1, 5-Benzoxathiepin Derivatives. II. Synthesis and Serotonin S₂-Receptor-Blocking Activity of Aminoalkyl-Substituted 3, 4-Dihydro-2H-1, 5-benzoxathiepin-3-ols and Related Compounds

Abstract

Novel 1, 5-benzoxathiepin derivatives, 3, 4-dihydro-2H-1, 5-benzoxathiepin-3-ols with an aminoalkyl group at the 2-, 3- or 4-position, were synthesized and evaluated for serotonin S₂-receptor-blocking activity and adrenergic α₁-receptor-blocking activity. Methyl 4-aminoalky1-3-hydroxy-3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylates showed significant S₂-receptor-block-ing activities. Structure-activity relationships (including the results of a conformational study and skeletal modifications) were examined. In the series of 1, 5-benzoxathiepin, 1-benzoxepin and 1-benzothiepin derivatives, methyl cis-3-hydroxy-7-methoxy-4- [3- (4-phenyl -1-piperazinyl) propyl] -3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylatehydrochloride (CV-5197) showed the most potent and the most selective S₂-receptor-blocking activity in the binding profile, and was chosen as a candidate for further pharmacological evaluation.