维司力农类似物的分子设计、合成及其正性肌力活性研究

发布时间：2018-06-07 11:01

本文选题：正性肌力作用 + 强心药　；参考：《延边大学》2014年博士论文

【摘要】：本论文根据生物电子等排和拼合原理,以维司力农为先导化合物,设计合成了7个系列117个全新的维司力农衍生物及其类似物。对所合成的目标物通过测定其对家兔离体左心房搏出量的影响,对化合物的正性肌力活性进行了初步评价,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研究。结果显示,一些衍生物在测试浓度下显示出比上市药物米力农更好的正性肌力活性。目标化合物结构均经1HNMR和MS确证了结构,部分化合物测试了13C NMR和IR。本论文的研究工作可分为三个部分： 1、设计合成了4个系列三唑乙酰胺类化合物(共75个),测定其对家兔离体左心房搏出量的影响,对化合物的正性肌力活性进行了初步评价。结果显示,发现有2个系列的目标化合物(1和2)在测试浓度下显示出比对照药物米力农更好的正性肌力活性,其中活性最好的化合物是8a,在浓度为3×10-5M时,增强左心房搏出量的强度达20.29±0.18%(米力农：2.46±0.07%),是米力农的8倍。 2、设计合成了1个系列喹喔啉类化合物(共16个),并初步评价了它们的体外正性肌力活性。结果显示,只有少部分目标化合物的活性强于对照药米力农,其中化合物14k的活性最好,在浓度为3×10-5M时,增强左心房搏出量的强度达5.34±0.05%(米力农：2.46±0.07%),是米力农的2倍。 3、设计合成了2个系列呔嗪类化合物(共26个),并初步评价了它们的体外正性肌力活性。发现大部分目标化合物都表现出了很好的活性,其中化合物25m的活性最好,在浓度为3×10-5M时,增强左心房搏出量的强度达12.02±0.20%(米力农：2.46±0.07%),是米力农的5倍。本论文对维司力农进行了结构修饰,并对目标化合物进行了正性肌力活性的初期筛选。活性筛选结果显示大部分化合物达到了预期的活性增强的设计目的,且获得了正性肌力活性优于对照药物米力农的几个优选化合物。这一点与我们当初的设计思想不谋而合,也与实验数据基本相互符合。
[Abstract]:In this paper, according to the principle of equal arrangement and splicing of biological electrons, seven series of 117 new derivatives of Visrinon and their analogues were designed and synthesized with Visrinon as the leading compound. The positive inotropic activity of the compound was preliminarily evaluated by measuring the effect of the target compound on the left atrial beat volume of rabbits in vitro. Meanwhile, the chronotropic experiments of those compounds with positive myotropic activity were carried out. The results showed that some derivatives showed more positive inotropic activity than milrinone at the test concentration. The structures of the target compounds were confirmed by 1HNMR and MS, and some of the compounds were identified by 13C NMR and IR. The research work of this thesis can be divided into three parts: 1. Four series of triazolacetamide compounds (75) were designed and synthesized. The effects of these compounds on isolated left atrial beats were determined and the positive inotropic activity of the compounds was evaluated. The results showed that two series of target compounds (1 and 2) showed positive inotropic activity at the test concentration, which was better than that of the control drug milrinone. The most active compound was 8 a, and at the concentration of 3 脳 10 ~ (-5) M, the positive inotropic activity was better than that of the control drug milrinone at the concentration of 3 脳 10 ~ (-5) M. The intensity of enhancement of left atrial output was 20.29 卤0.18. (Milinon: 2.46 卤0.07) was 8 times higher than that of milrinone. 2. A series of quinoxaline compounds (16 of them) were designed and synthesized, and their positive inotropic activities in vitro were preliminarily evaluated. The results showed that only a few of the target compounds were more active than those of the control drug milrinone, and the activity of compound 14k was the best. When the concentration was 3 脳 10 ~ (-5) M, the intensity of enhancing the left atrial beat was 5.34 卤0.05 (milrinon: 2.46 卤0.07), twice as much as that of milrinone. 3. Two series of pyrazines were designed and synthesized, and their positive inotropic activities in vitro were preliminarily evaluated. It was found that most of the target compounds showed good activity, of which 25 m had the best activity, and the intensity of enhancement of left atrial beat was 12.02 卤0.20 when the concentration was 3 脳 10 ~ (-5) M (Milinon: 2.46 卤0.07), which was 5 times of that of milrinone. In this paper, the structure of Visrinon was modified, and the initial screening of positive myotropic activity of the target compound was carried out. The results of activity screening showed that most of the compounds had achieved the design purpose of expected activity enhancement, and the positive inotropic activity was better than that of the control drug milrinone. This is consistent with our original design idea, but also with the experimental data is basically in line with each other.
【学位授予单位】：延边大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5;R96

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