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2-Indolone derivative with tyrosine kinase inhibition activity, and preparation method and application thereof

A tyrosine kinase and inhibitory activity technology, which is applied in the directions of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as the need to improve the efficiency

Active Publication Date: 2014-12-17
INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above research results show that the drug has important clinical applications, but the effective rate still needs to be improved

Method used

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  • 2-Indolone derivative with tyrosine kinase inhibition activity, and preparation method and application thereof
  • 2-Indolone derivative with tyrosine kinase inhibition activity, and preparation method and application thereof
  • 2-Indolone derivative with tyrosine kinase inhibition activity, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1, 3-[3-(2-dimethylaminoethoxy)-4-methoxybenzylidene]-5-[N-methyl-1-(3-hydroxyl-4-fluoro- Synthesis of anilinosulfo]-2-indolone hydrochloride (T1)

[0135]Add 2 mL of absolute ethanol to 0.1 g (0.3 mmol) of compound M3, add 0.08 g (0.36 mmol, 1.2 eq) of compound M4 under stirring, add two drops of piperidine, reflux in an oil bath for 30 min, and TLC detects that the reaction is complete. After standing overnight, a yellow solid precipitated out, which was filtered by suction, washed with a large amount of absolute ethanol, and detected by TLC as a single point. Dry to obtain 67.8mg, yield 42.4%. The solid was just dissolved in absolute ethanol, and HCl-ether solution was added dropwise until the pH was 2. After standing still, a yellow solid precipitated out. Suction filtration, washing with a large amount of ether until the filtrate is neutral. The yellow solid was dried to yield 52.5 mg. 1H-NMR (400Hz, DMSO-d6) δ (ppm): 2.20 (s, 3H), 2.61 (t, 2H), 3.00 (s...

Embodiment 2

[0137] Example 2, 3-{3-[2-(pyrrol-1-yl)ethoxy]-4-methoxybenzylidene}-5-[N-methyl-1-(3-hydroxyl- Synthesis of 4-fluoro-anilinosulfo]-2-indolone hydrochloride (T2)

[0138] Add 2 mL of absolute ethanol to 0.13 g (0.4 mmol) of compound M3, add 0.12 g (0.48 mmol, 1.2 eq) of compound M5 with stirring, add two drops of piperidine, reflux in an oil bath for 30 min, and TLC detects that the reaction is complete. Separation by column chromatography and gradient elution of dichloromethane-methanol gave 0.14 g of a yellow oil with a yield of 62.5%. The oily substance was just dissolved in absolute ethanol, and HCl-ether solution was added dropwise until the pH was 2. After standing still, a yellow solid precipitated out. Suction filtration, washing with a large amount of ether until the filtrate is neutral. The yellow solid was dried to yield 55.5 mg. 1H-NMR (400Hz, DMSO-d6) δ (ppm): 1.69 (m, 4H), 2.55 (m, 4H), 2.87 (t, 2H), 3.10 (s, 3H), 3.86 (s, 3H), 4.15(t,2H),6.41-6.49(m,1H),6.70...

Embodiment 3

[0140] Example 3, 3-{3-[2-(piperidin-1-yl)ethoxy]-4-methoxybenzylidene}-5-[N-methyl-1-(3-hydroxyl -Synthesis of 4-fluoro-anilinosulfo]-2-indolone hydrochloride (T3)

[0141] Add 2 mL of absolute ethanol to 0.13 g (0.4 mmol) of compound M3, add 0.12 g (0.48 mmol, 1.2 eq) of compound M6 while stirring, add two drops of piperidine, reflux in an oil bath for 30 min, and TLC detects that the reaction is complete. Separation by column chromatography and gradient elution of dichloromethane-methanol gave 0.21 g of a yellow oil with a yield of 91.3%. The oily substance was just dissolved in absolute ethanol, and HCl-ether solution was added dropwise until the pH was 2. After standing still, a yellow solid precipitated out. Suction filtration, washing with a large amount of ether until the filtrate is neutral. The yellow solid was dried to give 24.2 mg. 1H-NMR (400Hz, DMSO-d6) δ (ppm): 1.36-1.51 (m, 6H), 2.43-2.46 (m, 4H), 2.64 (t, 2H), 3.01 (s, 3H), 3.85 (s ,3H),4.05(t,2H),6.42-6.5...

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Abstract

The invention discloses a 2-indolone derivative with tyrosine kinase inhibition activity, geometric isomers and medicinal salts thereof, and a preparation method and an application of the above compounds. Tyrosine kinase inhibition activity evaluation confirms that the derivative is a compound with good tyrosine kinase activity, so the derivative has potential antitumor activity, and can be used to prepare tumor disease prevention and treatment medicines (antitumor medicines) as an active component. The derivative provides research and enforcement foundation for tumor treatment, and has a wide application prospect.

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 having tyrosine kinase inhibitory activity, geometric isomers thereof, medicinal salts thereof, preparation methods of these compounds and their Application in the preparation of drugs (anti-tumor drugs) for the prevention and treatment of tumor diseases. 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 devel...

Claims

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Application Information

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IPC IPC(8): C07D209/34C07D403/12C07D403/06C07D401/06A61K31/404A61K31/454A61K31/496A61K31/4184A61K31/4439A61P35/00A61P35/02
CPCC07D209/34C07D401/06C07D403/06C07D403/12
Inventor 王林王洁颖颜海燕张首国彭涛温晓雪王刚丁锐李鲁
Owner INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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