Design, Synthesis And Platelet Aggregation Inhibitory Activity Of 4, 5-dihydro-3(2H)-pyridazinones

In an effort to search for new potent, less toxic antithrombotic agents, fourty-seven derivatives of 6-(4-subtituted of aminophenyl)-5-methyl-4,5-dihydro- 3(2H)-pyridazinones were designed and synthesized according to mechanism of action and relationship of dihydropyridazinones. Thirty-eight of them were first reported. All intermediates and title compounds were confirmed by element analysis, 1H-NMR, MS and IR.Born method was applied for preliminary pharmacological test in vitro. Results of pharmacological test showed that the title compounds have the potent activities against the human platelet aggregation induced by adenosine diphosphate (ADP) in vitro. The IC50s of compounds A4,A6,A12,A14,A17,A19 and A24, are respectively 0.08, 0.09, 0.02, 0.05,0.04,0.02 and 0.04μmol/L. They were more potent than the control compound MCI-154 (IC50 3.6μmol/L) and CCI-17810 (IC50 2.3μmol/L). The inhibitory effect against platelet aggregation of compound (A12, A19) was about 180 times than that of MCI-154 and about 115 times than that of CCI-17810.Preliminary structure and activity relationship(SAR) suggested that compounds with substituted piperazidine were more potent than compounds with substituted piperidine and other group substituted compounds. In the substituted piperazidine compounds, long and straight chains were benefit for the bioactivity.