【摘要】：本文綜述了血栓病的形成機制和危害，介紹了抗血小板聚集藥物研究的意義及發(fā)展前景。 運用新藥設計原理以及生物電子等排原理，在實驗室前期的研究工作基礎上，以通過體外抗血小板聚集反應活性初篩試驗選出的N1, N3-二-(4-乙�；交�)-4-甲氧基-1,3-苯二磺酰胺為先導化合物，通過對吡考他胺兩個1,3-側鏈進行改造，設計并合成了17種4-甲氧基-1,3-苯二磺酰胺類化合物P1~P17，其中10種未見文獻報道。對新近制得化合物進行了IR和1H NMR等光譜表征分析及熔點測定，部分目標化合物經(jīng)質(zhì)譜確認。 采用Born比濁法，對17種目標化合物進行的體外抗血小板聚集反應活性初篩試驗結果表明，8種目標化合物表現(xiàn)出不同程度的抗血小板聚集活性，高于陽性對照藥吡考他胺(Picotamide)和阿司匹林，其中化合物P13的活性最高，IC50值為0.46。 對較高活性的化合物P10，P13，P15和P17進行急性毒性試驗，結果表明四種受試物都表現(xiàn)出較低的毒性，有進一步研究開發(fā)的價值。繼續(xù)對化合物P10、P13和P15進行與L929細胞的作用研究，實驗結果顯示，三種受試物在中高給藥濃度下細胞存活率均相對較高，進一步證明了目標化合物具有較低的毒性。根據(jù)藥理試驗結果，對目標化合物的構效關系做出初步的推測和總結，，為實驗室今后類似研究工作提供了新的依據(jù)和參考。
[Abstract]:In this paper, the mechanism and harm of thrombosis were reviewed, and the significance and development prospect of antiplatelet aggregation drugs were introduced. Using the principles of new drug design and the principle of equal arrangement of biological electronics, on the basis of the preliminary research work in the laboratory, Using N _ 1, N _ 3-di-(4-acetylphenyl) -4-methoxy-3-benzenesulfonamide as a lead compound, two 1o 3- side chains of picotadamine were modified by the primary screening test of antiplatelet aggregation reaction activity in vitro. Seventeen kinds of 4-methoxy -1o 3-benzenedisulfonamide compounds P _ (1) P _ (17) have been designed and synthesized, of which 10 have not been reported in literature. The newly synthesized compounds were characterized by IR and 1H NMR spectra and the melting point was determined. Some of the target compounds were confirmed by mass spectrometry. Born turbidimetric assay was used to screen the antiplatelet aggregation activity of 17 target compounds in vitro. The results showed that 8 target compounds showed different degree of antiplatelet aggregation activity. The activity of compound P13 was higher than that of picotadine (Picotamide) and aspirin, and the highest activity of compound P13 was 0.46. The acute toxicity tests were carried out on the high activity compounds P10, P13, P15 and P17. The results showed that the four tested compounds showed lower toxicity, and were valuable for further research and development. The effects of compounds P10, P13 and P15 on L929 cells were further studied. The results showed that the cell survival rate of the three compounds was relatively high at medium and high concentrations, which further proved that the target compounds had lower toxicity. Based on the results of pharmacological tests, the structure-activity relationship of the target compounds was preliminarily speculated and summarized, which provided a new basis and reference for similar research in laboratory.
【學位授予單位】：天津理工大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5

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