Medicinal chemical studies on antiplasmin drugs. V. 4-Aminomethylcyclohexanecarboxylic acid derivatives having a methyl group at C2 or C3.

Abstract

Four isomers of 4-aminomethyl-2-methylcyclohexanecarboxylic acid (9) were synthesized from 4-cyano-o-toluic acid (2) or cis or trans 2-methyl-4-oxocyclohexanecarboxylic acid (5), and the isomers of 4-aminomethyl-3-methylcyclohexanecarboxylic acid (23) were also synthesized from 4-cyano-m-toluic acid (13) or ethyl cis or trans 7-methyl-1, 4-dioxaspiro [4. 5] decane-8-carboxylate (15). The configurations of these isomers were determined on the basis of those of the starting materials and by leading them to dimethyl 2-methylcyclohexane-1, 4-dicarboxylate (12), which was compared with 12 obtained from 5-methylbicyclo [2. 2. 2] oct-2-ene (10). The preferred conformations of the isomers in aqueous solution were deduced from the nuclear magnetic resonance spectra. The antiplasmin activity of t-4-aminomethyl-c-3-methyl-r-1-cyclohexanecarboxylic acid (23B), which is thought to exist in the 1-e, 3-e, 4-e form in aqueous solution, and which was the most active among the compounds tested in this study, was only about 0.64 times that of trans 4-aminomethylcyclohexanecarboxylic acid (1B).