Substance with tyrosine kinase inhibitory activity, its preparation method and use

A tyrosine kinase and activity-inhibiting technology, applied in organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve the problem of low efficiency and achieve the effect of inhibiting tyrosine kinase activity

Active Publication Date: 2015-10-14
INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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This shows that the effectiveness of the drug is not high

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  • Substance with tyrosine kinase inhibitory activity, its preparation method and use
  • Substance with tyrosine kinase inhibitory activity, its preparation method and use
  • Substance with tyrosine kinase inhibitory activity, its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: 3-(1H-benzimidazole-2-methylene)-2-indolinone (L001) and its preparation

[0083] Suspend 0.05g (0.25mmol) of 2-indolinone and 0.04g (0.27mmol) of 1H-benzimidazole-2-carbaldehyde in 2ml of absolute ethanol, add 2 drops of piperidine, and heat to reflux in an oil bath for 30min , a large amount of orange-yellow solid was precipitated, filtered, and washed with absolute ethanol to obtain 0.05 g of light yellow solid, with a yield of 62.5%.

[0084] The analysis result of its nuclear magnetic resonance spectrum is: 1 H-NMR (DMSO-d6) δ (ppm): δ 13.99 (s, 1H, NH), 11.30 (s, 1H, NH), 7.95 (s, 1H, CH), 7.93 (d, 1H, J= 7.6Hz, Ar-H), 7.79(d, 1H, J=8.0Hz, Ar-H), 7.75(d, 1H, J=8.0Hz, Ar-H), 7.29-7.37(m, 3H, Ar- H), 7.08 (t, 1H, Ar-H), 6.95 (d, 1H, J = 7.6 Hz, Ar-H). ESI-MS m / z: 262 [M+H]+ (100).

[0085] After analysis, the light yellow solid is 3-(1H-benzimidazole-2-methylene)-2-indolinone, its structural formula is as formula I, wherein, R 1 for hydrogen, R 2 fo...

Embodiment 2

[0086] Example 2: 3-(1H-benzimidazole-2-methylene)-5-(methylaminosulfonyl)-2-indolone (L002)

[0087] Suspend 0.12g (0.5mmol) 5-(methylaminosulfonyl)-2-indolinone and 0.10g (0.685mmol) 1H-benzimidazole-2-formaldehyde in 6ml absolute ethanol, add 2 Droppiperidine was heated to reflux in an oil bath for 30 minutes, a large amount of yellow solids precipitated, filtered, and washed with absolute ethanol to obtain 0.16 g of light yellow solids, with a yield of 88.9%.

[0088] The analysis result of its nuclear magnetic resonance spectrum is: 1 H-NMR (DMSO-d 6 )δ(ppm): δ13.86(s, 1H), 11.76(s, 1H), 8.35(d, 2H), 7.84(m, 2H), 7.68(d, 2H), 7.38(s, 1H), 7.32(s, 1H), 7.15(d, 1H, J=8.4Hz), 2.92(s, 3H). After analysis, the light yellow solid is 3-(1H-benzimidazole-2-methylene)-5-(methylaminosulfo)-2-indolone, and its structural formula is as formula I, wherein, R 1 is methylaminosulfo group, R 2 for hydrogen.

Embodiment 3

[0089] Example 3: 3-(1H-benzimidazole-2-methylene)-5-(ethylaminosulfonyl)-2-indolone (L003)

[0090] Suspend 0.12g (0.5mmol) of 5-(ethylaminosulfonyl)-2-indolinone and 0.10g (0.685mmol) of 1H-benzimidazole-2-formaldehyde in 6ml of absolute ethanol, add 2 drops Piperidine was heated under reflux in an oil bath for 30 minutes, a large amount of yellow solid precipitated out, filtered, and washed with absolute ethanol to obtain 0.10 g of light yellow solid with a yield of 55.6%.

[0091] The analysis result of its nuclear magnetic resonance spectrum is: 1 H-NMR (DMSO-d 6)δ(ppm): δ13.86(s, 1H), 11.69(s, 1H), 8.33(s, 1H), 8.11(s, 1H), 7.83(d, 1H, J=8.0Hz), 7.79( d, 1H, J=8.0Hz), 7.75(dd, 1H, J=16.8Hz), 7.36-7.42(m, 2H), 7.30(t, 1H), 7.12(d, 1H, J=8.0Hz), 2.82-2.87 (m, 2H), 1.01 (t, 3H). ESI-MS m / z: 367[M-H] + (100). After analysis, the light yellow solid is 3-(1H-benzimidazole-2-methylene)-5-(ethylaminosulfo)-2-indolinone, and its structural formula is as formula I, wherein, ...

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Abstract

The invention discloses a substance having tyrosine kinase inhibition activity, a preparation method and an application, the substance is a compound having a structure of a general formula I, a geometric isomer and its medicinal salt, in a formula I, R1 is selected from hydrogen atom or -SO2NR3R4; R2 is selected from hydrogen atoms or nitro group; R3 and R4 are independently selected from hydrogen atoms, substituted or unsubstituted C1-12 straight chain or branched chain alkyl group, alicyclic group, aryl alkyl group, substituted or unsubstituted five or six-element monocyclic aromatic base, or condensed ring aromatic base, wherein, R3 and R4 can be same or different. The substance can confirm that the compounds have good tyrosine kinase inhibition activity by tyrosine kinase inhibition activity evaluation, and can be taken as a candidate medicine for preventing and treating tumor diseases.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a class of novel compounds, in particular to a class of 2-indolinone derivatives (general formula I), their geometric isomers, their pharmaceutically acceptable salts and the preparation methods of these compounds and their role in preventing and treating tumors. application in disease. Background technique [0002] Tumor is a major disease that threatens human health. The number of patients who die from malignant tumors every year in the world accounts for the second place in the number of deaths from all diseases. The research of anticancer drugs has been paid close attention to all over the world. Traditional chemotherapy drugs can non-specifically block cell division or directly cause cell death, so while killing tumor cells, they also destroy normal human cells. With the in-depth understanding of the mechanism of tumorigenesis and development, it has become an important direction of a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06A61K31/4184A61K31/5377A61P35/00
Inventor 杨晓明王林刘靖李长燕颜海燕术凌飞张首国李围温晓雪詹轶群彭涛李鲁
Owner INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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