Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

一种蛋白激酶、抑制剂的技术，应用在含有效成分的医用配制品、药物组合、有机化学等方向，能够解决再生能力受损、不足以补偿肝细胞和器官功能、丧失等问题

Active Publication Date: 2019-09-27
HEPAREGENIX GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The liver has a remarkable regenerative capacity, however, this regenerative capacity may be impaired in disease states and thus may not be sufficient to compensate for loss of hepatocyte and organ function

Method used

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  • Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
  • Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
  • Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0386] Example 1: Propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl}amide, such as WO The preparation is disclosed in 2007 / 002433:

[0387]

Embodiment 2

[0388] Example 2: Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- Phenyl}-amides, prepared as disclosed in WO 2007 / 002433:

[0389]

[0390] For the preparation of compounds of the invention, the general procedures (GP) aa to ae are used:

[0391] General process aa:

[0392] Oxalyl chloride (1.1 equiv) was added to a suspension of the carboxylic acid (1.0 equiv) in anhydrous DCM (0.5m). A few drops of DMF were added and the resulting mixture was stirred at room temperature until gas formation was complete. Excess MeOH was added to the solution, and the solvent was evaporated under reduced pressure. The residue was dried in vacuo and the product was used without further purification.

[0393] General process ab:

[0394] Pd / C (0.1 equiv) was added to a solution of nitrobenzene (1.0 equiv) in EtOH (0.2m). The suspension was washed with H 2 The gas was degassed, and the reaction was stirred at room temperature to ...

Embodiment 3

[0437] Example 3: The above N-(2,4-difluoro-3-(5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl base) phenyl) propane-1-sulfonamide)

[0438]

[0439] Process: follow GP ad The title compound was obtained.

[0440] Yield: 22.7 mg, 47 μmol, 36% (white solid)

[0441] TLC: DCM / MeOH 5%

[0442] 1 H NMR (DMSO-d 6 ,400MHz,ppm):δ12.96(s,1H),9.78(s,1H),8.67(d,J=1.7Hz,1H),8.57(s,1H),8.21(s,1H),7.68( d,J=8.5Hz,2H),7.59(dd,J=14.8,8.9Hz,1H),7.28(t,J=8.5Hz,1H),7.08(d,J=8.6Hz,2H),3.82( s,3H),3.19–3.06(m,2H),1.74(dq,J=14.7,7.2Hz,2H),0.96(t,J=7.4Hz,3H); 13 C NMR (DMSO-d 6 ,101Hz,ppm): δ180.5,159.0,156.0(dd,J=246.6,6.9Hz),152.4(dd,J=258.5,8.9Hz),148.5,143.7,138.4,131.3,130.4,128.7(d,J= 8.7Hz), 128.2, 126.4, 121.9(dd, J=13.1, 3.6Hz), 118.2(dd, J=25.0, 23.0Hz), 117.5, 115.6, 114.6, 112.2(dd, J=22.5, 3.3Hz), 55.2, 53.5, 16.74, 12.5. TLC-MS: C 24 h 21 f 2 N 3 o 4 S([M-H] - ) calculated value of m / z: 484.1, found value: 484.2.

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PUM

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Abstract

The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.

Description

technical field [0001] The present invention relates to protein kinase inhibitors which inhibit mitogen-activated protein kinase 4 (MKK4), in particular selectively inhibiting MKK4 relative to the protein kinases JNK1 and MKK7. Background technique [0002] Liver disease can be caused by infection, injury, exposure to toxic compounds such as alcohol or drugs, autoimmune processes, genetic defects, and other factors. The liver has a remarkable regenerative capacity, however, this regenerative capacity may be impaired in disease states and thus may not be sufficient to compensate for loss of hepatocyte and organ function. [0003] WO 2007 / 002433 describes compounds as protein kinase inhibitors which are useful in the treatment of diseases and conditions associated with abnormal activity of protein kinases. These compounds are inhibitors of Raf protein kinases, especially B-Raf and c-Raf and their mutations, and are therefore useful in cancer therapy. In addition, they are sa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P1/16A61K31/437
CPCC07D471/04A61P1/16A61K31/437A61K31/501
Inventor 沃尔夫冈·阿尔布雷希特斯特凡·劳弗罗兰·赛利格菲利普·克鲁维科恩本特·普拉夫克
Owner HEPAREGENIX GMBH
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