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Inhibitors of mutant EGFR family tyrosine-kinases

A tyrosine kinase and inhibitor technology, which can be used in medical preparations containing active ingredients, compounds containing elements of Group 3/13 of the periodic table, drug combinations, etc., and can solve problems such as side effects

Pending Publication Date: 2020-08-14
SPECTRUM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Second-generation EGFR inhibitors, such as afatinib, dacomitinib, poziotinib, and neratinib, although developed to overcome acquired resistance, have caused multiple serious complications due to simultaneous inhibition of wild-type EGFR. side effects

Method used

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  • Inhibitors of mutant EGFR family tyrosine-kinases
  • Inhibitors of mutant EGFR family tyrosine-kinases
  • Inhibitors of mutant EGFR family tyrosine-kinases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Embodiment 1: prepare the compound of intermediate formula III

[0164] (1-1) 6,7-Dimethoxyquinazolin-4(3H)-one

[0165] 36.9 g of 4,5-dimethoxyanthranilic acid and 25.0 g of formamidine hydrochloride were mixed, and the mixture was stirred at 210° C. for 30 minutes. After completion of the reaction, the solid thus obtained was cooled to room temperature, stirred with 200 ml (0.33 M) of aqueous sodium hydroxide solution and filtered under reduced pressure. The solid thus obtained was washed with water and air-dried to obtain the title compound (24.6 g, 64%).

[0166] 1 H-NMR (300MHz, DMSO-d 6 )δ7.99(s,1H),7.44(s,1H),7.13(s,1H),3.90(s,3H),3.87(s,3H).

[0167] (1-2) 6-Hydroxy-7-methoxyquinazolin-4(3H)-one

[0168] 3.06 g of the compound obtained in (1-1) was diluted with 20 ml of methanesulfonic acid. 2.66 g of L-methionine was added to the resulting solution, and stirred at 100° C. for 22 hours. Ice was added to the reaction mixture and neutralized with 40% aqueou...

Embodiment 2

[0181] Example 2 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1 Preparation of -yl)-2,2-difluorobutane-1,3-dione

[0182]

[0183] At room temperature, a part of the compound (1 mmol) obtained in (1-6) was mixed with benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBop) (1.5 equivalents), triethylamine (3.0 equivalents), dichloromethane (30 ml) and 2,2-difluoro-3-oxobutanoic acid (1.3 equivalents) were mixed and stirring was continued for 12 hours.

Embodiment 3

[0184] Example 3 4-(4-((4-(3,4-dichloro-2fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl Preparation of )-N,3,3-trimethyl-2,4-dioxobutyramide

[0185]

[0186] At room temperature, part of the compound (1 mmol) obtained in (1-6) was mixed with benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate (PyBop) (1.5 equivalents), triethylamine (3.0 equivalents), dichloromethane (30 ml) and 2,2-dimethyl-4-(methylamino)-3,4-dioxobutanoic acid (1.3 equivalents) were mixed and stirring was continued for 12 hours.

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PUM

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Abstract

An epidermal growth factor receptor (EGFR) family tyrosine kinase inhibitor comprises a functional group that can bind to the serine S797 residue in EGFR having a C797S mutation or the serine S805 residue in HER2 having a C805S mutation.

Description

technical field [0001] The present disclosure relates generally to inhibitors of mutant epidermal growth factor receptor (EGFR) family tyrosine kinases, pharmaceutically acceptable salts or solvates thereof, and inhibitors comprising EGFR family tyrosine kinases, salts or solvates thereof Pharmaceutical composition as active ingredient. More specifically, the present disclosure relates to an EGFR family tyrosine kinase inhibitor selective to the C797S mutation in EGFR and / or the C805S mutation in HER2, which effectively inhibits the EGFR family tyrosine kinases induced by overexpression or activation of EGFR family tyrosine kinases. growth of cancer cells. Background technique [0002] There are many signal transduction systems in cells, which are functionally interconnected to control cell proliferation, growth, metastasis and apoptosis. The destruction of the intracellular control system by genetic and environmental factors can lead to abnormal amplification or destructi...

Claims

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Application Information

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IPC IPC(8): A61K31/47C07D239/94
CPCC07D403/04A61K31/517A61K31/506A61K31/69C07D401/12A61P35/00C07F5/025C07D403/12C07D413/14C07D471/04C07F5/027C07D495/04A61K31/519C07D239/94
Inventor P·V·查特福杜尔P·科利
Owner SPECTRUM PHARMA INC
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