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5-Chloropyrimidines and their use as EGFR tyrosine kinase inhibitors

A compound, pyrimidine technology, applied in the field of medicine, can solve the problems of drug resistance, difficult to achieve concentration, etc., and achieve the effect of reducing mutation selectivity

Active Publication Date: 2015-08-12
BEIJING HANMI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical trials have shown that the subsequent amplification or high expression of T790M mutations will lead to resistance to these irreversible inhibitors; on the other hand, due to limited pharmacokinetic properties, it is difficult for them to inhibit T790M mutations clinically required concentration

Method used

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  • 5-Chloropyrimidines and their use as EGFR tyrosine kinase inhibitors
  • 5-Chloropyrimidines and their use as EGFR tyrosine kinase inhibitors
  • 5-Chloropyrimidines and their use as EGFR tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Embodiment 1, the preparation of compound

[0136] 1-(3-(3-(5-chloro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidin-4-yloxy)anilino)azetidin-1 -yl)prop-2-en-1-one

[0137]

[0138] 1: 3-(2,5-Dichloropyrimidin-4-yloxy)aniline

[0139] 2,4,5-Trichloropyrimidine (3.67g, 20mmol), m-hydroxynitrobenzene (2.78g, 20mmol) and diisopropylethylamine (7mL, 40mmol) were added to 30mL absolute ethanol. After stirring at room temperature, the system gradually became turbid, and a large amount of off-white precipitates could be seen. After 2 hours, TLC monitoring showed that the raw materials had been basically completely converted. Suction filtration under reduced pressure, the filter cake was washed twice with n-hexane, and dried to obtain 5.32 g (93%) off-white solid.

[0140]Dissolve all the white solid in 30mL tetrahydrofuran, add zinc powder (6g, 93mmol), water (8mL) and ammonium chloride (5g, 93mmol) and heat to reflux for 5 hours, TLC monitoring shows no raw material poin...

Embodiment 2

[0151] Embodiment 2, the preparation of compound

[0152] 4-(4-(3-(1-acryloylazetidin-3-ylamino)phenoxy)-5-chloropyrimidin-2-ylamino)-N-(1-ylpiperazine -4-yl)benzamide

[0153]

[0154] 1: 4-Amino-N-(1-methylpiperidin-4-yl)benzamide

[0155] 1-Methylpiperidin-4-amine (228mg, 2mmol), p-nitrobenzoic acid (335mg, 2mmol) and diisopropylethylamine (1.04mL, 6mmol) were dissolved in N,N-dimethyl In acetamide (10 mL), HATU (1.14 g, 3.0 mml) was dissolved in N,N-dimethylacetamide (10 mL), added to the above reaction solution, and reacted at room temperature for 3 hours. Evaporate N,N-dimethylacetamide under reduced pressure, add saturated aqueous sodium bicarbonate solution (100mL), remove insoluble matter by filtration, neutralize the aqueous phase with 2N hydrochloric acid and extract with dichloromethane, and use saturated brine for the organic phase After washing, drying over anhydrous sodium sulfate, and purification by normal-pressure column chromatography, 500 mg (95.0%) o...

Embodiment 3

[0170] Embodiment 3, cell growth inhibition experiment

[0171] 1. Materials and methods

[0172] Cell growth medium: RPMI1640 (Gibco, 22400089) plus 10% FBS (Gibco, 10099141)

[0173] Detection kit: CCK-8 detection reagent (DojinDo, CK04-20)

[0174] Cell lines: A431 (EGFR WT, Shanghai Cell Bank, Chinese Academy of Sciences), NCI-H1975 (EGFR L858R / T790M, Shanghai Cell Bank, Chinese Academy of Sciences), HCC827 (EGFR Del E746_A750,

[0175] Korea Hanmi Pharmaceutical), Hs-27 (human skin fibroblasts, Korea Hanmi Pharmaceutical)

[0176] TECANIF200 microplate reader

[0177] Invitrogen Countess Cell Counter (C10227)

[0178] 2. Cell Seeding

[0179]Cells in logarithmic growth phase were digested with 0.25% trypsin. A single cell suspension was prepared with RPMI1640 medium containing 10% FBS. Invitrogen Countess for cell counting. A431, NCI-H1975, HCC827 and Hs-27 were seeded in 96-well plates (experimental plate and control plate) at 5000 cells / well / 100uL. Add 100uL me...

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PUM

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Abstract

The invention discloses an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and the structural formula of the inhibitor is shown as in the formula (I). The invention further discloses an application of any compound shown as in the formula (I) and pharmacy-acceptable salt of the compound. The invention further provides a medicine compound for curing, and the medicine compound comprises the compound shown as in the formula (I) and an EGFR modifier.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an EGFR tyrosine kinase inhibitor and application thereof. Background technique [0002] Cancer, also known as malignant tumor, has become the second largest disease that seriously endangers human life and health. According to statistics, among the 6.6 billion people in the world, there are about 10 million new cancer patients every year, and about 5 million people die of cancer, and this number is still showing an increasing trend. According to the "China Cancer Prevention and Control Plan Outline (2004-2010)" issued by the Ministry of Health of China, eight types of cancer, including lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, breast cancer, cervical cancer and nasopharyngeal cancer, accounted for 10% of cancer deaths. More than 80%, it is the main cancer that our country will focus on prevention and treatment in the future. [0003] Studies have f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D401/14C07D401/12C07D403/14C07D413/14A61K31/506A61K31/55A61K31/5377A61K31/541A61K31/551A61P35/00A61P3/10A61P37/02A61P25/00A61P9/00
Inventor 张波李功马涛辛宝娟张烜王鹏文圣焕
Owner BEIJING HANMI PHARMA CO LTD
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