KR20130004616A - Novel kojic acid derivatives, preparation method thereof, and compositions containing the same for skin whitening - Google Patents

Abstract

PURPOSE: A kojic acid derivative and a cosmetic composition containing the same for skin whitening are provided to suppress melanogenesis and pigmentation with skin safety and to be applied to an external use skin formulation. CONSTITUTION: A kojic acid derivative is denoted by chemical formula 1. A method for preparing the derivative of chemical formula 1 and a pharmaceutically acceptable salt thereof comprises a step of reacting halo kojic acid of chemical formula 2 and inorganic salts of benzoic acid containing an adamantane group of chemical formula 3 to prepare a kojic ester compound. A method for preparing a derivative and pharmaceutically acceptable salt comprises: a step of reacting the kojic acid with halo-thionyl and preparing halo kojic acid; a step of reacting adamantane with benzoic acid containing a substituent of hydrogen, hydroxyl, or alkoxy of 1-3 carbon atoms and preparing benzoic acid containing the adamantane group; a step of reacting an inorganic compound with the benzoic acid and preparing inorganic salts; and a step of reacting prepared kojic acid chloride and inorganic salt of benzoic acid and preparing a kojic acid ester compound. A composition for whitening contains 0.01-20 wt% of the derivative and pharmaceutically acceptable salts thereof as active ingredients.

Description

Novel kojic acid derivatives, preparation method thereof and skin whitening composition containing the same as an active ingredient {NOVEL KOJIC ACID DERIVATIVES, PREPARATION METHOD THEREOF, AND COMPOSITIONS CONTAINING THE SAME FOR SKIN WHITENING}

The present invention relates to a novel kojic acid derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof and a composition for skin whitening containing 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 exist in the epidermal layer, which is the outer skin of the skin, and protect the proteins and genes in the skin by free radical scavenging, which protects the skin organs under the dermis by blocking ultraviolet rays. However, melanin produced by internal and external stress is a stable substance that does not disappear until it is released to the outside through keratinization of skin, and enzymes such as tyrosinase (Tyrosinase) based on tyrosine or dopa (DOPA) in vivo It is produced through a polymerization oxidation process using a catalyst. In particular, free radicals, inflammatory reactions, and ultraviolet light in the skin are factors that increase melanin production. In particular, melanin, which is partially increased by ultraviolet light, may develop into blemishes, resulting in undesired or worse results. It may cause skin cancer, which may be dangerous to life. Tyrosinase is known as a major enzyme in the production of such melanin and many studies have been conducted to inhibit the enzyme. To date, tyrosinase inhibitors include phenolic compounds and thio compounds such as hydroquinone, monoquineyl monobenzyl ether (MBHH), 4-isopropylcatechol, and rucinol. It is reported. However, these agents are not used as effective and safe treatments due to side effects such as skin irritation.

Another well-known tyrosinase inhibitor is kojiic acid. Kojic acid is less effective in inhibiting tyrosinase than the phenolic compounds mentioned above, but its application to cosmetics is active because skin irritation does not appear. For this reason, various 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 the tyrosinase activity of kojic acid by introducing various groups at the hydroxymethyl position of kojic acid.

However, it was still true that melanin production was less effective than phenolic compounds such as hydroquinone, monobenzyl ether of hydroquinone (MBHH), 4-isopropylcatechol, and rucinol. .

It is an object of the present invention to provide novel kojic acid derivatives and their pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for preparing the material.

Still another object of the present invention is to provide an external preparation composition for skin containing the active ingredient.

Still another object of the present invention is to provide a composition for whitening comprising the substance as an active ingredient.

The present invention to solve the above object provides a kojic acid derivative represented by the following formula (1) and pharmaceutically acceptable salts thereof.

≪ Formula 1 >

(In the above formula, R ₁ and R ₂ are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen.)

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

In one embodiment of the present invention, R ₁ and R ₂ is one selected from the group consisting of methoxy, hydroxy and hydrogen, it may be excluded when both R ₁ and R ₂ are hydrogen.

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

(5-hydroxy-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.

In addition, the present invention is represented by the formula (1) comprising the step of preparing a kojic acid ester compound by reacting a benzoic acid inorganic salt containing the halokoji acid represented by the formula (2) and the adamantane group represented by the formula (3) Provided are methods for preparing kojic acid derivatives and pharmaceutically acceptable salts thereof.

≪ Formula 1 >

(In the above formula, R1 and R2 are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen.)

<Formula 2>

(Wherein, X is a halogen element.)

<Formula 3>

(In the formula, M is an inorganic element.)

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

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

In one embodiment of the present invention, the production method comprises the steps of a) preparing a kojic acid chloride by refluxing the kojic acid under thionyl chloride and 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 organic solvent and acid conditions to prepare benzoic acid containing adamantane group Then, preparing an inorganic salt by reacting the benzoic acid containing the adamantane group with an inorganic compound; And

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

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

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

In one embodiment of the present invention, the ratio of benzoic acid to adamantanol including one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms in 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 of step c) may be N, N-dimethylformamide, tetrahydrofuran and a mixed solvent thereof.

The present invention also provides a composition for skin whitening containing the kojic acid derivative and its pharmaceutically acceptable salts as an active ingredient.

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

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

The composition for skin whitening containing kojic acid derivatives and pharmaceutically acceptable salts thereof according to the present invention as an active ingredient is excellent in inhibiting melanin production while having safety on the skin and thus inhibiting pigmentation of the skin, thereby whitening the skin. It can be usefully applied to a desired external skin preparation.

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.

"Alkyl" as used herein means a monovalent saturated aliphatic hydrocarbon chain. The hydrocarbon chain may be straight or branched chain. In one aspect of the invention an "alkyl" may have 1-5 carbon atoms ("C ₁ -C ₅ alkyl") and in another aspect 1-4 carbon atoms ("C ₁ -C ₄ alkyl" ), And in another aspect may have 1-3 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" refers to an -OR group, where R refers to an alkyl group as defined above. Specifically "alkoxy" means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy or 1,2-dimethylbutoxy and the like. Including but not limited to.

As used herein, "hydroxy" refers to the radical -OH.

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

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. Received, approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, "pharmaceutically acceptable salts" means salts according to one aspect of the invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, acid addition salts formed with organic acids such as tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

The present invention provides a kojic acid derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

&Lt; Formula 1 >

In the above formula, R1 and R2 are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen. Preferably it may be one selected from the group consisting of methoxy, hydroxy and hydrogen. Wherein R ₁ and R ₂ may each independently be selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy and hydrogen, wherein R ₁ and R ₂ are both Except for hydrogen. Preferably it may be one selected from the group consisting of methoxy, hydroxy and hydrogen, except where both R ₁ and R ₂ are hydrogen.

The kojic acid derivative may be, for example, a compound as described below, and may be selected from pharmaceutically acceptable salts, solvates thereof, and solvates thereof, but is not limited thereto.

(5-hydroxy-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 kojic acid derivative, a pharmaceutically acceptable salt thereof, which is a novel compound according to the present invention, may be prepared by the following preparation method.

The present invention is prepared by reacting the halocozi acid represented by the following formula (2) and the benzoic acid inorganic salt containing the adamantane group represented by the following formula (3) to produce a kojic acid ester compound; Provided are methods for preparing kojic acid derivatives and pharmaceutically acceptable salts thereof.

<Formula 2>

(Wherein, X is a halogen element.)

<Formula 3>

(In the formula, M is an inorganic element.)

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

Specifically, the preparation method comprises the steps of a) preparing a halocozi acid by refluxing the kojic acid under a halothionyl and 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 organic solvent and acid conditions to prepare benzoic acid containing adamantane group Then, preparing an inorganic salt by reacting the benzoic acid containing the adamantane group with an inorganic compound; And

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

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

First, a) koji acid is refluxed with halothionyl in an organic solvent to produce halocozi 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. In particular, it is preferable to use a 1: 1 to 1: 5 mixed solvent of dichloromethane and tetrahydrofuran.

And b) reacting the 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 acid conditions to include an adamantane group. Prepare benzoic acid (III). Thereafter, the benzoic acid containing the adamantane group is reacted with an inorganic compound to prepare an inorganic salt (V). The benzoic acid including the substituent is preferably one 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 Scheme 2 below.

<Reaction Scheme 2>

The ratio of benzoic acid to adamantanol including one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms may be 1: 1 to 1: 1.5, preferably 1 Can be 1.2. Less than this ratio leaves unreacted reactant, while more than this ratio leaves extra adamantanol, which is difficult to separate from the product.

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

The acid may be sulfuric acid, trifluoroacetic acid, or the like, but is not limited thereto.

The reaction temperature may be 20 to 65 ° C., preferably about 60 ° C.

Benzoic acid (ADA) containing adamantane groups is formed by reacting benzoic acid with adamantanol containing one substituent selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms. Thereafter, the 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 ethanol to prepare a metal salt as an inorganic salt.

Finally, the co-acid ester compound (I) is prepared by reacting halocolic acid (II) obtained in step a) and benzoic acid inorganic salt (V) containing adamantane group obtained in step b) under an organic solvent. . This reaction is shown in Scheme 3 below.

<Reaction Scheme 3>

R ₁ and R ₂ are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen. Preferably the alkoxy may be methoxy.

The ratio of the benzoic acid inorganic salt containing the halocoric acid to the adamantane group may be 1: 1 to 1: 1.5, and preferably 1: 1.2. If the benzoic acid salt is less than the ratio, the halocogiic acid remains unreacted, and if it is more than the ratio, the extra bezo acid inorganic salt is left.

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

Kojic acid derivatives according to one embodiment of the present invention, pharmaceutically acceptable salts thereof are novel compounds that do not exist previously, can be used as a skin external preparation.

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

In addition, kojic acid derivatives and pharmaceutically acceptable salts thereof according to an embodiment of the present invention may be used as an active ingredient of the whitening composition.

The kojic acid derivative, the pharmaceutically acceptable anti-salt thereof, in the whitening composition is an active ingredient, and its content is preferably 0.01 to 20% by weight based on the total weight of the composition. When the active ingredient is included in less than 0.01% by weight relative to the total weight, the whitening effect is insignificant, and if it is more than 20% by weight may result in safety or formulation difficulties.

Kojic acid derivatives according to one embodiment of the present invention, pharmaceutically acceptable salts thereof are characterized in that the skin whitening through the inhibition of melanin production. As can be seen in the test examples to be described later, the kojic acid derivatives according to the present invention, unlike the active ingredient of the conventional whitening composition achieved the skin whitening effect through the inhibition of tyrosinase activity, does not show the inhibition of tyrosinase activity. Nevertheless, since it exhibits an excellent skin whitening effect, the kojic acid derivative according to the present invention inhibits melanin production by a new mechanism.

In addition, the whitening composition is characterized in that the skin whitening through the prevention and inhibition of hyperpigmentation. Whitening in the present invention includes not only inhibition of hyperpigmentation but also prophylaxis.

The pharmaceutical composition may further contain pharmaceutical aids such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances, and various parenterals according to conventional methods. It may be formulated in a sphere dosage form. Parenteral dosage forms, and may be, for example, but not limited to lotions, ointments, gels, creams, patches or spray formulations.

Determination of the dosage of the active ingredient is within the level of those skilled in the art, and the daily dosage of the drug depends on various factors such as less progression, onset, age, health condition, complications, etc. of the subject to be administered. Generally, the composition may be administered by dividing 1 μg / kg to 200 mg / kg, preferably 50 μg / kg to 50 mg / kg, once or three times a day, and the dosage may be determined by any method. Nor does it limit the scope of the invention.

The cosmetic composition is not particularly limited in formulation, and may be appropriately selected as desired. 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, and especially in the case of spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane 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 included in an amount of 0.01 to 20 wt% based on the total weight of the composition. When the active ingredient satisfies the content, it may exhibit excellent efficacy without side effects.

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

In addition to the said functional additive, you may mix | blend the component contained in a general cosmetic composition with the cosmetic composition of this invention as needed. In addition to the other components included, oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, blood circulation And accelerators, cooling agents, limiting agents, purified water, and the like.

Furthermore, the present invention relates to an external preparation for skin comprising the kojic acid derivative, a pharmaceutically acceptable salt thereof, and the external preparation for skin is a generic term that may include any applied to the outside of the skin, and cosmetics and medicines of various formulations. This can be included here.

The present invention has found excellent skin lightening effects using compositions containing kojic acid derivatives, pharmaceutically acceptable salts thereof. Skin whitening composition according to the present invention, as can be seen in the test example described later, can have a melanin production inhibitory function to promote skin whitening.

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

[ Example 1 ]

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

50 g of kojic acid was dissolved in 200 ml of dichloromethane in a 500 ml round flask. 50.2 g of thionyl chloride dissolved in 200 ml of tetrahydrofuran was added thereto at 25 ° C, and further 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, and then the organic layer was washed twice with dilute hydrochloric acid solution and three times with water, and the organic layer was separated and dried. Concentrated under reduced pressure and left overnight with petroleum ether. The resulting solid was filtered and dried to give 46.7 g (yield: 83%) of pale brown chloride acid.

In a 500 ml round flask, 50 g of 4-hydroxybenzoic acid and 55 g of adamantanol were dissolved in 1000 ml of dichloromethane. 50 ml of sulfuric acid was added thereto, and 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, and then the organic layer was washed twice with dilute hydrochloric acid solution and three times with water, and the organic layer was separated and dried. Concentrated under reduced pressure and left overnight with petroleum ether. The resulting solid was filtered and dried to give 78.9 g (yield: 80%) of white 4-hydroxy-5-adamantyl benzoic acid.

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

 The 4-hydroxy-5-adamantyl benzoic acid potassium salt and 2.94 g of kojic chloride obtained in the previous step were dissolved in 20 ml of N, N-dimethylformamide, and the reaction temperature was reacted at 110 ° C-120 ° C for 2 hours. After completion of the reaction, the product was distilled under reduced pressure to remove N, N-dimethylformamide. The reaction product was dissolved in 250 ml of dichloromethane, washed with distilled water (100 ml), dried over anhydrous manganese (100 g), filtered and concentrated to ethanol. After crystallization with filtration, 5.45 g (yield = 75%) of (5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 4-hydroxy-5-adamantylbenzoate was obtained.

¹ H NMR (DMSO-d ₆ ): δ 10.32 (s, 1H), 9.20 (s, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz ), 6.81 (d, 1H, J = 8.4 Hz), 6.42 (s, 1H), 5.09 (s, 2H), 2.00 (s, 9H), 1.67 (s, 6H).

[ Example 2 ]

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

A target product (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 instead of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ): δ 9.21 (s, 1H), 8.09 (s, 1H), 7.84 (d, 1H J = 8.4 Hz), 7.80 (s, 1H), 7.10 (d, 1H, 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 ((5-hydroxy-4-oxo-4H-pyran-2-yl ) methyl 2,4-dihydroxy-5-adamantylbenzoate)

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

¹ H NMR (DMSO-d ₆ ): δ 10.50 (s, 1H), 10.19 (s, 1H), 9.18 (s, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 6.48 (s , 1H), 6.37 (s, 1H), 5.21 (s, 2H), 3.65 (s, 3H), 2.00 (s, 9H), 1.70 (s, 6H).

[ Example 4 ]

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

A target product (4.93 g, 70%) was obtained as an off-white solid in the same manner as in Example 1 except for using 2-hydroxy-4-methoxybenzoic acid instead of 4-hydroxybenzoic acid.

¹ H NMR (DMSO-d ₆ ): δ 10.35 (s, 1H), 9.16 (s, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 6.56 (s, 1H), 6.49 (s , 1H), 5.23 (s, 2H), 3.84 (s, 3H), 3.65 (s, 3H), 2.01 (s, 9H), 1.70 (s, 6H).

[ Example 5 ]

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

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

¹ H NMR (DMSO-d ₆ ): δ 9.18 (s, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 5.12 (s , 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.65 (s, 3H), 1.99 (s, 9H), 1.71 (s, 6H).

[Test Example 1] melanogenesis inhibitory effect measured using pigment cells in rats

In order to determine the melanin production inhibitory effect of the kojic acid derivative compounds obtained in Examples 1 to 5, the following experiment was performed.

At this time, the degree of melanin production in the cell was measured by Dooley's method, using kojic acid and hydroquinone as a positive control, and melanin production inhibition was measured in comparison with each compound of Examples 1-5. The cell line was a Mel-Ab cell line (supplied from Dr Thomas P. Dooley) derived from skin pigment cells of C57BL / 6. The culture was performed in DMEM medium containing 10% fetal placental serum, 100 nM 12-O-tetradecanoyl Phobol-13-acetate, 1 nM Cholera Toxin, 37 ° C., 5% CO ₂ Under the conditions of. Cultured Mel-Ab cells were detached with 0.25% Trypsin-EDTA, and again plated on the same well (1 × 10 ⁵ cells / well) in a 24-well vessel and then 10 μM for 3 consecutive days from the second day. The test material was treated in such a manner as to replace the medium containing the samples (each compound of Examples 1 to 5, the positive control koji acid, hydroquinone). After 5 days of treatment with 1N NaOH to melt the melanin contained in the cell to measure the amount of melanin by measuring the absorbance at 400nm, 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% Compound of Example 1 45.2% Compound of Example 2 89.1% 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 exhibited an effect of suppressing melanin production higher than kojic acid, and in particular, the compounds of Examples 2 and 5 than hydroquinone It was found to exhibit excellent effects.

[Test Example 2] Measurement tyrosinase activity inhibition effect

In order to determine the tyrosinase inhibitory effect of the kojic acid derivative compounds obtained in Examples 1 to 5, the following experiment was performed. Mushroom-derived tyrosinase and tyrosine were purchased from Sigma Chemical. Tyrosinase activity was correlated with 150 microliters of 0.1 M phosphate buffer (pH 6.5) and 8 microliters of mushroom tyrosinase (2,100 unit / ml, 0.05 M phosphate buffer, pH 6.5) and 36 microliters of L-tyrosine at a concentration of 1.5 mM. It was treated with 10 μM concentration of fatty acid derivative. Tyrosinase activity was measured at 490 nm using a microplate reader (Bio-Rad 3550, Richnmond, CA, USA) after 20 minutes of enzyme reaction at 37 degrees. The tyrosinase inhibition effect by the reaction product of Examples 1-5 was calculated | required based on the following formula.

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

The obtained results are shown in Table 2.

Inhibitory effect of tyrosinase activity Test substance Inhibition of tyrosinase activity (10 μM) Kojic acid 32.4% Hydroquinone 50.0% Compound of Example 1 8.1% Compound of Example 2 0 % 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 show the effect of inhibiting tyrosinase, unlike kojic acid. As a result, it was found that each of the compounds of Examples 1 to 5 acted in a mechanism different from that of tyrosinase activity, indicating inhibition of melanin production.

Although the formulation example of the composition containing the kojic acid derivative of this invention is demonstrated below, the composition of this invention is not limited only to this example.

[ Formulation Example  1] lotion formulation

Kojic acid derivative of Example 1 3.00

L-ascorbic acid-2-magnesium phosphate 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

Kojic acid derivative of Example 2 1.00

Polyethylene Glycol Monostearate 2.00

Self-emulsifying glycerin monostearate 5.00

Cetyl Alcohol 4.00

Squalene 6.00

Tri-2-ethylhexane glyceryl 6.00

Sphingolipids 1.00

1,3-butylene glycol 7.00

Purified water balance

(Unit: wt%)

[ Formulation Example  3] Packed  Formulation

Kojic Acid Derivatives of Example 3 5.00

Polyvinyl Alcohol 13.00

L-ascorbic acid-2-magnesium phosphate 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] Cosmetic liquid type  Formulation

Kojic Acid Derivatives 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)

Kojic acid derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof.
&Lt; Formula 1 >

(In the above formula, R ₁ and R ₂ are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen.) The method of claim 1,
R ₁ and R ₂ are each independently one selected from the group consisting of methoxy, hydroxy, and hydrogen, except that when R ₁ and R ₂ are all hydrogen, a kojic acid derivative and pharmaceutically acceptable thereof Possible salts. The method of claim 1,
Kojic acid derivatives selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof.
(5-hydroxy-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. To prepare a kojic acid ester compound by reacting a halokoji acid represented by the formula (2) and a benzoic acid inorganic salt containing an adamantane group represented by the formula (3); Koji acid derivative represented by the formula (1) comprising: Method for preparing a pharmaceutically acceptable salt thereof.
&Lt; Formula 1 >

(In the above formula, R ₁ and R ₂ are each independently selected from the group consisting of alkoxy, hydroxy and hydrogen having 1 to 3 carbon atoms, except that both R ₁ and R ₂ are hydrogen.)
(2)

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

(In the formula, M is an inorganic element.) 5. The method of claim 4,
R ₁ and R ₂ are each independently one selected from the group consisting of methoxy, hydroxy, and hydrogen, except that when R ₁ and R ₂ are all hydrogen, a kojic acid derivative and pharmaceutically acceptable thereof Preparation of possible salts. 5. The method of claim 4,
The ratio of the benzoic acid inorganic salt containing halokoji acid to adamantane group is 1: 1 to 1: 1.5 method for producing a kojic acid derivative and a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
M is sodium (Na) or potassium (K) Koji acid derivative and a method for producing a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein X is chlorine (Cl) Koji acid derivatives and a method for producing a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
The manufacturing method
a) reacting kojic acid with halothionyl to produce halokozi acid;
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 to prepare benzoic acid containing adamantane groups, and then Preparing an inorganic salt by reacting a benzoic acid including a carbon group with an inorganic compound; And
c) reacting the kojic acid chloride obtained in step a) and the benzoic acid inorganic salt containing the adamantane group obtained in step b) to produce a kojic acid ester compound. Process for preparing acceptable salts. The method of claim 9,
The benzoic acid including the 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 derivatives and pharmaceuticals thereof A method for preparing a salt which is generally acceptable. The method of claim 9,
The ratio of benzoic acid to adamantanol containing a substituent in the step b) is from 1: 1 to 1: 1.5, the preparation of kojic acid derivatives and pharmaceutically acceptable salts thereof. The method of claim 9,
The inorganic compound in step b) is sodium or potassium hydroxide koji acid derivatives and a method for producing a pharmaceutically acceptable salt thereof. The method of claim 9,
The organic solvent of step c) is tetrahydrofuran, N, N- dimethylformamide or a mixed solvent thereof Koji acid derivative and a method for producing a pharmaceutically acceptable salt thereof. A composition for whitening containing the kojic acid derivative of any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 14,
The amount of the kojic acid derivative and its pharmaceutically acceptable salt is 0.01 to 20% by weight based on the total weight of the composition. The method of claim 14,
The whitening composition is a whitening composition, characterized in that for whitening the skin through the inhibition of melanin production. The method of claim 14,
The whitening composition is a whitening composition, characterized in that for whitening the skin through prevention and inhibition of hyperpigmentation.