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Synthesis of Serotonergic Agents SYNTHESIS OF SEROTONERGIC AGENTS A Thesis Presented by PARVIZ GHARAGOZLOO According to the Requirements o f the University of London for the Degree of DOCTOR OF PHILOSOPHY 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 the copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without prior consent of the author. Signature: Date: Department of Chemistry, University College London, December 1991 London. ProQuest Number: 10797729 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 com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10797729 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 To those whom I love and so greatly miss ACKNOWLEDGMENTS I wish to express my sincere thanks to Professor C. R. Ganellin for suggesting and supervising the serotonin project. I am also deeply indebted to him for his continuous encouragement, guidance, enthusiasm and friendship throughout this work. I would also like to thank Professor J. H. Wyllie and Dr. M. Beer for their invaluable work in determining the biological activities of the compounds and many stimulating discussions. Thanks are also due to Mr. W. Tertiuk for all his help and contributions to the practical work throughout the project. I am also indebted to Dr. P. J. Garratt, Dr. P. Demonchaux and Dr. D. Crich for their contributions to the discussion of synthesis and Mr. C. Cooksey for his assistance in obtaining computer and spectroscopic data. I should also like to acknowledge the help of all those in the microanalytical and mass spectrometry sections of the Chemistry Department for their expert technical assistance, especially Mr. S. Corker (HPLC), Mr. A. Stones (microanalysis), Mrs. J. Maxwell (microanalysis and N.M.R.) and Dr. M. Mruzek (mass spectroscopy). I would like to acknowledge all my colleagues and friends for their suggestions and discussions, in particular Miss D. Waterworth, Dr. M. Perera and Dr. S. Lazareno. Finally, I would like to thank Miss D. Terry for all her help and support over the past years. 4 ABSTRACT Serotonin and its receptors have been the focus of intense research over the past decade. The identification of many serotonin receptor subtypes and the greater understanding of their physiological properties, has initiated many projects in search of potent and selective agents in the hope that novel therapeutic drugs may be identified. This is one such research project. This work has led to the discovery of several potent and selective 5-HT1A agents. This was achieved by structural modification of the lead compounds, p-blockers, aryloxypropanolamines. An historical review of the properties of serotonin, the classification and characterisation of serotonin receptors, and the structural requirements for activity at 5-HT1A and 5-HT1B receptors for many classes of compounds is presented. Structure-activity relationship for aryloxypropanolamines at p-adrenoceptors has also been discussed. Structural features which are known to be essential for p-adrenergic activity of pindolol, were modified and compounds with moderate affinities and selectivities for 5-HT1A receptors were obtained. Introduction of electron withdrawing substituents at the 6 -position of the naphthalene ring of propranolol significantly reduced affinity at 5-HT1A and 5-HT1B receptors. Other structural modifications in this series, also yielded compounds with less affinity than propranolol. Novel analogues of 5-HT were also prepared and tested. These agents possessed reasonable affinities and selectivities for 5-HT1A receptors and displayed weak mixed agonistic and antagonistic activities at 5-HT1B receptors. Recent publication on structure-activity relationships for a number of propranolol analogues enabled us to design a novel series of compounds, analogous to cyanopindolol. These agents are potent and highly specific partial agonists at 5-HT1A receptors. All of the target analogues were prepared via the condensation reaction of epichlorohydrin or an aminoalkyl halide with a hydroxyindole or a substituted naphthol, followed by amminolysis. An effective procedure for the synthesis of 5-hydroxy-2-naphthoic acid, the key intermediate for the preparation of propranolol analogues, is described. The procedure for the preparation of other key intermediates in the synthesis of the analogues is also presented. 6 CONTENTS Page Acknowledgements ................................................................................................... 3 A bstract ...................................................................................................................... 4 Contents ..................................................................................................................... 6 1.0 Review: Serotonin and Serotonin Receptors ........................ 10 1.1. Introduction ........................................................................................................ 11 1.2. Serotonin ................................................................................................................. 11 1.2.1. Biosynthesis and catabolism of 5-HT ....................................................... 13 1.3. SerotoninReceptors ............................................................................................. 14 1.3.1. 5-HTi_Like recePtors ................................................................................ 17 1.3.2. 5-HT1A and 5-HT1B receptors ................................................................ 17 1.3.3. 5-H Tlc receptors ....................................................................................... 17 1.3.4. 5-H T1D receptors ...................................................................................... 18 1.3.5. 5-HTjp and 5-HT1R receptors ............................................................... 19 1.3.6. 5-HT2 receptors ....................................................................................... 19 1.3.7. 5-HT3 receptors ....................................................................................... 20 1.3.8. 5-HT4 receptors .......................................................................................... 21 1.4. 5-HT1A Receptors ............................................................................................... 21 1.5. 5-HTlfi Receptors .............................................................................................. 23 1.5.1. Characterisation of 5-HT1B receptors in mouse urinary bladder ................... 24 1.6. 5-HT1A and 5-HT1B Receptor Ligands ............................................................. 27 1.6.1. SAR for indolylalkylamines at 5-HT1A and 5-HT1B receptors ................... 27 1.6.1.1. Modification of the terminal amine .................................................... 28 1.6.1.2. Modification of the hydroxyl group .................................................... 29 1.6.1.3. Modification of the side chain .......................................................... 29 1.6.1.4. Other structural modifications ............................................................. 30 1.6.2. Aryloxypropanolamines ........................................................................... 30 1.6.2.1. SAR for aryloxypropanolamines at 5-HT1A and 5-HT1B receptors .................................................................................................. 32 7 1.6.2.2. Analogues of propranolol as 5-HT1A and 5-HT1B agents ... 33 1.6.2.3. Miscellaneous compounds with 5-HT1A and 5-HT1B activity 35 1.7. SAR for Aryloxypropanolamines at |3-Adrenoceptors ........................................ 38 1.8. Aims and Objectives ............................................................................................. 40 1.9. References .............................................................................................................. 41 2.0 Synthesis of Propranolol Analogues ....................................... 48 2.1. Introduction ........................................................................................................ 49 2.2. Strategy .......................................................................................................... 49 2.3. Synthesis of 1,6-DisubstitutedNaphthalenes ..................................................... 53 2.3.1. Preparation of 5-hydroxy-2-naphthoic acid ............................................... 56 2.3.2. Esterification of 5-hydroxy-2-naphthoic acid ............................................. 60 2.3.3. Preparation of l-[3-(alkylamino)propoxy]-6-(carboalkoxy)naphthalenes ..... 62 2.3.4. Preparation of 1 -(2,3-epoxypropoxy)-6-(carboalkoxy)naphthalenes ................ 64 2.3.5. Preparation of l-[3-(alkylamino)-2-hydroxypropoxy]-6-(carboalkoxy)- naphthalenes ................................................................................................. 66 2.3.6. Amide analogues
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