KR101873884B1 - Skin-whitening composition containing esculin derivatives - Google Patents

Abstract

The present invention discloses a skin whitening composition comprising an esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

Description

[0001] The present invention relates to skin-whitening compositions containing esculin derivatives,

The present invention relates to a skin whitening composition comprising esculin derivatives.

Melanin protects the skin by blocking the ultraviolet rays from the epidermis layer, protecting the dermis organs below the skin, and absorbing free radicals. In addition, melanin is a major factor in determining the color of skin, and when it is present in excess, melanin is a cause of skin pigmentation such as spots, freckles, and spots.

Melanin is produced in melanocytes in the basal layer of the skin, which is known to be stimulated by stimulation of ultraviolet light or inflammation. Therefore, it is possible to reduce the external stimulus, block the signal transmission, or inhibit the synthesis of melanin producing enzyme tyrosinase or inhibit the activity of melanin.

At present, it is known that accelerating the degradation of tyrosinase or regulating glycosylation, such as kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butyl resorcinol, resveratrol, ceramide, sphingosine- It is known that melanin production can be regulated. However, they are not used because of unsatisfactory whitening effect, low stability, and skin irritation. Therefore, it is necessary to develop a substance having a good whitening effect and a low side effect.

Ardhaoui et al., &Quot; Effect of acyl donor chain length and substitution patterns on the enzymatic acylation of flavonoids ", Journal of Biotechnology 110 (2004) 265-271. Ardhaoui et al, " Acylation of natural flavonoids using lipase candida antarctica as biocatalyst ", Journal of Molecular Catalysis B: Enzymatic 29 (2004) 63-67.

The present invention is to provide a skin whitening composition comprising an esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

An aspect of the present invention provides a composition for skin whitening comprising, as an active ingredient, an Esculin derivative of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

Wherein R is selected from the group consisting of C ₁ to C ₃₀ alkyl, C ₂ to C ₃₀ alkene, C ₃ to C ₁₀ cycloalkyl, and C ₁ to C ₃₀ haloalkyl.

Another aspect of the present invention provides a skin whitening cosmetic and pharmaceutical composition comprising an esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

An esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof according to an aspect of the present invention inhibits tyrosinase activity and inhibits melanogenesis and has an excellent skin whitening effect.

The inventors of the present invention have synthesized esculin derivatives and found that they can inhibit tyrosinase activity and inhibit melanin production, thus completing the present invention.

As used herein, the term "skin" refers to a tissue covering the body surface of an animal, and is a concept of the broadest notion including a scalp and hair as well as a tissue covering a body surface such as a face or a body.

As used herein, "esculin" refers to 7-Hydroxycoumarin-6-yl beta-D-Glucoside.

As used herein, "alkyl" means a monovalent saturated aliphatic hydrocarbon group. The hydrocarbon group may be linear or branched. In one aspect of the invention, "alkyl" may have 1 to 30 carbon atoms ( "C ₁ to C ₃₀ alkyl"), a particular 3 to 25 carbon atoms ( "C ₃ to C ₂₅ alkyl") It may have, may have a more specifically 5 to 15 carbon atoms ( "C ₅ to C ₁₅ alkyl").

As used herein, "alkene" means a monovalent olefinically unsaturated hydrocarbon group having one or more double bonds, which may be linear or branched. In one aspect of the present invention "alkenyl" is from 2 to 30 carbon atoms ( "C ₂ -C ₃₀ alkenyl") may have, in particular 3 to 25 carbon atoms ( "C ₃ to C ₂₅ alkenyl") And more specifically may have from 5 to 15 carbon atoms ("C ₅ to C ₁₅ alkenes").

As used herein, "cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group. In one aspect of the invention, "cycloalkyl" has 3 to 30 carbon atoms ( "C ₃ to C ₃₀ cycloalkyl") may have, in particular 3 to 25 carbon atoms ( "C ₃ to C ₂₅ cycloalkyl, may have a ") can have and, more specifically 5 to 15 carbon atoms (" C ₅ to C ₁₅ cycloalkyl ").

As used herein, "haloalkyl" includes "alkyl" groups as defined above substituted with one or more halogen which may be the same or different. As used herein, "halogen" includes fluoro, chloro, bromo or iodo. The "haloalkyl" In one aspect of the invention is from 1 to 30 carbon atoms may have a ( "C ₁ to C ₃₀ alkyl"), in particular 3 to 25 carbon atoms ( "C ₃ to C ₂₅ alkyl") And more specifically from 5 to 15 carbon atoms ("C ₅ to C ₁₅ alkyl").

As used herein, the term "isomers" refers in particular to optical isomers (for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof) as well as morphological isomers (i. e., isomers differing only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g., cis-trans isomers) do.

As used herein, "essentially pure ", when used in reference to an enantiomer or partial isomer, means that at least about 90%, preferably at least about 95%, of a specific compound, such as an enantiomer or partial isomer, , More preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).

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; (3-hydroxybenzoyl) benzoic acid, or an 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- 4-methylbicyclo [2,2,2] -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, laurylsulfuric 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.

As used herein, the term " prodrug "refers to a drug that chemically changes a drug to control its physical and chemical properties. Although it does not exhibit physiological activity itself, The drug can be turned into a drug.

As used herein, "hydrate " means a compound to which water is bound, and is a broad concept that includes an inclusion compound having no chemical bonding force between water and the compound.

As used herein, "solvate" means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.

One aspect of the present invention includes the Esculin derivative, isomer, pharmaceutically acceptable salts thereof, prodrug thereof, a hydrate thereof or a solvate thereof of Formula 1 as an active ingredient, and R is R is C ₁ to C It provides a ₃₀ alkyl, C ₂ to C ₃₀ alkene, C ₃ to C ₃₀ cycloalkyl, and C ₁ to a composition for skin whitening selected from the group consisting of haloalkyl of C _30.

Another aspect of the present invention includes an esculin derivative of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof, wherein R is C ₃ to C ₃₀ By weight of the composition.

In another aspect of the present invention there is provided an esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof,

Hexanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran- Oxa-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, octanoic acid 3 (4-hydroxy- , 4-hydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl- , 5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, -Tetrahydropyran-2-yl-methyl ester, undecanoic acid, 3,4,5-tri (4-hydroxy-2-oxo-2H- Hydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, dodecanoic acid 3,4,5-trihydroxy -6- (7-Hydro 2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, tridecanoic acid 3,4,5-trihydroxy-6- (7- 2-yl-methyl ester, tetradecanoic acid 3,4,5-trihydroxy-6- (7-hydroxy-isoquinolin- 2-yl-methyl ester, pentadecanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo- Yl-methyl ester, hexadecanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2- Yl-methyl ester, heptadecanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo Yl) -methyl ester, octadecanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo- 2H-crown 6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, nonadecanoic acid 3,4,5-trihydroxy-6- (7-hydroxy- -6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, icosanoic acid 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H- Yl) -methyl ester, henicosanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H- Yl-methyl ester, docosanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen- Hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran-2-yl-methyl ester, tricoxanoic acid 3,4,5-trihydroxy-6- (7- 2-yl-methyl ester, tetrakisanoic acid, 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen- Tetraheta 2-yl-methyl ester and the pentacosanoic acid 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydro Pyran-2-yl-methyl ester.

The above esculin derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof inhibit melanin production and inhibit the activity of tyrosinase, .

The composition according to one aspect of the present invention comprises 0.001% to 20% by weight, specifically 0.01% to 10% by weight, more specifically 0.1% to 5% by weight, based on the total weight of the composition, of the esculin derivative, An isomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. When it is included in the above range, it is not only suitable for exhibiting the intended effect of the present invention but also can satisfy both the stability and safety of the composition and may be suitably included in the above range in terms of cost effectiveness. Specifically, when the amount of the esculin derivative, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or solvate thereof is less than 0.001% by weight, sufficient skin whitening effect can not be obtained. Safety and formulation stability may be lowered.

One aspect of the present invention relates to a composition for an external application comprising the esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient, to provide.

Another aspect of the present invention provides a cosmetic composition comprising the esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient. The cosmetic composition may exhibit an excellent skin whitening effect and specifically improve or prevent spots, freckles, dots and skin pigmentation.

The cosmetic composition according to the present invention may be provided in all formulations suitable for topical application. For example, it may be provided as a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an oil phase in water, a suspension, a solid, a gel, a powder, a paste, a foam or an aerosol composition. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may contain, in addition to the above-mentioned substances, other ingredients which can give a synergistic effect to the main effect, so long as they do not impair the main effect. Specifically, the cosmetic composition according to the present invention may further comprise an arbutin or ascorbic acid derivative capable of enhancing the skin whitening effect. The cosmetic composition according to the present invention may further comprise a moisturizing agent, an emollient agent, a surfactant, an ultraviolet absorber, an antiseptic, a bactericide, an antioxidant, a pH adjuster, an organic or inorganic pigment, a fragrance, have. The compounding amount of the above components can be easily selected by those skilled in the art within a range not to impair the objects and effects of the present invention. The amount thereof may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight, have.

An aspect of the present invention provides a pharmaceutical composition comprising the esculin derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient. The pharmaceutical composition may exhibit an excellent skin whitening effect and specifically improve or treat spots, freckles, dots and skin pigmentation.

The pharmaceutical composition according to one aspect of the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like. Formulations for oral administration may be in the form of tablets, pills, soft and hard capsules, granules, powders, granules, solutions, emulsions or pellets, It is not. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or spray formers. The formulations may be readily prepared according to conventional methods in the art and may be prepared by conventional means including, but not limited to, surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, Other commonly used adjuvants may be used.

The effective ingredients of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathological condition and severity of the subject to be administered, route of administration, or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / / Day, but is not limited thereto.

Hereinafter, the constitution and effects of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these examples and experimental examples are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited thereto.

Example 1 Synthesis of hexanoic acid 3,4,5-trihydroxy-6- (7-hydroxy-2-oxo-2H-chromen-6-yl-oxy) -tetrahydropyran- Preparation of methyl ester

25 mg (0.057 mmol) of esculin, 125 mg (500% by weight) of Novozyme 435, 0.5 ml of hexanoic acid and 500 mg of 3 Å molecular sieve are dissolved in 5 ml of dried acetonitrile and stirred at 40 ° C for 5 hours. After the reaction is complete, it is filtered and the filtrate is extracted three times with diethyl ether. The diethyl ether layer was dried under reduced pressure and then separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 24.7 mg (yield: 90%) of the product as a white solid.

[Examples 2 to 21]

Examples 2 to 21 were prepared in substantially the same manner as in Example 1.

The chemical formulas and NMR analysis data of Examples 1 to 21 are shown in the following Chemical Formula 1 and Table 1.

[Chemical Formula 1]

Example R _{1H NMR (DMSO- d 6, 300MHz} ) One C ₅ alkyl d 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz) , 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 8H), 0.85 (t, , 3H, J = 6.6 Hz) 2 C ₆ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 10H), 0.85 (t, 3H, J = 6.6 Hz) 3 C ₇ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 12H), 0.85 (t, 3H, J = 6.6 Hz) 4 C ₈ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 14H), 0.85 (t, 3H, J = 6.6 Hz) 5 C ₉ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 16H), 0.85 (t, 3H, J = 6.6 Hz) 6 C ₁₀ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 18H), 0.85 (t, 3H, J = 6.6 Hz) 7 C ₁₁ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 20H), 0.85 (t, 3H, J = 6.6 Hz) 8 C ₁₂ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 22H), 0.85 (t, 3H, J = 6.6 Hz) 9 _C13 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 24H), 0.85 (t, 3H, J = 6.6 Hz) 10 C ₁₄ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 26H), 0.85 (t, 3H, J = 6.6 Hz) 11 _C15 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 28H), 0.85 (t, 3H, J = 6.6 Hz) 12 _C16 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 30H), 0.85 (t, 3H, J = 6.6 Hz) 13 _C17 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 32H), 0.85 (t, 3H, J = 6.6 Hz) 14 C ₁₈ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 34H), 0.85 (t, 3H, J = 6.6 Hz) 15 C ₁₉ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 36H), 0.85 (t, 3H, J = 6.6 Hz) 16 C ₂₀ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 38H), 0.85 (t, 3H, J = 6.6 Hz) 17 _C21 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 40H), 0.85 (t, 3H, J = 6.6 Hz) 18 C ₂₂ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 42H), 0.85 (t, 3H, J = 6.6 Hz) 19 _C23 alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 44H), 0.85 (t, 3H, J = 6.6 Hz) 20 C ₂₄ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz ), 3.31 (m, 3H) , 3.21-3.18 (m, 1H), 2.26 (t, 2H, J = 6.9Hz), 1.44 (m, 2H), 1.23-1.14 (m, 46H), 0.85 (t, 3H, J = 6.6 Hz) 21 C ₂₅ alkyl 7.83 (d, 1H, J = 9.6Hz), 7.30 (s, 1H), 6.82 (s, 1H), 6.22 (d, 1H, J = 9.6Hz), 5.31 (d, 1H, J = 9.6Hz), 5.21 (br, 1H), 4.85 (d, 1H, J = 6.9Hz), 4.33 (d, 1H, J = 11.1Hz), 4.13-4.07 (m, 1H), 3.62 (t, 1H, J = 8.1Hz 2H, J = 6.9 Hz), 1.44 (m, 2H), 1.23-1.14 (m, 48H), 0.85 (t, 3H, J = 6.6 Hz)

[Experimental Example 1] Evaluation of inhibitory effect of tyrosinase activity

The inhibitory effect of esculin derivatives of Examples 1 to 21 on tyrosinase activity was measured in comparison with arbutin, which is known to have an excellent whitening effect.

Mushroom-derived tyrosinase and tyrosine were obtained from Sigma Chemical. Arbutin, the esculin derivatives of Examples 1 to 21, together with 150 μl of 0.1 M phosphate buffer (pH 6.5), 8 μl of mushroom tyrosinase (2,100 unit / ml) and 0.05 M of L- Treated with the concentrations shown in Table 2. The tyrosinase activity was evaluated by measuring the absorbance at 490 nm using a microplate reader (Bio-Rad 3550, Richnmond, CA, U.S.A.) after an enzymatic reaction at 37 ° C for 20 minutes.

The inhibitory effect (IC ₅₀ ) of tyrosinase activity by each test substance was calculated and shown in Table 2.

Test substance IC ₅₀ ([mu] M) Test substance IC ₅₀ ([mu] M) Control group - Example 11 89 Arbutin 145 Example 12 82 Example 1 85 Example 13 76 Example 2 83 Example 14 80 Example 3 86 Example 15 86 Example 4 80 Example 16 88 Example 5 78 Example 17 95 Example 6 76 Example 18 110 Example 7 70 Example 19 116 Example 8 81 Example 20 160 Example 9 82 Example 21 200 Example 10 79

As can be seen from the above results, the esculin derivatives of Examples 1 to 21 have significantly higher tyrosinase activity inhibitory effect (IC ₅₀ ) than the untreated control group, and the effect is superior to that of arbutin. In particular, Example 7 showed the most excellent tyrosinase activity inhibitory effect.

On the basis of this, esculin derivatives inhibit the activity of intracellular tyrosinase and thus have excellent skin whitening effect.

[Experimental Example 2] Evaluation of inhibitory effect on melanin formation

The melanin production inhibitory effect of the esculin derivatives of Examples 1 to 21 was measured in comparison with kojic acid, which is known to have an excellent whitening effect.

The degree of intracellular melanin production was measured by Dooley's method. The cell line used was a Mel-Ab cell line derived from a skin pigment of C57BL / 6. The culture was carried out in DMEM medium containing 10% fetal bovine serum, 100 nM 12-O-tetradecanoylphorbol-13-acetate and 1 nM cholera toxin at 37 ° C, 5 It was done under the condition of% CO _2. The cultured Mel-Ab cells were removed with 0.25% Trypsin-EDTA and inoculated again into the 24-well plate with the same number (1x10 ⁵ cells / well) The test substance was treated by replacing the medium with the medium containing the test compound. As test substances, Examples 1 to 21, kojic acid and 100 ppm and DMSO (control group) were used. After 5 days, the melanin contained in the cells was treated with 1N-NaOH, and the amount of melanin was measured by measuring the absorbance at 400 nm. The concentration (IC ₅₀ ) of each test substance required to reduce the melanin production of melanocytes in half was calculated, and the results are shown in the table below.

Test substance IC ₅₀ (ppm) Test substance IC ₅₀ (ppm) Control group - Example 11 23 Kojic acid 39.36 Example 12 18 Example 1 15 Example 13 14 Example 2 10 Example 14 16 Example 3 13 Example 15 20 Example 4 22 Example 16 22 Example 5 15 Example 17 17 Example 6 18 Example 18 29 Example 7 13 Example 19 35 Example 8 17 Example 20 45 Example 9 21 Example 21 42 Example 10 19

As can be seen from the above results, the esculin derivatives of Examples 1 to 21 showed excellent melanin production inhibitory effect, which was superior to kojic acid. In particular, Example 7 showed the most excellent melanin production inhibitory effect.

Based on this, it can be seen that the esculin derivatives have excellent skin whitening effect by inhibiting intracellular melanin production.

Formulation examples of compositions according to one aspect of the present invention are described below, but may be applied to various other formulations, which are not intended to be limiting but merely illustrative of the invention.

[Formulation Example 1] Lotion

Lotion is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) Example 2.0 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 PEG 12 nonyl phenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 2] Nourishing cream

Nutritive creams are prepared according to the usual methods with the composition shown in the table below.

ingredient Content (% by weight) Example 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 hardened castor oil 2.0 Liquid paraffin 10.0 Squalane 5.0 Caprylic / caproic triglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 3] Massage cream

A massage cream is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) Example 1.0 Wax 10.0 Polysorbate 60 1.5 PEG 60 hardened castor oil 2.0 Sorbitan sesquioleate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprylic / capric triglyceride 4.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 4] Pack

A pack is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) Example 1.0 Polyvinyl alcohol 13.0 Sodium carboxymethylcellulose 0.2 glycerin 5.0 Allantoin 0.1 ethanol 6.0 PEG 12 nonyl phenyl ether 0.3 Polysorbate 60 0.3 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 5]

The gel is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) Example 0.5 Ethylenediamine sodium acetate 0.05 glycerin 5.0 Carboxyvinyl polymer 0.3 ethanol 5.0 PEG 60 hardened castor oil 0.5 Triethanolamine 0.3 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 6] ointment

Ointments are prepared by conventional methods with the compositions listed in the table below.

ingredient Content (% by weight) Example 0.1 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / capric triglyceride 3.0 Squalane 1.0 Cetearyl glucoside 1.5 Sorbitan stearate 0.4 Cetearyl alcohol 1.0 Wax 4.0 Preservative, coloring, fragrance Suitable amount Purified water Balance

Claims (7)

A cosmetic composition for skin whitening comprising, as an active ingredient, an Esculin derivative, an optical isomer thereof, a geometric isomer thereof, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,
[Chemical Formula 1]

In the general formula 1 R is a C ₁₁ alkyl.
delete delete The method according to claim 1,
The composition comprises a skin whitening agent comprising an esculin derivative, an optical isomer thereof, a geometric isomer thereof, a geometric isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof in an amount of 0.001 to 20% / RTI >
The method according to claim 1,
Wherein the composition inhibits tyrosinase activity and melanin production.
delete delete