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Diaryl urea derivative and application thereof

An aryl and phenyl technology, which is applied in the field of synthesis and preparation of tyrosine kinase inhibitors, can solve the problems of poor treatment effect of AML patients and other problems

Inactive Publication Date: 2010-06-02
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Axl kinase expression is associated with poor treatment outcomes in AML patients

Method used

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  • Diaryl urea derivative and application thereof
  • Diaryl urea derivative and application thereof
  • Diaryl urea derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] 2-[4-(4-Aminophenoxy)phenyl]thiazole (5)

[0088]

[0089] step 1

[0090] Add 60g (0.75mol) of 70% sodium hydrosulfide, 76g (0.375mol) of magnesium chloride hexahydrate, and 50g (0.375mol) of p-methoxybenzonitrile into a 1L three-necked flask, dissolve in 500mL DMF, and stir mechanically at room temperature for 8h. Stop the reaction, pour the reaction solution into 1L of water, precipitate a yellow solid, filter, suspend the filter cake in 1N dilute hydrochloric acid (1.5L), stir for 30min, filter, and dry to obtain 56.2g of a light yellow solid (1). 89.7%, mp 149-151°C.

[0091] step 2

[0092] 20 g (0.12 mol) of compound (1), 18.6 mL (0.12 mol) of bromoacetaldehyde diethyl acetal, and 500 mL of absolute ethanol were added to a 1L eggplant-shaped bottle, and the mixture was stirred and refluxed for 10 h. The reaction was stopped, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, the obtained solid was dissol...

Embodiment 2

[0100] 1-(4-Chlorophenyl)-3-{4-[4-(2-thiazolyl)phenoxy)]phenyl}urea (Ia-1)

[0101]

[0102]Add 0.6g (2.24mmol) of compound (5) into a 100mL three-necked flask, dissolve in 40mL of anhydrous tetrahydrofuran, then add 1.8g (11.2mmol) of N,N'-carbonyldiimidazole (CDI), reflux reaction under nitrogen protection, point After the board monitors that the reaction of the raw materials is complete, 0.36 g (2.35 mmol) of p-chloroaniline is added, and the reflux reaction is continued for 3 h. Stop the reaction, cool the reaction solution to room temperature, evaporate the solvent under reduced pressure, add 50 mL of water to remove excess CDI, extract with ethyl acetate (3×30 mL), combine the organic layers, wash with water (30 mL) and saturated brine (30 mL) respectively , dried over anhydrous sodium sulfate overnight. After filtration, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 as th...

Embodiment 3

[0104] 1-(4-Chloro-3-trifluoromethylphenyl)-3-{4-[4-(2-thiazolyl)phenoxy)]phenyl}urea (Ia-2)

[0105]

[0106] Using the method of Example 2, input compound (5) 0.6g (2.24mmol) and 4-chloro-3-trifluoromethylaniline 0.46g (2.35mmol), obtain white solid (Ia-2) 0.58g, yield 52.9%, mp 135-136°C. IR (KBr, cm -1 ): 3304.98, 1645.91, 1601.07, 1556.23, 1501.78, 1415.30, 1251.96, 1175.09, 1139.86, 823.38; 1 H-NMR (DMSO-d 6 , 300MHz) δ (ppm): 7.04-7.11 (m, 4H, Ar-H), 7.51-7.54 (m, 2H, Ar-H), 7.59-7.67 (m, 2H, Ar-H), 7.73 (d , J=3.26Hz, 1H, Ar-H), 7.88(d, J=3.25Hz, 1H, Ar-H), 7.92-7.97(m, 2H, Ar-H), 8.11(d, J=2.27Hz , 1H, Ar-H), 8.87(s, 1H,- NH CONH-), 9.14(s, 1H, -NHCO NH -); 13 C-NMR (DMSO-d 6 , 125MHz) δ(ppm): 117.61, 118.17, 119.77, 120.32, 121.75, 127.67, 127.96, 128.69, 136.27, 139.63, 143.60, 149.68, 152.53, 159.40, 166.54; ESI-MS m / z: ] + .

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Abstract

The invention relates to a diaryl urea derivative with a structure shown as a formula (1), a pharmaceutically acceptable salt and an application thereof. Proved by pharmacological experiments, the compound and pharmaceutically acceptable salts thereof can inhibit the proliferation of tumor cells.

Description

technical field [0001] The present invention relates to a synthesis and preparation technology of tyrosine kinase inhibitors, that is, diaryl urea derivatives and uses thereof, and also relates to intermediates of such compounds. Background technique [0002] The following is provided as background information and is not admitted to be prior art to the present invention. [0003] At present, many diaryl urea small molecule compounds have tried to be identified as protein kinase inhibitors, and are widely used in the treatment of a variety of diseases related to abnormal kinase activity, such as tumors, psoriasis, liver cirrhosis, diabetes, angiogenesis, ophthalmic diseases, Rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis and various kidney diseases. Currently, many diarylureas have been described as kinase inhibitors for the treatment of cancer. [0004] Protein Kinases include Protein Tyrosine Kinase ...

Claims

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Application Information

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IPC IPC(8): C07D277/24C07D417/12C07D233/64C07D409/12A61K31/426A61K31/427A61K31/4178A61P35/00
Inventor 吉民孙敏吴晓晴
Owner SOUTHEAST UNIV
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