Chem. Pharm. Bull., 48(11),1644-1651, November 2000

Regular Articles

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

Yoshiaki SHIMADA, Nobuaki TANIGUCHI, Akira MATSUHISA, Kenichiro SAKAMOTO, Takeyuki YATSU, and Akihiro TANAKA^*

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.

A series of compounds structurally 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_1A and V₂ receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.

Key words YM-35471; arginine vasopressin antagonist; difluorination; congestive heart failure