4-甲氧基-1，3-苯二甲酰胺衍生物的合成及其体外抗血小板聚集活性测定

发布时间：2018-06-02 11:48

本文选题：合成 + 4-甲氧基-1　；参考：《天津理工大学》2014年硕士论文

【摘要】：近年来，，血栓性疾病的发病率逐年增高，究其原因主要有两个方面：生活水平的提高和不良生活习惯，如膳食不合理、吸烟、饮酒和缺乏运动等。因此，抗血小板聚集药物作为临床上治疗心脑血管栓塞性疾病的特效药物，有着巨大的临床需求和广阔的市场前景，因此，本论文旨在研究结构新颖、高效、毒副作用较低的抗血小板药物。本论文在1987年上市的抗血小板聚集药物吡考他胺(Picotamide)结构基础上进行改造，参照实验室前期研究所得出的计算机辅助药物设计模型，运用电子等排原理，共设计并合成了13个具有4-甲氧基-1,3-苯二甲酰胺类结构的化合物：PN477、PN478、PN479、PN480、PN481、PN482、PN483、PN484、PN485、PN486、PN487、PN488、PN489。各目标化合物的结构由IR，1HNMR和MS分析确证并进行了熔点测定。采用Born比浊法，对13个目标化合物和对照药物Picotamide和Asprin进行了ADP诱导大鼠的体外抗血小板聚集活性初筛试验，试验结果表明，其中7个化合物PN477、PN478、PN479、PN480、PN481、PN483和PN484有着较好的体外抗血小板聚集活性，高于阳性对照药Picotamide和Asprin，化合物PN481的IC50值最小，抗血小板聚集活性最高；继续将这7个经体外抗血小板聚集活性初筛选出的目标化合物进行急性毒性试验，发现其中6个受试物(PN477、PN478、PN479、PN480、PN481、PN483)毒性较低，有进一步研究开发的价值；此外，为了初步了解化合物的细胞毒性，以吡考他胺为对照药，挑选出抗血小板聚集活性和急性毒性结果都比较理想的三个化合物PN478、PN480和PN481与L929细胞进行相互作用试验研究。结果显示：受试物PN481在低剂量给药浓度(10μmol/L)下细胞存活率要高于对照药Picotamide，对测试细胞具有较低毒性；在高剂量给药浓度下(100μmol/L)PN478、PN481的细胞存活率虽然要比Picotamide要稍低，但仍然有着较高的细胞存活率，具有很高的继续开发和研究价值。根据以上药理试验的结果，对所设计合成的目标化合物的构效关系作了初步的推测和总结。
[Abstract]:In recent years, the incidence of thrombotic diseases has increased year by year. There are two main reasons: the improvement of living standard and bad living habits, such as unreasonable diet, smoking, drinking and lack of exercise. Therefore, antiplatelet aggregation drugs, as special drugs for the treatment of cardiovascular and cerebrovascular embolism, have great clinical demand and broad market prospects. Antiplatelet drugs with low toxicity and side effects. In this paper, the structure of the anti-platelet aggregation drug Picotamide, which was listed in 1987, was modified. According to the computer aided drug design model developed in the laboratory, the principle of electronic isodrainage was used. A total of 13 compounds with 4-methoxy-1- (3-) -benzodiamides have been designed and synthesized. The compounds: PN477, PN478, PN478, PN480, PN481, PN482, PN483, PN485, PN486PN487, PN488PN489. The structure of the target compounds was confirmed by IR 1H NMR and MS analysis and the melting point was determined. Born turbidimetric assay was used to screen the anti-platelet aggregation activity of 13 target compounds and control drugs Picotamide and Asprin in vitro in rats induced by ADP. Seven compounds, PN477, PN478, PN479, PN480, PN481, PN483 and PN484, had better anti-platelet aggregation activities in vitro, which were higher than those of Picotamide and Asprin, and the IC50 value of compound PN481 was the lowest, and the activity of anti-platelet aggregation was the highest. The acute toxicity tests of the seven target compounds, which were initially screened by anti-platelet aggregation activity in vitro, were continued, and six of them were found to be of low toxicity and of value for further research and development, including PN477, PN478, PN479, PN480, PN481C, PN483, and PN477, PN478, PN478, PN478, PN479, PN479, PN479, and PN483. In order to understand the cytotoxicity of the compounds, three compounds, PN478PN480 and PN481, which had good antiplatelet aggregation activity and acute toxicity, were selected to study the interaction of PN478PN480 and PN481 with L929 cells. The results showed that the cell survival rate of PN481 was higher than that of Picotamide at a low dose of 10 渭 mol / L, and it was less toxic to the test cells than Picotamide, and the cell survival rate of 100 渭 mol / L PN478PN481 was slightly lower than that of Picotamide. But it still has high cell survival rate and has high value of further development and research. Based on the results of the above pharmacological tests, the structure-activity relationships of the target compounds were preliminarily inferred and summarized.
【学位授予单位】：天津理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R965

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