KR20210141386A - Novel polyphenol compounds and antifungal composition comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel polyphenol compound and an antifungal composition containing the same as an active ingredient, and the novel compound of the present invention has an excellent antifungal effect and can be usefully used as the antifungal composition. The present invention relates to a compound having at least one chemical formula selected from a group consisting of the following chemical formulas 1 to 3, or a salt thereof.

Description

Novel polyphenol compounds and antifungal composition comprising the same as an active ingredient

The present invention relates to a novel compound and an antifungal composition containing the same as an active ingredient.

Fungus refers to a group of microorganisms including mold, yeast, and mushrooms. Most of them cannot synthesize nutrients themselves, so they live as parasites in other organisms. In humans, most of the infections are on the skin, such as the scalp, hair, face, arms, legs, nails or toenails, where a lot of dead and peeling cells are distributed, but it can also be infected with the gastrointestinal mucosa or vaginal mucosa, and it can cause systemic infection by infection with internal organs, etc. also cause On the other hand, fungal infections are caused by immunodeficiency, old age, use of immunosuppressants or steroids, nutritional deficiencies, poor hygiene, and contact with infected patients.

An antifungal agent refers to a substance for preventing or treating symptoms caused by a fungal infection by inhibiting the growth or reproduction of fungi.

Fungal infectious diseases in humans and animals can be largely divided into two types, systemic mycosis and epidermal mycosis, depending on the location of the infected tissue. Among them, systemic mycosis is a disease that rarely causes disease in healthy people, but is often caused by opportunistic infections in people with weak immunity. ), and aspergillosis. Cryptococcosis is caused by infection with Cryptococcus neoformans and infects all parts of the body including the skin in patients with weakened immunity such as AIDS patients, especially the brain and meninges. infection, leading to meningitis, brain abscesses and brain tumors. Candidasis is a mycosis caused by Candida albicans and was first isolated from thrush patients and causes vaginitis in women and diaper rash in infants. Ringworm is a skin disease caused by Trichophyton such as Trichophyton rubrum and Trichophyton mentagrophytes. It is known to cause skin lesions.

In recent years, the incidence of systemic fungal infections has increased significantly with the increase in immunocompromised patients or acquired immunosuppressive syndrome (AIDS) patients due to the administration of immunosuppressive agents after chemotherapy or organ transplantation, and its importance is increasing day by day. In fact, in cases of cancer or AIDS, the cause of death is not the disease itself, but rather the fungal infection of organs or blood. In addition, the causative bacteria of fungal infections are gradually diversifying, and it is predicted that more types of fungi will cause invasive infections in the future.

As antifungal agents currently clinically used, most of the synthetic substances of the azole series are used except for amphotericin B. However, there is a disadvantage that side effects appear severe when these antifungal agents are used.

In addition, commercially available antifungal agents have disadvantages in that they are toxic, a narrow activity range, and a fungistatic rather than a fungicide. Some of these also exhibit drug-drug interactions, resulting in very complex treatment. According to the recent trend in which a lot of fungal infections occur in immunosuppressed patients and the patient population is steadily increasing, there is an increasing demand for new antifungal agents having broad-spectrum activity and excellent pharmacological properties.

Republic of Korea Patent Registration No. 10-1302678

Accordingly, the present inventors have completed the present invention by discovering novel compounds that exhibit strong antifungal effects.

Accordingly, an object of the present invention is to provide a compound having at least one chemical formula selected from the group consisting of the following Chemical Formulas 1 to 3, or a salt thereof.

[Formula 1]

[Formula 2]

[Formula 3]

Another object of the present invention comprises the steps of (a) extracting Woodpodia uniflora with water or an organic solvent having 1 to 4 carbon atoms;

(b) fractionating the extract obtained in step (a) with ethyl-acetate or butyl alcohol; and

(c) to provide a method for preparing the compound comprising the step of separating and purifying the fraction obtained in step (b) by gradient chromatography.

Another object of the present invention is to provide an antifungal composition comprising a compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 4]

(In Formula 4,

또는 헤테로시클로알킬이고,The R ₁ to R ₃ are each independently H, OH, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, gallic acid,

or heterocycloalkyl;

또는

이고,wherein R ₄ and R ₇ are each independently H, O, OH, C ₁ to C ₃ alkyl group, C ₁ to C ₃ alkoxy group, O-gallic acid, O-glucose, O-rhamnose, O-Glucogalic acid,

or

ego,

Wherein R ₈ and R ₉ are each independently H, OH, O- gallic acid, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy,

The R ₅ and R ₆ are single or double bonded to each other to form a ring structure.)

[Formula 5]

(In Formula 5, X or Y is each independently H, methyl or ethyl.)

Another object of the present invention is to provide an antifungal composition comprising a Woodpodia uniflora extract or a fraction thereof as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

Accordingly, the present invention provides a compound having at least one chemical formula selected from the group consisting of the following Chemical Formulas 1 to 3, or a salt thereof.

[Formula 1]

[Formula 2]

[Formula 3]

In addition, the present invention comprises the steps of (a) extracting Woodpodia uniflora with water or an organic solvent having 1 to 4 carbon atoms;

(b) fractionating the extract obtained in step (a) with ethyl-acetate or butyl alcohol; and

(c) provides a method for preparing the compound comprising the step of separating and purifying the fraction obtained in step (b) by gradient chromatography.

In addition, the present invention provides an antifungal composition comprising a compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 4]

(In Formula 4,

또는 헤테로시클로알킬이고,The R ₁ to R ₃ are each independently H, OH, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, gallic acid,

or heterocycloalkyl;

또는

이고,wherein R ₄ and R ₇ are each independently H, O, OH, C ₁ to C ₃ alkyl group, C ₁ to C ₃ alkoxy group, O-gallic acid, O-glucose, O-rhamnose, O-Glucogalic acid,

or

ego,

Wherein R ₈ and R ₉ are each independently H, OH, O- gallic acid, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy,

The R ₅ and R ₆ are single or double bonded to each other to form a ring structure.)

[Formula 5]

(In Formula 5, X or Y is each independently H, methyl or ethyl.)

In addition, the present invention provides an antifungal composition comprising a Woodpodia uniflora extract or a fraction thereof as an active ingredient.

In an embodiment of the present invention, the compound may be isolated from Woodfordia uniflora or a culture thereof, but is not limited thereto.

In another embodiment of the present invention, the compound may have an antifungal effect, but is not limited thereto.

In another embodiment of the present invention, the organic solvent of step (a) is methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, dichloromethane and petroleum ether It may be one or more selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the antifungal composition has antifungal activity against at least one selected from the group consisting of Candida spp. , Cryptococcus spp. , and Trichophyton spp. may have, but is not limited thereto.

In another embodiment of the present invention, the compound of Formula 4 is

Wherein R ₁ is H or OH,

이고, Wherein R ₂ is H, methoxy, methyl, ethyl, gallic acid or

ego,

Wherein R ₃ is H or OH,

이고,Wherein R ₄ is H, O or

ego,

, OH, O-람노서스, 또는 O-갈산이고, The R ₇ is

, OH, O-rhamnosus, or O-gallic acid,

The R ₅ and R ₆ may be single or double bonded to each other to form a ring structure, but is not limited thereto.

In another embodiment of the present invention, the compound of Formula 4 may be represented by the following Formula 6, but is not limited thereto.

[Formula 6]

(In Formula 6,

이고,wherein R ₂ is H, gallic acid, or

ego,

이고,wherein R ₄ is H or

ego,

R ₇ is H, OH or gallic acid.)

In another embodiment of the present invention, the compound of Formula 5 is

wherein X is H;

Y may be methyl, but is not limited thereto.

In another embodiment of the present invention, the compound of Formula 4 is woodfordiamycin, (+)-catechin 7-O-gallate ((+)-catechin7-O-gallate) and procyanidin B3-3 -O- gallate (procyanidin B3-3- O -gallate) may be one selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the extract may be an extract using water or an organic solvent having 1 to 4 carbon atoms, but is not limited thereto.

In another embodiment of the present invention, the fraction may be obtained by fractionation with ethyl acetate or n-butanol, but is not limited thereto.

In addition, the present invention provides an antifungal method comprising administering to a subject a composition comprising the compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the antifungal method may be a method of treating a fungal infection.

In addition, the present invention provides an antifungal use of the compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides the use of the compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof for the preparation of an antifungal agent.

In addition, the present invention provides an antifungal method, comprising administering to a subject a composition comprising the Woodpodia uniflora extract or a fraction thereof.

In one embodiment of the present invention, the antifungal method may be a method of treating a fungal infection.

In addition, the present invention provides an antifungal use of a composition comprising an extract of Woodpodia uniflora or a fraction thereof.

In addition, the present invention provides the use of an extract of Woodpodia uniflora or a fraction thereof for the preparation of an antifungal agent.

The compounds of the present invention have excellent antifungal activity and can be usefully used as antifungal compositions.

1 is a structural formula for 19 compounds isolated and purified from Woodfordia uniflora.

In order to achieve the above object of the present invention, the present inventors have discovered compounds having excellent antifungal effect, and completed the present invention.

Accordingly, the present invention provides a compound having at least one chemical formula selected from the group consisting of the following Chemical Formulas 1 to 3, or a salt thereof.

[Formula 1]

[Formula 2]

[Formula 3]

A compound having a chemical formula selected from the group consisting of Chemical Formulas 1 to 3 was first identified by the present inventors, and this is well shown in Examples of the present specification.

In the present invention, the compound of Formula 1 may be named woodfordiamycin by the present inventors, and 2-(3,4-dihydroxyphenyl)-5-hydroxychroman-7-yl 3,4,5- It can have the IUPAC name of trihydroxybenzoate.

In the present invention, the compound of Formula 2 may be named wood capsule diksan (woodfordic acid) by the present inventors, (S) -4-oxo- 3 - ((2 R, 3 S) -3,5, It may have the IUPAC name of 7-trihydroxychroman-2-yl)pentanoic acid.

In the present invention, the compound of Formula 3 is rhamnetin 3-O-(6′′-galloyl)-β-glucopyranoside (rhamnetin 3-O-(6′′-galloyl)-β-glucopyranoside). can be named ((2 R ,3 S ,4 S ,5 R ,6 S )-6-((2-(3,4-dihydroxyphenyl)-5-hydroxy-7-methoxy-4-oxo-4 H- chromen-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2 H- pyran-2-yl)methyl 3,4,5-trihydroxybenzoate may have the IUPAC name.

In the present invention, the compound may be one isolated from Woodfordia uniflora or a culture thereof, but is not limited thereto.

In the present invention, the compound may have an antifungal effect, but is not limited thereto.

The compounds may have non-aromatic double bonds and one or more asymmetric centers. Thus, they may occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures and cis- or trans-isomers. All such isomeric forms are contemplated.

In addition, the present invention may include a derivative compound such as a hydrate of a compound represented by a formula selected from the group consisting of Chemical Formulas 1 to 3 or a glycoside in which a compound such as a sugar is bonded to each side chain.

The compound according to the present invention can be isolated from nature or prepared by chemical synthesis of compounds known in the art.

Preferably, the compounds of the present invention can be isolated and purified from natural plants. That is, it can be obtained from a plant or a part of a plant using a conventional method for extracting and isolating a substance. Stems, roots or leaves are properly dried and macerated to obtain the desired extract, or simply dried and extracted with an appropriate organic solvent, and the desired extract is purified using a purification method known to those skilled in the art to which the present invention pertains. can be purified. Preferably, the compound of the present invention can be isolated and purified from Woodfordia uniflora or a culture thereof.

As used in the present invention, the term "culture" refers to the culture medium culturing Woodfordia uniflora according to the present invention in a suitable liquid medium, the culture medium filtered or centrifuged to remove the strain (filtrate) or centrifuged supernatant), and a cell lysate obtained by sonicating the culture solution or treating the culture solution with a lysozyme, preferably means a supernatant after centrifugation, but is limited thereto no. In addition, the culture solution may include both a concentrated solution of the culture solution and a dried product of the culture solution.

In addition, the present invention comprises the steps of (a) extracting Woodpodia uniflora with water or an organic solvent having 1 to 4 carbon atoms;

(b) fractionating the extract obtained in step (a) with ethyl-acetate or butyl alcohol;

(c) provides a method for preparing the compound comprising the step of separating and purifying the fraction obtained in step (b) by gradient chromatography.

In the step (a), the whole Woodpodia uniflora plant, leaves, stems, and roots may be used as they are or their dried bodies may be used, and those obtained by pulverizing the dried plants with a grinder may be used to increase extraction efficiency. As a drying method, both dry drying, shade drying, hot air drying, freeze drying, and natural drying methods can be used.

The organic solvent having 1 to 4 carbon atoms used for the Woodpodia Uniflora extraction is methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, dichloromethane or petroleum ether. can be In an embodiment of the present invention, Woodpodia uniflora was extracted with ethanol, methanol, or acetone.

In step (b), the extract obtained in step (a) is fractionated, followed by distribution extraction using ethyl-acetate or butyl alcohol. The fraction obtained in step (b) is separated by gradient chromatography. As the chromatography, column chromatography or high performance liquid chromatography (HPLC) filled with various synthetic resins such as silica gel or activated alumina can be used alone or in combination. Preferably, among the fractions obtained in step (b), an ethyl-acetate fraction or a butyl alcohol fraction is applied to a silica gel column, and various fractions can be obtained while gradually increasing the polarity by adjusting the composition of the elution solvent. Concentration gradient silica gel chromatography in which the polarity is gradually increased by adjusting the composition of the elution solvent again to the active fraction among the fractions obtained in the above process can be performed. However, the extraction and separation and purification methods of the compounds are not necessarily limited to the above methods.

In step (c), the ethyl-acetate fraction obtained in step (b) is separated and purified by gradient chromatography.

As the chromatography, column chromatography filled with various synthetic resins such as silica gel or activated alumina and high performance liquid chromatography (HPLC) can be used alone or in combination. Preferably, the compound can be separated and purified using high-performance liquid chromatography.

In addition, the present invention provides an antifungal composition comprising a compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 4]

(In Formula 4,

또는 헤테로시클로알킬이고,The R ₁ to R ₃ are each independently H, OH, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, gallic acid,

or heterocycloalkyl;

또는

이고,wherein R ₄ and R ₇ are each independently H, O, OH, C ₁ to C ₃ alkyl group, C ₁ to C ₃ alkoxy group, O-gallic acid, O-glucose, O-rhamnose, O-Glucogalic acid,

or

ego,

Wherein R ₈ and R ₉ are each independently H, OH, O- gallic acid, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy,

The R ₅ and R ₆ are single or double bonded to each other to form a ring structure.)

[Formula 5]

(In Formula 5, X or Y is each independently H, methyl or ethyl.)

In the present invention, the compound of Formula 4 is

Wherein R ₁ is H or OH,

이고, Wherein R ₂ is H, methoxy, methyl, ethyl, gallic acid or

ego,

Wherein R ₃ is H or OH,

이고,Wherein R ₄ is H, O or

ego,

, OH, O-람노서스, 또는 O-갈산이고, The R ₇ is

, OH, O-rhamnosus, or O-gallic acid,

The R ₅ and R ₆ may be single or double bonded to each other to form a ring structure, but is not limited thereto.

In the present invention, the compound of Formula 4 may be one represented by the following Formula 6, but is not limited thereto.

[Formula 6]

(In Formula 6,

이고,wherein R ₂ is H, gallic acid, or

ego,

이고,wherein R ₄ is H or

ego,

R ₇ is H, OH or gallic acid.)

In the present invention, the compound of Formula 5 is

wherein X is H;

Y may be methyl, but is not limited thereto.

In the present invention, the compound may be named IUPAC name listed in the table below, but is not limited thereto.

In the present invention, the compound of Formula 4 is woodfordiamycin, (+)-catechin 7-O-gallate ((+)-catechin7-O-gallate) and procyanidin B3-3-O-gallate. (procyanidin B3-3- O- gallate) may be at least one selected from the group consisting of, but is not limited thereto.

In the present invention, the compound of Formula 4 or 5 may be separated and purified from Woodpodia uniflora, or may be prepared by a chemical synthesis method known in the art. For example, the compounds of the present invention can be extracted from Woodpodia uniflora. The compound may be extracted from Woodpodia uniflora by a known method commonly used in the art, such as organic solvent extraction and chromatography.

In addition, the present invention provides an antifungal composition comprising a Woodpodia uniflora extract or a fraction thereof as an active ingredient.

In the present invention, the extract may be an extract using water or an organic solvent having 1 to 4 carbon atoms, but is not limited thereto. The organic solvent having 1 to 4 carbon atoms used for the Woodpodia Uniflora extraction is methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, dichloromethane or petroleum ether. can be In an embodiment of the present invention, Woodpodia uniflora was extracted with ethanol, methanol, or acetone.

Woodpodia uniflora of the present invention can be used as it is without damaging its original form, or after performing a pretreatment process in consideration of the process speed and process (manufacturing) efficiency intended by those skilled in the art, the pretreatment process includes examples For example, it may be subjected to conventional screening, washing, cutting, powdering, drying, and the like steps.

The Woodpodia uniflora extract of the present invention can be obtained from the whole plant or a part of a plant, for example, it can be obtained from a site comprising one or more selected from the group consisting of stems, roots, leaves, fruits, and flowers. have.

Woodpodia uniflora of the present invention can be used by conventional extraction methods such as cold chim, warm chim, and heating using the solvent.

In the present invention, the fraction may be obtained by fractionation with ethyl acetate or n-butanol, but is not limited thereto.

In the present invention, the antifungal composition may have antifungal activity against one or more selected from the group consisting of Candida spp. , Cryptococcus spp. , and Trichophyton spp. , but is not limited thereto.

In the present invention, the antifungal composition is for treating a fungal infection caused by one or more fungi selected from the group consisting of Candida spp. , Cryptococcus spp. , and Trichophyton spp. It may be used, but is not limited thereto.

In the present invention, the fungal infection includes, for example, cryptococcosis, candidiasis, ringworm (trichophytosis), aspergillosis, and the like, but is not limited thereto. Cryptococcosis is caused by infection with Cryptococcus neoformans and infects all parts of the body including the skin in patients with weakened immunity such as AIDS patients, especially the brain and meninges. infection, leading to meningitis, brain abscesses and brain tumors. Candidasis is a mycosis caused by Candida albicans and was first isolated from thrush patients and causes vaginitis in women and diaper rash in infants. Ringworm is a skin disease caused by Trichophyton such as Trichophyton rubrum and Trichophyton mentagrophytes. This causes skin lesions.

In the present invention, the composition may be a pharmaceutical composition, a food composition or a cosmetic composition, but is not limited thereto.

The present invention may also include a pharmaceutically acceptable salt of the compound of Formula 4 or 5 as an active ingredient. As used herein, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of an excess of acid, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can also be prepared by heating an equimolar amount of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or by suction filtration of the precipitated salt.

Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. The alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The content of the compound of Formula 4 or 5 in the composition of the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 based on the total weight of the composition. to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount from which the solvent is removed.

The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. The excipient may be, for example, at least one selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a humectant, a film-coating material, and a controlled-release additive.

The pharmaceutical composition according to the present invention can be prepared according to a conventional method according to a conventional method, such as powders, granules, sustained-release granules, enteric granules, liquids, eye drops, elsilic, emulsions, suspensions, alcohols, troches, fragrances, and limonaade. , tablets, sustained release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusates, Warnings, lotions, pasta, sprays, inhalants, patches, sterile injection solutions, or external preparations such as aerosols can be formulated and used, and the external preparations are creams, gels, patches, sprays, ointments, warning agents , lotion, liniment, pasta, or cataplasma.

Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, phosphoric acid as additives for tablets, powders, granules, capsules, pills, and troches according to the present invention Calcium monohydrogen, calcium sulfate, sodium chloride, sodium hydrogen carbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methyl excipients such as cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin , hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch powder, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. Hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, calcium carboxymethylcellulose, calcium citrate, sodium lauryl sulfate, silicic anhydride, 1-hydroxy Propylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodite, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, polyethylene glycol 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, A lubricant such as sodium chloride, sodium acetate, sodium oleate, dl-leucine, light silicic anhydride; may be used.

The liquid additives according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like can be used.

In the syrup according to the present invention, a sucrose solution, other sugars or sweeteners may be used, and if necessary, a fragrance, colorant, preservative, stabilizer, suspending agent, emulsifying agent, thickening agent, etc. may be used.

Purified water may be used in the emulsion according to the present invention, and if necessary, an emulsifier, preservative, stabilizer, fragrance, etc. may be used.

In the suspending agent according to the present invention, a suspending agent such as acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, HPMC 2910 may be used. and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.

Injectables according to the present invention include distilled water for injection, 0.9% sodium chloride injection, ring gel injection, dextrose injection, dextrose + sodium chloride injection, PEG (PEG), lactated ring gel injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; Solubilizing aids such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tweens, nijeongtinamide, hexamine, and dimethylacetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, buffers such as albumin, peptone, gum; isotonic agents such as sodium chloride; sodium bisulfite (NaHSO ₃ ) carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₃ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), stabilizers such as ethylenediaminetetraacetic acid; sulphating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, acetone sodium bisulfite; analgesic agents such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; suspending agents such as SiMC sodium, sodium alginate, Tween 80, and aluminum monostearate.

The suppository according to the present invention includes cacao fat, lanolin, Witepsol, polyethylene glycol, glycerogelatin, methyl cellulose, carboxymethyl cellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lanet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolene (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Butyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium, A, AS, B, C, D, E, I, T, Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository IV type (AB, B, A, BC, BBG, E, BGF, C, D, 299), supostal (N, Es), Wecobi (W, R, S, M, Fs), tester triglyceride base (TG-95, MA, 57) and The same mechanism may be used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate talc are also used.

Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. 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 sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

The pharmaceutical 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 with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention pertains.

The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration can be envisaged, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal (intrathecal) injection, sublingual administration, buccal administration, rectal insertion, vaginal It can be administered according to internal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, and the like.

The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with several related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease.

In the present invention, "individual" means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cattle, etc. It may be a mammal of, but is not limited thereto.

In the present invention, "administration" means providing a predetermined composition of the present invention to an individual by any suitable method.

In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, and “treatment” means that the target disease and metabolic abnormalities are improved or It means all actions that are beneficially changed, and “improvement” means all actions that reduce the parameters related to the desired disease, for example, the degree of symptoms by administration of the composition according to the present invention.

In addition, the composition of the present invention may be provided in the form of a quasi-drug composition.

The quasi-drug composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent if necessary in addition to the above components. The pharmaceutically acceptable carrier, excipient or diluent is not limited as long as it does not affect the effect of the present invention, for example, a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, a lubricant, a sweetener, a fragrance, a preservative and the like.

Representative examples of acceptable carriers, excipients or diluents for the quasi-drug composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, gelatin, glycerin, acacia gum, alginate, calcium phosphate, calcium Carbonate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, propylene glycol, polyethylene glycol, vegetable oil , injectable esters, Witepsol, Macrogol, Tween 61, cacao butter, laurage, and the like.

The quasi-drug composition of the present invention may include, but is not limited to, disinfection cleaner, shower foam, ointment, wet tissue, coating agent, etc. It may be appropriately selected from the techniques of

In addition, the composition of the present invention may be provided in the form of a food composition.

When the compound of Formula 4 or 5 of the present invention is used as a food additive, the compound of Formula 4 or 5 may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). In general, when preparing food or beverage, the compound of Formula 4 or 5 of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material. However, in the case of long-term intake for health and hygiene or health control, 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 above the above range.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and includes all health functional foods in the ordinary sense.

The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. The above-mentioned natural carbohydrates are 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. As the sweetener, natural sweeteners such as taumatine and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, Carbonating agents used in carbonated beverages, etc. may be contained. In addition, the composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.

In addition, the composition of the present invention may be provided in the form of a cosmetic composition.

The compound of Formula 4 or 5 of the present invention can be used as a cosmetic additive to prepare a cosmetic composition for keeping hands or feet clean. For example, soap (solid soap, liquid soap, bounty soap, body soap, hand soap, etc.), cleansing foam, shampoo (hair shampoo, dry shampoo, etc.) may be mentioned. Among them, soap is preferable, and in particular, it can be used in formulations such as liquid soap and body soap.

The formulation of the cosmetic composition according to the present invention includes skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, mist, moisture cream, hand cream, hand lotion, foundation, It may be in the form of essence, nutritional essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion or body cleanser.

The cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, and sphingolipids.

As water-soluble vitamins, any type of vitamin can be used as long as it can be formulated in cosmetics. Examples include vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine hydrochloride, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, and vitamin H. and their salts (thiamine hydrochloride, sodium ascorbate salt, etc.) and derivatives (ascorbic acid-2-phosphate sodium salt, ascorbic acid-2-phosphate magnesium salt, etc.) are also included in the water-soluble vitamins that can be used in the present invention. Included. Water-soluble vitamins can be obtained by conventional methods such as a microbial transformation method, a purification method from a microbial culture, an enzymatic method or a chemical synthesis method.

The oil-soluble vitamins may be any as long as they can be formulated in cosmetics. For example, vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), etc. are mentioned. , their derivatives (ascorbine palmitate, ascorbine stearate, ascorbine dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherol nicotinic acid, vitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenyl ethyl ethers, etc.) are also included in the oil-soluble vitamins used in the present invention. Oil-soluble vitamins can be obtained by conventional methods such as a microbial transformation method, a purification method from a microbial culture, an enzyme or a chemical synthesis method, and the like.

The macromolecular peptide may be any as long as it can be formulated in cosmetics, and examples thereof include collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, and keratin. Polymeric peptides can be purified and obtained by conventional methods such as purification from a microbial culture solution, enzyme method or chemical synthesis method, or can be purified and used from natural products such as dermis of pigs or cattle, silk fibers of silkworms, etc.

The high molecular weight polysaccharide may be any compound as long as it can be formulated in cosmetics, and examples thereof include hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate or a salt thereof (sodium salt, etc.). For example, chondroitin sulfate or a salt thereof can be used after purification from mammals or fish.

The sphingolipid may be any as long as it can be formulated in cosmetics, and examples thereof include ceramide, phytosphingosine, and sphingoglycolipid. The sphingolipid can be purified by a conventional method from mammals, fish, shellfish, yeast or plants, or can be obtained by chemical synthesis.

In the cosmetic composition of the present invention, in addition to the above essential ingredients, other ingredients usually blended in cosmetics may be blended as needed.

Other ingredients that may be added include oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohols, colorants, fragrances, A blood circulation promoter, a cooling agent, a restrictive agent, purified water, etc. are mentioned.

Examples of the fat and oil component include ester fats and oils, hydrocarbon oils and fats, silicone oils and fats, fluorine oils and fats, animal oils and fats, and vegetable oils and fats.

Examples of ester-based oils and fats include glyceryl tri-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, stearic acid. Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine Diisopropyl acid, isoalkyl neopentanoate, tri (caprylic acid, capric acid) glyceryl, trimethylol propane tri-2-ethylhexanoate, trimethylol propane triisostearate, pentaelysitol tetra2-ethylhexanoate , cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isostea laurate Lil, isotridecyl myristate, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isostear isopropyl, 2-ethylhexanoate cetoster Aryl, 2-ethyl stearyl hexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicapric acid, di(caprylic acid, capric acid) propylene glycol, dicaprylic acid propylene glycol, dicaprylate Neopentyl glycol phosphate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate , octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerol oleate, polyglycerol isostearate, Triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, trioctyl citrate, dimalate Isostearyl, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, Cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytsteryl isostearate, phytsteryl oleate, 12-stealoyl Ester types, such as isocetyl hydroxy stearate, 12-stealoyl hydroxy stearyl stearate, and 12-stealoyl hydroxy stearate isostearyl, etc. are mentioned.

Examples of hydrocarbon-based oils and fats include hydrocarbon-based oils and fats such as squalene, liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybudene, microcrystalline wax, petrolatum.

Examples of silicone oils and fats include polymethyl silicone, methylphenyl silicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane/methylcetyloxysiloxane copolymer, dimethylsiloxane/methylstealloxysiloxane copolymer, and alkyl Modified silicone oil, amino modified silicone oil, etc. are mentioned.

Perfluoropolyether etc. are mentioned as fluorine-type fats and oils.

Animal or vegetable oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, saffron oil, soybean oil, corn oil, rapeseed oil, passerine oil, palm kernel oil, palm oil, castor oil, sunflower oil, grape seed oil , cottonseed oil, palm oil, kukui nut oil, wheat germ oil, rice germ oil, shea butter, cranberry colostrum, marcadeumia nut oil, meadow home oil, egg yolk oil, tallow oil, horse oil, mink oil, orange rapie oil, jojoba oil , animal or plant oils and fats, such as candelabra wax, carnauba wax, liquid lanolin, and hydrogenated castor oil.

Examples of the moisturizing agent include a water-soluble low-molecular moisturizer, a fat-soluble molecular moisturizer, a water-soluble polymer, and a fat-soluble polymer.

As water-soluble low molecular weight moisturizers, serine, glutamine, sorbitol, mannitol, pyrrolidone-sodium carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (polymerization degree n = 2 or more), polypropylene Glycol (polymerization degree n=2 or more), polyglycerol B (polymerization degree n=2 or more), lactic acid, lactic acid salt, etc. are mentioned.

Cholesterol, cholesterol ester, etc. are mentioned as a fat-soluble low molecular weight humectant.

Examples of the water-soluble polymer include carboxyvinyl polymer, polyaspartate, tragacanth, xanthan gum, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, water-soluble chitin, chitosan, and dextrin. can

Examples of the fat-soluble polymer include polyvinylpyrrolidone/eicocene copolymer, polyvinylpyrrolidone/hexadecene copolymer, nitrocellulose, dextrin fatty acid ester, and high molecular weight silicone.

Examples of the emollient include long-chain acylglutamic acid cholesteryl ester, hydroxystearic acid cholesteryl, 12-hydroxystearic acid, stearic acid, rosin acid, and lanolin fatty acid cholesteryl ester.

Nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, etc. are mentioned as surfactant.

Nonionic surfactants include self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerol fatty acid ester, sorbitan fatty acid ester, POE (polyoxyethylene) sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE Glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE/POP (polyoxyethylene/polyoxypropylene) copolymer, POE/POP alkyl ether, polyether-modified silicone, lauric acid alkanolamides, alkylamine oxides, hydrogenated soybean phospholipids, and the like.

Examples of the anionic surfactant include fatty acid soap, alpha-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate, alkyl amide sulfate, alkyl phosphate, POE alkyl phosphate, and alkyl amide phosphate. , alkyloylalkyltaurine salts, N-acylamino acid salts, POE alkylether carboxylate salts, alkylsulfosuccinate salts, alkylsulfoacetate sodium, acylated hydrolyzed collagen peptide salts, perfluoroalkylphosphate esters, and the like. .

Examples of the cationic surfactant include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, chloride Benzalkonium, diethylaminoethylamide stearate, dimethylaminopropylamide stearate, quaternary ammonium salt of lanolin derivative, etc. are mentioned.

Examples of the amphoteric surfactant include carboxybetaine type, amidebetaine type, sulfobetaine type, hydroxysulfobetaine type, amidesulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, amidamine type, etc. Amphoteric surfactant etc. are mentioned.

Examples of organic and inorganic pigments include silicic acid, silicic anhydride, magnesium silicate, talc, sericite, mica, kaolin, bengala, clay, bentonite, titanium-coated mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, aluminum oxide. inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, ultramarine blue, chromium oxide, chromium hydroxide, calamine, and complexes thereof; Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenol resin, fluororesin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene/styrene copolymer, and organic pigments such as silk powder, cellulose, CI pigment yellow and CI pigment orange, and composite pigments of these inorganic pigments and organic pigments.

Examples of the organic powder include metal soaps such as calcium stearate; alkyl phosphate metal salts such as sodium cetylate, zinc laurylate, and calcium laurylate; acylamino acid polyvalent metal salts such as calcium N-lauroyl-beta-alanine, zinc N-lauroyl-beta-alanine, and calcium N-lauroyl glycine; amidesulfonic acid polyvalent metal salts such as calcium N-lauroyl-taurine and calcium N-palmitoyl-taurine; N such as N-epsilon-lauroyl-L-lysine, N-epsilon-palmitoylizine, N-alpha-paritoylolnithine, N-alpha-lauroylarginine, N-alpha-hydrogenated beef fatty acid acylarginine, etc. -Acyl basic amino acid; N-acyl polypeptides, such as N-lauroyl glycyl glycine; alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid; Polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, a divinylbenzene-styrene copolymer, ethylene tetrafluoride, etc. are mentioned.

As UV absorbers, para-aminobenzoic acid, ethyl para-aminobenzoate, amyl para-aminobenzoate, octyl para-aminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomentyl salicylate, benzyl cinnamate , para-methoxycinnamic acid-2-ethoxyethyl, para-methoxycinnamic acid octyl, dipara-methoxycinnamic acid mono-2-ethylhexane glyceryl, para-methoxycinnamic acid isopropyl, diisopropyl diisopropyl cinnamic acid ester mixture, uro Cannic acid, ethyl urokanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and salts thereof, dihydroxymethoxybenzophenone, sodium dihydroxymethoxybenzophenonedisulfonate, dihydroxybenzophenone , tetrahydroxybenzophenone, 4-tert-butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxy)-1 and 3,5-triazine and 2-(2-hydroxy-5-methylphenyl)benzotriazole.

Examples of disinfectants include hinokitiol, triclosan, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zinc phyllithione, benzalkonium chloride, photosensitizer. So, No. 301, mononitroguaial sodium, undecyrenic acid, etc. are mentioned.

Examples of the antioxidant include butylhydroxyanisole, propyl gallic acid, and ellisorbic acid.

Examples of the pH adjuster include citric acid, sodium citrate, malic acid, sodium malate, fmalic acid, sodium fumarate, succinic acid, sodium succinate, sodium hydroxide, sodium monohydrogen phosphate, and the like.

Examples of the alcohol include higher alcohols such as cetyl alcohol.

In addition, blending components that may be added are not limited thereto, and any of the above components can be blended within a range that does not impair the object and effect of the present invention, but 0.01-5% by weight or 0.01-3 based on the total weight. % by weight.

When the formulation of the present invention is a lotion, paste, cream or gel, animal fiber, vegetable fiber, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. can be used

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, additional chlorofluorohydrocarbon, propane /may contain propellants such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solvating agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylglycol oil, glycerol fatty esters, fatty acid esters of polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used.

When the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide as carrier components Ether sulfate, alkylamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linolin derivative or ethoxylated glycerol fatty acid ester and the like can be used.

In addition, the compound of Formula 4 or 5 can be used in various ways as antifungal building materials, pesticides, household goods additives, and the like, and can be used by mixing with known antifungal agents used in the field. In one example, pesticide-related antifungal agents are described, for example, in the Pesticide Manual (Pesticide Manual, 12th ed., British Crop Protection Council, 2000).

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

<Experimental Example 1> Oman plants Woodfordia uniflora Isolation of polyphenol compounds from

100 g of each dried leaf of Woodfordia uniflora was added to 500 mL of 100% ethanol, 100% methanol, 90% methanol, and 100% acetone, and extracted at room temperature for 12 to 14 hours. This was filtered through a filter and concentrated to obtain four extracts. The obtained four extracts were confirmed to have no significant difference through LC/MS analysis, and 12.4 g of crude extract was obtained by mixing them with each other. The obtained crude extract was dissolved in 700 mL of tertiary distilled water, and the solvent was fractionated with 700 mL of ethyl acetate and 700 mL of butyl alcohol, and as a result of concentration, 8.3 g of an ethyl acetate fraction and 1.5 g of a butyl alcohol fraction were obtained.

The two fractions showed antifungal effects against Cryptococcus neoformans and Candida albicans , and as a result of LC/MS analysis, there was no difference in components.

Then, Diaion HP-20 column chromatography (0% methanol, 50% methanol, 100% methanol) was performed to obtain fractions W1 (2.0 g), W2 (2.5 g), and W3 (3.5 g). Then, in order to obtain a small fraction of the W3 fraction, Sephadex LH-20, silica gel column chromatography and column chromatography were performed using methanol and tertiary distilled water. The small fractions obtained here were subjected to high-performance liquid chromatography (HPLC) using acetonitrile and tertiary distilled water, and as a result, compounds 1-6 , 8 , 11 , 12 , 14 , 15 and 17 were separated by 13.2 mg, 3.0 mg, 2.5 mg, 1.2 mg, 6.9 mg, 1.3 mg, 1.5 mg, 1.5 mg, 1.6 mg, 4.2 mg, 8.5 mg, and 4.0 mg, respectively. Sephadex LH-20, silica gel column chromatography and column chromatography were also performed for the W2 fraction, which is another fraction, using methanol and tertiary distilled water, thereby obtaining a small fraction of the W2 fraction. The obtained small fraction was subjected to high-performance liquid chromatography (HPLC) using acetonitrile and tertiary distilled water, and compounds 9 , 10 , 13 , 16 , 18 and 19 were treated with 2.4, respectively. mg, 3.3 mg, 1.1 mg, 4.3 mg, 6.1 mg, and 20.7 mg were separated. Among the isolated substances (±)-woodfordiamycin ( 1 ), woodfordic acid ( 2 ) and rhamnetin 3-O-(6′′-galloyl)-β-D-glucopyranoside ( 3 ) was confirmed to be a novel compound isolated and reported for the first time from natural products (see FIG. 1 ).

The NMR analysis results of the novel compounds 1 to 3 are shown in Table 1 below.

position One 2 3 δ _H (J in Hz) δ _C δ _H (J in Hz) δ _C δ _H (J in Hz) δ _C One 2 4.86 d (4.5) 77.6 d 4.07 dd (8.0, 5.5) 80.1 d 158.0 s 3 β 2.16 m
α 1.97 m 29.0 t 3.84 td (8.0. 5.5) 65.4 d 133.7 s 4 β 2.67 ddd (17.0, 5.5, 3.0)
α 2.77 ddd (17.0, 11.0, 6.0) 19.1 t α 2.92 m
β 2.42 dd (16.0, 8.0) 28.9 t 178.1 s 5 151.9 s 157.5 s 161.0 s 6 6.19 d (2.0) 100.1 d 5.92 d (2.0) 96.3 d 6.20 d (2.0) 97.6 d 7 150.1 s 157.2 s 165.8 s 8 6.16 d (2.0) 101.1 d 5.78 d (2.0) 95.3 d 6.38 d (2.0) 91.6 d 9 156.4 s 155.7 s 156.7 s 10 107.2 s 100.0 s 104.8 s One' 133.3 s 3.46 ddd (10.0, 5.5, 4.0) 51.1 d 121.6 s 2' 6.86 d (1.5) 113.0 d b 2.92 m
a 2.63 dd (17.0, 4.0) 32.2 t 7.52 d (2.0) 115.9 d 3' 144.7 s 174.7 s 144.4 s 4' 144.8 s 210.3 s 148.3 s 5' 6.76 d (8.0) 114.8 d 2.27 s 30.5 q 6.74 d (8.0) 114.5 d 6' 6.73 dd (8.0, 1.5) 117.4 d 7.53 dd (8.0, 2.0) 122.1 d One'' 119.4 s 5.24 d (7.5) 102.1 d 2'' 7.16 s 109.2 d 3.51 m 74.3 d 3'' 145.3 s 3.46 t (9.0) 76.7 d 4'' 139.0 s 3.40 t (9.0) 70.5 d 5'' 145.3 s 3.49 m 74.4 d 6'' 7.16 s 109.2 d a 4.39 dd (12.0, 6.5) b 4.24 dd (12.0, 2.0) 63.0 t 7'' 165.7 s One''' 119.7 s 2''' 6.86 s 108.6 d 3''' 144.8 s 4''' 138.2 s 5''' 144.8 s 6''' 6.86 s 108.6 d 7''' 166.7 s 7-OCH ₃ 3.84 s 55.0 t

^α signal multiplicity and coupling constant (Hz) in parentheses; Assignments were based on HSQC, HMBC and ¹ H- ¹ H COZY experiments.

<Experimental Example 2> Woodfordia uniflora Evaluation of antifungal activity of extracts, fractions and polyphenol compounds

Woodfordia uniflora crude extract, ethyl acetate fraction, n-butanol compound isolated against 5 human pathogenic fungi ( Cryptococcus neoformans H99, Cryptococcus neoformans JEC21, Candida albicans SC5314, Trichophyton rubrum KCTC6375, and Trichophyton mentagrophytes 784) Antifungal activity was confirmed. MIC values were determined using a standard broth serial dilution method according to the Clinical and Laboratory Standard Institute (CLSI) guidelines. Fluconazole or Itraconazole was used as a positive control here.

<Example 1> Antifungal activity of polyphenol compounds against human fungal pathogens

It was confirmed whether the compounds obtained from the crude Woodfordia uniflora extract, the ethyl acetate fraction, the n-butanol fraction and the Woodfordia uniflora extract had antifungal activity against the five human pathogenic fungi. Fluconazole or Itraconazole, a representative antifungal agent, was used as a positive control. Specifically, Cryptococcus neoformans H99, Cryptococcus neoformans JEC21 , and Candida albicans was a Fluconazole, the activity was measured for the three fungi SC5314 used as positive control, Trichophyton rubrum KCTC6375, and Trichophyton activity measurement for two fungi mentagrophytes 784 has Itraconazole was used as a positive control.

As a result, as shown in Table 2, the Woodfordia uniflora crude extract, ethyl acetate fraction, and n-butanol fraction had a MIC value of 0.98 μg/mL for C. neoformans H99, which was significantly superior to that of Fluconazle, a positive control. will indicate

In addition, it was confirmed that the MIC value for C. neoformans JEC21 was also 0.98 to 3.91 μg/mL, which was superior to or comparable to that of the positive control Fluconazle.

For C. albicans , the MIC value of 7.81 to 15.63 μg/mL was shown, indicating that the antifungal effect was significant compared to the water residue (negative control).

MIC (μg/mL) C. neoformans H99 C. neoformans JEC21 C. albicans SC5314 crude extract 0.98 1.95 15.63 ethyl acetate fraction 0.98 1.95-3.91 15.63 n-butanol fraction 0.98 0.98 7.81 water residue 1000 250 >1000 Fluconazole 7.81 1.95 0.49

Positive control: Fluconazole

In addition, as shown in Table 3, compounds (+)- 1 and (-)- 1 were observed to have MIC values of 0.78 μg/mL and 1.56 μg/mL for C. neoformans, higher than the positive control, Fluconazole. activity was confirmed.

In addition, compound 8 was also observed to have a MIC value of 0.78 μg/mL for C. neoformans , and higher activity than the positive control, Fluconazole, was confirmed.

In addition, compounds (+)- 1 , (-)- 1 and 19 showed significant MIC values for C. albicans as 6.25 to 25 μg/mL, which is comparable to Fluconazole.

compounds MIC (μg/mL) C. neoformans H99 C. neoformans JEC21 C. albicans SC5314 (+)- 1 0.78 1.56 6.25 (-)- 1 0.78 1.56 6.25 2 50 50 >50 3 6.25 n.t. >200 4 1.56-3.125 n.t. >200 5 25 50 >50 6 12.5-25 n.t. >200 7 25 50 >50 8 0.78-3.125 n.t. 25-50 9 50 50 >50 10 50 50 25 11 25 25 >50 12 12.5-25 50 >50 13 3.125 n.t. >200 14 50 50 >50 15 12.5 50 >50 16 25 25-50 >50 17 25 50 >50 18 3.12-6.25 3.12 >50 19 3.12 6.25 12.5 Fluconazole 7.81 1.95 0.49

* n.t. means not tested.

In addition, as shown in Table 4, for compounds (+)-1 and (-)-1 , MIC values for T. rubrum were observed as 100 μg/mL and 50 μg/mL, respectively, and MIC values for T. mentagrophytes were observed. Values were observed as 50 μg/mL and 25-50 μg/mL, respectively, confirming that both compounds had excellent antifungal activity against Trichophyton genus fungi.

In addition, compounds 18 and 19 were observed to have an MIC value of 100 μg/mL for T. rubrum and T. mentagrophytes, confirming that they had antifungal activity against fungi of the genus Trichophyton.

These results show that the compound according to the present invention has antifungal activity against fungi of the genus Trichophyton.

compounds MIC (μg/mL) T. rubrum KCTC6375 T. mentagrophytes 784 (+)- 1 >100 50 (-)- 1 50 25-50 18 >100 >100 19 >100 >100 Itraconazole 0.25 0.25

From the above results, a slight structural modification of polyphenol compounds not only provides very meaningful information on the structure-activity relationship for the development of novel antifungal agents, but also the compounds of the present invention are classified in the genus Candida, Cryptococcus, and Trichophyton. Since the antifungal effect against mold is significant, it is expected that it can be used as an antifungal composition.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (15)

A compound having at least one chemical formula selected from the group consisting of the following Chemical Formulas 1 to 3, or a salt thereof.
[Formula 1]

[Formula 2]

[Formula 3]

The compound or salt thereof according to claim 1, wherein the compound is isolated from Woodfordia uniflora or a culture thereof.
The compound or salt thereof according to claim 1, wherein the compound has an antifungal effect.
(a) extracting the Woodpodia uniflora with water or an organic solvent having 1 to 4 carbon atoms;
(b) fractionating the extract obtained in step (a) with ethyl-acetate or butyl alcohol; and
(c) a method for preparing the compound of claim 1, comprising the step of separating and purifying the fraction obtained in step (b) by gradient chromatography.
5. The group of claim 4, wherein the organic solvent in step (a) is methanol, ethanol, propanol, isopropanol, butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, dichloromethane and petroleum ether. Manufacturing method, characterized in that selected from.
An antifungal composition comprising a compound of Formula 4 or Formula 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 4]

(In Formula 4,
The R ₁ to R ₃ are each independently H, OH, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, gallic acid,

or heterocycloalkyl;
wherein R ₄ and R ₇ are each independently H, O, OH, C ₁ to C ₃ alkyl group, C ₁ to C ₃ alkoxy group, O-gallic acid, O-glucose, O-rhamnose, O-Glucogalic acid,

or

ego,
wherein R ₈ and R ₉ are each independently H, OH, O- gallic acid, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy;
The R ₅ and R ₆ are single or double bonded to each other to form a ring structure.)

[Formula 5]

(In Formula 5, X or Y is each independently H, methyl or ethyl.)
7. The method of claim 6,
The antifungal composition is characterized in that it has antifungal activity against one or more selected from the group consisting of Candida spp. , Cryptococcus spp. , and Trichophyton spp. .
7. The method of claim 6,
The compound of Formula 4 is
Wherein R ₁ is H or OH,
Wherein R ₂ is H, methoxy, methyl, ethyl, gallic acid or

ego,
Wherein R ₃ is H or OH,
Wherein R ₄ is H, O or

ego,
The R ₇ is

, OH, O-rhamnosus, or O-gallic acid,

The R ₅ and R ₆ are single or double bonds to each other to form a ring structure, antifungal composition.
7. The method of claim 6,
The compound of formula (4) is characterized in that represented by the following formula (6), antifungal composition.
[Formula 6]

(In Formula 6,
wherein R ₂ is H, gallic acid, or

ego,
wherein R ₄ is H or

ego,
R ₇ is H, OH or gallic acid.)
7. The method of claim 6,
The compound of Formula 5 is
wherein X is H;
The Y is methyl, characterized in that the antifungal composition.
7. The method of claim 6,
The compound of Formula 4 is woodfordiamycin, (+)-catechin7-O-gallate ((+)-catechin7-O-gallate) and procyanidin B3-3-O-gallate (procyanidin B3-). 3- O -gallate) characterized in that one selected from the group consisting of, antifungal composition.
An antifungal composition comprising a Woodpodia uniflora extract or a fraction thereof as an active ingredient.
13. The method of claim 12,
The extract is characterized in that the extract by water or an organic solvent having 1 to 4 carbon atoms, antifungal composition.
13. The method of claim 12,
The fraction is characterized in that obtained by fractionation with ethyl acetate or n-butanol, antifungal composition.
13. The method of claim 12,
The antifungal composition is Candida spp. , Cryptococcus spp. , and Trichophyton spp. Antifungal composition, characterized in that it has antifungal activity against at least one selected from the group consisting of, .

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