The Synthesis and Structure-Activity Relations of some Benzomorphan Analogues


A brief review of the history of analgesics leading to the introduction of the 6,7-benzomorphans is presented In the hope of obtaining compounds of biological interest, some 6-cycloalkylamino derivatives of -nethylS-azebicyclo[3.3.1] nonan-9-one have been synthesised and submitted for pharmacological testing. The route adopted consisted of the addition of acrolein to the various cycloalkylamino enamines of N-methyl-piperidone, to give in each case, a mixture of two stereoisomeric ketones. A Successful separation of these pairs of ketones was not achieved. However, after reduction of each pair of ketones to the corresponding tertiary alcohols, a successful route has been established to the isolation of three of the four possible stereoisomeric alcohols. The stereochemistry of each of the amino-alcohols has been defined by a study of their chemical properties, pKa values, NMR, infrared, and mass spectra. Of special interest, is the discovery of a new band in the infrared spectra of certain amino-alcohol salts which confirms their stereochemistry. In addition, each series of alcohols contains at least one compound containing the piperidine ring in a boat form. Further proof of the boat form is at present being sought by X-ray analysis. A further series of compounds have also been prepared by the reaction between cinnamaldehyde and the pyrrolidine enamine of N-methyl-l,-piperidone, to yield, S-nethy1-3-azabicyelo [3.3.1] nonenee derivatives substituted at the 6- and 8- positions. In order to facilitate the interpretation of the NMR spectra of the 6- and 6,8-disubstituted compounds obtained, a number of model compounds of known stereochemistry were prepared. The reaction between the morpholine enamine of cyclohexanone and acrolein yielded 6-substituted bicyclo [5.3.4] nonenes, and the reaction with cinnamaldehyde yielded 6,8- disubstituted bicyclo [3.3.1] nonanes of known stereochemistry. The infrared spectra of all, and the NWR spectra of a number of the new compounds have been recorded. A brief consideration of the mass spectra of the 6-substituted and 6,8-disubstituted S-nethyl-3-azabicyolo[3.3-1] nonananes and bicycle [5.3.1] nonanes has been recorded, and possible fragmentation pathways for these compounds have been suggested. A correlation between the stereochemistry of the amino-alcohols and their fragmentation pathways has been discovered. Selected compounds were tested for pharmacological activity, but a variety of differing results have been obtained.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
Additional Information: Copyright © O'Sullivan, 1973. J. O'Sullivan asserts their moral right to be identified as the author of this thesis. 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 appropriate permission or acknowledgement. If you have discovered material in Aston Publications Explorer which is unlawful e.g. breaches copyright, (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please read our Takedown Policy and contact the service immediately.
Institution: Aston University
Uncontrolled Keywords: pharmacy,synthesis,benzomorphan analogues
Last Modified: 19 Oct 2023 12:09
Date Deposited: 17 Feb 2014 13:03
Completed Date: 1973
Authors: O'Sullivan, J.

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