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A class of kinase inhibitors

A compound and pharmaceutical technology, applied in the field of aminopyrimidine ring derivatives and their pharmaceutically acceptable salts, can solve problems such as dose-dependent toxicity

Active Publication Date: 2020-09-11
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Drugs currently in development, including second-generation covalent inhibitors such as afatinib, neratinib, canertinib, and dacomitinib, are effective against the T790M resistance mutation but exhibit dose-dependent toxicities such as diarrhea and rash, due to simultaneous inhibition of wild-type EGFR

Method used

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  • A class of kinase inhibitors
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxy-5-(4-(1-methyl-1H-indole-3- Base) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (1)

[0228] 6-Chloro-2-methoxy-3-nitropyridine (1a)

[0229] To a solution of 2,6-dichloro-3-nitropyridine (5.79g, 30.0mmol) in dry tetrahydrofuran (30mL), add methanol (1.15mL, 28.5mmol) at 0°C, and then add hydrogenation in 4 batches Sodium (60%, 1.20 g, 30.0 mmol). After stirring at 0° C. for 1 h, it was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness, and the residue was recrystallized from n-hexane to obtain 6-chloro-2-methoxy-3-nitropyridine (1a) as a pale yellow solid (4.04 g, 71%).

[0230] N 1 -(6-methoxy-5-nitropyridin-2-yl)-N 1 ,N 2 ,N 2 -Trimethylethane-1,2-diamine (1b)

[0231] 6-Chloro-2-methoxy-3-nitropyridine (1a...

Embodiment 2

[0245] N-(6-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1H-indole-3- Base) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2)

[0246] tert-butyl 2-((6-methoxy-5-nitropyridin-2-yl)(methyl)amino)ethyl(methyl)carbamate (2b)

[0247] 1a (4.00g, 21.3mmol) and tert-butylmethyl (2-(methylamino) ethyl) carbamate (2a, 4.38g, 22.3mmol) (prepared according to literature, J.Med.Chem., 1992, 35,565) in ethanol (47 mL) was heated to reflux for 3 h, the solvent was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with 15-30% ethyl acetate / n-hexane as the eluent to obtain tert-butyl 2-(( 6-Methoxy-5-nitropyridin-2-yl)(methyl)amino)ethyl(methyl)carbamate (2b) (4.65 g, 63%) as a yellow solid. MS-ESI(m / z):341[M+1] + .

[0248] tert-butyl 2-((3-bromo-6-methoxy-5-nitropyridin-2-yl)(methyl)amino)ethyl(methyl)carbamate Esters (2c)

[0249] At 0 ° C, to tert-butyl 2-((6-methoxy-5-nitropyridin-2-yl) (methy...

Embodiment 3

[0261] N-(2-((2-(Ethyl(methyl)amino)ethyl)(methyl)amino)-6-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)pyridin-3-yl)acrylamide (3)

[0262] At room temperature, in N-(6-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1H-indole-3 -yl)pyrimidin-2-yl)amino)pyridin-3-yl)acrylamide (2) (15.4mg, 0.0317mmol) in 1,2-dichloroethane (1mL) solution was added acetaldehyde (water content 40 %, 9.0mg, 0.082mmol) and sodium triacetoxyborohydride (8.7mg, 0.041mmol), the mixture was stirred at room temperature for 1h, diluted with saturated aqueous sodium bicarbonate (5mL), extracted with dichloromethane (2×5mL ), the extract was dried over sodium sulfate, the solvent was evaporated to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and the eluent was dichloromethane / methanol / ammonia (95:4:1), to obtain N-(2-( (2-(Ethyl(methyl)amino)ethyl)(methyl)amino)-6-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine -2-yl)ami...

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Abstract

The invention relates to a kind of mutated EGFR selective inhibitor, pharmaceutical composition and application method.

Description

technical field [0001] The present invention relates to a new class of aminopyrimidine ring derivatives and pharmaceutically acceptable salts thereof. These compounds can selectively inhibit the kinase activity of mutated epidermal growth factor (EGFR) and can be used as drugs to treat hyperplasia in mammals, especially humans. Diseases, such as cancer. The invention also relates to the use of said compounds in the treatment of cancer, and pharmaceutical preparations containing said compounds. Background technique [0002] Protein tyrosine kinases catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue of a protein substrate. Protein tyrosine kinases can be classified as receptor (eg EGFR, HER-2, VEGFR, FGFR) or non-receptor (eg Src, Jak, Abl). The role of receptor tyrosine kinases is to activate secondary signaling factors through phosphorylation to transmit signals from the extracellular to the intracellular. A variety of cellular processes are ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D401/12C07D401/04C07D403/12C07D471/04A61K31/505A61K31/506A61P35/00
CPCC07D401/14A61K31/506C07D471/04A61K45/06C07D403/04A61P35/00A61K2300/00
Inventor 李同双赵兴东田强张卫鹏刘洪彬王宪龙谭浩瀚谭锐刘启洪姜立花刘研新令狐莉林敏孙婧王为波
Owner SHANGHAI ALLIST PHARM CO LTD