The Synthesis and Structure-Activity Relations of some Benzomorphan Analogues

Abstract

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.