New 5-HT₃ (Serotonin-3) Receptor Antagonists. V. Synthesis and Structure-Activity Relationships of Pyrrolo[2, 1-c][1, 4]benzoxazine-6-carboxamides

Abstract

This paper describes the discovery of structurally novel heterocyclic carboxamides which are highly potent 5-HT₃ (serotonin-3) receptor antagonists. Pyrrolo[2, 1-c][1, 4]benzoxazine-6-carboxamides (12 and 20) were found to possess potent 5-HT₃ receptor antagonist activity on the von Bezold-Jarisch reflex in anesthetized rats. Structure-activity studies showed that compounds with small and lipophilic substituents such as chloro and methyl at the 8-position of the aromatic ring portion retained high potency, whereas those with bulky substituents showed essentially no activity. A dimethyl group at the 4-position slightly decreased the potency. 1-Azabicyclo[2.2.2]octan-3-amine as the amine part afforded the most potent activity. From this series, 20a was found to be the most potent 5-HT₃ receptor antagonist, being 40-fold more potent than ondansetron (1).