CN104211661A - 查尔酮类化合物及其制法和药物用途 - Google Patents

查尔酮类化合物及其制法和药物用途 Download PDF

Info

Publication number
CN104211661A
CN104211661A CN201310207361.9A CN201310207361A CN104211661A CN 104211661 A CN104211661 A CN 104211661A CN 201310207361 A CN201310207361 A CN 201310207361A CN 104211661 A CN104211661 A CN 104211661A
Authority
CN
China
Prior art keywords
substituted
unsubstituted
compound
amino
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201310207361.9A
Other languages
English (en)
Inventor
肖志艳
高佳娣
方成
汤雁波
杨颖�
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN201310207361.9A priority Critical patent/CN104211661A/zh
Publication of CN104211661A publication Critical patent/CN104211661A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Abstract

本发明公开了式Ⅰ化合物所示新型查尔酮类化合物及其生理上可接受的盐，含有所述化合物的药物制剂，以及所述化合物的抗肿瘤和抗HIV作用。

Description

查尔酮类化合物及其制法和药物用途
技术领域
本发明涉及通式Ⅰ的新型查尔酮类化合物以及生理上可接受的盐，这些化合物在肿瘤和艾滋病治疗中的用途，以及含有所述化合物的药物组合物。
背景技术
恶性肿瘤是当今社会威胁人类健康的严重疾病，并且由于生活环境的恶化，各种致癌因素增多，肿瘤的发病率逐年增高，在中国乃至全世界成为了导致人类死亡的第二大原因。因此，各国政府、研究机构及制药公司长期以来一直对肿瘤研究和抗肿瘤药物予以高度重视,据不完全统计，截止2010年全球正处于临床研究阶段的抗肿瘤新药达470多个，共涉及2760余项临床研究，其中Ⅲ期临床试验达231项，涉及新药50多个。随着肿瘤药理、分子药理学研究的飞速发展，靶向抗肿瘤药物的研发已成为当今抗肿瘤药物研究开发的重要方向。
人类获得性免疫缺陷综合征（acquired immunodeficiency syndrome,AIDS,艾滋病）是一种由人类免疫缺陷病毒（human immunodeficiency virus,HIV）感染后，因免疫***受到破坏而引起多种疾病侵染的致死性传染疾病。自1981年首例艾滋病被报道以来，已经造成全球范围内2500万人死亡，而且每天以超过7000例新感染病例的速度增长，严重威胁人类生命和健康。迄今为止尚无有效的艾滋病疫苗问世，化学药物以及高效抗逆转录病毒疗法（highly active antiretroviraltherapy,HAART）仍然是控制AIDS的主要手段。
细胞周期蛋白依赖性激酶（Cyclin-dependent kinases，CDKs）是与细胞周期调控和基因转录过程密切相关的丝氨酸/苏氨酸蛋白激酶。CDK通过与细胞周期蛋白（Cyclin）结合后激活，催化底物磷酸化，从而使细胞周期得以正常进行。CDK以及Cyclin蛋白的异常表达或者功能缺失可能会导致细胞周期的紊乱，使细胞增殖失控。因此，CDK被认为是肿瘤、艾滋病、自身免疫性疾病等治疗药物的潜在靶点。
小分子CDK抑制剂的研究是当前抗肿瘤、抗艾滋病新药研发的热点之一。本发明旨在设计合成具有抗肿瘤、抗艾滋病作用的新型查尔酮类CDK抑制剂。
发明内容
本发明的目的在于提供一种式I所示的新型查尔酮类化合物。
本发明的另一目的在于提供式I所示的新型查尔酮类化合物及其类似物的制备方法。
本发明的又一目的在于提供式I所示的化合物在抑制细胞周期蛋白依赖性激酶(CDK)中的用途，以及在治疗与CDK相关的疾病，如恶性肿瘤、艾滋病，中的用途。
为了完成本发明的目的，本发明采用如下技术方案：
本发明是涉及具有通式Ⅰ的新型化合物及其立体异构体和生理上可接受的盐：
其中，R1、R2独立地选自-(CH2)n-XR，n选自1、2或3，X选自N或O，R为氢或C1-C3烷基；或R1、R2构成五元或六元杂环基，如：
Ar选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的呋喃基、取代或未取代的吲哚基、取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的噻吩基、取代或未取代的喹啉基、取代或未取代的萘基；
取代基选自1个或多个硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、含有1～3个杂原子的五元、六元或七元环烷基。
R3选自羟基、卤素、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基。
优选的R1、R2为：
优选的Ar为取代或未取代的苯基，优选的取代基为硝基、羟基、卤素、羧基、三氟甲基、氨基或取代氨基、或1,3-间二氧杂环；
优选的R3为羟基或甲氧基。
优选的式（I）化合物，包括但不限定于，通式(IA)所示的化合物及其立体异构体和生理上可接受的盐：
其中，R1选自：
Ar选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的呋喃基、取代或未取代的吲哚基、取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的噻吩基、取代或未取代的喹啉基、取代或未取代的萘基；
取代基选自1个或多个硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、含有1～3个杂原子的五元、六元或七元环烷基。
R3选自羟基、卤素、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基；
优选的式（IA）化合物，包括但不限定于，通式(IAa)所示的化合物及其立体异构体和生理上可接受的盐：
其中，R1选自
R2、R3均选自氢、硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、或1,3-间二氧杂环；
最优选的化合物选自下列群组：
本发明还公开了制备本发明化合物的方法，包括以下步骤：
式II化合物经偶联反应得到式III化合物，后者与芳醛反应生成的式I化合物：
其中，R1、R2、R3及Ar的定义与上相同。
根据本发明，本发明化合物可以异构体的形式存在，而且通常所述的“本发明化合物”包括该化合物的异构体。
本发明化合物可存在双键的顺反异构体，本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。如果存在顺/反异构体，本发明涉及顺式形式和反式形式以及这些形式的混合物，如果需要单一异构体可根据常规方法分离。
本发明再一方面还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、***、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药***。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.01-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
药理学研究表明，本发明的通式I化合物对多种肿瘤细胞具有抑制作用且对HIV-1的复制亦有抑制作用，因此，可以用于治疗恶性肿瘤或艾滋病。
具体实施方式
以下结合实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
化合物的结构是通过核磁共振（NMR）或质谱（MS）、高分辨质谱（HRMS）来确定的。NMR位移（δ）以百万分之一（ppm）的单位给出。m.p.是以℃给出的熔点，温度未加校正。柱层析一般使用200～300目硅胶为载体。NMR测定是用MERCURY300，测定溶剂为CD3OD、DMSO-D6和CDCl3，内标为TMS，化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSD TOF液质联用仪。
缩写：
TLC：薄层色谱；
DMSO：二甲基亚砜；
CDCl3：氘代氯仿；
DMF：N,N-二甲基甲酰胺；
DCM：二氯甲烷
min：分钟；
h：小时。
通式化合物Ⅲ的制备：
将5-溴-2-甲氧基苯乙酮Ⅱ（0.228g,1mmol），吗啉（0.174g,2mmol），CuI（0.019g,0.1mmol），L-脯氨酸（0.023g,0.2mmol），K2CO3（0.276g）溶于DMSO（10ml）中。于氮气保护条件下，于100℃下搅拌48小时，反应液倒入水中，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩后进行硅胶柱层析分离（石油醚：乙酸乙酯=50：1），得黄色油状物Ⅲ-10.12g,产率51.1%。MS(ESI):236[M+H]+;1H NMR(300MHz,ACETONE-d6)：δ7.23(d,J=3.0Hz,1H),7.16(dd,J=3.0,9.0Hz,1H),7.07(d,J=9.0Hz,1H),3.89(s,3H),3.77(t,J=6.0Hz,4H),3.05(t,J=6.0Hz,4H),2.52(s,3H)。
以5-溴-2-甲氧基苯乙酮Ⅱ和N-甲基哌嗪为起始原料，按照制备Ⅲ-1操作的方法，得黄色油状物Ⅲ-2(1g)，产率30.5%。MS(ESI):249[M+H]+;1H NMR(300MHz,ACETONE-d6)：δ7.22(d,J=3.0Hz,1H),7.15(dd,J=3.0,9.0Hz,1H),7.05(d,J=9.0Hz,1H),3.91(s,3H),3.08(t,J=6.0Hz,4H),2.52(s,3H),2.49(t,J=6.0Hz,4H),2.25(s,3H)。
通式化合物I的制备
往化合物Ⅲ（0.235g,1mmol）的3%(w/v)NaOH的甲醇溶液中（20ml），逐滴滴入合适的醛（1.66mmol）。室温搅拌12小时后，停止反应。滤出固体，甲醇洗，乙酸乙酯洗，干燥，得橙红色固体或油状物I-1，产率为4～90％。I-1（45.3mg,0.122mmol）溶于0.1M的三溴化硼二氯甲烷溶液，-78℃下反应30min,继续升至室温反应1h后加入冰水淬灭反应。用DCM和水萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤后蒸去溶剂，柱层析分离(石油醚：乙酸乙酯=1：1，加入1%三乙胺)，得到油状物，***溶解后通入盐酸气成盐，得浅红棕色固体Ⅰ-2，产率25%。
通式化合物I的理化数据
实施例1：
MS(ESI):324[M+H]+
1H-NMR(300MHz,CDCl3):δ7.67-7.62(d,J=15Hz,1H),7.61-7.58(m,2H),7.42(d,J=15Hz,1H),7.40-7.38(m,3H),7.22(d,J=3Hz,1H),7.06(m,1H),6.95(d,1H),3.88(s,3H),3.86-3.81(m,4H),3.11(t,J=4.5Hz,4H).
实施例2：
MS(ESI):369[M+H]+
1H-NMR(300MHz,CDCl3):δ8.25(d,J=8.1Hz,2H),7.73(d,J=8.4Hz,2H),7.63(d,J=15Hz,1H),7.57(d,J=15Hz,1H),7.55(s,1H),7.26(s,1H),7.11(dd,J=9.3,1.8Hz,1H),6.97(d,J=9.3Hz,1H),3.87(s,3H),3.89-3.85(m,4H),3.11(t,J=4.2Hz,4H).
实施例3：
MS(ESI):369[M+H]+
1H-NMR(300MHz,CDCl3):δ8.45(s,1H),8.23(d,J=9.6Hz,1H),7.88(d,J=7.5Hz,1H),7.69(d,J=15Hz,1H),7.59(d,J=15Hz,1H),7.59(d,J=2.1Hz,1H),7.54(s,1H),7.12(s,1H),6.98(d,J=8.7Hz,1H),3.90(s,3H),3.90-3.88(m,4H),3.13(t,J=4.5Hz,4H).
实施例4：
MS(ESI):368[M+H]+
1H-NMR(300MHz,CDCl3):δ7.57(d,J=15Hz,1H),7.25(d,J=15Hz,1H),7.22-7.21(m,1H),7.11(s,1H),7.08-7.55(m,2H),6.95(d,J=9Hz,1H),6.82(d,J=7.8Hz,1H),6.02(s,2H),3.87-3.84(m,7H),3.11(t,J=4.5Hz,4H).
实施例5：
MS(ESI):314[M+H]+
1H-NMR(300MHz,CDCl3):δ7.50(s,1H),7.43(d,J=15Hz,1H),7.30(d,J=15Hz,1H),7.22(m,1H),7.05(m,1H),6.94(d,J=8.7Hz,1H),6.67(d,J=3.3Hz,1H),6.49(m,1H),3.87-3.84(m,7H),3.10(m,4H).
实施例6：
MS(ESI):384[M+H]+
1H-NMR(300MHz,CDCl3):δ7.57(d,J=15Hz,1H),7.25(d,J=15Hz,1H),7.19-7.16(m,2H),7.11(s,1H),7.06-7.04(m,1H),6.95(d,J=8.7Hz,1H),6.88(d,J=8.4Hz,1H),3.92(s,6H),3.88-3.85(m,7H),3.11(t,J=4.5Hz,4H).
实施例7：
MS(ESI):363[M+H]+
1H-NMR(300MHz,CDCl3):δ8.61(s,1H),8.00-7.98(m,1H),7.92(d,J=15Hz,1H),7.55-7.54(m,1H),7.47(d,J=15Hz,1H),7.45-7.42(m,1H),7.30-7.25(m,3H),7.05(dd,J=2.4,8.7Hz1H),6.97(d,J=8.7Hz,1H),3.89(s,3H),3.86-3.85(m,4H),3.11(t,J=4.5Hz,4H).
实施例8：
MS(ESI):340[M+H]+
1H-NMR(300MHz,CDCl3):δ7.59(d,J=15Hz,1H),7.49(d,J=8.7Hz,2H),7.26(d,J=15Hz,1H),7.20(m,1H),7.05(m,1H),6.95(d,J=8.7Hz,1H),6.85(d,J=8.4Hz,2H),3.88-3.85(m,7H),3.11(t,J=4.5Hz,4H).
实施例9：
MS(ESI):359[M+H]+
1H-NMR(300MHz,DMSO):δ8.45(d,J=4.5Hz,1H),8.38(d,J=7.8Hz,1H),7.69(d,J=15.9Hz,1H),7.55(d,J=10.5Hz,1H),7.52(t,J=5.1Hz,1H),7.20(dd,J=3.3,9.3Hz,1H),7.13(s,1H),7.08(t,J=4.8Hz,1H),3.81(s,3H),3.72(t,J=4.5Hz,4H),3.03(t,J=4.5Hz,4H).
实施例10：
MS(ESI):367[M+H]+
1H-NMR(300MHz,CDCl3):δ7.56(d,J=15Hz,1H),7.48(d,J=9Hz,2H),7.16(d,J=15Hz,1H),7.16(d,J=3Hz,1H),7.01(dd,J=3,9Hz,1H),6.93(d,J=3Hz,1H),6.68(d,J=3Hz,2H),3.87-3.85(m,7H),3.11(t,J=4.5Hz,4H),3.03(s,6H).
实施例11：
MS(ESI):338[M+H]+
1H-NMR(300MHz,CDCl3):δ7.62(d,J=15Hz,1H),7.48(d,J=7.8Hz,2H),7.36(d,J=15Hz,1H),7.21-7.19(m,3H),7.01(dd,J=3,9Hz,1H),6.95(d,J=9Hz,1H),3.88-3.85(m,7H),3.10(t,J=4.5Hz,4H),2.38(s,3H).
实施例12：
MS(ESI):368[M+H]+
1H-NMR(300MHz,CDCl3):δ8.44(m,1H),8.06(d,J=15Hz,1H),7.80(s,1H),7.71(d,J=6.9Hz,1H),7.46-7.40(m,2H),7.35-7.31(m,2H),7.12(d,J=7.8Hz,1H),4.33(m,4H),3.97(s,3H),3.53(m,4H).
实施例13：
MS(ESI):402[M+H]+
1H-NMR(300MHz,CDCl3):δ8.42(m,1H),7.83(s,1H),7.64(d,J=15Hz,1H),7.54(d,J=8.1Hz,2H),7.46(d,J=8.4Hz,2H),7.40(d,J=15Hz,1H),7.12(d,J=6Hz,1H),4.35(s,4H),3.97(s,3H),3.50(t,J=4.5Hz,4H).
实施例14：
MS(ESI):368[M+H]+
1H-NMR(300MHz,CDCl3):δ8.40(d,J=7.5Hz,1H),8.11(d,J=8.1Hz,2H),7.87-7.83(m,1H),7.68(d,J=9Hz,2H),7.50(d,J=15Hz,1H),7.12(d,J=9Hz,1H),7.03(d,J=15Hz,1H),4.35(s,4H),3.97(s,3H),3.54(m,4H).
实施例15：
MS(ESI):341[M+H]+
1H-NMR(300MHz,CDCl3):δ8.46(s,1H),7.83(s,1H),7.66(d,J=15Hz,1H),7.42(d,J=15Hz,1H),7.31-7.28(m,3H),7.15(s,2H),4.36(s,4H),3.99(s,3H),3.53(m,4H).
实施例16：
MS(ESI):392[M+H]+
1H-NMR(300MHz,CDCl3):δ8.45(s,1H),7.88(s,1H),7.74-7.61(m,5H),7.48(d,J=15Hz,1H),7.13(s,1H),4.35(s,4H),3.98(s,3H),3.44(m,4H).
实施例17：
MS(ESI):352[M+H]+
1H-NMR(300MHz,DMSO-d6):δ8.62(d,J=5.7Hz,2H),7.68(d,J=5.7Hz,2H),7.64(d,J=16.2Hz,1H),7.45(d,J=16.2Hz,1H),7.06-7.21(m,3H),3.83(s,3H),3.72(t,J=4.8Hz,4H),3.05(t,J=5.1Hz,4H).
实施例18：
MS(ESI):327[M+H]+
1H-NMR(300MHz,ACETONE-d6):δ7.55(d,J=15.6Hz,1H),7.16(d,J=15.3Hz,1H),7.07-7.14(m,3H),6.95(s,1H),6.75(d,J=2.7,1H),6.13(s,1H),3.86(s,3H),3.77(s,3H),3.77(t,J=6.6Hz,4H),3.06(t,J=7.5Hz,4H).
实施例19：
MS(ESI):344[M+H]+
1H-NMR(300MHz,ACETONE-d6):δ8.28(dd,J=3Hz,J=9Hz,1H),8.15(d,J=3Hz,1H),7.81(d,J=15.6Hz,1H),7.54(d,J=5.4Hz,1H),7.36(d,J=9Hz,1H),7.10(d,J=15.6Hz,1H),7.00(d,J=5.4Hz,1H),4.27(bs,4H),4.01(s,3H),3.64(bs,4H),2.36(s,3H).
实施例20：
MS(ESI):392[M+H]+
1H-NMR(300MHz,CD3OD):δ7.79(d,J=1.8Hz,1H),7.63-7.73(m,2H),7.40-7.59(m,4H),7.31(d,J=9.6Hz,1H),3.99(t,J=4.2Hz,4H),3.93(s,3H),3.58(t,J=4.8Hz,4H).
实施例21：
MS(ESI):367[M+H]+
1H-NMR(300MHz,D2O):δ7.58(d,J=8.4Hz,2H),7.47(d,J=15Hz,1H),7.30(dd,J=9,3Hz,1H),7.17(m,2H),7.08(d,J=15Hz,1H),7.01(d,J=8.7Hz,2H),3.86(s,3H),3.82(s,3H),3.76-3.64(m,4H),3.28(m,2H),3.13(m,2H),2.98(s,3H).
实施例22：
MS(ESI):405[M+H]+
1H-NMR(500MHz,CDCl3):δ7.89(m,2H),7.66(s,1H),7.53(d,J=15Hz,1H),7.48(d,J=8.5Hz,1H),7.41(d,J=7.5Hz,1H),7.30(d,J=15Hz,1H),7.09(d,J=8Hz,1H),4.45(m,2H),4.10(m,2H),3.94(s,3H),3.67(m,4H),2.98(s,3H).
实施例23：
MS(ESI):415[M+H]+
1H-NMR(300MHz,ACETONE-d6):δ7.68(d,J=8.4Hz,2H),7.62(d,J=8.7Hz,2H),7.53(s,2H),7.06-7.18(m,3H),3.88(s,3H),3.11(t,J=4.5Hz,4H),2.50(t,J=5.1Hz,4H),2.26(s,3H).
实施例24：
MS(ESI):397[M+H]+
1H-NMR(300MHz,DMSO-d6):δ7.49(d,J=16.2Hz,1H),7.23-7.32(m,3H),6.98-7.14(m,4H),3.88(s,3H),3.85(s,6H),3.10(s,4H),2.49(m,4H),2.25(s,3H).
实施例25：
MS(ESI):372[M+H]+
1H-NMR(300MHz,CD3OD):δ8.35(dd,J=1.8Hz,J=4.8Hz,1H),8.24(dd,J=1.8Hz,J=7.8Hz,1H),7.80(d,J=16.2Hz,1H),7.50(d,J=15.9Hz,1H),7.43(dd,J=5.1,8.1Hz,1H),7.30-7.27(m,2H),7.11(d,J=9.6Hz,1H),3.85(s,3H),3.73(t,J=14.4Hz,2H),3.56(t,J=12Hz,2H),3.25(m,2H),3.07(t,J=12.6Hz,2H),2.92(s,3H).
实施例26：
MS(ESI):382.2[M+H]+
1H-NMR(300MHz,CD3OD):δ8.22(d,J=8.7Hz,2H),7.83(d,J=8.7Hz,2H),7.86(s,2H),7.10-7.32(m,3H),3.86(s,3H),3.70(t,J=6.9Hz,2H),3.61(t,J=11.4Hz,2H),3.26(t,J=1.8Hz,2H),3.13(t,J=11.1Hz,2H),2.93(s,3H).
实施例27：
MS(ESI):358[M+H]+
1H-NMR(300MHz,D2O):δ8.50(d,J=8.1Hz,1H),8.39(d,J=3.6Hz,1H),8.19(d,J=23.7Hz,1H),7.98(d,J=15.3Hz,1H),7.67(s,1H),7.47(t,J=5.7Hz,1H),7.35(d,J=9Hz,1H),6.95(d,J=8.7Hz,1H),3.72(t,J=11.1Hz,2H),3.59(t,J=11.1Hz,2H),3.27(s,3H),3.27(t,J=12.6Hz,2H),3.12(t,J=12.6Hz,2H),2.96(s,3H).
药理实验
实验例1：本发明的化合物对多种肿瘤细胞的抑制作用
方法:
采用SRB（Sulforhodamine B）法评价化合物对鳞癌细胞株KB及其耐药株KBvin、肺癌细胞株A549和***癌细胞株DU145的生长抑制作用。持续给药3天后，由剂量-效应曲线计算GI50值。
结果：
分别测定并计算几种本发明化合物的GI50值。结果如表1所示。
表1.受试化合物对多种肿瘤细胞的抑制作用
实验例2：本发明的化合物对HIV-1复制的抑制作用
方法:采用TZM-bl细胞感染的单一生活周期的HIV-1NL4-3作为报告基因，通过测定荧光素酶的基因表达水平来评价受试化合物对HIV-1复制的抑制作用（Bioorg Med Chem Lett.2012,22(16):5190-4）。
表2.受试化合物对HIV-1复制的抑制作用

Claims (9)

1.一种由下述通式(I)表示的新型查尔酮类化合物及其生理上可接受的盐，
其中，R1、R2独立地选自-(CH2)n-XR，n选自1、2或3，X选自N或O，R为氢或C1-C3烷基；或R1、R2构成五元或六元杂环基，如：
Ar选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的呋喃基、取代或未取代的吲哚基、取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的噻吩基、取代或未取代的喹啉基、取代或未取代的萘基；
所述的取代基可以是1个或多个，选自硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、含有1～3个杂原子的五元、六元或七元环烷基；
R3选自羟基、卤素、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基。
2.根据权利要求1所述的化合物，其特征在于，所述的化合物是通式(IA)所示的化合物及生理上可接受的盐：
其中，R1选自：
Ar选自取代或未取代的苯基、取代或未取代的噻唑基、取代或未取代的呋喃基、取代或未取代的吲哚基、取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的噻吩基、取代或未取代的喹啉基、取代或未取代的萘基；
所述的取代基可以是1个或多个，选自硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、含有1～3个杂原子的五元、六元或七元环烷基；
R3选自羟基、卤素、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基。
3.根据权利要求2所述的化合物，其特征在于，所述的化合物是通式(IAa)所示的化合物及生理上可接受的盐：
其中，R1选自：
R2、R3均选自氢、硝基、羟基、卤素、羧基、三氟甲基、氰基、氨基或取代氨基、C1-C3烷基、C1-C3烷氧基、或1,3-间二氧杂环。
4.根据权利要求1所述的化合物，其特征在于，所述的化合物选自：
5.权利要求1～4所述化合物的制备方法，其特征在于，包括以下步骤：
式II化合物经偶联反应得到式III化合物，后者与芳醛反应生成的式I化合物：
其中，R1、R2、Ar、R3的定义和权利要求1-4中任一项相同。
6.一种药物组合物，其特征在于，含有有效剂量的如权利要求1～4任一项所述的化合物和在药学上可接受载体的。
7.根据权利要求6所述的药物组合物，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药***。
8.如权利要求1～4任一项所述的化合物作为细胞周期蛋白依赖性激酶抑制剂的用途。
9.根据权利要求8所述的应用，所述的疾病选自肿瘤、艾滋病、自身免疫性疾病等。
CN201310207361.9A 2013-05-29 2013-05-29 查尔酮类化合物及其制法和药物用途 Pending CN104211661A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310207361.9A CN104211661A (zh) 2013-05-29 2013-05-29 查尔酮类化合物及其制法和药物用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310207361.9A CN104211661A (zh) 2013-05-29 2013-05-29 查尔酮类化合物及其制法和药物用途

Publications (1)

Publication Number Publication Date
CN104211661A true CN104211661A (zh) 2014-12-17

Family

ID=52093612

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310207361.9A Pending CN104211661A (zh) 2013-05-29 2013-05-29 查尔酮类化合物及其制法和药物用途

Country Status (1)

Country Link
CN (1) CN104211661A (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037194A (zh) * 2015-05-27 2015-11-11 厦门大学 一系列查尔酮、二氢查尔酮和黄酮化合物及其制备方法和用途
CN108295075A (zh) * 2018-04-09 2018-07-20 青岛市市立医院 一种用于防治牙周炎的药物及其制备方法
CN111269253A (zh) * 2019-11-29 2020-06-12 温州医科大学 一种查尔酮Sanjuanolide衍生物及其在制备抗去势***癌药物中的应用
WO2023011513A1 (zh) * 2021-08-04 2023-02-09 北京泰德制药股份有限公司 Shp2抑制剂、包含其的药物组合物及其用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037194A (zh) * 2015-05-27 2015-11-11 厦门大学 一系列查尔酮、二氢查尔酮和黄酮化合物及其制备方法和用途
CN108295075A (zh) * 2018-04-09 2018-07-20 青岛市市立医院 一种用于防治牙周炎的药物及其制备方法
CN111269253A (zh) * 2019-11-29 2020-06-12 温州医科大学 一种查尔酮Sanjuanolide衍生物及其在制备抗去势***癌药物中的应用
CN111269253B (zh) * 2019-11-29 2023-05-05 温州医科大学 一种查尔酮Sanjuanolide衍生物及其在制备抗去势***癌药物中的应用
WO2023011513A1 (zh) * 2021-08-04 2023-02-09 北京泰德制药股份有限公司 Shp2抑制剂、包含其的药物组合物及其用途

Similar Documents

Publication Publication Date Title
US10315990B2 (en) Isothiocyanate compounds and isothiocyanate XPO1 protein inhibitor drugs thereof
CN105461697A (zh) 喹唑啉酮类parp-1抑制剂及含有它们的组合物和抗肿瘤用途
WO2017189613A1 (en) Methods of using fasn inhibitors
CN104211661A (zh) 查尔酮类化合物及其制法和药物用途
CN102030700A (zh) 苯甲酰胺基羧酸类化合物及其制法和药物用途
CN102796124A (zh) 双β-咔啉碱类化合物、其制法和其药物组合物与用途
CN105777664B (zh) 2‑(2‑苄亚肼基)噻唑‑5‑羧酸酯及其制备方法与医药用途
CN1854130B (zh) 喹唑啉衍生物、及其制法和药物组合物与用途
CN101265275B (zh) 4-{6-[5-(2-氯-6-甲基苯胺甲酰基)-噻唑-2-氨基]-2-甲基嘧啶-4}-哌嗪-1-磷酸二乙酯
CN102531949A (zh) 一种取代苯甲酰胺类化合物及其制备方法和用途
CN104557909A (zh) 3-酰氧基取代右旋去氧娃儿藤宁衍生物、其制法和药物组合物与用途
CN102731488A (zh) 苯并咪唑类衍生物、及其制法和药物组合物与用途
CN102952151B (zh) 3位双β‑咔啉碱类化合物、其制法和其药物组合物与用途
CN105017221A (zh) 苯并咪唑衍生物及其制法和药物组合物与用途
CN104974109A (zh) 含噻唑的丙炔酰胺类衍生物及其制法和药物组合物与用途
CN103588766B (zh) 含1,3,4-恶二唑的3-(1h-3-吲哚基)-1h-吡唑衍生物及其制备方法和应用
CN104140395A (zh) 丁炔酰胺衍生物及其制法和药物组合物与用途
CN108456165B (zh) 磺酰脲类化合物及其制备方法和应用
CN101062925B (zh) 紫杉醇衍生物、其制备方法和其药物组合物与用途
CN105541591A (zh) 1-（4-羟基-3-芳基苯基）-2-丙酮及其制备方法与应用
CN101423513B (zh) 胺基嘧啶衍生物、及其制法和药物组合物与用途
CN109305979A (zh) 4-二甲基氨基苯甲醛在制备na抑制剂中的应用
CN107011337B (zh) N-[5-(1,2,4-***-1-基)噻唑-2-基]哌啶基酰胺及其医药用途
CN114031561B (zh) 含4-苯氧基喹唑啉类化合物及其应用
CN102389426A (zh) 异喹啉类生物碱及其衍生物在抑制hpv病毒感染药物制备中的应用

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20141217