CN106573926A - 杂环化合物及其使用方法 - Google Patents
杂环化合物及其使用方法 Download PDFInfo
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- CN106573926A CN106573926A CN201580042841.1A CN201580042841A CN106573926A CN 106573926 A CN106573926 A CN 106573926A CN 201580042841 A CN201580042841 A CN 201580042841A CN 106573926 A CN106573926 A CN 106573926A
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- stereoisomer
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- 150000003839 salts Chemical class 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 65
- -1 (trifluoromethyl) phenyl Chemical group 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 23
- 241000124008 Mammalia Species 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 238000012360 testing method Methods 0.000 claims description 16
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- 150000003053 piperidines Chemical class 0.000 claims description 10
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 9
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 7
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical group CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
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- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 claims description 4
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- YFXGICNMLCGLHJ-RSKRLRQZSA-N 2,2-dimethylpropyl (2s)-2-[[[(2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate Chemical compound C1=CC=C2C(OP(=O)(N[C@@H](C)C(=O)OCC(C)(C)C)OC[C@H]3O[C@H]([C@]([C@@H]3O)(C)O)N3C=4N=C(N)N=C(C=4N=C3)OC)=CC=CC2=C1 YFXGICNMLCGLHJ-RSKRLRQZSA-N 0.000 claims description 3
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- BVAZQCUMNICBAQ-PZHYSIFUSA-N elbasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=C3O[C@H](N4C5=CC=C(C=C5C=C4C3=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)C=2C=CC=CC=2)=CN1 BVAZQCUMNICBAQ-PZHYSIFUSA-N 0.000 claims description 3
- YMCAVGXTSCNFDE-BBACVFHCSA-N methyl n-[(2s)-1-[(2s)-2-[5-[4-[4-[2-[(8s)-7-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl]-1h-imidazol-5-yl]phenyl]phenyl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC=C(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2NC(=NC=2)[C@H]2N(CC3(C2)OCCO3)C(=O)[C@@H](NC(=O)OC)C(C)C)N1 YMCAVGXTSCNFDE-BBACVFHCSA-N 0.000 claims description 3
- JYLMWUZJMRNMDA-SPRBZRACSA-N methyl n-[(2s)-1-[(2s)-2-[5-[6-[2-[(2s)-1-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]naphthalen-2-yl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate;dihydrochloride Chemical compound Cl.Cl.COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC=C(C=2C=C3C=CC(=CC3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)N1 JYLMWUZJMRNMDA-SPRBZRACSA-N 0.000 claims description 3
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Abstract
公开了式(I)、式(II)和式(III)的化合物:其中Ar、R1、A和X如说明书中所定义。这些化合物是抗病毒剂并且被考虑用于治疗病毒感染,例如,丙型肝炎。这些化合物还被考虑用于治疗或预防癌症。
Description
相关申请的交叉引用
本专利申请要求于2014年6月12日提交的美国临时专利申请号62/011,462的权益,所述申请通过引用结合。
发明背景
丙型肝炎病毒(HCV)感染世界上约20亿人。许多经感染者发展成慢性肝病,包括具有发展成肝癌风险的肝硬化(cirrhosis)。迄今,对于丙型肝炎并无有效的疫苗。
当前基于聚乙二醇干扰素-α和利巴韦林(ribavirin)的组合的慢性丙型肝炎的标准治疗仅对约一半的患者有效,且具有显著不利作用。可以完成成功治疗的患有HCV的人的比例据估算不多于10%。针对HCV的直接作用抗毒病剂如蛋白酶和聚合酶抑制剂的近期开发是有希望的,但对于最大功效仍需要与聚乙二醇干扰素和利巴韦林组合。此外,这些药剂与高耐药率相关并且许多具有显著副作用。
鉴于前述,对于用于治疗或预防病毒感染的新型药剂存在未满足的需求。
发明简述
本发明提供式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
本发明还提供一种治疗或预防丙型肝炎的方法,所述方法包括向有需要的哺乳动物施用有效量的式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
本发明还提供一种用于在用抗-丙型肝炎化合物进行治疗的哺乳动物中协同地增强所述抗-丙型肝炎化合物的抗病毒效果的方法,所述方法包括将式(I)、(II)或式(III)的化合物与所述抗-丙型肝炎化合物联合施用于所述哺乳动物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
本发明另外地提供试剂盒,所述试剂盒包括:
(a)式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物,和
(b)不同于式(II)的化合物的抗-丙型肝炎化合物。
本发明还提供治疗或预防有需要的哺乳动物中的癌症的方法,所述方法包括向有需要的哺乳动物施用有效量的式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
附图的若干视图简述
图1A描绘了化合物1在PBS中的稳定性。
图1B描绘了化合物1在PBS/乙腈(1/1)中的稳定性。
图2A描绘了在50μM二硫苏糖醇存在下在PBS中化合物1的稳定性。
图2B描绘了在50μM二硫苏糖醇存在下在PBS/乙腈(1/1)PBS中化合物1的稳定性。
图3描绘了化合物1的抗-HCV活性(通过三角形显示的EC50)和细胞毒性(通过圆形显示的CC50)的滴定曲线。
发明详述
在一个实施方案中,本发明提供式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
现在提及本文中广义使用的术语,术语“烷基”意指含有,例如,1至约6个碳原子,优选1至约4个碳原子,更优选1至2个碳原子的直链或支链烷基取代基。这样的取代基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、己基等。
术语“烷氧基”意指含有,例如,1至约6个碳原子,优选1至约4个碳原子,更优选1至2个碳原子的直链或支链烷氧基取代基。这样的取代基的实例包括甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基(isoamyoxyl)、己氧基等。
如本文使用的,术语“卤代”或“卤素”意指选自第VIIA族的取代基,如,例如,氟、溴、氯和碘。
如本领域通常理解的,术语“芳基”是指未取代或取代的芳族碳环取代基,并且术语“C6-C14芳基”包括苯基、萘基和蒽基。要理解的是,术语芳基适用于平面的且包含根据Hückel规则的4n+2π电子的环状取代基。
无论什么时候指示结构中的原子数的范围(例如,C1-C12、C1-C8、C1-C6、C1-C4或C2-C12、C2-C8、C2-C6、C2-C4烷基、烷氧基等)时,具体考虑了落入指示范围内的碳原子的任何子范围或个体数量。因此,例如,如关于本文中提及的任何化学基团(例如,烷基、烷基氨基等)使用的,范围1-8个碳原子(例如,C1-C8)、1-6个碳原子(例如,C1-C6)、1-4个碳原子(例如,C1-C4)、1-3个碳原子(例如,C1-C3)或2-8个碳原子(例如,C2-C8)的叙述,如果合适,涵盖且具体描述1、2、3、4、5、6、7、8、9、10、11和/或12个碳原子,以及其任何子范围(例如,如果合适,1-2个碳原子、1-3个碳原子、1-4个碳原子、1-5个碳原子、1-6个碳原子、1-7个碳原子、1-8个碳原子、1-9个碳原子、1-10个碳原子、1-11个碳原子、1-12个碳原子、2-3个碳原子、2-4个碳原子、2-5个碳原子、2-6个碳原子、2-7个碳原子、2-8个碳原子、2-9个碳原子、2-10个碳原子、2-11个碳原子、2-12个碳原子、3-4个碳原子、3-5个碳原子、3-6个碳原子、3-7个碳原子、3-8个碳原子、3-9个碳原子、3-10个碳原子、3-11个碳原子、3-12个碳原子、4-5个碳原子、4-6个碳原子、4-7个碳原子、4-8个碳原子、4-9个碳原子、4-10个碳原子、4-11个碳原子和/或4-12个碳原子等)。类似地,如关于本文中提及的任何化学基团(例如,芳基)使用的,范围6-14个碳原子(例如,C6-C14)的叙述,如果合适,涵盖且具体描述了6、7、8、9、10、11、12、13和/或14个碳原子,以及其任何子范围(例如,如果合适,6-14个碳原子、6-13个碳原子、6-12个碳原子、6-11个碳原子、6-10、7-10个碳原子、7-9个碳原子、7-8个碳原子、8-10个碳原子和/或8-9个碳原子等)。
在一些实施方案中,Ar是任选被一个或多个选自以下各项的取代基取代的苯基:C1-C6烷基、C1-C6烷氧基、卤代和CF3。
在一些优选实施方案中,Ar选自2-甲基苯基、3,5-二甲氧基苯基、2-氯苯基、2-氯-6-甲基苯基、4-氯苯基、2-乙基苯基、3-甲基苯基、4-甲基苯基、3,4-二甲基苯基、2,6-二甲基苯基、3-氯苯基、3-甲基-4-氟苯基、3,5-二(三氟甲基)苯基、2,4-二甲基苯基、3,5-二甲基苯基、2-氯-6-氟苯基、2,5-二甲基苯基、2,6-二氯苯基、2-氟-6-甲氧基苯基、2-溴-6-甲氧基苯基、2-溴-6-氯苯基、2,6-二溴苯基、2-氯-6-三氟甲基苯基、2-甲基-6-甲氧基苯基、2-氟-6-甲基苯基、2,6-二氟苯基、3,4-二氯苯基、4-氟苯基、2,3,4,5,6-五甲基苯基和2,4,6-三甲基苯基。
在一些实施方案中,所述化合物具有式(I)。
在一些实施方案中,A是并且R2和R3独立地是C1-C6烷基。
在一些特别实施方案中,所述化合物是:
在一些实施方案中,A是Y是CR9R10,并且R5-R14独立地是氢或C1-C6烷基。
在一些优选实施方案中,A选自:
在一个特别实施方案中,当Ar是2-甲基苯基或2-氯-6-甲基苯基并且R1是甲基时,A不是
在一些特别实施方案中,所述化合物选自:
在某些更优选的实施方案中,A是:
其中在A的哌啶基环上的带有甲基的C-3和C-5碳原子具有绝对构型:(3S,5R)。
在一个特别优选的实施方案中,所述化合物是:
其中在A的哌啶环上的带有甲基的C-3和C-5碳原子具有绝对构型:(3S,5R)。
在一些实施方案中,Y是O。
在一个特别实施方案中,所述化合物是:
在一些实施方案中,A是
在一些优选实施方案中,R4是1-甲基哌啶-4-基或2-(二甲基氨基)乙基。在一些特别实施方案中,所述化合物是:
在一些实施方案中,A是
在一些优选实施方案中,A是
在一个特别实施方案中,所述化合物是:
在一些实施方案中,Ar选自萘-1-基、2-甲基-萘-1-基和蒽-1-基。
在一些特别实施方案中,所述化合物是:
在一些实施方案中,X是S。
在一个特别实施方案中,所述化合物是:
在一些实施方案中,所述化合物具有式(II)。
在这些实施方案的某些中,A是
在一个特别实施方案中,所述化合物是:
在一些实施方案中,所述化合物具有式(III):
在这些实施方案的某些中,A是
在一个特别实施方案中,所述化合物是:
在一个实施方案中,本发明提供式(I)或式(II)的化合物或药用盐以及药用载体。
短语“药用盐”意图包括通过常规化学方法从含有碱性或酸性部分的母体化合物合成的无毒盐。通常,这样的盐可以通过使这些化合物的游离酸或碱形式与化学计量量的恰当碱或酸在水或在有机溶剂中或者在这二者的混合物中反应而制备。通常,优选非水介质如醚、乙酸乙酯、乙醇、异丙醇或乙腈。合适盐的列举在Remington’s PharmaceuticalSciences,18th ed.,Mack Publishing Company,Easton,PA,1990,p.1445以及Journal ofPharmaceutical Science,66,2-19(1977)中找到。
合适碱包括无机碱如碱金属和碱土金属碱,例如,含有金属阳离子如钠、钾、镁、钙等的那些碱。合适碱的非限制性实例包括氢氧化钠、氢氧化钾、碳酸钠和碳酸钾。合适酸包括无机酸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等,以及有机酸如对甲苯磺酸、苯磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸、马来酸、酒石酸、脂肪酸、长链脂肪酸等。具有酸性部分的本发明化合物的优选药用盐包括钠和钾盐。具有碱性部分(例如,二甲基氨基烷基基团)的本发明化合物的优选药用盐包括盐酸和氢溴酸盐。含有酸性或碱性部分的本发明的化合物以游离碱或酸的形式或者以其药用盐的形式是有用的。
应认识到,形成本发明的任何盐的一部分的特定反离子通常不具有关键性,只要所述盐作为整体是可药用的并且只要该反离子不对作为整体的所述盐贡献非所需品质即可。
进一步理解的是,上述化合物和盐可以形成溶剂化物,或者以基本上未复合的形式如无水形式存在。如本文使用的,术语"溶剂化物"是指这样的分子复合物,其中溶剂分子,如结晶溶剂被结合到晶格中。当结合到溶剂化物中的溶剂是水时,该分子复合物称为水合物。药用溶剂化物包括水合物、醇化物如甲醇化物和乙醇化物、乙腈化物等。这些化合物也可以以多晶型物存在。
在任何上述实施方案中,式(I)、式(II)或式(III)的化合物或盐可以具有至少一个不对称碳原子。当化合物或盐具有至少一个不对称碳原子时,上述化合物或盐可以以外消旋体形式、以其纯光学异构体的形式或以其中一种异构体相对于另一种异构体富集的混合物的形式存在。特别地,根据本发明,当本发明化合物具有单个不对称碳原子时,本发明化合物可以作为外消旋物,即作为等量的光学异构体(即等量的两种对映异构体)的混合物的形式,或以单个对映异构体的形式存在。如本文使用的,"单个对映异构体"意图包括包含超过50%的单个对映异构体(即,对映异构体过量多至100%纯对映异构体)的化合物。
当化合物或盐具有超过过一个手性中心时,所述化合物或盐因此可以作为非对映异构体的混合物或以单个非对映异构体的形式存在。如本文使用的,“单个对映异构体”意图意指包含超过50%的单个非对映异构体(即,非对映异构体过量多至100%纯非对映异构体)的化合物。
本发明还提供一种药物组合物,所述药物组合物包含如上所述的化合物和药用载体。本发明提供一种药物组合物,所述药物组合物包含药用载体和有效量,例如,治疗有效量(包括预防有效量)的本发明的前述化合物或其盐中的一种或多种。
药用载体可以常规使用的且仅受化学-物理考虑如溶解度和缺乏与所述化合物的反应性以及受施用途径限制的那些中的任何载体。本领域技术人员将理解,除了以下所述的药物组合物之外;本发明的化合物还可以配制为包合复合物,如环糊精包合复合物或脂质体。
本文所述的药用载体,例如,媒介物、辅剂、赋形剂或稀释剂,对本领域技术人员是熟知的并且对公众易于获得。优选的是,药用载体是对于活性化合物为惰性的载体以及在使用的条件下不具有有害副作用或毒性的载体。
载体的选择将部分地由具体活性剂以及由用来施用组合物的具体方法决定。因此,存在广泛各种各样的本发明的药物组合物的合适制剂。以下用于经口、气溶胶、胃肠外、皮下、静脉内、动脉内、肌肉内、腹膜内、鞘内、直肠和阴道施用的制剂仅仅是示例性的而绝不是限制性的。
适用于经口施用的制剂可以由以下各项组成:(a)液体溶液,如溶于稀释剂如水、盐水或橙汁中的有效量的化合物;(b)胶囊、香囊、片剂、含片和锭剂,其各自含有预定量的活性成分(作为固体或颗粒);(c)粉剂;(d)在恰当液体中的混悬剂;和(e)适当乳剂。液体制剂可以包括稀释剂,如水和醇,例如,乙醇、苄醇和聚乙二醇,其中有或没有添加药用表面活性剂、悬浮剂或乳化剂。胶囊形式可以为普通硬或软壳明胶型,其含有,例如,表面活性剂、润滑剂和惰性填料,如乳糖、蔗糖、磷酸钙和玉米淀粉。片剂形式可以包括乳糖、蔗糖、甘露糖醇、玉米淀粉、马铃薯淀粉、海藻酸、微晶纤维素、阿拉伯树胶、明胶、瓜尔胶、胶体二氧化硅、交联羧甲基纤维素钠、滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸和其他赋形剂、着色剂、稀释剂、缓冲剂、崩解剂、湿润剂、防腐剂、增味剂中的一种或多种,以及药用载体。含片形式可以包含在香料(通常是蔗糖和阿拉伯树胶或黄蓍胶)中的活性成分,以及包含在惰性基质如明胶和甘油或者蔗糖和阿拉伯树胶中的活性成分的软锭剂,除了活性成分之外,其还含有如本领域已知的为恰当的这样的载体。
本发明的化合物,单独地或与其他合适组分组合地,可以被制成为经由吸入施用的气溶胶制剂。这些气溶胶制剂可以置于加压可接受推进剂,如二氯二氟甲烷、丙烷、氮气等中。它们也可以配制为用于非加压制剂的药物,如在喷雾器或雾化器中。
适用于胃肠外施用的制剂包括含水和非水、等张无菌注射液,其可以含有抗氧化剂、缓冲剂、抑菌剂和使得制剂与意图受体的血液等张的溶质,以及可以包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的含水和非水无菌悬浮液。化合物可以在有或没有添加药用表面活性剂如皂或去污剂,悬浮剂如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其他药物辅剂的情况下,在药物载体中的生理学可接受稀释剂,如无菌液体或液体的混合物,包括水,盐水,葡萄糖水溶液和相关糖溶液,醇如乙醇、异丙醇或十六烷醇,乙二醇如丙二醇或聚乙二醇,甘油缩酮如2,2-二甲基-1,3-二氧杂环戊烷-4-甲醇,醚如聚(乙二醇)400,油,脂肪酸,脂肪酸酯或甘油酯,或乙酰化脂肪酸甘油酯中施用。
可以用于胃肠外制剂中的油包括石油、动物油、植物油或合成油。油的具体实例包括花生、大豆、芝麻、棉籽、玉米、橄榄、矿脂和矿物。用于胃肠外制剂的合适脂肪酸包括油酸、硬脂酸和异硬脂酸。油酸乙酯和肉豆蔻酸异丙酯是合适脂肪酸酯的实例。用于胃肠外制剂的合适皂包括脂肪酸碱金属盐、铵盐和三乙醇胺盐,并且合适的去污剂包括(a)阳离子去污剂如,例如,二甲基二烷基卤化铵和卤化烷基吡啶鎓,(b)阴离子去污剂如,例如,烷基、芳基和烯基磺酸盐,烷基、烯基、醚和甘油一酯硫酸盐,以及磺基琥珀酸盐,(c)非离子去污剂如,例如,脂肪胺氧化物,脂肪酸烷醇酰胺,和聚氧乙烯-聚氧丙烯共聚物,(d)两性去污剂如,例如,烷基-β-氨基丙酸盐,和2-烷基-咪唑啉季铵盐,和(3)它们的混合物。
胃肠外制剂典型地将含有约0.5至约25重量%的在溶液中的活性成分。合适的方法及和缓冲剂可以用于这样的制剂。为了最小化或消除在注射位点处的刺激,这样的组合物可以含有一种或多种亲水-亲油平衡(HLB)为约12至约17的非离子表面活性剂。在这样的制剂中表面活性剂的量在约5至约15重量%的范围内。合适的表面活性剂包括聚乙烯失水山梨糖醇脂肪酸酯,如失水山梨糖醇单油酸酯,和通过氧化丙烯与丙二醇缩合形成的,氧化乙烯与疏水碱的高分子量加合物。胃肠外制剂可以存在于单位剂量或多剂量密封容器,如安瓿或小瓶中,并且可以储存在冷冻干燥(冻干)条件,在其将要使用之前仅需要添加注射用无菌液体载体,例如水。即席注射溶液和悬浮液可以从之前描述种类的无菌粉剂、颗粒剂和片剂制备。
本发明的化合物可以制成注射制剂。对于注射组合物用的有效药物载体的要求对于本领域技术人员是熟知的。参见Pharmaceutics and Pharmacy Practice,J.B.Lippincott Co.,Philadelphia,Pa.,Banker and Chalmers,eds.,第238-250页(1982),和ASHP Handbook on Injectable Drugs,Toissel,4th ed.,第622-630页(1986)。
另外地,本发明的化合物可以通过与各种各样的基质,如乳化基质或水溶性基质混合而制成栓剂。适用于阴道施用的制剂可以作为阴道栓剂、棉塞、霜剂、凝胶剂、糊剂、泡沫或喷雾剂(spray formulas)提供,除了活性成分之外,其还含有如本领域已知的为恰当的这样的载体。
在一个实施方案中,本发明提供治疗或预防有需要的哺乳动物中的病毒感染的方法,所述方法包括向所述哺乳动物施用有效量的式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
在这些方法实施方案中,所述化合物可以为如对于本发明的化合物实施方案所述的。
在一个优选实施方案中,本发明提供用于治疗或预防丙型肝炎的方法。
在一个实施方案中,本发明的方法还包括向哺乳动物施用有效量的不同于式(I)的化合物的抗-丙型肝炎化合物。合适抗-丙型肝炎化合物的非限制性实例包括利巴韦林(ribavirin)、干扰素-α(interferon-α)、特拉匹韦(telaprevir)、达卡他韦(daclatasvir)、环孢素A(cyclosporin A)、索非布韦(sofosbuvir)、阿孙普韦(asunaprevir)(BMS-650032)、波西普韦(boceprevir)、GS-9451、GS-9256、ABT-450、丹诺普韦(danoprevir)(RG7227)、福达瑞韦(faldaprevir)(BI 201335)、IDX320、MK-5172、西咪匹韦(simeprevir)(TMC435)、舒乏端韦(sovaprevir)(ACH-1625)、ABT-267、ACH-3102、BMS-791325、达卡他韦(daclatasvir)(BMS-790052)、GSK2336805、IDX719、JNJ-47910382、来地帕韦(ledipasvir)(GS-5885)、MK-8742、PPI-461、PPI-668、ABT-333、ALS-002200、BI207127、IDX184、INX-08189、美立他滨(mericitabine)(RO5024048)、PPI-383、PSI-352938、司屈布韦(setrobuvir)(ANA-598)、索非布韦(sofosbuvir)(PSI-7977或GS-7977)、特哥布韦(tegobuvir)(GS-9190)、TMC647055、菲利布韦(filibuvir)(PF-00868554)、GS-9669、GSK2878175、VX-135、VX-222、Algeron(西培干扰素α-2b(cepeginterferon alfa-2b))、BIP48(聚乙二醇干扰素α2b48kDA)、聚乙二醇化干扰素α2b、聚乙二醇化干扰素λ(BMS-914143)、聚乙二醇化-P-干扰素-α-2b(P1101)、阿拉泊韦(alisporivir)(DEB025)和IDX21437。
在一个实施方案中,本发明提供用于在用抗-丙型肝炎化合物进行治疗的哺乳动物中协同地增强所述抗-丙型肝炎化合物的抗病毒效果的方法,所述方法包括向所述哺乳动物施用式(I)、(II)或式(III)的化合物。式(I)、(II)或式(III)的化合物可以是如本文关于用于治疗或预防丙型肝炎的方法所述的。
在其他实施方案中,本发明的方法适用于治疗不同于丙型肝炎病毒的病毒。例如,本发明的方法适用于治疗选自以下各项的病毒:黄病毒科(Flaviviridae)病毒如西尼罗病毒(West Nile virus)、黄热病病毒(yellow fever virus)、日本脑炎病毒(Japaneseencephalitis virus)或登革热病毒(dengue virus),以及其他科的病毒如但不限于鼻病毒(rhinovirus)、脊髓灰质炎病毒(polio virus)、甲型肝炎病毒(hepatitis A virus)、乙型肝炎病毒(hepatitis B virus)、呼吸道合胞体病毒(respiratory syncytial virus)、严重急性呼吸综合症(severe acute respiratory syndrome)(SARS)和中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus)(MERS-CoV或MERS)等。
“治疗”是指疾病或病况已经开始发展滞后减轻其病征或症状的治疗性干预。如本文使用的,关于疾病或病况的术语“减轻”是指治疗的任何可观察到的有益效果。有益效果可以例如通过易感受试者中疾病的临床症状的延迟发作、疾病的部分或全部临床症状的严重度降低、疾病的较慢进展、受试者总体健康或幸福的改善或者通过对于特定疾病特异的本领域熟知的其他参数所证实。丙型肝炎的治疗可以例如通过病毒负荷的降低、由病毒感染所致的临床症状的减少或对病毒感染例如丙型肝炎感染特异的本领域熟知的其他参数所证实。如本文使用的,关于疾病或病况的术语“预防”是指在处于发展疾病的风险,例如,通过暴露于病毒的无症状受试者中阻断疾病或与疾病相关的症状例如存在病毒加载的出现。
术语“共同施用(coadminister)”意指在其中相应的生物活性期重叠的时间框架期间至少两种化合物的每一种被施用。因此,该术语包括两种以上药物化合物的顺序以及同延施用。所述化合物可以同时、分开(按时间顺序交叉的)、循环地或顺序地或以任何顺序例如之前或之后施用。
根据本发明,向哺乳动物,特别是人施用的式(I)或式(II)的化合物和/或抗-丙型肝炎化合物的剂量应足以实现所需响应。这样的响应包括需要治疗的疾病的有害作用的反转或防止或者以引起所需的益处。本领域技术人员将认识到,剂量将取决于多种因素,包括人的年龄、状况和体重,以及疾病的来源、具体类型,和人中的疾病的程度。剂量的大小也将由施用的途径、时间和频率、以及可能伴随特定化合物的施用的任何有害副作用的存在、性质和程度与所需的生理效果决定。本领域技术人员将理解,多种病症或疾病状态可能需要涉及多次施用的延长治疗。
合适的剂量和剂量方案可以通过对于本领域普通技术人员已知的常规范围发现技术来确定。通常,以低于化合物的最佳剂量的较小剂量开始治疗。之后,通过小增量增大剂量直至达到在这些情况下的最佳效果。本发明的方法典型地涉及每kg动物或哺乳动物体重施用约0.1至约300mg的一种或多种上述化合物。
施用的治疗有效量的化合物或多种化合物可以取决于所需的效果和上述的因素而变化。典型地,剂量将为0.01mg/kg至250mg/kg的受试者体重,并且更典型地为约0.05mg/kg至100mg/kg,如约0.2至约80mg/kg,约5至约40mg/kg或约10至约30mg/kg的受试者体重。因此,单位剂型可以基于合适的上述范围和受试者的体重配制。如本文使用的,术语“单位剂型”是指对于要治疗的受试者恰当的治疗剂的物理离散的单位。
备选地,剂量基于体表面积计算,并且每天向受试者将施用约1mg/m2至约200mg/m2,如约5mg/m2至约100mg/m2。在特别地的实施方案中,施用治疗有效量的化合物或多种化合物涉及每天向受试者施用约5mg/m2至约50mg/m2,如约10mg/m2至约40mg/m2。当前认为,化合物的单个剂量是合适的,然而治疗有效剂量可以在延长的时间期内供应或以多个剂量/天供应。因此,单位剂型也可以基于以上所述的合适范围和所需的用药安排,利用受试者体表面积计算。
根据一个实施方案,本发明提供治疗有需要的哺乳动物中的癌症的方法,所述方法包括向动物施用式(I)、式(II)或式(III)的化合物或其药用盐、立体异构体和包含立体异构体的混合物。根据这些实施方案,本发明的化合物或其盐、立体异构体或包含立体异构体的混合物以其自身(即,没有共同施用抗癌剂、放射或生物治疗剂)施用至哺乳动物。在一些实施方案中,本发明的化合物或其盐、立体异构体或包含立体异构体的混合物可以与放射和/或生物治疗剂伴随地施用。
癌症可以是任何合适癌症。例如,癌症可以是肾上腺皮质癌(adrenocorticalcarcinoma)、AIDS-相关的淋巴瘤(AIDS-related lymphoma)、AIDS-相关的恶性肿瘤(AIDS-related malignancies)、肛门癌(anal cancer)、小脑星形细胞瘤(cerebellarastrocytoma)、肝外胆管癌(extrahepatic bile duct cancer)、膀胱癌(bladdercancer)、骨肉瘤/恶性纤维组织细胞瘤(osteosarcoma/malignant fibroushistiocytoma)、脑干胶质瘤(brain stem glioma)、室管膜瘤(ependymoma)、视觉路径和下丘脑胶质瘤(visual pathway and hypothalamic gliomas)、乳腺癌(breast cancer)、支气管腺瘤/类癌(bronchial adenomas/carcinoids)、类癌瘤(carcinoid tumors)、胃肠道类癌肿瘤(gastrointestinal carcinoid tumors)、癌瘤(carcinoma)、肾上腺皮质(adrenocortical)、胰岛细胞癌(islet cell carcinoma)、原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma)、小脑星形细胞瘤(cerebellarastrocytoma)、宫颈癌(cervical cancer)、慢性淋巴细胞白血病(chronic lymphocyticleukemia)、慢性髓性白血病(chronic myelogenous leukemia)、腱鞘透明细胞肉瘤(clearcell sarcoma of tendon sheaths)、结肠癌(colon cancer)、结直肠癌(colorectalcancer)、皮肤t-细胞淋巴瘤(cutaneous t-cell lymphoma)、子宫内膜癌(endometrialcancer)、室管膜瘤(ependymoma)、食管癌(esophageal cancer)、尤文肉瘤家族肿瘤(Ewing’s sarcoma/family of tumors)、颅外生殖细胞肿瘤(extracranial germ celltumors)、性腺外生殖细胞肿瘤(extragonadal germ cell tumors)、肝外胆管癌(extrahepatic bile duct cancer)、眼癌(eye cancers)、包括眼内黑素瘤(intraocularmelanoma)和视网膜母细胞瘤(retinoblastoma)、胆囊癌(gallbladder cancer)、胃肠道类癌肿瘤(gastrointestinal carcinoid tumor)、卵巢生殖细胞肿瘤(ovarian germ celltumor)、妊娠性滋养层细胞瘤(gestational trophoblastic tumor)、多毛细胞白血病(hairy cell leukemia)、头颈癌(head and neck cancer)、霍奇金病(Hodgkin’sdisease)、下咽癌(hypopharyngeal cancer)、下丘脑和视神经胶质瘤(hypothalamic andvisual pathway glioma)、眼内黑素瘤(intraocular melanoma)、卡波西肉瘤(Kaposi’ssarcoma)、喉癌(laryngeal cancer)、急性成淋巴细胞白血病(acute lymphoblasticleukemia)、急性髓样白血病(acute myeloid leukemia)、肝癌(liver cancer)、非小细胞性肺癌(non-small cell lung cancer)、小细胞性肺癌(small cell lung cancer)、非霍奇金淋巴瘤(non-Hodgkin’s lymphoma)、Waldenstrom巨球蛋白血症(Waldenstrom’smacroglobulinemia)、恶性间皮瘤(malignant mesothelioma)、恶性胸腺瘤(malignantthymoma)、成神经管细胞瘤(medulloblastoma)、黑素瘤(melanoma)、眼内黑素瘤(intraocular melanoma)、merkel细胞癌(merkel cell carcinoma)、具有隐蔽的原发性、多内分泌肿瘤综合征的转移性鳞状颈癌(metastatic squamous neck cancer withoccult primary、multiple endocrine neoplasia syndrome)、多发性骨髓瘤/浆细胞瘤(multiple myeloma/plasma cell neoplasm)、蕈样肉芽肿(mycosis fungoides)、骨髓增生异常综合征(myelodysplastic syndrome)、慢性髓性白血病(chronic myelogenousleukemia)、髓样白血病(myeloid leukemia)、多发性骨髓瘤(multiple myeloma)、骨髓增殖性疾病(myeloproliferative disorders)、鼻腔和鼻窦癌(nasal cavity andparanasal sinus cancer)、鼻咽癌(nasopharyngeal cancer)、成神经细胞瘤(neuroblastoma)、口腔癌(oral cancer)、口腔和唇癌(oral cavity and lip cancer)、口咽癌(oropharyngeal cancer)、骨肉瘤/恶性骨纤维组织细胞瘤(osteosarcoma/malignantfibrous histiocytoma of bone)、卵巢癌(ovarian cancer)、卵巢低恶性潜能肿瘤(ovarian low malignant potential tumor)、胰腺癌(pancreatic cancer)、鼻旁窦和鼻腔癌(paranasal sinus and nasal cavity cancer)、甲状旁腺癌(parathyroid cancer)、阴茎癌(penile cancer)、嗜铬细胞瘤(pheochromocytoma)、垂体瘤pituitary tumor)、胸膜肺母细胞瘤(pleuropulmonary blastoma)、前列腺癌(prostate cancer)、直肠癌(rectal cancer)、肾细胞(肾)癌(renal cell(kidney)cancer)、过渡细胞癌(transitional cell cancer)(例如肾盂和输尿管)、视网膜母细胞瘤(retinoblastoma)、横纹肌肉瘤(rhabdomyosarcoma)、唾腺癌(salivary gland cancer)、骨恶性纤维组织细胞瘤(malignant fibrous histiocytoma of bone)、软组织肉瘤(soft tissue sarcoma)、塞扎里综合征(sezary syndrome)、皮肤癌(skin cancer)、小肠癌(small intestinecancer)、胃(胃部)癌(stomach(gastric)cancer)、幕上原始神经外胚层和松果体肿瘤(supratentorial primitive neuroectodermal and pineal tumors)、皮肤t-细胞淋巴瘤(cutaneous t-cell lymphoma)、睾丸癌(testicular cancer)、恶性胸腺瘤(malignantthymoma)、甲状腺癌thyroid cancer)、妊娠性滋养层细胞瘤(gestational trophoblastictumor)、尿道癌(urethral cancer)、子宫肉瘤(uterine sarcoma)、阴道癌(vaginalcancer)、外阴癌(vulvar cancer)和Wilms肿瘤(Wilms’tumor)。在一个优选实施方案中,癌症是非小细胞肺癌。
在本发明实施方案的任一个中,癌症可以是在任何器官中的任何癌症,例如,癌症选自由以下各项组成的组:神经胶质瘤(glioma)、甲状腺癌(thyroid carcinoma)、乳腺癌(breast carcinoma)、小细胞肺癌(small-cell lung carcinoma)、非小细胞肺癌(non-small-cell carcinoma)、胃癌(gastric carcinoma)、结肠癌(colon carcinoma)、胃肠道间质肿瘤(gastrointestinal stromal carcinoma)、胰腺癌(pancreatic carcinoma)、胆管癌(bile duct carcinoma)、CNS癌(CNS carcinoma)、卵巢癌(ovarian carcinoma)、子宫内膜癌(endometrial carcinoma)、前列腺癌(prostate carcinoma)、肾癌(renalcarcinoma)、间变性大细胞淋巴瘤(anaplastic large-cell lymphoma)、白血病(leukemia)、多发性骨髓瘤(multiple myeloma)、间皮瘤(mesothelioma)和黑素瘤(melanoma),及其组合。
在一个实施方案中,本发明提供药物包装或试剂盒,其包括式(I)、式(II)或式(III)的化合物以及不同于式(I)、式(II)或式(III)的化合物的抗-丙型肝炎化合物。所述药物包装或试剂盒包括一个或多个填充有式(I)、式(II)或式(III)的化合物以及不同于式(I)、式(II)或式(III)的化合物的抗-丙型肝炎化合物的容器。任选地,与这样的容器相关的可以是以由管理药物或生物产品的制造、使用或销售的政府机关规定的形式的须知,所述须知反映由对于人施用的制造、使用或销售的机关的批准。
以下实施例进一步举例说明本发明,但当然不应被解释为以任何方式限制本发明的范围。
通用化学方法。所有试剂如从以下供应商收到那样使用:Alfa Aesar,Ark Pharm,Aldrich和Fisher Scientific。乙腈和THF使用Innovative Technology PureSolv溶剂纯化系统纯化。1H和13C谱图在Bruker Avance 400MHz或500MHz光谱仪上记录。化学位移以百万分之几报告并且参考残留质子溶剂信号。急骤柱色谱分离利用使用RediSep RF硅胶柱的Teledyne Isco CombiFlash RF进行。TLC在Analtech UNIPLATE硅胶GHLF板(具有荧光的石膏无机硬质层)上进行。TLC板使用碘蒸气显影。自动化制备型RP HPLC纯化使用Agilent1200质量-定向分馏系统(Prep Pump G1361,具有梯度延伸、补充泵G1311A、pH调节泵G1311A、HTS PAL自动取样器、UV-DAD检测G1315D、级分收集器G1364B和Agilent 6120四极质谱仪G6120A)进行。制备型色谱条件包括Waters X-Bridge C18柱(19°—150mm,5μm,具有19°—10-mm保护柱),用水和乙腈梯度洗脱,其以20mL/min的流速在4min内将乙腈含量增加20%(通过辅助泵添加NH4OH调节至pH 9.8),以及在DMSO中进行样品稀释。根据各个粗样品的分析RP HPLC分析选择制备梯度、触发阈值和UV波长。分析方法使用具有UV检测(Agilent1200 DAD SL)和质量检测(Agilent 6224TOF)的Agilent1200RRLC系统。分析方法条件包括Waters Aquity BEH C18柱(2.1°—50mm,1.7μm)和用以0.4mL/min流速在pH 9.8缓冲的甲酸铵水溶液中的5%乙腈至100%乙腈的线性梯度进行洗脱。化合物纯度基于来自UV/vis吸光度(在214nm)的峰积分(曲线下面积)进行测量,并且化合物鉴别基于质量分析确定。用于生物学研究的所有化合物具有>90%的纯度。
实施例1
本实施例举例说明一种合成根据本发明一个实施方案的化合物的方法。
2-(2-氯-6-甲基苯基)-4,5-二甲基唑3-氧化物。在0℃向(E)-3-(肟基)丁-2-酮(0.417g,4.13mmol)和2-氯-6-甲基苯甲醛(0.702g,4.54mmol)在乙酸(25.0mL)中的混合物中加入HCl(1.55mL,4.0M,6.19mmol)。允许反应混合物温热至室温并搅拌16h,用MTBE稀释并过滤。收集固体,用乙醚洗涤并干燥,得到产物,为黄褐色固体,其在未经进一步纯化下使用(0.797g,3.35mmol,81%收率)。1H NMR(400MHz,CDCl3)δ7.52(t,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),2.53(s,6H),2.42(s,3H)。13C NMR(101MHz,CDCl3)δ153.8,147.5,143.0,134.5,129.3,127.3,118.9,20.4,11.2,7.4。HRMS(m/z):对于C12H13ClNO2([M]++H)的理论值238.0635;实验值238.0627;HPLC纯度:95.1%。
2-(2-氯-6-甲基苯基)-4-(氯甲基)-5-甲基唑。向2-(2-氯-6-甲基苯基)-4,5-二甲基唑-3-氧化物(789mg,3.32mmol)在DCE(20.0mL)中的溶液中加入POCl3(0.340mL,3.65mmol)。将反应在回流下加热30min,然后冷却至室温,小心地用水猝灭并用DCM(2x20.0mL)萃取。蒸发后的残余物经由利用EtOAc/己烷的硅胶色谱法纯化,得到无色油状物(327mg,1.28mmol,39%收率)。1H NMR(400MHz,CDCl3)δ7.33–7.21(m,2H),7.21–7.11(m,1H),4.58(s,2H),2.42(s,3H),2.26(s,3H);13C NMR(101MHz,CDCl3)δ156.9,147.0,141.0,134.7,132.2,131.0,128.5,127.6,127.0,37.2,20.3,10.3;HRMS(m/z):对于C12H12Cl2NO([M]++H)的理论值256.0296;实验值256.0288;HPLC纯度:98.1%。
1-((2-(2-氯-6-甲基苯基)-5-甲基唑-4-基)甲基)哌啶-4-甲酸。向哌啶-4-甲酸(98.0mg,0.759mmol)和氢氧化钾(85mg,1.52mmol)在乙醇(5.0mL)中的溶液中加入在EtOH(2.0mL)中的2-(2-氯-6-甲基苯基)-4-(氯甲基)-5-甲基唑(130mg,0.506mmol)。将混合物在室温搅拌16h。在真空下除去溶剂并将残余物经由利用MeCN/水的C-18硅胶柱色谱法纯化,得到无色油状物(113mg,0.323mmol,64%收率)。1H NMR(400MHz,DMSO-d6)δ7.50–7.40(m,2H),7.40–7.31(m,1H),3.42(s,2H),2.82–2.78(m,2H),2.36(s,3H),2.19(s,3H),2.05–1.98(m,3H),1.80–1.69(m,2H),1.56–1.46(m,2H);13C NMR(126MHz,DMSO-d6)δ176.8,155.0,146.4,140.7,133.4,131.5,131.4,128.9,127.7,126.9,52.7,52.3,41.5,28.6,19.7,9.9;HRMS(m/z):对于C18H22ClN2O3([M]++H)的理论值349.1319;实验值349.1340;HPLC纯度:97.8%。
1-((2-(2-氯-6-甲基苯基)-5-甲基唑-4-基)甲基)-N-(3-(顺式-3,5-二甲基哌啶-1-基)丙基)哌啶-4-甲酰胺(ML391)。将1-((2-(2-氯-6-甲基苯基)-5-甲基唑-4-基)甲基)哌啶-4-甲酸(80.0mg,0.229mmol)、3-((3S,5R)-3,5-二甲基哌啶-1-基)丙-1-胺(58.6mg,0.344mmol)、HOBT(35.1mg,0.229mmol),DIC(0.071mL,0.459mmol)和DMAP(1.4mg,0.011mmol)在MeCN(2.5mL)中的混合物在100℃在微波辐照下加热10min。除去溶剂并将残余物经由利用DCM/(MeOH,含有1%Et3N)的硅胶色谱法纯化。将所得的油状物通过制备型反相HPLC进一步纯化,得到无色油状物(70.8mg,0.141mmol,62%收率)。1H NMR(400MHz,CDCl3)δ7.36(t,J=4.6Hz,1H),7.31–7.23(m,2H),7.19–7.12(m,1H),3.53(s,2H),3.37–3.28(m,2H),3.04–2.99(m,2H),2.88–2.84(m,2H),2.40(t,J=9.1Hz,2H),2.39(s,3H),2.24(s,3H),2.14–2.07(m,2H),2.04–1.96(m,1H),1.89–1.53(m,9H),1.39(t,J=11.0Hz,2H),0.86(d,J=6.5Hz,6H),0.53(q,J=12.0Hz,1H);13C NMR(101MHz,CDCl3)δ174.7,156.1,146.4,140.8,134.8,131.6,130.6,128.3,128.2,126.8,61.8,58.3,53.4,52.8,43.4,42.1,40.0,31.3,29.0,24.8,20.2,19.6,10.3;HRMS(m/z):对于C28H42ClN4O2([M]++H)的理论值501.2996;实验值501.2995;HPLC纯度:96.1%。
实施例2
本实施例对于根据本发明一个实施方案的化合物提供表征数据。
N-(3-((3S,5R)-3,5-二甲基哌啶-1-基)丙基)-1-((5-甲基-2-(邻甲苯基)唑-4-基)甲基)哌啶-4-甲酰胺。收率:51.4mg,69%。1H NMR(400MHz,CDCl3)δ7.96–7.93(m,1H),7.39–7.32(m,1H),7.32–7.22(m,3H),3.50(s,2H),3.37–3.32(m,2H),3.07–3.03(m,2H),2.95–2.86(m,2H),2.66(s,3H),2.45(t,J=6.2Hz,2H),2.40(s,3H),2.17–1.97(m,3H),1.91–1.64(m,9H),1.44(t,J=11.0Hz,2H),0.88(d,J=6.5Hz,6H),0.63–0.49(m,1H)。13C NMR(101MHz,CDCl3)δ174.9,159.7,145.5,137.0,132.3,131.4,129.4,128.7,126.9,125.8,61.6,58.1,53.9,53.08,43.4,42.0,39.8,31.2,29.0,24.8,21.8,19.6,10.5.HRMS(m/z):对于C28H43N4O2([M]++H)的理论值467.3386;实验值467.3392;HPLC纯度:100%。
1-((2-(3,5-二甲基苯基)-5-甲基唑-4-基)甲基)-N-(3-((3S,5R)-3,5-二甲基哌啶-1-基)丙基)哌啶-4-甲酰胺。收率:46.7mg,64%。1H NMR(400MHz,CDCl3)δ7.66(s,2H),7.32(t,J=4.6Hz,1H),7.05(s,1H),3.45(s,2H),3.39–3.29(m,2H),3.04–3.00(m,2H),2.91–2.87(m,2H),2.43(t,J=6.1Hz,2H),2.39(s,3H),2.36(s,6H),2.12–1.97(m,3H),1.88–1.61(m,9H),1.43(t,J=11.0Hz,2H),0.88(d,J=6.5Hz,6H),0.56(q,J=11.9Hz,1H)。13C NMR(101MHz,CDCl3)δ174.9,159.7,145.8,138.2,132.6,131.5,127.5,123.8,61.7,58.2,54.0,53.2,43.4,42.0,39.8,31.3,29.0,24.8,21.2,19.6,10.4.HRMS(m/z):对于C29H45N4O2([M]++H)的理论值481.3543;实验值481.3547;HPLC纯度:100%。
N-(2-(二丙基氨基)乙基)-1-((5-甲基-2-(邻甲苯基)唑-4-基)甲基)哌啶-4-甲酰胺。收率:20.3mg,29%。1H NMR(400MHz,CDCl3)δ7.96–7.94(m,1H),7.35–7.21(m,3H),3.53(s,2H),3.46–3.38(m,2H),3.34–3.20(m,2H),3.10-3.04(m,2H),2.77(q,J=6.8Hz,2H),2.67(s,3H),2.64–2.56(m,2H),2.41(s,3H),2.18Page 28of 31–2.10(m,2H),2.04–1.87(m,2H),1.72–1.42(m,7H),0.98–0.84(m,6H)。13C NMR(101MHz,CDCl3)δ175.4,175.3,159.7,145.6,137.0,132.3,131.4,129.4,128.6,126.9,125.8,53.9,53.0,52.9,52.0,51.8,50.0,48.7,47.68,47.66,47.6,46.2,38.9,38.8,29.0,23.3,23.2,22.9,21.9,21.0,11.74,11.72,11.3,11.2,10.5.HRMS(m/z):对于C26H41N4O2([M]++H)的理论值441.3230;实验值441.3227;HPLC纯度:100%。
N-(3-(4-异丙基哌啶-1-基)丙基)-1-((5-甲基-2-(邻甲苯基)唑-4-基)甲基)哌啶-4-甲酰胺。收率:55.0mg,55%。1H NMR(400MHz,CDCl3)δ7.92(dd,J=8.0,1.7Hz,1H),7.59(t,J=4.6Hz,1H),7.33–7.17(m,3H),3.47(s,2H),3.34–3.30(m,2H),3.08–2.92(m,4H),2.65(s,3H),2.45–2.39(m,2H),2.38(s,3H),2.14–1.96(m,3H),1.91–1.73(m,6H),1.67–1.61(m,4H),1.40(dq,J=13.3,6.4Hz,1H),1.33–1.15(m,2H),1.08–0.99(m,1H),0.83(d,J=6.8Hz,6H)。13C NMR(101MHz,CDCl3)δ174.8,174.7,159.7,145.6,137.0,132.3,131.4,129.4,128.7,126.9,125.8,58.5,54.5,53.8,53.1,43.4,42.2,40.2,32.4,29.4,29.1,24.7,21.8,19.6,10.4.HRMS(m/z):对于C29H45N4O2([M]++H)的理论值481.3543;实验值481.3537;HPLC纯度:100%。
1-((5-甲基-2-(邻甲苯基)唑-4-基)甲基)-N-(3-(3-甲基哌啶-1-基)丙基)哌啶-4-甲酰胺。收率:49.0mg,68%。1H NMR(400MHz,CDCl3)δ7.94(dd,J=8.1,1.7Hz,1H),7.38(t,J=4.7Hz,1H),7.35–7.21(m,3H),3.50(s,2H),3.35(q,J=5.8Hz,2H),3.08–3.03(m,2H),2.95–2.83(m,2H),2.66(s,3H),2.43(t,J=6.1Hz,2H),2.40(s,3H),2.17–1.98(m,3H),1.90–1.61(m,10H),1.58–1.50(m,2H),0.97–0.82(m,4H)。13C NMR(101MHz,CDCl3)δ174.9,159.7,145.5,137.0,132.4,131.4,129.4,128.7,126.9,125.8,62.2,58.4,54.1,53.9,53.1,43.5,39.9,32.9,31.3,29.09,29.05,25.6,24.7,21.8,19.7,10.5.HRMS(m/z):对于C27H41N4O2([M]++H)的理论值453.3230;实验值453.3228;HPLC纯度:100%。
实施例3
本实施例举例说明对于根据本发明一个实施方案的化合物的水溶解度的确定。
水溶解度在室温(23℃)在磷酸盐缓冲盐水(PBS)中测量。通过定义,PBS是137mMNaCl、2.7mM KCl、10mM磷酸氢二钠、2mM磷酸二氢钾并且pH为7.4。在pH 7.4,化合物1的溶解度被确定为>74μg/mL(>147μM)。
实施例4
本实施例举例说明根据本发明一个实施方案的化合物1的稳定性。
程序:将化合物以10μM溶解在pH 7.4的PBS或PBS/乙腈(1/1)(1%DMSO)中并在室温不用硫醇源(作为阴性对照)温育或用50μM二硫苏糖醇(DTT)温育。混合物每一小时取样持续八小时或每8小时取样持续48小时并通过RP HPLC/UV/HRMS分析。用于分析的分析RPHPLCUV/HRMS系统是具有UV-检测和质量-检测的Waters Acquity系统(Waters SQD)。分析方法调节包括Waters Acquity HSS Atlantis C18柱(2.1x 50mm,1.8μm)并利用以0.6mL/min流速的99%水至100%CH3CN的线性梯度洗脱。在214nm色谱上的峰使用WatersOpenLynx软件积分。将在各个时间点的曲线下的绝对面积进行比较以确定剩余的相对百分比化合物。对最终样品研究可能加合物的质量以确定是否形成了任何可检测的加合物。所有样品一式两份地制备并描绘平均值。利尿酸(一种已知的Michael受体)用作阳性对照。发现10μM的化合物1在PBS缓冲液(图1A)和具有50%(v/v)乙腈溶剂的PBS缓冲液体系(图1B)二者中在48小时试验期内是稳定且可溶的。在48小时的取样之后,大于97%的样品在上清中仍然被检测到。为了确定探针化合物对亲核性降解的稳定性,在50μM二硫苏糖醇(DTT)存在下将化合物溶解在上述两种溶剂体系中(图2A和2B)。在8小时之后,在任一溶剂体系中都没有出现可测量的降解,表明1对亲核攻击具有强大抗性。
实施例5
本实施例举例说明对于根据本发明一个实施方案的化合物1的剂量响应曲线。
在增加浓度的测试化合物1存在下,使用带有萤光素酶报告基因的HCVcc(HCVcc-RLuc,基因型2a)来感染Huh7.5.1细胞。病毒感染和复制通过处理后48h的萤光素酶信号来测量。细胞毒性利用基于ATP的细胞存活性测定(ATPlite)平行地评价。结果是来自三次重复的平均值±SEM。EC50和CC50值使用非线性回归利用GraphPad Prism 5.0软件计算。结果示于图3,其中EC50曲线通过三角形显示而CC50曲线通过圆圈显示。
实施例6
本实施例举例说明根据实施例5中所述的HCVcc-RLuc报告基因测定的针对HCV的EC50和CC50值以及根据本发明一个实施方案的化合物的使用Huh 7.5.1 ATPlite测定的细胞毒性。结果提供在表1中。表1还含有关于大鼠肝微粒体测定、细胞渗透性和溶解度的数据。
表1
实施例7
本实施例举例说明根据实施例5中所述的HCVcc-RLuc报告基因测定的针对HCV的EC50和CC50值以及根据本发明一个实施方案的化合物的使用Huh 7.5.1 ATPlite测定的细胞毒性。结果提供在表2中。表2还含有关于大鼠肝微粒体测定、细胞渗透性和溶解度的数据。
表2
实施例8
本实施例举例说明根据本发明一个实施方案的基于细胞的测定。
为了考察其中本发明化合物作用的病毒生命周期的阶段,进行HCV单周期感染测定、HCV亚基因组复制子测定和HCV拟颗粒(HCVpp)测定。
A.将播种在96-孔板中的Huh 7.5.1细胞(104个细胞/孔)培养过夜。将细胞用感染性HCVsc连同测试化合物接种。在化合物处理之后48h测量细胞的荧光素酶活性。
B.HCV亚基因组复制子测定。将HCV复制子(GT 1b和2a)细胞铺板在96-孔板中(104个细胞/孔)并温育过夜。将细胞用测试化合物处理。在化合物处理之后48h测量细胞的荧光素酶活性。在瞬时复制子测定中,将接种在96-孔板中的Huh 7.5.1细胞(104个细胞/孔)培养过夜。然后将细胞用具有DMRIE-C的复制子mRNA瞬时转染达4h。在除去转染试剂后,细胞用含10μM的各化合物的DMEM培养基温育48h。测量荧光素酶活性。
C.HCVpp测定。将Huh 7.5.1细胞接种在96-孔板中(104个细胞/孔)并培养过夜。然后将细胞用10μM的化合物处理连同HCVpp GT 1a、1b、VSVpp和MLVpp感染4h。然后将细胞洗涤并培养48h,接着进行荧光素酶测定以检测HCV进入。显示的结果是至少五次重复的平均值±SEM。使用10μM的环孢素A和楸毒素(rottlerin)作为阳性对照。
在HCV单周期感染测定(Masaki,T.等,J.Virology,2010,84:5824-5835)中,使用单轮感染性HCV缺陷性颗粒(HCVsc,基因型2a)来感染Huh 7.5.1细胞。HCVsc可以感染和复制但不组装新的病毒粒子,因此此测定检测对于组装前的HCV生命周期事件具有抑制活性的化合物。HCV亚基因组复制子测定评价化合物是否靶向病毒RNA复制。HCVpp(GT 1a和1b)是显示HCV包膜糖蛋白的缺陷性逆转录病毒颗粒,并且使用它们来评估化合物处理对于病毒进入的作用。作为病毒选择性的对照病毒,在进入测定中还测试了VSVpp和MLVpp。
实施例9
本实施例举例说明根据本发明一个实施方案的化合物3的作用机制研究。
为了确定此化学型在病毒生命周期中的靶标,利用10μM的命中化合物3进行HCV单周期感染测定、HCV亚基因组复制子测定和HCV拟颗粒(HCVpp)测定。在HCV单周期感染测定中,使用单轮感染性HCV缺陷性颗粒(HCVsc,基因型2a)来感染Huh7.5.1细胞。HCVsc可以感染和复制但不组装新的病毒粒子,因此此测定检测对于组装前HCV生命周期事件具有抑制活性的化合物。化合物3在HCVsc感染水平方面引起显著抑制活性,表明此化学型靶向病毒生命周期的早期阶段。HCV亚基因组复制子测定评价化合物是否靶向病毒RNA复制。化合物3显示在利用GT 2a复制子RNA或GT 2a复制子细胞系的瞬时转染测定中对于HCV复制没有抑制作用。这意味着复制阶段不太可能是此化学型的靶标。另一方面,HCVpp(GT 1a和1b)是显示HCV包膜糖蛋白的缺陷性逆转录病毒颗粒,其已被用来评估化合物处理对于病毒进入的作用。使用化合物3作为病毒选择性的对照,还测试了来自水疱性口炎病毒的病毒拟颗粒(VSVpp)。化合物3显示在HCVpp GT 1a测定中的强抑制活性(<对照的30%RLU)和在VSVpp测定中的中度抑制(~50%RLU)。总之,HCV生命周期测定中的SID144187742(CID3244725)的结果表明,该化学型靶向病毒生命周期的早期阶段并且显示对于HCV进入的强抑制活性。结果提供在表3中。
表3
注:在HCV单周期感染测定中,将接种在96-孔板中的Huh7.5.1细胞(104个细胞/孔)培养过夜。将细胞用感染性HCVsc连同测试化合物接种。在化合物处理之后48h测量细胞的荧光素酶活性。在瞬时复制子测定中,将接种在96-孔板中的Huh7.5.1细胞(104个细胞/孔)培养过夜。然后将细胞用具有DMRIE-C的复制子RNA转录本瞬时转染4h。在除去转染试剂之后,将细胞用含有10μM各化合物的DMEM培养基温育48h。测量荧光素酶活性。在利用HCV复制子(GT 2a)细胞的HCV亚基因组复制子测定中,将细胞铺板到96-孔板中(104个细胞/孔)并温育过夜。将细胞用测试化合物处理。在化合物处理之后48h测量荧光素酶活性。在HCVpp测定中,将Huh7.5.1细胞接种在96-孔板中(104个细胞/孔)并培养过夜。然后将细胞用10μM的化合物处理连同HCVpp GT 1a或VSVpp感染4h。然后将细胞洗涤并培养48h,接着进行荧光素酶测定以检测HCV进入。显示的结果是五次重复的平均值±SEM。利巴韦林和聚乙二醇干扰素α(IFN-α)的组合已是关注的用于治疗慢性HCV感染的标准达许多年。直接作用抗病毒剂如特拉匹韦和达卡他韦最近被批准用于治疗丙型肝炎。这里考察了化合物3与这些不同种类的抗-HCV药物的组合。在与不同浓度的各药物组合的不同浓度的化合物3存在下,进行了与ATPlite测定平行的HCVcc-RLuc测定。化合物3和各个药物的组合在对细胞存活性没有毒性作用的情况下以剂量依赖性方式导致比它们任一个单独更大的HCV抑制作用。通过使用MacSynergy II程序,根据Bliss独立模型,生成了协同或拮抗作用的Log容量,并且协同作用容量概括在表4中。
表4
a值是从在或接近其当单独测试时的EC50值的测试化合物与SID144187742(CID3244725)的组合获得的组合指数(CI)的平均值±SEM。b协同作用水平定义为如下:“+/-”意指几乎是加合性的(0.9<CI<1.1),“++”意指中度协同作用(0.7<CI<0.85)并且“+++”意指协同作用(0.3<CI<0.7)。c协同作用水平定义如下:“++”意指中度协同作用(5<log容量<9)并且“+++”意指强协同作用(log容量>9)。
结果还利用CalcuSyn程序进行分析,其中组合指数计算自在或接近其单独测试时的EC50值的化合物3和测试药物的组合。总之,化合物3的抗病毒作用与利巴韦林、干扰素-γ、特拉匹韦(NS3/4A抑制剂)、达卡他韦(NS5A抑制剂)、环孢素A和2’-C-甲基胞嘧啶(NS5B抑制剂)是协同性的,同时没有显著细胞毒性,支持其在与这些药物的联合治疗中的用途。所观察到的协同作用表明,此化学型通过与这些药物中的任一个不同的机制抑制HCV感染。利巴韦林和IFN-α的作用机制通过宿主抗病毒响应介导。特拉匹韦是NS3/4A蛋白酶抑制剂并且达卡他韦抑制HCV NS5A。环孢素A靶向病毒RNA复制并且2’-C-甲基胞嘧啶是NS5B聚合酶抑制剂。化合物3与这些试剂的协同作用表明,其作用机制新颖且独特。这使得此化学型对于利用可能独特的机制并且在治疗期间选择耐药性病毒株的较低概率的开发具有吸引力。
除非本文中另有指明或与上下文明显相矛盾,在描述本发明的内容中(尤其是在所附权利要求的内容中),术语“一个”和“一种”以及“所述”和“至少一个”及相似提及的使用要被解释为覆盖单数和复数二者。除非本文中另有指明或与上下文明显相矛盾,在一个或多个项目例举之后的术语“至少一个”的使用(例如,“A和B中的至少一个”)要被解释为意指选自所列举项目中的一个项目(A或B)或者所列举项目中的两个以上的任意组合(A和B)。除非另有说明,术语“包括”、“具有”、“包含”和“含有”要被解释为开放式术语(即,意指“包括,但不限于”)。除非本文中另有指明,本文中数值范围的叙述仅意图用作个别地提及落入该范围内的各个单独值的简略方法,并且各个单独值如同其个别地在本文中叙述一样被结合到说明书中。除非本文中另有指明或与上下文明显相矛盾,本文中描述的所有方法可以以任何合适顺序进行。除非另有要求,本文中提供的任何和所有实施例、或者示例性语言(例如,“如”)的使用,仅意图更好地举例说明本发明并且不对本发明的范围施加限制。说明书中的语言都不应解释为指明任何非要求的要素对于本发明的实施是必须的。
本文中描述了本发明的优选实施方案,包括对于发明人知晓的用于实现本发明的最佳方式。在阅读前面的描述后,那些优选实施方案的变形对于本领域普通技术人员可以变得明显。当适当时,发明人预期技术人员采用这样的变形,并且发明人对于本发明预计以与本文具体所述不同的其他方式实现。因此,本发明包括如适用法律所允许的在所附权利要求书中所述的主题的所有更改和等同替换。此外,除非本文中另有指明或与上下文明显相矛盾,在其所有可能变性中的上述要素的任意组合也由本发明涵盖。
Claims (46)
1.式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
2.根据权利要求1所述的化合物、盐、立体异构体和包含立体异构体的混合物,其中Ar是任选被一个或多个选自以下各项的取代基取代的苯基:C1-C6烷基、C1-C6烷氧基、卤代和CF3。
3.根据权利要求2所述的化合物、盐、立体异构体或立体异构体的混合物,其中Ar选自2-甲基苯基、3,5-二甲氧基苯基、2-氯苯基、2-氯-6-甲基苯基、4-氯苯基、2-乙基苯基、3-甲基苯基、4-甲基苯基、3,4-二甲基苯基、2,6-二甲基苯基、3-氯苯基、3-甲基-4-氟苯基、3,5-二(三氟甲基)苯基、2,4-二甲基苯基、3,5-二甲基苯基、2-氯-6-氟苯基、2,5-二甲基苯基、2,6-二氯苯基、2-氟-6-甲氧基苯基、2-溴-6-甲氧基苯基、2-溴-6-氯苯基、2,6-二溴苯基、2-氯-6-三氟甲基苯基、2-甲基-6-甲氧基苯基、2-氟-6-甲基苯基、2,6-二氟苯基、3,4-二氯苯基、4-氟苯基、2,3,4,5,6-五甲基苯基和2,4,6-三甲基苯基。
4.根据权利要求1-3中任一项所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物具有式(I)。
5.根据权利要求4所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是并且R2和R3独立地是C1-C6烷基。
6.根据权利要求5所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
7.根据权利要求4所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是Y是CR9R10并且R5-R14独立地是氢或C1-C6烷基。
8.根据权利要求7所述的化合物、盐、立体异构体或立体异构体的混合物,其中A选自:
9.根据权利要求8所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物选自:
10.根据权利要求8所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是:
其中在A的哌啶基环上的带有甲基的C-3和C-5碳原子具有绝对构型:(3S,5R)。
11.根据权利要求10所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
其中在A的哌啶环上的带有甲基的C-3和C-5碳原子具有绝对构型:(3S,5R)。
12.根据权利要求7所述的化合物、盐、立体异构体或立体异构体的混合物,其中Y是O。
13.根据权利要求12所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
14.根据权利要求4所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是
15.根据权利要求14所述的化合物、盐、立体异构体或立体异构体的混合物,其中R4是1-甲基哌啶-4-基或2-(二甲基氨基)乙基。
16.根据权利要求15所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
17.根据权利要求4所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是
18.根据权利要求17所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是
19.根据权利要求18所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
20.根据权利要求4所述的化合物、盐、立体异构体或立体异构体的混合物,其中Ar选自萘-1-基、2-甲基-萘-1-基和蒽-1-基。
21.根据权利要求20所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
22.根据权利要求7所述的化合物、盐、立体异构体或立体异构体的混合物,其中X是S。
23.根据权利要求22所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
24.根据权利要求1-3中任一项所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物具有式(II)。
25.根据权利要求24所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是
26.根据权利要求25所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
27.根据权利要求1-3中任一项所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物具有式(III)。
28.根据权利要求27所述的化合物、盐、立体异构体或立体异构体的混合物,其中A是
29.根据权利要求28所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是:
30.药物组合物,所述药物组合物包含权利要求1-29中任一项的化合物、盐、立体异构体或立体异构体的混合物和药用载体。
31.治疗或预防有需要的哺乳动物中的病毒感染的方法,所述方法包括向有需要的哺乳动物施用有效量的式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
32.权利要求31所述的方法,其中所述病毒感染由丙型肝炎引起。
33.权利要求32所述的方法,所述方法还包括向所述哺乳动物施用有效量的至少一种抗-丙型肝炎化合物。
34.权利要求33所述的方法,其中所述抗-丙型肝炎化合物选自巴韦林、干扰素-α、特拉匹韦、达卡他韦、环孢素A、索非布韦、阿孙普韦(BMS-650032)、波西普韦、GS-9451、GS-9256、ABT-450、丹诺普韦(RG7227)、福达瑞韦(BI 201335)、IDX320、MK-5172、西咪匹韦(TMC435)、舒乏端韦(ACH-1625)、ABT-267、ACH-3102、BMS-791325、达卡他韦(BMS-790052)、GSK2336805、IDX719、JNJ-47910382、来地帕韦(GS-5885)、MK-8742、PPI-461、PPI-668、ABT-333、ALS-002200、BI 207127、IDX184、INX-08189、美立他滨(RO5024048)、PPI-383、PSI-352938、司屈布韦(ANA-598)、索非布韦(PSI-7977或GS-7977)、特哥布韦(GS-9190)、TMC647055、菲利布韦(PF-00868554)、GS-9669、GSK2878175、VX-135、VX-222、Algeron(西培干扰素α-2b)、BIP 48(聚乙二醇干扰素α2b 48kDA)、聚乙二醇化干扰素α2b、聚乙二醇化干扰素λ(BMS-914143)、聚乙二醇化-P-干扰素-α-2b(P1101)、阿拉泊韦(DEB025)和IDX21437。
35.权利要求33或34所述的方法,所述方法还包括向所述哺乳动物施用有效量的至少两种抗-丙型肝炎化合物。
36.权利要求31所述的方法,其中所述病毒感染由选自以下各项的病毒引起:黄病毒科(Flaviviridae)病毒、呼吸道合胞体病毒、严重急性呼吸综合症(SARS)和中东呼吸综合征冠状病毒(MERS-CoV或MERS)。
37.权利要求36所述的方法,其中所述黄病毒科病毒是登革热病毒。
38.用于在用抗-丙型肝炎化合物进行治疗的哺乳动物中协同地增强所述抗-丙型肝炎化合物的抗病毒效果的方法,所述方法包括向所述哺乳动物施用式(I)、(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
39.权利要求38所述的方法,其中所述抗-丙型肝炎化合物选自利巴韦林、干扰素-α、特拉匹韦、达卡他韦、环孢素A、索非布韦、阿孙普韦(BMS-650032)、波西普韦、GS-9451、GS-9256、ABT-450、丹诺普韦(RG7227)、福达瑞韦(BI 201335)、IDX320、MK-5172、西咪匹韦(TMC435)、舒乏端韦(ACH-1625)、ABT-267、ACH-3102、BMS-791325、达卡他韦(BMS-790052)、GSK2336805、IDX719、JNJ-47910382、来地帕韦(GS-5885)、MK-8742、PPI-461、PPI-668、ABT-333、ALS-002200、BI 207127、IDX184、INX-08189、美立他滨(RO5024048)、PPI-383、PSI-352938、司屈布韦(ANA-598)、索非布韦(PSI-7977或GS-7977)、特哥布韦(GS-9190)、TMC647055、菲利布韦(PF-00868554)、GS-9669、GSK2878175、VX-135、VX-222、Algeron(西培干扰素α-2b)、BIP 48(聚乙二醇干扰素α2b 48kDA)、聚乙二醇化干扰素α2b、聚乙二醇化干扰素λ(BMS-914143)、聚乙二醇化-P-干扰素-α-2b(P1101)、阿拉泊韦(DEB025)和IDX21437。
40.试剂盒,所述试剂盒包括:
(a)式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物,和
(b)至少一种不同于所述式(I)或式(II)的化合物的抗-丙型肝炎化合物。
41.权利要求40所述的试剂盒,其中所述试剂盒包括至少两种不同于所述式(I)或式(II)的化合物的抗-丙型肝炎化合物。
42.治疗或预防有需要的哺乳动物中的癌症的方法,所述方法包括向有需要的哺乳动物施用有效量的式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物。
43.根据权利要求1所述的化合物、盐、立体异构体或立体异构体的混合物,其中所述化合物是
44.式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物,
其用于治疗或预防有需要的哺乳动物中的病毒感染。
45.式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物,
其用于在用抗-丙型肝炎化合物进行治疗的哺乳动物中协同地增强所述抗-丙型肝炎化合物的抗病毒效果。
46.式(I)、式(II)或式(III)的化合物:
其中Ar是任选取代的C6-C14芳基,
X是O或S,
R1是氢、C1-C6烷基或CF3,
A是
其中n是1至3的整数,
o是0或1,
Y是CR9R10或O,
R2和R3独立地是C1-C6烷基,
R4是二(C1-C6烷基氨基)C2-C6烷基或5元或6元含N杂环,并且
R5-R14独立地是氢或C1-C6烷基,
或其药用盐、其立体异构体或包含其立体异构体的混合物,
其用于治疗或预防有需要的哺乳动物中的癌症。
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