Thesis, Stereochemistry and Structure-Activity Relationship of Opioid Ligands Related to 4-Aryl-1-Methylpiperidines and Phencyclidine

University of Bath PHD On the investigation of the synthesis, stereochemistry and structure-activity relationship of opioid ligands related to 4-aryl-1-methylpiperidines and phencyclidine Al-Deeb, Omar A. A. Award date: 1989 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 IN THE NAME OF. ALLAH THE MERCIFUL THE COMPASSIONATE ON THE INVESTIGATION OF THE SYNTHESIS, STEREOCHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF OPIOID LIGANDS RELATED TO 4-ARYL-l-METHYLPIPERIDINES AND PHENCYCLIDINE Thesis Submitted by OMAR A.A. AL-DEEB, B.SC., M.So., for the degree of Doctor of Philosophy of the University of Bath 1989 This research has been carried out in the School of Pharmacy and Pharmacology under the supervision of Dr. Alan F. Casy and Dr. George H. Dewar. Copyright Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. SIGNED: UMI Number: U526990 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U526990 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 IVERSITY OF 5A IJBRARY 15 r>EP ^ To my parents, all my brothers and sisters and to my wife Fatin without whose unfailing support and God's will made the completion of this work possible. ACKNOWLEDGEMENTS The author wishes to express his grateful thanks to Dr. Alan F. Casy and George H. Dewar for their initiation, patience, encouragement and helpful advice throughout the course of this work. To the staff in the Department of Pharmaceutical Chemistry, especially Dr. Alan R. Pascoe and his colleagues, and to a fellow research student, Mr. Sanjay S. Patel, the author extends thanks for stimulating discussion on many aspects of the work and for their friendship. Thanks are also due to Mr. Harry R. Hartell and Mr. Dave 1 13 Wood for skilled work in securing H and C NMR spectra. He wishes to express his gratitude to Dr. A.E. Jacobson of the National Institute of Health, Bethesda, and Janssen Pharmaceutics, Belgium, for the pharmacological evaluation of the compounds prepared. Appreciation is also extended to Mrs Judy Harbutt for typing this thesis. The author wishes to thank Mr S. Al-Theeb, Mr A. Al-Enzi and Dr A. Yasin for their friendship. Finally, the author gratefully thanks the King Saud University for financial support. SUMMARY A brief review of narcotic analgesics, with particular attention to the 4-arylpiperidine class, is presented in Chapter 1. Isomeric reversed esters of pethidine bearing 3-methyl substituents, together with the 4-alkyl-4-arylpiperidines, have been discussed from both a stereochemical and structure-activity point of view, and aspects of this are presented. A brief general introduction to phencyclidine (PCP) is also presented, with particular reference to new analgesics derived from phencyclidine by introduction of a phenyl and hydroxyl moiety at position 4 of the piperidine ring of this agent. In Chapter 2, the synthesis and characterisation of a novel series of potential analgesics based on 3-methyl substitution in the piperidine ring of this series of PCP analgesics is reported. This study was encouraged by the observation that such methyl substitution in the pethidine reversed ester significantly enhanced analgesic potency. The a-isomer of 4-hydroxy-3-methyl-4-phenyl-l-(1-phenylcyclohexyl)piperidine had a particularly interesting pharmacological profile, and therefore resolution of this compound was undertaken. The details of this resolution are reported. The synthesis and characterisation of a series of 4-alkyl-4- arylpiperidines and their 3-methyl analogues is also described in 1 13 Chapter 2. Extensive use of high field H and C NMR has been made in the conformational and, in appropriate cases, configurational analysis of the prepared compounds, and the data secured are discussed in detail. Finally, those pharmacological results available at the time of writing this thesis are reported and discussed. TABLE OF CONTENTS Page 1 INTRODUCTION 1.1 Historical Introduction 1 1.2 Morphine and its Derivatives 2 1.3 Synthetic Centrally-Acting Analgesics 6 1.3.1 The Morphinans 7 1.3.2 The 6,7-Benzomorphans 9 1.3.3 The 4-Phenylpiperidines 11 1.3.4 Diphenylpropylamine Analgesics 12 1.4 Arylpiperidines 14 1.4.1 4-Phenylpiperidine analgesics and related compounds 14 1.4.1.1 Introduction 14 1.4.1.2 Synthetic modifications of pethidine 16 a. Variation of the nitrogen substituent 16 b. The C4-oxygen function 18 c. Variation of the 4-aryl group 20 d. Alkylation of the piperidine ring 24 1.4.2 3-Arylpiperidines 32 1.4.3 4-Alkyl-4-arylpiperidines 37 1.4.3.1 Introduction 37 1.4.3.2 Chemical and pharmacological aspects of 4-alkyl-4-arylpiperidines and related compounds 38 1.5 Phencyclidine 45 1.5.1 Introduction 45 1.5.2 Some derivatives of phencyclidine 46 1.5.3 New analgesics derived from phencyclidine 49 Page 2 DISCUSSION 2.1 Introduction 52 2.2 Phencyclidine Derivatives Derived from a - and B-Prodine 55 2.2.1 Synthesis and separation of a- and £-prodine 55 2.2.2 The synthesis of a-4-hydroxy-3-methyl-4- phenylpiperidine by N-demethylation of a-prodine 64 2.2.3 The synthesis of a-l-(l-cyanocyclohexyl)-4- hydroxy-3-methyl-4-phenylpiperidine via the Strecker reaction 72 2.2.4 The synthesis of a-4-hydroxy-3-methyl-4-phenyl- l-(l-phenylcyclohexyl)piperidine and the corresponding acetoxy ester 76 2.2.5 The synthesis of j3-4-hydroxy-3-methyl-4-phenyl- l-(1-phenyl-cyclohexyl)piperidine 78 2.2.6 Resolution studies 79 2.2.6.1 a-Prodinol 79 2.2.6 .2 Qualitative determination of enantiomeric purity of resolved a-prodinol by NMR using £-cyclodextrin 82 2.2.6.3 The synthesis of (-)- and (+)-a- 4-hydroxy-3-methyl-4-phenyl-l- (1-phenylcyclohexyl) piperidine 84 2.3 The 4-Alkyl-4-arylpiperidines 87 2.3.1 Introduction 87 Page 2.3.2 Synthesis 93 2.3.2.1 The synthesis of 1,3,4-trimethyl-4- phenylpiperidine 93 2.3.2.2 The attempted synthesis of 4-(3-methoxyphenyl)-1,3,4-trimethylpiperidine using l-benzyl-3-methyl-4-piperidone 103 2.3.2.3 The synthesis of 4-alkyl-4-arylpiperidines using 4-aryl-l,2,5,6- tetrahydro-l-methylpyridine as a precursor 107 2.3.2.4 Miscellaneous syntheses 121 2.3.3 Stereochemical (conformational and configurational) assignments to 4-alkyl-4-arylpiperidines by 1 13 analysis of their H and C NMR spectra 127 2.3.3.1 Des C3-methyl analogues 128 2.3.3.2 The C3-methyl series 138 2.4 Pharmacological Evaluation 182 2.4.1 Janssen Pharmaceutics (JP) data 182 2.4.2 National Institutes of Health (NIH) data 187 3 EXPERIMENTAL 3.1 Introduction 202 3.2 Phencyclidine Derivatives Derived From a- and B- Prodine 203 3.2.1 Methyl 3-methylamino-2-methylpropionate 203 3.2.2 3[N-methyl-N-(2-ethyloxycarbonylmethyl)amine] 204 propionate 3.2.3 1,3-Dimethyl-4-piperidone 205 Page 3.2.4 a- and 8-1,3-Dimethyl-4-phenyl-4- propionoxypiperidine 206 3.2.5 a-4-Hydroxy-3-methyl-4-phenylpiperidine 208 3.2.6 a-1-(1-Cyanocyclohexyl)-4-hydroxy-3-methyl- 4-phenylpiperidine 211 3.2.7 a-4-Hydroxy-3-methyl-l-(1-phenylcyclohexyl)- -4-phenylpiperidine 212 3.2.8 a-4-Acetoxy-3-methyl-l-(1-phenylcyclohexyl)-4-phenylpiperidine 213 3.2.9 B-4-Hydroxy-3-methyl-l-(1-phenylcyclohexyl)-4-phenylpiperidine 213 3.2.10 Resolution of (±)-a-4-hydroxy-l,3- dimethyl-4-phenylpiperidine 214 3.2.11 (-)-a- and (+)-a-4-hydroxy-3-methyl-l- (1-phenylcyclohexyl)-4-phenylpiperidine 215 3.3 4-Alkyl-4-arylpiperidines 220 3.3.1 Dehydration of a-4-hydroxy-l,3-dimethyl- 4-phenylpiperidine 220 3.3.2 1,4,5,6-Tetrahydro-l,4,5-trimethyl-4- phenylpiperidine 221 3.3.3 1,3,4-Trimethyl-4-phenylpiperidine 224 3.3.4 1,3-Dimethyl-4-piperidone methiodide 225 3.3.5 l-Benzyl-3-methyl-4-piperidone 225 3.3.6 a- and ^-l-Benzyl-4-hydroxy-4-(3- methoxyphenyl)-3-methylpiperidine 226 3.3.7 Dehydration

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