Synthesis and biological properties of thiophene ring analogs of mianserin

Abstract

The synthesis of 2 thiophene-containing analogs of mianserin, i.e., 1,2,3,4,10,13b-hexahydro-2-methylpiperazino[1,2-.alpha.]thieno[2,3-c][1] benzazepine (2), and the corresponding [3,2-c] isomer (12) is described. The key step in the synthesis is the nucleophilic aromatic substitution reaction of the N-lithio derivative of 1-methyl-3-(2-thienyl)piperazine (4) with the oxazoline derivative of o-anisic acid (7) to give the N-phenylpiperazine. This substance was converted via ethyl ester to 1-[2-(hydroxymethyl)phenyl]-4-methyl-2-(2-thienyl)piperazine (3), which was cyclized with polyphosphate ester to a 5:1 mixture of 2 and 12. The antidepressant potential of 2 maleate (CGS 11049A) and 12 fumarate (CGS 15413A) were compared with that of mianserin hydrochloride in a variety of biochemical and pharmacological test systems. The 3 substances exhibited generally similar profiles. The 2 and 12 apparently bind more strongly to central presynaptic .alpha.-receptors in mice than does mianserin.