Substituted 8-perfluoroalkyl-6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives
View Patent ↗The invention relates to a substituted-pyrimidone derivative represented by formula (I) or a salt thereof: wherein X, Y, R1, R2, R3, R4, R5, n, p and q are as described 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 disease.
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 and naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a phenyl 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;
R3 represents a hydrogen atom, or a C 1-6 alkyl group;
R4 represents a C 1-2 perhalogenated alkyl group or a C 1-3 halogenated alkyl group;
R5 represents a hydrogen, a C 1-6 alkyl group or a halogen atom;
n represents 0 to 3; and p+q=0 to 3.
2. The compound of formula (I) according to claim 1 , wherein R4 represents a C 1-2 perhalogenated alkyl group.
3. The compound of formula (I) according to claim 1 , wherein:
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C 1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a halogen atom, a hydroxyl group or a C 1-2 alkoxy group;
R3 represents a hydrogen atom;
R4 represents a trifluoromethyl group;
R5 represents a hydrogen or fluorine atom or alternatively 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 2 , wherein:
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C 1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a halogen atom, a hydroxyl group or a C 1-2 alkoxy group;
R3 represents a hydrogen atom;
R4 represents a trifluoromethyl group;
R5 represents a hydrogen or fluorine atom or alternatively 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.
5. The compound of formula (I) according to claim 1 , which is selected from the group consisting of:
9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
3-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(Phenylmethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(2-Phenylethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Methylphenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Cyanophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one; and
9-(2-biphenyl-4-yl-2-oxoethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
or a salt thereof.
6. A compound of formula (III)
wherein:
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;
R4 represents a C 1-2 perhalogenated alkyl group or a C 1-3 halogenated alkyl group;
R5 represents a hydrogen, a C 1-6 alkyl group or a halogen atom; and
p+q=0 to 3.
7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 in combination with one or more pharmaceutically acceptable diluent, excipient or a carrier.
8. The pharmaceutical composition according to claim 7 , wherein the compound of formula (I) is selected from the group consisting of:
9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
3-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(Phenylmethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(2-Phenylethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Methylphenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Cyanophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one; and
9-(2-biphenyl-4-yl-2-oxoethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
or a salt thereof.
9. 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 pharmaceutically acceptable 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 and naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a phenyl 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;
R3 represents a hydrogen atom, or a C 1-6 alkyl group;
R4 represents a C 1-2 perhalogenated alkyl group or a C 1-3 halogenated alkyl group;
R5 represents a hydrogen, a C 1-6 alkyl group or a halogen atom;
n represents 0 to 3; and p+q=0 to 3.
10. The method according to claim 9 , wherein R4 represents a C 1-2 perhalogenated alkyl group.
11. The method according to claim 9 , wherein:
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C 1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a halogen atom, a hydroxyl group or a C 1-2 alkoxy group;
R3 represents a hydrogen atom;
R4 represents a trifluoromethyl group;
R5 represents a hydrogen or fluorine atom or alternatively 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.
12. The method according to claim 10 , wherein:
R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;
R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C 1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C 1-3 alkyl group, a halogen atom, a hydroxyl group or a C 1-2 alkoxy group;
R3 represents a hydrogen atom;
R4 represents a trifluoromethyl group;
R5 represents a hydrogen or fluorine atom or alternatively 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.
13. The method according to claim 9 , wherein compound of formula (I) is selected from the group consisting of:
9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
(−)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
3-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(Phenylmethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-(2-Phenylethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Bromophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(3-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Methylphenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
9-[2-(4-Cyanophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one; and
9-(2-biphenyl-4-yl-2-oxoethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;
or a salt thereof.
14. The method according to claim 9 , wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies.
15. The method according to claim 14 , wherein the disease is Alzheimer's disease.
16. The method according to claim 14 , wherein the disease is Parkinson's disease.
17. The method according to claim 14 , wherein the disease is taupathies.
18. The method according to claim 9 , wherein the disease is non-insulin dependent diabetes.