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WO2001070728A1 - Derives de la 2-[azote-heterocyclique]pyrimidone - Google Patents

Derives de la 2-[azote-heterocyclique]pyrimidone Download PDF

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Publication number
WO2001070728A1
WO2001070728A1 PCT/EP2001/003639 EP0103639W WO0170728A1 WO 2001070728 A1 WO2001070728 A1 WO 2001070728A1 EP 0103639 W EP0103639 W EP 0103639W WO 0170728 A1 WO0170728 A1 WO 0170728A1
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Prior art keywords
pyridin
ring
ylpyrimidin
piperazin
group
Prior art date
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Ceased
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PCT/EP2001/003639
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English (en)
Inventor
Antonio Almario Garcia
Ryoichi Ando
Jonathan Reid Frost
Adrien Tak Li
Aya Shoda
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Sanofi Aventis France
Mitsubishi Tanabe Pharma Corp
Original Assignee
Sanofi Synthelabo SA
Mitsubishi Tokyo Pharmaceuticals Inc
Mitsubishi Pharma Corp
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Publication date
Priority claimed from EP00400801A external-priority patent/EP1136483A1/fr
Priority claimed from EP00400803A external-priority patent/EP1136493A1/fr
Priority claimed from EP00400802A external-priority patent/EP1136489A1/fr
Application filed by Sanofi Synthelabo SA, Mitsubishi Tokyo Pharmaceuticals Inc, Mitsubishi Pharma Corp filed Critical Sanofi Synthelabo SA
Priority to AU2001262150A priority Critical patent/AU2001262150A1/en
Publication of WO2001070728A1 publication Critical patent/WO2001070728A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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.
  • R represents a 2,6-dichlorobenzyl group, a 2-(2-chlorophenyl)ethylamino group, a 3-phenylpropylamino group, or a 1-methyl-3-phenylpropylamino group.
  • the compounds represented by formula (A) are characterized by a 4-fluorophenyl group at the 5-position of the pyrimidine ring.
  • the main pharmacological activity disclosed for the compounds represented by formula (A) is an anti-inflammatory effect, whereas the compounds of the present invention represented by formula (I) herein below are useful as GSK3 ⁇ inhibitors or as medicaments for the therapeutic treatment of neurodegenerative diseases, and therefore, their pharmacological activities are totally different.
  • 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 the 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 pyrimidone derivatives represented by formula (I) or salts thereof, solvates thereof or hydrates thereof:
  • R1 represents a 2, 3 or 4-pyridyl group optionally substituted by a C 1 - 4 alkyl group, C 1 - 4 alkoxy group or a halogen atom;
  • R2 represents
  • heterocyclic ring having 1-4 hetero atoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5-10, or
  • n 1 or 2;
  • Z being selected from the group consisting of :
  • R3 represents a hydrogen atom or a C 1 - 6 alkyl group
  • the C- 6,10 aryl groups and heterocyclic ring being optionally substituted by 1 to 3 substituents selected from a C ⁇ . 6 alkyl group, halogen atom, a C 1-2 perhalogenated alkyl group, a C ⁇ . 3 halogenated alkyl group, a hydroxyl group, a C 1 . 6 alkoxy group, methylenedioxy group, a nitro, a cyano or a phenyl group.
  • a medicament comprising as an active ingredient a substance selected from the group consisting of the pyhmidone 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 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 the 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 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-dimethylpropyI group, n-hexyl group, isohexyl group, and the like;
  • the C 3 .6 cycloalkyl group represents a cyclic alkyl group of 3 to 6 carbon atoms, for example, cyclopropyl, 2-methyl cyclopropyl, 2-ethyl cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and the like;
  • the C ⁇ -6 alkoxy group represents an alkyloxy group having 1 to 6 carbon atoms for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, 1 ,1-dimethylpropyloxy group;
  • the halogen atom represents a fluorine, chlorine, bromine or iodine atom
  • the C1-2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been substituted by a halogen atom, for example a CF 3 or C 2 F 5 ;
  • the Ci. 3 halogenated alkyl group represents an alkyl group wherein at least one hydrogen has not been substituted by a halogen atom
  • the C ⁇ .io aryl group represents a phenyl group, 1-naphthyl group, 2- naphthyl group and tetrahydronaphthyl group;
  • the heterocyclic ring having 1-4 hetero atoms selected from oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5-10 represents a furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, furopyridine ring, isobenzofuran ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, thienopyridine ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, imidazopyridine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring,
  • 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, tarta c 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- tolu
  • 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 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 pyrimidone 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.
  • 1 H-4-one compound of may exist as tautomers.
  • the existence of such tautomers is readily apparent to those skilled in the art, and these tautomers fall within the scope of the present invention.
  • Preferred compounds of the present invention represented by formula (I) include also:
  • R1 represents a 3- or 4-pyridyl group and more preferably 4-pyridyl group, which may be substituted by a C ⁇ - 2 alkyl group, C ⁇ . 2 alkoxy group or a halogen atom;
  • More preferred compounds of the present invention represented by formula (I) include also:
  • R1 represents an unsubstituted 4-pyridyl group
  • Particularly preferred compounds of the present invention represented by formula (I) include:
  • the present invention concerns also methods for preparing the pyrimidone compounds represented by the aforementioned formula (I).
  • R represents an alkyl group, which may be substituted, and definitions of R1 , R2 and n are the same as those already described above for compound of formula (I)).
  • the 3-ketoester represented by the above formula (II) is allowed to react with the compound represented by formula (III) or a salt thereof to obtain the compound of the aforementioned formula(l) in the presence of a base such as lithium tert- butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, 1 ,8-diazabicyclo[5,4,0]undec-7-ene, triethylamine, diisopropyl- ethylamine, dimethylbenzylamine, dimethylaniline, diethylaniline and the like.
  • a base such as lithium tert- butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,
  • a solvent suitable for the reaction examples include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide and the like.
  • alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol
  • etheric solvents such as die
  • a single solvent or a mixture of two or more solvents may be used depending on the base used, and the reaction may be carried out for 1 hour to 14 days at a suitable temperature ranging from 0° to 250°C under nitrogen or argon atmosphere or in ordinary air.
  • compounds of formula (II), wherein R1 represent a 4-pyridyl group optionally substituted by a C1-4 alkyl group, C1-4 alkoxy group or a halogen atom can be prepared by reacting a nicotinic acid optionally substituted by a alkyl group, C 1 . 4 alkoxy group or an halogen, with a 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-1 H- imidazole in a solvent such as a tetrahydrofuran at a temperature ranging from 20 to 70°C.
  • pyrimidone compounds represented by the aforementioned formula (I) may be prepared according to scheme 2.
  • the 3-ketoester of formula (II) is allowed to react with a 2-methyl-2-thiopseudourea sulfate.
  • the reaction may be carried out in solvent such as water or an alcohol, such as ethanol, propanol and butanol, at a suitable temperature ranging from 25-100°C under ordinary air.
  • compound of formula (I) can be derivatised into other compound of formula (I), using well known methods in the art, for example when the C 6 , ⁇ o aryl groups or the heterocyclic ring is substituted by a hydroxyl group, the hydroxyl group can be alkylated to give a Ci- ⁇ alkoxy group.
  • protection or deprotection of a functional group may sometimes be necessary.
  • a suitable protecting group can be chosen depending on the type of a 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 GSK3 ⁇ . Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a medicament, which enables preventive and/or therapeutic treatment of a disease caused by abnormal GSK3 ⁇ activity and more particularly of neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for the preparation of a medicament for preventive and/or therapeutic treatment of neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g.
  • 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 of pharmaceutical additives.
  • a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more of 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.
  • a type of the 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 may be used.
  • 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. 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.
  • base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.
  • 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.
  • Example 1 Preparation of 2-[4-(R2 substitutent)piperazin-1-yl]-6-pyridin-4- ylpyrimidin-4(1 H)-one.
  • R1 4-pyridyl
  • 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 GSK3 ⁇ (total reaction volume : 100 microliters).
  • the reaction was stopped with 100 microliters of a solution made of 25 g polyphosphoric acid (85% 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 for the compound in the table 1 is between 0.1 to 10 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un dérivé de la pyrimidone (ou ses sels) de formule (I): dans laquelle: R1 représente un groupe 2, 3 ou 4-pyridyle facultativement substitué par un groupe C1-4 alkyle, un groupe C1-4 alkoxy, ou un atome d'halogène; et (a) représente un [anneau azote hététérocyclique] de formule (X), (Y) ou (Z). L'invention porte également sur un médicament comprenant comme principe actif ledit dérivé ou ses sels, et servant au traitement préventif et/ou curatif d'une maladie neurodégénérative due à une activité anormale du GSK3β telle que la maladie d'Alzheimer.
PCT/EP2001/003639 2000-03-23 2001-03-22 Derives de la 2-[azote-heterocyclique]pyrimidone Ceased WO2001070728A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001262150A AU2001262150A1 (en) 2000-03-23 2001-03-22 2-(nitrogen-heterocyclic)pyrimidone derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP00400801A EP1136483A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-[pipérazinyl]pyrimidinone
EP00400802.5 2000-03-23
EP00400803.3 2000-03-23
EP00400803A EP1136493A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-(thienopyridinyl)pyrimidones, 2-(furopyridinyl)pyrimidones, 2-(isoquinolinyl)pyrimidones, 2-(pyridoindolyl)pyrimidones et 2-(benzofuropyridinyl)pyrimidones
EP00400801.7 2000-03-23
EP00400802A EP1136489A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-[pipéridinyl]pyrimidinone

Publications (1)

Publication Number Publication Date
WO2001070728A1 true WO2001070728A1 (fr) 2001-09-27

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PCT/EP2001/003639 Ceased WO2001070728A1 (fr) 2000-03-23 2001-03-22 Derives de la 2-[azote-heterocyclique]pyrimidone

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AU (1) AU2001262150A1 (fr)
WO (1) WO2001070728A1 (fr)

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WO2004055007A1 (fr) * 2002-12-16 2004-07-01 Mitsubishi Pharma Corporation Derives 4-pyrimidones substitues en 3
EP1454908A1 (fr) * 2003-03-07 2004-09-08 Sanofi-Synthelabo Dérivés de pyridinyl-2-(diaza-bicyclo-alkyl)-pyrimidinone substitués
EP1454910A1 (fr) * 2003-03-07 2004-09-08 Sanofi-Synthelabo Dérivés de pyrimidinyl-2-(diaza-bicyclo-alkyl)-pyrimidones substitues
WO2004080977A1 (fr) * 2003-03-12 2004-09-23 Vertex Pharmaceuticals Incorporated 5-cyano-1h-pyrimidin-6-(thi)ones substitues en 4, utilises en tant qu'inhibiteurs de gsk-3
WO2005007648A3 (fr) * 2003-07-16 2005-03-24 Neurogen Corp Analogues de biaryl piperazinyl-pyridine
JP2006521370A (ja) * 2003-03-26 2006-09-21 三菱ウェルファーマ株式会社 ２，３，６−置換−４−ピリミドン誘導体
US7256199B1 (en) 1998-09-25 2007-08-14 Mitsubishi Chemical Corporation Pyrimidone derivatives
JP2008509932A (ja) * 2004-08-13 2008-04-03 ニューロジェン・コーポレーション 置換ビアリールピペラジニル−ピリジン類縁体
JP2008512347A (ja) * 2004-09-09 2008-04-24 田辺三菱製薬株式会社 ２−モルホリノ−４−ピリミドン化合物
WO2008078837A1 (fr) * 2006-12-26 2008-07-03 Mitsubishi Tanabe Pharma Corporation Dérivés de pyrimidone 2-substituée-6-hétérocyclique en tant qu'inhibiteurs de la protéine kinase tau 1
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US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7572793B2 (en) 2001-09-21 2009-08-11 Mitsubishi Tanabe Pharma Corporation 3-Substituted-4-pyrimidone derivatives
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
US20090233918A1 (en) * 2006-03-15 2009-09-17 Mitsubishi Tanabe Pharma Corporation 2-(cyclic amino)-pyrimidone derivatives
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
JP2011525907A (ja) * 2008-06-26 2011-09-29 田辺三菱製薬株式会社 神経変性疾患に対する置換三環式誘導体
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
JP2017533957A (ja) * 2014-11-03 2017-11-16 イオメット ファーマ リミテッド 医薬化合物

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WO2000018758A1 (fr) * 1998-09-25 2000-04-06 Mitsubishi Chemical Corporation Derives pyrimidone

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US7256199B1 (en) 1998-09-25 2007-08-14 Mitsubishi Chemical Corporation Pyrimidone derivatives
US7572793B2 (en) 2001-09-21 2009-08-11 Mitsubishi Tanabe Pharma Corporation 3-Substituted-4-pyrimidone derivatives
US7427615B2 (en) 2001-09-21 2008-09-23 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
JP2006510684A (ja) * 2002-12-16 2006-03-30 三菱ウェルファーマ株式会社 ３−置換−４−ピリミドン誘導体
US7683069B2 (en) 2002-12-16 2010-03-23 Mitsubishi Tanabe Pharma Corporation 3-substituted-4-pyrimidone derivatives
KR100956052B1 (ko) 2002-12-16 2010-05-06 미쓰비시 타나베 파마 코퍼레이션 3-치환-4-피리미돈 유도체
EA009027B1 (ru) * 2002-12-16 2007-10-26 Мицубиси Фарма Корпорейшн Производные 3-замещенного-4-пиримидона
WO2004055007A1 (fr) * 2002-12-16 2004-07-01 Mitsubishi Pharma Corporation Derives 4-pyrimidones substitues en 3
EP1454908A1 (fr) * 2003-03-07 2004-09-08 Sanofi-Synthelabo Dérivés de pyridinyl-2-(diaza-bicyclo-alkyl)-pyrimidinone substitués
AU2004218249B2 (en) * 2003-03-07 2009-04-30 Mitsubishi Pharma Corporation Substituted 2-(diaza-bicyclo-alkyl)-pyrimidone derivatives
EP1454910A1 (fr) * 2003-03-07 2004-09-08 Sanofi-Synthelabo Dérivés de pyrimidinyl-2-(diaza-bicyclo-alkyl)-pyrimidones substitues
CN100376576C (zh) * 2003-03-07 2008-03-26 赛诺菲安万特 取代的2-(二氮杂-双环-烷基)-嘧啶酮衍生物
WO2004080977A1 (fr) * 2003-03-12 2004-09-23 Vertex Pharmaceuticals Incorporated 5-cyano-1h-pyrimidin-6-(thi)ones substitues en 4, utilises en tant qu'inhibiteurs de gsk-3
US7217712B2 (en) 2003-03-12 2007-05-15 Vertex Pharmaceuticals Incorporated 4-Substituted-5-cyano-1H-pyrimidin-6-(thi)ones as GSK-3 inhibitors
US7504411B2 (en) 2003-03-26 2009-03-17 Mitsubishi Tanabe Pharma Corporation 2,3,6-Trisubstituted-4-pyrimidone derivatives
JP2006521370A (ja) * 2003-03-26 2006-09-21 三菱ウェルファーマ株式会社 ２，３，６−置換−４−ピリミドン誘導体
EP2305651A1 (fr) 2003-03-26 2011-04-06 Mitsubishi Tanabe Pharma Corporation Dérivés de 4-Pyrimidone à substitution 2,3,6
JP2007534624A (ja) * 2003-07-16 2007-11-29 ニューロジェン・コーポレーション ビアリールピペラジニル−ピリジン類縁体
WO2005007648A3 (fr) * 2003-07-16 2005-03-24 Neurogen Corp Analogues de biaryl piperazinyl-pyridine
US7566712B2 (en) 2003-07-16 2009-07-28 Neurogen Corporation Biaryl piperazinyl-pyridine analogues
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9499531B2 (en) 2004-07-15 2016-11-22 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8334382B2 (en) 2004-08-13 2012-12-18 Neurogen Corporation Substituted biaryl piperazinyl-pyridine analogues
US7662830B2 (en) 2004-08-13 2010-02-16 Neurogen Corporation Substituted biaryl piperazinyl-pyridine analogues
JP2008509932A (ja) * 2004-08-13 2008-04-03 ニューロジェン・コーポレーション 置換ビアリールピペラジニル−ピリジン類縁体
JP2008512347A (ja) * 2004-09-09 2008-04-24 田辺三菱製薬株式会社 ２−モルホリノ−４−ピリミドン化合物
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7531542B2 (en) 2005-05-18 2009-05-12 Wyeth Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
US20090233918A1 (en) * 2006-03-15 2009-09-17 Mitsubishi Tanabe Pharma Corporation 2-(cyclic amino)-pyrimidone derivatives
US8569294B2 (en) * 2006-03-15 2013-10-29 Mitsubishi Tanabe Pharma Corporation 2-(cyclic amino)-pyrimidone derivatives
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
JP2010514670A (ja) * 2006-12-26 2010-05-06 田辺三菱製薬株式会社 ２−置換―６−ヘテロ環ピリミドン誘導体
WO2008078837A1 (fr) * 2006-12-26 2008-07-03 Mitsubishi Tanabe Pharma Corporation Dérivés de pyrimidone 2-substituée-6-hétérocyclique en tant qu'inhibiteurs de la protéine kinase tau 1
US8592417B2 (en) 2006-12-26 2013-11-26 Mitsubishi Tanabe Pharma Corporation 2-substituted-6-heterocyclic pyrimidone derivatives as tau protein kinase 1 inhibitors
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
JP2011525907A (ja) * 2008-06-26 2011-09-29 田辺三菱製薬株式会社 神経変性疾患に対する置換三環式誘導体
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
JP2017533957A (ja) * 2014-11-03 2017-11-16 イオメット ファーマ リミテッド 医薬化合物
JP2020125349A (ja) * 2014-11-03 2020-08-20 イオメット ファーマ リミテッド 医薬化合物
JP6994538B2 (ja) 2014-11-03 2022-01-14 イオメット ファーマ リミテッド 医薬化合物

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