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The Art of Drug Synthesis
Douglas S. Johnson (Edited by), DS Johnson (Author), Jie Jack Li (Edited by)
9780471752158, Wiley
Hardback, published 20 July 2007
292 pages
25.4 x 18.5 x 2.3 cm, 0.703 kg
“This is a most topical and useful short primer on estab1ished drugs and their synthesis.” (American Journal of Therapeutics, June 2009) "The book is very felicitous and closes a gap in the literature by covering the subject of drug development in this particular way." (Angewandte Chemie, June 23, 2008) "This book is a very entertaining read." (ChemMedChem, 2008, 3) "The editors and contriubting authros have certainly provided a most useful book for the medicinal and organic chemistry community." (Journal of Medicinal Chemistry, March 2008) "Where I see the book being very useful is as a starting point for student seminars or discussion groups... Also, it is highly illuminating just to dip into for a browse and to marvel at some of the excellent chemistry that goes on in the pharmaceutical industry." (Chemistry World, January 2008)
The Art of Drug Synthesis illustrates how chemistry, biology, pharmacokinetics, and a host of other disciplines come together to produce successful medicines. The authors have compiled a collection of 21 representative categories of drugs, from which they have selected as examples many of the best-selling drugs on the market today. An introduction to each drug is provided, as well as background to the biology, pharmacology, pharmacokinetics, and drug metabolism, followed by a detailed account of the drug synthesis.
Foreword xi Preface xiii Contributors xv 1 THE ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY 1 1.1 Introduction 1 1.2 Hurdles in the Drug Discovery Process 2 1.3 The Tools of Medicinal Chemistry 3 1.4 The Role of Synthetic Chemistry in Drug Discovery 6 2 PROCESS RESEARCH: HOW MUCH? HOW SOON? 11 2.1 Introduction 11 2.2 Considerations for Successful Scale-up to Tox Batches and Phase I Material 15 2.3 Considerations for Phase 2 Material and Beyond 16 2.4 Summary 26 I CANCER AND INFECTIOUS DISEASES 3 AROMATASE INHIBITORS FOR BREAST CANCER: EXEMESTANE (AROMASIN), ANASTROZOLE (ARIMIDEX), AND LETROZOLE (FEMARA) 31 3.1 Introduction 32 3.2 Synthesis of Exemestane 35 3.3 Synthesis of Anastrozole 36 3.4 Synthesis of Letrozole 37 4 QUINOLONE ANTIBIOTICS: LEVOFLOXACIN (LEVAQUIN), MOXIFLOXACIN (AVELOX), GEMIFLOXACIN (FACTIVE), AND GARENOXACIN (T-3811) 39 4.1 Introduction 40 4.2 Levofloxacin 47 4.3 Moxifloxacin 57 4.4 Gemifloxacin 60 4.5 Garenoxacin (T-3811): A Promising Clinical Candidate 64 5 TRIAZOLE ANTIFUNGALS: ITRACONAZOLE (SPORANOX), FLUCONAZOLE (DIFLUCAN), VORICONAZOLE (VFEND), AND FOSFLUCONAZOLE (PRODIF) 71 5.1 Introduction 72 5.2 Synthesis of Itraconazole 74 5.3 Synthesis of Fluconazole 76 5.4 Synthesis of Voriconazole 77 5.5 Synthesis of Fosfluconazole 80 6 NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE INHIBITORS 83 6.1 Introduction 84 6.2 Synthesis of Nevirapine 85 6.3 Synthesis of Efavirenz 87 6.4 Synthesis of Delavirdine Mesylate 90 7 NEURAMINIDASE INHIBITORS FOR INFLUENZA: OSELTAMIVIR PHOSPHATE (TAMIFLU) AND ZANAMIVIR (RELENZA) 95 7.1 Introduction 95 7.1.1 Relenza 97 7.1.2 Tamiflu 97 7.2 Synthesis of Oseltamivir Phosphate (Tamiflu) 99 7.3 Synthesis of Zanamivir (Relenza) 110 II CARDIOVASCULAR AND METABOLIC DISEASES 8 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS FOR TYPE 2 DIABETES 117 8.1 Introduction 117 8.2 Synthesis of Rosiglitazone 121 8.3 Synthesis of Pioglitazone 122 8.4 Synthesis of Muraglitazar 124 9 ANGIOTENSIN AT1 ANTAGONISTS FOR HYPERTENSION 129 9.1 Introduction 130 9.2 Losartan Potassium 132 9.3 Valsartan 134 9.4 Irbesartan 135 9.5 Candesartan Cilexetil 136 9.6 Olmesartan Medoxomil 137 9.7 Eprosartan Mesylate 138 9.8 Telmisartan 139 10 LEADING ACE INHIBITORS FOR HYPERTENSION 143 10.1 Introduction 144 10.2 Synthesis of Enalapril Maleate 146 10.3 Synthesis of Lisinopril 147 10.4 Synthesis of Quinapril 148 10.5 Synthesis of Benazepril 150 10.6 Synthesis of Ramipril 151 10.7 Synthesis of Fosinopril Sodium 154 11 DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS FOR HYPERTENSION 159 11.1 Introduction 160 11.2 Synthesis of Nifedipine (Adalat) 162 11.3 Synthesis of Felodepine (Plendil) 163 11.4 Synthesis of Amlodipine Besylate (Norvasc) 164 11.5 Synthesis of Azelnidipine (Calblock) 165 12 SECOND-GENERATION HMG-CoA REDUCTASE INHIBITORS 169 12.1 Introduction 170 12.2 Synthesis of Fluvastatin (Lescol) 171 12.3 Synthesis of Rosuvastatin (Crestor) 174 12.4 Synthesis of Pitavastatin (Livalo) 177 13 CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE (ZETIA) 183 13.1 Introduction 183 13.2 Discovery Path to Ezetimibe 184 13.3 Synthesis of Ezetimibe (Zetia) 187 III CENTRAL NERVOUS SYSTEM DISEASES 14 DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SSNRIs) FOR DEPRESSION 199 14.1 Introduction 200 14.2 Synthesis of Venlafaxine 203 14.3 Synthesis of Milnacipran 205 14.4 Synthesis of Duloxetine 207 15 GABAA RECEPTOR AGONISTS FOR INSOMNIA: ZOLPIDEM (AMBIEN), ZALEPLON (SONATA), ESZOPICLONE (ESTORRA, LUNESTA), AND INDIPLON 215 15.1 Introduction 216 15.2 Synthesis of Zolpidem 217 15.3 Synthesis of Zaleplon 219 15.4 Synthesis of Eszopiclone 220 15.5 Synthesis of Indiplon 221 16 Alpha2Delta LIGANDS: NEURONTIN (GABAPENTIN) AND LYRICA (PREGABALIN) 225 16.1 Introduction 225 16.2 Synthesis of Gabapentin 227 16.3 Synthesis of Pregabalin 234 17 APPROVED TREATMENTS FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER: AMPHETAMINE (ADDERALL), METHYLPHENIDATE (RITALIN), AND ATOMOXETINE (STRATERRA) 241 17.1 Introduction 242 17.2 Synthesis of Amphetamine 244 17.3 Synthesis of Methylphenidate 247 17.4 Synthesis of Atomoxetine 253 References 257 Index 261
John A. Lowe, III
Neal G. Anderson
Jie Jack Li
Chris Limberakis
Andrew S. Bell
Arthur Harms
Douglas S. Johnson and Jie Jack Li
Jin Li
Larry Yet
Victor J. Cee and Edward J. Olhava
Daniel P. Christen
Jeffrey A. Pfefferkorn
Stuart B. Rosenblum
Marta Pineiro-Nunez
Peter R. Guzzo
Po-Wai Yuen
David L. Gray
Subject Areas: Chemistry [PN]
