CN103328466A - Hcv ns3蛋白酶抑制剂 - Google Patents
Hcv ns3蛋白酶抑制剂 Download PDFInfo
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- CN103328466A CN103328466A CN2011800638661A CN201180063866A CN103328466A CN 103328466 A CN103328466 A CN 103328466A CN 2011800638661 A CN2011800638661 A CN 2011800638661A CN 201180063866 A CN201180063866 A CN 201180063866A CN 103328466 A CN103328466 A CN 103328466A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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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
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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Abstract
本发明涉及用于在人类患者或其它动物宿主内治疗或预防病毒感染(特别是HCV)的化合物、组合物和方法。
Description
技术领域
本发明涉及作为丙型肝炎病毒(HCV)NS3蛋白酶的抑制剂有用的化合物方法和组合物,所述化合物的合成,和所述化合物用于治疗HCV感染和或降低HCV感染的可能性或症状的严重性的用途。
本申请要求2010年11月1日申请的美国临时申请第61/408,989号的优先权。
背景技术
丙型肝炎病毒(HCV)在全世界范围内已感染超过180,000,000人。估计每年有三百万至四百万人新感染,他们中的70%将发展成慢性肝炎。HCV要为所有肝癌病例的50-76%以及发达世界所有肝脏移植的三分之二负责。标准疗法(聚乙二醇干扰素α加利巴韦林)仅仅在50-60%的患者中是有效的;然而,对它的有效性没有很好的了解并且它与显著的副作用有关。因此,迫切需要新的药物以治疗和/或治愈HCV(1:Chen KX,Njoroge FG.A review of HCV proteaseinhibitors.Curr Opin Investig Drugs.2009 8,821-37;2:Garg G,Kar P.Managementof HCV infection:current issues and future options.Trop Gastroenterol.2009 30,11-8;3:Pereira AA,Jacobson IM.New and experimental therapies for HCV.Nat RevGastroenterol Hepatol.20097,403-11)。
HCV基因组包含被包封在核衣壳和脂质囊膜中的正链RNA并且由9.6kb核糖核苷酸组成,其编码了约3000个氨基酸的大的多肽(Dymock等,AntiviralChemistry&Chemotherapy 2000,11,79)。成熟后,该多肽被切割为至少10个蛋白质。位于NS3蛋白质的N末端结构域的NS3丝氨酸蛋白酶介导了随后在多蛋白中的下游的所有切割事件。由于其作用,所述NS3丝氨酸蛋白酶是一种理想的药物靶标并且在先研究已显示,六肽以及三肽显示出不同程度的抑制性,如在美国专利申请US2005/0020503、US2004/0229818和US2004/00229776中所讨论的。显示抗HCV活性的六环化合物也已在国际专利申请第W020061119061、W02007/015855和W02007/016441号(都是Merck&Co公司)中被公开
用于繁殖HCV的方便的细胞培养模式的缺乏已长时间妨碍发现选择性抑制HCV复制的新的抗病毒策略。随着在1999年复制子系统的确立(Bartenschlager,R.,Nat.Rev.Drug Discov.2002,1,911-916和Bartenschlager,R.,J.Hepatol.2005,43,210-216)和在2005年随着健壮的HCV细胞培养模式的发展(Wakita,T.,等,Nat.Med.2005,11,791-6;Zhong,J.,等,Proc.Natl.Acad.Sci.U.S.A.2005,102,9294-9;Lindenbach,B.D.,等,Science 2005,309,623-6),该障碍已被首先克服。
提供新的抗病毒或化学疗法药剂、包括这些药剂的组合物以及使用这些药剂治疗的方法,特别是要治疗耐药的或突变病毒,是有利的。本发明提供了这样的药剂、组合物和方法。
发明概述
本发明提供了用于在宿主中治疗或预防HCV感染的化合物、方法和组合物。所述化合物具有以下通式:
其中R、J和J1如下文所定义。
所述方法包含施用在治疗上或预防上有效量的至少一种如本文描述的化合物以治疗或预防感染,或者施用足够的量以降低HCV感染的生物活性。所述药物组合物包括与药学上可接受的载体或辅料结合的一种或多种在本文中描述的化合物,用于治疗患有HCV的宿主。所述制剂可进一步包括至少一种其它的治疗剂。此外,本发明包括用于制备所述化合物的工艺。
丙型肝炎复制子需要病毒解旋酶、蛋白酶和聚合酶按顺序起作用以使复制子的复制发生。所述复制子可用于大通量测定中,其评估待筛选活性的化合物是否抑制HCV解旋酶、蛋白酶和/或聚合酶起作用的能力,如通过抑制复制子的复制所证实的。
详细描述
本文中描述的化合物显示抗HCV的抑制活性。因此,所述化合物可用于治疗或预防宿主中的病毒感染,或降低病毒的生物活性。所述宿主可以为HCV感染的哺乳动物,并且特别是人类。所述方法包含施用有效量的一种或多种本文描述的化合物。
还公开了包括与药学上可接受的载体或辅料结合的一种或多种本文描述的化合物的药物制剂。在一个实施方案中,所述制剂包括至少一种本文描述的化合物和至少一种另外的治疗剂。
参照以下定义将更好地理解本发明:
I.定义
术语“独立地”在本文中使用以表明独立应用的变量从应用至应用独立地变化。因此,在化合物例如R”XYR”中,其中R”“独立地”为“碳或氮”,两个R”都可以为碳,两个R”都可以为氮,或者一个R”可以为碳并且另一个R”为氮。
如本文中所使用的,术语“对映异构纯”指包含至少大约95%,并且,优选大约97%、98%、99%或100%的该化合物的单一对映体的化合物组合物。
如本文中所使用的,术语“基本不含”或“基本不存在”指包括至少85-90%重量计,优选95-98%重量计,并且更优选99-100%重量计的该化合物的指定对映体的化合物组合物。在优选实施方案中,本文描述的化合物基本不含对映体。
类似地,术语“分离的(isolated)”指包括至少85-90%重量计,优选95-98%重量计,并且更优选99-100%重量计的该化合物的化合物组合物,余量包含其它的化学种类或对映体。
如本文中所使用的,术语“烷基”,除非另外说明,指的是饱和的直链、支链或环的一级、二级或三级烃,包括取代的和未取代的烷基基团两者。所述烷基基团可任选地由不妨碍反应的或者在工艺中提供改善的任意部分取代,包括但不限于卤素、卤代烷基、羟基、羧基、酰基、芳基、酰氧基、氨基、酰氨基、羧基衍生物、烷基氨基、二烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、巯基、亚胺、磺酰基、硫基(sulfanyl)、亚磺酰基、磺胺基(sulfamonyl)、酯、羧酸、酰胺、膦酰基、氧膦基、磷酰基、膦、硫酯、硫醚、酰卤、酸酐、肟、肼、氨基甲酸酯、膦酸、膦酸酯,未保护的或必要时被保护的,如本领域技术人员已知的,例如,如Greene,等,Protective Groups in Organic Synthesis,John Wiley and Sons,Second Edition,1991中所教导的,其通过引用并入本文。特别包括CF3和CH2CF3。
在文中,不论何时使用术语C(烷基范围),所述术语独立地包括那一类的每个成员,犹如具体并分别陈述。术语“烷基”包括C1-22烷基部分,并且术语“低级烷基”包括C1-6烷基部分。本领域普通技术人员理解,相关烷基原子团通过使用后缀“-基”替换后缀“-烷”命名。
术语“烯基”指不饱和的烃原子团,直链的或支链的,只要(in so much as)它包含一个或多个双键。本文中公开的烯基基团可任选地由不会对反应工艺有不利影响的任意部分取代,包括但不限于对烷基部分上的取代基描述的那些。烯基基团的非限制性的例子包括乙烯、甲基乙烯、异亚丙基、1,2-乙烷-二基、1,1乙烷-二基、1,3-丙烷-二基、1,2-丙烷-二基、1,3-丁烷-二基和1,4-丁烷-二基。
术语“炔基”指不饱和的无环的烃原子团,直链的或支链的,只要它包含一个或多个三键。所述炔基基团可任选地由不会对反应工艺有不利影响的任意基团取代,包括但不限于上文对烷基部分描述的那些。合适的炔基基团的非限制性的例子包括乙炔基、丙炔基、羟基丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、戊炔-2-基、4-甲氧基戊炔-2-基、3-甲基丁炔-1-基、己炔-1-基、己炔-2-基和己炔-3-基、3,3-二甲基丁炔-1-基原子团。
术语“烷基氨基”或“芳基氨基”分别指具有一个或两个烷基或芳基取代基的氨基基团。
术语“被保护”,如在本文中使用并且除非另外定义,指被加入氧、硫、氮或磷原子以防止它进一步反应或用于其它目的的基团。多种氧和氮保护性基团是有机合成领域技术人员已知的,并且被描述在例如Greene等,Protective Groupsin Organic Synthesis,supra中。
术语“芳基”,单独的或组合的,意为包含一个、两个或三个环的碳环芳香体系,其中所述环可以悬挂(pendent)的方式连接在一起或者可以是稠合的(fused)。芳基的非限制性的例子包括苯基、联苯基或萘基,或者从芳环去除氢后残留的其它芳香族基团。术语芳基包括取代的和未取代的部分两种。所述芳基基团可任选地由不会对在本文中描述的用于制备所述化合物的工艺有不利影响的任意部分取代,包括但不限于上文对烷基部分描述的那些。取代的芳基的非限制性的例子包括杂芳基氨基、N-芳基-N-烷基氨基、N-杂芳基氨基-N-烷基氨基、杂芳烷氧基、芳基氨基、芳烷基氨基、芳硫基、单芳基酰氨基磺酰基、芳基磺酰氨基、二芳基酰氨基磺酰基、单芳基酰氨基磺酰基、芳基亚磺酰基、芳基磺酰基、杂芳基芳硫基、杂芳基亚磺酰基、杂芳基磺酰基、芳酰基、杂芳酰基、芳烷酰基、杂芳烷酰基、羟基芳烷基、羟基杂芳烷基、卤代烷氧基烷基、芳基、芳烷基、芳氧基、芳烷氧基、芳氧基烷基、饱和杂环基、部分饱和的杂环基、杂芳基、杂芳氧基、杂芳氧基烷基、芳基烷基、杂芳基烷基、芳基烯基和杂芳基烯基、芳烷氧基羰基(carboaralkoxy)。
术语“烷芳基”或“烷基芳基”指具有芳基取代基的烷基基团。术语“芳烷基”或“芳基烷基”指具有烷基取代基的芳基基团。
如在本文中使用的术语“卤代”包括氯代、溴代、碘代和氟代。
术语“酰基”指羧酸酯,在其中,所述酯基团的非羰基部分选自直链、支链或环烷基或低级烷基、烷氧基烷基(包括但不限于甲氧基甲基)、芳烷基(包括但不限于苄基)、芳氧基烷基(例如苯氧基甲基)、芳基(包括但不限于由卤素(F、Cl、Br、I)、烷基(包括但不限于C1、C2、C3和C4)或烷氧基(包括但不限于C1、C2、C3和C4)任选地取代的苯基)、磺酸酯(例如烷基或芳烷基磺酰基,包括但不限于甲磺酰基)、单、二或三磷酸酯、三苯甲基或单甲氧基三苯甲基、取代的苄基、三烷基甲硅烷基(例如,二甲基叔丁基甲硅烷基)或二苯基甲基甲硅烷基。在所述酯中的芳基基团最优包括苯基基团。术语“低级酰基”指在其中非羰基部分为低级烷基的酰基基团。
术语“烷氧基”和“烷氧基烷基”包括具有烷基部分的直链或支链含氧原子团,例如甲氧基原子团。术语“烷氧基烷基”也包括烷基原子团,所述烷基原子团具有一个或多个与所述烷基原子团连接的烷氧基原子团,即,形成单烷氧基烷基和二烷氧基烷基原子团。所述“烷氧基”原子团可进一步由一个或多个卤素原子(例如氟、氯或溴)取代,以提供“卤代烷氧基”原子团。所述原子团的例子包括氟甲氧基、氯甲氧基、三氟甲氧基、二氟甲氧基、三氟乙氧基、氟乙氧基、四氟乙氧基、五氟乙氧基和氟丙氧基。
术语“烷基氨基”表示分别包含一个或两个与氨基原子团连接的烷基原子团的“单烷基氨基”和“二烷基氨基”。术语芳基氨基表示分别包含一个或两个与氨基原子团连接的芳基原子团的“单芳基氨基”和“二芳基氨基”。术语“芳烷基氨基”包括与氨基原子团连接的芳烷基原子团。术语芳烷基氨基表示分别包含一个或两个与氨基原子团连接的芳烷基原子团的“单芳烷基氨基”和“二芳烷基氨基”。术语芳烷基氨基还表示包含一个芳烷基原子团和与氨基原子团连接的一个烷基原子团的“单芳烷基单烷基氨基”。
如本文中所使用的,术语“杂原子”指氧、硫、氮和磷。
如本文中所使用的,术语“杂芳基”或“杂芳烃基”指在芳香烃环中包括至少一个硫、氧、氮或磷或者在芳香体系中包括两个或多个杂原子(O、S、N、P)的组合。五元和六元环杂芳基都被考虑在本文中,此时五元和六元环连接至苯环,例如苯并呋喃、苯并噻吩、苯并吡咯等。
术语“杂环”、“杂环基”和环杂烷基指非芳香族环基基团,其中在所述环中具有至少一个杂原子,例如氧、硫、氮或磷。
杂芳基和杂环基基团的非限制性的例子包括呋喃基(furyl)、呋喃基(furanyl)、吡啶基、嘧啶基、噻吩基、异噻唑基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、吲哚基、异吲哚基、苯并咪唑基、嘌呤基、咔唑基、恶唑基、噻唑基、异噻唑基、异噻唑基、1,2,4-噻二唑基、异恶唑基、吡咯基、喹唑啉基、噌啉基、酞嗪基、黄嘌呤、次黄嘌呤(hypoxanthinyl)、噻吩、呋喃、吡咯、异吡咯、吡唑、咪唑、1,2,3-三唑、1,2,4-三唑、恶唑、异恶唑、噻唑、异噻唑、嘧啶或哒嗪和蝶啶、氮丙啶、噻唑、异噻唑、1,2,3-恶二唑、噻嗪、吡啶、吡嗪、哌嗪、吡咯烷、oxaziranes、吩嗪、吩噻嗪、吗啉基、吡唑基、哒嗪基、吡嗪基、喹喔啉基、黄嘌呤、次黄嘌呤、喋啶、5-氮杂胞苷基、5-氮杂尿嘧啶基、三唑并吡啶基、咪唑并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、腺嘌呤、N6-烷基嘌呤、N6-苄基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤、N6-炔基嘌呤、N6-酰基嘌呤、N6-羟基烷基嘌呤、N6-烷硫基嘌呤、胸腺嘧啶、胞嘧啶、6-氮杂嘧啶、2-巯基嘧啶、尿嘧啶、N5-烷基嘧啶、N5-苄基嘧啶、N5-卤代嘧啶、N5-乙烯基哌嗪、N5-炔基嘧啶、N5-酰基嘧啶、N5-羟基烷基嘌呤和N6-烷硫基嘌呤以及异恶唑基。如上文对芳基的描述,所述咋芳基基团可任选地被取代。所述杂环基或杂芳基基团可任选地被一种或多种取代基取代,所述取代基选自卤素、卤代烷基、烷基、烷氧基、羟基、羧基衍生物、酰氨基、氨基、烷基氨基、二烷基氨基。如果需要,所述杂芳基可部分或完全氢化。作为非限制性的例子,可使用二氢吡啶代替吡啶。在需要或希望时,在杂环基或杂芳基基团上功能性氧和氮可以是被保护的。合适的保护性基团是本领域技术人员熟知的,并且包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基、三苯甲基或取代的三苯甲基、烷基基团、酰基基团例如乙酰基和丙酰基、甲磺酰基和对甲苯磺酰基。所述杂环基或杂芳基基团可由不会对反应有不利影响的任意部分取代,包括但不限于上文对芳基描述的那些。
如在本文中所使用的,术语“宿主”指病毒可在其中复制的单细胞或多细胞有机体,包括但不限于细胞株和动物,并且优选人类。可选地,所述宿主可携带一部分病毒基因组,其复制或作用可由本发明的化合物改变。术语宿主特别指被感染的细胞,被转染所有或部分病毒基因组的细胞和动物,特别是灵长类(包括但不限于黑猩猩)和人类。在本发明的大多数动物应用中,所述宿主为人类患者。然而,在某些适应症中,本发明也已清楚地考虑了兽医学应用(例如在治疗黑猩猩中的用途)。
术语“肽”指包含两个至一百个氨基酸的多种天然或合成化合物,所述氨基酸通过一个氨基酸的羧基基团至另一个的氨基基团连接。
术语“药学上可接受的盐或前药”在整个说明书中使用,以描述一种化合物的任意药学上可接受的形式,其在向患者施用时,提供了母体化合物。药学上可接受的盐包括衍生自药学上可接受的无机或有机碱和酸的那些。合适的盐包括在药学领域熟知的众多其它酸中衍生自碱金属(例如钾和钠)、碱土金属(例如钙和镁)的那些。药学可接受的前药指在宿主中被新陈代谢(例如被水解或氧化)以形成本发明的化合物的化合物。前药的典型的例子包括在活性化合物的功能性部分上具有生物学上易分解的保护性基团的化合物。前药包括可被氧化、还原、胺化、脱氨基、羟基化、脱羟基、水解、脱水、烷基化、脱烷基、酰化、脱酰基、磷酸化或去磷酸化以生产活性化合物的化合物。本发明的化合物的前药形式可具有抗病毒活性,可被新陈代谢以形成显示所述活性的化合物,或者两者都可以。
II 活性化合物
本文中描述的化合物具有以下通式:
或其药学上可接受的盐或前药,其中
J和J1可存在或不存在,并且当存在时,独立地选自低级烷基(C1-C6)、芳基、芳烷基、烷氧基、芳氧基、杂环基、杂环氧基、酮基、羟基、氨基、芳基氨基、羧基烷基、甲酰氨基(carboxamido)烷基、卤素、氰基、甲酰基、磺酰基或磺酰氨基;并且
R为C1-C10烷基,C3-8环烷基、芳基、杂芳基或杂环基。
III.立体异构和多态性
本文中所述化合物可具有不对称中心并且以外消旋体、外消旋混合物、单个(individual)非对映异构体或对映体的形式出现,本发明中包括所有的同质异构形式。具有手性中心的本发明的化合物可以光学活性或外消旋的形式存在或被分离。许多化合物可显示多态性。本发明包含本发明化合物的外消旋、光学活性、多态或立体异构体形式,或它们的混合物,它们具有本文中描述的有用的性能。所述光学活性形式的制备可通过,例如通过重结晶技术拆分外消旋形式,通过由光学活性原料合成,通过手性合成或通过使用手性固定相层析分离或通过酶法拆分。
所述化合物的光学活性形式可使用本领域已知的任意方法制备,包括但不限于,通过重结晶技术拆分外消旋形式,通过由光学活性原料合成,通过手性合成,或通过使用手性固定相层析分离。
得到光学活性材料的方法的例子包括至少以下所述。
i)晶体的物理分离:一种技术,借此,单一对映体的宏观晶体被手动分离。如果存在分离的对映体的晶体,即,所述材料是成团的,并且所述晶体在视觉上是清楚可见的,那么可使用本技术;
ii)同时结晶:一种技术,借此,单一对映体从外消旋体的溶液中分离结晶,其只有当后者在固体状态是成团的时候才是可能的;
iii)酶拆分:一种技术,借此,借助于对映体与酶反应的不同速率,部分或完全分离外消旋体;
iv)酶不对称合成:一种合成技术,借此,所述合成的至少一步使用酶反应以得到对映异构纯或富集的所需对映体的合成前体;
v)化学不对称合成:一种合成技术,借此,所需对映体在产生产品中的不对称(即,手性)的条件下由非手性前体合成,其可使用手性催化剂或手性助剂实现;
vi)非对映体分离:一种技术,借此,外消旋化合物与对映异构纯的试剂(所述手性助剂)反应,将单一对映体转化为非对映体。然后借助于它们现在更加明显的结构区别通过色谱法或结晶分离所得到的非对映体并且随后去除所述手性助剂以得到所需对映体;
vii)第一和第二级不对称转化:一种技术,借此,使来自于外消旋体的非对映体平衡,以在来自于所需对映体的非对映体溶液中占多数,或者其中来自于所需对映体的非对映体的优先结晶扰乱所述平衡,使得最终基本上所有材料转化为来自于所需对映体的结晶的非对映体。随后,所需对映体从所述非对映体释放;
viii)动力学拆分:该技术是指借助于对映体与手性、非外消旋试剂或者催化剂在动力学条件下不同的反应速率,实现将外消旋体部分或者完全拆分(或者将部分拆分的化合物进一步拆分);
ix)由非外消旋前体对映异构合成:一种合成技术,借此,从非手性原料得到所需对映异构体并且在合成过程中立体化学的完整性没有或者只是略微受到影响;
x)手性液相色谱法:一种技术,借此,在液体流动相中借助于外消旋体的对映异构体与固定相相互作用不同而将其分离(包括但不限于通过手性HPLC)。固定相可由手性材料制成,或者流动相可包含另外的手性试剂,以获得所述不同的相互作用;
xi)手性气相色谱法:一种技术,借此,外消旋体挥发并且借助于它们在气态流动相中与含有固定的非外消旋手性吸附相的柱相互作用的不同而将对映异构体分离;
xii)使用手性溶剂萃取:借助于一种对映异构体优先溶解于特定的手性溶剂中而分离对映异构体;
xiii)透过手性膜传输:一种技术,借此,放置外消旋体与薄膜屏障直接接触。在该方法中将外消旋体与薄膜屏障直接接触。该屏障典型地分离两种可混溶的流体,一种包含所述外消旋体,并且驱动力(例如浓度或压力差异)引起透过所述膜屏障的优先传输。只允许外消旋体中的一种对映体通过的膜的非外消旋手性特性,造成了分离的发生。
将手性色谱法(包括但不限于模拟移动床色谱法)用于一个实施方案中。所中手性固定相可通过市售得到。
IV.化合物盐或前药制剂
在化合物具有足够的碱性或酸性以形成稳定的无毒的酸或碱盐的情况下,作为药学上可接受的盐的化合物的施用可能是适当的。药学上可接受的盐的例子为酸形成的有机酸加成盐,所述酸形成药学上可接受的阴离子,例如,甲苯磺酸酯、甲磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸和α-磷酸甘油。也可形成合适的无机盐,包括但不限于,硫酸盐、硝酸盐、碳酸盐和碳酸氢盐。
药学上可接受的盐可使用本领域熟知的标准程序得到,例如,通过使足够碱性的化合物例如胺与合适的酸反应,提供一种药学上可接受的阴离子。也可制造羧酸的碱金属(例如,钠、钾或锂)或碱土金属(例如,钙、镁)盐。
V.治疗方法
感染HCV或其基因片段的宿主(包括但不限于人类)可通过在药学上可接受的载体或稀释剂存在下将有效量的活性化合物或其药学上可接受的前药或盐施用至患者来治疗。可通过任意合适的路径施用所述活性材料,例如,以液体或固体形式,口服施用、非肠道施用、静脉施用、皮内施用、皮下施用或局部施用。
VI.组合或可选疗法
在一个实施方案中,本发明的化合物可与至少一种其它的抗病毒剂一起应用。
被批准的或在临床前和临床研究中的抗HCV化合物的表
VII.药物组合物
感染丙型肝炎病毒(“HCV”)或其基因片段的宿主(包括但不限于人类)可通过在药学上可接受的载体或稀释剂存在下将有效量的活性化合物或其药学上可接受的前药或盐施用至患者来治疗。可通过任意合适的路径施用所述活性材料,例如,以液体或固体形式,口服施用、非肠道施用、静脉施用、皮内施用、皮下施用或局部施用。
所述化合物的优选剂量在每天约0.1和约100mg/kg受体体重之间,更一般地约1和50mg/kg受体体重之间,并且优选地约1和约20mg/kg受体体重之间的范围内。所述药学上可接受的盐和前药的有效剂量范围可基于待给药的母体化合物的重量来计算。如果所述盐或前药本身显示出有效性,那么,所述有效剂量可如上文使用所述盐或前药的重量估算,或者通过本领域技术人员已知的其它方法估算。
所述化合物以单位任意合适的剂型方便地施用,包括但不限于,包含7至3,000mg,优选70至1400mg活性成分每单位剂型的一种。50至1,000mg的口服剂量通常是方便的。
理想地,应当施用所述活性成分以实现约0.2至70μM,优选约1.0至15μM的所述活性化合物的峰值血浆浓度。这可通过以下方式实现,例如通过静脉注射所述活性成分的0.1至5%溶液(任选地,在盐水中),或者作为所述活性成分的丸剂施用。
在所述药物组合物中活性化合物的浓度将取决于所述药物的吸收、失活和排泄速率以及本领域技术人员已知的其它因素。应当注意的是剂量值也随着待缓和的病况的严重性变化。还应理解的是对于任意特殊的受试者,应当随着时间根据个体需要以及施用或监督所述组合物的施用的人员的专业判断来调整具体的剂量方案,并且本文中阐明的浓度范围仅仅是示例性的并且不是意在限制所要求的组合物的范围或实践。所述活性成分被一次施用,或可分成数个更小的剂量以不同的时间间隔施用。
所述活性化合物的优选的施用方式为口服。口服组合物将通常包括惰性稀释剂或可食用载体。它们可封闭在明胶胶囊内或压缩在片剂内。为了口服治疗施用的目的,所述活性化合物可掺入赋形剂并且以片剂、锭剂或胶囊的形式使用。药学上可相容的粘结剂和/或佐剂(adjuvant)材料可作为所述组合物的一部分被包括。
所述片剂、丸剂、胶囊剂、锭剂等等可包含任意以下成分或具有相似性质的化合物:粘结剂,例如微晶纤维素、黄蓍树胶或明胶;辅料,例如淀粉或乳糖,崩解剂,例如藻酸,Primogel或玉米淀粉润滑剂,例如硬脂酸镁或Sterotes;助流剂,例如胶态二氧化硅;甜味剂,例如蔗糖或糖精(sweetener);或调味剂,例如such as薄荷、水杨酸甲酯或橙味剂。当剂量单位形式为胶囊时,除了上述类型的材料外,它可包含液体载体,例如脂肪油。此外,单位剂型可包含改变所述剂量单位的物理形态的多种其它的材料,例如,包含糖、虫胶或其它肠溶制剂的涂层。
所述化合物可作为酏剂,混悬液、糖浆、圆片(wafer)、口香糖等等的一种组分施用。除了所述活性化合物(一种或多种)外,糖浆可包含作为甜味剂的蔗糖或糖精(sweetener)以及某些防腐剂、染料和着色剂以及香料。
所述化合物或其药学上可接受的前药或盐还可与不损害所需作用的其它活性材料混合,或与增补所需作用的材料混合,例如抗生素、抗真菌剂、抗炎药或其它抗病毒剂,包括但不限于,核苷化合物。用于肠胃外、真皮内、皮下或局部应用的溶液或混悬液可包括以下组分无菌稀释剂例如注射用水、盐溶液、固定油、聚乙二醇、甘油、丙二醇或其它合成的溶剂;抗菌剂,例如,苄醇或羟苯甲酸甲酯;抗氧化剂,例如,抗坏血酸或亚硫酸氢钠;螯合剂,例如,乙二胺四乙酸;缓冲剂,例如,乙酸盐、柠檬酸盐或磷酸盐,以及用于调节张力的试剂,例如,氯化钠或葡萄糖。所述母本制剂(parental preparation)可被封闭在玻璃或塑料制成的安瓶、一次性注射器或多剂量小瓶中。
如果静脉注射施用,优选的载体为生理盐水或磷酸盐缓冲盐水(PBS)。
在一个优选的实施方案中,使用载体制备活性化合物,所述载体将保护所述化合物免于从身体快速消除,例如控释制剂,包括但不限于,埋植和微胶囊化给药系统。可使用可生物降解的、生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。例如,肠溶涂层的化合物可用于保护胃酸造成的裂解。用于制备所述制剂的方法对于本领域的技术人员将是明显的。合适的材料可通过市售得到。
脂质体混悬液(包括但不限于靶向对病毒抗原具有单克隆抗体的被感染细胞的脂质体)也可优选作为药学上可接受的载体。这些可根据本领域技术人员已知的方法制备,例如,如美国专利第4,522,811号(通过引用并入)中所描述的。例如,脂质体制剂可通过以下步骤制备:将一种或多种合适的脂质(例如硬脂酰磷脂酰乙醇胺,硬脂酰磷脂酰胆碱,花生酰(arachadoyl)磷脂酰胆碱,和胆固醇)溶解在无机溶剂中,随后将所述无机溶剂蒸发,在容器的表面上遗留下干燥的脂质薄膜。然后将所述活性化合物的水性溶液引入至所述容器中。然后用手搅动所述容器,以从所述容器的各面释放脂质材料并且分散脂质聚集体,因此形成脂质体混悬液。
用于描述本发明的术语是通常使用的并且是本领域技术人员已知的。如在本文中所使用的,以下缩写词具有所表明的含义:
IX.制备活性化合物的一般程序
用于制备本发明的化合物的方法可如以下“具体实施例”部分中详细描述的来准备,或通过本领域技术人员已知的其它方法准备。一个本领域的普通技术人员将理解,这些方案绝不是限制性的并且可进行许多细节的变化,而不脱离本发明的精神和范围。
具体实施例
代表本发明的具体化合物按照以下实施例和反应顺序制备;描绘反应顺序的实施例和图表通过举例说明的方式提供,以帮助理解本发明,并且不应当被解释为以任意方式限制随后所附的权利要求书中陈述的发明。本化合物也卡在随后的实施例中被用作中间体,以生成本发明的其它化合物。已没有必要做出尝试以优化在任意反应中得到的收率。本领域技术人员将知道如何通过常规变化反应时间、温度、溶剂和/或试剂来提高所述收率。
试剂和溶剂可从商业供应商得到并且使用而无需进一步纯化。二氯甲烷通过CaCl2干燥并蒸馏并且在氩气下通过分子筛存储。四氢呋喃在氩气下通过纳/二苯甲酮干燥并且在使用前蒸馏。闪式层析纯化(Flash chromatographypurifications)在作为固定相的Macherey Nalgel硅胶柱(40-63μM)上进行或者使用填充的RediSep柱在Teledyne Isco CombiflashCompanion仪上进行。分析的高效液相色谱-质谱分析(HPLC-MS):HPLC-MS条件A1:HPLS-MS在装备有光电二极管阵列检测器Waters 996和Waters Micromass Q-Tof的Waters Alliance 2790仪上使用BDS Hypersil 50x2.1,3μm进行。洗脱条件包含线性梯度:在20分钟内0%-80%的MeCN/H2O(在正离子模式中包含0.1%TFA并且在负离子模式中不含TFA),流速0.2mL/min。HPLC-MS条件A2:HPLS-MS在装备有光电二极管阵列检测器Waters 996和Waters Micromass Q-Tof的Waters Alliance 2790仪上使用Nucleodur C18 Pyramid50x2.1,3μm进行。洗脱条件包含线性梯度:在20分钟内0%-80%的MeCN/H2O(在正离子模式中包含0.1%TFA并且在负离子模式中不含TFA),流速0.3mL/min。
HPLC-MS条件B:HPLS-MS在装备有光电二极管阵列检测器Agilent G1315A、polymerlabs ELS2100(DEDL)检测器和用于质谱分析的Agilent Simple Quad ESI的Agilent HP-1100仪上使用Agilent Zorbax XDB-C18 RP C18 45x4.6,3.5μm进行。洗脱条件包含线性梯度:在4.5分钟内10%-100%的MeCN/H2O(包含0.05%TFA),流速1.5mL/min。
低分辨率质谱(MS)由应用生物系统公司SCIEX 3200QTRAP在大气压电离条件(API)下在正(ES+)或负(ES-)模式得到。
高分辨率质谱(HRMS)由珀金埃尔默仪器得到。
在氘化的溶剂中在250MHz1H和63MHz13C NMR在BrukerAvance 250上记录NMR谱图并且其相对于溶剂残留峰以ppm计(referenced in ppm)(见参考文献Gottlieb H.E.等.J.Org Chem 1997(2)7512-7515)。
实施例1
P2羟基脯氨酸衍生物的合成:
方案1:P2羟基脯氨酸衍生物的化学路径
实施例2
10的合成:
方案2:10的合成路径
可制备化合物10的类似物(在其中J和J1存在),例如,通过使用原料的取代形式:
其中J和J1如在本文中所定义的,或者,当这些部分将妨碍在方案I中描述的偶联化学过程时,是被保护的基团,所述被保护的基团可在所述偶联化学过程完成之后或在整体合成中的末期步骤转化成为所需J和J1部分。
该式的化合物是已知的,并且可仅仅使用常规实验制备。本领域技术人员将容易理解,取代基至所述芳环上的结合可很容易地实现,或者在制备核心结构之前,或者在之后,即,在关键的偶联步骤过程中可存在所述取代基,或者可在已制备未被取代的化合物(即,不具有所述J和/或J1部分)之后添加所述取代基。所述取代基可提供在它们自身内和它们自身的有用的性能,或者用作进一步合成精制用的柄(handle)。一个附加条件是,所述取代基或者应当在所述合成条件下可以存在,或者否则应当在所述合成完成之后添加。
例如,所述芳环可以是使用各种已知的程序卤化的,所述程序根据具体的卤素而变化。合适的试剂的例子包括溶于浓缩的HBr的溴/水、氯化亚砜、pyr-ICL、氟和大孔树脂-A。在芳环的被重氮化的位置中具有取代基的众多其它类似物可由相应的苯胺化合物通过重氮盐中间体合成。所述重氮盐中间体可使用已知的化学过程制备,例如,在矿物酸存在下用亚硝酸钠处理芳香胺例如苯胺。
重氮盐可由苯胺形成,反过来所述苯胺可由硝基苯制备(并且类似的胺取代的杂芳环可由硝基取代的杂芳环制备)。可通过与亚硝酸盐反应将硝基衍生物还原为胺类化合物,典型地在酸存在下。其它被取代的类似物可使用本领域技术人员已知的一般技术由重氮盐中间体(包括,但不限于,羟基、烷氧基、氟、氯、碘、氰基和巯基)生产。同样地,烷氧基类似物可通过使重氮盐与醇类反应制成。所述重氮盐也可用于合成氰基或卤代化合物,如本领域技术人员将要知道的。巯基取代基可使用在Hoffman等,J.Med.Chem.36:953(1993)中描述的技术得到。这样生成的硫醇可转而通过与氢化钠和合适的烷基溴反应被转化成为烷硫基(alkylthio)取代基。然后随后的氧化将提供砜。上述化合物的酰胺类似物可通过使用有机合成领域的技术人员已知的技术使相应的氨基化合物与合适的酸酐或酰基氯反应制备。
羟基取代的类似物可用于通过与合适的酸、酰基氯或酸酐反应制备相应的烷酰氧基取代的化合物。同样地,所述羟基化合物是芳氧基和杂芳氧基两者通过在缺电子芳香环上的亲核芳香取代的前体。该化学过程是有机合成领域技术人员熟知的。醚类衍生物也可通过使用卤代烃和合适的碱烷化或通过通常使用三烷基或三芳基膦和偶氮二羧酸二乙酯的Mitsunobu化学过程由羟基化合物制备。参见Hughes,Org.React.(N.Y.)42:335(1992)和Hughes,Org.Prep.Proced.Int.28:127(1996)for typical Mitsunobu conditions。
可使氰基取代的类似物水解,以提供相应的甲酰胺基取代的化合物。进一步的水解导致形成了相应的羧酸取代的类似物。用氢化铝锂还原氰基取代的类似物产生了相应的氨甲基类似物。酰基取代的类似物可通过使用有机合成领域技术人员已知的技术与合适的烷基锂反应由相应的羧酸取代的类似物制备。
羧酸取代的类似物可通过与合适的醇和酸催化剂反应转化成为相应的酯。可使用硼氢化钠或氢化铝锂还原具有酯基的化合物,以生产相应的羟甲基取代的类似物。这些类似物反过来可通过使用常规技术与氢化钠和合适的卤代烷反应转化成为具有酯部分的化合物。可选地,所述羟甲基取代的类似物可与对甲苯磺酰氯反应,以提供相应的对甲苯磺酰氧甲基类似物,其可通过用亚硫酰氯和合适的烷基胺顺序处理转化成为相应的烷基氨酰基类似物。已知这些酰胺中的某些可很容易地经受亲核酰基取代以生产酮类。
羟基取代的类似物可用于通过与N-烷基-或N-芳基异氰酸酯反应制备N-烷基-或N-芳氨基甲酰氧基取代的化合物。氨基取代的类似物可通过使用有机合成领域技术人员已知的技术分别与氯甲酸烷基酯和N-烷基或-N-芳基异氰酸酯反应用于制备烷氧基甲酰胺基取代的化合物和尿素衍生物。
类似地,苯环可使用已知的化学过程取代,包括上文讨论的反应。例如,在硝基苯上的硝基基团可与亚硝酸钠反应以形成重氮盐,并且如上文所讨论操作所述重氮盐以在苯环上形成各种取代基。
上述取代基可因此被添加至起始苯环上,并且被掺入本文中描述的最终化合物中。
实施例3
HepG2细胞中线粒体毒性测定:
i)化合物对细胞互长和乳酸生产的影响:对HepG2细胞生长的影响通过在0μM、0.1μM、1μM、10μM和100μM药物存在下培养孵育细胞测定。将细胞(每孔5x104)置于最小必需培养基中的12孔细胞培养簇中并且在37℃培养4天,所述最小必需培养基具有补充了10%胎牛血清、1%丙酮酸钠、1%青霉素/链霉素的非必需氨基酸。在所述孵育期的最后,使用血细胞计测定细胞数目。也由Pan-Zhou X-R,Cui L,Zhou X-J,Sommadossi J-P,Darley-Usmer VM.″Differential effects of antiretroviral nucleoside analogs on mitochondrial function inHepG2 cells″Antimicrob.Agents Chemother.2000;44:496-503教导。为了测量化合物对乳酸生产的影响,将来自于原种培养(stock culture)的HepG2细胞稀释并以每孔2.5x104个细胞置于12孔培养板中。添加多种浓度(0μM、0.1μM、1μM、10μM和100μM)的测试化合物,将所述培养物在37℃在潮湿的5%CO2大气中孵育4天。在第4天测定每个孔中的细胞数目并且收集培养基。将所述培养基过滤并使用比色乳酸分析法(Sigma-Aldrich)测定所述培养基中的乳酸含量。由于乳酸产品可被看做是线粒体功能受损的标记,因此在测试化合物存在下在细胞生长中检测到的提高的乳酸生产水平将表明药物诱导的细胞毒性效应。
ii)化合物对线粒体DNA合成的影响:已进行实时PCR测定以精确定量线粒体DNA含量(参见Stuyver LJ,Lostia S,Adams M,Mathew JS,Pai BS,Grier J,Tharnish PM,Choi Y,Chong Y,Choo H,Chu CK,Otto MJ,Schinazi RF.Antiviralactivities and cellular toxicities of modified 2′,3′-dideoxy-2′,3′-didehydrocytidineanalogs.Antimicrob.Agents Chemother.2002;46:3854-60)。该测定被用于在本申请中描述的所有研究中,其测定了测试化合物对线粒体DNA含量的影响。在这一测定中,以5,000细胞/孔将第低传代数(low-passage-number)HepG2细胞接种于胶原蛋白包被的96孔板中。将化合物添加至所述培养基以得到0μM、0.1μM、10μM和100μM的最终浓度。在第7个培养日,通过使用可通过市售得到的柱(RNeasy 96试剂盒;Qiagen)制备细胞核酸。这些试剂盒共纯化RNA和DNA,并且因此,将全部的核酸从所述柱中洗脱。使用多重Q-PCR程序以及对于靶及参照物扩增(reference amplifications)都合适的引物和探针,从5μl洗脱的核酸扩增线粒体细胞色素c氧化酶亚基II(COXII)基因和β-肌动蛋白或rRNA基因。对于COXII,分别使用以下的有义、探针和反义引物:5′-TGCCCGCCATCATCCTA-3′,5′-四氯-6-羧基荧光素-TCCTCATCGCCCTCCCATCCC-TAMRA-3′和5′-CGTCTGTTATGTAAAGGATGCGT-3′。对于β-肌动蛋白基因(基因库登录号E01094)的外显子3,所述有义、探针和反义引物分别为5′-GCGCGGCTACAGCTTCA-3′,5′-6-FAMCACCACGGCCGAGCGGGATAMRA-3′和5′-TCTCCTTAATGTCACGCACGAT-3′。用于rRNA基因的引物和探针可从应用生物系统公司市售得到。由于得到了对于所有基因相等的扩增效率,使用竞争性CT法研究线粒体DNA合成的可能的抑制。所述竞争性CT法使用计算公式,在其中,将靶(COXII基因)的量对内源参考(endogenous reference)(β肌动蛋白或rRNA基因)的量标准化是相对于校准器(在第7天没有药物的一个参照)的。用于本方法的计算公式由2-ΔΔCT给出,其中所述ΔΔCT为(平均靶测试样品的CT-目标对照的CT)-(平均参照测试的CT-参照物对照的CT)(参见Johnson MR,K Wang,JB Smith,MJ Heslin,RB Diasio.Quantitation ofdihydropyrimidine dehydrogenase expression by real-time reverse transcriptionpolymerase chain reaction.Anal.Biochem.2000;278:175-184)。在药物存在下生长的细胞中线粒体DNA含量的减少将表明线粒体毒性。
iii)电子显微形态学评价:NRTI诱导的毒性已经显示会造成线粒体中的形态学变化(例如,嵴丧失、基质溶解和溶胀以及脂滴形成),其可使用透射电子显微镜观察分析超微结构(参见Cui L,Schinazi RF,Gosselin G,Imbach JL.Chu CK,Rando RF,Revankar GR,Sommadossi JP.Effect of enantiomeric and racemicnucleoside analogs on mitochondrial functions in HepG2 cells.Biochem.Pharmacol.1996,52,1577-1584;Lewis W,Levine ES,Griniuviene B,Tankersley KO,ColacinoJM,Sommadossi JP,Watanabe KA,Perrino FW.Fialuridine and its metabolitesinhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation,decrease mtDNA abundance,and cause mitochondrial structural defects in culturedhepatoblasts.Proc Natl Acad Sci U S A.1996;93:3592-7;Pan-Zhou XR,L Cui,XJZhou,JP Sommadossi,VM Darley-Usmar.Differential effects of antiretroviralnucleoside analogs on mitochondrial function in HepG2 cells.Antimicrob.AgentsChemother.2000,44,496-503)。例如,与10μM非阿尿苷(FIAU;1,2′-脱氧-2′-氟-1-D-阿拉伯呋喃糖基-5-碘-尿嘧啶)一起孵育的HepG2细胞的电子显微图显示了增大的线粒体的存在,所述线粒体具有与线粒体功能障碍相一致的形态学变化。为了确定化合物是否促进线粒体中的形态学变化,将HepG2细胞(2.5×104个细胞/mL)在0μM、0.1μM、1μM、10μM和100μM测试化合物存在时接种至组织培养皿(35×10mm)中。在第8天,固定细胞,脱水,并包埋入之前描述的Eponas中。制备薄切片,用乙酸双氧铀和柠檬酸铅着色,并且然后使用透射电子显微镜检查。
实施例4
骨髓细胞毒性分析
从Cambrex Bioscience(Walkersville,MD)市售得到原代人骨髓单核细胞。使用双层软琼脂,在有50单位/mL人重组粒细胞/巨噬细胞集落刺激因子存在下,进行CFU-GM测定,同时BFU-E测定使用含有1单位/mL红细胞生成素的甲基纤维素基质(参见Sommadossi JP,Carlisle R.Toxicity of 3’-azido-3’-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal humanhepatopoietic progenitor cells in vitro.Antimicrob.Agents Chemother.1987;31:452-454;Sommadossi,JP,Schinazi,RF,Chu,CK,and Xie,MY.Comparison ofCytotoxicity of the(-)and(+)enantiomer of 2’,3’-dideoxy-3’-thiacytidine in normalhuman bone marrow progenitor cells.Biochem.Pharmacol.1992;44:1921-1925)。在来自3个不同供体的细胞中,一式两份地进行每个实验。AZT用作阳性对照。在化合物存在下,在37℃、5%CO2下孵育细胞14-18天,并使用倒置显微镜计数大于50个细胞的集落以测定IC50。通过药物浓度的对数相对于BFU-E存活分数的最小二乘法线性回归分析得到50%抑制浓度(IC50)。使用独立的未配对样品的学生t检验进行统计分析。
实施例5
细胞毒性分析
如以前所述(参见Schinazi R.F.,Sommadossi J.-P.,Saalmann V.,Cannon D.L.,Xie M.-Y.,Hart G.C.,Smith G.A.&Hahn E.F.Antimicrob.Agents Chemorger.1990,34,1061-67),可以在Vero、人PBM、CEM(人类淋巴母细胞)、MT-2和HepG2细胞中测定化合物的毒性。包括作为阳性细胞毒性对照的环己酰亚胺,并包括接触溶剂的未处理细胞作为阴性对照。使用前述半数有效方法(参见ChouT.-C.&Talalay P.Adv.Enzyme Regul.1984,22,27-55;Belen’kii M.S.&SchinaziR.F.Antiviral Res.1994,25,1-11)从浓度-反应曲线得到细胞毒性IC50。
10的数据为
PBM>100μM(17%抑制100μM)
CEM>100μM(11%抑制100μM)
VERO>100(-0.8%抑制100μM)
实施例6
HCV复制子分析1
将含有HCV复制子RNA的Huh7克隆B细胞以5000个细胞/孔接种至96孔板中,并且在接种后立即在10μM一式三份地测试化合物。孵育(37℃,5%CO2)5天后,通过使用来自Gentra的versaGene RNA纯化试剂盒分离总细胞RNA。在单步多重实时RT-PCR测定中扩增复制子RNA和内部对照(TaqManrRNA对照试剂,Applied Biosystems)。通过从无药物对照的阈值RT-PCR循环中减去测试化合物的阈值RT-PCR循环(ΔCtHCV)计算化合物的抗病毒有效性。3.3的ΔCt等于在复制子RNA水平的1-log减少(等于少于原料90%)。还通过使用ΔCt rRNA值计算化合物的细胞毒性。(2′-Me-C)用作对照。为了测定EC90和IC50值2,首先将ΔCt:值转化成原料的分数3,并且然后用于计算%抑制。
参考文献:
1.Stuyver L等,Ribonucleoside analogue that blocks replication or bovine viraldiarrhea and hepatitis C viruses in culture.Antimicrob.Agents Chemother.2003,47,244-254.
2.Reed IJ&Muench H,A simple method or estimating fifty percent endpoints.Am.J.Hyg.27:497,1938.
3.Applied Biosystems Handbook
结果显示在下表1中:
表1
化合物 | Conc(μM) | DCt HCV | DCt rRNA | HCV | rRNA | EC50 | EC90 | CC50 |
10 | 0.01 | 1.16 | -0.21 | 54.99 | -15.99 | 0.01 | 0.03 | >0.3 |
0.03 | 3.29 | -0.49 | 89.67 | -40.10 | ||||
0.1 | 6.05 | -0.09 | 98.47 | -6.27 | ||||
0.3 | 8.72 | 0.14 | 99.76 | 9.35 | ||||
实施例7
在食蟹猴体内的生物利用度测定
下述程序可以用于测定化合物是否是生物可利用的。在研究开始之前1周内,可以通过外科手术给食蟹猴植入长期静脉导管和皮下静脉访问口(VAP)以便于血液收集,且可以经历体格检查,所述体格检查包括血液学和血清化学评价和体重记录。每只猴(共6只)接受2-20mg/kg剂量水平的化合物,通过静脉内推注(3只猴,IV)或者通过经口腔管饲法(3只猴,PO)。在给药之前称量每个给药注射器以根据重量确定施用的制剂的量。在指定的间隔(给药前大约18-0小时,给药后0-4、4-8和8-12小时),通过收集盘(pan catch)收集尿样,并处理。通过长期静脉导管和VAP或从末梢血管(如果长期静脉导管操作应当不可能的话),同样收集血样(给药前,给药后0.25、0.5、1、2、3、6、8、12和24小时)。分析血样和尿样的最大浓度(Cmax)、达到最大浓度时的时间(TmaX)、曲线下面积(AUC)、剂量浓度的半衰期(TV)、清除率(CL)、稳态体积和分布(Vss)和生物利用度(F)。
实施例8
HCV蛋白酶抑制剂对选定的人类蛋白酶的影响
HCV蛋白酶抑制剂已证明除了与宿主蛋白酶的抑制相关的令人关注的毒性外很好的抗病毒效能。为了避免类似的毒性,评估了新的蛋白酶抑制剂对一批重要的人类蛋白酶的抑制。所测试的酶为弹性蛋白酶(中性粒细胞)、血纤维蛋白溶酶、凝血酶和组织蛋白酶S。
中性白细胞弹性蛋白酶(或白细胞弹性蛋白酶),又称为ELA2(弹性蛋白酶2),是与胰凝乳蛋白酶相同种类的丝氨酸蛋白酶并且具有广泛的底物专一性。由中性粒细胞在炎症过程中分泌,它的主要作用之一是破坏宿主组织内的细菌。(Belaaouaj等,Science 289(5482):1185-8)。
纤溶酶是一种丝氨酸蛋白酶,其在血浆中通过纤溶酶原活化剂衍生自纤溶酶原的转化而来(Collen,D.Circulation,93,857(1996))。该酶(EC 3.4.21.7)降解许多血浆蛋白,最显著地为纤维蛋白凝块。纤溶酶还与许多病理学和生理学过程例如炎症、肿瘤、新陈代谢、伤口愈合、血管生成、胚胎发育和排卵相关(Vassalli,J.D等,J.Clin.Invest.88,1067(1991).
凝血酶是血流中的一种凝固蛋白质,其在凝固级联中具有许多作用,是凝血级联中最后的酶。它是一种丝氨酸蛋白酶,其将可溶纤维蛋白原转化成为不可溶的纤维蛋白丝,还催化许多其它的凝固相关的反应。
组织蛋白酶S,肽酶C1家族的一员,是一种溶酶体半胱氨酸蛋白酶,其可参与将抗原蛋白降解为在MHC类II分子上递呈的肽,因此它是免疫响应的关键。编码蛋白可在广泛的pH范围内作为弹性蛋白酶起作用。
材料:
●Victor 3酶标仪(Perkin Elmer)
●透明的96孔板(Phenix Research)
●黑色96孔板(Perkin Elmer)
●核糖核酸酶和脱氧核糖核酸酶纯水
方法:
弹性蛋白酶(人嗜中性粒细胞(Cat#16-14-051200 Athens Research andTechnology,Athens GA)):反应以每孔100μL的样品体积在透明的96孔板中进行。制成包含200mM Tris-HCl(pH 7.5)、150mM NaCl和50%丙三醇的2X测定缓冲液。对于每个样品,将50μL 2X测定缓冲液添加至每个孔中。添加底物(MeOSuc-AAPV-pNA,显色底物,Cat#P-213,Enzo Life Sciences,PlymouthMeeting,PA;在DMSO中的50mM原种)至1mM的最终浓度。在水中以4x的浓度添加(25μL)药物稀释物。最后,制成对于每个样品具有1μL弹性蛋白酶和22μL水的混合物并且将23μL添加至每个孔。在室温下孵育样品30min。在Victor 3酶标仪上读取405nM的吸光度。一式两份地测试所有的样品。结果显示为空白调整的(无弹性蛋白酶)最大吸光度的百分比,其由无抑制剂对照给出。
纤溶酶和凝血酶(Sensolyte RH110纤溶酶活性测定试剂盒和Sensolyte凝血酶活性测定试剂盒(Anaspec)):反应以每孔100μL的样品体积在黑色的96孔板中进行。遵照来自于试剂盒说明书的规程A,其中用去离子水1∶1稀释2X测定缓冲液。每个测定包括阳性对照(被稀释的酶并且无测试化合物)、抑制剂对照(包含被稀释的酶和纤溶酶抑制剂;来自于试剂盒的组分E或凝血酶抑制剂;N-α-NAPAP合成抑制剂)和底物对照(测定缓冲液和底物)。还进行媒介物和自体荧光对照。在测定缓冲液中以10x的浓度添加(10μL)药物稀释物。以0.25μg/mL(纤溶酶)和1μg/mL(凝血酶)的浓度以40μL/孔将酶添加至除了底物对照之外的所有孔。最后,将包含底物的50μL测定缓冲液添加至每个孔。添加底物至50nM(纤溶酶)或20nM(凝血酶)的最终浓度。在室温下孵育样品30min。在Victor 3酶标仪上在Ex/Em=490nm/520nm读取荧光强度。一式两份地测试所有的样品。结果显示为底物对照调整的最大吸光度的百分比,其由阳性对照给出。
组织蛋白酶S(Sensolyte组织蛋白酶S活性测定试剂盒(Anaspec)):反应以每孔100μL的样品体积在黑色的96孔板中进行。遵照来自于试剂盒说明书的规程A,其中将DTT添加至测定缓冲液中以产生5μM的浓度。每个测定包括阳性对照(被稀释的酶并且无测试化合物)、抑制剂对照(包含被稀释的酶和纤溶酶抑制剂;组分E或凝血酶抑制剂;N-α-NAPAP合成抑制剂)和底物对照(测定缓冲液和底物)。还进行媒介物和自体荧光对照。在测定缓冲液中以10x的浓度添加(10μL)药物稀释物。以2.5μg/mL的浓度以40μL/孔将组织蛋白酶S添加至除了底物对照之外的所有孔。最后,将包含底物的50μL测定缓冲液添加至每个孔。添加底物至16nM的最终浓度。在室温下培养样品30min。在Victor3酶标仪上在Ex/Em=490nm/520nm读取荧光强度。一式两份地测试所有的样品。结果显示为底物对照调整的最大吸光度的百分比,其由阳性对照给出。
结果显示在下表2中:
表2
实施例9
化合物对丙型肝炎病毒NS3/4A WT和突变蛋白酶的活性
结果显示在下表3和4中:
表3
表4
虽然前述说明书教导了本发明的原理,以及为了举例说明目的提供的实施例,但是应当理解,本发明的实施包含所有的常规变化、适应性修改和/或改变,同样在所附权利要求书及其等同的范围内。
Claims (10)
2.权利要求1的化合物,其中所述化合物或其药学上可接受的盐、前药或溶剂化物可以为单一对映体、立体异构体、旋转异构体、互变异构体、外消旋体或其混合物的形式。
3.一种用于治疗或预防HCV感染或降低HCV的生物活性的方法,包含将治疗上或预防上有效量的权利要求1的化合物施用于需要治疗或预防其的患者。
4.权利要求3的方法,其中所述化合物与其它的抗HCV剂组合施用。
5.一种用于抑制丝氨酸蛋白酶活性的方法,包含施用根据权利要求1的化合物至所述患者的步骤。
6.根据权利要求3-5任一项的方法,其中所述化合物被施用至患者并且与药学上合适的载体一起被配制至药学上可接受的组合物中。
7.权利要求1的化合物用于制备治疗或预防HCV感染或降低HCV生物活性用的药物的用途。
8.权利要求7的用途,其中所述药物进一步包含其它的抗HCV剂。
9.权利要求1的化合物用于制备抑制丝氨酸蛋白酶活性用的药物的用途。
10.权利要求7-9任一项的用途,其中所述药物进一步包含药学上合适的载体。
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