MEDICINAL CHEMISTRY A Series of Monographs EDITED BY GEORGE DESTEVENS Pharmaceuticals Division, CIBA-GEIGY Corporation Summit, New Jersey Volume 1. GEORGE DESTEVENS. Diuretics: Chemistry and Pharmacology. 1963 Volume 2. RODOLFO PAOLETTI (ED.). Lipid Pharmacology. Volume I. 1964. RODOLFO PAOLETTI AND CHARLES J. GLUECK (EDS.). Volume II. 1976 Volume 3. E. J. ARIENS (ED.) . Molecular Pharmacology: The Mode of Action of Biologically Active Compounds. (In two volumes.) 1964 Volume 4. MAXWELL GORDON (ED.). Psychopharmacological Agents. Volume 1.1964. Volume II. 1967. Volume III. 1974. Volume IV. 1976 Volume 5. GEORGE DESTEVENS (ED.). Analgetics. 1965 Volume 6. ROLAND H. THORP AND LEONARD B. COBBIN. Cardiac Stimulant Substances. 1967 Volume 7. EMIL SCHLITTLER (ED.). Antihypertensive Agents. 1967 Volume 8. U. S. VON EULER AND RUNE ELIASSON. Prostaglandins. 1967 Volume 9. G. D. CAMPBELL (ED.). Oral Hypoglycaemic Agents: Pharma- cology and Therapeutics. 1969 Volume 10. LEMONT B. KIER. Molecular Orbital Theory in Drug Research. 1971 Volume 11. E. J. ARIENS (ED.). Drug Design. Volumes I and II. 1971. Vol- ume III. 1972. Volume IV. 1973. Volumes V and VI. 1975. Volume VII. 1976 Volume 12. PAUL E. THOMPSON AND LESLIE M. WERBEL. Antimalarial Agents: Chemistry and Pharmacology. 1972 Volume 13. ROBERT A. SCHERRER AND MICHAEL W. WHITEHOUSE (Eds.). Antiinflammatory Agents: Chemistry and Pharmacology. (In two vol- umes.) 1974 Volume 14. LEMONT B. KIER AND LOWELL H. HALL. Molecular Connectiv- ity in Chemistry and Drug Research. 1976 Volume 15. JULIUS A. VIDA. Anticonvulsants. 1977 ANTICONVULSANTS Edited by Julius A. Vida Bristol Myers Company International Division New York, New York ACADEMIC PRESS New York San Francisco London 1977 A Subsidiary of Harcourt Brace Jovanovich, Publishers COPYRIGHT © 1977, BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER. ACADEMIC PRESS, INC. Ill Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NW1 Library of Congress Cataloging in Publication Data Main entry under title: Anticonvulsants. (Medicinal chemistry series ; no. ) Includes bibliographies and index. 1. Epilepsy—Chemotherapy. 2. Anticonvulsants— Therapeutic use. 3. Anticonvulsants-Testing. 4. Neuropharmacology. I. Vida, Julius A., Date II. Series: Medicinal chemistry, a series of monographs ; no. RC374.C48A57 616.8'53'θ61 76-19492 ISBN 0-12-721840-8 PRINTED IN THE UNITED STATES OF AMERICA TO MY WIFE, MARTHA LIST OF CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors' contributions begin. JOHN D. ALVIN (113), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania MILTON T. BUSH (113), Vanderbilt Medical School, Nashville, Tennessee BRIAN B. GALLAGHER (11), Departments of Pharmacology and Neurology, Schools of Medicine and Dentistry, Georgetown University, Washington, D.C. ELISABETH H. GERRY (151), Kendall Company, Lexington, Massachusetts LEMONT B. KIER (577), Department of Chemistry, Massachusetts College of Pharmacy, Boston, Massachusetts WALLACE J. MURRAY (577), Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska NICHOLAS P. PLOTNIKOFF (293), Abbott Laboratories, North Chicago, Illinois FRANK D. POPP* (329), Department of Chemistry, Clarkson College of Technology, Potsdam, New York JOHN F. REINHARD (57), Department of Pharmacology, Massachusetts College of Phar- macy, Boston, Massachusetts JOHN F. REINHARD, JR. (57), Laboratory of Neuroendocrine^Regulation, Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Mas- sachusetts JULIUS A. VIDA (1, 151), Bristol Myers Company, International Division, New York, New York HAROLD E. ZAUGG (293), Abbott Laboratories, North Chicago, Illinois *Present address: Department of Chemistry, University of Missouri, Kansas City, Missouri. xi PREFACE From 1960 to 1974 no new anticonvulsant drug was marketed in the United States (with the exception of diazepam, which was marketed primarily as a minor tranquilizer). With the approval in 1974 of car- bamazepine, the marketing in 1975 of clonazepam, and the anticipated marketing in 1977/1978 of sodium dipropylacetate, eterobarb, mexiletine, and possibly others, a resurgence of interest in anticonvulsant drugs is apparent in the United States. Interest in anticonvulsant drugs never ceased outside the United States as witnessed by the introduction of many new drugs to the international market since 1961. Many years have passed since the publication of the excellent chapter, Anticonvulsant Drugs, by W. J. Close and M. A. Spielman in "Medicinal Chemistry" (W. H. Härtung, ed., Wiley, New York, 1961). Although many other interesting books have appeared on the subject (e.g., "Basic Mechanisms of the Epilepsies," H. H. Jasper, A. A. Ward, and A. Pope, eds., Little, Brown, Boston, Massachusetts, 1969; "Anticonvulsant Drugs," D. M. Woodbury, J. K. Penry, and R. P. Schmidt, eds., Raven, New York, 1972; "Anticonvulsant Drugs, International Encyclopedia of Pharmacology and Therapeutics," J. Mercier, ed., Pergamon, Oxford, 2 volumes, 1973), none was intended specifically for the medicinal chemist. In the late 1960's and early 1970's the need for a new book became apparent to many of us working jointly for the Kendall Company in Cambridge, Massachusetts. Drs. John F. Reinhard, Milton T. Bush, Brian B. Gallagher, and myself, among others, were involved, respec- tively, in the laboratory evaluation, drug disposition, clinical evaluation, and synthesis and design of anticonvulsant drugs. Although hundreds of compounds have been synthesized since 1959, no systematic treatise on anticonvulsant drugs has been written since the chapter by Close and Spielman. I proposed writing this book to the aforementioned researchers and, later, to others. The idea appealed to all, for which I am grateful. Xlll Preface χιν Although this work was written specifically for the medicinal chemist, biochemists, neurologists, and pharmacologists should also find it of interest. Chapter 1 provides an overview and Chapter 2 a neurophar- macological background. Chapter 3 details the laboratory evaluation of compounds and Chapter 4 deals with drug disposition. Chapters 5 through 8 describe the chemistry and biological activities of the various classes of anticonvulsant compounds. Specifically, Chapter 5 contains the cyclic ureides, Chapter 6 the benzopyrans, Chapter 7 other heterocyclic drugs, and Chapter 8 the noncyclic anticonvulsants. Since compilation of data depends on availability in the literature, it was not possible to treat each topic uniformly. Since the chapter by Close and Spielman covered the literature through 1958, ours begins with 1959 and extends to 1976. I am grateful to the following people for their help: Mrs. Mary-Lou O'Shea (formerly with Kendall Co., presently with NIAMDD) and Dr. William R. Wilber (formerly with Kendall Co., presently with Rohm and Haas Co.) for literature searches; Mrs. Claire Gibbons and Miss Debbie Hudson (Kendall Co.), Mrs. Sandra Meech and Mrs. Sharon Yaddow (Bristol Laboratories), and the secretaries of the contributors for typing parts of the manuscript; Dr. J. Kiffin Penry and Mr. Lawrence D. Smith (National Institutes of Neurological and Communicative Disorders and Stroke, National Institute of Health) for providing data and literature printouts; Dr. Paul Szentmiklosi and Mrs. Alexandra Andor (Medimpex, Budapest) for providing data on decimemide; Mr. Louis Chauvet (Or- symonde S.A., Paris) for providing data on doxenitoin; my former classmate, Mrs. Martha Windholz (Merck, Sharp & Dohme Research Laboratories), for providing literature data; Mrs. Suzanne Woodbury (Georgetown University) for providing data and illustrations; Dr. Jonas A. Gylys (Bristol Laboratories) for reading part of the manuscript; Dr. George deStevens (Ciba-Geigy Corporation) and Dr. Warren J. Close (Abbott Laboratories) for their encouragement; and particularly Dr. Maxwell Gordon (Bristol Laboratories) for his help and encouragement. I wish to express my thanks to all of the contributors to the book. My special thanks are due Dr. Brian B. Gallagher for his constructive review of parts of the manuscript. Above all, my thanks are due my wife for her assistance and understanding during the genesis of this book. Julius A. Vida 1 ADVANCES IN ANTICONVULSANT DRUG DEVELOPMENT Julius A. Vida The first effective anticonvulsant drug, sodium bromide, was introduced by Charles Locock (1857). In the absence of other drugs, bromide therapy of epileptics became popular. The disadvantages of bromide therapy were discovered, however, quite early: The bromides have an unfavorable thera- peutic ratio. Prolonged treatment of epileptic patients with sodium bromide or other bromide preparations causes chronic toxicity manifested by seda- tion, psychic disturbances, skin rashes, increased glandular secretion, and gastric distress. The second and still one of the most important drugs for the treatment of epilepsy, phénobarbital, was introduced by Alfred Hauptmann (1912). Phénobarbital is generally considered to be the drug of choice for the treat- ment of generalized tonic-clonic seizures. It is also the drug of choice for the management of epileptic