【作者】 朱红元；

【导师】 陈立功； 姜申德； 仲伯华；

【作者基本信息】 天津大学 ， 应用化学， 2009， 博士

【摘要】 乙肝是严重危害人类的疾病,具有易感染、危害大、发病率高等特点。目前抗乙肝病毒药物品种不多,治愈率低,且常有一定的副作用或长期使用易于产生抗药性。我国乙肝发病率显著高于世界平均水平,开发新的抗乙肝药物意义重大。在抗乙肝病毒药物的研究及应用中,核苷类衍生物占据主导地位。拉米夫定是第一个用于治疗乙型肝炎的口服核苷类药物,但其主要缺点是易于产生抗药性。阿德福韦和替诺福韦,是无环核苷膦酸类(ANPs)药物,其具有广谱抗病毒活性,尤其是对于对拉米夫定产生耐药性的乙肝病毒株也敏感有效。近期,MCC-478(Alamifovir)等ANPs化合物在抗乙肝病毒研究中表现出优异性能而进入临床研究。ANPs化合物的基本结构是将磷酸基团通过脂肪醚链与嘌呤环或嘧啶环连结,从而使其在体内可以绕开磷酸化这一限速步骤。目前,此类化合物成为开发抗乙肝病毒药物研究中的热点之一。本文以MCC-478和替诺福韦为先导化合物,保持无环核苷类基本药效结构,在嘌呤环的6位引入不同取代基,设计并合成了系列化合物。首先以MCC-478为先导化合物,设计了第一类目标化合物,合成得到无环核苷膦酸酯类化合物23个(包括MCC-478),其中20个为新化合物。其次,以MCC-478和替诺福韦为先导化合物,将替诺福韦的支链结构和MCC-478的嘌呤环碱基结构相结合,设计了第二类目标化合物,合成得到无环核苷膦酸类化合物25个(包括替诺福韦),其中23个为新化合物;并且在此过程中,开发了关键中间体和替诺福韦的新的合成路线,使制备路线更加方便和经济。本文所合成的目标产物及部分中间体经核磁共振氢谱及质谱等方法分析确认。三个目标化合物用HepG2 2.2.15细胞系进行了体外抗乙肝病毒活性和细胞毒性测试,其中目标物Z-110表现出接近拉米夫定的抗乙肝病毒活性。更多还原

【Abstract】 Hepatitis B harms human enormously for its infectivity, great damage and high incidence. At present, a few drugs are currently available for the clinical treatment of hepatitis B. However, most of them usually have various problems, such as low cure rates, inducing drug resistance and side effects etc. In our country, the incidence of hepatitis B is higher than the average level of the world. Research and development of new anti-HBV agents are necessary and significant.Nucleoside analogues are in the lead in research and application of the anti-HBV drugs. Lamivudine (LAM) is the first nucleoside oral drug approved by the FDA for the treatment of hepatitis B, but it has the problem of inducing drug resistance. Adefovir and tenofovir, both belonging to acyclic nucleoside phosphonates (ANPs), are known to have broad spectrum of activity against viruses, even including the HBV species that have drug resistance to lamivudine. MCC-478, a new ANP derivative, has showed excellent anti-HBV activity in clinical trials.The main feature of ANP molecule is to combine a phosphonate group with purine or pyrimidine via an aliphatic ether chain. Bearing the phosphonate group, the ANP drug molecule can avoid the rate-limiting step of phosphorylation in vivo. At present, the ANP analogues have became a focus in research and development of new anti-HBV agents.Taking MCC-478 and tenofovir as lead compounds and keeping the ANP’s main pharmacophores, we designed and prepared series of derivatives by introducing different groups at purine ring’s 6-position. First, taking MCC-478 as the lead compound, we prepared 23 ANP trifluloroethyl ester compounds (including MCC-478) as the type I target compounds, 20 of them were novel ones. Secondly, taking MCC-478 and tenofovir as the lead compounds, we prepared 25 ANP compounds (including tenofovir) as the type II target compounds, 23 of them were novel ones. Furthermore, during the process of trying to synthesize the target compounds, we explored novel route to tenofovir and the key intermediates of the type II target compounds.The structures of the key intermediates and the target compounds were determined by 1H-NMR and MS.Three of the target compounds were evaluated for their anti-HBV activitity and cytotoxicity in HepG2 2.2.15 cells. One of them, Z-101 showed similar activitity to LAM.更多还原