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Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof

A piperazine, phenyl technology, applied in the field of medicinal chemistry, can solve the problems of uncontrollable growth and proliferation of cells

Inactive Publication Date: 2013-12-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the Raf kinase is mutated, it may cause allosteric activation of this signal transduction pathway, resulting in uncontrolled cell growth and proliferation

Method used

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  • Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof
  • Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof
  • Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] 1-(4-nitrophenyl)piperazine 2a

[0081] The starting material p-fluoronitrobenzene (4.20g, 30mmol), piperazine (8.61g, 10mmol), potassium carbonate (4.15g, 30mmol) and anhydrous acetonitrile 100ml were added to a 250ml round-bottomed bottle, at 90°C React for 5 hours, after cooling, concentrate under reduced pressure to remove acetonitrile, add about 200ml of water, then transfer to a separatory funnel, extract with ethyl acetate, 100ml×2, wash the organic phase with water, collect the organic phase and dry it, then concentrate by suction filtration After removal of ethyl acetate, it was poured into water to obtain light yellow solid 2a (4.00 g, 19.3 mmol), yield 64.4%. mp: 128~131℃; MS[M+H] + 208.0.

Embodiment 2

[0083] 1-(2-methyl-4-nitrophenyl)piperazine 2b

[0084] Using 1-fluoro-2-methyl-4-nitrobenzene as the starting material, the synthesis method of compound 2a was similar to that of compound 2a to obtain light yellow solid 2b with a yield of 50.3%. MS [M+H] 222.1.

Embodiment 3

[0086] 1-(2-Chloro4-nitrophenyl)piperazine 2c

[0087] Using 1-fluoro-2-chloro-4-nitrobenzene as the starting material, similar to the synthesis method of compound 2a, a light yellow solid 2c was obtained with a yield of 61.67%. MS [M+H] 242.1.

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a diaryl urea compound (A), wherein the definitions of R1-R13, Ar and X are shown in the specification. The invention also discloses a preparation method of the compounds of the general formula (A), medicinal compositions containing the compounds and medical application thereof, particularly application as the Raf kinase inhibitor.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of piperazine compounds, their preparation method, pharmaceutical composition containing these compounds and their medical application, especially the application as Raf kinase inhibitor. Background technique [0002] Raf kinase has become an important drug target for the treatment of tumors. An important component of the Ras / Raf / MEK / ERK signal transduction pathway. This signal transduction pathway plays an important role in cell growth and differentiation. If the Raf kinase is mutated, it may cause the allosteric activation of this signal transduction pathway and lead to uncontrollable growth and proliferation of cells. In 2005, the Raf-1 inhibitor Sorafenib (BAY43-9006) jointly developed by Onyx Pharmaceuticals (Emeryville, CA, USA) and Bayer (Leverkusen, Germany) was approved by the FDA for the treatment of advanced renal cancer; in 2007 The FDA has approv...

Claims

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Application Information

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IPC IPC(8): C07D235/24C07D209/42C07D207/34C07D231/12C07D295/192A61K31/496A61K31/495A61P35/00A61P35/02
Inventor 唐伟方吴增张帆陆涛陈亚东顾亚洲李同辉于志成胡诗合严明
Owner CHINA PHARM UNIV
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