CN1268335C - 具有甲脒修饰的单环碱基的核苷类似物 - Google Patents
具有甲脒修饰的单环碱基的核苷类似物 Download PDFInfo
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- CN1268335C CN1268335C CNB018077455A CN01807745A CN1268335C CN 1268335 C CN1268335 C CN 1268335C CN B018077455 A CNB018077455 A CN B018077455A CN 01807745 A CN01807745 A CN 01807745A CN 1268335 C CN1268335 C CN 1268335C
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- nucleoside
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Abstract
公开了新型核苷类似物化合物。所述新型化合物或其药学上可接受的酯或其盐可以用于药用组合物中，并且这类组合物可以用于治疗感染、侵染、肿瘤或自身免疫病。所述新型化合物也可以用来调节免疫系统的多个方面，包括调节1型和2型活性。
Description
本申请要求于2000年2月15日申请的美国临时申请第60/182676号、于2000年6月16日申请的美国发明专利申请(utility application)顺序号09/595365的优先权，所述每个专利申请的全部内容通过引用结合到本文中。
发明领域
本发明涉及核苷类似物领域。
发明背景
利巴韦林(1-β-D-呋喃核糖基-1，2，4-三唑-3-甲酰胺)是一种核苷类似物，它已经在治疗病毒性疾病的单一疗法(呼吸道合胞病毒，Hall，C.B.；McBride，J.T.；Walsh，E.E.；Bell，D.M.；Gala，C.L.；Hildreth，S.；TenEyck，L.G.；W.J.Hall.感染呼吸道合胞病毒的婴儿的气溶胶化利巴韦林治疗。N.Engl.J.Med.1983，308，1443-1447)和与干扰素α的联合疗法(丙型肝炎病毒，Reichard，O.；Norkrans，G.；Fryden，A.；Braconier，J-H.；Sonnerborg，A.；Weiland，O.干扰素α2B与利巴韦林以及干扰素α2B对于慢性丙型肝炎的随机化双盲、安慰剂对照试验。Lancet 1998，351，83-87)中证明有功效。最近报道的研究表明，利巴韦林的体内应用性可以不仅因为对病毒复制的直接抑制，而且因为其增强T细胞介导的免疫的能力(Hultgren，C.；Milich，D.R.；Weiland，O；Sllberg，M.抗病毒化合物利巴韦林在乙型肝炎病毒和丙型肝炎病毒特异性免疫应答中调节1型/2型T辅助细胞亚群的平衡。J.Gen.Virol.1998，79，2381-2391；Ning，O.；Brown，D.Parodo，J；Cattral，M.；Fung，L.；Gorczynski，R.；Cole，E.；Fung，L.；Ding，J.W.；Liu，M.F.；Rotstein，O.；Phillips，M.J.；Levy，G.利巴韦林抑制病毒诱导的巨噬细胞产生肿瘤坏死因子、白介素-1、促凝血活性fg12凝血酶原酶，并且保持Th1细胞因子产生，但抑制Th2细胞因子应答。J.Immunol.1998，160，3487-3493；Martin，M.J.；Navas，S.；Quiroga，J.A.；Pardo，M.；Carreno，V.利巴韦林-干扰素α组合对得自慢性丙型肝炎患者的培养的外周血单核细胞的影响。Cytokine 1998，79，2381-2391。在体外，通过测量得自人类和小鼠的活化T细胞产生的1型细胞因子水平以及其它测定，可证明利巴韦林的这种免疫调节作用(Tam，R.C.；Pai，B.；Bard，J.；Lim，C.；Averett，D.R.；Phan，U.T.；Milovanovic，T.利巴韦林将人类T细胞应答向1型细胞因子分布型极化。J.Hepatol.1999，30，376-382)。利巴韦林偏向诱导1型细胞因子，在鼠类系统中是功能上显著的(Tam，R.C.；Lim，C.；Bard，J.；Pai，B.利巴韦林体内治疗后的接触性过敏反应受1型细胞因子极化、IL-10表达的调节和共同刺激信号影响。J.Immunol.1999，163，3709-3717)。
哺乳动物的免疫系统有两大类淋巴细胞：B淋巴细胞(B细胞)，它们起源于骨髓；和T淋巴细胞(T细胞)，它们起源于胸腺。B细胞主要负责体液免疫(即抗体产生)，而T细胞主要负责细胞介导免疫。
一般认为T细胞分为两个亚类：辅助T细胞和细胞毒性T细胞。辅助T细胞通过释放参与细胞介导免疫的称为细胞因子的可溶性蛋白介质，激活其它淋巴细胞，包括B细胞和细胞毒性T细胞和巨噬细胞。本文所用的淋巴因子是一个细胞因子亚类。
一般认为，辅助T细胞也分类两个亚类-1型和2型。1型细胞产生白介素-2(IL-1)、肿瘤坏死因子(TNFα)和干扰素γ(IFNγ)，主要负责细胞介导免疫，例如迟发型过敏反应和抗病毒免疫。相反，2型细胞产生白介素IL4、IL-5、IL-6、IL-9、IL-10和IL-13，主要涉及辅助体液免疫应答，例如在对变应原的应答中所观察到的，例如IgE和IgG4抗体同种型转换(Mosmann，1989，Annu Rev Immunol，7：145-173)。
本文所用的术语1型和2型“应答”是指包括分别由于1型和2型淋巴细胞的诱导所引起的整个效应范围。其中，这类应答包括通过转录、翻译、分泌和可能的其它机制引起的相应细胞因子产生的变化、相应淋巴细胞增殖增加、和与细胞因子产生增加相关的其它效应，包括运动性效应。
先前的申请(09/462714、09/291097、09/291093、09/471513、60/164365、60/164366、60/172097、60/175111)(每个申请通过引用结合到本文中)涉及我们最近发现的多个方面，包括各种核苷(在本文中限定，以包括天然核苷的衍生物和类似物)对选择性调节相互之间相对的淋巴细胞应答的影响。其中，我们已经表明，1型和2型应答中任一种应答都可以被选择性地抑制，而另一种应答或者被诱导，或者保持相对不受影响，并且可以选择性地诱导或者1型或者2型应答，而另一种应答或者受抑制，或者保持相对不受影响。我们也发现了令人惊讶的事实：有效地相对选择性地调节相互之间相对的1型和2型应答的某些核苷往往具有双模式效应(bimodal effct)。其中，往往在相对高剂量下一般抑制或诱导1型和2型两者活性的某些核苷，往往在相对低的剂量下有效地相互之间相对地调节1型和2型。
已经表明ViramidineTM(1-β-D-呋喃核糖基-1，2，4-三唑-3-甲脒盐酸盐)在10种不同病毒中有相当于利巴韦林的活性。(J.T.Witkowski，R.K.Robins，G.P.Khare，R.W.Sidwell，J.Med.Chem.，
16，935-937，1973；R.W.Sidwell，J.H.Huffnan，D.L.Bamard，D.Y.Pifat，Antiviral Research，10，193-208，1988，B.Gabrielsen，M.J.Phelan，L.Barthel-Rosa，C.参见J.W.Huggins，D.F.Kefauver，T.P.Monath，M.A.Ussery，G.N.Chmurny，E.M.Schubert，K.Upadhya，C.Kwong，D.A.Carter，J.A.Secrist III，J.J.Kirsi，W.M.Shannon，R.W.Sidwell，G.D.Kini，R.K.Robins，J.Med.Chem.，
35，3231-3238，1992)。另外，ViramidineTM像利巴韦林一样，是一种IMP脱氢酶的抑制剂(R.C.Willis，R.K.Robins，J.E.Seegmiller，Molecular Pharmacology，
18，287-295，1980)。而且，初步的毒理学研究提示，ViramidineTM的毒性低于利巴韦林(D.Y.Pifat，R.W.Sidwell，P.G.Canonico，Antiviral Research，
9，136，1988)。另外，我们实验室最近的研究(R.Tam.K.Ramasamy，ICN Pharmaceuticals，Inc.，未发表的结果，1999)表明，ViramidineTM和利巴韦林表现出相似的免疫调节特性。这些结果与生物利用度低和利巴韦林相关的毒性结合，促使我们不仅开发了用于其它病毒性疾病的ViramidineTM，而且制备了ViramidineTM的其它衍生物，包括ViramidineTM前体药物的合成，并且筛选作为潜在抗病毒药的化合物。
对于其它核苷类似物化合物对选择性地调节相互之间相对的淋巴细胞应答的影响，先前尚未进行研究或有记载。我们发现了，在给予其它核苷类似物化合物(例如所述化合物的前体药物形式)之后，也发生1型和2型应答的双模式效应或者相互之间相对的选择性调节。
在使生物活性化合物发展为临床有用药物的过程中，有许多障碍有待克服。许多有效的生物活性化合物从未成为临床有用药物，因为它们有不合要求的生物药物特性，包括由于通过生物屏障(例如血脑屏障(BBB)和肠屏障)的通透性低所致的生物利用度低。虽然许多因素影响药物的生物利用度，但许多药物的不合要求的物理化学特性(例如电荷、亲脂性、形成氢键的潜能、大小)可能是阻碍药物透过生物屏障的最常见的因素之一。因此，对药物的物理化学特性(电荷、亲脂性、形成氢键的潜能、大小)进行优化，可能是促进药物转运通过这类膜屏障的最为可能的通用策略。
为了优化药物的物理化学特性，一种可能的策略是前体药物策略。(H.Bundgaard，Design of Prodrugs，Elsevier，Amsterdam，1985；N.Bodor，L.Prokai，W.M.Wu，H.Farag，S.Jonhalagadda，M.Kawamura，J.Simpkins，Science，
257，1698-1700，1992；H.E.Taylor，K.B.Sloan，J.Pharm.Sci.，
87，5-20，1998)。术语前体药物用来描述一种药物，所述药物在给药后必须经历化学转化或酶促转化成为活性药物或母体药物，使得所述代谢产物或母体药物随后可以表现出所需的药理学反应。通过将小有机分子中的某些极性官能团暂时生物可逆地衍生化，这些基团的不合要求的物理化学特性(例如电荷、形成氢键的潜能)被“掩蔽”，而不会永久性地改变所述分子的药理学特性。这种策略已经非常成功地用于前体药物的衍生化涉及将羧基或羟基官能团转化为酯的情况下，所述酯在体内可以容易地或者化学水解，或者酶促水解。这种有前景的前体药物概念，我们预期在母体药物中引入其它部分，将提高生物利用度、吸收和抗病毒效应。
尽管存在尚未确定的机制，但我们已经发现，许多潜在益处可能来源于对1型和2型应答相互之间的选择性调节。我们已经推断，例如，相对于2型而言对1型进行特异性调节，可能可用于治疗种类繁多的病症和疾病，范围从感染、侵染、肿瘤和过敏反应至自身免疫病。
这些发现尤为重要，因为现代对于许多以上所列疾病的治疗策略的效力有限、副作用显著或这两者都有。例如自身免疫病的治疗常常限于缓解措施、消除有毒抗体(如在重症肌无力中)和给予有害的药物包括皮质类固醇、氯喹衍生物和抗代谢药或抗肿瘤药以及靶向免疫系统细胞的药物例如环孢菌素。
发明概述
本发明涉及新型核苷类似物化合物和相关化合物例如前体药物、其治疗用途和合成。
在本发明的一方面，提供式1的核苷类似物化合物：
式1-ViramidineTM(ICN 3142)
在本发明的另一方面，一种药用组合物包含与至少一种药学上可接受的载体混合的治疗有效量的式1的甲脒或其药学上可接受的酯或盐。
在本发明的再一方面，一种药用组合物包含与至少一种药学上可接受的载体混合的式1甲脒的前体药物形式或其药学上可接受的酯或盐。
在本发明的又一方面，式1化合物用于治疗对按照达到阳性反应的任何配方和方案给予所述化合物有所述阳性反应的任何病症。其中，考虑了可以用式1化合物治疗感染、侵染、癌症、肿瘤或其它赘生物、巨细胞性动脉炎或自身免疫病。
附图简述
图1是合成式1化合物的示例性合成流程。
图2图示了所考虑化合物和其它化合物对SEB活化人T细胞中1型细胞因子合成的影响。
图3图示了0.625-10μM浓度的所考虑化合物对SEB活化人T细胞中1型细胞因子合成的影响。
图4图示了所考虑化合物对BALB/c小鼠体内CHS应答的影响。
图5图示了所考虑化合物和其它化合物对SEB活化人T细胞中1型细胞因子合成的峰反应和峰范围。
详细描述
当以下术语用于本说明书时，它们按如下定义使用。
术语“核苷”和“核苷类似物化合物”可互换使用，是指包含连接于杂环、芳族杂环的特定位置或者连接于嘌呤(9位)或嘧啶(1位)的天然位置或者连接于类似物的等同位置的任何戊糖或修饰戊糖部分的化合物。
术语“核苷酸”是指在核苷的5’位上取代的磷酸酯。
术语“杂环”是指环中具有至少一个杂原子(例如N、O或S)的单价饱和或不饱和碳环基团，杂环中的每个可利用的位置可以任选独立地被例如羟基、氧代基、氨基、亚氨基、低级烷基、溴、氯和/或氰基取代。在该类取代基中包括嘌呤和嘧啶。
术语“嘌呤”是指含氮二环杂环。
术语“嘧啶”是指含氮单环杂环。
术语“D-核苷”是指具有D-核糖糖部分的核苷化合物(例如腺苷)。
术语“L-核苷”是指具有L-核糖糖部分的核苷化合物。
术语“L-构型”和“D-构型”在本发明中用来描述所述化合物中与所述分子的吡咯并-嘧啶酮部分连接的呋喃核糖基部分的化学构型。
术语“C-核苷”在本说明书中用来描述核糖糖部分和杂环碱基之间形成的键合类型。在C-核苷中，所述键合起源于核糖糖部分的C-1位，并且连接杂环碱基的碳。在C-核苷中形成的所述键合是碳-碳型。
术语“N-核苷”在本说明书中用来描述核糖糖部分和杂环碱基之间形成的键合类型。在N-核苷中，所述键合起源于核糖糖部分的C-1位，并且连接杂环碱基的氮。在N-核苷中形成的所述键合是碳-氮型。
术语“保护基”是指加入至氧原子或氮原子、防止所述氧原子或氮原子在所述氧或氮所在的分子中的其它部分衍生化过程中进一步反应的化学基团。种类繁多的氧和氮的保护基是有机合成领域的技术人员已知的。
术语“低级烷基”是指甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或正己基。该术语的其它实例有具有1-6个碳原子的环状、支链或直链基团。
术语“芳基”是指具有一个单环(例如苯基)或两个稠环(例如萘基)的单价不饱和芳族碳环基团，它可以任选地被羟基、低级烷基、氯和/或氰基取代。
术语“杂环”是指环内具有至少一个杂原子(例如N、O、S、Se或P)的单价饱和或不饱和碳环基团，其每个可利用的位置可以任选地独立地被羟基、氧代基、氨基、亚氨基、低级烷基、溴、氯和/或氰基取代或是未取代的。
术语“单环”是指环内具有至少一个杂原子(例如N、O、S、Se或P)的单价饱和碳环基团，其每个可利用的位置可以任选地独立地被糖部分或任何其它基团(如溴、氯和/或氰基)取代，使得所述单环环系最终被芳香化[例如胸苷]。
术语“免疫调节剂”和“调节剂”在本文中可互换使用，是指能够通过刺激或抑制改变正常或异常的免疫系统的天然或合成产物。
术语“有效量”是指式(1)化合物使免疫功能恢复至正常水平、或者将免疫功能提高至正常水平以上以消除感染的量。
式1化合物可能具有多个不对称中心。因此，它们可以以或者旋光形式或者作为外消旋混合物制备。所描述的和要求保护的本发明范围包括式1化合物的单个的旋光异构体及其非外消旋混合物以及外消旋形式。
术语“α”和“β”是指所示化学结构中不对称碳原子上取代基的特定立体化学构型。
术语“对映体”是指相互之间为非重叠镜像的一对立体异构体。以1∶1比率的一对对映体的混合物是“外消旋”混合物。
术语“异构体”是指具有相同化学式的不同化合物。“立体异构体”是仅在所述原子在空间排列的方式上不同的异构体。
“药学上可接受的盐”可以是由无机和有机酸或碱衍生的任何盐。
化合物
本发明的核苷类似物化合物一般用式1来描述：
式1-ViramidineTM(ICN 3142)
其中该化合物的化学构型为L-构型或D-构型。所考虑化合物(此处：ViramidineTM)的示例性合成可以按照以下概述和示于图1的方案进行。
3-氰基-1-(2，3，5-三-O-乙酰基-β-D-呋喃核糖基)-1，2，4-三唑(7)：将3-氰基-1，2，4-三唑(18.8g，200mmol)(6)、1，2，3，5-四-O-乙酰基-β-D-呋喃核苷(63.66g，200mmol)和双(对硝基苯基)磷酸酯(1g)的混合物置于RB烧瓶(500ml)中。将烧瓶置于水泵真空下预热的165-175℃油浴中，同时将其搅拌25分钟。被置换的乙酸收集于置于水泵和RB烧瓶之间的冰阱中。从油浴取出烧瓶并让其冷却。当烧瓶的温度大致达到60-70℃时，加入EtOAc(300ml)和饱和NaHCO3(150ml)，在EtOAc中萃取。水层再用EtOAc(200ml)萃取。合并的EtOAc萃取液依次用饱和NaHCO3(300ml)、水(200ml)和盐水(150ml)洗涤。有机萃取液经无水硫酸钠干燥，过滤并将滤液蒸发至干。将残余物溶于乙醚(100ml)中，在0℃冷却12小时，得到无色晶体。将固体过滤，用最少量的冷EtOH(20ml)洗涤，并在高度真空下经固体NaOH干燥。产量：56.4g(80％)。mp 96-97℃。1HMR(CDCl3)：δ2.11(s，3H，COCH3)，2.13(s，3H，COCH3)，2.14(s，3H，COCH3)，4.22(dd，1H)，4.46(m，2H)，5.52(t，1H，J＝6.0Hz)，5.70(m，1H)，6.01(d，1H，C1，HJ＝3.6Hz)和8.39(s，1H，C5H)。C14H16N4O7(352.30)的分析计算值：C，47.73；H，4.58；N，15.90。实测值：C，47.70；H，4.63；N，16.01。
1-β-D-呋喃核糖基-1，2，4-三唑-3-甲脒(ViramidineTM)盐酸盐(8)：将(7)(14.08g，40.0mmol)、NH4Cl(2.14g，40.0mmol)和无水氨(150ml)的混合物在钢制反应釜中于85℃加热18小时。将钢制反应釜冷却，打开，将内容物蒸发至干。残余物从MeCN-EtOH中结晶，得到10.6g(95％)的8。Mp 177-179℃。1HMR(DMSO-d6)：δ3.44-4.2(m，3H)，4.40(m，2H)，5.04(t，1H)，5.29(m，1H)，5.74(m，1H)，5.87(d，1H，C1，H)，8.96(bs，3H)和9.17(s，1H，C5H)。C8H14ClN5O4(279.68)的分析计算值：C，34.35；H，5.05；N，25.04；Cl，12.69。实测值：C，34.39；H，5.10；N，25.14；Cl，12.71。
或者，可以如下由市售的RibavirinTM进行合成：
2’，3’，5’-三-O-乙酰基-1-β-D-呋喃核糖基-1，2，4-三唑-3-甲酰胺(9)。将1-β-D-呋喃核糖基-1，2，4-三唑-3-甲酰胺(RibavirinTM)(28.4g，116.4mmol)(5)的乙酸酐(200ml)和吡啶(50ml)悬浮液于室温搅拌过夜。将所得的澄清溶液真空浓缩，得到透明的泡沫状物(43.1g，定量的)。该泡沫状物在TLC上为均一的，无需纯化而直接用于下一步中。将少量经快速色谱纯化，得到分析级样品；1H NMR(300MHz，DMSO-d6)：δ2.01，2.08，2.09(3s，9H，COCH3)，4.10(m，1H)，3.52(m，2H)，5.58(t，1H)，5.66(m，1H)；6.33(d，.1H，J.＝3.0Hz，C1H)，7.73，7.92，(2s，2H，CONH2)，8.86(s，1H，C5H三唑)。(C10H18N4O8)的分析值：C，H，N。
3-氰基-2’，3’，5’-三-O-乙酰基-1-β-D-呋喃核糖基-1，2，4-三唑(10)。向9(43.1g，116.4mmol)的氯仿(500ml)溶液中加入三乙胺(244ml)，将混合物在冰-盐浴中冷却至0℃。在搅拌下滴加三氯氧化磷(30.7ml，330mmol)，将溶液温热至室温。将混合物于室温搅拌1小时后，TLC(己烷/丙酮3∶1)显示原料完全消失。将褐色反应混合物真空浓缩至干，残余物溶于氯仿(500ml)中。该有机溶液用饱和碳酸氢钠水溶液(3×200ml)洗涤，经无水硫酸钠干燥并真空浓缩。残余物经硅胶色谱(快速色谱)，用20％丙酮的己烷溶液洗脱，得到33.14g(从利巴韦林计81％)的纯10，为非晶形固体。该固体在所有方面与真实样品相同：mp101-103℃；IR(溴化钾)v 2250(CN)，1750(C＝O)，cm-1；1H NMR(300MHz，CDCl3)：δ2.04，2.06，2.07(3s，9H，乙酰基甲基)，4.15(dd，1H)，4.40(m，1H)，5.47(t，1H)，5.63(dd，1H)，5.95(d，1H，J＝3.2Hz，C1H)，8.34(s，1H，C5H三唑)。
1-β-D-呋喃核糖基-1，2，4-三唑-3-甲脒盐酸盐(8)：向10(4.0g，11.4mmol)的甲醇(100ml)悬浮液中加入1摩尔浓度的甲醇钠甲醇溶液(12ml)，将混合物于室温搅拌过夜。溶液用甲醇洗涤的Dowex H+树脂酸化至pH 4，将树脂过滤，将滤液真空浓缩至干。将残余物溶于最少量的甲醇(15ml)中，转移至耐压瓶中。加入氯化铵(0.61g，11.4mmol)和于0℃用干燥氨气饱和的甲醇溶液(75ml)，将瓶密封，溶液于室温搅拌过夜。将溶液真空浓缩至干，所得的残余物从乙腈/乙醇中结晶，得到8，为晶状固体(2.95g，93％)。该样品在所有方面与真实样品相同。
在某些药物剂型中，优选所述化合物的前体药物形式，尤其包括本发明化合物的酰化(乙酰化或其它)衍生物、吡啶酯和各种盐形式，在治疗患者病症的方法中，可以给予所述前体药物形式。本领域技术人员知道如何容易地将本发明化合物修饰为前体药物形式，以有助于将活性化合物传递至宿主生物或患者的靶部位。合适时，本领域技术人员也会利用所述前体药物形式的适宜药代动力学参数，以将本发明化合物传递至宿主生物或患者的靶部位中，以使所述化合物的目的效应最大化。
本文所公开化合物的前体药物形式的所考虑的生成的实施例如下。ViramidineTM的最简单的前体药物之一是ViramidineTM的三-O-乙酰基衍生物。所述三-O-乙酰基衍生物如流程1中的描述制备：
流程1
ViramidineTM的5’-视黄酰基衍生物是另一种简单的前体药物形式，如下制备：
流程2
ViramidineTM的其它5’-衍生物包括流程3中所示的以下衍生物：
流程3
这些化合物中的大多数化合物可以如已描述的方法获得(C.Sergheraert，C.Pierlot，A.Tartar，Y.Henin，M.Lemaitre，J.Med.Chem.，36，826-830，1993)。
ViramidineTM的基于香豆素的前体药物形式的合成可以如下获得：
流程4
认为氨基酸酯是更好的前体药物形式，因为它们可能涉及立体选择性转运蛋白。ViramidineTM的氨基酸衍生物可以如下所示合成：
流程5
为了将药物特异性地传递至肝和胆汁系统，内源胆汁酸转运系统是有吸引力的候选者。ViramidineTM的胆汁酸缀合物的合成可以如下所示完成：
核苷酸衍生物是另一类前体药物或前体药物形式。被护5’-一磷酸酯衍生物的制备示于下文。通过用中性取代基保护带负电荷的磷酸根，可能形成亲脂性更强的衍生物，预期所述衍生物在细胞中后，立即恢复为相应的一磷酸酯。
流程6
核苷酸衍生物是另一类前体药物或前体药物形式。被护5’-一磷酸酯衍生物的制备示于下文。通过用中性取代基保护带负电荷的磷酸根，可能形成亲脂性更强的衍生物，预期所述衍生物在细胞中后，立即恢复为相应的一磷酸酯。
流程7
其中R1是烷基，例如CH3C(O)S-CH2CH2-；(CH3)2CHC(O)S-CH2CH2-；(CH3)3CC(O)S-CH2CH2-；(CH3)3CC(O)OCH2-；C6H5C(O)S-CH2CH2-或HOCH2CH2SS-CH2CH2-。
氨基酸氨基磷酸酯是另一类前体药物，可以如下所示合成：
流程8
R＝氢以外的任何基团
以下显示一磷酸酯前体药物的其它衍生物：
R＝烷基、脂质、维生素、
胆汁酸、胆固醇衍生物
流程8A
ViramidineTM的基于水杨酸的前体药物可以按照以下流程获得：
流程9
核苷5’-二磷酸酯或三磷酸酯的前体药物可能更有价值，因为它们可能绕过更多的代谢步骤。
以下是潜在的核苷酸亲脂性前体药物，如下所示制备：
X＝CH2；M+＝NBu4 +
X＝O；M+＝NBu4 +
流程10
流程11
以下是ViramidineTM的另一类潜在膦酸酯前体药物：
流程12
其它可能的前体药物包括PCT专利申请WO 98/39342、WO98/39343、WO 98/39344和WO 99/45016中所示的基团的可能组合。
ViramidineTM的前体药物不仅可以通过修饰母体分子的糖部分而获得，而且也可以通过将脒官能团衍生化来获得。以下是少数类别的可以如下所述通过修饰脒基团制备的前体药物：
流程13
流程14
流程15
流程16
R＝CH3-
R＝苯基
R＝R1-S-S-Ph-且
R1＝烷基、脂质、维生素、
胆汁酸、胆固醇衍生物
应用
考虑了式1化合物可以用来治疗各种各样的病症，事实上可以用来治疗对给予一种或多种所述化合物有阳性反应的任何病症。其中尤其考虑了本发明化合物可以用来治疗感染、侵染、癌症或肿瘤或自身免疫病。还考虑了本发明化合物可以用来靶向患者特定器官(例如肝或心脏)的病症或疾病。
考虑用本发明化合物治疗的感染包括呼吸道合胞病毒(RSV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、1型和2型单纯疱疹、生殖器疱疹、疱疹性角膜炎、疱疹性脑炎、带状疱疹、人免疫缺陷病毒(HIV)、甲型流感病毒、汉坦病毒(出血热)、人乳头瘤病毒(HPV)、麻疹和真菌。
考虑用本发明化合物治疗的侵染包括原生动物侵染以及蠕虫和其它寄生物侵染。
考虑治疗的癌症或肿瘤包括由病毒引起的癌症或肿瘤，并且所述效应可以包括抑制受病毒感染的细胞转化为肿瘤状态、抑制病毒从转化细胞传播至其它正常细胞和/或阻滞病毒转化细胞的生长。
考虑治疗的自身免疫病和其它疾病包括关节炎、银屑病、肠病、青少年糖尿病、狼疮、多发性硬化、痛风和痛风性关节炎、类风湿性关节炎、移植排斥、巨细胞性动脉炎、变态反应和哮喘。
本发明化合物的其它考虑的应用包括用作其它核苷或核苷酸类似物化学合成的中间体，所述核苷或核苷酸类似物又可用作治疗药或用于其它目的。
再一方面，一种治疗哺乳动物的方法包括给予治疗和/或预防有效量的含本发明化合物的药物。在该方面，所述效应可以涉及调节所述哺乳动物免疫系统的某一部分，尤其是调节1型和2型相互之间的淋巴因子分布型。在发生1型和2型淋巴因子的调节的情况下，尤其考虑了所述调节可以包括抑制1型和2型两者，更优选刺激1型淋巴因子，或者1型应答相对于2型应答相对增加。
尤其考虑了，ViramidineTM(1.39μg/ml)增加(优选活化的)T淋巴细胞中1型细胞因子表达和合成，得自各种实验的结果示于图2-5中。图2描绘了5μMViramidineTM(一种式1化合物)、利巴韦林和levovirin对SEB活化的人T细胞(n＝5个供体)中1型细胞因子合成的影响，其中viramidine显示出与使用三唑的对照相比，1型应答明显增加。图3图示了0.625-10μM范围内的Viramidine对SEB(葡萄球菌肠毒素B)活化的人T细胞中1型细胞因子合成的剂量-反应效应(数据代表4个单独的供体)。在图4中清楚地显示出Viramidine在接触性过敏反应(CHS)测定中1型应答增加的体内效应，而图5显示了Viramidine和Levovirin/利巴韦林之间在峰反应核苷浓度和反应的峰范围方面的比较(y轴描绘特定实验中的应答者数目)。
人T细胞的制备和体外活化
通过密度梯度离心，然后用Lymphokwik(One Lambda，CanogaPark CA)进行T细胞富集，从健康供体或类风湿性关节炎患者中分离出外周血单核细胞。通过粘附于塑料上，除去污染的单核细胞。纯化的T细胞＞99％CD2+、＜1％HLA-DR+和＜5％CD25+，在RPMI-AP5(含有20mM HEPES缓冲液pH 7.4、5％自体血浆、1％L-谷氨酰胺、1％青霉素/链霉素和0.05％2-巯基乙醇的RPMI-1640培养基)中维持。
关于细胞因子蛋白水平的测定，通过加入10ng PMA+0.5μg离子霉素(两者都得自Calbiochem，La Jolla，CA)活化T细胞(1×106细胞，体积为1ml)，在24孔板中在0-20μM核苷存在下于37℃和5％CO2下在潮湿的培养箱中孵育至多48小时。活化后，分析上清液的细胞来源的细胞因子产生。对于增殖和生存力研究，将上述方案修改为96孔板，使用0.2×106细胞，体积为0.2ml，用2ng PMA和0.1μg离子霉素活化。在单独的实验中，用20ng PMA+1μg离子霉素活化2ml中的5×106T细胞。或者，按照已发表的方法，可以在体外用SEB活化细胞。这里，在6-24小时孵育后，从T细胞中分离出总RNA，通过RT-PCR分析，以测定各种细胞因子和炎性介质的mRNA水平。也在单独的实验中，进一步纯化人类T细胞(使用得自Stem CellTechnologies的细胞富集试剂，Vancouver，BC)，得到纯群体CD4+(＜1％CD8+，采用RosetteSep人CD4+T细胞分离试剂)和CD8+(＜1％CD4+，采用RosetteSep人CD4+T细胞分离试剂)T细胞亚群，此后，在全部T细胞实验中，用PMA和离子霉素活化1×106细胞/ml。
胞外细胞因子分析
在细胞上清液中，在适当稀释后，用对IL-2、IFNg、TNFα、IL-4和IL-5特异性的ELISA试剂盒(Biosource International，Camarillo，CA)，测定人细胞因子水平。用对鼠类IFNg和IL-4特异性的ELISA试剂盒(R and D Systems，Minneapolis，MN)，测定鼠类细胞因子水平。所有的ELISA结果都以pg/ml表示。某些数据以活化对照的百分率显示，以试验核苷存在下活化T细胞的细胞因子水平与未经处理的活化T细胞的细胞因子水平之比×100％来计算。试验核苷对细胞因子水平的零效应将给出100％的活化对照值的百分率。或者，数据以与活化对照的差异百分率([(试验pg/ml-活化对照pg/ml)/活化对照pg/ml]×100％)显示。试验核苷对细胞因子水平的零效应将是0％。
接触性过敏反应(CHS)
按照先前描述的方法(Ishii，N.，K.Takahashi，H.Nakajima，S.Tanaka，P.W.Askenase.1994.BALB/c和C3H/He小鼠中的DNFB接触敏感性(CS)。J.Invest.Dermatol.102：321)，在BALB/c小鼠中测定对接触性变应原DNFB的反应性。简而言之，通过应用20μl 0.3％DNFB的丙酮∶橄榄油4∶1溶液于首次用于实验的小鼠已剃毛的腹部上，使小鼠致敏。对于CHS的最适诱发，致敏后5天，小鼠在每只耳朵的两侧用20μl 0.12％DNFB攻击。也攻击未经致敏的小鼠，将其用作每个试验的对照。24小时后，测量耳部厚度，通过从攻击前数值中减去攻击后的数值，评价对DNFB的反应。表示时，通过在用DNFB攻击时腹膜内注射，给予50μlPBS中6.2μg(0.3mg/kg)或者100μl PBS中12.4μg(0.6mg/kg)剂量的7-β-D-呋喃核糖基-4-氧代吡咯并[2.3-d]嘧啶-5-甲脒。这些剂量的7-β-D-呋喃核糖基-4-氧代吡咯并[2.3-d]嘧啶-5-甲脒在初步优化研究中给出最大效应。在最后的耳部厚度测量后，通过颈椎脱臼处死小鼠，取出腋窝/腋侧淋巴结。从分离的淋巴结细胞中分离总细胞RNA后，进行RT-PCR和DNA印迹分析，以检测小鼠IFNg、IL-2和IL-10mRNA水平。
进一步的实验
一般考虑到，免疫应答向1型应答偏移是合适的。因此，考虑到按照本发明主题的化合物可能尤其可用于治疗病毒性疾病(优选用于其中1型应答减弱或受抑制的病毒感染)。为了证实调节免疫应答的效力，已经进行了各种实验，以下是用所考虑化合物进行的某些实验的示例性总结：
体外-Viramidine抑制LLC-MK2(恒河猴肾细胞)的Punta Toro病毒感染，EC50为8mg/ml(Adames品系)，12mg/ml(Balliet品系)-CC50为320mg/ml(1.0-1.2病毒评级)。
体内-皮下给予或口服给予viramidine导致皮下注射的PTV100％存活(10只C57BL/6只小鼠/gP)(Adames品系)。
对于PTV体内感染后24小时而言，对于皮下每日两次给予5天的利巴韦林的最低有效皮下剂量为32mg/kg，对于viramidine而言为96mg/kg。对于PTV体内感染后24小时而言，对于每日口服两次给予5天的利巴韦林的最低有效口服剂量为20mg/kg，对于viramidine而言为40mg/kg。
一般而言，按照本发明的最优选应用是所述活性化合物对于非靶宿主细胞的细胞毒性相对较低、而对于靶的活性相对较高的那些应用。在该方面，也可能有利的是，L-核苷的稳定性可能高于D-核苷，可能导致药代动力学更优。这一结果可以达到，因为L-核苷可能不为酶所识别，因此可能半寿期更长。
考虑了，按照本发明的化合物将在任何合适的药用制剂中、以任何合适的方案体内、体外或离体给予。因此，可以口服、胃肠外(包括皮下注射、静脉内、肌内、通过胸骨内注射或输注技术)、通过吸入喷雾或经直肠、局部等等、在含有常规无毒的药学上可接受的载体、佐剂和溶媒的剂量单位制剂中进行给药。
作为实例，考虑了按照本发明的化合物可以与药学上可接受的载体混合配制。例如，本发明的化合物可以作为药学上可接受的盐口服给予。因为本发明的化合物通常是水溶性的，因而它们可以在生理盐溶液(例如缓冲至pH约7.2-7.5)中静脉内给予。常规的缓冲剂例如磷酸盐、碳酸氢盐或柠檬酸盐可以用于此目的。当然，本领域技术人员可以在本说明书内容的范围内修改所述制剂，以便在不使得本发明的组合物不稳定或损害其治疗活性的情况下提供用于特定给药途径的多种制剂。具体地说，对本发明化合物进行修饰，以使其更溶于水或其它溶媒，例如可以通过本领域技术人员众所周知的微小的修饰(盐制剂、酯化等)容易地达到。本领域技术人员也熟知，为了控制本发明化合物的药代动力学以在患者体内获得最大有益效应，可改变特定化合物的给药途径和给药方案。
另外，按照本发明的化合物可以单独给予，获得与用于治疗上述感染或病症的其它药物联合给予。按照本发明的联合疗法包括给予至少一种本发明化合物或其功能性衍生物和至少一种其它药用有效成分。所述有效成分和药用有效成分可以分开给予，或者一起给予，并且当分开给予时，这可以同时给予或以任何顺序分开给予。选择所述有效成分和药用有效成分的量以及给药的相对定时，以便达到所需的联合治疗效应。最好是，所述联合疗法包括给予一种本发明化合物或其生理功能性衍生物和一种下文提及的药物。
考虑与按照式1的调节剂联合有效的其它药物或有效成分的实例是：抗病毒药，例如干扰素包括但不限于干扰素α和干扰素γ、利巴韦林、阿昔洛韦和AZTTM；抗真菌药，例如托萘酯、FungizoneTM、LotriminTM、MycelexTM、制霉菌素和两性霉素(Amphoteracin)；抗寄生虫药，例如MintezolTM、NiclocideTM、VermoxTM和FlagylTM；肠用药物(bowel agents)，例如ImmodinmTM、LomotilTM和PhazymeTM；抗肿瘤药，例如干扰素α和γ、AdriamycinTM、CytoxanTM、ImuranTM、氨甲蝶呤、MithracinTM、TiazofurinTM、TaxolTM；皮肤科用药，例如AclovateTM、CyclocortTM、DenorexTM、FloroneTM、OxsoralenTM、煤焦油和水杨酸；偏头痛制剂，例如麦角胺化合物；类固醇和以上未列出的免疫抑制药，包括环孢菌素、DiprosoneTM、氢化可的松；FloronTM、LidexTM、去氧米松(Topicort)和倍他米松戊酸酯(Valisone)；和代谢药物(metabolicagents)，例如胰岛素；以及可能不能很好地符合以上类别的其它药物，包括细胞因子如IL2、IL4、IL6、IL8、IL10和IL12。尤其优选的主要药物是AZT、3TC、8-取代的鸟苷类似物、2，3-二脱氧核苷、白介素II、干扰素例如IαB-干扰素、托卡雷琐、左旋咪唑、异丙肌苷和环木脂体。
这类其它治疗药的实例包括有效调节免疫系统或相关病症的药物，例如AZT、3TC、8-取代的鸟苷类似物、2’，3’-二脱氧核苷、白介素II、干扰素例如α-干扰素、托卡雷琐、左旋咪唑、异丙肌苷和环木脂体。按照本发明的某些化合物可以通过降低其它化合物的代谢或使其失活而有效增强某些按照本发明的药物的生物活性，因此可以共同给予以获得这一目的效应。
对于剂量，本领域技术人员会认识到，治疗有效量将随待治疗的感染或病症、其严重程度、待使用的治疗方案、所用药物的药代动力学以及所治疗的患者(动物或人类)而变。考虑了各种可供选择的剂量也是合适的，包括0.5mg/kg-0.1mg/kg的剂量和更低剂量，也包括0.5-1.0mg/kg的剂量和更高剂量。还考虑到，虽然对于某些病毒感染，在相对低血浆浓度的式1化合物下可以达到治疗成功，但其它病毒感染可能需要相对高的剂量。然而，考虑到通过给予小剂量，然后将该量增加，直至副作用变得过分不利，或者达到计划的效应为止，可发展合适的方案。
所述活性化合物的给予，其范围可以从连续(静脉内滴注)至每日数次口服(例如Q.I.D.)，给药途径其中可以包括口服、局部、胃肠外、肌内、静脉内、皮下、经皮(可以包括渗透增强剂)、口腔含化和栓剂给予。
为了制备按照本发明的药用组合物，最好将治疗有效量的一种或多种按照本发明的化合物与药学上可接受的载体按照常规药物混合技术进行完全混合，产生一定的剂量。根据给药所需的制剂形式(例如口服或胃肠外给药)，载体可以采用各种各样的形式。在制备口服剂型的药用组合物中，可以使用任何通常的药用介质。因此，对于液体口服制剂例如混悬剂、酏剂和溶液剂而言，可以使用合适的载体和添加剂，包括水、甘醇类、油类、醇类、矫味剂、防腐剂、着色剂等。对于固体口服制剂例如粉剂、片剂、胶囊剂以及对于例如栓剂的固体制剂而言，可以使用合适的载体和添加剂，包括淀粉、糖载体例如葡萄糖、甘露醇、乳糖和相关载体、稀释剂、制粒剂、润滑剂、粘合剂、崩解剂等。如果需要，可以将片剂或胶囊剂包肠衣，或通过标准技术缓释。
对于胃肠外制剂，载体通常将包含无菌水或氯化钠水溶液，虽然可以包括其它成分，包括有助于分散的成分。当然，当使用无菌水并保持无菌时，所述组合物和载体也必须灭菌。也可以制备注射用混悬剂，在这种情况下，可以使用合适的液体载体、悬浮剂等。
Claims (7)
1.式1的甲脒或其药学上可接受的盐在生产治疗丙型肝炎病毒(HCV)病毒感染和乙型肝炎病毒(HBV)病毒感染的药物方面的用途
式1
其中所述化合物为D-构型。
2.权利要求1的用途，其中所述药学上可接受的盐为根据式1的盐酸盐。
3.权利要求1的用途，其中所述病毒感染为HCV感染。
4.权利要求2的用途，其中所述病毒感染为HCV感染。
5.权利要求1-4中任一项的用途，其中所述药物配制用于口服给药。
6.权利要求1-4中任一项的用途，所述药物还包括干扰素。
7.权利要求6的用途，其中所述干扰素是干扰素α。
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| US3984396A (en) | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
| US3798209A (en) | 1971-06-01 | 1974-03-19 | Icn Pharmaceuticals | 1,2,4-triazole nucleosides |
| US3991078A (en) | 1971-06-01 | 1976-11-09 | Icn Pharmaceuticals, Inc. | N-substituted 1,2,4-triazoles |
| USRE29835E (en) | 1971-06-01 | 1978-11-14 | Icn Pharmaceuticals | 1,2,4-Triazole nucleosides |
| US3962211A (en) * | 1975-01-13 | 1976-06-08 | The University Of Utah | 7-substituted nucleoside compounds |
| US4093624A (en) | 1977-01-31 | 1978-06-06 | Icn Pharmaceuticals, Inc. | 1,2,4-Thiadiazolidine-3,5-dione |
| JPS6426593A (en) | 1987-07-21 | 1989-01-27 | Asahi Glass Co Ltd | Nucleoside derivative |
| US4892865A (en) * | 1987-12-01 | 1990-01-09 | The Regents Of The University Of Michigan | Pyrrolo[2,3-d]pyrimidine nucleosides as antiviral agents |
| US5767097A (en) * | 1996-01-23 | 1998-06-16 | Icn Pharmaceuticals, Inc. | Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes |
| CA2246162C (en) * | 1996-01-23 | 2000-04-04 | Icn Pharmaceuticals, Inc. | Modulation of th1/th2 cytokine expression by ribavirin.rtm. and ribavirin.rtm. analogs in activated t-lymphocytes |
| BR9712527A (pt) * | 1996-10-16 | 2000-03-08 | Icn Pharmaceuticals | L-nucleosìdeos monocìclicos, análogos e seus empregos |
| RU2002103501A (ru) * | 1999-08-27 | 2003-09-10 | Ай-Си-Эн Фармасьютикалз, Инк. (Us) | Пирроло[2,3-d] пиримидиновые нуклеозидные аналоги |
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2000
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