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A Kinase EGFR that acts on EGFR-sensitive mutants l858r ,egfr (d746‑750) 6-substituted aminopurine compounds and applications thereof

A technology of aminopurine and compound, which is applied in the field of medicinal chemistry, can solve the problems of large side effects and low effect of EGFR inhibitors, and achieve high-efficiency treatment of tumors

Active Publication Date: 2017-11-10
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] One of the purposes of the present invention is to provide a method of acting on EGFR sensitive mutant kinase EGFR in order to solve the problem of low effect of EGFR inhibitors and large side effects. L858R , EGFR (d746-750) 6-substituted aminopurine compounds and applications thereof

Method used

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  • A Kinase EGFR that acts on EGFR-sensitive mutants <sup>l858r</sup> ,egfr <sup>(d746‑750)</sup> 6-substituted aminopurine compounds and applications thereof
  • A Kinase EGFR that acts on EGFR-sensitive mutants <sup>l858r</sup> ,egfr <sup>(d746‑750)</sup> 6-substituted aminopurine compounds and applications thereof
  • A Kinase EGFR that acts on EGFR-sensitive mutants <sup>l858r</sup> ,egfr <sup>(d746‑750)</sup> 6-substituted aminopurine compounds and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis of embodiment 1 compound 6-(5-chloro-pyrrole-2-methylamino)purine (A1)

[0025] 1 Synthetic route of the compound

[0026] The specific synthetic route is as figure 1 shown.

[0027] 2 synthetic steps

[0028] 2.1 Preparation of 6-(5-chloro-pyrrole-2-methylamino)purine (A1)

[0029] Measure 5ml of n-butanol, weigh 80mg of 6-chloropurine and 100mg of (5-chloro-1H-pyrrol-2-yl)methylamine, put them into a 25ml round bottom flask, and add 50μl of triethyl Amines act as catalysts and are added to a stir bar. Heated to reflux in an oil bath at 110°C for 5h, cooled, until a white solid precipitated out, filtered under reduced pressure, washed twice with n-butanol, and dried to obtain 6-(5-chloro-pyrrole-2-methylamino)purine (A1 ).

[0030] 2.2 Physical characteristics of 6-(5-chloro-pyrrole-2-methylamino)purine (A1)

[0031] 1 H-NMR (DMSO-d 6 )δ(ppm): 12.987(s,1H,7'or 9'-Purine-H), 8.220(s,1H,-NH), 8.140-8.15(m, 2H,2',8'-Purine-H ), 7.858(s,1H,1'-Pyrrol...

Embodiment 2

[0032] The synthesis of embodiment 2 compound 6-(6-chloro-pyrimidine-4-methylamino)purine (A2)

[0033] 1 Synthetic route of the compound

[0034] The specific synthetic route is as figure 2 shown.

[0035] 2 synthetic steps

[0036] 2.1 Preparation of 6-(6-chloro-pyrimidine-4-methylamino)purine (A2)

[0037] Measure 5ml of n-butanol, weigh 80mg of 6-chloropurine and 120mg of (6-chloropyrimidin-4-yl)methylamine, put them into a 25ml round bottom flask, and add 50μl of triethylamine as a catalyst , add a stir bar. Heated to reflux in an oil bath at 110°C for 5h, cooled until a white solid precipitated, filtered under reduced pressure, washed twice with n-butanol, and dried to obtain 6-(6-chloro-pyrimidine-4-methylamino)purine (A2 ).

[0038] 2.2 Physical characteristics of 6-(6-chloro-pyrimidine-4-methylamino)purine (A2)

[0039] 1 H-NMR (DMSO-d 6 )δ(ppm): 13.276(s,1H,7'or 9'-Purine-H), 9.432(s,1H,2'-Pyrimidine-H), 8.720(s,1H,-NH-), 8.125- 8.243(m,2H,2',8'-Purine-H),...

Embodiment 3

[0040] Example 3 compound in vitro EGFR inhibitory activity test

[0041] Screening of EGFR kinase activity in vitro: The method used in the experiment is Caliper Mobility Shift Assay, which is a detection platform based on the mobility detection technology of microfluidic chip technology. The specific experimental steps are: configure 1.25x kinase reaction buffer (62.5mmol / L HEPES, pH7.5; 0.001875% Brij-35; 12.5mmol / LMgCl 2; 2.5mmol / L DTT) and kinase reaction stop solution (100mmol / L HEPES, pH7.5; 0.015% Brij-35; 0.2% Coating Reagent#3); in 5μl of 5x concentration compound solution (DMSO dissolved, diluted with water 10 times) add 10 μl of 2.5x EGFR kinase solution (add kinase in 1.25x kinase reaction buffer), react at room temperature for 10 minutes, then add 10 μl of 2.5x substrate peptide solution (add FAM in 1.25x kinase reaction buffer labeled peptide and ATP), after reacting at 28°C for a specific time, 25 μl of kinase reaction stop solution was added. Collect data on...

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Abstract

The invention discloses a 6-substitued aminopurine compound of the chemical structure as indicated in the specification and medicinal salt of the compound, wherein R can be found in the specification, and R1 is hydrogen or fluorine or chlorine or bromine or methoxyl or hydroxyl. According to the new 6-substitued aminopurine compound and the medicinal salt thereof, EGFR kinase is inhibited selectively, activity of the EGFR sensitive mutation kinase EGFR<L858R> and EGFR<(d746-750)> can be effectively inhibited, EGFRWT kinase cannot be inhibited, thus overexpression of EGFR mutant and proliferation of abnormally activated cells can be inhibited, and tumors are efficiently treated; a greater toxic or side effect and drug reactions such as rash and emesis caused by inhibition of phosphorylation of the EGFRWT kinase of normal tissues in the human body and activation of relevant signal channels can be avoided, the treatment effect is improved, and side reactions are reduced.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a method for selectively inhibiting EGFR sensitive mutant kinase EGFR L858R , EGFR (d746-750) Active 6-substituted aminopurine compounds and their applications. Background technique [0002] As people's life pressure is increasing, the living environment is getting worse, and the incidence of cancer is getting higher and higher than in the past. Therefore, the methods and effects of cancer treatment are more and more concerned by medical workers. with concern. In recent years, with the development of science and technology, anti-tumor drugs have also made new progress. So far, the most popular new anti-tumor drugs are: new cytotoxic drugs, endocrine therapy drugs, gene drugs, immunotherapy drugs and molecular targeted anti-tumor drugs. tumor drugs. Among them, receptor tyrosine kinase inhibitors and angiogenesis pathway inhibitors in molecularly targeted anti-tumo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/34A61K31/52A61P35/00
CPCC07D473/34
Inventor 叶发青王宇王跃武俞淑芳陈弟陈梁芳宋晓琴谢自新梁广李校堃刘志国林丹
Owner WENZHOU MEDICAL UNIV