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Bicyclic inhibitors of glycogen synthase kinase 3

A compound, low-level technology, applied in the direction of medical preparations containing active ingredients, drug combinations, organic active ingredients, etc.

Inactive Publication Date: 2003-08-06
CHIRON CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of lithium in inhibiting GSK3 activity has not been widely accepted, possibly because of its documented effects on molecular targets other than GSK3

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Characterization and Purification Methods

[0117] Compounds of the invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millennium chromatography system (Milford, Massachusetts) with a 2690 separation module. The analytical column was an Alltima C-18 reverse phase column from Alltech, 4.6 x 250 mm (Deerfield, Illinois). Gradient elution was used, typically starting with 5% acetonitrile / 95% water and proceeding to 100% acetonitrile over 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet (UV) absorption at 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Michigan), or fisher Scientific (Pittsburgh, Pennsylvania). In some cases, purity was assessed by thin layer chromatography (TLC) using glass or plastic lined silica gel plates, such as Baker-Flex Silica Gel 1B2-F. TLC results can be visualized under UV light, or using well known iodine vapor and var...

Embodiment 2

[0124] Synthesis of 1-[(tert-butyl)oxycarbonyl]-4-oxopiperidine-3-carboxylic acid methyl ester

[0125] HPLC was performed on a Waters 2690 separation module with a Column Engineering 5[mu] Reliasil C18 column (50 x 4.6 mm) and a gradient slope of 5%-80% acetonitrile in water in 18 minutes.

[0126] 4-oxopiperidine-3-carboxylic acid methyl ester (5.0 g, 25.8 mmol), sodium hydroxide (1.24 g, 31.0 mmol) in 1,4-dioxane and water (60 mL: 30 mL ) solution, di-tert-butyl dicarbonate (6.76 g, 31.0 mmol) was added in portions. The resulting solution was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, and washed with MgSO 4 Drying, filtration and concentration in vacuo afforded methyl 1-[(tert-butyl)oxycarbonyl]-4-oxopiperidine-3-carboxylate as a yellow viscous oil in quantitative yield. The crude product gave satisfactory NMR and was used in the next step without purifi...

Embodiment 3

[0128] Synthesis of tert-butyl 2-methylthio-4-oxo-3,5,6,7,8-pentahydropyrido[4,3-d]pyrimidine-6-carboxylate

[0129] A mixture containing methyl 1-[(tert-butyl)oxycarbonyl]-4-oxopiperidine-3-carboxylate (6.64 g, 25.8 mmol), 2-methyl-2-thiopseudouric acid ester ( A solution of 7.19 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was heated to 80°C overnight under nitrogen. Water was added to the reaction mixture to obtain a homogeneous solution, which was adjusted to pH 4-5 with glacial acetic acid. During this process a white precipitate formed. Filter the mixture. The collected solid was washed with water and ethyl acetate to give 2-methylthio-4-oxo-3,5,6,7,8-pentahydropyrido[4,3-d]pyrimidine-6- tert-butyl carboxylate (3.0 g). The filtrate was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO 4 ) and filter. The filtrate was concentrated in vacuo to give a yellow soli...

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PUM

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Abstract

Bicyclic based compounds of the formula (I), compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and a treatment of GSK3 mediated disorders in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of disorders mediated by GSK3 activity, such as in the treatment of diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.

Description

field of invention [0001] The present invention relates to novel bicyclic compounds that inhibit the activity of glycogen synthase kinase 3 (GSK3), pharmaceutical compositions containing these compounds, and the use of the compounds and compositions alone or in combination with other pharmaceutically active agents. The compounds and compositions provided by the present invention are effective in treating diseases mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative diseases, obesity, arteriosclerotic cardiovascular disease, essential hypertension, Utility in diseases such as polycystic ovary syndrome, syndrome X, ischemia (especially cerebral ischemia), traumatic brain injury, bipolar disorder, immunodeficiency or cancer. Background of the invention [0002] Glycogen synthase kinase 3 (GSK3) is a serine / threonine kinase for which two isoforms have been identified: alpha and beta. Woodgett, Trends Biochem Sci., 16:177-81 (1991). Both ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/99A61K31/519A61K45/00A61P3/04A61P3/10A61P9/10A61P9/12A61P15/00A61P17/02A61P25/28A61P35/00A61P37/00A61P43/00C07D471/04C12N5/07C12N5/078C12N5/09
CPCC07D471/04A61P15/00A61P17/02A61P25/28A61P3/04A61P35/00A61P37/00A61P43/00A61P9/10A61P9/12A61P3/10
Inventor J·M·努斯周晓辉
Owner CHIRON CORP
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