4-Aryl-3-(dimethylaminomethyl)thiacyclohexan-4-ols including the thia analogue of tramadol; Synthesis and analgetic activity

Abstract

Mannich reaction of thiacyclohexan-4-one with dimethylamine and paraformaldehyde afforded 3-(dimethylaminomethyl)thiacyclohexan-4-one (XIV) which was subjected to reactions with a series of arylmagnesium bromides. The products were mixtures of trans- and cis-amino alcohols III-XII from which the predominating trans-components were mostly obtained by crystallization of hydrochlorides or chromatography of bases. The tramadol (I) analogue, i.e. the 3-methoxy compound V, was prepared in the form of both racemates and their relative configuration was confirmed by the IR spectra. Compound V was demethylated to the 3-hydroxyphenyl analogue XIII, transformed to the bis-onium salt XVI, partially N-demethylated to the N-monodemethyl analogue XVII, and oxidized to the sulfoxide XX and to the sulfone N-oxide XXI. Some of the amino alcohols (III-V, VIII, IX, XIII) showed clear analgetic activity in the writhing syndrome inhibition test in mice; the 3-methoxy and 3-hydroxy compounds (V and XIII) were the most active ones, the latter being slightly more active than tramadol (I).