WO2012150829A2 - Dérivé de triazolopyridine noble ou sels pharmaceutiquement acceptables de celui-ci, procédé de production de celui-ci, et composition pharmaceutique comprenant celui-ci - Google Patents

Dérivé de triazolopyridine noble ou sels pharmaceutiquement acceptables de celui-ci, procédé de production de celui-ci, et composition pharmaceutique comprenant celui-ci Download PDF

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WO2012150829A2
WO2012150829A2 PCT/KR2012/003487 KR2012003487W WO2012150829A2 WO 2012150829 A2 WO2012150829 A2 WO 2012150829A2 KR 2012003487 W KR2012003487 W KR 2012003487W WO 2012150829 A2 WO2012150829 A2 WO 2012150829A2
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triazolo
pyridin
hydrochloride
propylamino
compound represented
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WO2012150829A3 (fr
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구일회
박지선
천광우
류동규
최정훈
김영하
조보영
이한창
김강전
김승현
구세광
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제일약품주식회사
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Priority claimed from KR1020120046919A external-priority patent/KR101360176B1/ko
Publication of WO2012150829A2 publication Critical patent/WO2012150829A2/fr
Publication of WO2012150829A3 publication Critical patent/WO2012150829A3/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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

Definitions

  • the present invention relates to a novel triazolopyridine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition comprising the same.
  • Glycogen synthase kinase-3 (GSK-3) is a highly expressed serine / threonine protein kinase in the brain, each composed of ⁇ and ⁇ isoforms encoded by different genes (Non-Patent Document 1).
  • GSK-3 was originally identified as an enzyme that inhibits activation by directly phosphorylating glycogen synthase (gS) involved in glycogen production (Non-Patent Document 3).
  • Non-Patent Document 4-6 amyloid precursor protein (APP), translation initiation factor eIF-2B, ATP citrate lyase, Axin and insulin receptor substrate-1 (IRS-1) are metabolic and signaling proteins.
  • Microstructure-associated protein Tau belongs to the structural protein, ⁇ -catenin, activator protein-1 (AP-1), cyclic AMP reactive element binding protein (CREB), Nuclear factor (NFAT), heat shock factor-1 (HSF-1), c-Jun, c-Myc, and NF- ⁇ B of activated T-cells are included (Non Patent Literature 7). These various targets are associated with GSK-3 in the regulation of cell metabolism, proliferation, differentiation and survival.
  • Non-Patent Document 8 Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia due to lack of insulin action and can be classified into insulin-dependent type 1 diabetes and insulin-independent type 2 diabetes. Type 1 diabetes is caused by insulin deficiency due to the destruction of pancreatic ⁇ cells, and type 2 diabetes is caused by decreased insulin secretion and insulin resistance. Type 1 diabetes is generally associated with reduced or almost absent levels of insulin and is therefore treated by injection of an alternate dose of insulin.
  • GSK-3 phosphorylates the insulin receptor substrate-1 (IRS-1) serine residues, impairing insulin action, and attenuating intracellular insulin effects by inhibiting glycogen synthase activity (Non Patent Literature 9). Furthermore, there have been reports of overexpression of GSK-3 in muscles of type 2 diabetic patients (Non-Patent Document 10). Thus, GSK-3 inhibitors are useful for treating diabetes that increases insulin activity.
  • GSK-3 activity is also associated with Alzheimer's disease.
  • Alzheimer's disease is a degenerative brain disease and is a representative disease that causes dementia in the elderly. The disease is largely composed of the accumulation of ⁇ -amyloid peptide (A ⁇ ), an abnormal product of the amyloid precursor protein (APP), and the formation of paired helical filaments (PHFs), composed mostly of hyperphosphorylated tau protein. It features.
  • Tau is highly expressed in the central and peripheral nervous system, and is a protein that enhances the safety of microtubules, which is present in large amounts in axons of neurons, providing structural support for forming axons and dendrites. .
  • the tau isomer is formed from another mRNA junction in a single gene, and has a molecular weight ranging from 50 to 70 kDa.
  • Phosphorylation at abnormal positions of tau by GSK-3 has been shown to promote filaments (PHF) forming neurofibrillary tan gles (Non Patent Literature 11-15).
  • PPF neurofibrillary tan gles
  • Non-Patent Document 14 As further evidence, in transgenic mice specifically overexpressing GSK-3, a markedly increased tau hyperphosphorylation and an abnormal form of neurons were found (Non-Patent Document 14).
  • inhibition of GSK-3 can treat Alzheimer's disease by preventing hyperphosphorylation of tau to mitigate or control the formation of nerve fiber bundles.
  • Bipolar disorder is characterized by mania and depression.
  • Lithium which has been used as a therapeutic agent for this disease, has been found to be a GSK-3 inhibitor (Non Patent Literature 15-17).
  • Non Patent Literature 20 The effects of lithium have been reported to activate glycogen synthesis (Non Patent Literature 20), stabilization and accumulation of ⁇ -catenin (Non Patent Literature 21), and protection of neuronal cell death (Non Patent Literature 22).
  • Non-Patent Document 23 valprophosphate, a commonly used bipolar disorder treatment agent, has been found to be an effective GSK-3 inhibitor.
  • the mechanism by this GSK-3 inhibitor is to increase the survival of abnormally high levels of excited neurons induced by the neurotransmitter glutamate (Non-Patent Document 24).
  • GSK-3 inhibitors will be useful therapeutics in these and other neurodegenerative disorders.
  • GSK-3 is also associated with immune response activation. Contrary to the effect of calcineurin, which dephosphorylates the transcription factor NF-AT and promotes migration to the nucleus, activating the transcription of early immune response genes, GSK-3 phosphorylates NF-AT to promote its escape from the nucleus. The activation of immune response genes by NF-AT is initially blocked (Non-Patent Document 26). Thus, GSK-3 inhibitors are believed to prolong and enhance the immunostimulatory effects of certain cytokines, which may enhance the potential of these cytokines for tumor immunotherapy or indeed for general immunotherapy.
  • GSK-3 can be used for breast cancer, colorectal cancer, thyroid cancer, T or B cell leukemia and tumors induced by various viruses (Non Patent Literature 27-31), cardiac hypertrophy (Non Patent Literature 32-34), and hair loss ( Non-patent document 35) and obesity (non-patent document 36) have important potential in the treatment of many diseases.
  • Lithium which is used as a therapeutic agent for manic or bipolar disorder mentioned above, is known to inhibit other targets such as inositol monophosphatase (IMPase) and inositol polyphosphate phosphatase (IPPase) as nonspecific inhibitors for GSK-3 (nonpatent Document 37).
  • IMPase inositol monophosphatase
  • IPPase inositol polyphosphate phosphatase
  • Nypta (NP-12, NP031112), developed by Noscira, SA (formerly Neuropharma, SA), among the various inhibitors that specifically inhibit GSK-3, is being developed for phase II clinical trials for the treatment of Alzheimer's disease or neurodegenerative diseases.
  • Nypta (NP-12) is a thiadiazolidinone (TDZD) derivative that is an uncompetitive GSK-3 inhibitor for ATP.
  • NP103 another GSK-3 inhibitor developed by Noscira, S.A, is under preclinical development as a treatment for Alzheimer's disease.
  • Non-Patent Document 38 Non-Patent Document 38
  • Chiron's CHIR98023 and CHIR99021 Patent Document 1 and Non-patent document 39
  • CNRS Aloisine A non-patent document 40
  • Alsterpaullone non-patent document 41
  • AstraZeneca's AR-A014418 (Non-Patent Document 42) has been developed for the treatment of depression, Vertex's VX608 for the treatment of stroke, and Sanofi-Aventis's SAR502250 for the treatment of diabetes and Alzheimer's disease.
  • the present inventors have been studying to develop a low molecular GSK-3 inhibitor which can be used for the treatment of various diseases caused by the excess activity of glycogen synthase kinase-3 (GSK-3), preparing a triazolopyridine derivative. And it was confirmed that the compound exhibits excellent GSK-3 inhibitory activity was completed the present invention.
  • GSK-3 glycogen synthase kinase-3
  • Another object of the present invention is to provide a method for preparing a triazolopyridine derivative.
  • the present invention provides a method for preparing a triazolopyridine derivative represented by the formula (1).
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) containing triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • novel triazolopyridine derivatives of the present invention inhibit GSK-3 ⁇ , thereby dementia, Alzheimer's disease, Parkinson's disease, Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology It can be usefully used to prevent or treat related diseases.
  • Alkyl is saturated containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8, even more preferably 1 to 6, most preferably 1 to 4 carbon atoms, Linear or ground hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2,2-dimethyl-butyl, n-octyl group and the like.
  • Aryl represents an aromatic group having one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms.
  • aryl represents a group in which one or more hydrogen atoms are replaced with fluorine, chlorine, bromine or iodine atoms or with —OH, —SH, —NH 2 , or —NO 2 groups. Examples include phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl, 4-hydroxyphenyl group and the like.
  • Heteroaryl represents an aromatic group having one or more rings, contains 5 to 14 ring atoms, preferably 5 to 10, more preferably 5 to 6 ring atoms, and one or more (preferably 1, 2, 3 or 4) by a ring system containing oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • heteroaryl refers to a group in which one or more hydrogen atoms are replaced with fluorine, chlorine, bromine or iodine atoms or with OH, SH, NH 2 , or NO 2 groups.
  • Examples include 4-pyridyl, 2-imidazolyl, 3-phenyl-pyrroylyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl , Quinolinyl, furinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuryl, 3-pyrazolyl, isoquinolinyl group, and the like.
  • Heterocycloalkyl refers to a cycloalkyl group in which one or more (preferably 1, 2 or 3) ring carbon atoms are replaced with oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen).
  • heterocycloalkyl group means heterocycloalkyl having a single or double ring containing 3 to 10, more preferably 3, 4, 5, 6 or 7 ring atoms.
  • Examples include piperidyl, morpholinyl, eurotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclopropyl, 2-pyrazolinyl group, lactam, lactone, Cyclic imides, cyclic anhydrides, and the like.
  • the present invention provides a triazolopyridine derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof:
  • R One Silver hydrogen, C One -C 10 Linear or branched alkyl of C, or One -C 4 C substituted by alkoxy 5 -C 12 Aryloxy C One -C 4 Alkyl;
  • R 2 is hydrogen; halogen; C 1 -C 5 straight or branched chain alkyl unsubstituted or substituted with halogen; Or C 5 -C 12 aryl unsubstituted or substituted with halogen; C 5 -C 12 aryl unsubstituted or substituted with C 1 -C 10 straight or branched alkyl substituted by halogen;
  • R 3 is hydrogen, C 1 -C 5 straight or branched alkyl
  • W is-(CH 2 ) 1 R 4 , -COR 4 or -R 4 ;
  • R 5 and R 6 are each independently hydrogen, C 1 -C 5 straight or branched alkyl, C 5 -C 12 aryl, C 5 -C 12 heteroaryl or C 5 -C 12 heterocyclo Alkyl;
  • aryl, heteroaryl and heterocycloalkyl are unsubstituted or C 1 -C 5 alkyl, alkoxy, 5-6 membered heterocyclo alkyloxy, amine, 5-6 membered heterocycloalkylamine, or hydroxy, halogen Substituted with one or more substituents selected from the group consisting of: wherein the 5-6 membered heterocycloalkyloxy or 5-6 membered heterocycloalkylamine may be substituted with 5-6 membered heterocyclochloro; l or m is an integer from 0 to 10; And the heteroaryl and heterocycloalkyl include at least one hetero atom of N, O and S.
  • R 1 is hydrogen, C 1 -C 5 straight or branched alkyl; or ego;
  • R 2 is hydrogen, —Cl, —F, —CF 3 , C 1 -C 5 straight or branched alkyl; Or phenyl unsubstituted or substituted with C 1 -C 5 straight or branched alkyl, -Cl, -F or -CF 3 ;
  • R 3 is hydrogen, C 1 -C 5 straight or branched alkyl
  • W is -CH 2 R 4 , -COR 4 and -R 4 ;
  • R 5 and R 6 are each independently hydrogen; C 1 -C 5 straight or branched alkyl; Unsubstituted or substituted with one or more substituents selected from the group consisting of -N (CH 3 ) 2 , -OCH 3 , -OH, -N (CH 2 ) n R 7 , and -O (CH 2 ) n R 7 Phenyl; Unsubstituted or -CH 3 , -NH 2 , -Cl, -F,
  • R 2 is selected from the group consisting of hydrogen, —Cl, —CH 3 , —CF 3 , fluorophenyl, trifluoromethylphenyl and t-butylphenyl;
  • R 3 is hydrogen or —CH 3 ;
  • W is -CH 2 R 4 , -COR 4 or -R 4 ;
  • R 5 is hydrogen or —CH 3 ;
  • R 6 is hydrogen, -CH 3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • n 0 to an integer of 4.
  • the triazolopyridine derivative is as follows:
  • the triazolopyridine derivatives of the general formula (1) of the present invention can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acid are useful as salts.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • Acid addition salt according to the present invention is a conventional method, for example, by dissolving the derivative of formula (1) in an organic solvent, such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and the organic acid or inorganic acid is added to filter the precipitate produced It may be prepared by drying, or may be prepared by distillation under reduced pressure of the solvent and excess acid, followed by drying or crystallization in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the triazolopyridine derivative represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, stereoisomers, and the like that can be prepared therefrom.
  • the present invention provides a method for preparing a triazolopyridine derivative represented by the formula (1).
  • step 2 Performing a halogenation reaction of the compound represented by Formula 9 obtained in step 1 to obtain a compound represented by Formula 10 (step 2);
  • step 3 Reacting with the compound represented by Formula 10 obtained in step 2 and hydrazine hydrate to obtain a compound represented by Formula 11 (step 3);
  • step 4 Performing a cyclization reaction on the compound represented by Chemical Formula 11 obtained in step 3 to obtain a compound represented by Chemical Formula 12 (step 4);
  • step 5 Performing a hydrogen reduction reaction on the compound represented by 12 obtained in step 4 to obtain a compound represented by Formula 13 (step 5);
  • step 6 Performing a protecting reaction on the compound represented by 13 obtained in step 5 to obtain a compound represented by Formula 14 (step 6);
  • Step 8 A process for preparing a compound represented by Chemical Formula 1a by performing a deprotection reaction on the compound represented by Chemical Formula 15 obtained in Step 7 (Step 8):
  • R 2 , R 6 and n are as defined in Formula 1, p is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy Benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • Step 1 is carried out by the nitrification and alcoholation of the 2-amino pyridine compound represented by the formula (8) prepared by a method that can be easily obtained commercially or known in the art using sulfuric acid, sodium nitrite and nitric acid It is a step of obtaining the compound represented by 9.
  • the nitration reaction can be carried out using sulfuric acid and nitric acid, sodium nitrate, nitric acid and silver nitrate, potassium nitrate and the like.
  • the solvent that can be used may perform the reaction without using an organic solvent, and preferably water may be used.
  • the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • reaction of substituting an amino group with an alcohol may be performed by using a sandmeyer reaction using sodium nitrite, and sodium nitrite is preferable to use t-butylammonium nitrate and isoamylnitrite. T-butyl ammonium nitrate may be used.
  • dichloromethane dichloromethane, chloroform, a mixed solution of benzene and water, acetonitrile, ethyl alcohol, carbon tetrachloride and water that do not adversely affect the reaction may be used, and preferably water may be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 2 is a step of obtaining a compound represented by the formula (10) by performing a halogenation reaction of the compound represented by the formula (9) prepared in step 1.
  • the halogenation reaction is hydrochloric acid, hydrobromic acid, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine and carbon tetrabromide, triethylphosphine dichloride, triethylphosphate.
  • Findibromide and the like can be used, but thionyl chloride can be preferably used.
  • usable organic solvents include benzene, toluene, xylene, hexane, heptane, chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane and N, which do not adversely affect the reaction.
  • N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphate triamide can be used, and preferably, the reaction can be carried out using a catalytic amount of N, N-dimethylformamide without using a solvent. Can be.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction temperature is -50 ° C to 150 ° C, preferably 0 ° C to 80 ° C.
  • the reaction time varies depending on the reaction reagent, the reaction temperature, the solvent, and the like, and is usually 30 minutes to 3 days, preferably 1 hour to 24 hours.
  • step 3 is a step of obtaining a compound represented by formula 11 by reacting the compound represented by formula 10 prepared in the second step with hydrazine hydrate.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, pyridine, N, N-dimethylformamide or butanol, which does not adversely affect the reaction.
  • Methanol can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the compound represented by Chemical Formula 10 may be dissolved in methanol, hydrazine hydrate may be added, stirred, and the resulting solid may be filtered to obtain a compound represented by Chemical Formula 11.
  • step 4 is a step of obtaining a compound represented by the formula (12) by performing a cyclization reaction of the compound represented by the formula (11) prepared in the third step with triphosgene.
  • the intramolecular cyclization reaction may be triphosphene, diphosgene, phosgene or carbodiimidazole, and the like, preferably triphosphene.
  • organic solvent which can be used, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc. which do not adversely affect the reaction can be used, and preferably tetrahydrofuran can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 5 is a step of obtaining a compound represented by formula 13 by performing a hydrogen reduction reaction to the compound represented by formula 12 prepared in step 4.
  • the reaction is carried out using a pressurized reaction using hydrogen gas in the presence of a small amount of palladium. After completion of the reaction, the palladium is removed by filtration under reduced pressure to obtain a compound represented by the formula (13).
  • the hydrogen reduction reaction used in this reaction is carried out by pressurization using hydrogen gas in the presence of a small amount of active metal catalysts such as Ranickel, Palladium-Activated Carbon, etc. which are widely used in the reduction reaction.
  • active metal catalysts such as Ranickel, Palladium-Activated Carbon, etc. which are widely used in the reduction reaction.
  • the reaction catalyst a reducing catalyst in which 5 to 10% by weight of palladium is supported on a support such as activated carbon, alumina, or silica may be used, and preferably, palladium is supported on activated carbon.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction.
  • a mixed solvent of methanol and ethyl acetate can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 6 is a step of obtaining a compound represented by the formula (14) by performing a protection reaction (protection reaction) using the compound represented by the formula (13) prepared in step 5 using a di-t-butyl dicarbonate and a base to be.
  • step 6 is carried out using a protecting group protecting an amide, and as a protecting group that can be generally used, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl Group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc) can be used, Preferably t-butoxycarbonyl group (t-Boc) can be used.
  • the reaction of step 6 may be performed without using a base, but in general, pyridine, triethylamine, diethylisopropylamine, dimethylaminopyridine, N-methylmorpholine, etc., which may be used in a protection reaction, may be used.
  • pyridine triethylamine, diethylisopropylamine, dimethylaminopyridine, N-methylmorpholine, etc.
  • dichloromethane chloroform
  • tetrahydrofuran diethyl ether
  • tetrahydrofuran tetrahydrofuran
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction is carried out by slowly adding di-butyl dicarbonate and dimethylaminopyridine at 0 °C, and after completion of the reaction, by performing column chromatography
  • the compound represented by Formula 14 can be obtained.
  • Step 7 is a step of obtaining a compound represented by Chemical Formula 15 by performing a reductive amination of the compound represented by Chemical Formula 14 prepared in Step 6 with the aldehyde compound represented by Chemical Formula 5 or Chemical Formula 7.
  • step 7 is carried out using a reducing agent, which generally can be used for reductive amination.
  • a reducing agent which generally can be used for reductive amination.
  • Sodium triacetoxyborohydride, sodium cyanoborohydride, triethylsilane, titanium tetra Isopropoxy / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate or zinc borohydride / zinc chloride can be used, preferably sodium cyanoborohydride.
  • step 7 is carried out using an acid catalyst.
  • an acid catalyst that can be used for reductive amination may use hydrochloric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, or formic acid.
  • hydrochloric acid can be used.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction. It is possible to use, preferably methanol.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction is carried out by slowly adding the aldehyde compound, sodium cyanoborohydride and hydrochloric acid represented by the formula (5) or (7) at 0 °C in order slowly, the reaction, After termination, column chromatography may be performed to obtain a compound represented by Chemical Formula 15.
  • step 8 is a step of obtaining a compound represented by Formula 1a by performing a deprotection reaction of the compound represented by Formula 15 prepared in Step 7.
  • hydrochloric acid sulfuric acid, nitric acid, acetic acid or trifluoroacetic acid, etc.
  • hydrochloric acid can be used as an acid which can be used, Preferably hydrochloric acid can be used.
  • dioxane dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not adversely affect the reaction, may be used as the solvent, and dioxane may be preferably used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • Another method for preparing a triazolopyridine derivative represented by Formula 1 according to the present invention is to obtain a compound represented by Formula 17 by performing a halogenation reaction on an aminopyridine compound represented by Formula 16, as shown in Scheme 2 below ( Step 1);
  • step 3 Performing a nitration and alcoholation reaction on the compound represented by Chemical Formula 19 obtained in step 2 to obtain a compound represented by Chemical Formula 20 (step 3);
  • step 4 Performing a halogenation reaction on the compound represented by Formula 20 obtained in step 3 to obtain a compound represented by Formula 21 (step 4);
  • step 6 Performing a cyclization reaction on the compound represented by Chemical Formula 22 obtained in step 5 to obtain a compound represented by Chemical Formula 23 (step 6);
  • step 7 Performing a hydrogen reduction reaction on the compound represented by Chemical Formula 23 obtained in step 6 to obtain a compound represented by Chemical Formula 24 (step 7);
  • step 8 Performing a protection reaction on the compound represented by Chemical Formula 24 obtained in step 7 to obtain a compound represented by Chemical Formula 25 (step 8);
  • Step 10 A process for preparing a compound represented by Chemical Formula 1b by performing a deprotection reaction on the compound of Chemical Formula 26 obtained in Step 9 (Step 10):
  • R 2 , R 3 , R 6 and n are as defined in Formula 1, p is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p -Methoxybenzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • Step 1 is a halogenated reaction of the 2-aminopyridine compound represented by the formula (16) prepared by a method known in the art or prepared by a conventionally known process using N-bromosuccinimide is represented by the formula (17) It is a step of obtaining a compound.
  • the usable organic solvent can be carried out using acetonitrile, dichloromethane, chloroform, tetrahydrofuran or ethyl acetate which does not adversely affect the reaction, preferably acetonitrile can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the mixture is stirred by adding N-bromosuccinimide at room temperature, and after completion of the reaction, the compound represented by Formula 17 may be obtained by filtration under reduced pressure.
  • step 2 is a compound represented by the formula (19) by performing a Suzuki reaction using the aryl boronic acid compound represented by the formula (18) and the transition metal catalyst to the compound represented by the formula (17) prepared in step 1 To get it.
  • the solvent which can be used is a solvent which does not adversely affect the reaction, for example, hexane, pentane, N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform, diethyl ether, dioxane, tetrahydro Furan, methyl acetate, ethyl acetate, acetonitrile, toluene, pyridine, 1,2-dichloroethane and the like are used, and preferably 1,2-dichloroethane can be used.
  • transition metal used in the reaction for example, 0 to 2 divalent palladium, nickel, copper, and the like are used, and these are triphenylphosphine, dibenzylidene acetone, bisdiphenylphosphinoferrocene, tetrakistriphenylphosphinepalladium, You may form a complex with triphenylphosphine palladium acetate, triethyl phosphite palladium acetate, etc. Preferably tetrakistriphenylphosphinepalladium can be used.
  • reaction temperature is not particularly limited, but may be carried out within the boiling point range of the room temperature to the solvent and usually at -80 ° C to 100 ° C, preferably 0 ° C to 100 ° C, and the reaction time is about 5 minutes to 5 days. Preferably 30 minutes to 20 hours.
  • the compound represented by Chemical Formula 17 is dissolved in 1,2-dichloroethane, and then an aryl boronic acid compound and tetrakistriphenylphosphine palladium, which is a compound represented by Chemical Formula 18, are added and stirred at room temperature. After completion of the reaction, column chromatography may be performed to obtain a coupling compound represented by Chemical Formula 19.
  • step 3 is a step of obtaining a compound represented by the formula 20 by performing the nitration and alcoholation reaction of the compound represented by the formula (19) prepared in the second step using sulfuric acid, sodium nitrite and nitric acid.
  • the nitration reaction can be carried out using sulfuric acid and nitric acid, sodium nitrate, nitric acid and silver nitrate, potassium nitrate and the like.
  • the solvent that can be used may perform the reaction without using an organic solvent, and preferably water may be used.
  • the reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • reaction of substituting an amino group with an alcohol may be performed by using a sandmeyer reaction using sodium nitrite, and sodium nitrite is preferable to use t-butylammonium nitrate and isoamylnitrite. T-butyl ammonium nitrate may be used.
  • dichloromethane dichloromethane, chloroform, dichloromethane, a mixed solution of benzene and water, acetonitrile, ethyl alcohol, carbon tetrachloride and water can be used, and preferably water can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 4 is a step of obtaining a compound represented by the formula 21 by performing a halogenation reaction of the compound represented by the formula (20) prepared in step 3.
  • the halogenation reaction is hydrochloric acid, hydrobromic acid, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine and carbon tetrabromide, triethylphosphine dichloride, triethylphosphate.
  • Findibromide etc. can be used,
  • thionyl chloride can be used.
  • usable organic solvents include benzene, toluene, xylene, hexane, heptane, chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, dioxane and N, which do not adversely affect the reaction.
  • N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphate triamide can be used, and preferably, the reaction can be carried out using a catalytic amount of N, N-dimethylformamide without using a solvent. have.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction temperature is -50 ° C to 150 ° C, preferably 0 ° C to 80 ° C.
  • the reaction time varies depending on the reaction reagent, the reaction temperature, the solvent, and the like, and is usually 30 minutes to 3 days, preferably 1 hour to 24 hours.
  • step 5 is a step of obtaining a compound represented by Chemical Formula 22 by reacting the compound represented by Chemical Formula 21 prepared in Step 4 with hydrazine hydrate.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, pyridine, N, N-dimethylformamide or butanol, which does not adversely affect the reaction.
  • Methanol can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the compound represented by Chemical Formula 21 may be dissolved in methanol, hydrazine hydrate may be added, stirred, and the resulting solid may be filtered to obtain the compound represented by Chemical Formula 22.
  • step 6 is a step of obtaining a compound represented by the formula 23 by performing a cyclization reaction of the compound represented by the formula (22) prepared in the fifth step with triphosgene.
  • the intramolecular cyclization reaction may be triphosphene, diphosgene, monophosgene or carbodiimidazole and the like, and preferably triphosphene may be used.
  • organic solvent which can be used, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc. which do not adversely affect the reaction can be used, and preferably tetrahydrofuran can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the compound represented by Chemical Formula 22 is dissolved in tetrahydrofuran, and then slowly added Triphosgene at room temperature, followed by stirring at 60 ° C. After completion of the reaction, it was filtered under reduced pressure to obtain a compound represented by the formula (23).
  • step 7 is a step of obtaining a compound represented by the formula (24) by performing a hydrogen reduction reaction to the compound represented by the formula (23) obtained in the step 6.
  • the reaction is carried out using a pressurized reaction using hydrogen gas in the presence of a small amount of palladium. After completion of the reaction, the palladium was removed by filtration under reduced pressure to obtain a compound represented by the formula (24).
  • the hydrogen reduction reaction used in the reaction is carried out by pressurization using hydrogen gas in the presence of a small amount of an active metal catalyst such as Ranickel, palladium-activated carbon, and the like, which are widely used in the reduction reaction.
  • an active metal catalyst such as Ranickel, palladium-activated carbon, and the like
  • a reducing catalyst containing 5 to 10% by weight of palladium may be used in a support such as activated carbon, alumina, silica, or the like, and preferably, palladium is supported on activated carbon.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction.
  • a mixed solvent of methanol and ethyl acetate can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 8 is a step of obtaining a compound represented by the formula (25) by performing a protecting reaction (protection reaction) using the compound represented by the formula (24) prepared in step 7 using di t-butyl dicarbonate and a base .
  • step 8 is carried out using a protecting group protecting an amide, and as a protecting group that can be generally used, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxybenzyl Group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc) can be used, Preferably t-butoxycarbonyl group (t-Boc) can be used.
  • the reaction of step 8 may be performed without using a base, but in general, pyridine, triethylamine, diethylisopropylamine, dimethylaminopyridine, N-methylmorpholine, etc., which may be used in a protection reaction, may be used.
  • pyridine triethylamine, diethylisopropylamine, dimethylaminopyridine, N-methylmorpholine, etc.
  • dichloromethane chloroform
  • tetrahydrofuran diethyl ether
  • tetrahydrofuran tetrahydrofuran
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction is carried out by slowly adding di-butyl dicarbonate and dimethylaminopyridine at 0 ° C., and after completion of the reaction, column chromatography is performed.
  • the compound represented by Formula 25 can be obtained.
  • step 9 is a step of obtaining a compound represented by Chemical Formula 26 by performing a reductive amination with the aldehyde compound represented by Chemical Formula 5 or Chemical Formula 25 prepared in Step 8 with the aldehyde compound represented by Chemical Formula 5 or Chemical Formula 7. to be.
  • step 9 is carried out using a reducing agent, which generally can be used for reductive amination, sodium triacetoxyborohydride, sodium cyanoborohydride, triethylsilane, titanium tetra Isopropoxy / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate or zinc borohydride / zinc chloride can be used, preferably sodium cyanoborohydride.
  • a reducing agent which generally can be used for reductive amination
  • sodium triacetoxyborohydride sodium cyanoborohydride, triethylsilane, titanium tetra Isopropoxy / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate or zinc borohydride / zinc chloride
  • sodium triacetoxyborohydride sodium cyanoborohydride
  • sodium cyanoborohydride triethylsilane
  • step 9 is carried out using an acid catalyst.
  • an acid catalyst which can be used for reductive amination may use hydrochloric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or formic acid. And preferably hydrochloric acid can be used.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction. It is possible to use, preferably methanol.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the reaction is carried out by slowly adding the aldehyde compound, sodium cyanoborohydride and hydrochloric acid represented by the formula (5) or (7) at 0 °C in order slowly, the reaction, After termination, column chromatography may be performed to obtain a compound represented by Chemical Formula 26.
  • step 10 is a step of obtaining a compound represented by Formula 1b by performing a deprotection reaction of the compound represented by Formula 26 prepared in Step 9.
  • hydrochloric acid sulfuric acid, nitric acid, acetic acid or trifluoroacetic acid, etc.
  • hydrochloric acid can be used as an acid which can be used, Preferably hydrochloric acid can be used.
  • dioxane dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not adversely affect the reaction, may be used as the solvent, and dioxane may be preferably used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • Another method for preparing a triazolopyridine derivative represented by Formula 1 according to the present invention is a compound represented by Formula 14 and an aldehyde compound represented by Formula 27 prepared in step 6 of Preparation Method 1, as shown in Scheme 3 below Performing a coupling reaction to obtain a compound represented by Chemical Formula 28 (step 1); And
  • Step 2 A process for preparing a compound represented by Chemical Formula 1c by performing a deprotection reaction on a compound represented by Chemical Formula 28 obtained in Step 1 (Step 2):
  • R 2 , R 6 and n are as defined in Formula 1, p is a protecting group, benzyloxycarbonyl group (Cbz), t-butoxycarbonyl group (t-Boc), p-methoxy Benzyl group (PMB) or 9-fluorenylmethoxycarbonyl group (Fmoc)).
  • the step 1 is a coupling reaction with the carboxylic acid compound represented by the formula (27) prepared by a method known in the art or can be easily obtained commercially obtained cyclic amine compound represented by the formula (14) prepared in step 6 of Preparation method ( performing a coupling reaction) to obtain a compound represented by Chemical Formula 28.
  • Step 1 is an amidation reaction of the carboxylic acid compound represented by the formula (27) prepared by a method known in the art or prepared in the prior art with a carbonyl chloride compound prepared using thionyl chloride or oxalyl chloride and the like ( An amidation reaction may be performed to prepare a compound represented by Chemical Formula 28.
  • step 1 may be performed without using a base, but generally, pyridine, triethylamine, diethyl isopropylamine, N-methylmorpholine, or the like, which may be used for the amidation reaction, may be used. And dimethylformamide may be preferably used.
  • dichloromethane chloroform, tetrahydrofuran, diethyl ether, toluene or dimethylformamide, etc., which do not affect the reaction, can be used, and preferably dichloromethane can be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • step 2 is a step of obtaining a compound represented by the formula (1c) by performing a deprotection reaction of the compound represented by the formula (28) prepared in step 1.
  • the compound represented by Chemical Formula 1c may be obtained by performing the same method as the method for obtaining the compound represented by Chemical Formula 1a in Step 8 of Scheme 1.
  • aldehyde compounds represented by the formulas (5) and (7) used in Preparations 1 and 2 according to the present invention may be prepared by the following method:
  • Compound (5) is a step of obtaining a compound represented by the formula (3) by performing a coupling reaction to the aldehyde compound represented by the formula (2) (step 1);
  • the compound represented by Chemical Formula 4 prepared in Step 2 may be prepared by a manufacturing method comprising a step (step 3) of performing acetal reaction to obtain a compound represented by Chemical Formula 5.
  • Step 1 is a step of obtaining a compound represented by Chemical Formula 3 by coupling the aldehyde compound represented by Chemical Formula 2, which is easily obtained commercially or prepared by a method known in the art, using alkyl phosphonium halogen. to be.
  • tetrahydrofuran normal hexane, normal pentane, cyclohexane, diethyl ether, or the like which does not adversely affect the reaction
  • the organic solvent preferably tetrahydrofuran may be used.
  • reaction temperature is carried out at a low temperature and then at room temperature after a certain time.
  • the compound represented by Chemical Formula 2 may be dissolved in tetrahydrofuran, and then stirred by addition of alkyl phosphonium halogen at ⁇ 43 ° C., and after completion of the reaction, column chromatography may be performed to obtain a compound represented by Chemical Formula 3 have.
  • step 2 is a step for preparing a compound represented by the formula (4) by performing a reduction reaction using the compound represented by the formula (3) prepared in step 1 using palladium and hydrogen.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol, dichloromethane, chloroform, tetrahydrofuran, diethyl ether or ethyl acetate, which do not adversely affect the reaction. It is possible to use, preferably methanol.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • Step 3 is a step of obtaining a compound represented by Chemical Formula 5 by deacetal reaction of the compound represented by Chemical Formula 4 prepared in Step 2 with 1N hydrochloric acid.
  • the reaction may be performed using methanol, ethanol, 2-propanol, isobutanol, butanol or water, which does not adversely affect the reaction, and preferably water may be used.
  • reaction temperature is not particularly limited, but may be performed within a boiling point range of room temperature to the solvent.
  • the compound represented by the formula (5) can be obtained by adding 1N hydrochloric acid aqueous solution to the compound represented by the formula (4).
  • the compound of formula 7 may be prepared by a preparation method comprising the step (step 1) of obtaining a compound represented by formula 7 by performing an oxidation reaction on the compound represented by formula 6:
  • Step 1 is a method for preparing a compound represented by the formula (7) by oxidizing the alcohol compound represented by the formula (6) which can be easily obtained commercially or prepared by a known method using oxalyl chloride and dimethyl sulfoxide Step.
  • organic solvent which can be used a solvent which does not adversely affect the reaction can be used, and preferably dichloromethane can be used.
  • reaction temperature is carried out at a low temperature
  • base used may be triethylamine or diethylisopropylamine, preferably triethylamine.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) containing triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) -related disorders include dementia, Alzheimer's disease, Parkinson's disease, frontal temporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology. Disease may be included.
  • the triazolopyridine derivative represented by Formula 1 according to the present invention exhibited an excellent IC 50 value of 0.1 ⁇ M or less as a result of the GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) enzyme inhibition experiment, and thus, GSK-3 ⁇ (glycogen synthase kinase) -3 ⁇ ) showed an excellent inhibitory effect on the enzyme (see Table 6), GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) inhibitory activity using a cell-based glucose production inhibition assay, 5.0 ⁇ M or less By showing an excellent IC 50 value of, it can be seen that it exhibits an excellent inhibitory effect on the GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) enzyme (see Table 7).
  • the triazolopyridine derivative represented by Formula 1 according to the present invention has an inhibitory effect on GSK-3 ⁇ (glycogen synthase kinase-3 ⁇ ) enzyme, dementia induced by GSK-3 ⁇ , Alzheimer's disease, Parkinson's disease, frontal It may be usefully used to prevent or treat diseases associated with the Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complications, HIV dementia or neurofibrillary pathology.
  • GSK-3 ⁇ glycose kinase-3 ⁇
  • the pharmaceutical composition containing the derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the triazolopyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and prepare a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg.
  • / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.
  • Step 2 Preparation of 3- [2- (1,3-dioxolan-2-yl) ethyl] -2-chloro-6-methylpyridine
  • step 1 The compound prepared in step 1 (100.0 mg, 0.44 mmol) was dissolved in methanol (5 mL) and 10% -palladium (5.0 mg, 5 wt%) was added. 1 atmosphere of hydrogen was added with a hydrogen balloon, followed by stirring at room temperature for 10 minutes. After confirming the reaction, 10% -palladium was removed by filtration, and the solvent was concentrated under reduced pressure to obtain the title compound (50.0 mg, reaction yield: 50%, colorless liquid).
  • Oxalyl chloride (37.5 mL, 437.3 mmol) was dissolved in dichloromethane (1000 mL), then N, N-dimethylformamide (59.5 mL, 838.31 mmol) was dissolved in dichloromethane (250 mL) at -70 ° C and slowly added. It was. 3- (pyridin-4-yl) propan-1-ol (50.0 g, 364.4 mmol) was dissolved in dichloromethane (250 mL) at -70 ° C and slowly added, followed by triethylamine (162.5 mL, 1166.3 mmol). The reaction mixture was added and stirred at rt for 1 h.
  • step 2 The compound (13.2 g, 76.37 mmol) prepared in step 2 was dissolved in methanol (120 mL), and then hydrazine hydrate (8.89 mL, 183.29 mmol) was added thereto. The reaction mixture was refluxed at 80 ° C. for 12 hours. After completion of the reaction, the reaction was cooled to room temperature and then filtered under reduced pressure. The residue was purified by water to give the title compound (11.4 g, reaction yield: 89%, brown solid).
  • Step 5 Preparation of 8-amino-6-methyl- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one
  • step 4 The compound (12.3g, 63.82 mmol) prepared in step 4 was dissolved in methanol (200 mL), and 10% -palladium (4.9 g, 40wt%) and formic acid (0.5 mL) were added and replaced with hydrogen. The reaction mixture was stirred at rt for 48 h. After completion of the reaction, the reaction was filtered under reduced pressure and the residue was purified by concentration under reduced pressure to give the title compound (8.0 g, reaction yield: 76%, gray solid).
  • Step 6 Preparation of t -butyl 8-amino-6-methyl-3-oxo- [1,2,4] triazolo [4,3-a] pyridine- 2 (3H) -carboxylate
  • step 5 The compound prepared in step 5 (8.0 g, 48.73 mmol) was dissolved in tetrahydrofuran (200 mL), and then di- t -butyl dicarbonate (12.76 g, 58.48 mmol) and 4- (dimethylamino) -pyridine (0.60 g, 4.87 mmol) was added and reacted. The reaction mixture was stirred at rt for 2 h.
  • Step 7 t-butyl-6-methyl-3-oxo-8- [3- (pyridin-4-yl) propylamino]-[1,2,4] triazolo [4,3-a] pyridine- Preparation of 2 (3H) -carboxylate
  • Step 8 of 6-methyl-8- (3- (pyridin-4-yl) propylamino)-[1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one hydrochloride Produce
  • step 7 The compound (2.2 g, 5.74 mmol) prepared in step 7 was dissolved in 4.0M hydrochloric acid (30 mL, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to give the title compound (1.8 g, reaction yield: 98%, ivory solid).
  • step 3 The compound prepared in step 3 (538 mg, 2.30 mmol) was lowered to 0 ° C. and then acetic acid (8.1 mL) and concentrated hydrochloric acid (9.72 mL) were added, respectively. Thereafter, sodium nitrite (477 mg, 6.92 mmol) was dissolved in water (2.7 mL), added to the reaction mixture, and reacted at room temperature for 2 hours. The mixture was terminated with cold ice water, basified with saturated sodium bicarbonate and extracted with ethyl acetate. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was dissolved in thionyl chloride (2 mL) without purification.
  • step 4 The compound (469 mg, 1.85 mmol) prepared in step 4 was dissolved in methanol (10 mL), hydrazine hydrate (0.22 mL, 4.45 mmol) was added thereto, and the mixture was heated to reflux for 3 hours. The resulting reaction mixture was lowered to 0 ° C. and the resulting solid compound was filtered, washed with water and hexane and dried to give the title compound (375 mg, reaction yield: 82%, orange solid) without purification.
  • Triphosphene (493 mg, 1.66 mmol) was dissolved in dried tetrahydrofuran (10 mL) and the compound (375 mg, 1.51 mmol) prepared in step 5 above at 60 ° C. was dried tetrahydrofuran (2 mL). It was dissolved in and slowly added dropwise. The reaction mixture was cooled down to room temperature, the solvent was concentrated under reduced pressure, and then water was added and stirred at room temperature for one day. The resulting solid compound was filtered, washed with water and hexane, and then dried under reduced pressure to obtain the title compound (427 mg, reaction yield: 98%, red solid).
  • Step 7 Preparation of Preparation of 8-Amino-6- (4-fluorophenyl)-[l, 2,4] triazolo [4,3-a] pyridin- 3 (2H) -one
  • step 6 The compound (670 mg, 2.44 mmol) prepared in step 6 was dissolved in tetrahydrofuran (10 mL) and ethanol (5 mL), and then palladium hydroxide (104 mg, 10% / wt) was added dropwise to the hydrogen environment. Under one day. The terminated reaction mixture was removed by palladium through celite filtration and the solvent was concentrated under reduced pressure to give the title compound (460 mg, reaction yield: 77%, red solid) without purification.
  • Step 8 t-Butyl 8-amino-6- (4-fluorophenyl) -3-oxo- [1,2,4] triazolo [4,3-a] pyridine -2 (3H) - carboxylate for Produce
  • step 7 The compound (462 mg, 1.88 mmol) prepared in step 7 was dissolved in dried tetrahydrofuran (10 mL) and then lowered to 0 ° C. and di- t -butyl dicarbonate (413 mg, 1.88 mmol) and 4-dimethyl Aminopyridine (23 mg, 0.18 mmol) was added and reacted at 0 ° C. for 1 hour.
  • the reaction mixture was terminated with water and extracted with ethyl acetate and the solvent was dried over anhydrous magnesium sulfate.
  • Step 9 t-butyl 6- (4-fluorophenyl) -3-oxo-8- [3- (pyridin-3-yl) propylamino ]-[1,2,4] triazolo [4,3 -a] Preparation of Pyridine-2 (3H) -carboxylate
  • step 8 The compound (100 mg, 0.29 mmol) prepared in step 8 was dissolved in methanol (5 mL), lowered to 0 ° C., and then 3- (pyridin-3-yl) propanal (59 mg, 0.43 mmol) and zinc chloride ( 28 mg, 0.20 mmol) and 1.25M hydrochloric acid (0.93 mL, 1.16 mmol) dissolved in methanol were added thereto, and then reacted at room temperature for 10 minutes. Sodium cyanoborohydride (22 mg, 0.34 mmol) was added to the reaction mixture, and the reaction was performed at room temperature for one day. The reaction was terminated with a saturated aqueous solution of calcium hydrogen carbonate.
  • reaction mixture was extracted with ethyl acetate and the solvent was dried over anhydrous magnesium sulfate.
  • Step 10 6- (4-Fluorophenyl) -8- [3- (pyridin-3-yl) propylamino]-[1,2,4] triazolo [4,3-a] pyridine-3 ( Preparation of 2H) -one Hydrochloride
  • step 9 The compound prepared in step 9 (30 mg, 0.064 mmol) was dissolved in 1,4-dioxane (1 mL), and 4M hydrochloric acid (1 mL) dissolved in 1,4-dioxane was slowly added dropwise. After reacting at room temperature for one day, the solvent was removed by concentration under reduced pressure and dried under reduced pressure. The reaction mixture was diluted with ethyl acetate, and the resulting solid was filtered, washed with ethyl acetate and hexane, and dried under reduced pressure to obtain the title compound (19.3 mg, reaction yield: 75%, brown solid).
  • Step 1 3-oxo-8- (3-pyridin-4-yl-acryloylamide)-[1,2,4] triazolo [4,3-a] pyridine-2-carboxylic acid t -butyl ester
  • step 1 The compound (78 mg, 0.20 mmol) prepared in step 1 was dissolved in 1,4-dioxane (1 mL), and 4M hydrochloric acid (2 mL) dissolved in 1,4-dioxane was added thereto. After stirring for 24 hours, the solvent was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, which was concentrated under reduced pressure, stirred for 30 minutes, filtered and washed with diethyl ether to obtain the title compound (43.2 mg, reaction yield: 66.5%, white solid).
  • Step 1 Preparation of (4-methoxy-phenoxy) -acetic acid methyl ester
  • Step 3 Preparation of 8-amino-2- [2- (4-methoxy-phenoxy) -ethyl] -2H- [1,2,4] triazolo [4,3- a] pyridin-3-one
  • step 2 The compound prepared in step 2 (50 mg, 0.29 mmol) was dissolved in N, N- dimethylformamide (5 mL), and then t -butyl 8-amino-3-oxo- [1,2,4 at 0 ° C. ] Triazolo [4,3-a] pyridine-2 (3H) -carboxylate (67 mg, 0.44 mmol) was added, triphenylphosphine (117 mg, 0.44 mmol) and diisopropylazodicarboxylate (0.087 Ml, 0.44 mmol) are added sequentially.
  • Example 1 The compound (30.0 mg, 0.08 mmol) prepared in the same manner as the compound prepared in step 7 was dissolved in N , N -dimethylformamide (3.0 mL) and stirred at 0 ° C. Sodium hydride (10.0 mg, 0.23 mmol) was added dropwise at the same temperature. After a while stirring iodine methane (43.0 mg, 0.30 mmol) was added dropwise. The reaction was stirred at 0 ° C for 1 h. After the reaction was completed, water was added dropwise to the reaction mixture.
  • step 1 The compound (9.0 mg, 0.02 mmol) prepared in step 1 was dissolved in 4M hydrochloric acid (5 mL) dissolved in 1,4-dioxane and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain the title compound (5.5 mg, reaction yield: 73%, ivory solid).
  • Example 1 The compound (30.0 mg, 0.08 mmol) prepared in the same manner as the compound prepared in step 7 was dissolved in N , N -dimethylformamide (3.0 mL) and stirred at 0 ° C. Sodium hydride (10.0 mg, 0.23 mmol) was added dropwise at the same temperature. After a while stirring iodine methane (43.0 mg, 0.30 mmol) was added dropwise. The reaction was stirred at 0 ° C for 1 h. After the reaction was completed, water was added dropwise to the reaction mixture.
  • step 1 The compound (10.0 mg, 0.03 mmol) prepared in step 1 was dissolved in 4.0M hydrochloric acid (5 mL, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain the title compound (4.8 mg, reaction yield: 43%, ivory solid).
  • Triethylol phosphate (29.0 g, 195.68 mmol) was dissolved in acetic anhydride (80 mL), and ethyl cyanoacetate (22.1 g, 195.68 mmol) was added dropwise and stirred under reflux for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with hexane to obtain the title compound (21.7 g, reaction yield: 64%, yellow solid).
  • Step 3 Preparation of (2E, 4Z) -ethyl-2-cyano-4-phenyl-5- (piperidin-1-yl) penta-2,4-dienoate
  • Step 5 Preparation of ethyl 2-chloro-5-phenylnicotinate
  • Lithium aluminum hydride (190 mg, 5.04 mmol) was dissolved in tetrahydrofuran (80 mL) and stirred at 0 ° C.
  • the compound (1.2 g, 4.59 mmol) prepared in step 5 was dissolved in tetrahydrofuran (20 mL) and then slowly added dropwise. The reaction was stirred at 0 ° C for 30 minutes. After the reaction was completed, water was added dropwise to the reaction mixture, which was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour.
  • Step 7 Preparation of 3- (benzyloxymethyl) -2-chloro-5-phenylpyridine
  • step 6 The compound (700.0 mg, 3.19 mmol) prepared in step 6 was dissolved in tetrahydrofuran (25 mL) and stirred at 0 ° C. Sodium hydride (147.0 mg, 6.37 mmol) was added dropwise at the same temperature. After brief stirring benzyl bromide (820.0 mg, 4.78 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. After the reaction was completed, water was added dropwise to the reaction mixture at 0 ° C.
  • Step 8 Preparation of 3- (benzyloxymethyl) -2-hydrazinyl-5-phenylpyridine
  • step 7 The compound (1.6 g, 5.16 mmol) prepared in step 7 was dissolved in hydrazine hydrate (30 mL) and pyridine (4.2 mL, 51.64 mmol) was added dropwise. It was refluxed at 120 ° C. for 3 days. After completion of the reaction, the reaction was filtered under reduced pressure and extracted with ethyl acetate. The organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (1.4 g, reaction yield: 85%, ivory solid).
  • Step 9 Preparation of 8- (benzyloxymethyl) -6-phenyl- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one
  • Step 10 Preparation of 8- (hydroxymethyl) -6-phenyl- [1,2,4] triazolo [4,3-a] pyridin- 3 (2H) -one
  • step 9 The compound (700.0 mg, 2.11 mmol) prepared in step 9 was dissolved in dichloromethane (50 mL) and stirred at 0 ° C. 1.0 M boron trichloride (8.5 mL, 8.45 mmol, tetrahydrofuran solution) was slowly added dropwise, followed by stirring at 0 ° C. for 10 minutes. After the reaction was completed, sodium hydrogencarbonate solution was added dropwise to the reaction mixture at 0 ° C. After extraction with ethyl acetate, the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was washed with dichloromethane to obtain the title compound (360.0 mg, reaction yield: 70%, white solid).
  • Step 11 Preparation of t-butyl 8- (hydroxymethyl) -3-oxo-6-phenyl- [1,2,4] triazolo [4,3- a] pyridine-2 (3H) -carboxylate
  • step 10 The compound prepared in step 10 (100.0 mg, 0.41 mmol) was dissolved in tetrahydrofuran (8 mL), and then di- t -butyl dicarbonate (100.0 mg, 0.46 mmol) and 4- (dimethylamino) -pyridine (5.1 mg, 0.04 mmol) was added and reacted.
  • Compound (100.0 mg, reaction yield: 71%, white solid) was obtained.
  • Step 12 t-butyl-8- (bromomethyl) -3-oxo-6-phenyl- [1,2,4] triazolo [4,3-a] pyridine -2 (3H) -carboxylate Produce
  • Step 14 6-phenyl-8- ⁇ [2- (pyridin-4-yl) ethylamino] methyl ⁇ -[1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one
  • step 14 The compound (8.0 mg, 0.02 mmol) prepared in step 14 was dissolved in 4.0M hydrochloric acid (3 ml, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to obtain the title compound (8.1 mg, reaction yield: 84%, ivory solid).
  • Step 1 Preparation of ethyl 2-hydrazinyl-5-phenylnicotinate
  • Example 51 The compound (1.0 g, 3.82 mmol) obtained in step 5 was dissolved in dioxane (10 mL), and then hydrazine hydrate (0.46 mL, 9.17 mmol) was added thereto. The reaction mixture was stirred at 60 ° C for 3 days. After completion of the reaction, the reaction was cooled to room temperature and then filtered under reduced pressure. The residue was purified by water to give the title compound (1.0 g, reaction yield: 98%, red solid).
  • Step 2 Preparation of ethyl 3-oxo-6-phenyl-2,3-dihydro- [1,2,4] triazolo [4,3-a] pyridine- 8-carboxylate
  • Triphosphene (1.73 g, 5.84 mmol) was dissolved in tetrahydrofuran (30 mL) and stirred at reflux for 30 minutes at 60 ° C.
  • the compound (1.0 g, 3.89 mmol) prepared in Step 1 was added dropwise, and the reaction mixture was refluxed at 80 ° C. for 2 hours. After completion of the reaction, the reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was added with water, stirred, and purified by filtration under reduced pressure to obtain the title compound (1.0 g, reaction yield: 90%, orange solid).
  • Step 3 Preparation of 2- t -butyl 8-ethyl 3-oxo-6-phenyl- [1,2,4] triazolo [4,3-a] pyridine- 2,8 (3H) -dicarboxylate
  • step 2 The compound prepared in step 2 (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (20 mL), followed by di- t -butyl dicarbonate (463 g, 2.12 mmol) and 4-dimethylaminopyridine (22 mg, 0.18). mmol) and reacted.
  • Step 4 Preparation of 3-oxo-6-phenyl-2,3-dihydro- [1,2,4] triazolo [4,3-a] pyridine-8- carboxylic acid
  • step 3 The compound prepared in step 3 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL) and water (5 mL), and lithium hydroxide hydrate (98 mg, 2.34 mmol) was added dropwise. After stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was depressurized, acidified with 2N hydrochloric acid, and filtered to obtain the title compound (100.2 mg, reaction yield: 51%, light yellow solid).
  • step 5 The compound (25 mg, 0.07 mmol) prepared in step 5 was dissolved in 4.0M hydrochloric acid (2 mL, 1,4-dioxane solution) and stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was filtered under reduced pressure to give a compound (21.1 mg, reaction yield: 77%, pale yellow solid).
  • GSK-3 ⁇ enzyme inhibitory activity of the compounds prepared in the above examples was obtained from recombinant human GSK-3 ⁇ (Cat No. 14-306) purchased from Upstate, Inc.
  • Phosphorylated GSK-3 substrate (GS2, Cat No. 12-241) was used to assay as follows with reference to the manufacturer's protocol.
  • GSK-3 ⁇ enzyme (1 ng / well), 6.67 uM phospho-glycogen synthase peptide- at various concentrations of the compounds of the examples at a final concentration of 1% DMSO in a 96 well round bottom plate (Cat No. 3365; Corning) at room temperature.
  • Reaction buffer containing 2 (GS2, YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE) [12 mM MOPS (pH 7.0), 1 mM DTT, 1 mM EDTA, 10 mM MgCl 2 ] and enzyme buffer [2 mM MOPS (pH 7.0), 0.01 mM EDTA, 0.001% Brij-35, 0.5% glycerol, 0.1 mg BSA, 0.01% 2-mercaptoethanol] was added and preliminarily reacted at 30 ° C. for 10 minutes. After 10 minutes, 0.2 ⁇ Ci [ 33 P-ATP] and unlabeled 1 ⁇ M ATP were added and reacted at 30 ° C. for 30 minutes.
  • the reaction was then terminated by adding 3% phosphoric acid to the plate.
  • the amount of phosphorylation formed by GSK-3 ⁇ enzyme was transferred to P81 cation exchange filter paper (Whatman, Cat No. 3698-915) using a cell harvester (INOTECH, model name IH-110), washed 4 times with 0.5% phosphoric acid. Finally after washing with acetone it is counted with 3 ml scintillation cocktail (PerkinElmer, Cat No. 1205-440) on a Liquid Scintillation counter (Wallac, Model: 1409).
  • the results obtained at each concentration for the compounds of the above examples are the average values obtained in three wells, and the result analysis was calculated using SigmaPlot 10 (Systat Software Inc., USA) to calculate the IC 50 values of the compounds.
  • a comparative experiment was performed using AR-A014418 (Calbiochem, Cat No. 361549), which is commercially available by the above method, as a control.
  • the experimental results are shown in Table 6 below, where AAA means IC 50 value ⁇ 0.1 ⁇ M, AA means IC 50 value ⁇ 0.3 ⁇ M, A means IC 50 value ⁇ 1.0 ⁇ M, and B means IC 50 value> 1.0 ⁇ M. do).
  • the compounds of Examples 15, 22, 24, 34-35, 37-39, 41-42, 45-47, 53 and 59 among the triazolopyridine derivatives according to the present invention have IC 50 values. It was found that 0.3 ⁇ M or less (indicated by A), and among them, the IC 50 values of the compounds of Examples 26-31 and 65-75 were 0.1 ⁇ M or less (indicated by AA), indicating a very good inhibitory effect.
  • the derivatives of the present invention inhibit GSK-3 ⁇ to prevent diseases associated with dementia, Alzheimer's disease, Parkinson's disease, Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology. Or may be usefully used for treatment.
  • H4IIE H4IIE (ATCC, CRL154) cells were seeded in 96-well tissue culture plates at 100,000 cells / well in 0.1 ml of cell culture medium (DMEM medium / 10% of fetal bovine serum) per well and then cultured at 37 ° C., 5% CO 2. Incubated for 3 hours under conditions. After 3 hours, washed once with 0.1 ml of PBS (phosphate buffered water) and exchanged with 0.1 ml of glucose producing medium (DMEM medium without glucose and serum, containing 20 mM sodium lactate and 2 mM sodium pyruvate) Then incubated for 21 hours.
  • DMEM medium phosphate buffered water
  • glucose producing medium DMEM medium without glucose and serum, containing 20 mM sodium lactate and 2 mM sodium pyruvate
  • the concentration of compound (IC 50 ) that inhibits glucose producing activity by 50% of DMSO alone was determined by fitting to the sigmoidal curve for the graphed data.
  • IC 50 concentration of compound that inhibits glucose producing activity by 50% of DMSO alone
  • SB415286 Sigma
  • the experimental results are shown in Table 7 (where AA means IC 50 value ⁇ 5.0 ⁇ M, A means IC 50 value ⁇ 10 ⁇ M and B means IC 50 value> 10 ⁇ M).
  • the derivatives of the present invention inhibit GSK-3 ⁇ to prevent diseases associated with dementia, Alzheimer's disease, Parkinson's disease, Frontotemporal dementia Parkinson's type, Guam Parkinson's dementia complex, HIV dementia or neurofibrillary pathology. Or may be usefully used for treatment.
  • the triazolopyridine derivative represented by the formula (1) according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • an injection was prepared by containing the above components in the contents shown.

Abstract

La présente invention concerne un dérivé de triazolopyridine noble ou des sels pharmaceutiquement acceptables de celui-ci, un procédé de production de celui-ci, et une composition pharmaceutique comprenant celui-ci. Le dérivé de triazolopyridine noble de la présente invention inhibe GSK-3, et peut donc être utilement utilisé pour prévenir ou traiter des maladies associées à la démence, la maladie d'Alzheimer, la démence frontotemporale, le parkinsonisme, le complexe de Guam Parkinson-démence, la démence liée au VIH, ou des maladies associées à une pathologie des enchevêtrements neurofibrillaires.
PCT/KR2012/003487 2011-05-04 2012-05-03 Dérivé de triazolopyridine noble ou sels pharmaceutiquement acceptables de celui-ci, procédé de production de celui-ci, et composition pharmaceutique comprenant celui-ci WO2012150829A2 (fr)

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KR1020120046919A KR101360176B1 (ko) 2011-05-04 2012-05-03 신규한 트리아졸로피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 약학적 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019043635A1 (fr) 2017-09-01 2019-03-07 Richter Gedeon Nyrt. Composés inhibiteurs de l'activité de d-amino acide oxydase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070004772A1 (en) * 2005-06-17 2007-01-04 Chongqing Sun Triazolopyridine cannabinoid receptor 1 antagonists
WO2010117926A1 (fr) * 2009-04-07 2010-10-14 Schering Corporation Triazolopyridines substituées et leurs analogues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070004772A1 (en) * 2005-06-17 2007-01-04 Chongqing Sun Triazolopyridine cannabinoid receptor 1 antagonists
WO2010117926A1 (fr) * 2009-04-07 2010-10-14 Schering Corporation Triazolopyridines substituées et leurs analogues

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019043635A1 (fr) 2017-09-01 2019-03-07 Richter Gedeon Nyrt. Composés inhibiteurs de l'activité de d-amino acide oxydase

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