JP2022113139A - Skin whitening composition containing dimethylphenylthiourea - Google Patents

Abstract

To provide a skin whitening composition containing dimethylphenylthiourea.SOLUTION: According to one embodiment, a skin whitening composition containing dimethylphenylthiourea has minimized skin irritation and shows excellent skin-whitening effect at a dose of low concentration. Furthermore, the composition can be synthesized at low cost and can be applied for various fields such as a cosmetic composition, a health functional food composition, an external preparation for skin or a pharmaceutical composition.SELECTED DRAWING: Figure 4

Description

There is an application for the application of Article 30, Paragraph 2 of the Patent Act Announcement through telecommunications line Date of publication: January 22, 2021 Address of publication: https://doi. org/10.3390/molecules26030566

The present invention relates to skin lightening compositions comprising dimethylphenylthiourea.

Human skin color is largely determined by melanin, hemoglobin, and carotene, among which melanin plays the most important role. Skin color or brightness is genetically determined by the concentration and distribution of melanin in a person's skin, but is also influenced by environmental or physiological conditions such as solar UV radiation, fatigue or stress. Melanin is converted to DOPA and dopaquinone by the enzyme tyrosinase, which acts as a catalyst on tyrosine, a kind of amino acid, and undergoes a non-enzymatic oxidation reaction. made. As such, the pathway by which melanin is produced is known, but it has not yet been clarified in detail what causes tyrosinase to be triggered in the mechanism that induces melanin synthesis. Recently, skin physiological studies for skin wrinkle improvement or skin whitening have been extensively conducted, and cosmetics containing ingredients such as vitamin C exhibiting antioxidant effects have been presented. Under such technical background, research on skin whitening compositions (KR Registered Patent No. 10-1449577) has been actively conducted, but research on skin whitening compositions involving artificially synthesized substances is still inadequate.

One aspect provides a cosmetic composition for skin whitening comprising, as an active ingredient, a compound represented by Formula I below, or a pharmaceutically acceptable salt thereof:

Another aspect provides a food composition for skin whitening comprising the compound represented by Formula I or a food-acceptable salt thereof as an active ingredient.

Yet another aspect provides an external preparation for skin whitening comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

Yet another aspect provides a pharmaceutical composition for preventing or treating hyperpigmentation, comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

Yet another aspect provides a skin whitening method comprising applying a cosmetic composition comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient to the skin of an individual. .

In yet another embodiment, a pharmaceutical composition for preventing or treating hyperpigmentation disease comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient is administered to an individual. Provided is a method of preventing, ameliorating or treating hyperpigmentation disorders comprising applying to the skin or administering to an individual.

One aspect provides a skin-whitening cosmetic composition comprising, as an active ingredient, a compound represented by Formula I below, or a pharmaceutically acceptable salt thereof:

The compound represented by Formula _I is a compound having a molecular _formula of _C9H12N2S and a molecular weight of about 175 to 185 g/mol, which is naturally derived and widely known in the art. It is also obtained by various synthetic methods.

The compound represented by Formula I includes dimethylphenylthiourea, 1-(2,4-dimethylphenyl)thiourea), (2,4-xylyl)thiourea, 2,4-xylylthiourea, 2-thio-1- (2,4-xylyl)-urea, 2-thio-1-(2,4-xylyl)urea, 2,4-dimethylphenylthiourea, 1-(2,4-dimethylphenyl)-2-thiourea, or 1 It can be the same compound as -(2,4-dimethylphenyl)thiourea.

The term "pharmaceutically acceptable salt" means any salt that possesses the desired biological and/or physiological activity of said compound and exhibits minimal undesired toxicological effects. do. As salts, acid addition salts formed with pharmaceutically acceptable free acids are useful. The acid addition salts are prepared by conventional methods such as dissolving the compound in excess aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. do. Equal molar amounts of the compound and an acid or alcohol (e.g. glycol monomethyl ether) in water can be heated and then the mixture can be evaporated to dryness or the precipitated salt can be suction filtered. At that time, as free acids, inorganic acids and organic acids can be used. As inorganic acids, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, stannic acid, etc. can be used. Examples include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid acid), citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, asparagine Acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used, but are not limited thereto.

Also, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts can be prepared, for example, by dissolving the compound in a solution of excess alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating the filtrate to dryness. let me get At that time, as the metal salt, it is particularly suitable to prepare a sodium salt, a potassium salt or a calcium salt, but it is not limited to them. Also, the corresponding silver salts can be obtained by reacting an alkali metal salt or an alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds represented by Formula I above mostly include salts of acidic or basic groups that may be present in said compounds, unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen salts of sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate); are also prepared via salt preparation methods known in the art.

The term "pharmaceutically acceptable salt" is used interchangeably with the terms "cosmetically acceptable salt", "foodstuff acceptable salt" or "cosmetically acceptable salt". This concept includes "acceptable salt" and "food-acceptable salt".

The term "cosmetically acceptable salt" is the same as or to the extent that the compound is a cosmetically acceptable salt as defined above under "pharmaceutically acceptable salt". It is also defined as a salt in a form that is combined with possible acids or bases.

In the cosmetic composition, the content of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is preferably about 0.00001 to 10% by weight based on the total weight of the composition.

In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof may be included in an amount of about 0.01 to 0.50% by weight based on the total weight of the cosmetic composition. . Specifically, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is about 0.01% to less than about 0.50% by weight based on the total weight of the cosmetic composition. , from about 0.03 to 0.50% by weight, from about 0.03% to less than about 0.50% by weight, from about 0.05% to 0.50% by weight, or from about 0.05% by weight to about 0% less than .50% by weight. According to one embodiment, the composition comprises about 0.01% or more to less than about 0.50% by weight of the compound represented by Formula I, or a pharmaceutically acceptable salt thereof. , it can show remarkably excellent skin whitening effect without causing skin irritation.

In one embodiment, the cosmetic composition also contains about 0.1 to 30,000 μM of the compound represented by Formula I, or a pharmaceutically acceptable salt thereof. Preferably, said cosmetic composition contains about 0.4 to 30,000 μM, about 1 to 30,000 μM, or about 1.7 to 30,000 μM of a compound represented by Formula I, or a pharmaceutically It also contains acceptable salts. According to one embodiment, when the composition comprises less than about 0.1 μM of the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, the skin lightening effect is significantly reduced, If it contains more than about 30,000 μM, it will induce skin irritation.

The term "skin whitening" means not only lightening skin tone, but also ameliorating skin hyperpigmentation caused by UV, hormones or genetics by inhibiting the synthesis of melanin pigment. The hyperpigmentation of the skin may also include chloasma, freckles, senile warts, age spots, senile blemishes or brown spots.

The term "amelioration" may mean any action that at least reduces the severity of a parameter, eg, symptom, associated with alleviation of a condition or treatment.

The cosmetic composition comprises a cosmetically effective amount of the compound represented by Formula I or a pharmaceutically acceptable salt thereof and/or a cosmetically acceptable carrier. There is also a thing.

The term "cosmetically effective amount" means an amount sufficient to achieve the skin lightening efficacy of said cosmetic composition. The cosmetically effective amount can be determined by a person skilled in the art based on common common sense to the extent that the desired skin whitening effect is exhibited.

The cosmetically acceptable carrier contained in the cosmetic composition varies depending on the dosage form. When the dosage form of the cosmetic composition is an ointment, paste, cream or gel, the carrier components include animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivatives, polyethylene glycol and silicone. , bentonite, silica, talc, zinc oxide, or mixtures thereof may be utilized. When the dosage form of the cosmetic composition is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof are used as carrier components, especially If it is a spray, it will also contain propellants such as chlorofluorohydrocarbons, propane/butane or dimethyl ether. When the dosage form of the cosmetic composition is a solution or an emulsion, a solvent, a solubilizer, or an emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, Ethyl acetate, benzyl benzoate, propylene glycol, 1,3-butyl glycol oils, especially cottonseed oil, peanut oil, maize germ oil, olive oil, castor oil and sesame oil, fatty acids of glycerol fatty esters, polyethylene glycol or sorbitan. there is an ester. When the dosage form of the cosmetic composition is a suspension, the carrier components include a liquid diluent such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene. Suspending agents such as ethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracanth and the like may be employed. When the cosmetic composition is in the form of soap, carrier components include alkali metal salts of fatty acids, fatty acid hemiester salts, fatty acid protein hydrolysates, isethionates, lanolin derivatives, fatty alcohols, vegetable oils, and glycerol. , sugar, etc. can be used.

The cosmetic composition contains colorants, pigments, preservatives, stabilizers, surfactants, thickeners, solubilizers, moisturizing agents, emollients, ultraviolet absorbers, preservatives, bactericides, emulsifiers, and antioxidants. agents, pH adjusters, organic and inorganic pigments, fragrances, purified water, dispersants, fillers, sweeteners, vitamins, free radical scavengers, sequestrants, cooling agents, or antiperspirants; Additives commonly used in the art may be further included. The amount of additional ingredients such as preservatives can be easily selected by those skilled in the art within a range that does not impair the object and effect of the present invention. 001 to 40% by weight.

The cosmetic composition can be manufactured in any dosage form commonly manufactured in the industry, such as solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant, etc. Agent-containing cleansers, oils, powder foundations, emulsions, foundations, wax foundations, sprays, etc. are also formulated, but not limited thereto. For example, it can be manufactured in the form of soft lotion, nutritional lotion, nutritional cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

Another aspect provides a skin-whitening food composition comprising a compound represented by Formula I below, or a food-acceptable salt thereof, as an active ingredient:

The term "food-acceptable salt" is the same as or to the extent that the compound is food-acceptable as defined in "pharmaceutically-acceptable salt" above. It is also defined as a salt in the form of a compound bound with an acid or base.

The food composition is also a health functional food composition.

The term "food with health claims" means that active ingredients are added to food materials such as beverages, teas, spices, gums, and confectionery, or manufactured into capsules, powders, suspensions, etc. It is a processed food, which means that when it is consumed, it brings about certain health effects. There is Therefore, the health functional food composition can be ingested on a daily basis, and is expected to have a high skin-whitening effect, and is very useful.

In the food composition, the compound represented by Formula I or a food-acceptable salt thereof is directly added to the food, or added together with other food or food ingredients, and the general method is can be added or used as appropriate. The amount of the compound represented by Formula I or its food-acceptable salt to be mixed can be appropriately determined depending on the purpose of use (for prevention or improvement).

In the food composition, the content of the compound represented by Formula I or its food-acceptable salt is preferably about 0.00001 to 10% by weight based on the total weight of the composition.

The food composition further comprises one or more of carriers, diluents, excipients and additives, and is selected from the group consisting of tablets, pills, powders, granules, powders, capsules and liquid formulations. It is also formulated into one selected from Foods to which the compound according to one aspect can be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gums, teas, vitamin complexes, health functional foods, and the like.

The food composition may contain other components as salt components without particular limitation, in addition to containing the compound represented by Formula I or its food-acceptable salts. For example, common beverages may include additional ingredients such as various flavoring agents or natural carbohydrates. The ratio of natural carbohydrates can be appropriately determined by the choice of those skilled in the art.

In addition to the foregoing, the food composition may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, coloring agents and fillers (cheese, chocolate, etc.), Pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated drinks, etc. be. Such ingredients can be used independently or in combination, and the proportions of such additives can also be appropriately selected by those skilled in the art.

The terms or elements referred to in the food composition are the same as those referred to in the description of the cosmetic composition above. is understood.

Yet another aspect provides a skin whitening topical preparation comprising a compound represented by Formula I below, or a pharmaceutically acceptable salt thereof, as an active ingredient:

The term "external preparation for skin" is a concept encompassing all compositions applied to the skin. For example, various cosmetics such as basic cosmetics, makeup cosmetics, and hair cosmetics; ointments, creams, This concept includes pharmaceutical compositions for topical administration, including drugs such as lotions and quasi-drugs. For example, the external preparation for skin contains an active ingredient alone, or further contains one or more pharmaceutically acceptable carriers, excipients, diluents, etc., and is provided as a pharmaceutical composition.

In the topical skin preparation, the content of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is preferably about 0.00001 to 10% by weight based on the total weight of the topical skin preparation.

Regarding the terms or elements referred to in the topical skin preparation, those mentioned in the description regarding the cosmetic composition and the food composition are referred to in the description regarding the cosmetic composition and the food composition as described above. is understood to be as mentioned in

Yet another aspect provides a pharmaceutical composition for the prevention or treatment of hyperpigmentation, comprising a compound represented by Formula I below, or a pharmaceutically acceptable salt thereof, as an active ingredient:

The term "prevention" means any act of preventing or delaying the onset of disease by administration of the composition. The term "treatment" refers to treating an individual suffering from, or at risk of developing, a disease by ameliorating a condition (e.g., one or more symptoms) of said individual, delaying disease progression, delaying the onset of symptoms, or It means any form of treatment that provides benefits, including slowing the progression of symptoms. Accordingly, the foregoing "treatment" and "prevention" are not intended to imply cure or complete elimination of symptoms.

The aforementioned “hyperpigmentation disease” refers to a disease in which excessive melanin pigment is produced and deposited in the skin, ie, a disease exhibiting symptoms of hyperpigmentation. Said hyperpigmentation diseases are for example chloasma, freckles, senile warts, age spots, senile blemishes or solar lentigines.

The pharmaceutical composition contains a pharmaceutically effective amount of the compound represented by Formula I or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable carrier. It also contains

The term "pharmaceutically effective amount" can mean an amount sufficient to effect the efficacy of the pharmaceutical composition for prevention or treatment of hyperpigmentation disorders.

In the pharmaceutical composition, the content of the compound represented by Formula I or a pharmaceutically acceptable salt thereof is preferably about 0.00001 to 10% by weight based on the total weight of the composition. .

The pharmaceutically acceptable carriers are those commonly used in formulations, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystals. cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition may further contain lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, preservatives, etc. in addition to the above ingredients, but is not limited thereto.
The pharmaceutical composition can be administered orally or parenterally, preferably parenterally. It can be administered by transdermal administration or the like, but is not limited thereto.

The dosage of the pharmaceutical composition depends on factors such as formulation method, administration method, patient's age, weight, sex, disease state, diet, administration time, administration route, excretion rate and reaction sensitivity. , can be prescribed in a variety of ways. Specifically, the dosage is determined by the form in which the composition is manufactured, the method by which the compound represented by Formula I or a pharmaceutically acceptable salt thereof is applied to the skin, and the time it stays on the skin. etc. For example, when the composition is manufactured as a pharmaceutical product, the compound represented by Formula I, or It may also contain a pharmaceutically acceptable salt thereof. Therefore, the daily dose is about 0.1 to 100 mg/kg, preferably about 30 to 80 mg, based on the amount of the compound represented by Formula I or its pharmaceutically acceptable salt. /kg, more preferably about 50 to 60 mg/kg, and can be administered 1 to 6 times daily.

The pharmaceutical composition contains a pharmaceutically acceptable carrier and/or excipient by a method that can be easily carried out by a person having general knowledge in the technical field to which the invention belongs. It can be formulated in a unit dose form or it can be contained in multi-dose containers.

Said dosage forms are also in the form of solutions, suspensions or emulsions in oily or aqueous media, also in the form of extracts, powders, granules, tablets or capsules, dispersing agents and/or stabilizing agents. It may further contain an agent.

Regarding the terms or elements referred to in the pharmaceutical composition, those mentioned in the description of the cosmetic composition, the food composition, and the topical skin preparation are the same as the cosmetic composition, It is understood that it is as mentioned in the explanations relating to food compositions and topical skin preparations.

Yet another aspect provides a skin whitening method comprising applying a cosmetic composition comprising a compound represented by Formula I below or a pharmaceutically acceptable salt thereof as an active ingredient to the skin of an individual. :

In still another embodiment, the step of applying to the skin of an individual or administering to the individual a pharmaceutical composition comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. A method for preventing, ameliorating or treating a hyperpigmentation disease is provided.

The term "applying" is used interchangeably with "applying" and "administering" to bring about at least partial localization of the composition to a desired site or route of administration according to one experiment. It is also the placement of a composition according to one aspect within an individual.

The aforementioned "individual" means mammals such as humans or non-human primates, mice, dogs, cats, horses and cows, and is also a subject in need of treatment for disease.

In the terms or elements referred to in the method above, those mentioned in the descriptions related to the cosmetic composition, food composition, topical skin preparation and pharmaceutical composition mentioned above are It is to be understood that they are as referred to in the descriptions relating to pharmaceutical compositions, food compositions, topical skin preparations and pharmaceutical compositions.

According to one embodiment of the skin whitening composition, skin irritation is minimized, and excellent skin whitening effect is exhibited even at a low concentration dose. Furthermore, the composition is inexpensive to synthesize, and can be used in various fields such as cosmetic compositions, health functional food compositions, external skin preparations, and pharmaceutical compositions.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram showing the preparation process of the compound represented by Formula I in one example. FIG. 2 is a diagram confirming the tyrosinase inhibitory effect of kojic acid in the control group. 1 is a diagram confirming the tyrosinase inhibitory effect of a compound represented by chemical formula I in one example. FIG. 1 is a diagram confirming the melanogenesis inhibitory effect of a compound represented by chemical formula I in one example. FIG.

Hereinafter, the present invention will be described in more detail through examples. However, the Examples and Experimental Examples according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as limited to the Examples and Experimental Examples detailed below. The examples and experimental examples of the present invention are provided to provide a more thorough explanation of the present invention to those skilled in the art. Also, although preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of this specification.

[Production Example 1: Preparation of compound represented by Chemical Formula I]
The compound represented by Formula I is a compound having a molecular _formula of _C9H12N2S and a molecular weight of about _180.27 g/mole, which is also naturally occurring and widely known in the art. It is also obtained by a variety of synthetic methods. FIG. 1 is an example and schematically shows the manufacturing process of the compound represented by Formula I above. The compound represented by Formula I used in the following experiments was purchased from Enamine, Inc., Cat# EN300-28852, and was designated as Compound I (BTB04770).

[Experimental Example 1: Confirmation of Tyrosinase Inhibitory Effect of Compound I (BTB04770)]
In order to confirm the tyrosinase inhibitory effect of Compound I (BTB04770), the following experiments were carried out.

In a 96-well plate, 110 μL of 0.1 M phosphate buffer (pH 6.6), 10 μL of sample solution containing compound I (BTB04770), mushroom tyrosinase solution (1,500 U/mL to 2,000 U/mL) (or human tyrosinase) were mixed in order. 20 μL of 1.5 mM tyrosine solution was added to the mixed solution, reacted at 37° C. for 20 to 30 minutes, and absorbance was measured at 490 nm. Experiments were conducted on various experimental groups with different concentrations of Compound I (BTB04770) contained in the mixed solution, and the tyrosinase inhibitory effect of Compound I (BTB04770) at different concentrations was analyzed. As a control group, the same experiment was performed by treating kojic acid instead of compound I (BTB04770). The concentrations of kojic acid and compound I (BTB04770) treated in the control group and experimental group are shown in Table 1 below.

As a result, as shown in FIGS. 2 and 3, it was confirmed that compound I (BTB04770) exhibited superior tyrosinase inhibitory effect at a lower concentration than the control group.

Through this, it was confirmed that compound I (BTB04770) exhibited a significant whitening effect compared to the control group.

[Experimental Example 2: Confirmation of melanogenesis inhibitory effect of compound I (BTB04770)]
In order to confirm the melanogenesis inhibitory effect of compound I (BTB04770), the following experiment was carried out.

6-well plates were seeded with 1.0×10 ⁵ melanocytes per well (3×10 ⁵ cells per dish in a 60 mm dish) and cultured for 24 hours in cell culture conditions. After removing the medium and washing the cells with Dulbecco's phosphate-buffered saline (DPBS), the medium contained α-melanocyte-stimulating hormone (α-MSH) to induce melanogenesis (final concentration 100 nM) samples and cultured for about 3-4 days. The cultured cells were then treated with Compound I (BTB04770). As a control group, the same experiment was performed by treating kojic acid or arbutin instead of compound I (BTB04770). The treatment concentrations of compound I (BTB04770), kojic acid or arbutin are shown in Table 2 below.

Then, after removing the medium, washing with DPBS, detaching the cells using trypsin, transferring them to a 1.5 ml tube, sinking the cells through centrifugation, removing the supernatant, and removing the melanin of the cells. The amount of production was first confirmed with the naked eye. Add 300 μl of 1N NaOH + 10% dimethyl sulfoxide (DMSO) to the cells, leave at 95° C. for about 30 to 40 minutes to dissolve intracellular melanin, add 200 μl each to a 96-well plate, and read at 405 nm using a plate reader. measured in Melanin from Sigma Aldrich (M8631-100MG) was then used as standard for quantification.

As a result, as shown in FIG. 4, it was confirmed that compound I (BTB04770) exhibited superior melanin production inhibitory effect at a lower concentration than the control group.
Through it, it was confirmed that Compound I (BTB04770) exhibited significant whitening effect compared to the control group.

[Experimental Example 3: Confirmation of safety of compound I (BTB04770)]
In order to confirm the safety of Compound I (BTB04770), a skin patch irritation experiment was performed.

After preparing various samples with different concentrations of Compound I (BTB04770), each sample was applied to the subject's skin via a patch. The patch was removed and a first reading attempt was made after about 30 minutes, and a second reading was taken after about 24 hours. To determine the intensity of skin irritation for each sample, a primary cutaneous irritation index (P.C.I.) was determined to determine skin irritation for each sample.

As a result, as shown in Table 3 below, it was confirmed that compound I (BTB04770) did not induce skin irritation at a concentration of less than about 0.5%.

Claims (6)

A skin-whitening cosmetic composition comprising a compound represented by the following chemical formula I or a pharmaceutically acceptable salt thereof as an active ingredient:

. [Claim 2] The compound represented by Formula I or a pharmaceutically acceptable salt thereof is contained in an amount of 0.01 to 0.50% by weight based on the total weight of the cosmetic composition. The described cosmetic composition for skin whitening. A food composition for skin whitening comprising a compound represented by the following chemical formula I or a food-acceptable salt thereof as an active ingredient:

. An external preparation for skin whitening comprising a compound represented by the following chemical formula I or a pharmaceutically acceptable salt thereof as an active ingredient:

. A pharmaceutical composition for the prevention or treatment of hyperpigmentation, comprising a compound represented by the following formula I or a pharmaceutically acceptable salt thereof as an active ingredient:

. 6. The pharmaceutical composition according to claim 5, wherein the hyperpigmentation disease is chloasma, freckles, senile warts, blemishes, senile blemishes or solar melanoma.

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