4-甲氧基-N,N'-二(2-取代苯基)-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性研究

Synthesis and in vitro activities on anti-platelet aggregation of N,N′-di(2-substituted-phenyl)-4-methoxybenzene-1,3-disulfonamides

目的寻找新的抗血小板聚集药物并研究4-甲氧基-N,N'-二(2-取代苯基)-1,3-苯二磺酰胺类化合物的不同2-位取代苯基对抗血小板聚集活性的影响。方法以吡考他胺为先导化合物,用取代苯磺酰氨基代替3-吡啶甲氨基对先导化合物进行结构改造:以苯甲醚为原料,采用文献方法与氯磺酸反应直接制得重要中间体4-甲氧基-1,3-苯二磺酰氯;该中间体与2-取代苯胺类化合物经胺解反应制得目标化合物。以吡考他胺和阿司匹林为阳性对照药物,采用Born比浊法对目标化合物进行体外抗血小板聚集活性初筛。结果与结论共制得12个化合物(4a～4l),其化学结构由IR、1H-NMR和MS谱确证,其中9个化合物(4a～4c、4e～4i和4l)未见文献报道。药理试验结果表明,5个化合物表现出较好的体外抗血小板聚集活性:化合物4g、4f和4b的活性优于吡考他胺和阿司匹林;化合物4i的活性略低于阿司匹林;化合物4h的活性与吡考他胺相当。

On the propose of obtaining novel antiplatelet aggregating drugs and searching their SAR,we have designed and synthesized twelve N,N＇-di（2-substituted-phenyl）-4-methoxybenzene-1,3-disulfonamides（4a-4l）.With 4-methoxybenzene-1,3-disulfonyldichloride and different 2-substituted-anilines as starting materials,twelve target compounds have been produced.The structures of nine compounds newly obtained have been characterized by IR,1H-NMR and MS firstly in this paper.The target compounds have been made preliminary screening of in vitro of antiplatelet aggregating activity by Born turbidimetric method.The results showed that the three compounds 4g（inhibitory rate：95.5%）,4f（inhibitory rate：95.0%） and 4b（inhibitory rate：85.0%） emerging as significant activities of antiplatelet aggregation are superior to two reference drugs picotamide（inhibitory rate：56.5%） and aspirin（inhibitory rate：69.6%）,and the compounds 4i（inhibitory rate：60.2%） and 4h（inhibitory rate：54.2%） are slightly inferior to aspirin and picotamide,respectively.The preliminary SAR shows that it is favorable for the 4 series to increase the activities via the steric hindrance substituents attached to the 2-position of the two side chain benzene rings.And electrostatic factors are related to the activities of the series.