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Kinase inhibitors with improved cyp safety profile

a technology of kinase inhibitors and safety profiles, applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of substantial increase or decrease in the blood and tissue concentration of a drug or metabolite, and the cyp enzyme is susceptible to inhibition

Inactive Publication Date: 2010-06-10
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Their low substrate specificity makes the CYP enzymes susceptible to inhibition by a wide variety of structurally distinct drugs.
As a result of CYP inhibition, abrupt changes can occur with a co-administered agent in a single individual leading to a substantial increase or decrease in the blood and tissue concentrations of a drug or metabolite.

Method used

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  • Kinase inhibitors with improved cyp safety profile
  • Kinase inhibitors with improved cyp safety profile
  • Kinase inhibitors with improved cyp safety profile

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea

example 1a

3-(4-aminophenyl)-7-iodothieno[3,2-c]pyridin-4-amine

[0178]A suspension of 3-bromothieno[3,2-c]pyridin-4-amine (13.7 g, 59.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (20 g, 62.7 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) and Na2CO3 (13.3 g, 125 mmol) in tetrahydrofuran (150 mL), methanol (40 mL) and water (80 mL) was degassed, then stirred at reflux overnight. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate and the combined organics were dried (using MgSO4), filtered and the filtrate was concentrated. The residue was purified via silica gel chromatography eluting with 50 to 70% ethyl acetate-hexanes to give crude tert-butyl 4-(4-aminothieno[3,2-c]pyridin-3-yl)phenylcarbamate. A solution of the crude product (59.7 mmol based on 100% yield) in N,N-dimethylformamide (80 mL) was treated with N-iodosuccinimide (...

example 1b

2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol

[0179]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask. The reaction was warmed from room temperature to 100° C. in an oil bath, by which time the carbonate had melted and served as the solvent for the reaction, which remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature and diluted with ethyl acetate, then filtered through Celite washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on an Analogix® Intelliflash™ purification system using a SF60-200 g column at a flow rate of 80 mL / min, eluting as follows: 5 minutes at 20% ethyl acetate / hexanes, then ramped from 40% to 90% ethyl acetate / hexanes over 35 minutes, then 100% ethyl acetate for another 20 minutes, to provide the tit...

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Abstract

Compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases, with an improved safety profile due to low CYP3A4 inhibition, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to provisional application Ser. No. 61 / 120,281, filed Dec. 5, 2008, and provisional application Ser. No. 61 / 223,760, filed Jul. 8, 2009.FIELD OF THE INVENTION[0002]This invention pertains to compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases, and which have an improved safety profile due to low CYP3A4 inhibition, compositions containing the compounds, and methods of treating diseases using the compounds.BACKGROUND OF THE INVENTION[0003]Mitosis is a process by which a complete copy of a duplicated genome is segregated by the microtuble spindle apparatus into two daughter cells. Aurora-kinases, key mitotic regulators required for genome stability, have been found to be overexpressed in human tumors. There is therefore an existing need in the therapeutic arts for compounds which inhibit Aurora-kinases, compositions comprising the inhibitors and methods of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4365C07D495/04A61P35/00
CPCC07D495/04A61P35/00A61P35/02A61K31/4365C07D333/36
Inventor MICHAELIDES, MICHAEL R.
Owner ABBVIE INC
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