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  • 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
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Definitions

• the present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
• glycogen synthase kinase-3 beta (GSK-3 ⁇ ) , a protein kinase, is involved in the causes of various diseases as noted in the following.
• Type-II diabetes is a disease in which the insulin reactivity of pancreatic ⁇ cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced.
• GSK-3 ⁇ acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GSK-3 ⁇ -inhibitory activity actually lowers glucose in blood by a GSK-3 ⁇ - inhibitory activity (Proc. Nat. Acad. Sci., 93, 8455
• medicaments having a GSK-3 ⁇ -inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.
• the developmental mechanism of Alzheimer's dementia has not yet been elucidated. However, it is considered that amyloid aggregation and neurofibril changes are closely related to the cause of the development.
• GSK-3 ⁇ is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)).
• Tat which is a protein produced by HIV virus that causes AIDS, enhances GSK-3 ⁇ activity in neurons to induce neuronal death (J. Neuroche ., 73, 578 (1999)).
• GSK-3 ⁇ inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
• Lithium and valproic acid which have anti-manic- depressive activity, have a GSK-3 ⁇ inhibitory activity (J. Neurochem., 72, 1327 (1999)).
• GSK-3 ⁇ inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.
• NF-AT a transcription factor, is dephosphorylated by calcineurin to increase immunological responses (Science,
• GSK-3 ⁇ acts for suppressing immunological function by conversely phosphorylating NF-AT.
• GSK-3 ⁇ inhibitors are considered to be medicaments effective for immunopotentiation.
• JP-A-3-272189 invention drawn to an improved synthesis method of mevalolacton intermediates
• JP-A-2-275878 therapeutic agents for hyperlipoproteinemia and atherosclerosis
• JP-A-1-272584 therapeutic agents for hyperlipoproteinemia
• JP-A-59-65089, JP-A-59-118786, JP-A-60-56979, JP-A-60-197685 and the like disclose 6- methyl-4-substituted phenyl-4, 7-dihydropyrazolo [3, 4—J] - pyridine-5-carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods.
• the present inventors reproduced the following reaction A according to the method described in JP-A-59- 65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo [1, 5-a] pyrimidine derivative represented by the formula (V) could be produced.
• the compound of the above formula (IV) can be synthesized according to the method described in J. Chem. Soc, Perkin Trans. 1, 947 (1996), and this publication discloses methyl 4- (2-chlorophenyl) -6-methyl-4, 7-dihydro- lif-pyrazolo [3, 4-b]pyridine-5-carboxylate and the like.
• An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3 ⁇ ) , and further, medicaments comprising them and pharmaceutical compositions comprising them.
• GSK-3 ⁇ glycogen synthase kinase-3 beta
• the present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo [3, 4-i)] pyridine derivatives have a selective and strong inhibitory activity on GSK-3 ⁇ , which resulted in the completion of the present invention. That is, the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-
• 3 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
• the present invention provides the following.
• R° is hydrogen, alkyl, aralkyl, acyl, cycloalkyl, for yl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , phenylalkyl optionally having substituent (s) , or a group of the formula: -COOR 8 (wherein R 8 is hydrogen, alkyl, aryl optionally having substituen (s) or a
• aromatic heterocyclic group (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
• R 6 and R 7 are each phenyl optionally having substituent (s) or an aromatic heterocyclic group, or R 2 and R 3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent (s) ;
• R 4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group optionally having substituent (s) , cyano or nitro; and R 5 is alkyl, phenylaminoalkyl, acyl, acylalkyl, aminocarbonyl, arylaminocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent, or a group of the formula:
• R 4 is alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkylsulfinyl, phenylsulfinyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, phenyl optionally having substituent (s) , an aromatic heterocyclic group having substituent (s) , cyano or nitro
• R 5 is alkyl, phenyla inoalkyl, acyl, acylalkyl, aminocarbonyl, aryla inocarbonyl, a saturated or unsaturated 4 to 7 membered heterocyclic ring optionally having substituent (s) , a saturated 3 to 7 membered carbocyclic ring having substituent (s) , alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1
• a medicament comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described [1] or [2], an optically active form thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
• a glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described [1], an optically active form thereof and a pharmaceutically acceptable salt thereof.
• the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Gu
• the formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring.
• the present invention encompasses each isomer of formulas (I-a) and (I-b), and a mixture of these isomers.
• Alkyl means a linear or branched hydrocarbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl (i.e., a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s).
• the alkyl of R 2 is preferably alkyl having 1 to 4 carbon atoms.
• the alkyl of R 5 is preferably alkyl having 2 to 8 carbon atoms.
• the "alkyl having 2 to 8 carbon atoms" concretely includes ethyl, propyl, butyl, pentyl (i.e., amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like.
• Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
• "Acyl” means C 2 -C ⁇ acyl, and includes “alkylcarbonyl” having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, at R 4 preferably having 2 to 5 carbon atoms, "C 7 _Ci 2 arylcarbonyl” such as benzoyl, naphthoyl and the like, and "C-Ci2 aralkylcarbonyl” such as benzylcarbonyl, 2-phenylethylcarbonyl, 3-phenylpropylcarbonyl and the like, and the like.
• the benzene and naphthalene rings may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
• “Acylalkyl” is acylalkyl consisting of the above Ci- C 8 alkyl and the above C2-C 1 4 acyl, and includes, for example, acetylmethyl, propionylmethyl, butyrylmethyl, isobutyryl ethyl, valerylmethyl, pivaloylmethyl, 2- acetylethyl, 2-propionylethyl, 3-acetylpropyl and the like.
• “Cycloalkyl” means a cyclic hydrocarbon chain of 3 to 8 carbon atoms.
• Cycloalkyl concretely includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl having 3 to 6 carbon atoms.
• the cycloalkyl may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
• Halogen represents fluorine, chlorine, bromine or iodine .
• Amino is primary amino, secondary or tertiary amino having the above C ⁇ -C 8 alkyl, and includes, for example, amino, mono- or di-C ⁇ -C 8 alkyl-substituted amino such as methylamino, dimethylamino, ethyla ino, diethylamino, propylamino, dipropylamino, butyla ino, dibutylamino and the like.
• Alkylthio is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio (i.e., amylthio) , hexylthio and structural isomers thereof, such as isopropylthio, isobutylthio, sec-butylthio, tert- butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom(s) .
• Phenylthio means phenylthio optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Haloalkyl is the above C ⁇ -C 8 alkyl substituted by 1 to 5 halogen (s), and represents fluoromethyl, chloromethyl, difluoro ethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl and the like.
• Aminoalkyl is C ⁇ -C 8 alkyl having primary amino, and includes, for example, aminomethyl, 2-aminoethyl, 3- aminopropyl, 4-aminobutyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom(s) .
• Acylamino is acylamino having the above C 2 -C 14 acyl, and represents, for example, acetylamino, propionyla ino, butyrylamino, valerylamino, pivaloylamino, benzoylamino, phenylacetyla ino, phenylpropionylamino, phenylbutyrylamino and the like.
• Alkoxy is alkoxy having the above C ⁇ -C 8 alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy (i.e., amyloxy) , hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert- butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy and the like, with a preference for alkoxy having 1 to 4 carbon atom(s) .
• Cycloalkoxy is cycloalkoxy having the above C ⁇ C 8 cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms .
• Phenoxy means phenyloxy optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenylalkoxy is phenylalkoxy having the above C ⁇ -C 8 alkoxy, and includes, for example, benzyloxy, 1- phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4- phenylbutoxy, 1-methyl-l-phenylethoxy, l-methyl-2- phenylethoxy, 1-phenylpropoxy, 2-pheylpropoxy, 1-methyl-l- phenylpropoxy, l-methyl-2-phenylpropoxy, l-methyl-3- phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s) .
• the phenylalkoxy optionally has 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• aminoalkoxy is aminoalkoxy consisting of the above amino and C ⁇ -C 8 alkoxy, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- (dimethylamino) ethoxy, 3- (dimethylamino)propoxy, 4- (dimethylamino) butoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s) , and alkoxy having 1 to 4 carbon atom(s) .
• Alkoxyalkyl is alkoxyalkyl consisting of the above Ci-Cs alkoxy and C ⁇ -C 8 alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
• Phenoxyalkyl is phenoxyalkyl consisting of the above phenoxy and C ⁇ -C 8 alkyl, and includes, for example, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
• the phenoxyalkyl optionally has 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Hydroalkyl is hydroxyalkyl having the above C ⁇ -C 8 alkyl, and includes, for example, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and the like, with a preference for hydroxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
• Alkoxycarbonyl is alkoxycarbonyl having the above C ⁇ -C 8 alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert- pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s) .
• the alkoxycarbonyl of R 4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms.
• "Phenoxycarbonyl” is phenoxycarbonyl optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Aminocarbonyl is aminocarbonyl having the above amino including mono- or di-C ⁇ -C 8 alkyl-substituted amino, and includes, for example, aminocarbonyl (i.e., carbamoyi), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propyla inocarbonyl, dipropylaminocarbonyl and the like.
• aminocarbonyl i.e., carbamoyi
• methylaminocarbonyl dimethylaminocarbonyl
• ethylaminocarbonyl ethylaminocarbonyl
• diethylaminocarbonyl diethylaminocarbonyl
• propyla inocarbonyl dipropylaminocarbonyl and the like.
• Alkylthiocarbonyl is alkylthiocarbonyl having the above C ⁇ -C 6 alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec- butylthiocarbonyl, tert-butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms.
• Carboxyalkyl is carboxyalkyl having the above C ⁇ -C 8 alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
• Cycloalkoxyalkyl is cycloalkoxyalkyl consisting of the above C 3 -C 8 cycloalkoxy and C ⁇ --C 8 alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxy ethyl, cyclopentyloxymethyl, cyclohexyloxymethyl and the like, with a preference for cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s) .
• the cycloalkoxyalkyl optionally has 1 to 3 substituent (s) on the cycloalkyl and substitution sites are not particularly limited.
• Alkylsulfinyl is alkylsulfinyl having the above Ci- C 8 alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 5 carbon atom(s) .
• the alkylsulfinyl of R 4 is preferably alkylsulfinyl having 1 to 4 carbon atoms.
• Phenylsulfinyl means phenylsulfinyl optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Alkylsulfonyl is alkylsulfonyl having the above C ⁇ C 8 alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 5 carbon atom(s) .
• the alkylsulfonyl of R 4 is preferably alkylsulfonyl having 1 to 4 carbon atoms.
• Phenylsulfonyl means phenylsulfonyl optionally having 1 to 5 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Mercaptoalkyl is mercaptoalkyl having the above C ⁇
• C 8 alkyl includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).
• Alkylthioalkyl is alkylthioalkyl consisting of the above C ⁇ -C 3 alkylthio and C ⁇ -C 8 alkyl, and includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
• Aryl is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1- anthryl, 2-anthryl and the like. They may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
• “Aralkyl” is aralkyl wherein the above C ⁇ -C 8 alkyl is substituted by the above C 6 -C 14 aryl, and includes benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent (s) on the aryl moiety and substitution sites are not particularly limited.
• Acyloxyacetyl is acyloxyacetyl having the above C 2 - C 14 acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyacetyl and the like.
• Acyloxyalkyl is acyloxyalkyl having the above C 2 -C ⁇ 4 acyl and C ⁇ -C 8 alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2- butyryloxyethyl, 2-benzoyloxyethyl and the like.
• substituent of the "phenyl optionally having substituent (s) " is exemplified by those mentioned for the "substituent” below, wherein the number of the substituent is generally 1 to 5, preferably 1 to 3. Phenyl having 1 or 2 substituent (s) is particularly preferable and substitution sites are not particularly limited.
• Aromatic heterocyclic group is, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophenyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, ,isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxadiazolyl (e.g., 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, etc.), and the like.
• the aromatic heterocyclic group may have 1 to 6 substituent (s) and substitution sites are not particularly limited.
• R 9 is each independently hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, a inoalkyl, phenylalkyl, alkoxyalkyl, phenoxyalkyl, guanyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkoxycarbonyl, phenoxycarbonyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , or phenylalkyl optionally having substituent (s) .
• R 10 is alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenylalkyl, phenoxyalkyl, amino, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, aryl optionally having substituent (s) , aromatic heterocyclic group optionally having substituent (s) , or phenylalkyl optionally having substituent (s) , and R 10 ' is hydrogen, alkyl, acyl, aralkyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl,
• Phenylalkyl is phenylalkyl consisting of phenyl and the above Cx-Cs alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 1- methyl-1-phenylpropyl, l-methyl-2-phenylpropyl, l-methyl-3- phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s) .
• phenylalkyl optionally having substituent (s) are the same as those for the above-mentioned “aromatic heterocyclic group” and substitution sites are not particularly limited.
• Dialkylphosphinyl is dialkylphosphinyl having the above C ⁇ -C 8 alkyl, and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).
• Dialkylphosphonyl is dialkylphosphonyl having the above Q L -C 8 alkyl, and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
• substituted includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic group, phenylalkyl, hydroxy, carboxy, thiol, halogen, amino, formyl, carbamoyi, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like.
• Ring optionally containing heteroatom (s) is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, with particular preference given to a ring containing sulfur atom.
• the ring may be substituted by one or more of the above substituents or oxo groups.
• the substitution site is not particularly limited.
• This ring is formed by R 2 and R3 in the formula (I) together with the attached carbon atom. By forming this ring, a spiro ring is formed in the compound of the formula (I) .
• the above ring can be fused with a benzene ring optionally having substituent (s) and substitution sites are not particularly limited.
• Such a ring includes, for example, 2, 3-dihydrobenzo [b] thiophene, 2, 3-dihydrobenzo [jb] thiophen-1-oxide and the like.
• a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring' represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthalene, indan and the like. Of these, naphthyl such as naphthalen-1-yl and the like, and indanyl such as indan-4-yl and the like are preferable.
• the group may have 1 to 4 substituent (s) and substitution sites are not particularly limited.
• a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom (s) includes the following groups and the like.
• 2, 1, 3-benzoxadiazole, dihydrobenzo [b] furan, methylenedioxyphenyl and 3, 4-dihydro-2H-benzopyrane are preferable, and 2, 1, 3-benzoxadiazol-4-yl, 2, 3-dihydrobenzo- [j] furan-7-yl, 2, 3- (methylenedioxy) phenyl and 3,4-dihydro- 2H-benzopyran-8-yl are particularly preferable.
• the group may have 1 to 3 substituent (s) and substitution sites are not particularly limited.
• a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroato (s) , which is fused with a benzene ring includes the following groups and the like.
• the group may have 1 to 5 substituent (s) and substitution sites are not particularly limited.
• Alkylcarbonylalkyl is, for example, C1-C4 alkyl- carbonyl-C ⁇ -C alkyl, and includes, for example, methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, butylcarbonylmethyl and the like.
• Arylaminocarbonyl is C 6 -C ⁇ o aryl-aminocarbonyl, and includes, for example, phenylaminocarbonyl, naphthylaminocarbonyl and the like.
• the arylaminocarbonyl optionally has 1 to 3 substituent (s) on the aryl and substitution sites are not particularly limited.
• Alkylaminocarbonyl is C-C ⁇ 4 aralkyl-aminocarbonyl, and includes, for example, benzylaminocarbonyl and the like.
• the aralkylaminocarbonyl optionally has 1 to 3 substituent (s) on the aryl and substitution sites are not particularly limited.
• Alkyl substituted by a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s), which optionally has a substituent means C ⁇ C 8 alkyl substituted by "a saturated or unsaturated 4 to 7 membered ring containing 1 or 2 nitrogen atom(s)", such as pyrrole, pyrroline, pyrazole, pyridine, piperidine, piperazine, homopiperadine or morpholine and the like, which optionally has a substituent such as C 1 -C4 alkyl, C6-C 10 aryl such as phenyl, naphthyl and the like, and includes, for example, (4-phenylpiperazin-l-yl) methyl, 2- (4-phenylpiperazin-l- yl) ethyl, 3- (4-phenylpiperazin-l-yl) propyl, (4- (naphthalen-1-yl) piperazin-1-yl) methyl, 2-
• Phenyla inoalkyl is phenylamino-C ⁇ -C alkyl, and includes, for example, phenylaminomethyl, 2- phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl and the like.
• the phenylaminoalkyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenylalkylcarbonyl is phenyl-C ⁇ -C 4 alkyl-carbonyl, and includes, for example, benzylcarbonyl, 2- phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4- phenylbutylcarbonyl and the like.
• the phenylalkylcarbonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• “Alkyl” in the R 11 is C 1 -C4 alkyl, and includes, for examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
• Alkylsulfonyl in the R u is C 1 -C 4 alkyl-sulfonyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.
• Phenylsulfonyl in the R 11 is phenylsulfonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenylalkylsulfonyl in the R 11 is phenyl-C ⁇ -C 4 alkyl- sulfonyl, and includes, for example, benzylsulfonyl, 2- phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4- phenylbutylsulfonyl and the like.
• the phenylalkylsulfonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Alkylsulfinyl in the R 11 is C 1 -C 4 alkyl-sulfinyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.
• Phenylsulfinyl in the R 11 is phenylsulfinyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenylalkylsulfinyl in the R u is phenyl-C ⁇ -C4 alkyl- sulfinyl, and includes, for example, benzylsulfinyl, 2- phenylethylsulfinyl, 3-phenylpropylsulfinyl, 4- phenylbutylsulfinyl and the like.
• the phenylalkylsulfinyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Alkoxycarbonyl in the R 11 is C ⁇ -C alkoxy-carbonyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
• Phenylalkoxycarbonyl in the R 11 is phenyl-C ⁇ -C4 alkoxy-carbonyl, and includes, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 3- phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl and the like.
• the phenylalkoxycarbonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Alkylcarbonyl in the R 11 is C 1 -C 4 alkyl-carbonyl and includes, for example, acetyl, propionyl, butylcarbonyl and the like.
• Phenylcarbonyl in the R 11 is phenylcarbonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenylalkylcarbonyl in the R 11 is phenyl-C ⁇ -C4 alkylcarbonyl, and includes, for example, benzylcarbonyl, 2- phenylethylcarbonyl, 3-phenylpropylcarbonyl, 4- phenylbutylcarbonyl and the like.
• the phenylalkylcarbonyl optionally has 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Phenoxycarbonyl in the R 11 means phenoxycarbonyl optionally having 1 to 3 substituent (s) on the phenyl and substitution sites are not particularly limited.
• Alkyl in the R 12 is C 1 -C 4 alkyl, and includes, for examples, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl and the like.
• the compounds represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention.
• acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like.
• R 2 , R 3 , R 4 and R 5 are as defined above.
• Me1drum' s acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII) in the presence of ammonium acetate to give an amide derivative of the formula (IX) .
• the reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction.
• a carboxylic acid solvent inert to the reaction.
• the solvent formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• R 2 , R 3 , R 4 and R 5 are as defined above.
• the obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X) ,
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 0°C to 60°C.
• the compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• the carbonyl derivative of the formula (VII) which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983) .
• the carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993) .
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
• the compounds (I) of the present invention can be produced by reacting a inopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII) .
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and X represents halogen, provided that R° is not hydrogen.
• the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base.
• a base includes, for example, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine and the like.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like.
• the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
• the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) such as acetic anhydride in the presence of a base.
• a base includes, for example, triethyla ine, pyridine, 4-dimethylaminopyridine and the like.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like.
• the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
• the compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography and the like.
• a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column packed with optically active carrier.
• the present invention also encompasses optically active compounds.
• the compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3 ⁇ such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3 ⁇ .
• the compounds of the present invention have a GSK-3 ⁇ -selective inhibitory activity and can be medicaments with small side-effect for diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer' s encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington' s disease, manic- depressive psychosis and the like) , alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.
• the compounds of the present invention are useful as immunopotentiators .
• Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation.
• the carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch such as corn starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and other conventionally used substances.
• Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration by injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like. While the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1 - 1,000 mg, preferably 50 - 200 mg per day for an adult person, which is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day. Examples
• Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples.
• Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples.
• the title compound was prepared from ethyl nipecotate,
• the title compound was prepared from ethyl morpholine-2- carboxylate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3-amino- pyrazole in the same manner as in Example 1.
• the title compound was prepared from benzoylchloride, ethyl isonipecotate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 25. MP:228°C. MS (FAB) :452 (M + +l) .
• the title compound was prepared from acetyl chloride, ethyl 1, 2, 3, 6-tetrahydropyridine-4-carboxylate, 2,1,3- benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
• the title compound was prepared from methanesulfonyl- chloride, ethyl isonipecotate, 2, 1, 3-benzoxadiazole-4- aldehyde and 3-aminopyrazole in the same manner as in Example 25. MP:243°C. MS (El) :425(M + ) .
• the title compound was prepared from 1-chloro-N, N- dimethylformamide, ethyl isonipecotate, 2, 1, 3-benzoxa- diazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 25.
• the title compound was prepared from acetyl chloride, ethyl nipecotate, 2, 1, 3-benzoxadiazole-4-aldehyde and 3- a inopyrazole in the same manner as in Example 25. MP:219°C.
• the title compound was prepared from ethyl nipecotate,
• the title compound was prepared from methanesulfonyl chloride, ethyl isonipecotate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 25. MP:>280°C. MS (El) :487 (M + ) .
• Example 62 4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (2- oxocyclohexan-1-yl) -2ff-pyrazolo [3, 4-b]pyridine
• the title compound was prepared from ethyl 2- cyclohexanonecarboxylate, 2-bromo-3-cyanobenzaldehyde and
• the title compound was prepared from ethyl acetoacetate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 58. MP:230°C.
• Example 70 4- (2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (pyrrolidin-2-yl) -2ff-pyrazolo [3, 4-b]pyridine
• the title compound was prepared from 4- (2,1,3- benzoxadiazol-4-yl) -6- (1-t-butoxycarbonylpyrrolidin-2-yl) -
• the title compound was prepared from ethyl 1-t-butoxy- carbonylpiperidine-4-carboxylate, 2, 3- (methylenedioxy) - benzaldehyde and 3-aminopyrazole in the same manner as in Example 1.
• the title compound was prepared from 2, 1, 3-benzoxa- diazole-4-aldehyde, 3-aminopyrazole and methyl 2,2- dimethoxypropionate in the same manner as in Example 1.
• methyl l-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2:1)) to give l-(l-tert- butoxycarbonylpyrrolidin-3-yl) -2-cyanoethan-l-one (2.35 g) as a colorless oil.
• the title compound was prepared from ethyl isonipecotate, 4-indancarboxaldehyde and 3-aminopyrazole in the same manner as in Example 1.
• the title compound was prepared from methanesulfonyl- chloride, ethyl pipecolinate, 2, 1, 3-benzoxadiazole-4- aldehyde and 3-aminopyrazole in the same manner as in Example 25.
• the title compound was prepared from 4- aminocyclohexanecarboxylic acid ethyl ester, 2-bromo-3- cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
• the title compound was prepared from ethyl nipecotate,
• the title compound was prepared from ethyl nipecotate,
• the title compound was prepared from ethyl nipecotate,
• the reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give colorless crystals (9.6 g) .
• An Ammonia solution (3.0 g) and GDI (2.8 g) were added to the obtained colorless crystals (4.2 g) in DMF (20 mL) , and the mixture was stirred overnight.
• the reaction mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oil.
• the residue in N,N- dimethylacetamide dimethyl acetal (30 mL) solution was heated for 2 hours, and the solvent was evaporated under reduced pressure.
• the title compound was prepared from 2, 2-dimethylglycine ethyl ester, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 15 and 2.
• Example 73 Example 74 Example 75
• Example 77 Example 78
• Example 81 Example 82 Example 83 Example 84
• Example 85 Example 86 Example 87 Example 88
• Example 89 Example 90
• Example 91 Example 91
• Example 93 Example 94 Example 95
• Example 96 Example 97
• Example 98
• Example 100 Example 101
• Example 102 Example 102
• Example 105 Example 106
• Example 107
• Example 108 Example 109 Example 110 Example 111
• Example 112 Example 113
• Example 114 Example 115
• Example 116 Example 117 Example 118 Example 119
• Example 120 Example 121 Example 122 Example 123
• Example 124 Example 125
• Example 126 Example 127
• Example 128 Example 129 Example 130
• Example 131 Example 131
• Example 132 Example 133
• Example 134 Example 135
• Example 136 Example 137
• Example 138 Example 139
• Example 140 Example 141
• Example 143 Example 143
• Example 144 Example 145
• Example 146 Example 147
• Example 152 Example 153
• Example 154 Example 155
• Example 156 Example 157
• Example 158 Example 159
• Example 2 The compound of Example 1 (0.5 part), lactose (25 parts) , crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded well with a binder made of corn starch (2 parts) . The kneaded product was passed through a 16 mesh sieve, dried in an oven at 50°C and passed through a 24 mesh sieve. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and compression-punched to give tablets containing 0.5 mg of the active ingredient per tablet.
• Formulation Example 2 Formulation Example 2
• Example 1 The compound of Example 1(1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection, and the solution was filtered to remove pyrogen. The filtrate was transferred into an ampoule under sterile conditions. After sterilization, the ampoule was weld-sealed to • give injection containing 1.0 mg of the active ingredient.
• glycogen synthase kinase-3 beta (GSK-3 ⁇ ) were evaluated and confirmed as follows.
• the compounds of the present invention showed the IC 5 o values of 1 to 1000 nmol/L.
• the IC50 values of the compounds are shown in the following Table 1.
• CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser- Arg-Arg-Pro-Ser ( P) -Tyr-Arg .
• Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid ⁇ (25-35) (20 ⁇ mol/L) and a test compound (GSK-3 ⁇ inhibitor) , and the culture was continued for 3 hours, whereby phosphorylation of Tau protein was induced. After the completion of culture, the level of phosphorylation of Tau protein was determined by EIA method using phosphorylated Tau-recognizing antibody
• Hippocampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippocampal neurons for 7 days, the neurons were treated with amyloid ⁇ (25-35) (20 ⁇ mol/L) and a test compound (GSK-3 ⁇ inhibitor) , and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined, and the effect of the GSK-3 ⁇ inhibitor on the amyloid ⁇ -induced cytotoxicity was evaluated.
• a test compound (GSK-3 ⁇ inhibitor) was intraperitoneally administered to gerbils, and 30 minutes later, brain ischemia was created by shutting off (for 4 minutes) all carotid arteries, whereby phosphorylation of Tau protein in the brain was induced.
• the hippocampus was obtained from the gerbil brain, and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3 ⁇ ) , based on which the GSK-3 ⁇ -inhibitory effect of the GSK-3 ⁇ inhibitor in the gerbil brain was evaluated.
• the compounds of the present invention show a selective and strong inhibitory action on glycogen synthase kinase-3 beta (GSK-3 ⁇ ) , and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications, neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington' s disease, manic-depressive psychosis and the like) , alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors, or as immunopotentiators,

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