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Pyrazole derivatives as protein kinase modulators

A technology of solvates and compounds, applied in the field of pyrazole derivatives as protein kinase regulators, can solve the problems of undisclosed inhibitory activity

Inactive Publication Date: 2007-02-28
ASTEX THERAPEUTICS LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PKB inhibitory activity not disclosed

Method used

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  • Pyrazole derivatives as protein kinase modulators
  • Pyrazole derivatives as protein kinase modulators
  • Pyrazole derivatives as protein kinase modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0828] 2-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

[0829]

[0830] To a suspension of 2-(4-chlorophenyl)-2-phenethylamine hydrochloride (134 mg, 0.5 mmol, 1.0 equiv) (Array PPA-Q02-1) in toluene (0.8 mL) was added bis( Tri-tert-butylphosphine)palladium(0) (3 mg, 1 mol%) (Strem), and the mixture was purged with nitrogen. Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg, 0.55 mmol, 1.1 equiv ) (Aldrich 52,505-7) in ethanol (0.8 mL), followed by the addition of potassium carbonate (415 mg, 3.0 mmol, 6 eq) in water (2.5 mL). The mixture was purged with nitrogen and sealed. Using 50 watts of power, the reaction mixture was placed in the CEM Explorer TM Heat to 135°C in microwave for 15 minutes. The solvent was removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO 4 ), concentrated under reduced pressure...

Embodiment 2

[0832] 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile

[0833] 2A. 2-(3-Bromo-phenyl)-3-phenyl-propionitrile

[0834]

[0835] A solution of 40% KOH (2.83 g in 5.0 mL of water) in ethanol (13 mL) was added to benzaldehyde (2.85 mL, 28.05 mmol) and 3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol ( 9 ml) solution. The reaction mixture was then stirred at room temperature for 2 hours and the precipitate was collected by suction filtration and washed with cold ethanol (6.68 g, 92%). The crude product (3.45 g, 12.14 mmol) was then dissolved in ethanol (35 mL) and heated to 65°C. Sodium borohydride (459 mg, 12.14 mmol) was added in several portions and the reaction mixture was maintained at this temperature for a further 2 hours. When cooled, water (10 mL) was added and the solvent was removed under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and dried (MgSO 4 ), filtered and ...

Embodiment 3

[0840] 2-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine

[0841]

[0842] Following the procedure of Example 1, but using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2- Base)-1H-pyrazole (boron molecule D03-BM152) instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-Pyrazole to give the title compound. (LC / MS: (PS-A)R t 1.79[M+H] + 292.

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Abstract

The invention provides compounds of the formula: (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between Rand NR<2>R<3> and a maximum chain length of 4 atoms extending between E and NR<2>R<3>, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the inker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the NR<2>R<3> group and provided that the oxo group when present is located at a carbon atom a with respect to the NR<2>R<3> group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R is an aryl or heteroaryl group; and R<2>, R<3>, R<4> and R<5> are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

Description

[0001] The present invention relates to aryl- and heteroaryl-alkylamine compounds containing pyrazoles, which can inhibit or regulate the activity of protein kinase B (PKB) and protein kinase A (PKA), and relate to the use of the compounds in the treatment or prevention of and PKA-mediated disease states or disorders, and relate to novel compounds having PKB and PKA inhibitory or modulatory activity. Pharmaceutical compositions containing the compound and new chemical intermediates are also provided. Background of the invention [0002] Protein kinases constitute a large family of structurally related enzymes responsible for the control of a variety of signal transduction processes in cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press , San Diego, CA). Kinases can be classified into families according to the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs generally corre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12C07D413/10C07D401/10A61K31/415A61P37/02
Inventor V·贝尔迪尼G·萨克斯蒂M·L·韦尔东克S·J·伍德赫德P·G·怀亚特R·G·博伊尔H·F·索尔D·W·沃尔克I·科林斯R·道恩哈姆R·A·E·卡尔
Owner ASTEX THERAPEUTICS LTD
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