STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN Second Edition DANIEL LEDNICER STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN Second Edition DANIEL LEDNICER Copyright # 2009 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Sections 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. 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Searle in Skokie, Upjohn’s Building 25 in Kalamazoo and the diminutive Chemistry Annex at the Adria Laboratories just outside Dublin, Ohio. CONTENTS PREFACE xv 1 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS 1 1.1 Prostaglandins / 1 1.2 Peptidomimetic Compounds / 19 1.2.1 Protease Inhibitors / 19 1.2.1.1 Introduction / 19 1.2.1.2 Renin Inhibitors / 20 1.2.1.3 Antiviral Compounds / 22 1.2.2 Fibrinogen Receptor Antagonists / 30 1.2.3 Antitumor Peptidomimetic / 34 1.3 Retinoids / 35 1.4 A Miscellaneous Drug / 38 References / 40 2 DRUGS BASED ON A SUBSTITUTED BENZENE RING 43 2.1 Arylethanolamines / 43 2.2 Aryloxypropanolamines / 54 2.2.1 b-Blockers / 54 2.2.2 Non-Tricyclic Antidepressants (SSRIs) / 57 vii viii CONTENTS 2.3 Arylsulfonic Acid Derivatives / 61 2.3.1 Antibacterial Sulfonamides / 61 2.3.2 Diuretic Agents / 63 2.3.3 Oral Hypoglycemic Agents / 65 2.3.4 Miscellaneous Arylsulfonamides / 70 2.4 Arylacetic and Arylpropionic Acids / 71 2.4.1 Arylacetic acid “Fenacs” / 71 2.4.2 Arylpropionic Acid “Profens” / 75 2.4.3 Arylacetamide Antiarrhythmic Compounds / 78 2.5 Leukotriene Antagonists / 81 2.6 Miscellaneous Compounds / 84 References / 86 3 INDENES, NAPHTHALENES, AND OTHER POLYCYCLIC AROMATIC COMPOUNDS 89 3.1 Indenes / 90 3.2 Naphthalenes / 94 3.2.1 Antifungal Agents / 94 3.2.2 Miscellaneous Naphthalenes / 97 3.3 Partly Reduced Naphthalenes / 99 3.3.1 Bicyclic Retinoids / 99 3.3.2 Another b-Blocker / 101 3.3.3 Aminotetralin CNS Agents / 102 3.4 Tricyclic Compounds / 105 3.4.1 Dibenzocycloheptane and Dibenzocycloheptene Antidepressants / 105 3.4.2 Antidepressants Based on Dihydroanthracenes / 110 3.4.3 Anthraquinones: The “Antrone” Chemotherapy Agents / 113 References / 116 4 STEROIDS; PART 1: ESTRANES, GONANES, AND ANDROSTANES 119 4.1 Introduction / 119 4.2 Steroid Starting Materials / 120 4.2.1 From Diosgenin / 121 4.2.2 From Soybean Sterols / 121 4.3 Estranes / 123 4.3.1 Synthesis of Estranes / 123 4.3.2 Drugs Based on Estranes / 125 CONTENTS ix 4.4 Gonanes, the 19-nor Steroids / 128 4.4.1 Progestational Compounds / 128 4.4.2 Progesterone Antagonists / 137 4.4.3 Androgenic Compounds / 140 4.5 Androstanes / 142 4.5.1 Starting Materials / 142 4.5.2 Androgenic Compounds / 143 4.5.3 Antiandrogens / 150 4.5.4 Aldosterone Antagonists / 153 References / 157 5 STEROIDS; PART 2: COMPOUNDS RELATED TO PROGESTERONE, CORTISONE, AND CHOLESTEROL 161 5.1 Introduction / 161 5.2 Progestins / 161 5.3 Corticosteroids / 169 5.4 Compounds Derived from Cholesterol / 186 References / 189 6 NONSTEROIDAL SEX HORMONES AND THEIR ANTAGONISTS 191 6.1 Introduction / 191 6.2 Estrogens / 191 6.2.1 Nonsteroidal Estrogens / 191 6.2.2 Nonsteroid Estrogen Antagonists / 195 6.2.2.1 Arylethylenes / 195 6.2.2.2 Carbocyclic Ethylenes Fused to a Benzene Ring / 200 6.2.2.3 Heterocyclic Ethylenes Fused to a Benzene Ring / 203 6.2.3 Nonsteroid Androgen Antagonists / 207 6.2.4 A Nonsteroid Progestin Agonist / 209 References / 210 7 OPIOID ANALGESICS 213 7.1 Introduction / 213 7.2 Drugs Derived from Morphine / 214 7.3 Compounds Prepared from Thebaine / 216 x CONTENTS 7.4 Morphinans / 219 7.5 Benzomorphans / 223 7.6 Analgesics Based on Nonfused Piperidines / 226 7.6.1 4-Arylpiperidines: Meperidine and Its Analogues / 226 7.6.2 4-Amidopiperidines: Compounds Related to Fentanyl / 229 7.6.3 Miscellaneous Compounds / 234 7.6.3.1 1,2-Bisaminoceclohexanes / 234 7.6.3.2 Open Chain Compounds / 236 References / 237 8 DRUGS BASED ON FIVE-MEMBERED HETEROCYCLES 239 8.1 Introduction / 239 8.2 Rings that Contain One Heteroatom / 239 8.2.1 Furans / 239 8.2.2 Pyrrole and Its Derivatives / 241 8.2.2.1 NSAIDS and a “Statin” / 241 8.2.2.2 ACE Inhibitors / 246 8.2.2.3 Miscellaneous Compounds / 251 8.3 Rings that Contain Two Heteroatoms / 258 8.3.1 Cyclooxygenase 2 (COX-2) Inhibitor NSAIDs / 258 8.3.2 Oxazoles, Isoxazoles, and their Derivatives / 262 8.3.3 Imidazoles / 269 8.3.4 Imidazolines / 287 8.3.5 Modified Imidazoles / 291 8.3.6 Pyrrazolones and Pyrrazolodiones / 295 8.3.7 Thiazoles and Related Sulfur–Nitrogen-Containing Heterocycles / 298 8.4 Rings that Contain Three or More Heteroatoms / 304 8.4.1 1,2,4-Oxadiazoles / 304 8.4.2 Triazoles / 306 8.4.3 Thiadiazoles / 311 8.4.4 Tetrazoles / 313 References / 314 9 DRUGS BASED ON SIX-MEMBERED HETEROCYCLES 319 9.1 Rings that Contain One Heteroatom / 319 9.1.1 Pyrans / 319 9.1.2 Pyridines / 323 9.1.3 1,4-Dihydropyridines / 329 CONTENTS xi 9.1.4 Piperidines / 332 9.1.4.1 Psychotropic Compounds / 332 9.1.4.2 Miscellaneous Piperidines / 336 9.1.5 Pyridones and Glutarimides / 337 9.2 Rings that Contain Two Heteroatoms / 341 9.2.1 Pyridazines / 341 9.2.2 Pyrimidines / 344 9.2.2.1 Antibacterial Agents / 344 9.2.2.2 Antiviral and Antineoplastic Pyrimidines / 348 9.2.2.3 Miscellaneous Pyrimidines / 356 9.2.3 Pyrimidones / 359 9.2.4 Triketopyrimidines: The Barbiturates / 363 9.2.5 Pyrazines / 364 9.2.6 Piperazines / 366 9.3 Rings Containing Three Heteroatoms: The Triazines / 376 References / 379 10 FIVE-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 383 10.1 Compounds that Contain One Heteroatom / 383 10.1.1 Benzofurans / 383 10.1.2 Indoles / 389 10.1.3 Indolines and Isoindolines / 401 10.2 Compounds that Contain Two Heteroatoms / 407 10.2.1 Indazoles / 407 10.2.2 Benzimidazoles / 408 10.2.3 Benzoxazoles and Benzisoxazoles / 419 10.2.4 Benzothiazoles / 421 10.3 Compounds that Contain Three Heteroatoms / 423 References / 425 11 SIX-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 429 11.1 Compounds that Contain One Heteroatom / 429 11.1.1 Coumarins / 429 11.1.2 Chromones / 432 11.1.3 Benzopyrans / 435 11.1.4 Quinolines / 440 11.1.4.1 Antimalarial Compounds / 440 11.1.4.2 Other Quinolines / 444 xii CONTENTS 11.1.5 Quinolones / 454 11.1.5.1 Antibacterial Agents / 454 11.1.5.2 Miscellaneous Quinolones / 462 11.1.6 Isoquinoline and Its Derivatives / 463 11.2 Compounds that Contain Two Heteroatoms / 467 11.2.1 Benzodioxans / 467 11.2.2 Miscellaneous Fused Rings that Include Oxygen / 470 11.2.3 Cinnolines and Phthalazines / 472 11.2.4 Quinazolines / 476 11.2.5 Quinazolones / 482 11.3 Compounds that Contain Three Heteroatoms / 488 References / 490 12 SEVEN-MEMBERED HETEROCYCLIC RINGS FUSED TO BENZENE 495 12.1 Compounds with a Single Heterocyclic Atom / 495 12.2 Compounds with Two Heteroatoms / 499 12.2.1 Benzodiazepine Anxiolytic Agents / 499 12.2.2 Other Seven-Membered Heterocycles Fused to a Benzene Ring / 508 References / 513 13 HETEROCYCLES FUSED TO TWO AROMATIC RINGS 515 13.1 Compounds Containing a Single Heteroatom / 515 13.1.1 Derivatives of Dibenzopyran and Dibenzoxepin / 515 13.1.2 Dibenzo Heterocycles Containing One Ring Nitrogen Atom / 520 13.1.3 Dibenzo Heterocycles with One Sulfur Atom / 527 13.2 Compounds Containing Two Heteroatoms / 532 13.2.1 Phenothiazines / 532 13.2.2 A Dibenzoxazine / 535 13.2.3 Dibenzodiazepines, Dibenzoxazepines, and a Dibenzothiazepine / 536 13.3 Pyridine-Based Fused Tricyclic Compounds / 540 References / 543 14 BETA LACTAM ANTIBIOTICS