2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application

A technology of arylaminopyrimidine and hydroxamic acid, which is applied in the field of 2-arylaminopyrimidine derivatives, can solve the problems of poor selectivity of proliferation inhibition and adverse drug reactions, and achieve good inhibitory effect

Inactive Publication Date: 2016-06-08
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Effect of second-generation irreversible EGFR inhibitors on human epidermal carcinoma cells A431 with high expression of EGFR WT,overexpression , Gefitinib-resistant human non

Method used

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  • 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application
  • 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application
  • 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1N

[0035] Example 1N 1 -2-fluoro-5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride (compound 1)

[0036]

[0037] Reagents and reaction conditions: 1) dichloromethane, room temperature, 3-5 hours; 2) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotri Azole, dichloromethane:N,N-dimethylformamide=2:1, 45°C, 5 hours; 3) 1M hydrochloric acid ether solution, 30 minutes.

[0038] Step 1: (Z)-4-((2-fluoro-5-((4-(N-methyl-3-indolyl)-2-pyrimidine)amino)phenyl)amino)-4-oxo - Preparation of 2-butenoic acid Raw material 1: 2-(4-fluoro-3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine According to J.Med.Chem.2014,57 , prepared by the method of 8249-8267.

[0039] Dissolve 2-(4-fluoro-3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine (1mmol) and maleic anhydride (1.2mmol) in 15mL dichloroethane , react for 3-5 hours. After the reaction, spin dry under reduced pressure. Recrystallization from acetone gives a...

Embodiment 2

[0048] Example 2N 1 -5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride

[0049] Its structural formula is:

[0050]

[0051] Yellowsolid; m.p.: 181.0-181.4℃; 1HNMR(500MHz,DMSO-d6)δ11.73(s,1H),10.98(s,1H),10.36(s,1H),8.85(s,1H),8.30(d,J=6.6Hz,2H), 8.07(s,1H),7.61(d,J=8.3Hz,1H),7.51(d,J=8.0Hz,1H),7.48–7.45(m,2H),7.39–7.23(m,3H),7.17 (t, J=7.4Hz, 1H), 6.38(d, J=12.1Hz, 1H), 6.24(d, J=12.1Hz, 1H), 3.93(s, 3H).

[0052] 13 CNMR (125MHz, DMSO-d6) δ169.1, 167.0, 158.1, 157.6, 157.3, 156.4, 137.1, 136.6, 135.3, 135.2, 131.9, 130.0, 126.5, 123.3, 122.7, 121.2, 116.0, 115.4, 100.8, 115 33.2. HRMS(ESI)calcd.forC 23 h 21 N 6 o 3 [M+H] + = 429.1670, found 429.1670.

Embodiment 3

[0053] Example 3N 1 -(2-(Dimethylamino)-5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride

[0054] Its structural formula is:

[0055]

[0056] Yellowsolid; m.p.: 217.9–218.3°C; 1 HNMR(500MHz,DMSO-d6)δ10.31(s,3H),7.65(d,J=7.8Hz,1H),7.47–7.39(m,6H),7.24–7.18(m,3H),6.99(s ,1H),6.78(d,J=12.1Hz,1H),6.28(d,J=12.1Hz,1H),3.81(s,3H),3.80(s,1H),2.08–2.01(m,6H) ,1.91(s,1H).HRMS(ESI)calcd.forC 25 h 26 N 7 o 3 [M+H] + = 472.2092, found 472.2095.

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Abstract

The invention provides 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments shown in the formulas I and II. 2-arylamine 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 derivatives has the remarkable anti-proliferative effect on tumor cells (an overexpression EGFR human epidermal carcinoma cell line A431 and a human pulmonary carcinoma cell line H1975 resisting Gefitinib) related to EGFR tyrosine kinase activity on the cellular level, and tumor cells (a human cervical carcinoma cell line Hela, a human hepatoma cell line HepG2, a human promyelocytic acute leukemia cell line HL60, a human oral epidermoid carcinoma cell line KB, a human colon cancer cell line SW620) 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 specifically relates to a 2-arylaminopyrimidine derivative containing a hydroxamic acid segment, a preparation method, an intermediate, and an application thereof. Background technique [0002] Protein tyrosine kinases play an important role in the signal transduction process and participate in the regulation of biological processes such as cell growth, proliferation and apoptosis. Its abnormal expression can lead to cell dysfunction. Epidermal growth factor receptor (EGFR) is a typical receptor with tyrosine kinase activity and a member of the epidermal growth factor (ErbB / HER) family. Current studies have shown that overexpression or mutation of EGFR exists in various solid tumors such as lung cancer, glioblastoma (brain tumor), breast cancer, colorectal cancer, gastric cancer, head and neck cancer, and pancreatic cancer. EGFR overexpression can enhance the signal of downstream signaling pathways....

Claims

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Application Information

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IPC IPC(8): C07D403/04A61P35/00A61P35/02
CPCC07D403/04
Inventor 俞永平罗婧陈文腾刘星雨舒可
Owner ZHEJIANG UNIV
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