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2,4-diarylaminopyrimidine derivatives containing hydroxamic acid fragments and their preparation and application

A technology of diarylaminopyrimidine and hydroxamic acid, applied in the field of 2,4-diarylaminopyrimidine derivatives and its preparation

Inactive Publication Date: 2019-10-01
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the third generation of non-reversible mutation-selective EGFR inhibitors can also cause new C797S mutations in EGFR

Method used

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  • 2,4-diarylaminopyrimidine derivatives containing hydroxamic acid fragments and their preparation and application
  • 2,4-diarylaminopyrimidine derivatives containing hydroxamic acid fragments and their preparation and application
  • 2,4-diarylaminopyrimidine derivatives containing hydroxamic acid fragments and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1N 1 -(3-((2-((4-(4-acetyl-piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl )-N 4 -Hydroxymaleamide hydrochloride

[0064]

[0065] Reagents and reaction conditions: a) N,N-dimethylformamide, 50°C, 3 hours; b) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1 -Hydroxybenzotriazole, N,N-dimethylformamide:dichloromethane=1:2, 45°C, 5 hours; c) 1M hydrochloric acid ether solution, 0°C, 30 minutes to 1 hour.

[0066] Step 1: (Z)-4-((2((2-((4-(4-acetylpiperazinyl)-2-methoxy)amino)-5-chloropyrimidine)amino)phenyl)amino) - Preparation of 4-oxo-2-butenoic acid

[0067] Starting material 1: 2-((2-methoxy-4-(N 4 -Acetylpiperazinyl)-aminophenyl)-4-(3-amino)aminophenyl)-5-chloropyrimidine was prepared according to the method of Nature, 2009, 462, 1070-1074.

[0068] 2-((2-methoxy-4-(N 4 -Acetylpiperazinyl)-aminophenyl)-4-(3-amino)aminophenyl)-5-chloropyrimidine (1mmol) and maleic anhydride (1.2mmol) were dissolved in 15mL dic...

Embodiment 2

[0076] Example 2: N 1 -(3-((2-((4-(4-acetyl-piperazin-1-yl)-phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride

[0077] With reference to the method of Example 1, only (Z)-4-((2((2-((4-(4-acetylpiperazinyl)-2-methoxy)amino)-5- Chloropyrimidine)amino)phenyl)amino)-4-oxo-2-butenoic acid was replaced by (Z)-4-((2((2-((4-(4-acetylpiperazinyl)amino) -5-chloropyrimidine) amino) phenyl) amino) -4-oxo-2-butenoic acid, the 2-((2-methoxy-4-(N 4 -Acetylpiperazinyl)-aminophenyl)-4-(3-amino)aminophenyl)-5-chloropyrimidine was replaced by 2-((4-(N 4 -Acetylpiperazinyl)-aminophenyl)-4-(3-amino)aminophenyl)-5-chloropyrimidine, the N in step 3 1 -(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-pyrimidin-4-yl)amino)phenyl)-N 4 -((tetrahydro-2H-pyran-2-yl)oxo)maleic acid diamine replaced by N 1 -(3-((2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5-pyrimidin-4-yl)amino)phenyl)-N 4 -((tetrahydro-2H-pyran-2-yl)oxo)maleic acid diamine.

[0078] ...

Embodiment 3

[0079] Example 3: 6-(4-(4-((4-((3-acryloyl-aminophenyl)amino)-5-chloropyrimidin-2-yl)amino)-phenyl)piperazine-1- base)-N-hydroxyacetamide hydrochloride

[0080]

[0081] Reagents and reaction conditions: 1) sec-butanol, reflux, 4 hours; 3) trifluoroacetic acid, dichloromethane, 1 hour; 4) acryloyl chloride, dichloromethane, -5-0 ° C, 30 minutes to 1 hour; 5) Tetrahydrofuran: water = 1:1, 1 hour; 6) Dichloromethane: N,N-dimethylformyl = 2:1, 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride, 1-hydroxybenzotriazole, 45°C, 5 hours; 7) 1M hydrochloric acid ether solution, 0°C, 30 minutes to 1 hour.

[0082] Step 1: 2-((2-Methoxy-4-(N 4 Preparation of -acetylpiperazinyl)-aminophenyl)-4-(3-amino)aminophenyl)-3-chloropyrimidine.

[0083] Raw material 1: tert-butyl 4-((2,5-dichloro-4-pyrimidinyl)amino)phenyl)carbamate was prepared according to the method of Cancerdiacovery, 2013, 3, 1404-1415.

[0084] 4-((2,5-dichloro-4-pyrimidinyl)amino)phenyl)carbamate tert-buty...

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Abstract

The invention provides 2,4-diarylamine pyrimidine derivatives containing hydroxamic acid fragments shown in formulas I and II. 2,4-diarylamine pyrimidine containing carboxyl fragments is mainly used as a parent nucleus and is subjected to single-step condensation and related modification with hydroxylamine protected by THP to obtain a target compound. An experiment proves that the remarkable anti-proliferative effect is achieved for tumor cells (a human lung adenocarcinoma cell line H1975 and an overexpression EGFR human epidermal carcinoma cell line A431) related to EGFR tyrosine kinase activity on the cellular level, and a human cervical carcinoma cell line Hela, a human oral epidermoid carcinoma cell line KB, a human promyelocytic acute leukemia cell line HL60, a human hepatoma cell line HepG2, a human colon cancer cell line SW620 and other tumor cells related to the HDAC histone acetylase activity, and the corresponding medicine for resisting cancer cells can be prepared. The general structural formula is shown in the description.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a 2,4-diarylaminopyrimidine derivative containing a hydroxamic acid fragment, a preparation method and application thereof. Background technique [0002] Studies have found that one or more EGFR family receptors are mutated or overexpressed in more than 60% of malignant tumors. Tyrosine kinases play an important regulatory role in the process of cell growth, proliferation and apoptosis. Small-molecule EGFR tyrosine kinase inhibitors compete with ATP to bind to the phosphorylation site in the intracellular region of EGFR, inhibit the autophosphorylation process of EGFR and block downstream signaling pathways, thereby achieving the purpose of inhibiting tumor cells. The first-generation reversible EGFR inhibitors, including gefitinib, have a good effect on patients with non-small cell lung cancer, however, acquired drug resistance appears in clinical use. Because the first-generation inhibi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/48A61K31/506A61K31/505A61P35/00
Inventor 俞永平罗婧陈文腾舒可刘星雨
Owner ZHEJIANG UNIV
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