WO2001070727A1 - Derives de 2-(arylalkylamino)pyrimidone et derives de 2-(heteroarylalkylamino)pyrimidone - Google Patents

Derives de 2-(arylalkylamino)pyrimidone et derives de 2-(heteroarylalkylamino)pyrimidone Download PDF

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WO2001070727A1
WO2001070727A1 PCT/EP2001/003638 EP0103638W WO0170727A1 WO 2001070727 A1 WO2001070727 A1 WO 2001070727A1 EP 0103638 W EP0103638 W EP 0103638W WO 0170727 A1 WO0170727 A1 WO 0170727A1
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group
amino
pyridin
ylpyrimidin
methyl
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PCT/EP2001/003638
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English (en)
Inventor
Antonio Almario Garcia
Ryoichi Ando
Keiichi Aritomo
Jonathan Reid Frost
Adrien Tak Li
Aya Shoda
Fumiaki Uehara
Kazutoshi Watanabe
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Sanofi-Synthelabo
Mitsubishi Pharma Corporation
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Priority claimed from EP00400805A external-priority patent/EP1136099A1/fr
Priority claimed from JP2000081938A external-priority patent/JP2001270884A/ja
Priority claimed from EP00400806A external-priority patent/EP1136491A1/fr
Priority claimed from EP00400804A external-priority patent/EP1136484A1/fr
Application filed by Sanofi-Synthelabo, Mitsubishi Pharma Corporation filed Critical Sanofi-Synthelabo
Priority to AU2001248365A priority Critical patent/AU2001248365A1/en
Publication of WO2001070727A1 publication Critical patent/WO2001070727A1/fr

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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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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
  • protein kinase B (AKT) phosphorylation of GSK3 ⁇ results in a loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors.
  • phosphorylation by GSK3 ⁇ of ⁇ -catenin results in its degradation by an ubiquitinilation dependent proteasome pathway.
  • GSK3 ⁇ inhibition may result in neurotrophic activity. Indeed there is evidence that lithium, an uncompetitive inhibitor of GSK3 ⁇ , enhances neuritogenesis in some models and also increases neuronal survival, through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.
  • 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 neuronai 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 supranuciear 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.
  • 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 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:
  • R2 represents a hydrogen atom, a d. 2 perhalogenated alkyl group or a C ⁇ - 6 alkyl group which may be substituted by 1 to 3 groups selected from a halogen atom, an amino, a (C ⁇ . 6 -alkyl)carbonylamino group, a (C ⁇ _ 6 -alkoxy)carbonylamino group, a C ⁇ - 6 alkylsulfonylamino group or a phenyl group;
  • R3 represents a 2, 3 or 4-pyridyl group optionally substituted by a alkyl, group, C ⁇ ⁇ » alkoxy group or a halogen atom;
  • an indole ring attached by a carbon atom, optionally substituted by 1 to 3 substituents (A), the nitrogen of the indole ring being optionally substituted by a C1- 6 alkyl group; the substituent (A) being selected from a C ⁇ . 6 alkyl group, halogen atom, a C ⁇ perhalogenated alkyl group, a C ⁇ . 3 halogenated alkyl group, a hydroxyl group, a C-
  • dialkylamino group a (Ci- ⁇ -alky carbonylamino group, a (C 6 , ⁇ o-aryl)carbonylamino group, a (C ⁇ . 6 -alkoxy)carbonylamino group, aminocarbonyl group, a (C 1 - 6 monoalkylamino)carbonyl group, a (C 2 .-
  • alkylsulfonyl group a C 6 , ⁇ o arylsulfonyl group, an aminosulfonyi group, a C- ⁇ - 6 monoalkylaminosulfonyl group, a C 2 - ⁇ 2 dialkylaminosulfonyl group, a phenyl group or a benzyloxy group; the C ⁇ . 6 alkyl groups and the alkoxy groups being optionally substituted by a halogen atom, a hydroxyl group, a C ⁇ . 6 alkoxy group, an amino, a C ⁇ _ 6 monoalkylamino group, a C 2 . ⁇ 2 dialkylamino group, a (C ⁇ alkyl)carbonylamino group, a
  • (C- 6 ,io aryl)carbonylamino group a (C-
  • aralkyl group a C 6 - ⁇ o aryl group, a fiuorenyl group, a C1- 6 alkoxy group, a C 3 . 8 cycloalkyloxy group, a C 7 . 20 aralkyloxy group, a C 6 . ⁇ 4 aryloxy group, a C1. 5 alkylthio group, a C 7 . 2 o aralkylthio group, a C 6 - ⁇ 4 arylthio group, a C 1 . 5 alkylsulfonyl group, a C 6 , ⁇ o arylsulfonyl group, a halogen atom, a C ⁇ .
  • R1 can represent in addition an unsubstituted phenyl group
  • R2 represents a d. 2 perhalogenated alkyl group or a C ⁇ . 6 alkyl substituted by 1 to 3 groups selected from a halogen atom, an amino, a (CT- ⁇ -alky carbonylamino group, a (C ⁇ -alkoxy)carbonylamino group and a Ci- ⁇ alkylsulfonylamino group.
  • 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 supranuciear 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 supranuciear 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; retinopathies
  • 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-butyi group, n-pentyl group, isopentyl group, neopentyl group, 1 ,1-dimethylpropyl group, n-hexyl group, isohexyl group, and the like;
  • the C M s alkyl group represents a straight or branched alkyl group having 1 to 18 carbon atoms, for example in addition to the C ⁇ - 6 alkyl group cited above, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, and octadecyl group;
  • the C 3 . 8 cycloalkyl group represents for example a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group;
  • the C 6 , ⁇ o aryl group represents a phenyl group, a naphth-1-yl group or a naphth-2- yl group;
  • the C 7 . 20 aralkyl group represents for example a benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group, and naphthylbutyl group;
  • the C 1- 6 alkoxy group represents an alkyl-oxy 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 C 3 . 8 cycloalkoxy group represents a cycloalkyl-oxy for example, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, and cyclooctyloxy group, and the like;
  • the C . 20 aralkyloxy group represents for example a benzyloxy group, phenylethyloxy group, phenylpropyloxy group, phenylbutyloxy group, naphthylmethyloxy group, naphthylethyloxy group, naphthypropyloxy group, and naphthylbutyloxy group;
  • the C 6 - ⁇ 4 aryloxy group represents for example a phenoxy group, and naphthoxy group
  • the C 1- 6 alkylthio group represents an alkyl-thio for example, methylthio group, ethylthio group, propylthio group, butylthio group and pentylthio group;
  • the C 7 . 2 o aralkylthio group represents for example a benzylthio group, phenylethylthio group, phenylpropylthio group, phenylbutylthio group, naphthylmethylthio group, naphthylethylthio group, naphthypropylthio group, and naphthylbutylthio group;
  • the C ⁇ - ⁇ 4 arylthio group represents for example a phenylthio group, and naphththio group;
  • the halogen atom represents a fluorine, chlorine, bromine or iodine atom
  • the C ⁇ - 2 perhalogenated alkyl group represents an alkyl group wherein all the hydrogen have been substituted by a halogeno, for example a CF 3 or C 2 F 5 ,
  • the C 1 - 3 halogenated alkyl or (or C 1 . 5 halogenated alkyl group) represents an alkyl group wherein at least one hydrogen has not been substituted by a halogeno,
  • the C 1 - 6 alkylcarbonyl group represents for example a acetyl group, propionyl group, butyryl group, and valeryl group;
  • the C 1 - 6 monoalkylamino group represents an amino substituted by one C ⁇ _ 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 _i 2 dialkylamino group represents an amino substituted by two C ⁇ - 6 alkyl groups, for example, dimethylamino group, ethylmethylamino group, diethylamino group, methylpropyiamino group and diisopropylamino group;
  • the (C1-6 alkyl)carbonylamino group represents an amino group substituted by a
  • C1-6 acyl group for example, formyl group, acetyl group, propionyl group, pivaloyl group, butyryl group, isobutyryl group, pentanoyi group, 3-methylbutyryl group, hexanoyl group;
  • the (C- 6 , 10 aryl)carbonylamino group represents an amino group substituted by a benzoyl group or a naphthylenecarbonyl group;
  • the (C 1 . 6 alkoxy)carbonylamino group represents an amino group substituted with a alkoxy)carbonyl group, such as for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, terf-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group;
  • the C1-6 monoalkylaminocarbonyl group represents an aminocarbonyl group substituted by one C 1 . 6 alkyl group, as defined and illustrated above, for example : methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, / ' -propylaminocarbonyl group, butylaminocarbonyl group, iso- butylaminocarbonyl group, tett-butylaminocarbonyl group, pentylaminocarbonyl group, neopentylaminocarbony group, 1 ,1-dimethylpropylaminocarbonyl group, n- hexylaminocarbonyl group, isohexylaminocarbonyl group, and the like;
  • the C 2 - 12 dialkylaminocarbonyl group represents an aminocarbonyl group substituted by two C ⁇ - 6 alkyl groups, as defined and illustrated above, for example : dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, di-/-propylaminocarbonyl group, butylaminocarbonyl group, iso- butylaminocarbonyl group, terf-butylaminocarbonyl group, dipentylaminocarbonyl group, di-neopentylaminocarbony group, di-(1,1-dimethylpropyl)aminocarbonyl group, di-n-hexylaminocarbonyl group, di-isohexylaminocarbonyl group, ethylmethylaminocarbonyl group, ethylpropylaminocarbonyl group, ethyl-tert- butylaminocarbonyl group, and the
  • the (C 6, ⁇ o-aryl)carbonyl group represents an arylcarbonyl group wherein the C 6 10 aryl group is as defined here above, such as, for example benzoyl group and a naphthylenecarbonyl group;
  • the C- ⁇ - 5 alkylsulfonyl group represents an alkylsulfonyl group having 1 to 6 carbon atoms, such as, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyi group, n-butyl group, isobutyisulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 1 ,1-dimethylpropylsulfonyl group;
  • the C 6, ⁇ o arylsulfonyl group represents an arylsulfonyl group wherein the
  • C 6 , ⁇ o aryl group is as defined here above, such as, for example, phenylsulfonyl group or naphthalenesulfonyl group;
  • the C 1 - 6 alkylsulfonylamino or C 6 , 10 arylsulfonylamino represents respectively a sulfonylamino group substituted by a C1-6 alkyl or C 6 , ⁇ 0 aryl group;
  • the C ⁇ is
  • 6 monoalkylaminosulfonyl group represents an aminosulfonyl group substituted by one C 1 - 6 alkyl group, as defined and illustrated above, for example : methylaminosuifonyl group, ethylaminosulfonyll group, propylaminosulfonyl group, /-propylaminocarbonyl group, butylaminosulfonyl group, / ' so-butylaminosulfonyl group, .erf-butylaminosulfonyl group, 1 ,1-dimethylpropyiaminosulfonyl group, n- hexylaminosulfonyl group, isohexylaminosuifonyl group, and the like;
  • the C 2 - 12 dialkyiaminosulfonyl group represents a aminosulfonyl group substituted by two C- ⁇ -6 alkyl group, as defined and illustrated above, for example : di
  • 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, ⁇ -hydroxyiysine, 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, ma ⁇ delic 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.
  • 1H-4-one compound 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 compounds wherein R3 represents a 3- or 4-pyridyl group and more preferably 4-pyridyl group, which may be substituted by a d-2 alkyl, group, C ⁇ _ 2 alkoxy group or a halogen atom.
  • n 1 to 5, and more preferably 1 to 4.
  • R1 is an indole ring
  • (A) is selected from a d- 6 alkyl group preferably a methyl, ethyl or propyl group; a halogen, a Ci- alkoxy group and benzyloxy group.
  • R1 is a furan ring, thiophene ring, pyrrole ring or imidazole ring
  • substituent (A) is selected from a Ci- 6 alkyl group, halogen atom, a C ⁇ . 2 perhalogenated alkyl group, a C- 1 - 3 halogenated alkyl group, a hydroxyl group, a C ⁇ . 6 alkoxy group, methylenedioxy group, a nitro, a cyano, an amino, a C 1 - 6 monoalkylamino group, a C 2 .-
  • R1 is a pyridine ring
  • R2 is a hydrogen atom, a d. 5 alkyl group optionally substituted by a phenyl group
  • R2 is a C 1 - 3 alkyl group optionally substituted by a phenyl group and more preferably a methyl, ethyl or n-propyl optionally substituted by a phenyl group.
  • R1 is a pyridine ring
  • 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, R3, and n are the same as those already described for compound of formula (I).
  • the 3-ketoester represented by the above formula (III) is allowed to react with the compound represented by formula (II) or a salt thereof to obtain the compound of the aforementioned formula (I) 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, diethylaniiine 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, potassium
  • 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.
  • 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.
  • a coupling agent such as 1 ,1'-carbonylbis-1 H- imidazole
  • a solvent such as a tetrahydrofuran
  • pyrimidone compounds represented by the aforementioned formula (I) may be prepared according to scheme 2.
  • R3 is as defined for compound of formula (I), is allowed to react with an amine of formula (IV) to obtain the compound of the aforementioned formula (I).
  • the reaction may be carried out in a solvent such as, for example, an alcoholic solvent such as n-pentanol or isoamyl alcohol at a suitable temperature ranging from 100 to 180 °C under ordinary air.
  • Compound of formula (V) may be prepared according to the method defined in scheme 3.
  • the 3-ketoester of formula (VI) 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) could be derivatised into other compound of formula (I), using well known methods in the art. This is the case, for example, when R1 or a substituent on an alkyl or alkoxy group, could be oxidized, hydrogenated, alkylated... , or be transformed using well known method in the art to give another R1 group or a substituent within the scope of the present invention.
  • 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 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 supranuciear 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 administrating 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 oieate, 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-(arylalkylamino)-6-pyridin-4-ylpyrimidin-4(1H)-one or 2-(heteroarylalkylamino)-6-pyridin-4-ylpyrimidin-4(1 H)-one.
  • Ethyl 3-(4-pyridyl)-3-oxopropionate (0.60g ; 3.1 mmol), compound of formula (II) (3.4 mmol) and potassium carbonate (1.15g ; 8.3mmol ) were added to 5 ml of ethanol, and the mixture was heated under reflux at 75° for 20 hours.
  • Acetic acid was added to the reaction mixture , and the solvent was removed by distillation. The residue was treated with water and then with acetic acid , and the resulting solid was separated by filtration, washed with water and ethyl acetate, and dried to obtain the desired compound.
  • Table 1 a list of chemical structures and physical data for compounds of the aforementioned formula (I) illustrating the present invention is given in table 1.
  • Me represents a methyl group and R3 represents a 4-pyridyl.
  • R3 4-Pyridyl
  • R3 is an unsubstituted 4-pyridyl group
  • 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).
  • 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 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 IC 5 o's for the compounds in table 1 is between 0,01 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 neurodegenerative diseases caused by abnormal activity of GSK3 ⁇ .

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Abstract

L'invention concerne un dérivé de pyrimidone représenté par la formule (I) ou un sel dudit dérivé. Dans ladite formule, R2 représente un atome d'hydrogène, un groupe alkyle C1-2 perhalogéné ou un groupe alkyle C1-6 éventuellement substitué par 1 à 3 groupes choisis entre un atome d'halogène, un amino, un groupe (C1-6-alkyl)carbonylamino, un groupe (C1-6-alcoxy)carbonylamino, un groupe C1-6 alkylsulfonylamino ou un groupe phényle ; R3 représente un groupe 2, 3 ou 4-pyridyle éventuellement substitué par un groupe alkyle C1-4, une groupe alcoxy C1-4 ou un atome d'halogène ; et lorsque n représente 1 à 10, R1 désigne un groupe naphth-1-yle non substitué ; un groupe naphth-2-yle non substitué ; un groupe aryle C6,10 substitué par 1 à 3 substituants (A) ; un cycle furanne, un cycle thiophène, un cycle pyrrole ou imidazole, lesdits cycles étant éventuellement substitués par 1 à 3 substituants (A) ; un cycle indole, fixé à un atome de carbone, éventuellement substitué par 1 à 3 substituants (A), l'azote dudit cycle indole étant éventuellement substitué par un groupe alkyle C1-6 ; un cycle pyridine éventuellement substitué par 1 à 3 substituants (B) ; lorsque n représente 4 à 10, R1 peut désigner, en outre, un groupe phényle non substitué ; et lorsque n représente 1 à 3 et R1 désigne un groupe phényle non substitué, R2 représente un groupe alkyle C1-2 perhalogéné ou un alkyle C1-6 substitué par 1 à 3 groupes choisis parmi un atome d'halogène, un amino, un groupe (C1-6-alkyl)carbonylamino, un groupe (C1-6-alcoxy)carbonylamino et un groupe C1-6 alkylsulfonylamino. L'invention concerne également un médicament comprenant ledit dérivé ou un sel dudit dérivé comme principe actif, lequel médicament est utilisé pour le traitement préventif et/ou thérapeutique d'une maladie neurodégénérative induite par une activité anormale de GSK3β.
PCT/EP2001/003638 2000-03-23 2001-03-22 Derives de 2-(arylalkylamino)pyrimidone et derives de 2-(heteroarylalkylamino)pyrimidone WO2001070727A1 (fr)

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EP00400805A EP1136099A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-(indolylalkylamino)pyridone comme inhibiteurs de GSK3bêta
EP00400806.6 2000-03-23
JP2000081938A JP2001270884A (ja) 2000-03-23 2000-03-23 ピリミドン誘導体
JP2000-81938 2000-03-23
EP00400806A EP1136491A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-[(hétéroaryl)alkylamino]pyrimidinones
EP00400804A EP1136484A1 (fr) 2000-03-23 2000-03-23 Dérivés de 2-(arylalkylamino)pyrimidine
EP00400805.8 2000-03-23
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Cited By (22)

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WO2003074072A1 (fr) * 2002-03-01 2003-09-12 Chiron Corporation Methodes et compositions destinees au traitement de l'ischemie
WO2004037791A1 (fr) 2002-10-21 2004-05-06 Chiron Corporation Inhibiteurs de glycogene synthase kinase 3
EP1439176A1 (fr) * 2001-10-22 2004-07-21 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes
EP1616568A2 (fr) * 2002-04-30 2006-01-18 Alcon, Inc Inhibiteurs de GSK-3 et de CDK comme agents antiglaucome
US7189717B2 (en) 2000-04-26 2007-03-13 Eisai Co., Ltd. Medicinal compositions promoting bowel movement
JP2007520558A (ja) * 2004-02-04 2007-07-26 スミスクライン・ビーチャム・コーポレイション キナーゼ阻害剤として有用なピリミジノン化合物
WO2008011113A3 (fr) * 2006-07-18 2008-02-28 Univ Rochester Dérivés de thiadiazolidinone
US7351407B2 (en) 2002-04-30 2008-04-01 Alcon, Inc. Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (CTGF) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
US7396836B2 (en) 2001-10-22 2008-07-08 Eisai R&D Management Co., Ltd. Pyrimidine compound and medicinal composition thereof
EP2041067A2 (fr) * 2006-07-11 2009-04-01 Emory University Antagonistes de cxcr4 comprenant des structures de diazine et de triazine pour le traitement de troubles médicaux
US7598288B2 (en) * 2001-09-27 2009-10-06 Alcon, Inc. Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
US20100292205A1 (en) * 2006-08-23 2010-11-18 Pfizer Inc. Pyrimidone Compounds As GSK-3 Inhibitors
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
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
US8008312B2 (en) 2005-01-07 2011-08-30 Emory University CXCR4 antagonists for the treatment of HIV infection
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

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US7189717B2 (en) 2000-04-26 2007-03-13 Eisai Co., Ltd. Medicinal compositions promoting bowel movement
US7598288B2 (en) * 2001-09-27 2009-10-06 Alcon, Inc. Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
EP1439176A1 (fr) * 2001-10-22 2004-07-21 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes
EP1439176A4 (fr) * 2001-10-22 2005-02-09 Eisai Co Ltd Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes
US7396836B2 (en) 2001-10-22 2008-07-08 Eisai R&D Management Co., Ltd. Pyrimidine compound and medicinal composition thereof
US7160892B2 (en) 2001-10-22 2007-01-09 Eisai Co., Ltd. Pyrimidone compounds and pharmaceutical compositions containing the same
WO2003074072A1 (fr) * 2002-03-01 2003-09-12 Chiron Corporation Methodes et compositions destinees au traitement de l'ischemie
EP1490093A1 (fr) * 2002-03-01 2004-12-29 Chiron Corporation Methodes et compositions destinees au traitement de l'ischemie
EP1490093A4 (fr) * 2002-03-01 2007-04-11 Novartis Vaccines & Diagnostic Methodes et compositions destinees au traitement de l'ischemie
EP1616568A2 (fr) * 2002-04-30 2006-01-18 Alcon, Inc Inhibiteurs de GSK-3 et de CDK comme agents antiglaucome
US7351407B2 (en) 2002-04-30 2008-04-01 Alcon, Inc. Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (CTGF) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
EP1616568A3 (fr) * 2002-04-30 2006-06-21 Alcon, Inc Inhibiteurs de GSK-3 et de CDK comme agents antiglaucome
US6989382B2 (en) 2002-10-21 2006-01-24 Chiron Corporation Carbocycle based inhibitors of glycogen synthase kinase 3
WO2004037791A1 (fr) 2002-10-21 2004-05-06 Chiron Corporation Inhibiteurs de glycogene synthase kinase 3
JP2007520558A (ja) * 2004-02-04 2007-07-26 スミスクライン・ビーチャム・コーポレイション キナーゼ阻害剤として有用なピリミジノン化合物
US8008312B2 (en) 2005-01-07 2011-08-30 Emory University CXCR4 antagonists for the treatment of HIV infection
US8114884B2 (en) 2005-01-07 2012-02-14 Emory University CXCR4 antagonists for the treatment of medical disorders
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
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
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
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
JP2009543802A (ja) * 2006-07-11 2009-12-10 エモリー・ユニバーシテイ 医学的疾患の治療のためのジアジン及びトリアジン構造を含むｃｘｃｒ４アンタゴニスト
EP2041067A4 (fr) * 2006-07-11 2009-11-25 Univ Emory Antagonistes de cxcr4 comprenant des structures de diazine et de triazine pour le traitement de troubles médicaux
EP2041067A2 (fr) * 2006-07-11 2009-04-01 Emory University Antagonistes de cxcr4 comprenant des structures de diazine et de triazine pour le traitement de troubles médicaux
US8080659B2 (en) 2006-07-11 2011-12-20 Emory University CXCR4 antagonists including diazine and triazine structures for the treatment of medical disorders
WO2008011113A3 (fr) * 2006-07-18 2008-02-28 Univ Rochester Dérivés de thiadiazolidinone
US9180118B2 (en) 2006-07-18 2015-11-10 University Of Rochester Thiadiazolidinone derivatives
US20100292205A1 (en) * 2006-08-23 2010-11-18 Pfizer Inc. Pyrimidone Compounds As GSK-3 Inhibitors
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
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

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