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Imidazole Substituted Pyrimidines Useful in the Treatment of Glycogen Synthase Kinase-3 Related Disorders such as Alzheimer's Disease

a glycogen synthase and kinase-related technology, applied in the field ofimidazole substituted pyrimidines useful in the treatment of glycogen synthase-related disorders such as alzheimer's disease, can solve the problems of lithium intoxication, axon and neuritic dystrophy, etc., and achieve the effect of good bioavailability and selective inhibition

Inactive Publication Date: 2012-03-29
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to new compounds of formula (I) and pharmaceutical formulations containing them. These compounds are glycogen synthase kinase 3 (GSK3) inhibitors that can be used to treat Alzheimer's disease and other neurodegenerative diseases. GSK3 is a protein that is involved in the phosphorylation of several substrates such as tau, β-catenin, and glycogen synthase. Inhibiting GSK3 can lead to the reduction of amyloid-β plaque formation, decrease in tau phosphorylation, protect against neuronal cell death, and improve memory function. The invention also includes a process for preparing the new compounds."

Problems solved by technology

This results in depolymerization of microtubules, which leads to dying of axons and neuritic dystrophy.
The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication.

Method used

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  • Imidazole Substituted Pyrimidines Useful in the Treatment of Glycogen Synthase Kinase-3 Related Disorders such as Alzheimer's Disease
  • Imidazole Substituted Pyrimidines Useful in the Treatment of Glycogen Synthase Kinase-3 Related Disorders such as Alzheimer's Disease
  • Imidazole Substituted Pyrimidines Useful in the Treatment of Glycogen Synthase Kinase-3 Related Disorders such as Alzheimer's Disease

Examples

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Effect test

working examples

[0145]The following working example will describe, but not limit, the invention.

example 1

5-Fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine

[0146]

[0147]5-Fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (5.12 g, 18.46 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (5.06 g, 18.46 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.152 g, 0.18 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.107 g, 0.18 mmol) and sodium tert-pentoxide (4.07 g, 36.92 mmol) in toluene (70 mL) were mixed and degased. The mixture was stirred at 110° C. under nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water were added and the phases were separated. The organic phase was concentrated and the crude was purified by preparative HPLC. The pooled fractions were concentrated to about half volume. The residue was extracted with EtOAc (×2). The combined organic phases were concentrated and the residue was dried in vacuum at 40° C. for ...

example 2

5-Fluoro-N-(2-fluoro-4-(((R)-3-methylmorpholino)methyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine hydrochloride

[0153]

[0154](R)-4-(4-Bromo-3-fluorobenzyl)-3-methylmorpholine (200 mg, 0.69 mmol), 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (192 mg, 0.69 mmol) and potassium tert-butoxide (78 mg, 0.69 mmol) were mixed in dioxane (4 ml) and the mixture was stirred under a stream of argon for 5 minutes. Pd2(dba)3 (76 mg, 0.08 mmol) and X-Phos (79 mg, 0.17 mmol) were added followed by DMF (1 ml) and the reaction mixture was heated in a microwave reactor at 120° C. for 40 minutes. The crude was filtered through diatomeous earth. The filtrate was diluted with dichloromethane and was washed with brine. The aquous phase was extracted with dichloromethane (×3). The organic phases were pooled, evaporated and purified by column chromatography on silica followed by preparative HPLC. Fractions containing product were ...

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Abstract

The present invention relates to a new compound of formula (I) wherein R1 is hydrogen or fluoro; R2 and R3 are independently selected from hydrogen or methyl; or a pharmaceutically acceptable salt thereof, pharmaceutical formulations containing said compound, to the use of said active compound in therapy, to the use for the treatment of conditions associated with glycogen synthase kinase-3 related disorders, such as Alzheimer's disease, as well as for the method of treatment of said disorders, comprising administering to a mammal, including human in need of such treatment, a therapeutically effective amount of said compound.

Description

FIELD OF THE INVENTION[0001]The present invention relates to new compounds of formula (I) or a pharmaceutically acceptable salt thereof, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates to a process for the preparation of said compounds of formula (I).BACKGROUND OF THE INVENTION[0002]Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it (Kannoji et al, Expert Opin. Ther. Targets 2008, 12, 1443-1455).Alzheimer's Disea...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61P25/24A61P25/28A61P25/18A61P31/14A61P25/16A61P3/00A61P31/00C07D413/14A61P25/00
CPCA61K31/5377C07D413/14C07D405/14A61P3/00A61P3/10A61P17/14A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/06A61P29/00A61P31/00A61P31/14A61P35/00C07D403/04
Inventor BURROWS, JEREMY NICHOLASARVIDSSON, PER I.TJERNELD, ERICAYNGVE, ULRIKA
Owner ASTRAZENECA AB
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