NEW 5-HT3 (SEROTONIN-3) RECEPTOR ANTAGONISTS .5. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PYRROLO[2,1-C][1,4]BENZOXAZINE-6-CARBOXAMIDES

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).