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Protein tyrosine kinase modulators and methods of use

A technology of selection and pharmacy, applied in the field of pyrimidine compounds, it can solve the problems such as the inability to increase the plasma level of the dose and the small effect of wild-type EGFR

Inactive Publication Date: 2016-03-02
BETTA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This inhibition of wild-type EGFR-induced toxicity prevents the inhibitor from increasing doses to effectively inhibit plasma levels of EGFRT790M
It is currently hoped to develop inhibitors that can recognize specific mutations in EGFR, but have little effect on wild-type EGFR

Method used

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  • Protein tyrosine kinase modulators and methods of use
  • Protein tyrosine kinase modulators and methods of use
  • Protein tyrosine kinase modulators and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] The synthesis of embodiment 1 compound 1

[0334]

[0335] Compound 1a (25g, 0.11mol), Compound 1b (20g, 0.11mol) and K 2 CO 3 (37.5g, 0.22mol) was dissolved in DMF (200ml), and the mixture was stirred at 70°C for 3 hours. Then water (300ml) was added to the mixture, extracted with EA (200ml×3), HCl (1mol / L) was added to the aqueous phase to adjust the pH to 3-4, filtered, and the precipitate was collected and washed with methanol (5ml). After drying in air for 5 hours, 23 g of compound 1c were obtained.

[0336] Under nitrogen protection, put (COCl) in an ice bath 2 (7.2ml(COCl) 2 dissolved in 10 ml DCM) was added to a DCM solution containing compound 1c (5.0 g) and 2 drops of DMF, and stirred. After 3.5 hours the solvent was removed, the residue was dissolved in DCM and 10 ml of ethanol was added. After stirring for 1 hour, the reaction mixture was quenched with water. The organic phase was separated, dried and concentrated. The residue was purified by chro...

Embodiment 2

[0338] The synthesis of embodiment 2 compound 2

[0339]

[0340] A methanol solution of compound 1 and NaOH (0.5 ml, 2 mol / L) was stirred at room temperature for 1 hour. HCl was then added to adjust the solution to a pH of approximately 5. Filtration and drying of the solid afforded compound 2 (37 mg). MS:524.2(M+H) + .

Embodiment 3

[0341] The synthesis of embodiment 3 compound 3

[0342]

[0343] Compound 2 (140mg) and NH 2 A mixture of OH (72mg), PyBOP (180mg) was dissolved in 10ml DMF and stirred at 45°C for 3 hours. The reaction solution was purified by preparative HPLC to obtain 30 mg of solid, namely compound 3. MS:539.2(M+H) + .

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PUM

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Abstract

Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and / or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative,and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.

Description

technical field [0001] The present invention relates to heterocyclic pyrimidine compounds with the activity of regulating the kinase activity of selectively mutated epidermal growth factor receptor (EGFR), which function by regulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemical invasion. More specifically, the pyrimidine compounds provided by the present invention can selectively inhibit, regulate and / or regulate kinase receptors, especially regulate the activities of various EGFR mutants related to the above-mentioned changes in cell activities. The present invention also relates to a pharmaceutical composition containing pyrimidine derivatives, and a method for treating diseases related to protein kinase activity, especially a method for treating diseases related to EGFR kinase activity such as non-small cell lung cancer by administering the pyrimidine derivatives. Background technique [0002] Epidermal growth ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D405/12C07D239/48C07D401/14A61K31/506A61P37/00A61P29/00
Inventor 胡邵京刘湘永白金龙龙伟
Owner BETTA PHARM CO LTD
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