USE OF 7-(PYRIMIDIN-4 YL)-IMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONES AS GSK-3BETA INHIBITORS
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 C 1-6 alkyl group, a C 1-2 perhalogenated alkyl group, a C 1-3 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.
1 . A method of treating a disease in a patient, said disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a physiologically acceptable salt thereof:
wherein:
X represents a covalent single bond, an ethenylene group, an ethynylene group, a methylene group optionally substituted by one or two groups selected from a C 1-6 alkyl group, a hydroxy group and a C 1-4 alkoxy group;
a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atom being optionally substituted by a C 1-6 alkyl group;
R 1 represents a 2, 4 or 5-pyrimidinyl optionally substituted by a C 1-4 alkyl group, C 1-4 alkoxy group or a halogen atom;
R 2 represents a C 1-6 alkyl group, a C 1-2 perhalogenated alkyl group, a C 1-3 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 by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group; and
n represents 0 to 3.
2 . The method according to claim 1 , wherein R 1 represents an unsubstituted 4-pyrimidine ring.
3 . The method according to claim 1 , wherein R 2 is a benzene ring, a naphthalene ring, or a 5,6,7,8-tetrahydronaphthalene ring, the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group.
4 . The method according to claim 2 , wherein R 2 is a benzene ring, a naphthalene ring, or a 5,6,7,8-tetrahydronaphthalene ring, the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group.
5 . The method according to claim 1 , wherein the compound is selected from the group consisting of:
1-(3-Phenyl-propyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[3-(2-Fluoro-phenyl)-propyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-methyl-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-(2-Naphthalen-1-yl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(3-Fluoro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(3-Chloro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(2-Methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
4-[2-[5-Oxo-7-(pyrimidin-4-yl)-5H-imidazo[1,2-a]pyrimidin-1-yl]-ethyl]-benzonitrile;
1-(2-Hydroxy-2-phenyl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-(2-Oxo-2-phenyl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Fluoro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Ethoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one; and
1-[2-(2,5-Dimethoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
or a physiologically acceptable salt thereof.
6 . The method according to claim 1 , wherein the disease is Alzheimer's disease.
7 . The method according to claim 1 , wherein the disease is Parkinson's disease.
8 . The method according to claim 1 , wherein the disease is taupathies.
9 . The method according to claim 1 , wherein the disease is non-insulin dependent diabetes.
10 . The method according to claim 1 , wherein the disease is obesity.
11 . The method according to claim 1 , wherein the disease is manic depressive illness.
12 . The method according to claim 1 , wherein the disease is schizophrenia.
13 . A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof:
wherein:
X represents a covalent single bond, an ethenylene group, an ethynylene group, a methylene group optionally substituted by one or two groups selected from a C 1-6 alkyl group, a hydroxy group and a C 1-4 alkoxy group;
a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atom being optionally substituted by a C 1-6 alkyl group;
R 1 represents a 2, 4 or 5-pyrimidinyl optionally substituted by a C 1-4 alkyl group, C 1-4 alkoxy group or a halogen atom;
R 2 represents a C 1-6 alkyl group, a C 1-2 perhalogenated alkyl group, a C 1-3 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 by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group; and
n represents 0 to 3.
14 . The method according to claim 13 , wherein R 1 represents an unsubstituted 4-pyrimidine ring.
15 . The method according to claim 13 , wherein R 2 is a benzene ring, a naphthalene ring, or a 5,6,7,8-tetrahydronaphthalene ring, the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group.
16 . The method according to claim 14 , wherein R 2 is a benzene ring, a naphthalene ring, or a 5,6,7,8-tetrahydronaphthalene ring, the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a benzene ring, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group.
17 . The method according to claim 13 , wherein the compound is selected from the group consisting of:
1-(3-Phenyl-propyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[3-(2-Fluoro-phenyl)-propyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-methyl-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-(2-Naphthalen-1-yl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(3-Fluoro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(3-Chloro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(2-Methoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
4-[2-[5-Oxo-7-(pyrimidin-4-yl)-5H-imidazo[1,2-a]pyrimidin-1-yl]-ethyl]-benzonitrile;
1-(2-Hydroxy-2-phenyl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-(2-Oxo-2-phenyl-ethyl)-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Fluoro-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
1-[2-(4-Ethoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one; and
1-[2-(2,5-Dimethoxy-phenyl)-ethyl]-7-(pyrimidin-4-yl)-1H-imidazo[1,2-a]pyrimidin-5-one;
or a pharmaceutically acceptable salt thereof.