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Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof

A purine and benzamide technology, applied in organic chemistry, antineoplastic drugs, extracellular fluid diseases, etc., can solve the problems of easy transfer and diffusion, low cure rate, and easy recurrence

Inactive Publication Date: 2013-11-13
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] With the development of living standards and medical standards, humans have overcome many diseases, but cancer is still a problem that cannot be completely overcome in medicine. It has distinctive characteristics different from other diseases, such as easy transfer and spread, and easy recurrence after treatment. very high mortality rate
Modern biomedical research tends to explain the proximate cause of cancer, and most cancer treatments directly target cancer cells themselves, such as surgery, radiation therapy and chemotherapy, but the side effects are quite serious, and the overall cure rate is also low. lower

Method used

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  • Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof
  • Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof
  • Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] 6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (P-1)

[0109] Add 2.0g (13mmol) of 6-chloro-9H-purine, 3.3g (39mmol) of 3,4-dihydro-2H-pyran, 50mg (0.3mmol) of p-toluenesulfonic acid and no Add 30 mL of ethyl acetate in water, stir, and heat to reflux for 3 hours. After cooling, excess ethyl acetate was distilled off under reduced pressure to obtain 3.0 g of light yellow oil (P-1), with a yield of 96.7% and a literature yield of 99.3%. The product does not need to be purified and is directly used for the next reaction.

Embodiment 2

[0111] 6-(2-fluoro-3-pyridyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (P-2)

[0112] Add P-13.0g (13mmol), 2-fluoro-3-pyridine boronic acid 2.7g (19.5mmol), NaCO 3 5.5g (51mmol), PdCl 2 (dppf) 180mg (0.24mmol), water 5mL and 1,4-dioxane 35mL, under stirring, N 2 Protection, reflux reaction for 14hr. After cooling, dissolve the reaction solution in 50mL water and 50mL ethyl acetate, let stand, separate the layers, collect the organic layer, extract the water layer with ethyl acetate three times (50mL×3), combine the organic layers and wash with 50mL saturated saline Wash, dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain the crude product. After silica gel column chromatography (developing solvent: ethyl acetate:petroleum ether=1:1), 2.0 g of light yellow solid (P-2) was obtained, yield 51.5%, mp: 125~127°C. MS(LR-ESI): 300.2[M+H] + . 1 HNMR (300MHz, CDCl 3 ): δ1.70~2.23 (6H, m, CH 2 ), 3.82 (1H, t, CH2 O, J=8.2Hz), 4.21 (1H, d, CH 2 O, J...

Embodiment 3

[0114] 4-Methyl-3-nitrobenzoyl chloride (I-1)

[0115] Add 725 mg (4 mmol) of 4-methyl-3-nitrobenzoic acid, 15 mL of thionyl chloride and 2 drops of N, N-dimethylformamide (DMF) into a 100 mL eggplant-shaped flask, and react under reflux for 5 hr with stirring. After cooling, the thionyl chloride was distilled off under reduced pressure to obtain 790 mg of light yellow oil (I-1), with a yield of 91.6%.

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Abstract

The invention relates to a kind of new aramide compounds based on a purine structure, a preparation method thereof, a medicinal composition containing the compounds and a medical application thereof, and particularly relates to an application of the compounds serving as a Raf kinase inhibitor. The composition of the new compounds can be independently used or can be used together with at least one of other medicines for treating the diseases regulated by protein kinase such as cancers.

Description

field of invention [0001] The present invention relates to a class of novel aromatic amides compounds based on purine structure, their preparation method, pharmaceutical composition containing these compounds and their medical application, especially the application as Raf kinase inhibitor. The novel composition of compounds can be used alone or in combination with at least one other drug for the treatment of diseases regulated by protein kinases, such as cancer. Background technique [0002] With the development of living standards and medical standards, humans have overcome many diseases, but cancer is still a problem that cannot be completely overcome in medicine. It has distinctive characteristics different from other diseases, such as easy transfer and spread, and easy recurrence after treatment. The death rate is extremely high. Modern biomedical research tends to explain the proximate cause of cancer, and most cancer treatments directly target cancer cells themselves...

Claims

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Application Information

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IPC IPC(8): C07D473/00A61K31/52A61P35/00A61P35/02A61P7/00
Inventor 唐伟方孙明杰杨巍敏顾亚洲陆涛陈亚东王霆张帆
Owner CHINA PHARM UNIV
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