CN103561739A - 可用于治疗hcv感染的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂 - Google Patents
可用于治疗hcv感染的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂 Download PDFInfo
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- CN103561739A CN103561739A CN201280025427.6A CN201280025427A CN103561739A CN 103561739 A CN103561739 A CN 103561739A CN 201280025427 A CN201280025427 A CN 201280025427A CN 103561739 A CN103561739 A CN 103561739A
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Abstract
本公开内容提供了可用作抗病毒剂的式(I)D-M-D(式I)的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂。在本文公开的某些实施方案中,M是基团-P-A-P-,其中A是式(I)。本文公开的某些经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂是强效和/或选择性的病毒复制(特别是丙型肝炎病毒复制)抑制剂。本公开内容还提供包含一种或更多种经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬和金属茂以及可药用载体的药物组合物/和组合。本公开内容提供了用于治疗病毒感染(包括丙型肝炎病毒感染)的方法。
Description
优先权信息
本申请要求2011年5月27日提交的美国临时申请No.61/490,881、2011年7月6日提交的美国临时申请No.61/504,905和2011年12月6日提交的美国临时申请No.61/567,216的优先权,其全部通过引用整体并入本文。
技术领域
本公开内容提供了可用作抗病毒剂的经取代的脂肪芬(aliphane)、环芬(cyclophane)、异芬(heteraphane)、杂芬(heterophane)、杂-异芬(hetero-heteraphane)以及金属茂(metallocene)。本文公开的某些经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂是强效和/或选择性的病毒复制(特别是丙型肝炎病毒复制)抑制剂。本公开内容还提供了包含一种或更多种经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬和金属茂以及可药用载体的药物组合物/和组合。本公开内容提供了用于治疗病毒感染(包括丙型肝炎病毒感染)的方法。
背景技术
据估计,世界人口的3%被丙型肝炎病毒感染。在暴露于HCV的人中,80%至85%变为慢性感染,至少30%发生肝硬化,1%至4%发生肝细胞癌。丙型肝炎病毒(HCV)是美国慢性肝病最重要的病因之一,据报道占急性病毒性肝炎的约15%,慢性肝炎的60%至70%,硬化、晚期肝病及肝癌多达50%。慢性HCV感染是美国、澳大利亚和大多数欧洲国家中肝移植最常见的原因。在美国,丙型肝炎每年造成估计10000至12000人死亡。尽管HCV感染的急性期通常伴随温和的症状,但是一些证据显示仅有约15%至20%的感染者会自主清除HCV。
HCV是带包膜的单链RNA病毒,其含有约9.6kb的正链基因组。HCV被归类为黄病毒科(Flaviviridae)丙型肝炎病毒属(Hepacivirusgenus)的成员。已表征出至少4种HCV病毒株,即GT-1至GT-4。
HCV生活史(life cycle)包括:进入宿主细胞;翻译HCV基因组、多蛋白加工和复制酶复合物的组装;RNA复制以及病毒体组装和释放。HCV RNA基因组的翻译产生超过3000个氨基酸长的多蛋白,其通过至少两个细胞蛋白酶和两个病毒蛋白酶来加工。HCV多蛋白是:
NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH。
已有报道,细胞信号肽酶和信号肽肽酶负责从非结构蛋白(NS2-NS3-NS4A-NS4B-NS5A-NS5B)切割所述多蛋白的N端三分之一(C-E1-E2-p7)。NS2-NS3蛋白酶介导在NS2-NS3位点处的第一顺式切割(cis-cleavage)。然后NS3-NS4A蛋白酶介导在NS3-NS4A连接处的第二顺式切割。然后NS3-NS4A复合物在三个下游位点处切割以分离余下的非结构蛋白质。所述多蛋白的精确加工被认为对于形成活性HCV复制酶复合物是至关重要的。
一旦所述多蛋白被切割,至少包含NS3-NS5B非结构蛋白质的复制酶复合物就进行组装。所述复制酶复合物在细胞质中并与膜相关联。所述复制酶复合物的主要酶活性包括在NS3的丝氨酸蛋白酶活性和NTP酶解旋酶活性以及NS5B的RNA依赖性RNA聚合酶活性。在RNA复制过程中,产生基因组RNA的互补负链拷贝。所述负链拷贝被用作模板以合成另外的正链基因组RNA,该正链基因组RNA可参与翻译、复制、包装或其任何组合以产生子代病毒。功能性复制酶复合物的组装已被描述为HCV复制机制的组成部分。2005年4月11日提交的美国临时申请No.60/669,872“Pharmaceutical Compositions and Methods of Inhibiting HCVReplication”因其公开内容涉及所述复制酶复合物的组装而通过引用整体并入本文。
目前对丙型肝炎感染的治疗通常包括与利巴韦林相组合施用干扰素,例如PEG化干扰素(IFN)。如持续病毒学应答(sustained virologicresponse,SVR)所测定的目前疗法的成功取决于患者所感染的HCV病毒株以及患者对治疗方案的遵守。只有50%的感染HCV GT-1株的患者表现出持续的病毒学应答。直接作用的抗病毒剂(例如ACH-1625、特拉匹韦(telaprevir)、BMS-790052和BMS-650032)正处于治疗慢性HCV的临床开发阶段。由于缺少治疗某些HCV株的有效疗法以及由于HCV的高突变率,需要新的疗法。本公开内容满足了此需要并且提供了另外的优点,所述优点在本文中进行了描述。
发明概述
本公开内容提供了式I的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂。本公开内容提供的式I化合物具有抗病毒活性。
本公开内容提供了作为强效和/或选择性的丙型肝炎病毒复制抑制剂的式I化合物。不受任何特定理论约束,认为本发明化合物是强效和选择性的HCV NS5a抑制剂。本公开内容还提供了包含一种或更多种式I化合物、或这些化合物的盐、以及一种或更多种可药用载体的药物组合物。本公开内容还提供了包含一种或更多种式I化合物、或这些化合物的盐、至少一种另外的活性剂、以及一种或更多种可药用载体的药物组合物。
本发明还公开了通过向患有某些病毒感染(特别是HCV感染)的患者提供有效减轻所述病毒感染之体征或症状之量的式I化合物或者提供式I化合物与一种或更多种其他治疗活性剂的组合来治疗这些患者的方法。治疗方法包括提供作为单一活性剂的式I化合物。
在第一方面中,本公开内容包括式I化合物或其可药用盐:
D-M-D(式I)。
在式I中,变量D和M具有下述定义。
D是T-R-,其中M与R共价相连。
M是-P-A-P-。
P是-J-W-,其中J与R共价相连,W与A共价相连,或者P是-J-,其中J与R和A共价相连。
J在每次出现时独立地选择,并且J是Ji,其中i是1至2的整数。
T在每次出现时独立地选择,并且T是Tk,其中k是1至2的整数;T1是-Y-Z,其中Y与R共价相连,Y是键、任选地被氧取代的C1-C4亚烷基;Z是5或6元杂环基团,在每种情况下T1(i)被选自-(C=O)OH、-(C=O)NH2、-(C=O)H、-C1-C4烷氧基、C2-C4烷酰基、C1-C4烷基酯、C1-C4烯基酯、单C1-C4烷基甲酰胺或二C1-C4烷基甲酰胺的至少一个取代基所取代;以及(ii)任选地被一个或更多个独立地选自以下的取代基所取代:卤素、羟基、C1-C2烷基以及C1-C2烷氧基;T2在每次出现时独立地选自:C2-C6烷酰基、C1-C6烷基酯、C1-C6烯基酯、C1-C6烷基磺酰胺、C1-C6烷基磺酰基、被单C1-C6烃基氨基甲酸酯或二C1-C6烃基氨基甲酸酯取代的C2-C6烷酰基、被脲或者单C1-C6烷基脲或二C1-C6烷基脲取代的C2-C6烷酰基以及被单C1-C6烷基甲酰胺或二C1-C6烷基甲酰胺取代的C2-C6烷酰基,在每种情况下T任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、(C1-C4烷氧基)C0-C4烷基、(单C1-C4烷基氨基和二C1-C4烷基氨基)C0-C4烷基、C1-C6烷基、(C1-C4硫代烷基)C0-C4烷基、C3-C7环烷基、苯基、C1-C4卤代烷基以及C1-C4卤代烷氧基;
R在每次出现时独立地选自:
(a)4至6元环,其含有一个或两个氮原子,其余环原子为碳,其中R是饱和的或者含有1个不饱和键并且任选地与亚甲基或亚乙基桥桥联,与苯基或5至6元杂芳基环稠合;和
(b)6至10元稠合或螺双环体系,其含有一个或两个氮原子,其余环原子为碳,其中6至10元双环是饱和的或者含有1个不饱和键;每个R任选地被一个或更多个独立地选自以下的取代基所取代:氰基、羟基、卤素、C1-C2烷基、C1-C2烷氧基、C1-C2卤代烷基、C1-C2卤代烷基、C1-C2卤代亚烷基以及C1-C2烷基磺酰基。
J1是苯基或含有1至3个独立地选自N、O和S的杂原子的5至6元杂芳基,其中每个J1任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
J2是8至10元杂芳基,其含有1至4个独立地选自N、O和S的杂原子,其中J2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
W在每次出现时独立地选择,并且是苯基、吡啶基或炔基,其任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
A是[j.k]-环芬、[j.k]-异芬、[j.k]-杂芬、[j.k]-异-杂芬或[j.k]-脂肪芬;其中j是1至4的整数,k是整数0至4,j与k之差不大于2,并且每个j和k接头任选地含有选自N、O和S的杂原子,并且任选地被1个氧代基团和一个或更多个独立地选自卤素、羟基、氨基、C1-C2烷基和C1-C2烷氧基的取代基所取代;或者
A是[j.k.j’.k’]-环芬,其中j、j’、k和k’是1至4的整数,j与k或k’之差不大于2,j’与k或k’之差不大于2,并且每个j、j’、k和k’接头任选地含有选自N、O和S的杂原子,并且任选地被1个氧代基团和一个或更多个独立地选自卤素、羟基、氨基、C1-C2烷基和C1-C2烷氧基的取代基所取代;
或者
A是式或基团,其中Q是中性金属或阳离子金属,在每种情况下A任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。在某些实施方案中,Q选自Fe、Co、Cr、Ni、V、Li、Rb以及K;或者
本公开内容提供了包含式I化合物和可药用载体的药物组合物和组合。本公开内容所提供的组合物和组合可以包含作为唯一活性剂的式I化合物或者可以包含一种或更多种另外的活性剂。在某些实施方案中,所述另外的活性剂是NS3a蛋白酶抑制剂。本公开内容还包括治疗患者丙型肝炎感染的方法,其包括向患者提供治疗有效量的一种或更多种式I化合物。式I化合物可以作为唯一活性剂提供或者可以与一种或更多种另外的活性剂(例如NS3a蛋白酶抑制剂)一起提供。
本文公开的某些式I化合物在下文的HCV复制测定(例如实施例9所示的HCV复制子测定)中表现出良好的活性。优选的式I化合物在HCV复制子复制测定中表现出约10微摩尔或更低的EC50,或者更优选约1微摩尔或更低的EC50,或者更优选约100纳摩尔或更低的EC50。
发明详述
化学描述和术语
在详细阐述本发明之前,提供本公开内容中将要用到的某些术语的定义可能是有帮助的。使用标准命名法来描述化合物。除非另有限定,否则本文所用的所有技术和科学术语具有与本发明所属领域之技术人员通常所理解的相同的含义。除非在上下文中被明确排除,否则每个化合物名称包括所述化合物的游离酸或游离碱形式以及所述化合物的所有可药用盐。
术语“式I化合物”涵盖满足式I的所有化合物,包括任何对映体、外消旋体和立体异构体,以及这些化合物的所有可药用盐。短语“式I化合物”包括式I的所有亚组,并且还包括式I化合物的可药用盐,除非在该短语所用的上下文中被明确排除。
“式II”涵盖满足式II的所有化合物,包括这些化合物的任何对映体、外消旋体和立体异构体,以及所有可药用盐。短语“式II化合物”包括式II的所有亚组,并且还包括式II化合物的可药用盐,除非在该短语所用的上下文中被明确排除。
不定冠词不表示对量的限制,而是表示存在至少一个所指的项目。术语“或”意指“和/或”。开放式过渡短语“包含”涵盖中间过渡短语“基本由...组成”和封闭式短语“由...组成”。引用这三个过渡短语之一或者替代过渡短语(例如“含有”或“包括”)的权利要求可以与任何其他过渡短语一同书写,除非在上下文或本领域中被明确排除。除非文中另有指明,否则数值范围的记载仅旨在作为单独指明落入该范围的每个单个值的简略方法,并且每个单个值也并入本说明书中,就如同在本文中分别单独引用每个单个值一样。所有范围的端点均包含在所述范围内并且可独立地组合。除非文中另有指明或者与上下文明显矛盾,否则本文中所述的全部方法都可以以合适的顺序实施。除非另外要求,否则任何以及所有实例或者示例性语言(例如“例如”)的使用仅旨在更好地举例说明本发明,而不对本发明的范围加以限制。说明书中的语言都不应解释为表明任何未要求保护的要素是实施如本文所用的本发明所必需的。除非另有限定,否则本文所用技术和科学术语具有与本发明所属领域技术人员通常所理解的相同的含义。
“活性剂”意指当单独或与另外的化合物、要素或混合物相组合施用给患者时,直接或间接地赋予所述患者生理效应的化合物(包括本文所公开的化合物)、要素或混合物。所述间接生理效应可以通过代谢物或其他间接机制而发生。
不在两个字母或符号之间的短线(“-”)用于表示取代基的连接点。例如,-(C=O)NH2通过酮基(C=O)的碳相连接。
本文中使用的“脂肪芬”是由一个或两个环烷基环构成的基团,其中至少一个脂肪族桥在单个环烷基环之两个非相邻位置之间或者在两个环烷基环之间。所述脂肪族桥含有1至4个碳原子。脂肪族桥任选地被氧代基团取代。
“烷酰基”是由酮基(-(C=O)-)桥与其所取代的基团共价相连的如本文所定义的烷基。烷酰基具有具体数目的碳原子,其中酮基中的碳被包括在计数的碳原子内。例如,C2烷酰基是具有式CH3(C=O)-的乙酰基。
“烷基”是支链或直链的饱和脂肪烃基,其具有具体数目的碳原子,一般为1至约12个碳原子。本文所用的术语C1-C6烷基指具有1、2、3、4、5或6个碳原子的烷基。其他实施方案包括具有1至8个碳原子、1至4个碳原子或者1或2个碳原子的烷基,例如C1-C8烷基、C1-C4烷基和C1-C2烷基。当本文中C0-Cn烷基与另一个基团(例如,(C1-C4烷氧基)C0-C4烷基)联合使用时,所指基团(在此情形下为烷氧基)是通过共价单键(C0烷基)直接相连,或者通过具有具体数目碳原子(在此情形下是1、2、3或4个碳原子)的烷基链相连。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基和仲戊基。
“炔基”是具有一个或更多个碳-碳三键的直链或支链脂肪族烃基,所述三键可以存在于链上的任何稳定点,所述炔基具有具体数目的碳原子。炔基的实例包括但不限于乙炔基和丙炔基。
“烷氧基”是通过氧桥(-O-)与其所取代的基团共价连接的具有具体数目碳原子的如上文所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、2-丁氧基、叔丁氧基、正戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。
术语“烷基酯”指通过酯键与其所取代的基团共价连接的如本文所定义的烷基。所述酯键可在任何位置上,例如式-O(C=O)烷基基团或式-(C=O)O烷基基团。
“烷基磺酰基”是式-SO2烷基基团,其中所述烷基具有本文所给出的定义。
“环烷基”是具有具体数目碳原子的饱和环烃基。单环环烷基通常具有3至约8个碳环原子,或3至7个(3、4、5、6或7)碳环原子。环烷基取代基可以是经取代之氮或碳原子的侧链(pendant),或者可具有两个取代基的经取代之碳原子可具有作为螺环基团(spiro group)相连接的环烷基。环烷基的实例包括环丙基、环丁基、环戊基和环己基。
本文中使用的“环芬”是由一个或两个芳香环(通常为苯环)构成的基团,其中至少一个脂肪族桥在单个芳香环之两个非相邻位置之间或者在两个芳香环之间。脂肪族桥在间位或对位或间位、对位(一个芳香环的间位和另一个芳香环的对位),并且含有1至4个碳原子。所述脂肪族桥任选地被氧代基团取代。
“卤代烷基”指被一个或更多个卤素原子(多至最大可允许数目的卤素原子)取代的具有具体数目碳原子的支链和直链烷基。卤代烷基的实例包括但不限于三氟甲基、二氟甲基、2-氟乙基以及五氟乙基。
“卤代烷氧基”指通过氧桥(醇基的氧)连接的本文所定义的卤代烷基。
“卤代”或“卤素”指氟、氯、溴和碘中的任一种。
“杂芳基”指具有具体数目环原子的稳定单环芳香环,其含有1至3个或在一些实施方案中1至2个选自N、O和S的杂原子,其余环原子为碳;或者指含有至少一个5至7元芳香环的稳定双环或三环体系,其含有1至3个或在一些实施方案中1至2个选自N、O和S的杂原子,其余环原子为碳。单环杂芳基通常具有5至7个环原子。在一些实施方案中,双环杂芳基是9至10元杂芳基,即含有9或10个环原子的基团,其中一个5至7元芳香环稠合至第二芳香环或非芳香环上。当杂芳基中S和O原子总数超过1时,这些杂原子彼此不相邻。优选杂芳基中S和O原子的总数不超过2。特别优选地,芳香杂环中S和O原子的总数不超过1。杂芳基的实例包括但不限于:唑基、吡喃基、吡嗪基、吡唑并嘧啶基、吡唑基、哒嗪基(pyridizinyl)、吡啶基、嘧啶基、吡咯基、喹啉基、四唑基、噻唑基、噻吩基吡唑基(thienylpyrazolyl)、噻吩基、***基、苯并[d]唑基、苯并呋喃基、苯并噻唑基、苯并苯硫基、苯并二唑基、二氢苯并二氧杂环己炔基(dihydrobenzodioxynyl)、呋喃基、咪唑基、吲哚基和异唑基。“杂芳基氧基”是通过氧桥与其所取代的基团相连的如所述的杂芳基。
本文中使用的“异芬”是由一个或两个芳香环(通常为苯环)构成的基团,其中至少一个脂肪族桥在单个芳香环的两个非相邻位置之间或者在两个芳香环之间,所述至少一个脂肪族桥含有杂原子。所述脂肪族桥在间位或对位或间位、对位(在一个芳香环的间位以及在另一个芳香环的对位),并且含有1至4个原子,其中至少一个是杂原子,而余下的原子为碳原子。所述脂肪族桥任选地被氧代基团取代。
本文中使用的“杂芬”是由一个或两个芳香环构成的基团,其中至少一个芳香环是杂芳基,其中至少一个脂肪族桥在单个芳香环之两个非相邻位置之间或者在两个芳香环之间。脂肪族桥在间位或对位或间位、对位(在一个芳香环的间位和另一个芳香环的对位),并且含有1至4个碳原子。所述脂肪族桥任选地被氧代基团取代。
本文中使用的“杂-异芬”是由一个或两个芳香环构成的基团,其中至少一个芳香环是杂芳基,其中至少一个脂肪族桥在单个芳香环之两个非相邻位置之间或者在两个芳香环之间,所述至少一个脂肪族桥包含选自N、O或S的杂原子,以及一个脂肪族桥在单个芳香环之两个非相邻位置之间或者在两个芳香环之间,所述一个脂肪族桥不包含杂原子。脂肪族桥在间位或对位或间位、对位(在一个芳香环的间位和另一个芳香环的对位),并且含有1至4个原子,其中至少一个是杂原子,其余原子为碳原子。所述脂肪族桥任选地被氧代基团取代。
“烃基”是含有指定数目碳原子的饱和的或不饱和的脂肪族基团。“烃基”可以与其他基团(例如氨基甲酸酯)联合使用,如在“单烃基氨基甲酸酯或二烃基氨基甲酸酯”中。单烃基氨基甲酸酯或二烃基氨基甲酸酯包括式(烷基1)NH(C=O)O-和(烷基1)N(烷基2)(C=O)O-基团以及其中烷基之一或二者被含有不饱和碳碳键的烃基所替代的基团。
“金属茂”是由两个与金属中心相连的5或6元芳香碳环基团组成的化合物,其中所述金属是中性的或阳离子的。金属茂的实例包括但不限于二茂铁。
术语“单烷基氨基和/或二烷基氨基”指仲烷基氨基或叔烷基氨基,其中所述烷基独立地选择的具有指定数目碳原子的如本文所定义的烷基。所述烷基氨基的连接点在氮上。单烷基氨基和二烷基氨基的实例包括乙氨基、二甲氨基和甲基-丙基-氨基。
“单烷基氨基甲酸酯和/或二烷基氨基甲酸酯”包括式(烷基1)O(C=O)NH-的单烷基氨基甲酸酯基团或式(烷基1)O(C=O)N(烷基2)-的二烷基甲酰胺基团,其中单烷基甲酰胺或二烷基甲酰胺取代基与其所取代的分子的连接点是在氨基甲酸酯氨基的氮上。术语“单烷基氨基甲酸酯和/或二烷基氨基甲酸酯”还包括式(烷基1)NH(C=O)O-和(烷基1)N(烷基2)(C=O)O-基团,其中所述氨基甲酸酯与其所取代的基团通过其非酮氧原子共价相连。基团烷基1和烷基2为独立地选择的烷基,其具有本公开内容给出的烷基定义并且具有指定数目的碳原子。
“单烷基甲酰胺和/或二烷基甲酰胺”指式(烷基1)-NH-(C=O)-的单烷基甲酰胺基团或式(烷基1)(烷基2)-N-(C=O)-的二烷基甲酰胺基团,其中所述单烷基甲酰胺或二烷基甲酰胺取代基与其所取代之分子的连接点在羰基的碳上。术语“单烷基甲酰胺和/或二烷基甲酰胺”还包括式(烷基1)(C=O)NH-和(烷基1)(C=O)(烷基2)N-基团,其中连接点是氮原子。所述基团烷基1和烷基2为独立地选择的具有指定数目碳原子的烷基。同样,“单烷基磺酰胺和/或二烷基磺酰胺”是式(烷基1)-NH-(SO2)-的单烷基磺酰胺基团、式(烷基1)-(SO2)-NH-的单烷基磺酰胺基团、式(烷基1)(烷基2)-N-(SO2)-的二烷基磺酰胺基团以及式(烷基1)-(SO2)-(烷基2)N-基团中的任一项。
“硫代烷基”是具有指定数目碳原子的与其所取代的基团通过硫桥(-S-)共价连接的如上文所定义的烷基。
本文中使用的术语“取代”意指所指示的原子或基团上的任意一个或更多个氢被选择的指定基团所替代,前提是不超过所指示原子的正常价。当取代基是氧代基团(即,=O)时,则所述原子上的2个氢被替代。当氧代基团取代芳香性部分时,相应的部分不饱和的环替代所述芳香环。例如,被氧代基团取代的吡啶基是吡啶酮。取代基和/或变量的组合是允许的,只要这样的组合得到稳定的化合物或可用的合成中间体即可。稳定的化合物或稳定的结构意指化合物足够坚固从而能在反应混合物分离中保留下来,并随后被配制成有效的治疗剂。除非另外指明,否则根据核心结构来命名取代基。例如,应当理解,当氨基烷基被列为可能的取代基时,此取代基与核心结构的连接点在烷基部分。
可存在于“取代”位置的合适基团包括但不限于例如卤素;氰基;羟基;硝基;叠氮基;烷酰基(如C2-C6烷酰基);甲酰胺;具有1至约8个碳原子或1至约6个碳原子的烷基(包括环烷基);烯基和炔基(包括具有一个或更多个不饱和键以及2至约8个或2至约6个碳原子的基团);具有一个或更多个氧连接以及1至约8个或1至约6个碳原子的烷氧基;芳氧基例如苯氧基;烷基硫基,包括具有一个或更多个硫醚键以及1至约8个碳原子或1至约6个碳原子的那些;烷基亚磺酰基,包括具有一个或更多个亚磺酰键以及1至约8个碳原子或1至约6个碳原子的那些;烷基磺酰基,包括具有一个或更多个磺酰键以及1至约8个碳原子或1至约6个碳原子的那些;氨基烷基,包括具有一个或更多个N原子以及1至约8个或1至约6个碳原子的那些;具有6个或更多个碳以及一个或更多个环的芳基(例如苯基、联苯基、萘基等,每个环是取代或未取代的芳香环);具有1至3个分开的或稠合的环以及6至约18个环碳原子的芳烷基,苄基是芳烷基的一个实例;具有1至3个分开的或稠合的环以及6至约18个环碳原子的芳基烷氧基,苄氧基是芳基烷氧基的一个实例;或者具有1至3个分开的或稠合的环的饱和、不饱和或芳香性杂环基,其每个环具有3至约8个成员以及一个或更多个N、O或S原子,例如香豆素基(coumarinyl)、喹啉基、异喹啉基、喹唑啉基、吡啶基、吡嗪基、嘧啶基、呋喃基、吡咯基、噻吩基、噻唑基、三嗪基、唑基、异唑基、咪唑基、吲哚基、苯并呋喃基、苯并噻唑基、四氢呋喃基、四氢吡喃基、哌啶基、吗啉基、哌嗪基和吡咯烷基。这些杂环基团可被进一步取代,例如被羟基、烷基、烷氧基、卤素和氨基取代。
“剂型”意指活性剂的施用单元。剂型的实例包括片剂、胶囊剂、注射剂、混悬剂、液体剂、乳剂、乳膏、软膏、栓剂、可吸入形式、透皮形式等。
“药物组合物”是包含至少一种活性剂(例如式I化合物或盐)和至少一种另外的物质(例如载体)的组合物。药物组合物任选地包含一种或更多种另外的活性剂。当被指明时,药物组合物符合美国FDA对于人用药物或非人用药物的GMP(good manufacturing practice,药品生产质量管理规范)标准。“药物组合”是至少两种活性剂的组合,根据所述活性剂待一起使用以治疗疾病(例如丙型肝炎)的说明书,所述至少两种活性剂可以在单个剂型中组合或者可以在分开的剂型中一起提供。
“可药用盐”包括所公开化合物的衍生物,其中通过制备母体化合物的无机和有机的无毒的酸加成盐或碱加成盐而对所述母体化合物进行修饰。本发明化合物的盐可通过常规的化学方法由含有碱性部分或酸性部分的母体化合物来合成。一般来说,这些盐可通过使游离酸形式的这些化合物与化学计量之量的合适的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或通过使游离碱形式的这些化合物与化学计量之量的合适的酸反应来制备。这些反应通常在水或有机溶剂或二者的混合物中进行。一般来说,当适用时,非水性介质优选例如醚、乙酸乙酯、乙醇、异丙醇或乙腈。本发明化合物的盐还包括所述化合物的溶剂合物和所述化合物之盐的溶剂合物。
可药用盐的实例包括但不限于碱性残基(例如胺)的矿物酸盐或有机酸盐;酸性残基(例如羧酸)的碱盐或有机盐等。可药用盐包括例如由无毒的无机酸或有机酸形成的母体化合物的常规无毒盐和季铵盐。例如,常规无毒的酸盐包括衍生自无机酸的那些,所述无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;由例如以下的有机酸制备的盐:乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲基苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟基乙磺酸、HOOC-(CH2)n-COOH(其中n为0至4)等。其他合适的盐的列表可见于例如Remington′sPharmaceutical Sciences,第17版,Mack Publishing Company,Easton,Pa.,第1418页(1985)。
用于本发明药物组合物/组合的术语“载体”指与活性化合物一起提供的稀释剂、赋形剂或载剂。
“可药用赋形剂”意指可用于制备药物组合物/组合的赋形剂,其一般安全、无毒并且没有生物学或其他方面的不期望的作用,并且包含对于兽药用途和人药用途而言可接受的赋形剂。本申请中使用的“可药用赋形剂”包括一种和多于一种这样的赋形剂。
“患者”是需要医学治疗的人或非人动物。医学治疗可包括对现有病症(例如疾病或紊乱)的治疗、预防性或预先的治疗或者诊断性治疗。在一些实施方案中,所述患者是人患者。
“提供”指给予、施用、销售、分发、转移(盈利或非盈利)、制造、调剂(compounding)或分配。
“提供式I化合物与至少一种另外的活性剂”指式I化合物和另外的活性剂在单个剂型中同时提供、在分开的剂型中相继提供、或者在一定时间内相隔一段时间在分开的剂型中提供而施用,在所述一定时间内式I化合物和所述至少一种另外的活性剂都在患者血流之中。在某些实施方案中,式I化合物和所述另外的活性剂不需要由同一医疗看护人员给患者开处方。在某些实施方案中,所述另外的活性剂或试剂不需要要求开处方。可通过任何适宜途径(例如口服片剂、口服胶囊、口服液体、吸入剂、注射剂、栓剂或局部接触)进行施用式I化合物或所述至少一种另外的活性剂。
本文中使用的“治疗”包括提供式I化合物作为唯一活性剂或者与至少一种另外的活性剂一起使得足以:(a)预防疾病或疾病症状以免其在可能易于患该疾病但尚未诊断为患此病的患者中发生(例如包括可能与原发性疾病相关或由其导致的疾病,如在慢性HCV感染的情形中可导致的肝纤维化);(b)抑制所述疾病,即阻止其发展;以及(c)缓解所述疾病,即,使所述疾病消退。“治疗”还指向感染有丙型肝炎或易于感染丙型肝炎的患者提供治疗有效量的式I化合物(作为唯一活性剂或者与至少一种另外的活性剂一起)。
本发明药物组合物和/或组合的“治疗有效量”指当施用给患者时有效提供治疗益处(例如缓解症状)的量,例如有效减少丙型肝炎感染症状的量。例如,感染丙型肝炎病毒的患者可表现出某些肝酶(包括AST和ALT)水平的升高。正常的AST水平是每升血清(血液的液体部分)5至40单位,正常的ALT水平是每升血清7至56单位。因此治疗有效量是足以使升高的AST和ALT水平显著降低的量,或者足以使AST和ALT水平返回到正常范围的量。治疗有效量还是足以预防患者血液、血清或组织中病毒或病毒抗体的可检测水平显著升高或显著降低的量。确定治疗功效的一种方法包括通过用于确定病毒RNA水平的常规方法(例如RocheTaqMan测定)来测量HCV RNA水平。在某些优选实施方案中,治疗将HCV RNA水平降至低于定量极限(30IU/mL,通过Roche TaqMan(R)测定测量),或者更优选降至低于检测极限(10IU/mL,Roche TaqMan)。
病毒或病毒抗体可检测水平的显著升高或降低是在统计学显著性的标准参数检验(例如t检验,其中p<0.05)中统计学上显著的任何可检测变化。
化学描述
式I和式II(如下所示)包括其所有子式。在某些情况下,式I或式II化合物可含有一个或更多个不对称要素,例如立体中心、立体轴等(例如非对称碳原子),使得所述化合物可以以不同的立体异构形式存在。这些化合物可以是例如外消旋体或光学活性形式。对于具有两个或更多个不对称要素的化合物而言,这些化合物还可以是非对应体的混合物。对于具有非对称中心的化合物而言,应理解涵盖了所有的光学异构体及其混合物。另外,具有碳-碳双键的化合物可以是Z型和E型,所述化合物的所有异构体形式均被包括在本发明中。在这些情况下,可以通过非对称合成、由光学纯的前体进行合成或者通过外消旋体的拆分来得到单个的对映体,即光学活性形式。外消旋体的拆分还可以例如通过常规方法来实现,所述常规方法例如在拆分试剂的存在下结晶,或使用例如手性HPLC柱来进行色谱方法。
当化合物以多种互变异构体形式存在时,本发明不限于具体的互变异构体中的任一种,而是包括所有的互变异构形式。
本发明旨在包括本发明化合物中所存在原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。一般性举例(而不旨在限制)来说,氢的同位素包括氚和氘,碳的同位素包括11C、13C和14C。
本文中使用包含变量(例如D、M、A、P、J和W)的通式来描述某些化合物。除非另有指明,否则该式中的每个变量均独立于其他变量而定义。因此,如果称某基团被取代,例如被0至2个R*取代,则此基团可以被多至两个R*基团取代,且R*每次出现时都独立地选自R*的定义。另外,只要取代基和/或变量的组合能得到稳定的化合物,这样的组合就是允许的。
除在发明概述部分中讨论的式I化合物和盐以外,本公开内容还包括式I化合物和盐以及这些化合物的药物组合物/组合,其中所述变量满足任何下述条件。
(i)D-M-D是以下的任一项:
T-R-J1-W-A-W-J1-R-T;
T-R-J1-A-J1-R-T;
T-R-J2-A-J2-R-T;
T-R-J1-W-A-J1-R-T;
T-R-J1-W-A-J2-R-T以及
T-R-J1-A-J2-R-T。
(xi)A是
(xv)至少一个P是J1-W并且W是苯基,其任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。
(xvii)至少一个P是J1,并且J1是
(xviii)至少一个P是J2并且J2是苯并咪唑基,其任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。
(xix)R独立地选自:
其中每一个任选地被一个或更多个独立地选自卤素、C1-C4烷基和C1-C4烷氧基的取代基所取代。
(xx)R独立地选自
(xxi)T是独立地选择的被单C1-C6烷基氨基甲酸酯和二C1-C6烷基氨基甲酸酯取代的C2-C6烷酰基,其中在每种情况下T任选地被(C1-C4硫代烷基)C0-C4烷基取代。
(xxii)还包括式T-R-J2-A-J2-R-T的化合物和盐。
在式T-R-J2-A-J2-R-T中,A是式基团。
J2是含有1或2个独立地选自N、O和S的杂原子的8至10元杂芳基,其中J2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
每个R是独立地选择的8至10元双环体系,其含有一个或两个氮原子,其余环原子为碳,所述8至10元双环是饱和的或者含有1个不饱和键;并且R任选地被一个或更多个独立地选自以下的取代基所取代:氰基、羟基、卤素、C1-C2烷基、C1-C2烷氧基、C1-C2卤代烷基、C1-C2卤代烷基、C1-C2卤代亚烷基以及C1-C2烷基磺酰基。
T2在每次出现时独立地选自:C2-C6烷酰基、C1-C6烷基酯、C1-C6烯基酯、C1-C6烷基磺酰胺、C1-C6烷基磺酰基、被单C1-C6烃基氨基甲酸酯或二C1-C6烃基氨基甲酸酯取代的C2-C6烷酰基、被脲或单C1-C6烷基脲或二C1-C6烷基脲取代的C2-C6烷酰基、以及被单C1-C6烷基甲酰胺或二C1-C6烷基甲酰胺取代的C2-C6烷酰基,其中在每种情况下T2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、(C1-C4烷氧基)C0-C4烷基、(单C1-C4烷基氨基和二C1-C4烷基氨基)C0-C4烷基、C1-C6烷基、(C1-C4硫代烷基)C0-C4烷基、C3-C7环烷基、苯基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
在xxii的某些实施方案中,优选地-J2-R-是式或更特别地基团。-J2-R-可以被一个或更多个独立地选自以下的取代基所取代或未被取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
在xxii的某些实施方案中,还优选T2是被单C1-C6烃基氨基甲酸酯或二C1-C6烃基氨基甲酸酯取代的C2-C6烷酰基,其中T2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、(C1-C4烷氧基)C0-C4烷基、(单C1-C4烷基氨基和二C1-C4烷基氨基)C0-C4烷基、C1-C6烷基、(C1-C4硫代烷基)C0-C4烷基、C3-C7环烷基、苯基、C1-C2卤代烷基以及C1-C2卤代烷氧基。
式I化合物的任何前述条件可以一起使用以定义式I的子式,只要得到稳定的化合物即可。所有这样的子式均包括在本公开内容之内。
除在发明概述部分讨论的式I化合物和盐以外,本公开内容还包括式I和式II的组合物和组合,其中式II是:
在式II中,变量R1’、R2’、R3’、R4’、R6’、R7’、R8’、R16和T’具有下文所述的定义。
R1’和R2’相连以形成含有1或2个独立地选自N、O和S的杂原子的5至7元杂环烷基环,该环任选地与苯基或5或6元杂芳基稠合以形成双环体系,其中每一个5至7元杂环烷基环或双环体系任选地被取代。
变量R3’至R8’满足下述条件之一。R3’、R4’、R5’和R6’独立地为氢、C1-C4烷基或(C3-C7环烷基)C0-C4烷基;并且R7’和R8’相连以形成任选地被取代的3至7元环烷基环。
R3’、R4’和R6’独立地为氢、C1-C4烷基或(C3-C7环烷基)C0-C4烷基;并且R8’是氢或C1-C4烷基;并且R5’与R7’通过C6-C10饱和的或不饱和的烃链相连。
R3’、R4’和R6’独立地为氢、C1-C4烷基或(C3-C7环烷基)C0-C4烷基;并且R7’和R8’相连以形成任选地被取代的3至7元环烷基环;并且R5’与由R7和R8通过C6-C10饱和的、部分不饱和的或不饱和的烃链形成的3至7元任选地被取代的环烷基环相连。
T’是式基团。
R9是羟基、氨基、-COOH、-NR10R11、-OR12、-SR12、-NR10(S=O)R11或-NR10SO2R11。R10、R11和R12在每次出现时独立地为氢或C1-C6烷基、C2-C6烯基、(芳基)C0-C2烷基、(C3-C7环烷基)C0-C2烷基、(杂环烷基)C0-C2烷基或(5至10元杂芳基)C0-C2烷基,其中每一个任选地被1至3个独立地选自卤素、羟基、氧代基团、C1-C2烷基、C1-C2烷氧基、三氟甲基和三氟甲氧基的取代基所取代。
Z’是
其中X1、X2、X3、X4和X5独立地为N或CH,并且X1至X5中为N的不超过两个。
R21表示0至3个独立地选自以下的基团:卤素、羟基、氨基、氰基、-CONH2、-COOH、C1-C4烷基、C2-C4烷酰基、C1-C4烷氧基、C1-C4烷基硫基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基和C1-C2卤代烷氧基。
R22是氢、卤素、羟基、氨基、氰基、-CONH2、-COOH、C1-C4烷基、C2-C4烷酰基、C1-C4烷氧基、C1-C4烷基硫基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C4烷基酯、C1-C2卤代烷基以及C1-C2卤代烷氧基;或者R22是(C3-C7环烷基)C0-C2烷基、(苯基)C0-C2烷基、(苯基)C0-C2烷氧基、(5或6元杂芳基)C0-C2烷基、(5或6元杂芳基)C0-C2烷氧基、萘基、茚满基、(5或6元杂环烷基)C0-C2烷基、或者9或10元双环杂芳基,其中每一个被0、1或2个独立地选自以下的取代基所取代:
(i)卤素、羟基、氨基、氰基、硝基、-COOH、-CONH2、CH3(C=O)NH-、C1-C4烷基、C1-C4烷氧基、C1-C4羟基烷基、单C1-C4烷基氨基和二C1-C4烷基氨基、-NR8SO2R11、-C(O)OR11、-NR8COR11、-NR8C(O)OR11、三氟甲基、三氟甲氧基,以及
(ii)苯基和5或6元杂芳基,其中每一个被卤素、羟基、C1-C4烷基以及C1-C2烷氧基中的0或1或更多个所取代;其中R8是氢、C1-C4烷基或C3-C6环烷基,R11如上文所定义。
R16表示0至4个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基。
式I化合物的任何前述条件可以一起使用以定义式I的子式,只要得到稳定的化合物即可,并且所有这些子式都包括在本公开内容之内。
本公开内容还包括包含式I化合物和式II化合物的药物组合物和组合,以及治疗方法,该方法包括向感染有丙型肝炎的患者施用这样的组合物/组合。
例如,本公开内容包括其中式II化合物如下的组合物和组合:
本公开内容还包括包含式I化合物和式II化合物的药物组合物和组合,以及治疗方法,该方法包括向感染有丙型肝炎的患者施用这样的组合物/组合。
例如,本公开内容包括其中式II化合物如下的组合物和组合:
可用于本文所述药物组合物和组合的式II的NS3a蛋白酶抑制剂在之前已有公开。2011年3月15日发布的美国专利No.7,906,619因其关于4-氨基-4-氧代丁酰基肽的教导而通过引用整体并入本文。在实施例部分特别地通过引用并入了‘619专利(从第50栏(column)至第85栏),其公开了可与本文所述式I化合物用于组合物/组合的化合物。
2010年8月26日公开的美国公开专利申请No.2010-0216725因其关于4-氨基-4-氧代丁酰基肽的教导而通过引用整体并入本文。在实施例部分特别地通过引用并入了‘725申请(从第22页至第100页),其公开了可与本文所述式I化合物用于组合物/组合的化合物。
2010年6月17日公开的美国公开专利申请No.2010-0152103因其关于4-氨基-4-氧代丁酰基肽环类似物的教导而通过引用整体并入本文。在实施例部分特别地通过引用并入了‘103申请(从第19页至第60页),其公开了可与本文所述式I化合物用于组合物/组合的化合物。
药物制剂
本文公开的化合物可作为纯化合物施用,但是优选作为药物组合物施用。因此,本公开内容提供了包含式I化合物或其可药用盐以及至少一种可药用载体的药物组合物。所述药物组合物/组合可包含式I化合物或盐作为唯一的活性剂,但优选地包含至少一种另外的活性剂。在某些实施方案中,优选所述另外的活性剂是NS3a蛋白酶抑制剂,例如式II化合物的盐。在某些实施方案中,所述药物组合物为在单位剂型中包含以下的剂型:约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的式I化合物以及任选的约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的另外的活性剂。所述药物组合物还可包含摩尔比的式I化合物与另外的活性剂。例如,所述药物组合物可包含摩尔比为约0.5:1、约1:1、约2:1、约3:1或约1.5:1至约4:1的式II NS3a蛋白酶抑制剂与式I NS5a抑制剂。
本文公开的化合物可以以含有常规可药用载体的剂量单位制剂通过口服、局部、肠胃外、吸入或喷雾、舌下、经皮、通过口腔施用、经直肠、作为眼用溶液或以其他方式施用。所述药物组合物可配制成任意药学上可用的形式,例如气雾剂、乳膏剂、凝胶剂、丸剂、胶囊剂、片剂、糖浆剂、经皮贴剂或眼用溶液剂。一些剂型(例如片剂和胶囊剂)可被分为含有合适量(例如达到所期望目的的有效量)活性成分的合适大小的单位剂量。
载体包括赋形剂和稀释剂,并且必须具有足够高的纯度和足够低的毒性,以使得它们适于施用给所治疗的患者。载体可以是惰性的或其本身可具有药学益处。与所述化合物联合使用的载体的量足以提供用于施用每单位剂量化合物的材料的实际量。
载体的类别包括但不限于粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、润滑剂、防腐剂、稳定剂、表面活性剂、压片剂和润湿剂。一些载体可列在一个以上的类别中,例如植物油在一些制剂中可用作润滑剂,在另外一些制剂中则可用作稀释剂。示例性的可药用载体包括糖、淀粉、纤维素、西黄蓍胶粉、麦芽、明胶、滑石和植物油。基本上不干扰本发明化合物活性的任选的活性剂可包含在药物组合物中。
所述药物组合物/组合可配制用于口服施用。这些组合物包含0.1重量%至99重量%(wt%)的式I化合物,通常为至少约5wt%的式化合物。一些实施方案包含约25wt%至约50wt%或者约5wt%至约75wt%的式化合物。
治疗方法
本文公开的药物组合物/组合可用于治疗患者的丙型肝炎感染。
本公开内容提供了通过向感染有丙型肝炎病毒的患者提供有效量的式I化合物或可药用盐来治疗病毒感染(包括丙型肝炎感染)的方法。式I化合物或盐可作为唯一活性剂提供或者可以与一种或更多种另外的活性剂一起提供。在某些实施方案中,式I化合物或盐与式II化合物或盐或者其他NS3a蛋白酶抑制剂一起施用。在某些实施方案中,所述药物组合物包含式I化合物和NS5b抑制剂,以及任选地包含另外的活性剂。
本发明药物组合物/组合的有效量可以是足以实现以下的量:(a)抑制丙型肝炎的进程;(b)使丙型肝炎感染消退,或(c)将丙型肝炎感染治愈,从而使得先前受感染患者的血液或血浆中不再能检测到HCV病毒或HCV抗体。有效抑制丙型肝炎进程或导致丙型肝炎消退的药物组合物/组合的量包括有效停止丙型肝炎症状恶化或减少感染有丙型肝炎病毒之患者所经历症状的量。或者,丙型肝炎发展的中止或消退可以通过此疾病的数种标志物中的任一项来指示。例如,患者血液中丙型肝炎病毒载量增加或减少的缺乏或者循环HCV抗体数量增加或减少的缺乏是丙型肝炎感染进程中止或消退的标志。其他丙型肝炎疾病标志物包括转氨酶水平,特别是肝酶AST和ALT的水平。正常的AST水平是每升血清(血液的液体部分)5至40单位,正常ALT水平是每升血清7至56单位。这些水平通常在HCV感染患者中较高。AST和ALT水平返回正常范围通常标志着疾病的消退。
可被有效量的本发明药物组合物/组合影响的丙型肝炎症状包括:肝功能降低、疲劳、流感样症状(发热、打冷战、肌痛、关节痛和头痛)、恶心、厌恶某些食物、原因不明的体重减轻、心理疾病(包括抑郁)、腹部压痛和黄疸。
“肝功能”指肝的正常功能,包括但不限于:合成功能,包括蛋白质例如血清蛋白(例如白蛋白、凝结因子(clotting factor)、碱性磷酸酶、转氨酶(如丙氨酸转氨酶、天冬氨酸转氨酶)、5’-核苷酶、y谷氨酰胺转肽酶等)的合成、胆红素的合成、胆固醇的合成和胆汁酸的合成;肝代谢功能,包括碳水化合物代谢、氨基酸和氨代谢、激素代谢和脂质代谢;对外源性药物的解毒;以及血液动力学功能,包括内脏血液动力学和门脉血液动力学(portal hemodynamic)。
有效量的本文所述组合物/组合还会在以浓度施用给患者时提供足够浓度的活性剂。活性剂的足够浓度是预防或对抗感染所必需的患者体内的药剂浓度。该量可以通过实验来确定,例如通过测定所述药剂的血液浓度,或者在理论上通过计算生物利用度来确定。可以使用用于病毒感染的常规测定(例如基于复制子的测定,其在文献中已有描述)来确定足以体外抑制病毒感染的活性剂的量。
本文包括药物组合物/组合以及其中提供式I化合物或盐和一种或更多种另外的活性剂的治疗方法。在一些优选实施方案中,式I化合物与NS3a蛋白酶抑制剂一起提供,根据一起使用式I化合物和另外的活性剂的对于患者的说明书以单独的药物组合物或者以分开的剂型提供。式II化合物和美国专利No.7,906,619、美国专利申请No.2010-0216725以及美国专利申请No.2010-0152103中公开的化合物(其中大多数在式II的范围内)是用于与式I化合物和盐组合的合适的NS3a蛋白酶抑制剂。在某些实施方案中,所述活性剂(或药剂)是HCV蛋白酶抑制剂或HCV聚合酶抑制剂。例如,所述蛋白酶抑制剂可以是特拉匹韦(telaprevir)(VX-950),所述聚合酶抑制剂可以是瓦洛他滨(valopicitabine)或NM107(瓦洛他滨在体内转变成的活性剂)。在某些实施方案中,至少一种另外的活性剂是利巴韦林、干扰素或PEG-干扰素α缀合物。在某些实施方案中,所述至少一种另外的活性剂是ACH-1625或ACH-2684。
根据本发明的方法,式I化合物或可药用盐和至少一种另外的活性剂可以:(1)在组合制剂中共同配制并且同时施用或递送;(2)作为分开的制剂交替递送或平行递送;或者(3)通过本领域已知的任何其他组合疗法方案。当在交替疗法中递送时,本发明的方法可包括依次施用或递送式I化合物或盐以及另外的活性剂,例如在分开的溶液剂、乳剂、混悬剂、片剂、丸剂或胶囊剂中,或者通过在分开的注射器中的不同注射剂。一般来说,在交替疗法期间,依次(即,连续)施用有效量的每种活性成分,而在同时治疗中,一起施用有效剂量的两种或更多种活性成分。也可以使用多种次序的间歇式组合疗法。
本公开内容提供了治疗方法和包含本文所述式I化合物或可药用盐与作为另外的活性剂的下述化合物和物质中的任意一种或组合的药物组合:
抗纤维化剂:IP-501(InterMune);
胱天蛋白酶(caspase)抑制剂:IDN-6556(Idun Pharmaceuticals)和GS-9450(Gilead);
亲环素(cyclophililn)抑制剂:NIM811(Novartis)、SCY-635(Scynexis)和DEBIO-025(Debiopharm);
细胞色素P450单加氧酶抑制剂:利托那韦、酮康唑、醋竹桃霉素(troleandomycin)、4-甲基吡唑、环孢菌素、氯美噻唑、西咪替丁、伊曲康唑、氟康唑、咪康唑、氟伏沙明、氟西汀、奈法唑酮、舍曲林、茚地那韦、萘非那韦、安普那韦、福沙那韦、沙奎那韦、洛匹那韦、地拉韦啶、红霉素、VX-944和VX-497(美泊地布(Merimebodib))。优选的CYP抑制剂包括利托那韦、酮康唑、醋竹桃霉素、4-甲基吡唑、环孢菌素和氯美噻唑;
糖皮质激素:氢化可的松、可的松、***、***龙、甲基***龙、曲安西龙、帕拉米松、倍他米松和***;
HCV蛋白酶抑制剂:例如ACH-1625和ACH-2684。美国专利号7,906,619因其关于抗-HCV化合物的教导而并入本文。美国专利申请No.12/635,270的第52至167页和美国专利申请No.12/635,049的第43至92页因其关于抗-HCV化合物的教导而通过引用并入本文,ACH1625和ACH2684(Achillion)、ABT-450(Abbott)、ACL-181以及AVL-192(Avila)、BI-335(Boehringer Ingelheim)、BMS-032(Bristol Meyers Squibb)、boceprevir(Merck)、TMC-435、MK-7152(Merck)、GS-9256(Gilead)、GS-9451(Gilead)、R7227(Intermune)、VX-500(Vertex)、VX-950(特拉匹韦、Vertex)、VX-985(Vertex)、TMC-435(Tibotec)、GW-433908(安普那韦的前药,Glaxo/Vertex)、茚地那韦(CRIXIVAN,Merck)、ITMN-191(Intermune/Array Biopharma)、BILN2061(Boehringer-Ingelheim)、TMC435350(Tibotec/Medivir)、BI201335(Boehringer Ingelheim)、PHX-1766(Phenomix)、MK-7009(Merck)、那拉匹韦(narlaprevir)(SCH900518、Schering);
***:***-1和***-2。***超家族的其他成员例如多种集落刺激因子(例如,(例如G-CSF、GM-CSF、M-CSF)、Epo和SCF(干细胞因子);
顺势疗法(Homeopathic Therapy):乳蓟(milk thistle)、水飞蓟素(silymarin)、人参、甘草甜素、甘草根(licorice root)、五味子(schisandra)、维生素C、维生素E、β-胡萝卜素和硒;
免疫调节化合物:沙利度胺(thalidomide);IL-2;***;IMPDH抑制剂,例如美泊地布(Merimepodib)(Vertex PharmaceuticalsInc.);干扰素,包括天然干扰素(例如OMNIFERON,Viragen和SUMIFERON,Sumitomo,天然干扰素的混合物)、天然干扰素α(ALFERON,Hemispherx Biopharma、Inc.)、来自淋巴母细胞(lymphblastoid cell)的干扰素αnl(WELLFERON,Glaxo Wellcome)、口服α干扰素、Peg-干扰素、Peg-干扰素α2a(PEGASYS,Roche)、重组干扰素α2a(ROFERON、Roche)、吸入干扰素α2b(AERX,Aradigm)、Peg-干扰素α2b(ALBUFERON,Human Genome Sciences/Novartis;PEGINTRON,Schering)、重组干扰素α2b(INTRON A,Schering)、peg化干扰素α2b(PEG-INTRON,Schering;VIRAFERONPEG,Schering)、干扰素β-1a(REBIF,Ares-Serono,Inc.和Pfizer)、复合干扰素α(consensus interferon alpha)(INFERGEN,Intermune)、干扰素γ-1b(ACTIMMUNE,Intermune,Inc.)、非peg化干扰素α、α干扰素及其类似物、合成胸腺素α1(ZADAXIN,SciClone Pharmaceuticals Inc.),以及λ干扰素(lamdba interferon)(BMS);
免疫抑制剂:西罗莫司(RAPAMUNE,Wyeth);
白细胞介素:(IL-1、IL-3、IL-4、IL-5、IL-6、IL-10、IL-11、IL-12)、UF、TGF-β、TNF-α)以及其他低分子量因子(例如,AcSDKP、pEEDCK、胸腺激素和微小细胞因子(minicytokine));
干扰素增强剂:EMZ702(Transition Therapeutics);
IRES抑制剂:VGX-410C(VGX Pharma);
单克隆和多克隆抗体:XTL-6865(HEPX-C,XTL)、HuMax-HepC(Genmab)、丙型肝炎免疫球蛋白(人)(CIVACIR,NabiBiopharmceuticals)、XTL-002(XTL)、利妥昔单抗(Rituximab)(RITUXAN,Genentech/IDEC);
核苷类似物:IDX-184(Idenix)、PSI-7977和PSI-938(Pharmasset)、INX-189(Inhibitex)、R7128(Roche)、R7348(Roche)、GS-6620(Gilead)、TMC-649(Tibotec)、拉米夫定(EPIVIR,3TC,GlaxoSmithKline)、MK-0608(Merck)、扎西他滨(HIVID、Roche USPharmaceuticals)、利巴韦林(包括COPEGUS(Roche)、REBETOL(Schering)、VILONA(ICN Pharmaceuticals,和VIRAZOLE(ICNPharmaceuticals)、艾沙托立宾(isatoribine)(Anadys Pharmaceuticals)、ANA971(Anadys Pharmaceuticals)、ANA245(Anadys Pharmaceuticals)以及viramidine(ICN)(利巴韦林的脒前药)。还可以使用核苷类似物的组合;
非核苷抑制剂:PSI-6130(Roche/Pharmasset)、ABT-333和ABT-072(Abbott)、地拉韦定(delaviridine)(RESCRIPTOR,Pfizer)、PF-868554(Pfizer)、GSK-852(GlaxoSmithKline)、IDX-325(Idenix)、ANA-598(Anadys)、VX-222和VX-759(Vertex)、MK-3281(Merck)、BI-127(Boehringer Ingelheim)、BMS-325(Bristol Meyers)以及HCV-796(Viropharm);
NS4a抑制剂:例如ACH-1095。美国专利申请No.US2007/0004711因其关于HCV抑制剂的教导而通过引用整体并入本文,并且美国专利申请No.12/125,554的第45至90页因其关于HCV抑制剂的教导而通过引用并入本文;
NS4b抑制剂:克立咪唑(Arrow Therapeutics);
NS5a抑制剂:A-382(Arrow Therapeutics)、BMS-790052(BMS);
NS5b抑制剂:INX-181、IDX-375、MK-3281、PSI-7977、PSI-7851、PSI-938、RG-9190、VX-222(Vertex)和BMS-791325(Bristol Meyers Squibb);
P7蛋白抑制剂:金刚烷胺(SYMMETREL,Endo Pharmaceuticals,Inc.);
聚合酶抑制剂:非利布韦(Filibuvir)(PF-00868554,Pfizer)、NM283(瓦洛他滨(valopicitabine))(Idenix)、JTK003(AKROS Pharma)、HCV-796(ViroPharma/Wyeth)、IDX184(Idenix)、VCH-916(Vertx)、R7128(PSI6130,Roche)、R1626(Roche)、MK-3281(Merck)、PSI-7851(Pharmasset)、ANA598(Anadys)、BI207127(Boehringer-Ingelheim)、GS9190(Gilead);
RNA干扰:SIRNA-034RNAi(Sirna Therapeutics)和ISI14803(IsisPharmaceutical/Elan);
治疗性疫苗:IC41(Intercell)、IMN-0101(Imnogenetics)、GI5005(Globeimmune)、Chronvac-C(Tripep/Inovio)、ED-002(Imnogenetics)、Hepavaxx C(ViRex Medical);
TNF激动剂:阿达木单抗(HUMIRA,Abbott)、依那西普(entanercept)(ENBREL,Amgen和Wyeth)、英夫利昔(infliximab)(REMICADE,Centocor,Inc.);
微管蛋白抑制剂:秋水仙素;
鞘氨醇-1-磷酸受体调节剂:FTY720(Novartis);
TLR激动剂:ANA-975(Anadys Pharmaceuticals)、TLR7激动剂(AnadysPharmaceuticals)、CPG10101(Coley)以及TLR9激动剂包括CPG7909(Coley);
疫苗:HCV/MF59(Chiron)、IC41(Intercell)、E-1(Innogenetics)。
接受丙型肝炎药物治疗的患者通常被给予干扰素和另一种活性剂。因此,作为实施方案包括了如下的治疗方法和药物组合,其中本发明化合物与作为所述另外的活性剂的干扰素(如peg化干扰素α2a)一起提供。类似地,本文提供了其中利巴韦林是另外的活性剂的方法和药物组合。
本文包括抑制HCV体内复制的方法,其包括向感染有HCV的患者提供式I化合物或可药用盐,所述式I化合物或盐的浓度足以抑制HCV复制子在体外复制。在这种情况下,所述浓度包括体内浓度,例如血液或血浆浓度。可以由复制子复制的测定(例如本文实施例9中所提供的测定)来确定足以抑制HCV复制子在体外复制的化合物浓度。
治疗方法包括向患者提供某些剂量的式I化合物或可药用盐。每种活性剂的约0.1mg至约140mg/kg体重/天的剂量水平可用于治疗上述病症(约0.5mg至约7g/患者/天)。可与载体材料组合以产生单个单位剂型的活性成分的量将根据受治疗的患者和特定施用方式而改变。在某些实施方案中,每天向患者提供约0.1mg至约2000mg、约10mg至约1500mg、约100mg至约1000mg、约200mg至约800mg或约300mg至约600mg的式I化合物和任选的约0.1mg至约2000mg、约10mg至约1500mg、约100mg至约1000mg、约200mg至约800mg、或约300至约600mg的另外的活性剂化合物(例如NS3a蛋白酶抑制剂,例如式II化合物)。优选每个单位剂型包含总计小于1200mg的活性剂。给药频率也可以根据所使用的化合物和所治疗的特定疾病而改变。但是,就大多数感染性疾病的治疗而言,优选每天4次或更少的给药方案,并且特别优选每天1次或2次的给药方案。
但是,应理解,就任何特定患者而言的特定剂量水平将取决于多种因素,包括所采用的特定化合物的活性、年龄、体重、一般健康、性别、饮食、施用时间、施用途径和***速率、药物组合以及经历治疗的患者特定疾病的严重程度。
经包装的制剂
本文包括这样的方法,所述方法包括提供容器中的式I化合物或盐和用于使用所述化合物来治疗患有丙型肝炎感染之患者的说明书。
本文还包括经包装的药物组合物/组合。这样的包装的组合包括容器中的式I化合物和用于使用所述组合来治疗或预防患者的病毒感染(例如丙型肝炎感染)的说明书。
所述经包装的药物组合物/组合可以包含一种或更多种另外的活性剂。在某些实施方案中,所述另外的活性剂是NS3a蛋白酶抑制剂,例如式II化合物。
所述经包装的药物组合可以包含式I化合物或可药用盐和另外的活性剂,其同时以单个剂型提供、伴随地以分开的剂型提供或者用于间隔一定时间(在式I化合物和另外的活性剂存在于患者血流内的时间内)分开施用的分开剂型提供。
所述经包装的药物组合可以包含在容器中提供的式I化合物或可药用盐和在同一或不同容器中提供的另外的活性剂,以及用于使用所述组合来治疗患者之HCV感染的说明书。
实施例
缩写
下述反应方案和合成实施例使用如下缩写。该列表不旨在为本申请中所使用的缩写的详尽列表,这是因为所述合成方案和实施例中还可使用另外的标准缩写,这些标准缩写是有机合成领域技术人员所易于理解的。
Ac 乙酰基
ACN 乙腈
aq 水性
BOC 叔丁氧基羰基
DCM 二氯甲烷
DIEA N,N-二异丙基乙胺
DIPEA N,N-二异丙基乙胺
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
dppf 1,1’-双(二苯基膦基)二茂铁
EDCI N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐
Et 乙基
Et2O ***
FCC 快速柱色谱
HATU O-(7-氮杂苯并***-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐
MTBE 甲基叔丁基醚
PTLC 制备型薄层色谱
rt 室温
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TPP 三苯基膦
一般考虑
所有非水性反应均在干燥氩气氛下使用经烘箱干燥的玻璃器具和无水溶剂进行。使用下述两种HPLC方法之一确定反应进程和目标化合物的纯度:(1)Waters AQUITY UPLC BEH C181.7μm2.1×50mm柱,以90:10水:乙腈(含0.05%甲酸)等度洗脱0.24分钟,接着以1.0ml/分钟的流速进行4.26分钟的线性梯度洗脱(从90:10至10:90),并进行UV(PDA)、ELS和MS(APCI模式中的SQ)检测(方法1);和(2)WatersAQUITY UPLC BEH C181.7μm2.1×50mm柱,以95:5水:乙腈(含0.05%甲酸)等度洗脱0.31分钟,接着以0.4mL/分钟的流速进行17.47分钟的线性梯度洗脱(95:5至5:95),并进行UV(PDA)、ELS和MS(APCI模式中的SQ)检测(方法2)。
通过制备型反相HPLC来纯化目标化合物,所述制备型反相HPLC使用YMC Pack Pro C185μm150×20mm柱,以95:5水:乙腈(含0.1%三氟乙酸)等度洗脱0.35分钟,接着以18.9mL/分钟的流速进行23.3分钟的线性梯度洗脱(95:5至5:95),并进行基于UV和质量的级分收集。
一般合成方案
实施例1.化合物10的合成
如之前所述(Reich,H.J.;Cram,D.J.J.Am.Chem.Soc.1969,91,3527-3533;Reich,H.J.;Cram,D.J.J.Am.Chem.Soc.1969,91,3534-3543),通过[2.2]对环芬的溴化制备化合物10。化合物1、2、6、8和10可获自商业来源。化合物3至7以及9使用本领域中已知的一般合成方法来制备。
实施例2.化合物11的合成
将二氧六环/水(5.5.mL/0.55mL)中的9(284.2mg)、10(52.3mg)、K3PO4(248.1mg)和PdCl2dppf·CH2Cl2(7.4mg)的去氧(氩)混合物在微波中于80℃照射2小时。在减压下蒸发所得混合物,用DCM萃取剩余的固体。通过PTLC(20cm×20cm×2000μm玻璃板;用45:50:5v/v/v DCM:EtOAc:MeOH洗脱,Rf0.28)纯化该粗制材料,以得到75.3mg的11。通过分析型反相HPLC确定11的纯度,所述分析型反相HPLC在Waters AQUITY UPLC BEH C181.7μm2.1×50mm柱上使用水中增加浓度的ACN(10%至90%)(含0.05%甲酸)以1.0mL/分钟的流速进行3.5分钟的梯度洗脱,进行UV(PDA)、ELS和MS(APCI模式中的SQ)检测。HPLC:tR1.57分钟(98%纯度)。MS m/z计算值:C56H64N8O6([M]+),945;实测值:946([M+1]+)。
实施例3.((2S,2′S)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯(20)的合成
步骤1
在0℃下,向(2R,3aS,7aS)-八氢-1H-吲哚-2-羧酸(250g,1.0当量)(12)的THF(3L)和水(1.5L)搅拌溶液中逐滴添加冷却的2.5M NaOH水溶液(1L)。在相同的温度下将反应混合物搅拌15分钟。然后,逐滴添加二碳酸二叔丁酯(1.3当量),将温度保持在0℃。将所得反应混合物在室温下搅拌12小时。用MTBE洗涤反应混合物(3次)。用1M柠檬酸水溶液酸化水相,并用乙酸乙酯萃取(3次)。经硫酸钠干燥合并的有机层,并浓缩至干以得到(2R,3aS,7aS)-1-(叔丁氧基羰基)八氢-1H-吲哚-2-羧酸(368g)(13)。
步骤2
在0℃下,向4-溴-1,2-二氨基苯(23.1g,1.2当量)、(2R,3aS,7aS)-1-(叔丁氧基羰基)八氢-1H-吲哚-2-羧酸(26.9g,1.0当量)13和EDCI(23.6g,1.2当量)的ACN(600mL)搅拌溶液中逐滴添加DIEA(21.5mL,1.3当量)。完成添加之后,将反应混合物再搅拌1小时。添加水(1.2L),将反应混合物搅拌过夜。收集固体粉末(14),用水洗涤,并干燥用于接下来的步骤而无需进一步纯化(39.1g)。
步骤3
将(2S,3aS,7aS)-2-((2-氨基-4-溴苯基)氨基甲酰基)八氢-1H-吲哚-1-羧酸叔丁酯和(2S,3aS,7aS)-2-((2-氨基-5-溴苯基)氨基甲酰基)八氢-1H-吲哚-1-羧酸叔丁酯(160g,0.36mol)的异构体混合物(14)溶解于乙酸(480mL)中,在65℃下搅拌反应混合物直至原料耗尽(如通过LC-MS分析判断的)。将反应冷却至室温,并在真空下除去溶剂。将剩余的残余物溶解于乙酸乙酯(500mL)中,并小心添加氨水(100mL)。再添加水(100mL),分离有机层并收集。用乙酸乙酯(2×300mL)萃取水相。用水(200mL)、接着用盐水(200mL)洗涤合并的有机相,经MgSO4干燥。浓缩溶液,并通过硅胶柱色谱(己烷/乙酸乙酯)纯化剩余的残余物,以得到(2S,3aS,7aS)-2-(6-溴-1H-苯并[d]咪唑-2-基)八氢-1H-吲哚-1-羧酸叔丁酯(15)(140g)。
步骤4
在氩气氛下,将无水1,4-二氧六环(300mL)中(2S,3aS,7aS)-2-(6-溴-1H-苯并[d]咪唑-2-基)八氢-1H-吲哚-1-羧酸叔丁酯(15)(30g,1.0当量)、双(频哪醇基)二硼烷(27.2g,1.5当量)、醋酸钾(21g,3.0当量)和Pd(dppf)Cl2(5.7g,0.098当量)的混合物在80℃至90℃加热约4小时(直至如通过LC-MS判断的反应完成)。用乙酸乙酯(300mL)稀释冷却的(室温)反应混合物,与活性炭(60g)搅拌1小时,并通过硅藻土垫过滤。在减压下浓缩滤液,并通过硅胶柱色谱(己烷/乙酸乙酯,5:1→1:2v/v)纯化所得棕色泡沫,以得到作为灰白色固体的(2S,3aS,7aS)-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-苯并[d]咪唑-2-基)八氢-1H-吲哚-1-羧酸叔丁酯(16)。
步骤5
将DCM(1.6L)中Br2(82.8g)和铁粉(4.6g)的混合物在室温下搅拌1小时。向该混合物中添加一部分[2.2]对环芬(200g,1.0当量)的DCM浆液。将所得混合物加热至回流,并向其中经3小时的时间缓慢添加Br2(228g)的DCM(400mL)溶液。完成添加之后,使继续回流3小时的反应混合物冷却至室温,同时搅拌过夜,然后用5%w/v Na2S2O3水溶液(2L)和水(2L)洗涤,经MgSO4干燥,并蒸发至干。将分离的粗制固体溶解于热的甲苯(1.2L,约100℃)中,使其在搅拌中缓慢冷却过夜至室温,并进一步冷却至5℃,保持3小时。收集所得固体,并用冷的甲苯(约100mL)洗涤以提供4,16-二溴[2.2]对环芬(17)(83g)。
1H NMR(300MHz,CDCl3,rt):δ2.79-3.00(m,4H),3.10-3.21(m,2H),3.44-3.54(m,2H),6.44(d,J=8.0Hz,2H),6.51(d,J=2.0Hz,2H),7.14(dd,J=8.0Hz,2.0Hz,2H).
步骤6
在氩气氛下,将4,16-二溴[2.2]对环芬(17)(20g,1.0当量)、(2S,3aS,7aS)-2-(6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-苯并[d]咪唑-2-基)八氢-1H-吲哚-1-羧酸叔丁酯(64g,2.5当量)、Cs2CO3(16)(44.5g,2.5当量)、Pd(PPh3)4(3.16g,0.05当量)、DMF(500mL)和水(25mL)的混合物在130℃下加热约2至3小时(直至如通过LC-MS判断的反应完成)。将反应混合物冷却至室温,并经用硅藻土分层的硅胶垫(30g)过滤。用DMF(2×50mL)洗涤该垫,并将合并的滤液添加到搅拌的水(2.5L)中,以得到浅黄色沉淀。通过过滤收集固体,用水(1L)和ACN(500mL)洗涤,并溶解在DCM(250mL)与MeOH(25mL)的混合物中。向该溶液中添加ACN(250mL),以产生良好浆液,然后在减压下于30℃至35℃浓缩,以除去约150mL的溶剂。再添加一部分ACN(500mL),在减压下于40℃至45℃除去其他溶剂(约100mL)。通过过滤收集固体,并在真空下干燥以得到作为浅黄色粉末的(2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-1-羧酸二叔丁酯(33.8g)。
步骤7
向(2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-1-羧酸二叔丁酯(18)(20.33g,1.0当量)的DCM/MeOH(4/1v/v,200mL)冷却(0℃)溶液中添加4N HCl/二氧六环溶液(100mL)。将反应混合物在室温下搅拌30分钟,并在减压下浓缩以得到浅黄色粉末(19)(21.7g)。在真空下干燥所得固体,直至通过1H NMR谱分析检测不到残余MeOH。该彻底干燥的材料在接下来的步骤中直接使用。
步骤8
在室温下,向(S)-2-((甲氧基羰基)氨基)-3-甲基丁酸(10g,2.3当量)、一水合HOBt(8.8g,2.3当量)和ACN(50mL)的混合物中添加EDCI(11.14g,2.3当量)。搅拌5分钟之后,将该活化的酸混合物添加到上述盐酸盐(19)(21.7g)和DIEA(32mL,7.2当量)的DMF(250mL)溶液中。在室温下搅拌该反应混合物直至如通过LC-MS分析判断的反应完成(约4小时),然后在搅拌下倒入水(1.2L)中。通过过滤收集沉淀,在ACN/水(4:1v/v,500mL)中搅拌过夜,再次通过过滤收集,并在真空中干燥以得到((2S,2′S)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯(20)(22.62g)。
1H NMR(300MHz,DMSO-d6,120℃):δ0.87(d,J=6.5Hz,6H),0.92(d,J=6.5Hz,6H),1.20-1.60(m,6H),1.65-2.10(m,12H),2.31(m,2H),2.38-2.52(m,2H),2.54-2.76(m,4H),2.85(m,2H),3.07(m,2H),3.45(m,2H),3.57(br s,6H),4.07(t,J=8.0Hz,2H),4.34(m,2H),5.28(t,J=8.5Hz,2H),6.51(br,2H),6.57(d,J=8.0Hz,2H),6.73(s,2H),6.76(d,J=8.0Hz,2H),7.33(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),7.72(s,2H).
实施例4.((2S,2′S,3R,3′R)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯(22)的合成
步骤1
将O-甲基-L-苏氨酸(25g,0.19mol)溶解于1,4-二氧六环(125mL)中,并冷却至0℃。然后在相同的温度下向反应混合物中添加2M NaOH(22.5g,0.56mol,3当量)水溶液之后添加氯甲酸甲酯(17.4mL,0.22mol,1.2当量)。将反应混合物升温至室温并搅拌16小时。用乙酸乙酯(500mL)洗涤反应混合物。用3N HCl(高至pH2)酸化水层,并用乙酸乙酯(3×250mL)萃取。经Na2SO4干燥合并的有机层,并浓缩以得到粗产物(23g)。向粗产物中添加乙酸乙酯(46mL),并在80℃加热以得到澄清溶液。然后将该溶液冷却至0℃。过滤所得固体并干燥以得到期望的纯产物(21)(18.75g)。
步骤2
在0℃下,向DMF(160mL)中的上述盐酸盐(32.0g,0.0384mol)、Moc-O-甲基-L-苏氨酸(18.3g,0.0960mol)和HATU(36.5g,0.09604mol)的混合物中逐滴添加DIEA(32.8mL,0.192mol)。将反应混合物升温至室温,搅拌16小时,并倒入水(1.6L)中。通过过滤收集所得固体,并溶解于DCM(500mL)中。将该溶液用水(100mL)、盐水(50mL)洗涤,经硫酸钠干燥,并在减压下浓缩。通过硅胶柱色谱纯化残余物,以得到((2S,2′S,3R,3′R)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯(22)(30g)。
1H NMR(400MHz,DMSO-d6,rt):δ0.91-1.04(m,6H),1.21-1.59(m,6H),1.64-1.88(m,6H),1.90-2.07(m,4H),2.23-2.49(m,6H),2.62(m,2H),2.85(m,2H),3.08(m,2H),3.19(s,3H),3.20(s,3H),3.42(m,2H),3.57(s,6H),4.15(表观t,J=8.0Hz,2H),4.47(m,2H),5.16(表观t,J=8.5Hz,2H),6.52(表观t,J=8.5Hz,2H),6.75(s,2H),6.82(m,2H),7.41(m,2H),7.71(表观t,J=6.0Hz,2H),7.64-7.79(m,4H).
实施例5.((2S,2′S,3R,3′R)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯(23)的合成
按照与上述((2S,2′S,3R,3′R)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯的合成相类似的方式制备((2S,2′S,3R,3′R)-((2S,2′S,3aS,3a′S,7aS,7a′S)-2,2′-(5,5′-(三环[8.2.2.24,7]十六-4,6,10,12,13,15-己烯-5,11-二基)双(1H-苯并[d]咪唑-5,2-二基))双(八氢-1H-吲哚-2,1-二基))双(3-羟基-1-氧代丁烷-2,1-二基))二氨基甲酸二甲酯。
1H NMR(400MHz,DMSO-d6,rt):1H NMR(400MHz,DMSO-d6,rt):δ0.95-1.04(m,6H),1.20-1.56(m,6H),1.64-1.85(m,6H),1.90-2.09(m,4H),2.25(m,2H),2.32-2.49(m,4H),2.63(m,2H),2.83(m,2H),3.06(m,2H),3.39(m,2H),3.57(s,6H),3.69(m,2H),4.06(表观t,J=7.5Hz,2H),4.46(m,2H),4.72(m,2H),5.13(m,2H),6.44-6.57(m,2H),6.68-6.87(m,4H),7.23-7.35(m,4H),7.53-7.78(m,4H).
实施例6通过四胺合成途径合成化合物29
步骤1
将1,2-二氨基-4-溴苯(10g,0.053mol)溶解于DCM(150mL)中,并冷却至0℃。在相同的温度下逐滴添加NaOH(50mL,2.5mol)溶液。15分钟之后,在相同的温度下,逐滴添加二碳酸二叔丁酯(58g,0.26mol)。然后,将反应混合物升温至室温,搅拌16小时,用DCM(100mL)稀释,并用水(100mL)洗涤。分离有机层,经Na2SO4干燥并浓缩。通过硅胶柱色谱(石油醚/乙酸乙酯,1:1v/v)纯化该粗制材料,以得到期望的产物(18g)。
步骤2
在氩气氛下,将1,4-二氧六环(360mL)中的(4-溴-1,2-亚苯基)二氨基甲酸二叔丁酯(24)(18g,0.046mol)、双(频哪醇基)二硼(17.7g,0.070mol)、乙酸钾(13.66g,0.14mol)和Pd(dppf)Cl2(3.8g,0.0046mol)的混合物在85℃下加热16小时。然后用乙酸乙酯(200mL)稀释反应混合物,经硅藻土床过滤。在减压下浓缩滤液,通过硅胶柱色谱(石油醚/乙酸乙酯,80:20v/v)纯化剩余的材料,以得到期望的产物(25)(16.0g)。
步骤3
在氩气氛下,将4,16-二溴[2.2]对环芬(17)(6g,0.014mol)、(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2-亚苯基)二氨基甲酸二叔丁酯(17.78g,0.032mol)、Cs2CO3水溶液(15.98g,0.049mol,在66mL水中)和Pd(PPh3)4(1.33g,0.0016mol)的混合物在密封管中于80℃加热16小时。将反应混合物倒入水(250mL)中,通过过滤收集所得沉淀,并用水洗涤。通过柱色谱(石油醚/乙酸乙酯,6:4v/v)纯化该粗制材料,以得到期望的产物(26)(5.0g)。
步骤4
在0℃至5℃下,向TFA(100mL)中添加上述四Boc保护的产物(26)(10g)。添加完成之后,将反应混合物升温至室温,并搅拌3小时。然后浓缩反应混合物,并与DCM(3×50mL)共同蒸发。粗制材料(27)直接在接下来的步骤中使用。
步骤5
在0℃下,向DMF(5mL)中的(S)-5-(叔丁氧基羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(0.5g,0.00057mol)、HOBt(0.35g,0.0026mol)、EDCI(0.5g,0.0026mol)和上述TFA盐(27)(0.343g,0.0014mol)的冷却(0℃)混合物中逐滴添加DIEA(1mL,0.0125mol)。添加完成过之后,将反应混合物升温至室温并搅拌16小时。将反应混合物倒入水中,通过过滤收集沉淀(28),并通过硅胶柱色谱纯化以得到期望的产物(0.32g)。
步骤6
向上述二酰胺产物(28)(0.32g,0.00035mol)中添加乙酸(5mL),并在45℃加热4小时。蒸发反应混合物,并用乙酸乙酯(95mL)稀释残余物,然后用NaHCO3水溶液(2×25mL)和水(2×30mL)洗涤。分离有机层,经Na2SO4干燥,并在减压下蒸发。通过柱色谱纯化粗制材料以得到期望的产物(29)(0.2g)。
步骤7
将上述boc保护的产物(0.09g)溶解于DCM(0.9mL)中,并在0℃冷却。然后,逐滴添加4N HCl/二氧六环(0.9mL)。将反应混合物升温热至室温,并搅拌3小时。然后,在真空下除去挥发物,并与DCM(3×50mL)共同蒸发。剩余的粗制材料(30)直接在接下来的步骤中使用而无需进一步纯化。
步骤8
将上述盐酸盐(30)(0.011g,0.0000141mol,1.0当量)溶解于DMF(1mL)中,并冷却至0℃。向该冷却溶液中添加(S)-2-((甲氧基羰基)氨基)-3-甲基丁酸(0.0062g,0.000033mol,2.5当量)、HOBt(0.0044g,0.000033mol,2.5当量)和EDCI(0.0063g,0.000033mol,2.5当量)。然后,在相同的温度下逐滴添加DIEA(0.02mL,0.00013mol,10当量)。将反应混合物升温至室温,并搅拌16小时。然后将反应混合物倒入水(25mL)中,通过过滤收集所沉淀的固体,干燥并通过硅胶柱色谱纯化以得到期望的产物(31)(3mg)。
1H NMR(400MHz,DMSO-d6,rt):δ0.91-1.04(m,6H),1.21-1.59(m,6H),1.64-1.88(m,6H),1.90-2.07(m,4H),2.23-2.49(m,6H),2.62(m,2H),2.85(m,2H),3.08(m,2H),3.19(s,3H),3.20(s,3H),3.42(m,2H),3.57(s,6H),4.15(表观t,J=8.0Hz,2H),4.47(m,2H),5.16(表观t,J=8.5Hz,2H),6.52(表观t,J=8.5Hz,2H),6.75(s,2H),6.82(m,2H),7.41(m,2H),7.71(表观t,J=6.0Hz,2H),7.64-7.79(m,4H).
实施例7.二茂铁NS5A抑制剂(32)的合成
通过Butler,I.R.等,“A Convenient Preparation of Iodoferrocenes,”Polyhedron(1993)12:129-131中所述的方法制备二茂铁化合物。在氩气氛下,向1,1’-二碘二茂铁(220mg,0.5mmol)的1,4-二氧六环(10mL)搅拌溶液中添加((S)-3-甲基-1-氧代-1-((2S,3aS,7aS)-2-(5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-苯并[d]咪唑-2-基)八氢-1H-吲哚-1-基)丁-2-基)氨基甲酸甲酯(1.1g,4当量)、K3PO4(853mg,2M水溶液,8当量)和PdCl2dppf(49mg,12mol%)。将所得混合物在80℃经历微波照射(CEM Discover System)1小时。将反应混合物冷却至室温,过滤并在真空中浓缩。通过制备型HPLC纯化剩余的残余物,以得到作为三氟乙酸盐的期望产物(43mg)。
1H NMR(400MHz,DMSO-d6,27℃):δ0.63(d,J=6.5Hz,6H),0.78(d,J=6.5Hz,6H),1.13-1.49(m,6H),1.55-1.87(m,10H),1.95(m,2H),2.26(m,2H),2.35(m,2H),2.42(m,2H),3.48(s,6H),3.83(t,J=8.0Hz,2H),4.18(m,4H),4.37(m,2H),4.67(m,4H),5.10(dd,J=10.0Hz,7.5Hz,2H),7.39(d,J=9.0Hz,2H),7.42(d,J=9.0Hz,2H),7.45(d,J=8.0Hz,2H),7.53(s,2H).
实施例9.鉴定抑制HCV复制之化合物的测定方法
在培养的细胞中测试本文所要求保护之化合物抑制丙型肝炎复制子之病毒复制的能力,所述培养的细胞中已经并入了HCV复制子构建体(construct)。HCV复制子***由Bartenschlager等人描述(Science,285,110-113页(1999))。该复制子***可预测体内抗HCV活性;对人有活性的化合物在该复制子测定中也一样显示出活性。
在该测定中,用不同浓度的测试化合物处理含HCV复制子的细胞,以确定测试化合物抑制HCV复制子复制的能力。作为阳性对照,用不同浓度的干扰素α(已知的HCV复制抑制剂)处理含HCV复制子的细胞。所述复制子测定***包括新霉素磷酸转移酶(NeomycinPhosphotransferase,NPT)作为复制子自身的一个组分,以检测宿主细胞中复制子基因产物的转录。HCV复制子复制活跃的细胞具有高水平的NPT;NPT水平与HCV复制成比例。HCV复制子不在其中复制的细胞也具有低水平的NPT,因此当用新霉素处理时不能存活。使用捕获ELISA测量每个样品的NPT水平。
测试化合物抑制丙型肝炎复制子在培养的细胞(其中已并入所述复制子构建体)中病毒复制之能力的方案如下。
9A.HCV复制子和复制子表达
HCV基因组由编码3000个氨基酸之多蛋白的单ORF组成。所述ORF侧翼的5’一侧是用作内部核糖体进入位点(internal ribosome entrysite,IRES)的非翻译区,3’一侧是病毒复制所必需的高度保守序列(3’-NTR)。病毒感染必需的结构蛋白位于所述ORF的5’端附近。命名为NS2至NS5B的非结构蛋白包含ORF的其余部分。
按5’-3’方向,HCV复制子含有HCV-IRES、新霉素磷酸转移酶(neo)基因、指导HCV序列NS3至NS5B翻译的脑心肌炎病毒的IRES、以及3’NTR。HCV复制子的序列已保存在GenBank中(登录号AJ242652)。
使用标准方法(例如电穿孔)将所述复制子转染进Huh-7细胞中。9B.细胞维持(cell maintenance)
设备和材料包括但不限于:含HCV复制子的Huh-7细胞、维持培养基(添加了10%FBS、L-谷氨酰胺、非必需氨基酸、青霉素(100单位/ml)、链霉素(100微克/ml)和500微克/ml的遗传霉素(Geneticin)(G418)的DMEM(达尔伯克氏改良伊格尔培养基(Dulbecco’s modified Eaglemedia)))、筛选培养基(添加了10%FBS、L-谷氨酰胺、非必需氨基酸、青霉素(100单位/ml)和链霉素(100微克/ml)的DMEM)、96孔组织培养板(平底)、96孔板(U形底,用于药物稀释)、用于阳性对照的干扰素α、固定试剂(例如甲醇:丙酮)、一抗(兔抗-NPTII)、二抗Eu-N1l、以及增强溶液。
当其密度合适时,含HCV复制子的细胞支持高水平的病毒RNA复制子复制。过度汇合(over-confluency)导致病毒RNA复制降低。因此,细胞必需在500微克/ml的G418存在下保持生长于对数期。一般地,细胞应以1:4-6的稀释度每周传代两次。按照下文所述进行细胞维持:
在显微镜下检查含HCV复制子的细胞,以确保细胞生长良好。用PBS冲洗细胞1次,添加2ml胰酶。将细胞/胰酶混合物于37℃下在CO2培养箱中孵育3至5分钟。孵育之后,添加10毫升完全培养基以使胰酶消化反应停止。轻轻吹起细胞,使其进入15ml管中,以1200rpm离心4分钟。除去胰酶/培养基溶液。添加培养基(5ml),小心混合细胞。对细胞计数。
然后将细胞接种于96孔板,密度为6000至7500个细胞/100微升/孔(6至7.5×105个细胞/10ml/板)。然后将所述板在37℃下于5%CO2培养箱中孵育。
接种后约24小时在显微镜下检查细胞,之后添加药物。如果正确进行计数和稀释,则细胞是60%至70%汇合度,并且几乎所有细胞都应贴壁并在孔中均匀铺展。
6C.用测试化合物处理含HCV复制子的细胞
用PBS清洗含HCV复制子的细胞1次,然后添加2ml胰酶。将细胞于37℃下在5%CO2培养箱中孵育3至5分钟。添加10毫升完全培养基以使反应停止。轻轻吹起细胞,使其进入15ml管中,以1200rpm离心4分钟。除去胰酶/培养基溶液,添加5ml培养基(500ml DMEM(高葡萄糖),来自BRL目录号12430-054),50ml10%FBS,5%遗传霉素G418(50mg/ml,BRL目录号10131-035),5ml MEM非必需氨基酸(100×BRL#11140-050)和5ml青霉素-链霉素(pen-strep)(BRL#15140-148)。将细胞和培养基小心混合。
用筛选培养基(500ml DMEM(BRL#21063-029),50ml FBS(BRL#10082-147)和5ml MEM非必需氨基酸(BRL#11140-050))以6000至7500个细胞/100μl/孔将细胞铺板至96孔板(6至7.5×105个细胞/10ml/板)。将板置于37℃的5%CO2培养箱中过夜。
4D.测定
第二天早上,根据所选用于筛选的最终浓度用培养基或DMSO/培养基在U形底96孔板中稀释药物(测试化合物或干扰素α)。一般使用每个测试化合物6个浓度,从10微摩尔至0.03微摩尔。将100μl测试化合物稀释物置于含HCV复制子细胞的96孔板的孔中。将不含药物的培养基添加到一些孔中作为阴性对照。已知DMSO影响细胞生长。因此,对于单个剂量筛选,如果使用在DMSO中稀释的药物,则包括阴性对照(仅培养基)孔和阳性对照(干扰素α)孔在内的所有孔都必须含有相同浓度的DMSO。将所述板在37℃下加湿的5%CO2环境中孵育3天。
在第4天,对NTPII测定进行定量。从板中倒出培养基,用200μl的PBS清洗所述板1次。然后倾倒出PBS,将所述板于纸巾上敲打以除去任何残留PBS。用100微升/孔的预冷(-20℃)甲醇:丙酮(1:1)将细胞原位固定,将所述板置于-20℃保持30分钟。
从板中倒出固定溶液,使所述板完全风干(约1小时)。记录干燥细胞层的外观,用肉眼对有毒孔中细胞的密度进行评分。或者,可以使用下文所述MTS测定来评估细胞活力。
在室温下,用200微升封闭溶液(10%FBS;3%NGS,在PBS中)封闭所述孔30分钟。除去封闭溶液,将在封闭溶液中按1:1000稀释的100μl兔抗NPTII添加到各孔中。然后将所述板在室温下孵育45至60分钟。孵育后,用PBS-0.05%吐温-20溶液清洗孔6次。将100μl在封闭缓冲液中按1:15000稀释的缀合铕(EU)的山羊抗兔抗体添加到各孔中,并在室温下孵育30至45分钟。再次清洗所述板,向每个孔中添加100μl增强溶液(Perkin Elmer#4001-0010)。在平板振摇器上振摇每个板(约30rpm)3分钟。从每个孔转移95μl至黑色板;在Perkin-Elmer VICTOR读板仪(EU-Lance)上对EU信号进行定量。
当在该测定中测试时,化合物11、16、25、33、38、39和40表现出的EC50值为约10微摩尔或更小。
实施例10.细胞毒性测定
为了确定复制子复制的降低是由于化合物抗HCV复制子活性而不是非特异性的,使用毒性测定来定量化合物细胞毒性。
10A.细胞毒性的细胞蛋白白蛋白测定
细胞蛋白白蛋白测量提供了一种细胞毒性的标志物。从细胞白蛋白测定中获得的蛋白质水平还可用于为化合物抗病毒活性提供归一化的参照。在所述蛋白质白蛋白测定中,用不同浓度的赛菊宁黄质(helioxanthin,已知在高浓度下具有细胞毒性的化合物)处理含HCV复制子的细胞3天。裂解细胞,将细胞裂解物用于在室温下(25℃至28℃)结合与板结合的山羊抗白蛋白抗体,持续3小时。然后用1X PBS清洗所述板6次。在洗去未结合的蛋白质之后,将小鼠单克隆抗人血清白蛋白用于结合板上的白蛋白。然后用磷酸酶标记的抗小鼠IgG作为第二抗体来检测复合物。
10B.细胞毒性的MTS测定
还可以通过单溶液细胞增殖测定试剂盒(CELLTITER96AQUEOUS ONE Solution Cell Proliferation Assay)(Promega,MadisonWI)(一种用于确定活细胞数的比色测定)来确定细胞活力。在该方法中,在固定细胞之前,按照生产商说明书将10μl至20μlMTS试剂添加到每个孔,将板在37℃孵育,并在OD490nm处读数。在孵育期间,活细胞将MTS试剂转变为吸收490nm处光的甲产物。因此490nm吸光度与培养物中活细胞的数目成正比。
可以按照如下所述获得用于确定细胞毒性的细胞白蛋白方法和MTS方法的直接比较:用不同浓度的测试化合物或赛菊宁黄质处理细胞3天时间。在按照上文所述的用于检测白蛋白的裂解之前,根据生产商说明书向每个孔添加MTS试剂,并在37℃孵育,在OD490nm处读数。然后如上文所述进行细胞白蛋白定量。
Claims (20)
1.式D-M-D的化合物或其可药用盐,
其中:
D是T-R-,其中M与R共价相连;
M是-P-A-P-;
P是-J-W-,其中J与R共价相连,W与A共价相连,或者P是-J-,其中J与R和A共价相连;
J在每次出现时独立地选择,并且J是Ji,其中i是1至2的整数;
T在每次出现时独立地选择,并且T是Tk,其中k是1至2的整数;
T1是-Y-Z,其中Y与R共价相连,并且Y是键、任选地被氧取代的C1-C4亚烷基;Z是5或6元杂环基团,在每种情况下T1(i)被选自-(C=O)OH、-(C=O)NH2、-(C=O)H、-C1-C4烷氧基、C2-C4烷酰基、C1-C4烷基酯、C1-C4烯基酯、单C1-C4烷基甲酰胺或二C1-C4烷基甲酰胺的至少一个取代基所取代以及(ii)任选地被一个或更多个独立地选自以下的取代基所取代:卤素、羟基、C1-C2烷基以及C1-C2烷氧基;
T2在每次出现时独立地选自:C2-C6烷酰基、C1-C6烷基酯、C1-C6烯基酯、C1-C6烷基磺酰胺、C1-C6烷基磺酰基、被单C1-C6烃基氨基甲酸酯或二C1-C6烃基氨基甲酸酯取代的C2-C6烷酰基、被脲或单C1-C6烷基脲或二C1-C6烷基脲取代的C2-C6烷酰基以及被单C1-C6烷基甲酰胺或二C1--C6烷基甲酰胺取代的C2-C6烷酰基,在每种情况下T2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、(C1-C4烷氧基)C0-C4烷基、(单C1-C4烷基氨基和二C1-C4烷基氨基)C0-C4烷基、C1-C6烷基、(C1-C4硫代烷基)C0-C4烷基、C3-C7环烷基、苯基、C1-C2卤代烷基以及C1-C2卤代烷氧基;
R在每次出现时独立地选自:
4至6元环,其含有一个或两个氮原子,其余环原子为碳,其中R是饱和的或者含有1个不饱和键,并且任选地与亚甲基或亚乙基桥桥联,或者与苯基或5至6元杂芳基环稠合;和
6至10元稠合或螺双环体系,其含有一个或两个氮原子,其余环原子为碳,所述6至10元双环是饱和的或者含有1个不饱和键;
每个R任选地被一个或更多个独立地选自以下的取代基所取代:氰基、羟基、卤素、C1-C2烷基、C1-C2烷氧基、C1-C2卤代烷基、C1-C2卤代烷基、C1-C2卤代亚烷基以及C1-C2烷基磺酰基;
J1是苯基或含有1至3个独立地选自N、O和S的杂原子的5至6元杂芳基,其中每种J1任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基;
J2是含有1至4个独立地选自N、O和S的杂原子的8至10元杂芳基,其中J2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基;
W在每次出现时独立地选择,并且W是苯基、吡啶基或炔基,任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基;以及
A是[j.k]-环芬、[j.k]-异芬、[j.k]-杂芬、[j.k]-杂-异芬或[j.k]-脂肪芬;其中j是1至4的整数,k是1至4的整数,j与k之差不大于2,并且每个j和k接头任选地含有选自N、O和S的杂原子,其任选地被1个氧代基团和一个或更多个独立地选自卤素、羟基、氨基、C1-C2烷基和C1-C2烷氧基的取代基所取代;或者
A是[j.k.j’.k’]-环芬,其中j、j’、k和k’是1至4的整数,j与k或k’之差不大于2,j’与k或k’之差不大于2,并且每个j、j’、k和k’接头任选地含有选自N、O和S的杂原子,并且任选地被1个氧代基团和一个或更多个独立地选自卤素、羟基、氨基、C1-C2烷基和C1-C2烷氧基的取代基所取代;或者
A是式基团,其中A任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。
2.根据权利要求1所述的化合物或盐,其中A是
6.根据权利要求1所述的化合物或盐,其中A是
8.根据权利要求1中任一项所述的化合物或盐,其具有式:
T-R-J1-W-A-W-J1-R-T;
T-R-J1-A-J1-R-T;
T-R-J2-A-J2-R-T;
T-R-J1-W-A-J1-R-T;
T-R-J1-W-A-J2-R-T;以及
T-R-J1-A-J2-R-T。
9.根据权利要求1中任一项所述的化合物或盐,其中:
至少一个P是J1-W,并且W是苯基,其任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。
12.根据权利要求1所述的化合物或盐,其中至少一个P是J2,并且J2是苯并咪唑基团,任选地被一个或更多个独立地选自卤素、C1-C2烷基和C1-C2烷氧基的取代基所取代。
14.根据权利要求15所述的化合物或盐,其中R独立地选自
15.根据权利要求1所述的化合物或盐,其中T是独立地选择的被单C1-C6烷基氨基甲酸酯和二C1-C6烷基氨基甲酸酯取代的C2-C6烷酰基,在每种情况下T任选地被(C1-C4硫代烷基)C0-C4烷基所取代。
16.根据权利要求1所述的化合物或盐,其具有式T-R-J2-A-J2-R-T,其中
J2是含有1或2个独立地选自N、O和S的杂原子的8至10元杂芳基,其中J2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、C1-C4烷基、C1-C4烷氧基、单C1-C4烷基氨基和二C1-C4烷基氨基、C1-C2卤代烷基以及C1-C2卤代烷氧基;
每个R是独立地选择的8至10元双环体系,其含有一个或两个氮原子,其余环原子为碳,所述8至10元双环是饱和的或者含有一个不饱和键;
每个R任选地被一个或更多个独立地选自以下的取代基所取代:氰基、羟基、卤素、C1-C2烷基、C1-C2烷氧基、C1-C2卤代烷基、C1-C2卤代烷基、C1-C2卤代亚烷基、以及C1-C2烷基磺酰基;并且
T2在每次出现时独立地选自:C2-C6烷酰基、C1-C6烷基酯、C1-C6烯基酯、C1-C6烷基磺酰胺、C1-C6烷基磺酰基、被单C1-C6烃基氨基甲酸酯或二C1-C6烃基氨基甲酸酯取代的C2-C6烷酰基、被脲或单C1-C6烷基脲或二C1-C6烷基脲取代的C2-C6烷酰基以及被单C1-C6烷基甲酰胺或二C1--C6烷基甲酰胺取代的C2-C6烷酰基,在每种情况下T2任选地被一个或更多个独立地选自以下的取代基所取代:氨基、氰基、羟基、卤素、(C1-C4烷氧基)C0-C4烷基、(单C1-C4烷基氨基和二C1-C4烷基氨基)C0-C4烷基、C1-C6烷基、(C1-C4硫代烷基)C0-C4烷基、C3-C7环烷基、苯基、C1-C2卤代烷基、以及C1-C2卤代烷氧基。
18.药物组合物,其包含权利要求1所述的化合物或盐,以及可药用载体。
19.根据权利要求24所述的药物组合物,其中所述组合物包含至少一种另外的活性剂。
20.治疗患者的丙型肝炎感染的方法,其包括向有此需要的患者提供治疗有效量的一种或更多种权利要求1所述的化合物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US201161490881P | 2011-05-27 | 2011-05-27 | |
US61/490,881 | 2011-05-27 | ||
US201161504905P | 2011-07-06 | 2011-07-06 | |
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WO2017076194A1 (zh) * | 2015-11-06 | 2017-05-11 | 江苏豪森药业集团有限公司 | 具有抑制hcv活性的化合物及其制备方法和应用 |
CN108348504A (zh) * | 2015-11-06 | 2018-07-31 | 江苏豪森药业集团有限公司 | 具有抑制hcv活性的化合物及其制备方法和应用 |
CN108348504B (zh) * | 2015-11-06 | 2021-06-29 | 江苏豪森药业集团有限公司 | 具有抑制hcv活性的化合物及其制备方法和应用 |
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WO2017121188A1 (zh) * | 2016-01-12 | 2017-07-20 | 深圳市塔吉瑞生物医药有限公司 | 一种丙型肝炎病毒抑制剂、药物组合物及其应用 |
CN106083829B (zh) * | 2016-01-12 | 2019-01-22 | 深圳市塔吉瑞生物医药有限公司 | 一种丙型肝炎病毒抑制剂、药物组合物及其应用 |
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