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Chemical compounds

A technology of compound and alkyl, applied in the field of treating human or animal body and preparing said compound, can solve problems such as poor prognosis

Inactive Publication Date: 2009-01-14
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Numerous studies have shown that overexpression of CSF-1R confers poor prognosis in some of these cancers

Method used

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preparation example Construction

[0287] Preparation of the compounds of the invention

[0288] Another aspect of the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0289] Method a-1) The amine of formula (A)

[0290]

[0291] React with the acid of formula B or its activated acid derivative:

[0292]

[0293] Method a-2) The amine of formula (A)

[0294]

[0295] React with R-N=C=O, where R is C 1-6 Alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;

[0296] Method a-3) The amine of formula (A)

[0297]

[0298] React with chloroformate or activator (such as carbonyl diimidazole, phosgene or other reagents known to the skilled person), then react with ROH or RR’NH, where R is C 1-6 Alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and R’ is H or C 1-6 alkyl;

[0299] Method b) The acid of formula C or its activated acid derivative:

[0300]

[0301] Reaction with amines of formula D:

[0302]

[0303] ...

Embodiment 1

[0506] 5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methyl-N-(2-methyl-1,3- Thiazol-5-yl)benzamide

[0507] At room temperature, add 5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylbenzoic acid (Method 7, 82mg, 0.25mmol), 2-methyl -1,3-thiazol-5-amine (Method 2, 28mg, 0.25mmol), HATU (101mg, 0.275mmol) and N,N-diisopropylethylamine (0.135mL) in DMF (0.5mL) The solution was stirred for 16 hours. The reaction mixture was partitioned between water and EtOAc, the organic layer was washed with brine and then dried (MgSO 4 ). Purified by reverse phase HPLC (5%-95% water-MeCN, 15 minutes), after solvent evaporation, 51 mg (48%) of the title compound was obtained.

[0508] 1 H NMR CDCl 3 11.80(s, 1H) 10.39(s, 1H) 8.64(s, 1H) 7.90-8.02(m, 3H) 7.78-7.81(m, 2H) 7.60(t, 1H) 7.35(d, 1H) 2.49(s, 3H) 2.39 (s, 3H) 1.76 (s, 6H); m / z 419.

Embodiment 2-24

[0510] By a method similar to Example 1, using 1,3-thiazol-5-amine (method 1), 2-methyl-1,3-thiazol-5-amine (method 2), 5-amino-N-methyl Yl-1,3-thiazole-2-carboxamide (method 3), 2-(morpholin-4-ylcarbonyl)-1,3-thiazol-5-amine (method 4), 5-amino-N-methyl Oxy-N-methyl-1,3-thiazole-2-carboxamide (Method 5), 2-isopropyl-1,3-thiazol-5-amine (Method 33) or 2-cyclopropyl-1 , 3-thiazol-5-amine (Method 34) and appropriate starting materials to prepare the following compounds. In some cases, alternative purification methods (column chromatography or recrystallization from EtOAc:hexane) are required.

[0511] Real

[0512] Real

[0513] Real

[0514] Real

[0515] Real

[0516] Real

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PUM

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Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula which possess CSF 1R kinase inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.

Description

Background of the invention [0001] The present invention relates to a compound or a pharmaceutically acceptable salt thereof, which has colony stimulating factor 1 receptor (CSF-1R) kinase inhibitory activity and thereby contributes to its anti-cancer activity, so it can be used in a method for treating human or animal bodies. The present invention also relates to a method for preparing the compound, a pharmaceutical composition containing the compound, and the use thereof in preparing a medicine for producing anticancer effects in warm-blooded animals such as humans. [0002] Receptor tyrosine kinases (RTK's) are a subfamily of protein kinases that play an important role in cell signal transduction and are involved in various cancer-related processes including cell proliferation, survival, angiogenesis, invasion and metastasis. It is believed that there are at least 96 different RTK's including CSF-1R. [0003] CSF-1R or c-fms was originally identified as an oncogene v-fms derive...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/46A61K31/426A61P35/00
CPCC07D277/46C07D417/12A61P1/04A61P1/18A61P13/12A61P19/02A61P19/10A61P25/28A61P29/00A61P35/00A61P3/04A61P37/02A61P37/06A61P43/00A61P9/10A61K31/426
Inventor B·阿奎拉D·库克L·达金S·伊奥阿尼迪斯P·利恩D·斯科特郑晓兰
Owner ASTRAZENECA AB