【作者】 胡平；

【导师】 吕子敏；

【作者基本信息】 华中科技大学 ， 药物化学， 2008， 硕士

【摘要】 目的:Asoprisnil的合成及合成工艺优化,及探讨其孕激素、雌激素、糖皮质激素、雄激素及同化激素激动和拮抗活性;方法:以3, 3-亚乙二氧基-△5(10), 9(11) -雌甾二烯-17-酮为原料,经5α,10α-环氧化、11β-芳香环取代、17β-环氧化、17位开环及17α-甲基化、17β-甲基化、水解、肟化多步反应制得asoprisnil及其衍生物。结合抗孕激素化合物及TAP制剂公司所报道的asoprisnil合成路线,在试验室已有合成工艺基础上,进一步对其中的11位侧链合成、11β-烷基化反应及17位开环反应等若干步进行了优化,并经UV、IR、MS、1H-NMR和13C-NMR对所有中间体和目标化合物结构进行鉴定。分别通过家兔子宫内膜转化试验、小鼠子宫湿重法、大鼠胸腺称重法、包皮腺称重法及提肛肌称重法,对asoprisnil的孕激素、雌激素、糖皮质激素、雄激素及同化激素的激动和拮抗活性进行了评价;结果:合成了asoprisnil及其代谢产物和前药共三个目标化合物。所有中间体及目标化合物的结构均经四大波谱确证。McPhail评分显示asoprisnil是一高效的孕酮受体调节剂,在孕酮富足时呈拮抗活性,而在孕酮缺乏时表现为激动活性,虽然活性不如分别米非司酮和孕酮对照组,并且呈现剂量依赖性。仅在高剂量下asoprisnil才显示出雌激素、糖皮质激素及雄激素拮抗活性(P<0.05)。所有试验中均未见明显的雌激素、糖皮质激素、雄激素激动活性及同化激素的激动和拮抗活性;结论:与文献相比,简化了合成asoprisnil的反应条件,提高了收率,适合工业化生产;试验结果显示其具有孕激素激动-拮抗双重活性,未见明显的雌激素、糖皮质激素、雄激素激动活性及同化激素激动和拮抗活性。提示asoprisnil具有广泛的妇科疾病治疗前景,为开发国产新型有效的子宫肌瘤临床治疗药物提供坚实的试验基础和依据。更多还原

【Abstract】 Aim To prepare asoprisnil and optimize its synthetic process, and studies on its progestagenic, estrogenic, glucocorticoid, androgenic and anabolic agonist or antagonist properties.Method Starting from 3,3-[1,2-ethanediylbis(oxy)]estra-△5(10),9(11)-diene-17-one, asoprisnil and another 2 derivatives had been prepared via 5α,10α-epoxidation, 11β-aryl substituted, 17β-epoxidation, 17-ring opening, 17α-methylation, 17β-methylation, hydration, oximation and so on. All structures of intermediates and three target compounds were verified by UV, IR, MS, 1H-NMR and 13C-NMR. Progestagenic, estrogenic, glucocorticoid, androgenic and anabolic agonistic and antagonistic properties were assessed by rabbit endometrial transformation model, mouse uterine wet weight, rat thymus weight, the weight of levator ani muscle.Result Asoprisnil and another 2 derivatives were synthesized. Structures of intermediates and three target compounds were confirmed by UV, IR, MS, 1H-NMR and 13C-NMR. McPhail scores indicated that asoprisnil was a potent selective progesterone receptor modulator, it was an antagonist in presence of progesterone and agonist in absence of progesterone, albeit weaker than mifepristone and progesterone, its strength were a dose-dependant. Weak anti-estrogenic, anti-glucocorticoid, anti-androgenic activities could only be seen at high doses. Asoprisnil didn’t exhibit conspicuous estrogenic, glucocorticoid, androgenic agonist and anabolic agonist or antagonist properties at thearapeutic doses in animal experiments.Conclusion Compared to the literature, the optimized route had simplified reaction condition, improved the overall yield and satisfied the requirement of industry exploitation. Results showed asoprisnil had partial agonism- antagonism. But it didn’t exhibit conscious estrogenic, glucocorticoid, androgenic agonist and anabolic agonist or antagonist properties. Asoprisnil had great clinical thearapeutic potential in gynecological diseases.更多还原