ChemInform Abstract: Synthesis and in vivo Pharmacology of New Derivatives of Isothiazolo[5,4-b]pyridine of Mannich Base Type

Recently we reported on 2 H -4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4- b ]pyridine ( V ), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3 – 5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine ( 2 ) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V , none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o -OCH 3 analog 3a , taken as an example, should be referred back to the conformational restriction incorporated by the o -substitution rather than effects of different lipophlicity or basicity of these compounds.