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.

Date of Award	Jul 1971
Original language	English
Awarding Institution	Aston University