Strategies for Organic Drug Synthesis

690 Pages·2008·29.8 MB·english

by  Daniel Lednicer

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