IP Library › Granted Patent US 7,247,638

Granted Patent B2

US 7,247,638 · App. 11/225,218 · Granted Jul 24, 2007

8-Substituted-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one derivatives.

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Quick Facts

Patent No.: US 7,247,638
App. No.: 11/225,218
Granted: Jul 24, 2007
Kind: B2

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Abstract

The invention relates to substituted-pyrimidone derivatives represented by formula (I) or a salt thereof: wherein X, Y, R1, R2, R3, R4, R5, n, p and q are as defined herein. 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's disease.

Claims (142)

1. A compound of formula (I) or a salt thereof

wherein:

X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom;

Y represents a bond, a carbonyl group, a methylene group optionally substituted by one or two groups chosen from a C 1-6 alkyl group, a hydroxyl group, a C 1-4 alkoxy group, a C 1-2 perhalogenated alkyl group or an amino group;

R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted by a C 1-4 alkyl group, a C 1-4 alkoxy group or a halogen atom;

R2 represents a phenyl group or a naphthalene ring; the phenyl group or the naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a methylenedioxy group, 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 1-5 monoalkylamino group, a C 2-10 dialkylamino group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring;

R3 represents a hydrogen atom or a C 1-6 alkyl group;

R4 represents a phenyl group, a naphthalene ring or a pyridinyl group, the groups and the ring being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a methylenedioxy group, 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 1-5 monoalkylamino group or a C 2-10 dialkylamino group;

R5 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom;

n represents 0 to 3; and p+q=0-3.

2. The compound of formula (I) according to claim 1 , wherein R4 represents a phenyl group or a pyridinyl group.

3. The compound of formula (I) according to claim 2 , wherein

R1 represents an unsubstituted 4-pyridinyl ring or a 4-pyrimidinyl ring;

R2 represents a phenyl group or a naphthalene ring, the phenyl group and the naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a halogen atom, a hydroxyl group, a C 1-2 alkoxy group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring;

R3 represents a hydrogen atom;

R5 represents a hydrogen atom;

X represents two hydrogen atoms;

Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and

n, p and q represent 0, 2 and 0, respectively.

4. The compound of formula (I) according to claim 1 , which is selected from the group consisting of:

1′-[(2S)-2-hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[(2S)-2-oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-(2-hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

(−)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

(+)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-(3-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

9-[2-hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one; and

9-[2-hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;

or a salt thereof.

5. A compound of formula (III)

wherein

p+q=0-3;

R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted by a C 1-4 alkyl group, a C 1-4 alkoxy group or a halogen atom;

R3 represents a hydrogen atom or a C 1-6 alkyl group;

R5 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom.

6. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 1 in combination with one or more pharmaceutically acceptable diluent, excipient or a carrier.

7. The pharmaceutical composition according to claim 6 , wherein the compound of formula (I) is selected from the group consisting of: