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N,N'-bis-substituted urea Raf kinase inhibitors and preparation method and application thereof

A C1-C6 compound technology, applied in the field of medicinal chemistry, can solve problems such as limited therapeutic range and adverse reactions

Active Publication Date: 2011-08-17
深圳澳美制药技术开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many cytotoxic drugs have limited therapeutic range and are prone to treatment-related adverse effects

Method used

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  • N,N'-bis-substituted urea Raf kinase inhibitors and preparation method and application thereof
  • N,N'-bis-substituted urea Raf kinase inhibitors and preparation method and application thereof
  • N,N'-bis-substituted urea Raf kinase inhibitors and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] 1H-Benzo[d]imidazole-2-carbonyl chloride (I-1)

[0088] Add 8.1 g (50 mmol) of 1H-benzo[d]imidazole-2-carboxylic acid and 40 mL of thionyl chloride into a 150 mL single-necked bottle, and heat to reflux for 4 hrs. The thionyl chloride was distilled off under reduced pressure to obtain 7.7 g of yellow solid (I-1) with a yield of 86.0%. The product did not need further purification and was directly used for the next reaction.

Embodiment 2

[0090] N-[2-(4-nitrophenyl)ethyl]-1H-benzo[d]imidazole-2-carboxamide (I-2)

[0091] Add 4-nitrophenethylamine 9.6g (58mmol), anhydrous chloroform 50mL and anhydrous triethylamine 5mL in 250mL three-necked bottle, slowly drop the chloroform suspension of 1-17.0g (38.7mmol) at room temperature ( 25 mL), heated to reflux for 4 hr after the addition, and TLC detected that the starting material disappeared (methanol:chloroform=1:30). Chloroform was distilled off, about 50 mL of water was added, stirred, allowed to stand, and filtered with suction to obtain 9.94 g of yellow solid (I-2), with a yield of 83.1%. The product did not need further purification and was directly used in the next reaction. 1 H-NMR [300MHz, DMSO-d 6 ]: δ13.16(1H, s, benzimidazole-NH); 9.04(1H, t, CO-NH); 8.13(2H, dd, ArH); 7.69(1H, m, ArH); 7.56(1H, m, ArH); 7.53 (2H, dd, ArH); 7.28 (2H, m, ArH); 83.61 (2H, q, CH 2 ); δ3.05(2H, t, CH 2 ).

Embodiment 3

[0093] N-[2-(4-aminophenyl)ethyl]-1H-benzo[d]imidazole-2-carboxamide (I-4)

[0094] Add I-29g (29mmol), iron powder 6.5g (116mmol), NH 4 Cl 3.1g (58mmol) and 75% ethanol (100mL) were heated to reflux for 5hrs, and the starting material disappeared as detected by TLC (methanol:chloroform=1:30). Suction filtration while hot, and the filter cake was washed with a small amount of ethanol. Most of the solvent was evaporated under reduced pressure, extracted three times with ethyl acetate (20mL×3), the combined extracts were washed once with water and saturated sodium chloride respectively (20mL×1), the solvent was evaporated under reduced pressure to obtain a yellow oil, The crude product was subjected to column chromatography (developing solvent: methanol: chloroform = 1:30) to obtain I-45.74g with a yield of 70.6%. 1 H-NMR [300MHz, DMSO-d 6 ]: δ13.16 (1H, s, benzimidazole); 8.82 (1H, t, CO-NH); 7.69 (1H, m, ArH); 7.53 (1H, m, ArH); 7.28 (2H, m, ArH) ; 6.88 (2H, dd, ArH); 6.74...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to N,N'-bis-substituted urea compounds, a preparation method thereof, a medicinal composition containing the compounds and medical application of the N,N'-bis-substituted urea compounds, particularly application of the N,N'-bis-substituted urea compounds used as a Raf kinase inhibitor.

Description

field of invention [0001] The present invention relates to the field of medicinal chemistry, in particular to a kind of N,N'-disubstituted urea compounds, their preparation method, pharmaceutical composition containing these compounds and their medical application, especially as the application of Raf kinase inhibitor . Background technique [0002] Tumor is a major disease that threatens human health. The treatment of tumor has been paid close attention to all over the world. Traditional chemotherapy drugs non-specifically block cell division and cause cell death. While killing tumor cells, they also destroy normal cells in the human body. Many cytotoxic drugs have limited therapeutic range and are prone to treatment-related adverse reactions. Targeting specific pathways can prevent tumor growth and reduce toxicity to normal cells. [0003] The Ras / Raf / MEK / ERK signal transduction pathway exists in most cells, and transduces extracellular stimulus signals to cells and th...

Claims

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Application Information

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IPC IPC(8): C07D235/24C07D209/42C07D207/34C07D471/04C07D233/90C07C275/40C07C273/18A61K31/437A61K31/4184A61K31/4164A61K31/404A61K31/401A61K31/17A61P35/00A61P35/02A61P19/00
Inventor 唐伟方陆涛颜彩虹林国武陈亚东张陆勇
Owner 深圳澳美制药技术开发有限公司
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