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Deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives, and applications thereof

A use and drug technology, applied in the field of anti-tumor drugs, can solve the problems of wild-type cytotoxic side effects, unable to solve the clinical needs of drug resistance, and low clinical tolerance of drugs.

Inactive Publication Date: 2018-03-27
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these molecules have poor selectivity to the T790M mutant of EGFR, resulting in a low clinically tolerated dose of the drug. At its maximum tolerated dose (MTD), the drug cannot reach its effective concentration in the body, making it ineffective for most drug-resistant patients
[0004] In short, the current EGFR-TKI still cannot solve the clinical needs caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinolineamine Toxic side effects caused by poor selectivity of wild-type cells are also inevitable
Therefore, there is an urgent need for new types of compounds, especially compounds with novel skeletons, to solve problems such as drug resistance and poor selectivity.

Method used

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  • Deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives, and applications thereof
  • Deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives, and applications thereof
  • Deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] The synthetic route is as follows:

[0041]

[0042] Compound 1

[0043]

[0044] Take a 250mL single-necked flask, add N-methylethanolamine (10g, 133.1mmol), TEA (26.9g, 266.3mmol), acetonitrile (100mL) respectively, and then slowly add benzyl chloride (23.9g, 139.8mmol) at 0°C Slowly added dropwise to the reaction solution, and continued to stir at room temperature for 1 h. TLC monitored that no raw material remained, and the solvent was distilled off under reduced pressure, and purified by column chromatography to obtain 21 g of a colorless liquid, namely compound 1, with a yield of 95.5%.

[0045] Compound 2

[0046]

[0047] Take a 250mL eggplant-shaped bottle, add compound 1 (21g, 127.1mmol), TEA (25.7g, 254.2mmol) and DCM (100ml), and then add MsCl (14.6g, 127.1mmol) dropwise at 0°C. The reaction solution was stirred at room temperature for 3 h, no raw materials were detected by TLC, the solvent was evaporated under reduced pressure, and pu...

Embodiment 2

[0078]

[0079] The synthetic route is as follows:

[0080]

[0081] Compound 12

[0082]

[0083] Take 120mL sealed tube and add compound 8 (500mg, 1.19mmol), N-methylethanolamine (107.26mg, 1.42mmol), DIPEA (307.59mg, 2.38mmol), DMA (5mL). Then seal the tube and react at 140°C for 6 hours. TLC monitors that there is no raw material remaining. Cool the reaction solution to room temperature, add 20mL of water, precipitate a solid, filter, then add the filter cake to 2mL of methanol for beating and washing, filter and dry to obtain 480mg of reddish-brown solid Namely compound 12, the yield is 85%.

[0084] Compound 13

[0085]

[0086] Take a 20 mL eggplant-shaped bottle and add compound 12 (450 mg, 1.05 mmol), TEA (159.39 mg, 1.57 mmol) and DCM (5 ml). Slowly add MsCl (120.28mg, 1.05mmol) dropwise at 0°C. After the dropwise addition, stir at this temperature. After 1h, TLC monitors that there is no raw material remaining. The solvent is distilled off under reduc...

Embodiment 3

[0098]

[0099] The synthetic route is as follows:

[0100]

[0101] Compound 17

[0102]

[0103] Take a 2L three-necked bottle and add CD respectively 3 OH (15 g, 415.8 mmol), THF (600 mL). Then n-BuLi (174.6 mL, 436.6 mmol) was slowly added dropwise at -40°C. After stirring for 1 h, a tetrahydrofuran solution of TsCl (79.3 g, 415.8 mmol) was added dropwise. After the addition was completed, stirring was continued for 3 h, and no raw material remained as monitored by TLC. Add 600mLH 2 O quenching, EA extraction (200mL*3), brine washing, anhydrous Na 2 SO 4 After drying, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain a crude compound, which was purified by column chromatography to obtain 73 g of a white solid, compound 17, with a yield of 92.7%.

[0104] Compound 18

[0105]

[0106] Take a 250mL eggplant-shaped bottle and add compound 17 (8g, 42.3mmol), N-benzylethanolamine (5.3g, 35.2mmol), triethylamine...

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Abstract

The present invention discloses a class of deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives, and applications thereof, wherein the deuterated 3-(4,5-substituted amino pyrimidine)phenyl derivatives are compounds having a structure represented by a formula (I) or pharmaceutically acceptable salts thereof, and the compounds or the salts thereof can be used for the treatment or prevention of diseases or conditions through epidermal growth factors with mutated forms, can effectively inhibit the growths of a variety of tumor cells, can inhibit other proteases of EGFR and Her family,and can be used for preparing antitumor drugs. The formula (I) is defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of antitumor drugs, in particular to deuterated 3-(4,5-substituted aminopyrimidine) phenyl derivatives and their application in the preparation of antitumor drugs. Background technique [0002] In the traditional cancer treatment process, chemotherapy is the main treatment method; chemotherapy drugs non-specifically block cell division and cause cell death. While killing tumor cells, they also greatly destroy the growth of normal human cells, resulting in Many adverse reactions. Many people feel pessimistic or even give up treatment because they are worried about the serious side effects of chemotherapy. Coupled with the drug resistance of chemotherapy drugs, the chemotherapy of non-small cell lung cancer (NSCLC) is not optimistic, and prolonging the cycle of chemotherapy will only increase the toxicity and side effects. did not increase efficacy. At the same time, cancer cells of non-small cell lung cance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/06A61K31/506A61P35/00A61P35/02
CPCC07D471/06
Inventor 朱永强刘兆刚冯超陈浩白恩赫王佳石晶淼
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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