IP Library › Granted Patent US 7,378,413

Granted Patent B2

US 7,378,413 · App. 11/035,264 · Granted May 27, 2008

2-amino-3-(alkyl)-pyrimidone derivatives

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Quick Facts

Patent No.: US 7,378,413
App. No.: 11/035,264
Granted: May 27, 2008
Kind: B2

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Abstract

A pyrimidone derivative represented by formula (I) or a salt thereof: Wherein: R1 represents a hydrogen atom or a C 1-6 alkyl group which may be substituted by a C 6,10 aryl group; R2 represents a C 1-10 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 3-6 alkynyl group which may be substituted, a C 3-6 cycloalkyl group which may be substituted, or a C 6-10 ARYL group which may be substituted; or R1 and R2 form together a C 2-6 alkylene group which may be substituted; or R1 and R2 form together a chain of formula —(CH 2 ) 2 —X—(CH 2 ) 2 — or —(CH 2 ) 2 —X—(CH 2 ) 3 — where X represents a oxygen atom, a sulfur atom, or a nitrogen atom which may be substituted; R3 represents a 2, 3 or 4-pyridyl group optionally substituted by a C 1-4 alkyl group, C 1-4 alkoxy group or halogen atom; and R4 represents a C 1-10 alkyl group optionally substituted by a hydroxyl group, amino, C 1-6 monoalkylamino group, C 2-12 dialkylamino group or C 6,10 aryl group which may be substituted. And 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's disease.

Claims (267)

1. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I)

wherein:

R1 represents a hydrogen atom or a C 1-6 alkyl group;

R2 represents a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 3-6 alkynyl group which may be substituted, a C 3-6 cycloalkyl group which may be substituted, or a C 6-10 aryl group which may be substituted;

or R1 and R2 form together a C 2-6 alkylene group which may be substituted;

or R1 and R2 form together a chain of formula —(CH 2 ) 2 —X—(CH 2 ) 2 — or —(CH 2 ) 2 —X—(CH 2 ) 3 — where X represents a oxygen atom, a sulfur atom, or a nitrogen atom which may be substituted;

R3 represents a 2,3 or 4-pyridyl group optionally substituted by a C 1-4 alkyl group, C 1-4 alkoxy group or a halogen atom; and

R4 represents a C 1-6 alkyl group optionally substituted by a C 6, 10 aryl group which may be substituted; or a salt thereof.

2. A method according to claim 1 wherein R 3 is unsubstituted 4-pyridyl.

3. A method according to claim 1 wherein R1 represents a hydrogen atom or a C 1-3 alkyl group and R2 represents a C 1-6 alkyl group which may be substituted by a C 3-6 cycloalkyl, a C 1-6 alkoxy group, a hydroxyl group, a phenyl group which may be substituted, or a heterocyclic ring selected from indole, substituted indole, thiophene, substituted thiophene, pyridine and piperidine.

4. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I):

wherein

R1 represents a hydrogen atom or a C 1-3 alkyl group;

R2 represents a C 1-6 alkyl group which may be substituted by a C 3-6 cycloalkyl, a C 1-6 alkoxy group, a hydroxyl group, a phenyl group which may be substituted, or a heterocyclic ring selected from indole, substituted indole, thiophene, substituted thiophene, pyridine and piperidine;

R3 represents an unsubstituted 4-pyridyl group; and

R4 represents a C 1-6 alkyl group optionally substituted by a C 6-10 aryl group which may be substituted;

or a salt thereof.

5. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, taupathies, non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of:

2-[[2-(phenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H )-one,

2-[[2-(4-methoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(3-methoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2-methoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2-fluorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(3-fluorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-fluorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-bromophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2-chlorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2,4-dichlorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-aminophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2,5-dimethoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-chlorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-hydroxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-methylphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one

2-[[2-(4-aminosulfonylphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(3-chlorophenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(thiophen-2-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[4-(phenyl)butyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-phenylmethoxyphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(4-phenylphenyl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[(phenylmethyl)amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[(2-methoxyphenyl)methyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(2,5-dimethoxyphenyl)ethyl]methylamino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[[3-(3-aminopropoxy)phenyl]methyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[[3-(aminomethyl)phenyl]methyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[3-(phenyl)propyl]amino]-3-phenylmethyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(1H-indol-3-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(5-methoxy-1H-indol-3-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(5-phenylmethoxy-1H-indol-3-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(7-methyl-1 H -indol-3-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(1-methyl-1H-indol-3-yl)ethyl]amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[[2-(1-methyl-1H-indol-3-yl)ethyl]methylamino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-(cyclopentylamino)-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-(ethylamino)-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-[(indan-2-yl)amino]-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-(piperidin-1-yl)-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-(pyrrolidin-1-yl)-3-methyl-6-pyridin-4-ylpyrimidin-4(3H)-one,

2-Cyclohexylamino-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-Butylamino-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-pentylamino-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-Hexylamino-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(2-Cyclopentyl-ethylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(3-piperidin-1-yl-propylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(Cyclohexylmethyl-amino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(2-propoxy-ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(3-Cyclohexyl-propylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(3-Ethoxy-propylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(5-Hydroxy-pentylamino)-3-methyl-6-pyridin-4-yi-3H-pyrimidin-4-one,

2-(4-Hydroxy-butylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(3-Isopropoxy-propylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(3-propoxy-propylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(2-Hydroxy-2-phenyl-ethylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-(2-Cyclohexyl-ethylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(3-piperidin-1-yl-propylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-[(3-Cyclohexyl-propyl)-methyl-amino]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

2-[3-(3-Hydroxy-propoxy)-benzylamino]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-methyl-2-[3-(2-piperidin-4-yl-ethoxy)-benzylamino]-6-pyridin-4-yl-3H-pyrimidin-4-one,

Acetic acid 3-{3-[(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-ylamino)-methyl]-phenoxy}-propyl ester

2-[3-(3-Dimethylamino-propoxy)-benzylamino]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-{methyl-[2-(4-methylaminomethyl-phenyl)-ethyl]-amino}-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(3-phenyl-propylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-6-pyridin-4-yl-2-[3-(3-pyridin-4-yl-propoxy)-benzylamino]-3H-pyrimidin-4-one,

3-Methyl-2-(3-phenyl-allylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one,

3-Methyl-2-(3-phenyl-propylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one, and

3-Methyl-6-pyridin-4-yl-2(2-pyridin-2-yl-ethylamino)-3H-pyrimidin-4-one

or a salt, thereof.

6. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I)

wherein:

R1 represents a hydrogen atom or a C 1-6 alkyl group;

or R1 and R2 form together a C 2-6 alkylene group which may be substituted;

R3 represents a 2, 3 or 4-pyridyl group optionally substituted by a C 1-4 alkyl group, C 1-4 alkoxy group or a halogen atom; and

R4 represents a C 1-6 alkyl group optionally substituted by a C 6,10 aryl group which may be substituted; or a salt thereof.

7. A method according to claim 6 wherein R 3 is unsubstituted 4-pyridyl.

8. A method according to claim 6 wherein R1 represents a hydrogen atom or a C 1-3 alkyl group and R2 represents a C 1-6 alkyl group which may be substituted by a C 3-6 cycloalkyl, a C 1-6 alkoxy group, a hydroxyl group, a phenyl group which may be substituted, or a heterocyclic ring selected from indole, substituted indole, thiophene, substituted thiophene, pyridine and piperidine.

9. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I):

wherein:

R1 represents a hydrogen atom or a C 1-3 alkyl group;

R3 represents an unsubstituted 4-pyridyl group; and

R4 represents a C 1-6 alkyl group optionally substituted by a C 6-10 aryl group which may be substituted;

or a salt thereof.

10. A method for the treatment of a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of: