Development of potent serotonin-3 (5-HT3) receptor antagonists. I. Structure-activity relationships of 2-alkoxy-4-amino-5-chlorobenzamide derivatives

Article abstract of DOI:10.1248/cpb.43.1364

A new series of 2-alkoxy-4-amino-5-chlorobenzamide derivatives hearing five- to seven-membered heteroalicyclic rings in the amine moiety was synthesized and evaluated for serotonin-3 (5-HT₃) receptor antagonistic activity by assaying the ability to antagonize the yon Bezold-Jarisch reflex in rats. The five- to seven-membered heteroalicycles comprise pyrrolidine, morpholine, 1,4-thiazine, piperidine, piperazine, 1,4-oxazepine, 1,4- thiazepine, azepine, and 1,4-diazepine rings. Among them, some benzamide derivatives having a 1,4-diazepine ring showed a potent 5-HT₃ receptor antagonistic activity. In particular, 4-amino-5-chloro-N-(1,4- dimethylhexahydro-1H-1,4-diazepin-6-yl)-2-ethoxyhenzamide (96) and the 1- benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 103 showed potent 5-HT₃ receptor antagonistic activity without 5-HT₄ receptor binding affinity.

Full text of DOI:10.1248/cpb.43.1364

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