Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof

A technology of benzamide and formamido, applied in the field of Raf kinase inhibitor, can solve the problems of unstable interaction, activation of downstream signals and uncontrolled cell growth.

Active Publication Date: 2016-07-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Normally these amino acid residues are responsible for maintaining the inactive conformation of B-Raf when B-Raf is not phosphorylated, but V599K or V600E mutations destabilize these interactions, causing activation and resulting in potential downstream signaling and cell growth. out of control

Method used

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  • Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof
  • Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof
  • Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] 4-Chloro-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (I-a)

[0126] Add 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 20mmo]) and triethylamine (6.1g, 60mmol) into a 250mL eggplant-shaped flask, add 100mL of anhydrous dichloromethane and stir to dissolve , added p-toluenesulfonyl chloride (2.6g, 24mmol), stirred at room temperature for 5h, and TLC detected that the starting point disappeared. The solvent was distilled off under reduced pressure, separated and purified by column chromatography to obtain 4.85 g of white solid I-a, and the yield was 79.2%. ESI-MSm / z: 308[M+H] + . 1 H-NMR (300MHz, DMSO-d 6 ): δ2.37 (3H, s, CH 3 ), 6.96 (1H, d, ArH, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, ArH, J = 4.0 Hz), 8.82 (1H, s, ArH).

Embodiment 2

[0128] Diethyl 2-[7-(4-methylbenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]malonate (I-b)

[0129] Diethyl malonate (5.3g, 33mmol) was added to a 250mL eggplant-shaped flask, dissolved in 50mL of anhydrous THF, sodium hydride (60%, 800mg, 33mmol) was slowly added under ice-cooling and stirred for 5min, and I-a (1.0g , 3.3mmol) was dissolved in 20mL of anhydrous THF and slowly added to the reaction flask, refluxed for 2.5h, and TLC detected that the raw material point disappeared. Cool to room temperature, pour into 100 mL of saturated ammonium chloride solution, extract with ethyl acetate (50 mL×3), combine the organic layers, wash with saturated sodium chloride (30 mL×3), and dry over anhydrous magnesium sulfate overnight. The solvent was distilled off under reduced pressure and purified by column chromatography to obtain 1.4 g of a colorless oily substance I-b with a yield of 98.6%. ESI-MSm / z: 432[M+H] + .

Embodiment 3

[0131] 2-[7-(4-Methylbenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethyl acetate (I-c)

[0132] Dissolve I-b (850mg, 2mmol) in 50mL of absolute ethanol, add sodium ethoxide (13mg, 0.2mmol), reflux for 2.5h, TLC detects that the raw material point disappears. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol / L), evaporate the solvent under reduced pressure, separate and purify by column chromatography to obtain 530 mg of white solid I-c, yield 77.0%. ESI-MSm / z: 360[M+H] + . 1 H-NMR (300MHz, DMSO-d 6 ): δ1.19 (3H, t, CH 2 C H 3 , J=7.1Hz), 2.36 (3H, s, ArCH 3 ), 4.08 (2H,q,C H 2 CH 3 , J=7.1Hz), 4.34 (2H, s, CH 2 CO), 7.03 (1H, d, ArH, J=4.0Hz), 7.46 (1H, d, ArH, J=8.2Hz), 7.99 (1H, d, ArH, J=4.0Hz), 8.04 (2H, d , ArH, J=8.2 Hz), 8.87 (1H, s, ArH).

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Abstract

The invention relates to novel aromatic amide compounds and a preparation method thereof, a medical composition containing the compounds and medical application of the compounds and the composition, and particularly application of the compounds and composition in serving as Raf kinase inhibitors. The novel compound composition can be used independently or used by combining at least one other drug for treating diseases such as cancers which are regulated by protein kinase. Please see the formula in the description.

Description

field of invention [0001] The present invention relates to a class of novel aromatic amide compounds, 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] Malignant tumors are common and frequently-occurring diseases that seriously threaten human life, and antineoplastic drugs play an important role in the clinical treatment of tumors. In recent years, with the development of molecular biology technology and further understanding of the pathogenesis of tumors, the development of targeted drugs targeting abnormal signal transduction systems in tumor cells has clear targets, few side effects, easy control and oral administration. and so on, significant progress has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D239/42C07D401/12C07D413/12C07D473/00C07D213/81C07D239/28A61K31/519A61K31/505A61K31/506A61K31/44A61P35/00
CPCC07D213/81C07D239/28C07D239/42C07D401/12C07D413/12C07D473/00C07D487/04
Inventor 唐伟方王路陆涛韩伟唐三植陈亚东周湘刘海春
Owner CHINA PHARM UNIV
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