Study On Design, Synthesis And Activity Of 4-Methoxybenzene-1, 3-isophthalamide Derivatives

The pathogenesis and formation of thrombus and platelet was described in this thesis. And mechanism and structure activity relationship of anti-platelet and anti-thrombus drugs was discussed including latest development and research.To find more effective, broad-spectrum and low toxically anti-platelet inhibitors, according to corresponding literature and previous works of our laboratory, Picotamide was chosen as a lead compound, which has simultaneously mechanism. Fourteen firstly aryl amide derivatives were designed and synthesized by bioisosterism and combination principle on the basis of the result of CoMFA. The structures of compounds have been determined by IR and ~1H-NMR. In vitro rat antiplatelet aggregation model, target compounds inhibited antiplatelet aggregation induced by collagen was tested with the method of Born turbidity. Nine had clearly higher antiplatelet aggregation activity than Picotamide and one had equivalent activity. According to pharmacology results, SAR of target compounds was summarized.In addition, Technological optimization of 4-methoxyl-1,3-phthalic acid , core intermediate of lead compound Picotamide, has accomplished by means of orthogonal design. Factors-reaction time, temperature, molar ratio of raw material to potassium permanganate and molar weight of TBAB has been effectively studied. The optimum reaction time was about 3 hours, temperature was around 80 degrees, molar ratio of raw material to potassium permanganate was 1 to 5 and molar weight of TBAB was 6 % of raw material. The yield that repeated experiment results have showed was 76 % under these conditions, which is more than that of before. The technological optimization will provide guarantee to the synthesis of target compounds and developmen.