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Urea derivatives as ABL modulators

a technology of urea derivatives and modulators, applied in the field of compounds, can solve problems such as poor patient prognosis, and achieve the effects of reducing the toxicity of inhibitory compounds, accurate targeting, and inhibiting kinase activity

Inactive Publication Date: 2005-07-28
AMBIT BIOSCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides compounds that can modulate the activity of kinases, particularly protein tyrosine kinases. These compounds can be used alone or in combination with other agents for the treatment and prevention of conditions and diseases such as cancer, hematologic malignancies, cardiovascular disease, inflammation, and multiple sclerosis. The compounds have specific structures and can be administered alone or in combination with other agents such as other compounds, other drugs, and other substances. The invention also provides methods for making and using the compounds."

Problems solved by technology

Such mutations also indicate a poor prognosis for the patient.

Method used

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  • Urea derivatives as ABL modulators
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  • Urea derivatives as ABL modulators

Examples

Experimental program
Comparison scheme
Effect test

example a

Synthesis of Isoxazole-Ureas

[0201]

[0202] A mixture of amine 1 (1 eq) in dry THF is stirred at room temperature under argon for an hour. Then the stirred suspension is cooled to 0° C. and to it is added dropwise a solution of phosgene or disuccinimidyl carbonate or carbonyl diimidazole (1.2 eq). The reaction is stirred at 0° C. for half an hour. An isoxazol-amine 2 in THF is added dropwise and the reaction is allowed to warm to room temperature and stirred overnight. The solvent is removed and extracted with ethyl acetate and water. The organic layer is dried over magnesium sulfate and solvent removed, and the product 3 purified by HPLC.

[0203] Alternatively, to a stirring solution of an isoxazol-amine 2 (1 eq) in THF, a mixture of 4-nitrophenyl chloroformate (1.2 eq) and triethyl amine (1.2 eq) is added dropwise at 0° C. The reaction is stirred for two hours at room temperature and the aniline 1 is added. The reaction is refluxed to 80° C. for six hours. The mixture is cooled to r...

example b

Synthesis of alkyl-ureas

Synthesis of Compound B1: 1-(4-methoxybenzyl)-3-(5-tert-butylisoxazol-3-yl)urea

[0209]

[0210] To a flask 5-tert-Butyl-3-isocyanato-isoxazole (242 mg, 1 eq) and substituted benzylamine (1 eq) was added and dissolved in toluene. The reaction was allowed to stir at 50° C. for three hours. The solvent removed and the mixture was purified by HPLC. Yield: 188 mg (47%).

[0211] Compounds B2 through B8 were synthesized in a manner analogous to Compound B1 using similar starting materials and reagents. The structures are shown below in Table B:

TABLE BNO.CHEMICAL STRUCTUREB1B2B3B4B5B6B7B8

example c

Synthesis of Reactive Ureas

Synthesis of Compound C1: 1-(5-tert-butylisoxazol-3-yl)-3-(4-aminophenyl)urea

[0212]

[0213] To a flask 5-tert-Butyl-3-isocyanato-isoxazole (242 mg, 1 eq) and substituted aniline (159 mg, 1 eq) was added and dissolved in toluene. The reaction was allowed to stir at 50° C. for three hours. The solvent removed and the mixture was purified by HPLC. Yield: 188 mg (47%).

[0214] Compounds C2 through C3 were synthesized in a manner analogous to Compound C1 using similar starting materials and reagents. The structures are shown below in Table C:

TABLE CNO.CHEMICAL STRUCTUREC1C2C3

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Abstract

The invention provides methods and compositions for treating conditions mediated by Bcr-Abl. The invention also provides methods of using the compounds and / or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 520,278, filed Nov. 13, 2003, U.S. Provisional Application No. 60 / 527,094, filed Dec. 3, 2003, U.S. Provisional Application No. 60 / 531,243, filed Dec. 18, 2003, and U.S. Provisional Application No. 60 / 531,082, filed Dec. 18, 2003, the contents of which are incorporated herein by reference in their entirety.BACKGROUND [0002] Protein kinases (PKs) play a role in signal transduction pathways regulating a number of cellular functions, such as cell growth, differentiation, and cell death. PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins, and can be conveniently broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). Growth factor receptors with PTK activity are known as receptor tyrosine kinases. Protein receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberran...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61KA61K31/42A61K31/47A61K31/4709A61K31/4745A61K31/503A61K31/517A61K31/519A61K31/52C07D215/38C07D231/12C07D231/40C07D261/06C07D261/08C07D261/14C07D261/18C07D277/46C07D277/82C07D405/12C07D413/00C07D413/02C07D413/04C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D471/06C07D473/10C07D487/04C07D495/04C07D513/04
CPCA61K31/42C07D231/12C07D231/40C07D261/08C07D261/14C07D261/18C07D277/46C07D277/82C07D405/12C07D413/04C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D471/06C07D487/04C07D495/04C07D513/04A61P11/00A61P11/08A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00A61P9/00A61P9/10Y02A50/30
Inventor GROTZFELD, ROBERTPATEL, HITESTMEHTA, SHAMALMILANOV, ZDRAVKOLAI, ANDILIYLOCKHART, DAVID
Owner AMBIT BIOSCIENCES
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