Highly potent and orally active non-peptide arginine vasopressin antagonists for both V(1A) and V2 receptors: Synthesis and pharmacological properties of 4'-[(4,4,-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)car bonyl]-2-phenylbenzanilide derivatives

Abstract

A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carb onyl]-2-phenylbenzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with a (Z)-olefin geometry at the 5-position of benzoazepine possessed potent affinity for both the V(1A) and V2 receptors. Further study has shown that one of these derivatives, (Z)-4'-({4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4 ,5-tetrahydro-1H-1-benzoazepin-1-yl}carbonyl)-2-phenylbenzanilide monohydrochloride (29, YM-35471), exhibits exceptionally potent affinity for both of V(1A) and V2 receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.