THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS

THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS

THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS Volume 7 DANIEL LEDNICER North Bethesda, MD

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

CONTENTS Preface xi 1 OPEN-CHAIN COMPOUNDS 1 1. Peptidomimetic Compounds / 2 A. Antiviral Protease Inhibitors / 2 1. Human Immunodeficiency Virus / 2 2. Human Rhinovirus / 9 2. Miscellaneous Peptidomimetic Compounds / 11 References / 19 2 ALICYCLIC COMPOUNDS 21 1. Monocyclic Compounds / 21 A. Prostaglandins / 21 B. Antiviral Agents / 25 C. Miscellaneous Monocyclic Compounds / 29 2. Polycyclic Compounds: Steroids / 31 A. 19-Nor Steroids / 31 B. Corticosteroid Related Compounds / 34 vii

viii CONTENTS 3. Polycyclic Compounds / 38 References / 40 3 MONOCYCLIC AROMATIC COMPOUNDS 43 1. Arylcarbonyl Derivatives / 43 2. Biphenyls / 47 3. Compounds Related to Aniline / 50 4. Compounds Related to Arylsulfonic Acids / 53 5. Diarylmethanes / 58 6. Miscellaneous Monocyclic Aromatic Compounds / 60 References / 67 4 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING 69 1. Indenes / 69 2. Naphthalenes / 73 3. Tetrahydronaphthalenes / 74 4. Other benzofused carbocyclic compounds / 79 References / 81 5 FIVE-MEMBERED HETEROCYCLES 83 1. Compounds with One Heteroatom / 83 2. Compounds with Two Heteroatoms / 91 A. Oxazole and Isoxazoles / 91 B. Imidazoles and a Pyrrazole / 94 C. Thiazoles / 99 D. Triazoles / 103 E. Tetrazoles / 109 References / 112 6 SIX-MEMBERED HETEROCYCLES 115 1. Compounds with One Heteroatom / 115 A. Pyridines / 115 B. Reduced Pyridines / 117 C. Miscellaneous / 119

CONTENTS ix 2. Compounds with Two Heteroatoms / 121 A. Pyrimidines / 121 B. Miscellaneous Six-Membered Heterocycles / 133 References / 136 7 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING 139 1. Compounds with One Heteroatom / 139 A. Benzofurans / 139 B. Indoles / 141 C. Indolones / 148 D. Miscellaneous Compounds with One Heteroatom / 153 2. Five-Membered Rings with Two Heterocyclic Atoms / 156 A. Benzimidazoles / 156 B. Miscellaneous Compounds / 158 References / 160 8 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING 163 1. Compounds with One Heteroatom / 163 A. Benzopyrans / 163 B. Quinolines and Their Derivatives / 167 C. Quinolone Antibacterial Agents / 172 2. Compounds with Two Heteroatoms / 176 A. Benzoxazines / 176 B. Quinazolines / 178 C. Miscellaneous Benzo-Fused Heterocycles / 184 References / 186 9 BICYCLIC FUSED HETEROCYCLES 189 1. Compounds with Five-Membered Rings Fused to Six-Membered Rings / 189 A. Compounds with Two Heteroatoms / 189 B. Compounds with Three Heteroatoms / 191 C. Compounds with Four Heteroatoms / 195

x CONTENTS 2. Compounds with Two Fused Six-Membered Rings / 208 3. Miscellaneous Compounds with Two Fused Heterocyclic Rings: Beta Lactams / 213 References / 215 10 POLYCYCLIC FUSED HETEROCYCLES 217 1. Compounds with Three Fused Rings / 217 2. Compounds with Four Fused Rings / 228 3. Compounds with Five or More Fused Rings: Camptothecins / 230 References / 232 Subject Index 233 Cross Index of Biological Activity 241 Cumulative Index 245

PREFACE The first volume of The Organic Chemistry of Drug Synthesis was originally visualized as a single free-standing book that outlined the syntheses of most drugs that had been assigned non-proprietary names in 1975 at the time the book was written. Within a year or so of publication in 1977, it had become evident that a good many drugs had been overlooked. That and the encouraging reception of the original book led to the preparation of a second volume. That second book not only made up for the lacunae in the original volume but also covered additional new drug entities as well. With that second volume assignment of non-proprietary names by USAN became the criterion for inclusion. That book, published in 1980, thus included in addition all agents that had been granted USAN since 1976. What had been conceived as a single book at this point became a series. The roughly 200 new USAN coined every five years over the next few decades turned out to nicely fit a new volume in the series. This then dictated the frequency for issuing new compendia. After the most recent book in the series, Volume 6, was published in 1999, it became apparent that a real decline in the number of new drug entities assigned non-proprietary names had set in. The customary half-decade interval between books was apparently no longer appropriate. A detailed examination of the 2005 edition of the USAN Dictionary of Drug Names turned up 220 new non-proprietary names that had been assigned since the appearance of Volume 6. Many of these compounds represent quite novel structural types first identified by sophisticated new xi

xii PREFACE cell-based assays. This clearly indicated the need for the present volume in the 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 their biological activities. This is occasionally awkward since compounds with the same biological activity but significantly different structures are relegated to different chapters, a circumstance particularly evident with estrogen antagonists that appear in three different chapters. The cross index found at the end of the book, it is hoped, partly overcomes this problem. The syntheses are discussed from an organic chemist s point of view, accompanied by the liberal use of flow diagrams. As was the case in the preceding volumes, a thumbnail explanation of the biological activity of each new compound precedes the discussion of its biological activity. Several trends in the direction of drug discovery research seemed to emerge during the preparation of this book. Most of the preceding volumes included one or more therapeutic classes populated by many structurally related potential drugs. Volume 6 for example described no fewer than a half dozen HIV-protease inhibitors and a similar number of the triptan drugs aimed at treating migraine. The distribution of therapeutic activities in the present volume is quite distinct from that found in the earlier books. This new set, for example, includes a sizeable number of antineoplastic and antiviral agents. These two categories together in fact account for just over one third of the compounds in the present volume. The antitumor candidates are further distinct in that specific agents act against very specific tumor-related biological end points. This circumstance combined with mechanism based design in other disease areas probably reflect the widespread adoption of in-vitro screening in the majority of pharmaceutical research laboratories. The use of combinatorial chemistry for generating libraries to feed in-vitro screens has also become very prevalent over the past decade. This book is silent on that topic since compounds are only included when in a quite advanced developmental stage. Some of the structures that include strings of unlikely moieties suggest that those compounds may have been originally prepared by some combinatorial process. The internet has played a major role in finding the articles and patents that were required to put this account together. The NIH-based website PubChem was an essential resource for finding structures of compounds that appear in this book; hits more often than not include CAS Registry Numbers. References to papers on the synthesis of compounds could sometimes be found with the other NIH source PubMed. The ubiquitous Google was also quite helpful for finding sources for syntheses. In some

PREFACE xiii of the earlier volumes, references to patents were accompanied by references to the corresponding CAS abstract since it was often difficult to access patents. The availability of actual images of all patents from either the U.S. patent office (www.uspto.gov) or those from European elsewhere (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 and organic chemists as well as graduate and advanced undergraduate students in organic and medicinal chemistry. The book assumes a good working knowledge of synthetic organic chemistry and some exposure to modern biology. As a final note, I would like to express my appreciation to the staff of the library in Building 10 of the National Institutes of Health. Not only were they friendly and courteous but they went overboard in fulfilling requests that went well beyond their job descriptions.