in the steroid series, accompanied by some inspired endocrinological probes, led to many signal successes. Research on estrogens and progestins thus led to the oral contraceptives, and corresponding efforts on cortisone and its derivatives culminated in a series of clinically important antiinflammatory agents. Few if any endogenous hormones seldom exert a single action. These compounds typically elicit a series of re81

82

STEROIDS

sponses on different biological end points and organ systems. It should thus not be surprising that both natural and modified steroids also show more than one activity; these ancillary activities, however, often consist of undesirable actions, and are thus considered side effects. Volumes 1 and 1 of this series detail the enormous amount of work devoted to the steroids inspired at least partly by the goal to separate the desired activity from those side effects. When it became apparent that this goal might not be achievable, there was a considerable diminution in the synthetic work in the steroid series; this is well illustrated by comparison of this section with its counterparts in the preceding volumes.

1 . ESTRANES The adventitious nitrogen

mustard

discovery of the antitumor action of the poison

war

gases

led

to

intensive

i n v e s t i g a t i o n of the mode of action of these compounds.

In

b r i e f , i t has been f a i r l y well established t h a t these agents owe t h e i r

effect

to

bis(2-chloroethyl)amine

the presence of the highly group.

The

cytotoxic

reactive

a c t i v i t y of

STEROIDS

83

these drugs is directly related to the ability of this group to form an irreversible covalent bond with the genetic material of cells, that is, with DNA. Since this alkylated material can then no longer perform its function, replication of the cell is disrupted. The slight selectivity shown for malignant cells by the clinically used alkylating agents depends largely on the fact that these divide more rapidly than those of normal tissue. There have been many attempts to achieve better tissue selectivity by any number of other stratagems. One of these involves linking the mustard function to a molecule that itself shows very specific tissue distribution. Steroids are prime candidates as such carriers since they are well known to exhibit highly selective organ distribution and tissue binding. Estramustine (4) and prednimustine (64; see Section 3 below) represent two such site directed cytotoxic agents.

(4)

84

STEROIDS

Reaction of bis(2-chloroethyl)amine with phosgene affords the corresponding carbamoyl chloride (2). Acylation of estradiol (3) with this reagent leads to estramustine (<\)i . Though reaction with the more nucleophilic alcohol function at 17 might at first sight lead to a competing reaction, the highly hindered nature of this alcohol greatly reduces its reactivity. Oral contraceptives almost invariably consist of a mixture of a progestational agent active by the oral route and a small amount of an estrogen. It was discovered quite early that, in contrast to the natural compounds, those lacking the 19 methyl group (19-nor) showed good oral activity; the availability of practical methods for total synthesis led to some emphasis on agents that possess an ethyl group at position 13 rather than the methyl of the natural steroids. ^Jery widespread use of oral contraceptives led to the recognition of some side effects that were associated with the progestin component; there has thus been a trend to design drugs that could be administered in smaller quantity and a corresponding search for ever more potent progestins. Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone 6; oxidation of the alcohol at 17 leads to dione _7_* Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group at the 15 position (&). Acetal formation with neopentyl glycol affords the protected ketone which consists of a mixture of the A5 and A 5 * 1 0 isomers (9); hindrance at position 17 ensures selective reaction of the 3 ketone. The

STEROIDS

85

hydroxyl is then converted to its mesylate (10). Treatment with sodium acetate leads to elimination of the mesylate and thus formation of the corresponding enone (11). Reaction of the ketone at 17 with ethynylmagnesium bromide introduces the requisite side chain. Removal of the ketal group by means of aqueous oxalic acid completes the synthesis of gestodene (13) 3 .

(6) R = II, OH (7) R = 0

(9) R = II (10) R = SO

cm

(12)

(13)

A rather more complex scheme is required for preparation of the analogue gestrinone (27) which contains unsaturation in rings A, B, and C. The key intermediate 24 can be obtained by Robinson annulation on dione 1A_ with enone 15 to give the bicyclic intermediate 16. Successive

86

STEROIDS

reduction of the double bond and the cyclopentyl carbonyl group followed by esterification of the thus obtained alcohol gives ketoester J7. This last can then be converted to the enol lactone j ^ b y successive partial saponification and treatment with acetic anhydride. Condensation with the Grignard reagent from bromoketal Jj)_ gives after hydrolysis the tricyclic intermediate 2Q. (This reaction can be rationalized as initial reaction of the organometallic with the lactone carbonyl; the diketone formed by hydrolysis would then cyclize under the reaction conditions.) Treatment of j20^ with pyrrolidine serves to close the last ring via its enamine (j2]J* Hydrolysis of the first formed 3enamine leads to the doubly unsaturated steroid 22. Treatment with dicyanodichloroquinone (DDQ) would serve to introduce the last double bond with consequent formation of the conjugated 5,9,10 triene (Z3)i hydrolysis of the ester at 17 and subsequent oxidation of the alcohol would give the key 3,17 diketone 24. Treatment with ethylene glycol in the presence of acid leads to formation of the 3 ketal• Reaction with ethynylmagnesium bromide (£6) followed by removal of the ketal group gives gestrinone (27)4>5. o 1L—J 0' (15)

(14)

~ "

C16)

3

2

(17)

STEROIDS

87

(18)

(19)

(22)

o

(20)

(24)

(23)

(25)

(21)

(26)

(27)

2. ANDROSTANES Despite some early hopes, the drugs related to the androgens have found rather limited use. This has in practice been confined to replacement therapy in those cases where endogenous hormone production is deficient; some agents that show reduced hormonal effects have found some application as anabolic agents as a consequence of their ability to rectify conditions that lead to loss of tissue nitrogen. In analogy with the estrogen antagonists, an antiandrogen would seem to offer an attractive therapeutic target for treatment of diseases characterized by excess androgen stimulation (e.g., prostatic hypertrophy) and androgen dependent tumors. Attempts to design specific antagonists to androgens have met with limited success, however.

88

STEROIDS Halogenation

of

steroid

3-ketones

can

lead

to

complicated mixtures by v i r t u e of the f a c t t h a t the k i n e t i c enol

leads to 3 halo products s whereas the

thermodynamic

product i s t h a t halogenated a t the 4 p o s i t i o n .

Carefully

controlled

2Q

reaction

chlorine

thus

Reaction

of

hydroxylamine

leads that affords

of

the

5a-androstanolone

to

the

2a-chloro

intermediate the

with

androgenic

derivative

with (29).

O(p-nitrophenyl)agent

nistremine

acetate (30)6.

OCOCH*

(28)

N ^ J

1

(30)

Replacement of the hydrogen at the 17 position of the prototypical androgen testosterone (31) by a propyl group interestingly affords a compound described as a topical antiandrogen. Reaction of the tetrahydropyranyl ether of dehydroepi androsterone (_32) with propyl magnesium bromide gives after removal of the protecting group the corresponding 17a-propyl derivative J3^ Oppenauer oxidation of the 3-hydroxy-A^ function leads to the corresponding conjugated ketone. There is thus obtained topterone (34)^. 0

Oil

(31)

(32)

OHC

(33)

STEROIDS

89

(34)

A highly modified methyl testosterone derivative also exhibits antiandrogenic activityOne synthesis of this compound involves i n i t i a l alkylation of methyl testosterone (35J by means of strong base and methyl iodide to afford the 4,4-dimethyl derivative JJ6L Formylation with alkoxide and methyl formate leads to the 2-hydroxymethyl derivative 37_* Reaction of this last with hydroxylamine leads to formation of an isoxazole ring. There is then obtained azastene 8 (38) .

(35)

(39)

(36)

(40)

(37)

(41)

90

STEROIDS 3.PREGNANES

With

very

few exceptions,

the b i o l o g i c a l

activities

of

synthetic steroids tend to p a r a l l e l those of the n a t u r a l l y occurring hormones on which they are patterned.

Compounds

with d i s t a n t pharmacological a c t i v i t y a r e , as a r u l e , quite rare.

I t i s thus intriguing that inclusion of a t e r t i a r y

amine at the 11 position of a pregnane leads to a compound with a c t i v i t y agent

in

far removed from i t s close analogues.

question,

activity.

minaxalone

Epoxidation

of

(47),

exhibits

progesterone

The

anesthetic

derivative

40,

obtainable i n several steps from 11-ketoprogesterone (39) , gives

the corresponding

compound with

alkoxide

a~epoxide Q/L, leads

to

Reaction of

diaxial

that

opening of

the

oxirane and consequent formation of the 2 3-ethoxy 3a-hydroxy derivative £2.

Reaction with ethylene glycol leads cleanly

to selective formation of the 17 ketal (£3) by reason of the highly hindered environment about the 11 carbonyl.

For the

same reason,

forcing

conditions.

formation of

the oxime 4A^ requires

Chemical reduction of that oxime leads to the

thermodynamically favored equatorial a-amine j45. (Catalytic reduction would have given the 3-amine*)

Methylation of the

amine by means of formic acid and formaldehyde leads to the corresponding dimethyl ami no derivative (46>).

Removal of the

ketal group completes the synthesis of minaxalone (47)

(42)

(43)

(44)

.

STEROIDS

91

(4 5) R = II (46) R = CH3

f48)

(47)

(50) R = II (51) R « COC(CII 3 ") 3

("49)

(CIL,) CCO 5 3 II 0

(5 3)

(54) R = COC(CIU) (55) R » II -7

Spironoiactone (48) has proved a very useful diuretic and antihypertensive agent. This drug, that owes its effect to antagonism of the endogenous steroid hormone that regulates mineral balance, aldosterone, exhibits in addition some degree of progestational and antiandrogenic activity. Further analogues have thus been prepared in an effort to prepare an agent free of those side effects. Preparation of the newest of these, spirorenone (6il_) , starts by 7-hydroxylation of dehydroepiandrosterone derivative 49. Though this transformation has also been accomplished by chemical means, microbiological oxidation by Botryodipioda malorum apparently proves superior. Acylation with pivalic anhydride proceeds selectively at the 3 hydroxyl group (5JLK Epoxidation by means of tertiary butylhydroperoxide and vanadium acetylacetonate affords exclusively the 3 epoxide (52). The remaining hydroxyl is

92

STEROIDS

then displaced by chlorine by means of triphenylphosphine and carbon tetrachloride (^3)« Sequential reductive elimination (J54J followed by saponifi cation gives the allylic alcohol 55. Reaction with the Simmons-Smith reagent affords the corresponding cyclopropane, B6j the stereochemistry being determined by the adjacent hydroxyl group. Addition of the dianion from propargyl alcohol to the carbonyl group at position 17 adds the required carbon atoms for the future lactone (5JJ* The side chain is then reduced by catalytic hydrogenation (^>8h Oxidation of this last intermediate by means of pyridinium chlorochromate simultaneously oxidizes the primary alcohol to an acid and the secondary alcohol at position 3 to a hydroxyketone; under the reaction conditions, the latter eliminates to give an enone while the hydroxy acid lactonizes. There is thus obtained directly the intermediate 6Ch Dehydrogenation by means of DDQ introduces the remaining double bond to afford spirorenone (61r . OH

,..CH2(:II2CH2OH

(57)

(56)

(58")

OH

(59)

(60)

STEROIDS

93

(61)

(6 3)

(62)

As noted above, the steroid nucleus has been a favorite for the design for site directed alkylating antitumor drugs. Thus reaction of prednisoione (62) with anhydride 63 affords the 21 acylated derivative, prednimustine (64) .

/ CH 2 CH 2 C1

(64)

A preponderance of the work devoted to steroids, as judged from the number of compounds bearing generic names, has clearly been that in the area of corticosteroids related

94

STEROIDS

to cortisone. Much of the effort, particularly that detailed in the earlier volumes was no doubt prompted by the very large market for these drugs as antiinflammatory agents. Heavy usage led to the realization that parenteral use of these agents carried the potential for wery serious mechanism related side effects. There has thus been a considerable recent effort to develop topical forms of these drugs for local application to rashes, irritation and other surface inflammations. A good bit of the work detailed below is aimed at improving dermal drug penetration. Because skin exhibits many of the properties of a lipid membrane, dermal penetration can often be enhanced by increasing a molecule's lipophilicity. Preparation of an ester of an alcohol is often used for this purpose since this stratagem simultaneously time covers a hydrophilic group and provides a hydrophobic moiety; the ready cleavage of this function by the ubiquitous esterase enzymes assures availability of the parent drug molecule. Thus acylation of the primary alcohol in flucinoione (j>5) with propionyl chloride affords procinonide (66) , the same transform employing cyclopropyl carbonyl chloride gives ciprocinonide (67)14

(66)

R = C2H5

(67) R = -<]

STEROIDS

95

(681

(69)

Further oxidation of the carbon at position 21 is interestingly consistent with antiinflammatory activity. Thus oxidation of flucinoione with copper (II) acetate affords i n i t i a l l y the hydrated ketoaldehyde ^68j exchange with methanol gives the 21 dimethyl acetal (69), flumoxonide. Omission of positions leads budesonide (71). the acetal of the

(70)

the fluoro substituents at the 6 and 9 to the antiinflammatory compound agent This compound is obtained by formation of 16,17 diol 7016 with butyraldehyde.17

(71)

It is a hallmark of the structure activity relationships of the corticoids that the effects of structural modifications that lead to increased potency are usually additive. The fact that more than half a dozen such modifications each lead to increased potency opens ever new possibilities for combinations and permutations. Meclorisone dibutyrate (74) thus combines the known potentiating effects of the replacement of the 11-hydroxyl by chlorine as well as incorporation of a 16a-methyl

96

STEROIDS

group. Addition of chlorine to the 9,11 double bond of Tl_ would afford the corresponding dichloro derivative, 73_. (Addition of halogen is initiated by formation of the chloronium ion on the less hindered alpha face; diaxial opening of the intermediate leads to the observed regio- and stereochemistry.) Acetylation of that intermediate with butyric acid in the presence of trifluroacetic acid leads to meclorisone dibutyrate (74).

(75)

(76)

(77)

Halogenation of the 7 position also proves compatible with good antiinflammatory activity. Construction of this compound, aclomethasone dipropionate (80), starts by introduction of the required unsaturation at the 6,7 position by dehydrogenation with DDQ (_76_)« The highly hindered nature of the hydroxyl at position 17 requires that a roundabout scheme be used for formation of the corresponding ester. Thus treatment of 1§^ with ethyl orthoformate affords first the cyclic orthoformate TL. This then rearranges to the 17 ester 7 ^ on exposure to acetic acid. Acylation of the 21 alcohol is accomplished in straightforward fashion with

STEROIDS

97

propionic anhydride (J79^). Addition of hydrogen chloride completes the synthesis of aciomethasone dipropionate (80) *^ (This last reaction may in fact involve 1,6 conjugate addition of the reagent; this would then ketonize to the observed product under the acidic reaction conditions).

(81")

(821

Incorporation of a vinylic bromide at the 2 position also gives a compound with good activity. Bromination of fluorohydrin Sir under carefully controlled conditions gives the 2 a bromo derivative 82^. The hydroxyl at the 11 position is then converted to its mesylate with methanesulfonyl chloride (83>h Reaction of that intermediate with acetic anhydride under forcing conditions (perchloric acid) gives the 5,17,21 triacetate SA_. Treatment with sodium acetate leads to elimination of the acetate at 5 and formation of the enone 85, The presence of that function

98

STEROIDS

(84)

(87)

HO CIO

(94)

eliminates possible future complication due to the known facile rearrangement of halogen from the 2 to the 4 position. Thus exposure of the intermediate _85^ to bromine gives the 2,2 dibromo derivative 86^ Elimination of one of those halogens by means of lithium carbonate and lithium bromide leads to the vinylic bromide 87j these basic conditions achieve simultaneous elimination of the 11 mesylate and formation of the 9,11 olefin. That last

STEROIDS

99

function i s then used f o r introduction of the 9 a - f l u o r o - l l ~ 3-alcohol

by the

standard

scheme.

Thus exposure of

the

o l e f i n to HOBr (aqueous NBS) gives bromohydrin 88 (diaxial opening of

the i n i t i a l l y

formed a-bromonium intermediate).

Treatment with base gives the 3-epoxide J39_. oxirane

with

hydrogen

fluoride

leads

antiinflammatory agent haioprednone (90).

Opening of the

finally

to

the

c

4.MISCELLANEOUS STEROIDS The cardiostimulant action of extracts of the leaves of the foxglove plant ( D i g i t a l i s purpurea) were recognized as early as the

eighteenth

extracts

led

cardiac

to

century. the

glycosides

generally

Careful

isolation

of

which consist

substituted

by

an

examination a series

of

of

of

hydroxylated

unsaturated

these

so-called steroids

five-membered

lactone at the 17 position and glycosidated by a series of sugars at the 3 p o s i t i o n . extremely failure

useful

in

the

heart

of

extremely t o x i c .

the

Though these drugs have proved treatment

muscle,

they

of

diseases

are

at

the

marked by same time

Only a very narrow margin exists between

e f f e c t i v e and toxic doses.

( I t i s of i n t e r e s t that the need

to carefully adjust blood levels of d i g i t a l i s contributed to he b i r t h of the science of pharmacokinetics.) is

a great

margin

of

Though there

need f o r

a digitalis-like

drug with a greater

safety,

there

surprisingly

has

been

little

synthetic e f f o r t devoted to t h i s area. I t i s known that the presence of the 14$-hydroxyl group and a sugar at the 3 position are absolute requirements for activity. reversal Reduction

A modified drug actodigin (100) demonstrates that of of

the

lactone

17 is

digitoxigenin

consistent

9 1 , the

with

activity.

aglycone of

digitoxin

100

STEROIDS

(92) with diisobutylaluminum hydride leads to the diol _93. Oxidation of that intermediate with triethyl amine-sulfur trioxide complex leads to the furan 95^ (This transformation can be rationalized by invoking the intermediacy of an unsaturated hydroxyaldehyde (94), followed by formation of internal acetal 9£.) The hydroxyl at the 3 position is then protected as its chloroacetate (JW- Reaction of the furan ring with MBS followed by hydrolysis of the halide leads to the furanone ring at 17 which is in effect the reversed lactone from ^L. The protecting group is then removed (98), and the alcohol glycosidated with the acetylated halo sugar 99. Removal of the acetate groups by saponification affords actodigin (101). 23

(96)

(9 5)

(97) R = C1CIUC0 L (98) R - H

-0 Br (OAc)

(100) R = Ac (101) R = H

(99)

(102)

STEROIDS

101

One of the triumphs of the science of nutrition is the careful investigation that linked childhood rickets with vitamin D deficiency. This work, which led to methods for treating the disease, is too familiar to need repetition. A direct consequence of these efforts was the elucidation of the pivotal role played by vitamin D in calcium metabolism, as well as the structural studies that revealed that this compound (102) is in fact a steroid derivative. The past several decades have seen the development of physical and spectroscopic methods which allow the study of ever smaller quantities of organic compounds. As a direct outgrowth of this, it has become possible to carry out very detailed studies on the metabolism of endogenous and exogenous organic compounds. Applications of such methods to vitamin D revealed that this agent in fact undergoes further hydroxylation in the body. The very high biological activity of the resulting compounds soon cast doubt on the question whether the vitamin (102) was in fact the ultimate biologically active agent. Detailed work revealed that this metabolism is in fact required for calcium regulatory action. It has been demonstrated that the mono and dihydroxy metabolites act more quickly than vitamin D and that they show much higher potency as antirachitic agents. This finding has some very practical significance since a number of disease states such as kidney failure, which are marked by calcium loss from bone, are associated with deficient vitamin D hydroxylation. The two hydroxylated metabolites, calcifediol (113) and calcitriol (145), have been introduced for clinical treatment of diseases associated with impaired vitamin D metabolism.

102

(104) (105) (106)

STEROIDS

R = H, R' = OH R = Ac, R1 = OH R = Ac, R1 = Cl

(100)

(107)

(108)

(110)

The reported synthesis of the monohydroxy metabolite (113) starts with acid 105 obtained as a by-product from oxidative cleavage of the side chain of cholesterol. This is transformed to the corresponding diazomethyl ketone 107 by reaction of the acetylated acid chloride 106 with diazomethane. Arndt-Eistert rearrangement of that intermediate affords the homologated ester 108. Allylic brornination (109) by means of dibromodimethylhydantoin followed by dehydrohalogenation with trimethyl phosphite establishes the cis diene functionality (110) required for opening of ring B. Reaction of the ester with methyl Grignard reagent completes construction of the side chain (111). Photolysis of that diene affords the product of electrocyclic ring opening (112). It now remains to isomerize the triene function. This is accomplished by thermal equilibration. There is thus obtained caicifidiol (113).^ The low yields reported leave it open to question that this is the commercial route.

STEROIDS

103

HOXAJ

—

tun

(112)

(113)

0

•Or (114)

V

(115)

(116)

Ac ((111178)) R RH

A rather complex stereospecific convergent total synthesis has been reported for caicitriol (145). Construction of the A ring fragment starts with epoxidation of chiral d-carvone (114) to afford epoxide 115. Condensation with the ylide from diethyl (carboxyethyl)phosphonate gives the corresponding ester largely as the E isomer. The epoxide is then opened with acetate (117) and acetylated to give diacetate 118. The methylene group on the side chain is then cleaved to the ketone by means of osmium tetroxide periodate reagent. Bayer-Villiger cleavage of the resulting methyl ketone (trifluoroperacetic acid) affords finally triacetate 120. This is then hydrolyzed (121) and converted to the bis trisilyl derivative 122. Dehydration under yery specialized conditions gives the exo-

104

STEROIDS

methylene derivative 123. The conjugated double bond is then isomerized by irradiation in the presence of a sensitizer (124). The carbethoxy group is then reduced to an alcohol (125) and this converted to the corresponding allylic chloride (126). This reactive function is displaced with lithium diphenylphosphide (127). Oxidation of phosphorus affords the A ring intermediate 128 functionalized so as to provide an ylide.

(120) R = R'1 (121) R = R (122) R = SiMc2tBu, R'

"OR (125) R = Oil (126) R = Cl

STEROIDS

105

The CD fragment is synthesized starting with resolved bicyclic acid 129. Sequential catalytic hydrogenation and reduction with sodium borohydride leads to the reduced hydroxy acid j.3iO, The carboxylic acid function is then converted to the methyl ketone by treatment with methyllithium and the alcohol is converted to the mesylate. Elimination of the latter group with base leads to the conjugated olefin 133. Catalytic reduction followed by equilibration of the ketone in base leads to the saturated methyl ketone 134. Treatment of that intermediate with peracid leads to scission of the ketone by Bayer Villiger reaction to afford acetate 135. The t-butyl protecting group on the alcohol on the five membered ring is then removed selectively by means of trimethylsilyl iodide (136). Oxidation by means of pyridinium chlorochromate gives the ketone 137. That function is then reacted with ethylidine phosphorane to afford the olefin 138. Ene reaction with ethyl propiolate proceeds stereo- and regioselectively to the extended side chain of 139; note particularly that the chiral center at C 2 Q has been introduced in the correct absolute configuration. Catalytic reduction leads to the saturated intermediate 140. The ester function is then reduced to the aldehyde by means of diisobutylaluminum hydride and the acetate saponified to afford 141. Condensation of the aldehyde on 141 with isopropyl phosphorane adds the last required carbon atoms (142). The tertiary hydroxy1 group at the future 25 position is then introduced by means of an oxymercuration reaction (143). Oxidation of the secondary hydroxy1 group completes the synthesis of the CD moiety, 144.

106

STEROIDS

Condensation of the ylide from 144 with the A ring fragment (as its TMS derivative) gives, after removal of the protecting groups, the vitamin D metabolite cacitriol (145). 25

f 129)

OR

R''R =1 C Oli 1((133101) R R = 1C 1H ,,^S R = M R= =H O >2 0

Cft —Cft ((113356)) R tH uO(1A3c7) R= =B

O(1A3c8)

(1•42)O ((114410)) R R= = R'' = =A Hc,, R Hli

(139) ((114443)) R H (145) R= = I0I, O

STEROIDS

107 REFERENCES

1.

K. B. Hogberg, H. J. Fex, I. Konyves, and H. 0. J. Kneip., German Patent 1,249,862 Chem. Abstr. 68, 3118J (1968).

2.

See D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol.1, Wiley, New York, 1977, p. 168.

3.

H. Hofmeister, R. Wiechert, K. Annen, H. Laurent and H. Steinbeck, German Offen. 2,546,062; Chem. Abstr. 87, 168265k (1977).

4.

L. Velluz, G. Nomine, R. Bucort, and J. Mathieu, Compt. Rend., 257, 569 (1963).

5.

D. Bertin and A. Pierdet, French Patent 1,503,984; Chem. Abstr. TO, 4391w (1969).

6.

A. Hirsch, German Offen. 2,327,509; Chem. Abstr. 80, 83401g (1974).

7.

A. L. Beyler and R. A. Ferrari, Ger. Offen., 2,633,925; Chem. Abstr., 86_161310s (1977).

8.

G. 0. Potts, U.S. Patent 3,966,926; Chem. Abstr. j*5, 83244 (1976); note this is a use patent.

9.

D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977, p. 191.

10.

G. H. Phillips and G. Ewan, German Offen. 2,715,078; Chem. Abstr. 88, 38078m (1978).

11.

D. Bittler, H. Hofmeister, H. Laurent, K. Nickiseh, R. Nickolson, K. Petzold and R. Wiechert, Angew. Chem. Int. _Ed_. Engi. _21, 696 (1982).

12. H. J. Fex, K. B. Hogberg and I. Konyves, German Offen. 2,001,305; Chem. Abstr. 73, 99119n (1970). 13. D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977, p. 202.

108

STEROIDS

14. B. J. Poulson, U.S. Patent 3,934,013; Chem. Abstr. 84, 111685f (1976). 15. M. Marx and D. J. Kertesz, German Offen. 2,630,270; Chem. Abstr., 8£, 140,345s (1977). 16.

D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 2, Wiley, New York, 1980, p. 180.

17. A. Thalen and R. Brattsand, Arzneim Forsch. 29, 1607 (1979). 18.

D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977, p. 198.

19. E. Shapiro, et.al. Steroids^, 143 (1967). 20. M. J. Green, H. J. Shue, E. L. Shapiro and M. A. Gentles, U.S. Patent 4,076,708; Chem. Abstr. 89, 110119r (1978). 21. D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977 p. 195. 22. M. Riva and L. Toscano; German Offen. 2,508,136; Chem. Abstr. 84, 31311 (1976). 23. J. M. Ferland, Caru J. Chem. 52, 1652 (1974). 24. J. A. Campbell, D. M. Squires, and J. C. Babcock, Steroids 13, 567 (1969). 25

E. G. Baggiolini, J. A. Iacobelli, B. M. Hennessy, and M. V. Uskokovic, J. Am. Chem. S o c , 104, 2945 (1982).

7 Compounds Related to Morphine Pain is probably the immediate stimulus for more visits to the physician's office than all other complaints combined. Since pain serves as an alert to injury, it is often the first harbinger of disease; pain is thus associated with a multitude of physical ills. The fact that this sensation often persists well beyond the point where it has served its alerting function makes its alleviation a prime therapeutic target. In a very general way, the sensation of pain can be divided into two segments. The first is the immediate stimulus that sets off the chain of events; this could be a surface injury such as a burn or a cut, an inflamed internal organ, or any other disorder that causes pain receptors to be triggered. Following a rather complex series of neurochemical transmissions, the signal reaches the brain, where it is processed and finally 109

COMPOUNDS RELATED TO MORPHINE presented as the sensation of pain. Treatment of pain follows a roughly similar duality. The pain receptors, for example, can be blocked by local anesthetics in those few cases where the insult is localized in the periphery of the body. (In practice, this is restricted to minor surgery and dentistry.) It has recently become recognized that the pain that accompanies inflammation and related conditions is actually triggered by the local synthesis of high levels of prostaglandins; compounds that inhibit this reaction will, in fact, attenuate the pain attendant to the causative inflammation. Cyclooxygenase inhibitors such as aspirin and other nonsteroid antiinflammatory agents have thus found a secure place in the treatment of the mild to moderate pain associated with elevated prostaglandin synthesis. There remains, however, a large category of pain that is not affected by interference at the receptor stage; intervention is achieved in this case at the level of the central nervous system; hence the sobriquet, central analgetics. Rather than blocking or in some way interfering with the pain signal, agents in this class change the perception of the signal. The opium alkaloid morphine (1) is the prototype central analgetic. The fact that its analgetic properties were discovered centuries ago make it clear that in this case theory came a good bit later than practice.

COMPOUNDS RELATED TO MORPHINE

111

Though morphine is an extremely effective analgesic, it has an associated series of side effects that limit its legitimate use. The most prominent among these is, of course, its propensity to cause physical addiction. A significant amount of work has thus been devoted to the synthesis of analogues with a view to modifying the pharmacological spectrum and, in particular, avoiding addiction potential. As will be noted from the following discussion (and that in the earlier volumes), this work has led to structures that have little in common with the prototype molecule. 1.BRIDGED POLYCYCLIC COMPOUNDS It has been found empirically that central analgesics that possess some degree of activity as antagonists of the effects of morphine tend to show a reduced propensity for causing physical addiction. Again empirically, it was noted that this could often be achieved by replacement of the Nmethyl group by allyl, cyclopropylmethyl, or cyclobutylmethyl; additional nuclear modifications often contributed to this activity. Exposure of the opium alkaloid thebaine (2) to mild acid leads to hydrolysis of the enol ether function followed by migration of the double bond to yield the conjugated enone ^. Addition of lithium diethylcuprate proceeds by 1,4 addition from the less hindered side to give the intermediate J-. Treatment of that with cyanogen bromide under von Braun conditions leads to the isol able aminocyanide (S). This is then coverted to the secondary amine (6) by treatment with aqueous base. Alkylation of

112

COMPOUNDS RELATED TO MORPHINE

that intermediate with cyclopropylmethyl chloride affords the analgesic codorphone (7).

(3)

f4")

CH2CH3

(41 R = C M->, (5) R =» CN (6") R = II

"0 (7")

The development of schemes for the total synthesis of the carbon skeleton of morphine revealed that the fused furan ring was not necessary for biological activity. More recently it has been found that substitution of a pyran ring for the terminal alicyclic is also consistent with biological activity. Starting material for this preparation is ketoester 8, available by one of the classical benzomorphan syntheses. Condensation with the ylide from diethyl(carbethoxyethyl)phosphonate affords diester 9. (The course of the reaction is probably helped by the fact that the 3-ketoester can not undergo tautomerism to its enol form.) Catalytic reduction proceeds from the less hindered face to afford the corresponding saturated diester (10). Reduction of the carbonyl function by means of lithium aluminum hydride gives the glycol JJj this undergoes internal ether formation on treatment with acid to form the pyran ring of 12. Treatment with cyanogen bromide (or ethyl chloroformate) followed by saponification of the

COMPOUNDS RELATED TO MORPHINE

113

intermediate leads to the secondary amine (14) • This is converted to the cycl opropyl methyl derivative JL6_ by acylation with cyclopropylcarbonyl chloride followed by reduction of the thus formed amide (JJ>) with lithium aluminum hydride. Cleavage of the 0-methyl ether with sodium ethanethiol affords proxorphan (17).

C8)

(10")

— CH-CH-OH

(15) (16)

(11)

(12)

X? = 0 X = H

(17)

(13) (14)

R = CN(CO 2 CH 3 ) R - H

Replacement of the alicyclic ring of morphine in addition to omission of the furan ring leads to a thoroughly investigated series of analgesic compounds known as the

114

COMPOUNDS RELATED TO MORPHINE

benzomorphans. Depending on the substitution pattern, these agents range in activity from potent agonists to antagonists. Reduction of the carbonyl group in oxygenated benzomorphan JL8_ affords the corresponding alcohol (19), This intermediate is then j^-demethylated by means of cyanogen bromide (20)* Acylation with cyclopropylcarbonyl chloride gives the amide 21. The alcohol is then converted to the ether 22 by treatment with methyl iodide and base. Treatment with lithium aluminum hydride serves to reduce the amide function (£3). Cleavage of the phenolic ether by one of the standard schemes affords moxazocine (24). u \ -on (20) R - II (21) R « COCH(CII2)2 CH2<| N — OC1I,

(23)

(22)

CH (25)

(26)

,-OQQ

(24)

CH,O' 3

H,C

(27)

A rather unusual reaction forms the key step in the preparation of a benzomorphan bearing a fatty side chain. The scheme used to form the benzomorphan nucleus, which is patterned after the Grewe synthesis originally developed for

COMPOUNDS RELATED TO MORPHINE

115

preparing morphinans, is fairly general for this class of compounds. Preparation of tonazocine (33) starts with the condensation of the Grignard reagent from 25 with the pyridinium salt 26. (Note that reaction actually occurs at the more sterically hindered center.) In the usual synthetic route, the enamine function would next be reduced and the olefin cyclized. In the case at hand, however, the diene function of _27_ is condensed with ethyl acrylate in a Diels-Alder reaction (28). Treatment with strong acid leads to cyclization of the olefin into the aromatic ring and formation of the benzomorphan nucleus (29)• Acylation of the anion obtained from that intermediate by means of lithium diisopropyl amide with hexanoyl chloride gives the 3-ketoester jJO. Heating of that compound with formic acid leads directly to the ring-opened benzomorphan 32. This transform can be rationalized as involving proton mediated cleavage of the blocked 3-ketoester to afford 31; decarbethoxylation under the strongly acidic conditions then leads to the observed product. Cleavage of the phenolic ether affords the analgesic agent tonazocine (33) # 5

(32)

(33)

COMPOUNDS RELATED TO MORPHINE

2.PIPERIDIMES S t i l l further simplification of the structural requirements for central analgesic activity came from the serendipitous observation that the simple phenylpi peri dine, meperidine (34), shows biological activity almost indistinguishable from that of morphine. Further elaboration of that molecule led to one of the most potent opioid analgesics, fentanyl (35).

CO2C2H5 C34)

COC H

25 (35)

In-depth investigation of the structure activity relationships in the fentanyl meperidine series in the Janssen laboratories revealed that additional substitution of the amide nitrogen-bearing center resulted in s t i l l further enhancement of analgesic potency. Several compounds were obtained as a result of this work, which showed analgesic activity in animal models at doses some five decade orders of magnitude lower than morphine; the biological profile of these agents i s , however, almost identical to that of the classical opioids. Reaction of the carbonyl group of pi peri done jK>. with cyanide and aniline leads to formation of a cyanohydrin-like function known as an a-aminonitrile (37); hydrolysis under

COMPOUNDS RELATED TO MORPHINE strongly

acidic

38.

conditions

(Although

particularly

under

117 gives

aminonitriles basic

the corresponding amide are

conditions,

aminoamide is a quite stable function.)

somewhat the

labile,

corresponding

The benzyl amine

protecting group is then removed by catalytic hydrogenation (39).

Alkylation with 2-phenethyl bromide proceeds on the

more nucleophilic aliphatic amine to afford j40^. of

the amide function

41.

Ethanolysis

leads to the corresponding

ester,

Acylation of the remaining secondary amine function

with propionyl chloride affords carfentanyl (42).

The same

sequence starting with the corresponding 3-methylpi peri done 7

affords lofentanyl (44).

(36)

(37)

(39)

(38)

(40) R - Nil 2

(42)

(41) R = OC 2 II 5

CH, /

/

3

yr-^

t

C »3 ( C0 9 C 9 !l

C 6 H 5 CH 2 N

COCJIr (43)

(44)

COMPOUNDS RELATED TO MORPHINE Alkylation of intermediate 39^ with 2-(24>romoethylHhiophene affords the corresponding thiophenecontaining compound ^-5. Ethanolysis then leads to ethyl ester (46). Reduction of the carbonyl function affords the carbinol 47. Alkylation of the alkoxide obtained from the alcohol with methyl iodide gives the methyl ether 4^. Acylation with propionyl chloride leads to the very potent opioid analgesic sulfentanyl (49).** In the absence of a specific reference, one may speculate that alkylation of heterocycle 50 with l~bromo-2chloroethane would give the chloroethyl derivative 51. Use of this for alkylation of 39 would give the heterocycle substituted intermediate 52. A similar scheme via structures S3, 53a, and j54^ would then afford alfentanil (55). COR ^

ff~\

/ v CHO 2U NH »» ArCU-CH7N Y

(45) Ator.-O;». = -\ c> ; R = NH9 (47) A0r - -<(,, R= (46) Ar = ~KS> ; OC M 25 0 (52) Ar = ENt N-; R - NH2 0u (53) Ar = EN t^^N- ; R = OC H 2 CH2OCH3 ArCH7CH > ^YCH2OCfH3 2 N Y jf\ (48) Ar = -<s> 0 Ji (54) Ar = EtN^N-

/ vCH n ArCH2CH2N Y

COC 05 2H

(49) Ar

g

0 ll (55) Ar = EtN^N

COMPOUNDS RELATED TO MORPHINE

119

Fusion of an ali cyclic ring onto the pi peri dine so as to form a perhydroisoquinoline is apparently consistent with analgesic activity. Synthesis of this agent, ciprefadol (68), starts with the Michael addition of the anion from cyclohexanone 56_ onto acrylonitrile (57). Saponification of the nitrile to the corresponding acid {58) followed by Curtius rearrangement leads to isocyanate J59. Acid hydrolysis of the isocyanate leads directly to the indoline 61, no doubt by way of internal Schiff base formation from the intermediate amine 6>CL Alkylation by means of trimethyloxonium fluoroborate affords ternary iminium salt 62. Treatment of that reactive carbonyl-like functionality with diazomethane gives the so-called azonia salt 63 (note the analogy to the hypothetical oxirane involved in ring expansion of ketones with diazomethane). Exposure of the aziridinium intermediate to base leads to ring opening and consequent formation of the octahydroisoquinoline (64). Reduction of the enamine (catalytic or borohydride) affords the perhydroisoquinoline 65. This compound is then subjected to one of the jJ~demethylation sequences and the resulting secondary amine (j66J alkylated with cyclopropylmethyl bromide (j>7)O-Demethylation of the phenol ether completes the preparation of ciprefadol (68). 0 EtN

0 NH

N=N (50)

^

EtN

NCH2CH2C1 N=N (51)

120

COMPOUNDS RELATED TO MORPHINE OCH-

OCH-

(56)

(57)

(58)

(59) (60)

R = R =

CO H2

(64)

(62)

An internally bridged arylpi peri dine in which the aryl group has been moved to the 3 position interestingly retains analgesic activity. It should be noted, however, that this compound has been described as nonnarcotic on the basis of its animal pharmacology. Reaction of the carbene obtained from treatment of bromoaryl acetate J5^ with ethyl acrylate affords the cyclopropane JO. The cis stereochemistry of the product probably represents the fact that this isomer shows fewer nonbonding interactions than does its trans counterpart. Saponification of the ester followed by reaction of the resulting diacid (11) with urea leads to the cyclic imidide 72. Reduction of the carbonyl groups is achieved by treatment with sodium aluminumbis[2(methoxy)ethoxy]hydride. There is thus obtained bicifadine (73).10

NCH? <] (65) R = CH, (66) (67) RR == HCH2<]

(68)

COMPOUNDS RELATED TO MORPHINE

121

Br i

3 \

/ C H C °22C 2 H55

2

225 RO 2 C CO 2 R (70) R = C 9 Hr (71) R = FT b

(69)

0 (72)

(73)

3.MISCELLANE0US COMPOUNDS The large amount of synthetic work devoted to central analgesic agents led to the elaboration of fairly sound structure activity relationships. Until fairly recently, structural requirements for analgesic activity could be reliably covered by the so-called Beckett and Casey rule. In its most general form, this requires an aromatic ring attached to a quaternary center with basic nitrogen at a distance of about two carbon atoms from that center. (Fentanyl and its analogues were incorporated by assuming that the fully substituted anilide nitrogen is equivalent to the quaternary center.) Some quite potent analgesics that have recently been prepared do not fit this generalization y/ery well, suggesting that it perhaps needs to be revised. The benzazepines, verilopam (79) and anilopam (81), for example, represent significant departures from the above generalization. Construction of the former starts with the alkylation of veratrylamine (74) with the dimethyl acetal of bromoacetal dehyde to give the secondary amine 7^5. Cyclization under acidic conditions leads to the benzazepine

122 76.

COMPOUNDS RELATED TO MORPHINE The benzylic methoxy group i s then removed by metal-

ammonia

reduction.* 1

Alkylation

with

p-nitrophenethyl

bromide would then give the intermediate 78.

Reduction of

the n i t r o group would thus afford veriiopam (79).

The same

sequence starting with amine 80 affords anilopam (81).

BrCH 9 CH(0CH,)_

(75)

(74)

CH3 NR,

(76)

(78) R = 0 (79) R - II

(77)

" • " • (80)

(81)

The good analgesic efficacy observed with ciramadol (87) and doxpicomine (92) show that location of the basic center directly on the quaternary benzylic center is quite consistent with activity. It is interesting to note in this connection that compound 82^ in which nitrogen is similarly located, shows analgesic potency in the range of suifentanyl that is, some five decade orders of magnitude greater than morphine. 1 9

COMPOUNDS RELATED TO MORPHINE

123

Aldol condensation of the methoxymethyl ether of mmethoxybenzaldehyde (S3) with cyclohexanone affords the conjugated ketone QQr_. Michael addition of dimethyl ami ne leads to the aminoketone W5. Reduction of the ketone proceeds stereospecifically to afford the cis aminoalcohol 86. Mild hydrolysis of the product gives the free phenol, ciramadol 0*7). 1 3

^tf^ (83)

(85)

°

CH3OCH2O^>^<^>f (84)

(86) R = CH 2 OCH 3 (87) R = H

In a similar vein, Knoevenagel condensation of nicotinal dehyde (88_) with di ethyl malonate gives the unsaturated ester 09. Michael addition of dimethyl amine gives the corresponding aminoester (90)* Reduction of the carbonyl groups with lithium aluminum hydride affords the glycol 9^. Formation of the acetal between the diol and acetone gives the analgesic agent doxpicomine (92). ^

124

COMPOUNDS RELATED TO MORPHINE

CO

(88)

2C2H5

(89)

CH-

U ((

O

^ N * ^ C( CH 3 CH 3 (90)

y- CHCH

H

N

(91)

ciuon

N

(92)

REFERENCES 1.

M. P. Kotick, D. L. Leland, J. 0. Polazzi, and R. N. Schut, J_. Med. Chem., 23, 166 (1980).

2*

See, for example, J. A. Baltrop, J. Chem. Soc., 1947 349.

3.

T. A. Montzka, J. D. Matiskella and R. A. Partyka, U.S. Patent 4,246,413; Chem. Abstr. 95, 43442z (1981).

4.

T. A. Montzka and J. D. Matiskella, German Offen. 2,517,220, Chem. Abstr. 84, 59832k (1976).

5.

U* F. Michne, T. R. Lewis, S. J. Michalec, A. K. Pierson, and F. J. Rosenberg, J. Med. Chem., 22, 1158 (1979). ~~

6.

P. G. H. YanDaele, M. L. F. DeBruyn, J. M. Boey, S. Sanczuk, J. T. M. Agten, and P. A. J. Janssen, Arzneim. Forsch., 26 1521 (1971).

7.

W. F. M. YanBever, C. J. E. Niemegeers, and P. A. J. Janssen, J. Med. Chem., 17, 1047 (1974).

COMPOUNDS RELATED TO MORPHINE

125

8.

W. F. M. VanBever, C. J. E. Niemegeers, K. H. Schellekens, and P. A. J. Janssen, Arzneim. Forsch., Wy, 1548 (1976),

9.

D. M. Zimmerman and VI. S. Marshall, U.S. Patent 4,029,796; Chem. Abstr. 87, 102192 (1977).

10. J. W. Epstein, H. J. Brabander, W. J. Fanshawe, C. M. Hofmann, T. C. McKenzie, S. R. Safir, A. C. Usterberg, D. B. Cosulich, and F. M. Lovell, J. Med. Chem., 24, 481 (1981). "~ 11. T. A. Davison and R. D. Griffith, German 2,946,794; Chem. Abstr. £3, 186198 (198 ).

Offen

12. D. Lednicer and P. F. VonVoigtlander, J. Med. Chem., 22, 1157 (1979). "" 13. J. P. Yardley, H. Fletcher, III, and P. B. Russell, Experientia _34, 1124 (1978). 14. R. N. Booher, S. E. Smits, W. W. Turner, Jr., and A. Pohland, J. Med. Chem., 20, 885 (1977).

8 Five-Mem bered Heterocycles A five-membered

heterocyclic

ring

packs a relatively

number of polarized bonds into a relatively space.

small

large

molecular

This provides a convenient framework to which to attach

necessary side chains.

In some cases, the framework i t s e l f

is

believed to be part of the pharmacophore.

1. PYRROLES AND PYRROLIDINES In recent years increasing attention has been paid to the possibility of delaying or even reversing the memory loss that accompanies old age or the more tragic loss of human capabilities associated with premature senility - Alzheimer's disease. Progress is hampered by the difficulty of identifying suitable animal tests, and there is presently no reliable therapy. A series of pyrrolidones shows promise of being cognitionenhancing agents. One of these, amacetam {3), is synthesized readily by ester-amide exchange between ethyl 2-oxo-l-pyrrolidineacetate (ji_) and JM-dii sopropyl ethyl enedi ami ne (2). 1 127

128

FIVE-MEMBERED HETEROCYCLES

*Q CH2CO2C2H5 (1)

A tragic

CH2CONHCH2CHN(CHMe2) (3)

(2)

amount of m o r b i d i t y

w i t h high blood pressure.

and m o r t a l i t y

is

associated

Many drugs operating by a wide v a r i -

ety of mechanisms have been employed to c o n t r o l t h i s c o n d i t i o n . Of the biochemical mechanisms employed by the body t o maintain blood pressure an important one involves conversion of a kidney p r o t e i n , angiotensinogen, t o the pressor hormone angiotensin by a series of enzymes. cleavage of

The l a s t step in the a c t i v a t i o n I t o the much more a c t i v e

angiotensin

I I by the so c a l l e d a n g i o t e n s i n - c o n v e r t i n g enzyme.

I t was be-

lieved

that

angiotensin

involves

inhibitors

of

hypertensive a c t i v i t y . this

converting

Captopril

(6)9

purpose, has found exceptional

of the several

enzyme would have clinical

syntheses of t h i s f a i r l y

ves amidation of t > b u t y l

designed expressly

p r o l i n a t e by

acceptance.

antifor One

simple molecule i n v o l 3-thio~2-methylpropionic

acid (£) followed by acid treatment of the protected i n t e r m e d i ate (5) t o give c a p t o p r i l

(6).2

CH 3 HSCH 2 CHCO 2 CMe 3

—*- HSCH 2CHCON

J C0 2 R

(5) R » CMe 3 (6) R = H

C4)

A nonsteroidal antiinflammatory agent i n which the benzeni ring

c a r r y i n g the

pyrrole

grouping

acetic is

acid moiety

zomepirac

(10)•

has been replaced by a It

is

synthesized

from

FIVE-MEMBERED HETEROCYCLES

129

CO C H c[f 2 2 5

(7) CH

(8)

3V •CH2 CO2R

'N

n V

CH3

| NH2

Cl (9) R « C7H (10) R = H2

(11)

diethyl acetonedicarboxylate, chioroacetone, and aqueous methylamine via modification of the Hantsch pyrrole synthesis to give key intermediate 7^. and thermal

Saponification,

decarboxyiation give ester j8.

monoesterification This is

acylated

with N^,J\[-dimethyl -£-chlorobenzamide (to give 9) and, f i n a l l y , saponification gives zomepirac (10) # 3 Treatment of £-benzoquinone with 1-pyrrolidinylamine

pro-

vides a convenient synthesis of the immunoregulator and a n t i bacterial agent, azarole (11) .^ 2.

FURANS

A biarylpropionic acid derivative containing a furan ring as a prominent feature has antiinflammatory activity.

The patented

synthesis involves a straightforward organometallic addition of ethyl lithioacetate to aldehyde JL2 followed by saponification OH Os.CHCH^CO^H (12)

130

FIVE-MEMBERED HETEROCYCLES

t o give orpanoxin (13) . 5

Installation of a different side chain completely alters the pharmacological p r o f i l e leading to a new class of muscle relaxants.

The synthesis begins with copper(II)-promoted d i -

azonium coupling between furfural (14) and 3,4-dichlorobenzenediazonium chloride (JJ5) to give biarylaldehyde JJ5. densation with 1-aminohydantoin clodanolene (17).

(14)

Next, con-

produces the muscle

relaxant

6

(15)

H (17) The pharmacological v e r s a t i l i t y of this general substitution strategy is further i l l u s t r a t e d by diazonium coupling of 24_ with 2-nitrobenzenediazonium chloride to produce b i a r y l a l dehyde IQ.

Formation of the oxime with hydroxylamine is f o l -

lowed by dehydration to the n i t r i l e .

Reaction with anhydrous

methanolic hydrogen chloride leads to imino ether J ^ and addition-elimination of ammonia leads to the antidepressant amidine,

nitrafudam (20). 7

(18)

(19) X = OCH3 (20) X = NH^

The presence of a furan ring is also compatible with

FIVE-MEMBERED HETEROCYCLES

131

cimetidine-1ike antiulcer a c t i v i t y ,

despite the prominent

session of an imidazole r i n g by h i s t a m i n e , the natural which served as a s t r u c t u r a l amine H2 a n t a g o n i s t s . with

linkage of Q

(25).

displacement

of

the

(25)

primary

histbegins

alcoholic

w i t h cysteamine t o give 22_. An a d d i t i o n - e l i m i n a -

reaction

elimination

of departure f o r the

The synthesis of r a n i t i d i n e

an a c i d - c a t a l y z e d

tion

point

pos-

agonist,

with

22_ ( i t s e l f

reaction)

made from 2A_ by an

completes

the

synthesis

of

additionranitidine

8

v^,

Q

NHCHT

. •* >=CHN0o (21)

7 X (23) X (24) X -

(22)

NHCH, SCH-" 5

(25)

3 . IMIDAZOLES Amoebal i n f e c t i o n s , p a r t i c u l a r l y of farm animals and the female human g e n i t a l i a , are at best only annoying. problem encountered leads to d i f f i c u l t nitroimidazoles

have a c t i v i t y

against

and consequently have been widely One such reaction

with

agent

is

epichlorohydrin

H

0

diarrheas.

A group

the causative

of

organisms

under

from 2-methylimidazole acidic

agent ornidazole

Oli 22 (26)

too often the

synthesized.

synthesized

produces the a n t i p r o t o z o a l

All

H

conditions. (26).9

O H ,223 (27)

by This

132

FIVE-MEMBERED HETEROCYCLES Similarly,

methoxypropane

reaction of 2-nitroimidazole with l,2-epoxy-3i n the presence of potassium carbonate

misonidazole (22.). potentially

useful

10

gives

This agent also has the i n t e r e s t i n g and

additional

property of s e n s i t i z i n g hypoxic

tumor c e l l s to i o n i z i n g r a d i a t i o n . Many nitroimidazoles possess antiprotozoal a c t i v i t y . of these is bamnidazole ( 2 9 ) .

One

Synthesis involves reaction of

imidazole carbonate 28 with ammonia. 11

CII2CH2OCONH2

(28)

(29)

Removal of the nitro group results in an alteration of antimicrobial spectrum leading to a series of antifungal agents. For example, reaction of 2,4-dichloroacetophenone with glycerol and tosic acid leads to dioxolane ^30. Under brominating conditions, sufficient carbonyl-like character exists to allow transformation of 3>0 to 3^ and this product, after esterification, undergoes displacement to 3|2_ with imidazole. Saponification and reaction with mesyl chloride then give 33^. The synthesis of antifungal ketoconazole (34) then concludes by displacement with the phenol ate derived from 4-acetylpiperazinylphenol. 12 n

n

n

COCH,

(30)

(31)

FIVE-MEMBERED HETEROCYCLES

CH2OCO0 ^VCH2N

y

"

(32)

r

133

j

,-CH2OSO2CH3

ii

""21:

N

w

.

| *•

r

C

X J

11

j-O^O-^y/ "n2j2

(33)

W (34)

Displacement of bromine on phenacyl halide 35_ with imidazole gives Ji6.

Reduction with sodium borohydride followed by

displacement with 2,6-dichloro-benzyl alcohol in HMPA then produces antifungal orconazole (37). 1 3

(35)

(36)

(37)

If the displacement reaction is carried out between imidazole derivative J38 and thiophene analogue 29_9 the antifungal agent tiaconazole (40) results.1Lf A rather slight variant of this sequence produces antifungal sulconazole (41J. 15 Obvious variants of the route explicated above for ketoconazole (34) lead to parconazole (_42,)16 and doconazole (j43_),17 instead. Insertion of a longer spacer is compatible with antifungal activity. Reaction of epichlorohydrin with 4-chlorobenzylmagnesium chloride leads to substituted phenylbutane 44. Dis-

(38)

; (39)

(40)

134

FIVE-MEMBERED HETEROCYCLES

Cl S M^M

L II Cl (41)

placement

(42)

with

(43)

sodium i m i d a z o l e ,

conversion

alcohol group t o the c h l o r i d e ( t h i o n y l ment w i t h 2 , 6 - d i c h l o r o t h i o p h e n o l a t e a n t i f u n g a l butoconazole

of

the

secondary

c h l o r i d e ) , and d i s p l a c e -

concludes the synthesis of

(45).18

Cl OH I ,CII2CII2CHCII2C1

S |

(44)

Progressive

(45)

departure

from the

fundamental

structure

of

the lead agent c i m e t i d i n e led t o the a n t i u l c e r agent oxmetidine (47)«

The synthesis

thiouracil elimination

involves ^ - m e t h y l a t i o n

intermediate reaction

4^6 and

with

is

(CH 3 I)

followed

by

the 2«

addition*

2-(5~methyl-4-imidazolylmethylthio)

ethylamine to give oxmetidine ( 4 7 ) . 1 9

(46)

an

of

(47)

0

FIVE-MEMBERED HETEROCYCLES

135

Another entry i n t o the a n t i u l c e r sweepstakes is (50).

It

is

synthesized

by displacement

chloromethyl-5-methylimidazole

of

etinfidine

halide

from 4-

(4^8) w i t h s u b s t i t u t e d t h i o l

4^.

The l a t t e r i s i t s e l f made from t h i o u r e a analogue _51^ by an addi t i o n - e l i m i n a t i o n r e a c t i o n w i t h cysteamine 5 2 . 2 0

CMHN

CH-C1 N

NCN

NCN II

O

+

(48)

(49)

(50)

NCN CH-SCNHCHyC SCH (51)

The a

9

ent

+

iio^n»vjn-n (52)

imidazole-containing

hypnotic/injectable

anesthetic

etomidate (58) is synthesized from 1-amino-l-phenylethane

starting with triethylamine mediated displacement with chloroacetonitrile leading to secondary amine _53. is preferred as starting material.

The d[-enantiomer

This is converted to the

formamide (J54) on heating with formic acid. methylene group is formylated by reaction

Next, the active of _54_ with

formate and sodium methoxide in order to give J55.

ethyl

The now

superfluous J^-formyl group is removed and the imidazole ring is established

upon reaction of J55 with potassium thiocyanate.

The key intermediate in this transformation is probably t h i o urea 55a.

Oxidative desulfurization

b^ with a mixture of sulfuric

occurs on treatment

and n i t r i c

of

acids and the re-

sulting 57_ is subjected to amide-ester interchange with anhydrous ethanolic hydrogen chloride to complete the synthesis of

FIVE-MEMBERED HETEROCYCLES

136

etomidate (58). 2 1 It is possible to form 2-imino-4-imidazolines, such as 59, 2 H situ from creatinine. Treatment of this heterocycle with 3-chlorophenylisocyanate leads to a sedative agent, fenobam (60). 2 2

a

CHCH-

(55)

(53) X - II (54) X - CHO

ru

C IH3-C IHO CHNCHCN I CHO

SH

i 3 A * CHN N

N N \ I COR

V s

NH-, (57) R ( 5 8 ) R - OC:

(561

(5Sa)

»&*** \r

H (59)

(60)

A substituted thiazole ring attached to a reduced imidazo1e moiety is present in a compound that displays antihypertensive activity. Reaction of thiourea 61 with methyl iodide to Cl

NHCNH-

(61)

(62)

FIVE-MEMBERED HETEROCYCLES

137

give the corresponding S-methyl analogue, followed by heating with ethylenediamine, completes the synthesis of tiamenidine (62). 2 3 4. TRIAZOLES Insertion of a triazole ring in place of an imidazole ring is consistent in some cases with retention of antifungal activity. The synthesis of one such agent, azoconazole (64), proceeds simply by displacement of halide j63 with l,2,4-triazole,2l+ The route to terconazole (65) is rather like that to ketoconazole (34)."

(63)

(64)

5.

(65)

PYRAZOLINES

Reaction of substituted hydrazine analogue 66_ with protected $dicarbonyl compound _67^ leads to a ring-forming two-site reaction and formation of the pyrazoline diuretic agent, muzolimine (68). 2 6

"' 2 +• (66)

H.NCOC.H. 2 ,| 2 5 CHCO2C2H5 (67)

^ (68)

As a bioisoteric replacement for a substituted pyrrole ring, a pyrazole ring is a key feature of the nonsteroidal

138

FIVE-MEMBERED HETEROCYCLES

antiinflammatory

agent,

reaction

4-fluorobenzenediazonium

between

pirazoiac

chloroacetate gives hydrazone 69^ morpholino-enamine

(72).

A

Japp-Klingemann

chloride

and ethyl

This i s condensed w i t h the

of £-chlorophenylacetaldehyde

corresponding 4,5-dihydropyrazole 22.*

to

give

Treatment with

the

hydrogen

c h l o r i d e gives an e l i m i n a t i v e aromatization reaction ( 7 1 ) . The

JCT'Q

C OCH

22S f -N— *

(69)

(70)

synthesis

i s completed by homologation through sequential

duction

with

primary

bromide w i t h

function pirazoiac oxide.

with

diisopropylaluminum hydrogen

bromide,

potassium cyanide,

(72), with

hydride,

potassium

converstion

displacement

and h y d r o l y s i s hudroxide

in

re-

t o the of

that

t o the a c i d ,

dimethyl

sulf-

27

(71)

\ ^ J

(72)

6. ISOXAZOLE The 2-aminooxazole analogue, isamoxole (74), is an antiasthmatic agent.

I t s synthesis follows the classic pattern of conden-

sation of hydroxy acetone with jv-propylcyanamide to establish the heterocyclic

ring

{TV).

The synthesis

of isamoxole

(74)

FIVE-MEMBERED HETEROCYCLES

139

concludes by a c y l a t i o n w i t h isopropyl

chloride.28

"3

n^n^ri-^Uj

^

vV

U

CH3

J 2

"** CH CH CH CH

CH3 (73)

(74)

7. TETRAZOLES Conversion of m-bromobenzonitrile to the tetrazole and addition of the elements of acrylic acid gives _75» starting material for the patented synthesis of the antiinflammatory agent, broperamole (76).

The synthesis concludes by activation with thionyl

chloride and a Schotten-Baumann condensation with piperidine. 2 9

NCH,CH,CO,H

(75)

I

\cH~

(76)

8. MISCELLANEOUS Ropitoin (79) is an antiarrythmic compound containing a hydantoin r i n g .

Its synthesis is accomplished by alkylating 77 with

chloride 78 with the aid of sodium methoxide. 30

(78)

(79)

140

FIVE-MEMBERED HETEROCYCLES Reaction

produces 80.

of

ethyl

cyanoacetate

with

ethyl

thiolacetate

a ~L_ and £ mixture of the d i h y d r o t h i a z o l e

This is JN[-alkylated w i t h methyl

derivative

iodide and base ( 8 1 ) , the

a c t i v e methylene group is brominated ( 8 2 ) , and then a d i s p l a c e ment w i t h p i p e r i d i n e

(83)

is

performed.

Hydrolysis

the synthesis of the d i u r e t i c agent, ozoiinone

(84),

F i n a l l y , a mesoionic sydnone, molsidomine as

an a n t i a n g i n a l

1-aminomorpholine give 85.

agent. with

Its

synthesis

formaldehyde

and

completes 31

( 8 8 ) , is

starts

by

hydrogen

active reacting

cyanide

to

N i t r o s a t i o n gives the N-nitroso analogue (86) which

NCCH2CO2C2H5 (80) R « H (81) R - CH3

(82) X «• Br (83) X - N(CH2)

HOCH N

3 —o (84)

cyclizes to the sydnone (87) on treatment with anhydrous acid. Formation of the ethyl carbonate with ethyl chlorocarbonate completes the synthesis of moisidomine (88). 3 2

o —o—o —a I NH 2

I

I

XNCH2CN (85) X » H (86) X » NO

N ^

I N

N (87)

(88)

FIVE-MEMBERED HETEROCYCLES

1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15. 16.

141

REFERENCES Y. L. L'ltalien and I. C. Nordin, U.S. Patent 4,145,347 (1979); Chem. Abstr., 91, 39332p (1979). M. A. Ondetti, B. Rubin, and D. W. Cushman, Science, 196, 441 (1977); Anon., Belgian Patent 851,361. J. R. Carson and S. Wong, J_. MedL Chem., J^6, 172 (1973). R. E. Johnson, Belgian Patent 16,542 (1974); Chem. Abstr., 83, 97007g (1975). S. S. Pelosi, Jr., U.S. Patent 3,962,284 (1976); Chem. Abstr., 85, 159860g (1976). H. R. Snyder, Jr., C. S. Davis, R. K. Bickerton, and R. P. Halliday, ±. Med. Chem., JK), 807 (1967). S. S. Petosi, Jr., R. E. White, R. L. White, G. C. Wright, and C.-N. You, U.S. Patent 3,919,231 (1975); Chem. Abstr., 84, 59168y (1976). Anon., French Patent 2,384,765 (1980); Chem. Abstr., 92!, 58595p (1980). M. Hoffer and E. Grunberg, jj. Med. Chem., J7, 1019 (1974). A. G. Beaman and W. P. Tantz, U.S. Patent 3,865,823 (1975); Chem. Abstr., 82, 170944w (1975). C. Jeanmart and M. N. Messer, German Offen. 2,035,573 (1969); Chem. Abstr., U_9 100044p (1971). J. Heeres, L. J. J. Backx, J. H. Mostmans, and J. van Cutsem, <J. Med. Chem., _22, 1003 (1979). E. F. Godefroi, J. Heeres, J. Van Cutsem, and P. A. J. Janssen, J.. Med_. Chem., JL^, 784 (1969). G. E. Gymer, U.S. Patent 4,062,966. K. A. M. Walker and M. Marx, U.S. Patent 4,038,409 (1976); Chem. Abstr., 87, 152210c (1977). J. Heeres, U.S. Patent 3,936,470.

142

FIVE-MEMBERED HETEROCYCLES

17. J. Heeres, German Offen. 2,602,770 (1976); Chem. Abstr., 86, 29811b (1977). 18. K. A. M. Walker, A. C. Braemer, S. Hitt, R. E. Jones, and T. R. Matthews, _J. MecU Chem., n_, 840 (1978). 19. T. H. Brown, G. J. Durant, J. C. Emmett, and C. R. Ganellin, U.S. Patent 4,145,546 (1979); Chem. Abstr., 90, 204137t (1979). 20. R. R. Crenshaw, G. Kavadias, and R. F. Santonge, U.S. Patent 4,157,340 (1979); Chem. Abstr., 91, 157312e (1979). 21. E. F. Godefroi, P. A. J. Janssen, C. A. M. Van der Eycken, A. H. M. T. Van Heertum, and C. J. E. Niemegeers, J_. Med. Chem., S9 220 (1965). 22. C. R. Rasmussen, U.S. Patent 3,983,135 (1976); Chem* Abstr., 86, 55441a (1977). 23. H. Rippel, H. Ruschig, E. Lindner, and M. Schorr, German Offen. 1,941,761 (1971); Chem. Abstr., 7±9 100054s (1971), 24. G. Van Reet, J. Heeres, and L. Wals, German Offen, 2,551,560 (1976); Chem. Abstr., <85, 94368f (1976). 25. J. Heeres, L. J. J. Backx, and J. H. Mostmans, German Offen. 2,804,096 (1978); Chem. Abstr., 89, 180014b (1978), 26. E. Moeller, K. Meng, E. Wehinger, and H. Horstmann, German Offen. DE 2,319,278 (1974); Chem. Abstr., 82, 57690X (1975). 27. H. Biere, E. Schroder, H. Ahrens, J.-F. Kapp, and I§ Bottcher, Eur.. J_. Medl. Chem., J7, 27 (1982). 28. W. J. Ross, R. G. Harrison, M. J. R. Jolley, M. C# Neville, A. Todd, J. P. Berge, W. Dawson, and W. J. Ff Sweatman, J.. Med. Chem., 229 412 (1979). 29. Anon., British Patent 1,319,357 (1973); Chem. Abstr., 79^ 92231h (1973).

FIVE-MEMBERED HETEROCYCLES

143

30. S. Hayao, H. J. Havera, and W. G. Stryker, U.S. Patent 4,006,232 (1977); Chem. Abstr., 87, 5968c (1977). 32. K. Masuda, T. Kamiya, Y. Imashiro, and T. Kaneko, Chem. Pharm. Bull., 19, 72 (1971).

9 Six-Membered Heterocycles The five-membered heterocycles discussed in the preceding chapter more often than not constituted the pharmacophoric moieties of the drugs in question. Drugs based on sixmembered rings, on the other hand, constitute a somewhat more diverse group. In many cases such as the dihydropyridines and the antibacterial pyrimidines, the ring system again provides the pharmacophore; this section, however is replete with agents in which the heterocyclic ring simply serves as surrogate for an aromatic ring. l.PYRIDIMES Derivatives of anthranilic acid have a venerable history as nonsteroid antiinflammatory agents. It is thus not surprising that the corresponding derivatives in which phenyl is replaced by pyridinyl show much the same activity. 145

146

SIX-MEMBERED HETEROCYCLES

Drugs that are too highly hydrophilic are often absorbed rather poorly from the gastrointestinal tract. It is sometimes possible to circumvent this difficulty by preparing esters of such compounds so as to change their water lipid partition characteristics in order to enhance absorption. Once absorbed, the esters are cleaved by the numerous esterase enzymes in the bloodstream, releasing free drug. Preparation of the first of these prodrugs starts with the displacement bromophthalide 2 by the anion of the derivative 1. Reaction of the intermediate leads to formation of talniflumate ($)•

antiinflammatory of halogen on nicotinic acid 3 with aniline 4

In much the same vein, the basic ester 7 can be obtained by reaction of the same chloroacid with morpholine derivative 6. Reaction with aniline 4 affords morniflumate (8).

(1)

Congestive heart failure represents the end result of a

SIX-MEMBERED HETEROCYCLES

147

complex process which leads eventually to death when the heart muscle is no longer able to perform its function as a pump. Cardiotonic agents such as digitalis (see Steroids) have proved of value in treatment of this disease by stimulating cardiac muscle. The toxicity of these agents has led to an extensive search for alternate drugs. The bipyridyl derivative amri none has shown promise in the clinic as a cardiotonic agent. Starting material for the synthesis is the enaminoaldehyde JJO, obtainable by some version of the Villsmeyer reaction on picoline derivative 9_. Condensation of that with cyanoacetamide in the presence of methoxide leads to pyridone 12. The reaction can be rationalized by assuming that the initial step consists in Michael addition of the anion from acetamide to the acrolein; elimination of dimethyl ami ne would afford the intermediate JLJL. Condensation of amide nitrogen with the aldehyde leads to the observed product. Saponification of the nitrile then gives acid JU3. Treatment under nitrating conditions leads to an interesting reaction that results ultimately in replacement of the carboxyl by a nitro group (14). Reduction of that last function affords the amine; there is thus obtained amrinone (15).

(9)

CHO (10)

OCI! H 2O,N (11)

0

148

SIX-MEMBERED HETEROCYCLES

N-0

H (12) R = CN (13) R = CO2H

(14)

(15)

0II HZNCH2CH2ONO2 (16)

(17)

(18)

Organic nitrite esters such as nitroglycerin have constituted standard treatment for anginal attacks for the better part of the century. These agents, which are thought to owe their efficacy to reducing the oxygen demand of the heart, as a class suffer from poor absorption and yery short duration of action. Nicordanil (18) represents an attempt to overcome these shortcomings by combining a nitrite with nicotinate, the latter moiety itself having some vasodilating action. The drug is obtained in straightforward manner by reaction of nicotinoyl chloride U 6 ) with the nitrite ester (17) of ethanolamine.^ r H

'2 S°2CCI1 ^ c •+ RO2CCI2CHCH2CfCI3) CH3 CH3 (19) (20)

—+- c2H,.o2ccn = CH )2 \ (21) n = C CUC , I!CHC , (CH L, * CH. acne The excessive production of sebum associated with has made life miserable for many an adolescent. Research on acne has, as a rule, concentrated on therapy rather than prophylaxis. A pyrimidone forms an interesting exceptionf being described as an antiseborrheic agent. Starting ketoester 21 can, at least in principle, be obtained by y-

SIX-MEMBERED HETEROCYCLES

149

acylation of the anion from acrylate JL^ with a derivative of acid 2!0. Reaction with hydroxylamine under basic conditions would afford i n i t i a l l y the oxinie 22. This cyclizes to the N-hydroxypyridine, piroctone (23) under the reaction conditions.

HC

I t. 0 N I

no

l

2

(22)

,

2

3 2

AM^

CH-CHCH-C Z j 2 (CH-) 3 2 CH 3 (2 3)

The so-called calcium channel blockers constitute a class of cardiovascular agents that have gained prominence in the past few years. These drugs, which obtund contraction of arterial vessels by preventing the movement of calcium ions needed for those contractions, have proved especially useful in the treatment of angina and hypertension. Dihydropyri dines such as nifedipine (30) are particularly effective for these indications. A variation of the Hantsch pyridine synthesis used to prepare the parent molecule provides access to unsymmetrically substituted dihydropyridines. Though preparation of such compounds by ester interchange of but one ester has been described, these schemes are marked by lack of selectivity and low yields. Thus condensation of enaminoester 23_ (obtained from the corresponding acetoacetate) with acetoacetate 2A_ and benzaldehyde 25 affords nimodipine (26). 5 In a similar

15

0

SIX-MEMBERED HETEROCYCLES

sequence, condensation of the enaminoester from methyl acetoacetate (28) with acetoacetate Zl^ and benzaldehyde gives the calcium channel blocker nicarpi dine (29).

0II 0II + C OCH(CH3) CHO , CH2CH2OC VC H (24) 0 H CH ^CH CH (II 65 2 22 ( (27)

CIO (25)

I2N^ VCI13 (23) + fro2CH, + 2 5 O II N VCH_ (28)

p-Fluorobutyrophenone deri vati ves of phenylpi peri di nes constitute a class of \rery effective antipsychotic agents. It is thus interesting to note that activity is retained when a carbonyl group is inserted between phenyl and the pi peri dine ring. The starting benzoylpi peri dine 32^ can be obtained by any of several schemes starting with the reduced derivative of isonicotinic acid 31. Alkylation with bromoacetal ^3^ 1 eads to the tertiary amine J14. Hydrolysis of the acetal group leads to cloperone (35).

CHT' (30)

SIX-MEMBERED HETEROCYCLES

HO2C-/\R

2 2

(31)

1

V-y

151

(32)

\

NCH CH CH C

2 2 2 "X/

(34)

(33)

F

(35)

2.PYRIDAZINES As noted earlier (Chapter 2) 3-adrenergic blocking agents have found extensive use in the treatment of hypertension. Drawbacks of these drugs include relatively slow onset of action and efficacy in only about half the patients treated. In an effort to overcome these shortcomings, considerable research has been devoted to 3-blockers which incorporate moieties associated with direct-acting vasodilating agents. (On the other side of the coin, the $blocking moiety should control some of the side effects characteristic of the vasodilators, such as increase in heart rate.) Condensation of ketoester J56^ with hydrazine affords the corresponding pyridazinone TL Reaction of that with phosphorus oxychloride leads to the chloro derivative 38. The target compound could then be obtained by first reacting the phenol with epichlorohydrin to give epoxide 39. Opening of the oxirane with tertiary butyl amine would then complete construction of the 3-blocking side chain (40). Displacement of chlorine by hydrazine then affords prizidiioi (41). 8

152

SIX-MEMBERED HETEROCYCLES

PH

.. ..

OH it

A.

-CU (36)

0 / 1\ICH7 OC117C OC117C1I-CH7 > (39)

(37)

9H • OCll?CHCH2NH-t-Bu (40)

(38)

OH I OQUCIiaUNHC (C1U) (41)

3.PYRIMIDINES Though the great majority of antiinflammatory agents contain some form of acidic proton, occasional compounds devoid of such a function do show that activity. Thus the nonacidic pyrazolylpyrimidine epirazole (47) is described as a nonsteroid antiinflammatory agent. Reaction of pyrimidinone jj? with phosphorus oxychloride leads to the chloro derivative 43. Replacement of halogen with hydrazine gives the intermediate 44. Reaction of that with the methyl acetoacetate derivative _45_ (obtained, for example, by pyrololysis of the orthoester) leads to formation of the pyrazole ring. The reaction may be rationalized by assuming initial formation of hydrazone 4^; addtion of the more basic hydrazine nitrogen to the masked carbonyl group followed by elimination of methoxide gives the observed product: there is thus obtained epirazole (47).

SIX-MEMBERED HETEROCYCLES

153 / 0 CH 3

CH, (45)

CH3 (42)

(44)

(43)

x? (47)

(46)

Two closely related diaminopyrimidines have been described as antineoplastic agents. In the absence of specific references, one may speculate that these can be prepared by a general method for the synthesis of aryl diaminopyrimidines. ^ Thus acylation of arylacetonitile 48 with ethyl acetate affords the corresponding cyanoketone (49). Reaction of that intermediate with guanidine can be visualized as first involving formation of the imine derivative J5Oj addition of a second amino group from guanidine to the nitrile gives the cyclized derivative 5JLj tautomerization then gives the observed product, metoprine (52). The same sequence starting with ethyl propionate instead of ethyl acetate will lead to etoprine (53). H I ?x N c c= I I

c=o CH

Cl (48) H

N

(49) Y

N

CH3 (50)

Y

CH, Cl (51)

(52)

(53)

154

SIX-MEMBERED HETEROCYCLES

I n t e r p o s i t i o n of a methylene group between the phenyl ring

and

the

heterocycle

leads

to

the

benzyldiamino-

pyrimidines, a class of compounds notable for t h e i r bacterial ethyl

activity.

anti-

Condensation of hydrocinnamate 54 with

formate leads to the hydroxymethylene derivative 55.

In t h i s case, too, the heterocyclic ring i s formed by r e action initial 56;

guanidine.

This

addition-elimination

cyclization

tion. 57.

with

sequence probably

to the fonnyl

is

carbon to form

in t h i s case involves simple amide forma-

Tautomerization then affords This

involves

converted

to

the hydroxy d e r i v a t i v e

tetroxoprim

(58)

by

first

replacing the hydro^yl by chlorine and then* displacement of halogen with ammonia. CO CJ1

C H

H 2 CO 2 C 2 H 5

(54)

3

O

V^V

C

"

2 C

(55) '"N2

H OCH3 (56)

•Ov<^vCnf^N

(58)

"" OCH3 ( 5 7 a ) R = OH ( 5 7 b ) R = Cl

9 U / 2"2 5 \\ CHOII

SIX-MEMBERED HETEROCYCLES Preparation

of

a l t e r n a t e approach,

155

the

analogue

metioprim

involves

an

Aldol condensation of aldehyde 59 w i t h

p r o p i o n i t r i l e J5(^ gives the c i n n a m o n i t r i l e 6U

Reaction of

t h i s intermediate w i t h guanidine probably i n v o l v e s d i s p l a c e ment

of the

Cyclization

a l l y l i c aniline followed

by

group as the f i r s t step ( 6 2 ) .

tautomerization

affords

metioprim

(63).n

= C

3

CN

^

(59)

(60)

(61)

NSC 2 YasNII •CHs c NH X CII-^ 1 (62)

^"3 (63)

The pyrimidine 5-fiuorouracil (64) is used extensively in the clinic as an antimetabolite antitumor agent. As a consequence of poor absorption by the oral route, the drug is usually administered by the intravenous route. A rather simple latentiated derivative, tegafur (66), has overcome this limitation by providing good oral absorption. Reaction of 5-fluorouracil with trimethylsilyl chloride in the presence of base gives the disilylated derivative (65). Reaction of this with dihydrofuran (obtained by dehydro-

156

SIX-MEMBERED HETEROCYCLES

halogenation

of 2 - c h l o r o f u r a n )

i n the presence o f

stannic

chloride affords directly tegafUr (66).

p

o

(CII3)3S (64)

(65)

(66)

An aryloxypyrimidone has been described as an antiulcer agent; this activity is of note since the agent does not bear any structural relation to better known antiulcer drugs. Displacement of halogen on the acetal of chloroacetaldehyde by alkoxide from m-cresol gives the intermediate §Tj This affords enaminoaldehyde 68_ when subjected to the conditions of the Villsmeyer reaction and subsequent hydrolysis. Condensation with urea may be rationalized by assuming the f i r s t step to involve displacement of the dimethyl ami no group by an addition-elimination sequence (69). Ring closure then leads to the pyrimidone and thus tolimidone (70). 14 CICII7CH(OC9II?)

^

*- v

2

y-ocii9cn(oc7iir)

V ,/

^

*~

Z

Cll 3 (67) CN(CH 3 ) 2

.oc V

CII=;O

(68)

^

^

,

CH-N^

(( y-o~c c=o N V=^ CHO NH, °

(69)

NH

•

V__/ ° \ _ ^ss0 N==N J=^ °

(70)

SIX-MEMBERED HETEROCYCLES

157

4.MISCELLANEOUS HETEROCYCLES A cinnamoylpiperazine is described as an antianginal agent. The key intermediate 12_ can, in principle, be obtained by alkylation of the monobenzyl derivative of piperazine 71 with ethyl bromoacetate (72). Removal of the protecting group then affords the substituted piperazine (73). Acylation of this with 3,4,5-trimethoxycinamoyl chloride gives cinepazet (74).

C,oH-CII 5 9N I. (71)

Mil _/

»• RN N<:H2CO2C2H5 V-/ (72) R =C6HSCH2 (73) R =H

»- CH3O~^ cn3o

V-CH=CHCN

NCH^O-^H,-

(74)

Though dental afflictions constitute a yery significant disease entity, these have received relatively l i t t l e attention from medicinal chemists. (The fluoride toothpastes may form an important exception.) This therapeutic target i s , however, sufficiently important to be the focus of at least some research. A highly functionalized piperazine derivative that has come out of such work shows prophylactic activity against dental caries. Condensation of the enol ether 75 of thiourea with n-pentylisocyanate gives the addition product Th Reaction of this with diamine 78, derived from piperazine, leads to substitution of the methylthio moiety by the primary amine, in all likelihood by an addition-elimination sequence. There is thus obtained ipexidine (79). 16

158

SIX-MEMBERED HETEROCYCLES

CH-(CH 9 ) NHCNHC •">

NH (75)

H9NCH9CH9N I

L

I

(78)

(80)

I

I

4

4

>

SCH,

(77)

(76)

NCH9CH9NH9

L

L

NHCONHCNHCH-CH-N NCH9CH9NHC~ NHC (CH~) CH' II v / 11 II ^4--) NH NH 0 (79)

(82)

(83)

Heterocycles that carry p-anisyl groups on adjacent positions such as indoxole^ and flumizole^ constitute an important subclass among the nonsteroid antiinf 1 ammatory agents that do not possess an acidic proton. It is thus not very surprising to note that a similarly substituted 1,2,4triazine also shows antiinflammatory activity. Condensation of the dibenzyl derivative 80 with semicarbazine affords the heterocyclic ring directly (8^). Reaction with phosphorus oxychloride serves to convert the hydroxyl to chloro (83). Taking advantage of a reaction pioneered by Taylor, this intermediate is then reacted with an excess of the ylide from methyltriphenylphosphoniurn bromide. The first equivalent in all probability displaces halogen to form the substituted phosphonium salt M. This is then converted to its ylide by excess phosphorane. Hydrolysis leads to loss of triphenylphosphine oxide. There is thus obtained 18 anitrazafen (85).

SIX-MEMBERED HETEROCYCLES

159

(84)

(85)

CH,OH HC = O I •+ H7NCH(CII,). + C = 0 (86)

(87) R = H (88) R = COCH 3

Acetylchoiine is one of the fundamental neurotransmitters involved in a wide variety of normal regulatory functions. A number of disease states that may be associated with local excesses of this compound can at least in theory be treated by suppressing its action. Anticholinergic drugs have in practice proved of limited utility because it has been difficult to devise molecules that show much selectivity. The very widespread distribution of necessary cholinergic responses leads to the manifestation of a multitude of side effects when anticholinergic drugs are used in therapy. However, a number of syndromes could in principle, be treated with these drugs if they are applied by the topical route; lack of systemic absorption should avoid the side effects. It should, for example, be possible to treat the stomach lining to suppress the cholinergically mediated acid secretion associated with gastric ulcers. By the same token, direct administration to

160

SIX-MEMBERED HETEROCYCLES

the lung should prevent the bronchoconstriction associated with asthma. Considerable work based on this concept has been occasioned by the observation that quaternary salts of atropine (93), which should not be absorbed systemically, do retain the anticholinergic activity of the parent base. One such salt, ipratropium bromide (92), has undergone considerable clinical investigation as an antiasthmatic agent administered by insufflation (j^e*, topical application to the bronchioles). The fact that the stereochemistry of this agent is the opposite from that which would be obtained by direct alkylation with isopropyl bromide requires that a somewhat longer sequence be employed for its synthesis. Preparation of the key tropine jS6^ is achieved by any one of several variations on the method first developed by Robinson, which involves reaction of a primary amine with dihydroxyacetone and glyoxal. Reduction of the carbonyl group in the product (86) followed by acylation affords the aminoester (88). Transesterification with ester aldehyde 89 CH(CH3)7 2 I (89)

(90) R - CHO (91) R = CHO ,I

. _ CCH,l2CH>.+^CI.3«r (92) °

HOCHC , HLCHN , HCHC , 1 — *- Li1 N-7 I CH2CH2C1 (94) (95)

(93)°

C1CH29CH9NH 2N ,CH2CH2C1 (96)

SIX-MEMBERED HETEROCYCLES

161

leads to J9O. The ester is then reduced to the atropic ester ^ by means of borohydride.19 Attack of methyl bromide occurs from the more open face of the molecule to give ipratropium bromide (92),

HOCH2CH

°v°"\ C1CH2CH2 / v ) CICHJJCH^

(100)

(^7)

£H

c n

c l

0 o-v

1 CH2CH2C1 (98) R « H (99) R = CH2CH2OH

Until the advent of the antitumor antibiotics, alkylating agents were the mainstay of cancer chemotherapy. The alkylating drug cyclophosphamide (100) found probably more widespread use than any other agent of this class. Two closely related agents, ifosfamide (96) and trofosfamide (97), show very similar activity; clinical development of these drugs hinges on the observation that the newer agents may show efficacy on some tumors that do not respond to the prototype. The common intermediate (JH5J to both drugs can be obtained from reaction of phosphorus oxychloride with ami no alcohol 9%. Reaction of the oxazaphosphorane oxide with 2-chloroethylamine gives ifosfamide (96); displacement on bi s(2-chl oroethyl )amine gives trofosf amide ( 9 7 ) . ^ In an alternate synthesis, the phosphorane is first condensed with the appropriate ami no alcohols to give respectively jM^ and 99. These are then converted to the nitrogen mustards by reaction with mesyl chloride, or thionyl chloride.

162

SIX-MEMBERED HETEROCYCLES REFERENCES

1.

M. A. Los, U.S. Patent 4,255,581; Chem. Abstr., 95, 62002x (1981).

2.

G. Y. Lesher and C. J. Opalka, Jr., U.S. Patent 4,107,315; Chem. Abstr. 90, 103844r (1979).

3.

H. Nagano, T. Mori, S. Takaku, I. Matsunaga, T. Kujirai, T. Ogasawara, S. Sugano, and M. Shindo, German Offen, 4,714,713; Chem. Abstr., 88, 22652h (1978).

4.

G. Lohaus and W. Dittmar, German Patent 1,795,831; Chem. Abstr., j», 197347k (1978).

5.

E. Wehinger, H. Meyer, F. Bossert, W. Vater, R. Towart, K. Stoepel, and S. Kazada, German Offen, 2,935,451; Chem. Abstr. 95», 42922u (1981).

6.

Anon. Japanese Patent, 74,109,384; Chem. Abstr. 82, 170642c (1975).

7.

J. W. Ward and C. A. Leonard, French Demande 2,227,868; Chem. Abstr. 82, 17O72Ov (1975).

8.

B. L. Lam, Eur. Pat. Appl. EP 47,164; Chem. Abstr., 96, 217866d (1982). ~

9.

Y. Morita, Y. Samejima, and S. Shimada, Japanese Patent 73 72,176; Chem. Abstr., 79, 137187s (1973).

10. B. Roth and J. Z. Sterlitz, J. Org. Chem., 34, 821 (1969). ~ 11. U. Liebenow and J. Prikryl, French Demande 2,221,147; Chem. Abstr., 82, 156363z (1975). 12. Anon. Belgian Patent 865,834; Chem. Abstr., 90, 54971u (1979). 13.

S. Hillers, R. A. Zhuk, A. Berzina, L. Serina, and A. Lazdins; U.S. Patent 3,912,734; Chem. Abstr., 84, 59538u (1976). ~~ ~~ ~~

SIX-MEMBERED HETEROCYCLES

163

14.

C. A. L i p i n s k i , J . G. Stam, G. D. DeAngelis, and H. J . E. Hess; U.S. Patent 3,922,345; Chem. A b s t r . , 8 4 , 59552U (1976).

15.

F. Faurau, G. Huguet, G. Raynaud, B. Pourias, and M. T u r i n ; B r i t i s h Patent 1,168,108; Chem. A b s t r . , 72, 12768 (1970).

16.

R. A. Wohl; South A f r i c a n A b s t r . . 90, 54980 (1979).

17.

D. Lednicer and L. A. M i t s c h e r , "The Organic Chemistry of Drug S y n t h e s i s " , V o l . 2, Wiley, New York, 1980, p. 255

18.

W. B. Lacefied and P. P. K. Ho, Belgian Patent 839,469; Chem. A b s t r . , 87j 68431 (1977).

19.

W. S c h u l t z , R. Banholzer, Forsch. 2£, 960 (1976).

20.

H. A r n o l d , N. Brock, F. Bourreaux, and H. B e k e l , U.S. Patent 3,732,340; Chem. A b s t r . , 79, 18772 (1973).

Patent

and K.

7,706,373;

H.

Pook,

Chem.

Arzneim

10 Five-Membered Heterocycles Fused to Benzene l.INDOLES Though the therapeutic u t i l i t y of aspirin has been recognized for well over a century, this venerable drug was not classified as a nonsteroid antiinflammatory until recently. The f i r s t drug to be so classified was in

into clinical practice within the past two-score years. Much of the work that led to the elucidation of the mechanism of action of this class of therapeutic agents was in fact carried out using indomethacin. This drug is often considered the prototype of cyclooxygenase (prostaglandin synthetase) inhibitors; it is still probably the most widely used inhibitor in various pharmacological researches. The undoubted good efficacy of the drug in the treatment of arthritis and inflammation at the same 165

166

FIYE-MEMBERED HETEROCYCLES FUSED TO BENZENE

time has led to very widespread use in medical practice. The relatively short duration of action of indomethacin resulted in various attempts to develop prodrugs so as to overcome this drawback. One of these consists of an ami no acid derivative. Thus, reaction of the drug with the chlorocarbonate derivative of dimethylethanol (2) affords the mixed anhydride _3* Reaction of that reactive intermediate with serine [4) leads directly to sermatacin (5). 1 0 0 ,H

8 -f C1COCH2CH2N(CH3)

(jJj ^ v _^CH 2 COCCH 2 CH 2 N(CH 3 ) 2

(2)

(4)

(5)

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate 6^ with p-nitrobenzoyl chloride leads to the corresponding amide [7). Saponification (8) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide; there is thus obtained zidomethacin (ID.12

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

167

H (6) (11)

Serotonin U 2 ) is a ubiquitous endogenous compound that has a multitude of biological activities. For example, the compound lowers in certain biological tests. A compound that would lead to a serotonin derivative after decarboxylation has been described as an antihypertensive agent. (Note, however, that decarboxylation would have to occur by a mechanism different from the well-known biosynthetic loss of carbon dioxide from a-amino acids.) Mannich reaction on indole J ^ with formaldehyde and dimethyl amine gives the gramine derivative 14. Reaction with cyanide leads to replacement of the dimethyl ami no group to give the nitrile jj5. Condensation of that intermediate with dimethyl carbonate and base gives the corresponding ester (j^). Catalytic reduction of the nitrile group [IT] followed by saponification affords indorenate (18).

CH,O>V^NK____

(13)

CIUOv>^v

^CIUR

II (14) R = N(CH3)2 (15) R = CN

C / O2CH, CH,O^^s. ^CH II (16)

168

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

/C02R 1 J| CH2NH2 H (17) R =CH, (18) R =II

CH 2 CH 2 NH 2

II (12)

(19)

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functional!*zed cyclohexanone 20 with phenylhydrazine OjO* The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenylhydrazine Z2_ with 4-hydroxycyclohexanone 123)* The resulting alcohol (240 is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26).

(20)

(22)

(23)

(21)

II F (24) R « 11 (25) R = p-SO2C6H4CH3

F

H (26)

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

169

N"NH2 COC6H5

COC6H5

(27)

(28)

Changing the

(29)

functionality

on the a l i c y c l i c

ring

from an amine to a carboxylic acid leads to a compound that

shows

means of tors.

antiallergic

inhibition

carboxylic

oxarbazole ( 2 9 ) .

0

(30)

acting

possibly

by

the release of a l l e r g i c media-

Thus, condensation

cyclohexanone

0

of

activity, of

acylated

acid

^

indole

affords

ZJ_ with directly

6

0 +

CH 3 CH(CO 2 C 2 H 5 ) 3

Z

(31)

2

5

2

[ I CO 2 C 2 H 5 \^C-CO2C2H I (32)

/C02H 5

(33)

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product [32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole M. This is then esterified (^) and dehydrogenated to the carbazole 36. Saponification leads to the acid and thus carprofen (37) .

170

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

"

(34) R = II (35) R = C 2 H 5

CHCO-R

(36) R (37) R

The salicylic acid functionality incorporated in a rather complex molecule interestingly leads to a compound that exhibits much the same activity as the parent. The 1,4 diketone required for formation of the pyrrole ring can be obtained by alkylation of the enamine from 2tetralone (38) with phenacyl bromide. Condensation of the product, J9, with salicylic acid derivative ^ leads to the requisite heterocyclic system U l ) . The acid is then esterified (4-2) and the compound dehydrogenated to the fully aromatic system (43J« Saponification affords fendosal (44). 8

o (40)

J (38)

*

(39)

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

(41) (42)

R = H R * C2?nH5

(43) (44)

171

R * C~H R H 2"5

An isoindolinone moiety forms part of the aromatic moiety of yet another antiinflammatory propionic acid derivative. Carboxylation of the anion from jp-nitroethylbenzene (45) leads directly to the propionic acid (46). Reduction of the nitro group followed by condensation of the resulting aniline (47J with phthalic anhydride affords the corresponding phthalimide (48). Treatment of that intermediate with zinc in acetic acid interestingly results in reduction of only one of the carbonyl groups to afford the isoindolone. There is thus obtained indoprofen (49).

°2N \

/"CH (45)

(49)

-Ov (46) R (47) R

/

CII

CO-ot (48)

172

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE 2.BENZIMIDAZOLES

A series of benzimidazole and benzimidazolone derivatives from the Janssen laboratories has provided an unusually large

number

particularly

of

biologically

active

compounds,

in the area of the central nervous system.

Reaction of imidazolone i t s e l f with isopropenyl leads

to

the

singly

51.

Alkylation

of

protected this

imidazolone

with

interintermediate Hydrolytic the

to

Chapter

alky l a t e 6)

sedative

Use of

this

j53_

(see

derivative

5*L

pi peri dine

affords

the

removal of the isopropenyl

veterinary

derivative

3~chloro-l~bromopropane

affords the functional!*zed derivative 5j£. cloperone,

acetate

group then gives

milenperone

(5J5)»

sequence using p-fluorobenzoyipiperidine

The

same

{56) gives the

antipsychotic agent declenperone (57). 0 A , ,

HN

(50)

(51)

(52)

A

JfCH2CII2Cll2 (54)

(55)

(53)

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

HN

173

o A0 NCH CH CH Nr~\ S V-C 2

(56)

2

2

(57)

Alkyiation of the monobenzhydryl derivative of piperazine (^8) with the same alkylating agent gives oxatomide (59), after removal of the protecting group• This agent shows antihistaminic activity as well as some mediator release inhibiting activity, a combination of properties particularly useful for the treatment of asthma. 0 ii UN UN

(58)

NCH~CH0CII9N

NCH

^

(59)

A somewhat more complex scheme is required for the preparation of benzimidazolones in which one of the nitrogen atoms is substituted by a 4-piperidyl group. The sequence starts with aromatic nucleophilic substitution on dichiorobenzene j>£ by protected ami nopi peri dine derivative 61_ to give J52. Reduction of the nitro group gives the diamine 63, which on treatment with urea affords the desired benzimidazolone J5£«12 The carbamate protecting group is then removed under basic conditions to give the secondary amine 65. Alkylation of this with the halide obtained by prior hydrolysis of

174

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

intermediate

j>2_

affords

domperi done

(66),

a

very

promising antiemetic agent. /—\ /-N

2H5O2CN

(61)

Cl (62) R * 0 (63) R * H

(601 0 ji

0 / v II HN NCH7CH,CH9N V-N Nil (66)

YCH2CH2N

V-N

Cl (67) Y = Cl (68) Y = NH2 Pi peridinobenzimidazole

(69) 6^ also serves as starting

material for the antipsychotic agent halopemide (69).

In

the absence of a specific reference, one may speculate that the f i r s t step involves alkylation with bromochloroethane to give halide 67.

The chlorine may then be con-

verted to the primary amine J58^ by any of several methods such

as

reaction

hydrazinolysis.

with

phthalimide

anion

followed by

Acylation with jD-fluorobenzoyl

then gives the desired product.

chloride

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

175

A still different scheme is used for the preparation of the benzimidazole buterizine (74). Alkylation of benzhydrylpiperazine 58 with substituted benzyl chloride 70_ gives the intermediate TL Nucleophilic aromatic displacement on this compound by means of ethyl amine leads to 11\ reduction of the nitro group then gives the diamine 73. Treatment of that with the orthoformate ester of pentanoic acid serves to form the imidazole ring. There is thus obtained the peripheral vasodilating agent buterizine (74).

/—\ CHN

NH

+ ClCH-ZVc^NO-

(58)

(70)

(71)

\ CHN

N-^^NR

(72) R = 0 (7 3) R » H

^ / N ^ N '

2 2 2 3

(74)

Amides and carbamates of 2-aminobenzimidazole have proved of considerable value as anthelminic agents, particularly in veterinary practice. A very considerable number of these agents have been taken to the clinic in the search for commercially exploitable agents. (See the section on Benzimidazoles in Chapter 11 of Volume 2 of this series.) A small number of additional compounds have been prepared in attempts to uncover superior agents.

176

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

In a typical synthesis, reduction of the nitro group in starting material 7 ^ leads to the corresponding diamine 76. Reaction with intermediate 77 obtained by acylation of the methyl ether of thiourea with methyl chloroformate, leads directly to fenbendazole (78).^

2 NR2 (75) R = 0 (76) R * II

(77)

(78)

Friedel-Crafts acylation of fluorobenzene with thiophene-1-carboxylic acid gives the ketone 79. Nitration proceeds ortho to the fluoro group to give the intermediate 80. Nucleophilic displacement by means of ammonia [SI) followed by reduction of the nitro group leads to the corresponding amine 81. Treatment of that with reagent 77 gives the anthelmintic agent nocodazole (83). 1 6

^*s C ^ ^ ?

II 0

2

II 0

(79)

^

1

^

0

?

^'S'^'C

" 0

(80)

(81)

HNHCO-CH-

ii 0 (82)

l

ii 0 (83)

I t is of particular note that slight changes in the functionality of this last-named compound lead to a pro-

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE found

change

question,

in

biological

enviroxime,

activity.

177

activity.

shows

The

agent

pronounced

in

antiviral

The synthesis of t h i s compound begins with the

reaction

of

diamine

84

with

cyanogen

bromide.

The

reaction may be r a t i o n a l i z e d by assuming t h a t cyanamide 85

is

the

initially

formed

remaining amine to the product. 86 with

nitrile

addition

will

give the

of

the

observed

Reaction of the anion obtained on treatment of sodium hydride with

apparently affords minor

product;

isopropylsulfonyl

87 as the sole product.

tautomeric

shifts

a l t e r n a t e products.)

could

prodvide

chloride (Note t h a t

at

least

two

Reaction with hydroxylamine affords

the E_ oxime as the predominant product. obtained enviroxime ( 8 § h

17

There i s

thus

Examination of the isomeric

oximes show the J^ isomer to be a good deal more active than the Z counterpart.

axx

H2

N

IN a

(84)

(86)

a

x

o

SO-CHCCH-) L

5

I n c o r p o r a t i o n m a j o r

r a t h e r

c h a n g e by

p o t e n t

i s o t h i o c y a n a t e

2

-

HO<"

o f

a

4 - a m i n o p i p e r i d i n e

b i o l o g i c a l m o d i f i c a t i o n ,

a n t i h i s t a m i n i c 8 9

o

(88)

i n

t h i s

-

N

(87)

o b t a i n e d

o

(85)

0

a

x

w i t h

m o i e t y

a c t i v i t y . a s t e m i z o l e

c o m p o u n d .

p h e n y l e n e d i a m i n e

The

t o

a g e n t

( 9 6 )

R e a c t i o n u n d e r

l e a d s

i s o f

a t h e

c a r e f u l l y

178

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

controlled conditions would lead to the thiourea J>0^. Alkylation with £-f1uorobenzyl bromide then leads to the alkylated derivative ^ . Cyclization of that intermediate gives the benzimidazole ^3.. The carbamate protecting group is then removed under basic conditions. Alkylation of the resulting secondary amine with substituted phenethyl bromide 9$^ proceeds to give astemizole (96). 18

(89)

(90)

(92)

(95)

F

V (93) R * CO 7 C 7 H, (94) R - H l L a

(96)

3.BENZOTHIAZOLES Bioisosteric relations constitute one of the more familiar tools in medicinal chemistry. There are thus sets of atoms that can often be interchanged without much

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

179

influence on the biological activity of the resulting molecules. In many series, for example, it may be quite useful to replace oxygen by sulfur; a sulfoxide sometimes serves in lieu of a ketone. Sulfur and nitrogen, on the other hand, are seldom considered to be a bioisosteric pair. It is thus of note that activity is retained in the antihelmintic compounds in the face of exactly such a substitution. Reaction of aminothiophenol 97 with reagent 98 obtainable from phenylurea and thiophosgene leads directly to the anthelmintic agent frentizole (99). In much the same vein, condensation of 100 with reagent 101 affords tioxidazole (102).

SI I || || »r~Tx + CICNHCNH-^ V ^NH2 \=r/ (97) (98)

(100)

^

(101)

CH^Ov^S^S || T H ^-NICNH ^V^^N (99)

(102)

REFERENCES 1.

H. Biere, H, Arens, C. Rufer, E, Schroeder, and H. Koch, German Offen. 2,413,125; Chem. Abstr., 84, 17731 (1976)

2.

S. Tricerri, E. Panto, A. Bianchetti, G. Bossoni, and R. Venturini, Eur. J. Med. Chem., 14, 181 (1979) -~

180

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

3.

R. N. Schut, M. E. Safdy, and E. Hong, German Of fen- 2,921,978; Chem. Abstr., 92_, 128724f (1980).

4.

A* Mooradian, U.S. Patent 3,959,309; Chem. Abstr., 85^ 123759s (1976).

5.

A. Mooradian, German Offen. 2,240,211 (1973); Chem. Abstr., 78, 136069x (1973).

6.

J. E. Alexander and A. Mooradian, U.S. Patent 3,905,998; Chem. Abstr., 84, 74101 (1976).

7.

L. Berger and A. J. Corraz, German Offen. 2,337,040; Chem. Abstr., 80, 108366g (1974).

8.

R. C. Allen and V. B. Anderson, U.S. Patent 3,931,457; Chem. Abstr., 8^, 105391r (1976).

9.

G. Nannini, P. N. Giraldi, G. Malgara, G. Biasoli, F. Spinel la, W. Logemann, E. Dradi, G. Zanni, A. Buttinoni, and A. Tommassini, Arzneim. Forsch. 23, 1090 (1973).

10.

J. Vandenberk, L. E. J. Kennis, M. J. M. C. Van der Aa, and A. H. M. T. Van Heertum, German Offen. 2,645,125; Chem. Abstr., _87, 102326 (1977).

11.

J. Vandenberk, L. E. J. Kennis, M. J. M. C. Van der Aa, and A. H. M. T. Van Heertum, German Offen. 2,714,437; Chem. Abstr., 88_, 50920n (1978).

12.

P. A. J. Janssen, A. H. M. T. Van Heertum, J. Vandenberk, and M. J. M. C. Van der Aa, German Offen. 2,257,261; Chem. Abstr., 84, 135657 (1976).

13.

J. Vandenberk, L. E. J. Kennis, M. J. M. C. Van der Aa, and A. H. M. T. Van Heertum, German Offen. 2,632,870; Chem. Abstr., 87^, 23274c (1977).

14.

A. H. M. Raeymaekers, J. L. H. Van Gelder, G. M. Boeckx, and L. L. Van Hemeldonck, German Offen., 2,813,523; Chem. Abstr., _90, 54975y (1979).

15.

H. Loewe, J. Urbanietz, R. Kirsch, and D. Duewel, German Offen. 2,164,690; Chem. Abstr., 79, 92217h (1973). "~~~

FIVE-MEMBERED HETEROCYCLES FUSED TO BENZENE

181

16.

J. L. H. Van Gelder, A. H. M. Raeymaekers, and L. F. C. Roevens, German Offen. 2,029,637; Chem. Abstr., 74, 100047s (1971).

17.

J. H. Wikel, C. J. Paget, D. C. DeLong, J. D. Nelson, C. Y. E. Wu, J. W. Paschal, A. Dinner, R. J. Templeton, M. 0. Chaney, N. D. Jones, and J. W. Chamberlin, 3. Med. Chem., 23, 368 (1980).

18.

F. Janssens, M. Luyckx, R. Stokbroekx and J. Torremans, U.S. Patent 4,219,559; Chem. Abstr., 94, 30579d (1981).

19.

C. J. Paget and J. L. Sands, German Offen. 2,003,841; Chem. Abstr., 73, 87920c (1970).

11 Benzof used Six-Membered Heterocycles A diversity of biological effects are possessed by benzofused six-membered

heterocycles.

These

range

from

antimicrobial

activity

to cardiovascular, CNS, and inflammation-influencing

agents.

It

primarily

can be inferred that

a molecular

characteristic volved.

scaffold

pharmacophore

for

the ring system i t s e l f upon which to the

various

is

assemble the receptors

in-

I t is interesting also to note that the range of bio-

a c t i v i t i e s involved d i f f e r

substantially from those seen with

the benzofused five-membered heterocycles described in Chapter 10.

1. QUINOLINE DERIVATIVES Various bioisosteric replacements for a phenolic hydroxyl have been explored.

One such, a lactam NH, is incorporated into the

design of the $-adrenergic blocker, carteolol

(3) m

The fun-

damental synthon is carbostyril derivative U

This is reacted

in the usual manner with epichlorohydrin to give 2, which is in turn

reacted with j>butylamine to complete the synthesis of

carteolol

{3)9 a drug that appears to have relatively

nonspecific myocardial depressant a c t i o n .

1

reduced

Carrying this de183

184

BENZOFUSED SIX-MEMBERED HETEROCYCLES

vice farther results in the pseudocatechol, procaterol (6). OH 0CH~,CHCHoNHC(Cll,)7

OH

rn

Friedel-Crafts alkylation of 8-hydroxycarbostyrils, such as _4, leads to substitution at the C~5 position, namely, 5^ case an a-haloacyl reagent is employed.

In this

Displacement with iso-

propylamine and careful sodium borohydride reduction (care is on (: 2 n 5

* N ^^^ 11 on

0"^ N " ^ ^ " on

(4)

0 "^ N " "

OH

(6)

(5)

needed to avoid reduction of the carbostyril double bond) leads t0

procaterol (6^).

t i v e for

Procaterol is an adren-ergic agonist selec-

32~i~6ceptors•

Thus i t dilates bronchioles without

significant cardiac stimulation. 2 N-aryl often i n h i b i t

anthranilic

acid

("fenamic

acids")

cyclooxygenase and thereby possess antiinflam-

matory and analgesic potency. (90,

derivatives

One such agent,

can also be regarded as a 4-aminoquinoline.

floctafenine The synthesis

begins with a Gould-Jacobs reaction of ni-trifluoromethylani line withdiethyl methoxymethy1ene malonate to give (after additionelimination and thermal cyclization)

quinoline 7_. Saponific-

ation and thermal decarboxylation gets rid of the now surplus carbethoxy group.

The phenolic OH is converted to a chloro

moiety with phosphorus oxychloride, which is displaced in turn

BENZOFUSED SIX-MEMBERED HETEROCYCLES

185

by methyl anthranilate to give fenamic acid 8_. This undergoes ester

exchange

upon

heating

in glycerol

to complete the

3

synthesis of prodrug floctafenine (9) .

OH CO C II

2 2 S

(7)

(8)

Interest in the antimicrobial

(9)

properties of quinol-4-one-

3-carboxylic acids continues at a significant l e v e l .

The syn-

thesis of rosoxacin (12) begins with a modified Hantsch pyridine synthesis employing as component parts ammonium acetate, two equivalents of methyl propiolate, and one of aldehyde. nitric

3-nitrobenz-

Oxidation of the resulting dihydropyridine (JJ3) with

acid followed by saponification, decarboxylation, and

reduction of the nitro group with iron and hydrochloric acid gives

aniline _TL

Gould-Jacobs form the ethyl

This

undergoes

the

classic

sequence

reaction with methoxymethylenemalonate

4-hydroxyquinoline

ring,

ester

and then alkylation

of to

with

iodide and saponification of the ester to complete the

synthesis of the antibacterial agent rosoxacin (12).^

'( w2^n3 «

<-U C III

+

s

fin

Droxacin useful

(16) is a carbabioisostere

antimicrobial

agent,

oxolinic

of the clinically

acid.

Its synthesis

186

BENZOFUSED SIX-MEMBERED HETEROCYCLES

begins w i t h nitrobenzofuran 1 ^ which i s reduced w i t h H2 and a p a l l a d i z e d charcoal reaction quinoline isomer.

with

c a t a l y s t t o give a n i l i n e 14_.

diethyl

ethoxymethylenemalonate

1 ^ along w i t h The synthesis

Gould-Jacobs

gives

some of the a l t e r n a t i v e

hydroxy-

cyclization

i s then completed i n the usual

J ^ - a l k y l a t i o n and s a p o n i f i c a t i o n t o droxacin ( 1 6 ) .

way by

5

ox (13)

(14)

(15)

(16) V

An interestingly complex analogue in t h i s family is flumequine (17).

As might be expected from the knowledge that the

bacterial target is an enzyme (DNAtopoisomerase I I ) , one of the enantiomers is quite potent but the other is not. 6

COC1IC12

^^H-

(18)

Quinfamide

(19) COC1IC12

(19) i s one of a r e l a t i v e l y

small

antiamoebic compounds c o n t a i n i n g a dichloroacetamide The synthesis begins by amidation of l i n e with dichloroacetyl

2-furoyl

of

function,

6-hydroxytetrahydroquino-

c h l o r i d e t o give 18>.

completed by a c y l a t i o n w i t h

family

chloride

The sequence 1i t o give

quinf•

amide (19) , 7

2. ISOQUINOLINE DERIVATIVES Nantradol (25) is an especially interesting agent in that it 1l a potent analgesic that does not act at the morphine receptorii

BENZOFUSED SIX-MEMBERED HETEROCYCLES

187

I t is quickly deacylated in vivo and may qualify as a prodrug. The published synthesis similarities

is

rather long and bears conceptual

to the synthesis of cannabinoids.

five asymmetric centers.

It

has some

Dane salt formation between 3,5-di-

methoxyaniline and ethyl acetoacetate followed by borohydride reduction gives synthon ^ 0 .

The ami no group is protected by

reaction with ethyl chlorocarbonate, the ester group is saponi f i e d , and then cyclodehydration with polyphosphoric acid leads to the dihydroquinolone ring system of 2A_*

Deblocking with HBr

is followed by etherification of the nonchelated phenolic hy~ droxyl to give 72^.

Treatment with sodium hydride and ethyl

formate results in both J^-formylation and C^formylation of the active methylene to give 23.

Michael addition of methyl vinyl

ketone is followed by successive base treatments to remove the

(25)

activating C-formyl group and then to complete the Robinson annulation to give 24_. olefinic

Lithium in l i q u i d ammonia reduces the

linkage and successive acetylation and sodium boro-

hydride reductions complete the synthesis of nantradol

(25). 8

188

BENZOFUSED SIX-MEMBERED HETEROCYCLES

The ]_-form is much the more potent, being two to seven times more potent than morphine as an analgesic. It is called levonantradol. 3. BENZOPYRAN DERIVATIVES The enzyme aldose reductase catalyzes the reduction of glucose to sorbitol. Excess sorbitol is believed to contribute to cataracts and to neuropathy by deposition in the lens and nerves of the eyes in the latter stages of diabetes meilitus. Spirohydantoins have been found to inhibit this enzyme and so are of potential value in preventing or delaying this problem. The S^ enantiomers are the more potent. The synthesis of sorbinil (32) illustrates a method developed for their chiral synthesis, A chiral imine (28) is prepared by titanium tetrachloride-mediated condensation of 6-fluorodihydrobenzopyran~4-one (,26) with ^-a-methyl benzyl ami ne (27) and this is reacted with hydrogen cyanide to give 29^ with a high degree of chirality transfer. The basic nitrogen is next converted to the urea (20) with

I

s

X 3 0 (26)

(27)

C31)

(28)

(29) X = H (30) X = C0NHS0.C1

"CO (32)

highly reactive chlorosulfonyl isocyanate. Treatment with hydrogen chloride results in cyclization to the spirohydantoiff

BENZOFUSED SIX-MEMBERED HETEROCYCLES

189

31^ whose extraneous atoms are removed by hydrogen bromide treatment to give 4-(S)-sorbinil (32). 9 Cannabinoids were used in medicine in the form of their crude extracts many centuries ago. Lately the use of cannabis for so-called recreational purposes has become a national vice of substantial proportions. Several attempts have been made to focus the potentially useful pharmacological properties of marijuana into drug molecules with no abuse potential. Nabilone (37) is a synthetic 9-ketocannabinoid with antiemetic properties. One of the best of the various published routes to nabilone starts with the enolacetate of nopinone (33), which on short heating with lead tetraacetate undergoes allylic substitution to give 34.* Treatment with p-toluenesulfonic acid in chloroform at room temperature in the presence of the modified olivetol derivative 35_ leads to condensation to ^36>. Finally, treatment with stannic chloride at room temperature opens the cyclobutane ring and allows subsequent phenol capture to give optically active nabilone (37). 1 0 OCOCII-

CH-CO-^-OCOCH,

3 (33)

(34)

(35)

(CH2) CH 5 3

(36)

190

BENZOFUSED SIX-MEMBERED HETEROCYCLES Nabitan (39) is a cannabis-inspired analgesic whose n i t r o -

gen atom was introduced in order to improve water

solubility

and perhaps to a f f e c t the pharmacological p r o f i l e as w e l l .

The

phenolic hydroxyl of benzopyran synthon j*8 i s e s t e r i f i e d with 4-(l-piperidino)butyric hexylcarbodimide.

11

sedative-hypnotic, codeine.

acid under the influence of In

addition

nabitran

to

being

dicyclo-

hypotensive and

(39) is a more potent

analgesic

The preparation of synthon J# begins with aceto-

(C112)4CII3 CM,

(38)

phenone _4|0, which undergoes a Grignard reaction and subsequent

(40)

(41)

OH

o ^o

yA

'

(42)

*• (38)

S^ s Y^^(cH 2 ) 4 cH 3 CH

3

(43)

hydrogenolysis to put the requisite alkyl side chain in pi act in ^ L

Ether cleavage (HBr/HOAc) is followed by condensation

with piperidone 42. to give tricyclic 43. Reaction with methylmagnesium bromide and hydrogenolysis of the benzylamine linkagi followed by alkylation gives 3 8 . 1 2

BENZOFUSED SIX-MEMBERED HETEROCYCLES 4.

191

BENZODIOXANE DERIVATIVES

In the 3-adrenergic blocking drug pyrroxan (48), the catechol moiety is masked in a doxane r i n g .

The synthesis begins by

alkylation of phenyl acetonitrile by 2-chloroethanol to produce alcohol 4£. undergoes

Recuction converts this to ami no alcohol 45_ which thermal

(44) X « N (45) X * H,NH9

cyclization

(46)

to

3-phenylpyrrolidine

(46).

(47)

F i n a l l y , a Mannich reaction of 4^ with formaldehyde and 4-acetyl-p-benzodioxane (47) leads to pyrroxan (48)« 1 3 5.

BENZOXAZOLINONE DERIVATIVES

One of a variety of syntheses of the antipsychotic agent brofoxine (50) begins with a Grignard reaction on methyl anthranilate.

The resulting product (4^9) is reacted with phosgene in

pyridine and the synthesis is completed by bromination in acetic acid to give brofoxine*1If

Cll 3

- 3

(49)

(50)

Another CNS active agent in this structural class is the tranquilizer-antidepressant

caroxazone

(52).

Its

published

synthesis begins by reductive ami nation of salicylaldehyde and glycinamide to give J5U

The synthesis is completed by reaction

with phosgene and sodium bicarbonate. 15

192

BENZOFUSED SIX-MEMBERED HETEROCYCLES

CH 2 NHCH 2 CONH 2

-^

(51)

->^ ^ C H

c

(52)

6. QUINAZOLINONE DERIVATIVES The clinical acceptance of the dihydrochlorothiazide diuretics led to the synthesis of a quinazolinone bioisostere, fenquizone (54). The synthesis follows the usual pattern of heating anthranilamide (53) with benzaldehyde whereupon aminal formation t#kes place, presumably via the intermediacy of the Schiffs base. 16

0 (54)

(53)

Synthesis of the CNS depressant/tranquilizer (59)

begins

by alkylation

4-chlorobutyronitrile

to

of piperazine

give J56u

tioperidone

derivative

^

with

Lithium aluminum hydride

reduction gives primary amine _57_, which is next reacted with isatoic anhydride to give anthranilamide a n a l o g u e ^ . reaction with phosgene gives tioperidone (59).

Finally,

17

o (55)

(56) R = CN (57) R • CH-NH-

T

^ SCH 0 CH 0 CH T

(59)

(58)

CH

3f

CH

2)2S

BENZOFUSED SIX-MEMBERED HETEROCYCLES

193

An apparently unexpected by-product

of

studies

on 1,4-

benzodiazepines is the antiinflammatory agent fluquazone (63). The synthesis

begins by reaction

synthon J50 with trifluoroacetyl 61,

Reaction of this

cyclization

last

of

typical

benzodiazepine

chloride to give intermediate

with ammonium acetate

and cleavage to fluquazone

presumably, through a variant

(63).

leads to

This occurs,

of a scheme involving

facile

cleavage of the labile trichloromethyl group, perhaps via _62, followed by cyclodehydration. 18

(60) A related traditional acetic

acid

antiinflammatory

agent

prepared

route is fluproquazone (65). results

(63)

(62)

(61)

in

transamidation

via

a more

Heating with urea in by

synthon

subsequent cyclodehydration completes the synthesis.

(64)

CH2CF3

6£ and

19

CH(CH3)2 (65)

An antipsychotic agent with a chemical structure somewhat similar to that of tioperidone (59) is ketanserin (68). The synthesis involves the straightforward

thermal

alkylation of

194

BENZOFUSED SIX-MEMBERED HETEROCYCLES

0 NCH2CH2C1 A (66)

(67)

(68)

J^3-(2-chloroethyl)quinazolinedione (66) with piperidinylketone 67.. 20 Alteration of the structural pattern produces a pair of adrenergic a-blocking agents which serve as antihypertensives. These structures are reminiscent of prazocin. Reaction of piperazine with 2-furoyl chloride followed by catalytic reduction of the furan ring leads to synthon 6£. This, when heated

NH2 0 (69)

(70)

(71)

in the presence of 2-chloro~4-aminoquinazoline derivative 7£t undergoes direct alkylation to terazocin (71^) . 2 1 On the other hand, acylation of quinazoline TL_ with oxadiazole derivative 1]^ gives the antihypertensive tiodazocin (74) J11

^

(72)

N

- N

+

a c o A

o

(73)

A

(74)

BENZOFUSED SIX-MEMBERED HETEROCYCLES 7.

195

PHTHALAZINES

Phthalazines commonly possess adrenergic activity. carbazeran (77), is a cardiotonic agent.

One such,

Its patented synthe-

sis involves nucleophilicaromatic displacement of chlorophthalazine derivative 75. with piperidinyl carbamate T6_ to give carbazeran 8.

(TV).23 BENZODIAZAPINES AND RELATED SUBSTANCES

The huge c l i n i c a l success of drugs in this class has spawned an enormous l i s t of congeners.

Synthetic a c t i v i t y has, however,

now slowed to the point that a separate chapter dealing with these heterocycles is no longer warranted. Elfazepam stimulates

(80)

not

feeding

in

only satiated

is

a tranquilizer, animals.

One

but of

also

several

syntheses involves reaction of benzophenone derivative ^78. with a glycine equivalent masked as an oxazolidine-2,5-dione (79). 2Lf

(75)

C1

(76)

(77)

A water-soluble phosphine derivative

-N

y

of diazepam allows

for more convenient parenteral tranquilizer therapy and avoids some complications due to blood pressure lowering caused by the propylene glycol medium otherwise required for administration. Fosazepam (82)

is

prepared from benzodiazepine Bl^ by sodium

hydride-mediated al kylation with oxide. 2 5

chloromethyldimethylphosphine

196

BENZOFUSED SIX-MEMBERED HETEROCYCLES

Cl(78)

(79)

(80)

Lormetazepam (84) is readily synthesized by Polonovski rearrangement of benzodiazepine oxide derivative J33 by heating with acetic anhydride followed by saponification of the resulting rearranged ester. 26 The mechanism of this rearrangement to analogous tranquilizers has been discussed previously in this series. 27 Quazepam (88) has a highly fluorinated sidechain so as to make this tranquilizer resistant to dealkylation. I t also incorporates a lipid-solubilizing 2-thione moiety. The synthesis begins with biarylketone derivative jte by Nkalkylation with 2,2,2-trifluoroethyltriclate to give 86. 0 II

CH2P(CH3)2 4-

C1CH2PO

(82)

(81)

(83)

(84)

BENZOFUSED SIX-MEMBERED HETEROCYCLES Next the product

is acylated w i t h bromoacetyl

g l y c i n e equivalent synthesis

197 c h l o r i d e and the

i s constructed in place by a Gabriel

(phthalamide anion followed by hydrazine)

t o which c y c l i z a t i o n t o benzodiazepine 87_ occurs. sis of the t r a n q u i l i z e r quazepam (88)

amine

subsequent The synthe-

is f i n i s h e d by thioamide

conversion with phosphorus p e n t a s u l f i d e . 2 8 A number of benzodiazepines have h e t e r o c y c l i c l a t e d t o them. Nitrosation

the t r a n q u i l i z e r

midazolam

(94).

(HONO) of secondary amine ^9_ leads to the J^-nitroso

analogue JK). undergo

One such is

rings anne-

Nitrosoamidines,

carbon-carbon

in the presence of

bond f o r m a t i o n .

Treatment

carbanions, of _90^ w i t h

nitromethane and potassium t>butoxide

results

in formation

91.

reduces

both the

Raney n i c k e l - c a t a l y z e d treatment

bond and the Treatment

with

alkyl

nitro

either

and polyphosphoric

group t o

ethyl

give

orthoacetate

acid r e s u l t s

saturated or

acetic

of

double

amine 92^. anhydride

in c y c l i z a t i o n t o JSK3 which

is

converted t o the fused imidazole 94^, midazolam, on dehydrogena t i o n w i t h manganese d i o x i d e . Another alprazoiam (95) analogue is adinazolam ( 9 8 ) .

+

(85)

(87) X = 0 (88) X = S

C1 3 CSO 3 CH 2 CF 3

^

(86)

This

BENZOFUSED SIX-MEMBERED HETEROCYCLES

198

substance is prepared from benzodiazepine synthon 96^ by amidation of the hydrazine moiety with chloracetyl chloride followed by thermal cyclization in acetic acid to 92.. Reaction with potassium iodide and diethylamine results in net displacement of the allylic halogen and formation of the tranquilizer and antidepressant, adinazolam (98). 3 0

(92)

(91)

CH-

(93)

(94)

9. MISCELLANEOUS The antianginal agent diltiazem (104) is synthesized starting with opening of the epoxide moiety of J9^ with the anion of 2nitrothiophenol to give 100. This is resolved with cinchoni-

(95)

(96)

(97) (98)

X = Cl X = N(CH3)2

BENZOFUSED SIX-MEMBERED HETEROCYCLES

199

dine and reduced to the amine (101) before cyclodehydration to lactam 102.

This was alkylated with

2-chloroethyldimethyl-

amine, using dimethylsulfinyl sodium as base, to give 103.

The

synthesis of the more active jd-form of cardioactive diltiazem (104)

is concluded by acetylation with acetic anhydride and pyridine. 31 OCH, NO?2 CHOH (99)

CO2CH3 (100) OCH-

(101)

1.

2. 3. 4. 5. 6.

(102) X = H (103) X - CH2C!I2N(CH3)2

CH2CH2N(CH3)2 (104)

REFERENCES K. Nakagawa, N. Murakami, S.Yoshizaki, M. Tominaga, H. Mori, Y. Yabuuchi, and S. Shintani, J_. Med. Chem., 17, 529 (1974). S. Yoshizaki, K. Tanimura, S. Tamada, Y. Yabuuchi, and K. Nakagawa, cL Med. Chem., JL9>, 1138 (1976). A. Allais, Chim. Ther., IB, 154 (1973). Y. Lescher and P. M. Carabateas, ILS. Patent 3,907,808 (1975); Chem. Abstr., 84, 43880p (1975). R. Albrecht, EJUT. JJ. Med^. Chem., Ij2, 231 (1977); Ann., 762, 55 (1972). J. F. Gerster, S. R. Rohlfing, and R. M. Winandy, Abstr. _N. Am. Med^. Chem. Symp. 20-24 June, 1982, p. 153.

200 7.

8. 9. 10.

11.

12.

13.

14. 15.

16. 17. 18.

BENZOFUSED SIX-MEMBERED HETEROCYCLES D. M. Bailey, E. M. Mount, J. Siggins, J. A. Carlson, A. Yarinsky, and R. G. Slighter, J^. Med. Chem., _2£, 599 (1979). M. R. Johnson and G. M. Milne, J_. Heterocyci. Chem., JT^ 1817 (1980). R. Sarges, H. R. Howard, Jr., and P. R. Kelbaugh, LL Org. Chem., 47, 4081 (1982). R. A. Archer, W. B. Blanchard, W. A. Day, D. W. Johnson, E. R. Lavagnino, C. W. Ryan, and J. E. Baldwin, J_. Org. Chem., j42, 2277 (1977). R. K. Razdan, B. Z. Terris, H. K. Pars, N. P. Plotnikoff, P. W. Dodge, A. T. Dren, J. Kyncl, and P. Somani, cL Med. Chem., L9, 454 (1976). M. Winn, D. Arendsen, P. Dodge, A. Dren, D. Dunnigan, R, Hallas, H. Hwang, J. Kyncl, Y.-H. Lee, N. Plotnikoff, P. Young, H. Zaugg, H. Dalzell, and R. K. Razdan, ^. Med, Chem., 19^ 461 (1976). V. A. Dobrina, D. V. Ioffe, S. G. Kuznetsov, and A. G, Chigarev, Khim. Pharm. Zhu, IB, 14 (1974); Chem. Abstr., 81_, 91445k (1974). L. Bernardi, S. Coda, A. Bonsignori, L. Pegrassi, and G, K. Suchowsky, Experientia, 24-, 774 (1968). L. Bernardi, S. Coda, V. Nicolella, G. P. Vicario, A, Minghetti, A. Vigevani, and F. Arcamone, Arzneim. Forsch«t 29^, 1412 (1979); L. Bernardi, S. Coda, L. Pegrassi, and K. G. Suchowsky, Experientia, 24, 74 (1968). G. Cantarelli, II Farmaco, Sci. Ed[., 2b_9 761 (1970). R. F. Parcel 1, Ul.Si. Patent^ 3,819,630; Chem. Abstr., 80j 146190k (1974). L. Bernardi, S. Coda, V. Nocolella, G. P. Vicario, A, Minghetti, A. Vigevani, and F. Arcamone, Arzneim. Forsch M

BENZOFUSED SIX-MEMBERED HETEROCYCLES

19. 20.

21. 22. 23.

24. 25. 26.

27.

28. 29.

201

29^ 1412 (1979); L Bernardi, S. Coda, L. Pegrassi, and K. G. Suchowsky, Experientia, J24, 774 (1968). P. G. Mattner, W. G. Salmond, and M. Denzer, French Patent 2,174,828 (1973). J. Vandenberk, L. E. J. Kennis, M. J. M. C. Van der Aa, and A. H. M. T. van Heertum, Eur. Patent Appi. 13,612 (1980); Chem. Abstr., ^ 4 ; 65718a (1981). M. Winn, J. Kyncl, D. A. Dunnigan, and P. H. Jones, U.S. Patent 4,026,894 (1977); Chem. Abstr., 8^; 68411m (1977). R. A. Partyka and R. R. Crenshaw, U.S. Patent 4,001,237 (1977); Chem. Abstr., 86; 140028r (1977). S. F. Campbell, J. C. Danilewicz, A. G. Evans, and A. L. Ham, British Patent Appl. GB 2,006,136 (1979); Chem. Abstr., 91; 193331u (1979). Anon., Japanese Patent JP 709,691 (1970); Chem. Abstr., 8£; 133497r (1974). E. Wolfe, H. Kohl, and G. Haertfelder, German Patent DE 2,022,503 (1971); Chem. Abstr., 16; 72570c (1972). S. C. Bell, R. J. McCaully, C. Gochman, S. J. Childress, and M. I. Gluckman, ^. Mech Chem., Jl, 457 (1968); S. C. Bell and J. C. Childress, £. 0r£. Chem., Z7, 1691 (1962). D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Wiley, New York, Vol. 1, p. 365; Vol. 2, p. 402. M. Steinman, J. G. Topliss, R. Alekel, Y.-S. Wong, and E. E. York, ±. Med. Chem., 16, 1354 (1973). A. Walser, L. E. Benjamin, Sr., T. Flynn, C. Mason, R. Schwartz, and R. I. Fryer, d_. £r£. Chem., 4-3, 936 (1978); R. I. Fryer, J. Blount, E. Reeder, E. J. Trybulski, and A. Walser, J^. 0r£. Chem., ^ 3 , 4480 (1978).

202

BENZOFUSED SIX-MEMBERED HETEROCYCLES

30. J. B. Hester, Jr., A. D. Rudzik, and P. Voigtlander, ^. MecL Chem., 23, 392 (1980), 31. H. Inoue, S. Takeo, M. Kawazu, and H. Kugita, Zasshi, 93^, 729 (1973); H. Kugita, H. Inoue, M. M. Konda, and S. Takeo, Chem. Pharm. Bull,, (1971).

F.

Von

Yakugaku Ikezaki, 19^, 595

12

Beta-Lactams

After 40 years of clinical use, benzyl penicillin {I) remains an extremely effective and useful drug for the treatment of infections caused by bacteria susceptible to it. It fails, however, to be a perfect drug on several grounds. Its activity spectrum is relatively narrow; it is acid and base unstable and so must be given by injection; increasingly strains carry enzymes (ft-lactamases) that inactivate the drug by hydrolysis; and it is haptenic so that many patients become allergic to it. Many analogues have been synthesized in order to overcome these drawbacks and a substantial number of semi synthetic penicillins, cephalosporins, cephamycins, and so forth, have subsequently been marketed. Recently new impetus has been added to the field by the discovery of new ring systems in fermentation liquors and through development of novel synthetic approaches so that the field of 3-lactam chemistry is now characterized by the feverish activity reflected in the number of entries in this chapter. 1. PENICILLINS One of the most successful penicillin analogues has been 203

204

BETA LACTAMS

ampiciilin (2). The relatively small chemical difference between ampicillin and benzylpeniciilin not only allows for substantial oral activity but also results in a substantial broadening of antimicrobial spectrum so as to allow for use against many Gram-negative bacteria. Many devices have been employed in order to enhance still further the oral absorption of ampiciliin. Bacampicillin (6) is a prodrug of ampicillin

•CHCONH-si

L-S

(1) R + H (2) R = NH 2 R I

II

(3)

H

J U

S 0

' CH3

0

(5) R = N 3 (6) R = Nil2

designed for this purpose. An azidopenicillin sodium salt (3) is reacted with mixed carbonate ester _4 (itself prepared from acetaldehyde and ethyl chlorocarbonate) to give ester ^. Reduction of the azido linkage with hydrogen and a suitable catalyst produces bacampicillin (6). Both enantiomers [starred (*) carbon] are active. The drug is rapidly and efficiently absorbed from the gastrointestinal tract and is quickly cleaved by serum esterases to bioactive ampiciTHjn (2J, acetaldehyde, carbon dioxide, and ethanol.1 Sarpicillin (10) is a double prodrug of ampicillin in that not only is the carboxy group masked as an ester, but i

BETA-LACTAMS

205

hetacillin-like acetonide has been added to the C-6 amide side chain. Its synthesis begins with the potassium salt of

(7) R = K (8) R = CH-OCH-

(9)

(10) X = H (11) X = OH

penicillin V^ (phenoxymethy1peni ci11 i n, 2) which is esterified with methoxymethyl chloride to give <8. This is reacted with phosphorus pentachloride and the resulting imino chloride is cleaved to the free amine with N.»J^~ dimethyl aniline. Amine 9^ then reacts with phenylglycyl chloride in acetone to complete the synthesis of sarpacillin (!£)« 2 The acetonide is presumably formed after acylation. A closely related prodrug °f arooxycillin, known as sarmoxicill in (11), is made in the same way but with reaction of amine 9_ with the hydrochloride of ]3-hydroxyphenyl glycyl chloride in acetone being involved instead. 3 An important molecular target of the 3-lactam antibiotics is an enzyme that acts as a transpeptidase in the stepwise polymerization leading to a thickened, strong bacterial cell wall. Several ami no acids are present in addition to the terminal J3-alanyl -ID-alanyl unit which the Strominger hypothesis suggests has the same overall shape and reactivity as ampiciiiin. This suggests that acylation of the ami no group of ampiciilin might lead to enhanced affinity or at least would be sterically allowable. It is interesting to find, therefore, that such acylation broadens the antimicrobial spectrum of the corresponding pencil 1 ins so that they now include the important

206

BETA-LACTAMS

Gram-negative pathogen Pseudomonas aeruginosa. Meziociilin (13), one such agent, can be made in a variety of ways including reaction of ampicillin with chlorocarbamate triethylamine.* 4

12 in the presence of

Chlorocarbamate }2_

0 u

I N

iNUULi N COC1 ,

^.

AM I

1NLUJNM

IUINHN.

J (12)

itself

^ J

N^A

(13) X = SO-CH(14) X = H

is made from ethylenediamine by reaction with phosgene

to form the cyclic urea followed by monoamide formation with methanesulfonyl

chloride

and

then

reaction

nitrogen atom with phosgene and t r i m e t h y l s i l y l

of

the

other

chloride.

The

closely related analogue a z l o c i l l i n (14) is made in essentially the same manner as for m e z l o c i l l i n , but with omission of the mesylation step. 5 of

Interestingly, a z l o c i i l i n is the more active

the two against

vitro.

many Pseudomonas

An interesting

alternative

aeruginosa synthesis

of

strains

j£

azlocillin

involves activation of the substituted phenylglycine analogue 1^ with l,3-dimethyl-2-chloro-l-imidazolihium chloride (16) and then condensation with 6-aminopenicillanic acid. C

Cl CH 3 N

NCH 3

j^S^CO 2 H

lA, (15)

5

>6

2H5

C i R

(16)

(17) R = H (18) R = C0C1

(19)

BETA-LACTAMS Another antimicrobial

207 acylated

ampicillin

derivative

spectrum is p i p e r a c i l T i n

with

expanded

Its

synthesis

(19),

begins with l - e t h y l - 2 , 3 - d i k e t o p i p e r a z i n e

(17_, which i t s e l f

is

made from J^-ethyl ethylenediami ne and diethyl o x a l a t e ) , which is activated by sequential reaction with t r i m e t h y l c h l o r o s i l a n e and then

trichloromethyl

chloroformate

to

give JLj8.

This

last

reacts with a m p i c i l l i n (2) t o give p i p e r a c i i l i n (19) which is active

against,

among

others,

the

Enterobacteriaceae

Pseudomonads that normally are not sensitive to a m p i c i l l i n . Continuing

this

theme,

pirbenicilTin

(22)

JN|~acylated antipseudomonal a m p i c i l l i n analogue. begins

by

acylating

j^-carbobenzoxyphenylglycine bodiimide group.

and J^-hydroxysuccinimide The protecting

CBZ group

acid

removed

treatment with sodium carbonate to give ^ £ ,

with

dicyclohexylcar-

to a c t i v a t e is

another

I t s synthesis

6-aminopenicillanic by reaction with

is

and 7

the

carboxyl

from JL9^ on

The synthesis of

p i r b e n i c i 11 i n is completed by reaction with 4-pyridoiminornethyl ether (21) ( i t s e l f prepared from 4-cyanopyridine and anhydrous methanolic hydrogen c h l o r i d e ) . 8

*"-C07H

(19) R = C,H[.CH7OCO (20) R = H

(21)

(22)

P i r i d i c i i l i n (27) is made by J^-acylating amoxycillin with a rather complex acid. The synthesis begins by reacting IN^-diethanolamine with £-acetylbenzene-sulfonyl chloride to give 23. Conversion (to 24) with ethyl formate and sodium

208

BETA-LACTAMS

methoxide with

is

followed

cyanoacetamide,

cyclodehydration

by

base-catalyzed

during

occurs

to

the

course

produce

S a p o n i f i c a t i o n of the c a r b o x y l i c acid ^

(HOCH 2 CH 2 ) N S 0 2 V * * K h 1 F II ^^COCH

addition-elimination of the

which pyridone

reaction (25).

is followed by carboxy

HN

*- ArCOCH=CHOCH,

(23)

*" Ar

3

(24)

(25) R - CN (26) R - CO 2 H

(27)

activation using the active ester method (dicyclohexylcarbodiimide and j^-hydroxysuccinimide) and condensation with amoxyciilin to produce the broad spectrum antibiotic, p i r i d i c i l l i n (27) . 9 There is only one clinically significant penicillin at present that does not have an amide side chain. Meciliinam (amidinociilin, 29) has, instead, an ami dine for a side chain• It has very l i t t l e effective anti-Gram positive activity but i t is quite effective against Gram-negative microorganisms. Its synthesis begins by reacting J^-formyl-1-azacycloheptane with oxalyl chloride to form the corresponding imino chloride (28)« This is then reacted with 6-aminopenicillanic acid to produce meciliinam.1Q A prodrug form, ami di noci11i n pi voxyi (30), is

BETA-LACTAMS made i n

the

209 same manner by

methyl 6-aminopenici11anoate

reaction instead.

of

2Q w i t h

pivaloyloxy-

11

V©

(29) R « H (30) R » CII2OCOC(CH3)

2. CEPHALOSPORINS Widespread clinical acceptance continues to be accorded to the cephalosporins, and the field is extremely active as firms search for the ultimate contender. Among the characteristics desired is retention of the useful features of the older members (relatively broad spectrum, less antigenicity than the penicillins, relative insensitivity toward 3-lactamases, and convenience of administration) while adding better oral activity and broader antimicrobial activity (particularly potency against Pseudomonas, anaerobes, meningococci, cephalosporinase-carrying organisms, and the like). To a considerable extent these objectives have been met, but the price to the patient has been dramatically increased. Cephachlor (35) became accessible when methods for the preparation of C-3 methylenecephalosporins became convenient. The allylic C-3-acetoxyl residue characteristic of the natural cephalosporins is activated toward displacement by a number of oxygen- and sulfur-containing nucleophiles. Molecules such as Q can therefore be prepared readily. Subsequent reduction with chromium(II) salts leads to the desired C-3 methylenecephems (_32)» which can in turn be ozonized at low temperatures to produce the C-3 keto analogues. These are

BETA-LACTAMS

210

isolated in the form of the C-3 hydroxycephem enolates

(33).

Next, treatment with a variety of chlorinating agents (SOC12, PCI 3 , POC13, (C0C1)2» and C0C12) in dry DMF solvent produces the C-3 chloro analogues (34.)* so that the C-7 side chain is

The reaction can be carried out removed by the imino chloride

method so as to allow i n s t a l l a t i o n of the 7-D-2~amino-2~phenylacetamido side chain of cephaclor (35).

H

H

RCONI

(31)

2

(32)

(33) X - OH (34) X - Cl

HH

(35)

Conceptually closely related, cefroxadine (40) can be prepared by several routes, including one in which the enol (33) is methylated with diazomethane as a key step, A rather more involved route starts with comparatively readily available phenoxymethylpenicillin sulfoxide benzhydryl ester (3>6). This undergoes fragmentation when treated with benzothiazole-2-thiol t ° 9^ve 2Z_Ozonolysis (reductive work-up) cleaves the olefinic linkage and the unsymmetrical disulfide moiety is converted to a tosyl thioester (38). The enol moiety is methylated with diazomethane, the six-membered ring is closed by reaction with l,5-diazabicyclo[5.4.0]undec-5-ene (DBU), and the ester protection is removed with trifluoroacetic acid to

BETA-LACTAMS 91ve

2i«

211 arrn

The

"de

side

chain

is

removed by the

phosphorus pentachloride/dimethylaniline

sequence followed by

reamidation with the appropriate acid chloride. all this is cefroxadine (40).

usual

The result of

13

I

N

**%COCH(C6H5)

°

"y-^4"

2

C0?CH(CfiHr)

(36)

(37)

u;

CO-CH (CM,) 2

(38)

2

2M

(39)

CO-H (40)

Possessing a side chain at C-7 amoxacillin and a more typical cefatrizine mediated

(44)

can

condensation

with JN-silyl

3-cephem

be of

reminiscent

of that

synthesized

by

the

active

ester

t-B0C-2-£-hydroxyphenylglycine

synthon

of

sulfur containing C-3 moiety,

42_.

The

(41)

t^-butyloxycarbonyl

protecting group of intermediate 4^3 is removed with formic acid in order to complete the synthesis of cefatrizine (44), a broad spectrum cephalosporin. l t f intermediate prepared

42_ from

from

(£-butyllithium)

7-aminocephalosporanic

l-Nkbenzyl-2-azoimidazole

acid

(4J5)

by

can

removed reductively

be

lithiation

followed by t h i o l a t i o n (hydrogen sulfide)

give intermediate %6_* synthon 47.

The t h i o l necessary for synthesis of

to

The protecting benzyl moiety is then

with

sodium in

liquid

ammonia to

give

212

BETA-LACTAMS

o

NHCO 2 C(CH 3 ) CCH 3 ) 3 SiNH^

T (41)

J

^S

, A

N^

gJL^

N ^H5<

010020(^13)^

(42)

CH.C.H,-

(43) R - C(CH,), (44) R « H ^ 3

(45) R » H (46) R - SH

(47)

Structurally rather similar to cefatrizine is cefaparole 12* ^ ^s Prepared in quite an analogous manner by active ester condensation of 41^ and 7-aminocephalosporanic acid analogue 48^. The blocking group is removed with trifluoroacetic acid in anisole (9:1) to give cefaparole; Racemization does not take place during the synthetic sequence so the desired R I stereochemistry of the side chain amino group is 11+ retained.

(48)

(49)

Analogous to azloci11i n-mezloci11i n, acylation of the amino group of 2-phenylglycine containing cephalosporins 1s consistent with antipseudomonal activity. There are many

BETA-LACTAMS

213

routes to cefoperazone (52). One of the more obvious is the condensation of cephalosporin antibiotic bO_ with 2,3-diketo-piperazine 51^ under modified Schotten-Baumann 15 conditions.

(50)

(51)

(52)

Cefonicid (55) is synthesized conveniently by nucleophilic displacement of the C-3 acetoxy moiety of 53^ with the appropriately substituted tetrazole thiol ( ^ ) . 1 6 The mandelic acid amide C-7 side chain is reminiscent of cefamandole.

H

tt.

HO^^CONHN

2

CH OSO H

(53)

(54)

(55)

Cefazaflur (58) stands out among this group of analogues because i t lacks an arylamide C-7 side chain (see cephacetrile for another example).17 Cefazaflur (58) is synthesized by reaction of 3-(l-methyl-lH-tetrazol-5-ylthiomethylene)~7~amino~ cephem-4-carboxylic acid {56) with trifluoromethylthioacetyl chloride (57). 18 H F 3 CSCH 2 CONH

J

" t 0^ (57)

C02H (56)

^H

3

H y

o I > *^^ CH S -^-N CO2H CH3 (58) N

214

BETA-LACTAMS Cefsuiodin (60) has a s u l f o n i c acid moiety on the C-7 acyl

side c h a i n .

This moiety

conveys

antipseudomonal

activity

to

certain penicillins, and i t is interesting to note that this artifice works with cefsulodin as well. It is also interesting that, in contrast to the other so-called third-generation cephalosporins, the spectrum of cefsulodin is rather narrow and its clinical success will place a premium upon accurate diagnosis. Its synthesis begins by acylation of 7-aminocephalosporanic acid with the acid chloride of 2-sulfonylpheny1acety1 chloride to give cephalosporin 59. Reaction of that intermediate with aqueous potassium iodide and isonicotinic acid amide results in acetoxyl displacement from C-3 and formation of cefsulodin (60). 2 1 The quaternary base at C-3 is reminiscent of the substitution pattern of cephaioridine. The structural feature of ceforanide that is of particular interest is the movement of the C-7 side chain ami no moiety from the position a to the amide carbonyl, where i t normally resides in ampici11in/cephalexin analogues, to lodgement on a methylene attached to the ortho position on the aromatic ring.

H3 N

(60) X = . _ V

C

°2H

C0NH

(61)

2

CH

2CO2H

(62)

2

CO2C2H,

2

H

H

0

^ C

(63)

°2 H

(64)

BETA-LACTAMS This

puts

215 it

considerably

geometrically

alters

upon p r o t o n a t i o n .

in

t h e same

the e l e c t r o n i c

general

character

area but

of the molecule

The synthesis of ceforanide (64) begins w i t h

a Beckmann rearrangement

of the oxime

of 2-indanone

(61J t o

give lactam 6#. Hydrolysis followed by p r o t e c t i o n of the amino group as the enamine (6>3) allows f o r subsequent mixed anhydride (isobutylchlorocarbonate)-mediated

amide

corresponding

synthon t o give

(64).

7-aminocephalosporin

formation

with

the

ceforanide

The r e q u i s i t e nucleophile f o r the C-3 moiety i s prepared

simply

by

carbonation

of

the

l-methyl-l-IH-tetrazol-5-ylthiol. Cefotiam bioisosteric

(67) with

has

an

acyl

an anilino

lithio

derivative

of

22

aromatic

ring.

It

C-7

side

chain

can be prepared by

acylation of the suitable acid moiety with 4-chloroacetoacetyl

H II C1CH9COCH.,CONH,J L S * j T C0 H

2

CH9CH2NCCH-) 2

(65)

0

0 (66)

chloride to give amide _65_. Chloride displacement with thiourea leads to cyclodehydration to the aminothiazole cefotiam (67), probably via intermediate 66. 23 The interposition the

amide carbonyl

of a syn-oximino ether moiety between

and the aromatic

ring has proved

richly

?2 CH, (''VCH2C0NH> t ^' n<J (68)

r- 5 ^ Ns^CH.OH CO2CH02

H N

T5^ N^^CH.OCONHX CO2CH02 (69) X = COCCl^ (70) X = H

2 -i >

..

JiOCH3 ^ Y ] 0 0

| J iN>^-LH2ULUNH2 CO2H (71)

216

BETA-LACTAMS

rewarding

in

that

substantial

resistance

s u l t s from t h i s s t e r i c hindrance. now

bear

this

feature,

for

to

$-lactamases

A large number of analogues

example,

cefuroxime

(71).

synthesis can be accomplished i n a v a r i e t y of ways. ester 68^ (preparable from cephalothin 2 1 *) chloroacetyl

reThe

Benzhydryl

i s acylated w i t h t r i -

isocyanate and the side chain at

C-7

is

removed

v i a the imino c h l o r i d e method ( p y r i d i n e and phosphorus pentac h l o r i d e followed by t o s i c acid) t o produce anic

acid

analogue ^ .

hydrolyzed hydrogen

to

give

chloride

chloride).

Next,

The

carbamate

_70. through

use

(generated the

of

with

benzhydryl

7-aminocephalospormoiety

is

anhydrous methanol

ester

is

partially methanolic

and

acetyl

cleaved w i t h

tri-

f l u o r o a c e t i c acid and the synthesis i s concluded by a SchottenBaumann a c y l a t i o n w i t h the appropriate

syn-oximinoether-bearing

acid c h l o r i d e so as t o produce c e f u r o x i m e . 2 5 An

analogous

third-generation

synthesis

illustrates

requisite

oximino

one

acid

of

the

side

cephalosporin

methods

chains

is

of

whose

preparing

cefotaxime

the (76).

syn-Oxime J72. i s methylated stepwise w i t h dimethyl s u l f o x i d e and base and then c h l o r i n a t e d

( C l 2 in chloroform)

to

produce 21»

A l k y l a t i o n of thiourea w i t h t h i s product r e s u l t s i n concomitant cyclodehydration amino

group

is

to

produce

then

aminothiazole

blocked w i t h

7*L

chloroacetyl

The

primary

chloride,

the

ester group is s a p o n i f i e d , and then the intermediate is used t o acylate

7-aminocephalosporanic

acid c h l o r i d e . then

cleverly

acid

i n the usual

The blocking chloroacetamide moiety removed by

reaction w i t h thiourea

unmask 3-lactamase stable cefotaxime ( 7 6 J . carries

the theme of

synthesis

way v i a

begins

26

of

the

75_ i s

i n order

to

Ceftazidime

(81)

bulky oximino ethers much f u r t h e r .

Its

with

nitrous

acetoacetate t o produce oxime 77.

acid This

treatment is

of

ethyl

next converted

to

BETA-LACTAMS

217

CH 3 C0CCO 2 C 2 H 5 II

-

C1CH 2 COCC0 2 C 2 H 5 II

NOH

^N

NOCH3

(72)

Yo

C73")

C74)

H H &v CONH sj is S NOCH7 CO 2 H (75)

X = COCH 9 C1

a 2-aminothiazoie (7^) by halogenation with sulfuryl chloride followed by thiourea displacement. The ami no group is

NOH

S(77)

(78)

(79)

CO2-t-Bu (80)

CO2H (81)

218

BETA-LACTAMS

protected ethyl

as the

trityl

amine and then ether

2-bromo-2-methylpropionate

Saponification

next

frees

gives

the carboxy

w i t h t_-butyl

7-aminocephalosporinate

carbodiimide

and

formation

with

intermediate

group f o r

79_.

condensation

mediated by d i c y c l o h e x y l -

1-hydroxybenzotriazole.

The

synthesis

is

completed by removal of the p r o t e c t i n g groups from 80^ with t r i fluoroacetic

acid and displacement of the acetoxyl moiety from

C-3 by treatment w i t h give

ceftazidime.

pyridine

Ceftazidime

and sodium iodide (81)

is

quite

in order

resistant

to

to $-

lactamases and possesses useful potency against pseudomonads. 25

Ceftizoxime (83) is structurally

of interest

in that

it

lacks any functionality at C-3 and therefore cannot undergo the usual metabolic deacetylation experienced by many cephalosporins.

Its synthesis involves condensation of the acid chloride

corresponding to ester V{_ (74a) with 3-lactam 82. 2 6

NOCH3 (74a)

COJI (82)

C83)

There are yevy few t o t a l l y synthetic antibiotics presently on the market. (96).

One of these is the 1-oxacephem, moxaiactam

One may speculate that the enhanced potency of moxa-

lactam stems in part from the substitution of the smaller oxygen atom for the sulfur normally present in the six-membered ring of cephalosporins thereby enhancing the reactivity of the adjoining four-membered r i n g .

I t is also partly a measure of

the present stage of development of chemical synthesis and of the relative economics of production of 7-aminocephalosporanic acid that such an involved synthesis apparently is economically competitive.

BETA-LACTAMS

219

Pieces of various routes t o moxaiactam have been published from which the f o l l o w i n g may be assembled as one of the p l a u s ible

pathways.

The

benzhydrol

ester

of

6-aminopenici1lanic

acid (84) is Sr-chlorinated and t r e a t e d w i t h base whereupon the intermediate

sulfenyl

chloride

fragments

( t o J35).

Next,

placement w i t h propargyl alcohol i n the presence of zinc

dis-

chlor-

ide gives predominantly the stereochemistry represented by d i a stereoisomer

8!6^

acetylamide;

the

The side chain triple

bond

is

is

protected

partially

as the phenyl-

reduced w i t h

Pd-CaC03 c a t a l y s t

and then epoxidized with

acid to give 8J_.

The epoxide is opened at the l e a s t

a 5%

rn-chloroperbenzoic hindered

end with the lithium salt of l-methyl-lH-tetrazol-5-ylthiol

to

put in place the future C-3 side chain and give intermediate 88.

Jones oxidation followed in turn by ozonolysis

work-up

with

zinc-acetic

acid)

and

reaction

(reductive

with

thionyl

chloride and pyridine give halide _89^* The stage is now set for an intramolecular

Wittig

reaction.

Displacement

phenylphosphine and Wittig olefination

with

tri-

gives 1-oxacephem J9CL

Next a sequence is undertaken of side chain exchange and i n t r o duction of a C-7 methoxyl

group analogous to that which

is

present in the cephamycins and gives them enhanced 3-lactamase stability.

First _90_ is converted to the imino chloride with

PCI 5 and then to the imino methyl ether next

hydrolyzed to

the

free

amine.

(with methanol) and Imine

3,5-di-t>butyl-4-hydroxybenzaldehyde

is

leading

nickel

to

91_.

Oxidation

with

next

formation

with

carried

out

peroxide

gives

iminoquinone methide _92, to which methanol is added in a conjugate sense and in the stereochemistry i l l u s t r a t e d 93.

in formula

The imine is exchanged away with Girard reagent T to give

94, and this is acylated by a suitable protected arylmalonate, as the hemiester hemiacid chloride, so as to give 9b_. Deblocking with aluminum chloride and anisole gives moxalactam (96).

220

BETA-LACTAMS Moxalactam

is

a synthetic

against Gram-negative b a c t e r i a e x c e l l e n t s t a b i l i t y against

H2NI

antibiotic including

3-lactamases.

Lx

with

good

activity

pseudomonads and has 27

^y

f> ° CH 2 CH

CH2CONH N

CH

2

X N %

CO9CH09

^XJ2^nv>2 (85) X - Cl (86) X - OCH-CSCH

(84)

H2CONH^

OH I 2 '2

/

CO (87)

I

^

^ y

CH2ONH s^

i (88)

CO

H (89)

2CH02

CO 2 CH0 2

^^

(90)

6 f92)

°2 a i *2

CH 3

(93) X - CH OH (94) X - H 2 •OCH-

3

2

OCH,

^CH.O" ^w v CH,O^"

^

CO ? CH0 ? 2 (95)

CO 2 H (96)

2

AH 3

CH

NN I A ,N CCHS N

BETA-LACTAMS

221

REFERENCES 1.

2. 3. 4.

5. 6. 7.

8. 9.

10. 11. 12. 13. 14.

B. A. Ekstrom, 0. K. J. Kovacs, and B. 0. H. Sjoberg, German Offen. 2,311,328 (1973); Chem. Abstr., 80, 14921q (1974). P. Sleezer and D. A. Johnson, German Offen. 2,244,915 (1973); Chem. Abstr., _78, 159590z (1973). P. Sleezer and D. A. Johnson, South African 75 04,722 (1976); Chem. Abstr., 86, 171440y (1977). W. Schroeck, H. R. Furtwaengier, H. B. Koenig, and K. G. Metzer, German Offen. 2,318,955 (1973); Chem. Abstr., 82, 31313b (1975). H. B. Koenig, K. G. Metzer, H. A. Offe, and W. Schroeck, Eur. J_. Med. Chem., J7, 59 (1982). V. J. Bauer and S. R. Safir, J^. Med[. Chem., 9>, 980 (1966). I. Saikawa, S. Takano, C. Yoshida, 0. Takashima, K. Momonoi, T. Yasuda, K. Kasuya, and M. Komatsu, Yakugaku Zasshi, 97_, 980 (1977). E. S. Hamanaka and J. G. Stam, South African 74 00,509 (1973); Chem. Abstr., S3_9 58808z (1975) J. S, Kaltenbronn, J. H. Haskell, L. Daub, J. Knobie, D. DeJohn, U. Krolls, N. Jenesei, G.-G. Huang, C. L. Heifitz, and M. W. Fischer, Jl. Antibiotics, 32, 621 (1978). F. Lund and L. Tybring, Nature, New Biol ., 236, 135 (1972). F. J. Lund, German Offen. 2,055,531 (1971); Chem. Abstr., ^ 5 , 49070k (1971). R. R. Chauvette and P. A. Pennington, J_. MecL Chem., 18^ 403 (1975). R. B. Woodward and H. Bickel, U.S. Patent 4,147,864 (1979); Chem. Abstr., 91, 74633J (1979). G. L. Dunn, J. R. E. Hoover, D. A. Berges, J. J. Taggart,

222

15.

16. 17. 18.

19. 20.

21.

22.

23. 24.

BETA-LACTAMS L. D. Davis, E. M. Dietz, D. R. Jakas, N. Yim, P. Actor, J. V. Uri and, J. A, Weisbach, J_. Antibiotics, 29, 65 (1976). I. Saikawa, S. Takano, Y. Shuntaro, C. Yoshida, 0. Takashima, K. Momonoi, S. Kuroda, M. Komatsu, T. Yasuda, and Y. Kodama, German Offen., DE 2,600,880 (1977); Chem. Abstr., 87_, 184533b (1977). D. A. Berges, U.S. Patent 4,093,723 (1978); Chem. Abstr., 89, 180025f (1978). D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Wiley, New York, 1980, Vol. 2, p. 441. R. M. deMarinis, J. C. Boehm, G. L. Dunn, J. R. E. Hoover, J. V. Uri, J. R. Guarini, L. Philips, P. Actor, and J. A. Weisbach, JL, M^d. Chem., £0, 30 (1977). H. Nomura, T. Fugono, T. Hitaka, I. Minami, T. Azuma, $• Morimoto, and T. Masuda, Heterocycies, £, 67 (1974). W. J. Gottstein, M. A. Kaplan, J. A. Cooper, V. H. Silver, S. J. Nachfolger, and A. P. Granatek, J^. Antibiotics, 29_, 1226 (1979). M. Namata, I. Minamida, M. Yamaoka, M. Shiraishi, T, Miyawaki, H. Akimoto, K. Naito, and M. Kida, £• Antibiotics, 31^, 1262 (1978). D. Lednicer and L. A. Mitscher, The Organic Chemistry o^ Drug Synthesis, Wiley, New York, 1977, Vol. 1, p. 417t 420. M. C. Cook, G. I. Gregory, and J. Bradshaw, German Offers DE2,439,880 (1975); Chem. Abstr., 83, 43354z (1975). M. Ochiai, A. Morimoto, T. Miyawaki, Y, Matsushitas Ti Okada, H. Natsugari, and M. Kida, J_. Antibiotics, 34, 171 (1981); R. Reiner, U. Weiss, U. Brombacher, P. Lanz, Mi Montavon, A. Furlenmeier, P. Angehrn, and P. J. Probsti J. Antibiotics, 33, 783 (1980).

BETA-LACTAMS

223

25. C. H. O'Callaghan, D. G. H. Livermore, and C. E. Newall, German Offen. DE 2,921,316 (1979); Chem. Abstr., 92, 198413c (1980). 26. T. Takaya, H. Takasugi, K. Tsuji, and T. Chiba, German Offen. DE 2,810,922 (1978); Chem. Abstr., _90, 204116k (1979). 27. H. Otsuka, W. Nagata, M. Yoshioka, M. Narisada, T. Yoshida, Y. Harada, and H. Yamada, Med. Res. Revs., 1_, 217 (1981); M. Narisada, H. Onoue, and W. Nagata, Heterocycles, 7_, 839 (1977); M. Narisada, T. Yoshida, 0. Onoue, M. Ohtani, T. Okada, T. Tsugi, I. Kikkawa, N. Haga, H. Satoh, H. Itani, and VI. Nagata, J_. Med. Chem., 22, 757 (1979).

13 Miscellaneous Fused Heterocycles Medicinal agents discussed to this point have been roughly classifiable into some common structural groups; biological activity often followed the same rough classification. As was the case in the preceding volumes in this series, a sizable number of compounds, often based on interesting heterocyclic systems, defy ready grouping by structure. These are thus discussed below under the cover of "miscellaneous." It might be added as an aside that this section may include compounds that will someday move to new chapters. If one of these drugs proves to be a major clinical or marketing success, it will no doubt occasion a considerable amount of competitive work. Since some of this work will undoubtedly result in agents with generic names, the class may well finally grow to the point where it will 225

226

MISCELLANEOUS FUSED HETEROCYCLES

require listing as a structural group. A rather simple derivative of imidazoimidazoline has been described as an antidepressant agent. Preparation of this compound starts with the displacement of the nitramine grouping in imidazoline derivative JL_ by phenylethanolamine 2. The product of this reaction is then treated with thionyl chloride. The probable chloro intermediate (4J cyclizes under the reaction conditions to afford imafen (5). Oil CHCI0NH~

H3 H CD

(2)

0 II CIICNH (6)

X I CHCIIn

(31 X = Oil (4) X = C\

(51

H 2 N-

(8)

(CII,) CHCNH'^*N5^CCH7NH--v' [I 2 " S"^ (9)

CIO)

The imidazothiazoline tetramisole (6_) has shown quite good activity as a broad spectrum anthelmintic agent. This drug has in addition aroused considerable interest as an agent which modifies the host immune response. Further substitution on the aromatic ring has proved compatible with activity. Displacement of halogen on the phenacyl bromide 7^ with ami nothi azol e S_ affords the alkylated product^. Catalytic hydrogenation serves to reduce both the heterocyclic ring and the carbonyl group (10). Cyclization by means of sulfuric acid completes the synthesis of butamisole (11).

MISCELLANEOUS FUSED HETEROCYCLES

227

0 II ) CHCNH 2 (11)

Benzofurans of the very general structure represented by 12 have formed the basis of several quite effective drugs for treatment of cardiovascular disease. It is thus of note that replacement of the aromatic nucleus by the isosteric indolizidine system affords a compound with quite similar activity. Friedel-Crafts type acylation of indolizidine JU^ with substituted benzoyl chloride J ^ gives the ketone (15). Removal of the protecting group gives the free phenol. Alkylation by means of N,N-di(jv-butyl )~2-chloroethylamine affords the corresponding basic ether. There is thus obtained the antiarrhythmic agent butoprizine (17). 3

(12)

(13)

(14)

OCH 2 CH 2 (n-C 4 H 9 )

^C=0

(17)

228

MISCELLANEOUS FUSED HETEROCYCLES

Aggregation of blood platelets is the requisite f i r s t event for the maintenance of intact circulation in the face of any break in a blood vessel. I t is the platelet clump that starts the long and complicated process leading to closure of the broken vessel by an organized blood clot. Though this property of platelets is vital to maintenance of the circulatory system, an excessive tendency to aggregation can also lead to problems. Thus platelet clumps formed in blood vessels in the absence of injury can lead to blockade of blood circulation and subsequent injury. Strokes and some types of myocardial infarcts have thus been associated with platelet clumps. The nonsteroid antiinflammatory agents as a class show platelet antiaggregation activity in a number of test systems; however, there has been a considerable amount of effort expended to uncovering agents from other structural classes that will not share the deficits of the nonsteroid antiinflammatories. Ticlopidine [2A)9 a drug that shows good activity in various animal models has undergone extensive clinical testing as a platelet antiaggregator. The key intermediate 21 is in principle accessible in any of several ways. Thus reaction of thiophenecarboxaldehyde J ^ with amninoacetal JL9^ would lead to the Schiff base ^Oj treatment with acid would result in formation of the fused thiophene-pyridine ring (21). Alkylation of that intermediate with benzyl chloride 22 gives the corresponding ternary i mini urn salt 23. Treatment with sodium borohydride leads to reduction of the quinolinium ring and thus formation of ticlopidine (24).

MISCELLANEOUS FUSED HETEROCYCLES

229

,^2

* s' (18)

(19)

(20)

(21)

Cl

•N CIU

(22)

(23)

^

Cl

(24)

The purines, as is well known, play a very central role in the biochemistry of life. This heterocyclic nucleus is involved in vital processes in a host of guises, from its participation in the genetic message to its part in the energy transmission system and perhaps even as a neurotransmitter. It is thus not surprising that considerable attention has been devoted to this heterocyclic system as a source for drugs; it is somewhat unexpected that so few of these efforts have met with success. The success of antibacterial therapy hinges largely on the fact that the metabolism of bacteria differs sufficiently from that of the host so that it is possible to interfere selectively with this process. Viral infections have been much more difficult to treat because the organism in effect takes over the metabolic processes of the host cell; selectivity is thus \zery slight. One of the signal breakthroughs in this field of therapy is an agent that takes advantage of one of those small differences, acting as a false substrate for a biochemical process necessary for viral replication. It is pertinent that this drug, acyclovir (21) may be viewed as an analogue of the nucleoside guanosine ^8_, in which two of the ring carbons of ribose (or deoxyribose) have been deleted. Preparation of

230

MISCELLANEOUS FUSED HETEROCYCLES

this agent starts with the alkylation of guanine (25) with the chloromethyl ether 25a. Removal of the protecting group (26) by saponification affords acyclovir (27). 0

0

L II > H N ^ N ^ N

L y H N ^ N ^ N 2 H

2

Oil (28)

0 +

ClCH-OCH,CII,OCCftH«.

*-

i I ^ N^M-^N 2 , ROCH3CH2OCII2

II

(OH) (25)

(25a)

(26) R = COC.Hr (2 7) R = H ° s

The uric acid derivative theophyliine (29) is one of the mainstays as a bronchodi lator drug for the treatment of asthma. side

This agent's narrow therapeutic index and host of

effects

derivative.

has led to

an active

search

for

a safer

Synthesis of one such compound starts with the

condensation of a m i n e ^ w i t h methyl isocyanate*

Acylation

of the resulting urea (31) with cyanoacetic acid gives the intermediate 32; this is then cyclized to the corresponding uracil 33_ by means of base.

Nitrosation (34) followed by

reduction of the newly introduced nitroso group gives the ortho

diamine

function

(3$)*

The

remaining

ring

is

constructed by f i r s t acylating 36^ with acetic anhydride (to give ^36J; cyclization again by means of base completes the purine nucleus.

There is thus obtained the bronchodilating

agent verofylline (37).

?N

2

+

CH3NCO

*

CH

3

I b 3

(30)

0

NH

« NH

CH 2 CHCH 2 CH 3

CH 2 CHCH 2 CH 3

(31)

CH 3

(32)

MISCELLANEOUS FUSED HETEROCYCLES

231

2

CH2CHCH2CH3 (33) CH3

(34) C RH=3 0 (35) R = H2

(36)

CH, I CII7

I CH7 (37)

(29)

Beta adrenergic agonists also exert bronchodilating effects. These drugs are thus often used in conjunction with theophiline in asthma therapy. A drug that combines both moieties, reproterol (40), has interestingly proved clinically useful as an antiasthmatic agent. This compound can in principle be obtained by f i r s t alkylating theophylline with l-bromo-3-chloropropane to give J8. Use of this halide to alkylate aminoalcohol j*9_ would then afford reproterol (40). OH O »n

—3*

-

11

™2CH2CH2C1

H

^',,_^

ik

_

C H .r

CH2CH2CH2RCH2CH- "~

Q yjn

""7V

ii

x

" "

CH ~ ( 3 8 )

( 3 9 )

( 4 0 )

As noted earlier (see Chapter 10), 4-acylpiperidines separated from benzimidazole by a three carbon chain often show antipsychotic activity. The heterocycle can apparently be replaced by a pyridopyrimidine ring. Thus alkylation of piperidine 41 with halide 42 affords pirenperone (43). 7

232

MISCELLANEOUS FUSED HETEROCYCLES

o (42)

(41)

(43)

Hydrazinopyridazines such as hydralazine have a venerable history as antihypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester 45 in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromoacetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (_48_K Displacement of halogen with hydrazine leads to the formation of endralazine (49).

(44)

(47) (48)

(45)

X = Oil X = Cl

(46)

(49)

Two closely related pyridotriazines have been described as antifungal agents. Displacement of halogen on nitro-

MISCELLANEOUS FUSED HETEROCYCLES

233

chloropyridine 50 with the monocarbamate of hydrazine affords intermediate 5^. This is then first hydrolyzed to the free hydrazine (52) and the nitro group reduced to the corresponding amine (^3). Condensation of this intermediate with phenylacetic acid leads to formation of the cyclic ami dine derivative 54. Oxidation with manganese dioxide introduces the remaining unsaturation; there is thus obtained triafungin (_55J-9 Condensation of _53_ with phenoxyacetic acid gives, after aromatization of the first formed product, the antifungal agent oxyfungin (56).

4- IIoNNI[C07C9IIc (50)

^

^ I

I

(51) R = C0,C7Flr

(52)

R = II

L

L

J

2

• r [I . 2 (53)

Or N i n (S4)

(55)

(56)

The enormous commercial success of the benzodiazepine anxiolytic agents has spurred a correspondingly large effort in many laboratories aimed at developing novel analogues (see, for example, Chapter 11). In this case it is probably no exaggeration to say that every part of the parent molecule has been modified in the search for novel patentable analogues. In the course of such work it has been found that replacement of the fused benzene ring by a

234

MISCELLANEOUS FUSED HETEROCYCLES

heterocyclic ring is compatible with tranquilizing activity. Preparation of one of the analogues in which benzene is replaced by pyrazole starts by nitration of pyrazole carboxylic acid 57. The product, ^58^ is then converted to the acid chloride (59)- This intermediate is then used to acylate benzene in a Friedel-Crafts reaction. The nitroketone is then reduced to the corresponding amine. Reaction with ethyl glycine can be visualized as involving initially formation of the Schiffs1 base (62)• Displacement of ethoxide by the ring ami no group leads to formation of the lactam. There is thus obtained ripazepam ( 6 3 ) . ^

(57)

(62)

(63)

A somewhat different strategy is employed for preparation of the desoxy analogue containing the reversed pyrazole. Acylation of chloropyrazole (>4_ with m-chlorobenzoyl chloride affords the ketone J>EK Reaction of that with ethyl enediamine leads directly to the anxiolytic agent zometapine (J56K 12 The overall sequence obviously involves sequential Schiff base formation and nucleophilic displacement of chlorine; the order of these steps is not clear.

MISCELLANEOUS FUSED HETEROCYCLES


•3 —• / JT

CH, H

CH

3

(64)

c

235

"3rS

3 "Cl

C65)

O-ci C661

In a similar vein, acylation of aminoketone 67 with chloroacetyl chloride affords the corresponding chloroamide 68. Reaction of that intermediate with ammonia serves to form the diazepine ring, possibly via the glycinamide. The product bentazepam (69) is described as a tranquilizer.

(67)

(68)

6

(69)

Carboxylic acid derivatives of heterocycles have proved a source of compounds that show the same allergic mediator release inhibiting activity as sodium cromoglycate. A number of these agents have been taken to the clinic for trial as antiallergic agents. Friedel-Crafts cyclization of phenoxy ether 70 leads to the corresponding xanthone TL. Exhaustive oxidation of the methyl group leads to the carboxyllic acid, xanoxate (72).

236

MISCELLANEOUS FUSED HETEROCYCLES

0

(70)

(71)

0

(72)

Preparation of the analogue in which isopropyloxy is replaced by a methylsulfoxide involves a somewhat more complex scheme. Aromatic nucleophilic displacement of halogen in dicarbo^yl ester 73 leads to diphenyl ether 7J5. The product is then saponified (_76), cyclized to the xanthone and again esterified (7_8)« The aromatic ether is then demethylated to the free phenol (_79). This group is converted to the thiocarbamate 80^ by means of dimethylthiocarbamoyl chloride. Thermal rearrangement of the thiocarbamate function by the method of Newman results in overall exchange of sulfur for oxygen to afford thiocarbamate SU This is then converted to the free thiol, with accompanying saponification (82). Methylation of the thiol group (83) followed by controlled oxidation of the thioether leads to the sulfoxide. There is thus obtained the antiallergic agent tixanox

(73)

(77) (78)

R = H R = CH 3

(74)

(79)

(75)

R =

(76)

R = H

CH 3

(80)

MISCELLANEOUS FUSED HETEROCYCLES

237

C81)

(82)

o

P. ,C0 o H

(83)

(84)

It has by now been well established that the tricyclic ring system of the phenothiazine tranquilizers is not an absolute requirement for antipsychotic activity; that moiety has been successfully replaced by ring systems as diverse as acridine and even dihydroanthracene. It should thus not be surprising to note that dibenzopyran derivatives also lead to active compounds. Thus reaction of xanthone 85 with the Grignard reagent from chloropiperi dine 86 gives after dehydration the antipsychotic agent clopipazam (87).

(85)

(86)

238

MISCELLANEOUS FUSED HETEROCYCLES

It is by now apparent that the nature of the aryl group in the arylacetic and arylpropionic acid antiinflammatory agents can be varied quite widely without loss of activity. The corresponding derivatives of homologous xanthones and thioxanthones thus both show activity as nonsteroid antiinflammatory agents. Starting material for the first of these agents can in principle be obtained by alkylation of phenol 88 with benzyl chloride J39^ Cyclization of the product (JJO) under FriedelCrafts conditions leads directly to isoxepac (91). 0

CO2H CH2C1 (89)

(92)

^^^

^S^COoH

(88)

(00)

(91)

(93) R - OH (94) R = Cl (95) R « CHN?

(96)

Preparation of the sulfur analogue involves as the f i r s t step cyclization of the terephthalic acid derivative 92. The acid is then converted to the acid chloride and this is allowed to react with diazomethane. Rearrangement of the resulting diazoketone (95) under the conditions of the Arndt-Eistert reaction leads to the homologated acid. There i s thus obtained t i o p i n a c

(96).

1 ft

MISCELLANEOUS FUSED HETEROCYCLES

239

C1CH 2 CH 2 CH 2 N(CH 3 ) 0

CHCH 2 CH 2 N(CH 3 )

(97)

(98)

Antidepressant agents show almost the same degree of tolerance as to the nature of the tricyclic moiety as do the antipsychotic agents. Thus the dehydration product(s) from the condensation of ketone J^with the Grignard reagent from 3-chl oroethyl -JMj[-clii methyl ami ne affords the anti depressant diothiepin (98). 1 9

O (99)

O

O . (100)

(101)

Historically, both the tricyclic antipsychotic and antidepressant agents are derived in almost direct line from a series of tricyclic antihistaminic compounds (see 104 below). Minor changes in structure in some of the newer compounds in fact lead to drugs in which antihistaminic activity predominates. Thus ketotifen, which differs from antipsychotic compounds such as 87 only in detail, is a rather potent antihistamine. Bromination of ketone 9|9_ occurs on the ethylene bridge to afford the 1,2 dibromide as a mixture of isomers (10Q); dehydrohalogenation by means of strong base gives the vinyl bromide 101 apparently as a single regioisomer. Reaction with the Grignard reagent from N-methyl-4-bromopiperi dine gives the alcohol 102. Exposure

240

MISCELLANEOUS FUSED HETEROCYCLES

of the intermediate to strong acid leads to dehydration of the alcohol and hydrolysis of the vinyl bromide to the corresponding ketone. There is thus obtained ketotifen (103). 20

p

NCH,

U02)

6 (103)

Since many of the uses of antihistamines involve conditions such as rashes, which should be treatable by local application, there is some rationale for developing drugs for topical use. The known side effects of antihistamines could in principle be avoided if the drug were functionalized so as to avoid systemic absorption. The known poor absorption of quaternary salts make such derivatives attractive for nonabsorbable antihistamines for topical use. Thus, reaction of the well-known antihistaminic drug promethazine (104) with methyl chloride leads to thiazinium chloride (105).

1

CH~CHN(CH-) 2, 32 (104)

i + CHOCHN (CH,) Cl 2, 3 3 (105)

MISCELLANEOUS FUSED HETEROCYCLES

241

(106)

N H (108)

(109)

(110)

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is described as an antianginal agent. Reduction of proline derivative 106 with lithium aluminum hydride gives the corresponding fused piperazine 107. Use of that base to alkylate the chloroamide 109, obtained from acylation of phenothiazine with 3-chloropropionyl chloride, leads to azaclorzine (110). 21

NHNI17 2 (112)

-

H

(111)

(113)

Fluorobutyrophenone deri vati ves of 4-a rylpi peri di nes are well-known antipsychotic agents. It is thus interesting to note that the pi peri dine can in fact be fused onto an

242

MISCELLANEOUS FUSED HETEROCYCLES

indole moiety with retention of activity. Fischer indole condensation of 4-piperi done 111 with phenylhydrazine 112 leads to the indole 113. Alkylation of the anion from the indole with p-bromofluorobenzene gives the corresponding Narylated derivative (114). Removal of the protecting group followed by alkylation on nitrogen with the acetal from pp-fluorobutyryl chloride gives intermediate 116. Hydrolysis of the acetal followed by reduction of the ketone by means of sodium borohydride gives the antipsychotic agent flutroiine (118). n

(1161 ( 1 L7")

(114) H = C 0 , C 9 l l r ( 115) R = 11 ^

X = 0CH?CH7O X - 0

Oil

A remarkably simple fused indole devoid of the traditional side chains is described as an antidepressant agent. Michael addition of the anion from indole ester 119 to acrylonitrile affords the cyanide 120. Selective reduction of the nitrile leads to the aminoester 121. This is then cyclized to the lactam (122). Reduction of the carbonyl group by means of lithium aluminum hydride leads to azepindole (123). 2 3

MISCELLANEOUS FUSED HETEROCYCLES

243

^^N^C (119)

(121)

(123)

(122)

A fused pyrazoioquinolone provides an exception to the rule that antiallergic agents must contain a strongly acidic proton. Entry to the ring system is gained by electrocyclic reaction of diazoindolone 124 (possibly obtained by reaction of the anion from indolone with p-toluenesulfonyl azide) with propargylaldehyde. The initial adduct to the 1,3dipole represented by the diazo group can be formulated as the spiro intermediate 125. Bond reorganization would then lead to the observed product (126). Reduction of the carbonyl with sodium borohydride leads to the corresponding alcohol, and thus pirquinozol (127).

(124)

(126) (127)

R = CHO R = CH 2 OH

244

MISCELLANEOUS FUSED HETEROCYCLES

An imidazoquinazoline constitutes still another compound that does not fall in the classification of a nonsteroid antiinflammatory agent yet shows good platelet antiaggregating activity. Condensation of benzyl chloride 128 with the ethyl ester of glycine gives alkylated product 129. Reduction of the nitro group leads to aniline 130. Reaction with cyanogen bromide possibly gives cyanamide 131 as the initial intermediate. Addition of aliphatic nitrogen would then lead to formation of the quinazoline ring (132). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring. Whatever the details of the sequence, there is obtained in one step anagrelide (133).^ 5

?NJII(

(1 (128)

(1 ( l/<)) (MO)

R R

H ? ( ().,( ,11,. o II

(M2)

A seemingly complex heterocycle which on close examination is in fact a latentiated derivative of a salicylic acid shows antiinflammatory activity. It might be speculated that this compound could quite easily undergo metabolic transformation to a salicylate and that this product is in fact the active drug. Condensation of acid j ^ with hydroxylamine leads to the hydroxamic acid 135. Reaction of that with the ethyl acetal from 4-chlorobutyraldehyde then leads to the cyclic carbinolamine derivative 136. Treatment

MISCELLANEOUS FUSED HETEROCYCLES

245

with mild base causes internal alkylation and consequent formation of the last ring. There is thus obtained 26 meseclazone (137).

I2( II,(

I <4) R

The observation that a carboxyl derivative of a pyrimidinoquinoline shows mediator release inhibiting activity is in consonance with the earlier generalization. Knoevenagel condensation of nitroaldehyde 138 with cyanoacetamide gives the product 139. Treatment with iron in acetic acid leads to initial reduction of the nitro group (140). Addition of that function to the nitrile leads to formation of the quinoline ring (141). Reaction of that compound with ethyl oxalate results in formation of the quinazoline ring. The product, pirolate (142), is described as an antiallergy agent.

(138)

(IV)) (140)

0 'N

H (142)

R 0 R - [I

(141)

246

MISCELLANEOUS FUSED HETEROCYCLES

A tetracyclic heterocycle that bears l i t t l e relation to any clinically used drug has been described as an antiinflammatory agent. The compound is prepared in rather straightforward manner by i n i t i a l condensation of dihalide 143 with 1,2-diaetcylhydrazine. Hydrolysis of this product gives cyclic hydrazone 145. Exposure to a second mole of dihalide leads to diftalone (146), The regiochemistry may be rationalized by assuming that the more reactive acid chloride attacks the more nucleophilic unacylated nitrogen. 0

o

II ,CC1

INCOCH-5

CII 2 Br

HNCOCH

(143)

U

(144) R = COCIW (145) R = H

0 (146)

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted to the acid chloride (148); reaction with diazomethane leads to the diazoketone 149. This is then subjected to photolytic rearrangement to afford the corresponding acetic acid (150). Condensation with methyl aniline then gives the amide 151. Reduction with lithium aluminum hydride affords

MISCELLANEOUS FUSED HETEROCYCLES

247

azipramine

y==J

(147) X = OH (148) X = Cl (149) X = CHN2

(150)

^ CFI3 X (151) X =0 (152) X = H2

Any migraine sufferer will willingly testify that this condition has little in common with the headaches to which the rest of mankind are subject. Recent medical studies too have shown fairly conclusively that, whatever the etiology of migraine, it is a condition quite distinct from the common headache. The syndrome is in fact so distinct as to be untouchable by the common headache cures such as aspirin. Drugs for treatment of migraine are unfortunately almost nonexistent. (The lack of appropriate animal models in no small way hinders the search for a treatment.) A benzofuranobenzoxepin has interestingly been described as an antimigraine agent. Bromination of benzofuran 153 proceeds on the methyl group to give the arylmethyl bromide 154. Displacement by phenoxide then leads to intermediate 155. Saponification (156) followed by Friedel-Crafts cyclization serves to form the seven-membered ring (157). Condensation of the ketone with the Grignard reagent from 3-chloropropylN9M~dimethyl amine gives the olefin on dehydration, possibly as a mixture of isomers. There is thus obtained oxetorene (158). 3 0

248

MISCELLANEOUS FUSED HETEROCYCLES

(153)

0 (157)

(154)

(155) R = C-H,(156) R = IP

CHCH2CH2N(CH3) (158)

In the steroid series, hormone antagonists usually bear some structural resemblance to the endogenous agonists. That is to say, antagonists are almost always steroids themselves. Even in the case of the nonsteroid estrogen antagonists, there is a fairly clear structural resemblance to estradiol. It is thus somewhat surprising to note a clearly nonsteroidal androgen antagonist. The compound in question, pentomone (163) is, as a result of this activity, a potential drug for treatment of prostate enlargement. Condensation of sal icy!aldehyde 159 with cyciohexanone 160 proceeds twice to give directly the pentacyclic intermediate 161. The reaction may be visualized as initial conjugate addition of phenoxide to the enone followed by interception of the resulting anion by the aldehyde carbonyl group. Hydrogenation of the intermediate reduces both the double bonds and the carbonyl group (162). Back oxidation of the alcohol thus formed with pyridinium chlorochromate affords pentomone (163).

MISCELLANEOUS FUSED HETEROCYCLES

249

CHO

CH 3 6 (159)

CH 3 O

(160)

3U

.3

H

3C

6CH3

(161)

OCH3 (163)

(162)

The ergolines have provided a number of drugs that show interaction with neurotransmitters. Depending on the substitution pattern, they may be dopamine agonists or antagonists, a-adrenergic blockers, or inhibitors of the release of prolactin. A recent member of the series, pergolide (167), shows activity as a dopamine antagonist. Reduction of ester 164 by means of lithium aluminum hydride gives the corresponding alcohol; this is then converted to its mesylate (166). Displacement with methanethiol affords pergolide (167). 32

(164)

(165) R = H

()

(167)

250

MISCELLANEOUS FUSED HETEROCYCLES

REFERENCES 1.

J. L. H. Van Gelder, A. H. M. Raeymaekers, L. F. C. Roevens and W. J. Van Laerhoven, U.S. Patent 3,925,383; Chem. Abstr., M, 180264e (1976).

2.

L. D. Spicer and J, J. Hand, French Demande 2,199,979; Chem. Abstr., £2, 16835e (1975).

3.

0. Gubin and G. Rosseels, German Offen 2,707,048; Chem. Abstr., 88, 6719e (1978).

4.

J . P. Maffrand and F. E l l o y , Eur. J . Med. Chem., 9, 483 (1974). ~~~

5.

H. J. Shaeffer, German Offen., 2,539,963 (1976).

6.

J. Diamond, German Offen., 2,713,389; Chem. Abstr., 88, 22984t (1978).

7.

L. E. J. Kennis and J. C. Mertens, U.S. Patent 4,347,287; Chem. Abstr., 98, 16716 (1983).

8.

E. Schenker, Swiss Patent 565,797; Chem. Abstr., 83, 206311Z (1975). ~"

9.

G. C. Wright, A. V. Bayless, and J. E. Gray, German Offen., 2,427,382; Chem. Abstr., £2, 171087f (1975).

10. G. C. Wright, A. V. Bayless, and J. E. Gray, German Offen., 2,427,377; Chem. Abstr., 82, 171088g (1975). 11.

I. C. Nordin, U.S. Patent 3,553,207; Chem. Abstr., 15, 5972b (1971).

12. H. A. DeWald and S. J. Lobbestael, South African Patent 73 07696; Chem. Abstr., 84, 59594J (1976).

MISCELLANEOUS FUSED HETEROCYCLES

251

13-

F. J. Tinney, U.S. Patent 3,558,606; Chem. Abstr., 74, 141896m (1971).

14.

D. E. Bays, German Offen., 2058295; Chem. Abstr., 75, 98447x (1971).

15.

J. R. Pfister, I. T. Harrison, and J. H. Fried, Chem. Abstr., 85, 21108g (1976).

16.

C. L. Zirkle, German Offen., 2,549,841; Chem. Abstr., 85, 78025m (1976).

17.

P. Herbst and D. Hoffmann, German Offen., 2,600,768; Chem. Abstr., 85, 143001s (1976).

18. J. Ackrell, Y. Antonio, F. Fidenico, R. Landeros, A. Leon, J. M. Muchowski, M. L. Maddox, P. H. Nelson, and W. H. Rooks, J. Med. Chem. n, 1035 (1978). 19. C. L. Zirkle, U.S. Patent 3,609,167; Chem. Abstr., 75, 151694d (1971). 20. J. P. Bourquin, G. Schwarb, and E. Waldvogel, German Offen. 2,144,490; Chem. Abstr., 77, 34296f (1972). 21.

N. V. Kaverina, G. A. Markova, G. G. Chichkanov, L. S. Nazarovo, A. M. Likhosherstor, and A. P. Skoldinov, Khim. Pharm. Zh., J2, 97 (1978)

22. J. J. Plattner, C. A. Harbert, J. R. Tretter, and W. M. Welch Jr., German Offen., 2,514,084; Chem. Abstr., 84, 44008x (1976). — 23.

B. Reynolds and J. Carson, German Offen. 1928726; Chem. Abstr., 72, 55528v (1970).

24.

B. R. Vogt, German Offen. 2,726,389; Chem. Abstr., 88, 121240d (1978).

25.

W. N. Beverung and R. A. Partyka, U.S. 3,932,407; Chem. Abstr., 84, 10564 (1976).

26.

D. B. Reisner, B. J. Ludwig, H. M. Bates, and F. M. Berger, German Offen., 2010418; Chem. Abstr., 73, 120644s (1970). ~~

Patent

252

MISCELLANEOUS FUSED HETEROCYCLES

27. T. H. Althuis, L. J. Czuba, H. J. E. Hess, and S. B. Kadin, German Offen., 2,418,498; Chem. Abstr., 82, 73015m (1975). 28. E. Bellasio and E. Testa, II Farmaco, Ed. Sci., 25, 305 (1970). 29. M. Riva, L. Toscano, A. Bianchetti, and G. Grisanti, German Offen., 2,529,792; Chem. Abstr., 84, 150530w (1976). ~ 30. F. Binon and M. Descamps, German Offen. 1963205; Chem. Abstr., 73, 77221n (1970). 31. D. Lednicer and L. A. Mitscher, "The Organic Chemistry of Drug Synthesis", Vol. 2, Wiley, New York, 1980, p. 479. 32. E. C. Kornfeld and N. J. Bach, Eur. Patent Appl., 3,667; Chem. Abstr., 92, 181450q (1980).

Cross Index of Drugs Aldosterone Antagonist Spirorenone Analgesic Alfentanil Anilopam Bicifadine Carfentanil Ciprefadol Ciramadol Codorphone Doxpicomine Drinden

Levonantradol Lofentanil Moxazocine Nabitan Natnradol Proxorphan Sulfentanil Tonazocine Verilopam Anaesthestic

Etomidate

Minoxalone Androgen

Nistermine Acetate Androgen Antagonist Azastene Flutamide

Pentomone Topterone 253

254

Cross Index of Drugs Antiacne Montretinide Piroctone

Etretinate Isotretinoin Antiallergic Isamoxole Lodoxamide ethyl Nivimedone Oxatomide

Pirolate Pirquinozol Tixanox Xanoxate Antiamebic

Quinfamide Antianginal Molsidomine Nicarpidine Nicordanil Nimodipine Tosifen

Azaclorzine Bepridil Cinepazet Diltiazem Droprenilamine Ant i arrhythmic

Lorcainide Meobentine Oxiramide Pirmenol Ropitoin Tocainide

Butoprozine Clofilium Phosphate Disobutamine Drobuline Encainide Emilium Tosylate Flecainide Antibacterial

Metioprim Rosoxacin Tetroxoprim

Droxacin Fludalanine Flumequine Antibiotic Amidinocillin Amidinocillin Pivoxyl Azolocillin

Cefroxadine Cefsulodin Ceftazidine

Cross Index of Drugs

255

Bacampicillin Cefaclor Cefaparole Cefatrizine Cefazaflur Cefoperazone Cefonicid Ceforanide Cefotaxime Cefotiam

Ceftizoxime Cefuroxime Mezlocillin Moxlactam Piperacillin Pirbencillin Piridicillin Sarmoxici11 in Sarpicillin Anticonvulsant

Cinromide Antidepressant Azepindole Azipramine Cyciopenzaprine Cyclindole Dothiepin Fluotracen Fluoxetine Imafen

Napactidine Nisoxetine Nitrafudam Pridefine Tametraline Viloxazine Zimelidine Antidiarheal

Nufenoxole Antiemetic Domperidone

Nabilone Antifungal

Azoconazole Butoconazole Doconazole Ketoconazole Naftidine Orconazole Oxifungin

Parconazole Sulconazole Terconazole Tioconazole Tolciclate Triafungin Antihelmintic

Butamisole

Frentizole

Cross Index of Drugs

256

Nocodazole Tioxidazole

Carbantel Felsantel Fenbendazole Antihistamine Astemizole Ketotifen

Thiazinium Chloride Antihypertensive Proroxan Terazocin Tiamenidine Tiodazocin

Captopril Endraiazine Guanfacine Indorenate Ketanserin

Antihypertensive - ft-Blocker

Penbutolol Primidolol Prizidolol

Bucindolol Diacetolol Exaprolol Pamatolol

Antihypertensive - a»3~Blocker Bevantolol Labetolol

Medroxalol Sulfinalol Anti-inflamatory - Steroid

Acolmethasone Dipropionate Budesonide Ciprocinonide Flumoxonide

Haloprednone Meclorisone Dibutyrate Procinonide

Anti-inflamatory - Non-Steroid

Anitrazafen Amefenac Bromperamole Carprofen Diftalone Epirizole Fencoiofenac Fenciosal Floctafenine

Indoprofen Isoxepace Oxarbazole Meseclazone Morniflumate Orpanoxin Pi razolac Sermetacin Talniflumate

Cross Index of Drugs

257 Tiopinac Zidometacin Zomepi rac

Fluquazone Fluproquazone Fluretofen Antimalarial Halofantrine Antimigraine Oxetorone Antineoplastic Ametant rone Cyclophosphamide Estramustine Etoprine Ifosfamide

Metoprine Mitoxantrone Prednimustine Tegafur Trofosfamide Antiprotozoa!

Bamnidazole Ornidazole

Misonidazole Antipsychotic

Clopipazam Cloroperone Declenperone Flucindole

Fluotracen Flutroline Halopemide Pipenperone Antiulcer Ranitidine Tolimidone

Arbaprostii Etintidine Oxmetidine Antiviral Acyclovir Aril done

Envi roxime Anxiolytic

Adinazolam Bentazepam

Lormetazepam Midazolam

258

Cross Index of Drugs

Brofoxi ne Caroxazone Elfazepam Fosazepam

Quazepam Ripazepam Ti open'done Zometapi ne Bronchodilator

Ipatropium Bromide

Verofylline

Brochociilator - 3-Adrenergic

Bitolterol Colterol Carteolol Dipirefrin

Nisobuterol Prenalterol Reproterol Cardiotanic

Actodi gi n Amri none

Butopami ne Carbazeran Catract Inhibitor (Aldose Reductase Inhibitors)

Alrestatin

Sorbinil Cognition Enhancer

Amacetam Diagnostic Aid (Pancreatic Function) Bentiromide Diuretic Azosemide Fenquizone

Muzolimine Ozolinone

Indacrinone

Pi retanide Dental Carries Prohylactic

Ipexidine

Cross Index of Drugs

259 Dopamine Antagonist

Pergolide Estrogen Antagonist Nitromifene Tamoxifen

Trioxifene

Hypoglycemic Glicetanile Gliflumide

Pi rigli ride

Hypolipidemic Benzafibrate Cetaben Ciprofibrate

Gemcadiol Gemfibrozil Immunomoduiator

Azarole Muscle Relaxant Clodanolene Lidamidine

Xilobam Uterine Stimulant/Oxytocic

Carboprost Mefenprost

Sulprostone Peri pheral Vasodi1ator

Buterizine Cetiedil

Suloctidil Tipropidil Platelet Agregation Inhibitor

Anagrelide Epoprostenol

Ticlopidine Progestin

Gestodene

Gestrinone

260

Cross Index of Drugs Sedative

Fenobam

Mi 1enperone Vasosilator

Alprostadil

Epoprostenol Vitamin (D3)

Calcifediol

Calcitriol

Cumulative Index, Vols. 1-3 Acebutolol 29 109 Aceclidine 2, 295 Acedapsone \9 112 Acenocoumarole 1, 331 Aceperone 2_9 337 Acephylline \j 425 Acetaminophen 1^ 111 Acetanilide 1_, 111; 2, 97 Acetazolamide l_f 249 Acetohexamide 1_, 138 Acetophenazine l_9 383 Acetyl methoxprazine JL^ 131 Acetylmethadol J^, 81 Aclomethasone 3, 96 Actodigin 3^9 9"? Acyclovir .3* 229 Adinazolam J^, 197 Adiphenine 1, 81 Adrenal one 7, 38 Albendazole 2_, 353 Albuterol _2, 43 Albutoin 2, 261 Alclofenac 1> 68 Aldosterone 1_, 206 Aletamine 2_, 48 Alfentanyl 3_> 118 Algestone acetonide 2, 171

Algestone acetophenide 1^ 171 Alipamide 2^, 94 Allobarbital _1, 269 Allopurinol 1, 152, 269 AllylestrenoT _1, 172 Alonimid 2^, 295 Aloxidone JU 232 Alpertine £, 342 Alpha eucaTne 1_9 8 Alphaprodine J^ 304; 2^, 328 Alprazolam 3^9 197 Alprenolol l_9 111 Alprostadil 3^9 2 Alrestatin 3, 72 Althiazide T, 359 Alverine 2, 55 Amacetam 7, 127 Amantidine 2_9 18 Ambucaine 2_, 11 Ambucetamide l^ 94 Ambuside 2^, 116 Amcinafal 2, 185 Amcinafide 2^, 185 Amedaline 2_9 348 Amet ant rone _3» 75 Amfenac 3^, 38 Ami ci bone 2_9 11 261

262 Amicycline £, 228 Amidephrine 2^ 41 Amidinocillin 3_9 208 Amidoquine l_9 342 Amiloride 1, 278 AminitrozoTe ]^, 247 Aminoglutethimide J^, 257 Aminometetradine 1_, 265 Aminophenazole l_9 248 Aminophylline J^, 427 Aminopromazine JU 390 Aminopropylon 1_, 234 Aminopyrine U 234; 29 262 Ami norex 2> 265 Amiquinsin 2_, 363 Amisometradine 1_, 266 Amitriptyline 1_, 151, 404 Amobarbital 1_, 268 Amoproxan 2j 91 Amopyroquine 1, 342 Amoxapine 2_, T28 Amoxycillin \j 414 Amphecloral 1* 48 Amphetamine, !_, 37, 70; 2_, 47 Amphetaminil 2:, 48 Ampicillin I, 413; 2, 437, 438 Amprolium l> 264 Ampyzine 2_, 298 Amquinate 2^, 370 Amrinone \ 147 Anagesterone acetate 2j 165 Anagrelide 3^ 244 Androstanolone I, 173 Anidoxime 2^, 125 Anileridine 1, 300 Anilopam 3_, T21 Anisindandione 1_, 147 Anitrazafen 3^, 158 Antazoline 1, 242 Antipyrine T, 234 Apazone 2^, 475 Aprindene 2, 208 Aprobarbital 1^, 268 Aprophen 1_, 91 Arbaprostil ^> 8

Cumulative Index, Vols, 1-3 Aril done 3^ ^ Astemizole 3^ ^7 Atenolol 2, 109 Atropine 1, 35, 71, 89, 93; 2, 71 Azabon ;2, 115 Azacosterol 2, 161 Azaclorzine T, 241 Azacyclonol 1, 47 Azanator 2_, T57 Azaperone 2^ 300 Azarole 3^ 129 Azastene 3, 89 Azatadine 2> 424 Azathioprine 2^, 464 Azepinamide Y, 137 Azepindole 3_» 242 Azipramine 3, 246 Azlocillin 1, 206 Azoconazole 3^ 137 Azolimine 2_, 260 Azomycin 1_, 238 Azosemide \ 27 Bacampicillin 3_9 204 Baclofen 2, 121 Bamethan 7, 39 Bamiphylline 1_, 426 Bamipine 1, 51 BamnidazoTe 3^9 132 Barbital J., 267 BAS Z, 96 BCNU 29 12 Becanthone 2_> 413 Beloxamide 2_9 56 Bemidone 1_, 305 Bemigride U 258 Benactyzine 1^, 93 Benapryzine 2, 74 Bendazac 2^, "J51 Bendrof1umethiazide 1, 358 Benfurodil 2_, 355, 3"56 Benorterone 2_9 156 Benoxaprofen 2_9 356 Benperidol 2^, 290

Cumulative Index, Vols. 1-3 Benproperine 2_9 100 Bentazepam 3_, 235 Benti romide _3, 60 Benzbromarone 2_9 354 Benzestrol _1, 103 Benzetimide 2, 293 BenziIonium bromide 2, 72 Benzindopyrine 2, 34T Benziodarone l_9 313 Benzocaine 1_, 9 Benzoctamine 2^ 220 Benzodepa 2, 122 BenzphetamTne J^, 70 Benzquinamide l_9 350 Benztriamide 2:, 290 Benzydamine 1_, 323; 2_9 350 Benzyl penicillin 1, 408 Bepridil 3, 46 Beta eucaine 1^ 9 Betahistine ,2, 279 Betamethasone l_9 198 Bethanidine 1_,2855 Bevantolol 2_9 Bezafibrate _3, 44 Bicifadine 2» I 2 0 Bi peri den 1_, 47 Bitolterol J3» 22 Bishydroxycoumarin 1^ 331 Bolandiol diacetate £, 143 Bolasterone j[, 173; 2_, 154 Boldenone 2_, 153 Bolmantalate 2, 143 Boxidine 2_9 9J Bretylium tosylate 1_» 55 Brofoxine 3^9 191 Bromperidol 2_9 331 Bromhexine 2^, 96 Bromindione 2, 210 Bromisovalum j^, 221 Bromodiphenhydramine U 42 Bromoxanide 2, 94 Bromperidol 7, 331 Broperamole 3>, 139 BrompheniramTne ^, 77 Bucainide 2_9 125 Bucindolol 3, 28

263 Buclizine ^ 59 Bucloxic acid 2, 126 Budesonide J3, "5"5 Buformin 1^, 221; 2, 21 Bufuralol 2^, 110 Bumetanide 2_9 87 Bunaftine 2^, 211 Bunamidine 2^ 212 Bunitridine £, 215 Bunitrolol 2^, 106, 110 Bunolol 29 110, 215 Bupicomide 2^, 280 Bupivacaine 2^, 17 Buprenorphine 2, 321 Bupropion 2_9 1"24 Buquinolate 2_, 346 Burimamide 2^, 251 Buspirone 2^, 300 Butabarbital 1, 268 Butacaine J^, T2 Butacetin 2^, 95 Butaclamol 2^, 226 Butalbital 1, 268 Butamirate 7, 76 Butamisole 3i> 226 Butaperazine ^, 381 Butazolamide j^, 249 Buterizine 3^, 175 Butethal J., 268 Butoconazole 3_9 134 Butorphanol 2^, 325 Butoxamine 1^, 68 Butriptyline l^ 151 Butropium bromide 2> 308 Butylallonal _1, 269 Butyl vynal 1^, 269 Caffeine j,, 111, 423 Calcifediol 3^, 101 Calcitriol 2_9 103 Calusterone 2^, 154 Cambendazole 2^, 353 Canrenoate 2^, 174 Canrenone 2^, 174 Capobenic acid 2, 94 Captodiamine 1^, 44

264 Captopril _3> 128 Caramiphen 1_, 90 Carbacephalothin j^, 420 Carbadox .2, 390 Carbamazepine 1_, 403 Carbantel 3_9 57 Carbaprost 3_9 7 Carbazeran 3_9 195 Carbenicillin I, 414; 2_9 437 Carbetidine 1_, 90 Carbidopa 2> 119 Carbimazole l_9 240 Carbinoxamine ]^, 43; j?, 32 Carbiphene 2^, 78 Carbromal J^ 221 Carbubarbital U 269, 273 Carbutamide J^ 138 Carbuterol 2, 41 Carfentanyl 3_9 117 Carisoprodol 1, 219 Carmantadine 7, 20 Carmustine 2^, 12 Carnidazole _2, 245 Caroxazone _3.> 191 Carphenazine 1_, 383 Carpi pramine 2^, 416 Carprofen 3_» 169 Cartazolate 2, 469 Carteolol 3^9 183 Cefacior 3, 209 CefadroxiT 29 440 Cefamandole 2,2i2441 Cefaparole 2» Cefatrizine 3, 211 Cefazaflur 2^ 213 Cefazolin 3, 442 Cefonicid T, 213 Ceforanide 3, 214 Cefotaxime 2, 216 Cefotiam 2» 215 Cefoxitin 2^, 435, 443 Cefroxadine 2»214210 Cefsulodin ^ Ceftazidine 2» 216 Ceftizoxime 3_» 218 Cefuroxime 3, 216

Cumulative Index, Vols. 1-3 Cephalexin 1^, 417; 29 439 Cephalogiycin 1, 417 Cephaloridine T, 417 Cephalothin 1, 417 420 Cephapirin 2^, 441 Cephradine 2, 440 Cetaben 2> *5"0 Cetophenicol 2_ 9 46 Cetiedil ^> ^2 Chioraminophenamide 1, 133 Chlofluperidol ^ 30F Chloramphenicol JL_, 75; 2^, 28, 45 Chlorazanil U 281 Chlorbenzoxamine j^, 43 Chlorcyclizine 2.9 58 Chlordiazepoxide 1^, 365; ^, 401 Chlorexolone 1_, 321 Chlorguanide 1^ 115 Chlorimpiphenine 1^, 385 Chlorindandione U 147 Chiormadi none acetate j^, 181; 2, 165 ChTormidazole ^, 324 Chlorophenylalanine 2> 52 Chloroprocaine JL^ 11 Chloropyramine 1, 402 Chloroquine 1_, "341 Chlorothen 1, 54 ChlorothiazTde l_9 321, 355; 2, 395 Chlorotrianisene j^, 104 Chlorphenamide l_9 133, 358 Chlorphendianol j^, 46 Chlorphenesin U 118 Chlorpheni ramine j^, 77 Chlorphenoxamine 1^9 44 Chlorphentermine 1_9 73 Chlorproethazine V, 379 Chlorproguanil _1, 115 Chlorpromazine 1, 319 378; 2, 409; 39 72 Chlorpropamide j ^ , 137 Chlorprothixene 1_, 399 Chiorpyramine 1_, 51

Cumulative Index, Vols. 1-3 Chlortetracycline U 212 Chio.rthalidone j_, 322 Chlorzoxazone 1^, 323 Chromoglycate 1, 313, 336 Chromonor \_9 3Tl Ciclafrine 2_9 266 Ciclopirox 2_9 282 Cicloprofen _2, 217 Cimetidine £, 253 Cinanserin 2_9 96 Cinepazet 3^9 157 Cinepazide 2^ 301 Cingestol _2, 145 Cinnamedrine 2^ 39 Cinnarizine J^, 58 Cinoxacin 2, 388 Cinromide T, 44 Cintazone 2_9 388, 474 Cintriamide £, 121 Ciprefadol 3, 119 CiprocinonicTe \ 94 Ciprofibrate 3, 44 Ciramadol X T22, 123 Citenamide 2!, 221 Clamoxyquin 2_9 362 Clazolam 2^, 452 Clazolimine 2_9 260 Clemastine 2^ 32 Clemizole J^ 324 Clioxanide £, 94 Cliprofen £, 65 Clobazam £, 406 Clobutinol 29 121 Clocapramine 2, 416 Clocental J^, "38 Clocortolone acetate 2* 193 Clodanolene 3, 130 Clodazon 2> 154 Clofenpyride 2, 101 Clofibrate 1, 119; 2, 79, 101, 432 Clofilium phosphate 3^ 46 Clogestone 2^ 166 Clomacran 2_, 414 Clomegestone acetate 2^, 170 Clometherone 2, 170

265 Clomifene 1., 105, 148; 29 127 Clominorex 2* 265 Clonidine 1^ 241 Clonitazene l_> 325 Clonixeril 29 281 Clonixin 2^, 281 Clopamide l_9 135; ^, 93 Clopenthixol 1^, 399 Cl open* done 2^, 387 Cloperone 3_9 150 Clopimozide 2_9 300 Clopipazam 2> 237 Clopirac 2_9 235 Cloprednol 2_9 182 Cloprostenol ^, 6 Clorprenaline 2, 39 Closantel 2> 4T Closiramine 2, 424 Clothiapine T, 406; 2, 429 Clothixamide 2, 412 Cloxacillin j j 413 Cloxazepam 1, 370 Clozapine 2^, 425 Codeine 1, 287; 2, 317 Codorphone 3, 117 Codoxime 2^, 318 Colchicine _1, 152, 426 Colterol 3^, 21 Cormethazone acetate 2^ 194, 196 Cortisone j,, 188; 29 176, 179 Cortisone acetate 2., 188, 190 Cortivazol ^, 191 Cotinine 2^, 235 Cromoglycate 3^9 66, 235 Cyclacillin 2^, 439 Cyclandelate l_9 94 Cyclazocine U 298; 2^, 327 Cyclindole ^9 168 Cyclizine l_9 58 Cyclobarbital _1, 269 Cyclobendazole 2j 353 Cyciobenzaprine 2, 77 Cycloguanil j^, 281 Cyclomethycaine l_9 14 Cyclopal 1_, 269

266 Cyclopentolate l_9 92 Cyclopenthiazide 1^, 358 Cyclophosphamide 3, 161 Cyclopryazate 1_, ¥2 Cycloserine 3s 14 Cyclothiazide lj 358 Cycrimine JU 47 Cyheptamide 2_, 222 Cypenamine 2, 7 Cyprazepam Y_9 402 Cyproheptadine l^9 151 Cyprolidol 2, 31 Cyproquinate 2* 368 Cyproterone acetate 2* 166 Cyrpoximide 2_, 293 Dacarbazine £, 254 Daledanin 2., 348 Danazol 21, 157 Dantrolene 2, 242 Dapsone 1_, 139; J2, 112 Dazadrol 1, 257 Debrisoquine 1_, 350; j?, 374 Declenperone 3_» 172 Decoquinate £, 368 Delmadinone acetate 2j 166 Demoxepam 2, 401 Deprostil 7, 3 Descinolone acetonide 2^, 187 Deserpidine 1, 320 Desipramine T, 402 Desonide 2, 179 Deterenol 2_, 39 Dexamethasone j^, 199 Dexbrompheniramine J^, 77 Dexchlorpheniramine £, 77 Dexivacaine 2, 95 Dexnorgestrel acetime 2, 152 Dextroamphetamine 1, 70 Dextromoramide ^, ^2 Dextromorphan l_9 293 Dextrothyroxine U 92 Diacetolol 3, 28 Diamocaine 7, 336 Dianithazole \_9 327 Diapamide 2_y 93

Cumulative Index, Vols, 1-3 Diaveridine 2^, 302 Diazepam ^ 365; ^, 452 Diazoxide 1_, 355; ^ 395 Dibenamine l^ 55 Dibenzepin 1^ 405; 2% 424, 471 Dibucaine ^ 15 Dichlorisone 1^, 203 Dichloroisoproterenol l_, 65; 2^, 106 Dichlorophenamide j^, 133 Diclofenac 2, 70 Dicloxacillin U 413 Dicoumarol J^, 147 Dicyclomine J,» 36 Dienestrol 1, 102 Diethyl carBamazine \j 278 Diethylstilbestrol j_, 101 Di ethyl thi ambutene j^, 106 Difenoximide 2, 331 Difenoxin 2, 331 DiflucortoTone 2, 192 Diflumidone 2_9 IS Diflunisal ^, 85 Difluprednate 2, 191 Diftalone 2» 2T6 Dihexyverine 1_, 36 Dihydralazine ^, 353 Dihydrocodeine U 288 Diltiazem 3> 198 Dimefadane ^» 210 Dimefline _2, 391 Dimetacrine jL^, 397 Dimethisoquine 1, 18 Dimethisterone T, 176, 187 Dimethothiazine j^, 374 Dimethoxanate 1^, 390 Dimethyl pyrindene 1_, 145 Dimethyl thi ambutene 1_, 106 Dimetridazole 1, 240 Dinoprost 1_, 27, 33 Dinoprostone ^ 27, 30, 33, 35 Dioxadrol 2, 285 Dioxyline U 349 Diphenhydramine j^, 41 Diphenidol \_9 45 Diphenoxylate 1_, 302; 2, 331

Cumulative Index, Vols. 1-3 Diphenylhydantion 1_, 246 Diphepanoi 1, 46 Dipipanone T, 80 Di pi proven" ne 1^, 94 Dipirefrin 3>> 22 Dipyridamcfle 1, 428 Dipyrone 2_9 HSl Disobutamide 3^ 41 Disopyramide £, 81; j$> 41 Disulfiram l_9 223 Dithiazanine U 327 Dixyrazine 1^ 384 Dobutamine 2, 53 Doconazole T, 133 Domazoline 2_f 256 Domperidone 3_, 174 Dopamantine 2_9 52 Dorastine 2, 457 Dothiepin T, 239 Doxapram £, 236 Doxaprost ly 3 Doxepin 1_, 404 Doxpicomine 3_> 122 Doxy 1 ami ne l^ 44 Drindene _3, 65 Drobuline 3_9 47 Drocinonide 2^, 186 Dromostanoione JL_, 173 Droprenylamine 3_9 47 Droperidol I, 308 Droxacin 2» 185 Dydrogesterone l^9 185 Econazole 2^, 249 Ectylurea U 221 Elantrine £, 418 Elfazepam ^, 195 Elucaine 2_9 44 Emilium tosylate 2> Encainide 3^, 56 Encyprate 2_9 27 Endraiazine 2 9 232 Endrysone 2_9 200 Enviroxime Z_9 111 Ephedrine l_9 66 Epimestrol 2^, 13

47

267 Epinephrine j^, 95, 241 Epirazole 3^, 152 Epithiazide j^, 359 Epoprostenol 3_9 10 Eprazinone 1_, 64 Eprozinoi 1_9 44 Eritadenine ^, 467 Erytriptamine 2., 317 Esproquin 2_9 373 Estramustine ^, 83 Estrazinol 2_9 142 Estradiol 1_, 162; 2_, 136 Estradiol benzoate j^, 162 Estradiol cypionate 1_, 162 Estradiol dipropionate 1, 162 Estradiol hexabenzoate T, 162 Estradiol valerate !_> 162 Estramustine 3_9 83 Estrofurate £, 137 Estrone 1_, 156, 161 Etafedrine 2^, 39 Etazolate Z, 469 Eterobarb ^, 304 Ethacrynic acid JL_, 120; £, 103 Ethambutol JL^, 222 Ethamivan 2^, 94 Ethionamide 1, 255 Ethisterone T, 163, 172 Ethithiazide l_9 358 Ethoheptazine 1_, 303 Ethonam 29 249 Ethopropazine 1_, 373 Ethosuximide 1, 228 Ethotoin 1_, 2T5 Ethoxzolamide 2_, 327 Ethylestrenol 2_, 170 Ethylmorphine 1, 287 Ethynerone 2? T46 Ethynodiol diacetate 1, 165, 186 Ethynodrel _1, 164 Ethynylestradiol 1_, 162 Etidocaine 2_9 95 Etinfidine 2_9 135 Etoclofene 2_9 89 Etomidate 3, 135

268 Etonitazene 1, 325 Etoprine 3_9 153 Etorphine 2,, 321 Etoxadrol 2, 285 Etapralol 1, 28 Famotine 2* 37 Fantridone 2,, 421 Felsantel \ 57 Fenalamide £, 81 Fenbendazole ^» 176 Fenbufen £, 126 FencamfamTne 2.» 74 Fenclofenac 2^, 37 Fenclorac 2^ 66 Fenclozic acid £, 269 Fendosal 3^, 170 Fenestrel _2, 9 Fenethylline l_f 425 Fenfluramine 1, 70 Fenimide 2^, 217 Fenisorex 2_9 391 Fenmetozole 2, 257 Fenobam £, 176 Fenoprofen £, 67 Fenoterol ,2, 38 Fenpipalone £, 293 Fenquizone 3^ 192 Fenspiriden 2, 291 Fentanyl 1_, 799, 306, 309; 116 Fenyripol 2_, 40 Fetoxylate 2:, 331 Flavoxate 2^, 392 Flazalone 2, 337 Flecainide"3, 59 Fletazepam 29 403 Floctafenine 3, 18^ Floxacillin U 413 Fluanisone \j 279 Fluazepam J^, 366 Flubanilate 1> 98 Flubendazole 2^ 354 Flubiprofen 1_, 86 Flucindol \ 168 Flucinolone 3, 94

Cumulative Index, Vols. 1-3 Flucinolone acetonide 2^, 202 Flucloronide 2_9 198 Fludalanine ^9 14 Fludorex £, 44 Fludrocortisone l_9 192 Fludroxycortide 1, 202 Flufenamic acid T, 110; 2^, 69 Flumequine 3_9 186 Flumethasone 1^ 200 Flumethiazide 1^, 355; 2^, 355 Flumetramide 2^9 306 Fluminorex 2, 265 Flumizole 2^, 254; J3» 158 Flumoxonide 2.» 95 Flunarizine 2^, 31 Flunidazole £, 246 Flunisolide 2^, 181 Flunitrazepam 2, 406 Flunixin ^, 28T Fluproquazone 3^» 193 Fluorocortolone U 204 Fluorometholone 1^, 203 Fluoroprednisolone, 9a, JU 292 Fluorouracil, 5-, ^., 155 Fluotracen 3, 73, 74 Fluoxetine T, 32 Fluoxymestrone 1, 175 Fluperamide 2, 134 Fluperolone acetate 2_9 185 Fluphenazine 1_, 383 Fluprostenol 2^9 6 Fluquazone 3^ 193 Flurandrenolide £, 180 Fluretofen 2> 39 Flurogestone acetate 2_9 183 Fluspiperone 2, 292 Fluspirilene 2, 292 Flutamide 3^, "57 Flutiazine 2^, 431 Flutroline 3_, 242 Formocortal _2, 189 Fosazepam 3^9 195 Frentizole 3, 179 Furaltadone U 229 Furazolidone 1^, 229 Furethidine 1, 301

Cumulative Index, Vols# 1-3 Furobufen 2_9 416 Furo,semide U 134; 2^ 87 Fusaric acid j?, 279 Gamfexine 1_9 56 Gemcadiol 2> ^ Gemfibrozil J3, 45 Gestaclone 2,, 169 Gestodene 3_9 85 Gestonorone ^, 152 Gestrinone 2» 85 Glaphenine 1^, 342 Gliamilide 1, 286 Glibornuride £, 61117 Glicetanile 3, 61 Gliflumide 3, Glipizide £, 117 Glutethemide l_9 257 Glyburide £, 139 Glybuthiazole J^ 126 Glycosulfone 1_, 140 Glyhexamide 1_, 138 Glymidine JL_, 125 Glyoctamide _2, 117 Glyparamide 2, 117 GlyprothiazoTe U 125 Griseofulvin ^ 314 Guaiaphenesin JL, 118 Guanabenz ^, 123 Guanacline 1_, 260 Guanadrel ^1, 400 Guanethidine U 282; _2, 100 Guanfacine ^» ^0 Guanisoquin 2_, 375 Guanocior JL, 117; Z9 101 Guanoxabenz 2, 123 Guanoxan 1^, "J52 Guanoxyfen 2, 101 Halcinonide 2_, 187 Halofantrine 3>9 76 Halofenate 2_, 80, 102 Halopemide 2* 174 Haloperidol U 306 Haloprednone 2» 99 Haloprogesterone 2> 173

269 Heptabarbital j., 269, 272 Hepzidine 2, 222 Heroin 1_, 788; £, 315 Hetacillin j^, 414 Heteronium bromide 1_9 11 Hexestrol J^ 102 Hexethal U 268 Hexobarbital \_9 273 Hexobendine ;2, 92 Hexylcaine 1_, 12 Histapyrrodine 1_, 50 Hoquizil 2^, 381 Hycanthone ^, 398; 2, 413 HydracarbazTne Z_9 3U5 Hydralazine 1_, 353 Hydrochl orobenzethy 1 ami ne J^, 59 Hydrochlorothiazide l_9 358 Hydrocodone l_9 288 Hydrocortisone l_9 190 Hydrocortisone acetate 1, 190 Hydroflumethiazide JL^, 3"5"8 Hydromorphone l_9 288 Hydroxyamphetamine 1_, 71 Hydroxychloroquine _1_, 342 Hydroxyphenamate 1_, 220 Hydroxyprocaine l^9 11 Hydroxyprogesterone 1, 176, 190 Hydroxyzine lj 59 Ibufenac l_9 86 Ibuprofen 1_, 86; 29 218, 356 Ifenprodil 2_9 39 Ifosfamide 3_9 151 Imafen 3.9 226 Imidoline £, 259 Imipramine 1_, 401; 1_9 420; 3^, 32 Imolamine 1_, 249 Indacrinone ^> ^7 Indapamide 1_9 349 Indomethacin 1, 318; 2, 345; 2, 165 Indoprofen 3^9 171 Indoramine 2, 344

270 Indorenate 2» 167 Indoxole 1_9 254, 340; Z, 158 Intrazole 1_9 345 Intriptyline Z> 223 Ipexidine 2> 157 Ipratropium bromide 2> 160 lodothiouracil JU 265 Iprindol I, 318 Ipronidazole 2* 244 Iproniazide l_9 254 Isamoxole 3^ 138 Isoaminile 1_, 82 Isobucaine J^, 12 Isobuzole 1_9 272 Isocarboxazide 1, 233; 29 266 Isoetharine 2j "5* Isomethadone j_, 79 Isomyiamine 2, 11 Isoniazide 1^, 254; 2, 266 Isopentaquine 1_, 346 Isoproterenol J^ 63; 2_9 37, 107; 2» 20, 21 Isopyrine 1_, 234 Isothipendyl 1_, 430 Isotretinoin 2> 12 Isoxepac 3, 238 Isoxicam 7, 394 Isoxsuprine _1.» 69 Ketanserin 3_, 193 Ketamine JL, 57; 2, 16 Ketasone JU 237 Ketazocine 2^, 328 Ketazolam U 369 Ketobemidone 1, 303 Ketoconazole 7, 132 Ketoprofen £, 64 Ketotifen ^ 239 Khellin 1, 313, 335 Labetolol 3, 24 Legotrile 7, 480 Leniquinsin ^, 363 Lenperone 2^, 286 Letimide ^, 393 Levalorphanoi 1, 293

Cumulative Index, Vois. 1-3 Levarterenol JL_, 63 Levonantrodol 2» Levonordefrine 1_, 68 Levophenacylmorphan J^, 294 Levopropoxyphene 1, 50 Levothyroxine 1^, Tl Lidamidine 2.* $& Lidocaine U 16; _2, 95, 449; 2 , 40 Lidoflazine ]_, 279 Lifibrate £, 103 Liothyronine ^, 97 Lobendazole 2_9 353 Lodoxamide 2> 57 Lofentanyl 2» 117 Lometraline 2^ 214 Lomustine ^, 12, 15 Loperamide 2!, 334 Lorazepam 1, 368 Lorbamate 7, 21 Lorcainide 3i» ^0 Lormetazepam 2» 196 Loxapine 2^ 427 Lucanthone 1_, 397; 2^, 413 Lynestrol J,, 166, 186 Mafenide 1, 114 Maprotiline 2^, 220 Mazindol 2, 462 MebendazoTe ^, 353 Mebeverine ;2, 54 Mebhydroline 1_, 319 Mebrophenhydramine \j 44 Mebutamate \_9 218 MeCCNU 2_, 12 Mecillinam Z_9 208 Meclastine 2^, 44 Meclizine 1_, 59 Meclocycline 2> 111 Meciofenamic acid 1, 110; 2, 88 "" Meclorisone butyrate 3_» 95 Medazepam j^, 368 Medibazine 2_, 30 Mediquox _2, 390 Medrogestone 1_, 182

Cumulative Index, Vols. 1-3

271

Medroxalol ^, 25 87 Methallenestril Medroxyprogesterone 1, 180, Methamphetamine l_9 37, 70 Methandrostenolone ^, 173 186; 29 165 Methantheline bromide l_9 393 Medrylamine J^, 41 Methaphencycline ^, 53 Medrysone 2^ 200 Mefenamic acid X, 110; 2^ 280 Methaphenilene 1, 52 Methaprylon 2.» "?59 Mefenorex 2, 47 Methapyrilene ^ 54 Mefexamide"4"^, 103 Methaqualone j^, 353 Mefruside I, 134 Metharbital l_9 273 Megesterol acetate 1_, 180 Melengesterol acetate 1, 182, Methazolamide J^, 250 Methdilazine I, 387 187 Methenolone acetate "L, 175 Melitracen 2, 220 Methicillin 1, 412 Melphalan 2, 120 Methimazole T, 240 Memotine £, 378 Methisazone 2^, 350 Menoctone 2, 217 Methitural I, 275 Meobentine 3, 45 Methixene L, 400;118 2_9 413 Meparfynol 1^ 38 Meperidine 1^ 300; 2, 328; jJ» Methocarbamol JL.» Methohexital 1_, 269 116 Methopholine ^ 349 Mephenhydramine J^, 44 Methopromazine 1, 374 Mephenesin lj 118 Methoxsalen h, 133 Mephenesin carbamate l_9 118 Methoxypromazine ^, 378 Mephenoxalone \j 119 Methsuximide 1_, 228 Mephentermine J^, 72 Methyclothiazide 1^, 360 Mephenytoin 1, 246 MethyIchromone j^, 335 MephobarbitaT 2, 273 Methyl di hydromorphi none l_9 292 Mepivacaine Y> 17 Methyldopa U 95 Meprobamate 1^ 218; 29 21 Methylphenidate \j 88 Mequoqualone J^» 354 Methyl predni sol one j^, 193 Meralluride 1_, 224 Methylprednisolone, I63-, 1, Mercaptomerine 1, 224 196 Meseclazone 2» "2^5 Methyltestosterone j ^ , 172 Mesoridazine I, 389 Methylthiouracil _1, 264 Mesterolone ^ 174 Methynodiol diacetate 2? 149 Mestranol 1_, 162 Methyridine J^, 265 Mesuprine 2_9 41 Methysergide 2_9 Ml Metabutoxycaine 2^, 11 Metiamide 2, 252 Metalol 2, 41 Metiapine 7, 429 MetampicTllin l_9 414 Metioprim _3, 155 Metaproterenol 1, 64 Metizoline 2_9 256 Metaxalone 1_, 1T9 Metolazone ,2, 384 Meteneprost ^, 9 Metopimazine ^ 386 Metformin 2_9 20 Metoprine 3^, 153 Methacycline 2^, 227 Methadone 1, 79,289,298; 2, 328 Metoprolol 2, 109

272

Cumulative Index, Vols. 1-3

Metronidazole 1, 240 Nalbuphine 2_, 319 Mexenone 2, 17F Nalidixic acid 1, 429; 2, 370, Mexrenoate 2_9 175 469 Nalmexone 2_, 319 Mezlocillin !3, 206 Nalorphine 1_, 288; 2>, 318 Mianserin 2, 451 Naloxone JL, 289; 2_, 318, 323 Mibolerone 2, 144 Naltrexone 2^, 319 Miconazole 7 , 249 Namoxyrate J^ 86 Midaflur 2_, 259 Nandrolone 2^, 164 Midazolam \ 197 Nandrolone decanoate h, 171 Milenperone 3^, 172 Nandrolone phenpropionate j^, Milipertine 2, 341 171 Mimbane £, 347 Nantradol _3, 186 Minaxalone 3_9 90 Napactidine 3, 71 Minocycline 1_, 214; £, 228 Naphazoline 1, 241 Minoxidil 1, 262 Naproxen l_f 5*6 MisonidazoTe 3, 132 Naranol 2_9 454 Mitoxantrone 2» ^5 Nefopam 2, 447 Mixidine 2, 54 NeostigmTne JL^, 114 Modaline 7 , 299 Nequinate 2, 369 Mofebutazone ^, 234 Nexeridine ^ , 17 Molinazone £, 395 Nialamide U 254 Molindone 2_9 455 Nicarpidine 3^, 150 Molsidomine 2.» 140 Nicergoline 2, 478 Moprolol 2, 109 Niclosamide 7 , 94 Morantel T, 266 Nicotinic acid 1, 253 Morazone 1* 261 Nicordanil 3, ff8 Morniflumate \ 146 Nicotinyl aTcohol 1_, 253 Morphazineamide 1_, 277 Nidroxyzone U 228 Morpheridine l_9 300 Morphine 1_, 286; 2^, 314; 3^, 110 Nifedipine 2, 283 Nifenazone l_9 234 Motretinide 3^, 12 Nifluminic acid 1, 256 Moxalactam 3, 218 Nifu rat rone 2_, 2i8 Moxazocine ^9 114 Nifurdazil ^ , 239 Moxisylyte 1^, 116 Nifurmide _2, 239 Moxnidazole ^, 246 Nifuroxime 2, 238 Muzolimine 3^, 137 Nabilone 3_, 189 Nabitan 3, 190 Nadolol 7, 110 Nafcillin 1, 412 Nafenopin 2_, 214 Nafomine 2_, 212 Nafoxidine 1_, 147; 3», 70 Nafronyl 29 213 Naftidine 39 372

NifurpirinoT 2^, 240 Nifurprazine 1_, 231 Nifurquinazol 2, 383 Nifursemizone 7, 238 Nifurthiazole 2_, 241 Nikethamide U 253 Nimazone 2^, 260 Ni modi pine 3_9 149 Nimorazole 2_9 244 Niridazole 2, 269

Cumulative Index, Vols. 1-3 Nisobamate _2, 22 Niso^uterol :3> 23 Nisoxetine _3» 32 Nistremine acetate 3_9 88 Nithiazole £, 268 Nitrafudam 3_, 130 Nitrazepam J^ 366 Nitrimidazine l_, 240 Nitrofurantoin 1_, 230 Nitrofurantel 1_, 229 Nitrofurazone l_9 229 Nitrofuroxime I, 228 Nitromifene 3^, 51 Nivazol £, 159 Nivimedone ^, 67 Nocodazole 3_, 176 Noracymethadol _2, 58 Norbolethone Zj 151 Norephedrine l^9 260 Norethandrolone J^, 170 Norethi ndrone acetate l_> 165 Norethindrone 1_, 164; £, 145 Norethynodrel 1_9 186 Norgestatriene 1_, 168 Norgestrel 1, 167; 2, 151; 3, 84 Norgestatnenone l_9 186 Normeperidine l^ 300 Normethandrone 2., 170 Normethadone j^, 81 Norpipanone j^, 81 Nortriptyl ine 2.» 151 Nufenoxole 2> 42 Nylidrin 1_, 69 Octazamide 2^, 448 Octriptyiine ^, 223 Orconazole ^, 133 Ormetoprim 29 302 Ornidazole 3_9 131 Orpanoxin 2» 130 Orphenadrine l_9 42 Oxacephalothin J^, 420 Oxacillin U 413 Oxamniquine 2^ 372 Oxanamide 1, 220

273 Oxandroione ^9 174 Oxantel 2^, 303 Oxaprozin 2^ 263 Oxarbazole 3>> l 6 ^ Oxatomide 2» 173 Oxazepam JL^ 366; 2, 402 Oxazolapam j^, 370 Oxeladine U 90 Oxethazaine JL^, 72 Oxetorene 3_.» 247 Oxfendazole 2^ 353 Oxibendazole 2_9 352 Oxilorphan 2, 325 Oxiperomide 2^ 290 Oxi ramide \ 40 Oxisuran 2_, 280 Oxmetidine \ 134 Oxoiamine 1_, 248 Oxolinic acid 2, 370, 387; 3, 185 Oxprenolol JU 117; ^ , 109 Oxybutynin 1_, 93 Oxycodone j _ , 290 Oxyfedrine 2, 40 Oxyfungin 2» 233 Oxymestrone J^, 173 Oxymetazoline l^ 242 Oxymetholone l_9 173 Oxymorphone J^ 290; 2^9 319 Oxypendyl 1^ 430 Oxypertine 2^, 343 Oxyphenbutazone l_9 236 Oxyphencyciimine 2^ 75 Oxyphenisatin ^ , 350 Oxyprenolol 1, 117 Oxypurinoi 17 426 OxytetracycTine ^1, 212; 29 226 Ozoiinone 3, 140 Paludrine j ^ , 115 Pamaquine 1 , 345 Pamatolol T, 28 Pancuronium chloride 2j 163 Papaverine l_9 347 Para-aminosalicylic acid l_9 109

274 Paraethoxycaine 1_, 10 Paramethadione 1_, 232 Paramethasone J^, 200 Paranyline 2_, 218 Parapenzolate bromide 2> 75 Parconazole 3^, 133 Pargyline 1_, 54; _2, 27 Pazoxide 2, 395 Pacazine T, 387 Pemerid 2, 288 PenfluricTol 29 334 Pentethylcyclanone 1_, 38 Pentapiperium j!, 76 Pentaquine 1^ 346 Pentazocine l_9 297; j£, 325 Pentobarbital 1, 268 Pentomone ,3» 2T8 Pentoxphylline 2_9 466 Pentylenetetrazole J^, 281 Perazine 1_, 381 Pergolide 3_9 249 Perlapine 2_, 425 Perphenazine l_9 383 Pethidine 1_, 300 Phenacaine 2., 19 Phenacemide 1^ 95 Phenacetemide 3_, 44 Phenacetin l_9 111 Phenadoxone 1^ 80 Phenaglycodol j^, 219 Phenazocine l_9 298 Phenazopyridine 1, 255 Phenbenidllin lj 410 Phenbenzamine 1^, 50 Phenbutalol _2, 110 Phencarbamide 2, 97 Phencyclidine 1_, 56 Phendimetrazine 1, 260; 2^ 261 Phenelizine J^ 7T Pheneridine 1, 301 PhenethicillTn U 410 Phenformin 1_, 75 Phenindandone l_9 147 Pheniprane U 76 Pheniprazine JL^ 74 Pheniramine 1, 77

Cumulative Index, Vols. 1-3 Phenmetrazine 2.» 260 Phenobarbital 1^, 268 Phenolphthalein U 316 Phenomorphan 1_9 294 Phenoperidine ^ 302 Phenoxybenzmine j_, 55 Phenoxymethy 1 penicillin jL^» 410 Phensuximide l_9 226 Phentermine j^, 72 Phentolamine 1, 242 Phenyl aminosTlicylate 2, 89 Phenylbutazone I, 236; 2,, 388, 474 Phenylephrine J^, 63; 2, 265; 2, 20 Phenylglutarimide \j 257 Phenyltoloxamine 2_» 115 Phenyramidol I, 165 Pholcodine 1_, 287 Phthaloyl sulfathiazole U 132 Physostigmine j[, 111 Pimetine £, 286 Piminodine 1^, 301 Pimozide ^, 290 Pindolol 29 342 Pinoxepin 2^, 419 Pipamazine l> 385 Pipamperone 2, 288 Pipazethate T, 390 Piperacillin \ 207 Piperacetazine ^, 386 Pi peri dol ate 1_, 91 Piperocaine l_9 13 Piperoxan I, 352 Pipobroman 2, 299 Piposulfan ][, 299 Pipradol _1, 47 Piprozolin 2, 270 Piquizil 2^, 381 Pirandamine 2_9 459 Pirazolac _3» 138 Pirbencillin 3_9 207 Pirbutorol 29 280 Pirenperone 2, 231 Piretanide 3, 58 Pirexyl U 115

Cumulative Index, Vols. 1-3

275

Piridici 11 in _3, 207 Piridocaine 1, 13 Pirindol \_9 75 Piritramide U 308 Pirmentol 3_9 48 Piroctone 3_» 149 Pirogliride 2_9 57 Pirolate 2» 245 Piromidic acid _2, 470 Pirprofen 2, 69 PirquinozoT 2_9 243 Pivampicillin \j 414 Pizoctyline £, 420 Pol dine methyl sul fate 2_9 74 Polythiazide l_9 360 Practolol £, 106, 108 Pranolium chloride £, 212 Pramoxine 1_, 18 Prazepam j?, 405 Prazocin 2, 382; 3, 194 Prednimustine 2> 93 Prednisolone 1_, 192; £, 178 Prednisolone acetate ^, 192 Prednisone j^, 192 Prednival J2, 179 Prednylene ][, 197 Prenalterol 3, 30 Prenylamine T,49 76 Pridefine 2» Prilocaine J^, 17 Primaquine ^ 346 Primidolol ^ 29 Primidone 2., 276 Prizidilol 3_, 151 Probarbital ^ 268 Probenecid 1, 135 Probucol 29 126 Procainamide U 14 Procaine 1_, 9 Procarbazine 2^, 27 Procaterol _3, 184 Prochlorperazine 2^, 381 Procinonide 3^, 94 Procyclidine l_, 47 Prodilidine 1_, 305 Prodolic acid 2, 459

Progesterone 2^ 164 Proglumide ^, 93 Proguanil j., 280 Prolintane 1_» 70 Promazine J^ 377 Promethazine l_9 373, 377 Pronethalol J^, 66 Propanidid 2^, 79 Propantheline bromide j^, 394 Proparacaine 1, 11 Propenzolate 7, 75 Properidine 1_, 299 Propicillin 1_9 410 Propiomazine \j 376 Propi onyl promazi ne j^, 380 Propizepine 2_9 472 Propoxorphan j^, 113 Propoxycaine 1, 10 Propoxyphene T, 50; 298; 29 57 Propranolol 1_, 117; 2^, 105, 107, 212 Propylhexedrine J^, 37 Propylphenazone JU 234 Propylthiouracil 1^ 265 Proquazone 2^, 386 Proquinolate 2, 368 Prorenone 2^, T75 Prostalene 2_9 5 Prothipendyl J., 430 Prontosil 1^, 121 Protriptyline U 152 Proxazole 2^, 271 Pyrantel JU 266; 2^, 303 Pyrathiazine l_9 373 Pyrazineamide \j 211 Pyrilamine J^, 51 Pyrimethamine J^, 262 Pyrindamine j^, 145 Pyrinoline 2^ 34 Pyrovalerone 2^, 124 Pyroxamine 2_9 42 Pyroxicam 2, 394 PyrrobutamTne j^, 78 Pyrrocaine l^ 16 Pyrrol iphene 2^ 57 Pyrroxan 3^, 191

276 Quazepam ^3, 196 Quazodine 2_9 379 Quinacrine U 396 Quinazosin 2, 382 Quinbolone 7, 154 Quindonium bromide 2, 139 Quinethazone 2.» 354 Quinfamide 2» 186 Quinidine 1^ 339 Quinine U 337 Quinterenol 2_9 366 Racemoramide I, 82 Racemorphan 1_, 293 Ranitidine \ 131 Reproterol 2> 231 Rescinnamine 1_, 319 Rimantadine 2^ 19 Rimiterol ^, 278 Ripazepam Z_9 234 Risocaine 2^, 91 Ritodrine £, 39 Rodocaine 2_, 450 Roletamide £, 103 Rolicyprine 2* 50 Rolitetracycline JL^, 216 Rolodine 2, 468 Ronidazole 2> 245 Ripitoin 3^, 139 Rosoxacin 3^, 185 Rotaxamine 2* 32 Salicylamide 1^ 109 Salbutamol 2_, 280 Sal sal ate 2, 90 Salvarsan 1^, 223 Sarmoxicillin \ 205 Sarpicillin ^ 204 Secobarbital 1, 269 Semustine 2, T2, 15 Sermetacin ^, 166 Solypertine 2* 342 Sontoquine 1_, 344 Sorbinil 3^ 188 Sotalol J,, 66; 29 41 Soterenol 2, 40

Cumulative Index, Vois. 1-3 Spirilene 2> 292 Spironolactone 1, 206; 2, 172;

2, 91 Spi ropiperone j^, 306 Spirorenone 2» 91 > 92 Spirothiobarbitai 1^, 276 Stanazole l_9 174 Stenbolone acetate 2_, 155 Styramate ^ 219 Succinyl sulfathiazole l^, 132 Sudoxicam 2, 394 Sulazepam 7, 403 Sulconazole 2» 133 Sulfabenzamide 2_, 112 Sulfacarbamide 1^, 123 Sulfacetamide I, 123 Sulfachloropyridazine 1, 124, 131 Sulfacytine 2* 113 Sulfadiazine Y> 124 Sulfadimethoxine jL_, 125, 129 Sulfadimidine U 125, 128 Sulfaethidole 1_, 125 Sulfaguanidine 1^, 123 Sulfaisodimidine 1^, 125, 129 Sulfalene U 125 Sulfamerazine 1, 124, 128 Sulfameter !_, T25, 129 Sulfamethizole ^, 125 SulfamethoxypyrTdazine jl^, 124, 131 Sulfamoxole 1^, 124 Sulfanilamide l_9 121; 29 112 Sulfanitran 2, 115 SulfaphenazoTe 1_, 124 Sulfaproxyline 2.» 123 Sulfapyridine j^, 124; 2, 114 Sulfasalazine 2_9 114 Sulfasomizole 1, 124 Sulfathiazole T, 124 Sulfathiourea 1, 123 Sulfazamet 2, T13 Sulfentanil Z, 118 Sulfinalol 2, 25 Sulfinpyrazone \_% 238 Sulfisoxazole 1, 124

Cumulative Index, Vols. 1-3 Sulfonterol 2, 42 Sulformethoxine 1_, 125, 130 Sulfoxone 1_, 140 Sulindac 2, 210 SulnidazoTe 2^ 245 Suloctidil 3_> 26 Sulpiride 2_9 94 Sulprostene 3^, 9 Sulthiame 2_9 306 Suprofen 2_9 65 Symetine 2_9 29 Syrosingopine 1_, 319

277 Theophylline U 423; ^ s 464; 3_, 230

Thiabendazole 2^, 325; 2, 352 Thiabutazide U 358 Thialbarbital J,, 275 Thiamphenicol 2? 45 Thiamprine 2, 464 Thiamylal U 274 Thiazinium chloride 3, 240 Thiazolsulfone 1^, 14T Thiethylperazine \_9 382 Thiobarbital 1, 275 Thiofuradene T, 231 Thioguanine 2, 464 Taclamine 2, 224 Thiopental J j 274 TalampicilTin 2^ 438 Thiopropazate j^, 383 Talniflumate 3, 146 Thioridazine l^9 389 Talopram 2, 3"57 Thiothixene 1_, 400; 2, 412 Tametral ine 3_9 68 Thonzylamine J_, 52 Tamoxifen 2, 127; _3> 70 Thozalinone 2_9 265 Tandamine 2, 347, 460 Thyromedan 2_9 79 Tazolol 2/"""110, 268 . Thyroxine 1_, 95; £, 78 Teclozan 2_9 28 Tiaconazole ^» 133 Tegafur _3, 155 Tiamenidine ^, 137 Temazepam 2, 402 Tibolone 2_9 147 Terazocin 7, 194 Tibric acid 2^, 87 Terconazole 3^ 137 Ticarcillin 2, 437 Terolidine 2, 56 Ticlopidine T, 228 Tesicam 2_, 179 Ticrynafen 2^, 104 Tesimide £, 296 Tigesterol 2, 145 Testolactone 2^ 160 Testosterone cypionate j^, 172 Tiletamine 7, 15 Tilorone 2, 219 Testosterone decanoate JL^ 172 Testosterone propionate \_9 172 Timolol 2, 2729 4 TiodazocTn 2.5 I Tetrabenazine J^, 350 Tioperidone \ 192 Tetracaine jL^, 110 Tiopinac 2» 238 Tetracycline l_9 212 Tioxidazole ^, 179 Tetrahydrocannabinol, A-l, 1, Tipropidil 3^ 28 394 Tiquinamide 2, 372 Tetrahydrozoline 1, 242 226 Tixanox 3^ 276 Tetramisole l_9 43T; 2» Tocainide 3_9 55 Tetrantoin l_9 246 Tofenacin 2, 32 Tetroxoprim 3, 154 Tolamolol 79 110 Tetrydamine 7, 352 Tolazamide 1, 137 Thalidomide j ^ , 257; 2, 296 Tolazoline T, 241; 29 106 Them* urn closylate 2^, 99 Tolbutamide 1, 136; 3, 62 Theobromine 1 , 423; 2, 456

278

Toicielate 2» 69 Tolipridone ^9 156 Tolindate 2_9 208 Tolmetin £ , 234 Toinaftate 2^ 211; \ 69 Tolpyrramide 2, 116 Tolycaine J^, T7 Tonazocine 3^, 115 Topterone 3», 88 Tosifen 3, 62 Tralonide 2, 198 Tramalol 2_9 17 Tramazoline l^9 243 Tranexamic acid 2, 9 Tranylcypromine T, 73; 2, 7, 50 Trazodone 2_9 472 Treloxinate 1* 432 Triafungin 2» 233 Triamcinolone j ^ , 201; ^ , 185 Triamcinolone acetonide , 201 Triampyzine 2, 298 Triamterine ^ , 427 Triazolam ^ 368 Triazuryl 2_% 305 Tricetamide 2^, 94 Tri chl ormethi azide J^, 359 Triclonide 2^, 198 T r i f l o c i n 2_, 1^1 Triflubazam 1> 406 Triflumidate ly 98 Trifluperidol \j 306 Triflupromazine 1 , 380 Trihexyphenidyl T, 47 Triiodothyronine \j 95 Trilostane 2^, 158 Trimazosin 2, 382 Trimeprazine 1_, 378 Trimethadone U 232 Trimethobenzamide 1, 110 Trimethoprim U 267; 2_9 302 Trimethoquinol 2_> 374 Trimetozine 2, 94 Trimoxamine 7 , 49 Trioxifene 3_9 70 Trioxsalen 1_, 334 Tripelennamine j ^ , 51

Cumulative Index, Vois. 1-3 Triprolidine J^ 78 Trofosfamide 3^, 161 Tropocaine J^ 7 Tybamate 2^ 22 Verilopam 2.5 121 Verofylline 2^ 230 Viloxazine 2^, 306; Z Vinbarbital J,, 269 Volazocine _2, 327 Warfarin

32

331

Xanoxate 3^ 235 Xilobam 3, 56 Xipamide 2, 93 Xylami dine 2, 54 Xylazine 2, 307 Xylometazol ine 1, 242 Zidomethacin 3, 166 Zimeldine 3 49 Zolamine 1,"*52 Zolterine 2 , 301 Zometapine "3, 234 Zompirac 3, 128

Index aclomethasone dipropionate, 96 acne, 12, 148 actodigin, 99 acyciovir, 229 a d d i c t i o n , 111

adinazoiam, 197 adrenergic agonist, 20, 23, 30, 40, 184 adrenergic blocking agents, 20, 24-30, 151, 191, 196 D-alanine, 13 L-alanine, 13 aldose reductase, 72, 188 aldosterone, 91 alfentanyl, 118 alkylcupate reagent, 111 a l l e r g i c mediators, 58 allergic mediations, 66 alprazoiam, 197 a l p r o s t a d i l , 2,4,5 a ] r e s t a t i n , 72 Alzheimer's disease, 127 amacetam, 127 amantadine, 45 ametantrone, 75 amfenac, 38 a m i d i n o c i l l i n , 208

aminal, 192 amitriptyline, 32 amitriptylene, 49, 77 amoxycillin, 205 ampiciilin, 204 amrinone, 147 anagreiide, 244 angiotensin converting enzyme, 128 anilopam, 121 anitrazafen, 158 antagonists, androgen, 81, 248 antagonists, histamine, 131, 134 a n t i f e r t i l i t y activity, 70 arachidonic acid, 10 arbaprostil, 8 ariidone, 45 astemizole, 177 atherosclerosis, 15 atropine, 160 azaclorzine, 241 azarole, 129 azastene, 89 azepindole, 242 azipramme, 246 a z l o c i l l i n , 206 279

280

carbantel, 57 carbaprost, 7 carbazeran, 195 cardiac glycosides, 99 bacampicillin, 204 carfentanyl, 117 bamnidazole, 132 caries, dental, 157 Bayer-Villiger cleavage, 103, caroxazone, 191 105 carprofen, 169 bentazepam, 235 carteoioT, 183 bentirormde, 60 cataracts, 72, 188 benzomorphans, 114 cefaparole, 212 benzyl penicillin, 203 cefatrizine, 211 benzyne, 69 cefazaflur, 213 bepridi1, 46 cefonicid, 213 bevantoiol, 28 ceforanide, 214 bezafibrate, 44 cefotaxime, 216 bicifadine, 120 cefotiam, 215 biocides, 76 cefroxadine, 210 bioisostere, see isosteric cefsulodin, 214 replacement ceftazidime, 216 biotransformation, 167 ceftizoxirne, 218 bitoiterol, 22 cefuroxime, 216 a-blockers, see adrenergic cell walls, bacterial, 13 antagonists cephachlor, 209 3-blockers, see adrenergic cetaben, 60 antagonists cetiedii, 42 3-blockers, synthesis, 27 chiorpromazine, 72 blood-brain barrier, 46 chymotrypsin, 60 blood l i p i d s , 15 cimetidine, 134 breast tumors, 70 cinepazet, 157 brofoxine, 191 cinromide, 44 broperamole, 139 ciprefadol, 119 bucindoiol, 28 ciprocmonide, 94 budesonidte*, 95 ciprofibrate, 44 butamisole, 226 ciramadol7T22, 123 buterizine", 175 clodanoiene, 130 butoconazole, 134 clofibrate, 15, 44 butopamine, 23 clofilium phosphate, 46 clomacran, 73 c a i c i f e d i o l , 101, 102 c1onidin¥, 40 c a i c i t r i o l , 101, 103 cloperone, 150 calcium channel blockers, 46, clopipazam, 237 149 closantel, 43 calcium metabolism, 101 112 cannabinoid synthesis, 187, 189 codorphone, cognition enhancers, 127 captopril, 128 a z o c o n a z o l e , 137 azosgrnide, 27

Index

Index coiterol, 21 Corey lactone, 2, 7 cromogiycate, 66, 235 eye]indole, 168 cyclobenzaprine, 77 cyclooxygenase, 39, 110, 165 cyclophosphamide, 161 cycloserine, 14 " declenperone, 172 diacetolol, 28 diazepam, 195 diethylstilbestrol, 50 diftaione, 246 Digitalis, 99, 147 digitoxin, 99 dihydropyridine synthesis, 185 dihydropyridines, 149 diltiazem, 198 dipirefrin, 22 disobutamide, 41 disopyramide, 41 DNA, disruption of, 83 docanazole, 133 domperidone, 174 dothiepin, 239 doxpicomine, 122, 123 drindene, 65 drobuiine, 47 droprenyiamine, 47 droxacin, 185 drug absorption, 22 drugs, site directed, 83 eifazepam, 195 emilium tosyiate, 47 encainide, 56 endralazine, 232 enviroxime, 177 epinephrine, 19 epirazole, 152 epoprostenoi, 10 ergolines, 249 esterases, 94, 146 estramustine, 83

281 ethacrynic acid, 87 etinfidine, 135 etomidate, 135 etoprine, 153 exapralol, 28 felsantel, 57 fenbendazole, 176 fenciofenac, 37 fendosai, 170 fenobam7 136 fenquizone, 192 fentanyl, 116 flecainide, 59 floctafenTne, 184 flucindole, 168 flucinoione, 94 fludaianine, 14 flumequine, 186 flumizole, 158 flumoxonide, 95 fluproquazone, 193 fluquazone, 193 fluretofen, 39 flutamid"e7 57 5-fiuorouracil, 155 fluotracen, 73, 74 fluoxetine, 32 flutroline, 242 fosazepam, 195 foxglove, 99 frentizole, 179 gemcadiol, 15 gemfibrozil, 45 gestodene, 85 gestnnone, 85 glicetanile, 61 gliflumide, 61 glycosidation, 100 Gould-Jacobs reaction, 184 guanfacine, 40 halofantrine, 76 haiopemide, 174

282

Index

haloprednone, 99 helminths, 57 hormone antagonists, 50 histamine, antagonists, 131 homo!ogation, 138

meciorisone butyrate, 95 medroxaiol, 25 Meerwein reagent, 71, 119 meobentine, 45 meperidi~ne, 116 meseclazone, 245 ifosfamide, 151 metabolic inactivation, 9, 21 imafen, 226 metabolic protection, 8, 9 imipramine, 32 metabolic transformation, 39, indacrinone, 67 55, 101 indomethacin, 165 meteneprost, 9 indoprofen, 171 metioprim, 155 indorenate, 167 metoprine, 153 indoxole, 158 mezlocillin, 206 inhibitors, mechanism based, 14 mTdazolam, 197 insulin, 61 migrane, 247 ipexidine, 157 milenperone, 172 ipratropium bromide, 160 minaxaione, 90 isamoxole, 135 misonidazole, 132 isoproterenol, 20, 21 mitoxantrone, 75 isosteric replacement, 9, 42, molsidomine, 140 45, 58, 59, 61, 118, 128, 137, morni flumate, 146 145, 169, 178, 183, 185, 192, morphinans, 115 234 morphine, 110 isotretinoin, 12 motretinide, 12 isoxepac, 238 moxaiactam, 218 moxazocine, 114 Janssen laboratories, 116, 172 muzolimine, 137 ketanserin, 193 ketoconazole, 132 ketotifen, 239 labetolol, 24 levonantTodol, 188 leucotrienes, 1 lidamidine, 56 lidocaine, 40 liver flukes, 43 lodoxamide, 57 lofentanyl, 117 lorcainide, 40 lormetaze~pam, 196 mecillinam, 208

nabilone, 189 nabitan, 190 nafoxidine, 70 naftidine, 72 nantradol, 186 napactidTne, 71 nervous system, sympathetic, 20 Newman thiophenol synthesis, 236 nicarpidine, 150 nicordanTT, 148 nifedipine, 149 mmodipme, 149 nisobuterol, 23 nisoxetine, 32

Index nistremine acetate, 88 nitrafudam, 130 nitrogen mustards, 82 nitromifene, 51 nivimedone, 67 nocodazole, 176 norepinephrine, 19, 24 norgestrei, 84 nonsteroidal anti i nf1ammatory agents, 37 nufenoxole, 42 oral contraceptives, 84 orconazole, 133 ornidazole, 131 orpanoxin, 130 oxarbazole, 169 oxatomide, 173 oxetorene, 247 oxidation, microbiological, 93 oxiramide, 40 oxmetidiTTe, 134 oxolinic acid, 185 oxyfungin, 233 ozolinone, 140 pain, 109 pamatolol, 28 parconazole, 133 pattern recognition, 42 penicillin V, 205 pentomone, 248 pergolidir, 249 pharmacokinetics, 99 phenacetamide, 44 phenoxymethylpenici11in, 205 phenylephrine, 2"0 piperacillin, 207 pirazolac, 138 pirbenciTlin, 207 pirenperone, 231 piretanide, 58 piridicilfin, 207 pirmentoi, 48 piroctone, 149

283 pirogliride, 57 pirolate, 245 pirquinozol, 243 Polonovski rearrangement, 196 prazocin, 194 prednimustine, 83, 93 premature senility, 127 prenalterol, 30 prenylamine, 47 pridefine, 49 primidolol, 29 prizidilol, 151 procateroT, 184 procinonide, 94 prodrug, 39, 94, 146, 155, 166, 187, 204, 209 propoxorphan, 113 prostacyclin, 10 prostaglandin F 2 a, 11 pyrroxan, 191 quazepam, 196 quinfamide, 186 ranitidine, 131 reduction, microbiological, 6 reprotero], 231 rickets, 101 ripazepam, 234 Robinson annulation, 85 Robinson, tropine synthesis, 160 ropitoin, 139 rosoxacin, 185 Rule, Beckett and Casey, 121 Sarmoxicillin, 205 sarpicillin, 204 screening, random, 75 sermetacin, 166 serotonin, 167 sorbinil, 188 spironoiactone, 91 spirorenone, 91, 92 SRS-A, 1

284 stereospecificity of drug action, 30 stereospecific synthesis, 3, 6, 9, 30, 103, 219 sulconazole, 133 suifentanyl, 118 sulfinalol, 25 suioctidil, 26 suiprostene, 9 sydnone, 140 sympathomimetic agents, see adrenergic agents synthesis, Grewe, 114 synthesis, stereospecific, 103, 219 talniflumate, 146 tametraiine, 68 tamoxifen, 51, 70 tegafur~155 terazocin, 194 terconazole, 137 testosterone, 88 tetramisole, 226 tetroxoprim, 154 thebaine, 111 theophylline, 230 thiazinium chloride, 240 thrombosis, 10 thromboxane A2, 10 tiaconazole, 133 tiamenidine, 137 ticiopidine, 228 tiodazocin, 194 tioperidone, 192 tiopinac, 238 tioxidazole, 179 tipropidii, 28 tixanox, 236 tocainide, 55 toibutamide, 62 tolciclate, 69 toli mi done", 156 tolnaftate, 69 tonazocine, 115

Index topterone, 88 tosifen, 62 triafungin, 233 trioxifene, 70 trofosfamide, 161 umpohlung, 6 uric acid, retention, 67 vasodilator, peripheral, 26 verilopam, 121 verofylline, 230 Villsmeyer reaction, 156 viloxazine, 32 vitamin D, 101 xanoxate, 235 xiIobam7 56 zidomethacin, 166 zimeidine, 49 zometapine, 234 zompirac, 128

THE ORGANIC OF DRUG

CHEMISTRY

SYNTHESIS

VOLUME 4

DANIEL LEDNICER National Cancer Institute Bethesda, Maryland LESTER A. MITSCHER Department of Medicinal Chemistry The University of Kansas Lawrence, Kansas with GUNDA I. GEORG Department of Medicinal Chemistry The University of Kansas Lawrence, Kansas

A Wiley-Interscience Publication John Wiley & Sons, Inc. New York / Chichester / Brisbane / Toronto / Singapore

Copyright © 1990 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: (Revised for volume 4) Lednicer, Daniel, 1929The organic chemistry of drug synthesis. "A Wiley-Interscience publication." Includes bibliographical references and Index. 1. Chemistry, Pharmaceutical. 2. Drugs. 3. Chemistry, Organic-Synthesis. I. Mitscher, Lester A., joint author. II. Title. [DNLM 1. Chemistry, Organic. 2. Chemistry, Pharmaceutical. 3. Drugs-Chemical synthesis. QV 744 L473o 1977] RS403.L38 615M9 76-28387 ISBN 0-471-85548-0(v. 4) Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

We dedicate this book to Beryle and Betty who continue to support us in every imaginable way and to the memory of Katrina Mitscher-Chapman (1958-1987) who was looking forward with her customary enthusiasm to helping us prepare the manuscript.

I cannot tell how the truth may be; I say the tale as 'twas said to me.

Sir Walter Scott, "The Lay of the Last Minstrel"

Preface

Over a decade and a half have flown by since we started on the preparation of the first volume in this series. We did not at that time envisage a series at all but simply a book which filled what we then perceived as a vacuum. There were not in print in the midnineteen seventies any contemporary monographs in the English language dedicated to the synthesis of medicinal agents. The result was the original Organic Chemistry of Drug Synthesis. The reception accorded that volume confirmed that there was indeed a place for a book devoted to that subject matter. Having laid the groundwork, it seemed worthwhile to rectify a number of omissions present in the book and at the same time to bring the coverage for compounds included in the compilation to a common date. The result was of course Volume 2 and the birth of a series. The next volume, 3, was produced at the time we again felt the need to update our narrative; a semidecenial period was settled upon since it seemed to represent the best compromise between currency and a sufficient body of material to merit treatment in a monograph. The volume at hand continues the series; it covers the chemistry of those compounds which have been granted a United States Adopted Name (USAN) in the five years between 1983 and 1987. The bulk of the references thus fall in the 1980s; the reader will note occasional much older references. We suppose that those represent compounds which were synthesized many years ago and set on the shelf at that time; they were then revived for clinical development for one reason or another and a USAN applied for. It is well known that regulatory approval of new chemical entities has slowed markedly over the past decade. Some would even argue that the very rate of decrease is accelerating. This phenomenon has been attributed to a wide variety of causes, none of which are particularly germane to this volume. It is thus surprising, and pleasing, to note that the decreased probability of bringing a given new chemical entity to market has not led to a diminution in the rate of acquisition of new generic names as noted in USAN and USP Dictionary of Drug Names. The 300 odd compounds discussed in this volume are within a few entities of the number covered in the preceding volume. The acquisition of 60 new generic names each year has been so uniform over the past decade that this should perhaps be recognized as a new physical constant! This relatively steady rate of addition of new generic names has resulted in books which are quite uniform in size, at least after accounting for the text which was used to bring the subject up to date . The individual chapter titles do not show a corresponding uniformity; the composition of

x

PREFACE

the more recent volumes in some ways represents a socio economic history of research in medicinal chemistry. The first volume in this series, for example, contained a sizable chapter devoted to compounds based on the phenothiazine nucleus. This had disappeared by the second volume due to a dearth of new material. This in all probability simply represents a shift away from the research which took place on these compounds in the midnineteen fifties. Occasional chapters have lasted through all four volumes. One of these, to the authors' surprise is that devoted to " Steroids." That particular chapter is, however, by now a mere shadow of those which appeared in the first two volumes. Some chapters have persisted but changed significantly in content. "Alicyclic Compounds" has evolved from a collection of miscellany to a virtual compendium of prostaglandin syntheses. The diligent reader will note that succeeding volumes increasingly show agents which are the result of rational drug design of the synthesis targets. The older rationale for preparing specific compounds—to produce a hopefully superior and clearly patentable modification of a successful new drug—still however persists. Note that the present volume lists seven quinolone antibacterial agents, the same number of dihydropyridine calcium channel blockers, and no fewer than an even dozen angiotensin-converting enzyme inhibitors. Once the initial lead is discovered, a very significant expenditure of effort takes place; this persists until it becomes clear that no further improvements are taking place and that new entries are unlikely to gain a share of the market, This book is addressed primarily to practitioners in the field who seek a quick overview of the synthetic routes which have been used to access specific classes of therapeutic agents. Publications of syntheses of such compounds in the open literature remains a sometimes thing. One can, however, be certain that any compound which has commercial potential will be covered by a patent application. Many of the references are thus to the patent literature. Graduate students in medicinal and organic chemistry may find this book useful as an adjunct to the more traditional texts in that it provides many examples of actual applications of the chemistry which is the subject of their study. This volume, like those which came before, presumes a good working knowledge of chemical synthesis and at least nodding acquaintance with biology and pharmacology. Finally, the authors express their gratitude to Ms. Vicki Welch who patiently and skillfully prepared the many versions of this book including the final camera ready copy. Rockville, Maryland Lawrence, Kansas Lawrence, Kansas January, 1990

DANIEL LEDNICER LESTER A. MITSCHER GUNDA I. GEORG

Contents Chapter 1.

Chapter 2.

Chapter 3.

Chapter 4.

Chapter 5.

Aliphatic and Alicyclic Compounds 1, Acyclic Compounds 2. Alicyclic Compounds 3. Prostaglandins 4. Organoplatinum Complexes References Monocyclic Aromatic Compounds 1. Phenylpropanolamines 2. Phenoxypropanolamines 3. Alkylbenzenes and Alkoxybenzenes 4. Derivatives of Aniline 5. Benzoic Acid Derivatives 6. Diphenylmethanes 7. Miscellaneous Compounds References Polycyclic Aromatic Compounds and Thier Reduction Products L Naphthalenes and Tetralins 2. Indanes and Indenes 3. Fluorenes 4. Anthraquinones 5. Reduced Anthracenes References Steroids 1. Estranes 2. Androstanes 3. Pregnanes References Five-Membered Ring Heterocycles 1. One Heteroatom 2. Two Heteroatoms 3. Three Heteroatoms References

1 1 4 8 15 17 19 19 25 29 35 39 46 49 52 55 55 58 62 62 63 64 65 65 68 70 77 79 79 85 98 98

CONTENTS Chapter 6.

Chapter 7.

Six-Membered Ring Heterocycles 1. Pyridines 2. Dihydropyridines 3. Pyrimidines 4. Piperazines 5. Miscellaneous Compounds References Five-Membered Ring Benzofused Heterocycles 1. Benzofuranes 2. Indolines 3. Benzothiaphenes 4. Benzisoxazoles 5. Benzoxazoles 6. Benzimidazoles 7. Benzothiazole References

Six-Membered Ring Benzofused Heterocycles 1. Chromones 2. Benzodioxanes 3. Quinolines and Carbostyrils 4. Quinolones 5. Tetrahydroisoquinolines 6. Benzazepines 7. Benzothiepins 8. Quinazolines and Quinazolinones 9. Phthalazines 10. Benzodiazepines References Bicyclic Fused Heterocycles Chapter 9. 1. Indolizines 2. Pyrrolizines 3. Cyclopentapyrroles 4. Imidazopyridines 5. Purinediones 6. Purines 7. Triazolopyrimidines 8. Triazolopyridazines 9. Pyrimidinopyrazines 10. Pyridazinodiazepines 11. Thiazolopyrimidones 12. Thienopyrimidines 13. Thienothiazines 14. Pyrazolodiazepinones References

Chapter 8.

101 101 106 112 118 120 123 125 125 128 129 130 131 131 134 135 137 137 138 139 141 146 146 148 148 151 153 153 157 157 157 158 161 165 165 168 168 169 169 171 172 173 174 174

CONTENTS

xm

Chapter 10.

111 111 181 182 193 197

Chapter 11.

199 199 200 201 201 202 203 203 205 205 205 206 208 208 209 210 210 211 212 212 213 213 214 215 215 217 217 218 219 219 220 221 223 231 249

p-Lactam Antibiotics 1. Penicillins 2. Carbapenems 3. Cephalosporins 4. Monobactams References

Miscellaneous Heterocycles 1. Phenothiazines 2. Benzocycloheptapyridines 3. Carbazoles 4. Dibenzazepines 5. Dibenzoxepines 6. Pyridobenzodiazepines 7. Benzopyranopyridines 8. Pyrroloisoquinolines 9. Pyrazoloquinolines 10. Naphthopyrans 11. Benzodipyrans 12. Furobenzopyrans 13. Pyranoquinolines 14. Dibenzopyrans 15. Benzopyranopyridines 16. Thiopyranobenzopyrans 17. Pyrazinopyridoindoles 18. Thienobenzodiazepines 19. Imidazoquinazolinones 20. Imidazopurines 21. Pyrazinoisoquinolines 22, Pyrazinopyrrolobenzodiazepines 23. Imidazoquinolines 24. Oxazoloquinolines 25. Thiazolobenzimidazoles 26. Pyrimidoindoles 27. Ethenopyrrolocyclobutisoindoles 28. Thienotriazolodiazepines 29. Imidazobenzodiazepines 30. Imidazobenzothiadiazepines References Cross Index of Drug! Cumulative Index, Vols. 1-4 Index

T H E ORGANIC OF D R U G VOLUME 4

CHEMISTRY

SYNTHESIS

1

Aliphatic and

Alicyclic C o m p o u n d s

1. ACYCLIC COMPOUNDS There are relatively few important drugs which are alicyclic. Other than inhalation anesthetics, which are a special case, the compounds in the acyclic aliphatic class owe their activity to the functionality present and its specific spacing on the aliphatic framework. Thus, in most instances, the framework itself is not of comparable importance to the functionality attached to it. Caracemide (3) is an antitumor agent. This simple molecule is constructed by reacting acetohydroxamic acid (1) with methylisocyanate (2) promoted by triethylamine. The resulting O,N-biscarbamate (3), caracemide, is metabolized readily either by deacetylation or by decarbamoylation and its antitumor properties are believed to result from the reactivity of the resulting metabolites with DNA [1]. MeCONHOH (1)

+

2 MeN=C = O (2)

—*~

MeCONOCONHMe CONHMe (3)

Viral infections continue to be significant causes of morbidity and mortality and at the same time continue to be resistant to treatment by small molecules. Avridine (6) is an antiviral compound which has shown some activity in a variety of animal tests apparently based upon its ability to stimulate a number of cells to produce the high molecular weight endogenous antiviral substance interferon. Thus, the compound is believed to operate indirectly by stimulating the body's own natural defenses against viral penetration into host cells. Avridine is synthesized by 1

2

Aliphatic and Alicyclic Compounds

alkylating N-(3-aminopropyl)diethanolamine (5) with octadecyl bromide (4) using potassium carbonate in the usual fashion [2]. Me(CH2)16CH2 v Me(CH2)nBr

+ H2N(CH2)3N(CH2CH2OH)2

-

CH2CH2OH N(CH2)3N

Me(CH2)16CH2 ' (4)

(5)

CH2CH2OH (6)

Much attention has been focused upon the exciting promise of enzyme activated enzyme inhibitors for potential use in therapy. In contrast to the ordinary alkylating agents which are aggressive chemicals in the ground state and, thus, lack specificity in the body and produce many side effects and unwanted toxic actions, the so-called K-cat inhibitors or suicide substrates turn the enzyme's catalytic action against itself. The enzyme first accepts the suicide substrate as though it were the normal substrate and begins to process it at its active site. At this point, it receives a nasty surprise. This intermediate now is not a normal substrate which peacefully undergoes catalytic processing and makes way for another molecule of substrate, but rather is an aggressive compound which attacks the active site itself and inactivates the enzyme. As the suicide substrate is only highly reactive when processed by the enzyme, it achieves specificity through use of the selective recognition features of the enzyme itself and it works out its aggression at the point of generation sparing more distant nucleophiles. Thus, much greater specificity is expected from such agents than from electrophiles which are highly reactive in the ground state. Eflornithine (10) represents such a suicide substrate. Cellular polyamines are widely held to be involved in cellular growth regulation and, in particular, their concentration is needed for accelerated growth of neoplastic cells. The enzyme ornithine decarboxylase catalyzes a rate determining step in cellular polyamine biosynthesis and a good inhibitor ought to have antitumor activity. The synthesis of eflornithine starts with esterification of the amino acid ornithine (7) followed by acid-catalyzed protection of the two primary amino groups as their benzylidine derivatives (8). The acidic proton is abstracted with lithium diisopropylamide and then alkylated with chlorodifluoromethane to give 9. This last is deprotected by acid hydrolysis to give eflornithine (10) [3].

Aliphatic and Alicyclic Compounds Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce vinylogue 12 which can alkylate the enzyme by conjugate addition. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. CHF2

H2N(CH2)3CHCO2H

I ==N(CH2)3CCO2Me

C6H5CH ==N(CH2)3CHCO2Me

NH2

N==CHC 6 H 5

(7)

(8) (9)

CHF 2

jCHF

„ CHF-Enz

H2N(CH2)3CCO2H NH2

(10)

+

^CHPy

(11)

+

^CHPy

(12)

+^CH

(13)

Py = pyridoxal phosphate O n e interesting metabolic theory is that glucose and lipid levels in the blood affect each other's metabolism. G l u c o s e metabolism is disturbed in sugar diabetes and s o m e of the toxic effects of the resulting metabolic imbalance is believed to be due to enhanced oxidation of fatty acids as an alternate food. It is theorized that inhibitors of fatty acid oxidation could reverse the cycle in favor of glucose utilization. S o d i u m palmoxirate (19) was selected as a potential oral antidiabetic agent of a n e w type based upon this premise. Its synthesis begins by alkylating

4

Aliphatic and Alicyclic Compounds

methyl malonate with tridecylbromide (14) to give 15 and partially hydrolyzing the product to monoester 16. Next, treating the monomethylester with diethylamine and aqueous formaldehyde gives the desired alkyl acrylate ester 17. This is epoxidized with m-chloroperbenzoic acid and the resulting glycidic ester (18) is carefully hydrolyzed to give palmoxiric acid as its water soluble sodium salt (19). Palmoxirate is a potent hypoglycemic agent following oral administration to several animal species [5]. Me(CH2)i3Br

(14)

^Me(CH2)13CHCO2Me I CO2R (15);R«Me (16); R « H

2. ALICYCLIC COMPOUNDS An interesting appetite suppressant very distantly related to hexahydroamphetamines is somanladine (24). The reported synthesis starts with conversion of 1-adamantanecarboxylic acid (20) via the usual steps to the ester, reduction to the alcohol, transformation to the bromide (21), conversion of the latter to a Grignard reagent with magnesium metal, and transformation to tertiary alcohol 22 by reaction with acetone. Displacement to the formarnide (23) and hydrolysis to the tertiary amine (24) completes the preparation of somantadine [6],

(20); R = CO2H (21); R = CH2Br

(22); X = OH (23); X = NHCHO (24); X » NH2

Brain tumors are hard to treat in part because many antitumor agents which might otherwise be expected to have useful activity are too polar to pass the blood brain barrier effectively and fail to reach the site of the cancer. Nitrogen mustards are alkylating agents which fall into the category of antitumor agents which do not penetrate into the CNS. It is well known that a number of hydantoins pass through the highly lipid capillary membranes and, indeed, a number of CNS

Aliphatic and Alicyclic Compounds

5

depressants possess this structural feature. Combination of a hydantoin moiety to serve as a carrier with a latentiated nitrogen mustard results in spiromustine (28). Spiromustine is metabolized in the CNS to the active moiety, bis(chloroethanamine) (29). The synthesis begins with 5,5pentamethylenehydantoin (25) which is alkylated to 26 by reaction with l-bromo-2-chloroethane. Reaction of 26 with diethanolamine promoted by in situ halogen exchange with sodium iodide (Finkelstein reaction) leads to tertiary amine 27. The synthesis is completed by reacting the primary alcoholic moieties of 27 with phosphorus oxychloride [7]. H N

C

H

o ^

NR

JP

£ ^ N ^ N ^

X

HN(CH2CH2C1)2

o

(25); R = H (26); R - CH2CH2C1

(27); X = OH (28); X = Cl

(29)

Some alicyclic 1,2-diamine derivatives have recently been shown to have interesting CNS properties. For example, eclanamine (34) is an antidepressant with a rapid onset of action. The reasons for its potency are not as yet clear but pharmacologists note that the drug desensitizes adrenergic alpha-2 receptors and antagonizes the actions of clonidine. The synthesis of eclanamine starts with attack of cyclopentene oxide (30) by dimethylamine (to give 31). This product is converted to the mesylate by reaction with sodium hydride followed by mesyl chloride. Attack of COEt

(30)

(31);X = OH (32); X = OSO2CH3 (33); X = NH

OO (35)

(34)

6

Aliphatic and Alicyclic Compounds

the product (32) by 3,4-dichloroaniline leads to trans-diamine 33. The stereochemical outcome represents a double rear side displacement. The synthesis is completed by acylation with propionic anhydride to give eclanamine (34) [8], A chemically related agent, bromadoline (36) is prepared by an analogous series of reactions starting with cyclohexene oxide (35). Bromadoline is classified as an analgesic [9]. A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with p-keto ester 37 and subsequent enamine formation with 3-amino-l-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cyclization to form the azetidine ring of tazadolene [10]. OH

cc — o (37)

,-CHPh .N(CH2)3OH H (38)

CHPh

H (39) (40) C e r t a x a e t ( 4 4 ) i s a p r o d r a g o f r t a n e x a m c i a c d i . T h e a l t e r i s a in ti n ighab istrtsion h t e a c v t i a o t i n o f p a l s m n i o g e n t o p a l s m n i . T h e r e s u t l i s t o p r e v i t e s n t i a l u c l e r s . P r o d r u g s a r e o f v a u l e a s h t e y a o l w g r e a e t r a b s o th rtaeotinesteb y s u p p r e s n i g , n i t h s i c a s e , h t e a m p h o e c t r i n a u t r e o f h t e d r u g . T r c f i a o t i n o f 3 £ ( h y d r o x y p h e n y p ) l r o p o i n c i a c d i ( 4 2 ) b y r t a n s 4 c y a n o c y c o l h e x a n e c can hd olrd ieRa(n 4ey1).nT h e p r o d u c t ( 4 3 ) i s r e d u c e d t o c e t r a x a t e b y c a t a y l t c i h y d r o cikel [11].

Aliphatic and Alicyclic Compounds

COC1

CH2CH2CO2H r r

c

o

n

(43); R - CN (44); R = CH2NH2 Among the most successful drugs of recent years have been the group of antihypertensive agents which act by inhibition of the important enzyme, angiotensin-converting enzyme (ACE). The renin-angiotensin-aldosterone system exerts an important control over blood pressure and renal function. One of the key steps in the process is the conversion of angiotensinogen to angiotensin I by the enzyme renin. Angiotensin I, an octapeptide (Asp-Arg-Val- Tyr-Ile-His-Pro-PheHis-Leu), is cleaved of two amino acids by ACE to a hexapeptide, angiotensin II (Asp-Arg-ValTry-Ile-His- Pro-Phe), a powerful pressor hormone. The majority of the inhibitors of this important enzyme are treated in a later chapter. One of the structurally more interesting representatives, however, is pivopril (50), an orally active prodrug with a masked sulfhydryl group (protected by a pivaloyl ester moiety) and, instead of possessing the usual chiral C-terminal proline residue, has an achiral N-cyclopentylglycine moiety. The synthesis begins with the reaction of the t-butylester of N-cyclopentyl glycine (45) with (S)-3-acetylthio-2-methylpropionyl chloride (46) to give amide 47. The acetyl group is selectively cleaved with ammonia in methanol to give 48. The thiol group is reprotected by reaction with pivaloyl chloride to give 49 and the carboxyl protecting group is removed by selective reaction with trimethylsilyl iodide to give pivopril (50) [12]. The structural relationship of pivopril to the commercially important analogues captopril (51) and enalaprilat (52) is readily apparent. Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretinide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with rj-aminophenol to give ester 54 [13].

Ap ilhacti and Acilyccil Compounds NHCH C C 2O 2M 3e C 1 (45) (46C )O

CC

64(7R = -AcH ((4498;)));; R R -M C CO 3e

M C OSCHj^ C O N C H C H 3e 2O 2 £O H rvef O tH 2 2 (50) (51) (52) C O R

((5534));; R = O H R - NH3. PROSTAGLAND N IS The prosatgalndnis connitue theri stateyl progres otwards cn ilcial use. Theri pr regualtors are wel estabsih led but theri use for oh ter h terapeucit neds is co weah tl of sd ie efects. Theri use as cytoprotecvtie agenst and anstiecretory age oloks promn sig,however,and there is osme hope for h te calsscial agenst svie agents; oh terwsei much of the curent excetiment wh ti these compounds control the boisynthesi of parctiualr prosatnodis or to moduaelt theri acotin at Motsn iterest centers around the oh ter producst of h te arachdionci acd i cascad boxanes and elucotreines where n itervenotin promseis controlof dsiorders of hem

Aliphatic and Alicyclic Compounds

9

inflammation. Few of these substances have progressed far enough to be the subject of paragraphs in this work as yet. Alfaprostol (55) is a luteolytic agent used injectably for scheduling of estrus in mares for purposes of planned breeding. It is also used for treatment of postweaning anestrus in economically important farm animals. For these purposes, alfaprostol is more potent than naturally occurring prostaglandin F2-alpha. Notable molecular features of the alfaprostol molecule are the acetylenic linkage at C-13, the methyl ester moiety (which is rapidly removed in vivo) and the terminal cyclohexyl moiety which inhibits some forms of metabolic inactivation. The synthesis begins with lactol 56 which undergoes Wittig reaction with methyl 5-triphenylphosphoniumvalerate (57) using dimsyl sodium as base. Dehalogenation occurs concomitantly to produce partially protected condensation product 58. Deblocking to alfaprostol is brought about by oxalic acid [14].

Othp

Othp (56)

(57)

(58); R = thp (55); R - H

Another luteolytic agent, fenprostalene (62) contains an alleneic linkage in the upper sidechain and terminates in a phenoxy moiety in the lower. Its synthesis begins with lactol 59 (presumably the product of a Wittig olefination of the Corey lactol and suitable functional group manipulation). Lactol 59 is reacted with lithio 4-carbomethoxybut-l-yne and the resulting secondary carbinol acetylated with acetic anhydride to give substituted acetylene 60. The allene moiety (61) is produced by reaction with copper (II) bromide and methyl lithium. The tetrahydropyranyl ether protecting groups are then removed by treatment with acetic acid, the ester groups are hydrolyzed with potassium carbonate, and the carboxy group is reprotected by diazomethane methylation to give fenprostalene [15].

10

Aliphatic and Alicyclic Compounds

OH

AcO AoO

i Othp Othp (59)

(60)

A prostaglandin closely related to fenprostalene is enprostil (63). Enprostil belongs to the prostaglandin E family and is orally active in humans in reducing gastric acid and pepsin concentration as well as output. It is effective in healing gastric ulcers in microgram doses and is under consideration as an antisecretory, antiulcerative agent. The synthesis begins with intermediate 61 by removing the protecting THP ether groups with acetic acid (64) andthen replacing them with t-butyldimethylsilyl groups by reaction with t-butyldimethylsilyl chloride and imidazole. This is followed by hydrolysis of the ester moieties with potassium carbonate and reesterification of the carboxy moiety with diazomethane to produce intermediate 65. The solitary free alcoholic hydroxyl at C-9 is oxidized with Collins' reagent and the silylether groups are removed with acetic acid to give enprostil (63) [15].

(64) R=Ac; Y=H (65)R=H; Y=SiMe2i-Bu

Aliphatic and Alicyclic Compounds

11

CO2Me

(63) Enisoprost (70) is an antiulcerative/cytoprotective prostaglandin. In addition to the wellknown property of E series prostaglandins to inhibit gastric secretion of HC1 and pepsin, these agents enhance ulcer healing by stimulating formation of the mucin protective layer over the stomach lining. The well-known ulcer promoting action of nonsteroidal antiinflammatory agents such as aspirin can be rationalized by invoking the reversal of this effect. Thus, useful antiulcer properties can be anticipated at very low doses of certain prostaglandins (offsetting their cost) and this has been confirmed in the clinic. One of the side effects of such prostaglandins which must be minimized is diarrhea and cramps. In the enisoprost molecule this has been accomplished by moving the C-15 OH group of ordinary prostaglandins to C-16. This is consistent with antiulcer activity but reduces other side effects. Presumably these results reflect different structural needs of the different receptors. The addition of the methyl group at C-16 prevents oxidative inactivation of the molecule which would involve ketone formation at C-16 otherwise. This devise is a common stratagem used previously, for example, with methyltestosterone. The presence of a cis double bond at C-4 is also known to inhibit oxidation beta to the carboxyl group. Thus enisoprost carries a number of interesting design features. The synthesis concludes by conjugate addition of mixed cuprate 68 to unsaturated ketone 69. The product, enisoprost, is the more stable isomer with the two new side chains trans. The mixed cuprate is made from protected acetylene alcohol 66 by photosensitized trans addition of tri-n-butyltin hydride to give organostannane 67. Successive transmetalations with butyl lithium and then copper 1-pentyne leads to the necessary mixed cuprate (68) for the above sequence [16], Gemeprost (73; 16,16-dimethyl-trans-A2-prostaglandin-E1) is dramatically more potent on a dosage basis as an abortifacient than prostaglandin E2 itself and has fewer side effects. The gem-dimethyl groups at C-16 protect the alcohol moiety at C-15 from rapid metabolic oxidation.

12

Aliphatic and Alicyclic Compounds

(66) > NsX
hC

(68) 0 1 a H6

(67) 0 / If - TO9Me 6SiEt3 (69)

^CO2Me (70)

It is synthesized by further transformation of bisnor prostaglandin 71, itself derived from Corey's lactone by Wittig reactions. Catalytic reduction of the cis double bond using hydrogen and palladium on charcoal is followed by esterification with diazomethane and then DIBAL reduction to the aldehyde 72. This undergoes Horner-Emmons olefination followed by oxidation of the free alcoholic function at C-9 to the ketone and deblocking with acetic acid to give gemeprost (73) HO

HO

/ X / ^

[I J (72)

(73)

Rioprostil (77) is also a gastric antisecretory and cytoprotective prostanoid. It is administered as the alcohol and presumably operates as a prodrug, being oxidized in vivo to the acid. An essential step in its synthesis is also a conjugate addition of a suitably substituted organocopper reagent to a suitable unsaturated ketone. The synthesis begins by Grignard addition of propargyl magnesium bromide to 2-hexanone to give alcohol 74 (compare to 66). This is protected as the tetrahydropyranyl (THP) ether in the usual way and then the triple bond is converted to the Eiodoolefin (75) by reduction with DIBAL and iodine. This sequence is the equivalent of reverse

Aliphatic and Alicyclic Compounds

13

iodoolefin (75) by reduction with DIBAL and iodine. This sequence is the equivalent of reverse addition of HI to protected 74. Mixed lithiocuprate 76 is prepared from 75 by reaction with copper pentyne and tert-butyl lithium. Conjugate addition to the appropriate cyclopentene and deblocking with acetic acid completes the synthesis of rioprostil (77) [18]. Me (75)

LiCu (77)

(76)

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. T h e methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. T h e synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 8 1 [19].

0

o •CO2tms Olms

(78)

(79)

(80); X = t m s ; Y = tms (81); X = H; Y = Me

Butaprost (82) not only has the typical C-15 hydroxyl of the natural prostaglandins moved to C-16, as do several of the analogues discussed above, but it has a rather interesting g e m dialkyl substitution at C-17, presumably for metabolic protection, in the form of a cyclobutyl ring. It is a bronchodilator and is prepared in a manner analogous to that of rioprostil discussed above [17].

14

Aliphatic and Alicyclic Compounds

(82) Prostacyclin (PGI2) (83) is a naturally occurring bicyclic prostaglandin produced by the vascular endothelium. It is a powerful vasodilator and a potent inhibitor of platelet aggregation. The latter effect makes it of interest in preventing blood clotting. It is too unstable in its own right for therapeutic application, having a biological half-life of seconds to minutes. Much work has been carried out on analogues in an attempt to stabilize, the molecule and yet retain significant activity. The carbon bioisostere, carbacycline (enol ether oxygen replaced by methylene), has some of these useful properties. One of the first of the prostacycline analogues to achieve International Nonproprietary Name status is ciprostene calcium (89b). It is rather less potent as a platelet antiaggregatory agent than prostacyclin (83) itself but is still effective in humans in nanogram quantities when given by steady infusion. Its synthesis begins with protected optically active Corey lactone 84 which is reacted with lithium dimethylmethylphosphonate to produce hemiketalphosphonate 85. Jones' oxidation produces diketone 86 which undergoes an intramolecular Wittig condensation to unsaturated ketone 87 when treated with potassium carbonate and 18-crown-6 in toluene. Conjugate addition of dimethylcopperlithium then leads to saturated ketone 88. The synthesis concludes by Wittig addition of the upper side chain. This step leads to a mixture of 1:1 Z and E olefins which must be separated by chromatography before therightolefin is deblocked in acid and converted to the calcium salt by treatment with CaO in aqueous THF [20].

H(

\.CH2PO(OMe)2 > c t 0

1 Othp (83)

Othp (84)

Othp Othp (85)

Aliphatic and Alicyclic Compounds

15

•PO(OMe)2 Me Othp

Qthp

Me Othp

othp

(87)

(86)

Othp

othp

(88)

Me '

(89a); X = H (89b); X = 1/2 Ca

4. ORGANOPLATINUM COMPLEXES Whereas the medical practice of the Middle Ages contained many inorganic medicaments, modern medicine is dominated by organic drugs. There are, however, notable exceptions. Among these, a number of organoplatinum complexes have shown high potency against a variety of tumors and much work has been carried out in order to reduce their toxicity, enhance their water solubility, and sharpen their anticancer potency. The work has demonstrated that the activity resides in the cis complexes and that the toxicity and pharmacokinetic features of the drugs are manipulable by changing the nature of the organic portion of these agents.

16

Aliphatic and Alicyclic Compounds The first of these agents to find use is cisplatin (93) itself [21]. Cisplatin was apparently

discovered by accident when it was seen that platinum electrodes used in monitoring bacterial cultures leaked platinum and that the consequences were antimicrobial activity. Subsequently, cisplatin was tested in tumor systems also and found to be active. These observations subsequently held up in the clinic but despite marked antitumor activity serious side effects such as kidney damage, damage to the intestinal mucosa, immunosuppression, mutagenicity, and bone marrow depletion, lead to the search for second generation agents. The molecular mode of action of cisplatin and its analogues appears to be cross linking of DNA bases on the same strand rather like some bifunctional alkylating agents. The synthesis proceeds by reduction of potassium hexachloroplatinate (90) with hydrazine to give potassium tetrachloroplatinate (91). This is converted to potassium tetraiodoplatinate (92) by treatment with potassium iodide and then reacted with 6M ammonium hydroxide to give crystals of cisplatin [22]. The iodine exchange enhances the trans effect.

K2(PtCl6)

*~

K2PtCl4

•- K2PU4

(91)

(92)

-

H3NS Cl

(90)

(93)

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a cis complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclobutanedicarboxylic acid to yield carboplatin [23]. P >i (94)

n^N

2

UJt-12

(95)

2_

H N

"

(96)

Spiroplatin (99) in animal studies showed excellent antileukemic activity and was less

Aliphatic and Alicyclic Compounds

17

nephrotoxic than cisplatin. Unfortunately when it was tried clinically, little antitumor activity could be demonstrated and it was hard to determine safe doses to use in humans so it was ultimately dropped. Its synthesis starts with potassium tetrachloroplatinate (91) which is reacted with spiro-l,3-propanediamine 97 and potassium iodide to give complex platinate 98. This is treated with silver sulfate to produce spiroplatin [24].

V _ A _ NH2

\

(97)

(98)

(99)

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropylamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25].

Me2CHNH2 ^

y

Pt

Me2CHM-I2

Cl

Cl (100)

Me2CHNH2

OH

-MeCONMe2 t Me2CHNH2' I XC1 OH (101)

OH Me2CHNH2 ^ | c , Me2CHNH2' | ^ Cl OH (102)

REFERENCES 1. W. Reifschneider, Ger, Offen., 3,305,107 (1983) via Chem. Abstr., 100: 6,101p (1984). 2. T. H. Cronin, H. Faubl, W. W. Hoffman, and J. J. Korst, U. S. Patent 4,034,040 (1977) via Chem. Abstr., 87: 134,479t (1977). 3. P. Bey and M. Jung, U. S. Patent, 4,330,559 (1982) via Chem. Abstr.t 97: 144,373z (1982). 4. B. W. Metcalf, P. Bey, C. Danzin, M. L. Jung, P. Casara, and J. P. Vevert, /. Am. Chem. Soc, 100,2551(1978). 5. W. Ho, G. F. Tutwiler, S. C. Cottrell, D. J. Morgans, O. Tarhan, and R. J. Mohrbacher, /.

18

Aliphatic and Alicyclic Compounds Med. Chem., 29, 2184 (1986).

6. B. V. Shetty, U. S. Patent, 4,100,170 (1978) via Chem. Abstr., 90: 86,875g (1978). 7. G. W. Peng, V. E. Marquez, and J. S. Driscoll, J. Med. Chem., 18, 846 (1975). 8. J. Szmuszkovicz, U. S. Patent, 4,159,340 (1979) via Chem. Abstr., 91: 157,342q (1979) and U. S. Patent, 4,156,015 (1979) via Chem. Abstr., 91: 74,259s (1979). 9. J. Szmuszkovicz, U. S. Patent, 4,215,114 (1980) via Chem. Abstr., 94: 103,032g (1980). 10. J. Szmuszkovicz, Eur. Pat. Appl., 85,811 (1983) via Chem. Abstr., 100: 6,31 lg (1983). 11. Anon., Japan Kokai, 59/134,758 (1984) via Chem. Abstr., 101: 230,035y (1984) and C. M. Svahn, F. Merenyi, and L. Karlson, J. Med. Chem., 29, 448 (1986). 12. J. T. Suh, J. W. Skiles, B. E. Williams, R. D. Youssefyeh, H. Jones, B. Loev, E. S. Neiss, A. Schwab, W. S. Mann, A. Khandwala, P. S. Wolf, and I. Weinryb, /. Med. Chem., 28, 57 (1985). 13. Y. F. Shealy, J. L. Frye, C. A. O'Dell, M. C Thorpe, M. C. Kirk, W. C. Coburn, Jr., and M. B. Sporn, /. Pharm. Sci., 73,745 (1984). 14. C. Gandolfi, R. Pellegata, R. Caserani, and M. M. Usardi, U. S. Patent 4,035,415 via Chem. Ator.,85:7,748n(1976). 15. J. M. Muchowski and J. H. Fried, U. S. Patent, 3,985,791 (1979) via Chem. Abstr., 92: 146,339p(1980). 16. P. W. Collins, E. Z. Dajani, R. Pappo, A. F. Gasiecki, R. G. Bianchi, and E. M. Woods, J. Med. Chem., 26, 786 (1983). 17. H. Suga, Y. Konishi, H. Wakatsuka, H. Miyake, S. Kori, and M. Hayashi, Prostaglandins, 15, 907 (1978). 18. H. C. Kluender, W. D. Woessner, and W. G. Biddlecom, U. S. Patent, 4,132,738 (1979) via Chem. Abstr., 90: 151,668h (1979). 19. J. E. Bimbaum, P. Cervoni, P. S. Chan, S. M. Chen, M. B. Floyd, C. V. Grudzinskas, and M. J. Weiss, /. Med. Chem., 25, 492 (1982). 20. P. A. Aristoff, P. D. Johnson, and A. W. Harrison, J. Org. Chem., 48, 5341 (1983). 21. B. Rosenberg, L. Van Camp, J. E. Trosko, and V. H. Mansour, Nature, 111, 385 (1969). 22. G. B. Kauffman and D. O. Cowan, Inorg. Syn., 7, 239 (1963). 23. R. C. Harrison, C. A. McAuliffe, and A. M. Zaki, Inorg. Chem. Acta, 46, L15 (1980). 24. J. Berg, F. Verbeek, and E. J. Bluten, U. S. Patent, 4,410,544 (1983) via Chem. Abstr., 100: 29,622y (1983). 25. P. C. Hydes and D. R. Hepburn, Belg. 890,209 (1982) via Chem. Abstr., 97: 61,004d (1982).

2

Monocyclic Aromatic

Compounds

Benzene rings constitute quiterigid,flat, relatively lipophilic moieties with considerable electron density. Groups attached to a benzene ring not only modulate these properties by their relative electron donating or withdrawing character, but also occupy well-defined spatial positions by virtue of the bond angles which form those links. These properties of the aromatic ring enhance uniqueness and fit to receptor sites for endogenous mediators. The benzene ring thus forms the nucleus for a number of pharmacophores. 1. PHENYLPROPANOLAMINES The adrenergic nervous system plays a key role in the regulation of the cardiovascular system. Functions such as performance of the heart muscle and blood pressure are directly affected by levels of the chemical transmitters of the adrenergic system, epinephrine (1) and norepinephrine (2). Drugs which act on the cardiovascular system by interacting with the adrenergic system have had a major impact on treatment of cardiovascular diseases. These agents range from compounds which act as antagonists at the receptors for beta adrenergic agents (beta blockers) to receptor agonists used to increase contractile force. Effects of epinephrine and norepinephrine result from interaction of those compounds with at least four adrenergic receptors: the alpha 1 and 2 receptors and the beta 1 and 2 receptors. Some of the side effects due to beta blockers such as the slowing of heart rate can be counteracted by administration of drugs which antagonize the alpha adrenergic receptors. The 19

20

Monocyclic Aromatic Compounds

antihypertensive agent labetalol (3) in fact includes both actions in a single molecule. The presence of two chiral centers in that molecule allows for the existence of two diastereomeric pairs. Preparation and testing of the individual optical isomers showed that each of these had a somewhat different combination of activities. A different conclusion would have been surprising in view of the fact that receptors themselves are made up of chiral molecules. In the event, it was ascertained that the R,R isomer exhibited the best combination of activities. The synthesis starts by condensation of readily available optically active (R)-(+)-alphamethylbenzylamine with 4-phenyl-2-butanone to form an imine which is itself reduced by hydrogenolysis (Raney nickel) to give a 9:1 mixture of the (R,R)-amine and the (R,S)-amine (4). This product (4) is then separated into its diastereomers by recrystallization of the corresponding hydrochlorides. Since the amine (4) was found to be inert to alkylation with phenacylhalides such as 7, it was debenzylated by hydrogenolysis (Pd/C) to give the primary (R)-amine 5. Reductive alkylation with benzaldehyde and hydrogen resulted in the formation of the N-benzyl derivative 6. Alkylation of the secondary amine 6 with bromoketone 7, followed by reduction (Pd/Pt/hydrogen) of the ketone group in 8 gives the alcohol 9. The relative remoteness of the ketone linkage from the chiral center leads to the formation of both diastereomers in a 1:1 mixture. The resulting diastereomers are separated by fractional crystallization. Removal of the benzyl substituents by means of catalytic reduction affords the secondary amine 10. There is thus obtained the optically active antihypertensive agent dilevalol (10) [1]. It has by now been well established that Parkinson's disease involves a deficiency of dopamine (11) in the brain. It has been further shown that any one of several stratagems for increasing levels of that neurotransmitter near the appropriate receptors will alleviate the symptoms of that disease. For example, a well-absorbed dopamine agonist which reaches the brain should thus be useful in treating that syndrome. Though ciladopa (16) at first sight closely resembles a beta blocker it should be noted that the presence of the hydroxyl group apparently does not interfere with dopaminergic activity. In addition, the compound lacks the secondary amino group which is thought to be indispensable for interaction with beta adrenergic receptors.

Monocyclic Aromatic Compounds

21

(2);R = Me

Me CM — NHCHCH C C 2H 2H 65 e H (4)

?+ M •rC —NH C eC H C — 2 2H H

R,R R,S .CONH2 -OCH2C6H5

O

II 2 BrCH^265

2~~ CHCHCH CH C H N 65 2

(7)

RHN— C —CH 2 CH—

-OCH 2 C 6 H 5

(8)

Me

'CONH?

C—CH 2 CH 2 C 6 H 5

OCHC 2H 65

CH 2 Ctt OH (9);(R,R

+R.S)

H

- HC H2NOC

(5); R = H (6);R = CHC 2H 65 O H C -HCH2NHCHCH C C 2H 2H 65 Me (3); (R,R +R,S + S,S (10); (R,R)

Monocyclic Aromatic Compounds

22

Condensation of piperazine with 2-methoxytropone gives the addition-elimination product 12 [2], Alkylation of the remaining secondary amino group with bromoketone 13, itself the product from acylation of dimethyl catechol, gives aminoketone 14. Reduction of the carbonyl group with sodium borohydride leads to secondary alcohols 15 and 16. Resolution of these two enantiomers was achieved by recrystallization of their tartrate salts to give ciladopa (16) [3].

- CH2CH2NH2 HO (11)

P -OMe +

HN

NH

-N

NH

(12)

p

OH r ~^NCFI CH-<( 2 -N \_

>— OMe OMe

(IS); (5) (16); (*) Condensation of adipic acid derivative 17 with phenylethylamine in the presence of carbonyldiimidazole affords the bis-adipic acid amide 18. The synthesis is completed by reduction of the carbonyl groups with diborane followed by demethylation of the aromatic methoxy groups with hydrogen bromide the afford dopexamine (19) [3].

Monocyclic Aromatic Compounds

23

MeO—^_y~(CH2)2NHCO(CH2)4CO2H + H2NCH2CH2(17)

MeO—/_y-CH2CH2NHCO(CH2)4CONHCH2CH2MeO

CH2CH2NH(CH2)6NHCH2CH2—/_^ (19) Interposition of an amide function in the norepinephrine-like side chain in midodrine (25) affords a compound which retains a good measure of adrenergic activity. Acylation of dimethylhydroquinone with chloroacetyl chloride gives the chloroketone 20. The halogen is then converted to the amine 21 by any of a set of standard schemes, and the ketone reduced to an alcohol with borohydride (22). Acylation of the amino group in this last intermediate with chloroacetyl chloride affords the amide 23. The halogen is then displaced by azide and the resulting product (24) reduced catalytically to the glycinamide, midodrine (25) [4]. A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27; the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 15].

Monocyclic Aromatic Compounds

24 O CCH2C1

MeO

MeO

(20)

OH MeO l.CHCH2NH2

MeO (f

V MeO

MeO (21)

MeO

(22)

OH O I II XCHCH2NHCCH2X

MeO

MeO

OH

O

,CHCH 2 NHCCH 2 NH 2

MeO (25)

(23);X = C1 (24); X = N3

s

NHCOMe

NHCOMe

(26)

(27)

OH . CN

Me2CHNHCH2Cv s

(29); R = COMe (30); R = H

(28)

NHCOMe

Monocyclic Aromatic Compounds

25

2. PHENOXYPROPANOLAMINES Compounds which act as antagonists at the receptors for beta sympathetic transmitters (beta blockers) have gained very wide acceptance as antihypertensive agents. It was found subsequent to their introduction that there are two populations of beta receptors; the beta-1 receptors are richest in the cardiovascular system; whereas beta-2 receptors are mostly found in the bronchi. Lack of receptor-type specificity led to bronchial spasm in some asthmatic individuals on ingestion of the earlier beta blockers. Much of the work outlined below had as its goal the preparation of agents which showed selectivity for beta-1 receptors. It will be noted that the great majority of beta blockers consist of phenoxypropanolamines. Many of the agents incorporate substituents ortho to the side chain in response to the observation that such groups increase potency; this is thought to be due to the bulk of that substituent, encouraging productive conformations. The synthetic schemes for these agents as a rule culminate in the introduction of the aminoalcohol side chain. The first step often consists in reaction of the appropriate phenolate with epichlorohydrin to give a glycidic ether such as 32; reaction with a primary amine, usually isopropylamine or tert-butylamine, leads to the amino alcohol. Application of this scheme to o-cyclohexylphenol (31), leads to exaprolol (33) [6],

OH

o(31)

o(32)

(3o 3)

Alkylation of the monobenzyl ether of hydroquinone 34 with mesylate 35, gives ether 36. Hydrogenolytic removal of the benzyl group gives phenol 37. This affords cicloprolol (38) when subjected to the standard alkylation scheme 17]. In much the same vein, alkylation of rj-hydroxyphenylethanol 39, obtainable from the corresponding phenylacetic acid, with epichlorohydrin

26

Monocyclic Aromatic Compounds

gives ether 40. Aminolysis with isopropylamine produces 41 which was alkylated with cyclopropylmethyl bromide to give betaxolol (42) [8]. Aminolysis with t-butylamine of epoxide 43 gives the beta blocker cetamolol (44) [9].

MeSO3CH2CH2OCH2—<| C6H5CH2O -

OCH2CH2OCHr
0H

(35)

(34)

(36); R - CH2C6H5 (37); R = H

OH

(38) HO—^

V~CH 2 CH 2 OH

-

(39)

(40)

OH H O C H a C H f - ^ V - OCH2CHCH2NHCHMe2 (41)

OH Me 2 CHNHCH 2 CHCH 2 O—ij— OCH2CH2OCH2—-<| (42) OH - OCH2CHCH2NHCMe3 Sv

OCH2CONHMe

(43)

"OCHaCONHMe (44)

Monocyclic Aromatic Compounds

27

Alkylation of tert-butylamine (46) with 45 affords celiprolol (47) [10].

0 OH II | Et2NCHN—' ( 7_ / — OCH2CHCH 2C1 + COMe (45)

(46)

0 OH || / = \ 1 Et2NCHN—(V )— OCHCHCHNHCMe 2 2 3 COMe (47) The medicinal chemist is only too familiar with the exciting lead which fails due to too short a duration of action caused by rapid metabolic destruction in vivo. Though a number of approaches have been developed for protecting compounds against such destruction these are not universally successful. It is thus refreshing to note a successful program in which a drug was carefully designed to be quickly inactivated by inclusion of a function which is a metabolic weak link. The profound effect of beta adrenergic agonists on cardiac function has led to the use of beta blockers in the treatment of heart diseases. Blood levels which are too low will fail to have a therapeutic effect while levels which are too high may cause excessive suppression of heart function. Careful adjustment of circulating levels of the drug is thus quite important in acute cardiac crises. Parenteral administration of the drug allows rough adjustment of blood levels; infusion of a drug which is quickly inactivated allows fine tuning of those levels. It will be noted that esmolol (50) incorporates a carboxylic ester on one of the pendant side chains; saponification by the ubiquitous serum esterase enzymes affords the corresponding carboxylic acid; this is rapidly excreted through the kidneys terminating activity. The compound is prepared in straightforward fashion by adding the propanolamine side chain to the methyl ester (49) of rj-hydroxyphenylpropionic acid (48) [11] as detailed above (see the synthesis of 33 in Scheme 2-6).

Monocyclic Aromatic Compounds

28

r - OCH2CHCH2NHCHMe2

—*~ MeOCCH^CHf(48); R - H (49); R = Me

(50)

Inclusion of one of the phenolic groups present in epinephrine in a compound which otherwise looks like a classic beta blocker, leads to an agent which displays agonist rather than antagonist activity [12]. This agent xamoterol (55) can, in principle, be prepared by a convergent synthesis which starts by reaction of the chloroformamide of morpholine (51) with ethylenediamine to give 52. Reaction of a singly protected derivative of hydroquinone (53) with epichlorohydrin will give epoxide 54. Condensation of 54 with 52 followed by removal of the protecting group on the phenol will afford xamoterol (55). C6H5CH2C (53)

O

O / \ -OCH2CH-CH

C6H5CH2O

NCC1

(54)

O

(51)

NCNHCH2CH2NH2 (52)

-OCH2CHCH2NHCH2CH2NHCN °H

O

(55)

One of the reasons for adding the propanolamine side chain at the last step in the syntheses described above is the reactive nature of that functional array. It is however possible to protect that side chain to permit modification of the aromatic ring in a preformed phenylpropanolamine. For example, reaction of aminoalcohol 56 with phosgene or ethyl orthoformate gives the cyclic carbamate 57. Chloromethylation by means of paraformaldehyde and hydrogen chloride gives derivative 58. Displacement of halogen with the anion from isopropoxyethanol leads to the ether 59. Removal of the carbamate protecting group by reaction with aqueous base affords bisoprolol (60) [13].

Monocyclic Aromatic Compounds

29

,CH2O-

MejCHN O

Me2CHNHCH2CHCH2O -

TO

OH (56)

(57)

,CH,OM^CHN

TO

-CH2C1

O

(58)

CH2OCH2CH2OCHMe2 (59)

Me2CHNHCH2CHCH2O -

-CH2OCH2CH2OCHMe2

OH (60)

3. A L K Y L B E N Z E N E S A N D A L K O X Y B E N Z E N E S T h e role of the aromatic ring in the alkoxy- and alkylbenzenes which follow is not nearly as well defined as it is with the adrenergic and antiadrenergic drugs. Alkylation of the protected azetidinyl bromide 6 1 with the anion from m-trifluormethylphenol gives ether 6 2 . R e m o v a l of the N-(alpha-methylbenzyl)- protecting group by catalytic hydrogenation gives the secondary amine 6 3 . Reaction of that compound with methyl isocyanate gives the anticonvulsant urea fluzinamide (64) [14].

Monocyclic Aromatic Compounds

30

Me

Me Br

(61)

CF,

(62)

(64)

(63)

The very slow onset of action and side effects which follow from the anticholinergic side effects characteristic of the tricyclic antidepressants has led to a continuing effort to find replacements from other structural classes which might thus be devoid of this defect. A series of alkoxy phenylpropylamines has been investigated extensively in this search for non-tricyclic antidepressants. The most recent analogue, tomoxetine (69), is accessible by the same route [15] used to prepare the earlier analogue, nisoxetine, in which methoxyl replaces the ortho methyl group. Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modern equivalent (reaction with alkyl chloroforrnate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16].

Monocyclic Aromatic Compounds

31

(65)

(66); X=OH (67); X=C1

Me 6

I

~~

,CHCH2CH2NMe2

^CHCH2CH2NHMe (68)

t) (69) L-(+) -MANDELIC ACID (-) (69) Phosphorus ranks with carbon, hydrogen, oxygen, nitrogen and sulfur as one of the key elements involved in the structure of compounds involved in vital processes. It is thus somewhat surprising to find few drugs that contain phosphorus. Important exceptions involve antiviral agents and some antineoplastic compounds. As an example though the antiviral compound acyclovir is itself devoid of phosphorus, it is phosphorylated in vivo within virus-infected cells to the active agent. If phosphorylated before administration, the compound fails to enter the cell and so is inactive. A recent antiviral candidate fosarilate (73) incorporates phosphorus in the form of a phosphite ester group. This function is electrically neutral, permitting ready entry into cells across typical lipid membranes. Alkylation of hydroquinone derivative 70 with 1,6 dibromohexane gives the ether 71. Reaction with triethyl phosphite gives initially the product from direct alkylation (72). In a classical Arbuzov reaction, the bromide counterion displaces one of the ethyl groups by attack on carbon. There is thus obtained fosarilate (73) [17].

Monocyclic Aromatic Compounds

32

OH

MeO-

+

Br(CH2)6Br

O(CH2)6Br

(70)

(71)

?

O(CH2)6P(OEt)?

MeO

(73)

(72)

Arvlacetic and 2-arylpropionic acids have been extensively investigated as potential nonsteroidal antiinflammatory agents (NSAIDs). A wide range of substituents have been shown to be consistent with the prostaglandin synthetase blocking activity to which this class of drugs o w e s its activity. Felbinac (77) [18] represents possibly the ultimate structural simplification in this therapeutic category. O n e of the more interesting routes to this c o m p o u n d starts with the condensation of chloroacetonitrile with glycol 74 to give the oxazine 7 5 . This heterocycle contains both a carboxyl group in its latent form and an activated allylic halogen. Displacement of the latter with the Grignard reagent from 4-bromobiphenyl leads to intermediate 76. Acid hydrolysis leads to felbinac (77) [191. Me

Me C1CH2CN

OH

Me. M

Me Me

OH

(75)

(74)

HO 2 CCH 2 (77)

O A , CH 2 C1

(76)

Monocyclic Aromatic Compounds

33

Virtually all drugs which have proven useful in the treatment of adult onset diabetes (also known as non-insulin dependent diabetes) contain sulfonylurea or biguanide functions. The thiazolidinedione function present in ciglitazone (82) represents a marked departure from the previous pattern. The synthesis of ciglitazone (82) starts with 4-(l-methylcyclohexylmethoxy)nitrobenzene (78) which was probably obtained by alkylation of g-nitrophenol with 1-bromomethyl-l-methylcyclohexane. Hydrogenation of 78 yielded the aniline derivative 79. Diazotization of 79 in the presence of copper (I) oxide followed by addition of methyl acrylate (Meerwein arylation) produced the alpha-chlorinated ester 80. Reaction of the chloro ester with thiourea probably proceeds through initial displacement of halogen by the nucleophilic sulfur; displacement of ethoxide by urea nitrogen leads, after bond reorganization, to the heterocycle 81. Acid hydrolysis of the exocyclic imme affords the target compound (82) [20].

V - / VbT T , CH2O(78); R = NO2 (79); R - NH2

CH2CHCO2Me Cl

(80)

CH2O (82)

(81)

An ester of alanine with an arylaliphatic alcohol has shown promise as a non-tricyclic antidepressant. It may be speculated that the hindered milieu of the ester linkage protects the compound from hydrolysis by endogenous esterases. The preparation starts by reaction of phenylacctate 83 with methyl magnesium iodide to give tertiary carbinol 84. Acylation with 2-bromopropionyl bromide leads to ester 85; displacement of halogen with ammonia leads to alaproclate (86) [21].

Monocyclic Aromatic Compounds

34

Me ~CH2CO2Me

-CH2COH (84)

(83)

Me

(86)

(85)

Verapamii (87) probably ranks chronologically as the first antianginal c o m p o u n d which acts by blocking the so-called slow calcium channels. It is of passing interest that elucidation of the d r u g ' s m e c h a n i s m of action awaited the discovery, some years later, of the dihydropyridine antianginals. Replacement of the quaternary center by an oxidized dithiane ring interestingly leads to retention of activity. Acetal formation of benzaldehyde 8 8 , with 1,3-propanedithiol leads to dithiane 89; treatment with hydrogen peroxide gives the bis-sulfone 9 0 . T h e side chain intermediate 92 is obtained by alkylation of phenethylamine 9 1 with l-bromo-3-chloropropane. Treatment of the anion from 90 with the side chain intermediate affords tiapamil (93) [221.

U c

Me CN I I CCH2CH2CH2NCH2CH

o j r

MeO Me

k

OMe

Me (87)

(89)

(88)

CH9CH,NH Me (91)

(90)

MeO—\__f— CH2CH2NCH2CH2CH2C1 MeO

Me (92)

CH2CH2CH2NCH2CH

OMe

Monocyclic Aromatic Compounds

35

Reductive amination of vanillin with ammonia leads to benzylamine 94. Acylation of that compound with (Z)-9-octadecenoyl chloride affords the analgesic olvanil (95) [23]. Condensation of m-fluorobenzaldehyde with malonic acid leads to the trans cinnamic acid 96; acylation of the acid chloride with cyclopropylamine leads to amide 97 (cinflumide), a muscle relaxant [24]. HO—{_y— CH2NH2 MeO (94)

o ^HO--(_y-CH2NHC(CH2)6CH2 CH2(CH2)6Me CH Me(/ —CH (95)

CH=CHX (96)

.

_

_ || (97) O

^

The free acid analogue of the antipsoriatic agent etretinate (103) is prepared in substantially the same way as the parent compound. Thus, the aldehyde group in 98 is converted finally to the phosphonate (101) by sequential reduction (99), conversion to the chloride (100), and finally reaction with triethyl phosphite. Condensation of the ylide from 101 with the benzaldehyde 102 gives etretinate (103); saponification affords acitretin (104) [25]. 4. DERIVATIVES OF ANILINE The broad category of helminths includes a host of parasitic worms such as tapeworms and flukes; infestations in domestic animals can have serious negative consequences on growth. Anthelmintic drugs as a result occupy an important place in the practice of veterinary medicine. Febantel (108) is representative of this class of agents. Acylation of nitroaniline 105 with methoxyacetyl chloride gives the corresponding amide 106. Reduction of the nitro group leads to the aniline 107. Reaction of that intermediate with the thiourea S-methyl ether probably proceeds by initial addition of the amine to the imine; loss of methylmercaptan gives the substituted guanidine function. There is thus obtained febantel (108) [26].

36

Monocyclic Aromatic Compounds

Me ,CO2Et + (98); R « CHO (99); R = CH2OH (100); R » CH2C1 (101); R * CH2PO(OEt)2

] (102)

Me s

Me (103); R « Et (104); R » H

In a somewhat similar vein, alkylation of the urea derivative 109 with methyl iodide affords the S-methyl ether 110. Condensation of that with taurine (111), leads to the guanidine 112, again by an addition elimination process. The product is the anthelmintic agent netobimin (112) [271. Nucleophilic aromatic substitution of the anion from arylacetonitrile 113 on the dichloronitrobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsalicylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydrolysis, the anthelmintic agent closantel (118) [28]. Reaction of 2,4-xylidine with methylamine and ethyl orthoformate leads to the amidine 119; condensation of that product with a second mole each of orthoformate and 2,4-xylidine gives the scabicide amitraz (120) [29].

Monocyclic Aromatic Compounds

37

(106); R = O (107); R = H

(105)

NHCOCH2OMe

MeSC C NHCO2Me s—f

VNHC

NHCO2Me NHCOCH2OMe (108)

CH3CH2CH:

CH3CH2CH2S, NHCNHCO2Me

SMe = CNHCO2Me

NaO3SCH2CH2NH2 (111)

CH3CH2CH2S,

>NCH2CH2SO3H k

NHCO2Me

Treatment of 2,6-dimethylaniline (121) with phosgene and triethylamine affords the corresponding isocyanate (122). Condensation of that reactive intermediate with N-isopropylpropylcne-l,3-cliamine leads to formation of urea 123. This product, recainam (123), acts as membrane stabilizing agent and thus exhibits both local anesthetic and antiarrhythmic activity [30].

Monocyclic Aromatic Compounds

38

-CH2CN (113)

(118)

Centrally acting alpha blocking agents such as clonidine (124) have proven useful as antihypertensive agents. Side effects of this drug have led to the search for better tolerated analogues. This effort has shown that there is considerable flexibility in the specific nature of the guanidine function. Preparation of a noncyclic analogue starts with reaction of aniline 125 with dicyanamine to give 126. Hydrolysis under strongly acidic conditions, interestingly, leads to hydrolysis of the nitrile without affecting the guanidine function. There is thus obtained biclodil (127) [311.

(119)

N=CHNCH= Me (120)

Monocyclic Aromatic Compounds

39

Me

-NH9

NHCNHCH2CH2CH2NHCHMe2

(122)

(121)

(123)

.CN H \

NH CN

NHCNHR

(126); R = CN (127); R = CONH2

5. B E N Z O I C A C I D D E R I V A T I V E S Pyrrolidone derivatives substituted on nitrogen with alkyl groups have shown some activity as cognition enhancing agents in the aged. It is thus of some interest that acylation on nitrogen also leads to active c o m p o u n d s . Thus, treatment of anisoyl chloride 128 with the anion from 2-pyrrolidinone affords a n i r a c e t a m (129) [32]. A n i r a c e t a m is the product of an effort to discover agents to treat precocious senility (Alzheimer's disease). Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with rj-chlorobenzoyl chloride gives the amide 130. This intermediate is sufficiently reactive to undergo ring opening on treatment with morpholine. T h e product is the antidepressant agent moclobemide (131) | 3 3 ] . Esters of tropine have a venerable place in medicinal chemistry. O n e such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of t o d a y ' s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another prominent natural product, atropine (133). The product, tropanserin (134), is described as an antiserotonergic agent intended for antimigraine use [34].

Monocyclic Aromatic Compounds

40

-COCl (128)

(129)

(130)

Me

(131)

0

II -CC1 Me (132)

(134)

[2OH

(133)

It has by n o w been reasonably well established that an ethanolamine function appropriately linked to an aromatic ring is a prerequisite for beta adrenergic activity and/or antagonism. E x a m ples have been m e t above where those two moieties are attached directly as well as examples where the functions are separated by an oxymethylene fragment. It has recently been found that beta blocking activity is retained even when a carbonyl is inserted between the extra oxymethylene

Monocyclic Aromatic Compounds

41

group and the aromatic ring. Activity is lost once the ester linkage is broken. These compounds will also thus serve as short acting beta-blockers since they will be expected to be substrates for serum esterases. Acylation of glycidol 136 with acid chloride 135 proceeds in straightforward fashion to give the ester 137. Condensation of that intermediate with amine 138, obtained by reaction of 1,1-dimethyl ethylenediamine with urea gives the short acting betablocker flestolol (139) [35].

-C0C1 F (135)

+

HOCH2CHCH2 \ / o

o / " \ _ COCH2CHCH2 \s=s/ \ / \ o F (137)

__

(136)

? r H2NCNHCH2CNH2 Me (138)

O

OH

Me

o

I ' ' I I \J COCH2CHCH2NHCCH2NHCNH2 F Me (139) The classical antipsychotic agents, such as the phenothiazines and butyrophenones, owe much of their efficacy to their dopamine antagonist activity. A number of these agents find some utility as antiemetic compounds since emesis is also at least partly mediated by dopaminergic nerves. A dopamine antagonist from a quite different structural class seems to show some selectivity for those GI functions which involve dopamine receptors. The prototype, metoclopramide (140), has been found useful as an antiemetic compound as well as an agent for the control of the motility of the upper GI system. The finding that this drug controls emesis not effected by earlier dopamine antagonists, for example, that induced by chemotherapeutic agents used in cancer patients, has led to increased interest in the benzamide class.

42

Monocyclic Aromatic Compounds The benzoic acid moiety common to many of the benzamides is prepared in straightfor-

ward manner from the methyl ether of £-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143; benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chloroformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. Activity is apparently retained when the aromatic amino group is deleted. Bromination of acid 148 followed by reaction of the product (149), as its acid chloride, with the (S)-(~)-aminomethylpyrrolidine 150, gives the dopamine antagonist, remoxipride (151) [37] with (S)-configuration. The synthesis of a benzamide with a somewhat more complex side chain starts by condensation of acid 144 with racernic cis-aminopiperidine 152. Removal of the benzyl group of 153 by hydrogenolysis gives the secondary amine 154. Alkylation on nitrogen with the halide 155 gives finally the dopamine antagonist, cisapride (156) [38,39]. Sulfasalazine (157) is one of the few drugs useful in the treatment of ulcerative colitis. It is well established that the compound undergoes reductive cleavage in the gut to p-aminosalicylic acid and sulfapyridine; the former is actually the active agent. Sulfasalazine thus serves as a sitedirected prodrug for the salicylate. A newer agent for this indication consists of two salicylates linked by an azo linkage; reductive cleavage should thus yield only salicylate. Treatment of methyl aminosalicylate 158 with nitrous acid leads to diazonium salt 159. Reaction of that with methyl salicylate gives the diazonium coupling product 160. Saponification then yields olsalazine (161) [40]. Flufenamic acid (162) is a reasonably well-established NSAED; (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassium salt with the hydroxyethyl ethyl ether of ethylenechlorohydrin affords the latentiated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic

Monocyclic Aromatic Compounds

43

substitution, gives the NSAE) lobenzarit (166) [42].

OMe CONHCH2CH2NEt2 H->N' Cl (140)

OMe CO2H

OMe L

RHN' (141); R = H (142); R - COCH3

OMe

r X CONH—/ ~

RHN Cl (143); R = COMe

Cl (145)

,(144); R == H H 2 N—/C^

CONH

(156)

Monocyclic Aromatic Compounds

44 Et OMe (150)

(151); (S)

(148); X = H (149);X = Br

MeO2C HO—/~\—NH 2 (158)

(161)

(159)

(160)

One of the early steps in an allergic reaction consists in the release of a series of endogenous compounds referred to as mediators from sensitized cells. The finding in the early 1960s that cromolyn sodium, still the only approved drug of this class, blunts this reaction has led to an intense search for additional examples. It is of interest that a relatively simple anthranilic acid derivative has shown mediator-release inhibiting activity. Reaction of 3,4-drmethoxybenzaldehyde (167) with isatoic anhydride 168 gives the condensation product 169, which, upon hydrolysis, affords tranilast (170) [43].

Monocyclic Aromatic Compounds

C O C C O H C O 2H 2H 2C 2H 2H ocN H (163) (162) C O H 2 C O H (165) 2 (166) M O e C H O M O e (169)

45

o.

o

(168)

M O e/ MO e z (170) A substu ited benzoci acd i serves as precursor for the nontrciycil a mol(175). Seelctvie saponcfiaotin of ester 171 aofrds h te haf-alcd i 172. cholrd ie derviedrofm thsi nietrmedaiet (173) wh ti ammoanigvies h te am d h te alst by means ofh tiluim u alm nium hydrdie gvies bpienamol(175) [ CO E O tC H O C H H N 2t E 2 2 C 2H 2 ( 1 7 5 ) (((111777234)));;; R = O H (171) R = C l R = NH 2

Monocyclic Aromatic Compounds

46

6. DffHENYLMETHANES The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacetic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177; displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyclic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney nickel. Saponification of intermediate 182 affords bromfenac (183) [46].

,CH2CO2Et

ra2 + cH3scH2co2Et — - [CH3SCH2CO2E7]

(178)

(177)

CO2Et S—Me

(180)

(181); R = SMe (182); R = H

(179)

(183)

Monocyclic Aromatic Compounds

47

Gamma-aminobutyric acid (GABA) ranks among the numerous brain neurotransmitters; it exerts inhibitory activity on certain pathways and abnormalities in levels of GABA or in its transport and/or metabolism have been implicated in various CNS diseases including convulsions. Attempts to treat such disorders by administration of exogenous GABA are rendered difficult by the compound's poor penetration of the blood brain barrier. A series of imines of GABA or its potential metabolic precursors with phenolic benzophenones are apparently well enough absorbed to show andepileptic and anticonvulsant activity. Acylation of jg-chlorophenol with o-chlorobenzoyl chloride gives, after Fries rearrangement, phenol 184; formation of the imine between this ketone and butylamine affords fengabine (185) [47]. In a similar vein, acylation of 2,4-dichlorophenol with 2-benzoyl chloride gives the benzophenone 186, after Fries rearrangement; acylation of r> fluorophenoi with the same acid chloride gives the rearranged benzophenone 188. Formation of the imines of these ketones with the amide of GABA gives respectively tolgabide (187) [48], and progabide (189) [49].

NCH2CH2CH2CH3

(184)

(185)

•NCH2CH2CH2CONH2

fCH2CH2CH2CONH2

48

Monocyclic Aromatic Compounds It has been shown that glycine amides of aminobenzophenones are readily converted to the

corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolically in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50].

O o II II R— CCH2NHCCH2NHC(C6H5)3

( 1 9 0)

(191); R-OH (192); R-Cl Me O

O

I II II ,N— CCH2NHCCH2NHR

(193); R - C(C6H5)3 (194); R = H The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agents, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),

Monocyclic Aromatic Compounds

49

starts by alkylation of 4-hydroxypiperidine with butyrophenone 195. Alkylation of the alcohol 196 at the 4 position with benzhydryl bromide leads to ebastine (197) [51]. O II

+

C1CH2CH2CH2C

(195)

II H O — ^ I S f C H 2 C H 2 C H 2 C — ^ y — CMe3 (196)

CMe3

(197)

H 0

—

c

— o—<

NCH 2 CH 2 CH 2 CH-/

J—CMe3

(198) 7. M I S C E L L A N E O U S C O M P O U N D S T h e antiarrhythmic activity of local anesthetics has been noted several times previously. Another such agent is prepared by first alkylating isopropylamine with sulfone 199. Reaction of the pioduct (200) with diethylethylenediamine and carbonyldiimidazole results in transfer of the C D I nirbonyl group and formation of the urea s u r i c a i n i d e (201) [52]. T h e transform in all likelihood involves stepwise replacement of the imidazole groups by the basic groups in the other reactants.

Monocyclic Aromatic Compounds

50

-SO2CH2CH2C1 + H2NCHMe2

•SO2CH2CH2NHCHMe2 (200)

(199)

Et2NCH2CH2NH2

o II - SO2CH2CH2NCNHCH2CH2NEt2 A Me Me (201) The antiparasitic drug clorsulon (206), contains a rather unusual trichloroethylene group. This function is established early in the synthesis by treatment of the perhalogenated compound 203 obtained from reduction of 202 with iron powder. Chlorosulfonation of 204 by means of chlorosulfonic acid, followed by conversion of sulfonyl chloride 205 to the amide, gives clorsulon (206) [53].

(202); R = O (203); R = H

(204)

(205); R = Cl (206);R = NH2

Thiazide diuretics have a venerable history as antihypertensive agents; until the advent of the angiotensin-converting e n z y m e (ACE) inhibitors this class of drugs completely dominated first line therapy for hypertension. T h e size of this market led until surprisingly recently to the syntheses of new sulfonamides related to the thiazides. Preparation of one of the last of these c o m p o u n d s starts by exhaustive reduction of the Diels-Alder adduct from cyclopentadiene and maleim i d e (207). Nitrosation of the product (208), followed by reduction of the nitroso group of 209,

Monocyclic Aromatic Compounds

51

gives the corresponding hydrazine (210). Acylation with acid chloride 211 gives tripamide (212) [54].

(207)

(208)

(209); R = O (21O);R = H2

COC1

(2T2) Cancer chemotherapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. D i a / j q u o n e (at one time k n o w n as A Z Q ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [55J.

Eto,CN: a

EtO

:CO2Et

JL.A

52

Monocyclic Aromatic Compounds

REFERENCES 1. E. H. Gold, W. Chang, M. Cohen , T. Baum, S. Ehrlich, G. Johnson, N. Prioli, and E. J. Sybeitz, /. Med. Chem.y 25,1363 (1982); J. E. Clifton, I. Collins, P. Hallett, D. Hartley, L. H. C. Lunts, and P. D. Wicks, J. Med. Chem., 25, 670 (1982). 2. J. Bagli, T. Bogri, and K. Voith, J. Med. Chem., 27, 875 (1984); J. Bagli, T. Bogri, K. Voith, and D. Lee, /. Med. Chem., 29,186 (1986). 3. J. B. Farmer, F. Ince, R. A. Brown, and J. Dixon, Eur. Pat. Appl. 72,061 (1983) via Chem. Abstr., 99: 53,408q (1983). Anon. Drugs of the Future, 10, 628 (1985). 4. G. Zoelss, Ger. Offen., 206,110 (1976) via Chem. Abstr., 85:159,718s (1975). 5. G. Engelhardt, J. Keck, G. Krueger, K. Noll, and H. Pieper, Ger. Offen. 2,261,914 (1974) via Chem. Abstr., 81:104,982k (1974). 6. M. Carissimi, P. Gentili, E. Grumelli, E. Milla, G. Picciola, and F. Ravenna, Arzneim.Forsch., 26, 506 (1976). 7. P. M. J. Manouri, I. A. G. Carero, H. Majer, and P. R. L. Giudicelli, Ger. Offen., 2,649,605 (1977) via Chem. Abstr., 87:134,543j (1977). 8. X. Cirera Dotti, Span., 539,110 (1986) via Chem. Abstr., 106:18,091x (1987). 9. HL Tucker, Ger. Offen., 2,453,324 (1975) via Chem. Abstr., 83:96,993p (1975). 10. G. Zoelss, H. Pittner, and H. Stormann-Menninger-Lerchenthal, Ger. Offen., 2,458,624 (1975) via Chem. Abstr., 84:4,702n (1976). 11. P. W. Erhardt, C. M. Woo, W. G. Anderson, and R. J. Gorczynski, /. Med. Chem., 25, 1408 (1982). 12. E. Malta, A. M. Mian, and C. Raper, Br. J. Pharmac, 85, 179 (1980). 13. R. Kirchlechner and R. Jonas, Ger. Offen., 3,205,457 (1983) via Chem. Abstr., 99:194,947b(1983). 14. A. D. Cale, Jr., Canadian Patent, 1,169,870 (1984) via Chem. Abstr., 102: 24,463d (1984). 15. B. B. Molloy and K. K. Schmiegel, Ger. Offen., 2,500,110 (1975) via Chem. Abstr., 83:192,809d(1975). 16. B. J. Foster and E. R. Lavagnino, Eur. Pat. Appl, 52,492 (1982) via Chem. Abstr., 97:215,718d(1982). 17. G. D. Diana, Ger. Offen., 2,922,054 (1979) via Chem. Abstr., 92:181,353k (1980). 18. R. G. Child, A. C. Osterberg, A. E. Sloboda, and A. S. Tomcufcik, /. Pharm. ScL, 66, 466 (1977). 19. G. R. Malone and A. I. Meyers, /. Org. Chem., 39, 618 (1974). 20. T. Sohda, K. Mizuno, E. Imamiya, Y. Sugiyama, T. Fujita, and Y. Kawamatsu, Chem. Pharm. Bull., 30, 3580 (1982).

Monocyclic Aromatic Compounds

53

21. U. H. Lindberg, S.-O. Thorberg, S. Bengtsson, A. L. Renyi, S. B. Ross, and S.-O. Oegren, /. Med. Chem., 21,448 (1978). 22. H. Ramuz, Arzneim.-Forsch., 28, 2048 (1978). 23. T. R. Lahann and B. L. Buckwalter, U. S. Patent, 4,493,848 (1985) via Chem. Abstr., 102:137,825s (1985). 24. E. Grivsky, Ger. Offen., 2,704,365 (1977) via Chem. Abstr., 87: 167,762h (1977). 25. W. Bollag, R. Rueegg, and G. Ryser, Patentschrift (Switz.), 616,134 (1980) via Chem. Abstr., 93:71,312j(1980). 26. H. Wollweber and H. Koelling, Ger. Offen., 2,548,910 (1977) via Chem. Abstr., 87:134,713q (1977). 27. M. M. Nafissi-Varechei, U. S. Patent, 4,406,893 (1983) via Chem. Abstr., 100:34,285v (1984). 28.R. F. Ambros, P. A. Agnesetti, and M. S. Regas, Span., 524,551 (1984) via Chem. Abstr., 107:23,097d (1987). 29. I. R. Harrison, J. F. McCartny, B. H. Palmer, and A. Kozlik, Ger. Offen., 2,061,132 (1971) via Chem. Abstr., 75:63,443r (1971). 30.T. S. Sulkowski, J. L. Bergey, and A. A. Mascitti, Brit. Pat. AppL, 2,025,406 (1980) via Chem. Abstr., 93:114,17lg (1980). 31. J. W. Tilley, H. Ramuz, P. Levitan, and J. F. Blount, Helv. Chim. Acta, 63, 841 (1980). 32. Anon., Jpn. Kokai, 79/117,468 (1979) via Chem. Abstr., 92:41,755t, (1980). 33. Anon., Austrian, 349,482 (1979) via Chem. Abstr., 91:123,741d (1979). 34. J. R. Fozard and M. W. Gittos, U. S. Patent, 4,563,465 (1986) via Chem. Abstr., 105:54,608j (1986). 35. S. T. Kam, W. L. Matier, K. X. Mai, C. Barcelon-Yang, R. J. Borgman, J. P. O'Donnell, H. F. Stampfli, C. Y. Sum, W. G. Anderson, R. J. Gorczynski, and R. J. Lee, J. Med. Chem., 27, 1007 (1984). 36. L. C. Teng, S. C. Bearekman, L. B. Turnbull, R. S. Alphin, and W. L. Smith, Ear. Pat. AppL, 237,281 (1987) via Chem. Abstr., 108:21,734f (1988). 37. L. Rorvall and S.-O. Oegren, J. Med. Chem., 25, 1280 (1982). 38. G. H. P. VanDaele, Eur. Pat. AppL, 76,530 (1983) via Chem. Abstr., 99:194,812d (1983). 39. G. H. P. VanDaele, M. L. F. De Bruyn, F. M. Somrnen, M. Janssen, J. M. VanNeuten, J. A. J. Schuurkes, C. J. E. Niemegeers, and J. E. Leysen, Drug. Dev. Res., 8, 225 (1986). 40. K. H. Agback and A. S. Nygren, Eur. Patent AppL, 36,636 (1981) via Chem. Abstr., 96:122,401j (1982).

54

Monocyclic Aromatic Compounds

41. K. H. Boltze, O. Brendler, andD. Lorenz, German Offen., 1,939,111 (1971) via Chem. Ator.,74:76,185n(1971). 42. M. Tanemura, T> Shinozaki, M. Shindo, S, Hata, K. Mizuno, M. Ono, K. Wakabayashi, T. Nakano, and Y. Nishii, German Offen., 2,526,092 (1976) via Chem. Abstr., 87:52,947e (1977). 43. Y. Kamijo, M. Kobayashi, and A. Ajisawa, Jpn. Kokai, 77/83,428 (1977) via Chem. Abstr., 88:6,569f (1978). 44. N. B. Mehta and L. E. Brieaddy, U. S. Patent, 4,044,014 (1977) via Chem. Abstr., 87:151,846c (1977). 45. P. G. Gassman, T. J. Van Bergen, and G. Gruetzmacher, /. Am. Chem. Soc, 95, 6508 (1973). 46. D. A. Walsb, H. W. Moran, D. A. Shamblee, I. M. Uwaydah, W. J. Welstead, L. F. Sancilio, and W. N. Dannenburg, J. Med. Chem., 27,1379 (1984). 47. J. P. Kaplan and B. Raizon, French Demande 2,475,543 (1981) via Chem. Abstr., 96:6,370z (1982). 48. J. P. Kaplan, German Offen., 3,242,442 (1983) via Chem. Abstr., 99:104,980e (1983). 49. C Berthier, J. P. Allaigre, and J. Debois, French Demande, 2,553,763 (1985) via Chem. Abstr., 103:141,480p (1985). 50. K. Hirai, T. Ishiba, K. Sasakura, and H. Sugimoto, Can. 1,091,652 (1980) via Chem. Abstr., 96:35,726a (1982). 51. J. M. Prieto Soto, A. Vega Noverola, J. Moragues Mauri, and R. G. W. Spickett, Eur, Patent AppL, 134,124 (1985) via Chem. Abstr., 103:104,852r (1985). 52. J. R. Shanklin and C. P. Johnson, III, U. S. Patent, 4,597,902 (1986) via Chem. Abstr., 106:49,797m (1987). 53. H. Mrozik, R. J. Bochis, P. Eskola, A. Matzuk, F. S. Wakamunski, L. E. Olen, G. Schwartz kopf, Jr., A. Grodski, B. O. Linn, A. Lusi, M. T. Wu, C. H. Shunk, L. H. Peterson, J. D. Milkowski, D. R. Hoff, P. Kulsa, D. A. Ostlind, W. C. Campbell, R. F. Riek, and R. E. Harmon, J. Med. Chem., 20, 1225 (1977). 54. H. Hamano, T. Nakamura, S. Kuriyama, and M. Yamanaka, Jpn. Kokai, 73/05,585 (1973) via Chem. Abstr., 78:136,070 (1973). 55. A. H. Khan and J. S. Driscoll, /. Med. Chem., 19, 313 (1976).

3

Polycyclic Aromatic Compounds and

Their Reduction Products

1 NAPHTHALENES AND TETRALINS I he diverse range of pharmacological actions of this structural class documents the belief that the naphthalene nucleus consists of a scaffold upon which various functional groups can be arranged md that the action elicited is a consequence of receptor response to the kind and spatial arrange ment of these functions Terbinafine (5) (formerly SF 86327) is an antidermatophytic (antifungal) agent apparent ly owing its selective action to an inhibition of squalene epoxidation Ergosterol is one of the possible end products of the pathway requiring squalene epoxide Ergosterol is an essential component of fungal membranes so a deficiency in its production brought about by terbinafine creates a serious problem for fungi Mammalian cell membranes are not as efficiently inhibited by lerbinafine accounting for the useful selective toxicity of this agent The original lead substance for this fungal class, naftifine (1) was discovered during loutine screening and a derivative generating program eventually led to 5 f 1] The synthesis of tei binafine begins by alkylation of the allyl acetylene derivative 2 with bromoacetylene denvative ^ mediated by CuBr and base 1 he asymmetrically coupled diyne (4) was reduced to the trans tneyne terbinafine (5) with dnsopropyl aluminum hydride Such reduction is a characteristic luiture of tertiary 2-propyneamines and contrasts with the better known production of cis olefins by hydride reduction of simpler acetylenes The selectivity of the reduction also follows from this mtiogen based directing influence 55

Polycyclic Aromatic Compounds and Their Reduction Products

56

-C—

—- CMe3

CH2NCH2C^= C— C ss C — CMe

(5)

(4)

T h e complex thioarnide tolrestat (8) is an inhibitor of aldose reductase. This e n z y m e catalyzes the reduction of glucose to sorbitol. The e n z y m e is not very active, but in diabetic individuals w h e r e blood glucose levels can spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoromethyl)naphthalene-l-carboxylic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with K O H , hydrolyzes to tolrestat (8) 121.

Me CONCH2CO2Me

CO2H

MeO

I CF 3 (6)

MeO"

'CH2CO2H

Polycyclic Aromatic Compounds and Their Reduction Products

57

The hydroquinone derivative lonapalene (12) is intended to be used topically for the treatment of the skin disease psoriasis in place of classical treatments such as coal tar, anthralin, and cortical steroids. These suffer from the defects of staining the skin and/or causing atrophy. Lonapalene inhibits 5-lipoxygenase in vitro and is believed to exert its effects by blocking leucotriene formation in vivo. A short synthesis [3] starts by Diels-Alder reaction of 3-chloro-lmethoxy-l,3-butadiene (9) and 2,3-dimethoxybenzoquinone (10) to give adduct 11 under defined conditions in which the air sensitive hydroquinone is intercepted by addition of acetic anhydride to give 12 in a one-pot reaction. Concomitant aromatization through loss of methanol occurs. A somewhat more involved synthesis is also available [4], MeO OH .OMe

(9)

h (10)

(11)

(12)

Sertraline (17) is a tetralin analogue possessing nonsedative antidepressant activity. At subtherapeutic doses it potentiates the action of a subthreshhold dose of morphine in the classic tail flick model for analgesia. This effect is apparently mediated through serotonin and adrenergic neurones and apparently therefore satisfies the stated goals of the program by possessing antidepressant activity by a different pharmacological mechanism than the classical agents (which appear to inhibit norepinephrine uptake at certain receptors). The synthesis starts with the Stobbe condensation of diethylsuccinate and 3,4-dichlorobenzophenone (13). The product (14) is hydrolyzed and decarboxylated to a cis-trans mixture of olefins (15). This last is reduced using a Pd/C catalyst and then undergoes unidirectional FriedelCrafts intramolecular acylation into the more reactiveringto produce substituted tetralone 16. This was converted to its imine with methylamine catalyzed by titanium tetrachloride and then sodium borohydride reduction produced 17 as a mixture of diastereomers. This was resolved by column chromatography to give sertraline [5]. Dextrorotatory cis sertraline is substantially more potent than its isomers.

Polycychc Aromatic Compounds and Their Reduction Products

58

(13)

2

INDANES AND INDENES

Following the development and introduction of captopril and enalapril, a great many investiga tions have resulted in a wide variety of hypotensive agents which exert their effects by inhibition of angiotensin converting enzyme (ACE) One such is the rather potent orally active and long acting agent delapnl (22) One of its syntheses starts with reductive animation of 2 mdanone (18) with the t butylester of glycine by use of NaCNBH3 The product (19) undergoes peptide bond formation with N carbobenzyloxy L alanine using carboxyl activation through use of the mixed anhydride method (ethyl chlonxarbonatt) The optically active product (20) is hydrogenohzed to free the primary amino group ot the alanyl moiety before undergoing reductive (Raney nickel) alkylation with ethyl 2 oxo 4 phenylbutyrate to give ester 21 as a diastereoisomenc mixture re solvable by chromatography The synthesis of delapnl (22) is completed by taking the major pioduct and selectively removing the t butylester moiety with HBr in acetic acid [61 Other syn theses are available [7J

I CH2CO2CMei (18)

(19)

CH2CO2R (21), R = CMe3 (22), R = H

Polycyclic Aromatic Compounds and Their Reduction Products

59

As a representative of the indenes, indeloxazine (26) is an antidepressant and a cognition activator. With an increasingly aged population, a significant amount of research is being devoted to finding compounds which enhance learning and memory by a believable mode of action. Cholinergic agents are receiving the most attention at present. Indeloxazine, on the other hand, has very little effect on known receptors but increases intrasynaptic norepinephrine and serotonin concentrations. The meaning of this is unclear, however, in clinical trials this compound has brought about improvement in patients with traumatic brain injury. In order to avoid as far as possible double bond positional isomers, a problem quite common in drugs with indene moieties, N-trityl-2-hydroxymethylmorpholine (23) was reacted with the potassium salt of 4-hydroxy-l-indanone (24) in DMSO solvent to give condensation product 25 in good yield. Reduction of 25 with LiAlH4 produced the hydroxyindane which was dehydrated and deprotected with HC1 to give indeloxazine (26) [8|.

c Nr I CPh, (23)

(24)

(25)

(26)

Dezocine (30) represents a class of bridged aminotetralins possessing morphine-like analgesic properties. It appears to be roughly equivalent in potency and addiction potential to morphine. The molecule combines molecular features of precedent aminotetralins and benzomorphans and its structure fits the classical Morphine Rule. The 1-enantiomer is the more active and the (3-epimer (equatorial NH2) is the active diastereomer. The synthesis begins with the l-methyl-7-methoxy-2-tetralone (27) which undergoes a two stage reaction with 1,5-dibromopentane and sodium hydride to give 28. The 1-hydrogen atom of 27 is the more acidic and, presumably, the reaction initiates by alkylation here. Vigorous reaction of 28 with hydroxylamine and pyridine followed by Raney nickel-catalyzed hydrogenation gives a mixture of amines which can be fractionally crystallized to give racemic tricycloamine 29. The ether linkage is then hydrolyzed with 48% HBr to give dezocine (30) [9].

Polycyclic Aromatic Compounds and Their Reduction Products

60 MeO

MeO.

Me,

(29); R = Me (30);R = H

(28)

(27)

Ketorphanol (36) contains a more usual morphine skeleton and, indeed, this analgesic agent is prepared from m o r p h i n e (31) itself. T h e synthesis begins by treatment of m o r p h i n e with diethyl chlorophosphate to produce diphosphonyl ester 32. This is converted to its dihydroanalogue by saturation of its olefinic linkage with 10% Pd-C. Cleavage of the phosphoryloxy ester moiety at C-3 and hydrolysis of the aliphatic phosphate ester group was achieved by dissolving metal reduction with Li in liquid a m m o n i a to give 3 3 . This selective oxyphosphoryl cleavage reaction is one of the few convenient methods for removal of phenolic O H groups from polyfunctional molecules. T h e synthesis proceeds by Oppenauer oxidation (benzophenone-t-BuOK) to the corresponding ketone (34). This intermediate requires three steps for transformation to its cyclopropylmethyl analogue (35). First, _N-methyl group exchange for N-cyano is accomplished by the von Braun reaction (with cyanogen bromide). Hydrolysis to the secondary amine requires 2N_ HC1 treatment during which the intermediate N.-carboxyamine dccarboxylates spontaneously. Finally, alkylation with cyclopropylmethyl bromide gives 3 5 . Reaction of 35 with Zn dust in a m m o n i u m chloride brings about the anticipated cleavage of the C - 0 bond alpha to the ketone to produce ketorphanol (36) 110]. An alternative synthesis is available [11).

NMe

NMe

NMe

(33)

(31); R = H (32); R = PO(OEt)2

(34)

NCH 2 —<]

(35)

Polycyclic Aromatic Compounds and Their Reduction Products

61

A somewhat related molecule, xorphanol (45), is an analgesic which possesses at the same time partial antagonist properties. For example, it antagonizes morphine's action when given in suitable doses and it precipitates the morphine abstinence syndrome. Its most interesting molecular feature is the alkylation pattern in the terminal alicyclic ring. The synthesis begins from the clinically useless but relatively abundant alkaloid thebaine (37). Sodium and liquid ammonia reduction cleaves the dihydrofuran ring on the aliphatic side; the phenolic product is converted to its 4-phenylether and this is also cleaved with dissolving metal to produce unconjugated dihydrothebaine analogue 38 and phenol. Acid (HC1) hydrolysis converts the enol ether grouping to a saturated ketone followed by olefin migration via enolization to give the conjugated ketone 39. The stereochemistry at theringjuncture is dictated by the geometric needs of the bridged tetracyclic ring system, Reaction of 39 with lithium dimethylcuprate results in the usual conjugate addition to give 40 as a single isomer which in turn undergoes the von Braun N-dealkylation procedure to give secondary amine 42 via the intermediate cyanogen bromide exchange product 41. Alkylation of 42 with cyclobutyhnethyl bromide produces 43 which undergoes methoxy ether cleavage with HBr to give ketone 44. The synthesis of xorphanol (45) concludes by Wittig methylenation of this last with mcthylenetriphenylphosphorane in DMSO (12,13j.

NMe

(40); X = Me (41); X = CN (42); X = H

(43)

(44);X = O (45);X = CH2

Polycychc Aromatic Compounds and Their Reduction Products

62

Another agent of this general type is nalmefene (47) Despite their useful characteristics, opiates display tolerance, addiction, abuse, and some toxic side effects Antagonists combat some of these effects, most notably respiratory depression and addiction Nalmefene reputedly has significant oral activity as a narcotic antagonist The synthesis of nalmefine concludes by Wittig olefination of naltrexone (46) to nalmefene (47) This molecular transformation resulted in a significant increase in oral potency as well [14]

3

FLUORENES

A very significant mortality in Western countnes is associated with cardiac arrhythmias Consequently an intensive search is underway for agents to combat this condition - particularly for compounds with an unusual mode of action A class Ic (local anesthetic-like) agent of interest in this context is indecainide (50) One ot several routes to this compound covered by patents begins with sodium amide mediated alkylation of 9 cyanofluorene (48) with 3 isopropylarmno-1 chloropropane to give amine 49 The synthesis concludes by partial hydrolysis of the nitnle func tion to a carboxamide linkage with sulfunc acid to produce indecainide (50) [15]

NHCHMe2 (49) 4

H2NOC ,
ANTHRAQUINONES

Bisantrene (56), also k n o w n as ' orange c r u s h " , is a broad spectrum intercalating antitumor agent c o m p e t i n g with doxorubicin and the somewhat more closely related quinone mitoxantrone (51)

Polycyclic Aromatic Compounds and Their Reduction Products

63

The synthesis of bisantrene begins with Diels-Alder reaction of anthracene (52) and ethylene carbonate (53) to produce adduct 54. Hydrolysis and glycol cleavage lead to bis-carboxaldehyde 55. This readily forms a bis-hydrazone with guanylhydrazine f 16]. -NHHO O NH

(53)

CHO (55)

(54) 5.

REDUCED ANTHRACENES

Oxaprotiline (60) is an antidepressant possessing an unusual structure. The clinically useful isomer is the S.-(+)-analogue. Several routes are available in patents for producing this agent. For example, acid chloride 57 (prepared by autoclaving anthracene-9-acetic acid with ethylene and then conversion to the acid chloride) undergoes Rosenmund reduction with partially poisoned PdC and hydrogen to produce the corresponding aldehyde linkage followed by cyanohydrin formation to produce 58. LiAlH4 reduction produces the primary amine which is converted to the corresponding oxazolidone (59) with phosgene. Strong base (NaH) mediated alkylation of the oxazolidone with iodomethane and hydrolysis follows. Alternatively the synthesis can conclude with ^ reduction. These last steps are clever means of achieving clean monoalkylation [17].

COCi

(57)

(58)

(59)

64

Polycyclic Aromatic Compounds and Their Reduction Products REFERENCES

1. A. Stuetz and G. Petranyi, J. Med. Chem., 27, 1539 (1984). 2. K. Sestanj, F. Bellini, S. Fung, N. Abraham, A. Treasurywala, L. Humber, N. SimardDuquesne, and D. Dvornik, /. Med. Chem., 27,255, (1984). 3. D. L. Flynn and D. E. Nies, Tetrahedron Lett., 27, 5075 (1986). 4. G. H. Jones, M. C. Venuti, J. M. Young, D. V. Krishna Murthy, B. E. Loe, R. A. Simpson, A. H. Berks, D. A, Spires, P. J. Maloney, M Kruseman, S. Rouhafza, K. C. Kappas, C C. Beard, S. H. Unger, and P. S. Cheung, J. Med. Chem., 29,1504 (1986). 5. W. M. Welch, A. R. Kraska, R. Sarges, and B. K. Koe, /. Med. Chem., 27, 1508 (1984). 6. A. Miyake, K. Itoh, and Y. Oka, Chem. Pharm. Bull, 34, 2852 (1986). 7. J. T. Suh, J. R. Regan, J. W. Skiles, J. Barton, J. W. Piwinski, I. Weinryb, A. Schwab, A. I. Samuels, W. S. Mann, R. D. Smith, P. S. Wolf, and A. Khandwala, Eur. J. Med, Chem., 20, 563 (1985). 8. T. Kojima, K. Niigata, T. Fujikura, S. Tachikawa, Y. Nozaki, S. Kagami, and K. Takahashi, Chem. Pharm. Bull, 33, 3766 (1985). 9. M. E. Freed, J. R. Potoski, E. H. Freed, G. L. Conklin, and J. L. Malis, J. Med. Chem., 16, 595(1973). 10. A. Manmade, H. C. Dalzell, J. F. Howes, and R. K. Razdan, /. Med. Chem., 24, 1437 (1981). 11. M. D. Rozwadowska, F. L. Hsu, A. E. Jacobson, K. C. Rice, and A. Brossi, Can. J. Chem., 58,1855(1980). 12. J. O. Polazzi, R. N. Schut, M. P. Kotick, J. F. Howes, P. F. Osgood, R. K. Razdan, and J. E. Villarreal, J. Med. Chem., 23, 174 (1980). 13. J. O. Polazzi, M. P. Kotick, J. F. Howes, and A. R. Bosquet, J. Med. Chem., 24, 1516 (1981). 14. E. F. Hahn, J. Fishman, and R. D. Heilman, J. Med. Chem., 18, 259 (1975). 15. Anon., Austrian Patent, AT 368,125B (1982) via Chem. Abstr., 98: 4,405g (1982). 16. K. C. Murdock, R, G. Child, Y. Lin, J. D. Warren, P. F. Fabio, V. J. Lee, P. T. Izzo, S. A. Lang, Jr., R. B. Angier, R. V. Citarella, R. E. Wallace, and F. E. Durr, J. Med. Chem., 25, 505 (1982). 17. M. Wilhelm, R. Bernasconi, A. Storni, D. Beck, and K. Schenker, Patentschrift (Switz.), 558,774 (1975) via Chem. Abstr., 83: 96,859z (1975).

4

Steroids

A quick glance at the various chapter titles which have occupied the pages in this series shows a high turnover rate in some of the more specialized structural classes. Some headings as, for example, "Phenothiazines" and "Tetracyclines" occur in the first volume only; "Benzodiazepines" merited separate sections in Volumes 1 and 2. Sufficient work has been devoted over the years to the steroid class, on the other hand, to occupy continuing discrete chapters in each volume. The profound biological activities of appropriately substituted steroids in large part account for the long-term interest in this structural class. The mid 1950s saw an impressive amount of work devoted to the synthesis of compounds related to cortisone for their antiinflammatory activity. This class is revisited in the current chapter as laboratories attempt to develop corticoids which have topical antiinflammatory activity but are devoid of side effects stemming from parenteral activity. 1. ESTRANES One of the key functions of the steroid sex hormones involves maintenance of gonads and secondary sexual characteristics. Excessive levels of the hormones or increased sensitivity on the part of the target organs can lead to hypertrophy of those targets. In addition, there exist at the extreme a series of malignant tumors which contain sex hormone receptors and are thus stimulated by those hormones. Hormone antagonists should thus be useful in the therapy of both benign and malignant hypertrophies. The utility of a series of synthetic antagonists to the estrogen receptor in the treatment of certain breast cancers (see, for example, tamoxifen, nafoxidine, and nitromifene in previous volumes) has led to the search for corresponding antagonists to the androgen receptor(s). 65

66

Steroids

The synthesis of the androgen antagonist oxendolone (13) starts with Knoevenagel condensation of acetaldehyde with dehydroepiandrosterone acetate (1) to give enone 2. Catalytic reduction proceeds by attack from the less hindered side to give what is in essence the product, 3, which would be obtained from a thermodynamically disfavored alkylation. Treatment of the ketone 3 with lithium aluminum hydride leads to reduction to the 17-p alcohol and reductive loss of the acetate at the 3 position to give the 3,17-diol 4; acetylation leads to diacetate 5. Addition of the elements of hypochlorous acid proceeds by the stereochemistry predicted by initial formation of a 5,6-a chloronium ion followed by diaxial ring opening by hydroxide to produce 6. The next step consists in oxidative functionalization of the methyl group at the 10 position so as to permit its elimination. Thus, treatment of the chlorohydrin with lead tetraacetate leads to attack of the methyl group at the 10 position by oxygen, probably by a free radical reaction and formation of the cyclic ether 7. The alcohol at the 3 position is then selectively saponified, and the resulting alcohol, 8, oxidized (9). The conjugated ketone in 10 is then established by base catalyzed beta elimination of chloride. Reductive cleavage of the cyclic ether by means of zinc leads to formation of the 10-hydroxymethyl derivative 11. Oxidation of the primary alcohol with pyridine chlorochromate gives the vinylogous p-ketoaldehyde 12. Decarbonylation by means of base finally affords oxendolone (13), f 1]. Most of the current oral contraceptives consist of combinations of estrogens and progestational 19-nor steroids. Some of the more potent 19-nor progestins can be used for estrus cycle regulation in their own right. (It may be speculated that a sufficient fraction of these drugs is converted metabollically to the aromatized derivative to provide the esirogenic component in vivo.) Compounds in this class have proven particularly useful in veterinary applications. Condensation of the 19-nor trienedione 14, in which the 3 ketone is protected as its oxime [2], with allylmagnesium bromide leads to the product of addition from the alpha side of 15. Removal of the protecting group by transoximation with pyruvic acid affords altrenogest (16) [3].

67

Steroids

me

T V

(i)

//

(2)

(4); R = (5); R = Ac

,OAc

(9)

(10)

(11)

,OAc

(13)

MeP

(12)

LCH 2 CH=CH 2

L.CH2CH=CH2

HON

HON' (14)

(15)

(16)

68

Steroids 2. ANDROSTANES

The familiar estrogen-progestin oral contraceptives owe their activity largely to inhibition of ovulation. Several other series of compounds have been identified which have potential as contraceptives at a later stage in the reproductive process. As interceptive agents these compounds inhibit further development of a fertilized ovum. A highly modified testosterone derivative, epostane (23) shows this activity. Reaction of methyltestosterone 17 with formaldehyde and thiophenol leads to the 4-thiomethyl derivative 18; removal of sulfur by means of Raney nickel gives the 4-methyl compound 19. Condensation of that intermediate with ethyl formate gives the 2-forrnyl derivative 20. Reaction of the beta dicarbonyl function with hydroxylamine affords isoxazole 21. Epoxidation with peracid (mCPBA) proceeds as expected from the alpha side to give 22. Treatment of 22 with sodium methoxide leads initially to removal of the sole proton on the isoxazole moiety. Ring opening of the resulting carbanion gives, after protonation of the enol oxygen at the 3 position, the enol-nitrile array in epostane (23) [4]. .OH

(17)

(19)

HOC1

(23)

Steroids

69

By far the greatest number of medicinal agents based on the steroid nucleus have been designed as agonists or antagonists for endogenous steroid hormones. There do however exist scattered examples of potential drugs which use the steroid nucleus as a nonspecific, rigid, and relatively lipophilic framework. The antiarrhythmic agent edifolone (31), for example, combines the androstane nucleus with a basic nitrogen. Acetylation of 19-hydroxy-4~androstene-3,17-dione 24, obtainable by a route analogous to that shown in Scheme 4.1, followed by reaction of 25 with ethylene glycol gives the bis-ketal 26. The acetate is then removed (27) and the alcohol oxidized to the aldehyde 28. Reaction of the aldehyde 28 with tosylmethyl isocyanide produces the nitrile derivative 29; which, followed by reduction by means of LAH, leads to the primary amine 30 [5].

ROH2(

rJC?L> Vo (26); R = Ac (27); R = H

(24); R = H (25); R = Ac

HN C C 2H 2H 2 oj Vo (30)

T

(31); MeCO2H

(28)

NCH2C

(29)

Yet another steroid-based pharmacological agent uses the nucleus as a framework for locating two quaternary nitrogen groups in the spatial positions required for curare-like neuromus cular blocking activity. Reaction of N-methylpiperazine with bis-epoxide 32, used also as starting material for the closely related agent pancuronium chloride [6], leads to the product 33 predic from diaxial opening of the oxiranes 32; the hemiacetal produced at the 17 position reverts to

70

Steroids

ketone under the reaction conditions Reduction of that ketone followed by acetylation gives diacetate 34 Reaction with bromomethane leads to alkylation of the stencally more accessible Nmethyl piperazine nitrogens There is thus produced pipecuronium bromide (35) [7]

N N—Me L

JL J

. ^

xyx/

AcOr (35)

3

(34)

PREGNANFS

E n d o g e n o u s corticosteroids such as cortisone are potent h o r m o n a l substances involved in the regulation of a host of biological parameters such as mineral and glucose balance

T h e serendipe

tous discovery that these agents possessed maiked antimflammatory activity when given in supra hormonal doses, led as noted above, to an enormous amount of synthetic work aimed at separating the antimflammatory activity from the hormonal activity d u b b e d 'side effects

T h e potency of

the later analogues often represented increases of orders of magnitude over the lead c o m p o u n d s , the goal of separating activity from side effects w a s never quite achieved M o r e recent work in the corticosteroid series has involved modification of the dihydroxyacetone side chain at the 17 position at the 17 position is omitted

Activity is retained, for example, when the hydroxyl group

T h u s , addition of the elements of hypobromous acid to t n e n e 3 6 [8],

gives the b r o m o h y d n n 37, treatment with base leads to internal elimination to form the p-epoxide 3 8 , opening of the oxirane with hydrogen fluoride gives d e s o x i m e t a s o n e , 39, [9]

Steroids

71

(37)

(36)

-Me

(38)

(39)

Condensation of prednisone, 40 with tetraethyl orthocarbonate leads to the cyclic orthocarbonate 4 1 ; hydrolysis proceeds by protonation on the most accessible ether oxygen (that on carbon 21) to give the 17 mixed carbonate ester 4 2 . Acylation with propionyl chloride proceeds on the remaining hydroxyl group to afford prednicarbate (43) [10].

HO

(43)

(42)

72

Steroids

Activity is also retained when the hydroxyl group at the 21 position is replaced by chlorine. Reaction of corticoid 44 with methanesulfonyl chloride proceeds preferentially at the 21hydroxyl (45) due to the hindered nature of the 11-alcohol Replacement of the mesylate by means of lithium chloride in DMF affords clobetasol propionate (46); a similar sequence starting with the 17- butyrate ester 47, via mesylate 48, should give clobetasone butyrate, (49) [11].

HO Mek •ocoir

(44); R1 = H; R2 = Et (45); R1 -SO2Mc;R2 =

(46);R =

•OCOR2 •Me (47); R1 = H; R2 - n-C3H7 (48); R1 = SO2Mc; B? = n-C3H7

(49)

OAc

(50)

(55)

(52); R = Ac (53); R = H (54);R = SO2Me

Steroids

73

In a similar vein, acylation of the corticoid 50 with furoyl chloride gives the diacyl derivative 51. Reduction with sodium borohydride serves to convert the 11-ketone to the alcohol 52. Hydrolysis under mild acid conditions preferentially removes the acyl group at the less hindered 21 position. The hydroxyl group in that derivative (53) is then converted to the mesylate 54. Replacement by chlorine affords rnometasone (55) [12]. Activity is also retained when oxygen at the 21 position is replaced by sulfur. Preparation of one of these compounds follows a route quite analogous to the foregoing; thus, displacement of the mesylate group in the cortisone (56) derivative 57 with the anion from thiopivalic acid affords thioester 58. Reduction of the 11-ketone by means of borohydride affords tixocortol pivalate (59) [13J.

HO

(56); R = OH (57); R = OSO2Mc

(58)

(59)

Further clinical investigations on corticosteroids revealed that these compounds had very useful activity against various inflammatory skin conditions when applied locally. A drawback to this form of therapy consisted in the fact that these drugs tend to be well absorbed through the skin into the blood stream; circulating levels of corticoids can lead to the typical side effects. This occasioned a second wave of research on corticosteroids; the goal of that work is to develop steroids which have potent topical activity and are so designed that they will be deactivated once they are absorbed parenterally, so as to avoid the typical corticoid side effects. Classical corticosteroids have in common an unsaturated ketone at the 3 position, oxygen at the 11 position and a dihydroxy-acetone side chain at the 17 position (see, for example, 56).

74

Steroids

Much of the current work is based on the fact that the side chain can be replaced by an alternative functionality, which contains sulfur. Metabolic destruction presumably involves the readily oxidized thioether groups. It is of passing interest that the preparations of these modified corticoids use classical corticoids as starting materials and involve degradation of the side chain as a first step. This is probably due in large part to the fact that those classical steroids are today available in abundant supply. Thus removal of the side chain in 60 by oxidation with sodium bismuthate gives the corresponding 17 keto derivative 61. Treatment with methyl mercaptan gives thioacetal 62. Elimination of methy mercaptan under acidic conditions leads to the enol thioacetal 63. When this last is exposed to ethyl mercaptan under acetal forming conditions, that reagent adds from the less hindered alpha face to give unsymmetrical thioketal 64. There is thus obtained the topical corticoid tipredane (64) [14].

(60)

(63) Somewhat milder oxidative conditions lead to loss of but one carbon. Periodic acid cleavage of the side chain in 65, leads to the so-called etio acid (66). Reaction with propionic anhydride leads to acylation of the 17-hydroxyl group (67). Possibilities for neighboring group participation severely limit the methods available for activating the acid for esterification. Best results seemed to have been obtained by use of a mixed anhydride from treatment with diphenyl chloro-

Steroids

75

phosphate. Reaction of the intermediate 67 with the salt from methyl mercaptan gives ticabesone propionate (68). The related 16-P methyl isomer timobesone acetate (70) is obtained by subjecting the corticoid 69 to the same scheme [15].

SMe

HO

(66); R = H (67); R = COEt

(70)

(69)

R e a c t i o n o f e t i o a c i d 61 w i t h N , N - d i m e t h y l t h i o f o r m a m i d o y l c h l o r i d e p r o b a b l y g i v e s i n i tially t h e m i x e d a n h y d r i d e 7 1 ; this is n o t i s o l a t e d b u t u n d e r g o e s O to S c a r b o n y l m i g r a t i o n to the a n h y d r i d e 7 2 . S a p o n i f i c a t i o n then leads to the t h i o a c i d 7 3 . R e a c t i o n of the s o d i u m salt of the acid with b r o m o c h l o r o m e t h a n e affords c l o t i c a s o n e p r o p i o n a t e (74). T h e c o r r e s p o n d i n g reaction with b r o m o f l u o r o m e t h a n e l e a d s to

fluticasone

p r o p i o n a t e (75) [16].

It h a s l o n g b e e n a s s u m e d t h a t t h e a c t i v i t y o f c o r t i c o i d s w h i c h c o n t a i n a n a d d i t i o n a l r i n g annulated to the 16,17 positions such as h a l c i n o n i d e (76), o w e d their activity to the h y d r o l y z e d p r o d u c t . I t i s t h u s o f n o t e t h a t full a c t i v i t y s e e m s t o b e r e t a i n e d b y a c o m p o u n d w h i c h i n c o r p o i n t c s a ring a t t h a t p o s i t i o n h e l d i n p l a c e b y c a r b o n - c a r b o n b o n d s . D i e l s - A l d e r c o n d e n s a t i o n o f halcinonide precursor 7 7 , with benzocyclobutadiene, obtained by heating benzocyclobutane 7 8 , leads after h y d r o l y s i s of the acetate to naflocort (79) [17].

Steroids

76

:NMe2 (67)(72)

(71)

:—-SH

(73)

(74); X = Cl (75); X = F

Me

(76)

(78)

(79)

Steroids

77 REFERENCES

1. G, Goto, K. Hiraga, T. Mild, and M. Sumi, Yakugaku Zasshi, 103,1042 (1983) via Chem. Abstr., 100:85,983d (1984). 2. D, Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol.1, p. 169 (1977). 3. A, Pierdet and M. Vignau, Fr. M., 5,183 (1967) via ChemAbstr., 71:81,631x (1969). 4. R. G. Christiansen, Ger. Offen., 2,855,091 (1979) via Chem. Abstr., 92: 6,812n (1980). 5. L. N. Nysted, Eur. Pat. AppL, 104,489 (1984) via Chem. Abstr., 101:38,728k (1984). 6. D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 2, p. 163, Wiley, New York, (1980). 7. Z. Tuba, Arzneim.-Forsch., 36, 342 (1980). 8. D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Vol. 2, p. 193, Wiley, New York, (1980), 9. R. Joly, J. Warnant, B. Goffinet, J. Jelly, and J. Prost-Marechal, Arzneim.-Forsch., 24, 1 (1974). 10. U. Stache, W. Fritsch, H. Rupp, V. Hitzel, and H. W. Fehlhaber, Arzneim.-Forsch., 35, 1753 (1985). 11. J. Elks and G. H. Phillipps, Ger. Offen., 1,902,340 (1969) via Chem. Abstr., 72: 44,021y (1970). 12. E. L. Shapiro, M. J. Gentles, R. L. Tiberi, T. L. Popper, J. Berkenkopf, B. Lutsky, and A. S. Watnick, J. Med. Chem., 30, 1581 (1987). 13. S. S. Simons, E. B. Thompson, M. J. Merchlinsky, and D. F. Johnson, /. SteroidBiochem., 13, 311 (1980). D. R. Torossian, G. G. Aubard, and J. M. G. A. Jacky, Ger. Offen. 2,357,778(1984) via Chem. Abstr., 82: 156,584x (1975). 14. R. K. Varma, U. S. Patent, 4,361,559 (1982) via ChemAbstr.,98: 143,722w (1983). 15. D. J. Kertesz and M. Marx, /. Org. Chem., 51, 2315 (1986). 16. Anon., Neth. AppL, 8,100,707 (1981) via Chem. Abstr., 96:163,044p (1982). 17. R. K. Varma and C. M. Cimarusti, U. S. Patent, 3,937,720 (1976) via Chem. Abstr., 85:21,722g(1976).

5

Five-Membered

Ring Heterocycles

1. ONE HETEROATOM Cardiovascular disease is a major killer. Although it has proven difficult to make a clear causative association of dietary and blood levels of cholesterol with this condition, the evidence cumulatively makes this a reasonable assumption. In any case, most physicians now ask patients at risk to lower their blood cholesterol levels by diet, if possible, or with drugs if need be. A dihydrofuranone, acifran (5), is a potential antihyperlipoproteinemic drug. Cholesterol is carried in the blood in various forms and in experimental animals oral acifran decreases total blood cholesterol levels as well as those of low-density lipoprotein and triglycerides. It is synthesized from acetophenone (I) and the anion of l~methyl-2,6-dithiolane (2) (prepared using n-BuLi). The latter is a reversed polarity version of acetaldehyde (Umpolung) whose condensation with 1 produces tertiary alcohol .) by carbonyl addition. Acid-catalyzed dithiolane exchange with pyruvate leads to oc-hydroxykctone 4. This last undergoes base-catalyzed oxalylation on the methyl ketone moiety and cyclodchydration and ester hydrolysis to produce acifran (5) [1]. This synthesis is satisfactory for producing radiolabeled drug.

^s^COMe

(1)

Me (2)

(3)

(5)

79

80

Five Membered Ring Heterocycles Pyrrohdine containing Hnogliride(lO) is a structural analogue of the clinically used oral

antidiabetic agent pirogliride (11) LinogHride, on oral administration, stimulates the secretion of insulin in noninsuhn dependent patients and the mechanism by which this is brought about, in expenmental animals, is apparently different from that involved in the action of sulfonylureas and biguamdes LinogHride is 2 8 fold more potent than pirogliride The synthesis of linogliride begins by condensation of phenyl lsocyanate (6) with 2 imino 1 tucthylpynolidine (7) to give complex thiourea 8 The lattei undergoes alkylation on S as t xpected on treatment with Mel to give 9 An addition elimination reaction with morphohne concludes this synthesis of linogliride

Me (6)

| Me

(7)

(8)

Q I Me (9) , \ = McS

(11)

Rolgamidine (14) is a dihydropyrrole denvative which has antidiarrheal activity It can be synthesized by alkylation of trans 2,5-dimethyl-3 pyrrohne (12) with methyl bromoacetate to give 13 An amide-ester exchange reaction with guanidme hydrochlonde completes the synthesis of rolgamidine (14) [3]

Five Membered Ring Heterocycles

81

Me /= CH2CO2Me

(12)

(13)

I

CH2CO

(14)

Ketorolac (24) is a nonsteroidal antunflammatory and analgesic agent possessing dramati cally greater oral activity than aspirin or acetaminophen In early clinical trials the drug was effec tive against mild and acute postoperative pain 1 he molecular mode of action appears to be inhibi tion oi arachidontc cycloox) genase The active enantiomer is (1) S, I he synthesis of ketorolac (24) involves some nonstandard pyrrole chemistry of interest Pyrrole (IS) is electrophihcalh substituted by reaction with the idduct of N chlorosuccimnimide and dimethyl sulfide to give 16 I his on thermolysis dealk)l ites to 2 thiomethylpyrrole (17) Under Vilsmcier Haack reaction conditions acylation to 18 occurs using N,N dirnethylbenzamide Biarylketone 18 reacts readily with Danishefsky's reagent (19) to produce N alkylated product 20 This Meldrum's acid ana logue is converted to the ^ulfone (21) by oxidation with m chloroperbenzoic acid The anion of 21 did not cychze readily until it was convened by methanolysis to substituted malonate 22 Heating this with sodium ethoxide gives an intramolecular nucleophihc aromatic displacement reaction to give malonate denvative 23 The synthesis of ketorolac (24) concludes by sapomfication, acidifi cation and heating to decarboxylate the auxiliary carboxyl group [4] I lie dramatic clinical success of the orally active angiotensin converting enzyme inhibitor, captopril (25) as an antihypertensive agent has led to preparation of a large number of analogues Enalapril (28), introduced to the market as an orally active prodrug, is the most successful of these to date Enalapnl differs most significantly from captopril in that it has a carboxy group, after metabolic unmasking, in place of the SH group of captopril The synthesis of enalapnl follows the normal course for such compounds in that L alanylL proline (27) was reductively alkylated with ethyl 2-oxo 4 phenylbutyrate (26) using sodium cyanoborohydnde as the reducing agent (catalytic reduction may also be used) The product is

Five-Membered Ring Heterocycles

82 Q H

(15)

(16)

0

(17)

(18)

(19)

0

Me Me (20) ; X= : (21) ; X - 0

(22)

1

CCXMe

(23)

f \

(24)

e n a l a p r i l ( 2 8 ) . A n e w a s y m m e t r i c c e n t e r is g e n e r a t e d in t h i s p r o c e s s , a n d , as t h e s e a r e d i a s t e r e o i s o m e r s , they can be resolved by c o l u m n c h r o m a t o g r a p h y o r by fractional crystallization of the m a l e a t e s a l t [ 5 ] , T h e c o r r e s p o n d i n g d i a c i d is t h e u l t i m a t e l y b i o a c t i v e s p e c i e s a n d i s k n o w n a s enalaprilat. Alternate syntheses are also available [6-8].

)2Et

Me

H

ri'\O2H

(26)

(28)

(27)

CO2H

(25)

y -

C 0 N

Five-Membered Ring Heterocycles

83

Lisinopril (30) is the lysine analog of enalapril and is prepared by an analogous process beginning with L-lysyl-L-proline protected at the terminal amino group by a T-BOC (tertbutoxycarbonyl) moiety (29). After reductive alkylation, the blocking group is removed and the diasteriomers separated to give lisinopril (30) [9]. Lisinopril has been shown to be an effective antihypertensive agent in the clinic. NHCO2CMc, H

H .CO,H (CH2)

(29)

(30)

Zofenopril (32) is constructed from hydroxyproline by conversion first to the cis-3thiophenylproline analogue (31). Hsterification with the appropriate acid analogue produces zofenopril (32) 110).

HO2C

H

(3D

(32)

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared from l-carbobenzyloxy-4-oxoproline methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4)nonane~8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11].

Five-Membered Ring Heterocycles

84

PhCH2OCON

XN Mc

ft

(33)

(34); X = PhCH 2 OCO (35); X = H (36); X = L-Ala

(37)

R a m i p r i l ( 4 6 ) is a n o t h e r a n a l o g u e in t h e e n a l a p r i l c l a s s w h o s e s t r u c t u r e i n d i c a t e s that c o n s i d e r a b l e l e e w a y e x i s t s f o r m o d i f i c a t i o n at t h e L - p r o l y l e n d . T h i s c l i n i c a l l y a c t i v e a n t i h y p e r t e n s i \ c a g e n t s h o w s a n u m b e r o f i n t e r e s t i n g a c t i o n s in v i t r o a n d in a n i m a l s in a d d i t i o n t o A C K i n h i b i t i o n . F o r e x a m p l e , the c o m p o u n d s h o w s s o m e a n t i i n f l a m m a t o r y activity d u e to inhibition of P G 1 O b i o s y n t h e s i s in v a s c u l a r t i s s u e , i n h i b i t s a d r e n e r g i c a c t i o n in t h e C N S a n d h e a r t , a n d i n h i b i t s enkephalinase

A l l o f t h e s e e f f e c t s m a y c o n t r i b u t e t o its c l i n i c a l a c t i v i t y .

In a c o n v e r g e n t s y n t h e s i s , L - a l a n y l b e n z y l ester u n d e r g o e s c o n j u g a t e a d d i t i o n to the unsatu r a t e d k e t o g r o u p in e t h y l 4 - p h e n y l - 4 ~ o x o - b u t - 2 - e n o a t e ( 3 8 ) t o g i v e d i e s t e r 3 9 a s a d i a s t e r e o i s o m e r i c m i x t u r e . T h i s is s e p a r a t e d b y f r a c t i o n a l c r y s t a l l i z a t i o n a n d h y d r o g e n a t e d t o g i v e 4 0 b y l o s s o f t h e b e n z y l o x y m o i e t y . T h e o t h e r p i e c e r e q u i r e d is a s s e m b l e d s t a r t i n g w i t h e n a m i n e a l k y l a tion of c y c l o p e n t e n o p y r r o l i d i n e (42) with c h l o r o m e t h y l e n e reagent 41 (prepared from N -

,CO 2 CH 2 Ph H (38)

(40)

(39)

CO 2 Me H — C—NHCOMc I CH 2 C1

o

-

b

(42)

(41)

(43)

(44)

£O 2 H (40)

+

(45)

(46)

Me

Five-Membered Ring Heterocycles

85

acetylserine methyl ester). The product, ketone 43, undergoes cyclization to the deblocked imine (44) on treatment with dilute HC1. Hydrogenation with a Pt catalyst gives the diastereoisomeric endo, cis-bicyclo amino acid 45. The latter is resolved as its benzyl ester. The synthesis of ramipril (46) concludes by peptide bond formation between 40 and 45 112,13], 2. TWO HETEROATOMS Acivicin (51) is a fermentation-derived antitumor agent possessing a highly icactive iminochloride linkage. The clinical use of this agent is limited by the usual toxicities associated with alkylating agents as well as by neurologic problems. The molecular mode of action of acivicin appears to involve irre\ersible inhibition of glutamate-requiring pathways needed for de novo nucleoside synthesis. The CNS toxicity most likely involves this also. The unusual structure of acivicin has inspired a number of synthetic attempts. A rather short process involves a 1,3-nitrone cycloaddition reaction using a chiral auxiliary to achieve chirality transfer, Nitrone 47 was prepared in situ from 2,3-O-isopropylidene-5-O-trityl-D-ribose oxime by reaction with paraformaldehyde. This was reacted with vinylglycine analogue 48. The resulting N-substituted isoxazolidine was freed of its auxiliary by formic acid hydrolysis and this was oxidized to 49 with N-chlorosuccinimide. Chlorine in t-BuOH produced the desired chloroisoxazoline 50. The synthesis was finished by removing the protecting groups with BC13 [14]. Some other syntheses are noted [15-17],

PluCOHX V

O

6 6 ^ (47)

N-/ Mddfi' (48)

io2Me (50)

*-

(51)

u

kirL CO2Mc (49)

86

Five Membered Ring Heterocycles It has proven to be difficult to find broad spectrum antiviral compounds which are satis

factonly nontoxic A substituted isoxazole, disoxanl (56), has proven effective in vitro and in vivo against a great many rhinovirus serotypes It has been shown to exert its effects by inhibiting the uncoating of the virus after it has been absorbed into the target cell The coated virus cannot reach the cell nucleus, thus effectively preventing viral replication Fhe synthesis begins by ester amide interchange of methyl £ hydroxybenzoate (52) with ethanolamine to give substituted amide 53 This could be cyclodehydrated with thionyl chloride to give the dihydrooxazole 54 1 his is reacted in the usual way with alkyl bromide 55 and base to complete the synthesis of clisoxaril (56)|18 19|

)\\

(52)

(53)

(54)

(55)

(56) One of the problems with cyclosenne (57) as an antibacterial agent is its tendency to dimenze In an attempt to overcome this, the prodrug penti/idone (59) has been prepared The primary ammo group essential for the dimenzation reaction is reversibly blocked to prevent this Penti/idone is synthesized conveniently from cyclosenne (57) by merely mixing it with acetyl acetone (58) and stirring for two days to achieve the dehydration The resulting pentizidone apparently requires enzymic assistance to release cycloserine in vivo [20]

"NH

(57)

(58)

(59)

Five Membered Ring Heterocycles

87

The pyrrazole analogue fezolamine (61) does not possess the classical fused tncychc structure classically associated with such activity but nonetheless possesses antidepressant activity in animal models, but with an apparently different side effect profiles as compared to precedent drugs Its s\nthesis is accomplished by reacting 3,4 diphenylpyrazole (60) with acrylonitnle under base catalysis The resulting mixture (both N atoms react but the desired N 1 substitution greatly predominates under these conditions) is separated by cryst llhzation Conversion to fe/olarnine wis accomplished by Pd C catah/tci reduction in the presence of dimethylamine Presumabl> the intermediate inline undergoes lmine exchange and then reduction to achieve this result [211

CH2CH2CH2NMt (61) The lmidazohne derivative cibenzohne (64) is a class I antiarrhythmic agent which has undergone clinical trials in the United States with apparently satisfactory results It is synthesized by diphenylcyclopropanation of acrylonitnle by thermal carbene generation from diphenyldiazo methane (62) to give 1 cyano 2,2 diphenylc>clopropane (63) Reaction of this with ethylenedia mine tosylate completes the synthesis of ciben/ohne (64) [221

Phv (63)

»-> (64)

Napamezole (68) is a dihydroimidazole derivative with antidepressant activity probably as a result of its combined a 2 adrenergic receptor blocking and serotonin uptake blocking proper ties It can be synthesized by Wittig olefination of p-tetralone (65) with diethyl (cyanomethyl) phosphonate (66) and base to give nitnle 67 lmidazohne construction on the latter was smoothly

88

Five-Membered Ring Heterocycles

accomplished by reaction with ethylenediamine and trimethylaluminum. The product (68) is napamezole 123],

[I T ]

+

(65)

(EtO)2POCH2CN (66)

(67)

(68)

Another imidazoline derivative, lofexidine (71), has different pharmacological properties, being an antihypertensive. It is pharmacologically reminiscent of clonidine. As expected for a central adrenergic a-blocker, a major side effect in the clinic was orthosiatic hypertension. The compound has been marketed. Its synthesis begins with alkylation of 2-ehloropropionitrile with 2,6-dichlorophenol (69), KI, and base. The ether produced (70) is converted to lofexidine by reaction with ethylene diamine and catalytic carbon disulfide |24) Mcv JCN I O

OH — (69)

C i

IN

x r a (70)

(71)

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2receptor blockade is imiloxan (75). Its synthesis begins by conversion of 2~cyanomethyl-l,4benzodioxane (72) to its imincxkthylether with anhydrous HC1 in ethanol (73), Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [25].

(72)

( X r f " _ ^ ^ c r OEt (73)

(74)

Five-Membered Ring Heterocycles

89

Mefenidil (78) is a cerebral vasodilator which may be of value in treating geriatric cerebral circulatory problems. It can be synthesized by reacting benzamidine (76) with biacetyl to produce the highly reactive methylene benzimidazole adduct 77. Reaction of the latter with sodium cyanide completes the synthesis [26].

H <76)

(77)

(78)

Trifenagrel (82) is an antithrornbotic agent which also has analgesic, antiinflammatory, and antipyretic properties and so is classed as a nonsteroidal antiinflammatory agent. Its synthesis begins by ether formation between o-hydroxybenzaldehyde (79) and ethylenedibromide to give 80. Displacement with dimethylamine produces aminoether 81. The synthesis is completed by reacting 81 with benzil (C6H5COCOC6H5) and NH4OAc/NH4OH [27 j.

OHC

<7(»

(80); X = Br (81); X = NMc2

(82)

Etintidine (84)> an imidazole-containing histamine H-2 receptor antagonist, is an antiulcer agent conceptually related to cimetidine and ranitidine. It can be synthesized by various routes one of which terminates by an addition-elimination reaction of propargylamine with substituted Ncyano-S-methylisothiourea derivative 83 to give etintidine (84) [28].

\

Me (83)

(84)

90

Five Membered Ring Heterocycles Lofemi/ole (86) is an arylalkylimidazole-containing agent with antiinflammatory, analge

sic, and antipyretic properties It is conveniently synthesized from 1 (4 chlorobenzoyl)ethanol (85) by reaction with ammonium formate or formamide [29] OH

Imazodan (also known as CI 914) (91) is a cardiotonic agent related conceptually to the established agents amnnone (87) and milrinone (88) FJius, it is considered as a potential substi tute for the use of digitalis glycosides in congestive heart failure Systemic vasodilators reduce the work load on the heait and are increasingly favored in such patients The s\ nthesis of ima/oduri (91) begins with y oxo £ fluorobenzenebutanoic acid (89) which is reacted with lmidazole to displace the fluoro group (which is activated by the r>keto moiety) to give 90 This is reacted with hydrazine to produce the dihydropyndazinone ring of ima/odan (91) [30,31]

(87), R = H X=NH2 (88),R=Me XP=CN

" TX (89)

(90)

" (91)

Nafimidone (93), an anticonvulsant compound, also contains an lmidazole moiety It seems to have been discovered by accident during a search for anufungal agents Its synthesis is straightforward involving displacement with lmidazole of the activated chlonne atom of chloromethyl-p-naphthylketone (92) [32]

Five Membered Ring Heterocycles

91

HoCl (93)

(92)

We continue to document the point that the imidazole ring rjer se though common enough in drugs, is not a general pharmacophore by considenng the antithrombotic agent dazoxiben (96) Imidazole itself has some thromboxane B 2 inhibitory action but is dramatically less active than analogues such as da/oxiben Inhibition of this important enzyme in the arachidonic acid cascade results in a surplus of prostacychne and net inhibition of blood clotting One convenient synthesis starts with the O chlorocthylether of p hydroxybcnzamidc (94) and proceeds bv displacement with imidazole to give 95 Hydrolysis of the amide function completes the s>nthesis of dazoxiben

CONH,

u

CONH,

CO2H

O

u

Cl

(96)

T u b u l o z o l e ( 1 0 1 ) is a n a n t i n e o p l a s t i c a g e n t b y v i r t u e o f its ability to inhibit formation

microtubule

M i c r o t u b u l e s are a sort of cellular scaffolding a n d cellular r e p r o d u c t i o n is

without the ability to m a k e microtubules Interestingly, o n l y the cis i s o m e r is active

T h u s , I a , t u m o r cell g r o w t h is i n h i b i t e d b y

impossible tubulo/ole

T h e s t r u c t u r e o f t u b u l o z o l e is s u c h a s to s u g g e s t t h a t it

w a s originally prepared as a potential antifungal agent

O n e o f t h e s y n t h e s e s s t a r t s w i t h rj

acetanilide (97) w h i c h condenses with c o m p l e x methanesulfonate 9 8 in the presence of K acetone to produce acetanilide 99

thio

2

Deblocking by hydrolysis via 100 followed by reaction

C O

3

with

in

Five-Mernbered Ring Heterocycles

92

ethylchloroformate completes this synthesis [35]. The synthesis of requisite intermediate 98 is straightforward from 2,4-dichloroacetophenone.

OSO2Mc (97)

(99); X = COMc (100); X = H (101); X = CO2Et

(98)

Infections by fungi are becoming increasingly prominent as more individuals undergo immunesuppression following intensive corticoid therapy, organ transplantation, anticancer therapy, or infection by the dreaded AIDS virus. Consequently an intensified search for relatively nontoxic, broad spectrum, and orally active antifungal agents has been undertaken. Many appropriately substituted imidazole derivatives, known collectively as the 'conazoles, have been prepared and some have found clinical use. Zinoconazole (103) is a typically complex example of the second generation of such compounds but is notable for its oral activity and for being fungicidal at realistic doses. In common with the other 'conazoles, zinoconazole blocks the enzymic demethylation of lanosterol by a cytochrome P-450 enzyme thus, preventing the formation of ergosterol, an important cell membrane constituent of many pathogenic fungi. Zinoconazole seems also to damage membranes, directly thereby exerting a 'cidal rather than a 'static effect. It is made readily by hydrazoue formation between ketone 102 and 2,6-dichlorophenylhydrazone [36].

(102)

(103)

Five-Membered Ring Heterocycles

93

Fenticonazole (106), on the other hand, is used topically to combat a wide variety of dermatophytes and yeasts, particularly Candida albicans. It can be synthesized from 2,4-dichlorophenacyl chloride (104) by reduction with borohydride and subsequent displacement with imidazole to give 105. This last undergoes ether formation with p-thiolphenylbenzyl chloride mediated by NaH to produce fenticonazole (106) [37].

OH (105)

(104)

E n i l c o n a z o l e ( 1 0 7 ) h a s b e e n m a r k e t e d f o r a n t i f u n g a l u s e in p l a n t s a n d a n i m a l s . It c a n b e s y n t h e s i z e d in a v a r i e t y of w a y s i n c l u d i n g o n e c l o s e l y a n a l o g o u s to that u s e d for f e n t i c o n a z o l e e x c e p t t h a t t h e a l k y l a t i n g g r o u p is a l l y l c h l o r i d e 1 3 9 ] .

Cl

(107)

B i f o n a z o l e ( 1 0 9 ) is c l a i m e d t o b e r e m a r k a b l y n o n - t o x i c a n d i s m a r k e t e d a s a t o p i c a l a n t i f u n g a l a g e n t o v e r s e a s . It c a n b e c o n v e n i e n t l y s y n t h e s i z e d i n t h e b y n o w f a m i l i a r w a y b y r e d u c t i o n of r > p h e n y l b e n z o p h e n o n e ( 1 0 8 ) with b o r o h y d r i d e , c o n v e r s i o n to the c h l o r i d e w i t h thionyl chloride, and then imidazole displacement to bifonazole (109) [39].

(108)

(109)

E n o x i m o n e (113), an i m i d a z o l i n o n e - c o n t a i n i n g m o l e c u l e , is a cardiotonic m o l e c u l e like i m a z o d a n a b o v e . Its m e c h a n i s m o f a c t i o n i s still n o t e s t a b l i s h e d b u t it is r e p o r t e d t o b e a p o t e n t

94

Five-Membered Ring Heterocycles

inhibitor of a cAMP phosphodiesterase isoenzyme It is synthesized by Fnedel Crafts acylation of 4 methyhmidazolm 2 one (111) with 4 fluorobenzoyl chlonde (110) to give unsymmetrical bi aryl ketone 112 The synthesis is concluded by a nucleophihc aromatic displacement reaction with methyl mercaptan to give enoximone (113) [40]

on

s^JK

^M.

A^

"Y" ~ (110)

(111)

012)

A related agent piroximone (116) is also an active cardiotonic agent by virtue of marked strengthening of the toue oi the heart beat and reducing after load Its synthesis is accomplished b\ I ncdel Crafts acylation oi 4 tthyhmida/ohn 2 one (115) with the acid chlonde oi lsonicouiue dud (114) [411

+

(114)

.El HN NH

_

(115)

o J[ 1A N^J HN NH (U6)

Amflutia/ole (119) is an isothiazole containing gout suppressant by virtue of its inhibitory action against xanthine oxidase, an important enzyme in the catabohsm of uric acid Gout is charactenzed by crystallization of sharp needles of excess unc acid in joints Decreasing its metabolic formation relieves this condition The drug is synthesized by reaction of the tosvloxime denvative 117 with methyl thioacetate to give 118 by addition elimination The latter undergoes intramolecular cychzation between the active methylene and the electrophihc CN moiety on treatment with base to produce amflutiazole [42]

(117)

(118)

Five Membered Ring Heterocycles

95

Faneti/ole (122) is a biological response modifier with significant immunosuppressant activity It can be synthesized by conversion of 2 phen\lethylamine (120) with ammonium thio cyanate to the corresponding thiourea analogue 121 The synthesis of faneti/ole (122) concludes by thiazole ring formation of 121 by reaction with phenacylbromide Thus its synthesis involves use of the classic Hantzsch procedure in which a bromoacetone analogue and an appropnate thio urea derivative are reacted [43]

(120)

[12\)

(122)

Another thnzole containing diug ni/atidme (128) is in intagomstot histamine at Ho nxcptois and thus is in intiulctr a^unt rtl Uui to unutidmt It h is shown oril activity in the clinic Ni/atidme can be synthesized by re iction of ethyl bromopyruvate (124) with dimeth \laminothioacetamide (123) Presumably h ihde displacement is followed by cyclodehydration in producing thiazole 125 Hydride ieduction uid HBr mediated displacement with 2 aminoethan ethiol gives 126 This last is rtacted with 1 (meth\lthio) 2 nitro 1 N methylethylene (127) to give ni/atidme (128) [44] yNH2 Me NCI I—^

+

BrCHCOCO2Et

NL^COEt Mc2NCH2—<7 J

(124)

(125) 1IINO,

N M 2NrH2—^T n ,

n?7r

(126)

s

NHMe (128)

Another antiulcer histamine H2 receptor antagonist containing a thiazole moiety is zaltidine (131) Its synthesis can be accomplished readily by brominating 4 acetyl 2 methyhmidazole (129) to give haloketone 130 Displacement with amidinothiourea completes the synthesis of zaltidme (131) via a displacement cyclodehydration sequence [45]

96

Five-Membered Ring Heterocycles

Br irNH McCO' (129)

0

HiNv

//X^"

2

(130)

(131)

Fentiazac (134) is a member of the biarylacetic acid class of nonsteroidal antiinflammatory agents. Its synthesis also involves the Hantzsch reaction. Thiobcnzamide (133) is reacted with 3-(4-chlorobenzoyl)-3-bromopropionic acid (132) to give fcnliazoc (134) [46].

Itazigrel (137) is an antithrombotic compound because of its inhibition of platelet aggregation induced by collagen. It is synthesized from 1-bromo-l-(4-methoxy)benzoyl-4-methoxytoluene (135) by reaction in the usual way with trifluorothioacetamide (136) to give itazigrel (47).

(135)

{lM})

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of imidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoacetate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48].

Five-Membered Ring Heterocycles

97

Other syntheses can be consulted [49,50].

H

w H O (138)Oli

CO E,t

OMc

H O H (139)O

HO OH (140)

CO .

CONH,

' n - o f VHO

on

no

(141)

on (\A2)

Cl •Et

(144)

(143)

(145)

r (147)

(146)

&

(148)

98

Five Membered Ring Heteroc>Ues

3 THREE HETEROATOMS fnazolone containing nefa/odone (148) is an antidepressant agent It is of particular interest because of its unusual spectrum of receptor interactions It interacts with both adrenergic and serotonin receptors but not with muscannic acetylchohne receptors or monoamine oxidase Of the various syntheses one of the more interesting starts with 2 ethyloxazolme (143) which reacts w ill phenol to pioduce the propionamidt ether 144 1 his is converted to tht lminochlonde (145) with phosgene Reaction of the latter with methyl carbazate produces 146 The latter cychzes to the triazolone 147 by ester amide mteichange in base 1 he sequence terminates with alk> lation of 148 by 1 (3 chlorophenyl) 4 0 chloropiopyl)piperazine [511 RLFfRLNCLS 1 M N Cayen, R Gonzalez, E S Fernandini E Giesehn, D R Hicks, M Krarm, and D Dvormk, Xenobiotica, 16, 2il (1986) 2 C R Rasmussen, U S Patent 4 211,867 (1980) via Chem Abstr , 93 204 452d (1980) 3 I J Ward, Patentschnft (Switz ), 641,160 (1984) via Chem Abstr , 101 23,328f (1984) 4 F Franco, R Greenhouse, and J M Muchowski, / Org Chem , 47, 1682 (1982) 5 A A Patchett,E Hams E W Tristram, M J Wyvratt, M T Wu, D Taub,E R Peter son, T J Ikeler, J ten Broeke L G Payne, D L Ondeyka, E D Thorsett, W J Greenlee, N S Lohr, R D Hoffsommer, II Joshua, W V Ruyle, J W Rothrock, S D Aster, A L Maycock, F M Robinson, R Hirschmann, C S Sweet, E H Ulm, D M Gross T C Vassil,andC A Stone, Nature 288,280(1980) 6 M J Wyvratt, E W Tristram, T J Ikeler, N S Lohr, H Joshua, J P Spnnger, B H Arison, and A A Patchett,/ Org Chem ,49, 2816 (1984) 7 A A Patchett.E E Hams, M J Wyvratt, and E W Tristram, Eur Pat Appl, 12,401 (1980) via Chem Abstr , 95 25,634j (1981) 8 A Miyake,K Itoh,andY Oka, Chem Pharm Bull, 34,2852 (1986) 9 M T Wu, A W Douglas, D L Ondeyka, L G Payne, T J Ikeler, H Joshua, and A A Patchett, J Pharm Sci, 74, 352 (1985) 10 M A OndettiandJ Krapcho, U S Patent, 4,316,906 (1982) via Chem Abstr 96 218,225f (1982)

Five-Membered Ring Heterocycles

99

11. E. H. Gold, B. R. Neustadt, and E. M. Smith, U. S. Patent, 4,470,972 (1984) via Chem, Abstr., 102:96,083c (1984). 12. V. Teetz, R. Geiger, R. Henning, and H. Urbach, Arzneim.-Forsch., 34, 1399 (1984). 13. V. Teetz, R. Geiger, and H. Gaul, Tetrahedron Lett., 25, 4479 (1984). 14. S. Mzengeza, C. M. Yang, and R. A. Whitney, /. Am. Chem. Soc, 109, 276 (1987). 15. R. B. Silverman and M. W. Holladay, J. Am. Chem. Soc, 103, 7357 (1981). 16. J. E. Baldwin, L. I. Kruse, and J.-K. Cha, J. Am. Chem. Soc, 103, 942 (1981). 17. J. E. Baldwin, J. K. Cha, and L. I. Kruse, Tetrahedron, 41, 5241 (1985). 18. G. D. Diana, R. C. Oglesby, V. Akullian, P. M. Carabateas, D. Cutcliffe, J. P. Mallamo, M. J. Otto, M. A. McKinley, E. G. Maliski, and S. J. Michalec, J. Med. Chem., 30, 383 (1987).

6

Six-Membered Heterocycles

As noted earlier, benzeneringsin biologically active compounds act largely as centers of defined electron density and as rigid nuclei for attachment of groups which have pharmacophoric action. Aromatic, monocyclic heterocycles often play a similar role. It is, for example, often possible to replace a benzene ring by a heterocycle such as pyridine without markedly affecting biological activity even in face of the presence of the unshared basic pair of electrons in pyridine. There are, however, cases where the heterocycle forms an indispensable part of the chromophore; for example, a dihydropyridine is, as far as is known, an absolute requirement for calcium channel blocking activity. In a similar vein, 2~amino-4-pyridones form an essential part of those histamine H-2 antagonists lacking the cyano- or nitroguanidine functions. L PYRIDINES A rather simple pyridine derivative shows activity as an immunoregulator. Alkylation of 4-chloromethylpyridine (2), available from 4-picoline (1), with l-hydroxyethane-2-thiol affords ristianol (3) [1]. One of the first classes of compounds which provided practical chemical control of hypertension was guanidine derivatives. The mechanism of action of these agents, peripheral sympathetic blockade, resulted in side effects which led the class to be superseded by agents which acted by more acceptable means. A recent guanidine antihypertensive, which incorporates a cyano group on one of the nitrogens - making the functionality more akin to a thiourea - may act by a different mechanism. Condensation of the isothiocyanate 4 from 4-aminopyridine with the appropriate sec-amine gives thiourea 5. Treatment of that intermediate with a mixture of triphenylphos101

102

Six-Membered Heterocycles

phine, carbon tetrachloride, and triethylamine leads to the unsymmetrical carbodiimide 6. Addition of cyanamid affords pinacidil (7) [2]. CH2SCH2CH2OH (D;X = H (2); X = Cl S Me II I -NHCNHCHCMc3 (5)

(3) Me *~

N -

N

(6) Me -C-S

(4)

\y-NHCL (7)

Replacement of one of the benzeneringsin a fenamic acid by pyridine interestingly leads to a compound which exhibits antihypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aromatic substitution of anthranilic acid (8) on 4-chloropyridine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) [31. The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions; the former show some relation to the opioids while the latter can be recognized as NSAID's. The triamino pyridine 17 is an analgesic which does not seem to belong structurally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chloroformate produces flupirtine (17) [4].

Six-Membered Heterocycles

103

v^/COR NH2 (8)

(9) ; R = OH (10); R = C1

+ F—/^—CH2NH2 (n);X = H2 (13);X = NO2

*~ F—C~\—CH2NH—i^—NR2 ( i5,. R

(14)

(11)

=o (16);R = H

N 2

"

d—C~\~ NHCO2Et NH2 (17) The causative agents of malaria, the plasmodia, have, in common with virtually all other microorganisms, developed tolerance to the chemotherapeutic agents which at one time seemed ready to wipe them from the face of the earth. Successful treatment of malaria has thus demanded a continuing effort to develop ever newer agents. The incentive for developing new antibiotics lies in the enormous market for these drugs in the so-called developed nations. No such incentive exists for research on new antimalarial drugs, since this is largely a disease of the third world. This accounts in part for the few entries in this category in recent volumes in this series. One of the newer drugs for treating malaria, enpiroline (22), interestingly incorporates a great many structural features of quinine (23). It is of note that this drug owes its existence to research sponsored by the U.S. Army's Walter Reed Institute rather than a pharmaceutical company. The starting nicotinic acid derivative 19 is the product of the rather complex condensation of keto-acid 18 with 1-trifluoroacylmethylpyridinium bromide and ammonium acetate patterned on the work of Kroehnke [5]. Condensation of the product with an excess of 2-lithiopyridine gives the ketone 20.

Six-Membered Heterocycles

104

Treatment with sodium borohydride leads to the alcohol 21. Catalytic reduction of the product in the presence of acid leads to preferential hydrogenation of the monosubstituted ring. Selectivity is probably due to the fact that pyridine rings must be protonated in order to be reduced; the larger number of electron withdrawing substituents on the disubstituted ring will reduce basicity of the nitrogen and favor protonation of the alternate pyridine nitrogen. Separation of the R*,R* isomer from the diastereomeric mixture affords enpiroline (22) [6].

Br" NH4OAc

fcCH=CHCO2H (18)

CO2H

F,C

F3O

(20);R = O (21); R « H, OH

(19)

McQF,O

(23)

(22);

R*,R*

T h e search for nonsedating H-1 antihistamines met its first success in terfenadine (see 198, Chapter 2). A different approach aimed at keeping such agents out of the C N S , by prevent-

Six-Membered Heterocycles

105

ing their crossing the blood brain barrier, consists in converting some known antihistamine to a zwitterion by incorporating a carboxyl group. Application of this strategy to triprolidine (28 minus the pendant acrylic acid chain) results in the antihistamine acrivastine (28). Synthesis of this compound starts by reaction of the mono lithio derivative from pyridine 24 with r>toluonitrile. Hydrolysis of the intermediate imine affords the benzophenone 25. Condensation of the carbonyl group with the ylide from triphenyl(2-N-pyrrolidinoethyl)phosphonium chloride gives the intermediate 26, probably as a mixture of geometric isomers. The remaining halogen on the pyridine ring is then converted to the lithio reagent by halogen metal interchange with an alkyl lithium. Condensation of the resulting organometallic with dimethylformamide gives, after hydrolysis, the aldehyde 27. This is again subjected to a Wittig type reaction, this time with the ylide from triethylphosphono acetate. This last reaction leads almost exclusively to the trans double bond isomer. Saponification of the ester group affords the amino acid. Separation of the E,E isomer affords acrivastine (28) [7].

.Me

• B xX yX Xr J

(26)

(27)

(28)

106

Six-Membered Heterocycles 2. DfflYDROPYRIDINES

The calcium channel blocking agents, typified by the dihydropyridine nifedipine, were approved initially for use in cases of atypical, nonexercise induced angina. Continued clinical investigations have shown these agents to be useful for a variety of additional indications, including all types of angina as well as hypertension. This resounding commercial success has spurred work in numerous laboratories in order to develop their own proprietary dihydropyridine calcium channel blocking agents. The Hantsch pyridine synthesis provides the final step in the preparation of all dihydropyridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. The need to produce unsymmetrically substituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate forms an aldol product (30) with aldehyde 29; conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8].

O MeCCH2CO2Et NHa

a

g^Me (31)

(32)

Six-Membered Heterocycles

107

CHO (33)

(34)

(35); R1 = CHMe2 ; R2 = Me (36);R1 = Et;R2 = Et

(37) R a n d o m incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. F o r example, treatment of ethyl acetoacetate with a m m o n i a gives the corresponding p-aminocrotonate 32. T h e aldehyde (34) required for preparation of such an unsymmetrical c o m p o u n d is prepared by reaction of the product from direct metallation of 3 3 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to i s r a d i p i n e (35) [9]. T h e same aldehyde with ethyl acetoacetate and the p-aminocrotonate from ethyl acetoacetate gives d a r o d i p i n e (36) [10]. In much the same vein, condensation of the benzaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords r i o d i p i n e (38) [in. Activity is apparently retained w h e n the ring nitrogen is alkylated as in f l o r d i p i n e (42). Aldol condensation of the benzaldehyde 3 9 with ethyl acetoacetate gives the unsaturated ester 40. T h e nitrogen containing reaction partner 4 1 is obtained by condensation of 32 with 2- morpholinoethylamine. Reaction of 40 with 4 1 leads to flordipine (42) [12]. The methyl groups adjacent to the pyridine nitrogens can also be modified without changing calcium channel blocking activity. T h e most significant change involves replacement of methyl by a nitrile group. Hantsch type condensation of the nitrobenzaldehyde 4 3 with methyl acetoacetate and the vinyl amine 44 from isopropyl 3-cyano-3-ketopropionate leads directly to nilvadipine(45)[13].

Six-Membered Heterocycles

108

EtO2CN Jl

F3C

(32)

HNCH2CH2N/

\)

(41)

CH2CH2N

O

(42) T h e preparation of an analogue containing an oxygenated methyl group starts by the displacement of halogen on the chloro acetoacetate 47 by the protected ethanolamine derivative 46. Condensation of the product (48) with the vinyl amine derivative of methyl acetoacetate and o-chlorobenzaldehyde gives the dihydropyridine 49. Removal of the benzyl protecting groups by catalytic hydrogenation, affords amlodipine (50) [14]. T h e search for opioid analgesics which show reduced addiction liability has centered largely on benzomorphan and morphinan derivatives. S o m e research has, however, been devoted to derivatives of the structurally simpler meperidine series. T h e preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 5 1 gives the intermediate 5 2 . Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 5 3 . In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function,

Six-Membered Heterocycles

cL CO Me M 2 2

109

+

NCC=CHCO2CHMe2

O (C6H5CH2)2NCH2CH2OH

ClCH2CCH2CO2Et (47)

(46)

O (C6H5CH2)2NCH2CH2OCH2CCH2CO2Et CH2OCH2CH2NR2 (48)

(49); R = CH2C6H5 (50); R = H

under Mannich reaction conditions (formaldehyde, dimethylamine) leads to the aminomethyl derivative 56. It m a y be speculated that the reaction proceeds initially through the methyl carbinol 5 5 . Hydrogenolysis of 56 involves initially removal of the allylic amino group to afford a transient intermediate such as 5 7 , followed by reduction of the enamine to produce 5 8 . Demethylation of the phenolic ether by m e a n s of hydrogen bromide and fractional crystallization to obtain the derivative with cis configuration of the two ring alkyl groups completes the synthesis of the analgesic picenadol (59) [15]. Reaction of dimethylformamide with dimethyl sulfate leads to the highly reactive O methyl ether 60. Exposure of this reagent to n-octylamine leads to the amidine 6 1 . A n exchange reaction between this last intermediate and the piperidine derivative 62, results in displacement of dimethylamine by the piperidine nitrogen. There is thus obtained the gastric antisecretory agent fenoctimine (63) [16]. T h e structural fragment represented by 62 is often used in H - l antihistamines; the fact that those c o m p o u n d s often exhibit some anticholinergic activity m a y account for the activity of 6 3 .

Six-Membered Heterocycles

110 OMe

OMe NMe

NMe (51)

(52)

OMe

OMe NMe

(53)

OMe

OMe

NMe

(57)

(60)

(63)

(58); R = Me (59); R = H

Six-Membered Heterocycles

111

A rather more complex compound, levocabastine (72), is described as an extremely potent, selective, H-l antihistaminic agent. The presence of a free carboxyl group suggests that this compound may have difficulty in crossing the blood brain barrier and may thus show reduced sedating activity. One leg of the convergent synthesis starts with the double conjugate addition of ethyl acrylate to the anion from r>fluorophenylacetonitrile (64). Base catalyzed cyclization of the product (65) affords the keto ester 66. Decarboethoxylation of that intermediate gives the cyanocyclohexanone 67. Esterification of the carboxyl group in the optically active meperidine-related compound 68 with benzyl chloride leads to ester 69. The tosyl protecting group is then removed by means of electrolytic reduction. Condensation of the ketone 67 with secondary amine 70, under reductive alkylation conditions affords predominantly (9:1 ratio) the intermediate 71, which is purified by recrystallization. The trans stereochemistry of the cyclohexane amino group and the aromatic ring result from the tendency to form equatorial nitrogen in the reduction of the intermediate imine. The benzyl protecting group is then removed by means of a second, more drastic hydrogenation step. The product of that reaction is then the levorotatory isomer, levocabastine (72) [17].

-CH2CN

\:H2CH2CO2Et

(64)

(66); R = CO2Et (67); R = H

(65)

TsN (68); (3£, 4£)

(69); R = Ts (70); R = H

,Me

NO

(72)

(71)

Six-Membered Heterocycles

112

Treatment of the piperidine 74, obtainable from an aminonitrile such as 73, under Nmethylation conditions leads to the dimethylamino derivative 75. The carbobenzoxy protecting group is then removed by catalytic hydrogenation. Reaction of the resulting secondary amine 76 with cyclohexene oxide leads to the alkylated trans aminoalcohol. There is thus obtained the antiarrhythmic agent transcainide (77) [18].

CN Me

RN

Me

(73)

(74); R = H (75); R = Me

CONH Q - C X ; •NMC2

(77)

(76)

3. PYRIMTDINES T h e discovery of the histamine H-2 blocking agents has virtually revolutionized the treatment of ulcers of the upper GI tract. Drugs such as cimetidine (78) and ranitidine (89) have proven so safe and effective that serious consideration is being given to granting approval for sale of these without prescriptions. This very success has engendered considerable work aimed at exploring the limits of the S A R . It was found early on that the cyanoguanidine function could be replaced by a pyrimidone (see The Organic Chemistry

of Drug Synthesis,

V o l u m e 3). M o s t of the recent work

in this series h a s apparently focused on such pyrimidones. Catalytic reduction of the nitrile 7 9 in the presence of semicarbazide affords initially the semicarbazone of 80. Hydrolysis-interchange, for example in the presence of pyruvic acid, gives the aldehyde 80. Condensation with the half ester of malonic acid leads to the acrylic ester 8 1 ; the double bond is then removed by means of catalytic reduction (82). B a s e catalyzed reaction of the

Six-Membered Heterocycles

113

ester with ethyl formate gives the corresponding formyl derivative 83. Condensation of this beta dicarbonyl compound with N-nitroguanidine leads to the pyrimidone 84. The reaction involves, as expected, the more nucleophilic (i.e., nonnitrated) guanidine nitrogens; the product, in addition, contains a built in good leaving group. Thus, displacement of the leaving group with pyridylpropylamine 85, affords the H-2 blocker icotidine (87) [19]. The same reaction using the bromopyridine 86 as the nucleophile, gives the H-2 blocker temelastine (88) [20].

Me.

NCN C —NHMe

.CH (78)

CH=CHCO2R NT

(79)

, X X

(80) I

:HOH

Me (83)

I

(82)

O N CH2CH2CH2CH2NH2

•Me

¥ ^^N H (84)

( 8 5 ) ; R ! = H ; R 2 = OMe (86); R1 = Br; R2 = Me

H (87)

H (88)

Six-Membered Heterocycles

114

Ranitidine (89), in which the imidazole ring has been replaced by a furylmethyl moiety has proven a particularly successful drug. Several pyrimidones thus incorporate that ring system. Repetition of the scheme used to prepare the pyrimidone intermediate 84, starting with the oxygenated pyridine 90 instead of 79, affords the key synthon 91. Displacement of the leaving group by the primary amine from the furyl alkylamine 92 leads to 93. Treatment of this last compound with dry hydrogen chloride leads to cleavage of the pyridine O-methyl ether and formation of the corresponding hydroxy derivative. This function is more usually depicted as a pyridone. There is thus obtained donetidine (94) [21].

(89)

.CN

(90)

MeHN^

OMe

(92)

(91)

CH2SCH2CH2NH ^

N H

(93)

CB MejNCHf

(94)

Six-Membered Heterocycles

115

An alternate scheme for preparing these compounds starts with a prefabricated pyrimidone ring. Aldol condensation of that compound (95), which contains an eneamide function, with pyridine-3-aldehyde (80), gives the product 96. Catalytic hydrogenation gives the product of 1,4 reduction. The resulting pyrimidinedione, of course exists in the usual tautomeric keto (97a) and enol (97b) forms. Reaction with phosphorus oxyxchloride leads to the chloro derivative 98. Displacement with methoxide gives 99. Reaction of this last intermediate with the furylalkylamine derivative 92 leads to the H-2 blocker lupitidine (100) [22]. O o

x_v

H

-Me

HN"" (95)

(96)

N

H

(97a)

^

r

-

Q

-

™

(97b);R = OH (98); R = Cl (99); R - OMc o

H (100) Pyridones such as amrinone (101) and milrinone (102) have proven to be very effective cardiotonic agents. It is of interest that activity is retained when an additional nitrogen is inserted into the ring to form a pyrimidone. Condensation of amidine 103 with intermediate 104 can be visualized as involving initially addition elimination of basic nitrogen to the highly electrophilic double bond and loss of the good, though odiferous, leaving group, methyl mercaptide (105). Cyclization by replacement of the ester methoxide group will then give pyrimidone 106. Re-

Six-Membered Heterocycles

116

placement of the remaining thiomethyl group by 3-methylaminopyridine affords the cardiotonic agent pelrinone (107) [23],

(102)

(101) HN

MeSw i2 MeS (103) (104)

SMe H (105)

O

NV 'N-^c H (107)

CN H (106)

Chemotherapy of diseases caused by microorganisms is at least conceptually very straightforward since it depends on deep seated metabolic differences between eukariotic and prokariotic species; ithas as consequence usually been possible to identify compounds which are uniquely toxic to disease causing organisms. In contrast to this, viral and neoplastic diseases have in common a derangement of the host cells' mechanism for replication; this process is taken over by the virus in one case and is no longer under tight genetic control in the other. The clean differences in metabolism simply do not exist. The fact that both disease types involve nuclear processes and thus also nucleosides has led to a long-term research effort to synthesize modified purines and pyrimidines in the hope that some subtle differences may exist between healthy and diseased cells. The success of the modified nucleoside, acyclovir, suggests that this approach has considerable merit.

Six-Membered Heterocycles

117

One such compound, bropirimine (112), is described as an agent which has both antineoplastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. O CO2H II / -C—CH N CO2Et

,CO2H CH,

COoEt

(109)

O

I -c—cH2co2a (112)

(111)

(110)

Compounds prepared from naturally occurring nucleosides are of course more closely related to genetic material and may have a better chance of interacting with infected cells. Mercuration of the 2'~deoxyuridine 113 leads to the organometallic derivative 114; reaction of that with ethylene in the presence dilithio palladium tetrachloride gives the alkylation product 115; this is reduced catalytically in situ. There is thus obtained the antiviral agent edoxudine (116) [25]. Todays' most famous virus is probably that which is responsible for AIDS. Though an actual cure is not yet in sight, a drug which slows progression of the disease by inhibiting replication of the virus was recently introduced. The published synthesis for the drug, known trivially as AZT, startsfromthymidine, possibly accounting for its very high cost when initially made available. Thus, treatment of thymidine (117) with chloropentafluorotriethylamine leads to the product from displacement of the sugarringhydroxyl by the hydroxyl from the pyrimidone eno-

118

Six-Membered Heterocycles

late (118). The potent nucleophile, azide, serves to open the somewhat strained bridgingring;this involves a second inversion and restoration to the natural stereochemistry. There is thus obtained zidovudine (119), formerly known as AZT [26]. O

(118)

O

(119)

4. PIPERAZINES Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function

Six-Membered Heterocycles

119

and restoration of the secondary amine 128. Alkylation of that center with iodide 129 followed by N-demethylation leads to the formation of mioflazine (130) [28]. cu NH + C1CH2CH2OCH2CONH2 (120)

HN NH MeHN r o (124)

NCH2CH2OCH2COR

(122); R = NH2 (123); R = OH

(121)

? C1CH C H 2N (126)C1

\ NH

7

0 (125)

H : CHC C I2 2H 2H

(129) (127)

oa N CHC H2N a H2 (130) The anxiolytic agent buspirone (131) is notable for the fact that it does not interact with the receptor for the benzodiazepines. This difference in biochemical pharmacology is reflected in the fact that buspirone (131) seems to be devoid of some of the characteristic benzodiazepine side effects. The spiran function is apparently not required for anxiolytic activity. Alkylation of 3,3-dimethylglutarimide with dichlorobutane in the presence of strong base yields the intermedi-

120

Six-Membered Heterocycles

ate 132; treatment of that with ethylenediamine leads to 133. Use of this diamine to alkylate 2chloropyrimidine proceeds at the terminal amino group to afford the open chain compound 134. Bisalkylation with 1,2-dichloroethane leads to ring closure to a piperazine. There is thus obtained gepirone (135) [29]. / NH X

—

Me/N

/ NR

—

t e

/ .—^ 1 N(CH2)4NHCH2CH2NH —(' x

0 (132);R = (CH2)4C1 (133); R « (CH2)4NHCH2CH2NH2

o / (134) /

(135)

(131) 5. MISCELLANEOUS COMPOUNDS A piridazine ring forms the nucleus for a rather unusual nontricyclic antidepressant Condensation of the keto ester 136 with hydrazine leads to the cyclic hydrazide 137. Oxidation, for example with bromine, gives the corresponding pyridazone 138. The oxygen is then replaced by chlorine by reaction with phosphorus oxychloride. Displacement of the halogen in 139 with N-ethylaminomorpholine affords minaprine 140 [30], Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamotrigine (144), is described as an anticonvulsant agent [31].

Six-Membered Heterocycles

121

(138)

(137)

(136)

(139)

(140)

•O

(141)

+

(142)

(143)

(144)

Replacement of heterocyclic rings in nucleosides by ring systems which do not occur in nature represents another approach to c o m p o u n d s which may have activity against viral and neoplastic diseases. One of the early successes in this category involves replacement of a pyrimidine ring by a triazine. T h e synthesis starts with a now classical glycosidation of a heterocycle as its silylated derivative (146) with a protected halosugar (145), in this case a derivative of arabinose

Six-Membered Heterocycles

122

[32]. Hydrogenation of the product 147 removes the benzyl protecting groups and at the same time reduces the triazine to its dihydro derivative 148. A roundabout scheme is required for dehydrogenation due to the sensitivity of the intermediates. The product is thus converted to its silyl ether 149; exposure to air results in oxidation and desilylation. There is thus obtained the antineoplastic agent fazarabine (150), also known as ara*A C.

NHSiMe.,

BzO

(146)

BzO

(147)

OH tin (150)

(149)

(148)

Alkylating agents represent the oldest class of antineoplastic agents. These compounds, whose actions are somewhat indiscriminate, disrupt genetic material by forming covalent bonds with the bases in DNA. Polydentate alkylating agents may be more effective, it is thought, due to their ability to crosslink adjacent DNA chains. One such compound is available from the reaction of cyanuric acid (151) with epichlorohydrin [33]. Each of the three epoxypropyl side chains contains a chiral center. The product will thus consist of a mixture of 4 enantiomers (2 diastereomers) [34]. The drug, teroxirone (152), in fact consists of the separated racemic (R S^ R S^ S R)-isomer.

Six-Membered Heterocycles

123

(151)

-b» (152); &*,£*, S.* REFERENCES

1. J. G. Lombardino and C. A. Harbert, Belg. Pat., 890,374 (1982) via Chem, Abstr., 97: 23,635c (1982). 2. H. J. Petersen, C. K. Nielsen, and E. A. Arrigoni-Martelli, /. Med. Chem., 21, 773 (1978). 3. D. M. Bailey, Eur, Pat. AppL, 98,951 (1984) via Chem. Abstr.1102: 203737t (1985). 4. W. Orth, J. Engel, P. Emig, G. Scheffler, and H. Pohle, Ger. Offen., 3,608,762 (1986) via Chem. Abstr., 106: 50,057b (1987). 5. F. Kroehnke, W. Zecher, J. Curtze, D. Drechsler, K. Pfleghar, K.-E. Schnalke, and W. Weis, Angew. Chem., 14, 811 (1962). 6. A. B. Ash, M. P. LaMontagne, and A. Markovac, U.S. Patent, 3,886,167 (1975) via Chem. Abstr., 83: 97,041p (1975). 7. G. G. Coker and J. W. A. Findlay, Eur. Pat. AppL, 85,959 (1983) via Chem. Abstr., 100: 6,345w (1984). 8. P. B. Berntsson, A. I. Carlsson, J. O. Gaarder, and B. R. Ljung, Swed. Patent, 442,298 (1985) via Chem. Abstr., 106: 4,878x (1987). 9. P. Neumann, Eur. Pat. AppL, 0,150 (1979) via Chem. Abstr., 92: 94,404j (1980). 10. M. Heitzmann, Patentschrift (Switz.), 661,728 (1987) via Chem. Abstr., 107: 236,717t (1987). 11. V. V. Kastron, G. J. Dubur, V. D. Shatz, and L. M. Yagupolsky, Arzneim- Forsch., 35, 668 (1985). 12. F. C. Huang, C. J. Lin, and H. Jones, Eur. Pat. AppL, 109,049 (1984) via Chem. Abstr., 101:110,747k (1984). 13. Y. Sato, Ger. Offen., 2,940,833 (1980) via Chem. Abstr., 93, 220,594g (1980). 14. S. F. Campbell, P. E. Cross, and J. K. Stubbs, US. Patent, 4,572,909 (1986) via Chem. Abstr., 105: 42,661h (1986).

124

Six-Membered Heterocycles

16. G. Feth and J. E. Mills, U.S. Patent, 4,499,274 (1985) via Chem. Abstr., 102: 166,624f (1985). 17. R. A. Stokbroekx, M. G. M. Luyckx, J. J. M. Willems, M Janssen, J. O. M. M. Bracke, R. L. P. Joosen, and J. P. Van Wauwe, Drug Dev. Res., 8, 87 (1986). G. Vanden Bussche, Drugs of the Future, 11, 841 (1986). 18. G. H. P. Van Daele, M. F. L. De Bruyn, and M. G. C. Verdonck, Eur. Pat. AppL, 121,972 (1984) via Chem. Abstr., 102: 149,116z (1985). 19. T. H. Brown, G. J. Durant, and C. R. Ganellin, Can., 1,106,375 (1981) via Chem. Abstr., 96: 35,288j (1982). 20. G. S. Sach, Eur. Pat. AppL, 68,833 (1983) via Chem. Abstr., 99: 22,483f (1983). 21. B. M. Adger and N. I Lewis, Eur. Pat. AppL, 141,560 (1985) via Chem. Abstr., 103: 178,273z(1985). 22. B. L. Lam and L. N. Pridgen, Eur. Pat. Appl, 58,055 (1982) via Chem. Abstr., 98: 16,719a (1983). 23. J. F. Bagli, Eur. Pat. AppL, 130,735 (1985) via Chem, Abstr., 103: 6,358q (1985). 24. H. I. Skulnick, S. D. Weed, E. E. Eidson, H. E. Renis, W. Wierenga, and D. A. Stringfellow,7. Med. Chem., 28, 1864 (1985). 25. D. E. Bergstrom and J. L. Ruth, J. Am. Chem. Soc, 98, 1587 (1976). 26. M. Imazawa and F, Eckstein, /. Org, Chem,, 43, 3044 (1978). 27. E. Baltes, J. De Lannoy, and L. Rodriguez, Eur. Pat. AppL, 58,146 (1982) via Chem. Abstr., 98: 34,599r (1982). 28. G. Van Daele, Eur. Pat. AppL, 68,544 (1983) via Chem. Abstr., 99: 22,493j (1983). 29. V. Aguirre Ormaza, Span., 550,086 (1986) via Chem. Abstr., 107: 39,628p (1987). 30. C. Wermuth, H. Davi, and K. Biziere, Eur. Pat. AppL, 72,299 (1983) via Chem. Abstr., 99: 105,265n(1983). 31. M. G. Baxter, A. R. Elphick, A. A. Miller, and D. A. Sawyer, Can., 1,133,938 (1982) via Chem. Abstr., 98: 89,397d (1983). 32. M. W. Winkley and R. K. Robins, J. Org. Chem., 35,491 (1970). 33. D. Joel and H. Becker, Plaste Kautsch., 23, 237 (1976); via Chem. Abstr., 85: 21,303w (1976). 34. M. Budnowski, Angew. Chem., 7, 827 (1968).

7

Five-Membered Ring

Benzofused Heterocycles

The vast majority of drugs contain an aromatic ring of some type or other as an important structural element. Biological systems are often quite forgiving in their acceptance of interchange of certain heteroatoms for carbon in such rings fe. g., N (benzene to pyridine), O (furan for pyrrole), S (thiophene for furan)] as shown by the popularity of the stratagem of bioisosteric replacement as an element of drug design. In this context, the heteroaromatic ring often appears to serve as a flat, electron rich framework upon which to attach functionality which may interact with specific receptors. These factors, the relative ease of construction of heterocycles, and the huge numbers of isomers this makes possible account for many of the very large family of drugs incorporating this structural feature. In such molecules the specific aromatic moiety is rarely essential for activity. As one consequence, the drugs discussed in this chapter display a very wide range of bioactivities. 1. BENZOFURANS Thromboxane A-2 has been implicated in a number of disorders of the circulatory system including coronary artery spasms, unstable angina pectoris, traumatic and endotoxic shock, and heart attacks. It is formed normally very near its receptors and is rapidly deactivated by metabolizing enzymes so circulating levels are quite low. Furthermore, it is opposed in its actions by the prostacyclins. When these controls are defective, pathology results and drugs can be the resort in attempts to restore the normal healthy balance. For one example, furegrelate (6) is a throm125

126

Five-Membered Ring Benzofused Heterocycles

boxane synthetase inhibitor which can reestablish homeostasis by banking down the synthesis of thromboxanes. A useful ancillary characteristic of this type of drug is that the precursor prostaglandin endoperoxides are largely diverted to the biosynthesis of prostanoids whose pharmacological actions antagonize those of thromboxanes. Thus, both of its major actions operate in the same direction and the drug has shown clinical value in some life-threatening conditions f 1]. One of the syntheses of furegrelate begins by catalytic hydrogenation (Pd/C) of 3-(4nitrobenzyl)pyridine (1) to the corresponding aminobenzylpyridine (2). This is followed by diazotization in the usual fashion; the diazoniurn salt is transformed to the corresponding phenol (3) by heating with hot aqueous acid. A formyl group is then introduced ortho to the phenolic function by use of hexamethylene tetramine in anhydrous trifluoroacetic acid (the Duff reaction). The key intermediate in this interesting transformation is believed to be the substituted benzylrnethylene imine formed by interception by the phenol of the highly reactive intermediate formed by partial depolymerization of the hexamethylene tetramine reagent. The resulting substituted benzylmethyleneimine is in turn thought to undergo double bond isomerization to the corresponding substituted benzaldehyde methylimine. Hydrolysis during workup gives the final product. Treatment with base and diethyl bromomalonate produces the desired benzofuran ring system of 5. It seems likely that this reaction proceeds by ether formation followed by cyclization to the 3-hydroxy-2,2-dicarbethoxydihydrofuran system which, on saponification undergoes decarboxylative ejection of hydroxyl giving aromatic ester 5. The synthesis concludes by saponification to furegrelate (6) [2].

(1)

(2)

(3)

(4)

(5); R = Et (6); R = H

Five-Membered Ring Benzofused Heterocycles

12'

A somewhat related nonsteroidal antiinflammatory agent, furaprofen (14), is much more active as its S-enantiomer. Its patented preparation depends upon a chiral enzymic hydrolysis in a late step. One synthesis begins by ether formation between 2-bromophenol (7) and phenacyl bromide (8) to give the aryloxyacetophenone 9. Treatment of 9 with polyphosphoric acid leads to cyclodehydration to benzofuran 10. The later is converted to the Grignard reagent and condensed with methyl pyruvate to give tertiary carbinol 11. Deoxygenation is accomplished by sequential dehydration with tosic acid and subsequent hydrogenation to produce racemic ester 12. Saponification produces racemic furaprofen (13). The use of a hydrolytic enzyme from Bacillus subtilis to convert 12 to 13 produces the optically active drug [3J.

BrCH2CO—f~\

—*-

Vsssas/

B r

( 8 )

( 9 )

( 1 0 )

A m i o d a r o n e

d e p r e s s a n t

T h e

o r i g i n a l l y

i o d o n a t e d

o f

1 5

g o u s

u s e f u l

i s

s t e p s

( 1 6 )

i n

1 5

d e t a i l e d

[ 6 ] .

h a s

b e e n

t r e a t i n g

p a t e n t e d

p h e n o l

n o t

(

t h e

c e n t e r

v e n t r i c u l a r

p r o c e d u r e

w i t h

i n

t h e

o f

m u c h

i n t e r e s t

a r r h y t h m i a

c o n c l u d e s

a n d

b e c a u s e

m a n y

o f

b y

e t h e r i f i c a t i o n

2 - h a l o d i e t h y l a m i n o e t h a n e

t o

g i v e

b u t

t h e

s y n t h e s i s

o f

; R

( 1 4 ) ;

R

i t s

a n a l o g u e s

s i m p l y

r e f e r e n c e

)

( 1 3 ) ;

o f

a m i o d a r o n e

b e n z b r o m a r o n e

= =

H H ,

S - e n a n i i o m c r

a c t i v i t y

h a v e

a s

b e e n

a

c a r d i a c

p r e p a r e d

[ 4 ) .

b e n z o f u r a n - c o n t a i n i n g

( 1 6 )

[ 5 ] .

c o n t a i n s

T h e

s y n t h e s i s

c l o s e l y

a n a l o -

128

Five-Membered Ring Benzofused Heterocycles

OH I *-o'

(15)

(16)

2. INDOLINES One of the many angiotensin-converting enzyme (ACE) inhibitors covered in this volume contains an indoline residue instead of a pyrrolidine. As such, it may be considered as a benzo analogue of the captopril series. The synthesis of pentopril (19) follows the classical amide forming condensation of hemiester 17 (itself prepared by alcoholysis of the corresponding 2,4-dimethylglutaric anhydride) with (S)-indoline-2-carboxylic acid (18), using l~[3~(dimethylamino)propyl)|~3~ethylcarbodiimide as condensing agent, in order to produce pentopril [7].

"**8

(17)

U - K V H

v>t

(18)

" I P * (19)

Saturation of the aromatic ring of pentopril analogues is also consistent with ACE inhibition as demonstrated by the oral activity of indolapril (23). The necessary heterocyclic component (21) can in principle be prepared by catalytic perhydrogenation (Rh/C, HOAc) of the corresponding indole. A single isomer predominates. The product is condensed by amide bond formation with the appropriate alanylhomophenylalanyl dipeptide ester 20 to give 22. Selective saponification to 23 could be accomplished by treatment with HC1 gas. Use of the appropriate stereoisomers (prepared by resolution processes) produces chiral indolapril [8].

Five-Membered Ring Benzofused Heterocycles

(20)

129

(21)

(22);R = *-Bu (23); R = H

3. BENZOTHIOPHENES Tipentosin (28) contains a partially reduced benzothiophene ring system and is of interest as an antihypertensive agent. Its synthesis begins with epoxidation of 3-acetamidocyclopentene (24) followed by epoxide opening with phenol, and then deacetylation to give amino alcohol 25. The second half of the molecule is prepared from 1,3-cyclohexanedione (26) by sequential alkylation with chloroacetone, isopropylidenation of the product (to the bisenolether), and cyclization to a thiophene moiety with hydrogen sulfide. The latter reaction appears to involve a sequential double Michael addition of hydrogen disulfide with consequent elimination of the acetonide in the form of acetone and water. Synthesis of this component is concluded by aminomethylation via a Mannich reaction followed by reverse Michael loss of dimethylamine to give 27. The synthesis of (ipentosin (28) concludes by Michael addition of the amino group of 25 to the conjugated linkage of 27 [9].

OH (25)

(24)

•Me o (26)

.

+

(27)

27

—

r r P V C bHH

n

(28)

^ I T

130

Five-Membered Ring Benzofused Heterocycles

4. BENZISOXAZOLES A diuretic of the phenoxyacetic acid class is brocrinat (35). Its synthesis begins with FriedelCrafts acylation of resorcinol dimethyl ether (29) with 2-fluorobenzoyl chloride to give unsymmetrical benzophenone 30. The ortho-phenolic ether moiety is cleaved selectively in this acylation reaction. The product is converted predominantly to its E-oxime analogue (31) in the usual fashion and then acetylated (Ac2O) to its acetyl ester 32. This synthesis of the benzisoxazole ring concludes by NaH treatment leading to cyclization to 33 involving an internal displacement reaction. Metallation with n-BuLi followed by bromination produced 34. Ether cleavage with pyridine hydrobromide followed by alkylation with NaH and ethyl bromoacetate and hydrolysis lead to the oxyacetic acid containing brocrinat (35). [10].

(29)

(30)

(31)

^ (33) Br

(34) (34)

(35) (35)

The anticonvulsant activity of some 1,3-benzisoxazoles was discovered in routine testing. One of the more interesting of the subsequent analogues prepared was zonisamide (39). One of its syntheses starts with l,2-benzisoxazole-3-acetic acid (36) which is brominated and subsequently decarboxylated to give 37. Displacement of halogen in 37 with sodium bisulfite interestingly

Five-Membered Ring B enzofused Heterocycles

131

proceeds by reaction on sulfur to produce l,2-benzisoxazole-3-methane sulfonic acid (38). Chlorination of 38 with phosphorous oxychloride to the corresponding sulfonyl chloride followed by reaction with ammonia gives the sulfonamide, zonisamide (39) [11]. Alternate syntheses are available [12].

CH2CO2H

(36)

CH2Br

(37)

CH2SO3Na a

CH2SO2NH2

2 3

(38)

(39)

5. BEN2OXAZOLES Eclazolast (41) is an antiallergy compound which inhibits release of mediators of allergy. One reported synthesis involves the simple ester exchange of methyl 2-benzoxazolecarboxylate (40) with 2-ethoxyethanol catalyzed by sulfuric acid [13].

(40)

(41)

6. BENZIMIDAZOLES The last step in one reported preparation of the antiviral agent enviradene (43) involves dehydration of 6-(l-hydroxy-l-phenylpropyl)-2-amino-l-isopropylsulfonyl-benzimidazole (42). The Eproduct predominates [14]. Precedent for this chemistry and a description of related intermediates can be found in Volume 3, p. 177 of this work.

132

Five-Membered Ring Benzofused Heterocycles

SO2CHMe2

Me-^H

(42)

SC^CHMe,

(43)

Benzimidazoles bearing a carboxamide function at the 2-position have provided the nucleus for a significant n u m b e r of anthelmintic agents. (See Chapter 11 of V o l u m e 2 and Chapter 10 of V o l u m e 3 of The Organic

Chemistry

of Drug Synthesis

for examples.) T h e high rate at which

resistant strains of parasites have developed has led to the need for ever newer drugs. Preparation of dribendazole (46) begins by reaction of the acetate of 2,5-dinitroaniline with cyclohexylmethylthiol; the product from the unusual displacement of one of the nitro groups (45) is then reduced to the diamine. Reaction of this intermediate with N,N~dicarbomethoxy~§-methylthiourea leads to the cyclized product [15].

(44)

(45)

(46)

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of o-nitroaniline with £-fluorobenzoyl chloride, with ethylene glycol leads to acetal 48. Sequential reduction of the nitro group and cyclization of the resulting diamine (49) with N,N-dicarbomethoxy~S~methylthiourea gives the benzimidazole etibendazole (50) f 16].

v o (47)

(48); X = NO2 (49); X = NH2

(50)

Five-Membered Ring Benzofused Heterocycles

13 3

The discovery of the antiulcer activity of H2 antihistamine antagonists has revolutionized the treatment of that disease. A benzimidazole, Omeprazole (55), inhibits gastric secretion and subsequent ulcer formation by a quite different mechanism. Studies at the molecular level suggest that this compound inhibits K+/H+ dependent ATPase and consequently shuts down the proton pumping action of this enzyme system. Treatment of pyridyl carbinol 51 with thionyl chloride leads to the corresponding chloride (52). Treatment of that intermediate with 5-methoxy-2-mercaptobenzimidazole (53), obtained from reaction of 4-methoxy-o-phenylenediamine with potassium ethylxanthate leads to displacement of halogen and formation of the sulfide (54). Finally, oxidation with 3~chloroperbenzoic acid produces the sulfoxide omeprazole (55) [17]. OMc

(51);X = OH

H (53)

(»);x.a

(CA\, y,. .

(ls)|x = b

The rj-fluorobutyrophenone group is one of the hoary traditions in the field of antidopaminergic antipsychotic drugs. First introduced in the neuroleptic haloperidol, this group has appeared in numerous drugs or drugs-to-be. It is of interest that an isoxazole serves as a surrogate for the carbonyl group in some ]>fluorobutyrophenones. Alkylation of l-(4-piperidinyl)-2~ benzimidazolinone (57), an intermediate closely related to one used for domperidone (see Volume 3, p. 174) with 3-(3-chloropropyl)-6-fluoro-l,2-benzisoxazole (56) affords neflumozide (58) [18,19].

(56)

(57)

(58)

tf

134

Five-Membered Ring Benzofused Heterocycles 7. BENZOTHIAZOLE

Calcium channel antagonists have proven of great value as antianginal and antihypertensive agents. Most of these agents fall into one of three rather narrow structural classes. It is thus of interest to find that a structurally quite different benzothiazole shows the same type of activity. It is of note too that the agent in question, fostedil (63), is one of the very few phosphorous containing agents to be developed for the clinic. Treatment of benzanilide 59 with phosphorous pentasulfide or Lawesson's reagent gives thioamide 60. Oxidative ring formation by reaction with potassium ferricyanide and base (presumably involving a free radical intermediate) constructs the benzothiazole ring of 61. Bromination of this compound with N-bromosuccinimide produces bromomethyl intermediate 62. The synthesis of fostedil (63) concludes with a Michaelis-Arbuzov reaction of 62 with triethyl phosphite f20].

c

r

u x (59)

.

-

c

r u (60)

x

. O

(61); X = H (62); X = Br

(63)

Tiaramide (67) is a benzothiazolinone containing antiasthmatic agent. One of its syntheses begins with alkylation of 5~chloro-2-aminobenzothiazole (64) by 4-(2-hydroxyethyl)-l~ piperazinylcarbonylmethyl chloride (65) to give 66 and concludes by gentle hydrolysis with methanolic hydrogen chloride to convert the imino moiety to the carbonyl of tiaramide [21].

v

(64)

(65)

_

7 O H

Y r^ CH2CON N s ^ ^ V—/ OH (66); X = NH (67); X = O

Five-Membered Ring Benzofused Heterocycles

135

REFERENCES 1. A. M. Lefer, Drugs of the Future, 11, 197 (1986). 2. R. A. Johnson, E. G. Nidy, J. W. Aiken, N. J. Crittenden, and R. R. Gorman, J. Med. Chem., 29,1461 (1986). 3. M. A. Bertola, W. J. Quax, B. W. Robertson, A. F. Marx, C. J. Van der Laken, H. S. Koger, G. T. Phillips, and P. D. Watts, Eur. Pat. Appl. 233,656 (1987) via Chem. Abstr., 108: 20,548m (1987). 4. D. Frehel, R. Boigegrain, and J.-P. Maffrand, Heterocycles, 22, 1235 (1984). 5. Anon,, Belg. Pat. 766,392 (1971); via Chem. Abstr. 76: 140,493g (1972). 6. D. L. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Wiley, New York, 1980, Vol. 2, p. 355. 7. N. Gruenfeld, J. L. Stanton, A. ML Yuan, F. H. Ebetino, L. J. Browne, C. Glide, and C. F. Huebner, J. Med. Chem., 26, 1277 (1983). 8. C. J. Blankley, J. S. Kaltenbronn, D. E. DeJohn, A. Werner, L. R. Bennett, G. Bobowski, U. Krolls, D. R. Johnson, W. M. Pearlman, M. L. Hoefle, A. D. Essenburg, D. M. Cohen, and H. R. Kaplan, /. Med. Chem., 30, 992 (1987). 9. J. R. McCarthy, D. L. Trepanier, and M. E. Letourneau, Eur. Pat. Appl. 127,143 (1984) via Chem. Abstr., 102: 149,101r (1985). 10. G. M. Shutske, L. L. Setescak, R. C. Allen, L. Davis, R. C. Effland, K. Ranbom, J. M. Kitzen, J. C. Wilker, and W. J. Novick, Jr., /. Med. Chem,, 25, 36 (1982). 11. H. Uno, M. Kurokawa, Y. Masuda, and H. Nishimura, J. Med. Chem., 22,180 (1979). 12. H. Uno and M. Kurokawa, Chem. Pharm. Bull., 26, 3498 (1978). 13. R. E. Brown, V. St. Georgiev, and B. Loev, 17.5. Patent 4,298,742 (1981) via Chem. Abstr., 96: 68,972f (1981). 14. T. A. Crowell, U.S. Patent 4,424,362 (1984) via Chem. Abstr., 100: 121,077x (1984). 15. R. J. Gyurik and W. D. Kingsbury, U. S. Patent 4,258,198 (1981) via Chem. Abstr., 95: 7,284r(1981) 16. A. H. M. Raeymalkers and J. H. L. VanGelder, U.S. Patent 4,032,536 (1977) via Chem. Ator.,87:168,033h(1977). 17. P. Lindberg, P. Nordberg, T. Alminger, A. Braudstrom, and B. Wallmark, /. Med. Chem., 29, 1327 (1986). ! 8. U. K. Junggren and S. E. Sjostrand, Eur. Pat. Appl. 5,129 (1979); via Chem. Abstr. 92: 198,392z (1979). 1(). L. Davis and J. T. Klein, U.S. Patent 4,390,544 (1983); via Chem. Abstr. 99: 122,458r (1983).

136

Five-Membered Ring Benzofused Heterocycles

20. K. Yoshino, T. Kohno, T. Uno, T. Morita, and G. Tsukamota, J. Med. Chem., 29, 820 (1986). 21. T. Masuko, Jpn, Kokai 55/145,673 (1980); via Chem. Abstr. 94: 192,376n (1980).

8

Six-Membered Ring

Benzofused Heterocycles

1. CHROMONES The great commercial success of the adrenergic p-receptor blockers has led to the synthesis of many other potential drugs by the incorporation of an oxypropanolamine functionality into a wide variety of aromatic rings. This has lead to the preparation of thousands of such analogues. An example of this is flavodilol (3), an antihypertensive agent, which is synthesized using chemistry standard for the purpose by starting with 7-hydroxyflavone (1). The side chain scaffolding is assembled by reaction with epichlorohydrin to give glycidylether 2 and this is in turn reacted with propylamine to giveflavodilol(3) 11]. Surprisingly, flavodilol does not block the effects of norepinephrine at either adrenergic a or p receptors, despite its formal structural similarity to the classical p-bloekers.

CH2CH2Mc

The attractive properties of cromolyn as an inhibitor of the release of mediators of anaphylaxis has inspired many attempts to improve on the antiasthmatic characteristics of that substance. One such agent is cromitrile (6). In this case, a tetrazolyl unit is introduced as a carboxy group 137

Six-Membered Ring Benzofused Heterocycles

138

bioisostere and the two aromatic ring systems are different from one another. One synthesis concludes in the classic manner by converting chromone ester 4 to the carboxamide (5) by ammonolysis, dehydrating the latter functionality to the nitrile with tosyl chloride in pyridine and adding sodium azide selectively across this functionality to produce the antiasthmatic agent cromitrile (6) [2], The chemical basis for the selectivity of the last reaction is not obvious.

NC (4); X = OEt (5); X = NH2

(6)

2. BENZODIOXANES Azaloxan (12) is an antidepressant agent. Its synthesis can be accomplished starting with the reaction of catechol (7) and 3,4-dibromobutyronitrile (obtained by addition of bromine to the olefin) to give l,4-benzodioxan-2-ylacetonitrile (8). A series of functional group transformations ensues [hydrolysis to the acid (9), reduction to the alcohol (10) and conversion to a tosylate (11)] culminating in an SN-2 displacement reaction on tosylate 11 with l~(4~piperidinyl)-2"-imidazolidinone to give azaloxan (12) [3].

S

OH

(7)

(8); X = CN (9); X = CO2H U0);X = CH2OH (11); X = CH2OTos

Six-Membered Ring Benzofused Heterocycles

139

3. QUINOLINES AND CARBOSTYRILS A partially reduced quinoline derivative with antiulcerative and antisecretory activities is isotiquimide (14). It may be synthesized by metallating (with n-BuLi) 4-methyl-5,6,7,8-tetrahydroquinoline and condensing this with dimethylmethoxysilylisothiocyanate to produce the desired thioamide isotiquimide (14) [4]. N { ^ Me (13) Losulazine (20) is an orally and parenterally active antihypertensive agent apparently acting on peripheral postganglionic sympathetic nerve terminals to deplete norcpinephrine stores. This prevents vasoconstriction by reducing levels of that neurotransmitter available following stimulation of adrenergic nerves. In this sense its calming action mimics that of reserpine. In a convergent synthesis, 4-nitrobenzoyl chloride (15) is used to monoacylate piperazine to give amide 16; the nitro moiety of this is then reduced to give substituted aniline synthon 17. A nucleophilic aromatic displacement reaction between 17 and 4~chloro-7-trifluoromethylquinoline (18) leads to 4-aminoquinoline derivative 19. The synthesis of losulazine concludes by formation of the sulfonamide (20) by reaction of the remaining secondary piperazine nitrogen with 4-fluorobenzenesulfonyl chloride [5J.

(16); X = 2 (17); X = NH2

(18)

CON NR

Six-Membered Ring Benzofused Heterocycles

140

The continuing development of resistant strains by the malaria parasite to chemotherapeutic agents has led to an ongoing, though sporadic, synthesis of new chemical entities aimed at that target in the hope of finding drugs which will overcome resistance. That there is still interest in the classical 4-aminoquinolines (see The Organic Chemistry of Drug Synthesis, Volume 1, p. 343) is attested to by the preparation of tebuquine (23), a hybrid compound combining structural elements of amodiaquine and some 2-(dialkylamino)-o~cresols which have shown antimalarial activity. The synthesis is closely analogous to the original method used for amodiaquine. It starts by reacting 4'-chloro-N-(6-hydroxyl[l,l'-biphenyl]-3-yl) acetamide (21) with formaldehyde and tbutylamine in an aromatic version of the Mannich reaction to give acetanilide 22. Hydrolysis to the free aniline with HC1 is followed by the standard nucleophilic aromatic displacement reaction with 4,7-dichloroquinoline to complete the synthesis of the antimalarial agent tebuquine (23) |6].

CH 2 NUCMc 3 OH

ACN:

AcNI(21)

(22)

P r o c a t e r o l (27) is a p - a d r e n e r g i c a g o n i s t w i t h b r o n c h o d i l a t o r y action i n t e n d e d for u s e in b r o n c h i a l a s t h m a . A c a r b o s t y r i l N H g r o u p i n t h i s m o l e c u l e is u s e d a s p a r t o f a b i o i s o s t e r e r e p l a c i n g t h e c a t e c h o l m o i e t y o f e p i n e p h r i n e . P h a r m a c o l o g i c a l l y it i s o f s p e c i a l i n t e r e s t i n t h a t it i s s a i d t o selectively stimulate adrenergic P-2 receptors w i t h o u t m u c h effect o n p-1 receptors, m i n i m i z i n g cardiac stimulation. Friedel-Crafts reaction between 8-hydroxycarbostyril (24) and 2b r o m o b u t y r y l b r o m i d e l e a d s t o t h e e x p e c t e d a c y l a t i o n at C - 5 i n t h e m o r e a c t i v a t e d ring ( 2 5 ) . H a l i d e d i s p l a c e m e n t w i t h i s o p r o p y l a m i n e (to g i v e 2 6 ) is f o l l o w e d b y b o r o h y d r i d e r e d u c t i o n to the m i x t u r e o f d i a s t e r e o i s o m e r i c a r y l e t h a n o l a m i n e s . T h e e r y t h r o - i s o m e r is p r o c a t e r o l ( 2 7 ) [ 7 ] .

Six-Membered Ring Benzofused Heterocycles

141 NHCHMe2

OH (24)

OH (26)

4. Q U I N O L O N E S Intense synthetic activity has resulted centered about congeners of the quinolone-3-carboxylic acids w h e n it was found that certain analogues, notably those with 6-fluoro~7~piperazinyl moieties (now k n o w n collectively as the fluoroquinolones) possess broad spectrum oral antimicrobial activity with potencies in the range of fermentation-derived antibiotics. Additional interest in these molecules was inspired by the discovery of their unusual molecular m o d e of action; strongly selective inhibition of the action of bacterial D N A gyrase, a type II (double strand D N A breaking) topoisomerase essential for dictating the conformation of bacterial circular D N A . The activity of D N A gyrase is essential for the orderly processing of D N A as several important enzymes are sensitive to the topological arrangement of the molecule. Several thousand furoquinolone analogues have been prepared and several (including norfloxacin, ciprofloxacin, and ofloxacin) have been introduced clinically and several others are advancing toward commercial use. Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic e n z y m e s in vivo. It has been launched in France for the treatment of a n u m b e r of infections including those caused by sensitive strains of Pseudomonas

aeruginosa.

It can be syn-

thesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes

Six-Membered Ring Benzofused Heterocycles

142

thermal cyclization to hydroxyquinoline ester 30. Despite the apparent asymmetric substitution pattern of 29 which might lead one to believe that mixtures would result from the pericyclic reaction, only one product is observed in any quantity. It is rationalized that the buttressing effect of the aryl chlorine atom is the cause of the observed steric preference. Next, alkylation on nitrogen with EtI leads to quinolone ester 31 which is itself readily hydrolyzed to the corresponding carboxylic acid 32. A nucleophilic aromatic displacement reaction of the 7-chloro moiety, activated by the pyridone carbonyl as a sort of vinylogous acid chloride, with N-methylpiperazine completes a synthesis of pefloxacin (33). This synthetic sequence is the classic route to this series of antimicrobial agents [8]. CO^El

(31), RsEt (32), R=H

(33)

O n e of the most promising newer members of the fluoroquinolone family is ofloxacin (40). In this case, the N~ethyl moiety has been m a d e rigid by incorporation into a heterocyclic ring. This creates a chiral center and subsequent chiral synthesis reveals that the S-enantiomer is significantly m o r e potent than its antipode and is rather more water soluble than the racemate. Of the various syntheses of ofloxacin, the more recent chiral process is illustrated. Starting with ethyl (2,3,4,5tetrafluoro)-3-oxopropionate (34), the ethoxymethylene function is introduced by cross condensation with ethylorthoformate and acetic anhydride to give 3 5 . Alaninol, prepared by reduction of optically active alanine, is incorporated in an addition-elimination reaction to give 36. Treatment of the latter with non-nucleophilic base leads to a nucleophilic aromatic displacement of fluorine and thus ring closure to give 37. T h e geometry of 3 6 appears to be unimportant as it is lost in the intermediate anion. Condensation, of course, depends upon proximity. Repetition of the base

Six-Membered Ring Benzofused Heterocycles

143

treatment and/or use of forcing conditions leads to a second displacement of aromatic fluorine and the closure of the second heterocyclic ring of 38. The remainder of the sequence follows the standard quinolone synthetic route in which saponification (to 39) and nucleophilic aromatic displacement with N-methylpiperazine leads to ofloxacin (40). The chirality of the alanine derivative employed dictates the stereochemistry of the final product [9,10,11].

(34)

(35)

U

F X^OH Me (37>

-^Mc

(38);Rs=Et (39);R = H

(36)

McN^J

VMe

(40)

JJ ~

Et (41)

Norfloxacin (41), the substance which triggered this avalanche of activity, has recently been introduced into clinical practice in the United States. Its synthesis parallels closely that of its Nmethyl analogue, pefloxacin, except that the nucleophilic aromatic displacement reaction of 32 is carried out with mono-N-carboethoxypiperazine instead and the final step encompasses deblocking of this carbamoyl ester moiety [8]. The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-l substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-l is an aromatic ring. The synthe-

Six-Membered Ring Benzofused Heterocycles

144

sis of difloxacin begins with 2,4-dichloro-5-fluoroacetophenone (42) which is carbethoxylated by reaction with diethyl carbonate and base to give ester 43. The rest of the synthesis parallels that described above for ofloxacin except that the addition-elimination reaction is carried out with 4fluoroaniline and 44 is the resulting product after cyclization and hydrolysis. Conclusion of the synthesis of difloxacin (45) involves displacement of the activated 7-chloro atom by Nmethylpiperazine [12]. CCXH

(44)

(45) Amifloxacin (48) demonstrates that the methylene group of the N-ethyl substituent can be replaced successfully by a bioisosteric N H group in the fluoroquinolone series. In one of two interesting syntheses, 4-hydroxyquinoline ester 4 6 is reacted with O-(2,4-dinitrophenyl)hydroxylamine with the aid of potassium carbonate to give the hydrazine analogue 47. Next, N-formylation is accomplished with aceticformic anhydride (formed in situ by reaction of A c 2 O + H C O 2 H ) . T h e formamide thus produced is methylated with iodomethane and base. This sequence allows for clean monoalkylation. T h e N-formyl group is hydrolyzed with N a O H and N-methylpiperazine displacement of the activated C-7 chloro atom completes the synthesis of amifloxacin (48) [13].

o COoEt

CO2Et

(46)

(47)

CO2H

(48)

Six-Membered Ring Benzofused Heterocycles

145

Alternately, amifloxacin can be prepared via the ofloxacin/difloxacin route using an additionelimination reaction with unsymmetrical N-methyl-N-formyl hydrazone to give 49 [14].

(48)

Enoxacin (58) is an analogue of the quinolones based on the 1,8-naphthyridine ring system. The drug is available commercially in Japan. The naphthyridine analogues of the fluoroquinolones, generally speaking, are not as potent as the quinolones in vitro but have favorable pharmacokinetic characteristics which help compensate for this in vivo. The synthesis of enoxacin begins by reaction of 2,6-dichloro-3-nitropyridine (50) with N-carboethoxypiperazine to give 51. The second, less reactive, halo group is then displaced with ammonia, and the resulting amine acetylated to 52, the nitro group is then reduced to give triaminopyridine derivative 53. Diazotization to 54 with sodium nitrite plus tetrafluoroboric acid, followed by heating in xylene, results in displacement of the diazonium salt by fluorine to give 55. The rest of the synthesis follows the well trodden path of acid hydrolysis followed by Gould-Jacobs reaction to 56. The alternate ortho-closure onto pyridine nitrogen does not take place presumably due to the steric interference by the piperazinyl group at C-7. Sequential hydrolyses to 57 and then 58 concludes the synthesis of enoxacin [15,16|. O2R EtOCON^ (50)

EtOCON^ 51

<>

(52);X = O (53);X = H OH

(54); X = N2 (55);X = F

(56)

(57); X = CO2Et (58);X = H

Six-Membered Ring Benzofused Heterocycles

146 5. TETRAHYDROISOQUINOLINES

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahydroisoquinoline analogue, nomifensine (60), departs from this structural pattern. Pharmacologically it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. NH-

NH-

NMe

N ' Mc

(59)

(60)

Given the well-established structural forgiveness available among angiotensin-converting enzyme (ACE) inhibitors, it is not surprising to find a tetrahydroisoquinoline analogue represented. Quinapril (64) is synthesized from the t-butyl ester of tetrahydroisoquinoline-3-carboxylic acid (61) by amide formation with 62 using mixed ester methodology. Subsequent partial deblocking of 63 upon acid treatment leads to quinapril (64) [18]. This is by now a familiar reaction sequence for construction of molecules in this class. J»CO2CMe3

(61)

,-CO2El (62)

(63);R (64); R = H

6. BENZAZEPINES Trepipam (69) is a sedative agent apparently acting via dopaminergic mechanisms. It can be synthesized by attack on the less hindered terminus of styrene oxide (66) by 4,5-dimethoxyphenethylamine (65) to give 67. Cyclodehydration catalyzed by strong acid then leads to 68 and N-

Six-Membered Ring Benzofused Heterocycles

147

methylation with formic acid and formaldehyde (Eschweiler-Clarke reaction) completes the synthesis of trepipam (69) [19].

(65)

(66)

(67)

(68);X = (69); X = Me

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are associated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of this last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Deaikylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9N HC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21].

OH (76)

Six-Membered Ring Benzofused Heterocycles

148 7. BENZOTHIEPINS

Enolicam (81) is a nonsteroidal antiinflammatory agent which may be viewed as a higher homologue of compounds in the pyroxicam series (see The Organic Chemistry of Drug Synthesis, Volume 2, p. 394). It is intended for use in the treatment of psoriasis and arthritis. It is active both orally and topically. Oxidation of 7-chlorotetrahydro-l-benzothiepen-5-one (77) with hydrogen peroxide leads to the sulfone 78. This is converted to the pyrrolidine enamine (79) using tosic acid as catalyst and this is then reacted at its electron rich center with 3,4-dichlorophenylisocyan~ ate to give amide 80. The synthesis concludes with hydrolysis of the enamine function with HC1 to produce enolicam (81). Enolicam is sufficiently acidic to be used primarily as its sodium salt [22].

(80)

(81)

8. QUINAZOLINES AND QUINAZOLINONES Doxazosin (84) is an adrenergic postsynaptic oc-1 receptor antagonist with antihypertensive properties. The discerning eye will recognize a structural resemblance to the antihypertensive quinazoline prazosin, also an a-1 receptor antagonist. Doxazosin was produced in an attempt to develop agents which could be administered once daily to combat hypertension. It is synthesized by reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline (82) with (l,4-benzodioxan-2-ylcarbonyl)piperazine (83) in an addition-elimination sequence leading to 84 [23].

Six-Membered Ring Benzofused Heterocycles

149

J

V

O

I

M< (82)

(84)

(83)

Trimetrexate (88) is an antineoplastic agent related to the well-established folic acid antimetabolite methotrexate. It can be synthesized by selective diazotization of the most basic ami no group of 2,4,6-triamino~5-methylquinazoline (85) followed by a Sandmeyer displacement with C u C N to give nitrile 8 6 . Careful reduction using Raney nickel produces the aminomethyl intermediate 87 or, if the reaction is carried out in the presence of 3,4,5-trimethoxyaniline, t r i m e t r e x a t e (88) [24]. O n e presumes that that outcome is a consequence of amine exchange at the partially reduced i m i n e stage and further reduction.

HUN OMc (88)

Alfuzosin (91) is a p r a z o s i n - l i k e hypotensive adrenergic ot-1 receptor blocker with the special structural feature that two carbons have been excised conceptually from the piperazine ring normally present in this series. Following the usual sequence for this series, reaction of 4-amino-2chloro-7-dimethoxyquinazoline (89) with the tetrahydro-2-furyl amide of 3-methylaminopropylamine (90) gives alfuzosin (91) [25]. Alfuzosin is claimed to cause less orthostatic hypotention (dizziness or fainting upon sudden rising) than prazosin.

150

Six-Membered Ring Benzofused Heterocycles

MeNHCH2CH2CH2NHCO—£ > (89)

2

-NC NH2 (91)

The quinazolinone-containing antiallergic agent tiacrilast (95) has many of the pharmacological properties of the mediator release inhibitor cromolyn sodium for treatment of bronchoconstriction and seems in animal models to be orally active as well. Its structure embodies a molecular simplification (molecular dissection strategm) of a lead series of pyrido[2,l-b|quinazolinecarboxylic acids. It is synthesized in straightforward fashion by reacting 5-methylthioanthranilic acid (92) with formamide to form the quinoxalone ring of 93. This is then subjected to an additionelimination reaction with E~3-chloroacrylate to give methyl ester 94 which itself is then hydrolyzed to produce tiacrilast (95) [26],

(92)

(93)

(94);R = Me (95); R = H

Fluproquazone (97) contains a 2-quinazolinone nucleus and is found to be an analgetic agent useful in mild to moderate pain. One of the preparations involves reaction of 2-isopropylamino-4methyl-4'-fluoro-benzophenone (96) with potassium cyanate in hot acetic acid [27].

Six-Membered Ring Benzofused Heterocycles

151

Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28].

S=C=NCH2CH2N~y— COs

C02Me (98)

(99)

T /\ fQ-c ,NCH2CH2NV~CO (100)

9. PHTHALAZINES Oxagrelate (104) is of interest as a platelet antiaggretory agent and is thus of potential value in preventing thrombus formation in blood vessels. It may also be of potential value in preventing arteriosclerotic lesions in coronary arteries - a substantial cause of morbidity and mortality in

Six-Membered Ring Benzofused Heterocycles

152

western countries. It is synthesized by reacting 4-ethoxycarbonyl~5-methylphthalic anhydride (101) (itself derived from the Diels-Alder product of dimethylacetylenedicarboxylate and ethyl isodehydroacetate) with excess malonic acid in pyridine to give phthalide 102; the reaction apparently proceeds by attack of malonate on the more electrophilic carbonyl group. The methyl group introduced into 101 is the remnant of the malonic acid moiety after decarboxylation. Oxidation of of the newly introduced methyl group of 102 with aqueous permanganate produces the keto acid; this is converted to the phthalazine carboxylic acid with hydrazine and that esterified to 103. Treatment of this last with sodium borohydride completes the synthesis of oxagrelate [29]. CO2Et

(101)

(102)

(103)

(104) Azelastine (107) is an antiallergic/antiasthmatic agent prepared from 4~chlorobenzyl~2'-carboxyphenylketone (105) by condensation with hydrazine to give the phthalazinone (106) followed by reaction of the sodium salt of this last with 2-(2-chloroethyl)-N-methylpyrrolidine (presumably involving nucleophilic ring expansion of the bicyclic quaternary salt putatively formed as a first product) to complete the synthesis [30].

(105)

(106)

(107)

Six-Membered Ring Benzofused Heterocycles

153

10. BENZODIAZEPINES That once well-represented class of compounds, the benzodiazepine anxiolytic agents, has declined precipitously in numbers in consecutive volumes of this series. Preparation of the sole classical representative in the present volume starts with the preformed 7~chloro-5-(ochlorophenyl)-2,3-dihydro~lH~l,4-benzodiazepine (108) (see The Organic Chemistry of Drug Synthesis, Volume 1, page 369). Condensation of that with 2-chloroacetylisocyanate proceeds on the more basic nitrogen of 108 to afford urea 109. Reaction of that with sodium iodide and base probably proceeds initially by halogen exchange of iodine for chlorine (Finkelstein reaction). Subsequent replacement of iodide by the enol anion of the urea oxygen results in formation of the oxazolone ring. There is thus obtained reclazepam (110) [31].

(108)

(109)

(110)

REFERENCES 1. E. S. C. Wu, Eur. Pat. Appl, 81,621 (1983) via Chem. Abstr., 99: 139,772r (1983). 2. J. W. Spicer and B. T. Warren, U. S. Patent 4,238,495 (1980) via Chem. Abstr., 94: 139,623q (1980). 3. C. F. Huebner, U. S. Patent 4,329,348 (1982) via Chem. Abstr., 97: 92,295d (1982). 4. R. Crossley, Brit. Pat. Appl. 2,122,615 (1984) via Chem. Abstr., 100: 191,753p (1984). 5. J. M. McCall, U. S. Patent 4,167,567 (1979) via Chem. Abstr., 92: 6,555f (1980). 6. L. M. Werbel, P. D. Cook, E. F. Elslager, J. H. Hung, J. L. Johnson, S. J. Kesten, D. J. McNamara, D. F. Ortwein, and D. F. Worth, J. Med. Chem., 29, 924 (1986).

154

Six-Membered Ring Benzofused Heterocycles

7. S. Yoshizaki, K. Tanimura, S. Tamada, Y. Yabuuchi, and K. Nakagawa, /. Med. Chem., 79,1138(1976). 8. H. Koga, A. Itoh, S. Murayama, S. Suzue, and T. Irikura, /. Med. Chem., 23,1358 (1980). 9. H. Egawa, T. Miyamoto, and J.-I. Matsumoto, Chem. Pharm. Bull, 34,4098 (1986). 10. I. Hayakowa, T. Hiramitsu, and Y. Tanaka, Chem. Pharm. Bull, 32,4907 (1984). 1L L. A. Mitscher, P. N. Sharma, L. L. Shen, and D. T. W. Chu, /. Med. Chem., 31, 2283 (1988). 12. D. T. W. Chu, P. B. Fernandes, A. K. Claiborne, E. Pihuleac, C. W. Nordeen, R. E. Maleczke, Jr., and A. G. Pernet,./. Med. Chem., 28, 1558 (1985). 13. M. P. Wentland, D. M. Bailey, J. B, Cornett, R. A. Dobson, R. G. Powles, and R. B. Wagner, J. Med. Chem., 27,1103 (1984). 14. D. T. W. Chu, /. Heterocycl. Chem., 22, 1033 (1985). 15. J.-I. Matsumoto, T. Miyamoto, A. Minamida, Y. Nishimura, H. Egawa, and H. Nishimura, J. Heterocycl. Chem., 21, 673 (1984). 16. J.-I Matsumoto, T. Miyamoto, A. Minamida, Y. Nishimura, H. Egawa, and H. Nishimura, J. Med. Chem., 27, 292 (1984). 17. E. Zara-Kaczian, L. Gyorgy, G. Deak, A. Seregi, and M. Doda, /. Med. Chem., 29, 1189 (1986). 18. S. Klutchko, C. J. Blankley, R. W. Fleming, J. M. Hinkley, A. E. Werner, I. Nordin, A. Holmes, M. L, Hoefle, D. M. Cohen, A. D. Essenburg, 'and H. R. Kaplan, J. Med. Chem., 29, 1953 (1986). 19. C. Kaiser, P. A. Dandridge, E. Garvey, R. A. Hahn, H. M. Sarau, P. E. Setler, L. S. Bass and J. Clardy, J. Med. Chem., 25, 697 (1982). 20. J. Weinstock, D. L. Ladd, J. W. Wilson, C. K. Brush, N. C. F. Yin, G. Gallagher, Jr., M. E. McCarthy, J. Silvestri, H. M. Saran, K. E. Flaim, D. M. Ackerman, P. E. Setler, A. J. Tobia, and R. A. Hahn, /. Med. Chem., 29, 2315 (1986). 21. J. Weinstock, J. W. Wilson, D. L. Ladd, C. K. Brush, F. R. Pfeiffer, G. Y. Juo, K. G. Holden, N. C. F. Yin, R. A. Hahn, J. R. Wardell, Jr., A. J. Tobia, P. E. Setler, H. M. Saran, and P. T. Ridley, J. Med. Chem., 23,973 (1980). 22. M. H. Rosen, US. Patent 4,185,109 (1980) via Chem. Abstr., 93:46,451w (1980). 23. S. F. Campbell, M. J. Davey, J. D. Hardstone, B. N. Lewis, and M. J. Palmer, /. Med. Chem., 30,49 (1987). 24. E. F. Elslager and L. M. Werbel, Brit. Pat. Appl. 1,345,502 (1973) via Chem. Abstr., 80: 133,461z (1974). 25. P. M. Manoury, J. L. Binet, A. P. Damas, F. Lefevre-Borg, and I. Cavero, J. Med. Chem., 29, 19 (1986).

Six-Membered Ring Benzofused Heterocycles

155

26. R. A. LeMahieu, M. Carson, W. C. Nason, D. R. Paixish, A. F. Welton, H. W. Baruth, and B. Yaremko, /. Med. Chem., 26,420 (1983). 27. G. E. Hardtmann, US. Patent 3,937,705 (1976) via Chem. Abstr., 84: 135,716t (1976). 28. V. Aguirre Ormaza, Span. 548,966 (1986) via Chem. Abstr., 106: 84,630y (1986). 29. M. Ishikawa, Y. Eguchi, and A. Sugimoto, Chem. Pharm. Bull, 28, 2770 (1980). 30. K. Tasaka and M. Akagi, Arzneim.-Forsch., 29,488 (1979). 31. P. K. Yonan, US. Patent 4,208,327 (1980) via Chem. Abstr., 94: 30,804y (1980).

9

Bicyclic Fused

Heterocycles

A large number of benzo-fused heterocyclic nuclei are of course possible in theory. This number is, however, dwarfed by the structural possibilities brought into play by fusing two heterocyclic rings. A large number of such structures have in fact been synthesized in the search for therapeutic agents. Part of the impetus probably comes from the fact that half the bases involved in genetic material, the purines, in fact consist of fused heterocycles, specifically imidazo[l,2-a]~ pyrimidines. Another motivation comes from the fact that the large number of structural possibilities opens the way for good patent exclusivity. 1. INDOLIZINES Aminoalkyl ethers of 3-benzoyl benzofurans such as amiodarone have been found to be very effective antiarrhythmie agents. Biological activity is retained when the heterocyclic nucleus is replaced by the nearly isosteric indolizine system. Reaction of 2-picoline (1) with ethyl chloroacetate leads to the acyl pyridinium salt 2; reaction of that with propionic anhydride leads to the indolizine 4, possibly via intermediate 3 (Chichibabin synthesis). Friedel-Crafts acylation of 4 with the 2-toluenesulfonate ester of rj-hydroxybenzoyl chloride gives the ketone 5. The rj-toluenesulfonate protecting group is then removed by saponification. Treatment of the resulting phenol 6 with 1,3dibromopropane and dibutylamine gives the antiarrhythmie agent butoprozine (7) [1]. 2. PYRROLIZINES Incorporation of the 2-aryl-2-methylacetic acid moiety characteristic of NSAID's as part of 157

Bicyclic Fused Heterocycles

158

a fused heterocyclic ring is consistent with good activity. A number of syntheses have been described for compounds in the anirolac series [2,3,4]. One of the more interesting preparations starts by acylation of 2-(methylthio)pyrrole 8 with anisoyl chloride (9). Oxidation of the product 10 with peracid leads to the sulfone 11. The nitrogen anion obtained from treatment of 11 with

Me V

(1)

B

o

(2)

OCH2C H2CH2N(C4H9)2 (7)

(5);R==u-CH3C6H4SO2 (6);R = H

(4)

base is then allowed to react with the Meldrum ester 12. Attack of the anion on the cyclopropyl carbon leads to ring opening and formation of the alkylation product 13. It was found empirically that the next step proceeds in better yield with a methyl ester; this intermediate (14) is obtained by ester interchange with methanol. T h e anion from malonate 14 then displaces the pyrrole sulfone group to give the cyclization product 15. Saponification, followed by decarboxylation of the resulting diacid, affords anirolac (16) [3,4].

3. C Y C L O P E N T A P Y R R O L E S T h e majority of e n d o g e n o u s prostaglandins tend to exert undesirable effects on the cardiovascular system. T h e s e c o m p o u n d s as a rule tend to cause vasoconstriction and promote platelet aggrega-

Bicyclic Fused Heterocycles

159

tion. An important exception to this trend is the last prostaglandin derivative to be discovered, PGI2, or prostacyclin, (epoprostenol, 24). Use of this compound in therapy is severely limited by its short biological half-life, which is measured in minutes. It has been found that compounds in which the ring containing the enol ether function is replaced by some more stable ring system retain a considerable portion of the activity of the endogenous compound. The starting material for an analogue in which that ring is replaced by a pyrrole, PGF2a (17), is interestingly the natural precursor for 24 as well. Treatment of PGF2a methyl ester (18) with base and iodine, gives COCl ^N>-SMe + H (8)

CH2CH2CH(CO2Mc)2 (14) (13)

McO CO2Me

C02H

CO2Me (15)

(16)

the iodolactonization product 19. Regiochemistry is controlled by the close approach which is

Bicyclic Fused Heterocycles

160

possible between the ring hydroxyl and the isolated olefin. The remaining free hydroxyl groups are then protected as their tetrahydropyranyl ethers (20). Dehydroiodination with DBN, followed by hydrolysis and then by oxidation of the C-9 hydroxyl group gives diketone 21. Condensation of 1,4 diketones with secondary amines is one of the classical methods for forming pyrroles. Reaction of 21 with aniline thus proceeds to give the highly substituted pyrrole 22. Saponification of the ester and removal of the tetrahydropyranyl groups completes the preparation of the antiasthmatic agent piriprost (23) [5].

CO2Mc

THPd

6THP

6THP

(21)

(22)

H0 2 C

6H

(23)

(24)

Bicyclic Fused Heterocycles

161

4. IMIDAZOPYRIDINES The continuing search for effective platelet aggregation inhibitors has covered a wide variety of structural types. One such candidate consists of a fatty acid chain attached to a fused heterocycle. (A somewhat fanciful relation to 24 can be imagined.) Reduction of cyanopicoline 25 leads to the primary amine 26; treatment of the corresponding formamide 27, with phosphorous oxychlonde results in cyclodehydration and formation of the imidazo[l,5-a]pyridine 28. The pendant methyl group readily forms an organometallic derivative with n-butyllithium. Treatment of that with the orthoester from 6-bromohexanoic acid gives the alkylation product 30. Hydrolytic removal of the orthoester grouping, leads to pirmagrel (31) [61.

.CN

CH2NH2

Me

Me

(25)

(26)

CH2NHCH Me

Me (27)

CH2(CH2)3CH2C(OEt)3 (30)

(28)

CH2Li (29)

T h e derivative from an isomeric fused system has been described as a sedative-hypnotic c o m p o u n d . T h e synthesis starts by condensation of the aminopicoline 32 with the haloketone 33. T h e resulting pyrrolo[l,2-a]pyridine 34 then undergoes a Mannich reaction with formaldehyde and dimethylamine to give the aminomethylated derivative 3 5 . After quaternization of the dim e t h y l a m i n o group in 3 5 with methyl iodide, the a m m o n i u m group is displaced by cyanide to

162

Bicyclic Fused Heterocycles

produce 36. Standard conversion of the nitrile to the amide concludes the synthesis of zolpidem (37) [7]. Selected modified pyrimidines which are closely related to nucleotides have, as noted in Chapter 6, shown therapeutic utility as antiviral and/or antineoplastic agents. Much the same rationale has been used to support the synthesis of compounds related to the purine nucleotides. An analogue of guanine which lacks one of the ring nitrogens, dezaguanine, (47) is, for example, used as an antineoplastic agent. Nitrosation of dimethyl acetone dicarboxylate (38) with nitrous acid gives the derivative 39. This is then reduced to the amine 40. Treatment of the latter with potassium thiocyanate leads initially to addition of the thiocyanate group to the amine to give the thiourea 41. That newly formed function, or more likely an intermediate toward its formation,

"xx

NH 2

(32)

(33)

(35) Me (37)

(34)

(36)

Bicyclic Fused Heterocycles

163

condenses intramolecularly with the ketone. There is thus obtained the imidazolethione 42. Ammonolysis proceeds preferentially at the ester on the longer chain to give 43. Treatment of 43 with Raney nickel gives imidazole 44. Exposure of that compound to phosphorus oxychloride serves to convert the amide to the nitrile 45. Exposure of the ester-nitrile to liquid ammonia leads to the amide 46, which is cyclized with sodium carbonate. There is thus obtained dezaguanine, (47) [8]. The narrow therapeutic range of digitalis related cardiotonic agents has resulted in an extensive effort to identify compounds in other structural classes which will improve cardiac function. The discovery of the heterocyclic cardiotonic drug, amrinone, led to research on other heterocyclic compounds for that indication. The imidazopyridine, isomazole (57), is representaCH2CO2Mc ^CH2CO2Mc

(38)

CH2CO2Me

CH2CO2Mc 0=< CHCO2Mc

^ CHCO2Me

NO

NH 2

(39)

(40)

CH2CO2Me

H2NCNH S (44)

(41)

MeO2< (45)

(46)

(47)

Bicyclic Fused Heterocycles

164

tive of some of the newer active compounds. Alkylation of the phenolic ester derivative 48 proceeds selectively at the least hindered phenol to give the monobenzyl ether 49. Methylation of the free hydroxyl group (50), followed by removal of the benzyl group by hydrogenolysis gives the phenol 51. This intermediate is then acylated with dimethylthioforrnamidoyl chloride to afford the thiocarbamate 52. This compound, on heating, undergoes an O to § migration of the aryl group to afford the product of replacement of aromatic oxygen by sulfur (53). Removal of the acyl group with aqueous base (54) is followed by methylation of both the thiophenol group and the benzoic acid. Hydrolysis of the methyl ester then gives the benzoic acid 55. Reaction of the carboxyl function with the amino groups in 56, leads to the formation of an imidazole ring. Oxidation of the sulfide moiety to the sulfoxide by MCPBA at low temperature gives isomazole (57) |9]. CO2Me

(48);R = H (49);R = CH2C6H5

CO2Me

CO>Mc

Mc<X

(50); R = CH2C6H5 (51);RSH

CO2H

MeO.

CO2Me

NH, NH, (56) O II SMe

(57)

Bicyclic Fused Heterocycles

165

5. PURINEDIONES The purinedione, theophylline (64) has been the mainstay for the treatment of asthma for the better part of a century. Few other drugs rival theophylline for its efficacy as a bronchodilating agent. This drug is, however, noted for its very narrow therapeutic window. Blood levels associated with efficacy range between 10 and 20 mcg/mL; toxic effects start to be seen when those blood levels exceed 25 mcg/mL. A considerable amount of research has thus been devoted to preparing analogues in the hopes of developing a safer agent. The synthesis of one such agent involves a variation on the classical method for the construction of purinones. Condensation of n-propylurea 58 with cyanoacetic acid gives product 59. Treatment of that intermediate with aqueous base leads to addition of urea nitrogen to the nitrile group and consequent formation of the aminouracil 60. Treatment with nitrous acid leads to nitrosation at the only open position on the ring (61); reduction of the newly introduced nitroso group leads to the 1,2 diamine 62. The required remaining carbon atom is then introduced by reaction with formic acid followed by cyclization with sodium hydroxide; there is thus obtained enprofylline (63) [10]. A somewhat more complex theophylline derivative includes both the purinone nucleus and a piperazine side chain more commonly associated with HI antihistaminic compounds. The starting epoxide, 66, is available from treatment of the anion of purinone 65 with epichlorohydrin. Alkylation of the epoxide with monosubstituted piperazine derivative 67, leads to tazifylline (68) [11]. 6. PURINES The deoxyguanine analogue of acyclovir, apparently retains the antiviral activity of the parent compound. Preparation of that agent starts by acylation of the amino group on purine 69. Treatment of that with diacetate 71 under typical glycosidation conditions leads to displacement of the reactive acetal acetate by imidazole nitrogen and the formation of the intermediate 72; removal of the acetate protecting groups with aqueous base affords desciclovir (73) [12]. Preparation of the coccidiostat arprinocid (80) starts by protection of two of the three amino groups on the pyrimidine 74; thus, reaction of 74 with thionyl chloride leads to reaction of

166 O

HN

H-C3H7NHCNH2 + HOCCH2CN (58)

Me (64) Me]

NH nC -H 37 (59)

HNT EC -IH 37 (63) H N NC ( HS 3)2~ (67)

Bicyclic Fused Heterocycels O

k

n-c3H7 (60)

oVNR HN N NH

2 n c H 3 7 (61); R a O (62); R = H2

O H C H C H H N C (H S3)-2 2C 2 N M e (68)

(65);R = (66)R

M C cO C H C H O C H O C O M e (71)

XX) R N H R N H |CH 222 2 R O C H C H O 2 2 2C ((7609));; R R= =» C H ((7723));; R = OMc R~H OMe adjacent amn io groups wtih the bd iendate reagent to ofrm a fused thiadiazole rn ig 75. symmerty of the starting materail guarantees regiochemistry. Reactoin of the product wtih benzyalmn ie 76 gives product 77 by apparent dsipalcement of an amn io group; it is ve that the reaction in fact involves addtion of benzyalmn ie to the pyrm id in ie 6 position, fo loss of ammonai rfom the same center. Acyaltoin of the newyl n itroduced ntirogen gives formamd ie 78. Desulfurization of this last compound wtih Raney nickel wil aford initialy transient formy-ldaimn ie 79. Cyclization of the ofrmamd ie wtih the adjacent amn io group

Bicyclic Fused Heterocycles

167 ^F

NH2

NH-

"CH 2 Cl

NH

(74) (77)

Cl

Cl

(80)

(79)

N—CHO

(78)

formation of an imidazole ring; there is thus obtained a r p r i n o c i d (80) [13]. T h e fluorinated derivative of an adenine arabinose glycoside, has shown useful antineoplastic activity. The requisite heterocyclic nucleus is obtained in classic fashion by reaction of the peraminated pyrimidine 8 1 with formamide. In this case too, the symmetry of the starting material means that only a single product, 82, is possible. The remaining free arnino groups are then protected by acetylation (83). Glycosidation of the diacyl compound with the protected chlorinated arabinose derivative 84 affords the protected nucleoside 8 5 . The free diamine 86 is obtained on saponification. Diazotization of this intermediate in the presence of fluoroboric acid in T H F gives the fluorinated derivative 87. T h e regiochemistry of that reaction can probably be attributed to the greater reactivity of the amino group at the 2-position as a consequence of the higher electron density and basicity at that position compared to the 4-amino group. Treatment of the fluorination product with boron trichloride leads to removal of the benzyl protecting groups and the formation offludarabine(88)[14].

168

Bicyclic Fused Heterocycles Bz( M

^ H

(81)

NHR

OBz (85);Rr:COMc (86); R = H

OBz (84);Bz = C6H5CH2

(82);R = H (83);R^COMe

NH2

NH2

OBz

OH

87

(88)

( )

7. TRIAZOLOPYRIMIDINES Inclusion of yet another nitrogen in the aromatic nucleus gives a product, bemitradine (95), described as a diuretic agent. The starting pyrimidine 90 is obtainable in straightforward fashion from condensation of the p-keto ester 89 with guanidine. After protection of 90 as its N-formyl derivative 91, chlorination with phosphorous oxychloride yields 92. Reaction of chloropyrimidine 92 with hydrazine produces hydrazinopyrimidine 93, which is then cyclized in the presence of ethyl orthoformate to give the bicyclic compound 94. Subsequent heating produces the Dimroth type rearrangement product bemitradine (95) [15]. 8. TRIAZOLOPYREDAZINES A derivative of an isomeric azapurine ring system interestingly exhibits bronchodilator activity, possibly indicating interaction with a target for theophylline. The starting pyridazine 97 is available from dichloro compound 96 by sequential replacement of the halogens. Treatment of 97 with formic acid supplies the missing carbon and cyclizes the intermediate formamide with consequent formation of zindotrine (98) [16].

Bicyclic Fused Heterocycles

169 [2CH2OEt OH

2CH2OEt

CO2Et (89)

(90); R = H (91); R = CHO

CH2OEt NHNH2

CH2OEt

(95) Me

(96)

(94) Me i.NHNH 2

(97)

(93) Me

(98)

9. PYRIMIDINOPYRAZINES Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimetabolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triaminopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysis. There is thus formed piritrexim (104) [17]. 10. PYREDAZINODIAZEPINES The ready acceptance of angiotensin converting enzyme inhibitors as antihypertensive agents has, as noted previously in this volume, engendered intensive investigation into the limits of the

Bicyclic Fused Heterocycles

170 CO2Et

OMe

OMe

COMe OMe

OMe

(101)

(100)

NH2Me

NHoMe OMe

(104)

OMe (102); R-OH (103); R~C1

SAR in this series. A fused heterocycle ranks among the more unexpected nuclei for an ACE inhibitor. The fact that the end product interacts with a receptor site on an enzyme means that a single enantiomer will be responsible for the activity of the drug. The synthesis takes cognizance of this fact by choosing that enantiomer as the target; the precursors for both starting materials (105,106) thus consist of S enantiomers. The amino group further removed from the carboxyl in the precursor to 106 is sufficiently more reactive to afford the monobenzylation product on alkylation. Acylation of that intermediate with the mono acid chloride of the protected glutamic acid 105 leads to amide 107. Hydrogenolysis then serves to remove the benzyl protecting groups so as to afford the aminoacid 108. This is then cyclized to the bicyclic amide 110 via the acid chloride 109. Reduction of the diamide with diborane interestingly occurs selectively at the less hindered amide grouping to afford 111. The phthaloyl (Phth) protecting group is then removed in the usual way by reaction with hydrazine to afford 112. Construction of the remainder of the molecule consists in the conversion of the R enantiomer of the hydroxy acid 113, to its triflate derivative 114. This very reactive leaving group is readily displaced by the primary amino group in 112 with inversion of configuration; the three chiral centers in the product thus all have the S configuration. Brief exposure of the alkylation product to anhydrous strong acid serves to remove

Bicyclic Fused Heterocycles

171

the tert-butyl protecting group. There is thus obtained cilazapril (116) [18]. CO2CH2C6H5 HN

(105)

l CO21 -Bu (106)

Ph

CO2t-Bu

(107); R1 = OCH2C6H5; R2 = CH2C6H5 (1O9);R1 = C1;R2 = H

Phth = 0

(112)

(111) OSO2CF3 -CH2CH2CCO2Et H (114)

O CO2 Jt -Bu (HO) OH -CH2CH2CCO2Et (113)

-CH2CH2C— NH1 CO2R k (); iu (116); R » H 11. THIAZOLOPYRIMIDONES The involvement of serotonin (5-hydroxytryptamine) in disease states has been recognized for several decades. Research on antagonists awaited the recent development of methodology involving serotonin receptors. A thiazolopyrimidone serves as the nucleus for a pair of serotonin antagonists. The key intermediate 118 is in fact simply the lactonized form of 2-hydroxyethyl acetoacetate. Condensation of this p-keto ester can be visualized to involve initial attack on the reactive

Bicyclic Fused Heterocycles

172

butyrolactone by the ring nitrogen of thiazole 117; cyclodehydration of that hypothetical intermediate 119 gives the fused heterocycle 120. The terminal hydroxyl group is then converted to the corresponding chloride 121. Displacement of the halogen by piperidine 122 affords ritanserin (123) [19]; the analogous reaction with the related dihydrothiazolopyrimidone using piperidine 124 leads to setoperone (125) [20]. Me Me [2CH2OH (117)

(119)

(118)

NH

(122)

/\:H2CH2X (120); X « OH (121); X ^ C l

(123)

O HN

V - C —f

V-F

(124)

0

Dihydro 121 "CH2CH2N

) — C —<'

V-F

(125) 12.

THffiNOPYRIMIDINES

T h e carboxylic acid derivative of an isomeric fused thienopyrimidine exhibits mediator release inhibiting activity. T h e apparently complex thiophene 126 can be obtained in a single step by

Bicyclic Fused Heterocycles

173

reaction of methyl isoamyl ketone with cyanoacetamide and sulfur. Acylation of the product with the acid chloride from the half ester of oxalic acid leads to the oxamate 127. This last cyclizes on heating to afford the pyrimidone 128. Saponification to the acid gives tiprinast (129) [21]. 13. THIENOTHIAZINES Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAED piroxicam, gives tenoxicam, 136, a drug with substantially the same activity. The synthesis of this compound starts by a multistep conversion of hydroxythiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycine ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p~keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine mi || Mc2CH(CHLvrup

2

NCCH2CONH2 ».

Me2HCH2C^l

\ /~

/^co2 (128); R= Et

(126); R = H (127); R = COCO2Et Me I

R

— •.!•••. |»

*CO2Et (130); R = OH (132);' R = SO3H (133); R = SO2C1 O2 yMe OH O (136)

SO2NCH2CO2Et ^s\;O(134) 2 Et

i

)2Et (135)

*~

174

Bicyclic Fused Heterocycles 14. PYRAZOLODIAZEPINONES

A more unusual strategy, which has proven particularly fruitful in the benzodiazepine series, involves replacement of benzene by pyrazole. One route to such an analogue involvesfirstFriedel-Crafts acylation of 137 with o-fluorobenzoyl chloride. The acetyl protecting group on product 138 is then removed and the product 139 acylated with chloroacetyl chloride to give chloroacetamide 140. Halogen is then displaced with azide (141), and the newly introduced function reduced to an amine (142). This last readily cyclizes with the aroyl keto group to form zolazepam (143) [23]. Me COMc I I —Me Me (137) (138); R = COMc (139); R = H

(143)

(14O);X = C1 (141);X = N3 (142); X =* NH2 REFERENCES

1. J. Gubin and G. Rosseels, Ger. Offen., 2,707,048 (1977) via Chem. Abstr., 88:6,719e (1978). 2. J. M. Muchowski and A. F. Kluge, Ger. Offen., 2,731,678 (1978) via Chem. Abstr., 89: 6,215h (1978). 3. F. Franco, R. Greenhouse, and J. M. Muchowski, /. Org. Chem., 47, 1682 (1982).

Bicyclic Fused Heterocycles

175

4. J. M. Muchowski, S. H. Unger, J. Ackrell, P. Cheung, G. R Cooper, J. Cook, P. Gallegra, O. Halpern, R. Koehler, A. F. Kluge, A. R. Van Horn, Y. Antonio, H. Carpio, F. Franco, E. Galeazzi, I. Garcia, R. Greenhouse, A. Guzman, J. Iriarte, A. Leon, A. Pena, V. Perez, D. Valdez, N. Ackerman, S. A. Ballaron, D. V. K. Murthy, J. R. Rovito, A, J. Tomolonis, J. M. Young, and W. H. Rooks, II, /. Med. Chem., 28,1037 (1985). 5. H. W. Smith, M. K. Bach, A. W. Harrison, H. G. Johnson, N. J. Major, and M. A. Wasserman, Prostaglandins, 24, 543 (1982). 6. N. F. Ford, L. J. Browne, T. Campbell, C. Gemenden, R. Goldstein, C. Gude, and J. W. F. Wasley, /. Med. Chem., 28, 164 (1985). 7. J. P. Kaplan and P. George, Eur. Pat. AppL, 50,563 (1982) via Chem. Abstr., 97: 92,280v (1982). M. Dimsdale, J, C. Friedmann, A. Prenez, J. P. Sauvanet, J. P. Thenot, and B. Zirkovic, Drugs of the Future, 12, 777 (1987). 8. P. D. Cook, R. J. Rousseau, A, M. Mian, P. Dea, R. B. Meyer, Jr., and R. K. Robins, J. Am. Chem. Soc, 98, 1492 (1976). 9. D. W. Robertson, E. E. Beedle, J. H. Krushinski, G. D. Pollock, H. Wilson, V. L. Wyss, and J.S. Hayes, J. Med. Chem., 28, 717 (1985). 10. Anon., Jpn. Kokai Tokkyo Koho, 80 57,517 (1980) via Chem. Abstr., 94: 47,360y (1981). 11. J.-C. Pascal, S. Beranger, H. Pinhas, A. Poizot, and J.-P. Desiles,./. Med. Chem., 28, 647 (1985). 12. H. J. Schaeffer, T. A. Krenitsky, and L. M. Beauchamp, Eur. Pat. AppL, 108,285 (1984) via Chem. Abstr., 101: 192,401e (1984). 13. R. J. Tull, G. D. Hartman, and L. M. Weinstock, U. S. Patent, 4,098,787 (1978) via Chem. Abstr., S9:2\5,435u(l97&). 14. J. A. Montgomery, U. S. Patent, 962,107 (1979) via Chem. Abstr., 92: 22,778m (1980). 15. H. Wagner, U. S. Patent, 4,405,780 (1983) via Chem. Abstr., 100: 6,550j (1984). R. D. Heilman and K, J. Rorig, Drugs of the Future, 10, 299 (1985). 16. J. Lewis and P. J. Shea, U. S. Patent, 4,136,182 (1979) via Chem. Abstr., 90: 145,958m (1979). 17. E. M. Grivsky, C. W. Sigel, D. S. Duch, and C. A. Nichol, Eur. Pat. AppL, 21,292 (1981) via Chem. Abstr., 94: 208,899y (1981). 18. M. R. Attwood, C. H. Hassall, A. Krohn, G. Lawton, and S. Redshaw, J. Chem. Soc, Perkin Trans. 1,1011(1986). 19. L. E. J. Kennis and J. C. Mertens, Eur. Pat. AppL, 70,053 (1983) via Chem. Abstr., 99: 70,750n (1983). L. E. J. Kennis, J. Vandenberk, J. M. Boey, J. C. Mertens, A. H. M. Van Heertum, M. Janssen, and F. Awouters, Drugs Dev. Res., 8, 133 (1986). 20. Anon. Drugs of the Future, 10,40 (1985). 21. D. L. Temple, Jr., Fr. Demande, 2,401,163 (1979) via Chem. Abstr., 92: 58,803e (1980).

176

Bicyclic Fused Heterocycles

22. O. Hromatka, D. Binder, R. Pfister, and P. Zeller, Ger. Offen., 2,537,070 (1976) via Chem. Abstr., 85: 63,077f (1976). 23. H. A. DeWald, S. Lobbestael, and D. E. Butler, /. Med. Chem., 20,1562 (1977).

1 0 (3-Lactam A n t i b i o t i c s

In the relatively few years since the preparation of the previous volume in this series, the explosion of synthetic and clinical experimentation on the semi and totally synthetic antibacterial (3lactam antibiotics has continued, providing a rich body of literature from which to assemble this chapter. The search for utopiasporin, the perfect cephalosporin, continues. The improvements in spectrum and clinical properties achieved to date, however, are largely incremental and have been achieved at the price of substantially higher costs to the patient. Nonetheless, these newer compounds are truly remarkable when compared with the properties of the fermentation-derived substances from which they have sprung. 1. PENICILLINS The vast majority of the (3-lactam antibiotics contain an amide side chain attached to the (3-lactam ring. A clear exception to this is amdinocillin (also known as mecillinam) (3). This parenterally active anti Gram-negative antibiotic has a formiminoyl moiety at C-6. Mecillinam is primarily used to treat urinary tract infections, particularly those caused by Escherichia coll. It is synthesized simply by reaction of 6-amino penicillanic acid triethylammonium salt (2) with imino ether 1 [1]. A slightly different synthesis of this agent was described in The Organic Chemistry of Drug Synthesis, Volume 3, page 208. ^s , ) X X

N

CHOMe

(2)

[V-CH=N ^ (3) 177

178

(3-Lactam Antibiotics

Resistance to p-lactam antibiotics by bacteria is a complex function of the elaboration of plactamases which hydrolyze penicillins and cephalosporins before they can reach their receptors, the ability of some bacteria to exclude these antibiotics from their cells, and a decreased tendency to bind P-lactams to the penicillin binding proteins which are their intercellular targets. Various devices have been developed to deal with these factors. For example, increased steric bulk strategically placed near the side chain amide linkage often conveys greater stability against p-lactamases without significant loss of potency. TemocHlin (11) is an embodiment of this stratagem in that it has a C-7 a-methoxy moiety to perform this service and it demonstrates nearly the same potency against many strains of Gram-negative bacteria which do and do not elaborate Plactamases. It does, however, have relatively little activity against Gram-positive bacteria and pseudomonads. One of the syntheses of temociUin begins by reaction of benzyl 6-aminopenicillanate (4) with formic acid and dicyclohexylcarbodiimide to give the corresponding formamide (5) and this is next dehydrated to the isocyanate (6) by reaction with phosgene. Reaction of 6 with methyl rnethoxycarbonyl disulfide and mild base introduces the 6-oc-methylthio moiety (7). Reaction of 7 with tosic acid hydrate in chloroform hydrolyzes the isocyanate moiety back to the primary amine (8). Reaction of 8 with mercury (II) chloride/pyridine and methanol results in replacement of the methylthio moiety by a methoxyl group (9). Mercury II ion has a strong affinity for sulfur, converting it to an excellent leaving group. The particular selectivity between sulfurs seen here stems from causes which are not so obvious. Acylation of 9 with 2-benzyloxycarbonyl-2-(thien-3yl)acetyl chloride produces dibenzyl ester 10. This synthesis of temocillin (11) then concludes by hydrogenolysis of the benzyl groups (Pd/C-hydrogen) [2].

tO2CH2C6H5 (4); R s NH2 (5); R = NHCHO (6);R = CN

tO2CH2C6H (7)

p-Lactam Antibiotics

179

CO2R T £O2CH2C6H5

(8); X » SMe (9);X 0Me

(10); R = CH2C6H5 (11)R H

One of the most popular orally active penicillins in present clinical use is amoxicillin (12). Its oral effectiveness and broad spectrum of activity against common pathogens as well as its better absorption than its closest precedent competitor, ampicillin (14), largely accounts for this. Higher blood and tissue levels of antibiotics is another means of dealing with resistance. In an attempt to achieve yet further improvements in oral bioavailability and hence blood and tissue levels of amoxicillin, the prodrug fumoxicillin (13) is prepared from amoxicillin (12) by treatment with furfural [3]. The imine moiety is less basic than the primary amine so that the isoelectric point of fumoxicillin is more on the acid side than is that of amoxicillin.

tO2H (12)

(J3)

Acylation of the primary amino group of ampicillin (14) with suitable acids leads to penicillins with activity against pseudomonads. Azlocillin, mezlocillin, and piperacillin are well-known examples of this. A newer derivative in this subclass is apalcillin (16). In this case, the acid is a 4-hydroxy-l,5-naphthyridine derivative. The synthesis is carried out by acylation of ampicillin (14) with the N-hydroxysuccinimide ester of 4-hydroxy-l,5-naphthyridine-3-carboxylic acid (15) to give apalcillin (16) [4]. The use of N-hydroxysuccinimide esters in amide bond forming reactions, including peptide synthesis, is becoming increasingly popular.

p-Lactam Antibiotics

180

(16) Another device for dealing with the (3-lactamase problem is to prepare substances which deactivate this class of enzyme. T h e chemical mechanisms by which this takes place are rather interesting [5]. T h e s e substances can be administered conjointly with an otherwise susceptible antibiotic and, if the pharmacokinetic characteristics match, protect the antibiotic from premature hydrolysis. T h e clinical success of the natural product clavulanic acid in a fixed ratio combination with atnoxicillin demonstrates clearly the utility of this approach. Sulbactam (20) is a partially synthetic agent possessing this type of activity. Its synthesis begins with diazotization of 6aminopenicillanic acid (2) to give unstable 6-diazopenicillanic acid (17); this can be brominated without isolation to produce relatively stable dibromide 18 by carrying out the diazotization in the presence of bromine. Formation of the corresponding sulfoxide (19) can be carried out subsequently or in situ with potassium permanganate. The synthesis concludes by hydrogenolysis with 5 % Pd/C-hydrogen [61. A n alternate synthesis of sulbactam is also available [7]. Br N^

(2)

(17)

B r

"-fr-V

(18)

(19); X = Br (20); X = H

^

p-Lactam Antibiotics

181

2. CARBAPENEMS The exceptional potency and breadth of spectrum of the naturally occurring carbon bioisostere of the penicillins, thienamycin (the primary amine corresponding to forrniminoyl derivative 24), makes this a truly exciting substance. One of its unfortunate properties, however, is its pronounced chemical instability. This is attributed in part to self-condensation between the primary amino moiety and the p-lactam ring of another molecule leading to inactive polymers. To avoid this complication, and yet retain bioactivity, it was decided to reduce the nucleophilicity of the amino moiety. This was accomplished by formation of the N-formiminoyl linkage of imipenem (24), One preparation of imipenem begins with p-nitrobenzyl 6-(l')-hydroxyethyl)-lazabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate (21) rather than unstable thienamycin itself. This is converted to the diphenoxyphosphate enol ester 22 and this in turn reacted with N,S-bistrimethylsilyl-N- formimidoylcysteamine with Hunnig's base (diisopropylethylamine) or DMAP (dirnethylaminopyridine) to produce 23. Use of the bistrimethylsilylated reagent was necessary in order to avoid side reactions caused by cyclization reactions. Removal of the protecting groups completes the synthesis of imipenem [8]. Alternate syntheses are available [9]. For commercial purposes, premature in vivo hydrolysis of the P-lactam ring by a kidney enzyme is prevented by coadministration of the inhibitor cilastatin.

(21)

, x \ x NHCH=NSiMe3

1

^

(22)

Me""" SsH—S s «^v^ NHCH=NH

(f

. CO2H (24)

182

p-Lactam Antibiotics 3. CEPHALOSPORINS

The past 10 years have seen the synthesis and evaluation of an exceptionally large number of cephalosporins. At least 16 cephalosporin type antibiotics are now commercially available in the United States and a larger number are available overseas. An even larger number have received generic names and so have made significant progress toward possible clinical use. Many of these agents possess exceptional stability toward p-lactamases and extraordinarily broad spectrum activity against pathogens. The very number of these agents suggests that the search for the perfect cephalosporin antibiotic is not yet over. The cephalosporins are classified for commercial reasons by so-called "generations." The distinction between the generations is not sufficiently clear cut that all compounds can be classified easily except by experts. Briefly, the oldest or first discovered substances largely comprise the first generation. The second generation agents have a broader activity spectrum than those of the first generation. The third generation cephalosporins have broader spectra than any of the preceding agents. Many more Gram-negative pathogens are now sensitive but usually at the cost of lesser potency against Gram-positive pathogens. Aside from their great expense to the patient and their general lack of oral efficacy for systemic infections, the best of these so-called "third generation" cephalosporins possess significant advantages including activity against a great many of the serious pathogens encountered in a hospital setting and have remarkably little toxicity. These come close to the ideal cephalosporin antibiotic being sought. Frenetic activity characterizes this area of medicinal chemistry. Cefroxadine (33) possesses an activity spectrum rather similar to that of cephalexin and so can be placed generally in the first generation of cephalosporins. Structurally, it has a side chain at C-7 identical with that of cephradine (D-absolute stereochemistry) so its oral efficacy is predictable. The side chain at C-3 of cephalosporins is significant not only for potency but also controls many pharmacokinetic features of these drugs. In the case of cefroxadine, an unprecedented (in these pages) enol methyl ether moiety is found. Of the various syntheses, cefroxadine can be made starting with the phenacetyl amide of 7-aminocephalosporanic acid (25). This is deacetylat-

p-Lactam Antibiotics

183

ed to the alcohol (26) using an immobilized bacterial enzyme to avoid damaging the other solvolytically sensitive molecular features and this is converted to the diphenylmethyl ester (27) by reaction with diphenyldiazomethane. The hydroxyl linkage is exchanged for an iodo (28) by reaction with N-methyl-N,N'-dicyclohexylcarbodiimidium iodide and the iodo group is then ejected to produce olefin 29 by reaction with zinc in 90% acetic acid. Double bond migration accompanies this transformation. Ozonolysis at low temperature produces ketone 30 (accompanied by some of the sulfoxide). Next, conversion to the enol ether (31) with diazomethane sets the stage for side chain exchange at C-7, Removal of this amide function in the presence of the more labile P-lactam bond requires a roundabout process which exploits the secondary amide character of the C-7 substituent as compared with the tertiary amide character of the p-lactam moiety. Thus, reaction with phosphorous pentachloride in pyridine produces the side chain iminochloride; this is intercepted with alcohol to produce the iminoether and careful hydrolysis produces the 7-aminocephalosporanic acid analogue (32). Amide formation with D-tert-butoxycarbonylamino-(l,4)cyclohexadienyl) acetic acid is brought about by isobutyl chloroformate and N-methylmorpholine treatment and this is followed by deblocking with trifluoroacetic acid to complete the synthesis of cefroxadine (33) [10].

CO2H (25);R = COMe (26);R = H

CO2CH(C6H5)2 (27); R * ( (28); R = ]

CO2CH(C6H5)2 (29);X = CH2 (30);X=*O

CO2CH(C6H5)2 (31)

C6H5CH2CONH«

CO2CH(C6H5)2 (32)

(3-Lactam Antibiotics

184

M a n y n e w e r cephalosporins incorporate a 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetic acid side chain at C-7. The syji oximino ethers convey high level resistance to p-lactamases (the anti o x i m i n o ethers are much m o r e susceptible) and the aminophenyl bioisostere seems to c o n v e y the ability to penetrate well into bacterial cells of species which would otherwise b e expected to be resistant. T h i s moiety is frequently found in third generation cephalosporins. A n e x a m p l e is the parenteral agent cefetamet (39) whose synthesis starts with ethyl syn-2-methoxyimino-3-oxobutyrate (34); this is chlorinated (chlorine) to chloroketone 35 and this is subjected to the Hantzsch reaction with thiourea to give the desired aminothiazole (36). This is followed by protection of the amino group as the trityl amine and hydrolysis of the ethyl ester function to produce the necessary protected acid (37) for the side chain. A m i d e formation in the usual way with 7-amino-3~desacetoxycephalosporanic acid gives protected antibiotic 3 8 and deblocking with acid completes this synthesis of c e f e t a m e t (39) [11]. fOMc

Me

NOMe

NOMe I^COzEt

CO2Et

X<^CO2Et H

a ' (35)

(34)

(36)

NOMe CO2H

_ ^

NJl S>

NOMe 1

Me y CO2H (38); X =•• C(C6H5)3 (39); X*= H 0

(37)1

Cefixime (47) is another cephalosporin antibiotic with an aminothiazole ring attached to an oximinoether containing side chain at C-7. An interesting and novel side chain is attached to C - 3 . T h e cephalosporins derived from naturally occurring 7-aminocephalosporanic acid have an acetyl function attached to the C-3 methylene. Esterases cleave this in the body and the resulting alcohols are less potent as antibiotics. O n e way of dealing with this undesirable metabolic transformation is to hydrogenolyze this moiety to a methyl function such as is seen with cefetamet above. In an apparent attempt to prepare homologues, transformation to an aldehyde followed by Wittig reactions produces a series of vinyl analogues with interesting properties in their own right.

(3-Lactam Antibiotics

185

One of these is cefixime. The reader will also note that the oximino ether moiety of cefixime is an acetic acid function rather than the methyl ether seen above. This substitution not only retains the p-lactamase resistance intended but also alters the isoelectric point of the drug allowing for more efficient absorption. This agent is found to have rather good activity against Gram-negative microorganisms, is resistant to many p-lactamases and is orally active. It does, however, have somewhat less potency against Gram-positives. This would apparently lodge it among the second generation cephalosporins. One of the syntheses of this agent starts with 7-aminocephalosporanic acid (40) which is hydrolyzed to the alcohol with base, converted to its Schiffs' base with salicylaldehyde, and esterified to its diphenylmethyl ester with diphenyldiazomethane to give protected intermediate 41. Reaction of this with phosphorous pentachloride and pyridine exchanges the hydroxyl function for a chlorine (42). The olefinic linkage of 43 is introduced by reaction with triphenylphosphine and Nal to produce the Wittig reagent; reaction with formaldehyde gives the methylene derivative. Careful acid treatment of 43 selectively removes the salicyl protecting group from C-7 and the desired side chain is put in place by reaction with blocked synthon 45 (prepared by activation of the carboxyl group by reaction with phosphoryl chloride and DMF [Vilsmeier reagent]). The resulting blocked C-3 vinyl analogue (46) is deprotected at the primary aromatic amino group by reaction with rnethanolic HC1 and the remaining protecting groups are removed by reaction with trifluoroacetic acid in anisole to complete this synthesis of cefixime (47) [12]. Other syntheses have been described for this agent and its analogues [13-151. Cefpimizole (51) appears to be less active in vitro than cefotaxime and cefoperazone and to have a somewhat narrower activity spectrum although some strains of Pseudomonas are susceptible. It is not orally active, but its performance in vivo appears superior to what would be expected from its in vitro data. Its synthesis begins by acylation of cephaloglycin (48) with the bis acid chloride of imidazole-4,5-dicarboxylic acid (49) to give amide 50. The acetyl moiety at C-3 of this intermediate is displaced with 4-pyridineethanesulfonic acid and sodium iodide to give cefpimazole (51) [16]. Just as with cefpimazole, cefepime (54) has a quaternary nitrogen substituent at C-3 whose electron withdrawing character and excellent nucleofugic properties increases the reactivity of the

P-Lactam Antibiotics

186 ••OH H2N. o

CO2H (40)

> y U o H

-

CO2CH(C6H5)2 (41)

•OH

CO2CH(C6H5)2 (42) NOCH2CO2CMc3

CO2CH(C6H5)2 (43) NOCH2CO2CMe3

(45)

-N. CO2CH(C6H5)2 (44)

(46) NOCH2CO2H

(47)

H N

H2N Me CO2H (48)

(49)

CO2H (50)

i v-coci N-4 COC1

CO2CH(C6H5)2

P-Lactam Antibiotics

187

C ' OzH CO2H (51) (3-lactam bond and also the antibacterial potency of the molecule. This derivative is prepared simply by displacement of the C-3 chloro moiety of suitably blocked cephalosporin 52 with Nmethylpyrrolidine to give intermediate 53 and this is deblocked with trifluoroacetic acid in the usual manner to give cefepime (54) [17]. NOMc

(54) Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it has a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocephalosporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 56. This can in turn be reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxybenzotriazole) to produce, after deprotecting, ceftiofur (57) [18], Cefmenoxime (61) is a third generation parenteral cephalosporin whose in vitro antimicrobial spectrum approximates that of cefotaxime. Its side chains consist of the common methyltetrazo lylthio group at C-3 and the familiar oximinoether aminothiazole moiety at C-7. It is synthesized

188

p-Lactam Antibiotics

(55)

(56) NOMe

CO2H (57) from acid chloride 58 and 7-aminocephalosporin synthon 59 to produce blocked amide 60. The utility of this blocking group is demonstrated by its ease of removal to give cefotaxime (61) by reaction with thiourea (displacement of chloride by sulfur and internal cyclization to remove the protecting group from the amine) [19]. NOMe it N

ClCH.CONH-^V (58)

„ VT H N

« \

s

_. . _ N-N

(59) OMe

CO2H (60); R = C1CH2CO (61); R - H Cefpiramide (64) is a third generation cephalosporin with a 1 -methyl-[lHJ-tetrazol-5-ylthiomethyl moiety at C-3 and an acylated r>hydroxyphenylglycine moiety at C-7. It includes in its activity spectrum reasonable potency in vitro against many strains of Pseudomonas. It can be synthesized in a variety of ways including condensation of cephalosporin antibiotic 63 with 6methyl-4-(l-H)-pyridone-3-carboxylic acid in the form of its active N-hydroxysuccinimide ester (62) to produce cefpiramide (64) [20,21]. Cefoperazone (66) is a third generation parenteral antipseudomonal cephalosporin containing an acylated C-7 side chain reminiscent of that of piperacillin. One of the simplest syntheses

p-Lactam Antibiotics

189

n ivovles acyalotin of antb ioitci 65 wh ti 4~ethy-2l3,~doixo~-lpp ierazn iecarbonyl cholrd ie treithO yaH lmn ie to gvie cefoperazone (66) [22]. O H

y H H 2 ,|fc (6C 5O )2 Ifc (66) CO The chemcial structure of ceb fuperazone (70) is somewhat anaolgous to that however,the C7- sd ie chan i ured io funcotin is atached to an ap ilhatci am aromacit one and n i fact consits of the amnio acd i threonn ie. (3a-lctamase is enhanced further by n icorporaotin of a C7- meh toxylmoeiyt dervied conce cephamycnis. One of the syntheses of this agent starts wh ti reacotin of threo doixo-1-pp ierazn iecarbonyl cholrd ie and subsequent trm i ethyslyialtoin to gvie synh ton is condensed wth i protected 7a-mniocephaolsporanci acd i ester 68 by means of maet and N-ethym l orphon ile. Aetfr debolckn ig,the product (69) is converetd to anaolgue by protecotin wh ti ethyvln iyl ether and acd i and sequenatil reacotin d ie and t-butyh lypocholrtei folwed by debolckn ig n i acd i to produce ceb fupera

(3-Lactam Antibiotics

190 Nfe OH EtN

H2N

N-N i N

NCONH""

f

CO2CHPh2 (67)

(68)

Me /—\, ^ ElN NCONtT o

N~N 6

o^

(69)

CO2H

Me

EtN

N

MCONH'

(70)

—i

N N

CO2H

Cefotriaxone (73) has a 2,5-dihydro-6-hydroxy-2-rnethyl-3-thia-5-oxo-l,2,4-triazine moiety at C-3 in order to avoid s o m e of the side effects of cephalosporins attributed to the presence of an alkylthiatetrazolyl moiety at C-3 (antabuse-like acute alcohol intolerance and prolonged blood clotting times). In animal studies, cefbuperazone has been shown to be m o r e effective than cefmetazole and cefoperazone in infected mice. Of the various syntheses, one proceeds from 7aminocephalosporanic acid itself (40) by condensation with (formarnidothiazolyl)(rnethoxyimino)acetic acid (71) promoted by l,r-(carbonyldioxy)dibenzotriazole (formed by reaction of 1-hydroxybenzotriazole with trichloromethylchlorocarbonate-this converts the carboxylic acid moiety to the activated 1-hydroxybenzotriazole ester of 71) to give cephalosporin 72. This synthesis of ceftriaxone (73) concludes by displacement of the acetoxyl moiety of 72 with 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-l,2,4-triazine and sodium bicarbonate [24]. Cefmetazole (78) is a cephamycin-inspired cephalosporin differing from the mainstream c o m p o u n d s in having an aliphatic amide moiety attached to C-7. Its antibacterial spectrum is similar to the second generation agent cefoxitin. T h e synthesis starts with 7-aminocephalosporan-

191

p-Lactam Antibiotics NOMe

(40)

(71)

NOMe

CO2H (72) NOMe

HoN' CO2H Me

(73)

ic acid derivative 59 which is converted to its S c h i f f s base (75) with 3,5~di~t-butyl-4-hydroxybenzaldehyde (74). T h e imine (75) is oxidized to the iminoquinonemethide (76) with lead dioxide. Methanol is added 1,8 to this conjugated system to produce desired intermediate 77. T h e protecting S c h i f f s base is removed by exchange with Girard T reagent and the 7-aminocephalosporanic acid derivative so produced is acylated with cyanomethylthioacetic acid as its acid chloride to produce ceftnetazole (78) [25].

CHO

QMc N-N -i N CO2H (76)

(77)

9Me NCCH2SCH2CONH - 4 - f

N-N

CO2H (78)

I Me

1 CO2H

I

192

p-Lactam Antibiotics

Cefotetan (84) stands out from the other cephalosporin antibiotics in that it possesses the unusual 1,3-dithietan side chain at C-7. This was introduced initially as the result of a molecular rearrangement and this interesting moiety was found to be consistent with excellent activity against many Gram-negative microorganisms (although not pseudomonads). Methods were developed for the deliberate incorporation of this functionality into molecules. The drug is rather similar to ceftazidime in its in vitro antimicrobial spectrum. Its synthesis begins with hydrolysis of 4-cyano-5-ethylthio-3-hydroxyisothiazole (79) with sodium hydroxide to produce acid 80. Reductive cleavage to thiol 81 was accomplished in good yield by reaction with sodium in liquid ammonia. This synthon was used to displace the bromo atom of cephalosporin antibiotic 82 to give antibiotic 83. Treatment of the latter with aqueous sodium bicarbonate leads to a facile rearrangement of the isothiazole, presumably by intramolecular displacement. The mechanism of this interesting reaction is not certain but may involve the process indicated by the arrows in formula 83. The product is in any case the antibiotic cefotetan (84) [26].

HO %

t

OMc 4

CO2H

N >-SH

(79);R = CN (80);R = CO2H

T CO2H (82)

(81)

CO2H

CO2H (83) 9Mc H?N< CO2H (84)

jjfe

p-Lactam Antibiotics

193

4. MONOBACTAMS Utilizing a specially designed and intensive screen for novel P-lactam antibiotics from bacterial species, a series of monobactams (monocyclic p-lactam antibiotics) were ultimately discovered which not only possessed interesting anti-Gram-negative activity but possessed an intriguing Nsulfonic acid moiety attached to the nitrogen of the p-lactam ring. This group mimics the function of the carboxyl moiety of penicillins and cephalosporins. Previously it had also been believed that a fused strained bicyclic p-lactam system was necessary for significant antibacterial activity. While the natural monobactams do not appear to have clinically useful activity, a number of their totally synthetic analogues do. This field has been explored intensively in recent years and some of the fruits of this work are reported here. Aztreonam (93) is a wholly synthetic agent directed primarily against Gram-negative bacteria. The total chemical synthesis of aztreonam begins with N-t-butoxycarbonyl threonine-O-benzylhydroxylamide (85) which cyclizes to the monocyclic P-lactam intermediate (86) by use of an intramolecular Mitsunobu reaction with triphenylphosphine and diethylazodicarboxylate ("DEAD"). Careful hydrogenolysis is employed to remove the benzyl protecting group without cleaving the N-0 bond to give intermediate 87. The now superfluous N-hydroxyl group is removed by reduction with titanium trichloride to give azetidin-2-one 88. The t-BOC protecting group is removed by hydrolysis with trifluoroacetic acid and then replaced by a carbobenzyloxy moiety by reaction with benzyl chloroforrnate. The protected intermediate (89) is sulfonated with sulfur trioxide in DMF to give sulfonamide 90. The CBZ protecting group is removed by hydrogenolysis to produce amphoteric azetidinone 91. The desired acyl side chain is installed in the form of its diphenylmethyl ester using N-hydroxybenzotriazole as condensing agent to produce 92. Hydrolysis with trifluoroacetic acid leads finally to aztreonam (93) [27]. Carumonam (103) differs from aztreonam structurally in having an acetic acid function attached as an ether to the oximino moiety in the side chain and a carbamoylmethyl group in place of the methyl group at C-3. Like aztreonam it is primarily effective against Gram-negative bacteria. An interesting synthesis starts with a 2 + 2 cycloaddition reaction using carbobenzoxyglycine

p-Lactam Antibiotics

194

CONHOCHC 2H 65 (85) if MeC CNkI . 3O (88) CH O NH. 6C 5H 2C O' (90) Iv^c M < •CO2CH(C6H5)2 N •\ SOH 3

S O R ((8867)R ;);=R CH=2C6H H5 CH O NH 6C 5H 2C

(89) (91) MeVlyie COH 2 N\SO3H

(92) (93) (94) and a complex imine prepared from methyl L-valinate (95). The requisite ketene deriva made in situ by reacting CBZ-glycine (94) with i-butyl chloroformate or i-propyl chloroforma The product of cycloadditon is primarily cis (96) and can be separated from the mixture by tional crystalization. Careful hydrolysis with potassium carbonate removes the w t o ester group (97) and then the carbamoyl moiety is introduced by reaction with dichlorophosphoryl isocyan folowed by reaction with aqueous bicarbonate to give 98. The chiral auxiliary now having its purpose can best be removed by anodic oxidation in acetic acid-triethylamine solution folow by hydrolysis with potassium carbonate to give partialy deblocked monobacatm 99. The rem der of the steps to carumonam consist of reaction with sulfur trioxide to the N-sulfonate (10 hydrogenolytic deblocking of the primary amine to amphoteric 101, additon of the protected s chain to give 102, and deblocking with trifluoroacetic acid to produce carumonam (103) [28 Other conceptualy interesting syntheses are available to the interested reader [29,30].

p-Lactam Antibiotics

195

^.CH2OCONH ^

CO2H (95)

(94)

(96) .CH2OCONH2

(101)

(100)

NOCH2CO2H

NOCH2CO2CMc3

^JM^CH2OCONH2

:H2OCONH2 X

SO3H

(102)

J - \ O' (103)

A n u m b e r of m o n o b a c t a m s have been prepared in which the N-sulfonic acid moiety has been replaced by various other acidic groups. O n e means of closing the (3-lactam ring in this d r u g class invokes the normally suppressed nucleophilicity of the N-atom of the oxime moiety. This leaves an oxygen atom which is either replaced by a sulfonic acid group (as with a z t r e o n a m ) or utilized as a functional group to which a bioisosterically equivalent appendage, such as an acetic acid moiety is attached. This works in part because the electronic character of the bridging oxygen is somewhat analogous to that of the sulfur but also because the molecular size of the oxygen and the methylene carbon are roughly equivalent to that of sulfur so that the position in space of the acidic

196

(3-Lactam Antibiotics

moiety is roughly the same in aztreonam and in gloximonam (after deblocking to oximonam). In order to enhance the oral bioavailability of oximonam (104), a prodrug has been made by esterification of the carboxyl group with the t-butyl ester of hydroxyacetic acid (105). The product is prodrug gloximonam (106) [31]. Gloximonam is efficiently converted to oximonam in the body by metabolic processes. NOMc ,-Me O°4)

+

H(XH2CO2CMe3

^

X

rf U

OCH2CO2H

(105)

NOMc •v-C (106) The drug latentiated in the previous paragraph is the parenteral antibacterial monobactam oximonam (104). Its subclass of monobactams is sometimes referred to as the monosulfactams. As with the other monobactams, oximonam is primarily active against Gram-negative microorganisms. The synthesis begins with methyl N-carbobenzoxythreonine (107) which is converted to its oximinoyl amide with hydroxylamine then acetylated and finally cyclized to protected monobactam 108 under modified Mitsunobu conditions (triphenylphosphine and dimethyldiazodicarboxylate). Deacetylation with sodium carbonate produces 109, Ether formation, aided by a water soluble carbodiimide, with 2-trimethylsilylethylbromo acetate (110) leads to ether-ester 111. Hydrogenolytic deblocking of the primary amino group (hydrogen, Pd-C, HC1) and acylation leads as in previous examples to 112. Final deblocking to oximonam (113) is carried out with tetrabutylamrnoniurn fluoride [32]. OH ^CH2OCONH\I^Mc T~~\H

^

^>CH 2 OCONH X Afe I T y-f (108);R = COMe (109); R = H

+

BrCH2CO2CH2CH2SiMc3 (110)

p-Lactam Antibiotics

197

(111) J° M e

NOMe H2N

(112)

rT

\)CH2CO2CH2CH2SiMc3

"V

" " >

(104)

REFERENCES 1. F. Sakamoto, S. Ikeda, R. Hirayama, M. Moriyama, M. Sotomura, and G. Tsukamoto, Chem. Pharm. Bull, 35, 642 (1987). 2. P. H. Bentley, J. P. Clayton, M. O. Boles, and R. J. Girven, /. Chem. Soc, Perkin Trans, 1, 2455 (1979). 3. J. B. A. Scalesciani, U. S. Patent 4,327,105 (1982) via Chem. Abstr., 97:72,191p (1982). 4. H. Tobiki, H. Yamada, T. Miyazaki, N. Tanno, H. Suzuki, K. Shimago, K. Okamura, and S. Ueda, Yakugaku Zasshi, 100,49 (1980). 5. D. G. Brenner and J. R. Knowles, Biochemistry, 23, 5833 (1984). 6. R. A. Volkmann, R, D. Carroll, R. B. Drolet, M. L. Elliot, and B. S. Moore, /. Org. Chem,, 47, 3344 (1982). 7. J. C. Kapur and H. P. Fasel, Tetrahedron Lett., 26, 3875 (1985). 8. I. Shinkai, R. A. Reamer, F. W. Hartner, T. Liu, and M. Sletzinger, Tetrahedron Lett., 23, 4903 (1982). 9. W. J. Leanza, K. J. Wildonger, T. W. Miller, and B. G. Christensen, /. Med. Chem., 22, 1435 (1979). 10. R. Scartazzini and K Bickel, Swiss, 605,990 (1978) via Chem. Abstr., 90: 54,959w (1978). 11. R. Boucourt, R. Heymes, A. Lutz, L. Penasse and J. Perronnet, Tetrahedron, 34, 2233 (1978). 12. H. Yamanaka, T. Chiba, K. Kawabata, H. Takasugi, T. Masugi, and T. Takaya, /. Antibiotics, 38,1738 (1985). 13. K. Kawabata, H. Yamanaka, H. Takasugi, and T. Takaya, /. Antibiotics, 39,404 (1986). 14. H. Yamanaka, K. Kawabata, K. Miyai, H. Takasugi, T. Kamimura, Y. Mine, and T. Takaya, /. Antibiotics, 39,101 (1986). 15. K. Kawabata, T. Masugi, and T. Takaya, /. Antibiotics, 39, 384 (1986).

198

(3-Lactam Antibiotics

16. Anon., Jpn. Kokai, Tokkyo Koho, 57/209,293 (1982) via Chem. Abstr., 98: 160,521 (1982). 17. T. Naito, S. Aburaki, H. Kamachi, Y. Narita, J. Okumura, and H. Kawaguchi, /. Antibiotics, 39,1092 (1986). 18. B. Labeeuw and A. Salhi, Eur. Pat. Appl, 36,812 (1981) via Chem. Abstr., 96: 68,712w (1981). 19. M. Ochiai, A. Morimoto, T. Miyawaki, Y. Matsushita, T. Okada, H. Natsugari, and M. Kida, J. Antibiotics, 39,171 (1981). 20. H. Yamada, H. Tobiki, K« Jimpo, K. Gooda, Y. Takeuchi, S. Ueda, T. Komatsu, T. Okuda, H. Noguchi, K. Irie, and T. Nakagome, J, Antibiotics, 36, 532 (1983). 21. H. Yamada, H. Tobiki, K. Jimpo, T. Komatsu, T. Okuda, H. Noguchi, and T. Nakagome, /. Antibiotics, 36, 543 (1983). 22. Anon., Jpn. Kokai Tokkyo Koho, 57/118,588 (1982) via Chem. Abstr., 99: 5,433x (1982). 23. S. Takano, I. Takadura, H. Ochiai, K. Momonoi, K. Tanaka, Y. Todo, T. Yasuda, M. Tai, Y. Fukuoka, H. Taki, and I. Saikawa, Yakugaku Zasshi, 102, 629 (1982). 24. W. J. Kim, C. H. Lee, B. J. Kim, and G. S. Lee, Brit. UK Pat. Appl 2,158,432 (1985) via Chem. Abstr., 105:152,813s (1985). 25. H, Nakao, H. Yanagisawa, B. Shimizu, M. Kaneko, M. Nagano, and S. Sugawara,./. Antibiotics, 2% 554 (1916). 26. M. Iwanami, T. Maeda, M. Fujimoto, Y. Nagano, N. Nagano, A. Yamazaki, TT. Shibanuma, K. Tamazawa, and K. Yano, Chem. Pharm. Bull., 28, 2629 (1980). 27. R. B. Sykes, W. L. Parker, C. M. Cimarusti, W. H. Koster, W. A. Slusarchyk, A. W. Fritz, and D. M. Floyd, Eur, Pat. Appl, 48,953 (1982) via Chem, Abstr., 97: 92,116w (1982). G. Loren, Drugs of the Future, 8, 301 (1983). 28. S. Hashiguchi, Y. Maeda, S. Kishimoto, and M. Ochiai, Heterocycles, 24, 2273 (1986). 29. M. Sendai, S. Hashiguchi, M. Tomimoto, S. Kishimoto, T. Matsuo, M. Kondo, and M. Ochiai, J. Antibiotics, 38, 346 (1985). 30. S. Kishimoto, M. Sendai, S. Hashiguchi, M. Tomimoto, Y. Satoh, T. Matsuo, M. Kondo, and M. Ochiai, /. Antibiotics, 36, 1421 (1983). 31. S. Kishimoto, M. Sendai, and M. Ochiai, Eur. Pat. Appl., 135,194 (1985) via Chem. Abstr., 104: 5,707m (1985). 32. S. R. Woulfe and M. J. Miller, /. Med. Chem., 28,1447 (1985).

11 Miscellaneous Heterocycles

The classification of medicinal agents in terms of their chemical structures has been a hallmark of this series. This system proves readily applicable for the majority of structural types. Rather complex structures which might strain such a scheme, such as for example, p-lactams, are often represented by a sufficient number of examples so that they can be collected in a special chapter. Some structures however, perhaps inevitably, do not readily fall into any neat category, hence this chapter on " Miscellaneous Heterocycles ." It is of passing interest that a number of the entries, such as, for example, the phenothiazines and benzodiazepines, belong to structural classes which merited chapters in their own right in previous volumes. The fact that the references to the preparation of these compounds tend to be somewhat old, suggest that they were in fact first prepared when those fields were under intensive investigation. The granting of an USAN to those agents in the much more recent period covered by this book (1982-1987) prdbably means that, for one reason or another, that they have been taken off the shelf for clinical development. 1. PHENOTHIAZINES The phenothiazine duoperone (5) combines structural elements found in phenothiazine and butyrophenone antipsychotic agents. Alkylation of substituted piperidine 1 with 3-chloropropanol affords the intermediate 2; treatment of this with thionyl chloride converts the terminal hydroxyl to chloride. Alkylation of the phenothiazine 4 with halide 3 affords the antipsychotic agent duoperone (5) [1]. A more polar phenothiazine derivative in which the side chain consists of an amino amide 199

200

Miscellaneous Heterocycles

exhibits the antiarrhythmic activity often found in such hindered amides. Acylation of phenothiazine 6 with 2-chloropropionyl chloride gives the haloamide 7; displacement of halogen with morpholine gives moricizine (8) [2].

(6)

rO 2. BENZOCYCLOHEPTAPYRIDINES Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10; acylation of that intermediate with ethyl chloroformate affords the nonsedating H-l antihistaminic agent loratidine (11) [3]. It is of interest that this compound does not contain the zwitterionic function which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds.

Miscellaneous Heterocycles

201

3. CARBAZOLES Alkylation of the dimethylpiperazine 12 with 3-chloropropanol followed by treatment of the product 13 with thionyl chloride gives the halide 14. Alkylation of the anionfromcarbazole (15) with that halide leads to the tricyclic antipsychotic agent rimcazole (16) [4].

>Et (11)

(9) j R « Me (10); R= H HN NH

RCH2CH2CH2N NH (13);R = OH (14)R C1

Me

(15)

CH2CH2CH2N NH (16)

Me

4. DEBENZAZEPINES The imipramine analogue in which one of the methyl groups on the side chain nitrogen is replaced by a phenacyl group retains antidepressant activity. The starting material for this analogue, desipratnine (19), interestingly is an antidepressant drug in its ownright.Alkylation of 19 with gchlorophenacyl bromide (20) leads to lofepramine (21) [5],

202

Miscellaneous Heterocycles

CH2CH2CH2R (18); R = Q (19); R a NHMe

(17)

O CH2CH2CH2NCH2CMe (21) 5. DIBENZOXEPINES Two related tncyclic heterocyclic systems provide the nuclei for analgesic compounds which are not related structurally to either NS AIDs or opioids. Saponification of the nitrile group in 22 leads, via the corresponding acid, to acid chloride 23. Friedel-Crafts cyclization of 23 affords the ketone 24, Reaction of that ketone with 2-dimethylamino ethanethiol in the presence of boron trifluoride leads to formation of the enol thioether. Demethylation with phenylchloroformate gives fluradoline (26) [6]. Acylation of the dibenzoazaoxepin 27 with ethylchloroforrnate leads to the carbamate 28. Hydrazinolysis of the ester gives the hydrazide 29. Acylation of the remaining basic nitrogen on that intermediate with 5-chloropentanoic acid affords pinadoline (30) [7]. O

(23)

(26)

(24)

Miscellaneous Heterocycles

203

? f CNHNHCC (H C )1 42 N(27)

(28); R = Et (29); R = NHNH2

(30)

6. P Y R I D O B E N Z O D I A Z E P I N E S Antidepressant activity is retained w h e n the two carbon bridge in i m i p r a m i n e is replaced by a larger, m o r e complex, function. Nucleophilic aromatic substitution on chloropyridine 3 1 by means of o-aminobenzophenone (32) gives the bicyclic intermediate 3 3 . Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 3 5 . Alkylation of the anion from 3 5 with l-dimethylamino-3-chloropropane leads to t a m p r a m i n e 36 [8].

N02 N

N—ci (32)

(31)

(33); R = O (34); R = H

H CH2CH2CH2NMe2 (35)

(36)

7. B E N Z O P Y R A N O P Y R I D I N E S T h e reaction of relatively simple starting materials, coumarin 4 0 , piperidone 3 7 and a m m o n i u m acetate, leads in a single step to the complex bridged tetracyclic c o m p o u n d 4 4 . T h e reaction can be rationalized by a s s u m i n g formation of the imine 3 8 from reaction of 3 7 , with ammonia. Conjugate addition of the eneamine-like tautomer 3 9 to the excellent Michael acceptor 4 0 will

204

Miscellaneous Heterocycles

lead to the adduct 41. This last is perfectly set up for intramolecular cyclization to the imide 42 by attack of imine nitrogen on the adjacent ester function. Ring opening of the lactone in 42 would afford the phenolic acid 43. This last intermediate is shown in neutral form; the reaction can be rationalized just as well by using the charged intermediate ions. Addition of the phenol ( or phenoxide) oxygen to the imide serves to close the last ring. Decarboxylation of the beta dicarbonyl grouping in 43 completes the reaction sequence. This last step can be visualized to occur either prior to or after the last ring is closed. The stereochemistry is probably thermodynamically controlled since the last ring closure in fact consists of carbinolamine formation from a ketone, a reaction which should be readily reversible. The product lortalamine (44) is described as an antidepressant agent [91.

NH

Me (38)

(44)

Me (39)

(43)

Miscellaneous Heterocycles

205

8. PYRROLOISOQUINOLINES Synthesis of the dopamine antagonist antipsychotic agent piquindone (53) starts by conversion of nicotinyl methyl ketone 45 to its acetal 46; alkylation with methyl iodide followed by reduction of the thus formed ternary iminium salt 47 by means of borohydride results in the tetrahydropyridine 48. Hydrolysis of the acetal group reveals the newly formed unsaturated ketone in 49. Conjugate addition of dimethyl malonate no doubt proceeds initially to the adduct 50; the reversible nature of the reaction as well as the ready enolization of the acetyl ring proton will result in formation of the more stable trans diequatorial isomer. The product cyclizes under the reaction conditions to perhydroisoquinolone 51. Hydrolysis of the ester in 51 is followed by decarboxylation to afford 52. Reaction of this last intermediate with 2-amino~3~pentanone under conditions for the Knorr reaction leads to formation of a pyrrole ring. The reaction sequence may be visualized by assuming initial imine formation between the quinolone and the aminoketone; cyclodehydration would complete the formation of the new ring. It is of note that a small amount of the isomeric angularly annulated product is formed as well. There is thus obtained piquindone (53) as the major reaction product [10]. 9. PYRAZOLOQUINOLINES Reaction of ethyl formate with perhydroisoquinolone 54, in the presence of strong base leads to the p-formylketone 55; condensation of that product with hydrazine leads to the formation of a new pyrazole ring. This product, quinpirole (56), is an antihypertensive agent [11], 10. NAPHTHOPYRANS The discovery of the utility of the bis-chromone carboxylic acid derivative cromolyn sodium in the treatment of asthma and related allergies has led to an intensive, and thus far not very fruitful, effort to discover analogues which would show oral activity in contrast to the lead which must be administered by inhalation. Preparation of a typical analogue, proxicromil (63), starts with the Oallylated phenol 57. Claisen rearrangement leads to the corresponding C-allylated product 58. The double bond is then reduced by catalytic hydrogenation (59). Base-catalyzed condensation

Miscellaneous Heterocycles

206 N V><s

o(46)

(45)

(47)

(48)

CO2Me CO2Me (51)

CO2Me J (50)

(49)

Mc\, Me

(52)

(53)

,N |

I n-CH2CH2CH3 (55) (54) (56) with diethyl oxalate can be envisaged as proceeding initially to the product from acylation of the n-CH 2 CH 2 CH 3

Q-CH2CH2CH3

ketone methyl group (60). Cyclodehydration of that product, shown in the enol form, will result in the formation of a pyran ring. There is thus obtained the chromone 61. Nitration of 61 produces nitro-pyran 62. The nitro group in 62 serves as a tool to introduce the phenolic hydroxyl group in 63 via reduction of the nitro group, diazotization of the resulting amino group, and treatment of the diazonium salt with aqueous sulfuric acid. During that treatment the ester functionality is hydrolyzed as well. There is thus obtained proxicromil (63) [12]. 11. BENZODIPYRANS In much the same vein, condensation of the difunctional o-hydroxyacetophenone 64 with diethyl

207

Miscellaneous Heterocycles

oxalate leads to the formation of two pyran rings on the same benzene ring. Workup under aqueous basic conditions leads to in situ saponification of the ester groups. There is thus obtained in a single step the mediator release inhibitor, probicromil (65) [13].

OCH2CH=CH2

CO2Et CH2CH2Me (61)

CH2CH2Me (60)

CO2H CH2CH2Me (63)

HO2C

CO2H CH2CH2Me (65) OMeO

+

MeSCH2COEt

IL.OH 'O*TCH2SMe

(67)

(68) OMeO

CH2SMe OMe (69)

J

Miscellaneous Heterocycles

208 12. FUROBENZOPYRANS

A closely related oxygenated heterocyclic system devoid of acidic groups interestingly shows quite different biological activity. Thus, condensation of the benzofuran hydroxyketone 66 with ethyl thiomethyl acetate (67) probably proceeds initially by formation of the acylation product 68. Intramolecular dehydration leads to formation of a pyran ring. There is thus obtained the hypocholesterolemic agent timefurone (69) [14]. 13. PYRANOQUINOLINES Mediator release inhibiting activity is, interestingly, retained when of one of the pyran rings in a molecule such as probicromil is replaced by a pyridine ring. The synthesis of such an agent starts with the allylation of hydroxyacetophenone 70 to give the ether 71. Rearrangement (72) followed by reduction gives the intermediate 73. The chromone ring is then added by base- catalyzed acylation with ethyl oxalate (74^. Removal of the acetyl group on nitrogen gives the intermediate, 75, required for construction of the pyridine ring. Thus, conjugate addition of the amino group in 75 to diethyl acetylene dicarboxylate gives the maleic ester 76. The ester function cyclizes onto the benzene ring on heating to form the pyridone 77. Saponification of the esters affords nedocromil (78) [15]. •N EC tOMc CH2R (70)

(72); R = CH=CH2 (73); R a Et

Et CHCO2Me %

CH2CH2Me (76)

R0 2 O MeCH2CH2 (77); R = Et (78); R = H

CO2Mc

Et02O

Et NR CH2CH2Mc (74); R = COMe (75);R = H

Miscellaneous Heterocycles

209

14. DIBENZOPYRANS Natural products have played an important role in the process of drug discovery. Several important medicinal agents were first identified as a result of the adventitious discovery of their biological activity. Familiar examples include the opioid analgesics, digitalis cardiotonic agents, and antihypertensive agents related to reserpine. The host of biological activities exhibited by marijuana suggested that this natural product should act as a lead to significant new classes of drugs. The identification and structural elucidation of the compound responsible for the biological activities, tetrahydrocannabinol (79), spurred interest in this compound. The development, in short order, of facile routes to this compound led to the synthesis of many new analogues. Acylation of the THC analogue 80, in which both the position of the double bond and the length of the side chain have been changed, with 4-(homopiperidino)butyric acid gives the ester nabazenil (82) which is described as an anticonvulsant agent. Esterification of the phenol in the isomeric THC-like compound 81 with 4-(diethylamino)butyric acid gives the ester 83, naboctate, in which antinauseant and antiglaucoma activity predominate [16].

OH

OH

(80); R = CHCH(CH2)4Me

(79)

MeMe Me

OCCH2CH2CH2NJ •CHCH(CH2)4Me MeMe

Me (82)

Me V J^ OCCH2CH2CH2NEt2 Me

| Me (83)

Miscellaneous Heterocycles

210 15. BENZOPYRANOPYRIDINES

The synthesis of THC analogues in which the carbocyclic ring is replaced by a heterocycle involves as a key step condensation of the resorcinol 84 with the appropriate (3-keto ester. Thus, condensation of that intermediate with piperidone 85, leads to the lactone 87. The reaction can be rationalized by assuming initial formation of the ester 86; the required carbon-carbon bond will then result from a cyclodehydration step. Reaction of the lactone with an excess of methyl Grignard reagent leads to the isolation of the THC analogue 88. This last reaction may in fact proceed initially to a tertiary carbinol of the general formula shown in 90. The tertiary carbocation formed under the acidic condition of the workup can in principle cyclize with the phenol to give the pyran ring of the product, 88, which is finally isolated. Debenzylation of 88 is followed by N-alkylation with propargyl bromide and acylation with 4,N-(l-methylpiperidino)-2-methylbutyric to afford the analgesic agent menabitan (89) [17]. 16. THIOPYRANOBENZOPYRANS The same sequence starting with the thiapyrone 91 affords via initially 92 the lactone 93. This intermediate gives the antihypertensive agent tinabinol (94) on reaction with excess methylmagnesium bromide (18).

(86)

CH2Ph

CH2Ph

(87)

(88)

CH 2 Ph

HOsaCCHo

OMe OCCHCH2CH2N~\

Me'

R

OH (90)

= CHCH(CH2)4Me Me Me

OH (91)

Miscellaneous Heterocycles

211

OH -l

OH

(92)

(93)

Me (94); R = CHCHCCH^Mc Me Me

17. PYRAZINOPYRIDOINDOLES Piperazine rings are a common structural feature in many compounds which act as antagonists at a-adrenergic receptors; it is of interest that a compound which incorporates a fused piperazine acts as an antihypertensive agent by virtue of a-blocking activity. Reaction of the indole 95 with ybutyrolactone leads to acid 96. Friedel-Crafts type cyclization affords the tricyclic ketone 97. Treatment of that intermediate with bromine gives the product from oc-bromination (98). Reaction of the bromoketone with ethylene diamine in the presence of borohydride leads to formation the fused piperazine ring(99). The sequence probably involves formation of the initial carbon-nitrogen bond by displacement of bromine; the second bond is then formed by reductive alkylation of the ketone. The steric environment around each of the two secondary amino groups is sufficiently different so that they show markedly different reactivities toward alkylation reactions. Thus, treatment with isopropyl bromide leads to the monoalkylation product 100. The remaining amino group is alkylated by reaction with ethyl bromide under more forcing conditions. There is thus produced atiprosin (101) [19].

•N H (95)

(96)

HR2 = H;R2 = (101);R1=Et;R2 =

(97); X = H (98); X = Br

Miscellaneous Heterocycles

212 18. THIENOBENZODIAZEPINES

Many examples of retention of activity in the face of replacement of benzene by thiophene have been noted so far. Application of this stratagem to a clozapine-like antipsychotic constitutes yet another example where activity is retained. The seven-membered ring of the compound in question is established by intramolecular amide formation on intermediate 102. Treatment of amide 103 with N-methylpiperazine in the presence of titanium tetrachloride affordsflumezapine(104) [20]. 19. IM1DAZOQUINAZOLINONES The growing awareness of the importance of chirality in biological activity has led to a trend to prepare new drugs in enantiomerically pure form. It is hoped by this means to spare the metabolic system the task of handling the inactive or even potentially toxic enantiomer. The more elegant solution to preparation of Such enantiomers involves the use of chiral synthons. Thus, alkylation of benzyl chloride 105 with ethyl D-alanine gives the chiral alkylation product 106, which is hydrogenated to produce the amine 107. Treatment with cyanogen bromide leads to the N-cyano intermediate 108. This undergoes a double ring closure under the reaction conditions to form the platelet aggregation inhibitor quazinone (109) [21]. ,NH2CO2Et

(102)

H (103) H2

93$ Cl M e (108) ^OEt

N

CH2C1

Cl (105)

O

(106); (107);

Cl

MeH (109)

Miscellaneous Heterocycles

213

20. IMIDAZOPURINES Imidazopyrimidines related to theophylline have been investigated extensively as a source for bronchodilating agents. Alkylation on nitrogen and fusion of an additional heterocyclic ring gives a bronchodilator which also displays some mediator release inhibiting activity. An additionelimination reaction of benzylamine 110 on imidazoline 111 leads to replacement of the thiomethyl group by the amino group (112). This intermediate is then treated in the same pot with nitroso cyanoacetamide (113). The reaction can be envisaged as involving addition of the benzylamine nitrogen to the cyano group and amide interchange between 113 and the imidazole nitrogen. The nitroso group is then reduced catalytically and the resulting diamine 115 cyclized by means of ethyl orthoformate and acetic anhydride to afford fenprinast (116) [22]. CH2NH2 MeS

(116) 21. PYRAZINOISOQUINOLINES One of the more interesting syntheses for the anthelmintic agent praziquantel (123) involves an Oppolzer type electrocyclization reaction. Reduction of the nitrile in benzocyclobutane 117 by means of LAH gives the corresponding amine 118. This is alkylated with chloroacet-

Miscellaneous Heterocycles

214

amide, and the product 119 is acylated with cyclohexylcarbonyl chloride. Reaction of the amide with formaldehyde in the presence of acetic anhydride leads to the carbinolamine acetate 121. Pyrolysis of this intermediate leads to ring opening of the benzocyclobutene to a bis-exomethylene cyclohexadiene and simultaneous loss of acetic acid from the carbinolamine acetate to form a methylene amine 122. Electrocyclic addition of the latter to the diene forms the required two rings at one time. There is thus obtained praziquantel (123) [23].

(117)

(118)

(119); R = H /—v (120); R = CO~\ ) \

f

-o (123) (122) 22. PYRAZ N IOPYRROLOBENZOD A IZEP N IES

(121)

Antidepressant activity is retained in a i n i a n s e r i n analogue in which a fused benzene ring is replaced by pyrrole e v e n though the t w o moieties differ in stereoelectronic properties. T h e starting nitrotoluene 124 is converted to the corresponding benzylamine 126 via bromide 125. Condensation of the a m i n e with the dimethoxy tetrahydrofuran 127 leads to formation of pyrrole 128; reduction of the nitro group then affords aniline 129. Reaction of that intermediate with the methyl hemiacetal from methyl glyoxylate leads to the tricyclic c o m p o u n d 130. This transformation may involve initial reaction of the aldehyde with the amino group; attack of the iminium derivative on the pyrrole will serve to close the ring. Acylation of the secondary amine with chloroacetyl chloride gives the amide 1 3 1 . T h e transient amine which results from displacement of chlorine b y methylamine reacts with the adjacent ester under the reaction conditions to form the r e m a i n i n g

Miscellaneous Heterocycles

215

ring of 132. Reduction of the amide functions by means of LAH leads to aptazapine (133) [24].

NR2

(124); R = H (125); R = Br (126); R = NH2

(128); R = 0 (129); R = H

R CO2Me (130); R = H (131); R = COCH2C1

u Me (133) 23. IMIDAZOQUINOLINES A pair of imidazoquinolines which differ only in substitution patterns differ markedly in biological activities. One of these agents, acodazole (139), shows antineoplastic activity while its seemingly close analogue, furodazole (143), is an anthelmintic agent. Synthesis of the former starts by reaction of 3,4-diaminonitrobenzene with formic acid. Reduction of the nitro group in the product 134 leads to the corresponding amine 135. Condensation of this last intermediate with ethyl acetoacetate proceeds initially to the imine 136; this cyclizes to quinoline 137 on heating. The hydroxyl group is then replaced by chlorine with phosphorus oxychloride (138). Displacement of halogen by means of N-methyl-N-acetyl-p,- phenylenediamine affords acodazole (139) [25]. Acylation of the common starting 3,4-diaminonitrobenzene with furoyl chloride proceeds on the more basic amino group meta to the nitro group to give 140. This is then cyclized to imidazole 141 by means of acetic anhydride. Reduction of the nitro group (142), followed by condensation with ethyl acetoacetate affords furodazole (143) [26]. 24. OXAZOLOQUINOLINES Nitration of quinoline 144 leads to the nitro derivative 145. Reduction of the nitro group leads to

Miscellaneous Heterocycles

216

the orf/io-aminophenol 146. Reaction of that intermediate with methyl trimethoxyacetate leads to formation of a benzoxazole ring. There is thus obtained the mediator release inhibitor agent quazolast (147) [27]. H

H2N H2N

S

NR2 •Me (136)

(134); R = O (135); R = H

NJLAN

H2N-

ccx,

^NO2

Me

(140)

(137);R = (138);R =

M^ (139)

(141); R a O (142); R = H

(143)

Cl

Cl

"NR, OH (144)

(145); R = O (146); R = H

CO2Me (147)

Miscellaneous Heterocycles

217

25. THIAZOLOBENZMIDAZOLES Thefindingthat the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28],

CH2CO2Et

CH2CO2Et

(151) 26. PYRIMIDOINDOLES The two carbonyl groups in isatin (153) show quite different reactivities since one is a ketone and the other an amide. Condensation of that compound with the Grignard reagent from o- chlorobromobenzene thus gives 154. Conjugate addition of the anion from that product to acrylonitrile affords the proprionitrile 155, The cyano group is then reduced to the primary amine by means of LAH. Internal imine formation leads to cyclization. There is thus obtained the antidepressant agent ciclazindol (157) [29].

Miscellaneous Heterocycles

218

27. ETHENOPYRROLOCYCLOBUTISOINDOLES The antineoplastic agent mitindomide (160) in fact represents the well-known product from irradiation of maleimide in benzene [30]. The activity of this old compound was uncovered by one of the large antitumor screens maintained by the National Cancer Institute. The structure is sufficiently complex and the starting materials sufficiently available to lead one to suspect that the product is still produced photochemically. The product can be rationalized by assuming successive 1,4 and 1,2 additions to benzene. Intermediate 159a involves the 1,4 followed by 1,2 addition; intermediate 159b presupposes the steps occur in the reverse order.

(153)

(154)

(155)

CH2CII2CN

CH2CH2CH2NH2 (157)

(156)

HH
1 NH

HH

O J

(159a)

(159b)

HN

Miscellaneous Heterocycles

219

28. THIENOTRIAZOLODIAZEPINES Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thioamide 165; reaction of that intermediate with hydrazine leads to the amino amidine 166. Condensation of this with ethyl orthoacetate gives the anxiolytic agent brotizolam (167) [31]. O

(162);R = C1 (163); R= NH2

(167) 29. IMIDAZOBENZODIAZEPINES

(164); R = O (165); R = S

(166)

Omission of the pendant aromatic ring from the benzodiazepine structure affords an agent which antagonizes the action of the more classical benzodiazepines at both receptor and whole animal levels. This agent thus finds some use in treatment of tranquilizer overdoses. Reaction of the substituted isatoic anhydride 168 with sarcosine may be envisaged as proceeding initially to the diamide 169 by ring opening by nucleophilic nitrogen. Amide interchange will give the observed product, benzodiazepinone 170. This intermediate is then condensed with the isonitrile 171. Addition of nitrogen from the secondary amide to the highly electrophilic isonitrile function will afford the intermediate amidine 172. This undergoes Claisen type condensation under the reaction

Miscellaneous Heterocycles

220

conditions to form an imidazole ring. There is thus obtained flumazenil (173) [32]. 30, IMEDAZOBENZOTfflADIAZEPINES The breadth of the SAR in the clozapine series is demonstrated by the fact that antipsychotic activity is retained when the dibenzdiazepine nucleus of the parent molecule is replaced by an imidazobenzothiadiazepine ring system which contains twice as many hetero atoms. Preparation H 9

S

C—NCH2CO2H

(168)

(169)

O M Me

"i N •M 6 (170) e CNC E 2t (1H 7C 12)O CH=NCH C E 2O 2t

(172) of that agent starts wth i nucelophcil aromacit substiutoin on 2u -florontriobenzene (174 means of m id iazoel-2-thoil to gvie sufld ie 175. The ntiro group is then reduced and this n itermedaite cycziled by means of thoiphosgene (177). Ak lyalotin of the th proceeds on suflur to gvie the meh tyl thoiether 178. Tream t ent of this last wth i zn ie resutls in repalcement of the thoimethyl group by the pp ierazn ie and ofrmaoitn psychotci agent pentaipn ie (179) [33]. S N O2 (174)

NRn2 H ((117756));; R = O ( 1 R = H 77)

Miscellaneous Heterocycles

221

(179)

\ Me

(178)

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Cross Index of Drugs

ACE Inhibitors Ciclazapril Delapril Enalapril Enalaprilate Indolapril Lisinopril

PentoprH Quinapril Ramipril Spirapril Zofenopril Adrenergic Alpha Blocker

Alfuzosin Atiprosin

Biclodil Doxazosin Adrenergic Beta Blocker

Betaxolol Bisoprolol Celiprolol Cetamolol Cicloprolol

Exaprolol Flavodilol Flestolol Xamoterol Aldose Reductase Inhibitor

Tolrestat 223

Cross Index of Drugs

224 Analgesic

Menabitan Nalmefine Olvanil Picenadol Pinadoline Xorphanol

Dezocine Flupirtine Fluproquazone Fluradoline Ketorolac Ketorphanol Androgen Antagonist Oxendolone Anthelmintic

Furodazole Netobimin Praziquantel

Closantel Dribendazole Etibendazole Febantel Antianginal

Mioflazine

Lidoflazine Antiarrhythmic

Indecainide Moricizine Recainam Suricainide Transcainide

Amiodarone Benzbromarone Butoprozine Cibenzoline Edifolone Antiasthmatic

Tazifylline Tiaramide

Azelastine Piriprost Procaterol Antibacterial Amdinocillin Amifloxacin Apalcillin Aztreonam

Carumonam Cefbuperazone Cefepime Cefetamet

Cross Index of Drugs

225

Cefixime Cefmenoxime Cefmetazole Cefoperazone Cefotaxime Cefotetan Cefotriaxone Cefpimizole Cefpiramide Cefroxadine Ceftiofur Difloxacin

Enoxacin Gloximonam Imipenem Mecillinam Norfloxacin Ofloxacin Oximonam Pefloxacin Pentizidone Sulbactam Temocillin Anticonvulsant

Fengabine Fluzinamide Lamotrigine Nabazenil

Nafimidone Progabide Tolgabide Zonisamide Antidepressant

Alaproclate Aptazapine Azaloxan Bipenamol Ciclazindol Fezolamine Indeloxazine Lofepramine Lortalamine Lorzafone

Meclobemide Minaprine Nafazodone Napamezole Nomifensine Oxaprotiline Sertraline Tampramine Tomoxetine Antidiabetic

Ciglitazone Linogliride

Sodium Palmoxirate Antidiarrheal

Rolgamidine Antiemetic Cisapride

Remoxipride

Cross i^ross Index of Drugs

226

Zacopride

Naboctate Antifungal

Terbinafine Zinoconazole

Bifonazole Enilconazole Fenticonazole Antiglaucoma Naboctate Antigout Amflutiazole Antihistaminic

Loratidine Terfenadine Triprolidine

Acrivastine Cetirzine Ebastine Levocabastine Antihy perli poproteinemic Acifran Antihypertensive

Ofornine Pinacidil Quinpirole Tinabinol Tipentosin

Dilevalol Fenoloopam Imiloxan Lofexidine Losulazine Midodrine Anti-Inflammatory - Non steroidal Anirolac Bromfenac Enolicam Felbinac Fentiazac Furaprofen

Lobenzarit Lofemizole Olsalazine Tenoxicam Trifenagrel

Cross Index of Drugs

227

Anti-Inflammatory - Steroidal Naflocort Prednicarbate Ticabesone Propionate Timobesone Acetate Tipredane Tixocortol Pivalate

Clobetasol Propionate Clobetasone Butyrate Desoximetasone Fluticasone Propionate Halcinonide Mometasone Antimalarial

Tebuquine

Enpiroline Antimigrane Tropanserin Antineoplastic Acivicin Acodazole Ara-AC Bisantrene Bropirimine Caracemide Dezaguanine Diaziquone Eflornithine

Fazarabine Fludarabine Mitindomide Piritrexim Teroxirone Tiazofurine Trimetrexate Tubulozole Teroxirone Antiparasitic

Clorsulon Antiparkinsonian Ciladopa Antiprotozoal Eflornithine Antipsoriatic Acitretin

Lonapalene

Cross Index of Drugs

228 Antipsychotic

Pentiapine Piquindone Rimcazole

Duoperone Flumezapine Neflumozide Antisecretory Fenoctimine Antithrombotic

Pirmagrel Quazinone

Dazoxiben Itazigrel Oxagrelate Antiulcer

Nizatidine Omeprazole Temelastine Zaltidine

Altanserin Donetidine Etintidine Isotiquimide Lupitidine Antiviral

Edoxudine Enviradene Fosarilate Zidovudine

Avridine AZT Bropirimine Desciclovir Disoxaril Anxiolytic

Reclazepam

Brotizolam Gepirone Benzodiazepine Antagonist Flumazenil Biological Response Modifier Fanetizole

Tilomisole

Cross Index of Drugs

229 Bronchodilator Zindotrine

Fenprinast Calcium Channel Blockers

Flordipine Fostedil Nilvadipine

Amlodipine Darodipine Felodipine Cardiovascular

Isomazole Pehinone Piroximone

Dopexamine Enoximone Imazodan Coccidiostat Arprinocid Cognition Enhancer Aniracetam Indeloxazine

Mefenidil Contraceptives

Altrenogest

Epostane Diuretic

Betnitradine Brocrinat

Tripamide Growth Promoter

Cimaterol Hypocolesterolemic Timefurone

Cross Index of Drugs

230 Immunoregulator Ristianol Local Anesthetic Recainam Mediator Release Inhibitor Cromitrile Eclazolast Nedocromil Probicromil Proxicromil

Quazolast Tiacrilast Tiprinast Tranilast

Muscle Relaxant Cinflumide Neuromuscular Blocker Pipecuronium Bromide Scabicide Amitraz Sedative Zolpidem

Trepipam Zolazepam Serotonin Antagonists Ritanserin

Setoperone

C u m u l a t i v e I n d e x , V o l s , 1-4

Acebutolol, 2,109 Aceclidine, 2,295 Acedapsone, 2,112 Acenocoumarole, 1, 331 Aceperone, 2,332 Acephylline, 1,425 Acetaminophen, 1,111 Acetanilide, 1, 111; 2,97 Acetazolamide, 1,249 Acetohexamide, 1,138 Acetyl methoxprazine, 1,131 Acetylmethadol, 1, 81 Acifran, 4,78 Acitretin, 4, 35 Acivicin, 4, 85 Aclomethasone, 3,96 Acodazole, 4,215 Acrivastine, 4, 105 Actodigin, 3,99 Acyclovir, 3,229; 4, 31,116, 165 Adinazolam, 2, 353 Adiphenine, 1, 81 Adrenalone, 2, 38 Alaproclate, 4, 33 Albendazole, 2,353 Albuterol, 2, 43 Albutoin, 2,261 Alclofenac, 2,68 Aldosterone, 1,206 Aletamine, 2,48 Alfaprostol, 4, 9 Alfentanyl, 3,118 Alfuzosin, 4,149 Algestone acetonide, 2,171 Alipamide, 2,94 Allobarbital, 1,269 Allopurinol, 1,152,269 Allylestrenol, 1,172 Alonimid, 2, 295 Aloxidone, 1,232 Alpertine, 2,342

Alphaprodine, 1, 304; 2,238 Alpha-eucaine, 1, 8 Alprazolam, 3,197 Alprenolol, 1,177 Alprostadil, 3, 2 Alrestatin, 3,72 Altanserin, 4,151 Althiazide, 1,359 Altrenogest, 4,66 Alverine, 2, 55 Amacetam, 3,127 Amantidine, 2,18 Ambucaine, 1,11 Ambucetamide, 1,94 Ambuside, 2,116 Amcinafal, 2,185 Amcinafide, 2,185 Amdinocillin, 4,177 Amedaline, 2,348 Ametantrone, 3,75 Amfenac, 3, 38 Amflutiazole, 4,94 Amicibone, 2,11 Amicycline, 2,228 Amidephrine, 2,41 Amidinocillin, 3,208 Amidoquine, 1, 342 Amifloxacin, 4,144,145 Amiloride, 1,278 Aminitrozole, 1, 247 Aminoglutetimide, 1,257 Aminometetradine, 1,265 Aminophenazole, 1,248 Aminophylline, 1,427 Aminopromazine, 1, 390 Aminopropylon, 1,234 Aminopyrine, 1,234; 2,262 Aminorex, 2,265 Amiodarone, 4,127,156 Amiquinsin, 2, 363 231

232 Amisometradine, 1, 266 Amitraz, 4, 36 Amitriptyline, 1,151, 404 Amlodipine, 4,108 Amobarbital, 1, 268 Amodiaquine, 4,140 Amoproxan, 2,91 Amopyroquine, 1, 342 Amoxapine, 2,428 Amoxicillin, 4,179, 180 Amoxycillin, 1, 414 Amphecloral, 2,48 Amphetamine, 1, 37,70; 2,47 Amphetaminil, 2,48 Arnpicillin, 1,413; 2,437; 4,179 Amprolium, 1,264 Ampyzine, 2, 298 Amqinate, 2, 370 Amrinone, 3, 147; 4,90,115,163 Anagesterone acetate, 2,165 Anagrelide, 3,244 Androstanolone, 1, 173 Anidoxime, 2,125 Anileride, 1, 300 Anilopam, 3, 121 Aniracetam, 4, 39 Anirolac, 4,158 Anisindandione, 1, 147 Anitrazafen, 1,147 Antazoline, 1,242 Antipyrine, 1, 234 Apalcillin, 4,179 Apazone, 2,475 Aprindene, 2, 208 Aprobarbital, 1, 268 Aprophen, 1,91 Aptazapine, 4, 215 Ara-A C, 4,122 Arbaprostil, 3, 8 Arildone, 3,45 Arprinocid, 4,165, 167 Astemizole, 3,177 Atenolol, 2,109 Atiprosin, 4, 211 Atropine,l,35,71,93;2,71 Atropine, 4, 39 Avridine, 4 , 1 Azabon, 2,115 Azaclorzine, 3, 241 Azacosterol, 2, 161 Azacyclonol, 1,47 Azaloxan, 4,138 Azanator, 2,457 Azaperone, 2, 300 Azarole, 3,129

Cumulative Index, Vol. 1-4 Azastene, 3, 89 Azatadine, 2,424 Azathioprine, 2,464 Azelastine, 4,152 Azepinamide, 1,137 Azepindole, 3,242 Azipramine, 3, 246 Azlocillin, 3,206; 4,179 Azoconazole, 3,137 Azolimine, 2,260 Azomycin, 1,238 Azosemide, 3,27 AZQ,4,51 AZT,4,118 Aztreonam, 4,193, 195 Bacampicillin, 3, 204 Baclofen, 2,121 Bamethan, 2, 39 Bamiphylline, 1,426 Bamipine, 1, 51 Bamnidazole, 3,132 Barbital, 1,267 BAS, 2,96 BCNU, 2, 12 Becanthone, 2,413 Beloxamide, 2, 56 Bemidone, 1,305 Bemigride, 1,258 Bemitradine, 4,168 Benactyzine, 1,93 Benaprizine, 2,74 Bendazac, 2, 351 Bendroflumethazide, 2, 358 Benfurodil, 2, 355 Benorterone, 2,156 Benoxaprofen, 2, 356 Benperidol, 2, 290 Benproperine, 2,100 Bentazepam, 3,235 Bentiromide, 3, 60 Benzbromarone, 2, 354; 4,127 Benzestrol, 1,103 Benzetimide, 2,293 Benzilonium bromide, 2, 72 Benzindopyrine, 2,343 Benziodarone, 1, 313 Benzocaine, 1,9 Benzoctamine, 2,220 Benzodepa, 2,122 Benzodiazepines, 4,48 Benzphatamine, 1,70 Benzquinamide, 1, 350 Benztriamide, 2,290 Benzydamine, 1, 323; 2, 350

233

Cumulative Index, Vol. 1-4 Benzylpenicillin, 1, 408 Bepridil, 3, 46 Betahistine, 2, 279 Betamethasone, 1,198 Betaxolol, 4,26 Beta-Eucaine, 1,9 Bethanidine, 1, 55 Bevantolol, 3, 28 Bezafibrate, 3,44 Bicifadine, 3, 120 Biclodil, 4, 38 Bifonazole, 4,93 Bipenamol, 4, 45 Biperiden, 1, 47 Bisantrene, 4, 62 Bishydroxycoumarin, 1, 331 Bisoprolol, 4, 28 Bitolterol, 3,22 Bolandiol diacetate, 2,143 Bolasterone, 1,173; 2,154 Boldenone, 2,153 Bolmantalate, 2,143 Boxidine, 2,99 Bretylium tosylate, 1, 55 Brocrinat, 4, 130 Brofoxine, 3, 191 Bromadoline, 4, 6 Bromdiphenhydramine, 1,42 Bromfenac, 4,46 Bromhexine, 2,96 Bromindione, 2, 210 Bromisovalum, 1, 221 Bromoxanide, 2,94 Brotnperidol, 2, 331 Brompheniramine, 1,77 Broperamole, 3,139 Bropirimine, 4,116 Brotizolam, 4, 219 Bucainide, 2, 125 Bucindolol, 3, 28 Buclizine, 1, 59 Bucloxic acid, 2,126 Budesonide, 3,95 Buformin, 1,221; 2, 21 Bufuralol,2, 110 Bumetanide, 2, 87 Bunaftine, 2, 211 Bunamidine, 2, 212 Bunitridine, 2, 215 Bunitrolol, 2, 106 Bunolol,2, 110,215,280 Bupicomide, 2, 280 Bupivacaine, 1,17 Buprenorphine, 2, 321 Bupropion, 2,124

Buquinolate, 1,346 Burimamide, 2,251 Buspirone, 2,300; 4,119 Butabarbital, 1,268 Butacaine, 1,12 Butacetin, 2,95 Butaclamol, 2,226 Butalbital, 1, 268 Butamirate, 2,76 Butamisole, 3, 226 Butaperazine, 1,381 Butaprost, 4,13 Butaxolamide, 1, 249 Buterizine, 3,175 Butethal, 1,268 Butoconazole, 3,134 Butoprozine, 4,156 Butorphanol, 2,325 Butoxamine, 1, 68 Butriptyline, 1,151 Butropium bromide, 2, 308 Butylallonal, 1,269 Butylvynal, 1, 269 Caffeine, 1,111,423 Calcifediol, 3,101 Calcitriol, 3,103 Calusterone, 2,154 Cambendazole, 2, 353 Canrenoate, 2, 174 Canrenone, 2,174 Capobenic acid, 2,94 Captodiamine, 1,44 Captopril, 3,128; 4,7, 58, 81,128 Caracemide, 4,1 Caramiphen, 1,90 Carbacephalothin, 2, 390 Carbacycline, 4,14 Carbadox, 2, 390 Carbamazepine, 1, 403 Carbantel, 3,57 Carbaprost, 3,7 Carbazeran, 3,195 Carbencillin, 1,414; 2,437 Carbetidine, 1,90 Carbidopa,2,119 Carbimazole, 1,240 Carbinoxamine, 1, 43; 2, 32 Carbiphene, 2,78 Carboplatin, 4,16 Carbromal, 1, 221 Carbubarbital, 1,269 Carbutamide, 1,138 Carbuterol, 2,41 Carfentanyl, 3,117

234 Carisoprododol, 1,219 Carmantidine, 2,20 Carmustine, 2,12 Carnidazole, 2, 245 Caroxazone, 3,191 Carphenazine, 1, 383 Carpipramine, 2,416 Carprofen, 2,169 Cartazolate, 2,469 Carteolol,3,183 Carumonam, 4,193 Cefaclor, 3, 209 Cefadroxyl, 2,440 Cefamandole, 2,441 Cefaparole, 3, 212 Cefatrizine, 3, 211 Cefazaflur, 3, 213 Cefazolin, 3, 442 Cefbuperazone, 4,189,190 Cefepime,4, 185,187 Cefetamet, 4, 184 Cefixime,4,184, 185 Cefmenoxirne, 4,187 Cefmetazole, 4, 190,191 Cefonicid, 3, 213 Cefoperazone, 4, 185,188,189, 190 Ceforanide, 3, 214 Cefotaxime, 3, 216; 4,185,187,188 Cefotetan,4, 191,192 Cefotiam, 3,215 Cefotriaxone, 4,190 Cefoxitin, 2,435; 4,190 Cefpimazole, 4,185 Cefpiramide, 4, 188 Cefroxadine, 3, 210; 4,182 Cefsulodin, 3,214 Ceftazidime, 4,192 Ceftazidine, 3, 216 Ceftiofur,4,187 Ceftizoxime, 3, 218 Cefuroxime, 3, 216 Celiprolol, 4, 27 Cephalexin, 1,417; 2,439; 4, 182 Cephaloglycin, 1,417; 4, 185 Cephaloridine, 1, 417 Cephalothin, 1, 420 Cephapyrin, 2,441 Cephradine, 2,440; 4,182 Cetaben, 3, 60 Cetamolol, 4,26 Cetiedil, 3,42 Cetirzine,4,118 Cetophenicol, 2,46 Cetraxate, 4, 6 Chloroquine, 1, 341

Cumulative Index, Vol. 1-4 Chloraminophenamide, 1,133 Chloramphenicol, 1,75; 2,28,45 Chlorazanil, 1,281 Chlorbenzoxamine, 1,43 Chlorcyclizine, 1,58 Chlordiazepoxide, 1, 365; 2,401 Chlorfluperidol, 1,306 Chlorguanide, 1,115 Chlorimpiphene, 1,385 Chlorindandione, 1,147 Chlormadinone acetate, 1,181; 2,165 Chlormidazole, 1,324 Chlorophenylalanine, 2, 52 Chloroprocaine, 1,11 Chloropyramine, 1,402 Chlorothen, 1, 54 Chlorothiazide, 1, 321; 2,395 Chlorotrianisine, 1,104 Chlorphenamide, 1,133, 358 Chlorphendianol, 1,46 Chlorphenesin, 1,118 Chlorpheniramine, 1,77 Chlorphenoxamine, 1,44 Chlorphentermine, 1,73 Chlorproethazine, 1, 379 Chlorproguanil, 1, 115 Chlorpromazine, 1, 319, 378; 2,409; 3, 72 Chlorpropamide, 1,137 Chlorprothixene, 1, 399 Chlorpyramine, 1, 51 Chlortetracycline, 1, 212 Chlorthalidone, 1, 322 Chlorzoxazone, 1, 323 Cholrexolone, 1, 321 Chromoglycate, 1, 313, 336 Chromonor, 1, 331 Cibenzoline, 4, 87 Ciclafrine, 2,226 Ciclazindol, 4, 217 Cicloprofen, 2, 217 Cicloprolol, 4, 25 Cicloprox, 2,282 Ciglitazone, 4, 33 Ciladopa, 4, 20,22 Cilastatin, 4,181 Cilazapril, 4,170 Cimaterol, 4,23 Cimetidine, 2, 253; 4, 89,95,112 Cinanserin, 2,96 Cinepazet, 3,157 Cinepazide, 2, 301 Cinflumide, 4, 35 Cingestol, 2,145 Cinnameridine, 2, 39 Cinnarizine, 1, 58

Cumulative Index, Vol. 1-4 Cinoxacin, 2, 388 Cinromide, 3, 44 Cintazone, 2, 388, 474 Cintriamide, 2, 121 Ciprefadol, 3,119 Ciprocinonide, 3,94 Ciprofibrate, 3,44 Ciprofloxacin, 4,141 Ciprostene calcium, 4,14 Ciramadol, 3,122 Cisapride, 4, 42 Cisplatin, 4,15,16,17 Citenamide, 2, 221 Clamoxyquin, 2, 362 Clavulanic acid, 4,180 Clazolam, 2, 452 Clazolimine, 2,260 Clebopride, 4,42 Clemastine, 2, 32 Clemizole, 1, 324 Clioxanide, 2, 94 Cliprofen, 2, 65 Clobazam, 2,406 Clobetasol propionate, 4, 72 Clobetasone butyrate, 4,72 Clobutinol, 2, 121 Clocapramine, 2,416 Clocental, 1, 38 Clocortolone acetate, 2,193 Clodanolene, 3, 130 Clodazon, 2, 354 Clofenpyride 2, 101 Clofibrate, 1,119; 2,79, 101,432 Clofilium phosphate, 3,46 Clogestone, 2,166 Clomacran, 2, 414 Clomegestone acetate, 2,170 Clomethrone, 2, 170 Clomifene, 1, 105,148; 2,127 Clominorex, 2, 265 Clonidine, 1,241; 4, 5, 38, 88 Clonitazene, 1, 325 Clonixeril,2,281 Clonixin, 2, 281 Clopamide, 1, 135; 2,93 Clopenthixol, 1, 399 Cloperidone, 2, 387 Cloperone, 3, 150 Clopimozide, 2, 300 Clopipazam, 3,237 Clopirac, 2, 235 Cloprednol, 2,182 Cloprenaline, 2, 39 Cloprostenol, 2, 6 Clorsulon, 4,50

235 Closantel, 3,43; 4, 36 Closiramine, 2,424 Clothiapine, 1,406; 2, 429 Clothixamide, 2,412 Cloticasone propionate, 4,75 Cloxacillin, 1,413 Cloxazepam, 1, 370 Clozapine, 2,425; 4,212,220 Cocaine, 4, 39 Codeine, 1, 287; 2,317 Codorphone, 3, 112 Codoxime, 2, 318 Colchicine, 1,152,426 Colterol, 3, 21 Cormethasone acetate, 2,194 Cortisone, 1,188; 2,176 Cortisone acetate, 1,190 Cortivazol, 2,191 Cotinine, 2, 235 Cromitrile, 4, 137 Cromoglycate, 3, 66,235 Cromolyn sodium, 4,44,137,150, 205 Cyclacillin, 2,439 Cyclandelate, 1,94 Cyclazocine, 1, 298; 2, 327 Cyclindole, 3,168 Cyclizine, 1,58 Cyclobarbital, 1, 269 Cyclobendazole, 2, 353 Cyclobenzaprine, 3,77 Cycloguanil, 1,281 Cyclomethycaine, 1,14 Cyclopal, 1,269 Cyclopenthiazide, 1,358 Cyclopentolate, 1,92 Cyclophosphamide, 3,161 Cyclopyrazate, 1,92 Cycloserine, 3,14; 4, 86 Cyclothiazide, 1, 358 Cycrimine, 1,47 Cyheptamide, 2,222 Cypenamine, 2,7 Cyprazepam, 2,402 Cyprlidol,2, 31 Cyproheptadine, 1,151 Cyproquinate, 2, 368 Cyproterone acetate, 2,166 Cyproximide, 2,293 Dacarbazine, 2,254 Daledanin, 2, 348 Danazol, 2,157 Dantrolene, 2,242 Dapsone,l, 139; 2,112 Darodipine, 4,107

236 Dazadrol, 2, 257 Dazoxiben, 4,91 Debrisoquine, 2, 374 Declenperone, 3,172 Decoquinate, 2, 368 Delapril, 4, 58 Delmadinone acetate, 2,166 Demoxepam, 2,401 Deprostil, 2, 3 Desciclovir, 4,165 Descinolone acetonide, 2,187 Deserpidine, 1,320 Desipramine, 1,402; 4,201 Desonide, 2,179 Desoximetasone, 4,70 Deterenol, 2, 39 Dexamethasone, 1,199 Dexbrompheniramine, 1, 77 Dexchlorpheniramine, 1,77 Dexivacaine, 2,95 Dexnorgestrel acetime, 2,152 Dextroamphetamine, 1,70 Dextromoramide, 1, 82 Dextromorphan, 1, 293 Dextrothyroxine, 1,92 Dezaguanine, 4, 162,163 Dezocine, 4, 59 Diacetolol, 3, 28 Diamocaine, 2, 336 Dianithazole, 1, 327 Diapamide, 2,93 Diaveridine, 2, 302 Diazepam, 1, 365; 2, 395 Diaziquone, 4, 51 Dibenamine, 1, 55 Dibenzepin, 1, 405; 2, 424,471 Dibucaine, 1, 15 Dichlorisone, 1, 203 Dichloroisoproterenol, 1,65; 2,106 Dichlorophen amide, 1,133 Diclofenac, 2, 70 Dicloxacillin, 1,413 Dicoumarol, 1,147 Dicyclomine, 1, 36 Dienestrol, 1,102 Diethylcarbamazine, 1,278 Diethylstilbestrol, 1,101 Diethylthiambutene, 1,106 Difenoximide, 2, 331 Difenoxin, 2, 331 Difloxacin, 4, 143,144,145 Diflucortolone, 2,192 Diflumidone, 2,98 Diflunisal, 2, 85 Difluprednate, 2,191

Cumulative Index, Vol. 1-4 Diftalone, 3,246 Dihexyverine, 1, 36 Dihydralizine, 1, 353 Dihydrocodeine, 1,288 Dilevalol, 4,20 Diltiazem, 3, 198 Dimefadane, 2, 210 Dimefline, 2, 391 Dimetacrine, 1, 397 Dimethisoquine, 1,18 Dimethisterone, 1,176,187 Dimethothiazine, 1, 374 Dimethoxanate, 1,390 Dimethylpyrindene, 1,145 Dimethylthiambutene, 1,106 Dimetridazole, 1, 240 Dinoprost, 1, 27 Dinoprostone, 1, 30 Dioxadrol, 2, 285 Dioxyline, 1, 349 Diphenhydramine, 1,41 Diphenidol, 1,45 Diphenoxylate, 1, 302, 331, Diphenylhydantoin, 1,246 Diphepanol, 1,46, Dipipanone, 1, 80 Dipireftin, 3, 22 Diproverine, 1, 94 Dipyridamole, 1,428 Dipyrone, 2, 262 Disobutamide, 3,41 Disopyramide, 2, 81; 3, 41 Disoxaril, 4, 86 Disulfiram, 1,223 Dithiazanine, 1, 327 Dixyrazine, 1, 384 Dobutamine, 2, 53 Doconazole, 3,133 Domazoline, 2, 256 Domperidone, 3,174 Domperidone, 4,133 Donetidine, 4,114 Dopamantine, 2, 52 Dopamine, 4, 20 Dopexamine, 4,22 Dorastine, 2,457 Dothiepin, 3, 239 Doxapram, 2,236 Doxaprost, 2, 3 Doxazosin, 4,148 Doxepin, 1,404 Doxorubicin, 4, 62 Doxpicomine, 3,122 Doxylamine, 1,44 Dribendazole, 4,132

Cumulative Index, Vol. 1-4 Drindene, 3, 65 Drobuline, 3,47 Drocinonide, 2,186 Dromostanolone, 1,173 Droperidol, 1, 308 Droprenylamine, 3, 47 Droxacin,3, 185 Duoperone, 4,199 Dydrogesterone, 1, 185 Ebastine, 4,48,49 Eclanamine, 4, 5, 6 Eclazolast, 4,131 Econazole, 2,249 Ectylurea, 1, 221 Edifolone, 4, 69 Edoxudine,4, 117 Eflornithine, 4, 2, 3 Elantrine, 2,418 Elfazepam, 3,195 Elucaine, 2, 44 Emilium tosylate, 3,47 Enalapril,4,58,81,82,83,84 Enalaprilat, 4,7, 82 Encainide, 3,56 Encyprate, 2, 27 Endralazine, 3,232 Endrysone, 2,200, Enilconazole, 4,93 Enisoprost, 4, 11 Enolicam, 4, 148 Enoxacin, 4, 145 Enoximone, 4, 93 Enpiroline, 4,103 Enprofylline, 4,165 Enprostil, 4, 10 Enviradene, 4, 131 Enviroxime, 3,177 Ephedrine, 1,66 Epimestrol, 2,13 Epinephrine, 1,95; 2, 241; 4, 19, 28 Epirazole, 3,152 Epithiazide, 1, 359 Epoprostenol, 3, 10; 4, 159 Epostane, 4, 68 Eprazinone, 1, 64 Eprozinol, 2,44 Ergosterol, 4,55 Eritadenine, 2,467 Erytriptamine, 1,317; 2, 373 Esmolol, 4,27 Estradiol, 1,162; 2,136 Estradiol benzoate, 1,162 Estradiol cypionate, 1, 162 Estradiol dipropionate, 1,162

237 Estradiol hexabenzoate, 1,162 Estramustine, 3, 83 Estrazinol, 2,142 Estrofurate, 2,137 Estrone, 1,156 Etafedrine, 2, 39 Etapralol, 3,28 Etazolate, 2,469 Eterobarb, 2,304 Ethacrynic acid, 1,120; 2,103 Ethambutol, 1,222 Ethamivan, 2,94 Ethionamide, 1,255 Ethisterone, 1,163 Ethithiazide, 1,358 Ethoheptazine, 1,303 Ethonam, 2, 249 Ethopropazine, 1, 373 Ethosuximide, 1,228 Ethotoin, 1, 245 Ethoxzolmide, 1,327 Ethylestrenol, 1,170 Ethylmorphine, 1, 287 Ethynerone, 2,146 Ethynodiol diacetate, 1,165 Ethynodrel, 1, 164 Ethynylestradiol, 1,162 Etibendazole, 4,132 Etidocaine, 2,95 Etinfidine, 3,135 Etintidine, 4, 89 Etoclofene, 2, 89 Etofenamate, 4,42 Etomidate, 3, 135 Etonitazine, 1,325 Etoprine, 3,153 Etorphine, 2,321 Etoxadrol, 2,285 Etretinate, 4, 35 Exaprolol, 4,25 Famotidine, 2, 37 Fanetizole, 4, 95 Fantridone, 2,421 Fazarabine, 4,122 Febantel, 4, 35 Felbinac, 4, 32 Felodipine, 4,106 Felsantel, 3,57 Fenalamide, 2, 81 Fenbendazole, 3,176 Fenbufen, 2,126 Fencamfine, 1,74 Fenclofenac, 3,37 Fenclorac, 2,66

238 Fenclozic acid, 2,269 Fendosal, 2,170 Fenestrel, 2,9 Fenethylline, 1,425 Fenfluramine, 1,70 Fengabine, 4,47 Fenimide, 2,237 Fenisorex, 2, 391 Fenmetozole, 2,257 Fenobam, 3,136 Fenoctimine, 4,109 Fenoldopam, 4,147 Fenoprofen, 2, 67 Fenoterol, 2, 38 Fenpipalone, 2, 293 Fenprinast, 4,213 Fenprostalene, 4, 9, 10 Fenquizone, 3,192 Fenretinide, 4,7 Fenspririden, 2,291 Fentanyl, 1,299, 306; 3,116 Fentiazac, 4,96 Fenticonazole, 4, 93 Fenyripol, 2, 40 Fetoxylate, 2, 331 Fezolamine, 4, 87 Flavodilol, 4, 137 Flavoxate, 2, 392 Flazolone, 2, 337 Flecainide, 3, 59 Flestolol, 4,41 Fletazepam, 2,403 Floctacillin, 1,413 Floctafenine, 3,184 Flordipine, 4,107 Fluandrenolide, 2,180 Fluanisone, 1, 279 Fluazepam, 1, 366 Flubanilate, 2,98 Flubendazole, 2, 354 Flucindolol, 3,168 Flucinolone, 3,94 Flucinolone acetonide, 1,202 Flucloronide, 2,198 Fludalanine, 3,14 Fludarabine, 4,167 Fludorex, 2,44 Fludrocortisone, 1,192 Fludroxycortide, 1, 202 Flufenamic acid, 1, 110; 2,69; 4,42 Flumazenil, 4, 220 Flumequine, 3,186 Flumethasone, 1, 200 Flumethiazide, 1, 355; 2, 355 Flumetramide, 2, 306

Cumulative Index, Vol. 1-4 Fluminorex, 2,265 Flumizole, 2,254; 3,158 Flumoxonide, 3,95 Flunarizine, 2, 31 Flunidazole, 2,246 Flunisolide, 2,181 Flunitrazepam, 2,406 Flunixin,2,281 Fluorocortolone, 1,204 Fluorogestone acetate, 2, 183 Fluorometholone, 1, 203 Fluoroprednisolone, 1, 292 Fluorouracil, 3,155 Fluotracen, 3,73 Fluoxetine, 3, 32 Fluoxymestrone, 1,175 Fluperamide, 2, 334 Fluperolone acetate, 2, 185 Fluphenazine, 1, 383 Flupirtine, 4,102 Fluproquazone, 3,193; 4,150 Fluprostenol, 2,6 Fluquazone, 3, 193 Fluradoline, 4,202 Flurbiprofen, 1, 86 Fluretofen, 3, 39 Fluspiperone, 2,292 Fluspirilene, 2,292 Flutamide, 3,57 Flutiazine, 2,431 Fluticasone propionate, 4,75 Flutroline, 3, 242 Fluzinamide, 4, 29 Formocortal, 2,189 Fosarilate, 4, 31 Fosazepam, 3, 195 Fostedil,4,134 Frentizole, 3,179 Fumoxicillin, 4,179 Furaltadone, 1, 229 Furaprofen, 4, 127 Furazolidone, 1,229 Furegrelate, 4,125,126 Furethidine, 1, 301 Furobufen, 2,416 Furodazole, 4, 215 Furosemide, 1,134; 2, 87 Fusaric acid, 2,279 Gamfexine, 2, 56 Gemcadiol, 3,15 Gemeprost, 4,11,12 Gemfibrozil, 3,45 Gepirone, 4,120 Gestaclone, 2,169

Cumulative Index, Vol. 1-4 Gestodene, 3, 85 Gestonorone, 2,152 Gestrinone, 3, 85 Glaphenine, 1, 342 Gliacetanile, 3,61 Gliamilide, 2, 286 Glibornuride, 2, 117 Gliflumide, 3, 61 Glipizide,2, 117 Gloximonam, 4,195 Glutethemide, 1, 257 Glyburide,2,139 Glybuthiazole, 1,126 Glycosulfone, 1, 140 Glyhexamide, 1,138 Glymidine, 1,125 Glyoctamide, 2, 117 Glyparamide, 2, 117 Glyprothiazole, 1,125 Griseofulvin, 1,314 Guaiaphenesin, 1,118 Guanabenz, 2, 123 Guanacycline, 1, 260 Guanadrel, 1,400 Guanethidine, 1, 28; 2,100 Guanfacine, 3,40, Guanisoquin, 2, 375 Guanoclor, 1,117; 2, 101 Guanoxabenz, 2, 123 Guanoxan, 1, 352 Guanoxyfen, 2,101 Halcinonide, 2,187; 4,75 Halofantrine, 3,76 Halofenate, 2, 80,102 Halopemide, 3,174 Haloperidol, 1, 306; 4, 133 Haloprednone, 3,99 Haloprogesterone, 3,173 Heptabarbital, 1,269 Hepzidine, 2, 222 Heroin, 1,288; 2, 315 Hetacillin, 1,414 Heteronium bromide, 2,72 Hexahydroamphetamine, 4,4 Hexesterol, 1, 102 Hexethal, 1, 268 Hexobarbital, 1,273 Hexobendine, 2,92 Hexylcaine, 1,12 Histapyrrodine, 1, 50 Hoquizil,2,381 Hycanthone, 1, 398; 2,413 Hydracarbazine, 2,305 Hydralazine, 1,353

239 Hydrochlorobenzethylamine, 1,59 Hydrochlorothiazide, 1, 358, Hydrocodone, 1,288 Hydrocortisone, 1,190 Hydrocortisone acetate, 1,190 Hydroflumethiazide, 1,358 Hydromorphone, 1,288 Hydroxyamphetamine, 1,71 Hydroxychloroquine, 1, 342 Hydroxyphenamate, 1,220 Hydroxyprocaine, 1,11 Hydroxyprogesterone, 1,176,190 Hydroxyzine, 1, 59; 4,118 Ibufenac, 1, 86 Ibuprofen, 1, 86; 2, 218, 356 Icotidine, 4,113 Ifenprodil, 2, 39 Ifosfamide, 3,151 Imafen, 3,226 Imazodan, 4,90,93 Imidoline, 2,259 Imiloxan, 4, 88 Imipenem, 4,181 Imipramine, 1,401; 2,420; 3, 32; 4,146,201,203 Imolamine, 1,249 Indacrinone, 3, 67 Indapamide, 2, 349 Indecainide, 4,62 Indeloxazine, 4, 59 Indolapril, 4, 128 Indomethacin, 1,318; 2, 345; 3, 165 Indoprofen, 3,171 Indoramine, 2,344 Indorenate, 3,167 Indoxole, 2,254; 3, 158 Interferon, 4,1 Intrazole, 2, 354 Intriptyline, 2, 223 Iodothiouracil, 1, 265 Ipexidine,3,157 Ipratropium Bromide, 3,160 Iprindol, 1, 318 Iproniazide, 1,254 Ipronidazole, 2, 244 Iproplatin, 4, 17 Isamoxole, 3, 138 Isoaminile, 1, 82 Isobucaine, 1,12 Isobuzole, 2,272 Isocarboxazide, 1,233; 2,266 Isoetharine, 2,9 Isomazole, 4,163,164 Isomethadone, 1,79

240 Isomylamine, 2,11 Isoniazide, 1,254; 2, 266 Isopentaquine, 1, 346 Isoproteronol, 1, 63; 2, 37,107; 3, 20 Isopyrine, 1, 234 Isothipendyl, 1,430 Isotiquimide, 4,139 Isotretinoin, 3,12 Isoxepac, 3, 328 Isoxicam, 2,394 Isoxsuprine, 1, 69 Isradipine, 4,107 Itazigrel, 4,96 Ketamine, 1, 57; 2, 16 Ketanserin, 3,193 Ketasone, 1, 237 Ketazocine, 2,238 Ketazolam, 1,369 Ketobemidone, 1, 303 Ketoconazole, 3, 132 Ketoprofen, 2, 64 Ketorolac, 4, 81 Ketorphanol, 4, 60 Ketotifen, 3, 239 Khellin, 1, 313, 335 Labetolol, 3, 24; 4, 20 Lamotrigine, 4,120 Legotrile, 2,480 Leniquinsin, 2, 363 Lenperone, 2, 286 Letimide, 2,393 Levalorphanol, 1,293 Levamisole, 4, 217 Levarterenol, 1, 63 Levocabastine, 4,110,111 Levonantrodol, 3,188 Levonordefrine, 1, 68 Levophenacylmorphan, 1, 294 Levopropoxyphene, 1, 50 Levothyroxine, 1,97 Lidamidine, 3, 56 Lidocaine, 1,16; 2,95,449; 3,40 Lidoflazine, 1,279; 4,118 Lifibrate, 1,103 Linogliride, 4, 80 Liothyronine, 1,97 Lisinopril, 4, 83 , Lobendazole, 2, 353 Lobenzarit, 4,43 Lodoxamide, 3,57 Lofemizole, 4,90 Lofentanyl, 3,117 Lofepramine, 4,201

Cumulative Index, Vol. 1-4 Lofexidine, 4, 88 Lometraline, 2,214 Lomustine, 2,12 Lonapalene, 4,57 Loperamide, 2,334 Loratidine, 4,200 Lorazepam, 1, 368 Lorbamate, 2, 21 Lorcainide, 3,40 Lormetazepam, 3,196 Lortalamine, 4,204 Lorzafone, 4,48 Losulazine, 4,139 Loxapine, 2,427 Lucanthone, 1, 397; 2,413 Lupitidine, 4,115 Lynestrol, 1,166,186 Mafenide,2,114 Maprotiline, 2,220 Marijuana, 4,209 Mazindol, 2,462 Mebendazole, 2, 353 Mebeverine, 2, 54 Mebhydroline, 1,319 Mebromphenhydramine, 1,44 Mebutamate, 1,218 MeCCNU, 2,12 Mecillinam, 3,208 Mecillinam, 4,177 Meclastine, 1,44 Meclizine, 1,59 Meclocycline Meclofenamic acid, 1,110; 2,88 Meclorisone butyrate, 3,95 Medazepam, 1, 368 Medibazine, 2,30 Mediquox, 2, 390 Medrogestone, 1,182 Medroxalol, 3,25 Medroxyprogesterone, 1,180; 2,165 Medrylamine, 1, 41 Medrysone, 2, 200 Mefenamic acid, 1,110; 2, 280 Mefenidil, 4, 89 Mefenorex, 2,47 Mefexamide, 2,103 Mefruside, 1,134 Megesterol acetate, 1,180 Melengesterol acetate, 1,182 Melitracen, 2, 220 Melphalan, 2,120 Memotine, 2, 378 Menabitan, 4,210 Menoctone, 2,217

Cumulative Index, Vol. 1-4 Meobentine, 3,45 Meparfynol, 1, 38 Meperidine, 1, 300; 2, 328; 3,116; 4,108,111 Mephenhydramine, 1,44 Mephenoxalone, 1,119 Mephensin, 1,118 Mephensin carbamate, 1,118 Mephentermine, 1, 72 Mephenytoin, 1,246 Mephobarbital, 1,273 Mepivacaine, 1,17 Meprobamate, 1, 218; 2,21 Mequoqualone, 1, 354 Meralluride, 1, 224 Mercaptomerine, 1,224 Meseclazone, 1,254 Mesoridazine, 1, 389 Mesterolone, 1,174 Mestranol, 1,162 Mesuprine, 2,41 Metabutoxycaine, 1,11 Metalol, 2,41 Metampicillin, 1,41 Metaproterenol, 1, 64 Metaxalone, 1, 119 Meteneprost, 3,9 Methacycline, 2, 227 Methadone, 1,79, 289; 2, 328 Methallenestril, 1,187 Methamphetamine, 1, 37 Methandrostenolone, 1,173 Methantheline bromide, 1, 393 Methaphencycline, 1, 53 Methaphenyline, 1, 52 Methaprylon, 1,259 Methapyriline, 1, 54 Methaqualone, 1, 353 Metharbital, 1, 273 Methazolamide, 1, 250 Methdilazine, 1, 387 Methenolone acetate, 1,175 Methicillin, 1,412 Methimazole, 1, 240 Methisazone, 2,350 Methitural, 1,275 Methixine, 1,400; 2,413 Methocarbamol, 1, 118 Methohexital, 1,269 Methopholine, 1,349 Methopromazine, 1, 374 Methotrexate, 4,149 Methoxsalen, 1,333 Methoxypromazine, 1, 387 Methsuximide, 1,228

241 Methyclothiazide, 1, 360 Methylchromone, 1, 335 Methyldihydromorphinone, 1,292 Methyldopa, 1,95 Methylphenidate, 1, 88 Methylprednisolone, 1,193,196 Methyltestosterone, 1,172; 4,11 Methylthiouracil, 1,264 Methynodiol diacetate, 2,149 Methyridine, 1,265 Methysergide, 2,477 Metiamide, 2,252 Metiapine, 2,429 Metioprim, 3,155 Metizoline, 2,256 Metoclopramide, 4,41 Metolazone, 2,384 Metopimazine, 1,153 Metoprolol, 2,109 Metronidazole, 1,240 Mexenone, 2,175 Mexrenoate, 2,175 Mezlocillin, 3, 206; 4,179 Mianserin,2,451;4,214 Mibolerone, 2,144 Miconazole, 2,249 Midaflur, 2, 259 Midazolam, 3,197 Midodrine, 4,23 Milenperone, 3,172 Milipertine, 2, 341 Milrinone, 4,90,115 Mimbane, 2,347 Minaprine, 4,120 Minaxalone, 3,90 Minocycline, 1,214; 2,228 Minoxidil, 1,262 Mioflazine, 4, 119 Misonidazole, 3,132 Mitindomide, 4,218 Mitoxantrone, 3,75; 4, 62 Mixidine, 2, 54 Moclobemide, 4, 39 Modaline, 2,299 Mofebutazone, 1,234 Molinazone, 2,395 Molindone, 2,455 Molsidomine, 3, 140 Mometasone, 4,73 Moprolol, 2,109 Morantel, 1,266 Morazone, 2,261 Moricizine, 4,200 Morniflumate, 3,146 Morphazineamide, 1,277

242 Morphedrine, 1, 300 Morphine, 1,286; 2, 314; 3,110; 4,60 Motretinide, 3,12 Moxalactam, 3,218 Moxazocine, 3,114 Moxisylyte, 1,116 Moxnidazole, 2, 246 Muzolimine, 3,137 Nabazenil, 4,209 Nabilone, 3,189 Nabitan, 3,190 Naboctate, 4,209 Nadolol,2,110 Nafcillin, 1,412 Nafenopin, 2,214 Nafimidone, 4,90 Naflocort, 4,75 Nafomine, 2, 212 Nafoxidine, 1, 147; 3,70; 4, 65 Nafronyl, 2, 213 Naftidine, 3, 372 Naftifme, 4, 55 Nalbufine,2,319 Nalidixic acid, 1, 429; 2, 370,469 Nalrnefene, 4, 62 Nalmexone, 2, 319 Nalorphine,l,288;2,318 Naloxone, 1,289; 2, 318 Naltrexone, 2, 319; 4, 62 Namoxyrate, 1, 86 Nandrolone, 1,164 Nandrolone decanoate, 1,171 Nandrolone phenpropionate, 1,171 Nantradol, 3,186 Napactidine, 3,71 Napamezole, 4, 87 Naphazoline, 1,241 Naproxen, 1, 86 Naranol, 2,454 Nedocromil, 4,208 Nefazodone, 4,98 Neflumozide, 4,133 Nefopam, 2, 447 Neostigmine, 1,114 Nequinate, 2, 369 Netobimin, 4, 36 Nexeridine, 2,17 Nialamide, 1, 254 Nicardipine, 3,150 Nicergoline, 2,478 Niclosamide, 2,94 Nicordanil, 3,148 Nicotinic acid, 1,253

Cumulative Index, Vol. 1-4 Nictotinyl alcohol, 1,253 Nidroxyzone, 1,228 Nifedipine, 2, 283; 4,106 Nifenazone, 1,234 Nifluminic acid, 1,256 Nifuratrone, 2,238 Nifurdazil, 2,239 Nifurmide, 2,239 Nifuroxime, 2,238 Nifurpirinol, 2,240 Nifurprazine, 1, 231 Nifurquinazol, 2,383 Nifursemizone, 2,238 Nifurthiazole, 2,241 Nikethamide, 1, 253 Nilvadipine, 4,107 Nimazone, 2, 260 Nimodipine, 3,149 Nimorazole, 2,244 Niridazole, 2, 269 Nisobamate, 2,22 Nisobuterol, 3, 23 Nisoxetine, 3, 32; 4, 30 Nistremine acetate, 3, 88 Nithiazole, 2,268 Nitrafudam, 3,130 Nitrazepam, 1, 366 Nitrimidazine, 1,240 Nitrofurantel, 1, 229 Nitrofurantoin, 1, 230 Nitrofurazone, 1,229 Nitrofuroxime, 1,228 Nitrornifene, 3, 51; 4, 65 Nivazol, 2,159 Nivimedone, 3, 67 Nizatidine, 4,95 Nocodazole, 3,176 Nomifensine, 4,146 Noracylmethadol, 2, 58 Norbolethone, 2,151 Norephedrine, 1,260 Norepinephrine, 4,19,139 Norethandrolone, 1, 170 Norethindrone, 1,164; 2,145 Norethindrone acetate, 1,165 Norethynodrel, 1,168 Norfloxacin, 4,141,143 Norgestatriene, 1,168 Norgestatrienone, 1,186 Norgestrel, 1,167; 2,151; 3, 84 Normeperidine, 1, 300 Normethadone, 1, 81 Normethandrone, 1, 170 Norpipanone, 1, 81 Nortriptyline, 1,151

Cumulative Index, Vol. 1-4 Nufenoxole, 3,42 Nylidrin, 1, 69 Octazamide, 2,448 Octriptyline, 2,223 Ofloxacin, 4, 141, 142,144, 145 Ofornine, 4,102 Olsalazine, 4,42 Olvanil, 4, 35 Omeprazole, 4,133 Orange crush, 4, 62 Orconazole, 3,133 Ormetoprim, 2, 302 Ornidazole, 3,131 Orpanoxin, 3, 130 Orphenadrine, 1,42 Oxacephalothin, 1,420 Oxacillin, 1,413 Oxagrelate, 4, 151,152 Oxamniquine, 2, 372 Oxanamide, 1, 220 Oxandrolone, 1, 174 Oxantel, 2, 303 Oxaprotiline, 4, 63 Oxaprozin, 2, 263 Oxarbazole, 3,169 Oxatomide, 3,173 Oxazepam, 1, 366; 2,402 Oxazolapam, 1, 370 Oxeladine, 1,90 Oxendolone, 4, 66 Oxethazine, 1,72 Oxetorene, 3, 247 Oxfendazole, 2, 353 Oxibendazole, 2, 352 Oxilorphan, 2,325 Oximonam, 4,195 Oxiperomide, 2,290 Oxiramide, 3,40 Oxisuran, 2,280 Oxmetidine, 3,134 Oxolamine, 1, 248 Oxolinic acid, 2, 370, 387; 3,185 Oxprenolol, 1,117; 2, 109 Oxybutynin, 1,93 Oxycodone, 1, 290 Oxyfedrine, 2,40 Oxyfungin, 3, 233 Oxymestrone, 1,173 Oxymetazoline, 1,242 Oxymetholone, 1,173 Oxymorphone, 1,290; 2,319 Oxypendyl, 1,430 Oxypertine, 2,343 Oxyphenbutazone, 1, 236

243 Oxyphencyclimine, 2,75 Oxypurinol, 1,426 Oxytetracycline, 1,212; 2,226 Ozolinone, 3,140 Pacazine, 1, 387 Palmoxirate sodium, 4 , 4 Paludrine, 1,115 Pamaquine, 1,345 Pamatolol, 3,28 Pancuronium chloride, 2,163; 4,69 Papaverine, 1,347 Paraethoxycaine, 1,10, Paramethadione, 1, 232 Paramethasone, 1,200 Paranyline, 2,218 Parapenzolate bromide, 2,75 Para-aminosalicylic acid, 1, 109 Parconazole, 3,133 Pargyline, 1, 54; 2, 27 Pazoxide, 2, 395 Pefloxacin, 4,141,142,143 Pelrinone, 4,116 Pemerid, 2,288 Penfluridol, 2, 334 Pentapiperium, 2,76 Pentaquine, 1, 346 Pentazocine, 1,297; 2, 325 Pentethylcyclanone, 1,38 Pentiapine, 4,220 Pentizidone, 4, 86 Pentobarbital, 1,268 Pentomone, 3,248 Pentopril, 4,128 Pentoxiphyline, 2,466 Pentylenetetrazole, 1, 281 Perazine, 1,381 Pergolide, 3, 249 Perlapine, 2, 425 Perphenazine, 1, 383 Pethidine, 1, 300 Phenacaine, 1,19 Phenacemide, 1,95 Phenacetemide, 3,44 Phenacetin, 1,111 Phenadoxone, 1, 80 Phenaglycodol, 1,219 Phenazocine, 1,298 Phenazopyridine, 1,255 Phenbencillin, 1,410 Phenbenzamine, 2, 50 Phenbutalol, 2,110 Phencarbamide, 2,97 Phencyclidine, 1, 56 Phendimetrazine, 1,260; 2,261

244 Phenelizine, 1, 74 Pheneridine, 1, 301 Phenethicillin, 1,410 Phenformin, 1,75 Phenindandone, 1,147 Pheniprane, 1,76 Pheniprazine, 1,74 Pheniramine, 1,77 Phenmetrazine, 1,260 Phenobarbital, 1, 268 Phenomorphan, 1, 294 Phenoperidine, 1, 302 Phenothiazine, 4,199 Phenoxybenzamine, 1, 55 Phenoxymethylpenicillin, 1,410 Phensuximide, 1, 226 Phentermine, 1,72 Phentolamine, 1, 242 Phenyl aminosalycilate, 2, 89 Phenylbutazone, 1,236; 2, 388,474 Phenylephrine, 1,63; 2,265; 3, 20 Phenylglutarimide, 1,257 Phenyltoloxamine, 1,115 Phenyramidol, 1,165 Pholcodeine, 1,287 Phthaloyl sulfathiazole, 1,132 Physostigmine, 1,111 Picenadol, 4,108, 109 Pimetine, 2, 286 Piminodine, 1, 301 Pimozide, 2, 290 Pinacidil, 4, 102 Pinadoline, 4, 202 Pindolol, 2, 342 Pinoxepin, 2,419 Pipamazine, 1, 385 Pipamperone, 2, 288 Pipazethate, 1, 390 Pipecuronium bromide, 4,70 Piperacetazine, 1, 386 Piperacillin, 3,207; 4,179,188 Piperidoiate, 1,91 Piperocaine, 1,13 Piperoxan, 1, 352 Pipobroman, 2,299 Piposulfan, 2, 299 Pipradol, 1, 47 Piprandamine, 2,459 Piprozolin, 2,270 Piquindone, 4,205 Piquizil,2,381 Pirazolac, 3,138 Pirbencillin, 3,207 Pirbutorol, 2,280 Pirenperone, 3,231

Cumulative Index, Vol. 1-4 Piretanide, 3, 58 Pirexyl, 1,115 Piridicillin, 1,260 Piridocaine, 1,13 Pirindol, 1,45 Piriprost, 4, 160 Piritramide, 1,308 Piritrexim, 4,169 Pirmagrel, 4,161 Pirmentol, 3,48 Piroctone, 3,149 Pirogliride, 3, 57 PirogMde, 4, 80 Pirolate, 3,245 Piromodic acid, 2,470 Piroxicam, 4,173 Piroximone, 4,94 Pirprofen, 2,69 Pirqinozol, 3, 243 Pivampicillin, 1,414 Pivopril, 4, 7 Pizoctyline, 2,420 Poldine mesylate, 2,74 Polythiazide, 1, 360 Practolol, 2,106 Pramoxine, 1, 18 Pranolium chloride, 2, 212 Prazepam, 2,405 Praziquantel, 4, 213,214 Prazosin, 2, 382; 3,194; 4,148,149 Prednicarbate, 4,71 Prednimustine, 3,93 Prednisolone, 1,192; 2,178 Prednisolone acetate, 1,192 Prednisone, 1,192; 4,71 Prednival, 2,179 Prednylene, 1,197 Prenalterol, 3,30 Prenylamine, 1,76 Pridefine, 3,49 Prilocaine, 1, 17 Primodolol, 3,29 Primodone, 1,276 Prizidilol, 3,151 Probarbital, 1,268 Probenecid, 1,135 Probicromil, 4, 207, 208 Probucol, 2,126 Procajnamide, 1,14 Procaine, 1,9 Procarbazine, 2,27 Procaterol, 3,184; 4,140 Prochlorperazine, 1, 381 Procinonide, 3,94 Procyclidine, 1,47

Cumulative Index, Vol. 1-4 Prodilidine, 1, 305 Prodolic acid, 2,459 Progabide, 4, 47 Progesterone, 2,164 Proglumide, 2,93 Proguanil, 1, 280 Prolintane, 1,70 Promazine, 1, 377 Promethazine, 1, 373 Pronethalol, 1,66 Prontosil, 1, 212 Propanidid, 2, 79 Propantheline bromide, 1, 394 Proparacaine, 1, 11 Propenzolate, 2, 75 Properidine, 1, 299 Propicillin, 1, 410 Propiomazine, 1, 376 Propionylpromazine, 1, 380 Propizepine, 2,472 Propoxorphan, 3,113 Propoxycaine, 1,10 Propoxyphene, 1, 50,298; 2, 57 Propranolol, 1,117; 2, 105, 212 Propylhexedrine, 1, 37 Propylphenazone, 1, 234 Propylthiouracil, 1,265 Proquazone, 2, 386 Proquinolate, 2, 368 Prorenone, 2, 175 Prostacyclin, 4,14,159 Prostaglandin E2,4, 11 Prostaglandin F2-a, 4, 9 Prostalene, 2, 5 Prothipendyl, 1,430 Protriptyline, 1, 152 Proxazole,2,271 Proxicromil, 4,205, 206 Pyrantel, 1,266; 2 303 Pyrathiazine, 1, 373 Pyrazineamide, 1, 277 Pyrilamine, 1, 51 Pyrimethamine, 1, 262 Pyrindamine, 1, 145 Pyrinoline, 2, 34 Pyrovalerone, 2, 124 Pyroxamine, 2,42 Pyroxicam, 2, 394; 4,148 Pyrrobutamine, 1, 78 Pyrrocaine, 1,16 Pyrroliphene, 2, 57 Pyrroxan,3, 191 P-Aminosalicylic acid, 4,42 Quazepam, 3,196

245 Quazinone, 4,212 Quazodine, 2,379 Quazolast, 4,216 Quinacrine, 1,396 Quinapril, 4, 146 Quinazocin, 2, 382 Quinbolone, 2,154 Quinethazone, 1, 354 Quinfamide, 3, 186 Quinine, 1, 337; 4,103 Quinodinium bromide, 2,139 Quinpirole, 4,205 Quinterol, 2, 366 Racemoramide, 1, 82 Racemorphan, 1, 293 Ramipril, 4, 84, 85 Ranitidine, 3,131; 4, 89,112,114 Recainam, 4, 37 Reclazepam, 4,153 Remoxipride, 4,42 Reproterol, 3,231 Rescinnamine, 1, 319 Reserpine, 4, 139,209 Retinoids, 4,7 Retinyl acetate, 4,7 Rimantidine, 2,19 Rimcazole, 4, 201 Rimiterol, 2, 278 Riodipine, 4, 107 Rioprostil, 4, 12,13 Ripazepam, 3,234 Ripitoin, 3, 139 Risocaine, 2, 91 Ristianol, 4,102 Ritodrine, 2, 39 Rodocaine, 2,450 Roletamide, 2,103 Rolgarnidine, 4, 80 Rolicyprine, 2,50 Rolitetracycline, 1,216 Rolodine, 2,468 Ronidazole, 2,245 Rosoxacin, 3, 185 Rotoxamine, 2, 32 Salbutamol, 2,280 Salicylamide, 1,109 Salsalate, 2,90 Salvarsan, 1,223 Sarmoxicillin, 3,205 Sarpicillin, 3, 204 Secobarbital, 1,269 Semustine, 2,12 Sermetacin, 3,166

246 Sertraline, 4, 57 Setoperone, 4,172 Sodium palmoxirate, 4, 3 Solypertine, 2,342 Somantadine, 4,4 Sontoquine, 1,344 Sotalol, 1,66; 2,41 Soterenol, 2,40 Spirapril, 4, 83 Spirilene, 2,292 Spiromustine, 4,5 Spkonolactone, 1,206; 2,172; 3,91 Spiropiperone, 1, 306 Spiroplatin, 4,16,17 Spirothiobarbital, 1, 276 Stanazole, 1, 174 Stenbolone acetate, 2,155 Styramate, 1, 219 Succinyl sulfathiazole, 1,132 Sudoxicam, 2,394 Sulazepam, 2,403 Sulbactam,4,180 Sulconazole, 3,133 Sulfabenzamide, 2, 112 Sulfacarbamide, 1,123 Sulfacetamide, 1, 123 Sulfachloropyridazine, 1, 124 Sulfacytine, 2, 113 Sulfadiazine, 1,125 Sulfadimethoxine, 1, 125 Sulfadimidine, 1,125 Sulfaethidole, 1,125 Sulfaguanidine, 1,123 Sulfaisodimidine, 1,125 Sulfalene, 1, 125 Sulfamerazine, 1,124 Sulfameter, 1,125 Sulfamethizole, 1,125 Sulfamethoxypyridine, 1, 124 Sulfamoxole, 1,124 Sulfanilamide, 1,121; 2,112 Sulfanitran, 2,115 Sulfaphenazole, 1,124 Sulfaproxyline, 1,123 Sulfapyridine, 1, 124; 2,114 Sulfapyridine, 4,42 Sulfasalazine, 2,114 Sulfasalazine, 4,42 Sulfasomizole, 1,124 Sulfathiazole, 1,124 Sulfathiourea, 1,123 Sulfazamet, 2,113 Sulfentanil, 3,118 Sulfinalol, 3,25 Sulfinpyrazone, 1, 238

Cumulative Index, Vol. 1-4 Sulfisoxazole, 1,124 Sulfonterol, 2,42 Sulformethoxine, 1,125 Sulfoxone, 1,140 Sulindac, 2,210 Sulnidazole, 2,245 Suloctidil, 3,26 Sulpiride, 2,94 Sulprostene, 3,9 Sulthiame, 2,306 Suporofen, 2,65 Suricainide, 4,49 Symetine, 2,29 Syrosingopine, 1, 319 Taclamine, 2,224 Talampicillin, 2,438 Talniflumate, 3,146 Talopram, 2, 357 Tametraline, 3,68 Tamoxifen, 2,127; 3,70; 4, 65 Tampramine, 4,203 Tandamine, 2, 347,460 Tazadolene, 4, 6 Tazifylline, 4,165 Tazolol,2,110,268 Tebuquine, 4,140 Teclozan, 2, 28 Tegafur, 3,155 Temazepam, 2,402 Temelastine, 4,113 Temocillin, 4,178 Tenoxicam, 4, 173 Terazocin, 3,194 Terbinafine, 4, 55 Terconazole, 3,137 Terfenadine, 4,48,104 Terolidine, 2,56 Teroxirone, 4, 122 Tertrabenazine, 1, 350 Tesicam, 2, 379 Tesirnide, 2, 296 Testolactone, 1,160 Testosterone cypionate, 1,172 Testosterone decanoate, 1, 172 Testosterone propionate, 1,172 Tetracaine, 1,110 Tetracycline, 1,212 Tetrahydrocannabinol, 1, 394 Tetrahydrocannabinol, 4,209 Tetrahydrozoline, 1, 242 Tetramisole, 1,431; 3, 226 Tetrantoin, 1,246 Tetroxyprim, 3,154 Tetrydamine, 2, 352

Cumulative Index, Vol. 1-4 Thalidomide, 1, 257; 2,296 Thebaine, 4, 61 Thenium closylate, 2, 99 Theobromine, 1,423; 2 456 Theophylline, 1,423; 2, 464; 3,230; 4,165,168,213 Thiabarbital, 1, 275 Thiabendazole, 1, 325; 2, 352 Thiabutazide, 1, 358 Thiamphenicol, 2,45 Thiamprine, 2,464 Thiamylal, 1, 274 Thiazinum chloride, 3,240 Thiazolsulfone, 1, 141 Thienamycin, 4, 181 Thiethylperazine, 1, 382 Thiofuradene, 1,231 Thioguanine, 2, 464 Thiopental, 1, 274 Thiopropazate, 1, 383 Thioridazine, 1, 389 Thiothixene, 1, 400; 2, 412 Thonzylamine, 1, 52 Thozalinone, 2, 265 Thyromedan, 2, 79 Thyroxine, 1, 95; 2, 78 Tiaconazole, 3, 133 Tiacrilast, 4, 150 Tiamenidine, 3, 137 Tiapamil, 4, 34 Tiaramide, 4, 134 Tiazofurine, 4,96 Tibolone, 2,147 Tibric acid, 2, 87 Ticabesone propionate, 4,75 Ticarcillin, 2,437 Ticlopidine, 3,228 Ticrynafen, 2,104 Tigesterol, 2, 145 Tiletamine, 2,15 Tilomisole, 4, 217 Tilorone, 2, 219 Timefurone, 4,208 Timobesone acetate, 4,75 Timolol, 2, 272 Tinabinol, 4, 210 Tiodazocin, 3,194 Tioperidone, 2,106; 3,192 Tiopinac, 3,238 Tioxidazole, 3, 179 Tipentosin, 4,129 Tipredane, 4,74 Tiprinast, 4,173 Tipropidil, 3, 28, 69 Tiquinamide, 2, 372

247 Tixanox, 3,236 Tixocortol pivalate, 4,73 Tocainide, 3,55 Tolamolol, 2,110 Tolazamide, 1,241 Tolbutamide, 1,136 Tolciclate, 3,69 Tolgabide, 4,47 Tolimidone, 2,7,50; 3,156 Tolindate, 2,208 Tolmetin, 2, 234 Tolnaftate, 2,211 Tolpyrramide, 2,116,185 Tolrestat, 4,56 Tolycaine, 1,17 Tomoxetine, 4, 30 Tonazocine, 3, 115 Topterone, 3, 88 Tosifen, 3,62 Tralonide, 2, 198 Tramalol, 2, 17 Tramazoline, 1,243 Tranexamic acid, 2,9; 4, 6 Tranilast, 4,44 Transcainide, 4,112 Tranylcypromine, 1,73 Trazodone, 2,472 Treloxinate, 2,432 Trepipam, 4, 146,147 Triacetamide, 2,94 Triafungin, 3,233 Triamcinolone, 1, 201 Triamcinolone acetonide, 1, 201; 2, 302 Triampyzine, 2,298 Triamterine, 1,427 Triazolam, 1,368 Triazuryl, 2, 305 Trichlormethiazide, 1,359 Triclonide, 2,198 Trifenagrel, 4, 89 Triflocin, 2,282 Triflubazam, 2,406 Triflumidate, 2,98 Trifluperidol, 1, 306 Triflupromazine, 1, 380; 3, 32 Trihexyphenidyl, 1,47 Triiodothyronine, 1,95 Trilostane, 2,158 Trimazocin, 2, 382 Trimeprazine, 1, 378 Trimethadone, 1,232 Trimethobenzamide, 1,110 Trimethoprim, 1, 262 Trimethoquinol, 2, 374 Trimetozine, 2,94

248 Trimetrexate, 4,149 Trioxasalen, 1, 334 Trioxyfene, 3,70 Tripamide, 4,51 Tripelennamine, 1, 51 Triprolidine, 1,78 Triprolidine, 4,105 Trofosfamide, 3,161 Tropanserin, 4,39 Tropocaine, 1,7 Tubulozole, 4, 91 Tybamate, 2,22 Verapamil, 4, 34 Verilopam, 3,121 Verofylline, 2,230 Viloxazine, 2, 306 Vinbarbital, 1, 269 Viprostol, 4,13 Vitamin A acetate, 4,7 Volazocine, 2, 327 Warfarin, 1,131 Xamoterol, 4,28 Xanoxate, 3,235 Xilobam, 3, 56 Xipamide, 2,93 Xorphanol, 4, 61 Xylamidine, 2, 54 Xylazine, 2, 307 Xylometazoline, 1,242 Xyphenisatin, 2, 350 Zacopride, 4,42 Zaltidine, 4,95 Zidomethacin, 3,166 Zidovudine, 4,118 Zimeldine, 3,49 Zindotrine, 4,168 Zinoconazole, 4,92 Zofenopril, 4, 83 Zolamine, 1,52 Zolazepam, 4,174 Zolpidem, 4,162 Zolterine, 2,301 Zometapine, 3,234 Zompirac, 3,128 Zonisamide, 4,130

Cumulative Index, Vol. 1-4

Index

Abortifacient, 11 Acifran, 78 Acitretin, 35 Acivicin, 85 Acodazole, 215 Acrivastine, 105 Acyclovir, 31,116, 165 Adrenergic beta-blockers, 137 Adrenergic beta-receptor agonists, 140 AIDS, 117 Alaproclate, 33 Alfaprostol, 9 Alfuzosin, 149 Altanserin, 151 Altrenogest, 66 Alzheimer's disease, 39 Amdinocillin, 177 Amflutiazole, 94 Amifloxacin, 144,145 Amiodarone, 127,156 Amitraz, 36 Amlodipine, 108 Amodiaquine, 140 Amoxicillin, 179,180 Ampicillin, 179 Amrinone,90,115,163 Analgesic, 6, 35, 61,210 Analgesics, 102 Androgen antagonist, 66 Angiotensin-converting enzyme inhibitor, 7, 58, 81,169 Aniracetam, 39 Anirolac, 158 Anthelmintic, 36,132,213, 215,217 Antiallergic agent, 131,150 Antianginal, 34,134 Antiarrhythmic, 37,49, 69, 87,112,156,200 Antibacterial agent, 86 Antibiotic, 177 Anticonvulsant, 29,90, 120,130,209

Antidepressant, 5, 33, 39, 57,59,63, 87,98, 120,138,201,203, 214,217 Antiemetic, 41 Antifungal, 55,93 Antiglaucoma, 209 Antihistamine, 104, 111, 118,200 Antihypertensive, 7,20, 25, 38,83,102,129, 134,137,139,148, 205,210 Antihypertensive renal vasodilator, 147 Antimigraine, 39 Antinauseant, 209 Antineoplastic, 3,91, 96,122, 149,162,167, 215,218 Antiparasitic, 50 Antiprotozoal, 3 Antipsoriatic agent, 35 Antipsychotic, 199,201,212,220 Antisecretory, 8 Antithrombotic, 89,96 Antitumor, 1,16, 17,62, 85 Antiulcer, 89,95,133 Antiulcerative, 11 Antiviral, 1, 31, 86,117,131,165 Anxiolytic, 119,219 Apalcillin, 179 Aptazapine, 215 Ara-A C, 122 Arprinocid, 165,167 Asthma, 165,205 Atiprosin, 211 Atropine, 39 Avridine, 1 Azaloxan, 138 Azelastine, 152 Azlocillin, 179 AZQ, 51 AZT, 118 Aztreonam, 193,195 Bemitradine, 168

249

250 Benzbromarone, 127 Benzodiazepines, 48 Betaxolol, 26 Beta-blockers, 19,25,41 Biclodil, 38 Bifonazole, 93 Biological response modifier, 95 Bipenamol, 45 Bisantrene, 62 Bisoprolol, 28 Brocrinat, 130 Bromadoline, 6 Bromfenac, 46 Bronchodilator, 168,213 Bropirimine, 116 Brotizolam, 219 Buspirone, 119 Butaprost, 13 Butoprozine, 156 Calcium channel blocking agents, 106,134 Captopril,7,58,81,128 Caracemide, 1 Carbacycline, 14 Carboplatin, 16 Cardiotonic agent, 90,94,115,163 Carumonam, 193 Cefbuperazone, 189, 190 Cefepime, 185,187 Cefetamet, 184 Cefixime, 184,185 Cefmenoxime, 187 Cefmetazole, 190,191 Cefoperazone, 185,188,189,190 Cefotaxime, 185,187,188 Cefotetan, 191,192 Cefotriaxone, 190 Cefoxitin, 190 Cefpimazole, 185 Cefpiramide, 188 Cefroxadine, 182 Ceftazidime, 192 Ceftiofur, 187 Celiprolol, 27 Cephalexin, 182 Cephaloglycin, 185 Cephradine, 182 Cerebral vasodilator, 89 Cetamolol, 26 Cetirzine, 118 Cetraxate, 6 Cibenzoline, 87 Ciclazindol, 217 Cicloprolol, 25 Ciglitazone, 33

Index Ciladopa, 20, 22 Cilastatin, 181 Cilazapril, 170 Cimaterol, 23 Cimetidine, 89,95,112 Cinflumide, 35 Ciprofloxacin, 141 Ciprostene calcium, 14 Cisapride, 42 Cisplatin, 15,16,17 Clavulanic acid, 180 Clebopride, 42 Clobetasol propionate, 72 Clobetasone butyrate, 72 Clonidine, 5, 38, 88 Clorsulon, 50 Closantel, 36 Cloticasone propionate, 75 Clozapine, 212,220 Cocaine, 39 Coccidiostat, 165 Cognition enhancing agents, 39, 59 Coronary vasodilators, 118 Cromitrile, 137 Cromolyn sodium, 44,137, 150, 205 Cycloserine, 86 Cytoprotective, 8,11,12 Darodipine, 107 Dazoxiben, 91 Delapril, 58 Desciclovir, 165 Desipramine, 201 Desoximetasone, 70 Dezaguanine, 162,163 Dezocine, 59 Diaziquone, 51 Difloxacin, 143,144, 145 Dilevalol, 20 Disoxaril, 86 Diuretic, 130,168 Domperidone, 133 Donetidine, 114 Dopamine, 20 Dopexamine, 22 Doxazosin, 148 Doxorubicin, 62 Dribendazole, 132 Duoperone, 199 Ebastine, 48,49 Eclanamine, 5, 6 Eclazolast, 131 Edifolone, 69 Edoxudine, 117

Index Eflornithine, 2, 3 Enalapril,58,81,82,83,84 Enalaprilat, 7, 82 Enilconazole, 93 Enisoprost, 11 Enolicam, 148 Enoxacin, 145 Enoximone, 93 Enpiroline, 103 Enprofylline, 165 Enprostil, 10 Enviradene, 131 Epinephrine, 19,28 Epoprostenol, 159 Epostane, 68 Ergosterol, 55 Eschweiler-Clarke reaction, 147 Esmolol, 27 Etibendazole, 132 Etintidine, 89 Etofenamate, 42 Etretinate, 35 Exaprolol, 25 Fanetizole, 95 Fazarabine, 122 Febantel, 35 Felbinac, 32 Felodipine31,106 Fengabine, 47 Fenoctimine, 109 Fenoldopam, 147 Fenprinast, 213 Fenprostalene, 9,10 Fenretinide, 7 Fentiazac, 96 Fenticonazole, 93 Fertilityregulators,8 Fezolamine, 87 Finkelstein reaction, 5,153 Flavodilol, 137 Flestolol, 41 Flordipine, 107 Fludarabine, 167 Flufenamic acid, 42 Flumazenil, 220 Flupirtine, 102 Fluproquazone, 150 Fluradoline, 202 Fluticasone propionate, 75 Fluzinamide, 29 Fosarilate, 31 Fostedil, 134 Fumoxicillin, 179 Furaprofen, 127

251 Furegrelate, 125,126 Furodazole, 215 GAB A, 47 Gamma-aminobutyric acid, 47 Gastric antisecretory, 12 Gastric ulcers, 8,10 Gemeprost, 11, 12 Gepirone, 120 Gloximonam, 195 Growth promoter, 23 Halcinonide, 75 Haloperidol, 133 Hemostatic, 6 Hexahydroamphetamine, 4 Histamine H-2 receptor antagonist, 89, 95 Hydroxyzine, 118 Hypocholesterolemic, 208 Hypotensive, 13,149 Icotidine, 113 Imazodan, 90,93 Imiloxan, 88 Imipenem, 181 Imipramine, 146,201, 203 Immunoregulator, 102 Immunosuppressant activity, 95 Indecainide, 62 Indeloxazine, 59 Indolapril, 128 Inhibitor of platelet aggregation, 14 Interferon, 1 Iproplatin, 17 Isomazole, 163,164 Isotiquimide, 139 Isradipine, 107 Itazigrel, 96 Ketorolac, 81 Ketorphanol, 60 Labetalol, 20 Lamotrigine, 120 Levamisole, 217 Levocabastine, 110, 111 Lidoflazine, 118 Linogliride, 80 Lisinopril, 83 Lobenzarit, 43 Local anesthetic, 37, 39 Lofemizole, 90 Lofepramine, 201 Lofexidine, 88 Lonapalene, 57 Loratidine, 200

252 Lortalamine, 204 Lorzafone, 48 Losulazine, 139 Lupitidine, 115 Luteolytic, 9 Malaria, 103,140 Marijuana, 209 Mecillinam, 177 Mediator release inhibitor, 207, 216 Mefenidil, 89 Menabitan, 210 Meperidine, 108, 111 Methotrexate, 149 Methyltestosterone, 11 Metoclopramide, 41 Mezlocillin, 179 Mianserin, 214 Midodrine, 23 Milrinone, 90,115 Minaprine, 120 Mioflazine, 119 Mitindomide,218 Mitoxantrone, 62 Moclobemide, 39 Mometasone, 73 Monobactam, 196 Moricizine, 200 Morphine, 60 Muscle relaxant, 35 Nabazenil, 209 Naboctate, 209 Nafimidone, 90 Naflocort, 75 Nafoxidine, 65 Naftifine, 55 Nalmefene, 62 Naltrexone, 62 Napamezole, 87 Narcotic antagonist, 62 Nedocromil, 208 Nefazodone, 98 Neflumozide, 133 Netobimin, 36 Neuromuscular blocker, 69 Nifedipine, 106 Nilvadipine, 107 Nisoxetine, 30 Nitromifene, 65 Nizatidine, 95 Nomifensine, 146 Nonsteroidal antiinflammatory agent, 32, 89, 96,127,148 Norepinephrine, 19,139

Index Norfloxacin, 141,143 Ofloxacin, 141,142,144,145 Ofornine, 102 Olsalazine, 42 Olvanil, 35 Omeprazole, 133 Oral antidiabetic agent, 3 Oral contraceptives, 66,68 Orange crush, 62 Organoplatinum complexes, 15 Oxagrelate, 151,152 Oxaprotiline, 63 Oxendolone, 66 Oximonam, 195 Palmoxirate sodium, 4 Pancuronium chloride, 69 Parkinson's disease, 20 Pefloxacin, 141,142,143 Pelrinone, 116 Pentiapine, 220 Pentizidone, 86 Pentopril, 128 Phenothiazine, 199 Picenadol, 108,109 Pinacidil, 102 Pinadoline, 202 Pipecuronium bromide, 70 Piperacillin, 179,188 Piquindone, 205 Piriprost, 160 Piritrexim, 169 Pirmagrel, 161 Pirogliride, 80 Piroxicam, 173 Piroximone, 94 Pivopril, 7 Platelet aggregation inhibitor, 151,161,212 Praziquantel, 213,214 Prazosin, 148,149 Prednicarbate, 71 Prednisone, 71 Probicromil, 207,208 Procaterol, 140 Prodrug, 6,7,12,42,48,196 Progabide, 47 Prostacyclin, 14,159 Prostaglandin E2,11 Prostaglandin F2-a, 9 Prostaglandins, 8,10,11,14,159 Proxicromil, 205,206 Psoriasis, 57 Pyroxicam, 148 P-aminosalicylic acid, 42

Index Quazinone, 212 Quazolast, 216 Quinapril, 146 Quinine, 103 Quinpirole, 205 Ramipril, 84, 85 Ranitidine, 89, 112,114 Recainam, 37 Reclazepam, 153 Remoxipride, 42 Reserpine, 139,209 Retinoids, 7 Retinyl acetate, 7 Rimcazole, 201 Riodipine, 107 Rioprostil, 12,13 Ristianol, 102 Rolgamidine, 80 Scabicide, 36 Serotonin antagonist, 151 Sertraline, 57 Setoperone, 172 Sodium palmoxirate, 3 Somantadine, 4 Spirapril, 83 Spiromustine, 5 Spiroplatin, 16,17 Suicide substrate, 2 Sulbactam, 180 Sulfapyridine, 42 Sulfasalazine, 42 Suricainide, 49 Tamoxifen, 65 Tampramine, 203 Tazadolene, 6 Tazifylline, 165 Tebuquine, 140 Temelastine, 113 Temocillin, 178 Tenoxicam, 173 Terbinafme, 55 Terfenadine, 48,104 Teroxirone, 122 Tetrahydrocannabinol, 209 Thebaine, 61 Theophylline, 165,168, 213 Thienamycin, 181 Tiacrilast, 150 Tiapamil, 34 Tiaramide, 134 Tiazofurine, 96

253 Ticabesone propionate, 75 Tilomisole, 217 Timefurone, 208 Timobesone acetate, 75 Tinabinol, 210 Tipentosin, 129 Tipredane, 74 Tiprinast, 173 Tixocortol pivalate, 73 Tolgabide, 47 Tolrestat, 56 Tomoxetine, 30 Tranexamic acid, 6 Tranilast, 44 Transcainide, 112 Trepipam, 146,147 Trifenagrel, 89 Trimetrexate, 149 Tripamide, 51 Triprolidine, 105 Tropanserin, 39 Tubulozole,91 Ulcerative colitis, 42 Utopiasporin, 177 Vasodilatory agent, 13 Verapamil, 34 Viprostol, 13 Vitamin A acetate, 7 Von Braun reaction, 30 Xamoterol, 28 Xorphanol, 61 Zacopride, 42 Zaltidine, 95 Zidovudine, 118 Zindotrine, 168 Zinoconazole, 92 Zofenopril, 83 Zolazepam, 174 Zolpidem, 162 Zonisamide, 130