WO2018199562A1 - 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1h-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is novel compound, and use thereof - Google Patents

2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1h-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is novel compound, and use thereof Download PDF

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WO2018199562A1
WO2018199562A1 PCT/KR2018/004641 KR2018004641W WO2018199562A1 WO 2018199562 A1 WO2018199562 A1 WO 2018199562A1 KR 2018004641 W KR2018004641 W KR 2018004641W WO 2018199562 A1 WO2018199562 A1 WO 2018199562A1
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formula
compound
disease
present
compound represented
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PCT/KR2018/004641
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French (fr)
Korean (ko)
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배재성
진희경
박민희
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경북대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function

Definitions

  • the present invention is a novel compound 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -L 1,2,3-triazol-4-yl) propane-1,3-di derivatives And it relates to the use thereof, and more particularly to the compound represented by the formula (1) and its use in the prevention, amelioration or treatment of degenerative neurological diseases or depression thereof.
  • ASM acid sph i ngomye 1 i nase
  • ASM inhibitor i.e., a substance capable of inhibiting the expression or activity of ASM, is promising as a useful treatment for various diseases caused by the increase of ASM including neurodegenerative diseases and depression. While no direct ASM inhibitor has been developed to date, several inhibitors have been identified that can indirectly inhibit ASM.
  • Tricyclic antidepressants eg amitriptyl ine (AMI), desipramine, imipramine, etc.
  • ASM amitriptyl ine
  • desipramine desipramine
  • imipramine imipramine
  • ASM indirect inhibitor Tricyclic antidepressants
  • the main pharmacological action of tricyclic antidepressants is increased neurotransmitter activity through reuptake inhibition of neurotransmitters in neurons.
  • the tricyclic antidepressants act on the nervous system and nerve cells, which can cause side effects such as palpitation, increased light sensitivity and vomiting.
  • Another object of the present invention to provide a method for producing a compound represented by the formula (1).
  • Another object of the present invention to provide a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition for treating degenerative neurological disease or depression, which is composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a food composition for improving degenerative neurological disease or depression, which is composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preparing a compound represented by the formula (1).
  • the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for the treatment of degenerative neurological disease or depression consisting essentially of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for improving neurodegenerative disorders or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for improving degenerative neurological disease or depression composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention is the formula 1 Provided is a food composition for improving degenerative neurological disease or depression consisting essentially of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, for the treatment of degenerative neurological disease or depression.
  • a method hereinafter, the present invention will be described in detail.
  • the present invention provides a compound represented by the following formula (1) or a salt thereof; ⁇ Formula 1>
  • 3 ⁇ 4 is hydrogen or an acetyl group, and n is a natural number of 2 ⁇ n ⁇ 5.
  • the compound of Formula 1 of the present invention includes a compound represented by the following Formula 1 (: (when this hydrogen is n is 2) and Formula 1 (when 3 ⁇ 4 is an acetyl group and n is 2)
  • formula lc is 2-amino-2- (1 ′ (2- (2-hydroxyhydroxy) ethyl) -1 ⁇ 1, 2,3-triazol-4-yl) propane-1, 3-diol (2-31 ⁇ 110-2- (1- (2- (2-hydroxyethoxy) ethyl) -l ⁇ l, 2,3-triazol-4-yl) propane-l, 3- (Hol)
  • 'JS-101_newPEG2' in the present specification
  • formula Id is 2-acetylamino-2- (1- (2- (2-hydroxyspecific) ethyl) -1 ⁇ 1, 2, 3-triazole-4-yl) propane-1,3-d
  • the present invention provides a process for preparing a compound represented by the following formula la as a compound of formula (I) wherein R ⁇ l hydrogen, comprising the following steps:
  • step (b) deprotecting the butyloxycarbonyl 7] and the acetonide groups from the compound of Formula 4 prepared in step (a);
  • n is a natural number of 2 ⁇ n ⁇ 5.
  • N is a natural number of 2 ⁇ n ⁇ 5.
  • the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 are reacted as in Scheme 1 to prepare and obtain a compound represented by Chemical Formula 4.
  • a cycloaddition reaction ((: 10) (1 (11 011)) occurs in the terminal alkyne of Formula 2 and the azide region of Formula 3 to form a triazole group.
  • n is a natural number of 2 ⁇ n ⁇ 5.
  • the reaction of Scheme 1 consists of stirring the compound of Formula 2 and the compound of Formula 3 in a suitable solvent.
  • the reaction solvent is not limited as long as it is a substance capable of dissolving the compound of Formula 2 and the compound of Formula 3 isochronous, for example, dimethyl formamide (DMF), dimethyl sulfoxide ( dimethyl sulfoxide (DMSO), dichloromethane (DCM), N- Methyl-2-pyridone (N-Methyl-2—pyrrolidone, NMP).
  • DMF dimethyl formamide
  • DCM dichloromethane
  • N- Methyl-2-pyridone N-Methyl-2—pyrrolidone, NMP
  • known catalyst means may be used to increase the speed and efficiency of triazole production reaction.
  • a copper catalyst may be used.
  • the copper catalyst may be, for example, a copper catalyst having an oxidation number of 1 including copper iodide (copper iodide, Cul), copper bromide (CuBr), copper chloride (CuCl), or copper sulfate (CuS0 4 ). , Oxidized water containing copper acetate (Cu (0Ac) 2 ), copper nitrate (Cu (N0 3 ) 2 ), trifluoromethanesulfonate (Cu (0Tf) 2 ), copper oxide (CuO) and the like A copper catalyst of 2 may be used, but is not limited thereto. Preferably copper iodide may be used.
  • a purification step may be optionally added to obtain a newly produced compound (that is, the compound represented by Formula 4) with high purity.
  • the purification is not particularly limited as long as it is by a compound purification method known in the art, but may be, for example, by a method of obtaining a precipitated solid material generated after addition by ethyl acetate.
  • Compound represented by the formula (2) is fe-butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate (Tert-but y 1 (5-ethi ny 1 -2) , 2-di me ty 1-1, 3-di oxan-5-y 1) carbamate).
  • Compounds represented by Formula 2 and Formula 3 may be purchased and used commercially available, or may be prepared by chemical
  • ⁇ is a natural number of 2 ⁇ 5
  • step (b) the butyloxycarbonyl group and the acetonide group are removed from the compound of Formula 4 prepared in step Deprotection to prepare and obtain the compound represented by the formula la.
  • the butyloxycarbonyl group (Boc) and acetonide group (acetonide group) is a protective ion (protect ion group), deprotection (deprotection) through step (b).
  • n is a natural number of 2 ⁇ n ⁇ 5.
  • the deprotection of the butyloxycarbonyl group or / and the acetonide group may be performed through reaction as in Scheme 2.
  • the reaction of Scheme 2 consists of stirring the compound of Formula 4 with any compound Z known to deprotect the protecting group in a suitable solvent.
  • the compound Z may be a single material capable of simultaneously deprotecting two functional groups of a butyl oxycarbonyl group and an acetonide group, or may be a mixture of heterogeneous compounds deprotecting each functional group.
  • the optional compound Z may be, for example, any one or more selected from the group consisting of trifluoroacetic acid, fluoroacetic acid, difluoroacetic acid, trichloroacetic acid, and the like, but is not limited thereto.
  • the deprotection of step (b) may be a method of reacting by adding trifluoroacetic acid (TFA) as compound Z in Scheme 2.
  • TFA trifluoroacetic acid
  • the deprotection may be performed under water or an aqueous cosolvent system.
  • the type is not particularly limited, but dichloromethane ( dichloromethane, DCM), dimethylformamide (dimethylformamide, DMF), dimethyl sulfoxide (dimethyl sulfoxide, DMSO), ⁇ _ methyl-2-pyrrolidone avoid -1 « ⁇ 1 ⁇ 1 to 2 g 3" 011 (101, ⁇ ) It may be, preferably, dichloromethane (DCM), etc.
  • the reaction temperature of Scheme 2 may be optionally set by the person skilled in the art according to the type of compound Z to be added, limited but not, for example when using trifluoroacetic acid to Talbot No. banung temperature may be set in the range of 0 ° C to 35 ° C, preferably in the range from room temperature to 1CTC It may be assigned.
  • step (b) grinding banong 2
  • newly produced compound i.e., Formula Purification step may optionally be added to obtain high purity).
  • the purification is not limited to this if it is by a compound purification method known in the art, for example, by dissolving by adding methanol (methanol) to remove some suspended matter with a filter, concentrated solvent, ethyl ether (ethyl ether) It may be by the method of recovering the solid (solid precipitate) by precipitation in a filter and then drying in vacuum.
  • the present invention provides a method for producing a compound represented by the following formula lb as a compound of Formula 1 wherein 3 ⁇ 4 is an acetyl group, comprising the step of N-acetylat ion of the compound represented by the formula la To provide.
  • n is a natural number of 2 ⁇ n ⁇ 5.
  • n is a natural water of 2 ⁇ ⁇ ⁇ 5
  • ⁇ -acetylation of the amine group may use a method known in the art, and may be, for example, by treatment with an acetylating agent.
  • Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride. More specifically, the present invention provides a method for preparing a compound represented by the following Chemical Formula lc, wherein 3 ⁇ 4 is hydrogen and ⁇ is 2, including the following steps: All:
  • step (ii) deprotection of a butyl oxycarbonyl group and an acetonide group in the compound of formula 4a prepared in step (i), wherein 3 ⁇ 4 is hydrogen and n is 2
  • step (ii) deprotection of a butyl oxycarbonyl group and an acetonide group in the compound of formula 4a prepared in step (i), wherein 3 ⁇ 4 is hydrogen and n is 2
  • step (ii) deprotection of a butyl oxycarbonyl group and an acetonide group in the compound of formula 4a prepared in step (i), wherein 3 ⁇ 4 is hydrogen and n is 2
  • n is 2
  • Compound represented by the formula (2) is 7fer-butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate ( carbamate), and the compound represented by Chemical Formula 3a means 2- (2-azidoethoxy) ethan-1-ol (2- (2-azidoethoxy) ethanol).
  • the compounds represented by Formula 2 and Formula 3a may be purchased and used commercially available, or may be prepared by chemical synthesis known in the art.
  • step (i) The solvent, reaction temperature, catalyst means, and further purification step required for the reaction in step (i) are as described above in step (a) of the washing process of the compound represented by the formula la.
  • step ( ⁇ ) the butyloxycarbonyl group and the acetonide group are deprotected from the compound of Formula 4a prepared in step (i), and are represented by Formula lc.
  • the compound is prepared and obtained.
  • the method for deprotecting the protecting ion group of the butyloxycarbonyl group (Boc) and the acetonide group (acetonide group) is the same as described above in step (b), and specifically as an example By compound Z It may be carried out through the reaction of Scheme 2a.
  • the solvent, reaction temperature and further purification steps necessary for reaction in step ( ⁇ ) are as described above in step (b) of the method for preparing a compound represented by Formula la.
  • the present invention also provides a compound of Formula 1 wherein 3 ⁇ 4 is an acetyl group and n is 2, comprising the step of N-acetylat ionizing the amine group (NH 2 group) of the compound represented by the formula (lc). It provides a method for producing a compound represented by the formula (Id) as.
  • N-acetylation of the amine group may use a method known in the art, for example, by acetylating agent treatment.
  • Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride.
  • the present invention includes not only the compound represented by Chemical Formula 1, but also pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which can be prepared therefrom.
  • the compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by the 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, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and From non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids All.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and From non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids All.
  • Acid addition salts according to the present invention can be prepared by conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid and dissolving the salt with a water-soluble organic solvent such as ' methane, ethanol, acetone or It may be prepared by precipitation with acetonitrile. In addition, the mixture may be prepared by evaporation of a solvent or excess acid, or by suction filtration of the precipitated salt. 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.
  • the metal salt it is pharmaceutically suitable to prepare sodium, potassium or calcium salts.
  • Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg silver nitrate).
  • the compound of Formula 1 has an excellent inhibitory effect on ASM cid sphingomyel inase. This is illustrated well in the specification examples of the present invention.
  • the compound of the present invention is very excellent in inhibiting the ASM, the therapeutic effect of reducing A ⁇ plaques in the Alzheimer's brain environment, improving memory and anxiety, alleviating neuro-inflammatory Degenerative neurological disease and depression, including Alzheimer's disease It was confirmed that it can be used as a prophylactic or therapeutic agent. Accordingly, the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting of the compound of formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting essentially of the compound of formula (1) or a pharmaceutically acceptable salt thereof.
  • the degenerative neurological disease is not particularly limited as long as it is a neurological disease in which sphingolipid target abnormalities and / or an increase in the activity or expression of ASM is a etiology.
  • Depression that is, depressive disorder of the present invention refers to a disease that causes various cognitive, mental and physical symptoms resulting in deterioration of daily function as the main symptoms of lowering motivation and feelings of depression.
  • the depression of the present invention is known in the art as a depressive disorder is not particularly limited in detail, for example, the depression is a major depressive disorder (MDD), vascular dementia depression, bipolar disorder (bipolar disorder), Unipolar depression, seasonal affective disorders (SAD), depression, dysthymia or depression associated with degenerative neuropathy.
  • MDD major depressive disorder
  • bipolar disorder bipolar disorder
  • Unipolar depression seasonal affective disorders
  • depression dysthymia or depression associated with degenerative neuropathy.
  • it may be a depression due to an abnormal increase in ASM activity (excess activity).
  • the pharmaceutical composition according to the present invention may contain a compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may be formulated in a suitable form with a pharmaceutically acceptable carrier, further comprising an excipient or diluent It may contain.
  • ⁇ pharmaceutically acceptable '' refers to allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when physiologically acceptable and administered to humans. It is a non-toxic composition that does not cause harm.
  • Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, it may include various drug delivery materials used for oral administration to the peptide formulation. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose, glycols, and the like, and may further include stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutane.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspension agent, and the like, in addition to the above components.
  • Other pharmaceutically acceptable carriers and formulations may be referenced in the following literature (Remington's Pharmaceut i cal Sciences, 19th ed., Mack Publ i shing Company, East on, PA, 1995) .
  • composition of the present invention may be administered to any mammal, including humans.
  • it can be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal administration.
  • the pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
  • compositions of the present invention are formulated using powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups 1, slurries, suspensions, etc. using methods known in the art.
  • oral formulations can be obtained by combining the active ingredient with solid excipients, grinding it, adding the appropriate adjuvant, and then processing it into granular mixtures to obtain tablets or dragees.
  • suitable excipients include sugars and corn starch, wheat starch, rice starch and potato starch, including lactose, dextrose, sucrose, solbi, manny, xili, erysri and malty.
  • Layered agents such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including starch, cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl-cellulose, and the like.
  • crosslinked polyvinylpyridone, agar, alginic acid or sodium alginate can be added as disintegrant.
  • the pharmaceutical composition of the present invention may further comprise an anticoagulant system, a lubricant, a humectant, a perfume, an emulsifier, and an antiseptic.
  • Formulations for parenteral administration may be formulated in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publing Company, East on, PA, 1995, a prescription generally known in all pharmaceutical chemistries.
  • the total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fract ionated treatment protocol which is administered for a long time in a multiple iple dose. .
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the degree of disease.
  • the preferred total dose of the pharmaceutical composition of the present invention is about O. Ol ⁇ g to 10,000 mg, most preferably O. lj to lOOmg.
  • the dosage of the pharmaceutical composition is determined in consideration of various factors such as the formulation method, route of administration and frequency of treatment, as well as various factors such as the age, weight, health status, sex, severity of the disease, diet and excretion rate of the patient. In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage of the composition of the present invention.
  • the pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.
  • the present invention provides a food composition for improving neurodegenerative disease or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for improving degenerative neurological disease or depression consisting of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for improving degenerative neurological disease or depression consisting essentially of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Food composition according to the present invention is a functional food (funct ional food), nutritional supplements It includes all forms, including nutritious supplements, health foods, and food addi- tives. These types can be prepared in various forms according to conventional methods known in the art.
  • the food composition itself of the present invention may be prepared in the form of tea, juice and drink for drinking, or granulated, encapsulated and powdered.
  • the food composition of the present invention may be prepared in the form of a composition by mixing with a known substance or active ingredient known to have the effect of preventing, improving or treating degenerative neurological diseases or depression.
  • Functional foods also include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage and conveyor). Etc.), breads and noodles (e.g.
  • the preferred content of the food composition according to the present invention is not limited thereto, but is preferably 0.01 to 50% by weight of the total weight of the finally prepared food.
  • the food composition of the present invention in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate.
  • the present invention provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a preparation for treating neurodegenerative disorders or depression.
  • the present invention provides a method for the treatment of degenerative planetary neuropathy or depression, comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for the treatment of degenerative neurological diseases or depression, characterized by administering to a subject in need thereof an effective amount of a composition consisting of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof It provides a method for the treatment of degenerative neurological diseases or depression, characterized in that for administering an effective amount of the composition consisting essentially of to a subject in need thereof.
  • the term 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, preventing, detecting, diagnosing a degenerative neurological disease or depression or reducing a degenerative neurological disease or depression when administered to an individual. It may be an animal, preferably a mammal, particularly an animal including a human, and may be a cell, tissue, organ or the like derived from the animal. The subject may be a patient in need of the effect.
  • treatment' of the present invention refers generically to ameliorating the symptoms of degenerative neuropathy or depression or degenerative neurological disease or depression, which includes treating, substantially preventing, or ameliorating the condition. May include, but are not limited to, alleviating, healing or preventing one or most of the symptoms resulting from degenerative neuropathy or depression.
  • the term 'compr i sing' of the present invention is used in the same way as 'containing' or 'characteristic', and any additional ingredient element or method step not mentioned in the composition or method, etc. Does not exclude The term 'cons i sting of' means to exclude additional elements, steps or components, etc., unless otherwise specified.
  • essentialt ial ly consi st ing of' includes, in the scope of a composition or method, a component element or step described, as well as a component element or step that does not substantially affect its basic properties, and the like. Means that.
  • FIG. 1A and 1B show JS-101_newPEG2 (FIG. 1A, compound name: 2-amino-2- (1- (2- (2-hydroxyhydroxy) ethyl) ethyl) — an ASM inhibitory novel compound— 1 — 1, 2, 3-triazol-4-yl) propane-1,3_diol) and JS-101_newPEG4 (FIG. IB, compound name: 2-amino-2- (l- (2- (2- (2- (2- (2- (2- (2- Hydroxyethoxy) ethoxy) ethyl) -1H-1,2,3-triazol-4-yl) propane # 1,3-di) shows the structural formula, chemical formula and molecular weight.
  • 3A and 3 ⁇ show the change in ASM concentration in serum (FIG. 3A) and brain tissue (FIG. 3B) of APP / PS1 mice after the negative supply of the novel compound JS-101_newPEG2 of the present invention to APP / PS1 mice.
  • FIG. 4 shows that the novel compounds of the present invention (typically JS-101_newPEG2) are degenerative.
  • FIG. 5A and FIG. 5B show cerebral medulla (Cortex, FIG. 5A) and hippocampus (Hippocampus, FIG. 5A) for APP / PS1 mice negatively supplied with JS-101_newPEG2, an ASM inhibitory novel compound, or APP / PS1 mice not supplied with the compound.
  • FIG. 7B shows the time spent in the target platform on day 11 of the MWM test.
  • 7D shows the results of the contextual and tone tasks during fear condit ioning experiments.
  • 8A shows the results of measuring the time the mouse spent on the wall during the open field test.
  • 8D shows the movement path of the mouse during the open field test.
  • 8E shows the results of measuring the time the mouse spent in the dark during the dark & right test.
  • FIG. 8G is the number of times the mouse has traveled between the dark and the light during the dark & right test.
  • FIG. 8H shows the measurement of the time the mouse first moved from the dark to the light during the dark & right test.
  • FIG. 9B shows inflammatory markers (TNF-a, IL- ⁇ in brain medulla of wild-type mice, APP / PS1 mice negatively fed with ASM inhibitory new compound JS-101_newPEG2, or APP / PS1 mice not fed the compound).
  • IL-6 m NA expression level was evaluated.
  • ⁇ is a natural number of 2 ⁇ ⁇ ⁇ 5.
  • 2-ethanol-specific) ethane-1-ol was obtained.
  • 3 ⁇ 4r-butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (1.3 g, 5.2 mmol) is dissolved in dimethylformamide (DMF, 17 mL) and then iodine Copper (Cul, 0.5 g, 2.6 mmol), 2- (2-azadoethoxy) ethane-1- (690 mg, 16 mmol), v, ⁇ diisopropylethylamine (DIPEA, 2.7 mL, 16 mmol) were added in order. The reaction mixture was stirred at room temperature for 12 hours under nitrogen.
  • DIPEA diisopropylethylamine
  • Tfer-butyl (5- (1- (2- (2-hydroxyethoxy) ethyl) -1 ⁇ 1, 2, 3-triazol-4-yl) -2,2-dimethyl-1,3-dioxane -5-yl) carbamate (1.1 g, 2.9 mmol) was added to a mixed aqueous solution of trifluoroacetic acid (TFA, 2.G mL), dichloromethane (DCM, 2.0 mL), water (1.0 mL). Stirred at room temperature for 12 hours.
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • water 1.0 mL
  • JS-101_newPEG2 In order to determine the neurodegenerative disease and antidepressant effects of the novel compounds JS-101_newPEG2, also according to the experimental outline (schedule) shown in FIG. 4 was administered to the "test substance to the animal model. Specifically, JS-101_newPEG2, a new compound, was supplied to the 7.5-month-old mouse at a negative dose of 100 mg / kg / day. The behavioral analysis was performed one month after the negative supply containing the compound, and the test substance was orally administered through the drinking water even during the behavior analysis period. The brain tissues of the mice were sampled after behavioral analysis (2 months after the negative feed containing compound, 9.5 weeks old mice).
  • R easy Plus mini kit Qiagen, Korea, Ltd
  • Clontech Meauntain View, CA
  • Real-time quantitative PCR was performed to repeat 40 cycles at 72 ° C for 20 seconds.
  • MWM trained the mice 4 times a day for 10 days, removed the platform on day 11, and performed a probe trial.
  • Fear conditioning on the first day put the mouse into the conditioning chamber and gave sound stimulation (10 kHz, 7 dB) and electrical stimulation (0.3 mA, 1 s).
  • the memory of the room was confirmed without stimulation in the same conditioning chamber as the first day.
  • the memory test for fear was performed when only the sound stimulation was given in the other conditioning chamber.
  • Openfield tests and dark and light tests were performed to assess activity and anxiety. Openfield testing The mouse was placed in a square box for 10 minutes to measure overall activity and time spent wandering around the wall and the center (center). The Dark and Right test put the mouse in a rectangular box of dark and light boxes for 10 minutes to measure the time it stayed in each box, the number of box round trips and the first time it went into the bright box.
  • Fibroblast lines (PS1 f ibroblast) of normal and Alzheimer's patients were obtained from Coriel l Inst i tute and used at 37 ° C. and 5% CO 2 in DMEM containing 1 FBS. Thereafter, the cell line was treated with JS-101—newPEG2 (lOuM) or JS-101_newPEG4 (10uM), a novel compound of the present invention, and then ASM activity change was measured.
  • the concentration level of ASM was measured as follows. Specifically, serum, brain tissue, or fibroblast samples of mice were stored at 37 ° C. in combination with ASM active supernatant. Ethane was added to terminate the hydrolysis reaction and then centrifuged.
  • the supernatant of was transferred to a glass vial and then 5 / ⁇ was applied to the UPLC system.
  • the ASM concentration levels were quantified by comparing Bod ipy (ami noacet aldehyde) combined with sphingomyelin and ceramide. Extraction and purification of the sphingomyelin and ceramide . Quantification was carried out by known methods. Briefly, extract and dry lipids from a sample, resuspend the dried lipid extracts in 0.2% Igepal CA-630 (Sigma-Aldr i ch), and quantify the concentration levels of each lipid using the UPLC system. It was.
  • Fibroblasts of Alzheimer's patients were treated with the novel compounds prepared in the present invention to confirm their efficacy.
  • the novel compound prepared in the above-described example To determine the effect of inhibiting ASM activity of JS-101_newPEG2 (FIG. 1A) or JS-101_newPEG4 (FIG. IB), treatment of JS-101_newPEG2 or JS-101—newPEG4 at 10 uM concentration in Alzheimer's patient-derived fibroblasts (psi f ibroblast). Afterwards, the change in activity of ASM was measured.
  • PS1 fibroblasts control significantly increased ASM activity compared to normal derived fibroblasts, but this was significantly reduced by the treatment of ASM inhibition novel compounds JS-101_newPEG2 or JS-101_newPEG4. Accordingly, the compounds represented by Formula 1 of the present invention were considered to have excellent ASM inhibitory effect.
  • JS-101_newPEG2 was typically used to confirm the efficacy against depression and degenerative neurological diseases in vivo.
  • the plasma and brain tissue levels of ASM in APP / PS1 mice were found to be significantly higher than the normal group (WT), compared to the novel compound JS-101_newPEG2 of the present invention. Plasma and brain tissue ASM concentrations of the mice administered were confirmed to be significantly low.
  • an ASM inhibitory compound on Alzheimer's lesion, two months of 100 mg / kg / day of JS_101_newPEG2 were applied to the Alzheimer's animal model APP / PS1 mouse (7.5 months old) according to the experimental schedule shown in FIG.
  • the amyloid- ⁇ ( ⁇ ) profile which is an Alzheimer's lesion, was identified from the mice.
  • the cerebral medulla (Cortex) and hippocampus (Hippocampus) sites of the mice were stained with thioflavin S (ThioS) according to a known method to confirm fibrillar amyloid - ⁇ deposition.
  • APP / PS1 mice have severe impairments in spatial memory, cognitive and memory formation. Although, it was confirmed that APP / PS1 mice to which the novel compound JS-101_newPEG2 of the present invention was ameliorated such disorders (see FIGS. 7A to 7C). JS—101_newPEG2 also showed an improvement in memory in fear condit ioning test (see FIG. 7D). In addition, open field tests and dark & light tests were conducted to determine the effects of JS-101_newPEG2 on activity and anxiety.
  • JS-101_newPEG2 and JS-101_newPEG4 could inhibit the increased ASM activity in Alzheimer's patient-derived fibroblasts.
  • the administration of JS-101_newPEG2, a new ASM inhibitory compound reduced the A ⁇ plaque deposition and inflammation in APP / PS1 mice.
  • JS-101_newPEG2, a new ASM inhibitory compound can be used as a treatment for degenerative brain diseases including Alzheimer's by improving learning and memory in animals with neurodegenerative diseases (particularly Alzheimer's).

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Abstract

The present invention relates to a 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is a novel compound represented by chemical formula 1, and a use thereof. The novel compound of chemical formula 1, of the present invention, has excellent ASM inhibitory effects and has a therapeutic effect on a decrease in Aβ plaques in Alzheimer's brain environment, improvement in memory and anxiety, alleviation of neurogenic inflammation, and the like, so as to be very useful in the development of an agent for preventing or treating degenerative neurological diseases including Alzheimer's disease, and depression, thereby having very excellent industrial applicability.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
신규 화합물 2-아미노-2-(1-(2-(2-히드록시에톡시)에틸)-1^1,2,3-트리아졸_ 4-일)프로판 -1ᅳ 3-디올 유도체 및 이의 용도  Novel compound 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -1 ^ 1,2,3-triazol_4-yl) propane-1'3-diol derivative and its Usage
【기술분야】 Technical Field
본 출원은 2017년 4월 28일에 출원된 대한민국 특허출원 게 10—2017-0055495 호를 우선권으로 주장하고， 상기 명세서 전체는 본 출원의 참고문헌이다. 본 발명은 신규 화합물 2-아미노 -2-(1-(2-(2-히드록시에톡시)에틸) -L 1,2, 3-트리아졸 -4-일)프로판 -1,3-디을 유도체 및 이의 용도에 관한 것으로 더욱 상세하게는 본 명세서에서 화학식 1로 표시되는 화합물과 이의 퇴행성 신경질환 또 는 우울증에 대한 예방, 개선 또는 치료 용도에 관한 것이다.  This application claims the priority of Republic of Korea Patent Application No. 10-2017-0055495, filed April 28, 2017, the entirety of which is a reference of the present application. The present invention is a novel compound 2-amino-2- (1- (2- (2-hydroxyethoxy) ethyl) -L 1,2,3-triazol-4-yl) propane-1,3-di derivatives And it relates to the use thereof, and more particularly to the compound represented by the formula (1) and its use in the prevention, amelioration or treatment of degenerative neurological diseases or depression thereof.
【배경기술】 Background Art
스핑고지질 대사는 정상적인 세포 신호전달을 조절하며， 스핑고지질 대사의 비정상적 변화는 알츠하이머병을 포함한 다양한 신경퇴행성 질환에 영향을 미친다. 한편, 스핑고지질 대사를 조절하는 효소인 ASM(acid sph i ngomye 1 i nase )은 거의 모 든 종류의 세포에서 발현되는 단백질로서， 스핑고지질 대사 및 세포막 턴 오버 (turnover)에 중요한 역할을 한다. 알츠하이머를 포함한 퇴행성 신경질환 환자의 뇌에서는 ASM의 발현이 정상인 에 비해 현저히 증가되어 있으며 , 과발현된 ASM의 발현을 저해하거나 ASM의 활성을 저해하면 아밀로이드 -β(Αβ)의 축적이 억제되고 학습 및 기억력이 개선되어 퇴행 성 신경질환의 치료효과가 나타날 수 있음이 보고된 바 있다 (한국 등록특허 10- 1521117). 또한 최근 우울증과 같은 신경 질환에서 ASM의 활성이 증가되어 있으며 이러한 ASM의 억제는 우울증 완화 효과를 보인다는 보고가 있다 (Nature medicine. 2013 Jul 19(7) :934-938， PLoS One. 2016 Sep 6; 11(9) :e0162498) . 따라서 ASM 억제 제, 즉 ASM의 발현 또는 활성을 억제할 수 있는 물질의 개발은, 신경퇴행성 질환 및 우울증을 포함하여 ASM의 증가로 인해 야기되는 다양한 질환들의 유용한 치료방 법으로서 유망하다. 한편， 현재까지 직접적인 ASM 억제제는 개발되지 않았으나 간접적으로 ASM을 억제할 수 있는 몇 가지 억제제가 동정되었다. 먼저 ASM 간접적 억제제로 가장 널 리. 사용되는 tricyclic antidepressants (e.g. amitriptyl ine (AMI) , desipramine, imipramine 등)는 항우울제 약물로 실제 임상에 사용되고 있다. 최초에 ASM 억제제 로 개발된 것은 아니나 다양한 연구결과들에 의해 본 약물들이 ASM 억제 효과를 나 타낸다는 것이 증명되었다. Tricyclic antidepressants의 주된 약리작용 (mode of action)은 신경세포에서 신경전달물질의 재흡수 억제를 통한 신경전달물질의 활성 증가이며， 부수적인 작용으로 ASM 억제 효과를 나타낸다. 그러나 tricyclic antidepressants의 경우 신경계 및 신경세포에 작용하여 몽통함, 빛 감수성 증가， 구토 등의 부작용을 유발할 수 있으므로 새로운 ASM 활성 억제 약물 개발이 필요하 다. Sphingolipid metabolism regulates normal cell signaling, and abnormal changes in sphingolipid metabolism affect various neurodegenerative diseases, including Alzheimer's disease. Meanwhile, acid sph i ngomye 1 i nase (ASM), an enzyme that regulates sphingolipid metabolism, is a protein expressed in almost all cell types and plays an important role in sphingolipid metabolism and membrane turnover. . In the brain of patients with degenerative neurological disorders, including Alzheimer's disease, the expression of ASM is significantly increased compared to the normal group, and inhibiting the expression of overexpressed ASM or inhibiting the activity of ASM inhibits the accumulation of amyloid-β (Αβ) and increases learning and memory. It has been reported that this can be improved to have a therapeutic effect of neurodegenerative diseases (Korea Patent 10-1521117). In addition, it has recently been reported that the activity of ASM is increased in neurological diseases such as depression, and that inhibition of ASM has a depressive effect (Nature medicine. 2013 Jul 19 (7): 934-938, PLoS One. 2016 Sep 6 11 (9): e0162498). Therefore, the development of an ASM inhibitor, i.e., a substance capable of inhibiting the expression or activity of ASM, is promising as a useful treatment for various diseases caused by the increase of ASM including neurodegenerative diseases and depression. While no direct ASM inhibitor has been developed to date, several inhibitors have been identified that can indirectly inhibit ASM. Firstly most widely used as an ASM indirect inhibitor . Tricyclic antidepressants (eg amitriptyl ine (AMI), desipramine, imipramine, etc.) are used in clinical practice as antidepressant drugs. It was not originally developed as an ASM inhibitor, but various studies have shown that these drugs have been shown to exhibit ASM inhibitory effects. The main pharmacological action of tricyclic antidepressants is increased neurotransmitter activity through reuptake inhibition of neurotransmitters in neurons. However, the tricyclic antidepressants act on the nervous system and nerve cells, which can cause side effects such as palpitation, increased light sensitivity and vomiting.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
이에 본 발명자는 신규 ASM 억제제를 개발하고자 노력하던 중, 화학식 1의 구조를 갖는 신규 화합물인 2-아미노 -2— (1-(2-(2-히드록시에톡시)에틸)ᅳ l^l,2,3- 트리아졸-4-일)프로판-l，3-디을 유도체가 ASM 활성 억제효과가 현저하여 퇴행성 신 경질환 및 우울증 치료에 있어서 우수한 효과를 보일 수 있음을 확인하고 본 발명 을 완성하였다. 따라서 본 발명의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공하는 것이다:  Therefore, the present inventors are trying to develop a novel ASM inhibitor, and a new compound having the structure of formula 1, 2-amino-2— (1- (2- (2-hydroxyethoxy) ethyl) ᅳ l ^ l, The present invention was completed by confirming that 2,3-triazol-4-yl) propane-l, 3-di-l derivative has a significant inhibitory effect on ASM activity and can show excellent effects in treating neurodegenerative diseases and depression. It is therefore an object of the present invention to provide a compound represented by the following formula (1) or a salt thereof:
<화학식 1>  <Formula 1>
Figure imgf000004_0001
상기 식에서 ^은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임. 본 발명의 다른 목적은， 상기 화학식 1로 표시되는 화합물의 제조방법을 제 공하는 것이다. 본 발명의 또 다른 목적은， 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물을 제공하는 것이다.
Figure imgf000004_0001
Where ^ is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5. Another object of the present invention, to provide a method for producing a compound represented by the formula (1). Another object of the present invention, to provide a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명의 또 다른 목적은， 상기 화학식 1의 화합물 또는 이의 약학적 으로 허용 가능한 염으로 구성되는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물을 제공하는 것이다.  Still another object of the present invention is to provide a pharmaceutical composition for treating degenerative neurological disease or depression, which is composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명의 또 다른 목적은， 상기 화학식 1의 화합물 또는 이의 약학적 으로 허용 가능한 염으로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 치 료용 약학적 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은， 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염올 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 개선용 식품 조성물을'제공하는 것이다.  Another object of the present invention, to provide a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting essentially of the compound of Formula 1 or a pharmaceutically acceptable salt thereof. Still another object of the present invention is to provide a food composition for improving degenerative neurological disease or depression, including the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명의 또 다른 목적은， 상기 화학식 1의 화합물 또는 이의 약학적 으로 허용 가능한 염으로 구성되는 퇴행성 신경질환 또는 우울증의 개선용 식품 조 성물을 제공하는 것이다.  Still another object of the present invention is to provide a food composition for improving degenerative neurological disease or depression, which is composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명의 또 다른 목적은, 상기 화학식 1의 화합물 또는 이의 약학적 으로 허용 가능한 염으로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 개 선용 식품 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은， 퇴행성 신경질환 또는 우울증 치료용 제제를 제 조하기 위한， 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 용 도를 제공하는 것이다. 본 발명의 또 다른 목적은 상기 화학식 1의 화합물 또는 이의 약학적으로 허 용 가능한 염을 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것 을 특징으로 하는 퇴행성 신경질환 또는 우울증의 치료 방법을 제공하는 것이다. 【기술적 해결방법】 Still another object of the present invention is to provide a food composition for improving degenerative neurological disease or depression, which is composed essentially of the compound of Formula 1 or a pharmaceutically acceptable salt thereof. Still another object of the present invention is to provide a use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, for preparing an agent for treating neurodegenerative disorders or depression. Another object of the present invention is to provide a method for the treatment of degenerative neuropathy or depression, comprising administering to a subject in need thereof an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof. To provide. Technical Solution
상기와 같은 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공한다:  In order to achieve the above object, the present invention provides a compound represented by the following formula (1) or a salt thereof:
<화학식 1>  <Formula 1>
Figure imgf000006_0001
상기 식에서 ¾은 수소 또는 아세틸기이고， 상기 n은 2≤ n ≤5의 자연수임 . 본 발명의 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1로 표시되 는 화합물의 제조방법을 제공한다. 본 발명의 또 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1의 화 합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경 질환또는 우울증의 치료용 약학적 조성물을 제공한다.
Figure imgf000006_0001
Wherein ¾ is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5. In order to achieve another object of the present invention, the present invention provides a method for preparing a compound represented by the formula (1). In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명의 또 다른 목적을 달성하기 위하여, 본 발명은 상기 화학식 1 의 화합물 또는 이의 약학적으로 허용 가능한 염으로 구성되는 퇴행성 신경질환 또 는 우울증의 치료용 약학적 조성물을 제공한다.  In addition, to achieve another object of the present invention, the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명의 또 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1 의 화합물 또는 이의 약학적으로 허용 가능한 염으로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물을 제공한다. 본 발명의 또 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1의 화 합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경 질환또는 우울증의 개선용 식품 조성물을 제공한다.  In addition, to achieve another object of the present invention, the present invention provides a pharmaceutical composition for the treatment of degenerative neurological disease or depression consisting essentially of the compound of Formula 1 or a pharmaceutically acceptable salt thereof. In order to achieve another object of the present invention, the present invention provides a food composition for improving neurodegenerative disorders or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명의 또 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1 의 화합물 또는 이의 약학적으로 허용 가능한 염으로 구성되는 퇴행성 신경질환 또 는 우울증의 개선용 식품 조성물을 제공한다.  In addition, in order to achieve another object of the present invention, the present invention provides a food composition for improving degenerative neurological disease or depression composed of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명의 또 다른 목적을 달성하기 위하여， 본 발명은 상기 화학식 1 의 화합물 또는 이의 약학적으로 허용 가능한 염으로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 개선용 식품 조성물을 제공한다. 본 발명의 또 다른 목적을 달성하기 위하여, 퇴행성 신경질환 또는 우울증 치료용 제제를 제조하기 위한 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다. 본 발명의 또 다른 목적올 달성하기 위하여， 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 특징으로 하는 퇴행성 신경질환 또는 우울증의 치료 방법을 제공한다. 이하 본 발명을 상세히 설명한다. 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 염을 제공한다; <화학식 1> In addition, in order to achieve another object of the present invention, the present invention is the formula 1 Provided is a food composition for improving degenerative neurological disease or depression consisting essentially of a compound of the present invention or a pharmaceutically acceptable salt thereof. In order to achieve another object of the present invention, there is provided a use of the compound of formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic agent for the treatment of degenerative neurological diseases or depression. In order to achieve another object of the present invention, an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, for the treatment of degenerative neurological disease or depression. Provide a method. Hereinafter, the present invention will be described in detail. The present invention provides a compound represented by the following formula (1) or a salt thereof; <Formula 1>
Figure imgf000007_0001
Figure imgf000007_0001
상기 식에서 ¾은 수소 또는 아세틸기이고， 상기 n은 2≤ n ≤ 5의 자연수임. ¾ is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5.
상기 화학식 1의 화합물은 구체적으로 하기 화학식 13(¾이 수소인 경우) 또 는 화학식 11)(¾이 아세틸기인 경우)로 표시되는 화합물을 포함하는 것일 수 있다. <화학식 la> The compound of Formula 1 may specifically include a compound represented by Formula 1 3 (when ¾ is hydrogen) or Formula 11) (when ¾ is an acetyl group). <Formula la>
Figure imgf000007_0002
상기 식에서 n은 2≤ n ≤5의 자연수임 .
Figure imgf000007_0002
In which n is a natural number of 2 ≦ n ≦ 5.
<화학식 lb> <Formula lb>
Figure imgf000008_0001
상기 식에서 n은 2≤ n ≤5의 자연수임 . 더욱 구체적으로 본원 발명의 화학식 1의 화합물은 하기 화학식 1(:( 이 수 소이며 n이 2인 경우) 및 화학식 1(3(¾이 아세틸기이며 n이 2인 경우)로 표시되는 화합물을 포함한다; 본 명세서에서 화학식 lc는 2-아미노 -2-(1ᅳ(2-(2-하이드록시에 록시)에틸) -1^1 , 2 ,3-트리아졸 -4-일 )프로판 -1， 3-디올(2-31^110-2-(1-(2-(2- hydroxyethoxy)ethyl)-l^l,2,3-triazol-4-yl)propane-l,3-(Hol)을 의미하며 본 명 세서에서 'JS-101_newPEG2' 으로 칭할 수 있고， 화학식 Id는 2-아세틸아미노 -2-(1- (2-(2-하이드록시에특시 )에틸 )-1^1， 2， 3-트리아졸 -4—일 )프로판 -1， 3-디올 (2-Acety 1 amino-2-(l-(2-( 2-hydr oxye t hoxy ) e t hy 1 )-l fz-l,2,3-triazol-4-yl )propane_l,3ᅳ diol ) 를 의미한다.
Figure imgf000008_0001
In which n is a natural number of 2 ≦ n ≦ 5. More specifically, the compound of Formula 1 of the present invention includes a compound represented by the following Formula 1 (: (when this hydrogen is n is 2) and Formula 1 (when ¾ is an acetyl group and n is 2) In the present specification, formula lc is 2-amino-2- (1 ′ (2- (2-hydroxyhydroxy) ethyl) -1 ^ 1, 2,3-triazol-4-yl) propane-1, 3-diol (2-31 ^ 110-2- (1- (2- (2-hydroxyethoxy) ethyl) -l ^ l, 2,3-triazol-4-yl) propane-l, 3- (Hol) It may be referred to as 'JS-101_newPEG2' in the present specification, and the formula Id is 2-acetylamino-2- (1- (2- (2-hydroxyspecific) ethyl) -1 ^ 1, 2, 3-triazole-4-yl) propane-1,3-diol (2-Acety 1 amino-2- (l- (2- (2-hydr oxye t hoxy) et hy 1) -lf z -l, 2 , 3-triazol-4-yl) propane_l, 3 ᅳ diol).
<화학식 lc> <Formula lc>
Figure imgf000008_0002
Figure imgf000008_0002
<화학식 ld>
Figure imgf000009_0001
<Formula ld>
Figure imgf000009_0001
본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다. 이하， 상기 화학식 1에서 ^의 구체적 잔기에 따른 각 화합물의 수득방법을 제공한다. The present invention provides a method for preparing a compound represented by Chemical Formula 1. Hereinafter, a method of obtaining each compound according to the specific moiety of ^ in Chemical Formula 1 is provided.
본 발명은 하기의 단계들을 포함하는， R^l 수소인 화학식 1의 화합물로서 하기 화학식 la로 표시되는 화합물의 제조방법을 제공한다: The present invention provides a process for preparing a compound represented by the following formula la as a compound of formula (I) wherein R ^ l hydrogen, comprising the following steps:
(a) 하기 화학식 2의 화합물과 하기 화학식 3으로 표시되는 화합물을 반웅시 켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계 ; 및  (a) preparing a compound represented by the following Chemical Formula 4 by reacting the compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3; And
(b) 상기 (a) 단계에서 제조한 하기 화학식 4의 화합물에서 부틸옥시카보닐 7] ( bu t y 1 oxyc ar bony 1 group) 및 아세토니드기 (acetonide group)를 탈보호 (deprotect ion)하여， ！^이 수소인 화학식 1의 화합물로서 하기 화학식 l a로 표시되 는 화합물을 제조 및 수득하는 단계 .  (b) deprotecting the butyloxycarbonyl 7] and the acetonide groups from the compound of Formula 4 prepared in step (a); A process for preparing and obtaining a compound represented by the following formula la as a compound of formula 1 wherein！ ^ is hydrogen.
<화학식 2>  <Formula 2>
Figure imgf000009_0002
Figure imgf000009_0002
<화학식 3>
Figure imgf000009_0003
상기 식에서 n은 2≤ n ≤5의 자연수임. <Formula 3>
Figure imgf000009_0003
Where n is a natural number of 2 ≦ n ≦ 5.
<화학식 4> <Formula 4>
Figure imgf000010_0001
Figure imgf000010_0001
상기 식에서 n은 2≤ n ≤5의 자연수임.  Where n is a natural number of 2 ≦ n ≦ 5.
<화학식 la> <Formula la>
Figure imgf000010_0002
Figure imgf000010_0002
상기 식에서 n은 2≤ n ≤5의 자연수임 . 상기 (a) 단계에서는 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응식 1과 같이 반웅시켜， 화학식 4로 표시되는 화합물을 제조 및 수득 한다. 하기 반응식 1의 반응을 통하여， 화학식 2의 말단 알킨 (terminal alkyne)과 화학식 3의 아자이드 (azide) 영역에서 고리화 첨가반웅( (：10 (1(11 011)이 일어나 트리아졸기를 형성한다. N is a natural number of 2≤n≤5. In the step (a), the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 are reacted as in Scheme 1 to prepare and obtain a compound represented by Chemical Formula 4. Through the reaction of Scheme 1, a cycloaddition reaction ((: 10) (1 (11 011)) occurs in the terminal alkyne of Formula 2 and the azide region of Formula 3 to form a triazole group.
Figure imgf000010_0003
상기 반응식 1에서 n은 2≤ n ≤5의 자연수임.
Figure imgf000010_0003
In Scheme 1, n is a natural number of 2 ≦ n ≦ 5.
상기 반응식 1의 반웅은 화학식 2의 화합물과 화학식 3의 화합물을 적당한 용매에서 교반시키는 것으로 이루어진다. 이때 반응 용매로는 상기 화학식 2의 화 합물과 화학식 3의 화합물을 등시에 용해시킬 수 있는 물질이라면 그 종류가 제한 되지 않으나， 예를 들어 디메틸포름아마이드 (dimethyl formamide, DMF), 디메틸설폭 사이드 (dimethyl sulfoxide, DMSO), 다이클로로메테인 (dichloromethane, DCM), N- 메틸 -2-피를리돈 (N-Methyl -2— pyrrolidone, NMP)일 수 있다. 바람직하게 디메틸포름 아마이드를사용하는 것 일 수 있다. 또한 상기 (a) 단계에서는 트리아졸 생성 반웅의 속도 및 효율을 높이기 위 한 공지의 촉매수단을 사용할 수 있으몌 일례로 구리 촉매를 사용할 수 있다. 상 기 구리 촉매는 일례로 요오드화구리 (아이오딘화 구리， Cul), 브롬화구리 (CuBr), 염화구리 (CuCl) 등을 포함하는 산화수가 1인 구리 촉매를 사용할 수 있고， 또는 황산구리 (CuS04), 초산구리 (Cu(0Ac)2), 질산구리 (Cu(N03)2), 트리플루오로메탄설 포네이트화구리 (Cu(0Tf)2), 산화구리 (CuO) 등을 포함하는산화수가 2인 구리 촉매 를 사용할 수 있으나， 이에 제한되지 않는다. 바람직하게는 요오드화 구리를 사용 할수 있다. 산화수가 1인 구리 촉매를 사용할 경우에는 염기도 함께 넣어주며, 중탄산 이온이나 탄산 이온의 알칼리 금속염， 또는 아민 염기인 트리에틸아민， 디이소프로 필에틸아민 피리딘， 루티딘， 콜리딘 등을 사용할 수 있으나， 이에 제한되지 않는 다. 산화수가 2인 구리 촉매를 사용할 경우 소듐-아스코베이트， 소듐 설파이트 (Na2S03), 디티오트레이를 (dithiothreitol)로 이루어진 환원제를 추가로 사용할 수 있으며， 이에 제한되지 않는다. 또한， 상기 반웅식 1에서의 반웅 온도는 실온 내지 용매의 비등점까지의 범 위 일 수 있고， 바람직하게 실온 내지 60°C의 범위 일 수 있다. 상기 (a) 단계의 반웅식 1의 반웅 이후에， 새롭게 생성된 화합물 (즉， 화학식 4로 표시되는 화합물)을 고순도로 수득하기 위하여 정제단계를 임의로 추가할 수 있다. 상기 정제는 당업계에 알려진 화합물 정제 방법에 의한 것이라면 특별히 제 한되지 않으나， 예를 들어 에틸아세테이트 (ethyl acetate)를 첨가하여 방치한 후 생기는 침전 고체물질을수득하는 방법에 의한 것일 수 있다. 상기 화학식 2로 표시되는 화합물은 fe -부틸 (5-에틴일 -2， 2-디메틸 -1,3-디 옥산 -5-일)카바메이트 ( Tert-but y 1 ( 5-e t h i ny 1 -2 , 2-d i me t y 1 - 1 , 3-d i oxan-5-y 1 ) carbamate)를 의미한다. 상기 화학식 3으로 표시되는 화합물은 n에 따라， n=2일 때 2-(2—아자이도에록시)에탄을 ((2-(2-azidoethoxy)ethanol)), n=3일 때 2-[2— (2-아자 이도에특시)에톡시] -에탄올 (2-[2-(2-azidoethoxy)ethoxy]-ethanol), n=4일 때 2- [2-[2-(2-아자이도에록시)에록시]에록시] -에탄을 (2-[2-[2-(2- az i doethoxy )ethoxy ] et hoxy ] -ethano 1 ) , n=5일 때 14-아자이도 -3, 6, 9， 12-테트라옥사 테트라데카놀 (14-Azi k)-3,6,9,12-tetraoxatetradecanol)을 의미한다. 상기 화학식 2 및 화학식 3으로 표시되는 화합물은 상업적으로 판매되는 것을 구입하여 사용할 수 있으며， 또는 당업계에 공지된 화학적 합성법으로 제조한 것을 사용할 수 있다. 일례로 본원 발명의 실시예에서는 하기 반응식 K에 따라 화학식 3의 화합물을 수득 한 바 있다. The reaction of Scheme 1 consists of stirring the compound of Formula 2 and the compound of Formula 3 in a suitable solvent. The reaction solvent is not limited as long as it is a substance capable of dissolving the compound of Formula 2 and the compound of Formula 3 isochronous, for example, dimethyl formamide (DMF), dimethyl sulfoxide ( dimethyl sulfoxide (DMSO), dichloromethane (DCM), N- Methyl-2-pyridone (N-Methyl-2—pyrrolidone, NMP). Preferably it may be to use dimethylformamide. In addition, in step (a), known catalyst means may be used to increase the speed and efficiency of triazole production reaction. For example, a copper catalyst may be used. The copper catalyst may be, for example, a copper catalyst having an oxidation number of 1 including copper iodide (copper iodide, Cul), copper bromide (CuBr), copper chloride (CuCl), or copper sulfate (CuS0 4 ). , Oxidized water containing copper acetate (Cu (0Ac) 2 ), copper nitrate (Cu (N0 3 ) 2 ), trifluoromethanesulfonate (Cu (0Tf) 2 ), copper oxide (CuO) and the like A copper catalyst of 2 may be used, but is not limited thereto. Preferably copper iodide may be used. When using a copper catalyst having 1 oxidation number, the base is also added, and an alkali metal salt of bicarbonate ions or carbonate ions, or an amine base triethylamine, diisopropylethylamine pyridine, rutidine, collidine, etc. may be used. It is not limited to this. When using a copper catalyst having 2 oxidation numbers, a reducing agent consisting of sodium ascorbate, sodium sulfite (Na 2 SO 3), and dithiothreitol may be additionally used, but is not limited thereto. In addition, the reaction temperature in the reaction formula 1 may range from room temperature to the boiling point of the solvent, and may preferably range from room temperature to 60 ° C. After the reaction in Step 1 of Step (a), a purification step may be optionally added to obtain a newly produced compound (that is, the compound represented by Formula 4) with high purity. The purification is not particularly limited as long as it is by a compound purification method known in the art, but may be, for example, by a method of obtaining a precipitated solid material generated after addition by ethyl acetate. Compound represented by the formula (2) is fe-butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate (Tert-but y 1 (5-ethi ny 1 -2) , 2-di me ty 1-1, 3-di oxan-5-y 1) carbamate). Compound represented by the formula (3) is 2- (2—azidoethoxy) ethane when n = 2, according to n ((2- (2-azidoethoxy) ethanol)), 2- [when n = 3 2— (2-aza isidoe) ethoxy] -ethanol (2- [2- (2-azidoethoxy) ethoxy] -ethanol), when n = 4 2- [2- [2- (2-aza Isoethoxy) ethoxy] ethoxy] -ethane (2- [2- [2- (2-az i doethoxy) ethoxy] et hoxy] -ethano 1), 14-azido-3 when n = 5 , 6, 9, 12-tetraoxa tetradecanol (14-Azi k) -3,6,9,12-tetraoxatetradecanol). Compounds represented by Formula 2 and Formula 3 may be purchased and used commercially available, or may be prepared by chemical synthesis known in the art. For example, in the examples of the present invention, a compound of Chemical Formula 3 was obtained according to Scheme K below.
[반웅식 K] [Bungungsik K]
CI
Figure imgf000012_0001
상기 반웅식 K에서 η은 2≤ η ≤5의 자연수임 상기 (b) 단계에서는 상기 ) 단계에서 제조된 화학식 4의 화합물에서 부틸 옥시카보닐기 (butyloxycarbonyl group) 및 아세토니드기 (acetonide group)를 탈보 호 (deprotection)하여， 화학식 la로 표시되는 화합물을 제조 및 수득한다. 상기 부틸옥시카보닐기 (butyloxycarbonyl group, Boc) 및 아세토니드기 (acetonide group)는 보호기 (protect ion group)로서， (b) 단계를 통해 탈보호 (deprotection) 시킨다. 기능기의 보호 및 탈보호는 당업계에 공지된 방법을 사용 할 수 있으며 다음의 문헌을 참고로 할 수 있다: "Protective Groups in Organic Chemistry" 3rd edition, T.W. Greene and P.G.M. Wuts , Wileyᅳ Interscience (1999) , "Protecting Groups" P.J. Kocienski , Georg Thieme Verlag (1994) . CI
Figure imgf000012_0001
In the reaction K, η is a natural number of 2≤η≤5 In the step (b), the butyloxycarbonyl group and the acetonide group are removed from the compound of Formula 4 prepared in step Deprotection to prepare and obtain the compound represented by the formula la. The butyloxycarbonyl group (Boc) and acetonide group (acetonide group) is a protective ion (protect ion group), deprotection (deprotection) through step (b). The protection and deprotection of functional groups can be made using methods known in the art and can be referred to the following literature: "Protective Groups in Organic Chemistry" 3rd edition, TW Greene and PGM Wuts, Wiley's Interscience (1999 ), "Protecting Groups" PJ Kocienski, Georg Thieme Verlag (1994).
[반응식 2]
Figure imgf000013_0001
Scheme 2
Figure imgf000013_0001
< ■학식 la>  <La
상기 반응식 2에서 n은 2≤ n ≤5의 자연수임 . 일례로， 상기 (b) 단계에서 부틸옥시카보닐기 또는 /및 아세토니드기의 탈보 호는 상기 반응식 2와 같은 반웅을 통하여 수행되는 것일 수 있다. 상기 반응식 2 의 반응은 상기 화학식 4의 화합물과 보호기를 탈보호하는 것으로 알려진 임의의 화합물 Z를 적당한 용매에서 교반시키는 것으로 이루어진다. 상기 화합물 Z는 부틸 옥시카보닐기 및 아세토니드기의 두 기능기를 동시에 탈보호화 할 수 있는 단일 물 질 일 수 있으며， 또는 각각의 기능기를 탈보호화하는 이종 화합물의 흔합물일 수 있다. 상기 임의의 화합물 Z는 예를 들어 트리플루오로아세트산， 플루오로아세트 산， 디프루오로아세트산， 트리클로로아세트산 등으로 이루어진 군에서 선택된 어느 하나 이상의 것 일 수 있으며 이에 제한되지 않는다. 바람직하게 상기 (b) 단계의 탈보호화는 상기 반응식 2에서 화합물 Z로서 트리플로오로아세트산 (trifluoroacetic acid, TFA)을 첨가하여 반응시키는 방법일 수 있다. 상기 탈보호는 물 또는 수용성 공용매 시스템 하에서 수행되는 것일 수 있 다. 상기 수용성 공용매 시스템에 있어서， 물 이외에 포함되는 용매로는 상기 화학 식 4의 화합물과 탈보호화를 위해 투입하는 물질을 동시에 용해시킬 수 있는 것이 라면 그 종류가 특별히 제한되지 않으나, 다이클로로메테인 (dichloromethane, DCM), 디메틸포름아마이드 (dimethylformamide, DMF), 디메틸설폭사이드 (dimethyl sulfoxide, DMSO) , ^메틸_2-피를리돈 -1«^1^1-2ᄀ3 "011(101 , ΝΜΡ) 등일 수 있 고， 바람직하게는 다이클로로메테인 (dichloromethane, DCM)일 수 있다. 상기 반응식 2의 반응 온도는， 첨가되는 화합물 Z의 종류에 따라 당업자가 선택적으로 반웅 온도를 설정할 수 있으며， 이에 제한되지 않으나 예를 들어 탈보 호를 위해 트리플루오로아세트산을 사용하는 경우 반웅 온도는 0°C 내지 35°C 의 범위에서 설정될 수 있고, 바람직하게 1CTC 내지 실온의 범위에서 설정될 수 있다. 상기 (b) 단계의 반응삭 2의 반옹 이후에, 새롭게 생성된 화합물 (즉， 화학식 la로 표시되는 화합물)을 고순도로 수득하기 위하여 정제단계를 임의로 추가할 수 있다. 상기 정제는 당업계에 알려진 화합물 정제 방법에 의한 것이라면 이에 제한 되지 않으나, 예를 들어 메탄올 (methanol )을 첨가하여 녹인 후 일부 부유물을 필 터로 제거하고 용매를 농축시킨 것을， 다시 에틸에테르 (ethyl ether)에 침전시켜 필터로 솔리드 (고체 침전물)를 회수한 후 진공으로 건조하는 방법에 의한 것일 수 있다. 또한 본 발명은 하기 화학식 la로 표시되는 화합물의 아민기를 N-아세틸화 (N-acetylat ion)하는 단계를 포함하는， ¾이 아세틸기인 화학식 1의 화합물로서 하 기 화학식 lb로 표시되는 화합물의 제조방법을 제공한다. In Scheme 2, n is a natural number of 2≤n≤5. For example, in step (b), the deprotection of the butyloxycarbonyl group or / and the acetonide group may be performed through reaction as in Scheme 2. The reaction of Scheme 2 consists of stirring the compound of Formula 4 with any compound Z known to deprotect the protecting group in a suitable solvent. The compound Z may be a single material capable of simultaneously deprotecting two functional groups of a butyl oxycarbonyl group and an acetonide group, or may be a mixture of heterogeneous compounds deprotecting each functional group. The optional compound Z may be, for example, any one or more selected from the group consisting of trifluoroacetic acid, fluoroacetic acid, difluoroacetic acid, trichloroacetic acid, and the like, but is not limited thereto. Preferably, the deprotection of step (b) may be a method of reacting by adding trifluoroacetic acid (TFA) as compound Z in Scheme 2. The deprotection may be performed under water or an aqueous cosolvent system. In the water-soluble cosolvent system, as long as it can dissolve the compound of Chemical Formula 4 and the material to be deprotected at the same time as the solvent included in addition to water, the type is not particularly limited, but dichloromethane ( dichloromethane, DCM), dimethylformamide (dimethylformamide, DMF), dimethyl sulfoxide (dimethyl sulfoxide, DMSO), ^ _ methyl-2-pyrrolidone avoid -1 «^ 1 ^ 1 to 2 g 3" 011 (101, ΝΜΡ) It may be, preferably, dichloromethane (DCM), etc. The reaction temperature of Scheme 2 may be optionally set by the person skilled in the art according to the type of compound Z to be added, limited but not, for example when using trifluoroacetic acid to Talbot No. banung temperature may be set in the range of 0 ° C to 35 ° C, preferably in the range from room temperature to 1CTC It may be assigned. After the reaction of step (b) grinding banong 2, newly produced compound (i.e., Formula Purification step may optionally be added to obtain high purity). The purification is not limited to this if it is by a compound purification method known in the art, for example, by dissolving by adding methanol (methanol) to remove some suspended matter with a filter, concentrated solvent, ethyl ether (ethyl ether) It may be by the method of recovering the solid (solid precipitate) by precipitation in a filter and then drying in vacuum. In another aspect, the present invention provides a method for producing a compound represented by the following formula lb as a compound of Formula 1 wherein ¾ is an acetyl group, comprising the step of N-acetylat ion of the compound represented by the formula la To provide.
<화학식 la>  <Formula la>
Figure imgf000014_0001
Figure imgf000014_0001
상기 식에서 n은 2≤ n ≤5의 자연수임 .  In which n is a natural number of 2 ≦ n ≦ 5.
<화학식 lb> <Formula lb>
Figure imgf000014_0002
상기 식에서 n은 2≤ η ≤5의 자연수임 아민기의 Ν-아세틸화는 당업계에 공지된 방법을 사용할 수 있으며， 일례로 아세틸화제 처리에 의한 것일 수 있다. 당업계에 공지된 아세틸화제로는 일례로 아 세트산무수물 또는 아세트산 클로라이드 등이 있으나 이에 제한되지 않는다. 더욱 구체적으로 본 발명은 하기의 단계들을 포함하는， ¾이 수소이며 η이 2 인 화학식 1의 화합물로서 하기 화학식 lc로 표시되는 화합물의 제조방법을 제공한 다:
Figure imgf000014_0002
In the above formula, n is a natural water of 2 ≦ η ≦ 5, and Ν-acetylation of the amine group may use a method known in the art, and may be, for example, by treatment with an acetylating agent. Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride. More specifically, the present invention provides a method for preparing a compound represented by the following Chemical Formula lc, wherein ¾ is hydrogen and η is 2, including the following steps: All:
(i) 하기 화학식 2의 화합물과 하기 화학식 3a로 표시되는 화합물을 반웅시 켜 하기 화학식 4a로 표시되는 화합물을 제조하는 단계 ; 및  (i) preparing a compound represented by the following Chemical Formula 4a by reacting the compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3a; And
(ii) 상기 (i) 단계에서 제조한 하기 화학식 4a의 화합물에서 부틸옥시카보 닐기 (butyl oxycarbonyl group) 및 아세토니드기 (acetonide group)를 탈보호 (deprotection)하여, ¾이 수소이며 n이 2인 화학식 1의 화합물로서 하기 화학식 lc 로 표시되는 화합물을 제조 및 수득하는 단계 .  (ii) deprotection of a butyl oxycarbonyl group and an acetonide group in the compound of formula 4a prepared in step (i), wherein ¾ is hydrogen and n is 2 Preparing and obtaining a compound represented by the following Chemical Formula lc as a compound of Formula 1.
<화학식 2>  <Formula 2>
Figure imgf000015_0001
Figure imgf000015_0001
<화학식 3a> <Formula 3a>
Figure imgf000015_0002
Figure imgf000015_0002
상기 (i) 및 (ii) 단계를 포함하는 화학식 lc로 표시되는 화합물의 제조방법 은, 전술한 (a) 및 (b) 단계를 포함하는 화학식 la로 표시되는 화합물의 제조방법 의 일례로서， 상기 화학식 3으로 표시되는 화합물 중 n=2인 구체적 일례로서 화학 식 3a에 해당하는 화합물올 이용하는 것을 특징으로 한다. 구체적으로 상기 ( i ) 단계에서는 화학식 2로 표시되는 화합물과 화학식 3a로 표시되는 화합물을 반응식 la와 같이 반응시켜， 화학식 4a로 표시되는 화합물을 제 조 및 수득한다. 하기 반응식 la의 반응을 통하여 , 화학식 2의 말단 알킨 (terminal alkyne)과 화학식 3a의 아자이드 (azide) 영역에서 고리화 첨가반응 (cycloaddi t ion) 이 일어나 트리아졸기를 형성한다. Method for producing a compound represented by the formula (lc) comprising the steps (i) and (ii), as an example of the method for producing a compound represented by the formula la comprising the above-mentioned steps (a) and (b), As a specific example in which n = 2 among the compounds represented by the formula (3), the compound corresponding to the formula (3a) is used. Specifically, in the step (i), the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3a are reacted as in Scheme la, thereby preparing and obtaining the compound represented by Chemical Formula 4a. Through the reaction of Reaction Scheme la, cycloaddi t ion occurs in the terminal alkyne of Formula 2 and the azide region of Formula 3a to form a triazole group.
[반응식 la]  Reaction la
Figure imgf000016_0001
Figure imgf000016_0001
상기 화학식 2로 표시되는 화합물은 7fer -부틸 (5-에틴일 -2, 2-디메틸 -1 ,3-디 옥산 -5-일)카바메이트 (
Figure imgf000016_0002
) carbamate)를 의미하며， 상기 화학식 3a로 표시되는 화합물은 2-(2-아자이도에톡 시)에탄 -1-올 (2-(2-azidoethoxy)ethanol )을 의미한다. 상기 화학식 2 및 화학식 3a 으로 표시되는 화합물은 상업적으로 판매되는 것을 구입하여 사용할 수 있으며， 또 는 당업계에 공지된 화학적 합성법으로 제조한 것을 사용할 수 있다. 일례로 본 발 명에서 화학삭 3a로 표시되는 화합물은， 반응식 K 중 n=2인 경우로서， 2-(2-클로로 에톡시)에탄 -1-을로부터 반응식 K— 1에 따라 수득된 바 있다. 상기 ( i ) 단계에서 반옹에 필요한 용매， 반웅온도， 촉매 수단 및 추가 정제 단계 등에 대해서는 상기 화학식 la로 표시되는 화합물의 쎄조방법 증 (a) 단계에 서 전술한 바와 같다. 상기 ( Π ) 단계에서는 상기 ( i ) 단계에서 제조된 화학식 4a의 화합물에서 부 틸옥시카보닐기 (butyloxycarbonyl group) 및 아세토니드기 (acetonide group)를 탈 보호 (deprotect ion)하여， 화학식 lc로 표시되는 화합물을 제조 및 수득한다. - 상기 부틸옥시카보닐기 (butyloxycarbonyl group, Boc) 및 아세토니드기 (acetonide group)의 보호기 (protect ion group)를 탈보호 시키는 방법에 대해서는 상기 (b) 단계에서 전술한 바와 같으며， 구체적 일례로 임의의 화합물 Z에 의하여 하기 반응식 2a의 반응을 통해 수행되는 것일 수 있다. Compound represented by the formula (2) is 7fer-butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate (
Figure imgf000016_0002
carbamate), and the compound represented by Chemical Formula 3a means 2- (2-azidoethoxy) ethan-1-ol (2- (2-azidoethoxy) ethanol). The compounds represented by Formula 2 and Formula 3a may be purchased and used commercially available, or may be prepared by chemical synthesis known in the art. In one embodiment, the compound represented by the chemical process 3a in the present invention, where n = 2 in Scheme K, has been obtained according to Scheme K-1 from 2- (2-chloroethoxy) ethane-1-. . The solvent, reaction temperature, catalyst means, and further purification step required for the reaction in step (i) are as described above in step (a) of the washing process of the compound represented by the formula la. In the step (Π), the butyloxycarbonyl group and the acetonide group are deprotected from the compound of Formula 4a prepared in step (i), and are represented by Formula lc. The compound is prepared and obtained. The method for deprotecting the protecting ion group of the butyloxycarbonyl group (Boc) and the acetonide group (acetonide group) is the same as described above in step (b), and specifically as an example By compound Z It may be carried out through the reaction of Scheme 2a.
[반응식 2a] Scheme 2a
H03 r ^
Figure imgf000017_0001
H 0 3 r ^
Figure imgf000017_0001
학석 4a > <¾학식 lc>  Academic 4a> <¾ lc>
상기 (π ) 단계에서 반웅에 필요한 용매, 반웅온도 및 추가 정제 단계 등에 대해서는 상기 화학식 la로 표시되는 화합물의 제조방법 중 (b) 단계에서 전술한 바와 같다. 또한 본 발명은, 화학식 lc로 표시되는 화합물의 아민기 (NH2 group)를 N-아 세틸화 (N-acetylat ion)하는 단계를 포함하는, ¾이 아세틸기이며 n이 2인 화학식 1 의 화합물로서 화학식 Id로 표시되는 화합물의 제조방법을 제공한다. 아민기의 N-아세틸화는 당업계에 공지된 방법을 사용할 수 있으며, 일례로 아세틸화제 처리에 의한 것일 수 있다. 당업계에 공지된 아세틸화제로는 일례로 아 세트산무수물 또는 아세트산 클로라이드 등이 있으나 이에 제한되지 않는다. 본 발명은 상기 화학식 1로 표시되는 화합물뿐만 아니라， 이의 약학적으로 허용 가능한 염, 이로부터 제조될 수 있는 가능한 용매화물, 수화물， 라세미체， 또 는 입체이성질체를 모두 포함한다. 본 발명의 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태 로 사용할 수 있으며， 염으로는 약학적으로 허용 가능한 유리산 ( free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산， 질산, 인산， 황산， 브롬화수소 산， 요드화수소산， 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르 복실레이트， 페닐-치환된 알카노에이트， 하이드록시 알카노에이트 및 알칸디오에이 트， 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는 다. 이러한 약학적으로 무독한 염류로는 설페이트， 피로설페이트， 바이설페이트， 설파이트， 바이설파이트， 니트레이트， 포스페이트， 모노하이드로겐 포스페이트, 디 하이드로겐 포스페이트, 메타포스페이트， 피로포스페이트 클로라이드， 브로마이드, 아이오다이드， 플루오라이드， 아세테이트， 프로피오네이트 , 데카노에이트， 카프릴 레이트， 아크릴레이트， 포메이트， 이소부티레이트， 카프레이트， 헵타노에이트， 프 로피올레이트， 옥살레이트， 말로네이트， 석시네이트， 수베레이트, 세바케이트, 푸 마레이트， 말리에이트， 부틴 -1，4-디오에이트， 핵산 -1 , 6-디오에이트， 벤조에이트， 클로로벤조에이트， 메틸벤조에이트， 디니트로 벤조에이트， 하이드록시벤조에이트， 메톡시벤조에이트， 프탈레이트， 테레프탈레이트， 벤젠설포네이트， 를루엔설포네이 트， 클로로벤젠설포네이트， 크실렌설포네이트， 페닐아세테이트， 페닐프로피오네이 트， 페닐부티레이트， 시트레이트， 락테이트， 하이드록시부티레이트， 글리콜레이트， 말레이트， 타트레이트， 메탄설포네이트, 프로판설포네이트， 나프탈렌 -1-설포네이 트， 나프탈렌 -2-설포네이트 또는 만델레이트를 포함한다. 본 발명에 따른 산 부가염은 통상의 방법， 예를 들면， 화학식 1로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고， 이 염을 수흔화성 유기 용매， 예를' 들면 메탄을, 에탄올， 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다ᅳ 또한， 이 흔합물에서 용매나 과량의 산을 증발시켜서 건조하거나 또는 석출 된 염을 흡입 여과시켜 제조할 수도 있다. 또한， 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알 칼리 금속 또는 알칼리 토금속 염은， 예를 들면 화합물을 과량의 알칼리 금속 수산 화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과 하고， 여액을 증발， 건조시켜 얻는다. 이때， 금속염으로는 나트륨， 칼륨 또는 칼슘 염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은염은 알칼리 금속 또 는 알칼리 토금속 염을 적당한 은 염 (예， 질산은)과 반웅시켜 얻는다. 본 발명에서 화학식 1의 화합물은 ASM cid sphingomyel inase) 억제효과가 탁월하다. 이는 본 발명의 명세서 실시예에 잘 나타나 있다. 본 발명의 일실시예에 따르면， 본 발명의 화합물은 ASM을 억제하는 활성이 매우 우수하여， 알츠하이머 뇌 환경에서 Αβ 플라크를 감소시키고 기억력 및 불안증을 개선시키며， 신경염증을 완 화하는 등의 치료효과가 있어 알츠하이머병을 포함하는 퇴행성 신경질환 및 우울증 의 예방 또는 치료제로 사용될 수 있음을 확인하였다. 따라서 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염 을유효성분으로 포함하는 퇴행성 신경질환또는 우울증의 치료용 약학적 조성물을 제공한다. The solvent, reaction temperature and further purification steps necessary for reaction in step (π) are as described above in step (b) of the method for preparing a compound represented by Formula la. The present invention also provides a compound of Formula 1 wherein ¾ is an acetyl group and n is 2, comprising the step of N-acetylat ionizing the amine group (NH 2 group) of the compound represented by the formula (lc). It provides a method for producing a compound represented by the formula (Id) as. N-acetylation of the amine group may use a method known in the art, for example, by acetylating agent treatment. Acetylating agents known in the art include, but are not limited to, acetic anhydride or acetic acid chloride. The present invention includes not only the compound represented by Chemical Formula 1, but also pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which can be prepared therefrom. The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by the 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, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and From non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids All. These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Rate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate , Methoxybenzoate, Phthalate, Terephthalate Mate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate Methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. Acid addition salts according to the present invention can be prepared by conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid and dissolving the salt with a water-soluble organic solvent such as ' methane, ethanol, acetone or It may be prepared by precipitation with acetonitrile. In addition, the mixture may be prepared by evaporation of a solvent or excess acid, or by suction filtration of the precipitated salt. 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. In this case, as the metal salt, it is pharmaceutically suitable to prepare sodium, potassium or calcium salts. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg silver nitrate). In the present invention, the compound of Formula 1 has an excellent inhibitory effect on ASM cid sphingomyel inase. This is illustrated well in the specification examples of the present invention. According to one embodiment of the present invention, the compound of the present invention is very excellent in inhibiting the ASM, the therapeutic effect of reducing Aβ plaques in the Alzheimer's brain environment, improving memory and anxiety, alleviating neuro-inflammatory Degenerative neurological disease and depression, including Alzheimer's disease It was confirmed that it can be used as a prophylactic or therapeutic agent. Accordingly, the present invention provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 구성되는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물을 제공한다. 또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물을 제공한다. 본 발명에서 상기 퇴행성 신경질환은， 당업계에 스핑고지질 대상 이상 또는 / 및 ASM의 활성 또는 발현의 증가가 병인 (病因)으로 작용하는 신경질환이라면 그 종 류가 특별히 제한되지 않으나， 예를 들어 알츠하이머병， 파킨슨병， 진행성 핵상마 비, 다계통 위축증， 감람핵 -뇌교 -소뇌 위축증 (0PCA) , 샤이-드래거 증후군， 선조체— 혹질 퇴행증, 헌팅톤병， 근위축성 측색 경화증 (ALS) , 본태성 진전증， 회질-기저핵 퇴행증， 미만성 루이 소체 질환, 파킨스 -ALS-치매 복합증， 픽병， 뇌허혈 및 뇌경색 으로 이루어진 군에서 선택될 수 있으나， 이에 제한되는 것은 아니다. 본 발명의 우울증， 즉 우울장애는 의욕 저하와 우을감을 주요 증상으로 하여 다양한 인지, 정신 및 신체적 증상을 일으켜 일상 기능의 저하를 가져오는 질환을 의미한다. 본 발명의 우울증은 당업계에 우울장애로 알려진 것이라면 그 세부 종류 가 특¾히 제한되지 않으나， 예를 들어 상기 우울증은 주요 우울 장애 (MDD) , 혈관 치매성 우울증， 양극성 장애 (이극성 장애)， 단극성 우을증， 계절성 정동 장애 (SAD) , 경우울증， 기분부전증 또는 퇴행성 신경질환과 동반되는 우울증 등을 포함 한다. 바람직하게 ASM 활성의 비정상적 증가 (활성 과잉)에 의한 우을증일 수 있다. 본 발명에 따른 약학적 조성물은 상기 화학식 1의 화합물 또는 이의 약학적 으로 허용가능한 염을 단독으로 함유하거나 약학적으로 허용되는 담체와 함께 적합 한 형태로 제형화 될 수 있으며， 부형제 또는 희석제를 추가로 함유할 수 있다. 상 기에서 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때， 통 상적으로 위장 장애， 현기증 등과 같은 알레르기 반옹 또는 이와 유사한 반웅을 일 으키지 않는 비독성의 조성물을 말한다 . 약학적으로 허용되는 담체로는 예컨대， 경구 투여용 담체 또는 비경구 투여 용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분， 셀를로스 유 도체， 마그네슴 스테아레이트， 스테아르산 등을 포함할 수 있다. 아울러， 펩티드 제제에 대한 경구투여용으로 사용되는 다양한 약물전달물질을 포함할 수 있다. 또 한， 비경구 투여용 담체는 물， 적합한 오일， 식염수， 수성 글루코오스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안 정화제로는 아황산수소나트륨， 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드， 메틸 -또는 프로필-파라벤 및 클 로로부탄을이 있다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤 제， 감미제， 향미제， 유화제, 현택제 등을 추가로 포함할 수 있다. 그 밖의 약학적 으로 허용되는 담체 및 제제는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있 다 (Remington ' s Pharmaceut i cal Sciences , 19th ed. , Mack Publ i shing Company, East on, PA, 1995) . 본 발명의 조성물은 인간을 비롯한 포유동물에 어떠한 방법으로도 투여할 수 있다. 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으 로는 이에 한정되지는 않으나， 정맥내, 근육내， 동맥내， 골수내， 경막내， 심장내， 경피， 피하， 복강내， 비강내， 장관, 국소， 설하 또는 직장내 투여일 수 있다. 본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다. 경구 투여용 제제의 경우에 본 발 명의 조성물은 분말， 과립， 정제, 환제， 당의정제, 캡슐제， 액제， 겔제， 시럽겨 1， 슬러리제， 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예 를 들어， 경구용 제제는 활성성분올 고체 부형제와 배합한 다음 이를 분쇄하고 적 합한 보조제를 첨가한 후 과립 흔합물로 가공함으로써 정제 또는 당의정제를 수득 할 수 있다. 적합한 부형제의 예로는 락토즈， 덱스트로즈， 수크로즈， 솔비를， 만니 를， 자일리를， 에리스리를 및 말티를 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀를로즈， 메틸 셀를로즈， 나트륨 카 르복시메틸셀를로오즈 및 하이드록시프로필 메틸-셀를로즈 등을 포함하는 셀를로즈 류， 젤라틴， 폴리비닐피롤리돈 등과 같은 층전제가 포함될 수 있다. 또한， 경우에 따라 가교결합 폴리비닐피를리돈， 한천， 알긴산 또는 나트륨 알기네이트 등을 붕해 제로 첨가할 수 있다. 나아가， 본 발명의 약학적 조성물은 항응집계， 윤활제， 습윤 제, 향료， 유화제 및 방부제 등올 추가로 포함할 수 있다. The present invention also provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting of the compound of formula (1) or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition for the treatment of degenerative neurological diseases or depression consisting essentially of the compound of formula (1) or a pharmaceutically acceptable salt thereof. In the present invention, the degenerative neurological disease is not particularly limited as long as it is a neurological disease in which sphingolipid target abnormalities and / or an increase in the activity or expression of ASM is a etiology. Alzheimer's disease, Parkinson's disease, advanced nuclear palsy, polyatrophic atrophy, olive nucleus-pons-cerebellar atrophy (0PCA), Shire-Dragger syndrome, striatum- rough degeneration, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Bonn It may be selected from the group consisting of thyroid tremor, gray matter-basal nucleus degeneration, diffuse Lewis body disease, Parkin-ALS-dementia complications, pick disease, cerebral ischemia and cerebral infarction. Depression, that is, depressive disorder of the present invention refers to a disease that causes various cognitive, mental and physical symptoms resulting in deterioration of daily function as the main symptoms of lowering motivation and feelings of depression. If the depression of the present invention is known in the art as a depressive disorder is not particularly limited in detail, for example, the depression is a major depressive disorder (MDD), vascular dementia depression, bipolar disorder (bipolar disorder), Unipolar depression, seasonal affective disorders (SAD), depression, dysthymia or depression associated with degenerative neuropathy. Preferably, it may be a depression due to an abnormal increase in ASM activity (excess activity). The pharmaceutical composition according to the present invention may contain a compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may be formulated in a suitable form with a pharmaceutically acceptable carrier, further comprising an excipient or diluent It may contain. As used herein, `` pharmaceutically acceptable '' refers to allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when physiologically acceptable and administered to humans. It is a non-toxic composition that does not cause harm. Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, it may include various drug delivery materials used for oral administration to the peptide formulation. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose, glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutane. The pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspension agent, and the like, in addition to the above components. Other pharmaceutically acceptable carriers and formulations may be referenced in the following literature (Remington's Pharmaceut i cal Sciences, 19th ed., Mack Publ i shing Company, East on, PA, 1995) . The composition of the present invention may be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal administration. Can be. The pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above. In the case of preparations for oral administration, the compositions of the present invention are formulated using powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups 1, slurries, suspensions, etc. using methods known in the art. Can be converted. For example, oral formulations can be obtained by combining the active ingredient with solid excipients, grinding it, adding the appropriate adjuvant, and then processing it into granular mixtures to obtain tablets or dragees. Examples of suitable excipients include sugars and corn starch, wheat starch, rice starch and potato starch, including lactose, dextrose, sucrose, solbi, manny, xili, erysri and malty. Layered agents such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including starch, cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl-cellulose, and the like. . Also, in case Thus, crosslinked polyvinylpyridone, agar, alginic acid or sodium alginate can be added as disintegrant. Furthermore, the pharmaceutical composition of the present invention may further comprise an anticoagulant system, a lubricant, a humectant, a perfume, an emulsifier, and an antiseptic.
비경구 투여용 제제의 경우에는 주사제， 크림제， 로션제， 외용연고제， 오일 제, 보습제， 겔제， 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문 헌 (Remington' s Pharmaceut ical Science, 19th ed. , Mack Publ i shing Company , East on, PA, 1995)에 기재되어 있다. 본 발명의 조성물의 총 유효량은 단일 투여량 (single dose)으로 환자에게 투 여될 수 있으며, 다중 투껴량 (mult iple dose)으로 장기간 투여되는 분할 치료 방법 (fract ionated treatment protocol )에 의해 투여될 수 있다. 본 발명의 약학적 조 성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게 본 발 명의 약학적 조성물의 바람직한 전체 용량은 1일당 환자 체중 1kg 당 약 O. Ol^g 내 지 10 ,000mg, 가장 바람직하게는 O . lj 내지 lOOmg일 수 있다. 그러나 상기 약학적 조성물의 용량은 제제화 방법， 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령， 체중, 건강 상태， 성별， 질환의 중증도， 식이 및 배설율 등 다양한 요인들을 고려 하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당분 야의 통상적인 지식을 가진 자라면 본 발명의 조성물의 적절한 유효 투여량을 결정 할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형， 투여 경로 및 투여 방법에 특별히 제한되지 아니한다. 또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 신경질환 또는 우울증의 개선용 식품조성물을 제공 한다.  Formulations for parenteral administration may be formulated in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publing Company, East on, PA, 1995, a prescription generally known in all pharmaceutical chemistries. The total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fract ionated treatment protocol which is administered for a long time in a multiple iple dose. . The pharmaceutical composition of the present invention may vary the content of the active ingredient according to the degree of disease. Preferably the preferred total dose of the pharmaceutical composition of the present invention is about O. Ol ^ g to 10,000 mg, most preferably O. lj to lOOmg. However, the dosage of the pharmaceutical composition is determined in consideration of various factors such as the formulation method, route of administration and frequency of treatment, as well as various factors such as the age, weight, health status, sex, severity of the disease, diet and excretion rate of the patient. In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown. In another aspect, the present invention provides a food composition for improving neurodegenerative disease or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 구성되는 퇴행성 신경질환 또는 우울증의 개선용 식품 조성물을 제공한다.  In another aspect, the present invention provides a food composition for improving degenerative neurological disease or depression consisting of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 필수적으로 구성되는 퇴행성 신경질환 또는 우울증의 개선용 식품 조성물을 제 공한다. 본 발명에 따른 식품용 조성물은 기능성 식품 (funct ional food) , 영양보조제 (nutri t ional supplement ) , 건강식품 (heal th food) 및 식품첨가제 ( food addi t ives) 등의 모든 형태를 포함한다. 상기 유형들은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. In another aspect, the present invention provides a food composition for improving degenerative neurological disease or depression consisting essentially of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Food composition according to the present invention is a functional food (funct ional food), nutritional supplements It includes all forms, including nutritious supplements, health foods, and food addi- tives. These types can be prepared in various forms according to conventional methods known in the art.
예를 들면, 건강식품으로는 본 발명의 식품용 조성물 자체를 차， 쥬스 및 드 링크의 형태로 제조하여 음용하도록 하거나， 과립화， 캡슐화 및 분말화하여 섭취할 수 있다. 또한 본 발명의 식품용 조성물은 퇴행성 신경질환 또는 우울증 예방， 개 선 또는 치료 효과가 있다고 알려진 공지의 물질 또는 활성 성분과 함께 흔합하여 조성물의 형태로 제조할 수 있다. 또한 기능성 식품으로는 음료 (알콜성 음료 포함)， 과실 및 그의 가공식품 (예 를 들어 과일 통조림， 병조림, 잼， 마아말레이드 등)， 어류， 육류 및 그 가공식품( 예를 들어 햄， 소시지콘비이프 등)， 빵류 및 면류 (예를 들어 우동， 메밀국수， 라 면， 스파게티， 마카로니 등) , 과즙， 각종 드링크， 쿠키， 엿， 유제품 (예를 들어 버 터， 치이즈 등) , 식용식물유지， 마아가린, 식물성 단백질， 레토르트 식품, 냉동식 품， 각종 조미료 (예를 들어 된장, 간장， 소스 등) 등에 본 발명의 식품용 조성물을 첨가하여 제조할 수 있다. 본 발명에 따른 식품용 조성물의 바람직한 함유량으로는 이에 한정되지 않지 만 바람직하게는 최종적으로 제조된 식품 총 중량 중 0.01 내지 50중량 % 이다. 본 발명의 식품용 조성물을 식품첨가제의 형태로 사용하기.위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다. 본 발명은 퇴행성 신경질환 또는 우울증 치료용 제제를 제조하기 위한 화학 식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 용도를 제공한다. 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함 하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 특징으로 하는 퇴 행성 신경질환 또는 우울증의 치료 방법을 제공한다.  For example, as a health food, the food composition itself of the present invention may be prepared in the form of tea, juice and drink for drinking, or granulated, encapsulated and powdered. In addition, the food composition of the present invention may be prepared in the form of a composition by mixing with a known substance or active ingredient known to have the effect of preventing, improving or treating degenerative neurological diseases or depression. Functional foods also include beverages (including alcoholic beverages), fruits and processed foods (e.g. canned fruit, canned foods, jams, marmalade, etc.), fish, meat and processed foods (e.g. ham, sausage and conveyor). Etc.), breads and noodles (e.g. udon, soba noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, candy, dairy products (e.g. butter, cheese), edible vegetable oils It may be prepared by adding the food composition of the present invention to margarine, vegetable protein, retort food, frozen food, various seasonings (for example, miso, soy sauce, sauce, etc.). The preferred content of the food composition according to the present invention is not limited thereto, but is preferably 0.01 to 50% by weight of the total weight of the finally prepared food. To use the food composition of the present invention in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate. The present invention provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a preparation for treating neurodegenerative disorders or depression. The present invention provides a method for the treatment of degenerative planetary neuropathy or depression, comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 구성되는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 특징으로 하는 퇴행성 신경질환 또는 우울증의 치료 방법을 제공한다.  The present invention also provides a method for the treatment of degenerative neurological diseases or depression, characterized by administering to a subject in need thereof an effective amount of a composition consisting of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
또한 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염으 로 필수적으로 구성되는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것 을 특징으로 하는 퇴행성 신경질환 또는 우울증의 치료 방법을 제공한다. 본 발명의 상기 '유효량' 이란 개체에게 투여하였을 때， 퇴행성 신경질환 또는 우울증의 개선， 치료， 예방， 검출, 진단 또는 퇴행성 신경질환 또는 우울증 억제 또는 감소 효과를 나타내는 양을 말하며, 상기 '개체' 란 동물, 바람직하게는 포유동물, 특히 인간을 포함하는 동물일 수 있으며， 동물에서 유래한 세포, 조직， 기관 등일 수도 있다. 상기 개체는 상기 효과가 필요한 환자 (pat ient ) 일 수 있다. 본 발명의 상기 '치료' 는 퇴행성 신경질환 또는 우울증 또는 퇴행성 신경 질환 또는 우울증의 증상을 개선시키는 것을 포괄적으로 지칭하고, 이는 이러한 질 환을 치유하거나, 실질적으로 예방하거나， 또는 상태를 개선시키는 것을 포함할 수 있으며， 퇴행성 신경질환 또는 우을증으로부터 비롯된 한 가지 증상 또는 대부분의 증상을 완화시키거나， 치유하거나 예방하는 것을 포함하나， 이에 제한되는 것은 아 니다. 본 발명의 용어 '〜을 포함하는 (compr i sing) ' 이란 '함유하는' 또는 '특징 으로 하는' 과 동일하게 사용되며， 조성물 또는 방법에 있어서， 언급되지 않은 추 가적인 성분 요소 또는 방법 단계 등을 배제하지 않는다. 용어 '〜로 구성되는 (cons i st ing of ) ' 이란 별도로 기재되지 않은 추가적인 요소， 단계 또는 성분 등을 제외하는 것을 의미한다. 용어 '필수적으로 구성되는 (essent ial ly consi st ing of ) ' 이란 조성물 또는 방법의 범위에 있어서, 기재된 성분 요소 또는 단계와 더불어 이의 기본적인 특성에 실질적으로 영향을 미치지 않는 성분 요소 또는 단계 등을 포함하는 것을 의미한다. The present invention also provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof It provides a method for the treatment of degenerative neurological diseases or depression, characterized in that for administering an effective amount of the composition consisting essentially of to a subject in need thereof. The term 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, preventing, detecting, diagnosing a degenerative neurological disease or depression or reducing a degenerative neurological disease or depression when administered to an individual. It may be an animal, preferably a mammal, particularly an animal including a human, and may be a cell, tissue, organ or the like derived from the animal. The subject may be a patient in need of the effect. The term 'treatment' of the present invention refers generically to ameliorating the symptoms of degenerative neuropathy or depression or degenerative neurological disease or depression, which includes treating, substantially preventing, or ameliorating the condition. May include, but are not limited to, alleviating, healing or preventing one or most of the symptoms resulting from degenerative neuropathy or depression. The term 'compr i sing' of the present invention is used in the same way as 'containing' or 'characteristic', and any additional ingredient element or method step not mentioned in the composition or method, etc. Does not exclude The term 'cons i sting of' means to exclude additional elements, steps or components, etc., unless otherwise specified. The term 'essent ial ly consi st ing of' includes, in the scope of a composition or method, a component element or step described, as well as a component element or step that does not substantially affect its basic properties, and the like. Means that.
[유리한 효과】 Advantageous Effects
본 발명의 화학식 1의 ASM신규 억제화합물은 ASM 억제 효과가 탁월하고， 알 츠하이머 뇌환경에서 Α 플라크 감소, 기억력 및 불안증 개선， 신경염증 완화 등 의 치료효과가 있어, 알츠하이머병을 포함하는 퇴행성 신경질환 예방 또는 치료제 개발에 매우 유용하게 사용될 수 있다. 또한， ASM의 억제는 우울증 완화에 효과적 이라는 종래 보고와 같이， 본 발명의 화학식 1의 ASM 신규 억제화합물은 우울증을 포함하는 신경 질환의 예방 또는 치료제로서도 유용하게 사용될 수 있다. 【도면의 간단한 설명】 The new ASM inhibitory compound of Formula 1 is excellent in inhibiting ASM and has a therapeutic effect such as A plaque reduction, memory and anxiety improvement, and neuroinflammatory relief in the Alzheimer's brain environment, including degenerative neurons including Alzheimer's disease. It can be very useful for the development of disease prevention or treatment. In addition, as the conventional report that the inhibition of ASM is effective in alleviating depression, the ASM novel inhibitory compound of the formula (1) of the present invention can be usefully used as a prophylactic or therapeutic agent for neurological diseases including depression. [Brief Description of Drawings]
도 1A 및 도 1B는 ASM 억제 신규화합물인 JS-101_newPEG2(도 1A , 화합물명 : 2-아미노 -2-( 1-(2-(2-히드록시에록시 )에틸)— 1 — 1， 2 ,3-트리아졸 -4-일 )프로판 -1，3_디 올)와 JS-101_newPEG4(도 IB, 화합물명: 2-amino-2-( l-(2-(2-(2-(2-히드록시에톡 시)에톡시)에록시)에틸) -1H-1 ,2 ,3-트리아졸 -4-일)프로판ᅳ1，3-디을)의 구조식 및 화 학식， 분자량을 나타낸다. 도 2는 ASM 활성이 증가된 알츠하이머 환자의 섬유아세포 (PS1 f ibroblast )에 본 발명의 신규화합물인 JS-101ᅳ newPEG2 또는 JS-101_newPEG4를 처리한 후 나타나 는 ASM 활성변화를 나타낸 결과이다 (n=3/그룹， *ρ<0 · 05) . 도 3Α 및 도 3Β는 APP/PS1 마우스에 본 발명의 신규화합물인 JS-101_newPEG2 를 음수공급한 후 APP/PS1 마우스의 혈청 (도 3A) 및 뇌조직 (도 3B)에서 ASM 농도 변화를 나타낸 결과이다 (n=3/그룹， *p<0.05) (WT: 야생형， AD: 알츠하이머 동물모 델 (APP/PS1 마우스) ) · 도 4는 본 발명의 신규화합물들 (대표적으로， JS-101_newPEG2)이 퇴행성 신경 질환 (특히， 알츠하이머병)에 미치는 영향을 알아보기 위하여 수행한 in vivo 실험 의 개요를 나타낸다. 도 5A 및 도 5B는 ASM 억제 신규화합물인 JS-101_newPEG2를 음수 공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스에 대하여 , 뇌 수질 (Cortex , 도 5A) 및 해마 (Hippocampus , 도 5B)에서 티오플라빈 S(Thi oS, 원섬 유성 아밀로이드 베타 플라그를 염색함)로 면역형광염색하고 원섬유성 아밀로이드 베타 플라그가 차지하고 있는 면적올 정량화한 결과이다 (n=3/그룹， **p<0.01) (AD : 알츠하이머 동물모델 (APP/PS1 마우스) )ᅳ 도 6A 및 도 6B는 ASM 억제 신규화합물인 JS-101_newPEG2를 음수 공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스의 뇌조직에서 A β 40(도 6Α) 및 Αβ 42(도 6Β)의 축적 정도를 면역형광염색하고， 이를 정량화하여 나타낸 결과이다 (η=3/그룹， *p<0.05 , **p<0.01) (AD : 알츠하이머 동물모델 (APP/PS1 마우스) ) . 도 7A 내지 도 7D는 APP/PS1 마우스에서 ASM 억제 신규화합물인 JS- 101_newPEG2 공급이 학습 및 인지기능을 회복시켰음을 나타내는 결과이다 (n=7-8/ 그룹， *p<0.05) (WT: 야생형， AD: 알츠하이머 동물모델 (APP/PS1 마우스 ) ) . 1A and 1B show JS-101_newPEG2 (FIG. 1A, compound name: 2-amino-2- (1- (2- (2-hydroxyhydroxy) ethyl) ethyl) — an ASM inhibitory novel compound— 1 — 1, 2, 3-triazol-4-yl) propane-1,3_diol) and JS-101_newPEG4 (FIG. IB, compound name: 2-amino-2- (l- (2- (2- (2- (2- Hydroxyethoxy) ethoxy) ethoxy) ethyl) -1H-1,2,3-triazol-4-yl) propane # 1,3-di) shows the structural formula, chemical formula and molecular weight. Figure 2 is a result showing the change in ASM activity after treatment of the new compound of the present invention JS-101 ᅳ newPEG2 or JS-101_newPEG4 to fibroblasts (PS1 f ibroblast) of Alzheimer's patients with increased ASM activity (n = 3 / group, * ρ <0 · 05). 3A and 3Β show the change in ASM concentration in serum (FIG. 3A) and brain tissue (FIG. 3B) of APP / PS1 mice after the negative supply of the novel compound JS-101_newPEG2 of the present invention to APP / PS1 mice. (n = 3 / group, * p <0.05) (WT: wild type, AD: Alzheimer's animal model (APP / PS1 mouse)) FIG. 4 shows that the novel compounds of the present invention (typically JS-101_newPEG2) are degenerative. An overview of in vivo experiments performed to investigate the effects on neurological diseases (particularly Alzheimer's disease) is presented. FIG. 5A and FIG. 5B show cerebral medulla (Cortex, FIG. 5A) and hippocampus (Hippocampus, FIG. 5A) for APP / PS1 mice negatively supplied with JS-101_newPEG2, an ASM inhibitory novel compound, or APP / PS1 mice not supplied with the compound. 5B) was immunofluorescent stained with Thioflavin S (Thi oS, which stains one-island amyloid beta plaques) and quantified the areaol occupied by fibrillar amyloid beta plaques (n = 3 / group, ** p). <0.01) (AD: Alzheimer's Animal Model (APP / PS1 Mouse)) FIG. 6A and FIG. 6B are APP / PS1 mouse negatively supplied with JS-101_newPEG2, an ASM inhibitory new compound, or APP / PS1 mouse not supplied with the compound. Immunofluorescence staining and quantification of the accumulation of A β 40 (FIG. 6 Α) and Αβ 42 (FIG. 6 Β) in brain tissues (η = 3 / group, * p <0.05, ** p <0.01 (AD: Alzheimer's Animal Model (APP / PS1 Mouse)). 7A to 7D show that JS-101_newPEG2 feeding, which is an ASM inhibitory new compound, restored the learning and cognitive function in APP / PS1 mice (n = 7-8 / group, * p <0.05) (WT: wild type , AD: Alzheimer's animal model (APP / PS1 mouse)).
도 7A는 야생형 마우스 (WT, n=8) , ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급한 APP/PS1 마우스 (n=7) 또는 상기 화합물을 공급하지 않은 APP/PS1 마우 스 (control , n=8)에 대하여, 모리스 워터메이즈 (MWM) 테스트를 이용하여 10일 동안 학습 및 기억력을 평가한결과이다.  FIG. 7A shows wild-type mice (WT, n = 8), APP / PS1 mice negatively fed with ASM inhibition novel compound JS-101_newPEG2 (n = 7) or APP / PS1 mice not fed the compound (control, n = 8) using the Morris Watermaze (MWM) test to evaluate learning and memory for 10 days.
도 7B는 MWM 테스트 11일째에 표적 플랫품에서 머무른 시간을 나타낸 결과이 다.  FIG. 7B shows the time spent in the target platform on day 11 of the MWM test.
도 7C는 MWM 테스트 시험 11일째에 표적 플랫폼의 타겟 지역 내로 들어간 횟 수를 나타낸다.  7C shows the number of times that entered the target area of the target platform on day 11 of the MWM test test.
도 7D는 fear condit ioning실험 동안에 contextual 및 tone task의 결과를 나타낸 것이다. 도 8A 내지 도 81는 APP/PS1 마우스에서 ASM 억제 신규화합물인 JS- 101_newPEG2의 공급이 활동성 및 불안감을 호전시켰음을 나타내는 결과이다 (n=7- 8/그룹， *p<0.05) (ASM 억제 신규화합물인 JS-101_newPEG2를 공급하지 않은 APP/PS1 마우스 (control , n=8) , ASM 억제 신규화합물인 JS-101_newPEG2를 공급한 APP/PS1 마우스 (n=7) ) .  7D shows the results of the contextual and tone tasks during fear condit ioning experiments. 8A to 81 show that the supply of JS-101_newPEG2, an ASM inhibitory new compound, improved activity and anxiety in APP / PS1 mice (n = 7-8 / group, * p <0.05) (ASM inhibition novel APP / PS1 mouse not supplied with the compound JS-101_newPEG2 (control, n = 8), APP / PS1 mouse supplied with the new compound JS-101_newPEG2 (n = 7)).
도 8A는 오픈필드 테스트 동안에 마우스가 벽면에서 소요한 시간을 측정한 결과이다.  8A shows the results of measuring the time the mouse spent on the wall during the open field test.
도 8B는 오픈필드 테스트 동안에 마우스가중심부에서 소요한 시간을측정한 결과이다.  8B is a result of measuring the time spent in the center of the mouse during the open field test.
도 8C는오픈필드 테스트 동안에 중심부의 비율을 나타낸 결과이다.  8C shows the ratio of the centers during the open field test.
도 8D는오픈필드 테스트 동안에 마우스의 이동 경로를 나타낸 것이다.  8D shows the movement path of the mouse during the open field test.
도 8E는 dark & l ight 테스트 동안에 마우스가 어두운 곳에서 소요한시간을 측정한 결과이다.  8E shows the results of measuring the time the mouse spent in the dark during the dark & right test.
도 8F는 dark & l ight 테스트 동안에 마우스가 밝은 곳에서 소요한 시간을 측정한 결과이다.  8F shows the results of measuring the time the mouse spent in the light during the dark & right test.
도 8G는 dark & l ight 테스트 동안에 마우스가 어두운 곳과 밝은 곳을 왕복 한 횟수이다. 도 8H는 dark & l ight 테스트 동안에 마우스가 최초로 어두운 곳에서 밝은 곳으로 옮겨간 시간을 측정한 결과이다. 8G is the number of times the mouse has traveled between the dark and the light during the dark & right test. FIG. 8H shows the measurement of the time the mouse first moved from the dark to the light during the dark & right test.
도 81는 dark & l ight 테스트 동안에 마우스의 이동 경로를 나타낸 것이다. 도 9A 및 도 9B는 APP/PS1 마우스 (AD)에서 증가된 신경염증이 ASM 억제 신규 화합불인 JS-101_newPEG2 공급에 와해 감소됨을 확인한 결과이다 (n=3/그룹， *p<0.05, **p<0.01) .  81 shows the movement path of the mouse during the dark & right test. 9A and 9B confirm that the increased neuroinflammatory in APP / PS1 mice (AD) is reduced by feeding JS-101_newPEG2, which is a new ASM inhibitory incompatibility (n = 3 / group, * p <0.05, ** p). <0.01).
도 9A는 야생형 마우스 (WT) , ASM 억제 신규화합물인 JS-101_newPEG2를 음수 공급한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스 (control )의 뇌 수질에서 별아교세포 (GFAP)의 면역형광 이미지 (왼쪽) 및 이를 정량 화환 결과 (오른쪽)를 나타낸다.  9A shows immunization of glial cells (GFAP) in cerebral medulla of wild-type mouse (WT), APP / PS1 mouse negatively fed with ASM-inhibiting novel compound JS-101_newPEG2, or APP / PS1 mouse not fed the compound Fluorescence images (left) and quantitative garland results (right) are shown.
도 9B는 야생형 마우스， ASM 억제 신규화합물인 JS-101_newPEG2를 음수공급 한 APP/PS1 마우스 또는 상기 화합물을 공급하지 않은 APP/PS1 마우스 (control )의 뇌 수질에서 염증성 마커 (TNF- a , IL-Ιβ , IL-6)의 m NA 발현수준을 평가한 결과이 다.  9B shows inflammatory markers (TNF-a, IL-Ιβ in brain medulla of wild-type mice, APP / PS1 mice negatively fed with ASM inhibitory new compound JS-101_newPEG2, or APP / PS1 mice not fed the compound). , IL-6) m NA expression level was evaluated.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하 본 발명을 상세히 설명한다.  Hereinafter, the present invention will be described in detail.
단， 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실 시예에 한정되는 것은 아니다.  However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.
<실시예 1> <Example 1>
신규 화합물 JS-101— newPEG2의 제작  Preparation of New Compound JS-101— newPEG2
2-아미노 -2-( 1-(2-(2-하이드록시에특시 )에틸 ) ， 2， 3-트리아졸 -4—일 )프로 판 - 1 , 3-디올 ( 2-am i no— 2- (1- ( 2- ( 2-hydroxyethoxy )ethyl )-1^1 ,2 , 3-triazol -4-y 1 ) propane-l ,3-diol , 'JS-101_newPEG2' 로 약칭)은 하기 일련의 공정을 통해 제작하 였다.  2-amino-2- (1- (2- (2-hydroxye) ethyl), 2, 3-triazol-4—yl) propane-1, 3-diol (2-am i no— 2- (1- (2- (2-hydroxyethoxy) ethyl) -1 ^ 1, 2, 3-triazol-4-y 1) propane-l, 3-diol, abbreviated as 'JS-101_newPEG2') It was produced through the process.
물질시료로서 2-(2-클로로에록시)에탄 -1-을， 소듐 아자이드, er -부틸 (5-에 틴일 -2, 2-디메틸 -1 ,3-디옥산 -5-일)카바메이트， 아이오딘화구리， 2-(2-아자이도에톡 시)에탄 -1-을, ，^디이소프로필에틸아민， -부틸 (5-α-(2-(2-하이드톡시에록 시)에틸 )-1^1 , 2， 3-트리아졸 -4-일 )-2 , 2-디메틸 -1， 3-다이옥산 -5-일 )카바메이트 ' 및 트리플루오르아세트산이 하기의 방법에 따라 제조에 이용되었으며， 100% 디메틸설 폭사이드 (DMS0)에서 현탁하여 -20°C에서 보관하며 사용하였다. 2- (2-chloroethoxy) ethane-1- as the material sample, sodium azide, er-butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate when the lock (2-hydroxy ethoxy), iodine Chemistry copper, ethane-1-2- (2-aza Messenger Ido), ^ diisopropylethylamine, t-butyl (5 -α- (2 Ethyl) -1 ^ 1, 2, 3-triazol-4-yl) -2, 2-dimethyl-1, 3-dioxane-5-yl) carbamate ' and trifluoroacetic acid were prepared according to the following method 100% dimethyl sulfide Suspended in foxside (DMS0) and stored at -20 ° C was used.
<1-1> 2-(2-아자이 £에톡시)에탄 -1-올 제조 <1-1> 2- (2-Azai ethoxy) ethane-1-ol
[반응식 K]  Scheme K
CI
Figure imgf000027_0001
상기 반웅식 K에서 η은 2≤η≤5의 자연수임 상기 반옹식 Κ에서 η=2일 때에 해당하는 2-(2-클로로에톡시)에탄 -1-올을 출 발물질로 하여 2-(2-아자이도에특시)에탄 -1-올을수득하였다. CI
Figure imgf000027_0001
In the reaction K, η is a natural number of 2 ≦ η ≦ 5. In the reaction reaction Κ, 2- (2-chloroethoxy) ethan-1-ol corresponding to η = 2 is used as a starting material. 2-ethanol-specific) ethane-1-ol was obtained.
[반웅식 K-1] [Bungungsik K-1]
ΟΗ
Figure imgf000027_0002
ΟΗ
Figure imgf000027_0002
ater, ,  ater,,
구체적으로 상기 반응식 K-1의 반웅을 일으키기 위하여， 2-(2-클로로에톡시) '에탄 -1—올 (1000 mg, 8.0 mmol)과 소듐 아자이드 (NaN3, 780 mg, 12隱 ol)를 2차증류 수 (6.0 mL)에 녹인 후, 80°C에서 26 시간동안 교반 및 환류하였다. 이후， 반웅 흔 합물을 디클로로메테인 (12 mL)로 회석하고 물을 추가하여 소듐 클로라이드 포화 수 용액으로 세척하였다. 유기층을 마그네슴 설페이트로 건조하고 용매를 감압, 제거 하여 목적 화합물인 2-(2-아자이도에록시)에탄 -1-을 (690 mg, 65% 수율)을 수득하였 다. Specifically, in order to react the reaction of Scheme K-1, 2- (2-chloroethoxy) 'ethane-1-ol (1000 mg, 8.0 mmol) and sodium azide (NaN 3 , 780 mg, 12 隱 ol) Was dissolved in secondary distilled water (6.0 mL), then stirred and refluxed at 80 ° C. for 26 hours. The reaction mixture was then distilled with dichloromethane (12 mL) and washed with sodium chloride saturated aqueous solution with the addition of water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-690 of a target compound, 2- (2-azidoethoxy) ethane-1- (690 mg, 65% yield).
H NMR [400 MHz, (CD3)2C0),d (ppm)]: 3.39 (t, J = 4.9 Hz, 2H) , 3.57 (m, 2H), 3.68 (m, 4H). H NMR [400 MHz, (CD 3 ) 2 C0), d (ppm)]: 3.39 (t, J = 4.9 Hz, 2H), 3.57 (m, 2H), 3.68 (m, 4H).
<l-2> Tfe/^-부틸 (5-( l-(2_(2—하이드록시에특시 )에틸 ， 2， 3-트리아졸 -4- 일 )-2， 2-디메틸 -1， 3-다이옥산 -5-일)카바메이트 제조 <l-2> Tfe / ^-butyl (5- (l- (2_ (2—hydroxye) ethyl), 2, 3-triazol-4-yl) -2, 2-dimethyl-1, 3 -Dioxane-5-yl) carbamate preparation
[반옹식 la]
Figure imgf000028_0001
[Rebellion la]
Figure imgf000028_0001
¾r -부틸 (5-에틴일 -2,2-디메틸 -1,3-디옥산 -5-일)카바메이트 (1.3g, 5.2mmol) 를 디메틸포름아마이드 (DMF, 17 mL)에 녹인 다음 아이오딘화구리 (Cul, 0.5 g, 2.6 mmol), 2-(2-아자이도에록시)에탄 -1-을 (690 mg, 16 mmol), v，^디이소프로필에틸아 민 (DIPEA, 2.7 mL ， 16 mmol)을 순서대로 추가하였다. 질소 하에 반응 흔합물을 상 온에서 12 시간 동안 교반하였다. 이후 암모늄 클로라이드 포화 수용액을 넣어 반 응을 마무리한 후 용매를 12 시간 동안 동결 건조하였다. 건조된 화합물에 물을 추 가하여 에틸아세테이트로 추출하였고 소듐 클로라이드 포화수용액으로 세척하였다. 마그네슴 설페이트로 건조한 뒤， 실리카겔 관 크로마토그래피 (에틸아세테이트 100% 로 부산물 (Rf=0.9)제거 후， 아세톤 10 로 용리액 변경)를 통해， 목적 화합물안 r -부틸 ( 5- ( 1- ( 2- ( 2-하이드록시에록시)에틸) - 1 , 2 , 3-트리아졸 -4-일) -2， 2-디메 틸 -1，3-다이옥산 -5-일)카바메이트 (1.1 g, 55%수율， Rf=0.3)를 수득하였다.  ¾r-butyl (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl) carbamate (1.3 g, 5.2 mmol) is dissolved in dimethylformamide (DMF, 17 mL) and then iodine Copper (Cul, 0.5 g, 2.6 mmol), 2- (2-azadoethoxy) ethane-1- (690 mg, 16 mmol), v, ^ diisopropylethylamine (DIPEA, 2.7 mL, 16 mmol) were added in order. The reaction mixture was stirred at room temperature for 12 hours under nitrogen. After adding the saturated aqueous ammonium chloride solution to complete the reaction, the solvent was lyophilized for 12 hours. Water was added to the dried compound, extracted with ethyl acetate, and washed with saturated aqueous sodium chloride solution. After drying with magnesium sulfate, silica gel column chromatography (removing the by-product (Rf = 0.9) with 100% ethyl acetate, changing the eluent to acetone 10) gave r-butyl (5- (1- (2- (2-Hydroxyethoxy) ethyl) -1,2,3-triazol-4-yl) -2,2-dimethyl-1,3-dioxan-5-yl) carbamate (1.1 g, 55% Yield, Rf = 0.3).
H NMR [(400 MHz, CD2Cl2)d (ppm)]: 1.40 (s, 9H), 1.48 (s, 4H), 2.44 (s, H NMR [(400 MHz, CD 2 Cl 2 ) d (ppm)]: 1.40 (s, 9H), 1.48 (s, 4H), 2.44 (s,
1H), 3.50 (t, J = 4.0 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H), 3.84 (t, / = 4.0 Hz, 2H), 4.11 (d, J = 8.0 Hz, 2H), 4.24 (d, J = 12.0 Hz, 2H), 4.51 (t, J = 4.0 Hz, 2H), 5.63 (s, 1H), 7.76 (s, 1H) . 1H), 3.50 (t, J = 4.0 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H), 3.84 (t, / = 4.0 Hz, 2H), 4.11 (d, J = 8.0 Hz, 2H) , 4.24 (d, J = 12.0 Hz, 2H), 4.51 (t, J = 4.0 Hz, 2H), 5.63 (s, 1H), 7.76 (s, 1H).
<l-3> 2-아미노 -2— ( 1- ( 2- ( 2-하이드록시에톡시)에틸) - 1 ^ 1 , 2 , 3-트리아졸 -4- 일)프로판 -1,3-디올 제조 <l-3> 2-amino-2— (1- (2- (2-hydroxyethoxy) ethyl) -1 ^ 1,2,3-triazol-4-yl) propane-1,3-diol Produce
[ 2a]  [2a]
Figure imgf000028_0002
Figure imgf000028_0002
Tfer -부틸 (5-( 1-(2-(2-하이드록시에록시)에틸 )-1^1， 2， 3-트리아졸 -4-일 )- 2,2-디메틸 -1，3-다이옥산 -5-일)카바메이트 (1.1 g, 2.9 mmol)을 트리플루오로아세트 산 (TFA, 2.G mL), 디클로로메테인 (DCM, 2.0 mL), 물 (1.0 mL)의 흔합 수용액에 추가 하여 상온에서 12 시간동안 교반하였다. 이후 질소 하에 건조 시킨 후， 메탄올과 디에틸에테르를 통해 재결정하여， 목적 화합물로서 화학식 lc에 해당하는 2-아미노 -2-( l-(2-(2-하이드록시에톡시)에틸) -L l， 2， 3-트리아졸 -4-일)프로판 -1， 3-디올 (570 mg, 80% 수율)을 수득하였다. 상기 수득된 목적 화합물을 이하에서 JS-101_newPEG2 으로 칭한다. 신규 화합물 JS— 101_newPEG2(C9H18N404)는 도 1A에서 보는 바와 같은 구조식올 지니며 분자량 246.2670(Exact mass: 246.1328)이었다. Tfer-butyl (5- (1- (2- (2-hydroxyethoxy) ethyl) -1 ^ 1, 2, 3-triazol-4-yl) -2,2-dimethyl-1,3-dioxane -5-yl) carbamate (1.1 g, 2.9 mmol) was added to a mixed aqueous solution of trifluoroacetic acid (TFA, 2.G mL), dichloromethane (DCM, 2.0 mL), water (1.0 mL). Stirred at room temperature for 12 hours. After drying under nitrogen, recrystallized with methanol and diethyl ether, 2-amino corresponding to formula lc as the target compound 2- (l- (2- (2-hydroxyethoxy) ethyl) -L l, 2,3-triazol-4-yl) propane-1,3-diol (570 mg, 80% yield) Obtained. The desired compound obtained above is referred to hereinafter as JS-101_newPEG2. The new compound JS—101_newPEG2 (C 9 H 18 N 4 O 4 ) had a structural formula as shown in FIG. 1A and had a molecular weight of 246.2670 (Exact mass: 246.1328).
H NMR [(400 MHz, (CD3)2S0)d (ppm)]： 3.43 (m, 2H), 3.47 (m, 2H), 3.77 H NMR [(400 MHz, (CD 3 ) 2 S0) d (ppm)]: 3.43 (m, 2H), 3.47 (m, 2H), 3.77
(s, 4H), 3.81 (t, J = 6.0 Hz, 2H), 4.55 (t, / = 4.0 Hz, 2H), 4.65 (s, 1H), 5.55 (s, 2H), 8.14 (s, 1H) , 8.32 (s, 2H). (s, 4H), 3.81 (t, J = 6.0 Hz, 2H), 4.55 (t, / = 4.0 Hz, 2H), 4.65 (s, 1H), 5.55 (s, 2H), 8.14 (s, 1H) , 8.32 (s, 2 H).
13C NMR [(100 MHz, (CD3)2S0)d (ppm)]: 49.7, 58.9, 60.1， 62.1, 68.7, 13 C NMR [(100 MHz, (CD 3 ) 2 S0) d (ppm)]: 49.7, 58.9, 60.1, 62.1, 68.7,
72.1， 123.9, 143.8. 72.1, 123.9, 143.8.
HRMS: Calcd. for [M + H]+, 247.1401;Found, 247.1356. HRMS: Calcd. for [M + H] + , 247.1401; Found, 247.1356.
<실시예 2> <Example 2>
신규 화합물 JS— 101_newPEG3의 제작  Preparation of New Compound JS— 101_newPEG3
상기 반응식 K에서
Figure imgf000029_0001
일 때에 해당하는 2-[2-(2-클로로에특시)에톡시] -에 탄올을 출발물질로 하여 2-[2-(2-아자이도에톡시)에특시] -에탄을을 수득하였다. 그 후 상기 실시예 1과 동일한 방법으로 부틸 (5-에틴일 -2, 2-디메틸 -1,3-디옥산- 5-일)카바메이트와 반웅시키고 부틸옥시카보닐기 및 아세토나드기를 탈보호화시켜 n=3인 화학식 la의 화합물안 2-amino-2-(l-(2_(2-(2-히드록시에톡시)에톡시)에틸) - 1H-1 , 2， 3-트리아졸 -4-일 )프로판 -1 , 3-디올을 수득하였다 . In Scheme K above
Figure imgf000029_0001
When 2- [2- (2-chloro-especial) ethoxy] -ethanol was used as a starting material, 2- [2- (2-azidoethoxy) -especial] -ethane was obtained. . Thereafter, the reaction was repeated with butyl (5-ethynyl-2, 2-dimethyl-1,3-dioxane-5-yl) carbamate in the same manner as in Example 1, and deprotection of the butyloxycarbonyl group and acetonide group was performed. 2-amino-2- (l- (2_ (2- (2-hydroxyethoxy) ethoxy) ethyl) -1H-1, 2, 3-triazole-4- in a compound of formula la with n = 3 Yl) propane-1,3-diol.
<실시예 3> <Example 3>
신규 화합물 JS— 101 newPEG4의 제작  Preparation of new compound JS— 101 newPEG4
상기 반웅식 K에서 n=4 일 때에 해당하는 2-[2-[2-(2-클로로에특시)에록시] 에록시] -에탄올올 출발물질로 하여 2-[2-[2-(2-아자이도에록시)에특시]에톡시] -에 탄올을 수득하였다. 그 후 상기 실시예 1과 동일한 방법으로 fe -부틸 (5-에틴일- 2, 2-디메틸 -1，3_디옥산 -5-일)카바메이트와 반웅시키고 부틸옥시카보닐기 및 아세토 니드기를 탈보호화시켜 n=4인 화학식 la의 화합물인 2-amino-2-(l-(2-(2-(2-(2-히 드록시에톡시)에톡시)에특시)에틸) -1H-1,2,3-트리아졸 -4-일)프로판 -1，3-디을을 수 득하였다. 신규 화합물 JS-101ᅳ newPEG4(C13H26N406)는 도 1B에서 보는 바와 같은 구조 식을 지니며 분자량 334.3730 (Exact mass: 334.1852)이었다. <실시예 4> 2- [2- [2- (2-chloro-specific) ethoxy] ethoxy] -ethanolol corresponding to the reaction when n = 4 in the reaction formula K is 2- [2- [2- ( 2-azadoethoxy) especial] ethoxy] -ethanol was obtained. Thereafter, in the same manner as in Example 1, fe-butyl (5-ethynyl-2, 2-dimethyl-1,3_dioxan-5-yl) carbamate was reacted and the butyloxycarbonyl group and acetonide group were removed. Gelatinized to 2-amino-2- (l- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) -1H-1 , 2,3-triazol-4-yl) propane-1,3-di was obtained. The new compound JS-101 ᅳ newPEG4 (C 13 H 26 N 4 0 6 ) had a structural formula as shown in FIG. 1B and had a molecular weight of 334.3730 (Exact mass: 334.1852). <Example 4>
신규 화합물 JS-101_newPEG5의 제작  Preparation of New Compound JS-101_newPEG5
상기 반옹식 K에서 n=5 일 때에 해당하는 14-클로로 -3,6,9,12-테트라옥사테 트라데카놀을 출발물질로 하여 14-아자이도 -3,6,9,12-테트라옥사테트라데카놀을 수 득하였다. 그 후 상기 실시예 1과 동일한 방법으로 ¾/^-부틸 (5-에틴일 -2，2-디메틸 -1， 3—디옥산 -5-일)카바메이트와 반웅시키고 부틸옥시카보닐기 및 아세토니드기를 탈보호화시켜 n=5인 화학식 la의 화합물인 2-아미노 -2ᅳ (1-(14-히드록시 -3，6,9,12- 테트라옥사테트라데실)-lH-l,2，3-트리아졸-4-일)프로판-l，3-디을을 수득하였다.  14-Azaido-3,6,9,12-tetraoxa using 14-chloro-3,6,9,12-tetraoxate tradecanol as a starting material in the reaction system K when n = 5. Tetradecanol was obtained. Thereafter, the reaction was repeated with ¾ / ^-butyl (5-ethynyl-2,2-dimethyl-1, 3-dioxan-5-yl) carbamate in the same manner as in Example 1, followed by butyloxycarbonyl group and acetonide. Deprotection of the group to yield 2-amino-2 '(1- (14-hydroxy-3,6,9,12-tetraoxatetradecyl) -lH-l, 2,3- Triazol-4-yl) propane-1,3-di was obtained.
<실시예 5> Example 5
신규 화합물의 ^경퇴행성 질환 및 우울증 억제 효능 확  Confirmation of Novel Compounds for Inhibitory Regression and Depression
[실험재료 및 실험방법] Experimental Materials and Methods
1. 마우스  1. Mouse
I ACUC ( Kyungpook National University Institutional Animal Care and Use Committee)에서 마우스 실험에 대한 승인을 받았다. 우울증 및 퇴행성 신경질환 (특 히， 알츠하이머) 동물모델로서, C57BL/6 마우스 (Charles River, UK)를 바탕으로 APPswe(hAPP695swe) 및 PSKpreseni Iin-1M146V)를 과발현시킨 형질전환 마우스 라 인을 이용하였다 [이하， APP/PS1 마우스 (AD로 표기)， GlaxoSmithKline 社]  I received approval for mouse experiments from Kyungpook National University Institutional Animal Care and Use Committee (ACUC). As a depressive and degenerative neurological disease (especially Alzheimer's) animal model, a transgenic mouse line overexpressing APPswe (hAPP695swe) and PSKpreseni Iin-1M146V based on C57BL / 6 mice (Charles River, UK) was used. APP / PS1 mouse (denoted by AD), GlaxoSmithKline Co., Ltd.
신규화합물 JS-101_newPEG2의 퇴행성 신경질환 및 우울증 치료효과를 확인하 기 위해， 도 4에 나타낸 실험 개요 (스케줄)에 따라 동물모델에 '실험물질을 투여하 였다. 구체적으로, 7.5개월령의 마우스에 신규화합물인 JS-101_newPEG2를 100mg/kg/day 용량으로 음수를 통해 공급하였다. 상기 화합물이 포함된 음수공급 1 개월 후 행동학적 분석을 실시하였고， 행동분석기간에도 지속적으로 시험물질이 음 수를 통해 구강 투여되었다. 행동학적 분석 후 (상기 화합물 포함 음수공급 2개월 차， 즉 마우스 9.5주령 차)에 마우스의 뇌조직을 샘플링하였다. In order to determine the neurodegenerative disease and antidepressant effects of the novel compounds JS-101_newPEG2, also according to the experimental outline (schedule) shown in FIG. 4 was administered to the "test substance to the animal model. Specifically, JS-101_newPEG2, a new compound, was supplied to the 7.5-month-old mouse at a negative dose of 100 mg / kg / day. The behavioral analysis was performed one month after the negative supply containing the compound, and the test substance was orally administered through the drinking water even during the behavior analysis period. The brain tissues of the mice were sampled after behavioral analysis (2 months after the negative feed containing compound, 9.5 weeks old mice).
2. 면역형광법 2. Immunofluorescence
마우스의 대뇌 및 해마를 고정 후, 0.5% thioflavin S (Sigma-Aldrich) , Αβ 42에 대한 항 -20G10 (마우스， 1:1000) 및 Αβ 40에 대한 항 _G30(토끼， 1:1000), 항- GFAP (토끼， 1:500, DAK0)을 함께 배양하였다. 상기 부위를 Fluoview SV1000 이미징 소프트웨어 (Olympus FV1000, Japan)를 장착한 레이저 스캐닝 공초점 현미경 또는 Olympus BX51 현미경을 이용하여 분석하였다. Metamorph sof tware(Molecular Devices)를 이용하여 총 조직의 넓이에 대한 염색된 부위의 넓이의 퍼센트를 정량 화하고 분석하였다. After fixation of the cerebral and hippocampus of mice, 0.5% thioflavin S (Sigma-Aldrich), anti -20G10 against Aβ 42 (mouse, 1: 1000) and anti_G30 against Aβ 40 (rabbit, 1: 1000), anti- GFAP (rabbit, 1: 500, DAK0) was incubated together. Fluoview SV1000 imaging of the site Analysis was performed using a laser scanning confocal microscope or Olympus BX51 microscope equipped with software (Olympus FV1000, Japan). Metamorph sof tware (Molecular Devices) was used to quantify and analyze the percentage of area of stained area to area of total tissue.
3. 실시간 정량 PCR(Real-time quantitative PCR) 3. Real-time quantitative PCR
염증반응 관련 사이토카인 (TNF-a, IL-Ιβ , IL-6)의 발현량을 측정하기 위 하여 실시간 정량 PCR법을 사용하였다. R easy Plus 미니 키트 (Qiagen, Korea, Ltd)를 사용하여 뇌조직으로부터 RNA를 추출하고， Clontech (Mountain View, CA)사 의 키트를 사용하여 총 5/ig의 RNA로부터 cDNA를 합성하였다. 또한, Corbett research RG-6000 real-time PCR 기기를 사용하여 , 95°C , 10분; 95°C， 10초; 58°C， 15초; 72°C, 20초를 1 사이클로 하여 40 사이클을 반복하는 실시간 정량 PCR을 수 행하였다. Real-time quantitative PCR was used to measure the expression level of cytokines related to inflammatory responses (TNF-a, IL-Ιβ, IL-6). RNA was extracted from brain tissue using R easy Plus mini kit (Qiagen, Korea, Ltd), and cDNA was synthesized from a total of 5 / ig of RNA using a kit of Clontech (Mountain View, CA). In addition, using a Corbett research RG-6000 real-time PCR instrument, 95 ° C, 10 minutes; 95 ° C., 10 seconds; 58 ° C., 15 seconds; Real-time quantitative PCR was performed to repeat 40 cycles at 72 ° C for 20 seconds.
상기 실시간 정량 PCR에 사용한 프라이머는 표 1과 같다.  Primers used for the real-time quantitative PCR are shown in Table 1.
【표 1】 Table 1
Figure imgf000031_0001
Figure imgf000031_0001
4. 행동실험 4. Behavioral experiment
학습 및 기억에 대한 잠재적 효과를 확인하기 위하여， MWM(Morris water maze)와 fear conditioning 실험을 수행하였다. MWM는 마우스에 대하여 10일 동안 하루에 4 번씩 과제를 학습시켰고， 11일째 되는 날에 플랫품을 제거하고， 탐침시험 (probe trial)을 수행하였다. Fear conditioning은 첫째 날은 마우스를 conditioning chamber에 넣고， 소리 자극 (10 kHz, 7으 dB) 및 전기자극 (0.3 mA, 1 s)을 주었다. 둘째 날은 첫째 날과 같은 conditioning chamber에서 자극 없이 공간 에 대한 기억력을 확인했고， 셋째 날은 다른 conditioning chamber에서 소리자극만 주었을 때 두려움에 대한 기억력 테스트를 수행하였다. 활동성과 불안감을 평가하 기 위해 오픈필드 테스트와 Dark and light 테스트를 수행하였다. 오픈필드 테스트 는 마우스를 10분 동안 사각형의 박스에 넣어 전반적인 활동성과 벽면 및 가운데 ( 중심부)를 돌아다닌 시간을 측정하였다. Dark and l ight 테스트는 마우스를 10분 동안 어두운 박스와 밝은 박스로 구성된 사각형의 박스에 넣어 각각의 박스 내에 머무른 시간, 박스 왕복 횟수 및 최초로 밝은 박스내로 들어간 시간을 측정하였다. In order to identify potential effects on learning and memory, fear water experiments with MWM were performed. MWM trained the mice 4 times a day for 10 days, removed the platform on day 11, and performed a probe trial. Fear conditioning on the first day put the mouse into the conditioning chamber and gave sound stimulation (10 kHz, 7 dB) and electrical stimulation (0.3 mA, 1 s). On the second day, the memory of the room was confirmed without stimulation in the same conditioning chamber as the first day. On the third day, the memory test for fear was performed when only the sound stimulation was given in the other conditioning chamber. Openfield tests and dark and light tests were performed to assess activity and anxiety. Openfield testing The mouse was placed in a square box for 10 minutes to measure overall activity and time spent wandering around the wall and the center (center). The Dark and Right test put the mouse in a rectangular box of dark and light boxes for 10 minutes to measure the time it stayed in each box, the number of box round trips and the first time it went into the bright box.
5. 세포배양 5. Cell Culture
정상 (Normal ) 및 알츠하이머 환자의 섬유아세포주 (PS1 f ibroblast )를 Coriel l Inst i tute에서 얻어 1 FBS를 포함하는 DMEM에서 37°C 및 5%의 C02에서 배 양하여 사용하였다. 이 후， 상기 세포주에 본 발명의 신규화합물인 JS-101— newPEG2 ( lOuM) 또는 JS-101_newPEG4 (10uM)를 처리 한 후 ASM 활성도 변화를 측정하였다. Fibroblast lines (PS1 f ibroblast) of normal and Alzheimer's patients were obtained from Coriel l Inst i tute and used at 37 ° C. and 5% CO 2 in DMEM containing 1 FBS. Thereafter, the cell line was treated with JS-101—newPEG2 (lOuM) or JS-101_newPEG4 (10uM), a novel compound of the present invention, and then ASM activity change was measured.
6. ASM 활성 측정 6. ASM Activity Measurement
ASM의 농도 수준을 아래와 같이 측정하였다. 구체적으로 마우스의 혈청， 뇌 조직 또는 섬유아세포 시료 를 ASM 활성 완층액과 흔합하여 37°C에서 보관하였 다. 의 에탄을을 가하여 가수분해 반응을 종료시킨 후， 원심분리하였다. The concentration level of ASM was measured as follows. Specifically, serum, brain tissue, or fibroblast samples of mice were stored at 37 ° C. in combination with ASM active supernatant. Ethane was added to terminate the hydrolysis reaction and then centrifuged.
의 상층액을 유리 바이알에 옮긴 후， 5/^를 UPLC 시스템에 적용시켰다. 상기 ASM 농도 수준을 스핑고미엘린 및 세라마이드와 결합된 Bod ipy( ami noacet aldehyde)와 비교함으로써 정량화하였다. 상기 스핑고미엘린 및 세라마이드의 추출 및 정.량화는 공지된 방법으로 수행하였다. 간략하게， 시료에서 지질을 추출 및 건조하고， 상기 건조된 지질 추출물을 의 0.2% Igepal CA-630(Sigma-Aldr i ch)에 재부유시키고， 각각의 지질의 농도 수준을 UPLC 시스템을 이용하여 정량화하였다. The supernatant of was transferred to a glass vial and then 5 / ^ was applied to the UPLC system. The ASM concentration levels were quantified by comparing Bod ipy (ami noacet aldehyde) combined with sphingomyelin and ceramide. Extraction and purification of the sphingomyelin and ceramide . Quantification was carried out by known methods. Briefly, extract and dry lipids from a sample, resuspend the dried lipid extracts in 0.2% Igepal CA-630 (Sigma-Aldr i ch), and quantify the concentration levels of each lipid using the UPLC system. It was.
7. 통계학적 분석 7. Statistical Analysis
두 그룹의 비교를 위하여 학생의 T— test를 수행하는 반면， 다수의 그룹의 비 교를 위해서는 SAS 통계학적 패키지 (release 9. 1； SAS Inst i tute Inc . , Cary, NC) 에 따라서 Tukey' s HSD 테스트 및 분산 테스트의 반복측정분석을 수행하였다. 찌05를 유의적인 것으로 간주하였다.  While the student's T-test is performed for comparison between the two groups, Tukey's according to the SAS statistical package (release 9.1; SAS Inst i Tute Inc., Cary, NC) for comparison of multiple groups. Repeated analysis of the HSD test and the variance test was performed. Tailings 05 were considered significant.
[실험결과] [Experiment result]
<5-1> in vitro본 발명 신규 화합물들의 ASM 활성 조절 효과 확인  <5-1> Confirmation of ASM activity regulation effect of the novel compounds of the present invention
알츠하이머 환자의 섬유아세포에 본 발명에서 제조한 신규화합물들을 처리하 여 이들의 효능을 확인하였다. 구체적으로 전술한 실시예에서 제조한 신규화합물인 JS-101_newPEG2(도 1A) 또는 JS-101_newPEG4 (도 IB)의 ASM 활성억제 효과를 확인 하기 위하여 알츠하이머 환자 유래 섬유아세포 (psi f ibroblast )에 JS-101_newPEG2 또는 JS-101— newPEG4를 10 uM농도로 처리한 후 ASM의 활성 변화를 측정하였다. 도 2에 나타난 바와 같이, PS1 섬유아세포 (control )에서는 정상인 유래 섬유 아세포에 비해 ASM 활성이 현저하게 증가되어 있었으나， 이는 ASM 억제 신규화합물 인 JS-101_newPEG2 또는 JS-101_newPEG4 처리에 의해 현저하게 감소되었다. 이에 따라 본 발명의 화학식 1로 표시되는 화합물들은 ASM 억제 효능이 우수한 것으로 사료되었다. Fibroblasts of Alzheimer's patients were treated with the novel compounds prepared in the present invention to confirm their efficacy. Specifically, the novel compound prepared in the above-described example To determine the effect of inhibiting ASM activity of JS-101_newPEG2 (FIG. 1A) or JS-101_newPEG4 (FIG. IB), treatment of JS-101_newPEG2 or JS-101—newPEG4 at 10 uM concentration in Alzheimer's patient-derived fibroblasts (psi f ibroblast). Afterwards, the change in activity of ASM was measured. As shown in Figure 2, PS1 fibroblasts (control) significantly increased ASM activity compared to normal derived fibroblasts, but this was significantly reduced by the treatment of ASM inhibition novel compounds JS-101_newPEG2 or JS-101_newPEG4. Accordingly, the compounds represented by Formula 1 of the present invention were considered to have excellent ASM inhibitory effect.
<5-2> 퇴행성 신경질환 in vivo모델에서 본 발명 신규 화합물들의 치료 효 과 확인 <5-2> Confirmation of therapeutic effect of novel compounds of the present invention in in vivo model of neurodegenerative disease
1. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 ASM 활성 변화 확인1. Confirmation of ASM Activity Change in APP / PS1 Mice Administered with Novel Compounds of the Invention
ASM 억제 효능이 있는 본 발명의 화학식 1로 표시되는 화합물들 중 대표적으 로 JS-101_newPEG2를 사용하여 in vivo 상에서 우울증 및 퇴행성 신경질환에 대한 효능을 확인하였다. Among the compounds represented by Formula 1 of the present invention having ASM inhibitory efficacy, JS-101_newPEG2 was typically used to confirm the efficacy against depression and degenerative neurological diseases in vivo.
구체적인 실험방법은 다음과 같다. 도 4에 나타낸 실험 스케즐에 따라， 우울 증 및 퇴행성 신경질환 (특히， 알츠하이머) 동물모델인 APP/PS1 마우스 (7.5개월령) 에 JS-101_newPEG2를 100mg/kg/day씩 2개월간 음수 (飮水)를 통해 구강투여 하였다. 음수를 통한 구강투여 종료 후 (9.5개월령) , 혈장 및 뇌조직에서 ASM 농도 (활성) 수준을 확인하였다. 상기 마우스에서 ASM의 농도 수준을 도 3A 및 도 3B에 나타내 었다.  The specific experimental method is as follows. In accordance with the experimental schedule shown in Figure 4, APP-PS1 mice (7.5 months old), which are depressive and degenerative neurological diseases (especially Alzheimer's disease), were treated with 100 mg / kg / day of JS-101_newPEG2 for 2 months. Oral administration through. After completion of the oral administration through the negative water (9.5 months old), the ASM concentration (activity) level in the plasma and brain tissues was checked. The concentration level of ASM in the mouse is shown in Figures 3A and 3B.
도 3A 및 도 3B에서 보는 바와 같이， APP/PS1 마우스의 혈장 및 뇌조직의 ASM 농도 수준이 정상군 (WT) 대비 상당히 높은 것으로 나타났으며， 이와 비교하여 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 마우스의 혈장 및 뇌조직의 ASM 농도는 그 수준이 현저히 낮음을 확인하였다.  As shown in Figures 3A and 3B, the plasma and brain tissue levels of ASM in APP / PS1 mice were found to be significantly higher than the normal group (WT), compared to the novel compound JS-101_newPEG2 of the present invention. Plasma and brain tissue ASM concentrations of the mice administered were confirmed to be significantly low.
2. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 아밀로이드 -β 침착 확인 2. Confirmation of Amyloid-β Deposition in APP / PS1 Mice Administered with Novel Compounds of the Invention
ASM 억제 신규화합물인 JS-101_newPEG2이 알츠하이머 병변에 미치는 영향을 확인하기 위해， 도 4에 나타낸 실험 스케줄에 따라 알츠하이머 동물모델인 APP/PS1 마우스 (7.5개월령)에 JS_101_newPEG2를 100mg/kg/day씩 2개월간 음수 (飮水)를 통해 구강투여하고, 상기 마우스로부터 알츠하이머 병변인 아밀로이드 -β (Αβ ) 프로파일 을 규명하였다. 먼저 마우스의 대뇌 수질 (Cortex) 및 해마 (Hippocampus) 부위를 공지된 방법에 따라 티오플라빈 S(ThioS)로 염색하여 원섬유성 아밀로이드 -β 침착 을 확인하였다. 또한， Αβ 40 및 Αβ 42의 면역형광 염색을 실시하여 아밀로이드 -β 침착을 확인하였다. 실험 결과, APP/PS1 마우스와 비교해 JS-101_newPEG2를 투여한 APP/PS1 마우 스에서 원섬유성 Αβ 침착 (도 5Α 및 도 5Β 참조) 및 Αβ 40과 Αβ 42의 침착이 현저 히 낮은 것을 확인하였다 (도 6Α 및 도 6Β 참조) . In order to confirm the effect of JS-101_newPEG2, an ASM inhibitory compound, on Alzheimer's lesion, two months of 100 mg / kg / day of JS_101_newPEG2 were applied to the Alzheimer's animal model APP / PS1 mouse (7.5 months old) according to the experimental schedule shown in FIG. Through negative water After oral administration, the amyloid-β (Αβ) profile, which is an Alzheimer's lesion, was identified from the mice. First, the cerebral medulla (Cortex) and hippocampus (Hippocampus) sites of the mice were stained with thioflavin S (ThioS) according to a known method to confirm fibrillar amyloid -β deposition. In addition, immunofluorescence staining of Aβ 40 and Aβ 42 was performed to confirm amyloid-β deposition. Experimental results showed that fibrillar Aβ deposition (see FIGS. 5A and 5B) and Aβ40 and Aβ42 were significantly lower in APP / PS1 mice administered with JS-101_newPEG2 compared to APP / PS1 mice (see FIG. 5A and 5B). 6A and 6B).
3. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 학습， 인지력, 활동 성 및 불안감의 호전 확인 3. Confirmation of improvement of learning, cognition, activity and anxiety in APP / PS1 mice administered the novel compound of the present invention
퇴행성신경질환에 있어서 본 발명 신규화합물의 학습 및 인지력에 대한 잠재 적 효과를 확인하기 위하여， 도 4에 나타낸 실험 스케줄에 따라 퇴행성 신경질환( 특히， 알츠하이머) 동물모델인 APP/PS1 마우스 (7.5개월령)에 JS-101_newPEG2를 100mg/kg/day씩 1개월간 음수 (飮水)를 통해 구강투여 하고， MWM(Morris water maze) 및 fear condi t ioning 테스트를 수행하였다.  APP / PS1 mouse (7.5 months old), which is an animal model of neurodegenerative diseases (particularly Alzheimer's disease) according to the experimental schedule shown in FIG. 4, in order to confirm the potential effects on the learning and cognition of the novel compounds in degenerative neurological diseases. JS-101_newPEG2 was orally administered for 1 month at 100 mg / kg / day for 1 month by drinking water, followed by MWM (Morris water maze) and fear conditon ionization tests.
도 7A 내지 도 7D에 나타낸 바와 같이 , APP/PS1 마우스는 공간기억， 인지력 및 기억력 형성에 심각한 장애를. 보였으나， 본 발명의 신규화합물인 JS- 101_newPEG2를 투여한 APP/PS1 마우스는 이러한 장애가 개선됨을 확인하였다 (도 7A 내지 도 7C 참조) . JS— 101_newPEG2는 fear condit ioning test에서도 기억력의 개선 효과를 나타냄을 확인하였다 (도 7D 참조) . 또한， JS-101_newPEG2 화합물이 활동성 및 불안감에 미치는 영향을 확인하기 위해 오픈필드 테스트와 Dark & Light 테스트를 실시하였다.  As shown in FIGS. 7A-7D, APP / PS1 mice have severe impairments in spatial memory, cognitive and memory formation. Although, it was confirmed that APP / PS1 mice to which the novel compound JS-101_newPEG2 of the present invention was ameliorated such disorders (see FIGS. 7A to 7C). JS—101_newPEG2 also showed an improvement in memory in fear condit ioning test (see FIG. 7D). In addition, open field tests and dark & light tests were conducted to determine the effects of JS-101_newPEG2 on activity and anxiety.
도 8A 내지 도 81에 나타난 바와 같이， APP/PS1 마우스에 비해 본 발명의 신 규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서 활동성 및 불안감이 크게 호전되는 현상올 확인하였다 (도 8A 내지 도 81 참조) .  As shown in Figure 8A to Figure 81, compared to the APP / PS1 mice, the phenomenon that the activity and anxiety is significantly improved in APP / PS1 mice administered the new compound JS-101_newPEG2 of the present invention (Fig. 8A to Fig. 81).
4. 본 발명의 신규화합물을 투여한 APP/PS1 마우스에서 신경염증 변화 확인4. Confirmation of neuroinflammatory changes in APP / PS1 mice administered the novel compounds of the present invention
APP/PS1 마우스에서 본 발명의 신규화합물인 JS-101_newPEG2 투여가 신경염 증 변화에 미치는 영향을 확인하기 위해서， 도 4에 나타낸 실험 스케줄에 따라 퇴 행성 신경질환 (특히， 알츠하이머) 동물모델인 APP/PS1 마우스 (7.5개월령)에 JS- 101_newPEG2를 100mg/kg/day씩 2개월간 음수 (飮水)를 통해 구강투여 하고， 마우스 를 희생하여 뇌에서 별아교세포의 변화를 관찰하였다. 실험 결과 도 9A 및 도 9B에서 보는 바와 같이 , APP/PS1 마우스와 비교하여 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서는 별아교세 포의 활성이 현저히 저하됨을 확인하였다 (도 9A 참조) . APP/PS1 마우스에서는 야생 마우스에 비해 염증성 사이토카인인 TNF- a , IL-Ι β 및 IL-6의 유전자 발현이 현저 히 증가되어 있었으나, 본 발명의 신규화합물인 JS-101_newPEG2를 투여한 APP/PS1 마우스에서는 염증성 사이토카인의 발현이 정상수준으로 회복됨을 확인하였다 (도 9B 참조) . 이러한 결과들을 통해 본 발명의 신규화합물인 JS-101_newPEG2의 투여는 퇴행성 신경질환 (특히， 알츠하이머) 뇌환경에서 신경 염증 반응을 조절한다는 것을 확인할 수 있었다 · 상기의 결과들을 종합하면， 본 발명의 신규 화합물들 (특히 , JS-101_newPEG2 와 JS-101_newPEG4)은 알츠하이머 환자 유래 섬유아세포에서 증가된 ASM 활성을 억 제시켜줄 수 있음을 알 수 있었다. 특히， APP/PS1 마우스에서 ASM 억제 신규화합물 인 JS-101_newPEG2의 투여는 Αβ 플라크 침착과 염증반웅을 감소시킴을 알 수 있었 다. 또한 ASM 억제 신규화합물인 JS-101_newPEG2은 퇴행성 신경질환 (특히， 알츠하 이머) 동물에서 학습， 기억능력을 향상시킴으로써， 알츠하이머를 포함하는 퇴행성 뇌질환 치료제로서 활용이 가능하다는 사실올 알 수 있었다. To determine the effect of JS-101_newPEG2 administration, a novel compound of the present invention, on neuroinflammatory changes in APP / PS1 mice, it was rejected according to the experimental schedule shown in FIG. APP-PS1 mouse (7.5 months old), an animal model of planetary neuropathy (particularly Alzheimer's disease), was given oral administration of JS-101_newPEG2 for 2 months at 100mg / kg / day for 2 months, and sacrificed mouse to glial Changes in the cells were observed. Experimental results, as shown in Figure 9A and 9B, compared with APP / PS1 mice, it was confirmed that the activity of astrocytic cells is significantly reduced in APP / PS1 mice administered the new compound JS-101_newPEG2 of the present invention (Fig. 9A Reference) . Gene expression of inflammatory cytokines TNF- a, IL-Ι β and IL-6 was significantly increased in APP / PS1 mice compared to wild mice, but APP / PS1 administered with JS-101_newPEG2, a novel compound of the present invention, was significantly increased. In mice, it was confirmed that the expression of inflammatory cytokines was restored to normal levels (see FIG. 9B). These results confirm that the administration of the novel compound JS-101_newPEG2 of the present invention modulates the neuro-inflammatory response in neurodegenerative diseases (especially Alzheimer's) brain environment. (In particular, JS-101_newPEG2 and JS-101_newPEG4) could inhibit the increased ASM activity in Alzheimer's patient-derived fibroblasts. In particular, the administration of JS-101_newPEG2, a new ASM inhibitory compound, reduced the Aβ plaque deposition and inflammation in APP / PS1 mice. In addition, it was found that JS-101_newPEG2, a new ASM inhibitory compound, can be used as a treatment for degenerative brain diseases including Alzheimer's by improving learning and memory in animals with neurodegenerative diseases (particularly Alzheimer's).
【산업상 이용가능성 ] Industrial Applicability
이상 살펴본 바와 같이， 본 발명은 화학식 1로 표시되는 신규 화합물 2-아미 노 -2-( 1-(2-(2-히 ^록시에특시 )에틸 )— L l， 2， 3-트리아졸—4-일 )프로판 -1， 3-디올 유 도체 및 이의 용도에 관한 것이다. 본 발명의 화학식 1의 ASM 신규 억제화합물은 ASM 억제 효과가 탁월하고， 알츠하이머 뇌환경에서 Αβ 플라크 감소， 기억력 및 불 안증 개선， 신경염증 완화 등의 치료효과가 있으며， 알츠하이머병을 포함하는 퇴행 성 신경질환의 예방 또는 치료제 개발에 매우 유용하게 사용될 수 있어 산업상 이 용가능성이 매우 우수하다. 또한 ASM의 억제는 우을증 완화에 효과적임이 이미 알 려져 있으므로 본 발명의 화학식 1의 ASM 신규 억제화합물은 우을증을 포함하는 신 경 질환의 예방 또는 치료제로서도 유용하게 사용될 수 있다.  As described above, the present invention is a novel compound represented by the formula (1) 2-amino-2- (1- (2- (2- hydroxy epoxy) ethyl) — L 1, 2, 3-triazole —4-yl) propane-1,3-diol derivatives and uses thereof. ASM novel inhibitory compounds of the formula (1) of the present invention is excellent in inhibiting ASM, has a therapeutic effect such as reducing Aβ plaque, improving memory and anxiety, relieving neuroinflammatory inflammation in the Alzheimer's brain environment, degenerative neurons including Alzheimer's disease It can be very useful in the development of preventive or therapeutic agents for diseases, and thus has excellent industrial applicability. In addition, since the inhibition of ASM is known to be effective in alleviating depression, the ASM novel inhibitory compound of Formula 1 of the present invention may be usefully used as a prophylactic or therapeutic agent for neurological diseases including depression.

Claims

【청구의 범위】 [Range of request]
【청구항 1】  [Claim 1]
하기 화학식 1로 표시되는 화합물 또는 이의 염 :  A compound represented by the following formula (1) or a salt thereof:
<화학식 1>  <Formula 1>
Figure imgf000036_0001
Figure imgf000036_0001
상기 식에서 은 수소 또는 아세틸기이고， 상기 n은 2≤ n ≤5의 자연수임 Is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5
【청구항 2】 [Claim 2]
계 1항에 있어서, 상기 화합물은 n=2일 때 2_(2-아자이도에록시)에탄을 ((2- (2-azidoethoxy)ethanoD), n=3일 때 2-[2-(2-아자이도에특시)에록시] -에탄올 (2- [2-(2-azidoethoxy)ethoxy]-ethanol ) , n=4일 때 2— [2-[2— (2-아자이도에록시)에록 시]에톡시] -에탄을 (2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]— ethanol), n=5일 때 14-아자이도 -3 ,6,9， 12-테트라옥사테트라데카놀 ( 14-Az i do-3 ,6,9,12- tetraoxatetradecanol)인 것을 특징으로 하는 화합물 또는 이의 염.  The compound according to claim 1, wherein the compound contains 2_ (2-azidoethoxy) ethane when n = 2 ((2- (2-azidoethoxy) ethanoD), and 2- [2- (2- when n = 3). Azaido special) ethoxy] -ethanol (2- [2- (2-azidoethoxy) ethoxy] -ethanol), n = 4, 2— [2- [2— (2-azidoethoxy) Ci] ethoxy] -ethane (2- [2- [2- (2-azidoethoxy) ethoxy] ethoxy] —ethanol), 14-azido-3,6,9, 12-tetraoxa when n = 5 Tetradecanol (14-Az i do-3,6,9,12-tetraoxatetradecanol) or a salt thereof.
【청구항 3】 [Claim 3]
하기의 단계들을 포함하는, ¾이 수소인 제 1항의 화합물로서 하기 화학식 la 로 표시되는 화합물의 제조방법:  A process for preparing a compound represented by the following formula la as the compound of claim 1, wherein ¾ is hydrogen, comprising the following steps:
(a) 하기 화학식 2의 화합물과 하기 화학식 3으로 표시되는 화합물을 반웅시 켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계 ; 및  (a) preparing a compound represented by the following Chemical Formula 4 by reacting the compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3; And
(b) 상기 (a) 단계에서 제조한 하기 화학식 4의 화합물에서 부틸옥시카보닐 7) (butyl oxycarbonyl group) 및 아세토니드기 (acetonide group)를 탈보호 (deprotection)하여， ¾이 수소인 계 1항의 화합물로서 하기 화학식 la로 표시되는 화합물을 제조 및 수득하는 단계.  (b) Deprotecting the butyl oxycarbonyl group 7 and the acetonide group from the compound of formula 4 prepared in step (a), wherein ¾ is hydrogen. Preparing and obtaining a compound represented by the formula la as the compound of claim.
<화학식 2> 3 <Formula 2> 3
Figure imgf000037_0001
식에서 n은 2≤ n ≤5의 자연수임.
Figure imgf000037_0001
Where n is a natural number of 2≤n≤5.
<화학식 la><Formula la>
Figure imgf000037_0002
Figure imgf000037_0002
상기 식에서 n은 2≤ n ≤5의 자연수임 . N is a natural number of 2≤n≤5.
【청구항 4】 [Claim 4]
하기 화학식 la로 표시되는 화합물의 아민기를 N-아세틸화 (N— acetylat ion)하 는 단계를 포함하는， ¾이 아세틸기인 제 1항의 화합물로서 하기 화학식 lb로 표시되 는 화합물의 제조방법 .  A process for preparing a compound represented by the following formula lb as a compound of claim 1, wherein ¾ is an acetyl group, comprising N-acetylating an amine group of the compound represented by the following formula la.
〈화학식 la> <Formula la>
Figure imgf000038_0001
Figure imgf000038_0001
<화학식 lb>
Figure imgf000038_0002
<Formula lb>
Figure imgf000038_0002
상기 식에서 n은 2≤ n ≤5의 자연수임 . N is a natural number of 2≤n≤5.
【청구항 5】 [Claim 5]
하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으 로 포함하는 퇴행성 신경질환 또는 우울증의 치료용 약학적 조성물:  A pharmaceutical composition for the treatment of degenerative neurological diseases or depression comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
< 1>  <1>
Figure imgf000038_0003
Figure imgf000038_0003
상기 식에서 ¾은 수소 또는 아세틸기이고， 상기 η은 2≤ η ≤5의 자연수임. Wherein ¾ is hydrogen or an acetyl group, and η is a natural number of 2 ≦ η ≦ 5.
【청구항 6】 [Claim 6]
제 5항에 있어서， 상기 화학식 1의 화합물은 ASM(acid sphingomyel inase) 활 성 억제 효과를 나타내는 것을 특징으로 하는 약학적 조성물.  The pharmaceutical composition according to claim 5, wherein the compound of Formula 1 exhibits an inhibitory effect on acid sphingomyel inase (ASM) activity.
【청구항 7】 [Claim 7]
제 5항에 있어서， 상기 퇴행성 신경질환은 알츠하이머병， 파킨슨병， 진행성핵 상마비， 다계통 위축증, 감람핵 -뇌교 -소뇌 위축증 (0PCA) , 샤이ᅳ드래거 증후군, 선 조체 -혹질 퇴행증, 헌팅톤병， 근위축성 측색 경화증 (ALS) , 본태성 진전증, 피질-기 저핵 퇴행증, 미만성 루이 소체 질환， 파킨스 -ALS-치매 복합증， 픽병， 뇌허혈 및 뇌경색으로 이루어진 군에서 선택된 1종 이상인 것을 특징으로 하는 약학적 조성 물. According to claim 5, wherein the neurodegenerative disease Alzheimer's disease, Parkinson's disease, advanced nucleus Epiplegia, Multiple System Atrophy, Olive Nucleus-Ponocytes-Cerebellar Atrophy (0PCA), Shinseng Dragger Syndrome, Striae-Hoarseness Degenerative, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS), Essential Tremor, Cortical-Base Hyponucleus A pharmaceutical composition, characterized in that it is at least one member selected from the group consisting of degenerative diseases, diffuse Lewis body disease, Parkin-ALS-dementia complications, pick disease, cerebral ischemia and cerebral infarction.
【청구항 8】 [Claim 8]
하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으 로 포함하는 퇴행성 신경질환 또는 우울증의 개선용 식품 조성물:  A food composition for improving degenerative neurological disease or depression comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
< 1>  <1>
Figure imgf000039_0001
Figure imgf000039_0001
상기 식에서 ^은 수소 또는 아세틸기이고， 상기 n은 2≤ n ≤5의 자연수임. ^ Is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5.
【청구항 9】 [Claim 9]
퇴행성 신경질환 또는 우울증 치료용 제제를 제조하기 위한， 하기 화학식 1 의 화합물 또는 이의 약학적으로 허용 가능한 염의 용도:  Use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a agent for treating neurodegenerative disorders or depression:
< 1>  <1>
Figure imgf000039_0002
상기 식에서 ¾은 수소 또는 아세틸기이고, 상기 n은 2≤ n ≤5의 자연수임.
Figure imgf000039_0002
Wherein ¾ is hydrogen or an acetyl group, and n is a natural number of 2 ≦ n ≦ 5.
【청구항 10] [Claim 10]
하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 특징으로 하는 퇴행성 신경질환 또는 우울증의 치료 방법:  A method of treating degenerative neurological disease or depression, comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
<화학식 1>
Figure imgf000040_0001
<Formula 1>
Figure imgf000040_0001
상기 식에서 ^은 수소 또는 아세틸기이고， 상기 n 2≤ n ≤5의 자연수임 .  Where ^ is hydrogen or an acetyl group and n 2 ≤ n ≤ 5 is a natural number.
【청구항 11] [Claim 11]
제 10항에 있어서， 상기 퇴행성 신경질환은 알츠하이머병， 파킨슨병， 진행성 핵상마비， 다계통 위축증， 감람핵 -뇌교 -소뇌 위축증 (0PCA) , 시:이-드래거 증후군， 선조체 -혹질 퇴행증, 헌팅톤병, 근위축성 측색 경화증 (ALS) , 본태성 진전증, 피질- 기저핵 퇴행증， 미만성 루이 소체 질환， 파킨스 -ALS-치매 복합증， 픽병， 뇌허혈 및 뇌경색으로 이루어진 군에서 선택된 1종 이상인 것을 특징으로 하는 치료 방법.  The neurodegenerative disease of claim 10, wherein the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, advanced nuclear palsy, polyatrophic atrophy, olive nucleus-brain gland-cerebellar atrophy (0PCA), poetry: D-Dragger syndrome, striatal-homogeneous degeneration, At least one member selected from the group consisting of Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortical-basal nucleus degeneration, diffuse Lewis body disease, Parkin's-ALS-dementia complex, pick disease, cerebral ischemia and cerebral infarction Treatment method.
PCT/KR2018/004641 2017-04-28 2018-04-20 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1h-1,2,3-triazole-4-yl)propane-1,3-diol derivative which is novel compound, and use thereof WO2018199562A1 (en)

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