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USE OF 7-(PYRIMIDIN-4 YL)-IMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONES AS GSK-3BETA INHIBITORS

a technology of pyrimidin and pyrimidin-4 yl, which is applied in the field of compounds, can solve problems such as neurotrophic activity

Inactive Publication Date: 2008-12-25
SANOFI SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds that can prevent and treat neurodegenerative diseases caused by abnormal GSK3β activity. These compounds are inhibitors of GSK3β, which is an enzyme involved in the development of Alzheimer's disease and other neurodegenerative diseases. The compounds have been found to have inhibitory activity against GSK3β and can be used as an active ingredient in a medicament for preventive and therapeutic treatment of these diseases. The invention also provides a method for preventive and therapeutic treatment of neurodegenerative diseases caused by abnormal GSK3β activity.

Problems solved by technology

Thus, it appears that inhibition of GSK3β activity may result in neurotrophic activity.

Method used

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  • USE OF 7-(PYRIMIDIN-4 YL)-IMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONES AS GSK-3BETA INHIBITORS
  • USE OF 7-(PYRIMIDIN-4 YL)-IMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONES AS GSK-3BETA INHIBITORS
  • USE OF 7-(PYRIMIDIN-4 YL)-IMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONES AS GSK-3BETA INHIBITORS

Examples

Experimental program
Comparison scheme
Effect test

example 1

Compound No 2 of Table 1

1-[3-(2-Fluoro-phenyl)-propyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one hydrochloride (1:1)

1.1. 7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one

[0073]A mixture containing 2.9 g (15 mmol) of 3-oxo-3-(pyrimidin-4-yl)-propionic acid ethyl ester (prepared by analogy to the method described in patent DE 2705582), 2 g (15 mmol) of 2-aminoimidazole hemisulfate and 1.2 g (15 mmol) of ammonium acetate was heated at 140° C. during 18 h.

[0074]The cooled mixture was treated with 30 ml of acetonitrile and filtered and the precipitate was added to water and heated at reflux temperature for 30 min.

[0075]The resulting solution was cooled and the precipitate recovered by filtration. The crude product thus obtained was recrystallized from ethanol to give 1.75 g of pure product as a gray solid.

[0076]Mp: 345-346° C.

1.2. 1-[3-(2-Fluoro-phenyl)-propyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one hydrochloride (1:1)

[0077]A suspension of 0.433 g (2.03 mmol) of ...

example 2

Compound No 3 of Table 1

1-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one

2.1 (4-Fluoro-2-methoxy-phenyl)-acetic acid methyl ester

[0080]To a suspension of 14.34 g (32.47 mmol) of lead (IV) acetate in 100 ml of anhydrous toluene was added a mixture of 5.2 g (30.92 mmol) of 1-(4-fluoro-2-methoxy-phenyl)-ethanone and 15.02 ml (123.13 mmol) of boron trifluoride etherate in 9 ml of methanol. The reaction mixture is further stirred at room temperature for 16 h. Water was added to the cooled mixture and the resulting solution extracted with toluene. The extracts were washed with saturated sodium hydrogen carbonate solution, saturated sodium chloride solution and dried with sodium sulfate. The solvent was evaporated to dryness to give 6 g of product as an oil which was used in the subsequent step without further purification.

2.2 2-(4-Fluoro-2-methoxy-phenyl)-ethanol

[0081]To a suspension of 1.72 g (45.41 mmol) of lithium aluminum hydride in 120 ml of ...

formulation example

(1) Tablets

[0097]The ingredients below were mixed by an ordinary method and compressed by using a conventional apparatus.

Compound of Example 1 30 mgCrystalline cellulose 60 mgCorn starch100 mgLactose200 mgMagnesium stearate 4 mg

(2) Soft Capsules

[0098]The ingredients below were mixed by an ordinary method and filled in soft capsules.

Compound of Example 1 30 mgOlive oil300 mgLecithin 20 mg

(1) Parenteral Preparations

[0099]The ingredients below were mixed by an ordinary method to prepare injections contained in a 1 ml ampoule.

Compound of Example 13 mgSodium chloride4 mgDistilled water for injection1 ml

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Abstract

The invention relates to a imidazo[1,2-a]pyrimidone derivative represented by formula (I) or a salt thereof:Wherein:X represents a bond, an ethenylene group, an ethynylene group, a methylene group optionally substituted;a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atom being optionally substituted;R1 represents a 2, 4 or 5-pyrimidinyl optionally substituted;R2 represents a C1-6 alkyl group, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a benzyl group, a benzene ring, a naphthalene ring, 5,6,7,8-tetrahydronaphthalene ring, a pyridine ring, an indole ring, a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring, the benzyl group and the rings being optionally substituted;and n represents 0 to 3.The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and / or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 10 / 504,679, filed Jan. 31, 2005, now allowed, which was the National Stage of International application No. PCT / EP03 / 02,652, filed Feb. 26, 2003, both of which are incorporated herein by reference in their entirety; which claims the benefit of priority of European Patent Application No. EP 02290487.4, filed Feb. 28, 2002.TECHNICAL FIELD[0002]The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and / or therapeutic treatment of neurodegenerative diseases caused by abnormal activity of GSK3β.BACKGROUND ART[0003]GSK3β (glycogen synthase kinase 3β) is a proline directed serine, threonine kinase that plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. It was later recognized that GSK3β was ident...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61P25/00A61P3/04A61K31/437A61P3/10A61P9/10A61P17/14A61P25/02A61P25/08A61P25/16A61P25/18A61P25/24A61P25/28A61P27/06A61P35/00C07D487/04
CPCC07D487/04A61P17/14A61P25/00A61P25/02A61P25/08A61P25/16A61P25/18A61P25/24A61P25/28A61P27/06A61P3/10A61P35/00A61P3/04A61P35/04A61P43/00A61P9/10C07D487/02A61K31/437
Inventor LOCHEAD, ALISTAIRSAADY, MOURADYAICHE, PHILIPPE
Owner SANOFI SA
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