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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

• 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 GSK3 ⁇ .
• GSK3 ⁇ (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.
• TPK1 tau protein kinase 1
• GSK3 ⁇ protein kinase B phosphorylation 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.
• inhibition of GSK3 ⁇ activity may result in neurotrophic activity.
• GSK3 ⁇ may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation.
• 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.
• ⁇ -amyloid-induced increase in GSK3 ⁇ activity results in the phosphorylation and, hence the inhibition of pyruvate dehydrogenase, a pivotal enzyme in energy production and acetylcholine synthesis.
• 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.
• tauopathies e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
• vascular dementia e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
• cerebrovascular accidents e.g. age related macular degeneration
• 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.
• 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.
• 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.
• 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 dihydrospiro-[cycloalkyl]-pyrimidone derivatives represented by formula (I) or salts thereof, solvates thereof or hydrates thereof:
• X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1 - 2 alkyl group and a hydrogen atom;
• Y represents a bond, a carbonyl group, a methylene group optionally substituted by one or two groups chosen from a C 1 .6 alkyl group, a hydroxyl group, a C 1 - 4 alkoxy group, a C ⁇ _ 2 perhalogenated alkyl group or an amino group;
• R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a C ⁇ -4 alkyl group, a C1- 4 alkoxy group, or a halogen atom;
• R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted by 1 to 4 substituents selected from a C ⁇ -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 Ci-s monoalkylamino group or a C2- 1 0 dialkylamino group;
• R3 represents a hydrogen atom, a C ⁇ , 6 alkyl group or a halogen atom
• 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.
• the aforementioned medicament which is used for preventive and/or therapeutic treatment of diseases caused by abnormal GSK3 ⁇ activity
• 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 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 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 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.
• Alzheimer's disease Parkinson's disease
• tauopathies e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy
• 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; retin
• the present invention further provides an inhibitor of GSK3 ⁇ activity comprising as an active ingredient a substance selected from the group consisting of the dihydrospiro-[cycloalkyl]-pyrimidone derivatives of formula (I) and the salts thereof, and the solvates thereof and the hydrates thereof.
• 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 dihydrospiro-[cycloalkyl]-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 dihydrospiro-[cycloalkyl]-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.
• the C ⁇ -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;
• 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 Ci_ 2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been subsituted by a halogeno, for example a CF 3 or C 2 F 5;
• the C 1 - 3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been subsituted by an halogen atom;
• the C 1 - 5 monoalkylamino group represents an amino group substituted by one C 1 - 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 C 2 - 10 dialkylamino group represents an amino group substituted by two C 1 - 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.
• the compounds represented by the aforementioned formula (I) may form a salt.
• 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)aminomethane, N,N- bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N- methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, ⁇ -hydroxylysine, and arginine.
• the base-addition salts of acidic compounds are prepared by standard procedures well known in the art.
• 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, glucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid; or salts with acidic amino acids such as aspartic acid, and glutamic acid.
• mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
• organic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluen
• 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.
• 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.
• the dihydrospiro-[cycloalkyl]-pyrimidone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms.
• 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, racemates 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 includes compounds of formula (I) wherein:
• R1 represents a 3- or 4-pyridine ring and more preferably a 4-pyridine ring; or a 4- or 5-pyrimidine ring and more preferably a 4-pyrimidine ring, the rings being optionally substituted by a C ⁇ - 2 alkyl group, a C1- 2 alkoxy group or a halogen atom; and/or
• R2 represents a benzene ring or a naphthalene ring, the ring being optionally substituted 1 to 4 substituents selected from a C1.3 alkyl group, a halogen atom, a hydroxyl group or a C1- 2 alkoxy group; and/or
• R3 represents a hydrogen atom, a C1.3 alkyl group or a halogen atom; more preferably a hydrogen atom; and/or
• Y represents a bond, a carbonyl group or a methylene group optionally substituted by one or two groups chosen from a C1-3 alkyl group, a hydroxyl group, a C ⁇ - 4 alkoxy group, a C ⁇ - 2 perhalogenated alkyl group or an amino group;
• p + q equals 2 or 3, preferably 2; and more particularly wherein R1 , R2, R3 and Y are as defined here-above.
• Another embodiment of the present invention include compounds of formula (I) wherein:
• R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring; and/or (2) R2 represents a benzene ring, the ring being optionally substituted 1 to 4 substituents selected from a C 1 -3 alkyl group, a halogen atom, a hydroxyl group or a C 1 - 2 alkoxy group; and/or
• R3 represents a hydrogen atom
• X represents two hydrogen atoms; and/or (5) Y represents a bond, a carbonyl group or a methylene group optionally substituted by a hydroxyl group; and/or
• p represents 2 and q represents 0 ; and more particularly wherein R1, R2, R3, X, Y, p and q are as defined here-above.
• Particularly compounds of the present invention represented by formula (I) include compounds of table 1 :
• the present invention concerns also methods for preparing the dihydrospiro-[cycloalkyl]-pyrimidone compounds represented by the aforementioned formula (I).
• Dihydrospiro-[cycloalkyl]-pyrimidone compounds represented by the aforementioned formula (I), may be prepared according to the method described in the scheme 1.
• a base such as sodium hydride, sodium carbonate or potassium carbonate
• a solvent such as ⁇ /, ⁇ /-dimethylformamide, ⁇ /-methylpyrrolidone, ⁇ /, ⁇ /-di
• 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 (III) may be prepared according to the method defined in scheme 2.
• the 3-ketoester of formula (IV), wherein R1 and R3 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).
• 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.
• compound of formula (III) wherein R3 represents a hydrogen atom may be halogenated in order to give compounds of formula (III) wherein R3 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.
• the present invention concerns also the compound of formula (III) as intermediate for preparing compound of formula (I).
• compounds of formula (IV), wherein R1 represent a pyridine ring or a pyrimidine ring, optionally substituted by a C M alkyl group, CM alkoxy 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, C alkoxy group or a halogen, with the corresponding malonic acid monoester.
• 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 , -carbonylbis-1/-/- imidazole in a solvent such as tetrahydrofuran at a temperature ranging from 20 to 70°C.
• a coupling agent such as 1 , -carbonylbis-1/-/- imidazole
• a solvent such as tetrahydrofuran
• compound of formula (V) when m represents 1 , p represents 2 and q represents 0, may be prepared according to the method defined in scheme 3 and according to the method described by Smith and Christensen (J. Org. Chem. 1955, 20, 829) for the last step.
• the conditions which may be used are given in the chemical examples.
• Compound of formula (VI) may be synthesized according to the method described by Bertus and Szymoniak (Chem. Commun. 2001,1792).
• Compound of formula (X) may be synthesized according to the method described by Suzuki et al. (Synthetic Communication 199 ⁇ , 28(4), 701).
• 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).
• the compounds of the present invention have inhibitory activity against
• 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.
• 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.
• 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).
• a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically 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.
• a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more pharmaceutical additives.
• 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.
• 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.
• 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.
• excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like.
• a conventional inert diluent such as water or a vegetable oil
• the liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, colorants, and preservatives.
• the liquid composition may be filled in capsules made of an absorbable material such as gelatin.
• 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.
• 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.
• 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.
• 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.
• the catalyst was removed by filtration and washed with isopropanol. The filtrate was evaporated to dryness to afford 6.22g of pure product as a viscous oil.
• the product was obtained by analogy with the method described in step 1.2 and using (l-aminocyclopentyl)acetonitrile. The compound was used as such in the next step.
• the product was obtained by analogy with the method described in step 1.7 and using 1 -(2-aminoethyl)cyclopentanamine hydrobromide (1 :2). The compound was used as such in the next step.
• the product was obtained by analogy with the method described in step 1.9 and using 3'-pyridinyl-4-yl-3',4'-dihydrospiro[cyclopentane-1 ,2'-pyrimido[1 ,2-a]- pyrimidin]-6'(1 'H)-one.
• the product was obtained by analogy with the method described in step 1.8, using ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582) and 6,8-Diazaspiro[4.5]dec-7-en-7amine hydrobromide (1 : 1) (prepared according to example 3.5).
• the compound obtained was treated with water and the precipitate recovered by filtration to give 2.92g of product. Mp. : 243-244°C.
• the product was obtained by analogy with the method described in step 1.9 and using ⁇ '-pyrimidinyl-4-yl-3',4'-dihydrospiro[cyclopentane-1 ,2'-pyrimido[1 ,2-a] ⁇ yrimidin]-6'(1 'H)-one.
• R1 is an unsubstituted pyrimidin-4-yl group or an unsubstituted pyridin-4-yl group
• p represents 2
• q represents 1
• Ph represents a phenyl group
• (S), (R) or (Rac.) indicates in the column "Y" the stereochemistry of the carbon atom: (rac.) means racemic mixture
• Test Example Inhibitory activity of the medicament of the present invention against GSK3 ⁇ :
• 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-HCI, pH 7.5, 0.6 mM DTT, 6 mM MgCI 2 , 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).
• the reaction was stopped with 100 microliters of a solution made of 25 g polyphosphoric acid (65% P 2 O 5 ), 126 ml 85% H 3 PO 4 , H 2 O 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 ⁇ inhibitory activity of the compounds of the present invention are expressed in IC 50 , and as an illustration the range of ICso's of the compounds in table 1 is between 1 nanomolar to 1 micromolar concentrations.
• the compounds of the present invention have GSK3 ⁇ 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 GSK3 ⁇ and more particularly of neurodegenerative diseases.

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