.4,5 - Dihydro--3 (2h) - Pyridazinone Derivatives And Their Inhibition Of Platelet Aggregation Activity

Here in this thesis briefly reviewed the development of platelet aggregation inhibitors. It is very important to further develop this kind of medicines for more clinic options. Based on our previous results, we continued to synthesize the compounds of 6-(4-substituted phenyl)-4,5-dihydro-3(2H)-pyridazinones and investigate their inhibitory activity of platelet aggregation.Derived from 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pvridazinone, seventeen compounds (ZJ01-14) were designed and synthesized by varying the length of chains (n=2⁴) and the number of substituents. Nine of them were mono-substituted type whist the remained eight were di-substituted type. It was firsttried to employ a "one-pot" process to get the two compounds of different types in the same reaction mixture. Unfortunately, when the reaction was carried out in methanol in the presence of water, an over-hydrolyzed by-product named JSJ (n=2) was obtained. It was also tried to perform the reaction by using additives such as K₂CO₃ without any meaningful result. The stepwise procedure eventually had to be used to getthe target molecules (Scheme 1). To the best of our knowledge, all of them haven't been reported in literatures except for JSJ.Fourteen compounds inhibited ADP-induced aggregation of rat platelets in vitro where thirteen had mild activity while ZJ14 exhibited significant inhibition with the IC50 value of 0.09 mM.Preliminary studies on the structure and activity relationship (SAR) suggested that long chain and di-substituted type would benefit for the bioactivity.