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2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds

A tri-substituted, pyrimidine technology, applied in the field of medicinal chemistry, to achieve the effect of good anti-tumor effect and good inhibitory effect

Active Publication Date: 2015-07-29
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no FGFR inhibitor with pyrimidine as the core in the market, so it is urgent to develop an FGFR inhibitor with pyrimidine as the core

Method used

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  • 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds
  • 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds
  • 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of N-{4-{{2-{[4-methylpiperazin-1-yl]phenyl}amine}-5-nitropyrimidin-4-yl}benzene}acetamide (compound 1)

[0037]

[0038] (1) Preparation of N-{4-[(2-chloro-5-nitropyrimidin-4-yl)amine]phenyl}acetamide

[0039]

[0040] Under the condition of ice bath, 2,4-dichloro-5-nitropyrimidine (5g, 25.7mmol) was dissolved in dichloromethane (100ml), and N,N-diisopropylethylamine (4.3ml , 25.7mmol) and acetaminoaniline (3.87g, 25.7mmol). The ice bath was removed, and the reaction mixture was reacted at room temperature for 5 h, and then saturated brine (200 ml) was added. The mixture was extracted with dichloromethane (300ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated to obtain a solid. The product was not further purified to obtain 6.34 g of a red solid with a yield of 90.0%.

[0041] (2) Preparation of N-{4-{{2-{[4-methylpiperazin-1-yl]phenyl}amine}-5-nitropyrimidin-4-yl}benzene}acetamide (compound 1)

[0042] ...

Embodiment 2

[0044] Example 2 N-{4-{{5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl}amine}phenyl}acetamide (Compound 2) Preparation

[0045]

[0046] (1) Preparation of N-{4-[(2,5-dichloropyrimidin-4-yl)amine]phenyl}acetamide

[0047] Weigh paracetamol (1.31g, 8.72mmol) and dissolve it in DMF (20ml), then add anhydrous potassium carbonate (2.42g, 17.5mmol) and 2,4,5-trichloropyrimidine (1.0ml, 8.72mmol) . The reaction mixture was heated to 60°C for 2h. After the reaction was completed, it was cooled to room temperature, and a large amount of ice water was added to precipitate a solid, which was filtered by suction and dried. The product was not further purified, and 2.3 g was obtained with a yield of 90%.

[0048] (2) N-{4-{{5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl}amine}phenyl}acetamide preparation of

[0049] Weigh N-{4-[(2,5-dichloropyrimidin-4-yl)amine]phenyl}acetamide (1.6g, 5.45mmol), 4-methylpiperazine aniline (1.24g, 6.46mmol) ...

Embodiment 3

[0055] Example 3 Determination of Compounds on FGFR Kinase Activity

[0056] The inhibitory activity of the compound on FGFR1 was determined by the LANCE ULTRA Assay method, and compared with the positive control drug, the compound with good activity was screened out. FGFR1 was purchased from CARNA Corporation.

[0057] Specific method: the tested compound, ATP, specific substrate and FGFR1 kinase are diluted with kinase diluent. Kinase reaction mixture contains FGFR1, ATP, substrate, HEPES (PH=7.5), MgCl 2 , EGTA, Tween-20. The group without any compound was used as the 100% phosphorylation control, and the EDTA termination reaction group immediately after adding FGFR1 kinase was used as the 0% phosphorylation control. After co-incubating the kinase reaction mixture for 1 h at room temperature, EDTA was added to stop the reaction for 5 min. Add the specific antibody again, continue co-incubating at room temperature for 1 h, and detect the excitation light with a PerkinElm...

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Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and an application of the 2,4,5-trisubstituted pyrimidine compounds. The compounds can selectively inhibit phosphorylation of FGFR kinase so as to be used for treating malignant tumors closely related with the kinase, and can reduce adverse reactions; the compounds can be used for treating tumors related with the FGFR kinase or relevant diseases. The general formula of the 2,4,5-trisubstituted pyrimidine compounds is shown in the specification, wherein R<1>, R<2> and R<3> can be selected from multiple substituents and can be combined randomly. The 2,4,5-trisubstituted pyrimidine compounds taking the FGFRs as the targets have a good inhibition function on the FGFR1 kinase, have an anti-proliferation function on FGFR1-dependent tumor cell line KG1 cells, can be used for preparing antitumor drugs and have better antitumor effects.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of 2,4,5-trisubstituted pyrimidine compounds targeting FGFR, a preparation method and application thereof. Background technique [0002] In the field of protein kinases, the FGFR family of fibroblast growth factor receptors is a very attractive target in cancer therapy. The FGFR family of receptor tyrosine kinases includes four members, FGFR1, FGFR2, FGFR3 and FGFR4. They have a high degree of similar sequence homology. Dysregulation of FGFR kinase is closely related to various malignant tumors, such as breast cancer, bladder cancer, gastric cancer, prostate cancer, rectal cancer and other cancers. Therefore, oncology medicine continues to study and diagnose and treat cancer. [0003] Inhibition of disease-related protein kinases, blocking and destroying the signal transmission of tumor cells, can be achieved through a variety of methods, but because the sy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/50C07D239/48C07D403/12A61K31/506A61K31/5377A61P35/00
CPCC07D239/48C07D239/50C07D403/12
Inventor 梁广刘志国王怡陈凌锋蔡跃飘冯建鹏张亚丽李校堃
Owner WENZHOU MEDICAL UNIV
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