Substituted diaminopyrimidine compound and application thereof in preparation of antineoplastic drugs

A technology of diaminopyrimidine and compound, which is applied in the field of medicinal chemistry to achieve the effects of inhibiting growth, good pharmacokinetic properties and overcoming drug resistance

Active Publication Date: 2017-06-13
药谷(温州)科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are certain defects in the drugs currently under clinical research or on the market.

Method used

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  • Substituted diaminopyrimidine compound and application thereof in preparation of antineoplastic drugs
  • Substituted diaminopyrimidine compound and application thereof in preparation of antineoplastic drugs
  • Substituted diaminopyrimidine compound and application thereof in preparation of antineoplastic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Nitrogen-(5-((5-bromo-4-((1-methylindol-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl Piperazin-1-yl)phenyl)acrylamide (compound 23)

[0038] N-(5-((5-bromo-4-((1-methyl-1H-indol-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1 -yl)phenyl)acrylamide

[0039] The synthetic route is as follows:

[0040]

[0041] Step 1: Nitrogen-(5-bromo-2-chloropyrimidin-4-yl)-1-methyl-1hydro-indole-6-amino (intermediate c)N-(5-bromo-2-chloropyrimidin- 4-yl)-1-methyl-1H-indol-6-amine

[0042]

[0043] 5-bromo-2,4-dichloropyrimidine (3.42g, 15mmol), 1-methyl-1-hydro-indole-6-amino (1.46g, 10mmol), DIPEA (N,N-diisopropyl Ethylamine, 0.1 mL) was dissolved in 20 mL of anhydrous DMF, and the reaction was started at -20°C on a low-temperature reactor, and the temperature was gradually raised to 0°C within 5 hours. After reacting for 7 hours, 200 mL of ice water was added, a large amount of solid precipitated out, filtered under reduced pressure, and dried t...

Embodiment 2

[0064] Nitrogen-(5-((4-((1hydro-indol-6-yl)amino)-5-bromopyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl ) (methyl) amino) phenyl) acrylamide (compound 25)

[0065]N-(5-((4-((1H-indol-6-yl)amino)-5-bromopyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl ) acrylamide

[0066]

[0067] The synthetic method is as embodiment 1

[0068] 1 H NMR (600MHz, DMSO-d 6 )δ(ppm): 11.027(s,1H,indole-H-1),10.129(s,1H,-NH-),9.132(s,1H,-NH-),8.510(s,1H,-NH- ),8.232(s,1H,Ar-H),8.232(s,1H,H-6),7.516(s,1H,Ar-H),7.470(d,J=8.4Hz,1H,Ar-H) ,7.414(d,J=9.0Hz,1H,Ar-H),7.309(t,J=3.0Hz,1H,indole-H-2),7.181(d,J=8.4Hz,1H,Ar-H) ,6.826(d,J=7.8Hz,1H,Ar-H),6.400(t,,J=2.4Hz,1H,indole-H-3),6.353(dd,J1=17.0Hz,J2=10.2 Hz, 1H, -C H =CH 2 ), 6.226 (d, J=16.8Hz, 1H, -CH=C H 2 ),5.950(d,J=12.0Hz,1H,-CH=C H 2 ),2.720(t,J=7.2Hz,2H,-C H 2 -CH 2 -N(CH 3 ) 2 ),2.569(s,3H,N-CH 3 ), 2.207(t, J=7.2Hz, 2H, -CH 2 -C H 2 -N(CH 3 ) 2 ),2.171(s,6H,-N(C H 3 ) 2 ). 13 C NMR(150MHz,DMS...

Embodiment 3

[0070] Nitrogen-(5-((4-((1-hydrogen-indol-6-yl)amino)-5-bromopyrimidin-2-yl)amino)-2-(4-methylpiperazin-1-yl ) phenyl) acrylamide (compound 20)

[0071] N-(5-((4-((1H-indol-6-yl)amino)-5-bromopyrimidin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0072] The synthetic method is as embodiment 1

[0073]

[0074] 1 H NMR (600MHz, DMSO-d 6 )δ(ppm):11.054(s,1H,indole-H-1),9.150(s,1H,-NH-),8.954(s,1H),8.532(s,1H,-NH-),8.137( s,1H,H-6),7.984(s,1H,-NH-),7.533(s,1H,Ar-H),7.502(d,J=8.4Hz,1H,Ar-H),7.478(d ,J=9.0Hz,1H,Ar-H),7.329(t,J=2.4Hz,1H,indole-H-2),7.169(d,J=8.4Hz,1H),6.689(d,J=5.4 Hz,1H,Ar-H),6.571(dd,J 1=17.0Hz,J 2=10.2Hz,1H,-C H =CH 2 ), 6.432(t, J=2.4Hz, 1H, indole-H-3), 6.209(d, J=17.4Hz, 1H, -CH=C H 2 ), 5.734 (d, J=10.2Hz, 1H, -CH=C H 2 ), 2.694(t, J=4.8Hz, 4H, piperazine-H×4), 2.510(t, J=4.8Hz, 4H, piperazine-H×4), 2.246(s, 3H, N-CH 3 ). 13 CNMR(150MHz,DMSO)δ162.83,158.27,157.28,156.89,137.34,136.50,135.80,132.31,132.23,131.81,126.37,125.33,125.0...

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Abstract

The invention provides a substituted diaminopyrimidine compound and medicinal salt thereof. The structure of the substituted diaminopyrimidine compound is as shown in a general formula (I). A pharmacodynamic test proves that the compound is capable of effectively inhibiting growth of multiple tumor cells and can be used for preparing anti-tumor drugs, and meanwhile, the drug resistance of EGFR T790M can be overcome.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a substituted diaminopyrimidine compound, its preparation method and its medical application, especially the application in the preparation of anti-malignant tumor drugs. Background technique [0002] Molecular targeted therapy is a method of selectively killing tumor cells by chemical or biological means, which has the characteristics of high selectivity, strong specificity, and mild side effects. This strategy has been developed rapidly in several years, and it is the hot spot and trend of tumor treatment at present. [0003] Malignant tumors, especially lung cancer, are the malignant tumors with the highest morbidity and mortality. According to the latest statistics, the number of new lung cancer patients in my country reached 733,000 in 2015, and the total number of deaths due to lung cancer reached about 610,000 within a year, accounting for the first of all ca...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D237/20C07D401/12A61K31/506A61K31/5377A61P35/00A61P35/02
CPCC07D237/20C07D401/12C07D403/12
Inventor 刘志国王怡蔡跃飘夏钦钦胡杰陈凌锋梁广
Owner 药谷(温州)科技发展有限公司
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