Synthesis And Positive Inotropic Activity Of 2-(4-benzyl-1, 4-diazepan-1-yl)-N-(4, 5-dihydro-1-phenyl-[1, 2, 4]triazolo[4, 3-a]quinolin-7-yl) Acetamide Derivatives

Congestive heart failure (CHF) is a reason of cardiovascular diseases whose mortality stands the first place in the world, positive inotropic agents play an important role in the treatment of CHF. Therefore, finding new inotropic agent for the treatment of CHF is still a great challenge in the cardiovascular field at current and in the near future.In our previous work to search for more potent positive inotropic agents, the compound PHR9612 showed moderate positive inotropic activity. Then we found compound 1 was a 2(1H)-quinoline derivative which exhibited favorable activity compared with vesnarinone. Therefore, the author designed to optimize the structure of compound 1, replacing the piperazine ring with a 1,4-diazepane ring, changing the substituents on the 2-position with benzyl instead of methyl, removed the benzyloxy group,and changing the substituents on the benzene ring simultaneously, to find novel compounds with stronger activity and to investigate the structure-activity relationship. A series of 2-(4-benzyl-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quino-lin-7-yl)acetamide derivatives has been synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(3,4-dichlorobenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl-[1,2,4] triazolo[4,3-a]quinolin-7-yl)acetamide 6o was the most potent increasing stroke volume by 9.17%±0.14% (milrinone:2.47%±0.08%) at 3×10-5 M in our in vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work. The compounds synthesized were characterized by IR,'H-NMR, MS.