Synthesis and Pharmacology of 3, 4-Dihydro-3-oxo-1, 4-benzoxazine-8-carboxamide Derivatives, a New Class of Potent Serotonin-3 (5-HT3) Receptor Antagonists

A series of 3, 4-dihydro-3-oxo-1, 4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50=1.3μg/kg i.v.), high affinity for 5-HT3 receptor (Ki=2.9nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1mg/kg i.v.