Substituted 8′-pyridinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a] pyrimidin-6-one and 8′-pyrimidinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a] pyrimidin-6-one derivatives
View Patent ↗The invention relates to therapeutic uses of a dihydrospiro-[cycloalkyl]-pyrimidone derivative represented by formula (I) or a salt thereof: wherein X, Y, R1, R2, R3, m, n, p and q are as described herein. Specifically, the invention relates 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 ring 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;
m represents 1 to 4;
n represents 0 to 3;
p represents 0 to 2; and
q represents 0 to 2, p+q being less than 4.
2. The method according to claim 1 , wherein R1 represents an unsubstituted 4-pyridinyl group or unsubstituted 4-pyrimidinyl group.
3. The method according to claim 2 , 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;
R3 represents a hydrogen atom;
X represents two hydrogen atoms;
Y represents a bond, a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and
p represents 2 and q represents 0.
4. The method according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′)-one;
1′-[2-Oxo-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(2-Oxo-2-phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one and;
1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
1′-(2-Hydroxy-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one; and
1′-(2-Oxo-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;
or a pharmaceutically acceptable salt thereof.