2-[5,6-双(4-甲氧基苯基)吡嗪-2-氧基]-2-甲基丙酸的合成及抗血小板聚集活性和安全性药理研究

Synthesis of 2-[5,6-bis(4-methoxyphenyl) pyrazin-2-oxy]-2-methylpropionic acid and its antiplatelet aggregation activity and safety pharmacology

目的设计合成2-[5,6-双(4-甲氧基苯基)吡嗪-2-氧基]-2-甲基丙酸,并进行抗血小板聚集活性及初步安全性评价。方法目标化合物的合成以对甲氧基苯乙酸为起始原料,经酰化、付克、氧化、环合、烷基化、水解共5步反应完成。通过灌胃及体外给药,用二磷酸腺苷、胶原、花生四烯酸等不同诱导剂,以阿司匹林和氯比格雷作阳性对照,进行了动物实验性抗血小板聚集和血小板依赖性血栓形成的药效学研究及安全性药理试验。结果与结论合成反应总收率达9. 6%,产品纯度大于99. 0%,经优化后的合成工艺易于操作,也易于放大生产。药效学试验显示,目标化合物对胶原、花生四烯酸诱导的血小板聚集有明显抑制作用,作用优于氯比格雷。大鼠体内外血栓形成实验显示,目标化合物对血栓形成有一定的预防作用。血小板黏附性实验显示,目标化合物可降低血小板黏附性,而阿司匹林没有明显作用。血液流变性实验显示,目标化合物可降低血瘀模型大鼠的血液黏度。一般药理试验显示,目标化合物对小鼠一般行为、自主活动及协调运动无明显影响,对麻醉犬血压、呼吸频率、幅度、心率无明显影响,与对照组比较无显著差异,但对小鼠阈下剂量戊巴比妥钠催眠有一定协同作用。小鼠肠蠕动实验和兔瞳孔实验显示,目标化合物对自主神经系统无明显影响。

2-[5,6-Bis ( 4-methoxyphenyl ) pyrazin-2-oxy ]-2-methylpropionic acid was designed and synthesized and evaluated for its antiplatelet aggregation activity and preliminary safety. The synthesis of the target compound was completed by 5 steps of reactions,acylation,Friedel-Crafts reaction,oxidation, cyclization,alkylation and hydrolysis. The pharmacodynamic study of experimental antiplatelet aggregation and platelet dependent thrombosis was carried out by using different kinds of inducers, such as adenosine diphosphate,collagen and arachidonic acid,and the positive controls as aspirin and clopidogrel,by gavage and in vitro administration. The total yield of the synthetic reaction reaches 9. 6%,and the purity of the product is more than 99%. The optimized synthetic process is easy to operate and easy to scale up production. The results of pharmacodynamic tests showed that the platelet aggregation induced by collagen and arachidonic acid was significantly inhibited,and the effect was better than that of clopidogrel. Experimental results of thrombosis in vivo and in vitro showed that there was a certain preventive effect on thrombosis. Platelet adhesion test results showed that platelet adhesion could be reduced,while aspirin had no obvious effect. The results of hemorheology test showed that the blood viscosity of blood stasis model rats could be reduced. The results of safety pharmacological tests showed that there was no obvious influence on general behavior,autonomic activity and coordinated movement in mice,no significant influence on blood pressure, respiratory frequency,amplitude and heart rate of anesthetized dogs,and there was no significant difference compared with the control group. But it has synergistic effect on the hypnotic effect of pentobarbital sodium in mice. The results of mouse intestinal peristalsis test and rabbit pupil test showed that there was no significant effect on autonomic nervous system.