本文選題：合成 + 4-甲氧基-1��； 參考：《天津理工大學(xué)》2014年碩士論文

【摘要】：近年來，，血栓性疾病的發(fā)病率逐年增高，究其原因主要有兩個(gè)方面：生活水平的提高和不良生活習(xí)慣，如膳食不合理、吸煙、飲酒和缺乏運(yùn)動(dòng)等。因此，抗血小板聚集藥物作為臨床上治療心腦血管栓塞性疾病的特效藥物，有著巨大的臨床需求和廣闊的市場(chǎng)前景，因此，本論文旨在研究結(jié)構(gòu)新穎、高效、毒副作用較低的抗血小板藥物。 本論文在1987年上市的抗血小板聚集藥物吡考他胺(Picotamide)結(jié)構(gòu)基礎(chǔ)上進(jìn)行改造，參照實(shí)驗(yàn)室前期研究所得出的計(jì)算機(jī)輔助藥物設(shè)計(jì)模型，運(yùn)用電子等排原理，共設(shè)計(jì)并合成了13個(gè)具有4-甲氧基-1,3-苯二甲酰胺類結(jié)構(gòu)的化合物：PN477、PN478、PN479、PN480、PN481、PN482、PN483、PN484、PN485、PN486、PN487、PN488、PN489。 各目標(biāo)化合物的結(jié)構(gòu)由IR，1HNMR和MS分析確證并進(jìn)行了熔點(diǎn)測(cè)定。采用Born比濁法，對(duì)13個(gè)目標(biāo)化合物和對(duì)照藥物Picotamide和Asprin進(jìn)行了ADP誘導(dǎo)大鼠的體外抗血小板聚集活性初篩試驗(yàn)，試驗(yàn)結(jié)果表明，其中7個(gè)化合物PN477、PN478、PN479、PN480、PN481、PN483和PN484有著較好的體外抗血小板聚集活性，高于陽性對(duì)照藥Picotamide和Asprin，化合物PN481的IC50值最小，抗血小板聚集活性最高；繼續(xù)將這7個(gè)經(jīng)體外抗血小板聚集活性初篩選出的目標(biāo)化合物進(jìn)行急性毒性試驗(yàn)，發(fā)現(xiàn)其中6個(gè)受試物(PN477、PN478、PN479、PN480、PN481、PN483)毒性較低，有進(jìn)一步研究開發(fā)的價(jià)值；此外，為了初步了解化合物的細(xì)胞毒性，以吡考他胺為對(duì)照藥，挑選出抗血小板聚集活性和急性毒性結(jié)果都比較理想的三個(gè)化合物PN478、PN480和PN481與L929細(xì)胞進(jìn)行相互作用試驗(yàn)研究。結(jié)果顯示：受試物PN481在低劑量給藥濃度(10μmol/L)下細(xì)胞存活率要高于對(duì)照藥Picotamide，對(duì)測(cè)試細(xì)胞具有較低毒性；在高劑量給藥濃度下(100μmol/L)PN478、PN481的細(xì)胞存活率雖然要比Picotamide要稍低，但仍然有著較高的細(xì)胞存活率，具有很高的繼續(xù)開發(fā)和研究?jī)r(jià)值。根據(jù)以上藥理試驗(yàn)的結(jié)果，對(duì)所設(shè)計(jì)合成的目標(biāo)化合物的構(gòu)效關(guān)系作了初步的推測(cè)和總結(jié)。
[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.
【學(xué)位授予單位】：天津理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5;R965

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本文編號(hào)：1968653