CN101547932B - 核苷芳基氨基磷酸酯及其作为抗病毒制剂处理丙型肝炎病毒的应用 - Google Patents
核苷芳基氨基磷酸酯及其作为抗病毒制剂处理丙型肝炎病毒的应用 Download PDFInfo
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- CN101547932B CN101547932B CN200780045190.7A CN200780045190A CN101547932B CN 101547932 B CN101547932 B CN 101547932B CN 200780045190 A CN200780045190 A CN 200780045190A CN 101547932 B CN101547932 B CN 101547932B
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- Prior art keywords
- compound
- naphthyl
- group
- methyl
- guanosine
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Abstract
衍生自嘌呤和鸟嘌呤之类的碱基的化学式I的核苷化合物的氨基磷酸酯衍生物有增强的治疗效力,尤其是对丙型肝炎病毒之类的病毒感染的预防或治疗有增强的效力。该核苷化合物的糖苷部分在β-2′位置被甲基和氨基磷酸酯基团适当地取代,适当地包含用-O-与P原子链接的1-萘基。
Description
本发明涉及一些化合物、它们的制备和它们在治疗和预防病毒感染方面(尤其是对于现代人)的用途。具体地说,虽然不排他,但是本发明涉及作为能对丙型肝炎病毒(HCV)起作用的抗病毒制剂有用的化合物。
WO2006/012078A描述特定的核苷芳基氨基磷酸酯、它们的合成和它们作为随RNA变化的RNA病毒聚合酶的抑制剂的前体的用途,具体地说,它们作为丙型肝炎病毒(HCV)NS5B聚合酶的抑制剂的前体、作为HCV复制的抑制剂的前体和治疗丙型肝炎感染的用途。
WO2006/100439A涉及克拉屈滨(cladribine)、异克拉屈滨(isocladribine)、fludaribine和氯法拉滨(clofarbine)的氨基磷酸酯和它们在治疗白血病之类的癌症方面的用途。
WO2006/100439A所描述的化合物与它们治疗癌症有关的细胞内激酶居间的激活作用不同于治疗和预防病毒感染所需要的细胞内激酶居间的激活作用。
本发明的目标是提供一些新的化合物,这些化合物改善现代人的病毒感染的预防和治疗,具体地说,改善丙型肝炎感染的预防和治疗。
依照本发明的第一方面,提供化学式I的化合物及其药学可接受的盐、溶剂化物和药物前体:
其中:
Ar包含两个以上融合的芳环而且选自由C9-30芳基和C6-30杂芳基组成的群体,其中任何环被非必选地取代;
T选自由氢(-H)、氟(-F)、叠氮基(-N3)、氨基(-NH2)、羟基(-OH)、C1-3烷基(C1-3-)、C1-3烷氧基(C1-3O-)、巯基(-SH)和C1-3硫代烷基(C1-3S-)组成的群体;
V选自由-OT′、氢(-H)、氟(-F)和氯(-Cl)组成的群体,其中T′选自由氢(-H)、甲基(-CH3)、C1-16烷基羰基(C1-16烷基-C(=O)-)、C2-18烯基羰基(C2-18烯基-C(=O)-)、C1-10烷氧基羰基(C1-10烷基-O-C(=O)-)、C3-6环烷基羰基(C3-6环烷基-C(=O)-)和C3-6环烷基氧代羰基(C3-6环烷基-O-C(-O)-)组成的群体;
T″选自由氢(-H)、甲基(-CH3)、C1-16烷基羰基(C1-16烷基-C(=O)-)、C2-18烯基羰基(C2-18烯基-C(=O)-)、C1-10烷氧基羰基、C3-6环烷基羰基(C3-6环烷基-C(=O)-)和C3-6环烷基氧代羰基(C3-6环烷基-O-C(=O)-)组成的群体;
n是O或1,其中当n是1的时候,X是=0,而当n是0的时候,双键在位置3和位置4之间,而且X选自由H、OH、F、Cl、Br、I、C1-6烷基组成的群体和NR5R6,R5和R6各自独立地选自H和C1-6烷基;
Z选自由H、OH、F、Cl、Br、I、C1-6烷基和NR5R6组成的群体,其中R5和R6各自独立地选自H和C1-6烷基;
Y选自由H、OH、F、Cl、Br、I、C1-6烷基、C2-8炔基和NR5R6组成的群体,其中R5和R6各自独立地选自H和C1-6烷基;
Q选自由O、S和CR7R8组成的群体,其中R7和R8各自独立地选自H和C1-6烷基;
R1和R2各自独立地选自H和由C1-20烷基、C2-20烯基、C1-20烷氧基、C1-20烷氧基C1-20烷基、C1-20烷氧基C6-30芳基、C2-20炔基、C3-20环烷基C6-30芳基、C6-30芳氧基、C5-20杂环基组成的群体,其中任何基团被非必选地取代;而且
R3和R4各自独立地选自H和由C1-2O烷基、C2-20烯基的团体被选择、C1-20烷氧基、C1-20烷氧基C1-20烷基、C1-20烷氧基C6-30芳基、C2-20炔基、C3-20环烷基C6-30芳基、C6-30芳氧基、C5-20杂环基组成的群体,其中任何基团被非必选地取代,优选R3是烷基、更优选R3选自由组成的群体从有甲基、乙基、2-丙基、n-丙基、环己基、2-丁基和苯甲基;
附带条件是R1和R4能一起组成-(CH2)3-亚烃基链。
依照本发明的另一方面,提供在治疗方法中、适合在病毒感染的预防或治疗中、更适合在丙型肝炎病毒的预防或治疗中使用的化学式I的化合物。
依照本发明的另一方面,提供化学式I的化合物在制造预防或治疗病毒感染的药物中,优选在制造预防或治疗丙型肝炎病毒的药物中的用法。
依照本发明的另一方面,提供病毒感染(尤其是丙型肝炎病毒个人)的预防或治疗方法,包括在需要这样的治疗时对患者(现代人)适当地施用有效剂量的化学式I的化合物。
依照本发明的另一方面,提供在与药学可接受的载体、稀释剂或赋形剂的组合中包含化学式I的化合物的药学组合物。
依照本发明的另一方面,提供制备药学组合物的方法,该方法包括使化学式I的化合物与药学可接受的赋形剂、载体或稀释剂结合的步骤。
依照本发明的另一方面,提供用来制备化学式I的化合物的方法,该方法包括使化学式III的化合物与化学式IV的化合物反应,
化学式III:
化学式IV:
其中Ar、T、V、T″、n、X、Y、Z、Q、R1、R2、R3和R4有前面关于化学式I陈述的意义。
人们将理解本发明延伸到化学式I的化合物的各种中间物,其中Ar是H,而R3是H或R3与前面定义的一样。
人们将领会到,注意到前面关于化学式I和III定义的化合物,在n是1而X是=0时的化合物是在n是0而X是OH时以别的方式等价的烯醇化合物的酮类互变异构体形式。
本发明在n是1、X是=O、Y是NH2而且没有双键存在于位置3和位置4之间(即,承接=0的碳环原子和邻环氮原子之间)的情况下特地包括鸟嘌呤作为碱基部分。
体现本发明的化合物已被令人惊讶地发现有增强的抗病毒活性。具体地说,体现本发明的化合物已被发现对于丙型肝炎病毒有增强的效力。
本发明的化合物的增强的抗病毒效力被认为应归于在T、V和T″与前面陈述的一样情况下化学式I的分子出现在氨基磷酸酯部分用于Ar的融合多环实体组合中和次甲基(-CH2-)基团在核苷的糖苷部分的β-2’位置。
所谓C9-30芳基指的是以芳基形式包含9到30粒环上碳原子的芳香族实体。所谓C6-30杂芳基指的是以芳基形式包含6到30粒环上碳原子的芳香族实体,而且至少一个芳基环包含环上杂原子。
适当地,Ar能包含两个、三个、四个、五个或六个融合的芳环。优选,Ar包含呈两个或三个融合芳环形式的芳基实体。更优选,Ar是选自C9到C20芳基和C6到C20杂芳基的双环融合芳香族实体。在Ar是杂芳基的情况下,1到12个杂原子适当地在芳基环之内而且被适当地独立地选自1到4个氮原子、1到4个氧原子和1到4个硫原子。优选,杂原子包括氮。
在Ar的芳基或杂芳基环***中可得的碳原子和/或杂原子可能在环上被一个或多个取代基取代,如同下面关于取代基陈述的那样,取代基可能出现在基团Ar上。优选Ar未被取代。
适当的是,Ar是萘基(C10H7)或喹啉基(C9H6N),每个基团可能被非必选地取代。
最适当的是,Ar是萘基。萘基实体优选与O-P实体在萘基基团上的1或α位置(即,在毗邻萘基基团中两个环之间的融合键的C原子处)链接。任何非必选的取代基优选出现在位置4。优选Ar是未被取代的1-萘基。
当Ar是喹啉基的时候,它优选在喹啉基基团(即,包含杂原子N的环)的位置4与O-P实体链接,其中N是作为位置1编号的。任何取代基优选出现在位置6,即在不包含杂原子N的环上,其中N是作为位置1编号的。
优选T选自由氢(H-)、氟(F-)、甲基(CH3-)和乙基(C2H5-)组成的群体。
优选V选自由氢(H-)、氟(F-)和OT′组成的群体,其中T′是氢(H-)或甲基(CH3-)。
优选T″是氢(H-)。
T、V和T″的优选组合是T=H、V=OH和T=H。用于Ar的上述优选实体与T=H、V=OH和T″=H的组合是特别优选的。
优选n是1,而X是=0。更优选n是1、X是=0、而Y是NH2,而且核苷碱部分对应于9-连接的鸟嘌呤。在Z是H的情况下,核苷碱部分对应于未被取代的9-连接的鸟嘌呤。在Z不是H的情况下,核苷碱部分对应于8-被取代的9-连接的鸟嘌呤。
作为替代,优选n是0,而X选自由NH2、F、Cl和NR5R6组成的群体其中R5和R6之一是H,而且R5和R6之一是C1-6烷基。在n 是0、X是NH2、Y是H、而Z是H的情况下,核苷碱基部分对应于9-连接的腺嘌呤。
优选,Y选自由H、F、Cl、NH2和NR5R6组成的群体,其中R5和R6之一是H而且R5和R6之一是C1-6烷基。
优选,Z选自由H、F和Cl组成的群体。
优选,Q是O。
优选,R3是烷基。更优选,R3选自由组成的群体从有甲基(-CH3)、乙基(CH3CH2-)、2-丙基((CH3)2CH-)、n-丙基(CH3-CH2-CH2-)、环己基(C6H11-)、2-丁基((CH3)C(H)(CH2CH3)-)和苯甲基(C6H5CH2-),甚至更优选R3选自由甲基、乙基、2-丙基和苯甲基组成的群体,甚至更优选R3选自由乙基和苯甲基组成的群体。
优选,R4是H或者与R1一起组成(-(CH2)3-),以便提供与脯氨酸相对应的基团。
优选,R1和R2独立地选自由H、2-丙基((CH3)2CH-)、苯甲基(C6H5CH2-)和-CH2异丙基((CH3)2C(H)-CH2-)组成的群体,或者是这样选定的,以致它们对应于天然氨基酸的侧链。
优选,R1和R2之一是甲基(-CH3),而且R1和R2之一是H,以致生出R1和R2的C原子有与在天然丙氨酸中一样的手性L。
优选的化合物在组合中有为上述的Ar、T、V、T′、T、X、Y、Z、Q、R1、R2、R3和R4优选的识别特征。
特别优选的化合物有:n=1,X==0,Y=NH2,Z=H,Q=O,T=H,V=OH,T″=H并因此起源于鸟嘌呤;以及n=O,X=NH2,Y=Z=H,Q=O,T=H,V=OH和T″=H并因此起源于腺嘌呤。
前面直接陈述的和这样起源于鸟嘌呤或腺嘌呤的每种特别优选的化合物当Ar、R1、R2、R3和R4都有上述的优选的识别特征的时候是特别优选的,而且当Ar是1-萘基而R3是苯甲基或乙基的时候是特别优选的。
特别优选的化合物是在实施例2、3、4、6、7、8和11中描述的并且被列在下面的表II中。
在化学式I的化合物中磷的中心可能是一个非对映异构体RP或SP,或者它可能是非对映异构体RP或SP的混合体。优选它是纯粹的非对映异构体。适当的是,选定更有活性的非对映异构体。
适当的是,化学式I的化合物的药学可接受的盐、溶剂化物和药物前体是在核苷基团糖苷部分的3′-OH处的酯或酰胺。
优选,用来制备化学式I的化合物的方法包括在核苷基团的糖苷部分上除了5′之外保护游离OH基团的步骤。氯磷酸酯可能是利用芳氧基氯磷酸酯和受到适当保护的氨基酸衍生物制备的。作为替代,磷酸盐化学可能连同适当的浓缩剂一起使用。
Ar、R1、R2、R3和R4每个都能用一个、两个、三个、四个、五个或多个独立地从包含捐赠电子部分和收回电子部分的基团选定的取代基取代。
Ar上的取代基适当地独立地选自由羟基(OH-)、酰基(R′C(=O)-)、酰氧基(R′C(=O)O-)、硝基(-NO2)、氨基(-NH2)、-SO3H、 -SH、R’S-(其中R′独立地选自上述的与R1相同的群体)组成的群体;、羧基(-COOH)、C1-6酯、C1-6醛、氰基(-CN)、C1-6烷氨基、C1-6二烷氨基、硫醇、氯、溴、氟、碘、C1-6烷基、C2-6烯基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C5-1O芳基、C5-7环烷基、C5-11环烷基-C1-6烷基、C5-7环烯基、C5-7环炔基、C5-11芳基C1-6烷基、C1-6烷基C5-11芳基、C5-11芳基、C1-6氟烷基和C2-6氟烯基。每个取代基能被任何其它取代基取代。
R1、R2、R3和R4上的取代基独立地选自由羟基(-OH)、酰基(R′C(C=O)-)、酰氧基(R′C(O=)O-)、硝基(-NO2)、氨基(-NH2)、酰氨基(-CONH2)、-SO3-H、-SH、-SR′(R′独立地选自上述的与R1相同的群体)、羧基(-COOH)、C1-6酯、C1-6醛、氰基(CN-)、C1-6烷基氨基、C1-6二烷基氨基、硫醇、氯、溴、氟、碘、C5-7环烷基、C5-7环烯基、C5-7环炔基、C5-11芳基、C5-11芳基C1-6烷基和C5-20杂环基组成的群体。每个取代基能被任何其它的取代基取代。
R1和R2适当地独立地选自由H、C1-10烷基、C2-10烯基、C2-10烷氧基C1-10烷基、C1-10烷氧基C6-10芳基、C2-10炔基、C3-20环烷基、C3-20环烯基、C4-20环炔基和C5-10杂环基组成的群体。
R1和R2适当地选自天然的或合成的氨基酸的侧链。
R1和/或R2优选是选自由甘氨酸、丙氨酸、缬氨酸、白氨酸、异白氨酸、苯基丙氨酸、酪胺酸、色氨酸、丝氨酸、苏氨酸、赖氨酸、精氨酸、组氨酸、天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、半胱氨酸和蛋氨酸组成的群体的天然氨基酸的侧链。明确地说,R1和/或R2优选选自由H、CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH(CH3)(CH2CH3)、-CH2Ph、-CH2Ph-OH、-CH2SH、-CH2CH2SCH3、-CH2OH、-CH(CH3)(OH)、-CH2CH2CH2CH2NH3 +、 -CH2CH2CH2NHC(=NH2 +)NH2、-CH2C(O)O-、-CH2CH2C(O)O-、-CH2C(O)NH2、-CH2CH2C(O)NH2组成的群体,
而且其中R1和R4能一起形成有下列结构的5-元杂环。
R3和R4适当地独立地选自由H、C1-1O烷基、C2-10烯基、C1-10烷氧基、C1-10烷氧基、C1-10烷氧基C1-10烷基、C1-10烷氧基C6-10芳基、C2-10炔基、C3-20环烷基、C3-20环烯基、C4-20环炔基和C5-20杂环基。
R3适当地选自由H、C1-18烷基、C3-20环烷基和苯甲基组成的群体。
R4适当地选自由H、C1-18烷基、C3-20环烷基和C5-20杂环基组成的群体。R4特别适宜选自由H、甲基、乙基、丙基、丁基、戊基、己基和环己基组成的群体。
在优选的实施方案中,R1和R2是甲基或链接成闭合的5-元杂环或碳环,举例来说,出现在脯氨酸中。
如同在此使用的那样,术语“烷基”指的是直链或支链的饱和的单价环形或非环形的烃基,该烃基有指出的碳原子数(或在 未指出的情况下,非环形的烷基优选有1-20个,更优选有1-6个,更优选有1-4个碳原子而环形的烷基优选有3-20个,优选有3-10个,更优选有3-7个碳原子),非必选地被一个、两个、三个或多个独立地选自前面关于可能出现在R1、R2、R3和R4上的取代基陈述的群体的取代基取代。作为非限制性实施例,适当的烷基基团包括甲基、乙基、丙基、丁基、戊基、己基、辛基、壬基和十二烷基。
如同在此使用的那样,术语“烯基”指的是直链或支链的不饱和的单价非环形或环形的烃基基团,该烃基基团有一个或多个C=C双键而且有指出的碳原子数(或在不指出碳原子数的情况下,非环形的烯基优选有2-20个,更优选2-6个,更优选2-4个碳原子而环形的烯基优选有4-20个,更优选4-6个碳原子),而且非必选地被一个、两个、三个或多个独立地选自前面就可能出现在R1、R2、R3和R4上的取代基陈述的群体的取代基取代。作为非限制性实施例,适当的烯基基团包括乙烯基、丙烯基、丁烯基、戊烯基和己烯基。
如同在此使用的那样,术语“炔基”指的是直链或支链的不饱和的单价非环形或环形的烃基基团,该烃基基团有一个或多个C≡C三键而且有指出的碳原子数(或在未指出碳原子数的情况下,非环形的炔基基团优选有2-20个,更优选2-6个,更优选2-4个碳原子而环形炔基基团优选有7-20个,更优选8-20个碳原子),而且非必选地被一个、两个、三个或多个独立地选自前面就可能出现在R1、R2、R3和R4上的取代基陈述的群体的取代基取代。
如同在此使用的那样,术语“烷氧基”或术语“氧代烷基”指的是烷基-O-,其中烷基与前面一样定义而且烷基部分可能被一个、两个、三个或多个前面针对烷基陈述的取代基取代。作为 非限制性实施例,适当的烷氧基基团包括甲氧基、乙氧基、n-丙氧基、异丙氧基、n-丁氧基、叔丁氧基、仲丁氧基、n-戊氧基、n-己氧基和1,2-二甲基丁氧基。术语“氧代环烷基”指的是环烷基-O-,其中环烷基有与前面一样的定义而且环烷基部分可能非必选地被一个、两个三个或多个前面针对烷基陈述的取代基取代。
如同在此使用的那样,术语“芳氧基”指的是基团芳基-O-,其中芳基有与前面一样的定义而且芳基部分可能非必选地被一个、两个、三个或多个前面关于基团Ar陈述的取代基取代。
如同在此使用的那样,术语“烷氧基烷基”指的是有烷氧基取代基的烷基基团。键联是通过烷基基团。烷基部分和烷氧基部分在此分别有与关于烷基和烷氧基的定义一样的定义。烷氧基部分和烷基部分两者都可能被一个、两个、三个或多个前面就烷基定义陈述的取代基取代。
如同在此使用的那样,术语“烷氧基芳基”指的是有烷氧基取代基的芳基基团。键联是通过芳基基团。烷氧基部分和芳基部分在此分别有与关于烷氧基和芳基的定义一样的定义。烷氧基部分和芳基部分两者可能分别被一个、两个、三个或多个在此就烷氧基和芳基的定义定义的取代基取代。
如同在此使用的那样,术语“环烷基芳基”指的是有环烷基取代基的芳基基团。键联是通过芳基基团。环烷基部分和芳基部分在此分别与关于环烷基和芳基的定义一样地定义。环烷基部分和芳基部分可能非必选地分别被一个、两个、三个或多个在此关于烷基和芳基的定义陈述的取代基取代。
除了以别的方式陈述关于“Ar”的定义的情况,在此使用的术语“芳基”指的是单价的不饱和的芳香族碳环基,该碳环基有一个、两个、三个、四个、五个或六个环,优选有一个、两个或三个环,所述的环可能是融合的或双环。芳基基团可能非必选地被一个、两个、三个或多个前面关于可能出现在基团Ar上的非必选的取代基陈述的取代基取代。优选的芳基基团是:包含6个碳原子的芳香族单环;包含7、8、9或10个碳原子的芳香族双环或融合环***;或包含10、11、12、13或14个碳原子的芳香族三环***。芳基的非限制性实施例包括苯基和萘基。优选的取代基基团独立地选自羟基(-OH)、酰基(R′-C(=O)-)、酰氧基(R′-C(O)-O-)、硝基(-NO2)、氨基(-NH2)、-SO3H、-SH、-SR′,其中R′独立地选自与R1一样的群体;羧基(-COOH)、氰基(-CN)、C1-6烷基氨基、C1-6二烷基氨基、硫醇、氯、溴、氟和碘。
如同在此使用的那样,术语“杂环基”指的是饱和的或部份不饱和的杂环***,该杂环***有一个、两个、三个、四个、五个或六个环,优选有一个、两个或三个可能被融合或呈双环的环,而且有包含在一个或多个环内的至少一个选自N、O和S的成员。用在杂环基前面的前缀“C5-20”或“C5-10”分别地意味着五到二十个成员的或五到十个成员的环***,至少这些成员之一选自由N、O和S组成的群体。优选的杂环基***是:有五个成员其中至少一个成员是N、O或S原子并且非必选地包含一个附加的O原子或一个、两个或三个附加的N原子的单环***;有六个成员其中一个、两个或三个成员是N原子的单环;有九个成员其中至少一个成员是N、O或S原子并且非必选地包含一个、两个或三个附加的N原子的双环***;或有十个成员其中一个、两个或三个成员是N原子的双环***。实施例包括但不限于:吡咯啉基、吡咯烷基,1,3-二氧戊环基(dioxolanyl),咪唑啉基、咪唑烷基、吡唑啉基、吡唑烷基、哌啶基、吗啉基或哌嗪基。
上述“杂环基”环***可得的碳原子和/或杂原子可能在环上被一个或多个杂原子取代。在环被一个或多个杂原子取代的情况下,杂原子取代基选自氧、氮、硫和卤素(F、Cl、Br和I)。在环被一个或多个杂原子取代的情况下,优选有1、2、3或4个选自由氧、氮和/或卤素组成的群体的杂原子取代基。优选的取代基基团独立地选自羟基、酰基、酰氧基、硝基、氨基、SO3H、SH、SR′(其中R′独立地选自与R一样的群体)、羧基、氰基、C1-6烷基氨基、C1-6二烷基氨基、硫醇、氯、溴、氟和碘。
本发明的方法优选在有适当的溶剂存在的情况下完成。
适当的溶剂包括诸如苯和甲苯之类的烃类溶剂;诸如二乙基醚、四氢呋喃、二苯基醚、苯甲醚和二甲氧基苯之类的醚类溶剂;诸如二氯甲烷、氯仿和氯苯之类的卤代烃溶剂;诸如丙酮、甲乙酮和甲基异丁酮之类的酮类溶剂;诸如甲醇、乙醇、丙醇、异丙醇、n-丁醇和叔丁醇之类的醇类溶剂;诸如乙腈、丙腈和苄腈之类的腈类溶剂;诸如醋酸乙酯和醋酸丁酯之类的酯类溶剂;诸如碳酸乙二酯和和碳酸丙二酯之类的碳酸酯型溶剂;等等。这些可能被单独使用或其中的两种或多种可能被混合使用。
优选将惰性溶剂用于本发明的方法。术语“惰性溶剂”意味着在与之结合描述的反应条件下惰性的溶剂,包括,举例来说,苯、甲苯、乙腈、四氢呋喃、二甲基甲酰胺、氯仿、次甲基氯化物(或二氯甲烷)、二乙基醚、醋酸乙酯、丙酮、甲乙酮、甲醇、乙醇、丙醇、异丙醇、叔丁醇、二氧杂环乙烷、嘧啶,等等。四氢呋喃是特别优选的。
优选,本发明的方法在基本上干燥的条件下完成。
如同在此使用的那样,术语“立体异构体”定义由相同的原子按相同的键序结合构成的但是有本发明的化合物可能拥有的不可互换的不同的三维结构的所有可能的化合物。
在依照这项发明的化合物有至少一个手性中心的情况下,它们可能因此作为对映异构体存在。在化合物拥有两个或多个手性中心的情况下,它们可能又作为非对映异构体存在。在依照本发明制备化合物的方法引起立体异构体混合的场合,这些异构体可以借助传统技术(例如,制备色谱)分离。这些化合物可能是以立体化学混合形式制备的,或者个别的对映异构体可能是借助熟悉这项技术的人已知的标准技术制备的,举例来说,借助对映结构专用的合成或分辨,先借助在有光学活性的酸的情况下形成盐形成非对映异构体对,而后借助游离碱的分离结晶和再生。化合物也可能是通过先形成非对映异构体的酯或酰胺,然后借助色析法分离和除去手性助剂分辨的。作为替代,化合物可能是使用手性HPLC柱分辨的。熟悉这项技术的人将理解所有这样的异构体及其混合物都被囊括在本发明的范围内。
此外,人们应该领会到磷酸盐中心在本发明的化合物中是手性的而且那些化合物可能作为RP和SP非对映异构体存在。化合物的组合物可能是混合的RP和SP或是一种纯粹的非对映异构体。优选,该化合物是实质上纯粹单一的异构体。
可能有RP非对映异构体与SP非对映异构体呈1∶1的混合物。作为替代,可能有RP非对映异构体与SP非对映异构体之比为1∶2、1∶3、1∶4、1∶5、1∶6、1∶7、1∶8、1∶9、1∶10、1∶15、1∶20、1∶50或1∶100的,反之亦然。
术语“溶剂化物”意味着在此定义的化合物,或结构(I)或(II)的化合物的药学可接受的盐,其中适当的溶剂分子被合并在晶格 之中。适当的溶剂是在给药的剂量下生理上可容忍的。适当的溶剂实施例是乙醇、水,等等。当水是溶剂的时候,该分子被称为水合物。
本发明的化合物也可能是以药学可接受的盐的形式出现的。作为药物使用,这项发明的化合物的盐指的是无毒的“药学可接受的盐”。食品药品管理局核准的药学可接受的盐的形式(参阅下列杂志:International J.Pharm.1986,33,201-217;J.Pharm.Sci.,1977,Jan,66(1))包括药学可接受的酸性的/阴离子的盐或碱性的/阳离子的盐。
药学可接受的酸性的/阴离子的盐包括但不限于醋酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙二胺四乙酸钙、右旋樟脑磺酸、碳酸盐、氯化物、柠檬酸盐、二氢氯化物、乙二胺四乙酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐、乙磺酸盐、反丁烯二酸盐、glyceptate、葡糖酸盐、谷氨酸盐、乙醇酰阿散酸盐、己基间苯二酚(hexylresorcinate)、哈胺(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、羟乙磺酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、硝酸甲酯、硫酸甲酯、粘酸盐、萘磺酸盐、硝酸盐、羟嗪、泛酸盐、磷酸盐、二磷酸盐(diphospate)、聚半乳糖醛酸盐(polygalacturonate)、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、单宁酸盐、酒石酸盐、8-氯茶碱盐、甲苯磺酸盐和三乙碘盐(triethiodide)。
药学可接受的碱性/阳离子盐包括但不限于铝、N,N′-双苄基乙撑二胺、钙、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、锂、镁、钾、普鲁卡因、钠和锌。
本发明将这项发明的化合物的药物前体包括在它的范围内。一般地说,这样的药物前体将是容易在活体内转化成所需化合物 的化合物功能衍生物。因此,在本发明的治疗方法中,术语“给药”将囊括与明确地揭示的化合物或可能未被明确地揭示但在对受治疗者给药之后在活体内转化成指定化合物的化合物一起描述的各种不同的紊乱的治疗。用来选择和制备适当的药物前体衍生物的传统方法是在,举例来说,H.Bundgaard,Elsevier于1985年编辑的“Design of Prodrugs(药物前体设计)”中描述的。
具体地说,其中一个或多个游离羟基基团以药学可接受的酯类形式酯化的药学可接受的酯类衍生物是可以在生理条件下借助溶剂分解作用转化成本发明的有游离羟基基团的化合物的酯类药物前体。
依照本发明使用的药学组合物可以以传统的方式被制定使用一种或多种生理学可接受的载体(包括促使活性化合物的处理变成药学上可用的制备的赋形剂和助剂)配制。这些药学组合物可能是以已知的方式制造的,例如,借助传统的混合方法、溶解方法、造粒方法、包裹糖衣方法、研细方法、乳化方法、装入胶囊方法、截留方法或冻干方法。适当的配方取决于选定的给药路径。
化学式I的化合物或依照本发明的药学组合物能用任何适当的方法对现代人或动物患者给药。
本发明中所用的药物能通过口服或非肠道路径给药,包括静脉给药、肌肉给药、腹膜内给药、皮下给药、穿过表皮给药、喷雾给药(气溶胶)、直肠给药、***给药和局部给药(包括口腔和舌下给药)。
对于口服给药,本发明的化合物通常将作为粉末或颗粒或作为水溶液或悬浮液以药片或胶囊的形式提供。
供口服用的药片可能包括与药学可接受的赋形剂(例如,惰性稀释剂)、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂混合的活性组分。适当的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙和乳糖,而玉米淀粉和褐藻酸是适当的崩解剂。粘合剂可能包括淀粉和凝胶,而润滑剂,如果有,通常将是硬脂酸镁、硬脂酸或滑石。如果需要,药片可能涂上一层诸如一硬脂酸甘油酯或二硬脂酸甘油酯之类的物质,以延迟胃肠道吸收。
供口服用的胶囊包括活性成分与固体稀释剂混合的硬凝胶胶囊活性成分与水或诸如花生油、液体石蜡或橄榄油之类的油混合的软凝胶胶囊。
用于直肠给药的配方可能是作为有适当的碱(包含,举例来说,可可油或水杨酸盐)的栓剂出现的。
适合***给药的配方可能是作为除了活性成分之外包含技术上已知作为适当载体的那些载体的***栓剂、棉球、凝脂、胶体、糊状物、泡沫或水雾配方。
为了供肌肉注射、腹膜内注射、皮下注射和静脉注射使用,本发明的化合物通常将以缓冲到适当的pH值和等渗压性的灭菌消毒的水溶液或悬浮液提供。适当的水质传送媒介包括林格溶液和等渗压氯化钠。依照本发明的水悬浮液可能包括诸如纤维素衍生物、藻酸钠、聚乙烯吡咯烷酮和黄蓍树胶之类的悬浮剂和诸如卵磷脂之类的润湿剂。适合水悬浮液的防腐剂包括p-羟基苯甲酸乙酯和p-羟基苯甲酸丙酯。
本发明的化合物也可能是作为脂质体配方呈现的。
一般地说。适当的剂量将在接受者每公斤体重每天0.1到300毫克的范围内。优选的低剂量是接受者每公斤体重每天0.5毫克,更优选的低剂量是接受者每公斤体重每天1毫克。适当的剂量优选在每公斤体重每天1到50毫克的范围内,更优选在每公斤体重每天1到10毫克的范围内。所需要的剂量优选作为在一整天当中按适当的时间间隔给药的两个、三个、四个、五个、六个或更多个子剂量呈现的。这些子剂量可能是以单位剂量形式给药的,举例来说,每单位剂量形式包含10到1500毫克,优选20到1000毫克,最优选50到700毫克的活性成分。
实施例
现在将仅仅通过下列的实施例描述本发明的实施方案。
目标化合物是通过使适当的核苷或它的改性前体与必需的氯磷酸反应制备的。后者反应物是用公开的方法利用二氯磷酸芳基酯与氨基酸酯盐酸盐制备的。一些实施例被给出。
标准方法C2:2,3-环次戊基(cyclopentylidyn)改性的核苷氨基磷酸酯的制备
tBuMgCl(2.0摩尔等价物)和2′,3′-亚环戊基-4′-叠氮基-胞啶(1.0摩尔等价物)被溶解在干燥的四氢呋喃(THF)(31摩尔等价物)中并且搅拌15分钟。然后,将适当的氯磷酸酯的1M溶液(2.0摩尔等价物)滴加到干燥的THF中,然后搅拌过夜。添加NH4Cl饱和溶液,而且在减压条件下除去溶剂,得到因此被提纯的黄色固体。
标准方法C3:改性核苷的氨基磷酸酯的制备
2′,3′-亚环戊基改性的核苷氨基磷酸酯被溶解在80%的甲酸水溶液中达4小时。然后,在减压条件下除去溶剂,得到因此提纯的白色固体。
标准方法C4:改性核苷的氨基磷酸酯的制备
2′,3′-异亚丙基(isopropilidene)改性的核苷氨基磷酸酯被溶解60%的醋酸水溶液中在90℃下过夜。然后,在减压条件下除去溶剂,得到因此被提纯的白色固体。
实施例1
β-2′-甲基腺苷(CHCl)的合成
N6-叔丁酰基-β-2′-甲基-2′,3′,5′-三苯甲酰-腺苷(400毫克,0.590毫摩尔)被加到用氨饱和的MeOH溶液中并且在室温下搅拌。12小时之后除去溶剂,然后用梯度柱色谱提纯获得的固体,从9∶1的CHCl3/MeOH混合物开始然后8∶2。纯产品是作为白色固体(120毫克,0.427毫摩尔,72%)获得的。δH(d6-DMSO):8.47(1H,s,H8-腺苷),8.15(1H,s,H2-腺苷),7.30(1H,s,NH26-腺苷),5.95(1H,s,Hl′-腺苷),5.25-5.21(3H,m,OH5′-腺苷,OH3′-腺苷,OH2′-腺苷),4.12-4.05(1H,d,H3′-腺苷,J=8.6赫兹),3.91(1H,m,H4′-腺苷),3.84(1H,m,H5′-腺苷),3.70(1H,m,H5′-腺苷),0.77(3H,s,CH32′-腺苷);δC(d6-DMSO):156.02(1C,C6-腺苷), 152.53(1C,C2-腺苷),149.01(1C,C4-腺苷),138.68(1C,C8-腺苷),118.67(1C,C5-腺苷),90.78(1C,Cl′-腺苷),82.52(1C,C4′-腺苷),78.46(1C,C2′-腺苷),71.63(1C,C3′-腺苷),59.47(1C,C5′-腺苷),19.83(1C,CH3-2′-腺苷)。对C11H15N5O4的分析计算:C46.97%,H5.38%,N24.90%。发现:C46.67%,H5.22%,N24.20%。
实施例2
合成2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2’-甲基-腺苷5′-O-[α-萘基(乙氧基-L-丙氨酸基(alaninyl))]磷酸盐
依照标准方法C2从2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷(60毫克,0.172毫摩尔),tBuMgCl(0.5毫升,1M的THF溶液,0.519毫摩尔)和α-萘基(乙氧基-L-丙氨酸基)氯磷酸酯(1M的THF溶液0.5毫升,0.519毫摩尔)制备。原材料借助柱色谱使用CHCl3/MeOH(95:5)作为洗脱液提纯。获得的纯产品是白色固体(30毫克,0.046毫摩尔,26%)。
δP(d4-CH3OH):4.31,4.26;δH(d4-CH3OH):8.19(1H,s,H2-腺苷),8.10(1H,s,H8-腺苷),7.88(1H,m,CH-萘基),7.73(1H,m,CH-萘基),7.57-7.52(4H,m,CH-萘基),7.45-7.43(1H,m,CH-萘基),6.26(1H,m,H1′-腺苷),4.56-4.42(4H,m,H4′-腺苷, H3′-腺苷,2H5′-腺苷),4.08(3H,m,CHα,CH2-乙基),2.21-2.09(2H,m,CH2-环戊基),1.76-1.71(6H,m,3CH2-环戊基),1.35(3H,d,CH3-丙氨酸,J=6.9赫兹),1.25(3H,m,CH3-乙基),0.95(3H,s,CH32′-腺苷)。
合成β-2′-甲基-腺苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐(CHC2)
依照标准方法C3从2’,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐(30毫克,0.036毫摩尔)和10毫升80%的HCOOH水溶液开始制备。原材料是先借助柱色谱使用CHCl3/MeOH(95:5)作为洗提液提纯,然后借助半制备型HPLC提纯。那获得的纯净产品是白色固体(4毫克,0.007毫摩尔,19%)。δP(d4-CH3OH):4.23,4.20;δH(d4-CH3OH):8.24-8.19(3H,m,H2-腺苷,H8-腺苷,CH-萘基),7.90(1H,m,CH-萘基),7.63(1H,CH-萘基),7.53(4H,m,CH-萘基),7.41(1H,m,CH-萘基),6.12(1H,d,Hl′-腺苷,J=2.1赫兹),4.61-4.59(2H,d,H3′-腺苷,H4′-腺苷),4.30(1H,m,H5′-腺苷),4.02-3.99(3H,m,CHα,CH2-乙基),1.37(3H,m,CH3-丙氨酸),1.27(3H,m,CH3-乙基),0.95(3H,s,CH3-2′-腺苷)。
MS(ES)m/e:609.2;(MNa+,100%);精确质量:C26H31N6O8NaP必需的609.1846,发现的609.1839。
实施例3
合成2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷(40毫克,0.115毫摩尔),tBuMgCl(0.35毫升,1M的THF溶液,30.345毫摩尔)和α-萘基(苯甲酸基-L-丙氨酸基)氯磷酸酯(0.35毫升,1M的THF溶液,0.345毫摩尔)制备。原材料借助柱色谱使用CHCl3/MeOH(95:5)作为洗提液被提纯。获得的纯净产品是白色固体(20毫克,0.028毫摩尔,24%)。
δP(d4-CH3OH):4.34,4.18;δH(d4-CH3OH):8.50(1H,s,H2-腺苷),8.17(1H,s,H8-腺苷),7.90(1H,m,CH-萘基),7.71(1H,m,CH-萘基),7.69(1H,CH-苯甲基),7.55-7.50(3H,m,CH- 萘基,2CH-苯甲基),7.42-7.27(6H,m,4CH-萘基,2CH-苯甲基),6.25(1H,d,Hl′-腺苷),5.10(2H,s,CH2-苯甲基),4.61(1H,m,H3′-腺苷),4.41(1H,m,H4′-腺苷),4.15(1H,m,CHα),3.95(1H,m,H5′-腺苷,J=12.2赫兹),3.85(1H,m,H5′-腺苷,J=12.2赫兹),2.12-2.03(2H,m,CH2-环戊基),1.79-1.72(6H,m,3CH2-环戊基),1.37(3H,d,CH3-丙氨酸,J=7.2赫兹),0.89(3H,s,CH3-2′-腺苷)。
合成β-2′-甲基-腺苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐(,CHC3)
依照标准方法C3从2′,′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐(30毫克,0.036毫摩尔)和10毫升80%的HCOOH水溶液制备。原材料助柱色谱先使用CHCl3/MeOH(95:5)作为洗提液提纯,然后借助半制备型HPLC提纯。获得的纯净产品是白色固体(5毫克,0.008毫摩尔,21%)。
δP(d4-CH3OH):4.25,4.14;δH(d4-CH3OH):8.04-7.95(3H,m,H2-腺苷,H8-腺苷,CH-萘基),7.68(1H,m,CH-萘基),7.48(1H, m,CH-萘基),7.32-7.23(3H,m,CH-萘基,2CH-苯甲基),7.16(1H,m,CH-萘基),7.05(6H,m,3CH-萘基,3CH-苯甲基),5.88(1H,d,H1′-腺苷,J=2.9赫兹),4.85-4.65(2H,m,CH2-苯甲基),4.37-4.35(2H,d,H3′-腺苷,H4′-腺苷),4.06(2H,m,H5′-腺苷),3.88-3.83(1H,m,CHα),1.35(3H,m,CH3-丙氨酸),0.88(3H,s,CH3-2′-腺苷)。
MS(ES)m/e:671.2(MNa+,100%);精确质量:C31H33N6O8NaP所需的671.1990,发现的671.1995。
实施例4
合成2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷(60毫克,0.172毫摩尔),tBuMgCl(0.51毫升,1M的THF溶液,0.51毫摩尔)和α-萘基(叔丁氧基-L-丙氨酸基)氯磷酸酯(1M的THF溶液0.5毫升,0.519毫摩尔)。原材料是借助柱色谱 使用CHCl3/MeOH(95:5)作为洗提液提纯的。获得的纯净产品是白色固体(27毫克,0.039毫摩尔,22%)。
δP(d4-CH3OH):4.37,4.28;δH(d4-CH3OH):8.21(1H,s,H2-腺苷),8.13(1H,s,H8-腺苷),7.85(IH5m,CH-萘基),7.73(1H,m,CH-萘基),7.57-7.52(4H,m,CH-萘基),7.43-7.41(1H,m,CH-萘基),6.25(1H,m,Hl′-腺苷),4.55-4.40(4H,m,H4′-腺苷,H3′-腺苷,2H5′-腺苷),4.05(1H,m,CHα),2.20-2.12(2H,m,CH2-环戊基),1.79-1.69(6H,m,3CH2-环戊基),1.36(9H,3CH3-叔丁基),1.25(3H,d,CH3-丙氨酸,J=6.9赫兹),0.96(3H,S,CH3-2′-腺苷)。
合成β-2′-甲基-腺苷5′-0-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐(CHC4)
依照标准方法C3从2′,3′-O,O-环次戊基(cyclopentylidyn)-β-2′-甲基-腺苷-5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐(27毫克,0.039毫摩尔)和10毫升80%的HCOOH水溶液制备。原材料先借助柱色谱使用第一CHCl3/Me0H(95:5)作为洗提液提纯,而后借助半-制备HPLC提纯。获得的纯净产品是白色固体(10毫克,0.016毫摩尔,41%)。
δP(d4-CH3OH):4.20,4.08;δH(d4-CH3OH):8.20-8.15(3H,m,H2-腺苷,H8-腺苷,CH-萘基),7.81(1H,m,CH-萘基),7.60(1H,CH-萘基),7.54(4H,m,CH-萘基),7.39(1H,m,CH-萘基),6.15(1H,d,Hl′-腺苷),4.63-4.57(2H,d,H3′-腺苷,H4′-腺苷),4.31(1H,m,H5′-腺苷),4.00-3.97(1H,m,CHa),1.39(9H,3CH3-叔丁基),1.27(3H,m,CH3-丙氨酸),0.97(3H,s,CH3-2′-腺苷)。
实施例5
合成β-2’-甲基-鸟苷(CHC5)
N2-乙酰基-β-2′-甲基-2′,3′,5′-三苯甲酰-鸟苷(1.42g,2.18毫摩尔)被加到以氨饱和的MeOH溶液中并且在室温下搅拌。12小时之后除去溶剂,所得固体是借助柱色谱使用8:2的CHCl3/MeOH混合物作为洗提液提纯的。纯净的产品是作为白色固体获得的(565毫克,1.90毫摩尔,87%)。
δH(d6-DMSO):10.52(1H,s,NHl-鸟苷),8.48(1H,s,H8-鸟苷),6.52(2H,s,NH22-鸟苷),5.73(1H,s,H1′-鸟苷),5.24(1H,d,OH3′-鸟苷,J=6.3赫兹),5.11(1H,m,OH5′-鸟苷),5.03(1H,s,OH2′-鸟苷),3.97(1H,m,H3′-鸟苷),3.85-3.79(2H,m,H4′,H5′-鸟苷),3.66(1H,d,H5′-鸟苷,J=12.2赫兹),0.81(3H,s,CH3-2′-鸟苷);δC(d6-DMSO):156.72(1C,C6-鸟苷),153.68(1C, C2-鸟苷),150.77(1C,C4-鸟苷),135.07(1C,C8-鸟苷),116.38(1C,C5-鸟苷),90.10(1C,Cl′-鸟苷),82.30(1C,C3′-鸟苷),78.52(1C,C2’-鸟苷),71.63(1C,C4′-鸟苷),59.40(1C,C5′-鸟苷),19.96(1C,CH3-2′-鸟苷)。
MS(ES)m/e:320.2(MNa+,100%);精确质量:C11H15N5O5Na所需的320.0968,发现的320.0971。
实施例6
合成2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷(170毫克,0.503毫摩尔),tBuMgCl(1.0毫升1M的THF溶液,1.006毫摩尔)和α-萘基(苯甲酸基-L-丙氨酸基)氯磷酸酯(1.0毫升1M的THF溶液,1.006毫摩尔)。原材料是借助柱色谱使用CHCl3/MeOH(95:5)作为洗提液提纯的。所获得的纯净产品是白色固体(70毫克,0.098毫摩尔,19%)。
δP(d4-CH3OH):4.53,4.40;δH(d4-CH3OH):8.28(1H,s,H8-鸟苷),7.84(1H,m,CH-萘基),7.77-7.71(1H,m,CH-苯甲基),7.55-7.49(4H,m,2CH-萘基,2CH-苯甲基),7.44-7.29(6H,m,4CH-萘基,2CH-苯甲基),6.06(1H,d,H1′-鸟苷),5.10(2H,s,CH2-苯甲基),4.59(1H,m,H3′-鸟苷),4.52-4.45(1H,m,H4′-鸟苷),4.34(2H,H5′鸟苷),4.14(1H,m,CHα),1.59(3H,d,CH3-异亚丙基,J=10.4赫兹),1.37(6H,d,CH3-丙氨酸,CH3-异亚丙基),0.99(3H,d,CH3-2′-鸟苷,J=20.11赫兹)。
合成β-2′-甲基-鸟苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐(CHC6)
依照标准方法C4从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐(70毫克,0.098毫摩尔)和10毫升60%的CH3COOH水溶液在90℃制备15小时。原材料先借助柱色谱使用CHC13/MeOH(85:5)作为洗提液提纯,而后借助半-制备HPLC提纯。获得的纯净产品是白色固体(12毫克,0.018毫摩尔,18%)。
δP(d4-CH3OH):4.25,4.14;δH(d4-CH3OH):8.17(1H,m,H8-鸟苷),7.88(1H,m,CH-萘基),7.79(1H,m,CH-萘基),7.53(2H, m,CH-萘基,CH-苯甲基),7.42-7.40(1H,m,CH-萘基),7.36-7.21(7H,m,3CH-萘基,4CH-苯甲基),6.05(1H,d,Hl′-鸟苷,J=8.4赫兹),5.15-4.90(2H,m,CH2-苯甲基),4.58-4.49(2H,d,H3′-鸟苷,H4′-鸟苷),4.44-4.34(2H,m,H5′-鸟苷),4.17-4.11(1H,m,CHα),1.37(3H,m,CH3-丙氨酸),1.00(3H,s,CH3-2′-鸟苷)。
MS(ES)m/e:687.2(MNa+,100%);精确质量:C31H33N6O9NaP必需的687.1954,发现的687.1944.
实施例7
合成2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷(220毫克,0.652毫摩尔),tBuMgCl(1.3毫升1M的THF溶液,1.30毫摩尔)和α-萘基(乙氧基-L-丙氨酸基)氯磷酸酯(1.3毫升1M的THF溶液,1.30毫摩尔)开始制备。原材料借助柱色谱以CHCl3/MeOH(95:5)为洗提液提纯。获得的纯净产品是白色固体(35毫克,0.054毫摩尔,9%)。
δP(d4-CH3OH):4.41,4.32;δH(d4-CH3OH):8.18(1H,s,H8-鸟苷),7.88(1H,m,CH-萘基),7.73(1H,m,CH-萘基),7.59-7.52(4H,m,4CH-萘基),7.46-7.42(1H,m,CH-萘基),6.08(1H,d,Hl′-鸟苷),4.62-4.40(4H,m,H3′-鸟苷,H4′-鸟苷,H5′鸟苷),4.11-4.09(3H,m,CHα,CH2-乙基),1.59(3H,d,CH3-异亚丙基,J=13.2赫兹),1.37(6H,m,CH3-丙氨酸,CH3-异亚丙基),1.20(3H,m,CH3-乙基),1.00(3H,m,CH3-2′-鸟苷)。
合成β-2’-甲基-鸟苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐(CHC7)
依照标准方法C4从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐(35毫克,0.054毫摩尔)和10毫升60%的CH3COOH水溶液在90℃下制备15小时。原材料借助柱色谱以CHCl3/MeOH(85:5)为洗提液提纯,而后借助半-制备HPLC提纯。获得的纯净产品是白色固体(10毫克,0.018毫摩尔,31%)。
δP(d4-CH3OH):4.25,4.14;δH(d4-CH3OH):8.18(1H,m,H8-鸟苷),7.87(1H,m,CH-萘基),7.71(1H,m,CH-萘基),7.53(4H,m,4CH-萘基),7.51-7.40(1H,m,CH-萘基),5.93(1H,d,Hl′-鸟苷),4.62-4.57(2H,m,H3′-鸟苷,H4′-鸟苷),4.24(2H,m, H5′鸟苷),4.03-3.98(3H,m,CHα,CH2-乙基),1.31(3H,d,CH3-丙氨酸,J=7.9赫兹),1.15(3H,m,CH3-乙基),1.00(3H,m,CH3-2′-鸟苷)。
MS(ES)m/e:625.3(MNa+,100%);精确质量:C26H31N6O9NaP必需的625.1795,发现的6251788.
对C26H31N6O9P的分析计算:C51.83%,H5.19%,N13.95%。发现:C51.86%,H5.10%,N12.04%。
实施例8
合成2’,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷(120毫克,0.355毫摩尔),tBuMgCl(0.70毫升1M的THF溶液,0.711毫摩尔)和α-萘基(叔丁氧基-L-丙氨酸基)氯磷酸酯(0.70毫升1M的THF溶液,0.711毫摩尔)制备。原材料借助柱色谱以CHCl3/MeOH(95:5)为洗提液提纯。获得的纯净产品是白色固体(24毫克,0.036毫摩尔,10%)。
δP(d4-CH3OH):4.41,4.32;δH(d4-CH3OH):8.20(1H,s,H8-鸟苷),7.89(1H,m,CH-萘基),7.73(1H,m,CH-萘基),7.59-7.54(4H,m,4CH-萘基),7.49-7.42(1H,m,CH-萘基),6.07(1H,d,H1′-鸟苷),4.62-4.40(4H,m,H3′-鸟苷,H4′-鸟苷,2H5′鸟苷),3.99-3.86(1H,m,CHα),1.58(3H,d,CH3-异亚丙基,J=13.7赫兹),1.44(9H,s,3CH3-叔丁基),1.38-1.34(6H,m,CH3-丙氨酸,CH3-异亚丙基),1.01(3H,m,CH32′-鸟苷)。
合成β-2′-甲基-鸟苷5′-0-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐(CHC8)
依照标准方法C4从2′,3′-O,O-异次丙基(isopropylidyn)-β-2′-甲基-鸟苷5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐(24毫克,0.036毫摩尔)和10毫升60%的CH3COOH水溶液制备。原材料先借助柱色谱使用CHCl3/MeOH(85:5)作为洗提液提纯,而后借助半制备HPLC提纯。获得的纯净产品是白色固体(4毫克,0.018毫摩尔,17%)。
δP(d4-CH3OH):4.23,4.10;δH(d4-CH3OH):8.20(1H,m,H8-鸟苷),7.85(1H,m,CH-萘基),7.67(1H,m,CH-萘基),7.57(4H,m,4CH-萘基),7.53-7.43(1H,m,CH-萘基),6.00(1H,d,Hl′-鸟苷),4.61-4.55(2H,m,H3′-鸟苷,H4′-鸟苷),4.25(2H,m, 2H5′鸟苷),4.00-3.97(1H,m,CHα),1.47(9H,s,3CH3-叔丁基),1.36(3H,m,CH3-丙氨酸),1.00(3H,m,CH32′-鸟苷)。
实施例9
合成2′,3′-0,0-异亚丙基-β-2′-甲基-鸟苷5′-O-[苯基(苯甲酸基-L-氨酸基)]磷酸盐
依照标准方法C2从2’,3′-O,O-异亚丙基-β-2′-甲基-鸟苷(120毫克,0.355毫摩尔),tBuMgCl(1.0毫升1M的THF溶液,51.07毫摩尔)和苯基(苯甲酸基-L-丙氨酸基)氯磷酸酯(1.0毫升1M的THF的溶液,1.07毫摩尔)制备。原材料借助柱色谱以CHCl3/MeOH(9:1)为洗提液提纯,而后借助半-制备HPLC提纯。获得的纯净产品是白色固体(40毫克,0.061毫摩尔,17%)。
δP(d4-CH3OH):4.63,4.37;δH(d4-CH3OH):7.85(1H,d,H8-鸟苷,J=5.7赫兹),7.36-7.34(5H,m,2CH-苯基,3CH-苯甲基),7.33-7.26(5H,m,2CH-苯甲基,3CH-苯基),6.02(1H,d,Hl′-鸟苷,J=11.4赫兹),5.16(2H,s,CH2-苯甲基),4.67(1H,d, H3′-鸟苷,J=1.1赫兹),4.54-4.43(1H,m,H4′-鸟苷),4.31(2H,H5′鸟苷),4.10(1H,m,CHα),1.61(3H,s,CH3-异亚丙基),1.53(3H,s,CH3-异亚丙基),1.39(3H,d,CH3-丙氨酸,J=8.4赫兹),1.00(3H,s,CH3-2′-鸟苷)。
合成β-2′-甲基-鸟苷5′-O-[苯基(苯甲酸基-L-丙氨酸基)]磷酸盐(CHC9)
依照标准方法C4从2′,3′-O,O-异亚丙基-β-2′-甲基-鸟苷5′-O-[苯基(苯甲酸基-L-丙氨酸基)]磷酸盐(40毫克,0.061毫摩尔)和10毫升60%的CH3COOH水溶液在90℃下处理15小时。原材料先借助柱色谱以HCl3/MeOH(85:5)为洗提液提纯,而后借助半-制备HPLC提纯。获得的纯净产品是白色固体(15毫克,0.024毫摩尔,40%)。
δP(d4-CH3OH):4.27,4.10;δH(d4-CH3OH):7.92(1H,d,H8-鸟苷,J=8.3赫兹),7.37-7.29(5H,m,2CH-苯基,3CH-苯甲基),7.25-7.18(5H,m,2CH-苯甲基,3CH-苯基),5.96(1H,d,H1′-鸟苷,J=2.3赫兹),5.15(2H,s,CH2-苯甲基),4.43-4.35(2H,m,H3′-鸟苷,H4′-鸟苷),4.33-4.28(1H,m,H5′-鸟苷),4.24-4.19(1H, m,H5′-鸟苷),4.08-3.93(1H,m,CHα),1.35(3H,m,CH3-丙氨酸),1.24(3H,s,CH3-2′-鸟苷)。
实施例10
合成2′,3′-0,0-异亚丙基-β-2′-甲基-鸟苷5′-0-[苯基(甲氧基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-异亚丙基-β-2′-甲基-鸟苷(140毫克,0.415毫摩尔),tBuMgCl(1.04毫升1M的THF溶液,31.04毫摩尔)和苯基(甲氧基-L-丙氨酸基)氯磷酸酯(1.04毫升1M的THF溶液,1.04毫摩尔)。原材料借助柱色谱以CHCl3/MeOH(97∶3)为洗提液提纯。获得的纯净产品是白色固体(21毫克,0.036毫摩尔,9%)。
δP(d4-CH3OH):4.09,3.91;δH(d4-CH3OH):7.88,7.80(1H,d,H8-鸟苷),7.41-7.35(2H,m,CH-苯基),7.30-7.20(3H,m,3CH-苯基),6.14(1H,d,H1′-鸟苷,J=11.8赫兹),4.69(1H,d,H3′-鸟苷,J=2.9赫兹),4.49-4.39(3H,m,H4′-鸟苷,H5′鸟苷),4.04-3.99(1H,m,CHα),3.70(3H,d,CH3-甲基,J=12.7赫兹),1.63(3H,d,CH3-异亚丙基,J=2.3赫兹),1.44(3H,d,CH3-丙 氨酸,J=3.1赫兹),1.41(3H,d,CH3-异亚丙基,J=6.8赫兹),1.10(3H,d,CH3-2′-鸟苷,J=6.5赫兹)。
合成β-2′-甲基-鸟苷5′-0-[苯基(甲氧基-L-丙氨酸基)]磷酸盐(CHC10)
依照标准方法C4从2’,3′-O,O-异亚丙基-β-2′-甲基-鸟苷5′-O-[苯基(甲氧基-L-丙氨酸基)]磷酸盐(21毫克,0.036毫摩尔)和10毫升60%的CH3COOH水溶液在90℃下处理15小时。原材料借助柱色谱以第一CHCl3/MeOH(92∶8)为洗提液提纯。获得的纯净产品是白色固体(7.0毫克,0.013毫摩尔,36%)。
δP(d4-CH3OH):4.15,3.90;δH(d4-CH3OH):8.96(1H,br,H8-鸟苷),7.40-7.35(2H,m,CH-苯基),7.29-7.20(3H,m,3CH-苯基),6.08(1H,d,H1′-鸟苷,J=8.5赫兹),4.55-4.49(2H,m,H3′-鸟苷,H4′-鸟苷),4.26(1H,m,H5′鸟苷),4.17-4.11(1H,m,H5′-鸟苷),4.00-3.97(1H,m,CHα),3.73(3H,d,CH3-甲基,J=11.1赫兹),1.36(3H,d,CH3-丙氨酸,J=7.1赫兹),1.41(3H,d,CH3-异亚丙基,J=6.8赫兹),1.14(3H,d,CH3-2′-鸟苷,J=4.9赫兹)。
实施例11
合成2′,3′-0,0-异亚丙基-β-2′-甲基-鸟苷5′-0-[萘基(甲氧基-L-丙氨酸基)]磷酸盐
依照标准方法C2从2′,3′-O,O-异亚丙基-β-2′-甲基-鸟苷(130毫克,0.385毫摩尔),tBuMgCl(0.96毫升1M的THF溶液,0.96毫摩尔)和α-萘基(甲氧基-L-丙氨酸基)氯磷酸酯(0.96毫升1M的THF溶液,0.96毫摩尔)制备。原材料借助柱色谱以CHCl3/MeOH(97∶3)为洗提液提纯。获得的纯净产品是白色固体(26毫克,0.041毫摩尔,11%)。
δP(d4-CH3OH):4.51,4.45;δH(d4-CH3OH):8.21(1H,d,H8-鸟苷,J=7.5赫兹),7.91-7.89(1H,m,CH-萘基),7.73(1H,m,CH-萘基),7.58-7.53(4H,m,4CH-萘基),7.48-7.45(1H,m,CH-萘基),6.09(1H,d,H1′-鸟苷,J=7.4赫兹),4.63(1H,d,H3′-鸟苷,J=3.0赫兹),4.57-4.53(2H,m,H4′-鸟苷),4.43-4.41(2H,m,H5′鸟苷),4.12-4.05(1H,m,CHα),3.62(3H,d,CH3-甲基,J=10.1赫兹),1.59(3H,d,CH3-异亚丙基,J=7.9赫兹),1.40(3H,d,CH3-丙氨酸,J=3.4赫兹),1.35(3H,d,CH3-异亚丙基,J=7.2赫兹),1.05(3H,d,CH3-2′-鸟苷,J=7.0赫兹)。
合成β-2′-甲基-鸟苷5′-O-[α-萘基(甲氧基-L-丙氨酸基)]磷酸盐(CHC11)。
依照标准方法C4从2′,3′-O,O-异亚丙基-β-2′-甲基-鸟苷5′-O-[α-萘基(甲氧基-L-丙氨酸基)]磷酸盐(26毫克,0.041毫摩尔)和10毫升60%的CH3COOH水溶液在90℃下处理15小时。原材料借助柱色谱以第一CHCl3/MeOH(92∶8)为洗提液提纯。获得的纯净产品是白色固体(4.1毫克,0.007毫摩尔,17%)。
δP(d4-CH3OH):4.35,4.26;δH(d4-CH3OH):8.20(1H,d,H8-鸟苷,J=5.8赫兹),7.91-7.87(2H,m,CH-萘基),7.70(1H,m,CH-萘基),7.58-7.52(3H,m,3CH-萘基),7.50-7.41(1H,m,CH-萘基),5.93(1H,s,H1′-鸟苷),4.58-4.56(2H,m,H3′-鸟苷,H4′-鸟苷),4.29-4.21(2H,m,H5′鸟苷),4.06-4.03(1H,m,CHα),3.56(3H,d,CH3-甲基,J=1.7赫兹),1.31(3H,d,CH3-丙氨酸,J=7.4赫兹),1.00(3H,d,CH3-2′-鸟苷,J=12.4赫兹)。
分别依照实施例1到11准备的CHC1到CHC9的每种化合物都对它关于HCV的效力做过测试。
所用的抗HCV如下:
Huh7细胞的抗HCV化验。包含HCV亚基因组复制子I389luc-ubi-neo/NS3-3’/5.1(Huh5-2)或I377/NS3-3’/wt(Huh9-13)的 Huh7细胞已有人描述过(Lohmann V,Korner F,Koch J,Herian U,Theilmann L,Bartenschlager R.(1999),“Replication of subgenomic hepatitis C virus RNAs in hepatoma cell line(在肝癌细胞系中丙型肝炎病毒亚基因组RNA的复制)”,Science285:110-113;Lohmann V,Korner F,Dobierzewska A,Bartenschlager R.(2001),“Mutations in hepatitis C virus RNAs conferring cell culture adaptation(赋予细胞培养适应的丙型肝炎病毒的突变)”,J Virol.75:1437-1449.)。细胞在补充了10%热失活的牛胎血清(FCS)(Integra,Zaandam,The Netherland)、1x非必需氨基酸(Gibco)、100IU/ml青霉素(Gibco)和100μg/ml链霉素(Gibco)并且对于Huh5-2细胞补充250μg/ml Geneticin(G418,Gibco)而对于Huh9-13细胞补充的1000μg/毫升G418的Dulbecco氏改进的Eagle介质(DMEM;Gibco,Merelbeke,Belgium)中生长的。
Huh5-2细胞的抗HCV化验。Huh5-2细胞以组织培养基处理过的白色的96孔观察平板(Packard,Canberra,Canada)每孔5×103的密度被播种在补充了250μg/ml G418的完全的DMEM中。在37℃下孵化24小时之后,(5%CO2)介质被除去,并且将测试化合物在完全DMEM(没有G418)中的连续稀释液加到100μ总体积中。在在37℃下孵化4天后,细胞培养介质被除去,并且使用稳态-Glo萤光素酶化验***(Promega,Leiden,The Netherland)确定萤光素酶的活性;萤光素酶信号是使用Luminoskan Ascent(Thermo,Vantaa,Finland)测量的。50%有效浓度(EC50)被定义为将萤光素酶信号减少50%的化合物浓度。
Huh9-13细胞的抗HCV化验。Huh9-13细胞以96孔细胞培养平板每孔5×103细胞的密度播种在补充了1000μg/ml G418的完全的DMEM中。在37℃下孵化24小时之后,除去细胞培养介质,而且将测试化合物在没有G418的完全DMEM中的连续稀释液添加到100μl的总体积中。在在37℃孵化4天之后,除去细胞培养 液,而且用磷酸盐缓冲的盐水将单层洗一次。依照制造商的用法说明书,细胞溶解在350μl RLT缓冲液(Qiagen,Venlo,TheNetherland)中,溶解产物被储存在-80℃下,直到被进一步使用。
RT-qPCR。25μL RT-qPCR反应包含12.5μl2×反应缓冲液(Eurogentec,Seraing,Belgium)、6.3μl H2O、5μl全部细胞RNA提取物并且在Huh9-13和HuH6样品的情况下包含300nmol/L新-正向引物[5′-CCG GCT ACC TGC CCA TTC-3′]、300nmol/L新-反向引物[5′-CCA GAT CAT CCT GAT CGA CAA G-3′]、300nmol/L新-探针[5′-FAM-ACA TCG CAT CGA GCG AGC ACG TAC-TAMRA-3’]或对于Huh-mono样品包含300nmol/LUTR-正向引物[5′-ACG CAG AAA GCG TCT AGC CAT GGC GTT AGT-3’]、300nmol/L UTR-反向引物[5′-TCC CGG GGC ACT CGC AAG CAC CCT ATC AGG-3’]、300nmol/L UTR-探针[5′-FAM-TGG TCT GCG GAA CCG GTG AGT ACA CC-TAMRA-3’]。RT步骤在48℃进行C30分钟,在95℃进行15分钟,随后40个周期的变性的PCR放大在94℃进行20秒,而在ABI7000序列检测器中的韧化和延申在60℃进行1分钟。50%有效浓度(EC50)被定义为将复制子RNA内容减少50%的化合物浓度。
用HCV EC50/μM和CC50/μM表示的结果在下面的表I中给出。
在表I中:
A指的是9-联腺嘌呤,G指的是9-联鸟嘌呤,Nap指的是1-萘基(-C10H9),Ph指的是苯基(-C6H5),Et指的是乙基(CH3CH2-),Bn指的是苯甲基(C6H5CH2-),t-Bu指的是叔丁基((CH3)3C-),而 Me指的是甲基(CH3-)。
表1
表I的数据表明体现本发明的每种化合物CHC6和CHC7呈现比与游离核苷9-联鸟嘌呤相对应的化合物CHC5大的关于HCV的效力。
在表I中关于每种化合物CHC6和CHC9和关于每种化合物CHC10和CHC11的数据比较结果表明关于HCV增强的效力可归因于分别在化合物CHC6和CHC11出现的Ar是1-萘基。
下面的表2根据上述的化学式I展示目前作为实施例的化合物CHC1到CHC11的结构,其中在每种情况下Z=H和Q=O。
表II
化合物 | X | Y | T” | V | T | Ar | R1 | R2 | R3 | R4 |
CHC1 | NH2 | H | H | OH | H | - | - | - | - | - |
CHC2 | NH2 | H | H | OH | H | C10H7 | CH3 | H | CH3CH2 | H |
CHC3 | NH2 | H | H | OH | H | C10H7 | CH3 | H | C6H5CH2 | H |
CHC4 | NH2 | H | H | OH | H | C10H7 | CH3 | H | t-C4H9 | H |
CHC5 | =O | NH2 | H | OH | H | - | - | - | - | - |
CHC6 | =O | NH2 | H | OH | H | C10H7 | CH3 | H | C6H5CH2 | H |
CHC7 | =O | NH2 | H | OH | H | C10H7 | CH3 | H | CH3CH2 | H |
CHC8 | =O | NH2 | H | OH | H | C10H7 | CH3 | H | t-C4H9 | H |
CHC9 | =O | NH2 | H | OH | H | C6H5 | CH3 | H | C6H5CH2 | H |
CHC10 | =O | NH2 | H | OH | H | C6H5 | CH3 | H | CH3 | H |
CHC11 | =O | NH2 | H | OH | H | C10H7 | CH3 | H | CH3 | H |
在Ar是C10H7的情况下,它是1-萘基。在X是NH2的情况下,n是O。在X是=0情况下,n是1。
化合物CHC1、CHC5、CHC9和CHC10每种都是比较化合物。
化合物CHC1对应于非氨基磷酸酯化的游离核苷9-联腺嘌呤。
化合物CHC5对应于非氨基磷酸酯化的游离核苷9-联鸟嘌呤。
Claims (17)
1.化学式I的化合物:
其中:
Ar是萘基;
T选自由氢、氟、甲基和乙基组成的群体;
V选自由氢、氟和OT′组成的群体,其中T′是氢或者甲基;
T″是氢;
n是0或1、其中当n是1的时候,X是=O;而当n是0的时候,双键存在于位置3和位置4之间,X选自由H、F、Cl、和NR5R6组成的群体,其中R5和R6中的一个是H并且R5和R6中的一个是C1-6烷基;
Z选自由H、F和Cl;
Y选自由H、F、Cl、NH2和NR5R6组成的群体,其中R5和R6之一是H而且R5和R6之一是C1-6烷基;
Q是O;
R1和R2独立地选自由H、2-丙基、苯甲基和-CH2异丙基组成的群体,或者是这样选定的,以致它们对应于天然氨基酸的侧链;
R3选自甲基、乙基、2-丙基、n-丙基、环己基、2-丁基和苯甲基;和R4是H或者与R1一起组成(-(CH2)3-),以便提供与脯氨酸相对应的基团;
以及
它们的药学可接受的盐。
2.根据权利要求1的化合物,其中Ar是未被取代的1-萘基。
3.根据权利要求1的化合物,其中T是H,V是OH,而T″是H。
4.根据权利要求1的化合物,其中n是1,X是=O,而Y是NH2。
5.根据前述任意一项权利要求的化合物,其中当n是0时,X是NH2,Y是H,而Z是H。
6.根据权利要求4的化合物,其中Z是H。
7.根据权利要求1的化合物,其中R3选自由甲基、乙基、2-丙基和苯甲基组成的群体。
8.根据权利要求7的化合物,其中R3选自由乙基和苯甲基所组成的组中。
9.根据权利要求1的化合物,其中R4是H。
10.根据前述任意一项权利要求的化合物,其中R1和R2之一是甲基而且R1和R2之一是H,以致生出R1和R2的C原子有与天然丙氨酸一样的手性L。
11.根据上述任意一项权利要求的化合物,包括非对映异构体RP、非对映异构体SP或非对映异构体RP和SP的混合。
12.一种选自下列群体的化合物:
β-2′-甲基腺苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐;
β-2′-甲基腺苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐;
β-2′-甲基腺苷5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐;
β-2′-甲基鸟苷5′-O-[α-萘基(苯甲酸基-L-丙氨酸基)]磷酸盐;
β-2′-甲基鸟苷5′-O-[α-萘基(乙氧基-L-丙氨酸基)]磷酸盐;
β-2′-甲基鸟苷5′-O-[α-萘基(叔丁氧基-L-丙氨酸基)]磷酸盐;以及
β-2′-甲基鸟苷5′-O-[α-萘基(甲氧基-L-丙氨酸基)]磷酸盐。
13.权利要求1-12任意一项所述的化合物在制备用于预防或者治疗病毒感染的药物中的应用。
14.根据权利要求13所述的应用,所述药物用于预防或者治疗丙型肝炎。
15.一种在与药学可接受的载体、稀释剂或赋形剂的组合中包含根据权利要求1到12之中任何一项的化合物的药学组合物。
16.一种制备药学组合物的方法,其中包括将根据权利要求1到12之中任何一项的化合物与药学可接受的赋形剂、载体或稀释剂合并的步骤。
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