THE ORGANICCHEMISTRY OFDRUG SYNTHESIS

Volume 7

DANIEL LEDNICERNorth Bethesda, MD

InnodataFile Attachment9780470180662.jpg

THE ORGANICCHEMISTRY OFDRUG SYNTHESIS

THE ORGANICCHEMISTRY OFDRUG SYNTHESIS

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 chemists 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 triptandrugs 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