Studies on the chemistry of thienoanellated O,N- and S,N-containing heterocycles. Part 30: synthesis and pharmacological properties of thieno[2,3-b][1,4]thiazines with potential vasopressin receptor antagonistic activity

Abstract

A series of new nonpeptide vasopressin antagonists with a 6-ethyl-thieno[2,3-b][1,4]thiazine or 6-benzyl-thieno[2,3-b][1,4]thiazine skeleton and structural modifications of the aryl side chain were synthesized in this study. The effects on guinea pig heart and smooth muscle preparations were investigated. In the presence of AVP the compounds showed an antagonistic effect. The compounds did not change spontaneous rate in right atria and exerted a slight but not significant negative inotropic effect in papillary muscles. The relaxing effect on vascular smooth muscle and terminal ileum was far more pronounced. Generally the relaxing effect on terminal ilea was more potent maybe due to difference in V1a receptor density. Our results demonstrate that compounds with an ethyl group in position six on the thienothiazine ring (14, 16, 18 and 22) exerted the most potent relaxing activity in terminal ilea, whereas compounds with a phenyl ring in position six reduced this effect.