the organic chemistry of drug synthesis vol 7 by daniel lednicer

THE ORGANICCHEMISTRY OFDRUG SYNTHESIS

Volume 7

DANIEL LEDNICERNorth Bethesda, MD


Volume 7

DANIEL LEDNICERNorth Bethesda, MD

Copyright # 2008 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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To the memory of I. Moyer Hunsberger and Melvin S. Newmanwho set me on course. . .

CONTENTS

Preface xi

1 OPEN-CHAIN COMPOUNDS 1

1. Peptidomimetic Compounds / 2A. Antiviral Protease Inhibitors / 2

1. Human Immunodeficiency Virus / 22. Human Rhinovirus / 9

2. Miscellaneous Peptidomimetic Compounds / 11References / 19

2 ALICYCLIC COMPOUNDS 21

1. Monocyclic Compounds / 21A. Prostaglandins / 21B. Antiviral Agents / 25C. Miscellaneous Monocyclic Compounds / 29

2. Polycyclic Compounds: Steroids / 31A. 19-Nor Steroids / 31B. Corticosteroid Related Compounds / 34

vii

3. Polycyclic Compounds / 38References / 40

3 MONOCYCLIC AROMATIC COMPOUNDS 43

1. Arylcarbonyl Derivatives / 432. Biphenyls / 473. Compounds Related to Aniline / 504. Compounds Related to Arylsulfonic

Acids / 535. Diarylmethanes / 586. Miscellaneous Monocyclic Aromatic Compounds / 60References / 67

4 CARBOCYCLIC COMPOUNDS FUSED TO ABENZENE RING 69

1. Indenes / 692. Naphthalenes / 733. Tetrahydronaphthalenes / 744. Other benzofused carbocyclic compounds / 79References / 81

5 FIVE-MEMBERED HETEROCYCLES 83

1. Compounds with One Heteroatom / 832. Compounds with Two Heteroatoms / 91

A. Oxazole and Isoxazoles / 91B. Imidazoles and a Pyrrazole / 94C. Thiazoles / 99D. Triazoles / 103E. Tetrazoles / 109

References / 112

6 SIX-MEMBERED HETEROCYCLES 115

1. Compounds with One Heteroatom / 115A. Pyridines / 115B. Reduced Pyridines / 117C. Miscellaneous / 119

viii CONTENTS

2. Compounds with Two Heteroatoms / 121A. Pyrimidines / 121B. Miscellaneous Six-Membered Heterocycles / 133

References / 136

7 FIVE-MEMBERED HETEROCYCLES FUSED TOONE BENZENE RING 139

1. Compounds with One Heteroatom / 139A. Benzofurans / 139B. Indoles / 141C. Indolones / 148D. Miscellaneous Compounds with

One Heteroatom / 1532. Five-Membered Rings with Two Heterocyclic

Atoms / 156A. Benzimidazoles / 156B. Miscellaneous Compounds / 158

References / 160

8 SIX-MEMBERED HETEROCYCLES FUSED TOONE BENZENE RING 163

1. Compounds with One Heteroatom / 163A. Benzopyrans / 163B. Quinolines and Their Derivatives / 167C. Quinolone Antibacterial Agents / 172

2. Compounds with Two Heteroatoms / 176A. Benzoxazines / 176B. Quinazolines / 178C. Miscellaneous Benzo-Fused Heterocycles / 184

References / 186

9 BICYCLIC FUSED HETEROCYCLES 189

1. Compounds with Five-Membered Rings Fusedto Six-Membered Rings / 189A. Compounds with Two Heteroatoms / 189B. Compounds with Three Heteroatoms / 191C. Compounds with Four Heteroatoms / 195

CONTENTS ix

2. Compounds with Two Fused Six-Membered Rings / 2083. Miscellaneous Compounds with Two Fused

Heterocyclic Rings: Beta Lactams / 213References / 215

10 POLYCYCLIC FUSED HETEROCYCLES 217

1. Compounds with Three Fused Rings / 2172. Compounds with Four Fused Rings / 2283. Compounds with Five or More Fused Rings:

Camptothecins / 230References / 232

Subject Index 233

Cross Index of Biological Activity 241

Cumulative Index 245

x CONTENTS

PREFACE

The first volume of The Organic Chemistry of Drug Synthesis was orig-inally visualized as a single free-standing book that outlined the synthesesof most drugs that had been assigned non-proprietary names in 1975 at thetime the book was written. Within a year or so of publication in 1977, it hadbecome evident that a good many drugs had been overlooked. That and theencouraging reception of the original book led to the preparation of asecond volume. That second book not only made up for the lacunae inthe original volume but also covered additional new drug entities aswell. With that second volume assignment of non-proprietary names byUSAN became the criterion for inclusion. That book, published in 1980,thus included in addition all agents that had been granted USAN since1976. What had been conceived as a single book at this point became aseries. The roughly 200 new USAN coined every five years over thenext few decades turned out to nicely fit a new volume in the series.This then dictated the frequency for issuing new compendia. After themost recent book in the series, Volume 6, was published in 1999, itbecame apparent that a real decline in the number of new drug entitiesassigned non-proprietary names had set in. The customary half-decadeinterval between books was apparently no longer appropriate.

A detailed examination of the 2005 edition of the USAN Dictionary ofDrug Names turned up 220 new non-proprietary names that had beenassigned since the appearance of Volume 6. Many of these compoundsrepresent quite novel structural types first identified by sophisticated new

xi

cell-based assays. This clearly indicated the need for the present volume inthe series The Organic Chemistry of Drug Synthesis.

This new book follows the same format as the preceding volumes.Compounds are classed by their chemical structures rather than by theirbiological activities. This is occasionally awkward since compoundswith the same biological activity but significantly different structures arerelegated to different chapters, a circumstance particularly evident withestrogen antagonists that appear in three different chapters. The crossindex found at the end of the book, it is hoped, partly overcomes thisproblem. The syntheses are discussed from an organic chemist’s point ofview, accompanied by the liberal use of flow diagrams. As was the casein the preceding volumes, a thumbnail explanation of the biological activityof each new compound precedes the discussion of its biological activity.

Several trends in the direction of drug discovery research seemed toemerge during the preparation of this book. Most of the preceding volumesincluded one or more therapeutic classes populated by many structurallyrelated potential drugs. Volume 6 for example described no fewer than ahalf dozen HIV-protease inhibitors and a similar number of the “triptan”drugs aimed at treating migraine. The distribution of therapeutic activitiesin the present volume is quite distinct from that found in the earlier books.This new set, for example, includes a sizeable number of antineoplastic andantiviral agents. These two categories together in fact account for just overone third of the compounds in the present volume. The antitumor candi-dates are further distinct in that specific agents act against very specifictumor-related biological end points. This circumstance combined withmechanism based design in other disease areas probably reflect the wide-spread adoption of in-vitro screening in the majority of pharmaceuticalresearch laboratories.

The use of combinatorial chemistry for generating libraries to feedin-vitro screens has also become very prevalent over the past decade.This book is silent on that topic since compounds are only includedwhen in a quite advanced developmental stage. Some of the structuresthat include strings of unlikely moieties suggest that those compoundsmay have been originally prepared by some combinatorial process.

The internet has played a major role in finding the articles and patentsthat were required to put this account together. The NIH-based websitePubChem was an essential resource for finding structures of compoundsthat appear in this book; hits more often than not include CAS RegistryNumbers. References to papers on the synthesis of compounds couldsometimes be found with the other NIH source PubMed. The ubiquitousGoogle was also quite helpful for finding sources for syntheses. In some

xii PREFACE

of the earlier volumes, references to patents were accompanied by refer-ences to the corresponding CAS abstract since it was often difficult toaccess patents. The availability of actual images of all patents fromeither the U.S. patent office (www.uspto.gov) or those from Europeanelsewhere (http://ep.espacenet.com) has turned the situation around.There was always the rather pricey STN online when all else failed.

This volume, like its predecessors, is aimed at practicing medicinal andorganic chemists as well as graduate and advanced undergraduate studentsin organic and medicinal chemistry. The book assumes a good workingknowledge of synthetic organic chemistry and some exposure to modernbiology.

As a final note, I would like to express my appreciation to the staff of thelibrary in Building 10 of the National Institutes of Health. Not only werethey friendly and courteous but they went overboard in fulfilling requeststhat went well beyond their job descriptions.

PREFACE xiii

CHAPTER 1

OPEN-CHAIN COMPOUNDS

Carbocyclic or heterocyclic ring systems comprise the core of chemicalstructures of the vast majority of therapeutic agents. This finding resultsin the majority of drugs exerting their effect by their actions at receptoror receptor-like sites on cells, enzymes, or related entities. These inter-actions depend on the receiving site being presented with a moleculethat has a well-defined shape, distribution of electron density, and arrayof ionic or ionizable sites, which complement features on the receptor.These requirements are readily met by the relatively rigid carbocyclic orheterocyclic molecules. A number of important drugs cannot, however,be assigned to one of those structural categories. Most of these agentsact as false substrates for enzymes that handle peptides. The central struc-tural feature of these compounds is an open-chain sequence that mimics acorresponding feature in the normal peptide. Although these drugs oftencontain carbocyclic or heterocyclic rings in their structures, these featuresare peripheral to their mode of action. Chapter 1 concludes with a fewcompounds that act by miscellany and mechanisms and whose structuresdo not fit other classifications.

The Organic Chemistry of Drug Synthesis, Volume 7. By Daniel LednicerCopyright # 2008 John Wiley & Sons, Inc.

1

1. PEPTIDOMIMETIC COMPOUNDS

A. Antiviral Protease Inhibitors

1. Human Immunodeficiency Virus. The recognition of acquiredimmune deficiency syndrome (AIDS) in the early 1980s and the subsequentexplosion of what had seemed at first to be a relatively rare disease into amajor worldwide epidemic, lent renewed emphasis to the study of virus-caused disease. Treatment of viral disease is made particularly difficultby the fact that the causative organism, the virion, does not in the exactmeaning of the word, replicate. Instead, it captures the reproductivemechanism of infected cells and causes those to produce more virions.Antiviral therapy thus relies on seeking out processes that are vital for pro-ducing those new infective particles. The first drugs for treating humanimmunodeficiency virus (HIV) infection comprised heterocyclic basesthat interfered with viral replication by interrupting the transcription ofviral ribonucleic acid (RNA) into the deoxyribonucleic acid (DNA)required by the host cell for production of new virions. The relativelyfast development of viral strains resistant to these compounds has provento be a major drawback to the use of these reverse transcriptase inhibitors.The drugs do, however, still form an important constituent in the so-calledcocktails used to treat AIDS patients. Some current reverse transcriptaseinhibitors are described in Chapters 4 and 6. The intense focus on theHIV virus revealed yet another point at which the disease may betackled. Like most viruses, HIV comprises a packet of genetic material,in this case RNA, encased in a protein coat. This protein coat providesnot only protection from the environment, but also includes peptides thatrecognize features on host cells that cause the virion to bind to the celland a few enzymes crucial for replication. Many normal physiologicalpeptides are often elaborated as a part of a much larger protein.Specialized peptidase enzymes are required to cut out the relevantprotein. This proved to be the case with the peptides required forforming the envelopes for newly generated virions. Compounds thatinhibit the scission of the protein elaborated by the infected host, theHIV protease inhibitors, have provided a valuable set of drugs for treatmentof infected patients. The synthesis of four of those drugs were outlined inVolume 6 of this series. Work on compounds in this class has continuedapace as evidenced by the half dozen new protease inhibitors that havebeen granted nonproprietary names since then.

As noted in Volume 6, the development of these agents was greatlyfacilitated by a discovery in a seemingly unrelated area. Research aimed

2 OPEN-CHAIN COMPOUNDS

at development of renin inhibitors as potential antihypertensive agents hadled to the discovery of compounds that blocked the action of this peptidecleaving enzyme. The amino acid sequence cleaved by renin was foundto be fortuitously the same as that required to produce the HIV peptidecoat. Structure–activity studies on renin inhibitors proved to be of greatvalue for developing HIV protease inhibitors. Incorporation of an aminoalcohol moiety proved crucial to inhibitory activity for many of theseagents. This unit is closely related to the one found in the statine, anunusual amino acid that forms part of the pepstatin, a fermentationproduct that inhibits protease enzymes.

This moiety may be viewed as a carbon analogue of the transition statein peptide cleavage. The fragment is apparently close enough in structureto such an intermediate as to fit the cleavage site in peptidase enzymes.Once bound, this inactivates the enzyme as it lacks the scissile carbon–nitrogen bond. All five newer HIV protease inhibitors incorporate thisstructural unit.

One scheme for preparing a key intermediate for incorporating thatfragment begins with the chloromethyl ketone (1) derived from phenyl-alanine, in which the amine is protected as a carbobenzyloxy (Cbz)group. Reduction of the carbonyl group by means of borohydrideaffords a mixture of aminoalcohols. The major syn isomer 2 is then iso-lated. Treatment of 2 with base leads to internal displacement of halogenand formation of the epoxide (3).1

1. PEPTIDOMIMETIC COMPOUNDS 3

The corresponding analogue (4) in which the amine is protected as atert-butyloxycarbonyl function (t-BOC) comprises the starting material forthe HIV protease inhibitor amprenavir (12). Reaction of 4 withisobutyl amine leads to ring opening of the oxirane and formation of theaminoalcohol (5). The thus-formed secondary amine in the product isconverted to the sulfonamide (6) byexposure top-nitrobenzenesulfonyl chlor-ide. The t-BOC protecting group is then removed by exposure to acid leadingto the primary amine (10). In a convergent scheme, chiral 3-hydroxytetra-hydrofuran (8) is allowed to react with bis(N-succinimidooxy)carbonate (7).The hydroxyl displaces one of the N-hydroxysuccinimide groups to affordthe tetrahydrofuran (THF) derivative (9) equipped with a highly activatedleaving group. Reaction of this intermediate with amine 10 leads to displace-ment of the remaining N-hydroxysuccinimide and incorporation of thetetrahydrofuryl moiety as a urethane (11). Reduction of the nitro group thenaffords the protease inhibitor (12).2

Much the same sequence leads to a protease inhibitor that incorporates asomewhat more complex furyl function-linked oxygen heterocyclic. Thisfused bis(tetrahydrofuryl) alcohol (16) was designed to better interactwith a pocket on the viral protease. The first step in preparing this inter-mediate consists of reaction of dihydrofuran (13) with propargyl alcoholand iodosuccinimide to afford the iodoether (14). Free radical dis-placement of the iodine catalyzed by cobaloxime leads to the fused


perhydrofuranofuran (15). The exomethylene group in the product is thencleaved by means of ozone; reductive workup of the ozonide leads toracemic 16. The optically pure single entity (17) is then obtained by resol-ution of the initial mixture of isomers with immobilized lipase.3

That product (17) is then converted to the activatedN-hydoxysuccinimidederivative 18 as in the case of the monocyclic furan. Reaction withthe primary amine 10 used to prepare amprenavir then leads to the urethane(19). Reduction of the nitro group then affords darunavir4 (20).

The synthesis of the amprenavir derivative, which is equipped with asolubilizing phosphate group, takes a slightly different course from thatused for the prototype. The protected intermediate 5 used in the synthesisof 12 is allowed to react with benzyloxycarbonyl chloride to provide the


doubly protected derivative 21, a compound that bears a t-BOC groupon one nitrogen and a Cbz grouping on the other. Exposure to acidserves to remove the t-BOC group, affording the primary amine 22. Thiscompound is then condensed with the activated intermediate 9 used inthe preparation of the prototype to yield the urethane 23. Catalytichydrogenation then removes the remaining protecting group to givethe secondary amine 24. Reaction as before with p-nitrobenzenesulfonylchloride gives the sulfonamide 25. This intermediate is allowed toreact with phosphorus oxychloride under carefully controlled conditions.Treatment with aqueous acid followed by a second catalytic hydrogenationaffords the water soluble protease inhibitor fosamprenavir (26).5

The preceding three antiviral agents tend to differ form each other byonly relatively small structural details. The next protease inhibitor includessome significant structural differences though it shares a similar centralaminoalcohol sequence that is presumably responsible for its activity.Construction of one end of the molecule begins with protection of thecarbonyl function in p-bromobenzaldehyde (27) as its methyl acetal (28)by treatment with methanol in the presence of acid. Reaction of that inter-mediate with the Grignard reagent from 4-bromopyridine leads to unusual


displacement of bromine from the protected benzaldehyde and formationof the coupling product. Mild aqueous acid restores the aldehyde functionto afford 29. This compound is then condensed with carbethoxy hydrazineto form the respective hydrazone; reduction of the imine function leads tothe substituted hydrazine (30). Reaction of 30 with the by-now familiaramino-epoxide (4) results in oxirane opening by attack of the basic nitro-gen in the hydrazine (30) and consequent formation of the addition product31. The t-BOC protecting group is then removed by treatment withacid. The final step comprises acylation of the free primary amine in 32with the acid chloride from the O-methyl urethane (33). This last com-pound (32) is a protected version of an unnatural a-aminoacid that canbe viewed as valine in with an additional methyl group on what hadbeen the side-chain secondary carbon atom. Thus, the protease inhibitoratazanavir (34) is obtained.6

A terminal cyclic urea derivative of valine is present at one terminusin lopinavir (43). Preparation of this heterocyclic moiety begins with con-version of valine (35) to its phenoxycarbonyl derivative by reaction withthe corresponding acid chloride. Alkylation of the amide nitrogen with3-chloropropylamine in the presence of base under very carefully con-trolled pH results in displacement of the phenoxide group to give the


urea intermediate (37). This compound then spontaneously undergoesinternal displacement of chlorine to form the desired derivative (38).

The statine-like aminoalcohol function in this compound differs fromprevious examples by the presence of an additional pendant benzylgroup; the supporting carbon chain is of necessity longer by onemember. Condensation of that diamine (39),7 protected at one end as itsN,N-dibenzyl derivative, with 2,6-dimethylphenoxyacetic acid (40) givesthe corresponding amide (41). Hydrogenolysis then removes the benzylprotecting groups to afford primary amine 42. Condensation of that withintermediate 34 affords the HIV protease inhibitor 43.8


2. Human Rhinovirus. Human rhinoviruses are one of the most fre-quent causes of that affliction that accompanies cooling weather, thecommon cold. This virus also consists of a small strand of RNA envelopedin a peptide coat. Expression of fresh virions in this case depends on pro-vision of the proper peptide by the infected host cell. That in turn hinges onexcision of that peptide from the larger initially produced protein. Proteaseinhibitors have thus been investigated as drugs for treating rhinovirusinfections. The statine-based HIV drugs act by occupying the scissionsite of the protease enzyme and consequently preventing access by theHIV-related substrate. That binding is, however, reversible in the absenceof the formation of a covalent bond between drug and enzyme. A differentstrategy was employed in the research that led to the rhinovirus proteaseinhibitor rupinavir (58). The molecule as a whole is again designed to fitthe protease enzyme, as in the case of the anti-HIV compounds. In contrastto the latter compound, however, this agent incorporates a moiety that willform a covalent bond with the enzyme, in effect inactivating it with finality.The evocative term “suicide inhibitor” has sometimes been used for thisapproach since both the substrate and drug are destroyed.

The main part of the somewhat lengthy convergent synthesis consists ofthe construction of the fragment that will form the covalent bond with theenzyme. The unsaturated ester in this moiety was designed to act as aMichael acceptor for a thiol group on a cysteine residue known to bepresent at the active site. The preparation of that key fragment starts withthe protected form of chiral 3-amino-4-hydroxybutyric acid (44); notethat the oxazolidine protecting group simply comprises a cyclic hemi-aminal of the aminoalcohol with acetone. The first step involves incorpor-ation of a chiral auxiliary to guide introduction of an additional carbonatom. The carboxylic acid is thus converted to the corresponding acidchloride and that reacted with the (S )-isomer of the by-now classic oxazo-lidinone (45) to give derivative 46. Alkylation of the enolate from 46 withallyl iodide gives the corresponding allyl derivative (47) as a single enan-tiomer. The double bond is then cleaved with ozone; reductive workup ofthe ozonide affords the aldehyde (48). Reductive amination of the carbonylgroup with 2,6-dimethoxybenzylamine in the presence of cyanoboro-hydride proceeds to the corresponding amine 49. This last step in effectintroduced a protected primary amino group at that position. The chiralauxiliary grouping is next removed by mild hydrolysis. The initiallyformed amino acid (50) then cyclizes to give the five-membered lactam(51). Treatment under stronger hydrolytic conditions subsequently servesto open the cyclic hemiaminal grouping to reveal the free aminoalcohol


(52). Swern-type oxidation of the terminal hydroxyl group in this last inter-mediate affords an intermediate (53) that now incorporates the aldehydegroup required for building the Michael acceptor function. Thus reactionof that compound with the ylide from ethyl 2-diethoxyphosphonoacetateadds two carbon atoms and yields the acrylic ester (54).

The remaining portion of the molecule is prepared by the condensationof N-carbobenzyloxyleucine with p-fluorophenylalanine to yield theprotected dipeptide (55). Condensation of that intermediate with theMichael acceptor fragment (54) under standard peptide-forming conditionsleads to the tripeptide-like compound (53). Reaction of 53 with dichloro-dicyanoquinone (DDQ) leads to unmasking of the primary amino groupat the end of the chain by oxidative loss of the DMB protecting group.Acylation of that function with isoxazole (55) finally affords the rhinovirusprotease inhibitor rupinavir (58).9


2. MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS

Polymers of the peptide tubulin make up the microtubules that form themicroskeleton of cells. Additionally, during cell division these filamentspull apart the nascent newly formed pair of nuclei. Compounds that interferewith tubulin function and thus block this process have provided some valu-able antitumor compounds. The vinca alkaloid drugs vincristine and vinblas-tine, for example, block the self-assembly of tubulin into those filaments.Paclitaxel, more familiarly known as Taxol, interestingly stabilizes tubulinand in effect freezes cells into mid-division. Screening of marine naturalproducts uncovered the cytotoxic tripeptide-like compound hemiasterlin,which owed its activity to inhibition of tubulin. A synthetic programbased on that lead led to the identification of taltobulin (69), an antitumorcompound composed, like its model, of sterically crowded aminoacid ana-logues. The presence of the nucleophile-accepting acrylate moiety recalls 58.

One arm of the convergent synthesis begins with the construction of thatacrylate-containing moiety. Thus, condensation of the t-BOC protecteda-aminoaldehyde derived from valine with the carbethoxymethylene phos-porane (60) gives the corresponding chain extended amino ester (61).Exposure to acid serves to remove the protecting group to reveal theprimary amine (62). Condensation of that intermediate with the tertiarybutyl-substituted aminoacid 33, used in a previous example leads to theprotected amide (63); the t-BOC group in this is again removed withacid unmasking the primary amino group in 64. Construction of theother major fragment first involves addition of a pair of methyl groups

2. MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 11

to the benzylic position of pyruvate (65). This transform is accomplishedunder surprisingly mild conditions by simply treating the ketoacid withmethyl iodide in the presence of hydroxide. Treatment of product 66with methylamine and diborane results in reductive amination of thecarbonyl group, and thus formation of a-aminoacid 67 as a mixture ofthe two isomers. Condensation of that with the dipeptide-like moiety 64under standard peptide-forming conditions gives the amide 68 as amixture of diastereomers. The isomers are then separated by chromato-graphy; saponification of the terminal ester function of the desired (SSS)-isomer affords the antitumor agent taltobulin (69).10

The alkylating agent cyclophosphamide is one of the oldest U.S. Foodand Drug Administration (FDA)-approved antitumor agents, having beenin use in the clinic for well over four decades. Though this chemothera-peutic agent is reasonably effective, it is not very selective. The drugaffects many sites and is thus very poorly tolerated. Over the years, therehas been much research devoted to devising more site-selective relatedcompounds. It was established that a heterocyclic ring in this compoundis opened metabolically and then discarded. The active alkylating metab-olite comprises the relatively small molecule commonly known as the“phosphoramide mustard”.


This result opens the possibility of delivering this active fragment or arelated alkylating function in a large molecule that would itself be recog-nized by an enzyme involved in cancer progression. As an example, itwas observed that many types of cancer tissues often have elevatedlevels of glutathione transferase, the agent that removes glutathione. Aversion of the modified natural substrate, glutathione, which carries aphosphoramide alkylating function, has shown activity on variouscancers. Reaction of bromoethanol with phosphorus oxychloride affordsintermediate 70. This compound reacts without purification with bis-2-chloroethylamine to give the phosphoramide (71), which is equippedwith two sets of alkylating groups. Compound 71 is then reacted withthe glutathione analogue 72, in which phenylglycine replaces the glycineresidue normally at that position. The bromine atom in intermediate 71is apparently sufficiently more reactive than the chlorines in the mustardsso that displacement by sulfur preferentially proceeds to 73. Oxidation ofthe sulfide with hydrogen peroxide affords canfosfamide (74).11,12

The D(R) isomer of the amino acid N-methyl-D-aspartate, more com-monly known as NMDA serves as the endogenous agonist at a numberof central nervous system (CNS) receptor sites. This agent is not onlyinvolved in neurotransmission, but also modulates responses elicited byother neurochemicals. A relatively simple peptide-like molecule hasbeen found to act as an antagonist at NMDA receptors. This activity ismanifested in vivo as antiepileptic activity. This agent in addition blocksthe nerve pain suffered by many diabetics, which is often called neuro-pathic pain. The synthesis begins by protecting the unnatural D-serine


(75) as its carbobenzyloxy derivative 76. This is accomplished by reacting75 with the corresponding acid chloride. Reaction of the productwith methyl iodide in the presence of silver oxide alkylates both thefree hydroxyl and the carboxylic acid to give the ether ester (77).Saponification followed by coupling with benzylamine leads to the benzy-lamide (78). Hydrogenolysis of the Cbz protecting group (79) followedby acylation with acetic anhydride affords lacosamide (80).13

As noted in the discussion of canfosfamide, alkylating agents have a longhistory as a class of compounds used in chemotherapy. The trend is to attachthe active electrophillic groups to molecules that will deliver them to specificsites. A simple alkylating agent, cloretazine (83), is being actively pursuedbecause of its promising antitumor activity. Exhaustive methanesulfonationof hydroxyethyl hydrazine with methanesulfonyl chloride yields the N,N,O-trimesylate (81). Reaction of this intermediate with lithium chloride leads todisplacement of the O-mesylate by chlorine and formation of the alkylatinggroup in 82. Treatment of 82 with the notorious methylisocyanate (MCI)yields the antitumor agent cloretazine (83).14,15


The relatively simple homologue of taurine, 3-aminosulfonic acid(84a), also known as homotaurine, is an antagonist of the neurochemicalgamma-aminobutyric acid (GABA). Homotaurine has been found to sup-press alcoholism in various animal models. Speculation is that this occursbecause of its activity against GABA to which it bears a some resemblance.The calcium salt (84b) of the N-acetyl derivative has been used to helpalcoholics maintain abstinence from alcohol by preventing relapse. Thecompound is prepared straightforwardly by acylation of homotaurine inthe presence of calcium hydroxide and acetic anhydride.16 The product,acamprosate calcium (84b), was approved by FDA for use in the UnitedStates in 2004.

A relatively simple derivative of phenylalanine shows hypoglycemicactivity. This compound, nateglinide, is usually prescribed for use as anadjunct to either metformin, or one of the thiazolidine hypoglycemicagents. Catalytic reduction of the benzoic acid (85) leads to the correspond-ing substituted cyclohexane as a mixture of isomers. This compound is thenesterified with methanol to give the methyl esters (86). Treatment withsodium hydride leads 86 to equilibrate to the more stable trans isomer 87via its enolate. Condensation of 87 with the ester of phenylalanine (88)yields nateglinide (89) after saponifications.17

The hypoglycemic agent repaglinidemay loosely be classed as a peptid-omimetic agent, because it essentially shows the same activity as nateglinide.The actual synthetic route is difficult to decipher from the patent in which it


is described. No description is provided for the origin of the startingmaterials. It is speculated that condensation of the protected monobenzylester (90) with diamine 91 would lead to the amide (92). Hydrogenolysisof the benzyl ester in the product would afford the free acid. Thus, repagli-nide (93) would be obtained.18

Formation of blood clots is the natural process that preserves the integrityof the circulatory system. Damage to the vasculature sets off an intricatecascade of reactions. These reactions culminate in the formation of a fibrinclot that seals the damaged area preventing the further loss of blood.Surgery, heart attacks, and other traumatic events lead to inappropriateformation of clots that can result in injury by blocking the blood supplyto organs and other vital centers. The drugs that have traditionally beenused to prevent formation of clots, coumadin and heparin have a verynarrow therapeutic ratio, necessitating close monitoring of blood levels ofthese drugs in patients. One of the first steps in the formation of a clotinvolves the binding of fibrinogen to specific receptors on the plateletsthat start the process. A number of fibrinogen inhibitors have recentlybeen developed whose structure is based on the sequence of amino acidsin the natural product. Two more recent compounds, melagartan, andxymelagartan, both contain the amidine (or guanidine) groups that areintended to mimic the similar function in fibrinogen and that characterizethis class of drugs.19

The synthesis of these agents begins with the hydrogenation of phenyl-glycine t-BOC amide (94) to the corresponding cyclohexyl derivative 95.The free carboxyl group is then coupled with the azetidine (96) to afford


the amide (97). Saponification with lithium hydroxide yields the free acid(98). The carboxyl group in that product is then coupled with thebenzylamine (99), where the amidine group at the para position is protectedas the benzyloxycarbonyl derivative to give intermediate 100. Theprotecting group on the terminal amino group is then removed byhydrolysis with acid (101). The primary amine in this last intermediate isthen alkylated with benzyl bromoacetate. Hydrogenolysis removes theprotecting groups on the terminal functions in this molecule to affordmelagartan (102).20

Intermediate 100 serves as the starting material for the structurallyclosely related fibrinogen inhibitor xymelagartan. Hydrogenation overpalladium on charcoal removes the protecting group on the amidinefunction (103). This compound is then allowed to react with what isin effect and unusual complex ester of carbonic acid (104). The basicnitrogen on the amidine displaces nitrophenol, a good leaving groupto afford 106. Regiochemistry is probably dictated by the greater basicityof the amidine group compared to the primary amine at the other endof the molecule. The amine is then alkylated with the trifluoromethyl-sulfonyl derivative of ethyl hydroxyacetate. Reaction of this last inter-mediate (107) with hydroxylamine result in an exchange of thesubstitutent on the amidine nitrogen to form an N-hydroxyamidine.Thus, xymelagartan (108) is obtained.20 This drug is interestinglyrapidly converted to 102 soon after ingestion and is in effect simply aprodrug for the latter.


Drugs that inhibit the conversion of angiotensin 1 to the vasocon-stricting angiotensin 2, the so-called angiotensin converting enzyme(ACE) inhibitors, block the action of angiotensin converting enzyme,one of a series of zinc metalloproteases. A closely related enzymecauses the degradation of the vasodilating atrial natriuretic peptide. Acompound that blocks both metalloproteases should in principle lowervascular resistance and thus blood pressure by complementary mechan-isms. A drug that combines those actions, based on a fused two-ringheterocyclic nucleus, omapatrilat, is described in Chapter 10. A relatedcompound that incorporates a single azepinone ring shows much thesame activity. The synthesis begins by Swern oxidation of the terminalalcohol in the heptanoic ester 109. Reaction of the product 110 with tri-methylaluminum proceeds exclusively at the aldehyde to afford themethyl addition product (111). A second Swern oxidation, flowed thistime by methyl titanium chloride, adds a second methyl group toafford the gem-dimethyl derivative (112). Construction of the azepinonering begins by replacement of the tertiary carbinol in 112 with an azidegroup by reaction with trimethylsilyl azide and boron trifluoride.Hydrogenation of the product (113) reduces the azide to a primaryamine and at the same time cleaves the benzyl ester to the correspondingacid (114). Treatment of this intermediate with a diimide leads to for-mation of an amide, and thus the desired azepinone ring (115). The


phthalimido function, which has remained intact through the precedingsequence, is now cleaved in the usual way by reaction with hydrazine.The newly freed amine is again protected, this time as it triphenylmethylderivative. The anion on the amide nitrogen from treatment of 116 withlithium hexamethyl disilazane is then alkylated with ethylbromoacetate;exposure to trifluoracetic acid (TFA) then cleaves the protecting groupon the other nitrogen to afford 117. The primary amino group isacylated with (S )acetylthiocinnamic acid (118). Saponification cleavesboth the acetyl protection group on sulfur and the side-chain ethylester to afford gemopatrilat (119).21

REFERENCES

1. D.P. Getman et al., J. Med. Chem. 36, 288 (1993).

2. R.D. Tung, M.A. Murcko, G.R. Bhisetti, U.S. Patent 5,558,397 (1996). Thescheme shown here is partly based on that used to prepare darunavir andphosamprenavir due to difficulty in deciphering the patent.

3. A.K. Ghosh, Y. Chen, Tetrahedron Lett. 36, 505 (1995).

4. D.L.N.G. Surleraux et al., J. Med. Chem. 48, 1813 (2005).

5. L.A. Sobrera, L. Martin, J. Castaner, Drugs Future, 23, 22 (2001).

REFERENCES 19

6. G. Bold et al., J. Med. Chem. 41, 3387 (1998).

7. For a scheme for this intermediate see D. Lednicer,“The Organic Chemistry ofDrug Synthesis”, Vol. 6, John Wiley & Sons, Inc., NY 1999, pp. 12,13.

8. E.J. Stoner et al., Org. Process Res. Dev. 4, 264 (2000).

9. P.S. Dragovich et al., J. Med. Chem. 42, 1213 (1999).

10. A. Zask et al., J. Med. Chem. 47, 4774 (2004).

11. L.M. Kauvar, M.H. Lyttle, A. Satyam, U.S. Patent 5,556,942 (1996).

12. A. Satyam, M.D. Hocker, K.A. Kane-Maguire, A.S. Morgan, H.O. Villar,M.H. Lyttle, J. Med. Chem. 39, 1736 (1996).

13. J.A. McIntyre, J. Castaner, Drugs Future 29, 992 (2004).

14. A. Sartorelli, K. Shyam, U.S. Patent 4,684,747 (1987).

15. A. Sartorelli, K. Shyam, P.G. Penketh, U.S. Patent 5,637,619 (1997).

16. J.P. Durlach, U.S. Patent 4,355,043 (1982).

17. S. Toyoshima, Y. Seto, U.S. Patent, 4,816,484 (1989).

18. W. Grell, R. Hurnaus, G. Griss, R. Sauter, M. Reiffen, E. Rupprecht, U.S.Patent, 5,216,167 (1993).

19. See Ref. 7, pp. 15–18.

20. L.A. Sobrera, J. Castaner, Drugs Future, 27, 201 (2002).

21. J.A. Robl et al., J. Med. Chem. 42, 305 (1999).


CHAPTER 2

ALICYCLIC COMPOUNDS

The slimness of this chapter very aptly reflects the importance of aromaticand heterocyclic moieties as cores for therapeutic agents. This sectionincludes several agents that depend on the presence of on a single alicyclicgroup for their activity. Though a few of the compounds included in thischapter do include a benzene ring, that group does not seem to play amajor role in their biological activity. Sizeable chapters were devoted inthe earlier volumes in this series to the discussion of drugs based on thesteroid nucleus. This area, in common with the prostaglandins that openthis chapter, has received relatively little attention in recent years. Ahandful of steroids thus round out this section.

1. MONOCYCLIC COMPOUNDS

A. Prostaglandins

The discovery of the prostaglandins in the mid-1960s led to an enormousamount of research in both industrial and academic laboratories.1 Much ofthis work was arguably based on the mistaken premise that these hormone-like compounds would provide the basis for the design of major newclasses of therapeutic agents. Analogy with the large number of important


21

drugs that had emerged from manipulation of the structure of the steroidhormones provided at least some of the impetus for research on the pros-taglandins. The expectation of major classes of new drugs was to someextent dispelled by the findings in the late 1960s that prostaglandins andother products derived from arachidonic acid tended to mediate injuriousresponses, such as inflammation rather than hormonal effects. In spite ofthis, several compounds based on this structure have found uses in theclinic. These include, for example, misoprostol, a drug based on the ben-eficial effect of this class of compounds on the mucous lining of thestomach. This compound differs from the naturally occurring prostaglandinE (PGE) by the removal of the side chain hydroxyl to one carbon furthestfrom the cyclopentane and presence of an additional methyl group on thatposition. Other compounds based on this structure provide several ophthal-mic products. These topical prostaglandins are used to lower intraocularpressure in glaucoma patients. They are believed to cause the outflowof fluid within the eye by binding to specific intraocular receptors. Thesecompounds are classed as PGFs. Since both ring oxygens comprisealcohols.

O

HO CH3

CO2H

OH

Misoprotol

The first two agents, both used to lower intraocular pressure due to glau-coma, differ from natural prostaglandins by the presence of an aromaticring at the end of the neutral side chain. Construction of the terminalgroup on travoprost (9) starts with the reaction of the anion frommethyl dimethoxyphophonate with the aryloxy acid chloride (1).Displacement of halogen affords product 2. Treatment of 2 with strongbase leads to formation of the corresponding ylide. A key intermediatefor the synthesis of many prostaglandins is the so-called Corey lactone.This compound, shown as its dibenzylcarboxylic ester (3), provides func-tionality for immediate attachment of the neutral side chain as well as, inlatent form a junction point for the addition of the carboxylic acidbearing side chain. Reaction of this reactive species from 2 with 3 leadsto the condensation product of the ylide with the aldehyde. The trans

22 ALICYCLIC COMPOUNDS

stereochemistry of the newly formed olefin follows from the normal courseof this reaction. Reduction of the side-chain carbonyl group with zinc bor-ohydride gives the alcohol 5 after separation of the isomers. Reaction withmild base results in hydrolysis of the diphenyl ester protecting group (6).The newly revealed alcohol, as well as that on the side chain, are then pro-tected as their tetrahydropyranyl ethers by reaction with dihydropyran inthe presence of acid (7). Controlled reduction of the lactone ring with dii-sobutylaluminum hydride (DIBAL-H) stops at the lactol stage (8).Condensation with the zwitterionic salt-free ylide, 4-triphenylphosphino-butyrate, results in condensation with the open aldehyde form of thelactol. The “salt free” conditions of this reaction account for theformation of the new olefin with cis stereochemistry. The acid is thenconverted to its isopropyl ester by reaction of the carboxylate salt withisopropyl iodide. There is thus obtained travaprost (9).2

O

CF3

1

(CH3O)2POCH3

BuLi

2

O

OOH3C

H3CO

O

CH=OO

O

O

O

O

CF3

Cl

O

O

CF3

O

P

O

O

O

O

O

CF3

OH

Separate

C6H5C6H4

O

C6H5C6H4

O

C6H5C6H4

O

K2CO3

45

O

O

HO

O

CF3

OH

6

ZnBH4

DihydropyranTsOH

O

O

THPO

O

CF3

OTHP

7

DIBAL-H

O

OH

THPO

O

CF3

OTHP

1. (C6H5)3P+(CH2)3CO2

–

2. (CH3)2CHI

HO

HOO

CF3

OH3. H

+

CO2CH(CH3)2

89

3

The rather simpler ophthalmic prostaglandin latanoprost (10),3 carries asimple benzene ring directly at the end of the side chain. The amide of thisdrug is said to be better tolerated because of the absence of an acidiccarboxyl group. Reaction of 10 with 1,8-diazobicyclo[5.4.0]undec-7-ene

1. MONOCYCLIC COMPOUNDS 23

(DBU) flowed by methyl iodide leads to the corresponding methyl ester 11.Heating 11 with ethylamine leads to ester interchange and formation of theethyl amide bimatoprost (12).4

HO

OH OH

CO2H

10

HO

OH OH

CO2CH

3

11

HO

OH OH

CO2NHC

2H

5

12

DBU

CH3I

C2H

5NH

2

A PGE related compound, lubiprostone (23) displays a quite differentspectrum of activity. This compound has been recently approved for treat-ment of chronic constipation and is being investigated for its effect onconstipation-predominant irritable bowel syndrome. It has been ascertainedthat the drug interacts with specific ion channels in the GI tract causingincreased fluid output into the lumen. Starting material for the synthesis(13) comprises yet another variant on the Corey lactone. Condensation

O

O

CH=OTHPO

13

+

O

F F

P

O

OOH3C

H3C

O

O

THPOO

F F

1415

O

O

THPOO

F F

16

H2

O

O

THPOOH

F F

17

O

OH

THPOO

F F

18

NaBH4DiBAL

(C6H5)3P+(CH2)3CO2–

OH

THPOO

F

19

FCO2H

OH

THPOO

F

20

FCO2CH2C6H5

1. CrO3

2. AcOH

O

HOO

F

21

F

CO2CH2C6H5

O

HOO

F F

H2

CO2H

O

F F

CO2H

22

O

HO

23

t BuOK


of this aldehyde with the ylide from the difluorinated phosphonate 14 leadsto the addition product 15. The double bond in thef olefin has the expectedtrans geometry though the next step, hydrogenation, makes this point moot.Sodium borohydride then reduces the side-chain ketone function to give 17as a mixture of isomers. The lactone is then reduced to the key lactol in theusual fashion by means of diisobutyl aluminum hydride. This compoundis then condensed with the ylide obtained from reaction of the zwitterion4-triphenylphosphoniumbutyrate to give the chain-extended olefin (19).The carboxylic acid in this intermediate is next protected as the benzylester by alkylation of its salt with benzyl chloride. Oxidation of the ringalcohol by means of chromium trioxide followed by exposure to mildacid to remove the tetrahydropyranyl group establishes the keto–alcoholPGE-like function in the five-membered ring (21). Catalytic hydrogenationof this last intermediate at the same time reduces the remaining doublebond and removes the benzyl protecting group on the acid to give theopen-chain version (22) of the product. The electron-withdrawing powerof the fluorine atoms adjacent to the side-chain ketone cause the carbonylcarbon to become a reasonable electrophile. The electron-rich oxygen onthe ring alcohol thus adds to this to give a cyclic hemiacetal. This form(23), greatly predominates in product 23.5

B. Antiviral Agents

The enzyme neuraminidase plays a key role in the replication of influenzaviruses. Newly formed virions form blister-like buds on the inside of thehost cell membrane. This proteolytic enzyme, known as sialidase, facili-tates scission of the base of the bud and thus release of the new virion.Research on structurally modified neuraminidase congeners culminatedin the development of a derivative that blocked the action of theenzyme. This complex dihydropyran, zanamivir (24), was found to beeffective against influenza viruses and most notably avian influenza A(H5N1), better known as bird flu. The lengthy complex route to thatdrug encouraged the search for alternative structures that would fit thesame site. Two more easily accessible agents based on carbocyclic ringsthat have the same activity as the natural product based drugs have beenidentified to date.

There has been much recent anxious speculation that the bird flu viruswill mutate to a form that will spread from person to person. A worldwideinfluenza epidemic, at worst comparable to that which followed the GreatWar, could well be the net result of such an event. The efficacy of the firstcarbocyclic neuraminidase inhibitor, oseltamivir (34), known familiarly


by its trade name Tamiflu, has focused considerable attention on this drug.A significant amount of work has been devoted to its preparation in theexpectation of the very large quantities that would be required in theevent that the pandemic materializes. The choice of starting material isconstrained by the fact that virtually every carbon atom on the six-membered ring in the molecule bears a chirally defined substituent. Allthe early syntheses start with either shikimic (25) or gallic acid fromplant sources. A typical approach involves construction of the epoxide27 as an early step. Shikimic acid is first converted to its ethyl ester. Thetwo syn disposed adjacent hydroxyl groups are then tied up as theacetonide (26) by reaction with acetone. The remaining free alcohol isthen converted to its mesylate by means of methanesulfonyl chloride.Hydrolysis of the mesylate followed by reaction with base leads to internaldisplacement of the mesylate and formation of the key epoxide (27).The free hydroxyl group is then protected as its methoxymethylene ether(MEM) (28). Reaction with the nucleophile (sodium azide) then servesto open the oxirane to give the azide (29). The next series of steps inessence establishes the presence of adjacent trans disposed aminogroups. The free hydroxyl is thus first converted to a mesylate; catalytichydrogenation then reduces the azide to a primary amine (30). This dis-places the adjacent mesylate to form an aziridine (31). Treatment of thisintermediate or a derivative with acetic anhydride then affords the activatedintermediate (32).

O CO2H

HNAcHN

HO

OH

NH

NH224

CO2HHO

HO

OH

25

CO2C

2H

5HO

O

27

CO2C

2H

5

O

CO2C

2H

5MEMO MEMO

HO

N3

1. MsCl2. H

2

CO2C

2H

5MEMO

MsO

NH2

CO2C

2H

5MEMO

AcHN

CO2C2H5

OH

O

O

26

1. MsCl2. H+

3. B–

282930

CO2C

2H

5

N3

AcHN

HO

31

32

CO2C

2H

5

N3

CO2C

2H

5

NH2

AcHN

O

NHAc

33 34


Sodium azide again opens a strained reactive three-membered ring. Thereis thus obtained the acetamido azide (33). Repeat of the sequence, mesylateformation followed by catalytic hydrogenation leads to formation of anew aziridine (33), in which the ring has moved over by one carbonatom. Reaction of this last intermediate with 3-pentanol in the presenceof base leads to opening the aziridine ring to give the correspondingether. The azide in this last intermediate is again reduced with hydrogen.Finally (34) is obtained.6–8

The importance of this drug to meet a potential worldwide pandemichas attracted the attention of academic chemists. This finding hasresulted in the development of a relatively short but elegant synthesis.The approach is notable in that it does not involve difficult to obtainnatural product starting material and completely obviates the use ofpotentially explosive azide intermediates. The first step involves buildingthe carbocyclic ring equipped with a chiral carbon atom that willdetermine the stereochemistry of the many remaining ring substituents.Thus, 2 þ 4 cycloaddition of acrylate 5 to cyclobutadiene in the pre-sence of the pyrrolidine derivative (36) as a chiral catalyst affords theester (37) as a virtually pure optical isomer. The ester group is then con-verted to an amide (38) by simple interchange with ammonia. Reactionwith iodine under special conditions leads to the nitrogen counterpart ofan internal iodo-lactonization reaction and formation of the bridgediodolactam (39). The amide nitrogen is then protected as its tert-butoxycarbonyl derivative. Dehydroiodination with DBU introduces adouble bond giving 41. Free radical bromination of that intermediatewith N-bromosuccinimide (NBS) proceed with the shift of the olefinto give the allylic bromide 42. Dehydrobromination with cesium oxideintroduces an additional double bond in the ring. The presence ofethanol leads the lactam ring to open at the same time. (For ease in visu-alization, the product diene (43) is drawn both as produced and in theorientation that matches that in the scheme above.) The second nitrogenrequired for the product is introduced by an unusual novel reaction. Theproduct (44) obtained from treatment of diene 43 with acetonitrile andNBS in the presence of stannic bromide can be rationalized by positinginitial addition of bromide to the olefin to form a cyclic bromonium ion;addition of the unshared pair of electrons on the nitrile nitrogen wouldaccount for the connectivity. Hydrolysis of the initial imine-like inter-mediate would account for the observed product 44. Treatment withbase leads to internal displacement and formation of the aziridine ringin 45. Reaction as above with 3-pentanol followed by removal of thet-BOC group affords oseltamivir (34).9


CO2C2H5

NH2

AcHN

O

34

CO2CH2CF3

+

35

N BO

C6H5

C6H5H

H

+

CO2CH2CF336

37

NH3

CO2NH2

38

I2

HN

I

O39

t-BOCN

I

O

40

DBU

t-BOCN

O

41

NBS

AIBnt-BOCN

O

Br

42

CsO2

t-BOCHN

43

EtOHCO2C2H5

CH3CN

NBASnBr4

CO2C2H5

t-BOCHN

43

CO2C2H5

t-BOCHN

44

Br

AcHN CO2C2H5

t-BOCHN

45

NHAc

(t -BuOCO)2O

Neuraminidase blocking activity is interestingly retained when thecentral ring is contracted by one carbon atom. Note that the cyclopentanering in the antiviral agent peramivir (53) carries much the samesubstituents as its cyclohexane-based counterpart. The presence of theguanidine substituent, however, traces back to the tertrahydropyranzanamivir (24). The relatively concise synthesis of peramivir starts bymethanolysis of the commercially available bicyclic lactam 46.Reaction of the thus-obtained amino-ester with t-BOC anhydride leadsto the N-protected intermediate (47). The key reaction involves additionof both a functionalized carbon substituent and a hydroxyl group in asingle step. Reaction of the nitroalkane (48) with phenyl isocyanateleads to the formation of a nitrone. That very reactive species thenundergoes 2 þ 3 cycloaddition to the double bond in the cyclopentene(47). The isoxazolidine (49) is the predominant isomer from thatreaction. Catalytic hydrogenation then cleaves the scissile nitrogen-to-oxygen bond leading to ring opening and formation of the corre-sponding aminoalcohol. This compound is converted to acetamide (50)with acetic anhydride. The ring amino group is next revealed byremoval of the t-BOC group by means of acid to yield 51. An exchangereaction of that primary amine with pyrazole carboxamidine (52) thenintroduces the guanidine group. Thus the antiviral compound 53is obtained.10


HNO

46

2. (t -BuOCO)2O

1. CH3OH

t-BOCNH CO2CH3

47

NO2

t-BOCNH CO2CH3

NO

N OH

48

49

1. H2

2. Ac2O

tBOCNH CO2CH3

NHAcOH

50

H+

H2N CO2CH3

NHAcOH

51

NH CO2CH3

NHAcOH

53

NH

H2N

NN

NHH2N

52

C6H5N=C=O

C. Miscellaneous Monocyclic Compounds

The venerable drug theophylline has been used to treat asthmatic attacksfor many years. Research on the mechanism of action of this purine ledto the discovery that it acted by blocking the action of the enzyme phos-phodiesterase (PDE). The clinical utility of this compound pointed to thepotential of PDE inhibitors as a source for new drugs. Modern method-ology has led to the subdivision of PDE receptors into a number of sub-types, each of which seems to be involved in the regulation of a discreteorgan system. It is of interest that a newly developed PDE inhibitor, inthis case specific for PDE 4, has shown clinical activity in alleviatingthe symptoms of chronic obstructive pulmonary disease. This finding ofcourse involves the same organ that led to the discovery of the fieldmany decades ago. The first sequence in the synthesis of this new PDEinhibitor comprises homologation of the benzaldehyde (54) to phenyl-acetonitrile (56). Reduction of the aldehyde in the presence of lithiumbromide gives the corresponding benzyl bromide; displacement ofhalogen by reaction with potassium cyanide gives the substituted aceto-nitrile (56). Condensation of that intermediate with ethyl acrylate in thepresence of base leads to Michael addition of two molecules of the acrylateand formation of the diester (57). Treatment of this last intermediate withstrong base leads to internal Claisen condensation with consequent for-mation of the carberthoxycyclohexanone derivative 58. Heating the keto-ester with acid initially leads to hydrolysis of the ester to an acid. Thisdecarboxylates under reaction conditions to give the cyclohexanone (59).Condensation of the ring carbonyl group in this intermediate with theanion from 1,3-dithiane leads to 60, in what in effect comprises addition


to the ring of a carbon atom at the acid oxidation stage. Oxidation of thesulfur atoms in this intermediate with mercuric chloride in the presenceof methanol converts that carbon to the methyl ester. The product inwhich the nitrile and carboxyl are cis to each other predominate in an11 : 1 ratio over the trans isomer, probably reflecting thermodynamicfactors. Saponifaction of the ester group completes the synthesis ofcilomilast (61).11

O

CH3O

CH=O

54

O

CH3O

CH2Br

55

KCNO

CH3O

56

CN

CO2C

2H

5

O

CH3O

57

CN

CO2C

2H

5

CO2C

2H

5

O

CH3O

58

CN

O

O

CH3O

CN

S

S

60

O

CH3O

CN

61

CO2H1. CH

3OH

HgCl2

2. NaOH

NaOC2H

5

CO2C

2H

5O

CH3O

59

CN

O

The vitamin A related compound, all trans retinoic acid, is a ligand forcells involved in epithelial cell differentiation. It has found clinical useunder the name tretinoin (62), for treatment of skin diseases, such as acne,and for off-label application as a skin rejuvenation agent. The recently dis-covered closely related 9-cis isomer in addition binds to a different set ofreceptors involved in skin cell growth. This new compound has beenfound to control proliferation of some cancer cells. The drug is thus indicatedfor topical use in controlling the spread of Kaposi sarcoma lesions.Reduction of the ester group in compound 63, which incorporates the requi-site future 9-cis linkage with lithium aluminum hydride, leads to the corre-sponding alcohol. This compound is then oxidized to aldehyde 64 bymeansof manganese dioxide. Condensation of the carbonyl group with the ylidederived by treatment of the complex phosphonate (65) adds the rest of thecarbon skeleton (66). Saponification of the ester then gives the correspond-ing acid, alitretinoin (67).12


CO2H

62

CO2CH3

63

1. LiAlH4

2. MnO2 CH=O

64

CO2C2H5

(C2H5O)2PO

66; R = C2H5

67; R = H

CO2R

65

NaH

2. POLYCYCLIC COMPOUNDS: STEROIDS

The first five volumes in this series each feature a separate chapter thatbears the title Steroids. The steady diminution of research on this structuralclass is illustrated by the regularly decreasing extent of those chapters. Bythe time Volume 6 appeared, the discussion of steroid-based drugs takes upbut a section in the chapter on Carbocyclic Compounds. The relativelysmall amount of research devoted to this area is reflected in the presentvolume as well. The compounds that follow are organized by structuralclass as they each display quite different biological activities from oneanother.

A. 19-Nor Steroids

Virtually all known antiestrogens comprise non-steroidal compoundsbased more or less closely on triphenyl ethylene (see ospemifene,Chapter 3). Tamoxifen ranks as the success story in this class of drugshaving found widespread use in the treatment of women suffering fromestrogen receptor positive breast cancer. It is thus notable that a derivativeof estradiol itself, which carries a very unusual substituent, also acts as anestrogen antagonist. Unlike its non-steroid forerunners, all of which showsome measure of agonist activity, this agent is devoid of any estrogenicactivity. Conjugate 1,4 addition of the Grignard reagent from long-chainbromide 69 to the dienone 68 affords the 7-alkylated product 70 as amixture of epimers at the new linkage. The 7-a isomer is separated fromthe mixture before proceeding; the hydroxyl group at the end of the longchain is then unmasked by hydrolytic removal of the silyl protectinggroup. Reaction with cupric bromide serves to aromatize ring A; saponifi-cation with mild base preferentially removes the less sterically hinderedacetate at the end of the long chain. Acylation by means of benzoylchloride converts the phenol to the corresponding ester 72.13 The synthetic

2. POLYCYCLIC COMPOUNDS: STEROIDS 31

route from this point on is speculative as details are not readily accessible.Reaction of this last literature intermediate (72) with methanesulfonylchloride would then lead to mesylate 73. This group could then be dis-placed by sulfur on the fluorinated mercaptan (74). Controlled oxidationof sulfur, for example, with periodate, would then lead to the correspond-ing sulfone. Saponification of the ester groups at the 3 and 17 positionswould afford the estrogen antagonist fluverestant, (75).13 Note that thisspecific compound is but one from a sizeable group of similarly substitutedestradiol derivatives that shows pure antagonist activity.

OAc

O

OBrSi

CH3

t BuH3C

Mg

OAc

O

Si

CH3

tBuCH3

68

69

70

1. H+

2. Ac2O

OAc

O

71

1. CuBr22. NaOH3. C6H5COCl

OAc

C6H5CO

72

OAc

C6H5CO

73

OH

HO

OH OAc

O

SO

CF3

1. HS

2. [O]

FF

3. OH–

75

CF3

FF

74

OSO2CH3

Synthesis of 19-norandrostanes, which carried a functionalized benzenering at the 11 position, led to the surprising discovery of compounds thatantagonized the action of progestins and glucocorticoids. One of thosecompounds, mifepristone (76), more familiarly known as RU-486, wasquickly enveloped in controversy, as a result of its use for terminating preg-nancy by nonsurgical means. A more recent example, asoprinosil (84) is amore selective progesterone antagonist with reduced binding to glucocor-ticoid receptors. Treatment of the diene 77, a total synthesis derived 19-nor


gonane, with hydrogen peroxide, results in selective reaction at the 5,10double bond to give the epoxide 78. The proximity of the acetaloxygens at the 3 position accounts for the regiochemistry of the product;attack from the more open a-side accounts for the stereochemistry.Condensation of 78 with the Grignard reagent from the methyl acetalof p-bromobenzaldehyde in the presence of cuprous salts leads toconjugate addition to the 11 position with concomitant shift of thedouble bond to the 5,9 position (79). Construction of the side chainat the 17 position starts with the addition of the ylide from the tri-methylsulfonium iodide to the carbonyl group give the oxirane 80.Reaction of the product with sodium methoxide opens the epoxide ringto give the ether–alcohol 81. Alkylation of the hydroxyl group at 17with methyl iodide and base affords the bis(methyl ether) 82. Exposureof that intermediate to acid leads to hydrolysis of the acetal protectinggroups on the ketone at 3 as well as the aromatic aldehyde; the tertiaryalcohol on the AB ring junction dehydrates under those conditions,restoring the double bond (83). Reaction of this last intermediate withhydroxylamine leads to formation of the aldoxime in a 95 : 5 (E)/(Z ) ratio.

O

CH3(CH3)2N

76

H2O2

O

CH3O

CH3O

78

O

BrOCH3

OCH3

Mg,Cu2+

O

CH3O

CH3O

77

O

CH3O

CH3O OH

CH3O

CH3O

79

O

CH3O

CH3O OH

CH3O

CH3O

80

(CH3)3SO+

tBuOK

OH

CH3O

CH3O OH

CH3O

CH3O

81

CH3ONa

OCH3

OCH3

CH3O

CH3O OH

CH3O

CH3O

OCH3

CH3I

CH3ONa

82

TsA

OCH3

O=HC

OCH3

O

83

OCH3

OCH3

O

84

NHO

NH2OH


The purified isomer (84)14 is currently used in the clinic as a treatment forendometriosis, as well as other conditions related to excess progesteronestimulation.

The total synthesis based 17-ethyl norgonane, levonorgestrel (85), hasbeen in use for many years. The corresponding oxime has recently beenintroduced as the progestational component of an oral contraceptive. Inthe absence of a specific reference, it may be speculated that the compoundnorelgestimate (86), is prepared by simply reactioning 85 with hydroxyl-amine in analogy to the preparation of the corresponding 17 acetoxyderivative.15

OH

O

85

OH

HON

86

B. Corticosteroid Related Compounds

The soybean sterols that comprise one of the principal sources for proges-tins and corticoids consist almost entirely of a mixture of stigmasterol andsitosterol. The lack of a double bond in the side chain renders the latteruseless as a starting material since that function is key to the Upjohnprocess for removing the long terpinoid side chain present in thesesterols. As a result, tonnage quantities of this steroid thus accumulated ina Kalamazoo storage lot over the years. A microorganism was finallyfound in the late 1970s that would feed on this rich source of carbon, meta-bolizing the fatty side chain at the 17 position and at the same time intro-ducing an oxygen function at position 9 that could be used later tointroduce the crucial double bond in ring C. Considerable work was thendevoted to developing methods for building up the highly functionalizedtwo-carbon side chains found in corticoids at the now bare 17 positionfound in these biodegradation products. One of the intermediates fromone of those schemes has interestingly recently becomes a drug in itsown right. Wet macular degeneration, one variant of the disease thatleads to loss of vision with age, is marked by excessive growth of newblood vessels in the retina. This process, neovascularization, in effectdestroys photoreceptor areas of the retina. The drug, anecortave (95),which needs to be administered locally within the eyeball, inhibits the


growth of those new blood vessels thus saving still-intact areas the retina.The sequence for preparation of the agent begins with the conversion of theketone at 3 to its enol ether 88, for example, with methyl orthoformate.Addition of cyanide to the carbonyl at 17 initially leads to a mixture of epi-meric cyanohydrins. Conditions were developed for converting this to thedesired isomer 89, by crystallization under equilibrating conditions. The17b cyano isomer is apparently less soluble that its epimers. The hydroxylgroup at 17 is then protected as its trimethylsylyl ether (90). Reduction bymeans of diisobutylaluminumhydride followedbyproticworkup converts thecyano group to an aldehyde. Condensation of this intermediatewith the anionfrom methylene bromide probably leads initially to adduct 92. Excess base,lithium diisopropylamide (LDA), is thought to remove one of the bromineatoms. The resulting intermediate then rearranges to give the observed bromo-ketone. Removal of the protecting groups leads to diketone 94, which lacksonly oxygen at positon 21. Displacement of bromine atom at that positionwith sodium acetate completes construction of the corticosteroid side chainat position 17.16 Thus 96 is obtained.

O

O

O

CH3O

(CH3)3CH

87 88

KCN

AcOH

CN

CH3O

89

OH

(CH3)3SiCl

CN

CH3O

90

OTMSCH=O

CH3O

91

OTMS

DIBAL-H

CH3O

92

OTMS

CH2Br

2

LDA

CH3O

93

OTMS

LiO Br

LiOBr

Br

O

94

OH

OBr

NaOAc

O

95

OH

OOCOCH

3

Topically applied corticosteroids have proven very effective in treatingasthma. The amount of drug from the inhaled dose that reaches thesmall airways has a critical effect on relieving asthmatic episodes. Theacetal at positions 16,17 of the diol (97) with acetone,17 desonide, has


long been indicated for treating asthma. It has recently been foundthat the acetal containing cylcohexane carboxaldehyde penetrates furtherinto the small airways. The first step in this brief sequence comprisesreaction of the syn diol (96) with isobutyric anhydride to afford thetriply esterified intermediate 97. Reaction of this compound with cylco-hexane carboxaldehyde in aprotic solvent in the presence of acid leadsto formation of the acetal by a transesterification-like sequence. Thepresence of the very bulky alkyl groups on the esters favors formationof that isomer of the acetal in which the cyclohexane is oriented awayfrom the face of the steroid. The product (98) thus predominantlycomprises the desired isomer. Saponication of the remaining ester at 17followed by separation from the small amount of epimeric acetal thenaffords cicledesonide (99).18

O

HO

O

OH

OH

OH

96

CH3

CH3 2

O

O

HO

O

O

O

O

97

O

O

O

O

HO

O

O

O

O

O

98

O

HO

O

OH

O

O

99

OH–

Separate

O

Replacement of carbon 4 in androstane by nitrogen leads to androgenantagonists. These drugs have proven useful for treating a conditionmarked by excess androgen or sensitivity there to such a benign prostatichypertrophy and even hair loss. Earlier examples are covered in Volumes 5and 6 of this series. Synthesis of the most recent example starts by for-mation of the amide between steroid carboxylic acid 100 and 1,4-bis(trifluoromethylaniline) (101) via the acid chloride. Ring A is then


opened to the corresponding keto acid (102) by oxidation of the doublebond in ring A by means of permanganate. Reaction of that compoundwith ammonia at elevated temperature can be visualized as proceedingthrough an amide–enamine, such as 103. Amide interchange closes thering to form the enamide 104. Catalytic hydrogenation followed byreaction with DDQ completes the synthesis of dutasteride (105).19

CO2H

O

100

H2N

F3C

CF3

F3C

CF3

O

101

OHN

KMnO4

F3C

CF3

HO2CO

102

OHN

F3C

CF3

NH

O

104

OHN

F3C

CF3

H2NOCH2N

103

OHN

NH3

2.DDQ

1.H2

F3C

CF3

NH

O

105

OHN

Vitamin D actually consists of a set of closely related compounds whosestructures are based on the steroid nucleus with an opened ring B. Thesecompounds control various metabolic processes from bone deposition toskin growth. One of the vitamins (D3), calcitrol, has been used to treatpsoriasis and acne. A recent semisynthetic Vitamin D congener hasshown an improved therapeutic index over the natural product. The syn-thetic sequence to this analogue hinges on selective scission of the isolateddouble bond in the side chain. The key step thus involves inactivation ofthe conjugated diene centered on ring A. This is accomplished byformation of a Diels–Alder-like adduct between the starting material106, in which the hydroxyl groups are protected as the diisopropylsilylether and sulfur dioxide.20 Ozonolysis of the adduct 107 followed bywork-up of the ozonide, gives the chain-shortened aldehyde. Heating theproduct restores the diene by reversing the original cylcoaddition reaction(108). The carbonyl group is then reduced to the alcohol by means ofborohydride and the resulting alcohol converted to its mesylate 109. Thechain is next homologated by first displacing the mesylate with theanion form diethyl malonate. Saponification of the ester groups followedby heating the product in acid cause the malonic acid to lose carbondioxide. Thus, the chain extended acid 110 is obtained. The carboxyl


group is next converted to the activated imidazolide by reaction withcarbonyl diimidazole. Condensation of this intermediate with pyrrolidinegives the corresponding amide. Removal of the silyl protection groupswith fluoride leads to ecalcidine (111).21

RO OR R = Si(CH(CH3))2 RO OR

SO2

SO21. O3

2. heat

RO OR

CH=O

106 107 108

RO OR

109

1. NaBH4

2. CH3SO2Cl

OSOCH3

1.

2. NaOH3. HCl

CO2C2H5

CO2C2H5

RO OR

110

CO2H

1. CDI,

2. F –

HO OH

111

O

N

HN

3. POLYCYCLIC COMPOUNDS

A sequiterpinoid fulvene from the Jack O’Lantern mushroom was foundsome years ago to show very promising antitumor activity in a numberof in vitro assays. This compound, Iludin S (112) was, however, foundto be too toxic in follow-up in vivo tests to be considered for furtherdevelopment. The semisynthetic analogue irofulven (114) is far better tol-erated and has been taken to the clinic where it demonstrated activityagainst several tumors. Though a total synthesis has been published,22

the compound is most efficiently prepared by semisynthesis from IludinS itself. Treatment of the natural product with dilute acid leads to loss ofthe elements of water and formaldehyde in what may be considered areverse hydroformylation reaction to yield intermediate 113. Reaction ofthat product with formaldehyde in dilute acid in essence reverses the lastreaction, though with a different regiochemistry. Formaldehyde thus


adds to the last open position of the extended eneone system. Thus, 114is obtained.23

HOO

OH

OH

112

H2SO4

HOO

113

HOO

OH

OH H2SO4HO

O

OH

114

H2C=O

Pain receptors become sensitized during inflammation or from arelated stimuli, and consequently often release glutamate. That aminoacid then acts on NMDA receptors on neurons, and in the processfurther sensitizes those to pain stimuli. This sequence then causesthe pain to become chronic. Specific NMDA antagonists would thusbe expected to relieve chronic pain by interrupting that chain.Consequently, such compounds would offer a potentially nonaddictivealternative to the opiates currently used to treat chronic pain. Reductiveamination of the acetaldehyde derivative 116 with monocarbobenzyloxyethylenediamine (116) leads to the now-disubstituted ethylenediamine116. Reaction of this amine with the commercially available cyclo-butenedione derivative 117 leads to replacement of one of the ethoxygroups in 117 by the free amino group in 116 by what is probablyan addition–elimination sequence to afford the coupled product 118.

NHCO2CH2C5H6H2N

115

PO

OC2H5C2H5O

CH=O

PO

OC2H5C2H5O

116

NaCNBH3

NHCO2CH2C5H6HN

116

O

O

OC2H5

O

O

OC2H5

OC2H5

117P

O

OC2H5C2H5O

NHCO2CH2C5H6N

Pt

118

O

O

OC2H5

PO

OC2H5C2H5O

NH2N

119

N

HNO

O

PO

OC2H5C2H5O

120

(CH3)3SiBrN

HNO

O

PO

OHHO

121

3. POLYCYCLIC COMPOUNDS 39

Reduction of this intermediate by hydrogen transfer from 1,4-cyclohexa-diene in the presence of platinum leads to loss of the carbobenzoxygroup and formation of the transient primary amine 119. The terminalprimary amino group in that product then participates in a secondaddition–elimination sequence to form an eight-membered ring (120).Treatment of this intermediate with trimethylsilyl bromide then cleavesthe ethyl ethers on phosphorus to give the free phosphonic acid and thusperzinfotel (121).24

REFERENCES

1. See, for example, Chemistry of the Prostaglandins and Leukotrienes,J.E. Pike, D.R. Morton, Eds., Raven Press, NY, 1985.

2. J. Castaner, L.A. Sobrera, Drugs Future 25, 41 (2000).

3. See D. Lednicer, The Organic Chemistry of Drug Synthesis, Vol. 6, JohnWiley & Sons, Inc., NY 1999, p. 98.

4. D.A. Woodward, S.W. Andrews, R.M. Burk, M.E. Garst, U.S. Patent5,352,708 (1994).

5. L.A. Sobrera, J. Castaner, Drugs Future 29, 336 (2004).

6. C.U. Kim et al., J. Am. Chem. Soc. 119, 681 (1997).

7. C.U. Kim et al., J. Med. Chem. 41, 2451 (1998).

8. N. Bischofberger, C.U. Kim, W. Lew, H. Liu M.A. Williams, U.S. Patent5,763,483 (1998).

9. Y.-Y. Yeung, S. Hong, E.J. Corey, J. Am. Chem. Soc. 128, 6310 (2006).

10. Y.S. Babu et al., J. Med. Chem. 43, 3482 (2000).

11. S.B. Christensen et al., J. Med. Chem. 41, 821 (1998).

12. M.F. Boehm, M.R. McClurg, C. Pathirana, D. Mangelsdorf, S.K. White,J. Herbert, D. Winn, M.E. Goldman, R.A. Hayman, J. Med. Chem. 37, 408(1994).

13. J. Bowler, T.J. Lilley, J.D. Pittman, A.E. Wakelin, Steroids 54, 71 (1989).

14. G. Schubert, W. Eiger, G. Kaufmann, B. Schneider, G. Reddersen,K. Chwalisz, Semin. Reprod. Med. 23, 58 (2005).

15. A.P. Shroff, U.S. Patent 4,027,019 (1977).

16. J.G. Reid, T. Debiak-Krook, Tetrahedron Lett. 31, 3669 (1990).

17. S. Bernstein, R. Littell, J. Am. Chem. Soc. 81, 4573 (1959).

18. J. Calatayud, J.R. Conde, M. Lunn, U.S. Patent 5,482,934 (1996).

19. K.W. Batchelor, S.W. Frye, G.F. Dorsey, R.A. Mook, U.S. Patent 5,565,467(1996).


20. R. Hesse, U.S. Patent 4,772,433 (1988).

21. R.H. Hesse, G.S. Reddy, S.K.S. Setty, U.S. Patent 5,494,905 (1996).

22. T.C. McMorris, Y. Hu, M. Kellner, Chem. Commun. 315 (1997).

23. T.C. McMorris, M.D. Staake, M.J. Kellner, J. Org. Chem. 69, 619 (2004).

24. W.A. Kinney et al., J. Med. Chem. 41, 236 (1998).

REFERENCES 41

CHAPTER 3

MONOCYCLIC AROMATICCOMPOUNDS

Free-standing benzene rings have provided the core for a very large numberof biologically active compounds. This ubiquitous unit provides the rigid flatskeleton onwhich to attach functional groups and alsomanifests the electrondensity required for recognition at various receptor sites. The ubiquitousoccurrence of aromatic rings in endogenous effector molecules as, forexample, the chatecholamines, is a reflection of this importance. The 30odd drugs described in Chapter 3 represent a wide variety of structuraltypes; their biological activities are equally diverse. Consequently, it isoften not readily apparent just which parts of the structures form part ofthe pharmacophore. Thus, compounds are included in this chapter largelyon the basis of structure. The grouping in the discussions that follow areadmittedly somewhat arbitrary.

1. ARYLCARBONYL DERIVATIVES

A relatively simple benzamide inhibitor of phosphodiesterase 4 has provenuseful for treating congestive obstructive pulmonary disease (COPD).The synthesis of this compound begins by alkylation of the free phenol onaldehyde 1 with chlorodifluromethane in the presence of base. Oxidation of


43

the carbonyl group in 2 with hypochlorite followed by reaction withthionyl chloride leads to the acid chloride (3). Condensation of thelast intermediate (3) with the substituted aminopyridine (4) affords thebenzamide roflumilast (5).1

HO

O CH=O

1

F2CHCl

F2CHO

O CH=O

2

1. NaClO2

2. SO2ClF2CHO

O CO2Cl

3

NCl

ClF2CHO

ONH

O

5

NCl

Cl

H2N

4

The discovery of the “statin” mevalonic acid synthesis inhibitorsfocused new attention on control of blood lipid levels as a measure tostave off heart disease. A number of compounds have been found thattreat elevated lipid levels by other diverse mechanisms. The phosphonicacid derivative ibrolipim (9) is believed to lower those levels by accelerat-ing fatty acid oxidation. The phosphorus-containing starting material 7 canin principle be obtained by the Arbuzov reaction of a protected from ofp-bromomethylbenzoic acid (6) with triethyl phosphate. Removal of theprotecting group and conversion of the acid to an acyl chloride thenaffords 7. Condensation of this intermediate with substituted aniline 8leads to the hypolipidemic agent (9).2

P(OC2H5)3

ClOC

PO

OO

C2H5C2H5

7

PO2C

Br

6

NH2

CN

Br

8

PO

OO

C2H5C2H5

CN

Br

+

HN

O

9

44 MONOCYCLIC AROMATIC COMPOUNDS

Red blood cells in patients afflictedwith sickle-cell anemia showa reducedcapacity for holding oxygen. The adventitious discovery that the lipid lower-ing agent clofibrate (10) possessed some antisickling activity led to furtherinvestigation of related compounds. It was found that this unexpected activityof these agents resulted from their bringing about an increased oxygen-carrying capacity of normal blood cells. One of the compounds from thiswork, efaproxiral (15), is now used to deliver oxygen to hypoxic tumortissues to improve the efficacy of radiation therapy. Oxygen, whose presenceis crucial to the generation of cell-killing radicals, is often in short supply insolid tumors. Reaction of the arylacetic acid (11) with thionyl chloride leadsto the corresponding acyl chloride. Condensation of that intermediate with3,5-dimethylaniline leads to the anilide 14. Treatment of that product withacetone and chloroform in the presence of strong aqueous base adds thedimethyl acyl function to the phenol group. Thus, 15 is obtained.3 Thisunusual reaction can be visualized by assuming intitial formation of ahemiacetal between the phenol and acetone (a); displacement of the hydroxylby the anion from chloroform would lead to the intermediate (b); simplehydrolysis would then convert that group to a carboxylic acid.

ClOHO2C

CH3H3C

10

OH

COR

11; R = OH

12; R = Cl

H2N CH3

CH3

13OH

CH3

CH3

HN

O

14

(CH3)2CO

CHCl3

CH3

CH3

HN

OO

HO2C

CH3H3C 15

OOH

–CHCl2

OCl

H Cl

a b

Over the past few years, it has been established that several apparently quiteunrelated drug classes owe their activity to effects on a shared biochemicalsystem. The blood lipid lowering effect of the fibrates, such as, 10, and thehypoglycemic action of the recently introduced hypoglycemic thiazolidine-diones both trace back to action on subtypes of the peroxisome proliferator-activated receptors (PPAR), which regulates lipid and glucose metabolism.Research targeted at PPAR has led to several novel hypoglycemic agents,which are unrelated structurally to drugs previous used to treat diabetes.

1. ARYLCARBONYL DERIVATIVES 45

The synthesis of the first of these starts with the formation of the enamide(18) from tyrosine (16) and 2-benzoylcyclohexanone (17). Treatment of thatproduct with palladium on charcoal leads to dehydrogenation of the ene-amide ring with consequent aromatization. Condensation of the terminalhydroxyl group on the side chain in the substituted oxazole (21) with thephenol function on 20 in the presence of triphenylphosphine and diethyl azo-dicorboxylate (DEAD) leads to formation of an ether bond. This reactionaffords the hypoglycemic agent farglitazar (22).4

HO

CO2CH3

NH2

16

+O

HO

17

HO

CO2CH3

HO

N

18

HO

CO2CH3

O

HN

19

HO

CO2CH3

O

HN

20

N

O

CH3

(C6H5)3 P, DEAD

O

CO2CH3

O

HN

N

O

CH3

OH

21

22

An aryl carbamate replaces the tyrosine moiety in a related analogue.The preparation of this compound first involves activation of the side-chain oxygen in the same oxazole used above (21) by conversion to itsmesylate (21a) by means of methanesulfonyl chloride. This intermediate

N

O

CH3

R

21; R = H21a; R = OSO2CH3

+CH=O

23

K2CO3N

O

CH3

O

CH=O

HO

1. H2NCH2CO2CH32. NaBH4

N

O

CH3

O

NH

CO2CH3

O

Cl

O

OCH3

24

25

26

N

O

CH3

O

N CO2CH3

OO

OCH327


is used to alkylate the phenol group on p-hydroxybenzaldehyde (23).Condensation of the aldehyde group in 24 with glycine methyl esterleads to the corresponding imine. Reduction of that function with boro-hydride yields the intermediate 25. Acylation of the amino group in 25compound with p-anisyl chloroformate (26) yields muraglitazar (27).5

A very simple triketone has proven useful for treating the rare geneticdisease tyrosinemia. The drug alternately known as nitisinone (30) ororfadin actually bears a very close relation to a pesticide. The analoguein which methylsulfonyl replaces the trifluoromethyl group, mesotrione,is an important corn herbicide. Acylation of cyclohexan-1,3-dione,shown as an enol (28) with acid chloride (29), leads in a single stepto 30.6

O

OH CF3

NO2

Cl

O

+

O

OH CF3

NO2O

28 29 30

Et3N

2. BIPHENYLS

Excision of malignant tumors comprises first line treatment for cancer ofsolid tissues. This procedure not infrequently misses small fragments ofthe tumor that may have broken off before surgery from the principalsite of the disease. These fragments, metasteses, often proliferate at quiteremote locations where they cause much of the pathology of cancer. Aseries of proteolytic enzymes present in tumor cells, known as matrixmetalloproteinases, help establish growth of these metasteses at thenewly invaded sites; these proteases are also involved in the formationof new blood vessels that will nourish the invasive cell masses.Consequently, considerable research has been devoted to matrix metallo-proteinases as a target for anticancer drugs. Clinical results with thesecompounds have to date produced equivocal results.7

Construction of one biphenyl-based metaloproteinase inhibitor starts withthe Friedel–Crafts acylation of 4-chlorobiphenyl (31) with itaconic anhydride(32). Attack proceeds on the less inactivated ring to give the acylated product(33). Michael addition of phenylmercaptan to the exomethylene group givesthe proteinase inbitor tanomastat (34).8

2. BIPHENYLS 47

Cl+ O

O

O AlCl3

Cl

CO2H

O

31 32 33 34Cl

CO2H

O S

C6H5SH

Research on the prostaglandins several decades ago revealed a secondpathway in the arichidonic acids cascade. Products from this alternateroute consisted of long-chain fatty acids instead of the cyclic prostanoids.Subsequently, it was ascertained that these straight-chain acids, called eico-sanoids, reacted with endogenous sulfur-containing oligopeptides, such as,glutathione, to form a series of compounds called leukotrienes that elicitedallergic reactions. These were found to be the same as the previouslyknown slow-reacting substance of anaphylaxis (SRS-A). Drugs that coun-teract this factor would provide an alternate means to antihistamines fordealing with allergies. The majority of antagonists developed to dateconsist of long-chain compounds that terminate in an acidic function.This last comprises a tetrazole rather than a carboxylic acid in virtuallyall compounds reported to date. A very recent entry interestingly terminatesin a carboxylic acid. The convergent synthesis starts with the alkylation ofthe enolate from resorcinol monomethylether (35) with propyl iodide. Theuse of aprotic conditions favors alkylation on carbon over oxygen to afford(36). The enolate from this product is then used to displace the halogenatom in o-fluorobenzonitrile to give the aromatic ether. The nitrile isthen hydrolyzed to the corresponding acid with potassium hydroxide.Treatment of that product with methanol in the presence of acid convertsthe latter to its methyl ester. The O-methyl ether in the product is thencleaved with boron tribromide to afford the phenol (39). Synthesis of thesecond half of the compound begins with the reduction of the acetylgroup in 40 to an ethyl group (41) with tirethylsilane. Bromination ofthis intermediate with NBS proceeds, as expected at the position adjacentto the benzyl ether to afford 42. The side chain that will connect thetwo halves is then put in place by alkylating the free phenol group with1-bromo-2-chloroethane (43). Reaction of the aromatic bromo functionin this last intermediate with p-fluorophenylboronic acid (44) leads to for-mation of the biphenyl group and thus 45. The Finkelstein reaction, withpotassium iodide, leads to replacement of chlorine by the better leavinggroup, iodine in 46. Alkylation of the enolate from the acid moiety39 with iodide in 46 completes construction of the framework.


Saponification of the methyl ester followed by hydrogenolysis of thebenzyl ether completes the synthesis of the leukotriene B4 antagonistetalocib (47).9

CH3O OH

35

C3H7I

BuLi

CH3O OH

37

KF

CH3O OF

CNCN

HO OCO2CH3

1. KOH

2. MeOH

OCH2C6H5

OH

O

40

(C2H5)3SiH

OCH2C6H5

OH

41

OCH2C6H5

OH

BrNBS

F

B(OH)3

OCH2C6H5

O

44

F

BrCl

OCH2C6H5

O

43

Br

Cl

R

OH

O

F

36 3738 3. BBr3

1. 39

2. NaOH

42

45; R = Cl46; R = I

O OCO2H

3. H2

39

47

The discovery, close to half a century ago that beta adrenergic receptorsfell into two broad classes, led to major advances in drug therapy. Agoniststhat act on beta 2 receptors, for example, include the majority agents fortreating asthma. The large number of beta blockers act as beta-1 selectiveadrenergic antagonist. The discovery of a third subset of binding sites, thebeta-3 receptors has led to a compound that provides an alternate methodto currently available anticholinergic agents for treating overactive blad-ders. There is some evidence too that beta-3 agonists may have someutility in treating Type II diabetes. Synthesis of the compound beginswith construction of the biphenyl moiety. Thus, condensation of methylm-bromobenzoate (48) with m-nitrophenylboronic acid (49) in the pre-sence of palladium leads to the coupling product (50). The nitro groupis then reduced to the corresponding amine (51). Alkylation of 51 withthe t-BOC protected 2-bromoethylamine (52) leads to intermediate 53.Treatment with acid removes the protecting group to give the primaryamine (54). Condensation of this last product with m-chlorostyreneoxide leads to formation of 56, a molecule that incorporates the aryl

2. BIPHENYLS 49

ethanolamine moiety present in the great majority of compounds that act onadrenergic receptors. Thus, solabegron (56) is obtained.10

CO2CH3

BrNO2

(HO3)BPdP(C6H5)3

CO2CH3

NR2

Br NHCO2C(CH3)3

52

CO2H

HN

NH

H+

CO2CH3

HN

NHCO2C(CH3)3

CO2CH3

HN

NH2OH

OCl

+

48 49

50; R = O51; R = H

53

54

55

56

Cl

3. COMPOUNDS RELATED TO ANILINE

The structures of many monocyclic aromatic compounds have little incommon; the same is often the case for their biological activities. Theyare consequently grouped here on the basis of some shared structuralelement rather than biological activity. The three compounds that followhave in common a nitrogen atom attached to the benzene ring.

A wide variety of compounds were tested as lipid-lowering agents somefive decades agowhen association between heart disease and hyperlipdemiawas established. One of themore effective agents discovered in the course ofthis research was the endogenous hormone thyroxin. Use of this compoundwas severely limited by its effect on metabolic function and cardiac activity.More detailed recent research has the thyroid receptor, like those for manyother hormones, exists as a pair of subtypes that are unevenly distributed.11

One of these, the b-receptor, is virtually absent in cardiac tissue. Researchhas thus started to identify compounds aimed at this receptor. The synthesisof a selective blocker for theb selective agent axitirome (66), starts with thereaction of the dianisyl ioidonium salt (57) with the nitrophenol (58) in thepresence of a cupric salt to give the product from displacement of iodine bythe phenoxide to give the diaryl ether (59). Acylation of intermediate (59)with p-fluorobenzoyl chloride (60) in the presence of titanium tetrachlorideyields the benzophenone (61). Reaction intermediate (61) with boron tribro-mide then serves to cleave the methyl ether (62). Catalytic hydrogenationserves to reduce the nitro group to afford aniline (63). This intermediate is


then treated with ethyl oxalate (64) to afford the oxamic ester 65. Thecarbonyl group is then reduced to the corresponding alcohol; saponificationaffords the hypolipidemic agent 66.12

I+

CH3O OCH3

BF4–

57

+

HO

CH3

NO2H3C

58

Cu2+

CH3O

CH3

NO2H3C

O

F

COCl

59

60

CH3O

CH3

NO2H3C

O

61

O

F

HO

CH3

NR2H3C

OO

F

1. BBr3

2. H2

1. NaBH42. NaOH

CO2C2H5

CO2C2H5

HO

CH3

NH

H3C

OO

F

CO2C2H5

O

65

CO2C2H5

HO

CH3

NHH3C

OHO

F

CO2H

O

66

62; R = O63; R = H

64

The few drugs currently available for treating hair loss act by very differentmechanisms, Finasteride and structurally related steroids act to diminish theeffect of testosterone, the hormone closely associated with male pattern hairloss. The mechanism of action of the older hair growth stimulant, minoxidil(67) on the other hand, is believed to involve the compound’s vasodilatoryactivity. The more recent hair growth stimulant, namindinil (74), alsoshows vasodilator action. It is of note that the nitrogen-rich functionality inthe latter somewhat resembles a ring-opened version of 67. The synthesis ofthe newer compound reflects the current trend to prepare drugs in chiralform. One branch in the convergent scheme thus involves preparation of thecomplex alkyl group as a single enantiomer. Thus reductive alkylation(R)-a-methylbenzylamine (69), with pinacolone (68), gives the secondaryamine as a mixture of diastereomers. These are then separated by

3. COMPOUNDS RELATED TO ANILINE 51

chromatography. Catalytic hydrogenation of the appropriate diastereomers leadsto scission of the benzylic carbon-to-nitrogen bond to afford the (R)-amine (71)as a single isomer. Construction of the second part of the molecule startsby addition of sodium cyanamide to the isothiocyanate (72), itself, for example,available from reaction of the aniline with thiophosgene. The thiourea product(73) is then condensed with the chiral amine (71) to afford 74.13

H3C

OCH3

CH3

CH3

67

+

NH2

CH3

H3C

CH3CH3

CH3

HN

CH3

68

1. Separate

2. H2

H3C

NH2CH3

CH3

CH3

6970

CN

N=C=S

72

NaNCN

CN

HN

73

S

NH

71

CN

CN

HN NH

HNCN

CH3

CH3

CH3

H3C

74

N

N

OH

NH2

N NH2

71

The activity against urinary incontinence of the adrenergic beta-3 recep-tor agonist solabegron (56) was noted above. An agent that acts on a subsetof alpha receptors, specifically, alpha-1A/1L receptors, has also shownactivity on the same clinical end point. The synthesis starts withMitsonobu alkylation of the nitrophenol (75) with trityl protected imida-zole carbinol (76) to yield the ether (78). The nitro group on thebenzene ring is then reduced by any of several methods (79). The resultinganiline is then converted to the corresponding sulfonamide (80), byreaction with methanesulfonyl chloride. Hydrolysis with mild acid thenremoves the trityl protecting group to afford dabuzalgron (81).14

75

O2NCH3

OH

Cl

+

N

NHO

C(C6H5)3

76

(C6H5)P

DEAD

O2N

CH3

Cl

+

N

NO

C(C6H5)3

78

H2N

CH3

Cl

+

N

NO

C(C6H5)3

79

SnCl2

CH3SO2Cl

HN

CH3

Cl

+

N

NO

C(C6H5)3

80

SO2

HN

CH3

CH3

Cl

+

N

NH

O

81

SO2

CH3 H3O+


4. COMPOUNDS RELATED TO ARYLSULFONIC ACIDS

The title for this section aptly illustrates the almost arbitrary criteria used togroup potential drugs in this chapter. The few entries in this section com-prise an interesting contrast to a full sizeable chapter that was devoted tosulfonamide related drugs in Volume 1 of this series. Arylsulfonic acidderived moieties formed an essential part of the pharmacophore in virtuallyevery one of the 40 odd antibacterial, diuretic, and antidiabetic agentsdescribed in that chapter. In the case at hand, by way of contrast, thisfunctionality is no more than a convenient handle by which to coral agroup of compounds with otherwise widely divergent structures, as wellas biological activities.

A benzene ring that contains two sulfonic acid groups, as well as anitrone, is currently being investigated as a treatment for stroke. The freeradical scavenging properties of this compound, disufenton (89), will, itis hoped, translate into neuroprotective action on brain tissue when admi-nistered during the first 6 h after a cerebral stroke. The synthesis of thiscompound starts with the preparation of the highly substituted hydroxyl-amine (86). Thus, reaction of benzaldehyde with tert-butylamine leads toimine 83. Oxidation of intermediate 83 with m-perchlorobenzoic acid(MCPBA) gives the oxazirane (84); this rearranges to the correspondingnitrone (85) on heating. Hydrogen sulfide then serves to reduce that inter-mediate to the requisite hydroxylamine (86). In a somewhat unusual reac-tion, treatment of 2,4-dichlorobenzaldyde with sodium sulfite at elevatedtemperature leads to displacement of each of the halogens by sulfur togive the disulfonic acid (88) as its sodium salt. This SN2-like reaction isprobably facilitated by the lowered electron density at the 2 and 4 positionsof the starting benzaldehyde (87). Reaction of the products (88) with theintermediate (86), leads to formation of the nitrone (89) by hydroxylamineinterchange. Thus 89 is obtained.15

C6H5 CH=O

82

H2NC(CH3)3 C6H5

83

NC(CH3)3 C6H5

84

NC(CH3)3MCPBA

O

86

NC(CH3)3

OH

Heat C6H5

85

NC(CH3)3

CH=O

Cl

Cl

87

Na2SO3CH=O

SO2Na

NaO3S88

C6H5 SO2Na

NaO3S

89

NC(CH3)3

O

O

H2S

4. COMPOUNDS RELATED TO ARYLSULFONIC ACIDS 53

Elastase is an inflammatory protease associated with lung injury causedby infection or any of a number of other tissue insults. Inhibitors of thisenzyme would thus be expected to aid in treatment of lung injuries. A com-pound that includes a sulfonamide linkage has shown activity againstneutrophil elastase. Protection of the phenol in p-hydroxyphenylsulfonate(90) as its tert-butyl ester (91), comprises the first step in the constructionof an elastase inhibitor. The sulfonate function is then activated as the sul-fonyl chloride (92) by reaction with thionyl chloride. In the other arm ofthe convergent scheme, condensation of o-nitrobenzoyl chloride (93)with glycine benzyl ester (94) leads to the second half of the molecule.The nitro group in this intermediate is then reduced to an amine withiron in the presence of acid. Reaction of the newly revealed amino groupwith sulfonyl chloride in 92 yields the corresponding sulfonamide (97).Hydrogenolysis of the benzyl protecting group affords the free acid andthus sivelestat (98).16

OH

NaO3S

(CH3)3COCl

90

O

NaO3S

91

C(CH3)3

O

SO2ClO

ClO2S

92

C(CH3)3

O

NO2

COCl

93

+ H2NO

O

CH2C6H5

94

NO2

O

O

CH2C6H5HN

O

HN

O

O

CH2C6H5HN

O

O

SO2

C(CH3)

O

95

NH2

O

O

CH2C6H5HN

OFe/HCl

96

92

97

HN

OH

O

HN

O

O

SO2

C(CH3)

O

98

H2

The potential antimetastatic activity of inhibitors of metalloproteinaseshas generated considerable work in the area as noted in the discussion oftanomastat (34). The very different structure of the inhibitor prinomastat(107) illustrates the considerable structural freedom that seems to exist forinhibitors of these enzymes. Displacement of halogen in 4-chloropyridine(99) by phenoxide leads to the diaryl ether (100). Reaction of inter-mediate 100 with chlorosulfonic acid affords the sulfonyl chloride (101).


Construction of the thiomorpholine moiety starts by protection of the car-boxylic acid in penicillamine (102) by reaction with hexyl dimethylsilane(Dmhs). Condensation of 103 with 1,2-dichloroethane leads to formationof the heterocyclic ring by sequential displacement of halogen by nitrogenand sulfur to yield 104. Reaction of intermediate 104 with the benzophe-none (101), leads to formation of the sulfonamide (105). Mild acid thenserves to reveal the free carboxylic acid (106). This function is then con-verted to the acid chloride with oxalyl chloride. Treatment of this reactiveintermediate with hydroxylamine leads to acylation on nitrogen to affordthe proteinase inhibitor 107.17

SH

NH2

CO2H

102Dmhs =C6H13(CH3)2Si

SH

NH2

CO2Dmhs

103

ClCl

DBU

S

NH

104

OH

+ N

Cl

99

N

O

100

ClSO3H

N

O

101

ClO2S

N

OS

N

CO2Dmhs

CO2Dmhs

SO2

105

N

OS

N

CO2H

SO2

106

N

OS

NSO2

O NHOH

1. (COCl)2

2. NH2OH

107

Endothelins comprise a group of vasoconstrictive peptides generated bythe endothelium of blood vessels, as well as other tissues. Studies oninhibitors or frank antagonist suggest that such compounds will be ofvalue in treating various cardiovascular diseases. The synthesis of anantagonist starts by forming a sulfonamide linkage. Thus, reaction ofo-bromobenzenesulfonyl chloride (108) with aminoisoxazole (109) givesthe sulfonamide (110). The somewhat acidic sulfonamide function isthen tied up as its methoxymethylene (MOM) derivative. Lithium–halogen interchange of the bromine in 111 followed by reaction withtrimethyl borate gives the borate ester (112). Mild acid leads to the corre-sponding boric acid derivative. Reaction of that compound with the substi-tuted bromobenzene (114) in the presence of a palladium–triphenylphosphine complex leads to aryl coupling and formation of the biphenyl(115). The MOM group is lost along the line, most likely during hydrolysisof the borate ester. Reductive amination of the aldehyde function in


115 with methylamine gives intermediate 116. Acylation of the secondaryamine with pivaloyl chloride affords the corresponding amide and thus theendothelin receptor antagonist edonentan (117).18

Br

SO2Cl

108

+

O N

H2NCH3

CH3

109

Br O N

NH CH3

CH3O2S

110

Br O N

NCH3

CH3O2S

MOM

111; MOM = CH3OCH2

(CH3O)2B O N

NCH3

CH3O2S

MOM

1. BuLi

3. (CH3O)3B

H+

(HO)2B O N

NCH3

CH3O2S

MOM

112113O = HC

NO

Br114

O N

NH CH3

CH3O2S

O = HC

NO

Pd, (C6H5)3P

CH3NH2

[H]O N

NH CH3

CH3O2S

NO

HN

H3C O N

NH CH3

CH3O2S

NO

NH3C

O

115 116 117

Cholesterol is not absorbed from the intestine as such, but needs to beesterified first. This process requires a special enzyme, ACAT (acyl-CoA : cholesterol acyltransferase). Inhibitors of this enzyme shouldprovide a means of reducing serum cholesterol levels by limiting theamount absorbed from the diet. The inhibitor avasamibe (125) is includedin this section though the sulfur-containing function, which comprises anunusual sulfonamide linked through oxygen rather than carbon.Chloromethylation of commercially available 1,3,5-triisopropylbenzene(118) with formaldehyde and hydrogen chloride affords the chloromethy-lated derivative (119). Displacement of the benzylic chlorine by cyanidegives the corresponding nitrile (120). The cyano group is then hydrolyzedwith base to give the arylacetic acid (121). The other branch of the conver-gent synthesis starts with reaction of the hindered phenol (122) withisocyanosulfonyl chloride to give the O-sulfonated product (123).Hydrolysis then leads to O-sulfonamide (124). Acylation of intermediate124 with the acid chloride obtained from acid 122 and thionyl chlorideleads to the ACAT inhibitor (125).19


HOOCNSO2Cl

OSO2

H2O

HCl

CH2ClKCN CN CO2HOH

–

OCN OSO2

H2N

OSO2

HN

118 119 120 121

122 123 124

125

O

CH2=O

The pH of intracellular space is known to fall during ischemic episodes,heart surgery, and other events that compromise cardiac function. Thisencourages entry of sodium and calcium into cardiac cells. The resultingcalcium overload may then compromise contractile function. The recentlydeveloped antiarrhythmic agent cariporide (130) has been found to act byspecifically inhibiting the sodium–proton exchange that leads to furtherinjury. Chlorosulfonation of p-isopropylbenzoic acid leads to the chloro-sulfonyl derivative (127). Treatment of intermediate 127 with sodiumsulfite in base serves to reduce the newly introduced function to the

CO2H

126

CO2HClSO3H

ClO2S

127

Na2SO3

CO2HHO2S

128

CH3Br

NaOH

CO2HO2S

H3C1. SO2Cl

2. H2NNH

NH2

O2S

H3C NH

O

NH2

NH

129130


sulfenic acid (128). Alkylation by means of base and methyl bromide givesthe corresponding aryl methyl sulfone (129). The carboxylic acid is thenactivated as the acid chloride by treatment with thionyl chloride.Reaction of this intermediate with guanidine gives the aroyl guanidine(130).20

5. DIARYLMETHANES

Prolonged treatment of cancer patients with chemotherapeutic agents notinfrequently results in the development of drug resistance. The smallnumber of malignant cells that survive exposure to the drug proliferateand become the dominant population. A far more serious case involvesthe development of cell lines that develop resistance to more than oneclass of drugs, a condition known as multidrug resistance. The structurallyrelatively simple compound tesmilifene (133) has been shown to enhancethe antitumor activity of several classes of chemotherapy agents againstmultidrug resistant cancers. The mechanism of action of this drug is asyet unclear. This compound is prepared by alkylation of p-benzylphenol(131) with 2-chlorotriethylamine (132).21

OH

+Cl

N(C2H5)

131

132

133

ON(C2H5)

Moving the side chain bearing the amino group to the benzylic carbonleads to compounds with very different activities. Anticholinergic agentsspecific for muscarinic receptors have proven to be very useful for treatingurinary incontinence. The synthesis of a recent example speculatively startswith the Fries rearrangement of the ester (134) to the benzophenone (135).This compound is then treated with the organometallic reagent obtained

CH3

O O

134

CH3

OH

135

OAlCl3Cl N CH(CH3)2

CH(CH3)2

BuLi

CH3

OH

N

OH

CH(CH3)2

CH(CH3)2

CH3

OH

NCH(CH3)2

CH(CH3)2

137

138

H2136


from 2-chloroethyl diidopropyl amine (136) to afford the benzhydrol(137). Hydrogenolysis over palladium would then afford tolterodine(138).22

The release of large amounts of the neurotransmitter glutamate during astroke lead to flood nerve cell receptors, such as that for N-methyl-D-aspartate (NMDA) causing excessive stimulation. The NMDA receptorantagonists have as a result been investigated as agents for preventingsome of the injury from strokes. Relatively small changes in the structureof tolterodine, lead to an NMDA antagonist. Condensation of 3,3-difluoro-benzophenone (139) with the lithio reagent from acetonitrile yields thebenzydrol (140). The nitrile group is then reduced to the correspondingamine by means of diborane. Treatment with acid leads to loss of thetertiary hydroxyl group and formation of the olefin (141). The doublebond is reduced by catalytic hydrogenation (142).23 The primary aminogroup can then be converted to the N-methyl derivative by any of anumber of procedures, such as, treatment with formaldehyde and formicacid. Then the NMDA receptor antagonist delucemine (143) is obtained.

O

FF

139

LiCH2CN

FFHO

CN

1. BH3

2. H+FF

140 NH2

141

H2

FF

NH2

142

FF

NHCH3

143

The first product from one of the branches of the arachidonic acidcascade comprises a bridged bicylic compound where a pair of oxygenatoms form one of the rings. One route from this leads to thefamiliar five-membered ring prostaglandins; an alternate path leads tothromboxanes, one of the principal injurious products of the cascade.Compounds that block thromboxanes would be useful in treating the vaso-constricting and platelet aggregating action of this compound. Thesynthesis of a recent thromboxanes A2 receptor antagonist starts with theWittig condensation of the ylide from v-phosphinocarboxylic acid (145)with the ketone (144) to give the olefin (146). The reaction apparently

5. DIARYLMETHANES 59

proceeds to give exclusively to the (E) olefin isomer. Acid hydrolysisremoves the acetyl protection. Reaction of that intermediate with thecyanoimidate 148 leads to displacement of one phenoxy groups by theamine in 147. This reagent may be viewed formally as the phenolacetal of cyanamide formate. Reaction of the intermediate 149 withtert-butylamine displaces the remaining phenoxy group to form thecorresponding cyanoguanidine. Thus terbogrel (150) is obtained.24

O

NCH3CONH

144

(C6H5)3P(CH2)4CO2HN

CH3CONH145

CO2H

NH2N

CO2H

H+

146 147

C6H5O OC6H5

N

148

NNH

CO2H

149

C6H5O

NCN

NC

NNH

CO2H

150

(CH3)3CNH2

NCN

(CH3)3CNH2

tBuOK

6. MISCELLANEOUS MONOCYCLIC AROMATICCOMPOUNDS

Damage to peripheral nerves, termed peripheral neuropathy, is among oneof the more common consequences of diabetes; it may also be caused byParkinson’s disease or various toxins. Neurophilins are agents that reversethat condition and encourage new nerve growth. The small molecule tim-codar (157) has shown promising activity in animal models and severalearly clinical trials. Aldol condensation of pyridine-4-carboxaldehyde(152) with acetone dicarboxylic acid (151) proceeds to the keto acid(153). This transient intermediate decarboxylates under reaction conditionsto afford the bis(enone) 154. Hydrogenation over platinum proceeds togive the saturated ketone (155). Treatment of 155 with benzylamine inthe presence of cyanoborohydride leads to the product from reductiveamination (156). Acylation with hydrocinnamoyl chloride affords theamide 157.25


HO2C CO2H

O

151

+

N

CH=O

152

HO2C CO2H

O O

NN

153 154

O

NN

155

H2

C6H5CH2NH2

NaBH3CNHN

NN

156

N

NN

O

157

The discovery several decades ago of the nontricyclic antidepressantdrugs, exemplified by Prozac (fluoxetine), has revolutionized society’sview of depression. Use of these agents has mushroomed to the pointwhere they are indiscriminately consumed to overcome moods inducedby mild disappointments. The enormous market for drugs that act bythis mechanism has led to the introduction of a host of more or lessclosely structurally analogues. A very recent stereoselective synthesisfor one of these drugs, (S,S )reboxetine (166), starts with the commer-cially available chiral (S )-3-aminopropanediol (158). Acylation withchloroacetyl chloride leads to the amide (159). Treatment of intermediate159 with strong base result in internal displacement of halogen with con-sequent formation of the morpholine ring (160). Reduction of the amidefunction with the hydride Red-Al forms the desired morpholine (161).The secondary amino group is protected as its t-BOC derivative (162)by acylation with t-BOC chloride. The next step involves oxidation ofthe primary alcohol with the unusual reagent combination consisting of2,2,6,6-tetramethylpiperidinyl-N-oxide (TEMPO) and trichloroisocya-nuryl chloride. Thus aldehyde 163 is obtained. Condensation of thiswith diphenyl zinc, obtained by treating phenylmagnesium bromide withzinc bromide, affords the secondary carbinol (164). The same reaction inthe absence of zinc leads to recovery of unreacted aldehyde. The desireddiastereomers was formed in an �3 : 1 ratio with its isomer. The finalpiece could be added by conventional means, for example, by reactionwith 2-ethoxyphenol in the presence of DEAD and carbon tetrachloride.Reaction of 104 with the chromyl reagent (165) followed by oxidative

6. MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 61

removal of chromium by iodine gave the product in high yield. Removalof the t-BOC protecting group with trifluoroacetic acid (TFA) completesthe synthesis of (166).26

HO

NH2

OH

158

HO2C Cl

HO

NH

OH

O NH

O

OH

159

Cl

O

160

Red-Al

NH

O

OH

161

N

O

OH

162OCOtBu

N

OO=HC

OCOtBu

[O]

(C6H5)2Zn

N

O

OCOtBu

OH

163164

OC2H5

F

(CO)3Cr

165

NH

O

O

166

OC2H5

2. TFA

tBuOK tBuOCOCl

Many, if not most, cancer chemotherapy agents can be consideredselective toxins with a rather narrow therapeutic index. The administrationof these agents is quite frequently accompanied by nausea and vomiting,the reflex whereby the body seeks to reject toxins. Classical antiemeticcompounds, such as the phenothiazines, have little effect on chemo-therapy induced emesis. The more recently introduced serotonin antagon-ists are far more effective. They however, are, not universally effectiveand elicit severe CNS side effects in some patients. A pair of closelyrelated antiemetics act by a very different mechanism: these drugsoppose emesis by acting as antagonists at tachykinin receptors. The syn-thesis of the common moiety starts with aldol-like condensation of theanion from the acetonitrile (168) generated with a strong base with theester group on the piperidine (167). Heating the product (169) fromthat reaction with strong acid leads to hydrolysis of the nitrile group tothe corresponding acid. The transient intermediate then decarboxylatesto afford the ketone (170). Reaction of 170 with bromine then gives thebromoketone (171). This undergoes spontaneous internal displacementof bromine by the piperidine nitrogen. The formation of this bridgeleads to the quinuclidine (172) as a quaternary salt. The benzyl protectinggroup on nitrogen is then removed by hydrogenolysis over palladiumto yield the substituted quinuclidone (173). Reductive amination with2-methoxy-4-isopropylbenzylamine (174) affords ezlopipant (175); thesame reaction using 2-methoxy-4-tert-butylylbenzylamine leads tomaropitant (176).27,28


N

CO2C2H5

167

NC

N

+

Base

O

NC

H+

N

O

N

O

Br2

Br

N+

O

H2N

O

168 169

170

171172173

N NH

175

OCH3

H3C

CH3

H2N

OCH3

H3C

CH3

174

N NH

176

OCH3

H3C

CH3H3C

Most paradigms for treating Parkinson’s disease involve increasing dopa-mine levels at synapses in the brain. Administration of dopamine itself isruled out since the polarity of this compound prevents it from crossing theblood–brain barrier. Dopamine, like most neurotransmitters, is taken backby the presynaptic fiber after it has triggered action. A compound that inhibitsthis processwould as a consequence increase levels of dopamine in the synap-tic cleft. The starting material (177) for a dopamine reuptake inhibitor in factcomprises the free acid form of cocaine. Hydrolysis in mild acid serves toremove the benzoate (178). Reaction of this hydroxyl acid with phosphorusoxychloride leads to loss of the hydroxyl and formation of the conjugatedacid. This compound is then converted to its methyl ester (179).Condensation with the Grignard reagent from 3,4-dichlorobromobenzene inthe presence of copper leads to conjugate addition of the organometalic


reagent and formation of 180. The ester grouping is next reduced to the corre-sponding carbinol (181). Swern oxidation with oxalyl chloride then leads toaldehyde 182. Treatment of this intermediate with O-methylhydroxylamineleads to the O-methlyloxime. Thus the dopamine reuptake inhibitor braso-fensine (183) is obtained.29

NCH3

O

HO2C

O

177

HCl

NCH3

HO

HO2C

178

1. POCl3

NCH3

CH3O2C

179

2. CH3OH

NCH3

CH3O2C

Cl

Cl

180

LiAlH4

NCH3

Cl

Cl

181

HO

ClCl

MgBr

NCH3

Cl

Cl

182

(COCl)2

O

CH3ONH2

NCH3

Cl

Cl

183

N

CH3O

Both the older tricyclic antidepressants and the more recent drugsrelated to fluoxetine owe their efficacy to interaction with receptorsfor the neurotransmitters epinephrine, serotonin, and dopamine. The

HO2C

184

+

Br

185

HO2C

186

Base

H3C

1. SO2Cl

2. NaN3

187

N3

O

H3C

N

188

OC

LiAlH4

CH3NH

189

COClN

190

O

NLiAlH4

191


antidepressant igemsine (191) acts by some other as yet undefined mecha-mism. The compound is described as a ligand for sigma receptors, a sub-class of opiate receptors not associated with pain pathways. Alkylation ofthe anion from 2-phenylbutyric acid with the allylic halide (185) yields theacid (186). The carboxylic acid is then converted to the correspondingazide by reaction in turn with thionyl chloride and sodium azide.Heating this compound in an aprotic solvent then affords the isocyanaterearrangement product. Reduction with LiAlH4 gives the N-methylamine189. This compound is then acylated with the acid chloride from cyclopro-pyl carboxylic acid (190). Reduction of the amide, again with hydride,gives the antidepressant 191.30

Virtually all estrogen antagonists that have been in the clinic incorporatea basic side chain in the form of an tertiary-aminoethoxy aromatic ether.An exception, published in the 1960s, reported that the amine could bereplaced by a glycol.31 The estrogen antagonist ospemifene (195) takesthis one step further. Antiestrogenic activity is retained when the basic

HO

OH

192

OCl

NaOH

HO

OO

193

Cl

OO

194

CCl4,(C6H5)3P

C6H5

C6H5

C6H5

Cl

OHO

Cl

N(CH3)2O

195

196

H2


ether in the antagonist toremifene (196)32 is replaced by a simplehydroxyethyl group. This agent is prepared starting with an intermediate(192) used to prepare 196. Alkylation of the phenol in 192 withthe choroethanol benzyl ether affords 193. The free hydroxyl atthe end of the chain is then converted to the halide (194) byreaction with carbon tetrachloride and triphenyl phosphine. Removal ofthe benzyl group by means of hydrogen over palladium then affords195.33

There is some evidence that points to an association betweenAlzheimer’s disease and a defict in brain acetylcholine levels.Considerable attention has thus focused on cholinesterase inhibitors aspotential drugs for treating the affliction. The preparation of a relativelysimple inhibitor is prepared by acylation of the benzylamine (197)with chloroformamide (198). The resulting urethane is then resolvedto afford rivastigmine (199).34

(CH3)2NOH

+(CH3)2N

O NCH2CH3

CH3

O

NCH2CH3

CH3

O

Cl

197 198 199

The lipidemic compound ezetimibe (207), whose structure differsmarkedly from the ACAT inhibitor avasamibe (125), discussed previously,also inhibits absorption of cholesterol from the gut. The key to the con-struction of this compound involves formation of an azetidone. Enamineformation between the p-benzyloxybenzaldehyde (200) and aniline (201)provides one of the required reactants, imine 202. This compound isthen treated with a half-acid chloride of ethyl adipate (203) and triethyl-amine. In all likelihood, this first dehydrohalogenates under reactionconditions to form the substituted ketene. The transient intermediatereacts with the imine in a 2 þ 2 cylcoaddition to afford a four-memberedring and thus 204. The reaction proceeds to give the trans isomer almostexclusively. The ester group is then hydrolyzed by means of lithiumhydroxide. Condensation with the zinc reagent formed in situ fromp-fluoromagnesium bromide and zinc chloride affords the ketone (205).The carbonyl group is then reduced with diborane to afford the alcohol(206). Removal of the benzyl protecting group by hydrogenolysis overpalladium finally affords 207.35


200

O=HC

OCH2C6H5

+

F

H2N

201

OCH2C6H5

F

N

202

OCH2C6H5

F

N

CH3O2C

COCl

CH3O2C

203

204

O

Bu3N

C=O

CH3O2C

1. LiOH

2.MgBr

F

ZnCl2

OCH2C6H5

F

N

205

O

O

F

BH3

OCH2C6H5

F

NO

OH

F

H2

Pd/C

OH

F

NO

OH

F

206 207

REFERENCES

1. H. Amschler, U.S. Patent 5,712,298 (1998).

2. K. Tsutsumi, T. Sagimoto, Y. Tsuda, E. Uesaak, K. Shinomiya, Y. Shoji,A. Shima, U.S. Patent 5,081,112 (1989).

3. R.S. Randad, M.A. Mahran, A.S. Mehanna, D.J. Abraham, J. Med. Chem. 34,752 (1991).

4. B.R. Henke et al., J. Med. Chem. 41, 5020 (1998).

5. P.V. Devasthale et al., J. Med. Chem. 48, 2248 (2005).

6. Anon U.S. Application 1992-903691.

7. L.M. Coussens, B. Fingleton, L.M. Matrisian, Science 295, 2387 (2002).

8. H.C.E. Kluender et al., U.S. Patent 5,789,434 (1998).

9. J.S. Sawyer et al., J. Med. Chem. 38, 4411 (1995).

10. K.H. Donaldson, B.G. Shearer, D.E. Uehling, U.S. Patent 6,251,925 (2001).

11. J. Malm, Curr. Pharm. Design 10, 3525 (2004).

12. N. Yokoyama et al., J. Med. Chem. 38, 695 (1995).

13. K.S. Atwal, U.S. Patent 6,013,668 (2000).

14. R.L. Cournoyer, P.F. Keitz, C. O’Yang, D.M. Yasuda, U.S. Patent 6,057,349(2000).

REFERENCES 67

15. L.A. Sobrera, P.A. Leeson, J.A. Castaner, M. del Fresno, Drugs Future 29,240 (2002).

16. K. Imaki, Y. Arai, T. Okegawa, U.S. Patent 5,017,610 (1991).

17. L. Bender, M.J. Melnick, U.S. Patent 5,753,653 (1998).

18. N. Murugesan et al., J. Med. Chem. 46, 125 (2003).

19. H.T. Lee et al., J. Med. Chem. 39, 5031 (1998).

20. H.-J. Lang, A. Weichert, H.-W. Kleeman, H. Englert, W. Scholtz, U. Albus,U.S. Patent 5,591,754 (1997).

21. L.J. Brandes, M.W. Hermonat, U.S. Patent 4,803,227 (1989).

22. N.A. Johnsson, B.A. Sparf, L. Mikiver, P. Moses, L. Nilvebrant, G. Glas, U.S.Patent 5,382,600 (1995).

23. S.T. Moe, D.L. Smith, K. By, J.A. Egan, C.N. Filer, J. Label. Comp.Radiopharm. 41, 535 (1998).

24. R. Soyka, B.D. Guth, H.M. Weisenberger, P. Luger, T.H. Muller, J. Med.Chem. 42, 1235 (1999).

25. R. Zelle, M. Su, U.S. Patent 5,840,736 (1998).

26. E. Brenner, R.M. Baldwin, G. Tramagnan, Org. Lett. 7, 937 (2005).

27. J.A Lowe, U.S. Patent 5,451,586 (1995).

28. I. Fumitaka, H. Kondo, M. Nakane, K. Shimada, J.A. Lowe, T.J. Rosen, U.S.Patent 5,807,867 (1998).

29. L.A. Sobrera, J.A. Castaner, Drugs Future 25, 196 (2000).

30. G.G. Aubard et al., U.S. Patent 5,034,419 (1991).

31. D. Lednicer, D.E. Emmert, S.C. Lyster, G.W. Duncan, J. Med. Chem. 12, 881(1969).

32. D. Lednicer, The Organic Chemistry of Drug Synthesis, Vol. 5, John Wiley &Sons, Inc., NY, 1995, p. 33.

33. M. DeGregorio, V. Wiebe, L. Kangas, P. Harkonen, K. Vaananen, A. Laine,U.S. Patent 5,750,576 (1998).

34. R. Amstuz, M. Marzi, M. Boelsterli, M. Walsinshaw, Helv. Chim. Acta 73,739 (1990).

35. W.D. Vaccaro, R. Sher, H.R. Davis, Bioorg. Med. Chem. 6, 1429 (1998).


CHAPTER 4

CARBOCYCLIC COMPOUNDSFUSED TO A BENZENE RING

The nucleus of a modest number of new compounds comprise a two- orthree-ring fused system, one of which consists of a benzene ring. As wasthe case for free-standing benzene rings in Chapter 3, the annelatedrings in most instances serve merely as supports for the pharmacophoricsubstituents.

1. INDENES

Imidazolines have a venerable history as a-adrenergic agents. Compoundsthat include this group variously act as a1- and a2-agonists or antagonistsdepending on the substitution pattern in the rest of the molecule. Theindene fadolmidine (5), is an effective a2-agonist that blocks painresponses. The compound does not cross the blood–brain barrier as aresult of its hydrophobic character; it has as a consequence been developedas a drug for use as a spinal analgesic. Preparation of the compound startswith a crossed version of the McMurray reaction. Thus treatment of amixture of the indanone (1) with N-benzyl protected imidazolecarbox-aldehyde (2) in the presence of TiCl2, preformed from TiCl4 and zincpowder, gives the coupling product 3. Catalytic hydrogenation serves to


69

both reduce the double bond and to remove the benzyl protecting group(4). Reaction of 4 with hydrogen bromide then cleaves the methyl etheron benzene to afford the free phenol and 5.1

CH3O

1

O

+

N

NO=HC TiCl4CH3O

N

N

3

H2

CH3O

N

NH

4

HBrHO

N

NH

5

2

The antidepressant compound lubazodone (8) illustrates the breadth ofthe structural requirements for serotonin selective reuptake inhibitors; thestructure of this agent departs markedly from that of fluoxetine, the firstdrug in this class. The compound at hand also exemplifies the currenttrend for preparing drugs in chiral form. Thus reaction of the indanol (6)with the mesylate from chiral glycidic oxide in the presence of baseleads to the epoxypropyl ether (7) with retention of chirality. Treatmentintermediate 7 with aminoethylsulfonic acid closes the morpholine ring.Product 8 consists of pure (S ) enantiomer.2

OH

F

6

OSO2CH3O

F

7

OO

H2NOSO3H

F

8

O

NH

O

Alzheimer’s disease, as noted earlier, is associated with decreased levelsof acetyl choline in the brain. Most of the drugs that have been introducedto date for treating this disease thus comprise anticholinergic agentsintended to raise the deficient levels by inhibiting loss of existing acetyl-choline. A compound-based on an indene perhaps surprisingly, shows

70 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING

anticholinergic activity, and has been proposed for treatment ofAlzheimer’s disease. Condensation of piperidine aldehyde (10) with theindanone (9) leads to the olefin (11). Catalytic reduction removes thedouble bond to afford donepezil (12).3

CH3O

CH3O

O

+

9

N

O=HC

CH2C6H5

10

CH3O

CH3O

O

NCH2C6H511

CH3O

CH3O

O

NCH2C6H5

H2

12

More recent work indicates that monoamine oxidase (MAO) inhibitorsmay be useful as well. The indene ladostigil (17) is intended to addressboth of those targets; the compound thus incorporates a carbamate groupassociated with anticholineric activity and a propargyl moiety found inMAO inhibitors. The synthesis involves juggling protecting groupson two reactive functions. Thus, reaction of amino-indanol (13) withbis-tert-butoxy carbonate affords the corresponding t-BOC protectedderivative 14. Treatment of derivative 14 with N-methy-N-ethyl carbamoylchloride affords the O-acylated carbamate (15). The t-BOC protectinggroup is then removed by means of hydrogen chloride to give the freeamine (16). Reaction of 16 with propargyl bromide gives 17. This drugalso consists of a single (R) enantiomer; it is not clear from the source4

at which stage the resolution takes place.

NH2HO

13

NHCO2BOC

14

tBuO2COHO

NHBOCN

CH3CH2

H3CO

O

15

HCl

NH2N

CH3CH2

H3CO

O

16

Br

HNN

CH3CH2

H3CO

O

17

NCH3CH2

H3C

Cl

O

1. INDENES 71

The hormone melatonin (30) is intimately involved in the diurnal cyclewith levels rising late in the day prior to sleep. Congeners have as a resultbeen prepared in the search for a sleep inducing drugs. Ramelteon (29), anindene that incorporates several structural features of the hormone, hasbeen approved by the FDA as a sleeping aid. The first part of the synthesisinvolves construction of the ethylamine side chain. Thus condensation ofindanone (18) with the yilde from 2-diethoxyphoshonoacetonitrile attachesthe requisite two carbon chain (19). The nitrile is then reduced to the cor-responding primary amine (20) by means of Raney nickel. This drug alsofollows the current trend toward a chiraly defined substance. Reductionof the double bond with rhodium in the presence of the chiral catalyst2,20-bis(diphenylphosphino)-1,10-binaphthyl (BiNAP) affords the intermedi-ate (21) as the (S) enantiomer. This compound is then acylated with propionylchloride to afford 22. The remainder of the scheme involves constructionof the fused furan ring. Bromination proceeds at the slightly less hinderedposition. The methoxy group is then cleaved with boron tribromide toyield the bromophenol (23). Alkylation of the phenol with allyl

OCH3O

18

(C2H5O)2POCH2CNCH3O

19

CN

NiCH3O

20

NH2

CH3O

21

NH2

Rh

BiNAP

C2H5COCl

CH3O

NHCOC2H5

22

HO

NHCOC2H5

23Br

1. Br22. BBr3Br

NHCOC2H5

Br

O

24

200°C

NHCOC2H5

Br

HO

25

NHCOC2H5

Br

HO

O=HC

O3 NaBH4

NHCOC2H5

Br

HO

HO

26 27

NHCOC2H5

HO

HO

28

H2/Pd

1. CH3SO2Cl

2. TEA

NHCOC2H5

29

O

NH

NHCOCH3

30

CH3O


bromide proceeds to the allyl ether (24). Heating compound 24 leads to aClaisen rearrangement to the C-allyl derivative (25); bromine at the otherortho position prevents formation of the alternate undesired isomer. Ozoniza-tion followed by reductive workup leads to 26; treatment of the aldehydewith sodium borohydride reduces that function to an alcohol providing27. The blocking bromine atom is then replaced by hydrogen by means ofhydrogenation over palladium to yield 27. Construction of the furan ringstarts by conversion of the primary alcohol to its mesylate with methane-sulfonyl chloride. Treatment of the product with triethylamine (TEA)forms the phenoxide, which then displaces the mesylate group. This internaldisplacement forms the furan ring. Thus, ramelteon (29) is obtained.5

2. NAPHTHALENES

The parathyroid glands comprise one of the principal centers for regulationof calcium levels. The parathyroid hormone secreted by those glands intothe bloodstream directly controls levels of calcium and phosphorus. In thenormal course of events, low levels of calcium will result in release of thehormone and vice versa. Patients with kidney disease who are on dialysis, aswell as those with parathyroid gland neoplasms, tend to have significantlyelevated calcium levels, a condition that can lead to hypertension and conges-tive heart failure. A structurally relatively simple naphthalene derivative lowersparathyroid levels by binding to calcium receptors on the gland. Reaction ofcommercially available (R)-ethyl-a-naphthyl amine (31) with the aldehyde(32) affords the Schiff base (33). Reduction of intermediate 33 with cyano-borohydride leads to the calcium mimetic compound cinalcet (34).6

NH2

31

+

O=HC

CF3

32

CF3

33 34

NaCNBH3

N

CF3

HN

It is now recognized that protein kinases play an important role in intra-and intercellular communications. These enzymes are consequentlydirectly involved in cell proliferation. The p38 kinase, for example, regu-lates the production of key inflammatory mediators. Excess expressionof this factor is involved in the pathology of rheumatoid arthritis, psoriasis,and Crohn’s disease. A rather complex protein kinase inhibitor, which

2. NAPHTHALENES 73

includes a substituted naphthyl moiety, has shown preliminary in vivoactivity. The convergent synthesis starts with construction of a heterocyclicfragment. Condensation of the keto-nitrile (35) with p-tolylhydrazine (36)proceeds to give the pyrazole (37). The overall transform can be rational-ized by initial formation of a hydrazone; addition of the remaining hydra-zine nitrogen to the nitrile would then form the pyrazole ring. Reaction ofthis intermediate with phosgene then converts the primary amine to an iso-cyanate (38). The other branch of the scheme first involves alkylation of thet-BOC protected naphthylamine (39) in the presence of base with chloro-ethyl morpholine (40). Exposure to acid then cleaves the t-BOC group toafford the free amine (41). Addition of the amino group in this intermediateto the reactive iscocyanate in 38 connects the two halves via a newlyformed urea function. Thus, the p38 kinase inhibitor doramapimod (42)is obtained.7

O

(CH3)3C

CN

35

+

NHH2N

NN

(CH3)3C

NH2

CH3

CH336

OH

tBuOCHN

39

+N

O

40

H2N

N

O

ClO

1. Base

2. H+

COCl2

N

ONH

OO

NN

(CH3)3C

NH

CH3 42

NN

(CH3)3C

N=C=O

CH3

37 38

41

3. TETRAHYDRONAPHTHALENES

Drug therapy for treating Parkinson’s disease involves supplementing thedeficient levels of dopamine in the brain that characterize the disease. Theblood–brain barrier virtually dictates that the agents need to be lipophillic;


dopamine itself is too hydrophilic to penetrate the brain from the circula-tion. A tetrahydronaphthalene derivative that incorporates one of thephenolic hydroxyls, as well as an ethylamine-like sequence of dopamine,shows the same activity as the neurotransmitter. The lipophilicity of rotigo-tine (52) allows it not only to cross the blood–brain barrier, but to alsoreach the circulation when administered topically. The drug is in fact pro-vided in a skin patch formulation that provides prolonged blood levels. Thepreparation of this dopaminergic agent begins with the conversion of thedihydroxynaphthalene (43) to its methyl ether by means of dimethylsulfate. Treatment of 44 with sodium in alcohol initially leads to thedihydro intermediate (45). The regiochemistry follows from the fact thatonly the right-hand ring has two open positions in a 1,4 relationship tothe methyl ether for forming the initial metal adduct. Treatment of 45with acid then hydrolyzes the enol ether to afford the b-tetralone (46).The carbonyl group is next converted to a Schiff base (47) by reactionwith propylamine. Catalytic hydrogenation of the intermediate thenaffords the secondary amine. This intermediate is resolved via its dibenzoyltartrate salt (48). The methyl ether in the (S ) enantiomer is cleaved bymeans of hydrogen bromide to give the corresponding phenol (49).Reaction with an activated form of 2-thienylacetic acid (50) followed byreduction of the amide (51) with diborane gives the corresponding tertiaryamine, 52.8

HO

OH

43

(CH3)2SO4

CH3O

OCH3

44

Na

C2H5OH

CH3O

OCH3

45

CH3O

O

46

C3H7NH2

CH3O

NHC3H7

47

CH3O

NHC3H7

48

Resolve

HBr

HO

NHC3H7

49

HO

N

51

SHO2C

50C3H7

O

S

HO

N

52

C3H7

SBH3

3. TETRAHYDRONAPHTHALENES 75

The effects on cell proliferation of retinoids has led to the investigationof structurally related compounds as potential antineoplastic drugs. Thefinding many years ago that the cyclobexyl moiety in the naturally occur-ring compound can be replaced by a tetrahydronapthalene has simplifiedwork in this area. It is of interest that in each of the examples that followa benzene ring serves as a surrogate for the unsaturated carbon chainfound in natural retinoids. The tetralin-based compound tamibarotene(59) has been tested as an agent for treating leukemias. Reaction of thediol (53) with hydrogen chloride affords the corresponding dichloroderivative (54). Aluminum chloride mediated Friedel–Crafts alkylationof acetanilide with the dichloride affords the tetralin (55). Basic hydrolysisleads to the primary amine (56). Acylation of the primary amino groupwith the half acid chloride half ester from terephthalic acid (57) leads tothe amide (58). Basic hydrolysis of the ester grouping then affords 59.9

OH

OH

53

HCl

Cl

Cl

54

NHCOCH3

55

NHCOCH3

NaOH

56

NH2

ClOC

CO2CH3

57

HN

O

CO2CH3

58

NaOH

HN

O

CO2H

59

The retinoid-like compound bexarotene (63) is approved for treatingskin lesions associated with T-cell lymphomas. The starting tetralin (60)is probably obtained by alkylation of toluene with dichloride (54).Friedel–Crafts acylation with the acid chloride (57), gives the ketone(61). This intermediate is then treated with the ylide from triphenylmethyl-phosphonium bromide. The carbonyl oxygen in the product (62) is nowreplaced by a methylene group. Saponfication of the ester affords thefree acid and thus 63.10


60

CH3

+

ClOC

CO2CH3

57

AlCl3

CH3

O

CO2CH3

61

(C6H5)PCH3+

CH3 CO2CH3CH3 CO2H

NaOH

6263

The saga of estrogen antagonists had its start in the mid-1960s whenseveral series of compound related to diethylstilbestrol were investigatedas nonsteroidal antifertility agents. The early work culminated in the devel-opment of tamoxifen, an estrogen antagonist that was and still is widelyused as adjuvant treatment for breast cancer. The benzothiophene-basedanalogue raloxifene, which retains some estrogenic activity, was intro-duced more recently as a drug for treating osteoporosis. Other morerecent examples will be found scattered throughout this volume. A tetralinring forms the nucleus of another recent entry, lasofoxifene (74). One syn-thesis for the penultimate intermediate starts with the formylation of thedesoxybenzoin (64) with ethyl formate and sodium ethoxide to itssodium salt (65). In a convergent step, the benzyl chloride (66) isallowed to react with triphenylphosphine to give the corresponding phos-phonium salt (67). Reaction of 67 with the salt (65) leads directly to theproduct from coupling with the ylide as a mixture of isomers. Thismixture is then hydrogenated to give the ketone (68). Treatment of 68with 3 equiv of aluminum chloride results in scission of the methylether on the most electron-deficient ether to give the phenol (69). Thiscompound is then cyclized to the corresponding dihydronaphthalenewith toluenesulfonic acid (TSA). The basic ether side chain required forantagonist activity is added by alkylation with 2-chloroethyl pyrrolidineto afford, nafoxidine (72). Catalytic hydrogenation of this product givesthe tetralin (73).11 Reaction of 73 with boron tribromide results in cleavageof the methyl ether in the fused ring to give (74).12

3. TETRAHYDRONAPHTHALENES 77

O

OCH3

64

HCO2C2H5

NaOC2H5 O

OCH3

CHO- Na+CH3O CH2ClCH3O CH2P(C6H5)3

(C6H5)3P

65 6667

O

OCH3

CH3O68

2.H2

AlCl3O

OH

CH3O69

TSA

CH3O

70

ON

OH

CH3O

Cl N

72

71

H2

CH3O

ON

ON

73

BBr3

HO

74

The more recent synthesis for lasoxifene (74) takes a very different course.The first step comprises displacement of one of the halogens in 1,4-dibromo-benzene by the alkoxide from N-2-hydroxyethylpyrrolidine 75 in the presenceof 18-crown ether to afford 76. Condensation of the lithium salt from 76with 6-methoxytetralone (77) followed by dehydration of the initiallyformed carbinol yields intermediate 78, which incorporates the importantbasic ether. Reaction of this compound with pridinium bromide perbromideleads to displacement of the vinylic proton by halogen and formation of thebromide 79. Condensation of this product with phenylboronic acid in the pre-sence of a palladium catalyst leads to coupling of the phenyl group by formaldisplacement of bromine. The product (79), is then taken on to 74 as above.12

HON

Br

Br

+

75 Br

ON

76

O

CH3O

77

CH3O

ON

78

PyBr3+

CH3O

ON

Br

79

C6H5B(OH)2

CH3O

ON

74

[Pd]


4. OTHER BENZOFUSED CARBOCYCLIC COMPOUNDS

Multidrug resistance, as noted earlier, is the all too prevalent phenomenonwhere a patient’s resistance to one class of cancer chemotherapy agentscomes to encompass mechanistically quite different drugs. Compoundswith a wide variety of structural features have shown at least preliminaryactivity in resolving this problem. The structurally rather complex agentzosuquidar (87) has shown promising activity against this problem.Reaction of dibenzosuberone (80) with the difluorocarbene from chlorodi-fluoroacetate affords the cyclopropyl adduct (81). Reduction of the ketonewith borohydride proceeds to afford the derivative wherein the fusedcyclpropyl and alcohol are on the same side of the seven-membered ring.

O

80

ClCF2CO2Na

O

81

FF

NaBH4

OH

82

FF

SOCl2

Cl

FF

NCH=O

HN

N

FF

NH

83

84

N

OH

N

OO

85

86

TsOO

NF

FN

N

O

OH

87

4. OTHER BENZOFUSED CARBOCYCLIC COMPOUNDS 79

The carbinol (82) is then converted to the halide with thionyl chlorideapparently with retention of configuration (83). Displacement with pipera-zine monoformamide leads to the alkylated product in which the groups arenow anti. Hydrolysis of the formamide grouping then affords secondaryamine 84. In a convergent sequence, 5-hydroxyquinoline (85) is allowedto react with the tosyl derivative of chiral glycidol. The epoxy group inthe product (86) retains configuration. Condensation of piperazine (84)with the quinoline (86) opens the epoxide to afford 87. Configuration ofthe alcohol is again retained as the reaction takes place at the nonchiralterminal of the side-chain to be. Thus, 87 is obtained.13

Most of the products from the arachidonic acid cascade exert deleteriouseffects. Prostacylin (100) is a notable exception because of its vasodilataryactivity. The compound is destroyed far too quickly to be used as a drug.An analogue in which a fused tetralin moiety replaces the furan and part ofthe side chain is approved for use as a vasodilator for use in patients withpulmonary hypertension. The lengthy complex synthesis starts with theprotection of the hydroxyl group in benzyl alcohol (88) by reaction withtert-butyl dimethyl silyl (TMBDS) chloride (89). Alkylation of theanion from 89 (butyllithium) with ally bromide affords 90. The protectinggroup is then removed and the benzylic hydroxyl is oxidized with oxalylchloride in the presence of triethylamine to give the benzaldehyde (91).The carbonyl group is then condensed with the organomagnesium deriva-tive from treatment of chiral acetylene (92) with ethyl Grignard to afford93. (The triple bond is not depicted in true linear form to simplify thescheme.) The next few steps adjust the stereochemistry of the newlyformed alcohol in 93. This group is first oxidized back to a ketone with pyr-idinium chlorochromate. Reduction with diborane in the presence of chiral2-(hydroxyl-diphenylmethyl)pyrolidine affords the alcohol as a singleenantiomer. This compound is then again protected as its TMBDS ether.Heating 94 with cobalt carbonyl leads to formation of the tricyclicring system (95). Mechanistic considerations aside, the overall sequenceto the product (95) involves eletrocylic formation of the six-memberedring from the olefin and acetylenic bond, as well as insertion of theelements of carbon monoxide to form the five-membered ring. Catalytichydrogenation of 95 leads to reduction of the double bond in the enone, aswell as hydrogenolysis of the benzylic TMBDS ether on the six-memberedring (96). Reduction of the ketone then leads to the alcohol apparently as asingle enantiomer. Acid leads to loss of the tetrahydropyrany protectinggroup to afford intermediate 97. The presence of labile groups in this com-pound precludes the usual methods, such as hydrogen bromide or borontribromide, for cleaving the methyl ether. Instead, in an unusual sequence,


the phenol (98) is obtained by treatment of 97 with butyllithium and diph-enylphosphine. The product (98) is then alkylated with 2-chloroacetonitrile.Hydrolysis of the cyano group to an acid finally affords the vasodilatortreprostinil (99).14–16

O

CO2H

HO OH

100

OH

CH3O

88

OTMBDS

CH3O

89

TMBDS = tBuMe2Si-

Br

BuLi

OH

CH3O

90

[O] CH=O

CH3O91

OTHP92

CH3O

OTHP

OH

93, THP = tetrahydropyranyl

1. [O]

2. BH3,Aux.

CH3O

OTHP

OTMBDS

3. TMBDSCl

Co(CO)8

94

CH3O

O OTHP

OTMBDS

95

H2

CH3O

O OTHP

96

1. NaBH4

2H+.

CH3O

OH OH

HO

OH OH

97

O

OH OH

HO2C

9899

REFERENCES

1. A. Karjalainen, P. Huhtala, S. Wurster, M. Eloranta, M. Hillila, R. Saxlund,V. Cockroft, A. Karjalainen, U.S. Patent 6,313,322 B1 (2001).

2. M. Fuji, T. Suzuki, S. Hayashibe, S. Tsukamoto, S. Yatsugi, T. Yamaguchi,U.S. Patent 5,521,180 (1996).

3. Y. Imura, M. Mishima, M. Sugimoto, J. Label. Comp. Radiopharm 27, 835(1989).

REFERENCES 81

4. M. Chorev, T. Goren, Y. Herzig, J. Sterling, M. Weinstock-Rosin,M.B.H. Youdim, U.S. Patent 6,462,222 (2002).

5. K. Chilma_Blair, J. Castaner, J.S. Silvestre, H. Bayes, Drugs Future 28, 950(2003).

6. B.C. Van Wagenen, S.T. Moe, M.F. Balandrin, E.G. DelMar, E.F. Nemeth,U.S. Patent 6,211,244 (2001).

7. J. Regan et al., J. Med. Chem. 45, 2994 (2002).

8. N.J. Cusack, J.V. Peck, Drugs Future 18, 1005 (1993).

9. Y. Hamada, I. Yamada, M. Uenaka, T. Sakata, U.S. Patent 5,214,202 (1993).

10. M.F. Boehm, R.A. Heyman, L. Zhi, C.K. Hwang, S. White, A. Nadzan, U.S.Patent 5,780,676 (1998).

11. D. Lednicer, D.E. Emmert, S.C. Lyster, G.W. Duncan, J. Med. Chem. 12, 881(1969).

12. C.O. Cameron, P.A. Dasilva Jardine, R.L. Rosati, U.S. Patent 5,552,412(1996).

13. J.R. Pfister et al., Bioorg. Med. Chem. Lett. 5, 2473 (1995).

14. P.A. Aristoff, U.S. Patent 4,306,075 (1981).




CHAPTER 5

FIVE-MEMBERED HETEROCYCLES

The specific chapter to which a given drug is assigned is to some extentarbitrary. More than a few compounds in the preceding chapters includeda heterocyclic ring in their structures. That fragment more often that not,however, comprised a cyclic base, for example, piperidine. The compoundin question was not classified as a heterocycle as it is quite likely that itwould show the same qualitative biological activity if that moiety wasreplaced by a noncyclic base. Heterocyclic moieties do, however, seemto play a role in the biological activity beyond simply providing a basiccenter for a good many agents. Compounds 7 and 18 provide a particularlyapt example; the pyrrolidine ring in these enzyme inhibitors acts as a sur-rogate for a proline moiety that occurs in the natural substrate. Compoundsmeeting that criterion will be found in this and the following sections. Notethat close to two-thirds of the compounds in this volume have been judgedto meet that criterion and will be met in the following chapters.

1. COMPOUNDS WITH ONE HETEROATOM

The protease enzyme dipeptidal peptidase (DPP) is closely involved inglucose control. This enzyme regulates levels of the hormone-like


83

peptide incretin, which stimulates release of insulin by cleaving themolecule to an inactive form. Inhibition of DPP in effect extends the actionof incretin. This helps prevent the increased levels of blood glucose thatmark diabetes. The protease inhibitor vidagliptin (7), which is modeledin part on the terminal sequence in DPP, has been found to sustainlevels of insulin in Type 2 diabetics. Inhibition is apparently reversiblein spite of the presence in the structure of the relatively reactivea-aminonitrile function. Construction of one intermediate in the conver-gent synthesis comprises reaction of amino adamantamine (1)with amixtureof nitric and sulfuric acid. This reaction affords the product 2 from nitrationof one of the remaining unsubstituted ternary positions. Treatment of thisproduct with strong base leads to solvolysis of the nitro group to giveaminoalcohol 3. Preparation of the other moiety involves first acylationof the pyrrolidine (4) with chloroacetyl chloride to give amide 5.Reaction of that intermediate with trifluoracetic anhydride (TFAA) con-verts the amide at the 2 position to the correspounding nitrile. Alkylationof the adamantamine (3) with 6 proceeds on nitrogen to afford 7.1

NH2

1

HNO3

H2SO4NH2

2

NO2

KOHNH2

3

OH

HN

CONH2

4

Cl COClN

CONH2

5

O

ClTFAA N

CN

6

O

Cl

OH

N

CNO

NH

7

A substituted pyrrolidine, which acts as a DPP inhibitor, comprisesanother example in which this ring serves as a surrogate for proline.This compound is being investigated as an anticancer drug as a result ofthe finding that it inhibits growth of tumors in various animal models.The structure of this compound is notable for the rare occurrence ofboron in the structure; in this case in the form of a covalently boundboronic acid. The final compound, talabostat (18), is comprised of asingle enantiomer. This is accomplished in the case at hand by a stereo-selective synthesis rather than by resolution of the final compound or anintermediate. The first step in the synthesis comprises protecting theamine in pyrrolidine (8) by conversion to its tert-butoxycarbonyl(9, t-BOC) derivative with tert-butoxycarbonyl anhydride. Reaction of

84 FIVE-MEMBERED HETEROCYCLES

the product with butyllithium generates an anion on carbon next to nitro-gen. Treatment of this compound with triethyl borate displaces one ofthe ethoxy groups in the reagent to form a carbon–boron bond. Theproduct is comprised of a 1 : 1 mixture of enantiomers. Hydrolysis ofthis intermediate then affords the corresponding boronic acid (10). A keystep involves formation of the acetal-like compound of 12 with naturallyoccurring (þ) pinanediol (11). The initial product is comprised of two dia-stereomers due to the fact that the starting boronic acid (10) consists of twoenantiomers. The pair of diastereomers of 13 are then separated by recrys-tallization. In the next step, the desired isomer is coupled with the to t-BOCderivative from valine to give amide 16. The pinane diol group is thenremoved by exchange with excess phenyl boronic acid. The final com-pound is converted to a salt (18) in order to avoid the formation of astable zwitterion between the amine and the boronic acid function. Thus,18 is obtained.2

HN Nt-BOC t-BOC

t-BOC

t-BOC

t-BOC

t-BOC

1. BuLi

2. B(OC2H5)3

9

N

B(OH)2

10

3. H+

HOHO

N

BOO

11

NH

NH

NH

CO2H

14

COCl

15

8

HN

BOO

N

BOO

12

13

16

H3O+

N

BOO

H2N

17

N+H2N

18

OOO 1. C6H5B(OH)2

2. HCl

B(OH)2

(t-BuO)2CO

(t -BuO)2CO

As noted in Chapter 3, endothelins rank among the most potentknown vasoconstricting agents; they have been implicated in a numberof diseases including cerebral vasospasm and pulmonary hypertension.The stereoselective synthesis of an endothelin antagonist begins with the

1. COMPOUNDS WITH ONE HETEROATOM 85

establishment of the chiral locus that will dictate the remaining asymmetriccenters. Oxazolidone (20), derived from valine serves as the chiral auxili-ary for that step. Condensation of the mixed-anhydride (19) from pipero-nalacetic acid, with the anion from auxiliary 20, give the correspondingamide (21). Treatment of this intermediate with strong base followed bytert-butyl bromoacetate leads to the alkylation product 22 as virtually asingle isomer. The auxiliary heterocycle is then removed by means oflithium hydroperoxide to afford the half ester (23). Reaction of 23 withdiborane selectively reduces the free acid to give the esteralcohol (24).The hydroxyl group is then activated by conversion to its tosylate (25).Treatment of that intermediate with anisyl hydroxylamine (26) in the pre-sence of cesium carbonate affords the O-alkylated derivative 27. The estergrouping is then exchanged with methylorthoformate to afford the methylester (28). Reaction of this last intermediate with trimethylsilyl triflate andbutylamine in the presence of 1,2-dichloroethane presumably forms ananion-like species on the carbon adjacent to the ester. This then addsinternally to the oxime carbon atom to yield a 1,2-oxazine. This product(29) predominates over the diastereomer in a 9 : 1 ratio.

O

O OCOtBu

19

+ HN O

O

20

O

O N O

OO

21

OBr CO2t Bu

O

O N O

OO

tBuO2C22

O

O OH

O

23

LiOOH

CO2tBu

BH3

O

O

24

CO2tBu

OH

BuLi

NaHMDS

O

O

CO2tBu

OSO2C6H4CH3

25OCH3

NHO

Cs2CO3

CO2CH3

O

O

CO2R

OCH3

NO

26

27; R = tBU28; R = CH3

ClCl

TMSOTf

ONH

O

O

OCH3

29

Catalytic hydrogenation of 29 over palladium on charcoal results inscission of the weak N22O bond and formation of aminoalcohol 30.This compound is converted to a pyrrolidine by an internal alkylation


reaction. Thus, reaction of the intermediate with carbon tetrabromide andtriphenyl phosphine presumably converts the alcohol to a bromide; internaldisplacement by the primary amine forms the five-membered ring.Alkylation of that amine with the complex bromo amide 32 affords theendothelin antagonist atrasentan (33).3

N

O

N

Br

O

N

O

O

OCH3

32

OHNH2

O

O

CO2CH3CO2CH3

CO2CH3

OCH3

CBr4

(C6H5)3PNH

O

O

OCH3

3031

33

29H2

Research on anticholinergic compounds has experienced something of aresurgence as a result of their utility in treating conditions such as urinaryincontinence. The structures of these compounds are quite varied as shownby darfenacin (44), which differs considerably from other compounds inthis class, for example, tolterodine (Chapter 3). The synthesis of this com-pound (44) is also designed to produce a single enantiomer. Heat induceddecarboxylation of proline (34) affords the key intermediate 35 as a pureenantiomer. The amino group is then converted to its tosylate (36) withtosyl chloride; the hydroxyl group interestingly does not react underthose conditions. Converting that group to its derivative is accomplishedby the Mitsonobu reaction with methyl tosylate to give the doubly deriva-tized intermediate 37. Condensation of 37 with the anion from diphenylacetonitrile (38), produced by reaction with sodium hydride, yields thealkylation product 39. Treatment of this intermediate with hydrogenbromide removes the protecting group on nitrogen. The nitrile is thenconverted to the corresponding amide with sulfuric acid. In a convergingscheme, acylation of benzofuran (41) with chloroacetyl chloride and


aluminum chloride yields the chloroketone (42). Reaction of that withpyrrolidine (40) leads to the alkylation product 43. Catalytic hydrogenationover palladium reduces the aryl carbonyl group to a methylene probablyvia the initially formed labile benzyl alcohol. Thus the anticholinergicagent 44 is obtained.4

NHHO

CO2H

34

heatNHHO

35

CH3C6H4SO2CH3NSO3C6H4CH3CH3C6H5SO2DEAD; Ph3P

NSO3C6H4CH3HO

36

CH3C6H4SO2Cl

CN

CN

NSO3C6H4CH3

39

37

38

NaH

1. HBr

2. H2SO4

CONH2

NH

40

O

41

Cl COCl

O

42

O

Cl

CONH2

43

OO

N

H2 CONH2

44

O

N

Protein kinases comprise a series of closely related enzymes that cata-lyze the phosphorylation of hydroxyl groups in enzymes, which regulatea wide range of physiological processes. Phosphorylation may either turnthe function of the target on or off. Inhibitors of the protein C kinases(PKC) that are involved in cell proliferation have attracted particular

HN

NN

O

OO

N(CH3)2

Ruboxystaurin


attention as potential drugs. The complex fermentation product Staurosprinis a PKC inhibitor that has shown antineoplastic activity in a range of bio-logical assays, but proved to be too toxic for use as a drug. The somewhatsimpler analogue, ruboxystaurin shows greater potency and selectivity forspecific PKCs. It has been pursued in the clinic to treat complicationsfrom diabetes. The synthetic acyclic product enzastaurin (54) is evenmore specific, inhibiting a subclass of PKCs involved in cell proliferation.

Reaction of the pyridyl methylamine (45) with methyl acrylate resultsin Michael addition of 2 equiv of the reagent to afford the diester (46).

N

OO

NH2

45

CO2C2H5

CO2C2H5

NN

N

H5C2O2C

46

1. t BuOK

2. LiOHN

N

O

47

C6H5NH2N

N

NH

48

NC Cl

BCl3

N

N

NH

49

Cl

O

NaBH4

heat

50

(COCl)2

N

N

N

51

N

N

N

O

O

Cl

NH

52

N

N

Et3N

HN

NH

HNOCH(CH3)2

H+

HN

NH

N

OO

N

N

OH

53 54


Base-catalyzed Claisen condensation forms the desired six-membered ring.Heating that intermediate with base leads to saponification of the ester. Thebeta ketoacid decarboxylates under reaction conditions to form 47.5

Reductive amination of the carbonyl group in the ketone in this intermediatewith aniline would then lead to the substituted aniline (48). Treatment of 48with chloroacetontrile in the presence of boron trichloride leads to acylationon the benzene ring. The regiochemistry is attributable to the strongly acidicreaction conditions that inactivate the pyridine moiety. Aqueous workupthen affords the chloroacetyl derivative (49). The ketone is then reducedby means of sodium borohydride. On heating, the product undergoesinternal alkylation; the first formed compound then dehydrates to affordthe substituted indole (50).6 The next step in the scheme involves construc-tion of the pyrrolodione moiety. The required carbon atoms are added byacylation of 50with oxalyl chloride to afford 51. This compound is then con-densed with the imidate (52) from indole acetamide to afford an intermedi-ate, such as 53. The reaction may be visualized as involving first formationof an amide from imidate nitrogen with the acid chloride followed byaddition of the anion from the methylene group in 52 to the carbonyl. Theinitially formed pyrroline is then dehydrated with strong acid.7 Thus, thePKC inhibitor 54 is obtained.

Leukotrienes, products from one branch of the arachidonic cascade, areclosely associated with symptoms of allergy, as well as asthma (seeChapter 3, etalocib). The benzothiophene-based leukotriene antagonist,zileuton, one of the first agents in this class, is now on the market. Arelated compound, atreluton (60), that omits the fused benzene ringpresent in the prototype, shows improved potency and duration ofaction over its predecessor. Condensation of benzyl bromide (55) withthe anion from thiophene and butyllithium in the presence of the Heckcatalyst [tetrakis(triphenylphosphine) palladium(0) gives the couplingproduct 56. Reaction with NBS leads to the bromothiophene (57).Condensation of that intermediate with the methyl–ethynyl carbinol inthe presence of triphenylphosphine, Heck catalyst, and cupric iodideleads to the coupling product 58. The requisite functionality is constructedby first replacing the hydroxyl next to the acetylene by nitrogen.Mitsonobu-like reaction with O,N bis(phenyloxycarbonyl hydroxylamine)in the presence of triphenylphosphine and DEAD affords 59. Reaction ofthis intermediate with ammonia leads to displacement of both phenoxygroups. This leads to formation of the free hydroxyl from theO-carbonate and a urea from the phenoxy ester, yielding the leukotrieneantagonist 60.8


S

FF

BrS

+ BuLi

(Ph3P)4.Pd

55 56

NBS

S

F

57

Br

OH

(Ph3P)4.P, PPH3, CuI

S

F

58

OH

HN O

CO2C6H5

Ph3P, DEAD

S

F

NH3

C6H5O

O

CO2C6H5

O

OC6H5

S

O

NH2

59

60

N OH

ON

2. COMPOUNDS WITH TWO HETEROATOMS

A. Oxazole and Isoxazoles

The discovery that non-steroid antiinflammatory agents (NSAID) owe theirefficacy to inhibition of cyclooxygenase (COX), the enzyme that catalyzesthe formation of prostaglandins was followed some time later by thefinding that the enzyme occurred in several subtypes. The almost simul-taneous discovery of specific inhibitors of COX-2, promised NSAIDSthat reduced inflammation that spared the production of prostaglandinsthat maintain integrity of the stomach wall. The enormous success of thefirst agent on the market celecoxib, led to detailed investigation of thestructure–activity relationship (SAR) of this class in competing labora-tories. Minimum requirement for activity seemed to involve two aromaticrings on adjacent positions on a five-membered heterocyle. The very recententry, tilmacoxib (67), shows that one of those benzene rings can bereplaced by cyclohexane. Condensation of m-fluorobenzyl bromide (62)with the acid chloride (61) from cyclohexane carboxylic acid in the pre-sence of the Heck reagent affords the ketone (63) that incorporates therequisite two rings. Bromination proceeds on the benzylic position toafford 64. This reactive halogen is displaced with acetate to give the key

2. COMPOUNDS WITH TWO HETEROATOMS 91

intermediate (65). Construction of the heterocyclic ring involves reactionof 65with ammonium acetate. The reaction can be viewed for bookkeepingconsiderations as proceeding through the initial reaction of ammonium ionwith the ketone to form an imine. This imine cyclizes with the adjacent car-bonyl on the acetate to afford 66. Treatment of 66 with chlorosulfonic acidgives the sulfonyl chloride; that sulfonyl chloride is immediately allowedto react with ammonia to yield the corresponding sulfonamide. This com-pound then affords the COX-2 inhibitor 67.9

Cl

O

Br+

Pd(PPh3)4

Zn

F

O

F

F

O

Br

61 62 63 64

F

O

OCOCH3

Br2

NaOCOCH3

65

O

N

F66

CH3 NH4COCH31. ClSO3H

2. NH3

O

N

F67

CH3

H2NO2S

The large number of compounds that have been reported illustratethe wide selection of heterocyclic five-membered rings that are com-patible with COX-2 inhibitory activity. The oxazole ring can, forexample, be replaced by an isoxazole. Reaction of deoxybezoin (68)with hydroxylamine affords the oxime (69). Treatment of this intermediatewith 2 equiv of butyllithium followed by acetic anhydride goes to thehydroxyl isoxazoline (71). The transform can be rationalized by assumingthat this proceeds via the O-acylated intermediate (70). The anion fromthe benzylic position would add to the acetyl carbonyl group to affordthe observed product. Reaction of this compound with chlorosulfonicacid results in sulfonation of the aromatic ring nearest nitrogen.The first step probably comprises dehydration of tertiary alcohol in 71under the strongly acidic conditions to give 72. Subsequent addition ofammonia converts the chlorosulfonic acid to the corresponding sulfona-mide and thus valdecoxib (73).10 Reaction of 73 with acetic anhydrideleads to acylation of the amide nitrogen, which increases the acidity ofthat already acidic function. Treatment with base affords the watersoluble salt parecoxib (74),11 which is suitable for use in injectableformulations.


O

68

NH2OHN

69

OH

BuLi

Ac2ON

70

O

CH3O

O

N

HOCH3

ON

CH3

ON

CH3

1. ClSO3H

2. NH3

71

7273

H2NO2S

1. Ac2O

2. NaOHO

N

CH3

74

O2S

NH3C

O–

Na+

The immune system is believed to play a role in rheumatoid arthritis, incontrast to the far more common osteoarthritis, which is related to aging. Anagent that has immunosuppressive action has proven useful for treatingrheumatoid arthritis. This compound lenflunomide (77), can be preparedin a single step by acylation of p-trifluoromethylaniline (76) with the com-mercially available isoxazole (75).12 The isoxazole ring, it was later found,is readily cleaved in vivo to give the cyano ketone, teriflunomide (78).Lenfluomides is consequently considered to be a prodrug for the latter.This agent can be prepared by condensation of the sodium salt from cyanoa-cetone (79) with p-trifluoromethylphenyl isocyanate (80),13 itself readilyaccessible from the aniline (76). Teriflunomide, is used in the clinic as apotential drug for relieving some of the effects of multiple scelerosis.

ON

H3C

O

Cl

+

H2N

CF3O

N

H3C

OHN

HN

CF3

O CN

H3C

HO

CF3CNO

+

CF3

NCO

75 76 77

7879 80

Metabolism


B. Imidazoles and a Pyrrazole

By now, it is well established that “conazole” antifungal agents attackfungi by inhibiting the synthesis of steroids essential to the fungal lifecycle. Virtually every antifungal agent in this class incorporates an imida-zole ring into its structure. This moiety is thus, not surprisingly, found inthe form of an enamine in a recent conazole. The starting material for thisagent (83), could, for example, be prepared by bromination of the propio-phenone (81) followed by displacement of halogen with imidazole.Alkylation of the enolate from the ketone with the side-chain fragment(84), yields the antifungal agents omoconazole (85).14

R

Cl

Cl

O

N

N

HN

N

Cl

Cl

O

81; R = H

82; R = Br 83

BrO

Cl84

NaH

N

N

Cl

Cl

OO

Cl

85

HistamineH3 receptors have been found tomodulate the release of neuro-transmitters, such as acetyl choline, dopamine, and serotonin, involved inalertness and cognitive function. Compounds that act as antagonists atthose sites favor release of those neurotransmitters and result in increasedalertness in animal models. Antagonists would hold promise for treatmentof attention deficit syndrome and related conditions including even poss-ibly Alzheimer’s disease. The first step in the synthesis toward the antag-onist cipralisant (92) comprises separation of the enantiomers of thecarboxylic acid 86. To this end, the acid is reacted with a chiral sultamderived from camphor. The resulting diastereomers (87) are then separatedby chromatography. Each of the diastereomerically pure derivatives, onlyone of which is shown, is then treated in the cold with DIBAL-H toafford the corresponding aldehyde (88). Reaction with the anion fromC-trimethylsilyl diazomethane gives the acetylene (89) in a single step.The chain is then extended by reaction of the acetylide anion with the tri-flate derivative from 3,3-dimethylbutanol. Exposure to strong acid serves toremove the triphenylmethyl protecting group on nitrogen. This last stepaffords 92.15 The absolute stereochemistry was derived from X-ray struc-ture determination of one isomer of the sultam (87).


NN CO2H

(C6H5)3C (C6H5)3C

(C6H5)3C

(C6H5)3C

(C6H5)3C

N

N

H

N

N CH=O

H

N

N

HCF3SO2

BuLIN

N

H

N

HN

H

HCl

86 8788

89

90

9192

O2S

N

ODIBAL-H

(CH3)SiCHN2

BuLi

The three part so-called cocktail used to treat HIV positive patientstypically comprise a proteinase inhibitor, such as those discussed inChapter 1; a nucleoside-based reverse transcriptase inhibitor, such as thosein Chapter 6, and a non-nucleoside inhibitor of reverse transcriptase(NNRTI). Most of the compounds in the first two classes share a goodmany structural features with other agents in the class. Chemical structuresof the various NNRTIs on the other hand have little in common.Capravirine (103), is notable in the fact that it fails to include any ofthe fused ring systems that provide the nucleus for other compounds inthis class. Chlorination of 3-methylbutyraldehyde (94) provides one ofthe components for building the imidazole ring. For bookkeeping pur-poses, the condensation of 94 with O-benzyl glyoxal and ammonia can be

R

R+ O

OCH2C6H5

O

Cl

Cl NH2

OCH2C6H5

O H2N

93; R = H

94; R = Cl

95

NH4OH

N

HN

OCH2C6H5

96

N

HN

OCH2C6H5

97

I2, NaOH

ICl

Cl

S–Cl

Cl2

N

HN

OCH2C6H5

98

S

99

N

N

Cl

100

Cl

Cl

N

N

OCH2C6H5

S

101

HClN

Cl

Cl

N

N

OHS

102

94

ClSO2N=C=O

N

Cl

Cl

N

NS

103

O NH2

O


envisaged as proceeding thorough the aminal (95) of the glyoxal. Imineformation with dichloro reagent 94 by displacement of halogen then leadsto imidazole 96. Reaction of that intermediate with iodine in base leads tothe iodo derivative (97). Displacement of iodine by the anion from dichlorolsulfide (98) proceeds to give the thioether (99). The still-free imidazolenitrogen is next alkylated with 2-chloromethyl pyridine to afford 101. Thebenzyl protecting group on oxygen is then removed by treatment withstrong acid. The thus-revealed carbinol in 102 is condensed with chlorosul-fonyl isocyanate to form the corresponding carbamate. Thus, the NNRTI103 is obtained.16

The imidazole ring takes its place in this example among a wide varietyof heterocyclic rings that serve as the nucleus for COX-2 NSAID anti-inflammatory compounds. Reaction of sulfonyl chloride (104), availablefrom chlorosulfonation of acetanilidewith tert-butylamine, gives the corres-ponding sulfonamide (105). The acetyl group on nitrogen is then removedby heating with strong base to give the aniline (106). Reaction of 106 withthe fluoro anisaldehyde (107) gives imine 108, which incorporates the twoadjacent aromatic rings characteristic of COX-2 inhibitors. Reaction of theimine with toluenesulfonyl isocyanate in the presence of potassiumcarbonate leads to what may be viewed as 2 þ 3 cycloaddition of the nitro-gen analogue of a ketene to form the imidazole ring (109). This ring is thenchlorinated with N-chlorosuccinimide (NCS) possibly to adjust the elec-tron density on the heterocyclic ring. Heating this last intermediate (110)with acid removes the protecting group to give the free sulfonamide andthus cimicoxib (111).17

SO2Cl

CH3COHN

104

H2NC(CH3)3

CH3COHN

KOHSO2NHC(CH3)3

H2N

O=HC

OCH3

F105 106 107

SO2NHC(CH3)3

SO2NHC(CH3)3

N

OCH3

F

108

TsCH2N=C

SO2NHC(CH3)3

N

OCH3

F

109

NNCS

SO2NHC(CH3)3

N

OCH3

F

N

Cl

SO2NH2

N

OCH3

F

N

Cl

HClK2CO3

110111

The enzyme dopamine-b-hydroxylase, as the name indicates, catalyzeshydroxylation of the side chain of dopamine in sympathetic nerves to form


epinephrine. Direct antagonism of the enzyme shuts down production ofthat neurotransmitter. This achieves an effect on the cardiovascularsystem more directly than do either a- or b-blockers. The most immediateeffect is manifested as a decrease in blood pressure. The synthesis of thespecific hydroxylase inhibitor nepicastat (122) starts by reaction of aspar-tic acid with trifluoroactetic anhydride. This reagent results in conversionof the amine to its trifloroacetamide derivative and the acid to an anhydride(113). Reaction of this intermediate with 1,3-difluorobenzene in the pre-sence of aluminum chloride gives the Friedel–Crafts acylation product(114). Catalytic hydrogenation then reduces the ketone to a methylenegroup (115). A second acylation reaction, this time via the acid chlorideleads to the tertralone (116). The new carbonyl group is again reducedby means of hydrogenation; saponification then removes the protecting tri-fluoroacyl group to give the primary amine (117) as a single enantiomer.Reaction of that amine with formaldehyde and potasium cyanide leads toformation of what is essentially an a-aminonitrile, the nitrogen analogueof a cyanohydrin. The amino group is then taken to a formamide by reac-tion with butyl fomate. Formylation of the carbon adjacent to the nitrile bymeans of ethyl formate and sodium ethoxide puts into place the last carbonfor the imidazole ring (120). Reaction of this last compound as its enolatewith thiocyanate forms the cyclic thiourea (121). Catalytic hydrogenationserves to reduce the nitrile to the corresponding amino-methylene deriva-tive and thus 122.18

H2OCCO2H

NH2112

(CF3C0)2CO OCCO2H

NHCOCF2 2

CO

F

F

F

F

113AlCl3 HO2C

NHCOCF3

O

F

FHO2C

NHCOCF3

1. PCl52. AlCl3

F

F

NHCOCF3

O

F

F

NH2

114 115

116117

H2

1. H2

2. NaOHNaCN

F

NH

NC

F

N

NC

CHO HCO2Bu

118119

F

N

NC

CHO

HCO2C2H5

NaOC2H5

OC2H5

120

KSCN

FF

F

F

N

NCF

NH

S

121

F

N

FNH

S

NH2122

H2

CH2=O

Collagenase enzymes are intimately involved in the destruction of car-tilage that accompanies rheumatoid arthritis. Considerable attention has as


a consequence been focused on finding inhibitors of that enzyme. The firststep in the convergent synthesis starts by protection of the chiral hydroxyacid (123) as its benzyl ester (124). The hydroxyl is activated toward dis-placement by conversion to its triflate 125. Reaction of 125 with the anionfrom the unsymmetrical malonate leads to triester 126.

The a-aminonitrile (127) from acetone and methylamine comprisesstarting material for the heterocyclic moiety. Reaction of 127 with chloro-sulfonyl isocyanate and hydrochloric acid gives hydantoin (128).Treatment of intermediate 128 with formaldehyde leads to a carbinolfrom addition to the free amino group on the imidazole dione. Thehydroxyl group is then converted to the bromo derivative (129) with phos-phorus tribromide.19 Use of this intermediate (129) to alkylate the enolatefrom 126 yields 130. Catalytic hydrogenation of this product leads to theformation of the corresponding ester-diacid by loss the benzyl protectiongroups on two of the esters. Heating this last intermediate in the presenceof N-methylmorpholine causes the free acid on the carbon bearing the tert-butyl ester to decarboxylate (131). The desired stereoisomer (131) predomi-nates, in effect reflecting the selectivity of alkylation step (126! 130)

NH

CN

123

NH

N O

O

124

1. CH2=O

2. PBr3

N

N O

O

125

Br

CO2HHO

CO2CH2C6H5HO

CO2CH2C6H5CF3SO3

C6H5O2C

ButO2C

ButO2C

ButO2CButO2C

CO2CH2C6H5

C6H5CH2O2C

NaH

126

127 128129

CO2CH2C6H5

C6H5CH2O2C

CO2tBu

N

N O

O

130

NaH

H2

N

N O

O

131

– CO2N

NO

O

132

CO2HN

O

HO2C

N

N O

O N

O N

N O

O N

O

O

HOHN

133 134

1. C6H5CH2ONH2

2. H2

ClSO3N=C=O


caused by the presence of the preexisting adjacent chiral center. The free car-boxylic acid is condensed with piperidine to form 132. The remaining esteris then hydrolyzed in acid to afford the acid (133). Reaction of 133 withO-benzylhydroxylamine followed by hydrogenolysis of the benzyl groupthen leads to the hydroxamic acid. Thus, the collagenase inhibitor cipema-stat (134) is obtained.20

The discovery of canabinol receptors has led to the search for syntheticagonists and antagonists based on different structures from the hemp-related product. One of the first antagonists to come out of those programs,rimonabant (140) has shown activity as an appetite suppressant weightloss agent. Addition of the anion from the propiophenone (135) to theanion from ethyl oxalate gives the enolate (136). Condensation of thatwith 2,4-dichlorophenylhydrazine (147) results in formation ofimines between carbonyl groups and the basic nitrogen thus forming thepyrrazole ring (138). Saponification of the ester affords the correspondingacid (139). This is then reacted with N-aminopiperidine in the presence ofDCC to form the amide 140.21

Cl

O

135

(CO2C2H5)2

BuLi Cl

OLi

136

C2H5O2C

O

+NH

H2N

Cl Cl

Cl

Cl

Cl

137

C2H5O2C

Cl

Cl

ClHO2C

138139

NaOH N NN NN N

Cl

Cl

Cl

HN

N

O

140

C6H10NHNH2

C. Thiazoles

A relatively simple thiazole has been shown to be a quite potent antiinfla-matory agent.Darbufelone (143), which is quite different in structure fromall preceding NSAIDs inhibits both arms of the arachidonic acid cascade atthe very inception of the process. This in effect shuts off production of bothprostaglandins and leukotrienes. This agent is prepared in a single step bycondensation of substituted benzaldehyde 141 with the enolate fromthiazolone (142).22


HO

CH=O

+

SNH

NH

O

SNH

NH

O

NaOAc

AcOH

HO

141 142 143

Uric acid comprises one of the principal products from metabolism ofendogenous nitrogen-containing compounds. Metabolic disorders thatcause this pyrimidine base to accumulate in the bloodstream can causegout, a painful condition that results from deposits of uric acid in joints.The uricosoric thiazole febuxostat (147), like its venerable predecessorallopurinol, inhibits the enzyme xanthine oxidase, which is central to theproduction of uric acid. Febuxostat, whose structure is significantly differ-ent from its predecessor, has recently been introduced as treatment forgout. Reaction of the dinitrile compound (144) with hydrogen sulfide inbase proceeds to convert the one of the two cyanide groups to the corre-sponding thioamide (145). Regioselectivity is speculatively due to reactionat the less hindered of the two nitriles. Condensation of this with thediketo-ester (146) leads to formation of the thiazole ring. Saponificationof the ester completes the preparation of 147.23

CN

NC

O

144

H2S

NaOH NC

O

145

S NH2

CH3O2C

O O

2. OH–NC

O

147

NS

HO2C

146

Reactive oxygen species released by neutrophils may play a role in con-ditions, such as inflammatory bowel disease and chronic pulmonaryobstructive disease. A thiazole that inhibits in vitro production of super-oxide by human neutrophils is currently being investigated in the clinic.In a convergent scheme, bromination of acyl pyridine carboxylic acid


(148) affords the acyl bromide. The product is then converted to the ester(149), by treatment with methanol in the presence of acid. Catechol estersundergo ready electrophillic attack as a result of the high electron densityin the ring. Thus, reaction of diethyl catechol with isothiocyanate in thepresence of acid leads to ring substitution. The initially formed thiocyanatehydrolyzes to the observed thiourea (150) under reaction conditions. In aclassic method for forming heterocyclic rings, reaction of bromoketone(149) with the thiourea (150) proceeds to the thiazole 151.Saponification of the ester then affords tetomilast (152).24

NHO2C

O148

1. Br2

2. CH3OH NCH3O2C

O149

Br

KSCN

H+

OC2H5OC2H5

OC2H5

OC2H5

OC2H5OC2H5

OC2H5

OC2H5H2N

S150

S

N

NCH3O2C

151

S

N

NCH3O2C

152

NaOH

Heterocyclic compounds bearing nitro groups were among some of theearliest antiparasitic agents. A nitrothiazole has recently been approved fortreating diarrhea due to such infections. This rather venerable compound,nitazoxanide (155) is prepared in a single step by reaction of the acidchloride (153) from aspirin with the aminonitrothiazole (154).25

NS

O2N

H2N

154

OCOCH3

ClONS

O2N

+

OCOCH3

O NH

153

155

Many peptides contain reasonably reactive amines, as well as anoccasional free guanidine function. By the same token, the sugars that


make up polysaccharide can be viewed as acetals of aldehydes. These func-tions on endogenous peptides and saccharides do occasionally interactchemically to form cross-links. Accumulation of cross-linked proteinswith age is believed to lead to stiffening of tissues. Some of these processesmay go as far as to result in pathologic changes. A structurally very simplethiazolium salt has shown activity in reversing such changes by breakingcross-links. The compound is probably prepared by reaction ofdimethylthiazole (156) with phenacyl chloride (157). The product alageb-rium chloride (158) is said to show promise in treating effects traceable toloss of tissue elasticity.

S

NH

+

O

Cl

156 157

S

O

N+Cl+

158

The “glitazones” comprise a large series of antidiabetic compounds thatwere introduced about a decade ago. The original hypoglycemic drugsused for control of Type 2 diabetes were marked by the presence of a sul-fonyurea pharmacophore. This function is replaced by a thiazolidinedionegroup in the more recent glitazones. The synthesis of a very recent drugcandidate in this group begins with reduction of the carboxylic acid inthe naphthol (159) with diborane. The resulting carbinol is oxidized back

HO

CO2H

159

1. BH3

2. MnO2 HO

CH=O

160

NH

S O

ONH

S O

OHO

161

H2

NH

S O

OHO

162

F

Cl

NH

S O

O

163

F

O


to an aldehyde (160) by means of manganese dioxide. Aldol-type conden-sation of 160 with the active methylene group in thiazolidinedione itselfleads to the unsaturated intermediate 161. Next, catalytic hydrogenationserves to reduce the double bond. The free phenol in the other ring is thenalkylated with o-fluorobenzyl chloride. Thus, the hypoglycemic agentnetoglitazone (163) is obtained.26

D. Triazoles

Antifungal activity is retained in compounds in the “conazole” series whenan additional nitrogen atom is inserted into the all-important heterocyclicring. The preparation of a triazole-based antifungal agent starts with theconstruction of the pyrimidine ring. Thus, condensation of b-ketoester(164) with formamidine leads to pyrimidine 165. Treatment of intermedi-ate 165 with phosphorus oxychloride leads to the corresponding chlori-nated compound (166). The key intermediate 168 could be obtained, forexample, by alkylation of 1,2,4-triazole with phenacyl chloride (167).Addition of the enolate from treatment of the pyrimidine (166) withstrong base to addition to the carbonyl group in 168. The resulting tertiaryalcohol (169) is obtained as a mixture of diastereomers. The chlorine atom,having served its function, is now removed by catalytic hydrogenation.Separation of diastereomers followed by resolution of the desired enantio-mer pair affords the antifungal agent voriconazole (170).27

F

OC2H5

O O

+HN NH2

N NH

F

O

F

ON

F

O

NHN

N

N N

F

Cl

POCl3

IDA

N

N

F

NN

N N N

F

ClHO

F F

F1. H2

2. Resolve

F

NN

N N N

F

F

HO

164 165 166

167 168

169170

Cl


A rather more complex antifungal compound incorporates in its struc-ture both a triazole and a triazolone ring. The lengthy sequence beginswith displacement of chlorine in 171 by acetate. Reaction of theproduct with the ylide from methyl triphenylphosphonium bromideaffords the methylene derivative (173). The acetate group is next saponifiedto give the free alcohol. The double bond is then oxidized in the presenceof L-ethyl tartrate to afford epoxide 174 as a single enantiomer. The firstheterocyclic ring is now introduced by opening of the oxirane with1,3,4-triazole proper to afford 175. Reaction with methenesulfonyl chlor-ide gives the corresponding mesylate (176). Treatment with base leads toformation of an alkoxide on the teriary carbinol; internal displacementforms a new oxirane. This ring is then opened by the anion from diethyl-malonate. The alkoxide that is formed as the initial product displaces theethoxide group on one of the esters to form a lactone (178). Reductionwith borohydride takes both carbonyl groups to alcohols affording thediol (179). This last intermediate (179) is again treated with toluene-sulfonyl chloride to afford the bis(tosylate). Treatment with base leads toformation of an alkoxide from the still free tertiary alcohol. This compoundundergoes internal displacement of one of the tosylate groups to form aTHF ring (180). The remaining tosylate function serves as a leaving

OCl

F

F

171

NaOCOCH3

OOCCH3

F

F

172

1. (C6H50)3P=CH2

2. NaOH

H2COH

F

F

173

OOH

F

F

174

N

NNH

OH

F

F

175

OH

N

N

N

CH3SO2Cl

OSO2CH3

F

F

176

OH

N

N

N

BaseF

F177

O

N

N

N

CO2C2H5

CO2C2H5

NaOHF

F

178

N

N

N

O

O

CO2C2H5

NaBH4

F

F

N

N

N

OHOH

OH

179

1. TsSO2Cl

2. NaH

F

F

N

N

N

180

N NHO NO2+

181a

O OTs

Ti(OiPr)3


group for the next reaction. This last intermediate (180) is reacted with thediaryl piperazine (181a) in the presence of base.

The thus formed phenoxide displaces the toluenesulfonate to form theextended coupling product (181b). The nitro group is reduced to the cor-responding amine. That function is then reacted with phenoxycarbonylchloride to give the phenoxy carbamate. Treatment with hydrazine displacethe phenoxide yielding the semicarbazone (182). Ethyl orthoformatesupplies the remaining carbon atom to form the triazolone (183). Thelast step in the sequence comprises alkylation of the heterocyclic ringwith the chiral methoxymethyl protected 2,3-pentanediol 3-tosylate(184). Thus, the antifungal agent posaconazole (185) is obtained.28

F

F

N

N

NO

NO2

181b

1. H2

2. C6H

5OCOCl

3. NH2NH

2

182

184

NHNH2

O

NN

NH

O

OTsO

O

N

N

O

OH

F

F

N

N

N

ON N NHO

F

F

NN

N

ON NO

F

F

NN

N

ON NO

183

185

O N N

N

Administration of cancer chemotherapeutic agents is more often thannot accompanied by serious bouts of nausea and vomiting. The serotoninantagonists, such as ondansetron, were the first class of antiemetic drugs toprovide relief to patients undergoing chemotherapy . The involvement ofsubstance P in mediation of the emesis reflex offers another target in thesearch for compounds for treating nausea. The demonstration that thesubstance P related neurokinin hNK-1 is directly involved in that reflexhas led to the search for specific antagonists. The stereoselective synthesisof the antagonist aprepitant (200) begins with the preparation of chiralp-fluorophenylglycine (190). Coupling of the phenylacetic ester (187)with the chiral auxiliary (186) affords the amide (188). The requisite


nitrogen atom is then introduced by treating the enolate from 188with tosylazide. Catalytic hydrogenation then reduces the azide to the correspondingprimary amine (189). The chiral auxiliary, having done its work, is thenremoved. Thus hydrolysis with base leads to amino acid 190 as a singleenantiomer. The benzyl protection group is next introduced by reductivealkylation with benzaldehyde. Reaction of the product (191) with1,2-dibromoethane in the presence of mild base leads to formation of anester with the carboxylic acid and then alkylation on nitrogen, thoughnot necessarily in that order. The net result is formation of the morpholinering (192). Treatment of the product with Selectride reduces the ester car-bonyl to the aldehyde oxidation stage, present here as a cyclic acetal (193).

F

NH

O O

C6H5

+

186

187F

O O

C6H5

N O

188 F

O O

C6H5

N O

189

TsN3

KN(SiMe3)2 N3

1. H2

2. LiOH

F

O

H2N

HO

190

F

O

HN

HO

BrBr

F

N

O O

191

192

CO2CH3

Selectride

F

N

O

F

N

O

193

OH

O

OCF3

CF3ClOC CF3

CF3

194

195

F

N

O O

CF3

CF3

196

Cp2TiMe2

ClHN

NH2N

F

N

O O

CF3

CF3

NH

N

H2N

F

N

O O

CF3

CF3

N

HN NH

O

199200

F

NH

O O

CF3

CF3

H2

197

198CO2CH3

O

CH3O

C6H5CH=O


The ring hydroxyl group is then acylated with the fluorinated benzoyl chlor-ide (194) to yield ester 195. Reaction with the carbenoid species from theTebbe reagent leads to formal replacement of carbonyl oxygen by a methyl-ene group to form the enol ether (196). Catalytic hydrogenation reduces theenol to the corresponding ether at the same time deleting the benzyl protect-ing group. The presence of two adjacent chiral centers result in formation ofproduct 197 as largely a single enantiomer. The remaining task involves for-mation of the pendant pyrrazolone ring. Alkylation of the morpholine nitro-gen with substituted semicarbazide 198 leads to 199. Compound 199undergoes internal displacement of the methoxy group on nitrogen, whichresults in formation of the triazolone ring and thus 200.29

The virus that leads to AIDS is renowned for its ability to develop resist-ance to antiviral drugs. Successful treatment depends in some measure onfinding agents that act on the virus by novel mechanisms. Current therapythus combines drugs that act on three different stages of the viral

HN

O

201

C6H5CH2Cl

N

O

202

C6H5CH2 N

NOH

203

C6H5CH2

NH2OH Na

ROH N

NH2

204

C6H5CH2

ClCO

NC6H5CH2

OPOCl3

HN

205

NC6H5CH2

ClN

206

CH3CONHNH2NC6H5CH2

NHN

207

NHO

NC6H5CH2

NN

N

208

H2

HN

NN

N

209

CH=O

NHO

FF

NN

N

212

N

NHO

FF

CO2C2H5

NHO

FF

210211

NaB(OAc)3H

life cycle. A new class of agents depends on the fact that the virus needs tobind with specific receptor sites on the immune system cells in order to gainentry into these cells. The very recent antiviral agentmaraviroc (212) bindsto the same sites as HIV and thus prevents the very first stage in the


process of infection. Synthesis of this agent starts by protection of the aminogroup in the bridged bicyclic amine (201). The carbonyl group at the otherend of the molecule is then converted to its oxime. Treatment of this inter-mediatewith sodium in alcohol reduces that group to a primary amine (204).Construction of the triazole ring first involves acylation of the aminewith theacid chloride from isobutyric acid to form the isobutyramide (205). Reactionof 205with phosphorus oxychloride converts the amide into the correspond-ing chlorinated imine (206). Treatment with acylhydrazide leads toaddition–elimination of the basic hydrazide nitrogen to the imino chlorideand thus formation of the imino–amide (207). Heating in the presence ofacid leads to reaction of the imino nitrogen with the carbonyl group. Thiscloses the ring and affords the triazole (208). Catalytic reduction removesthe benzyl protecting group ummasking the basic ring nitrogen (209). In aconverging scheme, the ester in the peptide-like fragment (210) isreduced to afford aldehyde 211. Reductive amination of 211 with amine209 and sodium triacetoxy borohydride leads to the coupled product 212.30

A substituted 1,2,3-triazole ring provides the pharmacophore for an anti-epileptic drug. Reaction of the 2,5-difluorobenzyl bromide (213) withsodium azide leads to displacement of the benzylic halogen and formationof azide 214. Treatment of 214 with propargylic acid leads to a 2 þ 3cycloaddition reaction and thus formation of the 1,2,3-triazine ring (215).The carboxylic acid is then converted to its amide via the acid chloride.Thus, the antiepileptic agent rufinamide (216) is obtained.31

F F

Br

213

NaN3F F

N

214

N NH

CO2H F F

N

215

NN

CO2H

F

N

216

NN

CONH2

1. SO2Cl

2. NH3

As noted earlier, protein kinases play a pivotal role in cell proliferation.Inhibitors of these enzymes show promise as antitumor agents particularly,those that show preference for malignant cells. The kinase inhibitormubritinib (221) is currently being evaluated as a drug for treating breastcancer. The first step in the convergent synthesis comprises displacementof a leaving group, such as methanesulfonate, from a suitably protectedphenol (217) by 1,2,3-triazine proper. Removal of the protecting groupleads to the free phenol (218). Preparation of the second moiety involvesreaction of one of the classical methods for forming of an oxazole: reaction


of a halomethyl carbonyl group with an amide. Thus, condensation of thecinnamic amide (219) with 1,3-dichloroacetone leads to formation ofoxazole 220, which retains a leaving group for a displacement reaction.Treatment of 220 with the alkoxide from treatment of 218 with baseleads to the corresponding ether (221).32

F3C

F3C

O

NH2

219

Cl Cl

O

220

N

O

O OSO2CH3

NN

HN

2. H2

HO NN

N

217 218

O NN

N

F3C

N

O

Cl

221

C6H5CH2

E. Tetrazoles

Though the exact cause of Alzheimer’s disease is still unclear, evidencepoints to the utility of increasing acetylcholine (AcCh) levels for treatingthat condition. Most approaches are aimed at devising inhibitors of cholin-esterase, the enzyme that destroys AcCh. A quite different tack involvesdeveloping compounds that have cholinergic activity in their own right.The tetrazole alvameline (230), for example, was developed as a bio-isostere of the muscarinic cholinergic compound arecoline (222). Thedesign devolves on the fact that the proton on a free tetrazole shows apKa comparable to that of a carboxylic acid. Fully substituted tetrazolesas in 230, may thus in some ways may be viewed as surrogate esters.Alkylation of nicotinonitrile (223) with methyl iodide affords methiodide224. Treatment of this intermediate with borohydride reduces it to tertrahy-dropyridine (225) in which the position of the double bond mimicsthat in arecoline. Reaction of 225 with ethyl chloroformate resultsin N-demethylation and consequent formation of the corresponding


carbamate. The nitrile group is then transformed to a tetrazole by reactionwith sodium azide in the presence of aluminum chloride, one of the stan-dard procedures for building that ring. The surrogate acid is then alkylatedwith ethyl iodide to afford 228. Treatment with acid then removes thecarbamate on the ring nitrogen (229). The methyl group on the piperidinering is restored by reaction with formaldehyde and formic acid, under stan-dard Clark–Eshweiler conditions. Thus, the muscarinic agonist 230 isobtained.33

N

CH3

CO2CH3

222

N

CNCH3I

N

CN

CH3

+

223 224

NaBH4

N

CN

CH3

225

ClCO2C2H5

N

CN

CO2C2H5

NaN3

AlCl3

N

CO2C2H5

226

N

NH

NN

227

C2H5I

NaOHN

CO2C2H5

NN

NN

228

CH2CH3

HBr

NH

NN

NN

229

CH2CH3

N

NN

NN

230

CH2CH3

CH3

K2CO3

HCO2H

CH2=O

A neurokinin inhibitor whose structure differs markedly from aprepitant(200) incorporates a substituted tetrazole ring. The synthesis of thetetrazole-containing moiety of vofopitant (241) start by acylation of sub-stituted aniline 231 with trifluoroacetyl chloride to afford the amide (232).Reaction of that under Mitsonobu conditions leads to the enol chloride(233). Treatment of 233 with sodium azide probablty starts with addition–elimination of azide ion; this undergoes internal 1,3-cycloadditionto form the tetrazole ring. Catalytic hydrogenation then removes the benzyl

C6H5CH2O

NH2

231

CF3COClC6H5CH2O

NH

232

O

CF3 CCl4

(C6H5)3P

C6H5CH2O

N

233

Cl

CF3NaN3

C6H5CH2O

N

N N

N

CF3

234H2

HO

N

N N

N

CF3

235

HO

N

N N

N

CF3

236

H3CO

HCO N

N N

N

CF3

237

HMTA

AcOHO=HC

CH3I

K2CO3


protecting group to reveal the free phenol (235). Reaction of 235 withhexamethylene tetramine (HMTA) in acid leads to formylation at theortho position to give the substituted hydroxybenzaldehyde (236). Thephenol is next converted to the corresponding methyl ether (237), byalkylation with methyl iodide in the presence of base.

Construction of the second part of the molecule starts with palladium-catalyzed coupling of the substituted pyridine (238) with phenylboronicacid to give 239. Hydrogenation reduces both the nitro group and the sup-porting pyridine ring to afford 240 as the cis isomer. The enantiomers ofthis are then separated by resolution. The desired isomer is then subjectedto reductive amination with aldehyde 237 affording 241.34

CH2O

N N

CF3

237

O=HCN

NO2

Cl

C6H5B(OH)2

Pd

238

N

NO2

239

H2

NH

NH2

240

resolve

NaB(OAc3)H

NH

241

CH3O

N N

N N

CF3

N NNH

The renin-angiotensin system plays a profound role in maintaining thecirculatory system. Elevated levels of angiotensin II are closely associatedwith hypertension. Angiotensin converting enzyme inhibitors, theso-called ACE inhibitors, lower blood pressure by preventing generationof that enzyme from its precursor. These now-widely used drugs werefirst introduced starting almost three decades ago. Attention has turnedmore recently to drugs that act directly on angiotensin receptors. The prep-aration of one of these non-peptide agents begins with the formation of animidazole. Thus, condensation of the diamine 242 with trimethoxy butyl-orthoformate affords the heterocycle 243. The nitrile groups are thenhydrolyzed to the corresponding acids; these groups are then esterifiedwith ethanol (244). Reaction of intermediate 244 with methylmagnesiumbromide leads to addition of but one of the ester groups. The presenceof the initial charged adduct arguably hinders addition to the secondester. The free amino group on the imidazole is then allowed to react


with the benzylic halide on the tetrazole-substituted biphenyl (246) toafford the alkylated product (247). Saponfication of the ester andremoval of the triphenylmethyl protecting group compeles the synthesisof the angiotensin antagonist olmesartan (248).35

NC

NC NH2

NH2

242

+

(CH3O)3C

NH

NNC

NC

243

1. NaOH

2. CH3CH2OH NH

NC2H5O3C

C2H5O2C

244

CH3MgBr

NH

N

C2H5O2C

HO

CH3

H3C

245

Br

NC(C6H5)3

NN

N

246

NC(C6H5)3

NN

N

247

N

C2H5O2C

HO

CH3

H3C

1. NaOH

NH

NN

N

248

HO2C

HO

CH3

H3C

2. H2

N

N N

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21. F. Barth, P. Casellas, C. Congy, S. Martinez, M. Rinaldi, G. Anne-Archard,U.S. Patent 5,624,940 (1997).

22. W.A. Cetenko, D.T. Connor, J.C. Sircar, R.J. Sorenson, P.C. Unangst,U.S. Patent 5,143,928 (1992).

23. T.A. Robbins, H. Zhu, J. Shan, U.S. Patent Appl. 2005/0075503 (2005).

24. M. Chihiro et al., J. Med. Chem. 38, 353 (1995).

25. J-.F. Rossignol, R. Cavier, U.S. Patent 3,950,351 (1976).

26. L.A. Sobrera, J. Castaner, M. del Fresno, J. Silvestre, Drugs Future 27, 132(2000).

27. R.O. Fromtling, Drugs Future 21, 266 (1996).

28. J. Heeres, L. Backx, J. Van Custem, J. Med. Chem. 27, 894 (1984).

29. J.J. Hale et al., J. Med. Chem. 41, 4607 (1998).

30. M. Perros, D.A. Price, B.L.C. Stammen, A. Wood, U.S. Patent 6,667,314(2003).

31. L.A. Sobrera, P.A. Leeson, J. Castaner, Drugs Future 25, 1145 (1998).

32. A. Tasaka, T. Hitaka, E. Matsutani, U.S. Patent 6,716,863 (2004).

33. E.K. Moltzen, H. Pedersen, K.P. Bogeso, E. Meier, K. Frederiksen,C. Sanchez, H.L. Lambol, J. Med. Chem. 37, 4085 (1994).

34. D.R. Armour et al., Bioorg. Med. Chem. Lett. 6, 1015 (1996).

35. H. Yanagisawa et al., J. Med. Chem. 39, 323 (1996).

REFERENCES 113

CHAPTER 6

SIX-MEMBERED HETEROCYCLES


A. Pyridines

Agents that interact with cholinergic receptors have been extensivelyinvestigated for the treatment of Alzheimer’s disease. Most of thecompounds discussed to this point bind at muscarinic sites. An alternateapproach involves administration of agents that bind to cholinergicnicotinic receptors. A compound closely related structurally to nicotineitself is currently being investigated in the clinic. The synthesis of thisagent starts with the dihalogenated pyridine (2) obtained from nicotine(1). Coupling of this with the monosilyl derivative from acetylene in thepresence of palladium: triphenyl phosphine and copper iodide replacesiodine on the aromatic ring by the acetylene moiety 3. The chlorine onthe ring is then removed by reduction with zinc in acetic acid 4.The silyl protecting group is then cleaved with fluoride ion to affordaltinicline (5).1


115

N

N

CH3

1

N

N

CH3

2

I

Cl

PdPh3PCl

CuI

i Pr3SiN

N

CH3Cl

i Pr3Si

3

N

N

CH3Cl

i Pr3Si

ZnAcOH

4

N

N

CH3Cl

5

Bu4N+ F-

As noted several times in Chapter 5, a five-membered ring containingone or more heteroatoms comprises the central element in a great majorityof COX-2 inhibitor NSAIDs. Interestingly, that moiety can be replaced by asix-membered pyridine ring. One of the two adjacent rings that characterizethese agents in this case include a nitrogen atom. One of the routes to thisagent starts with the nicotinic ester (6). The ester group is then reduced bymeans of DIBAL-H; back oxidation with manganese dioxide affords alde-hyde 7. Reaction with aniline and diphenylphosphate gives adduct 8 in areaction that parallels formation of a cyanohydrin. Treatment of intermedi-ate 8 with strong base generates an ylide on the carbon bearing nitrogen.Condensation of 8 with benzaldehyde 9 leads to enamine 10 which nowcontains two of the requisite rings. Hydrolysis of 10 leads to the

C6H5NH2

(C6H5O)2PH

N

8CH3

(C6H5O)P

NHC6H5

SO2CH3

O=HC

N

CH3

C6H5HN

SO2CH3

N

CH3

H3CO2CN

CH3

O=HC

6

1. DIBAL-H

2. MnO2

7 9

H3O=

N

CH3

O

SO2CH3

1011

ClCH2CO2H

N(CH3)2

+N(CH3)2Cl

1. DMF

2. NaOH3. HPF6

13

N

CH3

SO2CH3

15

N

Cl

N

CH3

SO2CH3

Me2N

Cl

O

NH4OH

14

12

t BuOK

t BuOK

116 SIX-MEMBERED HETEROCYCLES

ketone (11). The central ring is formed by a newly devised pyridine syn-thesis. The first step involves reaction of chloroacetic acid (12) withdimethylformamide (DMF); the initial adduct is then converted to its hexa-fluorophosphate salt (13). Condensation of 13 with ketone 11 involvesinitial displacement of one of the dimethylamino groups by the enolatefrom 11 to give the open-chain adduct (14). Reaction with ammoniumhydroxide then closes the ring forming the required pyridine. Thus, theNSAID etoricoxib (15) is obtained.2

B. Reduced Pyridines

Much effort has been devoted over the years to devise long acting forms ofdrugs. The occasion does, however, sometimes arise where blood levels ofa drug being administered by infusion need to be cut off abruptly. Severalexamples, such as the b-blocker esmolol or the analgesic agent remifenta-nyl, include in their structure a function that is quickly converted to a car-boxylic acid. This functional group both inactivates the drug and hastensits excretion. Dihydropyridines comprise a large group of calciumchannel blockers used to treat angina and hypertension. The short-actingexample, clevidipine (18) incorporates a methoxymethyl ester, a functionthat is readily cleaved to the corresponding acid by serum esterases. Theactual experimental details in patents3,4 describe the preparation of thiscompound by simple alkylation of the monoester (16) with chloromethylbutyrate (17). These sources are, however, mute as to source of the halfester starting material.

NH

O

Cl

CH3H3C

+O

O

ClCH3O OH

O Cl

O

O

K2CO3

NH

O

Cl

CH3H3C

CH3O O

O Cl

16

17

18

A very similar strategy underlies the design of the opiate-like analgesicalvimopan (30). Ileus, that is paralysis of the gastrointestinal tract, is acommon side effect from surgery. The shock of the operation accompaniedby heavy use of opiates causes a shut down of intestinal peristalsis. Thestructure of that drug in effect comprises a very potent synthetic opiatemodified by a polar glycine residue. That last moiety keeps the drug outof the CNS. Reversing postoperative ileus comprises one of the main


applications of this compound. The synthesis of this compound beginswith addition of the Grignard reagent from substituted the bromobenzene(20) to the piperidone (19). The hydroxyl group is then acylated with ethylchloroformate. Heating the resulting ester (22) leads to formation of thestyrene (23). Treatment with base under equilibrium conditions leads tomigration of the negative charge to the quarternary carbon adjacent tothe aromatic ring. Addition of dimethyl sulfate thus leads to alkylation atthat position.5 Reaction of 24 with sodium borohydride leads to reductionof what is now an enamine, and thus formation of the saturated piperidine(25). The methyl group is then removed using chloroformate in the modernversion of the Von Braun reaction. Treatment of product 26, with methylacrylate leads to Michael addition and formation of 27. The carbon adja-cent to the ester is next converted to its enolate with lithium diisopropyl-amine (LDA); addition of benzyl bromide leads to alkylation andformation of 28. The ester (29) is then saponified. Condensation withglycine ester followed by saponification yields 30.6

NO

19

+i PrO Br

20

MgCH3 N CH3

HOi PrO N CH3

C2H5OCOi PrO

ClCO2C2H5

Heat

N CH3

i PrO

21 22

BuLi

(CH3)2SO4

N CH3

H3Ci PrO

24

NaBH4N CH3

H3Ci PrO

25 231. ClCO2C6H5

2. HBr

NHH3C

HO

26

CO2CH3

N

N

O

CO2H

HN

H3C

H3C

HO

HO

CO2CH3

27

N

N

HO

HO

28

NaOH

C6H5CH2BrLDA H3C

H3C

CO2CH2

CO2H

29

Glycine

DCC

30

Multidrug resistance, where a tumor becomes immune to a broad rangeof compounds without regard to their mechanism of action, comprises one


of the more important pitfalls in cancer chemotherapy. Considerable efforthas been devoted to finding drugs, so-called chemosensitizing agents, thatreverse the process. The synthesis of one of these,biricodar (38) is presentedin outline formomitting several protection–deprotection steps.One armof theconvergent schemebeginswith the oxidation of trimethoxyacetophenone (31)with selenium dioxide to afford the corresponding acid (32). Compound 32 isthen condensedwith the silyl esterof pipecolic acid to afford the amide; depro-tection yields acid 33. Construction of the second moiety involves firstaddition of the addition of an organometallic derivative of propargylbromide to but-3-ynal (34). The anion from removal of the acetylenicprotons with strong base is then treated with 3-bromopyridine. This affordsthe product (36) from displacement of halogen by the terminal acetyleniccarbon. Catalytic hydrogenation then leads to intermediate 37. Esterificationof the acid (33) with alcohol 37 affords (38).7

O

OCH3

OCH3

CH3O

31

SeO2

O CO2H

OCH3

OC0H3

CH3O

32

NH

CO2Si(CH3)3O

OCH3

OCH3

CH3O

33

O

N CO2H

1.

2. H+

O=HC34

BrMg HO1. BuLi

N

BrHO

N

N

H2 HON

N

3536 37

O

OCH3

OCH3

CH3O

O

NO

N

NO

38

C. Miscellaneous

The design of the peptidomimetic antiviral agent (Chapter 1) ultimatelytraces back to the fact that structures of these protease inhibitors in someway act as surrogates for the natural substrate enzyme. The recent protease


inhibitor antiviral drug tiprinavir (52) notably departs from this pattern asit omits the peptide-like moiety present in the earlier agents; this drug isalso as a result said to be active against HIV strains that have developedresistance to the peptidomimetic agents. The convergent synthesis beginswith the addition of the enolate from methyl acetate to the carbonylgroup in 39. The product (40) is then saponified and the resulting acidresolved by way of its ephedrine salt. Treatment of the desired enantiomerwith chloromethyl p-hydroxybiphenyl gives the doubly alkylated deriva-tive 41. Reaction of that compound with DIBAL-H results in reductionof the ester to an alcohol (42). This function is then back-oxidized withhypochlorite in the presence of tetramethylpiperidol N-oxide to give thealdehyde (43).

O

39

1. CH3CO2CH3BuLi

2. NaOH3. Resolve

OH

CO2H

OCH2OR

CO2CH2OR

ROCH2Cl

R = C6H5C6H4-

40 41

DIBAL-H

OCH2OR

42

OH

NaOCl

N

OH

O

OCH2OR

43

O

Preparation of the other major fragment begins with Knoevenagel con-densation of m-nitrobenzaldehyde with dimethyl malonate to yield diester45. Treatment of intermediate bromide 45 with diethyl zinc in the presenceof cupric iodide leads to conjugate addition of an ethyl group (46). Thediacid obtained on saponification of that product then spontaneously dec-arboxylates on warming. The product obtained on esterifying the remain-ing carboxylic function acid is next resolved by chromatography over achiral column. Condensation of the enolate from treatment of 47 withthe aldehyde in the other fragment affords the adduct (48). The newlyintroduced hydroxyl group is oxidized to the ketone by means of pyridi-nium chlorochromate to afford the b-ketoester (49). The biphenoxy pro-tecting group on the tertiary alcohol is then removed by acid hydrolysis.


Reaction of this intermediate with base leads the anion of the newlyrevealed hydroxyl group to attack with the carboxylate in what amountsto an internal transesterification. This step forms the cyclic ester and thusthe requisite pyranone ring (50). Catalytic hydrogenation of 50 results inreduction of the nitro group to yield 51. Acylation of the newly formedamine with 5-trifluoromethylpyridinium-2-sulfonyl chloride affords 52.8

O=HC

NO2

CH3O2C

CH3O2C

BaseNO2

CH3O2C

CO2CH3

44 45

(C2H5)2Zn

CuBr

NO2

CH3O2C

CO2CH3

46

NO2

CO2CH3

47

1. HCl

2. CH3OH

3. Resolve

O

43

O

NO2

CO2CH3ROCH2

O

ROCH2

OH

48

1. PCC

2. H+NO2

CO2CH3OH

O

49

NaOH

NO2

O

OH

50

O

H2

NH2

O

OH

51

OHN

O

OH

52

O

SO2

N

CF3


A. Pyrimidines

The structures of all currently approved gastric acid secretion inhibitors thatact as inhibitors of the sodium–potassium pump consists of variously sub-stituted pyridylsulfonyl-benzimidazoles. A structurally very distinct com-pound based on a pyrimidine moiety has much the same activity as thebenzimidazole-based drugs. In yet another convergent synthesis, reactionof b-phenethylamine (53) with acetic anhydride affords amide 54.Treatment with polyphosphoric acid (PPA) then leads to ring closure toform the dihydroisoquinoline (55). Sodium borohydride then reduces theenamine function to afford fragment 56.


In a classic sequence for building a pyrimidine ring, the aniline (57) iscondensed with cyanamide. Addition of the basic nitrogen to the nitrile inthe reagent leads to formation of the guanidine (58). Condensation of 58with methyl ethyl acetoacetate results in formation of the pyrimidine(59); the residue of the carboxyl group appears as an enol oxygen (59;R ¼ OH). Treatment of this intermediate with phosphorus oxychloridereplaces the enol oxygen by chlorine. Displacement of this last group bythe basic amine in other moiety (56) leads to the coupling product (61).Thus, the sodium–potassium pump inhibitor revaprazan is obtained.9

NH253

Ac2O

NH

PPA

N

O

NaBH4

54 55

H2N

FH2NCN

NH

F

H2N

NH

57 58

OOC2H5

ONH

FN

N

R

59; R = OH

60; R = Cl

NH

FN

N

N

NH

56

612. POCl3

1.

A pyrimidine ring forms the nucleus for yet another nonnucleosidereverse transcriptase inhibitor (NNRTI) active against HIV. This hetero-cyclic ring is prepared in a manner analogous to that outlined above.The starting guanidine (62) can be prepared by reaction of 4-cyanoanilinewith cyanamide. Condensation of 62 with ethyl malonate leads to the sub-stituted pyrimidine 63 in a single step. The enolic hydroxyls are then

NC

HN NH2

NH2

62

C2H5O2C

C2H5O2C

HN

N

N

NC

OH

OH63

POCl3

HN

N

N

NC

Cl

Cl64

Br2

HN

N

N

NC

Cl

Cl65

Br

CH3H3C

CN

HN

N

N

NC

Cl

66

Br

HOCH3

H3C CN

O

CH3H3C

CN

HN

N

N

NC

NH2

67

Br

O NH3


replaced by chlorine by reaction with phosphorus oxychloride. Treatmentof product 64 with bromine replaces the remaining hydrogen on the pyri-midine ring by bromine (65). Reaction of intermediate 65 with the enolatefrom 2,6-dimethyl-4-cyanophenol displaces one of the halogens formingan ether linkage (66). The symmetrical nature of the pyrimidine ringrenders moot regiochemistry. Displacement of the remaining chlorinewith ammonia completes the synthesis of etravirine (67).10

The structure of the relatively simple pyrimidone emivirine (71) mightsuggest that this compound is a classical non nucleoside reverse transcrip-tase inhibitor. Detailed studies have, however, shown that instead this com-pound acts at the same site as other NNRTIs. Base-catalyzed alkylation ofthe pyrimidine (also called a uracil) (68) with ethyl chloromethyl etherperhaps surprisingly takes place at the nitrogen flanked by a single carbo-nyl to yield 69. Reaction with a second equivalent of base, this time LDA,followed by benzaldehyde results in addition of a benzyl group to the onlyopen-ring position. The reaction is then quenched with acetic anhydride toafford the acetoxy derivative (70). Catalytic hydrogenation then removesthe acetoxy group to afford 71.11

NH

NH

O

O

68

Cl O

N

NH

O

O

O

1. LDA

2. C6H5CH=O N

NH

O

O

O

AcO

3. Ac2O

6970

H2

N

NH

O

O

O

71

The efficacy and good tolerance of so-called statins has led to theirwidespread use in the treatment of elevated serum cholesterol. Theseagents act as a very early step in the endogenous synthesis of thatsteroid. This initial stage comprises reduction of the activated carboxylicacid group (COSCoA) (CoA is coenzyme A) in the glutaric acid derivativehydroxymethylglutaryl CoA to an alcohol (CH2OH); the product, meval-onic acid, then goes on to the isoprene equivalent, isopentenyl pyro-phosphate, in several more steps. This pivotal reaction is catalyzed by anenzyme hydroxymethylglutaryl CoA reductase (HMG–CoA); statins arethus more correctly classed as HMG–CoA inhibitors. All approved inhibi-tors feature a side chain that mimics the HMG–CoA substrate. The remain-der of the structure of drugs varies widely ranging from the decalins foundin the first statins produced by fermentation to monocyclic heterocyclicrings in some more of the recently introduced drugs. The synthesis of astatin based on a pyrimidine ring begins with Knoevnagel condensation


of methyl 4-methylacetoacetate (73) with p-fluorobenzaldehyde to affordthe acrylate (74). This last intermediate is then reacted with thiourea. Ina variation on the standard scheme for preparing pyrimidines. The reactionin this case involves conjugate addition to the double bond followedimine formation with the ketone though not necessarily in that order.The resulting dihydropyrimidine is then dehydrogenated with dichloro-dicynanoquinone (DDQ) to afford 75. The thioether function is next oxi-dized to the sulfoxide by mean of m-perbenzoic acid (MCPBA) toafford 76. Treatment with methylamine replaces the sulfoxide by nitrogenby an addition–elimination sequence. The thus-introduced amino group isthen converted to the sulfonamide (77) by reaction with methanesulfonylchloride. The ester group is then reduced to the corresponding alcoholby means of DIBAL-H and back-oxidized to aldehyde (78579) requiredfor attachment of the side chain.

F

CH=O

72

C2H5O2C

O

C2H5O2C

O

F

+

73 74

HN

SCH3

NH2C2H5O2C

N

F1.

2. DDQN

SCH3

75

MCPBA

C2H5O2C

N

F

N

O2SCH3

1. CH3NH2

2. CH3SO2Cl

76

C2H5O2C

N

F

N

NSO2CH3

77

CH3

1. DIBAL

2. [O]

CH=O

N

F

N

NSO2CH3

78

CH3

Condensation of aldehyde 79 with the ylide from chiral phosphorane(80) attaches the moiety that will become the statin side chain in a onefell swoop (81). The silyl protecting group on the alcohol is removednext by treatment with hydrogen fluoride. The side-chain ketone isreduced using a mixture of sodium borohydride and diethyl methoxyboron.This last reagent forms a chelate between the ketone and hydroxyl group inthe starting material, in effect transferring the chirality of the hydroxyl tothat which is to be introduced. The diol product (82) thus comprises asingle enantiomer. Saponification of the ester group affords rosuvastatin(83) as its sodium salt.12


(C6H5)P CO2CH3

OSiMe(CH3)2tBuOSiMe(CH3)2tBu

O

N

F

N

N

SO2CH3

79

+

N

F

N

N

SO2CH3

81

CH3

80

CH=O

O

CO2CH3

1. HF

2. NaBH4

N

F

N

N

SO2CH3

OH OH

CO2CH3

82

NaOH

N

F

N

N

SO2CH

OH OH

CO2Na

83

H3C

H3C H3C

Variously substituted benzyl diamino pyrimidines have a venerableplace in the history of antibiotics. These drugs, exemplified by the stillwidely used, trimethoprim, are known to inhibit the enzyme dihydrofolatereductase, crucial for bacterial replication. A very potent recently intro-duced example has shown promise for treating infections by antibioticresistant bacteria. The synthesis of a fragment necessary for building afused ring begins with aluminium chloride catalyzed acylation of bis-sylilated acetylene (84) with carboxycyclopropyl chloride. The reactioninterestingly stops with the introduction of a single acyl function (85).The newly introduced ketone is then reduced to the correspondingalcohol (86), with sodium borohydride. Mitsonobu reaction of thisalcohol with phenol 87 leads to the alkylation product, ether (88). Thisproduct undergoes a internal 2 þ 4 electrocyclic addition on heatingforming a dihydropyran ring and thus product 89. The ester grouping isthen subjected to a reduction-back oxidation sequence in order to convertester group to the corresponding aldehyde (90). Aldol condensation of the3-anilidopropionitrile carbonyl function, probably proceeds initially toadduct 91. The double bond then shifts out of conjugation with the aro-matic ring to give 92 as the observed product. The reaction of intermediate92 with guanidine can be viewed for bookkeeping purposes as involvingaddition of one of the guanidine nitrogens to the nitrile while another dis-places the anilide by an addition–elimination step to close the pyrimidinering. Thus, the antibacterial agent iclaprim (93) is obtained.13


CH3OC O

OCH3

Si(CH3)3(CH3)3Si Cl

O

(CH3)3Si

ONaBH4 (CH3)3Si

OH

AlCl3

CH3O2C OH

CH3O

OCH3

1. CH2Cl2,' PPh3,DEAD

84 85 86 87

88

2. HF

Heat

CH3OC

CH3O

OCH3

89

OO=HC

CH3O

OCH3

90

O

CH3O

OCH3

ONC

NCNHC6H5

C6H5NH

NH2

NH2

HN

CH3O

OCH3

ON

N

NH2

H2N

CH3O

91 93

CH3O

OCH3

ONC

C6H5NH

92

t BuOK

The search for endothelin antagonists as potential compounds for treat-ing cardiovascular disease was noted in Chapter 5 (see atrasentan). A com-posed with a considerably simpler structure incorporates a pyrimidine ringin the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of theenolate from the acetate to the benzophenone carbonyl. The alkoxideanion on the first-formed quaternary carbon then displaces chlorine onthe acetate to leave behind the oxirane in the observed product (95).Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether–alcohol (96). Reaction of this with the pyrimidine(97) in the presence of base leads to displacement of the methanesulfonylgroup by the alkoxide from 96. Saponification of the ester group in thatproduct gives the corresponding acid, ambrisentan (98).14

O

94

Cl CO2C2H5

NaOCH3

O CO2C2H5

95

CH3OH

BF3

OCH3

96

OH

CO2C2H5 N

N

CH3

CH3

N

N

CH3SO2

CH3

CH3

97

OCH3

O

CO2H

98


An entire new field of therapeutics arosewith the serendipitous discoveryof the effect of sildefanil, far better known as Viagra, on erectile function.The almost predictable wild success of that drug has led to the search forother inhibitors of phosphodiesterase 5, the enzyme responsible for thisactivity. The structures of many follow-on agents hewed fairly close tothe original PDE 5 inhibitor. Others, such as avanafil (107), differ markedlyin structure from sildefanil. The synthesis of agent 107 in effect consist of aseries of displacement reactions. Thus, reaction of the benzylamine (99)with chloropyrimidine (100) leads to displacement of chlorine and for-mation of the coupling product (101). The inert methylthio ether on the pyr-imidine ring is made labile by conversion to a sulfoxide (102) by meansof m-chloroperbenzoic (MCPBA) acid. Reaction of that product withL-prolinol (103) leads to the replacement of the sulfoxide by the basic nitro-gen in 103 and formation of coupling product 104. The ester group in thislast intermediate is then hydrolyzed to afford the corresponding acid (105).Reaction of this acid with 1-aminomethylpyrimidine (106) in the presenceof a carbodiimide leads to the amide (107).15

Cl

SCH3

CO2CH3

NH2

CH3O

Cl

99 100

+

SCH3

CO2CH3CH3O

ClNH

MCPBA

SO2CH3

CO2CH3CH3O

ClNH

NH

OH

101 102

103

CO2CH3CH3O

ClNH

NOH

CO2HCH3O

ClNH

NOH

NaOH

104105

N NN N N N

N NN NN N

CH3O

ClNH

NOH

NNH2N

O

N

NNH

106

107

The duration of action of venerable antitumor antimetabolite 5-fluoruracyl (5-FU, 108) is limited by its relatively fast destruction by liverenzymes. One approach to extending the half-life of the drug involves aprodrug in which the sites where degradation occurs are covered by moi-eties known to inhibit the metabolism of other uracils. The majorityof the drug in circulation would then consist of the prodrug. Slow loss ofthese protecting groups would then lead to extended therapeutic levels ofactive 5-FU. The first few steps in preparing emitefur (116) involves ascheme analogous to that used to prepare the prodrug tegafur. In this


sequence, 5-FU is first converted to the silylated derivative (109) by meansof trimethylsilyl chloride. Treatment of that with ethyl chloromethyl ether inthe presence of stannic chloride leads to ethoxymethylated intermediate 110with loss of the silyl groups. This compound (110) is then acylated with thebis acid chloride (111). In a convergent step, the pyridinol (113) isacylated with benzoyl chloride; reaction takes place at the stericallymore open hydroxyl to afford monobenzoate (114). This compound isthen allowed to react with the acid chloride (112) under more forcingconditions. Acylation of the remaining hydroxyl then affords theprodrug 115.16

HN

N

F

O

O

O

COClCiOCN

N

F

O

O

O

CiOC

O

N

CN

HO OH

HN

NH

F

O

O

N

N

F

O

O

Si(CH3)3

(CH3)3SiClCH2OEt

C6H5COClN

CN

O OH

N

N

F

O

O

O

OO

O

N

CN

O O

O

108 109 110

111

112

113 114

115

An important stage in the process of cell division comprises the for-mation of structures called microtubules that will pull apart the halves ofthe dividing cell nucleus in the course of replication.Microtubules normallydissolve after they have fulfilled their function. The very effective che-motherapy drug paclitaxel in effect stabilizes microtubules and halts celldivision in mid-process. The structurally relatively simple compoundmonasterol (120) hinders formation of tubules at their very inception byinhibiting a required enzyme. This compound is prepared in a singlestep by multicomponent reaction of m-hydroxybenzaldehyde (117),ethyl acetoacetate (118), and thiourea (119).17 One way this transformcan be visualized is to assume that the acetoacetate enolate adds to thealdehyde. The second step involves conjugate addition of one of the ureanitrogen to the resulting enone; reaction of the other nitrogen with theketone group would then close the ring.


HO

H O

117O

C2H5O

OH3C

118

H2N

NH2

S

119

+

SbCl3

HO

NH

NH

H3C S

C2H5O

O

120

Half of the bases in RNA and DNA consist of pyrimidine nucleosides.Analogues based on those nucleosides have, as result, been intensivelyinvestigated as sources for both antitumor and antiviral compounds. Suchanalogues, whether modified on the sugar portion or the base itself couldin theory act as false substrates for processes dependent on those nucleo-tides at target cells, and lead to their demise. Replacement of one of thehydrogen atoms in the sugar portion of cytidine by fluorine results in acompound that has shown activity against the hepatitis B virus.

OCOCH3

PhCO2 OCOPh

OPhCO2

Ph = C6H5121

OCOPhPhCO2 OH

OPhCO

OCOCH3PhCO2

OPhCO2

OSO2

N

HBr1. SO2Cl2

2. Pyrrole

122 123

OCOCH3PhCO2

OPhCO2

F

124

HBr

PhCO2

OPhCO2

FBr

N

N

H3C

OSi(CH3)3

Si(CH3)3

125

PhCO2

OPhCO2

F

126

N

NH

O

O

H3C

127

HO

OHO

F

N

NH

O

O

H3C

NaOH

128

Bu4N+F-


The preparation of this agent starts with the fully protected arabinosederivative (121). Treatment of 121 with hydrogen bromide leads tomigration of the benzoyl group to the anomeric position adjacent to thering oxygen with displacement of the acetate (122). The free ring hydroxylfunction is then converted to a good leaving group by reaction with sulfurylchloride followed by pyrrole to yield 123. Reaction of product 123 withtetrabutylammonium fluoride leads to displacement of the sulfonamidefragment by fluorine with inversion of configuration. The anomericacetate (124) is next replaced by bromine by means of hydrogenbromide. Compound 125 is then allowed to react with silylated thymine(126); this leads to the glycosylated base 127 with loss of the silylgroups. Treatment of intermediate 127 with mild base leads to hydrolysisof the last benzoyl protecting groups. Thus, the antiviral agent clevudine(128) is obtained.18

A cytosine derivative with a highly modified sugar showed significantantitumor activity in a variety of model systems. This activity did not,however, hold up in the clinic resulting in discontinuation of further clini-cal trials.19 Reaction of cytidine (129) with the bis(chlorotetraisopropyl-siloxane) (130) results in reaction with the hydroxyl groups at positions3 and 5 of the sugar, forming a bridged structure in which the oxygen atomsat those positions are protected. The difunctional reagent is apparently toolong to form the more common 2,3 cyclic protected derivative. Oxidationby means of oxalyl chloride in DMF then gives ketone 132. Thatfunction is then condensed with the ylide from the complex phosphonate133 to afford. The substituted exomethylene derivative (134). Reactionof 134 with tributyl tin hydride results in replacement of the phenyl sulfone

HO

OHO N

N

O

NH2

OH

129

+

ClSi

O

Si Cl

ON

N

O

NH2

OH

O

Si

O Si O

131

ON

N

O

NH2

O

O

Si

O Si O

132

Swern

p CHCH3O

CH3O F

SO2C6H5

O

1. LiN(SiMe3)2

ON

N

O

NH2

O

Si

O Si O

134

F

SO2C6H5

2.

Bu3SnHO

N

N

O

NH2

O

Si

O Si O

135

F

SnBu3

KF

ON

N

O

NH2

HO

HO

F

H

136

130

133


by tributyl tin (135). Treatment of 135 with potassium fluoride results incleavage of the silicon–oxygen bonds, as well as replacement of tin byhydrogen. This reaction leads to the antimetabolite tezacitabine (136).20

Zidovudine, better known as AZT, was the first drug that showed anyactivity against HIV. This compound comprises thymidine in which anazide group replaces hydroxyl on the sugar moiety. The finding that thisagent was effective against HIV set off the search for additional reversetranscriptase inhibitors in the hope that they would be active againststrains of the virus that had developed resistance to AZT. Replacementof one of the carbon atoms in the saccharide by another element hasproven a particularly fruitful stratagem. Plentiful ascorbic acid (137) com-prises the starting material for an early synthesis for troxacitabine (146).Reaction of 137 with the acetal (138) forms the cyclic acetal (139) fromthe two terminal hydroxyls as a mixture of enantiomers. Oxidation withperoxide cleaves the furenone ring with loss of a carbon atom to affordthe hydroxy acid (140). Ruthenium trichloride next cleaves off the terminalcarboxyl group to give 141. The two isomers are then separated by flashchromatography. Oxidation with lead tetraacetate disposes of the final car-boxyl group with concomitant transfer of an acetate (142). Catalytic hydro-genation results in loss of the benzyl protecting group. The thus-revealedhydroxyl group is acylated to afford the diacetate (143). Glycosylationwith cytidine involves the by now familiar theme. Thus, reaction of acetate

O

O

OH

OH

HO

HO

137

OCHOO

CH3O

C6H5

138

O

O

OH

OHO

O

OC6H5

C6H5

139

H2O2CO2H

CO2H

HO

O

OOC6H5

140

RuCl3

O

OOC6H5

141

1. Separate

2. PbOAc

OCOCH3

O

OO

142

OCOCH3

O

OAcO

143

1. H2

2. Ac2O

+

N

N

NHSi(CH3)

OSi(CH3)3

144

N

O

OAcO

O

NH2

1. Separate

2. NaOH N

O

OHO

O

NH2

145 146


142 with the silylated derivative 144 in the presence of Lewis acid leads tothe coupling product 145 with loss of the silyl groups. Separation of thediastereomers followed by treatment with dilute base affords the reversetranscriptase inhibitor (146).21

Replacement of one of the sugar carbon atoms by sulfur leads to the HIVreverse transcriptase inhibitor emtricitabine (151). As an additional depar-ture from the natural nucleoside, this agent features a fluorine atom on thepyrimidine ring. This compound (151) can be prepared by a scheme ana-logous to that used to prepare the des-fluoro predecessor lamivudine. Thus,reaction of the benzoyl ester of glycolaldehyde (147) with the dimethylactetal thioglycolaldehyde (148), affords the surrogate sugar (149) in asingle step. This condensation may be viewed as starting with additionof sulfur to the free carbonyl in aldehyde 148. Displacement of one ofthe methoxy acetals by the newly formed hydroxyl closes the ring. Thatproduct is next reacted with the trimethylsylilated cytidine derivative 150in the presence of a Lewis acid to afford the glycosilated fluorocytosine151. Separation of diastereomers followed by removal of the benzoate pro-tecting group affords 151.22

O

CH=O

C6H5CO

HS

OCH3

OCH3

+

S

OO

C6H5CO

OCH3

149

FNHSi(CH3)3

(CH3)3SiO

150

N

NH2

HO

F

S

HOO

N

151

147 148

N

N

Migraine headaches are quite resistant to conventional peripheral orcentral analgesics. The discovery of the indole-based triptamine HT1D

antagonists, such as sumatriptan for the first time provided a means forrelieving attacks of this sometimes disabling condition. The discovery ofa structurally unrelated antagonist broadened the SAR for the design oftriptamine HT1D antagonist. Reaction of the benzopyran acid (152) withthionyl chloride leads to the corresponding acid chloride. Hydrogenationof a solution of that intermediate in thiophene stops at the aldehydestage (153). Reductive amination with benzylamine gives the secondaryamine (154). Treatment with acrylonitrile leads to conjugate addition andformation of 155. Exhaustive hydrogenation of that product leads toreduction of the nitrile to a primary amine and at the same time removesthe benzyl protecting group. Thus, the diamine (156) is obtained. In onescheme for adding the terminal heterocycle, the diamine is alkylated


with 2-chloropyrimidine (157) to afford 158. Yet another hydrogenationreduces the heterocyclic ring to a tetrahydropyrimidine (159). The threeterminal nitrogen atoms in the product alniditan (159)23 in effect comprisea cyclized guanidine.

O

CO2H1. SO2Cl

2. H2

152

O

CH=O

153

C6H5CH2NH2

O

154

NH

H2

CN

CH2C6H5

CH2C6H5O

NCN

O

NH

NH2H2N

NCl

O

NH

N

NNH

H2

O

N

NH

NH

NH

155156157

158 159

B. Miscellaneous Six-Membered Heterocycles

The proteasome is an enzyme complex found in all cells that is responsiblefor the turnover of the proteins regulating the cell cycle, as well as othercellular processes. This complex becomes unregulated in tumor cells andleads to excessive degradation of cycle regulatory proteins and tumor sup-pression genes. The absence of these factors leads to run-away cell proli-feration. An unusual short peptide-like compound in which a boronicacid replaces the usual terminal carboxylic acid has proven to be an effec-tive blocker of the proteasome. The first step in preparing that compoundcomprises amide formation between the aminoboronic acid (161), wherethe boron is protected as the cyclic pinanediol ester, and the tert-butyloxycarbonyl (t-BOC) protected phenylalanine (160) using standardpeptide chemistry to afford 162. Removal of the protecting group on theN-terminal nitrogen followed by acylation with pyrazine carboxylic acid163 gives the amide (164). Reaction of intermediate 164 with excessisobutyl boronic acid leads to the free acid by transfer of the pinanediolprotecting group to the reagent. Thus, bortezomib (165) is obtained,24

which is a drug recently approved for treatment of multiple myeloma.


O

BO

H2N+tBuO2C tBuO2CNH

CO2H

160 161

NH

O

BO

HN

O

N

N

O

BO

HN

O

N

N

NH

O

162

164

IBuB(OH)2

OH

BOH

HN

O

N

N

NH

O

165

163

CO2H

A drug that inhibits HIV by binding with the specific receptor sites onthe immune system cells used by the virus to entry into the cells, mara-viroc, was discussed in the preceding chapter. The chemical structure ofthe inhibitor aplaviroc (179), which acts by the same mechanism, is,however, quite different from the drug discussed in Chapter 5. An enantio-selective synthesis for the key starting amino acid starts with the oxidationof the double bond in cyclohexyl acrylic ester (166) with potassium osmateto afford the cis diol (167). Reaction of intermediate 167 with sulfurylchloride affords the cylic sulfate ester (168). Treatment of intermediate168 with sodium azide leads to attack at the carbon bearing the carboxylategroup with inversion of configuration (169). Catalytic reduction followed

CO2C2H5 CO2C2H5

CO2C2H5

CO2C2H5CO2C2H5

166

[O]

167

OH

OH

SO2Cl2

O

SO2O

168

NaN3

N3

OH

1. H2

2. t-BOC2O

170

NHCO2tBu

OH

169


by reaction of the thus-formed amine with tert-butyloxycarbonic anhydrideleads to intermediate 170 as a single diastereomers.25

In a three component synthesis, the amide 171, obtained from ester 170and benzyl isocyanide, are reacted with the piperidone (172). The productfrom this transform consists of the addition product (173), where amidenitrogen in 170, as well as that on the isocyanide has added to the carbonylgroup on the piperidine. Treatment of adduct 173 with strong acid hydro-lyzes the urethane function on the t-BOC protecting group leaving behindthe primary amine (174). Intermediate 174 is not isolated, but undergoesdisplacement of the benzyl amine function in an intramolecular amideexchange to form the diketo pyridazine (175). Hydrogenation of 176removes the benzyl protecting group to reveal the free piperidine (177).

HO

H2N

O

171

N

+

O

172

BuNH2

N

HO

NHCO2tBuNHCO2tBu

O

HN

NH

O

173

CF3CO2H

N

CH2C6H5CH2C6H5CH2C6H5

CH2C6H5

CH2C6H5

HO

NH

O

HN

NH

O

C6H5CH2

C6H5CH2

C6H5CH2NC

N

NH

HNO

O

HO

N

NH

HNO

O

HO

H

H2

NH

NH

HNO

O

HO

O

CO2HO=HC

O

CO2H

H2

N

NH

HNO

O

HO

174175176

177

178

179


Reductive amination of 177 via the aldehyde group in the phenoxy acid178 affords 179.26

At least several weeks administration of virtually all antidepressantdrugs, be they the classical tricyclic compounds or the newer selective ser-otonin reuptake inhibitors (SSRI), is required before patients see relief fromtheir symptoms. A recently developed SSRI whose structure departs mark-edly from existing agents appears to differ from other agents, in that itappears to act in a much shorter time. The final step in the synthesis ofthis agent elzasonan (182) comprises aldol condensation of the benz-aldehyde (180) with the thiamorpholine (181).27

N

N

CH3

CH=O

180

+

N

S

Cl

Cl

O

181

LiOH

N

N

CH3

N

S

Cl

Cl

O

182

REFERENCES

1. F.F. Wagner, D.L. Comins, J. Org. Chem. 71, 8673 (2006).

2. I.W. Davies et al., J. Org. Chem. 65, 8415, (2000).3. K.H. Andersson, M. Norlander, R.C. Westerlund, U.S. Patent 5,856,346

(1999).

4. A. Mattson, C. Svensson, K. Thornblom, C. Odman, U.S. Patent 6,350,877(2002).

5. For a discussion of the stereochemistry in a related system see C.J. Barnett,C.R. Copley-Merriman, J. Maki, J. Org. Chem. 54, 4795 (1989).


7. D.M. Armistead, J.O. Saunders, J.S. Boger, U.S. Patent 5,620,971 (1997).

8. K.S. Fors, R.F. Heier, R.C. Kelly, W.R. Perrault, N. Wicnienski, J. Org.Chem. 63, 7348 (1998).

9. Y.W. Hong, Y.N. Lee, H.B. Kim, U.S. Patent 6,252,076 (2001).


10. D.W. Ludovici et al., Bioorg. Med. Chem. Lett. 11, 2235 (2001).

11. M. Ubasawa, S. Yuasa, U.S. Patent 5,604,209 (1997).

12. M. Watanabe, H. Koike, T. Ishiba, T. Okada, S. Seo, K. Hirai, Bioorg. Med.Chem. Lett. 5, 437 (1995).

13. R. Masciardi, U.S. Patent, 5,773,449 (1998).

14. H. Riechers et al., J. Med. Chem. 39, 2123 (1996).

15. K. Yamada, K. Matsuki, K. Omori, K. Kikkawa, U.S. Patent 6,797,709(2004).

16. M. Hirohashi, M. Kido, Y. Yamamoto, Y. Kojima, K. Jitsikawa, S. Fujii,Chem. Pharm. Bull. 41, 1498 (1993).

17. D. Russowsky, R.F.S. Canto, S.A.A. Sanches, M.G.M. D’Oca, A. de Fatima,R.A. Pilli, L.K. Kohn, M.A. Antonio, J.E. de Carvalho, Bioorg. Chem. 34,173 (2006).

18. C.H. Tann, P.R. Brodfuehrer, S.P. Brundidge, C. Sapino, H.G. Howell,J. Org. Chem. 50, 3644 (1985).

19. Anon. New York Times, March 20, 2004.

20. J.R. Mccarthy, D.P. Mathews, J.S. Sabol, J.R. McConnell, R.E. Donaldson,R. Doguid, U.S. Patent 5,760,210 (1998).

21. B.R. Belleau, C.A. Evans, H.L.A. Tee, Tetrahedron Lett. 33, 6949 (1992).

22. L.S. Jeong et al., J. Med. Chem. 36, 181 (1993).

23. G. Van Lommen, M. De Bruyn, M. Schroven, W. Verschueren, W. Janssens,J. Verrelst, J. Leysen, Bioorg. Med. Chem. Lett. 5, 2649 (1995).

24. J. Adams et al., Bioorg. Med. Chem. Lett. 8, 333 (1998).

25. M. Alonso, F. Santacana, L. Rafecas, A. Riera, Org. Proc. Resea. Dev. 9, 690(2005).

26. J.A. McIntire, J. Castaner, Drugs Future 29, 677 (2002).

27. J.P. Rainville, T.G. Sinay, S.W. Wallinsky, U.S. Patent 6,608,195 (2003).

REFERENCES 137

CHAPTER 7

FIVE-MEMBERED HETEROCYCLESFUSED TO ONE BENZENE RING


A. Benzofurans

The presence of two iodine atoms on one of the aromatic rings onvenerable antiarhythmic agent amiodarone may indicate that it was orig-inally conceived as an agent for treating various thyroid anomalies. Arecent halogen-free benzofuran that shares many structural features withits predecessor shows equal or even superior activity in controlling arryth-mias. The synthesis starts with an unusual scheme for building the furanring. Reaction of the benzyl bromide (1) with triphenylphosphine leadsto the phosphonium salt (2). Treatment of the salt with valeryl chloridein the presence of pyridine results in acylation on the now highly activatedbenzylic carbon. That product (3) cyclizes to the benzofuran (4) on heatingwith expulsion of triphenylphosphine. Friedel–Crafts acylation of 4 withanisoyl chloride in the presence of stannic chloride proceeds on the elec-tron-rich furan ring to afford 5. The nitro group is next reduced with stan-nous chloride to give amine 6. That newly formed amine is converted tothe corresponding sulfonamide (7) by means of methanesulfonyl chloride.Reaction of 7 with boron tribromide cleaves the methyl ether leading tothe free phenol (8). Alkylation of 8 with chloroethyldibutylamine in the


139

presence of mild base would then lead to the antiarrythmic agent dronedar-one (9).1

O2N

OH

1

PPh3O2N O2N

O2N

OH

2

OH

3

O

Br P+Ph3 P+Ph3

O

4

OCH3OCH3

COCl

AlCl3O

R2NCH3SO2Cl

O

CH3SO2HN

CH3SO2HN

OCH3

O

OH

O

CH3SO2HN

O

5; R = O6; R = H

BBr3

ClN(C4H9)2 N(C4H9)2

7

8 9

OO

O O

C4H9COCl

A benzoisofuran illustrates the breadth of the structures that demonstrateSSRI antidepressant activity. Condensation of the phthalide (10) with theGignard reagent (11) from 4-bromofluorobenzene leads to addition to thecarbonyl group to afford the ring-opened hydroxyketone (12). Addition ofa single organometallic group to the phtalide may be attributable to thestability of the first-formed addition complex. The benzylic hydroxylgroup is next converted to its t-BOC derivative 13. Condensation of thatintermediate with the Grignard reagent from 3-chloropropyl dimethyla-mine 14 leads to the addition product (15). The reason for specificity forthe ketone over the carbonate may be due to the sterically crowded con-dition about the latter. Treatment with acid then removes that protectinggroup. Reaction of the free alcohol with methanesulfonyl chloride formsthe mesylate of the primary alcohol. Exposure to triethylamine leads todisplacement of that function by the adjacent tertiary hydroxyl groupand thus closure to the isobenzofuran ring (16). The phenolic hydroxylis then converted into a leaving group, in this case a triflate, by acylationwith trifluoromethyl sulfonyl chloride. Reaction of this last with sodiumcyanide, in the presence of triphenylphosphine : palladium and cuprousiodide, replaces the triflate by cyanide. Thus, the antidepressant compoundcitalopram is obtained (17).2

140 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING

O

HO

O10

+

F

MgBr

11

OH

O

HO

F12

O

O

HO

F

OtBu

O

13

Br N(CH3)3

N(CH3)3N(CH3)3

OOH

HO

F

OtBu

O

15

1. H3O+

2. CH3SO2Cl3. Et3N

HO

F16

O

1. F3CSO2Cl

2. NaCN Pd(Ph3P)4,CuI

NC

F17

N(CH3)3O

14

t-BuCOCl

B. Indoles

A subclass of serotonin receptors dubbed 5-HT4 are involved in regulationof intestinal motility. The partial agonist tegaserod (22) has proven usefulin treating conditions characterized by decreased motility, such as irritablebowel syndrome. The drug is interestingly prescribed specifically foruse in women, since results from clinical trials indicated poor responsein men. Alkylation of thiosemicarbazone (18) with methyl iodide proceedson sulfur to the thioether (19). Treatment of intermediate 19 with pentyl-1-amine leads to addition of the amine to the thioether function followed by

HN

NH2

S

NH2

18

CH3I HN

NH2

SCH3

NH

H2NHN

NH2

NH

NH

NH

CH3O

CH=O

21

+

NH

CH3O

HN NH

NH

N

19 20

22


elimination of methyl mercaptan to afford the guanidine (20). Reaction of20 with the indole aldehyde (21) affords (22).3

Much of the damage that results from stroke is attributable to increasesof glutamate or N-methyl-D-aspartate (NMDA), which follow the localanoxia that accompany this event. Agents that inhibit the activity of theresulting abnormal levels of these neurotransmitters would, at least intheory, protect nerves. The NMDA antagonist gavestinel (28), has apowerful neuroprotective in animal models of stroke. This findingseems not to have held up in the clinic.4 Condensation of 2,5-dichlorophe-nylhydazine (23) with ethyl pyruvate affords the hydrazone (24).Treatment of this intermediate with phosphoric acids leads to rearrange-ment to the indole (25). The indole is treated with N-methyl-N-phenylfor-mamide in a classic Vilsmeyer reaction. This reaction introduces a formylgroup on the remaning open position on the fused pyrrole ring (26).Condensation of 26 with the ylide from the amide phosphonium saltleads to the chain extended product 27. Saponification of the estergroup then affords 28.5

Cl

Cl NH

NH2

23

+CO2C2H5

O

Cl

Cl NH

N CO2C2H5

24

H3PO3

NH

CO2C2H5

Cl

Cl

25

C6H5 NCH3

CH=O

PO3Cl

NH

CO2C2H5

Cl

Cl

26

CH=ONHC6H5O

Ph3P

LDANH

CO2C2H5

Cl

Cl

27

ONHC6H5

NH

CO2H

Cl

Cl

ONHC6H5

NaOH

28

Oglufanide (31), at one time called thymogen, is a dipeptide isolatedfrom calf thymus. The imunnomodulatory properties of both the naturalproduct and the subsequent synthetic version have been extensivelystudied as agents that enhances immune function. The compound currentlyis undergoing clinical trials in patients infected with the hepatitis C virus.In the absence of specific references one may imagine that this dipeptide isobtained using standard peptide chemistry where tryptophan 29 with a pro-tected carboxylic acid is condensed with suitably protected glutamate,(30). Removal of the protecting groups would the afford (31).


NH

CO2P

NH2

+

29

HO2CCO2P''

NHP'

30

NH

CO2H

HN CO2H

O

31

The substrate arachidonic acid, which often leads to formation ofinflammatory prostaglandins, is stored in tissues as one of a number ofphospholipids; these compounds, as the name indicates, comprisecomplex phosphate-containing esters. The antiinflammatory corticoste-roids inhibit the action of the enzyme, phospholipase A2, that frees arachi-donic acid. The many undesired effects of those steroids has led to thesearch for non-steroidal inhibitors of that enzyme. A highly substitutedindole derivative has shown good activity as a phospholipase A2 inhibitor.Alkylation of the anion from treatment of indole (32) with benzylchloride affords the corresponding N-benzylated derivative (33). Themethyl ether at the 4 position is then cleaved by means of boron tribromideto yield 34. Alkylation of the enolate from reaction of the phenol withsodium hydride with tert-butylbromoacetate affords the corresponding

NH

CH3O

32

NaH

C6H5CH2Cl

N

CH3O

BBr3

N

HO

33 34

BrCH2CO2tBu

NaH

N

O

35

CO2tBu

Cl

ClO

ON

O

36

CO2tBu

O

O

Cl

1. NH3

2. H+N

O

37

CO2H

O

O

NH2


O-alkyl product (35). Reaction of intermediate 35 with oxalyl chlorideproceeds on the only open position of the heterocyclic ring to yield theacylated derivative (36) as its acid chloride. Treatment of 36 withammonia gives the corresponding amide. The tert-butyl ester is thencleaved with acid to afford the phospholipase inhibitor varespladib (37).6

Retinopathy, that is, diminishing vision to the point of eventual blind-ness, is one of the many complications that results from uncontrolledlevels of blood sugar that characterize diabetes. The elevated bloodsugar that characterize the disease stimulate the enzyme aldose reductasethat catalyzes an alternate pathway for glucose metabolism. The sorbitolend-product from this route tends to accumulate in the ocular lens as opa-cities, a process that leads to increasingly reduced vision and finally totalblindness. There is also some evidence that an effective inhibitor wouldfind use in fending off diabetic neuropathy. Though many aldose reductaseinhibitors have been identified over the years, few if any have yet achievedregulatory approval. In a convergent synthesis for a recent entry, the aminogroup in the aniline (38) is first acylated with acetic anhydride. Treatment

F

F

H2N F

F

38

(CH3CO)2O

F

F

NH F

F

O

39

F

F

NH F

F

S

40F

F

F

NaHN

S

NaOH

F

HS

H2N F

F

41

44

NH

CN

42

NaH

BrCH2CO2C2H5

N

CN

CO2C2H5

CF3CO2H

N

CO2C2H5

S

N

FF

F

43

45

NaOH

N

CO2H

S

N

FF

F

46

P4S10

of the amide (39) with tetraphosphorus decasulfide replaces the amideoxygen with sulfur (40). Reaction of 40 with sodium hydride producesthe sulfide anion from the enol form of the thioamde. This compound dis-places the adjacent ring fluorine atom to form a benzothiazole (41). Base


hydrolysis opens the ring to afford the intermediate mercapto aniline, thesequence in effect having delivered sulfur to the ortho position. In the con-vergent arm treatment of the anion from sodium hydride and indole (42)with ethyl bromoacetate gives the alkylated product (43). Condensationof the mercaptoaniline (44) with the indole (43) in the presence ofstrong acid couples the two moieties via a new thiazole ring (45). The reac-tion can be rationalized by assuming addition of sulfur to the nitrile as theinitial step. Addition–elimination of the aniline nitrogen to the resultingimine then closes the ring. Saponification of the ester on the pendantacetate then affords lidorestat (46).7

Receptors for the estrogens, estrone and estradiol, are characteristicallyindiscriminate in terms of the structures of the compounds that they willbind. The estrogen antagonists show similarly loose structural require-ments for binding (see, e.g., fluvestant in Chapter 2, ospemifene inChapter 3, lasoxifene in Chapter 4 acolbifene in Chapter 8, and arzoxifene(141). An indole provides the nucleus for the estrogen antagonist bazedox-ifene (55); not only the ring system, but also the connectivity of thebenzene ring that carries the basic ether differs from earlier compounds.The convergent scheme starts with an unusual method for building anindole. Thus, reaction of the aniline (47) with the bromo acetophenone(48) in the presence of triethylamine leads to the benzo heterocycle (49)in a single step. The aromatic alkylation step required to close the five-membered ring is likely made possible by the high electron density in

C6H5CH2O

NH2

47

+O

Br

48

Et3NOCH2C6H

C6H5CH2O

NH

OCH2C6H

49

HO

OH50

BrCH2CO2C2H5

HO

O

51CO2C2H5

Cl

O

52 CO2C2H5

SO2Cl

C6H5CH2O

OCH2C6HN

O

CO2C2H553

1. LiAlH4

2. CBr4/Ph3P

C6H5CH2O

OCH2C6HN

O

54

1.

2. H2

HO

OHN

O

55 BrN

N


that ring due the presence of both the ether and the amine functions.Construction of the second ring begins with the alkylation of the phenolichydroxyl in 50 with ethyl bromoacetate to yield the ether (51). Thebenzylic hydroxyl is then replaced by chlorine by means of thionyl chlor-ide. Condensation of the anion from the indole with the benzylic chloride(52) introduces the remaining benzene ring (53). The ester on the pendantside chain is next reduced to the corresponding alcohol using lithiumaluminum hydride. The terminal hydroxyl is then replaced by brominein a reaction with carbon tetrabromide in the presence of triphenylpho-sphine to afford intermediate 54. Alkylation of 54 with azepine completesconstruction of the side chain. Catalytic hydrogenation removes the benzylprotecting groups, uncovering the phenolic hydroxyl groups. This affordsthe estrogen antagonist bazedoxifene (55).8

The “triptan” class of 5-HT3 serotonin antagonists have found extensiveuse as drugs for treating migraine headaches. The synthesis of one recentexample starts with reaction of the benzylsulfonyl chloride (56) with pyr-rolidine to afford the sulfonamide (57). Hydrogenation of this intermediatereduces the nitro group to the corresponding aniline (58). This function isthen transformed to a hydrazine by the conventional scheme involvingconversion to the diazonium salt by reaction with nitrous acid followedby reduction of this last compound with stannous chloride. Condensationof this product (59) with 4-chlorobutyraldehyde gives the hydrazone.Fischer indolization of this last derivative by means of acid affords theindole (60). Chlorine on the side chain is then replaced by a primaryamine (61). Reaction of 61 with formaldehyde and sodium borohydrideconverts the amine to its N,N-dimethyl derivative. Thus, the 5-HT3 anta-gonist almotriptan (62) is obtained.9

ClO2S

NO2

56

NH SO2

NR2

N

57; R = O

58; R = H

1. NaNO2, H+

2. SnCl2

SO2

NH

N

NH2

59

O=HC Cl

H+

SO

N

60

NH

Cl

NH3SO2

N

61

NH

NH2

NaBH4

SO2

N

62

NH

N(CH3)2CH2=O

The same general approach is used for the somewhat more complex“triptan” avitriptan (71). Synthesis of the substituted pyrimidine for


the side chain starts with the condensation of dimethylglyoxylate (63)with guanidine to afford the pyrimidol (64). The hydroxyl group isthen replaced by a leaving group, in this case chlorine, by reactionwith phosphorus oxychloride. The product from this reaction (65) isthen alkylated with N-carbethoxy piperazine to afford 66. Treatmentof 66 with acid removes the protecting group to afford piperazine 67,an intermediate suitable for alkylation. Preparation of the indoleportion of the molecule begins with the two-step conversion (diazotiza-tion then reduction) of the aniline (68) to the corresponding hydrazine(69). Heating this intermediate with v-chlorovaleraldehyde, itself pre-pared in two steps from tetrahydropyran in the presence of acid,leads directly to the indole (70), which has in place the requisiteside-chain link. Subsequent alkylation of the piperazine (67) with 70leads to the serotonin antagonist 71.10

SO2NHCH3

NH2

1. NaNO2

2. SnCl2

SO2NHCH3

NHNH2

SO2NHCH3

NH

ClO=HCCl

OCH3

O +

NH

H2N NH2

N

NHO

OCH3OCH3

POCl3N

NCl

OCH3

C2H5O2CN

HNC2H5O2CNN

NN

OCH3

NH

N

NN

OCH3

H+

SO2NHCH3

NH

N

N

NN

OCH3

63 64 6566

68 69 7067

71

The highly substituted indole, ecopladib (82), which shares manystructural elements with the phospholipase inhibitor varespladib (37),shows similar biological activity. Alkylation of hydroxy benzoate (72)with the dimethyl acetal from bromoacetaldehyde (73) affords the ether(74). Acid-catalyzed reaction of this intermediate with 2-methyl-5-chloroindole (75) in the presence of triethylsilane leads in effect to conden-sation of the acetal with the activated 3 position on the indole ring to afford76. The nature of the reduction of the aldehyde carbon is not immediatelyapparent. Alkylation of the anion on nitrogen from reaction of the indolewith sodium hydride and bromodiphenylmethane then adds the third


substituent to the fused heterocyclic ring (77). The methyl group at the 2position on this ring is next oxidized with NBS and benzoyl peroxide toyield aldehyde 78. Reaction of 78 with nitromethane in the presence ofammonium acetate extends the chain by one carbon (79). Treatment withzinc amalgam and acid reduces both the nitro group and the doublebond to afford the derivative with an ethylamine side chain (80).Acylation of that basic nitrogen with the benzylsulfonyl chloride 81 fol-lowed by saponification of the methyl ester affords the phospholipaseinhibitor 82.11

CO2CH3

HO

72

Br

H3CO OCH3

+

73

K2CO3

CO2CH3

O

H3CO OCH3

NH

Et3Si

CF3CO2H

CO2CH3

CH3

74

76

(C6H5)2CBrNaH

N

CH3

NBS

C6H5CO3H

N

CH=OCH3NO2N

NO2

777879

Zn(Hg0)H3O

+

N

NH2

1. ClO2S

2. NaOHN

NH Cl

SO2

80 82

81

Cl

ClClCl

ClCl

NH

ClCH3

75 O

CO2CH3OCO2CH3OCO2CH3O

CO2CH3OCO2CH3O

Cl

Cl

Cl

C. Indolones

As noted earlier tyrosine kinases play a major role in cell proliferationtyrosine kinases comprises a major theme in the search for antitumor


agents. Solid tumors are highly dependent on the growth of new bloodvessels, a process termed neoangiogenisis, which provide oxygen andnutrients to new tissue masses. The tyrosine kinase inhibitor semaxanib(86) has shown promising early activity against solid tumors; this com-pound inhibits neoangiogenisis and also shows antimetastatic activity.Villsmeyer-type reaction of 3,5-dimethylpyrrole (83) affords the corre-sponding carboxaldehyde (84). Condensation of 84 with indolone proper(85) in the presence of base affords 86.12

N

O

NH

NH

O

NH

O=HC

83 84

NH

85

86

DMF

POCl3

The synthesis of a structurally somewhat more complex indolone tyro-sine kinase inhibitor starts with the construction of the pyrrole ring.Reaction of tert-butyl acetoacetate (87) with nitrous acid leads to nitrosa-tion on the activated methylene carbon. This reaction introduces the nitro-gen atom that will appear in the target pyrrole. Condensation of 88 with

O

NH

NH

O

t-BuO

O

O

87

NaNO2

AcOHt-BuO

O

O

88

NOH

O

O

OC2H5

CO2C2H5

tBuO2C89

90

NH

NH

NH

H3O+

CO2C2H5

91

HC(OCH3)3

TFA

CO2C2H5

O=HC

92

85

93; R = C2H5

94; R = H

CO2R

O

NH

NHN

H

NH

O

95

H2NN(C2H5)2

N(C2H5)2

ethyl acetoacetate (89) completes formation of the pyrrole ring (90). Thestrategy depends on the presence of carboxyl groups at the 2 and 4 pos-itions bearing esters with different reactivity. Thus, treatment of thediester (90) with aqueous acid leads to hydrolytic decarboxylation of thecarboxyl adjacent to the ring nitrogen (91). Reaction of this intermediate


with methyl orthoformate in strong acid then introduces a formyl group atthe only open position on the ring (92). Condensation of this aldehyde withindolone 85, as above, leads to formation of the analogue of 86, which inaddition carries a carboxyl group on the pyrrole ring (93). Saponficationthen affords the free acid (94). Reaction of this compound with N,N-diethyl-ethylenediamine gives the corresponding amide. Thus, the tyrosine kinaseinhibitor sunitinib, (95) is obtained.13

The neurotransmitter dopamine is closely involved in many aspects ofthe central nervous system (CNS). It was demonstrated post-facto thatthe majority of antipsychotic agents owe their efficacy by blocking dopa-mine receptors in the brain. Parkinson’s disease is conversely traceable to adeficiency of dopamine. Most treatments for that disease involve adminis-tration of compounds that make up for that deficiency. The indoloneaplindore (106), acts as a partial agonists at the subclass of dopaminereceptors associated with Parkinson’s. The drug is currently in the clinicfor that indication. The compound also interestingly shows some promisefor treating “restless leg syndrome”. The synthesis begins with alkylation ofthe free phenol in catechol (96) with allyl bromide. The methyl ether in 97is then cleaved with strong base, a reaction specific for methyl ethers, toafford the phenol (98). The newly formed hydroxyl is then alkylated withchiral glycidyl tosylate 99, to afford the glycidic ether (100). Heating asolution of that compound leads first to Claisen rearrangement where theallyl group moves over to the benzene ring to form transient intermediate101. The phenol formed as a result of the rearrangement next opens the

O2N

OCH3

OH

Br

96O2N

OCH

O

97O2N

OH

O

98

NaOH

DMSO

OTsO O

O2N

O

O99

100

O

O2N

O

OH

101

O2N

O

OR

102; R = OH

103; R = Br

O2N

O

O

HO2C

Br

104

KMnO

O

OBr

HN

O

C6H5CH2NH2

O

O

HN

HN

O105 106

CBr4/PPh3


oxirane to form the dioxin ring (102). Reaction of this last compound withcarbon tetrabromide in the presence of triphenylphosphine replacesthe exocyclic hydroxyl group by bromine (103). Oxidation with per-manganate next cleaves the double bond in the pendant allyl group toafford the carboxylic acid (104). Catalytic hydrogenation of this intermedi-ate serves to reduce the nitro group to the corresponding amine. Thisproduct, which is not isolated, cyclizes to afford an amide an thus anindolone ring 105. Displacement of bromine on the short side-chain bybenzylamine completes the synthesis of 106.14

Many different strategies have been investigated to develop agents thatwill avoid injury to the nervous system that accompanies stroke.The recently developed agent flindokalner (112), is designed to open theso-called “maxi” potassium channels that enhance an endogenous neuro-protective mechanism. The first step in an enantioseletcive preparation ofthis compound comprises chlorination of the homosalicylate (107) bymeans of sulfuryl chloride. Fischer esterification in methanol affords the

CO2H

OCH3

107

1. SO2Cl2

2. CH3OH

CO2CH3

OCH3

108

ClKHDMS

NO2F3C

F

NO2F3C

CO2CH3

OCH3

Cl

_

[F+]

NO2F3C

CO2CH3

OCH3

110

Cl

F

2 Separate

3. Na2S2O4

1. NaOH

NH2F3C

CO2H

OCH3

111

Cl

FHN

F

O

F3C

Cl

112

109

methyl ester (108). Treatment with potassium hexamethylsisilazide leadsto formation of the benzylic anion. Reaction of this anion with the nitrocompound leads to nucleophilic aromatic displacement of the ring fluorineatom by the benzylic anion and formation of intermediate 109. Thepresence of the two electron-withdrawing groups in the nitro compound


facilitate this reaction. The anion is of course not isolated, and is nextquenched with N-fluorobenzenesulfonimide to afford 110 as a mixtureof enantiomers. The ester group in this mixture is then saponified;the isomers of the resulting carboxylic acid are next separated by wayof their (S )-benzylamine salts. The isomer that corresponds to the(S )-isomer is then treated with sodium dithionate in order to reduce thenitro group to the corresponding amine (111). Treatment of this orthoamino acid with acid closes the ring to an indolone. Thus, the neuroprotec-tive agent 112 is obtained.15

No biologically active compound has arguably had quite the effect onthe governmental regulations that affect the pharmaceutical industry ashas thalidomide. The profound malformations caused in offspring ofwomen taking this nonbarbiturate sedative caused reappraisal of govern-ment oversight of pharmaceuticals in most of western Europe. In theUnited States, the event provided the final push for a major revision ofthe Food and Drug Laws that govern the FDA. The low-level researchthat continued on this drug, in spite of its ill repute, unexpectedlyshowed that the compound affected immune function. The drug was, forexample, recently approved by the FDA for treatment of complicationsfrom leprosy; it has also been investigated as an adjunct for treatingsome malignancies. Recent research on related compounds has revealeda series that inhibits tumor necrosis factor (TNF-a). Synthesis of the ami-nosuccinimide moiety starts by cyclization of carbobenzyloxy glutamine(113) by treatment with carbonyl diimidazole (CDI). Catalytic hydrogen-ation of the product removes the protecting group. The aromatic moiety

OH

O

NBS OH

O

NO2NO2

Br

CO2H

CONH2C6H5CH2O2CNH 1. CDI

2. H2

NH

H2N O

O

NR2

NH

N O

O

113 114

115 116

117; R = O

118; R = H

H2

O

of the target compound is prepared by free radical bromination of themethyl group in the benzoic acid (115) to give the bromomethyl derivative(116). Condensation of this last with the succinimide (114), leads to


isoindolone (117). A second hydrogenation step reduces the nitro group toan aniline to afford lenalidomide (118).16

D. Miscellaneous Compounds with One Heteroatom

Growth hormone has long been used for treating children whose retardedgrowth was traceable to deficient levels of the polypeptide. This high mol-ecular weight compound that was used for treating deficiencies was orig-inally obtained from cadaver pituitary glands. Growth hormone producedby recombinant technology became available at almost the exactly timethat it was recognized that the cadaver derived drug could potentiallycarry the prions that cause fatal Creutzfelt–Jacob disease. The recombinantderived material has as a result completely replaced the pituitary-derivedhormone. The cost of this drug, which can run as high as $170 per dayof treatment, has encouraged the search for small molecules. The dihydro-indole ibutamoren (128), achieves much the same purpose as the

NH

N

CH3

119

C6H5CH2OCOCl

N

N

CH3

Cbz

120

Cbz = C6H5CH2OCO

N

HN

Cbz

121

ONHCO2tBu

NHCO2tBu

CO2H

122

N

N

Cbz

O

O

123

TFA

N

N

Cbz

ONH2

O

124

N

N

Cbz

O

O

126

HN

NHCO2tBu

O

HO2C NHCO2tBu

EDC

NH

N

O

O

127

HN

NHCO2tBu

O

H2

1. CH2SO2Cl

2. TFAN

N

O

O

HN

NH2

O

SO2CH3

128

125


polypeptide; the drug does so by stimulating secretion of growth hormonefrom the pituitary gland. This agent has shown promising results in theclinic. The reaction sequence for its preparation begins with acylation ofthe amino group in spiroindoline (119) with carbobenzyloxy chloride toafford 120. The methyl group on the piperidine ring in this product isthen removed using a modern version of the von Braun reaction (121).Acylation of this product with the t-BOC derivative of benzyloxyserine(122) using standard peptide-forming condition leads to the amide (123).Treatment of that intermediate with trifuoroacetic acid removes thet-BOC protecting group to reveal the free primary amine (124). Thepeptide-like side chain is next extended by acylation with t-BOC protectedaminoisobutyric acid (125) to give 126. Catalytic hydrogenation nextremoves the Cbz group that has protected the indoline nitrogen throughthe preceding steps (127). Reaction of 127 with methanesulfonyl chloridegives the corresponding sulfonamide. Trifluroacetic acid then removes theremaining t-BOC group to afford 128.17

Compounds whose structures include a quinone moiety have been inten-sively investigated as potential antitumor agents. At least two quinones,mitomycin C and diaziquone, that have found their way to the clinic.These compounds in addition include a reactive aziridine ring. A recententry that incorporates both those features, apaziquone (135), alsoknown as EO9, may be viewed as an oxidized indole. In the key reactionof a succinct synthesis to this agent, quinone 129 is allowed to react with

129

O

O

Br

CH3O CO2CH3

HN

CH3

+

130

O

O

CH3O

N

OCH3

OCH3

CO2CH3

131

DDQ

O

O

CH3O

NCH=O

CO2CH3

CO2CH3

CO2CH3

132

CH3 CH3

(CH3O)2P0CH2CO2CH3LiBr, Et3N

O

O

CH3O

N

133

CH3

DiBAL-H

O

O

CH3O

N

134

CH3CH3

OH

OH

O

O

N

N

135

OH

OH

NH

the N-methylenamine from 4-methoxyacetoacetate 130 to form the fusedpyrrole ring in a single step. The reaction can be rationalized by assumingthat the first step involves displacement (or addition–elimination) of


bromine by the basic nitrogen on the eneamine; conjugate addition of theactive methylene group to the quinone then closes the ring to afford theobserved product (131). Treatment with DDQ next oxidizes the exocyclicmethoxymethylene group to the corresponding aldehyde (132).Condensation of this product with the phosphorane from Emmon’sreagent results in the homologated product 133; the added salt assuresthe trans configuration of the newly introduced double bond. In the nextstep, reduction with DIBAL converts both esters to the correspondingalcohols (134). Reaction of this last intermediate with aziridine results indisplacement (or again, addition–elimination) of the ring methoxygroup. Thus, the antitumor agent 135 is obtained.18

In yet another illustration of the breadth of the SAR of estrogenantagonists, the carbonyl group in the estrogen antagonist raloxifenecan be replaced by ether oxygen. Reaction of the benzothiophene(136) with bromine leads to the derivative (136) halogenated at the3 position (137). The ring sulfur atom is next oxidized with hydrogenperoxide in order to activate that bromine toward displacement (138).Reaction of this intermediate with the anion from treatment of thephenol (139) with sodium hydride displaces bromine, and in a singlestep introduces the ring that carries the requite basic ether. The sulfox-ide function is next reduced to the sulfide oxidation state by means oflithium aluminum hydride (140). Scission of the methyl ethers withboron tribromide completes the synthesis of the estrogen antagonistarzoxifene (141).19

SCH3O

OCH3

136

Br

SCH3O

OCH3

137

Br

H2O2

CH3O

OCH3

OCH3

Br

SO

138

OHON

139

NaH

CH3O

O

SO

ON

140

1. LiAlH4

2. BBr3HO

OH

O

S

ON

141


2. FIVE-MEMBERED RINGS WITH TWOHETEROCYCLIC ATOMS

A. Benzimidazoles

Thrombin is an essential intermediate in the formation of blood clots.Inhibitors of this factor would prove useful in treating and preventinginappropriate clot formation that potentially leads to stroke and heartattacks. Reaction of the carboxylic acid (143) with thionyl chloride leadsto the corresponding acid chloride (144). Treatment of that intermediatewith the substituted pyridyl amine (142) leads to the amide (145).Catalytic hydrogenation of the product reduces the nitro group to theprimary amine (146). Condensation of this ortho diamine with the car-boxylic acid (147) in the presence of carbonyl diimidazole then formsthe imidazole ring (148). This reaction proceeds via the amide formedwith the primary amine followed by replacement of the amide carbonyloxygen by the adjacent amine. Reaction of the product with ammoniumcarbonate leads to addition of ammonia to the nitrile to form an amidine.Saponification of the side-chain ester affords the thrombin inhibitordabigartan (149).20

NH

NO2

CH3

ROC

+

N

NH

CO2C2H5

142 143; R = OH

144; R = Cl

NH

NR2

CH3

N

N

CO2C2H5

O

CNHN

HO2C

145; R = O

146; R = H

+

147

N

N

CH3

N

N

CO2C2H5

O

CNHN

CDI

1. (NH4)2CO3

2. NaOH

148

N

N

CH3

N

N

CO2H

O

HN

NH2

NH

149

Thioazolidinediones have by now achieved a major role in the treatmentof Type II, also called adult onset diabetes. A recent example includes abenzimidazole moiety as part of the structure. One of the syntheses forthis compound starts by nucleophilic aromatic displacement of fluorinein p-fluorobenzaldehyde (151) by the anion from treatment of the hydroxy-methylbenzimidazole (150) with strong base. The product (152) is then


treated with thiazolidinedione proper (153) in the presence of base. Theanion from the methylene group in 153 adds to the aldehyde; the transientalcohol dehydrates to form the observed product 154. Catalytic hydrogen-ation of that product then affords rivoglitazone (155).21

N

NCH3OCH3

OH

150

+F CH=O NaH

N

NCH3OCH3

152

O CH=O

151

NH

S

OO

NH

S

OO

153

N

NCH3OCH3

154

OH2

NH

S

OON

NCH3OCH3

155

O

Purines in which the sugar moiety is replaced by an abbreviated open-chain surrogate, for example, acyclovir, comprise an important group ofantiviral drugs. Antiviral activity is retained when the pyrimidine ring in

N

NH

Cl

Cl

Br +

O

AcO OAc

OAcAcO N

N

Cl

Cl

Br

O

AcO OAc

OAc

H2N

N

N

Cl

Cl

O

AcO OAc

OAc

N

N

Cl

Cl

O

HO OH

OH

NH NH

cat

[OH--]

156157

158

159160

2. FIVE-MEMBERED RINGS WITH TWO HETEROCYCLIC ATOMS 157

the heterocyclic part of those molecules is replaced by benzene, though theexample at hand includes a normal sugar. Thus, coupling of the benzimi-dazole (156), with the tetracetyl ribofuranoside (157) in the presence ofN,O-bis(trimethylsylil acetamide) affords the glycosilated benzimidazole(158). Treatment on this intermediate with isopropylamine leads to displa-cement of the bromine on the imidazole ring by isopropyl amine (159).Saponification with aqueous sodium carbonate removes the acetyl protect-ing groups to afford the antiviral agent maribavir (160).22

Antidepressant drugs, whether they belong to the tricyclic or newerSSRI series, do not as a rule become effective until �2 weeks after treat-ment has started. The recent 5HT antagonist fibanserin (166), departs fromthat pattern in that it starts to elevate patient’s mood within a short timeafter the treatment has started. Reaction of benzimidazolone (161) withbenzoyl chloride affords the singly protected derivative 162. Alkylationof the anion prepared from this intermediate with sodium hydride with1,2-dichloroethane adds the linking chain for attaching the next largemoiety (163). The benzoyl group on the other imidazolone nitrogen isthen hydrolyzed in the presence of acid (164). Displacement of the term-inal chlorine with the arylpiperazine 165 affords the alkylation product166 and thus 166.23

NH

HN

O

161

C6H5COCl

N

HN

O

162

O

ClCl

N

N

O

163

O

Cl

HCl

NH

N

O

ClN CF3

CF3

HN

164NH

N

O

N

N

166

165

Base

B. Miscellaneous Compounds

Many new antipsychotic compounds that have been introduced over theyears that showed decreased side effect in initial trials. The promise ofsuch “atypical” agents often did not stand up with chronic use. The most


recent atypical drug is a mixed agonist–antagonist at dopamine receptors.The partial agonist activity should in theory avoid the effects of excessiveblockade. The compound at hand also acts on 5-HT receptors; this shouldhelp patients who suffer from bipolar disorder in the depressed phase ofthe disease. Alkylation of the nitrogen on the piperazine (167) with the3-bromobenzyl mesylate (168), obtained by reaction of the correspondingalcohol with methanesulfonyl chloride, affords the intermediate (169). Theadditional benzene ring is added by Suzuki cross-coupling with phenyl-boronic acid. Thus, the antipsychotic compound, bifeprunox (170).24

N

NH

O

HN

167

O

+

OSO2CH3

Br

168

N

O

HN

O

N

Br

C6H5B(OH)2

N

O

HN

O

N

169 170

Pd

The search for compounds that have a neuroprotective effect followingischemic stroke is a recurrent theme in this chapter as well as in Chapter 3.This search for effective drugs has ranged over a variety of biochemical

F

F

OH

+Cl

O F

F

OO

C2H5CON

C2H5CON

NH2

N

S

+ CH3SO2

N

S

HN

N

SNH

HN

172 173 174175

176 177 178

F

F

O

OH

N

SN

HN

179

mechanisms, as well chemical structures. A benzothiazole moiety forms partof a compound that acts as a neuroprotectant in animal models. The (S)

2. FIVE-MEMBERED RINGS WITH TWO HETEROCYCLIC ATOMS 159

enantiomer of this compound is far more active than its antipode bothin vitro and in vivo. One of several methods for preparing the substitutedthiazole25 comprises displacement of the mesylate group in benzothiazole(173) by the free amine in protected aminopiperidine (172). Hydrolysisthen removes the protecting group to reveal the free piperidine amine(175). In a convergent step, the anion from difluorophenol (176) is reactedwith chiral epichlorohydrin (177) to afford 178. This reaction proceedswith overall retention of configuration whether initial attack is on chlorineor the epoxide. Reaction of this intermediate with the piperidine (175)affords the product with a linkage reminiscent of a b-blocker. This com-pletes the synthesis of the (S)-isomer of lubeluzole (179).26

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2. Anon, Drugs Future 25, 620 (2000).

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19. A.D. Palkowitz et al., J. Med. Chem. 40, 1407 (1997).

20. N.H. Hauel, H. Nar, H. Priepe, U. Ries, J.-M. Stassen, W. Wienen, J. Med.Chem. 45, 1757 (2002).

21. For general method see, T. Fujita, K. Wada, M. Oguchi, H. Yanagisawa,K. Fujimoto, T. Fujiwara, H. Horikoshi, T. Yoshioka, U.S. Patent 5,886,014(1999) and T. Fujita, T. Yoshioka, T. Fujiwara, M. Ogichi, H. YanagisawaH. Horikoshi, K. Wada, K. Fujimoto, U.S. Patent 6,117,893 (2000).

22. S.D. Chamberlain, G.W. Koszalka, J.H. Tidwell, N.A. Vandraanen, U.S.Patent 6,204,249 (2001).

23. G. Bietti, F. Borsini, M. Turconi, E. Giraldo, M. Bignotti, U.S. Patent5,576,318 (1996).

24. R.W. Feenstra, J. de Moes, J.J. Hofma, H. Kling, W. Kuipers, S.K. Long,M.T.M. Tulp, J.A.M. van der Heyden, C.G. Kruse, Bioorg. Med. Chem.Lett. 11, 2345 (2001).

25. R.A. Stokbroekx, M.G.M. Luyckx, F.E. Janssens, U.S. Patent 4,861,785(1989).

26. R.A. Stokbroekx, G.A.J. Grauwels, U.S. Patent 5,434,168.

REFERENCES 161

CHAPTER 8

SIX-MEMBERED HETEROCYCLESFUSED TO ONE BENZENE RING


A. Benzopyrans

A prominent feature in the majority of estrogen antagonists consists of apair of aromatic rings disposed on adjacent positions on either an acyclicethylene or a fused bicyclic ring system; in the latter case, one of thoserings is positioned next to the ring fusion. Those two moieties arepresent in the antagonist acolbifene (9); the structure of this agent,however, departs from previous examples by the fact they occupy the2,3- rather than 1,2-position of the bicylic system. This finding mayaccount for the report that this agent is a pure antagonist that, unlike itspredecessors, shows no partial agonist activity at estrogen receptors. Thesynthesis of this agent begins with Fiedel–Crafts acylation of resorcinol(1) with 4-hydroxyphenylacetic acid (2) to afford the desoxybenzoin (3).Reaction with dihydropyran (DHP) leads to formation of the bis(tetrahydropyrranyl) ether (4); the phenolic group adjacent to the ketone does not reactas a result of its chelation with that carbonyl group. Condensation of thatintermediate with p-hydroxybenzaldehyde in the presence of piperidineinitially leads to the chalcone (5). The phenol then adds to the doublebond conjugated with the carbonyl group to afford the benzopyranone


163

(6). The free phenol group on the newly introduced ring is then alkylatedwith N,4-chloroethylpiperidine to give the basic ether (7). Reaction of 7with methylmagnesium bromide followed by treatment with acid leadsthe first-formed alcohol to dehydrate; at the same time the tetrahydropyrra-nyl groups hydrolyze to reveal the free phenols 8. Separation on a chiralchromatographic column then affords the (S ) isomer, 9.1

OH

HO

1

+

HO2C

OH

2OH

HO

OH

O

3

DHP

OH

THPO

OTHP

O

4

CH=O

HO

[B–]

OH

THPO

OTHP

O

OH

O

THPO

OTHP

O

OH

56

O

THPO

OTHP

O

O

7

N

Cl N

Cs2CO3

1. CH3MgBr

O

HO

OH

ON

O

HO

OH

ON

2. AcOH

8 9

Chiralpak

Migraine was a condition that was refractory to treatment until the dis-covery of the serotonin receptor blocker, such as sumatriptan. This agentwas soon followed by several other drugs that acted by the same mechan-ism. Tidembersat (13) a compound more closely related, both in structureand mechanism of action, to antihypertensive benzopyrans that act on

164 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING

potassium channels showed early promise as an agent for treatingmigraine.2 Lack of recent references suggest that this activity did nothold up in the clinic. The synthesis that follows3 is somewhat conjecturalas it depends on a sketchy description in a patent. Thus stereoselectiveepoxidation of the benzopyran (10), using, for example, Sharpless con-ditions, affords the chiral oxirane (11). Ring opening that intermediatewith ammonia or an equivalent would then afford the trans aminoalcohol(12). Acylation with 3,5-difluoro-benzoyl chloride would give 13 as asingle diastreomer.

O

O

10

O

O

11

O

O

O

12

NH2

OH

O

O

13

NH

OHO

FF

Every cell in a living organism incorporates a time clock that marks itslongevity. The cell then dies at the end of its prescribed lifetime. Thisprocess, called apoptosis, is disrupted in cancer cells and results in theirimmortality. One of the approaches to treating neoplasms involves restor-ing this process. The benzopyran alvocidib (20), perhaps better known byits previous name flavoperidol, has shown promising activity as an agentthat restores apoptosis. The scheme below is based on that for the com-pound in which methyl replaces the pendant chlorobenzene ring.4 Thesequence starts with addition of diborane to the olefin in the tetrahydro-pyridine (14), itself available by addition of an organometallic reagent toN-methyl-4-piperidone followed by dehydration of the tertiary alcohol.Oxidation of the hydroborane adduct with a peroxide then affords thehydration product as its cis isomer (15). The stereochemistry at thatcenter is then reversed by oxidation to the corresponding ketone followedby reduction with sodium borohydride (16). This intermediate is acylatedwith acetic anhydride in the presence of boron trifluoride. Use of an excessof the latter leads to selective demethylation of the ether adjacent to thenewly introduce acyl function (17). Claisen condensation of this productwith methyl 2-chlorobenzoate gives the b-diketone (18). Treatment withacid causes the phenolic oxygen to add to the enone, thus forming thepyran ring by an addition–elimination sequence (19). Demethylation ofthe remaining phenolic ethers, for example, with boron tribromide,would then afford 20.5


N

OCH3CH3O

OCH3

H2O2

N

OCH3CH3O

OCH3

14 15

HO

1. [O]

2. NaBH4

N

OCH3CH3O

OCH3

16

HOAc2O

BF3

N

OHCH3O

OCH3

17

HO

O

N

OHCH3O

OCH3

HO

O

18

HO

ClH

+

NaHN

CH3O

OCH3

HO

O

19

Cl

O

N

HO

OH

HO

O

20

Cl

O

BBr3

CH3O2CCl

B2H6

The continuing search for better tolerated antipsychotic drugs has led tothe examination of subtype dopamine receptors in the hope that selectivitymight avoid the side effects that come with indiscriminate receptor block-ade. A benzopyran compound that shows preferential binding to the D4

dopamine receptors showed promising results in the laboratory; thisagent, however, subsequently failed in the clinic. The benzopyran nucleusis formed in a single step. Thus, reaction of phenethyl alcohol (21) with theacetal (22) in the presence of strong acid initially leads to the transientintermediate (23) in which one of the methoxy groups has been replacedby the hydroxyl group from the phenethyl reagent. The carbocationformed under the strongly acidic conditions by loss of the remaining meth-oxyl then attacks the aromatic ring to form a pyran (24). Alkylation of thesecondary amine in the piperazine (25) with the halogen in 24 then affords26. This last is resolved to afford sonepiprazole (27).6

OCH3

OH

21

OCH3

22

+

O OCH3CH3SO3HO

ClClCl

N

HN

SO2NH2

25

O

2324

NN SO2NH2

26

O

NN SO2NH2

27

resolve


B. Quinolines and Their Derivatives

Multidrug resistance poses an increasingly important problem forchemotherapy. Several compounds, zosuquidar (Chapter 4) and biriquidar(Chapter 6), that attempt to overcome this by interfering with the mechan-ism by which cells extrude drugs were noted earlier. A compound thatincludes in its structure both a quinoline and a perhydroisoquinolinemoiety shares the mechanism of action with its predecessors. The per-hydroisoquinoline moiety (31) can conjecturally be prepared by alkylationof 28 with the chloroethyl nitrobenzene (29). Catalytic hydrogenation ofthe product (30) would then reduce the nitro group to afford intermediate31. Acylation of the newly formed amine with the nitrobenzoic acid (32) inthe presence of cyclohexyl-morpholino-carbodiimide then yields amide33. Hydrogenation again converts the nitro group to the correspondinganiline (34). Acylation of intermediate 34 with quinoline-3-carboxylicacid (35) yield the extended antharanilamide. Thus tariquidar (36)is obtained.7

NH

CH3O

CH3O

Cl

NO2

+

CH3O

CH3ON

NR2

HO2C

O2N

R2N

CH3O

CH3ON

NH

O

OCH3

OCH3

OCH3

OCH3

N

CO2H

N

O

HN

CH3O

CH3ON

NH

O

OCH3

OCH3

28 29 30; R = O31; R = H

32

33; R = O 34; R = H

35

36

As noted in Chapters 4, 5, and 7, compounds aimed at disruptingtyrosine kinases have been intensively studied as potential antitumorcompounds. The quinoline-based inhibitor pelitinib (45) incorporates aMichael acceptor function in the side chain that can form a covalentbond with a nucleophile on the target enzyme. Such an interactionwould result in irreversible inhibition of the target kinase. Reaction ofthe aniline (37) with DMF acetal leads to the addition of a carbonatom to aniline nitrogen in the form of an amidine (38). This intermedi-ate is next reacted with nitric in acetic acid to form the nitrated product


(39). Condensation of the product from that reaction with ethyl cyano-acetate in the presence of acid affords the enamine (40) from displace-ment of dimethylamine. Heating this product in Dowtherm closes thering via the ester group to form the cyano quinoline (41). The nextstep invokes one of the standard schemes in heterocyclic chemistryused to transform a hydroxyl to a better leaving group. Treatment ofthe enol (41) with phosphorus oxychloride thus affords the chlorinatedderivative (42). Reaction of 42 with the halogenated aniline (43) leadsto displacement of chlorine by the basic nitrogen and formation of 43.Treatment of that intermediate with iron powder in acetic acid serves toreduce the nitro group that was put in place early in the sequence to theamine (44). Acylation of that newly introduced amine with 4-N,N-dimethylaminobut-2-enol chloride gives the irreversible kinase inhibitorpelitinib (45).8

C2H5O NH2

37

CH3O

H3CON

C2H5O N N

38

C2H5O N N

39

O2N

CN

CO2C2H5

C2H5O NH

40

O2N NC CO2C2H5Heat

C2H5O

O2N

OH

CN

41

POCl3

C2H5O

O2N

Cl

CN

42

F

Cl

H2N

F

Cl

C2H5O

R2N

HN

CN

F

Cl

C2H5O

HN

HN

CN

45

1. 2. Fe

43; R = O 44; R = H

O(CH3)2N

COCl(CH3)2N

Neurokinins comprise a group of peptides involved in nerve trans-mission. Specific members of this class of mediators control suchdiverse functions as visceral regulation, and CNS function. The non-peptide neurokinin antagonist talnetant (51), for example, is currentlybeing evaluated for its effect on irritable bowel syndrome, urinary


incontinence, as well as depression and schizophrenia.9 The quinolineportion of this compound is prepared by base-catalyzed Pfitzinger conden-sation of isatin (46) with the methoxy acetophenone (47). The methoxyether in the product (48) is next cleaved by means of hydrogen bromide.Amide formation of (49) with the chiral a-phenylpropylamine (50)affords the antagonist (51).10

NH

O

O

46

+

OCH3

O

47

N

KOHOCH3

CO2H

HBr

N

OH

CO2H

49

NH2

N

OH

O NH

51

48

50

Cholesterol is not absorbed from the intestine as such, it first needs to beesterified. Another enzyme, cholesteryl ester transfer protein (CETP), thencompletes absorption of cholesterol. Drugs that interfere with the action ofthese peptides would aid in lowering cholesterol levels by complementingthe action of the statins that inhibit endogenous production of cholesterol.The CEPT inhibitor torcetrapib (60), proved very effective in loweringcholesterol levels in humans; the drug not only lowered low-density lipo-proteins (LDL and VLDL) but also raised levels of high density, “good”lipoproteins (HDL). The drug was, however, withdrawn from the marketnot long after its introduction as a result of serious concerns as to itssafety. The synthesis of this compound involves an unusual method forpreparing the tetrahydroquinoline moiety. The sequence starts with thereaction of the trifluormethylaniline (52) with propanal in the presenceof benzotriazole (53) to produce the aminal 54. Condensation of 54 withthe vinyl carbamate (55) adds three carbon atoms in what may beviewed formally as a 3 þ 3 cycloaddition sequence. This yields the tetra-hydroquinoline ring (56) with expulsion of the benzotriazole fragment.The ring nitrogen is then protected as its ethyl carbamate by acylation


with ethyl chloroformate (57). The benzyl carbamate function on nitrogenat the 4 position is next removed by reduction with ammonium formateover palladium to afford the primary amine 58; this compound is thenresolved as its dibenzyl tartrate salt to afford the (2R, 4S ) isomer.Reductive amination with the bis(trifuoromethyl benzaldehyde) (59) inthe presence of sodium triacetoxy borohydride. Acylation with methylchloroformate completes the synthesis of 60.11

F3C

NH2

+O=HC

N

N

NN

NH

52

53F3C

NH

N

54

HN

O

O CH2C5H5

O

NH

F3C

HN OCH2C6H5

O

56

55

N

F3C

HN OCH2C6H5

O

O OC2H5

ClCO2C2H5

57

N

F3C

NH2

O OC2H5

58

1. HCO2–

NH4+

Pd

2. Resolve

CF3

CF3

O=HC CF3

CF3

1.

N

F3C

N

O OC2H5

O

O

59

602. CH3OCOCl

H3C

As noted previously, anticholinergic agents have undergone somethingof a renaissance due to their use as drugs to treat urinary incontinence. Thesynthesis of one of these muscarinic antagonsists starts with the classic

HN O

61

POCl3N 1. NaBH4

62

2. Resolve

NH

63

ClCO2C2H5

N

64

OC2H5

ON65

NaH

N

66

O

O

N

HO


Pictet–Spengler method for building a dihydroisoquinoline ring. Thus,treatment of the benzamide (61) from 2-phenethylamine with phosphorusoxychloride probably results in initial formation of a transient enol chlor-ide; this then cyclizes to 62 under reaction conditions. The imine is thenreduced with sodium borohydride 63. Resolution by means of the tartratesalt affords 64 in optically pure form. Acylation of this intermediate withethyl chloroformate leads to carbamate 64. Reaction of 64 with the anionfrom chiral quiniclidol (65) interestingly results in the equivalent ofan ester interchange. Thus, the anticholinergic agent solifenacin (66)is obtained.12

Addition of the terpene, farnesol, to cysteine residues near the end ofprotein chains is a crucial process for transporting some proteins to theintended membrane compartment. This process thus plays an importantrole in cell proliferation. Inhibitors of the enzyme that catalyzes farnesyla-tion, farnesyl transferase, provide yet one more mechanism for interruptingthe multiplication of malignant cells. One of several synthesis of this agent

HN

CH3

COCl

Cl

+

6768

Cl

O N

CH3

PPA

NO

CH3

Cl

NO

CH3

Cl

Cl

ClOC

Cl

ON

N

BuLi

NO

CH3

Cl

R

N

N

CH3CH3

6970

7172; R = OH

73; R = NH2

1.

2. Br2

starts with the acylation of N-methylaniline (68) with the cinnamoyl chlor-ide (67). Treatment of the resulting amide (69) with polyphosphoric acidleads to attack of the protonated olefin onto the adjacent benzene ringwith formation of the tetrahydroquinolone (70). This intermediate is thenreacted with 4-chlorobenzoyl chloride in the presence of a Friedel–Crafts catalyst to afford the corresponding ketone. The heterocyclic ringis next dehydrogenated by reaction with bromine. The initially formed


quaternary bromide apparent loses hydrogen bromide under reactionconditions to give the unsaturated quinolone (71). Treatment of 71 withthe anion obtained from N-methylimidazole and butyllithium leads toaddition of that heterocycle to the ketone. The thus formed carbinol (72)is then treated with ammonia. The quaternary carbinol then in essence sol-volyses so as to replace the hydroxyl group by a primary amine formingtipifarnib (73).13,14

HNO

OH

74

OCl HNO

OO

HNO

OOCH3

OCH3

NH2OCH3

OCH3

OH

NH

75

76

77

Agents that increase the force of contraction of the heart, often calledpositive inotropic agents, play an important role in treatment of congestiveheart failure. Many of the currently available drugs also increase heart rate,an undesired side effect. A compound that is based on a quinolone is saidto increase force of contraction without speeding up the heart rate. The finalsteps of synthesis on this agent closely parallel those used to prepareb-blockers. Thus, reaction of the carbostiryl (74) with epichlorohydrinaffords the glycidic ether (75). Treatment of this intermediate with thebenzylamine (76), opens the epoxide to afford the aminoalcohol torbori-none (77).15

C. Quinolone Antibacterial Agents

Research on the quinolone antibacterial agents crested a decade ago, asindicated by the fact that Volume 5 in this series described the synthesisof no fewer than 11 drugs in this structural class. The level of activitythen, not surprisingly, declined so that only four quinolones were describedin Volume 6, which was published in 1999. Two of the three quinolonesdiscussed below were actually prepared before that year; their absence inthe book is due to the circumstance that they had not yet, for some


reason, been assigned nonproprietary names. By way of a reminder, thequinolones act by interfering with the bacterial enzyme, DNA gyrase.An important step in cell replication involves reading the genome inorder to generate a corresponding RNA strand. The sheer size of thegenome requires that it be cut in order to gain access to the relevantsection. Gyrases and related topoisomerases temporarily hold the cut endsduring transcription; other enzymes reconnect those ends when theprocess is complete. Topoisomerase inhibitors cause the formation ofcovalent bonds so that the genome is frozen in the cut position and as a con-sequence can no longer function. Cell replication is thus brought to a halt.

The synthesis of one of the agents begins with nucleophilic aromaticdisplacement of bromine by cyanide in the highly fluorinated compound78. Acid hydrolysis of the nitrile (79), followed by esterification of thenewly formed acid, affords ester 80. Base-catalyzed condensation of theintermediate with diethyl malonate leads to the tricarbonyl derivative 81.

F

F

OCH3

Br

F

78

CuCNF

F

OCH3

CN

F

79

1. H2SO4

2. C2H5OH

F

F

OCH3

CO2C2H5

F

80

CO2CH3

CO2CH3

NaOC2H5

F

F

OCH3

F

O

81

F

F

OCH3

F

CO2CH3

O

TSA

82

F

F

OCH3

F

CO2CH3

O

83

CH(OC2H5)3

OC2H5

F

F

OCH3

F

CO2CH3

O

84

NH

NH2

NaF

F

F

OCH3

CO2CH3

O

N

85

HNNHH3C

HN

H3C

F

N

OCH3

CO2H

O

N

86

1.

2. NaOH

CO2CH3

CO2CH3

This loses one of the carboxylates on heating in the presence of toluene-sulfonic acid to afford the b-ketoester (82). Reaction of this intermediatewith ethylorthoformate then adds a carbon atom to the activated methylene.Heating that compound with cyclopropylamine in effect exchanges theethoxy group with the amine to afford enamine (84). Treatment 84 withsodium fluoride leads to displacement of one of the ring fluoro groupsby the basic nitrogen on the side chain. This step concludes the formation


of the quinolone (85). Reaction of 85 with 2-methylpiperazine leads to asecond displacement of fluorine, in this case by the less hindered of thebasic nitrogen atoms on the piperazine. Saponification of the ester thenaffords gatifloxacin (86).16

Replacing one of the protons on the cyclopropyl group by fluorine intro-duces an element of asymmetry into that moiety. A significant portion ofthe synthesis of sitaloxacin (98) is consequently devoted to the preparationof that substituent in chiral form. Reaction of the chiral auxiliary amino-alcohol (87) with phosgene closes the ring to afford the oxazolidone(88). This compound is then treated with the methyl acetal from acet-aldehyde; the ring amide nitrogen displaces one of the methoxy groupsto give the corresponding carbinolamine derivative 89. Heating 89 leadsto loss of methanol to yield the vinyl amine (90). Addition of fluoromethy-lene carbene, generated from fluoromethyl iodide and diethyl zinc leads toformation of the cyclopropyl group (91). The reaction proceeds to afford

C6H5

HO

H2N

87

COCl2NH

O C6H5

C6H5

O

88

(CH3O)2CHCH3 N

O C6H5

C6H5

O

89

CH3

CH3O

Heat O C6H5

C6H5

OICH2F

Et2Zn N

O C6H5

C6H5

O

F

NH2

F

92

CO2C2H5

O

F

F

Cl

FCO2C2H5

O

F

F

Cl

F NH

F

NaH

CO2C2H5

O

F

F

Cl

F

N

93

9495

NH

NHOCOtBu

CO2C2H5

O

F

Cl

F

N

97

N

tBuO2CNH

CO2H

O

F

Cl

F

N

98

N

NH2

1. TFA

2. NaOH

9091

H2

OC2H5

96

N

C6H5

the chiral cis isomer due to the steering influence of the proximate chiralauxiliary. Catalytic hydrogenation leads to scission of the benzyl–nitrogenand benzyl–oxygen bonds; the transient carbonate disintegrates on workup to afford chiral cis-amine (92). The scheme then proceeds much asthat above though details differ. Thus, reaction of 92with the ethoxymethy-lene intermediate (93) leads the amine to replace the ethoxy group to afford


94. The cyclization to a quinolone (95) in this case is effected with sodiumhydride. Treatment of this intermediate with the spiro diamine (96) leads todisplacement of fluorine and formation of alkylation product 97.Deprotection by acid-catalyzed cleavage of the t-BOC group flowed bysaponification yields the quinolone antibacterial agent 98.17

The first few reactions in the preparation of the most recent of this smallset of quinolones involves adjustment of the substitution pattern on thecentral benzene ring. Thus carbonation of the lithio derivative from 99with carbon dioxide gives the corresponding acid; this acid is then

F

OCH3

F

99

1. BuLi/CO2

2. CH2N2 F

OCH3

F

100

CO2CH3BBr3

F

OH

F

101

CO2CH3ClCH2F

F

FCH2O

F

102

CO2CH3

1. NaN32. H23. NaOH

NH2

FCH2O

F

103

CO2HHONO

HBrBr

FCH2O

F

104

CO2HCO2MgCO2C2H5

Br

FCH2O

F

105

CO2C2H5

O

Br

FCH2O

F

CO2C2H5

O

MeO2CHNMe2

OCH3

NH2

Br

FCH2O

F

CO2C2H5

O

NH

K2CO3

Br

FCH2O

CO2C2H5

O

N

N(C6H5)3C

FCH2O

CO2C2H

O

NN(C6H5)3C

HCl

FCH2O

CO2C2H5

O

NHN

106107 108

109

110111

B(OH)2

converted to the methyl ester with diazomethane to yield 100. The methylether is then cleaved by means of boron tribromide to yield 101. The newlyrevealed phenol is then alkylated with chlorofluromethane in the presenceof base to afford the ether (102). Reaction of the ester with sodium azideleads to nucleophilic aromatic displacement of the fluorine atom.


(The reagents used for these last two steps almost guarantee that this is notthe route used for larger scale synthesis.) Catalytic hydrogenation thenreduces the resulting azide to the corresponding aniline. Saponificationof the ester leads to amino acid 103. The amine is then diazotized andthe diazonium salt treated with hydrogen bromide to afford bromo deriva-tive 104. Condensation of this last intermediate with the magnesium saltfrom ethyl malonate leads in a single step to the requisite b-ketoester(105). The extra carbon required to build the fused ring is added in thiscase by reaction with DMF acetal (106). The methyl enol ether is then dis-placed as above by cyclopropylamine (107). Treatment of the product withbase closes the ring to afford the quinolone (108). Suzuki cross-coupling ofthe bromine atom in 108 with the boronic acid from dihydroisoindole 109leads to the coupling product (110). The trityl protecting group on isoin-dole nitrogen is then removed by treatment with acid. Thus the quinolonegarfenoxacin (111) is obtained.18


A. Benzoxazines

The multidrug regimen currently used to treat HIV infection includes threedrugs, a proteiase inhibitor, and two reverse transcriptase inhibitors. Inorder to try to avoid the development of drug resistance, one of the latterwill consist of a modified nucleoside, while the second will be one ofseveral nonnucleosides inhibitors, such as those noted earlier in thisvolume [capravirine (Chapter 5), etravirine (Chapter 6)]. The structure ofthe benzoxazine inhibitor efavirenz (121), which differs significantlyfrom earlier agent points up to the wide structural divergence among thisclass of antiviral agents. Acylation of p-chloroaniline (112) with pivaloylchloride affords the corresponding amide (113). Treatment with butyl-lithium followed by ethyltrifluoroacetate introduces the required trifluoro-acetyl group (114). Acid hydrolysis then removes the pivaloyl group toafford the free amine (115). This function is then protected from reagentsin the rest of the sequence by alkylation with p-methoxybenzyl bromide(116). The key reaction in the sequence involves stereospecific additionof the cyclopropylacetylene moiety. Thus, addition of the lithium acetylidefrom cyclopropylacetylene to the trifluoromethyl group in 117 in the pre-sence of the substituted ephedrine derivative 118 proceeds with high enan-tiomeric excess (ee). Reaction of the thus-obtained aminoalcohol (119)with phosgene closes the benzoxazine ring (120). The methoxybenzyl


group is then removed under reductive conditions. This last reaction affordsefavirenz (121) as a single enantiomer.19

Cl

NH2

112

ClOC(CH3)3Cl

NHCOC(CH3)3

113

1. BuLi

114

Cl

NHCOC(CH3)3

O

CF3

HCl

115

Cl

NH2

O

CF3

116

ClO

CF3

117

Li

NC6H5

OH

118

OCH3

Cl

NH

OH

F3C

COCl2

OCH3

NH

OCH3

Cl

OCH3

Cl

N

F3C

O

O

119120

Ce(NO3)2NH4NO3

Cl

NH

F3C

O

O

2. CF3CO2C2H5

121

The structural promiscuity of the estrogen receptors has led to the devel-opment of a host of nonsteroidal agonists and antagonist. Nonsteroidalcompounds that bind to either progestin or androgen receptors have, onthe other hand, proven far more elusive, arguably because of the morerigid structural demands at those sites. A benzoxazine has very recentlybeen found to act as a potent agonist at progesterone receptors bothin vitro and in vivo. Molecular modeling suggests that the benzoxazinemoiety in this compound fulfills the role of the steroid AB rings whilethe pyrrole fulfills the role of the D ring in progesterone.20 Constructionof the benzoxazine starts with the Grignard reaction of anthranilate 122with methylmagnesium bromide. Treatment of the product (123) withcarbonyl diimidazole closes the oxazole ring 124. In a convergentscheme, reaction of N-protected imidazole 125 with butyllithium followedby trimethyl borate affords the boric acid derivative 126. Condensation ofthis acid with benzoxazole 124 in the presence of the palladium/triphenyl-phosphine catalyst affords the coupling product 127. Treatment of 127 withisocyanosulfonyl chloride adds the required cyano function to the pyrrole128. The protecting group on the imidazole is then removed by means ofsodium ethoxide. The free amine is next methylated by means of methyl


iodide in the presence of potassium carbonate. The final step involvesconversion of the carbonyl group to its sulfur equivalent. Treatment of129b with Lawesson reagent from phosphorus sulfide (P4S10) andanisole, then affords the nonsteroidal progestin tanaproget 130.20

122

BrOCH3

NH2

O

CH3MgBr

123

BrOH

NH2

CDIBr

O

NH

O

124

1. LDA

2. B(OCH3)3

N

OCOt Bu

B(OH)2

126

Pd(Ph3P)4

O

NH

O

N

BuOt CO

127

N

OCOt Bu

125

ClSO2NCOO

NH

O

N

BuOtCO

128

NCNaOEtO

NH

H

O

N

129a

NC

Lawesson

O

NH

S

N

130

NC

H3C

O

NH

O

N

129b

NC

CH3I

K2CO3

H3C

B. Quinazolines

Benign prostatic hypertrophy (BPH) comprises an annoying though hardlylife-threatening condition that faces many men as they age. As the anti-hypertensive agent prazocin came into widespread use, reports began toaccumulate of relief of BPH symptoms by patients who were taking thisa-2 sympathetic blocker These reports were later substantiated by formalclinical trials. Detailed pharmacology then revealed that a-2 sympatheticreceptors occur in the prostate. The relief from BPH symptoms is nowattributed to the blockade of those receptors. This discovery was followedby the introduction of compounds targeted specifically at this new indi-cation. The a-2 blocker alfuzocin (139), shares the quinazoline moietywith prazocin and some of its later analogues. One arm the convergentsynthesis to this agent starts with acylation of amine 131 with the ethoxy-carbonate derivative (132) of tetrahydrofuroic acid to afford amide 133.Hydrogenation then reduces the cyano group to the correspondingprimary amine 134. Preparation of the quinazoline moiety first involvesreaction of the dicarbonyl compound 135 with phosphorus oxychloride


to afford the dichloro derivative (136). Treatment with ammonia results inthe displacement of the more labile halogen to give the monoamine (137).Reaction of this last intermediate with the future side-chain amine 134under more forcing conditions, leads to displacement of the remainingring halogen. Thus the a-2 blocker 139 is obtained.21

NH

NH

CH3O

CH3O

O

O

131

POCl3

N

NCH3O

CH3O

Cl

Cl

132

NH3

N

NCH3O

CH3O

NH2

Cl

133

NCNH

CH3

OC2H5OCO

ONC

CH3

O

O

NH2

CH3

O

O

NH2N+

134

135 136 137

N

NCH3O

CH3O

NH2

CH3

O

O

NNH

139

The particularly good activity against protein kinases of a-aminoquin-azoline derivatives is borne out by their activity against both in vitro andin vivo models of human tumor. The seven compounds that followreflect the large amount of research that has recently been devoted tothis structural class.

In the first example, nitration of the benzoate (140) with nitric acidaffords the nitro derivative. Hydrogenation converts this to the anthranilate(141). In one of the standard conditions for forming quinazolones, thatintermediate is then treated with ammonium formate to yield the hetero-cycle (142). Reaction of 142 with phosphorus oxychloride leads to the cor-responding enol chloride (143). Condensation of 143 with m-iodoaniline(144) leads to displacement of chlorine and consequent formation of theaminoquinazoline (145). Reaction with the trimethylsilyl derivative ofacetylene in the presence of tetrakis-triphenylphosphine palladium leadsto replacement of iodine by the acetylide. Tributylammonium fluoridethen removes the silyl protecting group to afford the kinase inhibitorerlotinib (146).22


O

O

CO2C2H5RR

140

1. HNO3

2. H2

R = CH3OCH2CH2–

O

O

CO2C2H5R

R

141

NH2

HCO2–

NH4+

O

O

R

R

142

N

NH

O

O

O

R

RN

N

Cl

[POCl]3

143

Si(CH3)3

Pd(Ph3P)4

O

O

R

RN

N

HN

O

O N

N

146

HN

144H3CO

H3CO

H2N I

144

I

145

1.

2. Bu3N+F

–

O

O

The nucleophile-accepting acrylamide group in the kinase inhibitorcanertinib (154) may lead to covalent binding of that group to sites on theenzyme and thus irreversible inhibition. The starting quinazolone (147) isavailable by some scheme such as that above. The carbonyl group is firstconverted to its enol chloride (148) by means of phosphorus oxychloride.

N

NHF

O2N

O

POCl3

147

N

NF

O2N

Cl

148

F

Cl

H2N

FCl

149

N

NF

O2N

HN

150

N OHO

N

O

151

F

Cl

N

NO

R2N

HN

152; R = O

153; R = H

N

O

F

Cl

N

NO

O

HN

COCl

NH

154

Displacement of this halogen by the amino group of the substituted aniline(149) then affords intermediate 150. The labile fluoride on the quinazoline


benzene is next displaced with the alkoxide from the morpholylpropylalcohol (151) to afford the ether 152. Catalytic hydrogenation servesto reduce the nitro group to the corresponding amine (153). Acylation ofthe newly formed amine with acryloyl chloride completes the synthesisof 154.23

The preparation of yet another variant on the theme starts with quina-zolone (155). Treatmment with methanesulfonic acid selectively cleavesthe ether at the more electron-rich position to give the phenol (156).This functional group is then acylated by means of acetic anhydride(157). The ring carbonyl group is next converted to the enol chloride(158), in this case by means of thionyl chloride. Condensation with thesame aniline used in the previous example leads to the secondary amine(159). The product is then saponified so as to remove the acetyl group(160). Alkylation of the enolate from treatment of the phenol with basewith the chloropropyl morpholine (161) then affords gefitinib (162).24

N

NHCH3O

CH3O

O

155

N

NHHO

CH3O

O

CH3SO3H Ac2O

N

NHCH3CO2

CH3O

O

SO2Cl

156157

N

NCH3CO2

CH3O

Cl

158

H2N

FCl

N

NRO

CH3O

HN

F

Cl

149

159; R = CH3CO

160; R = H

N

O

N ClO

N

NO

CH3O

HN

F

Cl

162

161

A somewhat different strategy is used to prepare vandetanib (171). Thestarting material in this case is analogous to 155 above with the ether andfree phenol ring oxygen atoms reversed. The ring nitrogen in this moleculeis protected as its pivaloyloxymethyl (POM) derivative, a group that isstable to most conditions, but can be selectively cleaved by ammonia.Mitsonobu coupling of the free phenol 163 with the alcohol oxygen onhydroxymethyl piperidine (164) leads to the ether (165). The t-BOC pro-tecting group on piperidine nitrogen is then removed with mild base 166.Reductive alkylation of the newly revealed amine with formaldehyde andborohydride then affords the N-methylated derivative (167). The POM pro-tecting group is then cleaved with ammonia (168). The quinazolone carbo-nyl is next converted to the enol chloride with thionyl chloride (169).


Displacement of that halogen by the amine on the aniline (170) adds thefinal ring affording 171.25

N

NCH3O

HO

O

163

OCOC(CH3)3

+ N

OH

tBuOCO164

Ph3P

DEADN

NCH3O

O

OCOC(CH3)3

NO

R165; R = tBuOCO

166; R = H

HCHONaB(OAc)3H

N

NCH3O

O

OCOC(CH3)3

N

O

H3C 167

NH3

N

NHCH3O

O

NO

H3C 168

SO2Cl

N

NCH3O

Cl

NO

H3C169

F Br

H2N

F Br

170 N

NCH3O

N

O

H3C171

HN

The structures of two recent quinazoline kinase inhibitors feature asomewhat different substitution pattern from the preceding compounds.Lapatinib (182), for example, features single side chain on the fusedbenzene ring; that group is, however, more complex than those in theearlier examples. Preparation of the ring that will attach at the 1 position

N

NH

O

I

N

N

Cl

I

176

O2N

Cl OH

BrF

172 173

+1. K2CO3

R2N

Cl OF

174; R = O 175; R = H 177

N

NI

HN

Cl OF

178

PdOAc2 Ph3P

O B(OH)2O = HC

179

N

N

HN

Cl OF

OO = HC

180


of the quinazoline involves first alkylation of the nitrophenol (172) with thebenzyl bromide (173) to afford the ether (174). The nitro group is nextreduced to the corresponding aniline. In a convergent sequence the quina-zolone (177) is then converted to its enol chloride (176). Reaction of theaniline (175) with the enol chloride leads to displacement of halogenand formation of 178. Suzuki coupling of this product with the furanboric acid (179) in the presence of the usual palladium catalyst attachesthe furyl aldehyde group to the fused benzene ring (180).

The aldehyde group on the newly attached furan ring is then used tofurther elaborate the side chain. Thus reductive amination of the carbonylgroup with ammonia leads to primary amine 181. This newly introducedfunction is next alkylated with 2-methylsulfonylethyl chloride. There isthus obtained the kinase inhibitor 182.26

N

N

HN

Cl OF

OO = HC

180

N

N

HN

Cl OF

O

181

H2NNH3

CH3SO2CH2CH2Cl

NaB(OAc)3H

N

N

HN

Cl OF

O

182

SO2

HNH3C

The preceding compounds all featured a more or less complex aromaticamine attached to the heterocyclic part of the quinazoline. Aliphatic nitro-gen by way of contrast occupies that position in the inhibitor tandutinib(189). Alkylation of the phenolic function in 183 with 3-chloropropyltosylate affords the ether (184) from displacement of the tosyl group.Reaction with nitric acid gives the ortho nitro derivative (185). Catalytichydrogenation then reduces this to the corresponding amine. Treatmentof this intermediate with formamide then adds the requisite atoms forforming the quinazoline ring. The carbonyl group is then converted tothe enol chloride (187) by means of thionyl chloride. The sequencedeparts from previous schemes by the use of an alycyclic amine in thenext step. Thus, the reactive enol halogen atom is displaced by the freeamine in the monoacylated piperazine to afford 188. Reaction of the


product with piperidine under somewhat more forcing conditions withreplaces the terminal chlorine on the ether-linked side chain to completethe synthesis of 189.27

183

CH3O

HO

CO2C2H5

185; R = O 186; R = H

ClOTs

184

CH3O

O

CO2C2H5 1. HNO3

2. SnCl2

CH3O

O

CO2C2H5

NR2

1, HCONH2

2. SO2Cl

CH3O

O N

NH

Cl

187

NH

NO

HN OCH(CH3)2

CH3O

O N

NH

N

N

OHN OCH(CH3)2

ClCl

ClCl

CH3O

O N

NH

N

N

OHN OCH(CH3)2

N

188

189

Piperidine

C. Miscellaneous Benzo-Fused Heterocycles

Aldose reductase inhibitors are expected to protect long-term diabeticpatients from the consquences of the accumulation of sorbitol that is oneof the consequences of the disease [see lidorestat (Chapter 7)]. A quinazo-lodione provides the nucleus for another potential drug in this class. Thesequence for the preparation of this agent starts with the heterocycle(190), which is in essence simply the cyclic carbonate of the correspondinganthranilic acid. Heating the compound with the substituted benzylamine(191). Result in formation of the ring-opened amide with loss of carbondioxide 192. The ring is close again this time as a quinolodione (193);the requisite carbonyl carbon is restored by means of carbonyl diimidazole.The anion from reaction of this last intermediate with sodium hydride isthen alkylated with ethyl bromoacetate. Saponification of the ester com-pletes the preparation of zenarestat (194).28


NH

O

Cl

O

O

190

+H2N

F

Br

191

NH2Cl

O

NH

F

Br

192

CDI

NH

Cl

O

N

F

BrO

193

NCl

O

N

F

BrO

1. BrCH2CO2C2H5

2. NaOH

CO2H

194

Fluid accumulation is one of the graver consequence of congestive heartfailure as this excess blood volume places additional strain on the weak-ening heart. The hormone vasopressin also known as antidiuretichormone contributes to this effect. Though diuretics are often used todecrease this the excess fluid these drugs often upset the balance of elec-trolytes in the remaining fluid can thus adversely affect kidney function.Thiazides are, for example, well known to cause excretion of potassium.A recently developed non-peptide vasopressin antagonist has shown prom-ising initial activity in relieving heart failure associated fluid retentionwithout an effect on electrolyte balance. Construction of the benzapinemoiety begins with esterification of anthranilic acid (195) followed byreduction of the nitro group with stannous chloride (196). The aniline nitro-gen is then converted to p-toluenesulfonamide (197). Reaction of 197 withethyl v-chlorobutyrate in the presence of potassium carbonate then givesthe alkylation product 198. Potassium tert-butoxide-catalyzed Claisen con-densation of this diester leads to azepinone 200 as a mixture of methyl andethyl esters resulting from alternate cyclization routes. Strong acid leads tothe transient ketoacid, which the decarboxylates; the toluenesulfonyl groupis lost under reaction conditions to afford the azepinone (201). This lastintermediate is then acylated with the benzoyl chloride 202 to affordamide 203. Catalytic reduction of the nitro group proceeds to the aniline(204). The chain is next extended by acylation of the newly formedamine with o-toluyl choride (205) to give 206. Reduction of


the azepinone carbonyl group with borohydride affords the vasopressinantagonist tolvaptan (207).29

NO2

CO2HCl

2. SnCl2

1 .(CH3)SO4

NH2

CO2CH3ClTsCl

NH

CO2CH3Cl

Ts195 196 197

CO3CH2H5

Cl CO3CH2H5N

CO2CH3Cl

Ts199

198

N

Ts

O CO2RCl

200

tBuOK

HCl

NH

O

Cl

201

NR2

CH3

ClOC

NR2

CH3

1.

2. H2

N

O

Cl

203; R = O 204; R = H

O

NH

CH3N

O

Cl

O O CH3

CH3

CH3

CH3ClOC

NH

N

HO

Cl

O O

NaBH4

206 207

202

205

REFERENCES

1. F. Labrie, Y. Merand, S. Gauthier, U.S. Patent 6,060,503 (2000).

2. V.A. Ashwood, R.E. Buckingham, F. Cassidy, J.M. Evans, E.A. Faruk,T.C. Hamilton, D.J. Nash, G. Stemp, K. Willcox, J. Med. Chem. 29, 2194(1986).

3. W.N. Chan, H.K.A. Morgan, M. Thompson, M. Evans, U.S. Patent 5,760,074(1998).

4. S.L. Kattiger, R.G. Naik, A.D. Lakdawalla, A.N. Dohadwalla, R.H. Rupp,N.J. de Souza, U.S. Patent 4,900,727 (1990).

5. R.G. Naik, B. Lal, R.H. Rupp, H.H. Sedlack, G. Dickneite, U.S. Patent5,284,856 (1994).

6. R.E. TenBrink, M.D. Ennis, R.A. Lahti, U.S. Patent 5,877,317 (1999).

7. M. Roe et al., Bioorg. Med. Chem. Lett. 9, 595 (1999).

8. C.J. Torrance, P.E. Jackson, E. Montgomery, A. Wissner, K.W. Kinzler,B. Vogelstein, P. Frost, C.M. Discafani, Nat. Med. 6, 1024 (2000).


9. S. Evangelista, Curr. Opin. Inevest. Drugs 6, 717 (2005).

10. G.A.M. Giardina et al., J. Med. Chem. 42, 1053 (1999).

11. D.B. Damon, R.W. Dugger, U.S. Patent 6,313,142 (2001).

12. N. Mealy, J. Castaner, Drugs Future 24, 871 (1999).

13. M.G. Venet, P.R. Angibaud, P. Muller, G.C. Sanz, U.S. Patent 6,037,350(2000).

14. P. Angibaud et al., Bioorg. Med. Chem. Lett. 13, 1543 (2003).

15. T. Fujioka, S. Teramoto, T. Mori, T. Hosokawa, T. Sumida, M. Tominaga,Y. Yabuuchi, J. Med. Chem. 35, 3607 (1992).

16. K. Masuzawa, S. Suzue, K. Hirai, T. Ishizaki, U.S. Patent 4,980,470 (1990).

17. J. Prous, J. Graul, J. Castaner, Drugs Future 19, 827 (1994).

18. A. Graul, X. Rabasseda, J. Castaner, Drugs Future 24, 1324 (1999).

19. A.S. Thompson, E.G. Corley, M.F. Huntington, E.J.J. Grabowski,Tetrahedron Lett. 36, 8937 (1995).

20. A. Fensome et al., J. Med. Chem. 48, 5092 (2005).

21. D.M. Manoury, J.L. Binet, A.P.D. Dumas, F. Lefevre-Borg, I. Cavero, J.Med. Chem. 29, 19 (1986).

22. R.C. Schnuur, L.D. Arnold, U.S. Patent 5,747,498 (1998).

23. J.B. Small et al., J. Med. Chem. 43, 1380 (2000).

24. A.J. Barker et al., Bioorg. Med. Chem. Lett. 11, 1911 (2001).

25. L.F. Henenquin et al., J. Med. Chem. 45, 1300 (2002).

26. K.G. Petrov et al., Bioorg. Med. Chem. Lett. 16, 4686, (2006).27. A. Pandey et al., J. Med. Chem. 45, 3772 (2002).

28. M. Hashimoto, T. Oku, Y. Ito, T. Namiki, K. Sawada, C. Kasahara, Y. Baba,U.S. Patent 4,734,419 (1988).

29. K. Kondo et al., Bioor. Med. Chem. 7, 1743 (1999).

REFERENCES 187

CHAPTER 9

BICYCLIC FUSED HETEROCYCLES

1. COMPOUNDS WITH FIVE-MEMBERED RINGSFUSED TO SIX-MEMBERED RINGS

A. Compounds with Two Heteroatoms

The platelet aggregation inhibitors ticlopidine and clopidogrel consist ofsubstitued thienopiperidines, as does the recent entry prasugrel (9).Alkylation of the enolate from treatment of N-(4-chlorobenzyl)piperidine,(1), with sodium hydride with ethyl chloroacetate affords the ketoester (2).Reaction of 2 with hydrogen sulfide leads to formation the thiolactone (3).1

This transform can be rationalized by assuming initial conversion of theketone to a thioenol; the thioenol attacks the ester to close the ring.Reaction of the product would then form the corresponding enol acetate(4). In a convergent sequence, the Grignard reagent from the benzylbromide (5) is added to cyanocyclopropane (6). This afford ketone 7after hydrolysis. Treatment of 7 with NBS leads to formation of the bromi-nated derivative (8). Reaction of this last with the thienopiperidine (4) leadsto displacement of bromine and formation of the alkylation product. Thus 9is obtained.2


189

N

O NaH

H5C2O2C Cl

1

N C6H4Cl

O

H5C2O2C

2

1. H2S

2. H2

NH

S

O

3

NH

S

CH3CO

4

F

Br

+ NC

6

Mg

F

O

N

S

CH3COO

FF

O

Br

NBS

5

7 89

C6H4Cl

g-Aminobutyric acid is the main inhibitory brain neurotransmitter and is thusinvolved in many psychological process. Muscimol (10), the GABA agonistfrom the amanitamushroom, for example, produces inebriation. A close ana-logue, gaboxadrol (15) in which the pendant side-chain amine is closed toform a piperidine is currently being investigated as a sleep aid. The drugreduces insomnia and improves the quality of sleep. The synthesis of thiscompound begins by forming the acetal from 11 by reaction of the com-pound with ethylene glycol. (12). Reaction of this intermediate with hydro-xylamine replaced the ethoxy group in the ester to addord the hydroxamicacid (13). Treatment of that intermediate with acid leads first to hydrolysisof the ketal; reaction of the terminal hydroxyl on the hydroxylamine groupwith the ketone leads to closure to the isoxazole ring. Hydrolysis undermore strenuous conditions frees the piperidine nitrogen to afford 15.3

O

NHH2N

10

NCH3O2C O

CO2C2H5

11

OH

OH

NCH3O2C

O

O

12

NH2OH

NCH3O2C

O

O

13

NH2OH

O

OC2H5

O

HCl

NCH3O2C

14

O

NH

O

HBr

HN

15

O

NH

O

Muscimol

O

The ACE inhibitors, first introduced almost three decades ago, expandedthe means of treating hypertension by providing yet another mechanism forlowering blood pressure. The pioneer drug, captopril, was followed on themarket by well over a dozen other ACE inhibitors. Current researchfocuses on compounds that will inhibit vasopeptidases, a category of

190 BICYCLIC FUSED HETEROCYCLES

endogenous substances that includes not only ACE but a number of otherenzymes involved in regulation of the cardiovascular function. The construc-tion of the bicyclic nucleus for one of these agents starts by forming theamide (18) between trifluoroacetamide-protected cysteine (16) with thedimethylacetal (17). Treatment of that disulfide intermediate (18) withtributylphosphine leads to reduction of the disulfide bond to a thiol ineffect cutting that precursor in two. That transient intermediate 19 is thenimmediately exposed to acid. The sequence that follows can be rationalizedby assuming the thiol exchanges with one of the methoxyl groups on theacetal function to form a seven-membered ring; the remaining acetalmethoxy is then replaced by the amide nitrogen to close the six-memberedring. Note that the carbon atom that results from this transform (20) hasnot changed oxidation state as it consists of the sulfur equivalent of a carbi-nolamine. Saponification of the trifluoroacetyl amide removes that protectinggroup to reveal the primary amine (21). This function is then acylatedwith the2-thioacetyl phenylacetic acid (22). Removal of the protecting groups on thislast intermediate affords the vasopeptidase inhibitor omapatrilat (24).4

CF3COHN S S NHCOCF3

CO2H CO2H

OCH3

H3CO

CO2CH3

OCH3

OCH3

CH3O2C

NH2CF3COHN S S NHCOCF3

H3CO

OCH3

CH3O2C

ONH

O NH

Bu3P

OCH3

H3CO

CO2CH3

HS NHCOCF3

O NHN

S NHCOCF3

CO2CH3

ON

S NH2

CO2CH3

O

N

S

CO2CH3

O

N

O

SCOCH3N

S

CO2H

O

N

O

SHHH

C6H5 CO2H

SCOCH3

16

17

18

19

2021

22

23 24

B. Compounds with Three Heteroatoms

Sleep inducing drugs go back to the very earliest days of medicinal chemistry.The earliest drugs comprise the barbiturates, which though effective had some

1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 191

serious limitations. The benzodiazepines that came along in the 1960s werebetter tolerated though these too had their drawbacks, such as drug hangoverand the propensity to induce dependence. These have now been largelyreplaced by drugs, such as zolpidem. The structures of these drugs share thepurine 6–5 fused rings system found in purines; the placement of ring nitro-gens atoms is usually quite different from that found in purines. The synthesisof a recent example begins with the condensation of the substituted acetophe-none (25) withDMFacetal. This reaction affords the chain-extended enamide(26). The amide nitrogen is then alkylated (27). Reaction of this intermediatewith the aminopyrrazole (28) leads to formation of the fused pyrimidinopyr-razole (29). For bookkeeping purposes, the transform may be visualized toinvolve addition–elimination of the enamide diethylamino group by theamine on the pyrrazole. Imine formation between the carbonyl and pyrrazolering nitrogen then closes the fused ring. The product (29) is next acylatedwiththiazole-carboxylic acid (30) in the presenceof aluminumchloride (31). Thus,indiplon (31) is obtained.5

O

HN

O

25

(H3C)2N

OCH3

O

HN

O CH3I

NaH

N(CH3)2

O

N

O

N(CH3)2

CH3

NHN

H2N

26 27

28

N

O

CH3

N

NN

29

SClOC

30

AlCl3

N

O

CH3

N

NN

O

S

31

The enzyme, purine nucleoside phosphorylase (PNP), is directlyinvolved with blood levels of T-cells. Low levels of this enzyme willinhibit T-cell proliferation. Drugs that inhibit the enzyme can also beexpected to act against proliferation of malignant T-cells. The PNP inhibi-tor forodesine (36) has shown early activity against T-cell malignancies.Treatment of the deazapurine (32) with lithium leads to derivative 33


lithiated on the pyrrole ring. Condensation of that species with the highlyprotected aminosugar (34) results in addition of the anion to the iminefunction on the sugar. Deprotection of that product (35) in several stepsthen affords 36.6

N

N

N

OCH3C6H5CH2OCH2

BuLi N

N

N

OCH3C6H5CH2OCH2

Li

N

O O

TbdmsO

Tbdms = t Bu(CH3)2Si–

N

N

N

OCH3C6H5CH2OCH2

HN

O O

TbdmsO

Bu4N+F+

H3O+

N

N

HN

OH

HN

HO OH

HO

H2

32 33

34

35

36

The pteridine, folic acid, comprises one of the essential factors requiredfor synthesis of DNA and by extension cell proliferation. As a result, folateantagonists have been intensively investigated as potential antitumorcompounds. The pteridine-based antagonist methotrexate, which was devel-oped many years ago, simply comprises folic acid in which the side-chainamine is methylated and nitrogen replaces the oxygen atom at the 4 pos-ition. This drug is widely used as an antitumor compound. Methotraxatein fact comprises the “M” in the acronym of the many multidrug cocktailsused by oncologists. Most of the more recent folate antagonist, as exempli-fied by palitrexate (202) and pelitrexol (213) described later in this chapter,retain the two fused six-membered rings found in folic acid and replace theside-chain amine group by a methylene group. Contraction of one of therings, is interestingly consistent with folate antagonism. The first fewsteps in the construction of the nucleus of pemetrexed (46) follow awell-precedented scheme. Reaction of the enolate from ethyl cyanoacetate(37) with the methyl acetal from bromoacetaldehyde (38) leads to the alky-lation product (39). Condensation of 39 with guanidine then forms the pyr-imidine (40). The transient side-chain aldehyde from treatment of thecompounds with acid then forms an imine with the adjacent amino group,thus closing the fused five-membered ring (41). The remaining primary


amino group is then protected as its tert-butyl carbamate (42). Reaction of 42with iodo sucinimide proceeds to form the 3-iodo derivative (43).

C2H5O2C

NC

37

Br(H2CO)2HC+

NaOC2H5

38

C2H5O2C

NC

39

H2N

NH2

NH

HN

NH2N

O

NH2

CH(CH3O)2

CH(CH3O)2

40

HCl

HN

NH2N

O

41

NH

t BuCOClHN

NtBuCOHN

O

42

NH

NIS

NIS = N -iodosuccinimide

HN

NtBuCOHN

O

NH

43

I

The key step in this synthesis comprises grafting the benzenzamido-glutamate moiety found in folic acid onto the heterocycle. Thus, conden-sation of the iodo-substituted (43) with acetylide (44) catalyzed bytetrakis-triphenylphosphine palladium affords the coupling product (45).The triple bond is then converted to the saturated bridge by catalytichydrogenation. Saponification then removes the protecting group and atthe same time hydrolyzes the esters on the glutamate fragment to afford 46.7

NH

O

CO2CH3

44

+43

NH

O

CO2CH3

Pd(Ph3P)4HN

NtBuCOHN

O

NH

45

1. H2

HN

NH2N

O

NH

46

HN

O

CO2H

2. NaOH

CO2CH3

CO2CH3

CO2H

N

N N

NN

NH2

H2N

NH

O

CO2H

CO2H

CH3

Methotrexate


C. Compounds with Four Heteroatoms

The A1 adenosine receptors fulfill a largely inhibitory role. Research hasthus recently focused on agonist with structures based on adenosineitself as agents that will overcome responses due to inappropriate exci-tation, such as tachycardia and some arrhythmias. Replacement of one ofthe hydrogen atoms on the exocyclic amine in adenosine by a tetrahydro-furyl group provides an effective A1 adenosine agonist. Preparation of thisfragment as a single enantiomer starts with a modern version of the Curtiusreaction. Thus, reaction of tetrahydrofuroic acid (47) with triphenyl-phosphoryl azide leads to isocyanate (48). Treatment of this intermediatewith benzyl alcohol then affords the corresponding carbamate (49).Catalytic hydrogenation removes the benzyloxy group leading to the freeprimary amine 50. The product is then resolved by way of its camphorsul-fonyl salt to afford 51. Reaction of this intermediate with desamino chloro-adenosine (52) affords tecadenoson (53).8

O CO2H

47

Ph2PON3

O NCO

48

C6H5CH2OH

O OCH2C6H5NH

O

49

H2

O NH2

50

Resolve

O NH2

51

N

N N

N

HO

OHHO

Cl

52

N

N N

N

HO

OHHO

O NH

53

Another approach to preparing A1 adenosine receptors agonists involvesconverting the hydroxymethyl group on the sugar moiety to an amide inaddition to adding a substituent to the amine of adenosine. The startingmaterial (56) is arguably obtainable by oxidation of inosine acetonide(54), followed by acetylation of the hydrolysis product. Reaction of theacid (55) with thionyl chloride followed by ethanol affords the correspond-ing ethyl ester (56). The ring oxygen on this intermediate is next replacedby chlorine by means of phosphorus oxychloride to yield 57. Reaction of57 with cyclopentylamine displaces the halogen to form the cyclopentyla-mino derivative (58). Treatment with triethylamine under somewhat morestrenuous conditions effects ester–amide interchange to form theamide; the acetyl protecting groups are cleaved under those reaction


conditions. Thus, the A1 adenosine receptors agonist selodenoson isobtained (59).9

N

N N

N

HO

OH

O O

54

N

N N

N

HO2C

OH

C2H5OCO OCOC2H5

55

1. SO2Cl

2. C2H5OH

N

N N

N

OH

C2H5OCO OCOC2H5

56

O O

POCl3

N

N N

N

Cl

C2H5OCO OCOC2H5

O O

N

N N

N

NH

C2H5OCO OCOC2H5

O O

57

NH2

58

CH3CH2NH2

N

N N

N

NH

HO OH

HN O

59

Yet another modification leading to an adenosine agonist involves con-version of one of the amino groups on the fused pyrimidine ring of adeno-sine to a pyrazole. The synthesis begins with the conversion of guanosineto its 50 acetate by reaction with acetic anhydride. The hydroxyl at the4 position is replaced by chlorine in the usual manner by treatment withphosphorus oxychloride to afford 61. In a variation on the Sandmeyer reac-tion, this last intermediate is allowed to react with amyl nitrite in the pre-sence of methylene iodide in an aprotic solvent. The low concentration ofnitrite ion from decomposition of its amyll ester serves to diazotize theamine; the diazonium intermediate then captures iodine from the otherreagent to form the iodo derivative (62). Reaction of 62 with ammoniainterestingly proceeds selectively at the 4 position on the purine toafford 63. Treatment of this product with hydrazine, presumably undermore strenuous conditions, displaces iodine to form 64. Condensation of64 with carbethoxymalonaldehyde (65) then affords the pyrazole ring,


the product from formation of an imine from each aldehyde (66).Replacing the ester with an amide by ester interchange with methylaminecompletes the synthesis of regadenoson (67).10

N

N N

N

OH

H2N

OHO

HO OH

60

1. Ac2O

2. POCl3

CH2l2

N

N N

N

Cl

H2N

OCH

3CO

2

HO OH

61

C5H

11ONO

N

N N

N

Cl

I

OCH

3CO

2 CH3CO

2

HO OH

62

NH3

N

N N

N

NH2

I

O

HO OH

63

N

N N

N

NH2

NH

O

HO OH

64

H2NNH2

H2N

CH=O

CH=OC

2H

5O

2C

65

N

N N

N

NH2NH

2

NH2

OCH

3CO

2

HO OH

66

N

N

CH3NH

2

N

N N

N

OCH

3CO

2

HO OH

67

N

N

O

OC2H

5

O

CH3CO

2

One of the most fruitful approaches for designing antiviral compoundscomprises administration of false substrates that will halt replication of theviruses. Such agents will bring replication to a stop in the event they aremistaken for the real thing. This strategy was validated some decadesago by the antiviral agent acyclovir in which the sugar moiety is replacedby an open-chain surrogate. Phosphorylation comprises one of the firststeps in incorporation of a nucleoside into DNA or RNA. Replacing thephosphate by an analogous function that is mistakenly taken up by thevirus, but cannot be further processed, comprises yet another strategy forhalting viral replication. The HIV reverse transcriptase inhibitor tenofovir(78), combines both those strategies in a single molecule. As a first step,hydroxy ester 68 is protected by reaction with THP to form the correspond-ing ether (69). The ester function is the reduced to the alcohol (70) bymeans of Selectride. The newly formed alcohol function is then activatedtoward displacement by conversion to its tosylate (71). Reaction of 71 withadenine (72) attaches the much abbreviated side chain to the five-membered ring (73). The exocyclic amine function is then protectedas its benzamide (74) by means of benzoyl chloride and the THPgroup removed with aqueous acid. The alkoxide from reaction of thislast intermediate (75) with sodium hydride is next alkylated with thetosyl derivative of methyleneisopropyl phosphate (76) to afford themethylene phosphoryl product (77). Removal of the protecting groupscompletes the synthesis (78).11


OHO

O

THPO

O

THPO

68 69

THP = tetrahydropyrranyl

Selectride

OH

70

CH3C6H4SO2Cl

N

N NH

N

NH2

N

N

N

NH2

THPO

N

OTHP

71

72

73

H3 O+ C6H5COClN

N

N

NHCOC6H5

OTHP

N

N

N

NHCOC6H5

OH

74

P

O

OO iPr

i PrCH3C6H5SO3

P

O

OO iPr

iPr

NaH

N

N

N

NHCOC6H5

O

O3SC6H4CH3

THPO

P

O

OO H

H

N

N

N

NH2

O

75

7778

76

N N

NN

Replacement of one of the carbon atoms in the sugar moiety by oxygen,in effect converting that ring to an acetal, leads to yet another false sub-strate for viral reverse transcriptase. Glycosilation of the silylated purine(79) with chiral dioxolane (80), prepared in several steps from anhydro-mannose, in the presence of ammonium nitrate affords the couplingproduct as a mixture of anomers. The mixture of products is then separatedon a chromatographic column. The desired diastereomer (81) is the reacted

N

N N

N

Cl

F

Si(CH3)3

+O

Ot BuPh3SiO

OCOCH3

7980

N

N N

N

Cl

F

O

OtBuPh3SiO

tBuPh3SiO

81

NH3

N

N N

N

NH2

H2N

O

O

83

Bu4F

N

N N

N

Cl

NH2

O

OtBuPh3SiO

82

N

N N

N

NH2

H2N

O

OHO

84

NH3


with ammonia to afford the product (82) from replacement of fluorine.Reaction of this intermediate with ammonia under more strenuousconditions replaces chlorine (83). Treatment 83 with fluoride ionremoves the silyl protecting group to afford the reverse transcriptase inhibi-tor amdoxovir (84).12

The surrogate sugar moiety in the antiviral omaciclovir (90) like that inacyclovir, consists of an open-chain alcohol. The presence of two hydroxylgroups more closely mimics the structure of a sugar than does the sidechain in the latter. This agent shows good activity against varicelazoster, the cause of chicken pox and shingles. The scheme for preparingthis compound differs from the preceding example in that the pendantgroup is attached via a Michael reaction. Thus reaction of the purine(85) with exomethylene glutarate (86) in the presence of base leads toconjugate addition of purine nitrogen to the double bond (87). The carbox-ylates are next reduced to the corresponding alcohols by means of boro-hydride to afford 88 as a mixture of enatiomers. Reaction with ammoniathen replaces chlorine on the purine by nitrogen to afford the diamine(89). This intermediate is then treated with the enzyme adenosine deami-nase immobilized on a solid support. The enzyme preferentially reactswith the isomer in which the stereochemistry of the secondary hydroxylgroup more closely resembles that in the furanoside in a natural nucleosideconverting the amine at the 4 position to a hydroxyl group. Separation ofthat from unreacted starting material affords 90.13

N

N NH

N

Cl

H2N

+

85

CO2H

CH3O2C

86

NaOH N

N N

N

Cl

H2N

CO2H

CH3O2C

87

LiBH4N

N N

N

Cl

H2N

OH

HO

88

N

N N

N

NH2

H2N

OH

HO

89

Enzyme

N

N N

N

OH

H2N

OH

HO

90


The concept of inhibiting cell growth by providing false substratesin fact well predates its application to antiviral agents. The first HIVreverse transcriptase drug, zidovudine (AZT) was actually first preparedas a potential anticancer agent. An enzymatic reaction provides aone-step entry to the antileukemia compound nelarabine (94). Thusreaction of 6-methoxyguanine (91), with uracyl arabinoside (92) in thepresence of the enzymes uridine phosphorylase and purine nucleotidephosphorylase in effect transfer the sugar from the pyrimidine to thepurine, yielding 93.14

N

N NH

N

OCH3

H2N

91

+

HN

N

O

O

O

OHHO

HO

92

EnzymesN

N N

N

OCH3

H2N

+

HN

NH

O

O

O

OHHO

HO

93

94

The antitumor chemotherapy agent clofarabine (104) sports halogenon the purine as well as on the sugar. The major portion of the synthesisinvolves preparation of the requisite fluorine-substituted furanose (101).The sequence begins with the conversion of the only free hydroxyl inallofuranose bis(acetonide) (95) to its tosylate (96). This group is thendisplaced by fluorine in its reaction with potassium fluoride to afford(97). Acid hydrolysis then removes the two acetonide protecting groups.Reaction with benzoyl chloride proceeds to form the benzoate ester(98) from the most sterically accessible hydroxyl group. Treatment of98 with periodate cleaves the 2,3 vicinal diol to form a transient inter-mediate, such as 99. What had been formerly one of the side-chainhydroxyl groups then forms an acetal with one of the newly revealed alde-hydes to afford the new furanose (100) (the product from attack on theother carbonyl would be a dioxolane, which would reopen under reactionconditions). Reaction with acetic anhydride converts the anomerichydroxyl to its acetate. That group is then replaced by the betterleaving group bromine by means of hydrogen bromide (101).Glycosylation of the trimethylsilylated purine (102) leads to the couplingproduct (103). Ammonia then replaces chlorine at 4 by an amine and atthe same time removes the benzoyl protecting group. Thus, clofarabine(104) is obtained.15


N

N N

N

Cl

Cl

N

N N

N

Cl

Cl

OC6H5CO2

O

O

O

O

O

HO

95

CH3C6H4SO3Cl O

O

O

O

O

TsO

96

KFO

O

O

O

O

F

1. H2SO4

2. C6H5COCl

O

OH

OH

HO

C6H5CO2

F

KIO4CH=O

CH=OO

HO

C6H5CO2

F

97

9899

OC6H5CO2

HO F

OH

1. Ac2O

2. HBr

OC6H5CO2

HO F

Br

100

101

SI(CH3)3102

HO F

NH3

N

N N

N

NH2

Cl

OHO

HO F

103 104

Nerve cells are known to elaborate proteins that guide early developmentof the nervous system and in later life play a role in cell repair and regen-eration. A purine that crosses the blood–brain barrier has shown activitysimilar to those endogenous factors in vitro as in in vivo models of nervedamage. Conjugate addition of adenine to ethyl acrylate in the presenceof base leads to the ester (106). Reaction of that product with sodium

N

N

NH

N

NH2

105 CO2C2H5

CO2C2H5

N

N

N

N

NH2

106

1. NaNO2

CO2H

N

HN

N

N

O

107

2. NaOH

O

NO2

F3C

O

108

N

HN

N

N

O

O

O

NO2

109

CO2H

CO2C2H5

H2N

110

2. NaOHN

HN

N

N

O

O

NH

111


nitrite in the presence of acid converts the amino group at the 4 position tothe corresponding hydroxyl derivative. Saponification then leads to the freecarboxylic acid, shown as its keto tautomer (107). The acid is next esteri-fied with trifluoroacetyl nitrophenol (108) in order to provide that functionwith a good leaving group (109). Ester–amide interchange with ethylp-benzoate (110) displaces nitrophenol to form the corresponding benza-mide. Base hydrolysis of the terminal ester then affords leteprinim (111).16

The xanthine theophylline has been used for well over a century fortreating asthmatic episodes by relaxing the constricted bronchioles thatare part of attacks. The discovery of the role of the phosphodiesteraseenzyme (PDE) by Sutherland in the early 1960s helped explain themode of action of this drug. Research over the past few decades has ledto the identification of a large number of subtypes of PDE receptors.Theophylline, for one, was found to interact mainly with PDE IV recep-tors. The relatively narrow therapeutic index of this drug has led to the con-tinued search for better tolerated agents. The synthesis of a recent examplestarts with nitrosation of the pyrimidinedione (112) with sodium nitrite inthe presence of acid to yield 113. Reduction of the newly introducednitroso group with sodium dithionite leads to the 1,2-diamine (114).Reaction of 114 with formamide closes the fused imidazole ring. Thus,the PDE IV inhibitor arofylline (115) is obtained.17

Cl

N

N

O

NH2O

112

NaNO2

HCO2H

Cl

N

N

O

NH2O

113

NO

NaS2O2

Cl

N

N

O

NH2O

114

NH2

Cl

N

N

O

NO

115

HN

HCONH2

Replacing the hydrogen atom on the imidazole ring of a purine with alarge lipophillic group effects a major change in the biological activity.The resulting compounds are no longer PDE inhibitors, but instead act asadenosine receptor antagonists. The first of these, istradefylline (120), selec-tively blocks A(2A) receptors and in addition inhibit monoamine oxidase B(MAO-B). The neuroprotective action of this agent in animal models forParkinson’s disease has been attributed to this mixed activity. Reaction ofthe diamine (116), with the dimethoxy cinnamic acid (117) in the presenceof a diimide leads to the formation of a mixture of the amides formedbetween the acid and one of the two amines on the pyrimidine (only one,118, is shown). Heating that mixture with sodium hydroxide leads to cycli-zation, forming the xanthine (119). The free amine on the fused imidazole isthen alkylated with methyl iodide in the presence of base to afford 120.18


N

N

O

NH2

NH2

116

O

+OCH3

OCH3

HO2C

117

EDAC

EDAC = 1-ethyl-3-(3-dimethylaminopropyl) carbodimide

N

N

O

NH2

NH

118

O OCH3

OCH3

O

NaOH

N

N

OHN

NO OCH3

OCH3

119

CH3I

K2CO3

N

N

O

N

NO OCH3

OCH3

120

CH3

Substitution by a somewhat complex bridged biyclic moiety provides acompound that acts as an adenosine A1 receptor antagonist. These ubiqui-tous receptors, which are involved in regulating oxygen consumption andthe flow of blood in cardiac tissue, generally suppress those functions. Anantagonist would thus be potentially useful for treatment of congestiveheart failure. The xanthine portion of this molecule is constructed muchas that in the previous case. Thus, acylation of the diamino pyrimidine (121)with acryloyl chloride in this case affords a single amide (123). Reactionwith base then closes the imidazole ring. Diels–Alder condensation of thevinyl group on this ring with cyclopentadiene proceeds to form the bridgedbicyclic system (125). Oxidation of the isolated double bond on that newlyformed moiety with (MCPBA) then affords the oxirane (126). Thus theadenosine antagonist naxifylline is obtained.19

N

N

O

NH2

NH2

121

O

+ ClOC

122

N

N

O

NH2

NH

O

O

123

NaOH N

N

OHN

NO

124

N

N

OHN

NO

125

MCPBA

N

N

OHN

NO

126

O


Adding yet another large substituent to the imidazole ring restores PDEinhibiting activity. The resulting compound dasantafil (137) blocks PDE 5and thus joins the growing list of agents that address erectile disfunction.The synthesis of this compound begins with the formation of the reductiveamination product (129) from anisaldehyde (128) and glycine. Thisproduct is then treated with reagent 130, obtained from reaction of triethylorthoformate and cyanamide in the presence of strong base. For bookkeep-ing purposes formation of the imidazole (131) can be rationalized byassuming initial addition–elimination of the amine in 129 to the reagent130; addition of the enolate from 129 to the nitrile then closes the ring.Condensation of the product (131) from this reaction with diethylcarba-mate again in the presence of strong base forms the pyrimidinedionering to afford the xanthine (132) after neutralization. The nitrogen atposition 1 is next alkylated with bromoethyl acetate (133). Reaction of 133

OCH3

O=HC

1.H5C2OCCH2NH2

OCH3

H5C2O2C

2. NaBH4

128

CH(OC2H5)3+NCNH2

NH

129 130

OCH3

N

NHO

H2N

O

131

tBuOK

NCN

OC2H5

1. C2H5NHCO2C2H5

tBuOK

2. AcOH

OCH3

N

NN

NH

O

O

132

OCH3

N

NN

N

O

O

BrCH2CH2OAc

OAc

K2CO3

133

NBS

OCH3

N

NN

N

O

O

OAc

Br

134

BrOH

H2NOH

OCH3

N

NN

N

O

O

OAc

Br

136

NH

NaHCO3

OH

OCH3

N

NN

N

O

O

OH

Br

137

NH135

with NBS results in bromination on both the aromatic ring and the carbonon the fused imidazole ring (134). Displacement of the latter bromine atomwith chiral aminocyclopentanol (135) completes construction of the


skeleton (136). Saponification of the acetate group on the pendant sidechain then affords the PDE V inhibitor 137.20

Moving one of the imidazole nitrogen atoms found in xanthines into thering junction provides the nucleus for another PDE 5 inhibitor. The othersubstituents in this compound more closely resemble those found insildenafil (aka Viagra) than those used in dasantafil. The convergentscheme starts with the acylation of alanine (138) with butyryl chloride.The thus-produced amide (140) is again acylated, this time with the halfacid chloride from ethyl oxalate in the presence of DMAP and pyridineto afford intermediate 141. In the second arm of the scheme, the benzoni-trile (142) is reacted with aluminate 143, itself prepared from trimethyl-aluminum and ammonium chloride, to form the imidate (144). Treatmentof 144 with hydrazine leads to replacement of one of the imidate nitrogenatoms by the reagent in an addition–elimination sequence to form145. Condensation of 145 with 141 leads to formation of the triazine(146). Phosphorus oxychloride then closes the second ring to afford 147.Reaction of this last intermediate with chlorosufonic acid affords thecorresponding sulfonyl chloride. Treatment of this compound withN-ethyl piperazine forms the sulfonamide and thus vardenafil (148) isobtained.21,22

O

CN

142

AlCH3ClNH2

Al(CH3)3 + NH4Cl

143

O

144

NH2

NH

H2NNNH2

O

145

NH

NH

NH2

HO2C

138

+ClOC

139

TMSCl

Et3N

NH2

HN

HO2C

O

ClOC2H5

O

ON

HO2C

O

C2H5O

O

O

140 141

O

N

HN

N

O

NH

O

O

146

POCl3

O

N

HN

N

O

N

O

N

HN

N

O

N 1. ClSO3H

N

SO

O

N

147N

HN

2.

148


The peptide hormone, glucagon-like peptide (GLP-1), which isreleased in response to intake of food, regulates insulin levels. Thehormone, in the normal course of events, exerts only momentaryactivity as it is quickly inactivated after its release by a dipeptidal pep-tidase (DPP). Inhibitors of that degrading enzyme should thus lead topersistent levels of GLP-1. The search for small molecule inhibitorsof DPP that prolong the action of GLP-1 has consequently been thefocus of research for finding alternate methods for controlling Type 2diabetes. Construction of the heterocyclic nucleus (153) begins withthe displacement of chlorine in pyrazine (149) with hydrazine toafford 150. Acylation with trifluoroacetic anhydride proceeds on themore basic terminal nitrogen to afford the trifluoroacetohydrazide(151). Treatment of this intermediate with polyphosphoric acid leadsthe enol form of the amide to undergo addition–elimination with thepyrazine nitrogen and to form the new fused ring (152). Catalytichydrogenation proceeds to selectively reduce the six-membered ringto afford the triazolopyrazine (153).

N

N

149

ClH2NNH2

N

N

150

HN

NH2 (CF3CO)2O N

N

151

HN

NH

O CF3

PPAN

NN

N

CF3

152

H2N

HNN

N

CF3

153

In the other arm of the convergent scheme, the bis(lactam) enol ether(154) can be viewed as a latent chiral carboxyl group since the transan-nular isopropyl group will transfer its chirality across the ring to a newentering moiety. Thus, alkylation of the enolate from 154 with the tri-fluorobenzyl chloride (155) yields (156) as virtually a single enantio-mer. Methanolysis of the product followed by bis-t-BOC affords thecorresponding t-BOC protected amino acid. Saponification then yieldsthe carboxylic acid 157. This product is next subjected to Arndt–Eistert homologation. The carboxylate is first converted to its acidchloride with tert-butyl chloroformate. This intermediate affords diazo-ketone 158 with diazomethane. Treatment with silver benzoate causesthis reactive species to rearrange to the homologated ester (159). Theacid (160) obtained on saponification is then coupled in the presenceof a diimide with the heterocyclic nucleus 153 to afford the amine161. Removal of the t-BOC protecting group from 105 with strongacid completes the synthesis of sitagliptan (162).23


N

N

OCH3

OCH3 F

F

F

Br

F

FF

154

155N

N

OCH3

OCH3

1. H3O+

2. t-BOC2O

F

F

F

OH

NH t-BOC

NH t-BOCNH t-BOC NH t-BOC

NH t-BOC

O

156

3. LiOH

1. i BuOCOCl

2. CH2N2

F

F

F

O

PhCO2Ag

N2

157

158

F

F

F

CO2CH3

159

CH3OH

LiOH

F

F

F

CO2H

160

153

NN

N

CF3

F

F

F

N

161

HCl

NN

N

CF3

F

F

F

NH2

N

162

OO

The majority of nucleoside antiviral agents, as noted previously,inhibit the production of new virions by acting as false substrates forthe enzymes that synthesize viral DNA or RNA. The nucleoside-likecompound, isatoribine (170) has shown activity against hepatitis C, aviral infection unusually refractory to treatment. This agent interestinglyowes its efficacy to its stimulation of the immune system rather than todirect antiviral action. Condensation of the substituted malonate (162)(obtained by alkylation of 2-bromomalonate with 2-trimethylsilyl ethyl-mercaptan) with guanidine affords the pyrimidine (163). The function atthe 4-position is then converted to the corresponding halide by reactionwith phosphorus oxychloride to yield 164. Addition–elimination of thepyrimidine hydroxyl with the aminated sugar (165) adds the requisitesaccharide moiety to the compound 166. The bridging amino group isnext acylated with ethyl chloroformate to yield 167. Treatment of 167with tributylammonium fluoride leads to loss of the silyl group on theterminus of the ethyl mercaptide. The chain on sulfur then collapsesto leave behind an anion on that atom. This ion then displaces the eth-oxide from the carbamate on the proximate nitrogen in effect closing thethiazolone ring; the silyl protecting group on the sugar also cleavesunder reaction conditions to yield the free carbinol (168). The chlorineatom at the 4 position, which has served to protect that function over thepreceding steps, is then replaced with sodium methoxide to form themethyl ether (169). Trimethyl silyl iodide then cleaves that ether to


leave behind a hydroxyl group. Acid hydrolysis then opens the acetonideto afford the immune system stimulant 170.24

CO2CH3

CH3O2C S

162

H2NNH2

NH HN

N

O

S

OHH2N

163

O

O O

tBuMe2SiONH2

POCl3

165

N

N

Cl

NHH2N

O

O O

tBuMe2SiO

166

Si(CH3)3Si(CH3)3 N

N

Cl

S

OHH2N

164

Si(CH3)3

SSi(CH3)3

C2H5OCOCl

N

N

Cl

NH2N

O

O O

tBuMe2SiO

167

SSi(CH3)3

OC2H5

O

Bu3NF

N

N

Cl

NH2N

O

O O

HO

168

S

O NaOCH3

N

N

OCH3

NH2N

O

O O

HO

169

S

O1. (CH3)3SiI

2. H3O+

N

N

OCH3

NH2N

O

HO OH

HO

170

S

O

2. COMPOUNDS WITH TWO FUSEDSIX-MEMBERED RINGS

Benzodiazepines provided the first relatively well-tolerated drugs fortreating anxiety. These drugs were a major advance over the previouslyused barbiturates. A series of side effects, however, became evident overtime as the benzodiazepine gained mass usage. The most common ofthese was habituation, a condition just short of true addiction. The morerecent anxiolytic compounds of the “spirone” class introduced by buspir-one are generally free of those limitations. A compound with a markedlydifferent structure from these agents showed promising activity in animalmodels. The pyridine dicarboxylic acid (171) is first converted to itsacid chloride with thionyl chloride; reaction with methanol then affordsthe ester 172. Catalytic hydrogenation then serves to reduce the pyridinering to a piperidine of undefined stereochemistry (173). Reaction of 173


with chloroacetonitrile affords 174. Treatment of 174 with Raney nickelreduces the cyano group to the corresponding primary amine; thisproduct then undergoes internal ester–amine interchange to yield thecyclized amide 175. Lithium aluminum hydride then serves to reducethe amide to an amine; the ester on the other ring is converted to a carbinolin the process, affording the amino alcohol (176). The basic function isnext alkylated with 2-chloropyrimidine (177). Reaction of the alcoholin 178 with methanesulfonyl chloride leads to the mesylate; this group isnext displaced by means of sodium azide and the newly introduce azidegroup reduced to the primary amine. Resolution of this last product asits mandelate salt then yields 179 as a single enantiomer. Reaction of179 with succinic anhydride converts the pendant amine to a succinimideaffording the anxiolytic agent sunepitron (180).25

N

CO2H

HO2C

171

SOCl2

CH3OH

N

CO2CH3

CH3O2C

172

H2

NH

CO2CH3

CH3O2C

173

CN

Cl CN

N

CO2CH3

CH3O2C

174

Ni

NCH3O2C

175

NH

O

LiAlH4N

176

NH

HO

N

NN

NClN

178

N

HO

1. CH3SO2Cl2. NaN33. N2H44. Resolve N

N

N

179

N

H2N

N

N

N

N

H H

180

N

O

O

O

O

O

177

The principal metabolite of one of the more recent antipsychotic drugs,risperidone, has significant dopamine blocking activity in its own right. Asis often the case, where a metabolite has the same effect as the ingesteddrug, this opens the possibility that the metabolite is responsible for theobserved effect. Condensation of acetoacetamide (182), arguably availablein several steps from risperidone intermediate 181,26 with the cyclicimidate (183) affords the metabolite as its O-methyl ether 184. Cleavageof that ether, for example, with boron tribromide, would then affordpaliperidone (185).27

2. COMPOUNDS WITH TWO FUSED SIX-MEMBERED RINGS 209

NO NH

181

NO N

182

O

NH2

O

N

NH2

183

OCH3

F F

NO N

O

N

F

N OCH3

NO N

O

N

F

N OH

184185

The structure of a recent quinolone antibiotic differs from the majorityof those agents in the nature of the substituent on the fused aromatic ring;the inclusion of nitrogen in that ring is unusual though not unprece-dented. This structural feature in fact harks back to the very firstquinolone, nalidixic acid, as well as the compound nofloxacin, whichled to the revival of this field some two decades ago. Synthesis of thenovel side-chain amine comprises the larger part of the preparation ofthe quinolone antibiotic gemifloxacin (196). The sequence starts withconjugate addition of glycine ethyl ester 186 to acrylonitrile. Reactionof 187 with strong base leads to addition of the enolate adjacent to thenitrile to the ester carbonyl to afford the pyrrolidinone (188). Theamine is then protected as its tert-butoxycarbamate (189) by reactionwith bis-t-BOC. Treatment with sodium borohydride serves to reducethe ring carbonyl to the alcohol. The cyano group is next reduced tothe corresponding primary amine by means of lithium aluminumhydride and this new function then also protected as its tert-butoxycarba-mate (191). Oxydation of the ring alcohol with the sulfur trioxide:pyridine complex restores the ring carbonyl group (192). This functionis then converted to its methoxime (193) by reaction withO-methylhydroxylamine. Treatment with acid then removes the tert-butoxycarbamate protecting groups to reveal the basic amino groups(194). Reaction of 194 with the often used quinolone starting material195 results in displacement of chlorine by the more basic of the twoamino groups in 194. Thus, the antibiotic 196 is obtained.28


186

C2H5O2C NH2 + CN C2H5O2C NH

187

NaH NHO

NC

188

NC

(t BuOC)2ONCOt Bu

O

NC

189

1. NaBH4

NCOt BuHO

NC

190

1. LiAlH4

2. (t BuOC)2O

NCOt BuHO

191

t BuOCNH

SO3.PyNCOt BuO

192

t BuOCNH

NCOtBuN

193

t BuOCNH

CH3ONH2

CH3O

CH3CO2H NHN

194

H2N

CH3O N N

F

Cl

OCO2H

N N

F

O

CO2H

N

H2N

CH3O

195

196

The search for better tolerated folate antagonist antitumor agentscontinues to produce yet more variants on methotrexate [see pemetrexed(46) for structure]. The analogue pralatrexate (202) retains most of thefeatures of the prototype, but replaces the side-chain tertiary amine by a

N

N N

N

NH2

H2N

CO2H

CO2H

CO2CH3

H3CO2C

197

+

Br

KH

CO2CH3

H3CO2C

198

Br

199

N

N N

N

NH2

H2N

CO2CH3

H3CO2C

200

NaOH

heat

N

N N

N

NH2

H2N

CO2H

N

N N

N

NH2

H2N

1. Diethylglutamate2. NaOH

201

202

2. COMPOUNDS WITH TWO FUSED SIX-MEMBERED RINGS 211

methylene–propargyl group. Alkylation of the enolate from dimethylho-motetrephthalate (197) with propargyl bromide attaches that group to thebenzylic carbon to yield 198. Reaction of the enolate from that com-pound with the bromomethylpteridine (199) yields the alkylationproduct 200. Saponification of the esters in that product that leads tothe free acid. The carboxyl group on the tertiary benzylic carbon decar-boxylates on heating to yield the key intermediate 201. This compound isthen converted to a folate-like compound by reaction of the acid chloridewith diethylglutamine. Saponification of diethylglutamine yields the freeacid and thus 202.29

A more recent example omits one of the nitrogen atoms in the pteridinering and replaces the linking benzene ring of the side chain by thiophene.The convergent synthesis begins with the palladium-catalyzed coupling ofthe brominated pyridopyrimidone (203) with trimethylsilyl acetylene toafford the ethynyl derivative 203. The silyl protecting group is thenremoved to afford 204. In the second arm of the scheme, thiophene-carboxylic acid (205) is treated with bromine to afford the brominatedderivative 206. The carboxylic acid is then esterified with ethanol toyield 207. Palladium-catalyzed coupling of the thiophene derivative(207) with the ethynyl derivative 204 then affords 208. Catalytic hydrogen-ation reduces both the acetylene bond and the heterocyclic ring to which itis attached to afford 209 as a mixture of enatiomers.30


The fact that the final compound will contain chiral atoms at two remotelocations on the fused piperidine ring and on the yet-to-be added gluta-mine moiety adds complications to the preparation of an enantiometricallypure product. The problem was solved by resorting to the use of enzymes.The first step comprises treatment of intermediate 209 with base to hydro-lyze the ester. The secondary amine on the fused piperidine ring is thenconverted to an oxamate (210) by reaction with the half acid chloride ofethyl oxalate. The glutamate side chain is then added (211). Digestion ofthis intermediate with a lipase from Candida antarctica selectively hydro-ylizes the terminal ester on the glutamate of the (S ) enantiomer allowingthis compound to be easily separated from its epimers. Base hydrolysisof this compound then provides pelitrexol (213).31

HN

N N

O

tBuCOHN

SCO

2H

H3C

COCl

COC2H

5

OO

OC2H

5

HN

CO2C

2H

5

CO2C

2H

5HN

N N

O

t BuCOHN

S

H3C

OO

OC2H

5

2091.NaOH

2.Et-L-glutamine

EDC

EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodeimide hydrochloride

210 211

Enzymatic

HN

CO2C

2H

5

CO2H

HN

N N

O

t BuCOHN

S

H3C

OO

OC2H

5

NaOHHN

CO2H

CO2H

HN

N NH

O

H2N

S

H3C

212213

O

OO

3. MISCELLANEOUS COMPOUNDS WITH TWO FUSEDHETEROCYCLIC RINGS: BETA LACTAMS

The overwhelming majority of semisynthetic beta-lactam antibiotics, thepenicillins and cephalosporin, currently available to physicians tracetheir origins to the intense research effort devoted to this field severaldecades ago. The emergence of pathogens resistant to those antibioticshas led some laboratories to revisit this field. The modified cephalosporinceftobiprole (220), a compound with a rather complex extended sidechain, has shown activity in the clinic against some strains of multidrugresistant bacteria. The synthesis starts with the well-precedented acylationof the of the cephalosporin (215), available in several steps from the com-mercially available 7-acetoxy cephalosporanic acid, with the activated

3. MISCELLANEOUS COMPOUNDS WITH TWO FUSED HETEROCYCLIC RINGS 213

thiadiazole carboxylic acid (214). The hydroxyl group in the product (216)is then oxidized with manganese dioxide to afford the correspondingaldehyde (217). This product is condensed with the bis(pyrrolidyl phos-phonium) salt (218), itself protected with the complex carbonate (219).Removal of the several protecting groups then affords the highly modifiedcephalosporin 220.32

S N

NH2N O

N

O

OSi(CH3)3

P(OC2H5)2

SN

S

O

H2N

OH

CO2CHPh2

N

S

OOH

CO2CHPh2

S N

NH2N

N

O

OSi(CH3)3

MnO2

N

S

O CH=O

CO2CHPh2

S N

NH2N

N

O

OSi(CH3)3

NNH

O

N

S

OCO2H

S N

NH2N

N

O

OH

NN

OPh3P

+

R

O

OO

O

214

+

215216

217

218

220 R =

219

NH

NH

HN

Yet another recent beta-lactam active against multidrug resistantorganisms is based on the “unnatural” carbapenem nucleus first usedfor the antibiotic imipenem. The preparation of the side chain startswith the protection of the nitrogen in hydroxyproline (221) as its diiso-propyl phosphoryl derivative (222). The carboxyl is then activated as themixed anhydride (223) by reaction with diphenylphosphinic anhydride.The ring hydroxyl is next converted to its mesylate (224) by reactionwith methanesulfonyl chloride. Treatment of 224 with sodium sulfideserves to replace phosphorus on the carboxyl group by sulfur (225).Under somewhat basic reaction conditions, the sulfide anion slowly dis-places the transannular mesylate group to form a bridged thiolactonering. The stereochemistry at the new carbon sulfur bond is inverted inthe process (226). This intermediate is then treated with 3-aminobenzoicacid. The thiolactone now opens to form amide 228 thus completing theside-chain. The requisite beta-lactam intermediate 229 is perhaps surpris-ingly available commercially. Reaction of that with the side-chainintermediate (228) leads to replacement of phosphorus by the side-chain thiol function. Removal of the protecting groups then affords thecarbapenem ertapenem (230).33


NH

HO

CO2H

221

N

HO

CO2H

POi PrO

i PrO

222

(Ph2PO)2O

N

HO

POi PrO

i PrO

223

POPh2

O

CH3SO2ClN

CH3SO2

POi PrO

i PrO

224

POPh2

O

Na2+S

–

N

CH3SO2

POi PrO

i PrO

225

S–

ON

S

POi PrO

i PrO

226

O

CO2H

H2N CO2H

227N

HS

POi PrO

i PrO

HN

O

228

N

HO

O

O P

Ph

Ph

O

OO

O2NC6H4CH2

CO2H

NH

HN

O

N

HO

O

S

HOO

229 230

REFERENCES

1. J.-P. Maffrand, N. Suzuki, K. Matsubayashi, S. Ashida, U.S. Patent 4,424,356(1984).

2. J. Brandt, N.A. Farid, J.A. Jakubowski, K.J. Winters, World Patent 2004/098713 (2004).

3. P. Krogsgaard-Larsen, U.S. Patent 4,301,287 (1981).

4. J.L. Moniot et al., U.S. Patent 6,162,913.

5. R.S. Gross, K.M. Wilcoxen, R. Ogelsby, U.S. Patent 6,472,528.

6. G.B. Evans, R.H. Fourneaux, V.L. Schramm, V. Singh, P.C. Tyler, J. Med.Chem. 47, 3275 (2004).

7. E.C. Taylor, D. Kuhnt, C. Shih, M. Rinzel, G.B. Grindey, J. Barredo,M. Jannatipour, R.G. Moran, J. Med. Chem. 35, 4450 (1992).

8. R.T. Lum, J.R. Pfister, S.R. Schow, M.M. Wick, M.G. Nelson,G.F. Schreiner, U.S. Patent 5,789,416 (1998).

9. H.C. Williams, W.C. Patt, U.S. Patent 4,868,160 (1989).

10. J.A. Zabocki, E.O. Elzein, V.P. Palle, U.S. Patent 6,403,567.


12. R.F. Shinazi, U.S. Patent 5,444,063 (1995).

13. P. Engelhardt, M. Hogberg, N.-G. Johanssen, X.-X. Zhou, B. Lindborg, U.S.Patent 5,869,493 (1999).

14. R.N. Patel, Curr. Opin. Drug Disc. Dev. 9, 744 (2006).

15. K. Chilman-Blair, N.E. Mealy, J. Castaner, Drugs Future 29, 112 (2004).

REFERENCES 215

16. A. Graul, J. Castaner, Drugs Future 22, 945 (1997).

17. A.V. Averola, J.M.P. Soto, J.M. Mauri, R.W. Gristwood, U.S. Patent5,223,504 (1993).

18. J.P. Petzer, S. Steyn, K.P. Castagnoli, J.-F. Chen, M.A. Schwartzschild,C.J. Van der Schyf, N. Castagnoli, Bioor. Med. Chem. 11, 1299 (2003).

19. L. Belardinelli, R. Olsson, S. Baker, P.J. Scammells, U.S. Patent 5,466,046(1995).

20. V.A. Dahanukar, H.A. Nguyen, C.A. Orr, F. Zhang, A. Zavialov, U.S. Patent7,074,923 (2006).

21. H. Haning, U. Niewohner, T. Schlenke, M. Es-Sayed, G. Schmidt, T. Lampe,E. Bischoff, Bioorg. Med. Chem. Lett. 12, 865 (2002).

22. For alternate methods, see P.J. Dunn, Org. Proc. Res. Dev. 9, 88 (2005).

23. D. Kim et al., J. Med. Chem. 48, 141 (2005).

24. M.G. Goodman, E.P. Gamson U.S. Patent 5,166,141 (1992).

25. G.N. Bright, K.A. Desai, U.S. Patent 5,122,525 (1992).

26. D. Lednicer, “The Organic Chemistry of Drug Synthesis”, Volume 5, JohnWiley & Sons, Inc., NY, 1995, p. 151.

27. C.G.M. Janssen, A.G. Knaeps, E.J. Kennis, J. Vandenberk, U.S. Patent5,158,952 (1992).

28. C.Y. Hong, Y.K. Kim, J.H. Chang, S.H. Kim, H. Choi, D.H. Nam, Y.Z. Kim,J.H. Kwak, J. Med. Chem. 40, 3584 (1997).

29. J.I. DeGraw, W.T. Colewell, J.R. Piper, F.M. Sirotnak, J. Med. Chem. 36,2228 (1993).

30. E.Z. Dovalsantos, J.E. Flahive, J.B. Halden, M.B. Mitchell, W.R.L. Notz,Q. Tian, S.A. O’Neil-Slawecki, World Patent, WO2004113337 (2004).

31. S. Hu, S. Kelly, S. Lee, J. Tao, E. Flahive, Org. Lett. 8, 1653 (2006).

32. P. Hebeisen, H. Hilpert, R. Humm, U.S. Patent 6,504,025 (2003).

33. K.M. Brands et al., J. Org. Chem. 67, 4771 (2002).


CHAPTER 10

POLYCYCLIC FUSEDHETEROCYCLES

A number of compounds defy ready assignment to one of the structuralcategories that have been used to organize the agents described so far inthis volume. The structures of the agents in this chapter, except for ofthe two camptothecins, have little in common with each other beyondthe fact that they do not fit previous categories. The bibliographic detailson several compounds indicate that they were first prepared as much asthree decades ago. They appear here because they were granted a nonpro-prietary name relatively recently.

1. COMPOUNDS WITH THREE FUSED RINGS

Some of the very earliest antitumor compounds incorporated in their struc-ture a bis(chloroethylamino) moiety, a group often referred to as a nitrogenmustard. This quite reactive group kills cells by alkylating DNA, and ineffect inactivating this genetic material by forming covalent cross-linksbetween the bases. Alkylating activity is, however, not restricted toDNA as these highly reactive agents attack many other tissues. Drugsthat include this moiety are, as a result, associated with a veritable hostof very serious side effects. The indiscriminate killing action of alkylating


217

agents is not restricted to eukaryotic cells; the compounds also inactivatemicrobes. A recent nitrogen mustard-containing compound is proposedfor use ex vivo to inactivate pathogens in blood transfusion supplies. Theacridine portion of amustaline (6) is intended to intercalate in DNA, awell-known property of this structural element, and thus bring themustard to the intended site of action. Excess drug that is not complexedcan be expected to be destroyed by blood enzymes or even by simplehydrolysis. This will minimize exposure to unreacted mustard by apatient who received treated blood. Construction of this agent starts by dis-placement of chlorine from 9-chloroacrdine (1) by the terminal amine on aso-called b-alanine ester (2) in the presence of sodium methoxide.Saponification then yields the corresponding acid (3). Esterification ofthe carboxyl group with triethanolamine (4) leads to the ester (5). Thefree hydroxyl groups on this intermediate are then replaced by chlorineby reaction with thionyl chloride. Thus, 6 is obtained.1

N

Cl

1

N

H2N OC2H5

O

2

+

1. NaOCH3

2. NaOH

N

HN OH

O

OH

OH

HON OH

OH

N

HN O

O

NCl

Cl

N

HN O

O

SO2Cl

3

4

56

Increased awareness and the rising incidence of Type 2 diabetes amongthe aging population has led to the search for alternate drugs to the tra-ditional hypoglycemic agents for treating the disease. Agents, such as vida-gliptin (Chapter 5) and sitagliptan (Chapter 9) represent antidiabetic agentsfor that act by mechanisms that differ significantly from the traditionaldrugs. A naphthothiophene moiety provides the nucleus for a drug thatacts as an insulin sensitizer. This compound in addition acts as a peroxisomeproliferator activated receptor agonist (PPAR). In broad terms this agent

218 POLYCYCLIC FUSED HETEROCYCLES

activates liver enzymes that metabolize fatty acids thus lowering serum tri-glyceride levels. Reaction of the lithio reagent from 2,3-dimethylthiophene(7) with benzaldehyde leads to the carbonyl addition product (9). Thebenzylic hydroxyl is next removed by hydrogenation over palladium toyield 10. This intermediate is then treated with the substituted benzoylchloride (11) in the presence of stannic chloride to afford the productfrom acylation on the carbon with highest electron density, thus yieldingthe thiophene (12). Exposure of 12 to boron tribromide in the cold leadsto formation of a new ring; the methyl ether on the pendant benzene ringis cleaved to the corresponding phenol in the process (13). The enolatefrom treatment of that phenol with potassium carbonate with the a-bromoester (14), affords the corresponding alkylation product as a mixture ofenantiomers. Saponification of the ester affords corresponding carboxylicacid. Resolution as its salt completes the synthesis of ertiprotafib (15).2

S+

O=HC

8

BuLi

S OH

9

H2

S

10

OCH3

COCl

11

SnCl4

S

O

H3CO

12

BBr3

S

OH

13

CO2H

BrCO2CH31.

2. LiOH3. Resolve

S

O

15

14

7

A compound whose structure bears some slight resemblance to 15, basedon a phenoxazine nucleus, also shows PPAR activity and increases sensi-tivity to insulin as well. The synthesis of the side chain begins withEmmons–Smith condensation of benzaldehyde 16 with the ylide fromphosphonate 17 and base to afford the enol ether 18 as a mixture ofisomers. Hydrogenation of the resulting intermediate reduces the doublebond and at the same time removes the benzyl group to afford the freephenol (19). Reaction of this compound with a hydrolase enzyme leads toselective hydrolysis of the ester, which leads to the (S ) enantiomer (20).This kinetic resolution affords the acid as a virtually single stereoisomer.The carboxyl group is then protected for the next step as its isopropyl ester(21). In a convergent scheme, the anion on nitrogen from phenoxazine

1. COMPOUNDS WITH THREE FUSED RINGS 219

proper (22) and butyllithium is treated with ethylene oxide. The hydroxylgroup on the end of the ethyl group in 23 is next converted to its mesylate(24). Displacement of this newly introduced leaving group by the phenoxidefrom 21 and potassium carbonate leads to the alkylated derivative 25.Saponification of the terminal ester then yields ragaglitazar (26).3

NH

O

BuLi

O

N

O

OH

CH3SO3Cl

N

O

CH3O2SO

CH=O

OC6H5CH2

O

CO2C2H5(C2H5O)2PO

C6H5CH2

CO2C2H5

O 1. H2HO

CO2C2H5

O

Enzyme

HO

CO2H

O

HO

CO2CH(CH3)2

O

N

O

CO2CH(CH3)2

O

N

O

CO2H

O

NaOHK2CO3

16 1819

20

21

22

23 24

2526

17O

i PrOH

tBuOK

OO

Irritable bowel syndrome (IBS) is said to rank among the largest causesfor physician office visits. There are, in spite of this, very few means fortreating this very prevalent condition. The newly approved indication forthe recently introduced 5-HT serotonin antagonist tegoserod (see Chapter7) comprises one of the first specific treatments for IBS. Acylation of theindole (27) with trichloroacetyl chloride affords the ketone (28).Treatment of that intermediate with methanolic base leads to loss of the tri-chloromethyl group via the haloform reaction with concomitant esterifica-tion of the carbonyl group 29. The benzyl protecting group is thenreplaced by acetyl with successive hydrogenation and reaction of the result-ing phenol with acetic anhydride (30). Reaction of 30 with NCS leads tointroduction of chlorine at the 2-position on the indole ring (31). This lastintermediate is then treated with 3-chloropropan-1-ol in the presence ofmethylsulfonic acid, which forms the oxazine ring (32). Though the exactsequence is unstated, this reaction involves replacement of chlorine on theindole by oxygen and subsequent displacement of side-chain chlorine byindole nitrogen. The acetyl function on the phenol, having served its


function, is next replaced by benzyl with successive saponification, and thenalkylation of the resulting phenol with benzyl bromide (33). Heating 33 withthe substituted piperidine (34), exchanges the methyl group on the ester withthe primary amino group in 34 to form the corresponding amide (35).Catalytic hydrogenation then cleaves the benzyloxy group to yield the freephenol and thus the serotonin 5-HT receptor antagonist piboserod (36).4

NH

C6H5CH2O

27

Cl3COCl

NH

C6H5CH2O

28

OCCl3

NHC6H5CH2O

29

OOCH3

CH3OH

NaOH

1. H22. Ac2O

NHCH3CO2

30

OOCH3

NCS

NHCH3CO2

31

OOCH3

ClNCH3CO2

32

OOCH3

OHO Cl

1. NaOH

2. C6H2CH2Cl

C6H5CH2O

33

OOCH3

O

NHC4H9NHC4H9H2N

C6H5CH2O

35

O

O

NHC4H9

HO

36

O

OH234

DABCO

DABCO = 1,4-Diazabicyclo[2,2,2]octane

N N N

HN

HN

The pituitary hormone arginine vasopressin (AVP) plays a pivotal rolein regulating blood volume. Broadly speaking, excessive release of thehormone will cause the kidneys to reabsorb water and thus increaseblood volume. The AVP antagonist would thus be useful in treatingdisease marked by excessive water retention, such as congestive heartfailure. A pyrrolobenzazepine forms an important part of a non-peptideAVP antagonists. Acylation of the known pyrrolobenzazepine (37) with

NH

N

37

+ClOC

38

N

N

Cl

Cl

ONO2

NR2

39; R = O40; R = H

N

N

Cl

O

NH

F

ClOC

F

41O

42


the nitrobenzoyl chloride 38 proceeds in straightforward fashion to theamide (39). Reduction of the nitro group by means of hydrogenation orstannous chloride affords the corresponding aniline (40). Acylation of thenewly formed amino group with the benzoyl chloride (41) then affordslixivaptan (42). An alternate approach assembles the full side chain andthen attaches that to the heterocycle 37.5

Antiandrogens have proven very useful in treating BPH, an all too fre-quent accompaniment of aging. These agents, in addition, have a minorplace in the treatment of prostatic cancer. They are also, on a moretrivial note, used to reverse hair loss due to male pattern baldness. Drugsthat act as antiandrogens, such finasteride and dutasteride (Chapter 2),generally act by inhibiting the enzyme 5-a-reductase, which converts pre-cursors, such as testosterone, to their active form by reducing the doublebond at the 4-position in the steroid A ring. These drugs, formallyderived from steroids, all retain the bulk of the precursor nucleus. A pairof more recent, closely related, compounds retain the lactam A ring ofthe steroid-derived agents, but replace steroid rings C and D by a simplearomatic ring. These agents retain the 5-a-reductase activity and have asa result been tested in the clinic as potential agents for treating cancer ofthe prostate. The first step in the synthesis of bexlosteride (49) comprisesconversion of the tetralone (43) to its enamine by reaction with pyrrolidine.Reaction of 44 with a large excess of acrylamide under carefully controlledconditions leads to formation of the unsaturated lactam (45). The sequencecan be rationalized by assuming that the first step comprises conjugateaddition to the acrylamide; displacement of the pyrrolidine by amide nitro-gen completes ring formation. The double bond at the ring fusion is nextreduced with triethylsilane in the presence of trifluoroacetic acid. Thus,the saturated lactam that consists largely of racemic isomer with the trans

Cl

O

Cl

N

CONH2

Cl

NH

O

Cl

NO

43 44 4546

HCl

Cl

HNCH3O2C

CH3

47

Cl

HNCH3O2C

CH348

CH3

1. Et3SiH

2. CH3Cl

Cl

NO

49

CHR

H

H

Separate

Resolve

CH3OH

Na2CO3


ring fusion. The amide nitrogen in the product, which still contains a smallamount of cis isomer, is next alkylated with methyl chloride in the presenceof base to yield 46. Reaction of that intermediate with methanol opens thelactam ring to yield the corresponding methyl ester 47; the small amountof cis isomer can be separated at this stage since it resists methanolysis.The amino–ester is then resolved via its ditoluyl tartrate salt. Heating theresolved aminoester (48) with sodium carbonate then regenerates thelactam ring to afford 49.6

The scheme used to produce a somewhat more complex 5-a-reductaseinhibitor relies on a chiral auxiliary to yield the final product as a singleenantiomer. The first step in a sequence similar to that above, starts with thereaction of bromotetralone (50) with (R)-a-phenethyl amine (51) to affordthe enamine (52). Reaction with methyl iodide adds the methyl group atwhat will be a steroid-like AB ring junction. This product is then treatedwith acryloyl chloride. The initial step in this case probably involves acy-lation of nitrogen on the enamine; conjugate addition completes formationof the lactam ring. Treatment of 54 with triethylsilane then reduces the ringunsaturation and cleaves the benzylic nitrogen bond to yield 55 as the opti-cally pure trans isomer. Displacement of bromine with the mercapto-benzthiasole (56) completes the synthesis of izonsteride (57).7

Br

O

50

C6H5

NH2

H

+

51

Br

C6H5

HN

H52

CH3I

H3C

H3C

H3C

H3C

H3C

H3CH3C

H3C

Br

C6H5

HN

53

COCl

Br

C6H5

N

54

O

Et3SiH

Br

NH

O

55

N S

N S

HSS

NH

O

57

56

H

H

H

H

The aggregation of blood platelets, the prelude to formation of bloodclots, is a very necessary process for preserving the integrity of the circu-latory system. Inappropriate platelet aggregation on the other hand canresult in the formation of clots that block vital organs leading to strokesand heart attacks. Various approaches have been followed in the search


for agents that decrease platelet aggregability: Widely used clopidogrel, forexample, blocks adenosine diphosphate receptors on platelets, newer can-didates, such as the “gartans” (Chapter 1), act further down the line by inhi-biting fibrinogen. The compound at hand apafant (67) antagonizes theaction of the platelet activating factor (PAF), a substance that not onlyinduces platelet aggregation, but is a factor in inflammatory processesand hypersensitivity. Reaction of the b-ketoaldehyde, diester 58 with thebenzoyl nitrile (59) in the presence of sulfur leads to formation of the amino-thiophene (60). Overlooking the diester for the moment, the reaction can berationalized for bookkeeping purposes by assuming condensation of thealdehyde with the activated ketonitrile methylene group, conversion ofthe ketone to a thioketone and addition of that to the cyano group as itsenolate, though not necessarily in that order. Heating the product instrong acid cause the diester in the product to decarboxylate. The resultingacid is then reesterified with methanol (61). Construction of the diazepinering starts by alkylation of the amino group with bromoacetamide in thepresence of base to afford 62. Strong acid, for example, polyphosphoricacid, the causes the side-chain amide nitrogen to react with the ketone toform a cyclic imine affording 63. The ester grouping is then restored and

O

CO2C2H5

58ClO

59

S8

S

O

CO2C2H5

H2N

C2H5O2C

CO2C2H5

Cl

O = HC NC

60

1. HCl

S

OH2N

CO2CH3

Cl

61

2. CH3OH

H2NOC Br

S

OHN

CO2CH3

Cl

ONH2

62

PPAS

CO2H

Cl

63

HN N

O

2. P4S10S

CO2CH3

Cl

64

HN N

S

S

CO2CH3

ClHN N

N

+

CH3CH(OC2H5)3

H2N

S

CO2CH3

Cl

66

N N

N N

H3C

1. CH3OH

S

Cl

67

N N

N N

H3C

N

O

HNO

O

65

N2H4


the amide carbonyl is converted to a thioamide with phosphorus pentoxide64. Reaction of this last intermediate with hydrazine gives the cyclic amino-amidine (65) putting in place the nitrogen atoms of the future triazole ring.Condensation of that product with ethylorthoacetate leads to formation ofthe last fused heterocyclic ring. Ester–amide interchange of this lastproduct with morpholine completes the synthesis of apafant (67).8

The adventitious discovery of the utility of a-adrenergic blockers fortreating benign prostatic hypetrophy led to the introduction of several ofthese agent. The majority of these compounds, for example, alfuzocin(Chapter 8), consist of modified quinazolines. A structurally quite distantheterocyclic compound has been found to have much the same activity atadrenergic receptors in experimental system. This activity extends toa-adrenergic receptors located in the prostate. One arm of the convergentsynthesis starts with the condensation of the anion from dimethylresorcinolwith DMF. Hydrolysis of the initial product then yields the aldehyde.Reaction with aluminum chloride leads to scission of one of the methylethers to give the phenol (68). Heating 68 with acetic anhydride probablyleads initially to formation of the acetylated phenol. The presence of basethen causes the phenol to cyclize to coumarin (69). Condensation of 69with the azomethine ylide from 70 leads to 3 þ 2 cycloadditon to the cou-marin double bond. The presence of the chiral auxiliary a-phenethylamineleads to the formation of the addition product as an essentially single enan-tiomer (71). Reduction of the coumarin carbonyl with lithium borohydridegives the ring-opened hydroxy phenol (72). A mixture of mesylates (phenoland hydroxymethyl) is obtained on treating 72with methanesulfonyl chlor-ide. In the next step, treatment with strong base leads to internal displace-ment of the mesylate closing the ring to afford the correspondingbenzopyran (73). Hydrogenation then cleaves the phenethyl group to afford

OH

OCH3

68

CH=O

O

OCH3

OAc2O

69

N

C6H5

OCH3

H3C

Me3SiN

C6H5

OCH3

H3C

Me3Si–

O

OCH3

O

N

H3CC6H5

71

LiBH4

OH

OCH3

OH

N

H3C

C6H5

72

1. CH3SO2Cl

2. t BuOK

O

OCH3 N

H3CC6H5

73

H2

O

OCH3 NH

74

70


product 74, which contains the secondary amine required for coupling withthe other major fragment.

Synthesis of the second heterocyclic fragment begins with the conden-sation of phenylglyoxal oxime (75) with guanidine to form the pyrazineN-oxide (76). Treatment with triethylphosphine reduces the N-oxide func-tion leading to pyrazine (77). The amino group is next treated with nitrousacid and the resulting diazonium salt reacted with hydrogen bromide toafford the brominated derivative (78). Reaction of 78 with ethyl thioglyco-late in the presence of sodium carbonate arguably begins by displacementof bromine by sulfur to form the transient thioether (79). Addition of theenolate on carbon adjacent to the ester then attacks the cyano group toform the fused thiophene ring 80. The newly formed amine on the thio-phene ring is then converted to the corresponding isocyanate (81), by reac-tion with phosgene.

O

NOH

75

NH2H2N

NH

N

N

O

CN

NH2

76

P(OC2H5)3

N

N CN

NH2

77

HONOHBr

N

N CN

Br

N

N

S

NH2

CO2C2H5

N

N CN

HSCO2C2H5

SCO2C2H5

78

7980

N

N

S

N=C=O

CO2C2H5

81

COCl2

Na2CO3

There remains the task of joining together the two heterocyclic frag-ments. To this end the free secondary amino group on the benzoxazine (74)

N

N

S

O=C=N

C2H5O2C

81

O

OCH3 NH

74

Br CN1.

2. Ni

O

OCH3 NNH2

N

N

S

NH

C2H5O2C

O

OCH3 NHN

O

83

N

N

S

NHN

O

O

O

OCH3

N

84

82


is alkylated with 3-bromopropionitrile; the terminal cyano group is thenreduced to the primary amine by means of Raney nickel (82).Condensation of 82 with the pyridazothiophene (81) leads to addition ofthe amine to the isocyano group to afford the transient coupled urea(83). The urea nitrogen furthest from the ring then displaces the ethoxidefrom the nearby ester group to form a fused pyrimidone ring. Thus, thea1-adrenergic blocker fiduxosin (84) is finally obtained.9

Anthraquinones have been investigated in some detail over the pastseveral decades as sources for antitumor agents. Several compoundswhose structure includes this three-ring fragment have gone as far as theclinic. It has since been established that cytotoxic activity of these com-pounds is due mainly to their activity on topoisomerase 2. The anthra-quinone mitoxantrone, was approved by the FDA close to two decadesago. An analogue in which one of the benzene rings is replaced by pyridine,perhaps not surprisingly, retains antitumor activity. Reaction of the lithioreagent from 4-chlorofluorobenzene (86) with the pyridine equivalent (85)of phthalic anhydride affords the acylation product (87). Treatment withacid leads to internal acylation and formation of the aza-anthraquinone(88). Condensation of this intermediate with the substituted hydrazine(89) leads to formation of the fused pyrrazole (90). The regiochemistry ofthis reaction would suggest that the first step involves displacement ofhalogen and is thus guided by greater ease of replacing fluorine overchlorine; ordinary imine formation then closes the ring. Displacementof chlorine by N,N-dimethylethylenediamine (91) completes the synthesisof topixantrone (92).10

NO

O

O

85

+

Cl

F

86

BuLiN

HCO2

O F

Cl

87

N

O F

ClO

H2N NHNH

OH

N

N

ClO

88

89

NNH

OH

N

N

O

NNH

OH

90

NH2N

HNN

91

92


2. COMPOUNDS WITH FOUR FUSED RINGS

The serious side effects associated with long-term use of dopamine anta-gonist antipsychotic agents have led to the continuing search for bettertolerated drugs. This research has to some extent been encouraged bythe identification of ever more subtypes of dopamine receptors; thisraises the possibility there may be drugs found that act on a subtype recep-tor more specific for treating schizophrenia than for the receptors associ-ated with side effects. Ecopipam (101) which differs markedly instructure from most of the widely used antipsychotic drugs, is specificfor D1 dopamine receptors. Though this compound was found to be notparticularly effective for treating schizoid patients, it does have an effectagainst addictive behaviors. One of several routes to this compoundstarts with the decalin trans aminoalcohol (93). This compound is thenalkylated with the methyl acetal (94) from bromoacetaldehyde. The ringhydroxyl in 95 is then converted to its chlorophenylsulfonate (96). Thisintermediate spontaneously closes to the aziridinium salt (97) by displace-ment of the sulfonate by the adjacent amine. Condensation of 97 withGrignard reagent 98 leads to addition at the tertralin 1 position with con-comitant ring opening to yield 99. Treatment of 99 with strong acidleads to attack of the newly revealed aldehyde on the aromatic ring andthus formation of the azepine ring. The double bond formed in thecourse of this last reaction is then reduced with diborane (100). Scissionof the methyl ether with boron trichloride the affords (101).11

93

NHH3C

OH Br OCH3

OCH3N

H3C

OH

94

95

OCH3H3CO

NH3C

OSO2C6H4Cl

96

CH3O OCH3

N+

OCH3H3CO

97

ClCH3O

ClCH3O

MgBr98

NOCH3

H

H

CH3

CH3 OCH3

99

1. CH3SO3HN

H

H CH32. BH3

100

Cl

CH3O

BCl3N

H

H CH3

Cl

HO

101

Yet another potential antipsychotic drug with an unusual pattern ofreceptor affinity consists of a dibenzoxapine. This compound asenapine


(107) was interestingly first described in a 1979 patent.12 Data on this agentusing more recent pharmacological methods apparently led to its beingpulled off the shelf. Condensation of the acid chloride (102) withN-methylglycine ethyl ester leads to the amide (103). Treatment of 103with potassium tert-butoxide leads the enolate adjacent to the aromaticring to add to the ester at the end of the side chain, thus forming the pyr-rolidine ring (104 ¼ 105). Heating this intermediate (105) in PPA leads toreaction of the ketone carbonyl group with the other aromatic ring to formthe benzoxazine (106). The unsaturation in the seven-membered ring isthen reduced by means of sodium in liquid ammonia leading to theproduct with a trans ring junction. The amide function is then taken onthe amine by means of a metal hydride. Resolution, not described in thepatent, will then afford chiral 107.

O

Cl

102Cl

O

O

Cl

N

O

O

OC2H5

O

ClO

N O

O

ClO

N O

PPA

103104

105

O

Cl

N O

NH

CO2C2H5

[H]

O

Cl

N

H H

106107

tBuOK

The structures of the vast majority of PD-5 inhibitor compounds aimedat erectile dysfunction consist of modified purines. The structure of therecently approved drug for this indication tadalafil (113) differs markedlyfrom the prototypes. Tryptophan methyl ester (108) provides the startingmaterial for large scale enantioselective synthesis. Condensation of thatcompound with piperonal (109) in the presence of acid leads to formationof the tricyclic intermediate (110). This transform involves initial additionof the amine to the aldehyde. The carbocation from the newly formedcarbinolamine then attacks the indole 2-position to form the the fusedpiperidine. The stereochemistry of the new chiral center is guided bythat from the tryptophan carbon across the ring. The secondary amine isnext acylated with chloroacetyl chloride in the presence of triethylamineto afford 111. Reaction of this intermediate with methylamine goes on toform the desired product in a single step. This reaction can be rationalized

2. COMPOUNDS WITH FOUR FUSED RINGS 229

by assuming initial displacement of terminal chlorine by the amine to givethe transient intermediate 112. This amino group then takes part in anester–amide interchange in the presence of base to form the new ring.Thus, 113 is obtained.13

NH

NH2

108

CO2CH3

+

CH = O

OO

109

HClNHN

H

CO2H3

OO

ClOC Cl

110

NNH

CO2H3

OO

111

Cl

O

CH3NH2

NNH

CO2H3

OO

112

NH

O

NNH

OO

113

N

O

O

3. COMPOUNDS WITH FIVE OR MORE FUSEDRINGS: CAMPTOTHECINS

Though the potent cytotoxic activity of camptothecin (114) was recognizedby the middle 1960s, the drug was not used in the clinic until just over adecade ago. The very poor solubility of the compound initially led tothe use in clinics of the ring opened acid. It was later found that theintact lactone was essential for activity. Clinical trials in the early 1990sconfirmed that finding. The mechanism of action of this drug as an inhibi-tor of topoisomerase I sets it aside from many other widely used com-pounds, such as the anthracyclines that act on topoisomerase II.A number of analogues that mainly include the addition of solubilizingfunctions, such as topotecan, lurtotecan, and irinotecan, and havebeen approved for use in patients. An intermediate on the way to acompound that includes a solubilizing amino group has interestinglybeen assigned a nonproprietary name. This compound camptogen (115)is available from the natural product in a single step using classicalnitration conditions.14


N

N O

O

OHO

HNO3

H2SO4

N

N O

O

OHO

O2N

114 115

The production by total synthesis of an analogue that incorporates anadditional fused ring, by way of contrast, includes a good many moresteps. The lengthy synthesis starts with the aluminum chloride-catalyzedacylation of fluorotoluene (116) with succinic anhydride to afford theacid (117). The ketone group is then reduced to methylene by means ofhydrogen over palladium; the acid is then esterified with methanol toyield 118. Reaction with nitric acid proceeds in a straightforward mannerto afford the nitro derivative (119). The ester grouping is then saponified.Heating the resulting acid in polyphosphoric acid results in ring closureand thus formation of a tetralone ring (120). The next few steps establishthe requisite functionality in this newly added ring. This sequence includesformal transfer of the carbonyl group to the alternate benzylic position.

O

O

OHO

F116

O

O

O

AlCl3 F

CO2H

O

1. H2

2. MeOH F

CO2CH3

117 118

HNO3F

CO2CH3

119NO2

1. NaOH2. PPA

F NO2

O1. NaBH42. TsOH

3. H2F NH2

120121

1. Ac2O

2. KMnO4F NHCOCH3

122

OBuONO

F NHCOCH3123

O

NOH

Zn/Ac2O

F NHCOCH3124

O

NHCOCH31. OH–

2. CF3COCl

F NH2125

O

NHCOCF3

O

O

OHO

O

126

F

NHCOCF3

base

127

tBuOK

N

N

N

3. COMPOUNDS WITH FIVE OR MORE FUSED RINGS: CAMPTOTHECINS 231

Sequential reduction of the ketone and dehydration of the resulting alcoholintroduces a double bond. Hydrogenation then both reduces the unsatura-tion and takes the nitro group on to the amine (121). The amino group isthen acylated with acetic anhydride. Reaction with permanganate intro-duces a ketone at the alternate position from that remaining after cycliza-tion (122). Reaction of this last intermediate with butyl nitrite in thepresence of strong base introduces nitrogen at the position adjacentto the ketone in the form of an oxime (123). This group is then reduced tothe corresponding amine by means of zinc in acetic acid and anhydride.This reaction affords the acetamide (124). Sequential hydrolysis ofthe amides followed by acylation with trifluorcacetyl chloride yields theamide (125). This last reaction is apparently specific for the amine adjacentto the ketone, leaving that on the aromatic ring as a free amine. This bicyc-lic compound is then condensed with the known total synthesis intermedi-ate 126, in the presence of acid to afford exatecan (127).15 Again, forbookkeeping purposes, this last transform can be viewed as reaction ofthe ketone in 126 with the aniline nitrogen and condensation of the result-ing enamine with the tetralone carbonyl group.

REFERENCES

1. D. Cook, J.E. Meritt, A. Nerio, H. Rapoport, A. Stassinopoulos, S. Wolowitz,J. Matejovic, W.A. Denny, U.S. Patent 6,514,987 (2003).

2. J.E. Wrobel, A.J. Dietrich, M.M. Antane, U.S. Patent 6,251,936 (2001).

3. S. Ebdrup et al., J. Med. Chem. 46, 1306 (2003).

4. M. Fedouloff, F. Hossner, M. Voyle, J. Ranson, J. Powles, G. Riley,G. Sanger, Bioorg. Med. Chem. 9, 2119 (2001).

5. J.D. Albright et al., J. Med. Chem. 41, 2442 (1998).

6. B.A. Astelford, J.E. Audia, J. Deeter, P.C. Heath, S.K. Janisse, T.J. Kress,J.P. Wepsiec, L.O. Weigel, J. Org. Chem. 61, 4450 (1996).

7. J.R. Audia, L.A. McQuaid, B.L. Neubauer, V.P. Rocco, U.S. Patent5,662,962 (1997).

8. K.H. Weber, Drugs Future 13, 242 (1988).

9. A.R. Haight et al., Org. Proc. Res. Devel. 8, 897 (2004).

10. A.P. Krapcho, E. Menta, A. Oliva, S. Spinelli, U.S. Patent 5,596,097 (1997).

11. D. Hou, D. Schumacher, Curr. Opinion Drug Res. Devel. 4, 792 (2001).

12. J. van der Burg, U.S. Patent 4,145,434.

13. P.J. Dunn, Org. Proc. Res. Devel. 9, 88 (2005).

14. M. Wani, A.W. Nicholas, M.E. Wall, J. Med. Chem. 29, 2358 (1986).

15. H. Terasawa, A. Ejima, S. Ohsuki, K. Uoto, U.S. Patent 5,834,476 (1998).


SUBJECT INDEX

Bold numerals refer to syntheses

Abortion, non-surgical, 32Acamprosate, 15Acne, 37Acolbifene, 163Acyl-CoA: cholesterol acyltransferase,

see ACATAdamantamine, nitration, 84Agonist, adenosine, 195–197Agonist, GABA, 190Agonist, alpha-adrenergic, 69Alagebrium, 102Alcoholism, treatment, 15Alfuzocin, 178Alitretoin, 30Alkylating agent, 12, 218Almotriptan, 146Alniditan, 133Altinicline, 115Alvameline, 109Alvimopam, 117Alvocidib, 165Alzheimer’s disease, 66, 70, 94, 109, 115

Ambrisentan, 126Amdoxovir, 199Amiodarone, 139Amprenavir, 4Amustaline, 218Analgesic, spinal 69Anecortave, 34Angiotensin converting enzyme,

see ACEAngiotensin, 18Angiotensin, antagonist, 112Anticholinergic agent, 49, 56, 70, 87, 170Apafant, 224Apaziquone, 154Aplaviroc, 134Aplindore, 150Apoptosis, 165Aprepitant, 105Arachidonic acid, 22, 48, 59, 80, 90, 143Arecoline, 109Arofylline, 202Arzoxyfene, 155


233

Asenapine, 228Asoprinosil, 32Asthma, treatment, 29, 35, 90, 202Atazanavir, 7Atrasentan, 87Atreluton, 90Atrial natriuretic peptide, 18Avanafil, 127Avasimibe, 56Avitriptan, 146Azepinone synthesis, 19Azetidone synthesis, 67

Bazedoxifene, 145Benign prostatic hypertrophy see BPHBenzimidazole synthesis, 156Benzothiazole synthesis, 144Bexarotene, 76Bexlosteride, 222Bifeprunox, 159Bimatoprost, 24Biricodar, 119Bladder, overactive, see Urinary

incontinenceBlood clots, generation, 16Blood-brain barrier, 63, 69, 74Bortezomib, 133BPH, treatment, 36, 176, 225Brasofensine, 64Breast cancer, 31Buspirone, 207

Calcium, serum levels, 73Camptogen, 230Canabinol receptor, 99Canertinib, 180Canfosfamide, 13Capravirine, 95Carbapenem, 214Cariporide, 57Ceftobiprole, 213Celecoxib, 92Cell-cycle regulation, 133Chemosensitizing agent, 119Chicken pox, 199Chiral adjunct, 27Chiral auxiliary, 51, 85, 86, 94, 106, 174,

177, 207, 223

Cholesterol, absorption, 56, 66, 169Cholesteryl ester transfer protein, (CETP),

169Chronic pulmonary obstructive disease,

see (COPD)Ciclesonide, 36Cilomilast, 30Cimicoxib, 96Cinacalcet, 73Cipemastat, 99Cipralisant, 94Citalopram, 140Clevipidine, 117Clevudine, 130Clofarabine, 200Clofibrate, 45Cloretazine, 14Cobalt carbonyl, annulation, 81Cocaine, 64Collagenase, in rheumatoid arthritis, 97Common cold, 9Conazole antifungals, 94Congestive heart failure, 172, 203Constipation, 24Controversy, RU-486, 32COPD, treatment, 29, 43Corey lactone, 22–24Coupling, acetylene, 194, 212Coupling, arylboric acid, 78, 92COX in inflammation, 92Creutzfeld–Jacob disease, 153Crohn’s disease, 73Cyclooxygenase, see also COX, 91Cyclophosphamide, 12

Dabigatran, 156Dabuzalgron, 52Darbufelone, 99Darfenacin, 87Darunavir, 5Dasantafil, 204Delucemine, 59Diaziquone, 154Diene, protection, 38Dipeptidal peptidase see DPPDisappointment, mild, 61Disufenton, 53DNA gyrase, 173

234 SUBJECT INDEX

Donepezil, 1Dopamine D4 receptor, 166Dopamine, 63, 75Dopamine, partial agonist, 150, 159Doramapimod, 74DPP, in diabetes, 84Dronaderone, 140Dutasteride, 37

Ecalcidene, 38Ecopipam, 228Ecopladib, 147Edonentan, 56Efaproxiral, 45Efavirenz, 177Eicosanoids, 48Elasatase, 54Elzasonan, 136Emesis, 62Emitefur, 127Emivirine, 123Emtricitabine, 132Endometriosis, treatment, 34Enzastaurin, 89Erlotinib, 179Ertapenem, 214Ertiprotafib, 219Estradiol, 31Etalocib, 49Etoricoxib, 117Etravirine, 123Exatecan, 232Ezetimibe, 66Ezlopitant, 62

Fadolmidine, 69Farglitazar, 46Farnesol, 171Fatty acid, oxidation, 44Febuxostat, 10Fibrinogen, receptor, 16Fiduxosin, 227Fisher indole synthesis, 142, 146, 147Flibanserin, 158Flindokalner, 1515-Fluorouracyl, 127Fluoxetine, 61, 64Forodesine, 192

Fosamprenavir, 6Fulvene, 38Fulvestrant, 32

Gaboxadol, 190Gamma-aminobutyric acid, see GABAGarfenoxacin, 176Gatifloxacin, 174Gavistinel, 142Gefitinib, 181Gemifloxacin, 210Gemopatrilat, 19Glaucoma, 22Glucagon-like peptide, in diabetes, 206Glycosylation, 157, 196–201Gout, 100Growth hormone, 153

Hair loss, 36, 51Heck reagent, 92Hemiasterlin, 11Herbicide, corn, 47HIV, 2Hypoxia, solid tumors, 45

Ibrolipim, 44Ibutamoren, 153Iclaprim, 125Igmesine, 64Ileus, postoperative, 117Iludin S, 38Imidazole synthesis, 96, 97Imipenem, 214Incretin, 84Indiplon, 192Indolone synthesis, 150Influenza, avian, 25Inhibition, HMG-CoA reductase, 123

proteasome, 133Inhibitor(PNP), 192ACAT, 56, 66ACE, 18alpha-2-adrenergic, 178, 225canabinol receptor, 99cholinesterase, 66, 109collagenase, 97COX-2, 92

SUBJECT INDEX 235

Inhibitor (Continued )dihydrofolate reductase, 125dopamine hydroxylase, 97dopamine, re-uptake, 63DPP, 83, 84elastase, 54endothelin, 55, 85, 126farnesyl transferase, 171fibrinogen, 16folate, 193, 211–213fungal steroid synthesis, 94GABA, 15glutathione transferase, 13hitsamine H3, 94leukotriene, 48, 49, 90, 99MAO, 71, 202neuraminidase, 26, 28neurokinin, 105, 168NMDA, 13, 39, 59, 142NMDA, 39PDE-4, 29, 43, 202PDE-5, 127, 204, 205, 229phospholipase, 143, 147PKC, 73, 88, 179–184platelet aggregation, 60, 224PPAR, 45protease, mode of action, 2, 3retinoid, 30reverse transcriptase, 95, 122, 131, 197,

198serotonin, 154SSRI, 61, 136, 140, 156Suicide, 9superoxide, 100tachykinin, 62thromboxane A2, 59topoisomerase, 227, 230triptamine HT1D, 132, 146tubulin, 11tumor necrosis factor, 152tyrosine kinase, 148, 167varicela virus, 199vasopeptidase, 190vasopresin, 185viral surface receptor, 107, 134

Inotropic agent, 172Irofulven, 38Isatoribine, 207Isoxazole synthesis, 93

Istradefylline, 202Izonsteride, 223

Kalamazoo, 34Kaposi’s sarcoma, 30

Lacosamide, 14Ladostigil, 71Lapatinib, 182Lasofoxifene, 77Latanoprost, 23Leflunomide, 93Lenalidomide, 153Leprsosy, 152Leteprinim, 202Leukotrienes, 48Lidorestat, 145Lixivaptan, 222Lopinavir, 7Lubazodone, 70Lubeluzole, 160Lubiprostone, 23Lymphoma, T-cell, 76

Macular degeneration, 34Maraviroc, 107Maribavir, 158Maropitant, 62Melagartan, 16Melatonin, diurnal cycle regulation, 72Melatonin, mimic, 72Mesotrione, 47Metaloproteases, 18, 47, 54Metasteses, prevention, 54Methotrexate, 193Mevalonate, 44Microtubules, 128Mifepristone, 32Minoxidil, 51Mitomycin C, 154Mitoxantrone, 227Mitsonobu reaction, 46, 52, 87Monasterol, 128Monoamine oxidase, see MAOMorpholine, synthesis, 106Mubritinib, 108Multiple myeloma, 133Muraglitazar, 47Mushroom, amanita, 190Jack O’Latern, 38

236 SUBJECT INDEX

Namindinil, 51Nateglinide, 15Naxifylline, 203Nelarabine, 200Neovascularixation, 34, 47, 140Nepicastat, 97Netoglitazone, 103Neuraminidase, 25Neurokinin hNK-1, in nausea, 105Neuropathy, peripheral, 60Neurophillin, 60Neuroprotective agent, 53, 142, 151,

159, 202Neutrophil, superoxide from, 100Nitazoxinide, 101Nitisinone, 47N-methyl-D-aspartate, see NMDANNRTI, 96, 122, 123, 176Non-nucleoside reverse transcriptase

inhbitor, see NNRTINorelgestimate, 34NSAID, 91

Odansetron, 105Oglufanide, 142Olmesartan, 111Omaciclovir, 199Omapatrilat, 191Omoconazole, 94Orfadin, 47Oseltamivir, 25Ospemifene, 65Osteoporosis, 77Oxazole synthesis, 109

Paclitaxel, 128Pain, neuropathic, 13, 60Paliperidone, 209Parathyroid, hormone, 73Parecoxib, 92Parkinson’s disease, 60, 63, 74, 150, 202PDE-4, 29Pelitinib, 167Pelitrexol, 212Pemetrexed, 193Pepstatin, 3Peramavir, 53Perzinfotel, 39Phosphodiesterase see PDE

Piboserod, 22PKC, role, 73Posaconazole, 105Potassium channel opener, 150Pralatrexate, 211Prasurgel, 189Prazocin, 176Prinomastat, 54Pro-drug, 17, 127Promiscuity, estrogen receptor, 177Prostacyclin, 80Prostaglandins, discovery, 21Proteasome, 133Protein cross-linking, 102Protein kinase, see PKCProzac, 61Psoriasis, 37Purine nucleoside phosphorylase (PNP),

192Purine, synthesis, 204Pyridine synthesis, 116, 124Pyrimidine synthesis, 103, 122, 129

Radiation therapy, 45Ragaglitazar, 220Ramelteon, 72Reboxetine, 61Receptor, acetylcholine, 115Receptor, alpha adrenergic, 52Receptor, angiotensin, 111Receptor, beta-adrenergic, 49Receptor, glucocorticoid, 32Receptor, progesterone, 32Receptor, retinoid, 30Receptor, sertonin 5-HT4, 141Receptor, thyroid, 50Receptors, pain, 39Receptors, peroxisome proliferator

activated, see PPARRegadenoson, 197Repaglinide, 15Resolution,Chromatographic, 52enzymatic, 213, 220salt formation, 71, 75, 120

Retinoic acid, 30Retinoids, 76Revaprazan, 122Rimonabant, 99

SUBJECT INDEX 237

Risperidone, metabolite, 209Rivastigmine, 66Rivoglitazone, 157Roflumilast, 44Rosuvastatin, 124Rotigotine, 75RU-486, 32Ruboxystaurin, 89Rufinamide, 108Rupinavir, 9

Selodenoson, 196Semaxanib, 149Sharpless oxidation, 165Shingles, 199Sialidase, 25Sickle-cell anemia, 45Sildefanil, 127Sitafloxacin, 174Sitagliptan, 206Sitosterol, 34Sivelstat, 54Skin, cell growth, 30Solabegron, 50Solifenacin, 171Solublizing, phosphate, 5Sonepiprazole, 166Sorbitol, occular accumulation, 145, 184Specific serotonin reuptake see SSRIStatin lipid lowering drugs, 44, 123Statine, 3, 8Staurosporin, 89Stigmasterol, 34STNOnline, alternatives, xiiiStroke, 53Substance P, 105Sunepitron, 204Sunitinib,150

Tachykinin, emesis, 62Tadalafil, 229Talabostat, 84Talnetant, 168Taltobulin, 11Tamibarotene, 76Tamiflu, 25Tamoxifen, 31, 77Tanaproget, 178

Tandutinib, 183Tanomastat, 47Tariquidar, 167Taurine, 15Taxol, 11Tecadenoson, 195Tegafur, 127Tegaserod, 141Tenofovir, 197Terbogrel, 60Teriflumonide, 93Tesmilifene, 58Tetomilast, 101Tetrazole synthesis, 110Tezacitabine, 131Theophylline, 29Thiazole synthesis, 101Thiomorpholine synthesis, 55Thymogen, 142Thyroxin, 50Tidembersat, 164Tilmacoxib, 91Timcodar, 60Tipifarnib, 192Tiprinavir, 120Tolterodine, 59Tolvaptan, 186Topixantrone, 227Topoisomerase-I, 230Topoisomerase, 173, 227Torborinone, 172Torcetrapib, 169Travoprost, 22Trepostinil, 81[1,2,3]Triazole synthesis, 108Troxacitabine, 131Tubulin, 11Tyrosenemia, 47

Upjohn, 34Uric acid, 100Urinary incontinence, 49, 52, 87, 170

Valdecoxib, 92Vandetanib, 181Vardefanil, 205Varespladib, 144Vasopresin, 185, 221

238 SUBJECT INDEX

Viagra, 127Vidagliptin, 84Vinblastine, 11Vincristine, 11Virus, avian influenza, 25Virus, cell-surface receptor, 107, 134Virus, HIV, 2, 96, 132Virus, varicela, 199Vitamin A, 30

Vitamin D, 38Vofopitant, 110Voriconazole, 103

Ximelagatran, 16

Zenarestat, 184Zidovudine (AZT), 131, 200Zosuquidar, 79

SUBJECT INDEX 239

CROSS INDEX OF BIOLOGICALACTIVITY

Alcoholism TreatmentAcamprosate, 15

Aldose Reductase InhibitorsLidorestat, 145Zenarestat, 184

Alzheimer’s Disease TreatmentAltinicline, 115Alvameline, 109Cipralisant, 94Donepezil, 71Ladostigil, 71Leteprinim, 202

AnalgesicAlvimopam, 117Fadolmidine, 69Lacosamide, 14Perzinfotel, 39

AndrogenBexlosteride, 222Izonsteride, 223

AntiallergicEtalocib, 49

AntiandrogenDutasteride, 37

AntiarrhythmicArofylline, 202Cariporide, 57Dronaderone, 140Regadenoson, 197Selodenoson, 196Tecadenoson, 195

AntiasthmaticAtreluton, 90Ciclesonide, 36Cilomilast, 30Roflumilast, 44

AntibacterialAmustaline, 218Ceftobiprole, 213Ertapenem, 214Garfenoxacin, 176Gatifloxacin, 174Gemifloxacin, 210Iclaprim, 125


241

Antibacterial (Continued )Sitafloxacin, 174

AntidepressantCitalopram, 140Elzasonan, 136Flibanserin, 158Igmesine, 64Lubazodone, 70Reboxetine, 61Vofopitant, 110

AntidiabeticErtiprotafib, 219Muraglitazar, 47Nateglinide, 15Netoglitazone, 103Ragaglitazar, 220Repaglinide, 15Rivoglitazone, 157Sitagliptan, 206Vidagliptin, 84

AntiemeticAprepitant, 105Ezlopitant, 62Maropitant, 62

AntiepilepticRufinamide, 108

AntiestrogenAcolbifene, 163Arzoxyfene, 155Bazedoxifene, 145Fulvestrant, 32Lasofoxifene, 77Ospemifene, 65

AntifungalOmoconazole, 94Posaconazole, 105Voriconazole, 103

AntihpertensiveAtrasentan, 87Gemopatrilat, 19Clevipidine, 117Edonentan, 56Nepicastat, 97Olmesartan, 111

AntiinflammatoryDarbufelone, 99Ecopladib, 147Pelitinib, 167

Varespladib, 144Antiinflammatory COX-2Cimicoxib, 96Etoricoxib, 117Parecoxib, 92Tilmacoxib, 91Valdecoxib, 92

AntiparasiticNitazoxinide, 101

AntiprogestinAsoprinosil, 32

AntipsychoticAsenapine, 228Bifeprunox, 159Ecopipam, 228Paliperidone, 209Sonepiprazole, 166

AntitumorAlitretoin, 30Alvocidib, 165Apaziquone, 154Bexarotene, 76Bortezomib, 133Camptogen, 230Canertinib, 180Canfosfamide, 13Clofarabine, 200Cloretazine, 14Doramapimod, 74Emitefur, 127Enzastaurin, 89Erlotinib, 179Exatecan, 232Forodesine, 192Gefitinib, 181Irofulven, 38Istradefylline, 202Lapatinib, 182Monasterol, 128Mubritinib, 108Nelarabine, 200Pelitrexol, 212Pemetrexed, 193Pralatrexate, 211Prinomastat, 54Semaxanib, 149Sunitinib, 150Talabostat, 84

242 CROSS INDEX OF BIOLOGICAL ACTIVITY

Taltobulin, 11Tamibarotene, 76Tandutinib, 183Tanomastat, 47Tezacitabine, 131Tipifarnib, 172Topixantrone, 227Troxacitabine, 131Vandetanib, 181

AntipsoriaticEcalcidine, 38

AntiviralAmdoxovir, 199Amprenavir, 4Aplaviroc, 134Atazanavir, 7Capravirine, 95Clevudine, 130Darunavir, 5Efavirenz, 177Emivirine, 123Emtricitabine, 132Etravirine, 123Fosamprenavir, 6Lopinavir, 7Maraviroc, 107Maribavir, 158Omaciclovir, 199Oseltamivir, 25Peramavir, 53Rupinavir, 9Tenofovir, 197Tiprinavir, 120

AnxiolyticSunepitron, 209

Apetite SupressantRimonabant, 99

CardiotonicNaxifylline, 203Torborinone, 172

Collagenase InhibitorCipemastat, 99

DiureticLixivaptan, 222Tolvaptan, 186

Elastase InhibitorSivelstat, 54

Erection Disfunction TreatmentAvanafil, 127Dasantafil, 204Tadalafil, 229Vardefanil, 205

Fibrinogen InhibitorMelagartan, 16Ximelagatran, 16

Gastric Acid InhibitorRevaprazan, 122

Glaucoma TreatmentBimatoprost, 24Travoprost, 22

Growth Hormone StimulantIbutamoren, 153

Hair Growth RestorerNamindinil, 51

Immune ModulatorOglufanide, 142Isatoribine, 207Leflunomide, 93Lenalidomide, 153Teriflumonide, 93

Irritable Bowel Syndrome TreatmentLubiprostone, 23Piboserod, 221Talnetant, 168Tegaserod, 141

Lipid Lowering AgentAvasimibe, 56Axitirome, 50Ezetimibe, 66Farglitazar, 46Ibrolipim, 44Rosuvastatin, 124Torcetrapib, 169

Macular Degeneration TreatmentAnecortave, 34

Migraine TreatmentAlmotriptan, 146Alniditan, 133Avitriptan, 146Tidembersat, 164

Multidrug Resistance TreatmentBiricodar, 119Tariquidar, 167Tesmilifene, 58Zosuquidar, 79

CROSS INDEX OF BIOLOGICAL ACTIVITY 243

NeuroprotectiveDelucemine, 59Disufenton, 53Flindokalner, 151Gavistinel, 142Lubeluzole, 160Timcodar, 60

Oral ContraceptiveNorelgestimate, 34

Parathyroid InhibitorCinacalcet, 73

Parkinson’s TreatmentAplindore, 150Brasofensine, 64Rivastigmine, 66Rotigotine, 75

Platelet Aggregation InhibitorApafant, 224Prasurgel, 189Terbogrel, 60

ProgestinTanaproget, 178

Prostatic Hypertrophy TreatmentAlfuzocin, 178Fiduxosin, 227

Protein Cross Link InhibitorAlagebrium, 102

Radiation SensitizerEfaproxiral, 45

Sleep AidGaboxadol, 190Indiplon, 192Ramelteon, 72

Superoxide InhibitorTetomilast, 101

Thrombin InhibitorDabigatran, 156

Tyrosenemia TreatmentNitisinone, 47

UricosoricFebuxostat, 100

Urinary Incontinence TreatmentDabuzalgron, 52Darfenacin, 87

Solabegron, 50

Solifenacin, 171

Tolterodine, 59VasodilatorAmbrisentan, 126

Atrasentan, 87,126Omapatrilat, 91

Trepostinil, 81

244 CROSS INDEX OF BIOLOGICAL ACTIVITY

CUMULATIVE INDEX

Abacavir, 6, 184Ablukast, 5, 128Acadesine, 6, 75Acamprosate, 7, 15Acebutolol, 2, 109Aceclidine, 2, 295Acedapsone, 2, 112Acenoumarole, 1, 331Aceperone, 2, 332Acephylline, 1, 425Acetaminophen, 1, 111Acetanilide, 1, 111Acetazolamide, 1, 249Acetohexamide, 1, 138Acetylmethadol, 1, 81Acetylmethoxpromazine, 1, 131Acifran, 4, 78Acitretin, 4, 35Acivicin, 4, 85Aclomethasone, 3, 96Acodazole, 4, 215Acolbifene, 7, 163Acrivastine, 4, 105Actisomide, 5, 150

Actodigin, 3, 99Acyclovir, 3, 229Adapalene, 5, 38Adaprolol, 5, 18Adatanserin, 6, 116Adefovir, 6, 182Adinazolam, 2, 353Adiphenine, 1, 81Adozelesin, 5, 171Adrenalone, 2, 38Aglepristone, 6, 65Alagebrium, 7, 102Alaproclate, 4, 33Alatrofloxacin, 6, 154Albendazole, 2, 353Albuterol, 2, 43Albutoin, 2, 261Albutoin, 2, 261Alclofenac, 2, 68Aldosterone, 1, 206Alentomol, 5, 39Aletamine, 2, 48Alfaprostol, 4, 9Alfentanyl, 3, 118


245

Alfuzocin, 4, 149Alfuzocin, 7, 178Algestone acetonide, 2, 171Alipamide, 2, 94Alitame, 6, 29Alitretoin, 7, 30Alizapride, 6, 143Allobarbital, 1, 269Allopurinol, 1, 152Allylestrenol, 1, 172Almotriptan, 6, 124Almotriptan, 7, 146Alniditan, 6, 146Alniditan, 7, 133Alonimid, 2, 295Alosetron, 6, 194Alovudine, 6, 112Aloxidone, 1, 232Alpertine, 2, 342Alpha eucaine, 1, 8Alphaprodine, 1, 304Alpidem, 5, 142Alprazolam, 3, 197Alprenolol, 1, 177Alprenoxime, 5, 18Alprostadil, 3, 2Alrestatin, 3, 72Altanserin, 4, 151Althiazide, 1, 359Altinicline, 7, 115Altrenogest, 4, 66Altretamine, 6, 118Alvameline, 7, 109Alverine, 2, 55Alvimopam, 7, 117Alvocidib, 7, 165Amacetam, 3, 127Amantidine, 2, 18Ambrisentan, 7, 126Ambucaine, 1, 11Ambucetamide, 1, 94Ambuside, 2, 116Amcinafal, 2, 185Amcinafide, 2, 185Amdinocillin, 4, 177Amdoxovir, 7, 199Amedaline, 2, 348Ameltolide, 5, 20

Amesergide, 6, 204Ametantrone, 3, 75Amfenac, 3, 38Amflutizole, 4, 94Amicibone, 2, 11Amicycline, 2, 228Amidephrine, 2, 41Amidinocillin, 3, 208Amidoquine, 1, 342Amifloxacin, 4, 144Amifostine, 5, 1Amiloride, 1, 278Aminitrozole, 1, 247Aminoglutetimide, 1, 257Aminometetradine, 1, 265Aminophenazole, 1, 248Aminophylline, 1, 427Aminopromazine, 1, 390Aminopropylon, 1, 234Aminopyrine, 1, 234Aminorex, 2, 265Amiodarone, 4, 127Amiquinsin, 2, 363Amisometradine, 1, 266Amitraz, 4, 36Amitriptyline, 1, 151Amlexanox, 6, 196Amlodipine, 4, 108Amobarbital, 1, 268Amodiaquine, 4, 140Amoproxan, 2, 91Amopyroquine, 1, 342Amorolfine, 5, 99Amoxapine, 2, 428Amoxycillin, 1, 414Amphecloral, 2, 48Amphetamine, 1, 37Amphetaminil, 2, 48Ampicillin, 1, 413Amprenavir, 7, 4Amprolium, 1, 264Ampyzine, 2, 298Amqinate, 2, 370Amrinone, 3, 147Amustaline, 7, 218Anagesterone acetate, 2, 165Anagrelide, 3, 244Anastrozole, 6, 86

246 CUMULATIVE INDEX

Androstanolone, 1, 173Anecortave, 7, 34Anidoxime, 2, 125Anileride, 1, 300Anilopam, 3, 121Aniracetam, 4, 39Anirolac, 4, 158Anisindandione, 1, 147Anitrazafen, 1, 147Antazoline, 1, 242Antipyrine, 1, 234Apafant, 7, 224Apalcillin, 4, 179Apaxifylline, 6, 179Apaziquone, 7, 154Apazone, 2, 475Aplaviroc, 7, 134Aplindore, 7, 150Apraclonidine, 5, 2Aprepitant, 7, 105Aprindene, 2, 208Aprobarbital, 1, 268Aprophen, 1, 91Aptazapine, 4, 215Aptiganel, 6, 59Ara A, 4, 122Arbaprostil, 3, 8Arbutamine, 5, 15Argatroban, 6, 16Arildone, 3, 45Aripiprazole, 6, 115Arofylline, 7, 202Arprinocid, 4, 165Arteflene, 6, 158Artilide, 6, 33Arzoxyfene, 7, 155Asenapine, 7, 228Asoprinosil, 7, 32Astemizole, 3, 177Atazanavir, 7, 7Atenolol, 2, 109Atevirdine, 6, 131Atipamezole, 5, 71Atiprimod, 6, 71Atiprosin, 4, 211Atorvastatin, 6, 70Atovaquone, 6, 61Atrasentan, 7, 87

Atreluton, 7, 90Atropine, 1, 35Avanafil, 7, 127Avasimibe, 7, 56Avitriptan, 7, 146Avridine, 4, 1Azabon, 2, 115Axitirome, 7, 50Azaclorzine, 3, 241Azacosterol, 2, 161Azacyclonol, 1, 47Azalanstat, 6, 76Azaloxan, 4, 138Azanator, 2, 457Azaperone, 2, 300Azarole, 3, 129Azastene, 3, 89Azatadine, 2, 424Azathioprine, 2, 464Azelastine, 4, 152Azepinamide, 1, 137Azepindole, 3, 242Azimilide, 6, 80Azipramine, 3, 246Azlocillin, 3, 206Azoconazole, 3, 137Azolimine, 2, 260Azomycin, 1, 238Azosemide, 3, 27Azthreonam, 4, 193Azumolene, 5, 68

Bacampicillin, 3, 204Baclofen, 2, 121Balsalazide, 6, 49Bamethan, 2, 39Bamiphylline, 1, 426Bamipine, 1, 51Bamnidazole, 3, 132Barbital, 1, 267Barmastine, 6, 175Bas, 2, 96Batanopride, 5, 21Batelapine, 5, 169Batimastat, 6, 15Bazedoxifene, 7, 145Becanthone, 2, 413Belfosdil, 5, 2

CUMULATIVE INDEX 247

Beloxamide, 2, 56Bemarinone, 5, 131Bemesetron, 5, 66Bemidone, 1, 305Bemigride, 1, 258Bemitradine, 4, 168Bemoradan, 5, 133Bemsetron, 5, 66Benactyzine, 1, 93Benapryzine, 2, 74Benazepril, 5, 135Bendacalol, 5, 134Bendazac, 2, 351Bendroflumethazide, 2, 358Benfurodil, 2, 355Benorterone, 2, 156Benoxaprofen, 2, 356Benperidol, 2, 290Benproperine, 2, 100Bentazepam, 3, 235Bentiromide, 3, 60Benzbromarone, 2, 354Benzestrol, 1, 103Benzetimide, 2, 293Benzilonium bromide, 2, 72Benzindopyrine, 2, 343Benziodarone, 1, 313Benzocaine, 1, 9Benzoctamine, 2, 220Benzodepa, 2, 122Benzphetamine, 1, 70Benzquinamide, 1, 350Benztriamide, 2, 290Benzydamine, 1, 323Benzylpenicillin, 1, 408Bepridil, 3, 46Beraprost, 5, 176Berefrine, 6, 50Besipirdine, 6, 132Beta eucaine, 1, 9Betahistine, 2, 279Betamethasone, 1, 198Betaxolol, 4, 26Bethanidine, 1, 55Bevantolol, 3, 28Bexarotene, 7, 76Bexlosteride, 7, 222Bezafibrate, 3, 44

Biapenem, 6, 163Bicalutamide, 6, 46Bicifadine, 3, 120Biclodil, 4, 38Bidisomide, 5, 87Bifeprunox, 7, 159Bifonazole, 4, 93Bimatoprost, 7, 24Binafloxacin, 5, 125Bindarit, 6, 141Binfloxacin, 5, 2Binospirone, 5, 134Bipenamol, 4, 45Biperiden, 1, 47Biricodar, 7, 119Bisantrene, 4, 62Bishydroxycoumarin, 1, 331Bisnafide, 6, 201Bisoprolol, 4, 28Bitolterol, 3, 22Bizelesin, 5, 173Bolandiol diacetate, 2, 143Bolasterone, 1, 173Boldenone, 2, 153Bolmantalate, 2, 143Bortezomib, 7, 133Bosentan, 6, 107Boxidine, 2, 99Brasofensine, 7, 64Brequinar, 5, 121Bretazenil, 5, 177Bretylium tosylate, 1, 55Brifentanil, 5, 84Brimodine, 5, 132Brinzolamide, 6, 190Brocrinat, 4, 130Brofoxine, 3, 191Bromadoline, 4, 6Bromdiphenhydramine, 1, 42Bromfenac, 4, 46Bromhexine, 2, 96Bromindione, 2, 210Bromisovalum, 1, 221Bromoxanide, 2, 94Bromperidol, 2, 331Brompheniramine, 1, 77Brompirimine, 4, 116Broperamole, 3, 139


Brotizolam, 4, 219Bucainide, 2, 125Bucindolol, 3, 28Buclizine, 1, 59Bucloxic acid, 2, 126Bucromanone, 5, 128Budesonide, 3, 95Buformin, 1, 221Bufuralol, 2, 110Bumetanide, 2, 87Bunaftine, 2, 211Bunamidine, 2, 212Bunaprolast, 6, 58Bunitridine, 2, 215Bunitrolol, 2, 106Bunolol, 2, 110Bupicomide, 2, 280Bupivacaine, 1, 17Buprenorphine, 2, 321Bupropion, 2, 124Buquinolate, 1, 346Burimamide, 2, 251Buspirone, 2, 300Butabarbital, 1, 268Butacaine, 1, 12Butacetin, 2, 95Butaclamol, 2, 226Butalbital, 1, 268Butamirate, 2, 76Butamisole, 3, 226Butaperazine, 1, 381Butaprost, 4, 13Butazolamide, 1, 249Butenafine, 6, 57Buterizine, 3, 175Butethal, 1, 268Butoconazole, 3, 134Butoprozine, 4, 156Butorphanol, 2, 325Butoxamine, 1, 68Butriptyline, 1, 151Butropium bromide, 2, 308Butylallonal, 1, 269Butylvynal, 1, 269

Cabergoline, 6, 204Caffeine, 1, 111Calcifediol, 3, 101

Calcipotriene, 5, 60Calcitriol, 3, 103Calusterone, 2, 154Cambendazole, 2, 353Camptogen, 7, 230Candesartan, 6, 23Candoxatril, 6, 56Canertinib, 7, 180Canfosfamide, 7, 13Canrenoate, 2, 174Canrenone, 2, 174Capecitabine, 6, 110Capobenic acid, 2, 94Capravirine, 7, 95Captodiamine, 1, 44Captopril, 3, 128Caracemide, 4, 1Caramiphen, 1, 90Carbacephalothin, 2, 390Carbacycline, 4, 14Carbadox, 2, 390Carbamazepine, 1, 403Carbantel, 3, 57Carbazeran, 3, 195Carbencillin, 1, 414Carbetidine, 1, 90Carbidopa, 2, 119Carbimazole, 1, 240Carbinoxamine, 1, 43Carbiphene, 2, 78Carboplatin, 4, 16Carboprost, 3, 7Carbromal, 1, 221Carbubarbital, 1, 269Carbutamide, 1, 138Carbuterol, 2, 41Carfentanyl, 3, 117Cariporide, 7, 57Carisoprododol, 1, 219Carmantidine, 2, 20Carmustine, 2, 12Carnidazole, 2, 245Caroxazone, 3, 191Carphenazine, 1, 383Carpipramine, 2, 416Carprofen, 2, 169Carsatrin, 6, 179Cartazolate, 2, 469


Carteolol, 3, 183Carumonam, 4, 193Carvedilol, 5, 163Carvotroline, 6, 194Carzelesin, 5, 171Cefaclor, 3, 209Cefadroxyl, 2, 440Cefamandole, 2, 441Cefaparole, 3, 212Cefatrizine, 3, 211Cefazaflur, 3, 213Cefazolin, 3, 442Cefbuperazone, 4, 189Cefdinir, 6, 170Cefepime, 6, 167Cefetamet, 4, 184Cefixime, 4, 184Cefmenoxime, 4, 187Cefmetazole, 4, 190Cefonicid, 3, 213Cefoperazone, 4, 185Ceforanide, 3, 214Cefotaxime, 3, 216Cefotetan, 4, 191Cefotiam, 3, 215Cefoxitin, 2, 435Cefpimizole, 4, 185Cefpiramide, 4, 188Cefpiromine, 5, 158Cefpodoxime proxetil, 5, 158Cefprozil, 5, 158Cefquinome, 6, 169Cefroxadine, 3, 210Cefsulodin, 3, 214Ceftazidine, 3, 216Ceftibuten, 5, 160Ceftiofur, 4, 187Ceftizoxime, 3, 218Ceftobiprole, 7, 213Ceftriaxone, 4, 190Cefuroxime, 3, 216Celgosivir, 6, 171Celiprolol, 4, 27Cephalexin, 1, 417Cephaloglycin, 1, 417Cephaloridine, 1, 417Cephalothin, 1, 420Cephapyrin, 2, 441

Cephradine, 2, 440Cerivastatin, 6, 98Ceronapril, 5, 65Cetaben, 3, 60Cetamole, 4, 26Cetececol, 5, 160Cetiedil, 3, 42Cetirizine, 4, 118Cetophenicol, 2, 46Cetraxate, 4, 6Cevimeline, 6, 106Chloraminophenamide, 1, 133Chloramphenicol, 1, 75Chlorazanil, 1, 281Chlorbenzoxamine, 1, 43Chlorcyclizine, 1, 58Chlordiazepexoxide, 1, 365Chlorexolone, 1, 321Chlorfluperidol, 1, 306Chlorguanide, 1, 115Chlorimpiphene, 1, 385Chlorindandione, 1, 147Chlormadinone acetate, 1, 181Chlormidazole, 1, 324Chlorophenylalanine, 2, 52Chloroprocaine, 1, 11Chloropyramine, 1, 402Chloroquine, 1, 341Chlorothen, 1, 54Chlorothiazide, 1, 321Chlorotrianisine, 1, 104Chlorphenamide, 1, 133Chlorphendianol, 1, 46Chlorphenesin, 1, 118Chlorpheniramine, 1, 77Chlorphenoxamine, 1, 44Chlorphentermine, 1, 73Chlorproethazine, 1, 379Chlorproguanil, 1, 115Chlorpromazine, 1, 319Chlorpropamide, 1, 137Chlorprothixene, 1, 399Chlorpyramine, 1, 51Chlortetracycline, 1, 212Chlorthalidone, 1, 322Chlorzoxazone, 1, 323Chromoglycate, 1, 313Chromonar, 1, 331


Cibenzoline, 4, 87Ciclafrine, 2, 226Ciclazindol, 4, 217Ciclesonide, 7, 36Cicletanine, 5, 143Cicloprofen, 2, 217Cicloprolol, 4, 25Cicloprox, 2, 282Cidofovir, 6, 108Ciglitazone, 4, 33Ciladopa, 4, 22Cilazapril, 4, 170Cilomilast, 7, 30Cilostazol, 6, 88Cimaterol, 4, 23Cimetidine, 2, 253Cimicoxib, 7, 96Cinacalcet, 7, 73Cinalukast, 6, 81Cinanserin, 2, 96Cinepazet, 3, 157Cinepazide, 2, 301Cinflumide, 4, 35Cingestol, 2, 145Cinnameridine, 2, 39Cinnarizine, 1, 58Cinoxacin, 2, 388Cinromide, 3, 44Cintazone, 2, 388Cintriamide, 2, 121Cioteronel, 5, 11Cipamfylline, 6, 177Cipemastat, 7, 99Cipralisant, 7, 94Ciprefadol, 3, 119Ciprocinonide, 3, 94Ciprofibrate, 3, 44Ciprofloxacin, 4, 141Ciprostene, 4, 14Ciramadol, 3, 122Cisapride, 4, 42Cisatracurium, 6, 155Cisplatin, 4, 15Cisplatin, 5, 11Citalopram, 7, 140Citenamide, 2, 221Citicoline, 6, 108Cladribine, 6, 181

Clamoxyquin, 2, 362Clavulanic acid, 4, 180Clazolam, 2, 452Clazolimine, 2, 260Clebopride, 4, 42Clemastine, 2, 32Clemizole, 1, 324Clentiazem, 5, 139Clevipidine, 7, 117Clevudine, 7, 130Clinafloxacin, 5, 125Clioxanide, 2, 94Cliprofen, 2, 65Clobazam, 2, 406Clobetasol propionate, 4, 72Clobetasone butyrate, 4, 72Clobutinol, 2, 121Clocapramine, 2, 416Clocental, 1, 38Clocortolone acetate, 2, 193Clodanolene, 3, 130Clodazon, 2, 354Clofarabine, 7, 200Clofenpyride, 2, 101Clofibrate, 1, 119Clofilium phosphate, 3, 46Clogestone, 2, 166Clomacran, 2, 414Clomegestone acetate, 2, 170Clomethrone, 2, 170Clomifene, 1, 105Clominorex, 2, 265Clonidine, 1, 241Clonitazene, 1, 325Clonixeril, 2, 281Clonixin, 2, 281Clopamide, 1, 135Clopenthixol, 1, 399Cloperidone, 2, 387Cloperone, 3, 150Clopidogrel, 6, 172Clopimozide, 2, 300Clopipazam, 3, 237Clopirac, 2, 235Cloprednol, 2, 182Cloprenaline, 2, 39Cloprostenol, 2, 6Cloretazine, 7, 14


Clorsulon, 4, 50Closantel, 3, 43Closiramine, 2, 424Clothiapine, 1, 406Clothixamide, 2, 412Cloticasone propionate, 4, 75Cloxacillin, 1, 413Cloxazepam, 1, 370Clozapine, 2, 425Codeine, 1, 287Codorphone, 3, 112Codoxime, 2, 318Colchicine, 1, 152Colestolone, 5, 55Colterol, 3, 21Cormethasone acetate, 2, 194Cortisone, 1, 188Cortisone acetate, 1, 190Cortivazol, 2, 191Cotinine, 2, 235Crilavastine, 5, 64Crisnatol, 5, 44Cromitrile, 4, 137Cromoglycate, 3, 66Cyclacillin, 2, 439Cyclandelate, 1, 94Cyclazocine, 1, 298Cyclindole, 3, 168Cyclizine, 1, 58Cyclobarbital, 1, 269Cyclobendazole, 2, 353Cyclobenzaprine, 3, 77Cycloguanil, 1, 281Cyclomethycaine, 1, 14Cyclopal, 1, 269Cyclopenthiazide, 1, 358Cyclopentolate, 1, 92Cyclophosphamide, 3, 161Cyclopyrazolate, 1, 92Cycloserine, 3, 14Cyclothiazide, 1, 358Cycrimine, 1, 47Cyheptamide, 2, 222Cypenamine, 2, 7Cyprazepam, 2, 402Cyproheptadine, 1, 151Cyprolidol, 2, 31Cyproquinate, 2, 368

Cyproterone acetate, 2, 166Cyproximide, 2, 293

Dabigatran, 7, 156Dabuzalgron, 7, 52Dacarbazine, 2, 254Daledalin, 2, 348Daltroban, 5, 22Dalvastin, 5, 87Danazol, 2, 157Danfloxacin, 5, 125Danofloxacin, 5, 125Dantrolene, 2, 242Dapiprazole, 5, 143Dapoxetine, 5, 35Dapsone, 1, 139Darbufelone, 7, 99Darfenacin, 7, 87Darglitazone, 6, 83Darodipine, 4, 107Darunavir, 7, 5Dasantafil, 7, 204Dazadrol, 2, 257Dazepinil, 5, 137Dazoxiben, 4, 91Debrisoquine, 2, 374Decitabine, 5, 100Declenperone, 3, 172Decoquinate, 2, 368Delapril, 4, 58Delavirdine, 6, 131Delmadinone acetate, 2, 166Delucemine, 7, 59Demoxepam, 2, 401Deprostil, 2, 3Desciclovir, 4, 165Descinolone acetonide, 2, 187Deserpidine, 1, 320Desipramine, 1, 402Desogestrel, 5, 52Desonide, 2, 179Desoximetasone, 4, 70Deterenol, 2, 39Detomidine, 5, 71Devazepide, 5, 137Dexamethasone, 1, 199Dexbrompheniramine, 1, 77Dexchlorpheniramine, 1, 77


Dexivacaine, 2, 95Dexmedetomidine, 5, 71Dexnorgestrel acetime, 2, 152Dexormaplatin, 5, 11Dexrazoxone, 5, 95Dextroamphetamine, 1, 70Dextromoramide, 1, 82Dextromorphan, 1, 293Dextrothyroxine, 1, 92Dezaguanine, 4, 162Dezinamide, 6, 48Dezocine, 4, 59Diacetolol, 3, 28Diamocaine, 2, 336Dianithazole, 1, 327Diapamide, 2, 93Diaveridine, 2, 302Diazepam, 1, 365Diaziquone, 4, 51Dibenamine, 1, 55Dibenzepin, 1, 405Dibucaine, 1, 15Dichlorisone, 1, 203Dichloroisoproterenol, 1, 65Dichlorophenamide, 1, 133Diclofenac, 2, 70Dicloxacillin, 1, 413Dicoumarol, 1, 147Dicyclomine, 1, 36Didanosine, 5, 146Dienestrol, 1, 102Diethyl carbamazine, 1, 278Diethylstibestrol, 1, 101Diethylthiambutene, 1, 106Difenoximide, 2, 331Difenoxin, 2, 331Difloxacin, 4, 143Diflucortolone, 2, 192Diflumidone, 2, 98Diflunisal, 2, 85Difluprednate, 2, 191Diftalone, 3, 246Dihexyverine, 1, 36Dihydralizine, 1, 353Dihydrocodeine, 1, 288Dilevalol, 4, 20Diltiazem, 3, 198Dimefadane, 2, 210

Dimefline, 2, 391Dimetacrine, 1, 397Dimethisoquine, 1, 18Dimethisterone, 1, 176Dimethothiazine, 1, 374Dimethoxanate, 1, 390Dimethylpyrindene, 1, 145Dimethylthiambutene, 1, 106Dimetridazole, 1, 240Dinoprost, 1, 27Dinoprostone, 1, 30Dioxadrol, 2, 285Dioxyline, 1, 349Diphenhydramine, 1, 41Diphenidol, 1, 45Diphenoxylate, 1, 302Diphenylhydantoin, 1, 246Diphepanol, 1, 46Dipipanone, 1, 80Dipiproverine, 1, 94Dipivefrin, 3, 22Dipyridamole, 1, 428Dipyrone, 2, 262Disobutamide, 3, 41Disopyramide, 2, 81Disoxaril, 4, 86Disufenton, 7, 53Disulfiram, 1, 223Ditekiren, 5, 4Dithiazanine, 1, 327Dixyrazine, 1, 384Dizocilpine, 5, 136Dobutamine, 2, 53Docebenone, 5, 8Doconazole, 3, 133Dofetilide, 6, 34Dolasetron, 5, 109Domazoline, 2, 256Domperidone, 3, 174Donepezil, 7, 71Donetidine, 4, 114Dopamantine, 2, 52Dopexamine, 4, 22Doramapimod, 7, 74Dorastine, 2, 457Doretinel, 5, 38Dorzolamide, 5, 147Dothiepin, 3, 239


Doxapram, 2, 236Doxaprost, 2, 3Doxazocin, 4, 148Doxepin, 1, 404Doxofylline, 5, 144Doxpicomine, 3, 122Doxylamine, 1, 44Draflazine, 6, 117Dribendazole, 4, 132Drindene, 3, 65Drobuline, 3, 47Drocinonide, 2, 186Droloxifene, 6, 44Dromostanolone, 1, 173Dronaderone, 7, 140Droperidol, 1, 308Droprenylamine, 3, 47Droxacin, 3, 185Droxinavir, 6, 7Duloxetine, 6, 59Duoperone, 4, 199Dutasteride, 7, 37Dydrogesterone, 1, 185

Ebastine, 4, 48Ecadotril, 6, 35Ecalcidene, 7, 38Eclanamine, 4, 5Eclazostat, 4, 131Econazole, 2, 249Ecopipam, 7, 228Ecopladib, 7, 147Ectylurea, 1, 221Edatrexate, 5, 152Edifolone, 4, 69Edonentan, 7, 56Edoxudine, 4, 117Efaproxiral, 7, 45Efavirenz, 7, 177Efegatran, 6, 16Eflornithine, 4, 2Elacridar, 6, 197Elantrine, 2, 418Eldacimibe, 6, 48Eletriptan, 6, 127Elfazepam, 3, 195Elucaine, 2, 44Elzasonan, 7, 136

Embutramide, 6, 34Emedastine, 6, 138Emilium tosylate, 3, 47Emitefur, 7, 127Emivirine, 7, 123Emtricitabine, 7, 132Enadoline, 6, 121Enalapril, 4, 81Enalkiren, 5, 4Enazadrem, 6, 107Encainide, 3, 56Enciprazine, 5, 92Encyprate, 2, 27Endralazine, 3, 232Endrysone, 2, 200Englitazone, 6, 85Enilconazole, 4, 93Eniluracil, 6, 107Enisoprost, 4, 11Enloplatin, 6, 91Enofelast, 6, 43Enolicam, 4, 148Enoxacin, 4, 145Enoximone, 4, 93Enpiroline, 4, 103Enprofylline, 4, 165Enprostil, 4, 10Enrofloxacin, 5, 125Enviradene, 4, 131Enviroxime, 3, 177Enzastaurin, 7, 89Eperezolid, 6, 73Ephedrine, 1, 66Epimestrol, 2, 138Epinephrine, 1, 95Epirazole, 3, 152Epithiazide, 1, 359Eplerenone, 6, 68Epoprostenol, 3, 10Epostane, 4, 68Eprazinone, 1, 64Epristeride, 6, 68Eprosartan, 6, 78Eprozinol, 2, 44Erbulozole, 6, 77Eritadenine, 2, 467Erlotinib, 7, 179Ertapenem, 7, 214


Ertiprotafib, 7, 219Erytriptamine, 1, 317Esmolol, 4, 27Esmolol, 5, 18Esproquin, 2, 373Estradiol, 1, 162Estradiol benzoate, 1, 162estradiol cypionate, 1, 162estradiol dipropionate, 1, 162estradiol hexabenzoate, 1, 162Estramustine, 3, 83Estrazinol, 2, 142Estrofurate, 2, 137Estrone, 1, 156Etafedrine, 2, 39Etalocib, 7, 49Etanidazole, 5, 73Etarotene, 5, 37Etazolate, 2, 469Eterobarb, 2, 304Ethacrynic acid, 1, 120Ethambutol, 1, 222Ethamivan, 2, 94Ethionamide, 1, 255Ethisterone, 1, 163Ethithiazide, 1, 358Ethoheptazine, 1, 303Ethonam, 2, 249Ethopropropazine, 1, 373Ethosuximide, 1, 228Ethotoin, 1, 245Ethoxzolmide, 1, 327Ethylestrenol, 1, 170Ethylmorphine, 1, 287Ethynerone, 2, 146Ethynodiol diacetate, 1, 165Ethynodrel, 1, 164Ethynylestradiol, 1, 162Etibendazole, 4, 132Etidocaine, 2, 95Etintidine, 3, 135Etintidine, 4, 89Etoclofene, 2, 89Etofenamate, 4, 42Etomidate, 3, 135Etonitazine, 1, 325Etonogestrel, 6, 64Etoperidone, 5, 92

Etoprine, 3, 153Etoricoxib, 7, 117Etorphine, 2, 321Etoxadrol, 2, 285Etravirine, 7, 123Exaprolol, 3, 28Exaprolol, 4, 25Exatecan, 7, 232Ezetimibe, 7, 66Ezlopitant, 7, 62

Fadolmidine, 7, 69Fadrozole, 5, 141Famciclovir, 6, 183Famotidine, 2, 37Fananserin, 6, 116Fanetizole, 4, 95Fantridone, 2, 421Farglitazar, 7, 46Fazarabine, 4, 122Febantel, 4, 35Febuxostat, 7, 10Felbinac, 4, 32Felodipine, 4, 106Felsantel, 3, 57Fenalamide, 2, 81Fenbendazole, 3, 176Fenbufen, 2, 126Fencamfine, 1, 74Fenclofenac, 3, 37Fenclorac, 2, 66Fenclozic acid, 2, 269Fendosal, 2, 170Fenestrel, 2, 9Fenethylline, 1, 425Fenfluramine, 1, 70Fengabine, 4, 47Fenimide, 2, 237Feniprane, 1, 76Fenisorex, 2, 391Fenleutron, 6, 43Fenmetozole, 2, 257Fenobam, 3, 136Fenoctimine, 4, 109Fenoldapam, 4, 147Fenoprofen, 2, 67Fenoterol, 2, 38Fenpipalone, 2, 293


Fenprinast, 4, 213Fenprostalene, 4, 9Fenquizone, 3, 192Fenretidine, 4, 7Fenspririden, 2, 291Fentanyl, 1, 299Fentiazac, 4, 96Fenticonazole, 4, 93Fenyripol, 2, 40Fetoxylate, 2, 331Fexofenadine, 6, 38Fezolamine, 4, 87Fiacitabine, 5, 98Fialuridine, 6, 110Fiduxosin, 7, 227Filaminast, 6, 40Finasteride, 5, 49Flavodilol, 4, 137Flavoxate, 2, 392Flazolone, 2, 337Flecainide, 3, 59Fleroxacin, 5, 125Flestolol, 4, 41Fletazepam, 2, 403Flibanserin, 7, 158Flindokalner, 7, 151Floctacillin, 1, 413Floctafenine, 3, 184Flordipine, 4, 107Flosequinan, 5, 127Fluandrenolide, 2, 180Fluanisone, 1, 279Fluazepam, 1, 366Flubanilate, 2, 98Flubendazole, 2, 354Flucindolol, 3, 168Flucinolone, 3, 94Flucinolone acetonide, 1, 202Flucloronide, 2, 198Fluconazole, 5, 75Fludalanine, 3, 14Fludarabine, 4, 167Fludorex, 2, 44Fludrocortisone, 1, 192Fludroxycortide, 1, 202Flufenamic acid, 1, 110Flumazenil, 4, 220Flumequine, 3, 186

Flumethasone, 1, 200Flumethiazide, 1, 355Flumetramide, 2, 306Fluminorex, 2, 265Flumizole, 2, 254Flumoxonide, 3, 95Flunarizine, 2, 31Flunidazole, 2, 246Flunisolide, 2, 181Flunitrazepam, 2, 406Flunixin, 2, 281Fluorocortolone, 1, 204Fluorodopa 18F, 5, 27Fluorogestone acetate, 2, 183Fluorometholone, 1, 203Fluoroprednisolone, 1, 292Fluorouracil, 3, 155Fluotracen, 3, 73Fluoxetine, 3, 32Fluoxetine, 5, 25Fluoxymestrone, 1, 175Fluparoxan, 5, 170Fluperamide, 2, 334Fluperolone acetate, 2, 185Fluphenazine, 1, 383Flupirtine, 4, 102Fluproquazone, 3, 193Fluprostenol, 2, 6Fluquazone, 3, 193Fluradoline, 4, 202Flurbiprofen, 1, 86Fluretofen, 3, 39Fluspiperone, 2, 292Fluspirilene, 2, 292Flutamide, 3, 57Flutiazine, 2, 431Fluticasone propionate, 4, 75Flutroline, 3, 242Fluvastatin, 5, 105Fluvoxamine, 6, 40Fluzinamide, 4, 29Forasartan, 6, 23Formocortal, 2, 189Forodesine, 7, 192Fosamprenavir, 7, 6Fosarilate, 4, 31Fosazepam, 3, 195Fosinopril, 5, 65


Fosphentoin, 6, 80Fosquidone, 5, 181Fostedil, 4, 134Frentizole, 3, 179Fulvestrant, 7, 32Fumoxicillin, 4, 179Furaltadone, 1, 229Furaprofen, 4, 127Furazolidone, 1, 229Furegrelate, 4, 125Furethidine, 1, 301Furobufen, 2, 416Furodazole, 4, 215Furosemide, 1, 134Fusaric acid, 2, 279

Gaboxadol, 7, 190Galdansetron, 6, 192Gamfexine, 2, 56Ganciclovir, 5, 146Garfenoxacin, 7, 176Gatifloxacin, 7, 174Gavistinel, 7, 142Gefitinib, 7, 181Gemcadiol, 3, 15Gemcitabine, 5, 96Gemeprost, 4, 11Gemfibrozil, 3, 45Gemifloxacin, 7, 210Gemopatrilat, 7, 19Gepirone, 4, 120Gestaclone, 2, 169Gestodene, 3, 85Gestonorone, 2, 152Gestrinone, 3, 85Gevotroline, 5, 164Glaphenine, 1, 342Glemanserin, 6, 101Gliamilide, 2, 286Glibornuride, 2, 117Glicetanile, 3, 61Gliflumide, 3, 61Glimepiride, 6, 72Glipizide, 2, 117Gloxinonam, 4, 195Glutethemide, 1, 257Glyburide, 2, 139Glybuthiazole, 1, 126

Glycosulfone, 1, 140Glyhexamide, 1, 138Glymidine, 1, 125Glyoctamide, 2, 117Glyparamide, 2, 117Glyprothiazole, 1, 125Granisetron, 5, 118Grepafloxacin, 6, 151Griseofulvin, 1, 314Guaiaphenesin, 1, 118Guanabenz, 2, 123Guanacycline, 1, 260Guanadrel, 1, 400Guanethidine, 1, 282Guanfacine, 3, 40Guanisoquin, 2, 375Guanoclor, 1, 117Guanoxabenz, 2, 123Guanoxan, 1, 352Guanoxyfen, 2, 101Gusperimus, 6, 26

Halcinonide, 2, 187Halobetasol, 5, 57Halofantrine, 3, 76Halofenate, 2, 80Halopemide, 3, 174Haloperidol, 1, 306Haloprednone, 3, 99Haloprogesterone, 3, 173Heptabarbital, 1, 269Hepzidine, 2, 222Heroin, 1, 288Hetacillin, 1, 414Heteronium bromide, 2, 72Hexahydroamphetamine, 4, 4Hexesterol, 1, 102Hexethal, 1, 268Hexobarbital, 1, 273Hexobendine, 2, 92Hexylcaine, 1, 12Histapyrrodine, 1, 50Hoquizil, 2, 381Hycanthone, 1, 398Hydracarbazine, 2, 305Hydralazine, 1, 353Hydrochlorobenzethylamine, 1, 59Hydrochlorothiazide, 1, 358


Hydrocodone, 1, 288Hydrocortisone, 1, 190Hydrocortisone acetate, 1, 190Hydroflumethiazide, 1, 358Hydromorphone, 1, 288Hydroxyamphetamine, 1, 71Hydroxychloroquine, 1, 342Hydroxyphenamate, 1, 220Hydroxyprocaine, 1, 11Hydroxyprogesterone, 1, 176Hydroxyzine, 1, 59

Ibafloxacin, 5, 127Ibrolipim, 7, 44Ibufenac, 1, 86Ibuprofen, 1, 86Ibutamoren, 7, 153Ibutilide, 5, 23Iclaprim, 7, 125Icopezil, 6, 137Icotidine, 4, 113Idarubicin, 5, 47Idoxifene, 6, 44Ifenprodil, 2, 39Ifetroban, 6, 93Ifosfamide, 3, 151Igmesine, 7, 64Ilepcimide, 6, 42Ilmofosine, 6, 26Ilonidap, 6, 133Iloperidone, 6, 103Imafen, 3, 226Imazodan, 4, 90Imidoline, 2, 259Imiloxan, 4, 88Imipenem, 4, 181Imipramine, 1, 401Imiquimod, 5, 173Imolamine, 1, 249Indacrinone, 3, 67Indapamide, 2, 349Indecainide, 4, 62Indeloxazine, 4, 59Indinavir, 6, 12Indiplon, 7, 192Indolapril, 4, 128Indolidan, 5, 117

Indomethacin, 1, 318Indoprofen, 3, 171Indoramine, 2, 344Indorenate, 3, 167Indoxole, 2, 254Inocoterone, 5, 49Intrazole, 2, 354Intriptyline, 2, 223Iodothiouracil, 1, 265Ipazilide, 5, 70Ipexidine, 3, 157Ipratropium bromide, 3, 160Iprindol, 1, 318Iproniazide, 1, 254Ipronidazole, 2, 244Iproplatin, 4, 17Ipsapirone, 5, 91Irbesartan, 6, 23Irinotecan, 6, 206Irofulven, 7, 38Irtemazole, 5, 117Isamoxole, 3, 138Isatoribine, 7, 207Isbogrel, 6, 42Isoaminile, 1, 82Isobucaine, 1, 12Isobuzole, 2, 272Isocarboxazide, 1, 233Isoetharine, 2, 9Isomazole, 4, 163Isomethadone, 1, 79Isomylamine, 2, 11Isoniazide, 1, 254Isopentaquine, 1, 346Isoproteronol, 1, 63Isoproteronol, 5, 15Isopyrine, 1, 234Isothipendyl, 1, 430Isotiquamide, 4, 139Isotretinoin, 3, 12Isoxepac, 3, 328Isoxicam, 2, 394Isoxsuprine, 1, 69Isradipine, 4, 107Istradefylline, 7, 202Itasetron, 6, 141Itazigrel, 4, 96Izonsteride, 7, 223


Ketamine, 1, 57Ketanserin, 3, 193Ketasone, 1, 237Ketazocine, 2, 238Ketazolam, 1, 369Ketobemidone, 1, 303Ketoconazole, 3, 132Ketoprofen, 2, 64Ketorfanol, 4, 60Ketorolac, 4, 81Ketotifen, 3, 239Khellin, 1, 313

Labetolol, 3, 24Lacidipine, 5, 82Lacosamide, 7, 14Ladostigil, 7, 71Lamifiban, 6, 19Lamivudine, 5, 99Lamotrigine, 4, 120Lanoconazole, 6, 75Lansoprazole, 5, 115Lapatinib, 7, 182Lasofoxifene, 7, 77Latanoprost, 6, 52Latanoprost, 7, 23Lavoltidine, 5, 77Lazabemide, 6, 95Lecimibide, 6, 78Leflunomide, 7, 93Lenalidomide, 7, 153Leniquinsin, 2, 363Lenperone, 2, 286Lergotrile, 2, 480Leteprinim, 7, 202Letimide, 2, 393Letrozole, 6, 86Levalorphanol, 1, 293Levamisole, 4, 217Levarterenol, 1, 63Levcromakalim, 6, 147Levocabastine, 4, 110Levonantrodol, 3, 188Levonordefrine, 1, 68Levophenacylmorphan, 1, 294Levopropoxyphene, 1, 50Levothyroxine, 1, 97Lexipafant, 6, 177

Liarozole, 6, 76Lidamidine, 3, 56Lidocaine, 1, 16Lidoflazine, 1, 279Lidorestat, 7, 145Lifarizine, 5, 92Lifibrate, 1, 103Lilopristone, 6, 65Linarotene, 5, 37Linezolid, 6, 74Linogrilide, 4, 80Linopirdine, 6, 134Liothyronine, 1, 97Lisinopril, 4, 83Lisofylline, 6, 177Lixazinone, 5, 166Lixivaptan, 7, 222Lobendazole, 2, 353Lobenzarit, 4, 43Lobucavir, 6, 186Lodelaben, 5, 22Lodoxamide, 3, 57Lofemizole, 4, 90Lofentanyl, 3, 117Lofepramine, 4, 201Lofexidine, 4, 88Lomefloxacin, 5, 125Lometraline, 2, 214Lometrexol, 5, 151Lomustine, 2, 12Lonapalene, 4, 57Loperamide, 2, 334Lopinavir, 7, 7Loracarbef, 5, 162Loratidine, 4, 200Lorazepam, 1, 368Lorbamate, 2, 21Lorcainide, 3, 40Lorcinadol, 5, 94Loreclezole, 5, 78Lorglumide, 5, 20Lormetazepam, 3, 196Lornoxicam, 6, 188Lortalamine, 4, 404Lorzafone, 4, 48Losartan, 5, 73Losoxantrone, 5, 43Losulazine, 4, 139


Loteprednol, 5, 56Lovastatin, 5, 88Loviride, 6, 48Loxapine, 2, 427Loxoribine, 5, 145Lubazodone, 7, 70Lubeluzole, 7, 160Lubiprostone, 7, 23Lucanthone, 1, 397Lufironil, 6, 95Lupitidine, 4, 115Lurosetron, 6, 194Lurtotecan, 6, 208Lynestrol, 1, 166

Mafenide, 2, 114Mafosfamide, 5, 102Malotilate, 5, 75Maprotiline, 2, 220Maraviroc, 7, 107Maribavir, 7, 158Marimastat, 6, 15Maropitant, 7, 62Masoprocol, 5, 31Mazapertine, 6, 114Mazindol, 2, 462Mebendazole, 2, 353Mebeverine, 2, 54Mebhydroline, 1, 319Mebromphenhydramine, 1, 44Mebutamate, 1, 218MeCCNU, 2, 12Mecillinam, 3, 208Meclastine, 1, 44Meclizine, 1, 59Meclofenamic acid, 1, 110Meclorisone butyrate, 3, 95Medazepam, 1, 368Medetomidine, 5, 71Medibazine, 2, 30Mediquox, 2, 390Medorinone, 5, 149Medrogestone, 1, 182Medroxalol, 3, 25Medroxyprogesterone, 1, 180Medrylamine, 1, 41Medrysone, 2, 200Mefenamic acid, 1, 110

Mefenidil, 4, 89Mefenorex, 2, 47Mefexamide, 2, 103Mefruside, 1, 134Megesterol acetate, 1, 180Melagartan, 7, 16Melengesterol acetate, 1, 182Melitracen, 2, 220Melphalan, 2, 120Memotine, 2, 378Menabitan, 4, 210Menoctone, 2, 217Meobentine, 3, 45Meparfynol, 1, 38Meperidine, 1, 300Mephenhydramine, 1, 44Mephenoxalone, 1, 119Mephensin, 1, 118Mephensin carbamate, 1, 118Mephentermine, 1, 72Mephenytoin, 1, 246Mephobarbital, 1, 273Mepivacaine, 1, 17Meprobamate, 1, 218Mequoqualone, 1, 354Meralluride, 1, 224Mercaptomerine, 1, 224Meropenem, 6, 164Meseclazone, 1, 254Mesoridazine, 1, 389Mesterolone, 1, 174Mestranol, 1, 162Mesuprine, 2, 41Metabutoxycaine, 1, 11Metalol, 2, 41Metampicillin, 1, 41Metaproterenol, 1, 64Metaxalone, 1, 119Meteneprost, 3, 9Metesind, 6, 200Methacycline, 2, 227Methadone, 1, 79Methallenestril, 1, 187Methamphetamine, 1, 37Methandrostenolone, 1, 173Methantheline bromide, 1, 393Methaphencycline, 1, 53Methaphenyline, 1, 52


Methaprylon, 1, 259Methapyriline, 1, 54Methaqualone, 1, 353Metharbital, 1, 273Methazolamide, 1, 250Methdilazine, 1, 387Methenolone acetate, 1, 175Methicillin, 1, 412Methimazole, 1, 240Methisazone, 2, 350Methitural, 1, 275Methixine, 1, 400Methocarbamol, 1, 118Methohexital, 1, 269Methopholine, 1, 349Methopromazine, 1, 374Methoxsalen, 1, 333Methoxypromazine, 1, 387Methsuximide, 1, 228Methyclothiazide, 1, 360Methylchromone, 1, 335Methyldihydromorphinone, 1, 292Methyldopa, 1, 95Methylphenidate, 1, 88Methylprednisolone, 1, 193Methyltestosterone, 1, 172Methylthiouracil, 1, 264Methynodiol diacetate, 2, 149Methyridine, 1, 256Methysergide, 2, 477Metiamide, 2, 252Metiapine, 2, 429Metioprim, 3, 155Metipronalol, 5, 17Metizoline, 2, 256Metoclopramide, 5, 20Metolazone, 2, 384Metopimazine, 1, 153Metoprolol, 2, 109Metrenperone, 5, 150Metronidazole, 1, 240Mexrenoate, 2, 175Mexrenone, 2, 175Mezlocillin, 3, 206Mianserin, 2, 451Mibefradil, 6, 61Mibolerone, 2, 144Miconazole, 2, 249

Midaflur, 2, 259Midazolam, 3, 197Midodrine, 4, 23Mifepristone, 5, 53Miglitol, 6, 100Milameline, 6, 98Milenperone, 3, 172Milipertine, 2, 341Mimbane, 2, 347Minalrestat, 6, 157Minaprine, 4, 120Minaprine, 5, 96Minaxolone, 3, 90Minocycline, 1, 214Minoxidil, 1, 262Mioflazine, 4, 119Mirfentanil, 6, 101Mirisetron, 6, 155Mirtazapine, 5, 177Misonidazole, 3, 132Mitindomine, 4, 218Mitoxantrone, 3, 75Mivobulin, 6, 188Mixidine, 2, 54Moclobemide, 4, 39Modafinil, 6, 38Modaline, 2, 299Modecainide, 5, 86Moexipril, 6, 156Mofebutazone, 1, 234Mofegiline, 6, 35Molinazone, 2, 395Molindone, 2, 455Molsidomine, 3, 140Mometasone, 4, 73Monasterol, 7, 128Monatepil, 6, 198Montelukast, 6, 150Moprolol, 2, 109Morantel, 1, 266Morazone, 2, 261Moricizine, 4, 200Morniflumate, 3, 146Morphazineamide, 1, 277Morphedrine, 1, 300Morphine, 1, 286Motretinide, 3, 12Moxalactam, 3, 218


Moxazocine, 3, 114Moxisylyte, 1, 116Moxnidazole, 2, 246Mubritinib, 7, 108Muraglitazar, 7, 47Muzolimine, 3, 137

Nabazenil, 4, 209Nabilone, 3, 189Nabitan, 3, 190Naboctate, 4, 209Nadolol, 2, 110Nafamostat, 6, 59Nafcillin, 1, 412Nafenopin, 2, 214Nafimidone, 4, 90Naflocort, 4, 75Nafomine, 2, 212Nafoxidine, 1, 147Nafronyl, 2, 213Naftidine, 3, 372Naftifine, 4, 55Nalbufine, 2, 319Nalidixic acid, 1, 429Nalmefene, 4, 62Nalmexone, 2, 319Nalorphine, 1, 288Naloxone, 1, 289Naltrexone, 2, 319Namindinil, 7, 51Namoxyrate, 1, 86Nandrolone, 1, 164Nandrolone decanoate, 1, 171Nandrolone phenpropionate, 1, 171Nantradol, 3, 186Napactidine, 3, 71Napamazole, 4, 87Naphazoline, 1, 241Napitane, 6, 60Naproxen, 1, 86Napsagatran, 6, 17Naranol, 2, 454Naratriptan, 6, 128Nateglinide, 7, 15Naxifylline, 7, 203Naxogilide, 5, 175Nebivolol, 5, 128Nedocromil, 4, 209

Nefazodone, 4, 98Neflumozide, 4, 133Nefopam, 2, 447Nelarabine, 7, 200Nelezaprine, 5, 168Nelfinavir, 6, 8Nemazoline, 6, 79Neostigmine, 1, 114Nepicastat, 7, 97Nequinate, 2, 369Netobimin, 4, 36Netoglitazone, 7, 103Nevirapine, 6, 199Nexeridine, 2, 17Nialamide, 1, 254Nicardipine, 3, 150Nicergoline, 2, 478Niclosamide, 2, 94Nicordanil, 3, 148Nicotinic acid, 1, 253Nictotinyl alcohol, 1, 253Nidroxyzone, 1, 228Nifedipine, 2, 283Nifenazone, 1, 234Nifluminic acid, 1, 256Nifuratrone, 2, 238Nifurdazil, 2, 239Nifurimide, 2, 239Nifuroxime, 2, 238Nifurpirinol, 2, 240Nifurprazine, 1, 231Nifurquinazol, 2, 383Nifursemizone, 2, 238Nifurthiazole, 2, 241Nikethamide, 1, 253Nilutamide, 6, 46Nilvadipine, 4, 107Nimazone, 2, 260Nimodipine, 3, 149Nimorazole, 2, 244Niridazole, 2, 269Nisbuterol, 3, 23Nisobamate, 2, 22Nisoxetine, 3, 32Nistremine acetate, 3, 88Nitazoxinide, 7, 101Nithiazole, 2, 268Nitisinone, 7, 47


Nitrafudam, 3, 130Nitrazepam, 1, 366Nitrimidazine, 1, 240Nitrofurantel, 1, 229Nitrofurantoin, 1, 230Nitrofurazone, 1, 229Nitrofuroxime, 1, 228Nitromifene, 3, 51Nivazol, 2, 159Nivimedone, 3, 67Nizatidine, 4, 95Noberastine, 5, 144Noberastine, 6, 139Nocodazole, 3, 176Nomifensine, 4, 146Noracylmethadol, 2, 58Norbolethone, 2, 151Norelgestimate, 7, 34Norephedrine, 1, 260Norethandrolone, 1, 170Norethindrone, 1, 164Norethindrone acetate, 1, 165Norethynodrel, 1, 168Norfloxacin, 4, 141Norgestatriene, 1, 168Norgestatrienone, 1, 186Norgestrel, 1, 167Normeperidine, 1, 300Normethadone, 1, 81Normethandrolone, 1, 170Norpipanone, 1, 81Nortriptyline, 1, 151Nufenoxole, 3, 42Nylidrin, 1, 69

Ocaperidone, 6, 103Ocfentanil, 5, 83Ocinaplon, 6, 173Octazamide, 2, 448Octopamine, 5, 23Octriptyline, 2, 223Ofloxacin, 4, 141Ofornine, 4, 102Oglufanide, 7, 142Olanzapine, 5, 169Olmesartan, 7, 111Olopatadine, 6, 97Olsalazine, 4, 42

Olvanil, 4, 35Omaciclovir, 7, 199Omapatrilat, 7, 191Omeprazole, 4, 133Omoconazole, 7, 94Onapristone, 5, 53Ondansetron, 5, 164Ontazolast, 6, 137Orbofiban, 6, 21Orconazole, 3, 133Orfadin, 7, 47Orlistat, 6, 28Ormaplatin, 5, 11Ormetoprim, 2, 302Ornidazole, 3, 131Orpanoxin, 3, 130Orphenadrine, 1, 42Oseltamivir, 7, 25Ospemifene, 7, 65Oxacephalothin, 1, 420Oxacillin, 1, 413Oxagrelate, 4, 151Oxamisole, 5, 14Oxamniquine, 2, 372Oxanamide, 1, 220Oxandrolone, 1, 174Oxantel, 2, 303Oxaprotiline, 4, 63Oxaprozin, 2, 263Oxarbazole, 3, 169Oxatomide, 3, 173Oxazepam, 1, 366Oxazolapam, 1, 370Oxeladin, 1, 90Oxendolone, 4, 66Oxethazine, 1, 72Oxetorene, 3, 247Oxfendazole, 2, 353Oxibendazole, 2, 352Oxiconazole, 5, 72Oxifungin, 3, 233Oxilorphan, 2, 325Oximonam, 4, 195Oxiperomide, 2, 290Oxiramide, 3, 40Oxisuran, 2, 280Oxmetidine, 3, 134Oxolamine, 1, 248


Oxolinic acid, 2, 370Oxprenolol, 1, 117Oxybutynin, 1, 93Oxycodone, 1, 290Oxyfedrine, 2, 40Oxymestrone, 1, 173Oxymetazoline, 1, 242Oxymetholone, 1, 173Oxymorphone, 1, 290Oxypendyl, 1, 430Oxypertine, 2, 343Oxyphenbutazone, 1, 236Oxyphencyclimine, 2, 75Oxyphenisatin, 2, 350Oxypurinol, 1, 426Oxytetracycline, 1, 212Ozolinone, 3, 140

Pagoclone, 6, 136Palinavir, 6, 10Paliperidone, 7, 209Palmoxiric acid, 4, 4Palonosetron, 6, 201Paludrine, 1, 115Pamaquine, 1, 345Pamatolol, 3, 28Panadiplon, 5, 173Pancopride, 5, 21Pancuronium chloride, 2, 163Pantoprazole, 5, 115Papaverine, 1, 347Para aminosalicylic acid, 1, 109Paraethoxycaine, 1, 10Paramethadione, 1, 232Paramethasone, 1, 200Paranyline, 2, 218Parapenzolate bromide, 2, 75Parconazole, 3, 133Parecoxib, 7, 92Pargyline, 1, 54Paroxetine, 5, 87Pazinaclone, 6, 135Pazoxide, 2, 395Pecazine, 1, 387Pefloxacin, 4, 141Pelanserin, 5, 94Peldesine, 6, 173Pelitinib, 7, 167

Pelitrexol, 7, 212Pelretin, 5, 8Pelrinone, 4, 116Pemedolac, 5, 165Pemerid, 2, 288Pemetrexed, 7, 193Pemirolast, 5, 150Penciclovir, 6, 183Penfluridol, 2, 334Pentamorphone, 5, 42Pentapiperium, 2, 76Pentaquine, 1, 346Pentazocine, 1, 297Pentethylcyclanone, 1, 38Pentiapine, 4, 220Pentizidone, 4, 86Pentobarbital, 1, 268Pentomone, 3, 248Pentopril, 4, 128Pentoxiphyline, 2, 466Pentylenetetrazole, 1, 281Peramavir, 7, 53Perazine, 1, 381Perfosfamide, 5, 102Pergolide, 3, 249Perindopril, 5, 111Perlapine, 2, 425Perphenazine, 1, 383Perzinfotel, 7, 39Pethidine, 1, 300Phenacaine, 1, 19Phenacemide, 1, 95Phenacetin, 1, 111Phenadoxone, 1, 80Phenaglycodol, 1, 219Phenazocine, 1, 298Phenazopyridine, 1, 255Phenbencillin, 1, 410Phenbenzamine, 2, 50Phenbutalol, 2, 110Phencarbamide, 2, 97Phencyclidine, 1, 56Phendimetrazine, 1, 260Phenelizine, 1, 74Pheneridine, 1, 301Phenethicillin, 1, 410Phenformin, 1, 75Phenindandone, 1, 147


Pheniprazine, 1, 74Pheniramine, 1, 77Phenmetrazine, 1, 260Phenobarbital, 1, 268Phenomorphan, 1, 294Phenoperidine, 1, 302Phenoxybenzamine, 1, 55Phenoxymethylpenicillin, 1, 410Phensuximide, 1, 226Phentermine, 1, 72Phentolamine, 1, 242Phenyl aminosalycilate, 2, 89Phenylbutazone, 1, 236Phenylephrine, 1, 63Phenylglutarimide, 1, 257Phenyltoloxamine, 1, 115Phenyramidol, 1, 165Pholcodeine, 1, 287Phthaloyl sulfathiazole, 1, 132Physostigmine, 1, 111Piboserod, 7, 221Picenadol, 4, 108Piclamilast, 6, 41Picumetrol, 5, 16Pimetine, 2, 286Piminodine, 1, 301Pimobendan, 5, 117Pimozide, 2, 290Pinacidil, 4, 102Pinadoline, 4, 202Pindolol, 2, 342Pinoxepin, 2, 419Pioglitazone, 5, 74Pipamazine, 1, 385Pipamperone, 2, 288Pipazethate, 1, 390Pipecurium bromide, 4, 70Piperacetazine, 1, 386Piperacillin, 3, 207Piperidolate, 1, 91Piperocaine, 1, 13Piperoxan, 1, 352Pipobroman, 2, 299Piposulfan, 2, 299Pipradol, 1, 47Piprandamine, 2, 459Piprozolin, 2, 270Piquindone, 4, 205

Piquizil, 2, 381Pirazolac, 3, 138Pirbencillin, 3, 207Pirbuterol, 2, 280Pirenperone, 3, 231Piretanide, 3, 58Pirexyl, 1, 115Piridicillin, 1, 260Piridocaine, 1, 13Pirindol, 1, 45Pirintramide, 1, 308Piriprost, 4, 160Piritrexim, 4, 169Pirmagrel, 4, 161Pirmenol, 3, 48Piroctone, 3, 149Pirodavir, 6, 101Pirogliride, 3, 57Pirolate, 3, 245Piromidic acid, 2, 470Piroxantrone, 5, 43Piroxicam, 2, 394Piroximone, 4, 94Pirprofen, 2, 69Pirqinozol, 3, 243Pirsidomine, 6, 88Pivampicillin, 1, 414Pivopril, 4, 7Pizotyline, 2, 420Plomestane, 5, 50Pobilukast, 6, 37Poldine mesylate, 2, 74Polythiazide, 1, 360Ponalrestat, 5, 132Posaconazole, 7, 105Practolol, 2, 106Pralatrexate, 7, 211Pramipexole, 6, 142Pramoxine, 1, 18Pranolium chloride, 2, 212Prasurgel, 7, 189Pravadoline, 5, 108Prazepam, 2, 405Praziquantel, 4, 213Prazocin, 2, 382Prednicarbate, 4, 71Prednimustine, 3, 93Prednisolone, 1, 192


Prednisolone acetate, 1, 192Prednisone, 1, 192Prednival, 2, 179Prednylene, 1, 197Premafloxacin, 6, 152Prenalterol, 3, 30Prenylamine, 1, 76Pridefine, 3, 49Prifelone, 5, 67Prilocaine, 1, 17Primidone, 1, 276Primodolol, 3, 29Prinomastat, 7, 54Prinomide, 5, 64Prinoxodan, 5, 130Prizidilol, 3, 151Probarbital, 1, 268Probenecid, 1, 135Probicromil, 4, 207Probucol, 2, 126Procainamide, 1, 14Procaine, 1, 9Procarbazine, 2, 27Procaterol, 3, 184Prochlorperazine, 1, 381Procinonide, 3, 94Procyclidine, 1, 47Prodilidine, 1, 305Prodolic acid, 2, 459Progabide, 4, 47Progesterone, 2, 164Proglumide, 2, 93Proguanil, 1, 280Prolintane, 1, 70Promazine, 1, 377Promethazine, 1, 373Pronethalol, 1, 66Prontosil, 1, 212Propafenone, 5, 17Propanidid, 2, 79Propantheline bromide, 1, 394Proparacaine, 1, 11Propenzolate, 2, 75Properidine, 1, 299Propicillin, 1, 410Propiomazine, 1, 376Propionylpromazine, 1, 380Propizepine, 2, 472

Propoxorphan, 3, 113Propoxycaine, 1, 10Propoxyphene, 1, 50Propranolol, 1, 117Propylhexedrine, 1, 37Propylphenazone, 1, 234Propylthiouracil, 1, 265Proquazone, 2, 386Proquinolate, 2, 368Prorenone, 2, 175Prostalene, 2, 5Prothipendyl, 1, 430Protriptyline, 1, 152Proxazole, 2, 271Proxicromil, 4, 205Pyrantel, 1, 266Pyrathiazine, 1, 373Pyrazineamide, 1, 277Pyrilamine, 1, 51Pyrimethamine, 1, 262Pyrindamine, 1, 145Pyrinoline, 2, 34Pyrovalerone, 2, 124Pyroxamine, 2, 42Pyrrobutamine, 1, 78Pyrrocaine, 1, 16Pyrroliphene, 2, 57Pyrroxan, 3, 191

Quazepam, 3, 196Quazinone, 4, 212Quazodine, 2, 379Quazolast, 4, 216Quetiapine, 6, 198Quiflapon, 6, 130Quilostigmine, 6, 195Quinacrine, 1, 396Quinapril, 4, 146Quinazocin, 2, 382Quinbolone, 2, 154Quinelorane, 5, 167Quinethazone, 1, 354Quinfamide, 3, 186Quinine, 1, 337Quinodinium bromide, 2, 139Quinpirole, 4, 205Quinterol, 2, 366


Rabeprazole, 6, 140Racemoramide, 1, 82Racemorphan, 1, 293Ragaglitazar, 7, 220Ralitoline, 6, 81Raloxifene, 5, 114Raltitrexed, 6, 159Raluridine, 6, 112Ramelteon, 7, 72Ramipril, 4, 84Ranitidine, 3, 131Ranolazine, 5, 94Rasagiline, 6, 57Reboxetine, 7, 61Recainam, 4, 37Reclazepam, 4, 153Regadenson, 7, 197Remifentanil, 5, 84Remiprostol, 6, 56Remoxipride, 4, 42Repaglinide, 7, 15Repirinast, 5, 175Reproterol, 3, 231Rescinnamine, 1, 319Revaprazan, 7, 122Ridogrel, 5, 80Riluzole, 6, 142Rimantidine, 2, 19Rimcazole, 4, 201Rimexolone, 5, 56Rimiterol, 2, 278Rimonabant, 7, 99Riodipine, 4, 107Rioprostil, 4, 13Ripazepam, 3, 234Risedronate, 6, 30Risocaine, 2, 91Risotilide, 5, 24Risperidone, 5, 150Ristianol, 4, 102Ritodrine, 2, 39Ritolukast, 5, 120Ritonavir, 6, 12Rivastigmine, 7, 66Rivoglitazone, 7, 157Rizatriptan, 6, 125Rocastine, 5, 153Rodocaine, 2, 450

Roflumilast, 7, 44Rogletimide, 5, 81Roletamide, 2, 103Rolgamidine, 4, 80Rolicyprine, 2, 50Rolitetracycline, 1, 216Rolodine, 2, 468Romazarit, 5, 68Ronidazole, 2, 245Ropinirole, 6, 132Ropitoin, 3, 139Roquinimex, 6, 150Rosoxacin, 3, 185Rosuvastatin, 7, 124Rotigotine, 7, 75Rotoxamine, 2, 32Roxatidine, 5, 26Roxifiban, 6, 21Rufinamide, 7, 108Rupinavir, 7, 9

Sabeluzole, 5, 86Salbutamol, 2, 280Salicylamide, 1, 109Salmeterol, 5, 16Salnacedin, 6, 49Salsalate, 2, 90Salvarsan, 1, 223Sanfetrinem, 6, 165Saperconazole, 6, 86Saprisartan, 6, 123Saquinavir, 6, 4Sarafloxacin, 5, 125Sarmoxicillin, 3, 205Sarpicillin, 3, 204Secalciferol, 5, 59Secobarbital, 1, 269Sedoxantrone, 6, 203Selfotel, 6, 99Selodenoson, 7, 196Sematilide, 5, 24Semaxanib, 7, 149Semustine, 2, 12Seproxetine, 5, 25Seratrodast, 6, 38Serazepine, 5, 177Sermetacin, 3, 166Sertindole, 6, 129


Sertraline, 4, 57Setoperone, 4, 172Sezolamide, 5, 147Sibopirdine, 6, 195Sibutramine, 5, 25Sildenafil, 6, 181Sitafloxacin, 7, 174Sitagliptan, 7, 206Sivelstat, 7, 54Solabegron, 7, 50Solifenacin, 7, 171Solypertine, 2, 342Somantidine, 4, 4Sonepiprazole, 7, 166Sontoquine, 1, 344Sorivudine, 6, 111Sotalol, 1, 66Sotalol, 5, 23Soterenol, 2, 40Sparfloxacin, 5, 126Spiradoline, 5, 9Spirapril, 4, 83Spirilene, 2, 292Spiromustine, 4, 5Spironolactone, 1, 206Spiropiperone, 1, 306Spiroplatin, 4, 16Spirothiobarbital, 1, 276Stanazole, 1, 174Statine, 5, 3Stavudine, 6, 114Stenbolone acetate, 2, 155Styramate, 1, 219Succinyl sulfathiazole, 1, 132Sudoxicam, 2, 394Sufentanil, 3, 118Sufotidine, 5, 77Sulazepam, 2, 403Sulbactam pivoxil, 4, 180Sulconazole, 3, 133Sulfabenzamide, 2, 112Sulfacarbamide, 1, 123Sulfacetamide, 1, 123Sulfachloropyridazine, 1, 124Sulfacytine, 2, 113Sulfadiazine, 1, 124Sulfadimethoxine, 1, 125Sulfadimidine, 1, 125

Sulfaethidole, 1, 125Sulfaguanidine, 1, 123Sulfaisodimidine, 1, 125Sulfalene, 1, 125Sulfamerazine, 1, 124Sulfameter, 1, 125Sulfamethizole, 1, 125Sulfamethoxypyridine, 1, 124Sulfamoxole, 1, 124Sulfanilamide, 1, 121Sulfanitran, 2, 115Sulfaphenazole, 1, 124Sulfaproxyline, 1, 123Sulfapyridine, 1, 124Sulfasalazine, 2, 114Sulfasomizole, 1, 124Sulfathiazole, 1, 124Sulfathiourea, 1, 123Sulfazamet, 2, 113Sulfinalol, 3, 25Sulfinpyrazone, 1, 238Sulfisoxazole, 1, 124Sulfonterol, 2, 42Sulformethoxine, 1, 125Sulfoxone, 1, 140Sulindac, 2, 210Sulnidazole, 2, 245Suloctidil, 3, 26Sulofenur, 5, 35Sulopenem, 6, 167Sulotraban, 5, 22Sulpiride, 2, 94Sulprostene, 3, 9Sulthiame, 2, 306Sulukast, 5, 28Sumarotene, 5, 37Sumatriptan, 5, 108Sunepitron, 7, 204Sunitinib, 7, 150Suporofen, 2, 65Suricainide, 4, 49Suritozole, 6, 88Suronacrine, 5, 167Symetine, 2, 29Syrosingopine, 1, 319

Taclamine, 2, 224Tacrine, 5, 166


Tadalafil, 7, 229Talabostat, 7, 84Talampicillin, 2, 438Talnetant, 7, 168Talniflumate, 3, 146Talopram, 2, 357Talsaclidine, 6, 105Taltobulin, 7, 11Taludipine, 5, 83Tameridone, 5, 144Tametraline, 3, 68Tamibarotene, 7, 76Tamoxifen, 2, 127Tamoxifen, 5, 32Tampramine, 4, 203Tamsulosin, 6, 48Tanaproget, 7, 178Tandamine, 2, 347Tandospirone, 5, 91Tandutinib, 7, 183Tanomastat, 7, 47Tariquidar, 7, 167Tasosartan, 6, 188Tazadolene, 4, 6Tazarotene, 6, 148Tazifylline, 4, 165Tazobactam, 5, 156Tazofelone, 6, 83Tazolol, 2, 110Tazomeline, 6, 198Tebufelone, 5, 30Tebuquine, 4, 28Tecadenoson, 7, 195Teclozan, 2, 28Tegafur, 3, 155Tegaserod, 7, 141Telinavir, 6, 7Telmisartan, 6, 140Teloxantrone, 6, 62Temafloxacin, 5, 123Tematropium, 5, 66Temazepam, 2, 402Temlastine, 4, 113Temocapril, 6, 119Temocillin, 4, 178Temodox, 6, 160Temozolomide, 6, 186Tenidap, 5, 109

Tenofovir, 7, 197Tenoxicam, 4, 173Tepoxalin, 5, 68Terazocin, 3, 194Terbinafine, 4, 55Terbogrel, 7, 60Terconazole, 3, 137Teriflumonide, 7, 93Terlakiren, 5, 4Terolidine, 2, 56Teroxirone, 4, 122Tertrabenazine, 1, 350Tesicam, 2, 379Tesimide, 2, 296Tesmilifene, 7, 58Testolactone, 1, 160Testosterone cypionate, 1, 172testosterone decanoate, 1, 172testosterone propionate, 1, 172Tetomilast, 7, 101Tetracaine, 1, 110Tetracycline, 1, 212Tetrahydrocannabinol, 1, 394Tetrahydrozoline, 1, 242Tetramisole, 1, 431Tetrantoin, 1, 246Tetrazolast, 5, 181Tetroxyprim, 3, 154Tetrydamine, 2, 352Tezacitabine, 7, 131Thalidomide, 1, 257Thenium closylate, 2, 99Theobromine, 1, 423Theophylline, 1, 423Thiabarbital, 1, 275Thiabendazole, 1, 325Thiabutazide, 1, 358Thiamphenicol, 2, 45Thiamprine, 2, 464Thiamylal, 1, 274Thiazinum chloride, 3, 240Thiazolsulfone, 1, 141Thiethylperazine, 1, 382Thiofuradene, 1, 231Thioguanine, 2, 464Thiopental, 1, 274Thiopropazate, 1, 383Thioridazine, 1, 389


Thiothixene, 1, 400Thonzylamine, 1, 52Thozalinone, 2, 265Thyromedan, 2, 79Thyroxine, 1, 95Tiaconazole, 3, 133Tiacrilast, 4, 150Tiacrilast, 5, 130Tiagabine, 6, 101Tiamenidine, 3, 137Tiapamil, 4, 34Tiaramide, 4, 134Tiazofurin, 4, 96Tibolone, 2, 147Tibric acid, 2, 87Ticabesone propionate, 4, 75Ticarcillin, 2, 437Ticlopidine, 3, 228Ticolubant, 6, 96Ticrynafen, 2, 104Tidembersat, 7, 164Tifurac, 5, 111Tigemonam, 5, 155Tigesterol, 2, 145Tiletamine, 2, 15Tilmacoxib, 7, 91Tilomisole, 4, 217Tilorone, 2, 219Tiludronate, 6, 30Timcodar, 7, 60Timefurone, 4, 208Timobesone propionate, 4, 75Timolol, 2, 272Tinabinol, 4, 210Tiodazocin, 3, 194Tioperidone, 3, 192Tiopinac, 3, 238Tiospirone, 5, 91Tioxidazole, 3, 179Tipentosin, 4, 129Tipifarnib, 7, 192Tiprednane, 4, 74Tiprinast, 4, 173Tiprinavir, 7, 120Tipropidil, 3, 28Tiquinamide, 2, 372Tirapazamine, 6, 160Tirilazad, 5, 61

Tirofiban, 6, 21Tixanox, 3, 236Tixocortol, 4, 73Tizanidine, 6, 144Tocainide, 3, 55Tolamolol, 2, 110Tolazamide, 1, 241Tolbutamide, 1, 136Tolcapone, 6, 41Tolciclate, 3, 69Tolgabide, 4, 47Tolimidone, 3, 156Tolindate, 2, 208Tolmetin, 2, 234Tolnaftate, 2, 211Tolpyrramide, 2, 116Tolrestat, 4, 56Tolterodine, 7, 59Toltrazuril, 5, 99Tolvaptan, 7, 186Tolycaine, 1, 17Tomelukast, 5, 30Tomoxetine, 4, 30Tonazocine, 3, 115Topiramate, 5, 90Topixantrone, 7, 227Topotecan, 5, 179Topterone, 3, 88Torborinone, 7, 172Torcetrapib, 7, 169Toremifene, 5, 33Torsemide, 5, 82Tosifen, 3, 62Tosufloxacin, 5, 126Tralonide, 2, 198Tramadol, 2, 17Tramazoline, 1, 243Tranexamic acid, 2, 9Tranilast, 4, 44Transcainide, 4, 112Tranylcypromine, 1, 73Travoprost, 7, 22Trazodone, 2, 472Trefentanil, 6, 102Treloxinate, 2, 432Trepipam, 4, 146Trepostinil, 7, 81Triacetamide, 2, 94


Triafungin, 3, 233Triamcinolone, 1, 201Triamcinolone acetonide, 1, 201Triampyzine, 2, 298Triamterine, 1, 427Triazolam, 1, 368Triazuryl, 2, 305Trichlormethiazide, 1, 359Triclonide, 2, 198Trifenagrel, 4, 282Triflocin, 2, 282Triflubazam, 2, 406Triflumidate, 2, 98Trifluperidol, 1, 306Triflupromazine, 1, 380Trihexyphenidyl, 1, 47Triiodothyronine, 1, 95Trilostane, 2, 158Trimazocin, 2, 382Trimeprazine, 1, 378Trimethadone, 1, 232Trimethobenzamide, 1, 110Trimethoprim, 1, 262Trimethoquinol, 2, 374Trimetozine, 2, 94Trimetrexate, 4, 149Trioxasalen, 1, 334Trioxyfene, 3, 70Tripamide, 4, 51Tripelennamine, 1, 51Triprolidine, 1, 78Trofosfamide, 3, 161Troglitazone, 6, 83Tropanserin, 4, 39Tropocaine, 1, 7Trovafloxacin, 6, 154Troxacitabine, 7, 131Tubulozole, 4, 91Turosteride, 6, 65Tybamate, 2, 22

Valacyclovir, 6, 182Valdecoxib, 7, 92Valsartan, 6, 23Vandetanib, 7, 181Vapiprost, 5, 5Vardefanil, 7, 205Varespladib, 7, 144

Vedaprofen, 6, 58Velnacrine, 5, 167Venlafaxine, 5, 26Verilopam, 3, 121Verlukast, 5, 121Verofylline, 2, 230Vesnarinone, 5, 122Vidagliptin, 7, 84Viloxazine, 2, 306Vinbarbital, 1, 269Viprostol, 4, 13Vofopitant, 7, 110Volazocine, 2, 327Voriconazole, 7, 103Vorozole, 6, 144

Warfarin, 1, 131

Xamoterol, 4, 28Xanomeline, 6, 98Xanoxate, 3, 235Xemilofiban, 6, 20Xenalipin, 5, 19Xilobam, 3, 56Ximelagatran, 7, 16Xipamide, 2, 93Xorphanol, 4, 61Xylamidine, 2, 54Xylazine, 2, 307Xylometazoline, 1, 242

Zacopride, 4, 42Zafirlukast, 6, 130Zalcitabine, 5, 98Zaldaride, 6, 199Zalepon, 6, 173Zalospirone, 6, 117Zaltidine, 4, 95Zanamivir, 6, 95Zankiren, 6, 2Zanoterone, 6, 65Zatosetron, 5, 111Zenarestat, 7, 184Zeniplatin, 5, 12Zidomethacin, 3, 166Zifrosilone, 6, 42Zileutron, 5, 113


Zimeldine, 3, 49Zindotrine, 4, 168Zinoconazole, 4, 92Ziprasidone, 6, 134Zofenopril, 4, 83Zolamine, 1, 52Zolamine, 1, 52Zolazepam, 4, 174

Zoledronate, 6, 30Zolmitriptan, 6, 126Zolpidem, 4, 162Zolpidem, 4, 83Zolterine, 2, 301Zoniclezole, 6, 137Zopolrestat, 5, 132Zosuquidar, 7, 79


the organic chemistry of drug synthesis vol 7 by daniel lednicer

Health & Medicine

irritable

john wiley

narrow therapeutic

congestive

strongly acidic

trityl protecting

membered heterocycles

silyl protecting