CN101189249B - 膦酰基-戊-2-烯-1-基核苷和类似物 - Google Patents
膦酰基-戊-2-烯-1-基核苷和类似物 Download PDFInfo
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- CN101189249B CN101189249B CN2006800193224A CN200680019322A CN101189249B CN 101189249 B CN101189249 B CN 101189249B CN 2006800193224 A CN2006800193224 A CN 2006800193224A CN 200680019322 A CN200680019322 A CN 200680019322A CN 101189249 B CN101189249 B CN 101189249B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明提供了用于治疗、预防、或改善与病毒感染和/或细胞增生相关的多种疾病的化合物和组合物。本发明提供的化合物是膦酰基-戊-2-烯-1-基核苷和它的酯。
Description
权利信息
本发明是在国立过敏和感染性疾病研究所/国立卫生研究院的政府资助下完成的,基金号为5R37AI29164。美国政府在本发明中有一定的权利。
相关申请数据
本申请基于35 U.S.C.]119(e)要求2005年4月1日申请的属于Hostetler等人的美国临时申请60/667,740,标题为“膦酰基-戊-2-烯-1-基核苷和类似物”。该临时申请的内容通过引用被纳入本文。
领域
本发明提供了5-膦酰-戊-2-烯-1-基核苷和它们的酯。在一个实施方案中,所述化合物是具生物活性的核苷和它们的类似物的单酯。在另一个实施方案中,本发明提供了用本发明的化合物和组合物治疗、预防、或改善多种与病毒感染和细胞增殖相关的医学病症的方法。
背景技术
很长时间以来,核苷膦酸酯被认为具有抗病毒、抗增殖和很多其它治疗效果。其中,包括抗病毒的核苷膦酸酯,例如西多夫韦、环西多夫韦、阿德福韦、特洛福韦等,还包括齐多夫定(AZT)、更昔洛韦、阿昔洛韦等的5’- 磷酸酯和亚甲基膦酸酯。在这些化合物中,糖基团或不含完整糖基团的开环核苷(更昔洛韦、喷昔洛韦、阿昔洛韦)中的等价基团的5’-羟基被磷-碳键取代。在亚甲基磷酸酯的情况下,亚甲基团取代了5’-羟基或它的等价基团,而其碳原子反过来共价连接在磷酸酯上。
这样的化合物的活性可以与抗病毒或抗增殖的核苷一样。当细胞代谢时,又发生了两次磷酸化形成核苷磷酸酯二磷酸酯,该化合物代表了核苷三磷酸酯的等同物。抗病毒的核苷磷酸酯二磷酸酯是病毒RNA或DNA聚合酶或反转录酶的选择性抑制剂。即,它们对病毒聚合酶的抑制效果远大于它们对哺乳动物细胞DNA聚合酶α、β和γ或哺乳动物细胞RNA聚合酶的抑制程度。相反地,抗增殖的核苷磷酸酯二磷酸酯抑制癌细胞DNA和RNA聚合酶,并且对正常的细胞DNA和RNA聚合酶表现出了更低的选择性。
仍然需要毒性更低,更有效的药物制剂来治疗很多与病毒感染和细胞增殖相关的病症。
发明概述
本发明提供了5-膦酰-戊-2-烯-1-基核苷和它的疏水酯。本发明还提供了组合物和使用所述化合物和组合物来治疗各种疾病的方法。在一个实施方案中,本发明提供的化合物和组合物有抗病毒活性。在另一个实施方案中,本发明提供了在治疗、预防或改善与细胞增殖相关的一种或多种症状中有用的化合物和组合物。
在一个实施方案中,所述化合物是5-磷酸-戊-2-烯-1-基核苷和它的药学上可接受的衍生物。在另一个实施方案中,所述化合物是5-磷酸-戊-2-烯-1- 基核苷的疏水酯。
在一个实施方案中,本发明提供的组合物和方法中使用的化合物具有式IA或IB:
结构式IA 结构式IB
或它们的具有药学活性的衍生物,
其中,R是氢、单价离子或疏水基团,B是嘌呤或嘧啶碱基或它们的类似物。
本发明还提供了药学上可接受的衍生物,包括本发明所述化合物的盐、酯、烯醇醚、烯醇酯、溶剂化物、水合物和前药。本发明还提供了含有本发明提供的化合物和药学上可接受的载体的药物组合。在一个实施方案中,药物组合被配制成单剂量施用的剂型。
本发明提供了使用本发明提供的化合物和组合物进行治疗的方法。本发明提供了使用本发明提供的化合物和组合物治疗、预防、或改善与病毒感染和细胞增殖相关的疾病的一种或多种症状的方法。在实施所提供的方法时,施用有效量的化合物或含有有疗效浓度所述化合物的组合物。
本发明也提供了制造物品,其包含包装材料、本发明提供的用于治疗、预防、或改善与病毒感染或细胞增殖相关的疾病或病症的一种或多种症状的化合物或组合物、和用以标明所述化合物和组合物是用于治疗、预防、或减轻与病毒感染或细胞增殖相关的疾病或病症的一种或多种症状的标签。
发明详述
A.定义
除非特别标明,在此使用的所有技术和科学术语具有与本发明所属行业普通技术人员所理解的同样含义。所有专利、申请、公开的申请和其它出版物在这里通过引用而全部纳入。如果对某一个术语有很多定义,除非特别声明,否则以本部分的描述为准。
本文中,术语“核苷碱”指天然的或非天然的嘌呤和嘧啶碱基,包括腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤和尿嘧啶和它们的类似物。
当核苷碱基含有一个或多个功能基团,而这些功能基团在用来制备本发明化合物的反应条件下会起反应形成不需要的产物时,例如胞嘧啶和腺嘌呤的氨基基团和鸟嘌呤的2-氨基和6-氧基团,则可以采用核苷化学中常用的保护基团来封闭这样的功能基团。例如,腺嘌呤和胞嘧啶的氨基基团可以采用苯甲酰基来保护。鸟嘌呤的2-氨基和6-氧基团可以采用三苯甲基基团来保护。选择引入和随后去除这样的保护基团的方法为相关领域的普通技术人员所熟知。
本文中,术语“疏水”或“长链”指环状的、分支的或直链的化学基团,当它们共价连接在磷酸上时形成膦酰单酯。与亲代核苷膦酸酯相比,它们增强了核苷膦酸酯口服时的生物可利用度和活性。这些疏水基团包括但不限于烷基、烷氧基烷基和烷基甘油基。在一个实施方案中,烷基基团含有8-26个碳原子或8、10、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子,可以是直链的或支链的基团。
术语“核苷膦酸酯”和“开环核苷膦酸酯”指有生物活性的,例如,抗病毒、抗癌或抗寄生虫的膦酰甲氧基烷基或膦酰取代的核苷衍生物,
术语“核苷膦酸酯的疏水性的单酯”是指那些疏水基团通过酯键共价连接到核苷膦酸酯上的化合物。
化合物的药学上可接受的衍生物包括它的盐、酯、烯醇醚、烯醇酯、乙缩醛、缩酮、原酸酯、半缩醛、半缩酮、酸、碱、溶剂化物、水合物或前药。这样的衍生物可以由本领域技术人员使用已知的这种衍生化方法来容易地制备。制成的化合物可以给动物或人施用且没有大的毒性,它们具有药学活性或者它们是前药。药学上可接受的盐包括但不限于胺盐,例如但不限于N,N`-二苯甲基乙基二氨、氯普鲁卡因、胆碱、铵、二乙醇胺和其它的羟基烷基氨、乙基二氨、N-甲基葡萄糖胺、普鲁卡因,N-苯甲基苯乙基胺、1-邻-氯苯甲基-2-吡咯烷-1’-基甲基-苯并咪唑、二乙基胺和其它的烷基氨、吡嗪和三(羟基甲基)氨基甲烷;碱金属盐,例如但不限于锂、钾和钠;碱土金属盐,例如但不限于钡、钙、镁;过度金属盐,例如但不限于锌;其它金属盐,例如但不限于磷酸氢钠和磷酸二钠;还包括但不限于硝酸盐、硼酸盐、甲基磺酸盐、苯基磺酸盐、甲苯磺酸盐;矿物酸盐,例如但不限于氢氯酸盐、氢溴酸盐、氢碘酸盐和硫酸盐;和有机酸盐,例如但不限于乙酸盐、三氟乙酸盐、马来酸盐、乙二酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐、琥珀酸盐、丁酸盐、戊酸盐和富马酸盐。药学上可接受的酯包括但不限于酸性基团的烷基、烯基、炔基和环烷基酯,所述酸性基团包括但不限于羧酸、磷酸、次磷酸、磺酸、亚磺酸和硼酸。药学上可接受的烯醇醚包括但不限于式C=C(OR)的衍生物,其中R是氢、烷基、烯基、炔基和环烷基。药学上可接受的烯醇酯包括但不限于式C=C(OC(O)R)的衍生物,其中R是氢、烷基、烯基、炔基、或环烷基。药学上可接受的溶剂化物和水合物是化合物与一个或多个 溶剂分子或水分子,或1到大约100,或1到大约10,或1到大约2、3或4个溶剂或水分子的复合物。
在本文中,治疗指任何用来改善疾病或病症的一种或多种症状、或其它有益改变的方式。治疗也包括本发明组合物的任何药学使用,例如,用来治疗病毒感染和细胞增殖疾病或病症。
在本文中,通过施用具体化合物或药物组合物来减轻具体疾病的症状指归因于或与施用该组合物有关的任何改善,无论永久性的或短暂的,持续的或暂时的。
在本文中,EC50指某一待测化合物能引起剂量依赖的、其程度为该待测化合物所诱导的、引起的或加强的具体反应的最大程度的50%时的剂量、浓度或量。
在本文中,前药是指一种化合物,当它在体内施用时,可以通过一个或多个步骤或过程或其它方式被代谢而转化成该化合物的生物学、药学或治疗活性形式。为了制备前药,将药学活性形式的化合物进行修饰以便该活性化合物通过代谢过程重新生成。可以设计前药来改变药物的代谢稳定性或药物的转运特征,以屏蔽它的负作用或毒性,改进药物的味道或改变药物的其它特征或属性。利用药物的体内动力学过程和药物代谢的知识,一旦了解了具体药物活性化合物,本领域技术人员就能设计出该药物的前药(参见,Nogrady(1985)《药物化学:生物化学方法》,牛津出版社,纽约,388-392)。本发明中使用的其它前药在本文的其它地方描述。
应该理解是本发明提供的化合物可以含有手性中心。这样的手性中心可以是R或S构型,或是它们的混合物。因此,本发明提供的化合物可以是光学纯的、或立体异构体或非对映异构体的混合物。应该理解的是本发明 提供的化合物包括本发明化合物的任何外消旋的、光学活性的、多晶形的、或立体异构体的形式,或它们的混合物,这些化合物都具有本发明描述的有用特性,本领域技术人员都知道怎样制备这些光学活性形式的化合物,怎样使用本发明描述的标准测试、或本领域熟知的其它类似测试来测定它们的抗增值活性。能够被用来获得本发明化合物的光学异构体的方法的实例包括以下:
i)晶体的物理分离-单个的对映异构体的肉眼可见晶体可以通过手工进行分离的技术。如果分离的旋光异构体的晶体存在,例如,该材料是聚结的,且肉眼看起来晶体是明显分开,那么该项技术就可以采用。
ii)同步结晶-单个的对映异构体可以通过从外消旋混合物的溶液中单独结晶分离出来的技术,很可能该项技术只有在外消旋混合物在固体状态下是聚结的时才能使用。
iii)酶法拆分-利用对映异构体与酶的反应速率不同来部分或彻底分离外消旋体的技术;
iv)酶促不对称合成-合成步骤中至少一步使用了酶促反应来获取对映体纯的或富含所需对映体的合成前体的合成技术;
v)化学不对称合成-在可以在产物中生成不对称的(例如,手性)条件下,从非手性的前体中合成所需要的对映异构体的合成技术,这可以通过使用手性的催化剂或手性的助剂来完成;
vi)非对映异构体的分离-外消旋化合物与对映异构体纯的制剂(手性助剂)反应,将单个的对映异构体转化成非对映异构体的技术。利用非对映异构体更明显的结构差异通过色谱法或结晶法对它们进行分离,然后除去手性助剂得到需要的对映体;
vii)第一顺序和第二顺序的不对称转化-来自外消旋平衡体的非对映异构体在所需对映异构体的非对映异构体的溶液中形成优势的的技术,或者从所需对映异构体优先结晶所述非对映异构体打破这种动态平衡从而最终在原理上所有材料都被转化成所需对映异构体的结晶非对映异构体的技术。然后,所需对映异构体就从非对映异构体上释放出来。
viii)动力学拆分-这项技术是指在动力学条件下利用对映异构体与手性、去消旋的制剂或催化剂的不同反应速率对外消旋体进行部分或完全拆分(或对部分拆分的化合物进行进一步拆分);
ix)从非消旋前体对映专一性合成-从非手性起始材料获得所需对映异构体的合成技术,且在合成过程中,立体化学的完整性并未或仅仅极少被损害。
x)手性液体色谱法-利用外消旋体的对映异构体与固定相的不同反应在液体流动相中对它们进行分离的技术。为了引起不同的反应,固定相可以由手性材料组成或移动相可以含有其它手性材料。
xi)手性气相色谱-将外消旋体挥发并利用它们在气体移动相中与含有固定的非外消旋手性吸附相的柱子的不同相互作用对它们进行分离的技术;
xii)用手性溶剂进行抽提-利用一种对映异构体优先溶解于某一具体手性溶剂的性质来分离对映异构体的技术;
xiii)通过手性膜的转运-将外消旋异构体与一层薄隔膜接触放置的技术。隔膜分离两种易混合的液体,一种含有外消旋体,驱动力例如浓度、或压力差引起了优先转运通过隔膜。由于隔膜的非外消旋手性的特性仅仅允许外消旋体的一种对映异构体通过,结果完成了分离。
在本文中,基本上纯的指足够均一以至于不存在可通过标准分析方法(例 如本领域技术人员用来检测这样的纯度所用的,例如薄层层析(TLC)、凝胶电泳、高效液相色谱(HPLC)和质谱(MS))可容易探测到的不纯物,或者足够纯以至于进一步的纯化不会明显改变物质的物理或化学属性,例如酶和生物学活性。制备基本上化学纯的化合物的纯化方法为本领域技术人员所熟知。但是,基本上化学纯的化合物可以是立体异构体的混合物。在这样的情况下,进一步纯化可能会增强化合物的具体活性。
在本文中,术语“烷基”指单价的直链或支链或环状的基团。在某些实施方案中,烷基基团含有1到24个碳原子,包括甲基、乙基、正丙基、异丙级、正丁基、异丁基、叔丁基、正己基、十八烷基、十九烷基、二十烷基、18-甲基-十九烷基、19-甲基-二十烷基等。低级烷基指含有1到6个碳原子的烷基基团。
在本文中,“取代的烷基”指还含有一个或多个取代基的烷基,该取代基包括但不限于选自下列的取代基:较低级的烷基、羟基、烷氧基(低级烷基基团)、巯基(低级烷基基团)、环烷基、取代的环烷基、杂环基、取代的杂烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、芳氧基、取代的芳氧基、卤素、三氟甲基、氰基、叠氮基、硝基、硝酮、氨基、酰氨基、甲酰基、酰基、氧酰基、羧基、氨基甲酸酯、磺酰基、磺胺、和磺酰胺,它们可以根据需要被保护起来或未被保护,参见Greene等人《有机合成中的保护基团》,John Wiley and Sons,第二版1991,该书通过引用被纳入本文中。
在本文中,术语“烯基”指直链的或支链的含有一个或多个碳-碳双键的羟基团。在某些实施方案中,烯基基团含有2到最多24个碳原子,而“取代的烯基”指基团上还含有一个或多个如上定义的取代基。
术语“炔基”指直链的或支链的具有一个或多个碳-碳三键的羟基团。在某 些实施方案中,炔基基团含有2到最多24个碳原子,而“取代的炔基”指基团上还含有一个或多个如上定义的取代基。
在本文中,“芳基”指具有6个到最多14个碳原子的芳基基团,取代的芳基基团指基团上还具有一个或多个如上定义的取代基。
在本文中,术语“杂芳基”指含有一个或多个杂原子(例如,N、O、S等),且杂原子是环结构的一部分的芳香基团,其可以具有3个到最多14个碳原子,而“取代的杂芳基”指还含有一个或多个如上所述的取代基的杂芳基团。
在本文中,术语“个体”是动物,例如哺乳动物,包括人例如患者。
本文中的术语“有效量”指预防、治疗、或改善包括那些与病毒感染、细胞增殖和/或骨代谢相关的疾病或病症的一种或多种症状所需要的量。
当给定的取代基(例如,卤代烷基)的数目没有具体指定时,可以存在一个或多个取代基。例如,“卤代炕基”可以包括一个或多个同样的或不同的卤原子。
在本文中,术语“胃肠外”包括皮下、静脉内、动脉内、肌肉内、或玻璃体内的注射,或输注技术。
在本文中,术语“局部”包括直肠和吸入雾化给药,以及皮肤和口腔和鼻粘膜的更常用的途径给药以及牙膏内给药。
在本文中,除非特别说明,任何保护基团、氨基酸和其它化合物的缩写与它们的通常用法、公认的缩写,或生物化学命名的IUPAC-ILTB协议(参见1972生物化学77:942-944)一致。
本文中使用的某些缩写如下:
5-膦酰-戊-2-烯-1基腺嘌呤=PPen-A,
5-膦酰-戊-2-烯-1基胞嘧啶=PPen-C,
5-膦酰-戊-2-烯-1基鸟嘌呤=PPen-G,
5-膦酰-戊-2-烯-1基胸腺嘧啶=PPen-T,和
5-膦酰-戊-2-烯-1基尿嘧啶=PPen-U,
十六烷氧基丙基=HDP,
十八烷氧基乙基=ODE,
油氧乙基=OLE,和
油氧丙基=OLP。
B化合物
在某些实施方案中,本发明提供的是5-膦酰-戊-2-烯-1-基核苷和它的疏水性酯。在一个实施方案中,本发明提供的组合物和方法中使用的化合物具有式IIA或IIB:
或它们的具药学活性的衍生物,
其中R是氢、单价离子或疏水基团,而B是嘌呤或嘧啶碱基或它们的类似物。
在某些实施方案中,R是氢、单价离子、取代的或未取代的C8-C24烷基或取代的或未取代的具有1到6个双键的C8-C24烯基,其中取代基(当存在时)选自一个或多个,在一个实施方案中为1到4个,在另一个实施方案中,为1个、2个或3个卤素、烷基、-OH、-SH、环烷基和环氧化物;或R是乙酰基、缬氨酰、双特戊酰氧甲基(dipivoxil)、双(戊酰氧甲基)或双索罗基(disoproxil)。在具体实施方案中,R具有下式:
R1和R1a各自独立地为-H、-O(C1-C24)烷基、-O(C1-C24)烯基、-O(C1-C24)酰基、-S(C1-C24)烷基、-S(C1-C24)烯基、或-S(C1-C24)酰基,其中R1和R1a中至少一个不是氢,其中烯基或酰基基团任选地具有1到6个双键,
R2和R2a各自独立地为-H、-O(C1-C7)烷基、-O(C1-C7)烯基、-S(C1-C7)烷基、-S(C1-C7)烯基、-O(C1-C7)酰基、-S(C1-C7)酰基、-N(C1-C7)酰基、-NH(C1-C7)烷基、-N((C1-C7)烷基)2、氧、卤素、-NH2、-OH、或-SH;
R6,当存在时,是:
m是0到6的整数;
式中R1、R1a、R2、R2a、R7和R7a任选地被1到4个取代基取代;在一个具体的实施方案中为1个、2个或3个取代基,各自独立地选自烷基、烯基、炔基、卤素、羟基、类卤(pseudohalo)、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
在某些实施方案中,m=0、1或2。在某些实施方案中,m=0或1。在某些实施方案中,m=0。在某些实施方案中,m=1。在某些实施方案中,R2和R2a是H。
在一个实施方案中,本发明提供的化合物中的烷基、烯基和炔基基团被一个或多个,在一个实施方案中,被1个、2个、3个或4个选自烷基、烯基、炔基、卤素、羟基、类卤、氨基、硝基、环烷基、杂环基、芳基和杂芳基的取代基取代。
在具体实施方案中,R具有下式:
其中,R1和R1a与本文中其它地方定义的一样。
在一个实施方案中,R具有下式:
其中R1和R1a与本文中其它地方定义的一样。
在一个实施方案中,R具有下式:
其中R1和R1a与本文中其它地方定义的一样。
在某些实施方案中,R是乙酰基、缬氨酰、双特戊酰氧甲基、双(戊酰氧甲基)或双索罗基(disoproxil)。任选地,膦酸酯的两-OH部分可被前面提到的取代基取代。
在一个实施方案中,R是十六炕氧基丙基、十八烷氧基乙基或油酸氧乙基。
在具体实施方案中,R1是具有式-O-(CH2)t-CH3的烷氧基团,其中t是0到24。在其它实施方案中,t是8、10、12、13、14、15、16、17、18、19或20。在其它实施方案中,t是13、14、15、16、17、18、19或20。在其它实施方案中,t是15、16、17、1 8、19或20。在其它实施方案中,t是17、18、19或20。在其它实施方案中,t是15或17。
在某些实施方案中,R是取代的或未取代的C8-C24烷基,具有1到6个双键的取代或未取代的C8-C24烯基、具有1到6个三键的取代或未取代的C8-C24炔基,其中,取代基(当存在时)选自一个或多个,在一个实施方案中为1到4个,在另一个实施方案中为1个、2个或3个卤原子、烷基、-ORW、-SRW、环烷基或环氧化物,其中RW是氢或烷基,而所述烷基、烯基、炔基基团可以被进一步取代或不被取代。
在某些实施方案中,R选自含有8、10、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子的烷基、烯基、炔基基团,这些基团可以是直链的或支链的。在某些实施方案中,R基团是C16-C23的直链或支链烷基或是C16-C23的直链或支链烯基。在其它实施方案中,R是C17-C19直链或支链烷基或C17-C19直链或支链烯基。在其它实施方案中,R是C17烷基、C18烷基或C19烷基。在其它实施方案中,R是C17-烯基、C18-烯基或C19-烯基。在其它实施方案中,R是C17-C22烷基。在其它实施方案中,R是C17 烷基、C18烷基、C19烷基、C20炕基、C21烷基或C22烷基。
在其它实施方案中,R是被一个或多个,在一个实施方案中,为1到4个,在另一个实施方案中为1、2个或3个选自低级烷基和卤素的取代基取代的C16-C23烷基。在某些实施方案中,R被1个或多个,在一个实施方案中为1到4个,在另一个实施方案中为1个、2个或3个甲基基团取代。在某些实施方案中,R被1个或多个,在一个实施方案中为1到4个,在另一个实施方案中为1个、2个或3个氟基团取代。在某些实施方案中,R是C16-C23烷基,且被一个或多个,在一个实施方案中为1到4个,在另一个实施方案中为1个、2个或3个甲基或氟基团取代。在某些实施方案中,甲基或氟基团取代基存在于炕基、烯基、或炔基链的倒数第二个碳原子上。在某些实施方案中,R是7-甲基-辛基、8-甲基-壬基、9-甲基-癸基、10-甲基-十一烷基、11-甲基-十二烷基、12-甲基-十三烷基、13-甲基-十四烷基、14-甲基-十五烷基、15-甲基-十六烷基、16-甲基-十七烷基、17-甲基-十八烷基、18-甲基-十九烷基、19-甲基-二十烷基、20-甲基-二十一烷基、21-甲基-二十二烷基、22-甲基-二十三烷基、7-氟-辛基、8-氟-壬基、9-氟-癸基、10-氟-十一烷基、11-氟-十二烷基、12-氟-十三烷基、13-氟-十四烷基、14-氟-十五烷基、15-氟-十六烷基、16-氟-十七烷基、17-氟-十八烷基、18-氟-十九烷基、19-氟-二十烷基、20-氟-二十一烷基、21-氟-二十二烷基、22-氟-二十三烷基。
在某些实施方案中,B选自于天然的或非天然的嘌呤或嘧啶碱基。在某些实施方案中,B是
其中R3是H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、羟基、卤素、芳基或杂芳基;
R6是H或C1-6烷基、C2-6烯基、C2-6炔基或环烷基;
R7是H、羟基、卤素、C1-6烷基、C2-6烯基、C2-6炔基、环烷基或NR4R5;
R8是H、C1-6烷基、C2-6烯基、C2-6炔基或环烷基;以及
R9是H、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素或NR4R5,其中R4和R5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、或C3-6环烷基。
在某些实施方案中,R3是H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、羟基、卤素、芳基或杂芳基。在某些实施方案中,R3是H或C1-6烷基。在一个实施方案中,R3是H。在另一个实施方案中,R3是甲基。
在另一个实施方案中,R4和R5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、或C3-6环烷基。在其它实施方案中,R4是H、C1-6烷基或C3-6环烷基。在一个实施方案中,R4是H、甲基或环丙基。在其它实施方案中,R5是H、C1-6烷基或C3-6环烷基。在一个实施方案中,R5是H、甲基或环丙基。
在一些实施方案中,R6是H或C1-6烷基、C2-6烯基、C2-6炔基或环烷基。在其它实施方案中,R6是H或C1-6烷基。在一个实施方案中,R6是H或甲基。在另一个实施方案中,R6是H。在另一个实施方案中,R6是甲基。
在一些实施方案中,R7是H、羟基、卤素、C1-6烷基、C2-6烯基、C2-6炔 基、环烷基或NR4R5。在其它实施方案中,R7是H、C1-6炕基或NR4R5。在一个实施方案中,R7是甲基。在另一个实施方案中,R7是NR4R5。在其它实施方案中,R7是NH2。
在一些实施方案中,R8是H、C1-6烷基、C2-6烯基、C2-6炔基或环烷基。在一个实施方案中,R8是H。
在一些实施方案中,R9是H、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素或NR4R5。在其它实施方案中,R9是H。
在其它实施方案中,B选自嘧啶-1-基、嘧啶-3-基、嘌呤-3-基、嘌呤-7-基和嘌呤-9-基。在某些实施方案中,B是胸腺嘧啶-1-基、胞嘧啶-1-基、腺嘌呤-9-基或鸟嘌呤-9-基。
在一个实施方案中,B选自:
在另一个实施方案中,本发明化合物选自5-膦酰-戊-2-烯-1基腺嘌呤(PPen-A)、5-膦酰-戊-2-烯-1基胞嘧啶(PPen-C)、5-膦酰-戊-2-烯-1基鸟嘌呤(PPen-G)、5-膦酰-戊-2-烯-1基胸腺嘧啶(PPen-T)、和5-膦酰-戊-2-烯-1基尿嘧啶(PPen-U)和它们的疏水性酯。在一些实施方案中,疏水性酯是十六烷氧基丙基(HDP)酯、十八烷基氧基乙基(ODE)酯、油氧乙基(OLE)酯。在某些实施方案中,化合物选自
(Z)-3-(十六烷基氧基)丙基氢 5-(6-氨基-9H-嘌呤-9-基)戊-3-烯基磷酸酯或HDP-PPen-A,
(Z)-3-(十六烷基氧基)丙基氢5-(4-氨基-2-氧嘧啶-1(2H)-基)戊-3-烯基磷酸酯或HDP-Ppen-C
(Z)-3-(十六烷基氧基)丙基氢 5-(2-氨基-6-氧-1,6-二氢嘌呤-9-基)戊-3-烯基磷酸酯或HDP-PPen-G
(3Z)-3-(十六烷基氧基)丙基氢5-(3,4-二氢-5-甲基- 2,4-二氧嘧啶-1(2H)-基)戊-3-烯基磷酸酯或HDP-Ppen-T
(3Z)-3-(十六烷基氧基)丙基氢5-(3,4-二氢-2,4-二氧嘧啶-1(2H)-基)戊-3-烯基磷酸酯或HDP-Ppen-U
(Z)-2-(十六烷基氧基)乙基氢 5-(2-氨基-6-氧-1,6-二氢嘌呤-9-基)戊-3-烯基磷酸酯或ODE-PPen-G,和
(Z)-2-(十六-9-烯基氧基)乙基氢 5-(2-氨基-6-氧-1,6-二氢嘌呤-9-基)戊-3-烯基磷酸酯或OLE-PPen-G
C.化合物的制备
下文和实施例描述了用于本发明提供的组合物和方法中的5-磷酸-戊-2-烯-1-基核苷和它的酯的示例性制备方法。还可以使用本领域中已知的其它方法来制备本发明所提供的5-磷酸-戊-2-烯-1-基核苷和它的酯。
方案I概括了关键中间体9的合成。实施例1提供了合成化合物9的条件。在这个过程中,用DHP和PPTS处理3-丁烯-1-醇1得到化合物2。对化合物2进行羟基甲基化得到化合物3,用TBDPSC1保护化合物3得到化合物5。通过溴化作用和阿尔布佐夫反应,化合物5被转化成磷酸酯化合物7。对化合物7部分氢化后,去掉TBDPS的保护基团得到关键的中间体9。
方案I
制剂和条件a)DHP,PPTS,CH2Cl2,室温,b)n-BuLi,(CH2O)n,-78℃,c)TBDPSCl、咪唑、CH2Cl2,室温,d)MeOH,PPTS,室温,e)CBr4,PPh3,CH2Cl2,-78℃,f)P(OEt)3,回流,g)H2,Lindlar′s催化剂,MeOH,室温,h)TBAF,乙腈,0℃。
方案Ia概述了合成具有式IB的E型异构体中所需要的关键中间体9a的合成。可以使用上面方案I中描述的类似步骤制备中间体7。在存在碱金属(Li或Na)的条件下,在低温的液氨或乙基氨中氢化中间体7得到中间体8a,将中间体8a去保护得到中间体9a。
方案Ia
方案II阐明了使用关键的中间体9合成本发明提供的化合物的过程。实 施例2中详细描述了PPen-A的合成。关键的中间体9与腺嘌呤进行三信反应得到化合物10,在酸性条件下,对化合物10水解得到PPen-A(13)。在实施例3中,描述了PPen-G(15)的合成。与2-氨基-6-氯嘌呤进行三信反应得到化合物11,将化合物11的核苷碱转化成鸟嘌呤得到化合物12。使用TMSBr对化合物12水解得到PPen-G(15)。在实施例4中,PPen-A被转化为它的相应的单磷酸酯,HDP-PPen-A。在实施例5中,化合物11被转化成HDP-PPen-G。在酸性条件下对化合物11进行水解得到化合物14,它与3-十六烷基氧基-丙-1-醇(HDP-OH)进行DCC偶连得到化合物17。在回流条件下用88%HCOOH处理化合物17得到HDP-PPen-G(18)。
方案II
制剂和条件:a)DIAD,PPh3,核苷碱基,DMF 0℃或室温,b)HCOOH,回流,c)TMSBr,乙腈,室温,d)HDP-OH,DCC,DMAP,DMF,60℃,e)i)2,4,6-三异丙基苯磺酰氯,TEA,DMAP,乙腈,室温,ii)NH4OH。
D药物组合的配制
本发明提供的药物组合含有有效量的一种和多种本发明提供的化合物和药学上可接受的载体,这些化合物在预防、治疗或改善与病毒感染和不 适宜的细胞增殖相关的疾病或病症的一种或多种症状中有用。适合施用本发明提供的化合物的药物载体包括任何本领域技术人员所知适合具体给药模式的载体。
此外,化合物可以配制成是组合物中的唯一具药学活性的成分,化合物也可以与其它相成分联合。
组合物含有一种或多种本发明提供的化合物。在一个实施方案中,化合物被配制成合适的药物制剂,如溶液、悬浮液、片剂、可分散的片剂、药丸、胶囊、粉剂、持续释放的制剂或药剂,口服施用制剂或肠胃外注射的无菌溶液或悬浮液,还有透皮贴剂和干粉吸入剂。在一个实施方案中,使用本领域熟知的技术和步骤将上面描述的化合物配制成药物制剂(参见,例如,Ansel Introduction to Pharmaceutical Dosage Forms,第七版,1999)。
在组合物中,有效浓度的一种或多种化合物或它的药学上可接受的衍生物与合适的药物载体混合。在配制之前,可以按上面描述的方法将化合物衍生成相应的盐、酯、烯醇醚或酯、乙缩醛、缩酮、原酸酯、半缩醛、半缩酮、酸、碱、溶剂化物、水合物或前药。组合物中化合物的浓度在施用时递送的量能有效地治疗、预防、或改善与病毒感染或不适宜的细胞增殖相关的疾病或病症的一种或多种症状。在一个实施方案中,组合物被配制成单一剂量施用。为了配制组合物,将一定质量的化合物溶解、悬浮、分散、或以其它方式混合于选定的载体中,其浓度要达到使治疗的病症得以缓解、预防或一种或多种症状得以改善的有效浓度。
活性化合物被包含在药学上可接受的载体中,其量足以对接受治疗的患者发挥有用的治疗效果,而不出现不需要的副作用。有效治疗浓度可以通过使用本领域技术人员所熟知的体外或体内系统来测试化合物,之后外推 出人施用时的剂量。
药物组合中活性化合物的浓度取决于活性化合物的吸收、失活和排泄率,所述化合物的生理化学特征、剂量进度、和施用的量,还有本领域技术人员熟知的其它因素。例如,递送的量足以减轻本文描述的与病毒感染或不适宜的细胞增殖相关的疾病或病症的一种或多种症状。
在一个实施方案中,治疗有效剂量应使得活性成分在血清中的浓度大约为0.1ng/ml到大约50-100μg/ml。在另一个实施方案中,所述药物组合每剂量单位应提供的剂量为大约0.001mg到大约2000mg化合物/千克体重/天。制备的药物剂量单位形式每剂量单位形式可提供大约0.01mg、0.1mg或1mg到大约500mg,1000mg或2000mg,在一个实施方案中,大约为10mg到大约500mg的活性成分或必须成分的组合。
活性成分可以一次施用,或分成许多更小的剂量在一定时间间隔内施用。应该理解的是精确的剂量和治疗时间的长短是所治疗疾病的函数,它可以使用已知的测试方案经实验测定得到,或根据体内或体外的实验结果外推得到。应该注意到浓度和剂量值也可以随需要改善的疾病的严重性而变化。还应该理解的是,对任何具体治疗对象,给药方案应该按照个人需要和对施用的人或监督组合物施用的人的职业判断来调整。还应该理解的是本发明提出的浓度范围仅仅是举例说明性的,并不是限制组合物的范围或施用。
在化合物表现出溶解性不足的情况下,可以采用使化合物增溶的方法。这样的方法为本领域技术人员所熟知,包括但不限于:使用助溶剂如二甲基亚砜(DMSO),使用表面活性剂如Tween,或溶解于碳酸氢钠水溶液中。化合物的衍生物,如化合物的前药也可以被用于配制有效的药物组合。
当混合或加入化合物后,所得的混合物可以是溶液、悬浮液、乳浊液等。所得混合物的形式取决于很多因素,包括预定的给药模式和化合物在选定的载体或媒介物中的溶解度。有效浓度足以改善受治疗的疾病、病症或不适的症状,并可通过实验确定。
药物组合物以单位剂量形式,例如含有合适量的化合物或它们的药学上可接受的衍生物的片剂、胶囊、丸剂、粉剂、颗粒剂、无菌的注射液或悬浮液,和油-水乳浊液,施用给人和动物。在一个实施方案中,药学上治疗活性的化合物和它们的衍生物以单位剂量形式或多剂量形式被配制和施用。本发明使用的单位剂量形式指适合人类和动物个体的物理性分散的单位,并且像本领域所熟知的那样单独包装。每一个单位剂量含有预先确定量的足以产生所需治疗效果的治疗活性化合物,和与之相关的所需药物载体、媒介物或稀释剂。单位剂量形式的实例包括安瓿、针剂、和单独包装的片剂或胶囊。单位剂量形式可以分多部分施用或同时施用多份。多剂量形式是包装于单个容器中的多个完全一样的单位剂量形式,以分散的单位剂量形式适用。多剂量形式的实例包括小瓶或瓶装的片剂或胶囊,或品脱或加仑瓶。因此,多剂量形式是包装上并未分开的多个单位剂量。
液体的药学上可施用的组合物可以,例如,通过将上面定义的活性化合物和任选的药学上的佐剂溶解、分散或混合于载体中,例如水、生理盐水、液体葡萄糖、甘油、乙二醇、乙醇等中形成溶液或悬浮液来制备。如果需要,被施用的药物组合物可以含有少量无毒辅助物质,如湿润剂、乳化剂、促溶剂,PH缓冲剂等,例如,乙酸、柠檬酸钠、环糊精衍生物、山梨醇单月桂酸酯、三羟醇胺乙酸钠、三乙醇胺油酸酯和其它这种制剂。
制备这样的剂量形式的实际方法是对本领域技术人员来说已知的或显 而易见的;例如,参见Remington′s Pharmaceutical Sciences,Mack出版公司,Easton,Pa.,第十五版,1975。
可以制备含有0.005%到100%活性成份、其余部分是无毒载体的剂量形式或组合物。制备这些组合物的方法为本领域技术人员所熟知。这样得到的组合物含有0.001%到100%的活性成分,在一个实施方案中,为0.1%到95%,在另一个实施方案中,为75%到85%。
在某些实施方案中,组合物是不含乳糖的组合物,它含有本领域技术人员所熟知的赋形剂,例如,美国药典(USP)25-NF20(2002)所列举的那些。通常,不含乳糖的组合物含有活性成份、药学上相容的和药学上可接受的量的粘结剂/充填剂和润滑剂。具体的不含乳糖的剂量形式含有活性成份、微晶纤维素、预糊化淀粉、和硬脂酸镁。
本发明还提供含有活性成份的无水药物组合物和剂量形式,因为水使某些化合物容易降解。例如,添加水(例如,5%)广泛用于药学领域作为一种模拟药物长期储存的方式以测定制剂随时间变化的特征,例如储存期和稳定性,参见,例如,Jens T.Carstensen,Drug Stability:Principles&Practice,第二版,Marcel Dekker,NY,NY,1995,第379-80页。实际上,水和热会加速一些化合物的分解。因此,水对制剂的效果具有重大意义,因为在制剂的制造、处理、包装、储存、运输和使用的过程中,经常是潮湿的和/或湿润的。
可以使用无水的或含水量低的成分在低湿度或低潮湿的条件下制备本发明提供的无水药物组合物和剂量形式。
无水的药物组合物在制备和储存时应该保持它的无水状态。相应的,要使用已知可防止暴露于水的材料来包装无水组合物,这样它们可以被包装 于合适的制剂盒中。合适的包装实例包括但不限于密封金属膜、塑料、单位剂量的容器(例如,小瓶)、泡罩包装、和条带包装。
1.口服的组合物
口服的药物剂量形式可以是固体、凝胶或液体。固体剂量形式是片剂、胶囊、颗粒剂和散装粉剂。口服片剂的种类包括压缩的、可咀嚼的锭剂和片剂,它们可以是肠溶性的、糖包被的、或薄膜包被的。胶囊可以是硬的或软的明胶胶囊,而颗粒剂和粉剂可以以非泡腾片的形式或泡腾片的形式与其它本领域技术人员所熟知的成份一起提供。
a.口服的固体组合物
在某些实施方案中,制剂可以是固体剂量形式,在一个实施方案中,是胶囊或片剂。片剂、丸剂、胶囊、含片等可以含有一种或多种下列成分,或具有类似属性的化合物:粘结剂;润滑剂;稀释剂;助流剂;崩解剂;着色剂;甜味剂;调味剂;湿润剂;催吐包衣;和薄膜包衣。粘结剂的实例包括微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶粘液、明胶溶液、糖蜜、多聚吡咯烷、聚维酮、交聚维酮、蔗糖和淀粉糊。润滑剂包括滑石、淀粉、硬脂酸镁或硬脂酸钙、石松粉、和硬脂酸。稀释剂包括,例如乳糖、蔗糖、淀粉、高岭土、盐、甘露醇和磷酸二钙。助流剂包括但不限于,胶态二氧化硅。崩解剂包括交联羧甲基纤维素钠、乙醇酸淀粉钠、藻酸、玉米淀粉、土豆淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素。着色剂包括例如,任何批准认证的水溶性的FD和C染料,它们的混合物;悬浮在水化氧化铝的非溶解性的FD和C染料。甜味剂包括蔗糖、乳糖、甘露醇和 人工甜味剂例如糖精,和任何数目的喷雾干燥的调味剂。调味制剂包括从植物,如水果中抽提出来的天然调味剂和能使人产生愉悦感觉的合成的化合物的混合物,例如,但不限于薄荷和甲基水杨酸酯。湿润剂包括单硬脂酸丙二醇酯、山梨醇单油酸酯、二乙二醇单月桂酸酯、聚环氧乙烷月桂基乙醚。催吐包衣包括脂肪酸、脂肪、蜡、虫胶、充氨虫胶、醋酸邻苯二甲酸纤维素。薄膜包衣包括羟乙基纤维素、羧甲基纤维素纳、聚乙二醇4000和醋酸邻苯二甲酸纤维素。
化合物,或其药学上可接受的衍生物可以以组合物的形式提供,这样就保护了化合物免受胃部酸性环境的影响。例如,组合物可以被配制在肠包衣中,这样就维持了它在胃中的完整性,而在肠中它就可以释放出活性化合物。组合物也可以与抗酸或其它这样的成分联合配制。
当剂量单位形式是胶囊时,除上述类型的材料外,它还可以含有液体载体,如脂肪油。此外,剂量单位形式可以含有各种其它修饰剂量单位的物理形式的材料,例如,糖包衣和其它肠制剂。化合物可以以酏剂、悬浮液、糖浆、糯米纸囊剂、喷撒剂、咀嚼口胶等的组分施用。除活性化合物外,糖浆可以含有作为甜味剂的蔗糖和某些防腐剂、染料和着色剂和调味剂。
活性材料也可以与其它不影响所需作用的其它活性材料,或补充所需作用的材料,如抗酸剂、H2阻滞剂和利尿剂混合。活性成分是化合物或上面描述的它的药学上可接受的衍生物。可以含有高浓度,质量百分比高达大约98%的活性成分。
在所有实施方案中,为了修饰或保持活性成分的溶解性,片剂和胶囊制剂可以按本领域技术人员所熟知的方法进行包被。这样,例如,它们可以被包被传统的在肠中可消化的包衣,如水杨酸苯酯、石蜡和醋酸邻苯二甲 酸纤维素。
b.口服的液体组合物
液体的口服剂量形式包括水溶液、乳状液、悬浮液、由非-泡腾颗粒剂制备的溶液和/或悬浮液和由泡腾颗粒剂制备的泡腾制剂。水溶液包括,例如,酏剂和糖浆剂。乳状液既可以是溶在水中的油也可以是溶在油中的水。
酏剂是清澈的、甜的、水醇制剂。酏剂中使用的药学上可接受的载体包括溶剂。糖浆剂是浓缩的糖例如蔗糖的水溶液,且可以含有防腐剂。乳状液是两相系统,其中,一种液体以小液滴的形式分散于另一种液体中。乳状液中使用的药学上可接受的载体是非水性液体、乳化制剂和防腐剂。悬浮液使用药学上可接受的悬浮制剂和防腐剂。非-泡腾颗粒剂中使用的将要被重新形成液体口服剂量形式的药学上可接受的物质,包括稀释剂、甜味剂和湿润剂。泡腾的粒剂中使用的将要被重新形成液体口服剂量形式的药学上可接受的物质,包括有机酸和二氧化碳源。着色剂和调味制剂被用于所有上面的剂量形式中。
溶剂包括甘油、山梨醇、乙醇和糖浆。防腐剂的实例包括甘油、对羟基苯甲酸甲酯和丙酯,苯甲酸、苯甲酸钠和乙醇。乳状液中使用的非水性液体的实例包括矿物油和棉籽油。乳化剂的实例包括明胶、阿拉伯胶、黄芪胶、膨润土、和表面活性剂例如聚氧乙稀山梨醇酐单油酸酯。悬浮剂包括羧甲基纤维素钠、果胶、黄芪胶、硅酸镁铝和阿拉伯胶。甜味剂包括蔗糖、糖浆、甘油和人造甜味剂例如糖精。湿润剂包括单硬脂酸丙二醇酯、山梨醇酐单油酸酯、二乙二醇单月桂酸酯和聚氧乙烯月桂醚。有机酸包括柠檬酸和酒石酸。二氧化碳源包括碳酸氢钠和碳酸钠。着色剂包括任何经批准 的合格的水溶性的FD和C染料,和它们的混合物。调味剂包括从植物中,如水果中抽提出的天然调味剂,和能使人产生愉悦的味觉感觉的人造的化合物的混合物。
对于固体剂量形式,例如,在碳酸丙烯酯、植物油或甘油三酯中的溶液或悬浮液,在一个实施方案中,被包装在明胶胶囊中。这样的溶液,和其制备和包装,被公布在美国专利号4,328,245、4,409,239和4,410,545中。对于液体剂量形式,例如,在聚乙二醇的溶液,可以用足够量的药学上可接受的液体载体例如水进行稀释,从而很容易在施用时进行测定。
可选择地,可以通过将活性化合物或盐溶解或分散于植物油、乙二醇、甘油三脂、丙二醇酯(例如,碳酸丙二酯)和其它这样的载体中,并将这些溶液或悬浮液包裹于硬的或软的明胶胶囊壳中的方式制备液体或半固体口服制剂。其它有用的制剂包括美国专利号RE28,819和4,358,603中定义的那些。简要地说,这样的制剂包括但不限于,含有本发明提供的化合物、二烷基化的单或多聚亚烃基二醇(包括但不限于1,2-二甲氧基乙烷、二甘醇二甲醚、三甘醇二甲醚、四乙醇二甲醚、聚乙烯乙二醇-350二甲醚、聚乙烯乙二醇-550二甲醚、聚乙烯乙二醇-750二甲醚,其中350、550和750指聚乙烯乙二醇的大约平均分子量),和一种或多种抗氧化剂,例如丁基化羟基甲苯(BHT)、丁基化羟基茴香醚(BHA)、丙基没食子酸、维生素E,对苯二酚、羟基香豆素类、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨醇、磷酸、硫代二丙酸和它的酯,以及二硫代氨基甲酸盐(酯)。
其它的制剂包括但不限于,含有药学上可接受的乙缩醛的酒精水溶液。这些制剂中使用的醇是任何药学上可接受的易与水混合的具有一个或多个羟基基团的溶剂,包括但不限于丙二醇和乙醇。乙缩醛包括但不限于,低 级烷基醛例如乙醛二乙缩醛这样的二(低级烷基)乙缩醛。
2.注射剂、溶液和乳浊液
肠胃外给药,在一个实施方案中特征为注射,具体可以是皮下、肌肉内或静脉内注射,在本发明中也被考虑。可以以传统方式制备可注射的制剂,该制剂可以是液体溶液或悬浮液、也可以是适合在注射前配制成液体溶液或悬浮液的固体形式、或乳浊液。注射剂、溶液和乳浊液也可以含有一种或多种赋形剂。合适的赋形剂是,例如水、生理盐水、葡萄糖、甘油或乙醇。此外,如果需要,施用的药物组合也可以含有少量无毒辅助剂,如湿润或乳化制剂、pH缓冲制剂、稳定剂、溶解增强剂、和其它这样的制剂,例如乙酸钠、山梨醇单月桂酸酯、三乙醇胺油酸酯和环糊精。
植入缓释或持续释放系统,以便维持恒定水平的剂量(参见,例如,美国专利号3,710,795)也在本发明中考虑到了。简要地说,将本发明提供的化合物分散于固体内部基质中,例如,聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化的或未塑化聚氯乙烯、塑化尼龙、塑化的聚对苯二甲酸乙二醇酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、硅氧烷橡胶、聚二甲基硅氧烷、聚硅氧烷碳酸酯共聚物、亲水性聚合物例如丙烯酸和异丁烯酸的酯的水凝胶、胶原、交联聚乙烯醇和交联的部分水解的聚乙酸乙烯酯中,然后在外面包附一层聚合物的膜,例如,聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/乙基丙烯酸酯共聚物、乙烯/乙酸乙烯酯共聚物、硅氧烷橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯共聚物、偏二氯乙烯、乙烯和丙烯、聚对苯二甲酸乙烯酯离子聚合物、丁基橡胶均聚氯醇橡胶、乙烯/乙烯醇共聚物、乙 烯/乙酸乙烯/乙烯醇三元共聚物,和乙烯/乙烯氧基乙醇共聚物,这在体液中是不可溶的。化合物在释放速率控制步骤中通过外层聚合物膜分散。在这样的肠胃外组合物中含有的活性化合物的百分比高度取决于化合物本身的特性,以及化合物的活性和个体的需要。
组合物的肠胃外施用包括静脉内、皮下和肌肉内施用。肠胃外施用的制剂包含可注射的无菌水溶液、在使用之前可与溶剂混合的无菌干燥可溶性产品,例如冷冻干燥的粉末,包括皮下注射用的片剂、可注射的无菌悬浮液、在使用之前可与媒介物结合的无菌干燥不溶性产品和无菌乳状液。溶液可以是水溶液或非水性溶液。
如果在静脉内施用,合适的载体包括生理盐水或磷酸缓冲液(PBS),和含有增稠剂和增溶剂例如葡萄糖、聚乙烯乙二醇和聚丙烯乙二醇和它们的混合物的溶液。
肠胃外制剂中使用的药学上可接受的载体包括水性媒介物、非水性媒介物、抗菌剂、等渗剂、缓冲液、抗氧化剂、局部麻醉药、悬浮剂和分散剂、乳化剂、螯合剂和其它药学上可接受的物质。
水性媒介物的实例包括氯化钠注射液、林格注射液,等渗葡萄糖注射液、无菌水注射液、葡萄糖和乳酸化林格氏注射液。非水性肠胃外媒介物包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油。必须将抑制细菌或抑制真菌浓度的抗菌剂加入到装在多剂量容器中的肠胃外制剂中,所述抗菌剂包括酚或甲酚、汞制剂、苯甲基醇、三氯叔丁醇、对羟基苯甲酸甲酯或丙酯、硫汞撒、苯扎氯铵和苄索氯铵。等渗制剂包括氯化钠和葡萄糖。缓冲液包括磷酸盐和柠檬酸盐。抗氧化剂包括硫酸氢钠。局部麻醉剂包括盐酸普鲁卡因。悬浮和分散剂包括羧甲基纤维素钠、羟丙基甲基纤维素和 聚乙烯吡咯炕酮。乳化剂包括聚山梨脂80(Tween80)。金属离子的螯合剂包括EDTA。药学载体也包括做为水易混合的媒介物的乙基醇、聚乙二醇和丙二醇,以及用于调节pH值的氢氧化钠、盐酸、柠檬酸或乳酸。
调节药学活性化合物的浓度以便注射可提供有效的量从而得到所需的药理效果。确切的剂量取决于患者的年龄、体重和病症,这一点为本领域所共知。
单位剂量的肠胃外制剂被包装在安瓿、小瓶或带针注射器中。肠胃外施用的所有制剂都必须是无菌的,这是本领域所熟知和实行的。
示例性地,含有活性化合物的无菌水溶液的静脉或动脉内的输入是一种有效的施用模式。另一个实施方案是含有活性材料的无菌水性或油性溶液或悬浮液,按需注射从而产生需要的药理效果。
注射剂被设计成局部施用或系统施用。在一个实施方案中,给处理的组织配制治疗有效的剂量,其含有浓度至少为大约0.1%(w/w)到约90%(w/w)或更多,在另一个实施方案中,大于1%(w/w)的活性化合物。
化合物可以被悬浮在微粒化的或其它合适形式的溶剂中,或化合物可以被衍生得到可溶性更好的活性产品,或得到前药。产生的混和物的形式取决于很多因素,包括预定的给药模式和化合物在选定的载体或媒介物中的可溶性。有效浓度足以减轻病症的症状且由实验确定。
3.持续释放的剂量形式
本发明提供的活性成分可以通过控释的方式施用,或通过本领域普通技术人员所熟知的递送装置施用。实例包括但不限于,美国专利号3,845,770;3,916,899;3,536,809;3,598,123和4,008,719;5,674,533;5,059,595; 5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5,739,108;5,891,474;5,922,356;5,972,891;5,980,945;5,993,855;6,045,830;6,087,324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,376,461;6,419,961;6,589,548;6,613,358;6,699,500和6,740,634中所描述的那些,这些专利的每一个通过引用被纳入本文。这样的剂量形式可以被用来提供一种或多种活性成分的缓慢释放或受控释放,使用例如羟基丙基甲基纤维素、其它聚合物基质、凝胶、渗透膜、渗透系统、多层包衣、微颗粒、脂质体、微球体,或它们的联合,来提供需要的不同比例的释放特征。为本领域技术人员所熟知的合适的控释的制剂,包括本文中所描述的那些,可以被选择来与本发明提供的活性成分一起使用。
所有控释药物产品都有一个共同的目标,那就是提高它们的药物疗效,从而使之超越它们对应的非控释产品所取得的疗效。理想情况下,采用最少量的药物物质在最短时间内治愈或控制病症是最优设计的控释制剂在医学治疗中应用中的特点。控释制剂的优点包括药物活性延长,剂量频率减少,和患者的顺应性增加。此外,控释制剂能够被用来影响药物起作用时的时间或其它特征,如药物在血液中的水平,因而可以影响副作用(例如,不良作用)的发生。
大多数控释制剂被设计在最初释放一定量的可迅速产生所需治疗效果的药物(活性成分),逐渐和持续性地释放其余量的药物来维持药物在延长的一段时间内的治疗或预防效果。为了维持药物在体内的这种恒定水平,药物必须以一定的速率从剂量形式中释放出来以替代正被代谢和从体内排泄出来的药物量。活性成分的控释可以被各种条件所刺激,包括但不限于pH、温度、酶、水、或其它生理条件或药物。
在某些实施方案中,可以采用静脉输入、可植入的渗透泵、透皮贴剂、脂质体、或其它施用方式来施用制剂。在一个实施方案中,可采用泵(参见Sefton,CRC CnL Ref.Biomed.Eng.14:201(1987);Buchwald等人,Surgery88:507(1980);Saudek等,N.Engl J.Med.321:574(1989))。在另一个实施方案中,可以使用聚合材料。在又一个实施方案中,控释系统被植入治疗靶点附近,也就是说,仅需要系统剂量的一部分(参见,例如,Goodson,Medical Applications of Controlled Release,vol.2,第115-138页(1984))。在某些实施方案中,控释系统被植入到个体体内的不适宜的免疫激活位点或肿瘤附近。其它控释系统在Langer的综述中讨论(Science249:1527-1533(1990))。活性成分可以被分散在固体内部基质中,例如,聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化或未塑化(硬质)的聚氯乙烯、塑化尼龙、塑化的聚乙烯对苯二甲酸酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-醋酸乙烯共聚物、硅氧烷橡胶、聚二甲基矽氧烷、硅氧烷碳酸共聚物、亲水性聚合物例如丙烯酸和异丁烯酸的酯的水凝胶、胶原、交联聚乙烯醇和交联部分水解的聚醋酸乙烯酯中,然后在外面包被一层聚合物的膜,例如聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/乙基丙烯酸酯共聚物、乙烯/乙酸乙烯酯共聚物、硅氧烷橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯共聚物、偏二氯乙烯、乙烯和丙烯、聚对苯二甲酸乙烯酯离子聚合物、丁基橡胶均聚氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯/乙烯醇三元共聚物,和乙烯/乙烯氧基乙醇共聚物,这在体液中是不可溶的。活性成分在释放速率控制步骤中通过外层聚合物膜分散。在这样的肠胃外组合物中含有的活性化合物的百分比取决于化合物本身的特性和个体的需要。
4.冻干粉剂
冻干粉剂也是本发明感兴趣的,它可以被重新配制成溶液、乳浊液和其它混合物。它们也可以被重新配制成固体或凝胶。
通过将本发明提供的化合物,或它的药学上可接受的衍生物溶解于合适的溶剂中制备无菌冻干粉剂。溶剂可以含有可提高稳定性的赋形剂,或其它粉剂的或重新配制溶液的药理成分。可以使用的赋形剂包括但不限于,抗氧化剂、缓冲液和膨胀剂。在某些实施方案中,赋形剂选自右旋糖、山梨糖醇、果糖、玉米糖浆、木糖醇、甘油、葡萄糖、蔗糖、和其它合适制剂。溶剂可以含有缓冲液,例如,pH值大约中性的的柠檬酸、磷酸钠或磷酸钾、或其它本领域技术人员所知的这样的缓冲液。随后对溶液进行无菌过滤,在本领域技术人员所熟知的标准条件下进行冷冻干燥得到需要的制剂。在一个实施方案中,将所得溶液分装到小管中进行冷冻干燥。每个小管含有单一剂量的化合物或多剂量的化合物。将冷冻干燥的粉末储存在合适的条件下,例如大约4℃到室温。
用注射用水将冷冻干燥溶解得到肠胃外施用的制剂。为了重新溶解,将冷冻干燥的粉末加入到无菌水或其它合适的载体中。精确的量取决于选定的化合物。这样的量可通过经验确定。
5.局部施用
按本文描述的方法制备局部混合物来进行局部和系统施用。所得混合物可以是溶液、悬浮液、乳浊液等,并且可以被配制成乳膏、凝胶、软膏、乳浊液、溶液、酏剂、洗剂、悬浮液、酊剂、泥膏剂、泡沫剂、气溶胶、 冲洗液、喷雾剂、栓剂、绷带、透皮贴剂、或适合局部施用的任何其它制剂。
化合物或其药学上可接受的衍生物可以被配制成气溶胶供局部施用,例如通过吸入法施用(参见,例如美国专利号4,044,126;4,414,209和4,364,923,这些专利描述了气溶胶递送治疗炎症性疾病特别是哮喘的甾族化合物)。供呼吸道施用的这些制剂可以是气溶胶或供喷雾的溶液、供吸入的微细粉末,它们可以单独施用或与惰性载体如乳糖一起施用。在这样的情况下,制剂的颗粒,在一个实施方案中,直径小于50微米,在一个另一个实施方案中,小于10微米。
化合物可以被配制成凝胶、乳膏和洗剂供局部施用,例如,用于皮肤和粘膜例如眼的粘膜,用于眼睛或脑池或脊柱的局部施用。局部施可以是透皮给药,也可以是眼睛和粘膜施用,或用于吸入疗法。单独的活性化合物或与其它药学上可接受的赋形剂联合的鼻内溶液也可以被施用。
对于鼻内给药,制剂可以含有溶解或悬浮于液体载体,特别是水性载体的酯化的膦酸酯化合物,用于气溶胶。载体可以含有助溶剂例如丙二醇、表面活性剂、吸收增强剂例如卵磷脂或环湖精,或防腐剂。
这些溶液,特别是供眼科应用的那些溶液,可以被配制成0.01%-10%的等渗溶液,pH值大约为5-7,并含有适当的盐。
6.其它途径给药的组合物
其它的给药途径,如透皮贴片,包括等渗和电泳装置以及直肠施用也是本发明所考虑的。
透皮贴片,包括等渗和电泳装置都是本领域技术人员所熟知的。例如, 这样的贴片公开于美国专利号6,267,983、6,261,595、6,256,533、6,167,301、6,024,975、6,010,715、5,985,317、5,983,134、5,948,433和5,860,957。
例如,直肠施用的药物剂量形式是直肠栓剂、胶囊和具有系统效果的片剂。本文中的直肠栓剂意指用于插入直肠的固体,在体内温度下,它会溶解或变软并释放出一种或多种药学或治疗活性成分。直肠栓剂中使用的药学上可接受的物质是碱或媒介物和提高熔点的制剂。碱的实例包括可可溶油、甘油-明胶、碳蜡(聚氧乙烯乙二醇)和脂肪酸的甘油单-、二-和三-酯的适当混合物。可以使用各种碱的组合。提高栓剂熔点的制剂包括鲸油和蜡。可以通过压缩方法或塑形方法制备直肠栓剂。直肠栓剂的重量,在一个实施方案中是大约2到3gm。使用同样的药学上可接受的物质,并采用与制备口服制剂的一样的方法来制备直肠施用的片剂和胶囊。
7.靶向制剂
本发明提供的化合物,或它的药学上可接受的衍生物,也可以被配制成靶向特定组织、受体、或个体身体其它区域的制剂。许多这样的靶向方法都为本领域技术人员所熟知。所有这些靶向方法都被考虑用于即时组合物中。靶向方法的非限制性实例参见美国专利号6,316,652、6,274,552、6,271,359、6,253,872、6,139,865、6,131,570、6,120,751、6,071,495、6,060,082、6,048,736、6,039,975、6,004,534、5,985,307、5,972,366、5,900,252、5,840,674、5,759,542和5,709,874。
在一个实施方案中,脂质体悬浮液,包括组织靶向的脂质体,例如,肿瘤靶向的脂质体,可能适合作为药学上可接受的载体。按照本领域技术人员所熟知的方法制备这些物质。例如,可以按美国专利号4,522,811中描述 的方法制备脂质体制剂。简单说来,像传统多层脂质体(MLV)这样的脂质体可以通过将冻干的蛋黄磷脂酰胆碱和脑磷脂酰丝氨酸(7∶3的摩尔比)置于烧瓶内来制备。加入本发明提供的化合物的缺二价离子的磷酸缓冲液(PBS),摇动烧瓶直到脂质体薄膜分散开。清洗产生的小泡来去除没有被包围起来的化合物,离心沉淀,然后重悬于PBS中。
8.制造物品
化合物或药学上可接受的衍生物可以被包装成制造物品,其包括包装材料、包装材料内的本发明提供的治疗、预防或改善与病毒感染或不适宜的细胞增殖相关的疾病或病症的一种或多种症状有效的化合物或它的药学上可接受的衍生物、和标明化合物或组合物或其药学上可接受的衍生物是被用来治疗、预防或改善与病毒感染或不适宜的细胞增殖相关的疾病或病症的一种或多种症状的标签。
本发明提供的制造物品含有包装材料。用于包装药物产品的包装材料为本领域技术人员所熟知。参见,美国专利号5,323,907、5,052,558和5,033,252。药物包装材料的实例包括但不限于泡罩包装、瓶子、管子、吸入器、泵、袋子、小瓶、容器、注射器、瓶子、和适合选定的制剂和预定的施用和治疗模式的任何包装材料。本发明提供的化合物和组合物制剂的多种配置被认为是治疗与病毒感染或不适宜的细胞增殖相关的疾病或病症的多种方式。
E.剂量
在人类治疗中,医生将会按照预防或治疗的性质和个体的年龄、体重、 和疾病所处的阶段和个体其它特有的因素来决定最合适的剂量方案。药物组合物,在另一个实施方案中,会提供大约0.001mg到大约2000mg的化合物/每千克体重/天的剂量。制备药物剂量单位形式来提供例如每剂量单位大约0.01mg、0.1mg或1mg到大约500mg、1000mg或2000mg,在一个实施方案中,大约10mg到大约500mg的活性成分或必需成分的组合。
本发明提供的制剂中的,在治疗或预防疾病或其一种或多种症状中有效的活性成分的量,会随着疾病或病症的性质和严重性、以及活性成分施用的方式而改变。频率和剂量也会根据每一个个体的具体因素(取决于所采用的具体疗法,例如,治疗剂或预防剂),病症、疾病、或症状的严重性,给药方式,以及个体的年龄、体重、反应性和既往病史而改变。
制剂的示例性剂量包括毫克或微克活性化合物/千克个体或样品质量(例如,大约1微克/千克到大约50毫克/千克,大约10微克/千克到大约30毫克/千克,大约100微克/千克到大约10毫克/千克,或约100微克/千克到大约5毫克/千克)。
在某些情况下,需要使用的活性成分的剂量在本文公开的范围之外,这一点对于本领域普通技术人员而言是显而易见的。而且,应该理解临床或主治医生知道如何和何时根据病人的反应而中断、调整或终止治疗。
不同的治疗有效量可以适用于不同的疾病和病症,这是本领域普通技术人员所知的。类似地,足以预防、控制、治疗或改善这样的病症,但不足以引起或足以降低与本发明提供的组合物相关的不良效果的量也是上述剂量和剂量频率方案所包括的。而且,当给个体施用多副剂量的本发明提供的组合物时,并不是所有的剂量都必须一样。例如,可以增加给个体施用的剂量从而提高组合物的预防或治疗效果,也可以降低剂量从而减少特定 的个体正经历的一种或多种不良作用。
在某些实施方案中,可以重复施用本发明提供的相同化合物,施用时间也可以间隔至少1天、2天、3天、5天、10天、15天、30天、45天、2个月、75天、3个月、或6个月。
F.化合物活性的评价
可以用本领域已知的标准实验测定作为抗病毒制剂的化合物的活性。典型的实验包括但不限于:HFF细胞的空斑形成减少实验、MRC-5细胞的DNA还原试验、MT-2细胞的p24还原试验、HFF细胞的CPE试验和Daudi细胞的EBV Elisa试验。
在表1中,提供了本发明提供的化合物的EC50值。
表15-膦酰-戊-2-烯-1-基核苷和它们的炕氧基烷基膦酰基酯的抗病毒活性
有效浓度的50%,EC50,μM;1AD169,HFF细胞的空斑形成减少实验;2HSV-1,MRC细胞的DNA减少试验;3牛痘苗WR,HFF细胞的空斑形成减少实验;4牛痘Brighton,HFF细胞的空斑形成减少实验;5HIV-1Lai,MT-2细胞的p24减少试验;6VZV,HFF细胞的CPE试验;7HBV,2.2.15细胞的DNA减少试验;Daudi细胞的8EBV Elisa试验。缩写:HDP-,十六烷氧基丙基;ODE-,十八烷氧基乙基-;OLE-,油氧乙基。ND=未测定。
表2中,示例性化合物的活性进一步提供如下:
表2 ODE-和OLE-PPen-G对人类和小鼠CMV的体外抗病毒活性
[0231] 表3提供了HDP-PPen-A和HDP-PPen-G对3TC和阿德福韦酯耐受的B型肝炎病毒突变体的效果的体外实验数据。
表3抗野生型HBV和药物耐受的HBV的体外抗病毒活性
B型肝炎病毒耐受突变体。数据是胞内HBV复制中间体(HBVR.I.)的EC50,μM。括号中的化合物是突变体耐受的HBV药物。
PPen-A的十六烷氧基丙基酯对已经对3TC(Epivir)耐受的B型肝炎病毒(突变体M204V、M204I、L180M和双突变体L180M/M204V)有完全活性。HDP-PPen-A对阿德福韦酯(Hepsera)耐受的(由于N236T突变)HBV也有完全活性。HDP-PPen-G对某些3T3耐受的病毒,M204V和M204I有活性,但对L180M无活性。HDP-PPen-G对阿德福韦酯耐受的有N236T突变的突变体有完全活性。
G.化合物和组合物的使用方法
本发明提供了使用所述化合物和组合物来治疗、预防或改善与病毒感染或不适宜的细胞增殖相关的疾病或病症的一种或多种症状的方法。在实施这些方法时,施用有效量的化合物或含有治疗有效浓度的化合物的组合物。 在某些实施方案中,本发明提供的方法是预防或减轻与病毒感染相关的疾病或病症的一种或多种症状的方法,所述病毒感染包括但不限于流感病毒;B型和C型肝炎病毒;巨细胞病毒(CMV);疱疹感染,例如由水痘-带状疱疹病毒、单纯疱疹1型或2型病毒、EB病毒、6型疱疹病毒(HHV-6)和8型疱疹病毒(HHV-8)所引起的那些感染;水痘带状庖疹病毒感染,如带状疱疹或水痘;EB病毒感染,包括但不限于感染性的单核细胞增多[症]/腺瘤;反转录病毒,包括但不限于SIV、HIV-1和HIV-2;埃博拉病毒;腺病毒和乳头瘤病毒。
在又一个实施方案中,本发明提供的方法是治疗、预防或减轻由原痘病毒导致的病毒感染的一种或多种症状的方法,所述原痘病毒例如大天花和小天花、牛痘苗、天花、牛痘、驼痘和猴痘病毒。在某些实施方案中,疾病是药物耐受的B型肝炎。
在某些实施方案中,本发明提供的方法是治疗、预防或减轻与细胞增殖(包括但不限于癌症)相关的疾病的一种或多种症状的方法。癌症的实例包括但不限于肺癌、头和颈部的鳞状癌、结肠癌、前列腺癌、乳腺癌、急性淋巴细胞白血病、成人急性髓系白血病、成人非霍奇金淋巴瘤、脑癌、颈癌、儿童癌症、儿童肉瘤、慢性淋巴性白血病、慢性髓系白血病、食管癌、毛细胞白血病、肾癌、肝癌、多发性骨髓瘤、成神经细胞瘤、口腔癌、胰腺癌、原发性中枢神经系统淋巴癌、和皮肤癌。
H.联合疗法
本发明提供的化合物和组合物也可以与一种或多种其它活性成分联合使用。在某些实施方案中,化合物可以与另一种治疗制剂联合或依次使用。 这样的其它治疗制剂包括那些已知用来治疗、预防或减轻与病毒感染或不适宜的细胞增殖相关的一种或多种症状的制剂。这样的治疗制剂包括但不限于抗病毒制剂和抗肿瘤制剂。
最近,已经证明可以通过使化合物与第二种,也许第三种抗病毒化合物(它们引起的变化与主化合物引起的变化不同)联合或交替施用的方法来延长、增强或恢复药物对抗HIV感染的效果。可选择地,可以通过使用这样的联合或交替疗法来改变药物的动力学、生物分布或其它参数。
在某些实施方案中,本发明提供了预防或治疗的方法,包括施用第二种治疗或预防病毒感染如HIV和/或HCV感染的有效制剂。该第二种制剂可以是本领域技术人员所知的对于治疗、预防或改善病毒感染如HIV和/或HCV感染有效的任何制剂。该第二种制剂可以是本领域技术人员目前了解的第二种制剂,或该第二种制剂可以是后来开发出来的用于病毒感染的治疗、预防或改善的第二种制剂。在某些实施方案中,所述第二种制剂可以被批准用于治疗或预防HIV或HCV感染。
在某些实施方案中,本发明提供的化合物与一种第二种制剂联合施用。在又一个实施方案中,本发明提供的化合物与两种第二种制剂联合施用。在又一个实施方案中,本发明提供的化合物与两种或多种第二种制剂联合施用。
在一个实施方案中,第二种治疗HIV的抗病毒制剂是反转录酶抑制剂(RTI),它可以是合成的核苷(NRTI)或非-核苷化合物(NNRTI)。在另一个实施方案中,在HIV的情况下,第二种(或第三种)抗病毒制剂是蛋白酶抑制剂。在其它实施方案中,第二(或第三)种化合物可以是焦磷酸酯类似物,或融合的结合性抑制剂。
在某些实施方案中,用于联合或交替疗法治疗HBV的化合物包括但不限于3TC、FTC、L-FMAU、干扰素、β-D-二氧戊环-鸟嘌呤(DXG)、β-D-二氧戊环-2,6-二氨基嘌呤(DAPD)、和β-D-二氧戊环-6-氯嘌呤(ACP)、泛昔洛韦、喷昔洛韦、BMS-200475、二匹伏酯(阿地福韦酯)、洛布卡韦、更昔洛韦和利巴韦林。
在又一个实施方案中,能够与本发明公开的化合物联合或交替使用来进行HIV治疗的抗病毒制剂的实例包括顺-2-羟基甲基-5-(5-氟胞嘧啶-1-基)-1,3-氧硫杂环戊烷(FTC);2-羟甲基-5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷(3TC)的(-;+)对映异构体;卡巴韦、阿昔洛韦、膦甲酸钠、干扰素、AZT、DDI、DDC、D4T、CS-87(3’-叠氮-2’,3’-双脱氧尿苷);和β-D-二氧戊环核苷,例如,β-D-二氧戊环-鸟嘌呤(DXG)、β-D-二氧戊环-2,6-二氨基嘌呤(DAPD)、和β-D-二氧戊环-6-氯嘌呤(ACP)、MKC442(6-苄基-1-(乙氧基甲基)-5-异丙基尿嘧啶。
蛋白酶抑制剂包括茚地那韦(Merck)、奈非那韦(Agouron)、利托那韦(Abbott)、沙奎那韦(Roche)、DMP-266(Sustiva)和DMP-450(DuPont Merck)。
能够与本发明提供的任何一种化合物联合或交替施用的其它化合物包括(1S,4R)-4-[2-氨基-6-环丙基-氨基)-9H-嘌呤-9-基]-2-环戊烯-1-甲醇琥珀酸盐或酯(“1592”,卡巴韦的类似物);3TC;-β-L-2′,3′-二脱氧-3′-硫胞嘧啶;a-APA R18893:a-硝基-苯胺基-苯乙酰胺;A-77003:C2基于对称的蛋白酶抑制剂;A-75925:C2基于对称的蛋白酶抑制剂;AAP-BHAP:bisheteroarylpiperazine类似物;ABT-538:C2基于对称的蛋白酶抑制剂;AzddU:3′-叠氮-2′,3′-二脱氧尿苷;AZT:3′-叠氮-3′-脱氧胸腺嘧啶核苷;AZT-p-ddI:3′-叠氮-3′-脱氧胸腺嘧啶基-(5′,5′)-2′,3′-二脱氧肌苷酸;BHAP: bisheteroarylpiperazine;BILA 1906:N-{1S-[[[3-[2S-{(1,1-二甲基乙基)氨基]羰基}-4R-]3-吡啶甲基)硫]-1-哌啶基]-2R-羟基-1 S-(苯甲基)丙基]氨基]羰基]-2-甲基丙基}-2-喹啉甲酰胺;BILA 2185:N-(1,1-二甲基乙基)-1-[2S-[[2-2,6-二甲基苯氧基]-1-氧基乙基]氨基]-2R-羟基-4-苯基丁基]4R-吡啶基硫代)-2-哌啶-甲酰胺;BM+51.0836:噻唑基-异吲哚啉酮衍生物;BMS186,318:氨基二醇衍生物HIV-1蛋白酶抑制剂;d4API:9-[2,5-二氢-5-(膦酰甲氧基)-2-呋喃基]腺嘌呤;d4C:2′,3′-二脱氢-2′,3′-二脱氧胞甙;d4T:2′,3′-二脱氢-3′-脱氧胸苷;ddC:2′,3′-二脱氧胞苷;ddI:2′,3′-双脱氧肌苷;DMP-266:a 1,4-二氢-2H-3,1-氧氮杂萘-2-酮;DMP-450:{[4R-(4-a,5-a,6-b,7-b)]-hexabydro-5,6-双(羟基)-1,3-双(3-氨基)苯基]甲基)-4,7-双(苯基甲基)-2H-1,3-二氮杂-2-酮}-双甲磺酸;DXG:(-;)-β-D-二氧戊环-鸟苷;EBU-dM:5-乙基-1-乙氧基甲基-6-(3,5-二甲基苄基)尿嘧啶;E-EBU:5-乙基-1-乙氧基甲基-6-苄基尿嘧啶;DS:硫酸葡聚糖;E-EPSeU:1-(乙氧基甲基)-(6-苯基硒)-5-乙基尿嘧啶;E-EPU:1-(乙氧基甲基)-(6-苯基-硫代)-5-乙基尿嘧啶;FTC:β-2′,3′-二脱氧-5-氟-3′-硫胞嘧啶核苷(Triangle);HBY097:S-4-异丙氧基羰基-6-甲氧基-3-(甲基硫代-甲基)-3,4-二氢喹喔啉-2(1H)-硫酮;HEPT:1-[(2-羟基乙氧基)甲基]-6-(苯基硫代)胸腺嘧啶;HIV-1:人类免疫缺陷病毒1型;JM2763:1,1’-(1,3-丙二基)-双-1,4,8,11-四氮杂环十四烷;JM3100:1,1′-[1,4-次苯基双-(亚甲基)]-双-1,4,8,11-四氮杂环十四烷;KNU-272:含有(2S,3S)-3-氨基-2-羟基-4-苯基丁酸-的三肽;L-697,593:5-乙基-6-甲基-3-(2-苯二酰亚氨基-乙基)吡啶-2(1H)-酮;L-735,524:羟基-氨基戊烷酰胺HIV-1型蛋白酶抑制剂;L-697,661:3-{[(4,7-二氯-1,3-苯并噁唑-2-基)甲基]氨基}-5-乙基-6-甲基吡啶-2(1H)-酮;L-FDDC:(-;)-β-L-5-氟-2′,3′- 二脱氧胞苷;L-FDOC:(-;)-β-L-5-氟-二氧戊环胞嘧啶;MKC442:6-苄基-1-乙氧基甲基-5-异丙基尿嘧啶(I-EBU);奈维拉平:11-环丙基-5,11-二氢-4-甲基-6H-二吡啶酚[3,2-b:2′,3′-e]二氮杂卓-6-酮;NSC648400:1-苄氧甲基-5-乙基-6-(α-吡啶基硫代)尿嘧啶(E-BPTU);P9941:[2-吡啶乙酰基-IlePheAla-y(CHOH)]2;PFA:膦甲酸钠;PMEA:9-(2-膦酰基甲氧基乙基)腺嘌呤;PMPA:(R)-9-(2-膦酰基-甲氧基丙基)腺嘌呤;Ro 31-8959:羟乙胺衍生的HIV-1型蛋白酶抑制剂;RPI-312:肽基蛋白酶抑制剂,1-[(3s)-3-(n-α-苄氧基羰基)-1-天冬酰胺基)-氨基-2-羟基-4-苯基丁基]-n-叔丁基-1-脯氨酸酰胺;2720:6-氯-3,3-二甲基-4-(异苯氧基羰基)-3,4-二氢-喹喔啉-2(1H)硫酮;SC-52151:羟乙基脲等配物的蛋白酶抑制剂;SC-55389A:羟乙基-脲等配物蛋白酶抑制剂;TIBO R82150:(+)-(5S)-4,5,6,7-四氢-5-甲基-6-(3-甲基-2-丁烯基)咪唑[4,5,1-jk][1,4]-苯并二氮杂卓-2(1H)-硫酮;TIBO 82913:(+)-(5S)-4,5,6,7-四氢-9-氯-5-甲基-6-(3-甲基-2-丁烯基)咪唑[4,5,1jk]-[1,4]苯并-二氮杂卓-2(1H)-硫酮;TSAO-m3T:[2′,5′-双-O-(叔丁基二甲基甲硅烷基)-3′-螺-5′-(4′-氨基-1′,2′-oxathiole-2′,2′-二氧)]-b-D-pentofiaranosyl-N3-甲基胸腺嘧啶;U90152:1-[3-[(1-甲基乙基)-氨基]-2-吡啶]-4-[[5-[(甲基磺酰)-氨基]-1H-吲哚-2-基]羰基]-哌嗪;UC:硫代甲酰苯胺衍生物(Uniroyal);UC-781=N-[4-氯-3-(3-甲基-2-丁烯氧基)苯基]-2-甲基-3-呋喃羰硫酰胺;UC-82=N-[4-氯-3-(3-甲基-2-丁烯氧基)苯基]-2-甲基-3-噻吩硫代苯甲酰胺;VB 11,328:羟乙基-磺胺蛋白酶抑制剂;VX-478:羟乙基-磺胺蛋白酶抑制剂;XM 323:环脲蛋白酶抑制剂。
在某些实施方案中,合适的第二制剂包括小分子口服的生物可获得的HCV酶抑制剂,攻击病毒RNA的核酸类制剂,能调节宿主免疫反应的制剂。 示例性的第二制剂包括:(i)当前批准的疗法(peg-干扰素加利巴韦林),(ii)靶向HCV酶的化合物,(iii)靶向病毒基因组的疗法(例如,RNA干扰素或RNAi),和(iv)免疫调节制剂例如利巴韦林、干扰素(INF)和Toll-受体激动剂。
在某些实施方案中,第二制剂是NS3-4A蛋白酶的调节剂。NS3-4A蛋白酶是异源二聚体的蛋白酶,包括NS3蛋白和小NS4A辅助因子的氨基末端结构域。它的活性对于病毒RNA复制复合物成分的产生是必须的。
一种有用的NS3-4A蛋白酶抑制剂是BILN2061(Ciluprevir;BoehringerIngelheim),一种多肽产物抑制剂的大环模拟物。尽管用BILN2061所作的临床实验被停止了(临床前期出现了心脏中毒现象),但它是在人体内测试过的第一个NS3抑制剂。参见Lamarre等人,2003,Nature 426:186-189,该文献的全部内容通过引用被纳入本文中。
另一种有用的NS3-4A蛋白酶抑制剂是VX-950(Vertex/Mitsubishi),一种NS3-4A蛋白酶的蛋白酶切除产物衍生的肽模拟物的抑制剂。通常认为它是通过酮氨基稳定到酶活性位点上。参见Lin等人2005,J Biol Chem.草稿M506462200(电子出版物);Summa,2005,Curr Opin Investig Drugs.6:831-7,这些文献的内容通过引用被完全纳入本文中。
在某些实施方案中,第二制剂是HCV NS5B(RNA依赖的RNA聚合酶(RdRp))的调节剂。在NS5B蛋白中,RdRp使用RNA模版来合成RNA。在哺乳动物细胞中,这种生物化学活性并不存在。
RdRp的一种有用的调节剂是NM283(Valopicitabine;Idenix/Novartis)。NM283,是NM107(2-C-甲基-胞嘧啶)的口服前药(缬氨酸的酯),它用于治疗或预防HCV感染,已进入II期临床。参见,例如,美国专利申请公开号20040077587,该申请的内容通过引用被全部纳入本文中。
RdRp的其它有用的调节剂包括7-deaza核苷类似物。例如,7-deaza-2′-C-甲基-腺苷是C型肝炎病毒复制的强的和选择性的抑制剂,它有极好的药物动力学特征。Olsen等人,2004,Antimicrob.Agents Chemother.48:3944-3953,该文献通过引用被全部纳入本文中。
在又一个实施方案中,第二制剂是NS5B的非-核苷调节剂。至少有三种不同类型的NS5B非核苷抑制剂正在进行临床评估。
有用的NS5B的非核苷调节剂包括JTK-003和JTK-009。JTK-003已经进展到临床II期。有用的NS5B的非核苷调节剂包括基于苯并咪唑或吲哚核心的6,5-融合的杂环化合物。参见,例如,Hashimoto等人,WO 00147883,该申请通过引用被全部纳入本文中。
进一步有用的聚合酶NNI包括R803(Rigel)和HCV-37l、HCV-086和HCV-796(ViroPharma/Wyeth)。其它有用的NNI包括噻吩衍生物,它是NS5B聚合酶的可逆变构抑制剂,并且结合位点靠近但不同于苯并咪唑类的抑制剂所占据的位点。参见,例如,Biswal等人,J.Biol.Chem.280,18202-18210(2005)。
对本发明提供的方法进一步有用的NNI包括苯并噻二嗪类,例如,苯并-1,2,4-噻二嗪。苯并-1,2,4-噻二嗪的衍生物已被证明是HCV的RNA聚合酶的高度选择性抑制剂。Dhanak等人,2002,J.Biol.Chem.277:38322-38327,该文献的内容通过引用被全部纳入本文中。
对本发明提供的方法进一步有用的NNI以及它们的机制在下列文献有讨论,LaPlante等人,2004 Angew Chem.Int.Ed.Engl.43:4306-4311;Tomei等人,2003,J.Virol.77:13225-13231;Di Marco等人,2005,J.Biol.Chem.280:29765-70;Lu,H.,WO 2005/000308;Chan等人,2004,Bioorg.Med. Chem.Lett.14:797-800;Chan等人2004,Bioorg.Med.Chem.Lett.14:793-796;Wang等人2003,J.Biol.Chem.278:9489-9495;Love等人,2003,J.Virol 77:7575-7581;Gu等人,2003,J.Biol.Chem.278:16602-16607;Tomei等人,2004,J.Virol 78:938-946;和Nguyen等人,2003,Antimicrob.Agents Chemother.47:3525-3530;这些文献通过引用被全部纳入本文中。
在又一个实施方案中,第二制剂是能够干扰HCV的RNA,例如靶向HCV多聚核苷的小的抑制性RNA或短的发夹RNA(shRNA)的制剂。在组织培养物中,靶向病毒基因组的siRNA和载体编码的短发夹RNAshRNA,有效地阻止HCV复制子的复制。参见,Randall等人,2003,Proc.NatlAcad.Sci.USA100:235-240,该文献通过引用被全部纳入本文中。
在又一个实施方案中,第二制剂是可调节个体免疫反应的制剂。例如,在某些实施方案中,第二制剂是目前已被批准的HCV感染的疗法,如,干扰素(IFN)、聚乙二醇化干扰素、干扰素加利巴韦林或聚乙二醇化干扰素加利巴韦林。在某些实施方案中,干扰素包括IFNα、IFNα2a和IFNα2b,以及特别是聚乙二醇化的IFNα2a(PEGASYS)或聚乙二醇化的IFNα2b(PEG-INTRON)。
在又一个实施方案中,第二制剂是Toll样受体(TLR)的调节剂。通常认为TLR是刺激天生的抗病毒反应的靶标。合适的TLR包括但不限于TLR3、TLR7、TLR8和TLR9。通常认为Toll样的受体感受侵入的微生物,如细菌、病毒和寄生物的存在。它们由免疫细胞包括巨噬细胞、单核细胞、树突状细胞和B细胞表达。刺激或激活TLR能够诱导抗微生物基因和促炎细胞因子和趋化因子的表达,从而起始急性炎症反应。
在某些实施方案中,第二制剂是含有CpG基序的多核苷酸。合成的含有未甲基化的CpG基序的寡核苷酸是TLR-9的有效激动剂。用这些寡核苷酸刺激树突状细胞会引起肿瘤坏死因子-α、白介素-12和干扰素-α的产生。TLR-9的配基也是B细胞增殖和抗体分泌的强刺激因子。一种有用的含有CpG的寡核苷酸是CPG-10101(Actilon;Coley Pharmaceutical Group),它已经在进行临床试验。
TLR的另一个有用的调节剂是ANA975(Anadys)。ANA975被认为是通过TLR-7起作用,已经知道它通过诱导和释放炎症细胞因子,如IFN-α来引起强的抗病毒反应。
在又一个实施方案中,第二制剂是Celgosivir。Celgosivir是α-糖甙酶I的抑制剂,并通过宿主介导的糖基化起作用。在临床前期的研究中,Celgosivir被证明与IFN-α加利巴韦林有很强的协同性。参见,Whitby等人,2004,Antivir Chem Chemother.15(3):141-51。在加拿大,Celgosivir当前正在慢性HCV患者中进行的II期单疗法研究中接收评估。
其它的免疫调节制剂,和它们的机制或靶标在Schetter&Vollmer,2004,Czar.Opin.Drug Discov.Dev.7:204-210;Takeda等人2003,Annu.Rev.Immunol 21:335-376;Lee等人2003,Proc.Natl Acad.ScI USA 100:6646-6651;Hosmans等人2004,Hepatology 40(Suppl.1),282A;和美国专利号6,924,271中有描述,这些文献中都通过引用各自被纳入本文。
在某些实施方案中,本发明提供的化合物可以与一种或多种抗癌制剂联合施用。与本发明提供的化合物联合施用的抗癌制剂包括但不限于,antifolate;5-氟嘧啶(包括5-氟尿嘧啶);胞苷类似物,如β-L-1,3-二氧戊环胞苷,或β-L-1,3-二氧戊环5-氟胞苷;抗代谢物(包括嘌呤抗代谢物、阿糖 孢苷、fudarabine、氟尿苷、6-巯基嘌呤、甲氨蝶呤和6-硫鸟嘌呤);羟基脲;有丝分裂抑制剂(包括CPT-11,依托泊苷(VP-21)、紫杉醇,和长春花属生物碱例如长春新碱和长春花碱);烷基化制剂(包括但不限于甲磺酸丁二醇二酯、苯丁酸氮芥、环膦酰胺、异环膦酰胺、氮芥、左旋苯丙氨酸氮芥和噻替派),非经典的烷基化制剂、含铂化合物、博莱霉素、抗肿瘤的抗生素、蒽环类药物例如阿霉素和dannomycin、蒽二酮、拓扑异构酶II的抑制剂、激素制剂(包括但不限于皮质类固醇(地塞米松、脱氢可的松和甲基脱氢可的松)、雄激素例如氟甲睾酮和甲睾酮、雌激素例如己烯雌酚、抗雌激素制剂例如三苯氧胺、LHRH类似物例如亮丙瑞林,抗睾丸素制剂例如氟他胺、氨鲁米特、甲地孕酮、和甲羟孕酮)、天门冬酰胺酶、亚硝基脲氮芥、罗氮芥、六甲基-三聚氰胺、达卡巴嗪、米托坦、链脲霉素、顺铂、卡铂、levamasole和甲酰四氢叶酸。本发明的化合物也可以与酶疗法制剂和免疫系统调节剂如干扰素、白介素、肿瘤坏死因子、巨噬细胞集落刺激因子和集落刺激因子联合使用。
应该理解的是本发明提供的化合物与一种或多种上面提到的化合物和任选的另外一种或多种药物活性物质的合适联合使用被认为在本发明的范围之内。在又一个实施方案中,本发明提供的化合物在一种或多种其它活性成分之前或之后施用。
提供下面的实施例仅仅是为说明性的目的,并不是要限制本发明的范围。
实施例
在实施例6、7和8中,详细描述了PPen-U 22、PPen-C 23和PPen-T 24 的合成。尿嘧啶和胸腺嘧啶的三信酯化反应提供了相应的二乙基膦酰酯,将其水解,得到PPen-U 22和PPen-T 24。用PPen-U的二乙基膦酰酯19合成PPen-C的二乙基膦酰酯20。通过使用TMSBr将化合物20转化为PPen-C23。实施例9、10、11显示了PPen-U 22、PPen-C 23和PPen-T 24的HDP衍生物的合成。
实施例1
(5-羟基-戊-3-烯基)-磷酸二乙基酯的合成
A.2-丁-3-炔氧基-四氢-吡喃(2)
将二氢吡喃(1.7mL,19mmol)滴加到3-丁炔-1-醇(1.00g,14.3mmol)和PPTS(0.72g,2.9mmol)的CH2Cl2溶液中,将所得混合物搅拌过夜。用CH2Cl2(80mL)稀释反应混合物,并用0.02N NaOH(50mL)和盐水(100mL)清洗反应混合物。将有机层用MgSO4干燥浓缩,用硅胶柱层析法,3-5%EtOAc的己烷溶液纯化剩余物得到1.90g的化合物2(12.3mmol,86%的产率):1H NMR(CDCl3)δ4.63(t,J=3.4Hz,1H),3.92-3.77(m,2H),3.59-3.45(m,2H),2.47(td,J=7.1,2.8Hz,2H),1.96(t,J=2.5Hz,1H),1.90-1.44(m,6H)。
B.5-(四氢-吡喃-2-基氧基)-戊-2-炔-1-醇(3)
在0℃下,在20分钟的时间内,将1.6 M的n-BuLi己烷溶液(58mL,92.8mmol)滴加到化合物2(11.0g,71.3mmol)的THF(80mL)溶液中。30分钟后,在0℃下,将多聚甲醛(6.4g)加入到反应混合物中。5小时后,在0℃下,用NH4Cl水溶液来终止反应混合物,并用EtOAc(200mL)来稀释反应混合物, 用NH4Cl水溶液和盐水清洗反应混合物。将有机层置于MgSO4干燥浓缩。用硅胶柱层析法,用20%EtOAc的己炕溶液对残余物进行纯化得到8.15g的化合物3(44.2mmol,62%的产率):1H NMR(CDCl3)δ4.63(t,J=3.4Hz,1H),4.22(t,J=2.1Hz,2H),3.91-3.76(m,2H),3.59-3.46(m,2H),2.51(tt,J=7.1,2.2Hz,2H),1.86-1.46(m,6H)。
C.叔-丁基-二苯基-[5-(四氢-吡喃-2-基氧基)-戊-2-炔氧基]-硅烷(4)
在0℃下,在2小时的时间内,将TBDPSCl滴加到化合物3和咪唑的CH2Cl2的溶液中。用CH2Cl2(300mL)稀释反应混合物并用水(200mL)洗涤。将有机层至于MgSO4干燥浓缩。用硅胶柱层析法,用10%EtOAc的己烷溶液纯化残余物得到18.0g的化合物4(42.6mmol,96%的产率):1H NMR(CDCl3)δ7.80-7.64(m,4H),7.49-7.34(m,6H),4.63(t,J=3.6Hz,1H),4.31(t,J=1.9Hz,2H),3.93-3.83(m,1H),3.77(dt,J=9.7,7.1Hz,1H),3.55-3.44(m,2H),2.48(tt,J=7.1,2.1Hz,2H),1.89-1.46(m,6H),1.06(s,9H)。
D.5-(叔-丁基-二苯基-硅烷氧基)-戊-3-炔-1-醇(5)
在室温下,用PPTS(0.36g,1.43mmol)将化合物4(6.12g,14.5mmol)的MeOH溶液(100mL)处理过夜。浓缩后,用硅胶柱层析法,用20%EtOAc的己烷溶液纯化残余物得到3.84g的产物5(11.3mmol,78%的产率):1HNMR(CDCl3)δ7.80-7.66(m,4H),7.49-7.35(m,6H),4.33(t,J=1.9Hz,1H),3.60(t,J=6.0Hz,2H),2.40(tt,J=2.2,6.1Hz,2H)1.05(s,9H)。
E.(5-溴-戊-2-炔氧基)-叔-丁基-二苯基-硅烷(6)
在-78℃下,将Ph3P(1.27g,4.84mmol)的CH2Cl2(30mL)溶液滴加到化合物5(1.09g,3.22mmol)和CBr4(1.28g,3.86mmol)的CH2Cl2(70mL)溶液中。30分钟后,在2小时内逐步将反应混合物加热到室温,然后搅拌过夜。将反应混合物倒在硅胶垫上。将滤出液浓缩到干燥状态。浓缩后,用硅胶柱层析法,用0-2%EtOAc的己烷溶液纯化残余物得到1.28g的产物6(3.19mmol,99%的产率):1H NMR(CDCl3)δ7.80-7.65(m,4H),7.50-7.32(m,6H),4.34(t,J=1.9Hz,1H),3.35(t,J=5.8Hz,2H),2.73(tt,J=2.1,6.0Hz,2H),1.08(s,9H)。
F.[5-(叔-丁基-二苯基-硅烷氧基)-戊-3-炔基]-磷酸二乙酯(7)
在氮气下,将化合物6(3.24g,80.7mmol)和磷酸三乙酯(40mL)的混合物回流过夜。当蒸发后,用硅胶柱层析法,用50%EtOAc的己烷溶液纯化残余物得到3.26g的产物7(7.90mmol,98%的产率):1H NMR(CDCl3)δ7.77-7.64(m,4H),7.46-7.32(m,6H),4.29(t,J=1.9Hz,2H),4.16-4.02(m,4H),2.50-2.34(m,2H),1.96-1.82(m,2H),1.31(t,J=7.1Hz,6H),1.04(s,9H);31P NMR(CDCl3)δ 30.43。
G.[5-(叔-丁基-二苯基-硅烷氧基)-戊-3-烯基]-磷酸二乙酯(8)
用气囊用H2处理化合物7(5.00g,10.9mmol)和Lindlar’s催化剂(5%铅中毒的碳酸钙载钯)的MeOH的混合物。过夜后,过滤反应混合物,并浓缩干燥得到2.50g的产物8(5.5mmol,50%的产率):1H NMR(MeOH-dA)δ7.73-7.56(m,4H),7.44-7.32(m,6H),5.68-5.57(m,1H),5.45-5.34(m, 1H),4.25(d,J=6.0Hz,2H),4.08-3.97(m,4H),2.24-2.10(m,2H),1.74-1.61(m,2H),1.26(t,J=7.1Hz,6H),1.03(s,9H);31P NMR(MeOH-dA)δ32.17。
H.(5-羟基-戊-3-烯基)-磷酸二乙酯(9)
在0℃下,用1.0M的TBAF的THF溶液(1.7mL)处理化合物8(0.67g,1.46mmol)的乙腈(20mL)溶液。1小时后,浓缩反应混合物,用硅胶柱层析法,用5%MeOH的CH2Cl2溶液纯化混合物得到0.32g的化合物9(1.44mmol,99%的产率):1H NMR(CDCl3)δ5.66-5.47(m,2H),4.16-4.02(m,6H),2.43-2.28(m,2H),1.94-1.79(m,2H),1.32(t,J=7.1Hz,6H);31P NMR(CDCl3)δ 33.47。
实施例2
9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤(13,PPen-A)的合成
A.9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤二乙基膦酰酯(10)
将腺嘌呤的(0.49g,0.36mmol)的DMF溶液加入到装有化合物9(0.32g,1.4mmol)的烧瓶中。在0℃下,用Ph3P(0.94g,0.36mmol)和DIAD(0.70mL,0.36mmol)依次处理所得混合物。过夜后,浓缩混合物,用硅胶柱层析法,用5-10%MeOH的CH2Cl2溶液纯化残余物得到0.2g的化合物10(0.589mmol,42%的产率):1HNMR(CDCl3)δ8.36(s,1H),7.86(s,1IH),5.83(brs,2H),5.82-5.61(m,2H),4.86(d,J=6.6Hz,2H),4.18-4.02(m,4H),2.63-2.49(m,2H),1.88(dt,J=17.9,7.4Hz,2H),1.32(t,J=6.9Hz,6H); 31P NMR(CDCl3)δ31.71;MS(ESI)m/z 340(M+H)+。
B.9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤(13,PPen-A)
室温下,用TMSBr(5mL)将化合物10(0.300g,0.884mmol)的已腈溶液处理过夜。浓缩后,将残余物溶于水中(20mL),将所得混合物搅拌1小时。将反应混合物浓缩到干燥。将残余物溶于水中(4mL),并矫正pH值到8。将所得混合物加入到含有DOWEX-1X2树脂的柱子上,用梯度洗脱的方式(0 M到0.25 M HCO2H)纯化混合物得到0.180g的产物13(0.636mmol,72%的产率):1H NMR(MeOH-dA)δ8.20(s,1H),8.13(s,1H),5.74-5.62(m,1H),5.53-5.41(m,1H),4.78(d,J=6.9Hz,1H),2.33-2.19(m,2H),1.57-1.43(m,2H):31P NMR(DMSO-d6)δ26.31;MS(ESI)m/z 284(M+H)+,282(M+H)-。
实施例3
9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤(15,PPen-G)的合成
A.2-氨基-6-氯-9-(5-膦酰-戊-2-烯-1-基)-嘌呤二乙基膦酰酯(11)。
使用实例2A的步骤从2-氨基-6-氯嘌呤和化合物9进行制备。1H NMR(CDCl3)δ 7.76(s,1H),5.75(br s,2H),5.72-5.48(m,2H),4.67(d,J=6.1Hz,2H),4.17-4.01(m,4H),2.74-2.56(m,2H),1.94-1.78(m,2H),1.30(t,J=7.1Hz,6H);31P NMR(CDC13)δ32.37;MS(ESI)m/z 374(M+H)+,372(M-H)-。
B.9-(5-膦酰-戊-2-烯-1-基)-鸟嘌呤二乙基膦酰酯(12)
在100℃下,将化合物11(0.200g,0.535mmol)的88%的HCO2H溶液(30mL)搅拌8小时。浓缩后,用硅胶柱层析法,用10%MeOH的CH2Cl2溶液纯化残余物得到0.170g的产物12(0.478mmol,89%的产率):1H NMR(MeOH-dA)δ8.97(s,1H),5.90-5.77(m,1H),5.75-5.63(m,1H),4.89(d,J=7.1Hz,1H),4.17-4.04(m,4H),2.70-2.50(m,2H),2.06-1.87(m,2H),1.33(t,J=6.9Hz,6H);31PNMR(CDCl3)δ33.48;MS(ESI)m/z 356(M+H)+,354(M-H)-。
C.9-(5-膦酰-戊-2-烯-1-基)-鸟嘌呤(15,PPen-G)。
参见制备化合物13的步骤。标题化合物15是在0.563mmol规模上制备的,95%的产率;1H NMR(MeOH-dA)δ 8.71(s,1H),5.84-5.73(m,1H),5.54-5.48(m,1H),4.74(d,J=6.9Hz,1H),2.44-2.29(m,2H),1.79-1.65(m,2H);31P NMR(MeOH-dA)δ29.97;MS(ESI)m/z 300(M+H)+,298(M-H)-。
实施例4
9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤单-(3-十六烷氧基-1-丙基)膦酰酯(16,HDP-PPen-A)的合成
A.9-(5-膦酰-戊-2-烯-1-基)-腺嘌呤单-(3-十六烷氧基-1-丙基)膦酰酯(16)
室温下,用DCC(0.262g,1.26mmol)处理化合物13(0.120g,0.424mmol)、3-十六烷氧基-1-丙-1-醇(HDPOH)(0.191g,0.64mmol)和DMAP(0.078g,0.64mmol)的DMF(10mL)溶液。将反应混合物加热到80℃,并搅拌过夜。浓缩后,用硅胶柱层析法,用氯仿、甲醇、氨水和水的梯度混合物(80∶20∶1∶1到100∶40∶3∶3)做层析液纯化残余物得到0.065g的产物16(0.115mmol,27%产率):1H NMR(MeOH-dA)δ8.21(s,1H),8.19(s,1H)5.84-5.74(m,1H),5.65-5.57(m,1H),4.92(d,J=7.0Hz,2H),3.94(q,J=6.2Hz,2H),3.52(t,J=6.2Hz,2H),3.37(t,J=6.6Hz,2H),2.58-2.44(m,2H),1.90-1.78(m, 2H),1.74-1.62(m,2H),1.54-1.43(m,2H),1.36-1.14(m,12H),0.89(t,J=7.0Hz,3H);31P NMR(MeOH-dA)δ25.89;MS(ESI)m/z 566(M+H)+,564(M-H)-。
实施例5
9-(5-膦酰-戊-2-烯-1-基)-鸟嘌呤单-(3-十六烷氧基-1-丙基)膦酰酯(18,HDP-PPen-G)的合成
A.2-氨基-6-氯-9-(5-膦酰-戊-2-烯-1-基)-嘌呤(14)
参见化合物13的制备步骤。标题化合物14是从化合物11获得的,其制备规模为0.563mmol。不需进一步的纯化,化合物14即可被用于下一个反应;1H NMR(MeOH-dA)δ9.09(s,1H),5.93-5.81(m,1H),5.78-5.63(m,1H),4.91(d,J=7.4Hz,1 H),2.72-2.54(m,2H),1.96-1.81(m,2H);31PNMR(MeOH-dA)δ30.23。
B.2-氨基-6-氯-9-(5-膦酰-戊-2-烯-1-基)-嘌呤单-(3-十六烷氧基-1-丙基)膦酰酯(17)
参见化合物16的制备步骤。标题化合物17的制备规模为0.598mmol,产率为56%;1H NMR(MeOH-dA)δ7.79(s,1H)5.76-5.68(m,1H),5.57-5.49(m,1H),4.72(d,J=7.3Hz,2H),3.95(q,J=6.6Hz,2H),3.53(t,J=6.2Hz,2H),3.39(t,J=6.6Hz,2H),2.62-2.52(m,2H),1.90-1.82(m,2H),1.74-1.64(m,2H),1.56-1.46(m,2H),1.36-1.12(m,12H),0.89(t,J=6.6Hz,3H);31P NMR(MeOH-dA)δ26.46。
C.9-(5-膦酰-戊-2-烯-1-基)-鸟嘌呤单-(3-十六烷氧基-1-丙基)膦酰酯(18,HDP-PPen-G)
在100℃下,将化合物17(0.200g,0.333mmol)的88%HCO2H(40mL)溶液搅拌过夜。浓缩后,用氯仿、甲醇、氨水和水(80∶20∶1∶1至70∶58∶8∶8)纯化残余物得到0.12g的产物18(0.206mmol,62%的产率);1H NMR(MeOH-dA)δ7.75(s,1H)5.76-5.66(m,1H),5.56-5.48(m,1H),4.71(d,J=7.3Hz,2H),3.94(q,J=5.9Hz,2H),3.53(t,J=6.6Hz,2H),3.39(t,J=6.6Hz,2H),2.62-2.52(m,2H),1.90-1.82(m,2H),1.72-1.62(m,2H),1.54-1.47(m,2H),1.34-1.22(m,12H),0.89(t,J=7.0Hz,3H);31P NMR(MeOH-dA)δ26.14;MS(ESI)m/z 582(M+H)+,580(M-H)-。
实施例6
1-(5-膦酰-戊-2-烯-1-基)-尿嘧啶(22,PPen-U)的合成
A.1-(5-膦酰-戊-2-烯-1-基)-尿嘧啶二乙基膦酰酯(19)
在0℃下,将DIAD(0.21mL,1.1mmol)滴加到化合物9(0.20g,0.90mmol),3-苄氧基-尿嘧啶(0.24g,1.1mmol)和Ph3P(0.29g,1.1mmol)的DMF溶液中。2小时后,浓缩反应混合物,用硅胶柱层析法,用2%甲醇的CH2Cl2溶液纯化反应混合物。将苄氧基保护的中间体溶解在2N的氨的甲醇(50mL)溶液中,并搅拌过夜。用硅胶柱层析法,用5%甲醇的CH2Cl2溶液纯化反应混合物得到0.23g的产物19(0.73mmol,81%的产率);1HNMR(CDCl3)δ8.66(br s,1H),7.31(d,J=8.1Hz,1H),5.76-5.66(m,1H),5.69(dd,J=7.7,2.0Hz,1H),4.41(d,J=7.0Hz,2H),4.16-4.02(m,4H),2.53-2.42(m,2H),1.89-1.80(m,2H),1.32(t,J=7.0Hz,3H);31P NMR(CDCl)δ31.80;MS(ESI)m/z 317(M+H)+,315(M-H)-。
A.1-(5-膦酰-戊-2-烯-1-基)-尿嘧啶(22,PPen-U)
参见化合物13的制备步骤。标题化合物22的制备规模为1.26mmol,产率为98%;1H NMR(DMSO-dA)δ11.23(s,1H),7.69(d,J=7.6Hz,1H),5.68-5.57(m,1H),5.52(d,J=6.7Hz,1H),5.39-5.18(m,1H),4.28(d,J=6.6Hz,2H),2.36-2.22(m,2H),1.64-1.51(m,2H);31P NMR(DMSO-dA)δ 26.38;MS(ESI)m/z 261(M+H)+,259(M-H)-。
实施例7
1-(5-膦酰-戊-2-烯-1-基)-胞嘧啶(23,PPen-C)的合成
A.1-(5-膦酰-戊-2-烯-1-基)-胞嘧啶二乙基膦酰酯(20)
室温下,用2,4,6-三异丙基苯磺酸氯(2.1g,6.9mmol)将化合物19(0.73g,2.3mmol)、TEA(0.97mL,7.0mmol)和DMAP(0.28g,2.3mmol)的乙腈溶液处理3小时。将氨水(5mL)加入到反应混合物中。将所得混合物搅拌1小时。浓缩后,用硅胶柱层析法,用氯仿、甲醇、氨水和水(240∶20∶1∶1)纯化残余物得到0.55g的产物20(1.74mmol,75%产率);1H NMR(CDCl3)δ7.34(d,J=7.1Hz,1H),5.80(d,J=7.4Hz,1H),5.72-5.61(m,1H),5.56-5.46(m,1H),4.44(d,J=6.9Hz,2H),4.16-4.02(m,4H),2.54-2.39(m,2H),2.17(br s,2H),1.91-1.78(m,2H),1.32(t,J=7.1Hz,6H);31P NMR(CDCl)δ32.06;MS(ESI)m/z 316(M+H)+,314(M-H)-。
B.1-(5-膦酰-戊-2-烯-1-基)-胞嘧啶(23,PPen-C)
参见化合物13的制备步骤。标题化合物23的制备规模为1.30mmol,产率为71%;1H NMR(DMSO-dA)δ7.52(d,J=7.1Hz,1H),7.04(br s,1H),6.98(br s,1H),5.62(d,J=7.7Hz,1H),5.66-5.53(m,1H),5.37-5.26(m,1H),4.26(d,J=6.9Hz,2H),2.37-2.23(m,2H),1.63-1.50(m,2H);31PNMR(DMSO-d6)δ26.14;MS(ESI)m/z 260(M+H)+,258(M-H)-。
实施例8
1-(5-膦酰-戊-2-烯-1-基)-胸腺嘧啶(24,PPen-T)的合成
A.1-(5-膦酰-戊-2-烯-1-基)-胸腺嘧啶二乙基膦酰酯(21)
参见化合物19的制备步骤。标题化合物21的制备规模为1.44mmol,产率为78%;1H NMR(CDCl)δ8.46(br s,1H),7.11(s,1H),5.78-5.66(m,1H),5.52-5.41(m,1H),4.38(d,J=6.6Hz,2H),4.20-4.02(m,4H),2.55-2.41(m,2H),1.91(s,3H),1.91-1.78(m,2H),1.33(t,J=7.1Hz,6H);31P NMR(CDCI3)δ31.84;HRMS观察值:m/z330.1352,C14H23N2O5P的计算值:m/z330.1339 M+。
B.1-(5-膦酰-戊-2-烯-1-基)-胸腺嘧啶(24,PPen-T)。
参见化合物13的制备步骤。标题化合物24的制备规模为1.12mmol,产率为85%;1H NMR(MeOH-dA)δ7.41(s,1H),5.80-5.65(m,1H),5.53-5.41(m,1H),4.39(d,J=5.5Hz,2H),2.56-2.40(m,2H),1.85(s,3H),1.85-1.74(m,2H);31P NMR(MeOH-dA)δ30.40;HRMS观察值:m/z 274.0727,C10H15N2O5P计算值:m/z 270.0713 M+。
实施例9
1-(5-膦酰-戊-2-烯-1-基)-尿嘧啶单-(3-十六烷氧基-1-丙基)膦酰酯(25,HDP-PPen-U)的合成
参见化合物16的制备步骤。标题化合物25的制备规模为0.50mmol,产率为44%;1H NMR(MeOH-dA)δ7.62(d,J=8.0Hz,1H),5.82-5.71(m,1H),5.65(d,J=8.0Hz,1H),5.50-5.37(m,1H),4.44(d,J=5.8Hz,2H),3.93(q,J=6.3Hz,2H),3.53(t,J=6.3Hz,2H),3.41(t,J=6.6Hz,2H),2.50-2.36(m,2H),1.90-1.81(m,2H),1.70-1.48(m,4H),1.40-1.20(m,12H),0.89(t,J=6.2Hz,3H);31P NMR(MeOH-dA)δ25.90;MS(ESI)m/z 543(M+H)+,541(M-H)-。
实施例10
1-(5-膦酰-戊-2-烯-1-基)-胞嘧啶单-(3-十六烷氧基-1-丙基)膦酰酯(26,HDP-PPen-C)的合成
参见化合物16的制备步骤。标题化合物17的制备规模为0.58mmol,产量为38%;1H NMR(MeOH-dA)δ7.86(d,J=7.4Hz,1H),5.96(d,J=7.6Hz,1H),5.84-5.72(m,1H),5.52-5.51(m,1H),4.50(d,J=6.6Hz,2H),3.92(q,J=6.3Hz,2H),3.53(t,J=6.0Hz,2H),3.41(t,J=6.6Hz,2H),2.49-2.35(m,2H),1.91-1.80(m,2H),1.70-1.45(m,4H),1.36-1.22(m,12H),0.89(t,J=6.6Hz,3H);31P NMR(MeOH-dA)δ 25.93;HRMS(xx)观察值:m/z 541.3645,C28H52N3O5P计算值:m/z 541.3639 M+。
实施例11
1-(5-膦酰-戊-2-烯-1-基)-胸腺嘧啶单-(3-十六烷氧基-1-丙基)膦酰酯(27,HDP-PPen-T)的合成
参见化合物16的制备步骤。标题化合物17的制备规模为0.58mmol,产率为15%;1H NMR(MeOH-dA)δ7.44(d,J=1.1Hz,1H),5.80-5.69(m,1H),5.47-5.36(m,1H),4.42(d,J=6.9Hz,2H),3.92(q,J=6.3Hz,2H),3.53(t,J=6.3Hz,2H),3.41(t,J=6.6Hz,2H),2.50-2.36(m,2H),1.91-1.81(m,2H),1.87(d,J=1.1Hz,3H),1.70-1.48(m,4H),1.35-1.24(m,12H),0.89(t,J=6.6Hz,3H);31P NMR(MeOH-dA)525.62;HRMS(xx)观察值:m/z 556.3643,C29H53N2O6P计算值:m/z 556.3636 M+。
因为改进对于本领域技术人员来说是显而易见的,因此本发明的范围仅由附加的权利要求书限制。
Claims (29)
1.式IA或IB的化合物或所述式IA或IB的化合物的药学可接受的盐:
其中,每个R独立地是氢、单价离子或疏水基团,B是嘌呤或嘧啶碱基或嘌呤或嘧啶碱基的类似物,其中所述类似物选自
其中R3是H、C1-C6烷基、C2-C6烯基、C1-C6炔基、C3-C6环烷基、羟基、卤素、芳基或杂芳基;
R6是H或C1-6烷基、C2-6烯基、C2-6炔基或环烷基;
R7是H、羟基、卤素、C1-6烷基、C2-6烯基、C2-6炔基、环烷基或NR4R5;
R8是H、C1-6烷基、C2-6烯基、C2-6炔基或环烷基;
R9是H、C1-6烷基、C2-6烯基、C2-6炔基、环烷基、卤素或NR4R5;和
R4和R5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基。
3.权利要求1的化合物,其中R是氢、单价离子、取代的或未经取代的C8-C24烷基或取代的或未经取代的具有1到6个双键的C8-C24烯基,其中,当取代基存在时,该取代基选自一个或多个卤素、烷基、-OH、-SH、环烷基或环烷氧基。
4.权利要求1-3的任一项的化合物,其中R具有下式:
其中,R1和R1a独立地是-H、-O(C1-C24)烷基、-O(C1-C24)烯基、-O(C1-24)酰基、-S(C1-C24)烷基、-S(C1-C24)烯基或-S(C1-C24)酰基,其中R1和R1a中至少有一个不是氢,而烯基或酰基部分任选地有1-6个双键,
R2和R2a独立地是-H、-O(C1-C7)烷基、-O(C1-C7)烯基、-S(C1-C7)烷基、-S(C1-C7)烯基、-O(C1-C7)酰基、-S(C1-C7)酰基、-N(C1-C7)酰基、-NH(C1-C7)烷基、-NH((C1-C7)烷基)2、氧、卤素、-NH2、-OH或-SH;
其中,当R6存在时,是:
m是0到6的整数;
式中R1、R1a、R2、R2a、R7和R7a可选择地被1到4个取代基取代,一个所述取代基都各自独立地选自烷基、烯基、炔基、卤素、羟基、卤素、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
5.权利要求4的化合物,其中R1a、R2和R2a各自为氢,并且R1为-O(C1-C24)烷基、-O(C1-C24)烯基或-O(C1-24)酰基。
8.权利要求6的化合物,其中R1a为氢,并且R1为-O(C1-C24)烷基、-O(C1-C24)烯基或-O(C1-24)酰基。
9.权利要求7的化合物,其中R1a为氢,并且R1为-O(C1-C24)烷基、-O(C1-C24)烯基或-O(C1-24)酰基。
11.权利要求1-3的任一项的化合物,其中R是十六烷氧基丙基、十八烷氧基丙基或十八烷氧基乙基。
12.权利要求1-3任一项的化合物,其中R是乙酰基、缬氨酰、双特戊酰氧甲基、双(戊酰氧甲基)或双索罗基。
13.权利要求1的化合物,其中一个R为氢,并且另一R为疏水基团。
14.权利要求1-3任一项的化合物,其中B是胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、腺嘌呤-9-基或乌嘌呤-9-基。
15.权利要求1-3任一项的化合物,其中,B选自:
16.权利要求1-3任一项的化合物,其中所述化合物选自5-膦酰-戊-2-烯-1-基腺嘌呤、5-膦酰-戊-2-烯-1-基胞嘧啶、5-膦酰-戊-2-烯-1-基鸟嘌呤、5-膦酰-戊-2-烯-1-基胸腺嘧啶和5-膦酰-戊-2-烯-1-基尿嘧啶。
18.药物组合物,其含有权利要求1-17任一项的化合物和药学上可接受的载体。
19.权利要求1-17任一项的化合物在制备治疗、预防或减轻病毒感染的药物中的用途。
20.权利要求19的用途,其中所述病毒感染由流感病毒、B型肝炎病毒、C型肝炎病毒、巨细胞病毒、水痘病毒、单纯庖疹病毒1型和2型、EB病毒、疱疹病毒6型和8型、水痘病毒、EB病毒感染、逆转录病毒、天花病毒、牛痘病毒、伊波拉病毒、腺病毒和乳头瘤病毒引起。
21.权利要求19的用途,其中所述病毒感染是药物耐受的B型肝炎。
22.权利要求1-17任一项的化合物在制备治疗、预防或改善生长性肿瘤的药物中的用途。
23.权利要求1-17任一项的化合物在制备调节细胞增殖的药物中的用途。
24.权利要求1-17任一项的化合物在制备治疗癌症的药物中的用途。
25.权利要求24的用途,其中所述癌症选自肺癌、头部和颈部的鳞状癌、直肠癌、前列腺癌、乳腺癌、急性淋巴细胞性白血病、成人急性髓系白血病、成人非霍奇金淋巴瘤、脑瘤、宫颈癌、儿童癌症、儿童肉瘤、慢性淋巴细胞白血病、慢性髓系白血病、食管癌、毛细胞性白血病、肾癌、肝癌、多发性骨髓瘤、神经母细胞瘤、口腔癌、胰腺癌、原发性中枢神经系统淋巴瘤和皮肤癌。
26.用于治疗病毒感染的权利要求1-17任一项的化合物。
27.用于治疗细胞增殖疾病的权利要求1-17任一项的化合物。
28.权利要求1-17任一项的化合物在制备治疗病毒感染的药物中的应用。
29.权利要求1-17任一项的化合物在制备治疗细胞增殖疾病的药物中的应用。
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2006
- 2006-03-30 JP JP2008504456A patent/JP5242375B2/ja not_active Expired - Fee Related
- 2006-03-30 WO PCT/US2006/012117 patent/WO2006137953A1/en active Application Filing
- 2006-03-30 EP EP06799899A patent/EP1866319B1/en active Active
- 2006-03-30 CN CN2006800193224A patent/CN101189249B/zh not_active Expired - Fee Related
- 2006-03-30 US US11/887,502 patent/US8222257B2/en not_active Expired - Fee Related
- 2006-03-30 AT AT06799899T patent/ATE534652T1/de active
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2012
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CN1120338A (zh) * | 1993-04-01 | 1996-04-10 | 默里尔多药物公司 | 嘌呤和嘧啶的不饱和膦酸酯衍生物 |
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Also Published As
Publication number | Publication date |
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ATE534652T1 (de) | 2011-12-15 |
US8222257B2 (en) | 2012-07-17 |
EP1866319B1 (en) | 2011-11-23 |
JP2008534615A (ja) | 2008-08-28 |
WO2006137953A1 (en) | 2006-12-28 |
JP2013035841A (ja) | 2013-02-21 |
JP5242375B2 (ja) | 2013-07-24 |
EP1866319A1 (en) | 2007-12-19 |
US20090215726A1 (en) | 2009-08-27 |
CN101189249A (zh) | 2008-05-28 |
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