Nonpeptide arginine vasopressin antagonists for both V-1A and V-2 receptors: Synthesis and pharmacological properties of 4 '-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]benzanilide and 4 '-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide derivatives

Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and wat er reabsorption via V-1A and V-2 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 serie s of AVP antagonists for both V-1A and V-2 receptors based on the hypothesi s that the blockade of both V-1A and V-2 receptors might be beneficial to C HF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carb onyl]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dih ydro-1H-1-benzoazepine-1-carbonyl (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V-1A and V-2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more poten t binding affinity compared with endo-olefin isomers. Among these (E)-exo-o lefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-te trahydro-1H-1-benzoazepin-5-ylidene}acetamide (14) exhibited the most poten t binding affinitiy and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoyl-amino ]benzoyl}-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidiene)acetamide (20) exh ibited a high AVP antagonist activity for both V-1A and V-2 receptors after intravenous administration. Details of the synthesis and pharmacological p roperties of this series are presented.