Arylaminopyrimidine compounds and their applications, as well as pharmaceutical compositions and pharmaceutical compositions prepared therefrom

A technology of arylaminopyrimidines and compounds, which is applied in the field of arylaminopyrimidines and their application as EGFR tyrosine kinase inhibitors, and can solve problems such as intolerable toxicity

Active Publication Date: 2017-06-30
SHANGHAI HAIYAN PHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The concentration required to inhibit the growth of drug-resistant cells is much higher than that of normal cells, and the toxicity is often unacceptable at this dose

Method used

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  • Arylaminopyrimidine compounds and their applications, as well as pharmaceutical compositions and pharmaceutical compositions prepared therefrom
  • Arylaminopyrimidine compounds and their applications, as well as pharmaceutical compositions and pharmaceutical compositions prepared therefrom
  • Arylaminopyrimidine compounds and their applications, as well as pharmaceutical compositions and pharmaceutical compositions prepared therefrom

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0173] Preparation of 3-amino-6-morpholinopyridine

[0174]

[0175] step 1:

[0176] At room temperature, 2-bromo-5-nitropyridine (2 g, 10 mmol) was added to 10 ml of morpholine solution, and vigorously stirred at room temperature for 4 hours. After the reaction, a yellow solid precipitated out. After filtration, the yellow solid was washed with 50 mL petroleum ether to give 4-(5-nitropyridin-2-yl)morpholine (1.9 g, 92%). Spectral data: MS m / z (ESI): 210.1 [M+H] +

[0177] Step 2:

[0178] At room temperature, palladium on carbon (100 mg, 10% wt) was added to 4-(5-nitropyridin-2-yl) morpholine (1 g, 9.1 mmol) in 60 ml of methanol solution, vigorously stirred at room temperature under a hydrogen atmosphere 20 hours. After the reaction, the palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure to obtain the product 3-amino-6-morpholinylpyridine, which was directly used in the next reaction. Spectral data: MS m / z (ESI): 180.1 [M+...

Embodiment 1

[0291] N-(3-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin4-yl)ureido)phenyl)propene Preparation of amides (cpd-1)

[0292]

[0293] Step 1: Synthesis of 2-chloro-4-pyrimidine isocyanate

[0294] At 0 degrees Celsius, 4-amino-2-chloropyrimidine (4.8g, 37.0mmol) was added to a solution of triphosgene (5.5g, 18.5mmol) in 200ml of tetrahydrofuran (THF), and then N,N- - Diisopropylethylamine (DIEA) (6.23 g, 48.2 mmol). Stir vigorously at room temperature for 4 hours. The progress of the reaction was detected by TLC. After the substrate was completely reacted, the product 2-chloro-4-pyrimidine isocyanate was directly used in the next reaction.

[0295] Step 2: Synthesis of 1-(2-chloropyrimidin-4-yl)-3-(3-nitrophenyl)urea

[0296] At room temperature, triethylamine (TEA) (11 g, 110 mmol) and 3-nitroaniline (5.6 g, 40.3 mmol) were added to a solution of 2-chloro-4-pyrimidine isocyanate (5.7 g, 36.6 mmol) in 200 ml of THF , stirred vigorously at room temper...

Embodiment 2

[0303] N-(3-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ureido)phenyl)acrylamide (cpd-2 ) preparation

[0304]

[0305] Step 1: Synthesis of 1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-(3-nitrophenyl)urea

[0306] 4-(4-Methylpiperazin-1-yl)aniline (392 mg, 2.00 mmol) and trifluoroacetic acid (700 mg, 6.0 mmol) were added to 1-(2-chloropyrimidin-4-yl)-3-( 3-Nitrophenyl)urea (600mg, 2.00mmol) in 14ml of n-butanol was stirred vigorously at 130°C for 7 hours. After the reaction, the system was cooled to room temperature and filtered to obtain a brown solid. Wash the brown solid with 50 ml of ethanol to give compound 1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-(3-nitro Phenyl)urea (500 mg), the product was used directly in the next step. Yield: 56%, purity: 72%, spectral data: MS m / z (ESI): 449.2 [M+H] +

[0307] Step 2: Synthesis of 1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-(3-aminophenyl)urea...

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Abstract

The invention discloses an arylaminopyrimidine compound with inhibitory effect on EGFR tyrosine kinase and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in formula I, in which each The definition of the group is detailed in the specification. In addition, the present invention also discloses the pharmaceutical composition, pharmaceutical composition and application of the compound.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an arylaminopyrimidine compound and its application as an EGFR tyrosine kinase inhibitor, as well as a pharmaceutical composition and a pharmaceutical composition prepared therefrom. Background technique [0002] Lung cancer is the cancer with the highest incidence rate in the world. The incidence rate of lung cancer in China ranks first among all cancers. The mortality rate exceeds 3 / 10000; and the number of cases is increasing year by year. In addition, China's air pollution is serious, and the high level of PM2.5 will lead to a higher incidence of lung cancer in the future. [0003] Among Chinese lung cancer patients, 30% of patients have EGFR mutations, among which L858R and exon 19 deletion mutations account for more than 90%. Such patients have higher EGFR activity after mutation, and patients are more sensitive to EGFR inhibitors. The first-generation EGFR inhibitors alr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/48C07D401/12C07D401/14C07D239/42A61K31/506A61K31/5377A61P35/00A61P3/10A61P37/02A61P25/00A61P9/00
CPCA61K31/505A61K31/506A61K31/5377C07D239/42C07D239/48C07D401/12C07D401/14A61P3/10A61P9/00A61P25/00A61P35/00A61P37/02
Inventor 兰炯崔玉敏张亮金云舟周福生程鹏飞
Owner SHANGHAI HAIYAN PHARMA TECH
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