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Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of drug resistance and lack of selectivity in patients

Inactive Publication Date: 2015-12-23
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical use has found that after an average of 10 months of treatment with EGFR inhibitors such as gefitinib and erlotinib, patients will develop drug resistance. Studies have shown that drug resistance is related to EGFR gene T790M, L858R mutations and MET oncogenes
At the same time, the first-generation EGFR inhibitors lack the selectivity between wild-type EGFR and mutant EGFR

Method used

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  • Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof
  • Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof
  • Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-(1-methylcarbamoylbenzene base))-1,3,5-triazine-2-amino)phenyl)acrylamide

[0089]

[0090] Step 1: Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine

[0091]

[0092] In a 100ml reaction flask, add 4-fluoro-2-methoxy-5-nitroaniline (4.0g, 21.5mmol) and DIPEA (8.32g, 64.5mmol) successively, dissolve with 60ml tetrahydrofuran, cool to 0-2 ℃, add 2,4-dichloro-1,3,5-triazine (3.14g, 21.08mmol) in batches, after the addition is complete, react for 5h, stop the reaction, add 60ml of water, stir, filter, and wash the filter cake with water, The title compound was dried and used directly in the next step.

[0093] Step 2: N-(4-fluoro-2-methoxy-5-nitrophenyl)-3-(1-N-methyl-benzoyl)-1,3,5-triazine-2- Amine Synthesis

[0094]

[0095] In a 30ml microwave reaction vial, add 3-(N-methylformamido)phenylboronic acid (900mg, 5.03mmol) and 4-chloro-N-(4-fluoro-2-methoxy ...

Embodiment 2

[0106]Example 2N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3,4-(methylenedioxy )phenyl))-1,3,5-triazine-2-amino)phenyl)acrylamide

[0107]

[0108] With 4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4-(methylenedioxy)phenylboronate, Using N,N,N'-trimethylethylenediamine and allyl chloride as raw materials, the title compound was prepared according to the method in Example 1.

[0109] 1 H-NMR (500MHz, DMSO-d 6 )δ:2.25(6H,d),2.40(2H,s),2.70(4H,s),2.91(2H,m),3.81(3H,s),5.74-5.76(1H,d),6.12(2H ,s),6.27-6.30(1H,m),6.40-6.45(1H,m),7.02(2H,s),7.90(1H,s),8.09-8.14(1H,d),8.66(1H,s ), 8.90-8.95(1H,s), 10.02(1H,s).

[0110] ESI-Msm / z: 492.3 [M+H].

Embodiment 3

[0111] Example 3N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxyphenyl)-1 ,3,5-triazine-2-amino)phenyl)acrylamide

[0112]

[0113] With 4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxyphenyl borate, N,N,N'- Using trimethylethylenediamine and allyl chloride as raw materials, the title compound was prepared according to the method in Example 1.

[0114] 1 H-NMR (300MHz, DMSO-d 6 )δ:2.21(s,6H),2.36-2.39(t,2H),2.68(s,3H),2.88-2.89(t,2H),3.80(s,3H),3.82(s,3H),5.73 -5.77(d,1H),6.23-6.29(d,1H),6.39-6.48(dd,1H),6.99-7.04(m,3H),8.28(s,1H),8.39-8.42(m,2H) , 8.64 (s, 1H), 8.96 (brs, 1H), 10.10 (s, 1H).

[0115] ESI-Msm / z: 478.3 [M+H].

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Abstract

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a class of phenyl substituted triazine compounds having epidermal growth factor receptor inhibition effects, a pharmaceutical composition containing the compound, and uses of the compounds or the pharmaceutical composition as cancer treatment drugs. According to the present invention, the compounds have good inhibition activity on mutant EGFR kinase, exhibit excellent selectivity, and are expected to be the drugs providing specific treatment effects on drug resistance tumors, especially EGFR mutation-causing drug resistance tumors.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of phenyl-substituted triazine compounds with epidermal growth factor receptor inhibitory effects, a pharmaceutical composition containing the compound, and the compound or pharmaceutical composition as a drug for treating cancer use. Background technique [0002] Epidermal Growth Factor Receptor (EpidermalGrowthFactorReceptor, EGFR) is the expression product of the proto-oncogene C-erbB-1, and is one of the members of the EGFR family. The EGFR family includes four members: EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3) and ERBB4 (HER-4). EGFR is divided into three parts: the extracellular region, the transmembrane region and the intracellular region. The extracellular region is a ligand-binding region composed of 621 amino acids at the amino terminal. When it binds to a ligand, dimerization occurs. Further cross-linked phosphorylation of the receptors activat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D251/22C07D405/04C07D403/04C07D401/04A61K31/53A61P35/00
CPCA61K31/53C07D251/18C07D251/22C07D401/04C07D403/04C07D405/04
Inventor 王勇徐信项仪宾王小伟张小猛蔡建峰廖文辉黄丹丹张仓
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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