KR20200040684A - Usnic acid derivatives having TSLP suppressing effect and composition for prevention or treatment of allergic disease comprising thereof - Google Patents

Abstract

The present invention relates to: a novel usnic acid derivative or a pharmaceutically acceptable salt thereof which exerts a TSLP secretion inhibitory effect; and a composition for preventing, treating, relieving, and alleviating allergic diseases containing the same as an active component. According to the present invention, the usnic acid derivative or the pharmaceutically acceptable salt thereof has an excellent effect of suppressing the secretion of TSLP, which is an immune response factor.

Description

Usnic acid derivatives having the ability to inhibit TSLP secretion and compositions for the prevention or treatment of allergic diseases containing the same {Usnic acid derivatives having TSLP suppressing effect and composition for prevention or treatment of allergic disease comprising thereof}

The present invention relates to a sonic acid derivative having the ability to inhibit TSLP secretion, and more particularly, to a snic acid derivative having a prophylactic or therapeutic effect against allergic diseases.

Atopic dermatitis, also called advanced type incurable disease, is a globally common disease that can occur at any age. 70% to 95% develop in infants under 5 years of age. In Korea, the problem of atopic dermatitis has already reached a serious social and medical level. According to various reports, about 15% of the entire Korean population is atopic dermatitis patients, of which 18 to 22 out of every 100 infants aged 0 to 4 years are atopic. In addition, there is a phenomenon of 'atopic march' in which over 50% of patients with atopic dermatitis develop allergic rhinitis and asthma.

The exact pathophysiology of allergic diseases including atopic dermatitis as described above is not yet fully understood, but it is thought that immunological and environmental factors will be involved with genetic predisposition, especially asthma, allergic rhinitis, and atopic dermatitis. Immune imbalance is common in patients with allergic diseases such as, and many studies have been conducted from an immunological point of view.

On the other hand, the underlying cause of allergic diseases is known as immune imbalance, which is the result of various biological signals. The highest protein for this abnormal signaling is the thymic stromal lymphopoietin (TSLP) cytokine. When allergens penetrate the body, substances such as TSLP stimulate and respond to dendritic cells. In this process, symptoms of allergic diseases such as atopic dermatitis and asthma appear.

This TSLP was an IL-7-like cytokine and was first discovered in a culture of thymic stromal cells. TSLP is an important factor that regulates the immune response at the interface between the body and the environment (skin, respiratory system, digestive system, eyeball, etc.), and is mainly secreted from skin epidermal cells and skin epithelial cells. According to a recent study, in addition to epithelial cells and epidermal keratinocytes, TSLP is secreted from mast cells, airway smooth muscle, fibroblasts, dendritic cells, etc. to regulate the immune response. It is known that overexpression causes imbalance.

According to the known literature, TSLP protein and mRNA were found to be increased in the lesions of atopic dermatitis patients, and showed severe allergic disease in human and animal models (mouse) that increased TSLP expression in the skin (Steven F. Ziegler) et al., J Allergy Clin Immunol, 2012; 130: 845-52). In addition, TSLP was detected in the bronchial fluid of asthma patients, and it was reported that there is a correlation between the sensation of the disease and the increase in TSLP expression in airway epidermal cells, and the allergic inflammatory response is exacerbated when the antigen is exposed due to TSLP secreted from skin cells and the development of asthma It has been found that this is facilitated (Juan et al., Journal of Investigative Dermatology, 2012).

Causes that promote TSLP secretion include viruses, bacterial and bacterial products, protease allergens, inflammatory cytokines, chemicals, and physical irritation (scratching). When overexpressed, it causes imbalance. The mechanism causing the imbalance is as described below.

TSLP receptor (TSLPR) is mainly expressed in hematopoietic cells, and is most frequently expressed in dendritic cells (DC). The survival time of dendritic cells increases due to TSLP, which increases the expression of major histocompatibility complex II, co-stimulatory molecules CD86 and CD40, and Th2 CD4 + T cells and naive ( naive) CCL17 and CCL22 secretion, respectively, which increase CD4 + T cell influx, respectively. Moreover, OX40L expression, which increases Th2 differentiation, increases, and IL-12 expression, which is involved in Th1 differentiation, decreases, resulting in TSLP promoting the mechanism by which dendritic cells induce Th2 responses. In addition, TSLP promotes the influx of eosinophils, mast cells, natural killer T cells, and cytokine secretion, such as IL-13, intensifying immune imbalance.

The present inventors have studied the well-known usnic acid in order to develop an effective therapeutic agent for atopic dermatitis, and as a result, confirm that the unusic acid derivative of the present invention inhibits the expression of TSLP and various cytokines. The present invention has been completed.

An object of the present invention is to provide a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of allergic diseases having the ability to inhibit TSLP secretion, which contains the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a cosmetic composition for alleviating or improving an allergic disease having the ability to inhibit TSLP secretion, which contains the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for alleviating or improving an allergic disease having TSLP secretion inhibiting ability containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to solve the above problems, there is provided a usnic acid derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

<Formula 1>

In addition, in order to solve the above problems, to provide a pharmaceutical composition for the prevention or treatment of allergic diseases containing the unusic acid derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and having the ability to inhibit TSLP secretion do.

"TSLP (thymic stromal lymphopoietin)" of the present invention is an IL-7-like hematopoietic cytokine, which is produced in epithelial cells, stromal cells and mast cells, and is an important factor that regulates the body's immune response. Therefore, when TSLP is over-expressed (over-secreted) in the human body including skin cells, it causes an imbalance in the immune system, and may induce the onset and deepening of the development of allergic diseases.

"Allergic disease" of the present invention means an allergic predisposition, that is, a disease developed by an allergic reaction (immune hypersensitivity reaction). Although the exact cause of the pathogenesis has not been identified, an imbalance of immunity is observed in most patients with allergic diseases, and treatments or treatment methods for controlling imbalance are actively being studied.

In the present invention, such allergic diseases include atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, and dermatitis (hives). And it may be one or more selected from the group consisting of food allergy (food allergy), but is not limited thereto.

Atopic dermatitis of the present invention is a chronic recurrent inflammatory skin disease that begins mainly in infancy or childhood, and is a disease accompanied by pruritus (itching), dry skin, and characteristic eczema.

The unusic acid derivative represented by Chemical Formula 1 of the present invention (MW 604.61) is a compound synthesized by reacting unusic acid with cinnamoyl chloride. More specifically, it is characterized by being prepared through the reaction process of the following Reaction Scheme 1.

<Scheme 1>

The composition containing the unusnic acid derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may have the ability to prevent or treat allergic diseases caused by imbalance.

 "Prevention" of the present invention means any action to suppress or delay the disease by administration of a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. In addition, the term "treatment" used in the present invention, by the administration of a composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, refers to all actions that the symptoms of the disease is improved or cured.

The compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and such salts include an acid addition salt formed by a pharmaceutically acceptable free acid or a metal salt formed by a base. There is this.

An inorganic acid and an organic acid may be used as the free acid, and hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid or phosphoric acid may be used as the inorganic acid. Examples of the metal salt include alkali metal salts or alkaline earth metal salts, and sodium, potassium, or calcium salts are useful.

 For administration, the composition of the present invention may include a pharmaceutically acceptable carrier, excipient, or diluent in addition to the active ingredients described above. The carrier, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

 The "pharmaceutical composition" of the present invention is formulated in the form of an oral dosage form such as powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, external preparation, suppository, or sterile injectable solution according to a conventional method Can be used. In detail, when formulated, it may be prepared using diluents or excipients such as fillers, weights, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. The solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. In addition, lubricants such as magnesium stearate and talc may be used in addition to simple excipients. In addition to liquids for oral administration and liquid paraffin, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be added. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and challenges. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrosol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.

The suitable dosage of the composition of the present invention depends on the patient's condition and body weight, the degree of disease, the drug form, and the time, but can be appropriately selected by a person skilled in the art. The daily dosage of the acceptable salt is preferably 1 mg / kg to 500 mg / kg, and can be divided and administered once to several times per day as needed.

In order to achieve the above other object, the present invention is a cosmetic composition for alleviating or improving an allergic disease containing the unusic acid derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and having the ability to inhibit TSLP secretion. to provide.

<Formula 1>

The cosmetic composition containing the compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may inhibit over-expression of TSLP in the skin, and the allergic disease is atopic dermatitis, asthma, It may be at least one selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic dermatitis, dammajin and food allergies.

The cosmetic composition of the present invention may include ingredients that are generally allowed in addition to the active ingredient, and may include, for example, antioxidants, stabilizers, solubilizers, conventional adjuvants such as vitamins, pigments and fragrances, and carriers.

The cosmetic composition of the present invention can be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing , May be formulated as an oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be prepared in the form of flexible lotion (skin), nutrition lotion (milk lotion), nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder. .

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, trakant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. may be used as a carrier component. You can.

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, and in particular, in the case of a spray, additionally chloro fluorohydrocarbon, propane / Propellant such as butane or dimethyl ether.

 When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, And fatty acid esters of 1,3-butyl glycol oil, glycerol aliphatic esters, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, liquid diluents such as water, ethanol or propylene glycol as carrier components, ethoxylated isostearyl alcohol, suspensions such as polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystals Sex cellulose, aluminum metahydroxide, bentonite, agar or trakant, etc. can be used.

When the formulation of the present invention is a surfactant-containing cleansing, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosate, fatty acid amide as a carrier component Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

 In order to achieve the above another object, the present invention contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and has a functional function for alleviating or improving allergic diseases with TSLP secretion inhibiting ability Provided is a composition.

<Formula 1>

The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof , Organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonic acid used in carbonated beverages, and the like. In addition, it may contain flesh for the production of natural fruit juices, synthetic fruit juices and vegetable drinks. These ingredients can be used independently or in combination. In addition, the health functional food composition is a form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol and vitamin complex Can be

In addition, the health functional food composition may further include a food additive, and whether or not it is suitable as a "food additive" is applicable according to the general rules of food additives and general test methods approved by the Ministry of Food and Drug Safety unless otherwise specified. It is judged according to the standards and standards for items.

Items listed in the "Food Additives Fair" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid, natural additives such as chromosomes, licorice extract, crystalline cellulose, high-cooling pigment, and guar gum, L -Mixed preparations, such as a sodium glutamate preparation, an alkali addition agent for a noodles, a preservative preparation, and a tar dye preparation, etc. are mentioned.

At this time, the compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof, which is added to food in the process of manufacturing a health functional food composition, may appropriately adjust its content as necessary, preferably food. It is preferable to add such that 100 parts by weight to 1 part by weight to 15 parts by weight.

According to the present invention, the composition according to the present invention is atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, because the unusic acid derivative or a pharmaceutically acceptable salt thereof has an excellent effect of inhibiting the secretion of TSLP, an immune response factor. , Allergic diseases, including allergic dermatitis, can be utilized for the prevention, treatment, alleviation and improvement.

1A is a reaction scheme for preparing a snic acid derivative of the present invention.
1B is a result of NMR analysis of the usnic acid derivative of the present invention.
2 is a real-time PCR results for measuring the change in expression level of the TSLP gene.
3 is a real-time PCR results for measuring the change in expression level of the IL-1β gene.
4 is a real-time PCR results for measuring the change in expression level of the IL-13 gene.
5 is a real-time PCR results for measuring the change in expression level of the IL-25 gene.
6 is a real-time PCR results for measuring the change in expression level of the IL-31 gene.
7A to 7E are biopsy histological examination results for confirming hypertrophic scar relieving efficacy.
8A to 8E are pathological examination results of skin tissue for confirming hypertrophic scar relieving efficacy (K: keratin layer, EP: epidermis, PD: papillary dermis, RD: reticular dermis).

In order to help the understanding of the present invention will be described in detail with examples. However, the following examples are provided to more fully describe the present invention to a person having average knowledge in the art, and the scope of the present invention is limited to the following examples because they are merely illustrative of the contents of the present invention. It is not.

Example 1. Synthesis and separation of a sonic acid derivative (hereinafter UA-CA)

After dissolving 0.85g (2.47mmole) of R-(+)-Usnic acid in 50ml of DCM, cool it with an ice bath, and slowly add 1.0ml (7.4mmol, 3.0 eq) of TEA and 0.9g (5.4mmol, 2.2eq) of Cinnamoyl chloride. After adding, the mixture was stirred at 0 ° C for 20 minutes. Accordingly, it was synthesized through the following reaction scheme.

<Reaction Scheme 2>

After confirming that the reaction was complete by TLC, the reaction solution was diluted in 60 ml of water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off under reduced pressure. The remaining residue was purified by silica gel column chromatography (developing solvent: n-Hex / EtOAc = 5/1) to obtain 1.19 g (79%) of the target compound ( A ) as an orange solid.

The NMR analysis results for Compound A are as follows (see FIG. 1B).

(A) : ¹ H NMR (500 MHz, CDCl ₃ ) : δ 13.33 (s, 1H, OH), 10.54 (s, 1H, OH), 7.84 (d, 1H), 7.70 (d, 1H), 7.29- 7.51 (m, 10H), 6.58 (d, 1H), 6.42 (d, 1H), 6.01 (s, 1H), 5.60 (d, J = 54.2 Hz, 2H), 2.67 (s, 3H), 2.12 (s , 3H), 1.87 (s, 3H)

Example 2. Cytokine gene expression level experiments of the unusic acid derivative

<1> Culture of human keratinocyte line

HaCaT, an immortalized human keratinocyte cell line, was added to DMEM (Dulbecco's modified Eagle's media) medium containing 2 mM glutamine 2 mM, penicillin 400 U / ml, streptomycin 50 mg / ml, and 10% FBS at 37 ° C with 5% CO ₂ Cultured in humid atmosphere. For treatment of UA-CA, the cells were cultured with 80% confluence and then cultured for 24 hours without FBS addition. After incubation, the cells were washed with phosphate buffered saline (PBS), and then the prepared UA-CA was added to the medium.

<2> Confirmation of expression level of atopic inflammatory cytokine gene through qRT-PCR

To confirm mRNA expression of inflammatory cytokines related to atopic dermatitis (TSLP, IL-1β, IL-13, IL-25, and IL-31), UA is induced after inflammatory cytokines are induced through TNF-a stimulation in HaCaT cells. -Expression control by CA treatment was confirmed. Total RNA was isolated using RNAiso Plus (Takara Bio Inc., Shiga, Japan) and 2 μg of total RNA was converted to cDNA using the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, MA, USA). The cytokine and endogenous standard quantification index 36B4 cDNA was performed using a 7500 real-time polymerase chain reaction (PCR) system (Applied Biosystems, Foster City, CA, USA). This assay can detect RT-PCR products directly without downstream processing and monitors the increase in fluorescence of dye-labeled DNA probes specific for each factor, with probes specific for the 36B4 gene used as an endogenous control. It was feasible. TB Green Premix Ex Taq? (Takara Bio Inc., Shiga, Japan) was used and the reaction was carried out in a final reaction volume of 10 μl. The sequences of the forward and reverse primers for cytokines and 36B4 were designed as in Table 1 below. The qRT-PCR cycling conditions were 50 ° C 2 minutes, 95 ° C 10 minutes, 95 ° C 15 seconds, and 64 ° C 40 seconds. Data were analyzed using the 2-DDCT (delta delta C [T]) method. After normalizing to 36B4, relative mRNA levels were determined. Each experiment was repeated at least three times, and data were expressed as mean SEM.

h36B4-forward primer 5'-TCG ACA ATG GCA GCA TCT AC-3 ' h36B4-reverse primer 5'-TGA TGC AAC AGT TGG GTA GC-3 ' hTSLP-forward primer 5'-TAT GAG TGG GAC CAA AAG TAC CG-3 ' hTSLP-reverse primer 5'-GGG ATT GAA GGT TAG GCT CTG G-3 ' hIL-1β forward primer 5'-CTC CAG GGA CAG GAT ATG GA-3 ' hIL-1β reverse primer 5'-TCT TTC AAC ACG CAG GAC AC-3 ' hIL-13-forward primer 5'-CCT CAT GGC GCT TTT GTT GAC-3 ' hIL-13-reverse primer 5'-TCT GGT TCT GGG TGA TGT TGA-3 ' hIL-25-forward primer 5'-CTC CTG TCT CTT CCT CTT TTC C-3 ' hIL-25-reverse primer 5'-TGC ACC CAA AGT AGA TGC TC-3 ' hIL-31-forward primer 5'-CAC GTT GCC CGT CCG TTT A-3 ' hIL-31-reverse primer 5'-TCT TCG AGA GGG ACT GTA ATT CC-3 '

As a result of the experiment, the TNF-a-treated group showed a significantly increased expression level of the cytokine gene compared to the TNF-a-untreated group, and the respective TNF-a-treated and UA-CA-treated groups had a higher concentration of UA-CA. Independently, it was shown that the expression level of the cytokine gene decreased. Accordingly, it can be seen that the UA-CA of the present invention acts to reduce atopic dermatitis-related cytokine expression (by TNF-a treatment) (see FIGS. 2 to 6).

Example 3. Experiment for confirming the efficacy of relieving scars on hypertrophic scars of a derivative of unusnic acid

In order to confirm the efficacy of alleviating hypertrophic scars of the unusic acid derivative, the degree of scar relief by UA-CA treatment in the hypertrophic scar samples was confirmed by biopsy and histological comparison and pathological examination of skin tissue.

Four rabbits (N2W conventional, female, 30 weeks old) of 3.5 kg were reared for 1 week in an environment of 21 ± 1 ℃ and 12-hour light / dark cycle, and then experiments were conducted. After administering intravenous administration of ketamine (60 mg / kg) + xylazine (5 mg / kg), both ears of the rabbit were sufficiently sterilized with betadine, and each wound was wound with a diameter of 6 mm and a neck collar was placed with a biopsy punch. . Management and supervision were performed to become a hypertrophic scar model for 2 weeks after wound surgery. After confirming the hypertrophic scar model, the test substance was treated twice a week for 2 weeks (untreated hypertrophic scar sample (Control), hypertrophic scar sample treated with 1, 5, and 10 mM UA-CA, 100 Hypertrophic scar samples treated with ug / ml tranilast). After 2 weeks, a visual evaluation and a biopsy of the wound were performed, and H & E staining was performed, and then the epidermal thickness changes were compared at 200 and 400 times under a microscope.

As a result, as shown in FIGS. 7A to 7E, it was confirmed that the scar relief was more advanced in the sample treated with UA-CA compared to the untreated hypertrophic scar, and in particular, the hypertrophic scar treated with the tranilast, a positive control group. When compared with the sample treated with UA-CA 1 mM, the degree of scar remission was similar, and the sample treated with UA-CA 10 mM was found to have better scar relieving efficacy.

In addition, as shown in FIGS. 8A to 8E, it was confirmed that the thickness of the epidermis became thinner as the scar relaxation progressed more in the samples treated with UA-CA compared to the untreated hypertrophic scar.

Claims (7)

Usnic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
<Formula 1>

A pharmaceutical composition for the prevention or treatment of allergic diseases, comprising the unusic acid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 2, wherein the allergic diseases include atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, and dammargin , hives) and food allergy (food allergy) pharmaceutical composition for the prevention or treatment of allergic diseases, characterized in that at least one selected from the group consisting of. A cosmetic composition for alleviating or ameliorating allergic diseases, comprising the unusic acid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 4, wherein the allergic diseases are atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, and dammajin , hives) and food allergy (food allergy) cosmetic composition for alleviating or improving allergic diseases, characterized in that at least one selected from the group consisting of. A health functional food composition for alleviating or improving an allergic disease, comprising the unusic acid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 6, wherein the allergic diseases include atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, and dammajin. , hives) and food allergy (food allergy) health functional food composition for alleviating or improving allergic disease, characterized in that at least one selected from the group consisting of.

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