CN103816174B - 用于治疗病毒感染的化合物和方法 - Google Patents
用于治疗病毒感染的化合物和方法 Download PDFInfo
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- CN103816174B CN103816174B CN201310362314.1A CN201310362314A CN103816174B CN 103816174 B CN103816174 B CN 103816174B CN 201310362314 A CN201310362314 A CN 201310362314A CN 103816174 B CN103816174 B CN 103816174B
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Abstract
本发明提供了用于治疗易感性病毒感染的化合物和方法,尤其是丙肝病毒(HCV)感染以及HCV与其他病毒例如HBV和/或HIV的共感染。在一个实施方案中,本发明提供了具有通式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂化物、前药或其组合,及它们在治疗病毒感染中的用途:
Description
本申请是同名发明名称的中国专利申请第200980120778.3号的分案申请,原案国际申请号为PCT/US2009/039424,国际申请日为2009年4月3日。
相关申请
本申请要求2008年4月3日提交的美国临时申请No.61/072,794;2008年4月3日提交的美国临时申请No.61/072,799;和2008年6月20日提交的美国临时申请No.61/074,421的权利。在此将以上申请的全部内容引入本文作参考。
背景技术
全世界有超过1亿7千万人受到丙肝病毒的感染。目前的治疗方法具有剂量限制性毒性并存在重要的未满足的医疗需求。几种针对HCV聚合酶、HCV蛋白酶和HCV NS5A的化合物正在研发中。然而,病毒复制循环是明显易出错的,导致抗性突变体的出现,特别是在抗病毒治疗的选择性压力下。这给研发抗病毒治疗方案提出了意义重大的挑战。
迄今为止,已经研发的大部分抗-HCV药剂是HCV聚合酶抑制剂。NS3蛋白酶抑制剂BILN-2061是在人体中测试的第一种化合物,在患者体内产生了明显的病毒负荷降低。核苷类似物NM283在HCV感染患者中显示出抗病毒作用。然而,在临床中使用少数化合物时已经注意到了明显的抗药性和毒性。几种抗病毒化合物正在临床研发中。例如,已经发现了非核苷苯并噻二嗪、酰基吡咯烷、苯并呋喃、苯丙氨酸、取代的噻吩、二氢吡喃酮、吡喃并吲哚、苯并咪唑和吲哚是NS5B聚合酶结构域的抑制剂。然而,体外复制子试验揭示了与不同的药物有明显交叉的抗药性。
因为对抗病毒药物产生抗药性事实上是确定的,一种对抗方式是联合治疗,包括不会促进交叉抗药性突变体的药物。通常,影响不同病毒酶的药物不会显示出交叉抗药性并可以成功联合使用。因此,具有不同作用机理的没有交叉抗药性的不同药物的组合将是成功的抗病毒治疗的关键。
与20-聚体相比具有较少数量电荷和较小分子量的较短链寡核苷酸(少于8-聚体)代表一类具有前景的新分子,其具有作为抗病毒剂的潜在治疗特性。实际上,最近的报道表明单-、二-、三-和短链寡核苷酸具有可以开发用于各种治疗应用的重要生物活性。然而,仍然需要具有改进特性的改进短链寡核苷酸,用于口服、经皮或其他非侵害性方式递送给患者,用作单独的治疗剂或联合治疗。
发明内容
本发明提供用于治疗易感性病毒感染的化合物和方法,所述病毒感染尤其是丙肝病毒(HCV)感染以及HCV与其他病毒如HBV和/或HIV的共感染。在一个实施方案中,本发明提供了具有通式(I)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂化物、前药或其组合,及其在治疗病毒感染中的用途:
其中:
N1和N2独立地选自天然产生的核苷或修饰的核苷;
W、X、Y和Z各自独立地选自O、S和NR1,其中R1独立地选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团;
R2、R3、R4和R5各自独立地选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团;
n是0、1、2、3、4或5;
A不存在,或是取代或未取代的芳香族基团;
J是不存在、CR6R7、O、S或NR1,其中R6和R7各自独立地选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团,并且R1如上定义;
M是不存在、CR8R9、O、S或NR1,其中R8和R9各自独立地选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团,并且R1如上定义;
V是取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
Q不存在,或是修饰或未修饰的核苷酸;和
m是1、2、3或4。
具体实施方式
本发明提供了用于治疗易感性病毒感染(尤其是丙肝病毒感染)的短核苷酸化合物和方法。术语“短核苷酸”是指从1至约6个连接的核苷单体形成的单核苷酸、二核苷酸或多核苷酸。本发明还包括单核苷化合物。本文所用的术语“易感性病毒感染”是指由多种RNA和DNA病毒引起的病毒感染,所述病毒包括但不限于以下各科的病毒,如黄病毒科——包括黄病毒属,库宁病毒是其成员的瘟病毒属,丙肝病毒是其成员的肝炎病毒,西尼罗病毒是其成员的虫媒病毒,正粘病毒,副粘病毒,沙粒病毒、布亚病毒、疱疹病毒、腺病毒、痘病毒和逆转录病毒。典型的合适的“易感性病毒感染”包括A型流感和B型流感病毒感染;副流感病毒感染、呼吸道合胞病毒(“RSV”)感染,如RSV细支气管炎和RSV肺炎,尤其如儿童和婴儿中的RSV感染以及患有预先存在的心肺疾病的患者中的RSV肺炎,麻疹病毒感染,拉沙热病毒感染,朝鲜出血热感染,乙肝病毒(HBV)感染,克里米亚-刚果出血和HCV感染和HIV-1感染,脑炎感染,如由西尼罗病毒或库宁病毒引起的,或圣路易斯脑炎感染,以及在免疫受损患者中发现的病毒感染。美国专利No.4,211,771在第2栏第21行至第3栏第37行中公开了其他易感性病毒感染;在第3栏第4行至第9栏第5行中公开了剂量和给药方案和制剂。在一个实施方案中,病毒感染不仅仅是HBV感染,然而,病毒感染可以是HBV与另一种病毒(如HCV)的共感染。
本发明的适用于治疗易感性病毒感染,特别是HCV感染以及HCV与其他病毒(如HBV和/或HIV)的共感染的化合物是由通式I-IV的化合物表示的。应当注意到在以下的一些通式中,核苷单体由国际上公认的线条画惯例来表示。在以下的实例中,以常规的结构和相应的线条画形式来表示2′-取代的核糖核苷:
连接B1和B2产生α或βN-或C-核苷的糖单体包括但不限于呋喃糖、脱氧呋喃核糖、核糖和阿拉伯糖。
在第一个实施方案中,本发明化合物是由以上所示的通式I表示的化合物、或其外消旋物、对映异构体、非对映异构体、几何异构体、互变异构体。
通式I的优选亚属是由以下所示的通式(II)表示的化合物,或其外消旋物、对映异构体、非对映异构体、几何异构体、互变异构体。
其中V、M、J、A、R2、R3、R4、R5、N1、N2、Q、m和n与之前通式I中所定义的相同。
本发明的代表性化合物是选自通式A1的化合物(1)-(8)的化合物:
其中,各实施例的V、M、R10和R11描述于表1中。
表1
本发明的代表性化合物是选自通式B1的化合物(9)-(16)的化合物:
其中,各实施例的V、M、R10和R11描述于表2中。
表2
通式I的化合物的实例包括但不限于:
通式I的化合物的其他实例包括但不限于:
其中B1和B2是天然产生的核碱基或修饰的碱基。
在另一个实施方案中,本发明提供了具有通式(III)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、溶剂化物、前药或其组合及它们在治疗病毒感染中的用途:
其中:
M′和M′′各自独立地选自CH2、NH、NR′′、O和S;其中R′′是取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
X′是O、NH、NR′′或S;其中R′′是如上述所定义的;
Y′是OR12、NHR12和SR12;其中各R12独立地选自H、取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
Z′和Z′′各自独立地是O、NR13和S;其中R13是H、取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
R和R′各自独立地是H、OH、O-烷基、O-芳基、O-杂芳基、O-芳烷基、O-烷基杂芳基、-NH2、-NHR14、-NR15NR16、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的芳基、取代或未取代的芳烷基、或者取代或未取代的杂环,其中R14、R15和R16各自独立地选自H、取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
B1和B2各自独立地选自不存在、H、天然产生的核碱基和修饰的碱基;且
Q′是不存在或
其中,X′和Y′是如上述所定义的,并且A是OH、O-烷基、O-芳基、O-杂芳基、O-芳烷基或O-烷基杂芳基。
在优选的实施方案中,B1和B2中的至少一个独立地是以下的通式:
通式III的化合物的具体实例包括但不限于:
其中,在以上的通式中,R是具有高达10个原子的主链的取代或未取代的脂肪族基团,并优选R是长链脂肪酸。
通式III的其他化合物包括但不限于以下的化合物:
其中,在以上的那些通式中,B1和B2独立地是天然产生的核碱基或修饰的碱基。
在另一个实施方案中,本发明提供了具有通式(IV)的化合物及其在治疗病毒感染中的用途:
M′选自CH2、NH、NR′′、O和S;其中R′′是取代或未取代的脂肪族基团或者取代或未取代的芳香族基团;
X是O、NH、NR′′或S;其中R′′是如上述所定义的;
Z′是H、OH、OR′′、OR17、COOH、COOR′′、NH2、NHR′′、NHR17,其中R′′是如上述所定义的,并且R17是芳酰基(CO-Ph)、磺酰基(SO2-R)、脲基(ureidyl)(CO-NH-R)、硫脲基(thioureidyl)(CS-NH-R),其中R选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团,然而,M′是O时,Z′不是OH;
R′是H、OH、O-烷基、O-芳基、O-杂芳基、O-芳烷基、O-烷基杂芳基、O-芳酰基、-NH2、-NHR1、-NR1NR2烷基、取代的烷基、环烷基、芳基、取代的芳基、芳烷基或杂环,其中R1和R2各自独立地选自氢、取代或未取代的脂肪族基团和取代或未取代的芳香族基团,然而,M′是O时,R′不是OH;
B1是H、天然产生的核碱基或修饰的碱基。
在优选的实施方案中,通式IV的R、R1和R2是取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的芳基、取代或未取代的芳烷基,或者取代或未取代的杂环。
通式(IV)化合物的非限制性实例包括:
以下所示的是用于描述本发明的各个术语的定义。不管是单独使用时还是作为较大基团的一部分使用,这些定义都适用于本说明书和权利要求中所用的术语,除非在特定的情况中有另外限定。
“脂肪族基团”是可以含有碳原子、氢原子、卤原子、氧、氮、硫或其他原子的任意组合并任选含有一个或多个不饱和单元(例如,双键和/或三键)的非芳香族部分。脂肪族基团可以是直链、支链或环状的,并且优选含有约1至约24个碳原子,更常见为约1至约12个碳原子。除了脂肪族烃基团以外,脂肪族基团包括,例如,聚烷氧基烷基,如聚亚烷基二醇、聚胺和聚亚胺。应理解,本文所述的任何烷基、烯基、炔基和环烷基部分也可以是脂肪族基团、脂环族基团或杂环基团。这样的脂肪族基团可以被进一步取代。
本文所用的术语“芳基”是指单-或多环碳环环系,包括但不限于,苯基、萘基、四氢萘基、茚满基、茚基。术语芳基包括但不限于,具有由两个环组成的环系的双环芳基或双环杂芳基,其中至少一个环是芳香族的。术语芳基包括但不限于具有由三个环组成的环系的三环芳基或三环杂芳基,其中至少一个环是芳香族的。
本文所用的术语“杂芳基”是指具有一个或多个选自S、O和N的环原子的单-或多环芳香族基团;并且剩余的环原子是碳,其中环内所含的任一个N或S可以任选地是被氧化的。杂芳基包括但不限于吡啶基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、唑基、异唑基、噻二唑基、二唑基、噻吩基、呋喃基、喹啉基、异喹啉基、苯并咪唑基、苯并唑基、喹喔啉基。
根据本发明,本文所述的芳基、取代的芳基、杂芳基和取代的杂芳基中的任一种也可以是任意的芳香族基团。因此,本文所用的术语“芳香族基团”包括所有这样的芳基、取代的芳基、杂芳基和取代的杂芳基。芳香族基团可以是取代的或未取代的。
本文所用的术语“烷基”是指含有一个或多个碳原子并优选含有1-24个碳原子的饱和的直链或支链烃基团。烷基的实例包括但不限于,甲基、乙基、丙基、异丙基、正丁基、叔丁基、新戊基、正己基、庚基和辛基、癸基、十二烷基。
本文所用的术语“烯基”是指含有至少2个、优选2-8个碳原子、并通过除去单个氢原子而具有至少一个碳-碳双键的直链或支链烃基。烯基包括但不限于,例如,乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
本文所用的术语“炔基”是指含有至少2个碳原子、优选2-8个碳原子、并通过除去单个氢原子而具有至少一个碳-碳三键的直链或支链烃基。代表性的炔基包括但不限于,例如,乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
本文所用的术语“环烷基”是指单环或多环饱和碳环化合物。环烷基的实例包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基和环辛基;二环[2.2.1]庚基和二环[2.2.2]辛基。
本文所用的术语“环烯基”是指具有至少一个碳-碳双键的单环或多环碳环化合物。环烯基的实例包括但不限于,环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基等。
应该理解,本文所述的任何烷基、烯基、炔基和环烷基部分也可以是如上定义的脂肪族基团、脂环族基团或杂环基团。
本文所用的术语“脂环族”表示通过除去单个氢原子而源自单环或双环饱和碳环化合物的单价基团。实例包括但不限于,环丙基、环丁基、环戊基、环己基、二环[2.2.1]庚基和二环[2.2.2]辛基。这样的脂环族基团可以进一步被取代。
术语“杂环”或“杂环烷基”可以互换使用,是指非芳香族环或双-或三-环基团稠合系统,其中(i)各环系含有至少一个独立地选自氧、硫和氮的杂原子,(ii)各环系可以是饱和或不饱和的;(iii)氮和硫杂原子可以任选是被氧化的,(iv)氮杂原子可以任选是季胺化的,(v)以上的任一种环可以与芳香族环稠合,且(vi)剩余的环原子为可任选被氧代取代的碳原子。代表性的杂环基团包括但不限于,1,3-二氧戊环、吡咯烷基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、哌嗪基、唑烷基、异唑烷基、吗啉基、噻唑烷基、异噻唑啉基、喹喔啉基、哒嗪酮基和四氢呋喃。这种杂环基团可以进一步被取代。
术语“取代的”是指如芳香族基团或脂肪族基团等部分上的一个、两个或三个或多个氢原子被取代基单独替代的取代,取代基包括但不限于,-F、-Cl、-Br、-I、-OH、被保护的羟基、-NO2、-CN、-NH2、被保护的氨基、氧代、硫代、甾族、-NH-C1-C12-烷基、-NH-C2-C8-烯基、-NH-C2-C8-炔基、-NH-C3-C12-环烷基、-NH-芳基、-NH-杂芳基、-NH-杂环烷基、-二烷基氨基、-二芳基氨基、二杂芳基氨基、-O-C1-C12-烷基、-O-C2-C8-烯基、-O-C2-C8-炔基、-O-C3-C12-环烷基、-O-芳基、-O-杂芳基、-O-杂环烷基、-C(O)-C1-C12-烷基、-C(O)-C2-C8-烯基、-C(O)-C2-C8-炔基、-C(O)-C3-C12-环烷基、-C(O)-芳基、-C(O)-杂芳基、-C(O)-杂环烷基、-CONH2、-CONH-C1-C12-烷基、-CONH-C2-C8-烯基、-CONH-C2-C8-炔基、-CONH-C3-C12-环烷基、-CONH-芳基、-CONH-杂芳基、-CONH-杂环烷基、-OCO2-C1-C12-烷基、-OCO2-C2-C8-烯基、-OCO2-C2-C8-炔基、-OCO2-C3-C12-环烷基、-OCO2-芳基、-OCO2-杂芳基、-OCO2-杂环烷基、-OCONH2、-OCONH-C1-C12-烷基、-OCONH-C2-C8-烯基、-OCONH-C2-C8-炔基、-OCONH-C3-C12-环烷基、-OCONH-芳基、-OCONH-杂芳基、-OCONH-杂环烷基、-NHC(O)-C1-C12-烷基、-NHC(O)-C2-C8-烯基、-NHC(O)-C2-C8-炔基、-NHC(O)-C3-C12-环烷基、-NHC(O)-芳基、-NHC(O)-杂芳基、-NHC(O)-杂环烷基、-NHCO2-C1-C12-烷基、-NHCO2-C2-C8-烯基、-NHCO2-C2-C8-炔基、-NHCO2-C3-C12-环烷基、-NHCO2-芳基、-NHCO2-杂芳基、-NHCO2-杂环烷基、-NHC(O)NH2、-NHC(O)NH-C1-C12-烷基、-NHC(O)NH-C2-C8-烯基、-NHC(O)NH-C2-C8-炔基、-NHC(O)NH-C3-C12-环烷基、-NHC(O)NH-芳基、-NHC(O)NH-杂芳基、-NHC(O)NH-杂环烷基、NHC(S)NH2、-NHC(S)NH-C1-C12-烷基、-NHC(S)NH-C2-C8-烯基、-NHC(S)NH-C2-C8-炔基、-NHC(S)NH-C3-C12-环烷基、-NHC(S)NH-芳基、-NHC(S)NH-杂芳基、-NHC(S)NH-杂环烷基、-NHC(NH)NH2、-NHC(NH)NH-C1-C12-烷基、-NHC(NH)NH-C2-C8-烯基、-NHC(NH)NH-C2-C8-炔基、-NHC(NH)NH-C3-C12-环烷基、-NHC(NH)NH-芳基、-NHC(NH)NH-杂芳基、-NHC(NH)NH-杂环烷基、-NHC(NH)-C1-C12-烷基、-NHC(NH)-C2-C8-烯基、-NHC(NH)-C2-C8-炔基、-NHC(NH)-C3-C12-环烷基、-NHC(NH)-芳基、-NHC(NH)-杂芳基、-NHC(NH)-杂环烷基、-C(NH)NH-C1-C12-烷基、-C(NH)NH-C2-C8-烯基、-C(NH)NH-C2-C8-炔基、-C(NH)NH-C3-C12-环烷基、-C(NH)NH-芳基、-C(NH)NH-杂芳基、-C(NH)NH-杂环烷基、-S(O)-C1-C12-烷基、-S(O)-C2-C8-烯基、-S(O)-C2-C8-炔基、-S(O)-C3-C12-环烷基、-S(O)-芳基、-S(O)-杂芳基、-S(O)-杂环烷基-SO2NH2、-SO2NH-C1-Cl2-烷基、-SO2NH-C2-C8-烯基、-SO2NH-C2-C8-炔基、-SO2NH-C3-C12-环烷基、-SO2NH-芳基、-SO2NH-杂芳基、-SO2NH-杂环烷基、-NHSO2-C1-C12-烷基、-NHSO2-C2-C8-烯基、-NHSO2-C2-C8-炔基、-NHSO2-C3-C12-环烷基、-NHSO2-芳基、-NHSO2-杂芳基、-NHSO2-杂环烷基、-CH2NH2、-CH2SO2CH3、-芳基、-芳基烷基、-杂芳基、-杂芳基烷基、-杂环烷基、-C3-C12-环烷基、聚烷氧基烷基、聚烷氧基、-甲氧基甲氧基、-甲氧基乙氧基、-SH、-S-C1-C12-烷基、-S-C2-C8-烯基、-S-C2-C8-炔基、-S-C3-C12-环烷基、-S-芳基、-S-杂芳基、-S-杂环烷基或甲基硫代甲基。可以理解,芳基、杂芳基、烷基、甾族等可以进一步被取代。
本文所用的术语“卤素”是指选自氟、氯、溴和碘的原子。
本文所用的术语“甾族”是指众多天然存在的或合成的脂溶性有机化合物中的任意一种,其在四个环中排列了作为基础的17个碳原子,包括甾醇和胆汁酸、肾上腺激素和性激素、某些天然药物,如洋地黄化合物,和某些维生素的前体。甾族结构的实例包括但不限于,胆固醇、胆甾烷醇、3α-环-5-α-胆甾烷-6-β-醇、胆酸、胆固醇甲酸酯、胆甾烷醇甲酸酯。
对于本发明的目的,术语“短核苷酸”是指由1至约6个连接的核苷单体形成的单、二或多核苷。这样的短核苷酸可以获自现有的核酸来源,包括基因组或cDNA,但优选通过合成方法来产生。核苷残基可以通过各种已知的核苷间键合中的任一种来彼此结合。这样的核苷间键合可以是修饰或未修饰的,包括但不限于,磷酸二酯、硫代磷酸酯、二硫代磷酸酯、烷基膦酸酯、烷基硫代膦酸酯、磷酸三酯、氨基磷酸酯、硅氧烷、碳酸酯、烷氧羰基、乙酰氨化物、氨基甲酸酯、吗啉代、borano、硫醚、桥接氨基磷酸酯、桥接亚甲基膦酸酯、桥接硫代磷酸酯和砜核苷间键合。术语“短(链)核苷酸”还包括具有一个或多个立体特异性核苷间键合(例如,(Rp)-或(Sp)-硫代磷酸酯、烷基膦酸酯或磷酸三酯键合)的多核苷。本发明的短核苷酸包括任何这样的核苷间键合,不管是否该连接包含磷酸酯基团。在特定的优选实施方案中,这些核苷间键合可以是修饰的或未修饰的,包括但不限于,磷酸二酯、硫代磷酸酯或二硫代磷酸酯键合,或其组合。
术语“短核苷酸”还包括其他取代基,包括但不限于,蛋白质基团、亲脂性基团、嵌入剂、二胺、叶酸、胆固醇和金刚烷。
术语“短核苷酸”还包括任何其他含有核碱基的聚合物,包括但不限于,肽核酸(PNA)、具有磷酸酯基团的肽核酸(PHONA)、锁定核酸(LNA)。PNA和LNA的实例如下所示:
“核苷酸”是指核酸(不管是DNA或是RNA或其类似物)的亚基,其包括核苷酸间键合,糖基和杂环碱基,以及这些亚基的类似物。“核苷”是指包括糖基和杂环碱基的核酸亚基。将认识到,本文所用的术语“核苷”和“核苷酸”将包括如下的那些部分,其不仅含有天然产生的核苷酸间键合(相对于“核苷酸”)(如,磷酸二酯核苷酸间键合);天然产生的糖部分(如,核糖和脱氧核糖部分)和天然产生的核碱基(如,嘌呤和嘧啶碱基,例如,腺嘌呤(A)、胸腺嘧啶(T)、胞嘧啶(C)、鸟嘌呤(G)或尿嘧啶(U)),而且还含有修饰的核苷酸间键合、修饰的糖部分和修饰的嘌呤和嘧啶碱基或其类似物,或修饰和未修饰的核苷酸间键合、糖部分和嘌呤和嘧啶碱基的任意组合。修饰的核苷的其他实例包括无环核苷,其由核糖和脱氧核糖部分的开环形式组成。相应地,这样的开环核苷可以用于形成修饰的核苷酸。修饰的核苷的其他实例包括C-核苷,如伪异胞苷,和核苷模拟物,包括核苷等排物,如肽核酸单体。
天然产生的嘌呤和嘧啶核碱基的修饰包括但不限于甲基化嘌呤或嘧啶,酰化嘌呤或嘧啶等,或添加保护基团,如乙酰基、二氟乙酰基、三氟乙酰基、异丁酰基、苯甲酰基等。嘌呤或嘧啶碱基还可以是之前的类似物;合适的类似物是本领域技术人员已知的并且描述于相关的教科书和文献中。常见的类似物包括但不限于,1-甲基腺嘌呤、2-甲基腺嘌呤、N6-甲基腺嘌呤、N6-异戊基腺嘌呤、2-甲基硫-N-6-异戊基腺嘌呤、N,N-二甲基腺嘌呤、8-溴腺嘌呤、2-硫代胞嘧啶、3-甲基胞嘧啶、5-甲基胞嘧啶、5-乙基胞嘧啶、4-乙酰基胞嘧啶、1-甲基鸟嘌呤、2-甲基鸟嘌呤、7-甲基鸟嘌呤、2,2-二甲基鸟嘌呤、8-溴鸟嘌呤、8-氯鸟嘌呤、8-氨基鸟嘌呤、8-甲基鸟嘌呤、8-硫鸟嘌呤、5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、5-乙基尿嘧啶、5-丙基尿嘧啶、5-甲氧基尿嘧啶、5-羟甲基尿嘧啶、5-(羧基羟甲基)尿嘧啶、5-(甲基氨基甲基)尿嘧啶、5-(羧甲基氨甲基)-尿嘧啶、2-硫尿嘧啶、5-甲基-2-硫尿嘧啶、5-(2-溴乙烯)尿嘧啶、尿嘧啶-5-氧醋酸、尿嘧啶-5-氧醋酸甲酯、假尿嘧啶、1-甲基假尿嘧啶、queosine、肌苷、1-甲基肌苷、次黄嘌呤、黄嘌呤、2-氨基嘌呤、6-羟基氨基嘌呤、6-硫代嘌呤、2,6-二氨基嘌呤5-三氟甲基胸腺嘧啶、6-氯-腺嘌呤、7-脱氮-腺嘌呤。
还应当理解“修饰的碱基”还是指“修饰的核碱基”,包括可以是或不是杂环的含氮化合物。这样优选的含氮化合物包括但不限于-NHR18,其中R18是氢、丁氧基羰基(Boc)、苄氧基羰基、烯丙基、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的芳烷基、取代或未取代的芳基、取代或未取代的杂芳基或杂环。
术语“修饰的碱基”进一步用来包括在大部分传统意义下不是核苷碱基但可以充当核苷碱基的杂环化合物。这样的化合物包括本领域已知的“通用碱基”。通用碱基可以包括芳香族环部分,其可以含有或不含有氮原子。在一些实施方案中,通用碱基可以共价连接核苷的戊糖的C-1′糖。通用碱基的实例包括3-甲基-丙炔基羰苯乙烯基(PIM)、3-甲基异羰苯乙烯基(MICS)和5-甲基异羰苯乙烯基部分。其他实例包括肌苷衍生物、唑甲酰胺类似物、硝基唑和硝基咪唑。
修饰的核苷酸和核苷的糖部分的实例包括但不限于:海藻糖、阿拉伯糖、2′-脱氧-2′-取代的戊糖部分、2′-O-取代的戊糖部分、来苏糖和木糖,或己糖糖基。对于本发明的目的,术语所述任一个糖基的“2′-取代的”,如“2′取代的核糖核苷”或“2′-取代的阿拉伯糖苷”包括其中戊糖部分的2′位羟基被取代而产生2′-取代或2′-O-取代的核糖核苷或阿糖核苷的核糖核苷或阿糖核苷。优选这样的取代是使用含有1-6个饱和或不饱和碳原子的低级烷基,或使用具有6-10个碳原子的芳基,其中这样的烷基或芳基可以是未取代的或可以是取代的,例如,被卤素、羟基、三氟甲基、氰基、硝基、酰基、酰氧基、烷氧基、羧基、烷氧羰基或氨基来取代。2′-O-取代的核糖核苷或2′-O-取代的阿拉伯糖苷的实例包括但不限于,2′-O-甲基核糖核苷(在此也称为2′-OMe)或2′-O-甲基阿拉伯糖苷和2′-O-甲氧基乙基核糖核苷或2′-O-甲氧基乙基阿拉伯糖苷。术语“2′-取代的核糖核苷”或“2′-取代的阿拉伯糖苷”还包括其中2′-羟基被含有1-6个饱和或不饱和碳原子的低级烷基或被氨基或卤素替代的核糖核苷或阿糖核苷。这样的2′-取代的核糖核苷或2′-取代的阿拉伯糖苷的实例包括但不限于2′-氨基、2′-氟、2′-烯丙基和2′-炔丙基核糖核苷或阿拉伯糖苷。
修饰的核苷酸间键合的实例包括但不限于:取代和未取代的硫代磷酸酯、二硫代磷酸酯、膦酸烷基酯、烷基硫代膦酸酯、磷酸三酯、氨基磷酸酯、硅氧烷、碳酸酯、烷氧羰基、乙酰胺化物、氨基甲酸酯、吗啉代、borano、硫醚、桥接氨基磷酸酯、桥接亚甲基膦酸酯、桥接硫代磷酸酯和砜核苷间键合。修饰和未修饰的核苷酸间键合的取代包括以下部分:
其中V、M、J、R2、R3、R4、R5和n全部是之前通式I中定义的。
本发明的化合物含有一个或多个不对称中心并因此可以作为外消旋物和外消旋混合物、单个对映异构体、非对映异构体混合物和单独的非对映异构体出现。本发明旨在包括对于五元呋喃糖环具有β-D立体化学构型的短核苷酸化合物,即,其中在五元呋喃糖环的C-1和C-4处的取代基具有β-立体化学构型的短核苷酸化合物(在本文所示的一些通式中,通常通过粗线表示“向上的”取向)。
缩写
以下图解和实施例的描述中所用的缩写是:
Ac表示酰基;
AcOH表示乙酸;
Boc2O表示二碳酸二叔丁酯;
Boc表示叔丁氧羰基;
Bpoc表示1-甲基-1-(4-联苯基)乙基羰基;
Bz表示苯甲酰基;
Bn表示苄基;
BocNHOH表示叔丁基N-羟基氨基甲酸酯;
t-BuOK表示叔丁醇钾;
Bu3SnH表示氢化三丁锡;
CDI表示羰基二咪唑;
CH2Cl2表示二氯甲烷;
CH3表示甲基;
CH3CN表示乙腈;
DMSO表示二甲亚砜;
EtOAc表示乙酸乙酯;
EtOH表示乙醇;
Et2O表示乙醚;
HCl表示盐酸;
MeOH表示甲醇;
MOM表示甲氧基甲基;
Ms表示甲磺酰基或-SO2-CH3;
Ms2O表示甲磺酸酐或甲磺酰酐;
NaCl表示氯化钠;
NaH表示氢化钠;
NaHCO3表示碳酸氢钠;
Na2CO3表示碳酸钠;
NaOH表示氢氧化钠;
Na2SO4表示硫酸钠;
NaHSO3表示亚硫酸氢钠;
Na2S2O3表示硫代硫酸钠;
NH2NH2表示肼;
NH4HCO3表示碳酸氢铵;
NH4Cl表示氯化铵;
OH表示羟基;
OMe表示甲氧基;
OEt表示乙氧基;
TEA或Et3N表示三乙胺;
TFA表示三氟乙酸;
THF表示四氢呋喃;
TPP或PPh3表示三苯膦;
Ts表示甲苯磺酰基或-SO2-C6H4CH3;
Ts2O表示甲苯磺酸酐或甲苯磺酰酐;
TsOH表示对甲苯磺酸;
Ph表示苯基;
TBS表示叔丁基二甲基甲硅烷基;或
TMS表示三甲基甲硅烷基;
TMSCl表示三甲基甲硅烷基氯。
本发明还包括包含本发明的短寡核苷酸化合物及其衍生物以及药学上可接受的载体的药物组合物。本发明的另一个实例是通过将上述任一种化合物与药学上可接受的载体组合制得的药物组合物。本发明的另一个说明是制备药物组合物的方法,其包括将上述任一种化合物和药学上可接受的载体组合。
本发明的另一个方面提供了短核苷酸化合物及其衍生物和药物组合物的用途,用于制造抑制易感性病毒感染、特别是HCV复制的药物,和/或治疗一种或多种易感性病毒感染的药物,特别是治疗HCV感染和/或HCV感染结合另一种病毒感染,如HBV或HIV的药物。本发明的再一个方面提供了短寡核苷酸化合物及其衍生物和它们的药物组合物用作药物,用于抑制RNA-依赖性RNA病毒复制,特别是HCV复制,和/或用于治疗RNA-依赖性RNA病毒感染,特别是HCV感染。
本发明的药物组合物包含至少一种本发明的化合物或其药学上可接受的盐作为活性成分,并且还可以含有药学上可接受的载体和赋形剂,并任选其他治疗性成分。“药学上可接受的”是指载体、稀释剂或赋形剂必须与制剂的其他成分相容并且对其接受者是无害的。组合物包括适于口服、直肠、局部、非肠道(包括皮下、肌内和静脉内)、眼部(眼睛)、肺部(鼻或颊吸入)或鼻给药的组合物,尽管在任何给定情况中的最合适途径将取决于待治疗病症的性质和严重程度以及取决于活性成分的性质。它们可以方便地存在于单位剂型中,并通过药物领域中公知的任一种方法来制备。
在实践使用中,本发明的化合物作为活性成分可以根据常规药物混合技术在紧密混合中与药物载体混合。载体可以根据给药(例如,口服或非肠道(包括静脉内))所需的制剂形式而采用各种形式。在制备口服剂型组合物中,如在口服液体制剂的情况中,例如,在混悬液、酏剂和溶液中,可以使用任一种常用的药物介质,例如,水、甘油、油、醇、调味剂、防腐剂、着色剂等;或在口服固体制剂中,例如,在粉末、硬和软胶囊和片剂中,可以使用载体,如淀粉、糖、微晶体纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等,并且固体口服制剂优于液体制剂。
由于易于给药,片剂和胶囊代表了最有利的口服单位剂型,在这种情况中,显然使用固体药物载体。如果需要,可以通过标准的含水或非水技术来覆盖片剂。这样的组合物和制剂应当含有至少0.1%的活性化合物。这些组合物中的活性化合物的百分比当然可以改变并可以方便地为单位重量的约2%至约60%。这些治疗有效组合物中的活性化合物的含量使得将获得有效剂量。活性化合物也可以鼻内给药,例如通过液体滴剂或喷雾。
片剂、丸剂、胶囊等还可以含有粘合剂,如黄芪胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸二钙;崩解剂,如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂,如硬脂酸镁;和甜味剂,如蔗糖、乳糖或糖精。当单位剂型是胶囊时,除了以上类型的材料外,可以含有液体载体,如脂肪油。各种其他材料可以作为涂层存在或用于改变单位剂型的物理形式。例如,可以用虫胶、糖或两者将片剂包衣。除了活性成分以外,糖浆或酏剂可以含有作为甜味剂的蔗糖,作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯,染料和调味剂,如樱桃或橙子香精。可以添加各种稳定剂如氨基酸或聚胺,以稳定活性药物成分,对抗降解。其他赋形剂可以包括但不限于PEG400、甘氨酸、维生素E衍生物、山梨糖醇酐单油酸酯、壳聚糖、柠檬酸胆碱、山梨糖醇酐单硬脂酸酯、吐温80、Igepal CA630、Brij35、NP-40及其类似的衍生物。
本发明的化合物也可以非肠道给药。可以在水中与表面活性剂如羟丙基纤维素适当地混合来制备这些活性化合物的溶液或混悬液。还可以在油中、在甘油、液体聚乙二醇及其混合物中制备分散体。在普通条件的存储和使用下,这些制剂含有防腐剂以防止微生物的生长。适于注射使用的药物形式包括无菌水溶液或分散体和用于使无菌注射溶液或分散体即时复原的无菌粉末。在制造和存储条件下必须稳定,并且必须防止微生物(如细菌和真菌)的污染作用。载体可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇),及其合适的混合物,和植物油的溶剂或分散介质。
可以使用任何合适的给药途径,用于向哺乳动物尤其是人提供治疗有效剂量的本发明的化合物。术语化合物的“给药”和“给药”化合物应当理解为将本发明的化合物提供给有需要的个体。根据本发明的治疗方法,通过将治疗有效量或抑制量的本发明的化合物给予患者来治疗或预防患者(如,人或低等哺乳动物)的病毒感染,以获得所需结果所需要的含量并持续这样的时间。本发明的其他方法是用抑制量的本发明组合物中的化合物处理生物样品,以获得所需结果所需要的含量并持续这样的时间。
术语本发明化合物的“治疗有效量”是指使得降低生物样品或患者中病毒负荷的充分剂量化合物。如医疗领域公知的,本发明化合物的治疗有效量将是适用于任何医学治疗的合理的收益/风险比例。
术语本发明化合物的“抑制量”是指足以降低生物样品或患者中丙肝病毒负荷的充分剂量。本发明化合物的抑制量或剂量可以为约0.1mg/kg至约500mg/kg,或者为约1-约50mg/kg。抑制量或剂量还将根据给药途径以及与其他药剂共同使用的可能性而改变。
本文所用的术语“生物样品”是指用于给予患者的生物来源的物质。生物样品的实例包括但不限于,血液及其成分,如血浆、血小板、血细胞的亚群等;器官,如肾脏、肝脏、心脏、肺等;精子和卵子;骨髓及其成分;或干细胞。因此,本发明的另一个实施方案是通过将所述生物样品与抑制量的本发明的化合物或药物组合物接触来处理生物样品的方法。
患者病症改善时,如果需要,可以给药维持剂量的本发明的化合物、组合物或混合物。随后,可以作为症状的函数,将给药的剂量或频率或两者降至维持改善状况的水平,当症状已经缓解至所需水平时,治疗应当停止。然而,基于疾病症状的任何复发,患者可能需要长期的间歇性治疗。
然而,应理解,本发明化合物和组合物的总日剂量将由主治医生在合理医疗判断范围内来决定。对于任何特定患者的特定抑制剂量将取决于各种因素,包括待治疗的病症和病症的严重程度;所用特定化合物的活性;所用的具体组合物;患者的年龄、体重、一般状况、性别和饮食;所用特定化合物的给药时间、给药途径和排泄速率;治疗的持续时间;联合使用的药物或与所用特定化合物的一致性;以及医疗领域公知的类似因素。
以单次、多次或分开剂量给予患者的本发明化合物的总日抑制剂量可以为,例如,0.01-50mg/kg体重或更高的含量,通常为0.1-25mg/kg体重。单次剂量组合物可以含有这样的含量或其约数,以构成日剂量。多剂量可以是在不同时间间隔下服用的多个单次剂量。通常,根据本发明的治疗方案包括在单次或多次剂量中将约10mg至约1000mg本发明的化合物/天给予需要该治疗的患者。
本发明的另一个方面包括将本发明的化合物与一种或多种用于治疗HCV感染的药剂组合来抑制或治疗HCV感染。这样的对抗HCV的活性药剂包括但不限于:病毒唑(ribavirin)、利巴韦林(levovirin)、Viramidine、胸腺素α-1、干扰素-β、干扰素-α、聚乙二醇干扰素-α(peginterferon-α)、干扰素-α和病毒唑的组合、聚乙二醇干扰素-α和病毒唑的组合、干扰素-α和利巴韦林的组合以及聚乙二醇干扰素-α和利巴韦林的组合。干扰素-α包括但不限于:重组干扰素-α2a(如,获自Hoffmann-LaRoche,Nutley,N.J.的Roferon干扰素)、聚乙二醇干扰素-α2a(PegasysTM)、干扰素-α2b(如,获自Schering Corp.,Kenilworth,N.J.的Intron-A干扰素)、聚乙二醇干扰素-α2b(PegIntronTM)、重组集成干扰素(如,干扰素alphacon-1)和纯化的干扰素-α产品。Amgen重组集成干扰素具有商标利巴韦林是病毒唑的L-对映异构体,其显示出与病毒唑相似的免疫调节活性。Viramidine表示WO01/60379(属于ICN Pharmaceuticals)中公开的病毒唑的类似物。根据本发明的方法,组合的单独成分可以在治疗过程中的不同时间分开给药或以分开或单个组合形式同时给药。因此,可以理解本发明包括所有这样的同时或交替治疗的方案,并且因此解释了术语“给药”。应理解,本发明化合物与用于治疗HCV感染的其他药剂的组合的范围在原则上包括与用于治疗HCV感染或HCV与另一种病毒(如,HBV或HIV)的共感染的任何药物组合物的任意组合。将本发明的化合物或其药学上可接受的盐结合第二种对抗HCV的治疗活性剂使用时,每种化合物的剂量可以与该化合物单独使用时的剂量相同或不同。
对于HCV感染的治疗,本发明的化合物也可以与作为HCV NS3丝氨酸蛋白酶抑制剂的药剂组合来给药。HCV NS3丝氨酸蛋白酶是基本的病毒酶并且已经被描述为是用于抑制HCV复制的极佳目标。在B.W.Dymock,“Emerging therapies for hepatitis C virusinfection(用于丙肝病毒感染的新兴疗法)”,Emerging Drugs,6:13-42(2001)中讨论了HCV NS3蛋白酶作为用于HCV复制抑制剂的研发和用于HCV感染治疗的目标。
病毒唑、利巴韦林和viramidine可以通过经由胞内酶——肌苷一磷酸脱氢酶(IMPDH)的抑制来调节鸟嘌呤核苷酸的胞内集合,由此发挥它们的抗-HCV作用。IMPDH是鸟嘌呤核苷酸重新生物合成中生物合成途径上的速率限制酶。病毒唑容易在胞内磷酸化,并且一磷酸衍生物是IMPDH的抑制剂。因此,IMPDH的抑制表示了用于HCV复制抑制剂的发现的另一个有用目标。因此,本发明的化合物也可以与IMPDH的抑制剂组合给药[参见,A.C.Allison和E.M.Eugui,Agents Action,44(增刊):165(1993)]。
对于HCV感染的治疗,本发明的化合物可以与抗病毒剂——金刚烷(1-氨基金刚烷)[对于该药剂的全面描述,参见J.Kirschbaum,Anal.Profiles Drug Subs.12:1-36(1983)]组合给药。本发明的化合物还可以与在R.E.Harry-O′kuru等,J.Org.Chem.,62:1754-1759(1997);M.S.Wolfe等,Tetrahedron Lett.,36:7611-7614(1995)中公开的抗病毒2′-C-支链核糖核苷组合用于治疗HCV感染。这样的2′-C-支链核糖核苷包括但不限于:2′-C-甲基-胞苷、2′-C-甲基-尿苷、2′-C-甲基-腺苷、2′-C-甲基-鸟苷和9-(2-C-甲基-β-D-核糖呋喃酰基)-2,6-二氨基嘌呤。本发明的化合物还可以与具有抗-HCV特性的核苷组合用于HCV感染的治疗。本发明的化合物还可以与HCV聚合酶的非核苷抑制剂组合用于HCV感染的治疗。
可以组合本发明化合物使用的抗病毒化合物包括但不限于拉米夫定、阿德福韦、替诺福韦、FTC、恩替卡韦、阿昔洛韦、喷昔洛韦、丙氧鸟苷、干扰素、聚乙二醇干扰素、病毒唑和其他已知的用于治疗病毒感染和病毒共感染(如HCV结合HIV和/或HBV)的治疗性组合物。
通过以下非限制性实施例来进一步说明本发明。
实施例1:3′-dApsU2′-OMe的合成
在本发明的研究中,使用固相亚磷酰胺化学(Beaucage,S.L.;Iyer,R.P.Tetrahedron1993,49,1925)并结合特别制造的LOTUS反应器(Padmanabhan,S.;Coughlin,J.E.;Iyer,R.P.Tetrahedron Lett.2005,46,343;Iyer,R.P.;Coughlin,J.E.;Padmanabhan,S.Org.Prep.Proc.Intl.2005,37,205)大规模地(I毫摩尔的装载有核苷的可控多孔玻璃(CPG)载体)合成实施例2中所示的硫代磷酸酯类似物3′-dApsU2′-OMe的Rp,Sp混合物。使用对固体载体的超速官能化和负载方法制备这种dA-连接的CPG载体。为了进行核苷酸间双核苷亚磷酸酯偶合产品的硫化作用,使用了3H-1,2-苯并二硫杂环戊二烯-3-酮-1,1,-二氧化物溶液(干CH3CN中0.4M)(Iyer,R.P.;Regan,J.B.;Egan,W.;Beaucage,S.L.J.Am.Chem.Soc.1990,112,1253)。通过2.5%二氯乙酸的二氯甲烷溶液来实现5′-三苯甲基的去除。通过在室温下用28%氢氧化铵处理结合载体的产物几个小时,来进行碱基和磷酸酯的保护基团的去除和核苷酸与载体的分离。在处理、色谱纯化和冷冻干燥之后,获得纯度>96%的Rp,Sp 3′-dApsU2′-OMe 的钠盐(~60∶40混合物),通过31P和1H NMR来进行表征。
31P NMR,(D2O),57.0和57.7ppm。
或者,还可以通过溶液-相方法来制备标题化合物。通常,在活化剂(如,惰性气氛中作为溶剂的无水二氯甲烷或乙腈中的四唑或硫代乙基四唑)的存在下,将3′-保护的5′-羟基Nbz-dA与5′-DMT-2′-OMe-3′-尿苷亚磷酰胺接触。3′-保护的核苷的实例包括,levulinyl、叔丁基二甲基甲硅烷基、苄基、4-叔丁基苯甲酰基等。用水猝灭含有二核苷单亚磷酸酯的反应混合物并用3H-1,2-苯并二硫杂环戊二烯-3-酮-1,1-二氧化物溶液(干CH3CN中0.4M)(Iyer,R.P.;Regan,J.B.;Egan,W.;Beaucage,S.L.J.Am.Chem.Soc.1990,112,1253)的溶液来处理。使用DCA/DCM将反应混合物去三苯甲基化,用水稀释溶液并用二氯甲烷萃取。用NaHCO3、水和盐水洗涤合并的有机层。将有机层浓缩来获得经过反应的完全保护的二核苷磷酸三酯。如上所述进行保护基团的去三苯甲基化和除去保护基团。在处理、色谱纯化和冷冻干燥之后,获得纯度>96%的Rp,Sp5的钠盐(~60∶40混合物),如通过反相HPLC所确定的。
使用以上相似的程序还可以制备本发明要求保护的其他二核苷酸。相关的提示是本领域技术人员将能够使用传统的磷酸三酯方法或H-膦酸酯方法(Beaucage,S.L.;Iyer,R.P.,Tetrahedron1993,49,1925)合成相似的化合物。
实施例2:3′dApsU2′OMe的S-异丙基羰基氧基甲基硫代磷酸酯(6k)
在两个步骤中制备目标化合物6k(也是表1中指定的化合物2)。
步骤1.碘甲基异丙基碳酸酯的制备:向无水碘化钠(6g,40mmol)在无水乙腈(20mL)中的溶液中,在20min的时间内逐滴加入无水乙腈(10mL)中的氯甲基异丙基碳酸酯(2.9g,19mmol)。将用铝箔遮盖(避光)的反应混合物在室温下搅拌过夜。将分离的固体滤出,用乙腈洗涤并将滤液在减压下浓缩。将残余物溶解于水(10mL)中并在乙醚(25mL)中萃取有机物。用亚硫酸氢钠(5%,10mL)洗涤醚萃取物,接着用盐水(10mL)洗涤。将有机层通过无水硫酸钠干燥、过滤、浓缩并在高干燥真空下干燥。收量2.72g(58%);1H-NMRδ1.3(d,6H),4.95(m,1H),5.95(s,2H)ppm。
步骤2.二核苷酸3′-ApsU2′OMe的烷基化。在搅拌下,向实施例1的二核苷酸(60mg,0.098mmol)的水溶液中(HPLC,400mL),加入碘甲基异丙基碳酸酯(80mg,0.0166mmol,3.33eq)丙酮(1mL)溶液。
加入另外的丙酮(1mL),以获得澄清的溶液来避免烷化剂的油性液滴的任何分离。将铝箔覆盖的反应混合物搅拌3h,在旋转蒸发条件下浓缩,再随后在高真空下浓缩,以获得白色固体的反应混合物。最初使用氯仿,再缓慢使用含有2%至最终8%甲醇的氯仿,通过硅胶柱色谱来纯化。将含有主要成分的级分合并、浓缩并在高真空下干燥过夜。以几乎定量的收量(68mg)来分离所需的纯化产物6k;31P-NMR(MeOH-d4)δ27.7,28.6。
实施例3:3′dApsU2′OMe的S-甲基胆酸酯6l的制备
步骤1.氯甲基脱氧胆酸酯的合成。向乙醇(4mL)中的脱氧胆酸(120mg,0.306mmol)中,加入碳酸铯(53mg,0.160mmol)的水溶液(3mL)。将反应混合物搅拌30分钟,最初通过旋转蒸发6l,随后在高真空下,除去乙醇。将残余物冻干以获得作为白色粉末的铯盐。在室温下,向铯盐在N,N-二甲基甲酰胺(DMF,3mL)中的溶液中,加入溴氯甲烷(10mL),并将铝箔覆盖的反应混合物在室温下搅拌24h。除去溶剂并在二氯甲烷(20mL)中萃取反应混合物,用水(5mL)、盐水(5mL)洗涤,并通过无水硫酸钠干燥除去溶剂,以获得氯甲基化合物(100mg,74%)。没有进一步纯化将其用于转化成相应的碘甲基衍生物。
步骤2.碘甲基脱氧胆酸酯的制备。向无水乙腈(3mL)中的碘化钠(304mg,2.03mmol)溶液中,缓慢加入乙腈(6mL)和二氯甲烷(2mL)混合物中的氯甲基酯(438mg,0.99mmol)。在室温下,将反应混合物避光搅拌超过48小时。浓缩后,在二氯甲烷(15mL)中萃取反应混合物,用水(5mL)、亚硫酸氢钠(5%,5mL)和最后用盐水(5mL)洗涤有机层。通过无水硫酸钠干燥,并在除去溶剂后获得粗制产物,并通过硅胶柱色谱纯化来获得碘化合物(110mg,21%)。
步骤3.碘甲基脱氧胆酸酯的偶合。向实施例1的3′dApsU2′OMe(50mg,0.082mmol)的水溶液(400mL)中,加入碘甲基脱氧胆酸酯(110mg,2.066mmol)的丙酮(3mL)溶液。通过加入更多的丙酮(~6mL)来溶解分离的固体,并将反应混合物搅拌过夜。在真空下浓缩,使用氯仿至含有甲醇(2至10%)的氯仿,通过硅胶柱色谱来纯化。将级分合并、浓缩并在高真空下干燥,以获得所需的产物6l(40mg,49%);31P-NMR(MeOH)δ28.2,29.1ppm。
实施例4:N-(叔丁氧羰基)-L-苯丙氨酸酯(6m)的制备
N-(叔丁氧羰基)-L-苯丙氨酸碘甲基酯。向乙醇(3mL)中的N-(叔丁氧羰基)-L-苯基甘氨酸(663mg,2.49mmol)中,加入碳酸铯(427mg,1.31mmol)的水溶液(2mL)。在停止气体蒸发后,将反应混合物搅拌1h。除去溶剂并冻干以获得铯盐。向铯盐(270mg,0.82mmol)的N,N-二甲基甲酰胺(DMF,2mL)溶液中,加入溴氯甲烷(5mL)并将铝箔覆盖的反应混合物搅拌过夜。滤出分开的固体,用DMF(2ml)洗涤固体,并将滤液在高真空下浓缩。通过TLC(Hex:EtOAc4:1)将产物(206mg,80%)纯化。没有进一步纯化,将该中间产物用于转化成碘化合物。向碘化钠(196mg,1.31mmol)的无水乙腈(3mL)溶液中,加入无水乙腈(1mL)中的氯甲基苯丙氨酸酯衍生物(206mg,0.656mmol)。将反应混合物在室温下避光搅拌过夜。过滤、用DMF(3mL)洗涤固体并在真空下浓缩滤液。将残余物在二氯甲烷(10mL)和水(5mL)中萃取,用NaHSO3(5%,5mL)和盐水(饱和,5mL)洗涤有机层。将有机层通过无水Na2SO4干燥,并浓缩,以产生所需的碘化合物(199mg,75%)。
3′dApsU2′OMe的烷化。向实施例1的3′dApsU2′OMe(44mg,0.072mmol)的水(400μL)溶液中,加入丙酮(800ul)中的碘化物(100mg,0.25mmol)并将反应混合物搅拌过夜。在真空下将反应混合物浓缩、冻干并通过硅胶柱色谱纯化,使用氯仿和含有氯仿和甲醇(2%至10%)的混合物。收集级分、合并、浓缩并在高真空下干燥,以获得t-Boc保护的苯丙氨酸偶合的产物6m(40mg,65%);31P-NMR(MeOH-d4)δ28.7,27.9ppm。
实施例5:3′dApsU2′OMe的4-乙酰氨基苄基衍生物6n的制备
4-乙酰氨基苄醇的制备。在室温下,向4-乙酰氨基苯甲醛(10g,61.3mmol)的甲醇(100mL)溶液中,逐份加入硼氢化钠(800mg)。将反应混合物搅拌过夜,并通过TLC检查反应的进程,使用4:1的己烷:EtOAc作为洗脱剂。起始原料的不存在表示反应完成,将反应混合物在旋转蒸发中浓缩。将残余物在水(25mL)和乙酸乙酯(4x50mL)之间分级,并用盐水(25mL)洗涤有机层。将乙酸乙酯层通过无水磷酸钠干燥,并除去溶剂,产生了浅黄色固体的醇,将其在高真空下干燥。8.6g(85%);1H NMR(DMSO-d6):δ2.0(s,3H),4.5(d,2H),5.2(t,1H),7.25(d,2H),7.55(d,2H),9.95(s,1H)ppm。
4-乙酰氨基苄基碘的制备。向冷却的无水DMF(5mL)溶液中,加入亚硫酰氯(0.2mL,2.8mmol)。将混合物搅拌10min并加入KI(2.49g,15mmol)的无水DMF(12mL)溶液,接着加入上述制得的醇(0.165g,1mmol)。将反应混合物在冰浴中搅拌3h,并使其在室温下搅拌过夜。将反应混合物倒入冰水中(25mL)并用乙醚萃取(3x25mL)。用盐水洗涤乙醚层,通过无水磷酸钠干燥并浓缩来除去溶剂。获得作为澄清黄色固体的产物(138mg,50%)。(TLC Hex:EtOAc(1∶1))。1H NMR(CDCl3):δ2.17(s,3H),4.45(s,2H),7.17(br.s,1H),7.33(d,2H),7.43(d,2H)ppm。该化合物还可以使用乙腈中的碘化铯和三氟化硼醚合物以提高的收率(~75%)来制备。按照之前对于胆酸类似物所述的,进行4-乙酰氨基苄基碘与3′dApsU2′OMe的偶合。
实施例6:3′dApsU2′OMe的4-苯甲酰氨基丁基类似物6o的合成
4-苯甲酰氨基丁基碘的制备。在0-5℃下,向冷的无水DMF(5mL)中,加入亚硫酰氯(0.2mL),并将混合物搅拌15分钟。加入碘化钾(2.4g,5mmol)的无水DMF(8mL)溶液,接着加入4-苯甲酰丁醇(193mg,1mmol)的无水DMF(2mL)溶液。将有色的反应混合物搅拌过夜。通过倒入冰冷的水中(~10mL)并用乙醚萃取(3x15mL)来处理反应混合物。最后,用水、盐水洗涤乙醚层,并通过无水硫酸钠干燥。将过滤和除去溶剂后获得的粗制产物通过柱色谱纯化(使用己烷和乙酸乙酯(4∶1)的混合物),以获得作为油状物的碘化合物,45%。1H NMR(CDCl3):δ1.77(m,2H),1.93(m,2H),3.23(t,2H),3.55(q,2H),6.26(br.s,1H),7.48(m,3H),7.75(m,2H)ppm。
按照之前所述的,进行4-苯甲酰氨基丁基碘与3′dApsU2′OMe的偶合,来获得标题化合物6o。
实施例7:3′dApsU2′OMe的5-苯甲酰氧基戊基类似物的合成
5-苯甲酰氧基戊-1-醇的制备。将苯甲酸(1g)、1,5-戊二醇(5mL)和对甲苯磺酸(110mg)的混合物在100℃的油浴中加热过夜。将反应混合物冷却至室温,倒入水(50mL)中,并用EtOAc(2x25mL)萃取,用碳酸钠(5%,20mL)洗涤,接着用盐水(15mL)洗涤。将有机层通过无水硫酸钠干燥,过滤并浓缩来获得几乎纯的产物(1.15g,67%)。
5-苯甲酰氧基-1-碘戊烷的制备。36%的收率。
1H NMR(CDCl3):δ1.57(m,2H),1.85(m,4H),3.22(t,2H),4.33(t,2H),7.44(m,2H),7.57(m,1H),8.04(m,2H)ppm。
按照之前所述的,进行5-苯甲酰氧基-1-碘戊烷与3′dApsU2′OMe的偶合。
5-苯甲酰氧基丁-1-醇的制备。该化合物在用于5-苯甲酰戊-1-醇的工序中使用1,4-丁二醇以73%的收率制备。
实施例8:3′dApsU2′OMe的4-乙酰氧基苄基类似物6q的合成
步骤1.4-乙酰氧基苄醇的制备。在冰浴中,向冷却的4-羟基苄醇(1.95g,14mmol)的乙酸乙酯(25mL)混悬液中,在搅拌下一次性加入三乙胺(2.1mL,14.9mmol)。由另外的漏斗逐滴加入乙酰氯(1.1mL,15.5mmol)的乙酸乙酯(12mL)溶液。将反应混合物搅拌过夜。滤出固体,用乙酸乙酯洗涤,并在浓缩后,通过柱色谱纯化残余物,最初使用己烷,之后逐渐使用至40%的乙酸乙酯。收率40%。1H-NMR(CDCl3):δ2.02(br.s,1H),2.29(s,3H),4.65(s,2H),7.07(d,2H),7.36(d,2H)ppm。
步骤2.4-乙酰氧基苄基碘的制备。在氮气下,向4-乙酰氧基苄醇(0.332g,2mmol)和碘化铯(0.571g,2.2mmol)的无水乙腈(10mL)溶液中,引入乙腈(5mL)中的三氟化硼醚合物(0.28mL,2.2mmol)。搅拌过夜后,将反应混合物倒入冰冷水(20mL)中,滤出分开的固体,用水洗涤,接着用己烷洗涤。将产物在高真空下干燥。收率,0.39g,71%;TLC,己烷:EtOAC(4∶1)。1H NMR(CDCl3):δ2.3(s,3H),4.35(s,2H),7.05(d,2H),7.5(d,2H)ppm。
步骤3.3′dApsU2′OMe的4-乙酰氧基苄基类似物的合成。按照之前所述的,进行用4-乙酰氧基苄基碘对3′dApsU2′OMe进行烷化。
实施例9:初抗和二抗HCV试验
初抗-HCV试验:在3-天试验中测定了对HCV的抗病毒活性(Okuse等,2005;Antiviral.Res.65:23;Korba等,2008,Antiviral Res.77:56),使用作为96孔板上的分汇合培养物而维持的稳定表达HCV复制子的细胞系,AVA5[亚基因组(CON1),基因型1b](Blight等,2000,Science290:1972)。通过胞内HCV RNA(在各培养物样品中,标准化至细胞B-肌动蛋白RNA的水平)的斑点杂交分析测定抗病毒活性。通过维持于平行平板中的培养物的中性红染料吸收来测定细胞毒性。
使用来自所有经处理培养物(Korba&Gerin,1992,Antivir.Res.19:55;Okuse等,2005,Antivir.Res.65:23)的合并数据,通过线性回归分析计算EC50、EC90和CC50值。由回归分析产生的标准误差计算EC50和EC90的标准偏差。EC50和EC90是分别观察到胞内HCV RNA被2倍或10倍抑制(相对于未处理培养物的平均水平)时各自的药物浓度。CC50是观察到中性红染料吸收降低了2倍水平(相对于未处理培养物中的平均水平)时的药物浓度。以CC50/EC50来计算选择性指数(S.I.)。重组人干扰素2b(PBLlaboratories,Inc.)用作试验对照。
二抗-HCV试验:本试验使用在初抗试验中所述的形式,测定了对抗不同HCV基因型的活性。包括将对抗基因型1b HCV的活性用于比较。目前可用的是含有H/FL-Neo的复制子细胞系(基因型1a(H77),全长构建体)(Blight等,2003,J.Virol.77:3181)。复制子细胞系AVA5(亚基因组(CON1),基因型1b;(Blight等,2000,Science290:1972))。
初抗和二抗试验的结果显示于表3中。
表3
实施例10:细胞毒性试验
进行化合物对抗一组细胞系的细胞毒性特征分析。在96孔板中进行标准MTT试验,使用Promega CellTiter96非放射性细胞增殖试验试剂盒,结合96-孔板阅读器(ThermoMax,Molecular devices),并使用MDBK、Vero和HFF细胞系(获自ATCC)。使用了许多对照,包括核苷类似物3TC、AZT和ddC,以及不含药物的培养基。使用SDS作为阳性细胞毒素对照。在100μM、300μM和1000μM浓度下测试化合物,重复三次进行。在用测试物质培养细胞24小时后,进行MTT试验。数据显示于表4中。
表4.化合物在各种细胞系中的体外细胞毒性研究
实施例11:抑制试验
可以在以下试验中测量作为HCV NS5B RNA-依赖性RNA聚合酶(RdRp)抑制剂的本发明化合物的有效性。
HCV NS5B聚合酶抑制试验
将该试验用于测量本发明化合物在杂聚RNA模板上抑制丙肝病毒(HCV)的RNA-依赖性RNA聚合酶(NS5B)的酶活性的能力。
操作:
试验缓冲条件:(50μl-总/反应)20mM Tris,pH7.550μM EDTA5mM DTT2mMMgCl280mM KCl0.4U/μL RNAsin(Promega,储液是40单位/μL)0.75μg t500(使用T7失控转录制得的500-nt RNA,其具有来自丙肝基因组的NS2/3基因座的序列)1.6μg纯化的丙肝NS5B(使用C-末端截短的21个氨基酸形成)1μM A、C、U、GTP(三磷酸核苷混合物)[α-33P]-GTP或[α-32P]-GTP。
在高达100μM终浓度的不同浓度下测试化合物。
制得合适体积的反应缓冲剂,其包括酶和模板t500。将本发明的硫代核苷衍生物吸移至96孔板的孔中。制得包括放射性标记的GTP的三磷酸核苷(NTP)的混合物,并移液至96孔板的孔中。通过加入酶-模板反应溶液来启动反应并使其在室温下反应1-2h。
通过加入20μL0.5M EDTA,pH8.0来猝灭反应。包括空白反应,其中在加入反应缓冲剂之前将猝灭溶液加入NTP中。
将50μL猝灭的反应液在DE81滤盘上(Whatman)并使其干燥30min。用0.3M甲酸铵,pH8洗涤该滤盘(150mL/洗涤,直至1mL洗涤物中的cpm低于100,通常洗涤6次)。在闪烁计数器中的5-mL闪烁流体中计数该滤盘。
根据以下公式来计算抑制百分比:
%抑制=[1-(测试反应物中的cpm-空白中的cpm)/(对照反应物中的cpm-空白中的cpm)]x100。
反向筛选
在以下试验中测量本发明的化合物抑制人DNA聚合酶的能力。
a.人DNA聚合酶α和β的抑制
反应条件
50μL反应体积的反应缓冲剂成分:20mM Tris-HCl,pH7.5,200μg/mL牛血清白蛋白,100mM KCl,2mMβ-巯基乙醇,10mM MgCl2,1.6μM dA、dG、dC、dTTP,α33P-dATp酶和模板:0.05mg/mL缺口的鱼精DNA模板0.01U/μL DNA聚合酶α或β。缺口鱼精DNA模板的制备:将5μL1M MgCl2加入500μL激活的鱼精DNA中(USB70076);温热至37℃,并加入30μL65U/μL的核酸外切酶III(GibcoBRL18013-011);在37℃下培养5min;通过加热至65℃10分钟来终止反应;将50-100μL等份试样装载至装备有20mM Tris-HCl,pH7.5的Bio-spin6色谱柱(Bio-Rad732-6002)上;通过在1,000xg下离心4min来洗脱;合并洗脱液并在260nm下测量吸光度来测定浓度。
将DNA模板稀释至合适体积的20mM Tris-HCl,pH7.5中,并将酶稀释至合适体积的20mM Tris-HCl(含有2mMβ-巯基乙醇和100mMKCl)中。将模板和酶吸移至微离心管或96孔平板中。还各自使用酶稀释缓冲剂和测试化合物溶剂制得了排除酶的空白反应液和排除测试化合物的对照反应液。用含有如上所示成分的反应缓冲剂来启动反应。将反应在37℃下培养1小时。通过加入20μL0.5M EDTA来猝灭反应。将50μL猝灭的反应液点在Whatman DE81滤盘上并风干。用150mL0.3M甲酸铵,pH8重复洗涤滤盘,直至1mL的洗涤物<100cpm。用150mL无水乙醇将滤盘洗涤两次,并用150mL无水乙醚洗涤一次,干燥,并在5mL闪烁流体中计数。
根据以下公式来计算抑制百分比:
%抑制=[1-(测试反应物中的cpm-空白中的cpm)/(对照反应物中的cpm-空白中的cpm)]x100。
人DNA聚合酶γ的抑制
在包括以下物质的反应物中测量对人DNA聚合酶γ抑制的潜能:0.5ng/μL酶;10μMDATP、dGTP、dCTP和TTP;2μCi/反应物[α33P]-dATP,和购自US Biochemical的0.4μg/μL激活的鱼精DNA,它们存在于含有以下物质的缓冲剂中:20mM Tris pH8,2mMβ-巯基乙醇,50mMKCl,10mM MgCl2和0.1μg/μL BSA。使反应在37℃下进行1h,并通过加入0.5M EDTA至142mM终浓度来猝灭反应。通过阴离子交换滤器结合法和闪烁计数来定量产物形成。在高达50μM下测试化合物。
根据以下公式来计算抑制百分比:
%抑制=[1-(测试反应物中的cpm-空白中的cpm)/(对照反应物中的cpm-空白中的cpm)]x100。
在以下试验中测量了本发明化合物抑制HIV感染性和HIV传播的能力。
HIV感染力试验:
使用所选择的用于低背景β-半乳糖苷酶(β-gal)表达的同时表达CXCR4和CCR5的HeLa Magi细胞的变体进行了试验。将细胞感染48h,并且用化学发光物质(GalactolightPlus,Tropix,Bedford,Mass.)定量来自整合HIV-1LTR启动子的β-gal产生量。从100μM开始,在两倍连续稀释中滴定(一式两份)抑制剂;相对于对照感染计算各浓度下的百分比抑制。
HIV传播的抑制:
通过美国专利No.5,413,999(1995年5月9日)和J.P.Vacca等,Proc.Natl.Acad.Sci.,91:4096-4100(1994)中所述的方法来测量本发明的化合物抑制人免疫缺陷病毒(HIV)的能力,在此将这两篇文献的全部内容引入本文作参考。
采用以下试验来测量本发明化合物对抗其他RNA-依赖性RNA病毒的能力:化合物对抗鼻病毒的体外抗病毒活性的测定(细胞病变抑制试验);试验条件描述于Sidewall和Huffman的论文中,“Use of disposable microtissue culture plates for antiviraland interferon induction studies”,Appl.Microbiol.22:797-801(1971)。
病毒:
2型鼻病毒(RV-2),株系HGP,与Sidwell和Huffman的参考文献中所述的KB细胞和培养基(0.1%NaHCO3,无抗生素)一起使用。获自ATCC的病毒是来自患有轻度急性发烧上呼吸道疾病的成年男性的咽喉拭子。
9型鼻病毒(RV-9),株系211,和14型鼻病毒(RV-14),株系2,也是获自Rockville,Md.的美国典型培养物收集所(ATCC)。RV-9来自人咽喉冲洗物,RV-14来自患有上呼吸道疾病的年轻人的咽喉拭子。这两种病毒都与作为人颈部类上皮癌细胞的HeLa Ohio-1细胞(Dr.Fred Hayden,Univ.of VA)一起使用。将含有5%胎牛血清(FBS)和0.1%NaHCO3的MEM(Eagle′s最小必需培养基)用作生长培养基。
用于所有3种病毒类型的抗病毒测试培养基是含有5%FBS,0.1%NaHCO3,50μg庆大霉素/mL和10mM MgCl2的MEM。
2000μg/mL是用于测试本发明化合物的最高浓度。在测试化合物后大约5min,将病毒加入试验平板中。还进行了适当的对照。用潮湿的空气和5%CO2在37℃下培养试验平板。通过显微镜观察形态变化来监控对照细胞中的细胞毒性。病毒CPE数据和毒性对照数据的回归分析获得了ED50(50%有效剂量)和CC50(50%细胞毒性浓度)。通过公式:SI=CC50/ED50来计算选择性指数(SI)。
化合物对抗登革热病毒、Banzi病毒和黄热病毒的体外抗病毒活性的测定(CPE抑制试验)。
在以上的Sidewall和Huffman参考文献中提供了试验详细内容。
病毒:
2型登革热病毒,新几内亚株系,获自疾控中心。将两个非洲绿猴肾细胞系用于培养病毒(Vero)并进行抗病毒测试(MA-104)。黄热病毒,17D株系,从感染的小鼠大脑制得,和Banzi病毒,H336株系,分离自南非发烧男孩的血清,这两种病毒都获自ATCC。将Vero细胞与这两种细胞一起使用并用于试验。
细胞和培养基:
MA-104细胞(BioWhittaker,Inc.,Walkersville,Md.)和Vero细胞(ATCC)用于含有5%FBS和0.1%NaHCO3并且不含抗生素的培养基199中。用于登革热、黄热和Banzi病毒的试验培养基为MEM、2%FBS、0.18%NaHCO3和50μg庆大霉素/mL。
根据Sidewall和Huffman参考文献和与以上鼻病毒抗病毒测试相似的方法来进行本发明化合物的抗病毒测试。在5-6天后,获得了这些病毒中每一种适当的致细胞病变效应(CPE)情况。
化合物对抗西尼罗病毒的体外抗病毒活性的测定(CPE抑制试验)。
在以上引用的Sidewall和Huffman参考文献中提供了试验详细内容。西尼罗病毒,源自乌鸦大脑的New York分离物,获自疾控中心。如上所述生长和使用Vero细胞。测试培养基是MEM,1%FBS,0.1%NaHCO3和50μg庆大霉素/mL。
按照Sidewall和Huffman的方法进行本发明化合物的抗病毒测试,该方法与用于测试鼻病毒活性的方法相似。在5-6天后,获得了适当的细胞病变效应(CPE)情况。
化合物对抗鼻病毒、黄热病毒、登革热病毒、Banzi病毒和西尼罗病毒的体外抗病毒活性的测定(中性红吸收试验)。
进行了以上的CPE抑制试验后,使用了另外的细胞病变检测方法,该方法描述于“Microtiter Assay for Interferon:Microspectrophotometric Quantitation ofCytopathic Effect”,Appl.Environ.Microbiol.31:35-38(1976)。使用型号EL309微平板阅读器(Bio-Tek Instruments Inc.)来阅读试验平板。如上计算ED50和CD50。
实施例12:化合物2与抗-HCV化合物、病毒唑、干扰素、核苷类似物2′CmeC和蛋白酶 抑制剂VX-950组合的协同抗病毒活性。
使用实施例9中所述的初级复制子试验进行了表1的化合物2(其在该治疗方案中也称为6k)与干扰素、病毒唑、VX-950(蛋白酶抑制剂)和2′CmeCyt(聚合酶抑制剂)的联合治疗。简言之,基于每种化合物的EC90值(观察到HCV RNA减少10倍时的药物浓度),以预定的单独药剂的相对比例将两种药剂混合在一起。对于药剂的每种组合,使用了三个浓度比例,集中于使用等效抗病毒浓度的化合物。然后产生了稀释系列(六次三倍浓缩步骤,从接近约EC90开始),在各稀释步骤中,两种药剂的浓度比保持相同。按照以上对于单独治疗时所述的进行了毒性分析。通过使用CALCUSYN程序(Biosoft,Inc.,Cambridge,英国)测定了联合研究中药物相互作用的分析。该程序使用几种方法来评价协同、叠加或对抗效果,这些方法包括Chou和Talalay,使用Monte Carlo技术的统计分析来提供置信界限、受级分影响的置信区间(FA-CI)图、等效线图和中值作用图。(Belenkii,M.S.Schinazi,R.A method for theanalysis of combination therapies with statistical analysis。Antiviral Res.25,11,2005)。数据显示于表5中。
表5
实施例13:化合物2的体外细菌突变性试验
操作:在干的二甲亚砜(DMSO)中配制化合物2,并使用细菌突变试验的预培养形式,在5000μg/平板(用于该试验的标准极限剂量)的最大浓度下进行测试,并一起使用了合适数量的半-log10稀释液。无菌检测平板上不存在菌落证实了微生物污染的不存在。对于载体对照的平均回复体菌落数与实验室历史对照范围相近或在实验室历史对照范围之内。
将100微升等份的合适细菌培养物分配至存储在冰上的样品试管中。将等份的载体、阳性对照或给药制剂分配至合适的样品试管中。将2mL顶层琼脂和HBT帽加入样品试管中,倒置3次再倒入MG平板中。将盖子放回平板上并置于水平表面上使琼脂固化。将平板在培养箱中培养48至72h。检查各平板的背景菌苔和回复体数量。
对照:合适的阳性对照化合物(在需要的情况中,使用S9混合物)诱导回复体菌落数量提高至同时的使用合适细菌菌株的载体对照水平(对于菌株TA100,1.5×)的至少两倍,证实了测试系统的灵敏度和S9混合物的活性。
结果:暴露于化合物2后获得了非回复体细菌的背景菌苔的不明显变薄,表明测试物质在所测试的水平下对细菌是无毒的。没有观察到沉淀。
在S9混合物不存在或存在下,暴露于测试物质化合物2后,使用任何菌株获得了回复体菌落计数中没有实质性提高。因此,推断化合物2在该体外突变性试验中没有显示出任何基因毒性活性的证据。数据显示于以下的表6、7、8、9和10中。
表6S9不存在下测试的化合物2
*:如果适用,对平板或背景菌苔的注释:污染(C),不完整菌苔(IL),无菌苔(NL),不需要(NR),差菌苔(PL),沉淀(ppt)
与同时进行的载体对照相比的平均回复体中的倍数应答
SD:样本标准偏差(注意,基于两个值的SD可能是不可靠的)
A:由于不是剂量相关的,也没有在历史对照范围之外,因此菌落计数的显著降低被认为可能是由于正常变化,而不是因为毒性。
表7S9不存在下测试的化合物2
*:如果适用,对平板或背景菌苔的注释:污染(C),不完整菌苔(IL),无菌苔(NL),不需要(NR),差菌苔(PL),沉淀(ppt)。
与同时进行的载体对照相比的平均回复体中的倍数应答
表8S9存在下测试的化合物2
*:如果适用,对平板或背景菌苔的注释:污染(C),不完整菌苔(IL),无菌苔(NL),不需要(NR),差菌苔(PL),沉淀(ppt)
与同时进行的载体对照相比的平均回复体中的倍数应答
SD:样本标准偏差(注意,基于两个值的SD可能是不可靠的)
表9S9存在下测试的化合物2
*如果适用,对平板或背景菌苔的注释:污染(C),不完整菌苔(IL),无菌苔(NL),不需要(NR),差菌苔(PL),沉淀(ppt)
与同时进行的载体对照相比的平均回复体中的倍数应答
SD:样本标准偏差(注意,基于两个值的SD可能是不可靠的)
表10测试的阳性对照
与同时进行的载体对照相比的平均回复体中的倍数应答
SD:样本标准偏差(注意,基于两个值的SD可能是不可靠的)
所有阳性对照均是已知的诱变剂
实施例14:化合物2在uPA SCID(KMT)小鼠中的耐受性研究
该研究的目标是评价化合物2(药物)在14天给药过程中在KMT小鼠中的耐受性和确定药物在研究动物中的药物动力学特性。用载体对照或用300mg/kg的日药物剂量处理两个分开组的动物14天。在第1天(第一次给药)、第7天和第14天(最后一次给药)给药后15分钟采集血样,用于测量研究动物血清中的药物浓度。每日监控体重和健康指数评分,以测定研究动物对给药方案和药物的耐受性。在研究的各早晨,将一瓶化合物2溶解于0.05M柠檬酸载体(pH3.0)中,至所需的40mg/mL浓度。将溶液以7.5ml/kg的体积用于给药动物。柠檬酸缓冲剂也用于载体对照动物的给药。
采用10只具有人肝细胞低植入(6周时低于20的hAAT值)的KMT转基因动物进行该研究。在治疗之前和研究过程中的每一天,记录单个动物体重。还对动物的临床体征每天评价一次(在早晨给药时),并监控发病率和死亡率。将研究动物分成2组,每组5只动物。对于每只动物,使用无菌注射器和饲喂针,通过口服管饲,将化合物2或柠檬酸载体对照每天给药一次。对于所有组,给药体积为7.5mL/kg(150μL/20g体重)。基于各单独动物的每日体重调节给药体积。组1动物接受了柠檬酸对照,组2动物接受了300mg/kg的化合物2。在第1天时,在早晨使用第一次药物给药开始研究,并继续至第14天,这是药物治疗的最后一天。在第1天的第一次给药后15分钟、第7天的给药后15分钟和第14天的最后一次给药后15分钟时,通过从每组所有动物的中央尾动脉收集血液。使血样凝固并从以上的凝结血块中取出血清。在运送至研究委托人之前,将血清储存在-80℃。最终实验时间表概括于以下的表11中。
表11.研究NEA-1的实验时间表
在处理之前和研究过程中的每天,记录单个动物的体重。还对动物的临床体征每天评价一次,并监控发病率和死亡率。用于监控研究动物的发病率(健康指数)的标准化评分概括于以下的表12中。
表12.小鼠发病率指数等级
研究动物通常能很好地耐受化合物2。载体对照组中的一只动物从研究的第11天至第14天呈现出适度升高的健康指数。药物治疗组中的两只动物也呈现出适度升高的健康指数值。所有其他研究动物完成了研究,具有等于最初值或高于最初值一半分数的健康指数值。
健康指数值显示于表13中。
表13.所有处理组中单个动物的健康指数值。
载体对照组中的2只动物(F139和F170)从研究的第1天至第14天具有最低的体重净损耗。药物组中的1只动物(F187)也显示出小的体重降低。
研究方案、药物和药物载体对研究动物的健康具有不同的作用。在本研究中,10只动物中只有3只显示出任何程度的不良影响,并且总而言之,这在对照组和药物组之间是平均分布的。因此,这个给药方案和300mg/kg的药物剂量是动物非常耐受的。
本文涉及的专利和科学文献建立起本领域普通技术人员可以使用的知识。将本文引用的所有美国专利和公开或未公开的美国专利申请引入本文作参考。将本文引用的所有公开的外国专利和专利申请引入本文作参考。将本文引用的所有其他公开的参考文献、文件、稿件和科学文献引入本文作参考。
尽管本发明已经通过其优选的实施方案进行了具体的显示和描述,本领域普通技术人员应当理解,在不脱离所附权利要求所概括的本发明范围的情况下,可以在形式和细节方面进行各种变化。还应当理解,本文所述的实施方案不是相互排斥的并且来自各个实施方案的特征可以根据本发明整体或部分结合。
Claims (2)
1.通式III的化合物或其药学上可接受的盐、立体异构体、互变异构体、或其组合在制备用于治疗HCV的药物中的应用:
其中:
M'和M”各自独立地为O,
X'是O或S,
Y'是OR12、NHR12和SR12,其中各R12独立地选自H、C1-C12脂肪族基团或者芳香族基团,其中各C1-C12脂肪族基团或者芳香族基团任选地被以下基团取代:芳基、NHC(O)-芳基、OC(O)2-C3-C12环烷基、OC(O)2-芳基、OC(O)2-杂芳基、或OC(O)2-C1-C12烷基,
Z'和Z”各自是O,
R和R'各自独立地是H、OH、O-C1-C6烷基、O-芳基、或O-杂芳基,
B1和B2各自独立地选自不存在、腺嘌呤、胞嘧啶、鸟嘌呤、胸腺嘧啶、或尿嘧啶,且
Q'是H、或
其中,X'和Y'是如上述所定义的,并且A是OH、O-C1-C6烷基、O-芳基、O-杂芳基、O-芳基C1-C24烷基、或O-C1-C24烷基杂芳基,
所述芳基是指双环芳基或三环芳基,其中至少一个环是芳香族的,
所述杂芳基是指吡啶基、吡嗪基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、噻吩基、呋喃基、喹啉基、异喹啉基、苯并咪唑基、苯并噁唑基、喹喔啉基,
所述芳香族基团是指所述芳基或所述杂芳基。
2.化合物在制备用于治疗HCV的药物中的应用,其中所述化合物选自:
或其药学上可接受的盐、立体异构体、互变异构体。
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2013
- 2013-03-13 US US13/800,931 patent/US9138442B2/en not_active Expired - Fee Related
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2014
- 2014-11-28 HK HK14112051.5A patent/HK1198516A1/zh not_active IP Right Cessation
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2015
- 2015-08-11 US US14/823,359 patent/US9539276B2/en not_active Expired - Fee Related
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2016
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KR20100132058A (ko) | 2010-12-16 |
US9539276B2 (en) | 2017-01-10 |
KR101620394B1 (ko) | 2016-05-12 |
KR101806314B1 (ko) | 2017-12-07 |
US9138442B2 (en) | 2015-09-22 |
EP2271351A2 (en) | 2011-01-12 |
GB201018497D0 (en) | 2010-12-15 |
KR101927905B1 (ko) | 2018-12-11 |
US20170304344A1 (en) | 2017-10-26 |
US20110207690A1 (en) | 2011-08-25 |
CN102123716B (zh) | 2013-09-18 |
EP2271351A4 (en) | 2016-08-31 |
US10376533B2 (en) | 2019-08-13 |
HK1250936A1 (zh) | 2019-01-18 |
WO2009146123A2 (en) | 2009-12-03 |
HK1198516A1 (zh) | 2015-05-15 |
CN107753499A (zh) | 2018-03-06 |
KR20160031021A (ko) | 2016-03-21 |
US20160038527A1 (en) | 2016-02-11 |
CN103816174A (zh) | 2014-05-28 |
KR20170137947A (ko) | 2017-12-13 |
GB2471806A (en) | 2011-01-12 |
US8404651B2 (en) | 2013-03-26 |
CN102123716A (zh) | 2011-07-13 |
US20130197066A1 (en) | 2013-08-01 |
GB2471806B (en) | 2012-12-19 |
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