CN115135646B - 取代的多环化合物及其药物组合物和用途 - Google Patents
取代的多环化合物及其药物组合物和用途 Download PDFInfo
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- CN115135646B CN115135646B CN202080095375.4A CN202080095375A CN115135646B CN 115135646 B CN115135646 B CN 115135646B CN 202080095375 A CN202080095375 A CN 202080095375A CN 115135646 B CN115135646 B CN 115135646B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种取代的多环化合物及其药物组合物和用途,所述取代的多环化合物如式(I)所示,其中各基团的定义详见说明书,可用于抗流感病毒;
Description
技术领域
本发明涉及但不限于药物化学技术领域,尤其涉及一种取代的多环化合物及其药物组合物和用途。
背景技术
巴洛沙韦酯(baloxavir marboxil),商品名XofluzaTM,是由盐野义制药株式会社研发的首个单剂量口服抗病毒药物,2018年分别在日本和美国被批准上市。
中国专利CN103228653B公开了巴洛沙韦酯化合物,其化学结构为:
该药物对病毒帽依赖性核酸内切酶具有抑制作用,并通过抑制流感病毒mRNA的合成而抑制病毒蛋白质的合成,最终抑制病毒增殖。
由于病毒容易产生抗药性,因此,本领域仍渴望开发新型抗病毒药物。
发明内容
本发明人开发了一种新型结构的多环化合物,该化合物具有抗病毒作用。
本发明一方面提供一种如(I)所示的多环化合物、互变异构体、立体异构体、及其药学上可接受的盐:
式(I)中,A为N、C(H)或C;
与A相连的--在A为C时表示双键,而A为N或C(H)时表示不存在;
R1为氢、R4-C(O)-、R4-O-C(O)-或R4-O-C(O)-O-(CH2)m-;其中,R4选自氢,芳烃基,杂芳基,C1-C18的烷基,C2-C6的烯烃,被羟基、氨基、羧基、卤素、杂芳基、芳烃基中的一个或多个所取代的C1-C18的烷基,未取代的C3-C6的环烷基,C3-C6的环烷基取代的C1-C18的烷基,被羟基、氨基、羧基、卤素、芳基中的一个或多个所取代的C3-C6环烷基,被羟基、氨基、羧基、卤素、芳基中的一个或多个所取代的C3-C6环烷基取代的C1-C18的烷基;m为1、2、3或4;
R2和R3各自独立地选自氢,未取代的C1-C6的烷基,C6-C10的芳烃基,被羟基、氨基、羧基、卤素、C1-C4烷氧羰基或C1-C4烷氧基中的一个或多个所取代的C1-C6的烷基,C1-C4烷酰基,C3-C5烯酰基(例如烯丙酰基等),或者被羟基、氨基、羧基、卤素、烷氧羰基中一个或多个所取代的芳烃基;或者R2和R3相连接形成含氧的六元杂环、不含氧的六元杂环,或者所述六元杂环任选地被羟基、氨基、羧基、卤素、烷氧羰基中一个或多个所取代;
G为-CH2-、-NH-、-O-、-C(O)-,或不存在,此时Z直接与双键碳原子相连;
Z选自羟基,C1-C6烷氧基,未取代的芳烃基,未取代的杂芳基,被羟基、氨基、羧基、卤素、烷氧羰基中的一个或多个所取代的芳烃基,或者被羟基、氨基、羧基、卤素、烷氧羰基中的一个或多个所取代的杂芳基;
Y为下列基团中的一种:
其中,R10、R11和R12各自独立地氢、卤素、C1-C6烷基、或C1-C6烷氧基;而且,任选地,R10和R11在各自的苯环上可以是一个或多个。
在本发明的实施方案中,本发明提供的多环化合物,如式(II)所示:
式(II)中取代基的定义如式(I)所定义的。
在本发明的实施方案中,本发明提供的多环化合物,如式(III)所示:
式(III)中取代基的定义如式(I)所定义的。
在本发明的实施方案中,本发明提供的多环化合物,如式(IV)所示:
式(IV)中取代基的定义如式(I)所定义的。
在一些实施方案中,R1为氢或R4-O-C(O)-O-(CH2)m-,其中,R4为C1-C4烷基,m为1;在一些更优选的实施例中,R1为氢。
在一些实施方案中,R2为氢或取代或未取代的以下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基,所述取代基为卤素或羧基,而R3为氢。
在一些实施方案中,R2为甲酰基、乙酰基、丙酰基、烯丙酰基、或丁酰基,而R3为氢。
在一些实施方案中,R2为羧基取代的甲基、羧基取代的乙基、羧基取代的正丙基、羧基取代的异丙基、羧基取代的正丁基、羧基取代的异丁基、或羧基取代的叔丁基,而R3为氢。
在一些实施方案中,R2为氢,而R3为苯基,或被羧基、羟基、卤素任意一种或几种取代的苯基;在一种优选的实施方案中,R3为对羧基苯基。
在一些实施方案中,R2和R3相连接形成含氧的六元杂环、不含氧的六元杂环,所述杂环没有取代或者任选地被羟基、氨基、羧基、卤素、C1-C4烷氧羰基中一个或多个所取代。
在一些实施方案中,Z为羟基或取代或未取代的以下基团:苯基、咪唑基、吡唑基或吡啶基;所述取代基选自羧基或C1-C4烷氧羰基;优选的取代基为羧基。
在一些实施方案中,Y为下列基团中的一种:
在一些实施方案中,本发明提供的上述多环化合物,选自下列化合物:
另一方面,本发明提供了包含上述多环化合物、互变异构体、立体异构体、及其药学上可接受的盐的药物组合物。
本发明公开了一种药物组合物,其以本发明所述的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的载体组成。
第三方面,本发明还提供式(I)所示的多环化合物的制备路线,该路线包括如下步骤:
在上述路线中涉及的取代基定义如式(I)中相应基团的定义。
第四方面,本发明提供了上述多环化合物、互变异构体、立体异构体、及其药学上可接受的盐,可用于抗流感病毒,用于治疗和/或预防流感病毒引起的疾病。
本发明所述多环化合物可以被配制为药用组合物,按照多种合适选择的给予方式给患者用药,这些途径包括全身例如口服或胃肠外,通过静脉内、肌肉、透皮或皮下等。
定义:
构成本发明的一部分是药学上可接受的溶剂化物,可以使结晶水合物或者是与其它溶剂结晶物,如乙醇等。
构成本发明的一部分是药学上可接受的盐:
如果本发明化合物为碱性的,则适当的“药学上可接受的盐”包括本发明化合物和无机酸或有机酸反应形成的本发明化合物的常规无毒盐。例如,包括得自无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐,也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”是指本发明化合物通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。
术语“芳烃基”表示被芳基取代的烃基。
术语“杂芳基”表示5至12个环原子的单环或稠合环基团,含有一个、两个、三个或四个选自N、O或S的环杂原子,其余环原子是C,另外具有完全共轭的π电子系统。未取代的杂芳基地非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑。
术语“烷基”表示1-20个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-18”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括18个碳原子)。烷基可以是取代的或未取代的。当是取代的烷基时,该取代基优选是一或多个,更优选1-3个,最优选1或2个取代基。
术语“羟基”表示-OH基团.
术语“氨基”表示-NH2基团。
术语“羧基”表示-COOH基团。
术语“卤素”表示氟、氯、溴或碘,优选为氟或氯。
术语“环烷基”表示全部为碳的单环或稠合的环(“稠合”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团,其中一个或多个环不具有完全连接的π电子系统,环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基可为取代的和未取代的。
术语“芳基”表示1至12个碳原子的全碳单环或稠合多环基团,具有完全共轭的π电子系统。芳基的非限制性实例有苯基、萘基和蒽基。芳基可以是取代的或未取代的。当被取代时,取代基优选为一个或多个,更优选为一个、两个或三个,进而更优选为一个或两个。
本发明所述的多环化合物对病毒具有抑制作用,并抑制病毒增殖。本发明所述的多环化合物可作为新型结构的抗病毒药物。
在本发明的一些实施例中,本发明所述的多环化合物在制备抗流感病毒药物中的应用;在一些具体的实施例中,本发明所述的流行性感冒病毒为A型流感病毒。
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MS确定。
实施例1:制备化合物DSC126
本实施例合成路线为:
步骤1:
反应瓶中加入6.09克化合物1和30毫升四氢呋喃,缓慢滴入4.76克二氯亚砜,体系加热50度反应2小时后,浓缩至干,再次加入20毫升DMF溶解。溶液滴入已冰水浴的浓氨水中,滴毕,体系在室温下反应至完全。体系加水析晶、过滤得到粗品,粗品用甲醇和水结晶,得到化合物2,收率90%,MS:m/z304.08[M+H]+。
步骤2:
反应瓶中加入5.46克化合物2,1.0克80%水合肼,0.62克对甲苯磺酸和20毫升四氢呋喃,升温至55度反应,反应结束后,自然冷却至室温,加入碳酸氢钠水溶液和乙酸乙酯萃取,有机相干燥后浓缩、打浆、过滤即得化合物3,收率92%,MS:m/z318.10[M+H]+。
步骤3:
反应瓶中加入4.74克化合物3,472毫克多聚甲醛,90毫克乙酸及30毫升甲苯,反应体系100度加热至反应结束。冷却至室温,体系浓缩至干,用正庚烷和异丙醇结晶得到化合物4,收率95%,MS:m/z330.10[M+H]+。
步骤4:
4.94克化合物4溶于50毫升DMF中,加入5.89克化合物L1和14.66克碳酸铯,体系室温下反应。反应结束后加入水析晶得到粗品,粗品用乙酸乙酯和正庚烷结晶得到化合物5,收率71%,MS:m/z576.15[M+H]+。
步骤5:
反应瓶中加入4.6克化合物5,3毫升三乙胺,45毫升二氯甲烷,室温下缓慢加入1.6克丙烯酰氯。体系在室温下反应至结束。体系加20毫升水淬灭,萃取,有机相浓缩至干。乙酸乙酯和正庚烷结晶,得到化合物6,收率82%,MS:m/z630.18[M+H]+。步骤6:
反应瓶中加入3.78克化合物6,20毫升四氢呋喃和20毫升甲醇,然后加入15毫升2N氢氧化钠水溶液,体系室温反应至结束。加酸调节PH至3-5,体系加乙酸乙酯和水萃取,有机相干燥、浓缩后用乙酸乙酯和正庚烷结晶,得到化合物7,收率89%,MS:m/z616.08[M+H]+。
步骤7:
反应瓶加入1.85克化合物7和0.64克氯化锂,然后加入DMA18毫升。反应体系升温至80度至反应完全,反应结束后将反应液滴入冰水中,然后用乙酸乙酯萃取。有机相干燥、浓缩至干,再用甲基叔丁醚打浆,即得到目标产品DSC-126,收率76%,MS:m/z526.12[M+H]+。
实施例2:制备化合物DSC144
本实施例合成路线为:
步骤1:
反应瓶中加入9.13克化合物1和50毫升四氢呋喃,缓慢滴入7.14克二氯亚砜,体系加热50度反应2小时后,浓缩至干,再次加入20毫升DMF溶解。溶液滴入已冰水浴的甲氨水溶液中,滴毕,体系在室温下反应至完全。体系加水析晶、过滤得到粗品,粗品用甲醇和水结晶化合物8,收率91%,MS:m/z318.08[M+H]+。
步骤2:
反应瓶中加入7.93克化合物8,1.4克80%水合肼,0.86克对甲苯磺酸和30毫升四氢呋喃,升温至55度反应,反应结束后,自然冷却至室温,加入碳酸氢钠水溶液和乙酸乙酯萃取,有机相干燥后浓缩、打浆、过滤即得产品9,收率90%,MS:m/z332.18[M+H]+。
步骤3:
反应瓶中加入6.63克化合物9,630.6毫克多聚甲醛,150毫克乙酸及30毫升甲苯,反应体系100度加热至反应结束。冷却至室温,体系浓缩至干,用正庚烷和异丙醇结晶得到化合物10,收率93%,MS:m/z344.02[M+H]+。
步骤4:
称取4.81克化合物10溶于50毫升DMF中,加入4.15克化合物L1和13.68克碳酸铯,体系室温下反应。反应结束后加入水中析晶得到粗品,粗品用乙酸乙酯和正庚烷结晶得到化合物11,收率71%,MS:m/z510.34[M+H]+。
步骤5:
反应瓶中加入4.6克化合物11,45毫升四氢呋喃,室温下通往氨气直至反应至结束。体系加水析晶,过滤,滤饼用水洗涤后得到粗品,粗品用乙酸乙酯和正庚烷结晶,得到化合物12,收率88%,MS:m/z495.18[M+H]+。
步骤6:
称取1.16克氢氧化钠溶解于20毫升水中,在-5度剧烈搅拌,2.33克液溴缓慢滴入得到澄清黄色溶液。加入3.6克化合物12分批加入至反应体系,温度不高于0度。加毕,体系升温至45度反应至结束。体系降温至0度,加酸调节PH至中性,体系过滤,滤饼用水洗涤得到粗品,粗品用甲醇和水结晶得到化合物13,收率83%,MS:m/z467.38[M+H]+。
步骤7:
氮气保护下,反应瓶加入2克化合物13,0.97克间溴苯甲酸甲酯,0.27克BINAP,2.96克碳酸钾,95毫克醋酸钯和50毫升甲苯。反应体系升温至120度至反应完全,反应结束后体系冷却至室温过滤,用乙酸乙酯洗涤滤饼。合并滤液浓缩至干,过柱分离得到化合物14,收率76%,MS:m/z601.24[M+H]+。
步骤8:
反应瓶加入1.2克化合物14和0.43克氯化锂,然后加入DMA15毫升。反应体系升温至80度至反应完全,反应结束后将反应液滴入冰水中,然后用乙酸乙酯萃取。有机相干燥、浓缩至干,再用甲基叔丁醚打浆,即得到化合物15,收率81%,MS:m/z511.21[M+H]+。
步骤9:
称取0.7克化合物15加入5毫升乙醇,室温下加入4N氢氧化钠溶液2毫升。反应体系升温至40度至反应完全。体系减压除去乙醇,加盐酸调节ph至4-5,有大量产品析出,过滤,用水洗涤,即得到目标产品DSC144,收率87%,MS:m/z497.2[M+H]+。
按照与上述实施例同样的方法,使用市售化合物或由市售化合物适当合成的中间体化合物,合成了下列实施例化合物。
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本发明实施例制备的化合物对病毒具有抑制作用。
实施例3:体外生物活性研究和细胞毒性研究。
细胞处理:将MDCK细胞以2000细胞每孔的密度接种于384孔组织培养板中,随后细胞置于37℃,5%CO2培养箱中培养过夜。
化合物处理:待测化合物将用DMSO倍比稀释好后,分别加入细胞培养板中。
病毒接种:在抗病毒活性检测孔内加入稀释好的病毒液(influenza A/Weiss/43(H1N1)),细胞毒性测试孔中不加病毒,DMSO终浓度为0.5%。将细胞置于37℃,5%CO2培养箱培养5天,直到病毒对照孔(无化合物)中的细胞病变率达到80-95%。
细胞活性检测:每孔加入细胞活性检测试剂CCK-8检测试剂,37℃,5%CO2培养箱培养3-4小时,随后,用微盘分析仪测吸光值。化合物剂量反应曲线及其EC50和CC50值通过GraphPad Prism软件分析后得出(结果见下表一)。
表一.流感病毒的抑制活性及细胞毒性试验结果
化合物编号 | EC50/nM | CC50/nM | 化合物编号 | EC50/nM | CC50/nM |
DSC126 | 1.19 | >1000 | DSC127 | 0.89 | >1000 |
DSC133 | 0.72 | >1000 | DSC137 | 1.15 | >1000 |
DSC138 | 0.45 | >1000 | DSC139 | 0.77 | >1000 |
DSC140 | 0.88 | >1000 | DSC141 | 0.57 | >1000 |
DSD142 | 0.32 | >1000 | DSC143 | 0.49 | >1000 |
DSC144 | 0.37 | >1000 | DSC145 | 0.97 | >1000 |
DSC146 | 0.56 | >1000 | DSC147 | 0.82 | >1000 |
DSC148 | 0.51 | >1000 | DSC149 | 0.39 | >1000 |
DSC150 | 1.03 | >1000 | DSC151 | 0.65 | >1000 |
DSC152 | 0.44 | >1000 | Baloxavir | 1.25 | >1000 |
从上表可以看出,本发明化合物表现出较高的抑制流感病毒活性的作用。
实施例4:感染流感病毒小鼠存活率试验
将雄性小鼠(BALB/C,雄性,体重约20克)分组,每组10只。制备含有500pfu的A型流感病毒(又称甲型流感病毒,H1N1)的磷酸盐缓冲液,除空白对照组外,通过鼻内滴入感染所选小鼠。24小时后,除对照组外其它每组分别给予上述化合物,每种化合物以5mg/kg、15mg/kg、30mg/kg的剂量口服给药,每天给药两次,连续用药5天。观察14天内小鼠的存活情况。
表二.感染流感病毒小鼠存活率试验结果
其中,空白对照组在观察期14天内全部存活,而病毒对照组小鼠在观察期内全部死亡;在5mg/kg剂量组中,巴洛沙韦酯治疗的小鼠约有20%的存活率,而服用化合物DSC138至DSC152的小鼠表现出20%至50%的存活率;在15mg/kg剂量组中,巴洛沙韦酯治疗的小鼠约有40%的存活率,而服用化合物DSC138至DSC152的小鼠表现出60%至70%的存活率;在30mg/kg剂量组中,巴洛沙韦酯治疗的小鼠约有60%的存活率,而服用化合物DSC138至DSC152的小鼠表现出70%至90%的存活率;这表明化合物DSC138至DSC152显示出高效的治疗效果。
Claims (3)
1.一种多环化合物、及其药学上可接受的盐,其特征在于,选自下列化合物:
2.包含权利要求1所述的多环化合物、及其药学上可接受的盐的药物组合物。
3.权利要求1所述的多环化合物、及其药学上可接受的盐,或者权利要求2所述的药物组合物在制备抗流感病毒药物中的应用。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102482219A (zh) * | 2009-03-26 | 2012-05-30 | 盐野义制药株式会社 | 吡喃酮和吡啶酮衍生物的制备方法 |
CN102803260A (zh) * | 2009-06-15 | 2012-11-28 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物 |
CN103228653A (zh) * | 2010-09-24 | 2013-07-31 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物的前药 |
AR104428A1 (es) * | 2015-04-28 | 2017-07-19 | Shionogi & Co | Derivados de piridona policíclica sustituida y profármaco de los mismos |
JP2017137291A (ja) * | 2016-02-03 | 2017-08-10 | 塩野義製薬株式会社 | 多環性ピリドン誘導体およびそのプロドラッグ |
CN107709321A (zh) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | 经取代的多环性吡啶酮衍生物及其前药 |
CN109311911A (zh) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | 用于制备取代多环吡啶酮衍生物及其晶体的方法 |
CN109503625A (zh) * | 2018-01-19 | 2019-03-22 | 赵蕾 | 一种多环吡啶酮化合物及其药物组合和用途 |
CN110041327A (zh) * | 2018-01-17 | 2019-07-23 | 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 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010011814A1 (en) * | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Chemical compounds |
KR20140090197A (ko) * | 2011-10-12 | 2014-07-16 | 시오노기세야쿠 가부시키가이샤 | 인터그라아제 억제 활성을 갖는 폴리사이클릭 피리돈 유도체 |
CR20190123A (es) * | 2016-08-10 | 2019-04-30 | Shionogi & Co | Composiciones farmacéuticas que contienen derivados de piridona policíclicos sustituídos y profármacos de los mismos |
JOP20170169A1 (ar) * | 2016-08-29 | 2019-01-30 | Novartis Ag | مركبات بيريدازين ثلاثية الحلقة مندمجة تفيد في علاج العدوى بفيروس أورثوميكسو |
CN111848615B (zh) * | 2018-01-17 | 2022-05-17 | 江西彩石医药科技有限公司 | 吡啶酮衍生物及包含其的抗流感病毒药物组合物 |
-
2020
- 2020-12-22 WO PCT/CN2020/138256 patent/WO2021129602A1/zh active Application Filing
- 2020-12-22 CN CN202080095375.4A patent/CN115135646B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102482219A (zh) * | 2009-03-26 | 2012-05-30 | 盐野义制药株式会社 | 吡喃酮和吡啶酮衍生物的制备方法 |
CN104151234A (zh) * | 2009-03-26 | 2014-11-19 | 盐野义制药株式会社 | 吡喃酮和吡啶酮衍生物的制备方法 |
CN102803260A (zh) * | 2009-06-15 | 2012-11-28 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物 |
CN103228653A (zh) * | 2010-09-24 | 2013-07-31 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物的前药 |
AR104428A1 (es) * | 2015-04-28 | 2017-07-19 | Shionogi & Co | Derivados de piridona policíclica sustituida y profármaco de los mismos |
CN107709321A (zh) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | 经取代的多环性吡啶酮衍生物及其前药 |
JP2017137291A (ja) * | 2016-02-03 | 2017-08-10 | 塩野義製薬株式会社 | 多環性ピリドン誘導体およびそのプロドラッグ |
CN109311911A (zh) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | 用于制备取代多环吡啶酮衍生物及其晶体的方法 |
CN110041327A (zh) * | 2018-01-17 | 2019-07-23 | 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 |
CN109503625A (zh) * | 2018-01-19 | 2019-03-22 | 赵蕾 | 一种多环吡啶酮化合物及其药物组合和用途 |
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