含吡啶结构的二苯基丙酸衍生物的合成及生物活性研究

目的 设计合成一类以 (S)-2-羟基-3-甲氧基-3,3-二苯基丙酸为母体的新型内皮素受体拮抗剂并对其生物活性进行研究。方法 二苯甲酮和氯乙酸甲酯在甲醇钠存在下发生 Darzen 反应，再经过开环反应和水解反应得到 α-羟基酸，α-羟基酸经拆分得到手性羟基丙酸中间体，该中间体与硝基吡啶系列化合物发生双分子亲核取代反应制得目标化合物。通过大鼠离体动脉环实验测定目标化合物对内皮素受体的拮抗作用。结果 合成了 5 个未见报道的新化合物，化合物的结构经¹H-NMR 谱确证，并且对它们的比旋光度进行了测定。结论 大鼠离体动脉环实验结果显示目标化合物具有明显的内皮素受体拮抗作用。

Design, synthesis and biological activity of pyridine-bearing diphenylpropionic acid derivatives

Five pyridine-bearing endothelin receptor antagonists based on ambrisentan as structural template were designed and synthesized. The synthetic procedure started from benzophenone, which underwent Darzens condensation to afford an epoxide. The epoxide was opened when treated with p-toluenesulfonic acid in refluxing methanol to give methyl 3,3-diphenyl-2-hydroxy-3-methoxypropionoate, which was saponified to yield the corresponding acid followed by revolution with (S)-1-(p-chlorophenyl)ethylamine to furnish the enantiomerically pure (S)-3,3-diphenyl-2-hydroxy-3-methoxypropionic acid in the form of an aminium salt. Coupling of the aminium salt of this enantiomerically pure hydroxyl carboxylic acid and the pyridine-bearing electrophiles in the presence of lithium amide furnished the desired title compounds, (S)-3,3-diphenyl-3-methoxy-2-(substituted pyridinyloxy)propionic acids. Biological activity evaluated with rat aortic ring relaxation model revealed that the potency order of endothelin receptor antagonism was 9b > 9a > 10b > 9c > 10a, indicating that more substituents at m-positions more potent were their endothelin receptor antagonism.