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Compounds with MEK inhibitory function and their preparation methods and applications

A compound, coumarin technology, applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve problems such as large toxic and side effects, low kinase selectivity, and inability to produce specific effects.

Inactive Publication Date: 2015-11-18
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since this inhibitor is not highly selective for kinases and cannot produce specific effects, it may cause greater toxicity and side effects

Method used

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  • Compounds with MEK inhibitory function and their preparation methods and applications
  • Compounds with MEK inhibitory function and their preparation methods and applications
  • Compounds with MEK inhibitory function and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] The synthesis of embodiment 1,3-benzyl-4-methyl-7-dimethylcarbamate base coumarin (compound M2)

[0071] first step

[0072]Slowly add metal sodium (50mmol, 1.15g) into 20ml of absolute ethanol to form sodium alkoxide, add 50mmol of ethyl acetoacetate under stirring at 80°C, and continue stirring for 10 minutes; Bian dehydrated ethanol solution, heated to reflux until the reactant is almost neutral. Cool, filter to remove solid sodium bromide, dry the filtrate over anhydrous magnesium sulfate, and separate by column chromatography (petroleum ether: ethyl acetate = 50:1) (v / v) to obtain ethyl 3-benzyl acetoacetate, a yellow oily liquid 7.17 g, yield 65.1%. 1 HNMR (300MHz, CDCl 3 ):δ1.16-1.21(t,J=7.1Hz,3H,CH 3 ),2.17(s,1H,CH 3 ), 3.14-3.16 (d, J=7.5Hz, 2H, PhCH 2 ),3.76-3.81(t,J=7.5Hz,1H,CH),4.09-4.17(d,J=7.2Hz,2H,C H 2 CH 3 ), 7.16-7.28 (m, 5H, PhH).

[0073] second step

[0074] Resorcinol (5mmol, 0.55g) and ethyl 3-benzyl acetoacetate (5mmol, 1.10g) were dis...

Embodiment 2

[0077] The synthesis of embodiment 2,3-benzyl-4-methyl-6-chloro-7-dimethylcarbamate base coumarin (compound M4)

[0078] first step

[0079] 4-chlororesorcinol (5mmol, 0.72g) and ethyl 3-benzyl acetoacetate (5mmol, 1.10g) were dissolved in 11ml of 70% sulfuric acid and reacted at room temperature for 24h. Ice water was added to the mixture solution to precipitate a solid, which was filtered and washed with water to obtain a crude product. The crude product was recrystallized from ethanol to obtain 0.652 g of the product 3-benzyl-4-methyl-6-chloro-7-hydroxycoumarin (compound M3), a white powder, yield 43.5%, mp: 261-263°C. 1 HNMR(400MHz,DMSO):δ2.40(s,3H,CH 3 ),3.93(s,2H,CH 2 ), 6.89 (s, 1H, PhH), 7.15-7.28 (m, 5H, PhH), 7.79 (s, 1H, PhH), 11.26 (s, 1H, OH).

[0080] second step

[0081] 3-Benzyl-4-methyl-6-chloro-7-hydroxycoumarin (1mmol, 0.30g) was dissolved in 12ml of DMF, and sodium hydride (1.25mmol, 0.038g) was added under nitrogen protection, and reacted at room temp...

Embodiment 3

[0082] Embodiment 3, the synthesis of 3-p-fluorobenzyl-4-methyl-7-dimethylcarbamate base coumarin (compound M5)

[0083] first step

[0084] Add ethyl acetoacetate (10mmol, 1.26ml) to 3.76ml (10mmol) 21% sodium ethoxide solution, reflux reaction at 80°C, when the reactant slightly boils, add dropwise the dehydrated ethanol solution of 4-fluorobromide, continue React until the solution is almost neutral. Cool, remove solid sodium bromide by filtration, dry the filtrate over anhydrous magnesium sulfate, and separate by column chromatography (petroleum ether: ethyl acetate = 50:1) (v / v) to obtain 1.41 g of ethyl 3-fluorobenzyl acetoacetate , yellow oily liquid, yield 59%.

[0085] 1 HNMR (400MHz, CDCl 3 ):δ1.18-1.23(t,J=7.2Hz,3H,CH 2 C H 3 ),2.12(s,3H,C H 3 CO),3.11-3.14(dd,J=1.2,7.2Hz,2H,CH 2 Ph),3.70-3.75(t,J=7.6Hz,1H,CH),4.12-4.16(ddd,J=1.2,7.2,11.6Hz,2H,C H 2 CH 3 ), 6.93-6.98 (m, 2H, PhH), 7.12-7.16 (m, 2H, PhH).

[0086] second step

[0087] Dissolve resorcin...

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Abstract

The invention discloses a compound with an MEK (Mitogen-activated and Extracellular signal-regulated Kinase) inhibiting function as well as a preparation method and application of the compound. The structure of the compound disclosed by the invention is as shown in a formula (I). The preparation method of the compound disclosed by the invention comprises the steps of forming a coumarin ring by adopting a Pechmann reaction mainly and carrying out structural modification of different sites. In the binding experiment of the compound disclosed by the invention and MEK, the binding activity is up to 54.57nM; the anti-proliferation effect IC50 (half maximal inhibitory concentration) value on the melanoma cell A375 is up to 1.23 micrometers; the anti-proliferation effect IC50 value on the colon cancer cell HT-29 is up to 2.13 micrometers; and the activity is higher than that of a positive control U0126. The novel structure type coumarins compound with the MEK inhibiting function shows good MEK binding activity, MEK inhibiting activity, ERK (Extracellular signal Regulated Kinase) pathway inhibiting activity, anti-tumor effect and antiviral effect and has broad application value. The formula (I) is as shown in the specification.

Description

technical field [0001] The present invention relates to a compound and its preparation method and application, in particular to a compound with MEK inhibitory function and its preparation method and application. The compounds have obvious antitumor and antiviral effects, and thus may be used in the treatment of tumors and viral diseases. Background technique [0002] Mitogen-activated protein kinase (MAPK) is an important protein kinase discovered in the mid-1980s and is an important core signaling pathway in cells. The MAPK pathway is mainly divided into four subfamilies: extracellular signal-regulated kinase ERK (extracellular signal-regulated kinase) pathway, JNK pathway, p38 pathway and ERK5 pathway. The ERK pathway is an important family in the MAPK pathway. It is mainly composed of three core protein kinases Raf, MEK (Mitogen-activated and Extracellular signal-regulated Kinase) and ERK, which are activated sequentially to form an accurate and efficient signaling netwo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/16C07D417/04A61P35/00A61P31/12A61P31/22
Inventor 徐萍彭宜红王超牛彦张浩许凤荣
Owner PEKING UNIV
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