Synthesis Of 4-Methoxy(Ethoxy)-1,3-Benzenedicarboxamide Derivatives And Comparison On Anti-Platelet Aggregation Activity

Thirty compounds are included in the paper, 16 of which have not been reported. Based on preliminary studies, in terms of the use of new drugs in the row design principles such as the principle of electronics, Picotamide as the lead compound was used to obtain 74-methoxybenzene-1,3-isophthalamides(PN491-PN497). Preliminary laboratory results showed that the increase of 4-position of the phenyl ring substituents volume will improve anti-platelet activity, and 9 4-ethoxybenzene-1,3-isophthalamides(PN498-PN506) were designed.For speculation of SAR, 14 compounds(PN507*-PN520*) which have been reported before were selected. The chemical structure of all target compounds were confirmed by1H-NMR, IR and ESI-MS spectra.The antiplatelet aggregation activities of 16 target compounds were tested using ADP as an inducer by Born test and the results showed that of which 6 compounds PN491, PN492,PN493, PN494, PN495, PN496, PN507*, PN516* and PN517* have higher anti-platelet aggregation than Aspirin and Picotamide. PN493 has minimum IC50, and its anti-platelet aggregation activity is the highest. PN491, PN492, PN493, PN494, PN495 and PN496 which have smaller IC50 values were further selected to measure aggregation activities induced by collagen and arachidonic acid. The results showed that PN493 and PN494 have higher aggregation activity than Aspirin and Picotamide induced by collagen; and PN494 have slightly higher aggregation activity than Picotamide, but lower than Aspirin. Further test of these six compounds were continued in mice acute toxicity. Compounds PN491, PN492,PN493, PN494, PN495 and PN496 have low toxicity equal to Picotamide and much lower to Aspirin at three concentrations considerably. In the test of PN491, PN492, PN493, PN494,PN495, PN496 also carried out with L929 cell by Picotamide as the control drug. The test showed that the cell survival of PN491, PN492, PN494 and PN495 were higher than Picotamide at lower drug concentration(10μmol/L); while PN493 and PN494 were higher than Picotamide at high drug concentration(100μmol/L).PN494 showed high anti-platelet aggregation induced respectively by ADP, collagen and arachidonic acid, and PN494 had low acute toxicity test in mice. In L929 cytotoxicity test, the cell survival of PN494 at different concentrations were higher than Picotamide. The data suggested that PN494 deserve further research. According to the results of the pharmacological experiments, preliminary speculation and summarize are made for structure-activity relationships(SAR) of target compounds.