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Novel epidermal growth factor receptor inhibitor and application thereof

A technology of atoms and isomers, applied in the field of cancer therapeutic drugs, can solve problems affecting patient compliance, occupying a large space, and not being able to effectively block EGFR activation signals

Active Publication Date: 2017-05-31
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because methionine occupies a larger space than threonine, it forms steric hindrance, which changes the affinity of ATP in the kinase region of EGFR, resulting in the inability of EGFR-TKI small molecule drugs to effectively block EGFR activation signals, leading to drug resistance production
At the same time, the first-generation EGFR inhibitors lack the selectivity between wild-type EGFR and mutant EGFR, and commonly have side effects such as rash and diarrhea, which affect patient compliance

Method used

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  • Novel epidermal growth factor receptor inhibitor and application thereof
  • Novel epidermal growth factor receptor inhibitor and application thereof
  • Novel epidermal growth factor receptor inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dihydro-1H- Synthesis of pyrrolo[1,2-a]-indol-9-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0160]

[0161] Step a Synthesis of 1-(3-bromopropyl)-1H-indole

[0162]

[0163] In a 100ml reaction flask, add NaH (60% content, 1.23g, 30.73mmol) and DMF (10ml) in turn, stir at room temperature for 5min and cool to 0-4°C, slowly add 10mL of dissolved indole (3g, 25.61mmol) DMF solution, after the addition was completed, raised to room temperature and reacted for 20 minutes to obtain an indole activation solution.

[0164] Another 250ml reaction flask was taken, and 1,3-dibromopropane (15.51g, 76.82mmol) and DMF (50ml) were added. Slowly add the indole activation solution prepared above dropwise at 0-4°C, and react at room temperature for 0.5 h after the drop is complete. After the reaction was completed, water (100ml) was added to quench the reaction, extracted with ethyl acetate, the ethyl a...

Embodiment 2

[0195] Example 2 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra Synthesis of Hydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)acrylamide

[0196]

[0197] Step a Synthesis of 1-(4-bromobutyl)-1H-indole

[0198]

[0199] In a 100mL reaction flask, add NaH (60% content, 1.23g, 30.73mmol) and DMF (10mL) in sequence, stir at room temperature for 5min and cool to 0-4°C, slowly add 10mL of dissolved indole (3g, 25.61mmol) DMF solution, after the addition was completed, raised to room temperature and reacted for 20 minutes to obtain an indole activation solution.

[0200] Another 250mL reaction flask was taken, and 1,4-dibromobutane (16.59g, 76.82mmol) and DMF (50mL) were added. Slowly add the indole activation solution prepared above dropwise at 0-4°C, and react at room temperature for 0.5 h after the drop is complete. After the reaction, quenched by adding water (100 mL), extracted with ethyl acetate, combined the ethyl acetate layers...

Embodiment 3

[0219] Example 3 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(6,7, Synthesis of 8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0220]

[0221] Step a Synthesis of 10-(2-chloro-5-methylpyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole

[0222]

[0223] Using the 6,7,8,9-tetrahydropyrido[1,2-a]indole and 5-methyl-2,4-dichloropyrimidine obtained in step c of Example 2 as raw materials, follow the steps in Example 2 The title compound was prepared by the method of d.

[0224] Step b N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(6,7,8 , Synthesis of 9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0225]

[0226] 10-(2-Chloro-5-methylpyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2 -Methoxy-5-nitroaniline, N,N,N'-trimethylethylenediamine and allyl acyl chloride were used as raw materials, and the title compound was obtained according to ...

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Abstract

The invention belongs to the technical field of medical chemistry, and specifically relates to a novel epidermal growth factor receptor inhibitor, a pharmaceutical composition containing the novel epidermal growth factor receptor inhibitor and use of the novel epidermal growth factor receptor inhibitor or the pharmaceutical composition as a cancer prevention and / or treatment medicament. The compounds exhibit excellent EGFR (Epidermal Growth Factor Receptor) inhibition activity, especially for mutative EGFR, and is expected to become a pharmaceutical with a special treatment effect and smaller side effect on resisting pharmaceutical-resistant tumors caused by EGFR mutation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new epidermal growth factor receptor inhibitor, a pharmaceutical composition containing the inhibitor, and the use of the inhibitor or the pharmaceutical composition as cancer treatment drugs. Background technique [0002] Epidermal Growth Factor Receptor (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). It has been shown that EGFR overexpression or mutations generally cause tumors. EGFR mutations lead to continuous activation of EGFR, enhanced function of autocrine loop, disruption of receptor downregulation mechanism, and activation of abnormal signaling pathways, which play an important role in tumor progression. [0003] EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy against EGFR has become the go...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D498/04C07D471/04C07D513/04A61K31/506A61K31/5383A61K31/542A61P35/00
CPCC07D471/04C07D487/04C07D498/04C07D513/04A61K31/506A61K31/5383A61K31/542
Inventor 王勇张小猛赵立文王小伟韩璐薇戴雪娟
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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