Synthesis of Essential Drugs

-., f Synthesis of Essential Drugs R.vS. Vardanyan V.J. Hruby Dt pml»u nl nt Chcini\lr\ IMH> I I ~m\cr\it\ I /m. / M;\ <>! \nroiui I in son. I S\ HiiEVIER Amsterdam - Boston - Heidelberg - London - New York - Oxford Paris - San Diego - San Francisco - Singapore - Sydney - Tokyo

Preface vii 1 General Anesthetics 1 1.1 Inhalation anesthetics 1 1.2 Noninhalation anesthetics 4 2 Local Anesthetics 9 2.1 Local Anesthetics of the Aminoether Series 12 2.2 Local Anesthetics of the Aminoamide Series 14 2.3 Topical Anesthetics 17 3 Analgesics 19 3.1 Opioid Analgesics 20 3.1.1 Agonists 21 3.1.2 Mixed agonists/antagonists 33 3.1.3 Opioid antagonists 37 3.2 Nonsteroid Anti-Inflammatory Drugs and Anti-Fever Analgesics 38 3.2.1 Salicylic acid derivatives 39 3.2.2 Pyrazolonees 40 3.2.3 p-aminophenol derivatives 42 3.2.4 Anthranylic acid derivatives 42 3.2.5 Propionic acid derivatives 44 3.2.6 Acetic acid derivatives 46 3.2.7 Indolyl/indeneacetic acids 47 3.2.8 Oxicames 51 4 Soporific Agents (Hypnotics and Sedative Drugs) 57 4.1 Barbiturates 58 4.1.1 Long-acting barbiturates 59 4.1.2 Intermediate-acting barbiturates 60 4.1.3 Short-action barbiturates 61 4.1.4 Ultrashort-action barbiturates 62 4.2 Benzodiazepines 62 4.3 Other Hypnotics and Sedative Drugs 65 5 Anxiolytics (Tranquilizers) 69 5.1 Benzodiazepines 69 5.2 Anxiolytic of Nonbenzodiazepine Structures 78

6 Antipsychotics (Neuroleptics) 6.1 Phenothiazine derivatives 84 6.2 Thioxanthene derivatives 88 6.3 Butyrophenone derivatives 91 6.4 Dihydroindolone derivatives 93 6.5 Dibenzoxazepine and dibenzdiazepine derivatives 94 6.6 Diphenylbutylpiperidine derivatives 96 6.7 Other neuroleptics 99 6.8 Lithium derivatives 99 83 7 Antidepressants 103 7.1 Tricyclic Antidepressants 104 7.1.1 Tertiary amines representatives of tricyclic antidepressants 104 7.1.2 Secondary amines representatives of tricyclic antidepressants 107 7.2 Monoaminooxidase Inhibitors 110 7.3 Second-Generation Antidepressants (Atypical Antidepressants) 112 7.4 Amphetamines and other CNS Stimulators 114 8 Central Nervous System Stimulants 117 8.1 Psychomotor Stimulants 117 8.1.1 Methylxanthines 117 8.1.2 Amphetamines, methylphenidate, and pemoline 118 8.2 Respiratory Stimulants or Analeptics 121 8.3 Appetite Suppressants or Anorectics 123 9 Antiepileptic Drugs 125 9.1 Hydantoin Derivatives 126 9.2 Barbiturates 127 9.3 Succinimides 128 9.4 Valproic Acid 129 9.5 Carbamazepine 129 9.6 Benzodiazepines 130 9.7 Acetazolamide 131 9.8 Oxazolidines 131 10 Antiparkinsonian Drugs 135 10.1 Drugs Affecting the Dopaminergic Systems of the Brain 135 10.2 Anticholinergic Drugs (Central Cholinoblockers) 138 VI Adrenergic (Sympathomimetic) Drugs 143 11.1 Direct-Acting Agonists 146 11.1.1 Drugs stimulating a- and /3-adrenoreceptors 146

11.1.2 Drugs stimulating predominantly ^-adrenoreceptors 148 11.1.3 Drugs stimulating predominantly a-adrenoreceptors 153 11.1.4 Antiedema sympathomimetics 153 11.2 Indirect-Acting Agonists 155 11.3 Agonists of Mixed Action 155 12 Adrenoblocking Drugs 161 12.1 J3-Adrenoblockers 162 12.2 a-adrenoblockers 167 12.2.1 Long-lasting noncompetitive antagonists 168 12.2.2 Nonselective, reversible competitive adrenoblockers 169 12.2.3 Reversible, competitive a,-selective adrenoblockers 170 12.2.4 Ergot alkaloids (alkaloids of ergot) 171 12.2.5 Selective 0,-adrenoblockers 172 12.3 Adrenergic Neuron Blockers 172 13 Cholinomimetics 179 13.1 Direct-Acting Cholinomimetics 180 13.1.1 Choline esters 180 13.1.2 Natural muscarinic alkaloids 183 13.1.3 Natural nicotinic alkaloids 185 13.2 Indirect-Acting Cholinomimetics 186 13.2.1 Reversible cholinesterase inhibitors 187 13.2.2 Carbamates 187 13.2.3 Quaternary amines 189 13.2.4 Irreversible cholinesterase inhibitors 190 13.2.5 Other organophosphorous cholinesterase inhibitors 191 14 Anticholinergic Drugs 195 14.1 Antimuscarinic Drugs 195 14.1.1 Alkaloids 196 14.1.2 Anticholinergics of the quaternary amine series 198 14.1.3 Antiparkinsonian drugs of the quaternary amine series 202 14.1.4 Antispasmodics of the tertiary series 202 14.1.5 Mydriatics of the tertiary amine series 204 14.2 Ganglioblocking Substances 205 15 Muscle Relaxants 209 15.1 Neuromuscular Junction Blocking Agents 210 15.1.1 Antidepolarizing neuromuscular junction blockers 210 15.1.2 Depolarizing neuromuscular blockers 213 15.2 Direct-Acting Muscle Relaxants 214 15.3 Centrally Acting Muscle Relaxants 215

16 Antihistamine Drugs 219 16.1 H, Antihistamine Drugs 221 16.1.1 Aminoalkyl esters 222 16.1.2 Ethylenediamines 224 16.1.3 Alkylamines 225 16.1.4 Piperazines 226 16.1.5 Phenothiazines 227 16.1.6 Piperidines 228 16.2 H, Receptor Antagonists 230 17 Cardiotonic Drugs 237 17.1 Cardiac Glycosides 238 17.2 Other Positive Inotropic Drugs 241 18 Antiarrhythmic Drugs 245 18.1 Group I Drugs 246 18.1.1 Subgroup IA 246 18.1.2 Subgroup IB 248 18.1.3 Subgroup IC 250 18.2 Group II Drugs 251 18.3 Group III Drugs 252 18.4 Group IV Drugs 253 19 Antianginal Drugs 257 19.1 Nitrates and Nitrites 257 19.2 js-adrenoblockers 259 19.3 Calcium channel blockers 261 19.4 Other drugs 265 20 Hypolipidemic Agents 269 20.1 Bile acid sequesters 270 20.2 Drugs that inhibit cholesterol synthesis 272 20.3 Other drugs 275 21 Diuretics 277 21.1 Osmotic Diuretics 277 21.2 Carbonic anhydrase Activity Suppressing Diuretics 278 21.3 Thiazide Diuretics 280 21.3.1 Drugs related to thiazide diuretics 284 21.4 Loop Diuretics 286 21.5 Potassium Sparing Diuretics 288

22 Antihypertensive Drugs 295 22.1 Diuretics 296 22.1.1 Thiazide diuretics 297 22.1.2 Thiazide-related drugs 297 22.1.3 Potassium sparing diuretics 297 22.2 /3-adrenoblockers 298 22.3 Centrally acting adrenergic drugs (sympatholytics) 299 22.4 Peripherally acting sympatholytics (a-adrenoblockers) 300 22.4.1 Reversible competitive «-selective adrenoblockers 301 22.4.2 Adrenergic neuron blockers 301 22.5 Calcium channel blockers 303 22.6 Myotropic hypotensive drugs 304 22.7 Angiotensin-converting enzyme inhibitors 305 22.8 Calcium channel activators 308 23 Drugs for Treating Respiratory System Illnesses 311 23.1 Antiedema, Vasoconstricting Drugs 311 23.2 Anticough and Expectorant Agents 312 23.2.1 Narcotic anticough drugs 312 23.2.2 Non-narcotic anticough drugs 313 23.2.3 Expectorant drugs 313 23.3 Bronchodilators (Broncholytics) 314 23.3.1 Methylxanthines 314 23.3.2 Anticholinergic drugs 316 23.3.3 Inhibitors of allergy mediator release 316 23.3.4 Corticosteroids 317 23.3.5 Adrenergic drugs (/J : -receptor agonists, sympathominietics) 318 24 Anticoagulants, Antiaggregants, Thrombolytics, and Hemostatics 323 24.1 Anticoagulants 324 24.1.1 Direct-acting coagulants or parenteral anticoagulants 324 24.1.2 Direct-acting coagulants, or enteral anticoagulants 325 24.2 Antiaggregants 328 24.3 Fibrinolytics (Thrombolytics) 330 24.4 Hemostatics (Procoagulants) 332 24.4.1 Systemic hemostatics 332 24.4.2 Local procoagulants 333 25 Thyroid Hormone and Antithyroid Drugs 337 25.1 Drugs for Treating Hypothyroidism }}H 25.2 Drugs for Treating Hyperthyroidism 339 26 Insulin and Synthetic Hypoglycemic Agents 343 26.1 Insulin 343 26.2 Synthetic Hypoglycemic Drugs 344

27 Corticosteroids 349 27.1 Glucocorticoids 350 27.2 Mineralocorticoids 360 28 Female Sex Hormones 365 28.1 Estrogens 365 28.2 Antiestrogens 371 28.3 Progestins 373 29 Male Sex Hormones and Anabolic Steroids 381 29.1 Androgens 381 29.2 Androgen Antagonists 383 29.3 Anabolics 385 30 Antineoplastics 389 30.1 Antimetabolites 390 30.1.1 Folic acid antagonists 390 30.1.2 Purine derivatives 392 30.1.3 Pyrimidine derivatives 393 30.2 Alkylating agents 395 30.2.1 Nitro-containing mustard derivatives 396 30.2.2 Ethylenimine derivatives 398 30.2.3 Alkyl sulfonates 399 30.2.4 Nitrosoureas 399 30.3 Antibiotics 402 30.3.1 Dactinomycines 402 30.3.2 Bleomycins 402 30.3.3 Anthracyclines 403 30.4 Compounds isolated from plants 405 30.4.1 Epipodophyllotoxins 406 30.5 Hormonal drugs 408 30.5.1 Androgens 408 30.5.2 Estrogens 409 30.5.3 Progestins 409 30.5.4 Corticosteroids 409 30.5.5 Nonhormonal drugs 410 30.6 Other antineoplastic drugs 412 31 Immunopharmacological Drugs 419 31.1 Immunostimulants 420 31.2 Immunodepressants 421 31.2.1 Glucocorticoids 421 31.2.2 Cytotoxic drugs 422

32 Antibiotics 425 32.1 Beta-Lactam Antibiotics 427 32.1.1 Penicillins 430 32.1.2 Cephalosporins 441 32.1.3 Penems and carbapenems 463 32.1.4 Monobactams 465 32.2 Macrolide Antibiotics 467 32.3 Tetracyclines 470 32.4 Aminoglycosides 475 32.5 Lincosamides 482 32.6 Chloramphenicol 483 32.7 Other Antibiotics 485 33 Antimicrobial Drugs 499 33.1 Sulfonamide Drugs and Trimethoprim 499 33.1.1 Diaminopyrimidines (trimethoprim. pyrimethamine. and trimethoprim-sulfamethoxazole) 509 33.2 Quinolones 513 33.3 Nitrofuranes 519 34 Antimycobacterial Drugs 525 34.1 Antituberculosis Drugs 525 34.1.1 Drugs of the first group 526 34.1.2 Drugs of the second group 529 34.2 Drugs for Treating Leprosy 532 35 Antifungal Drugs 535 35.1 Polyene Antifungal Drugs 536 35.2 Imidazoles (Triazoles) 537 35.3 Allylamines 543 35.4 Others 543 36 Antiviral Drugs 549 37 Drugs for Treating Protozoan Infections 559 37.1 Antimalarial Drugs 559 37.1.1 Drugs effective against the erythrocvte stage of plasmodia infection... 560 37.1.2 Drugs effective against the hepatic (exoerythrocyte) stage of plasmodia infection 570

37.1.3 Drugs effective against hepatic and erythrocyte forms of plasmodia infection 570 37.2 Drugs for Treating Amebiasis 573 37.3 Drugs for Treating Leishmaniasis 577 37.4 Drugs for Treating Trypanosomiasis 578 37.5 Drugs for Treating Other Protozoan Infections 580 38 Antihelmintic Drugs 583 Index 595