CN110041327B - 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用 - Google Patents
吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用 Download PDFInfo
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- CN110041327B CN110041327B CN201810044308.4A CN201810044308A CN110041327B CN 110041327 B CN110041327 B CN 110041327B CN 201810044308 A CN201810044308 A CN 201810044308A CN 110041327 B CN110041327 B CN 110041327B
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- 239000003814 drug Substances 0.000 title claims abstract description 33
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 27
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- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 6
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- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 5
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
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- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
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Abstract
本发明属于医药化学抗病毒领域,涉及一种式(I)所示的新型吡啶酮衍生物或其立体异构体、可药用盐、溶剂化物或结晶及其用于制备预防或治疗流感A型或/及流感B型等病毒性感染疾病的药物的应用,特别是作为PA亚基帽依赖性内切酶抑制剂在预防或治疗流感A型或/及流感B型病毒性感染疾病中的应用。本发明的化合物具有显著的抑制流感内切酶和流感DNA的活性,可以单独或和神经氨酸酶抑制剂、核苷类药物、PB2抑制剂、PB1抑制剂、M2抑制剂或其他抗流感药物联合用药,显著缩短流感感染的时间和降低死亡率,有极好的临床应用前景。
Description
技术领域
本发明属于医药化学领域,具体涉及一类新型吡啶酮衍生物或其立体异构体,含有前述吡啶酮衍生物或其立体异构体的药物组合物以及它们作为抗病毒药物的用途,特别是作为制备帽依赖性内切核酸酶抑制剂(Cap dependent endoclease inhibitor)的药物用于预防和/或治疗感染流感病毒的用途,具体例如用于制备预防和/或治疗流感病毒A型和流感病毒B型感染的药物的用途。
背景技术
流感是感染流感病毒引起的急性呼吸道感染病。每年流行性感冒可以导致上千人死亡,而大规模的流感爆发在全球范围内可导致百万人死亡。尽管流感疫苗和金刚烷(amantadine)可以用于预防和治疗流感,但他们的预防和疗效非常有限,需要开发更广谱的疫苗和更有效的抗流感药物。
神经氨酸酶抑制剂奥塞米韦(Oseltamivir)和扎那米韦(Zanamivir)可以压制病毒出芽和释放,但是在临床上神经氨酸酶抑制剂的疗效是可疑的,特别是对于重症患者可能没有效果,另外耐药性也是神经氨酸酶抑制剂必须考虑的问题。对于高致死性的新型流感病毒大流行的担心,临床上迫切需要全新机理的抗流感药物。
在流感病毒的生命历程中,8段RNA片段的转录是一个关键的步骤。这个步骤需要进行病毒反义RNA的转录和复制。RNA聚合酶包括PA、PB1和PB2三个亚基组成的三聚体,在感染的细胞核内负责病毒RNA的复制和转录。流感病毒RNA的转录具有特殊的“夺帽”机制,PB2亚基负责识别和结合宿主前体mRNA的“帽子结构”,PA亚基剪切宿主mRNA作为引物,启动转录过程PA亚基的内切酶活性位点,负责切割宿主的mRNA,在PB1亚基中用作进一步病毒mRNA合成的引物。因为PA亚基的帽依赖性内切核酸酶是病毒生命过程所必须的,且具有宿主所不具备的病毒特异性酶活性,因此适合作为抗流感药物的靶位开发新型的抗流感药物。
CN102803260A公开了被取代的多环性氨基甲酰基吡啶酮衍生物,其对于帽依赖性内切核酸酶具有抑制活性,可用作流感传染病的治疗剂和/或预防剂。
发明内容
本发明的目的在于提供一种强效的新型吡啶酮衍生物抗病毒药物,与现有多环性氨基甲酰基吡啶酮衍生物相比,具有改善的预防或抑制流感病毒的活性和/或生物利用度,特别是通过具有帽依赖性内切核酸酶抑制剂来预防或抑制流感病毒A和流感病毒B感染的活性。本发明更进一步提供一种前药改善药物的吸收,提高药物的生物利用度,从而达到优秀的临床治疗效果。总之,本专利提供了一种通过PA内切酶抑制活性治疗流感病毒A和流感病毒B的药物,单独或联合用药可以快速治愈流感感染的患者。
为实现上述目的,本发明采用如下技术方案:
一种式(I)所示的吡啶酮衍生物或其立体异构体、可药用盐、溶剂化物或结晶,
其中:
(1)A选自N或CR1,R1选自H、氘、氰基、羟基、卤素、羧基、酯基、酰胺基、磺酰胺;或者,R1选自未取代或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、肼酰基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基亚硫酰基、C1-6烃基氨基羰基氨基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷氨基羰基、C3-6环烷羰基氨基、C3-6环烷氨基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧基烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳羰基、C1-6烃基砜基、C1-6烃基磺酰基氨基、C3-6环烷砜基、C3-6环烷基磺酰基氨基、C5-10芳砜基、C5-10芳基磺酰基氨基、氨基草酰基氨基、氨基草酰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基;
(2)M选自N或CR2,R2选自H、氘、氰基、羟基、卤素、羧基、酯基、酰胺基、磺酰胺基;或者,R2选自未取代或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、肼酰基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基亚硫酰基、C1-6烃基氨基羰基氨基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷氨基羰基、C3-6环烷羰基氨基、C3-6环烷氨基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧基烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳基羰基、C1-6烃基砜基、C1-6烃基磺酰基氨基、C3-6环烷砜基、C3-6环烷基磺酰基氨基、C5-10芳砜基、C5-10芳基磺酰基氨基、氨基草酰基氨基、氨基草酰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基;或者,R1和R2连接形成第一环或R2和R7连接形成第二环,所述第一环、第二环分别是未被间断或被选自杂原子、硅基、C=O、S=O、SO2中的一个或多个所间断且未取代或取代的碳环,且第一环、第二环分别是单环、螺环、并环、桥环或多环;
(3)Q选自N或CR3,R3选自H、氘、氰基、羧基、酯基、酰胺;或者,R3选自未取代或取代的下列基团:C1-6烃基、C3-6环烷基、C4-8杂环烷基、C5-10芳基、螺环、桥环、环烷基巯基C1-6烃基、环烷基C1-6烃基硫基C1-6烃基、环烷基C1-6烃基巯基环烃基、环烃基氧基环烃基、环酰胺基C1-6烃基、环酰胺基环烃基、环砜基C1-6烃基、环砜基环烃基;或者,R3和R4连接形成第三环,所述第三环是未被间断或被选自杂原子、硅基、C=O、S=O、SO2中的一个或多个所间断且未取代或取代的碳环,且第三环是单环、螺环、并环、桥环或多环;
(4)R选自NH、羰基或CR4R5,R4、R5独立选自H、氘、氰基、羧基、酯基、酰胺基;或者,R4、R5独立选自未取代或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基胺酰胺基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷基氨基羰基、C3-6环烷氨基羰基氨基、C3-6环烷基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧C1-6烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳基羰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基;或者,R4和R5连接形成第四环,所述第四环是未被间断或被选自杂原子、硅基、C=O、S=O、SO2中的一个或多个所间断且未取代或取代的碳环,且第四环是单环、螺环、并环、桥环或多环;
(5)R6选自H、氘、氰基、羟基、酯基、酰胺基、磺酰胺基;或者,R6选自未取代或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、肼酰基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基亚硫酰基、C1-6烃基氨基羰基氨基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷氨基羰基、C3-6环烷羰基氨基、C3-6环烷氨基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧基烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳羰基、C1-6烃基砜基、C1-6烃基磺酰基氨基、C3-6环烷砜基、C3-6环烷基磺酰基氨基、C5-10芳砜基、C5-10芳基磺酰基氨基、氨基草酰基氨基、氨基草酰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基;或者,R6为第五环,所述第五环是未被间断或被选自杂原子、硅基、C=O、S=O或-SO2中的一个或多个所间断且为未取代或取代的碳环,所述第五环是螺环、并环、桥环或多环;或者,R6和R连接形成第六环,所述第六环是单环、螺环、并环、桥环或多环,且所述第六环含有至少一个N和选择性的S、O、硅基、C=O、S=O或-SO2中的一个或多个;
(6)m为0、1、2、3、4或5,R7独立选自H、氘、羟基、氰基、卤素、羧基、酯基、磺酰胺基、酰胺基;或者,R7选自未取代或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、肼酰基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基亚硫酰基、C1-6烃基氨基羰基氨基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷氨基羰基、C3-6环烷羰基氨基、C3-6环烷氨基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧基烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳羰基、C1-6烃基砜基、C1-6烃基磺酰基氨基、C3-6环烷砜基、C3-6环烷基磺酰基氨基、C5-10芳砜基、C5-10芳基磺酰基氨基、氨基草酰基氨基、氨基草酰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基,或者,m为2、3、4或5,一组或多组相邻的两个R7连接形成第七环,所述第七环是未被间断或被选自杂原子、硅基、C=O、S=O或-SO2中的一个或多个所间断且为未取代或取代的碳环,所述第七环是单环、螺环、并环、桥环或多环;或者,R2和R7连接形成第八环,所述第八环是未被间断或被选自杂原子、硅基、C=O、S=O、SO2中的一个或多个所间断且未取代或取代的碳环,且第八环是单环、螺环、并环、桥环或多环;
(7)X选自Y(CH2)n、-CH(OCH3)、-CH(SCH3)、N、O或S,Y为化学键、NH、O或S,n为0、1、2或3;
(8)W为H或依靠化学方法或在体内酶的作用下代谢为原药的基团;
(9)Ar1和Ar2独立的选自苯环、含有一个或多个杂原子的芳杂环。
根据本发明的一个具体方面,Ar1和Ar2均为苯环,吡啶酮衍生物如下式(II)所示:
根据本发明的又一方面,Ar1和Ar2中的至少一个为芳杂环。
根据本发明,所述的杂环或芳杂环中杂原子优选独立地选自N、O、S。
在根据本发明的一些实施方式中,A为CR1,M为CR2,R1和R2形成所述第一环。
在根据本发明的一些实施方式中,Q为CR3,R为CR4R5,R3和R4形成所述第二环。
在根据本发明的某些实施方式中,R为CR4R5,R4和R6连接形成所述第六环。
根据本发明,式(I)中所述的W包括但不限于下列基团:
(a)-C(=O)-R8;(b)-C(=O)-(CH2)k-R8,k选自1-3;(c)-C(=O)-O-(CH2)k-R8,k选自1-3;(d)-CH2-O-R8;(e)-CH2-O-C(=O)-R8;(f)-CH2-O-C(=O)-O-R8;(g)-CH(-CH3)-O-C(=O)-R8;(h)-CH(-CH3)--O-C(C=O)-O-(CH2)k-R8,k选自0-3;(i)-CH2O-P(=O)(OH)8;(j)-CH2-O-P(=O)(OPh)(NHR8);(k)-CH2-O-P(=O)(OCH2OC(=O)OR8)2;所述R8为未取代的或取代的下列基团:C1-6烃基、C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、肼酰基、C1-6烃基羰基、C1-6烃基氨基羰基、C1-6烃基羰基氨基、C1-6烃基氧基羰基、C1-6烃基亚硫酰基、C1-6烃基氨基羰基氨基、C3-6环烷基、C3-6环烷氧基、C3-6环烷胺基、C3-6环烷巯基、C3-6环烷羰基、C3-6环烷氨基羰基、C3-6环烷羰基氨基、C3-6环烷氨基羰基氨基、C4-8杂环烷基、C4-8杂环烷氧基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基羰基、C4-8杂环烷基氨基羰基、C5-10芳基、C5-10芳氧基、C5-10芳氧基烃基、C5-10芳胺基、C5-10芳巯基、C5-10芳羰基、C1-6烃基砜基、C1-6烃基磺酰基氨基、C3-6环烷砜基、C3-6环烷基磺酰基氨基、C5-10芳砜基、C5-10芳基磺酰基氨基、氨基草酰基氨基、氨基草酰基、C5-10芳胺基羰基或C5-10芳胺基羰基氨基。
根据本发明的某些优选实施方案,R6选自如下基团:
根据本发明,所述的吡啶酮衍生物具体可以是且优选是例如如下化合物:
根据本发明,除去活泼氢之外,其余所有的氢原子都可以分别独立地被氘取代。
本发明还进一步提供含有本发明的式(I)所示的吡啶酮衍生物、其立体异构体、可药用盐、溶剂化物或结晶的药物组合物。
进一步的,该药物组合物为抗病毒药物组合物,其中还选择性地包含一种或多种治疗剂,所述治疗剂治选自以下组成的群:神经氨酸酶抑制剂、核苷类药物、PB2抑制剂、PB1抑制剂、M2抑制剂或其他抗流感药物。优选的,抗病毒药物组合物含有至少一种治疗剂。
本发明还涉及本发明的式(I)所示的吡啶酮衍生物、其立体异构体、可药用盐、溶剂化物或结晶或药物组合物在制备预防和/或治疗病毒性感染疾病的药物中的应用,所述病毒感染性疾病优选是流感A型或流感B型引起的感染性疾病。
本发明还另外涉及本发明的式(I)所示的吡啶酮衍生物、其立体异构体、可药用盐、溶剂化物或结晶或药物组合物在制备抗病毒药物中的应用,所述抗病毒药物优选是抑制流感帽依赖性内切核酸酶活性的药物或试剂。本发明还进一步提供一种制备本发明的吡啶酮衍生物的方法,采取如下路线:
根据本发明的一个具体实施方式,上述反应可以按如下步骤来实施:
步骤-1:A和B溶解于例如50%T3P的乙酸乙酯溶液中,在封管中于例如100℃反应1小时,得到中间体C。
步骤-2:中间体C溶解到例如氯化锂的DMA溶液中,反应液在例如100℃反应例如12小时,纯化得到化合物D。
步骤-3:得到的化合物D和酰氯或卤代物在碱的存在下得到羟基保护的前药(I),其中碱包括有机碱和无机碱,有机碱选自三乙胺、DIPEA、DBU、吡啶等;无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、氢化钠、氢化钾、碳酸氢钠等。
本发明中,为描述方便,某些地方,将本发明的式(I)所示的吡啶酮衍生物、其立体异构体、可药用盐、溶剂化物统称为本发明化合物。
根据本发明的药物组合物,其中本发明所化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体,如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明还提供本发明化合物在制备预防或治疗病毒感染疾病中的用途,优选其中病毒感染疾病为流感A和流感B的病毒感染。
本发明的药物组合物组成可以由下配比构成:
由于以上技术方案的实施,本发明与现有技术相比存在如下优势:
本发明提供了新型吡啶酮衍生物,该类化合物有极强的抑制流感病毒A型和流感病毒B型的活性。为了进一步提高药物的生物利用度,合成的前药化合物具有优异的药代动力学特性。
进一步地,本发明化合物具有高效的抑制流感病毒的活性,可以单独用于临床治疗或和其他抗流感药物例如神经氨酸酶抑制剂、核苷类药物、PB2抑制剂联合用药,在临床上可能快速治愈流感病人。
术语定义
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“未取代的”,当其用于限定某个基团时,意思是,该限定的基团没有为氢原子之外的其他基团所取代,此时该某个基团具有按照本发明所属领域的普通技术人员通常理解的相同的含义。例如未取代的C1-6烷基即本领域技术人员通常所理解的甲基、乙基等。
术语“取代的”,当其用于限定某个基团时,意思是,其限定的基团上的某一个或多个氢原子被取代基所取代,此时该某个基团的含义应结合取代基来理解。本发明中,除非特别说明,当提及“取代的”,意指由其限定的基团中的氢原子由选自下列中的某一个或多个取代基所取代:
氘、氰基、卤素、羟基、羧基、酯基、砜基、磺酰胺基、酰胺基、羰基(-C(=O)-)、C1-6烃基S(=O)(=NH)-、胺基、肼酰基、C1-6烃基、卤代的C1-6烃基、羟基取代的C1-6烃基、酰胺取代的C1-6烃基、C1-6烃氧基、卤代的C1-6烃氧基、C1-6烃氧基C1-6烃基、C1-6烃氧基C1-6烃氧基、C1-6烃胺基、C1-6烃巯基、C1-6烃基羰基、C1-6烃基胺酰基、C1-6烃基酰胺基、卤代C1-6烃基酰胺基、C1-6烃基氧酰基、C1-6烃基胺酰胺基、C1-6烃基砜基、C1-6烃基磺酰胺基、C3-6环烷基、卤代C3-6环烷基、C3-6环烷氧基、卤代C3-6环烷氧基、C3-6环烷基C1-6烃基、C3-6环烷基氧C1-6烃基、C3-6环烷基C1-6烃氧基、C3-6环烷基C1-6烃氧基C1-6烃氧基、C3-6环烷胺基、C3-6环烷基C1-6烃胺基、C3-6环烷巯基、卤代C3-6环烷巯基、C3-6环烷基C1-6烃巯基、C3-6环烷基砜基、C3-6环烷基C1-6烃砜基、C3-6环烷基磺酰胺基、C3-6环烷基C1-6烃基磺酰胺基、C3-6环烷羰基、C3-6环烷基C1-6烃基羰基、C3-6环烷胺酰基、C3-6环烷基C1-6烃基胺酰基、C3-6环烷酰胺基、C3-6环烷基C1-6烃基酰胺基、C3-6环烷胺酰胺基、C4-8杂环烷基、C4-8杂环烷基氧基、卤代C4-8杂环烷基氧基、C4-8杂环烷基氧C1-6烃基、卤代C4-8杂环烷基氧C1-6烃基、C4-8杂环烷基C1-6烃氧基、卤代C4-8杂环烷基C1-6烃氧基、C4-8杂环烷基C1-6烃基、C4-8杂环烷基C1-6烃氧基C1-6烃基、C4-8杂环烷胺基、C4-8杂环烷巯基、C4-8杂环烷基C1-6烃基巯基、C4-8杂环烷基砜基、C4-8杂环烷基C1-6烃砜基、C4-8杂环烷基磺酰胺基、C4-8杂环烷基C1-6烃基磺酰胺基、C4-8杂环烷基羰基、C4-8杂环烷基C1-6烃基羰基、C4-8杂环烷基被羰基取代、C4-8杂环烷基胺酰基、C4-8杂环烷基酰胺基、C4-8杂环烷基C1-6烃基酰胺基、C5-10芳基、C5-10芳氧基、C5-10芳氧基C1-6烃基、C5-10芳基C1-6烃基、C5-10芳基C1-6烃氧基、C5-10芳胺基、C5-10芳巯基、C5-10芳基C1-6烃巯基、C5-10芳基砜基、C5-10芳基C1-6烃砜基、C5-10芳基磺酰胺基、C5-10芳基C1-6烃基磺酰胺基、C5-10芳羰基、C5-10芳基C1-6烃基羰基、C5-10芳胺酰基、C5-10芳酰胺基或C5-10芳胺酰胺基。
作为优选,上述的取代基选自氘、氰基、卤素(优选F、Cl、Br)、羟基、羧基、酯基、砜基、磺酰基氨基、羰基氨基、羰基、C1-6烃基亚磺酰基氨基、胺基、肼酰基、C1-6烃基、卤代的C1-6烃基、羟基取代的C1-6烃基、酰胺取代的C1-6烃基、C1-6烃氧基、卤代的C1-6烃氧基、C1-6烃氧基C1-6烃基、C1-6烃氧基C1-6烃氧基。
进一步优选地,上述的取代基选自氘、氰基、F、Cl、Br、羟基、羧基、酯基、砜基、磺酰胺基、酰胺基、羰基、甲基亚磺酰基氨基、乙基亚磺酰基氨基、异丙基亚磺酰基氨基、叔丁基亚磺酰基氨基、胺基、肼酰基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、卤代甲基(具体例如三氟甲基)、卤代乙基、卤代正丙基、卤代异丙基、卤代环丙基、卤代正丁基、卤代异丁基、卤代叔丁基、卤代环丁基、羟基甲基、羟基乙基、羟基正丙基、羟基异丙基、羟基环丙基、羟基正丁基、羟基异丁基、羟基叔丁基、羟基环丁基、羟基正戊基、羟基异戊基、羟基新戊基、羟基环己基、甲氧基、乙氧基、丙氧基。
在涉及到具体命名时,取代基通常置于被取代的基团之前,例如“C1-3烷氧基C3-8环烷基C1-6烷基”指C1-6烷基,其被C3-8环烷基取代,而该C3-8环烷基又为C1-3烷氧基取代,举例:甲氧基环丁基甲基的结构式为:
术语“未被间断”,当其用于限定某个基团时,意思是,该限定的基团的共价键没有被其他基团所间断,此时该某个基团具有按照本发明所属领域的普通技术人员通常理解的相同的含义。例如未间断的环烷基即本领域技术人员通常所理解的环丁基、环戊基等。
术语“间断”或“间断的”,当其用于限定某个基团时,意思是,其限定的基团上的某一处或多处共价键个被间断原子或基团所间断,此时该某个基团的含义应结合间断原子或基团来理解。本发明中,除非特别说明,当提及“间断的”,意指由其限定的基团中的共价键由选自杂原子(O、N、S)、硅基、C=O、S=O或-SO2中的一个或多个所间断。间断的位置可以是任意化学上可以成立的位置,当间断原子或基团由多个时,多个间断原子或基团之间的相对位置没有限定,只要他们在化学上是可以成立的。
术语“立体异构体”是指由、分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体,或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐,所述的酸可以是有机酸或无机酸,具体可选自例如:磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂合物的特殊形式,其中与水发生配位。在本发明范围内,溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定形。
术语“烃基”是指烷基,烯基烷基和炔基烷基。
术语“烷基”是指直链、支链或环状的饱和的由碳和氢构成的取代基。优选1-20个碳原子,更优选1-12个碳原子。术语“烷基”是指直链、支链或环状的饱和烃基。烷基具体包括例如甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基、16-烷基、18-烷基。术语“C1-20烷基”是指含有1-20个碳原子的直链、支链或环状的饱和烃基。当烷基被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。例如取代基可以是烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代。
术语“烯基”和“炔基”分别是指直链、支链或环状的含有双键和三键的不饱和烃基,优选2-20个碳原子,更优选2-12个碳原子。当被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。例如取代基可以是选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代。
术语“环烷基”指饱和单环环烃基。单环一般包括3-10个碳原子。环烷基的非限制实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基等。本发明中,螺环、稠环和桥环的环烷基还被统称为多环环烷基。
术语“环”,在没有特别限定时,指任何环状结构,不限形式和组成,可以是单环、桥环、螺环、并环和多环中的任何形式,可以是碳环或杂环或其他形式的环,例如被羰基间断的碳环,可以是未取代的或取代的。
术语“碳环基”或“碳环”是指碳原子数为3~20、优选碳原子数为3~16、更优选碳原子数为4~12的碳环基,包含环烷基、环烯基、芳基、双环碳环和多环碳环基等。术语“杂环基”或“杂环”是指环的结构上含由至少一个杂原子,具体可以是例如含义1个或1个以上的从O、S和N中任意选择的相同或不同杂原子的杂芳基、非芳族杂环基、双环杂环基和多环杂环基等。
术语“芳基”取广义理解,不仅包括碳环芳基,也包括杂芳基。
术语“碳环芳基”指6-10元全碳单环或多环的芳香基团,包括苯基,萘基,联苯基等。碳环芳基可以是取代的或未取代的。取代基独立的选自例如烷基、环烷基(例如环丙烷基、环丁烷基和环戊烷基等)、烯基、炔基、叠氮、氨基、氘、烷氧基、烷硫基、烷基氨基,卤素、硫醇、羟基,硝基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、烷基硅基等。
术语“杂芳基”指包含1-10个杂原子的杂芳香体系的基团,包括单环杂芳基和稠环杂芳基。杂原子包括氧,硫,氮,磷等。其中单环杂芳基包括但不限于呋喃、噻吩、吡咯、噻唑、咪唑、1,2,3-三氮唑、1,2,4-三氮唑、1,2,3-噻二唑,噁唑、1,2,4-噁二唑、1,3,4-噁二唑、吡啶、嘧啶、哒嗪、吡嗪、四氢呋喃、四氢吡咯、哌啶、哌嗪、吗啉、异噁唑啉等。稠环杂芳基包括但不限于喹啉、异喹啉、吲哚、苯并呋喃、苯并噻吩、嘌呤、吖啶、咔唑、芴、色烯酮、芴酮、喹喔啉、3,4-二氢萘酮、二苯并呋喃、氢化二苯并呋喃、苯并噁唑基等。杂芳基可以是取代的和未取代的。取代基例如是选自烷基、环烷基(如环丙烷基、环丁烷基和环戊烷基等)、烯基、炔基、叠氮、氨基、氘、烷氧基、烷硫基、烷基氨基,卤素、硫醇、羟基,硝基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、烷基硅基等。
术语“卤素”是指氟、氯、溴、碘,优选为氟、氯、溴。
术语“氘”是氢的同位素,原子质量是后者的2倍,与碳的结合更强。氘化“和”氘“表示氢在指定位置被替换为氘。一个“氘化的取代基”是取代基,其中至少一个氢被以指定的百分比富集的氘取代。
术语“卤代烷基”是指至少被一个卤素原子取代的烷基。
术语“杂环基”是指至少含有一个杂原子的环状基团,其中杂原子可以为氮、氧、硫、硫等。杂环基包括单杂环基和多杂环基。
具体实施方式
以下实施例可以使本专业技术人员更全面地理解本发明,但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下:
DCM:二氯甲烷
EtOAc:乙酸乙酯
THF:四氢呋喃
DME:乙二醇二甲醚
1,4-Dioxane:1,4-二氧六环
TEA:三乙胺
T3P:1-丙基磷酸酐
PPA:多聚磷酸
TBAF:四丁基氟化铵
NBS:N-溴代丁二酰亚胺
AIBN:偶氮二异丁腈
HATU:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
TFA:三氟醋酸
下面结合具体实施例,对本发明做进一步的说明:
实施例1:制备(I-1)
化合物1b的制备:化合物1a(2.0g,8.1mmol),DBU(1.85g,12.2mmol)和碘乙烷(2.28g,14.6mmol)在20mLDMF中室温反应16小时。然后加入100mL水稀释,EA萃取。有机相合并,依次用硫代硫酸钠、0.5NHCl和饱和食盐水洗,然后经无水硫酸钠干燥后旋干得到2.1g油状产物。
化合物1c的制备:化合物1b(2.1g,7.7mmol)、Boc肼(1.53g,11.6mmol)和吡啶对甲苯磺酸盐(5.78g,23.1mmol)在N,N-二甲基乙酰胺(20mL)中于60℃反应16小时。反应结束后往反应液中加入100mL水,然后用乙酸乙酯萃取(50mL×3)。合并有机相,饱和食盐水洗,无水硫酸钠干燥后浓缩,粗品用柱层析分离得到1.9g黄色油状物。ESI-MS m/z 389.2(M+H)+
化合物1d的制备:化合物1c(1.9g,4.9mmol)溶于10mL乙醇,加入1N aq.NaOH溶液(14.7mL,14.7mmol),然后在60℃反应24小时。用3N HCl酸化,DCM萃取。有机相合并,饱和食盐水洗,干燥后浓缩。粗产品用二氯甲烷/石油醚(5mL/50mL)打浆,得到1.1g白色固体。ESI-MS m/z 361.2(M+H)+
化合物1f的制备:化合物1d(360mg,1mmol),1e(133mg,1.2mmol),TEA(303mg,3.0mmol)和HATU(570mg,1.5mmol)在DCM中室温搅拌过夜,然后加水稀释,DCM萃取。有机相合并,饱和食盐水洗,干燥浓缩后柱层析分离得到350mg白色固体。ESI-MS m/z 454.2(M+H)+
化合物1g的制备:化合物1f(350mg,0.77mmol)溶于4mLDCM,加入1mLTFA并于0℃反应6小时。旋干,加入1N NaOH调至碱性,DCM/iPrOH萃取。有机相合并,饱和食盐水洗,干燥后浓缩得到210mg油状物,直接用于下一步。
化合物1h的制备:化合物1g(210mg,0.59mmol)溶于5mL甲苯,加入30mg多聚甲醛和100mg醋酸,于100℃反应3小时。浓缩,薄板层析得到145mg产品。ESI-MS m/z 366.2(M+H)+
化合物1j的制备:化合物1h(140mg,0.38mmol)和1i(114mg,0.5mmol)在T3P的乙酸乙酯溶液中于100℃密闭反应3小时。冷却,加饱和NaHCO3稀释,然后乙酸乙酯萃取。有机相合并,干燥后浓缩,制备板分离得170mg产品。ESI-MS m/z 576.2(M+H)+。
化合物I-1的制备:化合物1j(170mg,0.29mmol)溶于5mL甲醇,加入钯碳,催化加氢。6小时后过滤,滤液浓缩后制备板分离得40mg产品。ESI-MS m/z 486.2(M+H)+。
实施例2:制备(I-26)
化合物26b的制备:化合物1d(360mg,1mmol),26a(116mg,1.2mmol),TEA(303mg,3.0mmol)和HATU(570mg,1.5mmol)在DCM中室温搅拌过夜,然后加水稀释,DCM萃取。有机相合并,饱和食盐水洗,干燥浓缩后柱层析分离得到320mg白色固体。ESI-MS m/z 440.2(M+H)+
化合物26c的制备:化合物26b(320mg,0.73mmol)溶于4mLDCM,加入1mLTFA并于0℃反应6小时。旋干,加入1N NaOH调至碱性,DCM/iPrOH萃取。有机相合并,饱和食盐水洗,干燥后浓缩得到195mg油状物,直接用于下一步。
化合物26d的制备:化合物26c(195mg,0.57mmol)溶于5mL甲苯,加入30mg多聚甲醛和100mg醋酸,于100℃反应3小时。浓缩,薄板层析得到130mg产品。ESI-MS m/z 352.2(M+H)+
化合物26e的制备:化合物26d(130mg,0.37mmol)和1i(114mg,0.5mmol)在T3P的乙酸乙酯溶液中于100℃密闭反应3小时。冷却,加饱和NaHCO3稀释,然后乙酸乙酯萃取。有机相合并,干燥后浓缩,制备板分离得130mg产品。ESI-MS m/z 562.2(M+H)+。
化合物I-26的制备:化合物26e(130mg,0.23mmol)溶于5mL甲醇,加入钯碳,催化加氢。6小时后过滤,滤液浓缩后制备板分离得35mg产品。ESI-MS m/z 472.2(M+H)+。
实施例3:制备(I-27)
化合物27b的制备:化合物1d(360mg,1mmol),27a(136mg,1.2mmol),TEA(303mg,3.0mmol)和HATU(570mg,1.5mmol)在DCM中室温搅拌过夜,然后加水稀释,DCM萃取。有机相合并,饱和食盐水洗,干燥浓缩后柱层析分离得到345mg黄色固体。ESI-MS m/z 456.2(M+H)+
化合物27c的制备:化合物27b(345mg,0.76mmol)溶于4mLDCM,加入1mLTFA并于0℃反应6小时。旋干,加入1N NaOH调至碱性,DCM/iPrOH萃取。有机相合并,饱和食盐水洗,干燥后浓缩得到170mg油状物,直接用于下一步。
化合物27d的制备:化合物27c(170mg,0.48mmol)溶于5mL甲苯,加入30mg多聚甲醛和100mg醋酸,于100℃反应3小时。浓缩,薄板层析得到80mg产品。ESI-MS m/z 368.2(M+H)+
化合物27e的制备:化合物27d(80mg,0.22mmol)和1i(68mg,0.3mmol)在T3P的乙酸乙酯溶液中于100℃密闭反应3小时。冷却,加饱和NaHCO3稀释,然后乙酸乙酯萃取。有机相合并,干燥后浓缩,制备板分离得55mg产品。ESI-MS m/z 578.2(M+H)+。
化合物I-27的制备:化合物27e(55mg,0.09mmol)溶于2mL甲醇,加入钯碳,催化加氢。6小时后过滤,滤液浓缩后制备板分离得15mg产品。ESI-MS m/z 488.2(M+H)+。
实施例4:制备(I-33)
化合物33b的制备:将化合物33a(2.0g,12.8mmol)溶于20mL甲醇中,氮气保护下,于0℃置换氮气3次。缓慢滴加二氯亚砜(2.35mL,0.032mol),滴加完毕转至油浴回流反应3h至原料反应完毕,旋干反应溶剂,甲苯带2-3次,硅胶柱层析PE:EA=100:1得产品黄色油状物1.00g,产率45.8%。
化合物33c的制备:将化合物33b(0.500g,2.97mmol)溶于10mL四氯化碳中,加入NBS(1.16g,6.54mmol),和AIBN(0.06g,0.36mmol),于80℃反应过夜,TLC监测原料基本反应完毕,过滤,滤液旋干硅胶柱层析PE:EA=50:1得红棕色油状物600mg。1H-NMR(CDCl3,400MHz):7.41-7.36(m,1H),7.22-7.20(m,1H),7.11-7.06(m,1H),4.66(s,2H),3.99(s,3H)。
化合物33e的制备:将化合物33c(0.52g,2.1mmol)溶于5mL无水四氢呋喃中,冰浴条件下加入化合物33d(0.52mL,2.5mmol)和TBAF(2.5mL,1.0M)溶液,加毕搅拌反应10min。然后加入碳酸钾(0.581g,4.2mmol,)和2mLDMF,室温条件下搅拌过夜,TLC监测原料反应完毕,加30mL水淬灭,然后用二氯甲烷萃取(30mL*3),有机相合并,饱和NaCl洗,干燥后浓缩,粗产物经制备板层析得到400mg油状物。1H-NMR(CDCl3,400MHz):7.39-7.36(m,1H),7.33-7.22(m,5H),7.03-6.97(m,2H),4.27(s,2H),3.95(s,3H)。
化合物33f的制备:将化合物33e(0.2g,0.72mmol)溶于5mL甲醇中,加入32%氢氧化钠0.718mL,加热至65℃反应2h.TLC监测原料反应完毕,用7N盐酸调PH 1-2.二氯甲烷(30mL*3)萃取,饱和食盐水洗涤有机相,无水硫酸钠干燥浓缩得产品180mg。
化合物33g的制备:将化合物33f(180mg,0.69mmol)溶于1mL环丁砜中,加入5mLPPA170℃反应1.5h,TLC监测原料反应完毕,将反应液倒入冰水中,二氯甲烷萃取(30mL*3),饱和碳酸氢钠洗涤有机相,饱和食盐水洗涤,干燥后浓缩得产品130mg。
化合物33h的制备:将化合物33g(130mg,0.53mmol)溶于5mL甲醇中,加入硼氢化钠(42mg,1.1mmol),室温反应3小时。将反应液倒入水中,二氯甲烷萃取(20mL*3),有机相合并,饱和食盐水洗涤,干燥后浓缩得产品110mg。
化合物33i的制备:化合物33h(110mg,0.4mmol)和化合物1h(146mg,0.4mmol)在3mLT3P的乙酸乙酯溶液中于100℃密闭反应3小时。冷却,加饱和NaHCO3稀释,然后乙酸乙酯萃取。有机相合并,干燥后浓缩,制备板分离得83mg产品。ESI-MS m/z 594.2(M+H)+。
化合物I-33的制备:化合物33i(80mg,0.13mmol)溶于1mL甲醇,加入钯碳,催化加氢。1小时后过滤,滤液浓缩后制备板分离得20mg产品。ESI-MS m/z 504.2(M+H)+。
实施例5.体外生物活性研究和细胞毒性研究
待测化合物:本发明的化合物:化合物I-1、化合物I-26、化合物I-27、化合物I-33;对照化合物:VX-787。
体外生物活性研究的试验方法:将MDCK细胞以2,000细胞每孔的密度种入384孔细胞培养板中,随后置于37℃,5%CO2培养箱中培养过夜。第二天化合物稀释后分别加入到细胞孔内(3倍倍比稀释,8个测试浓度点),流感病毒A/PR/8/34(H1N1)株随后以每孔2*TCID90加入细胞培养孔中,培养基中DMSO终浓度为0.5%。细胞板置于37℃,5%CO2培养箱中培养5天。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用GraphPad Prism软件对化合物的抑制率和细胞毒性进行非线性拟合分析,得到EC50值(结果参见表1)。
细胞毒性研究的研究方法:化合物的细胞毒性测定和抗病毒活性测定平行进行,除了不加病毒,其它的实验条件和抗病毒活性实验一致。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用于化合物细胞毒性(CC50)计算(结果参见表1)。
表1.化合物对于流感病毒A/PR/8/34(H1N1)的抑制活性以及毒性
结论:化合物I-1,I-26,I-27,I-33具有优秀的抑制H1N1的活性,活性低于10nM,并且具有很低的细胞毒性。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (9)
1.一种式(II)所示的吡啶酮衍生物、其立体异构体或可药用盐,
其中:
(1)A为CR1,R1选自H、氘;
(2)M为CR2,R2选自H、氘;
(3)Q为N;
(4)R为CR4R5,R4、R5独立选自H、氘;
(5)R6是螺环且R6选自以下基团:
(6)m为0、1、2、3、4或5,R7选自H、氘、羟基、氰基、卤素、羧基、C1-6烃基、C1-6烃氧基;
(7)X为S;
(8)W为H或W选自以下基团:(d)-CH2-O-R8;(e)-CH2-O-C(=O)-R8;(f)-CH2-O-C(=O)-O-R8;(g)-CH(-CH3)-O-C(=O)-R8;(h)-CH(-CH3)-O-C(C=O)-O-(CH2)k-R8,k选自0-3;(j)-CH2-O-P(=O)(OPh)(NHR8);(k)-CH2-O-P(=O)(OCH2OC(=O)OR8)2;所述R8选自C1-6烃基、C1-6烃氧基。
2.根据权利要求1所述的吡啶酮衍生物、其立体异构体或可药用盐,其特征在于,所述R7选自H、氘、羟基、氰基、卤素、C1-6烃基、C1-6烃氧基。
3.根据权利要求1或2所述的吡啶酮衍生物、其立体异构体或可药用盐,其特征在于,所述R7选自H、氰基、卤素;和/或,m为0或1或2。
4.根据权利要求1所述的吡啶酮衍生物、其立体异构体或可药用盐,其特征在于,所述R7选自H、氰基、氟、氯、溴;和/或,R8为C1-6烷基、C1-6烷氧基。
5.含有如权利要求1~4中任一项权利要求所述的式(II)所示的吡啶酮衍生物、其立体异构体或可药用盐的药物组合物,其特征在于,所述药物组合物为抗病毒药物组合物。
6.根据权利要求5所述的药物组合物,其特征在于,所述药物组合物还选择性地包含一种或多种治疗剂,所述治疗剂选自以下组成的群:神经氨酸酶抑制剂、核苷类药物、PB2抑制剂、PB1抑制剂、M2抑制剂或其他抗流感药物。
7.权利要求1~4中任一项权利要求所述的式(II)所示的吡啶酮衍生物、其立体异构体或可药用盐或权利要求5或6中的药物组合物在制备预防和/或治疗病毒性感染疾病的药物中的应用。
8.根据权利要求7所述的应用,其特征在于:所述病毒性感染疾病是流感A型或流感B型引起的感染性疾病。
9.权利要求1~4中任一项权利要求所述的式(II)所示的吡啶酮衍生物、其立体异构体或可药用盐或权利要求5或6中的药物组合物在制备抗病毒药物中的应用,所述抗病毒药物是抑制流感帽依赖性内切核酸酶活性的药物。
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EP19741336.2A EP3753936A4 (en) | 2018-01-17 | 2019-01-16 | PYRIDONE DERIVATIVE, COMPOSITION THEREOF AND USE THEREOF AS AN AGAINST FLU MEDICATION |
PCT/CN2019/071902 WO2019141179A1 (zh) | 2018-01-17 | 2019-01-16 | 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用 |
CA3088926A CA3088926A1 (en) | 2018-01-17 | 2019-01-16 | Pyridone derivative, composition and use as antiviral drug thereof |
CN202010817035.XA CN111848614B (zh) | 2018-01-17 | 2019-01-16 | 吡啶酮衍生物及抗流感病毒药物组合物 |
CN202010817435.0A CN111848616B (zh) | 2018-01-17 | 2019-01-16 | 吡啶酮衍生物及其用于制备抗流感病毒药物的用途 |
US16/487,088 US11247993B2 (en) | 2018-01-17 | 2019-01-16 | Pyridone derivative, composition and use as antiviral drug thereof |
PH12020551264A PH12020551264A1 (en) | 2018-01-17 | 2020-08-17 | Pyridone Derivative, Composition And Use As Antiviral Drug Thereof |
ZA2020/07143A ZA202007143B (en) | 2018-01-17 | 2020-11-16 | Pyridone derivative, composition thereof and application thereof as anti-influenza drug |
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JOP20170169A1 (ar) | 2016-08-29 | 2019-01-30 | Novartis Ag | مركبات بيريدازين ثلاثية الحلقة مندمجة تفيد في علاج العدوى بفيروس أورثوميكسو |
CN111303147A (zh) * | 2018-12-12 | 2020-06-19 | 银杏树药业(苏州)有限公司 | 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用 |
PE20210403A1 (es) | 2018-02-28 | 2021-03-02 | Novartis Ag | Derivados de 10-(di(fenil)metil)-4-hidroxi-8,9,9a,10-tetrahidro-7h-pirrolo [1',2':4,5]pirazino[1,2-b]piridazina-3,5-diona y compuestos relacionados como inhibidores de la replicacion del ortomixovirus para el tratamiento de la influenza |
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WO2021129799A1 (zh) * | 2019-12-27 | 2021-07-01 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
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WO2021180147A1 (zh) * | 2020-03-13 | 2021-09-16 | 北京凯因科技股份有限公司 | 一种流感病毒抑制剂 |
CN113527296A (zh) * | 2020-03-13 | 2021-10-22 | 北京凯因科技股份有限公司 | 一种流感病毒抑制剂 |
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CN114907365B (zh) * | 2021-02-09 | 2023-12-01 | 扬子江药业集团有限公司 | 一种流感病毒抑制剂及其用途 |
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