Design and Synthesis of 6-Chloro-3,4-dihydro-4-methyl-2H-1,4-benzoxazine -8-carboxamide Derivatives as Potent Serotonin-3 (5-HT_3) Receptor Antagonists

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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 aromaitc moiety by a 3-dimethyl-amino 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 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-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.
公益社団法人日本薬学会の論文
1996-04-15