KR20040076112A - Whitening composition for external application to the skin containing hydroxy pyranone derivatives - Google Patents

Abstract

PURPOSE: A skin whitening composition for external application containing hydroxy pyranone derivatives having inhibitory activities against tyrosinase and skin whitening efficacy is provided. It is effective in inhibiting the formation of unwanted skin pigmentation. CONSTITUTION: The skin whitening composition for external application contains hydroxy pyranone derivatives represented by the formula 1. In formula, R1 is -CH2- or -CH2CH2-, R2 is -C(O)OCH2-, -CH=CHC(O)OCH2- or -CH=CH-. The hydroxy pyranone derivatives are characterized in that it inhibits tyrosinase activity or melanin formation. For an example, 50g 5-hydroxy-2-(hydroxymethyl)-4H-pyrane-4-one is melted in 250ml N,N-dimethylformamide and added with 50ml thionyl chloride after cooling. It is agitated for 2hr at room temperature, filtered and melted in 1,000ml ethyl acetate to produce 39.5g 5-hydroxy-2-(chloromethyl)-4H-pyrane-4-one(70%).

Description

Whitening composition for external application to the skin containing hydroxy pyranone derivatives}

The present invention relates to an external preparation composition for skin whitening containing a hydroxy pyranone derivative, more specifically, a compound represented by the following general formula (1), which inhibits the activity of tyrosinase that promotes melanin synthesis and inhibits melanin production. As a result, the present invention relates to an external preparation for skin whitening containing a hydroxy pyranone derivative having an effect of skin whitening as an active ingredient.

[Formula 1]

Wherein R ₁ is -CH ₂ -or -CH ₂ CH _2- , and R ₂ is -C (O) OCH _2- , -CH = CHC (O) OCH ₂ -or -CH = CH- .)

Recently, skin pigmentation abnormalities are steadily increasing due to the aging population, increased exposure to ultraviolet light due to an increase in leisure population, increased social stress, and destruction of the ozone layer due to environmental pollution. Accordingly, the interest in skin whitening is increasing day by day, the demand for materials that are bio-friendly and high whitening activity is increasing.

In Korea, research on this has been actively conducted, and as a result, more than 40 drugs for treating skin pigmentation have been developed, and a lot of cosmetics having a whitening effect have been developed as whitening products.

Human skin color depends on the amount of melanin, carotene and hemoglobin, in particular melanin acts as a decisive factor. Melanin is synthesized from melanocytes, which are pigment cells in the basal layer of the skin epidermis, and transferred to the surrounding keratinocytes (keratinocytes). Melanin in the epidermal layer, which is the outer skin of the skin, acts as a sunscreen to protect the skin organs under the dermis and to capture free radicals generated in the skin. Play a useful role in protecting them. However, melanin, produced by internal and external stress stimuli, is a stable substance that does not disappear until it is released to the outside through skin keratinization even when stress disappears. It is a problem.

Looking at the synthesis process of melanin in vivo, melanin is known to be produced through a polymerization oxidation process catalyzed by enzymes such as tyrosinase (tyrosinase) based on tyrosine or dopa (DOPA) as a substrate. In addition, melanin production is increased when free radical generation is increased, an inflammatory reaction, or stimulation such as ultraviolet rays is applied to the skin.

Examples of substances that inhibit the formation of melanin include polyhydroxyphenol compounds such as phenol, catechol, resorcinol, and hydroquinone, ascorbic acid and 5-hydroxy-2- (hydroxymethyl) -4H. -Pyran-4-one and the like are known. The polyhydroxy compound inhibits the activity of tyrosinase by an antioxidant effect, and has a positive effect of inhibiting enzyme activity, but has a disadvantage such as irritation or toxicity when applied to the skin. In addition, natural plant extracts such as ascorbic acid derivatives, baekbaekpi, aloe and licorice, which are mainly used in the cosmetics industry, are not sufficient for their whitening effect alone, and most of these substances have reductive properties. In addition to the unstable in the phase, when applied to cosmetic formulations for long-term storage it is unstable, there is a problem in terms of stability, such as the whitening effect is reduced or discoloration is required to develop a more excellent whitening agent.

In particular, hydroquinone, a melanin-producing substance used mainly for whitening in the pharmaceutical field, cannot be used except for pharmaceuticals due to its high skin toxicity. Since it causes severe skin irritation such as causing, there is a problem in terms of stability to apply to the skin as it is.

Therefore, the important thing in the development of a new whitening agent is to develop a material that is excellent in whitening activity and at the same time biocompatible and stable even for long-term storage. Synthesis is an important technical issue.

Substances that can be used as inhibitors of tyrosinase activity include 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one, vitamin C, arbutin and the like.

Among them, particularly 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one is known as a compound showing relatively low cytotoxicity with an inhibitory effect on tyrosinase activity. The reason for such low cytotoxicity is that the mechanism of inhibiting tyrosinase activity of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one is not due to antioxidant activity, but kills against copper ions contained in tyrosinase. This is due to the conversion, which is the effect of the 5-hydroxy group and the carbonyl group of the pyran structure.

For this reason, there is an urgent need for the development of a substance having an inhibitory effect on tyrosinase activity while maintaining low cytotoxicity of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one.

In order to solve the problems of the whitening agent as described above and to develop a whitening substance which is safe and excellent in the whitening effect by applying to the skin, the present inventors are known as 5-hydroxy-2- (hydroxymethyl) widely known as a whitening agent Of -4H-pyran-4-one or 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one derivative (USP, 5523421; Bioorganic & Medicinal chemistry letter , 1996, 6, 1303-1308). 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4 in a very stable state with little irritation on the skin, stable under light irradiation conditions, and no irritation even when applied to human skin in view of its efficacy After the -one derivative was developed, the present invention was completed by identifying the tyrosinase inhibitory effect and the whitening effect of this 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one derivative.

Accordingly, an object of the present invention is to provide a skin whitening method using hydroxy pyranone represented by the following formula (1).

Still another object of the present invention is to provide an external composition for skin whitening containing the hydroxy pyranone component as an active ingredient.

In order to achieve the above object, the present invention is characterized by providing a hydroxy pyranone derivative represented by the following formula (1).

[Formula 1]

Wherein R ₁ is -CH _2- , -CH ₂ CH _2- , and R ₂ is -C (O) OCH _2- , -CH = CHC (O) OCH _2- , -CH = CH- .)

In addition, the present invention is characterized by providing a method for producing a hydroxy pyranone derivative represented by the formula (1). That is, 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one and 3,4-methylene dioxy benzoic acid, 3,4-ethylene dioxy benzoic acid, 3,4-methylene dioxy Process for making ester bonds with cinnamic acid or 3,4-ethylene dioxy cinnamic acid and 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one with 3,4-methylene dioxy benzaldehyde or 3 Provided is a method for linking, 4-ethylene dioxy benzaldehyde by a double bond.

The present invention also provides a novel use of the hydroxy pyranone derivative represented by the formula (1) as a skin whitening agent.

Hereinafter, the present invention will be described in more detail.

The hydroxy pyranone derivative represented by Chemical Formula 1 according to the present invention is a novel skin whitening component, which may be prepared through the following two preparation methods as specific examples below.

The manufacturing method according to method (A) is as follows. First, 5-hydroxy-2- (chloromethyl) -4H in which the hydroxy group of the hydroxy methyl group in 2-position of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one is substituted with a halogen element. Prepare pyran-4-one. Then, benzoic acid or cinnamic acid is reacted with an inorganic base in a polar solvent to prepare a benzoic acid salt or cinnamic acid salt, and then the 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one and There is a method of preparing a hydroxy pyranone derivative by reacting the benzoic acid salt or cinnamic acid salt.

The manufacturing method according to the method (B) is as follows. First, 5-hydroxy-2- (chloromethyl) -4H in which the hydroxy group of the hydroxy methyl group in 2-position of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one is substituted with a halogen element. Prepare pyran-4-one. Then, 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one is reacted with triphenyl phosphine to form a phosphonium salt, and then the phosphonium salt and 3,4- There is a method of preparing hydroxy pyranone derivatives by reacting methylene dioxy benzaldehyde or 3,4-ethylene dioxy benzaldehyde.

In the above two production methods, the halogen element may be bromine, chlorine, or iodine.

The preparation method according to the present invention will be described in more detail through the following scheme.

The production method according to the above method (A) will be described taking the following scheme (1) as an example.

(Wherein R ₁ is —CH ₂ — or —CH ₂ CH ₂ —, and R ₂ is —C (O) OCH ₂ —, —CH═CHC (O) OCH ₂ —.)

The thionyl chloride was used to transform the primary alcohol of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one to chloride, with N, N-dimethylformamide and methylene as solvents. Chloride, chloroform and the like can be used. In addition, in order to convert benzoic acid and cinnamic acid into salts, inorganic bases such as sodium hydroxide and potassium hydroxide may be used, and polar solvents such as methanol, ethanol, dioxane and tetrahydrofuran may be used as the solvent.

As a solvent for reacting the synthesized 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one with the benzoic acid salt or cinnamic acid salt, a solvent such as N, N-dimethylformamide, methylene chloride or chloroform But N, N-dimethylformamide is most preferred. The reaction temperature is most preferably 70 to 110 ° C, and at lower temperatures, 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one, which remains a reactant, is not easy to remove from the reaction product. At temperatures above 110 ° C, the reaction product 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one is decomposed to reduce the yield of the reaction product.

Next, the production method according to the above method (B) will be described taking the following scheme (2) as an example.

(Wherein, R ₁ is -CH ₂ -or -CH ₂ CH _2- , R ₂ is -CH = CH-.)

The phosphonium salt is synthesized by reacting 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one synthesized in the above method (A) with triphenyl phosphine. At this time, methylene chloride, chloroform, dioxane, tetrahydrofuran, benzene, toluene and the like can be used as the solvent.

Ilide is made using a base in the phosphonium salt, and as the base, n-BuLi, sodium methoxide, sodium ethoxide and the like can be used. Ilide and aldehyde produced in this way are reacted to obtain a stilbene compound.

In the above two preparation methods, 5-hydroxy-2- (bromomethyl) -4H-pyran-4-one can be obtained using thionyl bromide in addition to thionyl chloride, and 5-hydroxy-2- ( Chloromethyl) -4H-pyran-4-one can be reacted with sodium iodine or potassium iodine to afford 5-hydroxy-2- (iodsimethyl) -4H-pyran-4-one. Reaction using 5-hydroxy-2- (bromomethyl) -4H-pyran-4-one and 5-hydroxy-2- (iodinemethyl) -4H-pyran-4-one obtained in this manner You can also proceed.

Specific examples of the hydroxy pyranone derivative of the formula (1) obtained by the above production method include Compound 1: (5-hydroxy-4-oxo-4 hydrogen-pyran-2-yl) methyl dihydrogen-benzo [3, 4-d] 1,3-dioxolane-5-carboxylate {(5-Hydroxy-4-oxo-4H-pyran-2-yl) methyl 2H-benzo [3,4-d] 1,3- dioxolan-5-carboxylate}, compound 2: (5-hydroxy-4-oxo-4 hydrogen-pyran-2-yl) dihydrogen, tritium-benzo [3,4-e] 1,4-dioxane- 6-carboxylate {(5-Hydroxy-4-oxo-4H-pyran-2-yl) 2H, 3H-benzo [3,4-e] 1,4-dioxane-6-carboxylate}, compound 3: 2 -((3E) -4 (dihydrogen, tritium-benzo [3,4-d] 1,3-dioxolan-5-yl) -2-oxobut-3-enyloxy) -5-hydroxy- 4-hydrogen-4-pyran-4-one {2-((3E) -4 (2H, 3H-benzo [3,4-d] 1,3-dioxolan-5-yl) -2-oxobut-3-enyloxy ) -5-hydroxy-4H-pyran-4-one}, compound 4: 2-((3E) -4 (dihydrogen, trihydrogen-benzo [3,4-e] 1,4-dioxane-6- Yl) -2-oxobut-3-enyloxy) -5-hydroxy-4hydrogen-pyran-4-one {2-((3E) -4 (2H, 3H-benzo [3,4-e] 1 , 4-dioxan-6-yl) -2-oxo but-3-enyloxy) -5-hydroxy-4H-pyran-4-one}, compound 5: 2-((1E) -2- (dihydrogen, tritium-benzo [3, 4-d] 1,3 -Dioxolane-5-yl) vinyl) -5-hydroxy-4hydrogen-pyran-4-one {2-((1E) -2- (2H, 3H-benzo [3,4-d] 1,3 -dioxolan-5-yl) vinyl) -5-hydroxy-4H-pyran-4-one}, compound 6: 2-((1E) -2- (dihydrogen, tritium-benzo [3,4-e] 1,4-dioxan-6-yl) vinyl) -5-hydroxy-4hydrogen-pyran-4-one {2-((1E) -2- (2H, 3H-benzo [3,4-e] 1,4-dioxan-6-yl) vinyl) -5-hydroxy-4H-pyran-4-one}, etc. are mentioned.

In the present invention, the hydroxy pyranone derivative represented by the formula (1) has the effect of inhibiting the activity of tyrosinase through the enzyme activity experiment, it was found that the action of reducing the content of melanin pigment through the test using skin cells. Clinical trials were conducted to confirm that these in vitro effects were observed when used in real products. As a result, uv deposition induced by UV rays was improved. Through the above results, it can be seen that the external preparation composition for skin containing the hydroxy pyranone derivative according to the present invention inhibits the activity of tyrosinase and reduces melanin production, thereby having a skin whitening effect.

The hydroxy pyranone derivative represented by Formula 1 prepared by the preparation method may be contained as an active ingredient of a drug or an external preparation for skin that has a skin whitening effect. That is, the hydroxy pyranone derivative represented by Formula 1 according to the present invention may be contained as an active ingredient of the external preparation composition for skin whitening. At this time, the hydroxy pyranone derivative is preferably contained in an amount of 0.0001 to 20% by weight based on the total weight of the composition.

The external preparation for skin whitening according to the present invention may further include conventional ingredients which are used as components of the external preparation for skin according to the formulation or purpose of use. That is, the external preparation composition for skin whitening according to the present invention may further contain other existing skin whitening components in addition to the hydroxy pyranone derivatives described above for the skin whitening effect.

The external preparation composition for skin according to the present invention may be formulated into a conventional formulation applicable to the skin, and examples of such formulations include liquid soaps, solids, as well as cosmetics such as lotion, cream, lotion, skin lotion, pack, foundation, etc. It may be formulated with a human cleanser such as soap, facial foam, and the like. Each of these formulations may further contain a variety of bases and additives necessary and appropriate for the formulation of the formulation.

Hereinafter, the preparation method and efficacy of the hydroxy pyranone derivative according to the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Reference Example 1 Preparation of 5-hydroxy-2- (chloromethyl) -4 hydrogen-pyran-4-one

50 g of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one (0.35 mol) was dissolved in 250 ml of N, N-dimethylformamide, cooled in a 10 ° C. ice-water bath and cooled with thionyl chloride. 50 mL (0.42 mol) was added dropwise over 30 minutes. After stirring for 2 hours at room temperature, the stirring solution was added to 2000 ml of ice water. The resulting solid was filtered off and the filtrate was dissolved in 1000 ml of ethyl acetate. Magnesium sulfate and activated carbon were added, dried, decolorized, filtered, and the filtrate was concentrated and nucleic acid was added to obtain crystals. Drying in vacuo gave 39.5 g (70%) of the reaction product, 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one as a yellow solid.

[Reference Example 2] Preparation of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one triphenylphosphoran

30 g (0.18 mol) of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one was dissolved in 500 ml of methylene chloride, and 49 g (0.18 mol) of triphenylphosphine were added thereto for 6 hours. It was refluxed. The reaction proceeded to produce a solid. After the reaction was completed, the resulting solid was filtered to give 63 g (75% yield) of phosphonium salt.

Example 1 Compound 1: (5-hydroxy-4-oxo-4 hydrogen-pyran-2-yl) methyl dihydrogen-benzo [3,4-d] 1,3-dioxolane-5-car Preparation of Cyclate

(5-hydroxy-4-oxo-4hydrogen-pyran-2-yl) methyl dihydrogen-benzo [3,4-d] 1,3-dioxolane-5- according to method (A) described above Carboxylate was prepared.

5 g (0.03 mol) of 3,4-methylene dioxy benzoic acid and 1.8 g (0.45 mol) of sodium hydroxide were dissolved in 40 ml of methanol, and the residue remaining after distilling methanol was dissolved in 70 ml of N, N-dimethylformamide. 4.8 g (0.03 mol) of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one was added thereto, and the mixture was heated and stirred for 2 hours in a 110 ° C oil bath. The solvent was distilled off, the residue was dissolved in 300 ml of ethyl acetate, the ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, and magnesium sulfate and activated carbon were added to dry and decolorize. The insolubles were filtered off and the filtrate was evaporated under reduced pressure to give 5.6 g (65% yield) of the reaction product as an off-white solid. Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 1); R _f = 0.54

1 H NMR (DMSO, δ); 9.43 (S, 1H), 8.16 (S, 1H), 7.69 (d, 1H, J = 8.4 Hz), 7.48 (S, 1H), 7.12 (d, 1H, J = 8.4 Hz), 6.60 (S, 1H ), 6.20 (S, 2H), 5.22 (S, 2H).

Example 2 Compound 2: (5-hydroxy-4-oxo-4hydrogen-pyran-2-yl) dihydrogen, tritium-benzo [3,4-e] 1,4-dioxane-6- Preparation of Carboxylate

The target product (6.2 g, 68%) was obtained as an off-white solid using the same method as Example 1 except for using 3,4-ethylene dioxy benzoic acid instead of 3,4-methylene dioxy benzoic acid. . Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 2); R _f = 0.53

1 H NMR (DMSO, δ); 9.42 (S, 1H), 8.15 (S, 1H), 7.65 (d, 1H, J = 8.4 Hz), 7.49 (S, 1H), 7.10 (d, 1H, J = 8.4 Hz), 6.63 (S, 1H ), 6.18 (S, 2H), 4.27 (S, 2H).

Example 3 Compound 3: 2-((3E) -4 (Dihydrogen, trihydrogen-benzo [3,4-d] 1,3-dioxolan-5-yl) -2-oxobut-3- Preparation of enyloxy) -5-hydroxy-4hydrogen-4-pyran-4-one

The target product (5.8 g, 62%) was obtained as an off-white solid, using the same method as Example 1 except for using 3,4-methylene dioxy cinnamic acid instead of 3,4-methylene dioxy benzoic acid. . Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 4) R _f = 0.50

1 H NMR (DMSO, δ): 9.40 (S, 1H), 8.09 (S, 1H), 7.63 (d, 2H, J = 15.9 Hz), 7.44 (S, 1H), 7.21 (d, 1H, J = 8.47 Hz), 6.95 (d, 1H, 8.4 Hz), 6.61 (d, 1H, J = 15.9 Hz), 6.50 (S, 1H), 6.07 (S, 2H), 5.05 (S, 2H).

Example 4 Compound 4: 2-((3E) -4 (Dihydrogen, Hydrogen-Benzo [3,4-e] 1,4-Dioxan-6-yl)-2-Oxobert-3- Preparation of enyloxy) -5-hydroxy-4hydrogen-pyran-4-one

The target product (5.9 g, 60%) was obtained as an off-white solid using the same method as Example 1 except for using 3,4-ethylene dioxy cinnamic acid instead of 3,4-methylene dioxy benzoic acid. . Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 4); R _f = 0.51

1 H NMR (DMSO, δ); 9.39 (S, 1H), 8.09 (S, 1H), 7.62 (d, 1H, J = 15.9 Hz), 7.16 (S, 1H), 7.02 (d, 1H, J = 8.47 Hz), 6.82 (d, 1H , 8.4 Hz), 6.59 (d, 1H, J = 15.9 Hz), 6.50 (S, 1H), 5.06 (S, 2H), 4.30 (m, 2H).

Example 5 Compound 5: 2-((1E) -2- (Dihydrogen, Hydrogen Tri-benzo [3,4-d] 1,3-dioxolan-5-yl) Vinyl) -5-hydroxy Preparation of -4Hydrogen-Pyran-4-one

2-((1E) -2- (dihydrogen, trihydrogen-benzo [3,4-d] 1,3-dioxolan-5-yl) vinyl) -5-hydride according to the method (B) described above Roxy-4 hydrogen-pyran-4-one was prepared.

20 g (0.047 mol) of phosphonium salt was dissolved in 200 ml of anhydrous tetrahydrofuran, and the reaction solution was cooled to 0 ° C. To this solution was slowly added dropwise 19 ml (0.047 mol) of 2.5 M n-butyllithium solution. After the reaction solution was stirred for an additional 30 minutes, 7 g (0.047 mol) of 3,4-methylene dioxy benzaldehyde was dissolved in 50 ml of anhydrous tetrahydrofuran and slowly added dropwise thereto. After the reaction was completed, the reaction solution was concentrated and 100 ml of ethyl acetate was added to dissolve the reaction mixture. The mixture was washed twice with distilled water, dried over anhydrous forget-me-not, filtered, concentrated and subjected to column chromatography to obtain the target substance (7.2 g, 60%) as an off-white solid. Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 4); R _f = 0.50

1 H NMR (CDCl 3, δ); 9.12 (s, 1H), 8.02 (s, 1H), 7.2.8-7.32 (m, 2H), 7.14 (d, 1H, J = 7.8 Hz), 6.97 (s, 1H), 6.90 (d, 1H, J = 14.5 Hz), 6.41 (s, 1 H), 6.41 (s, 2H).

Example 6 Compound 6: 2-((1E) -2- (Dihydrogen, Hydrogen Tri-benzo [3,4-e] 1,4-dioxan-6-yl) vinyl) -5-hydroxy Preparation of -4Hydrogen-Pyran-4-one

Using the same method as in Example 5, except that 3,4-ethylene dioxy benzaldehyde was used instead of 3,4-methylene dioxy benzaldehyde, the target product (7.8 g, 61%) was obtained as an off-white solid. Thin layer chromatography and nuclear magnetic resonance analysis of the obtained solids are as follows.

TLC (ethyl acetate: hexane = 1: 4); R _f = 0.51

1 H NMR (CDCl 3, δ); 9.10 (s, 1H), 8.02 (s, 1H), 7.29 (d, 1H, J = 16.2 Hz), 7.20 (s, 1H), 7.13 (m, 1H), 6.91 (m, 2H), 6.43 (s , 1H), 4.26 (m, 4H).

[Test Example 1] Tyrosinase activity inhibition experiment

Activity measurements of tyrosinase are described in Pomerantz (Pomerantz, S. (1969) Science 164, 838-839) and Oikawa et al. (Oikawa, AM, Nakayasu, M., Nohara, M., and Tchen, TT (1972) Biochim. Biophys. Acta 148, 548-557). First, Mel-ab cells 2 × 10 ⁴ cells were seeded in a 6 well culture dish, and kojic acid derivatives and kojic acid of compounds 1 to 6 were treated at the concentrations shown in Table 1 and incubated for 24 hours. ^{after, 2Ci [3 H] [3H} ] processes the L- tyrosine ([3H] L-tyrosine), and was further cultured for 24 hours tyrosine ^{/ ㎖ (2 Ci [3 H} ] tyrosine / ㎖). Thereafter, the cell culture was obtained to quantify the amount of ³ H ₂ O, and the results are shown in Table 1.

Test substance Tyrosinase Activity (%) Vehicle 100 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one 300 ppm 85 Compound 1 1 ppm 80 Compound 2 1 ppm 71 Compound 3 1 ppm 55 Compound 4 1 ppm 60 Compound 5 1 ppm 69 Compound 6 1 ppm 82

Through the above results, the hydroxy paranon derivatives of the compounds 1 to 6 exhibited an excellent inhibitor of the tinosinase at a concentration 300 times lower than that of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one. It can be seen that. In particular, the activity of compound 6 was very excellent.

[Test Example 2] Melanin production inhibitory effect in melanin pigment producing cells

The degree of intracellular melanin production of the hydroxy pyranone derivatives 1-6 was measured by Dooley's method. The cell line was a Mel-Ab cell line derived from C57BL / 6 skin pigment cells, the culture was 10% fetal placental serum, 100 nM 12-O-tetradecanoyl Phobol-13-acetate, On DMEM medium containing 1 nM Cholera toxin under 37 ° C., 5% CO ₂ . Cultured Mel-Ab cells were detached with 0.25% Trypsin-EDTA and attached again to the 24-well plate with the same number (1 × 10 ⁵ cells / well) for 2 days to 3 days. Subsequently, hydroxy pyranone derivatives 1 to 6 were replaced with a medium containing 10 ppm each. In addition, to compare the effects of the present invention, experiments were also performed on 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one, which is known as a whitening agent component. After 5 days, melanin contained in the cells was dissolved by treatment with 1N NaOH, and the amount of melanin was measured by measuring absorbance at 400 nm. The results are shown in Table 2 below.

Test substance Melanin production rate (% control) 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one 88.0 Compound 1 67.8 Compound 2 52.2 Compound 3 44.6 Compound 4 48.9 Compound 5 50.0 Compound 6 69.1

From Table 2, it was confirmed that the hydroxy pyranone derivatives of Compounds 1 to 6 were excellent in inhibiting melanogenesis.

Test Example 3 Whitening Effect Test on Human Skin

After attaching an opaque tape with a hole of 1.5 cm in diameter to the upper part of the subject, 12 healthy men were irradiated with ultraviolet rays (UVB) of 1.5 to 2 times the minimum erythema of each subject to blacken the skin. Induced. After ultraviolet irradiation, apply 1% of each of the compounds of the hydroxypyranone derivatives 1 to 6 (using 1,3-butylene glycol: ethanol = 7: 3 as a solvent) for 10 weeks (no one at all) Skin color was measured on a weekly basis with Chromameter CR2002 (Minolta, Japan), and the difference in the "L" value from the untreated part, ie, the degree of increase (ΔL), was evaluated. In addition, application of 3% 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one and vehicle for comparison was also tested. The measurement results are shown in Table 3 below.

Test substance Skin color brightness degree (△ L) Solvent 0.50 ± 0.15 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one 0.99 ± 0.11 Compound 1 1.35 ± 0.25 Compound 2 1.54 ± 0.13 Compound 3 1.70 ± 0.11 Compound 4 1.69 ± 0.18 Compound 5 1.41 ± 0.12 Compound 6 1.22 ± 0.11

From Table 3, the hydroxy pyranone derivatives of Compounds 1 to 6 show a marked increase in the value of skin color brightness compared to 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one, It was confirmed that the whitening effect is excellent.

[Formulation Examples 1 to 6 and Comparative Formulation Example 1]

In order to evaluate the clinical whitening effect in the formulation containing the hydroxy pyranone derivative of the present invention, it was formulated as a cream as shown in Table 4 below. Each formulation first weighed each of groups A, B, and C, and then slowly added A to B, followed by primary emulsification using a homomixer, and then gradually added C, followed by secondary emulsification. Prepared by stirring and cooling.

ingredient weight% Formulation Example 1 Formulation Example 2 Formulation Example 3 Formulation Example 4 Formulation Example 5 Formulation Example 6 Comparative Formulation Example 1 Control (A) Stearyl alcohol 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Polysorbate 60 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Sorbitan sesquioleate 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Liquid paraffin 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Squalane 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 antiseptic 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Triethanolamine 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 (B) glycerin 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 ethanol 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Purified water to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 (C) Carboxy Vinyl Polymer 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Compound 1 1.0 - - - - - - - Compound 2 - 1.0 - - - - - - Compound 3 - - 1.0 - - - - - Compound 4 - - - 1.0 - - - - Compound 5 - - - - 1.0 - - - Compound 6 - - - - - 1.0 - - Kojisan - - - - - - 1.0 - incense Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity

[Test Example 4] Whitening clinical effect

Formulations 1 to 6 containing hydroxy pyranone derivatives and 5-hydroxy-2- (chloromethyl) -4H, a known whitening agent, were used in 80 subjects with pigmentation such as blemishes on the face. Comparative Formulation Example 1 containing pyran-4-one was applied to the spot of the face for 3 months, once each morning and evening. In addition, as a control, the formulation containing only the solvent was evaluated.

<Evaluation method>

The improvement degree of pigmentation after using the said formulation was judged according to the following criteria, and the result which averaged the judgment value of ten users is shown in Table 4 below.

-Excellent effect (3): Pigmentation is hardly noticeable.

-Effective (2): Pigmentation is very soft.

-Slightly effective (1): Pigmentation is softened.

-No effect (0): No change.

Test substance Whitening effect judgment mean Control 0.4 ± 0.12 Comparative Formulation Example 1 1.4 ± 0.21 Formulation Example 1 1.7 ± 0.22 Formulation Example 2 2.4 ± 0.18 Formulation Example 3 2.2 ± 0.13 Formulation Example 4 1.7 ± 0.17 Formulation Example 5 2.1 ± 0.15 Formulation Example 6 1.6 ± 0.19

From the above Table 5, in the case of the cosmetic containing the present invention hydroxy pyranone derivative, it was confirmed that exhibits an excellent whitening effect.

As described above, since the hydroxy pyranone derivatives according to the present invention have an excellent effect of inhibiting the production of melanin, it is a very useful invention in the cosmetic or pharmaceutical manufacturing industry for improving the pigmentation of the skin by containing it.

Claims (2)

The external preparation composition for skin whitening which contains the hydroxy pyranone derivative represented by following General formula (1). [Formula 1] Wherein R ₁ is -CH ₂ -or -CH ₂ CH _2- , and R ₂ is -C (O) OCH _2- , -CH = CHC (O) OCH ₂ -or -CH = CH- .) The external preparation composition for skin whitening according to claim 1, wherein the hydroxy pyranone derivative inhibits tyrosinase activity or inhibits melanin production.