【作者】 叶柏军；

【导师】 朴虎日；

【作者基本信息】 延边大学 ， 药物化学， 2010， 硕士

【摘要】 目前人类由心血管疾病引起的死亡率在逐年下降,但由充血性心力衰竭引起的死亡率却还在上升。据纽约心脏病学会统计,严重的心力衰竭病人年死亡率高达50%。目前,心力衰竭的治疗方法已倍受专家和学者的关注。我课题组对三唑并二氢喹啉衍生物的合成及正性肌力活性研究已有多年,1999年朴虎日等根据电子等排原理设计合成了取代哌嗪乙酰氨基喹啉酮衍生物20个,并从中筛选出了活性较好的化合物PHR9612。PHR0007是2003年我课题组合成的活性显著的喹啉酮衍生物,其活性在各浓度条件下均强于或等于米力农(milrinone)。在PHR0007的基础上,我们又合成了化合物PHR0701-PHR0716,该系列化合物也显示出较好的生理活性。所以作者设想了以PHR0007为先导化合物对其进行结构修饰,即将哌嗪环变为高哌嗪环,同时改变支链苯环上的取代基,企图能找到正性肌力作用更强的化合物,这对于寻找新药和探索此类型化合物的构效关系具有一定的意义。本论文设计合成了一系列N-(4,5-二氢-1-甲基-[1,2,4]三氮唑并[4,3-a]喹啉-7-基)-2-(高哌嗪-1-基)乙酰胺衍生物,同时通过测定这些化合物对家兔离体左心房搏出量的影响,初步评价了此系列化合物的正性肌力活性。结果显示,7个化合物在测试浓度下正性肌力作用优于对照药物米力农(3×10-5 M),尤其是化合物2-(4-甲基-苯基-1,4-高哌嗪-1-基)-N-(4,5-二氢-1-甲基-[1,2,4]三唑并[4,3-a]喹啉-7-基)乙酰胺(6m)以增强左心房搏出量8.38±0.16%的强度(米力农：2.45±0.06%)成为此系列衍生物中正性肌力活性最强的化合物。我们同时对那些具有正性肌力活性的化合物进行了变时性实验。论文中所合成的化合物都通过IR,1H-NMR, MS进行了确证。更多还原

【Abstract】 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.更多还原