HK1085740B - 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 and their use against neurogenerative diseases - Google Patents

Description

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

Technical Field

The present invention relates to a compound useful as an active ingredient in a prophylactic and/or therapeutic agent for neurodegenerative diseases caused by abnormal activity of GSK3 β.

Background

GSK3 β (glycogen synthase kinase 3 β) is a proline directed serine, threonine 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 tauopathies (taupathy or 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. Moreover, 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, an uncompetitive inhibitor of GSK3 β, also increases neuronal survival by inducing survival factors such as Bc 1-2 and inhibiting the expression of pro-apoptotic factors such as P53 and Bax, increasing synaptogenesis in certain models.

Recent studies have demonstrated that β -amyloid increases GSK3 β activity and tau phosphorylation. Moreover, this hyperphosphorylation and the neurotoxic effects of β -amyloid can be blocked or 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 or 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 have utility in the treatment of neuropathological consequences and cognitive 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, tauopathy (e.g., 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 neurodegenerative diseases; retinopathy and glaucoma.

In addition, GSK3 β may find use 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

An object of the present invention is to provide a compound useful as an active ingredient in a prophylactic and/or therapeutic agent for diseases caused by abnormal activity of GSK3 β, more specifically, neurodegenerative diseases. More specifically, the object of the present invention is to provide a novel compound useful as an active ingredient in a medicament 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- [ cycloalkyl ] -pyrimidone derivative represented by 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 (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, the ring being optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substitution;

r2 represents a benzene ring or a naphthalene ring; the ring is optionally substituted with 1-4 substituents selected from: c_1-6Alkyl, methylenedioxy, 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;

m represents 1 to 4;

n represents 0 to 3;

p represents 0 to 2;

q represents 0 to 2, and p + q is less than 4.

In another aspect of the present invention, there is provided a medicament comprising as an active ingredient a substance selected from the group consisting of: a pyrimidone derivative represented by 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 and 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 the disease is a neurodegenerative disease selected from the group consisting of alzheimer's disease, parkinson's disease, T disease (tauopathy) (e.g. 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 neurodegenerative diseases; 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 [ cycloalkyl ] -pyrimidone derivatives of formula (I) and salts thereof, solvates thereof and hydrates thereof.

In a further aspect of the present 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 [ cycloalkyl ] -pyrimidone derivatives of formula (I), salts thereof, solvates thereof and hydrates thereof; and the use of a substance selected from the group consisting of: dihydrospiro [ cycloalkyl ] -pyrimidone derivatives of 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_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 are replaced by halogensE.g. CF₃Or C₂F₅；

C_1-3Haloalkyl represents alkyl in which at least one hydrogen is not substituted 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-glucamine; 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, examples include 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, malic acid, oxalic 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. Although it is preferred to use pharmaceutically acceptable salts of the basic compounds, all acid addition salts are within the scope of the invention.

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

The dihydrospiro [ cycloalkyl ] -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 the compounds of the present invention are shown in table 1 below. However, the scope of the present invention is not limited to these compounds.

One embodiment of the present invention includes compounds represented by formula (I) as follows, wherein:

(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, these rings optionally being 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 radicalHalogen atom, hydroxy group or C_1-2An alkoxy group; and/or

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

(4) Y represents a bond, a carbonyl group, a methylene group (optionally substituted by one or two substituents selected from C_1-3Alkyl, hydroxy, C_1-4Alkoxy radical, C_1-2Perhaloalkyl or amino);

(5) p + q is equal to 2 or 3, preferably 2; more particularly wherein R1, R2, R3 and Y are as defined above.

Another embodiment of the present invention includes compounds of formula (I) wherein:

(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, hydroxy, or C_1-2An alkoxy group; and/or

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

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

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

(6) p represents 2 and q represents 0; more particularly wherein R1, R2, R3, X, Y, p and q are as defined above.

Specific compounds of the invention represented by formula (I) include the compounds of table 1:

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

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

3: 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,

4: 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,

5: 1 ' - [ (2R) -2-hydroxy-2-phenylethyl ] -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

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

7: 1 ' - (2-oxo-2-phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

8: 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,

9: 1 ' - (2-oxo-2-phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

10: 1 ' - (2-oxo-2-phenylethyl) -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

11: 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,

12: 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,

13: 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,

14: 1 ' - (phenylmethyl) -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

15: 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,

16: 1 ' - (phenylmethyl) -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

17: 1 ' - (phenylmethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopropane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

18: 1 ' - (phenylmethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

19: 1 ' - (phenylmethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

20: 1 ' - (phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin ] -6 ' (1 ' H) -one,

21: 1 ' - (phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

22: 1 ' - (phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopropane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin ] -6 ' (1 ' H) -one,

23: 1 ' - (phenylethyl) -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclobutane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

24: 1 ' - (phenylethyl) -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro- [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one,

25: 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,

26: 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,

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

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

Preparation method

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

Reaction scheme 1

(in the above reaction scheme, R1, R2, R3, X, Y, m, n, 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, m, N, 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 at a suitable temperature ranging from 0 to 130 ℃ in ordinary air, and then reacted with a compound of the formula (II) wherein R2, X, Y, 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 a compound 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 purchased or prepared according to methods known in the art.

The compound of formula (III) can be prepared according to the method of reaction formula 2

Reaction formula 2

(in the above reaction formulae, R1, R3, m, p and q are the same as defined above).

According to this process, 3-keto esters of formula (IV), in which R1, R3 are as defined for the compounds of formula (I) and R represents an alkyl group (e.g. methyl or ethyl), are reacted with compounds of formula (V). The reaction can be carried out in the presence of a base such as potassium carbonate in an alcoholic 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 to give 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 the formula (III) in which R3 represents a fluorine atom can be obtained in a similar manner to that described in Tetrahedron Letters, Vol.30, No. 45, p.6113-6116, 1989.

Yet another object of the present invention is also directed to compounds of formula (III) as intermediates for the preparation of compounds of formula (I).

The compounds of formula (IV) can be purchased or prepared according to methods known in the art.

For example, a compound of formula (IV) (wherein R1 represents a pyridine or pyrimidine ring, which ring is optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy or halogen) by reacting, respectively, isonicotinic acid or pyrimidine-carboxylic acid (optionally substituted by C)_1-4Alkyl radical, C_1-4Alkoxy or halogen atom substituted) with the corresponding malonic acid monoester. The reaction can 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 20-70 ℃.

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

For example, the compound of formula (V) (when m is 1, p is 2, and q is 0) can be prepared according to the method described in reaction formula 3 and according to the method of Smith and Christensen (j.org.chem.1955, 20, 829) for the last step. The reaction conditions used are described in the chemical examples.

Reaction formula 3

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

Another example of a compound of formula (V) wherein m is 3, p is 2 and q is 0, can be prepared according to the method of scheme 4 and according to the method of Smith and Christensen (j. org. chem.1955, 20, 829) for the last step. The reaction conditions used are described in the chemical examples.

Reaction formula 4

(in the above reaction scheme, Pg represents a protecting group)

The compound of formula (VI) may be prepared as described by Bertus and szymniaak (chem. commum.2001, 1792).

The compounds of formula (X) may be prepared according to the methods described by Suzuki et al (Synthetic Communication 1998, 28(4), 701).

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

As an active ingredient of the drug of the present invention, a substance selected from the group consisting of the compounds represented by the following formula (I), and pharmaceutically acceptable salts, solvates, and hydrates thereof can be used. 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 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 pharmaceutical compositions, such as capsules, microcapsules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, and the like, or as parenteral compositions, such as intravenous, intramuscular, or subcutaneous injections, 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 polymers can be administered directly into the cerebral cortex.

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 0.01-1000mg (weight of active ingredient), and the dosage may be administered once daily or divided into several portions to be administered several times daily, once daily. 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).

Chemical examples

The present invention will be more specifically explained with reference to the following general examples, however, the scope of the present invention is not limited by these examples.

Example 1 (Compound 1 of Table 1)

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. (1:1) (hydrochloride)

1.12- (1-amino-cyclopropyl) ethanol hydrochloride (1:1)

To a solution of 8.63g (45.11mmol) of 1- (2-benzyloxy-ethyl) cyclopropylamine and 3g10 wt% Pd/C in 100ml isopropanol was added a solution of 100ml hydrochloric acid in isopropanol (5-6N). The mixture was shaken under 4 atmospheres of hydrogen at 40 ℃ until hydrogen uptake ceased.

The catalyst was removed by filtration and washed with isopropanol. The filtrate was evaporated to dryness to give 6.22g of pure product as a viscous oil.

1.21- (2-hydroxyethyl) cyclopropylcarbamic acid tert-butyl ester

To a solution of 6.21g (45.11mmol) of 2- (1-amino-cyclopropyl) ethanol hydrochloride (1:1) in 63ml of tetrahydrofuran were added 1ml of water, 12.68ml (90.22mmol) of triethylamine and a solution of 9.84g (45.11mmol) of di-tert-butyl dicarbonate in 21ml of tetrahydrofuran. The resulting solution was stirred at room temperature for 16 hours.

The mixture is evaporated, dissolved in 100ml of diethyl ether and treated with aqueous hydrochloric acid (0.1N). The combined extracts were washed with saturated aqueous sodium chloride and evaporated. The crude product was triturated with water, filtered and 6.68g of pure product as a white solid.

Mp：93-95℃

1.32- {1- [ (tert-Butoxycarbonyl) amino ] cyclopropyl } ethylmethanesulfonate

To a solution of 6.472g (32.16mmol) tert-butyl 1- (2-hydroxyethyl) cyclopropylcarbamate in 61ml dry dichloromethane was added 12.79ml (91mmol) dry triethylamine. The resulting mixture was cooled at-20 ℃. A solution of 3.54ml (45.66mmol) of methanesulfonyl chloride in 11ml of anhydrous dichloromethane was then added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into ice-water and the organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The crude product was triturated with petroleum ether and filtered to give 7.82g of pure product as an orange solid.

Mp：88-89℃

1.41- [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) ethyl ] -cyclopropylcarbamic acid tert-butyl ester

To a solution of 7.82g (28mmol) of 2- {1- [ (tert-butoxycarbonyl) amino ] cyclopropyl } ethyl methanesulfonate in 35ml of anhydrous dimethylformamide was added 5.45g (29.4mmol) of potassium phthalimide. The resulting mixture was stirred at 150 ℃ for 18 hours. The mixture was filtered and washed with diethyl ether. The filtrate was evaporated to dryness, the crude product was heated in water and the precipitate was filtered. The product was dried to give 4.63g of pure compound as an orange solid.

Mp：125-127℃

1.51- (2-aminoethyl) cyclopropylcarbamic acid tert-butyl ester

To a solution of 4.57g (13.83mmol) of tert-butyl 1- [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) ethyl ] -cyclopropylcarbamate in 80ml of ethanol was added 3.36ml (69.16mmol) of hydrazine hydrate, and the resulting mixture was heated under reflux for 16 hours. The mixture was filtered and washed with diethyl ether. The filtrate was evaporated to dryness to give 2.3g of pure compound as orange oil.

1.61- (2-aminoethyl) cyclopropaneamine hydrobromide (1: 2)

To a solution of 20ml hydrobromic acid (33%) in acetic acid was added 2.29g (11.46mmol) of tert-butyl 1- (2-aminoethyl) cyclopropylcarbamate and the resulting mixture was stirred at 60 ℃ for 1 h.

The mixture was cooled and diethyl ether was added. The resulting precipitate was filtered. The product was dried to give 2.69g of pure compound as a brown solid.

Mp：233-235℃

1.74, 6-diazaspiro [2.5] oct-5-ene-5-amine hydrobromide (1:1)

To a solution of 2.65g (10.11mmol) of 1- (2-aminoethyl) cyclopropaneamine hydrobromide in 21ml of methanol was added 3.83ml (21.24mmol) of sodium methoxide in methanol (5.55N). The mixture was stirred at room temperature for 2 hours. The precipitate was filtered and the filtrate was evaporated. The crude product was dissolved in 9ml of water and 1.07g (10.11mmol) of cyanogen bromide were added in portions. The resulting mixture was stirred at room temperature for 2 hours and evaporated to dryness to give 2.08g of pure compound as an orange oil.

1.88 '-pyridin-4-yl-3', 4 '-dihydrospiro [ cyclopropane-1, 2' -pyrimido [1, 2-a ] pyrimidin-6 '(1' H) -one

A mixture of ethyl 3- (pyridin-4-yl) -3-oxopropanoate (1.77 g, 9.19mmol), 4, 6-diazaspiro [2.5] oct-5-ene-5-amine hydrobromide (2.084 g, 10.11mmol) and potassium carbonate (2.79 g, 20.22mmol) in 17ml ethanol was heated at reflux for 12 h. The cooled solution was evaporated to remove the solvent, the residue was treated with water and the precipitate was filtered to give 0.88g of the product as a yellow powder.

Mp：277-278℃

1.91 ' - [ (2S) -2-hydroxy-2-phenylethyl ] -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro [ cyclopropane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one (1:1) (hydrochloride)

To a solution of 0.5g (1.97mmol)8 '-pyridin-4-yl-3', 4 '-dihydrospiro [ cyclopropane-1, 2' -pyrimido [1, 2-a ] pyrimidin-6 '(1' H) -one in 10ml anhydrous dimethylformamide was added 0.173g (4.33mmol) sodium hydride (60% suspension in mineral oil). The mixture was stirred at 50 ℃ for 1 hour. Then 0.4g (2.56mmol) of (1-S) -2-chloro-1-phenylethanol was added and the mixture was stirred at 120 ℃ for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried and evaporated to give the crude product. Chromatography on silica eluting with a dichloromethane/methanol mixture (ratio: 100/0-95/5) affords the compound in the form of the free base. The base was converted to the hydrochloride salt to give 0.443g of pure product.

Mp：219-221℃，[α]_D＝-9.5(c＝0.4，CH₃OH)

RMN(200MHz；DMSO-d⁶)：δ 8.90(d，2H)；8.35(d，2H)；7.12-7.46(m，5H)；6.61(s，1H)；4.88(t，1H)；3.40-4.05(m，4H)；1.83(t，2H)；1.03-1.33(m，2H)；0.58-0.85(m，2H).

Example 2 (Compound 2 of Table 1)

1 ' - (2-oxo-2-phenylethyl) -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro [ cyclopropane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin ] -6 ' (1 ' H) -one (1:1) (hydrochloride salt)

0.31g (0.83mmol) 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 are dissolved in 8ml of anhydrous dichloromethane and mixed with 0.145g (1.24mmol) of N-methylmorpholine N-oxide, 0.003g (0.0083mmol) of tetra-N-propylammonium perruthenate and 1g of pulverulent molecular sieves (4A). The mixture was stirred at 20 ℃ under nitrogen atmosphere for 12 hours.

The mixture was filtered. The filtrate was washed with saturated aqueous ammonium chloride, dried and evaporated to give the crude product. Chromatography on silica gel eluting with a dichloromethane/methanol mixture (ratio: 100/0-95/5) gave the compound as the free base which was converted to the hydrochloride salt to give 0.078g of pure product.

Mp：232-234℃

RMN(200MHz；DMSO-d⁶)：δ 8.62(d，2H)；8.03(d，2H)；8.00(d，2H)；7.51-7.78(m，3H)；6.61(s，1H)；5.15(s，2H)；4.01(t，2H)；2.04(t，2H)；1.17(t，2H)；0.78(t，2H).

Example 3 (Compound 3 of Table 1)

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 (1:1) (hydrochloride)

3.1 (1-Aminocyclopentyl) acetonitrile

A solution of 15.91g (0.15mol) cyclopentylideneacetonitrile in 170ml of aqueous ammonia solution (29%) and 57ml of methanol is heated in a sealed tube at 100 ℃ for 24 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel chromatography, eluting with a dichloromethane/methanol mixture (ratio: 90/10), to give 12.15g of the product as a colorless oil.

3.21- (cyanomethyl) cyclopentylcarbamic acid tert-butyl ester

Using (1-aminocyclopentyl) acetonitrile, the product was obtained by a method similar to that used in step 1.2. The compound was used as such in the next step.

3.31- (2-aminoethyl) cyclopentylcarbamic acid tert-butyl ester

To a suspension of 8.48g (223.63mmol) lithium aluminium hydride in 687ml diethyl ether a solution of 16.7g (74.54mmol) tert-butyl 1- (cyanomethyl) cyclopentylcarbamate in 344ml diethyl ether is added dropwise at 0 ℃. The resulting mixture was stirred at 0 ℃ under nitrogen for 1 hour. The reaction mixture was diluted with 100ml of ether at 0 ℃ and treated with an excess of saturated aqueous solution of sodium sulfate. Solid sodium sulfate was added and the organic phase was filtered to remove salts. The solvent was evaporated to dryness to give 13.83g of product as an oil.

3.41- (2 aminoethyl) cyclopentanamine hydrobromide (1: 2)

The product was obtained in analogy to step 1.6 using tert-butyl 1- (2-aminoethyl) cyclopentylcarbamate. The compound was used as such in the next step.

Mp：194-196℃

3.56, 8-diazaspiro [4.5] dec-7-en-7-amine hydrobromide (1:1)

The product was obtained in analogy to step 1.7 using 1- (2 aminoethyl) cyclopentanamine hydrobromide (1: 2). The compound was used as such in the next step.

3.68 '-pyridin-4-yl-3', 4 '-dihydrospiro [ cyclopentane-1, 2' -pyrimido [1, 2-a ] pyrimidin-6 '(1' H) -one

The product was obtained in analogy to step 1.8 using 6, 8-diazaspiro [4.5] dec-7-en-7-amine hydrobromide (1: 1). The compound was used as such in the next step.

Mp：241-243℃

3.71 ' - [ (2S) -2-hydroxy-2-phenylethyl ] -8 ' -pyridin-4-yl-3 ', 4 ' -dihydrospiro [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidine ] -6 ' (1 ' H) -one (1:1) (hydrochloride salt)

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

Mp：221-223℃，[α]_D＝-32.8(c＝1.036，CH₃OH)

RMN(200MHz；DMSO-d⁶)：δ 8.91(d，2H)；8.41(d，2H)；7.13-7.47(m，5H)；6.67(s，1H)；5.22(dd，1H)；3.71-4.04(m，3H)；3.38-3.59(m，1H)；2.26-2.62(m，2H)；1.76-2.15(dm，2H)；1.30-1.76(m，6H).

Example 4 (Compound 4 of Table 1)

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

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

The product was obtained analogously to step 1.8 from ethyl 3- (4-pyrimidinyl) -3-oxopropanoate (prepared analogously to German patent 2705582) and 6, 8-diazaspiro [4.5] dec-7-en-7-amine hydrobromide (1:1) (prepared as in example 3.5). The resulting compound was treated with water, and the precipitate was collected by filtration to obtain 2.92g of a product.

Mp：243-244℃

4.21 ' - [ (2S) -2-hydroxy-2-phenylethyl ] -8 ' -pyrimidin-4-yl-3 ', 4 ' -dihydrospiro [ cyclopentane-1, 2 ' -pyrimido [1, 2-a ] pyrimidin-6 ' (1 ' H) -one

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

Mp：157-158℃，[α]_D＝-28.9(c＝1.018，CH₃OH)

RMN(200MHz；DMSO-d6)：δ 9.28(s，1H)；9.01(d，1H)；8.14(d，1H)；7.15-7.50(m，5H)；6.72(s，1H)；5.19(t，1H)；3.70-4.04(m，3H)；3.38-3.58(m，1H)；2.26-2.55(m，2H)；1.74-2.12(dm，2H)；1.25-1.74(m，6H).

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, R1 is unsubstituted pyrimidin-4-yl or unsubstituted pyridin-4-yl, p represents 2, q represents 0, Ph represents phenyl, (S), (R) or (Rac.) represents 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

TABLE 1

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 M ATP (containing 300000cpm 33P-ATP) in the presence of GSK3 β in 25mM Tris-HCl, pH7.5, 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 muM Pre-phosphorylated GS1 peptide and 42. mu.M ATP (containing 260000cpm 33P-ATP) in the presence of GSK 3. beta. in 80mM Mes-NaOH, pH6.5, 1mM Mg (OAc)₂0.5mM EGTA, 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%).

The reaction was stopped with 100 microliters of a solution having the following composition: 25g polyphosphoric acid (85% P2O)₅)，126ml 85％H₃PO₄Water was added to 500ml and then diluted to 1: 100. 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。

GSK3 beta inhibitory Activity of Compounds of the invention as IC₅₀Illustrative IC of the Compounds shown in Table 1₅₀In the range of 1 nanomolar to 1 micromolar.

For example, IC for Compound 10 of Table 1₅₀It was 0.0006. 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

(1) 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 (11)

1. A dihydrospiro [ cycloalkyl ] -pyrimidone derivative represented by 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, the methylene groupMethyl is optionally substituted with 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_1-4An alkoxy group, or a halogen atom;

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_1-2Perhaloalkyl, 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;

m represents 1 to 4;

n represents 0 to 3;

p represents 0-2

q represents 0 to 2 and p + q is less than 4.

2. A dihydrospiro- [ cycloalkyl ] -pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein R1 represents an unsubstituted 4-pyridyl group or an unsubstituted 4-pyrimidyl group.

3. A dihydrospiro- [ cycloalkyl ] -pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1 or 2, wherein

R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;

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

p represents 2 and q represents 0.

4. A dihydrospiro- [ cycloalkyl ] -pyrimidinone derivative selected from:

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 ' H) -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,

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,

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 salt thereof, or a solvate thereof, or a hydrate thereof.

5. A compound of formula (III)

Wherein: r1, R3, m, p, q and q are as defined for compounds of formula (I) according to claim 1.

6. A medicament comprising as an active ingredient a dihydrospiro- [ cycloalkyl ] -pyrimidone derivative represented by the formula (I) or a salt thereof, or a solvate thereof, or a hydrate thereof, according to claim 1.

7. The use of a compound as claimed in any one of claims 1 to 4 in the manufacture of a medicament for the prophylaxis and/or treatment of diseases which are caused by abnormal GSK3 β activity.

8. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis and/or treatment of neurodegenerative diseases.

9. The use of a compound according to claim 8, wherein the neurodegenerative disease is selected from the group consisting of: alzheimer's disease, Parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injury; cerebrovascular accident, brain cord trauma, spinal cord trauma; peripheral neurodegenerative diseases; retinopathy or glaucoma.

10. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis and/or treatment of: non-insulin dependent diabetes mellitus, obesity, maniac depression, schizophrenia, hair loss, or cancer.

11. The use according to claim 10, wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia or a virus-induced tumor.