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Phenyl urazan nitrogen nitric oxide donor 2-aniline pyrimidine derivatives, preparation method, compound containing the same and use thereof

A compound and oxide technology, applied in the field of novel phenylfurazan nitrogen monoxide donor 2-aniline pyrimidine derivatives, can solve the problems of poor controllability, short half-life, instability, etc.

Active Publication Date: 2011-09-21
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as a gas signal molecule, NO has a short half-life in the body, is unstable, and has poor controllability. Therefore, more and more researches focus on using specific carriers to couple with NO donors to release NO in specific parts of the body. achieve the effect of killing cancer cells

Method used

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  • Phenyl urazan nitrogen nitric oxide donor 2-aniline pyrimidine derivatives, preparation method, compound containing the same and use thereof
  • Phenyl urazan nitrogen nitric oxide donor 2-aniline pyrimidine derivatives, preparation method, compound containing the same and use thereof
  • Phenyl urazan nitrogen nitric oxide donor 2-aniline pyrimidine derivatives, preparation method, compound containing the same and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (A) and compound intermediate of general formula (II)

[0072] Preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (A)

[0073] Add N,N-dimethylformamide dimethyl acetal (N,N-dimethylformamide dimethyl acetal) (156.5g, 1.27mol) to 3-acetylpyridine (100g, 0.826mol) and reflux for 23 hours, then cool to 0°C , add the mixed solution diethyl ether and n-hexane (3:2, v / v) (500ml), stir for 4 hours, filter the obtained solid and rinse with diethyl ether and n-hexane (3:2, v / v) (400ml), dry to obtain 3-Dimethylamino-1-(3-pyridyl)-2-propen-1-one;

[0074] 2-Methyl-5-nitroaniline (100g, 0.657mol) was dissolved in 250ml of absolute ethanol, at 30-40°C, 65% nitric acid (54.5ml, 0.788mol) was added dropwise within 1 hour, when the exothermic When the reaction stopped, cyanamide: water (42g: 42g) was added thereto, the brown solution was refluxed for 24 hours, cooled to 0°C, filtered, eth...

Embodiment 2

[0100] 2-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]acetic acid-4-phenyl-1,2,5-oxadiazole-2 -Oxide-3-methyl ester

[0101] 3-Hydroxymethyl-4-phenyl-1,2,5-oxadiazole-2-oxide (2) (2.4g, 12.5mmol) was dissolved in 40ml of anhydrous dichloromethane, and bromoacetic acid ( 1.91g, 13.74mmol), DCC (3.86g, 18.74mmol) and a catalytic amount of DMAP were added in batches under an ice bath and stirred to dissolve, stirred at room temperature for three hours, filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain Light yellow solid 3-bromoacetic acid (-4-phenyl-1,2,5-oxadiazole-2-oxide) methyl ester 3.58g. Yield 91.8%. N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (2.22g, 8.01mmol) and triethylamine (1.45ml, 10.41mmol) were dissolved in 50ml of chloroform , after stirring to dissolve, add 3-bromoacetic acid (-4-phenyl-1,2,5-oxadiazole-2-oxide) methyl ester 3.01g, 9.62mmol) and polyethylene g...

Embodiment 3

[0107] 3-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]methyl-4-phenyl-1,2,5-oxadiazole- Synthesis of 2-oxides

[0108] N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (A) (2.77g, 10mmol) was dissolved in anhydrous potassium carbonate (1.79g, 13mmol) In 60ml tetrahydrofuran, after stirring for 20 minutes, add 3-chloromethyl-4-yl-1,2,5-oxadiazole-2-oxide (3) (2.10g, 10mmol) and a catalytic amount of tetrabutyl Ammonium bromide (TBAB) was heated to reflux for 4 hours. Filtration, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with 10% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, column chromatography (ethyl acetate:petroleum ether=5:1), ethyl acetate Crystallization gave 3-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]methyl-4-phenyl-1,2,5-oxadi Azole-2-oxide 1.35 g. Yield 74.83%, mp: 154.9-157.0°C, ESI-MS m / z: 451, 474 [M+Na] + ;

[0109] IR (KBr, v (cm -1 )) 3257(N-H), 302...

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Abstract

The present invention discloses a compound used as a general formula (I) of protein kinase inhibitor, the salt accepted pharmaceutically and the preparation method; wherein, X is -(CH2)m-COO-; m is equal to 1 to 5 or direct bond; Y is -(CH2)n-O- or -(CH2)n-PhO-; n is equal to1 to 10 or direct bond; the preparation method comprises a step which uses N-(5-amino-2- methyl-phenyl)-4- (3-pyridyl)-2-pyrimidinamine and general formula (II) compound as raw material synthesis. The present invention also discloses the preparation method of the compound, comprising the compound and the treatment of being used as tyrosine protein kinase inhibitor in diseases such as cancer relative to tyrosine in particular to Bcr-Abl.

Description

technical field [0001] The present invention relates to a novel phenylfurazan nitric oxide (NO) donor 2-aniline pyrimidine derivative, its preparation process, as a tyrosine protein kinase inhibitor for cancer, etc. and tyrosine kinase, especially Bcr -Treatment of Abl-related diseases. It specifically relates to the synthesis of NO donor and 2-aniline pyrimidine coupling compound through bromoacetic acid or direct coupling, and its application in antitumor activity. Background of the invention [0002] Cancer is a great threat to human health. With the development of life sciences, molecular biology, and cytology, processes such as signal transduction, cell cycle regulation, and apoptosis induction in malignant tumor cells have been gradually elucidated. Taking some key enzymes in the cell signal transduction pathways related to the differentiation and proliferation of tumor cells as drug screening targets, the development of new anti-tumor drugs that selectively act on sp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14A61K31/506A61P35/00
Inventor 董伟兵周微张广明
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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