KR101875317B1 - A pharmaceutical composition comprising costunolide, dehydrocostus lactone, or pharmaceutically acceptable salt thereof as an active ingredient for prevention or treatment of inflammatory diseases or allergic diseases or malaria - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating inflammation, allergic diseases, and malaria, comprising costunolide, dehydrocostus lactone, or a pharmaceutically acceptable salt thereof as an effective component; and to a cosmetic composition. The compounds of the present invention, when used to treat cells induced by inflammatory stimuli, were found to inhibit inflammatory cytokine IL-8. In the present invention, a mouse model of ovalbumin-induced bronchial asthma and rhinitis was prepared and treated with costunolide and dehydrocostus lactone, and it was confirmed that the secretion of inflammatory cells and IL-5 was reduced in bronchoalveolar lavage fluid; that the infiltration of inflammatory cells was reduced in lung tissues; and that mucous secretions in bronchial tubes were reduced. Further in the present invention, an animal model of atopic dermatitis was prepared and treated with costunolide, and it was confirmed that the thickness of skin of the mouse with atopic dermititis decreased. Thus, the costunolide and dehydrocostus lactone may be beneficially used as a pharmaceutical composition for preventing and treating inflammation, allergic diseases, and malaria, or as a cosmetic composition.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for preventing or treating inflammation, allergic diseases, and malaria containing, as an active ingredient, a cosurinolide, a dihydrocoster lactone, or a pharmaceutically acceptable salt thereof. as an active ingredient for prevention or treatment of inflammatory diseases or allergic diseases or malaria}

The present invention relates to a pharmaceutical composition for preventing or treating inflammation, allergic diseases and malaria containing as an active ingredient cosunolide, dehydrocostus lactone, or a pharmaceutically acceptable salt thereof, To a cosmetic composition.

An allergic disease is a disease caused when an immune mechanism of an individual exhibits a more sensitive response to an external substance (allergen) than usual. Such an allergic disease is an immune disease that occurs frequently due to climate change such as temperature and humidity, climate, environmental pollution, occupation, etc. However, a fundamental therapeutic agent has not yet been developed.

Anti-allergic drugs that have been developed to date inhibit many levels of chemical messengers produced by inflammatory cells that are the origin of seizures. That is, when mast cells are degranulated by various kinds of allergens, chemicals such as histamine, heparin and proteolytic enzymes stored in the granules of mast cells are liberated, resulting in immediate allergic reaction and inflammatory reaction. Almost all antihistamines that inhibit the above-mentioned chemicals are used as a therapeutic agent for alleviating the symptoms of allergic diseases, and steroids are administered in combination in severe cases. However, such synthetic products can not be expected to be completely cured, have a disadvantage in that they are ineffective when used for a long period of time and seriously cause systemic side effects.

Other methods of treatment include allergen-related allergies, which are then alleviated by administering them in small doses for several years. However, this method has a disadvantage in that the treatment period first takes several years and it can cause anaphylactic shock and the like. Next, there is a therapeutic approach such as the use of DNA vaccines, the treatment of blocking IgE binding to receptors in mast cells, and the treatment of antibodies to IL-4, an allergen-inducing cytokine. However, these approaches have the problem that they are costly or have not yet been fully characterized.

Recently, cytokines produced by Th2 cells by several research groups have been found to be key to allergy development (O'Garra, A. Immunity 8: 275, 1998; Glimcher LH et al., Genes Dev. 14: 1693 Murphy KM et al., Annul Rev. Immunol. 18: 451,2000). Accordingly, studies for developing a drug targeting the inhibition of Th2 cytokine activity have been actively conducted. Schering-Plow, for example, is conducting clinical trials to develop a single antibody against human IL-5 as an allergen, and Roche is using isothiazolone (isothiazolone) derivatives, but it has a limitation in developing a drug as a non-specific reaction to other proteins.

Inflammatory disease refers to a pathological state caused by chronic or acute inflammation and may be caused by an abnormality of the immune system. Inflammation is a normal and protective in vivo defense manifestation that is localized to physical trauma, harmful chemicals, microbial infections, or tissue damage caused by stimuli in vivo metabolites. These inflammations are triggered by various chemical mediators produced from damaged tissues and migrating cells, and these chemical mediators are known to vary according to the type of inflammation process. In normal cases, the organism neutralizes or eliminates the cause of inflammation through the inflammation reaction, regenerates the upper tissue and regenerates the normal structure and function, but if not, the disease state such as chronic inflammation also proceeds. In addition, when the inflammation is improperly induced by an autoimmune reaction such as a harmless substance such as pollen, asthma or rheumatoid arthritis, the defense reaction itself rather damages the tissue, and therefore, an inflammatory disease prevention or treatment agent is required. Inflammatory reactions can be observed in almost all clinical diseases. Some of these inflammatory diseases are bacterial diseases that can be cured by antibiotic treatment, but most of them are due to tissue damage due to autoimmune reaction, so there is no specific treatment It is known as an incurable disease.

One example of an inflammatory disease is atopic disease. Atopic diseases include asthma, allergic bronchiectasis, hay fever, conjunctivitis, rhinitis, dermatitis, eczema, dandruff, urticaria, food, air, drugs, pollen, mold, dust and animal allergies, sera and anaphylactic shock These diseases may occur alone or in a variety of diseases. In general, immunosuppressive inflammatory diseases including atopic dermatitis are representative examples. Although the cause of the immune-sensitized inflammatory disease including atopic dermatitis, which is known to date, is not known precisely, it is generally believed that genetic and immunological factors are involved, and other environmental and psychological factors act as deteriorating factors It is a universal viewpoint.

Currently, dexamethasone, which is known to be a steroid agent, is the most widely used treatment for immunosuppressive inflammatory diseases including atopic dermatitis. However, it is effective for short-term treatment, but it is not stable and effective in long- (2009). In the present study, there was a significant increase in the incidence of skin irritation, skin irritation, and skin discoloration.

Another example of an inflammatory disease is arthritis. Arthritis includes rheumatoid arthritis (RA), osteoarthritis (OA), fibromyalgia, lupus, gout, and bursitis. Of these, osteoarthritis is characterized by destruction of articular cartilage, changes in bones such as sclerosis, osteophytosis, cysts in the subchondral bone of the involved joint, and often symptoms of inflammation (1): 27-32). This is the first case of a degenerative disease that progresses slowly with the onset of disease.

Another example of an inflammatory disease is conjunctivitis. Conjunctivitis is the most common inflammatory condition of the conjunctiva caused by bacteria, viruses, allergies, or environmental factors. In some cases, it is fatal and can lead to blindness due to tissue damage. Conjunctivitis is classified as infectious conjunctivitis and non-infectious conjunctivitis, depending on the cause.

Allergic conjunctivitis is treated with steroids such as antihistamines, glucocorticoids, allergies, blocking agents and the like (Korean Patent No. 10-0926387, Korean Patent Application No. 10-2006-0090665). However, most of these therapeutic agents are produced not by natural substances but by chemical synthesis, resulting in a problem of causing side effects in the body.

Another example of an inflammatory disease is nephritis. Nephritis is inflammation of the kidneys, also called pyelitis. The kidney is located on both sides of the upper part of the abdomen of the glomeruli, abnormalities in the glomeruli of hematuria or hematogenous albumin, a major nutrient of the urine to escape the protein urine phenomenon appears. It also swells and sometimes accompanies high blood pressure. However, specific nephritis may cause abnormalities in other organs such as the lungs, joints, skin, nerves, eyes, and brain as well as the kidneys. Nephritis may include acute nephritis that lasts for several days or weeks, is fully recovered, and chronic nephritis, which lasts for months or longer and does not recover and chronic renal failure.

Inflammatory diseases such as dermatitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohns disease, colitis, hepatitis, cystitis and Sjogren's disease.

The most common inflammatory disease preventive or therapeutic agents for treating such inflammatory diseases are largely divided into steroidal and nonsteroidal inflammatory disease preventive or therapeutic agents. Most of synthetic inflammatory disease preventive or therapeutic agents have various side effects It is necessary to develop a prophylactic or therapeutic agent for inflammatory diseases, which is excellent in efficacy and has few side effects.

Malaria is a very serious and complex disease that threatens human health in the 21st century. Approximately three million people worldwide are infected with malaria, and 1.5 million die each year. Malaria is an infectious disease caused by four kinds of Plasmodium , the most serious of which is the tropical fungal malaria Plasmodium falciparum . Malaria is becoming a serious problem especially in developing countries such as Africa. When infected with a malaria strain, red blood cells become malformed. When they accumulate in the blood vessel wall, they block blood flow and cause complications such as brain, kidney, and liver. Therefore, pesticides and anti-malarial drugs are being developed to control mosquitoes that become infectious sources. However, the increase of resistance of mosquitoes to existing insecticides and the emergence of resistant strains to anti - malaria medicines are increasing the incidence of malaria. Furthermore, as the possibility of malaria outside the area of malaria due to the global warming phenomenon becomes higher, development of a new mosquito insecticide and anti-malaria drug is urgently required.

Accordingly, the present inventors have made efforts to find a prophylactic and therapeutic agent for inflammation, allergic diseases and malaria which can solve the above-mentioned problems, and have found that costunolide and dehydrocostus lactone can be used for inflammatory stimuli- (IL-8). In addition, ovalbumin-induced bronchial asthma and rhinitis mouse models were prepared and administered with cosunoride and dihydrocoster lactone As a result, it was confirmed that inflammatory cells and IL-5 secretion were suppressed in bronchoalveolar lavage fluid, inflammatory cell infiltration was reduced in lung tissue, and bronchial mucus secretion was reduced. In addition, as a result of preparing an animal model of atopic dermatitis and administering a cosurinide, it was confirmed that the skin thickness of the atopic dermatitis mouse decreased, and the cosurinolide, dihydrocosterolactone, , An allergic disease, and malaria. The present invention has been accomplished on the basis of these findings.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating inflammation, allergic diseases and malaria containing as an active ingredient cosunolide, dihydrocostus lactone, or a pharmaceutically acceptable salt thereof, Composition or cosmetic composition.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating an allergic disease, comprising a compound selected from the group consisting of the following Formulas 1 and 2, or a pharmaceutically acceptable salt thereof as an active ingredient: to provide:

[Chemical Formula 1]

; 및

; And

(2)

.

.

The present invention also provides a health functional food for preventing or ameliorating an allergic disease, comprising a compound selected from the group consisting of the above-mentioned formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising a compound selected from the group consisting of the above-mentioned formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food for preventing or ameliorating an inflammatory disease, comprising a compound selected from the group consisting of the above-mentioned formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention or treatment of malaria comprising a compound selected from the group consisting of the above-mentioned formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a cosmetic composition comprising a compound selected from the group consisting of the above-mentioned formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

When the costunolide or dehydrocostus lactone of the present invention was treated with inflammatory stimuli, the secretion of cytokines (IL-8) involved in inflammation and allergy was suppressed. In addition, ovalbumin-induced bronchial asthma and rhinitis mouse models were prepared and the administration of cosunoride or dihydrocoster lactone resulted in inhibition of inflammatory cells and IL-5 secretion in bronchoalveolar lavage fluid, , Inflammatory cell infiltration was decreased, and bronchial mucus secretion was decreased. In addition, since an animal model of atopic dermatitis was prepared and the cosurinolide was administered, the skin thickness of the atopic dermatitis mouse was decreased. Therefore, the cosurinolide and the dihydrocosterolactone were used for prevention or treatment of inflammation, allergic diseases and malaria May be usefully used as a pharmaceutical composition or a cosmetic composition.

Brief Description of the Drawings Fig. 1 is a diagram showing an inhibitory effect on IL-8 (interleukin-8) secretion in cells by a cosuronolide treatment:
NC: negative control; And
HRF: HRF (histamine releasing factor) group.
FIG. 2 is a graph showing the effect of suppressing IL-8 secretion in cells by dihydrocoster lactone treatment. FIG.
FIG. 3 shows the effect of eosinophil reduction on inflammatory cells by treatment with cosuronolide and dihydrocortisone:
NC: negative control group
PC: positive control group
Cos: Cosurinolide treated group; And
Deh: dihydrocosterolactone group.
4 is a graph showing the inhibitory effect of cosunolide on IL-5 secretion in bronchoalveolar lavage fluid.
FIG. 5 is a view showing the effect of improving the inflammation of the cosurinolide and dihydrocoster lactone in the lung tissue of the bronchial asthma and rhinitis mouse models.
FIG. 6 is a graph showing the bronchial mucus-reducing effect of cosunolide and dihydrocosterolactone in lung tissues of bronchial asthma and rhinitis mouse models.
FIG. 7 is a diagram showing the anti-atopic dermatitis effect of cosurinolide in a mouse induced atopic dermatitis with biostir.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating an allergic disease, comprising a compound selected from the group consisting of the following formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

; 및

; And

(2)

.

.

The compound 1 is a costunolide and the compound 2 is a dehydrocostus lactone. The compound is characterized by inhibiting the secretion of inflammatory cytokines associated with allergy.

The allergic disease can be, but is not limited to, asthma, rhinitis, biliary, anaphylaxis, anaphylactic shock, seropositivity, hay fever, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis.

In a specific example of the present invention, the present inventors prepared ovalbumin-induced bronchial asthma and rhinitis mouse models, and then administered cosunoride and dihydrocoster lactone, and found that eosinophil infiltration was reduced (See FIG. 3), the IL-5 secretion in the bronchoalveolar lavage fluid of the mouse model was inhibited by 50% or more compared to the positive control (see FIG. 4), infiltration of inflammatory cells around the bronchus (see FIG. 5) And the accumulation was decreased (see FIG. 6). In addition, since it has been confirmed that cosurinolide reduces skin thickness in atopic dermatitis mice (see FIG. 7), the cosuronolide and dihydrocosterolactone are useful as pharmaceutical compositions for the prevention or treatment of allergic diseases .

The present invention includes not only the compounds represented by the above general formulas (1) and (2) but also their pharmaceutically acceptable salts, possible solvates, hydrates, racemates or stereoisomers thereof, and mixtures thereof.

The present invention can be used in the form of a compound represented by the above general formulas (1) and (2) or a pharmaceutically acceptable salt thereof, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Octaic acid, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinic acid, succinic acid, succinic acid, succinic acid, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene sulfonate, chlorobenzene sulfoxide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be produced by a conventional method, for example, by dissolving the compound represented by the general formula (1) or (2) in an excess amount of an acid aqueous solution, and then mixing the salt with a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. It is also possible to prepare by heating the same amount of the compound represented by the general formulas (1) and (2), and an acid aqueous solution or alcohol, and then evaporating the mixture or drying the precipitated salt by suction filtration.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

When the composition is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used.

In one embodiment of the present invention, the composition or preparation may be in the form of an oral preparation, an injection, a mucosal administration preparation, an oral mucosal administration preparation, a nasal administration preparation, an ophthalmic preparation, a vaginal administration preparation, an inhalant, , A transplant preparation, and a suppository, but is not limited thereto.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, which may contain one or more excipients such as one or more excipients such as, for example, , Starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances and preservatives may be included. have.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. The base material of the suppository can be any one selected from witepsol, macrogol, tween 81, cacao paper, taurine paper, glycerol, gelatin and the like, But is not limited thereto.

The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the dosage unit according to the present invention may contain, for example, 1, 2, 3 or 4 times, or 1/2, 1/3 or 1/4 times the individual dose. The individual dosages preferably contain amounts in which the active drug is administered in one go, which usually corresponds to the full, half, one-third or one-fourth of the daily dose. The effective dose of the composition of the present invention is 0.001 to 10,000 mg / kg, preferably 0.1 g to 5 g / kg, and can be administered 1 to 6 times a day. However, the dose may be varied depending on the administration route, severity of disease, sex, weight, age, etc., and therefore the dose is not limited to the scope of the present invention by any means.

The composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The present invention also provides a health functional food for preventing or ameliorating an allergic disease comprising, as an active ingredient, a compound selected from the group consisting of the following formulas (1) and (2), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

; 및

; And

(2)

.

.

The allergic disease may be, but is not limited to, asthma, rhinitis, dermatitis, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis.

In a specific example of the present invention, the present inventors prepared ovalbumin-induced bronchial asthma and rhinitis mouse models, and then administered cosunoride and dihydrocoster lactone, and found that eosinophil infiltration was reduced (See FIG. 3), the IL-5 secretion in the bronchoalveolar lavage fluid of the mouse model was inhibited by 50% or more compared to the positive control (see FIG. 4), infiltration of inflammatory cells around the bronchus (see FIG. 5) And the accumulation was decreased (see FIG. 6). In addition, since it has been confirmed that cosuronolide reduces skin thickness in atopic dermatitis mice (see FIG. 7), the cosuronolide and dihydrocosterolactone can be usefully used in health functional foods for the prevention or improvement of allergic diseases have.

As used herein, the term " health functional food " is produced by using raw materials or ingredients (functional raw materials) having functions useful for nutrients or human body that are likely to be deficient in daily eating, and is intended to maintain the normal function of the human body, But is not limited to, and is not meant to exclude health food in the usual sense.

The composition of the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). In general, the amount of the compound in the health functional food may be 0.01 to 90 parts by weight based on the total weight of the food. However, when consumed for a long period of time for the purpose of health and hygiene or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The health functional beverage composition of the present invention is not particularly limited to other components other than those containing the above-mentioned composition as an essential ingredient at the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As a flavor other than the above, a natural flavoring agent {tau martin, stevia extract (for example, rebaudioside A, glycyrrhizin etc.)} and synthetic flavorings (saccharin, aspartame, etc.) have. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention, but is not limited thereto.

In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. Although the ratio of such additives is not so important, it is generally but not limited to be selected from the range of 0.1 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention also provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising a compound selected from the group consisting of the following formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

; 및

; And

(2)

.

.

The compound preferably inhibits the secretion of inflammatory cytokines and the inflammatory diseases are selected from the group consisting of dermatitis, atopy, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, Inflammatory bowel disease, gout, ankylosing spondylitis, rheumatic fever, systemic lupus erythematosus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, shoulder periitis, tendonitis, Sjogren ' s disease, multiple sclerosis or acute and chronic inflammatory diseases. The composition may have the characteristics as described above.

In a specific example of the present invention, we treated BEAS-2B cells with an HRF (histamine-releasing factor) -influorescent stimulus and then treated with the compound, resulting in the secretion of IL-8 in BEAS-2B cells (Fig. 1 and Fig. 2). After preparing ovalbumin-induced bronchial asthma and rhinitis mouse models, the administration of cosunoride resulted in reduction of the inflammatory cell eosinophil (See FIG. 3), the compound of the present invention can be usefully used as a pharmaceutical composition for the prevention or treatment of inflammatory diseases.

The present invention also provides a health functional food for preventing or ameliorating an inflammatory disease comprising, as an active ingredient, a compound selected from the group consisting of the following formulas (1) and (2), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

; 및

; And

(2)

.

.

The inflammatory diseases are selected from the group consisting of dermatitis, atopy, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, gout, ankylosing spondylitis, rheumatic fever, lupus erythematosus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendinitis, hay fever, tendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's disease, multiple sclerosis or acute and chronic inflammatory diseases But is not limited thereto. The health functional food may have the above-described characteristics.

In a specific example of the present invention, we treated BEAS-2B cells with an HRF (histamine-releasing factor) -influorescent stimulus and then treated with the compound, resulting in the secretion of IL-8 in BEAS-2B cells (Fig. 1 and Fig. 2). After preparing ovalbumin-induced bronchial asthma and rhinitis mouse models, the administration of cosunoride resulted in reduction of the inflammatory cell eosinophil (See FIG. 3), the compounds of the present invention can be usefully used in health functional foods for the prevention or improvement of inflammatory diseases.

The present invention also provides a pharmaceutical composition for the prevention or treatment of malaria comprising a compound selected from the group consisting of the following formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

; 및

; And

(2)

.

.

In a specific example of the present invention, we treated BEAS-2B cells with an HRF (histamine-releasing factor) -influorescent stimulus and then treated with the compound, resulting in the secretion of IL-8 in BEAS-2B cells (See Figs. 1 and 2), the compound of the present invention can be usefully used as a pharmaceutical composition for preventing or treating malaria.

The present invention also provides a cosmetic composition comprising a compound selected from the group consisting of the following Formulas (1) and (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

In a specific example of the present invention, we treated BEAS-2B cells with an HRF (histamine-releasing factor) -influorescent stimulus and then treated with the compound, resulting in the secretion of IL-8 in BEAS-2B cells (Fig. 1 and Fig. 2). After administration of ovalbumin-induced bronchial asthma and rhinitis mouse model, cosunoride and dihydrocoster lactone were administered. As a result, infiltration of eosinophils (See FIG. 3), IL-5 secretion in the bronchoalveolar lavage fluid of the mouse model was inhibited by more than 50% as compared with the positive control (see FIG. 4), infiltration of inflammatory cells around the bronchus It was confirmed that accumulation of internal mucus decreased (see FIG. 6). In addition, since it has been confirmed that cosurinolide reduces skin thickness in atopic dermatitis mice (see Fig. 7), the compounds of the present invention can be usefully used as a cosmetic composition.

The cosmetic composition of the present invention includes components commonly used in cosmetic compositions in addition to the above-mentioned compounds, and includes conventional auxiliary agents such as sulfating agents, stabilizers, solubilizing agents, vitamins, pigments and fragrances, and carriers.

In the cosmetic composition of the present invention, the peptide of the present invention may be added to the cosmetic composition usually contained in an amount of 0.1 to 50% by weight, preferably 1 to 10% by weight.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used in the form of solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a flexible lotion (skin), a nutritional lotion (milk lotion), a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder .

When the formulation of the present invention is a paste, a cream or a gel, an animal oil, vegetable oil, wax, paraffin, starch, tragacantha, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tragacantha, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component is selected from aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

< Example  1> HRF  Preparation of transformants and HRF  Separation purification

A recombinant HRF (histamine releasing factor) protein for use in giving inflammatory stimulation to BEAS-2B cells (ATCC) was prepared by the following method.

Specifically, the recombinant expression vector pRSET-A-Del-N11HRF was transformed into Escherichia coli BL21 (DE3) pLysS (Novagen). The pRSET-A-Del-N11HRF recombinant expression vector contained Del-N11TCTP having residues 11 to 172 with an oligonucleotide primer [forward primer: 5'-CGGGATCC (BamHI) GACGAGCTGTCCTCCGACAT-3 '(SEQ ID NO: 1); reverse primer: 5'-CCCAAGCTT (HindIII) ACATTTTTCCATCTCTAA-3 '(SEQ ID NO: 2)] was used for cloning into pRSET A (Invitrogen) vector.

The E. coli transformant was cultured in LB medium containing ampicillin and chloramphenicol, and when OD reached 0.6, IPTG (isopropyl beta -D-thiogalactoside) was added to a final concentration of 1 M and cultured for another two hours Followed by centrifugation at 5500 rpm for 10 minutes. The recovered Escherichia coli was resuspended in a binding buffer (5 mM imidazole, 500 mM NaCl, 20 mM Tris-HCl, pH 7.9) and then pulverized using ultrasonic waves. The lysed E. coli was centrifuged at 15500 rpm and the supernatant was purified using a Ni column (ELPis). The HRF cloned into the pRSET-A vector had six histidine-linked N-terminal residues. The HRF was bound to a 1 mM imidazole (500 mM NaCl, 20 mM Tris-HCl, pH 7) containing imidazole. 9), and a large amount of salt was removed using a PD-10 column. The purified HRF was purified again using an NaCl concentration gradient on Hitrap-Q anion exchange column (GE Healthcare, USA) and used in the following experiments.

< Example  2> Costunorid  And DiHidroCoaster  Separation of lactones

The following experiments were carried out in order to separate the compound cosolanoids and dihydrocosterolactones of the present invention.

Specifically, 5.4 kg of the dried hull was placed in 5 L of 100% acetone and extracted at room temperature for 24 hours. This procedure was repeated three times, and the combined extracts were concentrated under reduced pressure to obtain 250 g of a mica extract. The obtained crude extract was subjected to silica gel column chromatography (silica gel 60, 230 to 400 mesh, Merck) using a mixture of hexane: methylene chloride: methanol (3: 1: 0 to 0: 1: 49) The fractions 2, 3 and 4 (71 g) of the fractions were combined and again subjected to silica gel column chromatography (silica gel 60, silica gel 60, 230 to 400 mesh, Merck) was performed, in which 2 g of courseinolide and 10 g of dihydrocoster lactone were separated and obtained.

< Experimental Example  1> Costunorid  And DiHidroCoaster  Lactone BEAS -2B cells HRF  Inhibition of IL-8 secretion by IL-8

BEAS-2B cells were cultured in 48-well plates until they grew to about 70%, and then treated with 1% penicillin streptomycin / BEBM (Lonza) for each concentration of cosuronolide and dihydrocosterolactone. The cells were cultured in a 5% CO ₂ incubator at 37 ° C for 10 minutes, and the recombinant HRF prepared in Example 1 was treated at a concentration of 5 μg / mL in each well. After 24 hours, the supernatant was taken and the liberated IL-8 was quantitated by enzyme immunoassay (Biolegend). IL-8 enzyme immunoassay was performed using the protocol of Biolegend Human IL-8 ELISA kit with precoated plates (431508). The plate was pre-coated with IL-8 antibody, and 300 μl of wash buffer was added per well. After washing 4 times in total, 50 μl of the supernatant was added and the mixture was kept at room temperature for 2 hours. After 2 hours, the supernatant in the plate was removed and 300 μl of wash buffer was added per well. After washing 4 times in total, 100 μl of detection antibody solution was added and the mixture was kept at room temperature for 1 hour. After that, 300 μl of wash buffer was added per well and washed 4 times in total. 100 μl of Avidin-HRP A solution was added and incubated at room temperature for 30 minutes. Finally, add 300 μl of wash buffer per well and wash 5 times. Add 100 μl of substrate solution F, incubate at room temperature for 10 minutes in a dark room, add 100 μl of stop solution 450, and 570 nm, respectively. Wash buffer, detection antibody solution, avidin HRP A solution, substrate solution F, and stop solution were all used as reagents in kit (431508, biolegend).

As a result, as shown in Fig. 1, it was confirmed that the co-tunolide inhibited IL-8 secretion in BEAS-2B cells by HRF in a concentration-dependent manner (Fig. 1). In addition, as shown in FIG. 2, it was confirmed that the dihydrocoster lactone inhibited IL-8 secretion in BEAS-2B cells by HRF in a concentration-dependent manner (FIG. 2).

< Experimental Example  2> With ovalbumin  Induced bronchial asthma and rhinitis mouse models and Costunorid  administration

The bronchial asthma and rhinitis animal models were prepared by the following method. Ovalbumin solution was prepared by dissolving ovalbumin in an aluminum hydroxide solution at a concentration of 1 mg / ml before the start of bronchial asthma and rhinitis 21, 14, and 7 days. . After 7 days of final sensitization, mice were treated with saline / PBS (normal control; NC) or 0.1% ovalbumin solution (positive control, positive control; PC) was instilled with a pipette to induce bronchial asthma and rhinitis. At the same time as the above-mentioned PC group, 200 μl of Cosuronolide or dihydrocoster lactone was simultaneously administered at a concentration of 10 mg / kg while inducing bronchial asthma and rhinitis under the same conditions.

< Experimental Example  3> Bronchial alveoli  Washing solution ( bronchoalveolar lavage  Within the fluid course Costunolide, DiHidroCoaster  Lactone ( Dehydrocostus lactone ) To confirm eosinophilia inhibitory effect

In the animal model of Experimental Example 2, mice were intraperitoneally injected with a mixture of jorret (250 mg / kg) and rumun (50 mg / kg) A 22-gauge catheter was inserted into the trachea, and 0.6 ml of PBS was injected three times at a time, and the collection rate was set at 80%. The collected bronchoalveolar lavage fluid was centrifuged at 3000 rpm for 10 minutes at 4 ° C, and the cell precipitate was re-dispersed in 0.1 ml of PBS. 20 μL of the cell suspension was centrifuged using a hemodynamic analyzer HEMAVET 950 FS (Drew Scientific, Inc.) The composition of the cells was analyzed.

As a result, as shown in Fig. 3, it was confirmed that eosinophil, an inflammatory cell, was reduced in the group treated with cosuronolide or dihydrocosterolactone as compared with the positive control group (Fig. 3).

< Experimental Example  4> Bronchoalveolar lavage fluid  Within Costunorid  And DiHidroCoaster  IL-5 secretion of lactone Inhibition  Confirm

The amount of IL-5 in the supernatant obtained by centrifuging the bronchoalveolar lavage fluid in Experimental Example 3 was measured by enzyme immunoabsorption detection using a Mouse IL-5 ELISA Kit (Thermo Scientific, USA) and quantified.

As a result, as shown in Fig. 4, it was confirmed that cosunoride and dihydrocoster lactone inhibited IL-5 secretion in the bronchoalveolar lavage fluid by about 50% as compared with the positive control (Fig. 4).

Experimental Example 5 Effect of ovalbumin- induced bronchial asthma and rhinitis mouse lung tissue on the improvement of inflammation of cosolide and dihydrocoster lactone

In order to confirm the improvement of inflammation of the cosurinolide and dihydrocoster lactone in the bronchial asthma and rhinitis models after the completion of the experiment in the animal model of the above <Experimental Example 2>, the following experiment was conducted.

After the experiment was completed, the lungs of the mice were excised and histologically examined. Specifically, mouse lung tissue was fixed overnight in 10% formaldehyde, embedded in paraffin, and sectioned to a thickness of 5 μm. After deparaffinization, the sections were stained with hematoxylin / eosin (H & E) and the morphology of the tissue was observed.

As a result, as shown in Fig. 5, it was confirmed that infiltration of inflammatory cells around the bronchus was reduced when the cosurinolide and dihydrocoster lactone were treated as compared with the positive control (Fig. 5).

< Experimental Example  6> With ovalbumin  Bronchial mucin clearance of cosunoride and dihydrocoster lactone in lung tissue of induced bronchial asthma and rhinitis mouse models

In order to confirm the removal effect of bronchial mucus of cosurinolide and dihydrocosterolactone in the bronchial asthma and rhinitis model after completion of the experiment in the animal model of Experimental Example 2, the following experiment was conducted.

After the experiment was completed, the lungs of the mice were excised and histologically examined. Specifically, mouse lung tissue was fixed overnight in 10% formaldehyde, embedded in paraffin, and sectioned to a thickness of 5 μm. After deparaffinization, the sections were stained with periodic acid-Schiff (PAS) and the morphology of the tissue was observed.

As a result, as shown in Fig. 6, it was confirmed that the accumulation of intrathoracic mucus decreased when the cosurinolide and dihydrocoster lactone were treated as compared with the positive control (Fig. 6).

< Experimental Example  7> Biostarro  Induced atopic dermatitis in mouse skin Of Cosunorid  Confirmation of treatment effect of atopic dermatitis

In order to confirm the inhibitory effect of atorvastatin on atopic dermatitis lesions in atopic dermatitis, the following experiment was conducted.

Specifically, female NC / Nga mice were divided into 5 groups and treated with untreated control group, group with atopic dermatitis caused by biostir, group with atopic dermatitis treated with Protopic ointment, Five groups were assigned to each group to induce atopic dermatitis by Viosta and to receive cosunoride. At 8 weeks old NC / Nga mice, atopic dermatitis skin lesions were induced, hair was removed from mice, and 4% sodium dodecyl sulfate was applied. Viosta AD ointment was applied twice a week for 3 weeks to induce atopic dermatitis lesion . Protopic ointment (50 mg) was applied to the same skin four times a week for 3 weeks in mice. PBS or cortunolide (25 mg / kg) was administered intraperitoneally four times per week. After the experiment was completed, the dorsal skin of the mouse was excised and histologically examined. Specifically, mouse isoforms were fixed in 10% formaldehyde overnight, embedded in paraffin, and sectioned to a thickness of 5 μm. After deparaffinization, the sections were stained with hematoxylin / eosin (H & E) and the morphology of the tissue was observed.

As a result, as shown in FIG. 7, it was confirmed that the skin thickness decreased when the cosurinolide was treated as compared to the PBS (PBS), and it was confirmed that the treatment effect of atopic dermatitis was obtained 7).

<110> Ewha University - Industry Collaboration Foundation <120> A pharmaceutical composition comprising costunolide,          dehydrocostus lactone, or pharmaceutically acceptable salt          as an active ingredient for prevention or treatment of          inflammatory diseases or allergic diseases or malaria <130> 2015P-08-025 <160> 2 <170> KoPatentin 3.0 <210> 1 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> forward primer <400> 1 cgggatccga cgagctgtcc tccgacat 28 <210> 2 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> reverse primer <400> 2 cccaagctta catttttcca tctctaa 27

Claims (12)

1. A pharmaceutical composition for preventing or treating an allergic disease comprising, as an active ingredient, a compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof,
Wherein said allergic disease is asthma or rhinitis.
(2)

.
delete The pharmaceutical composition according to claim 1, wherein the compound is an inhibitor of the secretion of inflammatory cytokines.
1. A health functional food for preventing or ameliorating an allergic disease comprising, as an active ingredient, a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof,
Wherein said allergic disease is asthma or rhinitis;
(2)

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