WO2022019362A1 - Composé dérivé de tpp et composition pharmaceutique pour le traitement ou la prévention du vieillissement ou de maladies associées au vieillissement le comprenant - Google Patents

Composé dérivé de tpp et composition pharmaceutique pour le traitement ou la prévention du vieillissement ou de maladies associées au vieillissement le comprenant Download PDF

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WO2022019362A1
WO2022019362A1 PCT/KR2020/009780 KR2020009780W WO2022019362A1 WO 2022019362 A1 WO2022019362 A1 WO 2022019362A1 KR 2020009780 W KR2020009780 W KR 2020009780W WO 2022019362 A1 WO2022019362 A1 WO 2022019362A1
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group
formula
substituted
compound
pharmaceutical composition
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PCT/KR2020/009780
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Korean (ko)
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김채규
유자형
김상필
정혜원
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울산과학기술원
건국대학교 글로컬산학협력단
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Priority to PCT/KR2020/009780 priority Critical patent/WO2022019362A1/fr
Publication of WO2022019362A1 publication Critical patent/WO2022019362A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds

Definitions

  • the present invention relates to a pharmaceutical composition or a health functional food composition for the treatment or prevention of aging or aging-related diseases, including a TPP derivative.
  • the present invention is supported by the Ministry of Science and ICT under Project No. 2017R1E1A1A01073964 (Project name: Development of a therapeutic agent for age-related macular degeneration through removal of senescent retinal cells), and NRF-2018R1E1A2A02058946 (Project name: Selective senescent cell removal by self-assembly of peptides in mitochondria It is the result of recovery of the regenerative capacity of living tissue).
  • the aging process is a decrease in the biochemical or physiological functions of various bodies along with the aging of cells over time. can limit human lifespan.
  • Cellular senescence means that cells no longer divide. During cell division, due to the exhaustion of the length of telomeres, which are the nucleotide sequences at the ends of chromosomes, the cells no longer divide due to replication aging, UV rays, virus infection, and chemicals. Stress-induced cellular senescence is known as a mechanism for suppressing the occurrence of cancer due to external stimuli or stress.
  • SASP senescent cell secretory activity
  • senescent cells that secrete secretory activity related to inflammatory response are removed by the immune system after performing various physiological roles to maintain body homeostasis, so that living things are active in a stable state while performing healthy life activities.
  • the immune system degenerates and the self-healing ability of cells decreases, senescent cells gradually accumulate in the body, and eventually the organism reaches an abnormal state of chronic inflammation and death, increasing the risk of cancer or various geriatric diseases do.
  • Macular degeneration one of the geriatric diseases, has a prevalence of about 5-10% in the elderly over 65 years old (1.21 million people in Korea as of 2014), and is one of the serious eye diseases whose prevalence is already rapidly increasing as the aging society enters. .
  • the etiology of age-related macular degeneration can be caused by a complex mechanism of environmental factors based on genetic factors.
  • SNP single-nucleotide polymorphism
  • the accumulated senescent cells can be selectively removed, it can be an innovative method for treating various diseases including macular degeneration caused by aging by improving the body homeostasis or the regeneration ability of the living tissue to restore the chronic inflammatory response of the organism.
  • various diseases including macular degeneration caused by aging by improving the body homeostasis or the regeneration ability of the living tissue to restore the chronic inflammatory response of the organism.
  • degenerative diseases such as degenerative arthritis and cardiovascular disease by using senolytics that remove senescent cells has been reported. Since this is not clear, research to discover drug candidates that can only remove senescent cells with various clinical values is urgently needed.
  • One aspect is to provide a compound or a pharmaceutically acceptable salt thereof.
  • Another aspect is a pharmaceutical composition for the prevention or treatment of aging-related diseases, comprising the compound of one aspect or a pharmaceutically acceptable salt thereof as an active ingredient; A method of treating aging-related diseases comprising administering the pharmaceutical composition to a subject; And to provide a pharmaceutical use of an aspect of the compound or a pharmaceutically acceptable salt thereof for preventing or treating age-related diseases.
  • Another aspect is a pharmaceutical composition for the prevention or treatment of macular degeneration, comprising the compound of one aspect or a pharmaceutically acceptable salt thereof as an active ingredient; A method of treating macular degeneration comprising administering the pharmaceutical composition to a subject; And to provide a pharmaceutical use of an aspect of the compound or a pharmaceutically acceptable salt thereof for preventing or treating macular degeneration.
  • Another aspect is to provide a functional health food composition for improving eye health, comprising the compound of one aspect or a salt thereof as an active ingredient
  • Another aspect is to provide a functional health food composition for the improvement of macular degeneration, comprising the compound or salt thereof according to one aspect as an active ingredient.
  • One aspect provides a compound represented by the following Chemical Formula 1 or Chemical Formula 2 or a pharmaceutically acceptable salt thereof.
  • l 0 to 15
  • k, m and n are each 2 to 15;
  • A is a nitrogen (N) atom or a carbon (C) atom
  • R 1 and R 2 are the same as or different from each other, and each independently hydrogen; heavy hydrogen; halogen group; -CN; a substituted or unsubstituted alkyl group; a substituted or unsubstituted alkenyl group; a substituted or unsubstituted alkynyl group; a substituted or unsubstituted alkoxy group; a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted heterocycloalkyl group; a substituted or unsubstituted aryl group; a substituted or unsubstituted heteroaryl group; and an amine group unsubstituted or substituted with a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • substitution means that a hydrogen atom bonded to a carbon atom of a compound is replaced with another substituent, and the position to be substituted is not limited as long as the position at which the hydrogen atom is substituted, that is, a position where the substituent is substitutable, is not limited, and two or more substitutions are made. In this case, two or more substituents may be the same as or different from each other.
  • halogen may be fluorine, chlorine, bromine or iodine.
  • alkyl group includes a straight or branched chain having 1 to 60 carbon atoms, and may be further substituted by other substituents.
  • the number of carbon atoms in the alkyl group may be 1 to 60, specifically 1 to 40, more specifically, 1 to 20.
  • Specific examples include methyl group, ethyl group, propyl group, n-propyl group, isopropyl group, butyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, 1-methyl-butyl group, 1- Ethyl-butyl group, pentyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 4-methyl- 2-pentyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, heptyl group, n-heptyl group, 1-methylhexyl group, cyclopentylmethyl group, cyclohexylmethyl group, octyl group, n-octyl group,
  • alkenyl group includes a straight or branched chain having 2 to 60 carbon atoms, and may be further substituted by other substituents.
  • the carbon number of the alkenyl group may be 2 to 60, specifically 2 to 40, more specifically, 2 to 20.
  • Specific examples include a vinyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 3-methyl-1 -Butenyl group, 1,3-butadienyl group, allyl group, 1-phenylvinyl-1-yl group, 2-phenylvinyl-1-yl group, 2,2-diphenylvinyl-1-yl group, 2-phenyl-2 -(naphthyl-1-yl)vinyl-1-yl group, 2,2-bis(diphenyl-1-yl)vinyl-1-yl group, stilbenyl group, styrenyl group, etc., but are not limited thereto.
  • alkynyl group includes a straight or branched chain having 2 to 60 carbon atoms, and may be further substituted by other substituents.
  • the carbon number of the alkynyl group may be 2 to 60, specifically 2 to 40, more specifically, 2 to 20.
  • alkoxy group may be a straight chain, branched chain, or cyclic chain. Although carbon number of an alkoxy group is not specifically limited, It is preferable that it is C1-C20. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, Isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, p-methylbenzyloxy, etc. may be, but is not limited thereto.
  • cycloalkyl group includes a monocyclic or polycyclic ring having 3 to 60 carbon atoms, and may be further substituted by other substituents.
  • polycyclic means a group in which a cycloalkyl group is directly connected to another ring group or condensed.
  • the other ring group may be a cycloalkyl group, but may be a different type of ring group, for example, a heterocycloalkyl group, an aryl group, a heteroaryl group, or the like.
  • the carbon number of the cycloalkyl group may be 3 to 60, specifically 3 to 40, more specifically 5 to 20.
  • heterocycloalkyl group includes O, S, Se, N, or Si as a hetero atom, and includes a monocyclic or polycyclic ring having 2 to 60 carbon atoms, and may be further substituted by other substituents.
  • polycyclic refers to a group in which a heterocycloalkyl group is directly connected or condensed with another ring group.
  • the other ring group may be a heterocycloalkyl group, but may be a different type of ring group, for example, a cycloalkyl group, an aryl group, a heteroaryl group, or the like.
  • the heterocycloalkyl group may have 2 to 60 carbon atoms, specifically 2 to 40 carbon atoms, and more specifically 3 to 20 carbon atoms.
  • aryl group includes a monocyclic or polycyclic ring having 6 to 60 carbon atoms, and may be further substituted by other substituents.
  • polycyclic means a group in which an aryl group is directly connected or condensed with another ring group.
  • the other ring group may be an aryl group, but may be another type of ring group, such as a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and the like.
  • the aryl group includes a spiro group.
  • the carbon number of the aryl group may be 6 to 60, specifically 6 to 40, more specifically 6 to 25.
  • aryl group examples include a phenyl group, a biphenyl group, a triphenyl group, a naphthyl group, an anthryl group, a chrysenyl group, a phenanthrenyl group, a perylenyl group, a fluoranthenyl group, a triphenylenyl group, a phenalenyl group, a pyrethyl group Nyl group, tetracenyl group, pentacenyl group, fluorenyl group, indenyl group, acenaphthylenyl group, benzofluorenyl group, spirobifluorenyl group, 2,3-dihydro-1H-indenyl group, condensed ring groups thereof and the like, but is not limited thereto.
  • heteroaryl group includes S, O, Se, N or Si as a hetero atom, and includes monocyclic or polycyclic rings having 2 to 60 carbon atoms, and may be further substituted by other substituents.
  • the polycyclic refers to a group in which a heteroaryl group is directly connected or condensed with another ring group.
  • the other ring group may be a heteroaryl group, but may be a different type of ring group, for example, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or the like.
  • the heteroaryl group may have 2 to 60 carbon atoms, specifically 2 to 40 carbon atoms, and more specifically 3 to 25 carbon atoms.
  • heteroaryl group examples include a pyridyl group, a pyrrolyl group, a pyrimidyl group, a pyridazinyl group, a furanyl group, a thiophene group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group group, isothiazolyl group, triazolyl group, furazanyl group, oxadiazolyl group, thiadiazolyl group, dithiazolyl group, tetrazolyl group, pyranyl group, thiopyranyl group, diazinyl group, oxazinyl group , thiazinyl group, deoxynyl group, triazinyl group, tetrazinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, isoquinazol
  • amine group refers to a monoalkylamine group; monoarylamine group; monoheteroarylamine group; -NH 2 ; dialkylamine group; diarylamine group; diheteroarylamine group; an alkylarylamine group; an alkyl heteroarylamine group; And it may be selected from the group consisting of an aryl heteroarylamine group, the number of carbon atoms is not particularly limited, but is preferably 1 to 30.
  • the amine group include a methylamine group, a dimethylamine group, an ethylamine group, a diethylamine group, a phenylamine group, a naphthylamine group, a biphenylamine group, a dibiphenylamine group, an anthracenylamine group, 9- Methyl-anthracenylamine group, diphenylamine group, phenylnaphthylamine group, ditolylamine group, phenyltolylamine group, triphenylamine group, biphenylnaphthylamine group, phenylbiphenylamine group, biphenylfluorene
  • the term "pharmaceutically acceptable” means that the benefit/risk ratio is reasonable without undue toxicity, irritation, allergic reaction, or other problems or complications, so that it is suitable for use in contact with the tissues of a subject (eg, a human) and means a composition within the scope of sound medical judgment.
  • the term “pharmaceutically acceptable salt” refers to an acid addition salt formed by a pharmaceutically acceptable free acid.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda.
  • the acid addition salt is prepared by a conventional method, for example, by dissolving the compound represented by Formula 1 or Formula 2 in an excess aqueous acid solution, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or aceto.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • 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 the undissolved compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • the compound represented by the formula (2) may be one represented by the following formula (3).
  • n and l are as defined above.
  • the compound represented by Formula 1 may be one represented by Formula 4 below.
  • the compound represented by Formula 2 may be one selected from the group consisting of compounds represented by Formulas 5 to 12 below.
  • Another aspect is a pharmaceutical composition for the prevention or treatment of aging-related diseases, comprising the compound of one aspect or a pharmaceutically acceptable salt thereof as an active ingredient; A method of treating aging-related diseases comprising administering the pharmaceutical composition to a subject; And it provides a pharmaceutical use of an aspect of the compound or a pharmaceutically acceptable salt thereof for preventing or treating a senescence-related disease.
  • Another aspect is a pharmaceutical composition for the prevention or treatment of macular degeneration comprising the compound of one aspect or a pharmaceutically acceptable salt thereof as an active ingredient;
  • a method of treating macular degeneration comprising administering the pharmaceutical composition to a subject; and a pharmaceutical use of the compound of one aspect or a pharmaceutically acceptable salt thereof for preventing or treating macular degeneration.
  • prevention refers to any action of inhibiting aging-related diseases or delaying the onset of diseases by administration of the pharmaceutical composition according to the present invention.
  • treatment refers to any action in which symptoms for aging-related diseases are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.
  • the aging-related disease may be at least one selected from the group consisting of geriatric cardiovascular diseases and disorders, geriatric lung disease, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, osteoarthritis, ocular disease in the elderly, and skin aging.
  • geriatric cardiovascular diseases and disorders geriatric lung disease, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, osteoarthritis, ocular disease in the elderly, and skin aging.
  • senescent cells that secrete secretory activity related to inflammatory response are removed by the immune system after performing various physiological roles to maintain body homeostasis, so that living things are active in a stable state while performing healthy life activities.
  • the immune system degenerates and the self-healing ability of cells decreases, senescent cells gradually accumulate in the body, and eventually the organism reaches an abnormal state of chronic inflammation and death, increasing the risk of cancer or various geriatric diseases do. Accordingly, if it is possible to selectively remove the senescent cells accumulated by the pharmaceutical composition or compound, it can be an effective substance for treating the aging-related diseases by improving the homeostasis or the regeneration ability of the living body to restore the chronic inflammatory response of the organism. .
  • the pharmaceutical composition is accumulated in the mitochondria of senescent cells to destabilize the integrity of the mitochondrial membrane, and can induce the generation of superoxide and apoptosis in the mitochondria, thereby selectively removing senescent cells can do. Accordingly, the pharmaceutical composition may be used as an effective material for the prevention or treatment of age-related diseases.
  • the pharmaceutical composition may be administered orally (orally) or parenterally (for example, as an injection, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, for example, subcutaneously (i.e., external application for skin) or oral (ie, oral preparation) administration. It may also be an eye drop.
  • eye drops includes formulations of eye drops, ophthalmic reflux solution, eye ointment or lyophilisate, ie, all formulations relating to the treatment of the eye.
  • the eye drop is used as a treatment or prophylactic agent for corneal epithelial cell disorder in any formulation, but it may be particularly preferable to use the formulation as eye drops, ophthalmic reflux, cream, eye ointment, or freeze-drying agent, but is not limited thereto.
  • eye drops, eye ointments, or creams as additives, preservatives such as sodium dehydroacetate and methyl paraoxybenzoate, isotonic agents such as sodium chloride and glycerin, thickeners such as carboxymethyl cellulose and polyvinyl alcohol , EDTA, it is possible to use a general stabilizer such as polysaccharides, but is not limited thereto, as long as it is physiologically acceptable.
  • an isotonic, non-irritating solution of pH 4-9 and pH 5-9.
  • the dosage varies depending on the condition and weight of the patient, the degree of disease, the drug form, the administration route and time, but may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the type, severity, activity of the drug, and the drug in the patient. Sensitivity, administration time, administration route and excretion rate, duration of treatment, factors including concomitant 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 single or multiple. Taking all of the above factors into consideration, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition may vary depending on the patient's age, sex, condition, body weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, and generally 1 kg of body weight per day
  • the sugar may be in the range of 0.1 to 500 mg, and may be administered daily or every other day, or may be administered in divided doses within the range of 1 to 5 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc., the dosage is not limited in any way.
  • Another aspect provides a pharmaceutical composition for preventing or treating macular degeneration, comprising the compound of one aspect or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition may target the mitochondria of macular cells. Furthermore, the composition may be to destabilize the integrity of the mitochondrial membrane of the macular cell.
  • the compound of one aspect included in the composition has a structure in which a hydrophobic alkyl group and a positive charge moiety are bonded to a triphenylphosphate (TPP) group that is directed toward the mitochondria, which is accumulated in the mitochondria and the integrity of the mitochondrial membrane (membrane) integrity) can be compromised.
  • TPP triphenylphosphate
  • the composition further interferes with the integrity of the mitochondrial membrane of senescent cells compared to normal cells, thereby giving oxidative stress to senescent cells, thereby selectively inducing apoptosis of senescent cells. Therefore, according to one embodiment, the composition can selectively remove senescent eye cells.
  • the macular degeneration is one of serious eye diseases that show a prevalence of about 5-10% in the elderly over 65 years old (1.21 million people in Korea as of 2014), and whose prevalence is already rapidly increasing with the entry of an aging society.
  • the pathogenesis of macular degeneration may be caused by a complex mechanism of environmental factors based on genetic factors, mainly genes related to inflammation and immune response. Therefore, age-related macular degeneration can be caused by aging and external harmful environments (such as chronic oxidative stress) and chronic inflammation accompanying it. That is, in one embodiment, the macular degeneration may be caused by aging.
  • composition according to one embodiment is mitochondria-specific accumulation of macular degeneration cells to destabilize the integrity of the mitochondrial membrane, and induce the generation or apoptosis of superoxide in the mitochondria.
  • the composition may be an oral preparation, an injection, an eye drop, or an eye ointment.
  • Another aspect provides a functional health food composition for improving eye health, comprising the compound of one aspect or a salt thereof as an active ingredient.
  • the term “improvement” refers to any action that at least reduces a parameter associated with an abnormal condition, for example, the severity of a symptom.
  • the health functional food composition may be used simultaneously with or separately from a drug for treatment before or after the onset of the disease in order to prevent or improve aging.
  • salt refers to a pharmaceutically acceptable salt, and these salts may be prepared according to conventional methods in the art.
  • the food composition may be used as an active ingredient added to food or used together with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient may be appropriately determined depending on the purpose of its use (for prevention or improvement).
  • the composition of the present invention is added in an amount of 60% by weight or less, preferably 40% by weight or less, based on the raw material.
  • the amount may be less than or equal to the above range.
  • the food composition is not particularly limited in other ingredients added other than containing the active ingredient as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the ratio of the natural carbohydrate may be appropriately determined by the selection of those skilled in the art.
  • the food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof , organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. These components may be used independently or in combination. The proportion of these additives may also be appropriately selected by those skilled in the art.
  • the food composition according to an embodiment can selectively remove the aged eye cells by generating superoxide in the mitochondria of the aged eye cells and inducing apoptosis. Therefore, the food composition according to an embodiment may be used as an effective material for improving eye health.
  • Another aspect provides a health functional food composition for improving macular degeneration, comprising the compound of one aspect or a salt thereof as an active ingredient.
  • the macular degeneration may be caused by aging.
  • the compound according to an aspect and a pharmaceutical composition or health functional food composition comprising the same selectively accumulate in the mitochondria of senescent cells, generate a cytotoxic effect, and thus can be removed, thereby reducing the symptoms of aging-related diseases, including macular degeneration. Since it can prevent, improve, or treat, it may be utilized as an effective substance that can replace existing therapeutic agents.
  • Figure 1a is a diagram showing a chemical reaction schematic diagram and NMR results of the compound Ada-C3-TPP of one embodiment.
  • Figure 1b is a diagram showing a chemical reaction schematic diagram and NMR results of the compound C12-DA-C6-DA-C3-TPP of one embodiment.
  • FIG. 2 is an image showing IMR90 non-senescent cells (normal cells) and senescent cells derived therefrom.
  • Figures 3a and 3b is a graph showing the cytotoxic effect after treatment of the compound of one embodiment on senescent cells and non-senescent cells.
  • 5A and 5B are images showing whether or not superoxide is generated in mitochondria of senescent cells and non-senescent cells treated with the compound of one embodiment.
  • FIG. 6 is a graph showing the apoptosis effect of senescent cells and non-senescent cells treated with the compound of one embodiment.
  • FIG. 7A is a diagram schematically illustrating an experimental procedure for confirming the effect of removing senescent cells in the eye.
  • 7b is a result of confirming the effect of removing senescent cells in the eyeball according to the treatment of the mouse senescent eye cells with a low concentration of the compound of one embodiment through an image.
  • Figure 7c is a result of quantitatively comparing the effect of removing senescent cells in the eyeball according to the treatment of the compound of one embodiment to the mouse senescent eye cells at a low concentration.
  • 8A is a diagram schematically illustrating an experimental procedure for confirming the effect of removing senescent cells in the eye.
  • 8B is a result of confirming the effect of removing senescent cells in the eyeball according to the treatment of the mouse senescent eye cells with a high concentration of the compound of one embodiment through an image.
  • Figure 8c is a result of quantitatively comparing the effect of removing senescent cells in the eye according to the treatment of the compound of one embodiment to the mouse senescent eye cells at a high concentration.
  • 3-bromopropyl-TPP 1.30 mmol (0.5 g) and N,N,N',N'-tetramethyl-1,6-diaminohexane 6.5 mmol (1.2 g) were mixed with 12 mL of acetonitrile (ACN) was dissolved in After heating at 110 °C for 24 hours, the mixture was purified by HPLC to obtain (6-dimethylaminohexyl)-3-dimethylamino-propyl-triphenylphosphate ((6-dimethylaminohexyl)-3-dimethylammonio-propyl-TPP). generated. The product was a yellow oil.
  • normal IMR90 cells were treated with 250 nM of doxorubicin and cultured for 24 hours. After culturing in fresh DMEM medium for 7 days, senescent cells were identified. As a result, it was confirmed that more than 90% of normal IMR90 cells were senescent cells. The results are shown in FIG. 2 .
  • Example 1 the effect of the two compounds prepared in Example 1 on the cell viability of the senescent cells cultured in Reference Example 1 was investigated.
  • Example 1 Each compound produced in Example 1 was treated in each of the senescent and non-senescent cells cultured in Reference Example 1, and the number of cells was counted over 24, 48, and 72 hours, respectively. The corresponding results are shown in FIGS. 3A and 3B, respectively.
  • both compounds were found to induce more apoptosis in senescent cells than in non-senescent normal cells. This means that, as described in the above examples, both compounds can selectively induce cytotoxicity in senescent cells rather than non-senescent cells.
  • the concentration of the compound was increased to 363.6ng/ml (Ada-C3-TPP) and 516.0ng/ml (C12-DA-C6-DA-C3-TPP), respectively, administered. And on the 7th day, the effect of the compound was confirmed through ⁇ -galactosidase staining.
  • 7B and 7C show the results when a relatively low concentration of the compound was administered.
  • 7B and 7C the expression of ⁇ -galactosidase green staining in the control group indicated that senescence of the eye cells was induced, and when the two compounds were administered, the expression of ⁇ -galactosidase green staining was significantly reduced, which This means that the compound showed a cytotoxic effect on senescent cells in the eye.

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Abstract

La présente invention concerne une composition pharmaceutique ou une composition alimentaire naturelle fonctionnelle pouvant traiter ou prévenir des maladies et des troubles liés au vieillissement par destruction sélective de cellules sénescentes.
PCT/KR2020/009780 2020-07-24 2020-07-24 Composé dérivé de tpp et composition pharmaceutique pour le traitement ou la prévention du vieillissement ou de maladies associées au vieillissement le comprenant WO2022019362A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495803B1 (fr) * 1989-10-09 1995-05-10 Fabricom Air Conditioning S.A. Composition desinfectante et procede de desinfection
US6331532B1 (en) * 1998-11-25 2001-12-18 University Of Otago Mitochondrially targeted antioxidants
WO2003016323A1 (fr) * 2001-08-13 2003-02-27 Antipodean Biotechnology Limited Synthese de quinols et quinones de triphenylphosphonium
KR101003960B1 (ko) * 2003-08-22 2010-12-30 안티포딘 파마슈티칼스, 인코포레이티드 미토콘드리아 표적화 산화방지제로서 사용되는 미토퀴논 유도체를 포함하는 약제학적 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495803B1 (fr) * 1989-10-09 1995-05-10 Fabricom Air Conditioning S.A. Composition desinfectante et procede de desinfection
US6331532B1 (en) * 1998-11-25 2001-12-18 University Of Otago Mitochondrially targeted antioxidants
WO2003016323A1 (fr) * 2001-08-13 2003-02-27 Antipodean Biotechnology Limited Synthese de quinols et quinones de triphenylphosphonium
KR101003960B1 (ko) * 2003-08-22 2010-12-30 안티포딘 파마슈티칼스, 인코포레이티드 미토콘드리아 표적화 산화방지제로서 사용되는 미토퀴논 유도체를 포함하는 약제학적 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JACEK ZIELONKA, JOY JOSEPH, ADAM SIKORA, MICAEL HARDY, OLIVIER OUARI, JEANNETTE VASQUEZ-VIVAR, GANG CHENG, MARCOS LOPEZ, BALARAMAN: "Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications", CHEMICAL REVIEWS, AMERICAN CHEMICAL SOCIETY, US, vol. 117, no. 15, 9 August 2017 (2017-08-09), US , pages 10043 - 10120, XP055639154, ISSN: 0009-2665, DOI: 10.1021/acs.chemrev.7b00042 *

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