Substituted 8′-pyri(MI)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2-
View Patent ↗The invention relates to a dihydrospiro-[cycloalkylamine]-pyrimidone derivative represented by formula (I) or a salt thereof: wherein: X, Y, R1, R2, R3, R4, o, m, 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 disease.
1. 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 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 benzene ring or a naphthalene ring; the rings 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;
R3 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom;
R4 represents a hydrogen atom, a C 1-4 alkoxy carbonyl group, a C 3-6 cycloalkyl carbonyl group, a benzoyl group, a C 1-6 alkyl group, the groups being optionally substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group or a C 1-4 alkoxy group;
o and m represent 1 to 2;
n represents 0 to 3;
p represents 0 to 2; and
q represents 0 to 2.
2. The method according to claim 1 , wherein R 4 represents a hydrogen atom, a C 1-4 alkoxy carbonyl group, a C 1-6 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group or a C 1-4 alkoxy group.
3. The method according to claim 1 , wherein R1 represents an unsubstituted 4-pyridinyl group or unsubstituted 4-pyrimidinyl group.
4. The method according to claim 3 , wherein
R2 represents a benzene ring, the ring 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; and
R3 represents a hydrogen atom; and
R4 represents a C 1-4 alkoxy carbonyl group, a C 3-6 cycloalkyl carbonyl group, a benzoyl group or a C 1-3 alkyl group optionally substituted by 1 to 4 substituents selected from a halogen atom or a hydroxyl group; and
X represents two hydrogen atoms; and
Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and
p represents 2 and q represents 0.
5. The method according to claim 1 , wherein the compound is selected from the group consisting of:
Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3 ′, 4′,6′tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate
Ethyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyridin-4-yl)-1 ′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate
1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(.pyridin-4-yl)-3′,4′-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H-one
1-Methyl-1′-(2-oxo-2-phenylethyl)-8′-(pyridin-4-yl)-3′,4′-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1 H)-one
Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyrimidin-4-yl)-1′,3′,4′, 6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate
Ethyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyrimidin-4-yl)-1′,3′,4′, 6′-tetrahydro-1H-spiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate
1-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyrimidin-4-yl)-3′,4′,-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(Cyclohexylcarbonyl)-1′-[(2S)-2-hydroxy-2-phenylethyl]-8′-pyridin-4-yl- 3′,4′-dihyclrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(Cyclohexylcarbonyl)-1′-(2-oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(3-Fluorobenzoyl)-1′-[(2S)-2-hydroxy-2-phenylethy]-8′-pyridin-4-yl-3′, 4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1 (3-Fluorobeuzoyl)-1′-(2-oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(Cyclobutylcarbonyl)-1′-[(2S)-2-hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′, 4′-dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(Cyclobutylcarbonyl)-1′-(2-oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′- dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-(Cyclopropylcarbonyl)-1′-[(2S)-2-hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′, 4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1 H)-one
1-( Cyclopropylcarbonyl)-1′-(2-oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′- dihydrospiro [piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one
1-Methyl-1-(2-oxo-2-phenylethyl)-8′-(pyrimidin-4-yl)-3′,4′. dihydrospiro[piperidine-4,2′-pyrimido[1,2a]pyrimidin]′6′(1′H)-one
Ethyl 1-[(2S)-2-hydroxy-2-phenylethyl]-6-oxo-8-(pyridin-4-yl)-1,3,4,6 -tetrahydro-1′H-spiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate
Ethyl 6-oxo-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-1,3,4,6-tetrahydro-1′H-spiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate
1-[(2 S)-2-hydroxy-2-phenylethyl]-1′-methyl-8-(pyridin-4-yl)-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one 1′-Methyl-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-3,4- dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one
Ethyl 1-[(2S)-2-hydroxy-2-phenylethyl]-6-oxo-8-pyrimidin-4-yl-1,3,4,6 -tetrahydro-1′H-spiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate
Ethyl 6-oxo-1-(2-oxo-2-phenylethyl)-8-pyrimidin-4-yl-1,3,4,6-tetrahydro-1′H-spiro [pyrimido [1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate
1′-(3-Fluorobenzoyl)-1-[(2S)-2-hydroxy-2-phenylethyl]-8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(3-Fluorobenzoyl)-1-(2-oxo-2-phenylethyl)-8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(3-Fluorobenzoyl)-1-[(2S)-2-hydroxy-2-phenylethyl]-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(3-Fluorobenzoyl)-1-(2-oxo-2-phenylethyl)-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one
1′-(Cyclopropylcarbonyl)-1-[(2S)-2-hydroxy-2-phenylethyl]-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclopropylcarbonyl)-1-(2-oxo-2-phenylethyl)-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one
1′-(Cyclopropylcarbonyl)-1-[(2 S)-2-hydroxy-2-phenylethy]-8-pyrimidin-4-yl- 3,4-dihydrospiro [pyrimidot 1,2-a]pyrimidine-2,3′-pyrrolidinl-6(1 H)-one
1′-(Cyclopropylcarbonyl)-1-(2-oxo-2-phenylethyl)-8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclobutylcarbonyl)-1-[(2S)-2-hydroxy-2-phenylethyl]-8-pyrimidin-4-yl-3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclobutylcarbonyl)-1-(2-oxo-2-phenylethyl)-8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclobutylcarbonyl)-1-[(2S)-2-hydroxy-2-phenylethyl]-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclobutylcarbonyl)-1-(2-oxo-2-phenylethyl)-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclohexylcarbonyl)-1-[(2 S)-2-hydroxy-2-phenylethyl]-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one
1′-(Cyclohexylcarbonyl)-1-(2-oxo-2-phenethyl)-8-pyridin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one
1′-(Cyclohexylcarbonyl)-1-[(2 S)-2-hydroxy-2-phenylethyl]-8-pyrimidin-4-yl- 3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one
1′-(Cyclohexylcarbonyl)-1-(2-oxo-2-phenethyl)-8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1 H)-one;
or a pharmaceutically acceptable salt thereof.