丁苯酞-哒嗪酮衍生物的设计、合成及其抗凝活性研究

Design,Synthesis and Anticoagulant Activity of Butylphthalide-Pyridazinone Derivatives

为了提高丁苯酞的抗血小板凝集活性,以6-氨基丁苯酞为起始原料,经重氮化/还原、环化、水解、脱氯、醚化和磺酰化反应合成了20个新型的丁苯酞-哒嗪酮衍生物,其结构经1H NMR、13C NMR和HRMS确证。体外抗血小板凝集活性测试结果表明,化合物6a、6b和6k对二磷酸腺苷(ADP)诱导的血小板凝集的抑制活性(IC_(50)=44.9~180.0μmol/L)优于先导化合物丁苯酞(IC_(50)=1252μmol/L)和阳性对照阿司匹林(IC_(50)=1140μmol/L);同时,化合物6b(IC_(50)=63.6μmol/L)和6k(IC_(50)=191.9μmol/L)对花生四烯酸(AA)诱导的血小板凝集也表现出显著的抑制活性。本研究为丁苯酞-哒嗪酮骨架在治疗缺血性脑卒中方面的研究提供了理论参考。

In order to improve the antiplatelet agglutination activity of butylphthalide,6-aminobutylphthalide was used as the starting material,twenty novel butylphthalide-pyridazinone derivatives were synthesized by diazotization/reduction,cyclization,hydrolysis,dechlorination,etherification and sulfonation acylation.Their structures were confirmed by 1H-NMR,13C-NMR and HRMS.The results of antiplatelet agglutination activity test in vitro showed that compounds 6a,6b and 6k exhibited better inhibitory activity(IC_(50)=44.9-180.0μmol/L)against ADP-induced platelet aggregation than the lead compound butylphthalide(IC_(50)=1252μmol/L)and positive control aspirin(IC_(50)=1140μmol/L).Meanwhile,compound 6b(IC_(50)=63.6μmol/L)and 6k(IC_(50)=191.9μmol/L)also possessed significant inhibitory activity against AA-induced platelet aggregation.This study provides a theoretical reference for the study of butylphthalide-pyridazinone skeleton in the treatment of ischemic stroke.