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

Abstract

Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT-3) receptor binding affinity. The 5-HT₃ receptor antagonistic activity of zacopride, a representative 5-HT₃ receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromaitc moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT₃ receptor antagonist. Consequently, a new series of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamides was obtaiend and these compounds were found to be more potent than 3, 4-dihydro-3-oxo-2H-1, 4-bvenzoxazine-8-carboxamids. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3, 4-dihydro-4-methyl-2H-1, 4-benzoxazine-8-carboxaminde showed a high affinity for 5-HT₃ receptors (K_i=0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED₅₀=0.089 μg/kg i.v.) in rats.