Strategies for Organic Drug Synthesis and Design, Second Edition

689 Pages·2008·26.46 MB·English

by  Daniel Lednicer(auth.)

STRATEGIES FOR
ORGANIC DRUG
SYNTHESIS AND DESIGN
STRATEGIES FOR
ORGANIC DRUG
SYNTHESIS AND DESIGN
Second Edition
DANIEL LEDNICER
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ISBN978-0-470-19039-5
PrintedintheUnitedStatesofAmerica
10 9 8 7 6 5 4 3 2 1
To the memory of now-defunct laboratories where once I practiced
my craft: Building H at G.D. 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 Ringsthat 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 Ringsthat 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 Ringsthat 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 Ringsthat 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 Ringsthat 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 TOA
BENZENE RING 383
10.1 Compoundsthat Contain One Heteroatom / 383
10.1.1 Benzofurans / 383
10.1.2 Indoles / 389
10.1.3 Indolines and Isoindolines / 401
10.2 Compoundsthat 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 Compoundsthat Contain Three Heteroatoms / 423
References / 425
11 SIX-MEMBERED HETEROCYCLES FUSED TOA
BENZENE RING 429
11.1 Compoundsthat 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 Compoundsthat Contain Two Heteroatoms / 467
11.2.1 Benzodioxans / 467
11.2.2 Miscellaneous Fused Ringsthat Include Oxygen / 470
11.2.3 Cinnolines and Phthalazines / 472
11.2.4 Quinazolines / 476
11.2.5 Quinazolones / 482
11.3 Compoundsthat 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 TOTWOAROMATIC 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 545
14.1 Penicillins / 546
14.2 Cephalosporins / 558