The synthesis and physical properties of some cyclohexane derivatives of potential biological interest

Abstract

The historical development of analgetic drugs has been reviewed with respect to structural modifications of morphine, pethidine, methadone, morphinans and 6,7-benzomorrhans. The development of analgetic receptor site theories has also been surveyed. A brief review of the application of Hansch-type analysis to structure-activity relationships has also been carried out. Some basic derivatives of cyclohexane have been synthesised. The route consisted of a modification of the Strecker synthesis to yield an ∝-aminocyclohexylnitrile which was reduced to the corresponding primary amine using lithium aluminium hydride. The primary amine was benzoylated using several benzoylating agents, The Benzamides so produced were tested for CNS activity and several were found to have analgetic properties. Tentative relationships between structure and activity have been suggested.   A Hansch-type analysis of the structure-activity relationship of these benzamides was attempted. The parameters used in this analysis were pKa values, carbonyl stretching frequency values, calculated log P values and analgetic activity. In order to compare their biological activity with the previously mentioned benzamides, an attempt was made to prepare some rigid analogues. The first route proposed was a ring closure, to form isoquinolones, of urethans derived from various α-aninonitriles and α-aminoesters. The second route proposed was a ring expansion of l-indanones to form isoquinolones. Included in this study is an investigation into the course of a reaction between 2-bromo-2-rethyl-l-indanone and diethylamine. It is also shown that 2-substituted-l-ield, almost without exception, isoquinolones on ring expansion with hydrazoic acid. The 2-substituted-indanones and 3-substituted-isoquinolones prepared in this stucy were tested for potential CNS activity. Several of them were found to have analgetic properties and are being further investigated. A brief consideration of the mass spectra of all the classes of compounds synthesised has been made and possible fragmentation pathways have been suggested.