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Synthesis of Best-Seller Drugs Ruben Vardanyan Victor Hruby Department of Chemistry and Biochemistry University of Arizona AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-411492-0 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at http://store.elsevier.com/ Dedication Dedicated to my daughters, Anna, Marina, and Irena, established personalities and professionals whom I infinitely love and am very proud of. Ruben Vardanyan Dedicated to my three sons, Timothy, Stephen, and Patrick, for encouraging my passion for science. Victor Hruby Preface This book represents our effort to give a panoramic view of the most popular medications on the pharmaceutical market, accenting the reader’s attention on the uses of these medications and schemes of synthesis of the best-selling phar- maceutical drugs in 2010s. Although there are numerous books on the medicinal chemistry and drug design, this book is much different than the other books. Here we present the synthesis of various groups of drugs, classifying them in accordance with the order and manner in which they are traditionally presented in gold-standard pharmacological curriculums, focusing on recently developed synthetic methods for the preparation of the most important best-selling drugs. This book covers the basic, essential pharmacological classes of drugs and is separated into 38 chapters. It includes 208 schemes of synthesis, 463 figures, and 4597 references. The basic philosophy of this book is to help understand where we are and what we are doing in the area of drug creation. Recent years have seen major advances in the understanding of how to improve the chances of discovering all categories of drugs: essential, new-first- in-class, best-in-class, and yet-to-be-developed. The approaches and technologies split into empirical and in silico efforts at many different levels, and modern paradigms of drug design include sophisticated titles such as computational chemistry and molecular modeling, combinatorial synthesis and high-throughput screening, target-based molecular modeling strategies, structure-based drug-design approaches, fragment-based drug design, diversity-oriented synthesis, and others. But is there any design approach that one can claim to be perfect? Most of the drugs now in use were discovered by chance through painstak- ing trial and error rather than by design. Formal approaches cannot replace a scientist’s intuition that is based on special knowledge and experience. The way to enhance the productivity in Big Pharma is not only by improving and “perfecting” techniques such as combi- natorial chemistry or high-throughput screening, cutting-edge tools, and soft- ware programs for design, but also by giving scientists the freedom to use their imagination to explore the whole drug universe rather than focusing only on the details of some narrow area of a single class of drugs. The tools themselves are no substitute for first-rate scientific minds—a fool with a tool is still a fool. xxi xxii Preface The journey of a new drug from the scientist’s idea to the pharmacy shelf is a filled with victories and defeats, detours and delays. We fully agree with the words of Sir James Whyte Black, winner of the 1988 Nobel Prize in Physiology or Medicine: “The most fruitful basis for the discovery of a new drug is to start with an old drug.” Finally, we think that this book could become a resource for both newcom- ers to the field of medicinal chemistry, organic chemistry, and pharmacology, and for experienced researchers and scientists in academia and industry wanting to know about the existing remedies for different diseases and about synthetic routes implemented for the synthesis of best-selling pharmaceutical drugs in 2010s. We earnestly hope that the time we spent writing this book has resulted in the kind of information that will interest those who work or plan to begin work in the area of medicinal drug design and synthesis. Ruben Vardanyan Victor Hruby Chapter 1 General Anesthetics The use of inhaled ether for surgical anesthesia was first demonstrated in 1846. Since then, the development of new safe anesthetics has contributed greatly to the advancement of surgery and other invasive procedures. General anesthesia is the state of controlled, reversible unconsciousness and loss of protective reflexes, controlled level of nervous system suppression to allow adequate surgical access, obstetric, and diagnostic procedures to be completed painlessly. The patient receives medications for amnesia, analgesia, muscle paralysis, and sedation. Anesthesia includes the following components: analgesia (absence of pain), amnesia (absence of memory), suppression of reflexes such as bradycardia, laryngospasm, and loss of skeletal muscle tonicity. In medical practice, general anesthesia is a complex procedure involving: preanesthetic assessment, administration of general anaesthetic drugs, cardio- respiratory monitoring, analgesia, airway management, and fluid management. In a typical clinical procedure, the patient is premedicated with a sedative intended to relieve anxiety and facilitate the induction of anesthesia itself. For this purpose it is accepted to use tranquilizers, such as diazepam, lorazepam, or midazolam, or a central nervous system depressant-barbiturate such as thio- pental, methohexital, or the hypnotic agent propofol. Sedation is followed by intravenous injection of an opioid analgesic such as morphine, fentanyl, alfent- anil, or ketamine, which has a wide range of effects in humans, including anal- gesia and anesthesia. In addition, a nondepolarizing curare-like derivative like vecuronium or d-tubocurarine, or a depolarizing drug such as succinylcholine, is administered to induce muscle paralysis. After connection to artificial res- piration, general anesthesia is maintained by a mixture of oxygen and nitrous oxide, often in combination with a volatile agent such as halothane, enflurane, or isoflurane. At the conclusion of the surgery, muscle relaxation is reversed by neostigmine or other anticholinesterase, and normal breathing is restored. The ideal general anesthesia must include the aforementioned characteris- tics, as well as have a wide therapeutic index and no significant side effects. The underlying neurocellular mechanisms by which the state of general anesthesia is achieved are only just beginning to be understood. Components of general anesthesia formally are divided into two groups: noninhalation, (barbiturates, ketamine, and etomidate), and inhalation (halo- thane, enflurane, isoflurane, desflurane and nitrous oxide). Since the publica- tion of our first book [1] in 2006 where the synthesis of all above mentioned Synthesis of Best-Seller Drugs. http://dx.doi.org/10.1016/B978-0-12-411492-0.00001-8 Copyright © 2016 Elsevier B.V. All rights reserved. 1 2 Synthesis of Best-Seller Drugs drugs are described, no novel entities that address fundamentally new general anesthesia approaches have entered the clinic. That is the reason we limit dis- cussion to the structural formulas of anesthetic agents in current clinical use. 1.1 NONINHALATION COMPONENTS FOR GENERAL ANESTHESIA Tranquilizers Benzodiazepines—diazepam (1.1.1), lorazepam (1.1.2), and midazolam (1.1.3)—which have anxiolytic, sedative, and anticonvulsant effects, and cause amnesia and muscle relaxation, are frequently used to relieve patient’s anxiety during anesthesia. (Fig. 1.1.) FIG. 1.1 Benzodiazepines used during anesthesia. Central Nervous System Depressants (Barbiturates and Hypnotic Agents) Two barbiturates primarily used in surgical practice are thiopental (1.1.4) and methohexital (1.1.5). Barbiturates are hypnotics, and at therapeutic doses have a very weak analgesic and muscle relaxant effect. Intravenous injection of a therapeutic dose of propofol (1.1.6) produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection. Etomidate (1.1.7) classified as a sedative hypnotic drug because of the quick loss of con- sciousness upon intravenous administration. It has an anticonvulsant activity and does not display analgesic characteristics. Duration of its action depends on the administered dose. (Fig. 1.2.) FIG. 1.2 Barbiturates and hypnotic agents used during anesthesia. G e n e ra l A n FIG. 1.3 Opioid analgesics used during anesthesia. es th e tic s C h a p t e r 1| 3 4 Synthesis of Best-Seller Drugs Opioid Analgesics Opioid analgesics, in particular morphine (1.1.8), fentanyl (1.1.9), alfentanil (1.1.10), and sufentanil (1.1.11), are widely used in the practice of anesthesiol- ogy as adjuncts. Recently, remifentanil (1.1.12) became popular for the mainte- nance of anesthesia due to its short-acting nature. (Fig. 1.3.) Ketamine Ketamine (1.1.13) is a specific drug for noninhalation narcosis which is used in brief surgical procedures. It causes a condition known as dissociative anesthesia, which ensures amne- sia and analgesia, and preserves normal respiration and muscle tonicity in the patient. Ketamine is practically void of muscle relaxant capabilities. (Fig. 1.4.) FIG. 1.4 Structure of ketamine. Muscle Relaxants Nondepolarizing neuromuscular-blocking agents as d-tubocurarine (1.1.14) and vecuronium (1.1.15), or a depolarizing drug such as succinylcholine (1.1.16), are used in surgery as muscle relaxants. Currently, atracurium (1.1.17) and rocuronium (1.1.18) are considered safer alternatives. (Fig. 1.5.) Reversible Acetylcholinesterase Inhibitors Neostigmine (1.1.19) is a parasympathomimetic that acts as a reversible ace- tylcholinesterase inhibitor. It is used at the end of an operation to reverse the effects of nondepolarizing muscle relaxants. (Fig. 1.6.) 1.2 INHALATION ANESTHETICS The fluorinated inhalation anaesthetics used in current practice are halothane (1.2.1), sevoflurane (1.2.2), desflurane (1.2.3), isoflurane (1.2.4), nitrous oxide (1.2.5) (Fig. 1.7.), and xenon, which produce dose-dependent central nervous system, cardiovascular, and respiratory depressant effects. Despite proof that inhaled anesthetics act on multiple molecular targets, it is hypothesized that their mechanism of action could be better explained by physical phenomena G e n e ra l A n e s th e tic s FIG. 1.5 Muscle relaxants used during anesthesia. C h a p t e r 1| 5

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