Synthesis and biological properties of thiophene ring analogues of mianserin.
The synthesis of two thiophene-containing analogues of mianserin, i.e., 1,2,3,4,10,13b-hexahydro-2-methylpiperazino[1,2-a]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 8. This substance was converted via ethyl ester 10 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 three substances exhibited generally similar profiles. However, the results suggest that 2 and 12 bind more strongly to central presynaptic alpha-receptors than does mianserin.
D000818:Animals; D001921:Brain / Q000378:metabolism; D003984:Dibenzazepines / Q000138:chemical synthesis*; D006636:Histamine Release / Q000187:drug effects; D008803:Mianserin / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D051379:Mice; D011224:Prazosin / Q000378:metabolism
D003984:Dibenzazepines; D008803:Mianserin; D011224:Prazosin