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N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof

A methyl and amino technology, applied in the field of N--4--2-pyrimidinamine derivatives, can solve the problems of short half-life, poor controllability, instability, etc.

Active Publication Date: 2008-08-20
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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  • N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof
  • N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof
  • N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]acetic acid-2-nitrooxyethyl ester (I 1 )

[0063] 2-Nitroxyethanol

[0064] Under ice bath and nitrogen protection, ethylene glycol (2.48g, 40mmol) was dissolved in 100ml of ethyl acetate, and concentrated nitric acid (4.36g, 45mmol), 12ml of glacial acetic acid, and 10ml of acetic anhydride were added successively. Stir overnight at room temperature. Adjust the pH to neutral with 10% aqueous sodium bicarbonate solution, separate the organic layer, wash with saturated brine, dry over anhydrous potassium carbonate, and concentrate to obtain a yellow oily crude product. Column chromatography (ethyl acetate:petroleum ether=2:1) ​​yielded 1.78g.

[0065] 2-Nitrooxyethyl bromoacetate

[0066] 2-Nitroxyethanol (1.42g, 13.27mmol) was dissolved in 40ml of anhydrous dichloromethane, bromoacetic acid (1.83g, 13.27mmol) was added under ice cooling, stirred and dissolved, DCC (2.74g, 13.30mmol) was added in batches ) an...

Embodiment 2

[0071] N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]acetic acid-6-nitrooxyhexyl ester (I 5 )

[0072] With reference to the preparation method of Example 1, N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]acetic acid is prepared from 1,6-hexanediol as starting material -6-Nitroxyhexyl ester, yield: 58.64%, mp: 123.07-124.8°C.

[0073] ESI-MS m / z: 481, 504 [M+Na] + ;

[0074] IR (KBr, v (cm -1 )): 3407(N-H), 3038(C-H, Ar), 1724(C=O), 1579(C=C), 1453(N-H), 1118(C-O-C), 1007(N-H)

[0075] 1 H-NMRδ (ppm): 9.3 (d, 1H, J = 1.81.NH), 8.7 (m, 2H), 8.4 (m, 2H,), 7.5 (dd, 1H, J1 = 4.76, J2 = 7.94), 7.4 (d, 1H, J = 5.13), 6.9 (d, 1H, J = 8.20), 6.8 (d, 1H, J = 2.07), 6.3 (dd, 1H, J = 210, J = 8.06), 5.87 ( s, 1H), 4.76(dd, 2H, J1=3.24, J2=5.40), 4.43(m, 8H), 3.94(d, 2H, J1=6.38), 2.1(s, 3H), 1.89(m, 2H )

Embodiment 3

[0077] N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl]acetic acid-10-nitroxydecyl ester (I 9 )

[0078] Referring to the preparation method of Example 1, it is prepared from 1,10-decanediol as a starting material, N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]-phenyl] 10-Nitroxydecyl acetate, yield 53.43%, mp: 145.3-146.7°C.

[0079] ESI-MS m / z: 524[M+1] + , 546[M+Na] + ;

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Abstract

The invention provides an N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine derivative, in particular to a compound which is obtained by connecting the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine with an NO(nitric oxide) supply body for nitrate esters by ester bonds or amide bonds. The compound is obtained by coupling the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and the corresponding NO supply body for nitrate esters by different connecting groups for carrying out substitution reaction. The dual-coordination anti-tumor mechanism demonstrates good functions on inhibiting the cell apoptosis or inducing the apoptosis of tumor cells.

Description

technical field [0001] The present invention relates to N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine derivatives, in particular to N-(5-amino-2-methylphenyl) -Coupling derivatives of 4-(3-pyridyl)-2-pyrimidinamine and nitrate NO donors. The present invention also relates to the preparation method of these compounds and their application in the preparation of antitumor drugs. Background technique [0002] Protein tyrosine kinase (PTK) is a class of proteins with tyrosine kinase activity strictly controlled in vivo, which can catalyze the transfer of the γ-phosphate group on adenosine triphosphate (ATP) to many proteins related to cell life activities Phosphorylation of tyrosine residues in the cell, thereby regulating a series of physiological processes such as cell growth, differentiation, and apoptosis. Dysregulation of PTKs function causes a series of diseases in organisms. Existing data show that more than 70% of proto-oncogenes...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/506A61P35/00
Inventor 董伟兵周微张广明
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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