CN102858344A - 氘化5,6-二氢-1h-吡啶-2-酮化合物 - Google Patents
氘化5,6-二氢-1h-吡啶-2-酮化合物 Download PDFInfo
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- CN102858344A CN102858344A CN201080060443XA CN201080060443A CN102858344A CN 102858344 A CN102858344 A CN 102858344A CN 201080060443X A CN201080060443X A CN 201080060443XA CN 201080060443 A CN201080060443 A CN 201080060443A CN 102858344 A CN102858344 A CN 102858344A
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Abstract
本发明涉及氘化5,6-二氢-1H-吡啶-2-酮化合物,和用于治疗丙肝病毒的含这类化合物的药物组合物。
Description
发明领域
本发明涉及氘化5,6-二氢-1H-吡啶-2-酮化合物和用于治疗丙肝病毒感染的含这类化合物的药物组合物。
发明背景
丙肝是世界范围内的重大健康问题。世界卫生组织估计有1.7亿人为丙肝病毒(HCV)慢性携带者,光美国就有四百万携带者。在美国,HCV感染占慢性肝病40%,HCV病是肝移植最常见的病因。HCV感染引起慢性感染,约70%感染的人发展成肝脏慢性组织学病变(慢性肝炎),10-40%有肝硬化危险,预计4%有肝细胞癌的终身风险。美国疾病预防控制中心(CDC)估计每年美国HCV感染新病例有35,000患者例约一万人死于丙肝病毒疾病。
当前护理的标准用药是聚乙二醇化干扰素/利巴韦林的组合,费用大约$30,000/年。这些药物存在剂量困难问题和副作用,在数量显著的确诊患者中不能达到持续的病毒学反应。聚乙二醇化干扰素治疗与险恶的流感样症状、刺激性、注意力不能集中、自杀意念和白细胞减少有关。而利巴韦林与溶血性贫血症和出生缺陷有关。
对这种标准疗法的总体反应低;大约三分之一的患者无反应。在有反应患者中,一些人完成6-12个月治疗后在6个月内复发。结果,进入治疗的所有患者的长期反应率仅约50%。当前抗HCV药物治疗的相对低反应率和显著副作用,加上慢性HCV感染的负面长期影响导致医学上对改进疗法的持续需求。治疗RNA病毒疾病(如HCV)的抗病毒药物很少,而且如上所述常常伴有多种副作用。
许多发表的文献描述了用于治疗丙肝感染的NS5B抑制剂。参见,例如,美国专利申请公开号2008/0031852(描述了[1,2-b]吡嗪酮化合物);美国专利申请公开号US2006/0189602(描述了某些吡嗪酮类);美国专利申请公开号US2006/0252785(描述了选择的杂环类);国际专利公开号WO03/059356、WO02/098424和WO01/85172(各自描述了特定种类的取代噻二唑)。
虽然有些病例现有药物能减轻疾病症状,但几乎没有药物能有效地抑制该病毒的复制。RNA病毒疾病的意义和流行包括但不限于,由于丙肝病毒的慢性感染,加上目前可得的抗病毒药物有限和效果,而产生了对治疗这些疾病新药的急迫和持续需求。
发明概述
本发明描述用于治疗或预防需要的患者丙肝病毒感染的氘化5,6-二氢-1H-吡啶-2-酮化合物及其药学上可接受的盐,包括给予该患者患者治疗或预防有效量的氘化5,6-二氢-1H-吡啶-2-酮化合物。
总的来说,本发明涉及下式I化合物或其药学上可接受的盐、水合物、溶剂合物、互变异构体或立体异构体:
式中,R1,R2,R3,R4,R5,R6,R7,R8,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22和R23独立地选自氢和氘,和
R9是F,其中R1,R2,R3,R4,R5,R6,R7,R8,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22和R23中至少一个是氘。
在本发明的一个方面R2,R3或R4取代基中至少一个是氘,其余R取代基是氢。
在本发明的一个方面,R12或R13取代基中至少一个是氘,其余R取代基是氢。
在本发明的一个方面,R7,R8,R10,R11,R12,R13取代基中至少一个是氘,其余R取代基是氢。
在本发明的一个方面,R16或R17是氘,且R18或R19是氘,其余R取代基 是氢。
在本发明的一个方面,R7,R8,R10,R11,R16或R17中至少一个是氘,且R18或R19是氘,其余R取代基是氢。
在本发明的一个方面,R12,R13,R16或R17中至少一个是氘,且R18或R19是氘,其余R取代基是氢。
在本发明的一个方面,R7,R8,R10,R11,R12,R13,R16或R17中至少一个是氘,且R18或R19是氘,其余R取代基是氢。
在本发明的一个方面,R2,R3,R4,R12和R13取代基中至少一个是氘,其余R取代基是氢。
在本发明的一个方面,R2,R3,R4,R7,R8,R10,R11,R12和R13取代基中至少一个是氘,其余R取代基是氢。
在本发明的一个方面,R2,R3,R4,R16或R17中至少一个是氘,且R18或R19是氘,其余R取代基是氢。
在本发明的一个方面,R2,R3,R4,R7,R8,R10,R11,R12,R13,R16或R17中至少一个是氘,且R18或R19是氘,其余R取代基是氢。
本发明也涉及式I化合物的药学上可接受的盐和药学上可接受的溶剂合物。也描述了制备式I化合物的优选方法。
在一个方面,本发明包括治疗或预防需要的哺乳动物,优选需要的人丙肝病毒感染方法,包括患者给予患者治疗或预防有效量的式I化合物。在一个实施方式中,本发明包括通过给予需要的患者治疗或预防有效量的式I化合物,治疗或预防丙肝病毒感染的方法,所述的式I化合物是HCV NS5B聚合酶的抑制剂。
在另一方面,本发明包括治疗或预防需要的患者中丙肝病毒感染的方法,包括给予该患者治疗或预防有效量的式I化合物和药学上可接受的赋形剂、载体或运载体。
在另一方面,本发明包括治疗或预防需要的患者丙肝病毒感染的方法,包括给予该患者治疗或预防有效量的式I化合物和其他治疗剂,优选其他抗病毒药物或免疫调节剂。
发明详述
本说明书中使用的下列术语定义如下:
本文使用的术语“包含”、“具有”、“包括”具有开放的、非限制含义。
本文所用术语“烷基”,除非另有说明,包括含有直链、支链或环部分的C1-C12饱和单价烃基团(包括稠合和桥连的双环和螺环部分),或上述部分的组合。对于含有环部分的烷基,该基团必需含至少三个碳原子。
术语“免疫调节剂”指能通过刺激或抑制调节正常或异常免疫系统的天然或合成产物。
术语“预防”指本发明的化合物或组合物预防经诊断患有本文所述疾病或有发生这疾病危险的患者这类疾病的能力。该术语也包括预防已患这类疾病或有症状的患者病情的进一步发展。
术语“患者”或“对象”指动物(如牛、马、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔子、豚鼠等)或哺乳动物,包括嵌合和转基因动物和哺乳动物。在治疗或预防HCV感染中,术语“患者”或“对象”粗指猴子或人,最优选人。在一具体实施方式中,患者或对象受丙肝病毒感染或接触了丙肝病毒。在某些实施方式中,患者是婴儿(0-2岁),儿童(2-17岁),青年(12-17岁),成人(18岁及以上)或老人(70岁及以上)患者。另外,患者包括免疫缺陷患者,如HIV阳性患者、癌症患者、经受免疫疗法或化疗的患者。在一具体实施方式中,患者是健康个体,即未显示其它病毒感染症状的患者。
术语“治疗有效量”指本发明化合物的用量足以提供治疗或预防病毒疾病延缓或最大程度减轻与病毒感染或病毒引起疾病相关症状的效益,或治愈或改善疾病或感染或其病因。具体说,治疗有效量表示足以提供体内治疗效益的用量。与本发明化合物用量相连使用时,该术语优选地包括改善总体疗效、减轻或避免疾病症状或病因、或增强另一种治疗剂疗效或协同作用的无毒性用量。
术语“预防有效量”指本发明的化合物或其他活性成分的用量足以预防感染、病毒感染的复发或传播。预防有效量指足以预防初始感染或感染或感染相关疾病的复发或传播的用量。与本发明化合物用量相连使用时,该术语优选包括改善总体预防效果,或增强另一种治疗剂预防效果或协同作用的无毒性用量。
术语“组合”指同时或相继采用一种以上预防和/或治疗制剂的方法,它们各自的效果可叠加或产生协同作用。
术语“治疗”指:
(i)预防动物发生疾病、失调或病症,所述动物可能有发生疾病、失调或病症的倾向但尚未作出诊断;
(ii)抑制疾病、失调或病症,即阻止其发生;和
(iii)减轻疾病、失调或病症,即使疾病、失调或病症消退。
术语“R”和“S”指化学结构中不对称碳原子取代基的特定立体化学构型。
术语“rac”指外消旋化合物,其定义为一对对映异构体的等摩尔量混合物。外消旋化合物不显示光学活性。消旋物的化学名或分子式用前缀(±)-或rac-(或racem-)或用符号RS和SR来区分对映异构体。
术语“endo(内)”和“exo(外)”是对连接于双环[x.y.z]烷烃(x≥y>z>0)中非桥头键原子取代基相对朝向的描述符。术语“syn(顺)”和“anti(反)”是对连接于双环[x.y.z]烷烃(x≥y>z>0)中桥头键原子取代基相对朝向的描述符。
术语“exo(向外)”赋予朝向朝向最高编号桥(z桥,如以下实施列的C-7)的取代基(如以下实施连接于C-2的Br);如果该取代基的朝向背离最高编号的桥,它被描述为“endo(向内)”。
术语“syn”指连接于最高编号桥的取代基(z桥,如连接于以下实施C-7的F)朝向最低标号的桥(x桥,如以下实施的C-2和C-3);如果该取代基的朝向背离最低编号的桥,它被称为“anti.”。
2-exo-溴-7-syn-氟-双环[2.2.1]庚烷
2-endo-溴-7-anti-氟-双环[2.2.1]庚烷
术语“cis(顺)”和“trans(反)”是显示连接于由双键连接或包含在环中的独立原子的两个配基之间关系的描述符。如果两个配基位于一平面的同一侧,它们称为顺位。如果它们位于相反侧,它们的相对位置称为反位。双键合适的参照平面垂直于相关的σ-键并穿过该双键。对于环来说,它指环的平面。
术语″氘富集度(deuterium enrichment)″指在分子中某给定位置替代氢掺入的氘百分率。例如,在某给定位置1%氘富集度表示在给定样品中1%分子在该特定位置含氘。由于氘的天然分布约为0.0156%,故用非富含氘原料合成的化合物中任何位置的氘富集度约为0.0156%。可采用该技术领域普通技术人员已知的常规分析方法,包括质谱和核磁共振光谱来测定氘富集度。
术语″是氘″当用来描述分子中的某给定位置,例如R1-R23或符号“D”(当用于提供分子结构图中某给定位置时),表示该特定位置所含的氘比天然分布氘丰富。在一实施方式中,该特定位置的氘富集度不低于约25%,在另一实施方式中不低于约50%,在另一实施方式中不低于约75%,或在再一个实施方式中不低于约95%。
本发明化合物可显示互变异构现象。虽然式I不能显示所有可能的互变异构体形式,但应该明白,式I化合物代表所示化合物的任何互变异构形式,而不仅仅限于该结构式图所示的特定化合物。
有些本发明化合物可能显示为单一立体对映异构体(即基本上没有其它立体异构体)、消旋体和/或对映异构体的混合物和/或非对映异构体的混合物。所有这类单一立体对映异构体(即基本上没有其它立体异构体)、消旋体和其混合物都属于本发明的范围内。优选本发明化合物是光学活性化合物和以光学纯形式使用。
该领域技术人员一般都知道,具有一个手性中心(即一个不对称碳原子)的光学纯化合物是基本上由两种可能的对映异构体之一组成的化合物(即对映体纯化合物),具有一个以上手性中心的光学纯化合物是非对映体纯和对映体纯二者(组成)的化合物。本发明所用化合物的形式优选至少90%没有其它对映体或非对映体,即含有至少90%单一异构 体(80%过量的对映体(“e.e.”)或过量的非对映体(“d.e.”))的形式,更优选至少95%(90%e.e.或d.e.),甚至还要优选至少97.5%(95%e.e.或d.e.),最优选至少99%(98%e.e.或d.e.)单一异构体形式。
此外,式I化合物包括结构相同的溶剂化物和非溶剂化物形式。例如,式I化合物包括水合和非水合形式的化合物。其它的溶剂化物的例子包括与异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸戊酯、乙酸或乙醇胺组合的结构。
除了式I化合物外,本发明包括这类化合物及其代谢产物的药学上可接受的前药、药物活性代谢产物和药学上可接受的盐。
“药学上可接受的前药”是在展示其药理效应前,在生理条件下可转化的化合物,或通过溶剂化转变成特定的化合物或这类化合物的药学上可接受的盐。通常配制前药的目的是改进化学稳定性、改进患者接受度和顺应性、改进生物利用度、延长作用时间、改进对器官的选择性、改进制剂(如提高水溶性)和/或降低副作用(如,毒性)。采用该技术领域已知的方法,如Burger’s医学化学和药物化学(Burger’s Medicinal Chemistry and Drug Chemistry),1,172-178,949-982(1995)所述方法,不难制备式I化合物的前药。也可参见Bertolini等,药物化学杂志(J.Med.Chem.,40,2011-2016(1997);Shan等,药物科学杂志(J.Pharm.Sci.),86(7),765-767;Bagshawe,药物发展研究(Drug Dev.Res.),34,220-230(1995);Bodor,Advances in Drug Res.,13,224-331(1984);Bundgaard,前药设计(Design of Prodrugs)(Elsevier出版社1985);Larsen,前药设计和应用(Design and Application of Prodrugs),药物设计和发展(Krogsgaard-Larsen等编辑,Harwood学术出版社,1991);Dear等,色谱学杂志(J.Chromatogr.B),748,281-293(2000);Spraul等,药理学和生物医药分析杂志(J.Pharmaceutical & Biomedical Analysis),10,601-605(1992);以及Prox等,Xenobiol.,3,103-112(1992)。
“药学活性代谢产物”指特定化合物或其盐通过体内代谢产生的药理活性产物。进入体内后,大多数药物是化学反应的底物,这会改变它们的物理性质和生物效应。这些代谢转化反应通常会影响式I化合物的极性,改变药物在体内的分布和从体内排出。然而在某些情况下,药物代谢为其疗效所需。例如,抗代谢类型的抗癌药物在被转运进入癌细胞后必需转化成它们的活性形式。
由于大多数药物都将经历某种类型的代谢转化,在药物代谢中起作用的生化反应数量众多和多种多样。药物代谢的主要部位是肝脏,虽然其它组织也可能参与。
许多这些转化反应的特征是代谢产物或“代谢物”的极性比母体化合物高,虽然极性药物有时也产生会产生极性较低的产物。具有高的脂质/水分配系数的物质容易通过膜,也容易从输尿管反向扩散通过肾小管细胞进入血浆。因此,这类物质有肾廓清率低的倾向而在体内长期存留。如果药物被代谢成为极性更强的化合物,即分配系数低的化合物,其被肾小管重吸收将大为减少。而且,操纵近曲肾小管和肝实质细胞对于阳离子和阴离子的特定分泌机制是针对高极性物质的。
作为一个特定例子,非那西丁(乙酰氧乙苯胺)和乙酰苯胺都是温和的止痛退热药,但在体内转化为更极性更有效的代谢产物--当今广泛应用的对-羟基乙酰苯胺(醋氨酚)。当对人给予一个剂量乙酰苯胺时,血浆中依次出现接连的代谢产物峰和衰减。第一小时期间,乙酰苯胺是血浆的主要成分。第二小时,随乙酰苯胺水平下降,代谢产物醋氨酚浓度达到峰值。最后,数小时后,血浆主要成分是惰性的可从体内排泄的进一步代谢产物。这样,一种或多种代谢产物以及药物本身的血浆浓度在药理学上至关重要。
“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。本发明的化合物可拥有足够的酸性、碱性或两性官能团,因此,能与许多无机碱或有机碱、无机酸或有机酸反应,形成药学上可接受的盐。药学上可接受的盐的例子包括使本发明化合物与无机酸或有机酸或无机碱反应制备的那些盐,包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐(monohydrogenphosphates)、磷酸二氢盐(二氢genphosphates),偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐(propionates)、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙酸盐(propiolates)、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、γ-羟基丁酸盐、甘醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
如果本发明化合物是碱,可用本领域现有的任何合适方法,例如,用无机酸,如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或用有机酸,如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙二醇酸、水杨酸;吡喃糖苷酸(pyranosidyl acid),如葡萄糖酸或半乳糖醛酸;α-羟酸,如柠檬酸或酒石酸;氨基酸,如天冬氨酸或谷氨酸;芳族酸,如苯甲酸或肉桂酸;磺酸,如对-甲基苯磺酸或乙磺酸等,处理游离碱来制备所需的药学上可接受的盐。
如果本发明化合物是酸,可用任何合适的方法,例如,用无机碱或有机碱,如胺(伯、仲或叔胺);碱金属氢氧化物或碱土金属氢氧化物等处理游离酸来制备所需的药学上可接受的盐。合适盐的示例性例子包括衍生自氨基酸,如甘氨酸和精氨酸,氨,伯胺,仲胺和叔胺;环胺,如哌啶,吗啉和哌嗪的有机盐,和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
对于固体制剂,本领域技术人员明白,存在的本发明化合物和盐可以是不同的晶体、共晶体或多形晶型,所有这些都属于本发明的范围和特定分子式范围内
治疗和预防丙肝病毒感染的方法
本发明提供了在需要的患者中治疗或预防丙肝病毒感染的方法。
本发明还提供了将治疗有效量的式I化合物或其组合引入被治疗和/或预防丙肝病毒感染患者血液中的方法。
本发明式I化合物或其药学上可接受的盐、溶剂化物或水合物在急性或慢性治疗或预防感染中的预防或治疗剂量,与视感染的性质和严重程度、活性组分的给药途径而不同变。该剂量,有时给药频率也视所治疗的感染、患者个体的年龄、体重和反应而不同。本领域技术人员考虑到这类因素,不难选择合适的剂量方案。
本发明的方法特别适合人类患者。特别是,本发明的方法和剂量可用于免疫缺陷患者,包括但不限于癌症患者、HIV感染患者和免疫退化疾病患者此外,该方法可用于目前处于缓解状态的免疫缺陷患者。本发明的方法和剂量也可用于经受其它抗病毒治疗的患者。本发明的预防方法对于有病毒感染危险的患者特别有用。这些患者包括但不限于:健康护理工作人员,如医生、护士、临终关怀提供者;军事人员;教师;育儿工作者;旅行或居住国外,特别是第三世界国家的患者,包括社会救助工作者、教牧传道人员和外交使节。最后,本发明的方法和组合物包括治疗难治患者或对治疗有抗药性,例如对逆转录酶抑制剂、蛋白酶抑制剂等有抗药性的患者。
剂量
用标准的药学方法,在培养细胞或实验动物中测定本发明化合物的毒性和药效,如测定LD50(对群体50%致死的剂量)和ED50(对群体50%有效的剂量)。毒性和疗效的剂量比率是治疗指数,表示为LD50/ED50之比。
可利用细胞培养试验和动物研究得到的数据可用来调配人体中使用的化合物剂量范围。这类化合物的剂量优选在其血循环浓度范围内,包括ED50和几乎没有或没有毒性的范围内。根据采用的剂型和给药途径在此范围内变化剂量。对用于本发明方法中的任何化 合物,可先从细胞培养试验估计其治疗有效剂量。动物模型用的剂量为达到的循环血浆浓度范围,包括IC50(即抑制症状达到在细胞培养中测得的最大程度一半时的测试化合物浓度)或者,动物模型中所用的式I化合物剂量能使该化合物的循环血浆浓度达到获得固定幅度反应所需浓度相对应的范围。可利用这类信息更精确地确定人体所用的剂量。例如,可用高效液相色谱来测定血浆水平。
本发明的方法和组合物在用于人体之前,优选进行体外试验,然后进行体内试验,检测有无所需的治疗或预防活性。例如,可用体外试验来决定是否给予所示的特定治疗案式,包括用体外细胞培养试验,分析细胞对接触配体的式I化合物效力的反应,并用合适的技术来检测反应的幅度。然后就式I化合物的效力和式I化合物前药转化程度来评估式I化合物。人体试验前可在合适的动物模型系统中试验用于本发明方法的化合物,所述的动物包括但不限于:大鼠、小鼠、鸡、牛、猴子、兔子、仓鼠等。然后将该化合物用于合适的临床试验。
在急性或慢性感染的治疗或预防中,本发明式I化合物的前药或其药学可接受的盐、溶剂合物或水合物的预防剂量或治疗剂量的大小随感染的性质和严重程度以及活性组分给药途径而不同。剂量,或许给药频率也视所治疗的感染、患者个体的年龄、体重和反应而不同。本领域技术人员考虑到这类因素不难选择合适的剂量。在一个实施方式中,给药剂量取决于所给予的具体化合物和患者的体重和病情。该剂量也视不同的具体式I化合物而不同;可根据上述体外试验的根据动物研究预计合适的剂量,如果对于式I化合物而言,较小的剂量合适,在本文所述或参照系统中进行测定时,采用比其他式I化合物更低的浓度也显示有效果。一般而言,每日剂量范围为约0.001-100mg/kg,优选1-25mg/kg,更优选约5-到15mg/kg。对于治疗丙肝病毒感染的人体,每天给予约1-4次,每天约0.1mg-15g,优选每天100mg-12g,更优选每天约100mg-8000mg。
另外,推荐的每日剂量可作为单次药剂或与其它治疗剂联合循环给予。在一个实施方式中,每日剂量以单次剂量给予或分成等份剂量给予。在一相关的实施方式中,推荐的每日剂量可每周给予一次,每周给予两次,每周给予三次,每周给予四次或每周五次。
在一个实施方式中,本发明的化合物给药后在患者体内全身分布。在一相关的实施方式中,给予本发明的化合物在体内产生全身作用。
在本发明另一个实施方式中,本发明化合物通过口服、粘膜(包括舌下、颊部、直肠、鼻内或阴道)、胃肠道外(包括皮下、肌肉内、输液、动脉内或静脉内)、透皮或局部给药。在一具体实施方式中,本发明化合物通过粘膜(包括舌下、颊部、直肠、鼻内或 阴道),胃肠道外(包括皮下注射、肌肉内、输液、动脉内或静脉内)、透皮或局部给药。在一其他具体实施方式中,本发明化合物通过口服给药。在一其他具体实施方式中,本发明化合物不通过口服给药。
对不同感染可采用不同的治疗有效量,这是本领域普通技术人员所熟知的。类似地,足以治疗或预防这类感染,但不足以引起与常规治疗相关的副作用或足以降低这种副作用的剂量也包括在上述的剂量和给药频率方案内。
联合治疗
本发明特定的方法还包括给予其他治疗剂(即非本发明化合物的治疗剂)。在本发明某些具体实施方式中,本发明化合物可与至少一种其它治疗剂联用。所述治疗剂包括但不限于:抗生素、止吐剂、抗抑郁药、抗真菌药、消炎药、抗病毒药、抗癌药、免疫调节药、α-干扰素、β-干扰素、利巴韦林、烷化剂、激素、细胞因子或toll样受体调节剂。在一个实施方式中,本发明包括给予对HCV有特异性的或显示抗-HCV活性的其他治疗剂。
本发明的式I化合物可与抗生素联合给药或一起配制。例如,它们可与下列药物一起配制:大环内酯类(如,托普霉素(Tobi )),头孢菌素(如,头孢氨苄(Keflex ),头孢环己烯(Velosef ),头孢呋新(Ceftin )、头孢丙烯(Cefzil )、头孢克罗(Ceclor )、头孢克肟(Suprax )或头孢羟氨苄(Duricef ))、克拉霉素(如克拉霉素(Biaxin ))、红霉素(如红霉素(EMycin ))、青霉素(如青霉素V(V-Cillin K 或Pen Vee K ))或喹诺酮(如氧氟沙星(Floxin )、卷须霉素(Cipro )或诺氟沙星(Noroxin ))、氨基糖苷类抗生素(如阿拉伯霉素、阿贝卡星、班贝霉素、丁苷菌素、地贝卡星、新霉素、新霉素、十一烯酸酯、奈替米星、巴龙霉素、核糖霉素、西索米星和壮观霉素);胺酰醇(amphenicol)抗生素(如叠氮氯霉素、氯霉素、氟苯尼考和甲砜氯霉素);袢霉素抗生素(如利福米特和利福平);碳头孢烯类(如氯碳头孢);碳青霉烯类(如比阿培南和亚胺培南);头孢菌素类(如头孢克罗、头孢羟氨苄、头孢孟多、头孢曲秦、头孢西酮、头孢唑兰、头孢咪唑、头孢匹胺和头孢匹罗);头孢菌素(如头孢布宗、头孢美唑和头孢米诺);单杆菌素类(如噻肟单酰胺菌素、卡芦莫南和替吉莫南);杂头孢类(oxacephems)(如氟氧头孢和羟羧氧酰胺菌素);青霉素类(如氮卓西林、氮卓脒青霉素匹酯、阿莫西林,、巴卡西林、苄基青霉酸、苄基青霉素钠、依皮西林、芬贝西林、氟氯青霉素、培那西林(penamccillin),、青霉素G二乙氨基乙酯、o-苯明青霉素、青霉素0、青霉素V、苄星青霉素V、海巴青霉素V、青哌环素和非西林钾(phencihicillin potassium));林可酰胺类(如克林霉素和林可霉素);安福霉素、杆菌肽、卷曲霉素、粘菌素、恩霉素、恩维霉素;四环素类(如阿哌环素、金 霉素、氯莫环素和地美环素);2,4-二氨基嘧啶(如溴莫普林);硝基呋喃类(如呋喃他酮和呋唑氯铵);喹诺酮类及其类似物(如西诺沙星、克林沙星、氟甲喹和grepagloxacin);磺酰胺类(如乙酰磺胺甲氧吡嗪、基磺胺、诺丙磺胺、酞磺醋胺、磺胺柯定和磺胺西汀);砜类(如地百里砜、葡胺苯砜钠和苯丙砜);环丝氨酸、莫匹罗星和马铃薯球蛋白。
本发明式I化合物也可与止吐药联合给药或一起配制。合适的止吐药包括但不限于:灭吐灵、多潘立酮、丙氯拉嗪、异丙嗪、氯丙嗪、曲美苄胺、恩丹西酮、格拉司琼、羟嗪、乙酰亮氨酸、阿立必利、阿扎司琼、苯喹胺、氨醇醋茶碱、溴必利、安其敏、氯波必利、赛克利嗪、乘晕宁、地芬尼朵、多拉司琼、美克洛嗪、美沙拉妥、美托哌丙嗪、大麻隆、oxyperndyl、匹哌马嗪、莨菪碱、舒必利、四氢大麻醇、硫乙拉嗪、硫丙拉嗪、托烷司琼和它们的混合物。
本发明的式I化合物可与抗抑郁药联合给药或一起配制。合适的抗抑郁药包括但不限于:苯奈达林、卡罗沙酮、西酞普兰、二甲沙生、芬咖明、吲达品、盐酸茚洛秦、奈福泮、诺米芬辛、羟色氨酸、奥昔哌汀、帕罗西汀、舍曲林、硫西新、曲拉唑酮、苯莫辛、异丙氯肼、异丙烟肼、异卡波肼、尼亚拉胺、奥他莫辛、苯乙肼、可替宁、罗利普林、咯利普兰、马普替林、美曲吲哚、米安舍林、米氮平、阿地唑仑、阿米替林、氧阿米替林、阿莫沙平、布替林、氯米帕明、地美替林、地昔帕明、二苯西平、二甲他林、度硫平、多塞平、三氟丙嗪、丙咪嗪、丙咪嗪N-氧化物、伊普吲哚、洛非帕明、美利曲辛、美他帕明、去甲替林、肟替林、奥匹哌醇、苯噻啶、丙吡西平、普罗替林、奎纽帕明、噻奈普汀、曲米帕明、阿屈非尼、苯乃静、安非他酮、布他西丁、地奥沙屈、度洛西汀、依托哌酮、非巴氨酯、非莫西汀、芬戊二醇、氟西汀、氟伏沙明、血卟啉、金丝桃素、左芬氟拉明、美地沙明、米那普仑、苯哒吗啉、吗氯贝胺、吗氯贝胺、奥沙氟生、吡贝拉林、普罗林坦、吡琥胺酯、利坦色林、罗克吲哚、氯化铷、舒必利、坦度螺酮、托扎啉酮、托芬那辛、托洛沙酮、苯环丙胺、L-色氨酸、文拉法辛、维洛沙秦和齐美定。
本发明的式I化合物可与抗真菌药联合给药或一起配制。合适的抗真菌药包括但不限于:两性霉素B、伊曲康唑、酮康唑、氟康唑、鞘内注射用的氟胞嘧啶、咪康唑、布康唑、克霉唑、制霉菌素、特康唑、噻康唑、环吡酮、益康唑、卤丙烷、萘替芬、特比萘芬、十一烯酸酯和灰黄霉素。
本发明的式I化合物可与消炎药联合给药或一起配制。合适的消炎药包括但不限于:非甾体类消炎药,如水杨酸、乙酰水杨酸、水杨酸甲酯、水杨酸乙酯、二氟尼柳、双水杨酯、奥沙拉秦、柳氮磺胺吡啶、扑热息痛、吲哚美辛、舒林酸、依托度酸、甲灭酸、甲氧 胺苯酸钠、托美丁、酮咯酸、双氯芬酸、布洛芬、萘普生、萘普生钠、非诺洛芬、酮洛芬、氟比洛芬、奥沙普秦、吡罗昔康、洛昔康、安吡昔康、屈噁昔康、吲哚美辛、替诺昔康、美洛昔康、保泰松、羟布宗、安替比林、氨基比林、阿扎丙宗和尼美舒利;白三烯拮抗剂,包括但不限于齐留通、硫代葡萄糖金、苹果酸金钠和金诺芬;甾体类,包括但不限于二丙酸阿氯米松、安西奈德、二丙酸倍氯米松、倍他米松、苯甲酸倍他米松、二丙酸倍他米松、倍他米松磷酸钠、新戊酸倍他米松、丙酸氯倍他索、新戊酸氯可托龙、氢化可的松、氢化可的松衍生物、羟泼尼缩松、去羟米松、地塞米松、氟尼缩松、flucoxinolide、氟氢缩松、氯氟舒松、甲羟松、甲泼尼龙、乙酸甲基强的松龙、甲基强的松龙琥珀酸钠、糠酸莫米他松、乙酸帕拉米松、泼尼松龙、乙酸泼尼松龙、泼尼松龙磷酸钠、泼尼松龙、tebuatate、强的松、曲安西龙、曲安奈德、二乙酸曲安西龙和己曲安奈德;和其他消炎药,包括但不限于甲氨蝶呤、秋水仙素、别嘌醇、丙磺舒、磺吡酮和苯溴马隆。
本发明的式I可与另一种抗病毒药聚合给药或一起配制。有用的抗病毒药包括但不限于:蛋白酶抑制剂、核苷类似物逆转录酶抑制剂、非核苷类似物逆转录酶抑制剂和核苷类似物。抗病毒药包括但不限于:齐多夫定、阿昔洛韦、gangcyclovir、阿糖腺苷、碘苷、三氟尿苷、左旋抗病毒素(levovirin)、viramidine、利巴韦林和taribavirin以及膦甲酸钠、金刚烷胺、金刚乙胺、沙奎那韦、茚地那韦、安普那韦、洛匹那韦、利托那韦、α-干扰素、β-干扰素、阿德福韦、clevadine、恩替卡韦、普来可那利、BMS-824393和GI-5005。
本发明的式I可与免疫调节剂聚合起给药或一起配制。免疫调剂剂包括但不限于:甲氨蝶呤、来氟米特、环磷酰胺、环孢素A、麦考酚酸酯、雷帕霉素(西罗莫司)、咪唑立宾、脱氧精瓜素、布喹那、malononitriloamindes(如来氟米特)、T细胞受体调节剂和细胞因子受体调节剂、肽模拟物和抗体(如人抗体、人源化抗体、嵌合抗体、单克隆抗体、多克隆抗体、Fv、ScFv、Fab或F(ab)2片段或表位结合片段);核苷酸分子(如反义核苷酸分子和三螺旋);小分子有机化合物和无机化合物。T细胞受体调节剂包括但不限于:抗-T细胞受体抗体(如抗-CD4抗体(如cM-T412(Boehringer)、IDEC-CE9.1 (IDEC和SKB)、mAB 4162W94、Orthoclone和OKTcd r4a(Janssen-Cilag));抗-CD3抗体(如Nuvion(Product Design Labs)、OKT3(Johnson & Johnson)或Rituxan(IDEC));抗-CD5抗体(如抗-CD5蓖麻毒素连接的免疫偶联物);抗-CD7抗体(如CHH-380(Novartis));抗-CD8抗体;抗-CD40配体单克隆抗体(如IDEC-131(IDEC));抗-CD52抗体(如CAMPATH 1H(IIex));抗-CD2抗体;抗-CD11a抗体(如Xanelim(Genentech));抗-B7抗体(如IDEC-114(IDEC))、CTLA4-免疫球蛋白和toll样受体(TLR) 免疫调节剂(如ANA773、IMO-2125、PF-04878691)。细胞因子受体免疫调节剂的例子包括但不限于:可溶性细胞因子受体(如TNF-α受体的胞外域或其片段、IL-1β受体的胞外域或其片段、IL-6受体的胞外域或其片段);细胞因子或其片段(如白介素(IL)-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-15、TNF-α、干扰素(IFN)-α、IFN-β、IFN-γ和GM-CSF);抗-细胞因子受体抗体(如抗-IFN受体抗体、抗-IL-2受体抗体(如Zenapax(Protein Design Labs))、抗-I L-4受体抗体、抗-IL-6受体抗体、抗-IL-10受体抗体、和抗-IL-12受体抗体);抗-细胞因子抗体(如抗-IFN抗体、抗-TNF-α抗体、抗-IL-1β抗体、抗-IL-6抗体、抗-IL-8抗体(如ABX-IL-8(Abgenix))和抗-IL-12抗体)。
本发明的式I可与抑制病毒酶的药物联合给药或一起配制,所述药物包括但不限于:HCV蛋白酶抑制剂,如VX-500、VBY-376、BMS-650032、MK-7009(vaniprevir)、TMC-435350、BI-201335、SCH-503034(boceprevir)、ITMN-191(danoprevir)、VX-950(telaprevir)、SCH900518(narlaprevir)、VX-813、VX-985、PHX1766、ABT-450、ACH-1625、ACH-1095、IDX136、IDX316和ITMN-5489;NS5B聚合酶抑制剂,如GS-9190、MK-3281、VCH-759(VX-759)、VCH-916、ABT-333、BMS-791325、PF-00868554(filibuvir)、IDX-184、R7128、PSI-6130、R1626、PSI-7851、VCH-222(VX-222)、ABT-072和BI207127;以及NS5A蛋白抑制剂,如BMS-790052、A-831和AZD2836。
本发明的式I可与抑制HCV聚合酶的药物联合给药或一起配制,所述药物例如Wu,Curr Drug Targets Infect Disord.2003,3(3),207-19中所述的那些,或可与抑制病毒螺旋酶功能的化合物联用,例如Bretner M等,Nucleosides Nucleotides Nucleic Acids.2003,22(5-8),1531中所述的那些;或与其他特异性靶向HCV的抑制剂,例如Zhang X.,IDrugs 2002,5(2),154-8所述的那些联用。
本发明的式I化合物可与抑制病毒复制的药物联合给药或一起配制。
本发明的式I化合物可与抑制亲环素的药物联合给药或一起配制。亲环素抑制剂的例子包括但不限于Debio-025,NIM-811和SCY-635。
本发明的式I化合物可与细胞因子联合给药或一起配制。细胞因子的例子包括但不限于:白介素-2(IL-2)、白介素-3(IL-3)、白介素-4(IL-4)、白介素-5(IL-5)、白介素-6(IL-6)、白介素-7(IL-7)、白介素-9(IL-9)、白介素-10(IL-10)、白介素-12(IL-12)、白介素15(IL-15)、白介素18(IL-18)、血小板源生长因子(PDGF)、促红细胞生成素(Epo)、表皮生长因子(EGF)、成纤维细胞生长因子(FGF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集 落刺激因子(G-CSF)、巨噬细胞集落刺激因子(M-CSF)、促乳素和干扰素(IFN),如IFN-α和IFN-γ)。
本发明的式I化合物可与激素联合给药或一起配制。激素的例子包括但不限于:促黄体生成激素释放激素(LHRH)、生长激素(GH)、生长激素释放激素、ACTH、生长抑素、促生长素、生长调节素、甲状旁腺激素、下丘脑释放因子、胰岛素、胰高血糖素、脑啡肽、加压素、降血钙素、肝素、低分子量肝素、肝素类似物、合成和天然阿片类、胰岛素甲状腺刺激激素和内啡肽。
本发明的式I化合物可与β-干扰素联合给药或一起配制。β-干扰素包括但不限于干扰素β-1a、干扰素β-1b。
本发明的式I化合物可与α-干扰素联合给药或一起配制。α-干扰素包括但不限于:干扰素α-1、干扰素α-2a(罗扰素)、干扰素α-2b、内含子、Peg化-内含子、Pegasys、同义干扰素(干复津)和albuferon。本发明的化合物也可与干扰素,如BLX-883(Locteron)、ω干扰素和PEG-化干扰素λ联合给药或一起配制。
本发明的式I化合物可与吸收增强剂联合给药或一起配制。具体靶向淋巴系统的吸收增强剂包括但不限于:甘氨胆酸钠;癸酸钠;N-月桂基-β-D-麦芽糖苷;EDTA;混合胶粒和Muranishi Crit.Rev.Ther.Drug Carrier Syst.,7,1-33中报道的那些,该文献全文纳入本文供参考。也可采用其他已知的吸收增强剂。因此,本发明也包括含一种或多种本发明的式I化合物和一种或多种吸收增强剂的药物组合物。
本发明的式I化合物可与细胞色素P450单加氧酶抑制剂,例如但不限于利托那韦或其药学上可接受的盐、酯和前药联合给药或一起配制,以改善细胞色素P450单加氧酶代谢式I化合物的药物动力学(如提高半衰期、增加到达峰值的时间、提高血药水平)。因此,本发明还包括含本发明的式I化合物和一种或多种细胞色素P450单加氧酶的药物组合物。本发明的式I化合物可与食品一起给予,以提高胃肠道对式I化合物的吸收和提高式I化合物的生物利用度。
本发明的式I化合物可与烷化剂联合给药或一起配制。烷化剂的例子包括但不限于:氮芥类(nitrogen mustards)、氮丙啶、甲基三聚氰胺\磺酸烷酯\、亚硝基脲\、三嗪、氮芥(mechlorethamine),、环磷酰胺、异环磷酰胺、苯丙氨酸氮芥、苯丁酸氮芥、六甲基三聚氰胺、噻替派、白消安、卡氮芥、链佐星、达卡巴嗪和替莫唑胺。
本发明化合物和其他治疗剂的作用可以叠加或优选协同。在一实施方式中,包含本发明化合物的组合物可与作为同一组合物或不同组合物中一部分的另一种治疗剂同时给药。 在另一个实施方式中,给予本发明的化合物之前或之后给予另一种治疗剂。在一个独立实施方式中,将本发明的化合物给予以前或目前没用另一种治疗剂,特别是抗病毒剂治疗的患者。
在一个实施方式中,本发明方法包括给予一种或多种本发明的式I化合物而没有其他治疗剂。
药物组合物和剂型
本发明也包括含本发明式I化合物或其药学上可接受的盐或水合物的药物组合物和单位剂型。本发明的单位剂型适合于口服、粘膜(包括舌下、颊部、直肠、鼻内或阴道、胃肠道外(包括皮下、肌肉内、推注、动脉内和静脉内)、透皮或局部给药。本发明的药物组合物和剂型通常还包含一种或多种药学上可接受的赋形剂。也考虑无菌剂型。
在另一个实施方式中,此实施方式包括的药物组合物包含本发明式I化合物或其药学上可接受的盐或水合物,以及至少一种其他治疗剂。其他治疗剂例子包括但不限于上述所列那些。
本发明组合物,剂型的形状和类型通常视其用途而不同。例如,用于急性治疗疾病或相关疾病剂型的一种或多种活性组分含量可比慢性治疗同一疾病剂型的含量更多。相似地,胃肠道外剂型一种或多种活性组分含量可比用于治疗同一疾病或病症口服剂型的更少。本领域技术人员不难理解在这些和其他方法中本发明包括的具体剂型互相有所不同。参见,例如“雷明顿药物科学”,第18版,Mack出版社,美国宾夕法尼亚州Easton(1990)。剂型的例子包括但不限于:片剂、小胶囊、胶囊如软弹性明胶胶囊、扁囊剂、药锭、糖锭、分散剂、栓剂、药膏、泥罨剂(湿敷药物)、药糊、药粉、敷料、药霜、橡皮膏、溶液、贴剂、气溶胶(如鼻喷雾或吸入)、凝胶;适合口服或粘膜给予患者的液体剂型,包括悬浮剂(如水性或非水性悬浮液、水包油或油包水乳液);溶液和酏剂;适合胃肠道外给予患者的液体剂型;和能重建为适合胃肠道外给予患者液体剂型的无菌固体(如晶体或无定形固体)。
典型的药物组合物和剂型包含一种或多种载体、赋形剂或稀释剂。合适的赋形剂是药学领域技术人员熟知的,本文提供合适赋形剂的非限制性例子。某特定赋形剂是否适合于掺入药物组合物或剂型中取决于该领域已知的各种因素,包括但不限于将要给予患者的剂型。例如,片剂等口服剂型可含有不适合用于胃肠道外剂型的赋形剂。具体赋形剂的合适程度也取决于该剂型中的具体活性组分。
本发明还包括含活性组分的无水药物组合物和剂型,因为水可能加速某些化合物的降解。例如,为了测定制剂特性,如货架寿命或稳定性随时间的变化,在药学领域中作为模拟长期贮存的方法可加入广泛接受的水(如5%)。参见如,Carstensen,“药物稳定性:原理和实践(Drug Stability:Principles & Practice)”,第2版,Marcel Dekker,美国纽约,1995,379-80页。水和热的作用可加速一些化合物的分解。因此,水对制剂的作用很明显,因为制造、处理、包装、贮存、货运和使用制剂时经常会遭遇水气和/或潮湿。
可用无水或含水量低的组分或在低湿度或低潮湿条件下制备本发明的无水药物组合物和剂型。
应当这样制备和贮存无水药物组合物以保持其无水性质。因此,优选用已知可防止接触水的材料包装无水组合物,将其装在合适的制剂盒中。合适的包装包括但不限于:密封的铝箔、塑料、单位剂型容器(如小瓶)、泡罩包装和窄条包装。
本发明还包括含有能降低活性组分分解速率的一种或多种化合物的药物组合物和剂型。这类化合物称为“稳定剂”,包括但不限于抗氧化剂如抗坏血酸、pH缓冲剂或盐缓冲剂。
像赋形剂含量和种类一样,剂型中活性组分的含量和具体视各种因素而不同,所述因素包括但不限于给予患者药物的途径因而,本发明的典型剂型每剂包含0.1mg-1500mg式I化合物或其药学上可接受的盐或水合物,每天提供约0.01-200mg/kg剂量。
口服剂型
适合口服给药的本发明药物组合物可以是不连续的剂型,例如但不限于:片剂(如可咀嚼药片)、小胶囊、胶囊和液体(如调味糖浆)。这类剂型含有预定量的活性组分,可用药学领域技术人员熟知的方法制备。一般参见“雷明顿药物科学”,第18版,Mack出版社,美国宾夕法尼亚Easton(1990)。
可按照常规的药物配料技术紧密混合活性组分与至少一种赋形剂而制备本发明典型的口服剂型。根据给药所需的剂型,可采取各种形式的赋形剂。例如,适合用于口服液体或气溶胶剂型的赋形剂包括但不限于:水、乙二醇、油、醇、调味剂、防腐剂和着色剂。适合用于固体口服剂型(如粉末、药片、胶囊和小胶囊)的赋形剂例子包括但不限于:淀粉、糖、微晶纤维素稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
由于容易给予,片剂和胶囊代表了最好的口服剂型,其中采用了固体赋形剂。若需要,可用标准的水或非水技术包衣片剂。可用任何制药方法制备这类剂型。一般而言,通 过均匀紧密地混合活性组分与液体载体、细分散的固体载体或二者,需要时将产品塑造成所需的形状,从而制备药物组合物和剂型。
例如,通过压制或模压制备片剂。在合适的机器里将自由流动形式,如粉末或颗粒形式的活性组分任选地与赋形剂混合,制备压制的片剂。在合适的机器里模压用惰性液体稀释剂湿润的粉末化合物制备模压片剂。
可用于本发明口服剂型的赋形剂例子包括但不限于:粘合剂、填充剂、崩解剂和润滑剂。适合用于药物组合物和剂型的粘合剂包括但不限于:玉米淀粉、土豆淀粉或其它淀粉;明胶、天然或合成胶,如阿拉伯胶、藻酸钠、藻酸、其它藻酸盐、黄蓍胶粉、瓜尔胶;纤维素及其衍生物(如乙基纤维素、纤维素醋酸酯、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯吡咯烷酮、甲基纤维素、预明胶化的淀粉、羟丙基甲基纤维素(如2208、2906、2910号)、微晶纤维素和它们的混合物。
适合用于本发明药物组合物和剂型的填充剂的例子包括但不限于:滑石粉、碳酸钙(如颗粒或粉末)、微晶纤维素、粉末化纤维素、葡聚糖结合剂(dextrates)、高岭土、甘露醇、硅酸、山梨醇、淀粉、预明胶化淀粉和它们的混合物。本发明药物组合物中存在的粘合剂或填充剂含量占药物组合物或剂型的约50-约99%重量。
微晶纤维素的合适形式包括但不限于固体物质,如AVICEL-PH-101、AVICEL-PH-103 AVICEL RC-581、AVICEL-PH-105(购自FMC公司,美国粘胶分公司,Avicel销售部,美国宾夕法尼亚Marcus Hook)和它们的混合物。具体粘合剂是微晶纤维素与羧甲基纤维素的混合物,销售的商品名为AVICEL RC-581。合适的无水或低水分赋形剂或添加剂包括AVICEL-PH-103TM和淀粉1500LM。
本发明组合物采用的崩解剂可提供当接触水性环境时可崩解的片剂。含有太多崩解剂的片剂贮存时会崩解,而含太少崩解剂的片剂则在所需条件下不能以所需的速率崩解。因此,应采用能明显改变活性组分释放的既不太多也不太少的足量崩解剂来制备本发明的固体口服剂型。所用崩解剂的含量根据制剂类型而不同,这是该领域普通技术人员容易明的的。典型的药物组合物包含占组合物约0.5-15重量%的崩解剂,具体约1-5重量%的崩解剂。
可用于本发明药物组合物和剂型的崩解剂包括但不限于:琼脂、海藻酸、碳酸钙、微晶纤维素、交联羧甲纤维素钠、聚维酮、波拉克林钾、羟乙酸淀粉钠\土豆或木薯淀粉、预明胶化淀粉、其它淀粉、粘土、其他藻酸、其它纤维素类、胶以及它们的混合物。 可用于本发明药物组合物和剂型中的润滑剂包括但不限于:硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨醇、甘露醇、聚乙二醇、其他二醇、硬脂酸、十二烷基硫酸钠、滑石粉、氢化植物油(如花生油、棉籽油、葵花籽油、芝麻油、橄榄油、玉米油和大豆油);硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂和它们的混合物。其他润滑剂包括,例如气相微粉硅胶(syloid silica gel)(AEROSIL 200,美国马里兰州巴尔的摩的W.R.Grace公司制备)、合成硅胶的凝聚气溶胶(美国德克萨斯州的Degussa公司出售)、CAB-O-SIL(美国马里兰州波士顿Cabot公司出售的热解二氧化硅产品)以及它们的混合物。如果都用,掺入的润滑剂含量通常低于药物组合物或剂型的约1%重量。
缓释剂型
本发明的活性组分可以本领域普通技术人员熟知的控释方法或递送装置给药。例子包括但不限于:美国专利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和5,733,566中所述的那些,各专利纳入本文作参考。例如,可采用羟丙基甲基纤维素、其它的聚合物基质、凝胶、渗透膜、渗透系统、多层包衣、微粒、脂质体、微球或它们的组合提供不同比例的所需释放模式,利用这类剂型来提供一种或多种活性组分的缓慢释放或控释。该领域普通技术人员已知的合适控释制剂包括本文描述那些,不难从中选择用于本发明的活性组分。本发明因此包括适合口服的单次单位剂型,例如但不限于适合控释的片剂、胶囊、凝胶胶囊(gelcaps)和小胶囊。
所有控释药品的共同目的是改进药物疗效超过它们的非控释对照。理想上采用最佳设计的控释制剂的特征在于在最短时间内使用于治愈或控制疾病的药物用量最少。控释制剂的优点包括药物活性延长,给药频率减少,患者顺应性增加。另外,可利用控释制剂来影响药物作用的开始时间或其它特性,如血药水平度,和影响副作用(如不良效应)的发生。
设计的大多数控释制剂开始时释放一定量的药物(活性组分)而迅速产生所需的治疗效应,和在一段延长的时间里逐渐连续地释放其它量的药物而维持此水平的治疗或预防效应。为了维持体内药物的恒定水平,药物从剂型中释放的速率必须能替代被分解代谢从体内排出的药物剂量。可通过各种条件,包括但不限于pH、温度、酶、水或其它生理条件或化合物来激发活性组分的控释。
胃肠道外剂型
可通过各种途径,包括但不限于:皮下、静脉内(包括推注)、肌肉内和动脉内给药,给予患者胃肠道外剂型。由于它们的给药绕过了患者对抗污染的天然防御屏障,胃肠道外剂型优选无菌,或在给予患者前灭菌。胃肠道外剂型的例子包括但不限于:注射用溶液、易于溶解或悬浮于药学上可接受的注射用运载体的干燥和/或冻干产品(可重建的粉末)、注射用悬浮液和乳液。
可用于提供本发明胃肠道外剂型的合适赋形剂是本领域技术人员熟知的。例子包括但不限于:注射用水(美国药典);液体运载体,例如但不限于:氯化钠注射液、林格氏(Ringer’s)注射液、葡萄糖注射液、葡萄糖和氯化钠注射液、和乳酸化的林格氏注射液;水易混溶的运载体,例如但不限于乙醇、丙醇和聚丙二醇;和非水性运载体,例如但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、豆蔻酸异丙酯和苯甲酸苄酯。
也可将能提高本发明一种或多种活性组分溶解度的化合物掺入本发明的胃肠道外剂型中。
透皮剂型
透皮剂型包括“储库型”或“基质型”贴剂,可将它们施涂到皮肤上在一定时间后消失让所需量的活性组分渗透入皮肤。
合适的赋形剂(如载体和稀释剂)和可用于提供本发明包括的透皮局部外用剂型的其他材料是制药领域技术人员熟知的,取决于将要施涂药物组合物或剂型的具体组织。由于该事实,常用的温和赋形剂包括但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、豆蔻酸异丙酯,棕榈酸异丙酯、矿物油及它们的混合物。
根据要治疗的具体组织,在用本发明活性组分治疗前或治疗后也可采用其他组分。例如,可采用渗透增强剂辅助向组织递送活性组分。合适的渗透增强剂包括但不限于:丙酮;各种醇,如乙醇、油醇和四氢呋喃;烷基亚砜类如二甲亚砜、二甲基乙酰胺、二甲基甲酰胺、聚乙二醇;吡咯烷酮类如聚乙烯吡咯烷酮、Kollidon级(维酮、聚维酮);脲和各种水溶性或水不溶性糖酯如吐温80(聚山梨醇酯80)和司盘60(聚氧乙烯脱水山梨醇单硬脂酸酯)。
也可调节药物组合物或剂型或该药物组合物或剂型施涂处组织的pH,以改善一种或多种活性组分的递送。相似地,可调节溶剂载体的极型、其离子强度或张力(tonicity)来促进递送。也可将例如硬脂酸酯类化合物可加到药物组合物或剂型中以利于改变一种或多种活性组分的亲水性或亲脂性而促进递送。就此而言,硬脂酸酯可用作制剂的脂质 运载体,乳化剂或表面活性剂,用作递送增强剂或渗透增强剂。可采用活性组分的不同盐,水合物或溶剂合物来进一步调节所得组合物的性能。
局部用剂型
本发明的局部用剂型包括但不限于:药霜、洗剂、药膏、凝胶、溶液、乳液、悬浮液或本领域技术人员已知的其他形式。参见如“雷明顿药物科学”,第18版,Mack出版社,美国宾夕法尼亚(1990);和“药物剂型引言(Introduction to Pharmaceutical Dosage Forms)”,第4版,Lea & Febiger,美国费城(1985)。
合适的赋形剂(如载体和稀释剂)以及可用于提供本发明透皮和局部剂型的其他材料是制药领域技术人员熟知,取决于将施涂给定药物组合物或剂型的的具体组织。记住该事实,赋形剂通常包括但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和它们的混合物。
根据被治疗的具体组织,用本发明活性组分治疗前或治疗后也可采用其他组分。例如,可采用渗透增强剂辅助向组织递送活性组分。合适的渗透促进剂包括但不限于:丙酮;各种醇如乙醇、油醇和四氢呋喃;烷基亚砜类如二甲亚砜、二甲基乙酰胺、二甲基甲酰胺、聚乙二醇;吡咯烷酮类如聚乙烯吡咯烷酮、Kollidon级(维酮、聚维酮);脲和各种水溶性或水不溶性糖酯如吐温80(聚山梨醇酯80)和司盘60(聚氧乙烯失水山梨醇单硬脂酸酯)。
粘膜剂型
本发明的粘膜剂型包括但不限于眼用溶液、喷雾剂和气溶胶,或该领域技术人员已知的其他形式。参见如“雷明顿药物科学”,第18版,Mack出版社,美国宾夕法尼亚(1990);和“药物剂型引言(Introduction to Pharmaceutical Dosage Forms)”第4版,Lea & Febiger,美国费城(1985)。适合治疗口腔粘膜组织的剂型可配制成口腔洗剂或口腔用凝胶。在一个实施方式中,气溶胶包含载体。在另一个实施方式中,气溶胶没有载体。
本发明的式I化合物也可通过吸入直接经肺部给药。对于吸入给药,可用多不同的装置方便地将式I化合物递送到肺部。例如,采用罐子的计量吸入器(“MDI”),,装入适当的低沸点推进剂,如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体,可将式I化合物直接递送入肺部。MDI装置可购自许多供货商,如3M公司、安万特(Aventis)公司、Boehringer Ingelheim,Forest实验室公司、葛兰素-维尔康(Glaxo-Wellcome)公司、先灵葆亚(Schering Plough)公司和威达(Vectura)公司。
或者,可用干粉吸入器(DPI)将式I化合物给予肺部(参见如,Raleigh等,Proc.Amer.Assoc.Cancer Research Annual Meeting,1999,40,397,此文纳入本文作参考)。DPI装置通常采用的机制是使气体爆发在容器内部产生干粉云雾然后由患者吸入。DPI装置也是本领域熟知的,可从许多供货商购得,例如Fisons公司、Glaxo-Wellcome公司、Inhale Therapeutic Systems公司、ML实验室、Qdose和Vectura公司。流行的变化是多剂量DPI(“MDDPI”)系统,它允许递送一次以上的治疗剂量。MDDPI装置可购自:阿斯利康(AstraZeneca)公司、GlaxoWellcome公司、IVAX公司、Schering Plough公司、SkyePharma和Vectura公司。例如,可配制用于这些系统的吸入器或吹药器中所用的含有本发明化合物与合适粉末基如乳糖或淀粉的混合粉末的明胶胶囊和药筒。
可将式I化合物递送到肺部的另一类装置是液体喷雾装置,例如Aradigm公司提供的装置。液体喷雾系统采用极小的喷雾孔使液体药物制剂气化为溶胶,从而能直接吸入肺部。
在一个实施方式中,用喷雾装置将式I化合物递送到肺部。喷雾器利用(例如)超声波能量形成易于吸入的细小颗粒,从液体药物制剂产生气溶胶。(参见如,Verschoyle等,British J.Cancer,1999,80,增刊2,96,,此文内容纳入本文作参考)。喷雾器的例子包括Sheffield/Systemic Pulmonary Delivery公司提供的设备,(参见Armer等,美国专利5,954,047;van der Linden等,美国专利5,950,619;van der Linden等,美国专利5,970,974,它们的内容纳入本文作参考),Aventis和B atelle Pulmonary Therapeutics公司。
在一个实施方式中,采用电液体力学(“EHD”)气溶胶装置被将式I化合物递送到肺部。EHD气溶胶装置利用电能气雾化液体药物溶液或悬浮液。(参见如,Noakes等的美国专利4,765,539;Coffee的美国专利4,962,885;Coffee的PCT申请WO 94/12285;Coffee的PCT申请WO 94/14543;Coffee的PCT申请WO 95/26234,Coffee的PCT申请WO 95/26235,Coffee的PCT申请WO 95/32807,它们的内容纳入本文作参考)。当用EHD气溶胶装置将式I化合物递送到肺部时,式I化合物的电化学性质是优化的重要参数,这类优化常规由该领域技术人员完成。EHD气溶胶装置比现有的肺递送技术更为有效。式I化合物肺内递送的其他方法是该领域技术人员已知的,属于本发明范围内。
适合用于喷雾器和液体喷雾装置及EHD气溶胶装置的液体药物制剂通常包含式I化合物和药学上可接受的载体。药学上可接受的载体优选是液体,如醇、水、聚乙二醇或全氟化碳。任选加入另一种材料以改变式I化合物溶液或悬浮液的气溶胶性质。该材料优选液体,如醇、二元醇、聚乙二醇或脂肪酸。配制适用于气溶胶装置的液体药物溶液或悬浮液的其他方法是该领域技术人员已知的(参见如Biesalski的美国专利5,112,598;Biesalski的5,556,611,其内容纳入本文作参考)。也可将式I化合物配制成直肠或阴道组合物,如栓剂或保留灌肠液,如含常规栓剂基质,如可可脂或其他甘油类)。
除了上述制剂外,也可将式I化合物配制成可贮存制剂。这类长时间作用的制剂可通过植入(例如皮下或肌肉内植入)给药,或肌肉内注射给药。因此,例如本发明化合物可用合适的聚合或疏水材料(如在可接受油中作为乳剂)或离子交换树脂配制,或作为略溶衍生物,例如作为略溶盐。
或者,可采用其他药物递送系统。脂质体和乳液是可用于递送式I化合物的从所周知的递送运载体例子。也可采用某些有机溶剂如二甲亚砜,但通常要考虑其毒性大的代价。也可在控释系统中递送式I化合物。在一个实施方式中,利用泵(Sefton,CRC Crit.Ref Biomed Eng.,1987,14,201;Buchwald等,Surgery,1980,88,507;Saudek等,N.Engl.J.Med.,1989,321,574)。在另一个实施方式中,利用聚合材料(参见“控释的医学应用(Medical Applications of Controlled Release)”,Langer和Wise(编辑),CRC出版社,Boca Raton,Fla.(1974);“控释药物的生物利用度,药物产品的设计和行为(Controlled Drug Bioavailability,Drug Product Design and Performance)”,Smolen和Ball(编.),Wiley,美国纽约(1984);Ranger和Peppas,J.Macromol.Sci.Rev.Macromol.Chem.,1983,23,61;也参见Levy等,Science,1985,228,190;During等,Ann.Neurol.,1989,25,351;Howard等,J.Neurosurg.,71,105(1989)。在另一个实施方式中,可将控释系统放在本发明化合物的靶子如肺部附近,这样只需要全身剂量的一部分(参见如Goodson,Medical Applications of Controlled Release,同上,第2卷,115页(1984))。也可采用其他的控释系统(参见如,Langer,Science,1990,249,1527)。
合适的赋形剂(如载体和稀释剂)和可用于提供本发明包括的粘膜剂型的其他材料是制药领域技术人员熟知的,取决于给予药物组合物或剂型的具体给药部位或方法。记住该事实,赋形剂通常包括但不限于:水、乙醇、乙二醇、丙二醇、丁-1,3-二醇、豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和它们的混合物,它们是无毒和药学上可接受的。这类添加组分的例子是本领域熟知的。参见如“雷明顿药物科学”,第18版,Mack出版社,美国宾夕法尼亚(1990)。
也可调节药物组合物或剂型的pH,或药物组合物或剂型施加处组织的pH认促进一种或多种活性组分的递送。相似地,可调节溶剂载体的极性、其离子强度或张力以促进递送。也可在药物组合物或剂型中加入例如硬脂酸酯等化合物以利于改变一种或多种活性组分的亲水性或亲脂性。就此而言,硬脂酸酯可用作该制剂的脂质运载体,用作乳化剂或表面活性剂,和用作递送增强剂或渗透增强剂。可采用活性组分的不同盐,水合物或溶剂合物来进一步调节所得组合物的性能。
药盒
本发明提供的药物包装或药盒中,装有一个或多个含有用于治疗或预防丙肝感染的式I化合物的容器。在其它实施方式中,本发明提供的药物包装或药盒中,装有一个或多个含用于治疗或预防丙肝感染的式I化合物的容器,以及装有一个或多个含其他治疗剂的容器,所述的其他治疗药物包括但不限于以上所列的那些药物,特别是抗病毒药物、干扰素、抑制病毒酶的药剂、或抑制病毒复制的药剂,优选的其他治疗药物为对HCV特异的,或显示有抗-HCV活性的药物。
本发明也提供装有一个或多个含含本发明药物组合物一种或多种组分的容器的药物包装或药盒。任选其中装有与这类容器相关的、政府机构对管理制造、使用或出售药品或生物制品所制定的的公告,此公告反映已批准了可给予人的该药物的制造、使用或销售。
可用下文所述的反应途径和合成方案制备本发明化合物,采用了该技术领域已知的通用技术和易于得到的原材料。可通过所属领域技术人员懂得的修饰,例如通过适当地保护干扰性基团,通过改换用其他合适的试剂,或通过对反应条件的常规修改,可成功地实施本发明非示范性化合物的合成。或者,本文描述的一般为现有技术知道的其它反应也可认为对于制备本发明其它化合物具有应用价值。
化合物的制备
以下方案1-4提供了可用于制备式I氘化5,6-二氢-1H-吡啶-2-酮化合物的通用方法。
流程1
如流程1所示,可将顺3-氨基-双环[2.2.1]庚烷-2-羧酸酯(US 2010/0034773A1和PCT WO2008/124450A1)可从相应的1-[卤代(2H2)甲基]-4-氟苯或1-[卤代(2H2)甲基]-4-氟-(2H4)苯转化为氘标记的3-(4-氟-苄基氨基)-双环[2.2.1]庚烷-2-羧酸酯,然后与(7-甲磺酰氨基-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸(US 2010/0034773A1和PCT WO2008/124450A1)形成酰胺并环化转变成最终产物。
流程2
或者,制备氘标记的N-{3-[3-(4-氟-苄基)-6-羟基-4-氧-3-氮杂-三环[6.2.1.02,7]十一碳-5-烯-5-基]-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-7-基}-甲磺酰胺,可通过用氰基溴氘化物还原性胺化起始的顺3-氨基-双环[2.2.1]庚烷-2-羧酸酯和[4-氟苯基](2H)甲醛或[4-氟(2H2)苯基](2H)甲醛而完成(流程2)。如方案1所示,可用(7-甲磺酰基氨基-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸将该氘标记的3-(4-氟-苄基氨基)-双环[2.2.1]庚烷-2-羧酸酯转化为最终产物。
流程3
在另一种典型合成途径(方案3)中,在用氘催化的条件下还原不饱和的顺3-氨基-双环[2.2.1]庚-5-烯-2-羧酸酯(US 2010/0034773A1和PCT WO2008/124450A1)并去保护。在合适的还原胺化条件下,继续将顺3-氨基-(5,6-2H2)-双环[2.2.1]庚烷-2-羧酸酯转化为N-苄基氨基酯。如流程1所述,用(7-甲磺酰基氨基-1,1-二氧代-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸,将氘标记的3-(4-氟-苄基氨基)-双环[2.2.1]庚烷-2-羧酸酯转化成最终产物。
流程4
为了将氘掺入7-甲磺酰基氨基-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸中,可采用流程4所示的合成步骤。在标准的磺酰基氨基形成条件下,从2,5-二氨基苯磺酰胺(US 2010/0034773A1和PCT WO2008/124450A1)和甲烷-2H3-磺酰氯制备2-氨基-5-(2H3)甲磺酰基氨基-苯磺酰胺。在US 2010/0034773A1和PCT WO2008/124450A1所列出的相应未标记的7-甲磺酰基氨基-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸的合成步骤后,使2-氨基-5-(2H3)甲磺酰基氨基-苯磺酰胺转化为7-(2H3)甲磺酰基氨基-1,1-二氧代-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸。采用流程1-3描述的酰胺形成和环化条件,可使7-(2H3)甲磺酰基氨基-1,1-二氧-1,4-二氢-1λ6-苯并[1,2,4]噻二嗪-3-基)-乙酸进一步转化为最终产品。
应当明白,以上描述是示范性和例举性的,意图是说明本发明和其优选的实施方式。通过常规的实验,本领域技术人员知道可在本发明的范围内做出修改和变化。
Claims (16)
2.如权利要求1所述的化合物,其中,R2,R3或R4取代基中至少一个是氘,其余的R取代基是氢。
3.如权利要求1所述的化合物,其中,R12或R13取代基中至少一个是氘,其余的R取代基是氢。
4.如权利要求1所述的化合物,其中,R7,R8,R10,R11,R12,R13取代基中至少一个是氘,其余的R取代基是氢。
5.如权利要求1所述的化合物,其中,R16或R17是氘,R18或R19是氘,其余的R取代基是氢。
6.如权利要求1所述的化合物,其中,R7,R8,R10,R11,R16或R17中的至少一个是氘,R18或R19是氘,其余的R取代基是氢。
7.如权利要求1所述的化合物,其中,R12,R13,R16或R17中的至少一个是氘,R18或R19是氘,其余的R取代基是氢。
8.如权利要求1所述的化合物,其中R7,R8,R10,R11,R12,R13,R16或R17中的至少一个是氘,R18或R19是氘,其余的R取代基是氢。
9.如权利要求1所述的化合物,其中R2,R3,R4,R12和R13取代基中的至少一个是氘,其中剩余的R取代基是氢。
10.如权利要求1所述的化合物,其中,R2,R3,R4,R7,R8,R10,R11,R12和R13取代基中的至少一个是氘,其余的R取代基是氢。
11.如权利要求1所述的化合物,其中,R2,R3,R4,R16或R17中的至少一个是氘,R18或R19是氘,其余的R取代基是氢。
12.如权利要求1所述的化合物,其中,R2,R3,R4,R7,R8,R10,R11,R12,R13,R16或R17中的至少一个是氘,R18或R19是氘,其余的R取代基是氢。
13.一种治疗或预防需要的哺乳动物丙肝病毒感染的方法,包括给予患者有效量的权利要求1所述式I化合物。
14.如权利要求13所述的方法,还包括一种或多种其他治疗剂。
15.如权利要求14所述的方法,其中治疗剂之一是抗病毒药物或免疫调节剂。
16.一种治疗或预防需要的患者丙肝病毒感染的方法,包括给予该患者治疗有效量的权利要求1所述的式I化合物和药学上可接受的赋形剂,载体。
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TW200840572A (en) | 2006-12-12 | 2008-10-16 | Anadys Pharmaceuticals Inc | 5,6-dihydro-1H-pyridin-2-one compounds |
WO2008073987A1 (en) | 2006-12-12 | 2008-06-19 | Anadys Pharmaceuticals, Inc. | Saturated fused [1,2-b] pyridazinone compounds |
US20080188466A1 (en) | 2006-12-21 | 2008-08-07 | Anadys Pharmaceuticals, Inc. | Pyridazinone compounds |
US20080275032A1 (en) | 2006-12-29 | 2008-11-06 | Yuefen Zhou | Pyridazinone compounds |
US20080227774A1 (en) | 2007-03-15 | 2008-09-18 | Frank Ruebsam | 5,5-disubstituted-indolizinone compounds |
UA100120C2 (en) * | 2007-04-03 | 2012-11-26 | Анадис Фармасьютикалз, Инк. | 5,6-dihydro-1h-pyridin-2-one compounds |
US7834009B2 (en) | 2007-08-27 | 2010-11-16 | Anadys Pharmaceuticals, Inc. | 4-hydroxy-5,6-dihydro-1H-pyridin-2-one compounds |
-
2010
- 2010-10-27 RU RU2012121847/04A patent/RU2012121847A/ru unknown
- 2010-10-27 KR KR1020127013646A patent/KR20120092142A/ko not_active Ceased
- 2010-10-27 JP JP2012536997A patent/JP2013509420A/ja active Pending
- 2010-10-27 WO PCT/US2010/054276 patent/WO2011056647A1/en active Application Filing
- 2010-10-27 EP EP10828886.1A patent/EP2493476A4/en not_active Withdrawn
- 2010-10-27 MX MX2012004922A patent/MX2012004922A/es not_active Application Discontinuation
- 2010-10-27 CN CN201080060443XA patent/CN102858344A/zh active Pending
- 2010-10-27 US US13/504,711 patent/US8586578B2/en not_active Expired - Fee Related
- 2010-10-27 BR BR112012009796-2A patent/BR112012009796A2/pt not_active Application Discontinuation
- 2010-10-27 CA CA2778907A patent/CA2778907A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
BR112012009796A2 (pt) | 2020-08-18 |
CA2778907A1 (en) | 2011-05-12 |
US8586578B2 (en) | 2013-11-19 |
MX2012004922A (es) | 2012-05-29 |
WO2011056647A1 (en) | 2011-05-12 |
US20120283251A1 (en) | 2012-11-08 |
JP2013509420A (ja) | 2013-03-14 |
EP2493476A4 (en) | 2013-06-19 |
KR20120092142A (ko) | 2012-08-20 |
RU2012121847A (ru) | 2013-12-10 |
EP2493476A1 (en) | 2012-09-05 |
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