WO2023214836A1 - Novel berberine analogue and use thereof - Google Patents

Novel berberine analogue and use thereof Download PDF

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WO2023214836A1
WO2023214836A1 PCT/KR2023/006144 KR2023006144W WO2023214836A1 WO 2023214836 A1 WO2023214836 A1 WO 2023214836A1 KR 2023006144 W KR2023006144 W KR 2023006144W WO 2023214836 A1 WO2023214836 A1 WO 2023214836A1
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formula
isomer
acceptable salt
compound represented
disease
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조종현
윤진호
최세명
김영연
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주식회사 알트메디칼
동아대학교 산학협력단
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Publication of WO2023214836A1 publication Critical patent/WO2023214836A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to new berberine analogs and their uses.
  • mitochondria organelles that exist within cells and are known as the “powerhouse of the cell.” Mitochondria not only produce energy through oxidative phosphorylation in cells, but also play a role in apoptosis, ion homeostasis, sugar and fat metabolism, pyrimidine synthesis, urea and heme ( It performs essential functions for maintaining the life of cells and organisms, such as heme) synthesis.
  • Mitochondrial activity in vivo is maintained by the balance of mitochondrial creation, fusion, and fission mechanisms, as well as the creation of new mitochondria and mitophagy activity, which removes expired or damaged mitochondria.
  • Free radicals generated from damaged mitochondria induced by abnormal mitophagy activity have been considered a major cause of aging, and the accumulation of damaged mitochondria is known to be closely related to various metabolic diseases, including diabetes, and age-related degenerative diseases ( Bratic and Larsson, 2013).
  • Mitophagy is an intracellular decomposition mechanism that removes damaged or unnecessary mitochondria. When mitochondrial damage occurs, it surrounds itself with a membrane to form an autophagosome and fuses it with a lysosome to selectively destroy the damaged mitochondria. It has been reported to play a role in eliminating It is known that this activity of mitophagy is important for regulating mitochondrial function and maintaining tissue function in various cells, including nerve cells.
  • Mitophagy is a selective decomposition mechanism of mitochondria. It was initially thought to be a part of autophagy, which decomposes various elements within the cell for survival under conditions of nutrient deficiency, but later completely decomposes mitochondria by surrounding them with a membrane and fusing them with lysosomes. It was confirmed that it is a mechanism that can effectively remove damaged or unnecessary mitochondria. Mitophagy plays a role in protecting mitochondria from the release of pro-apoptotic proteins, generation of reactive oxygen species, and hydrolysis of useless ATP in aged, damaged, and depolarized mitochondria.
  • CCCP and FCCP are mitochondrial membrane potential inhibitors (uncouplers) that depolarize the mitochondrial membrane potential, and rotenone acts as a Complex I inhibitor. They induce mitophagy activity, which is a removal mechanism for damaged mitochondria, by directly inducing mitochondrial damage, but because they are highly toxic to cells, they cannot be used as drugs to promote mitophagy activity.
  • the purpose of the present invention is to provide a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • X is F, Cl, Br, I or OH
  • R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
  • R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
  • R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
  • Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1);
  • X A is halogen
  • Another object of the present invention is to provide a composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is done.
  • Another object of the present invention is to provide a food composition for preventing or improving diseases caused by mitochondrial dysfunction, which contains the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is provided.
  • Another object of the present invention is to provide a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to induce intracellular mitophagy, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. ) is to provide a method of increasing the activity of.
  • Another object of the present invention is to treat mitochondrial dysfunction, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. ) is to provide a method of suppressing.
  • the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • X is F, Cl, Br, I or OH
  • R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
  • R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
  • R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
  • X is F, Cl, Br, I or OH
  • R is C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, where the C 1-10 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-10 is characterized by a triple bond at the terminal;
  • R 1 and R 2 are independently C 1-3 alkyloxy
  • R 3 and R 4 may be connected to each other to form 1,3-dioxolane, but the present invention is not limited thereto.
  • X is F, Cl, Br, I or OH
  • R is C 3-5 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, where the C 3-5 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 3-5 is characterized by a triple bond at the terminal;
  • R 1 and R 2 are independently C 1-2 alkyloxy
  • R 3 and R 4 may be connected to each other to form 1,3-dioxolane, but the present invention is not limited thereto.
  • the compound represented by Formula 1 may be a compound represented by the following Formula 1A, but is not limited thereto:
  • X is as defined in Formula 1 of Clause 1).
  • Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1);
  • a method for producing a compound represented by Formula 1 above is provided.
  • X A is halogen
  • the basic solution in step 1 may be an aqueous sodium hydroxide solution, but is not limited thereto.
  • the organic solvent in step 2 is dichloromethane, ethanol, tetrahydrofuran, benzene, methanol, toluene, hexane, dimethylformamide, diisopropyl ether, diethyl ether, dioxane, dimethyl It may be one or more selected from the group consisting of acetamide, dimethyl sulfoxide, and chlorobenzene, but is not limited thereto.
  • the present invention provides a composition for preventing, improving, or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention provides a food composition for preventing or improving diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the present invention provides a method for preventing diseases caused by mitochondrial dysfunction, comprising the step of administering the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof. , improvement, and/or treatment methods are provided.
  • the present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the production of a drug for preventing, improving, and/or treating diseases caused by mitochondrial dysfunction. Provides a purpose.
  • the present invention provides a use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention, improvement, and/or treatment of diseases caused by mitochondrial dysfunction. .
  • the present invention provides a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for promoting mitophagy activity, comprising the step of administering the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.
  • the present invention provides the use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the production of a drug for promoting mitophagy activity.
  • the present invention provides the use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to increase the activity of intracellular mitophagy.
  • a method for increasing the activity of intracellular mitophagy comprising treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the method may be performed in vitro.
  • the present invention provides a method for inhibiting mitochondrial dysfunction, comprising treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the method may be performed in vitro.
  • the compound promotes the activity of mitophagy, but is not limited thereto.
  • the promotion of mitophagy activity may include, but is not limited to, removing dysfunctional mitochondria.
  • the disease caused by mitochondrial dysfunction may be a degenerative disease, but is not limited thereto.
  • the degenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and immune system abnormalities. It may be selected from the group consisting of cerebral dysfunction, progressive neurodegenerative disease, metabolic brain disease, Niemann-Pick disease, and dementia due to cerebral ischemia and cerebral hemorrhage, but is not limited thereto.
  • the disease caused by mitochondrial dysfunction may be MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or Charcot Marie Tooth disease (CMT). It is not limited.
  • the present invention relates to CD1-410, a novel berberine analogue. It has been confirmed that the novel berberine analogue promotes the activity of mitophagy, thereby reducing mitochondria with damaged structures and/or functions. Therefore, the new berberine analog according to the present invention can be used to prevent, improve, and/or treat various diseases that may be caused by abnormal mitochondria.
  • Figure 1 is a diagram showing the structure of CD1-410, a novel berberine analog of the present invention.
  • Figure 2 is a diagram analyzing the effect of increasing mitophagy activity of CD1-410 of the present invention by flow cytometry (A: flow cytometry results, B: quantification of flow cytometry results).
  • the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • compound is a concept that includes all of the above compounds, isomers thereof, and pharmaceutically/foodologically acceptable salts thereof.
  • X is F, Cl, Br, I or OH
  • R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
  • R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
  • R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
  • the compound of Formula 1 of the present invention may further include the following analogs.
  • the active substance of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • pharmaceutically acceptable salt refers to a concentration that has an effective effect that is relatively non-toxic and harmless to patients, and is defined as any organic or It means inorganic addition salt.
  • inorganic acids and organic acids can be used as free acids.
  • Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine can be used as organic acids.
  • Acids gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethane sulfuric acid Fonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid can be used.
  • these salts include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.).
  • acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, mally.
  • ate malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharide Latex, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salt, etc. may be included, and among these, hydrochloride or trifluoroacetate is preferable.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the active substance in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate. It can be manufactured by distilling the solvent and excess acid under reduced pressure, drying it, or crystallizing it in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the present invention includes not only the active substance and its pharmaceutically acceptable salt, but also all possible solvates, hydrates, isomers, optical isomers, etc. that can be prepared therefrom.
  • X is F, Cl, Br, I or OH
  • R is C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, where the C 1-10 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-10 is characterized by a triple bond at the terminal;
  • R 1 and R 2 are independently C 1-3 alkyloxy
  • R 3 and R 4 may be connected to each other to form 1,3-dioxolane.
  • X is F, Cl, Br, I or OH
  • R is C 3-5 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, where the C 3-5 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 3-5 is characterized by a triple bond at the terminal;
  • R 1 and R 2 are independently C 1-2 alkyloxy
  • R 3 and R 4 may be connected to each other to form 1,3-dioxolane.
  • the compound represented by Formula 1 may be a compound represented by Formula 1A below:
  • X is as defined in Formula 1 above.
  • the compound of Compound 1A of the present invention is 13-(but-3-yn-1-yl)-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[ It may be named 3,2-a]isoquinolin-7-ium bromide.
  • Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1);
  • a method for producing a compound represented by Formula 1 above is provided.
  • X A is halogen
  • the basic solution in step 1 may be an aqueous sodium hydroxide solution.
  • the organic solvent in step 2 is dichloromethane, ethanol, tetrahydrofuran, benzene, methanol, toluene, hexane, dimethylformamide, diisopropyl ether, diethyl ether, dioxane, It may be one or more types selected from the group consisting of dimethylacetamide, dimethyl sulfoxide, and chlorobenzene.
  • the present invention provides a composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • prevention used in the present invention refers to all actions that suppress the symptoms or delay the progression of a specific disease by administering the composition of the present invention.
  • treatment refers to any action that improves or beneficially changes the symptoms of a specific disease by administering the composition of the present invention.
  • the term “mitophagy” refers to an intracellular decomposition mechanism that removes damaged or unnecessary mitochondria. Mitophagy generally forms an autophagosome when mitochondrial damage occurs and fuses with lysosomes to selectively decompose and remove damaged mitochondria. Mitophagy decomposes and decomposes unnecessary components within the cell (old proteins, protein aggregates, organelles, pathogens that have infiltrated the cell, etc.) to generate macromolecular precursors and generate energy when the cell is in a state of nutritional deficiency. It is a mechanism that is distinct from autophagy, which is a recycling mechanism. Mitophagy is regulated independently of regulatory signals such as nutrients, energy, and stress that regulate autophagy. In the present invention, 'promoting mitophagy' includes promoting or increasing the activity, frequency, extent, level, etc. of mitophagy.
  • composition according to the present invention may further include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means that the composition exhibits non-toxic properties to cells or humans exposed to the composition.
  • the carrier may be used without limitation as long as it is known in the art, such as a buffer, preservative, analgesic agent, solubilizer, isotonic agent, stabilizer, base, excipient, lubricant, etc.
  • composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. there is. Furthermore, it can be used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or external skin preparation in the form of a gel.
  • Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the Cycotria rubra extract with at least one excipient, such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectable ester such as ethyl oleate.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and It can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains.
  • composition according to the present invention can be administered to an individual through various routes. All modes of administration are contemplated, for example, by oral, intravenous, intramuscular, subcutaneous, or intraperitoneal injection.
  • the content of the compound in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the patient's condition, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight, based on the total weight of the composition. However, it is not limited to this.
  • the content ratio is a value based on the dry amount with the solvent removed.
  • the dosage of the pharmaceutical composition according to the present invention is selected taking into account the age, weight, gender, physical condition, etc. of the individual. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be selected in various ways depending on the target, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 ⁇ g/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 ⁇ g/ml, it may be toxic to the human body.
  • “individual” refers to a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cows, etc. refers to mammals of
  • “administration” means providing a given composition of the present invention to an individual by any suitable method.
  • prevention refers to any action that suppresses or delays the onset of the desired disease
  • treatment refers to the improvement or improvement of the desired disease and its associated metabolic abnormalities by administration of the pharmaceutical composition according to the present invention. It refers to all actions that are beneficially changed, and “improvement” refers to all actions that reduce parameters related to the desired disease, such as the degree of symptoms, by administering the composition according to the present invention.
  • the compound may promote the activity of mitophagy.
  • the promotion of mitophagy activity may be removing dysfunctional mitochondria.
  • the disease caused by mitochondrial dysfunction may be a degenerative disease
  • the degenerative disease may include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, immune system abnormalities, brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Niemann-Pick disease, and dementia caused by cerebral ischemia and cerebral hemorrhage. It may have been chosen by the military.
  • the disease caused by mitochondrial dysfunction may be MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or Charcot Marie Tooth disease (CMT).
  • MELAS syndrome mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
  • CMT Charcot Marie Tooth disease
  • diseases caused by mitochondrial dysfunction may further include cancer or allergic diseases.
  • the cancers include colon cancer, CTH-producing tumor, acute lymphoblastic or lymphoblastic leukemia, acute or chronic lymphocytic leukemia, acute non-lymphocytic leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, chronic myeloid leukemia, intestinal cancer, T- John's lymphoma, endometriosis, esophageal cancer, gallbladder cancer, Ewing's sarcoma, head and neck cancer, tongue cancer, Hopkins lymphoma, Kaposis sarcoma, kidney cancer, liver cancer, lung cancer, mesothelioma, multiple myeloma, neuroblastoma, non-Hopkin lymphoma , osteosarcoma, ovarian cancer, neuroblastoma, mammary cancer, cervical cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, stomach cancer, thyroid cancer, uterine cancer, testicular cancer, Wilms tumor, and troph
  • the allergic diseases include atopic dermatitis, allergic dermatitis, contact dermatitis, urticaria, itching, insect allergy, food allergy, drug allergy, edema, anaphylaxis, and allergic rhinitis ( It may be selected from the group consisting of allergic rhinitis, asthma, and allergic conjunctivitis.
  • the present invention provides a food composition for preventing or improving diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a food-acceptable salt thereof as an active ingredient.
  • the food composition includes a health functional food composition.
  • the term “foodologically acceptable salt” includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.
  • the term “improvement” refers to any action that results in at least a reduction in the severity of the parameters associated with the condition being treated, such as symptoms, as described above.
  • the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a normal food composition.
  • Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the above-described flavoring agents include natural flavoring agents (thaumatin), stevia extracts (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods.
  • Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes, health supplements, etc. There is.
  • the food composition contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, It may contain alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • the food composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages.
  • the functional food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating diseases caused by mitochondrial dysfunction.
  • 'health functional food composition' refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and refers to food that is related to the structure and function of the human body. It means taking it for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects.
  • the health functional food of the present invention may contain common food additives, and its suitability as a food additive is determined in accordance with the general provisions and general test methods of the food additive code approved by the Food and Drug Administration, unless otherwise specified. Judgment is made according to specifications and standards.
  • Items listed in the 'Food Additive Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as dark pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; Examples include mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations.
  • the health functional food in the form of a tablet is made by granulating a mixture of the active ingredient of the present invention with excipients, binders, disintegrants and other additives in a conventional manner, and then adding a lubricant and compression molding, or The mixture can be directly compression molded.
  • the health functional food in the form of tablets may contain flavoring agents, etc., if necessary.
  • hard capsules can be manufactured by filling a regular hard capsule with a mixture of the active ingredient of the present invention mixed with additives such as excipients, and soft capsules can be prepared by mixing the active ingredient of the present invention with additives such as excipients.
  • the soft capsule may contain plasticizers such as glycerin or sorbitol, colorants, preservatives, etc., if necessary.
  • the health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention, excipients, binders, disintegrants, etc., by a known method. If necessary, it can be coated with white sugar or another coating agent. Alternatively, the surface can be coated with substances such as starch or talc.
  • Health functional food in the form of granules can be manufactured into granules by mixing a mixture of excipients, binders, disintegrants, etc. of the active ingredients of the present invention by a known method, and may contain flavoring agents, flavoring agents, etc., if necessary. You can.
  • the compound of the present invention When using the compound of the present invention, its derivative, or its foodologically acceptable salt as a food additive, the compound can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. .
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). In general, when manufacturing food or beverages, the compound of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • foods to which the above substances can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, These include alcoholic beverages and vitamin complexes, and include all health functional foods in the conventional sense.
  • the health drink composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional drinks.
  • the above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • a sweetener natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame can be used.
  • the proportion of natural carbohydrates is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
  • the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may contain carbonating agents used in carbonated drinks.
  • the composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients can be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • “health functional food” is the same term as food for special health use (FoSHU), and refers to food with high medical and medical effects that has been processed to efficiently exhibit bioregulatory functions in addition to supplying nutrients. This means that the food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to achieve useful effects in preventing or improving peripheral neuropathy.
  • the health functional food of the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and components commonly added in the art.
  • it is made from food, so it has the advantage of not having any side effects that may occur when taking the drug for a long time, and it can be highly portable.
  • the present invention provides a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the mitophagy activity may remove dysfunctional mitochondria, and the dysfunctional mitochondria may induce neurodegenerative diseases.
  • the present invention provides a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a foodologically acceptable salt thereof as an active ingredient.
  • the present invention provides a method of intracellular mitophagy, comprising the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. Provides a method for increasing activity.
  • the cells of the present invention may be cells expressing mt-Keima, and the "mt-Keima (mitochondrion-targeted Keima)" of the present invention is a coral-derived product whose fluorescence characteristics change depending on pH.
  • mt-Keima mitochondrion-targeted Keima
  • Mito Keima is characterized by a significantly stronger fluorescence signal at 458 nm in a neutral environment (pH 7), and a stronger fluorescence signal at 561 nm in acidic conditions (pH 4) due to changes in protein structure.
  • the present invention provides a method for treating mitochondrial dysfunction, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. Provides a method of suppression.
  • the variable when a range is written for a variable, the variable will be understood to include all values within the stated range, including the stated endpoints of the range.
  • the range “5 to 10” includes the values 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood that it also includes any values between integers that fall within the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9, etc.
  • the range "10% to 30%” includes values such as 10%, 11%, 12%, 13%, etc. and all integers up to and including 30%, as well as 10% to 15%, 12% to 12%, etc. It will be understood that it includes any subranges, such as 18%, 20% to 30%, etc., and any value between reasonable integers within the range of the stated range, such as 10.5%, 15.5%, 25.5%, etc.
  • the precursor berberine (3 g, 7.7 mmol), 5 ml of acetone, and 20 ml of 5 N aqueous sodium hydroxide solution were sequentially added to a round flask, and stirred at room temperature for 6 hours. Afterwards, the solid obtained by concentration under reduced pressure was washed five times with 20 ml of cold distilled water. Afterwards, it was vacuum dried to obtain compound (2) in the above synthesis process with a yield of 90%.
  • the Mitocheima fluorescent protein quantification method which can quantitatively measure mitophagy activity in living cells.
  • Mitocheima fluorescent protein was expressed in the BEAS-2B cell line, a human normal lung cell line, and treated with the berberine analog prepared in Example 1 at a concentration of 10 ⁇ M for 24 hours, and then the activity of mitophagy was measured using a flow cytometer. was measured.
  • a control group a control group (Control, con) that was not treated with a compound was used, and as a positive control group, CCCP (10 ⁇ M), which experimentally induces mitophagy activity, was used.
  • the activity of mitophagy was 9.8% in the con group, but increased to 86% in the CCCP group, and increased to 84% in the group treated with CD1-410 of the present invention. It was confirmed that CD1-410 of the present invention significantly increases the activity of mitophagy.
  • the berberine analog of the present invention promotes the activity of mitophagy. Specifically, the decrease in mitochondria due to mitophagy was confirmed by the mitochondrial protein expression level, and the mitochondrial proteins from each group of cells in Example 2-1 were analyzed by Western blot.
  • the present invention synthesized CD1-410, a novel berberine analogue, and confirmed that the novel berberine analogue promotes the activity of mitophagy, and that the activity of mitophagy is promoted to reduce mitochondria.
  • the present invention relates to CD1-410, a novel berberine analogue. It has been confirmed that the novel berberine analogue promotes the activity of mitophagy, thereby reducing mitochondria with damaged structures and/or functions. Therefore, the new berberine analog according to the present invention can be used to prevent, improve, and/or treat various diseases that may be caused by abnormal mitochondria.

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Abstract

The present invention relates to a novel berberine analogue CD1-410. It has been identified that the novel berberine analogue promotes the activity of mitophagy, and thus can reduce mitochondria with a damaged structure and/or function. Therefore, the novel berberine analogue according to the present invention can be used for preventing, alleviating and/or treating various diseases that can be caused by abnormal mitochondria.

Description

신규 베르베린 유사체 및 이의 용도New berberine analogues and their uses
본 발명은, 신규 베르베린 유사체 및 이의 용도에 관한 것이다.The present invention relates to new berberine analogs and their uses.
본 발명은 2022년 5월 6일에 출원된 한국특허출원 제10-2022-0056056호에 기초한 우선권을 주장하며, 상기 출원들의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.The present invention claims priority based on Korean Patent Application No. 10-2022-0056056 filed on May 6, 2022, and all contents disclosed in the specifications and drawings of the above applications are incorporated in this application.
일반적으로 미토콘드리아는 세포 내에 존재하는 소기관으로 "세포의 발전소"로 알려져있다. 미토콘드리아는 세포에서 산화적 인산화에 의한 에너지를 생산할 뿐 아니라 세포사멸(apoptosis), 이온 항상성(ion homeostasis), 당 및 지방 대사(intermediary metabolism), 피리미딘(pyrimidine)합성, 유레아(urea) 및 헴(heme) 합성 등 세포 및 개체의 생명유지에 필수적인 기능을 수행한다.In general, mitochondria are organelles that exist within cells and are known as the “powerhouse of the cell.” Mitochondria not only produce energy through oxidative phosphorylation in cells, but also play a role in apoptosis, ion homeostasis, sugar and fat metabolism, pyrimidine synthesis, urea and heme ( It performs essential functions for maintaining the life of cells and organisms, such as heme) synthesis.
생체 내 미토콘드리아의 활성은 미토콘드리아 생성과 융합(fusion), 분열(fission) 기전과 더불어 새로운 미토콘드리아의 생성 및 수명을 다했거나 손상을 입은 미토콘드리아를 제거하는 미토파지 활성의 균형에 의해 유지된다. 미토파지 활성의 이상으로 유도되는 손상된 미토콘드리아로부터 발생하는 활성산소는 노화의 주요 원인으로 여겨져 왔으며, 손상된 미토콘드리아의 축적은 당뇨병을 비롯한 여러 대사질환과 노화 관련 퇴행성 질환들과 밀접한 연관이 있는 것으로 알려져 있다(Bratic and Larsson, 2013).Mitochondrial activity in vivo is maintained by the balance of mitochondrial creation, fusion, and fission mechanisms, as well as the creation of new mitochondria and mitophagy activity, which removes expired or damaged mitochondria. Free radicals generated from damaged mitochondria induced by abnormal mitophagy activity have been considered a major cause of aging, and the accumulation of damaged mitochondria is known to be closely related to various metabolic diseases, including diabetes, and age-related degenerative diseases ( Bratic and Larsson, 2013).
미토파지 (mitophagy)는 손상되었거나 불필요한 미토콘드리아를 제거하는 세포 내 분해기전으로서, 미토콘드리아 손상이 발생하였을 때 막으로 둘러싸 오토파고좀(autophagosome)을 형성하고 이를 리소좀(lysosome)과 융합함으로써 손상된 미토콘드리아를 선택적으로 제거하는 역할을 수행하는 것으로 보고되었다. 이러한 미토파지의 활성은 신경세포를 비롯한 여러 세포들에서 미토콘드리아 기능을 조절하고 조직의 기능을 유지하는데 중요하다는 것이 알려져 있다.Mitophagy is an intracellular decomposition mechanism that removes damaged or unnecessary mitochondria. When mitochondrial damage occurs, it surrounds itself with a membrane to form an autophagosome and fuses it with a lysosome to selectively destroy the damaged mitochondria. It has been reported to play a role in eliminating It is known that this activity of mitophagy is important for regulating mitochondrial function and maintaining tissue function in various cells, including nerve cells.
미토파지는 미토콘드리아의 선택적 분해 기전으로, 처음에는 영양결핍 조건에서 생존을 위해 세포 내 여러 요소를 분해하는 자식작용(autophagy)의 일부로 여겨졌으나 이후에 미토콘드리아를 막으로 둘러싼 후 리소좀과 융합시켜 완전히 분해시킴으로써 손상되거나 불필요한 미토콘드리아를 효과적으로 제거할 수 있는 기전임이 확인되었다. 미토파지는 세포자살촉진 단백질(pro-apoptotic protein)의 방출, 활성산소의 발생, 노화되고 손상되며 감극된 미토콘드리아의 쓸데없는 ATP의 가수분해로부터 미토콘드리아를 보호하는 역할을 한다.Mitophagy is a selective decomposition mechanism of mitochondria. It was initially thought to be a part of autophagy, which decomposes various elements within the cell for survival under conditions of nutrient deficiency, but later completely decomposes mitochondria by surrounding them with a membrane and fusing them with lysosomes. It was confirmed that it is a mechanism that can effectively remove damaged or unnecessary mitochondria. Mitophagy plays a role in protecting mitochondria from the release of pro-apoptotic proteins, generation of reactive oxygen species, and hydrolysis of useless ATP in aged, damaged, and depolarized mitochondria.
최근 연구에 따르면, 미토파지의 활성 저해는 손상된 미토콘드리아의 축적을 통해 운동신경의 사멸을 야기하여 파킨슨병과 같은 퇴행성 뇌질환을 일으킬 수 있다는 것이 밝혀졌다. 또한, 미토파지 활성의 이상이 파킨슨병, 알츠하이머병, 루게릭병과 같은 퇴행성 뇌질환을 비롯하여, 말초신경병증, 심장질환, 대사질환, 암 등 광범위한 인체질환들과 관련되는 것으로 보고되면서 인체질환에서 미토파지의 역할과 질환치료에 이용가능성에 대한 연구자들의 관심이 높아지고 있다.According to recent research, it has been revealed that inhibition of mitophagy activity can cause death of motor neurons through the accumulation of damaged mitochondria, causing degenerative brain diseases such as Parkinson's disease. In addition, abnormalities in mitophagy activity have been reported to be associated with a wide range of human diseases, including degenerative brain diseases such as Parkinson's disease, Alzheimer's disease, and Lou Gehrig's disease, as well as peripheral neuropathy, heart disease, metabolic disease, and cancer. Researchers' interest in the role and possibility of use in disease treatment is increasing.
현재 실험적으로 미토파지 활성을 유도하는 방법은 CCCP, FCCP, rotenone 등과 같이 미토콘드리아의 기능이상을 유도하는 소위 '미토콘드리아 독소들 (mitochondrial toxins)'을 처리하는 것이다. CCCP와 FCCP는 미토콘드리아 막전위 저해제 (uncoupler)로서 미토콘드리아 막전위를 탈분극시키며, rotenone은 Complex I 저해제로 작용한다. 이들은 직접적으로 미토콘드리아 손상을 유도함으로써 손상된 미토콘드리아의 제거기전인 미토파지 활성을 유도하지만, 세포에 대한 독성이 강하기 때문에 미토파지 활성 촉진을 위한 약물로는 사용할 수 없는 제한이 있다.Currently, the experimental way to induce mitophagy activity is to treat so-called 'mitochondrial toxins' that induce mitochondrial dysfunction, such as CCCP, FCCP, and rotenone. CCCP and FCCP are mitochondrial membrane potential inhibitors (uncouplers) that depolarize the mitochondrial membrane potential, and rotenone acts as a Complex I inhibitor. They induce mitophagy activity, which is a removal mechanism for damaged mitochondria, by directly inducing mitochondrial damage, but because they are highly toxic to cells, they cannot be used as drugs to promote mitophagy activity.
본 발명의 목적은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.The purpose of the present invention is to provide a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023006144-appb-img-000001
Figure PCTKR2023006144-appb-img-000001
상기 화학식 1에서,In Formula 1,
X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
R은 C1-20의 알킬, C1-20의 알케닐 또는 C1-20의 알카이닐이고, 여기서 상기 C1-20의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-20의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있고;R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
R3 및 R4는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있다.R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
본 발명의 다른 목적은 하기 반응식 1에 나타낸 바와 같이,Another object of the present invention is, as shown in Scheme 1 below,
염기성 용액에서, 화합물 2 및 아세톤을 반응하여 화합물 3을 제조하는 단계(단계 1); 및Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1); and
유기용매에서, 화합물 3 및 화합물 4를 반응하여 화합물 1을 제조하는 단계(단계 2);를 포함하는,Comprising: reacting Compound 3 and Compound 4 in an organic solvent to prepare Compound 1 (Step 2);
상기의 화학식 1로 표시되는 화합물의 제조방법을 제공하는 것이다.To provide a method for producing a compound represented by Formula 1 above.
[반응식 1][Scheme 1]
Figure PCTKR2023006144-appb-img-000002
Figure PCTKR2023006144-appb-img-000002
상기 반응식 1에서,In Scheme 1 above,
X, R, R1, R2, R3 및 R4는 상기의 화학식 1에서 정의한 바와 같고,X, R, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 above,
XA는 할로겐이다.X A is halogen.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 치료용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is done.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 개선용 식품조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving diseases caused by mitochondrial dysfunction, which contains the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is provided.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 식품조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 시험관 내(in vitro)에서, 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 세포 내 미토파지(mitophagy)의 활성을 증가시키는 방법을 제공하는 것이다.Another object of the present invention is to induce intracellular mitophagy, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. ) is to provide a method of increasing the activity of.
본 발명의 또 다른 목적은 시험관 내(in vitro)에서, 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)을 억제시키는 방법을 제공하는 것이다.Another object of the present invention is to treat mitochondrial dysfunction, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. ) is to provide a method of suppressing.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object, the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023006144-appb-img-000003
Figure PCTKR2023006144-appb-img-000003
상기 화학식 1에서,In Formula 1,
X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
R은 C1-20의 알킬, C1-20의 알케닐 또는 C1-20의 알카이닐이고, 여기서 상기 C1-20의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-20의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있고;R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
R3 및 R4는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있다.R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
본 발명의 일 구현예에서, X는 F, Cl, Br, I 또는 OH이고;In one embodiment of the invention, X is F, Cl, Br, I or OH;
R은 C1-10의 알킬, C1-10의 알케닐 또는 C1-10의 알카이닐이고, 여기서 상기 C1-10의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-10의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, where the C 1-10 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-10 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-3의 알킬옥시이고;R 1 and R 2 are independently C 1-3 alkyloxy;
R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것을 특징으로 할 수 있으나, 이에 한정되지 않는다.R 3 and R 4 may be connected to each other to form 1,3-dioxolane, but the present invention is not limited thereto.
본 발명의 다른 구현예에서, X는 F, Cl, Br, I 또는 OH이고;In another embodiment of the invention, X is F, Cl, Br, I or OH;
R은 C3-5의 알킬, C3-5의 알케닐 또는 C3-5의 알카이닐이고, 여기서 상기 C3-5의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C3-5의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 3-5 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, where the C 3-5 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 3-5 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-2의 알킬옥시이고;R 1 and R 2 are independently C 1-2 alkyloxy;
R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것을 특징으로 할 수 있으나, 이에 한정되지 않는다.R 3 and R 4 may be connected to each other to form 1,3-dioxolane, but the present invention is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1A로 표시되는 화합물일 수 있으나, 이에 한정되지 않는다:In another embodiment of the present invention, the compound represented by Formula 1 may be a compound represented by the following Formula 1A, but is not limited thereto:
[화학식 1A][Formula 1A]
Figure PCTKR2023006144-appb-img-000004
Figure PCTKR2023006144-appb-img-000004
(상기 화학식 1A에서,(In Formula 1A above,
X는 제 1항의 화학식 1에서 정의한 바와 같다).X is as defined in Formula 1 of Clause 1).
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,In addition, the present invention, as shown in Scheme 1 below,
염기성 용액에서, 화합물 2 및 아세톤을 반응하여 화합물 3을 제조하는 단계(단계 1); 및Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1); and
유기용매에서, 화합물 3 및 화합물 4를 반응하여 화합물 1을 제조하는 단계(단계 2);를 포함하는,Comprising: reacting Compound 3 and Compound 4 in an organic solvent to prepare Compound 1 (Step 2);
상기의 화학식 1로 표시되는 화합물의 제조방법을 제공한다.A method for producing a compound represented by Formula 1 above is provided.
[반응식 1][Scheme 1]
Figure PCTKR2023006144-appb-img-000005
Figure PCTKR2023006144-appb-img-000005
상기 반응식 1에서,In Scheme 1 above,
X, R, R1, R2, R3 및 R4는 상기의 화학식 1에서 정의한 바와 같고,X, R, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 above,
XA는 할로겐이다.X A is halogen.
본 발명의 일 구현예에서, 상기 단계 1의 염기성 용액은 수산화나트륨 수용액일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the basic solution in step 1 may be an aqueous sodium hydroxide solution, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 단계 2의 유기용매는 다이클로로메탄, 에탄올, 테트라하이드로퓨란, 벤젠, 메탄올, 톨루엔, 헥산, 디메틸포름아미드, 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드, 디메틸설폭사이드 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the organic solvent in step 2 is dichloromethane, ethanol, tetrahydrofuran, benzene, methanol, toluene, hexane, dimethylformamide, diisopropyl ether, diethyl ether, dioxane, dimethyl It may be one or more selected from the group consisting of acetamide, dimethyl sulfoxide, and chlorobenzene, but is not limited thereto.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방, 개선, 또는 치료용 조성물을 제공한다.In addition, the present invention provides a composition for preventing, improving, or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .
뿐만 아니라, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방, 개선, 및/또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing diseases caused by mitochondrial dysfunction, comprising the step of administering the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof. , improvement, and/or treatment methods are provided.
뿐만 아니라, 본 발명은 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방, 개선, 및/또는 치료용 약제의 제조를 위한, 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In addition, the present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the production of a drug for preventing, improving, and/or treating diseases caused by mitochondrial dysfunction. Provides a purpose.
뿐만 아니라, 본 발명은 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방, 개선, 및/또는 치료를 위한, 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In addition, the present invention provides a use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention, improvement, and/or treatment of diseases caused by mitochondrial dysfunction. .
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 약학적 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 식품 조성물을 제공한다.Additionally, the present invention provides a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
뿐만 아니라, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 미토파지(mitophagy) 활성 촉진방법을 제공한다.In addition, the present invention provides a method for promoting mitophagy activity, comprising the step of administering the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.
뿐만 아니라, 본 발명은 미토파지(mitophagy) 활성 촉진용 약제의 제조를 위한, 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In addition, the present invention provides the use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the production of a drug for promoting mitophagy activity.
뿐만 아니라, 본 발명은 세포 내 미토파지(mitophagy)의 활성을 증가시키기 위한, 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.In addition, the present invention provides the use of the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to increase the activity of intracellular mitophagy.
또한, 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 세포 내 미토파지(mitophagy)의 활성을 증가시키는 방법을 제공한다. 상기 방법은 시험관 내(in vitro)에서 이루어지는 것일 수 있다.In addition, a method for increasing the activity of intracellular mitophagy is provided, comprising treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The method may be performed in vitro.
또한, 본 발명은 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)을 억제시키는 방법을 제공한다. 상기 방법은 시험관 내(in vitro)에서 이루어지는 것일 수 있다.Additionally, the present invention provides a method for inhibiting mitochondrial dysfunction, comprising treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The method may be performed in vitro.
본 발명의 일 구현예에서, 상기 화합물은 미토파지(mitophagy)의 활성을 촉진시키는 것이나, 이에 한정되지 않는다.In one embodiment of the present invention, the compound promotes the activity of mitophagy, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 미토파지 활성 촉진은, 기능이상 미토콘드리아를 제거하는 것일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the promotion of mitophagy activity may include, but is not limited to, removing dysfunctional mitochondria.
본 발명의 또 다른 구현예에서, 상기 미토콘드리아 기능이상으로 인한 질환은 퇴행성 질환일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the disease caused by mitochondrial dysfunction may be a degenerative disease, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 퇴행성 질환은 알츠하이머병 (Alzheimer's disease), 파킨슨병 (Parkinson's disease), 루게릭병(amyotrophic lateral sclerosis), 헌팅턴병 (Huntington's Disease), 다발성 경화증(Multiple sclerosis), 면역계이상 뇌기능 부전, 진행성 신경퇴행질환, 대사성 뇌질환, 니만-픽병(Niemann-Pick disease), 뇌 허혈 및 뇌출혈로 인한 치매(dementia)로 이루어진 군에서 선택될 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the degenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and immune system abnormalities. It may be selected from the group consisting of cerebral dysfunction, progressive neurodegenerative disease, metabolic brain disease, Niemann-Pick disease, and dementia due to cerebral ischemia and cerebral hemorrhage, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 미토콘드리아 기능이상으로 인한 질환은 MELAS 증후군 (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) 또는 샤르코 마리 투스 질환(Charcot Marie Tooth disease, CMT)일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the disease caused by mitochondrial dysfunction may be MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or Charcot Marie Tooth disease (CMT). It is not limited.
본 발명은 신규 베르베린 유사체인 CD1-410에 관한 것으로서, 상기 신규 베르베린 유사체는 미토파지의 활성을 촉진시키며, 이에 따라 구조 및/또는 기능이 손상된 미토콘드리아를 감소시킬 수 있음이 확인되었다. 따라서, 본 발명에 따른 신규 베르베린 유사체는 비정상 미토콘드리아로 야기될 수 있는 다양한 질환의 예방, 개선, 및/또는 치료 용도로 활용될 수 있다.The present invention relates to CD1-410, a novel berberine analogue. It has been confirmed that the novel berberine analogue promotes the activity of mitophagy, thereby reducing mitochondria with damaged structures and/or functions. Therefore, the new berberine analog according to the present invention can be used to prevent, improve, and/or treat various diseases that may be caused by abnormal mitochondria.
도 1은 본 발명의 신규 베르베린 유사체인 CD1-410의 구조를 나타낸 도이다.Figure 1 is a diagram showing the structure of CD1-410, a novel berberine analog of the present invention.
도 2는 본 발명의 CD1-410의 미토파지 활성 증가효과를 유세포분석으로 분석한 도이다(A: 유세포분석 결과, B: 유세포분석 결과 정량화).Figure 2 is a diagram analyzing the effect of increasing mitophagy activity of CD1-410 of the present invention by flow cytometry (A: flow cytometry results, B: quantification of flow cytometry results).
이하 첨부된 도면을 참조하여 본 발명의 실시예들을 상세히 설명한다. 이하의 설명에 있어, 당업자에게 주지 저명한 기술에 대해서는 그 상세한 설명을 생략할 수 있다. 또한, 본 발명을 설명함에 있어서, 관련된 공지 기능 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있다. 또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다.Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. In the following description, detailed descriptions of techniques well known to those skilled in the art may be omitted. Additionally, when describing the present invention, if it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the gist of the present invention, the detailed description may be omitted. In addition, the terminology used in this specification is a term used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user or operator or the customs of the field to which the present invention belongs.
따라서 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Therefore, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part is said to “include” a certain element, this means that it may further include other elements rather than excluding other elements, unless specifically stated to the contrary.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다. 본 명세서 전반에서, "화합물"이라 함은 상기 화합물, 이의 이성질체, 및 이의 약학적/식품학적으로 허용 가능한 염을 모두 포함하는 개념이다.The present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof. Throughout this specification, the term “compound” is a concept that includes all of the above compounds, isomers thereof, and pharmaceutically/foodologically acceptable salts thereof.
Figure PCTKR2023006144-appb-img-000006
Figure PCTKR2023006144-appb-img-000006
상기 화학식 1에서,In Formula 1,
X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
R은 C1-20의 알킬, C1-20의 알케닐 또는 C1-20의 알카이닐이고, 여기서 상기 C1-20의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-20의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있고;R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
R3 및 R4는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있다.R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane.
본 발명의 상기 화학식 1의 화합물은, 하기의 유사체(analogs)를 더 포함할 수 있다.The compound of Formula 1 of the present invention may further include the following analogs.
Figure PCTKR2023006144-appb-img-000007
Figure PCTKR2023006144-appb-img-000007
본 발명의 유효물질은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 유효물질의 염기 화합물의 이로운 효능을 떨어뜨리지 않는 유효물질의 염기 화합물의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를 들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있으며, 이들 중 하이드로클로라이드 또는 트리플루오로아세테이트가 바람직하다.The active substance of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. The term “pharmaceutically acceptable salt” refers to a concentration that has an effective effect that is relatively non-toxic and harmless to patients, and is defined as any organic or It means inorganic addition salt. For these salts, inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine can be used as organic acids. Acids, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethane sulfuric acid Fonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid can be used. Additionally, these salts include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, mally. ate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharide Latex, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, zinc salt, etc. may be included, and among these, hydrochloride or trifluoroacetate is preferable.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 유효물질을 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the active substance in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate. It can be manufactured by distilling the solvent and excess acid under reduced pressure, drying it, or crystallizing it in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염(예, 질산은)과 반응시켜 얻는다.Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
나아가, 본 발명은 유효물질 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체, 광학 이성질체 등을 모두 포함한다.Furthermore, the present invention includes not only the active substance and its pharmaceutically acceptable salt, but also all possible solvates, hydrates, isomers, optical isomers, etc. that can be prepared therefrom.
본 발명의 일실시예에 따르면, X는 F, Cl, Br, I 또는 OH이고;According to one embodiment of the invention, X is F, Cl, Br, I or OH;
R은 C1-10의 알킬, C1-10의 알케닐 또는 C1-10의 알카이닐이고, 여기서 상기 C1-10의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-10의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, where the C 1-10 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-10 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-3의 알킬옥시이고;R 1 and R 2 are independently C 1-3 alkyloxy;
R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것일 수 있다.R 3 and R 4 may be connected to each other to form 1,3-dioxolane.
본 발명의 일실시예에 따르면, X는 F, Cl, Br, I 또는 OH이고;According to one embodiment of the invention, X is F, Cl, Br, I or OH;
R은 C3-5의 알킬, C3-5의 알케닐 또는 C3-5의 알카이닐이고, 여기서 상기 C3-5의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C3-5의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 3-5 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, where the C 3-5 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 3-5 is characterized by a triple bond at the terminal;
R1 및 R2는 독립적으로 C1-2의 알킬옥시이고;R 1 and R 2 are independently C 1-2 alkyloxy;
R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것일 수 있다.R 3 and R 4 may be connected to each other to form 1,3-dioxolane.
본 발명의 일실시예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1A로 표시되는 화합물인 것일 수 있다According to one embodiment of the present invention, the compound represented by Formula 1 may be a compound represented by Formula 1A below:
[화학식 1A][Formula 1A]
Figure PCTKR2023006144-appb-img-000008
Figure PCTKR2023006144-appb-img-000008
상기 화학식 1A에서,In Formula 1A,
X는 상기의 화학식 1에서 정의한 바와 같다.X is as defined in Formula 1 above.
본 발명의 상기 화합물 1A의 화합물은 13-(but-3-yn-1-yl)-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium bromide로 명명될 수 있다.The compound of Compound 1A of the present invention is 13-(but-3-yn-1-yl)-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolino[ It may be named 3,2-a]isoquinolin-7-ium bromide.
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,In addition, the present invention, as shown in Scheme 1 below,
염기성 용액에서, 화합물 2 및 아세톤을 반응하여 화합물 3을 제조하는 단계(단계 1); 및Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1); and
유기용매에서, 화합물 3 및 화합물 4를 반응하여 화합물 1을 제조하는 단계(단계 2);를 포함하는,Comprising: reacting Compound 3 and Compound 4 in an organic solvent to prepare Compound 1 (Step 2);
상기의 화학식 1로 표시되는 화합물의 제조방법을 제공한다.A method for producing a compound represented by Formula 1 above is provided.
[반응식 1][Scheme 1]
Figure PCTKR2023006144-appb-img-000009
Figure PCTKR2023006144-appb-img-000009
상기 반응식 1에서,In Scheme 1 above,
X, R, R1, R2, R3 및 R4는 상기의 화학식 1에서 정의한 바와 같고,X, R, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 above,
XA는 할로겐이다.X A is halogen.
본 발명의 일실시예에 따르면, 상기 단계 1의 염기성 용액은 수산화나트륨 수용액인 것일 수 있다.According to one embodiment of the present invention, the basic solution in step 1 may be an aqueous sodium hydroxide solution.
본 발명의 일실시예에 따르면, 상기 단계 2의 유기용매는 다이클로로메탄, 에탄올, 테트라하이드로퓨란, 벤젠, 메탄올, 톨루엔, 헥산, 디메틸포름아미드, 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드, 디메틸설폭사이드 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상인 것일 수 있다.According to one embodiment of the present invention, the organic solvent in step 2 is dichloromethane, ethanol, tetrahydrofuran, benzene, methanol, toluene, hexane, dimethylformamide, diisopropyl ether, diethyl ether, dioxane, It may be one or more types selected from the group consisting of dimethylacetamide, dimethyl sulfoxide, and chlorobenzene.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 치료용 조성물을 제공한다.Additionally, the present invention provides a composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 사용되는 용어 "예방"은 본 발명의 조성물의 투여로 특정 질환의 증상을 억제하거나 진행을 지연시키는 모든 행위를 의미한다.The term “prevention” used in the present invention refers to all actions that suppress the symptoms or delay the progression of a specific disease by administering the composition of the present invention.
본 발명에서 사용되는 용어 "치료"는 본 발명의 조성물의 투여로 특정 질환의 증상을 호전 또는 이롭게 변경시키는 모든 행위를 의미한다.The term “treatment” used in the present invention refers to any action that improves or beneficially changes the symptoms of a specific disease by administering the composition of the present invention.
본 발명에 있어서, 용어 "미토파지 (mitophagy)"는 손상되었거나 불필요한 미토콘드리아를 제거하는 세포 내 분해기전을 지칭한다. 미토파지는 일반적으로 미토콘드리아의 손상이 발생한 경우 오토파고좀 (autophagosome)을 형성하고 리소좀과 융합하여 손상된 미토콘드리아를 선택적으로 분해하여 제거하는 역할을 한다. 미토파지는 세포가 영양결핍상태 등에 놓였을 때 거대분자 (macromolecular) 전구체를 생성하고 에너지를 생성하기 위해 세포 내의 불필요한 성분 (오래된 단백질, 단백질 집합체, 세포소기관, 세포에 침투한 병원균 등)을 분해 및 재활용하는 기작인 오토파지 (autophagy)와는 구별되는 기전이다. 미토파지는 오토파지를 조절하는 영양소, 에너지, 및 스트레스 등의 조절 신호와는 독립적으로 조절된다. 본 발명에 있어서, '미토파지를 촉진한다'는 것은 미토파지의 활성, 빈도, 정도, 수준 등을 촉진 내지 증가시키는 것을 모두 포함한다.In the present invention, the term “mitophagy” refers to an intracellular decomposition mechanism that removes damaged or unnecessary mitochondria. Mitophagy generally forms an autophagosome when mitochondrial damage occurs and fuses with lysosomes to selectively decompose and remove damaged mitochondria. Mitophagy decomposes and decomposes unnecessary components within the cell (old proteins, protein aggregates, organelles, pathogens that have infiltrated the cell, etc.) to generate macromolecular precursors and generate energy when the cell is in a state of nutritional deficiency. It is a mechanism that is distinct from autophagy, which is a recycling mechanism. Mitophagy is regulated independently of regulatory signals such as nutrients, energy, and stress that regulate autophagy. In the present invention, 'promoting mitophagy' includes promoting or increasing the activity, frequency, extent, level, etc. of mitophagy.
본 발명에 따른 조성물은 약학적으로 허용가능한 담체를 추가로 포함할 수 있다. 본 발명에서 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제, 기제, 부형제, 윤활제 등 당업계에 공지된 것이라면 제한없이 사용할 수 있다. The composition according to the present invention may further include a pharmaceutically acceptable carrier. In the present invention, the term “pharmaceutically acceptable” means that the composition exhibits non-toxic properties to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art, such as a buffer, preservative, analgesic agent, solubilizer, isotonic agent, stabilizer, base, excipient, lubricant, etc.
또한, 본 발명의 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 나아가, 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태의 피부 외용제의 형태로 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.In addition, the composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. there is. Furthermore, it can be used in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel, or external skin preparation in the form of a gel. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 싸이코트리아 루브라 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the Cycotria rubra extract with at least one excipient, such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여된다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and It can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 본 발명이 속하는 기술분야에 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains.
본 발명에 따른 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention can be administered to an individual through various routes. All modes of administration are contemplated, for example, by oral, intravenous, intramuscular, subcutaneous, or intraperitoneal injection.
본 발명의 조성물 내의 상기 화합물의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 또는 0.001 내지 50중량%일 수 있으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.The content of the compound in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the patient's condition, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight, based on the total weight of the composition. However, it is not limited to this. The content ratio is a value based on the dry amount with the solvent removed.
본 발명에 따른 약학 조성물의 투여량은 개체의 연령, 체중, 성별, 신체 상태 등을 고려하여 선택된다. 상기 약학 조성물 중 포함되는 유효성분의 농도는 대상에 따라 다양하게 선택할 수 있음은 자명하며, 바람직하게는 약학 조성물에 0.01 ~ 5,000 ㎍/ml의 농도로 포함되는 것이다. 그 농도가 0.01 ㎍/ml 미만일 경우에는 약학 활성이 나타나지 않을 수 있고, 5,000 ㎍/ml를 초과할 경우에는 인체에 독성을 나타낼 수 있다.The dosage of the pharmaceutical composition according to the present invention is selected taking into account the age, weight, gender, physical condition, etc. of the individual. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be selected in various ways depending on the target, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg/ml. If the concentration is less than 0.01 ㎍/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 ㎍/ml, it may be toxic to the human body.
본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐 (mouse), 쥐 (rat), 개, 고양이, 말, 및 소 등의 포유류를 의미한다.In the present invention, “individual” refers to a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cows, etc. refers to mammals of
본 발명에서 "투여"란 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.In the present invention, “administration” means providing a given composition of the present invention to an individual by any suitable method.
본 발명에서 "예방"이란 목적하는 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미하고, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 목적하는 질환과 그에 따른 대사 이상 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하며, "개선"이란 본 발명에 따른 조성물의 투여에 의해 목적하는 질환과 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다.In the present invention, “prevention” refers to any action that suppresses or delays the onset of the desired disease, and “treatment” refers to the improvement or improvement of the desired disease and its associated metabolic abnormalities by administration of the pharmaceutical composition according to the present invention. It refers to all actions that are beneficially changed, and “improvement” refers to all actions that reduce parameters related to the desired disease, such as the degree of symptoms, by administering the composition according to the present invention.
본 발명의 일실시예에 따르면, 상기 화합물은 미토파지(mitophagy)의 활성을 촉진시키는 것일 수 있다.According to one embodiment of the present invention, the compound may promote the activity of mitophagy.
본 발명의 일실시예에 따르면, 상기 미토파지 활성 촉진은, 기능이상 미토콘드리아를 제거하는 것일 수 있다.According to one embodiment of the present invention, the promotion of mitophagy activity may be removing dysfunctional mitochondria.
본 발명의 일실시예에 따르면, 상기 미토콘드리아 기능이상으로 인한 질환은 퇴행성 질환인 것일 수 있으며, 상기 퇴행성 질환은 알츠하이머병 (Alzheimer's disease), 파킨슨병 (Parkinson's disease), 루게릭병(amyotrophic lateral sclerosis), 헌팅턴병 (Huntington's Disease), 다발성 경화증(Multiple sclerosis), 면역계이상 뇌기능 부전, 진행성 신경퇴행질환, 대사성 뇌질환, 니만-픽병(Niemann-Pick disease), 뇌 허혈 및 뇌출혈로 인한 치매(dementia)로 이루어진 군에서 선택된 것일 수 있다.According to one embodiment of the present invention, the disease caused by mitochondrial dysfunction may be a degenerative disease, and the degenerative disease may include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, immune system abnormalities, brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Niemann-Pick disease, and dementia caused by cerebral ischemia and cerebral hemorrhage. It may have been chosen by the military.
본 발명의 일실시예에 따르면, 상기 미토콘드리아 기능이상으로 인한 질환은 MELAS 증후군 (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) 또는 샤르코 마리 투스 질환(Charcot Marie Tooth disease, CMT)인 것일 수 있다.According to one embodiment of the present invention, the disease caused by mitochondrial dysfunction may be MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or Charcot Marie Tooth disease (CMT).
또한, 상기 미토콘드리아 기능이상으로 인한 질환은 암 또는 알러지성 질환을 더 포함할 수 있다.In addition, diseases caused by mitochondrial dysfunction may further include cancer or allergic diseases.
상기 암은 대장암, CTH 생성 종양, 급성 림프구성 또는 림프아구성 백혈병, 급성 또는 만성의 림포구성 백혈병, 급성 비림프구성 백혈병, 방광암, 뇌종양, 유방암, 경관암, 만성 골수성 백혈병, 장암, T-존 림프종, 자궁내막증, 식도암, 담즙 방광암, 에윙스 육종(Ewing's sarcoma), 두 및 목암, 설암, 홉킨스 림프종, 카포시스 육종, 신장암, 간암, 폐암, 중피종, 다발성 골수종, 신경아세포종, 비홉킨 림프종, 골육종, 난소암, 신경아세포종, 유선암, 경관암, 전립선암, 췌장암, 페니스암, 레티노블라스토마, 피부암, 위암, 갑상선암, 자궁암, 고환암, 윌름스 종양, 및 트로포블라스토마로 이루어진 군에서 선택된 것일 수 있다.The cancers include colon cancer, CTH-producing tumor, acute lymphoblastic or lymphoblastic leukemia, acute or chronic lymphocytic leukemia, acute non-lymphocytic leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, chronic myeloid leukemia, intestinal cancer, T- John's lymphoma, endometriosis, esophageal cancer, gallbladder cancer, Ewing's sarcoma, head and neck cancer, tongue cancer, Hopkins lymphoma, Kaposis sarcoma, kidney cancer, liver cancer, lung cancer, mesothelioma, multiple myeloma, neuroblastoma, non-Hopkin lymphoma , osteosarcoma, ovarian cancer, neuroblastoma, mammary cancer, cervical cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, stomach cancer, thyroid cancer, uterine cancer, testicular cancer, Wilms tumor, and trophoblastoma. You can.
상기 알러지성 질환은, 아토피성 피부염(atopic dermatitis), 알러지성 피부염(allergic dermatitis), 접촉성 피부염, 두드러기, 가려움증, 곤충 알러지, 식품 알러지, 약품 알러지, 부종, 과민증(anaphylaxis), 알러지성 비염(allergic rhinitis), 천식(asthma) 및 알러지성 결막염(allergic conjunctivitis)으로 이루어진 군에서 선택된 것일 수 있다.The allergic diseases include atopic dermatitis, allergic dermatitis, contact dermatitis, urticaria, itching, insect allergy, food allergy, drug allergy, edema, anaphylaxis, and allergic rhinitis ( It may be selected from the group consisting of allergic rhinitis, asthma, and allergic conjunctivitis.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 개선용 식품 조성물을 제공한다. 상기 식품 조성물은 건강기능식품 조성물을 포함한다.In addition, the present invention provides a food composition for preventing or improving diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1, an isomer thereof, or a food-acceptable salt thereof as an active ingredient. . The food composition includes a health functional food composition.
본 발명에서 용어, "식품학적으로 허용 가능한 염"이란 식품학적으로 허용되는 유기산, 무기산, 또는 염기로부터 유도된 염을 포함한다.In the present invention, the term “foodologically acceptable salt” includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.
본 발명에서 사용되는 용어 "개선"은 상술한 바와 같이 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that results in at least a reduction in the severity of the parameters associated with the condition being treated, such as symptoms, as described above.
본 발명의 식품 조성물은 본 발명의 유효성분을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition to containing the active ingredient of the present invention, the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a normal food composition.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The above-described flavoring agents include natural flavoring agents (thaumatin), stevia extracts (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes, health supplements, etc. There is.
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the extract as an active ingredient, the food composition contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, It may contain alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the food composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages.
본 발명의 기능성 식품 조성물은 미토콘드리아 기능이상으로 인한질환의 예방 또는 치료 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 '건강기능성 식품 조성물'이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강기능식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강기능식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The functional food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating diseases caused by mitochondrial dysfunction. In the present invention, 'health functional food composition' refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and refers to food that is related to the structure and function of the human body. It means taking it for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects. The health functional food of the present invention may contain common food additives, and its suitability as a food additive is determined in accordance with the general provisions and general test methods of the food additive code approved by the Food and Drug Administration, unless otherwise specified. Judgment is made according to specifications and standards. Items listed in the 'Food Additive Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as dark pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; Examples include mixed preparations such as sodium L-glutamate preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations. For example, the health functional food in the form of a tablet is made by granulating a mixture of the active ingredient of the present invention with excipients, binders, disintegrants and other additives in a conventional manner, and then adding a lubricant and compression molding, or The mixture can be directly compression molded. Additionally, the health functional food in the form of tablets may contain flavoring agents, etc., if necessary. Among capsule-type health functional foods, hard capsules can be manufactured by filling a regular hard capsule with a mixture of the active ingredient of the present invention mixed with additives such as excipients, and soft capsules can be prepared by mixing the active ingredient of the present invention with additives such as excipients. It can be manufactured by filling the mixture with a capsule base such as gelatin. The soft capsule may contain plasticizers such as glycerin or sorbitol, colorants, preservatives, etc., if necessary. The health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention, excipients, binders, disintegrants, etc., by a known method. If necessary, it can be coated with white sugar or another coating agent. Alternatively, the surface can be coated with substances such as starch or talc. Health functional food in the form of granules can be manufactured into granules by mixing a mixture of excipients, binders, disintegrants, etc. of the active ingredients of the present invention by a known method, and may contain flavoring agents, flavoring agents, etc., if necessary. You can.
본 발명의 화합물, 이의 유도체, 또는 이의 식품학적으로 허용 가능한 염을 식품 첨가물로 사용할 경우, 상기 화합물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 화합물은 원료에 대하여 15 중량% 이하, 또는 10 중량% 이하의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When using the compound of the present invention, its derivative, or its foodologically acceptable salt as a food additive, the compound can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. . The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). In general, when manufacturing food or beverages, the compound of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There are no special restrictions on the types of foods above. Examples of foods to which the above substances can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, These include alcoholic beverages and vitamin complexes, and include all health functional foods in the conventional sense.
본 발명에 따른 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 및 과당과 같은 모노사카라이드, 말토오스 및 수크로오스와 같은 디사카라이드, 덱스트린 및 시클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨 및 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 0.01-0.20g, 또는 약 0.04-0.10g 이다.The health drink composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional drinks. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame can be used. The proportion of natural carbohydrates is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01-0.20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may contain carbonating agents used in carbonated drinks. In addition, the composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients can be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
본 명세서에 있어서, "건강기능식품"이란 특정보건용 식품(food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미하는데, 상기 식품은 말초신경병증의 예방 또는 개선에 유용한 효과를 얻기 위하여 정제, 캡슐, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.In this specification, “health functional food” is the same term as food for special health use (FoSHU), and refers to food with high medical and medical effects that has been processed to efficiently exhibit bioregulatory functions in addition to supplying nutrients. This means that the food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to achieve useful effects in preventing or improving peripheral neuropathy.
본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.The health functional food of the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and components commonly added in the art. In addition, unlike general drugs, it is made from food, so it has the advantage of not having any side effects that may occur when taking the drug for a long time, and it can be highly portable.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 약학적 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 따르면, 상기 미토파지 활성은, 기능이상 미토콘드리아를 제거하는 것일 수 있고, 상기 기능이상 미토콘드리아는, 퇴행성 신경질환을 유도하는 것일 수 있다.According to one embodiment of the present invention, the mitophagy activity may remove dysfunctional mitochondria, and the dysfunctional mitochondria may induce neurodegenerative diseases.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for promoting mitophagy activity, comprising the compound represented by Formula 1, an isomer thereof, or a foodologically acceptable salt thereof as an active ingredient.
또한, 본 발명은 시험관 내(in vitro)에서, 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 세포 내 미토파지(mitophagy)의 활성을 증가시키는 방법을 제공한다.In addition, the present invention provides a method of intracellular mitophagy, comprising the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. Provides a method for increasing activity.
본 발명의 세포는 미토케이마(mt-Keima)를 발현하는 세포일 수 있으며, 본 발명의 "미토케이마(mt-Keima, mitochondria-targeted Keima)"는 pH 의존적으로 형광특성이 변화하는 산호유래 형광단백질 (Katayama H et al, 2011, Chem Biol)을 말한다. 미토케이마는 중성환경 (pH 7)에서는 458nm에서 형광신호가 현저히 강해지며, 산성조건 (pH 4)에서는 단백질 구조의 변화로 561nm에서 형광 신호가 강해지는 특징이 있다. 이러한 특성을 활용하여, 미토콘드리아에만 미토케이마를 발현시키도록 한 후 458nm 및 561nm에서의 형광신호를 통합분석함으로써 중성환경의 미토콘드리아 (pH=7.4~7.8)가 미토파지로부터 전달된 리소좀(lysosome)에 의하여 산성환경(pH=4.5)으로 변환될 때의 형광신호를 분석하여, 미토파지의 활성을 정량적으로 측정할 수 있다.The cells of the present invention may be cells expressing mt-Keima, and the "mt-Keima (mitochondrion-targeted Keima)" of the present invention is a coral-derived product whose fluorescence characteristics change depending on pH. Refers to fluorescent protein (Katayama H et al, 2011, Chem Biol). Mito Keima is characterized by a significantly stronger fluorescence signal at 458 nm in a neutral environment (pH 7), and a stronger fluorescence signal at 561 nm in acidic conditions (pH 4) due to changes in protein structure. Taking advantage of these characteristics, Mitocheima was expressed only in mitochondria and then integrated analysis of fluorescence signals at 458 nm and 561 nm allowed mitochondria in a neutral environment (pH = 7.4 to 7.8) to be activated by lysosomes delivered from mitophagy. By analyzing the fluorescence signal when converted to an acidic environment (pH = 4.5), the activity of mitophagy can be quantitatively measured.
또한, 본 발명은 시험관 내(in vitro)에서, 세포에 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)을 억제시키는 방법을 제공한다.In addition, the present invention provides a method for treating mitochondrial dysfunction, including the step of treating cells with the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in vitro. Provides a method of suppression.
달리 명시되지 않는 한, 본 명세서에서 사용된 성분, 반응 조건, 성분의 함량을 표현하는 모든 숫자, 값 및/또는 표현은, 이러한 숫자들이 본질적으로 다른 것들 중에서 이러한 값을 얻는 데 발생하는 측정의 다양한 불확실성이 반영된 근사치들이므로, 모든 경우 "약"이라는 용어에 의해 수식되는 것으로 이해되어야 한다. 또한, 본 기재에서 수치범위가 개시되는 경우, 이러한 범위는 연속적이며, 달리 지적되지 않는 한 이러한 범 위의 최소값으로부터 최대값이 포함된 상기 최대값까지의 모든 값을 포함한다. 더 나아가, 이러한 범위가 정수를 지칭하는 경우, 달리 지적되지 않는 한 최소값으로부터 최대값이 포함된 상기 최대값까지를 포함하는 모든 정수가 포함된다.Unless otherwise specified, all numbers, values and/or expressions used herein to express components, reaction conditions or contents of components are intended to refer to, among other things, the measurements that occur to obtain these values. Since they are approximations reflecting uncertainty, they should be understood in all cases as being qualified by the term “approximately.” Additionally, where a numerical range is disclosed herein, such range is continuous and, unless otherwise indicated, includes all values from the minimum to the maximum of such range inclusively. Furthermore, when such range refers to an integer, all integers from the minimum value up to and including the maximum value are included, unless otherwise indicated.
예컨대, 본 명세서에 있어서, 범위가 변수에 대해 기재되는 경우, 상기 변수는 상기 범위의 기재된 종료점들을 포함하는 기재된 범위 내의 모든 값들을 포함하는 것으로 이해될 것이다. 예를 들면, "5 내지 10"의 범위는 5, 6, 7, 8, 9, 및 10의 값들뿐만 아니라 6 내지 10, 7 내지 10, 6 내지 9, 7 내지 9 등의 임의의 하위 범위를 포함하고, 5.5, 6.5, 7.5, 5.5 내지 8.5 및 6.5 내지 9 등과 같은 기재된 범위의 범주에 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다. 또한 예를 들면, "10% 내지 30%"의 범위는 10%, 11%, 12%, 13% 등의 값들과 30%까지를 포함하는 모든 정수들뿐만 아니라 10% 내지 15%, 12% 내지 18%, 20% 내지 30% 등의 임의의 하위 범위를 포함하고, 10.5%, 15.5%, 25.5% 등과 같이 기재된 범위의 범주 내의 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다.For example, herein, when a range is written for a variable, the variable will be understood to include all values within the stated range, including the stated endpoints of the range. For example, the range "5 to 10" includes the values 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood that it also includes any values between integers that fall within the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9, etc. Also, for example, the range "10% to 30%" includes values such as 10%, 11%, 12%, 13%, etc. and all integers up to and including 30%, as well as 10% to 15%, 12% to 12%, etc. It will be understood that it includes any subranges, such as 18%, 20% to 30%, etc., and any value between reasonable integers within the range of the stated range, such as 10.5%, 15.5%, 25.5%, etc.
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
<실시예 1> 베르베린 유사체의 합성<Example 1> Synthesis of berberine analogues
본 발명의 베르베린 유사체의 합성 과정을 하기 도면에 나타내었다.The synthesis process of the berberine analog of the present invention is shown in the figure below.
Figure PCTKR2023006144-appb-img-000010
Figure PCTKR2023006144-appb-img-000010
구체적으로, 둥근 플라스크에 전구물질인 베르베린(berberine, 3g, 7.7 mmol)과 아세톤 5 ml 및 5 N의 수산화나트륨 수용액 20 ml을 순차적으로 넣고, 상온에서 6 시간 교반하였다. 이 후 감암농축하여 수득된 고체를 차가운 증류수 20ml로 5회 세척하였다. 그 후 진공건조하여 상기 합성 과정에서의 화합물 (2)를 90%의 수율로 수득하였다.Specifically, the precursor berberine (3 g, 7.7 mmol), 5 ml of acetone, and 20 ml of 5 N aqueous sodium hydroxide solution were sequentially added to a round flask, and stirred at room temperature for 6 hours. Afterwards, the solid obtained by concentration under reduced pressure was washed five times with 20 ml of cold distilled water. Afterwards, it was vacuum dried to obtain compound (2) in the above synthesis process with a yield of 90%.
그 후 수득된 화합물 2(100 mg, 0.25 mmol)를 pressure tube에 넣고, CH2Cl2(5 ml)에 용해시킨 후 4-bromo-1-butyne (338 mg, 2.5 mmol)을 첨가한 후 100 ℃에서 4시간 동안 교반하였다. 그 후 혼합물을 감압농축하고, 실리카겔에 흡착시킨 후, 실리카겔 크로마토그래피(CH2Cl2 : MeOH = 50:1 to 15:1 v/v)로 정제하여 본 발명의 CD1-410 화합물을 20%의 수율로 수득하였다.After that, the obtained Compound 2 (100 mg, 0.25 mmol) was placed in a pressure tube, dissolved in CH 2 Cl 2 (5 ml), and 4-bromo-1-butyne (338 mg, 2.5 mmol) was added, followed by 100 mg. It was stirred at ℃ for 4 hours. Afterwards, the mixture was concentrated under reduced pressure, adsorbed on silica gel, and purified by silica gel chromatography (CH2Cl2: MeOH = 50:1 to 15:1 v/v) to obtain the CD1-410 compound of the present invention in a yield of 20%. did.
수득된 화합물의 구조를 분석하기 위하여 NMR 분석을 시행하였으며, 그 결과를 하기에 나타내었으며, 화합물의 구조를 도 1에 나타내었다.NMR analysis was performed to analyze the structure of the obtained compound, and the results are shown below, and the structure of the compound is shown in Figure 1.
CD1-410: 1H NMR (MeOH d4, 400 MHz) δ 9.76 (s. 1H), 8.70 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.65 (s, 1H), 6.95 (s, 1H), 6.10 (s, 2H), 4.93 (t, J = 6.0 Hz, 2H), 4.20 (s, 3H), 4.10 (s, 3H), 3.26 (d, J = 6.0 Hz, 2H), 2.03 (d, J = 9.2 Hz, 1H)CD1-410: 1H NMR (MeOH d4, 400 MHz) δ 9.76 (s. 1H), 8.70 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.65 (s, 1H), 6.95 (s, 1H), 6.10 (s, 2H), 4.93 (t, J = 6.0 Hz, 2H), 4.20 (s, 3H), 4.10 (s, 3H), 3.26 (d, J = 6.0 Hz, 2H), 2.03 (d, J = 9.2 Hz, 1H)
<실시예 2> CD1-410 화합물의 미토파지 활성촉진 확인<Example 2> Confirmation of promotion of mitophagy activity by CD1-410 compound
<2-1> 미토케이마 발현 분석<2-1> Mitocheima expression analysis
본 발명의 베르베린 유사체가 미토파지의 활성을 촉진시키는지 분석하였다. 구체적으로 살아있는 세포에서 미토파지 활성을 정량적으로 측정할 수 있는 미토케이마 형광단백질 정량법을 사용하였다. 인간 정상폐세포주인 BEAS-2B 세포주에 미토케이마 형광단백질을 발현시키고, 상기 실시예 1에서 제조된 베르베린 유사체를 10 μM의 농도로 24시간 동안 처리한 후, 유세포분석기를 이용하여 미토파지의 활성을 측정하였다. 대조군으로는 화합물을 처리하지 않은 대조군(Control, con)을 이용하였으며, 양성대조군으로는 실험적으로 미토파지 활성을 유도하는 CCCP(10 μM)을 이용하였다.It was analyzed whether the berberine analog of the present invention promotes the activity of mitophagy. Specifically, the Mitocheima fluorescent protein quantification method, which can quantitatively measure mitophagy activity in living cells, was used. Mitocheima fluorescent protein was expressed in the BEAS-2B cell line, a human normal lung cell line, and treated with the berberine analog prepared in Example 1 at a concentration of 10 μM for 24 hours, and then the activity of mitophagy was measured using a flow cytometer. was measured. As a control group, a control group (Control, con) that was not treated with a compound was used, and as a positive control group, CCCP (10 μM), which experimentally induces mitophagy activity, was used.
그 결과, 도 2에 나타낸 바와 같이, con 군에서는 미토파지의 활성이 9.8%였으나, CCCP 군에서는 86%로 증가하였으며, 본 발명의 CD1-410을 처리한 군에서는 84%로 증가한 것을 확인하여, 본 발명의 CD1-410이 미토파지의 활성을 유의적으로 증가시키는 것을 확인하였다.As a result, as shown in Figure 2, the activity of mitophagy was 9.8% in the con group, but increased to 86% in the CCCP group, and increased to 84% in the group treated with CD1-410 of the present invention. It was confirmed that CD1-410 of the present invention significantly increases the activity of mitophagy.
<2-2> 미토콘드리아 단백질 발현 확인<2-2> Confirmation of mitochondrial protein expression
본 발명의 베르베린 유사체가 미토파지의 활성을 촉진시키는지 확인하였다. 구체적으로 미토콘드리아가 미토파지에 의하여 감소되는 것을, 미토콘드리아 단백질 발현량으로 확인하였으며, 상기 실시예 2-1의 각 군의 세포로부터 미토콘드리아 단백질을 웨스턴블랏으로 분석하였다.It was confirmed whether the berberine analog of the present invention promotes the activity of mitophagy. Specifically, the decrease in mitochondria due to mitophagy was confirmed by the mitochondrial protein expression level, and the mitochondrial proteins from each group of cells in Example 2-1 were analyzed by Western blot.
그 결과 도 3에 나타낸 바와 같이, 본 발명의 CD1-410을 처리하면, 미토콘드리아 단백질의 양이 감소한 것을 확인하였으며, 상기의 결과로, 본 발명의 CD1-410이 미토파지 활성을 촉진시켜, 미토콘드리아의 양을 감소시키는 것을 확인하였다.As a result, as shown in Figure 3, it was confirmed that the amount of mitochondrial protein decreased when treated with CD1-410 of the present invention. As a result, CD1-410 of the present invention promoted mitophagy activity, It was confirmed that the amount was reduced.
따라서, 본 발명은 신규한 베르베린 유사체인 CD1-410을 합성하였으며, 신규한 베르베린 유사체가 미토파지의 활성을 촉진시키며, 미토파지의 활성이 촉진되어 미토콘드리아가 감소하는 것을 확인하였다.Therefore, the present invention synthesized CD1-410, a novel berberine analogue, and confirmed that the novel berberine analogue promotes the activity of mitophagy, and that the activity of mitophagy is promoted to reduce mitochondria.
본 발명은 신규 베르베린 유사체인 CD1-410에 관한 것으로서, 상기 신규 베르베린 유사체는 미토파지의 활성을 촉진시키며, 이에 따라 구조 및/또는 기능이 손상된 미토콘드리아를 감소시킬 수 있음이 확인되었다. 따라서, 본 발명에 따른 신규 베르베린 유사체는 비정상 미토콘드리아로 야기될 수 있는 다양한 질환의 예방, 개선, 및/또는 치료 용도로 활용될 수 있다. The present invention relates to CD1-410, a novel berberine analogue. It has been confirmed that the novel berberine analogue promotes the activity of mitophagy, thereby reducing mitochondria with damaged structures and/or functions. Therefore, the new berberine analog according to the present invention can be used to prevent, improve, and/or treat various diseases that may be caused by abnormal mitochondria.

Claims (26)

  1. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2023006144-appb-img-000011
    Figure PCTKR2023006144-appb-img-000011
    (상기 화학식 1에서,(In Formula 1 above,
    X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
    R은 C1-20의 알킬, C1-20의 알케닐 또는 C1-20의 알카이닐이고, 여기서 상기 C1-20의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-20의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-20 alkyl, C 1-20 alkenyl, or C 1-20 alkynyl, where the C 1-20 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-20 is characterized by a triple bond at the terminal;
    R1 및 R2는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있고;R 1 and R 2 may independently be C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane;
    R3 및 R4는 독립적으로 C1-3의 알킬옥시, 또는 서로 연결되어 1,3-다이옥솔란을 형성할 수 있다).R 3 and R 4 may be independently C 1-3 alkyloxy, or may be connected to each other to form 1,3-dioxolane).
  2. 제1항에 있어서,According to paragraph 1,
    X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
    R은 C1-10의 알킬, C1-10의 알케닐 또는 C1-10의 알카이닐이고, 여기서 상기 C1-10의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C1-10의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, where the C 1-10 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 1-10 is characterized by a triple bond at the terminal;
    R1 및 R2는 독립적으로 C1-3의 알킬옥시이고;R 1 and R 2 are independently C 1-3 alkyloxy;
    R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것을 특징으로 하는,R 3 and R 4 are connected to each other to form 1,3-dioxolane,
    화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제2항에 있어서,According to paragraph 2,
    X는 F, Cl, Br, I 또는 OH이고;X is F, Cl, Br, I or OH;
    R은 C3-5의 알킬, C3-5의 알케닐 또는 C3-5의 알카이닐이고, 여기서 상기 C3-5의 알케닐은 말단에 2중결합이 있는 것을 특징으로 하고, 상기 C3-5의 알카이닐은 말단에 3중결합이 있는 것을 특징으로 하며;R is C 3-5 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, where the C 3-5 alkenyl is characterized by a double bond at the terminal, and the C Alkynyl of 3-5 is characterized by a triple bond at the terminal;
    R1 및 R2는 독립적으로 C1-2의 알킬옥시이고;R 1 and R 2 are independently C 1-2 alkyloxy;
    R3 및 R4는 서로 연결되어 1,3-다이옥솔란을 형성하는 것을 특징으로 하는,R 3 and R 4 are connected to each other to form 1,3-dioxolane,
    화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,According to paragraph 1,
    상기 화학식 1로 표시되는 화합물은 하기 화학식 1A로 표시되는 화합물인 것을 특징으로 하는, 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염:The compound represented by Formula 1 is a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound represented by the following Formula 1A:
    [화학식 1A][Formula 1A]
    Figure PCTKR2023006144-appb-img-000012
    Figure PCTKR2023006144-appb-img-000012
    (상기 화학식 1A에서,(In Formula 1A above,
    X는 제 1항의 화학식 1에서 정의한 바와 같다).X is as defined in Formula 1 of Clause 1).
  5. 하기 반응식 1에 나타낸 바와 같이,As shown in Scheme 1 below,
    염기성 용액에서, 화합물 2 및 아세톤을 반응하여 화합물 3을 제조하는 단계(단계 1); 및Preparing compound 3 by reacting compound 2 and acetone in a basic solution (step 1); and
    유기용매에서, 화합물 3 및 화합물 4를 반응하여 화합물 1을 제조하는 단계(단계 2);를 포함하는,Comprising: reacting Compound 3 and Compound 4 in an organic solvent to prepare Compound 1 (Step 2);
    제1항의 화학식 1로 표시되는 화합물의 제조방법.A method for producing a compound represented by Formula 1 of claim 1.
    [반응식 1][Scheme 1]
    Figure PCTKR2023006144-appb-img-000013
    Figure PCTKR2023006144-appb-img-000013
    (상기 반응식 1에서,(In Scheme 1 above,
    X, R, R1, R2, R3 및 R4는 제 1항의 화학식 1에서 정의한 바와 같고,X, R, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 of claim 1,
    XA는 할로겐이다).X A is halogen).
  6. 제5항에 있어서,According to clause 5,
    상기 단계 1의 염기성 용액은 수산화나트륨 수용액인 것을 특징으로 하는 제조 방법.A production method characterized in that the basic solution in step 1 is an aqueous sodium hydroxide solution.
  7. 제5항에 있어서,According to clause 5,
    상기 단계 2의 유기용매는 다이클로로메탄, 에탄올, 테트라하이드로퓨란, 벤젠, 메탄올, 톨루엔, 헥산, 디메틸포름아미드, 디이소프로필에테르, 디에틸에테르, 디옥산, 디메틸아세트아미드, 디메틸설폭사이드 및 클로로벤젠으로 이루어지는 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 제조 방법.The organic solvent in step 2 is dichloromethane, ethanol, tetrahydrofuran, benzene, methanol, toluene, hexane, dimethylformamide, diisopropyl ether, diethyl ether, dioxane, dimethylacetamide, dimethyl sulfoxide, and chlorine. A production method comprising at least one selected from the group consisting of benzene.
  8. 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상(mitochondrial dysfunction)으로 인한 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 제8항에 있어서,According to clause 8,
    상기 화합물은 미토파지(mitophagy)의 활성을 촉진시키는 것인, 약학적 조성물.A pharmaceutical composition wherein the compound promotes the activity of mitophagy.
  10. 제9항에 있어서,According to clause 9,
    상기 미토파지 활성 촉진은, 기능이상 미토콘드리아를 제거하는 것인, 약학적 조성물.A pharmaceutical composition that promotes mitophagy activity by removing dysfunctional mitochondria.
  11. 제8항에 있어서,According to clause 8,
    상기 미토콘드리아 기능이상으로 인한 질환은 퇴행성 질환인 것인, 약학적 조성물.A pharmaceutical composition, wherein the disease caused by mitochondrial dysfunction is a degenerative disease.
  12. 제11항에 있어서, According to clause 11,
    상기 퇴행성 질환은 알츠하이머병 (Alzheimer's disease), 파킨슨병 (Parkinson's disease), 루게릭병(amyotrophic lateral sclerosis), 헌팅턴병 (Huntington's Disease), 다발성 경화증(Multiple sclerosis), 면역계이상 뇌기능 부전, 진행성 신경퇴행질환, 대사성 뇌질환, 니만-픽병(Niemann-Pick disease), 뇌 허혈 및 뇌출혈로 인한 치매(dementia)로 이루어진 군에서 선택된 것인, 약학적 조성물.The degenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, immune system abnormalities, brain dysfunction, progressive neurodegenerative diseases, A pharmaceutical composition selected from the group consisting of metabolic brain disease, Niemann-Pick disease, dementia due to cerebral ischemia and cerebral hemorrhage.
  13. 제8항에 있어서,According to clause 8,
    상기 미토콘드리아 기능이상으로 인한 질환은 MELAS 증후군 (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) 또는 샤르코 마리 투스 질환(Charcot Marie Tooth disease, CMT)인 것인, 약학적 조성물.A pharmaceutical composition, wherein the disease caused by mitochondrial dysfunction is MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) or Charcot Marie Tooth disease (CMT).
  14. 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는, 미토콘드리아 기능이상으로 인한 질환의 예방 또는 개선용 식품 조성물.A food composition for preventing or improving diseases caused by mitochondrial dysfunction, comprising the compound represented by Formula 1 of claim 1, an isomer thereof, or a foodologically acceptable salt thereof as an active ingredient.
  15. 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 약학적 조성물.A pharmaceutical composition for promoting mitophagy activity, comprising the compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  16. 제15항에 있어서,According to clause 15,
    상기 미토파지 활성은, 기능이상 미토콘드리아를 제거하는 것인, 약학적 조성물.The mitophagy activity is a pharmaceutical composition that removes dysfunctional mitochondria.
  17. 제16항에 있어서,According to clause 16,
    상기 기능이상 미토콘드리아는, 퇴행성 신경질환을 유도하는 것인, 약학적 조성물.A pharmaceutical composition wherein the dysfunctional mitochondria induce neurodegenerative diseases.
  18. 제17항에 있어서,According to clause 17,
    상기 퇴행성 신경질환은, 알츠하이머병 (Alzheimer's disease), 파킨슨병 (Parkinson's disease), 루게릭병(amyotrophic lateral sclerosis), 헌팅턴병 (Huntington's Disease), 다발성 경화증(Multiple sclerosis), 면역계이상 뇌기능 부전, 진행성 신경퇴행질환, 대사성 뇌질환, 니만-픽병(Niemann-Pick disease), 뇌 허혈 및 뇌출혈로 인한 치매(dementia)로 이루어진 군에서 선택된 것인, 약학적 조성물.The degenerative neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, immune system abnormalities, brain dysfunction, and progressive neurodegeneration. A pharmaceutical composition selected from the group consisting of diseases, metabolic encephalopathy, Niemann-Pick disease, dementia due to cerebral ischemia and cerebral hemorrhage.
  19. 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는, 미토파지(mitophagy) 활성 촉진용 식품 조성물.A food composition for promoting mitophagy activity, comprising the compound represented by Formula 1 of claim 1, an isomer thereof, or a foodologically acceptable salt thereof as an active ingredient.
  20. 세포에 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 세포 내 미토파지(mitophagy)의 활성을 증가시키는 방법.A method for increasing the activity of intracellular mitophagy, comprising: treating cells with the compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  21. 세포에 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 처리하는 단계;를 포함하는, 미토콘드리아 기능이상을 억제시키는 방법.A method for inhibiting mitochondrial dysfunction, comprising: treating cells with the compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  22. 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 미토콘드리아 기능이상으로 인한 질환의 예방 또는 치료방법.A method for preventing or treating diseases caused by mitochondrial dysfunction, comprising administering a compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.
  23. 미토콘드리아 기능이상으로 인한 질환의 예방 또는 치료용 약제의 제조를 위한, 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도.Use of the compound represented by Formula 1 of Claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of diseases caused by mitochondrial dysfunction.
  24. 미토콘드리아 기능이상으로 인한 질환의 예방 또는 치료를 위한, 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도.Use of the compound represented by Formula 1 of Claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases caused by mitochondrial dysfunction.
  25. 세포 내 미토파지의 활성을 증가시키기 위한, 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도.Use of the compound represented by Formula 1 of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to increase the activity of intracellular mitophagy.
  26. 세포 내 미토파지의 활성 촉진용 약제의 제조를 위한, 제1항의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염의 용도.Use of the compound represented by Formula 1 of Claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the production of a drug for promoting the activity of mitophagy in cells.
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