HK1096401B

HK1096401B - Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2-a]pyrimidin-6-one derivatives

Info

Publication number: HK1096401B
Application number: HK07103939.1A
Authority: HK
Inventors: N‧切列兹; A‧洛切德; M‧沙迪; F‧斯洛温斯基; P‧雅齐
Original assignee: 赛诺菲-安万特; 三菱制药株式会社
Priority date: 2003-12-19
Filing date: 2004-12-17
Publication date: 2011-06-24

Description

Substituted 8' -pyrimidinyl-dihydrospiro- [ cycloalkylamine ] -pyrimido [1, 2-a ] pyrimidin-6-one derivatives

Technical Field

The present invention relates to compounds useful as active ingredients in medicaments for the prevention and/or treatment of neurodegenerative diseases caused by abnormal activity of GSK3 β.

Background

GSK3 β (glycogen synthase kinase 3 β) is a proline-directed serine, tyrosine kinase that plays an important role in the control of metabolism, differentiation and survival. It was originally identified as an enzyme that phosphorylates and thus inhibits glycogen synthase. It was later recognized that GSK3 β and tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein at an epitope, are the same enzyme. This epitope is also found to be hyperphosphorylated in alzheimer's disease and several tau diseases (tauopathy). Interestingly, protein kinase b (akt) phosphorylation of GSK3 β results in loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors. Furthermore, phosphorylation of β -catenin, a protein involved in cell survival, by GSK3 β causes its degradation through an ubiquitination-dependent proteasome pathway.

Thus, it appears that inhibition of GSK3 β activity may lead to neurotrophic activity. Indeed, it is argued that lithium (a counter-competitive inhibitor of GSK3 β) increases neuritogenesis and also neuronal survival in certain models by inducing survival factors such as Bcl-2 and inhibiting expression of pro-apoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β -amyloid increases GSK3 β activity and tau phosphorylation. Furthermore, this hyperphosphorylation and the neurotoxic effects of β -amyloid can be blocked by lithium chloride and by GSK3 β antisense mRNA. These observations strongly suggest that GSK3 β may be the two major pathological processes in alzheimer's disease: a link between abnormal APP (amyloid precursor protein) processing and tau hyperphosphorylation.

Although tau hyperphosphorylation leads to destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK3 β activity are most likely not only due to pathological phosphorylation of tau protein, since, as mentioned above, overactivity of this kinase may influence survival by modulating the expression of apoptotic and anti-apoptotic factors. Furthermore, it has been shown that amyloid-beta-induced increase in GSK3 β activity results in phosphorylation of pyruvate dehydrogenase thereby inhibiting the enzyme. Pyruvate dehydrogenase is a key enzyme in energy production and acetylcholine synthesis.

All these experimental observations suggest that GSK3 β may find utility in the treatment of neuropathological consequences and cognitive (intellectual) and attention deficits associated with alzheimer's disease as well as other acute and chronic neurodegenerative diseases. These diseases include, but are not limited to, parkinson's disease, tau diseases (such as fronto-temporal parietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementias (including vascular dementia); acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; peripheral neuropathy; retinopathy and glaucoma.

In addition, GSK3 β may also be useful in the treatment of other diseases, such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; cancers (e.g., breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and some virus-induced tumors).

Disclosure of Invention

The object of the present invention is to provide compounds useful as active ingredients in drugs for the prevention and/or treatment of diseases caused by abnormal activity of GSK3 β, more particularly neurodegenerative diseases. More specifically, the object of the present invention is to provide novel compounds useful as active ingredients in drugs for the prophylaxis and/or treatment of neurodegenerative diseases such as Alzheimer's disease.

Thus, the present inventors have identified compounds having inhibitory activity against GSK3 β. As a result, they found that a compound represented by the following formula (I) has a desired activity and is useful as an active ingredient in a medicament for preventing and/or treating the above-mentioned diseases.

The present invention therefore provides a dihydrospiro- [ cycloalkylamine ] -pyrimidone derivative represented by the general formula (I) or a salt thereof, a solvate thereof, or a hydrate thereof:

wherein:

x represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C_1-2Alkyl and one hydrogen atom;

y represents a bond, a carbonyl group, a methylene group, said methylene group being optionally substituted by one or two groups selected from: c_1-6Alkyl, hydroxy, C_1-4Alkoxy radical, C_1-2Perhaloalkyl, or amino;

r1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, which ring is optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substitution;

r2 represents a benzene ring or a naphthalene ring; these rings are optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, methyleneDioxy group, halogen atom, C_1-2Perhaloalkyl, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyano, amino, C_1-5Monoalkylamino or C_2-10A dialkylamino group;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r4 represents a hydrogen atom, C_1-4Alkoxycarbonyl group, C_3-6Cycloalkyl carbonyl, benzoyl, C_1-6Alkyl, these radicals being optionally substituted by 1 to 4 substituents selected from halogen atoms, hydroxy or C_1-4Substituent substitution of alkoxy;

o and m represent 1 to 2;

n represents a number of 0 to 3,

p represents 0-2, and

q represents 0 to 2.

In another aspect, the invention provides a dihydrospiro- [ cycloalkylamine of the general formula (I)]Pyrimidone derivatives or salts thereof, solvates thereof and hydrates thereof, wherein X, Y, R1, R2, R3, o, n, p and q are as defined above, and R4 represents a hydrogen atom, C_1-4Alkoxycarbonyl group, C_1-6Alkyl, these radicals being optionally substituted by 1 to 4 substituents selected from halogen atoms, hydroxy or C_1-4Substituent of alkoxy.

Another aspect of the present invention provides a medicament comprising as an active ingredient a substance selected from the group consisting of: a pyrimidone derivative represented by general formula (I), a physiologically acceptable salt thereof, a solvate thereof, and a hydrate thereof. As a preferred pharmaceutical embodiment, there is provided the above-mentioned medicament useful for the prevention and/or treatment of diseases caused by abnormal activity of GSK3 β, and for the prevention and/or treatment of neurodegenerative diseases as well as other diseases such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; such drugs for cancer (e.g., breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and some virus-induced tumors).

In another preferred embodiment of the present invention, there is provided the medicament as described above, wherein said disease is a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, tau diseases (e.g., fronto-temporal parietal dementia, cerebral cortical basal degeneration, pick's disease, progressive supranuclear palsy) and other dementias (including vascular dementia); acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; peripheral neuropathy; retinopathy and glaucoma; the above-mentioned medicaments are presented in the form of pharmaceutical compositions containing the above-mentioned substances as active ingredients in admixture with one or more pharmaceutical additives.

The present invention also provides an inhibitor of GSK3 β activity, comprising as an active ingredient a substance selected from the group consisting of: dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives of the general formula (I) and salts thereof, solvates thereof, and hydrates thereof.

In a further aspect of the invention there is provided a method for the prevention and/or treatment of a neurodegenerative disease caused by abnormal GSK3 β activity, the method comprising the step of administering to a patient a prophylactically and/or therapeutically effective amount of a compound selected from the group consisting of: dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives of the general formula (I), physiologically acceptable salts thereof, solvates thereof and hydrates thereof; the invention also provides the use of a substance selected from the group consisting of: dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives of the general formula (I), physiologically acceptable salts thereof, solvates thereof and hydrates thereof.

C as used herein_1-6Alkyl represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl and the like;

C_3-6cycloalkyl represents a cyclic alkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

C_1-4alkoxy represents alkoxy having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like;

the halogen atom represents a fluorine, chlorine, bromine, or iodine atom;

C_1-2perhaloalkyl represents alkyl in which all hydrogens have been replaced by halogen, e.g. CF₃Or C₂F₅；

C_1-3Haloalkyl represents alkyl in which at least one hydrogen is replaced by a halogen atom;

C_1-5monoalkylamino radicals being represented by a C_1-6Alkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino;

C_2-10dialkylamino represents two C_1-5Alkyl-substituted amino groups, such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino;

the leaving group L represents a group which is easily cleaved and substituted, such as tosyl, mesyl, bromo, etc.

The compound represented by the above formula (I) may form a salt. Examples of the salts include, when an acidic group is present, salts of alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines, such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucosamine; or salts with basic amino acids, such as lysine, delta-hydroxylysine, and arginine. Base addition salts of acidic compounds are prepared according to standard procedures known in the art.

When a basic group is present, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids, such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, tannic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid and salicylic acid; or salts with acidic amino acids such as aspartic acid, glutamic acid.

Acid addition salts of basic compounds are prepared by standard procedures known in the art including, but not limited to, dissolving the free base in a hydroalcoholic solution containing the appropriate acid, isolating the salt by evaporating the solution, or reacting the free base and acid in an organic solvent, in which case the salt is isolated directly, or precipitated with a second organic solvent, or may be obtained by concentrating the solution. Acids which may be used to prepare acid addition salts preferably include those which, when combined with the free base, produce a pharmaceutically acceptable salt, i.e., whose anion is relatively harmless to animal tissue at the pharmaceutical dosage of the salt, so that the beneficial properties inherent in the free base are not impaired by side effects produced by the anion. Pharmaceutically acceptable salts of the basic compounds are preferred, but all acid addition salts are within the scope of the invention.

In addition to the dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives of formula (I) above and salts thereof, solvates and hydrates thereof are also within the scope of the present invention.

The dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives of formula (I) above may have one or more asymmetric carbon atoms. The stereochemistry of such asymmetric carbon atoms may be in the (R) and (S) configurations, and the derivatives may exist as stereoisomers, such as optical isomers or diastereomers. Any stereoisomer in pure form, any mixture of stereoisomers, racemates and the like are within the scope of the present invention.

Examples of preferred compounds of the invention are shown in table 1 below. However, the scope of the present invention is not limited to these compounds.

Preferred compounds of the invention represented by the general formula (I) include the following compounds, among others:

(1) r1 represents a 3-or 4-pyridine ring, more preferably a 4-pyridine ring, or a 4-or 5-pyrimidine ring, more preferably a 4-pyrimidine ring, which ring may be substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogen atom substitution; and/or

(2) R2 represents a benzene ring or a naphthalene ring, which ring is optionally substituted with 1 to 4 substituents selected from: c_1-3Alkyl, halogen atom, hydroxy or C_1-2An alkoxy group; and/or

(3) R3 represents a hydrogen atom, C_1-3An alkyl group, or a halogen atom, more preferably a hydrogen atom; and/or

(4) R4 represents a hydrogen atom, C_1-4Alkoxycarbonyl group, C_3-6Cycloalkyl carbonyl, benzoyl, C_1-3Alkyl, these radicals being optionally substituted by 1 to 4 substituents selected from halogen atoms, hydroxy or C_1-4Substituent substitution of alkoxy;

(5) y represents a carbonyl group or a methylene group optionally substituted by one or two groups selected from: c_1-3Alkyl, hydroxy, C_1-4Alkoxy radical, C_1-2Perhaloalkyl, amino; more specifically, R1, R2, R3, R4 and Y are as defined above.

More preferred compounds represented by the general formula (I) of the present invention include the following compounds, among others:

(1) r1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; and/or

(2) R2 represents a benzene ring, which ring is optionally substituted with 1 to 4 substituents selected from: c_1-3Alkyl, halogen atom, hydroxy or C_1-2An alkoxy group; and/or

(3) R3 represents a hydrogen atom; and/or

(4) R4 represents C_1-4Alkoxycarbonyl group, C_3-6Cycloalkyl-carbonyl, benzoyl or C_1-3Alkyl, these radicals being optionally substituted by 1 to 4 substituents selected from halogen atoms or hydroxy groupsSubstituted with the substituent(s); and/or

(5) X represents two hydrogen atoms; and/or

(6) Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and/or

(7) p represents 2 and q represents 0; more specifically, R1, R2, R3, X, Y, p, q, m, o and n are as defined above.

Particularly preferred compounds of the present invention represented by general formula (I) wherein R1 is a pyridine ring or a pyrimidine ring include the compounds of table 1:

1.1 '- [ (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-carboxylic acid ethyl ester

2.6 '-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-carboxylic acid ethyl ester

3.1 ' - [ (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

4.1-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

5.1 '- [ (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-carboxylic acid ethyl ester

6.6 '-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-carboxylic acid ethyl ester

7.1 ' - [ (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 ' -dihydrospiro [ 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-phenylethyl ] -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one

1- (3-fluorobenzoyl) -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

16.1-methyl-1 ' - (2-oxo-2-phenylethyl) -8 ' - (pyrimidin-4-yl) -3 ', 4 ' -dihydrospiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidin ] -6 ' (1 ' H) -one

And the compounds of table 2:

1.1- [ (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 ' carboxylic acid ethyl ester

2.6-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 ' -carboxylic acid ethyl ester

1- [ (2S) -2-hydroxy-2-phenylethyl ] -1 '-methyl-8- (pyridin-4-yl) -3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

4.1 '-methyl-1- (2-oxo-2-phenylethyl) -8- (pyridin-4-yl) -3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

5.1- [ (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 ' -carboxylic acid ethyl ester

6.6-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 ' -carboxylic acid ethyl ester

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(1H) -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(1H) -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(1H) -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 ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

12.1 '- (Cyclopropylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

13.1 '- (Cyclopropylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

14.1 '- (Cyclopropylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclobutylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

16.1 '- (Cyclobutylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclobutylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(H) -one

18.1 '- (Cyclobutylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

19.1 '- (Cyclohexylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

20.1 '- (Cyclohexylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

21.1 '- (Cyclohexylcarbonyl) -1- [ (2S) -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-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

As a further object, the present invention also relates to a process for preparing a dihydrospiro- [ cycloalkylamine ] -pyrimidone compound represented by the above formula (I).

These compounds can be prepared, for example, by the following methods.

Preparation method

The dihydrospiro- [ cycloalkylamine ] -pyrimidone compound represented by the above general formula (I) can be prepared according to the process of scheme 1.

Scheme 1

(in the above scheme, R1, R2, R3, R4, X, Y, m, n, o, p and q are as defined for the compound of formula (I))

According to this process, a pyrimidone derivative represented by the above formula (III), wherein R1, R3, R4, m, N, o, p and q are as defined for the compound of the formula (I), is reacted with a base such as sodium hydride, sodium carbonate or potassium carbonate in a solvent such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide or chloroform, etc., at a suitable temperature in the range of 0 to 130 ℃ in ordinary air, and then reacted with a compound of the formula (II) wherein R2, X, Y and N are as defined for the compound of the formula (I) and L represents a leaving group, preferably bromine or methanesulfonyl group, to produce the compound of the above formula (I).

Alternatively, compounds of formula (I) wherein Y represents a carbonyl group may be prepared by oxidation of compounds of formula (I) wherein Y represents a methylene group substituted by a hydroxy group, according to methods known in the art.

The compounds of formula (II) may be obtained commercially or prepared according to methods known in the art.

Compounds of formula (III) can be prepared according to scheme 2

Scheme 2

(in the above scheme, R1, R3, R4, m, o, p and q are as defined above)

According to this process, 3-ketoesters of formula (IV), in which R1 and R3 are as defined for the compound of formula (I) and R represents an alkyl group (such as methyl or ethyl), are reacted with a compound of formula (V). The reaction can be carried out in the presence of a base such as potassium carbonate in an alcohol solvent such as methanol, ethanol, etc., or without a solvent, at a suitable temperature range of 25-140 deg.C in ordinary air.

Alternatively, the compound of formula (III) wherein R3 represents a hydrogen atom may be halogenated so as to obtain a compound of formula (III) wherein R3 represents a halogen atom such as a bromine atom or a chlorine atom. The reaction may be carried out in an acidic medium (e.g. acetic acid or propionic acid) in the presence of bromosuccinimide or chlorosuccinimide or bromine.

Furthermore, the compounds of formula (III) wherein R3 represents a fluorine atom can be obtained in a similar manner to that described in Tetrahedron Letters, Vol.30, No.45, pp.6113-6116, 1989.

The compounds of formula (IV) may be obtained commercially or synthesized according to methods known in the art.

For example, a compound of formula (IV) wherein R1 represents a pyridine or pyrimidine ring, optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen atoms, can be prepared as follows: separately reacting isonicotinic acid or pyrimidine carboxylic acid (optionallyQuilt C_1-4Alkyl radical, C_1-4Alkoxy or halogen substitution) with the corresponding malonic acid monoester. The reaction may be carried out by methods known in the art, for example in the presence of a coupling agent such as 1, 1' -carbonyldi-1H-imidazole in a solvent such as tetrahydrofuran at a temperature in the range of 20 to 70 ℃.

The compounds of formula (V) may be synthesized according to methods known in the art.

For example, compounds of formula (V) (when m and o are 2, p is 2, and q is 0) can be prepared according to the procedures described in scheme 3 starting from compounds of general formula (VI) (wherein R4 is as defined by (I)). The reaction conditions used are described in the chemical examples.

Scheme 3

(in the above scheme, Pg represents an amino protecting group, L is a leaving group)

The compounds of formula (VI) may be prepared according to the methods described in j.med.chem.1991, 34, 90-97.

The compounds of formula (VII) may be prepared as described in Synthetic Communication 28(4), 701-712 (1998).

Another subject of the invention relates to compounds of formula (III), which are intermediates for the compounds of formula (I).

In the above reaction, protection and deprotection of a functional group is sometimes necessary. The appropriate protecting group Pg may be selected according to the type of functional group, and the methods described in the literature may be used. Examples of protecting Groups, methods of protection and deprotection are found, for example, in Greene et al Protective Groups in organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).

The compounds of the invention have inhibitory activity against GSK3 β. Accordingly, the compounds of the present invention are useful as active ingredients for the preparation of medicaments for the prevention and/or treatment of diseases caused by abnormal GSK3 beta activity, more particularly neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention can be used as active ingredients for the preparation of medicaments for the prevention and/or treatment of neurodegenerative diseases such as Parkinson's disease, tau diseases (e.g. frontotemporal parietal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy) and other dementias (including vascular dementia); acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; peripheral neuropathy; retinopathy and glaucoma; other diseases such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; maniac depressive disorder; schizophrenia; alopecia; cancers (e.g., breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and some virus-induced tumors).

The present invention also relates to methods of treating neurodegenerative diseases caused by abnormal GSK3 β activity and the diseases described above comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).

As active ingredients of the medicament of the present invention, the following substances may be used: selected from the group consisting of compounds represented by formula (I) and pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof. The substance may be used as such as a medicament according to the invention, but it is more desirable to administer the medicament in the form of a pharmaceutical composition comprising the substance as an active ingredient and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the above-mentioned compounds may be used in combination. The pharmaceutical composition may be supplemented with other drugs for treating the above-mentioned diseases. The type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the compositions may be formulated as oral compositions, such as capsules, microcapsules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, and the like, or as compositions for parenteral administration, such as intravenous, intramuscular, or subcutaneous injection, infusion drops, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories, and the like. Injections or drops for infusion can be prepared as powder preparations such as freeze-dried preparations, which are dissolved in a suitable aqueous medium such as physiological saline before use. Sustained release formulations such as those coated with a polymer can be administered directly into the brain.

The type of the pharmaceutical additive used for manufacturing the pharmaceutical composition, the content ratio of the pharmaceutical additive to the active ingredient, and the method for preparing the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. In general, the pharmaceutically acceptable additives may be incorporated in an amount of 1 to 90% by weight based on the weight of the active ingredient.

Examples of excipients used to prepare solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. For the preparation of liquid compositions for oral administration, conventional inert diluents such as water or vegetable oils may be used. In addition to the inert diluent, the liquid composition may contain adjuvants such as wetting agents, suspending aids, sweeteners, aromatics, colorants, and preservatives. The liquid composition may be filled into capsules made of an absorbable material such as gelatin. Solvents or suspending media for preparing compositions for parenteral administration (e.g., injections, suppositories) include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. Examples of bases for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauryl ester, witepsol.

The dose and frequency of administration of the medicament of the present invention are not particularly limited and may be suitably selected depending on the circumstances such as the purpose for prevention and/or treatment, the type of disease, the body weight or age of the patient, the severity of the disease and the like. In general, the daily dosage for oral administration to an adult is 0.01 to 1000mg (weight of active ingredient), and the dosage may be administered once a day or in several portions several times a day, or once a few days. When the medicament is used as an injection, it is preferably administered continuously or intermittently to an adult at a daily dose of 0.001 to 100mg (weight of active ingredient).

Detailed Description

Example 1 (Compound 1 of Table 1)

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-carboxylic acid ethyl ester (1: 1) (hydrochloride salt)

1.14-Cyanomethylene-piperidine-1-carboxylic acid ethyl ester

To a suspension of 12.85g (321.28mmol) sodium hydride (60% suspension in mineral oil) in 500ml dry tetrahydrofuran was added 56.91g (321.28mmol) diethyl (cyanomethyl) -phosphonate at 0 ℃ over 10 minutes. The reaction mixture was stirred at room temperature for 2 hours, and 44.05g (292.07mmol) of ethyl 4-oxo-piperidine-1-carboxylate in 230ml of anhydrous tetrahydrofuran was then added dropwise over 30 minutes. The resulting mixture was stirred at room temperature for another 16 hours.

The mixture was dissolved in 1L diethyl ether, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated. The crude product was triturated in petroleum ether and filtered to give 51.63g of pure product as a yellow solid.

Melting point: 95-96 deg.C

1.24-amino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester

A solution of 51.38g (264.53mol) of 4-cyanomethylene-piperidine-1-carboxylic acid ethyl ester in 301ml of an aqueous ammonia solution (29%) and 50ml of methanol was heated in a closed test tube at 110 ℃ for 48 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a dichloromethane/methanol 100/0 to 96/4 mixture to give 40g of product as a white solid.

Melting point: 68-69 deg.C

1.34-tert-Butoxycarbonylamino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester

A solution of 4.3ml of water, 23.58ml (167.79mmol) of triethylamine and 36.61g (167.79mmol) of di-tert-butyl dicarbonate in 50ml of tetrahydrofuran is added to a solution of 35.44g (167.79mmol) of 4-amino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester in 200ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 16 hours.

The mixture was dissolved in dichloromethane, washed with saturated aqueous ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was triturated in pentane and filtered to give 46.49g of pure product as a white solid.

Melting point: 135 ℃ of 133-

1.44- (2-amino-ethyl) -4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid ethyl ester

To a solution of 5g (16.06mmol) of 4-tert-butoxycarbonylamino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester in 107ml of methanol was added 4.71g of Raney nickel catalyst. The hydrogenation reaction was carried out at a suspension temperature and a pressure of 55psi for 3 hours.

The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. Purification by silica gel chromatography eluting with a mixture of dichloromethane/methanol/aqueous ammonia (29%) 100/0/0 to 70/30/3 gave the compound as an oil (2.86 g).

1.54-amino-4- (2-amino-ethyl) -piperidine-1-carboxylic acid ethyl ester hydrochloride (2: 1)

To a solution of 3.01g (9.56mmol) of ethyl 4- (2-amino-ethyl) -4-tert-butoxycarbonylamino-piperidine-1-carboxylate in 19ml of isopropanol was added a solution of 8ml of hydrochloric acid (5.6N) in isopropanol, and the resulting solution was stirred at room temperature for 3 hours.

The mixture was cooled and diethyl ether was added. The resulting precipitate was filtered off. The product was dried to give 2.49g of pure compound as a white solid.

Melting point: 119 ℃ C

Ethyl 1.62-amino-1, 3, 9-triaza-spiro [5.5] undec-2-ene-9-carboxylate hydrobromide (1: 1)

To a solution of 15.65g (54.33mmol) of 4-amino-4- (2-amino-ethyl) -piperidine-1-carboxylic acid ethyl ester hydrochloride (2: 1) in 108ml of methanol was added 21.73ml (114.09mmol) of a solution of sodium methoxide in methanol (5.55N).

The mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was evaporated. The crude product was dissolved in 108ml of water and 5.75g (54.33mmol) of cyanogen bromide were added portionwise. The resulting mixture was stirred at room temperature for 16 hours, evaporated to dryness, redissolved in ethanol and evaporated to dryness to give 17.56g of pure compound as a brown solid.

1.76 ' -oxo-8 ' - (pyridin-4-yl) -1 ', 3 ', 4 ', 6 ' -tetrahydro-1H-spiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidine ] -1-carboxylic acid ethyl ester

3g (15.57mmol) of ethyl 3- (pyridin-4-yl) -3-oxopropanoate, 5g (15.57mmol) of ethyl 2-amino-1, 3, 9-triaza-spiro [5.5] undec-2-ene-9-carboxylate hydrobromide (1: 1), 4.52g (32.70mmol) of potassium carbonate and 28ml of ethanol were mixed and the resulting mixture was heated at reflux temperature for 12 h.

The solution was cooled and the solvent was removed by evaporation. The mixture was dissolved in dichloromethane, washed with saturated aqueous ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue was treated with water, the precipitate was filtered off, the crude product was triturated in diethyl ether and filtered to give 2.94g of pure product as a white solid.

Melting point: 209 ℃ C

1.81 '- [ (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-carboxylic acid ethyl ester (1: 1) (hydrochloride salt)

0.085g (2.11mmol) of sodium hydride (60% suspension in mineral oil) was added to a solution of 0.6g (1.62mmol) of 6 ' -oxo-8 ' - (pyridin-4-yl) -1 ', 3 ', 4 ', 6 ' -tetrahydro-1H-spiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidine ] -1-carboxylic acid ethyl ester in 13ml of anhydrous dimethylformamide. The mixture was stirred at 50 ℃ for 1 hour. A further 0.25g (2.11mmol) of (S) -phenyloxirane are added, and the mixture is stirred at 110 ℃ for 12 hours.

0.25g (2.11mmol) of (S) -phenyloxirane are added and the mixture is stirred at 110 ℃ for 6 hours. Water was added and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride, dried and evaporated to give the crude product. Purification by silica gel chromatography eluting with a dichloromethane/methanol mixture 100/0 to 90/10 gave the compound as the free base. The base was converted to its hydrochloride salt to give 0.144g of pure product.

Melting point: 169 ℃, [ alpha ] at 170 ℃ -]_D13.7(c 0.99, dimethyl sulfoxide)

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：8.95(br d，2H)；8.35(d，2H)；7.12-7.42(m，5H)；6.66(s，1H)；5.02(m，1H)；4.00(q，2H)；3.52-3.95(m，6H)；2.78-3.11(m，2H)；1.95-2.4(m，4H)；1.65-1.90(m，2H)；71.15(t，3H)。

Example 2 (Compound 2 of Table 1)

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-carboxylic acid ethyl ester (1: 1) (hydrochloride salt)

0.138g (0.28mmol) 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 were dissolved in 2.82ml of anhydrous dichloromethane and combined with 0.049g (0.42mmol) of N-methylmorpholine N-oxide, 0.001g (0.0083mmol) of tetra-N-propylamine perruthenate and 1g of powdered molecular sieve (4A). The mixture was stirred at 20 ℃ under a nitrogen atmosphere for 12 hours.

0.049g (0.42mmol) of N-methylmorpholine N-oxide, 0.001g (0.0014mmol) of tetra-N-propylamine perruthenate and 1g of powdered molecular sieve (4A) were added, and the mixture was stirred at 20 ℃ for 3 hours under a nitrogen atmosphere.

The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol 100/0 to 95/5 to give the compound as the free base which was then converted to its hydrochloride salt to give 0.045g of pure product.

Melting point: 227 ℃ 229 DEG C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：8.46(br d，2H)；8.05(d，2H)；7.51-7.82(m，5H)；6.63(s，1H)；5.22(s，2H)；3.85-4.08(m，6H)；2.89-3.25(m，2H)；2.21-2.37(m，2H)；1.95(td，2H)；1.66(d，2H)；1.15(t，3H)。

Example 3 (Compound 3 of Table 1)

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 (2: 1) (hydrochloride salt)

3.11-methyl-8 '- (pyridin-4-yl) -3', 4 '-dihydrospiro [ piperidine-4, 2' -pyrimido [1, 2-a ] pyrimidin ] -6 '(1' H) -one

0.185g (4.87mmol) of lithium aluminium hydride are added to a solution of 0.6g (1.62mmol) of ethyl 6 ' -oxo-8 ' - (pyridin-4-yl) -1 ', 3 ', 4 ', 6 ' -tetrahydro-1H-spiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidine ] -1-carboxylate dissolved in 3.25ml of tetrahydrofuran at 0 ℃. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours.

The reaction mixture was treated with an excess of saturated aqueous sodium sulfate solution. Some additional solid sodium sulfate was added, the organic phase was filtered and the salts removed. The solvent was evaporated and purified by silica gel chromatography eluting with a mixture of dichloromethane/methanol 100/0 to 70/30 to give the compound (0.328g) as a yellow solid.

Melting point: 232 ℃ and 234 DEG C

3.21 ' - [ (2S) -2-hydroxy-2-phenylethyl ] -1-methyl-8 ' - (pyridin-4-yl) -3 ', 4 ' -dihydrospiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidin-e ] -6 ' (1 ' H) -one (2: 1) (hydrochloride salt)

The product was obtained in a similar manner to step 1.9 using 1-methyl-8 '- (pyridin-4-yl) -3', 4 '-dihydrospiro [ piperidine-4, 2' -pyrimido [1, 2-a ] pyrimidin-6 '(1' H) -one.

Melting point: 271-]_D10.2(c 0.829, methanol)

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：10.75(br s，1H)；8.91(d，2H)；8.31(d，2H)；7.20-759(m，5H)；6.71(s，1H)；5.12(m，1H)；3.58-4.50(m，4H)；3.00-3.45(m，4H)；2.85(m，1H)；2.75(s，3H)；2.08-2.44(m，3H)；1.89(br d，1H)；1.45(br d，1H)。

Example 4 (Compound 5 of Table 1)

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-carboxylic acid ethyl ester

4.16-oxo-8 '- (pyrimidin-4-yl) -1', 3 ', 4', 6 '-tetrahydro-1H-spiro [ piperidine-4, 2' -pyrimido [1, 2-a ] pyrimidine ] -1-carboxylic acid ethyl ester

The product was obtained in analogy to example 1 (step 1.7) using 3-oxo-3-pyrimidin-4-yl-propionic acid methyl ester.

Melting point: 231 ℃ 233-

4.21 '- [ (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-carboxylic acid ethyl ester

The product was obtained in analogy to the procedure of step 1.8 using ethyl 6 ' -oxo-8 ' - (pyrimidinyl-4-yl) -1 ', 3 ', 4 ', 6 ' -tetrahydro-1H-spiro [ piperidine-4, 2 ' -pyrimido [1, 2-a ] pyrimidine ] -1-carboxylate.

Melting point: 118-]_D13.2(c 1.028, methanol)

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：9.27(s，1H)；8.98(d，1H)；8.10(d，1H)；7.15-7.43(m，5H)；6.70(s，1H)；5.48(d，1H)；5.05(m，1H)；4.04(q，2H)；3.52-4.10(m，5H)；2.92(br q，2H)；

1.90-2.39(m，3H)；1.63-1.90(m，3H)；1.15(t，3H)。

Example 5 (Compound 7 of Table 1)

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

5.11-methyl-8 '- (pyrimidin-4-yl) -3', 4 '-dihydrospiro [ piperidine-4, 2' -pyrimido [1, 2a ] pyrimidin ] -6 '(1' H) -one

The product was obtained in analogy to example 3 (step 3.1) using 3-oxo-3-pyrimidin-4-yl-propionic acid methyl ester.

Melting point: 194 ℃ and 196 DEG C

5.21 ' - [ (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

The product was obtained in a similar manner to step 1.8 using 1-methyl-8 '- (pyrimidin-4-yl) -3', 4 '-dihydrospiro [ piperidine-4, 2' -pyrimido [1, 2a ] pyrimidin-6 '(1' H) -one.

Melting point: 180 ℃ 182 DEG C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：9.35(s，1H)；9.05(d，1H)；8.17(d，1H)；7.25-7.45(m，5H)；6.75(s，1H)；5.57(d，1H)；5.10(m，1H)；3.67-4.05(m，4H)；2.67(br dd，2H)；2.22(s，3H)；

1.82-2.35(m，5H)；1.67(br d，1H)；1.20(m，1H)。

Example 6 (Compound 1 of Table 2)

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 ' -carboxylic acid ethyl ester (1: 1) (hydrochloride)

6.13-Cyanomethylene-pyrrolidine-1-carboxylic acid ethyl ester

The product was obtained by using ethyl 3-oxo-pyrrolidine-1-carboxylate prepared as described in reference to Visconti, M et al 9Helvetica Chimica Acta 1967, 50(5)1289-93) in a similar manner to example 1 (step 1.1).

6.23-amino-3- (cyanomethyl) pyrrolidine-1-carboxylic acid ethyl ester

The product was obtained in analogy to example 1 (step 1.2) using 3-cyanomethylene-pyrrolidine-1-carboxylic acid ethyl ester.

6.33- [ (tert-butoxycarbonyl) amino ] -3- (cyanomethyl) pyrrolidine-1-carboxylic acid ethyl ester

The product was obtained in analogy to the procedure of example 1 (step 1.3) using ethyl 3-amino-3- (cyanomethyl) pyrrolidine-1-carboxylate.

6.43- (2-aminoethyl) -3- [ (tert-butoxycarbonyl) amino ] pyrrolidine-1-carboxylic acid ethyl ester

The product was obtained in a similar manner to example 1 (step 1.4) using ethyl 3- [ (tert-butoxycarbonyl) amino ] -3- (cyanomethyl) pyrrolidine-1-carboxylate.

6.53-amino-3- (2-aminoethyl) pyrrolidine-1-carboxylic acid ethyl ester hydrochloride (2: 1)

The product was obtained by using ethyl 3- (2-aminoethyl) -3- [ (tert-butoxycarbonyl) amino ] pyrrolidine-1-carboxylate in a similar manner to example 1 (step 1.5).

Ethyl 6.67-amino-2, 6, 8-triazaspiro [4.5] dec-6-ene-2-carboxylate hydrobromide (1: 1)

The product was obtained in analogy to the procedure of example 1 (step 1.6) using ethyl 3-amino-3- (2-aminoethyl) pyrrolidine-1-carboxylate hydrochloride (2: 1).

6.76-oxo-8-pyridin-4-yl-1, 3, 4, 6-tetrahydro-1 ' H-spiro [ pyrimido [1, 2-a ] pyrimidine-2, 3 ' -pyrrolidine ] -1 ' -carboxylic acid ethyl ester

The product was obtained in a similar manner to example 1 (step 1.7) using ethyl 3-oxo-3-pyridin-4-yl-propionate and ethyl 7-amino-2, 6, 8-triazaspiro [4.5] dec-6-ene-2-carboxylate hydrobromide (1: 1).

Melting point: 171 ℃ 172 ℃

6.81- [ (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 ' -carboxylic acid ethyl ester (1: 1) (hydrochloride)

The product was obtained in analogy to example 1 (step 1.8) using ethyl 6-oxo-8-pyridin-4-yl-1, 3, 4, 6-tetrahydro-1 ' H-spiro [ pyrimido [1, 2-a ] pyrimidine-2, 3 ' -pyrrolidine ] -1 ' -carboxylate.

Melting point: 194 ℃ C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：8.87(m，2H)；8.26(m，2H)；7.14-7.46(m，5H)；6.65(br s，1H)；5.19(br s，1H)；2.88-4.36(m，10H)；1.71-2.28(m，4H)；1.13(t，3H)。

Example 7 (Compound 2 of Table 2)

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 ' -carboxylic acid ethyl ester (1: 1) (hydrochloride)

The product was obtained in a similar manner to example 2 using 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.

Melting point: 190 ℃ 191 DEG C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：8.51(d，2H)；8.05(d，2H)；7.79(d，2H)；7.69(d，1H)；7.57(t，2H)；6.59(s，1H)；5.25(dd，2H)；3.82-4.18(m，2H)；3.98(q，2H)；3.22-3.56(m，4H)；1.85-2.46(m，4H)；1.12(t，3H)。

Example 8 (Compound 7 of Table 2)

1 '- (3-fluorobenzoyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidine ] -6(1H) -one

18-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

1.0g (2.81 mmol) 6-oxo-8-pyrimidin-4-yl-1, 3, 4, 6-tetrahydro-1 ' H-spiro [ pyrimido [1, 2-a ] pyrimidine-2, 3 ' -pyrrolidine ] -1 ' -carboxylic acid ethyl ester was dissolved in 25ml hydrobromic acid solution (33% in acetic acid) and the resulting solution was stirred at 100 ℃ for 12 hours.

The mixture was cooled and diethyl ether was added. The precipitate formed is filtered off. The product was dissolved in concentrated sodium hydroxide solution (30%) and the resulting solution was extracted with dichloromethane/methanol/concentrated aqueous ammonia solutions 100/0/0 to 70/30/3. The extract was dried over sodium sulfate and evaporated to give the crude product. The crude product was triturated in diethyl ether to give 0.64g (86%) of a yellow solid.

Melting point: 228 ℃ 226-

8.21 '- (3-fluorobenzoyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

To a solution of 0.3g (1.055mmol) 8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one dissolved in 5ml tetrahydrofuran were added 0.18ml (1.27mmol) triethylamine and 0.152ml (1.27mmol) 3-fluoro-benzoyl chloride at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution, extracted with dichloromethane/methanol 100/0 to 80/20, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol 100/0 to 70/30 to give 0.310g (72%) of pure product as a grey solid.

Melting point: 296 ℃ 298 DEG C

8.31 '- (3-fluorobenzoyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one

The product was obtained in a similar manner to example 1 (step 1.8) using 1 '- (3-fluorobenzoyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one.

Melting point: 180 ℃ 182 DEG C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：9.28(s，1H)；9.01(t，1H)；8.11-8.21(m，1H)；7.02-7.63(m，9H)；6.72(s，1H)；5.53(AB，1H)；5.04-5.31(m，1H)；3.12-4.11(m，8H)；1.65-2.33(m，4H)。

Example 9 (Compound 8 of Table 2)

1 '- (3-fluorobenzoyl) -1- (2-oxo-2-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidine ] -6(1H) -one

The product was obtained in a similar manner to example 2 using 1 '- (3-fluorobenzoyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidin-2, 3' -pyrrolidin ] -6(1H) -one.

Melting point: 267 and 268 DEG C

RMN¹H(DMSO-δ⁶；200MHz)

δ(ppm)：9.15(s，1H)；8.42(d，1H)；8.09(t，2H)；7.74(t，1H)；7.61(t，2H)；7.20-7.53(m，5H)；6.60-6.75(m，1H)；5.13-5.40(m，2H)；3.87-4.25(m，2H)；3.37-3.87(m，4H)；1.84-2.52(m，4H)。

Table 1 shows the chemical structures and physical data of the above compounds of formula (I) according to the invention. These compounds are prepared according to the methods of the examples.

In the table, Ph represents a phenyl group; et represents ethyl; (S), (R) or (Rac.) denotes the stereochemistry of the carbon atom in column "Y":

(rac.) means a racemic mixture

(R) denotes the absolute configuration R

(S) means the absolute configuration S

In Table 1, R1 is unsubstituted pyrimidin-4-yl or unsubstituted pyridin-4-yl, p, o and m represent 2, and q represents 0.

TABLE 1

In Table 2, R1 is unsubstituted pyridin-4-yl or unsubstituted pyrimidin-4-yl, p and m represent 2, o represents 1 and q represents 0.

TABLE 2

Test examples: the inhibitory activity of the medicine of the invention on GSK3 beta is as follows:

two different schemes may be used.

The first scheme is as follows: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ MATP (containing 300000cpm 33P-ATP) in the presence of GSK3 β in 25mM Tris-HCl, pH 7.5, 0.6mM DTT, 6mM MgCl₂0.6mM EGTA, 0.05mg/ml BSA buffer (total reaction volume 100. mu.l) was incubated at room temperature for 1 hour.

The second scheme is as follows: 4.1 μ M of the pre-phosphorylated GS1 peptide and 42 μ M ATP (containing 260000cpm 33P-ATP) in the presence of GSK3 β in 80mM Mes-NaOH, pH 6.5, 1mM Mg (OAc)₂0.5mM MEGTA, 5mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer at room temperature for 2 hours. The inhibitor was dissolved in DMSO (final solvent concentration in the reaction medium is 1%).

With the following compositionThe reaction was stopped with 100. mu.l of solution: 25g polyphosphoric acid (85% P)₂O₅)，126ml 85％H₃PO₄Water was added to 500ml and then diluted to 1: 100 before use. Then 1 aliquot of the reaction mixture was transferred to a Whatman P81 cation exchange filter and rinsed with the above solution. Bound 33P radioactivity was measured with a liquid scintillation spectrometer.

The sequence of the phosphorylated GS-1 peptide is as follows:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH(Woodgett，J.R.(1989)Analytical Biochemistry 180，237-241)。

GSK3 beta inhibitory Activity of Compounds of the invention as IC₅₀Illustrative IC of the Compounds shown, Table 1 and Table 2₅₀In the range of 1 nanomolar to 1 micromolar.

For example, IC of Compound No.4 of Table 1₅₀At 0.007. mu.M, IC of Compound No.4 of Table 2₅₀It was 0.006. mu.M.

Formulation examples

(1) Tablet formulation

The following ingredients were mixed by conventional methods and tableted by conventional machinery.

EXAMPLE 1 Compound 30mg

Crystalline cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) Soft capsule

The following ingredients were mixed by a conventional method and filled into soft capsules.

EXAMPLE 1 Compound 30mg

Olive oil 300mg

Lecithin 20mg

(3) Parenteral formulation

The following ingredients were mixed by a conventional method to prepare an injection, and the injection was filled in a 1ml ampoule.

EXAMPLE 1 Compound 3mg

Sodium chloride 4mg

1ml of distilled water for injection

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3 beta inhibitory activity and are useful for the prevention and/or treatment of diseases caused by abnormal GSK3 beta activity, more specifically neurodegenerative diseases.

Claims

1. A dihydrospiro- [ cycloalkylamine ] -pyrimidone derivative represented by the general formula (I):

wherein:

y represents a bond, a carbonyl group, a methylene group,said methylene group being optionally substituted with one or two groups selected from: c_1-6Alkyl, hydroxy, C_1-4Alkoxy radical, C_1-2Perhaloalkyl or amino;

r2 represents a benzene ring or a naphthalene ring; these rings are optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl, methylenedioxy, halogen atom, C_1-3Haloalkyl, hydroxy, C_1-4Alkoxy, nitro, cyano, amino, C_1-5Monoalkylamino or C_2-10A dialkylamino group;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

o and m represent 1 to 2;

n represents a number of 0 to 3,

p represents 0-2, and

q represents 0 to 2.

2. A dihydrospiro- [ cycloalkylamine according to claim 1]-a pyrimidone derivative or a salt thereof, wherein R4 represents a hydrogen atom, C_1-4Alkoxycarbonyl group, C_1-6Alkyl, these radicals being optionally substituted by 1 to 4 substituents selected from halogen atoms, hydroxy or C_1-4Substituent of alkoxy.

3. A dihydrospiro- [ cycloalkylamine ] -pyrimidone derivative or a salt thereof according to claim 1, wherein R1 represents an unsubstituted 4-pyridine ring or an unsubstituted 4-pyrimidine ring.

4. A dihydrospiro- [ cycloalkylamine ] -pyrimidone derivative or a salt thereof according to claim 2, wherein R1 represents an unsubstituted 4-pyridine ring or an unsubstituted 4-pyrimidine ring.

5. A dihydrospiro- [ cycloalkylamine ] -pyrimidone derivative or a salt thereof according to claim 1, wherein:

r2 represents a benzene ring, which ring is optionally substituted with 1 to 4 substituents selected from: c_1-3Alkyl, halogen atom, hydroxy or C_1-2An alkoxy group; and

r1 represents an unsubstituted 4-pyridine ring or an unsubstituted 4-pyrimidine ring; and

r3 represents a hydrogen atom; and

r4 represents C_1-4Alkoxycarbonyl group, C_3-6Cycloalkyl-carbonyl, benzoyl or C_1-3Alkyl, these groups being optionally substituted with 1 to 4 substituents selected from halogen atoms or hydroxyl groups; 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.

6. A dihydrospiro- [ cycloalkylamine according to claim 1]-a pyrimidone derivative or a salt thereof, wherein said C_1-3Haloalkyl is selected from C_1-2A perhaloalkyl group.

7. A dihydrospiro- [ cycloalkylamine ] -pyrimidinone derivative selected from the group consisting of compounds within the following group or salts thereof:

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-carboxylic acid ethyl ester

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-carboxylic acid ethyl ester

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

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-carboxylic acid ethyl ester

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 ' -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, 2-a ] pyrimidin ] -6 ' (1 ' H) -one

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 ' -carboxylic acid ethyl ester

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 ' -carboxylic acid ethyl ester

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

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 ' -carboxylic acid ethyl ester

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 ' -carboxylic acid ethyl ester

1 '- (cyclopropylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -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- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (cyclopropylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -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(1H) -one

1 '- (Cyclobutylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclobutylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclohexylcarbonyl) -1- [ (2S) -2-hydroxy-2-phenylethyl ] -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclohexylcarbonyl) -1- (2-oxo-2-phenylethyl) -8-pyridin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one

1 '- (Cyclohexylcarbonyl) -1- [ (2S) -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-phenylethyl) -8-pyrimidin-4-yl-3, 4-dihydrospiro [ pyrimido [1, 2-a ] pyrimidine-2, 3' -pyrrolidin ] -6(1H) -one.

8. A compound represented by the general formula (III),

wherein R1, R3, R4, m, o, p and q are as defined for the compounds of formula (I) according to claim 1.

9. A medicament comprising, as an active ingredient, a substance selected from the group consisting of dihydrospiro- [ cycloalkylamine ] -pyrimidone derivatives represented by the general formula (I) or salts thereof as claimed in claim 1.

10. The use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and/or treatment of diseases which are caused by abnormal activity of glycogen synthase kinase 3 β.

11. The use according to claim 10, wherein the disease is selected from the group consisting of: alzheimer's disease, parkinson's disease, tau disease, vascular dementia; acute stroke; cerebrovascular accident, brain cord trauma, spinal cord trauma; peripheral neuropathy; retinopathy or glaucoma.

12. The use of claim 10, wherein the disease is a traumatic injury.

13. The use of claim 10, wherein the disease is a neurodegenerative disease.

14. The use according to claim 10, wherein the disease is selected from the group consisting of: non-insulin dependent diabetes mellitus, obesity, manic depression, schizophrenia, alopecia or cancer.

15. The use according to claim 14, wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia or a virus-induced tumor.