JNK (stress-activated kinases,SAPK) inhibitor compound

A compound, alkyl technology, applied in the field of JNK inhibitor compounds

Inactive Publication Date: 2014-10-15
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no JNK inhibitor drugs on the market. Therefore, it is necessary to develop more structural types of JNK inhibitors and select compounds with better efficacy and safety for respiratory diseases, fatty liver, liver fibrosis, and liver cirrhosis. , Treatment of chronic inflammatory diseases

Method used

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  • JNK (stress-activated kinases,SAPK) inhibitor compound
  • JNK (stress-activated kinases,SAPK) inhibitor compound
  • JNK (stress-activated kinases,SAPK) inhibitor compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Example 1 trans-4-(1-((S)-tetrahydrofuran-3-yl)-2-(2,4,6-trifluoroanilino)-1H-imidazo[4,5-c]pyridine Preparation of -6-ylamino)cyclohexanol (compound 1)

[0197]

[0198] 1. Preparation of (S)-2-chloro-5-nitro-N-(tetrahydrofuran-3-yl)pyridin-4-amine

[0199]

[0200] Dissolve 2,4-dichloro-5-nitropyridine (1.93g, 10.0mmol) and diisopropylethylamine (1.55g, 12.0mmol) in dichloromethane (30mL) in batches under ice-water bath Add (S)-3-aminotetrahydrofuran hydrochloride (1.35g, 10.9mmol), after the addition is complete, stir for half an hour, then transfer to room temperature for 24 hours of reaction, concentrate under reduced pressure, silica gel column chromatography (petroleum ether: ethyl acetate =5:1) 2.16g of yellow solid was obtained with a yield of 88.6%.

[0201] 2. Preparation of trans-4-(5-nitro-4-((S)-tetrahydrofuran-3-ylamino)pyridin-2-ylamino)cyclohexanol

[0202]

[0203] (S)-2-Chloro-5-nitro-N-(tetrahydrofuran-3-yl)pyridin-4-amine (2.16g, 8.86mmo...

Embodiment 2

[0218] Example 2 trans-N-methyl-4-(1-((S)-tetrahydrofuran-3-yl)-2-(2,4,6-trifluoroanilino)-1H-imidazo[4, Preparation of 5-c]pyridin-6-ylamino)cyclohexylcarboxamide (compound 3)

[0219]

[0220] 1. Preparation of trans-4-(tert-butoxycarbonylamino)cyclohexylcarboxylic acid

[0221]

[0222] Trans-4-amino-cyclohexylcarboxylic acid (3.1g, 21.6mmol), potassium carbonate (3.3g, 23.9mmol) and Boc2O (5.2g, 23.8mmol) in a mixed solution of acetone and water (100mL, v / v=5:1), reacted at room temperature for 18 hours, concentrated most of it, adjusted to acidity with citric acid, precipitated white solid, filtered with suction, washed with petroleum ether, and dried to obtain 4.86 g of white solid with a yield of 92.6%.

[0223] 2. Preparation of tert-butyl trans-4-(methylcarbamoyl)cyclohexylcarbamate

[0224]

[0225]Trans-4-(tert-butoxycarbonylamino)cyclohexylcarboxylic acid (4.86g, 20mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.4g, 69.9 mmol) and ...

Embodiment 3

[0239] Example 3 2-(trans-4-(1-((S)-tetrahydrofuran-3-yl)-2-(2,4,6-trifluoroanilino)-1H-imidazo[4,5- c] Preparation of pyridin-6-ylamino)cyclohexyl)propan-2-ol (compound 4)

[0240]

[0241] 1. Synthesis of trans-4-(dibenzylamino)cyclohexylcarboxylate benzyl ester

[0242]

[0243] Trans-4-aminocyclohexylcarboxylic acid (4.0g, 27.9mmol) and K 2 CO 3 (13.53g, 97.9mmol) was dissolved in 100mLTHF, then benzyl bromide (16.74g, 97.9mmol) was added dropwise, stirred at room temperature for 16h, the reaction solution was spin-dried, and passed through the column (PE / AE=1:4) to obtain light yellow Solid 6.2g, yield: 53.8%.

[0244] 2. Synthesis of 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol

[0245]

[0246] Dissolve trans-4-(dibenzylamino)benzylcyclohexylcarboxylate (4g, 9.67mmol) in dry 25mL THF, slowly add 32.3mL 3M methylmagnesium bromide ether solution (96.9 mmol), stirred at room temperature for 5h, slowly added 100mL saturated NH 4 Cl aqueous solution was ex...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a JNK (stress-activated kinases,SAPK) inhibitor compound as shown in the general formula (I), pharmaceutically acceptable salts or stereoisomers thereof, preparation method of the compounds, pharmaceutical preparations containing the compounds, and use of the compounds in preparing medicines for treatment and / or prevention of ischemia reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver and liver cirrhosis, wherein R1, R2, R3, R4 and R5 are as defined in the specification.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and specifically relates to JNK inhibitor compounds, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, and preparation of these compounds for treatment and / or Or use in medicines for preventing ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or liver cirrhosis. 2. Background technology [0002] JNK, also known as stress-activated kinases (SAPK), is a mitogen-activated protein kinase discovered in 1990 and is one of the main members of the MAPK family. Mitogen-activated protein kinase (MAPK) is a class of serine / threonine protein kinase widely present in mammalian cells, and four family members have been identified, which are extracellular signal-regulated kinases. (extracellular signal-regulated kinase1 / 2, ER...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/4545A61P9/10A61P3/10A61P25/28A61P29/00A61P11/00A61P1/16
CPCC07D471/04
Inventor 李丽张艳
Owner KBP BIOSCIENCES CO LTD
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