Novel compounds and compositions as protein kinase inhibitors

A compound, alkyl technology, applied in the field of new compounds and compositions as protein kinase inhibitors, can solve the problem of drug resistance of STI-571

Inactive Publication Date: 2006-07-05
IRM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some patients in the blast crisis phase of CML are resistant to STI-571 due to mutations in the Bcr-abl kinase

Method used

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  • Novel compounds and compositions as protein kinase inhibitors
  • Novel compounds and compositions as protein kinase inhibitors
  • Novel compounds and compositions as protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0065] B. Preparation of compounds

[0066] The invention also includes processes for the preparation of the compounds of the invention. In the reactions described, when reactive functional groups such as hydroxyl, amino, imino, mercapto or carboxyl are desired in the final product, it may be necessary to protect these groups from their participation in the reaction. Conventional protecting groups can be used according to standard operating procedures, see, eg, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

[0067] Compounds of formula I wherein L is a bond can be prepared using the procedure in Reaction Scheme I below:

[0068] Reaction Flow Diagram I

[0069]

[0070] where X 1 、X 2 , R 1 , R 2 and R 3 The definition of is as described above for formula I, Q represents a halogen group, such as iodine or chlorine, preferably chlorine.

[0071] Compounds of formula I can be prepared by reacting ...

reference example 1

[0135] Reference Example 1. (6-Chloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine

[0136]

[0137] 1.0 g of 4,6-dichloropyrimidine (6.7 mmol) and 1.2 g of p-trifluoromethoxyaniline (6.7 mmol) were dissolved together in 15 mL of ethanol, and then 1.75 mL of DIEA (10 mmol) was added thereto. The reaction was carried out at reflux for 2 hours, then it was cooled to room temperature. After evaporating off the solvent, the crude product was purified by flash chromatography (EA / hexane=3:7) to obtain 1.94 g of (6-chloro-pyrimidin-4-yl)-(4-trifluoromethoxy base-phenyl)-amine.

reference example 2

[0138] Reference Example 2.4-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzoic acid

[0139]

[0140] 200 mg (4-chloro-pyrimidin-6-yl)-(4-trifluoromethoxy-phenyl)-amine (0.69 mmol) prepared in Reference Example 1 was added to 115 mg of 4-carboxyphenylboronic acid (0.69 mmol), 40 mg tetrakis(triphenylphosphine) palladium (0.034 mmol) and 292 mg sodium carbonate (2.76 mmol) in a flask. To this flask was added 10 mL of solvent MeCN / H 2 O(1:1). After filling with argon, the flask was heated to 90° C. for 8 hours. The hot reaction solution was filtered and collected. To this solution was added 6N HCl solution until its pH was below 5. The pale solid 4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzoic acid (220 mg) was collected by filtration and washed twice with 5 mL of water .

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Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated tyrosine kinase activity, particularly diseases associated with the activity of PDGF-R, c-Kit and Bcr-abl.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Application Serial No. 60 / 460,838, filed April 4, 2003, which is incorporated herein by reference. Background technique [0003] technical field [0004] The present invention provides a new class of compounds, pharmaceutical compositions containing the compounds and the use of the compounds for the treatment or prevention of diseases or conditions associated with abnormal or uncontrolled tyrosine kinase activity, particularly those associated with PDGF-R, c -A method for Kit and Bcr-abl related diseases. [0005] Background technique [0006] Protein kinases represent a large class of proteins that play key roles in the regulation and maintenance of many cellular processes controlling cellular function. These kinases include receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGF-R), receptor kinase for stem c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/02C07D239/02C07D251/18C07D401/04C07D401/12C07D403/04A61K31/505A61K31/53A61K31/513A61P29/00
Inventor 丁强申太甫张国宝F・阿德里安N・S・格雷
Owner IRM
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