Substituted indole or indole pyrimidine derivative as well as preparation method and application of substituted indole or indole pyrimidine derivative

A compound and selected technology can be used in drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., which can solve the problem of limiting clinical drug dosage, failing to reach the effective exposure of drug-resistant tumors, and showing no obvious drug-resistant tumors. issues of efficacy

Inactive Publication Date: 2017-08-01
QILU PHARMA
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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-resis

Method used

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  • Substituted indole or indole pyrimidine derivative as well as preparation method and application of substituted indole or indole pyrimidine derivative
  • Substituted indole or indole pyrimidine derivative as well as preparation method and application of substituted indole or indole pyrimidine derivative
  • Substituted indole or indole pyrimidine derivative as well as preparation method and application of substituted indole or indole pyrimidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: 2-((2-acrylamido-4-(4-(5-fluoro-1-methyl-1H-indol-3-yl)-5-methylpyrimidin-2-ylamine Synthesis of 5-methoxyphenyl)(methyl)amino)ethyl(methyl)carbamate tert-butyl (compound 1):

[0086]

[0087] a. Synthesis of 3-(2-chloro-5-methylpyrimidin-4-yl)-5-fluoro-1-methyl-1H-indole

[0088]

[0089] The raw material 5-fluoroindole (10g, 1eq) was added in a round bottom flask, 150ml of DMF was added, the temperature was cooled to about -10 degrees Celsius and 60% sodium hydride (6g, 2eq) was added, and after stirring for about 20 minutes, methyl iodide ( 15.7g, 1.5eq), the temperature was raised to room temperature and the reaction was stirred. After the reaction was detected by TLC, the system was poured into 1L of water, extracted twice with an equal amount of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate 11 g of 5-fluoro-1-methyl-1H-indole.

[0090] Add 2,4-di...

Embodiment 2

[0098] Example 2: N-(5-(4-(5-fluoro-1-methyl-1H-indol-3-yl)-5-methylpyrimidin-2-ylamino)-4-methoxy - Synthesis of 2-(methyl(2-(methylamino)ethyl)amino)phenyl)acrylamide (compound 2):

[0099]

[0100] Dissolve compound 1 (2.0 g) obtained in Example 1 in 8 ml of dichloromethane, add 4 ml of trifluoroacetic acid, stir at room temperature for 2 h, TLC detects that the reaction of the raw materials is complete, cool to below 0 degrees Celsius, add 80 ml of saturated sodium bicarbonate and 80 ml of Dichloromethane, stirred for 30 minutes, separated, the aqueous phase was extracted 3 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) (1.53g, yield 91 %).

[0101] 1 H-NMR (400MHz, DMSO-d6, δppm): 10.38(s,1H), 9.90(s,1H), 9.63(s,1H), 8.62(s,1H), 8.15(s,2H), 7.59( m,1H),7.30(m,1H),7.16(s,1H),7.00(s,1H),6.18(d,1H,J=16.8Hz),5.78(s,1...

Embodiment 3

[0103] Example 3: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(5-fluoro-1-methyl-1H-indole- 3- Synthesis of (yl)-5-methylpyrimidin-2-ylamino)-4-methoxy-phenyl)acrylamide (compound 3):

[0104]

[0105] a. N 1 -(2-(Dimethylamino)ethyl)-N 4 -(4-(5-fluoro-1-methyl-1H-indol-3-yl)-5-methylpyrimidin-2-ylamine base)-5-methoxy-N 1 -Synthesis of methylbenzene-1,2,4 triamine:

[0106]

[0107] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(5-fluoro-1-methyl-1H-indol-3-yl)-5-methylpyrimidine- 2-amine (see Example 1 for the synthesis method) (7g, 1eq), trimethylethylenediamine dihydrochloride (5.7g, 2eq), triethylamine (8.3g, 5eq), trifluoroethanol (100ml) Add it into a sealed tube, raise the temperature to 100 degrees Celsius, and gradually dissolve as the reaction progresses. After about 8 hours, the reaction is completed by TLC and liquid mass monitoring, and concentrated to dryness under reduced pressure to obtain 7.5 g of crude product, which is directly used in the...

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Abstract

The invention relates to a substituted indole or an indole pyrimidine derivative as well as a preparation method, a pharmaceutical composition and application of the substituted indole or the indole pyrimidine derivative, in particular relates to a compound shown in a formula I or pharmaceutically acceptable salt or solvate of the compound, wherein the definitions of R1 to R7, X and Y are claimed as the description and claims. The invention also relates to the preparation method of the compound shown in the formula I, the pharmaceutical composition including the compound, and pharmaceutical application of the compound and the pharmaceutical composition. The compound shown in the formula I provided by the invention is an effective tyrosine kinase irreversible inhibitor, which particularly has a stronger inhibition effect in EGFR-T790M drug-resistant tumors. The formula (1) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a new class of substituted indole or indazole pyrimidine derivatives with antitumor activity and a preparation method thereof. The substituted indole or indazole pyrimidine derivatives have effective tyrosine Acid kinase inhibitory effect, having the aspect 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) use. 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 repor...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00A61P35/02
CPCC07D403/04
Inventor 张龙赵树雍陈栋郑善松周豪杰李玉浩杨莹莹郑庆梅范传文
Owner QILU PHARMA
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