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WO2022168650A1 - Homocysteine derivative and method for producing same, composition, and anti-inflammatory agent - Google Patents

Homocysteine derivative and method for producing same, composition, and anti-inflammatory agent Download PDF

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Publication number
WO2022168650A1
WO2022168650A1 PCT/JP2022/002372 JP2022002372W WO2022168650A1 WO 2022168650 A1 WO2022168650 A1 WO 2022168650A1 JP 2022002372 W JP2022002372 W JP 2022002372W WO 2022168650 A1 WO2022168650 A1 WO 2022168650A1
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mass
composition
less
compound
salts
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PCT/JP2022/002372
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French (fr)
Japanese (ja)
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淳 松本
邦男 小坂
恵介 松山
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長瀬産業株式会社
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Priority to JP2022579446A priority Critical patent/JPWO2022168650A1/ja
Publication of WO2022168650A1 publication Critical patent/WO2022168650A1/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton

Definitions

  • the present invention relates to homocysteine derivatives, methods for producing them, compositions containing them, and anti-inflammatory agents containing them.
  • compositions having an anti-inflammatory action for example, cosmetics having an effect of suppressing MMP-9 production have been known so far (see Patent Documents 1 and 2, for example).
  • the present invention aims to provide a novel homocysteine derivative, a method for producing the same, a composition containing the compound, an anti-inflammatory agent containing them, and the like.
  • the inventors of the present invention have made intensive studies to solve the above problems, and as a result, have succeeded in creating the novel homocysteine derivatives shown below, and found that the above objects can be achieved by the above compounds, thereby completing the present invention. .
  • the present invention provides the compounds listed below.
  • the present invention provides the compositions listed below.
  • Section 4 A composition comprising the compound of any one of Items 1-3.
  • Item 5 The composition according to item 4, further comprising L-ergothioneine (hereinafter also referred to as "EGT").
  • Item 6. The composition according to item 5, wherein the content of the compound is 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
  • Item 7. The composition according to item 5 or 6, wherein the content of the compound is 0.0001 parts by mass or more relative to 100 parts by mass of the L-ergothioneine.
  • the present invention relates to the following anti-inflammatory agents.
  • Item 8. Item 4. An anti-inflammatory agent comprising the compound according to any one of items 1 to 3.
  • Item 9. An anti-inflammatory agent comprising the composition according to any one of Items 4 to 7.
  • the present invention relates to the manufacturing method listed below.
  • Item 10 A method for producing the compound according to any one of items 1 to 3, comprising a step of reacting ribosylhomocysteine (hereinafter also referred to as "SRH") with a reducing agent.
  • RSH ribosylhomocysteine
  • Item 11 The production method according to Item 10, wherein the reducing agent includes lithium borohydride, sodium borohydride, or zinc borohydride.
  • the compound of the present invention or a composition containing it can be suitably used, for example, as an anti-inflammatory agent.
  • the compound or the composition can be easily obtained.
  • the anti-inflammatory agent of the present invention can exhibit, for example, an anti-inflammatory effect leading to maintenance of retinal pigment epithelial cells.
  • FIG. 1 is a graph showing evaluation results of anti-inflammatory action in Example 2.
  • FIG. 1 is a graph showing evaluation results of anti-inflammatory action in Example 2.
  • the homocysteine derivative of the present invention is a compound represented by Formula 1 below.
  • homocysteine derivative is, for example, a compound represented by Formula 2 below.
  • homocysteine derivative is, for example, a compound represented by Formula 3 below.
  • homocysteine derivatives also include derivatives such as solvates such as hydrates and substituted products in which part or all of the structure is substituted as appropriate.
  • hydroxyl groups may be appropriately substituted with, for example, an alkyl ether group, an aryl ether group, or an ester group.
  • the carboxyl group may be appropriately substituted with an ester group, an amide group, an acid anhydride, a salt, or the like.
  • the amino group may be appropriately substituted with an alkylated product, an amide group, a salt, or the like.
  • the sulfide group may be appropriately substituted with an alkylated salt, sulfoxide, or sulfone.
  • the above homocysteine derivative can be produced by appropriately using a known technique, but it is preferable to use a production method including a step of reducing ribosylhomocysteine and the like.
  • the method for producing the compound of the present invention preferably includes a step of reacting ribosylhomocysteine with a reducing agent.
  • Ribosylhomocysteine is a homocysteine derivative in which homocysteine (2-amino-4-sulfanylbutanoic acid) is S-ribosylated, and its structure is represented by the following formula.
  • SRH can be obtained by known methods such as synthesis, extraction, and fermentation.
  • SRH may be in the form of a free form or in the form of a salt.
  • the salt of SRH may be a salt formed with a carboxyl group or a salt formed with an amino group in these structures.
  • Ribosylhomocysteine or ribosylhomocysteine analogues may also be solvates such as hydrates.
  • the salt of SRH is not particularly limited as long as it is pharmacologically or physiologically acceptable.
  • Specific examples include organic acid salts, inorganic acid salts, salts with organic bases, or salts with inorganic bases I can give you the salt of
  • organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; Polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate.
  • inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates.
  • salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine and ethylenediamine.
  • Salts with inorganic bases include, for example, ammonium salts; various salts such as salts with alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; and salts with metals such as aluminum. These salts may be used singly or in any combination of two or more.
  • “Pharmaceutically or physiologically acceptable salts” may include solvates or hydrates of salts.
  • the above reducing agent can be used as appropriate as long as it can reduce ribosylhomocysteine to produce the above compound.
  • the reducing agent include lithium borohydride, sodium borohydride, zinc borohydride, and the like. Among them, sodium borohydride can be mentioned as a suitable reducing agent.
  • the reducing agent can be appropriately used in the reduction step using a known method.
  • a solvent such as water
  • 0.01 to 1000 mol% of a reducing agent for example, at a temperature range of -10 ° C. to 30 ° C. , for example, 10 minutes to 48 hours.
  • the above compound can be produced, for example, according to the following reaction scheme.
  • a step of removing salts by electrodialysis or the like may be included.
  • compositions of the invention include the compounds described above. These compounds may be contained singly or in combination of two or more.
  • the content of the above compound is appropriately adjusted depending on the application of the composition, the type and content of other components, etc., and is not limited, but for example, 0.000001 with respect to the total amount of the composition. 0.000005% by mass or more, 0.00001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, 0.001% by mass or more etc. can be given. Further, the content of the above compound can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98% by mass or less, relative to the total amount of the composition.
  • the content of the compound is not limited, but can be, for example, 80% by mass or less with respect to the total amount of the composition, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, or 1% by mass or less.
  • the content of the compound is not limited, but can be, for example, 80% by mass or less with respect to the total amount of the composition, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc. .
  • composition can further contain L-ergothioneine (EGT).
  • EGT L-ergothioneine
  • EGT is a histidine derivative (N,N,N-trimethyl-L-2-thiohistidine), and its structure is represented by the following formula.
  • EGT can be obtained by known methods such as synthetic methods, extraction methods, and fermentation methods, and it is also possible to obtain and use commercially available products.
  • EGT products include, for example, Ergoneine (R) (manufactured by Tetraedron).
  • EGT may be in the form of a free form or in the form of a salt.
  • the salt of EGT may be a salt formed with a carboxyl group in these structures, or a salt formed with a trimethylamino group.
  • L-ergothioneine or L-ergothioneine analogues may be solvates such as hydrates.
  • the salt of EGT is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt.
  • Specific examples include organic acid salts, inorganic acid salts, salts with organic bases, or salts with inorganic bases I can give you the salt of
  • organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; Polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate.
  • inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates.
  • salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine and ethylenediamine.
  • Salts with inorganic bases include, for example, various salts such as salts with alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, and salts with metals such as aluminum. These salts may be used singly or in any combination of two or more.
  • “Pharmaceutically or physiologically acceptable salts” may include solvates or hydrates of salts.
  • the content of EGT is appropriately adjusted depending on the application of the composition, the type and content of other components, etc., and is not limited, but for example, 0.00% relative to the total amount of the composition.
  • 000001% by mass or more, 0.000005% by mass or more, 0.00001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, 0.001% by mass I can give you the above.
  • the content of EGT can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98.9% by mass or less, based on the total amount of the composition.
  • the content of EGT is not limited, but can be, for example, 80% by mass or less, and 70% by mass, relative to the total amount of the composition. % or less, 60 mass % or less, 50 mass % or less, 40 mass % or less, 30 mass % or less, 20 mass % or less, 10 mass % or less, 5 mass % or less, 1 mass % or less, and the like.
  • the daily intake (applied amount) is, for example, 0.005 to 4,000 mg, preferably 0.1 to 3,000 mg, or 0.1 to 3,000 mg. 5 to 2,000 mg, 1 to 1,000 mg, 2 to 500 mg, 5 to 30 mg, etc. can be used.
  • the pH of the composition of the present invention is appropriately set according to the type and content of other compounding ingredients, application, formulation form, method of use, etc., and is not limited as long as it is within a pharmaceutically or physiologically acceptable range.
  • the pH of the composition of the present invention is, for example, pH 2 to 10, pH 2 to 9, pH 2 to 8, pH 2 to 7, pH 3 to 10, pH 3 to 9, pH 3 to 8, pH 3-7, pH 4-10, pH 4-9, pH 4-8, pH 4-7, pH 5-10, pH 5-9, pH 5-8, pH 5-7, pH 6-10, pH 6-9, pH 6-8, It is possible to set the pH to 6 to 7 or the like.
  • composition of the present invention can further contain active ingredients and additives that can be used in foods and drinks, foods with function claims, foods for specified health uses, quasi-drugs, pharmaceuticals, cosmetics, daily necessities, feeds, etc., as appropriate. Also, it can be appropriately formulated by a known formulation method used for the item.
  • cosmetics and daily necessities include lotions, milky lotions, gels, serums, creams, sunscreen creams, packs, masks, foundations, powders, bath agents, body lotions, shampoos, rinses, hair treatments, hair conditioners, and hair styling products. , hair tonic, toothpaste, mouthwash, etc.
  • EGT when the composition contains EGT, EGT has physiological activities such as antioxidant, brain function improvement, anti-aging, eye disease, whitening, ultraviolet absorption, and suppression of melanin production. Eliminates reactive oxygen species, inhibits elastase activity, suppresses wrinkle formation, suppresses skin sagging, suppresses formation of dark spots on the skin, suppresses dark circles around the eyes, reduces skin damage caused by UV rays (suppresses photoaging) ), for dry skin, for sensitive skin, for improving hair, for promoting autophagy, and the like.
  • physiological activities such as antioxidant, brain function improvement, anti-aging, eye disease, whitening, ultraviolet absorption, and suppression of melanin production. Eliminates reactive oxygen species, inhibits elastase activity, suppresses wrinkle formation, suppresses skin sagging, suppresses formation of dark spots on the skin, suppresses dark circles around the eyes, reduces skin damage caused by UV rays (suppresses photoaging) ), for dry skin, for sensitive skin, for
  • the composition of the present invention includes, for example, solid formulations such as tablets, capsules, granules, and powders; It can also be administered orally or parenterally (including external use) as a liquid preparation such as a type emulsion, multiple emulsion, microemulsion, PET-emulsion, Pickering emulsion), gel (hydrogel, alcohol gel), suspension, etc. can.
  • a liquid preparation such as a type emulsion, multiple emulsion, microemulsion, PET-emulsion, Pickering emulsion), gel (hydrogel, alcohol gel), suspension, etc.
  • a liquid preparation such as a type emulsion, multiple emulsion, microemulsion, PET-emulsion, Pickering emulsion), gel (hydrogel, alcohol gel), suspension, etc.
  • a liquid preparation such as a type emulsion, multiple emulsion, microemulsion, PET-emulsion, Pickering emulsion), gel (hydr
  • excipients include sugar alcohols such as sorbitol, mannitol, and xylitol; sugars such as glucose, sucrose, lactose, and fructose; crystalline cellulose, carmellose sodium, croscarmellose sodium, calcium hydrogen phosphate; Starch, corn starch, potato starch, dextrin, ⁇ -cyclodextrin, light anhydrous silicic acid, titanium oxide, magnesium aluminometasilicate, talc, kaolin, olive oil and the like can be mentioned.
  • sugar alcohols such as sorbitol, mannitol, and xylitol
  • sugars such as glucose, sucrose, lactose, and fructose
  • crystalline cellulose carmellose sodium, croscarmellose sodium, calcium hydrogen phosphate
  • Binders include, for example, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, Examples include sodium alginate and propylene glycol alginate.
  • disintegrants include starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, and the like.
  • solvents examples include water, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like.
  • lubricants include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax, white beeswax, and the like.
  • solubilizing agents include polyethylene glycol, propylene glycol, mannitol, benzyl benzoate, ethanol, tris(hydroxymethyl)aminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • Suspending agents/emulsifiers include surfactants such as stearylamine, triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; , polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; hydrophilic polymers such as shellac wax, beeswax, carnauba wax, spermaceti wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin , lanolin wax, candelilla wax, Japanese wax, montan wax, rice wax and the like.
  • surfactants such as stearylamine, triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkon
  • isotonizing agents examples include sodium chloride, glycerin, D-mannitol, and the like.
  • buffering agents include buffers such as phosphate, acetate, carbonate, and citrate.
  • antiseptics examples include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidants examples include sulfites and ascorbic acid.
  • a manufacturing method known in the art can be used. For example, a method of kneading the composition and passing it through a screen to form extruded granules, pulverizing and sizing them, or adding kneading water to the composition and forming it with a vertical granulator by stirring granulation.
  • a method of pulverizing and sieving using a combill can be mentioned after the above.
  • pulverizing with a roll granulator and sieving can be mentioned after compressing the said pharmaceutical composition with a roller compactor.
  • a method of performing fluidized bed drying after stirring granulation can be mentioned.
  • the composition is produced by direct compression, the composition may be mixed and directly put into a tableting machine to be tableted.
  • the anti-inflammatory agent of the present invention contains the compounds described above. These compounds may be contained singly or in combination of two or more.
  • compositions include the above composition. These compositions may be contained singly or in combination of two or more.
  • the anti-inflammatory agent may be able to exert, for example, an anti-inflammatory action that leads to maintenance of retinal pigment epithelial cells.
  • the composition of the present invention can also be used as a food and drink composition, and can be provided by being contained in food or functional food.
  • foods or functional foods include cooked rice; various types of noodles including soba, udon, vermicelli, Chinese noodles, instant noodles, and cup noodles; soft drinks, carbonated drinks, nutritional drinks, fruit drinks, lactic acid drinks, and sports drinks.
  • Beverages such as curry roux, stew, various soups; Frozen desserts such as ice cream, ice sherbet, and shaved ice; Candies, cookies, candies, gums, chocolates, tablets, snacks, biscuits, jelly, jams, creams, and other baked goods
  • Processed fish and livestock foods such as fish paste, hampen, ham, sausage
  • Dairy products such as processed milk and fermented milk
  • Fats and oils such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressing Processed foods; seasonings such as sauces, dressings, miso, soy sauce, sauce; soups, stews, salads, side dishes, furikake, pickles; other various forms of health foods, dietary supplements, foods with function claims, foods for specified health uses, etc. are exemplified.
  • supplements powder, granule, soft capsule, hard capsule, tablet, chewable tablet, rapidly disintegrating tablet, syrup, liquid, etc.
  • composition of the present invention may be prepared.
  • composition of the present invention can also be contained in food for animals such as pets.
  • Additives are added to food and drink as needed.
  • additives include glucose, fructose, sucrose, maltose, sorbitol, trehalose, stevioside, rubusoside, corn syrup, lactose, mannitol, dextrin, citric acid, sodium citrate, tartaric acid, malic acid, succinic acid, Lactic acid, L-ascorbic acid, tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, vitamin B group, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, surfactants, pigments, fragrances, preservatives and the like can be mentioned.
  • composition of the present invention can be used for foods and drinks that are permitted to be labeled as improving, preventing, improving, etc. various symptoms and conditions.
  • food and drink that are permitted to display symptoms and conditions such as improvement, prevention, improvement, etc. are food and drinks that have efficacy permitted or designated by the country or public organizations.
  • These include foods with function claims, foods with health claims such as foods for specified health uses, and foods for special dietary uses.
  • the names and regulations change depending on the situation, the times, and the systems of each country, those that are essentially the same are included in the present invention.
  • the amount of the composition of the present invention is not particularly limited, and the purpose of application (type of target disease or symptom, etc.), target site for application, gender and age of the applicant, food and drink, food with function claims , foods for specified health uses, quasi-drugs, pharmaceuticals, cosmetics, daily necessities, feeds, and other product forms;
  • composition which further contains L-ergothioneine.
  • composition wherein the content of the compound is 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
  • composition wherein the content of the compound is 0.0001 parts by mass or more with respect to 100 parts by mass of the L-ergothioneine.
  • composition wherein the content of the compound is 0.0001 parts by mass or more and 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
  • An anti-inflammatory agent containing the above composition.
  • a compound as described above for use in suppressing inflammation is provided.
  • composition for use in suppressing inflammation.
  • a method for producing the above compound comprising a step of reacting ribosylhomocysteine with a reducing agent.
  • the reducing agent contains lithium borohydride, sodium borohydride, or zinc borohydride.
  • SRH ribosylhomocysteine
  • reaction solution was desalted using an electrodialyzer (manufactured by Astom) and then concentrated to prepare 10 mL of an aqueous SRH reductant solution (containing 108 mg of SRH reductant of 1.08% by qNMR).
  • HPLC analysis HPLC analysis was performed under the following conditions. Column: YMC-Pack ODS-AQ S-5 ⁇ M, 12 nm, 250 ⁇ 4.6 mm I.D. D. Flow rate: 0.5 mL/min, temperature: 30°C Detector: PDA (210 nm) Eluent: 0.1% formic acid aqueous solution Retention time: 6.2 minutes (SRH reductant), 6.6 minutes (SRH)
  • Example 2 Evaluation of anti-inflammatory effect
  • Human retinal pigment epithelial cell line ARPE-19 was seeded in a 6-well plate using 10% FBS-DMEM/F12 medium, and cultured for 48 hours in a carbon dioxide gas incubator under conditions of 5% CO 2 and 37°C. rice field.
  • the medium After confirming that it has reached confluence, the medium is replaced with fresh 10% FBS-DMEM/F12 medium (control group) or 10% FBS-DMEM/F12 medium containing 5 g/L of fructose (metabolic stress model group), Alternatively, the medium was changed to 10% FBS-DMEM/F12 medium containing SRH reductant (4 mM) and fructose 5 g/L (under metabolic stress, SRH reductant test group), and culture was continued.
  • IL-12p40 (Forward) 5′-aaggaggcgaggttctaagc-3′, (Reverse) 5′-aagagcctctgctgcttttg-3′
  • IL-1beta (Forward) 5′-gggcctcaaggaaaagaatc-3′, (Reverse) 5′-ttctgcttgagaggtgctga-3′
  • MMP-9 (Forward) 5′ ttgacagcgacaagaaagtgg-3′, (Reverse) 5′-gccattcacgtcgtcttat-3′
  • TNFalpha (Forward) 5′-tccttcagacacctcaacc-3′, (Reverse) 5′-cagggatcaaagctgtaggc-3′
  • TBP (Forward) 5′-tataatcccaagc
  • IL-1b and TNF increased due to high fructose load, and that an inflammatory reaction occurred.
  • a Th1-type reaction occurred from the increase in IL-12.
  • the system to which 4 mM of the SRH reductant was added showed an inhibitory effect on the above reaction.
  • the basement membrane is essential for the maintenance of retinal pigment epithelial cells, and the SRH reduced form was also effective in suppressing the increase in MMP-9, an enzyme that degrades the basement membrane. From the above, it was confirmed that the reduced SRH has an effect of suppressing inflammatory reactions and that it can contribute to the maintenance of retinal pigment epithelial cells.

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Abstract

Provided are a novel homocysteine derivative and a method for producing the same, a composition comprising the compound, and an anti-inflammatory agent comprising the compound and/or the composition.　A compound represented by formula 1.

Description

ホモシステイン誘導体及びその製造方法、組成物、並びに、炎症抑制剤HOMOCYSTEINE DERIVATIVE, METHOD FOR PRODUCING THEREOF, COMPOSITION, AND INFLAMMATION SUPPRESSOR
　本発明は、ホモシステイン誘導体及びその製造方法、それを含む組成物、並びに、それらを含む炎症抑制剤に関する。 The present invention relates to homocysteine derivatives, methods for producing them, compositions containing them, and anti-inflammatory agents containing them.
　炎症抑制作用を有する組成物として、これまでに、例えば、ＭＭＰ－９産生抑制効果を有する化粧料等が知られている（例えば、特許文献１、２参照）。 As a composition having an anti-inflammatory action, for example, cosmetics having an effect of suppressing MMP-9 production have been known so far (see Patent Documents 1 and 2, for example).
　しかしながら、炎症抑制作用が求められる用途や使用対象等は多岐にわたり、新たな炎症抑制剤の開発が求められている。 However, there is a wide variety of applications and targets for which anti-inflammatory effects are required, and the development of new anti-inflammatory agents is required.
特開２００５－２９８３９１号公報JP 2005-298391 A 特開２０１５－２４９８５号公報JP 2015-24985 A
　本発明は、このような事情に照らし、新規なホモシステイン誘導体及びその製造方法、当該化合物を含む組成物、並びに、それらを含む炎症抑制剤等を提供することを目的とする。 In view of such circumstances, the present invention aims to provide a novel homocysteine derivative, a method for producing the same, a composition containing the compound, an anti-inflammatory agent containing them, and the like.
　本発明者らは、上記課題を解決するため鋭意検討した結果、以下に示す新規ホモシステイン誘導体の創製に成功し、上記化合物により上記目的を達成できることを見出して、本発明を完成するに至った。 The inventors of the present invention have made intensive studies to solve the above problems, and as a result, have succeeded in creating the novel homocysteine derivatives shown below, and found that the above objects can be achieved by the above compounds, thereby completing the present invention. .
　すなわち、本発明は、下記に掲げる化合物を提供する。 That is, the present invention provides the compounds listed below.
　項１．
　下記式１で表される化合物。
Figure JPOXMLDOC01-appb-C000004
 Section 1.
A compound represented by the following formula 1.
Figure JPOXMLDOC01-appb-C000004
　項２．
　下記式２で表される、項１に記載の化合物。
Figure JPOXMLDOC01-appb-C000005
 Section 2.
Item 1. The compound according to item 1, represented by the following formula 2.
Figure JPOXMLDOC01-appb-C000005
　項３．
　下記式３で表される、項１又は２に記載の化合物。
Figure JPOXMLDOC01-appb-C000006
 Item 3.
3. The compound according to item 1 or 2, represented by the following formula 3.
Figure JPOXMLDOC01-appb-C000006
　また、本発明は、下記に掲げる組成物を提供する。 In addition, the present invention provides the compositions listed below.
　項４．
　項１～３のいずれか１項に記載の化合物を含む、組成物。 Section 4.
A composition comprising the compound of any one of Items 1-3.
　項５．
　さらにＬ－エルゴチオネイン（以下、「ＥＧＴ」ともいう）を含む、項４に記載の組成物。 Item 5.
Item 5. The composition according to item 4, further comprising L-ergothioneine (hereinafter also referred to as "EGT").
　項６．
　上記Ｌ－エルゴチオネイン１００質量部に対して、上記化合物の含有量が、５０質量部以下である、項５に記載の組成物。 Item 6.
Item 6. The composition according to item 5, wherein the content of the compound is 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
　項７．
　上記Ｌ－エルゴチオネイン１００質量部に対して、上記化合物の含有量が、０．０００１質量部以上である、項５又は６に記載の組成物。 Item 7.
Item 7. The composition according to item 5 or 6, wherein the content of the compound is 0.0001 parts by mass or more relative to 100 parts by mass of the L-ergothioneine.
　また、本発明は、下記に掲げる炎症抑制剤に関する。 In addition, the present invention relates to the following anti-inflammatory agents.
　項８．
　項１～３のいずれか１項に記載の化合物を含む、炎症抑制剤。 Item 8.
Item 4. An anti-inflammatory agent comprising the compound according to any one of items 1 to 3.
　項９．
　項４～７のいずれか１項に記載の組成物を含む、炎症抑制剤。 Item 9.
Item 8. An anti-inflammatory agent comprising the composition according to any one of Items 4 to 7.
　また、本発明は、下記に掲げる製造方法に関する。 In addition, the present invention relates to the manufacturing method listed below.
　項１０．
　リボシルホモシステイン（以下、「ＳＲＨ」ともいう。）と還元剤とを反応させる工程を含む、項１～３のいずれか１項に記載の化合物の製造方法。 Item 10.
Item 4. A method for producing the compound according to any one of items 1 to 3, comprising a step of reacting ribosylhomocysteine (hereinafter also referred to as "SRH") with a reducing agent.
　項１１．
　上記還元剤は、水素化ホウ素リチウム、水素化ホウ素ナトリウム、又は水素化ホウ素亜鉛を含む、項１０に記載の製造方法。 Item 11.
Item 11. The production method according to Item 10, wherein the reducing agent includes lithium borohydride, sodium borohydride, or zinc borohydride.
　本発明の化合物ないしそれを含む組成物は、例えば、炎症抑制剤として好適に用いることができる。 The compound of the present invention or a composition containing it can be suitably used, for example, as an anti-inflammatory agent.
　また、本発明の化合物の製造方法を用いることにより、上記化合物ないし上記組成物を簡便に得ることができる。 Also, by using the method for producing the compound of the present invention, the compound or the composition can be easily obtained.
　また、本発明の炎症抑制剤は、例えば、網膜色素上皮細胞の維持につながる炎症抑制作用を奏することができ得る。 In addition, the anti-inflammatory agent of the present invention can exhibit, for example, an anti-inflammatory effect leading to maintenance of retinal pigment epithelial cells.
図１は、実施例２における炎症抑制作用の評価結果を示すグラフである。FIG. 1 is a graph showing evaluation results of anti-inflammatory action in Example 2. FIG.
　以下、本発明の実施の形態について詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
　〔化合物〕
　本発明のホモシステイン誘導体は、下記式１で表される化合物である。
Figure JPOXMLDOC01-appb-C000007
 〔Compound〕
The homocysteine derivative of the present invention is a compound represented by Formula 1 below.
Figure JPOXMLDOC01-appb-C000007
　また、上記ホモシステイン誘導体は、例えば、下記式２で表される化合物である。
Figure JPOXMLDOC01-appb-C000008
 Further, the homocysteine derivative is, for example, a compound represented by Formula 2 below.
Figure JPOXMLDOC01-appb-C000008
　また、上記ホモシステイン誘導体は、例えば、下記式３で表される化合物である。
Figure JPOXMLDOC01-appb-C000009
 Further, the homocysteine derivative is, for example, a compound represented by Formula 3 below.
Figure JPOXMLDOC01-appb-C000009
　上記ホモシステイン誘導体は、適宜、当該構造の一部又は全部が置換された置換体、水和物等の溶媒和物などの誘導体も含む。 The above homocysteine derivatives also include derivatives such as solvates such as hydrates and substituted products in which part or all of the structure is substituted as appropriate.
　上記ホモシステイン誘導体において、一部又は全部の水酸基は、例えば、アルキルエーテル基、アリールエーテル基、又はエステル基に適宜置換されていてもよい。 In the above homocysteine derivative, some or all of the hydroxyl groups may be appropriately substituted with, for example, an alkyl ether group, an aryl ether group, or an ester group.
　また、上記ホモシステイン誘導体において、カルボキシル基は、エステル基、アミド基、酸無水物、又は塩等に適宜置換されていてもよい。 In addition, in the above homocysteine derivative, the carboxyl group may be appropriately substituted with an ester group, an amide group, an acid anhydride, a salt, or the like.
　また、上記ホモシステイン誘導体において、アミノ基は、アルキル化体、アミド基、又は塩等に適宜置換されていてもよい。 In addition, in the above homocysteine derivative, the amino group may be appropriately substituted with an alkylated product, an amide group, a salt, or the like.
　また、上記ホモシステイン誘導体において、スルフィド基は、アルキル化体の塩、スルホキシド、又はスルホン体に適宜置換されていてもよい。 In addition, in the above homocysteine derivative, the sulfide group may be appropriately substituted with an alkylated salt, sulfoxide, or sulfone.
　〔化合物の製造方法〕
　上記ホモシステイン誘導体は、公知の手法を適宜用いて製造することができるが、リボシルホモシステイン等を還元する工程を含む製造方法を用いることが好ましい。 [Method for producing compound]
The above homocysteine derivative can be produced by appropriately using a known technique, but it is preferable to use a production method including a step of reducing ribosylhomocysteine and the like.
　例えば、本発明の化合物の製造方法は、リボシルホモシステインと還元剤とを反応させる工程を含むことが好ましい。 For example, the method for producing the compound of the present invention preferably includes a step of reacting ribosylhomocysteine with a reducing agent.
　リボシルホモシステイン（ＳＲＨ）は、ホモシステイン（２－アミノ－４－スルファニルブタン酸）がＳ－リボシル化されたホモシステイン誘導体であり、その構造は下記式で表される。 Ribosylhomocysteine (SRH) is a homocysteine derivative in which homocysteine (2-amino-4-sulfanylbutanoic acid) is S-ribosylated, and its structure is represented by the following formula.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　ＳＲＨは、合成法、抽出法、発酵法等の公知の方法により得ることが可能である。 SRH can be obtained by known methods such as synthesis, extraction, and fermentation.
　ＳＲＨは、遊離体の形態であってもよく、塩の形態であってもよい。ＳＲＨの塩は、これらの構造におけるカルボキシル基で形成された塩であってもよいし、アミノ基、で形成された塩であってもよい。また、リボシルホモシステイン又はリボシルホモシステイン類縁体は水和物等の溶媒和物であってもよい。 SRH may be in the form of a free form or in the form of a salt. The salt of SRH may be a salt formed with a carboxyl group or a salt formed with an amino group in these structures. Ribosylhomocysteine or ribosylhomocysteine analogues may also be solvates such as hydrates.
　ＳＲＨの塩としては、薬理学的に又は生理学的に許容される塩であれば、特に制限されないが、具体的には、有機酸塩、無機酸塩、有機塩基との塩、又は無機塩基との塩をあげることができる。有機酸塩としては、例えば、酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等のモノカルボン酸塩；フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等の多価カルボン酸塩；乳酸塩、酒石酸塩、クエン酸塩等のオキシカルボン酸塩；メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩等の有機スルホン酸塩が例示される。無機酸塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩が例示される。有機塩基との塩としては、例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、ジエタノールアミン、モルホリン、ピペラジン、ピロリジン、エチレンジアミン等の有機アミンとの塩をあげることができる。無機塩基との塩としては、例えば、アンモニウム塩；ナトリウム又はカリウム等のアルカリ金属、カルシウム又はマグネシウム等のアルカリ土類金属、アルミニウム等の金属との塩等の各種の塩をあげることができる。これらの塩は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。「薬学的に又は生理学的に許容される塩」には、塩の溶媒和物又は水和物を含んでいてもよい。 The salt of SRH is not particularly limited as long as it is pharmacologically or physiologically acceptable. Specific examples include organic acid salts, inorganic acid salts, salts with organic bases, or salts with inorganic bases I can give you the salt of Examples of organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; Polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate. Examples of inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates. Examples of salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine and ethylenediamine. Salts with inorganic bases include, for example, ammonium salts; various salts such as salts with alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; and salts with metals such as aluminum. These salts may be used singly or in any combination of two or more. "Pharmaceutically or physiologically acceptable salts" may include solvates or hydrates of salts.
　上記還元剤は、リボシルホモシステインを還元して上記化合物を製造できるものであれば、適宜用いることができる。上記還元剤としては、例えば、水素化ホウ素リチウム、水素化ホウ素ナトリウム、又は水素化ホウ素亜鉛等を含むことができる。なかでも、水素化ホウ素ナトリウムが好適な還元剤としてあげることができる。 The above reducing agent can be used as appropriate as long as it can reduce ribosylhomocysteine to produce the above compound. Examples of the reducing agent include lithium borohydride, sodium borohydride, zinc borohydride, and the like. Among them, sodium borohydride can be mentioned as a suitable reducing agent.
　上記還元剤は、適宜、公知の手法を用いて還元工程に用いることができる。例えば、水等の溶媒に溶解又は分散させたリボシルホモシステインに対して、例えば、０.０１～１０００ｍｏｌ％の還元剤を存在させた系中で、例えば、－１０℃～３０℃の温度域で、例えば、１０分～４８時間反応させることができる。 The reducing agent can be appropriately used in the reduction step using a known method. For example, with respect to ribosylhomocysteine dissolved or dispersed in a solvent such as water, for example, in a system in which 0.01 to 1000 mol% of a reducing agent is present, for example, at a temperature range of -10 ° C. to 30 ° C. , for example, 10 minutes to 48 hours.
　上記化合物は、例えば、下記の反応式のように製造することができる。
Figure JPOXMLDOC01-appb-C000011
 The above compound can be produced, for example, according to the following reaction scheme.
Figure JPOXMLDOC01-appb-C000011
　また、上記反応後に、電気透析等で塩を除く工程を含んでもよい。 In addition, after the above reaction, a step of removing salts by electrodialysis or the like may be included.
　〔組成物〕
　本発明の組成物は、上記化合物を含む。これらの化合物は単独で含んでいてもよく、また２種以上を含んでいてもよい。 〔Composition〕
The compositions of the invention include the compounds described above. These compounds may be contained singly or in combination of two or more.
　本発明の組成物において、上記化合物の含有量は、組成物の用途、他の成分の種類や含有量等により適宜調整され、限定はされないが、例えば、組成物全量に対して、０．０００００１質量％以上とすることができ、０．０００００５質量％以上、０．００００１質量％以上、０．００００５質量％以上、０．０００１質量％以上、０．０００５質量％以上、０．００１質量％以上等をあげることができる。また、上記化合物の含有量は、例えば、組成物全量に対して、９９．９９９質量％以下とすることができ、９９．９質量％以下、９９．５質量％以下、９９質量％以下、９８．５質量％以下、９８質量％以下、８０質量％以下とすることができ、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、１０質量％以下、５質量％以下、１質量％以下等をあげることができる。別の実施態様において、例えば、液状組成物や液状製剤として調製される場合、限定はされないが、化合物の含有量は、例えば、組成物全量に対して、８０質量％以下とすることができ、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、１０質量％以下、５質量％以下、１質量％以下等をあげることができる。 In the composition of the present invention, the content of the above compound is appropriately adjusted depending on the application of the composition, the type and content of other components, etc., and is not limited, but for example, 0.000001 with respect to the total amount of the composition. 0.000005% by mass or more, 0.00001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, 0.001% by mass or more etc. can be given. Further, the content of the above compound can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98% by mass or less, relative to the total amount of the composition. .5% by mass or less, 98% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less , 10% by mass or less, 5% by mass or less, or 1% by mass or less. In another embodiment, for example, when prepared as a liquid composition or liquid preparation, the content of the compound is not limited, but can be, for example, 80% by mass or less with respect to the total amount of the composition, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, etc. .
　また、上記組成物は、さらにＬ－エルゴチオネイン（ＥＧＴ）を含むことができる。 In addition, the composition can further contain L-ergothioneine (EGT).
　ＥＧＴは、ヒスチジン誘導体（Ｎ，Ｎ，Ｎ－トリメチル－Ｌ－２－チオヒスチジン）であり、その構造は下記式で表される。 EGT is a histidine derivative (N,N,N-trimethyl-L-2-thiohistidine), and its structure is represented by the following formula.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　ＥＧＴは、合成法、抽出法、発酵法等の公知の方法により得ることも可能であり、市販品を入手して用いることも可能である。 EGT can be obtained by known methods such as synthetic methods, extraction methods, and fermentation methods, and it is also possible to obtain and use commercially available products.
　ＥＧＴの市販品としては、例えば、エルゴネイン(R)（テトラエドロン社製）等をあげることができる。 Commercially available EGT products include, for example, Ergoneine (R) (manufactured by Tetraedron).
　ＥＧＴは、遊離体の形態であってもよく、塩の形態であってもよい。ＥＧＴの塩は、これらの構造におけるカルボキシル基で形成された塩であってもよいし、トリメチルアミノ基で形成された塩であってもよい。また、Ｌ－エルゴチオネイン又はＬ－エルゴチオネイン類縁体は水和物等の溶媒和物であってもよい。 EGT may be in the form of a free form or in the form of a salt. The salt of EGT may be a salt formed with a carboxyl group in these structures, or a salt formed with a trimethylamino group. In addition, L-ergothioneine or L-ergothioneine analogues may be solvates such as hydrates.
　ＥＧＴの塩としては、薬理学的に又は生理学的に許容される塩であれば、特に制限されないが、具体的には、有機酸塩、無機酸塩、有機塩基との塩、又は無機塩基との塩をあげることができる。有機酸塩としては、例えば、酢酸塩、トリフルオロ酢酸塩、酪酸塩、パルミチン酸塩、ステアリン酸塩等のモノカルボン酸塩；フマル酸塩、マレイン酸塩、コハク酸塩、マロン酸塩等の多価カルボン酸塩；乳酸塩、酒石酸塩、クエン酸塩等のオキシカルボン酸塩；メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩等の有機スルホン酸塩が例示される。無機酸塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩が例示される。有機塩基との塩としては、例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、ジエタノールアミン、モルホリン、ピペラジン、ピロリジン、エチレンジアミン等の有機アミンとの塩をあげることができる。無機塩基との塩としては、例えば、；ナトリウム又はカリウム等のアルカリ金属、カルシウム又はマグネシウム等のアルカリ土類金属、アルミニウム等の金属との塩等の各種の塩をあげることができる。これらの塩は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。「薬学的に又は生理学的に許容される塩」には、塩の溶媒和物又は水和物を含んでいてもよい。 The salt of EGT is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt. Specific examples include organic acid salts, inorganic acid salts, salts with organic bases, or salts with inorganic bases I can give you the salt of Examples of organic acid salts include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; Polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate. Examples of inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates. Examples of salts with organic bases include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine and ethylenediamine. Salts with inorganic bases include, for example, various salts such as salts with alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, and salts with metals such as aluminum. These salts may be used singly or in any combination of two or more. "Pharmaceutically or physiologically acceptable salts" may include solvates or hydrates of salts.
　また、本発明の組成物において、ＥＧＴの含有量は、組成物の用途、他の成分の種類や含有量等により適宜調整され、限定はされないが、例えば、組成物全量に対して、０．０００００１質量％以上とすることができ、０．０００００５質量％以上、０．００００１質量％以上、０．００００５質量％以上、０．０００１質量％以上、０．０００５質量％以上、０．００１質量％以上等をあげることができる。また、ＥＧＴの含有量は、例えば、組成物全量に対して、９９．９９９質量％以下とすることができ、９９．９質量％以下、９９．５質量％以下、９９質量％以下、９８．５質量％以下、９８質量％以下等をあげることができる。別の実施態様において、液状組成物や液状製剤として調製される場合、限定はされないが、ＥＧＴの含有量は、例えば、組成物全量に対して、８０質量％以下とすることができ、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、１０質量％以下、５質量％以下、１質量％以下等をあげることができる。 In addition, in the composition of the present invention, the content of EGT is appropriately adjusted depending on the application of the composition, the type and content of other components, etc., and is not limited, but for example, 0.00% relative to the total amount of the composition. 000001% by mass or more, 0.000005% by mass or more, 0.00001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, 0.001% by mass I can give you the above. In addition, the content of EGT can be, for example, 99.999% by mass or less, 99.9% by mass or less, 99.5% by mass or less, 99% by mass or less, 98.9% by mass or less, based on the total amount of the composition. 5 mass % or less, 98 mass % or less, etc. can be mentioned. In another embodiment, when prepared as a liquid composition or liquid preparation, the content of EGT is not limited, but can be, for example, 80% by mass or less, and 70% by mass, relative to the total amount of the composition. % or less, 60 mass % or less, 50 mass % or less, 40 mass % or less, 30 mass % or less, 20 mass % or less, 10 mass % or less, 5 mass % or less, 1 mass % or less, and the like.
　ＥＧＴが含まれる組成物を使用する場合には、ＥＧＴが本来有する生理活性を発揮できる有効量を１日当たりの摂取量（適用量）とすることが可能である。例えば、健常の成人が摂取（適用）する場合、ＥＧＴの１日当たりの摂取量（適用量）は、例えば、０．００５～４，０００ｍｇ、好ましくは０．１～３，０００ｍｇ、又は、０．５～２，０００ｍｇ、１～１，０００ｍｇ、２～５００ｍｇ、５～３０ｍｇ等で使用することができる。 When using a composition containing EGT, it is possible to set the daily intake (applied amount) as an effective amount that allows EGT to exert its intrinsic physiological activity. For example, when ingested (applied) by healthy adults, the daily intake (applied amount) of EGT is, for example, 0.005 to 4,000 mg, preferably 0.1 to 3,000 mg, or 0.1 to 3,000 mg. 5 to 2,000 mg, 1 to 1,000 mg, 2 to 500 mg, 5 to 30 mg, etc. can be used.
　また、本発明の組成物のｐＨは、他の配合成分の種類及び含有量、用途、製剤形態、使用方法等に応じて適宜設定され、薬学的又は生理学的に許容できる範囲であれば制限されないが、例えば、ｐＨ２～１０とすることができる。本発明の効果を安定的に発揮する観点から、本発明の組成物のｐＨは、例えば、ｐＨ２～１０、ｐＨ２～９、ｐＨ２～８、ｐＨ２～７、ｐＨ３～１０、ｐＨ３～９、ｐＨ３～８、ｐＨ３～７、ｐＨ４～１０、ｐＨ４～９、ｐＨ４～８、ｐＨ４～７、ｐＨ５～１０、ｐＨ５～９、ｐＨ５～８、ｐＨ５～７、ｐＨ６～１０、ｐＨ６～９、ｐＨ６～８、ｐＨ６～７等とすることが可能である。 In addition, the pH of the composition of the present invention is appropriately set according to the type and content of other compounding ingredients, application, formulation form, method of use, etc., and is not limited as long as it is within a pharmaceutically or physiologically acceptable range. can be, for example, pH 2-10. From the viewpoint of stably exhibiting the effect of the present invention, the pH of the composition of the present invention is, for example, pH 2 to 10, pH 2 to 9, pH 2 to 8, pH 2 to 7, pH 3 to 10, pH 3 to 9, pH 3 to 8, pH 3-7, pH 4-10, pH 4-9, pH 4-8, pH 4-7, pH 5-10, pH 5-9, pH 5-8, pH 5-7, pH 6-10, pH 6-9, pH 6-8, It is possible to set the pH to 6 to 7 or the like.
　〔用途〕
　本発明の組成物は、さらに飲食品、機能性表示食品、特定保健用食品、医薬部外品、医薬品、化粧品、日用品、飼料等に使用可能な有効成分や添加剤を適宜配合することができ、また、当該品目で使用される公知の製剤化方法により、適宜製剤化することができる。 [Use]
The composition of the present invention can further contain active ingredients and additives that can be used in foods and drinks, foods with function claims, foods for specified health uses, quasi-drugs, pharmaceuticals, cosmetics, daily necessities, feeds, etc., as appropriate. Also, it can be appropriately formulated by a known formulation method used for the item.
　化粧品や日用品としては、例えば、化粧水、乳液、ジェル、美容液、クリーム、日焼け止めクリーム、パック、マスク、ファンデーション、おしろい、浴用剤、ボディローション、シャンプー、リンス、ヘアトリートメント、ヘアコンディショナー、整髪料、ヘアトニック、歯磨き粉、マウスウォッシュ等に製剤化することが可能である。 Examples of cosmetics and daily necessities include lotions, milky lotions, gels, serums, creams, sunscreen creams, packs, masks, foundations, powders, bath agents, body lotions, shampoos, rinses, hair treatments, hair conditioners, and hair styling products. , hair tonic, toothpaste, mouthwash, etc.
　また、例えば、上記組成物がＥＧＴを含有する場合、ＥＧＴが本来有する生理活性である、抗酸化用、脳機能改善用、抗老化用、眼疾患用、美白用、紫外線吸収用、メラニン産生抑制用、活性酸素種の消去用、エラスターゼ活性阻害用、シワ形成抑制用、肌のたるみ抑制用、肌のシミの形成抑制用、眼周囲のクマ抑制用、紫外線による肌ダメージ軽減（光老化の抑制）用、乾燥肌用、敏感肌用、毛髪改善用、オートファジー促進用等に好適に用いることが可能となる。 Further, for example, when the composition contains EGT, EGT has physiological activities such as antioxidant, brain function improvement, anti-aging, eye disease, whitening, ultraviolet absorption, and suppression of melanin production. Eliminates reactive oxygen species, inhibits elastase activity, suppresses wrinkle formation, suppresses skin sagging, suppresses formation of dark spots on the skin, suppresses dark circles around the eyes, reduces skin damage caused by UV rays (suppresses photoaging) ), for dry skin, for sensitive skin, for improving hair, for promoting autophagy, and the like.
　〔製剤〕
　本発明の組成物は、例えば、錠剤、カプセル剤、顆粒剤、散剤等の固形製剤；又は液剤、シロップ剤、注射剤、クリーム、ローション、ペースト、軟膏、エマルジョン（水中油型エマルジョン、油中水型エマルジョン、多重エマルジョン、ミクロエマルジョン、ＰＥＴ－エマルジョン、ピッカリング・エマルジョン）、ゲル（ヒドロゲル、アルコールゲル）、懸濁液等の液状製剤として経口又は非経口的（外用を含む）に投与することもできる。固形製剤には、賦形剤、滑沢剤、結合剤、崩壊剤；液状製剤には、溶剤、溶解補助剤、乳化剤、乳化安定剤、増粘剤、保湿剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等を用いることができる。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤、香料等の添加物を用いることもできる。 〔pharmaceutical formulation〕
The composition of the present invention includes, for example, solid formulations such as tablets, capsules, granules, and powders; It can also be administered orally or parenterally (including external use) as a liquid preparation such as a type emulsion, multiple emulsion, microemulsion, PET-emulsion, Pickering emulsion), gel (hydrogel, alcohol gel), suspension, etc. can. For solid preparations, excipients, lubricants, binders, and disintegrants; Agents, buffers, soothing agents and the like can be used. Additives such as preservatives, antioxidants, coloring agents, sweetening agents, and flavoring agents can also be used as necessary.
　賦形剤としては、例えば、ソルビトール、マンニトール、キシリトール等の糖アルコール、ブドウ糖、白糖、乳糖、果糖等の糖類、結晶セルロース、カルメロースナトリウム、クロスカルメロースナトリウム、リン酸水素カルシウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、デキストリン、β－シクロデキストリン、軽質無水ケイ酸、酸化チタン、メタケイ酸アルミン酸マグネシウム、タルク、カオリン、オリーブ油等をあげることができる。 Examples of excipients include sugar alcohols such as sorbitol, mannitol, and xylitol; sugars such as glucose, sucrose, lactose, and fructose; crystalline cellulose, carmellose sodium, croscarmellose sodium, calcium hydrogen phosphate; Starch, corn starch, potato starch, dextrin, β-cyclodextrin, light anhydrous silicic acid, titanium oxide, magnesium aluminometasilicate, talc, kaolin, olive oil and the like can be mentioned.
　結合剤としては、例えば、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等のセルロース誘導体、ポリビニルピロリドン、ポリビニルアルコール、アクリル酸系高分子、ゼラチン、アラビアガム、プルラン、アルファー化デンプン、カンテン、トラガント、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル等をあげることができる。 Binders include, for example, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, Examples include sodium alginate and propylene glycol alginate.
　崩壊剤としては、例えば、デンプン、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、ヒドロキシプロピルスターチ、部分アルファー化デンプン等をあげることができる。 Examples of disintegrants include starch, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, and the like.
　溶剤としては、例えば、水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油等をあげることができる。 Examples of solvents include water, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like.
　滑沢剤としては、例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸ポリオキシル、セタノール、タルク、硬化油、ショ糖脂肪酸エステル、ジメチルポリシロキサン、ミツロウ、サラシミツロウ等をあげることができる。 Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax, white beeswax, and the like.
　溶解補助剤としては、例えば、ポリエチレングリコール、プロピレングリコール、マンニトール、安息香酸ベンジル、エタノール、トリス（ヒドロキシメチル）アミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等をあげることができる。 Examples of solubilizing agents include polyethylene glycol, propylene glycol, mannitol, benzyl benzoate, ethanol, tris(hydroxymethyl)aminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
　懸濁化剤・乳化剤としては、例えば、ステアリルアミン、トリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤；例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子；例えばシェラックロウ、ミツロウ、カルナバロウ、鯨ロウ、ラノリン、液状ラノリン、還元ラノリン、硬質ラノリン、環状ラノリン、ラノリンワックス、キャンデリラロウ、モクロウ、モンタンロウ、ライスワックス等ワックス類等をあげることができる。 Suspending agents/emulsifiers include surfactants such as stearylamine, triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; , polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; hydrophilic polymers such as shellac wax, beeswax, carnauba wax, spermaceti wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin , lanolin wax, candelilla wax, Japanese wax, montan wax, rice wax and the like.
　等張化剤としては、例えば、塩化ナトリウム、グリセリン、Ｄ－マンニトール等をあげることができる。 Examples of isotonizing agents include sodium chloride, glycerin, D-mannitol, and the like.
　緩衝剤としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等をあげることができる。 Examples of buffering agents include buffers such as phosphate, acetate, carbonate, and citrate.
　防腐剤としては、例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等をあげることができる。 Examples of antiseptics include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
　抗酸化剤としては、例えば、亜硫酸塩、アスコルビン酸等をあげることができる。 Examples of antioxidants include sulfites and ascorbic acid.
　本発明の組成物を固形製剤とする場合、当該分野で公知の製造方法を用いることができる。例えば、組成物を練合し、スクリーンを通過させることで成型する押出造粒物を、粉砕し、整粒する方法、上記組成物に練合水を加え、バーチカルグラニュレーターによって成型する攪拌造粒の後に、コーミルを用いて粉砕・篩過する方法をあげることができる。また、上記製剤組成物をローラーコンパクターで圧縮した後、ロールグラニュレーターで粉砕し篩過する方法をあげることができる。また、撹拌造粒の後に、流動層乾燥する方法をあげることができる。また、例えば、直打により製造する場合には、組成物を混合した後、直接、打錠機に投入して打錠すればよい。 When the composition of the present invention is made into a solid formulation, a manufacturing method known in the art can be used. For example, a method of kneading the composition and passing it through a screen to form extruded granules, pulverizing and sizing them, or adding kneading water to the composition and forming it with a vertical granulator by stirring granulation. A method of pulverizing and sieving using a combill can be mentioned after the above. Moreover, after compressing the said pharmaceutical composition with a roller compactor, the method of grind|pulverizing with a roll granulator and sieving can be mentioned. Further, a method of performing fluidized bed drying after stirring granulation can be mentioned. Alternatively, for example, when the composition is produced by direct compression, the composition may be mixed and directly put into a tableting machine to be tableted.
　〔炎症抑制剤〕
　本発明の炎症抑制剤は、上記化合物を含む。これらの化合物は単独で含んでいてもよく、また２種以上を含んでいてもよい。 [Inflammatory inhibitor]
The anti-inflammatory agent of the present invention contains the compounds described above. These compounds may be contained singly or in combination of two or more.
　また、本発明の他の炎症抑制剤は、上記組成物を含む。これらの組成物は単独で含んでいてもよく、また２種以上を含んでいてもよい。 In addition, another anti-inflammatory agent of the present invention includes the above composition. These compositions may be contained singly or in combination of two or more.
　上記炎症抑制剤は、例えば、網膜色素上皮細胞の維持につながる炎症抑制作用等を奏することができ得る。 The anti-inflammatory agent may be able to exert, for example, an anti-inflammatory action that leads to maintenance of retinal pigment epithelial cells.
　〔飲食品〕
　本発明の組成物は、飲食品組成物としても使用することができ、食品又は機能性食品に含有させて提供され得る。このような食品又は機能性食品としては、米飯；そば、うどん、はるさめ、中華麺、即席麺、カップ麺を含む各種の麺類；清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳酸飲料、スポーツ飲料等の飲料；カレールー、シチュー、各種スープ類；アイスクリーム、アイスシャーベット、かき氷等の冷菓；飴、クッキー、キャンディー、ガム、チョコレート、錠菓、スナック菓子、ビスケット、ゼリー、ジャム、クリーム、その他の焼き菓子等の菓子類；かまぼこ、はんぺん、ハム、ソーセージ等の水産・畜産加工食品；加工乳、発酵乳等の乳製品；サラダ油、てんぷら油、マーガリン、マヨネーズ、ショートニング、ホイップクリーム、ドレッシング等の油脂及び油脂加工食品；ソース、ドレッシング、味噌、醤油、たれ等の調味料；スープ、シチュー、サラダ、惣菜、ふりかけ、漬物；その他種々の形態の健康・栄養補助食品・機能性表示食品・特定保健用食品等が例示される。 [Food and drink]
The composition of the present invention can also be used as a food and drink composition, and can be provided by being contained in food or functional food. Examples of such foods or functional foods include cooked rice; various types of noodles including soba, udon, vermicelli, Chinese noodles, instant noodles, and cup noodles; soft drinks, carbonated drinks, nutritional drinks, fruit drinks, lactic acid drinks, and sports drinks. Beverages such as curry roux, stew, various soups; Frozen desserts such as ice cream, ice sherbet, and shaved ice; Candies, cookies, candies, gums, chocolates, tablets, snacks, biscuits, jelly, jams, creams, and other baked goods Processed fish and livestock foods such as fish paste, hampen, ham, sausage; Dairy products such as processed milk and fermented milk; Fats and oils such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressing Processed foods; seasonings such as sauces, dressings, miso, soy sauce, sauce; soups, stews, salads, side dishes, furikake, pickles; other various forms of health foods, dietary supplements, foods with function claims, foods for specified health uses, etc. are exemplified.
　また、本発明の組成物を含有するサプリメント（散剤、顆粒剤、ソフトカプセル、ハードカプセル、錠剤、チュアブル錠、速崩錠、シロップ、液剤等）を調製してもよい。 Also, supplements (powder, granule, soft capsule, hard capsule, tablet, chewable tablet, rapidly disintegrating tablet, syrup, liquid, etc.) containing the composition of the present invention may be prepared.
　また、ペット等の動物用の餌に対して本発明の組成物を含有させることもできる。 The composition of the present invention can also be contained in food for animals such as pets.
　飲食品には、必要に応じて、添加物が加えられる。このような添加物としては、例えばブドウ糖、果糖、ショ糖、マルトース、ソルビトール、トレハロース、ステビオサイド、ルブソサイド、コーンシロップ、乳糖、マンニトール、デキストリン、クエン酸、クエン酸ナトリウム、酒石酸、リンゴ酸、コハク酸、乳酸、Ｌ－アスコルビン酸、トコフェロール、エリソルビン酸ナトリウム、グリセリン、プロピレングリコール、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、アラビアガム、カラギーナン、カゼイン、ゼラチン、ペクチン、寒天、ビタミンＢ類、ニコチン酸アミド、パントテン酸カルシウム、アミノ酸類、カルシウム塩類、界面活性剤、色素、香料、保存剤等をあげることができる。 Additives are added to food and drink as needed. Examples of such additives include glucose, fructose, sucrose, maltose, sorbitol, trehalose, stevioside, rubusoside, corn syrup, lactose, mannitol, dextrin, citric acid, sodium citrate, tartaric acid, malic acid, succinic acid, Lactic acid, L-ascorbic acid, tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, vitamin B group, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, surfactants, pigments, fragrances, preservatives and the like can be mentioned.
　本発明の組成物は、各種症状や状態の改善・予防・向上等の表示が許可されている飲食品ために用いることができる。ここで、本発明において、症状や状態の改善・予防・向上等の表示が許可されている飲食品とは、国や公共団体が許可・指定している効能を有する飲食品であり、例えば、機能性表示食品、特定保健用食品等の保健機能食品、特別用途食品等である。なお、状況や時代、各国の制度により名称や規程が変化するが、本質的に同じであるものは本発明に含まれる。 The composition of the present invention can be used for foods and drinks that are permitted to be labeled as improving, preventing, improving, etc. various symptoms and conditions. Here, in the present invention, food and drink that are permitted to display symptoms and conditions such as improvement, prevention, improvement, etc. are food and drinks that have efficacy permitted or designated by the country or public organizations. These include foods with function claims, foods with health claims such as foods for specified health uses, and foods for special dietary uses. Although the names and regulations change depending on the situation, the times, and the systems of each country, those that are essentially the same are included in the present invention.
　本発明において、本発明の組成物の配合量は、特に制限されず、適用の目的（対象疾患や症状の種類等）、適用対象部位、適用者の性別や年齢、飲食品、機能性表示食品、特定保健用食品、医薬部外品、医薬品、化粧品、日用品又は飼料等の製品形態、これらの投与又は摂取方法や回数、嗜好等に応じて適宜設定される。 In the present invention, the amount of the composition of the present invention is not particularly limited, and the purpose of application (type of target disease or symptom, etc.), target site for application, gender and age of the applicant, food and drink, food with function claims , foods for specified health uses, quasi-drugs, pharmaceuticals, cosmetics, daily necessities, feeds, and other product forms;
　〔実施形態〕
　上述した実施の形態に関し、限定はされないが、本発明は以下の実施形態を開示する。 [Embodiment]
With respect to the embodiments described above, the present invention discloses the following embodiments, although not limited thereto.
　下記式１で表される化合物。
Figure JPOXMLDOC01-appb-C000013
 A compound represented by the following formula 1.
Figure JPOXMLDOC01-appb-C000013
　下記式２で表される、上記化合物。
Figure JPOXMLDOC01-appb-C000014
 The compound represented by the following formula 2.
Figure JPOXMLDOC01-appb-C000014
　下記式３で表される、上記化合物。
Figure JPOXMLDOC01-appb-C000015
 The above compound represented by the following formula 3.
Figure JPOXMLDOC01-appb-C000015
　上記記載の化合物を含む、組成物。 A composition containing the compound described above.
　さらにＬ－エルゴチオネインを含む、上記組成物。 The above composition, which further contains L-ergothioneine.
　上記Ｌ－エルゴチオネイン１００質量部に対して、上記化合物の含有量が、５０質量部以下である、上記組成物。 The composition, wherein the content of the compound is 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
　上記Ｌ－エルゴチオネイン１００質量部に対して、上記化合物の含有量が、０．０００１質量部以上である、上記組成物。 The composition, wherein the content of the compound is 0.0001 parts by mass or more with respect to 100 parts by mass of the L-ergothioneine.
　上記Ｌ－エルゴチオネイン１００質量部に対して、上記化合物の含有量が、０．０００１質量部以上であり、かつ、５０質量部以下である、上記組成物。 The composition, wherein the content of the compound is 0.0001 parts by mass or more and 50 parts by mass or less with respect to 100 parts by mass of the L-ergothioneine.
　上記化合物を含む、炎症抑制剤。 An anti-inflammatory agent containing the above compounds.
　上記組成物を含む、炎症抑制剤。 An anti-inflammatory agent containing the above composition.
　炎症抑制剤の製造のための上記化合物の使用。 　The use of the above compounds for the manufacture of anti-inflammatory agents.
　炎症抑制剤の製造のための上記組成物の使用。 　Use of the above composition for the manufacture of an anti-inflammatory agent.
　炎症抑制における使用のための上記化合物。 A compound as described above for use in suppressing inflammation.
　炎症抑制における使用のための上記組成物。 The above composition for use in suppressing inflammation.
　リボシルホモシステインと還元剤とを反応させる工程を含む、上記化合物の製造方法。 A method for producing the above compound, comprising a step of reacting ribosylhomocysteine with a reducing agent.
　上記還元剤は、水素化ホウ素リチウム、水素化ホウ素ナトリウム、又は水素化ホウ素亜鉛を含む、上記製造方法。 The above production method, wherein the reducing agent contains lithium borohydride, sodium borohydride, or zinc borohydride.
　次に、実施例により本発明を具体的に説明するが、本発明は以下の実施例に限定されるものではない。 EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.
　〔実施例１〕
　（ＳＲＨ還元体の調製）
　リボシルホモシステイン（ＳＲＨ）はカーボハイドレートリサーチ、２０１４、３９４巻、３２ページに記載の方法に準じて調製した。 [Example 1]
(Preparation of SRH reductant)
Ribosylhomocysteine (SRH) was prepared according to the method described in Carbohydrate Research, 2014, 394, 32 pages.
　上記で調製したリボシルホモシステイン（ＳＲＨ）水溶液２０ｍＬ（ＳＲＨとして１２３ｍｇ含有、０．４６ｍｍｏｌ）に、水素化ホウ素ナトリウム１７．４ｍｇ（０．４６ｍｍｏｌ）を加え、１時間攪拌（ｐＨ９－１０）した後、ＨＰＬＣで反応をモニターしたところ、ＳＲＨがほとんどＳＲＨ還元体に変化していた。反応液に１０％ＮＨ４Ｃｌ５ｍＬ、１ＮＨＣｌ５００μＬを加え、ｐＨ６．７とした。 To 20 mL of the ribosylhomocysteine (SRH) aqueous solution prepared above (containing 123 mg of SRH, 0.46 mmol), 17.4 mg (0.46 mmol) of sodium borohydride was added and stirred for 1 hour (pH 9-10). When the reaction was monitored by HPLC, most of SRH was changed to SRH reductant. 5 mL of 10% NH 4 Cl and 500 μL of 1N HCl were added to the reaction solution to adjust the pH to 6.7.
　反応液を、電気透析装置（アストム社製）により脱塩し、その後、濃縮し、ＳＲＨ還元体水溶液１０ｍＬ（ｑＮＭＲによりＳＲＨ還元体１．０８％、１０８ｍｇ含有）を調製した。 The reaction solution was desalted using an electrodialyzer (manufactured by Astom) and then concentrated to prepare 10 mL of an aqueous SRH reductant solution (containing 108 mg of SRH reductant of 1.08% by qNMR).
　（ＨＰＬＣ分析条件）
　ＨＰＬＣ分析は、以下の条件で行った。
　カラム：ＹＭＣ－Ｐａｃｋ　ＯＤＳ－ＡＱ　Ｓ－５μＭ，１２ｎｍ、２５０ｘ４．６ｍｍ　Ｉ．Ｄ．
　　流速：０．５ｍＬ／ｍｉｎ、温度：３０℃
　　検出器：ＰＤＡ（２１０ｎｍ）
　　溶離液：０．１％ギ酸水溶液
　　保持時間：６．２分（ＳＲＨ還元体）、６．６分（ＳＲＨ） (HPLC analysis conditions)
HPLC analysis was performed under the following conditions.
Column: YMC-Pack ODS-AQ S-5 μM, 12 nm, 250×4.6 mm I.D. D.
Flow rate: 0.5 mL/min, temperature: 30°C
Detector: PDA (210 nm)
Eluent: 0.1% formic acid aqueous solution Retention time: 6.2 minutes (SRH reductant), 6.6 minutes (SRH)
　（高分解能質量分析）
　以下に液体クロマトグラフィー高分解能質量分析（ＬＣ－ＨＲＭＳ）の結果を示す。
　　［Ｍ＋Ｈ］＋　計算値　Ｃ９Ｈ２０ＮＯ６Ｓ　２７０．１０１１；実測値　２７０．１０１６
　　　（ＬＣ－ＨＲＭＳ分析条件）
　　装置：Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ　６２２４　ＴＯＦ　ＬＣ／ＭＳ（アジレントテクノロジー社製）
　　カラム：ＹＭＣ－Ｐａｃｋ　ＯＤＳ－ＡＱ　Ｓ－５μＭ，１２ｎｍ、２５０ｘ４．６ｍｍ　Ｉ．Ｄ．
　　流速：０．５ｍＬ／ｍｉｎ、温度：３０℃
　　溶離液：０．１％ギ酸水溶液
　　イオン化条件：ＥＳＩ　キャピラリー電圧　３５００Ｖ　フラグメンター電圧　１００Ｖ
　　保持時間：６．６分（ＳＲＨ還元体）、７．２分（ＳＲＨ） (high resolution mass spectrometry)
The results of liquid chromatography high resolution mass spectrometry (LC-HRMS) are shown below.
[M+H] + calculated C9H20NO6S 270.1011 ; found 270.1016 .
(LC-HRMS analysis conditions)
Apparatus: Agilent Technologies 6224 TOF LC/MS (manufactured by Agilent Technologies)
Column: YMC-Pack ODS-AQ S-5 μM, 12 nm, 250×4.6 mm I.D. D.
Flow rate: 0.5 mL/min, temperature: 30°C
Eluent: 0.1% formic acid aqueous solution Ionization conditions: ESI Capillary voltage 3500 V Fragmentor voltage 100 V
Retention time: 6.6 minutes (SRH reductant), 7.2 minutes (SRH)
　（１Ｈ－ＮＭＲ測定）
　以下に１Ｈ－ＮＭＲ測定の結果を示す。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）ＤＳＳ－ｄ６を０ｐｐｍとした。
　δ　３．８８（ｍ，２Ｈ），３．７９（ｍ，２Ｈ），３．６７（ｍ，２Ｈ），２．９４（ｍ，１Ｈ），２．７１（ｍ，３Ｈ），２．１６（ｍ，２Ｈ） ( 1 H-NMR measurement)
The results of 1 H-NMR measurement are shown below.
1 H-NMR (400 MHz, D 2 O) DSS-d 6 was taken as 0 ppm.
δ 3.88 (m, 2H), 3.79 (m, 2H), 3.67 (m, 2H), 2.94 (m, 1H), 2.71 (m, 3H), 2.16 ( m, 2H)
　〔実施例２〕
　（炎症抑制効果の評価）
　ヒト網膜色素上皮細胞株ＡＲＰＥ－１９を、１０％ＦＢＳ－ＤＭＥＭ／Ｆ１２培地を用いて６ウェルプレートに播種し、５％ＣＯ２、３７℃条件下で、炭酸ガスインキュベーターにて４８時間培養を行った。 [Example 2]
(Evaluation of anti-inflammatory effect)
Human retinal pigment epithelial cell line ARPE-19 was seeded in a 6-well plate using 10% FBS-DMEM/F12 medium, and cultured for 48 hours in a carbon dioxide gas incubator under conditions of 5% CO 2 and 37°C. rice field.
　コンフルエントに達しているのを確認した後、培地を新しい１０％ＦＢＳ－ＤＭＥＭ／Ｆ１２培地（コントロール区）もしくは、フルクトース５ｇ／Ｌを含有した１０％ＦＢＳ－ＤＭＥＭ／Ｆ１２培地（代謝ストレスモデル区）、もしくは、ＳＲＨ還元体（４ｍＭ）及びフルクトース５ｇ／Ｌを含有した１０％ＦＢＳ－ＤＭＥＭ／Ｆ１２培地（代謝ストレス下、ＳＲＨ還元体試験区）に交換し、引き続き培養を行った。 After confirming that it has reached confluence, the medium is replaced with fresh 10% FBS-DMEM/F12 medium (control group) or 10% FBS-DMEM/F12 medium containing 5 g/L of fructose (metabolic stress model group), Alternatively, the medium was changed to 10% FBS-DMEM/F12 medium containing SRH reductant (4 mM) and fructose 5 g/L (under metabolic stress, SRH reductant test group), and culture was continued.
　７２ｈ後に培地を除去し、ＴＲＩｚｏｌ（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ社）を用い、プロトコールに従いＲＮＡを回収した。ＲＮＡをｃＤＮＡ作成キット（ＴＡＫＡＲＡ社）を用いプロトコールに従って調製した。 After 72 hours, the medium was removed, and RNA was recovered using TRIzol (Thermo Fisher) according to the protocol. RNA was prepared using a cDNA preparation kit (TAKARA) according to the protocol.
　これらの結果を図１に示す。なお、プライマーは以下の配列のものを用いた。
　ＩＬ－１２ｐ４０：（Ｆｏｒｗａｒｄ）５’－ａａｇｇａｇｇｃｇａｇｇｔｔｃｔａａｇｃ－３’、（Ｒｅｖｅｒｓｅ）５’－ａａｇａｇｃｃｔｃｔｇｃｔｇｃｔｔｔｔｇ－３’
　ＩＬ－１ｂｅｔａ：（Ｆｏｒｗａｒｄ）５’－ｇｇｇｃｃｔｃａａｇｇａａａａｇａａｔｃ－３’、（Ｒｅｖｅｒｓｅ）５’－ｔｔｃｔｇｃｔｔｇａｇａｇｇｔｇｃｔｇａ－３’
　ＭＭＰ－９：（Ｆｏｒｗａｒｄ）５’ｔｔｇａｃａｇｃｇａｃａａｇａａｇｔｇｇ－３’、（Ｒｅｖｅｒｓｅ）５’－ｇｃｃａｔｔｃａｃｇｔｃｇｔｃｃｔｔａｔ－３’
　ＴＮＦａｌｐｈａ：（Ｆｏｒｗａｒｄ）５’－ｔｃｃｔｔｃａｇａｃａｃｃｃｔｃａａｃｃ－３’、（Ｒｅｖｅｒｓｅ）５’－ｃａｇｇｇａｔｃａａａｇｃｔｇｔａｇｇｃ－３’
　ＴＢＰ：（Ｆｏｒｗａｒｄ）５’－ｔａｔａａｔｃｃｃａａｇｃｇｇｔｔｔｇｃ－３’、（Ｒｅｖｅｒｓｅ）５’－ｇｃｔｇｇａａａａｃｃｃａａｃｔｔｃｔｇ－３’ These results are shown in FIG. The primers used had the following sequences.
IL-12p40: (Forward) 5′-aaggaggcgaggttctaagc-3′, (Reverse) 5′-aagagcctctgctgcttttg-3′
IL-1beta: (Forward) 5′-gggcctcaaggaaaagaatc-3′, (Reverse) 5′-ttctgcttgagaggtgctga-3′
MMP-9: (Forward) 5′ ttgacagcgacaagaaagtgg-3′, (Reverse) 5′-gccattcacgtcgtccttat-3′
TNFalpha: (Forward) 5′-tccttcagacacctcaacc-3′, (Reverse) 5′-cagggatcaaagctgtaggc-3′
TBP: (Forward) 5′-tataatcccaagcggtttgc-3′, (Reverse) 5′-gctggaaaacccaacttctg-3′
　図１に示されるように、フルクトース高負荷によってＩＬ－１ｂ、ＴＮＦが上昇することから炎症性の反応が起こっていることが確認された。また、ＩＬ－１２が高まることからＴｈ１型の反応が起こっていると推察された。各処方において、ＳＲＨ還元体４ｍＭを加えた系では、いずれも、上記の反応に対して抑制効果を示した。また、基底膜は網膜色素上皮細胞の維持に欠かせないが、基底膜を分解する酵素であるＭＭＰ－９の上昇をＳＲＨ還元体が抑制する効果も認められた。以上のことからＳＲＨ還元体には、炎症性の反応を抑制する効果があること、及び網膜色素上皮細胞の維持に寄与しうることが確認できた。
  As shown in FIG. 1, it was confirmed that IL-1b and TNF increased due to high fructose load, and that an inflammatory reaction occurred. In addition, it was speculated that a Th1-type reaction occurred from the increase in IL-12. In each formulation, the system to which 4 mM of the SRH reductant was added showed an inhibitory effect on the above reaction. In addition, the basement membrane is essential for the maintenance of retinal pigment epithelial cells, and the SRH reduced form was also effective in suppressing the increase in MMP-9, an enzyme that degrades the basement membrane. From the above, it was confirmed that the reduced SRH has an effect of suppressing inflammatory reactions and that it can contribute to the maintenance of retinal pigment epithelial cells.

Claims (11)

  1. 　下記式１で表される化合物。
    Figure JPOXMLDOC01-appb-C000001
         A compound represented by the following formula 1.
    Figure JPOXMLDOC01-appb-C000001
  2. 　下記式２で表される、請求項１に記載の化合物。
    Figure JPOXMLDOC01-appb-C000002
         2. The compound according to claim 1, represented by Formula 2 below.
    Figure JPOXMLDOC01-appb-C000002
  3. 　下記式３で表される、請求項１又は２に記載の化合物。
    Figure JPOXMLDOC01-appb-C000003
         3. The compound according to claim 1 or 2, represented by the following formula 3.
    Figure JPOXMLDOC01-appb-C000003
  4. 　請求項１～３のいずれか１項に記載の化合物を含む、組成物。 A composition comprising the compound according to any one of claims 1 to 3.
  5. 　さらにＬ－エルゴチオネインを含む、請求項４に記載の組成物。 The composition according to claim 4, further comprising L-ergothioneine.
  6. 　前記Ｌ－エルゴチオネイン１００質量部に対して、前記化合物の含有量が、５０質量部以下である、請求項５に記載の組成物。 The composition according to claim 5, wherein the content of said compound is 50 parts by mass or less with respect to 100 parts by mass of said L-ergothioneine.
  7. 　前記Ｌ－エルゴチオネイン１００質量部に対して、前記化合物の含有量が、０．０００１質量部以上である、請求項５又は６に記載の組成物。 The composition according to claim 5 or 6, wherein the content of said compound is 0.0001 parts by mass or more with respect to 100 parts by mass of said L-ergothioneine.
  8. 　請求項１～３のいずれか１項に記載の化合物を含む、炎症抑制剤。 An anti-inflammatory agent comprising the compound according to any one of claims 1 to 3.
  9. 　請求項４～７のいずれか１項に記載の組成物を含む、炎症抑制剤。 An anti-inflammatory agent comprising the composition according to any one of claims 4 to 7.
  10. 　リボシルホモシステインと還元剤とを反応させる工程を含む、請求項１～３のいずれか１項に記載の化合物の製造方法。 A method for producing the compound according to any one of claims 1 to 3, comprising a step of reacting ribosylhomocysteine with a reducing agent.
  11. 　前記還元剤は、水素化ホウ素リチウム、水素化ホウ素ナトリウム、又は水素化ホウ素亜鉛を含む、請求項１０に記載の製造方法。
          11. The manufacturing method according to claim 10, wherein the reducing agent comprises lithium borohydride, sodium borohydride, or zinc borohydride.
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Citations (1)

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