KR101826747B1 - Novel kojic acid derivatives, preparation method thereof, and compositions containing the same for skin whitening - Google Patents

Abstract

(상기 식 중, 상기 R₁ 및 R₂는 각각 독립적으로 탄소수 1 내지 3의 알콕시, 히드록시 및 수소로 이루어진 군에서 선택되는 하나이고, R₁ 및 R₂가 모두 수소인 경우는 제외한다.)
본 발명에 따른 코지산 유도체 및 그의 약학적으로 허용가능한 염을 유효성분으로 함유하는 피부 미백용 조성물은 피부에 대한 안전성을 가지면서 멜라닌 생성 억제 효과가 우수하여 피부의 색소침착을 억제하므로, 미백을 목적으로 하는 피부 외용제에 유용하게 적용될 수 있다.The present invention provides a kojic acid derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, a process for producing the same, and a composition for skin whitening comprising the same as an active ingredient.
≪ Formula 1 >

Wherein R ₁ and R ₂ are each independently selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen, and R ₁ and R ₂ are not hydrogen.
The skin whitening composition containing the kojic acid derivative and the pharmaceutically acceptable salt thereof according to the present invention as an active ingredient is excellent in skin safety and has an excellent melanin production inhibiting effect and inhibits skin pigmentation, It can be usefully applied to a desired external preparation for skin.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel kojic acid derivative, a process for producing the same, and a skin whitening composition containing the same as an active ingredient. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to a novel kojic acid derivative, a pharmaceutically acceptable salt thereof, a process for producing the same, and a composition for skin whitening comprising the same as an active ingredient.

Skin color of a person is determined by red blood cells, carotene, and melanin in blood, but melanin is the effect of skin color difference between different races and hypercholesterolemia such as spots and freckles. These melanins are present in the outer skin layer of the skin and protect the skin organs below the dermis by blocking the ultraviolet rays. At the same time, it plays a useful role in protecting proteins and genes in the skin by free radical scavenging in the skin. However, the melanin produced by internal and external stress is a stable substance that does not disappear until it is excreted through skin keratinization. It is an enzyme that inhibits tyrosine or tyrosine (DOPA) Is catalyzed by a polymerization oxidation process. In particular, free radicals, inflammation, and ultraviolet rays in the skin are factors that increase melanin production. Particularly, melanin, which is partially increased by ultraviolet rays, may develop into spots and the like, resulting in undesirable cosmetic effects. Skin cancer, and the like, which may lead to life-threatening effects. Tyrosinase is known to be a major enzyme in the production of melanin, and many studies have been conducted to suppress this enzyme. So far, tyrosinase inhibitors have been shown to be effective against phenolic compounds or thio compounds such as hydroquinone, monobenzyl ether of hydroquinone (MBHH), 4-isopropylcatechol and rucinol . However, these drugs have not been used as effective and safe treatments due to side effects such as skin irritation.

Another well-known inhibitor of tyrosinase is Kojic acid. Kojisan has less efficacy to inhibit tyrosinase than the above-mentioned phenol compounds, but has no application to skin because it does not show skin irritation. For this reason, a variety of kojic acid derivatives have been synthesized for the purpose of enhancing the inhibitory activity of tyrosinase of kojic acid. That is, there have been attempts to increase tyrosinase activity of kojic acid by introducing various groups into the hydroxymethyl position of kojic acid.

However, it was still found that phenol compounds such as hydroquinone, monobenzyl ether of hydroquinone (MBHH), 4-isopropylcatechol and rucinol were inferior in the effect of inhibiting melanin formation .

It is an object of the present invention to provide a novel kojic acid derivative and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for producing the above-mentioned material.

It is still another object of the present invention to provide a composition for external application for skin comprising the above-mentioned active ingredient.

It is still another object of the present invention to provide a whitening composition comprising the above-mentioned substance as an active ingredient.

In order to solve the above-mentioned problems, the present invention provides a koji acid derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

≪ Formula 1 >

Wherein R ₁ and R ₂ are each independently selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen, and R ₁ and R ₂ are not hydrogen.

In one embodiment of the present invention, R ₁ and R ₂ are one selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy and hydrogen, and R ₁ and R ₂ are It may be excluded if it is all hydrogen.

In one embodiment of the present invention, R ₁ and R ₂ may be the same as or different from each other selected from the group consisting of methoxy, hydroxy and hydrogen, and may be excluded when R ₁ and R ₂ are both hydrogen.

In one embodiment of the present invention, it may be selected from kojic acid derivatives as described below and pharmaceutically acceptable salts thereof.

4-oxo-4H-pyran-2-yl) methyl 4-hydroxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 4-methoxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dihydroxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-4-methoxy-5-adamantylbenzoic acid, and

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dimethoxy-5-adamantylbenzoic acid.

The present invention also relates to a process for preparing a kojic acid ester compound by reacting an inorganic salt of benzoic acid containing halocosilicic acid represented by the following formula (2) and adamantane represented by the following formula (3) The present invention provides a method for producing a kojic acid derivative and a pharmaceutically acceptable salt thereof.

≪ Formula 1 >

Wherein R ₁ and R ₂ are each independently selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen, and R ₁ and R ₂ are not hydrogen.

(2)

(Wherein X is a halogen element).

(3)

(Wherein M is an inorganic element).

In one embodiment of the present invention, the ratio of the inorganic salt of benzoic acid comprising halocosilicic acid to adamantane group may be from 1: 1 to 1: 1.5.

In one embodiment of the present invention, M is sodium (Na) or potassium (K), and X is chlorine (Cl).

In one embodiment of the present invention, the method comprises the steps of: a) preparing kojic acid chloride by refluxing koji acid with thionyl chloride in an organic solvent;

b) reacting benzoic acid containing one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms with adamantanol under an organic solvent and acidic conditions to prepare benzoic acid containing adamantane group Reacting the adamantane-containing benzoic acid with an inorganic compound to prepare an inorganic salt; And

c) reacting the kojic acid obtained in the step a) and the benzoic acid inorganic salt containing the adamantane group obtained in the step b) in an organic solvent to prepare a kojic acid ester compound.

In one embodiment of the present invention, the organic solvent in step a) is selected from the group consisting of chloroform, dichloromethane, N, N-dimethylformamide, toluene, tetrahydrofuran and benzene Can be every day.

In one embodiment of the present invention, the organic solvent in step b) may be one selected from the group consisting of chloroform, dichloromethane, toluene, and benzene, or a mixture thereof.

In one embodiment of the present invention, the proportion of the benzoic acid to adamantanol containing one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms in the step b) is 1: 1 To 1: 1.5.

In one embodiment of the present invention, the inorganic compound in step b) may be sodium hydroxide or potassium hydroxide.

In one embodiment of the present invention, the organic solvent in step c) may be N, N-dimethylformamide, tetrahydrofuran and a mixed solvent thereof.

The present invention also provides a skin whitening composition comprising the kojic acid derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the content of the koji acid derivative and the pharmaceutically acceptable salt thereof may be 0.01 to 20% by weight based on the total weight of the composition.

In one embodiment of the present invention, the skin whitening composition may be characterized by whitening the skin through inhibition of melanin production.

The skin whitening composition containing the kojic acid derivative and the pharmaceutically acceptable salt thereof according to the present invention as an active ingredient is excellent in skin safety and has an excellent melanin production inhibiting effect and inhibits skin pigmentation, It can be usefully applied to a desired external preparation for skin.

Hereinafter, preferred embodiments of the present invention will be described in detail in order to facilitate the present invention by those skilled in the art.

As used herein, "alkyl" means a monovalent saturated aliphatic hydrocarbon chain. The hydrocarbon chain may be linear or branched. "Alkyl" In one aspect of the invention is 1 to 5 carbon atoms ( "C ₁ -C ₅ alkyl") may have, and 1-4 carbon atoms ( "C ₁ -C ₄ alkyl" in other aspect ), And in another aspect may have 1 to 3 carbon atoms ("C ₁ -C ₃ alkyl"). Specifically, "alkyl" includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or t-amyl.

As used herein, "alkoxy" means an -OR group, wherein R is an alkyl group as defined above. Specifically, "alkoxy" means an alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec- But is not limited thereto.

As used herein, "hydroxy" means a radical -OH.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo or iodo.

As used herein, the term " pharmaceutically acceptable "refers to the approval of a government or equivalent regulatory agency that can be used on animals, and more specifically on humans, by avoiding significant toxic effects when used in conventional medicinal dosage Received, approved, or listed in pharmacopoeia or other general pharmacopoeia.

As used herein, "pharmaceutically acceptable salt" means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt may be (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (4-hydroxybenzoyl) benzoic acid, acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, acid addition salts formed with organic acids such as tert-butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.

The present invention provides a kojic acid derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof.

≪ Formula 1 >

Wherein R ₁ and R ₂ are each independently selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen, and the case where R ₁ and R ₂ are both hydrogen is excluded. Preferably one selected from the group consisting of methoxy, hydroxy and hydrogen. Wherein R ₁ and R ₂ are each independently selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy and hydrogen, wherein R ₁ and R ₂ are both Hydrogen is excluded. Preferably one selected from the group consisting of methoxy, hydroxy and hydrogen, except where R ₁ and R ₂ are both hydrogen.

The kojic acid derivative may be, for example, a compound as described below, or a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate thereof, but is not limited thereto.

4-oxo-4H-pyran-2-yl) methyl 4-hydroxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 4-methoxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dihydroxy-5-adamantylbenzoic acid,

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-4-methoxy-5-adamantylbenzoic acid, and

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dimethoxy-5-adamantylbenzoic acid.

The koji acid derivative, a pharmaceutically acceptable salt thereof, which is a novel compound according to the present invention can be prepared by the following production process.

The present invention relates to a process for preparing a kojic acid ester compound by reacting an inorganic salt of benzoic acid comprising halocosilicic acid represented by the following formula (2) and adamantane represented by the following formula (3) The present invention provides a method for producing a kojic acid derivative and a pharmaceutically acceptable salt thereof.

(2)

(Wherein X is a halogen element).

(3)

(Wherein M is an inorganic element).

Preferably, the M is sodium (Na) or potassium (K), and X may be fluorine, chlorine, bromine, iodine, or chlorine (Cl), but is not limited thereto.

Specifically, the method comprises the steps of: a) preparing a halocoumaric acid by refluxing kojiic acid with halothionyl in an organic solvent;

b) reacting benzoic acid containing one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms with adamantanol under an organic solvent and acidic conditions to prepare benzoic acid containing adamantane group Reacting the adamantane-containing benzoic acid with an inorganic compound to prepare an inorganic salt; And

c) reacting the halocobiotic acid obtained in the step a) and the benzoic acid inorganic salt containing the adamantane group obtained in the step b) in an organic solvent to prepare a kojic acid ester compound.

Hereinafter, a method for preparing the kojic acid derivative and its pharmaceutically acceptable salt according to the present invention will be described in more detail.

First, a) kojic acid is subjected to a reflux reaction with halothionyl in an organic solvent to prepare halocosylic acid (II). This reaction is shown, for example, in Scheme 1 below.

<Reaction Scheme 1>

The organic solvent may be one or more selected from the group consisting of chloroform, dichloromethane, N, N-dimethylformamide, toluene, tetrahydrofuran and benzene. Particularly, it is preferable to use a mixed solvent of dichloromethane and tetrahydrofuran in a ratio of 1: 1 to 1: 5.

Then, b) benzoic acid containing one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms is reacted with adamantanol under an organic solvent and acidic conditions to obtain an adamantanyl group Benzoic acid (III). Thereafter, benzoic acid containing the adamantane group is reacted with an inorganic compound to prepare an inorganic salt (V). The benzoic acid containing the substituent is preferably a compound selected from the group consisting of hydroxybenzoic acid, dihydroxybenzoic acid, methoxybenzoic acid, dimethoxybenzoic acid, and hydroxymethoxybenzoic acid. This reaction is shown, for example, in the following reaction formula (2).

<Reaction Scheme 2>

The ratio of benzoic acid to adamantanol containing one substituent selected from the group consisting of alkoxy of 1 to 3 carbon atoms, hydroxy and hydrogen may be 1: 1 to 1: 1.5, preferably 1: : 1.2. If the ratio is less than the above ratio, the unreacted material remains. If the ratio is larger than the above ratio, extra adamantanol remains and separation from the product is difficult.

The organic solvent may be one selected from the group consisting of chloroform, dichloromethane, toluene, and benzene, or a mixture thereof.

As the acid, sulfuric acid, trifluoroacetic acid, or the like may be used, but it is not limited thereto.

The reaction temperature may be from 20 to 65 占 폚, preferably about 60 占 폚.

A benzoic acid containing one substituent selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen reacts with adamantanol to produce benzoic acid (III) containing an adamantane group. Thereafter, benzoic acid containing the adamantane group thus obtained is reacted with an inorganic compound such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) in methanol or an ethanol solvent to prepare a metal salt, which is an inorganic salt.

Finally, c) a kojic acid ester compound (I) is prepared by reacting the halocobiotic acid (II) obtained in the step a) and the benzoic acid inorganic salt (V) containing the adamantane group obtained in the step b) in an organic solvent . This reaction is shown in the following reaction formula (3).

<Reaction Scheme 3>

R ₁ and R ₂ are each independently selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen, and R ₁ and R ₂ are not hydrogen. Preferably, the alkoxy may be methoxy.

The ratio of the inorganic salt of benzoic acid containing halocosilicic acid to adamantane group may be 1: 1 to 1: 1.5, preferably 1: 1.2. When the inorganic salt of benzoic acid is less than the above ratio, the halocubic acid remains unreacted. If the amount of inorganic salt of benzoic acid is larger than the above ratio, extra benzoic acid inorganic salt remains, which is difficult to separate due to the similar physical properties to the product.

The organic solvent may be tetrahydrofuran, N, N-dimethylformamide or a mixed solvent thereof. In particular, a mixed solvent of tetrahydrofuran and N, N-dimethylformamide may complete the reaction in the shortest time Therefore, it is preferable. At this time, the mixing ratio of N, N-dimethylformamide and tetrahydrofuran is 1: 1 to 1: 6, and the mixing ratio is 1: 5.

The kojic acid derivative according to one embodiment of the present invention, a pharmaceutically acceptable salt thereof, can be used as an external preparation for skin as a novel compound which has not existed.

The external preparation for skin may be used, for example, as a cosmetic composition or a medical composition.

Also, the kojic acid derivative according to one embodiment of the present invention, its pharmaceutically acceptable salt may be used as an active ingredient of a whitening composition.

In the whitening composition, it is preferable that the content of the kojic acid derivative and its pharmaceutically acceptable anti-salt as an active ingredient is 0.01 to 20% by weight based on the total weight of the composition. When the active ingredient is contained in an amount of less than 0.01% by weight based on the total weight, the whitening effect is insignificant. When the active ingredient is contained in an amount of more than 20% by weight, safety or formability may be difficult.

The kojic acid derivative according to one embodiment of the present invention, its pharmaceutically acceptable salt, is characterized by whitening the skin through inhibition of melanin production. As can be seen from the test examples to be described later, the kojic acid derivatives and the like according to the present invention do not show inhibition of tyrosinase activity, as opposed to achieving a skin whitening effect through inhibition of tyrosinase activity by an effective ingredient of a conventional whitening composition. Nevertheless, since it exhibits excellent skin whitening effect, the kojic acid derivatives according to the present invention inhibit melanin production by a new mechanism.

In addition, the whitening composition is characterized by whitening the skin through prevention and inhibition of hyperpigmentation. In the present invention, whitening includes prevention as well as prevention of hypercholesterolemia.

The pharmaceutical composition may further contain a preservative, a stabilizer, a wetting agent or an emulsifying accelerator, a pharmaceutical adjuvant such as a salt and / or a buffer for controlling osmotic pressure, and other therapeutically useful substances, May be formulated into oral administration forms. Parenteral dosage forms, and may be, for example, but not limited to lotions, ointments, gels, creams, patches or spray formulations.

The dosage of the active ingredient is within the level of those skilled in the art, and the daily dose of the drug depends on various factors such as the degree of progress of the subject to be administered, the age of onset, age, health condition, As a standard, it is generally possible to administer the composition at a dose of 1 / / kg to 200 mg / kg, preferably 50 / / kg to 50 mg / kg, once or twice a day, Are not intended to limit the scope of the present invention.

The formulation of the cosmetic composition is not particularly limited and may be appropriately selected according to the purpose. For example, skin lotion, skin softener, skin toner, astringent, lotion, milky lotion, moisturizing lotion, nutrition lotion, massage cream, nutritional cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, pack, soap, cleansing But the present invention is not limited thereto, and may be manufactured by any one or more formulations selected from the group consisting of a foam, a cleansing lotion, a cleansing cream, a body lotion and a body cleanser.

When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

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

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

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

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

The content of the active ingredient is not particularly limited, but may be 0.01 to 20% by weight based on the total weight of the composition. When the active ingredient satisfies the above content, it can exhibit excellent efficacy without side effects.

The cosmetic composition may further contain a functional ingredient in addition to the kojic acid derivative, a pharmaceutically acceptable salt thereof, and components contained in a general cosmetic composition. The functional additives may include water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymeric polysaccharides, sphingolipids and seaweed extracts.

The cosmetic composition of the present invention may further contain, in addition to the above-described functional additive, components contained in a general cosmetic composition as required. Examples of the other ingredients that can be included in the composition include humectants, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbents, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, Accelerators, coolants, antiperspirants, purified water, and the like.

Further, the present invention relates to an external preparation for skin comprising the kojic acid derivative and a pharmaceutically acceptable salt thereof, wherein the external preparation for skin is a generic term including any of those applied outside the skin, May be included herein.

The present invention employs a composition containing a kojic acid derivative, a pharmaceutically acceptable salt thereof, and an excellent skin whitening effect. The composition for skin whitening according to the present invention has a function of inhibiting melanin formation, as can be seen in a test example to be described later, and can improve skin whitening.

The present invention will be described in more detail through the following examples. However, the examples are for illustrating the present invention, and the scope of the present invention is not limited thereto.

[ Example 1 ]

4-oxo-4H-pyran-2-yl) methyl 4-hydroxy-5-adamantylbenzoic acid (5-hydroxy- -hydroxy-5-adamantylbenzoate &lt; / RTI &gt;

In a 500 ml round flask, 50 g of kojic acid was dissolved in 200 ml of dichloromethane. 50.2 g of thionyl chloride dissolved in 200 ml of tetrahydrofuran was added thereto at 25 占 폚, and the mixture was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed twice with diluted hydrochloric acid solution and three times with water, and the organic layer was separated and dried. The mixture was concentrated under reduced pressure, and petroleum ether was added thereto to allow it to stand overnight. The resulting solid was filtered and dried to obtain 46.7 g (yield: 83%) of pale brown kochic acid chloride.

50 g of 4-hydroxybenzoic acid and 55 g of adamantanol were dissolved in 1000 ml of dichloromethane in a 500 ml round-bottomed flask. 50 ml of sulfuric acid was added thereto, and the mixture was stirred at the same temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed twice with diluted hydrochloric acid solution and three times with water, and the organic layer was separated and dried. The mixture was concentrated under reduced pressure, and petroleum ether was added thereto to allow it to stand overnight. The resulting solid was filtered and dried to obtain 78.9 g (yield: 80%) of 4-hydroxy-5-adamantylbenzoic acid as white.

In a 500 ml round-bottomed flask, 3 g of potassium hydroxide was dissolved in 10 ml of methanol. To this solution was added 5 g of 4-hydroxy-5-adamantylbenzoic acid dissolved in 10 ml of methanol. After stirring for 30 minutes, methanol was distilled off under reduced pressure to obtain 4-hydroxy-5-adamantylbenzoic acid potassium salt.

 The potassium salt of 4-hydroxy-5-adamantylbenzoic acid obtained in the previous step and 2.94 g of potassium koji acid were dissolved in 20 ml of N, N-dimethylformamide and reacted at a reaction temperature of 110 to 120 ° C for 2 hours. After the reaction was completed, N, N-dimethylformamide was removed by distillation under reduced pressure, and the reaction product was redissolved in 250 ml of dichloromethane, washed with distilled water (100 ml), dried over anhydrous manganese (100 g), filtered, concentrated, To obtain 5.45 g (yield: 75%) of (5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 4-hydroxy-5-adamantylbenzoate.

¹ H NMR (DMSO-d ₆ ):? 10.32 (s, IH), 9.20 (s, IH), 8.04 (s, IH), 7.70 ), 6.81 (d, 1H, J = 8.4 Hz), 6.42 (s, 1H), 5.09 (s, 2H), 2.00 (s, 9H), 1.67 (s,

[ Example 2 ]

4-oxo-4H-pyran-2-yl) methyl 4-methoxy-5-adamantylbenzoic acid (5-hydroxy- -methoxy-5-adamantylbenzoate &lt; / RTI &gt;

The title compound (5.01 g, 70%) was obtained as an off-white solid in the same manner as in Example 1, except that 4-methoxybenzoic acid was used in place of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ):? 9.21 (s, IH), 8.09 (s, IH), 7.84 J = 8.4 Hz), 6.48 (s, 1H), 5.17 (s, 2H), 3.88 (s, 3H), 2.03 (s, 3H), 1.73 (s, 6H).

[ Example 3 ]

(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dihydroxy-5-adamantylbenzoic acid ) methyl 2,4-dihydroxy-5-adamantylbenzoate

(5.36 g, 75%) was obtained as an off-white solid in the same manner as in Example 1, except that 2,4-dihydroxybenzoic acid was used instead of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ): δ 10.50 (s, 1H), 10.19 (s, 1H), 9.18 1H), 6.37 (s, 1H), 5.21 (s, 2H), 3.65 (s, 3H), 2.00 (s, 9H), 1.70 (s, 6H).

[ Example 4 ]

4-oxo-4H-pyran-2-yl) methyl 2-hydroxy-4-methoxy-5-adamantylbenzoic acid ((5-hydroxy- -yl) methyl 2-hydroxy-4-methoxy-5-adamantylbenzoate

The title compound (4.93 g, 70%) was obtained as an off-white solid in the same manner as in Example 1, except that 2-hydroxy-4-methoxybenzoic acid was used instead of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ):? 10.35 (s, 1H), 9.16 (s, IH), 8.18 (s, IH), 7.56 2H), 3.84 (s, 3H), 3.65 (s, 3H), 2.01 (s, 9H), 1.70 (s, 6H).

[ Example 5 ]

4-oxo-4H-pyran-2-yl) methyl 2,4-dimethoxy-5-adamantylbenzoic acid (5-hydroxy- methyl 2,4-dimethoxy-5-adamantylbenzoate)

(5.01 g, 72%) was obtained as an off-white solid in the same manner as in Example 1, except that 2,4-dimethoxybenzoic acid was used instead of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ): 隆 9.18 (s, IH), 8.16 (s, IH), 7.60 (s, IH), 6.68 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.65 (s, 3H), 1.99 (s, 9H), 1.71 (s, 6H).

[ Test Example 1] Measuring effect of inhibiting melanin formation by using mouse pigment cells

In order to examine the inhibitory effect of the kojic acid derivative compounds obtained in Examples 1 to 5 on melanogenesis, the following experiment was conducted.

At this time, the degree of intracellular melanin production was measured by Dooley's method, and the inhibitory effect of melanin formation was measured in comparison with each compound of Examples 1 to 5 using kojic acid and hydroquinone as positive control groups. The cell line used was a Mel-Ab cell line (supplied by Dr Thomas P. Dooley) derived from skin pigment cells of C57BL / 6. The culture is 10% bovine serum placenta, 100nM 12-O- tetra-decanoyl phorbol (Tetradecanoyl Phobol) -13- acetate (Acetate), 1nM cholera toxin (Cholera Toxin) containing a DMEM medium, 37 ℃, 5% CO ₂ Lt; / RTI &gt; The cultured Mel-Ab cells were removed with 0.25% Trypsin-EDTA, and the same number (1 × 10 ⁵ cells / well) was added to a 24-well plate. (Each compound of Examples 1 to 5, positive control kojic acid, hydroquinone) in the same manner as described above. After 5 days, 1N NaOH was added to dissolve the melanin contained in the cells, and the amount of melanin produced was measured by measuring absorbance at 400 nm. The results are shown in Table 1 below.

 Melanin production inhibitory effect Test substance Melanin production inhibition rate (10 μM) Kojic acid 10.1% Hydroquinone 70.2% The compound of Example 1 45.2% The compound of Example 2 89.1% The compound of Example 3 25.3% The compound of Example 4 65.8% The compound of Example 5 90.2%

As a result, as shown in Table 1, it was found that each of the compounds of Examples 1 to 5 had an effect of inhibiting higher melanin production than kojic acid. In particular, in the case of the compounds of Examples 2 and 5, hydroquinone And showed excellent effect.

[ Test Example 2] Measurement of inhibitory effect of tyrosinase activity

In order to examine the tyrosinase inhibitory effect of the kojic acid derivative compounds obtained in Examples 1 to 5, the following experiment was conducted. Mushroom-derived tyrosinase and tyrosine were purchased from Sigma Chemical. The tyrosinase activity was measured with 150 microliters of 0.1 M phosphate buffer (pH 6.5), 8 microliters of mushroom tyrosinase (2,100 unit / ml, 0.05 M phosphate buffer, pH 6.5), 36 microliters of 1.5 mM L- Lt; RTI ID = 0.0 &gt; 10 M &lt; / RTI &gt; The tyrosinase activity was measured at 490 nm using a microplate reader (Bio-Rad 3550, Richnmond, CA, USA) after the enzymatic reaction at 37 ° C for 20 minutes. The tyrosinase inhibitory effect of the reaction products of Examples 1 to 5 was determined on the basis of the following formula.

Tyrosinase activity inhibition rate (%) = 100 - ((reaction absorbance of each sample / reaction absorbance of control group) x 100)

The obtained results are shown in Table 2.

Tyrosinase inhibitory activity Test substance Tyrosinase activity inhibition rate (10 μM) Kojic acid 32.4% Hydroquinone 50.0% The compound of Example 1 8.1% The compound of Example 2 0 % The compound of Example 3 0 % The compound of Example 4 10.0% The compound of Example 5 0 %

As a result, as shown in Table 2, the compounds of Examples 1 to 5 did not exhibit the effect of inhibiting tyrosinase differently from kojic acid. As a result, it was found that each of the compounds of Examples 1 to 5 acted as a different mechanism from the inhibition of tyrosinase activity and thus showed inhibition of melanogenesis.

Formulation examples of the composition containing the koji acid derivative of the present invention are described below, but the composition of the present invention is not limited to this example.

[ Formulation Example  1] lotion type formulation

The kojic acid derivative of Example 1 3.00

L-ascorbic acid-2-phosphate magnesium salt 1.00

Water soluble collagen (1% aqueous solution) 1.00

Sodium citrate 0.10

Citric acid 0.05

Licorice extract 0.20

1,3-butylene glycol 3.00

Purified water balance

(Unit: wt%)

[ Formulation Example  2] Cream type  Formulation

The koji acid derivative of Example 2 1.00

Polyethylene glycol monostearate 2.00

Self emulsifying monostearate glycerin 5.00

Cetyl alcohol 4.00

Squalane 6.00

Tri-2-ethylhexane glyceryl 6.00

Sphingo glycolipid 1.00

1,3-butylene glycol 7.00

Purified water balance

(Unit: wt%)

[ Formulation Example  3] Pack type  Formulation

The koji acid derivative of Example 3 5.00

Polyvinyl alcohol 13.00

L-ascorbic acid-2-phosphate magnesium salt 1.00

Lauroylhydroxyproline 1.00

Water soluble collagen (1% aqueous solution) 2.00

1,3-butylene glycol 3.00

Ethanol 5.00

Purified water balance

(Unit: wt%)

[ Formulation Example  4] Beauty liquid  Formulation

The kojic acid derivative of Example 4 2.00

Hydroxyethylene Cellulose (2% aqueous solution) 12.00

Xanthan gum (2% aqueous solution) 2.00

1,3-butylene glycol 6.00

Dark glycerin 4.00

Sodium hyaluronate (1% aqueous solution) 5.00

Purified water balance

(Unit: wt%)

Claims (17)

A kojic acid derivative represented by the following formula (1):
&Lt; Formula 1 >

(Wherein R &lt; ₁ &gt; is methoxy and R &lt; ₂ &gt; is hydrogen or methoxy) delete The method according to claim 1,
A kojic acid derivative and a pharmaceutically acceptable salt thereof, wherein the kojic acid derivative is selected from the group consisting of the following compounds.
(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 4-methoxy-5-adamantylbenzoic acid, and
(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2,4-dimethoxy-5-adamantylbenzoic acid. Reacting a benzoic acid inorganic salt comprising halocobi acid represented by the following formula (2) and adamantane group represented by the following formula (3) to prepare a kojic acid ester compound; and a kojic acid derivative represented by the following formula Lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt thereof.
&Lt; Formula 1 &gt;

(Wherein R &lt; ₁ &gt; is methoxy and R &lt; ₂ &gt; is hydrogen or methoxy)
(2)

(Wherein X is a halogen element).
(3)

(Wherein M is an inorganic element). delete 5. The method of claim 4,
Wherein the ratio of the inorganic salt of benzoic acid comprising halocosilicic acid to the adamantane group is from 1: 1 to 1: 1.5, and a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein the M is sodium (Na) or potassium (K), and a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein X is chlorine (Cl), and a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
The above-
a) reacting kojic acid with halothionyl to produce halocausis acid;
b) benzoic acid containing one substituent selected from the group consisting of alkoxy having 1 to 3 carbon atoms, hydroxy and hydrogen is reacted with adamantanol to prepare benzoic acid containing adamantane group, Reacting benzoic acid with an inorganic compound with an inorganic compound to prepare an inorganic salt; And
c) reacting the kojic acid chloride obtained in the step a) and the benzoic acid inorganic salt containing the adamantane group obtained in the step b) to prepare a kojic acid ester compound and a pharmacologically acceptable salt thereof Acceptable salt. 10. The method of claim 9,
Wherein the benzoic acid containing a substituent in the step b) is one compound selected from the group consisting of hydroxybenzoic acid, dihydroxybenzoic acid, methoxybenzoic acid, dimethoxybenzoic acid, and hydroxymethoxybenzoic acid, and its pharmacology Lt; / RTI &gt; acceptable salt. 10. The method of claim 9,
Wherein the ratio of benzoic acid to adamantanol containing a substituent in step b) is from 1: 1 to 1: 1.5, and a pharmaceutically acceptable salt thereof. 10. The method of claim 9,
Wherein the inorganic compound in step b) is sodium hydroxide or potassium hydroxide, and a pharmaceutically acceptable salt thereof. 10. The method of claim 9,
Wherein the organic solvent in step c) is tetrahydrofuran, N, N-dimethylformamide or a mixed solvent thereof, and a pharmaceutically acceptable salt thereof. A cosmetic composition for whitening comprising the kojic acid derivative of any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof as an active ingredient. 15. The method of claim 14,
Wherein the content of the koji acid derivative and the pharmaceutically acceptable salt thereof is 0.01 to 20% by weight based on the total weight of the composition. 15. The method of claim 14,
Wherein the whitening composition whitens the skin through inhibition of melanin formation. 15. The method of claim 14,
Wherein the whitening composition whitens the skin through prevention and inhibition of hypercholesterolemia.