CN1427722A - 用核苷类似物治疗或预防黄病毒感染的方法 - Google Patents
用核苷类似物治疗或预防黄病毒感染的方法 Download PDFInfo
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- CN1427722A CN1427722A CN01808127A CN01808127A CN1427722A CN 1427722 A CN1427722 A CN 1427722A CN 01808127 A CN01808127 A CN 01808127A CN 01808127 A CN01808127 A CN 01808127A CN 1427722 A CN1427722 A CN 1427722A
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- chemical compound
- purine
- denitrogenation
- azepine
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Abstract
本发明涉及一种在宿主体内用核苷类似物治疗或预防黄病毒感染的方法,包括施用治疗有效剂量的含有结构式(I)的化合物或其药学上可接受的盐。
Description
发明领域
本发明涉及用核苷类似物治疗或预防黄病毒感染的方法。
发明背景
肝炎是一种发生在全世界的疾病。它通常是病毒性的,尽管也知道还有其它的原因。到目前为止,病毒性肝炎是肝炎最普通的形式。每年约有750,000美国人受到肝炎的袭击,且这其中有超过150,000的人受到丙型肝炎病毒(HCV)的袭击。
HCV是一种属于黄病毒科的正链RNA病毒,与包括猪瘟病毒和牛病毒性腹泻病毒(BVDV)在内的瘟病毒属的关系最为密切。HCV被认为是通过产生互补的负链RNA模板而复制。由于缺乏有效的培养复制这种病毒的体系,HCV粒子是从混合人血浆中分离出来的,电子显微镜显示其直径为约50-60nm。HCV染色体组是约9,600bp的单链、正义RNA,编码3009-3030个氨基酸的多蛋白,后者被细胞的或两种病毒的蛋白酶共翻译和翻译后裂解成成熟的病毒蛋白(核心、E1、E2、p7、NS2、NS3、NS4A、NS4B、NS5A、NS5B)。一般认为结构蛋白E1和E2这两种主要的糖蛋白被包埋进病毒的脂质包被中并形成稳定的异源二聚体。还认为结构核心蛋白会和病毒RNA染色体组相作用形成核衣壳。称为NS2到NS5的非结构蛋白包括在病毒复制和蛋白合成中有酶功能的包括聚合酶、蛋白酶和解旋酶在内的蛋白。
HCV的主要污染源是血液。作为健康问题的HCV感染的量度是通过高危人群中的流行率来表示的。例如,西方国家中60%-90%的血友病患者和超过80%的静脉毒品滥用者都受到HCV的慢性感染。对静脉毒品滥用者而言,根据被研究的群体其流行率可从28%变化到70%。由于用于筛选血液供体的诊断工具的进步,与输血后相关的新HCV感染的比例最近有显著的降低。
现有的用于治疗HCV感染的只有干扰素-α(IFN-α)。然而,根据不同的临床研究,只有70%的受试病人血清中的丙氨酸转氨酶(ALT)水平恢复正常,并且在中断IFN治疗后,有35%-45%的有效病例复发。通常,只有20%-25%的患者对IFN有长期响应。临床实验表明将IFN与病毒唑(RIBA)联合治疗将导致比单独使用IFN强的临床反应。不同基因型的HCV对IFN治疗的响应不同,1b基因型较2型和3型更能耐受IFN治疗。
因此进一步开发抗病毒药剂有很大的必要。
发明概要
其中
B选自嘌呤、嘧啶或其类似物;
Ra选自H,单磷酸,二磷酸,三磷酸,被C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基取代的羰基,和
其中每一个Rc都是独立选自H、C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基和羟基保护基团;
Z是卤素或ORb,其中,Rb选自H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6酰基或羟基保护基团;
D1和D2是独立选自N3、F或H,D1和D2也可以合在一起选自C3-环烷基、-=CH2、或-=CF2,并且其中所述化合物是单一对映体或其混合物(包括外旋混合物)的形式;
附带条件是,当B是腺嘌呤时,Z是ORb,D1是H,D2是H,Rb是H,Ra不是三磷酸或H。
另一方面,这里提供了一种与药学上可接受的载体或赋形剂组合的含有本发明化合物的药物制剂。
再另一方面,这里提供了一种在宿主体内治疗或预防病毒感染的方法,包括施用含有至少一种如结构式I的化合物和至少一种其它治疗剂的复合物。
本发明另一方面是使用一种有结构式I的化合物,以制备一种治疗或预防宿主体内病毒感染的药物。发明详述
在一个实施方案中,病毒感染选自黄病毒感染。
在一个实施方案中,黄病毒感染选自丙型肝炎病毒(HCV)、牛病毒性腹泻病毒(BVDV)、猪瘟病毒和黄热病毒。
在另一个实施方案中,黄病毒感染是丙型肝炎病毒。
在一个实施方案中,还提供了一种在宿主体内抑制或降低病毒聚合酶活性的方法,包括使用治疗有效剂量的有结构式I的化合物。
在另一个实施方案中,病毒聚合酶是HCV聚合酶。
本发明涉及在宿主体内用核苷类似物治疗或预防黄病毒感染的方法,包括施用治疗有效剂量的含有结构式Ia的化合物或其药学上可接受的盐:
其中
B选自嘌呤、嘧啶或其类似物;
Ra选自H,单磷酸,二磷酸,三磷酸,被C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基取代的羰基,和
其中每一个Rc都是独立选自H、C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基和羟基保护基团;
Z是卤素或ORb,其中,Rb选自H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6酰基或羟基保护基团;并且
其中所述化合物是单一对映体或其混合物(包括外旋混合物)的形式;
附带条件是,当B是腺嘌呤时,Z是ORb,Rb是H,Ra不是三磷酸或H。
在一个实施方案中,本发明的化合物和方法包括以下的实施方案,或者单独使用或者结合使用。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基、1-脱氮-腺嘌呤-9-基、1-脱氮-鸟嘌呤-9-基、1-脱氮-肌苷-9-基、1-脱氮-2-氨基-嘌呤-9-基、1-脱氮-2-氨基-6-氯-嘌呤-9-基、1-脱氮-2-6-二氨基-嘌呤-9-基、3-脱氮-腺嘌呤-9-基、3-脱氮-鸟嘌呤-9-基、3-脱氮-肌苷-9-基、3-脱氮-2-氨基-嘌呤-9-基、3-脱氮-2-氨基-6-氯-嘌呤-9-基、3-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-腺嘌呤-9-基、7-脱氮-鸟嘌呤-9-基、7-脱氮-肌苷-9-基、7-脱氮-2-氨基-嘌呤-9-基、7-脱氮-2-氨基-6-氯-嘌呤-9-基、7-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-8-氮杂-腺嘌呤-9-基、7-脱氮-8-氮杂-鸟嘌呤-9-基、7-脱氮-8-氮杂-肌苷-9-基、7-脱氮-8-氮杂-2-氨基-嘌呤-9-基、7-脱氮-8-氮杂-2-氨基-6-氯-嘌呤-9-基、7-脱氮-8-氮杂-2-6-二氨基-嘌呤-9-基、8-氮杂-腺嘌呤-9-基、8-氮杂-鸟嘌呤-9-基、8-氮杂-肌苷-9-基、8-氮杂-2-氨基-嘌呤-9-基、8-氮杂-2-氨基-6-氯-嘌呤-9-基、8-氮杂-2-6-二氨基-嘌呤-9-基、2-氮杂-腺嘌呤-9-基、2-氮杂-鸟嘌呤-9-基、2-氮杂-肌苷-9-基、2-氮杂-2-氨基-嘌呤-9-基、2-氮杂-2-氨基-6-氯-嘌呤-9-基、2-氮杂-2-6-二氨基-嘌呤-9-基、3-脱氮-胸腺嘧啶-1-基、3-脱氮-胞嘧啶-1-基、3-脱氮-尿嘧啶-1-基、5-氮杂-胸腺嘧啶-1-基、5-氮杂-胞嘧啶-1-基、5-氮杂-尿嘧啶-1-基、6-氮杂-胸腺嘧啶-1-基、6-氮杂-胞嘧啶-1-基、6-氮杂-尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基、3-脱氮-腺嘌呤-9-基、3-脱氮-鸟嘌呤-9-基、3-脱氮-肌苷-9-基、3-脱氮-2-氨基-嘌呤-9-基、3-脱氮-2-氨基-6-氯-嘌呤-9-基、3-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-腺嘌呤-9-基、7-脱氮-鸟嘌呤-9-基、7-脱氮-肌苷-9-基、7-脱氮-2-氨基-嘌呤-9-基、7-脱氮-2-氨基-6-氯-嘌呤-9-基、7-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-8-氮杂-腺嘌呤-9-基、7-脱氮-8-氮杂-鸟嘌呤-9-基、7-脱氮-8-氮杂-肌苷-9-基、7-脱氮-8-氮杂-2-氨基-嘌呤-9-基、7-脱氮-8-氮杂-2-氨基-6-氯-嘌呤-9-基、7-脱氮-8-氮杂-2-6-二氨基-嘌呤-9-基、8-氮杂-腺嘌呤-9-基、8-氮杂-鸟嘌呤-9-基、8-氮杂-肌苷-9-基、8-氮杂-2-氨基-嘌呤-9-基、8-氮杂-2-氨基-6-氯-嘌呤-9-基、8-氮杂-2-6-二氨基-嘌呤-9-基、2-氮杂-腺嘌呤-9-基、2-氮杂-鸟嘌呤-9-基、2-氮杂-肌苷-9-基、2-氮杂-2-氨基-嘌呤-9-基、2-氮杂-2-氨基-6-氯-嘌呤-9-基、2-氮杂-2-6-二氨基-嘌呤-9-基、3-脱氮-胸腺嘧啶-1-基、3-脱氮-胞嘧啶-1-基、3-脱氮-尿嘧啶-1-基、5-氮杂-胸腺嘧啶-1-基、5-氮杂-胞嘧啶-1-基、5-氮杂-尿嘧啶-1-基、6-氮杂-胸腺嘧啶-1-基、6-氮杂-胞嘧啶-1-基、6-氮杂-尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基、3-脱氮-腺嘌呤-9-基、3-脱氮-鸟嘌呤-9-基、3-脱氮-肌苷-9-基、3-脱氮-2-氨基-嘌呤-9-基、3-脱氮-2-氨基-6-氯-嘌呤-9-基、3-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-腺嘌呤-9-基、7-脱氮-鸟嘌呤-9-基、7-脱氮-肌苷-9-基、7-脱氮-2-氨基-嘌呤-9-基、7-脱氮-2-氨基-6-氯-嘌呤-9-基、7-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-8-氮杂-腺嘌呤-9-基、7-脱氮-8-氮杂-鸟嘌呤-9-基、7-脱氮-8-氮杂-肌苷-9-基、7-脱氮-8-氮杂-2-氨基-嘌呤-9-基、7-脱氮-8-氮杂-2-氨基-6-氯-嘌呤-9-基、7-脱氮-8-氮杂-2-6-二氨基-嘌呤-9-基、8-氮杂-腺嘌呤-9-基、8-氮杂-鸟嘌呤-9-基、8-氮杂-肌苷-9-基、8-氮杂-2-氨基-嘌呤-9-基、8-氮杂-2-氨基-6-氯-嘌呤-9-基、8-氮杂-2-6-二氨基-嘌呤-9-基、5-氮杂-胸腺嘧啶-1-基、5-氮杂-胞嘧啶-1-基、5-氮杂-尿嘧啶-1-基、6-氮杂-胸腺嘧啶-1-基、6-氮杂-胞嘧啶-1-基、6-氮杂-尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在进一步的实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在进一步的实施方案中,B选自鸟嘌呤-9-基、胞嘧啶-1-基、尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在进一步的实施方案中,B选自胞嘧啶-1-基,它被NHR3、C1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在进一步的实施方案中,B选自鸟嘌呤-9-基,它被NHR3、C1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在进一步的实施方案中,B选自尿嘧啶-1-基,它被NHR3、C1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、5-氟-胞嘧啶-1-基、尿嘧啶-1-基、5-氟尿嘧啶或1,2,4-三唑-3-羧酰胺碱基(病毒唑碱基)。
在一个实施方案中,B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、5-氟-胞嘧啶-1-基、尿嘧啶-1-基或1,2,4-三唑-3-羧酰胺碱基(病毒唑碱基)。
在一个实施方案中,B选自鸟嘌呤-9-基、胞嘧啶-1-基、5`-氟-胞嘧啶-1-基、5`-氟尿嘧啶-1-基或尿嘧啶-1-基。
在一个实施方案中,B选自鸟嘌呤-9-基、胞嘧啶-1-基、5’-氟-胞嘧啶-1-基、5’-氟尿嘧啶-1-基或尿嘧啶-1-基。
在一个实施方案中,B是胞嘧啶-1-基。
在一个实施方案中,B是5-氟-胞嘧啶-1-基。
在一个实施方案中,B是5-氟尿嘧啶。
在一个实施方案中,B是鸟嘌呤-9-基。
在一个实施方案中,B是尿嘧啶-1-基。
其中,
X是H、卤素或NHR10、其中R10是H、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
Y是H、卤素或NHR11、其中R11是H、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
Y2是H、卤素或NHR12、其中R12是H、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
R9是H、羟基保护基团、C1-6酰基、C1-6烷基、C1-6烯基、或C2-6炔基;
Y3是H、卤素或NHR13、其中R13是H、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
R7是H、卤素、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
R8是H、卤素、C1-6酰基、C1-6烷基、C2-6烯基、或C2-6炔基;
在一个实施方案中,
X是H、卤素或NHR10,其中R10是H。
Y是H、卤素或NHR11,其中R11是H。
Y2是H、卤素或NHR12,其中R12是H。
R9是H、羟基保护基团、C1-6烷基。
Y3是H、卤素或NHR13,其中R13是H。
R7是H、卤素或C1-6烷基。
R8是H、卤素或C1-6烷基。
在进一步的实施方案中,
X是H、F或NHR10,其中R10是H。
Y是H、F或NHR11,其中R11是H。
Y2是H、F或NHR12,其中R12是H。
R9是H。
Y3是H、F或NHR13,其中R13是H。
R7是H、F或C1-6烷基。
R8是H、F或C1-6烷基。
在本发明的一个实施方案中,Ra选自H,单磷酸,二磷酸,和三磷酸。
在本发明的另一个实施方案中,Ra是H。
在一个实施方案中,Z是F或ORb,其中,Rb选自H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6酰基或羟基保护基团。
在一个实施方案中,Z是F。
在一个实施方案中,Z是ORb,其中,Rb选自H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6酰基或羟基保护基团。
在一个实施方案中,Z是ORb,其中,Rb选自H、C1-6烷基、或羟基保护基团。
在一个实施方案中,Z是ORb,其中,Rb选自H、或甲基。
在一个实施方案中,Z是ORb,其中,Rb是H。
D1和D2独立选自N3、F或H,D1和D2也可以合在一起选自环丙基、二氟环丙基、-=CH2、或-=CF2。
D1和D2是独立选自F、或H,D1和D2也可以合在一起选自环丙基、二氟环丙基-=CH2、或-=CF2。
D1和D2合在一起且为环丙基。
D1和D2合在一起且为二氟环丙基。
D1和D2合在一起且为-=CH2。
D1和D2合在一起且为-=CF2。
在一个实施方案中,D1是H或F。
在一个实施方案中,D2是H或F。
在一个实施方案中,D1是H。
在一个实施方案中,D2是H。
在一个实施方案中,D1是F。
在一个实施方案中,D2是F。
在一个实施方案中,D1是N3且D2是H。
在一个实施方案中,D1是H且D2是N3。
在一个实施方案中,D1是N3且D2是F。
在一个实施方案中,D1是F且D2是N3。
在一个实施方案中,D1是H且D2是F。
在一个实施方案中,D1是F且D2是H。
在一个实施方案中,D1和D2都是H。
在一个实施方案中,D1和D2都是F。
其中,Ra、B、D1、D2和Z如上定义。
其中,Ra、B、D1、D2和Z如上定义。
在进一步的实施方案中,本发明涉及一种在宿主中用核苷类似物治疗或预防黄病毒感染的方法,包括施用治疗有效剂量的含有结构式Id的化合物或其药学上可接受的盐类:
其中,Ra、B、D1、D2和Z如上面的定义。
其中,Ra、B、D1、D2和Z如上面的定义。
其中,Ra、B和Z如上面的定义。
在进一步的实施方案中,本发明涉及一种在宿主中用核苷类似物治疗或预防黄病毒感染的方法,包括施用治疗有效剂量的含有结构式Ig的化合物或其药学上可接受的盐类:
其中,Ra、B和Z如上面的定义。
在进一步的实施方案中,本发明涉及一种在宿主中用核苷类似物治疗或预防黄病毒感染的方法,包括施用治疗有效剂量的含有结构式Ih的化合物或其药学上可接受的盐类:
其中,Ra、B和Z如上面的定义。
其中,Ra、B和Z如上面的定义。
精通这一技术的技术人员将会理解,结构式(I)的化合物含有至少三个以1、2和3表示的手性中心。当D1与D2不同时,结构式(I)的化合物含有至少四个以1、2、3和4表示的手性中心。因此结构式(I)的化合物以不同的旋光异构体(例如β-L和β-D)和几何异构体(反式或α和顺式或β)的形式存在。所有的这些对映异构体、几何异构体和它们的混合物(包括外消旋混合物)都包含在本发明的范围之内。单个的旋光异构体或对映异构体都可用本技术领域中熟知的方法获得,例如手性HPLC、酶拆分以及使用手性助剂(chiralauxiliary)。
根据一个实施方案,用1和2标记的原子是顺式或β构型。
根据一个实施方案,用1和2标记的原子是顺式或β构型,而用3标记的原子对原子1和2是反式或α构型。
根据一个实施方案,本发明结构式I的化合物主要是以β-D构型的形式提供的。
根据一个实施方案,本发明结构式I的化合物主要是以β-L构型的形式提供的。
“主要”是指有一种对映异构体多于另一对映异构体。
在另一个实施方案中,本发明结构式I的化合物至少有95%没有相应的β-D对映异构体。
在另一个实施方案中,本发明结构式I的化合物至少有97%没有相应的β-D对映异构体。
仍在另一个实施方案中,本发明结构式I的化合物至少有99%没有相应的β-D对映异构体。
在另一个实施方案中,本发明结构式I的化合物至少有95%没有相应的β-L对映异构体。
在另一个实施方案中,本发明结构式I的化合物至少有97%没有相应的β-L对映异构体。
仍在另一个实施方案中,本发明结构式I的化合物至少有99%没有相应的β-L对映异构体。
还提供了本发明结构式I的化合物的药学上可接受的盐类。结构式(I)的化合物的药学上可接受的盐类是指那些来自于药学上可接受的无机和有机酸和碱的盐类。合适的酸类包括盐酸、氢溴酸、硫酸、硝酸、高氯酸、延胡索酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、醋酸、柠檬酸、甲磺酸、甲酸、安息香酸、丙二酸、萘-2-磺酸和苯磺酸。
来自合适的碱的盐类包括碱金属(例如钠)、碱土金属(例如镁)、铵和NR4 +(其中R是C1-4烷基)的盐。
除非另有说明,这里所使用的所有的技术术语和科学术语都与本发明所属技术领域的一般技术人员的通常的理解有相同的含义。这里所提到的所有的出版物、专利申请、专利、和其它的资料将全文并入以供参考。当发生冲突时,本说明书,包括定义,将作核对。此外,材料、方法、以及实施例仅是为了说明而不是为了限制。
本申请中所使用的“结构式(I)的化合物”是指所有以结构式(I)和结构式(Ia)至(Ii)表示的化合物。
本申请中所使用的“嘌呤或嘧啶或它们的类似物”是指在核苷酸中发现的嘌呤或嘧啶或是其模仿这种碱基的类似物,它们的结构(原子的种类和它们的排列方式)与天然碱基是类似的,但有额外的或缺少天然碱基的某些官能团。这种类似物包括那些用氮原子替换CH衍生而来的物质(例如,5-氮杂嘧啶类,如5-氮杂胞嘧啶)或者反过来(例如,7-脱氮嘌呤类,如7-脱氮腺苷或7-脱氧鸟苷)或两者皆有(例如,7-脱氮-8-氮杂嘌呤类)。这些碱基的类似物还包括那些化合物,其中的环取代基已被包括、除去或被本技术领域中常用的取代基(例如卤素、羟基、氨基、C1-6烷基)修饰。这些嘌呤或嘧啶碱基、类似物和衍生物将是本技术领域的技术人员熟知的。
本申请中所使用的“烷基”是指未取代或取代的(用卤素、硝基、CONH2、COOH、O-C1-6烷基、O-C2-6烯基、O-C2-6炔基、羟基、氨基、或COOQ,其中Q是C1-6烷基、C2-6烯基、C2-6炔基)直链、支链或环状烃部分(例如,异丙基、乙基、氟代己基或环丙基)。烷基这一术语还包括其中的一个或多个氢原子被卤素(最好是氟,例如CF3-或CF3CH2-)取代的烷基。
本申请中所使用的“环烷基”是指形成环的如上述定义的“烷基”。
“烯基”和“炔基”是指含有至少一个不饱和基团的烷基(例如,烯丙基)。
“羟基保护基团”这一术语在有机化学领域是被人熟知的。这种保护基团可在T.Greene的
Protective Groups In Organic Synthesis(John Wiley & Sons,1981)中找到。羟基保护基团的例子包括(但不限于)乙酰-2-硫乙酯、新戊酰氧甲酯和异丙氧基羰基氧甲酯(isopropyloxycarbonyloxymethyl ester)。
“芳基”这一术语是指不饱和的碳环,可以被OH、SH、氨基、卤素或C1-6烷基单取代或双取代。
“杂芳基”这一术语是指至少有一个碳环原子被杂原子(例如,N、O、或S)取代的芳基。
“胺基烷基”这一术语是指通过氮原子与邻近的原子共价结合的烷基。
“硫代烷基”这一术语是指通过硫原子与邻近的原子共价结合的烷基。
“烷氧基”这一术语是指通过氧原子与邻近的原子共价结合的烷基。
卤素选自F、Cl、I、和Br。
“宿主”这一术语是指包括人在内的动物。
在一个实施方案中,宿主是人。
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3’)-methyleneuridine(and cytidine)derivatives from uridineketonucleosides.Synthesis(1991),(4),282-8.A novel example of unsaturatedbranched chain sugar nucleoside:3’-deoxy-3’-methylideneadenosine.Helv.Chim.Acta(1981),64(2),425-9.Synthesis of 2’(and 3’)-deoxy-2’(and 3’)-methyleneadenosines and bis(methylene)furan 4’,5’-didehydro-5’-deoxy-2’(and3’)-methyleneadenosines.Inhibitors of S-adenosyl-L-homocysteine hydrolase andribonucleotide reductase.J.Org.Chem,.(1991),56(25),7108-13.Radical andpalladium-catalyzed deoxygenation of the allylic alcohol systems in the sugarmoiety of pyrimidine nucleosides.Nucleosides Nucleotides(1992),11(2-4),197-226.Synthesis and NMR spectra of some new carbohydrate modified uridinephosphoramidites.Nucleosides Nucleotides(1997),16(7-9),1529-1532.New methodfor the preparation of 3’-and 2’-phosphoramidites of 2’-and 3’-difluoromethyleneuridine.Tetrahedron(1996),52(23),7929-7938.Nucleic acidrelated compounds.83.Synthesis of 3’deoxyadenosine-3’-spirocyclopropane,3’-deoxyuridine-3’-spirocyclopropane,and 5’-deoxy-4’,5’-methanoadenosine。本发明的一些化合物在Sigma或Aldrich公司有售。
根据一个实施方案,可以理解治疗中需要使用的本发明的结构式I的化合物的量不仅会随着所选特定化合物而变化,而且也会因给药途径、需治疗的状况的性质以及病人的年龄与状况而变,这最终决定于临床医师或兽医。然而通常,合适的剂量约每天0.01-750mg/kg体重,较好是在0.5-60mg/kg/天,最好是在1-20mg/kg/天。
根据一个实施方案所需剂量通常是以一次或以分次经合适的间隔给药,例如每天两次、三次、四次或更多次。
在另一个实施方案中,化合物通常以单位剂型给药;例如每单位剂型中活性成分的含量为10-1500mg,较方便的是20-1000mg,最方便的是50-700mg。
根据本发明的另一个实施方案,施用活性成分而达到的活性化合物的血浆浓度峰值约为2-75μM,较好的约为2-50μM,最好约为3-30μM。这可以通过,例如,静脉注射0.1-5%的活性成分的溶液(可选择盐溶液),或口服含有约1-500mg活性成分的药丸而获得。通过连续输注每小时约0.01-5.0mg/kg的活性成分或间歇输注约0.4-15mg/kg的活性成分可以保持所需的血液水平。
用于治疗时,以未经加工成制剂的化学物质施用本发明的结构式I的化合物是可以的,根据本发明的一个实施方案,活性成分以药物制剂的形式给予较好。本发明的实施方案进一步提供了一种,它包含结构式(I)的化合物或是其药学上可接受的盐以及一种或多种药学上可接受的载体和(最好含有)其它治疗和/或预防成分。载体必需是“可接受的”,即与制剂的其它成分要相配伍且对其接受者没有毒性。
根据本发明的另一个实施方案,药物制剂包括(但不限于)那些适合口部、直肠、鼻、局部(包括口腔和舌下)、透皮、阴道或非肠道(包括肌肉、皮下和静脉)给药或以适合吸入法或吹入法给药的药物制剂。合适的话,制剂以分散的剂量单位给予较为方便且可用药剂学领域中熟知的方法来制备。根据这个实施方案,所有的方法都含有以下步骤,即使活性化合物与液态载体或良好粉碎的固态载体或这两者组合,需要的话,再将产品制成所需制剂的形状。
根据另一个实施方案,适合口服的药物制剂以分散的单位给予较为方便,比如含有预定量活性成分的胶囊、扁囊剂或片剂;或作为粉剂或颗粒。在另一个实施方案中,制剂以溶液剂、悬浮剂或乳剂的形式给予。在另一个实施方案中,活性成分以丸剂、药糖剂或糊剂给予。口服的片剂或胶囊可以含有常用的赋形剂,比如粘合剂、填充剂、润滑剂、崩解剂、或保湿剂。片剂可用本技术领域熟知的方法进行包衣。口服液态制剂可以是以下形式,例如,水性或油性悬浮剂、溶液剂、乳剂、糖浆剂或酏剂,或以使用前需和水或其它合适载体配制的无水制品存在。这种液态制剂可以含有常用的添加剂,比如悬浮剂、乳化剂、非水载体(包括食用油)、或防腐剂。
根据本发明一个实施方案,结构式I的化合物制成肠道外给药的形式(例如,通过注射,如推注注射或连续输注),可以安瓿、预装注射器、小体积输注液以单位剂型存在,或存在于添加有防腐剂的多剂量容器中。这种组合物可以是悬浮剂、溶液剂、或是油性或水性载体中的乳剂,还可以含有象悬浮剂、稳定剂和/或分散剂之类的配方成分。或者,活性成分也可以是粉末形式,这种粉末是通过灭菌固体的无菌分离或将溶液冻干获得的,在使用前用合适的载体(如无菌、无热原的水)配制。
当对表皮局部给药时,根据本发明的一个实施方案,结构式I的化合物被制成软膏、霜剂或洗剂、或者是透皮贴剂(transdermal patch)。这种透皮贴剂可以含有象里哪醇、香芹酚、麝香草酚、柠檬醛、薄荷醇和t-茴香脑之类的渗透增强剂。软膏和霜剂可以,例如,用水性或油性的基质以及合适的增稠剂和/或胶凝剂一起制备。洗剂可用水性或油性的基质制备,通常还将含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂、或着色剂。
适合口中局部给药的制剂(包括锭剂)含有存在于调味基质(通常是蔗糖和阿拉伯树胶或西黄芪胶)中的活性成分;锭剂含有存在于惰性基质(如明胶和甘油或蔗糖和阿拉伯树胶)中的活性成分;漱口药含有存在于合适的液态载体中的活性成分。
适合直肠给药的药物制剂其中的载体是固体。在另一个实施方案中,它们是以单位剂量栓剂的形式出现的。合适的载体包括可可脂和其它的本技术领域中通常使用的物质,通过混合活性成分和软化或融化的载体(类)再在模具中冷却成形可以方便的制作这种栓剂。
根据一个实施方案,适合阴道给药的制剂被制成阴道栓剂、棉塞、霜剂、凝胶、糊剂、泡沫剂或喷雾剂,除了活性成分外还含有本技术领域中已知的合适的载体。
在本发明的一个实施方案中,鼻内给药的化合物通常以液体喷雾或可分散的粉末的形式使用,或是滴鼻液的形式。滴鼻液通常是用含水或不含水的基质制成,还可以含有分散剂、增溶剂或悬浮剂。液体喷雾可以从加压的包装中方便的输递。
根据本发明的一个实施方案,通过吹入器、喷雾器或加压包装或其它输递气溶胶喷雾的简便方式可以很方便的进行化合物的吸入给药。在另一个实施方案中,加压包装包括合适的挥发剂,比如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在另一个实施方案中,加压的气溶胶的剂量单位是由阀门确定的,从而可输递测量的量。
或者,在另一个实施方案中,通过吸入或吹入给药时,本发明结构式I的化合物为干粉组合物的形式,例如化合物和合适粉末基质(如乳糖或淀粉)的粉末混合物。在另一个实施方案中,粉末组合物以单位计量的形式存在于(例如)胶囊或药筒中或是明胶或泡罩包装(blister pack)中,通过吸入器或吹入器的帮助可以给予其中的粉末。
在一个实施方案中,可使上述制剂持续释放活性成分。
本发明的化合物也可以和其它的抗病毒剂结合施用。
在一个实施方案中,本发明的化合物可以和至少一种选自蛋白酶抑制剂、聚合酶抑制剂、和解旋酶抑制剂的其它的抗病毒剂一起使用。
本申请中使用的“干扰素”包括:象干扰素(IFN)、干扰素α-2a、干扰素α-2b、共有序列干扰素(CIFN)以及其它类型的干扰素分子之类的干扰素。
在一个实施方案中,本发明的化合物可以和至少一种选自干扰素(IFN)、干扰素α-2a、干扰素α-2b、共有序列干扰素(CIFN)、病毒唑、金刚烷、金刚烷乙胺、白细胞介素-12、熊脱氧胆酸(UDCA)、甘草甜素和silybum marianum的其它抗病毒剂一起使用。
在一个实施方案中,本发明的化合物可以和至少一种选自干扰素-α、病毒唑和金刚烷的其它抗病毒剂一起使用。
在一个实施方案中,本发明的化合物可以和至少一种选自干扰素-α、病毒唑(REBETRON)的其它抗病毒剂一起使用。
在一个实施方案中,本发明的化合物可以和干扰素-α一起使用。
在一个实施方案中,本发明的化合物可以和病毒唑一起使用。
上述组合可方便地以药物制剂的形式出现以供使用,因此,含有上述组合和药学上可接受载体的药物制剂便构成了本发明进一步的方面。
这种组合的各个组分在分离的或结合的药物制剂中可以相继或同时施用。
当化合物(I)或其药学上可接受的盐类与第二种抗相同病毒的治疗剂一起使用时,每种组分的剂量可以与单独施用这种组分时相同或不同。
本技术领域的技术人员很容易发现合适的剂量。
下面的实施例只是为了列举本发明的各种实施方案而不能理解为是限制本发明的范围。实施例13’-脱氧胞苷-5’-三磷酸三铵(化合物#2)的制备
步骤:向搅动的无水二甲基甲酰胺(DMF)(0.60ml)中的3’-脱氧-2’-乙酰氧胞苷(15.0mg,0.056mmol)悬浮液中加入无水吡啶(0.20ml),再加入新鲜制备的溶于1,4-二噁烷的0.5M的2-氯-4-氢-1,3,2-苯并二氧杂磷杂苯-4-酮(2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one)溶液(111μl,0.056mmol)。将混合物在室温下搅拌30分钟,然后同时加入三丁胺(36μl,0.152mmol)和0.5M溶于DMF的焦磷酸三丁铵溶液(101μl,0.051mmol)。再将混合物搅拌30分钟。加入1%的溶于吡啶/水(98∶2)的碘溶液(1.01ml,0.081mmol的碘)并将混合物搅拌30分钟。加入0.2ml5%的亚硫酸氢钠水溶液破坏多余的碘。搅拌15分钟后将其减压浓缩除去所有的溶剂。将残余物溶于水中,用二氯甲烷洗涤两次并用乙酸乙酯洗涤一次。浓缩水层并用炭柱按以下方法纯化:将约400mg炭放在置于布氏漏斗(funnel with fritted disk)中的硅藻土薄层上,加入甲醇将碳预洗涤,然后加去离子水洗涤(用真空)。用最少的水将粗残余物稀释,加入几滴1N的HCl使其酸化至pH为1-2,然后放在碳柱的顶端。用去离子水(35ml)洗脱柱子以除去无机盐,然后用0.5N的氨水(15ml)收集所需三磷酸。将收集的三磷酸浓缩并用去离子水(1ml)和浓氨水(2ml)稀释。将混合物在室温下搅拌一小时以裂解乙酰基,然后浓缩至干。将残余物置于C18反相硅胶垫上纯化,用去离子水洗脱(所需的三磷酸会很快出来)。收集含有所需三磷酸的洗脱液并将其冻干,得到3’-脱氧胞苷-5’-三磷酸三铵的微黄固体(18mg,收率69%,用1H和31P核磁共振(NMR)评价,其纯度>85%),1H NMR(400MHz,D2O)δ:7.90(d,1H,7.5Hz),5.99(d,1H,7.5Hz),5.73(s,1H),4.55(s,1H),4.35(d,1H,5.0Hz),4.26(m,1H),4.04(m,1H),2.05(m,1H),1.94(m,1H)ppm。31P NMR(162MHz,D2O)δ:-5.9(br.s),-10.4(d,19Hz),-21.5(br.s)ppm。用同样的方式,可以获得本发明的各化合物。实施例2.三磷酸类似物的评价
在HCV的RNA依赖性RNA聚合酶分析中,下面列出了在实施例中参考的参考资料,以供参考。
1.Behrens,S.,Tomei,L.,De Francesco,R.(1996)EMBO15,12-22
2.Harlow,E和Lane,D.(1988)Antibodies:A Laboratory Manual.冷泉港实验室,纽约,冷泉港。
3.Lohmann,V.,Korner,F.,Herian,H.,和Bartenschlager,R.(1997)J.Virol.71,8416-8428
用含有纯化的重组HCV RNA依赖性RNA聚合酶(NS5B蛋白)的体外聚合酶分析法评价了化合物。用重组的杆状病毒作为载体HCV NS5B可以在昆虫细胞中表达。下面描述了用于克隆、表达和纯化HCV NS5B蛋白的实验过程。下面是用于测试化合物的RNA依赖性RNA聚合酶分析的细节。
昆虫细胞中HCV NS5B蛋白的表达
用含有全长HCV染色体组cDNA的质粒作为模板,以PCR扩增编码HCV-Bk毒株(基因型1b)整个NS5B蛋白的cDNA。设计用于扩增HCV这一区域的寡核苷酸以在NS5B编码区域5’末端的ATG之前引入NheI位点,以及在3’末端紧接翻译终止密码子的下游引入BamHI位点。用NheI和BamHI消化扩增的序列(1.8kb)并连接到预先消化的pBlueBacII质粒(Invitrogen)。所得的重组质粒被称为pBac/NS5B。像制造者的方法所描述的那样,用3μgpBac/NS5B和1μg线性杆状病毒DNA(Invitrogen)共转染Sf9细胞。两轮噬斑纯化后,NS5B-重组杆状病毒---BacNS5B被分离出来。用HCV NS5B特异性兔多克隆抗血清(抗NS5B)对BacNS5B感染的Sf9细胞进行Western印迹分析(Harlow和Lane,1988)可以确定重组NS5B蛋白的存在情况。在一升的旋转烧瓶中使Sf9细胞被经噬菌斑纯化的病毒感染,其细胞密度为1.2×106细胞/毫升,感染复数为5。
可溶性重组NS5B蛋白的制备
用上述方法感染Sf9细胞。感染60小时后收集细胞并用磷酸缓冲盐溶液(PBS)洗涤两次。如Lohmann等(1989)所述,并作一些改进,使总蛋白溶解。简单地说,用三个步骤提取蛋白:S1、S2、S3,分别使用裂解缓冲液(LB)I、LBII和LBIII(Lohmann等,1997)。对LBII的成分作了改进,使其含有0.1%的Triton X-100和150mM的NaCl,以在这一步骤中降低溶解的NS5B蛋白的量。此外,在整个过程中要避免用超声法处理细胞提取液以保持蛋白质结构的完整性。
用快速蛋白质液相色谱(FPLC)纯化重组的NS5B
将S3流分中可溶性NS5B蛋白稀释以使NaCl浓度降低至300mM,再像Behrens等(1989)所描述的那样,在4℃下和DEAE琼脂糖珠(Amersham-Pharmacia)一起分批温育2小时。在4℃下用SW41离心机转头(Bechman)以25,000rpm离心15分钟以除去未结合的物质。将上清进一步稀释使NaCl浓度降低至200mM,然后在流速为1ml/min的、连接到FPLC系统(Amersham-Pharmacia)的5ml的HiTrap肝素柱(Amersham-Pharmacia)上上样。以连续的NaCl梯度(从0.2至1M)洗脱结合的蛋白质,每一流分1ml,洗脱体积大于25ml。用十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)鉴别含有NS5B的流分,然后以1∶2000的稀释度用抗NS5B的抗血清进行western印迹。合并阳极流分,并用PD-10柱(Amersham-Pharmacia)将洗脱缓冲液换成50mM的NaPO4(pH=7.0)、20%的甘油、0.5%的Triton X-100和10mM的DTT。然后以1ml/min的流速在1ml的HiTrapSP柱(Amersham-Pharmacia)上上样。用连续的NaCl梯度(从0至1M)洗脱结合的蛋白质,洗脱体积大于15ml。洗脱的流分以SDS-PAGE和western印迹法进行分析。或者,在SDS-PAGE后用银染试剂盒(Silver Stain Plus Kit)(BioRad)按制造者的说明进行银染以使蛋白质可见。测试阳极流分中的RdRp活性(见下文)并收集活性最强的部分,并将其保存在-70℃40%的甘油溶液中。
用于评价核苷类似物三磷酸的体外RNA依赖性RNA聚合酶分析
用体外转录的杂聚RNA模板进行RdRp分析。
在总体积为50μl的含有20mM Tris-HCl(pH=7.5)、1mM DTT、50mM NaCl、0.5mM MnCl2和5mM MgCl2的缓冲液中进行RdRp反应。标准HCV的RdRp反应含有200ng纯化的NS5B蛋白。分析中包含的底物混合物依赖于被测试的核苷三磷酸的碱基(腺嘌呤、鸟嘌呤、胞嘧啶或尿嘧啶类似物)。以两倍的所测Km加入与抑制剂有类似碱基的核苷三磷酸(NTP)底物。这一浓度包括5μCi(3000Ci/mmol)[32P]形式的核苷。以100μM使用其余的三种底物。所测四种底物的Km值如下:ATP为18μM,CTP和GTP为0.5μM、UTP为1.2μM。22℃温育两小时后加入100μg经超声处理过的鲑鱼精子DNA(Life Technologies)和1ml10%三氯乙酸(TCA)-0.5%焦磷酸四钠(PPi)以终止反应。使核酸在4℃下沉淀30分钟,然后用GF/C玻璃纤维滤器(Millipore)过滤样品。随后用25ml1%TCA-0.1%PPi溶液洗涤滤膜,再用空气干燥。用液体闪烁计数仪(1450-Microbeta,Wallac)定量其中的放射性。失控转录可产生杂聚RNA模板。以含有HCV基因eDNA形式的重组pcDNA3质粒(Invitrogen)作为这些转录反应的模板,这种质粒被称作pcDNA/HCVf1。按制造商的建议,用MEGAscriptTM试剂盒(Ambion)进行体外转录。简单地说,用EcoRI使pcDNA/HCVf1质粒线性化以产生约6900个核苷酸的截短的HCV转录物。以1∶1体积的苯酚/氯仿提取线性DNA,用乙醇沉淀,然后以1μg这种线性DNA作为由T7 RNA聚合酶驱动的体外转录反应的模板。用TRIZOL试剂(Life Technologies)提取转录物并将一份(1μg)用作RdRp分析的模板。
化合物 | HCV聚合酶 |
IC50 | |
化合物#2 | 0.036μM |
化合物#4 | 0.3μM |
化合物#6 | 0.26μM |
化合物#8 | 1.98μM |
化合物#10 | 6.4μM |
化合物#12 | 0.048μM |
化合物#14 | 3.1μM |
化合物#16 | 0.36μM |
化合物#18 | 6.88μM |
化合物#20 | 0.18μM |
化合物#22 | 0.12μM |
化合物#24 | 0.055μM |
化合物#26 | 0.91μM |
化合物#28 | 2.1μM |
化合物#30 | 2.9μM |
化合物#32 | 6.8μM |
化合物#54 | 9.0μM |
Claims (18)
其中
B选自嘌呤、嘧啶或其类似物;
Ra选自H,单磷酸,二磷酸,三磷酸,被C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基取代的羰基,和
其中每一个Rc都是独立选自H、C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基和羟基保护基团;
Z是0Rb,其中,Rb选自H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6酰基或羟基保护基团;
D1和D2是独立选自N3、F或H,D1和D2也可以合在一起选自C3-环烷基、-=CH2或-=CF2;
附带条件是,当B是腺嘌呤时,Z是ORb,D1是H,D2是H,Rb是H,Ra不是三磷酸或H。
2.根据权利要求1所述的方法,其中Z是0H。
3.根据权利要求2所述的方法,其中D1是H,D2是F。
4.根据权利要求2所述的方法,其中Ra选自H、单磷酸、二磷酸、三磷酸。
5.根据权利要求2所述的方法,其中Ra是三磷酸。
6.根据权利要求2所述的方法,其中Ra是H。
7.根据权利要求3所述的方法,其中Ra选自H、单磷酸、二磷酸、三磷酸。
8.根据权利要求3所述的方法,其中Ra是三磷酸。
9.根据权利要求3所述的方法,其中Ra是H。
10.根据权利要求2所述的方法,其中B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基、3-脱氮-腺嘌呤-9-基、3-脱氮-鸟嘌呤-9-基、3-脱氮-肌苷-9-基、3-脱氮-2-氨基-嘌呤-9-基、3-脱氮-2-氨基-6-氯-嘌呤-9-基、3-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-腺嘌呤-9-基、7-脱氮-鸟嘌呤-9-基、7-脱氮-肌苷-9-基、7-脱氮-2-氨基-嘌呤-9-基、7-脱氮-2-氨基-6-氯-嘌呤-9-基、7-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-8-氮杂-腺嘌呤-9-基、7-脱氮-8-氮杂-鸟嘌呤-9-基、7-脱氮-8-氮杂-肌苷-9-基、7-脱氮-8-氮杂-2-氨基-嘌呤-9-基、7-脱氮-8-氮杂-2-氨基-6-氯-嘌呤-9-基、7-脱氮-8-氮杂-2-6-二氨基-嘌呤-9-基、8-氮杂-腺嘌呤-9-基、8-氮杂-鸟嘌呤-9-基、8-氮杂-肌苷-9-基、8-氮杂-2-氨基-嘌呤-9-基、8-氮杂-2-氨基-6-氯-嘌呤-9-基、8-氮杂-2-6-二氨基-嘌呤-9-基、5-氮杂-胸腺嘧啶-1-基、5-氮杂-胞嘧啶-1-基、5-氮杂-尿嘧啶-1-基、6-氮杂-胸腺嘧啶-1-基、6-氮杂-胞嘧啶-1-基、6-氮杂-尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
11.根据权利要求3所述的方法,其中B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、尿嘧啶-1-基、3-酰胺基-1,2,4-三唑-1-基、3-脱氮-腺嘌呤-9-基、3-脱氮-鸟嘌呤-9-基、3-脱氮-肌苷-9-基、3-脱氮-2-氨基-嘌呤-9-基、3-脱氮-2-氨基-6-氯-嘌呤-9-基、3-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-腺嘌呤-9-基、7-脱氮-鸟嘌呤-9-基、7-脱氮-肌苷-9-基、7-脱氮-2-氨基-嘌呤-9-基、7-脱氮-2-氨基-6-氯-嘌呤-9-基、7-脱氮-2-6-二氨基-嘌呤-9-基、7-脱氮-8-氮杂-腺嘌呤-9-基、7-脱氮-8-氮杂-鸟嘌呤-9-基、7-脱氮-8-氮杂-肌苷-9-基、7-脱氮-8-氮杂-2-氨基-嘌呤-9-基、7-脱氮-8-氮杂-2-氨基-6-氯-嘌呤-9-基、7-脱氮-8-氮杂-2-6-二氨基-嘌呤-9-基、8-氮杂-腺嘌呤-9-基、8-氮杂-鸟嘌呤-9-基、8-氮杂-肌苷-9-基、8-氮杂-2-氨基-嘌呤-9-基、8-氮杂-2-氨基-6-氯-嘌呤-9-基、8-氮杂-2-6-二氨基-嘌呤-9-基、5-氮杂-胸腺嘧啶-1-基、5-氮杂-胞嘧啶-1-基、5-氮杂-尿嘧啶-1-基、6-氮杂-胸腺嘧啶-1-基、6-氮杂-胞嘧啶-1-基、6-氮杂-尿嘧啶-1-基,每一个都被NHR3、C1-6烷基、-OC1-6烷基、Br、Cl、F、I或OH中的至少一种取代或不取代,其中,R3是H、C1-6烷基或C1-6酰基。
12.根据权利要求2所述的方法,其中B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、5-氟-胞嘧啶-1-基、尿嘧啶-1-基、5-氟尿嘧啶或1,2,4-三唑-3-羧酰胺碱基(病毒唑碱基)。
13.根据权利要求3所述的方法,其中B选自腺嘌呤-9-基、鸟嘌呤-9-基、肌苷-9-基、2-氨基-嘌呤-9-基、2-氨基-6-氯-嘌呤-9-基、2-6-二氨基-嘌呤-9-基、胸腺嘧啶-1-基、胞嘧啶-1-基、5-氟-胞嘧啶-1-基、尿嘧啶-1-基、5-氟尿嘧啶或1,2,4-三唑-3-羧酰胺碱基(病毒唑碱基)。
14.根据权利要求1所述的方法,其中结构式I的化合物选自:
化合物#1:3’-脱氧胞苷;
化合物#2:3’-脱氧胞苷-5’三磷酸;
化合物#3:5-氟-3’-脱氧胞苷;
化合物#4:5-氟-3’-脱氧胞苷-5’三磷酸;
化合物#5:3’-脱氧尿苷;
化合物#6:3’-脱氧尿苷-5’三磷酸;
化合物#7:5-氟-3’-脱氧尿苷;
化合物#8:5-氟-3’-脱氧尿苷-5’三磷酸;
化合物#9:3’-脱氧胸苷;
化合物#10:3’-脱氧胸苷-5’三磷酸;
化合物#11:3’-脱氧鸟苷;
化合物#12:3’-脱氧鸟苷-5’三磷酸;
化合物#13:2-N-乙酰-3’-脱氧鸟苷;
化合物#14:2-N-乙酰-3’-脱氧鸟苷-5’三磷酸;
化合物#15:5-甲基-3’-脱氧胞苷;
化合物#16:5-甲基-3’-脱氧胞苷-5’三磷酸;
化合物#17:5-碘-3’-脱氧胞苷;
化合物#18:5-碘-3’-脱氧胞苷-5’三磷酸;
化合物#19:5-氯-3’-脱氧胞苷:
化合物#20:5-氯-3’-脱氧胞苷-5’三磷酸;
化合物#21:3’-氟-3’-脱氧鸟苷;
化合物#22:3’-氟-3’-脱氧鸟苷-5’三磷酸;
化合物#23:3’-氟-3’-脱氧胞苷;
化合物#24:3’-氟-3’-脱氧胞苷-5’三磷酸;
化合物#25:5-碘-3’-脱氧胞苷;
化合物#26:5-碘-3’-脱氧胞苷-5’三磷酸;
化合物#27:5-氯-3’-脱氧尿苷;
化合物#28:5-氯-3’-脱氧尿苷-5’三磷酸;
化合物#29:5-溴-3’-脱氧尿苷;
化合物#30:5-溴-3’-脱氧尿苷-5’三磷酸;
化合物#31:6-氯-3’-脱氧鸟苷;
化合物#32:6-氯-3’-脱氧鸟苷-5’三磷酸;
化合物#33:3’-螺环丙基-3’-脱氧鸟苷;
化合物#34:3’-螺环丙基-3’-脱氧鸟苷-5’三磷酸;
化合物#35:3’-二氟-螺环丙基-3’-脱氧鸟苷;
化合物#36:3’-二氟-螺环丙基-3’-脱氧鸟苷-5’三磷酸;
化合物#37:3’-亚甲基-3’-脱氧鸟苷;
化合物#38:3’-亚甲基-3’-脱氧鸟苷-5’三磷酸;
化合物#39:3’-二氟亚甲基-3’-脱氧鸟苷;
化合物#40:3’-二氟亚甲基-3’-脱氧鸟苷-5’三磷酸;
化合物#41:3’-螺环丙基-3’-脱氧胞苷;
化合物#42:3’-螺环丙基-3’-脱氧胞苷-5’三磷酸;
化合物#43:3’-二氟-螺环丙基-3’-脱氧胞苷;
化合物#44:3’-二氟-螺环丙基-3’-脱氧胞苷-5’三磷酸;
化合物#45:3’-亚甲基-3’-脱氧胞苷;
化合物#46:3’-亚甲基-3’-脱氧胞苷-5’三磷酸;
化合物#47:3’-二氟亚甲基-3’-脱氧胞苷;
化合物#48:3’-二氟亚甲基-3’-脱氧胞苷-5’三磷酸;
化合物#49:9-β-D-呋喃木糖基-鸟苷;
化合物#50:9-β-D-呋喃木糖基-鸟苷-5’三磷酸;
化合物#51:9-β-D-呋喃木糖基-胞苷;
化合物#52:9-β-D-呋喃木糖基-胞苷-5’三磷酸;
化合物#53:3’-叠氮基-3’-脱氧胞苷;
化合物#54:3’-叠氮基-3’-脱氧胞苷-5’三磷酸;或它们的药学上可接受的盐类。
15.根据权利要求1-14中任何一项所述的方法,其中所述的化合物和至少一种选自干扰素(IFN)、干扰素α-2a、干扰素α-2b、共有序列干扰素(CIFN)、病毒唑、金刚烷、金刚乙胺、白细胞介素-12、熊脱氧胆酸(UDCA)、甘草甜素和silybum marianum的其它治疗剂一起使用。
16.在制造治疗或预防丙型肝炎感染的药物中使用如权利要求1-14中任何一项所述的结构式(Ib)的化合物或其药学上可接受的盐。
17.一种抗黄病毒的药物组合物,含有与药学上可接受载体合用的、治疗有效剂量的如权利要求1-14中任何一项所述的结构式(Ib)的化合物或其药学上可接受的盐。
18.在制造治疗或预防黄病毒感染的药物中使用如权利要求1-14中任何一项所述的结构式(Ib)的化合物或其药学上可接受的盐。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102666562A (zh) * | 2009-12-17 | 2012-09-12 | 诺威戴克斯医药公司 | 新颖的3’-脱氧-3‘-亚甲基-β-L-核苷 |
CN108276463A (zh) * | 2017-01-06 | 2018-07-13 | 米文君 | 一类新的化合物及其用途 |
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HUP0301112A2 (hu) | 2003-08-28 |
CZ20022825A3 (cs) | 2003-05-14 |
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EA200200778A1 (ru) | 2003-06-26 |
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NZ521210A (en) | 2004-11-26 |
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US6784161B2 (en) | 2004-08-31 |
MXPA02008078A (es) | 2002-11-29 |
NO20023884D0 (no) | 2002-08-16 |
EP1296690A2 (en) | 2003-04-02 |
ZA200206506B (en) | 2003-11-14 |
JP2003523978A (ja) | 2003-08-12 |
HUP0301112A3 (en) | 2005-04-28 |
US20040248844A1 (en) | 2004-12-09 |
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