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WO2013012118A1 - Nouveau composé d'ester de phényle et compositions pharmaceutiques destinées à prévenir ou à traiter les maladies inflammatoires le contenant - Google Patents

Nouveau composé d'ester de phényle et compositions pharmaceutiques destinées à prévenir ou à traiter les maladies inflammatoires le contenant Download PDF

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WO2013012118A1
WO2013012118A1 PCT/KR2011/006096 KR2011006096W WO2013012118A1 WO 2013012118 A1 WO2013012118 A1 WO 2013012118A1 KR 2011006096 W KR2011006096 W KR 2011006096W WO 2013012118 A1 WO2013012118 A1 WO 2013012118A1
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WIPO (PCT)
Prior art keywords
compound
composition
paeonia suffruticosa
preventing
inflammatory
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Ceased
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PCT/KR2011/006096
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English (en)
Inventor
Jeong Min Lee
Jung Ho Choi
Ji Na Choi
Yun Hyeok Choi
Ill Chan Noh
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Sinil Pharmaceutical Co Ltd
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Sinil Pharmaceutical Co Ltd
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Publication date
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Publication of WO2013012118A1 publication Critical patent/WO2013012118A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C07C69/736—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/005—Preparations for sensitive skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material

Definitions

  • the present invention relates to a 2-ethoxy-4-(3-hydroxy-2-oxopropyl) phenyl 2-oxoacetate compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and a method for preparing the same, Also, the present invention relates to a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the same or the pharmaceutically acceptable salt as an active ingredient, and a quasi-drug composition, a health functional food composition and a cosmetic composition for preventing or improving inflammation all comprising the compound, and a method for treating an inflammatory disease, comprising administering the pharmaceutical composition to a subject suspected of having the inflammatory disease.
  • Inflammation is a biological response of tissue to harmful stimuli, such as tissue damage, external irritants, or pathogens, characterized by complex pathological events produced by the organic interaction between various inflammatory mediators within vessels and body fluids and various immune cells, including enzyme activation, the release of inflammatory mediators, cellular infiltration and fluid exudation, circulatory disturbance, tissue degradation, hypertrophy, etc.
  • the process of inflammation is initiated by cells already present in all types of tissue, mainly resident macrophages. At the onset of an infection, macrophages gather at the site of the injury and attack the invaders. Then, plasma accumulates because of the increased blood flow to the injured site, causing increased heat, redness, swelling, pain, etc.
  • pathological phenomena e.g., hypersensitive allergy, chronic inflammatory diseases
  • Non-steroidal anti-inflammatory drugs widely used to treat most inflammatory diseases, function to inhibit cyclooxygenase (COX), an enzyme involved in the biosynthesis of prostaglandin from arachidonic acid, and have anti-inflammatory effects.
  • COX cyclooxygenase
  • their long-term use is problematic because they cause significant adverse effects on the gastrointestine, the liver and the kidney (Rainsford KD., Subcell biochem., 42, pp3-27, 2007; Guruprasad P. Aithal., Rheumatology., 7, pp139-150, 2011; Praveen P. N. Rao et al., Pharmaceuticals., 3, pp1530-1549, 2010). Therefore, there has been a widespread need for novel drugs that have excellent anti-inflammatory effects without causing adverse effects after long-term use, which is the reason why material development following the validation of the effects of natural resources has been actively studied.
  • LPS lipopolysaccharide
  • iNOS isoform in monocytes/macrophages
  • TLR4 toll-like receptor 4
  • cytokine genes such as IL-6 (interleukin-6) and chemokines, which culminates in inflammation
  • IL-6 interleukin-6
  • chemokines which culminates in inflammation
  • iNOS inducible nitric oxide synthase
  • NF ⁇ B a transcription factor of inflammatory response that complexes with I ⁇ B when inactivated.
  • the activated NF ⁇ B translocates to the nucleus where it promotes the expression of the cytokine genes involved in the induction of inflammatory responses, such as iNOS, IL-1 ⁇ and TNF- ⁇ . Inflammatory responses can be suppressed by inhibiting these factors (Karin M. et al., Cold Spring Harb Perspect Biol., 1, pp1-14, 2009).
  • nitric oxide is produced from L-arginine, which is catalyzed by three major nitric oxide synthase isoforms (NOS), nNOS (neuronal NOS), eNOS (endothelial NOS) and iNOS (inducible NOS).
  • NOS nitric oxide synthase isoforms
  • nNOS and eNOS are regulated by Ca2+/calmodulin
  • iNOS is regulated at the transcription level by inflammatory stimuli such as interleukin, interferon, LPS, etc.
  • the nitric oxide produced in a small amount by nNOS or eNOS accounts for normal physiological functions such as vasodilation, neurotransmission, disruption of pathogens, etc.
  • nitric oxide generated by phagocytes armed with iNOS is involved in a variety of pathophysiological processes including inflammation and cancer and reacts with superoxides to produce peroxynitrite, which acts as a strong oxidant to damage cells.
  • the nitric oxide is also known to activate NF- ⁇ B in the phagocytes activated by inflammatory stimuli to cause chronic diseases such as inflammation, cancer, arteriosclerosis, etc. (Gupta SC et al., Exp Biol Med., 236:658-671, 2011; Riehemann et al., FEBS Lett., 442:89-94, 1999; Stamleret al., Science, 258:1898-1902, 1992).
  • tumor necrosis factor- ⁇ TNF- ⁇
  • interleukin-6 IL-6
  • interleukin-1 ⁇ IL-1 ⁇
  • rheumatoid arthritis Jang C. H. et al., Rheumatology, 2006, 45(6):703-710
  • fibromyalgia Hernandez M. E. et. al., BMC Res. Notes., 2010, 3(1):156
  • sjogren’s syndrome (Baturone R. et. al., Scand J Rheumatol., 2009, 38(5):386-389).
  • Paeonia suffruticosa Andrews is prescribed for inflammatory extravasated blood, dysmenorrhea and used for pain alleviation, spasmolysis, and drainage of pus in herbal medicine.
  • the herb is prescribed for macular papularlesion, hematemesis, nasal hemorrhage, fever during the menstrual period, wasting fever, extravasated blood-induced dysmenorrheal, and purulent disease in clinics for herbal medicine.
  • Representative among the ingredients of Paeonia suffruticosa Andrews are paeonol, paeonoside, paeonolide, paeoniflorin, oxypaeoniflorin, and benzoylpaeoniflorin.
  • instructions pertaining to and disclosure of the anti-inflammatory activity of the phenylester compounds isolated from Paeonia suffruticosa Andrews have not been disclosed in previous documents.
  • the compositions of the present invention are useful for preventing, treating, and improving inflammatory diseases.
  • the phenylester compound can be used as a safe therapeutic relatively free of fungal infection or other side-effects, compared to synthetic medicines.
  • FIG. 1 is a diagram showing the separation of an extract of Paeonia suffruticosa Andrews, fractions thereof, and a phenylester compound from the fractions.
  • FIG. 2 is a 1 H NMR spectrum of the phenylester compound isolated from Paeonia suffruticosa Andrews.
  • FIG. 3 is a 13 C NMR spectrum of the phenylester compound isolated from Paeonia suffruticosa Andrews.
  • FIG. 4 is an ESI-MS spectrum of the phenylester compound isolated from Paeonia suffruticosa Andrews.
  • FIG. 5 is a curve showing the data of an assay for the cytotoxicity of an extract of Paeonia suffruticosa Andrews, a fraction thereof, and a phenylester compound from the fraction.
  • FIG. 6 is a graph showing the data of an assay for the inhibitory activity of an extract of Paeonia suffruticosa Andrews, a fraction thereof, and a phenylester compound from the fraction against tumor necrosis factor- ⁇ (TNF- ⁇ ).
  • FIG. 7 is a graph showing the data of an assay for the inhibitory activity of an extract of Paeonia suffruticosa Andrews, a fraction thereof, and a phenylester compound from the fraction against interleukin-1 ⁇ (IL-1 ⁇ ).
  • IL-1 ⁇ interleukin-1 ⁇
  • FIG. 8 is a graph showing the data of an assay for the inhibitory activity of an extract of Paeonia suffruticosa Andrews, a fraction thereof, and a phenylester compound from the fraction against nitric oxide (NO).
  • FIG. 9 is a graph showing the data of an assay for the inhibitory activity of an extract of Paeonia suffruticosa Andrews, a fraction thereof, and a phenylester compound from the fraction against interleukin-6 (IL-6).
  • IL-6 interleukin-6
  • the present invention provides a 2-ethoxy-4-(3-hydroxy-2-oxopropyl) phenyl 2-oxoacetate compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound of Chemical Formula 1 is a novel phenylester compound named 2-ethoxy-4-(3-hydroxy-2-oxopropyl) phenyl 2-oxoacetate.
  • the compound of the present invention may be chemically synthesized, but is preferably isolated from a natural source such as Paeonia Suffruticosa Andrews, and more preferably from an extract of Paeonia Suffruticosa Andrews or a fraction thereof.
  • the extract of Paeonia Suffruticosa Andrews may be obtained from various tissues including the roots, stems, leaves, flowers, flesh and peel of the fruit, and a plant tissue culture.
  • a novel phenylester compound was isolated from Paeonia Suffruticosa Andrews, and was identified as 2-ethoxy-4-(3-hydroxy-2-oxopropyl) phenyl 2-oxoacetate by analyzing its structure using molecular weight measurement, molecular formula estimation and nuclear magnetic resonance (NMR).
  • the pharmaceutically acceptable salt of the compound of Chemical Formula 1 may be an acid addition salt formed with a pharmaceutically acceptable free acid which may be an organic acid or an inorganic acid.
  • a pharmaceutically acceptable free acid which may be an organic acid or an inorganic acid.
  • the inorganic acid include chloric acid, bromic acid, sulfuric acid, sulfurous acid, and phosphoric acid.
  • organic acid useful in the present invention are citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, metal sulfonic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, and aspartic acid.
  • the addition salt of the present invention may be prepared per typical methods.
  • the compound of Chemical Formula 1 is dissolved in a water-miscible organic solvent, e.g., acetone, methanol, ethanol or acetonitrile, followed by adding an equivalent or excess amount of an organic acid or an aqueous inorganic acid solution to the solution.
  • a water-miscible organic solvent e.g., acetone, methanol, ethanol or acetonitrile
  • the addition salt thus formed can be obtained by precipitation or crystallization, or by evaporating the solvent or excess acid and drying or suction-filtering the precipitated salt.
  • the present invention provides a method for preparing the compound of Chemical Formula 1 comprising (a) extracting Paeonia suffruticosa Andrews with an extraction solvent, followed by filtrating and concentrating to obtain an extract of Paeonia suffruticosa Andrews; (b) fractionating the extract of Paeonia suffruticosa Andrews of step (a) with organic solvents and performing column chromatography to obtain a fraction; and (c) performing high-performance liquid chromatography to isolate the compound from the fraction of step (b).
  • step (a) of the method Paeonia suffruticosa Andrews is extracted with an extraction solvent, then filtrated and concentrated to obtain an extract of Paeonia suffruticosa Andrews.
  • Paeonia suffruticosa Andrews refers to a root peel of peony that is non-toxic to the body and is used as a medicinal material in herbal medicine.
  • the physiologically active ingredients found in the herb include paeonoside (paeonol glucoside), paeonolide (paeonol-rhamnoglucoside) and paeonol. During the storage of the herb, paeonoside is degraded into sugar and paonol.
  • paeoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, paeonolide tannin, procyanidin B1, benzoyloxypaeoniflorin, paeonin, astragalin, and pelargonin were detected. Histochemistry showed that these ingredients are present in the lignin as well as the root peel.
  • aerial parts, roots and seeds of Paeonia suffruticosa Andrews may be used without limitation.
  • any extraction solvent may be used in the present invention.
  • water, alcohols of 1 to 6 carbon atoms, or combination thereof may be used as the extraction solvent.
  • Preferred is ethanol, methanol or butanol.
  • the extraction solvent may be added in an amount 2- to 20-fold greater than the amount to be reduced, and preferably in an amount 4- to 10-fold greater, and more preferably in an amount 5-fold greater.
  • Preferred examples of the extraction method include, but are not limited to, boiling extraction, hot-water extraction, cold precipitation, reflux condensation, and ultrasonication, with a greater preference for boiling extraction or cold precipitation.
  • the extraction solvent may be maintained preferably at a temperature of 20 to 100°C and more preferably at room temperature, but the present invention is not limited thereto.
  • the time of extraction may preferably take place over, but is not limited to, 5 to 8 days and more preferably for 7 days.
  • the number of the extractions may be preferably one to five and more preferably three, but the present invention is not limited thereto. Under these extraction conditions, Paeonia suffruticosa Andrews may be extracted with an extraction solvent, followed by filtration, concentration and lyophilization to afford an extract.
  • step (b) of the method the Paeonia suffruticosa Andrews extract of step (a) is fractionated with an organic solvent and column chromatography is performed to obtain fraction.
  • the organic solvent is a liquid organic compound capable of dissolving solids, gases and liquids and may be one typically used in the art.
  • methanol, chloroform, acetate, hexane, dichloromethane, acetone, acetonitrile, benzene or a combination thereof may be used as the organic solvent for creating the fractions.
  • the column is filled with particles as a stationary phase.
  • suitable fillers may be selected before several rounds of chromatography are conducted.
  • the filler suitable for use in isolation and purification may be selected from among silica gel, Sephadex, RP-18, polyamide, toyoperal, and XAD resin.
  • step (c) of the method the compound of interest is isolated from the fraction of step (b) performing HPLC.
  • HPLC is a chromatography technique which can separate a mixture of compounds at high speed typically using a column, different types of stationary phases, and a pump, and is used to finally isolate the compound of Chemical Formula 1.
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention features the anti-inflammatory activity of the compound or its pharmaceutically acceptable salt.
  • the compound or the pharmaceutically acceptable salt its description is as given above.
  • the compound of Chemical Formula 1 was found to have little toxicity as measured by a cytotoxicity assay and thus could be safely used in pharmaceutical compositions.
  • the compound was identified to have an excellent ability to suppress the production and release of the inflammatory factors nitric oxide (NO), TNF- ⁇ , IL-6 and IL-1 ⁇ , and thus is useful for the prevention or treatment of inflammatory diseases (FIGS. 6 to 9).
  • the pharmaceutical composition of the present invention may be characterized by the ability to suppress the release of nitric oxide (NO), TNF- ⁇ , IL-6 or IL-1 ⁇ .
  • inflammatory disease is a generic name of the diseases having inflammation as their main damaging factor.
  • examples of the inflammatory disease include, but are not limited to, edema, dermatitis, allergy, atopy, asthma, conjunctivitis, peridontitis, rhinitis, otitis media, laryngopharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn’s disease, colitis, hemorrhoid, gout, ankylosing spondylitis, rheumatic fever, systemic lupus erythematosus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis of shoulder, tendonitis, tenosynovitis, myositis, hepatitis, cystitis, nephritis, sjogren's syndrome or multiple sclerosis, with preference for r
  • prevention is intended to refer to any action resulting in the suppression or delay of the onset of an inflammatory disease thanks to the administration of the pharmaceutical composition according to the present invention.
  • treatment is intended to refer to any action resulting in improvements in symptoms of an inflammatory disease or the beneficial alteration of the inflammatory state thanks to the administration of the composition according to the present invention.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable vehicle.
  • the pharmaceutical composition comprising a pharmaceutically acceptable vehicle may be in various oral or non-oral dosage forms.
  • the pharmaceutical composition of the present invention may be formulated in combination with a diluents or excipient such as a filler, a thickener, a binder, a wetting agent, a disintegrant, a surfactant, etc.
  • Solid preparations intended for oral administration may be in the form of tablets, pills, powders, granules, capsules, and the like.
  • the compound of the present invention is formulated in combination with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin.
  • a lubricant such as magnesium stearate, talc, etc.
  • liquid preparations intended for oral administration are suspensions, internal use solutions, emulsion, syrups, and the like.
  • various excipients such as wetting agents, sweeteners, aromatics, preservatives, and the like may be contained in the liquid preparations.
  • the pharmaceutical composition of the present invention may be in a parenteral dosage form such as sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizates, suppositories, and the like.
  • Injectable propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and esters such as ethyl oleate may be suitable for the non-aqueous solvents and suspensions.
  • the basic materials of suppositories include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.
  • the form of the dosage of the pharmaceutical composition of the present invention may be selected from the group consisting of a tablet, a pill, a powder, a granule, a capsule, a suspension, an internal use solution, an emulsion, a syrup, a sterile aqueous solution, a non-aqueous solution, a lyophilizate, and a suppository.
  • the pharmaceutical composition of the present invention is administered in a therapeutically or pharmaceutically effective amount.
  • therapeutically or pharmaceutically effective amount is intended to refer to an amount of a pharmaceutical composition for treating a disease that is sufficient, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the effective amount may vary depending on various factors including the severity of the disease being treated, the patient’s age and sex, drug activity, sensitivity to the drug, the time of administration, the route of administration, the rate of excretion, the period of time of treatment, the co-administration of drugs, and other parameters well known in the art.
  • the dose of the pharmaceutical composition of the present invention is not imparted with special limitations, but varies depending on various factors including in vivo absorption rate, patient’s age, sex, health state and diet, the time of administration, the route of administration, excretion rate, and the severity of disease.
  • the extract from Paeonia suffruticosa Andrews may be administered at a daily dose of from 0.1 to 100 mg/kg, preferably at a daily dose of from 30 to 80 mg/kg and more preferably at a dose of from 50 to 60 mg/kg.
  • the pharmaceutical composition of the present invention is formulated in consideration of the effective amount range.
  • the unit dosage formulations thus obtained may be administered using a specialized regimen or at regular intervals of time in multiple doses according to the decision of an expert who is responsible for monitoring or observing the administration of the drug, or according to personal demands.
  • the present invention provides a quasi-drug composition for the preventing or improving inflammation, comprising the compound represented by Chemical Formula 1.
  • the quasi-drug composition may comprise a pharmaceutically acceptable salt of the compound.
  • the composition of the present invention may be added to a quasi-drug composition to be used to prevent or improve inflammation.
  • the term “quasi-drug” may be defined as 1) articles made from fiber, rubber, or similar materials used in humans or animals for the purpose of curing, alleviating, treating, or preventing diseases; 2) articles, other than instruments, machines or the like, which have a mild action on or have no direct influence on the human body; and, 3) articles, falling within the range of agents used to sterilize, kill insects and for similar purposes. All of the articles exclude those intended at the same time to be prescribed to diagnosing, curing, alleviating, treating or preventing diseases in humans or animals, and for pharmaceutically affecting the structure and function of humans or animals.
  • the composition of the present invention When used as a quasi-drug additive, the composition of the present invention may be suitably used as it is, or in combination with another quasi-drug or quasi-drug component using a typical method. Its amount in the mixture may be properly determined depending on the purpose of use.
  • Examples of the quasi-drug to which the composition of the present invention may be applied include, but are not limited to, disinfectants, shower foams, mouthwash, wet tissues, detergent soap, handwashing materials, a humidifier fillers, masks, ointments, and a filter coating.
  • the present invention provides a health functional food composition for the preventing or improving inflammation, comprising the compound represented by Chemical Formula 1.
  • the health functional food composition may comprise a pharmaceutically acceptable salt of the compound.
  • the composition of the present invention may be added to a health functional food composition to be used to prevent or improve inflammation.
  • the composition of the present invention When used as a health functional food additive, the composition of the present invention may be suitably used in unchanged form, or in a combination with another health functional food or health functional food component made using a typical method. Its amount in the mixture may be properly determined depending on the purpose of use. When used to prepare foods or drinks, typically, the composition of the present invention may be used in an amount of 15 parts by weight or less, based on 100 parts by weight of the total material, and preferably in an amount of 10 parts by weight or less. If the foods or drinks are designed for long-term ingestion to provide health control and sanitation, the amount may be further decreased, but no problems are caused when used in greater amounts because the active ingredient is not toxic to the body.
  • health functional food there is no particular limitation on the kind of health functional food to which the composition of the present invention can be added.
  • examples of such a health functional food include meats, sausages, breads, chocolates, candies, snacks, confectionery, pizzas, ramen noodles, other noodles, gums, dairy products such as ice-creams, various soups, beverages, teas, drinks, alcoholic beverages, and vitamin complexes. All typically accepted health functional foods may contain the active ingredient according to the present invention. Also, animal feeds fall within the scope of the present invention.
  • the health functional food composition of the present invention may further comprise various sweeteners, fragrances or natural carbohydrates.
  • natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • the amount of the natural carbohydrate may be approximately 0.01 ⁇ 0.04 grams based on 100 mL of the beverage composition of the present invention, and preferably approximately 0.02 ⁇ 0.03 grams.
  • the sweeteners may be natural sweeteners such as thaumatin or a stevia extract, or synthetic sweeteners such as saccharin or aspartame.
  • the health functional food composition of the present invention may comprise various nutrients, vitamins, minerals, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH modifiers, stabilizers, antiseptics, glycerin, alcohols, and carbonating agents used in carbonated beverages.
  • the composition of the present invention may contain the fruit flesh used to prepare natural fruit juices, fruit beverages and vegetable beverages.
  • the present invention provides a cosmetic composition for preventing or improving inflammation, comprising the compound represented by Chemical Formula 1.
  • the cosmetic composition may comprise a pharmaceutically acceptable salt of the compound.
  • the composition of the present invention may be added to a cosmetic composition to be used to prevent or improve inflammation.
  • the cosmetic composition of the present invention may be formulated into a general emulsion or water-soluble form.
  • the emulsion cosmetics include nutrition lotions, creams, essences and the like.
  • a skin lotion is a kind of the water-soluble cosmetic forms.
  • the suitable cosmetic forms include, but are not limited to, solutions, gels, solid or paste preparations, oil-in-water emulsions, suspensions, microemulsions, microcapsules, microgranules or ionic liposomes, non-ionic vesicle dispersions, creams, skins, lotions, powders, ointments, sprays, conceal sticks, etc.
  • it may be prepared into a foam form or an aerosol form having a quantity of compressed propellant.
  • the cosmetic composition may comprise lipids, organic solvents, dissolving agents, thickening agents, gelling agents, softeners, anti-oxidants, suspending agents, stabilizers, foaming agents, aromatics, surfactants, water, ionic or non-ionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, UV blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic activators, liposomes, and/or other general supplements used in the skin science field.
  • the present invention provides a method of treating an inflammatory disease, comprising administering the pharmaceutical composition to a subject suspected of having the inflammatory disease.
  • subject suspected of having an inflammatory disease means an animal including human, which has been attacked with or is apt to be attacked by an inflammatory disease.
  • An inflammatory disease may be cured by administering the pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject suspected of having the inflammatory disease.
  • the inflammatory disease its description was given above.
  • administration is intended to refer to introduction of the pharmaceutical composition of the present invention into a subject suspected of having an inflammatory disease in a suitable manner. So long as it allows the compound of the present invention to reach a target tissue, any administration, whether oral or parenteral, may be taken.
  • the treatment method of the present invention includes administering a pharmaceutically effective amount of the pharmaceutical composition comprising the compound. It will be apparent to those skilled in the art that the suitable total daily dose may be determined by an attending physician within the scope of sound medical judgment. Also, the composition may be administered in a single dose or it may be spread out over multiple doses per day.
  • the therapeutically effective dose for a certain patient depends on various factors including the kind and extent of the response sought to be achieved, the use of any other agents according to the intended use, patient’s age, weight, general health state, sex and diet, the time of administration, the route of administration, the rate of excretion of the composition, the duration of the treatment, other drugs mixed with or concurrently administered together with the composition, and other factors well known in the medical art.
  • Extraction and fractionation processes were used to isolate a phenylester compound from Paeonia suffruticosa Andrews.
  • Paeonia suffruticosa Andrews was boiled for 2 hours in 95% ethanol in a water bath (80°C) to a concentration of 20:1 and the concentrate was fractioned with chloroform and water. Thereafter, ten fractions were primarily obtained by silica gel column chromatography using a gradient of from 100:0 to 1:1 of methanol to chloroform as an eluent. Among them, the fifth fraction was purified using the same method to afford eight fractions. Among these, the third fraction was subjected to high-performance liquid chromatography using 60% methanol as a mobile phase to separate an active compound (FIG. 1).
  • Example 1 The compound eluted at 10 min upon the HPLC of Example 1 was structurally identified by the measurement of molecular weight, the estimation of molecular formula, and nuclear magnetic resonance (NMR) analysis (FIGS. 2 to 4).
  • the compound was measured to have a molecule weight of 266.
  • hydrogens of a benzene ring were detected by peaks at ⁇ 6.76 - 7.06, four ester groups by peaks at ⁇ 3.45 and 4.69, and an ethoxy group by peaks at ⁇ 1.32 and 4.09.
  • carbon NMR data identified two carbonyl groups and a hydroxy group.
  • the mouse macrophage RAW 264.7 was purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA) and maintained at 37°C in DMEM supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin, and 100 ⁇ g/ml streptomycin under a 5% CO2 condition.
  • FBS fetal bovine serum
  • RAW 264.7 macrophages were treated with different concentrations (0, 1, 3, 10, 30, 100 ⁇ g/ml) of the samples and cultured for 24 hours and then incubated for 1 hour at 37oC with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; 500 ⁇ g/ml). After removal of the culture medium, a dimethylsulfoxide (DMSO) solution was added to the cells to dissolve the formed formazan, followed by measuring absorbance at 570 nm. Measurements were compared to the control to calculate relative cell viability (% of control).
  • DMSO dimethylsulfoxide
  • mice macrophage RAW 264.7 was incubated with lipopolysaccharide (LPS) (0.2 ⁇ g/ml) in the presence of each sample (100 ⁇ g/ml) for 18 hours, followed by quantitatively analyzing the inflammatory cytokines and chemokines, such as tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 ⁇ (IL-1 ⁇ ), nitric oxide (NO), and interleukin-6 (IL-6), released into the medium, using an ELISA kit or an NO Griess reagent system (Promega).
  • LPS lipopolysaccharide
  • the production amounts of the inflammatory cytokines and chemokines from the groups treated with the samples were compared to those from the control treated with LPS only to calculate relative amounts (% of the control). All measurements were expressed in mean ⁇ SE (standard error). Data was analyzed for statistical significance between experimental groups using Student’s t-test.
  • TNF- ⁇ was produced in an amount 9.9% reduced by the Paeonia suffruticosa Andrews extract, 20.4% reduced by the chloroform fraction and 43.2% reduced by the phenylester compound, compared to the control (FIG. 6).
  • IL-1 ⁇ was produced in an amount 10.9% reduced by the Paeonia suffruticosa Andrews extract, 43.7% by the chloroform fraction, and 79.5% by the phenylester compound, compared to the control (FIG. 7).
  • NO was produced in an amount 20.4% reduced by the Paeonia suffruticosa Andrews extract, 44.1% by the chloroform fraction, and 70.2% by the phenylester compound, compared to the control (FIG. 8).
  • IL-6 was produced in an amount 33.4% reduced by the Paeonia suffruticosa Andrews extract, 57.1% by the chloroform fraction, and 80.8% by the phenylester compound, compared to the control (FIG. 9).
  • Paeonia suffruticosa Andrews extract, the fraction, and the phenylester compound according to the present invention inhibit the production and release of the inflammatory cytokines and chemokines TNF- ⁇ , IL-1 ⁇ , NO and IL-6 and thus are useful for preventing or treating various inflammatory diseases.
  • Bovine type II collagen and an adjuvant were formulated into an emulsion which was subcutaneously injected at a dose of 100 ⁇ g into the tail. Three weeks later, a booster was achieved by the intraperitoneal injection of 100 ⁇ g of bovine type II collagen to induce arthritis. Immediately after the induction, drugs were administered and their inhibitory activity against arthritis was measured. Suspensions of the Paeonia suffruticosa Andrews extract, the fraction and the phenylester compound were orally administered at different doses. Severity of edema was measured in the test mice and compared to that of a normal group (arthritis not induced), a control (administered with vehicle), and the mice administered with a reference drug (commercially available medicine).
  • the Paeonia suffruticosa Andrews extract, the fraction and the phenylester compound in accordance with the present invention were found to have reduced edema in a dose-dependent manner and to show similar inhibitory activity against arthritis compared to the reference drug.
  • the compound of the present invention has the therapeutic function of suppressing and alleviating inflammation.
  • Example 1 To 100 mg of milk was added 1 mg of the compound of Example 1 and the milk was used to prepare various dairy products such as butter and ice-cream.
  • Unmilled rice, barley, glutinous rice, and unshelled adlay were pre-gelatinized using a typical method, dried and roasted before grinding into powder with a particle size of 60 mesh.
  • Black soybean, black sesame and wild sesame were steamed according to a typical method, dried and roasted before grinding into powder with a particle size of 60 meshes.
  • the grains, the seeds, and the compound of Example 1 were formulated at the following ratios to yield a zen food.
  • Grains unmilled rice 30 wt %, unshelled adlay 15 wt %, barley 20 wt %)
  • ingredients were homogeneously formulated according to a typical method and the formulation was heated at 85°C for about 1 hour with stirring, loaded into a 2 L sterilized bottle, subjected to pasteurization and stored in a refrigerator until used.
  • composition was given as a preferred example suitable for use in beverages, but may be changed depending on regional and national factors, such as consumer classes, countries, etc.
  • Example 1 To 1,000 mL of typical tomato or carrot juice was added 1 mg of the compound of Example 1 to give a health-improving vegetable juice.
  • Example 1 To 1,000 mL of typical apple or grape juice was added 1 mg of the compound of Example 1 to give a health-improving fruit juice.
  • the Paeonia suffruticosa Andrews extract, its fractions and the phenylester compound isolated from the fractions in accordance with the present invention may be used as an active ingredient of a cosmetic for the prevention or improvement of inflammation.
  • emulsion-type cosmetics such as nutrition lotion, cream, essence, etc.
  • water-soluble cosmetics such as skin lotion were prepared.
  • Emulsion-type cosmetics were prepared from the composition given in Table 1 as follows.
  • step 3 During the heating of step 3), the mixture of step 2 was slowly added, followed by emulsification at 8,000 rpm for 2 ⁇ 3 min.
  • step 6) The mixture of step 6) was deaerated and cooled to 25 ⁇ 35°C to produce emulsion-type cosmetics
  • Emulsion Type 1 Emulsion Type 2 Emulsion Type 3 1 Stearic acid 0.3 0.3 0.3 2 Stearyl alcohol 0.2 0.2 0.2 3 Glyceryl monostearate 1.2 1.2 1.2 4 Beeswax 0.4 0.4 0.4 5 Polyoxyethylene sorbitan monolauric acid ester 2.2 2.2 2.2 6 Methyl paraoxybenzoate 0.1 0.1 0.1 7 Propyl paraoxybenzoate 0.05 0.05 0.05 8 Cetylethylhexanoate 5 5 5 5 9 Triglyceride 2 2 2 10 Cyclomethicone 3 3 3 11 Distilled water ⁇ 100 ⁇ 100 ⁇ 100 12 Conc.
  • Water-soluble-type cosmetics were prepared from the composition given in Table 2, as follows.
  • Materials 2 ⁇ 6 were dissolved in material 1 (purified water) using an agitation mixer.
  • step 2) The solution of step 2) was slowly added to the mixture of step 1) to produce water-soluble type cosmetics

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Abstract

Cette invention concerne un nouveau composé, appelé 2-oxoacétate de 2-éthoxy-4-(3-hydroxy-2-oxopropyl)phényle, ou un sel pharmaceutiquement acceptable de celui-ci, qui manifeste une activité anti-inflammatoire, et un procédé pour le préparer. Une composition pharmaceutique destinée à prévenir ou à traiter les maladies inflammatoires, contenant le composé ou un sel pharmaceutiquement acceptable de celui-ci à titre de principe actif, est également décrite. Avec une activité thérapeutique vis-à-vis des maladies inflammatoires, le composé d'ester de phényle selon l'invention peut également être appliqué à une composition quasi-médicamenteuse, une composition alimentaire bienfaitrice pour la santé, et une composition cosmétique, toutes ces compositions étant destinées à prévenir ou à améliorer l'inflammation. Une méthode destinée à traiter une maladie inflammatoire par administration de la composition pharmaceutique selon l'invention à un sujet en ayant besoin est également décrite. En tant que matériau naturel, le nouveau composé d'ester de phényle peut être utilisé à titre d'agent thérapeutique sûr, relativement exempt d'infection fongique ou autres effets secondaires, comparativement aux médicaments de synthèse.
PCT/KR2011/006096 2011-07-20 2011-08-18 Nouveau composé d'ester de phényle et compositions pharmaceutiques destinées à prévenir ou à traiter les maladies inflammatoires le contenant Ceased WO2013012118A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
KR20000067187A (ko) * 1999-04-24 2000-11-15 김상회 목단피 추출물을 함유하는 화장료
WO2002049589A1 (fr) * 2000-12-21 2002-06-27 Lg Household & Health Care Ltd. Compositions orales contre la mauvaise haleine

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KR100732886B1 (ko) * 2005-11-07 2007-06-27 한국화학연구원 목단피 추출물 또는 이로부터 분리된 활성성분을 포함하는 혈압강하용 조성물
KR100822781B1 (ko) * 2006-09-01 2008-04-17 원광대학교산학협력단 항균 효과를 갖는 목단피의 추출물로부터 분리된 신규구조의 6‘-오-바닐릴옥시파에오니플로린 화합물을유효성분으로 함유하는 조성물.
KR20110067555A (ko) * 2009-12-14 2011-06-22 애경산업(주) 염증 예방 및 완화용 조성물

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KR20000067187A (ko) * 1999-04-24 2000-11-15 김상회 목단피 추출물을 함유하는 화장료
WO2002049589A1 (fr) * 2000-12-21 2002-06-27 Lg Household & Health Care Ltd. Compositions orales contre la mauvaise haleine

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CHUN, SEOUNG-CHUL ET AL.: "Anti-Inflammatory Activity of the Methanol Extract of Moutan Cortex in LPS-Activated Raw 264.7 Cells", EVID BASED COMPLEMENT ALTERNAT. MED., vol. 4, 2007, pages 327 - 333 *

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