DESIGN AND SYNTHESIS OF -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 an d evaluated for serotonin-3 (5-HT3) receptor binding affinity, The 5-H T, receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 1-amino substituent on the aromatic moiety by a 3-dimethylammino substituent, This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist, Consequently, a new series of 3,4-dihydro-2 H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 4-dihydro-3-oxo-2H-1,4-benzoxazine-8-car boxamides. In particular, bicyclo[2.2.2]oct-3-yl)-6-chloro-3,4,4-benzo xazine -8-carboxamide showed a high affinity for 5-HT3 receptors (K-i = 0.051 nM) and especially potent antagonistic activity against the vo n Bezold-Jarisch reflex (ED(50) = 0.089 mu g/kg i.v.) in rats.