Micromolecular methyl ethyl ketone (MEK) protein kinase inhibitor

A compound and pharmaceutical technology, applied in the field of small-molecule MEK protein kinase inhibitors, can solve problems such as inability to bind

Inactive Publication Date: 2012-02-22
JINAN SAIWEN PHARMTECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most known MEK inhibitors cannot bind to the ATP-docking region of MEK

Method used

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  • Micromolecular methyl ethyl ketone (MEK) protein kinase inhibitor
  • Micromolecular methyl ethyl ketone (MEK) protein kinase inhibitor
  • Micromolecular methyl ethyl ketone (MEK) protein kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: 4-(2-fluoro-4-iodo-aniline)-1,5-bismethyl-6-oxo-1,6 dihydro-2H-pyridine-3-carboxylic acid (2-hydroxy- Synthesis of 1-hydroxymethyl-ethoxy)amide

[0019] The synthesis method is as follows:

[0020]

[0021] Step 1: Preparation of ethyl 2-methylacetoacetate

[0022] Dissolve ethyl acetoacetate (0.24mol) in THF (240mL), add NaH (0.264mol), stir at room temperature for 30min, N 2 For protection, add MeI (0.264mol) dropwise, after the addition was completed, overnight at 40°C, TLC showed that the raw material disappeared, adding water to quench the reaction, removing the solvent under reduced pressure, extracting with ethyl acetate, drying over anhydrous sodium sulfate, concentrating, distilling under reduced pressure, and collecting The distillate at 90°C / 0.1Mpa yielded 28g of light yellow liquid, yield: 81%. Mass spectrum: 145[(M+H) + ]

[0023] Step 2: Preparation of 2,N-dimethyl-3-oxo-butanamide

[0024] Add ethyl 2-methylacetoacetate (0.188mol) into...

Embodiment 2

[0033] Example 2: 4-(2-chloro-4-iodo-aniline)-1,5-bismethyl-6-oxo-1,6-dihydro-2H-pyridine-3-carboxylic acid (2-hydroxy -Synthesis of 1-hydroxymethyl-ethoxy)amide

[0034] The synthesis method is as follows:

[0035]

[0036] Step 1: Preparation of 4-(2-chloro-4-iodo-aniline)-1,5-bismethyl-6-oxo-1,6-dihydro-2H-pyridine-3-carboxylic acid

[0037] 4-Chloro-1,5-dimethyl-6-oxo-1,6-dihydro-2H-pyridine-3-acid (2g, 0.0099mol) was dissolved in THF, cooled to minus 78 degrees, added 19.8 ml 0.5M THF solution of lithium bis(trimethylsilyl)amide, and stirred at minus 78 degrees for half an hour. 2-Chloro-4-iodo-aniline (2.5 g, 0.0099 mol) was added, then warmed to room temperature and stirred overnight. Water was added, separated in a separatory funnel, the organic phase was dried and evaporated to dryness. The residue was separated with a silica gel column to obtain 4-(2-chloro-4-iodo-aniline)-1,5-bismethyl-6-oxo-1,6-dihydro-2H-pyridine-3-carboxylic acid 0.8g, yield: 19.3%. Mass...

Embodiment 3

[0040] Example 3: 4-(2-fluoro-4-iodo-aniline)-1,5-bismethyl-6-oxo-1,6-dihydro-2H-pyridine-3-carboxylic acid (2-hydroxy Determination of Inhibition of MEK Protein Kinase Activity by -1-Hydroxymethyl-Ethoxy) Amide

[0041] With the assay kit of the MEK protein kinase inhibitor activity assay that buys from Sigma-Aldrich Company, analyze and get 4-(2-fluoro-4-iodo-aniline)-1,5-bismethyl-6-oxo- The half inhibitory dose of 1,6-dihydro-2H-pyridine-3-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethoxy)amide to inhibit MEK protein kinase activity was 7nM.

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Abstract

The invention discloses a micromolecular methyl ethyl ketone (MEK) protein kinase inhibitor, a preparation method of the MEK protein kinase inhibitor and applications of the MEK protein kinase inhibitor in preparation of medicaments for treating diseases such as tumors, rheumatic arthritis and the like.

Description

technical field [0001] The invention relates to a small molecule MEK protein kinase inhibitor, its preparation method and its use in the preparation of medicines for treating tumors, rheumatoid arthritis and other diseases. Background technique [0002] The ERK / MAPK signal transduction pathway is closely related to physiological processes such as cell proliferation, survival, differentiation, and apoptosis. MEK protein kinase is a link in the ERK / MAPK signal transduction pathway. ERK and its signaling pathway play an important regulatory role in the growth of tumors. ERK overactivation has been found in many human tumors. If a compound that inhibits the overactivation of ERK can be found, then this compound may be developed into a potential anticancer drug. We blocked the overactivation of ERK by inhibiting the activity of MEK protein kinase. [0003] The mitosis-activated protein kinase (MAPK) pathway is an important connector between intracellular and extracellular sti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/78A61K31/465A61P35/00A61P11/00A61P11/06A61P19/02A61P25/28A61P25/16A61P3/10A61P31/18A61P43/00A61P9/04
Inventor 巩宪昌钟鸣
Owner JINAN SAIWEN PHARMTECH
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