KR20050006622A - Novel Whitening Agents and Cosmetic Formulations containing them - Google Patents

Abstract

PURPOSE: Provided are a novel skin whitening agent which inhibits tyrosinase activity and melanogenesis and a cosmetic composition containing the same as an active ingredient. CONSTITUTION: The novel skin whitening agent contains a compound manufactured by binding glucose to the phenol derivative and represented by the formula(I), wherein R1 and R2 are independently hydrogen, glucose, galactose, mannose, sucrose, ribose, fructose, provided that one of R1 and is hydrogen; and R3 is one of hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl and butoxycarbonylmethyl.

Description

Novel Whitening Agents and Cosmetic Formulations containing them

The present invention relates to a skin lightening agent having a significant melanin production inhibitory effect by tyrosinase activity inhibition and a composition containing the same, more specifically, a compound in which a sugar is bound to a phenol derivative represented by the following general formula (I), and Or salts thereof and compositions containing at least one thereof.

(I)

Wherein R ₁ and R ₂ are each hydrogen, glucose, galactose, mannose, sucrose, ribose, fructose and the like and _one of R ₁ and R ₂ is hydrogen. R ₃ is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, carboxymethyl, It is characterized in that it is one of methoxycarbonyl methyl, ethoxycarbonyl methyl, poroxycarbonyl methyl, isopropoxycarbonyl methyl, butoxycarbonyl methyl.

The present invention also relates to a process for the preparation of linking sugars to said compounds.

Skin is a very important tissue that has direct contact with the external environment, protects the human body and has biochemical and physical functions. This tissue is largely divided into three parts: the epidermis, the dermis, and the hypodermis. Melanin is a black pigment produced in the epidermis and is produced in cells called melanocytes. Melanin absorbs the light energy of sunlight UV and protects cells deeper from UV damage. However, abnormally low production of melanin causes skin lesions such as vitiligo, and on the contrary, excessive synthesis of melanin by UV rays not only damages the skin, but also forms spots and freckles. Sometimes.

The above-described whitening action is described in detail. Skin has many important functions. Among them, the typical one is the function of producing melanin normally to protect the body from ultraviolet rays of sunlight. Melanin is produced from melanocytes, a kind of skin cells, and has a natural screening function that is distributed on the surface of the skin and blocks ultraviolet rays harmful to the human body. Underlying melanogenesis is an enzyme called tyrosinase that is synthesized in melanocytes. Tyrosinase generates dopaquinone via dopa (DOPA) using an amino acid called tyrosine as a substrate, and melanin, which is a black pigment, is produced by several stages of oxidative condensation reaction from dopaquinone. Ascorbic acid (Japanese Patent Application Laid-Open No. 4-9320), hydroquinone (Japanese Patent Application Laid-Open No. 6-192062), kojic acid (Japanese Patent Application Laid-Open No. 56-7710), arbutin (Japanese Patent Application Laid-Open No. 4-9315), and some extracts have already been shown to inhibit tyrosinase activity. Although it has been used as a whitening cosmetics, the stability in the prescription system is poorly degraded and colored, or its use is limited due to the occurrence of off-flavor, efficacy at the biological level, unclear effect and safety problems. And the inhibitory effect of tyrosinase has been demonstrated, but the effect is low in experiments similar to the actual biologic level. Therefore, the inhibitory effect of the melanoma cell culture similar to the biological level is required. In addition, hydroquinone has been banned because it is defined as a carcinogenic substance. Recently, kojic acid was found to be inducing liver cancer as a result of animal testing. In addition, kojic acid and ascorbic acid have the disadvantage that it is difficult to be formulated as a cosmetic raw material because of poor stability against light, heat, and pH. Occurs. Therefore, in the present invention, in order to improve these disadvantages, a phenolic glycoconjugate that inhibits tyrosinase activity was synthesized, the whitening activity was tested, and a cosmetic composition containing them was prepared.

Accordingly, an object of the present invention is to provide a compound and / or salt thereof in which a sugar is bound to a phenol derivative having a significant melanin production inhibitory effect by tyrosinase activity inhibition represented by formula (I) by an organic synthesis method. It is.

Still another object of the present invention is to prepare a cosmetic composition containing a composition comprising a compound in which a sugar is bound to a phenol derivative represented by the general formula (I), and / or salts thereof, thereby whitening the skin. It is to provide a cosmetic composition showing.

Another object of the present invention is to provide a compound in which a sugar is bound to a phenol derivative represented by the general formula (I) and / or a method for producing a salt thereof.

Methyl gentiate of formula (1) and glucopyranose pentaacetate of formula (2) shown in the following chemical formula (1) using triethylamine as boron trifluoride diethyl ether and a base And reacted with 3- (methoxycarbonyl) -4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside of formula (3) Synthesized. The position of methyl gentiate was all substituted with beta position with respect to the sugar ring, and it was confirmed by NMR analysis that only the hydroxyl group at position 5 of the hydroxyl group of methyl gentiate was bound. 3- (methoxycarbonyl) -4-hydroxyphenyl-beta-D-glucopyranoside of formula (4) is obtained by hydrolysis of the compound of formula (3) using sodium methoxide as a base catalyst 3- (carboxylic acid) -4-hydroxyphenyl-beta-D-glucopyranoside of formula (5) was obtained by hydrolyzing the compound of formula (3) using sodium hydroxide as a strong base catalyst. Could.

Wherein Ac is an acyl group.

Chemical Reaction Formula (1)

To 2,5-dihydroxyphenyl acetic gamma-lactone of formula (6) shown in chemical formula (2), glucopyranose pentaacetate of formula (2) and boron trifluoride diethyl ether as a Lewis catalyst 3-acetic-gamma-lactone-4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta- of formula (7) using triethylamine as base D-glucopyranoside was synthesized. The positions of 2,5-dihydroxyphenyl acetic gamma-lactone of formula (7) were all substituted with beta positions with respect to the sugar ring, and in the case of 2,5-dihydroxyphenyl acetic gamma-lactone, a hydroxyl group Since there is only one, the position of the hydroxyl group connected to the sugar is set to 4. 3- (methoxyacetyl) -4-hydroxyphenyl-beta-D-glucopyranoside of formula (8) is 3-acetic-gamma-lactone-4-hydroxyphenyl-2 of formula (7) ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside was hydrolyzed using sodium methoxide as the base catalyst.

Where Ac is an acyl group.

Chemical reactions (2)

In the monomethoxyhydroquinone of formula (9) shown in the following chemical formula (3), ribopyranose tetraacetate of the formula (10) is used as a Lewis catalyst boron trifluoride diethyl ether as a base and triethylamine 4- (acetoxyphenyl) -2 ', 3', 5'-tri-O-acetyl-beta-ribofuranoside of (11) was synthesized in the following chemistry. The position of the monomethoxyhydroquinone was all substituted with beta position relative to the sugar ring. In the case of using hydroquinone, a monomethoxy hydroquinone in which one hydroxyl group is protected is used to rule out two glucose groups. 4-hydroxyphenyl-beta-D-ribofuranoside of formula (12) is 4- (acetoxyphenyl) -2 ', 3', 5'-tri-O-acetyl-beta of formula (11) -Ribofuranoside could be obtained by hydrolysis using the base catalyst sodium methoxide.

Where Ac is an acyl group.

Chemical reaction formula (3)

To methylhydroquinone of formula (13) shown in the following chemical formula (4), glucopyranose pentaacetate of formula (2) was used as a Lewis catalyst using boron trifluoride diethyl ether of formula (14) Methyl-4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside was synthesized. The position of methylhydroquinone was all substituted with beta position with respect to the sugar ring, and it was confirmed by NMR analysis that only the hydroxyl group at position 5 of the hydroxyl group of methylhydroquinone was bound. 3- (Methyl) -4-hydroxyphenyl-beta-D-glucopyranoside of formula (15) is 3-methyl-4-hydroxyphenyl-2 ', 3', 4 'of formula (14) The 5'-tetra-O-acetyl-beta-D-glucopyranoside was hydrolyzed using sodium methoxide as the base catalyst.

Wherein Ac is an acyl group.

Chemical reactions (4)

As the organic acid used as the catalyst of the present invention, paratoluenesulfonic acid, benzenesulfonic acid, etc. may be used, and as Lewis acid, tin tetrachloride, boron trifluoride, boron trichloride, zinc chloride, iron trichloride, trimethylsilyl trifluoro Boric trifluoride is advantageous for use with Lewis acids such as methanesulfonate, phosphoryl chloride, aluminum chloride and mixtures thereof. The amount used may be 0.01-4 equivalents, but preferably 1-2 equivalents.

As the base used with the Lewis acid catalyst of the present invention, organic bases such as triethamine, tributyamine, pyridine, and lutidine, as well as inorganic bases such as potassium carbonate and sodium carbonate, and these organic and inorganic bases may be mixed and used. Do. 0.01-4 equivalent can be used as a usage-amount, It is preferable to use 0.5-2 equivalent.

As the solvent, toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether and a mixture of these solvents may be used. The reaction temperature is between room temperature and 100 ° C, preferably from room temperature to 40 ° C.

As the hydrolysis catalyst, sodium methoxide, sodium ethoxide, potassium tert-butylate, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium hydroxide, potassium hydroxide, anion exchange resin, and a mixed catalyst thereof are also possible. The hydrolysis reaction solvent may be water, methanol, ethanol, propanol, acetonitrile, tetrahydrofuran, dioxane and a mixed solvent thereof. The reaction temperature is between reflux conditions at room temperature and up to 80 ° C at room temperature. After completion of the hydrolysis reaction, the reaction solution is neutralized with cation exchange resin or formic acid, acetic acid and mixtures thereof, followed by water, methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, ethyl acetate, hexane or mixtures thereof. It recrystallized using the solvent and obtained the compound which couple | bonded sugar with the phenol derivative represented by General formula (1), and / or its salt.

The invention is illustrated in detail by the following examples. However, the following examples are only for illustrating the present invention and the contents of the patent are not limited to the examples.

Example 1.

Synthesis of 3- (methoxycarbonyl) -4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (2006.01)

Methyl 2,5-dihydroxy benzoate (1.68 g, 0.01 mol) and beta-D-glucopyranose pentaacetate (3,9 g, 0.01 mol) were dissolved in 30 mL of dried dichloromethane, followed by stirring at room temperature for 10 minutes. It was stirred for 48 hours. After completion of the reaction, 40 mL of water and 20 mL of dichloromethane were added for extraction. The organic layer was dried over anhydrous MgSO ₄ , filtered, evaporated under reduced pressure, and recrystallized with ethanol. Yield: 55%, mp: 94 ~ 96 ℃. ¹ H-NMR (200 MHz, CDCl ₃ , ppm) 2.1 (q, 12H), 3.90 (s, 3H), 4.10-4.40 (m, 2H), 6.90 (d, 1H), 7.17 (m, 1H), 7.42 (s, 1H), 10.5 (s, 1H)

Example 2.

Synthesis of 3- (methoxycarbonyl) -4-hydroxyphenyl-beta-D-glucopyranoside (2006.01)

Methanol in 3- (methoxycarbonyl) -4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (2.7 g, 5.4 mmol) 50 mL and 0.01 g of sodium methoxide were added thereto, and the mixture was refluxed for 6 hours. After completion of the reaction, the mixture was neutralized with 0.01N hydrochloric acid, evaporated, and recrystallized with ethanol. Yield: 65%, mp: 148 ~ 150 ℃. ¹ H-NMR (200 MHz, D ₂ O, ppm) 3.30-3.50 (m, 4H), 3.65 (s, 3H), 3.60-3.90 (m, 2H), 4.60-4.80 (d, 1H), 6.55 (d , 1H), 7.00 (q, 1H), 7.13 (d, 1H)

Example 3.

Synthesis of 3- (carboxylic acid) -4-hydroxyphenyl-beta-D-glucopyranoside (2006.01)

3- (methoxycarbonyl) -4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (4.2 g, 8.4 mmol) After dissolving in 40mL, sodium hydroxide (1.08g, 28.88mmol) dissolved in 10mL of water was added and refluxed for 12 hours. After completion of the reaction, the mixture was neutralized with 0.01 N hydrochloric acid, evaporated under reduced pressure, and recrystallized with isopropyl alcohol / hexane. Yield: 44%, mp: 178-180 ° C

¹ H-NMR (200 MHz, D ₂ O, ppm) 3.33-3.42 (m, 4H), 3.55-3.63 (m, 1H), 3.75-3.81 (m, 1H), 4.83-4.86 (d, 1H), 6.76 -6.80 (d, 1H), 7.12-7.17 (q, 1H), 7.41 (s, 1H)

Example 4.

Synthesis of 3-acetic-gamma-lactone-4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (7)

Dissolve 2,5-dihydroxy phenylacetic gamma-lactone (1.5 g, 0.01 mol) and beta-D-glucopyranose pentaacetate (3.9 g, 0.01 mol) in 30 mL of dried dichloromethane and for 10 minutes at room temperature After stirring, triethylamine (2 g, 0.02 mol) and boron trifluoride diethyl ether (5.62 g, 0.04 mol) were slowly added, followed by stirring at room temperature for 48 hours. After completion of the reaction, 40 mL of water and 20 mL of dichloromethane were added for extraction, and the organic layer was dried by filtration with anhydrous MgSO ₄ , evaporated under reduced pressure, and recrystallized from hexane / ethanol. Yield: 45%, mp: 182-184 ° C. 1 H-NMR (200 MHz, CDCl ₃ , ppm) 2.10 (q, 12H), 3.70 (s, 2H), 3.70-3.90 (m, 1H), 4.10-4.40 (m, 2H), 5.00 (d, 1H), 5.10-5.40 (m, 3 H).

Example 5.

Synthesis of 3- (methoxyacetyl) -4-hydroxyphenyl-beta-D-glucopyranoside (8)

Methanol in 3-acetic-gamma-lactone-4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (2.16 g, 4.5 mmol) 50 mL was added, and 0.01 g of sodium methoxide was added thereto while stirring to reflux for 6 hours. After completion of the reaction, the mixture was neutralized with 0.01 N hydrochloric acid, evaporated under reduced pressure, and recrystallized with ethyl acetate / ethanol. Yield: 50%, mp: 154-156 ° C. ¹ H-NMR (200 MHz, D ₂ O, ppm) 3.40-3.70 (m, 3H), 3.70 (s, 4H), 3.70-4.00 (m, 2H), 6.80-7.10 (m, 3H).

Example 6.

Synthesis of 4- (acetoxyphenyl) -2 ', 3', 5'-tri-O-acetyl-beta-ribofuranoside (11)

Monoacetylhydroquinone (1.54 g, 0.01 mol) and beta-D-ribofuranose 1,2,3,5-tetraacetate (3.18 g, 0.01 mol) were dissolved in 30 mL of dried dichloromethane, followed by stirring at room temperature for 10 minutes. Triethylamine (2 g, 0.02 mol) and boron trifluoride diethyl ether (5.62 g, 0.04 mol) were added slowly and stirred for 48 hours at room temperature. After completion of the reaction, 40 mL of water and 20 mL of dichloromethane were added for extraction. The organic layer was dried over anhydrous MgSO ₄ , filtered, evaporated under reduced pressure, and recrystallized with ethyl acetate / hexane. Yield 35%, mp 64-66 ° C. ¹ H-NMR (200MHz, CDCl ₃ , ppm) 1.95 (s, 3H), 2.10 (s, 3H), 2.15 (s, 3H), 2.30 (s, 3H), 4.00-4.10 (m, 1H), 4.35 -4.50 (m, 2H), 5.45-5.55 (m, 2H), 5.60 (s, 1H), 7.00 (s, 4H).

Example 7.

Synthesis of 4-hydroxyphenyl-beta-D-ribofuranoside (12)

To 4- (acetoxyphenyl) -2 ', 3', 5'-tri-O-acetyl-beta-ribofuranoside (1.43 g, 3.5 mmol), add 50 mL of methanol and 0.01 g of sodium methoxide for 6 hours. It was refluxed. After completion of the reaction, the mixture was neutralized with 0.01 N hydrochloric acid, evaporated under reduced pressure, and recrystallized with isopropyl alcohol. Yield: 75%, mp: 155-156 ° C. ¹ H-NMR (200 MHz, D ₂ O, ppm) 3.50-3.60 (m, 2H), 3.70-4.10 (m, 3H), 4.70 (t, 1H), 5.00 (d, 1H), 5.25 (s, 2H ), 6.60-6.90 (q, 4H).

Example 8.

Synthesis of 3- (methyl) -4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (14)

Methylhydroquinone (4.47 g, 0.036 mol) and beta-D-glucopyranose pentaacetate (11.7 g, 0.03 mol) were dissolved in 20 mL of dried isopropyl ether, followed by stirring for 10 minutes at room temperature, followed by boron trifluoride diethyl ether ( 6.38 g, 0.045 mol) was added slowly and stirred at room temperature for 24 hours. After completion of the reaction, isopropyl ether was evaporated under reduced pressure, 60 mL of water and 50 mL of dichloromethane were added for extraction, and the organic layer was extracted with saturated sodium bicarbonate, followed by 60 mL of water. The organic layer was taken up, evaporated under reduced pressure, and recrystallized from ethanol. Yield: 16%, mp: 112-114 ° C. ¹ H-NMR (200 MHz, CDCl ₃ , ppm) 2.05-2.08 (t, 12H), 2.15 (s, 3H), 4.20-4.33 (m, 2H), 6.80 (s, 2H), 6.91 (d, 1H) .

Example 9.

Synthesis of 3- (methyl) -4-hydroxyphenyl-beta-D-glucopyranoside (15)

3-Methyl-4-hydroxyphenyl-2 ', 3', 4 ', 5'-tetra-O-acetyl-beta-D-glucopyranoside (16 g, 0.035 mol) was dissolved in 50 mL methanol and sodium methoxide 0.01 g was added and refluxed for 6 hours. After completion of the reaction, the mixture was neutralized with 0.01 N hydrochloric acid, evaporated under reduced pressure, and recrystallized with ethanol. Yield: 60%, mp: 218-220 ° C.

¹ H-NMR (200 MHz, D ₂ O, ppm) 2.11 (s, 3H), 3.34-3.42 (m, 4H), 3.55-3.63 (m, 1H), 3.75-3.81 (m, 1H), 4.84-4.91 (m, 1H), 6.78-6.87 (m, 2H), 6.95-7.00 (d, 1H)

Experimental Example 1.

Inhibitory Effect of Tyrosinase

Inhibitory activity of tyrosinase is generally measured by spectroscopic methods, and in this experiment was measured by Vanni et al. Mix 1.0 mL of L-tyrosine (0.3 mg / mL), 1.0 mL of phosphate buffer (pH 6.8, 0.1 M), and 0.1 mL of 1250 U / mL tyrosinase, and then add 0.2 mL of sample solution to each concentration. The enzyme reaction was carried out for 10-20 minutes at 37 ℃. The absorbance of the reaction solution was measured at 475 nm, and the enzyme inhibitory activity of the sample was obtained according to the following equation, and the value that inhibited 50% of the enzyme activity was represented by IC ₅₀ . Table 1 shows the results.

Tyrosinase Inhibition Rate (%) = [(A-B) / A] × 100

A: Absorbance at 475 nm of reaction solution without sample

B: absorbance at 475 nm of the reaction solution to which the sample was added

Table 1. Inhibitory effect of tyrosinase activity of compounds 4, 5, 8, 12 and 15

compound IC ₅₀ (μg / ml) Arbutin 95 4 > 300 5 > 1000 8 > 300 12 92 15 > 1000

Experimental Example 2.

Determination of Melanin Biosynthesis Inhibition in B16 Melanoma Cells

Melanogenesis inhibitory function was assayed at the cellular level through melanocyte culture. B16 melanoma cells were incubated for 10 days in 10% bovine melanoma cells in the presence of 5% carbon dioxide until the 1.0 × 10 ⁸ cells / T25 flask. Then, the samples were added by concentration and incubated for 2 days in the presence of 5% carbon dioxide. Thereafter, trypsin was added to collect the cells, and the degree of cell blackening was observed. Melanin was quantified by measuring the absorbance at 475 nm, taking the supernatant of the T25 flask discharged and melanin, and the number of cells was mixed in a ratio of collected cells: tryptophan blue = 1: 9 and observed under a microscope By counting the amount of melanin produced per unit cell was shown an inhibitory effect in%. The experimental results are shown in Table 2.

Table 2. Melanin Biosynthesis Inhibitory Effects of Compounds 4, 5, 8, 12, and 15

compound Concentration (μg / ml) Melanin production inhibition rate (%) Control 0 0.00 Arbutin 10 5.61 50 16.10 100 20.20 4 10 4.00 50 20.70 100 18.10 5 10 5.10 50 12.30 100 15.10 8 10 1.50 50 7.70 100 8.70 12 10 5.60 50 25.00 100 36.06 15 10 4.80 50 8.10 100 12.00

Prescription Example 1.

Prescription examples of the flexible lotion (skin) in the cosmetic containing the compound of formula (4) are as follows.

Raw material Weight part Compound of formula (4) 1.0 glycerin 3.0 Butylene Glycol 2.0 Propylene glycol 2.0 Carboxy Vinyl Polymer 0.1 ethanol 10.0 Triethanolamine 0.1 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Prescription Example 2.

Prescription examples of nutritional longevity (lotion) in cosmetics containing the compound of formula (5) are as follows.

Raw material Weight part Compound of formula (5) 2.0 Beeswax 4.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 Liquid paraffin 5.0 Squalane 5.0 Caprylic / Capric Triglycerides 5.0 glycerin 3.0 Butylene glycol 3.0 Propylene glycol 3.0 Carboxy Vinyl Polymer 0.1 Triethanolamine 0.2 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Prescription Example 3

Prescription examples of nutritional creams in cosmetics containing the compound of formula (5) are as follows.

Raw material Weight part Compound of formula (5) 5.0 Beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 Liquid paraffin 10.0 Squalane 5.0 Caprylic / Capric Triglycerides 5.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Prescription Example 4.

A prescription example of a massage cream in cosmetics containing the compound of formula (8) is as follows.

Raw material Weight part Compound of formula (8) 1.0 Beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprylic / Capric Triglycerides 4.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Prescription Example 5.

Prescription examples of packs in cosmetics containing the compound of formula (12) are as follows.

Raw material Weight part Compound of formula (12) 2.0 Polyvinyl alcohol 13.0 Sodium Carboxymethylcellulose 0.2 Allantoin 0.1 ethanol 5.0 Nonylphenyl Ether 0.3 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Prescription Example 6

Prescription examples of emulsified foundations in cosmetics containing the compound of formula (15) are as follows.

Raw material Weight part Compound of Formula (15) 2.0 Beeswax 2.0 Pyromethicone 2.0 Liquid paraffin 5.0 Squalane 5.0 Stearic acid 2.0 Caprylic / Capric Triglycerides 4.0 glycerin 4.0 Propylene glycol 3.0 Butylene glycol 3.0 Triethanolamine 1.0 Aluminum Magnesium Silicate 0.5 Pigment 12 antiseptic a very small amount Pigment a very small amount Spices a very small amount Purified water Remaining amount

Since the compounds prepared by the present invention and their salts have tyrosinase inhibitory activity and skin melanin pigmentation inhibitory effect, it can be added as an active ingredient of the whitening cosmetic to provide a whitening cosmetic showing the skin whitening effect.

Claims (14)

Skin whitening agent which consists of a compound which couple | bonded sugar with the phenol derivative of the following general formula (I), or its salt. Wherein R ₁ and R ₂ are each selected from hydrogen, glucose, galactose, mannose, sucrose, ribose, fructose and only one of R ₁ and R ₂ is hydrogen, R ₃ is hydrogen, hydroxy, methyl, ethyl, propyl, Isopropyl, Butyl, Isobutyl, Pentyl, Carboxy, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Isopropoxycarbonyl, Carboxymethyl, Methoxycarbonylmethyl, Ethoxycarbonylmethyl, Poroxy Carbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl. Methyl gentiate, 2,5-dihydroxyphenyl acetic gamma-lactone, monomethoxyhydroquinone or methylhydroquinone and glucopyranose pentaacetate or ribopyranose tetraacetate as the reaction catalyst alone or with organic acid or Lewis acid The sugar is bound to the phenol derivative of claim 1, wherein the organic acid and the base or the Lewis acid and the base are used at the same time, and reacted for 3-72 hours in the range of -20 to 100 ° C. in the presence of an organic solvent. Method for preparing the compound. The method of claim 2, wherein the organic solvent is toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, diisopropyl At least one mixed solvent selected from the group consisting of ether, diethyl ether. The organic acid of claim 2 or 3, wherein the organic acid is paratoluenesulfonic acid or benzenesulfonic acid, and Lewis acid is tin tetrachloride, boron trifluoride, boron trichloride, zinc chloride, iron trichloride, trimethylsilyltriple. And one or two or more mixtures selected from the group consisting of rocromethanesulfonate, phosphoryl chloride, aluminum chloride. The method according to claim 4, wherein the amount of the organic acid used is 0.01-4 equivalents to the sugar compound used. 5. The method according to claim 4, wherein the amount of Lewis acid used is 0.01-4 equivalents to the sugar compound used. 3. The method according to claim 2, wherein the base is one or a mixture of two or more selected from the group consisting of triethylamine, tributylamine, pyridine, organic bases of rutidine and inorganic bases of potassium carbonate and sodium carbonate. 8. A method according to claim 7, wherein the amount of base used is 0.01-4 equivalents to the sugar compound used. Wherein said hydrolysis is carried out for 3 to 24 hours in the range of -20 to 100 DEG C in the presence of water, an organic solvent or a mixed solvent thereof using 0.01-4 equivalents of a base as a reaction catalyst. 10. The method of claim 9, after the completion of the hydrolysis reaction, the reaction solution is neutralized with a cation exchange resin or formic acid, acetic acid and mixtures thereof and then water, methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, ethyl Obtained by recrystallization using acetate, hexane or a mixed solvent thereof. 10. The hydrolysis catalyst according to claim 9, wherein the hydrolysis catalyst is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium tertiary butyrate, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, calcium hydroxide, potassium hydroxide, anion exchange resin. 1 or 2 or more mixtures selected. The method of claim 9, wherein the hydrolysis solvent is one or two or more mixtures selected from the group consisting of water, methanol, ethanol, propanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide Characterized in that the method. A cosmetic composition comprising at least one compound or a salt thereof in which a sugar is bound to a phenol derivative represented by the general formula (I) of claim 1. The cosmetic composition according to claim 13, wherein the cosmetic composition has a formulation of lotion, nutrition lotion, nutrition pack, nutrition cream, massage cream, nutrition essence, or emulsified foundation.