Double-aryl maleimide compound, pharmaceutically acceptable salt thereof, method for preparing double-aryl maleimide compound and pharmaceutically acceptable salt and application of double-aryl maleimide compound and pharmaceutically acceptable salt

A maleimide and compound technology, applied in the field of bisarylmaleimide compounds, can solve problems such as tumors and activity decline

Inactive Publication Date: 2016-07-20
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above two reasons will make some dioxygenases dependent on α-KG include prolylhydroxylase (prolylhydroxylase, PHD), DNA hydroxylase Tet family and histonelysine demethylases (histonelysinedemethylases, KDMs) and other activities decreased, eventually leading to the occurrence of tumors

Method used

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  • Double-aryl maleimide compound, pharmaceutically acceptable salt thereof, method for preparing double-aryl maleimide compound and pharmaceutically acceptable salt and application of double-aryl maleimide compound and pharmaceutically acceptable salt
  • Double-aryl maleimide compound, pharmaceutically acceptable salt thereof, method for preparing double-aryl maleimide compound and pharmaceutically acceptable salt and application of double-aryl maleimide compound and pharmaceutically acceptable salt
  • Double-aryl maleimide compound, pharmaceutically acceptable salt thereof, method for preparing double-aryl maleimide compound and pharmaceutically acceptable salt and application of double-aryl maleimide compound and pharmaceutically acceptable salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: 1-methyl-3-(tributyltinyl)-1H-pyrazol[3,4-b]pyridine (2a)

[0029] Add 2.0g (4.9mmol) 3-(tributyltinyl)-1H-pyrazol[3,4-b]pyridine and 30mL anhydrous DMF into the three-necked flask, control the temperature at 0-5°C, and add 0.22g in batches (5.5mmol) 60% NaH, after adding, keep stirring for 30min, then dropwise add 0.84g (5.9mmol) methyl iodide, react at 0~5°C for 1h after dropping, then rise to room temperature for 0.5h, after the reaction, put The reaction solution was poured into 600mL water, extracted with dichloromethane (50mL×3), the organic layers were combined, washed with saturated brine (150mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column Purification by analysis (petroleum ether: ethyl acetate = 6:1, v / v) gave 1.56 g of oil 2a with a yield of 75.5%. 1 HNMR (CDCl 3 )δ:0.89(9H,t,J=7.5Hz),1.21-1.26(6H,m),1.33-1.38(6H,m),1.58-1.63(6H,m),4.19(3H,...

Embodiment 2

[0030] Example 2: 1-Ethyl-3-(tributyltinyl)-1H-pyrazol[3,4-b]pyridine (2b)

[0031] The synthesis method is the same as that in Implementation 1, except that ethyl bromide is used instead of methyl iodide to obtain oil 2b, yield: 62.3%, 1 HNMR (CDCl 3 )δ:0.89(9H,t,J=7.5Hz),1.22-1.27(6H,m),1.34-1.40(6H,m),1.54(3H,t,J=7.5Hz),1.57-1.64(6H ,m),4.63(2H,q,J=7.5Hz),7.04-7.07(1H,m),8.00(1H,dd,J=8.0,1.5Hz),8.50(1H,dd,J=4.5,1.5 Hz).

Embodiment 3

[0032] Example 3: 1-Butyl-3-(tributyltinyl)-1H-pyrazol[3,4-b]pyridine (2c)

[0033] The synthetic method is the same as that in Implementation 1, except that methyl bromide is used instead of methyl iodide to obtain oil 2c with a yield of 58.3%. 1 HNMR (CDCl 3 )δ:0.89(9H,t,J=7.5Hz),0.95(3H,t,J=7.5Hz),1.20-1.29(8H,m),1.32-1.39(8H,m),1.56-1.63(6H ,m),4.57(2H,t,J=7.5Hz),7.03-7.08(1H,m),8.01(1H,dd,J=8.0,1.5Hz),8.50(1H,dd,J=4.5,1.5 Hz).

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PUM

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Abstract

The invention discloses a double-aryl maleimide compound, pharmaceutically acceptable salt thereof, a method for preparing the double-aryl maleimide compound and the pharmaceutically acceptable salt and application of the double-aryl maleimide compound and the pharmaceutically acceptable salt. The double-aryl maleimide compound and the pharmaceutically acceptable salt can be particularly used as isocitrate dehydrogenase 1 (IDH1) mutant inhibitors and can be applied to treating malignant tumor such as glioma and acute myeloid leukemia. The double-aryl maleimide compound, the pharmaceutically acceptable salt, the method and the application have the advantages that the double-aryl maleimide compound has efficiently selective IDH1 mutant inhibitory activity, and accordingly the double-aryl maleimide compound and the pharmaceutically acceptable salt can be used for treating the IDH1 mutant mediated malignant tumor such as the glioma and the acute myeloid leukemia; the double-aryl maleimide compound, the pharmaceutically acceptable salt and the method are reasonable in design, and the method is simple and practical.

Description

technical field [0001] The present invention mainly relates to a kind of bisarylmaleimide compound and its pharmaceutically acceptable salt as well as its preparation method and application. Application in the treatment of malignant tumors such as glioma and acute myeloid leukemia mediated by IDH1 mutation. Background technique [0002] Malignant tumors are one of the major diseases that threaten human health. Worldwide, 8.5 million people died of cancer in 2008, and according to current trends, by 2020 it is expected that there will be 20 million new cancer cases, of which the death toll will reach 12 million. The prevention and treatment of tumors has become an important research topic in the medical circles of various countries. Although people have a deeper understanding of the cause and development of tumors, and a large number of anti-tumor drugs are used clinically. However, these widely used antitumor drugs often have problems such as high toxicity and side effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D403/14C07D491/048A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D403/14C07D471/04C07D491/048
Inventor 叶青李佳周宇波高安慧高立信胡圆圆励雪高建荣
Owner ZHEJIANG UNIV OF TECH
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