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Triazine epidermal growth factor acceptor inhibitor and application thereof

A technology of isomers and solvates, applied in the field of cancer treatment drugs, can solve the problems of drug resistance and lack of selectivity in patients

Active Publication Date: 2016-01-27
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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  • Triazine epidermal growth factor acceptor inhibitor and application thereof
  • Triazine epidermal growth factor acceptor inhibitor and application thereof
  • Triazine epidermal growth factor acceptor inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methylindol-4-yl) -1,3,5-Triazine-2-amino)phenyl)acrylamide

[0109]

[0110] Step a Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine

[0111]

[0112] In a 100ml reaction flask, sequentially add 4-fluoro-2-methoxy-5-nitroaniline (4.0g, 21.5mmol), DIPEA (8.32g, 64.5mmol) and 60ml tetrahydrofuran, dissolve and cool to 0-2 ℃, add 2,4-dichloro-1,3,5-triazine (3.14g, 21.08mmol) in batches, after the addition is complete, continue the reaction for 5h, stop the reaction, add 60ml of water, stir, filter, and wash the filter cake with water , and dried to obtain the title compound, which was directly used in the next step.

[0113] Step bN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-4-yl)-1,3,5-triazin-2-amine synthesis

[0114]

[0115] In a 30ml microwave reaction vial, add 1-methylindole-4-boronate (800mg, 3.11mmol) and 4-chloro-N-(4-fluoro-2-methoxy-5...

Embodiment 2

[0127] Example 2N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methylindol-2yl)- 1,3,5-Triazine-2-amino)phenyl)acrylamide

[0128]

[0129] Step aN-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-2-yl)-1,3,5-triazin-2-amine synthesis

[0130]

[0131] 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine and 1-methyl Using indole-2-boronic acid as starting material, the title compound was prepared according to the method in step b of Example 1.

[0132]Step b2 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methylindol-2yl)-1 , Synthesis of 3,5-triazine-2-amino)phenyl)acrylamide

[0133] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-2-yl)-1,3,5-triazine- Using 2-amine, N,N,N'-trimethylethylenediamine and allyl acid chloride as raw materials, the title compound was prepared according to the methods in step c, step d and step e of Example 1.

[0134] 1 H-NMR (300MHz, DMSO-d 6 )δ:2.50-2.73(8H,m),3.09-3.21(5H,m...

Embodiment 3

[0136] Example 3N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-(1-methylcarbamoylbenzene base))-1,3,5-triazine-2-amino)phenyl)acrylamide

[0137]

[0138] With 4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-(methylcarbamoyl)phenylboronate, N,N, N'-trimethylethylenediamine and allyl acid chloride were used as raw materials, and the title compound was prepared according to the method of Example 1.

[0139] 1 H-NMR (500MHz, DMSO-d 6 )δ:2.25(6H,d),2.37-2.41(m,2H),2.72(3H,s),2.80(3H,s),2.92(2H,m),3.81(3H,s),5.75-5.77 (1H,d),6.24-6.(1H,d),6.42-6.48(1H,m),7.02(1H,s),7.62(1H,s),8.02-8.03(1H,d),8.27( 1H,s), 8.59(2H,s), 8.77(1H,s), 8.83, (1H,s), 9.27(1H,s), 10.11(1H,s).

[0140] ESI-Msm / z: 505.3 [M+H].

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Abstract

The invention relates to a triazine epidermal growth factor acceptor inhibitor and application thereof. The invention relates to the technical field of medicine and chemistry, and more concretely relates to a kind of compound having epidermal growth factor acceptor inhibition effect, pharmaceutical composition including the compound, and application of the compound and the pharmaceutical composition as medicines for treating cancers. The triazine epidermal growth factor acceptor inhibitor of the invention has good inhibition effect on a mutant type EGFR kinase, expresses an excellent selectivity, and is likely to be a cancer medicine with special therapeutic effect for medicine-resistant tumors, especially medicine-resistant tumors arising from EGFR mutation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a compound with inhibitory effect on epidermal growth factor receptors, a pharmaceutical composition containing the compound, and the use of the compound or the pharmaceutical composition as a cancer treatment drug. 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 activates the TK subregion in the in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D251/18C07D401/04C07D251/22C07D405/04C07D409/04C07D495/04A61K31/53A61P35/00
CPCA61K31/53C07D251/18C07D251/22C07D401/04C07D403/04C07D405/04C07D409/04C07D495/04
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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