抗乙肝病毒的嘌呤类无环核苷膦酸衍生物的合成研究
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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。
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.
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。
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.
引文
[1]http://www.who.int/mediacentre/factsheets/fs204/zh/index.html
[2]叶维法,钟振义,肝炎学大典,天津:天津科学技术出版社,1996,(a) 1215; (b) 298～310;(c) 402;(d) 811～821;(e) 881～883;(f) 883～886;(g) 898～916
[3]中华人民共和国卫生部,2006年～2010年全国乙型病毒性肝炎防治规划,中国实用乡村医生杂志,2006,13(8):1～4
[4]http://www.moh.gov.cn/open/web_edit_file/20080326083022.doc
[5]Lee W M. Hepatitis B Virus Infection, N Engl J Med, 1997, 337 (24):1733~1745
[6]Dane D S, Cameron C H, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis, Lancet, 1970, 295(7649): 695~698
[7]姚桢,分子乙型肝炎病毒相关病学,北京:中国医药科技出版社,1998,(a)1～2;(b)2～3;(c)3～4;(d) 8～9
[8]陈紫榕,病毒性肝炎,北京:人民卫生出版社,2002,(a)5;(b)6～7;(c)7～8;(d)5～6;(e)100;(f) 302;(g) 399
[9]王健,王平平,乙肝病毒变异与免疫逃避,现代预防医学,2006,339(9):1553～1555
[10]Galibert F, Mandart E, Fitoussi F, et al. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E coli, Nature, 1979, 281(5733): 646~650
[11]Magnius L O, Espmark J A, New specificities in Australia antigen positive sera distinct from the Le Bouvier determinants, J Immunol, 1972, 109(5): 1017~1021
[12]Miller R H. Organization of the X gene region of the hepatitis B virus genome, Gastroenterol Jpn, 1990, 25(Suppl. 2): 1~5
[13] Beck J, Nassal M. Hepatitis B virus replication, World J Gastroenterol, 2007, 13 (1): 48~64
[14]Locarnini S. Molecular virology of hepatitis B virus, Semin Liver Dis, 2004, 24 (Suppl.1): 3~10
[15]Scullard G H, Smith C I, Merigan T C, et al. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B, Gastroenterology, 1981, 81(6): 987 ~ 991
[16]孟宪镛,肾上腺皮质激素在肝病中的实用,实用内科杂志,1989,9(2):65～66
[17]Lee S D,Tong M J, Wu J C, et al. A randomised double-blind placebo-controlled trial of prednisolone therapy in HBeAg and HBV DNA positive Chinese patients with chronic active hepatitis B, J Hepatol, 1991, 12(2): 246~250
[18]Minuk G Y, German G B, Bernstein C, et al. A pilot study of steroid withdrawal followed by oral acyclovir in the treatment of chronic type B hepatitis, Clinical Investigation Medicion, 1992, 15(6): 506～512
[19]Takano S, Omata M, Yokosuka O, et al. Effects of antiviral agents on chronic hepatitis B, Digestive Disease Science, 1992, 37 (11): 1633~1643
[20]张绪清,聂青和,糖皮质激素在治疗重型肝炎中的应用及评价,实用肝脏病杂志,2004,7(2):7～9
[21]Mutchnick M G, Appelman H D,Chung H T, et al. Thymosin Treatment of chronic active hepatitis B: A placebo-controlled pilot trial, Hepatology, 1991, 13(3): 409 ~ 415。
[22]Mutchnick M G, Lindsay K L, Schiff E R, et al. Thymosin alpha 1 treatment of chronic hepatitis B: result of a phase III multicentre, randomized, double-blind and placebo-controlled study, J viral Hepat, 1999, 6: 397
[23]Rost K L,Wierich W, Masayukif F, et al. Pharmacokinetics of thymosinα1 after subcutaneous injection of three different formulations in the healthy volunteers, Int J Clin Pharmacol Ther, 1999, 37(1):51~57
[24]Nishioka M. Effects of human recombinant interleukin 2 in patients with chronic active hepatitis B: A preminary report, Am J Gastroenterol, 1987, 82: 438
[25]王长嘉,路洪艳,房长茂等,白细胞介素2穴位注射治疗慢性乙肝的观察,临床肝胆病杂志,1998,14(2):121～122
[26]韩立卓,张玉玲,丁振强等,白细胞介素-2穴位注射治疗慢性乙肝疗效观察,中国老年学杂志,2005,25:1538
[27]王建设,朱启镕,白细胞介素12和慢性病毒性肝炎治疗,肝脏,2000,(2):124～125
[28]苏琴,王嘉玺,白细胞介素15研究进展,国外医学分子生物学分册,2000,(2):101～104
[29]解慧,韩捷,王树宽等,抗乙肝iRNA在动物间传递特异性免疫活性的研究,免疫学杂志,1994,10(1):51
[30]张以华,王常雨,抗乙肝免疫核糖核酸治疗慢性病毒性肝炎146例疗效观察,现代诊断与治疗,1995,6(5):268～270
[31]蔡聪麟,蔡卫民,刘荣华,大剂量抗乙肝免疫RNA腹腔注射治疗慢乙肝的疗效观察,临床肝胆病杂志,1998,14(1):63～64,56
[32]宁云山,姜德建,刘珊珊,卡介苗及卡介菌多糖核酸提取物的免疫调节作用及临床应用,中国生物制品学杂志,2008,21(1):47～50
[33]王玉祥,和杰,曾松柏等,卡介苗的临床应用进展,武警医学院学报,2008,17(6):543～545
[34]咸建春,闽万洪,卡介苗素治疗慢性乙型肝炎疗效分析,世界感染杂志, 2001,1 (5) :457～458
[35]张玉芳,郭德云,潘建忠,潘生丁与卡介苗治疗慢性乙肝病毒感染100例疗效观察,山东医药,1998,38(8):23
[36]党昶永,侯斌,殷书平,卡介苗不良反应研究进展,中国新医药,2003,2(5):50～51
[37]方鑫,梁争论,乙型肝炎治疗性疫苗的研究进展,中国预防医学杂志,2007,8(4):499～502
[38]蔺忠龙,李维薇,治疗性疫苗最新研究进展,红河学院学报,2008,6(5):40～43
[39]陈伟,卢建溪,治疗性HBV基因疫苗的研究进展,中华生物医学工程杂志,2007,13(5):340～343
[40]Greenberg H B, Pollard R B, Lutwick L I, et al. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis, N Engl J Med, 1976, 295(10): 517~522
[41]Perrillo R P, Schiff E R, Davis G L, et al, A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatmentof chronic hepatitis B, N Engl J Med, 1990, 323(5): 295~301
[42]Lok A S. Hepatitis B Infection: pathogenesis and management, J Hepatol, 2004, 32(suppl. 1): 89~97
[43]Manns M P. Current state of interferon therapy in the treatment of chronic hepatitis B, Semin Liver Dis, 2002, 22(Suppl.1): 7~13
[44]Park W, Keeffe E B. Diagnosis and treatment of chronic hepatitis B, Minerva Gastroenterol Dietol, 2004, 50: 289~303
[45]Munoz R, Castellano G, Fernandez I, et al. A pilot study of beta interferon for treatment of patients with chronic pepatitis B who failed to respond to alpha–interferon, J Hepatol, 2002, 37: 655~659
[46]Cooksley WG, Piratvisuth T, Lee S D, et al. Peginterferon alpha-2a (40 kDa) : an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B, J Viral Hepat, 2003, 10 (4): 298~305
[47]Lau G K, Piratvisuth T, Luo K X, et al. Peginterferon Alfa-2a , lamivudine , and the combination for HBeAg-positive chronic hepatitis B, N Engl J Med, 2005, 352 (26): 2682~2695
[48]Thome J, Knopf U. Acute pshchosis after injection of pegylated interferon alpha-2a, Eur Psychiatry, 2003, 18 (3): 142 ~143
[49]Formann E , Stauber R , Denk DM, et al. Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin, Am J Gastroenterol, 2004, 99 (5): 873~877
[50]徐丙发,范清林,魏伟等,干扰素-α及长效干扰素抗肝炎病毒作用机制的研究进展,中国药理学通报,2008,24(10):1276～1279
[51]Karrayinnis P. Hepatitis B virus: old, new and future approaches to antiviral treat- ment, J Antimicrob Chemother, 2003, 51(4): 761~85
[52]De Clercq E, Holy A. Acyclic nucleoside phosphonates: a key class of antiviral drugs, Nature Reviews Drug Discovery, 2005, 4: 928~940
[53]Lai C L, Yuen M F. Profound suppression of hepatitis B virus replication with lamivudine, J Med Virol, 2000, 61: 367~73
[54]Dienstag J L, Schill E R, Wright F L, et al. Lamivudine as initial treatment for ch- ronic hepatitis B in the united stated, N Engl J Med, 1999, 341 (17): 1256 ~ 1263
[55]Leung N. Nucleoside analogues in the treatment of chronic hepatitis B, J Gastroe- nterol Hepatol, 2000, 15(suppl.2): E53~60
[56] Hadziyannis S J,Tassopoulos N C,HeatheoteE J,et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen negative chronic hepatitis B, N Engl J Med,2003, 348(9): 800~807
[57]Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novelmutationin the HBV polymerase, Gastroenterology, 2003, 125 ( 2 ): 292~297
[58]Hadziyannis S, Tassopouloe N, Chang T T, et al. Three year study of adefovir dip- ivoxil(ADV) demonstrates sustained efficacy in presumed precore mutant chronic hepatitis B (CHB) patients in a long term safety and efficacy study (LTSES), J Hepatol, 2004, 40 (Suppl. 1): 17
[59]RistigM B, Cripp in J, Aberg J A, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitisB in human immunodeficiency virus/hepatitis B virus coinfected individuals for whom interferon-alpha and lamivudine therapy have failed, J Infect Dis, 2002, 186: 1844~1847
[60]Heathcote J, George J, Gordon S, et al. Tenofovir disoproxil fumarate (TDF) for thetreatment of HBeAg positive chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 103), J Hepatol, 2008, 48(Suppl. 2): S32
[61]Antoniou T, Raboud J, Chirhin S, et al. Incidence of and risk factors for tenofovir-induced nephrotoxicity: a retrospective cohort study, HIV Med, 2005, 6: 284~290
[62]Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and casecontrol study, J Acquir Immune Defic Syndr, 2004, 37: 1489~1495
[63]Lacombe K, Boyd A, Bonnard P, et al. Mdrd creatinine clearance is not altered in HIV-HBV co-infected patients with a normal renal function and treatedwith tenofovir, J Hepatol, 2008, 48: S259
[64]Chang T T, Gish R J, de Man R A, et al. Entecavir is superior to lamivudine for the treatment of HBeAg (+) chronic hepatitis B: results of phase III study ETV-022 in nucleoside-naive patients, Hepatology, 2004, 40(suppl.1): 193A
[65]Shouyal D, Lai C L, Cheinquer H, et al. Entecavir demonstrates superior histologic an virologic efficacy over lamivudine in nucleoside-naive HBeAg(-) chronic hepatitis B: results of phase III trial ETV-027, Hepatology, 2004, 40(4 suppl.1): 728A
[66]Shiff E R, Chang T T, Gish R J, et al. Entecavir 10 mg is consistently superior to lamivudine at 48 weeks across multiple baseline HBV disease characteristics in lamivudine-refractory patients, J Hepatol, 2004, 40(suppl.1):131
[67]Lai C L, Rosmawati M, Lao J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection, Gastroenterology, 2002, 123(6): 1831~1838
[68]Yao G B, Xu D Z, Wang B E, et al. A phase II study in China of the safety and antiviral activity of entecavir in adults with chronic hepatitis B infection, Hepatology, 2003, 38( 4 suppl.1): 711A
[69]Bryant M L, Bridges E G, Placid I L, et al. Antiviral L-nucleosides specific for hepatitis B virus infection, Antimicrob Agents Chemother, 2001, 45 (1): 229 ~ 235
[70]Lai C L, Gane E, Hsu C W, et al. Two-year results from the GLOBE Trial in patients with hepatitisB: greater clinical and antiviral efficacy for telbivudine vs lamivudine, Hepatology, 2006, 44 ( Suppl 1): 222A
[71]Bzowe J N, Chanl Y H, Lai C L, et al. A randomized trial of telbivudine vs. adefovir for HbeAg positive chronic hepatitis B: final week 52 results, Hepatology, 2006, 44 (Suppl. 1): 563A
[72]Gish RG, Trinh H, Leung N, et al. Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study, J Hepatol, 2005, 43: 60~66
[73]Marcellin P, Mommeja M H, Sacks S L, et al. A phase II dose escalating trial of clevudine in patients with chronic hepatitis B, Hepatology, 2004, 40(1): 140~148
[74]Lai C L, Yuen M F, Hui C K, et al. A comparison of the efficacy of lamivudine and famciclovir in Asian patients with chronic hepatitis B: Results of 24 weeks of therapy, J Med Virol, 2002, 67(3): 334~338
[75]Otto M J. New nucleoside reverse transcriptase inhibitors for thetreatment of HIV infections, Curr Opin Pharmacol, 2004, 4(5): 431~ 436
[76]Lim S G, Lai C L, Myers M, et al. Final results of a phase I/II dose escalation trial of valtorcitabine in patients with chronic hepatitis B, J Hepatol, 2005, 42 (Suppl. 2): 16
[77]Sekiya K, Takashima H, Ueda N, et al. 2-Amino-6-arylthio-9-[2-(phosphonomet- hoxy)ethyl]purine bis(2,2,2-trifluoroethyl) esters as novel HBV-specific antiviral reagents, J Med Chem, 2002, 45(14): 3138~3142
[78]Ono Nita S K, Kato N, Shiratori Y, et al. Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or Lamivudine-resistant hepatitis B virus, Antimicrob Agents Chemother, 2002, 46(8): 2602~2605
[79]Chan C, Abu-Raddad E, Golor G, et al. Clinical Pharmacokinetics of Alamifovir and Its Metabolites, Antimicrob Agents Chemother, 2005, 49 (5): 1813 ~ 1822
[80]Danny K W, Stephen L, Lowe C T, et al. Safety and efficiency of alamifovir in patients with chronic hepatitis B virus infection, J Hepatol, 2004, 41: 852~858
[81]夏广强,赵国明,郑志兵,非核苷类抗乙型肝炎病毒药物的研究进展,国外医学药学分册,2007,34(3):161～164
[82]郭宗儒,药物化学总论,北京:中围医药科技出版社,2003,(a):602～606;(b):423～427;
[83]Yuan H J, Lee W M. Molecular mechanisms of resistance to antiviral therapy in patients with chronic hepatitis B, Curr Mol Med, 2007, 7(2): 185~197.
[84]Kramata P, Votruba I, Otova B, et al. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases a, d and e, Mol Pharmacol, 1996, 49, 1005~1011
[85]姚其正,核苷化学合成,北京:化学工业出版社,2005,23～31;36～41
[86]Erik D C, Hugh J F. Antiviral prodrugs: the development of successful prodrug strategies for antiviral chemotherapy, Br J Pharmacol, 2006, 147 (1): 1~11
[87]Starrett J J, Tortolani D R, Hitchcock M J, et al. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl) adenine, Antiviral Res, 1992, 19(3): 267~273
[88]Naesens L, Bischofberger N, Augustijns P, et al. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonyl- methoxypropyl)adenine in mice, Antimicrob Agents Chemother, 1998, 42(7): 1568~1573
[89]Kamiya N, Kubota A, Iwase Y, et al. Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B virus, Antimicrob Agents Chemother, 2002, 46(9): 2872~2877
[90]Colledge D, Shaw T, Bowden S, et al. The purine nucleotide analogue LY592563 (MCC-478) inhibits replication of wild type and drug resistant hepatits B virus, J Hepatol, 2002, 36(Suppl. 1): 88
[91]王进京,新的无环核苷膦酸酯及其医药用途,CN1704424A,2005-12-7
[92]Marcellin P, Jacobson I, Habersetzer F, et al. Tenofovir disoproxil fumarate (TDF) for thetreatment of HBeAg negative chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 102), J Hepatol, 2008, 48: S26
[93]Jindrich J, Holy A, Dvorakova H, et al. Synthesis of N-(3-fluoro-2-phosphonome- thoxypropyl) (FPMP) derivatives of heterocyclic bases, Collect Czech Chem Commun, 1993, 58, 1645~1667
[94]Balzarini J, Holy A, Jindrich J, et al. Differential antiherpesvirus and antiretrovir- us effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phos- phonomethoxypropyl)-2,6-diaminopurine, Antimicrob Agents Chemother, 1993, 37(2): 332~338
[95]Heijtink R A, Kruining J, Wilde G A, et al. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture, Antimicrob Agents Chemother,1994, 38(9): 2180~2182
[96]Zidek Z, Potmesil P, Holy A, et al. Cytostatic activity of antiviral acyclic nucleoside phosphonates in rodent lymphocytes, Toxicol Appli Pharmacol, 2003, 192( 3): 246~253
[97]Ogle C A, Wilson T E, Stowe J A, et al. A convenient one-pot method for the hydroxymethylation of Grignard reagents, Synthesis, 1990, 6, 495~496;
[98]Timperley C M, Kirkpatricka S, Sandford M, et al. Fluorinated phosphorus compounds: Part 10. Bis(fluoroalkyl) S-alkyl phosphorothiolates and tris(fluoroalkyl) phosphorothionates, J Fluorine Chem, 2005, (126): 902~906;
[99]李庶心,张奉学,赵砚瑾等,核苷膦酸酯化合物,CN1724549A,2006-01-25
[100]吴秋业,马维勇,肖旭华等,6-O-取代阿昔洛韦衍生物的合成及其抗病毒活性,第二军医大学学报,2005,26(2):218～219
[101]吴秋业,马维勇,肖旭华等, 6-O-取代苯基阿昔洛韦衍生物的合成及其抗病毒活性,中国药物化学杂志,2005,15(1):22～23,38
[102]Adebambo K F, Zanoli S, Thomas M G, et al. N2-benzyloxycarbonylguan-9-yl acetic acid derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors with decreased loss of potency against common drug-resistance mutations, ChemMedChem, 2007, 2(10): 1405~1409,
[103]Balsiger R W, Montgomery J A. Synthesis of potential anticancer agents XXV Preparation of 6-alkoxy-2-aminopurines, J Org Chem, 1960, 25 (9): 1573~1575
[104]Huang L K, Cherng Y C, Cheng Y R. An efficient synthesis of substituted cytosines and purines under focused microwave irradiation, Tetrahedron, 2007, 63(24), 5323~5327,
[105]Novák J, Hasník Z, Linhart I. Syntheses of O6-alkyl- and arylguanine derivatives: nucleobase adducts derived from styrene 7,8- and 3,4-oxides, Eur J Org Chem, 2006, 2: 507~515
[106]Linn J A, Mc Lean E D, Kelley J L. 1,4-Diazabicyclo[2.2.2]octane (DABCO)- catalysed hydrolysis and alcoholysis reactions of 2-amino-9-benzyl-6- chloro-9H-purine, J Chem Soc Chem Commun, 1994, 8: 913~914
[107]余长泉,邵越水,邓琼等,3-巯基噻吩化学研究进展,浙江化工,2004,35(2):9～11
[108]Caesar P D, Branton P D. By-products of the thiophene synthesis, Ind Eng Chem, 1952, 44: 122~125
[109]Robert D S, Wayne L F. A new synthesis of thiophene and thianaphthenethiols, J Org Chem, 1962, 27:1301~1304
[110]Jones E, Moodie I M. 2-Thiophenethiol, Org Synth Coll Vol. 1988, 6: 979~980
[111]Nakayama J, Katano N, Shimura Y, et al. Preparation of Oligo(thio-2,5-thienyle- nes), J Org Chem, 1996, 61, 7608~7610
[112]Testaferri L, Tingoli M, Tiecco M, A convenient synthesis of aromatic thiols from unactivated aryl halides, Tetrahedron Lett, 1980, 21(32): 3099~3100
[113]陈德海,张甜,2-巯基噻唑的合成研究,河南化工,2003,10:18～19
[114]Bowden M C. Preparation of mercaptothiazole, GB: 2323595A, 1998-09-30;
[115]仲伯华,陈兰福,刘河等,无环核苷膦酸酯衍生物,CN1670024A,2005-09-21
[116]Thirtle R J. 2-Mercaptopyridine, J Am Chem Soc, 1946, 68 (2): 342~343
[117]Jones R A, Katritzky A R. Tautomeric pyridines. Part I. Pyrid-2- and -4-thione, J Chem Soc, 1958, 9: 3610~3613
[118]陈煦,李永强,张和等,2-巯基吡啶的合成及结构测定,天津化工,2000,5,26～27
[119]Phillips M A, Shapiro H. The preparation of certain 2-thiolpyridine derivatives, J Chem Soc, 1942, 584
[120]Jones P C. Process for preparing unsubstituted mercaptothiazole, US2426397A1, 1947-08-26
[121]Keck G E, Webb R R. Alkaloid synthesis via intramolecular ene reactions. 1. Application to (±)-crinane, J Am Chem Soc, 1981, 103(11): 3173~3177
[122]Verkruijsse, H D, Keegstra, M A, Brandsma L. A high-yield preparative-scale method for 2-bromofuran, Synth Commun, 1989, 19(5&6):1047~1050
[123]Politis J K, Nemes J C, Curtis M D. Synthesis and characterization of regiorandom and regioregular poly(3-octylfuran), J Am Chem Soc, 2001,123(11): 2537~2547
[124]Goldfarb Y L, Marakatkina M A, Belenki L I. The synthesis of 3-bromofuran and the product of its acetylation, Chem Heterocycl Comp, 1970,6(1): 132~133
[125]Nazarova Z N, Babaev Y A, Umanskaya L G. Synthesis and reactions ofβ-subst- ituted furans, Chem Heterocycl Comp, 1969, 5:12
[126]Schultze L M, Chapman H H, Dougherty J P, et al. Synthesis of the anti-HIV drug PMPA, Tetrahedron Lette, 1998, 39: 1853~1856
[127]Munger J D, Rohloff J C, Schultze L M. Nucleotide analog composition and synthesis method, US5935946A1, 1999-08-10
[128]Arimilli M N, Cundy K C, Dougherty J P, et al. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavarilability, US5922695A, 1999-07-13
[129]Holy A, Masojidkova M. Synthesis of enantiomiric N-(2-phosphinomethoxypro- pyl)derivatives of purine and pyrimidine bases.I. The stepwise approach, Collect Czech Chem Commun, 1995, 60:1196~1212
[130]Holy A, Dvorakova H, DeClerq E, et al. Antiretroviral enantiomeric nucleoside analogs, US6653296B1, 2003-11-25
[131]Holy A, Dvorakova H, Masojidkova M. Synthesis of enantiomiric N-(2-phosph- inomethoxypropyl)derivatives of purine and pyrimidine bases.II.The stepwise approach, Collect Czech Chem Commun, 1995, 60(8): 1390~1409
[132]Prekupec S, Svedru?i? D, Gazivoda T, et al. Synthesis and biological evaluation of iodinated and fluorinated 9-(2-hydroxypropyl) and 9-(2-hydroxyethoxy)me- thyl purine nucleoside analogues, J Med Chem, 2003, 46(26): 5763~5772
[133]Fakhraian H, Mirzaei A. Reconsideration of the base-free batch-wise esterification of phosphorus trichloride with alcohols, Org Process Res Dev, 2004, 8(3): 401 ~ 404
[134]Hammerschmidt F, K?hlig H, Müller N. Biosynthesis of natural products with a P–C bond. Part 6. Preparation of deuterium- and carbon-13-labelled L-alanyl- and L-alanyl-L-alanyl-(2-aminoethyl)phosphonic acids and their use in biosynthetic studies of fosfomycin in streptomyces fradiae, J Chem Soc Perkin Trans 1, 1991, 2: 365~369
[135]Yu K L, Bronson J J, Yang H, et al. Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine, J Med Chem, 1992, 35(16): 2958~2969
[136]Rabinowitz R. The reactions of phosphonic acid esters with acid chlorides: a very mild hydrolytic route, J Org Chem, 1963, 28 (11): 2975~2978
[137]宁永成,有机化合物结构鉴定与有机波谱学,北京:科学出版社,2000,48～50
[138]石鸿昌,张晓霞,亚磷酸三异丙酯的合成工艺研究,合成化学,2000,8(3)238～241
[139]徐叔云,卞如濂,陈修等,药理实验方法学,北京:人民卫生出版社,2005,1740～1743
[140]黄祯祥,医学病毒学基础及实验技术,北京:科学出版社,1990,143～146
[2]叶维法,钟振义,肝炎学大典,天津:天津科学技术出版社,1996,(a) 1215; (b) 298～310;(c) 402;(d) 811～821;(e) 881～883;(f) 883～886;(g) 898～916
[3]中华人民共和国卫生部,2006年～2010年全国乙型病毒性肝炎防治规划,中国实用乡村医生杂志,2006,13(8):1～4
[4]http://www.moh.gov.cn/open/web_edit_file/20080326083022.doc
[5]Lee W M. Hepatitis B Virus Infection, N Engl J Med, 1997, 337 (24):1733~1745
[6]Dane D S, Cameron C H, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis, Lancet, 1970, 295(7649): 695~698
[7]姚桢,分子乙型肝炎病毒相关病学,北京:中国医药科技出版社,1998,(a)1～2;(b)2～3;(c)3～4;(d) 8～9
[8]陈紫榕,病毒性肝炎,北京:人民卫生出版社,2002,(a)5;(b)6～7;(c)7～8;(d)5～6;(e)100;(f) 302;(g) 399
[9]王健,王平平,乙肝病毒变异与免疫逃避,现代预防医学,2006,339(9):1553～1555
[10]Galibert F, Mandart E, Fitoussi F, et al. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E coli, Nature, 1979, 281(5733): 646~650
[11]Magnius L O, Espmark J A, New specificities in Australia antigen positive sera distinct from the Le Bouvier determinants, J Immunol, 1972, 109(5): 1017~1021
[12]Miller R H. Organization of the X gene region of the hepatitis B virus genome, Gastroenterol Jpn, 1990, 25(Suppl. 2): 1~5
[13] Beck J, Nassal M. Hepatitis B virus replication, World J Gastroenterol, 2007, 13 (1): 48~64
[14]Locarnini S. Molecular virology of hepatitis B virus, Semin Liver Dis, 2004, 24 (Suppl.1): 3~10
[15]Scullard G H, Smith C I, Merigan T C, et al. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B, Gastroenterology, 1981, 81(6): 987 ~ 991
[16]孟宪镛,肾上腺皮质激素在肝病中的实用,实用内科杂志,1989,9(2):65～66
[17]Lee S D,Tong M J, Wu J C, et al. A randomised double-blind placebo-controlled trial of prednisolone therapy in HBeAg and HBV DNA positive Chinese patients with chronic active hepatitis B, J Hepatol, 1991, 12(2): 246~250
[18]Minuk G Y, German G B, Bernstein C, et al. A pilot study of steroid withdrawal followed by oral acyclovir in the treatment of chronic type B hepatitis, Clinical Investigation Medicion, 1992, 15(6): 506～512
[19]Takano S, Omata M, Yokosuka O, et al. Effects of antiviral agents on chronic hepatitis B, Digestive Disease Science, 1992, 37 (11): 1633~1643
[20]张绪清,聂青和,糖皮质激素在治疗重型肝炎中的应用及评价,实用肝脏病杂志,2004,7(2):7～9
[21]Mutchnick M G, Appelman H D,Chung H T, et al. Thymosin Treatment of chronic active hepatitis B: A placebo-controlled pilot trial, Hepatology, 1991, 13(3): 409 ~ 415。
[22]Mutchnick M G, Lindsay K L, Schiff E R, et al. Thymosin alpha 1 treatment of chronic hepatitis B: result of a phase III multicentre, randomized, double-blind and placebo-controlled study, J viral Hepat, 1999, 6: 397
[23]Rost K L,Wierich W, Masayukif F, et al. Pharmacokinetics of thymosinα1 after subcutaneous injection of three different formulations in the healthy volunteers, Int J Clin Pharmacol Ther, 1999, 37(1):51~57
[24]Nishioka M. Effects of human recombinant interleukin 2 in patients with chronic active hepatitis B: A preminary report, Am J Gastroenterol, 1987, 82: 438
[25]王长嘉,路洪艳,房长茂等,白细胞介素2穴位注射治疗慢性乙肝的观察,临床肝胆病杂志,1998,14(2):121～122
[26]韩立卓,张玉玲,丁振强等,白细胞介素-2穴位注射治疗慢性乙肝疗效观察,中国老年学杂志,2005,25:1538
[27]王建设,朱启镕,白细胞介素12和慢性病毒性肝炎治疗,肝脏,2000,(2):124～125
[28]苏琴,王嘉玺,白细胞介素15研究进展,国外医学分子生物学分册,2000,(2):101～104
[29]解慧,韩捷,王树宽等,抗乙肝iRNA在动物间传递特异性免疫活性的研究,免疫学杂志,1994,10(1):51
[30]张以华,王常雨,抗乙肝免疫核糖核酸治疗慢性病毒性肝炎146例疗效观察,现代诊断与治疗,1995,6(5):268～270
[31]蔡聪麟,蔡卫民,刘荣华,大剂量抗乙肝免疫RNA腹腔注射治疗慢乙肝的疗效观察,临床肝胆病杂志,1998,14(1):63～64,56
[32]宁云山,姜德建,刘珊珊,卡介苗及卡介菌多糖核酸提取物的免疫调节作用及临床应用,中国生物制品学杂志,2008,21(1):47～50
[33]王玉祥,和杰,曾松柏等,卡介苗的临床应用进展,武警医学院学报,2008,17(6):543～545
[34]咸建春,闽万洪,卡介苗素治疗慢性乙型肝炎疗效分析,世界感染杂志, 2001,1 (5) :457～458
[35]张玉芳,郭德云,潘建忠,潘生丁与卡介苗治疗慢性乙肝病毒感染100例疗效观察,山东医药,1998,38(8):23
[36]党昶永,侯斌,殷书平,卡介苗不良反应研究进展,中国新医药,2003,2(5):50～51
[37]方鑫,梁争论,乙型肝炎治疗性疫苗的研究进展,中国预防医学杂志,2007,8(4):499～502
[38]蔺忠龙,李维薇,治疗性疫苗最新研究进展,红河学院学报,2008,6(5):40～43
[39]陈伟,卢建溪,治疗性HBV基因疫苗的研究进展,中华生物医学工程杂志,2007,13(5):340～343
[40]Greenberg H B, Pollard R B, Lutwick L I, et al. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis, N Engl J Med, 1976, 295(10): 517~522
[41]Perrillo R P, Schiff E R, Davis G L, et al, A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatmentof chronic hepatitis B, N Engl J Med, 1990, 323(5): 295~301
[42]Lok A S. Hepatitis B Infection: pathogenesis and management, J Hepatol, 2004, 32(suppl. 1): 89~97
[43]Manns M P. Current state of interferon therapy in the treatment of chronic hepatitis B, Semin Liver Dis, 2002, 22(Suppl.1): 7~13
[44]Park W, Keeffe E B. Diagnosis and treatment of chronic hepatitis B, Minerva Gastroenterol Dietol, 2004, 50: 289~303
[45]Munoz R, Castellano G, Fernandez I, et al. A pilot study of beta interferon for treatment of patients with chronic pepatitis B who failed to respond to alpha–interferon, J Hepatol, 2002, 37: 655~659
[46]Cooksley WG, Piratvisuth T, Lee S D, et al. Peginterferon alpha-2a (40 kDa) : an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B, J Viral Hepat, 2003, 10 (4): 298~305
[47]Lau G K, Piratvisuth T, Luo K X, et al. Peginterferon Alfa-2a , lamivudine , and the combination for HBeAg-positive chronic hepatitis B, N Engl J Med, 2005, 352 (26): 2682~2695
[48]Thome J, Knopf U. Acute pshchosis after injection of pegylated interferon alpha-2a, Eur Psychiatry, 2003, 18 (3): 142 ~143
[49]Formann E , Stauber R , Denk DM, et al. Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin, Am J Gastroenterol, 2004, 99 (5): 873~877
[50]徐丙发,范清林,魏伟等,干扰素-α及长效干扰素抗肝炎病毒作用机制的研究进展,中国药理学通报,2008,24(10):1276～1279
[51]Karrayinnis P. Hepatitis B virus: old, new and future approaches to antiviral treat- ment, J Antimicrob Chemother, 2003, 51(4): 761~85
[52]De Clercq E, Holy A. Acyclic nucleoside phosphonates: a key class of antiviral drugs, Nature Reviews Drug Discovery, 2005, 4: 928~940
[53]Lai C L, Yuen M F. Profound suppression of hepatitis B virus replication with lamivudine, J Med Virol, 2000, 61: 367~73
[54]Dienstag J L, Schill E R, Wright F L, et al. Lamivudine as initial treatment for ch- ronic hepatitis B in the united stated, N Engl J Med, 1999, 341 (17): 1256 ~ 1263
[55]Leung N. Nucleoside analogues in the treatment of chronic hepatitis B, J Gastroe- nterol Hepatol, 2000, 15(suppl.2): E53~60
[56] Hadziyannis S J,Tassopoulos N C,HeatheoteE J,et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen negative chronic hepatitis B, N Engl J Med,2003, 348(9): 800~807
[57]Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novelmutationin the HBV polymerase, Gastroenterology, 2003, 125 ( 2 ): 292~297
[58]Hadziyannis S, Tassopouloe N, Chang T T, et al. Three year study of adefovir dip- ivoxil(ADV) demonstrates sustained efficacy in presumed precore mutant chronic hepatitis B (CHB) patients in a long term safety and efficacy study (LTSES), J Hepatol, 2004, 40 (Suppl. 1): 17
[59]RistigM B, Cripp in J, Aberg J A, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitisB in human immunodeficiency virus/hepatitis B virus coinfected individuals for whom interferon-alpha and lamivudine therapy have failed, J Infect Dis, 2002, 186: 1844~1847
[60]Heathcote J, George J, Gordon S, et al. Tenofovir disoproxil fumarate (TDF) for thetreatment of HBeAg positive chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 103), J Hepatol, 2008, 48(Suppl. 2): S32
[61]Antoniou T, Raboud J, Chirhin S, et al. Incidence of and risk factors for tenofovir-induced nephrotoxicity: a retrospective cohort study, HIV Med, 2005, 6: 284~290
[62]Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and casecontrol study, J Acquir Immune Defic Syndr, 2004, 37: 1489~1495
[63]Lacombe K, Boyd A, Bonnard P, et al. Mdrd creatinine clearance is not altered in HIV-HBV co-infected patients with a normal renal function and treatedwith tenofovir, J Hepatol, 2008, 48: S259
[64]Chang T T, Gish R J, de Man R A, et al. Entecavir is superior to lamivudine for the treatment of HBeAg (+) chronic hepatitis B: results of phase III study ETV-022 in nucleoside-naive patients, Hepatology, 2004, 40(suppl.1): 193A
[65]Shouyal D, Lai C L, Cheinquer H, et al. Entecavir demonstrates superior histologic an virologic efficacy over lamivudine in nucleoside-naive HBeAg(-) chronic hepatitis B: results of phase III trial ETV-027, Hepatology, 2004, 40(4 suppl.1): 728A
[66]Shiff E R, Chang T T, Gish R J, et al. Entecavir 10 mg is consistently superior to lamivudine at 48 weeks across multiple baseline HBV disease characteristics in lamivudine-refractory patients, J Hepatol, 2004, 40(suppl.1):131
[67]Lai C L, Rosmawati M, Lao J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection, Gastroenterology, 2002, 123(6): 1831~1838
[68]Yao G B, Xu D Z, Wang B E, et al. A phase II study in China of the safety and antiviral activity of entecavir in adults with chronic hepatitis B infection, Hepatology, 2003, 38( 4 suppl.1): 711A
[69]Bryant M L, Bridges E G, Placid I L, et al. Antiviral L-nucleosides specific for hepatitis B virus infection, Antimicrob Agents Chemother, 2001, 45 (1): 229 ~ 235
[70]Lai C L, Gane E, Hsu C W, et al. Two-year results from the GLOBE Trial in patients with hepatitisB: greater clinical and antiviral efficacy for telbivudine vs lamivudine, Hepatology, 2006, 44 ( Suppl 1): 222A
[71]Bzowe J N, Chanl Y H, Lai C L, et al. A randomized trial of telbivudine vs. adefovir for HbeAg positive chronic hepatitis B: final week 52 results, Hepatology, 2006, 44 (Suppl. 1): 563A
[72]Gish RG, Trinh H, Leung N, et al. Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study, J Hepatol, 2005, 43: 60~66
[73]Marcellin P, Mommeja M H, Sacks S L, et al. A phase II dose escalating trial of clevudine in patients with chronic hepatitis B, Hepatology, 2004, 40(1): 140~148
[74]Lai C L, Yuen M F, Hui C K, et al. A comparison of the efficacy of lamivudine and famciclovir in Asian patients with chronic hepatitis B: Results of 24 weeks of therapy, J Med Virol, 2002, 67(3): 334~338
[75]Otto M J. New nucleoside reverse transcriptase inhibitors for thetreatment of HIV infections, Curr Opin Pharmacol, 2004, 4(5): 431~ 436
[76]Lim S G, Lai C L, Myers M, et al. Final results of a phase I/II dose escalation trial of valtorcitabine in patients with chronic hepatitis B, J Hepatol, 2005, 42 (Suppl. 2): 16
[77]Sekiya K, Takashima H, Ueda N, et al. 2-Amino-6-arylthio-9-[2-(phosphonomet- hoxy)ethyl]purine bis(2,2,2-trifluoroethyl) esters as novel HBV-specific antiviral reagents, J Med Chem, 2002, 45(14): 3138~3142
[78]Ono Nita S K, Kato N, Shiratori Y, et al. Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or Lamivudine-resistant hepatitis B virus, Antimicrob Agents Chemother, 2002, 46(8): 2602~2605
[79]Chan C, Abu-Raddad E, Golor G, et al. Clinical Pharmacokinetics of Alamifovir and Its Metabolites, Antimicrob Agents Chemother, 2005, 49 (5): 1813 ~ 1822
[80]Danny K W, Stephen L, Lowe C T, et al. Safety and efficiency of alamifovir in patients with chronic hepatitis B virus infection, J Hepatol, 2004, 41: 852~858
[81]夏广强,赵国明,郑志兵,非核苷类抗乙型肝炎病毒药物的研究进展,国外医学药学分册,2007,34(3):161～164
[82]郭宗儒,药物化学总论,北京:中围医药科技出版社,2003,(a):602～606;(b):423～427;
[83]Yuan H J, Lee W M. Molecular mechanisms of resistance to antiviral therapy in patients with chronic hepatitis B, Curr Mol Med, 2007, 7(2): 185~197.
[84]Kramata P, Votruba I, Otova B, et al. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases a, d and e, Mol Pharmacol, 1996, 49, 1005~1011
[85]姚其正,核苷化学合成,北京:化学工业出版社,2005,23～31;36～41
[86]Erik D C, Hugh J F. Antiviral prodrugs: the development of successful prodrug strategies for antiviral chemotherapy, Br J Pharmacol, 2006, 147 (1): 1~11
[87]Starrett J J, Tortolani D R, Hitchcock M J, et al. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl) adenine, Antiviral Res, 1992, 19(3): 267~273
[88]Naesens L, Bischofberger N, Augustijns P, et al. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonyl- methoxypropyl)adenine in mice, Antimicrob Agents Chemother, 1998, 42(7): 1568~1573
[89]Kamiya N, Kubota A, Iwase Y, et al. Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B virus, Antimicrob Agents Chemother, 2002, 46(9): 2872~2877
[90]Colledge D, Shaw T, Bowden S, et al. The purine nucleotide analogue LY592563 (MCC-478) inhibits replication of wild type and drug resistant hepatits B virus, J Hepatol, 2002, 36(Suppl. 1): 88
[91]王进京,新的无环核苷膦酸酯及其医药用途,CN1704424A,2005-12-7
[92]Marcellin P, Jacobson I, Habersetzer F, et al. Tenofovir disoproxil fumarate (TDF) for thetreatment of HBeAg negative chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 102), J Hepatol, 2008, 48: S26
[93]Jindrich J, Holy A, Dvorakova H, et al. Synthesis of N-(3-fluoro-2-phosphonome- thoxypropyl) (FPMP) derivatives of heterocyclic bases, Collect Czech Chem Commun, 1993, 58, 1645~1667
[94]Balzarini J, Holy A, Jindrich J, et al. Differential antiherpesvirus and antiretrovir- us effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phos- phonomethoxypropyl)-2,6-diaminopurine, Antimicrob Agents Chemother, 1993, 37(2): 332~338
[95]Heijtink R A, Kruining J, Wilde G A, et al. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture, Antimicrob Agents Chemother,1994, 38(9): 2180~2182
[96]Zidek Z, Potmesil P, Holy A, et al. Cytostatic activity of antiviral acyclic nucleoside phosphonates in rodent lymphocytes, Toxicol Appli Pharmacol, 2003, 192( 3): 246~253
[97]Ogle C A, Wilson T E, Stowe J A, et al. A convenient one-pot method for the hydroxymethylation of Grignard reagents, Synthesis, 1990, 6, 495~496;
[98]Timperley C M, Kirkpatricka S, Sandford M, et al. Fluorinated phosphorus compounds: Part 10. Bis(fluoroalkyl) S-alkyl phosphorothiolates and tris(fluoroalkyl) phosphorothionates, J Fluorine Chem, 2005, (126): 902~906;
[99]李庶心,张奉学,赵砚瑾等,核苷膦酸酯化合物,CN1724549A,2006-01-25
[100]吴秋业,马维勇,肖旭华等,6-O-取代阿昔洛韦衍生物的合成及其抗病毒活性,第二军医大学学报,2005,26(2):218～219
[101]吴秋业,马维勇,肖旭华等, 6-O-取代苯基阿昔洛韦衍生物的合成及其抗病毒活性,中国药物化学杂志,2005,15(1):22～23,38
[102]Adebambo K F, Zanoli S, Thomas M G, et al. N2-benzyloxycarbonylguan-9-yl acetic acid derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors with decreased loss of potency against common drug-resistance mutations, ChemMedChem, 2007, 2(10): 1405~1409,
[103]Balsiger R W, Montgomery J A. Synthesis of potential anticancer agents XXV Preparation of 6-alkoxy-2-aminopurines, J Org Chem, 1960, 25 (9): 1573~1575
[104]Huang L K, Cherng Y C, Cheng Y R. An efficient synthesis of substituted cytosines and purines under focused microwave irradiation, Tetrahedron, 2007, 63(24), 5323~5327,
[105]Novák J, Hasník Z, Linhart I. Syntheses of O6-alkyl- and arylguanine derivatives: nucleobase adducts derived from styrene 7,8- and 3,4-oxides, Eur J Org Chem, 2006, 2: 507~515
[106]Linn J A, Mc Lean E D, Kelley J L. 1,4-Diazabicyclo[2.2.2]octane (DABCO)- catalysed hydrolysis and alcoholysis reactions of 2-amino-9-benzyl-6- chloro-9H-purine, J Chem Soc Chem Commun, 1994, 8: 913~914
[107]余长泉,邵越水,邓琼等,3-巯基噻吩化学研究进展,浙江化工,2004,35(2):9～11
[108]Caesar P D, Branton P D. By-products of the thiophene synthesis, Ind Eng Chem, 1952, 44: 122~125
[109]Robert D S, Wayne L F. A new synthesis of thiophene and thianaphthenethiols, J Org Chem, 1962, 27:1301~1304
[110]Jones E, Moodie I M. 2-Thiophenethiol, Org Synth Coll Vol. 1988, 6: 979~980
[111]Nakayama J, Katano N, Shimura Y, et al. Preparation of Oligo(thio-2,5-thienyle- nes), J Org Chem, 1996, 61, 7608~7610
[112]Testaferri L, Tingoli M, Tiecco M, A convenient synthesis of aromatic thiols from unactivated aryl halides, Tetrahedron Lett, 1980, 21(32): 3099~3100
[113]陈德海,张甜,2-巯基噻唑的合成研究,河南化工,2003,10:18～19
[114]Bowden M C. Preparation of mercaptothiazole, GB: 2323595A, 1998-09-30;
[115]仲伯华,陈兰福,刘河等,无环核苷膦酸酯衍生物,CN1670024A,2005-09-21
[116]Thirtle R J. 2-Mercaptopyridine, J Am Chem Soc, 1946, 68 (2): 342~343
[117]Jones R A, Katritzky A R. Tautomeric pyridines. Part I. Pyrid-2- and -4-thione, J Chem Soc, 1958, 9: 3610~3613
[118]陈煦,李永强,张和等,2-巯基吡啶的合成及结构测定,天津化工,2000,5,26～27
[119]Phillips M A, Shapiro H. The preparation of certain 2-thiolpyridine derivatives, J Chem Soc, 1942, 584
[120]Jones P C. Process for preparing unsubstituted mercaptothiazole, US2426397A1, 1947-08-26
[121]Keck G E, Webb R R. Alkaloid synthesis via intramolecular ene reactions. 1. Application to (±)-crinane, J Am Chem Soc, 1981, 103(11): 3173~3177
[122]Verkruijsse, H D, Keegstra, M A, Brandsma L. A high-yield preparative-scale method for 2-bromofuran, Synth Commun, 1989, 19(5&6):1047~1050
[123]Politis J K, Nemes J C, Curtis M D. Synthesis and characterization of regiorandom and regioregular poly(3-octylfuran), J Am Chem Soc, 2001,123(11): 2537~2547
[124]Goldfarb Y L, Marakatkina M A, Belenki L I. The synthesis of 3-bromofuran and the product of its acetylation, Chem Heterocycl Comp, 1970,6(1): 132~133
[125]Nazarova Z N, Babaev Y A, Umanskaya L G. Synthesis and reactions ofβ-subst- ituted furans, Chem Heterocycl Comp, 1969, 5:12
[126]Schultze L M, Chapman H H, Dougherty J P, et al. Synthesis of the anti-HIV drug PMPA, Tetrahedron Lette, 1998, 39: 1853~1856
[127]Munger J D, Rohloff J C, Schultze L M. Nucleotide analog composition and synthesis method, US5935946A1, 1999-08-10
[128]Arimilli M N, Cundy K C, Dougherty J P, et al. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavarilability, US5922695A, 1999-07-13
[129]Holy A, Masojidkova M. Synthesis of enantiomiric N-(2-phosphinomethoxypro- pyl)derivatives of purine and pyrimidine bases.I. The stepwise approach, Collect Czech Chem Commun, 1995, 60:1196~1212
[130]Holy A, Dvorakova H, DeClerq E, et al. Antiretroviral enantiomeric nucleoside analogs, US6653296B1, 2003-11-25
[131]Holy A, Dvorakova H, Masojidkova M. Synthesis of enantiomiric N-(2-phosph- inomethoxypropyl)derivatives of purine and pyrimidine bases.II.The stepwise approach, Collect Czech Chem Commun, 1995, 60(8): 1390~1409
[132]Prekupec S, Svedru?i? D, Gazivoda T, et al. Synthesis and biological evaluation of iodinated and fluorinated 9-(2-hydroxypropyl) and 9-(2-hydroxyethoxy)me- thyl purine nucleoside analogues, J Med Chem, 2003, 46(26): 5763~5772
[133]Fakhraian H, Mirzaei A. Reconsideration of the base-free batch-wise esterification of phosphorus trichloride with alcohols, Org Process Res Dev, 2004, 8(3): 401 ~ 404
[134]Hammerschmidt F, K?hlig H, Müller N. Biosynthesis of natural products with a P–C bond. Part 6. Preparation of deuterium- and carbon-13-labelled L-alanyl- and L-alanyl-L-alanyl-(2-aminoethyl)phosphonic acids and their use in biosynthetic studies of fosfomycin in streptomyces fradiae, J Chem Soc Perkin Trans 1, 1991, 2: 365~369
[135]Yu K L, Bronson J J, Yang H, et al. Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine, J Med Chem, 1992, 35(16): 2958~2969
[136]Rabinowitz R. The reactions of phosphonic acid esters with acid chlorides: a very mild hydrolytic route, J Org Chem, 1963, 28 (11): 2975~2978
[137]宁永成,有机化合物结构鉴定与有机波谱学,北京:科学出版社,2000,48～50
[138]石鸿昌,张晓霞,亚磷酸三异丙酯的合成工艺研究,合成化学,2000,8(3)238～241
[139]徐叔云,卞如濂,陈修等,药理实验方法学,北京:人民卫生出版社,2005,1740～1743
[140]黄祯祥,医学病毒学基础及实验技术,北京:科学出版社,1990,143～146