Piperidine-Based Drug Discovery 9780128051573

Citation preview

Piperidine-Based Drug Discovery

This page intentionally left blank

Heterocyclic Drug Discovery Series

Piperidine-Based Drug Discovery

Ruben Vardanyan University of Arizona Tucson, AZ, USA

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright r 2017 Elsevier Ltd. 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. 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 ISBN: 978-0-12-805157-3 For Information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: John Fedor Acquisition Editor: Anneka Hess Editorial Project Manager: Anneka Hess Production Project Manager: Anitha Sivaraj Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India

Contents 1.

Introduction 1.1 The Scope of the Material Under Consideration 1.2 General Methods of the Synthesis of Piperidine Compounds Nucleophilic Substitution Reactions Intermolecular Michael Reactions Catalyzed Hydroamination Reactions Aza-Diels
Alder Reactions Intramolecular Ene Reactions Ring-Closing Metathesis Reactions Synthesis of Piperidin-4-Ones Nucleophilic Addition Reactions to the Carbonyl Group of Piperidin-4-Ones Nucleophilic Substitution Reactions Involving α-Carbon of Piperidin-4-Ones Piperidin-3-Ones Piperidin-2-Ones 4-Cyano-4-Phenylpiperidines References

2.

1 5 6 9 12 13 18 22 23 30 39 45 49 56 57

1-Substituted Piperidines 2.1 Derivatives of 1-Phenyl-3-(Piperidin-1-yl)Propan-1-ol Trihexyphenidyl Biperiden Pridinol Cycrimine 2.2 Derivatives of 1-Phenyl-4-(Piperidin-1-yl)Butan-1-ol Diphenidol Pirmenol 2.3 Derivatives of 2-(Piperidin-1-yl)Ethan-1-ol and 3-(Piperidin-1-yl)Propan-1-ol Cloperastine Benproperine Pipazethate Raloxifene Flavoxate Piperocaine

83 83 84 85 85 86 86 87 88 88 89 89 90 92 93 v

vi

Contents

2.4 Derivatives of 3-(Piperidin-1-yl)Propane-1,2-Diol and 3-(Piperidin-1-yl)Propane-1,1-Diol Diperodon Pipoxolan 2.5 Derivatives of 1-Phenyl-3-(Piperidin-1-yl)Propan-1-One Dyclonine 2.6 Derivatives of 2,2-Diphenyl-4-(Piperidin-1-yl)Butanamide Fenpiverinium Bromide References

3.

2-Substituted and 1,2-Disubstituted Piperidines 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14

Methylphenidate Perhexiline Pipradrol Mefloquine Mepivacaine Ropivacaine Bupivacaine and Levobupivacaine Flecainide Encainide Thioridazine Rimiterol Lobeline Argatroban Ascomycin, Pimecrolimus, Tacrolimus, Sirolimus, Everolimus, and Temsirolimus References

4.

94 94 95 95 96 96 96 97

103 103 104 105 106 106 107 109 110 110 112 112 115 117 118

3-Substituted and 1,3-Disubstituted Piperidines 4.1 Methixene 4.2 Tipepidine 4.3 Timepidium 4.4 Tiagabine 4.5 Piperidolate 4.6 Mepenzolate 4.7 Pipenzolate 4.8 Benidipine 4.9 Paroxetine and Femoxetine 4.10 Troxipide 4.11 Linagliptin 4.12 Tofacitinib References

127 127 128 129 130 131 131 132 133 136 137 138 140

Contents

5.

vii

4-Substituted and 1,4-Disubstituted Piperidines 5.1 4-Piperidinols and Their Derivatives Periciazine Diphenylpyraline Ebastine Bepotastine Lamifiban Eucatropine Propiverine Pentapiperide 5.2 4-Phenylpiperidin-4-ols and Their Derivatives Haloperidol Bromperidol Moperone Trifluperidol Penfluridol Loperamide Alpha-Prodine 5.3 Derivatives of 4-Phenylpiperidine-4-Carboxylic Acids Pethidine Phenoperidine Diphenoxylate Levocabastine 5.4 Derivatives of (4-Phenylpiperidin-4-yl)Ketones Ketobemidone Ketanserin 5.5 Derivatives of 4-Phenylpiperidine-4-Carboxamide Metopimazine Pipamazine 5.6 Derivatives of Piperidin-4-Amines Indoramin Clebopride Cinitapride Prucalopride Lomitapide Cisapride Astemizole 5.7 Derivatives of 4-Anylinopiperidines Fentanyl Carfentanil Remifentanil Sufentanil Alfentanil Lorcainide 5.8 Derivatives of 4-(N,N-Disubstituted)-Piperidines Bamipine and Thenalidine Mizolastine

147 147 148 149 150 150 151 153 153 154 154 155 156 157 158 159 160 163 163 165 168 168 169 169 170 172 172 172 173 173 174 175 176 176 178 181 181 182 184 187 188 189 190 191 191 192

viii

Contents

Sabeluzole Lubeluzole 5.9 Derivatives of 4-(Dialkylamino)Piperidine-4-Carboxamide Pipamperone Piritramide Carpipramine Clocarpramine 5.10 Alvimopan References

6.

Piperidin-4-Ylidene Substituted Tricyclic Compounds 6.1 Cyproheptadine 6.2 Azatadine 6.3 Loratadine and Desloratadine 6.4 Rupatadine 6.5 Ketotifen 6.6 Pizotifen 6.7 Alcaftadine 6.8 Ritanserin References

7.

193 194 195 195 196 197 197 198 199

223 225 225 228 228 229 231 232 234

Piperidine-Based Nonfused Biheterocycles With C
N and C
C Coupling 7.1 Piperidine-Based Nonfused Biheterocycles With C
N Coupling Droperidol Benperidol Timiperone Pimozide Zaldaride Domperidone Bezitramide Benzpiperylon and Piperylon 7.2 Piperidine-Based Nonfused Biheterocycles With C
C Coupling Risperidone Paliperidone Iloperidone Naratriptan Sertindole References

241 242 243 243 245 246 246 247 248 250 250 252 253 254 256 257

Contents

8.

Piperidine-Based Fused Biheterocycles 8.1 Thienopyridine Derivatives Ticlopidine Clopidogrel Prasugrel 8.2 γ-Carbolines Mebhydrolin Gevotroline and Carvotroline 8.3 5,6,7,8-Tetrahydropyrido[4,3-c]pyridazines Endralazine Phenindamine References

9.

ix

269 270 271 273 275 275 275 276 276 277 279

Piperidine-Based Spiro-Fused Biheterocycles 9.1 Spiperone Fluspirilene Mosapramine Fenspiride Clospirazine Pazinaclone References

288 288 289 290 291 292 294

10. Classes of Piperidine-Based Drugs 10.1 Piperidine-Based Analgesics 4-Phenylpiperidines 4-Anilidopiperidines Miscellanous Analgesic Piperidine Derivatives 10.2 Piperidine-Based Antipsychotics Butyrophenones Diphenylbutylpiperidines Benzisoxazoles Phenothiazines Dibenzazepines Tetrahydro-γ-Carbolines and 3-(Piperidin-4-yl)-1H-Indoles 10.3 Piperidine-Based Antihistamine Drugs Piperidin-4-Ylidene Diaryl[a,d][7]Annulenes 4-(Benzhydryloxy)Piperidines Miscellanous Antihistamine Piperidine Derivatives 10.4 Piperidine-Based Anticholinergic Drugs Muscarinic Receptor Antagonists 10.5 Piperidine-Based Local Anesthetics Aminoamide-Type Local Anesthetics Amino Ester
Type Local Anesthetics

299 300 301 301 303 303 305 306 306 307 307 308 308 308 309 310 311 313 313 314

x

Contents

10.6 Piperidine-Based Antithrombotic Drugs Antiplatelet Drugs Anticoagulant Drugs 10.7 Piperidine-Based Antiarrhythmic Drugs 10.8 Piperidine-Based Antihypertensive Drugs 10.9 Piperidine-Based Drugs for Treating Respiratory System Diseases Cough Suppressants 10.10 Piperidine-Based Antidepressants Selective Serotonin Reuptake Inhibitors Norepinephrine-Dopamine Reuptake Inhibitors 10.11 Piperidine-Based Antiparkinsonian Drugs 10.12 Piperidine-Based Hypolipidemic and Antihyperlipidemic Drugs 10.13 Piperidine-Based Adrenergic (Sympathomimetic) Drugs 10.14 Piperidine-Based Central Nervous System Stimulants 10.15 Piperidine-Based Selective Estrogen Receptor Modulators 10.16 Piperidine-Based Antianginal Drugs 10.17 Piperidine-Based Drugs for Treating Protozoan Infections 10.18 Piperidine-Based Antimigraine Drugs 10.19 Piperidine-Based Nootropic and Neuroprotective Drugs 10.20 Piperidine-Based Antiemetics 10.21 Piperidine-Based Antidiarrheal and Prokinetic Drugs Antidiarrheals Prokinetics 10.22 Piperidine-Based Gastric Antisecretory Drugs 10.23 Piperidine-Based Hypoglycemic Drugs 10.24 Piperidine-Based Drugs Used in the Treatment of Rheumatoid Arthritis 10.25 Piperidine-Based Nicotinic Cholinomimetics 10.26 Piperidine-Based Immunosuppresant Drugs 10.27 Conclusion Index
Trade Names Index
Substance Classes

315 315 316 317 318 319 319 320 321 321 322 322 323 323 324 324 325 325 325 326 327 327 328 328 329 330 330 330 331 333 337

Chapter 1

Introduction 1.1 THE SCOPE OF THE MATERIAL UNDER CONSIDERATION Heterocyclic compounds constitute the largest and most varied family of organic chemistry that is gaining enormous importance in chemical and pharmaceutical industry. Numerous agrochemicals, information storages, electronics, plastics and optics modifiers and stabilizers, cosmetics additives, etc., are heterocyclic in nature. Piperidine and its functionalized derivatives are increasingly popular building blocks in a vast array of synthetic protocols. The piperidine ring can be recognized in the structure of many synthetic compounds of practical interest and in the structure of many alkaloids and other natural or synthetic compounds with various biological activities known today. Piperidine is the compound which gives black pepper its spicy taste and gave the name of the compound in question. Today it is possible to assert unequivocally that the mainstream of pharmaceuticals is heterocyclic and the leading heterocycle in the structure of pharmaceuticals is piperidine, which is the most encountered heterocycle found in pharmaceutical agents [1]. A search of the chemical and patent literature reveals thousands of references to this simple ring system, which is present in the structures of potential drugs in clinical and preclinical research. As of October 8, 2015, the day of beginning the work on this monograph, 93,984 references containing the concept “piperidine” were found in SciFinder
the world’s largest and most reliable collection of chemistry and related science, which, of course, is not an exhaustive number of publications on the subject under consideration. By January 10, 2017, the date on which work on this monograph was completed, that number grew to 97,972, which constitutes the appearance of roughly 4000 additional publications within a year and a half. Information about piperidine-containing compounds exists in publications and patents that do not contain the word piperidine as well as in other sources of scientific information, which we did not use. For example, by analyzing the scaffold content of the CAS Registry from more than 24 million organic compounds it has been found that the most frequently occurring references on heterocycles concern piperidine (191.803) [2].

Piperidine-Based Drug Discovery. DOI: http://dx.doi.org/10.1016/B978-0-12-805157-3.00001-6 Copyright © 2017 Elsevier Ltd. All rights reserved.

1

2

Piperidine-Based Drug Discovery

The huge contribution in the development of piperidine-derived series of drugs belongs to Otto Eisleb, Anton Ebnother, Solomon Snyder, Samuel McElvain, Ivan Nazarov, Miroslav Protiva, and, of course, the great Dr. Paul Janssen, the most prolific drug inventor of all time: his team has produced more than 60 new therapeutics, most of which belong to the piperidine series [3
5]. This book was conceived as an attempt to show the panorama of drugs, the structure of which contains a piperidine ring, and to show methods for their synthesis. It is necessary to emphasize here the word “drugs.” Any attempt to create a more or less complete picture of a biologically active compound containing a piperidine ring in its structure was doomed to fail due to the inability to “grasp the immensity” and to show the entire existing material in reasonable frames. But even the relatively limited list of piperidine drugs also creates a number of problems, the first of which is the mode of their classification and, consequently, the presentation. One alternative classification is the attempt to build material based on their pharmacological properties thereby putting them into a traditional order according to, e.g., a generally accepted narration in pharmacology textbooks, just as we did in our two previous books [6,7]. However, to put the emphasis on the structure and methods of the synthesis of drugs requires another way of presentation that is more acceptable from the standpoint of an organic chemist. It was decided that the order and degree of substitution of the piperidine ring would be the best way to sort existing piperidine drugs. So, the collected factual material in general was divided and distributed into chapters and subchapters according to the following generalization: derivatives of 1-substituted piperidines (such as trihexyphenidyl (Artane) (1.1.1)); derivatives of 2-substituted piperidines or 1,2-disubstituted piperidines (such as bupivacaine (Marcaine)) (1.1.2)); derivatives of 3-substituted piperidines and 1,3-substituted piperidines (such as troxipide (Aplace)) (1.1.3)); and tofacitinib (Xeljanz) (1.1.4) (Fig. 1.1). O O

N OH

N NH

O

O Trihexyphenidyl (Artane) 1.1.1

Bupivacaine (Marcaine) 1.1.2

N

H N

O

N

N N H

Troxipide (Aplace) 1.1.3

HN

N O

N

Tofacitinib (Xeljanz) 1.1.4

FIGURE 1.1 Construction of subchapters in the book.

More diverse groups are represented by derivatives of 4-substituted and 1,4-disubstituted piperidines
fexofenadine (Allegra) (1.1.4), ebastine (Evastin) (1.1.5), astemizole (Hismanal) (1.1.6), indoramin (Baratol) (1.1.7), fentanyl (Sublimaze) (1.1.8), metopimazine (Vogalene) (1.1.9), ketanserin (Sufrexal) (1.1.10) (Fig. 1.2).

3

Introduction Chapter | 1

OH

O

OH

O

N

O

N

HO Ebastine (Evastin) 1.1.5

Fexofenadine (Allegra) 1.1.4 O

R2

O

O

N N

N

F

HN

N R1

O

N H

N

N F

Ketanserin (Sufrexal) 1.1.10

Astemizole (Hismanal) 1.1.6

O NH2

O

N

HN O S O

N

N

N

O NH

N

S Metopimazine (Vogalene) 1.1.9

Fentanyl (Sublimaze) 1.1.8

Indoramin (Baratol)1.1.7

FIGURE 1.2 Structures of some of 1,4-disubstituted piperidine-based drugs.

No less common in the market are 1,4,4-trisubstituted piperidines exemplified by haloperidol (Haldol) (1.1.11), loperamide (Imodium) (1.1.12), trimeperidine (Promedol) (1.1.13), pethidine (Meperidine) (1.1.14), ketobemidon (Cliradon) (1.1.15), pipamperone (Dipiperon) (1.1.16), piritramide (Dipidolor) (1.1.17), alfentanil (Alfenta) (1.1.18), and remifentanil (Ultiva) (1.1.19), which in turn can be subdivided to alcohols, amines, ketones, amides, etc. Examples of these compounds are presented on the (Fig. 1.3). Cl HO N

Cl

N

HO

Loperamide (Imodium) 1.1.12

O

O N

O N O

F Haloperidol (Haldol) 1.1.11

O

Trimeperidine (Promedol) 1.1.13

N

R2

O

R3

O

O N

O

O

N

N R1

O

Pethidine (Meperidine) 1.1.14

Remifentanil (Ultiva) 1.1.19

O

O N N N N N

N

N NH 2

O N

O Alfentanil (Alfenta) 1.1.18

O

H 2N O

N

N

O

HO

N

N

F Piritramide (Dipidolor) 1.1.17

Pipamperone (Dipiperon) 1.1.16

FIGURE 1.3 Structures of some of 1,4,4-trisubstituted piperidine-based drugs.

Ketobemidone (Cliradon) 1.1.15

4

Piperidine-Based Drug Discovery

Another group of piperidine drugs could be represented as a combination of a piperidine ring with another heterocycle, and they can be classified as biheterocyclic compounds where the piperidine ring is not fused with another heterocycle and, in turn, is subdivided to those where: it is just bonded to another heterocycle by single C
C bond (such as naratriptan (Amerge) (1.1.20)); it is bonded to another heterocycle by double CQC bond (such as ketotifen (Zaditor) (1.1.21)); or by single C
N bond (such as pimozide (Orap)) (1.1.22). Another group could be represented as derivatives of piperidines fused with another heterocycle at 3,4-positions (such as clopidogrel (Plavix) (1.1.23)). The third group is described as derivatives of piperidines with spirofusion with another heterocycle at 4,4-positions (such as spiperone, (Spiropitan) (1.1.24)) (Fig. 1.4). O S

O S N O H

HN

NH N

O

N F

N

N

Ketotifen (Zaditor) 1.1.21

Pimozide (Orap) 1.1.22

Naratriptan (Amerge) 1.1.20 N R1

NH N O

F

+ other heterpcycle

S

O N

N

Cl

O O

F Spiperone (Spiropitan) 1.1.24

Clopidogrel (Plavix) 1.1.23

FIGURE 1.4 Structures of some of drugs represented as a combination of piperidine ring with another heterocycle.

In this book we have described the synthesis of about 150 piperidine drugs, but we did not know how to determine their relative importance. Building a panorama of about 150 drugs, derivatives of piperidine, we did not know how to determine their relative importance and the relevance of a drug in the entire arsenal of piperidine drugs. The same general question also relates to the entire list of existing drugs in medicinal practice. So we had to come up with a way to determine some Comparative Drug Significance Index (DSI) or Comparative Drug Impact Factor (CDIF). In our opinion, one of the simplest possible solutions of the problem could be a determination of a number of publications on the drug that definitely shows a real interest in the scientific community of the drug.

Introduction Chapter | 1

5

Of course, this parameter depends on the influence of Pharma at every time interval, which, of course, also reflects a real significance of a drug. Therefore, after mentioning the name of a medicine described in this book, we decided to mention and bring in the number of publications devoted to it in SciFinder. It seems that this approach to some extent could reflect the Comparative DSI. Perhaps it will be much more correct to determine Comparative DSI as a sum of certain indicators. For instance, as a sum of some conditional figures derived from the number of publications divided by one thousand and sales, divided by one billion, e.g., as: X Citations Salesð$Þ 5 1 103 109

1.2 GENERAL METHODS OF THE SYNTHESIS OF PIPERIDINE COMPOUNDS Piperidine (1.2.1) itself and most of its derivatives are easily produced by catalytic hydrogenation of the corresponding pyridine (1.2.2) derivatives over nickel, palladium, or ruthenium catalysts at 170
200 C [8
11]. Other reducing agents are sodium in ethanol or tin in hydrochloric acid [12]. Pyridine itself was first synthesized from acetylene and hydrogen cyanide [13,14]. More affordable sources of pyridine are coal tar, light-oil, and middle-oil fractions. Pyridine has been produced commercially from coal-tar sources contains only about 0.1% pyridine since the 1920s. Nowadays, most pyridine is produced synthetically via a number of synthetic processes. Reaction of acetaldehyde and formaldehyde with ammonia is the most widely used industrial method for pyridine production (Chichibabin pyridine synthesis) [14
17]. This thermal cyclocondensation reaction that occurs by passing on heating aldehydes and ammonia over a contact catalyst such as alumina is a low-yield process. Besides aldehydes, ammonia gas also reacts with acetylene or acetonitrile to give pyridine derivatives. The transformation is regarded as aldol condensations in conjunction with a Michael-type reaction and ring closures with ammonia. Pyridine can also be prepared from furfuryl alcohol or furfural by passing a mixture of tetrahydrofurfuryl alcohol, H2, and NH3 over a Ni catalyst at about 200 C under high pressure [18,19] from glutaric acid, its anhydride or alkyl glutarates with ammonia, and H2 at high temperatures and under high pressure in the presence of Ru-C or Co catalysts [20,21]. Pyridine can be prepared by oxidative dealkylation of alkylated pyridines, which are obtained as by-products via the synthesis of other pyridines using air over vanadium-, nickel-, silver- or platinum-based catalysts [22
24] (Fig. 1.5).

6

Piperidine-Based Drug Discovery

OH

Al2O3, 250ºC

H 2 / Ni-Al2O3, or Pd-Al 2O3

H

or

O

O O

NH3 + HCHO +

NH3, 200–500ºC,