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    公开号:AU2004222596A1
    申请号:U2004222596
    申请日:2004-03-19
    公开日:2004-09-30
    发明作者:Alistair Lochead；Mourad Saady；Franck Slowinski；Philippe Yaiche
    申请人:Sanofi Aventis France；Mitsubishi Pharma Corp；
    IPC主号:A61K
    专利说明:
    WO 2004/082577 PCT/EP2004/004014 8-SUBSTITUTED-6,7,8,9-TETRAHYDROPYRIMIDO[1,2-a] PYRIMIDIN-4-ONE DERIVATIVES Specification 5 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 10 neurodegenerative diseases caused by abnormal activity of GSK303. Background Art GSK30 (glycogen synthase kinase 303) is a proline directed serine, 15 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 GSK3P3 was identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that are also found to be 20 hyperphosphorylated in Alzheimer's disease and in several taupathies. Interestingly, protein kinase B (AKT) phosphorylation of GSK30 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 GSK303 of 3-catenin, a protein involved in cell survival, results in its degradation by an 25 ubiquitinilation dependent proteasome pathway. Thus, it appears that inhibition of GSK33 activity may result in neurotrophic activity. Indeed there is evidence that lithium, an uncompetitive inhibitor of GSK303, enhances neuritogenesis in some models and also increases neuronal survival, 30 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 P3-amyloid increases the GSK30 activity and tau protein phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic effects of P3-amyloid are blocked by lithium chloride and by a GSK3P 35 antisense mRNA. These observations strongly suggest that GSK303 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 2004/082577 PCT/EP2004/004014 2 Although tau hyperphosphorylation results in a destabilization of the neuronal cytoskeleton, the pathological consequences of abnormal GSK303 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 5 through the modulation of the expression of apoptotic and antiapoptotic factors. Moreover, it has been shown that -amyloid-induced increase in GSK303 activity results in the phosphorylation and, hence the inhibition of pyruvate dehydrogenase, a pivotal enzyme in energy production and acetylcholine synthesis. 10 Altogether these experimental observations indicate that GSK303 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 15 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; 20 retinopathies and glaucoma. In addition GSK33 may find application in the treatment of other diseases such as: Non-insulin dependent diabetes (such as diabetes type II) and obesity; manic 25 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 30 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 GSK303 activity, more particularly of neurodegenerative diseases. More specifically, the object is to provide novel 35 compounds useful as an active ingredient of a medicament that enables prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease.
    WO 2004/082577 PCT/EP2004/004014 3 Thus, the inventors of the present invention have identified compounds possessing inhibitory activity against GSK303. 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 5 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: R1 NNR5 X N 1 R5 R2 n N N O q( K )P 10 (I) R3 R4 wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C1- 2 alkyl group and a hydrogen atom; 15 Y represents a bond, a carbonyl group, a methylene group optionally substituted by one or two groups chosen from a Ci- 6 alkyl group, a hydroxyl group, a C-4 alkoxy group, a C1-2 perhalogenated alkyl group or an amino group; 20 R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the rings being optionally substituted by a C 1
    -
    4 alkyl group, a C 1
    -
    4 alkoxy group, or a halogen atom; R2 represents a phenyl group or a naphthalene ring; the phenyl group and the 25 naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C.e alkyl group, a methylendioxy group, a halogen atom, a C1-2 perhalogenated alkyl group, a Cls-3 halogenated alkyl group, a hydroxyl group, a CI-4 alkoxy group, a nitro, a cyano, an amino, a C 1 -s monoalkylamino group, a C 2
    -
    1 0 dialkylamino group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring; 30 R3 represents a hydrogen atom or a CI-6 alkyl group; WO 2004/082577 PCT/EP2004/004014 4 R4 represents a phenyl group, a pyridinyl group or a naphthalene ring, the groups and the ring being optionally substituted by 1 to 4 substituents selected from a
    C
    1
    -
    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, 5 a nitro, a cyano, an amino, a C1-s monoalkylamino group or a C 2 -1 0 dialkylamino group; R5 represents a hydrogen atom, a C1_6 alkyl group or a halogen atom; n represent 0 to 3; and p+q=0-3. 10 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 15 thereof. As preferred embodiments of the medicament, there are provided the aforementioned medicament which is used for preventive andlor therapeutic treatment of diseases caused by abnormal GSK303 activity, and the aforementioned medicament which is used for preventive and/or therapeutic treatment of neurodegenerative diseases and in addition other diseases such as: 20 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. 25 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, corticobasal degeneration, Pick's disease, progressive supranuclear 30 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 35 ingredient together with one or more pharmaceutical additives. The present invention further provides an inhibitor of GSK3P3 activity comprising as an active ingredient a substance selected from the group consisting WO 2004/082577 PCT/EP2004/004014 5 of the substituted pyrimidone derivatives of formula (I) and the salts thereof, and the solvates thereof and the hydrates thereof. According to further aspects of the present invention, there is provided a 5 method for preventive and/or therapeutic treatment of neurodegenerative diseases caused by abnormal GSK3j3 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 10 the hydrates thereof; and a use of a substance selected from the group consisting of the substituted pyrimidone derivatives of formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof for the manufacture of the aforementioned medicament. 15 As used herein, the C 1
    -
    6 alkyl group represents a straight or branched alkyl 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; 20 The C 1
    .-
    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; 25 The C 1
    -
    2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been subsituted by a halogeno, for example a CF 3 or 0 2
    F
    5 ; The C-3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been subsituted by an halogen atom; The CI-5 monoalkylamino group represents an amino group substituted by 30 one CI-6 alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino 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, 35 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.
    WO 2004/082577 PCT/EP2004/004014 6 P+q = 0 to 3, indicates that the addition of p and q equals 0, 1, 2 or 3. 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 5 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)aminomethane,
    N,N
    bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1l-propanol, ethanolamine, N methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, 10 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; 15 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, and 20 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 25 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 30 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. 35 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.
    WO 2004/082577 PCT/EP2004/004014 7 The substituted pyrimidone derivatives represented by the 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 5 such as optical isomers, or diastereoisomers. Any stereoisomers in pure form, any mixtures of stereoisomers, racemates and the like fall within the scope of the present invention. Examples of compounds of the present invention are shown in table 1 10 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 R1, R2, R3, R4, R5, X, Y, n, p and q are as 15 defined here-under: (1) R1 represents a 3- or 4-pyridine ring and more preferably 4-pyridinyl ring or a 4- or 5-pyrimidine ring and more preferably 4-pyrimidinyl ring, which may be substituted by a C1- 2 alkyl group, a C1- 2 alkoxy group or a halogen atom; 20 (2) R2 represents a phenyl group or a naphthalene ring, the phenyl group and the naphthalene ring being optionally substituted 1 to 4 substituents selected from a
    C
    1 _3 alkyl group, a halogen atom, a hydroxyl group, a C-2alkoxy group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring; (3) R3 represents a hydrogen atom; 25 (4) R4 represents a phenyl group, a pyridinyl group or a naphthalene ring; (5) R5 represents a hydrogen atom; (6) X represents two hydrogen atoms; (7) Y represents a carbonyl group or methylene group being optionally substituted by one or two groups chosen from a 01-3 alkyl group, a hydroxyl group, a 01-4 30 alkoxy group, a C1-2perhalogenated alkyl group, an amino group; (8) n, p and q represent 0, 2 and 0, respectively.
    WO 2004/082577 PCT/EP2004/004014 8 Another embodiment of the present invention include compounds represented by formula (1) wherein R1, R2, R3, R4, R5, X, Y, n, p and q are as defined here-under: (1) R1 represents an unsubstituted 4-pyridinyl ring or 4-pyrimidinyl ring; 5 alternatively R1 represents an unsubstituted 4-pyridinyl ring; (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 halogen atom, a hydroxyl group, a C 1
    -
    2 alkoxy group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring; 10 (2) R3 represents a hydrogen atom; (3) R4 represents a phenyl group or a pyridinyl group; (4) R5 represents a hydrogen atom; (5) X represents two hydrogen atoms; (6) Y represents a carbonyl group or a methylene group optionally substituted by a 15 hydroxyl group; (7) n, p and q represent 0, 2 and 0, respectively. Particularly compounds of the present invention represented by formula (I), wherein R4 is a 8-phenyl or a 8-pyridinyl group, include compounds of table 1 : 20 1. 1'-[(2S)-2-Hydroxy-2-phenyl-ethyl]- 8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one 2. 9-(2-Oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H 25 pyrimido[1,2-a]pyrimidin-4-one 3. 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one 30 4. 9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one 5. 9-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one 35 6. 9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one WO 2004/082577 PCT/EP2004/004014 9 7. 9-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 8. 9-[2-(Oxo-2-(4-pyrrolidin-1 -yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 5 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 9. 9-(2-Biphenyl-4-yI-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one 10 10. 9-(2-Oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one 11. 9-(2-Naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1.2-a]pyrimidin-4-one 15 12.9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrim i do[1, 2-alpyri mid in-4-one 13.9-[2-(2-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 20 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 14. 9-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yI-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one 25 15. 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one 16. 9-(2-Hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2 a]pyrimidin-4-one 30 17. 9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-alpyrimidin-4-one 18. 9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro 35 pyrimido[1,2-a]pyrimidin-4-one 19. 9-[2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one WO 2004/082577 PCT/EP2004/004014 10 20. 9-(2-Hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one 5 21. (-)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one 22. (+)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one 10 23. 9-[2-Hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one 24. 9-[2-Hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 15 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one 25. 9-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one 20 26. 9-[2-Hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one 27. 9-[2-Hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one; and 25 28. 9-[2-Hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one. As a further object, the present invention concerns also methods for preparing the 30 substituted pyrimidone compounds represented by the aforementioned formula (I). These compounds can be prepared, for example, according to methods explained below.
    WO 2004/082577 PCT/EP2004/004014 11 Preparation method Substituted pyrimidone compounds represented by the aforementioned formula (I), may be prepared according to the method described in the scheme 1. 5 X RI R1 RS R2 n L R5 HN N 0 . R2 n N ,N 0O q( )p q( )p R3 R4 R3 R4 (Ill) (1) Scheme 1 10 Following this method, the pyrimidinone derivative represented by the above formula (111), wherein R1, R3, R4, 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-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide or chloroform at a suitable 15 temperature ranging from 0 to 130 0 C under ordinary air, then with a compound of formula (11), 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). 20 Alternatively compounds of formula (I) wherein Y represents a carbonyl 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. 25 Compound of formula (11) 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. 30 WO 2004/082577 PCT/EP2004/004014 12
    NH
    2 RI HN 'N N 1 R5 R15 RIRSY HN N 0 O0 R3 R4 (V) RO 0 R3 R4 (IV) (Ill) Scheme 2 (In the above scheme L represents a leaving group, preferably a bromide or a mesyl group) 5 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 the same as those already described for compound 10 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 250 to 140 0 C under ordinary air. 15 Alternatively, compound of formula (111) 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 be carried out in an acidic medium such as acetic acid or propionic acid, in presence of bromosuccinimide or chlorosuccimide, or bromine. 20 In addition, compounds of formula (111) 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. 25 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 C 1-4 alkyl group, C 1 4 alkoxy 30 group or a halogen atom, can be prepared by reacting respectively an isonicotinic acid or a pyrimidine-carboxylic acid, optionally substituted by a C 1
    .
    4 alkyl group, WO 2004/082577 PCT/EP2004/004014 13
    C
    1
    -
    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 5 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 10 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 15 according to well-known methods to 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. NH i) Amino NH2 NH O protection NHPg ii) Reduction N N R4 OH RuiR4 R3 L R4 R iii) Introduction of a (V) (X) (VI) leaving group Hydrogenation Amination If R3 = H
    NH
    2 Cyclisation NH Deprotection NHPg HN 'N R4 NH 2 R4R3 NPg R4 R3 R3 R3 20 (V) (IX) (VIII) Scheme 3 (In the above scheme Pg represents an amino-protecting group and L a leaving group, preferably a bromide group or mesyl group) WO 2004/082577 PCT/EP2004/004014 14 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. 5 The 3-aminoacid of formula (Vl), 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 C 1
    .
    6 alkyl group, may be synthesized by analogy to the method described in Journal of Organic Chemistry, 10 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). 15 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 20 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. 25 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 30 formula (111) as intermediate for preparing compounds of formula (I). The compounds of the present invention have inhibitory activity against GSK3P3. Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a medicament, which enables preventive 35 and/or therapeutic treatment of a disease caused by abnormal GSK3p3 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 WO 2004/082577 PCT/EP2004/004014 15 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 5 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 10 induced tumors. The present invention further relates to a method for treating neurodegenerative diseases caused by abnormal activity of GSK313 and of the aforementioned diseases which comprises administering to a mammalian 15 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 20 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 25 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 30 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 35 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 WO 2004/082577 PCT/EP2004/004014 16 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. 5 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 10 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 15 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, 20 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 25 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 30 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, 35 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.
    WO 2004/082577 PCT/EP2004/004014 17 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 5 limited to these examples. Example 1 (Compound No. 2 of table 1) 9-(2-Oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H 10 pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:1) 1.1 6-Phenyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) To a solution of 5g (29.2 mmoles) of 2-amino-4-phenylpyrimidine in 30ml of a 6N 15 solution of hydrochloric acid in isopropanol was added 0.1 g of palladium on carbon catalyst (10% wt/wt). The suspension was hydrogenated under 40psi pressure at room temperature during 3h. The catalyst was removed by filtration and the solvent evaporated under reduced 20 pressure. Diethyl ether was added and the resulting solution was refiltered and the solvent removed by evaporation under reduced pressure to give 4.0g (55%) of compound as a crude oil which was used as such. 1.2 8-Phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4 25 one A suspension containing 4g (16.12 mmoles) of 6-Phenyl-1,4,5,6-tetrahydro-2 pyrimidinamine hydrochloride (1:2), 3.11g (16.12 mmoles) of ethyl 3-(pyridin-4-yl) 3-oxopropionate, 6.68g (48.36 mmoles) of anhydrous potassium carbonate in 30 50ml of ethanol were reflux for 18h. The cooled solution was evaporated and the residue was treated with water and allowed to stir at 0 0 C during 2h. The precipitate which formed was recovered by filtration and dried at 90 0 C during 18h. 4.80g (98%) of product was thus obtained. 35 1.3 9
    -(
    2 -Oxo- 2 -phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:1) A solution of 0.3g (98 mmoles) of 8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H- WO 2004/082577 PCT/EP2004/004014 18 pyrimido[1.2-a]pyrimidin-4-one in 8ml of anhydrous dimethylformamide was treated with 51mg (1.28 mmoles) of sodium hydride (60% in mineral oil). The resulting suspension was stirred at 0 0 C during 30min and then treated with 0.255g (1.28 mmoles) of 2-bromoacetophenone. 5 After stirring for 18h at room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of aqueous sodium chloride and was evaporated under reduced pressure to give crude product. Purification using silica gel chromatography eluting with a gradient comprising 10 dichloromethane/methanol in the proportions 99/1 to 95/5 gave pure product which was dissolved in ethanol and treated with 1 equivalent of a solution of hydrochloric acid in isopropanol. The resulting salt was recrystallised from a mixture of isopropanol/diispropylether to give 0.16g (39%) of pure product. Mp: 134-137 0 C. 15 RMN 1 H (200 MHz; DMSO-d 6 ): 5 (ppm) 8.6 (d, 2H); 8.0 (d, 2H); 7.6 (d, 1H); 7.5 (t, 2H); 7.3 (m, 5H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (brs, 1H) ;4.5 (m, 2H); 3.2 (ddd, 1 H); 2.2 (m, 2H). 20 Example 2 (Compound No. 1 of table 1) 1'-[(2S)-2-Hydroxy-2-phenyl-ethyl]- 8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1) 25 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by (1IS)-2-chloro-1 -phenyl ethanol. Mp :254-256 0 C RMN 'H (200 MHz; DMSO-d 6 ): 5 (ppm) 8.9 (m, 2H); 8.3 (m, 2H); 7.5-7.1 (m, 10H); 6.6 (m, 1H) ; 5.3-5.0 (m, 2H); 4.6-4.0 (m, 3H); 3.2-2.7 (m, 2H); 2.5-1.8 30 (m, 2H).
    WO 2004/082577 PCT/EP2004/004014 19 Example 3 (Compound No. 3 of table 1) 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1) 5 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 3-bromo-(2-bromoacetophenone) Mp: 143-145 0 C RMN 1 H (200 MHz; DMSO-d 6 ): 5 (ppm) 8.7 (d, 2H); 8.2-7.8 (m, 5H); 7.5-7.2 (m, 10 7H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H) ; 4.5 (d, 1H); 4.3 (m, 1H); 3.2 (ddd, 1H) 2.4-2.1 (m, 2H). Example 4 (Compound No. 4 of table 1) 15 9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-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 1.3, but replacing 2-bromoacetophenone by 4-chloro-(2-bromoacetophenone) 20 Mp :145-147°C RMN 1 H (200 MHz; DMSO-d 6 ): 8 (ppm) 8.7 (d, 2H); 8.1 (m, 4H); 7.6 (d, 2H); 7.4 (m, 5H) ; 6.7 (s, 1H); 5.7 (d, 1H); 5.1 (brs, 1H); 4.5(d, 1H) ; 4.3 (m, 1H); 3.2 (ddd, 1H) ; 2.4-2.1 (m, 2H). 25 Example 5 (Compound No. 5 of table 1) 9-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6, 7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1) 30 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 4-fluoro-(2-bromoacetophenone) Mp: 145-147oC. RMN 1 H (200 MHz; DMSO-d 6 ): 6 (ppm) 8.7 (d, 2H); 8.1 (m, 4H); 7.6 (m, 8H); 6.6 (s, 1H); 5.7 (d, I H) ; 5.1 (br s, I H) ; 4.5 (m, 1 H) ; 4.3 (br s, 1 H); 3.2 (ddd, 1H) ; 2.4 35 2.1 (m, 2H).
    WO 2004/082577 PCT/EP2004/004014 20 Example 6 (Compound No. 6 of table 1) 9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6, 7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1) 5 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 3-fluoro-(2-bromoacetophenone) Mp: 167-169°C RMN 1 H (200 MHz; DMSO-d 6) : 5 (ppm) 8.7 (d, 2H); 8.1 (d, 2H); 7.8 (m, 2H); 7.6 10 7.2 (m, 7H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H) ; 4.5 (d, 1H) ; 4.4 (m, 1H); 3.2 (ddd, 1H); 2.4-2.1 (m, 2H). Example 7 (Compound No. 7 of table 1) 15 9-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl )-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 1.3, but replacing 2-bromoacetophenone by 4-methoxy-(2-bromoacetophenone) 20 Mp :197-1990C RMN 1 H (200 MHz; CDCl 3 ): 8 (ppm) 8.5 (d, 2H); 8.0 (d, 2H); 7.6-7.2 (m, 7H); 7.0 (d, 2H); 6.5 (s, 1H); 5.8 (d, 1H) ; 5.0 (dd, 1H); 4.5 (m, 1H); 4.1 (d, IH); 3.9 (s, 3H); 3.5 (ddd, 1 H); 2.6 (m, 1 H); 2.3 (m, 1 H). 25 Example 8 (Compound No. 8 of table 1) 9-[2-(Oxo-2-(4-pyrrolidin-1 -yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 30 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 4-N-pyrrolidinyl-(2-bromoacetophenone) Mp :253-255°C RMN 'H (200 MHz; CDCI 3 ): 6 (ppm) 8.5 (d, 2H); 7.9 (d, 2H); 7.6 (d, 2H); 7.5-7.3 (m,7H); 6.6 (d, 2H); 6.4 (s, 1H); 5.9 (d, 1H); 5.0 (brs, 1H); 4.5 (m, 1H); 4.1 (d, 35 1H); 3.6-3.3 (m, 5H); 2.6 (m, 1H); 2.3-2.0 (m, 5H).
    WO 2004/082577 PCT/EP2004/004014 21 Example 9 (Compound No. 9 of table 1) 9-(2-Biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one 5 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 4-phenyl-(2-bromoacetophenone) Mp: 222-224°C RMN 'H (200 MHz; CDC3) : 5 (ppm) 8.5 (d, 2H); 8.2 (d, 2H); 7.8-7.6 (m, 4H); 10 7.5-7.3 (m,8H); 7.2 (d, 2H); 6.5 (s, 1H); 5.9 (d, 1H); 5.0 (br s, 1H); 4.5 (m, 1H) 4.2 (d, 1H); 3.6 (ddd, 1 H) ; 2.7 (m, 1H); 2.3 (m, 1 H). Example 10 (Compound No. 10 of table 1) 15 9-(2-Oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-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 1.3, but replacing 2-bromoacetophenone by 4-methyl-(2-bromoacetophenone). 20 Mp: 209-211°C RMN 1 H (200 MHz; CDCI 3 ): 8 (ppm) 8.5 (d, 2H); 7.9 (d, 2H); 7.6-7.2 (m, 9H); 6.5 (s, IH); 5.8 (d, 1H) ; 4.9 (brs, 1H); 4.5 (m, 1H) ; 4.1 (d, IH); 3.6 (ddd, 1H) ; 2.6 (m, 1 H); 2.5 (s, 3H);2.2(m,1 H). 25 Example 11(Compound No. 11 of table 1) 9-(2-Naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one 30 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 2-bromoacetylnaphthalene. Mp: 226-228 0 C RMN 'H (200 MHz; CDCI3) : 6 (ppm) 8.6 (s, 1H); 8.4 (d, 2H); 8.1-7.9 (m, 4H); 7.7-7.5 (m,2H); 7.4-7.2 (m, 7H); 6.45 (s, 1H); 6.0 (d, 1H); 5.0 (br s, 1 H); 4.6 (m, 35 1 H) ; 4.3 (d, 1 H); 3.6 (ddd, 1 H) ; 2.7 (m, 1H); 2.3 (m, 1H).
    WO 2004/082577 PCT/EP2004/004014 22 Example 12 (Compound No. 12 of table 1) 9
    -[
    2 -(3-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one 5 The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 3 -methoxy-(2-bromoacetophenone). Mp :216-218 0 C RMN 1 H (200 MHz; CDCl 3 ): 8 (ppm) 8.5 (d, 2H); 7.7-7.2 (m, 11H); 6.45 (s, 1 H); 5.85 (d, 1H); 4.9 (brs, 1H); 4.65 (m, 1H) ; 4.15 (d, 1H); 3.85 (s, 3H); 2.55 (ddd, 10 1H); 2.65 (m, 1H);2.3(m,1H). Example 13 (Compound No. 13 of table 1) 9
    -[
    2
    -(
    2 -Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 15 4H-pyrimido[1l,2-a]pyrimidin-4-one The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 2 -methoxy-(2-bromoacetophenone). Mp :142-144oC RMN 1 H (200 MHz; DMSO-d 6 ): 8 (ppm) 8.7 (d, 2H); 8.0 (d, 2H); 7.6 (m, 2H); 7.4 20 (m, 5H); 7.2 (d, 1H) ; 7.1 (t, 1H) ; 6.6 (s, 1H); 5.5 (d, 1H); 5.0 (br s, 1H); 4.3 (d, 2H); 3.8(s,3H) ; 3.5(m,1H); 3.3(ddd, 1H) ; 2.4-2.1(m,2H). Example 14 (Compound No. 14 of table 1) 25 9-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:2) 14.1 6-(4-Pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) 30 To a solution of 5g (29.2 mmoles) of 2 -amino-4-(4-pyridinyl)-pyrimidine (Journal of Medicinal Chemistry (1978), 21(7), 623-8) in 30ml of a 6N solution of hydrochloric acid in isopropanol was added 5ml of water and 0.2g of palladium on carbon catalyst (10% wt/wt). 35 The suspension was hydrogenated under 40psi pressure at 50 0 C temperature during 8h. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Isopropanol was added and the resulting solution was refiltered and the WO 2004/082577 PCT/EP2004/004014 23 solvent removed by evaporation under reduced pressure to give 2.0g (27%) of compound as a white powder which was used as such. 14.2 2,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one 5 A suspension containing 1.0g (4.01 mmoles) of 6-(4-pyridinyl)-1,4,5,6-tetrahydro 2-pyrimidinamine dihydrochloride in 30ml of ethanol was treated with 1.94g (14.05 mmoles) of potassium carbonate and allowed to stir for 5min. 1.0g (4.01 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate were added and the resulting mixture was 10 heated at reflux temperature during 18h. The cooled solution was evaporated to remove solvent and the residue was dissolved in water and extracted with dichloromethane. The organic extracts were washed with a saturated solution of aqueous sodium chloride, dried and the solvent evaporated under reduced pressure. The crude product thus obtained was 15 purified using silica gel chromatography eluting with a gradient of dichloromethane/methanol/concentrated aqueous ammonia solution in the proportions 95/5/0.5 to 80/20/2. 0.26g (21%) of pure product was obtained. Mp : 268-270°C. 20 14.3 9-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:2) A suspension of 0.30g (0.98 mmole) of 2 ,8-di-4-pyridinyl-6,7,8,9-tetrahydro-4H pyrimido[l.2-a]pyrimidin-4-one in 6ml of dimethylformamide was treated with 25 51 mg (1.28 mmole) of sodium hydride (60% in mineral oil) and the resulting suspension stirred at 350C during 30min. The mixture was then cooled to 00C and was treated with 0.235g (1.18 mmole) of 2-bromoacetophenone and stirred for 4h at room temperature. Water was added and the mixture extracted with dichloromethane. The organic 30 extracts were washed with a saturated aqueous solution of sodium chloride and dried and evaporated. The crude product thus obtained was purified using silica gel chromatography eluting with a gradient of dichloromethane/methanol in the proportions 99/1 to 90/10. The pure product obtained was then dissolved in ethanol and treated with 1 equivalent of a solution of hydrochloric acid in 35 isopropanol to give the hydrochloride salt. The resulting salt was recrystallised from a mixture of isopropanol/diispropylether to give 0.20g (48%) of pure product. Mp: 246-248oC. RMN 1 H (200 MHz; DMSO-d 6 ): 6 (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m, 6H); 7.8- WO 2004/082577 PCT/EP2004/004014 24 7.5 (m, 3H) ; 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d, 1H); 4.5(m,1H); 3.1(ddd, IH); 2.5(m,2H). Example 15 (Compound No. 15 of table 1) 5 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:2) The product was obtained by analogy with the method described in example 2.3, but replacing 2-bromoacetophenone by 3-bromo-(2-bromoacetophenone). 10 Mp: 215-217'C RMN 1 H (200 MHz; DMSO-d 6 ): 5 (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.3-7.8 (m, 7H); 7.5 (t, 1 H) ; 6.7 (s, 1H); 5.75 (d, 1 H); 5.3 (br s, 1H); 4.7 (d, 1H); 4.5(m,1 H); 3.1(ddd,1 H); 2.5(m,2H). 15 Example 16 (Compound No. 16 of table 1) 9-(2-Hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2 a]pyrimidin-4-one hydrochloride (1:2) The product was obtained by analogy with the method described in example 2.3, 20 but replacing 2-bromoacetophenone by (1-S)-2-chloro-1-phenyl ethanol. Mp: 204-206°C RMN 1 H (200 MHz; DMSO-d 6 ) : 5 (ppm) 9.0 (m, 2H); 8.8 (m, 2H); 8.45 (m, 2H); 7.9 (d, 1 H) ; 7.8-7.6(m,IH) ; 7.5-7.2(mn,5H) ; 6.8 (s, 1H) ; 6.2-5.7 (brd, IH) ; 5.3 5.1(m,1H); 4.6-4.1(m,2H); 3.3(m,2H); 2.9(m,1H); 2.5-2.2(m,2H). 25 Example 17 (Compound No. 17 of table 1) 9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one 30 The product was obtained by analogy with the method described in example 2.3, but replacing 2-bromoacetophenone by 2-chloro-1l-(3-bromo-phenyl)-ethanol. Mp: 190-192 0 C RMN 1 H (200 MHz; CDCI 3 ) : 8 (ppm) 8.8 (d, 2H); 8.7 (d, 2H); 7.8 (m, 2H); 7.7-7.4 (m, 2H); 7.3(m,2H) ; 7.1(d,2H); 6.5 (s, 1H); 5.2 (m, 2H); 4.8-4.4 (m,3H) ; 3.2 35 (m,2H); 2.3(m,2H).
    WO 2004/082577 PCT/EP2004/004014 25 Example 18 (Compound No. 18 of table 1) 9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one one hydrochloride (1:2) 5 The product was obtained by analogy with the method described in example 2.3, but replacing 2-bromoacetophenone by 3-fluoro-(2-bromoacetophenone). Mp: 132-134°C RMN 1 H (200 MHz; DMSO-d 6 ): 5 (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.1 (d, 2H); 8.0 (d, 2H); 7.9-7.7(m,2H) ;7.7-7.5(m,2H); 6.8 (s, 1H); 5.7 ( d, 2H); 5.3 (brs,1H); 10 4.7(d,1H); 4.4(m,1H); 3.1(ddd, 1H); 2.4(m,1H). Example 19 (Compound No. 19 of table 1) 9-[2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9 15 tetrahydro-pyrimido[1,2-a]pyrimidin-4-one The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 2-chloro-1 -(4-methoxy-phenyl) ethanol. Mp: 150-152 0 C RMN 'H (200 MHz; CDCl 3 ): 6 (ppm) 8.8 (d, 2H); 7.9 (d, 2H); 7.6-7.2 (m, 6H); 7.1 20 (m, 2H); 6.9 (m,2H) ; 5.3-5.0 (m, 2H); 4.8-4.4 (m, 3H); 3.8 (m,3H); 3.4-3.0 (m,2H); 2.4-2.0(m,2H). Example 20 (Compound No. 20 of table 1) 25 9-(2-Hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro pyrimido[1,2-a]pyrimidin-4-one The product was obtained by analogy with the method described in example 1.3, but replacing 2-bromoacetophenone by 2-chloro-1 -(4-methylphenyl)- ethanol. Mp :198-200'C 30 RMN 1 H (200 MHz; CDCI 3 ): 5 (ppm) 8.8 (d, 2H); 7.8 (d, 2H); 7.4-7.0 (m, 8H); 6.5 (s, 1H); 5.2 (m,IH) ; 4.8-4.4 (m, 5H); 3.4-3.0 (m, 2H); 2.5-2.0 (m,5H) WO 2004/082577 PCT/EP2004/004014 26 Example 21 (Compound No. 21 of table 1) (-)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2 a]pyrimidin-4-one hydrochloride (1:2) 5 21.1 (+)-2,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1l.2-a]pyrimidin-4-one 1.2 g (3.93 mmol) of 2
    ,
    8 -dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2 a]pyrimidin-4-one (compound No.14.2) was separated by chiral preparative HPLC (CHIRALPAK ® AS) eluting with n-heptane/ethanol in the proportions 50/50 to give 10 0.572 g of pure product obtained in the form of free base. tR : 7 min. Mp : 235-238 0 C. [aC]D 20 = +11.3' (c=0.44, DMSO). 21.2 (-)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:2) 15 The product was obtained by analogy with the method described in example 14.3. Mp : 225-227°C. [aUD 20 = -63.1' (c=0.356, DMSO). RMN 1 H (200 MHz; DMSO-d 6) : 8 (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m, 6H); 7.8 7.5 (m, 3H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (brs, 1H); 4.7 (d, IH); 4.5(m,1H); 20 3.1(ddd,lH); 2.5(m,2H). Example 22 (Compound No. 22 of table 1) (+)-9-(2-Oxo-2-phenyl-ethyl)-2, 8 -dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2 a]pyrimidin-4-one hydrochloride (1:2) 25 22.1 (-)-2,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one 1.2 g (3.93 mmol) of 2
    ,
    8 -dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2 a]pyrimidin-4-one (compound No.14.2) was separated by chiral preparative HPLC 30 (CHIRALPAK ® AS) eluting with n-heptane/ethanol in the proportions 50/50 to give 0.572 g of pure product obtained in the form of free base. tR : 1 2 min. Mp: 235-238 0 C. [C]D 20 = -11.5' (c=0.394, DMSO).
    WO 2004/082577 PCT/EP2004/004014 27 22.2 (+)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H pyrimido[1.2-a]pyrimidin-4-one hydrochloride (1:2) The product was obtained by analogy with the method described in example 14.3. 5 Mp: 225-227 0 C. [aID 20 = +65.40 (c=0.521, DMSO). RMN 1 H (200 MHz; DMSO-d 6 ) : 5 (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m, 6H); 7.8 7.5 (m, 3H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d, 1H); 4.5(m,1H); 3.1(ddd,1 H); 2.5(m,2H). 10 A list of chemical structures and physical data for compounds of the aforementioned formula (1), illustrating the present invention, is given in table 1. The compounds have been prepared according to the methods of the examples. 15 In the table 1, R1 is an unsubstituted pyrimidin-4-yl group or an unsubstituted pyridin-4-yl group, p represents 2, q represents 0, Ph represents a phenyl group, Me represents a methyl group; (+) and (-) indicates respectively a dextro and levo isomer; (S), (R) or (Rac.) indicates in the column "Y" or R4, the stereochemistry of 20 the carbon atom: (rac.) means racemic mixture; (R) means absolute R configuration; (S) means absolute S configuration.
    WO 2004/082577 PCT/EP2004/004014 28 R1 X N R5 "Y R2 n N /-N 0 q( )P (I) R3 R4 Table I R4 R5 p No. R2 Y X R1 R3 q n Mp *C salt N r IPh H 2 (1:1) CH(OH) 1 1. Ph H,H H (Rac.) 0 0 254-256 (hydro (S) _ chloride) N N Ph H 2 (1:1) 2. Ph CO H,H H (Rac.) 0 0 134-137 (hydro chloride) N SPh H 2 (1 :1) 3. 3-Br-Ph CO H,H H (Rac.) 0 0 143-145 (hydro I chloride) N _. Ph H 2 (1:1) 4. 4-CI-Ph CO H,H H (Rac.) 0 0 145-147 (hydro I _IIchloride) N N Ph H 2 (1:1) 5. 4-F-Ph CO H,H H (Rac.) 0 0 145-147 (hydro chloride) Ph H 2 (1:1) 6. 3-F-Ph CO H,H H (Rac.) 0 0 167-169 (hydro chloride) N Ph H 2 (1:1) 7. 4-MeO-Ph CO H,H H (Rac.) 0 0 197-199 (hydro chloride) N 4-N- Ph H 2 8. Pyrrolidine CO H,H H (Rac.) 0 0 253-255 Base -Ph WO 2004/082577 PCT/EP2004/004014 29 R4 RS p No. R2 Y X R1 R3 R4 R5q n Mp C salt N Ph H 2 9. 4-Ph-Ph CO H,H H (Rac.) 0 0 222-224 Base N Ph H 2 10. 4-Me-Ph CO H,H H (Rac.) 0 0 209-211 Base Ph H 2 11. 2-Naphthyl CO H,H H (Rac.) 0 0 226-228 Base N Ph H 2 12. 3-MeO-Ph CO H,H H (Rac.) 0 0 216-218 Base N N Ph H 2 13. 2-MeO-Ph CO H,H H (Rac.) 0 0 142-144 Base N Hydro 14. Ph CO H,H H 0 0 246-248 chloride (Rao.) (1:2) N N N H 2 Hydro 15. 3-Br-Ph CO H,H H 0 0 215-217 chloride (1:2) (Rac.) N N H 2Hydro 16. Ph (S)-CH(OH) H,H H 0 0 204-206 chloride (1:2) (Rac.) N Hydro CH(OH) I 17. 3-Br-Ph H,H H 0 0 190-192 chloride (Rac.) (1:2) - (Rac.)_______
    ___
    WO 2004/082577 PCT/EP2004/004014 30 No. R2 Y X R1 R3 R4 R5 p n Mp C salt q n Mp sl N N H 2 N Hydro 18. 3-F-Ph CO H,H H 0 0 132-134 chloride (1:2) (Rac.) N CH(OH) I Ph H 2 19. 4-MeO-Ph H,H H (Rac.) 0 0 150-152 Base (Rac.) N CH(OH) N Ph H 2 20. 4-Me-Ph H,H H (Rac.) 0 0 198-200 Base (Rac.) N N N H 2 S 2Hydro 21. Ph CO H,H - H 0 0 225-227 chloride (1:2) N NN H 2 H d o Hydra 22. Ph CO H,H H 0 0 225-227 chloride (1:2) (+) C' OH' Ph H 2 23. 3-Br-Ph (Rac.) H,H H (Rac.) 0 0 170-172 Base (Rac.) N NHOH Ph H 2 24. 4-CI-Ph CH(OH) H,H H (Rac.) 0 0 220-222 Base (Rac.) N CH(OH) 25. 3-F-Ph H,H H 0 0 218-220 Base (Rac.) (Rac.) CH(OH) Ph H 2 CH(OH) H 26. 4-F-Ph H,H H (Rac.) 0 0 201-203 Base (Rac.) WO 2004/082577 PCT/EP2004/004014 31 No. R2 Y X R1 R3 R4 R5 p n Mp C salt q n M C sl N CH(OH)I Ph H 2 CH(OH) 27. 4-Ph-Ph H,H H (Rac.) 0 0 145-147 Base (Rac.) N CH(OH) 28. 2-Naphthyl (O) H,H H (Rac.) 0 0 190-192 Base (Rac.) WO 2004/082577 PCT/EP2004/004014 32 Test Example: Inhibitory activity of the medicament of the present invention against GSK3P3: Two different protocols can be used. 5 In a first protocol : 7.5 pIM of prephosphorylated GS1 peptide and 10 pM ATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mM Tris-HCI, 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 10 microliters). In a second protocol: 4.1 pM of prephosphorylated GS1 peptide and 42 pM 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, 15 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 microliters of a solution made of 25 g 20 polyphosphoric acid (85% P 2 0 5 ), 126 ml 85% H 3
    PO
    4 , H 2 0 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. 25 The phosphorylated GS-1 peptide had the following sequence: NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. The GSK33 inhibitory activity of the compounds of the present invention are expressed in IC5o, and as an illustration the range of ICso's of the compounds in 30 table 1 is between 1 nanomolar to 1 micromolar concentrations. For example compound No.15 of table 1 shows an IC 5 0 of 0.007 pM.
    WO 2004/082577 PCT/EP2004/004014 33 Formulation Examples (1) Tablets The ingredients below were mixed by an ordinary method and 5 compressed by using a conventional apparatus. Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100 mg Lactose 200 mg 10 Magnesium stearate 4 mg (2) Soft capsules The ingredients below were mixed by an ordinary method and filled in soft capsules. 15 Compound of Example 1 30 mg Olive oil 300 mg Lecithin 20 mg (1) Parenteral preparations 20 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 25 Distilled water for injection 1 ml Industrial Applicability 30 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 GSK30 and more particularly of neurodegenerative diseases. 35
    权利要求:
    Claims (7)
    [1] 1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: R1 NNR5 X N R5 R2 n N N 0O q( )P 5 (I) R3 R4 wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1 - 2 alkyl group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted 10 by one or two groups chosen from a C 1 -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 C 1 -4 alkyl group, a C1- 4 alkoxy group or a halogen atom; 15 R2 represents a phenyl group or a naphthalene ring; the phenyl group or the naphthalene ring being optionally substituted by 1 to 4 substituents selected from a C 6 .e alkyl group, a methylendioxy group, a halogen atom, a C 1-2 perhalogenated alkyl group, a C--3 halogenated alkyl group, a hydroxyl group, a C 1 -4alkoxy group, a nitro, a cyano, an amino, a C 1 - 5 monoalkylamino group, a C 2 - 0 dialkylamino 20 group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring; R3 represents a hydrogen atom or a C 1 - 6 alkyl group; R4 represents a phenyl group, a naphthalene ring or a pyridinyl group, the groups and the ring being optionally substituted by 1 to 4 substituents selected from a Ci-.e alkyl group, a methylendioxy group, a halogen atom, a C 1 - 2 perhalogenated 25 alkyl group, a C 1 - 3 halogenated alkyl group, a hydroxyl group, a C1-4alkoxy group, a nitro, a cyano, an amino, a C1.-5 monoalkylamino group or a C2-10 dialkylamino group; R5 represents a hydrogen atom, a CjE alkyl group or a halogen atom; n represents 0 to 3; and p+q=0-3. 30 WO 2004/082577 PCT/EP2004/004014 35
    [2] 2. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein R4 represents an phenyl group or a pyridinyl group. 5 3. A 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-pyridinyl ring or a 4-pyrimidinyl ring; * R2 represents a phenyl group or a naphthalene ring, the phenyl group and the naphthalene ring being optionally substituted 1 to 4 substituents selected from 10 a C1-3 alkyl group, a halogen atom, a hydroxyl group, a C1-2 alkoxy group, a phenyl group, a pyrrolidine ring, a piperidine ring or an azepine ring; * R3 represents a hydrogen atom; * R4 represents a phenyl group or a pyridinyl group; * R5 represents a hydrogen atom; 15 * X represents two hydrogen atoms; * Y represents a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and a n, p and q represent 0, 2 and 0, respectively. 20 4. A pyrimidone derivative which is selected from the group consisting of: * 1l'-[(2S)-2-Hydroxy-2-phenyl-ethyl]-
    [3] 8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one o 9 -( 2 -Oxo- 2 -phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one 25 * 9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one * 9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one * 9-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 30 4H-pyrimido[1,2-a]pyrimidin-4-one * 9-[2-(3-Fluoro-phenyl)- 2 -oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro 4H-pyrimido[1,2-a]pyrimidin-4-one * 9 -[ 2 -( 4 -Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one 35 * 9-[2-(Oxo-2-(4-pyrrolidin-1 -yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one * 9-(2-Biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H pyrimido[1,2-a]pyrimidin-4-one WO 2004/082577 PCT/EP2004/004014 36 0 9-(2-Oxo-2-p-tolyl-ethyI)-8-phenyl-2-(4-pyridiny)6,78,
    [4] 9-tetrahydro-4H pyrimido[1 ,2-a]pyrimidin-4-one * 9-(2-Naphthalen-2-yI-2-oxo-ethy)8pheny-2(4-pyridinyl)-6,7,8, 9-tetrahydro 4H-pyrimido[1 .2-a]pyrimidin-4-one 5 * 9-[2-(3-Methoxy-phenyI)-2-oxo-ethy]8pheny2(4-pyridinyl)-6,7,8,9 tetrahydro-4H-pyrimido[1 ,2-a]pyrimidin-4-one * 9 -[2-(2-Methoxy-pheny)2oxoethy]8pheny-2-(4-pyridinyI>-6 7,8,9 tetrahydro-4H-pyrimido[1 ,2-a]pyrimidin-4-one * 9-[(2 S)-2-Oxo-2-phe nyl -ethyl ]-2, 8-d ipyri d in-4-yl-6,7, 8,9-tetrahydro-4H 10 pyrimido[1 ,2-alpyrimidin-4-one 0 9-[2-(3-Bromo-phenyl )-2-oxo-ethyl]-2, 8-dipyridin-4-y-6, 7,8, 9-tetrahydro pyrimido[1 ,2-a]pyrimidin-4-one * 9-(2-Hydroxy-2-phenyl-ethyl )-2, 8-dipyridin-4-yl-6, 7,8, 9-tetrahydro-pyrimidof 1,2 a]pyrimidin-4-one 15 * 9-[2-(3-Bromo-phenyi)-2-hydroxy-ethyl]-2,8-dipyridin-4-yI-6,7,8, 9-tetrahydro pyrimido[1 ,2-ajpyrimidin-4-one 9-[2-(3-Fiuoro-phenyl)-2-oxo-ethyl]-2, 8-di pyrid in-4-yl-6,7, 8, 9-tetrahydro pyrimido[1 ,2-a]pyrimidin-4-one *9-[2-Hydroxy-2-(4-methoxy-phenyl)-ethy]-8phenyl-2pyri di n-4-yl-6, 7,8,9 20 tetrahydro-pyrimido[1 ,2-a]pyrimidin-4-one * 9-(2-Hydroxy-2-p-tolyI-ethyl)-8-phenyl-2-pyridin-4-yl6,7, 8, 9-tetrahydro pyrimidoll ,2-a]pyrimidin-4-one 0 (-)-9-(2-Oxo--2-phenyl-ethyl)-2, 8-dipyridin-4-yi-6,7,8, 9-tetrahydro-4H pyrimido[1 .2-a]pyrimidin-4-one 25 @ (+)-9-(2-Oxo-2-phenyl-ethyl )-2 ,8-dipyridi n-4-yl-6, 7,8, 9-tetrahydro-4H pyrimido[1 .2-ajpyrimidin-4-one * 9-[2-Hydroxy-2-(3-brom o-phenyl)-ethyl]-8-phenyl-2-pyridi n-4-yI-6, 7,8,9 tetrahydro-pyrimido[1 ,2-alpyrimidin-4-one * 9-[2-Hydroxy-2-(4-chl oro-p henyl) -ethy ]-8ph enyl-2pyri di n-4-yI-6,7, 89 30 tetrahydro-pyrimido[1 ,2-a]pyrimidin-4-one * 9-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin4yl-6,7,8, 9-tetrahydro pyrimido[1 ,2-a]pyrimidin-4-one * 9-[2-Hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl2pyridin4yl-6,7,8,9 tetrahydro-pyrimido[1 ,2-a]pyrimidin-4-one 35 * 9-[2-Hydroxy-2-(4-pheny-phenyl)-ethyl]-8pheny2pyridin4yl-6,7, 8,9 tetrahydro-pyrimido[1 ,2-a]pyrimidin-4-one; and a 9-[2-Hydroxy-2-naphthalen-2-y-ethyl]-8-pheny2pyridin4yl-6,7, 8,9 tetrahydro-pyrimido[1 ,2-a]pyrimidin-4-one; or a salt thereof, or a solvate thereof WO 2004/082577 PCT/EP2004/004014 37 or a hydrate thereof. 5. A compound of formula (111) R1 N 1R5 HN N 0 q( )P R3 R4 (Ill) 5 wherein R1, R3, R4, R5, p and q are as defined for compound of formula (I) according to claim 1. 6. A medicament comprising as an active ingredient a substance selected from the group consisting of a pyrimidone derivative represented by formula (I) or 10 a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1. 7. A GSK33 inhibitor selected from the group of a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1. 15 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 GSK3P3 activity. 20 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.
    [5] 10. Use of a compound according to claim 9, wherein the 25 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. WO 2004/082577 PCT/EP2004/004014 38
    [6] 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. 5
    [7] 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.
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    公开号 | 公开日
    JP2006520767A|2006-09-14|
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    DE602004024770D1|2010-02-04|
    EA009197B1|2007-12-28|
    KR101070149B1|2011-10-05|
    US8093256B2|2012-01-10|
    WO2004082577A2|2004-09-30|
    AU2004222596B2|2008-08-28|
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    EP1608654B1|2009-12-23|
    NO20054330L|2005-12-21|
    KR20050111782A|2005-11-28|
    NO20054330D0|2005-09-20|
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    CY1109890T1|2014-09-10|
    EA200501315A1|2006-04-28|
    ES2338325T3|2010-05-06|
    TW200504070A|2005-02-01|
    BRPI0408591A|2006-03-21|
    EP1608654A2|2005-12-28|
    US20060035885A1|2006-02-16|
    PT1608654E|2010-03-05|
    AT452892T|2010-01-15|
    IL170680A|2012-10-31|
    MXPA05010158A|2006-05-19|
    US7247638B2|2007-07-24|
    JP4572195B2|2010-10-27|
    CA2518299C|2011-10-25|
    SI1608654T1|2010-04-30|
    DK1608654T3|2010-04-26|
    EP1460075A1|2004-09-22|
    PL1608654T3|2010-07-30|
    AR043658A1|2005-08-03|
    CN1784408A|2006-06-07|
    TWI330186B|2010-09-11|
    US20080021046A1|2008-01-24|
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    法律状态:
    2009-01-08| FGA| Letters patent sealed or granted (standard patent)|
    2013-10-17| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
    优先权:
    申请号 | 申请日 | 专利标题
    EP03290727.1||2003-03-21||
    EP03290727A|EP1460075A1|2003-03-21|2003-03-21|Substituted 8-Pyridinyl-6,7,8,9-Tetrahydropyrimido[1,2-a]Pyrimidin-4-one and 8-Phenyl-6-7,8,9-Tetrahydropyrimido[1,2-a]Pyrimidin-4-one derivatives|
    PCT/EP2004/004014|WO2004082577A2|2003-03-21|2004-03-19|8-SUBSTITUTED-6, 7, 8, 9-TETRAHYDROPYRIMIDO[1,2-a] PYRIMIDIN-4-ONE DERIVATIVES|
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