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)carbonyl]-2-phenylbenzanilide Derivatives

Abstract

A series of compounds structually related to 4'-[(4, 4-difluoro-5-methylidene-2, 3, 4, 5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-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_1Aand V₂ receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.