CN103153280B - 丙型肝炎病毒抑制剂的组合 - Google Patents
丙型肝炎病毒抑制剂的组合 Download PDFInfo
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- CN103153280B CN103153280B CN201180048188.1A CN201180048188A CN103153280B CN 103153280 B CN103153280 B CN 103153280B CN 201180048188 A CN201180048188 A CN 201180048188A CN 103153280 B CN103153280 B CN 103153280B
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Abstract
本发明大体上涉及抗病毒化合物，且更具体地涉及可抑制丙型肝炎病毒(HCV)的化合物的组合产品、包含所述化合物的组合物以及使用所述组合产品治疗丙型肝炎的方法。为了达到最大功效和潜在性地根除所述病毒，关键的是采用组合治疗，特别是靶向不同的HCV病毒靶标的组合治疗。基于体外复制子的组合研究已经显示用HCV抑制剂的多种组合可达到加和效应至协同效应。
Description
相关申请的交叉引用
本申请要求2010年8月6日提交的美国临时申请61/371,399的权益。
技术领域
本发明大体上涉及抗病毒化合物，且更具体地涉及可抑制丙型肝炎病毒(HCV)的化合物的组合产品、包含所述化合物的组合物以及使用所述组合产品治疗丙型肝炎的方法。
背景技术
HCV是主要的人类病原体，其在世界范围内感染约一亿七千万人—大致是1型人类免疫缺陷病毒感染数量的5倍。这些HCV感染个体中相当大的部分发展成严重的进行性肝脏疾病，包括肝硬化和肝细胞癌。
HCV是正链RNA病毒。基于对所推断氨基酸序列进行的比较和5’-非翻译区的广泛类似性，已经将HCV归类为黄病毒科(Flaviviridae family)中独立的属。黄病毒科的所有成员都具有包封的病毒体(enveloped virion)，其含有的正链RNA基因组通过翻译单一的连续的可读框而编码所有已知的病毒专属性蛋白质。
在整个HCV基因组的核苷酸序列和所编码的氨基酸序列中发现了相当程度的异质性，这是由于缺乏校正读码能力的编码的RNA依赖性RNA聚合酶的高错误率。已经表征了至少6种主要的基因型，且在世界范围内已经描述了多于50种的亚型。HCV遗传异质性的临床重要性已经证实了在单一疗法治疗中突变发生的趋势，由此期望使用额外的治疗选择。
单链HCV RNA基因组的长度为约9500个核苷酸，且具有单一的可读框(ORF)，其编码由约3000个氨基酸组成的单一的大多蛋白。在被感染的细胞中，这种多蛋白在多个位点被细胞蛋白酶和病毒蛋白酶裂解，从而产生结构蛋白和非结构(NS)蛋白。就HCV而言，成熟的非结构蛋白(NS2、NS3、NS4A、NS4B、NS5A和NS5B)的产生受到两种病毒蛋白酶的影响。认为第一种病毒蛋白酶为金属蛋白酶且在NS2-NS3接合处进行裂解；第二种病毒蛋白酶是包含在NS3(本申请也称为NS3蛋白酶)的N-端区域内的丝氨酸蛋白酶，且介导NS3下游的所有随后裂解，既在NS3-NS4A裂解位点以顺式进行裂解，又在其余的NS4A-NS4B、NS4B-NS5A、NS5A-NS5B位点以反式进行裂解。NS4A蛋白似乎具有多种功能，其充当NS3蛋白酶的辅因子，且有助于NS3及其它病毒复制酶组分的膜定位。NS3-NS4A复合物的形成是导致增加的蛋白质水解事件的效能的适当的蛋白酶活性所必须的。NS3蛋白还显示出三磷酸核苷酶和RNA解螺旋酶活性。NS4B为涉及膜网形成的膜整合蛋白，认为HCV复制复合物在所述膜网中装配。NS5B(本申请也称为HCV聚合酶)是RNA依赖性的RNA聚合酶，在HCV与其它HCV蛋白(包括NS5A)在复制酶复合物中的复制中涉及所述酶。
用于治疗大多数患有慢性HCV感染的患者的现行护理标准为聚乙二醇化干扰素-α和利巴韦林的方案。然而，高比例的患者未能对此疗法应答且治疗伴随显著的副作用。因此，对开发更安全和更有效的疗法有极大的需求。尽管许多小分子HCV抑制剂目前正在临床试验，但是基于来自数个研究的临床数据，显然可能要求抑制剂的组合在HCV感染患者中实现持续的病毒应答。在用蛋白酶抑制剂以及核苷和非核苷HCV抑制剂的治疗时，已在治疗期间的患者中观察到抗性出现，以及治疗后病毒反弹。为了达到最大功效和可能地根除病毒，关键的是采用组合治疗，特别是靶向不同的HCV病毒靶标的组合治疗。基于体外复制子的组合研究已显示，用HCV抑制剂的多种组合可达到加和效应至协同效应。
共有专利申请WO2008/021927公开了抑制由HCV编码的NS5A蛋白功能的化合物。美国专利6,995,174公开了抑制由HCV编码的NS3蛋白酶功能的化合物。美国专利7,456,166公开了抑制NS5B聚合酶功能的化合物。本公开教导了可用于治疗HCV的特异性HCV NS5A抑制剂、特异性HCVNS3蛋白酶抑制剂和NS5B聚合酶抑制剂的组合产品。
发明内容
在第一方面，本发明提供了组合物，其包含：
治疗有效量的式(I)的化合物或者其药用盐
治疗有效量的式(II)的化合物或者其药用盐
治疗有效量的有效抑制HCV聚合酶功能的化合物以及药用载体。
在第一方面的第一个实施方案中，有效抑制HCV聚合酶功能的化合物选自PSI-6130、PF-00868554、ANA-598、IDX-375、IDX-184、INX-189、BI-207127、PSI-7851、PSI-938、PSI-879、VCH-759、VCH-916、VCH-222、BMS-929075、GS-9190、ABT-333和ABT-072。
在第二方面，本发明提供了组合物，其包含：
治疗有效量的式(I)的化合物或者其药用盐
治疗有效量的式(II)的化合物或者其药用盐
治疗有效量的式(III)的化合物或者其药用盐
药用载体。
在第二方面的第一个实施方案中，所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为约1:20:5。
在第二方面的第二个实施方案中，所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为约1:250:1000。
在第三方面，本发明提供了治疗患者的HCV感染的方法，包括对患者给予治疗有效量的组合物，其包含：
式(I)的化合物或者其药用盐
治疗有效量的式(II)的化合物或者其药用盐
治疗有效量的有效抑制HCV聚合酶功能的化合物以及药用载体。
在第三方面的第一个实施方案中，有效抑制HCV聚合酶功能的化合物选自PSI-6130、PF-00868554、ANA-598、IDX-375、IDX-184、INX-189、BI-207127、PSI-7851、PSI-938、PSI-879、VCH-759、VCH-916、VCH-222、BMS-929075、GS-9190、ABT-333和ABT-072。
在第四方面，本发明提供了治疗患者的HCV感染的方法，包括对患者给予治疗有效量的组合物，其包含：
治疗有效量的式(I)的化合物或者其药用盐
治疗有效量的式(II)的化合物或者其药用盐
治疗有效量的式(III)的化合物或者其药用盐
药用载体。
在第四方面的第一个实施方案中，所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为约1:20:5。
在第四方面的第二个实施方案中，所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为约1:250:1000。
本公开的其它方面可包括本申请公开的实施方案的适当组合。
其它的方面和实施方案可在本申请提供的描述中找到。
将说明书中引用的所有专利、专利申请和参考文献的全部内容通过引用的方式并入本申请。在不一致的情况下，以本公开(包括定义)为准。
本说明书中所用的下列术语具有所示含义：
除非上下文另有明确指示，否则本申请所用的单数形式“一个”、“一种”和“所述”也包括复数形式。
本公开的某些化合物可以可分离的不同稳定构象形式存在。由于关于不对称单键的阻碍旋转(例如由于位阻或环张力)所致的扭转不对称，可允许分离不同的构象异构体，通常称为阻转异构体。本公开包括这些化合物的每种构象异构体及其混合物。
本公开的化合物可作为药用盐存在。本申请所用的术语“药用盐”表示本公开化合物的盐或两性离子形式，其为水溶性或油溶性或可分散的，在合理医学判断的范围内，其适用于与患者的组织接触而没有过度的毒性、刺激、变应性应答或者与合理的益处/风险比相当的其它问题或并发症，并且对于它们预期的用途而言有效。所述盐可在所述化合物的最终分离和纯化期间制备，或独立地通过使适当氮原子与适当酸反应来制备。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐；二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟乙磺酸盐、乳酸盐、马来酸盐、均三甲基苯磺酸盐、甲磺酸盐、亚萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。可用于形成药用加成盐的酸的实例包括诸如盐酸、氢溴酸、硫酸和磷酸的无机酸，以及诸如草酸、马来酸、琥珀酸和柠檬酸的有机酸。
可通过使酸性质子与适当碱(诸如金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)或者与氨或有机伯胺、仲胺或叔胺反应，在所述化合物的最终分离和纯化期间制备碱加成盐。药用盐的阳离子包括锂、钠、钾、钙、镁和铝，以及无毒的季胺阳离子(诸如铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺和N,N’-二苄基乙二胺)。可用于形成碱加成盐的其它代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。
本公开提供药物组合物，所述药物组合物包含治疗有效量的式(I)和(II)的化合物或其药用盐、NS5B抑制剂和一种或多种药用载体、稀释剂或赋形剂。本申请所用的术语“治疗有效量”是指足以显示有意义的患者益处(例如，病毒载量的持续减少)的每种活性成分的总量。当应用于单独给药的单个活性成分时，该术语仅指该成分。当应用于组合产品时，不论组合、连续或同时给药，该术语均指引起疗效的活性成分的组合量。式(I)和(II)的化合物及其药用盐如上所述，且所述NS5B聚合酶抑制剂如上所述。载体、稀释剂或赋形剂必须在与制剂的其它成分相容且对其受者无毒的意义上而言为可接受的。依照本公开的另一个方面，也提供了用于制备药物制剂的方法，所述方法包括使式(I)和(II)的化合物或其药用盐与NS5B聚合酶抑制剂和一种或多种药用载体、稀释剂或赋形剂混合。本申请所用的术语“药用”是指下列化合物、材料、组合物和/或剂型，其在合理医学判断的范围内，适用于与患者的组织接触而没有过度的毒性、刺激、变应性应答或者与合理的益处/风险比相当的问题或并发症，并且对于它们预期的用途而言有效。
药物制剂可以单位剂型提供，每单位剂量包含预定量的活性成分。典型地，本公开的药物组合物将每天给药约1-约5次，或可选择地作为连续输注给药。这类给药可用作慢性或急性治疗。可与载体材料混合以产生单一剂型的活性成分的量将取决于所治疗的病症、病症的严重程度、给药时间、给药途径、所用化合物的排泄速率、治疗持续时间以及患者的年龄、性别、体重和条件而不同。优选的单位剂量制剂为含有活性成分的如本申请上述的日剂量或亚剂量或其适当分数的制剂。一般地，用远低于所述化合物最佳剂量的小剂量开始治疗。之后，以小增量增加剂量直至达到该情况下的最佳效果。一般而言，最希望在以下浓度水平给药所述化合物，所述浓度水平一般将提供在抗病毒方面的有效结果，而不引起任何有害或有毒副作用。
由于本公开的组合物包含具有抗HCV活性的三种或多种化合物的组合，因此所有化合物均可以这样的剂量存在，所述剂量低于或等于在单一疗法方案中正常给药的剂量。本公开每种化合物的约0.01-约250毫克/千克("mg/kg")体重/天、优选约0.05-约100mg/kg体重/天的剂量水平，在用于预防和治疗HCV介导疾病的单一疗法中为典型的。本公开的组合物可与一种或多种额外的治疗剂或预防剂共同配制(例如呈单片和/或双/多层片剂的形式)或者可与治疗剂或预防剂分开给药。
可使药物制剂适于通过任何适当途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或肠胃外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或皮内注射或输注)途径。这类制剂可通过药学领域已知的任何方法制备，例如通过使活性成分与载体或赋形剂混合。
适于口服给药的药物制剂可作为独立单位提供，诸如胶囊剂或片剂；粉末剂或颗粒剂；水性或非水性液体中的溶液剂或混悬剂；可食用泡沫剂或起泡制剂(whip)；或者水包油液体乳剂或油包水乳剂。
例如，对于以片剂或胶囊剂形式口服给药而言，可将活性药物组分与口服无毒的药用惰性载体(诸如乙醇、甘油、水等)混合。粉末剂通过将化合物粉碎至适宜细微大小并与同样粉碎的药物载体(诸如可食用糖类，如淀粉或甘露醇)混合来制备。还可存在调味剂、防腐剂、分散剂和着色剂。
胶囊剂通过制备如上所述的粉末混合物并填充成形的明胶鞘来制备。在填充操作之前，可向粉末混合物中加入助流剂和润滑剂(诸如胶态二氧化硅、滑石、硬脂酸镁、硬脂酸钙或固态聚乙二醇)。也可加入崩解剂或增溶剂(诸如琼脂、碳酸钙或碳酸钠)，以在摄入胶囊剂时改善药物的可利用性。
此外，当需要或必需时，也可将适宜的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。适宜粘合剂包括淀粉、明胶、天然糖类(诸如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(诸如阿拉伯胶、西黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇)等。这些剂型中使用的润滑剂包括油酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过例如以下来配制：制备粉末混合物，制粒或预压片，加入润滑剂和崩解剂，压制成片剂。通过使适当粉碎的化合物与如上所述的稀释剂或碱和任选地与粘合剂(诸如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻滞剂(诸如石蜡)、吸收促进剂(诸如季盐)和/或吸收剂(诸如膨润土、高岭土或磷酸二钙)混合来制备粉末混合物。粉末混合物可通过与粘合剂(诸如糖浆、淀粉糊、阿拉伯胶浆(acadia mucilage)或者纤维素材料或聚合材料的溶液)一起润湿并加压过筛来制粒。作为制粒的备选方法，可使粉末混合物通过压片机，结果为将成形不佳的预压片再击碎制成颗粒。可通过加入硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒，以防止粘到压片冲模。然后将润滑的混合物压制成片剂。也可将本公开的化合物与自由流动的惰性载体混合并直接压制成片剂，而不经历制粒或预压片步骤。可提供透明或不透明的由紫胶密封包衣、糖衣或聚合材料包衣和蜡抛光包衣组成的保护包衣。可向这些层中加入染料来区分不同的单位剂量。
可将口服流体(诸如溶液剂、糖浆剂和酏剂)制备成剂量单位形式，使得给定量含有预定量的化合物。糖浆剂可通过使化合物溶于适当调味的水溶液来制备，而酏剂通过使用无毒媒介物来制备。也可加入增溶剂和乳化剂(诸如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、味道添加剂(诸如薄荷油或天然甜味剂、或者糖精或其它人造甜味剂)等。
适当时，可将用于口服给药的剂量单位制剂微囊化。也可通过例如将微粒材料包衣或包埋在聚合物、蜡等中来制备所述制剂，以延长或维持释放。
式(I)和(II)的化合物及其药用盐以及NS5B聚合酶抑制剂也可以脂质体递送系统(诸如小单层囊泡、大单层囊泡和多层囊泡)的形式给药。脂质体可由各种磷脂形成，所述磷脂诸如胆固醇、硬脂酰胺或磷脂酰胆碱。
式(I)和(II)的化合物及其药用盐以及NS5B聚合酶抑制剂也可通过使用单克隆抗体作为单独的载体来递送，所述化合物分子与单独的载体偶联。也可将所述化合物与作为可靶向药物载体的可溶性聚合物偶联。这类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺酚、聚羟乙基天冬酰胺酚或用棕榈酰残基取代的聚环氧乙烷聚赖氨酸。此外，可将所述化合物与一类可用于实现药物控释的生物可降解聚合物偶联，所述生物可降解聚合物为例如聚乳酸、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
适于经皮给药的药物制剂可作为独立贴剂提供，预期保持该独立贴剂与接受者表皮长时间地紧密接触。例如，可通过如Pharmaceutical Research,3(6),318(1986)中一般描述的离子导入法从所述贴剂中递送活性成分。
可将适于局部给药的药物制剂制成软膏剂、乳膏剂、混悬剂、洗剂、粉末剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于治疗眼或其它外部组织(例如口和皮肤)而言，优选将制剂作为局部软膏剂或乳膏剂给药。当以软膏剂配制时，可将活性成分与石蜡或水混溶性软膏基质一起使用。可选择地，可用水包油乳膏基质或油包水基质将活性成分配制成乳膏剂。
适于局部给药于眼的药物制剂包括滴眼剂，其中活性成分溶解或悬浮于适当载体特别是水性溶剂中。
适于口中局部给药的药物制剂包括锭剂、软锭剂和漱口剂。
适于直肠给药的药物制剂可作为栓剂或灌肠剂提供。
其中载体为固体的适于经鼻给药的药物制剂，含有以鼻吸的方式(即通过经由鼻通道从保持靠近鼻子的粉末容器中迅速吸入)给药的过程粉末(course powder)。用于作为鼻腔喷雾剂或滴鼻剂给药的其中载体为液体的适当制剂，包括活性成分的水性或油性溶液剂。
适于通过吸入给药的药物制剂包括细颗粒粉剂(dust)或雾剂(mist)，其可通过多种类型的计量的剂量加压气溶胶、喷雾器或吹入器产生。
适于阴道给药的药物制剂可作为阴道栓剂、阴道塞、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾制剂提供。
适于肠胃外给药的药物制剂包括水性和非水性无菌注射溶液剂，其可含有抗氧化剂、缓冲剂、抑菌剂和使得所述制剂与预期接受者的血液等渗的溶质；水性和非水性无菌混悬剂，其可包含助悬剂和增稠剂。所述制剂可以单位剂量或多剂量容器(例如密封的安瓿和小瓶)提供，且可在冷冻干燥(冻干)条件下储存，仅需在使用前立即加入无菌液态载体，例如注射用水。可由无菌粉末剂、颗粒剂和片剂制备临时的注射溶液剂和混悬剂。
应当理解的是，除以上具体提及的成分之外，所述制剂还可包含本领域常用的与讨论中的该类型制剂有关的其它物质，例如适于口服给药的制剂可包含调味剂。
术语“患者”包括人和其它哺乳动物。
术语“治疗”是指：(i)防止疾病、障碍或病症出现于患者中，所述患者可易患该疾病、障碍和/或病症但尚未诊断为患有该疾病、障碍和/或病症；(ii)抑制疾病、障碍或病症，即阻止其发展；和(iii)减轻疾病、障碍或病症，即引起疾病、障碍和/或病症的消退。
下表1列举了可与本公开的组合物一起给药的化合物的一些示例性实例。在组合疗法中可将本公开的组合物与其它抗HCV活性化合物联合给药或分别给药，或者通过将所述化合物混合到组合物中来给药。
表1
| 商品名 | 生理学类别 | 抑制剂或者靶标的类型 | 来源公司 |
| HCV-796 | 抗病毒 | NS5B复制酶抑制剂 | Wyeth/Viropharma |
| NM-283 | 抗病毒 | NS5B复制酶抑制剂 | Idenix/Novartis |
| GL-59728 | 抗病毒 | NS5B复制酶抑制剂 | Gene Labs/Novartis |
| GL-60667 | 抗病毒 | NS5B复制酶抑制剂 | Gene Labs/Novartis |
| 2′C MeA | 抗病毒 | NS5B复制酶抑制剂 | Gilead |
| PSI-6130 | 抗病毒 | NS5B复制酶抑制剂 | Roche |
| R-1626 | 抗病毒 | NS5B复制酶抑制剂 | Roche |
| GL-59728 | 抗病毒 | NS5B复制酶抑制剂 | Genelabs |
| PF-00868554 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | Pfizer |
| 商品名 | 生理学类别 | 抑制剂或者靶标的类型 | 来源公司 |
| ABT-333 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | Abbott Laboratories |
| ABT-072 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | Abbott Laboratories |
| MK-0608 | 抗病毒 | 核苷聚合酶抑制剂 | Merck |
| MK-3281 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | Merck |
| GSK-625433 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | GSK |
| XTL-2125 | 抗病毒 | 非核苷NS5B聚合酶抑制剂 | Presidio |
本公开的组合物也可用作实验室试剂。化合物可有助于提供用于设计病毒复制测定、验证动物测定系统和结构生物学研究的研究工具，以进一步增加HCV疾病机制的知识。此外，本公开的化合物可用于通过例如竞争性抑制来建立或确定其它抗病毒化合物的结合位点。
本公开的化合物也可来处理或防止材料的病毒污染，并因此降低与这类材料接触的实验室或医务人员或患者病毒感染的风险，所述材料为例如血、组织、手术器械和衣服、实验室仪器和衣服以及血液采集或输注器具和材料。
现在将联系某些实施方案来描述本公开，意图所述实施方案不限制其范围。相反，本公开涵盖了可包含在权利要求范围之内的所有备选、修改和等价物。因此，下列包含具体实施方案的实施例，将示例说明本公开的一个实施，应该理解的是，所述实施例以示例说明某些实施方案为目的，并将其呈现以提供被认为是其操作和概念方面的最有用和容易理解的描述。
起始物质可获自商业来源或通过本领域技术人员已知的良好建立的文献方法制备。
具体实施方式
实施例
化合物
HCV NS5A抑制剂(式(I)化合物)可遵循在共有专利申请WO2008/021927或WO2009/020825中描述的操作制备。HCV NS3蛋白酶抑制剂(式(II)化合物)可遵循在共有美国专利系列号6,995,174和共有美国专利申请12/547,158中描述的操作制备。式(III)的HCV NS5B抑制剂可遵循在共有美国专利7,456,166中描述的操作制备。
研究HCV基因型1无效响应者中24周的单独的NS5A抑制剂(式(I);60mg QD)和NS3蛋白酶抑制剂(式(II);600mg BID)(组A)的抗病毒活性，或者其与PEG化干扰素α和利巴韦林的组合(组B)的抗病毒活性。主要目的是确定在治疗的第2和4周以及在治疗后24周的获得未检测到的HCV RNA(<10IU/mL)的受试者的比例。进行第12周中间时期分析。21个患者(11个组A患者，10个组B患者)随机分到标记组(sentinel cohort)中。年龄中位数为55岁；13个为男性患者且16个位白种人。
表2
RVR(快速病毒学应答)=治疗第4周的未检测到的HCV RNA
eRVR(延长的快速病毒学应答)=治疗第4和12周的未检测到的HCV RNA
cRVR(完整快速病毒学应答)=治疗第12周的未检测到的HCV RNA
*意在治疗分析；突破=失败
**再次测试时在第12周具有未检测到(UD,<10IU/mL)的HCV RNA<25IU/mL的一个患者。
如在表2中显示，6个(54.5%)受试者经历病毒突破，而组B中的所有受试者保持病毒抑制。病毒突破仅仅发生在感染有基因型1a的个体中，其最早在第3周发生且最晚在第12周发生。组A中的两个基因型1b受试者保持未检测到的HCV RNA。具有突破的6个受试者接受额外的PEG化干扰素α和利巴韦林。HCV RNA开始在两个受试者中检测不到且在另外两个受试者中达到<25IU/mL，而其它两个受试者具有>1.5log10的HCV RNA降低。在分析期间未记录有死亡、显著不良事件或者由于不良事件引起的中断。腹泻是最常见的不良事件且严重度主要为轻度至中度。
结果显示使用式(I)的NS5A抑制剂和式(II)的NS3蛋白酶抑制剂(有或无PEG化干扰素α和利巴韦林)的治疗证实了在HCV感染的基因型1无效响应者中相似的RVR，单独接受两个小分子的7个受试者中的6个在第12周时经历病毒突破，而在所有受试者中四种药物的组合保持了病毒抑制。因此，使用直接作用的抗病毒剂而不使用PEG化干扰素α和利巴韦林的治疗将需要一种或者多种额外的治疗剂以防止病毒突破。
细胞系
这些研究中使用的Huh-7细胞系获自Dr.Ralf Bartenschlager(Universityof Heidelberg,Heidelberg,Germany)并在含有10%FBS、10U/ml青霉素和10μg/ml链霉素的DMEM中持续培养。用于这些研究的HCV复制子使用WO2004014852中所述操作在Bristol-Myers Squibb生成。已公开的基因型1b HCV复制子(Lohmann,V.,F.Korner,J.-O.Koch,U.Herian,L.Theilmann,and R.Bartenschlager1999,Science285:110-113)的编码序列通过OperonTehnologies,Inc.(Alameda,CA)使用EMBL检索号AJ242652中所述序列(核苷酸1801-7758)合成。然后使用标准分子生物学技术将功能性复制子装配在质粒pGem9zf(+)(Promega,Madison,WI)中。为了构建编码萤光素酶报道分子的复制子，将编码人源化海肾(Renilla)萤光素酶蛋白的基因引入新霉素磷酸转移酶基因的上游。所生成的复制子由下列组成：(i)与衣壳蛋白的前12个氨基酸融合的HCV5’UTR，(ii)海肾萤光素酶基因，(iii)新霉素磷酸转移酶基因(neo)，(iv)来自脑心肌炎病毒(EMCV)的IRES，和(v)HCV NS3至NS5B基因及HCV3’UTR。
如Lohman等(Lohmann,V.,F.Korner,J.-O.Koch,U.Herian,L.Theilmann,and R.Bartenschlager1999,Science285:110-113)所述，从集落中分离HCV复制子细胞系并用于所有实验。简言之，用ScaI将复制子克隆线性化，并根据制造商的指导使用T7MegaScript转录试剂盒(Ambion,Austin,TX)在体外合成RNA转录物。遵循制造商的方案通过用DMRIE-C试剂(InvitrogenCorporation,Carlsbad,CA)转染，将10-20μg体外转录的复制子RNA引入4-5×106个Huh-7细胞中。24小时后，加入含有0.5mg/mL遗传霉素(G418,Gibco-BRL,Rockville,MD)的选择性培养基并且每3-5天更换培养基。约4周后，溶胀细胞用于进一步分析。在含有10%热灭活的小牛血清(Sigma)、青霉素/链霉素和0.5mg/ml G418的DMEM(Gibco-BRL,Rockville,MD)中37°C维持细胞。
细胞培养物细胞毒性和萤光素酶测定
为了确定化合物功效，将HCV复制子细胞以104个/孔的密度铺板到96孔板中的含有10%FBS的DMEM中。孵育过夜之后，向单个孔中加入用DMSO连续稀释的化合物或仅DMSO，以达到0.5%的最终DMSO浓度。然后在测定细胞毒性和HCV抑制之前将细胞板在37°C孵育3天。使用阿尔玛蓝(Alamar blue)测定来测量细胞存活率并使用中效方程(median effectequation)计算CC50值。
然后用PBS洗板两次并根据制造商的指导使用Dual-Glo萤光素酶测定系统(Promega Corporation,Madison,WI)测定海肾萤光素酶活性。在TopCountNXT微量培养板闪烁和荧光计数器(Packard Instrument Company)上读板。使用Excel Fit(版本2.0,Build30)计算50%有效浓度(EC50)。用表示为y=A+((B-A)/(1+((C/x)^D)))的Excel Fit方程205，使用已知的x(化合物浓度)和y(相对于仅DMSO对照孔的%)值计算EC50，其中A和B分别等于曲线的底部和顶部坪值，C等于曲线中部的x值，D等于斜率系数。
组合研究
对于抑制剂组合研究，各在11个浓度测试了HCV NS5A、NS3蛋白酶和NS5B聚合酶抑制剂。200倍于所需最终测定浓度的储备溶液通过在添加到细胞/培养基之前用DMSO稀释3倍来准备。将所述化合物作为单一疗法测试以及在不同浓度比来组合测试。使细胞暴露于化合物3天并随后使用如上所述的萤光素酶测定来确定HCV抑制的量。也通过阿尔玛蓝染色平行地分析这些组合药剂的潜在细胞毒性。在药物浓度范围内确定拮抗作用、加和性或协同作用的程度，并将组合响应曲线拟合以评价药物治疗组合的抗病毒效果。使用Chou Chou T.Theoretical Basis,Experimental Design,andComputerized Simulation of Synergism and Antagonism in Drug CombinationStudies.Pharmacological Reviews.2006;58(3):621-81的方法，分析组合中药物的组合效果。
所有估计量使用生物统计学软件SAS Proc NLIN和四参数逻辑法(four-parameter logistic)来计算。使用等效线图解法测试所有组合指数与加和性的偏差。也对每个组合指数计算渐近置信区间。将这些区间用于通过将上下限与1相比较来测试与加和性的偏差，即区间下限大于1表明拮抗作用，小于1的上限表明协同作用，而包含在区间中的值1表明加和性。
结果
表3: 使用NS3蛋白酶、NS5A和NS5B抑制剂进行三组组合研究
PI=蛋白酶抑制剂
a在250:1:1000摩尔比的NS3PI、NS5A抑制剂与NS5B抑制剂来测试的化合物
对抗病毒治疗的抗性已成为患有慢性病毒感染的患者管理中的主要问题。为了实现持续的病毒应答，关键是要利用组合治疗，尤其是靶向不同HCV病毒靶标的组合治疗。
这些结果表明复制子细胞用式(I)的NS5A抑制剂、式(II)的HCV NS3蛋白酶抑制剂和式(III)的NS5B抑制剂的组合治疗产生加和的抗病毒作用。重要的是，使用任何这些组合均未观察到拮抗作用或增强的细胞毒性。因此，这些组合为用于HCV感染患者中的组合给药方案的优秀候选者。
对本领域技术人员而言显而易见的是，本公开不限于前述示例性实施例，且其可以其它具体形式实施，而不会背离其本质属性。因此期望的是，在所有方面认为所述实施例为示例说明性而非限制性的，应参照所附权利要求而不是前述实施例，因此意图将在权利要求的等同含义和范围之内的所有改变都包含在其中。
Claims (6)
1.组合物，其包含：
治疗有效量的式(I)的化合物或者其药用盐
治疗有效量的式(II)的化合物或者其药用盐
治疗有效量的式(III)的化合物或者其药用盐
药用载体。
2.权利要求1的组合物，其中所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为1:20:5。
3.权利要求1的组合物，其中所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为1:250:1000。
4.权利要求1的组合物在制备用于治疗患者的HCV感染的药物中的用途。
5.权利要求4的用途，其中所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为1:20:5。
6.权利要求4的用途，其中所述式(I)的化合物或者其药用盐、式(II)的化合物或者其药用盐与式(III)的化合物或者其药用盐的摩尔比为1:250:1000。
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2011
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- 2011-08-02 EA EA201390155A patent/EA022303B1/ru not_active IP Right Cessation
- 2011-08-02 ES ES11815206.5T patent/ES2685174T3/es active Active
- 2011-08-02 AU AU2011285890A patent/AU2011285890B2/en not_active Ceased
- 2011-08-02 CN CN201510608270.5A patent/CN105148275A/zh active Pending
- 2011-08-02 SG SG2014008346A patent/SG2014008346A/en unknown
- 2011-08-02 MX MX2013001170A patent/MX2013001170A/es unknown
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- 2011-08-02 CN CN201180048188.1A patent/CN103153280B/zh not_active Expired - Fee Related
- 2011-08-02 KR KR1020137005628A patent/KR101846596B1/ko active IP Right Grant
- 2011-08-02 WO PCT/US2011/046285 patent/WO2012018829A1/en active Application Filing
- 2011-08-02 EP EP11815206.5A patent/EP2600835B1/en not_active Not-in-force
- 2011-08-02 SG SG2013005905A patent/SG187193A1/en unknown
- 2011-08-02 BR BR112013002922A patent/BR112013002922A2/pt not_active Application Discontinuation
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2013
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2014
- 2014-04-28 US US14/263,101 patent/US20140235617A1/en not_active Abandoned
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2015
- 2015-07-31 US US14/814,891 patent/US20150335655A1/en not_active Abandoned
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2016
- 2016-03-31 JP JP2016072377A patent/JP2016155844A/ja not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102655873A (zh) * | 2009-10-12 | 2012-09-05 | 百时美施贵宝公司 | 特异性hcv ns5a抑制剂与hcv ns3蛋白酶抑制剂的组合 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6196154B2 (ja) | 2017-09-13 |
| CA2807589C (en) | 2016-08-30 |
| EP2600835A1 (en) | 2013-06-12 |
| CA2807589A1 (en) | 2012-02-09 |
| SG187193A1 (en) | 2013-03-28 |
| EP2600835B1 (en) | 2018-05-30 |
| AU2011285890B2 (en) | 2014-12-18 |
| IL224369B (en) | 2019-08-29 |
| EA201390155A1 (ru) | 2013-05-30 |
| WO2012018829A1 (en) | 2012-02-09 |
| US20140235617A1 (en) | 2014-08-21 |
| MX2013001170A (es) | 2013-02-15 |
| ES2685174T3 (es) | 2018-10-05 |
| EA022303B1 (ru) | 2015-12-30 |
| JP2013535487A (ja) | 2013-09-12 |
| KR20140002611A (ko) | 2014-01-08 |
| US20120196794A1 (en) | 2012-08-02 |
| SG2014008346A (en) | 2014-05-29 |
| CN105148275A (zh) | 2015-12-16 |
| EP2600835A4 (en) | 2013-11-20 |
| CN103153280A (zh) | 2013-06-12 |
| BR112013002922A2 (pt) | 2016-06-07 |
| AU2011285890A1 (en) | 2013-03-21 |
| JP2016155844A (ja) | 2016-09-01 |
| US20150335655A1 (en) | 2015-11-26 |
| KR101846596B1 (ko) | 2018-04-06 |
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