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SYNTHESIS, STRUCTURAL and BIOLOGICAL STUDIES of POTENTIAL 5-HT3 RECEPTOR ANTAGONISTS. BRENDAN A. WHELAN Ph.D. 1994

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SYNTHESIS, STRUCTURAL and BIOLOGICAL STUDIES of POTENTIAL 5-HT3 RECEPTOR ANTAGONISTS. BRENDAN A. WHELAN Ph.D. 1994 SYNTHESIS, STRUCTURAL AND BIOLOGICAL STUDIES OF POTENTIAL 5-HT3 RECEPTOR ANTAGONISTS. BRENDAN A. WHELAN Ph.D. 1994 SYNTHESIS, STRUCTURAL AND BIOLOGICAL STUDIES OF POTENTIAL 5-HT3 RECEPTOR ANTAGONISTS. bv* Brendan /I.lA/h&Un, A Thesis presented to Dublin City University for the degree of Doctor of Philosophy. This work was carried out under the supervision of Dr. Paraic James at Dublin City University, Dublin and Dr. Enrique Galvez at Universidad de Alcala de Henares, Madrid. December 1994 mt? anc^ mtf/ parents (linttoy and /Cathie&n. I hereby certify that this material, which I now submit for assessment on the programme of study leading to the award of PhD is entirely my own work and has not been taken from the work of others save and to the extent that such work has been cited and acknowledged within the text of my own work Candidate Date: I ' tf></- Adnou/iedgements / wouid fiile to begin bp expressing my* pr-a.titu.dle, to mp superu-isor Or, Paraic (James a t Dublin City* {/(nio-ersitp and to Or.Fnritjue (jdbez and Dr. /satfriepa a t th e iyfniu-ersitp ofr Ahatfa de- nenareSj Madrid, To (lose, Sanz-Aporicio and /sabetf Fonseca / woutfd tfi£e to g/Ve mp than is faor collaborating with the X~rap studies and to Antonio Orga^es ofi F.A .F .S, ltd . faor the phar-mac oiogiG a / studies. liietoise, to Dr.tfracia (yfceda and Or, Antonio (jar cl a faor the, biochemical assays. Sincere thanis to affl mp department coffleagues and stafafa mem hers at A^caia. who toere u-erp patient token mp Spanish wasn ' t ijuite up to it/ and fa,or mailing the ia st faew pears in the iaboratorp not onfp hearable hat thorough^ e/y-opabfe, A Special thanks to mtf bench partner 7~oni faor her companionship and fa.or eu-en laughing a t some ^ A Speciai thanks to mu coifae Piiar faor her support during the difafaicuit moments ofa doing* a thesis and faor her patience in proofa reading the manuscript and tfiiewise to Or. Mari- Austin faor his meticulous scrutiny ofa the ujori. / am indebted to mp parents andfaamiip faor their encouragement throughout a iith e pears, Finn My,, mp utmost gratitude to the Commission ofa the European Community faor providing me with the means ofa carrying oat mg research with the aid ofa a ip farom the Science Programme. Table of Contents Chapter I Literature Review 1.1. 5-HTj Antagonists 2 1.1.1 Review. 2 1.1.2 Research Plan 13 1.2. Synthesis of 2-Imidazolines: Introduction 16 1.2.1 From 1,2-Diamines by reaction with 17 1.2.1.1 Monocarboxylic acids 17 1.2.1.2 Dicarboxylic acids 18 1.2.1.3 Esters 18 1.2.1.4 Imino ethers 19 1.2.1.5 Nitriles 21 1.2.1.6 Amides 23 1.2.1.7 Amidines and guanidines 23 1.2.2 From Monoacyl and Diacyl Derivatives 26 1.2.3 From Carbonyl Containing Compounds 26 1.2.4 From Miscellaneous Syntheses 27 1.3. Synthesis of 1,2,4-Oxadiazoles 31 1.3.1 Introduction 31 1.3.2 By Ring Closure on Carbon 33 1.3.2.1 O-acylamidoximes 33 1.3.2.2 N-acylimino ethers 41 1.3.3 1,3-Dipolar Cycloadditions 43 1.3.3.1. Nitrile oxides with nitriles 43 1.3.3.2. Hydroxamyl chlorides with nitriles 46 1.3.3.3. Hydroxamyl chlorides with iminoethers 47 i 1.3.3.4 Hydroxamyl chlorides with amidines 48 1.3.4 From Oxidations 49 1.3.4.1 Oxidation of amidoximes and oximes 49 1.3.4.2 Oxidation of oxadiazolines 52 Chapter II Synthesis of 2'Aryl-tropane-3-sptro-4'(5’)-imidazolines 2 .1 . Introduction 55 2.2. Preparation of 1 //-indole-3-carbonitrile 57 2.3. Synthesis of Imldate Salts 61 2.3.1 Introduction 61 2.3.2 Preparation of imidates (123 a-h) 63 2.4. Synthesis of a-aminonitriles 77 2.4.1 Introduction 77 2.4.2 Synthesis of 3(3-Amino-8-methyl-8-azabicyclo[3.2.1]- 80 octane-3a-carbonitrile (124) 2 .5 . Synthesis of 3a-Aminomethyl-8-methyl-8-azabicyclo[3.2.1 ]-octane- 3{i-amine (122) 84 2 .6 . Synthesis of 2’Aryl-8-methyl-8-azabicyclo[3.2.1 ]-octane-3-spiro- 4'(5)-imidazoiines (I a-g) 92 ii Chapter III Synthesis of 2'Aryl-l-azabicyclo[2.2.2]octane- 3-spiro-4'(5')-imidazolines 3.1. Introduction 96 3 .2 . Synthesis of 3-hydroxy-l-azabicyclo[2.2.2]octane-3-carbonitrile (157) 98 3.3. Synthesis of 3-amino-l-azabicyclo[2.2.2]octane-3-carbonitrile (158) 100 3 .4 . Preparation of 3-aminomethyl-l-azabicyclo[2.2.2]octyl-3-amine (159) 102 3 .5 . Preparation of 2'(aryl)-l-azabicyclo[2.2.2]octane-3-spiro- 4'(5')-Imidazolines (II a-g) 113 3 .6 . Preparation of 2'(3,5-difluorophenyl)-l-azabicyclo[2.2.2]octane- 3-spiro-4'(5')-imidazoline (II h) 115 Chapter IV Synthesis of exo-5'-(8-Methyl-8-azabicyclo[3.2.1]- octan-3-yl)-3'-(aryl)-l,2,4-oxadiazoles 4.1. Introduction 130 4 .2 . Synthesis of 3-( 1,3-dithiane-2-ylidene)-8-methyl-8-azabicyclo- [3.2.1]octane (170) 136 4 .3 . Synthesis of exo-3-carbomethoxy-8-methyl-8-azabicyclo- [3.2.1]octane (163) 140 4.4. Synthesis of aryl amidoximes (164) 155 4.5 Synthesis of exo-5'-(8-Methyl-8-Azabicyclo[3.2.1]- octan-3-yl)-3'-(Aryl)-l,2,4-oxadiazoles (III a-g) 163 iii Chapter V Structural and conformational study of Imidazolines and Oxadiazoles Introduction Study of tropane spiroimidazolines (I) 5.2.1 X-ray study of 2'(l//-indol-3-yl)-8-methyl-8- azabicyclo-[3.2.1]octane-3-spiro-4‘(5')- imidazoline dihydrochloride (I g) 5.2.2 NMR analysis of 2'(Aryl)-8-methyl-8-azabicyclo- [3,2.1]octane-3-spiro-4'(5')-imidazolines (I a-g) 5.2.3 Conformational study of tropane spiroimidazolines (I a-g) Study of tropane oxadiazoles (III) 5.3.1 X-ray study of exo-5'-(8-Methyl-8-azabicyclo[3.2.1]- octan-3-yl)-3'-(3,5-dimethoxyphenyl)-l,2,4-oxadiazole hydrochloride (III c) 5.3.2 NMR study and conformational analysis of exo-5'-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-3'- (aryl)-l,2,4-oxadiazole hydrochlorides (III a-g) Chapter VI Pharmacological and Biochemical Studies and Structure-Activity Relationship. Introduction. Pharmacological studies of I, II, and III (in vivo ) 6 .3 . Binding studies on compounds I, [I and III (in vitro ) 196 6 .4 . Discussion of biological results 202 6 .5 . Structure-Activity Relationship (SAR) 203 Chapter VII Experimental. 7.1. Materials and Methods. 209 7.2. Synthesis of I//-indole-3-carbonitrile (126) 209 7.3. Synthesis of carboximidate hydrochlorides (129 a-h, 141) 211 7 .4 . 3f}-Amino-8-methyl-8-azabicyclo[3.2.1]oclane-3a-carbonitrile (124) 214 7.5. 3a-Aminomethyl-8-methyl-8-azabicyclo[3.2.1]octyI-3p-amine (122) 214 7 .6 . 2'-( Aryl)-8-methyl-8-azabicyclo[3.2.1 ]octane-3-spiro- 4’(5')-imidazoline (la) 216 7.7. 3-Hydroxy-1-azabicyclo[2.2.2]octane-3-carbonitrile (157) 224 7.8. 3-Amino-l-azabicyclo[2.2.2]octane-3-carbonitrile (158) 224 7.9. 3-Aminomethyl-1 -azabicyclo[2.2.2]octyl-3-amine (159) 225 7.10. 2'-(3-Aryl)-1 -azabicyclo[2.2.2]octane-3-spiro-4'(5')- imidazolines (II a-g) 227 7.11. Synthesis of amidoximes (164) 234 v 7.12. 3-(l,3-Dithiane-2-ylidene)-8-methyl-8-azabicyclo[3.2.1]octane (170). 240 7.13. exo-3-Carbomethoxy-8-methyi-8-azabicyclo[3.2.1 ]octane (163). 241 7.14. Synthesis of tropane 1,2,4-oxadiazoles (III). 242 7.15. Pharmacological Methods. 251 7.16. Serotonin-Induced von Bezold-Jarisch Reflex in mice. 251 7.17. [3H]-GR65630 Binding. 252 8 Conclusions and Comments. 254 9 References. 260 APPENDIXES Appendix I Crystal Structure Data for 2'-(l//-indol-3-yl)-8-methyI-8-azabicycIo- [3.2.1 ]octane-3-spiro-4'(5')-imidazoline dihydrochloride (Ig) II Appendix II Crystal Structure Data for exo-5'-(8-Methyl-8-azabicyclo[3.2.1]- octan-3-yl)-3'-(3,5-dimethoxyphenyI)- 1,2,4-oxadiazoles (III c). XXII vi Appendix III LH NMR Spectra XLIV Appendix IV 13C NMR Spectra. LYE Appendix V Mass Spectra LXIII Appendix VI Infrared spectra LXXX Abstract This thesis involves the syntheses of new compounds as potential antagonists of the 5- HT3 receptor, a sub-group of the serotonin receptors. The objective of the work can be considered two fold: The primary aim, which can be regarded as the principal goal, was the design and chemical synthesis of new molecules which could antagonise the 5 -HT3 receptor and thus lead to new drug substances which could be effective in the treatment of illnesses associated with this receptor, among which may be included the control of emesis in cancer patients receiving chemotherapy. Secondly, by carrying out the structural and conformational studies of the synthesised compounds and relating these to the biological studies it was hoped to elucidate more information on the nature of the 5 -HT3 receptor, the structure of which is unknown. Three series of potential antagonists were synthesised. The first series involves a tropane spiroimidazoline molecule with various aromatic substituents in the 2 ' position of the imidazoline ring (the final compounds of this series have been numbered I a-g throughout the text, the number I referring to the number of the series and the letters a-g to the individual final products within the series) The structure represents a novel feature within the known 5 -HT3 antagonists.
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