孕酮受体拮抗剂米非司酮衍生物的合成及抗早孕作用

目的寻找单一的孕酮受体拮抗剂.方法对米非司酮的C11、C13、C17-取代基进行修饰,以3,3-乙撑二氧-5(10),9(11)-雌甾二烯-17-酮为原料,经环氧化、格氏加成、加成、还原、水解等反应,设计并合成了未见文献报道的7个目标化合物,经红外、核磁共振氢谱及高分辨质谱确证其结构.并对目标化合物的活性进行了初步的体内、体外试验.结果目标化合物的抗早孕作用类似或低于米非司酮,其中,化合物9d拮抗孕酮受体能力与米非司酮相似,但抗糖皮质激素受体作用小于米非司酮.结论C11位引入较大的取代基能够保持米非司酮的抗孕酮受体活性,C17位引入极性取代基可以降低其抗糖皮质激素受体活性.

Synthesis and effect of terminating early pregnancy of progesterone receptor antagonist mifepristone derivatives

Aim To search for novel progesterone receptor antagonist with higher efficiency and less antiglucocorticoid effects.Methods The structure of progesterone receptor antagonist mifepristone at C_ 11,C_ 13,C_ 17-substitute were modified.Seven mifepristone derivatives were synthesized from 3-ketal-5(10),9(11)-estradiene-17-one through epoxidation,the addition of aromatic Grignard agent,addition,reduction and hydrolysis.All of them have not been reported in literature previously.Their structures were confirmed by IR, 1H-NMR and MS spectra.Result All the compound showed similar or lower antagonistic effect on progesterone receptor.The antiprogesterone effect of compound 9d was similar to mifepristone with less antiglucocorticoid effects.Conclusion Introduction of bigger group at C_ 11 will not alter the antiprogesterone effect,while introduction of polar group at C_ 17 may induce less antiglucocorticoid effects.