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Inhibitors of glycogen synthase kinase 3

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

Inactive Publication Date: 2001-09-12
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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  • Inhibitors of glycogen synthase kinase 3

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 23

[0095] Resin Method G, described in more detail in Example 23, can be used to synthesize compounds of the invention having a carboxyl group at the 5-position.

[0096] The GSK3 inhibitor compound of the present invention can be purified by known methods such as chromatography, crystallization and the like.

[0097] Compounds of the invention preferably exhibit relatively sufficiently selective inhibitor activity for GSK3 compared to at least one other kinase. As used herein, the term "selectivity" refers to greater inhibition of GSK3 compared to at least one other kinase. Preferably, the GSK3 inhibitors of the invention are selective for GSK3 compared to the other two classes of kinases. Kinase activity assays for kinases other than GSK3 are well known. See Havlicek et al., J. Med. Chem., 40:408-12 (1997), which is incorporated herein by reference. GSK3 selectivity can be quantified according to the following formula: GSK3 selectivity=IC 50(其它激酶) ÷IC 50(GSK3) , where when...

Embodiment 1

[0134] Characterization and Purification Methods

[0135] 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 182-F flexible plates. TLC results can be visualized under UV light, or using well known iodine...

Embodiment 2

[0142] Solid Phase Synthesis of Pyrimidine Compounds

[0143] (Resin Method A)

[0144] Step A: Knoevenagel condensation

[0145] A suspension of benzaldehyde-bound resin (1 g, 0.52 mol) in 8 mL of a 1:1 ethanol:dioxane was treated with 2.2 mol of the β-ketoester and 1.3 mmol of an amine (eg, piperidine). The reaction mixture was shaken at room temperature for 20 hours, then the resin was filtered and washed with 4 x 10 mL of dichloromethane (DCM).

[0146] Step B: Cyclization and oxidation of the pyrimidine core

[0147] The product obtained in step A (100 mg, 0.052 mmol) was mixed with 0.26 mmol of pyrazole carboxamidine hydrochloride and 0.13 mmol of NaHCO 3 Mix in 1 ml of N-methylpyrrolidone. The reaction mixture was shaken at 70°C for 24 hours. After cooling, the reaction was washed successively with water, methanol, DMF, dichloromethane and ether, then dried. Cleavage of a small amount of resin indicated the presence of a high yield of the desired dihydropyrimidine...

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Abstract

New pyrimidine or pyridine based compounds, having the structure(I), compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and of 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 pyrimidine and pyridine derivatives that inhibit 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 have therapeutic effects on diseases mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative diseases, obesity, arteriosclerotic cardiovascular diseases, essential hypertension, multiple Utilization in diseases such as cystic 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, Currents in Biochemistry, 16:177...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4427A61K31/443A61K31/4433A61K31/4439A61K31/496A61K31/506A61K31/5377A61K31/55A61P3/04A61P3/10A61P9/00A61P9/10A61P9/12A61P15/00A61P25/28A61P35/00A61P37/04A61P43/00C07D213/74C07D213/85C07D239/48C07D401/12C07D401/14C07D403/04C07D403/12C07D405/14C07D409/14C07D413/14C07D417/12
CPCC07D401/14C07D401/12C07D239/48C07D405/14C07D403/12C07D417/12C07D409/14C07D213/74A61P15/00A61P25/28A61P3/04A61P35/00A61P37/04A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10
Inventor J·M·努斯S·D·哈里森D·B·林R·S·博伊斯S·P·布朗D·戈夫K·约翰逊K·B·普菲斯特S·拉穆塞P·A·伦豪L·西利S·苏布拉马尼亚姆A·S·韦格曼晓辉·A·周
Owner CHIRON CORP
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