Chemical and Pharmaceutical Bulletin p. 329 - 339 (1999)
Update date:2022-08-05
Topics:
Matsuhisa, Akira
Kikuchi, Kazumi
Sakamoto, Kenichiro
Yatsu, Takeyuki
Tanaka, Akihiro
Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V(1A) and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V(1A) and V2 receptors based on the hypothesis that the blockade of both V(1A) and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)2,3,4,5-tetrahydro- 1H-1-benzoazepine-1-carbonyl]benzanilide (exo-olefin isomer) and 4'-[5- (substituted methyl)2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V(1A) and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1- [4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzoazepin-5- ylidene}ac-etamide (14) exhibited the most potent binding affinitiy and (E)- N-methyl-(1-{4-12-(4'methylphenyl)benzoyl-amino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V(1A) and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.
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