Preparation of non-peptide, highly potent and selective antagonists of arginine vasopressin V1a receptor by introduction of alkoxy groups

Abstract

A series of compounds structurally related to 4′-[(4,4-difluoro-5- methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2′-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V 1A receptors. Consequently, we found that the (Z)-4′-({4,4- Difluoro-5-[(4-dimethylaminopiperidino) carbonylmethylene]-2,3,4,5-tetrahydro- 1H-1-benzoazepin-1-yl}carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4′-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5- tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper. © 2003 Pharmaceutical Society of Japan.