Pyrazolo 1,5-a pyrimidine derivatives

A derivative and biological technology, applied in the field of preparing the compound, preparing the composition, preventing and/or treating various diseases

Inactive Publication Date: 2009-04-29
TEIJIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Currently, the identity of these proteins is still under investigation

Method used

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  • Pyrazolo 1,5-a pyrimidine derivatives
  • Pyrazolo 1,5-a pyrimidine derivatives
  • Pyrazolo 1,5-a pyrimidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0496] [General method for synthesizing pyrazolo[1,5-a]pyrimidines of general formula (VI)]

[0497] To a stirred solution of sodium ethoxide (50mmol) in ethanol (100ml) was added the appropriate 2-substituted malonate diester (20mmol) and the appropriately substituted 3-aminopyrazole (VII) (20mmol). The mixture was heated at reflux for 18 hours, during which time a precipitate formed * . The reaction was cooled to room temperature, then the mixture was filtered through an A4 sinter filter (while washing with a small amount of cold ethanol). The residue was dried in vacuo. The dried precipitate was dissolved in water (about 100 ml), and the resulting solution was acidified (pH 2) with concentrated HCl. This gives a milky white precipitate (VI), which is filtered and dried. Typically non-optimized yields range from 20-40%.

[0498] * In several cases, no or very little precipitation occurred when the substituent was an alkyl chain. In these cases, ethanol was removed und...

Embodiment 2

[0502] [General method for synthesizing pyrazolo[1,5-a]pyrimidines of general formula (V)]

[0503] To a suspension of dihydroxy compound (VI) (2 g) in N,N-dimethylaniline (2 ml) was added phosphoryl chloride (or phenylphosphonyl dichloride) (20 ml). The mixture was heated at reflux for 18 hours, then excess phosphoryl chloride (or phenylphosphonyl dichloride) was removed in vacuo. The residue was poured into ice (50 g) and washed with CH 2 Cl 2 Extraction (5x). The organic phase was adsorbed on neutral (active I) alumina and purified by chromatography (typically using petroleum ether→30% ethyl acetate / petroleum ether as eluent). Appropriately substituted 5,7-dichloropyrazolo[1,5-a]pyrimidine intermediate (V) was obtained in about 40% yield.

[0504]

[0505] Compound number R 1 R 2 R 4 mp(°C) or

Embodiment 3

[0507] [General method for synthesizing pyrazolo[1,5-a]pyrimidines of general formula (V-02)]

[0508] At room temperature, a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (V-01) (0.01mol) in chloroform (50ml) was treated with N-chlorosuccinimide, N-bromo Succinimide or iodine monochloride (0.011mol) treatment. The mixture was boiled at reflux until all solids had dissolved and no starting material remained (by TLC). The mixture was poured into ice / water, then the organic layer was separated and washed with Na 2 CO 3 Washed with aqueous solution, over MgSO 4 Dry and remove solvent in vacuo. The residue was purified by silica gel chromatography to give 3-halo-5,7-dichloropyrazolo[1,5-a]pyrimidine (V-02).

[0509] Compound number R 1 R 2 R 4 1 H-NMR (400MHz, CDCl 3 )d(ppm) V-11 H Br H 8.2(s, 1H, Het-H), 7.05(s, 1H, Het-H). V-12 H I H 8.15(s, 1H, Het-H), 2.60(s, 3H, 6-Me).

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Abstract

The Pyrazolo[1,5-a]pyrimidine derivatives represented by formula I and their pharmaceutically acceptable salts exhibit excellent kinase inhibiting activity. Drugs comprising the compounds as effective ingredients are therefore expected to be useful as therapeutic or prophylactic agents for a protein kinase mediated disorder in which kinase is implicated, such as inflammatory disease, autoimmune disease, destructive bone disorder, cancer and / or tumour growth.

Description

field of invention [0001] The present invention relates to novel compounds, their use in the inhibition of protein kinases, their use in medicine, especially in the prevention and / or treatment of various diseases, including inflammatory diseases, cancer, angiogenesis , diabetes and neurological diseases. The invention also provides methods for preparing the compounds, compositions containing them and methods for preparing the compositions. Background technique [0002] Protein kinases are a family of enzymes that catalyze the hydroxyl phosphorylation of proteins. About 2% of the genes predicted to be encoded by the human genome encode protein kinases. Phosphorylation of specific tyrosine, serine, or threonine residues on a target protein can dramatically alter its function in several ways, including activating or inhibiting enzyme activity, creating or blocking binding sites for other proteins, altering Subcellular localization or control of protein stability. Thus, prot...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P19/08A61P35/00A61P37/02A61P43/00A61P3/10A61P13/12A61P17/00A61P27/00A61P19/02A61P7/00A61P1/16A61P21/04A61P1/00A61P17/06
Inventor 片冈健一郎铃木直贵小杉知巳今井穣牧野弘明高桑美香鹈木元藤野爱子大上泰弘山越优子彬浦聪D·R·米彻尔D·J·辛普森C·J·哈里斯J·勒
Owner TEIJIN PHARMA CO LTD
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