ChemInform Abstract: Design and Synthesis of 6-Chloro-3,4-dihydro-4-methyl-2H-1,4- benzoxazine-8-carboxamide Derivatives as Potent Serotonin-3 (5-HT3) Receptor Antagonists

Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT 3 ) receptor binding affinity. The 5-HT 3 receptor antagonistic activity of zacopride, a representative 5-HT 3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromatic moiety by a 3-dimethylamino substituent. This finding prompted a structural modification of azasetron, another 5-HT 3 receptor antagonist. Consequently, a new series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxamides. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzoxazine-8-carboxamide showed a high affinity for 5-HT 3 receptors (K i = 0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED 50 = 0.089 μg/kg i.v.) in rats.