CN115403566A - 3-取代吲哚-2-酮化合物及其制备方法和应用 - Google Patents
3-取代吲哚-2-酮化合物及其制备方法和应用 Download PDFInfo
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- CN115403566A CN115403566A CN202211150957.5A CN202211150957A CN115403566A CN 115403566 A CN115403566 A CN 115403566A CN 202211150957 A CN202211150957 A CN 202211150957A CN 115403566 A CN115403566 A CN 115403566A
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- indolone
- pyrrol
- methylene
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及有机化合物合成及医药应用领域,尤其涉及一种3-取代吲哚-2-酮化合物及其制备方法和应用。
背景技术
吲哚-2-酮是药物发现和药物开发中的一种特殊结构,由于取代的吲哚-2-酮与许多受体具有良好的亲和力,并且获批含有该分子骨架的药物数量众多,因此已被当作优先药物结构使用。(参见文献:Zhang L,Zheng Q,Yang Y,Zhou H,Gong X,Zhao S,Fan C.Synthesis and in vivo SAR study of indolin-2-one-based multi-targetedinhibitors as potential anticancer agents.EUR J MED CHEM.2014,82,139-151.)。
血管几乎滋养着身体的每个器官,如果血管生长不正常,就会引诱诸如中风、心脏异变、溃疡和神经细胞发育障碍等许多血管性病变的触发,而异常的血管失衡或出芽还会引发癌症。现在越来越可以肯定的是,血管生成或新血管的再造在癌症的转变和转移进程中起着核心作用。(参见文献:Yang J,Yan J,Liu B.Targeting VEGF/VEGFR to modulateantitumor immunity.FRONT IMMUNOL.2018,9,978-986)。抗血管生成和促血管生成信号之间的微妙动态平衡调度着血管生成过程中的复杂驱动事件。血管内皮生长因子(VEGF)是已知的最特异、最关键的血管生成调度因子之一。(参见文献: Sitohy B,Nagy J A,Dvorak HF.Anti-VEGF/VEGFR therapy for cancer:Reassessing the target.CANCER RES.2012,72,1909-1914.)。司马沙尼(Semaxanib,SU5416,(Z)-3-((3,5- 二甲基-1H-吡咯-2-基)亚甲基)吲哚啉-2-酮)是基于吲哚-2-酮分子骨架设计并发现的一种有效的和选择性的VEGFR抑制剂,并对VEGFR-2具有很高的选择性。化合物AA-2 (1-(3,4-二氯苄基)-1H-吲哚-2,3-二酮)是基于小分子凋亡诱导剂作用于直接激活某些基本的或特定的凋亡机制而发挥抗肿瘤作用的理论,设计并发现的一个小分子Caspase-3 激动剂,具备直接激活凋亡通路中的Caspase-3进而诱导肿瘤细胞凋亡的能力。化合物AA-2对白血病来源的癌细胞系显示出相当程度的杀伤作用,其IC50值在4-9μM之间。 (参见:Jack T N,James AW.DirectActivation of the Apoptosis Machinery as a Mechanism to Target CancerCells.PNAS.2003,100,7533-7538.)。
为了进一步提高对癌细胞的抑制能力,立足于司马沙尼、AA-2共有的吲哚-2-酮药效结构单元,研究一种全新结构的化合物,开发有效的蛋白激酶抑制剂或凋亡诱导剂,对于发现分子靶向抗肿瘤药物意义重大。
发明内容
本发明的目的在于提供一种3-取代吲哚-2-酮化合物及其制备方法和应用。该类化合物对人外周血T淋巴源性白血病细胞Jurkat、肺癌细胞A549和结肠癌细胞HCT116具有一定的生长抑制活性,可用于制备抗肿瘤药物。
为实现上述目的,本发明采用下述技术方案:
在本发明的第一方面,本发明提供一种3-取代吲哚-2-酮化合物,具有如下式(I)、(II) 或(III)所示结构:
其中,R1、R2独立地选自氢、卤素、氰基、三氟甲基或甲氧基;R3选自苯基、取代苯基、吡啶基、脂肪烃基或取代脂肪烃基。
根据本发明优选的,所述3-取代吲哚-2-酮化合物包含其几何异构体,如顺式构型和反式构型。
根据本发明优选的,R1、R2独立地选自氢、F、Cl、Br、I、三氟甲基、氰基或甲氧基;优选的,R1、R2独立地选自氢、F、Cl、Br、三氟甲基、氰基或甲氧基。
根据本发明优选的,所述3-取代吲哚-2-酮化合物选自以下化合物:
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-1);
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-2);
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-3);
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-4);
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-5);
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-6);
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-7);
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-8);
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-9);
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-10);
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-11);
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-12);
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-13);
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-1);
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-2);
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-3);
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-4);
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-5);
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-6);
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-7);
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-8);
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-9);
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-10);
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-11);
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-12);
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-13);
(Z)-3-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-1);
(Z)-4-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-2);
(Z)-3-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-3);
(Z)-3-溴-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-4);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-5);
(Z)-4-甲氧基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮 -5-基)苯甲酰胺(III-6);
(Z)-3-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5- 基)苯甲酰胺(III-7);
(Z)-4-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5- 基)苯甲酰胺(III-8);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)吡啶甲酰胺(III-9);
(Z)-2-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)乙酰胺(III-10);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)环丙甲酰胺(III-11);
(Z)-3-氟-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-12);
(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-13);
(Z)-3-甲基-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5- 基)苯甲酰胺(III-14);
(Z)-2-氯-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 乙酰胺(III-15);
或,(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 环丙甲酰胺(III-16);
在本发明的第二方面,提供上述3-取代吲哚-2-酮化合物的制备方法,合成路线如下所示:
其中,R1、R2独立地选自氢、卤素、氰基、三氟甲基或甲氧基;R3选自苯基、取代苯基、吡啶基、脂肪烃基或取代脂肪烃基。
根据本发明优选的,所述3-取代吲哚-2-酮化合物的制备方法,包括步骤:
以2-吲哚酮即化合物1为起始原料,与3,5-二甲基-1H-吡咯-2-甲醛经羟醛缩合反应生成中间体2;中间体2在K2CO3存在的条件下与取代苄氯或取代苄溴经亲核取代反应得式(I)化合物。
或者,以2-吲哚酮即化合物1为起始原料,经硝化反应生成中间体3;中间体3与3,5-二甲基-1H-吡咯-2-甲醛经羟醛缩合反应生成中间体4;中间体4在K2CO3存在的条件下与取代苄氯或取代苄溴经亲核取代反应生成中间体5;中间体5经铁粉还原得式(II)化合物;
或者,所得式(II)化合物与相应的羧酸经酰胺缩合反应,或在K2CO3存在的条件下与相应的酰氯经酰氯化反应得式(III)化合物。
本发明优选的实施方式中,可通过下述合成路线制备:
上述合成路线的试剂及条件:(a)3,5-二甲基-1H-吡咯-2-甲醛,哌啶,无水乙醇,N2,90℃,3h;(b)K2CO3,DMF,室温-80℃,3-5h;(c)发烟硝酸,浓硫酸,0℃-室温,2h;(d) 3,5-二甲基-1H-吡咯-2-甲醛,哌啶,无水乙醇,N2,90℃,3h;(e)K2CO3,DMF,室温-80℃, 3h;(f)Fe,NH4Cl,乙醇:水体积比=3∶1,85℃,7h;(g)HBTU(O-苯并三氮唑-四甲基脲六氟磷酸酯),DIEA(N,N-二异丙基乙胺),DMF,0℃-室温,12h;或者,K2CO3,DMF, 室温,12h。
进一步地,本发明优选的实施方式中,具体制备方法包括:
(1)将化合物1和3,5-二甲基-1H-吡咯-2-甲醛加入到茄形瓶中,加入无水乙醇作溶剂,室温搅拌下滴入3-5滴无水哌啶;滴毕,氮气保护,将反应体系转移至90℃油浴回流反应3h;待反应液自然冷却至室温,抽滤,滤饼用无水乙醇洗涤,干燥,得中间体2。
(2)将中间体2和K2CO3加入到茄形瓶中,用DMF作溶剂,室温搅拌30min后,再缓慢滴入取代苄氯或取代苄溴至反应液中,之后将反应体系转移至80℃油浴反应3-5h;冷却至室温,向反应液中倒入温度为15-20℃的冷水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂,所得产品经薄层层析纯化或用甲醇重结晶,得目标化合物I-1至I-13。
或者,
(3)将化合物1加入到茄形瓶中,搅拌下缓慢加入浓硫酸至溶解;在0℃冰浴条件下逐滴滴加发烟硝酸,滴毕,继续在0℃冰浴条件下反应20min,之后撤除冰浴,室温下反应2h;将反应液倒入冰水中,抽滤,滤饼水洗,干燥,得中间体3。
(4)将中间体3和3,5-二甲基-1H-吡咯-2-甲醛加入到茄形瓶中,加入无水乙醇作溶剂,室温搅拌下滴入3-5滴无水哌啶;滴毕,氮气保护,将反应体系转移至90℃油浴回流反应3h;待反应液自然冷却至室温,抽滤,滤饼用无水乙醇洗涤,干燥,得中间体4。
(5)将中间体4和K2CO3加入到茄形瓶中,用DMF作溶剂,室温搅拌30min 后,再缓慢滴入取代苄氯或取代苄溴至反应液中,之后将反应体系转移至80℃油浴反应3h;冷却至室温,向反应液中倒入15℃-20℃的冷水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂,所得固体用甲醇重结晶,得中间体5。
(6)将中间体5,活化后的还原性铁粉和氯化铵加入到茄形瓶中,以CH3CH2OH 和H2O的混合液作溶剂,85℃油浴回流反应7h;反应液用硅藻土趁热抽滤,浓缩滤液,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂,硅胶柱层析,得目标化合物II-1至II-13。
或者,
(7)称取苯甲酸或取代苯甲酸或吡啶甲酸和HBTU加入到茄形瓶中,加入DMF至溶解,反应体系在冰浴条件下搅拌至0℃后,逐滴滴加DIEA至反应液中,搅拌40min,溶液颜色由无色渐变成红棕色或黄棕色;化合物II-11或II-12用DMF溶解后逐滴滴入反应液中,滴毕,撤除冰浴,室温反应12h;将反应液倒入装有温度为0℃冰水的烧杯中,析出大量黄色固体,抽滤,水洗,干燥,得黄色固体粗品;所得固体粗品用乙酸乙酯打浆洗涤两次,再用甲醇超声洗涤,抽滤,干燥,得目标化合物III-1至III-9,III-12至III-14。
或者,
(8)称取化合物II-11或II-12加入到茄形瓶中,用DMF溶解,加入K2CO3,室温下搅拌30min后缓慢滴入氯乙酰氯或环丙甲酰氯,滴毕,室温反应12h;将反应液倒入装有温度为0℃冰水的烧杯中,抽滤,水洗,干燥,得黄色固体粗品;所得固体粗品用乙酸乙酯打浆洗涤,再用甲醇超声洗涤,抽滤,干燥,得目标化合物III-10、III-11、III-15、 III-16。
在本发明的第三方面,提供一种药物组合物,其包含上述第一方面中所述的3-取代吲哚-2-酮化合物或其药学上可接受的盐。
本发明所述“组合物”指包括治疗有效量的规定成分的药物产品,以及直接或间接地由规定量的规定成分的组合产生的任何产品。
在本发明的第四方面,提供一种药物制剂,其包含上述第一方面中所述的3-取代吲哚-2-酮化合物或其药学上可接受的盐和至少一种药学上可接受的辅料或载体。
本发明的3-取代吲哚-2-酮化合物或含有它的药物组合物或药物制剂可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明的药物组合或药物制剂中还可以含有常用的载体,这些载体包括但不局限于:离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清蛋白、缓冲物质(如磷酸盐、甘油、山梨酯、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐) 或电解质、硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜂蜡、羊毛酯等。载体在药物组合物或药物制剂中的含量可以是1wt%-98wt%,通常大约占到80wt%。为方便起见,局部麻醉剂、防腐剂、缓冲剂等可直接溶于载体中。
所述药学上可接受的辅料,包括但不限于赋形剂,所述赋形剂可以为粘合剂、填充剂、润滑剂、崩解剂、缓冲剂、稳定剂、防腐剂等等。所述辅料指药物组合物或药物制剂中除有效成分之外的成分,其对受试者无毒,且与药物活性成分可稳定共存或采用适当手段后稳定共存。
口服片剂和胶囊可以含有粘合剂,比如糖浆、阿拉伯胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮;可以含有填充剂,比如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇、氨基乙酸;可以含有润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土;可以含有崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液,溶液,乳浊液,糖浆,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂:山梨醇、纤维素甲醚、葡萄糖糖浆、凝胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化的食用油脂,如乳化剂:卵磷脂、山梨聚糖单油酸盐、阿拉伯树胶;或包含非水载体(可能包含可食用油),如杏仁油、油脂如甘油、乙二醇、或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质,如可可黄油或其它甘油酯。
对于胃肠外投药,液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同,化合物既可溶于载体中也可制成悬浮溶液,在制成注射用溶液时先将化合物溶于水中,过滤消毒后装入封口瓶或安瓿中。
在本发明的第五方面,提供上述第一方面中所述3-取代吲哚-2-酮化合物或上述第三方面中所述的药物组合物或上述第四方面中所述的药物制剂在制备人外周血T淋巴源性白血病细胞、肺癌细胞和/或结肠癌细胞生长抑制剂中的应用。
根据本发明优选的,所述人外周血T淋巴源性白血病细胞为Jurkat,所述肺癌细胞为A549,结肠癌细胞为HCT116。
在本发明的第六方面,提供上述第一方面中所述3-取代吲哚-2-酮化合物或上述第三方面中所述的药物组合物或上述第四方面中所述的药物制剂在制备抗肿瘤药物中的应用。
根据本发明优选的,所述肿瘤为白血病、肺癌或结肠癌。
以及,本发明还提供了一种治疗肿瘤的方法,其包括向受试者施用治疗有效剂量的上述第一方面中所述的3-取代吲哚-2-酮化合物或上述第三方面中所述的药物组合物或上述第四方面中所述的药物制剂,所述肿瘤尤其指白血病、肺癌或结肠癌;所述受试者术语是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指人。所述“治疗有效量”是指包括本发明化合物在内的活性化合物或药剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物或人的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。必须认识到,本发明所述活性成分的最佳给药剂量和间隔是由其性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等外部条件决定的,而这一最佳给药剂量可用常规的技术确定。同时也必须认识到,最佳的疗程,即同时化合物在额定的时间内每日的剂量,可用本领域内公知的方法确定。
本发明具有以下有益效果:
本发明所述的3-取代吲哚-2-酮化合物对人外周血T淋巴源性白血病细胞Jurkat、肺癌细胞A549、结肠癌细胞HCT116呈现出低微摩尔浓度的生长抑制活性,能够实现对上述癌细胞的有效抑制,能够用于抗肿瘤药物的制备。
相比药物司马沙尼(SU5416),本发明I-3、I-9、I-13、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、III-9对Jurkat细胞的生长抑制活性更优;其中Ⅱ-2、Ⅱ-3、Ⅱ-5、Ⅱ-10、Ⅱ-11和III-9对Jurkat细胞的生长抑制活性大于50%。Ⅱ-3、Ⅱ-5、Ⅱ-10、Ⅱ-11和III-9对Jurkat、A549或HCT116细胞呈现出低微摩尔浓度(小于8.5μM)的生长抑制活性;其中,Ⅱ-5对Jurkat和A549细胞的生长抑制活性优于阳性化合物AA-2(1-(3,4-二氯苄基)-1H-吲哚-2,3-二酮),而Ⅱ-11对Jurkat、A549和HCT116三株细胞系的生长抑制活性均优于阳性化合物AA-2。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1、中间体2的制备
称取2-吲哚酮(0.60g,4.51mmol)和3,5-二甲基-1H-吡咯-2-甲醛(0.67g,5.41mmol) 加入到茄形瓶(100mL)中,加入10mL无水乙醇作溶剂,室温搅拌下滴入3-5滴无水哌啶。滴毕,氮气保护,将反应体系转移至90℃油浴回流反应3h。待反应液自然冷却至室温,有大量黄色絮状固体析出。抽滤,滤饼用少量0℃冷无水乙醇洗涤两次,干燥,称重得橙黄色絮状固体0.99g,收率92.5%。所得产物的核磁数据如下:1H NMR(400MHz, DMSO-d6)δ13.36(s,1H),10.77(s,1H),7.71(d,J=7.5Hz,1H),7.56(s,1H),7.10(t,J=7.6 Hz,1H),6.97(t,J=7.5Hz,1H),6.87(d,J=7.6Hz,1H),6.02(s,1H),2.32(s,3H),2.30(s, 3H).
实施例2、中间体3的制备
称取2-吲哚酮(1.00g,7.51mmol)加入到茄形瓶(250mL)中,搅拌下缓慢加入质量浓度为98%的浓硫酸(20mL)至溶解。在0℃冰浴条件下逐滴滴加发烟硝酸(615.21mg,9.76mmol),滴毕,继续在0℃冰浴条件下反应20min,之后撤除冰浴,室温下反应2h。将反应液倒入250mL冰水中,析出大量棕黄色固体。抽滤,滤饼水洗三次,干燥,称重得棕黄色固体1.12g,收率83.6%。所得产物的核磁数据如下:1H NMR(400MHz, DMSO-d6)δ11.06(s,1H),8.16(d,J=8.6Hz,1H),8.10(s,1H),6.99(d,J=8.6Hz,1H),3.64 (s,2H).
实施例3、中间体4的制备
称取中间体3(1.00g,5.62mmol)和3,5-二甲基-1H-吡咯-2-甲醛(0.83g,6.74mmol) 加入到茄形瓶(100mL)中,加入20mL无水乙醇作溶剂,室温搅拌下滴入3-5滴无水哌啶。滴毕,氮气保护,将反应体系转移至90℃油浴回流反应3h。待反应液自然冷却至室温,有大量红棕色固体析出。抽滤,滤饼用少量0℃冷无水乙醇洗涤两次,干燥,称重得红棕色固体1.49g,收率93.7%。所得产物的核磁数据如下:1H NMR(400MHz, DMSO-d6)δ13.35(s,1H),11.43(s,1H),8.78(s,1H),8.03(d,J=8.6Hz,1H),7.95(s,1H), 7.03(d,J=8.6Hz,1H),6.10(s,1H),2.37(s,3H),2.36(s,3H).
实施例4、中间体5(A-M)的制备
称取中间体4(1equiv)和K2CO3粉末(2.5equiv)加入到茄形瓶(100mL)中,用DMF(10mL)作溶剂,室温搅拌30min后,再缓慢滴入取代苄氯(1.2equiv)或取代苄溴(1.2equiv)至反应液中,之后将反应体系转移至80℃油浴反应3h。冷却至室温,向反应液中倒入冷水(15℃-20℃)100mL,乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂,所得固体用甲醇重结晶,得中间体5(A-M)。
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5A)
棕黄色固体,产率78.9%。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.88(d,J=2.2Hz,1H),8.06(dd,J=8.0,2.9Hz,2H),7.39(d,J=6.2Hz,1H),7.24(d,J=8.7Hz,1H),7.20–7.08(m,4H),6.16(s,1H),5.22(s,2H),2.41(s,3H),2.39(s,3H).
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5B)
棕黄色固体,产率83.6%。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.87(d,J=2.2Hz,1H),8.05(dd,J=8.2,2.7Hz,2H),7.38(dd,J=8.5,5.5Hz,2H),7.25(d,J=8.7Hz,1H),7.17(t,J=8.9Hz,2H),6.15(s,1H),5.18(s,2H),2.41(s,3H),2.39(s,3H).
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5C)
棕绿色固体,产率72.9%。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.89(d,J=2.2Hz,1H),8.07(dd,J=8.4,2.4Hz,2H),7.41(s,1H),7.37(d,J=6.6Hz,2H),7.29–7.23(m,2H),6.16(s,1H),5.22(s,2H),2.42(s,3H),2.39(s,3H).
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5D)
棕绿色固体,产率75.1%。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.85(d,J=2.2Hz,1H),8.04(dd,J=7.7,3.2Hz,2H),7.40(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),7.21(d,J=8.7Hz,1H),6.14(s,1H),5.18(s,2H),2.40(s,3H),2.38(s,3H).
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5E)
棕黄色固体,产率78.3%。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.89(d,J=2.2Hz,1H),8.07(dd,J=7.9,2.9Hz,2H),7.55(s,1H),7.49(d,J=7.1Hz,1H),7.33–7.24(m,3H),6.16(s,1H),5.21(s,2H),2.42(s,3H),2.39(s,3H).
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5F)
棕黄色固体,产率75.8%。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.88(d,J=2.2Hz,1H),8.08–8.03(m,2H),7.54(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),7.22(d,J =8.7Hz,1H),6.16(s,1H),5.18(s,2H),2.41(s,3H),2.39(s,3H).
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5G)
棕黄色固体,产率80.6%。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.89(d,J=2.2Hz,1H),8.09–8.04(m,2H),7.84(s,1H),7.77(d,J=7.5Hz,1H),7.61(d,J=8.0Hz,1H),7.56(t,J=7.7Hz,1H),7.27(s,1H),6.16(s,1H),5.26(s,2H),2.42(s,3H),2.39(s,3H).
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5H)
棕黄色固体,产率77.1%。1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.89(s,1H),8.05(d,J=11.7Hz,2H),7.82(d,J=7.8Hz,2H),7.48(d,J=7.8Hz,2H),7.22(d,J=8.7Hz,1H),6.16(s,1H),5.30(s,2H),2.41(s,3H),2.38(s,3H).
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5I)
棕红色固体,产率78.9%。1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.88(d,J=2.2Hz,1H),8.06(dd,J=8.4,2.2Hz,2H),7.74(s,1H),7.66(d,J=7.6Hz,1H),7.57(dd,J=14.1,6.5Hz,2H),7.26(d,J=8.7Hz,1H),6.15(s,1H),5.31(s,2H),2.41(s,3H),2.38(s,3H).
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5J)
棕红色固体,产率80.9%。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.90(d,J=2.2Hz,1H),8.09–8.04(m,2H),7.72(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.23(d,J =8.7Hz,1H),6.16(s,1H),5.31(s,2H),2.42(s,3H),2.38(s,3H).
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5K)
棕黄色固体,产率76.8%。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.88(d,J=2.2Hz,1H),8.06(dd,J=7.8,3.1Hz,2H),7.49–7.36(m,3H),7.27(d,J=8.7Hz,1H),6.16(s,1H),5.19(s,2H),2.41(s,3H),2.39(s,3H).
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5L)
棕绿色固体,产率81.8%。1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.88(s,1H),8.06(s,2H),7.64(s,1H),7.60(d,J=8.0Hz,1H),7.25(d,J=8.7Hz,2H),6.15(s,1H),5.21(s,2H),2.41(s,3H),2.38(s,3H).
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-硝基-2-吲哚酮(5M)
棕红色固体,产率79.1%。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.86(s,1H),8.05(s,2H),7.23(d,J=8.7Hz,1H),7.03(s,1H),6.87(d,J=8.2Hz,1H),6.76(d,J=8.5Hz, 1H),6.15(s,1H),5.11(s,2H),3.72(s,3H),3.69(s,3H),2.40(s,3H),2.39(s,3H).
实施例5、目标化合物I-1至I-13的制备
称取中间体2(1equiv)和K2CO3粉末(2.5equiv)加入到茄形瓶(100mL)中,用DMF(10mL)作溶剂,室温搅拌30min后,再缓慢滴入取代苄氯(1.2equiv)或取代苄溴(1.2equiv)至反应液中,之后将反应体系转移至80℃油浴反应3-5h。冷却至室温,向反应液中倒入冷水(15℃-20℃)100mL,乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂,所得产品经薄层层析纯化(展开体系为石油醚∶乙酸乙酯体积比2∶1),或用甲醇重结晶,得目标化合物I-1 至I-13。
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-1)
橙黄色固体,产率71.2%,Mp:180-181℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),7.81(d,J=7.5Hz,1H),7.67(s,1H),7.41–7.35(m,1H),7.14(dd,J=14.6,7.5Hz,4H),7.08–7.05(m,1H),7.01(t,J=6.6Hz,1H),6.06(s,1H),5.12(s,2H),2.35(s,3H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ168.28(s),163.12(d,J=246.6Hz),139.14(d,J=7.0 Hz),138.60(s),137.02(s),132.73(s),130.31(d,J=8.3Hz),127.12(s),125.66(s),125.53(s), 123.51(s),122.56(d,J=2.9Hz),121.83(s),117.17(s),114.41(d,J=21.2Hz),114.01(d,J =22.0Hz),112.72(s),111.20(s),108.49(s),43.15(s),13.97(s),11.67(s).HRMS(ESI): calcd for C22H19FN2O[M+H]+347.1481,found 347.1533。
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-2)
橙黄色固体,产率70.2%,Mp:236-238℃。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),7.80(d,J=7.4Hz,1H),7.66(s,1H),7.38(dd,J=8.4,5.6Hz,2H),7.17(d,J=8.8Hz,2H),7.11(d,J=7.0Hz,1H),7.03(dd,J=14.8,7.5Hz,2H),6.06(s,1H),5.08(s,2H),2.36(s, 3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ168.28(s),144.29(d,J=490.5Hz),138.66(s),136.95(s),132.67(d,J=2.8Hz),132.25(d,J=3.0Hz),128.77(s),128.69(s),127.09(d, J=3.4Hz),125.67(s),125.54(d,J=5.1Hz),123.45(s),121.77(s),117.16(s),115.64(d,J= 21.6Hz),112.70(s),111.33(s),108.53(s),42.97(s),13.97(s),11.67(s).HRMS(ESI):calcd for C22H19FN2O[M+H]+347.1481,found 347.1535。
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-3)
橙黄色固体,产率64.4%,Mp:120-122℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),7.81(d,J=7.4Hz,1H),7.67(s,1H),7.37(d,J=10.8Hz,3H),7.27(d,J=7.0Hz,1H),7.13(t,J=7.4Hz,1H),7.06(d,J=7.4Hz,1H),7.02(t,J=6.3Hz,1H),6.06(s,1H),5.11(s, 2H),2.35(s,3H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ168.29(s),138.66(s),138.58(s),137.05(s),134.70(s),132.76(s),130.05(s),127.72(s),127.16(s),125.68(s),125.56(s), 125.18(s),123.53(s),121.86(s),117.19(s),112.74(s),111.19(s),108.48(s),43.15(s),13.97 (s),11.67(s).HRMS(ESI):calcd for C22H19ClN2O[M+H]+363.1186,found 363.1230。
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-4)
橙黄色固体,产率68.3%,Mp:127-130℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),7.81(d,J=7.3Hz,1H),7.67(s,1H),7.40(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),7.12(t,J=7.1Hz,1H),7.04(t,J=7.1Hz,1H),6.99(d,J=7.7Hz,1H),6.06(s,1H),5.09(s, 2H),2.35(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ168.28(s),138.59(s),137.01(s),135.06(s),133.26(s),132.73(s),128.93(s),128.45(s),127.12(s),125.68(s),125.53(s), 123.49(s),121.82(s),117.18(s),112.73(s),111.25(s),108.50(s),43.03(s),13.97(s),11.67 (s).HRMS(ESI):calcd for C22H19ClN2O[M+H]+363.1186,found363.1241。
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-5)
橙红色固体,产率73.7%,Mp:149-151℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),7.81(d,J=7.3Hz,1H),7.67(s,1H),7.52(s,1H),7.49–7.44(m,1H),7.30(d,J=5.0Hz,2H),7.13(t,J=7.2Hz,1H),7.05(d,J=7.5Hz,1H),7.01(t,J=5.6Hz,1H),6.06(s,1H), 5.10(s,2H),2.35(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ168.26(s),138.92(s), 138.55(s),137.04(s),132.75(s),130.66(s),130.33(s),130.05(s),127.12(s),125.67(s), 125.64(s),125.55(s),123.51(s),122.88(s),121.85(s),117.18(s),112.74(s),111.17(s), 108.47(s),43.09(s),13.98(s),11.67(s).HRMS(ESI):calcd forC22H19BrN2O[M+H]+ 407.0681,found 407.0742。
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-6)
橙红色固体,产率69.1%,Mp:180-181℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),7.80(d,J=7.4Hz,1H),7.66(s,1H),7.53(d,J=8.4Hz,2H),7.28(d,J=8.3Hz,2H),7.11(t,J=7.5Hz,1H),7.03(t,J=7.2Hz,1H),6.98(d,J=7.8Hz,1H),6.05(s,1H),5.07(s, 2H),2.35(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ168.26(s),138.55(s),137.00(s),135.57(s),132.73(s),131.86(s),128.78(s),127.11(s),125.66(s),125.51(s),123.48(s), 121.82(s),121.32(s),117.17(s),112.73(s),111.21(s),108.48(s),43.07(s),13.97(s),11.67 (s).HRMS(ESI):calcd for C22H19BrN2O[M+H]+407.0681,found407.0749。
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-7)
橙黄色固体,产率82.3%,Mp:171-173℃。1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),7.82(d,J=2.9Hz,2H),7.75(d,J=7.5Hz,1H),7.67(s,1H),7.62(d,J=7.9Hz,1H),7.55(t,J=7.7Hz,1H),7.13(t,J=7.5Hz,1H),7.04(dd,J=15.2,7.6Hz,2H),6.06(s,1H),5.15(s,2H),2.35(s,3H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ168.26(s),138.31(s),138.18(s),137.35(s),133.16(s),131.53(s),131.27(s),130.65(s),129.63(s),127.19(s), 125.75(s),125.54(s),123.78(s),122.06(s),118.59(s),117.33(s),112.98(s),112.91(s), 110.77(s),108.17(s),42.94(s),13.99(s),11.69(s).HRMS(ESI):calcd forC23H19N3O [M+H]+354.1528,found 354.1590。
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-8)
橙黄色固体,产率79.6%,Mp:194-196℃。1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),7.84–7.77(m,3H),7.68(s,1H),7.48(d,J=8.2Hz,2H),7.11(t,J=7.5Hz,1H),7.05(t, J=7.3Hz,1H),6.98(d,J=7.7Hz,1H),6.06(s,1H),5.19(s,2H),2.34(s,3H),2.33(s,3H). 13C NMR(100MHz,CDCl3)δ168.27(s),142.09(s),138.23(s),137.34(s),133.17(s),132.63 (s),127.67(s),127.18(s),125.72(s),125.53(s),123.59(s),122.07(s),118.63(s),117.31(s), 112.97(s),111.47(s),110.77(s),108.23(s),43.30(s),13.98(s),11.68(s).HRMS(ESI):calcd for C23H19N3O[M+H]+354.1528,found 354.1592。
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-9)
橙黄色固体,产率80.5%,Mp:126-128℃。1H NMR(400MHz,CDCl3)δ13.18(s,1H),7.59(s,1H),7.52(t,J=6.8Hz,2H),7.47–7.38(m,3H),7.13–7.03(m,2H),6.73(d,J=8.0Hz,1H),6.00(s,1H),5.13(s,2H),2.39(s,3H),2.35(s,3H).13C NMR(100MHz,CDCl3)δ168.33(s),138.49(s),137.67(s),137.14(s),132.87(s),131.29(s),130.97(s),130.32(s), 129.33(s),127.15(s),125.71(s),125.56(s),124.41(dd,J=7.6,3.7Hz),123.91(dd,J=7.6, 3.8Hz),123.61(s),121.92(s),117.24(s),112.79(s),111.07(s),108.37(s),43.29(s),13.97 (s),11.67(s).HRMS(ESI):calcd for C23H19F3N2O[M+H]+397.1449,found 397.1501。
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-10)
橙黄色固体,产率75.7%,Mp:125-127℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),7.82(d,J=7.5Hz,1H),7.74–7.68(m,3H),7.52(d,J=8.0Hz,2H),7.12(t,J=7.4Hz,1H),7.05(t,J=7.4Hz,1H),6.99(d,J=7.7Hz,1H),6.06(s,1H),5.20(s,2H),2.35(s,3H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ168.31(s),140.63(s),138.45(s),137.16(s),132.92(s),129.96(s),129.63(s),128.85(s),127.27(s),127.15(s),125.76(dd,J=7.8,4.0 Hz),125.54(s),123.62(s),121.94(s),117.24(s),112.81(s),111.03(s),108.38(s),43.23(s), 13.97(s),11.68(s).HRMS(ESI):calcd for C23H19F3N2O[M+H]+397.1449,found 397.1503。
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-11)
橙红色固体,产率67.8%,Mp:117-118℃。1H NMR(400MHz,CDCl3)δ13.17(s,1H),7.52(d,J=6.9Hz,1H),7.44(s,1H),7.14–7.02(m,5H),6.73(d,J=6.9Hz,1H),6.00(s,1H),5.03(s,2H),2.39(s,3H),2.35(s,3H).13C NMR(100MHz,CDCl3)δ168.23(s),151.37(dd,J=79.8,12.7Hz),148.90(dd,J=78.5,12.9Hz),138.37(s),137.17(s),133.61(dd,J= 5.1,3.8Hz),132.93(s),127.14(s),125.70(s),125.52(s),123.62(s),123.01(dd,J=6.4,3.6 Hz),121.93(s),117.54(d,J=17.4Hz),117.24(s),116.18(d,J=17.8Hz),112.81(s),111.01 (s),108.34(s),42.71(s),13.98(s),11.67(s).HRMS(ESI):calcd forC22H18F2N2O[M+H]+ 365.1387,found 365.1457。
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-12)
橙红色固体,产率72.7%,Mp:150-152℃。1H NMR(400MHz,CDCl3)δ13.16(s,1H),7.53(d,J=6.9Hz,1H),7.45(s,1H),7.38(dd,J=9.0,4.9Hz,2H),7.10(ddd,J=21.8,11.2, 4.5Hz,3H),6.72(d,J=7.1Hz,1H),6.00(s,1H),5.03(s,2H),2.39(s,3H),2.35(s,3H).13C NMR(100MHz,CDCl3)δ168.23(s),138.31(s),137.23(s),136.91(s),132.99(s),132.91(s), 131.60(s),130.76(s),129.04(s),127.15(s),126.45(s),125.70(s),125.56(s),123.67(s), 121.98(s),117.26(s),112.84(s),110.94(s),108.33(s),42.66(s),13.99(s),11.69(s).HRMS (ESI):calcd for C22H18Cl2N2O[M+H]+397.0796,found397.0889。
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-13)
橙黄色固体,产率65.1%,Mp:168-170℃。1H NMR(400MHz,CDCl3)δ13.25(s,1H),7.50(dd,J=10.9,7.5Hz,1H),7.42(d,J=15.5Hz,1H),7.08(dq,J=13.8,7.5Hz,3H),6.92–6.75(m,4H),5.98(s,1H),5.03(s,2H),3.83(s,3H),3.82(s,3H),2.39(s,3H),2.34(s,3H). 13C NMR(100MHz,CDCl3)δ168.32(s),149.30(s),148.44(s),138.99(s),136.74(s),132.39 (s),129.05(s),127.09(s),125.54(s),123.28(s),121.65(s),119.34(s),117.09(s),112.60(s), 111.63(s),111.27(s),110.45(s),109.18(s),108.74(s),55.93(s),43.48(s),13.96(s),11.65 (s).HRMS(ESI):calcd for C24H24N2O3[M+H]+389.1787,found389.1870。
实施例6、目标化合物II-1至II-13的制备
将还原铁粉(1equiv)与浓度为5wt%的盐酸(500mL)混合,室温搅拌30min后抽滤,用水冲洗铁粉直至洗脱液呈中性,将铁粉干燥后即得活化铁粉。称取中间体5(1 equiv),活化后的还原性铁粉(4equiv)和氯化铵(4equiv)加入到茄形瓶(100mL) 中,以CH3CH2OH∶H2O体积比=3∶1共24mL作溶剂,85℃油浴回流反应7h。反应液用硅藻土趁热抽滤,浓缩滤液,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压蒸除溶剂。硅胶柱层析,洗脱系统为石油醚∶乙酸乙酯体积比=5∶1,得目标化合物II-1至 II-13。
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-1)
鲜红色固体,产率54.1%,Mp:156-158℃。1H NMR(400MHz,DMSO-d6)δ13.30(s,1H),7.40(s,1H),7.39–7.34(m,1H),7.14–7.08(m,3H),6.98(d,J=1.9Hz,1H),6.67(d,J=8.2Hz,1H),6.38(dd,J=8.2,1.9Hz,1H),6.02(s,1H),4.99(s,2H),4.70(s,2H),2.33(s,3H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ167.67(s),162.69(d,J=244.0Hz), 144.48(s),140.72(d,J=7.0Hz),136.23(s),132.01(s),131.11(d,J=8.3Hz),130.07(s),126.80(s),125.96(s),123.62(s),123.17(s),114.64(s),114.46(d,J=5.1Hz),114.26(s), 112.82(d,J=32.3Hz),112.42(s),109.63(s),104.81(s),42.71(s),13.95(s),11.73(s). HRMS(ESI):calcd for C22H20FN3O[M+H]+362.1590,found 362.1602。
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-2)
鲜红色固体,产率52.1%,Mp:110-112℃。1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),7.40(s,1H),7.35(dd,J=8.1,5.7Hz,2H),7.14(t,J=8.8Hz,2H),6.98(s,1H),6.67(d, J=8.2Hz,1H),6.39(d,J=8.1Hz,1H),6.01(s,1H),4.96(s,2H),2.32(s,3H),2.29(s,3H), 1.22(s,2H).13C NMR(100MHz,DMSO-d6)δ167.62(s),161.82(d,J=243.0Hz),144.35(s),136.13(s),133.94(d,J=2.9Hz),131.91(s),130.15(s),129.74(d,J=8.2Hz),126.79(s), 125.98(s),123.08(s),115.81(d,J=21.4Hz),112.87(d,J=15.9Hz),112.44(s),109.66(s), 104.84(s),42.48(s),13.96(s),11.73(s).HRMS(ESI):calcd forC22H20FN3O[M+H]+ 362.1590,found 362.1605。
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-3)
鲜红色固体,产率57.6%,Mp:158-160℃。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),7.41(s,1H),7.39–7.31(m,3H),7.25(d,J=7.1Hz,1H),6.98(d,J=1.8Hz,1H),6.68(d,J=8.2Hz,1H),6.39(dd,J=8.2,1.9Hz,1H),6.02(s,1H),4.99(s,2H),4.70(s,2H),2.33 (s,3H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ167.67(s),144.57(s),140.40(s),136.22(s),133.64(s),132.00(s),131.03(s),130.00(s),127.72(s),127.36(s),126.80(s), 126.32(s),125.95(s),123.19(s),112.98(s),112.65(s),112.39(s),109.62(s),104.80(s), 42.64(s),13.98(s),11.75(s).HRMS(ESI):calcd for C22H20ClN3O[M+H]+378.1295,found 378.1338。
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-4)
鲜红色固体,产率55.8%,Mp:162-164℃。1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),7.39(d,J=8.2Hz,3H),7.32(d,J=8.3Hz,2H),6.98(s,1H),6.65(d,J=8.2Hz,1H),6.38(d,J=8.1Hz,1H),6.02(s,1H),4.97(s,2H),4.69(s,2H),2.33(s,3H),2.29(s,3H).13CNMR(100MHz,DMSO-d6)δ167.64(s),144.52(s),136.81(s),136.12(s),132.27(s),131.89(s),130.04(s),129.57(s),129.03(s),126.80(s),125.97(s),123.10(s),112.94(s),112.77(s), 112.37(s),109.64(s),104.79(s),42.54(s),13.98(s),11.74(s).HRMS(ESI):calcd for C22H20ClN3O[M+H]+378.1295,found 378.1316。
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-5)
鲜红色固体,产率41.4%,Mp:108-110℃。1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),7.46(d,J=8.2Hz,2H),7.40(s,1H),7.32–7.26(m,2H),6.98(s,1H),6.67(d,J=8.2Hz,1H),6.38(d,J=8.1Hz,1H),6.01(s,1H),4.98(s,2H),4.69(s,2H),2.33(s,3H),2.29(s, 3H).13C NMR(100MHz,DMSO-d6)δ167.65(s),144.55(s),140.64(s),136.22(s),132.00(s),131.30(s),130.61(s),130.22(s),129.98(s),126.79(s),126.68(s),125.94(s),123.18(s), 122.25(s),112.98(s),112.63(s),112.39(s),109.62(s),104.80(s),42.58(s),13.98(s),11.75 (s).HRMS(ESI):calcd for C22H20BrN3O[M+H]+422.0790,found422.0801。
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-6)
鲜红色固体,产率46.4%,Mp:180-182℃。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.52(d,J=8.3Hz,2H),7.40(s,1H),7.26(d,J=8.3Hz,2H),6.99(d,J=1.5Hz,1H),6.65(d,J=8.2Hz,1H),6.39(d,J=8.2Hz,1H),6.02(s,1H),4.96(s,2H),4.83(s,2H),2.33(s,3H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ167.65(s),144.21(s),137.23(s),136.17(s),131.95(s),130.16(s),129.92(s),126.81(s),125.98(s),123.15(s),120.77(s), 112.97(s),112.70(s),112.50(s),109.64(s),104.94(s),42.60(s),13.98(s),11.75(s).HRMS (ESI):calcd for C22H20BrN3O[M+H]+422.0790,found 422.0802。
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-7)
鲜红色固体,产率57.7%,Mp:178-180℃。1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),7.75(d,J=12.1Hz,2H),7.56(dt,J=14.4,7.1Hz,2H),7.41(s,1H),6.98(s,1H),6.68(d,J=8.3Hz,1H),6.38(d,J=8.1Hz,1H),6.02(s,1H),5.04(s,2H),4.70(s,2H),2.33(s,3H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ167.72(s),144.54(s),139.51(s),136.35(s),132.50(s),132.17(s),131.63(s),131.16(s),130.44(s),129.87(s),126.81(s),126.02(s), 123.27(s),119.13(s),113.03(s),112.51(s),112.43(s),111.94(s),109.57(s),104.85(s), 42.52(s),13.95(s),11.72(s).HRMS(ESI):calcd for C23H20N4O[M+H]+369.1637,found 369.1656。
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-8)
鲜红色固体,产率54.5%,Mp:190-191℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),7.80(d,J=7.6Hz,2H),7.46(d,J=7.5Hz,2H),7.41(s,1H),6.98(s,1H),6.64(d,J=8.0Hz,1H),6.37(d,J=7.9Hz,1H),6.02(s,1H),5.07(s,2H),4.70(s,2H),2.32(s,3H),2.29 (s,3H).13C NMR(100MHz,DMSO-d6)δ167.72(s),144.59(s),143.62(s),136.31(s),133.04(s),132.14(s),129.91(s),128.47(s),126.82(s),126.00(s),123.27(s),119.19(s), 113.02(s),112.52(s),112.39(s),110.49(s),109.56(s),104.83(s),42.95(s),13.95(s),11.74 (s).HRMS(ESI):calcd for C23H20N4O[M+H]+369.1637,found 369.1645。
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-9)
鲜红色固体,产率52.3%,Mp:112-114℃。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),7.68(s,1H),7.64(d,J=6.1Hz,1H),7.57(d,J=6.0Hz,2H),7.42(s,1H),6.99(d,J=1.6Hz,1H),6.69(d,J=8.2Hz,1H),6.39(dd,J=8.2,1.8Hz,1H),6.02(s,1H),5.09(s,2H),4.70(s,2H),2.33(s,3H),2.30(s,3H).13C NMR(100MHz,DMSO-d6)δ167.74(s),144.59 (s),139.38(s),136.25(s),132.05(s),131.65(s),130.26(s),129.97(s),129.87(s),129.55(s), 126.81(s),125.97(s),124.74–124.37(m),124.12(d,J=3.8Hz),123.23(s),113.00(s), 112.60(s),112.40(s),109.57(s),104.84(s),42.74(s),13.98(s),11.74(s).HRMS(ESI):calcd for C23H20F3N3O[M+H]+412.1558,found 412.1573。
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-10)
鲜红色固体,产率56.7%,Mp:160-162℃。1H NMR(400MHz,DMSO-d6)δ13.34(s,1H),7.75(d,J=7.9Hz,2H),7.54(d,J=7.8Hz,2H),7.46(s,1H),7.04(s,1H),6.70(d,J=8.2Hz,1H),6.43(d,J=7.7Hz,1H),6.06(s,1H),5.13(s,2H),4.75(s,2H),2.37(s,3H),2.34 (s,3H).13C NMR(100MHz,DMSO-d6)δ167.71(s),144.60(s),142.65(s),136.20(s),132.01(s),130.00(s),128.51(s),128.32(s),128.19(s),126.82(s),126.68–125.83(m),123.35(s),123.24(d,J=6.6Hz),112.98(s),112.66(s),112.39(s),109.58(s),104.82(s), 42.83(s),13.97(s),11.75(s).HRMS(ESI):calcd for C23H20F3N3O[M+H]+412.1558,found 412.1564。
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-11)
鲜红色固体,产率53.6%,Mp:150-152℃。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),7.42–7.35(m,3H),7.14(d,J=3.7Hz,1H),6.98(d,J=1.8Hz,1H),6.69(d,J=8.2Hz,1H),6.40(dd,J=8.2,1.9Hz,1H),6.02(s,1H),4.97(s,2H),4.71(s,2H),2.33(s,3H),2.29(s, 3H).13C NMR(100MHz,DMSO-d6)δ167.66(s),150.65(dd,J=69.4,12.6Hz),148.21(dd,J=68.3,12.6Hz),144.56(s),136.20(s),135.60(dd,J=5.0,4.1Hz),131.99(s),129.91(s), 126.81(s),125.98(s),124.46(dd,J=6.5,3.4Hz),123.18(s),118.17(d,J=17.2Hz),116.84 (d,J=17.3Hz),112.97(s),112.65(s),112.39(s),109.62(s),104.81(s),42.24(s),13.97(s), 11.74(s).HRMS(ESI):calcd for C22H19F2N3O[M+H]+380.1496,found 380.1516。
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-12)
鲜红色固体,产率61.6%,Mp:186-187℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),7.62–7.55(m,2H),7.41(s,1H),7.25(d,J=8.2Hz,1H),6.98(s,1H),6.68(d,J=7.8Hz,1H),6.39(d,J=8.4Hz,1H),6.02(s,1H),4.99(s,2H),4.71(s,2H),2.33(s,3H),2.29(s, 3H).13C NMR(100MHz,DMSO-d6)δ167.71(s),144.61(s),139.05(s),136.26(s),132.06(s),131.64(s),131.31(s),130.38(s),129.90(s),129.63(s),127.95(s),126.86(s),126.05(s), 123.22(s),112.99(s),112.58(s),112.43(s),109.58(s),104.86(s),42.17(s),13.97(s),11.75 (s).HRMS(ESI):calcd for C22H19Cl2N3O[M+H]+412.0905,found412.0926。
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮 (II-13)
鲜红色固体,产率43.6%,Mp:110-111℃。1H NMR(400MHz,DMSO-d6)δ13.36(s,1H),7.39(s,1H),6.98(s,2H),6.87(d,J=8.1Hz,1H),6.76(d,J=7.9Hz,1H),6.68(d,J=8.2Hz,1H),6.39(d,J=8.0Hz,1H),6.01(s,1H),4.89(s,2H),3.71(s,3H),3.69(s,3H),2.33 (s,3H),2.29(s,3H).13C NMR(100MHz,DMSO-d6)δ167.61(s),149.20(s),148.52(s),143.99(s),135.95(s),131.69(s),130.54(s),130.04(s),126.79(s),125.93(s),122.94(s), 119.79(s),112.99(s),112.88(s),112.54(s),112.42(s),111.97(s),109.83(s),104.91(s), 55.98(s),43.01(s),13.98(s),11.74(s).HRMS(ESI):calcd for C24H25N3O3[M+H]+404.1896, found 404.1922。
实施例7、目标化合物III-1至III-16的制备
称取苯甲酸或取代苯甲酸或吡啶甲酸(1.2equiv)和HBTU(1.2equiv)加入到茄形瓶(100mL)中,加入适量的DMF(10mL)至溶解,反应体系在冰浴条件下搅拌至0℃后,逐滴滴加DIEA(1.5equiv)至反应液中,搅拌40min,溶液颜色由无色渐变成红棕色或黄棕色。化合物II-11或II-12(1equiv)用10mL DMF溶解后逐滴滴入反应液中,滴毕,撤除冰浴,室温反应过夜。可观察到反应液中有固体生成,将反应液倒入装有冰水(温度0℃,100mL)的烧杯中,析出大量黄色固体,抽滤,水洗,干燥,得黄色固体粗品。所得固体粗品用少量乙酸乙酯打浆洗涤两次,再用少量甲醇超声洗涤,抽滤,干燥,得目标化合物III-1至III-9和III-12至III-14。
称取化合物II-11或II-12(1equiv)加入到茄形瓶(50mL)中,用适量的DMF(6 mL)溶解,加入K2CO3粉末(1.2equiv),室温下搅拌30min后缓慢滴入氯乙酰氯(1.2 equiv)或环丙甲酰氯(1.2equiv),滴毕,室温反应过夜(12h)。可观察到反应液中有固体生成,将反应液倒入装有冰水(0℃,100mL)的烧杯中,析出大量黄色固体,抽滤,水洗,干燥,得黄色固体粗品。所得固体粗品用少量乙酸乙酯打浆洗涤两次,再用少量甲醇超声洗涤,抽滤,干燥,得目标化合物III-10、III-11、III-15、III-16。
(Z)-3-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-1)
橙黄色固体,产率75.1%,Mp:273-275℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.26(s,1H),8.07(s,1H),7.82(dd,J=18.2,7.4Hz,2H),7.59(d,J=20.0Hz,4H),7.45 (d,J=1.6Hz,2H),7.27(d,J=6.1Hz,1H),7.10–6.98(m,1H),6.08(s,1H),5.11(s,2H), 2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ168.07(s),164.24(s),162.44(d, J=244.7Hz),138.75(s),137.61(d,J=4.7Hz),135.19(s),133.81(s),133.55(s),131.67(s), 131.43(s),131.06(d,J=8.0Hz),130.48(s),129.70(s),127.94(s),127.09(s),125.41(s), 124.26(d,J=6.1Hz),119.78(d,J=1.2Hz),118.96(s),118.76(s),114.93(s),114.69(s), 113.58(s),112.29(s),111.12(s),109.04(s),42.25(s),14.05(s),11.81(s).HRMS(ESI):calcd for C29H22Cl2FN3O2[M+H]+534.1073,found 534.1169。
(Z)-4-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-2)
橙黄色固体,产率66.3%,Mp:314-316℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.19(s,1H),8.06(d,J=8.0Hz,3H),7.60(d,J=8.1Hz,2H),7.56(s,1H),7.40(dd,J=13.3,8.7Hz,3H),7.27(d,J=8.3Hz,1H),7.02(d,J=8.4Hz,1H),6.08(s,1H),5.11(s,2H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ167.01(s),164.63(d,J=5.1Hz),163.49(d,J=1.4Hz),156.93(s),137.68(s),136.44(s),134.03(s),132.93(s),132.40(s), 130.59(s),130.34(s),129.66(s),129.57(s),129.39(s),128.62(s),126.86(s),126.01(s), 124.31(s),123.17(d,J=2.4Hz),118.73(d,J=1.6Hz),114.82(s),114.60(s),112.47(s), 111.25(d,J=3.1Hz),110.12(s),107.94(s),41.20(s),12.97(s),10.73(s).HRMS(ESI): calcd for C29H22Cl2FN3O2[M+H]+534.1073,found 534.1127。
(Z)-3-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-3)
橙黄色固体,产率59.9%,Mp:276-278℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.31(s,1H),8.05(d,J=8.9Hz,2H),7.95(d,J=7.3Hz,1H),7.67(d,J=8.5Hz,1H),7.59(dd,J=15.1,7.5Hz,4H),7.45(d,J=7.6Hz,1H),7.27(d,J=8.7Hz,1H),7.03(d,J=8.3Hz,1H),6.08(s,1H),5.11(s,2H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz, DMSO-d6)δ168.07(s),164.18(s),138.74(s),137.61(s),137.31(s),135.19(s),133.80(s),133.70(s),133.57(s),131.79(s),131.67(s),131.43(s),130.90(s),130.47(s),129.69(s), 127.93(s),127.77(s),127.09(s),126.84(s),125.40(s),124.30(s),119.76(s),113.59(s), 112.24(s),111.10(s),109.03(s),42.25(s),14.05(s),11.82(s).HRMS(ESI):calcd for C29H22Cl3N3O2[M+H]+550.0778,found 550.0847。
(Z)-3-溴-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-4)
橙黄色固体,产率60.1%,Mp:288-290℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.29(s,1H),8.17(s,1H),8.05(d,J=0.8Hz,1H),7.98(d,J=6.9Hz,1H),7.80(d,J=7.9Hz,1H),7.62(s,2H),7.57–7.49(m,2H),7.44(d,J=7.2Hz,1H),7.27(d,J=6.6Hz,1H),7.03(d,J=7.4Hz,1H),6.09(s,1H),5.11(s,2H),2.36(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)δ168.07(s),164.12(s),138.74(s),137.62(s),137.50(s),135.19(s),134.69(s),133.79(s),133.58(s),131.67(s),131.67(s),131.16(s),130.60(s),130.47(s), 129.69(s),127.93(s),127.21(s),127.09(s),125.41(s),124.31(s),122.18(s),119.76(s), 113.59(s),112.25(s),111.10(s),109.03(s),42.26(s),14.05(s),11.82(s).HRMS(ESI):calcd for C29H22BrCl2N3O2[M+H]+594.0272,found 594.0324。
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-5)
橙黄色固体,产率61.3%,Mp:288-289℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.17(s,1H),8.08(s,1H),7.99(d,J=7.3Hz,2H),7.64–7.52(m,6H),7.45(d,J=8.2Hz,1H),7.28(d,J=7.9Hz,1H),7.02(d,J=8.2Hz,1H),6.08(s,1H),5.11(s,2H),2.36(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)δ168.09(s),165.67(s),138.76(s),137.50(s),135.37(s),135.04(s),134.14(s),133.46(s),131.93(s),131.67(s),131.42(s),130.47(s), 129.70(s),128.85(s),127.99(s),127.93(s),127.08(s),125.37(s),124.24(s),119.75(s), 113.55(s),112.23(s),111.23(s),109.00(s),99.99(s),42.27(s),14.05(s),11.81(s).HRMS (ESI):calcd for C29H23Cl2N3O3[M+H]+516.1167,found516.1232。
(Z)-4-甲氧基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5- 基)苯甲酰胺(III-6)
棕黄色固体,产率59.1%,Mp:294-296℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.02(s,1H),8.05(s,1H),7.98(d,J=7.2Hz,2H),7.60(d,J=6.4Hz,2H),7.55(s,1H), 7.42(d,J=7.1Hz,1H),7.27(d,J=7.0Hz,1H),7.06(d,J=7.9Hz,2H),7.01(d,J=7.4Hz, 1H),6.07(s,1H),5.10(s,2H),3.84(s,3H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz, DMSO-d6)δ168.07(s),165.08(s),162.27(s),138.77(s),137.46(s),134.89(s),134.31(s), 133.42(s),131.66(s),131.43(s),130.46(s),129.90(s),129.69(s),127.93(s),127.39(s), 127.07(s),125.32(s),124.19(s),119.76(s),114.07(s),113.53(s),112.26(s),111.28(s), 108.97(s),55.89(s),42.26(s),14.05(s),11.81(s).HRMS(ESI):calcd for C30H25Cl2N3O3 [M+H]+546.1273,found 546.1321。
(Z)-3-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-7)
橙黄色固体,产率49.4%,Mp:264-266℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.13(s,1H),8.07(s,1H),7.82–7.75(m,2H),7.61(d,J=8.1Hz,2H),7.55(s,1H),7.43(dd,J=15.8,7.5Hz,3H),7.28(d,J=8.1Hz,1H),7.02(d,J=8.4Hz,1H),6.08(s,1H),5.11(s,2H),2.41(s,3H),2.36(s,3H),2.34(s,3H).13C NMR(100MHz,DMSO-d6)δ168.07(s),165.78(s),138.76(s),138.14(s),137.51(s),135.36(s),134.99(s),134.18(s),133.46(s), 132.50(s),131.67(s),131.42(s),130.47(s),129.69(s),128.76(s),128.49(s),127.93(s), 127.07(s),125.35(s),125.16(s),124.20(s),119.67(s),113.55(s),112.14(s),111.22(s), 108.99(s),42.25(s),21.46(s),14.05(s),11.81(s).HRMS(ESI):calcd for C30H25Cl2N3O2 [M+H]+530.1324,found 530.1374。
(Z)-4-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-8)
橙黄色固体,产率54.5%,Mp:296-298℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.09(s,1H),8.07(s,1H),7.90(d,J=8.0Hz,2H),7.61(d,J=7.8Hz,2H),7.56(s,1H), 7.44(d,J=9.4Hz,1H),7.34(d,J=7.9Hz,2H),7.28(d,J=7.9Hz,1H),7.02(d,J=8.3Hz, 1H),6.08(s,1H),5.11(s,2H),2.40(s,3H),2.36(s,3H),2.34(s,3H).13C NMR(100MHz, DMSO-d6)δ168.07(s),165.50(s),148.05(s),141.90(s),138.76(s),137.48(s),134.96(s), 133.45(s),132.48(s),131.66(s),131.42(s),130.47(s),129.69(s),129.38(s),128.02(s), 127.93(s),127.07(s),125.34(s),124.21(s),119.76(s),113.54(s),112.25(s),111.25(s), 108.98(s),42.25(s),21.47(s),14.05(s),11.81(s).HRMS(ESI):calcd for C30H25Cl2N3O2 [M+H]+530.1324,found 530.1381。
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)吡啶甲酰胺(III-9)
棕黄色固体,产率44.8%,Mp:268-270℃。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),10.39(s,1H),9.14(s,1H),8.77(d,J=3.5Hz,1H),8.32(d,J=7.2Hz,1H),8.08(s,1H), 7.65–7.55(m,4H),7.44(d,J=8.0Hz,1H),7.27(d,J=8.2Hz,1H),7.04(d,J=8.3Hz,1H), 6.08(s,1H),5.11(s,2H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ168.07 (s),164.16(s),152.52(s),149.08(s),138.73(s),137.61(s),135.78(s),135.23(s),133.75(s), 133.58(s),131.67(s),131.42(s),130.94(s),130.48(s),129.69(s),127.93(s),127.10(s), 125.44(s),124.31(s),123.99(s),119.70(s),113.58(s),112.19(s),111.08(s),109.06(s), 42.26(s),14.05(s),11.81(s).HRMS(ESI):calcd forC28H22Cl2N4O2[M+H]+517.1120,found 517.1182。
(Z)-2-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)乙酰胺(III-10)
棕黄色固体,产率45.1%,Mp:248-250℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.20(s,1H),7.91(s,1H),7.60(d,J=7.8Hz,2H),7.53(s,1H),7.29–7.24(m,2H),6.99(d,J=8.3Hz,1H),6.08(s,1H),5.09(s,2H),4.25(s,2H),2.36(s,3H),2.33(s,3H).13CNMR(100MHz,DMSO-d6)δ168.01(s),164.84(s),138.71(s),137.70(s),135.05(s),133.71(s),133.46(s),131.66(s),131.42(s),130.49(s),129.69(s),127.93(s),127.08(s),125.56(s), 124.43(s),118.53(s),113.62(s),110.98(s),109.17(s),43.96(s),42.22(s),14.05(s),11.80 (s).HRMS(ESI):calcd for C24H20Cl3N3O2[M+H]+488.0621,found488.0700。
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)环丙甲酰胺(III-11)
棕黄色固体,产率42.1%,Mp:264-266℃。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),10.08(s,1H),7.94(s,1H),7.63–7.57(m,2H),7.48(s,1H),7.29–7.22(m,2H),6.95(d,J=8.4Hz,1H),6.07(s,1H),5.08(s,2H),2.35(s,3H),2.32(s,3H),1.79–1.73(m,1H),0.78(t,J=6.0Hz,4H).13C NMR(100MHz,DMSO-d6)δ171.77(s),168.00(s),138.77(s), 137.44(s),134.59(s),134.40(s),133.40(s),131.64(s),131.41(s),130.45(s),129.68(s),127.93(s),127.01(s),125.37(s),124.11(s),118.09(s),113.52(s),111.26(s),110.51(s), 109.09(s),42.20(s),14.84(s),14.04(s),11.80(s),7.38(s).HRMS(ESI):calcdfor C26H23Cl2N3O2[M+H]+480.1167,found 480.1219。
(Z)-3-氟-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-12)
棕黄色固体,产率37.2%,Mp:254-256℃。1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),10.25(s,1H),8.06(s,1H),7.82(dd,J=21.2,7.7Hz,2H),7.65–7.54(m,2H),7.42(dd,J=14.3,12.1Hz,4H),7.16(d,J=4.3Hz,1H),7.04(d,J=7.5Hz,1H),6.08(s,1H),5.09(s,2H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ168.04(s),164.22(d,J=2.6Hz),162.44(d,J=244.5Hz),150.29(dd,J=20.2,12.8Hz),148.35(dd,J=85.0,16.6Hz),137.62(s),137.49(s),135.23(s),133.59(d,J=31.2Hz),131.06(d,J=7.9Hz),127.08 (s),125.40(d,J=1.2Hz),124.46(dd,J=5.3,2.3Hz),124.22(s),119.77(s),118.85(d,J= 20.9Hz),118.35(s),118.15(d,J=7.0Hz),117.00(d,J=2.9Hz),116.83(d,J=4.7Hz), 114.92(s),114.69(s),113.53(s),112.27(s),111.22(s),109.04(s),42.36(s),14.05(s),11.82 (s).HRMS(ESI):calcd for C29H22F3N3O2[M+H]+502.1664,found502.1722。
(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-13)
棕黄色固体,产率56.9%,Mp:248-249℃。1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),10.18(s,1H),8.08(s,1H),7.98(d,J=7.2Hz,2H),7.61–7.52(m,4H),7.47–7.37(m,3H),7.16(d,J=6.6Hz,1H),7.03(d,J=8.4Hz,1H),6.08(s,1H),5.09(s,2H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ168.04(s),165.64(s),148.58(d,J=13.0Hz),147.95(d,J=13.8Hz),137.41(s),135.34(s),135.08(s),134.07(s),133.36(s),131.94(s), 128.86(s),128.00(s),127.06(s),125.35(s),124.47(dd,J=6.7,3.1Hz),124.17(s),121.07 (s),119.74(s),118.27(d,J=17.2Hz),116.94(d,J=17.4Hz),113.51(s),112.24(s),111.31 (s),109.02(s),42.34(s),14.06(s),11.82(s).HRMS(ESI):calcd forC29H23F2N3O2[M+H]+ 484.1758,found 484.1805。
(Z)-3-甲基-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基) 苯甲酰胺(III-14)
棕黄色固体,产率53.7%,Mp:258-260℃。1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),10.13(s,1H),8.06(s,1H),7.82–7.75(m,2H),7.55(s,1H),7.46–7.37(m,5H),7.19–7.14(m,1H),7.03(d,J=8.4Hz,1H),6.08(s,1H),5.09(s,2H),2.41(s,3H),2.36(s,3H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ168.04(s),165.73(s),148.57(dd,J=12.9,2.8Hz),147.92(dd,J=9.1,5.6Hz),138.12(s),137.39(s),135.35(s),135.29(s),135.18(dd, J=8.9,3.9Hz),135.03(s),134.14(s),133.33(s),132.49(s),128.75(s),128.50(s),127.06(s), 125.33(s),125.17(s),124.47(dd,J=6.2,3.5Hz),124.13(s),119.66(s),118.27(d,J=17.1 Hz),116.94(d,J=17.5Hz),113.50(s),112.15(s),111.33(s),109.00(s),42.34(s),21.46(s), 14.05(s),11.81(s).HRMS(ESI):calcd for C30H25F2N3O2[M+H]+498.1915,found 498.1964。
(Z)-2-氯-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)乙酰胺(III-15)
棕黄色固体,产率40.6%,Mp:236-237℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),10.19(s,1H),7.90(s,1H),7.52(s,1H),7.41(d,J=6.2Hz,2H),7.26(d,J=6.7Hz,1H), 7.14(s,1H),7.00(d,J=6.8Hz,1H),6.07(s,1H),5.06(s,2H),4.24(s,2H),2.35(s,3H),2.33 (s,3H).13C NMR(100MHz,DMSO-d6)δ168.00(s),164.82(s),150.47(dd,J=63.4,47.4 Hz),149.00(dd,J=55.8,11.9Hz),137.58(d,J=1.1Hz),135.26(dd,J=5.5,1.5Hz),135.11 (s),133.50(d,J=16.0Hz),127.07(s),125.55(s),124.52(s),124.46(dd,J=5.0,2.2Hz), 124.36(s),118.52(s),118.35(s),118.18(s),116.93(d,J=17.2Hz),113.58(s),111.01(d,J= 8.8Hz),109.18(s),43.96(s),42.34(s),14.05(s),11.80(s).HRMS(ESI):calcd for C24H20ClF2N3O2[M+H]+456.1212,found 456.1273。
(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)环丙甲酰胺(III-16)
棕黄色固体,产率47.9%,Mp:260-262℃。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),10.07(s,1H),7.93(s,1H),7.47(s,1H),7.39(d,J=8.5Hz,2H),7.24(d,J=6.5Hz,1H), 7.14(s,1H),6.95(d,J=6.7Hz,1H),6.06(s,1H),5.05(s,2H),2.35(s,3H),2.31(s,3H),1.79 (dd,J=19.3,3.7Hz,1H),0.79(s,4H).13C NMR(100MHz,DMSO-d6)δ171.73(s),167.98 (s),150.25(d,J=170.6Hz),148.19(d,J=65.4Hz),137.30(s),135.32(d,J=2.5Hz), 135.25(s),134.51(d,J=9.2Hz),133.24(s),127.01(s),125.37(s),124.46(dd,J=6.4,3.2 Hz),123.99(s),118.33(s),118.12(d,J=8.2Hz),116.91(d,J=16.9Hz),113.46(s),111.39 (s),110.49(s),109.09(s),42.31(s),14.84(s),14.03(s),11.79(s),7.36(s).HRMS(ESI):calcd for C26H23F2N3O2[M+H]+448.1758,found 448.1804。
试验例
对人外周血T淋巴白血病细胞Jurkat、肺癌细胞A549和结肠癌细胞HCT116生长抑制活性测定实验
化合物对Jurkat细胞生长抑制活性实验、对Jurkat、A549和HCT116细胞的IC50值:
采用SRB(sulforhodamine B)试验法检测化合物对肿瘤细胞系的生长抑制活性。人外周血T淋巴源性白血病细胞Jurkat、肺癌细胞A549和结肠癌细胞HCT116用含有10%FBS、2mM谷氨酰胺、100IU/mL青霉素、100μg/mL链霉素的RPMI 1640培养液供应培养。所有细胞均置于37℃含5%CO2的培养箱(Thermo Forma)中,常规传代培养。将处于对数生长期的细胞以一定数量接种于96孔板(200μl/孔)中,培养24小时使之贴壁后加药。每个化合物的单个药物浓度设1个复孔,并设相应的调零组及空白对照组。药物作用72小时后,往Jurkat或A549或HCT116细胞中加入50%TCA(三氯乙酸)(50 μl/孔),4℃下固定1小时后倒掉固定液,用蒸馏水依次洗5次,自然干燥。向每孔中加入100μL 4mg/mL的SRB,室温染色15分钟,弃之,分别用1%冰醋酸洗5次,自然干燥。最后向每孔中加入150μL 10mM的Tris缓冲溶液,摇匀,用可调波长式微孔板酶标仪(VERSAmaxTM,Molecular Device)在565nm波长下测定OD值。用以下公式计算细胞生长抑制率。
抑制率(%)=(OD值对照孔-OD值给药孔)/OD值对照孔×100%
根据每个化合物的单个药物浓度设1个复孔计算各化合物的抑制率,数据表示为均值±SD值。
优选的目标化合物设计了9个梯度浓度,并设置了两个对照组,根据以上公式分别计算各浓度抑制率,采用LOGIT法计算半数抑制浓度IC50。实验重复进行1次,数据表示为均值±SD值,如表1、表2所示。
表1.目标化合物在10μM浓度下对Jurkat细胞的生长抑制活性
与对照药物司马沙尼(SU5416)相比,I-3、I-9、I-13、Ⅱ-2、Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、III-9对Jurkat细胞的生长抑制活性优于阳性化合物司马沙尼(SU5416),其中Ⅱ-2、Ⅱ-3、Ⅱ-5、Ⅱ-10、Ⅱ-11和III-9对Jurkat细胞的生长抑制活性大于50%。进一步地,我们优选了目标化合物Ⅱ-2、Ⅱ-3、Ⅱ-5、Ⅱ-10、Ⅱ-11和III-9,以化合物AA-2(1-(3,4-二氯苄基)-1H-吲哚-2,3-二酮)为对照药物,分别测定了它们对人外周血T淋巴白血病细胞Jurkat、肺癌细胞A549和结肠癌细胞HCT116的IC50值,实验结果见表2。
表2.优选的目标化合物对人外周血T淋巴白血病细胞Jurkat、肺癌细胞A549和结肠癌细胞HCT116的IC50值
注:ND:Not Detected.
Ⅱ-3、Ⅱ-5、Ⅱ-10、Ⅱ-11和III-9对Jurkat、A549或HCT116细胞呈现出低微摩尔浓度(小于8.5μM)的生长抑制活性。其中,Ⅱ-5对Jurkat和A549细胞的生长抑制活性优于阳性化合物AA-2,而Ⅱ-11对Jurkat、A549和HCT116三株细胞系的生长抑制活性均优于阳性化合物AA-2。
Claims (10)
2.根据权利要求1所述3-取代吲哚-2-酮化合物,其特征在于,R1、R2独立地选自氢、F、Cl、Br、I、三氟甲基、氰基或甲氧基;优选的,R1、R2独立地选自氢、F、Cl、Br、三氟甲基、氰基或甲氧基。
4.根据权利要求1所述3-取代吲哚-2-酮化合物,其特征在于,所述3-取代吲哚-2-酮化合物选自以下化合物:
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-1);
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-2);
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-3);
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-4);
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-5);
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-6);
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-7);
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-8);
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-9);
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-10);
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-11);
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-12);
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮(I-13);
(Z)-1-(3-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-1);
(Z)-1-(4-氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-2);
(Z)-1-(3-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-3);
(Z)-1-(4-氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-4);
(Z)-1-(3-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-5);
(Z)-1-(4-溴苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-6);
(Z)-1-(3-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-7);
(Z)-1-(4-氰基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-8);
(Z)-1-(3-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-9);
(Z)-1-(4-三氟甲基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-10);
(Z)-1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-11);
(Z)-1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-12);
(Z)-1-(3,4-二甲氧基苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-5-氨基-2-吲哚酮(II-13);
(Z)-3-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-1);
(Z)-4-氟-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-2);
(Z)-3-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-3);
(Z)-3-溴-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-4);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-5);
(Z)-4-甲氧基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-6);
(Z)-3-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-7);
(Z)-4-甲基-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-8);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)吡啶甲酰胺(III-9);
(Z)-2-氯-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)乙酰胺(III-10);
(Z)-N-(1-(3,4-二氯苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)环丙甲酰胺(III-11);
(Z)-3-氟-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-12);
(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-13);
(Z)-3-甲基-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)苯甲酰胺(III-14);
(Z)-2-氯-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)乙酰胺(III-15);
或,(Z)-N-(1-(3,4-二氟苄基)-3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-吲哚酮-5-基)环丙甲酰胺(III-16)。
6.根据权利要求5所述3-取代吲哚-2-酮化合物的制备方法,其特征在于,所述3-取代吲哚-2-酮化合物的制备方法,包括步骤:
以2-吲哚酮即化合物1为起始原料,与3,5-二甲基-1H-吡咯-2-甲醛经羟醛缩合反应生成中间体2;中间体2在K2CO3存在的条件下与取代苄氯或取代苄溴经亲核取代反应得式(I)化合物;
或者,以2-吲哚酮即化合物1为起始原料,经硝化反应生成中间体3;中间体3与3,5-二甲基-1H-吡咯-2-甲醛经羟醛缩合反应生成中间体4;中间体4在K2CO3存在的条件下与取代苄氯或取代苄溴经亲核取代反应生成中间体5;中间体5经铁粉还原得式(II)化合物;
或者,所得式(II)化合物与相应的羧酸经酰胺缩合反应,或在K2CO3存在的条件下与相应的酰氯经酰氯化反应得式(III)化合物。
7.一种药物组合物,其包含如权利要求1-4任意一项所述的3-取代吲哚-2-酮化合物或其药学上可接受的盐。
8.一种药物制剂,其包含如权利要求1-4任意一项所述的3-取代吲哚-2-酮化合物或其药学上可接受的盐和至少一种药学上可接受的辅料或载体。
9.权利要求1-4任意一项所述3-取代吲哚-2-酮化合物或权利要求7所述的药物组合物或权利要求8所述的药物制剂在制备人外周血T淋巴源性白血病细胞、肺癌细胞和/或结肠癌细胞生长抑制剂中的应用;
优选的,所述人外周血T淋巴源性白血病细胞为Jurkat,所述肺癌细胞为A549,结肠癌细胞为HCT116。
10.权利要求1-4任意一项所述3-取代吲哚-2-酮化合物或权利要求7所述的药物组合物或权利要求8所述的药物制剂在制备抗肿瘤药物中的应用;
优选的,所述肿瘤为白血病、肺癌或结肠癌。
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