【作者】 尹贻贞；

【导师】 刘兆鹏；

【作者基本信息】 山东大学 ， 药物化学， 2011， 硕士

【摘要】 1α,25(OH)2D3,又称为活性维生素D3或骨化三醇,是维生素D3在体内发挥生理作用的基本形式。活性维生素D3除了具有调节钙磷代谢的功能外,还是一种细胞循环调节剂,影响细胞的增殖、分化和凋亡。它通过与维生素D受体(VDR)结合,在体内发挥多种多样的生理学功能,临床上可用来治疗骨质疏松、炎症、皮肤病、心血管疾病、癌症和免疫疾病等。目前,我国仅有2个活性维生素D3类药物上市,分别是阿法骨化醇和骨化三醇,而二者均为第一代活性维生素D3类药物,由于它们是以维生素D3的活性形式在体内发生作用,各种生物作用相互交叉,长期使用会造成高血钙、高血钾等不良反应。马沙骨化醇(Maxacalcitol,OCT):由日本中外制药公司开发,其注射液(商品名Oxarol)于2000年上市,用于治疗肾透析患者的继发性甲状旁腺功能亢进症(SHPT);其软膏于2001年上市,商品名为Oxarol软膏,用于治疗银屑病等干癣类皮肤病。马沙骨化醇与VDR结合能力只是骨化三醇的1/7,但抑制甲状旁腺激素(PTH)的分泌作用与骨化三醇相当,诱导细胞分化的活性是骨化三醇的10倍,且钙代谢作用微弱,高血钙等不良反应较小。慢性肾衰的发病率比较高。据专家估计,全国大约有几百万慢性肾衰患者。由于肾透析患者都存在活性维生素D3缺乏,并发展成继发性甲状旁腺功能亢进症,因此开发不良反应较少的活性维生素D3类药物马沙骨化醇,既能满足患者的需要,市场应用前景也十分广阔。银屑病等皮肤病也是危害人类健康、影响人类生活质量的一类重大疾病。据统计,在我国银屑病等皮肤病患者高达400万。在国外,活性维生素D3类药物已成为银屑病等皮肤病的首选药物,而中国目前在这领域仍是空白。治疗皮肤病药物马沙骨化醇的开发成功,将给众多皮肤病患者带来福音。由于合成马沙骨化醇必需的手性原料须经微生物发酵而制备,国内外市场上均无销售,而这一技术和原料目前被日本中外制药公司所垄断。本研究以脱氢表雄酮为原料,经过TBS保护、魏悌希反应、硼氢化-氧化反应、脱掉TBS保护基、脱氢氧化、DHP保护20位羟基、环氧化、Li/NH3电子还原在1位引入了1α-羟基,TBS保护1,3位羟基,选择性脱掉THP保护基、Williamson反应、还原开环引入侧链,经NBS溴代、脱溴、脱掉1,3位TBS保护基、光化学反应、加热重排,最终制得马沙骨化醇。以脱氢表雄酮为原料经乙二醇保护17位羰基、脱氢氧化、环氧化、Li/NH3电子还原、脱掉乙二醇保护基后,我们合成了手性关键中间体1α-羟基脱氢表雄酮。我们开发的化学合成马沙骨化醇和1α-羟基脱氢表雄酮的新方法、新工艺,不但能打破国外的垄断,也将促进我国活性维生素D3类药物的研究,使我国在活性维生素D3类药物研究领域在世界上占有一席之地,为开发具有我国自主知识产权的活性维生素D3类一类新药奠定基础。更多还原

【Abstract】 1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3], or calcitriol, the hormonally active metabolite of vitamin D3, functionizes as a regulator of calcium and phosphorus homeostasis, simultaneously is well recognized as an important cell cycle regulator. Therefore, 1α,25-Dihydroxyvitamin D3 can influence cell proliferation, differentiation and apotosis. 1α,25(OH)2D3 and its anologues exert their functions by binding to the vitamin D receptor (VDR), and have been used or have high potential for application as drugs in treating a diverse range of human diseases such as osteoporosis, inflammation, dermatological indication, cardiovascular diseases, cancers and autoimmune diseases and so on.At present, alfacalcidol and calcitriol have been in clinical use in China. Since alfacalcidol is converted into calcitriol in the body, they exhibit the same biological activities and have the side effects like increasing the blood calcium and potassium levels. Maxacalcitol, developed by Chugai Pharmaceutical Co., Ltd, was launched as the brand name of Oxarol injection for the treatment of secondary hyperparathyroidism (SHPT) in 2000 and Oxarol ointment for psoriasis in 2001, in Japan. Maxacalcitol has high cell differentiating activity (10-fold activation) but has little affinity (about 1/7) for VDR, as compared to calcitriol. It also has the similar activity in suppressing the secrection of parathyroid hormone (PTH) with calcitriol and has poor calcemic activity. Chronic Renal Failure (CRF) has a high mobility, and there are several millions patients in China. It is not unusual for people with chronic kidney failure to have low levels of vitamin D3, which subsequently cause secondary hyperparathyroidism. Thus, the development of maxacalcitol will meet the requirement of the patients of CRF in China. Psoriasis has been shown to affect health-related quality of life to a great extent. Patients with psoriasis have been estimated more than four millions in China. Active vitamin D3 analogues have been used as the primary drugs for the treatment of psoriasis in abroad. However, it is still applied in China. Developing maxacalcitol will be of great benefit to patients with psoriasis.la-Hydroxydehydroepiandrosterone, the important building block for the preparation of maxacalcitol, is reported to be obtained from dehydroepiandrosterone (DHEA) by microbial oxidation. However, this material is not commercial available from the market. We report here a new synthetic route to maxacalcitol from DHEA. Protection of 3β-hydroxyl in DHEA as a TBS ether, followed by Wittig reaction and hydroboration-oxidation, generated the 20-hydroxyl intermediate. After the removal of TBS protective group and DDQ oxidation, the 20-hydroxyl group was protected with THP. Epoxide formation and reductive opening of the epoxide and isomerization with lithium in liquid ammonia, 1α-hydroxyl was introduced in the steroid A-ring. Protection of both 1α- and 3β-hydroxyl with TBS groups, followed by the selective removal of DHP group, Williamson ether formation, and reductive opening of the epoxide, the side chain of maxacalcitol was introduced. After bromination with NBS and debromination with y-collidine, the diene was formed. Removal of TBS groups, followed by UV irradiation and the thermal reaction, maxacalcitol was obtained successfully.We also set up a new synthetic route to la-hydroxydehydroepiandrosterone, the important building block for the preparation of active vitamin D analogues. Ethylene ketal formation protected the keto group in DHEA. A novel palladium catalyzed dehydrogenation led to the enone, which undergoes epoxidation and reductive reaction with lithium in liquid ammonia to introduce the 1α-hydroxyl group. Subsequent acetal hydrolysis led to 1α-hydroxydehydroepiandrosterone. This novel syhthesis of 1α-hydroxydehydroepiandrosterone will provide the useful intermediate both for the synthesis of many active vitamin D3 drugs and novel selective vitamin D derivatives.更多还原