Some Cyclohexane Derivatives of Potential Biological Interest

Abstract

Research involving the structural modifications of morphine, methadone, pethidine and prodine with emphasis on the structure-activity relationships has been reviewed. The mechanism of analgesic action including receptor site theory has been surveyed. In the hope of obtaining compounds of biologival interest some basic derivativeosf 1-tetralin have been synthesised and assessed pharmacologically. The route adopted consisted of Mannich additions to 1-tetralone to give the basic ketones. These ketones were reduced to the corresponding tertiary alcohols, acylation of which was only partially successful. The alcohols and esters were theoretically capable of. existing in stereoisomeric forms but successful separation of these was only achieved in the case of 2-(3-azabicyclo (5,2, 2] nonylmethy)-1- phenethynyl-1 , 2,3,4.-tetrahydronaphth-1-ols. Selected compounds were tested for pharmacological activity but the C.N.S. activity was found to be slight and no useful correlation between structure and activity could be made. Some basic derivatives of cyclohexane have also been prepared and assessed pharmacologically. The route adopted consisted of the modified Tieman-Strecker synthesis to give a-aminocyclohexylnitriles in which the amino function is dimethylamino, piperidino, pyrrolidino, azabicyclo APE nonano or N-methylpiperazino. Reactions of these α-aminonitriles with Grignard reagents and lithium aluminium hydride have been compared with respect to their ability to bring about nitrile replacement and an SN1 mechanism is proposed for this reaction. The α-aminonitriles were hydrolysed with sulphuric acid to give the corresponding amides, reduced with lithium aluminium hydride to give the primary amines and reduced with phenyl lithium to yield the arylimines. The primary amines were Soceplated and reduced in a four stage synthesis, benzoylated and acetylated while the arylimines were hydrolysed to the corresponding arylketones which were reduced to secondary alcohols and acylated. Selected compounds were tested for potential C.N.S. activity, several of which proved to have analgesic properties. Tentative correlations between structure and activity have been proposed. The i.r. spectra of all, and the n.m.r. spectra of a few of the new compounds have been recorded. brief consideration of the mass spectra of a selection of the 1-tetralones, 1,2,3,4-—tetrahydronaphth-1-ols and 1~(1-substituted cyclohexyl)-4-methylpiperazines has been recorded and possible fragmentation pathways for these compounds have been suggested.