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Apoptosis signal regulating kinase inhibitor and application thereof

A compound and selected technology can be used in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as fibrosis, extracellular matrix deposition, etc. Good inhibitory ability, low effect on normal cytotoxicity

Active Publication Date: 2020-04-17
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, when ASK1 is activated, it can lead to the activation of hepatic stellate cells, which leads to the deposition of extracellular matrix, which eventually leads to the occurrence of liver fibrosis

Method used

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  • Apoptosis signal regulating kinase inhibitor and application thereof
  • Apoptosis signal regulating kinase inhibitor and application thereof
  • Apoptosis signal regulating kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of compound 1, the structural formula is as follows:

[0039]

[0040] Dissolve 6-bromopicolinic acid (50g, 0.249mol) in 300mL of methanol, slowly add 100mL of concentrated sulfuric acid dropwise to the reaction solution under stirring at 0°C, stir at 0°C for 30min after the dropwise addition, and then raise the temperature to 65°C, Reflux reaction for 3h. After the reaction was completed, it was cooled to room temperature, and then the reaction solution was poured into 3 L of ice water. The precipitated solid was filtered, washed with cold water, and dried to obtain 51 g of white crystalline solid, yield: 95%. Melting point: 67-78°C; 1H NMR (300MHz, DMSO) δ (ppm) 8.08 (dd, J = 1.51Hz, 1.39Hz, 1H), 7.94 (d, J = 1.51Hz, 1H), 7.92 (d, J =1.39Hz,1H),3.90(s,3H).MS(TOF)m / z:215.9[M+H]+.

Embodiment 2

[0042]The preparation of compound 2, structural formula is as follows:

[0043]

[0044] Dissolve 4-methyl-2-aminobenzonitrile (50g, 0.378mol) in 400mL dimethyl sulfoxide, add potassium carbonate (78.5g, 0.568mol) under stirring, and add to the reaction solution at 0°C Slowly add 200mL of 30% hydrogen peroxide solution dropwise into the solution, stir at 0°C for 1h after the dropwise addition, then move to room temperature for 4h. After the reaction was completed, 500ml of water was added to the reaction solution at 0°C, and then the precipitated solid was filtered, washed with cold water, and dried to obtain 52g of a light yellow solid, yield: 92%. Melting point: 87-93°C; 1H NMR (300MHz, CDCl 3 )δ(ppm)7.42(d,J=8.07Hz,1H),6.46(s,1H),6.29(d,J=8.07Hz,1H),2.15(s,3H).MS(TOF)m / z :151.1[M+H]+.

Embodiment 3

[0046] The preparation of compound 3, structural formula is as follows:

[0047]

[0048] Compound 2 (52g, 0.346mol) was dissolved in 300mL 1,2 dichloroethane, triethylamine (52.5g, 0.519mol) was added under stirring, and dicarbonate dicarbonate was slowly added to the reaction solution at 0°C Tert-butyl ester (151.0 g, 0.692 mol), after the dropwise addition, stirred at 0°C for 30 minutes, then raised the temperature to 60°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, concentrated to remove most of the solvent, and then the solid was dissolved in 100 ml of ethyl acetate, and 150 ml of petroleum ether was added to the solution at 0° C. for recrystallization. The precipitated solid was suction filtered, washed with petroleum ether, and the recrystallization operation was repeated twice. Dry to obtain 65g of yellow solid, yield: 75%. Melting point: 59-73°C; 1H NMR (300MHz, CDCl 3 )δ(ppm)8.26(s,1H),7.40(d,J=7.91Hz,1H),6.83(d,J=7.91...

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PUM

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Abstract

The invention discloses an apoptosis signal regulating kinase inhibitor and an application thereof. The apoptosis signal regulating kinase inhibitor is a compound represented by general formula I, anda tautomer or a pharmaceutically acceptable salt thereof. The apoptosis signal regulating kinase inhibitor is a compound with a novel structure. Pharmacodynamic experiments prove that the compound has good inhibition capability on an ASK1 receptor, can be used for effectively inhibiting fibrosis in vitro and has low toxicity on normal cells. Therefore, the compound provided by the invention can be used for treating various fibrosis and related diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an inhibitor of cell apoptosis signal regulating kinase and application thereof. Background technique [0002] Mitogen-activated protein kinase (MAPK) signaling cascades link distinct extracellular and intracellular cohorts with appropriate cellular stress responses, including cell growth, differentiation, inflammation, and apoptosis. MAPK exists as three members MAP3K, MAP2K and MAPK that are activated in sequence. MAPK3 responds directly to environmental signals and phosphorylates MAP2K, which in turn specifically phosphorylates MAPKs, which in turn mediate appropriate cellular responses by phosphorylating cellular substrates including transcription factors that regulate gene expression. [0003] Apoptosis signal-regulated kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family that activates c-Jun N-terminal protein kinase (JNK) and ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/517A61K31/5377A61P25/00A61P9/00A61P13/12A61P29/00A61P11/00A61P3/00A61P37/06A61P35/00A61P3/10A61P1/16
CPCC07D401/04A61P25/00A61P9/00A61P13/12A61P29/00A61P11/00A61P3/00A61P37/06A61P35/00A61P3/10A61P1/16
Inventor 张灿王聪韩晓琳薛玲静
Owner CHINA PHARM UNIV
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