Title of Invention

A PYRIMIDONE DERIVATIVE

Abstract

The invention relates to a substititutud-pyrimidone derivative represented by formula (I) or a salt thereof , wherein: X represents two hydrogen atom, a sulfer atom, an oxygen atom or a c1-2 alkyl group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted; R1 rep- resents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted; R2 represents a phenyl group or a naphthalene ring; the phenyl group and the naphthalene ring be- ing optionally substituted;R3 represents a hydrogen atour or a C1-6 alkyl group; R4 represents a C1-2 perhalogenated alkyl group or a C1-3helogenated alkyl group; R5 represents a hydrogen atour; a C1-6 alkyl group or a halogen atom; n represents 0 to 3; and p+q+0to3. The invention relates also to a medecament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3ß, such as Alzheimer disease.

Full Text

WO 2004/083210 PCT/EP2004/004013 SUBSTITUTED 8-PERFLUOROALKYL-6,7,8,9-TETRAHYDROPYRIMIDO[1,2-a] PYRIMIDIN-4-0NE DERIVATIVES Specification Technical Field The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal activity of GSK3p. Background Art GSK3P (glycogen synthase kinase 3) is a proline directed serine, threonine kinase that plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. It was later recognized that GSK3 was identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that are also found to be hyperphosphorylated in Alzheimer's disease and in several taupathies. Interestingly, protein kinase B (AKT) phosphorylation of GSK3 results in a loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors. Moreover, phosphorylation by GSK3 of -catenin, a protein involved in cell survival, results in its degradation by an ubiquitinilation dependent proteasome pathway. Thus, it appears that inhibition of GSK3 activity may result in neurotrophic activity. Indeed there is evidence that lithium, an uncompetitive inhibitor of GSK3 enhances neuritogenesis in some models and also increases neuronal survival, through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax. Recent studies have demonstrated that p-amyloid increases the GSK3p activity and tau protein phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic effects of p-amyloid are blocked by lithium chloride and by a GSK3 antisense mRNA. These observations strongly suggest that GSK3p may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation. WO 2004/083210 PCT/EP2004/004013 2 Although tau hyperphosphorylation results in a destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK3 activity are, most likely, not only due to a pathological phosphorylation of tau protein because, as mentioned above, an excessive activity of this kinase may affect survival through the modulation of the expression of apoptotic and antiapoptotic factors. Moreover, it has been shown that p-amyloid-indueed increase in GSK3 activity results in the phosphorylation and, hence the inhibition of pyruvate dehydrogenase, a pivotal enzyme in energy production and acetylcholine synthesis. Altogether these experimental observations indicate that GSK3 may find application in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases. These include, in a non- limiting manner, Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma. In addition GSK3 may find application in the treatment of other diseases such as: Non-insulin dependent diabetes (such as diabetes type II) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors. Disclosure of the Invention An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 activity, more particularly of neurodegenerative diseases. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease. WO 2004/083210 PCT/EP2004/004013 3 Thus, the inventors of the present invention have identified compounds possessing inhibitory activity against GSK3. As a result, they found that compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases. The present invention thus provides substituted-pyrimidone derivatives represented by formula (I) or salts thereof, solvates thereof or hydrates thereof: wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1-2 alkyl group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted by one or two groups chosen from a C1-6 alkyl group, a hydroxyl group, a C1-4 alkoxy group, a C1-2perhalogenated alkyl group or an amino group; R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted by a C1-4 alkyl group, a C1-4 alkoxy group, or a halogen atom; R2 represents a phenyl group or a naphthalene ring; the phenyl group and naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C1-6 alkyl group, a phenyl group, a methylendioxy group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-4 alkoxy group, a nitro, a cyano, an amino, a C1-5 monoalkylamino group or a C2-10 dialkylamino group; R3 represents a hydrogen atom, or a C1-6 alkyl group; WO 2004/083210 , PCT/EP2004/004013 4 R4 represents a C1-2 perhalogenated alkyl group or a C1-3 halogenated alkyl group; R5 represents a hydrogen, a C1-6 alkyl group or a halogen atom; n represents 0 to 3; and p+q = 0 to 3. According to another aspect of the present invention, there is provided a medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivatives represented by formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof. As preferred embodiments of the medicament, there are provided the aforementioned medicament which is used for preventive and/or therapeutic treatment of diseases caused by abnormal GSK3P activity, and the aforementioned medicament which is used for preventive and/or therapeutic treatment of neurodegenerative diseases and in addition other diseases such as: Non-insulin dependent diabetes (such as diabetes type It) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors. As further preferred embodiments of the present invention, there are provided the aforementioned medicament wherein the diseases are neurodegenerative diseases and are selected from the group consisting of Alzheimer's disease, Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasai degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma, and the aforementioned medicament in the form of pharmaceutical composition containing the above substance as an active ingredient together with one or more pharmaceutical additives. The present invention further provides an inhibitor of GSK3p activity comprising as an active ingredient a substance selected from the group consisting of the substituted-pyrimidone derivatives of formula (I) and the salts thereof, and the solvates thereof and the hydrates thereof. WO 2004/083210 PCT/EP2004/004013 5 According to further aspects of the present invention, there is provided a method for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal GSK3 activity, which comprises the step of administering to a patient a preventively and/or therapeutically effective amount of a substance selected from the group consisting of substituted-pyrimidone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof; and a use of a substance selected from the group consisting of the substituted-pyrimidone derivatives of formula (1) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof for the manufacture of the aforementioned medicament. As used herein, the C1-6 alkyl group represents a straight or branched alky! group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n- propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, and the like; The C1-4 alkoxy group represents an alkyloxy group having 1 to 4 carbon atoms for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like; The halogen atom represents a fluorine, chlorine, bromine or iodine atom; The C1-2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been subsituted by a halogen atom, for example a CF3 or C2F5; The C1-3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been subsituted by an halogen atom; The C1-5 monoalkylamino group represents an amino group substituted by one C1-6 alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropyl amino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group and isopentylamino group; The C2-10 dialkylamino group represents an amino group substituted by two C1-5 alkyl groups, for example, dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group and diisopropylamino group; A leaving group L represents a group which could be easily cleaved and substituted, such a group may be for example a tosyl, a mesyl, a bromide and the like. P+q = 0 to 3, indicates that the addition of p and q equals 0,1, 2 or 3. WO 2004/083210 , PCT/EP2004/004013 6 The compounds represented by the aforementioned formula (I) may form a salt. Examples of the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane1 N,N- bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N- methylglucamine, and L-giucamine; or salts with basic amino acids such as lysine, 5-hydroxylysine, and arginine. The base-addition salts of acidic compounds are prepared by standard procedures well known in the art. When a basic group exists, examples include salts with mineral 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, gtucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid; or salts with acidic amino acids such as aspartic acid, and glutamic acid. The acid-addition salts of the basic compounds are prepared by standard procedures well know in the art which include, but are not limited thereto, dissolving the free base in an aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and an acid in an organic solvent, in which case the salt separates directly, or is precipitated with a second organic solvent, or can be obtained by concentration of the solution. The acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not compromised by side effects ascribable to the anions. Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention; In addition to the substituted-pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention. The substituted-pyrimidone derivatives represented by the WO 2004/083210 PCT/EP2004/004013 7 aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) and (S) configuration, and the derivative may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers in pure form, any mixtures of stereoisomers, racernates and the like fall within the scope of the present invention. Examples of compounds of the present invention are shown in table 1 hereinafter. However, the scope of the present invention is not limited by these compounds. One of the embodiments of the present invention include also compounds represented by formula (I) wherein Rl, R3, R4, R5, X, Y, n, p and q are as defined here above and R2 represents a phenyl group or a naphthalene ring; the phenyl group and naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C1-6 alkyl group, a methylendioxy group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-4 alkoxy group, a nitro, a cyano, an amino, a C1-5 monoaikylamino group or a C2-10 dialkylamino group. Another embodiment of the present invention include compounds represented by formula (I) wherein R1, R2, R3, R5, X, Y, n, p and q are as defined here above and R4 represents a C1-2 perhalogenated alkyl group. Another embodiment of the present invention include compounds represented by formula (I) wherein R1, R2, R3, R4, R5, X, Y, n, p and q are as defined hereunder: (1) R1 represents a 3- or 4-pyridine ring and more preferably 4-pyridine ring or a 4- or 5-pyrimidine ring and more preferably 4-pyrimidine ring, which may be substituted by a C1-2 alkyl group, a C1-2 alkoxy group or a halogen atom; (2) R2 represents a phenyl group or a naphthalene ring, the phenyl group and the naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a phenyl group, a halogen atom, a cyano, a hydroxyl group or a C1-2 alkoxy group or alternatively R2 represents a phenyl group or a naphthalene ring, the phenyf group and the naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a halogen atom, a hydroxyl group or a C1-2 alkoxy group; (3) R3 represents a hydrogen atom; WO 2004/083210 PCT/EP2004/004013 8 (4) R4 represents a C1-2 perhalogenated alkyl group and more preferably a perfluoroalkyl group; (5) R5 represents a hydrogen atom or a halogen atom or alternatively R5 represents a hydrogen atom; (6) X represents two hydrogen atoms; (7) Y represents a bond, a carbonyl group or methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C1-4 alkoxy group, a C1-2 perhalogenated alkyl group, an amino group or alternatively Y represents a carbonyl group or methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C1-4 alkoxy group, a C1-2 perhalogenated alkyl group, an amino group; (8) n, p, and q represent 0, 2 and 0, respectively. Another embodiment of the present invention include compounds represented by formula (I) wherein R1, R2, R3, R4, R5, X, Y, n, p and q are as defined hereunder: (1) R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; (2) R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C1-3 aikyl group, a halogen atom, a hydroxyl group or a C1-2 alkoxy group; (3) R3 represents a hydrogen atom; (4) R4 represents a trifluoromethyl group; (5) R5 represents a hydrogen or fluorine atom or alternatively R5 represents a hydrogen atom; (6) X represents two hydrogen atoms; (7) Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; (8) n, p, and q represent 0, 2 and 0, respectively. Particularly compounds of the present invention represented by formula (I), wherein R4 is a trifluoromethyi group, include compounds: 1. 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyi)-6,7I8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrirnidin-4-one WO 2004/083210 PCT/EP2004/004013 9 2. 9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin4-one 3. 9-[2-(3-Bromo-phenyl)-2Hoxo-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 4. 9-[2-(3-Bromo-phenyI)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifIuoromethyl)- 6,7,8,9-tetrahydro4H-pyrimido[1,2-a]pyrimidin-4-one 5. 9-[2-Oxo-phenyl-ethyl]-2-(4-pyrimidiny)-8-(trlfluoromethy)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-ajpyrimidin-4-one 6. (-)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 7. (+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifiuoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 8. (+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 9. (-)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidiny)-8-(trifiuoronnethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 10.3-Fiuoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluoromethyI)-6,7,8,9- tetrahydro-4H-pyrimidoI[1,2-a]pyrimidin-4-one 11.9-(Phenyimethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H- pyrimido[1,2-a]pyrimidin-4-one 12.9-(2-Phenylethyl)-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H- pyrimido[1,2-a]pyrimidtn-4-one 13.9-[2-(3-Bromophenyl)-2-oxoethyi]-2-pyrimidin-4-yl-8-(trifluoromethyl)- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 14.9-[2-(3-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yI-8-(trifIuoromethyl)-6,7,8,9- tetrahydro-4H-pyrimidoI[1,2-alpyrimidin-4-one WO 2004/083210 PCT/EP2004/004013 10 15-9-[2-(4-Methylphenyl)-2-oxoethyl]-2-pyrimiclin-4-yl-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 16.9-[2-(4-Fluorophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(rifluorornethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 17.9-[2-(4-Cyanophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 18.9-[2-(4-Cyanophenyl)-2-oxoethyl]-2-pyrimidin-4-yl-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one As a further object, the present invention concerns also methods for preparing the substituted-pyrimidone compounds represented by the aforementioned formula (I). These compounds can be prepared, for example, according to methods explained below. Preparation method Substituted-pyrimidone compounds represented by the aforementioned formula (I), may be prepared according to the method described in the scheme 1. Following this method, the pyrimidinone derivative represented by the above formula (III), wherein R1, R31R4,R5,p and q are as defined for compound of formula (I), is allowed to react with a base such as sodium hydride, sodium carbonate or potassium carbonate in a solvent such as N,N-dirnethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide or chloroform at a suitable WO 2004/083210 PCT/EP2004/004013 11 temperature ranging from 0 to 130°C under ordinary air, then with a compound of formula (ll), wherein R2, X, Y and n are as defined for compound of formula (I) and L represents a leaving group preferably bromide or mesyl group, to obtain the compound of the aforementioned formula (I). Alternatively compounds of formula (I) wherein Y represents a carbonyi group may be prepared by oxydation of a compound of formula (I) wherein Y represents a methylene group substituted by a hydroxyl group according to well known methods to one skilled in the art. Compound of formula (II) is commercially available or may be synthesized according to well-known methods to one skilled in the art. Compound of formula (111) may be prepared according to the method defined in scheme 2. Scheme 2 According to this method, the 3-ketoester of formula (IV), wherein R1 and R5 are as defined for compound of formula (I) and R is an alkyl group such as for example methyl or ethyl, is allowed to react with a compound of formula (V), wherein R3, R4, p and q are as described for compound of formula (I). The reaction may be carried out in the presence of a base such as potassium carbonate, in an alcoholic solvent such as methanol, ethanol and the like or without, at a suitable temperature ranging from 25° to 140°C under ordinary air. Alternatively, compound of formula (III) wherein R5 represents a hydrogen atom may be halogenated in order to give compounds of formula (111) wherein R5 is a halogen atom such as a bromine atom or a chlorine atom. The reaction may WO 2004/083210 PCT/EP2004/004013 12 be carried out in an acidic medium such as acetic acid or propionic acid, in presence of bromosuccinimide or chlorosuccimide, or bromine. In addition, compounds of formula (III) wherein R5 represents a fluorine atom may be obtained by analogy to the method described in Tetrahedron Letters, Vol.30.No.45.pp 6113-6116, 1989. Compound of formula (IV) is commercially available or may be synthesized according to well-known methods to one skilled in the art. For example compounds of formula (IV), wherein R1 represent a pyridine ring or a pyrimidine ring, optionally substituted by a C1-4 alkyl group, C1-4 alkoxy group or a halogen atom, can be prepared by reacting respectively an isonicotinic acid or a pyrimidine-carboxylic acid, optionally substituted by a C1-4 alkyl group, C1-4 alkoxy group or a halogen, with the corresponding malonic acid monoester. The reaction can be carried out using methods well known to one skilled in the art, such as for example in presence of a coupling agent such as 1,1'-carbonylbis-1H- imidazole in a solvent such as tetrahydrofuran at a temperature ranging from 20 to 70°C. In the above reactions protection or deprotection of a functional group may sometimes be necessary. A suitable protecting group Pg can be chosen depending on the type of the functional group, and a method described in the literature may be applied. Examples of protecting groups, of protection and deprotection methods are given for example in Protective groups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York). Compound of formula (V) is commercially available or may be synthesized according to well-known methods of one skilled in the art. Alternatively, compound of formula (V), wherein p represents 2 and q represents 0, may be prepared according to the method defined in scheme 3. WO 2004/083210 PCT/EP2004/004013 13 Scheme 3 (In the above scheme Pg represents an amino-protecting group and L a leaving group, preferably a bromide group or m'esyl group) According to this method, compound of formula (VI), wherein R4 is defined as for compound of formula (I), may be obtained through different manners, depending on R3. The 3-aminoacid of formula (VI), wherein R3 is a hydrogen atom, may be synthesized by analogy to the method described in Tetrahedron Letters, Vol. 43, No.11,pp 1977-1981, 2002. The 3-aminoacid of formula (Vi), wherein R3 is a C1-6 alkyl group, may be synthesized by analogy to the method described in Journal of Organic Chemistry, Vol.56, No.1,pp 4-6, 1991. In both cases, an amino-protecting group is necessary. Examples of protection and deprotection methods are given for example in Protective groups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York). By analogy to these methods, compounds of formula (VII) and (VIII) may be obtained by aminoprotection and compound of formula (IX) may be obtained by deprotection. Then, compound of formula (V) may be obtained by cyclisation, according WO 2004/083210 PCT/EP2004/004013 14 to well-known methods to one skilled in the art. Alternatively, if R3 represents H, compound of formula (V) may be obtained by hydrogenation of compound of formula (X), according to well-known methods to one skilled in the art. Compound of formula (X) is commercially available or may be synthesized according to well-known methods to one skilled in the art. As a further object, the present invention concerns also the compound of formula (III) as intermediate for preparing compounds of formula (I). The compounds of the present invention have inhibitory activity against GSK3p. Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a medicament, which enables preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 activity and more particularly of neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for the preparation of a medicament for preventive and/or therapeutic treatment of neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma; and other diseases such as non-insulin dependent diabetes (such as diabetes type II) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non- small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus- induced tumors. The present invention further relates to a method for treating neurodegenerative diseases caused by abnormal activity of GSK3 and of the aforementioned diseases which comprises administering to a mammalian organism in need thereof an effective amount of a compound of the formula (I). As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically WO 2004/083210 PCT/EP2004/004013 15 acceptable salts thereof, and solvates thereof and hydrates thereof. The substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned 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 aforementioned substances may be used in combination. The above pharmaceutical composition may be supplemented with an active ingredient of another.medicament for the treatment of the above mentioned diseases. The type of pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline. Sustained-release preparations such as those coated with a polymer may be directly administered intracerebrally. Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content ratios of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives may be incorporated in a ratio ranging from 1 % by weight to 90% by weight based on the weight of an active ingredient. Examples of excipients used for the preparation of 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, a conventional inert diluent such as water or a vegetable oil may be used. The liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, WO 2004/083210 PCT/EP2004/004013 16 colorants, and preservatives. The liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for the preparation of compositions for parenteral administration, e.g. injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol. The dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like. Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult. Chemical Examples The present invention will be explained more specifically with reference to the following general examples, however, the scope of the present invention is not - limited to these examples. Example 1 (Compound No. 1 of table 1) 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6l7,8,9-tetrahydro-4H- pyrimido[1,2-a]pyrimidin-4-one hydrochioride (1:1) 1.1 6-(Trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochioride (1:2) To a solution of 10g (45.11 mmol) of 4-trifluoromethyl-pyrimidin-2-ylamine and 0.065g of palladium 10 wt. % on activated carbon in 5 ml of isopropanol was added 45 ml of a solution of hydrochloric acid in isopropanol (5-6 N). The mixture was shaken at 40°C under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with isopropanol. The filtrate WO 2004/083210 PCT/EP2004/004013 17 was evaporated to dryness to afford 12.14g of pure product as a white solid. Mp:138-140°C. 1.2 2-(4-Pyridinyl)-8-(trifluoromethyI)-6,7,8,9-tetrahydro-4H-pyrimido[1,2- a]pyrimidin-4-one A mixture of 5.62g (29.09 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7g (29.09 mmol) of 6-(trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) and 10.05g (72.72 mmol) of potassium carbonate in 50ml of ethanol was heated at reflux temperature during 12 h. The cooled solution was evaporated to removed solvent, the residue was treated with water and the precipitate was filtered to give 4.82g of product as a yellow powder. Mp: 302-304°C. 1.3 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1). To a solution of 0.45g (1.52 mmol) of 2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10ml of anhydrous dimethylformamide was added 0.079g (1.98 mmol) of sodium hydride (60% suspension in mineral oil). The mixture was allowed to stir at 40°C for 15 min and cooled at 0°C. Then 0.363g (1.82 mmol) of 2-bromo-1 -phenyl-ethanone was added and the mixture allowed to stir at room temperature for 16h. Water was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/amrnonia in the proportions 95/5/0.5 gave free base which was transformed into the hydrochloride salt in the usual way to afford 0.358g of the product as a white solid. Mp: 247-249°C RMN 1H (200 MHz ; DMSO-d6): 5 8.7 (d, 2H); 8.21 (m, 4H); 7.7 (m, 3H); 6.8 (s, 1H); 5.8 (d, 1H); 4.95 (d, 1H); 4.85 (m, 1H); 4.45 (m, 1H); 3.5 (m, 1H); 2.7-2.2 (m, 2H). WO 2004/083210 PCT/EP2004/004013 18 Example 2 (Compound No. 2 of table 1) 9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trif!uoromethyI)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrirnidin-4-one hydrochloricie (1:1) The first and second steps of the method described in example 1 are the same. The third step can be detailed as follows : To a solution of 0.4g (1.35 mmol) of 2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 8ml of anhydrous dimethylformamide was added 0.12g (2.97 mmol) of sodium hydride (60% suspension in mineral oil). The mixture was allowed to stir at 50°C for 15mn. Then 0.28g (1.76 mmol) of (1-S)-2-chloro-1 -phenyl ethanol was added and the mixture allowed to stir at 110°C for 16h. Water was added and the mixture extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel elutingwith a mixture of ethyl dichloromethane/methanol in the proportions 100/0 to 95/5 led to compound in the form of free base. The base was transformed into its hydrochloride salt to give 0.1Og of pure product. Mp: 220-222°C RMN 1H (200 MHz; DMSO-d6): 6 8.9 (d, 2H); 8.4 (d, 2H); 7.6-7.2 (m, 5H); 6.8 (s, 1H); 5.2-4.7 (m, 2H); 4.6-4.1 (m, 2H); 3.6-3.2 (m, 2H); 2.5-2.3 (m, 1H); 1.9- 1.6(m,1H). Example 3 (Compound No. 3 of table 1) 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1) The product was obtained by analogy with the method described in example 1, but replacing 2-bromo-1 -phenyl-ethanone by 2-bromo-1 -[(3-bromo)-phenyl]-ethanone, in the third step. Mp: 292-294°C RMN 1H (200 MHz; DMSO-d6): 5 8.7 (d, 2H); 8.1 (m, 5H); 7.95 (m, 1H); 6.75 (s, 1H); 5.8 (d, 1H); 5.1 (d, 1H); 4.8 (m, 1H); 4.6 (m, 1H); 3.5 (m, 1H) 2.7-2.2 (m, 2H). WO 2004/083210 PCT/EP2004/004013 19 Example 4 (Compound No. 4 of table 1) 9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one The product was obtained by analogy with the method described in example 2. but replacing (1-S)-2-chloro-1-phenyl ethanol by 2-chloro-1-[(3-bromo)-phenyl] ethanol, in the third step. Mp:113-115°C RMN 1H (200 MHz; CDCI3): 6 8.9 (d, 2H); 8.4 (d, 2H); 7.6-7.2 (m, 5H); 6.5 (s, 1H); 5.3 (m, 1H); 5.0 (m, 1H); 4.5 (m, 1H); 3.9 (m, 1H); 3.5 (m, 2H); 2.45 (m, 1H);1.9(m, 1H). Example 5 (Compound No. 5 of table 1) 9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrimidin-4-one The product was obtained by analogy with the method described in example 1. but replacing ethyl-3-(pyridin-4-yl)-3-oxopropionate by ethyl-3-(pyrimidin-4-yl)-3- oxopropionate, in the second step. Mp: 247-249X RMN 1H (200 MHz; CDCI3): 6 9.3 (s, 1H); 8.5 (d, 1H); 8.1 (s, 1H); 7.8-7.4 (m, 4H); 7.1 (s, 1H); 6.1 (d, 1H); 4.9-4.7 (m, 1H); 4.5 (d, 1H); 4.2 (m, 1H); 3.8-3.6 (m, 1H);2.5(m,2H). Example 6 (compound No.6 of table 1) (-)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifIuoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1). 4.0 g (9.6 mmol) of 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifiuoromethyl)- 6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (compound No.1) was separated by chiral preparative HPLC (CHIRALPAK AD) eluting with n- heptane/isopropanol in the proportions 80/20 to give 1.43 g of pure product obtained in the form of free base. fR : 20 min. The base was transformed into its hydrochloride salt to give 1.52 g of pure product. WO 2004/083210 PCT/EP2004/004013 20 Mp : 233-235°C. []D20 = -85.1° (c=0.994, CH3OH). RMN 1H (200 MHz ; DMSO-d6): 8 8.7 (d, 2H); 8.21 (m, 4H); 7.7 (m, 3H); 6.8 (s, 1H) ; 5.8 (d, 1H); 4.95 (d, 1H); 4.85 (m, 1H); 4.45 (m, 1H); 3.5 (m, 1H); 2.7-2.2 (m, 2H). Example 7 (compound No.7 of table 1) (+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-6-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1). 4.0 g (9.6 mmol) of 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)- 6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (compound No.1) was separated by chiral preparative HPLC (CHIRALPAK AD) eluting with n- heptane/isopropanol in the proportions 80/20 to give 1.47 g of pure product obtained in the form of free base. fR : 32 min. The base was transformed into its hydrochloride salt to give 1.56 g of pure product. Mp : 233-235°C. []o20 = +86.2° (c=0.994, CH3OH). RMN 1H (200 MHz ; DMSO-d6) : 5 8.7 (d, 2H); 8.21 (m, 4H); 7.7 (m, 3H); 6.8 (s, 1H); 5.8 (d, 1H); 4.95 (d, 1H); 4.85 (m, 1H); 4.45 (m, 1H); 3.5 (m, 1H); 2.7-2.2 (m, 2H). Example 8 (compound N0.8 of table 1) (+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrirnidin-4-one 200 mg (0.48 mmol) of 9-[2-Oxo-2-phenyl-ethyI]-2-(4-pyrimidinyl)-8- (trifluoromethy-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (compound No.5) was separated by chiral preparative HPLC (CHIRALPAK AD) eluting with n- heptane/isopropanol in the proportions 80/20 to give 0.095g of pure product obtained in the form of free base. fR: 17 min. Mp : 234-235. []D20 = +107.4° (c=0.445, DMSO). RMN 1H (200 MHz; CDCI3): 5 9.3 (s, 1H); 8.5 (d, 1H); 8.1 (s, 1H); 7.8-7.4 (m, 4H); 7.1 (s, 1H); 6.1 (d, 1H); 4.9-4.7 (m, 1H); 4.5 (d, 1H); 4.2 (m, 1H); 3.8-3.6 (m,1H);2.5(m,2H). WO 2004/083210 PCT/EP2004/004013 21 Example 9 (compound No.9 of table 1) (-)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrimidin-4-one 200 mg (0.48 mmoi) of 9-[2-Oxo-2-phenyl-ethyI]-2-(4-pyrimidinyl)-8- (trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-alpyrimidin-4-one (compound No.5) was separated by chiral preparative HPLC (CHIRALPAK AD) eluting with n- heptane/isopropanol in the proportions 80/20 to give 0.099g of pure product obtained in the form of free base. tR : 30 min. Mp : 237-238. []D20 = -110.8° (c=0.445, DMSO). RMN 1H (200 MHz; CDCI3): 8 9.3 (s, 1H); 8.5 (d, 1H); 8.1 (s, 1H); 7.8-7.4 (m, 4H); 7.1 (s, 1H); 6.1 (d, 1H); 4.9-4.7 (m, 1H); 4.5 (d, 1H); 4.2 (m, 1H); 3.8-3.6 (m, 1H);2.5(m, 2H). A list of chemical structures and physical data for compounds of the aforementioned formula (I), illustrating the present invention, is given in table 1. The compounds have been prepared according to the methods of the examples. In the table 1, p represents 2, q represents 0, Ph represents a phenyl group;(+), (-) indicates respectively dextro and levo isomers; (S), (R) or (Rac.) indicates in the column "Y" or R4, the stereochemistry of the carbon atom: (rac.) means racemic mixture; (R) means absolute R configuration; (S) means absolute S configuration. WO 2004/083210 PCT/EP2004/004013 WO 2004/083210 PCT/EP2004/004013 23 WO 2004/083210 PCT/EP2004/004013 24 Test Example: Inhibitory activity of the medicament of the present invention against GSK3(3: Two different protocols can be used. In a first protocol: 7.5 M of prephosphorylated GS1 peptide and 10 M ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mM Tris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCI2, 0.6 mM EGTA, 0.05 mg/ml BSA buffer for 1 hour at room temperature in the presence of GSK3beta (total reaction volume : 100 microliters). In a second protocol: 4.1 M of prephosphorylated GS1 peptide and 42 M ATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH, pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer for 2 hours at room temperature in the presence of GSK3beta. Inhibitors were solubilised in DMSO (final solvent concentration in the reaction medium, 1%). The reaction was stopped with 100 microiiters of a solution made of 25 g polyphosphoric acid (85% P2O5), 126 ml 85% H3PO4, H2O to 500 ml and then diluted to 1:100 before use. An aliquot of the reaction mixture was then transferred to Whatman P81 cation exchange filters and rinsed with the solution described above. Incorporated 33P radioactivity was determined by liquid scintillation spectrometry. The phosphorylated GS-1 peptide had the following sequence : NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. The GSK3|3 inhibitory activity cf the compounds of the present invention are expressed in IC50, and as an illustration the range of IC50's of the compounds in table 1 is between 1 nanomolar to 1 micromolar concentrations. For example compound No. 6 of table 1 shows an IC50 of 3nM. WO 2004/083210 PCT/EP2004/004013 25 Formulation Examples (1) Tablets The ingredients below were mixed by an ordinary method and compressed by using a conventional apparatus. Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg Lactose ' 200 mg Magnesium stearate 4 mg (2) Soft capsules The ingredients below were mixed by an ordinary method and filled in soft capsules. Compound of Example 1 30 mg Olive oil 300 mg Lecithin 20 mg (1) Parenteral preparations The ingredients below were mixed by an ordinary method to prepare injections contained in a 1 ml ampoule. Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water for injection 1 ml Industrial Applicability The compounds of the present invention have GSK30 inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal activity of GSK3J3 and more particularly of neurodegenerative diseases. WO 2004/083210 PCT/EP2004/004013 26 What is claimed is: 1. A substituted-pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1-2 alky] group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted by one or two groups chosen from a C1-6 alkyl group, a hydroxyl group, a C1-4 alkoxy group, a C1-2 perhalogenated alkyl group or an amino group; R1 represents a 2, 3 or 4-pyridine ring or a 2,4 or 5-pyrimidine ring, the rings being optionally substituted by a C1-4 alkyl group, a C1-4 alkoxy group, or a halogen atom; R2 represents a phenyl group or a naphthalene ring; the phenyl group and naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C1-6 alkyl group, a phenyl group, a methylendioxy group, a halogen atom, a C1-2 perhalogenated alkyl group, a C1-3 halogenated alkyl group, a hydroxyl group, a C1-4 alkoxy group, a nitro, a cyano, an amino, a C1-5monoalkylamino group or a C2-10 dialkylamino group; R3 represents a hydrogen atom, or a C1-6 alkyl group ; R4 represents a C1-2 perhalogenated alkyl group or a C1-3 halogenated alkyl group; R5 represents a hydrogen, a C1-6 alkyl group or a halogen atom; n represents 0 to 3; and p+q = 0 to 3. WO 2004/083210 PCT/EP2004/004013 27 2. A substituted-pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein R4 represents a C1-2 perhalogenated alkyl group. 3. A substituted-pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1 or 2, wherein: o R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; o R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a phenyl group, a halogen atom, a hydroxyl group, a cyano or a C1-2 alkoxy group or alternatively R2 represents a phenyl group being optionally substituted by 1 to 4 substituents selected from a C1-3 alkyl group, a halogen atom, a hydroxyl group or a C1-2alkoxy group; • R3 represents a hydrogen atom; • R4 represents a trifluoromethyl group; • R5 represents a hydrogen or fluorine atom or alternatively R5 represents a hydrogen atom; • X represents two hydrogen atoms; • Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; • n, p, and q represent 0, 2 and 0, respectively. 4. A substituted-pyrimidone derivative which is selected from the group consisting of: • 9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrimido[1,2-a]pyrimidin-4-one • 9-[(2S)-2-Hydroxy-2-phenyl-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one • 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2-(4-pyridinyl)-8-(trifIuoromethyl)-6l7,8l9- tetrahydro-4H-pyrimido[1,2-alpyrimidin-4-one • 9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2-(4-pyridinyl)-8-(trifluoromethyl)- 6,7,8l9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one o 9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro- 4H-pyrirnido[1,2-a]pyrirnidin-4-one • (-)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifiuoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one • (+)-9-(2-Oxo-2-phenyl-ethyl)-2-(4-pyridinyl)-8-(trifiuoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one WO 2004/083210 PCT/EP2004/004013 28 • (+)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one • (-)-9-[2-Oxo-2-phenyl-ethyl]-2-(4-pyrimidinyl)-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one • 3-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-Fluoro-9-(2-oxo-2-phenylethyl)-2-pyridin-4-yl-8-(trifluromethyl)-6,7,8,9- tetrahydro-4H-pyrimtdo[1,2-a]pyrimidin-4-one • 9-(2-biphenyl-4-yl-2-oxoethyl)-2-pyrimidin-4-yI-8-(trifluoromethyl)-6,7,8,9- tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one or a salt thereof, or a solvate thereof or a hydrate thereof. 5. A compound of formula (III) wherein R1, R3.R4, R5, p and q are as defined for compound of formula (I) according to claim 1. WO 2004/083210 PCT/EP2004/004013 29 6 A medicament comprising as an active ingredient a substance selected from the group consisting of a substituted-pyrimidone derivative represented by formula (i) or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1. 7. A GSK3 inhibitor selected from the group of a substituted-pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1. 8. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 activity. 9. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for preventive and/or therapeutic treatment of a neurodegenerative disease. 10. Use of a compound according to claim 9, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injuries; cerebrovascular accidents, brain cord trauma, spinal cord trauma; peripheral neuropathies; retinopathies or glaucoma. 11. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for preventive and/or therapeutic treatment of non- insulin dependent diabetes; obesity; manic depressive illness; schizophrenia; alopecia; or cancers. 12. Use according to claim 11 wherein cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia or virus-induced tumors. The invention relates to a substititutud-pyrimidone derivative represented by formula (I) or a salt thereof , wherein: X represents two hydrogen atom, a sulfer atom, an oxygen atom or a c1-2 alkyl group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted; R1 rep- resents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted; R2 represents a phenyl group or a naphthalene ring; the phenyl group and the naphthalene ring be- ing optionally substituted;R3 represents a hydrogen atour or a C1-6 alkyl group; R4 represents a C1-2 perhalogenated alkyl group or a C1-3helogenated alkyl group; R5 represents a hydrogen atour; a C1-6 alkyl group or a halogen atom; n represents 0 to 3; and p+q+0to3. The invention relates also to a medecament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3ß, such as Alzheimer disease.

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