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Pyrimidine or triazine derivative, and preparation method and use thereof

A pyrimidine and compound technology, applied in the fields of pyrimidine or triazine derivatives and their preparation and use, can solve the problems of drug-resistant tumors showing no obvious curative effect, limiting clinical drug dosage, and failing to reach the effective exposure of drug-resistant tumors.

Active Publication Date: 2016-04-06
SHENZHEN FORWARD PHARMA LTD CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the second-generation irreversible inhibitors have shown good anti-drug-resistant tumor effects in preclinical studies, they have not shown significant clinical efficacy in drug-resistant tumors.
The reason is that the toxic reaction caused by excessive inhibition of wild-type EGFR limits its clinical dosage, which cannot reach the effective exposure to drug-resistant tumors in vivo

Method used

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  • Pyrimidine or triazine derivative, and preparation method and use thereof
  • Pyrimidine or triazine derivative, and preparation method and use thereof
  • Pyrimidine or triazine derivative, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1: 2-((2-acrylamido-5-methoxy-4-(4-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl) Synthesis of tert-butyl pyrimidin-2-ylamino)phenyl)(methyl)amino)ethyl(methyl)carbamate (compound 1):

[0134]

[0135] a. Synthesis of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-indole

[0136]

[0137] 5-(trifluoromethyl)pyrimidine-2,2-(1H,3H)-dione (18g, 0.1mol) was added to a 250ml three-necked flask, phosphorus oxychloride (45.8ml, 5eq) was added, Add phosphoric acid (0.1eq) under the protection of nitrogen, heat in an oil bath, slowly add diisopropylethylamine (16ml) dropwise between 85°C and 90°C, heat up to 100°C after dropping, reflux for 36h, evaporate to dryness under reduced pressure solvent, and column chromatography to obtain oily liquid 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.8 g, yield 17.7%).

[0138] Add 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.16g, 10mmol) into a 150ml single-necked bottle, add 30ml of anhydrous ethylene glycol ...

Embodiment 2

[0148] Example 2: N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-(4-(1-methyl-1H-indole-3 - yl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)acrylamide (compound 2):

[0149]

[0150] Compound 1 (354 mg) obtained in Example 1 was dissolved in 5 ml of dichloromethane, 3 ml of trifluoroacetic acid was added, stirred at room temperature for 2 h, TLC detected that the reaction of the raw materials was complete, the temperature was lowered to below 0 ° C, and 50 ml of saturated sodium bicarbonate and 50 ml of dichloromethane were added. Chloromethane, stirred for 30 min, separated, the aqueous phase was extracted three times with an equal amount of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product (compound 2) (246 mg, yield 82%).

[0151] 1 H-NMR (400MHz, DMSO-d6, δppm): 9.48(s,1H), 9.10(s,1H), 8.64(s,3H), 8.25(s,1H), 8.13(m,1H), 7.88( s,1H), 7.48(d,1H, J=7.2H...

Embodiment 3

[0154] Example 3: 2-((2-acrylamido-5-ethoxy-4-(4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-ylamino) Synthesis of phenyl) (methyl) amino) ethyl (methyl) tert-butyl carbamate (compound 3):

[0155]

[0156] a. Synthesis of 2-ethoxy-4-fluoro-5-nitroaniline:

[0157]

[0158] Suspend 5-fluoro-2-nitrophenol (6g, 1eq), potassium carbonate (15.8g, 3eq) in 150ml N,N-dimethylformamide, drop bromoethane (8.3g, 2eq), The temperature was raised to 37° C. and the reaction was stirred. After the reaction was detected by TLC, the system was poured into ice water, and the product was precipitated, filtered and washed with water to obtain 5-fluoro-2-nitrophenetole (6.8 g, yield 97%).

[0159] Dissolve 5-fluoro-2-nitrophenetole (6.8g) in 150ml of methanol, add 10% Pd / C (680mg), replace with hydrogen, stir and add hydrogen at room temperature, after the reaction is detected by TLC, filter, and the filtrate The solvent was distilled off under pressure to obtain 4-fluoro-2-ethoxyaniline (5...

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Abstract

The invention relates to an arylaminopyrimidine or triazine derivative, and a preparation method, a medicinal composition and a use thereof, and concretely relates to a compound represented by formula I, or a pharmaceutically acceptable salt or a solvate thereof. In the formula I, R1 to R7, X and Y are defined in the description and claims. The invention also relates to a preparation method of the compound of formula I, the medicinal composition containing the compound, and the pharmacy use of the compound and the medicinal composition. The compound of formula I is an effective tyrosine kinase irreversible inhibitor, and especially has a strong inhibition effect on EGFR-T790M drug-resistant tumors.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a new class of arylaminopyrimidine or triazine derivatives with anti-tumor activity and a preparation method thereof. The arylaminopyrimidine or triazine derivatives have effective tyrosine kinase inhibition It has the function of preparing medicines for treating or adjuvantly treating tumors mediated by receptor tyrosine kinases or proliferation and migration of tumor cells driven by receptor tyrosine kinases in mammals (including humans). Background technique [0002] According to the global cancer report (2014) released by WHO, the number of people who died of cancer in the world in 2012 reached 8.2 million. Due to the change of living environment and living habits, under the influence of adverse environment and some unfavorable factors, the morbidity and mortality of tumors are on the rise. According to the WHO report, the number of new cancer cases i...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D405/14C07D403/12A61K31/506A61K31/53A61P35/00A61P35/02
CPCC07D403/04C07D403/12C07D405/14
Inventor 张龙赵树雍范传文周豪杰杨莹莹陈栋郑庆梅李玉浩郑善松
Owner SHENZHEN FORWARD PHARMA LTD CO
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