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2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative

A diamine derivative and a disubstitution technology, applied in the field of medicine, can solve problems such as intolerable toxicity

Active Publication Date: 2015-08-26
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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  • 2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative
  • 2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative
  • 2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] N-(5-(5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amino)-2-((2-( Dimethylamino)ethyl)methylamino)-4-methoxyphenyl)propionamide (Z-1)

[0164]

[0165] The preparation method of compound 1a:

[0166]

[0167] Step a:

[0168]

[0169] Operation steps: Place the reaction substrate 1 (10.6g, 58mmol) in a 500mL single-port reaction flask, and add a tetrahydrofuran / water (100mL / 60mL) mixed solution to dissolve the substrate. At room temperature, ammonium chloride (15.5 g, 292 mmol) and reduced iron powder (26 g, 467 mmol) were sequentially added to the stirred reaction flask, and then the reaction system was heated to 65 degrees Celsius and kept stirring for 3 hours. The progress of the reaction was detected by TLC. After the substrate was completely reacted, excess iron powder was removed by filtration, and the filter cake was rinsed three times with ethyl acetate. The filtrate was extracted three times with ethyl acetate / water system, the org...

Embodiment 2

[0188] N-(5-(5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amino)-2-(4-(di Methylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (Z-2)

[0189]

[0190] Step 1: 5-Chloro-N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-methyl- 1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0191] The reaction substrate 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridine- 5-yl)pyrimidin-2-amine (260mg, 0.607mmol) and potassium carbonate (251mg, 1.822mmol) were placed in a 25mL single-port reaction flask, and DMF (10mL) was added to partially dissolve the substrate. Then N,N-dimethylaminopiperidine (85.4mg, 0.667mmol) was added and the reaction system was kept heated at 70°C for 3 hours. The progress of the reaction was detected by TLC. After the substrate was completely reacted, the reaction solution was extracted three times with ethyl acetate / water system, the organic layer was separated, washed with water, washed ...

Embodiment 3

[0197] N-(5-(5-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amino)-4-methoxy-2 -(4-Methylpiperazin-1-yl)phenyl)acrylamide (Z-3)

[0198]

[0199] Step 1: 5-Chloro-N-(2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl)-4-(1-methyl-1H-pyrrole And[2,3-b]pyridin-5-yl)pyrimidin-2-amine

[0200] N'-Methylpiperazine (126 mg, 1.26 mmol) and potassium carbonate (261 mg, 1.89 mmol) were added to compound 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl) -4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-amine (200mg, 0.47mmol) in 4 ml of DMF, vigorously stirred at 100 degrees Celsius for 2h . The progress of the reaction was detected by TLC. After the substrate was completely reacted, 10 milliliters of water was added, extracted three times with ethyl acetate / water system, the organic layer was separated and concentrated under reduced pressure to obtain the compound 5-chloro-N-(2-methoxy -4-(4-methylpiperazin-1-yl)-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyrid...

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Abstract

The present invention provides a class of 2,4-disubstituted phenylene-1,5-diamine derivatives, having an inhibiting effect on EGFR tyrosine kinases, and pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug of said derivatives. See the description for the definitions of each group in the formula. In addition, the present invention also discloses pharmaceutical compositions, pharmaceutically acceptable compositions, and applications thereof.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a 2,4-disubstituted benzene-1,5-diamine derivative and its application as an EGFR tyrosine kinase inhibitor, as well as a pharmaceutical composition and a medicine prepared therefrom. with composition. 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. Moreover, 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-gen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D239/48C07D413/04C07D413/14C07D401/12C07D401/04C07D401/14C07D403/04C07D491/08A61K31/506A61K31/5377A61K31/53A61K31/553A61K31/5386A61P35/00A61P3/10A61P37/02A61P25/28A61P9/00
CPCC07D239/48C07D401/04C07D401/12C07D401/14C07D403/04C07D413/04C07D413/14C07D471/04C07D491/08A61K31/506A61K31/53A61K31/5377A61K31/5386A61K31/553A61K45/06A61P25/28A61P35/00A61P37/02A61P43/00A61P9/00A61P3/10A61K2300/00A61K31/56C07D403/12C07D403/14
Inventor 兰炯金云舟周福生谢婧沈思达胡毅刘伟吕强
Owner SHANGHAI HAIYAN PHARMA TECH
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