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

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 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.