Synthesis And Positive Inotropic Evaluation Of N-(4,5-dihydro-1-methyl-[1,2,4] Triazolo [4,3-a] Quinolin-7-yl)-2-(Diazepan-1-yl) Acetamide Derivatives

At present, the death rate which caused by cardiovascular disease are gradually decreasing, however, the death rate which induced by congestive heart failure are still rising. According to the statistics of New York Cardiology Institute, the death rate of the patients who catch severe cardiac failure is about 50%. Now, more and more experts and scholars are paying close attention to the methods which can cure the cardiac failure.Our researching team have been searching for compounds with favorable positive inotropic activities and fewer side effects in a series of 3,4-dihydro-2(1H)-quinolinone derivatives for many years. According to the rule of isostere, Piao et al synthesized 20 derivates of 2-(piperazin-1-yl)-N-(quinolin-6-yl)acetamide in 1999, from wich PHR9612 was screened out. As reported, PHR0007 is a 2(1H)-quinoline derivative which exhibited favorable activity compared with milrinone. Therefore, the author designed to optimize the structure of PHR0007 by replacing the piperazine ring with a 1,4-diazepan ring and changing the substituents on the benzene ring simultaneously to find compounds with stronger activity and to investigate the structure-activity relationship.Thus, a series of N-(4,5-dihydro-l-methyl-[1.2,4]triazolo[4,3-a]quinolin-7-yl)-2- (diazepan-1-yl)acetamides was synthesized and evaluated for their 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 which2-(4-(4-methylbenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4, 3-a]quinolin-7-yl)acetamide (6m) was the most potent with 8.38±0.16%(Milrinone 2.45±0.06%) increased stroke volume at 3×10-5 M. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work. The compounds synthesized were characterized by IR,1H-NMR, MS.