WO2024181780A1 - Composition destinée à prévenir ou à traiter une neuropathie périphérique, comprenant un dérivé de diphényléther en tant que principe actif - Google Patents

Composition destinée à prévenir ou à traiter une neuropathie périphérique, comprenant un dérivé de diphényléther en tant que principe actif Download PDF

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WO2024181780A1
WO2024181780A1 PCT/KR2024/002540 KR2024002540W WO2024181780A1 WO 2024181780 A1 WO2024181780 A1 WO 2024181780A1 KR 2024002540 W KR2024002540 W KR 2024002540W WO 2024181780 A1 WO2024181780 A1 WO 2024181780A1
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peripheral neuropathy
mitophagy
present
pde701
chemical formula
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English (en)
Korean (ko)
Inventor
윤진호
이희승
임상우
김은미
그레이엄커티스
이지훈
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Altmedical Co Ltd
Research Foundation for Industry Academy Cooperation of Dong A University
Korea Institute of Ocean Science and Technology KIOST
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Altmedical Co Ltd
Research Foundation for Industry Academy Cooperation of Dong A University
Korea Institute of Ocean Science and Technology KIOST
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    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function

Definitions

  • the present invention relates to the use of diphenyl ether derivatives for preventing, improving, and/or treating peripheral neuropathy.
  • Peripheral neuropathy refers to a disease that causes various problems in bodily functions due to damage to the peripheral nervous system that spreads throughout the body, including the hands and feet.
  • Peripheral neuropathy is caused by diseases that directly or indirectly affect the nervous tissue, and can be classified into sensory neuropathy, motor neuropathy, and autonomic neuropathy depending on the type of nervous tissue affected.
  • sensory neuropathy the sense of touch or temperature changes is reduced, a tingling sensation or burning pain is felt, and allodynia is experienced in the skin.
  • Motor neuropathy is accompanied by loss of balance or muscle weakness, and in the case of autonomic neuropathy, the function of controlling the bladder is weakened depending on the organ affected by the nerve, causing urinary incontinence or abnormal blood pressure and heartbeat.
  • CIPN chemotherapy-induced peripheral neuropathy
  • axonal mitochondrial dysfunction is the cause of CIPN caused by anticancer drugs such as Paclitaxel, Vincristine, Taxol, Cisplatin, and Bortezomib.
  • anticancer drugs such as Paclitaxel, Vincristine, Taxol, Cisplatin, and Bortezomib.
  • paclitaxel when paclitaxel is treated, the following phenomena have been confirmed in cell and animal models: decreased mitochondrial membrane potential, increased mitochondrial reactive oxygen species, decreased ATP synthesis, and mitochondrial structural abnormalities.
  • mitochondria play an essential role in energy production, neuroplasticity, and stress resistance in neurons
  • anticancer drug-induced mitochondrial dysfunction is thought to play an important role in the occurrence and progression of CIPN.
  • a strategy to treat CIPN by improving mitochondrial dysfunction has not yet been developed.
  • mitophagy is an intracellular degradation mechanism that removes damaged or unnecessary mitochondria. It surrounds damaged mitochondria with a membrane to form an autophagosome, which fuses with a lysosome to selectively remove damaged mitochondria. This activity of mitophagy plays an important role in regulating mitochondrial homeostasis and maintaining tissue function in various cells including neurons. In addition, it has been reported that mitophagy has a protective effect against various stresses in neurons and is important for resistance to neurodegeneration. Recently, a decrease in mitophagy activity has been observed in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and it has been experimentally verified that promoting mitophagy improves mitochondrial dysfunction and alleviates pathological symptoms in animal models of Alzheimer's disease or Parkinson's disease.
  • neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease
  • CCCP CCCP
  • FCCP mitochondrial membrane potential uncouplers that depolarize mitochondrial membrane potential
  • rotenone acts as a Complex I inhibitor.
  • these mitochondrial toxins directly induce mitochondrial damage and induce mitophagy activity, which is a mechanism for removing damaged mitochondria, they have limitations in that they cannot be used as drugs for promoting mitophagy activity because of their strong toxicity to cells.
  • anticancer drugs including paclitaxel frequently induce peripheral neuropathy causing pain and sensory disturbances, but there is no effective treatment for this, and it is pointed out as a major cause of the decline in the quality of life of cancer patients.
  • the present invention was devised to solve the above problems, and it was confirmed that a diphenyl ether derivative isolated from a marine organism can improve the major symptoms of peripheral neuropathy as a novel mitophagy-promoting drug and can be utilized as a fundamental treatment for the above disease, and thus it was completed.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating peripheral neuropathy, comprising a compound represented by the following chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a kit for preventing or treating peripheral neuropathy, comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a food composition for preventing or improving peripheral neuropathy, comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating peripheral neuropathy, comprising a compound represented by the following chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for preventing or treating peripheral neuropathy, comprising a step of administering to a subject in need thereof a composition or component comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a use of a composition or component comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating peripheral neuropathy.
  • the present invention provides a use of a composition or component comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a drug for preventing or treating peripheral neuropathy.
  • the present invention provides a kit for preventing or treating peripheral neuropathy, comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof; or a composition comprising the same.
  • the present invention provides a food composition for preventing or improving peripheral neuropathy, comprising a compound represented by the chemical formula 1, a derivative thereof, or a food-wise acceptable salt thereof as an effective ingredient.
  • the compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof can promote mitophagy, but is not limited thereto.
  • the compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof may satisfy one or more characteristics selected from the group consisting of, but not limited to:
  • the compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof can improve mitochondrial dysfunction, but is not limited thereto.
  • the peripheral neuropathy may be, but is not limited to, chemotherapy-induced peripheral neuropathy.
  • the present invention relates to a pharmaceutical composition for preventing or treating peripheral neuropathy, and was completed by confirming that a diphenyl ether derivative isolated from a marine organism specifically promotes mitophagy activity, thereby exhibiting a therapeutic effect on peripheral neuropathy.
  • the compound according to the present invention improves hyperalgesia, a representative symptom of peripheral neuropathy, by promoting mitophagy independent of the PINK1-Parkin pathway, and can effectively improve mitochondrial dysfunction of sensory nerves caused by anticancer agents.
  • the compound of the present invention does not damage mitochondrial function or inhibit cell growth, and thus can be used as a safe therapeutic drug. Therefore, the diphenyl ether derivative according to the present invention has a low risk of side effects and enables fundamental treatment of peripheral neuropathy through promotion of mitophagy, and therefore is expected to be usefully utilized as a drug for preventing and treating peripheral neuropathy.
  • Figures 1a to 1c show the results of measuring mitophagy activity using a flow cytometer ( Figure 1a) or a confocal microscope ( Figure 1b) and measuring the amount of mitochondria using a confocal microscope ( Figure 1c) after treating cells with PDE701 at a concentration of 6 ⁇ M for 24 hours to confirm the mitophagy promoting effect of the compound PDE701 of the present invention.
  • Figures 2a and 2b show the results of measuring mitophagy activity according to the treatment concentration of PDE701 ( Figure 2a) and the results of measuring mitophagy activity according to the treatment time ( Figure 2b).
  • Figures 3a and 3b show the results of observing the fluorescence of peroxisome, Golgi, endoplasmic reticulum, and mitochondrial marker proteins by confocal microscopy ( Figure 3a) and calculating the intensity ( Figure 3b) after treating cells with PDE701 at a concentration of 6 ⁇ M to confirm whether PDE701 specifically promotes mitophagy.
  • Figures 3c and 3d show the results of Western blot analysis ( Figure 3c) and quantification ( Figure 3d) of the expression levels of peroxisome, Golgi, endoplasmic reticulum, and mitochondrial marker proteins after treating cells with PDE701 at a concentration of 6 ⁇ M for 18 or 24 h to determine whether PDE701 specifically promotes mitophagy.
  • Figures 4a and 4b show the results of measuring the mitochondrial membrane potential (Figure 4a) and mitochondrial reactive oxygen levels (Figure 4b) after treating cells with mitochondrial toxin (CCCP) or PDE701 at concentrations of 10 ⁇ M and 6 ⁇ M, respectively, to determine whether the mitophagy-promoting effect of PDE701 is due to the induction of mitochondrial dysfunction.
  • CCCP mitochondrial toxin
  • PDE701 mitochondrial toxin
  • Figures 5a and 5b show the results of counting cells over time after treating cells with CCCP or PDE701 at concentrations of 10 ⁇ M and 6 ⁇ M, respectively, to determine whether PDE701 inhibits cell proliferation (Figure 5a) and observing colony formation of cells ( Figure 5b).
  • Figure 6a shows the results of measuring mitophagy activity after treating ATG7-deficient cell lines (ATG7 KO) or wild-type cell lines (WT) with PDE701 at a concentration of 6 ⁇ M to confirm the mitophagy-promoting mechanism of PDE701.
  • Figure 6b shows the results of measuring mitophagy activity after treating PINK1 knockdown cell line (shPINK1) or wild-type cell line (shNT) with PDE701 at a concentration of 6 ⁇ M to confirm whether the mitophagy-promoting activity of PDE701 is dependent on the PINK1-Parkin pathway.
  • Figure 7a shows the results of measuring the withdrawal latency of larvae to a thermoprobe after treating fruit fly larvae with an anticancer drug (paclitaxel) and/or PDE701 to confirm the anticancer drug-induced peripheral neuropathy therapeutic effect of PDE701.
  • an anticancer drug paclitaxel
  • Figure 7b shows the results of measuring the size of larvae after treating fruit fly larvae with anticancer drugs and/or PDE701 to determine whether PDE701 inhibits fruit fly growth.
  • Figures 8a and 8b show the results of detecting the fluorescence signal of reactive oxygen species by confocal microscopy ( Figure 8a) and quantifying it ( Figure 8b) after treating fruit fly larvae expressing a fluorescent protein specifically in C4da neurons with anticancer drugs and/or PDE701 to confirm whether PDE701 improves mitochondrial dysfunction in C4da sensory neurons induced by anticancer drugs.
  • Figure 9 shows the results of confirming whether additional mitochondrial damage caused by anticancer drugs occurs in C4da sensory neurons when anticancer drugs and PDE701 are administered concurrently.
  • Figure 10 shows the results of measuring the avoidance response time of larvae to a thermoprobe after treating wild-type flies and ATG5/ATG7 knockdown flies with anticancer drugs and/or PDE701 to determine whether the peripheral neuropathy therapeutic effect of PDE701 is due to its mitophagy activation function.
  • the present invention relates to a pharmaceutical composition for preventing or treating peripheral neuropathy, and was completed by confirming that a diphenyl ether derivative isolated from a marine organism specifically promotes mitophagy activity, thereby exhibiting a peripheral neuropathy treatment effect.
  • the compounds according to the present invention are diphenyl ether derivatives having a mitophagy-specific promoting function, and were confirmed to promote mitophagy activity in a treatment concentration- and time-dependent manner in human cell lines (Examples 2 and 3).
  • the compound specifically promotes mitophagy without affecting peroxisomes, Golgi apparatus, endoplasmic reticulum, etc., and does not decrease the membrane potential of mitochondria or increase reactive oxygen species. Therefore, unlike existing drugs that activate mitophagy by damaging mitochondrial function, it was confirmed to activate mitophagy without damaging mitochondrial function or inhibiting cell growth (Examples 4 to 6).
  • the inventors of the present invention created a fruit fly model in which peripheral neuropathy was induced by an anticancer agent in order to confirm the peripheral neuropathy therapeutic effect of the compound in vivo , and when the model was treated with the compound of the present invention, symptoms of thermal hyperalgesia were alleviated to a normal level, and the mitochondrial function of the sensory nerves damaged by the anticancer agent was recovered, thereby improving peripheral neuropathy symptoms. They confirmed that such therapeutic effect was due to the mitophagy promoting activity of the compound (Examples 8 to 10).
  • the diphenyl ether derivative according to the present invention can improve or treat peripheral neuropathy through its strong mitophagy promoting effect, and is therefore expected to be utilized as a fundamental treatment agent for peripheral neuropathy, particularly, anticancer agent-induced peripheral neuropathy.
  • peripheral neuropathy particularly, anticancer agent-induced peripheral neuropathy.
  • the mitophagy activation mechanism of the compound since the mitophagy activation mechanism of the compound has been confirmed, it is expected that the treatment of peripheral neuropathy can be achieved in various patient groups through appropriate use considering the molecular mechanism of the compound.
  • the compound according to the present invention is a diphenyl ether derivative, and the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating peripheral neuropathy, comprising the diphenyl ethyl derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the diphenyl ether derivative may be a polybromo diphenyl ether compound.
  • the diphenyl ether derivative may be, but is not limited to, a compound represented by the following chemical formula 1, an analogue thereof, or a derivative thereof:
  • the compound represented by the chemical formula 1 may be referred to as, but is not limited to, 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol or PDE701.
  • pharmaceutically acceptable salt includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.
  • pharmaceutically acceptable means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problems or complications and with a reasonable benefit/risk ratio, and is within the scope of sound medical judgment.
  • acids examples include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
  • Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. They can also be prepared by heating an equimolar amount of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or by suction filtration of the precipitated salt.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, potassium, etc., alkaline earth metals such as magnesium, and ammonium.
  • the alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt and further, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
  • a suitable silver salt e.g., silver nitrate
  • the scope of the compounds of the present invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.
  • the diphenyl ether derivative may be manufactured by a manufacturing method comprising, but is not limited to, the following steps:
  • step (S4) A step of performing chromatography on the organic material obtained in step (S3) to obtain a diphenyl ether derivative.
  • the organic material in the step (S3) may have an intermediate polarity in the methanol layer, but is not limited thereto.
  • the manufacturing method may further include, but is not limited to, a step of purifying the diphenyl ether derivative obtained after step (S4).
  • the compound according to the present invention can be manufactured through various compound manufacturing methods (e.g., chemical synthesis methods), separation and purification methods, etc. known in the art.
  • the compound according to the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof is characterized by promoting mitophagy.
  • 'promoting mitophagy' includes promoting or increasing the activity, frequency, degree, level, etc. of mitophagy.
  • mitochondria refers to an intracellular decomposition mechanism that removes damaged or unnecessary mitochondria.
  • Mitophagy generally plays a role in selectively decomposing and removing damaged mitochondria by forming an autophagosome and fusing with a lysosome when damage to mitochondria occurs.
  • Mitophagy is a mechanism distinct from autophagy, which is a mechanism that decomposes and recycles unnecessary components (old proteins, protein aggregates, organelles, pathogens that have invaded cells, etc.) within cells to generate macromolecular precursors and generate energy when cells are under a state of nutrient deficiency, etc.
  • Mitophagy is regulated independently of regulatory signals such as nutrients, energy, and stress that regulate autophagy.
  • Mitophagy has various pathways, such as canonical mitophagy, alternative mitophagy (or non-canonical mitophagy), and receptor-mediated mitophagy.
  • ATG proteins such as ATG5 and ATG7 are known to play an essential role in the formation of early autophagosomes.
  • the compound of the present invention can promote mitophagy, but is not limited thereto.
  • the PINK1-Parkin pathway is a signaling pathway that mediates mitophagy in response to cellular stress. PINK1-Parkin activates mitophagy to degrade dysfunctional or unnecessary mitochondria, thereby preserving energy metabolism.
  • the present inventors have confirmed through specific examples that the compound according to the present invention specifically activates mitophagy, thereby improving the main symptoms of anticancer agent-induced peripheral neuropathy and restoring the mitochondrial function of sensory nerves damaged by the anticancer agent. Therefore, the compound according to the present invention, an analog thereof, a derivative thereof, and/or a pharmaceutically acceptable salt thereof can exhibit particularly excellent therapeutic effects in patients with peripheral neuropathy in which the mitophagy level/activity (e.g., the mitophagy level/activity of nerve cells, preferably, the mitophagy level/activity of sensory nerve cells) is reduced.
  • the mitophagy level/activity e.g., the mitophagy level/activity of nerve cells, preferably, the mitophagy level/activity of sensory nerve cells
  • the mechanism of peripheral neuropathy treatment by the compound of the present invention was dependent on ATG5 and ATG7, but independent of the PINK1-Parkin pathway. Therefore, the compound according to the present invention can exhibit excellent therapeutic effects in patients in whom the mitophagy level/activity is reduced due to mutations in the PINK1-Parkin pathway or other causes.
  • the 'mutation of the PINK1-Parkin pathway' includes inactivation or reduced activity of the PINK1-Parkin pathway, which may be due to mutations in the genes of proteins involved in the pathway (e.g., PINK1, Parkin, etc.) or a reduction in the level or activity of the protein due to other causes.
  • the compound of the present invention can promote mitophagy without causing mitochondrial dysfunction.
  • the compound of the present invention can promote mitophagy without causing a decrease in mitochondrial membrane potential and/or an increase in mitochondrial reactive oxygen. Therefore, unlike existing mitochondrial toxins, the compound of the present invention can specifically activate mitophagy without the risk of damaging the structure/function of mitochondria and various side effects caused by it, thereby achieving a therapeutic effect on peripheral neuropathy.
  • the compound of the present invention can promote mitophagy independent of the PINK1-Parkin pathway.
  • the compound of the present invention can improve mitochondrial dysfunction.
  • the compound of the present invention can improve mitochondrial dysfunction of sensory nerves. Improving mitochondrial dysfunction includes increasing the level and/or activity of mitochondria, or restoring impaired function.
  • the improvement of mitochondrial function of the compound of the present invention may be achieved through the mitophagy activating effect of the compound. Therefore, the compound according to the present invention can exhibit excellent therapeutic effects in patients with peripheral neuropathy in which the level and/or function of mitochondria (e.g., the level and/or function of mitochondria of neurons or sensory nerve cells) is reduced.
  • the compound of the present invention can improve mitochondrial dysfunction caused by chemical drugs, such as anticancer drugs.
  • the compound of the present invention can improve mitochondrial dysfunction of sensory nerves caused by anticancer drugs.
  • peripheral neuropathy refers to a neurological disorder in which various problems in bodily functions occur due to damage or dysfunction of the peripheral nervous system. Patients with peripheral neuropathy not only experience sensory abnormalities such as hyperalgesia, such as numbness, burning, numbness, and severe pain in the feet, but also experience loss of balance or muscle strength impairment. Peripheral neuropathy is induced by various causes that directly or indirectly affect nerve tissue. For example, acute peripheral neuropathy can be caused by infection, autoimmune reaction, drugs, and toxic substances such as anticancer agents, and chronic peripheral neuropathy is induced by metabolic diseases such as diabetes, alcoholism, malnutrition, renal failure, and liver failure.
  • peripheral neuropathy can be “chemotherapy-induced peripheral neuropathy (CIPN)” caused by an anticancer agent.
  • CIPN chemotherapy-induced peripheral neuropathy
  • This is a representative acquired peripheral neuropathy, which occurs in more than 60% of patients receiving chemotherapy, and mostly develops according to the cumulative dose of chemotherapy drugs, and causes severe pain such as sensory nerve abnormalities, allodynia, and hyperalgesia.
  • chemotherapy-induced peripheral neuropathy is known to be mainly caused by mitochondrial dysfunction induced by chemotherapy drugs.
  • the above chemotherapy drugs are not limited as long as they can cause dysfunction or damage to peripheral nerves, and include all of the platinum series, taxane series, vinca alkaloids, proteasome inhibitors, bortezomib, and thalidomide, and all chemotherapy drugs that can be used clinically, pharmaceutically, or biomedically.
  • the anticancer agent may be selected from Paclitaxel, Bortezomib, Oxaliplatin, Vincristine, Cisplatin, Taxol, Docetaxel, iXABEPILONE, Thalidomide, Velcade, Lenalidomide, and the like.
  • the compound of the present invention may be used for the purpose of alleviating, improving, preventing, and/or treating peripheral neuropathic pain caused by the anticancer agent.
  • the content of the compound, its derivative, or its pharmaceutically acceptable salt 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 condition of the patient, etc., and may be, for example, 0.0001 to 99.9 wt%, or 0.001 to 50 wt% based on the total weight of the composition, but is not limited thereto.
  • the content ratio is a value based on the dry amount after removing the solvent.
  • the compound of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof may be included in a concentration of 0.1 to 20 ⁇ M, 0.1 to 15 ⁇ M, 0.1 to 10 ⁇ M, 1 to 10 ⁇ M, 1 to 8 ⁇ M, or 1 to 6 ⁇ M relative to the total composition, but is not limited thereto.
  • the pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • the excipients may be, for example, at least one selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.
  • the pharmaceutical composition according to the present invention can be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipses, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigants, ointments, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external preparations can have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.
  • external preparations can have formulations such as creams, gels, patches, sprays
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.
  • Additives for tablets, powders, granules, capsules, pills and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methyl cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin,
  • Additives that can be used in the liquid formulation according to the present invention include water, diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc.
  • the syrup according to the present invention may use a solution of white sugar, other sugars or sweeteners, and may also use a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity increasing agent, etc., as needed.
  • Purified water may be used in the emulsion according to the present invention, and an emulsifier, a preservative, a stabilizer, a fragrance, etc. may be used as needed.
  • the suspension according to the present invention may use suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, and the like.
  • suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, and the like.
  • Surfactants, preservatives, stabilizers, colorants, and fragrances may also be used as needed.
  • the injection according to the present invention includes: solvents such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, nonvolatile oils such as sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizers such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, Tween, nitrile acid amide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; It may
  • the suppository according to the present invention comprises cocoa butter, lanolin, witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranette wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neos
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • the "pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dosage level can be determined according to the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the excretion rate, the treatment period, the concurrently used drugs, 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 in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art to which the present invention belongs.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosa administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, etc.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex, weight of the patient, and the severity of the disease.
  • the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, and is generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, administered daily or every other day, or divided into 1 to 3 times a day.
  • the dosage may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
  • subject means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.
  • “administration” means providing a composition of the present invention to a subject by any appropriate method.
  • prevention means any act of suppressing or delaying the onset of a target disease
  • treatment means any act of improving or beneficially changing a target disease and its resulting metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention
  • improvement means any act of reducing a parameter related to a target disease, for example, the degree of symptoms, by administering a composition according to the present invention.
  • the present invention provides a kit for preventing or treating peripheral neuropathy, comprising a compound according to the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the “kit” means a tool including the compound of the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, and used for the purpose of preventing or treating peripheral neuropathy.
  • the kit may include other components, compositions, solutions, devices, etc. that are usually necessary for the manufacture, storage, administration, etc. of the materials.
  • the kit may include instructions for instructing the characteristics of the compound according to the present invention, a derivative thereof, or a pharmaceutically acceptable salt thereof, the appropriate use and storage thereof, etc.
  • the present invention provides a food composition for preventing or improving peripheral neuropathy, comprising a compound according to the present invention, a derivative thereof, or a food-wise acceptable salt thereof.
  • the food composition includes a health functional food composition.
  • food-wise acceptable salt in the present invention includes a salt derived from a food-wise acceptable organic acid, inorganic acid, or base.
  • the compound of the present invention When the compound of the present invention, a derivative thereof, or a food-wise acceptable salt thereof is used as a food additive, the compound may be added as it is or used together with other foods or food ingredients, and may be used appropriately according to a conventional method.
  • the amount of the active ingredient mixed may be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the compound of the present invention may be added in an amount of 15 wt% or less, or 10 wt% or less, based on the raw material. 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 also be used in an amount greater than the above range.
  • foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the conventional sense.
  • the health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages.
  • the natural carbohydrates mentioned above are 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 natural sweetener such as thaumatin and stevia extract, or a synthetic sweetener such as saccharin and aspartame can be used.
  • the proportion of the natural carbohydrate 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.
  • composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.
  • composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These components may be used independently or in combination. The proportion of these additives is not particularly 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 means a food with high medical and healthcare effects that is processed to efficiently exhibit a bioregulatory function in addition to providing nutrition.
  • the food can be manufactured in various forms such as tablets, capsules, powder, granules, liquid, and pills in order to obtain a useful effect 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 ingredients commonly added in the art during the manufacturing process.
  • unlike general drugs it has the advantage of not having side effects that may occur when taking drugs for a long period of time by using food as a raw material, and can be highly portable.
  • the polybromo diphenyl ether compound having mitophagy promoting activity of the present invention was obtained from marine organisms. Specifically, a sample of the sponge Dysidea sp. collected at a depth of 20-30 m from Weno Island, Chuuk State, Micronesia was collected, freeze-dried, repeatedly extracted with methanol and dichloromethane, filtered, and then evaporated under reduced pressure to obtain a crude extract. The crude extract was fractionated into water and butanol to remove salt and polar substances from the water layer, and organic substances were secured from the butanol layer. This was then re-fractionated with methanol and hexane mixed with 15% water to obtain organic substances with moderate polarity from the methanol layer.
  • the mitophagy-promoting effect of PDE701 was verified by another experimental technique.
  • the amount of mitochondria in the cells was confirmed.
  • BEAS-2B cells expressing the mitochondrial marker fluorescent protein mito-YFP protein were treated with 6 ⁇ M PDE701 for 24 hours, and the mito-YFP fluorescence signal was analyzed by confocal microscopy.
  • the mito-YFP fluorescence signal was decreased by approximately 30%, confirming that the amount of mitochondria decreased as mitophagy activity increased (Fig. 1c).
  • Hela cell lines expressing markers (fluorescent proteins) of peroxisome, Golgi apparatus, endoplasmic reticulum, and mitochondria, respectively were prepared, and then each cell was treated with PDE701 to confirm any changes in the fluorescence intensity of each marker. Specifically, each cell line was treated with PDE701 at a concentration of 6 ⁇ M for 24 h, and then fluorescence images of each marker were captured using a confocal microscope and the fluorescence intensity was measured.
  • BEAS-2B cells were treated with PDE701 at a concentration of 6 ⁇ M for 18 or 24 h, and then the quantitative changes in the proteins that serve as indicators of each cellular organelle, PMP70 (membrane protein of peroxisome), GM130 (membrane protein of Golgi apparatus), P4HB (membrane protein of endoplasmic reticulum), and COX2 (complex IV cytochrome c oxidase of mitochondria), were confirmed through Western blotting.
  • PMP70 membrane protein of peroxisome
  • GM130 membrane protein of Golgi apparatus
  • P4HB membrane protein of endoplasmic reticulum
  • COX2 complex IV cytochrome c oxidase of mitochondria
  • MMP mitochondrial membrane potential
  • ROS mitochondrial reactive oxygen species
  • CCCP significantly decreased the mitochondrial membrane potential in BEAS-2B cells when treated with a concentration of 10 ⁇ M for 30 min, whereas no decrease in the mitochondrial membrane potential was observed with PDE701 when treated with a concentration of 6 ⁇ M for up to 12 h (Fig. 4a).
  • CCCP (10 ⁇ M) treatment for 24 h significantly increased mitochondrial reactive oxygen species, whereas PDE701 (6 ⁇ M) treatment did not increase mitochondrial reactive oxygen species even when treated with 12 h (Fig. 4b).
  • the compound PDE701 of the present invention is a compound that promotes mitophagy without inducing mitochondrial dysfunction.
  • BEAS-2B cells were treated with CCCP (10 ⁇ M) or PDE701 (6 ⁇ M) for 24 hours, and the number of cells was counted daily. As a result, cell proliferation was completely inhibited in the CCSP-treated group, whereas PDE701 treatment had no significant effect on cell proliferation (Fig. 5a).
  • BEAS-2B cells were treated with CCCP (10 ⁇ M) or PDE701 (6 ⁇ M) for 24 hours, cultured for 2 weeks, and colony formation was observed. Colony formation was significantly inhibited in the CCCP-treated group, whereas cells treated with PDE701 formed colonies to a degree comparable to the untreated control group (Fig. 5b).
  • ATG7 is known to play an essential role in the early autophagosome formation during the mitophagy process.
  • WT wild-type HeLa cells
  • mitophagy activity was measured using flow cytometry.
  • mitophagy activity increased from 10% to 64% by PDE701 treatment, whereas in the ATG7-deficient cell line, mitophagy activity was reduced by approximately 51% (Fig. 6a).
  • PDE701 was treated with 4 ⁇ M concentration together with paclitaxel (20 ⁇ M) in fruit flies, and the avoidance reaction time was found to increase to 6.6 seconds. This is 97% of the avoidance reaction time of wild-type fruit flies, and thus it could be seen that the decrease in the avoidance reaction time caused by paclitaxel was restored by PDE701.
  • the above results mean that the compound PDE701 of the present invention is effective in treating hyperalgesia caused by anticancer agents.
  • the size of fruit fly larvae was measured after treating them with paclitaxel and/or PD701.
  • the average size of the larvae treated with PDE70 alone was 3.09 mm 2 , which was not statistically significantly different from the average size of the control group larvae, which was 2.96 mm 2 (Fig. 7b).
  • the results demonstrate that PDE701 can exert an effect on the treatment of anticancer drug-induced peripheral neuropathy without toxicity to the growth of fruit fly larvae.
  • mitochondrial dysfunction is known to cause increased mitophagy activity, which removes damaged mitochondria.
  • Drosophila larvae ppk 1a > mt-Keima expressing the mitoKeima fluorescent protein specifically in C4da sensory neurons were treated with paclitaxel alone or in combination with PDE701 (4 ⁇ M), and mitophagy activity was measured using a confocal microscope.
  • the mitophagy activity of the sensory neurons treated with paclitaxel increased two-fold to 4.5% compared to 2.3% in the control group.
  • peripheral neuropathy fly model in which the expression of ATG5 and ATG7, key genes for autophagosome formation during the early stage of mitophagy, was suppressed.
  • flies expressing shRNA of ATG5 or ATG7 in C4da sensory neurons (ATG5 RNAi, ATG7 RNAi) and control flies were prepared, and each model was treated with paclitaxel (20 ⁇ M) alone or in combination with PDE701 (4 ⁇ M), and then a heat probe assay was performed using a 40°C heat probe.
  • the inventors of the present invention confirmed that the polybromo diphenyl ether compound PDE701 having mitophagy-specific promoting activity has a therapeutic effect on peripheral neuropathy, particularly, anticancer agent-induced peripheral neuropathy.
  • the compound according to the present invention can improve hyperalgesia, a representative symptom of peripheral neuropathy, and effectively restore mitochondrial function of sensory nerves damaged by anticancer agents.
  • PDE701 unlike existing mitochondrial toxins such as CCCP, PDE701 does not damage mitochondrial function such as decreasing mitochondrial membrane potential or increasing reactive oxygen species, and does not have cytotoxicity. Therefore, it can be utilized as a safe drug with a low risk of side effects in the treatment of peripheral neuropathy.
  • the excellent peripheral neuropathy therapeutic effect of PDE701 was confirmed to be due to the mitophagy-specific promoting activity of the compound, which is independent of the PINK1-Parkin pathway, a stress-induced mitophagy-mediated pathway, and dependent on ATG5 and ATG7. Therefore, the peripheral neuropathy therapeutic effect can be achieved in various patient groups through appropriate use considering the molecular mechanism of the mitophagy promoting activity of PDE701. Therefore, the PDE701 of the present invention is expected to be usefully utilized in the prevention and treatment of peripheral neuropathy as a substance capable of fundamentally treating peripheral neuropathy, including anticancer agent-induced peripheral neuropathy.
  • the effective substance according to the present invention can be formulated in various forms depending on the purpose.
  • the following are examples of several formulation methods containing the effective substance according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the powder was filled into a sealed bag to prepare a powder.
  • tablets were manufactured by pressing them according to the usual method for manufacturing tablets.
  • the mixture was filled into a gelatin capsule according to a conventional capsule manufacturing method to produce a capsule.
  • the effective substance according to the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 using diluted hydrochloric acid BP, the volume was adjusted using sodium chloride BP for injection, and the mixture was thoroughly mixed.
  • the solution was filled into a 5 ml type I ampoule made of transparent glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120°C for 15 minutes or more to prepare an injection solution.
  • each ingredient was dissolved in purified water, lemon flavor was added, the above ingredients were mixed, purified water was added, the total volume was adjusted to 100 mL, and the solution was filled into a brown bottle and sterilized to manufacture a liquid.
  • the effective substance according to the present invention can be manufactured into various types of health foods depending on the purpose.
  • the following are examples of manufacturing methods for several health foods containing the effective substance according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • 0.01-1 weight part of the effective substance of the present invention was added to milk, and various dairy products such as butter and ice cream were manufactured using the milk.
  • Brown rice, barley, glutinous rice, and Job's tears were alpha-treated and dried using a known method, and then roasted and ground into powder having a particle size of 60 mesh using a grinder.
  • Black beans, black sesame seeds, and perilla seeds were also steamed and dried using a known method, roasted, and ground into powder having a particle size of 60 mesh using a grinder.
  • the effective substance of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder.
  • the grains, seeds, and dry powders of the effective substance manufactured above were mixed in the following ratio to manufacture a composition.
  • Seeds (7 parts by weight of perilla seeds, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds),
  • the effective substance according to the present invention can be manufactured into various types of health functional foods depending on the purpose.
  • the following are examples of manufacturing methods for several health functional foods containing the effective substance according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • Vitamin mixture appropriate amount
  • Vitamin A acetate 70 ⁇ g
  • Vitamin B6 0.5 mg
  • Vitamin B12 0.2 ⁇ g
  • composition ratio of the above vitamin and mineral mixture is a preferred example of a mixture of ingredients relatively suitable for health functional foods, but the mixing ratio may be arbitrarily modified, and the above ingredients may be mixed according to a conventional health functional food manufacturing method, and then granules may be manufactured and used to manufacture a health functional food composition according to a conventional method.
  • the above ingredients are mixed, stirred and heated at 85°C for about 1 hour, the resulting solution is filtered, placed in a sterilized container, sealed and sterilized, and then stored in a refrigerator, and then used in manufacturing the health beverage composition of the present invention.
  • the above composition ratio is a preferred example of mixing ingredients relatively suitable for a favorite beverage, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, demand country, and intended use.
  • the present invention provides a compound represented by the following chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of peripheral neuropathy.
  • the present invention provides a composition comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of peripheral neuropathy.
  • the present invention provides a composition comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for use as a medicine.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating peripheral neuropathy.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating an animal having peripheral neuropathy, comprising administering to the animal an effective amount of a compound represented by the above chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a medicament (therapeutic agent) comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating peripheral neuropathy.
  • the present invention provides the use of a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical agent for treating peripheral neuropathy.
  • the present invention provides a peripheral neuropathy treatment agent characterized by containing a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for treating peripheral neuropathy, characterized in that it contains a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating peripheral neuropathy, comprising a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
  • the present invention provides the use of a compound represented by the chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical agent for treating peripheral neuropathy.
  • the present invention relates to a pharmaceutical composition for preventing or treating peripheral neuropathy, and was completed by confirming that a diphenyl ether derivative isolated from a marine organism specifically promotes mitophagy activity, thereby exhibiting a peripheral neuropathy therapeutic effect.
  • the compound according to the present invention improves hyperalgesia, a representative symptom of peripheral neuropathy, by promoting mitophagy independent of the PINK1-Parkin pathway, and can effectively improve mitochondrial dysfunction of sensory nerves caused by anticancer agents.
  • the compound of the present invention does not damage mitochondrial function or inhibit cell growth, and thus can be used as a safe therapeutic drug.
  • the diphenyl ether derivative according to the present invention has a low risk of side effects and enables fundamental treatment of peripheral neuropathy through promotion of mitophagy, and therefore, it is expected to be usefully utilized as a drug for preventing and treating peripheral neuropathy, and thus its industrial applicability is recognized.

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Abstract

La présente invention concerne une composition pharmaceutique et similaire destinée à prévenir ou à traiter une neuropathie périphérique et a été obtenue par l'identification du fait qu'un dérivé de diphényléther isolé à partir d'un organisme marin favorise spécifiquement l'activité de mitophagie et peut ainsi présenter un effet de traitement de neuropathie périphérique. Plus particulièrement, le composé selon l'invention favorise indépendamment la mitophagie dans la voie PINK1-Parkin de façon à soulager l'hyperalgésie, qui est un symptôme représentatif d'une neuropathie périphérique, et peut atténuer efficacement un dysfonctionnement mitochondrial de nerfs sensoriels induit par un agent anticancéreux. En particulier, le composé de la présente invention n'endommage pas la fonction mitochondriale ou n'inhibe pas la croissance cellulaire et peut ainsi être utilisé en tant que médicament thérapeutique sûr. Par conséquent, un dérivé de diphényléther selon la présente invention présente un faible risque d'effets secondaires et permet un traitement fondamental d'une neuropathie périphérique par l'intermédiaire du fait de favoriser la mitophagie et est ainsi censé être utilisé efficacement en tant que médicament pour prévenir et traiter une neuropathie périphérique.
PCT/KR2024/002540 2023-02-28 2024-02-27 Composition destinée à prévenir ou à traiter une neuropathie périphérique, comprenant un dérivé de diphényléther en tant que principe actif Ceased WO2024181780A1 (fr)

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