WO2007040006A1 - Activator for peroxisome proliferator-activated receptor (pparϝ) and composition containing the activator for preventing or ameliorating specific symptom - Google Patents

Activator for peroxisome proliferator-activated receptor (pparϝ) and composition containing the activator for preventing or ameliorating specific symptom Download PDF

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Publication number
WO2007040006A1
WO2007040006A1 PCT/JP2006/317485 JP2006317485W WO2007040006A1 WO 2007040006 A1 WO2007040006 A1 WO 2007040006A1 JP 2006317485 W JP2006317485 W JP 2006317485W WO 2007040006 A1 WO2007040006 A1 WO 2007040006A1
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Prior art keywords
acid
peroxisome proliferator
activator
disease
responsive receptor
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PCT/JP2006/317485
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French (fr)
Japanese (ja)
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Teruo Kawada
Min-Sook Kang
Tsuyoshi Goto
Yoichiro Ezaki
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Kyoto University
Arakawa Chemical Industries, Ltd.
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Priority to JP2007538669A priority Critical patent/JPWO2007040006A1/en
Publication of WO2007040006A1 publication Critical patent/WO2007040006A1/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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Peroxisome proliferator-responsive receptor PPAR / activator and a composition for preventing or ameliorating specific symptoms containing the activator
  • the present invention relates to a peroxisome proliferator-responsive receptor ⁇ activator and a composition for preventing or ameliorating a specific symptom comprising the active agent. More specifically, it acts as a peroxisome proliferator-activated receptor gamma activator and is selected from the group consisting of insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver
  • the present invention relates to a composition having an action of preventing or ameliorating at least one kind of symptom.
  • Peroxisome proliferator-activated receptor is an activator-dependent transcriptional regulator belonging to the nuclear receptor family that controls the expression of genes involved in lipid and sugar metabolizing sugars. .
  • PPAR-a is mainly expressed in adipose tissue, immune cells, adrenal gland, spleen, and small intestine
  • PPAR-a is expressed mainly in adipose tissue, liver, kidney, and skeletal muscle
  • PPAR- ⁇ is mainly observed in tissue specificity. It is known that it is universally expressed and is known!
  • PPAR- ⁇ is involved in adipocyte differentiation, and this activator (agonist) promotes adipocyte differentiation and actively takes up blood glucose. Increases the number of fat cells to lower blood sugar level, hypersensitivity to insulin insensitivity, suppresses hyperplasia of fat cells, increases insulin sensitivity! Increases sensitive small fat cells to lower blood sugar level It is known to decrease, increase adiponectin production, decrease blood lipids (particularly triglycerides), and control the function of vascular constituent cells (Non-Patent Documents 2, 3, 4, 5). 6).
  • PPAR- ⁇ activator is useful for reducing visceral fat, suppressing accumulation of visceral fat, improving lipid metabolism abnormality, improving glucose metabolism abnormality, insulin resistance, type 2 diabetes, hyperlipidemia, hypertension It is effective as an agent for preventing and improving or reducing visceral fat obesity, fatty liver and the like.
  • PPAR- ⁇ activator has conjugated triene structure or tetrane structure in the molecule.
  • Unsaturated fatty acids having 10 to 26 carbon atoms Patent Document 1
  • a unsaturated fatty acids such as linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, 9-hydroxyoctadecadienoic acid 13-hydroxyoctadedecadiene Hydroxy fatty acids such as acids, arachidonic acid metabolites such as 15 deoxy ⁇ 12 prostaglandin J2 and ⁇ 12 prostaglandin J2 (non-patent document 2), thiazolidine derivatives such as pioglitazone, troglitazone, and rosiglitazone (non-patent document) 4 and 7) are known.
  • the thiazolidine derivative has an excellent insulin improving action and is clinically used as a therapeutic agent for type 2 diabetes.
  • thiazolidine derivatives have problems that cause strong side effects such as liver damage and weight gain, and development of safer antidiabetic drugs is desired.
  • Non-Patent Document 8 It is known that it is an abietic acid PPAR- ⁇ activator, which is a kind of succinic acid constituting rosin (see Non-Patent Document 8). However, the activity of abietic acid is not strong, and Non-Patent Document 8 does not teach or suggest any of the activity of succinic acid other than abietic acid.
  • Patent Document 1 Japanese Unexamined Patent Publication No. 2000-355538
  • Non-Patent Document 1 History of Medicine, 1998, 184 ⁇ , 519-523
  • Non-Patent Document 2 Diabetology, 1999, 42 ⁇ , 1033-1049
  • Non-Patent Document 3 Japanese Clinical, 2005, 63 ⁇ , 4, 539-548
  • Non-Patent Document 4 Japanese Clinical Practice, 2005, 63 ⁇ , 4, 549-555
  • Non-Patent Document 5 Japanese Clinical Practice, 2005, 63 ⁇ , No. 4, pp. 557-562
  • Non-Patent Document 6 Japanese Clinical, 2005, 63 ⁇ , No. 4, pp. 631-642
  • Non-Patent Document 7 Journal of Pharmaceutical Sciences, 2002, 122 (11), 909-918
  • Non-Patent Document 8 F'B'B'S 'Letters, 2003, 550, 190-194 Disclosure of the Invention
  • the present invention provides a useful peroxisome proliferator-responsive receptor ⁇ activator with high safety, and insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, hyperlipidemia
  • the aim is to provide a thread and composition that has the effect of preventing or ameliorating hypertension, etc. Target.
  • the present inventors paid attention to the succinic acid component contained in rosin, which is a natural product, and as a result of earnestly examining its relationship with activation of peroxisome proliferator-responsive receptor ⁇ , And at least one compound selected from the group consisting of dehydroabietic acid, 13
  • the present inventors have found that it has an excellent peroxisome proliferator-responsive receptor ⁇ activation action, and further research based on this finding has led to the completion of the present invention.
  • the present invention provides:
  • Peroxisomes comprising at least one compound selected from the group consisting of dehydroabietic acid, 13 j8- ⁇ 8 -dihydroabietic acid and isopimaric acid or a pharmaceutically acceptable salt thereof as an active ingredient
  • Proliferator-responsive receptor ⁇ activator
  • peroxisome proliferator-activated receptor ⁇ The disease or symptom mediated by peroxisome proliferator-activated receptor ⁇ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat type obesity or fatty liver as described in (2) above Peroxisome proliferator-activated receptor ⁇ activator,
  • the peroxisome proliferator-responsive receptor 0 activator according to (1) above which is a composition for preventing or improving insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver ,
  • Insulin resistance type 2 diabetes, hyperlipidemia, hypertension, visceral fat-type obesity or peroxisome proliferator-responsive receptor ⁇ activator according to (1)
  • a composition for preventing or improving fatty liver A composition for preventing or improving fatty liver,
  • composition for prevention or improvement according to the above (5) which is a food
  • a peroxisome proliferator-responsive receptor comprising at least one compound selected from the group consisting of dehydroabietic acid, 13 j8- ⁇ 8 -dihydroabietic acid and isopimaric acid, or a pharmaceutically acceptable salt thereof a food characterized in that a disease or symptom mediated by ⁇ is prevented or improved
  • peroxisome proliferator-responsive receptor ⁇ The disease or symptom mediated by peroxisome proliferator-responsive receptor ⁇ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver as described in (8) above Food,
  • Peruokishisomu proliferator-activated receptor ⁇ is dehydroabietic acid for the manufacture of a medicament for improvement of were prevention or a disease or condition mediated, 13 ⁇ - ⁇ 8 - than Jihidoroabi Echin acid and isopimaric acid strength becomes the group Use of at least one selected compound or a pharmaceutically acceptable salt thereof,
  • Peruokishisomu proliferator-activated receptor ⁇ activator of the present invention Dehidoroabiechi phosphate, 13 j8- ⁇ 8 least one compound or a pharmaceutically selected from dihydroabietic acid and isopimaric acid force group consisting acceptable It contains a salt obtained as an active ingredient.
  • dehydroabietic acid is generally called succinic acid, and is an amber transparent glass having a softening point of about 70 to 80 ° C obtained by refining pine resin produced from pine trees. It is a component of rosin. 13 j8- ⁇ 8 Dihydroabietic acid is a component of hydrogenated rosin obtained by hydrogenating rosin. Isopimaric acid is a component of rosin. These are all known as active ingredients of force peroxisome proliferator-activated receptor ⁇ activators, which are known compounds, respectively!
  • the compound as the active ingredient can be easily isolated and purified or synthesized by a known method.
  • a strong salt examples include all pharmacologically acceptable ones.
  • a pharmacologically acceptable salt is preferably a less toxic salt.
  • Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetraptylammonium salt).
  • organic amines triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N -Methyl D glutamine etc.
  • organic amines triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N -Methyl D glutamine etc.
  • the PPAR y activating action (PPAR y agonist activity) of these active ingredients is measured by the method of, for example, EF I. B I. S Letters, 2002, 514 ⁇ , 315-322. it can. That is, a plasmid (pM—PPAR ⁇ ) that produces a chimeric protein of the ligand binding site of PPAR- ⁇ and the DNA binding site of GAL4 (yeast DNA-binding transcription factor activity factor), and the luciferase gene that is the reporter gene
  • the plasmid (4 X UASg-luc) containing 4 GAL4 response elements (UA Sg) incorporated upstream is cotransfected into the cultured cells of African green monkey kidney (CV-1) by the lipofussion method.
  • the obtained transformant is cultured for a certain period of time, and then contacted with the test compound to activate the PPAR ⁇ GAL4 chimeric protein and enhance the binding to UASg upstream of 4 X UASg-luc, thereby producing luciferase. increase.
  • the PPAR ⁇ activity can be evaluated by measuring the activity of the produced luciferase.
  • the protein at the ligand binding site of PPAR-y is a human PP AR- ⁇ amino acid conjugate [J (http://www.genome.jp/dbget-bin/www-bget? sp: PPAR—HUMA N)) corresponding to the amino acid sequence of 174 to 475%.
  • the protein of the DNA binding site of GAL4 (yeast DNA-binding transcription factor activator) is the amino acid sequence of GAL4 (see http://www.genome.jp/dbget—bin/www_bget?sp:GAL4_YEAST) It corresponds to amino acid sequence 1-147.
  • the active ingredient of the present invention is based on the PPAR ⁇ activity activity, and improves glucose metabolism, improves fat metabolism, lowers blood glucose, suppresses body fat accumulation, inhibits visceral fat accumulation,
  • the active ingredient of the present invention has an action of reducing cytodynamic force (for example, MCP-1) which is an inflammatory factor related to obesity.
  • Peruokishisomu proliferator-activated receptor ⁇ activator of the present invention the prevention of lifestyle-related diseases Ya metabolic syndrome associated with obesity, are useful as improvers, more specifically, I insulin resistance, 2 It is useful as a preventive / ameliorating agent for type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver.
  • peroxisome proliferator-responsive receptor ⁇ activator of the present invention and a composition containing the peroxisome proliferator-responsive receptor ⁇ activator (hereinafter, both are also referred to as a preparation) are used as pharmaceuticals, oral agents and injections together with conventional carriers are used. Suppositories, external preparations, suppositories or inhalants. Examples of oral preparations include dosage forms such as tablets, granules, fine granules, powders, capsules, solutions, emulsions, suspensions, and syrups. These preparations can be produced by a method known per se.
  • the active ingredient of the present invention and pharmaceutically acceptable additives such as excipients (eg lactose, starch, sucrose, glucose, Mantle, starch, inorganic salts, etc.), lubricants (eg talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, etc.), disintegrants ( Examples: carmellose, carmellose calcium, starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, etc.), binders (eg starch, dextrin, gum arabic powder, hydroxypropyl starch, crystalline cellulose, ethyl cellulose, methylcellulose, Sodium carboxymethyl cellulose, hydroxypropyl cellulose, polybule Mix by known methods, etc.) together with such pyrrolidone, granulation, can be produced by excipients (eg lactose, starch, sucrose, glucose, Mantle,
  • suitable coating agents eg, gelatin, sucrose, gum arabic, carnapa wax, etc.
  • enteric coating agents eg, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropyl cellulose phthalate
  • Carboxymethylethyl cellulose, etc. e.g., cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropyl cellulose phthalate
  • the active ingredient of the present invention is uniformly mixed with known excipients, or granulated or granulated, and if necessary, a more suitable coating agent.
  • excipients include, for example, magnesium stearate, calcium stearate, talc or light anhydrous key acid to improve fluidity and lubricity, crystalline cellulose and lactose for pressurized fluidity, or the above disintegration Agents and the like.
  • a stabilizer eg, sodium edetate
  • a suspending agent eg, gum arabic, carmellose, etc.
  • a flavoring agent eg, simple substance
  • Syrup e.g., glucose, etc.
  • fragrance e.g., purified water, butanol, vegetable oil, emulsifier and the like
  • purified water butanol, vegetable oil, emulsifier and the like
  • the injection may be an aqueous injection or an oily injection!
  • an aqueous solvent eg, distilled water for injection, physiological saline, aqueous glucose solution, etc.
  • a pharmaceutically acceptable additive eg, an isotonic agent (eg, Sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, glucose, propylene glycol, etc.), buffer (eg phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, epsilon aminocaproate buffer, etc.), preservative (eg, chlorobutanol, etc.), thickener (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polybutanol, polyethylene glycol) Etc.), stabilizers (eg, sodium hydrogen sulfite, sodium thiosul
  • an isotonic agent eg, Sodium chloride, potassium chloride,
  • solubilizers such as alcohols (ethanol, etc.), polyalcohols (propylene glycol, polyethylene glycol, etc.), nonionic surfactants (polysorbate 80, polyoxyethylene hydrogenated castor oil 50, etc.) can be used.
  • the oily solvent examples include sesame oil, peanut oil, and soybean oil. Corn oil or the like may be used, and benzyl benzoate, benzyl alcohol or the like may be used as a solubilizing agent.
  • the prepared injection solution is usually filled in an appropriate ampoule or vial.
  • the concentration of the active ingredient of the present invention in the injection is usually adjusted to about 0.001 to 10. OwZv%, preferably about 0.005 to OwZv%.
  • Examples of the external preparation include ointments, creams, lotions, and the like.
  • ointments and talums for example, water-absorbing ointments, hydrophilic ointments, simple ointments, white ointments or macrogols.
  • the lotion may contain commonly used additives.
  • additives include suspending agents, emulsifiers, wetting agents (for example, glycerin, propylene glycol, sorbitol, 1, 3-butylene glycol, dl-pyrrolidone carboxylic acid, sodium lactate, etc.) or preservatives (for example, noraoxybenzoates, salt benzalkonium, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sodium edetate, Boric acid, borax, etc.).
  • suspending agents for example, glycerin, propylene glycol, sorbitol, 1, 3-butylene glycol, dl-pyrrolidone carboxylic acid, sodium lactate, etc.
  • preservatives for example, noraoxybenzoates, salt benzalkonium, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sodium edetate, Boric acid, borax, etc.
  • Suppositories can also be prepared by a conventional formulation method using conventional bases (for example, cacao butter, laurin butter, glyce gelatin, macrogol, witepsol, etc.).
  • bases for example, cacao butter, laurin butter, glyce gelatin, macrogol, witepsol, etc.
  • Inhalants can also be adjusted by conventional means in the preparation.
  • the additive may be any additive generally used in inhalable preparations.
  • the above-mentioned excipients, binding Agents, lubricants, preservatives, stabilizers, tonicity agents, pH adjusting agents or flavoring agents taenoic acid, menthol, glycyrrhizin ammonium salt, glycine, fragrance, etc.
  • a propellant a liquefied gas propellant, a compressed gas, or the like is used.
  • the liquefied gas propellant examples include fluorinated hydrocarbons (alternative fluorocarbons such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, dimethyl ether, and the like.
  • the compressed gas examples include soluble gases (such as carbon dioxide and nitrous acid) and insoluble gases (such as nitrogen).
  • the preparation of the present invention is used as a food
  • it is an additive acceptable as a food additive (eg, glucose, fructose, sucrose, maltose, sorbitol, stepioside, rubusoside, corn syrup, lactose, quenate, tartaric acid.
  • a food additive eg, glucose, fructose, sucrose, maltose, sorbitol, stepioside, rubusoside, corn syrup, lactose, quenate, tartaric acid.
  • Ri may be tablets, granules, capsules and the like.
  • the preparation of the present invention can also be mixed with other food ingredients to make a food.
  • other food ingredients are not particularly limited and can be used for various foods.
  • foods that can be used include soy sauce, powdered soy sauce, miso, powdered miso, moromi, horsetail, fried potatoes, mayonnaise, dressing, vinegar, three cups of vinegar, powdered sushi vinegar, tentsuyu, katsuyu, sauce, ketchup, Yakiniku sauce, curry roux, Chinese element, stew element, soup element, dashi element, compound seasoning, mirin, new mirin, table sugar or coffee sugar, etc.
  • Fertilizer cocoon, manju, uirou, ann, mutton, water mutton, brocade, jelly, castella, candy, etc. , Candy, caramel, candy or gummy jelly, ice cream, eye Candy or sherbet ice confectionery, ice honey syrup, butter cream, force Stard cream, flower paste, peanut paste or fruit paste spreads and pastes, jam, marmalade, syrup pickled or confectionery processed fruits and vegetables Cereal processed foods such as bread, rice bran, cooked rice or artificial meat, oil and fat foods such as salad oil or margarine, Fukujinzuke, lettuce pickles, Senzuke pickles Pickles, pickled vegetables such as takuan pickles or Chinese cabbage pickles, livestock meat products such as ham or sausage, fish meat ham, fish sausages, fish products such as scallops, chiku mushrooms or hampen, uni-salted squid, squid Delicacy such as salted spices, vinegared combs, dried sardines or dried puffer
  • Soup, stew, oden, Happo vegetables, boiled beans, yakitori, steamed rice bowl or field Retort food such as boiled water, egg, milk drinks, egg products such as notter or cheese and dairy products, bottling and canning of fish meat, livestock meat, fruits or vegetables, synthetic liquor, brewed liquor, fruit liquor or Western liquor Alcohol, coffee, cocoa, juice, tea, tea, oolong tea, mineral beverages, carbonated beverages, soft drinks such as lactic acid beverages or lactic acid bacteria drinks, pudding mixes, hot cake mixes, instant juices, instant juices or instant soups Foods etc. are mentioned.
  • the content of the preparation of the present invention in the food varies depending on the type of food, but the content of the active ingredient is usually about 0.001 to 0.1% by mass.
  • CV-1 cells (cultured cells derived from male African green monkey kidney) were seeded in a 96-well culture plate at 6 X 10 3 per well, and cultured for 24 hours at 37 ° C and 5% CO.
  • the medium includes 10% FBS (Ushi Fetal Serum), lOmlZL penicillin 'streptomycin solution (5000 IU / ml, 5000 ⁇ g / ml, GIBCO, respectively), 37 mg / L ascorbic acid (Wako Pure Chemical Industries, Ltd.) DMEM (Dulbeccos Modified Eagle Medium: manufactured by GIBCO) was used. After washing the cells with OPTI-MEM (GIBCO), p M -PPAR ⁇ and 4 X UASg -luc using Lipofectamine 'Plus (GIBCO) Transfusion.
  • FBS Un Fetal Serum
  • lOmlZL penicillin 'streptomycin solution 5000 IU / ml, 5000 ⁇ g / ml, GIBCO, respectively
  • 37 mg / L ascorbic acid Wako Pure Chemical Industries, Ltd.
  • DMEM Dulbeccos Modified Eagle Medium: manufactured by GIBCO
  • PM-PPARy is a mammalian expression plasmid pM (Clontech), yeast-derived transcription factor GAL4 gene (amino acid sequence 1-147) and human PP AR- ⁇ ligand binding site gene (amino acid sequence 174-475).
  • test compound was dissolved in dimethyl sulfoxide (DMSO), DMSO was used as an untreated control, and 1/1000 amount was added to the medium. After washing the cells with Ca- and Mg-containing phosphate buffered saline (PB S +), add Looklite (Packard) and use TopCount 'Microplate Scintillation Z Luminescence Counter (Packard). The luminescence intensity of luciferase was measured.
  • DMSO dimethyl sulfoxide
  • the control group was measured using pM instead of pM-PPAR y.
  • calculate the ratio of the average value (n 4) of the luminescence intensity of the measurement group and the control group (measurement group Z control group), and determine the specific activity relative to the untreated control as the PPAR- ⁇ activity of the test compound. It was considered as a ⁇ action.
  • Table 1 The results are shown in Table 1.
  • dehydroabietic acid administration group significantly suppressed the increase in blood glucose level as compared to the control group, and the concentration of lebutin, insulin, MCP-1 and the amount of intraperitoneal fat Z body weight significantly decreased. I understand. From this result, it is clear that dehydroabietic acid has an effect of improving the metabolism of sugar and fat, an action of suppressing visceral fat accumulation, and an action of improving hyperinsulinemia.
  • RAW264.7 cells were suspended in the DMEM medium described in Example 1, and the suspension (lX10 6 cellsZml) was dispensed into a 12-well culture plate at a rate of 2000 / zl per well in a 37 ° C CO incubator. After 2 hours of incubation, lipopolysaccharide (LPS, lOOng / mU Sigma)
  • Magnesium stearate 0.4 g Add each of the above ingredients and mix well to make tablets for tableting according to the wet tablet preparation method. Add magnesium stearate and tablet, making 400 tablets. Tablets may be sugar-coated as necessary.
  • the syrup 300g sugar 650g were melted in the 0.99 ° C, after cooling to 120 ° C, the Kuen acid 10g after was Karoe, 13
  • the peroxisome proliferator-responsive receptor ⁇ activator according to the present invention suppresses or prevents insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, etc., hyperlipidemia, hypertension, etc. Can be used.

Abstract

An activator for peroxisome proliferator-activated receptor Ϝ characterized by containing at least one compound selected from the group consisting of dehydroabietic acid, 13β-Δ8-dihydroabietic acid and isopimaric acid or a pharmaceutically acceptable salt thereof. This activator is useful in preventing or ameliorating at least one symptom selected form the group consisting of insulin resistance, type 2 diabetes, hyperlipemia, hypertension, obesity of the visceral fat type and fatty liver.

Description

明 細 書  Specification
ペルォキシソーム増殖剤応答性受容体 PPAR /活性化剤、および該活 性化剤を含有する特定症状の予防または改善用組成物  Peroxisome proliferator-responsive receptor PPAR / activator and a composition for preventing or ameliorating specific symptoms containing the activator
技術分野  Technical field
[0001] 本発明は、ペルォキシソーム増殖剤応答性受容体 γ活性化剤、および該活性ィ匕 剤を含有する特定症状の予防または改善用組成物に関する。より詳細には、ペルォ キシソーム増殖剤応答性受容体 γ活性化剤として作用し、インスリン抵抗性、 2型糖 尿病、高脂血、高血圧、内臓脂肪型肥満および脂肪肝からなる群より選ばれる少なく とも一種の症状を予防または改善する作用を有する組成物に関する。  [0001] The present invention relates to a peroxisome proliferator-responsive receptor γ activator and a composition for preventing or ameliorating a specific symptom comprising the active agent. More specifically, it acts as a peroxisome proliferator-activated receptor gamma activator and is selected from the group consisting of insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver The present invention relates to a composition having an action of preventing or ameliorating at least one kind of symptom.
背景技術  Background art
[0002] ペルォキシソーム増殖剤応答性受容体 (PPAR)は、脂質や糖の代謝糖に関与す る遺伝子群の発現制御を担う核内受容体ファミリーに属する活性化剤依存性転写制 御因子である。 PPARには、 PPAR— a、 PPAR- δ、 PPAR- γの 3種が知られて いる。 PPAR- γは主に脂肪組織、免疫細胞、副腎、脾臓、小腸で、 PPAR- aは 主に脂肪組織、肝臓、腎臓、骨格筋で発現し、 PPAR- δは主に組織特異性が見ら れず普遍的に発現して 、ることが知られて!/、る（非特許文献 1)。  [0002] Peroxisome proliferator-activated receptor (PPAR) is an activator-dependent transcriptional regulator belonging to the nuclear receptor family that controls the expression of genes involved in lipid and sugar metabolizing sugars. . There are three known PPARs: PPAR-a, PPAR-δ, and PPAR-γ. PPAR-γ is mainly expressed in adipose tissue, immune cells, adrenal gland, spleen, and small intestine, PPAR-a is expressed mainly in adipose tissue, liver, kidney, and skeletal muscle, and PPAR-δ is mainly observed in tissue specificity. It is known that it is universally expressed and is known!
[0003] これら PPARのサブタイプのうち PPAR— γは脂肪細胞の分化に関わっており、こ の活性化剤 (ァゴ二スト）は脂肪細胞分化を促進すること、血中グルコースを活発に 取り込む脂肪細胞の数を増やして血糖値を下げること、インスリン非感受性の肥大化 脂肪細胞の過形成を抑えること、インスリンに対して高!、感受性をもった小型脂肪細 胞を増加させて血糖値を低下させること、アディポネクチン生成量を上昇させること、 血中脂質 (とくにトリグリセリド)を低下させること、血管構成細胞の機能を制御すること などが知られている（非特許文献 2、 3、 4、 5、 6)。このため、 PPAR— γ活性化剤は 、内臓脂肪低減、内臓脂肪の蓄積抑制、脂質代謝異常の改善、糖代謝異常の改善 に有用であり、インスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満、脂 肪肝等の予防および Ζまたは改善剤として有効である。  [0003] Among these PPAR subtypes, PPAR-γ is involved in adipocyte differentiation, and this activator (agonist) promotes adipocyte differentiation and actively takes up blood glucose. Increases the number of fat cells to lower blood sugar level, hypersensitivity to insulin insensitivity, suppresses hyperplasia of fat cells, increases insulin sensitivity! Increases sensitive small fat cells to lower blood sugar level It is known to decrease, increase adiponectin production, decrease blood lipids (particularly triglycerides), and control the function of vascular constituent cells (Non-Patent Documents 2, 3, 4, 5). 6). Therefore, PPAR-γ activator is useful for reducing visceral fat, suppressing accumulation of visceral fat, improving lipid metabolism abnormality, improving glucose metabolism abnormality, insulin resistance, type 2 diabetes, hyperlipidemia, hypertension It is effective as an agent for preventing and improving or reducing visceral fat obesity, fatty liver and the like.
[0004] PPAR- γ活性化剤としては、分子内に共役トリェン構造ゃテトラェン構造を有す る炭素数 10〜26の不飽和脂肪酸 (特許文献 1)、 a リノレン酸、エイコサペンタエ ン酸、ドコサへキサェン酸などの不飽和脂肪酸、 9ーヒドロキシォクタデカジエン酸ゃ 13 -ヒドロキシォクタデカジエン酸などのヒドロキシ脂肪酸類、また 15 デォキシ Δ 12 プロスタグランジン J2や Δ 12 プロスタグランジン J2などのァラキドン酸代謝 物（非特許文献 2)、ピオグリタゾン、トログリタゾン、ロシグリタゾンなどのチアゾリジン 誘導体 (非特許文献 4、 7)などが知られている。 [0004] PPAR-γ activator has conjugated triene structure or tetrane structure in the molecule. Unsaturated fatty acids having 10 to 26 carbon atoms (Patent Document 1), a unsaturated fatty acids such as linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, 9-hydroxyoctadecadienoic acid 13-hydroxyoctadedecadiene Hydroxy fatty acids such as acids, arachidonic acid metabolites such as 15 deoxy Δ 12 prostaglandin J2 and Δ 12 prostaglandin J2 (non-patent document 2), thiazolidine derivatives such as pioglitazone, troglitazone, and rosiglitazone (non-patent document) 4 and 7) are known.
[0005] これらの PPAR— y活性化剤のうち、前記チアゾリジン誘導体は優れたインスリン 改善作用を有し、 2型糖尿病の治療薬として臨床使用されている。しかしながら、チア ゾリジン誘導体は肝障害、体重増加などの強い副作用を引き起こすという問題点が あり、より安全な抗糖尿病薬の開発が望まれている。  [0005] Among these PPAR-y activators, the thiazolidine derivative has an excellent insulin improving action and is clinically used as a therapeutic agent for type 2 diabetes. However, thiazolidine derivatives have problems that cause strong side effects such as liver damage and weight gain, and development of safer antidiabetic drugs is desired.
[0006] ロジンを構成する榭脂酸の一種であるアビェチン酸力 PPAR— γ活性化剤である ことが知られている（非特許文献 8参照)。し力しながら、ァビエチン酸の当該活性は 強いとは言えず、また非特許文献 8ではアビェチン酸以外の榭脂酸の当該活性に関 しては、一切の教示も示唆もされていない。  [0006] It is known that it is an abietic acid PPAR-γ activator, which is a kind of succinic acid constituting rosin (see Non-Patent Document 8). However, the activity of abietic acid is not strong, and Non-Patent Document 8 does not teach or suggest any of the activity of succinic acid other than abietic acid.
[0007] 特許文献 1：特開 2000— 355538号公報  [0007] Patent Document 1: Japanese Unexamined Patent Publication No. 2000-355538
非特許文献 1 :医学のあゆみ， 1998年， 184卷， 519〜523頁  Non-Patent Document 1: History of Medicine, 1998, 184 卷, 519-523
非特許文献 2 :ダイアベトロジァ， 1999年， 42卷， 1033〜1049頁  Non-Patent Document 2: Diabetology, 1999, 42 卷, 1033-1049
非特許文献 3 :日本臨床， 2005年， 63卷， 4号， 539〜548頁  Non-Patent Document 3: Japanese Clinical, 2005, 63 卷, 4, 539-548
非特許文献 4:日本臨床， 2005年， 63卷， 4号， 549〜555頁  Non-Patent Document 4: Japanese Clinical Practice, 2005, 63 卷, 4, 549-555
非特許文献 5 :日本臨床， 2005年， 63卷， 4号， 557〜562頁  Non-Patent Document 5: Japanese Clinical Practice, 2005, 63 卷, No. 4, pp. 557-562
非特許文献 6 :日本臨床， 2005年， 63卷， 4号， 631〜642頁  Non-Patent Document 6: Japanese Clinical, 2005, 63 卷, No. 4, pp. 631-642
非特許文献 7 :薬学雑誌， 2002年， 122卷 (11号） , 909〜918頁  Non-Patent Document 7: Journal of Pharmaceutical Sciences, 2002, 122 (11), 909-918
非特許文献 8 :エフ'ィ一'ビ一'エス'レターズ， 2003年， 550号， 190〜194頁 発明の開示  Non-Patent Document 8: F'B'B'S 'Letters, 2003, 550, 190-194 Disclosure of the Invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] 本発明は、安全性が高ぐ有用なペルォキシソーム増殖剤応答性受容体 γ活性化 剤を提供すること、およびインスリン抵抗性、 2型糖尿病、内臓脂肪型肥満、脂肪肝、 高脂血、高血圧などを予防または改善する作用を有する糸且成物を提供することを目 的とする。 [0008] The present invention provides a useful peroxisome proliferator-responsive receptor γ activator with high safety, and insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, hyperlipidemia The aim is to provide a thread and composition that has the effect of preventing or ameliorating hypertension, etc. Target.
課題を解決するための手段  Means for solving the problem
[0009] 本発明者らは、天然物であるロジン中に含有される榭脂酸成分に着目し、そのペル ォキシソーム増殖剤応答性受容体 γ活性化との関係について鋭意検討した結果、口 ジン中の特定の榭脂酸やその誘導体、すなわち、デヒドロアビエチン酸、 13 |8— Δ8 —ジヒドロアビエチン酸およびイソピマル酸力もなる群より選ばれる少なくとも一種の 化合物またはその薬学的に許容される塩が、優れたペルォキシソーム増殖剤応答性 受容体 γ活性化作用を有することを見出し、この知見に基づいてさらに研究を進め、 本発明を完成するに至った。 [0009] The present inventors paid attention to the succinic acid component contained in rosin, which is a natural product, and as a result of earnestly examining its relationship with activation of peroxisome proliferator-responsive receptor γ, And at least one compound selected from the group consisting of dehydroabietic acid, 13 | 8— Δ 8 —dihydroabietic acid and isopimaric acid, or a pharmaceutically acceptable salt thereof. The present inventors have found that it has an excellent peroxisome proliferator-responsive receptor γ activation action, and further research based on this finding has led to the completion of the present invention.
[0010] すなわち、本発明は、  [0010] That is, the present invention provides:
(1)デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸から なる群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩を有効 成分として含有することを特徴とするペルォキシソーム増殖剤応答性受容体 γ活性 化剤、 (1) Peroxisomes comprising at least one compound selected from the group consisting of dehydroabietic acid, 13 j8- Δ 8 -dihydroabietic acid and isopimaric acid or a pharmaceutically acceptable salt thereof as an active ingredient Proliferator-responsive receptor γ activator,
(2)ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を予防ま たは改善するための前記（1)記載のペルォキシソーム増殖剤応答性受容体 γ活性 化剤、  (2) Peroxisome proliferator-responsive receptor γ activator according to (1) above for preventing or ameliorating a disease or condition mediated by peroxisome proliferator-responsive receptor γ,
(3)ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が、インス リン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満または脂肪肝である前 記（2)記載のペルォキシソーム増殖剤応答性受容体 γ活性化剤、  (3) The disease or symptom mediated by peroxisome proliferator-activated receptor γ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat type obesity or fatty liver as described in (2) above Peroxisome proliferator-activated receptor γ activator,
(4)インスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満もしくは脂肪 肝の予防または改善用組成物である前記（1)記載のペルォキシソーム増殖剤応答 性受容体 0活性化剤、  (4) The peroxisome proliferator-responsive receptor 0 activator according to (1) above, which is a composition for preventing or improving insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver ,
(5)前記（1)記載のペルォキシソーム増殖剤応答性受容体 γ活性化剤を含有するこ とを特徴とするインスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満もし くは脂肪肝の予防または改善用組成物、  (5) Insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat-type obesity or peroxisome proliferator-responsive receptor γ activator according to (1) A composition for preventing or improving fatty liver,
(6)医薬組成物である前記（5)記載の予防または改善用組成物、  (6) The preventive or ameliorating composition according to (5), which is a pharmaceutical composition,
(7)食品である前記（5)記載の予防または改善用組成物、 (8)デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸から なる群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩を含有 し、かつペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が予 防または改善される旨を表示したことを特徴とする食品、 (7) The composition for prevention or improvement according to the above (5), which is a food, (8) a peroxisome proliferator-responsive receptor comprising at least one compound selected from the group consisting of dehydroabietic acid, 13 j8- Δ 8 -dihydroabietic acid and isopimaric acid, or a pharmaceutically acceptable salt thereof a food characterized in that a disease or symptom mediated by γ is prevented or improved,
(9)ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が、インス リン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満または脂肪肝である前 記（8)記載の食品、  (9) The disease or symptom mediated by peroxisome proliferator-responsive receptor γ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver as described in (8) above Food,
(10)ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を有する 患者に、デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル 酸力 なる群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩 を投与することを特徴とするペルォキシソーム増殖剤応答性受容体 γが介在する疾 患または症状の予防または改善方法、および (10) At least one compound selected from the group consisting of dehydroabietic acid, 13 j8—Δ 8 —dihydroabietic acid and isopimaric acid, or a compound thereof, for a patient having a disease or symptom mediated by peroxisome proliferator-responsive receptor γ A method for preventing or ameliorating a disease or symptom mediated by a peroxisome proliferator-responsive receptor γ, comprising administering a pharmaceutically acceptable salt; and
(11)ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を予防ま たは改善する薬剤の製造のためのデヒドロアビエチン酸、 13 β— Δ 8—ジヒドロアビ ェチン酸およびイソピマル酸力 なる群より選ばれる少なくとも一種の化合物または その薬学的に許容される塩の使用、 (11) Peruokishisomu proliferator-activated receptor γ is dehydroabietic acid for the manufacture of a medicament for improvement of were prevention or a disease or condition mediated, 13 β- Δ 8 - than Jihidoroabi Echin acid and isopimaric acid strength becomes the group Use of at least one selected compound or a pharmaceutically acceptable salt thereof,
に関する。 About.
発明の効果 The invention's effect
本発明のペルォキシソーム増殖剤応答性受容体 γ活性化剤における有効成分で あるデヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸また はその薬学的に許容される塩は、いずれも優れたペルォキシソーム増殖剤応答性受 容体 γ活性化作用を有し、し力も天然物に由来するため安全性が高い。このため、 本発明のペルォキシソーム増殖剤応答性受容体 Ί活性化剤またはそれを含有した 組成物は、ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状、と くにインスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満および脂肪肝 力 なる群より選ばれる少なくとも一種の症状を予防または改善するため有用であり、 医薬または食品に適用できる。 Which is the active ingredient dehydroabietic acid in Peruokishisomu proliferator-activated receptor γ activator of the present invention, 13 j8- Δ 8 - salt or dihydroabietic acid and isopimaric acid are pharmaceutically acceptable are all excellent Peroxisome proliferator-responsive receptor has a gamma activation action, and its strength is derived from natural products, so it is highly safe. Therefore, compositions containing the same or Peruokishisomu proliferator-activated receptor Ί activator of the present invention, the disease or condition Peruokishisomu proliferator-activated receptor γ mediated, the country insulin resistance, type 2 diabetes mellitus It is useful for preventing or ameliorating at least one symptom selected from the group consisting of hyperlipidemia, hypertension, visceral fat type obesity and fatty liver power, and can be applied to medicines or foods.
発明を実施するための最良の形態 [0012] 以下、本発明を詳細に説明する。 BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
本発明のペルォキシソーム増殖剤応答性受容体 Ί活性化剤は、デヒドロアビエチ ン酸、 13 j8— Δ 8 ジヒドロアビエチン酸およびイソピマル酸力 なる群より選ばれる 少なくとも一種の化合物またはその薬理学的に許容される塩を有効成分として含有 することを特徴とする。 Peruokishisomu proliferator-activated receptor Ί activator of the present invention, Dehidoroabiechi phosphate, 13 j8- Δ 8 least one compound or a pharmaceutically selected from dihydroabietic acid and isopimaric acid force group consisting acceptable It contains a salt obtained as an active ingredient.
[0013] 本発明のペルォキシソーム増殖剤応答性受容体 γ活性化剤における有効成分 (遊 離酸)の構造式を示せば、次の通りである。  [0013] The structural formula of the active ingredient (free acid) in the peroxisome proliferator-activated receptor γ activator of the present invention is as follows.
[化 1]  [Chemical 1]
Figure imgf000006_0001
Figure imgf000006_0001
デヒ ドロアビエチン酸 1 3 (3 — Δ 8 ジヒ ドロアピエチン酸 イソ ピマル酸 Dehydroabietic acid 1 3 (3 — Δ 8 Dihydroapietic acid Isopimaric acid
[0014] 前記有効成分のうちデヒドロアビエチン酸は、一般的に榭脂酸と呼ばれ、松の木か ら製造される松脂を精製して得られる軟化点約 70〜80°Cの琥珀色の透明ガラス状 榭脂（ロジン）の成分である。 13 j8 - Δ 8 ジヒドロアビエチン酸はロジンを水素化し て得られる水素化ロジンの成分である。またイソピマル酸はロジンの成分である。これ らは、それぞれ公知の化合物である力 ペルォキシソーム増殖剤応答性受容体 γ活 性化剤の有効成分としては、本願以前には全く知られて!/、な 、。 [0014] Among the active ingredients, dehydroabietic acid is generally called succinic acid, and is an amber transparent glass having a softening point of about 70 to 80 ° C obtained by refining pine resin produced from pine trees. It is a component of rosin. 13 j8-Δ 8 Dihydroabietic acid is a component of hydrogenated rosin obtained by hydrogenating rosin. Isopimaric acid is a component of rosin. These are all known as active ingredients of force peroxisome proliferator-activated receptor γ activators, which are known compounds, respectively!
[0015] 該有効成分である化合物は公知の方法で容易に単離 '精製あるいは合成できる。  [0015] The compound as the active ingredient can be easily isolated and purified or synthesized by a known method.
例えば、メルクシ酸の場合は特開昭 51— 131899号公報に記載の方法、デヒドロア ビエチン酸の場合はジャーナル.ォブ.オーガニック.ケミストリー， 1966年， 31卷， 4 246〜4247頁に記載の方法、 13 Δ 8—ジヒドロアビエチン酸の場合は特開昭 5 1 149256号公報に記載の方法、イソピマル酸の場合はジャーナル ·ォブ ·オーガ ニック'ケミストリー， 1958年， 28卷， 25〜26頁に記載の方法等を採用できる。本発 明のペルォキシソーム増殖剤応答性受容体 γ活性化剤では、上記の方法で精製' 単離された少なくとも一種の榭脂酸またはその薬学的に許容される塩を、単独または 適宜に組合せて用いてもょ ヽ。 For example, in the case of mercucic acid, the method described in JP-A-51-131899, and in the case of dehydroabietic acid, the method described in Journal of Organic Chemistry, 1966, 31 卷, 4 pages 246-4247. , 13 delta 8 - the method described in JP-a 5 1 149 256 discloses the case of dihydroabietic acid, journal O Bed auger Nick 'chemistry for isopimaric acid, 1958, 28 Certificates, pp 25-26 The described method can be employed. In the peroxisome proliferator-responsive receptor γ activator of the present invention, at least one succinic acid or a pharmaceutically acceptable salt thereof purified or isolated by the above method is used alone or It can be used in combination as appropriate.
[0016] 本発明の有効成分が塩の場合、力かる塩としては、薬理学的に許容されるものす ベてが含まれる。薬理学的に許容される塩は毒性の少ないものが好ましい。適当な 塩として、例えばアルカリ金属 (カリウム、ナトリウム、リチウム等）の塩、アルカリ土類金 属（カルシウム、マグネシウム等）の塩、アンモ-ゥム塩 (テトラメチルアンモ -ゥム塩、 テトラプチルアンモ-ゥム塩等)または有機アミン（トリェチルァミン、メチルァミン、ジメ チルァミン、シクロペンチルァミン、ベンジルァミン、フエネチルァミン、ピぺリジン、モ ノエタノールアミン、ジエタノールァミン、トリス（ヒドロキシメチル)メチルァミン、リジン、 アルギニン、 N—メチル D グルタミン等）の塩等が挙げられる。  [0016] When the active ingredient of the present invention is a salt, examples of a strong salt include all pharmacologically acceptable ones. A pharmacologically acceptable salt is preferably a less toxic salt. Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetraptylammonium salt). -Um salt etc.) or organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N -Methyl D glutamine etc.) and the like.
[0017] これら有効成分の PPAR y活性化作用（PPAR yァゴ-スト活性）は、例えばエフ · ィ一.ビ一.エス レターズ， 2002年， 514卷， 315〜322頁等の方法で測定できる。 すなわち、 PPAR- γのリガンド結合部位と GAL4 (酵母の DNA結合性転写因子活 性ィ匕因子）の DNA結合部位のキメラタンパクを産生するプラスミド (pM— PPAR γ ) と、レポーター遺伝子であるルシフェラーゼ遺伝子の上流に GAL4の応答配列（UA Sg)が 4個組み込まれて ヽるプラスミド (4 X UASg-luc)を、アフリカミドリザル腎臓 由来培養細胞（CV— 1)にリポフエクシヨン法によりコトランスフエクシヨンし、得られた トランスフォーマントを一定期間培養後、被験化合物と接触させることにより、 PPAR γ GAL4キメラタンパクを活性化させ、 4 X UASg— luc上流の UASgへの結合を 亢進し、それによりルシレラーゼの産生を増加させる。 PPAR γ活性ィ匕作用は、産生 されたルシフェラーゼの活性を測定することにより評価することができる。  [0017] The PPAR y activating action (PPAR y agonist activity) of these active ingredients is measured by the method of, for example, EF I. B I. S Letters, 2002, 514 卷, 315-322. it can. That is, a plasmid (pM—PPARγ) that produces a chimeric protein of the ligand binding site of PPAR-γ and the DNA binding site of GAL4 (yeast DNA-binding transcription factor activity factor), and the luciferase gene that is the reporter gene The plasmid (4 X UASg-luc) containing 4 GAL4 response elements (UA Sg) incorporated upstream is cotransfected into the cultured cells of African green monkey kidney (CV-1) by the lipofussion method. The obtained transformant is cultured for a certain period of time, and then contacted with the test compound to activate the PPARγ GAL4 chimeric protein and enhance the binding to UASg upstream of 4 X UASg-luc, thereby producing luciferase. increase. The PPARγ activity can be evaluated by measuring the activity of the produced luciferase.
[0018] なお、上記測定法において、 PPAR- yのリガンド結合部位のタンパクは、ヒト PP AR- γアミノ酸配歹 [J (http://www.genome.jp/dbget— bin/www— bget?sp:PPAR—HUMA N参照）において、アミノ酸配列 174〜475〖こ相当する。また、 GAL4 (酵母の DNA 結合性転写因子活性化因子）の DNA結合部位のタンパクは、 GAL4のアミノ酸配列 (http://www.genome. jp/dbget— bin/www_bget?sp:GAL4_YEAST参照）にお 、て、アミ ノ酸配列 1〜 147に相当する。  [0018] In the above measurement method, the protein at the ligand binding site of PPAR-y is a human PP AR-γ amino acid conjugate [J (http://www.genome.jp/dbget-bin/www-bget? sp: PPAR—HUMA N)) corresponding to the amino acid sequence of 174 to 475%. The protein of the DNA binding site of GAL4 (yeast DNA-binding transcription factor activator) is the amino acid sequence of GAL4 (see http://www.genome.jp/dbget—bin/www_bget?sp:GAL4_YEAST) It corresponds to amino acid sequence 1-147.
[0019] また、本発明の有効成分は、 PPAR γ活性ィ匕作用に基づき、糖代謝改善作用、脂 質代謝改善作用、血糖降下作用、体脂肪蓄積抑制作用、内臓脂肪蓄積抑制作用、 インスリン低下作用などを発揮すると共に、本発明の有効成分は、肥満に関連する 炎症性因子であるサイト力イン (例えば、 MCP—1)の減少作用を有する。このため、 本発明のペルォキシソーム増殖剤応答性受容体 Ύ活性化剤は、肥満に伴う生活習 慣病ゃメタボリックシンドロームの予防、改善剤として有用であり、より具体的には、ィ ンスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満および脂肪肝などの 予防 ·改善剤として有用である。 [0019] Further, the active ingredient of the present invention is based on the PPAR γ activity activity, and improves glucose metabolism, improves fat metabolism, lowers blood glucose, suppresses body fat accumulation, inhibits visceral fat accumulation, In addition to exerting an insulin lowering action and the like, the active ingredient of the present invention has an action of reducing cytodynamic force (for example, MCP-1) which is an inflammatory factor related to obesity. Therefore, Peruokishisomu proliferator-activated receptor Ύ activator of the present invention, the prevention of lifestyle-related diseases Ya metabolic syndrome associated with obesity, are useful as improvers, more specifically, I insulin resistance, 2 It is useful as a preventive / ameliorating agent for type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity and fatty liver.
[0020] 本発明のペルォキシソーム増殖剤応答性受容体 γ活性化剤およびそれを含む組 成物 (以下、両者を合わせて製剤ともいう）を医薬とする場合、慣用の担体と共に経 口剤、注射剤、外用剤または坐剤または吸入剤等とされる。経口剤としては、例えば 錠剤、顆粒剤、細粒剤、散剤、カプセル剤、液剤、乳剤、懸濁剤、シロップ剤等の剤 形が挙げられる。これら製剤は自体公知の方法によって製造することができる。たとえ ば、顆粒剤、細粒剤、散剤および錠剤とする場合には、本発明の有効成分と、医薬 上許容される添加剤、例えば賦形剤（例.乳糖、デンプン、ショ糖、ブドウ糖、マン-ト ール、コンスターチ、無機塩類等）、滑沢剤（例.タルク、ロウ類、水素添加植物油、シ ョ糖脂肪酸エステル、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 酸アルミニウム等）、崩壊剤（例.カルメロース、カルメロースカルシウム、デンプン、結 晶セルロース、低置換ヒドロキシプロピルセルロース等）、結合剤（例.デンプン、デキ ストリン、アラビアゴム末、ヒドロキシプロピルスターチ、結晶セルロース、ェチルセル口 ース、メチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセ ルロース、ポリビュルピロリドン等)などと共に公知の方法で混和し、造粒、打錠または 粉砕することにより製造することができる。なお、顆粒剤および錠剤には、適当なコー ティング剤（例.ゼラチン、白糖、アラビアゴム、カルナパロウ等）、腸溶性コーティング 剤（例.酢酸フタル酸セルロース、メタアクリル酸コポリマー、ヒドロキシプロピルセル口 ースフタレート、カルボキシメチルェチルセルロース等）などで剤皮を施してもよ 、。  [0020] When the peroxisome proliferator-responsive receptor γ activator of the present invention and a composition containing the peroxisome proliferator-responsive receptor γ activator (hereinafter, both are also referred to as a preparation) are used as pharmaceuticals, oral agents and injections together with conventional carriers are used. Suppositories, external preparations, suppositories or inhalants. Examples of oral preparations include dosage forms such as tablets, granules, fine granules, powders, capsules, solutions, emulsions, suspensions, and syrups. These preparations can be produced by a method known per se. For example, in the case of granules, fine granules, powders and tablets, the active ingredient of the present invention and pharmaceutically acceptable additives such as excipients (eg lactose, starch, sucrose, glucose, Mantle, starch, inorganic salts, etc.), lubricants (eg talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, etc.), disintegrants ( Examples: carmellose, carmellose calcium, starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, etc.), binders (eg starch, dextrin, gum arabic powder, hydroxypropyl starch, crystalline cellulose, ethyl cellulose, methylcellulose, Sodium carboxymethyl cellulose, hydroxypropyl cellulose, polybule Mix by known methods, etc.) together with such pyrrolidone, granulation, can be produced by tabletting or grinding. For granules and tablets, suitable coating agents (eg, gelatin, sucrose, gum arabic, carnapa wax, etc.), enteric coating agents (eg, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropyl cellulose phthalate) , Carboxymethylethyl cellulose, etc.).
[0021] カプセル剤として製造する場合には、本発明の有効成分を公知の賦形剤と共に均 等に混和し、または粒状ィ匕し、若しくは粒状ィ匕し、必要によりさらに適当なコーティン グ剤で剤皮を施したのち、カプセルに充填するカゝ、適当なカプセル基剤（例.ゼラチ ン等）にグリセリンまたはソルビトール等を加えて塑性を増したカプセル基剤で被包成 形してもよい。該賦形剤としては、例えば、流動性と滑沢性を向上させるためのステア リン酸マグネシウム、ステアリン酸カルシウム、タルクまたは軽質無水ケィ酸、加圧流 動性のための結晶セルロースや乳糖、あるいは上記崩壊剤等が挙げられる。 [0021] In the case of producing as a capsule, the active ingredient of the present invention is uniformly mixed with known excipients, or granulated or granulated, and if necessary, a more suitable coating agent. After coating with capsule, encapsulate with capsule base with increased plasticity by adding glycerin or sorbitol to appropriate capsule base (eg gelatin) etc. You may shape it. Such excipients include, for example, magnesium stearate, calcium stearate, talc or light anhydrous key acid to improve fluidity and lubricity, crystalline cellulose and lactose for pressurized fluidity, or the above disintegration Agents and the like.
[0022] 乳剤、懸濁剤またはシロップ剤として製造する場合には、例えば安定剤（例.ェデト 酸ナトリウム等）、懸濁化剤 (例.アラビアゴム、カルメロース等）、矯味剤 (例.単シロッ プ、ブドウ糖等)、芳香剤、精製水、ヱタノール、植物油、乳化剤等を適宜選択して使 用することができる。  [0022] When manufactured as an emulsion, suspension, or syrup, for example, a stabilizer (eg, sodium edetate), a suspending agent (eg, gum arabic, carmellose, etc.), a flavoring agent (eg, simple substance) Syrup, glucose, etc.), fragrance, purified water, butanol, vegetable oil, emulsifier and the like can be appropriately selected and used.
[0023] 上記注射剤は、水性注射剤または油性注射剤の 、ずれでもよ!/ヽ。水性注射剤とす る場合、公知の方法に従って、例えば、水性溶媒 (例.注射用蒸留水、生理食塩水、 ブドウ糖水溶液等）に、医薬上許容される添加剤、例えば等張化剤 (例.塩ィ匕ナトリウ ム、塩化カリウム、グリセリン、マン-トール、ソルビトール、ブドウ糖、プロピレングリコ ール等）、緩衝剤（例.リン酸緩衝液、酢酸緩衝液、炭酸緩衝液、クェン酸緩衝液、ト リス緩衝液、グルタミン酸緩衝液、ィプシロンアミノカプロン酸緩衝液等）、保存剤（例 .クロロブタノール等）、増粘剤（例.ヒドロキシェチルセルロース、ヒドロキシプロピル セルロース、ポリビュルアルコール、ポリエチレングリコール等）、安定化剤（例.亜硫 酸水素ナトリウム、チォ硫酸ナトリウム、ェデト酸ナトリウム、クェン酸ナトリウム、ァスコ ルビン酸等）、懸濁剤（例.アラビアゴム、トラガント、デキストリン、メチルセルロース、 カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシェチ ルセルロース、アルギン酸ナトリウム、カルボキシビュルポリマー、ポリビュルアルコー ル、ポリビュルピロリドン、ベントナイト、ビーガムまたは無水ケィ酸等）、乳化剤（ラウリ ル硫酸ナトリウム、ソルビタン、脂肪酸エステル、ポリオキシエチレンソルビタン、ポリオ キシエチレン脂肪酸エステルまたはモノグリセリド等)または pH調整剤（例.塩酸、水 酸化ナトリウム、リン酸、酢酸等)などを適宜添加した溶液に、本発明の有効成分を溶 解した後、フィルタ一等で濾過して滅菌し、次いで無菌的な容器に充填することによ り調製することができる。また適当な溶解補助剤、例えばアルコール (エタノール等）、 ポリアルコール（プロピレングリコール、ポリエチレングリコール等）、非イオン界面活 性剤（ポリソルベート 80、ポリオキシエチレン硬化ヒマシ油 50等)などを使用してもよ い。油性注射剤とする場合、油性溶媒としては、例えば、ゴマ油、落花生油、大豆油 、トウモロコシ油等が用いられ、溶解補助剤として安息香酸ベンジル、ベンジルアル コール等を使用してもよい。調製された注射液は、通常、適当なアンプルまたはバイ アルに充填される。注射剤中の本発明の有効成分の濃度は、通常約 0. 001〜10. OwZv%程度、好ましくは約 0. 005-5. OwZv%程度に調整される。 [0023] The injection may be an aqueous injection or an oily injection! In the case of an aqueous injection, according to a known method, for example, an aqueous solvent (eg, distilled water for injection, physiological saline, aqueous glucose solution, etc.), a pharmaceutically acceptable additive, eg, an isotonic agent (eg, Sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, glucose, propylene glycol, etc.), buffer (eg phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, epsilon aminocaproate buffer, etc.), preservative (eg, chlorobutanol, etc.), thickener (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polybutanol, polyethylene glycol) Etc.), stabilizers (eg, sodium hydrogen sulfite, sodium thiosulfate, sodium edetate, sodium quenate, ascorbic acid, etc.) Suspending agents (eg, gum arabic, tragacanth, dextrin, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxycellulose, sodium alginate, carboxybule polymer, polybulal alcohol, polybulurpyrrolidone, bentonite, bee gum, anhydrous kelic acid Etc.), emulsifier (sodium lauryl sulfate, sorbitan, fatty acid ester, polyoxyethylene sorbitan, polyoxyethylene fatty acid ester, monoglyceride, etc.) or pH adjuster (eg hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.) The active ingredient of the present invention can be dissolved in the added solution, then sterilized by filtration with a filter or the like, and then filled into an aseptic container. Also suitable solubilizers such as alcohols (ethanol, etc.), polyalcohols (propylene glycol, polyethylene glycol, etc.), nonionic surfactants (polysorbate 80, polyoxyethylene hydrogenated castor oil 50, etc.) can be used. Good. In the case of an oily injection, examples of the oily solvent include sesame oil, peanut oil, and soybean oil. Corn oil or the like may be used, and benzyl benzoate, benzyl alcohol or the like may be used as a solubilizing agent. The prepared injection solution is usually filled in an appropriate ampoule or vial. The concentration of the active ingredient of the present invention in the injection is usually adjusted to about 0.001 to 10. OwZv%, preferably about 0.005 to OwZv%.
[0024] また、外用剤としては、軟膏剤、クリーム剤、ローション剤等挙げられ、軟膏剤やタリ ーム剤の場合には、例えば吸水軟膏、親水軟膏、単軟膏、白色軟膏またはマクロゴ ール軟膏あるいは、ステアリルアルコール、セタノール、パラフィン、流動パラフィン、 蜜蝌、ヤシ油等の公知の基剤と混和する等製剤上の常法により調製することができる [0024] Examples of the external preparation include ointments, creams, lotions, and the like. In the case of ointments and talums, for example, water-absorbing ointments, hydrophilic ointments, simple ointments, white ointments or macrogols. Can be prepared by conventional methods such as ointments or blended with known bases such as stearyl alcohol, cetanol, paraffin, liquid paraffin, beeswax and coconut oil.
[0025] ローション剤には、通常用いられる添加剤が含まれていてもよぐ例えばこのような 添加剤として、懸濁剤、乳化剤、湿潤剤（例えば、グリセリン、プロピレングリコール、ソ ルビトール、 1, 3—ブチレングリコール、 dl—ピロリドンカルボン酸、乳酸ナトリウム等） または保存剤（例えば、ノラオキシ安息香酸エステル類、塩ィ匕ベンザルコ-ゥム、クロ ロブタノール、ベンジルアルコール、デヒドロ酢酸ナトリウム、ェデト酸ナトリウム、ホウ 酸、ホウ砂等)などが挙げられる。上記したこれらの添加剤を用いて、常法に従って口 ーシヨン剤を調製することができる。 [0025] The lotion may contain commonly used additives. Examples of such additives include suspending agents, emulsifiers, wetting agents (for example, glycerin, propylene glycol, sorbitol, 1, 3-butylene glycol, dl-pyrrolidone carboxylic acid, sodium lactate, etc.) or preservatives (for example, noraoxybenzoates, salt benzalkonium, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sodium edetate, Boric acid, borax, etc.). Using these additives described above, mouth lotions can be prepared in accordance with conventional methods.
[0026] 坐剤も慣用の基剤（例えばカカオ脂、ラウリン脂、グリセ口ゼラチン、マクロゴール、 ウイテツプゾル等)を用いた製剤上の常法によって調製することができる。  [0026] Suppositories can also be prepared by a conventional formulation method using conventional bases (for example, cacao butter, laurin butter, glyce gelatin, macrogol, witepsol, etc.).
[0027] また、吸入剤も製剤上の常套手段によって調整することができる。吸入剤として製 造する場合、その添加剤としては、一般に吸入用製剤に使用される添加剤であれば いずれのものであってもよぐ例えば、噴射剤の他、上記した賦形剤、結合剤、滑沢 剤、保存剤、安定化剤、等張化剤、 PH調整剤または矯味剤 (タエン酸、メントール、 グリチルリチンアンモ-ゥム塩、グリシン、香料等)などが用いられる。噴射剤としては 、液化ガス噴射剤、圧縮ガス等が用いられる。液化ガス噴射剤としては、例えば、フッ 化炭化水素（HCFC22、 HCFC— 123、 HCFC—134a、 HCFC142等の代替フロ ン類等）、液化石油、ジメチルエーテル等が挙げられる。圧縮ガスとしては、例えば、 可溶性ガス (炭酸ガス、亜酸ィ匕窒素ガス等）、不溶性ガス（窒素ガス等)などが挙げら れる。 [0028] 本発明の製剤を医薬として用いる場合、有効成分の投与量は、患者の年齢、体重 、疾患の程度、剤型により異なるが、例えば注射剤の場合、成人に対する投与量は、 重量として通常約 0. Olmg〜： LgZ日であり、経口剤の場合は、重量として、通常約 0 . Olmg〜： LgZ曰である。 [0027] Inhalants can also be adjusted by conventional means in the preparation. When manufactured as an inhalant, the additive may be any additive generally used in inhalable preparations. For example, in addition to a propellant, the above-mentioned excipients, binding Agents, lubricants, preservatives, stabilizers, tonicity agents, pH adjusting agents or flavoring agents (taenoic acid, menthol, glycyrrhizin ammonium salt, glycine, fragrance, etc.) are used. As the propellant, a liquefied gas propellant, a compressed gas, or the like is used. Examples of the liquefied gas propellant include fluorinated hydrocarbons (alternative fluorocarbons such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, dimethyl ether, and the like. Examples of the compressed gas include soluble gases (such as carbon dioxide and nitrous acid) and insoluble gases (such as nitrogen). [0028] When the preparation of the present invention is used as a medicine, the dose of the active ingredient varies depending on the age, body weight, degree of disease, and dosage form of the patient. For example, in the case of an injection, the dose for an adult is expressed as weight. Usually, about 0. Olmg to: LgZ day, and in the case of an oral preparation, it is usually about 0. Olmg to: LgZ 曰.
[0029] 本発明の製剤を食品として使用する場合、食品添加物として許容される添加物 (例 .ブドウ糖、果糖、ショ糖、マルトース、ソルビトール、ステピオサイド、ルブソサイド、コ ーンシロップ、乳糖、クェン酸、酒石酸、リンゴ酸、コハク酸、乳酸、 Lーァスコルビン 酸、 dl— a—トコフエロール、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、プロピレングリコール脂肪酸エステル、アラビアガム、力 ラギーナン、カゼイン、ゼラチン、ぺクチン、寒天、ビタミン B類、ニコチン酸アミド、ノ ントテン酸カルシウム、アミノ酸類、カルシウム塩類、色素、香料または保存剤等）と共 に、公知の方法により、錠剤、顆粒剤、カプセル剤等とすることができる。  [0029] When the preparation of the present invention is used as a food, it is an additive acceptable as a food additive (eg, glucose, fructose, sucrose, maltose, sorbitol, stepioside, rubusoside, corn syrup, lactose, quenate, tartaric acid. , Malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-a-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid Ester, gum arabic, strength laginain, casein, gelatin, pectin, agar, vitamin B, nicotinic acid amide, calcium nontate, amino acids, calcium salts, pigments, fragrances or preservatives) On the way Ri may be tablets, granules, capsules and the like.
[0030] また本発明の製剤は、他の食品成分に混合して食品とすることもできる。この場合、 他の食品成分は特に限定はされず、様々な食品に利用可能である。利用可能な食 品としては、例えば、醤油、粉末醤油、味噌、粉末味噌、もろみ、ひしお、フリカケ、マ ヨネーズ、ドレッシング、食酢、三杯酢、粉末すし酢、天つゆ、麵つゆ、ソース、ケチヤ ップ、焼肉のたれ、カレールー、中華の素、シチューの素、スープの素、ダシの素、複 合調味料、みりん、新みりん、テーブルシュガーまたはコーヒーシュガー等の調味料 、せんべい、あられ、おこし、花林糖、求肥、餅、まんじゅう、ういろう、あん、羊羹、水 羊羹、錦玉、ゼリー、カステラまたは飴玉等の和菓子、ビスケット、クラッカー、クッキー 、パイ、プリン、シュークリーム、ワッフル、スポンジケーキ、ドーナッツ、チョコレート、 チューインガム、キャラメル、キャンデーまたはグミゼリー等の洋菓子、アイスクリーム、 アイスキャンデーまたはシャーベット等の氷菓、氷蜜等のシロップ、バタークリーム、力 スタードクリーム、フラワーペースト、ピーナッツペーストまたはフルーツペースト等の スプレッドおよびペースト、ジャム、マーマレード、シロップ漬または糖菓等の加工果 実および加工野菜、パン、麵、米飯または人造肉等の穀類加工食品、サラダオイル またはマーガリン等の油脂食品、福神漬、べつたら漬、千枚漬またはらつきよう漬等の 漬物、たくあん漬の素または白菜漬の素等の漬物の素、ハムまたはソーセージ等の 畜肉製品、魚肉ハム、魚肉ソーセージ、力マボコ、チクヮまたはハンペン等の魚肉製 品、ゥ二の塩辛、イカの塩辛、酢コンブ、さきするめまたはフグのみりん干し等の珍味 、農産物、畜産物または水産物等力 製造される煮物、焼物、炒め物、揚げ物、蒸し 物またはあえ物等の惣菜、えびフライ、コロッケ、シユーマイ、ぎょうざ、春卷、ハンバ ーグステーキ、ミートボール、フィッシュハンバーグまたはフィッシュボール等の冷凍 調理食品、ハンバーグ、ミートボール、赤飯、牛めし、とり釜めし、玄米がゆ、カレー、 ミートソース、ドミグラスソース、ポタージュスープ、コンソメスープ、シチュー、おでん、 八宝菜、煮豆、焼鳥、茶碗蒸しまたは野菜の水煮等のレトルト食品、錦糸卵、乳飲料 、ノターまたはチーズ等の卵製品および乳製品、魚肉、畜肉、果実または野菜等の 瓶詰および缶詰、合成酒、醸造酒、果実酒または洋酒等の酒類、コーヒー、ココア、 ジュース、茶、紅茶、ウーロン茶、ミネラル飲料、炭酸飲料、乳酸飲料または乳酸菌飲 料等の清涼飲料、プリンミックス、ホットケーキミックス、即席ジュース、即席しるこまた は即席スープ等の即席食品等が挙げられる。 [0030] The preparation of the present invention can also be mixed with other food ingredients to make a food. In this case, other food ingredients are not particularly limited and can be used for various foods. Examples of foods that can be used include soy sauce, powdered soy sauce, miso, powdered miso, moromi, horsetail, fried potatoes, mayonnaise, dressing, vinegar, three cups of vinegar, powdered sushi vinegar, tentsuyu, katsuyu, sauce, ketchup, Yakiniku sauce, curry roux, Chinese element, stew element, soup element, dashi element, compound seasoning, mirin, new mirin, table sugar or coffee sugar, etc. Fertilizer, cocoon, manju, uirou, ann, mutton, water mutton, brocade, jelly, castella, candy, etc. , Candy, caramel, candy or gummy jelly, ice cream, eye Candy or sherbet ice confectionery, ice honey syrup, butter cream, force Stard cream, flower paste, peanut paste or fruit paste spreads and pastes, jam, marmalade, syrup pickled or confectionery processed fruits and vegetables Cereal processed foods such as bread, rice bran, cooked rice or artificial meat, oil and fat foods such as salad oil or margarine, Fukujinzuke, lettuce pickles, Senzuke pickles Pickles, pickled vegetables such as takuan pickles or Chinese cabbage pickles, livestock meat products such as ham or sausage, fish meat ham, fish sausages, fish products such as scallops, chiku mushrooms or hampen, uni-salted squid, squid Delicacy such as salted spices, vinegared combs, dried sardines or dried puffer fish, agricultural products, livestock products, marine products, etc.Steamed foods, grilled foods, stir-fried foods, fried foods, fried foods, steamed foods, dried foods, fried shrimp, croquettes, shiyumai , Gyoza, spring salmon, hamburg steak, meatballs, fish hamburger or fishball, etc. Soup, stew, oden, Happo vegetables, boiled beans, yakitori, steamed rice bowl or field Retort food such as boiled water, egg, milk drinks, egg products such as notter or cheese and dairy products, bottling and canning of fish meat, livestock meat, fruits or vegetables, synthetic liquor, brewed liquor, fruit liquor or Western liquor Alcohol, coffee, cocoa, juice, tea, tea, oolong tea, mineral beverages, carbonated beverages, soft drinks such as lactic acid beverages or lactic acid bacteria drinks, pudding mixes, hot cake mixes, instant juices, instant juices or instant soups Foods etc. are mentioned.
[0031] 上記食品中の本発明の製剤の含有量は、食品の種類により異なるが、有効成分の 含有量として、通常約 0. 001-0. 1質量％程度である。  [0031] The content of the preparation of the present invention in the food varies depending on the type of food, but the content of the active ingredient is usually about 0.001 to 0.1% by mass.
[0032] 以下に本発明を実施例に基づいて、より具体的に説明するが、本発明はこれらに 限定されるものではない。 [0032] Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.
実施例  Example
[0033] [実施例 1] [0033] [Example 1]
(PPAR- yリガンド活性の測定方法）  (Method for measuring PPAR-y ligand activity)
CV- 1細胞 (雄性アフリカミドリザル腎臓由来の培養細胞）を 96穴培養プレートに 1 穴あたり 6 X 103個となるように植え込み、 37°C、 5%CO条件下で 24時間培養した CV-1 cells (cultured cells derived from male African green monkey kidney) were seeded in a 96-well culture plate at 6 X 10 3 per well, and cultured for 24 hours at 37 ° C and 5% CO.
2  2
。培地には、 10%FBS (ゥシ胎仔血清）、 lOmlZLペニシリン 'ストレプトマイシン溶 液（それぞれ 5000IU/ml、 5000 μ g/ml, GIBCO社製）、 37mg/Lァスコルビン 酸（和光純薬工業（株）製）を含む DMEM (Dulbeccos Modified Eeagle Medi um: GIBCO社製）を用いた。細胞を OPTI— MEM (GIBCO社製）で洗浄した後、 p M - PPAR γと 4 X UASg - lucをリポフエクトァミン'プラス（GIBCO社製）を用いて トランスフエクシヨンした。なお、 pM— PPAR yは、哺乳類発現プラスミドである pM ( Clontech社製）に酵母由来転写因子 GAL4遺伝子（アミノ酸配列 1〜147)とヒト PP AR- γリガンド結合部位遺伝子 (アミノ酸配列 174〜475)を結合したキメラタンパク の遺伝子を挿入したプラスミドであり、 4 X UASg— lucはルシフェラーゼ遺伝子の上 流に GAL4の応答配列（UASg)を 4回組み込んだレポータ一 ·プラスミドである（Cell , 1995年， 83卷， 803〜812頁などに記載の方法で作成可能）。トランスフエクショ ンの約 24時間後、サンプルを含む培地に交換し (n=4)、 24時間培養した。被験化 合物はジメチルスルホキシド（DMSO)に溶解したものを、無処置対照には DMSOを 用い、培地に 1/1000量添加した。細胞を Ca、 Mg含有リン酸緩衝生理食塩水（PB S + )で洗浄した後、ルックライト（Packard社製)を添加し、トップカウント 'マイクロプ レートシンチレーシヨン Zルミネッセンスカウンター（Packard社製）にてルシフェラー ゼの発光強度を測定した。 . The medium includes 10% FBS (Ushi Fetal Serum), lOmlZL penicillin 'streptomycin solution (5000 IU / ml, 5000 μg / ml, GIBCO, respectively), 37 mg / L ascorbic acid (Wako Pure Chemical Industries, Ltd.) DMEM (Dulbeccos Modified Eagle Medium: manufactured by GIBCO) was used. After washing the cells with OPTI-MEM (GIBCO), p M -PPAR γ and 4 X UASg -luc using Lipofectamine 'Plus (GIBCO) Transfusion. PM-PPARy is a mammalian expression plasmid pM (Clontech), yeast-derived transcription factor GAL4 gene (amino acid sequence 1-147) and human PP AR-γ ligand binding site gene (amino acid sequence 174-475). 4 X UASg-luc is a reporter plasmid in which GAL4 response element (UASg) is incorporated four times upstream of the luciferase gene (Cell, 1995, 83, 803-812, etc.). About 24 hours after transfection, the medium was replaced with a medium containing samples (n = 4) and cultured for 24 hours. The test compound was dissolved in dimethyl sulfoxide (DMSO), DMSO was used as an untreated control, and 1/1000 amount was added to the medium. After washing the cells with Ca- and Mg-containing phosphate buffered saline (PB S +), add Looklite (Packard) and use TopCount 'Microplate Scintillation Z Luminescence Counter (Packard). The luminescence intensity of luciferase was measured.
測定群と同様に、コントロール群として pM— PPAR yの代わりに pMを用いて測定 した。各被験化合物について、測定群及びコントロール群の発光強度の平均値 (n= 4)の比 (測定群 Zコントロール群)を算出し、無処置対照に対する比活性を被験化 合物の PPAR— γ活性ィ匕作用とした。結果を表 1に示す。  As in the measurement group, the control group was measured using pM instead of pM-PPAR y. For each test compound, calculate the ratio of the average value (n = 4) of the luminescence intensity of the measurement group and the control group (measurement group Z control group), and determine the specific activity relative to the untreated control as the PPAR-γ activity of the test compound. It was considered as a 匕 action. The results are shown in Table 1.
[表 1] [table 1]
被験化合物名 添力。 度 PPAR— r活性化作用 コント口一ル群 DMSO ― 1. 00 Test compound name Degree PPAR—r activation control group DMSO ― 1. 00
1. 5〃 g/ml  1. 5〃 g / ml
1. 45 (5 M)  1. 45 (5 M)
7. 5μ g/ml  7.5μg / ml
デヒド α7ビエチン フ.07 Dehydr α7 Bietin F.07
(25 U M)  (25 U M)
測定群 15 μ. g/ml  Measurement group 15 μg / ml
11.99 (実施例） (50/U M)  11.99 (Example) (50 / U M)
13/S— Δ8—ジヒドロ 3. 04μ gZml 13 / S— Δ 8 — Dihydro 3. 04μ gZml
3. フ 1 (10// M)  3.F 1 (10 // M)
3.02μ gZml  3.02μ gZml
イソピマ レ酸 2. 89  Isopimareic acid 2. 89
(^ Oμ M)  (^ Oμ M)
測定群 15. 1 g/ml  Measurement group 15.1 g / ml
ァビエチ^ 5. 34 Abiech ^ 5. 34
(比較例） (50 μ M) (Comparative example) (50 μM)
[0035] [実施例 2] [0035] [Example 2]
(PPARy活性を有する組成物の糖質代謝、脂質代謝改善の動物実験）  (Animal experiments for improving carbohydrate metabolism and lipid metabolism of compositions with PPARy activity)
4週齢の雄性 KKAy遺伝性肥満'糖尿病発症マウス（日本クレア社製)を市販固形 飼料（日本クレア社製)で 6日間予備飼育後、 1群 6〜7匹として 4群に分け、基礎精 製高脂肪飼料 (タンパク質エネルギー比 20%、炭水化物エネルギー比 20%、脂肪 エネルギー比 60%、リサーチダイエット社製 D12492)のみで、または基礎精製高 脂肪飼料に下記表 2に示す被験化合物を所定量添加した試料でペアフィーディング により 5週間飼育した。  Four-week-old male KKAy hereditary obesity 'diabetic mice (manufactured by CLEA Japan) were preliminarily raised on a commercial solid diet (manufactured by CLEA Japan) for 6 days, then divided into 4 groups as 6-7 animals per group. A high-fat diet made of protein (20% protein energy ratio, 20% carbohydrate energy ratio, 60% fat energy ratio, D12492 manufactured by Research Diet) alone, or a predetermined amount of test compound shown in Table 2 below is added to the basic purified high-fat diet The specimens were reared for 5 weeks by pair feeding.
[0036] [表 2] 飼料 [0036] [Table 2] feed
コントロール群 基礎精製高脂肪飼料  Control group Basic purified high fat feed
デヒドロアビエチン酸 0. 25%投与群 デヒドロアビエチン酸 0. 25 %を基礎精製高脂肪飼料に 添加した飼料  Dehydroabietic acid 0.25% administration group Feed with 0.25% dehydroabietic acid added to basic high-fat diet
デヒドロアビエチン酸 0. 5%投与群 デヒドロアビエチン酸 0. 5%を基礎精製高脂肪飼料に添 加した飼料  Dehydroabietic acid 0.5% administration group Feed with 0.5% dehydroabietic acid added to basic high-fat diet
ピオグリタゾン投与群 PPAR rァゴニストである塩酸ピオグリタゾン 0. 008%を 基礎精製高脂肪飼料に添加した飼料  Pioglitazone administration group PPAR ragonist pioglitazone hydrochloride 0. 008% added to the basic purified high fat diet
[0037] 試験期間中、血糖値の測定を行い、 5週目に体重測定後に、屠殺し、腹腔内脂肪 重量および血中パラメータの測定を行い、血糖値、レプチン、インスリンおよび MCP 1の分泌量、腹腔内脂肪量の体重に対する比を求めた。結果は表 3〜7の通りであ る。なお、統計解析は対応のある t検定で行い、表中の *印はコントロールに比べ危 険率 5%未満で有意差があることを示す。 [0037] During the test period, blood glucose levels were measured. After measuring body weight at the 5th week, the animals were sacrificed, the weight of intraperitoneal fat and blood parameters were measured, and blood glucose levels, leptin, insulin and MCP 1 secretion were measured. The ratio of intraperitoneal fat mass to body weight was determined. The results are shown in Tables 3-7. Statistical analysis is performed with a paired t-test, and the asterisk in the table indicates that there is a significant difference at a risk rate of less than 5% compared to the control.
[0038] [表 3]  [0038] [Table 3]
Figure imgf000015_0001
Figure imgf000015_0001
[0039] [表 4]  [0039] [Table 4]
Figure imgf000015_0002
Figure imgf000015_0002
[0040] [表 5] インスリン分泌量（ng ml) [0040] [Table 5] Insulin secretion (ng ml)
デヒドロアビエチン酸 デヒドロアビエチン酸 ピオグリタゾン コントロール群  Dehydroabietic acid Dehydroabietic acid Pioglitazone Control group
0. 25%投与群 0. 5%投与群 投与群 0.25% administration group 0.5% administration group Administration group
26. 82 + 5. 84 6. 31 ±1. 63* 3. 88±1. 5フ* 5. 39±2. 81 * 26. 82 + 5. 84 6. 31 ± 1.63 * 3. 88 ± 1.5 F * 5. 39 ± 2. 81 *
[表 6] [Table 6]
MCP— 1分泌量（ng ml) MCP-1 secretion volume (ng ml)
デヒドロアビエチン酸 ピオグリタゾン コント口一ル群  Dehydroabietic acid pioglitazone
0. 25%投与群 0. 5%投与群 投与群 0.25% administration group 0.5% administration group Administration group
0. 56 + 0. 08 0. 34±0. 09* 0. 42±0. 19 0. 91 ±0. 11 * 0. 56 + 0. 08 0. 34 ± 0. 09 * 0. 42 ± 0. 19 0. 91 ± 0. 11 *
[表 7] 腹腔内脂肪量ノ体重 [Table 7] Abdominal fat mass
デヒドロアビエチン酸 ピオグリタゾン コント口一ル群  Dehydroabietic acid pioglitazone
0. 25%投与群 0. 5%投与群 投与群 0.25% administration group 0.5% administration group Administration group
0. 088±0. 003 0. 076±0. 004* 0. 076±0. 007 0. 080±0. 003 0. 088 ± 0. 003 0. 076 ± 0. 004 * 0. 076 ± 0. 007 0. 080 ± 0. 003
[0043] 上記表から、デヒドロアビエチン酸投与群は、コントロール群に比べ有意に血糖値 上昇を抑制すると共に、レブチン、インスリン、 MCP— 1の濃度および腹腔内脂肪量 Z体重が有意に低下したことがわかる。この結果より、デヒドロアビエチン酸は、糖'脂 質の代謝改善作用、内臓脂肪蓄積抑制作用、高インスリン血症の改善作用を有する ことが明らかである。 [0043] From the above table, the dehydroabietic acid administration group significantly suppressed the increase in blood glucose level as compared to the control group, and the concentration of lebutin, insulin, MCP-1 and the amount of intraperitoneal fat Z body weight significantly decreased. I understand. From this result, it is clear that dehydroabietic acid has an effect of improving the metabolism of sugar and fat, an action of suppressing visceral fat accumulation, and an action of improving hyperinsulinemia.
[0044] [実施例 3]  [0044] [Example 3]
(in vitroにおける PPAR y活性を有する組成物の抗炎症活性の測定）  (Measurement of anti-inflammatory activity of compositions with PPAR y activity in vitro)
RAW264.7細胞 (マウス由来マクロファージ様細胞株)から分泌される炎症性サイ トカイン MCP— 1の抑制を評価した。  Inhibition of the inflammatory cytokine MCP-1 secreted from RAW264.7 cells (a mouse-derived macrophage-like cell line) was evaluated.
すなわち、実施例 1記載の DMEM培地中に RAW264.7細胞を懸濁し、該懸濁 液（lX106cellsZml)を 12穴培養プレートに 1穴あたり 2000/zl分注し、 37°C CO インキュベーターで 2時間培養後、リポポリサッカリド (LPS、 lOOng/mUシグマ社That is, RAW264.7 cells were suspended in the DMEM medium described in Example 1, and the suspension (lX10 6 cellsZml) was dispensed into a 12-well culture plate at a rate of 2000 / zl per well in a 37 ° C CO incubator. After 2 hours of incubation, lipopolysaccharide (LPS, lOOng / mU Sigma)
2 2
製）を 1穴あたり 2 1および所定量のデヒドロアビエチン酸を添カ卩し、 37°C COイン  Made by adding 2 1 per hole and a predetermined amount of dehydroabietic acid, 37 ° C CO
2 キュベータ一で 16時間刺激した。次いで、培養上清を回収し、上清中における MCP 1の産生量を常法により ELISA法で、 mRNA発現量を常法によりリアルタイム PC Rにて定量した。 MCP—1分泌量および MCP—1の mRNA発現量を、コントロール 100%とした場合の相対値で表した。その結果は、表 8および 9の通りである。なお、 統計解析は対応のある t検定で行い、表中の *印はコントロールに比べ危険率 5%未 満、 * *印はコントロールに比べ危険率 1%未満で有意差があることを示す。 2 Stimulated for 16 hours in one incubator. The culture supernatant is then collected and the MCP in the supernatant is recovered. The production amount of 1 was quantified by ELISA using a conventional method, and the mRNA expression level was quantified by real-time PCR using a conventional method. MCP-1 secretion and MCP-1 mRNA expression were expressed as relative values when the control was 100%. The results are shown in Tables 8 and 9. Statistical analysis is performed using a paired t-test. The * mark in the table indicates that there is a significant difference with a risk rate of less than 5% compared to the control, and the * mark indicates that there is a significant difference with a risk rate of less than 1%.
[0045] [表 8] [0045] [Table 8]
Figure imgf000017_0001
Figure imgf000017_0001
[0046] [表 9]  [0046] [Table 9]
Figure imgf000017_0002
Figure imgf000017_0002
[0047] 上記表から、 LPS刺激後、デヒドロアビエチン酸を添カ卩した各 RAW264. 7細胞で は、コントロールに比べて、タンパク質レベルでの MCP—1の分泌が有意に抑制され 、 mRNAレベルにおいても発現が有意に抑制されたことがわかる。この結果より、デ ヒドロアビエチン酸は、抗炎症活性、すなわち炎症性因子である MCP— 1の減少に より、肥満に関連する炎症抑制作用を有することが明らかである。  [0047] From the above table, in each RAW264.7 cell supplemented with dehydroabietic acid after LPS stimulation, MCP-1 secretion at the protein level was significantly suppressed compared to the control, and at the mRNA level. It can also be seen that the expression was significantly suppressed. From this result, it is clear that dehydroabietic acid has an anti-inflammatory activity, that is, an anti-inflammatory activity related to obesity due to a decrease in MCP-1, which is an inflammatory factor.
[0048] [製剤例 1]  [0048] [Formulation Example 1]
(錠剤）  (Tablets)
デヒドロアビエチン酸 5. Og  Dehydroabietic acid 5. Og
トウモロコシデンプン 12. Og  Corn starch 12. Og
乳糖 22. 6g  Lactose 22.6g
ステアリン酸マグネシウム 0. 4g 上記各成分を加えてよく混和し、湿性錠剤調製法に準じて打錠用顆粒とする。ステ アリン酸マグネシウムを加えて打錠し、錠剤 400錠とする。錠剤は、必要に応じて糖 衣を施してもよい。 Magnesium stearate 0.4 g Add each of the above ingredients and mix well to make tablets for tableting according to the wet tablet preparation method. Add magnesium stearate and tablet, making 400 tablets. Tablets may be sugar-coated as necessary.
[0049] [製剤例 2] [0049] [Formulation Example 2]
(^¾. p)  (^ ¾. P)
砂糖 650gに水飴 300gを 150°Cで加熱融解し、 120°Cに冷却後、クェン酸 10gを カロえた後に、 13 |8— Δ 8—ジヒドロアビエチン酸を 3g、香料 10gを添加後、撹拌し、 均一化した後に、成形し、冷却してキャンディーを得る。 The syrup 300g sugar 650g were melted in the 0.99 ° C, after cooling to 120 ° C, the Kuen acid 10g after was Karoe, 13 | 8- Δ 8 - after addition dihydroabietic acid 3g, perfumes 10g, stirring After homogenization, it is molded and cooled to obtain a candy.
産業上の利用可能性  Industrial applicability
[0050] 本発明によるペルォキシソーム増殖剤応答性受容体 γ活性化剤はインスリン抵抗 性、 2型糖尿病、内臓脂肪型肥満、脂肪肝等、高脂血、高血圧などを抑制 '防止する 医薬または食品等に利用することができる。 [0050] The peroxisome proliferator-responsive receptor γ activator according to the present invention suppresses or prevents insulin resistance, type 2 diabetes, visceral fat obesity, fatty liver, etc., hyperlipidemia, hypertension, etc. Can be used.

Claims

請求の範囲 The scope of the claims
[1] デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸からな る群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩を有効成 分として含有することを特徴とするペルォキシソーム増殖剤応答性受容体 γ活性ィ匕 剤。 [1] It contains at least one compound selected from the group consisting of dehydroabietic acid, 13 j8- Δ 8 -dihydroabietic acid and isopimaric acid, or a pharmaceutically acceptable salt thereof as an active ingredient. Peroxisome proliferator-responsive receptor γ-active agent.
[2] ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を予防また は改善するための請求の範囲第 1項記載のペルォキシソーム増殖剤応答性受容体 γ活性化剤 0 [2] Peroxisome proliferator-responsive receptor γ activator 0 according to claim 1 for preventing or ameliorating a disease or condition mediated by γ
[3] ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が、インスリ ン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満または脂肪肝である請求 の範囲第 2項記載のペルォキシソーム増殖剤応答性受容体 γ活性化剤。  [3] The disease according to claim 2, wherein the disease or symptom mediated by peroxisome proliferator-activated receptor γ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver. Peroxisome proliferator-responsive receptor gamma activator.
[4] インスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満もしくは脂肪肝 の予防または改善用組成物である請求の範囲第 1項記載のペルォキシソーム増殖 剤応答性受容体 γ活性化剤。 [4] The peroxisome proliferator-responsive receptor γ activity according to claim 1, which is a composition for preventing or improving insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver Agent.
[5] 請求の範囲第 1項記載のペルォキシソーム増殖剤応答性受容体 γ活性化剤を含 有することを特徴とするインスリン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型 肥満もしくは脂肪肝の予防または改善用組成物。 [5] Insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat type obesity or fat, comprising the peroxisome proliferator-responsive receptor γ activator according to claim 1 A composition for preventing or improving liver.
[6] 医薬組成物である請求の範囲第 5項記載の予防または改善用組成物。 [6] The preventive or ameliorating composition according to claim 5, which is a pharmaceutical composition.
[7] 食品である請求の範囲第 5項記載の予防または改善用組成物。 [7] The composition for prevention or improvement according to claim 5, which is a food.
[8] デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸からな る群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩を含有し[8] It contains at least one compound selected from the group consisting of dehydroabietic acid, 13 j8—Δ 8 —dihydroabietic acid and isopimaric acid, or a pharmaceutically acceptable salt thereof.
、かつペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が予防 または改善される旨を表示したことを特徴とする食品。 And a food that displays that a disease or symptom mediated by peroxisome proliferator-responsive receptor γ is prevented or ameliorated.
[9] ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状が、インスリ ン抵抗性、 2型糖尿病、高脂血、高血圧、内臓脂肪型肥満または脂肪肝である請求 の範囲第 8項記載の食品。 [9] The disease according to claim 8, wherein the disease or symptom mediated by peroxisome proliferator-responsive receptor γ is insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity or fatty liver. Food.
[10] ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を有する患 者に、デヒドロアビエチン酸、 13 j8— Δ 8—ジヒドロアビエチン酸およびイソピマル酸 からなる群より選ばれる少なくとも一種の化合物またはその薬学的に許容される塩を 投与することを特徴とするペルォキシソーム増殖剤応答性受容体 γが介在する疾患 または症状の予防または改善方法。 [10] Peroxisome proliferator-activated receptor gamma-mediated disease or condition is treated with dehydroabietic acid, 13 j8— Δ 8 — dihydroabietic acid and isopimaric acid A method for preventing or ameliorating a disease or symptom mediated by peroxisome proliferator-responsive receptor γ, comprising administering at least one compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
ペルォキシソーム増殖剤応答性受容体 γが介在する疾患または症状を予防また は改善する薬剤の製造のためのデヒドロアビエチン酸、 13 — Δ 8—ジヒドロアビエ チン酸およびイソピマル酸力 なる群より選ばれる少なくとも一種の化合物またはそ の薬学的に許容される塩の使用。 Peroxisome proliferator-responsive receptor Dehydroabietic acid for the manufacture of a drug that prevents or ameliorates diseases or symptoms mediated by γ, 13 — Δ 8 — at least one selected from the group consisting of dihydroabietic acid and isopimaric acid Or a pharmaceutically acceptable salt thereof.
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WO2018212362A1 (en) * 2017-05-19 2018-11-22 株式会社ヤマノビューティケミカル Agent for suppressing carbohydrate breakdown and absorption
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