3-(4,5-substituted pyrimidinamine) phenyl derivatives and application thereof

A technology of haloalkyl and oxoalkyl, applied in the field of 3-phenyl derivatives and its application in the preparation of antitumor drugs, can solve wild-type cytotoxic side effects, poor selectivity, and low clinically tolerated dose of drugs, etc. question

Active Publication Date: 2017-06-09
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 re

Method used

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  • 3-(4,5-substituted pyrimidinamine) phenyl derivatives and application thereof
  • 3-(4,5-substituted pyrimidinamine) phenyl derivatives and application thereof
  • 3-(4,5-substituted pyrimidinamine) phenyl derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090]

[0091] The synthetic route is as follows:

[0092]

[0093] Compound FHND004‐03‐1

[0094] Take 150mL sealed tube, add dimethylamine (40% in water) (8.87g, 78.76mmol), THF (80mL) respectively, and then add 1‐benzhydryl‐3‐methanesulfonic acid azetidine (25g , 78.76mmol) was refluxed and stirred for 8h, TLC monitored that no raw material was left, and the solvent was distilled off under reduced pressure to obtain (FHND004‐03‐1) as 10g of colorless liquid.

[0095] Compound FHND004‐03‐2

[0096] Take a 250mL single-necked flask, add (FHND004‐03‐1) (10g, 37.54mmol), Pd / C (1.05g, 7.5mmol), MeOH (100mL), vacuumize and change hydrogen 3 times, stir overnight at room temperature, and monitor by TLC No raw material remained, and the Pd / C was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a yellow-green solid, which was purified by column chromatography, eluent (DCM: MeOH: NH 3 h 2 O=10:1:0.1) was eluted to obtain 3.5 g of a ...

Embodiment 2

[0105]

[0106] The synthetic route is as follows:

[0107]

[0108] Compound FHND004‐04‐1

[0109] Take a 50mL single-necked flask, add TEA (3.99g, 39.47mmol), DCM (20mL), 1-benzhydryl-3-hydroxymethyl-azetidine (5g, 19.73mmol) and then MsCl (4.52 g, 39.47mmol) was slowly added dropwise to the reaction solution at 0°C, and continued to stir at room temperature for 2h. TLC monitored that no raw material remained, and the solvent was distilled off under reduced pressure to obtain (FHND004‐04‐1) as a colorless liquid 8g .

[0110] Compound FHND004‐04‐2

[0111] Take a 50mL sealed tube, add (FHND004‐04‐1) (8g, 24.14mmol), dimethylamine (40% in water) (10.88g, 96.55mmol), THF (10mL), reflux and stir for 6h, TLC monitoring has no The raw material remained, and the solvent was distilled off under reduced pressure to obtain a yellow-green liquid, which was purified by column chromatography, eluent (DCM: MeOH: NH 3 h 2 O=10:1:0.1) was eluted to obtain 6 g of yellow liquid pr...

Embodiment 3

[0122]

[0123] The synthetic route is as follows:

[0124]

[0125] Compound FHND004‐05‐2

[0126] Take 120mL sealed tube, add (FHND004‐05‐1) (2.0g, 4.77mmol), 1‐methylpiperazine (477.16mg, 4.77mmol), DIPEA (0.92g, 7.16mmol), DMA (10mL). Then the tube was sealed and reacted at 140°C for 6 hours. TLC monitored that there was no raw material remaining. The reaction liquid was cooled to room temperature, 20 mL of water was added to precipitate a solid, filtered, and then the filter cake was added to 2 mL of methanol for beating and washing, filtered, and dried to obtain a red solid product ( FHND004-05-2) 1.9g.

[0127] Compound FHND004‐05‐3

[0128] Take a 50mL single-necked flask, add (FHND004‐05‐2) (1.9g, 3.80mmol), Pd / C (404.75mg, 0.38mmol), MeOH (20mL), vacuumize and change hydrogen 3 times, stir overnight at room temperature, TLC Monitor that there is no raw material remaining, remove Pd / C by filtration, and distill off the solvent under reduced pressure to obtain...

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PUM

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Abstract

The invention discloses 3-(4,5-substituted pyrimidinamine) phenyl derivatives and application thereof. The 3-(4,5-substituted pyrimidinamine) phenyl derivatives are compounds having a structure as shown in a formula (I) or pharmacologically acceptable salts of the compounds; the compounds or the salts thereof can be used for treating or preventing diseases or states of illnesses by means of certain mutant forms of epidermal growth factor receptors (EGFRs), can effectively inhibit the growth of multiple tumor cells and have an inhibiting effect for other protease of EGFR and Her families, thus being used for preparing antitumor drugs. The formula I is described in the description.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, and in particular relates to 3-(4,5-substituted aminopyrimidine) phenyl derivatives and their application in the preparation of antineoplastic 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...

Claims

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Application Information

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IPC IPC(8): C07D471/06A61K31/506A61P35/00A61P35/02
CPCC07D471/06
Inventor 朱永强刘兆刚冯超王佳陈浩胡诗合
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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