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

作　　者：贾镇 张关丽 李毅 李永 汤磊 樊玲玲 Jia Zhen;Zhang Guanlit;Li Yi;Li Yong;Tang Lei;Fan Lingling(School of Pharmacy,Guizhou Medical University,Guizhou Province Engineering Technology Research Center for Chemical Drug R&D,Guiyang,550025)

机构地区：[1]贵州医科大学药学院贵州省化学合成药物研发利用工程技术研究中心,贵阳550025

出　　处：《化学通报》2024年第1期110-117,1,共9页Chemistry

基　　金：国家自然科学基金项目(32060627);贵州省科技计划项目(黔科合基础-ZK[2023]一般309);贵州省普通高等学校青年科技人才成长计划项目(黔教合KY字[2022]246号);贵州省2021年大学生创新创业训练计划项目(S202110660026)资助。

摘　　要：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.

关 键 词：丁苯酞衍生物 哒嗪酮 设计 合成 血小板凝集活性 

分 类 号：TQ460.1[化学工程—制药化工]