EGFR degradation agent containing 2, 8, 9-trisubstituted-9H-purine structure fragment and salt and application of EGFR degradation agent

A technology of structural fragments and three substitutions, applied in the field of anticancer drugs

Active Publication Date: 2021-11-30
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Even so, EGFR double mutant degraders have not yet been fully developed, and the discovery of EGFR double mutant degraders with good activity and high selectivity is expected to solve the problem of drug resistance after the first generation of EGFR inhibitors, and to avoid the third generation of EGFR inhibitors. EGFR third mutation after EGFR inhibitor use

Method used

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  • EGFR degradation agent containing 2, 8, 9-trisubstituted-9H-purine structure fragment and salt and application of EGFR degradation agent
  • EGFR degradation agent containing 2, 8, 9-trisubstituted-9H-purine structure fragment and salt and application of EGFR degradation agent
  • EGFR degradation agent containing 2, 8, 9-trisubstituted-9H-purine structure fragment and salt and application of EGFR degradation agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: (2S,4R)-1-((S)-2-(7-(4-(4-((9-((S)-1-acryloyl-3-pyrrolidinyl))-8 -anilino-9H-2-purinyl)amino)phenyl)-1-piperazinyl)heptanylamino)-3-(3,3-dimethyl)-butyryl)-4-hydroxyl-N- Synthesis of (4-(4-methyl-5-thiazolyl)benzyl)pyrrolidine-2-carboxamide (structural formula 1)

[0039] Step 1: (S)-2-((4-(4-(7-ethoxy-7-oxoheptyl)-1-piperazinyl)phenyl)amino)-8-phenylamino-9-( Synthesis of 3-pyrrolidinyl)-9H-purine (c1)

[0040]

[0041] References J.Med.Chem.2012,55,10685-10699, Eur.J.Med.Chem.2020,186,111888 and Eur.J.Med.Chem.2020,208,112781 synthetic intermediate b1; reference Eur.J.Med.Chem.2020,186,111888 prepared c1 with a yield of 60%.

[0042] Step 2: (S)-2-((4-(4-(7-ethoxy-7-oxoheptyl)-1-piperazinyl)phenyl)amino)-8-phenylamino-9-( Synthesis of N-acryloyl-3-pyrrolidinyl)-9H-purine (d1)

[0043]

[0044] Suspend c1 (0.27g, 0.57mmol) in acetone (2mL), cool and stir in an ice bath for 5min, then dissolve acryloyl chloride (70μL, 0.86mmol) in acetone (3mL) and...

Embodiment 2

[0051] Example 2: (2S,4R)-1-((S)-2-(7-(4-(4-((9-((S)-1-acryloyl-3-piperidinyl)-8) -anilino-9H-2-purinyl)amino)phenyl)-1-piperazinyl)heptanylamino)-(3,3-dimethyl)butyryl)-4-hydroxy-N-(4- Synthesis of (4-methyl-5-thiazolyl)benzyl)pyrrolidine-2-carboxamide (structural formula 2)

[0052] The preparation of compound 2 was the same as in Example 1. HRMS(ESI): Calculated value: 1064.56566[M+H] + , measured value: 1064.57031.

Embodiment 3

[0053] Example 3: (2S,4R)-1-((S)-2-(8-(4-(4-((9-((S)-1-acryloyl-3-piperidinyl)-8 -anilino-9H-2-purinyl)amino)phenyl)-1-piperazinyl)octanoylamino)-(3,3-dimethyl)butyryl)-4-hydroxy-N-(4- Synthesis of (4-methyl-5-thiazolyl)benzyl)pyrrolidine-2-carboxamide (structural formula 3)

[0054] The preparation of compound 3 was the same as in Example 1. HRMS(ESI): Calculated value: 1078.58131[M+H] + , measured value: 1078.58234.

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Abstract

The invention discloses an EGFR degradation agent containing a 2, 8, 9-trisubstituted-9H-purine structure fragment and salt and application of the EGFR degradation agent, and belongs to the technical field of anti-cancer drugs. The compound is novel in structure, has remarkable activity of degrading epidermal growth factor receptor (EGFR) tyrosine kinase, has remarkable inhibitory activity on growth of human lung cancer cells HCC827 (EGFR) single mutation and H1975 (EGFR) double mutation, can be used for treating cancers related to EGFR mutation, and has the advantages of easily available synthetic raw materials and easily realized synthetic method.

Description

technical field [0001] The invention belongs to the technical field of anticancer drugs, and specifically relates to an EGFR degradation agent containing 2,8,9-trisubstituted-9H-purine structural fragments, a salt thereof and applications thereof. Background technique [0002] At present, the main treatment methods for cancer are still surgical treatment, radiotherapy and drug treatment, but to a large extent, drug treatment is still the main treatment. Traditional anti-tumor drugs have strong activity, but they lack selectivity and high toxicity, so patients cannot take them for a long time. Therefore, it is of great significance to research and develop new anticancer drugs. [0003] In recent years, with the progress of tumor molecular biology research, more understanding of tumor pathogenesis has been obtained, and many new targets for anticancer drugs have been found, such as epidermal growth factor receptor (EGFR) tyrosine kinase, PI3Ks, BTK, etc. In non-small cell l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P35/00
CPCC07K5/06034A61P35/00A61K38/00
Inventor 张三奇赵宏义毛帅辛敏行吕社民
Owner XI AN JIAOTONG UNIV
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