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3-(4,5-substituted aminopyrimidine)phenyl derivatives and their applications

A drug and application technology, applied to 3-phenyl derivatives and its application field in the preparation of antitumor drugs, can solve the problems of low clinical tolerance of drugs, poor selectivity, and inability to solve clinical needs of drug resistance.

Active Publication Date: 2020-03-17
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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  • 3-(4,5-substituted aminopyrimidine)phenyl derivatives and their applications
  • 3-(4,5-substituted aminopyrimidine)phenyl derivatives and their applications
  • 3-(4,5-substituted aminopyrimidine)phenyl derivatives and their applications

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 a 150mL sealed tube, add dimethylamine (40% in water) (8.87g, 78.76mmol), THF (80mL), and then 1-dibenzyl-3-methanesulfonic acid azetidine (25g) , 78.76mmol) refluxed and stirred for 8h, no raw material remained in TLC monitoring, and the solvent was distilled off under reduced pressure to obtain (FHND004-03-1) as a colorless liquid 10g.

[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), vacuum for 3 times hydrogen, stir at room temperature overnight, TLC monitoring No raw material remained, 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) eluted to obtain 3.5 g of a yellow liquid product (FHND004-03-2).

[0097] C...

Embodiment 2

[0105]

[0106] The synthetic route is as follows:

[0107]

[0108] Compound FHND004‐04‐1

[0109] Take a 50mL single-necked flask, respectively add TEA (3.99g, 39.47mmol), DCM (20mL), 1-dibenzyl-3-hydroxymethyl-azetidine (5g, 19.73mmol) and then MsCl (4.52 g, 39.47 mmol) was slowly added dropwise to the reaction solution at 0 °C, and continued to stir at room temperature for 2 h. TLC monitoring showed that no raw materials 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 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 is no longer 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) eluted to obtain 6...

Embodiment 3

[0122]

[0123] The synthetic route is as follows:

[0124]

[0125] Compound FHND004‐05‐2

[0126] A 120 mL sealed tube was taken, and (FHND004-05-1) (2.0 g, 4.77 mmol), 1-methylpiperazine (477.16 mg, 4.77 mmol), DIPEA (0.92 g, 7.16 mmol), DMA (10 mL) were added. Then the tube was sealed at 140°C and reacted for 6h. TLC monitored no remaining raw materials. The reaction solution was cooled to room temperature, 20 mL of water was added, and the solid was precipitated, filtered, and then the filter cake was added to 2 mL of methanol to beat and wash, filter, and dry 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), vacuum for 3 times hydrogen, stir at room temperature overnight, TLC After monitoring that no raw material remained, Pd / C was removed by filtration, and the solvent was distilled off under reduced pressure to...

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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 anti-tumor drugs, and particularly relates to 3-(4,5-substituted aminopyrimidine) phenyl derivatives and their application in the preparation of anti-tumor drugs. Background technique [0002] In the traditional cancer treatment process, chemotherapy is the main treatment method; chemotherapeutic drugs non-specifically block cell division and cause cell death. While killing tumor cells, they also greatly destroy the growth of normal cells in the human body. Many adverse reactions. Many people feel pessimistic or even give up treatment because of 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 only increases the toxic and side effects. did not increase efficacy. At the same time, the cancer cells of non-small cell lung cancer are not sensitiv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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