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目的合成作用更强、选择性更好的血小板聚集抑制剂。方法按照前期吡考他胺衍生物的构效关系,设计了新的4-甲氧基-1,3-苯二磺酰胺类化合物,以苯甲醚为原料,通过磺酰化反应和胺解反应制得目标化合物。以吡考他胺(picotamide)、阿司匹林(aspirin)和氯吡格雷(clopidogrel)为阳性对照药物,采用Born比浊法进行体外抗血小板聚集活性初筛,并与具有相同母体结构的7个二取代苯基类化合物进行抗血小板聚集活性评价和比较。结果与结论合成了10个未见文献报道的新化合物,其结构均经13C-NMR、1H-NMR、IR和MS谱确证。在1.3μmol·L~(-1)时,5个化合物(1a、1b、1c、1e、1f)具有抗ADP诱导的家兔体外血小板聚集作用,且优于阳性对照药阿司匹林;化合物1b和1e的抑制活性优于阳性对照药吡考他胺;其中,活性最好的化合物1b的抑制率(62.3%)超过氯吡格雷(55.6%)。两个系列化合物的活性对比表明,新合成的目标化合物中具有抗血小板聚集活性的化合物的数目更多,此类化合物有进一步研究的价值。
Objective To synthesize stronger and more selective platelet aggregation inhibitors. Methods According to the structure-activity relationship of pirocratamine derivatives, a new 4-methoxy-1,3-benzenedisulfonamide compound was designed and synthesized by the sulfonylation reaction and amineysis The target compound was obtained by reaction. Taking picotamide, aspirin and clopidogrel as positive control drugs, Born turbidimetry was used to screen anti-platelet aggregation activity in vitro and compared with seven disubstituted Phenyl compounds for anti-platelet aggregation activity evaluation and comparison. RESULTS AND CONCLUSION Ten new compounds were synthesized and their structures were confirmed by 13C-NMR, 1H-NMR, IR and MS spectra. At 1.3 μmol·L -1, five compounds (1a, 1b, 1c, 1e, 1f) exhibited anti-ADP-induced platelet aggregation in vitro and were superior to the positive control aspirin. Compounds 1b and 1e Was superior to the positive control, picoxysalamine. Among them, the most active compound 1b had a higher inhibitory rate (62.3%) than clopidogrel (55.6%). The comparison of the activity of the two series of compounds shows that there are more compounds having the anti-platelet aggregation activity in the newly synthesized target compounds, and the compounds are of further research value.