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WO2001081345A1 - Composes d'amides aromatiques - Google Patents

Composes d'amides aromatiques Download PDF

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Publication number
WO2001081345A1
WO2001081345A1 PCT/JP2001/003329 JP0103329W WO0181345A1 WO 2001081345 A1 WO2001081345 A1 WO 2001081345A1 JP 0103329 W JP0103329 W JP 0103329W WO 0181345 A1 WO0181345 A1 WO 0181345A1
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Prior art keywords
pyridine
benzamide
pyrazo
mouth
pharmaceutically acceptable
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PCT/JP2001/003329
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English (en)
Japanese (ja)
Inventor
Kenji Fukunaga
Hirotaka Okabe
Toshiyuki Kohara
Masatake Fujimura
Hiroshi Tanaka
Shinichi Takanashi
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Mitsubishi Pharma Corporation
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Application filed by Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Priority to AU48786/01A priority Critical patent/AU4878601A/en
Publication of WO2001081345A1 publication Critical patent/WO2001081345A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel pharmaceutical compound having glycogencin inhibitory activity (GSK-3?) Inhibitory activity.
  • Glycogen synthase kinase (GSK-3?), A protein kinase, has been reported to be involved in the causes of various diseases as follows.
  • Type 2 diabetes is a disease in which the insulin responsiveness of Teng / 5 cells is decreased, and the darcos in the blood is increased. As a result, it induces complications such as diabetic nephropathy, retinopathy, and heart disease.
  • GSK-3 works by phosphorylating glycogen synthase to inhibit glycogen accumulation in peripheral tissues, decrease insulin responsiveness, and increase blood glucose. In fact, lithium, which has GSK-3 ⁇ inhibitory action, lowers blood glucose by GSK-3 ⁇ inhibitory action (Proceding of National Academy of Sciences “Ob. Science. United 'Steve of America' (Pro Nat. Acad. Sci.) Vol. 93, p. 8455 (1996)). Therefore, drugs with GSK-3? Inhibitory activity are considered to be effective drugs for improving type 2 diabetes and its complications.
  • amyloid aggregation and neurofibrillary tangles are thought to be closely related to the cause.
  • GSK-3? Is involved in both amyloid aggregation and neurofibrillary tangles as follows. (1) Binds to mutant presenilin to increase insoluble amyloid production (Procedures of National, Academy of Sciences, Science, Science, Science, The United Sciences, Science 'America (Proc. Nat. Acad. Sci.), Vol. 95, No. 9637 (1998)).
  • Tat a protein produced by the HIV virus that causes AIDS, increases GSK-3 ⁇ activity in neurons and causes neuronal death (J. Neurochem.), Vol. 73, p. 578 (1999)).
  • GSK-3y5 inhibitors are considered to be effective drugs for improving neurodegenerative diseases such as Alzheimer's type 1 dementia.
  • Lithium and valproic acid which have an anti-manic depressant effect, have a GSK-3 ⁇ inhibitory effect (J. Neurochem., Vol. 72, p. 1327 (1989)). ).
  • GSK-3 ⁇ inhibitory effect J. Neurochem., Vol. 72, p. 1327 (1989)).
  • the relationship between anti-manic depression and GSK-3? Inhibitory effect is not clear, but the inhibitory effect on glutamate toxicity (Proceeding of the National Academy of Sciences of Ob-The United States) Of America (Pro Nat. Acad. Sci.), Vol. 95, No. 2642
  • NF-AT a transcription factor
  • GSK-3 ⁇ acts to suppress immune function by phosphorylating NF-AT.
  • GSK-35 inhibitors can be used for immunostimulation. It is thought to be an effective drug.
  • WO 95/28387 describes penzamide compounds useful as preventive and therapeutic agents for cardiovascular diseases such as therapeutic agents for smooth muscle relaxation, therapeutic agents for hypertension, and therapeutic agents for angina pectoris. There is no suggestion for an effect on? Or on the central nervous system.
  • An object of the present invention is to provide a novel compound having a selective and strong inhibitory action on glycogen synthase kinase-3 (yet) (GSK-3 ⁇ ), and further provide a medicament containing these compounds. It is to be.
  • the present inventors have conducted intensive studies to achieve the above object, and found that the novel aromatic amide compound has a selective and potent inhibitory activity on GSK-3 / 3.
  • the present invention has been completed. That is, the present invention provides an aromatic amide compound represented by the following general formula (I), which has GSK-3 / 5 inhibitory activity and can be used as a medicament, a pharmaceutically acceptable salt thereof, or a hydration thereof. And a drug containing the compound as an active ingredient.
  • ⁇ ⁇ ⁇ 2 is the same or different and represents CH or ⁇ , respectively. I also represents hydrogen or alkyl.
  • Ar is selected from naphthyl which may have a substituent, or a group represented by the following formulas (11), (II 1), (IV), (V), (VI) and (VI I) Represents a group.
  • X represents C—R 1 or N.
  • Y represents CH 2 , N—R 7 , 0 or S.
  • RR 2 , R 3 , RR 5 , and R 6 may be the same or different.
  • R 7 represents hydrogen, alkyl or phenylalkyl
  • R 8 and R 9 may be the same or different and represent hydrogen, alkyl or oxo, respectively. Represents 1 or 2 carbon atoms.
  • Ar is a group represented by the formula (II), (111), (IV), (V) or (VI), An amide compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • Ar is naphthyl which may have a substituent or a group represented by the formula (VI I), wherein the aromatic amide compound according to the above (1), Pharmaceutically acceptable salts or hydrates thereof.
  • R 2 ⁇ R 3 , R 4 , R 5 , R 6 are the same or different and are each hydrogen, alkyl, alkoxy, alkylthio, halogen, haloalkyl or nitro
  • a medicament comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a GSK-33 inhibitor comprising the aromatic amide compound according to any one of (1) to (8) above, a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a therapeutic agent for diabetes comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  • a treatment for complications of diabetes comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. medicine.
  • a treatment for Alzheimer's dementia comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. medicine.
  • a therapeutic agent for a neurodegenerative disease comprising, as an active ingredient, the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a prophylactic / therapeutic agent for manic depression comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  • An immunostimulant comprising the aromatic amide compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient,
  • the compound represented by I) (hereinafter, also referred to as compound (I) of the present invention) will be described in detail below.
  • alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl ( Amyl), hexyl, or their structural isomers such as isopropyl, isobutyl, secondary butyl, tertiary butyl, 1,1-dimethylethyl, isopentyl, neopentyl, tertiary pentyl, and the like. Or alkyl having 1 to 4 carbon atoms.
  • Alkoxy is a straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy (amyloxy), hexyloxy, or a structural isomer thereof. Isobutoxy, isobutoxy, secondary butoxy, tertiary butoxy, isopentyloxy, neopentyloxy, tertiary pentyloxy, etc., preferably having 1 to 4 carbon atoms. Alkoxy.
  • Phenylalkoxy has the same meaning as the above-mentioned alkoxy, and examples thereof include benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy and 1-methyl- 1-phenylethoxy, 1-methyl-2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 1-methyl-1-phenylpropoxy, 1-methyl-2-phenylpropoxy, 1-methyl-3-phenyl And an alkoxy moiety having 1 to 4 carbon atoms.
  • Alkylthio refers to straight-chain or branched alkylthio having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio (amylthio), hexylthio, or structural isomers thereof. Certain isopropylthio, isopropylthio, secondary butylthio, tertiary butylthio, isopentylthio, neopentylthio, tertiary pentylthio and the like are preferable, and alkylthio having 1 to 3 carbon atoms is preferable.
  • Alkylamino is a secondary or tertiary amino in which the alkyl part has the same meaning as the above-mentioned alkyl and the alkyl part is substituted by one or two. Examples thereof include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, Examples thereof include propylamino, butylamino, dibutylamino and the like, and the preferred alkyl moiety has 1 to 4 carbon atoms.
  • Acylamino includes, for example, alkenylcarbonylamino having 2 to 6 carbon atoms, such as acetylamino, propionylamino, butyrylamino, valerylamino, and vivaloylamino; arylcarbonylamino such as benzoylamino; phenylacetylamino, phenyl. And aralkylcarbonylamino (alkyl has 1 to 4 carbon atoms) such as propionylamino and phenylbutyrylamino.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • Haloalkyl is the above-mentioned alkyl substituted with 1 to 5 halogens, for example, trifluoromethyl, 2,2,2-trifluoroethyl, 2, 2 3, 3, 3 — Penn fluoropentyl and the like.
  • Phenylalkyl has the same meaning as the above-mentioned alkyl in the alkyl part. Examples thereof include methylphenyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, 1-methyl-2-phenylethyl, Examples include 1-phenylpropyl, 2-phenylpropyl, 1-methyl-1-phenylpropyl, 1-methyl-2-phenylpropyl, 1-methyl-3-phenylpropyl, and the like. There are four.
  • Cycloalkoxy refers to cycloalkoxy having 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc. And preferably a cycloalkoxy having 5 to 6 carbon atoms.
  • aminoalkoxy has the same meaning as the above-mentioned alkoxy, and examples thereof include aminomethoxy, aminoethoxy, aminopropyloxy, aminopropyloxy, and aminobutyloxy. One to four.
  • Alkylaminoalkoxy means that the alkoxy part has the same meaning as the above-mentioned alkoxy, and the alkyl part has the same meaning as the above-mentioned alkyl, and the alkyl part has been substituted by one or two aminos.
  • Toxic acid dimethylaminomethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy and the like are preferred.
  • the preferred number of carbon atoms in the alkoxy moiety is 1 to 4, and the preferred carbon number in the alkyl moiety is The number is one to four.
  • Alkoxycarbonyl has the same meaning as the above-mentioned alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxypropyl, isopropoxycarbonyl, butoxycarbonyl, secondary butoxycarbonyl, and tertiary butoxycarbonyl. Butoxycarbonyl, etc., preferably alkoxycarbonyl having 2 to 5 carbon atoms.
  • substituents of "naphthyl which may have a substituent” halogen, Alkyl, alkoxy, hydroxy, alkylthio, amino, carboxy, nitro, cyano, trifluoromethyl, etc., and the number of substituents thereof is 1 to 7.c
  • phenyl, phenoxy, and phenyl Enylalkoxy "and
  • phenylalkyl may have a substituent such as halogen, alkyl, alkoxy, hydroxy, alkylthio, amino, carboxy, nitro, cyano, trifluoromethyl, etc., and the number of substituents is 1 to 5 Individual.
  • the compound (I) of the present invention can be used as an addition salt with a pharmaceutically acceptable acid, and such an acid addition salt is also included in the scope of the present invention.
  • acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, Salts with organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and glutamic acid.
  • the compound (I) of the present invention can form a solvate with hydrate, ethanol and the like, and a polymorph, and these are all included in the scope of the present invention.
  • an asymmetric carbon is present, an optically active substance, a racemic form thereof, and the like may be present, all of which are included in the scope of the present invention.
  • sigma 2 is: ⁇ a, where R is hydrogen, although there are tautomers as shown below, are encompassed this tautomers Te to base this onset light range.
  • the compound (I) of the present invention has the following structural formula
  • Ar is a group represented by the formula (II), (111), (IV :), (V) or (VI).
  • Ar is an optionally substituted naphthyl or a group represented by the formula (VI I).
  • the compound (I) of the present invention can be produced by the following method.
  • the compound (I) of the present invention is produced by reacting an aromatic amine represented by the general formula (VI II) with an aromatic carboxylic acid represented by the general formula (IX) in the presence of a condensing agent.
  • a condensing agent include, for example, dicyclohexylcarpoimide (DCC), diisopropylcarpoimide (DIPC), N-ethyl-N, 13-dimethylaminopropylcarpoimide (WSCI) and the like.
  • Hydrochloride benzotriazo-1-yl 1-yllute tris (dimethylamino) phosphoniumhexafluorophosphoride (B0P), diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI), getylphosphonyl cyanide (DPC), etc.
  • B0P diphenylphosphorylazide
  • CDI carbonyldiimidazole
  • DPC getylphosphonyl cyanide
  • the reaction is carried out in the presence of a solvent inert to the reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, and dimethylimidazolidinone are used. Solvent not used is used.
  • the reaction is carried out at any temperature, for example -10 to 200 ° C; preferably 0 to 100 ° C.
  • the compound (I) of the present invention comprises an aromatic amine represented by the general formula (VI II)
  • the aromatic carboxylic acid halide represented by (X) can be produced by reacting in the presence of a base.
  • bases include, for example, triethylamine, diisopropylethylamine and the like.
  • the reaction is performed in the presence of a solvent inert to this reaction, but usually does not contain hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, and dimethylimidazolidinone.
  • a solvent is used.
  • the reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to;
  • B is an active ester. 4-12-Trophenyl ester (ONp), N-hydroxysuccinimide ester (ONSu), pen
  • the compound (I) of the present invention comprises an aromatic amine represented by the general formula (VI II) and an aromatic amine represented by the general formula (VI II). It can be produced by reacting an aromatic carboxylic acid active ester represented by (XI).
  • the reaction is carried out in the presence of a solvent inert to this reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethan, dimethylformamide, and dimethylimidazolidinone are used. A solvent containing no is used.
  • the reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to 10 ° C.
  • D represents an active acyl, such as isobutyloxycarbonyl, getylacetyl, and trimethylacetyl.
  • the compound (I) of the present invention can be produced by reacting an aromatic amine represented by the general formula (VIII) with an aromatic carboxylic acid mixed anhydride represented by the general formula (XII).
  • the reaction is carried out in the presence of a solvent inert to this reaction, but usually, hydroxyl groups such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethan, dimethylformamide, and dimethylimidazolidinone are used.
  • a solvent containing no is used.
  • the reaction is carried out at any temperature, for example -10 to 200 ° C, preferably 0 to 10 ° C.
  • the compound (I) of the present invention thus produced is isolated or purified as it is or as a salt thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. When the purified product obtained is a racemic form, it is separated into a desired optically active substance, for example, by fractional recrystallization with an optically active acid or by passing through a column packed with an optically active carrier. can do.
  • the present invention also includes an optically active substance.
  • the compound (I) of the present invention is a compound showing a selective and potent inhibitory effect on glycogen synthase kinase-3 (GSK-3j3), and is useful for diabetes, complications of diabetes, and Alzheimer's disease. It is useful as a prophylactic / therapeutic agent for type dementia, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, cerebral ischemia), manic depression, etc., or a drug such as an immunostimulant.
  • GSK-3j3 glycogen synthase kinase-3
  • Formulations containing the compound (I) of the present invention, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient are prepared using carriers, excipients and other additives usually used in the formulation. Is done.
  • the carrier or excipient for the preparation may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter , Ethylene glycol and the like and other commonly used ones.
  • Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., oral administration, injections such as intravenous injections, intramuscular injections, suppositories, transdermals, etc. You may.
  • the dose is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, etc. of the administration subject. Usually, the dose is 1 to L / 00 Omg, preferably 50 to 100 mg / day for each adult. ⁇ 20 Omg Is orally administered once or several times daily in the range of 1 to 5 mg / day, or once to several times daily in adults in the range of 1 to 50 mg / day Or, it is administered intravenously continuously for 1 hour to 24 hours a day.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, pudose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, metasilicic acid and magnesium aluminate.
  • the composition may be prepared in a conventional manner using additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glucose, and stabilizing agents such as lactose.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as , Including purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.
  • Example 18 To a solution of 2-amino-1-N- (1H-pyrazo [3,4-b] pyridin-141-yl) benzamide (0.96 g) obtained in Example 8 in THF (5 OmL) was added. , Triethylamine (1.15 g) and acetyl chloride (0.9 g) were added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the mixture was filtered and the solvent was distilled off under reduced pressure to obtain a residue. After addition of methanol (10 OmL), the mixture was heated under reflux for 1 hour.
  • Example 6 Black mouth 3.4—Dihydro N— N.
  • H Pyrazo mouth “3.4—b Pyridine-1—4-yl) -2H—1.4—Ben, zo'oxazine-1 8—Carboxami ⁇ 1 / 4 f k Japanese
  • 6-Black mouth _4 (4-Black mouth benzyl) 1,3,4-Dihydro-1N— (1 H-pi Lazolo "3.4-b pyridine-1 4-yl) 1 2H-1.4-benzoxazine--8-carboxamide '1 / 27k
  • Example 1 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were thoroughly mixed, and then kneaded well with a binder made with 2 parts of corn starch. The kneaded mixture is sieved with 16 mesh, dried in an oven at 50 ° C, and sieved with 24 mesh. The kneaded powder obtained here was thoroughly mixed with 8 parts of corn starch, 11 parts of crystal cell mouth and 9 parts of talc, and then pressed to give tablets containing 0.5 mg of active ingredient per tablet. Obtained.
  • the compounds of the present invention exhibited an IC 50 value of 0. 1 ⁇ 100 mo 1 / L.
  • the CREB phosphopeptide is Lys-Arg-Arg-Glu-IleLeu-Ser-Arg-ArgProSer (P) -Tr-Arg.
  • Example 7 0.12
  • Example 10 1.3
  • Embryonic day 18 rat brain hippocampal neurons were collected and cultured for 7 days. Tau protein phosphorylation was induced by exposing cultured neurons to 5-amyloid (25-35) 20 ⁇ mo1 / L and a test compound (GSK13? Inhibitor) for 3 hours. . After completion of the culture, the phosphorylation level of tau protein was measured by EIA using an antibody recognizing phosphorylated tau protein (phosphorylation site by GSK-3?), And the GSK-3? The GSK-35 inhibitory effect was evaluated. As a result, the compound of Example 7 showed significant intracellular GSK- 3-showed inhibitory effect.
  • Test Example 3 Effect of amyloid on citrus dysfunction in citrus cells cultured on horses
  • Embryonic day 18 rat brain hippocampal neurons were collected and cultured for 7 days. Cultured nerve cells are exposed to amyloid (25-35) 2 Ojumo 1 / L and a test compound (GSK-3? Inhibitor), and cultured for 24 hours for neuropathy (extracellular LDH activity). Increased and decreased intracellular reductase activity). After completion of the culture, extracellular LDH activity and intracellular reductase activity were measured, and the effect of the GSK-3; 5 inhibitor on 5-amiloid-induced neuropathy was evaluated. As a result, the compound of Example 7 showed a significant inhibitory effect on ⁇ -amyloid-induced neuropathy at 1 mol / L. MM 4: 391! Harmful effects in gerbil H tfn model
  • the test compound (GSK-35 inhibitor) was intraperitoneally administered to gerbils, and 30 minutes later, the common carotid artery was subjected to ischemia for 4 minutes to induce phosphorylation of brain tau protein.
  • the hippocampus was collected 3 hours after cerebral ischemia, and the level of tau protein phosphorylation was measured by Western blotting using a phosphorylated tau protein-recognizing antibody (phosphorylated site by GSK-3 / 5).
  • a 3 — inhibitor on GSK-3 3 in gerbil brain.
  • the compound of Example 7 showed a significant intracerebral GSK-3 ⁇ inhibitory effect at 30 mg / kg when administered intraperitoneally 30 minutes before cerebral ischemia.
  • the compound of the present invention is a compound showing a selective and strong inhibitory action on glycogen synthase kinase-3 ⁇ yose (GSK-3 ⁇ ). Therefore, the compound of the present invention is a prophylactic or therapeutic drug for diabetes, complications of diabetes, Alzheimer's dementia, neurodegenerative diseases (AIDS encephalopathy, Huntington's disease, Parkinson's disease, cerebral ischemia), manic depression, etc. Useful as This application is based on a patent application No. 2000-111998 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

L'invention porte sur des composés d'amides aromatiques de formule générale (I) et leurs sels ou hydrates pharmacocompatibles. Dans ladite formule, Z1 et Z2 sont chacun CH ou N; R est H ou alkyle; et Ar est phényle, pyridyle, ou analogue, facultativement substitué. Lesdits composés, qui ont un effet inhibant fortement la glycogènesynthasekinase (GSK-3β), peuvent servir de médicaments préventifs ou curatifs du diabète et de ses complications, de la démence d'Alzheimer, des maladies neurodégénératives (telles que l'encéphalopathie du SIDA, la maladie d'Huntington, la maladie de Parkinson et l'ischémie cérébrale), de la psychose maniaco-dépressive ou analogues, ou comme immunopotentiateurs.
PCT/JP2001/003329 2000-04-20 2001-04-18 Composes d'amides aromatiques WO2001081345A1 (fr)

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AU48786/01A AU4878601A (en) 2000-04-20 2001-04-18 Aromatic amide compounds

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JP2000-119198 2000-04-20
JP2000119198 2000-04-20

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WO2001081345A1 true WO2001081345A1 (fr) 2001-11-01

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Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024694A1 (fr) * 2000-09-22 2002-03-28 Smithkline Beecham, P.L.C. Pyrazolopyridines et pyrazolopyridazines utilisees comme antidiabetiques
WO2002050073A1 (fr) * 2000-12-19 2002-06-27 Smithkline Beecham P.L.C. Pyrazolo[3,4-c]pyridine en tant qu'inhibiteurs de gsk-3
WO2002062795A3 (fr) * 2001-02-02 2003-05-30 Mitsubishi Pharma Corp Composes de dihydropyrazolopyridine et leur utilisation pharmaceutique
WO2003068773A1 (fr) * 2002-02-12 2003-08-21 Glaxo Group Limited Derives de pyrazolopyridine
WO2003080617A1 (fr) * 2002-03-27 2003-10-02 Glaxo Group Limited Derives pyrazolopyrimidines
WO2003080609A1 (fr) * 2002-03-27 2003-10-02 Glaxo Group Limited Derives pyrazolopyrimidines
WO2004014910A1 (fr) * 2002-08-07 2004-02-19 Mitsubishi Pharma Corporation Composes de dihydropyrazolopyridine
FR2856595A1 (fr) * 2003-06-27 2004-12-31 Exonhit Therapeutics Sa Methodes et compositions pour le traitement de deficits cognitifs.
US6977262B2 (en) 2001-02-02 2005-12-20 Mitsubishi Pharma Corporation Dihydropyrazolopyridine compounds and pharmaceutical use thereof
WO2006127587A1 (fr) * 2005-05-20 2006-11-30 Vertex Pharmaceuticals Incorporated Pyrrolopyridines utiles en tant qu'inhibiteurs de proteines kinases
JP2007516997A (ja) * 2003-12-24 2007-06-28 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤として活性のあるピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬品
JP2007534653A (ja) * 2003-12-24 2007-11-29 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
WO2007138408A1 (fr) 2006-05-25 2007-12-06 Ge Healthcare Limited Inhibiteurs marqués 11c/18 f de la glycogène synthase kinase-3
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
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WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
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US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
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US8722693B2 (en) 2007-06-13 2014-05-13 Incyte Corporation Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
WO2014114779A1 (fr) * 2013-01-28 2014-07-31 H. Lundbeck A/S Acides phtalamiques n-substitués-5-substitués utilisés en tant qu'inhibiteurs de la sortiline
US8933085B2 (en) 2010-11-19 2015-01-13 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
US8933086B2 (en) 2005-12-13 2015-01-13 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-B]pyridines and pyrrolo[2,3-B]pyrimidines as Janus kinase inhibitors
US8987443B2 (en) 2013-03-06 2015-03-24 Incyte Corporation Processes and intermediates for making a JAK inhibitor
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US9334274B2 (en) 2009-05-22 2016-05-10 Incyte Holdings Corporation N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
US9359358B2 (en) 2011-08-18 2016-06-07 Incyte Holdings Corporation Cyclohexyl azetidine derivatives as JAK inhibitors
US9358229B2 (en) 2011-08-10 2016-06-07 Novartis Pharma Ag JAK PI3K/mTOR combination therapy
US9464088B2 (en) 2010-03-10 2016-10-11 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US9487521B2 (en) 2011-09-07 2016-11-08 Incyte Holdings Corporation Processes and intermediates for making a JAK inhibitor
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US9862707B2 (en) * 2014-03-26 2018-01-09 Merck Sharp & Dohme Corp. TrkA kinase inhibitors, compositions and methods thereof
US9993480B2 (en) 2011-02-18 2018-06-12 Novartis Pharma Ag mTOR/JAK inhibitor combination therapy
US10166191B2 (en) 2012-11-15 2019-01-01 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10758543B2 (en) 2010-05-21 2020-09-01 Incyte Corporation Topical formulation for a JAK inhibitor
US10899736B2 (en) 2018-01-30 2021-01-26 Incyte Corporation Processes and intermediates for making a JAK inhibitor
JP2021525752A (ja) * 2018-05-31 2021-09-27 シー・アンド・シー・リサーチ・ラボラトリーズＣ＆Ｃ Ｒｅｓｅａｒｃｈ Ｌａｂｏｒａｔｏｒｉｅｓ 複素環誘導体及びその使用
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
CN114667282A (zh) * 2019-10-22 2022-06-24 昊运股份有限公司 嘧啶酰胺化合物及治疗癌症的方法
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048523A2 (fr) * 1998-03-26 1999-09-30 Glaxo Group Limited Antagonistes de mediateurs inflammatoires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999048523A2 (fr) * 1998-03-26 1999-09-30 Glaxo Group Limited Antagonistes de mediateurs inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EL HENDI JELLALI M. ET AL.: "Sur l'acylation et l'alkylation de l'amino-4 pyrazolo (3,4-d) pyrimidine", TETRAHEDRON, vol. 31, no. 6, 1975, pages 587 - 591, XP002943433 *

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US7297792B2 (en) 2000-09-22 2007-11-20 Smithkline Beecham Corporation Pyrazolopyridines and pyrazolopyridazines as antidiabetics
WO2002024694A1 (fr) * 2000-09-22 2002-03-28 Smithkline Beecham, P.L.C. Pyrazolopyridines et pyrazolopyridazines utilisees comme antidiabetiques
US7109199B2 (en) 2000-09-22 2006-09-19 Smithkline Beecham Corporation Pyrazolopyridines and pyrazolopyridazines as antidiabetics
WO2002050073A1 (fr) * 2000-12-19 2002-06-27 Smithkline Beecham P.L.C. Pyrazolo[3,4-c]pyridine en tant qu'inhibiteurs de gsk-3
US7105532B2 (en) 2000-12-19 2006-09-12 Smithkline Beecham Corporation Pyrazolo[3,4-c]pyridines as gsk-3 inhibitors
US6977262B2 (en) 2001-02-02 2005-12-20 Mitsubishi Pharma Corporation Dihydropyrazolopyridine compounds and pharmaceutical use thereof
WO2002062795A3 (fr) * 2001-02-02 2003-05-30 Mitsubishi Pharma Corp Composes de dihydropyrazolopyridine et leur utilisation pharmaceutique
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WO2004014910A1 (fr) * 2002-08-07 2004-02-19 Mitsubishi Pharma Corporation Composes de dihydropyrazolopyridine
WO2005000302A1 (fr) * 2003-06-27 2005-01-06 Exonhit Therapeutics Sa Utilisation de pyrazolopyridines pour le traitement de deficits cognitifs
FR2856595A1 (fr) * 2003-06-27 2004-12-31 Exonhit Therapeutics Sa Methodes et compositions pour le traitement de deficits cognitifs.
AU2004251466B2 (en) * 2003-06-27 2010-01-07 Exonhit Therapeutics Sa Use of pyrazolopyridines for the treatment of cognitive deficits
JP2007520427A (ja) * 2003-06-27 2007-07-26 エグゾニ・テラピューティック・ソシエテ・アノニム 認知障害の処置のためのピラゾロピリジンの使用
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8080666B2 (en) 2003-07-22 2011-12-20 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
JP2007534653A (ja) * 2003-12-24 2007-11-29 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
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JP2012121891A (ja) * 2003-12-24 2012-06-28 Pfizer Italia Srl キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
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US8921376B2 (en) 2005-05-20 2014-12-30 Vertex Pharmaceuticals Incorporated Pyrrolopyridines useful as inhibitors of protein kinase
JP2008545660A (ja) * 2005-05-20 2008-12-18 バーテックス ファーマシューティカルズ インコーポレイテッド プロテインキナーゼ阻害剤として有用なピロロピリジン化合物
JP2009179644A (ja) * 2005-05-20 2009-08-13 Vertex Pharmaceut Inc プロテインキナーゼ阻害剤として有用なピロロピリジン化合物
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US8226927B2 (en) 2006-05-25 2012-07-24 Farhad Karimi 11C/18F-labeled inhibitors of glycogen synthase kinase-3
WO2007138408A1 (fr) 2006-05-25 2007-12-06 Ge Healthcare Limited Inhibiteurs marqués 11c/18 f de la glycogène synthase kinase-3
US9376439B2 (en) 2007-06-13 2016-06-28 Incyte Corporation Salts of the janus kinase inhibitor (R)-3(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
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US8933085B2 (en) 2010-11-19 2015-01-13 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
US10640506B2 (en) 2010-11-19 2020-05-05 Incyte Holdings Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors
US9034884B2 (en) 2010-11-19 2015-05-19 Incyte Corporation Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors
US9993480B2 (en) 2011-02-18 2018-06-12 Novartis Pharma Ag mTOR/JAK inhibitor combination therapy
US11214573B2 (en) 2011-06-20 2022-01-04 Incyte Holdings Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
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US9193733B2 (en) 2012-05-18 2015-11-24 Incyte Holdings Corporation Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
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US11896717B2 (en) 2012-11-15 2024-02-13 Incyte Holdings Corporation Sustained-release dosage forms of ruxolitinib
US11337927B2 (en) 2012-11-15 2022-05-24 Incyte Holdings Corporation Sustained-release dosage forms of ruxolitinib
US10166191B2 (en) 2012-11-15 2019-01-01 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US10874616B2 (en) 2012-11-15 2020-12-29 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US11576865B2 (en) 2012-11-15 2023-02-14 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US10195186B2 (en) 2013-01-28 2019-02-05 H. Lundbeck A/S N-substituted-5-substituted phthalamic acids as sortilin inhibitors
JP2016505063A (ja) * 2013-01-28 2016-02-18 ハー・ルンドベック・アクチエゼルスカベット ソルチリン阻害剤としてのｎ置換された５置換フタルアミド酸
WO2014114779A1 (fr) * 2013-01-28 2014-07-31 H. Lundbeck A/S Acides phtalamiques n-substitués-5-substitués utilisés en tant qu'inhibiteurs de la sortiline
US9682967B2 (en) 2013-01-28 2017-06-20 H. Lundbeck A/S N-substituted-5-substituted phthalamic acids as sortilin inhibitors
US9714233B2 (en) 2013-03-06 2017-07-25 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US8987443B2 (en) 2013-03-06 2015-03-24 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US9221845B2 (en) 2013-03-06 2015-12-29 Incyte Holdings Corporation Processes and intermediates for making a JAK inhibitor
US9655854B2 (en) 2013-08-07 2017-05-23 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US11045421B2 (en) 2013-08-07 2021-06-29 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US12151026B2 (en) 2013-08-07 2024-11-26 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US10561616B2 (en) 2013-08-07 2020-02-18 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US9862707B2 (en) * 2014-03-26 2018-01-09 Merck Sharp & Dohme Corp. TrkA kinase inhibitors, compositions and methods thereof
US9498467B2 (en) 2014-05-30 2016-11-22 Incyte Corporation Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US11278541B2 (en) 2017-12-08 2022-03-22 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10899736B2 (en) 2018-01-30 2021-01-26 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
US12280054B2 (en) 2018-03-30 2025-04-22 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
JP2021525752A (ja) * 2018-05-31 2021-09-27 シー・アンド・シー・リサーチ・ラボラトリーズＣ＆Ｃ Ｒｅｓｅａｒｃｈ Ｌａｂｏｒａｔｏｒｉｅｓ 複素環誘導体及びその使用
JP7558066B2 (ja) 2018-05-31 2024-09-30 シー・アンド・シー・リサーチ・ラボラトリーズ 複素環誘導体及びその使用
CN114667282A (zh) * 2019-10-22 2022-06-24 昊运股份有限公司 嘧啶酰胺化合物及治疗癌症的方法
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

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