KR100294946B1 - Gallic acid derivatives and whitening cosmetic compositions containing the same - Google Patents

Abstract

The present invention relates to a molar asset derivative represented by the following general formula (I) and a whitening cosmetic composition comprising the same as an active ingredient.

(Ⅰ)

Wherein R 1 is a C _1-16 alkoxy group,

R 2 is a C _1-16 alkyl, alkenyl, C _1-16 alkyl group substituted with an aromatic ring,

X is NH or S.

Description

Malic acid derivatives and whitening cosmetic compositions containing the same

The present invention relates to a molar asset derivative represented by the following general formula (I) and a whitening cosmetic composition comprising the same as an active ingredient.

(Ⅰ)

Wherein R 1 is a C _1-16 alkoxy group,

R 2 is a C _1-16 alkyl, alkenyl, C _1-16 alkyl group substituted with an aromatic ring,

X is NH or S.

Human skin color is complexly determined by red blood cells, carotene and melanin in the blood, but differences in race skin color, hyperpigmentation such as blemishes and freckles are influenced by melanin. Melanin exists in the epidermal layer, which is the outer skin of the skin, and acts as a sunscreen to protect skin organs under the dermis and also to protect free radicals generated in the skin and to protect proteins and genes in the skin. Do it. However, melanin produced by internal and external stress stimulus does not disappear until it is released to the outside through skin keratinization even if the stress disappears. The production of melanin in vivo is a polymerization oxidation process catalyzed by an enzyme such as tyrosinase using tyrosine or dopa as a substrate, leading to the generation of free radicals in the skin or an inflammatory reaction. When there is, or when subjected to ultraviolet light, melanin production is increased. In particular, ultraviolet rays may increase the production of melanin, causing melanin, which is partially increased, to develop blemishes, resulting in undesired results, or even worse, inducing skin cancer.

Therefore, many melanogenesis inhibitors such as kojic acid, arbutin, glutathione, vitamin A, vitamin C, and hydroquinone have been developed under the name of a whitening agent, and ointments, creams, and lotions containing them are commercially available, but their effects are unstable. It is difficult to sustain, severe skin irritation is restricted to use, and the whitening action is not strong enough to be satisfied.

The present inventors have been trying to develop a safe and excellent whitening effect, found that the derivatives of the malic acid compound synthesized with a molar compound known as an antioxidant as a matrix is excellent in the melanin production inhibitory effect while safe for the skin. It was completed.

1 is a result of measuring the whitening effect of the molar derivatives of the present invention.

That is, an object of the present invention is to provide a derivative of formula (I), which is excellent in the melanin production inhibitory effect and safe for skin.

(Ⅰ)

Wherein R 1 is a C _1-16 alkoxy group,

R 2 is a C _1-16 alkyl, alkenyl, C _1-16 alkyl group substituted with an aromatic ring,

X is NH or S.

Another object of the present invention relates to a whitening cosmetic composition containing the above-mentioned molar derivative (I) in an amount of 0.01 to 20.0% by weight based on the total weight of the composition.

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

The molar derivatives (I) according to the present invention are whitening agents (Japanese Patent Laid-Open No. 8-283137), antioxidants (Biochimica et Biophysica Acta, 1996; Appl. Environ. Microbiol. 1982), human DNA polymerase inhibitors (Biochemical pharmacology, 1989), Amides of known alkyl esters such as anticancer agents (Journal of Natural product, 1992), HIV activity inhibitors (Biochemistry, 1990), NF- k B activation inhibitors (Patent No. 9-59151), fungicides (EP 307103 A2) Na derivatives have been converted to thioethers, and the derivatives are excellent for inhibiting tyrosinase enzyme activity and inhibiting melanin production and are safe for the skin.

That is, the molar asset derivative of the present invention represented by general formula (I) is prepared according to the following Scheme 1,

(a) The methyl gallate of general formula (II) is reacted with a base such as benzene or tetrahydro pyranone (THP; tetrahydro pyranone) to protect the hydroxyl group of methyl gallate, and then sodium chloride or potassium chloride is used. To prepare a carboxylic acid represented by the general formula (III);

(b) refluxing the carboxylic acid (III) prepared in step (a) in thionyl chloride (SOCl ₂ ) and dichloromethane, or bismeier reaction using dimethylformamide (DMF; dimethylforamide) and thionyl chloride Preparing a compound of formula IV;

(c) reacting the compound of formula (IV) with thiol or amine to prepare a compound of formula (V); And

(d) adding the compound of formula (V) into palladium (Pd / C) activated in ethyl acetate or methanol solvent, and pressing the compound to produce a compound of formula (I);

It includes.

Wherein R 1, R 2 and X are the same as defined in the general formula (I).

The molar asset derivative (I) of the present invention prepared by the above process may be contained as an active ingredient of a whitening cosmetic, the amount of which is effective to achieve a whitening effect, for example, 0.01 to 20.0% by weight of the total weight of the composition. It may be contained in an amount of and may have a variety of non-limiting formulations such as creams, lotions, lotions, massage creams, or essences.

The compositions of the present invention may also include other conventional ingredients depending on their formulations, and the types and amounts of these conventional ingredients are well known to those skilled in the art. The composition of the present invention may further contain other existing whitening components in addition to the above-mentioned molar derivative (I) for its whitening action, and the types and contents of these existing whitening components are well known to those skilled in the art.

Hereinafter, the present invention will be described in more detail with reference to various examples, but the present invention is not limited to these examples.

Reference Example 1. 4,5-Dibenzyloxy-3-methoxy benzoic acid

Methyl 4,5-dibenzyloxy-3-methoxy benzoate (51 g, 0.26 mol) was dissolved in 500 ml of dimethylformamide (DMF), and then three times (molar ratio) of potassium carbonate (K ₂ CO ₃ ) was added. It put, and the reaction temperature was raised to 100 degreeC. Then, 2.5 times benzyl bromide was slowly added dropwise while stirring well with a stirrer, followed by stirring at about 70 ° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated, and 500 ml of ethyl acetate was added to dissolve the reaction mixture. The mixture was washed twice with distilled water, dried over magnesium sulfate, filtered and concentrated to obtain an ester with a protecting group. Subsequently, the compound was dissolved in 500 ml of acetone and 200 ml of distilled water, and then 1.3 times sodium hydroxide was added and refluxed for 8 hours. The reaction mixture was concentrated and then dissolved in distilled water and acidified with hydrochloric acid to obtain a solid. The solid compound obtained was washed twice with distilled water, filtered and dried to obtain 71.7 g (76.3%) of the title compound.

¹ H NMR (DMSO-d ₆ , δ): 12.92 (bs, 1H), 7.46-7.13 (m, 12H), 5.17 (s, 4H), 3.03 (s, 3H)

Preparation Example 1 N-methyl-4,5-dihydroxy-3-methoxy benzamide

Dithionyl chloride (0.7 mL, 9.6 mmol) was slowly added dropwise to dimethylformamide (0.4 mL, 5.1 mmol), heated with a heat gun, and stirred for 30 minutes. 4,5-dibenzyloxy-3-methoxy benzoic acid (2.92 g, 8.0 mmol) was added to 20 ml of dichloromethane, and then refluxed for 1 hour. Then, the temperature was lowered to room temperature and a 2-fold 40% aqueous methylamine solution was slowly added dropwise, followed by stirring for 3 hours. The reaction solution was concentrated, dissolved in ethyl acetate, washed twice with an aqueous sodium carbonate solution and twice with distilled water, dried over magnesium sulfate, filtered and concentrated. This concentrate was separated by column chromatography (TLC (ethyl: acetate = 1: 1); R _f = 0.52) to afford the desired compound. After dissolving this compound in 150 ml of ethyl acetate, a small amount of activated palladium was added thereto, and the mixture was stirred for 4 hours by pressurizing hydrogen in a hydrogenation reactor. The reaction mixture was filtered through celite and 1 cm thick silica gel, and concentrated to give 1.04 g (72.0%) of the title compound.

¹ H NMR (DMSO-d ₆ , δ): 9.05 (bs, 1H), 8.73 (bs, 1H), 8.09 (q, 1H), 6.95 (s, 2H), 3.76 (s, 3H), 2.70 (d , 3H, J = 4.5Hz)

Preparation Example 2 N-ethyl-4,5-dihydroxy-3-methoxy benzamide

Dithionyl chloride (0.7 mL, 9.6 mmol) was slowly added dropwise to dimethylformamide (0.4 mL, 5.1 mmol), heated with a heat gun, and stirred for 30 minutes. 4,5-dibenzyloxy-3-methoxy benzoic acid (2.92 g, 8.0 mmol) was added to 20 ml of dichloromethane, and then refluxed for 1 hour. Then, the temperature was lowered to room temperature and a 2-fold ethylamine 70% aqueous solution was slowly added dropwise, followed by stirring for 3 hours. The reaction solution was concentrated, dissolved in ethyl acetate, washed twice with an aqueous sodium carbonate solution and twice with distilled water, dried over magnesium sulfate, filtered and concentrated. This concentrate was separated by column chromatography (TLC (ethyl: acetate = 1: 1); R _f = 0.26) to afford the desired compound. After dissolving this compound in 150 ml of ethyl acetate, a small amount of activated palladium was added thereto, and the mixture was stirred for 4 hours by pressurizing hydrogen in a hydrogenation reactor. The reaction mixture was filtered through celite and 1 cm thick silica gel, and concentrated to give 1.08 g (69.3%) of the title compound.

TLC (ethyl acetate) R _f = 0.33

¹ H NMR (DMSO-d ₆ , δ): 9.02 (bs, 1H), 8.75 (bs, 1H), 8.15 (t, 1H), 6.96 (s, 2H), 3.77 (s, 3H), 3.11 (m , 2H), 1.07 (t, 3H, J = 7.2 Hz)

Preparation Example 3 N-isopropyl-4,5-dihydroxy-3-methoxy benzamide

1.07 g (63.9%) of the title compound was obtained in the same manner as in Production Example 1, except that 2 times (molar ratio) of isopropylamine was used.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.39

¹ H NMR (DMSO-d ₆ , δ): 9.02 (bs, 1H), 8.73 (bs, 1H), 7.88 (d, 1H, J = 3.6 Hz)), 6.97 (s, 1H), 6.96 (s, 1H), 4.03 (m, 1H), 3.78 (s, 3H), 1.11 (d, 6H, J = 6.6 Hz)

Preparation Example 4 N-propyl-4,5-dihydroxy-3-methoxy benzamide

Except for using 2-fold propylamine, it was prepared in the same manner as in Preparation Example 2 to obtain 1.41 g (84.1%) of the title compound.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.42

¹ H NMR (CDCl ₃ , δ): 7.36 (d, 1H, J = 1.8 Hz) 7.22 (d, 1H, J = 1.8 Hz), 5.80 (bs, 2H), 4.03 (t, 2H. J = 6.9 Hz ), 3.92 (s, 3H), 2.79 (m, 2H), 1.02 (t, 3H, J = 7.5 Hz)

Preparation Example 5 N- (2-methyl) propyl-4,5-dihydroxy-3-methoxy benzamide

1.45 g (81.2%) of the title compound was obtained in the same manner as in Preparation Example 2, except that 2-fold of 2-methylpropylamine was used.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.14

¹ H NMR (CDCl ₃ , δ): 8.99 (bs, 1H), 8.72 (bs, 1H), 7.81 (d, 1H, J = 8.4 Hz)), 6.98 (s, 1H), 6.96 (s, 1H) , 3.85 (m, 1H), 3.78 (s, 3H), 1.50-1.40 (m, 1H), 1.08 (d, 3H, J = 6.3 Hz), 0.83 (t, 3H, J = 7.4 Hz)

Preparation Example 6 N-butyl-4,5-dihydroxy-3-methoxy benzamide

Except for using twice the butylamine was prepared in the same manner as in Preparation Example 1 to obtain 1.53 g (85.7%) of the title compound.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.09

¹ H NMR (DMSO-d ₆ , δ): 9.03 (bs, 1H), 8.77 (bs, 1H), 8.16 (t, 1H, NH), 7.02 (s, 1H), 7.01 (s, 1H), 3.77 (s, 3H), 3.20 (q, 2H, J = 6.4 Hz), 1.45 (m, 2H), 1.28 (m, 2H), 0.85 (t, 3H, J = 7.3 Hz)

Preparation Example 7 N-amyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.22 g, 3.4 mmol) dissolved in 20 ml of dichloromethane and 2 times amylamine were used. 0.63 g (78.0%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.03 (bs, 1H), 8.80 (bs, 1H), 8.16 (d, 1H, NH), 7.00 (s, 2H), 3.79 (s, 3H), 3.20 (q, 2H, J = 6.2 Hz), 1.46 (m, 2H), 1.26 (m, 4H), 0.86 (t, 3H, J = 6.5 Hz)

Preparation Example 8 N-hexyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.14 g, 3.13 mmol) dissolved in 20 ml of dichloromethane and two times hexylamine were used. 0.54 g (68.6%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.05 (bs, 1H), 8.76 (bs, 1H), 8.15 (d, 1H, NH), 6.99 (s, 2H), 3.79 (s, 3H), 3.19 (q, 2H, J = 6.3 Hz), 1.51 (m, 2H), 1.27 (m, 6H), 0.86 (t, 3H, J = 6.3 Hz)

Preparation Example 9 N-hexyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 1, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.14 g, 3.13 mmol) dissolved in 20 mL of dichloromethane and 2 times heptylamine were used. 0.62 g (yield = 74.6%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.04 (bs, 1H), 8.76 (bs, 1H), 8.16 (t, 1H, NH), 6.98 (s, 2H), 3.79 (s, 3H), 3.18 (q, 2H), 1.45 (m, 2H), 1.27 (m, 8H), 0.86 (t, 3H, J = 6.9 Hz)

Preparation Example 10 N-octyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.14 g, 3.13 mmol) dissolved in 20 ml of dichloromethane and 2 times octylamine were used. 0.73 g (79.8%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.06 (bs, 1H), 8.75 (bs, 1H), 8.15 (t, 1H, NH), 7.00 (s, 2H), 3.79 (s, 3H), 3.20 (q, 1H, J = 6.3 Hz), 1.48 (m, 2H), 1.25 (m, 10H), 0.84 (t, 3H, J = 6.8 Hz)

Preparation Example 11 N-phenyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 1, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.50 g, 4.11 mmol) and 2-fold phenylamine dissolved in 20 ml of dichloromethane were used. 0.72 g (72.0%) of a compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.95 (bs, 1H), 7.74 (d, 2H, J = 7.5 Hz), 7.34 (t, 2H), 7.13-7.05 (m, 3H), 3.85 (s , 3H)

Preparation Example 12 N-benzyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.50 g, 4.11 mmol) and 2-fold benzylamine dissolved in 20 ml of dichloromethane were used. 0.92 g (87.0%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.11 (bs, 1H), 8.82 (bs, 1H), 8.78 (t, 1H, NH), 7.35-7.25 (m, 3H), 7.06 (s, 2H) , 7.00 (m, 2H), 4.41 (d, 2H), 3.78 (s, 3H)

Preparation Example 13 N- (2-phenyl) ethyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (0.86 g, 2.36 mmol) and 2-phenylethylamine dissolved in 20 ml of dichloromethane were used. 0.43 g (67.2%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.00 (bs, 2H), 8.31 (bs, 1H), 7.28-7.15 (m, 5H), 6.97 (s, 2H), 3.75 (s, 3H), 2.78 (t, 2H), 1.08 (t, 2H),

Preparation Example 14 N- (3-phenyl) propyl-4,5-dihydroxy-3-methoxy benzamide

In the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.29 g, 3.54 mmol) dissolved in 20 ml of dichloromethane and 2-fold 3-phenylpropylamine were used. To give 0.87 g (86.1%) of the title compound.

TLC (hexane: ethyl acetate = 1: 2) R _f = 0.26

¹ H NMR (DMSO-d ₆ , δ): 9.06 (bs, 1H), 8.80 (bs, 1H), 8.19 (t, 1H, NH), 7.30-7.19 (m, 5H), 7.02 (s, 1H) , 7.01 (s, 1H), 3.80 (s, 3H), 3.23 (q, 2H, J = 6.3 Hz), 2.61 (t, 2H), 1.80 (m, 2H)

Preparation Example 15 N-allyl-4,5-dihydroxy-3-methoxy benzamide

Prepared in the same manner as in Preparation Example 2, except that 4,5-dibenzyloxy-3-methoxy benzoic acid (1.29 g, 3.54 mmol) dissolved in 20 ml of dichloromethane and 2 times allylamine were used. 0.52 g (65.8%) of compound was obtained.

¹ H NMR (DMSO-d ₆ , δ): 9.02 (bs, 1H), 8.78 (bs, 1H), 8.15 (d, 1H, NH), 7.00 (s, 2H), 6.05-5.90 (m, 1H) , 5.20-5.00 (dd, 2H), 3.89 (s, 3H), 3.32 (dd, 2H)

Reference Example 2. 4,5-Dibenzyloxy-3-propyloxy benzoic acid

Methyl 4,5-dihydroxy-3-propyloxy benzoate (58.8 g, 0.26 mol) was dissolved in 500 ml of dimethylformamide (DMF), and then tripled (molar ratio) of potassium carbonate (K ₂ CO ₃ ) Was added, and the reaction temperature was raised to 100 ° C. Then, 2.5 times benzyl bromide was slowly added dropwise while stirring well with a stirrer, followed by stirring at about 70 ° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated, and 500 ml of ethyl acetate was added to dissolve the reaction mixture. The mixture was washed twice with distilled water, dried over magnesium sulfate, filtered and concentrated to obtain an ester with a protecting group. Subsequently, the compound was dissolved in 500 ml of acetone and 200 ml of distilled water, and then 1.3 times sodium hydroxide was added and refluxed for 8 hours. The reaction mixture was concentrated and then dissolved in distilled water and acidified with hydrochloric acid to obtain a solid. The solid compound obtained was washed twice with distilled water, filtered and dried to give 66.3 g (65%) of the title compound.

¹ H NMR (DMSO-d ₆ , δ): 12.45 (bs, 1H), 7.43-7.10 (m, 12H), 5.16 (s, 4H), 4.04 (t, 2H), 1.84 (m, 2H), 1.04 (t, 3H)

Preparation Example 16 N-methyl-4,5-dihydroxy-3-propyloxy benzamide

Dithionyl chloride (0.7 mL, 9.6 mmol) was slowly added dropwise to dimethylformamide (0.4 mL, 5.1 mmol), heated with a heat gun, and stirred for 30 minutes. 4,5-Dibenzyloxy-3-propyloxy benzoic acid (2.92 g, 7.4 mmol) was added to 20 ml of dichloromethane, and then refluxed for 1 hour. Then, the temperature was lowered to room temperature and a 2-fold 40% aqueous methylamine solution was slowly added dropwise, followed by stirring for 3 hours. The reaction solution was concentrated, dissolved in ethyl acetate, washed twice with an aqueous sodium carbonate solution and twice with distilled water, dried over magnesium sulfate, filtered and concentrated. This concentrate was separated by column chromatography to afford the desired compound. After dissolving this compound in 150 ml of ethyl acetate, a small amount of activated palladium was added thereto, and hydrogen was pressed into a hydrogenation reactor, followed by stirring for 4 hours. The reaction mixture was filtered through celite and 1 cm thick silica gel, and concentrated to give 1.27 g (76%) of the title compound.

¹ H NMR (DMSO-d ₆ , δ): 9.05 (bs, 1H), 8.73 (bs, 1H), 8.09 (q, 1H, NH), 6.95 (s, 2H), 4.04 (t, 2H), 2.70 (d, 3H), 1.84 (m, 2H), 1.04 (t, 3H)

Reference Example 3. 4,5-Ditetrahydropyrioxy-3-methoxy benzoic acid

5.16 g (28.3 mmol) of methyl 4,5-dihydroxy-3-methoxy benzoate was dissolved in 60 ml of dichloromethane, followed by adding a catalytic amount of p-toluenesulfonate to three times 3,4-. Dihydro-2H-pyran was added and the reaction mixture was completely dissolved and the reaction was followed by TLC. After the reaction was completed, washed with distilled water, dried over magnesium sulfate, filtered and concentrated. This concentrated solution was dissolved in 100 ml of methanol, followed by adding sodium hydroxide twice to reflux for 5 hours. The reaction mixture was concentrated and dissolved in distilled water and acidified with 3N hydrochloric acid to give a white solid. The solid was dissolved in ethyl acetate, washed twice with distilled water, dried over magnesium sulfate, filtered and concentrated to obtain 7.2 g (72.3%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ , δ): 7.61 (s, 1H), 7.42 (s, 1H), 3.96 (s, 3H), 3.72-3.58 (m, 2H), 2.09-1.52 (m, 2H)

Preparation Example 17 4,5-dihydroxy-3-methoxy benzoic acid N-acetylaminoethyl thio ether

After dissolving 4,5-tetrahydropyroxy-3-methoxy benzoic acid (1.02 g, 3.03 mmol) in Reference Example 3 in 20 mL of dichloromethane, dimethylaminopyridine (DCC) was added thereto, stirred, and dissolved completely. Then, add N-acetyl cysteamine and stir at room temperature. After the reaction is completed, the produced solid is separated and removed. The organic solution is washed with distilled water, 5% acetic acid, ammonium chloride, and aqueous solution in that order. Then, dried over magnesium sulfate, filtered and concentrated. The concentrate was separated by column chromatography (TLC (ethyl acetate) R _f = 0.28), and then a catalytic amount of p-toluenesulfonic acid was added and stirred at room temperature for 8 hours. Upon completion of the reaction, the reaction mixture was concentrated, dissolved in ethyl acetate, washed twice with distilled water, dried over magnesium sulfate, filtered and concentrated and separated by silica gel to obtain 0.63 g (77.2%) of the title compound.

TLC (ethyl acetate: methanol = 10: 1) R _f = 0.52

¹ H NMR (DMSO-d ₆ , δ): 9.45 (bs, 2H), 8.11 (t, 1H, NH), 7.13 (d, 1H, J = 2.4 Hz), 7.01 (d, 1H, J = 2.1 Hz ), 3.81 (s, 3H), 3.24 (t, 2H), 3.05 (t, 2H), 1.80 (s, 3H)

Preparation 18. 4,5-dihydroxy-3-methoxy benzoic acid phenyl thio ether

Preparation Example 17, except that 4,5-tetrahydropyroxy-3-methoxy benzoic acid of Reference Example 3 was used in an amount of 1.03 g (3.06 mmol), and thiophenyl was used instead of N-acetylcysteamine. Prepared in the same manner as in the title compound 0.71g (89.1%) was obtained.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.42

¹ H NMR (CDCl ₃ , δ): 7.55-7.41 (m, 5H), 7.39 (d, 1H, J = 2.1 Hz), 7.16 (d, 1H, J = 2.1 Hz), 5.90 (bs, 1H), 3.88 (s, 3 H)

Preparation Example 19 4,5-dihydroxy-3-methoxy benzoic acid 4'-methoxy phenyl thio ether

Except for using 4,5-tetrahydropyroxy-3-methoxy benzoic acid of Reference Example 3 in an amount of 1.03 g (3.06 mmol) and using 4-methoxythiophenyl instead of N-acetylcysteamine. The title compound was prepared in the same manner as in Production Example 17, to obtain 0.74 g (83.3%) of the title compound.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.48

¹ H NMR (CDCl ₃ , δ): 7.40 (d, 2H, J = 9.0 Hz), 7.38 (d, 1H, J = 2.1 Hz), 7.16 (d, 1H, J = 2.1 Hz), 6.97 (d, 2H, J = 9.0 Hz), 5.98 (bs, 1H), 3.91 (s, 3H), 3.83 (s, 3H)

Preparation Example 20 4,5-dihydroxy-3-methoxy benzoic acid 3'-methoxy phenyl thio ether

Except for using 4,5-tetrahydropyroxy-3-methoxy benzoic acid of Reference Example 3 in an amount of 1.03 g (3.06 mmol) and using 3-methoxythiophenyl instead of N-acetylcysteamine. The preparation was carried out in the same manner as in Preparation Example 17, obtaining 0.69 g (77.7%) of the title compound.

TLC (hexane: ethyl acetate = 1: 1) R _f = 0.55

¹ H NMR (CDCl ₃ , δ): 7.37 (d, 1H, J = 2.1 Hz), 7.30 (t, 1H, J = 8.1 Hz), 7.14 (d, 1H, J = 2.1 Hz), 7.09-6.93 ( m, 3H), 6.15 (bs, 1H), 3.84 (s, 3H), 3.78 (s, 3H)

Test Example 1 Tyrosinase Activity Inhibitory Activity Test

Inhibition of tyrosinase activity on the molar derivatives, molar assets, kojic acid and methyl 3,4,5-trihydroxy benzoate of the present invention is shown in Table 1.

Experimental method: Tyrosinase activity inhibition was measured by Pomerantz method.

That is, one as a substrate L- dopa (DOPA), was used to L- tyrosine, L- tyrosine is labeled with ³ H, after circumcision of the newborn by treatment with 0.25% trypsin to the skin tissue is obtained, and then separating the epidermis, bovine pituitary 7.5 mg of bovine pituitary extract, 1 μg / ml of human fibroblast growth factor, 10 μg / ml of phorbol myristate acetate, 0.5 mg / ml of hydrocitisone, Cells were isolated by vortexing with a medium containing 50 mg / ml of gentamycin and 50 µg / ml of amphotericin, and cultured under 37 ° C. and 5% CO ₂ , followed by trypsin. The cultured cells were separated from the culture vessel, 0.1M phosphate buffer solution containing 1% tryptone X-100 (pH 6.8) was added to the isolated cell precipitate, and the cells were crushed by an ultrasonic grinder and then centrifuged. Body color prepared by taking supernatant Small cell lysate was used as tyrosinase. The reaction was done in 0.1 M phosphate buffer (pH 6.8). The amount of ³ H ₂ O released from the reaction solution during the reaction production is measured using a liquid scintillation counter (1209 RackBeta Liquid Scintillation Counter; Wallao, Finland). The lower the amount of ³ H ₂ O released, the higher the inhibitory effect on tyrosinase activity. will be.

Test Results: The results in Table 1 show the relative activity of the inhibitors when the vesicle-only effect of dissolving the inhibitors, ie, the substances listed in Table 1 below, was 100% control.

Compound name (10 ppm) Tyrosinase activity (%) Kojisan 30 Informal assets 109.8 3,4,5-tribenzyloxy benzoic acid 94.3 Methyl 3,4,5-trihydroxy benzoate 21.5 N-methyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 1) 47.6 N-ethyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 2) 37.2 N-isopropyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 3) 31.0 N-propyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 4) 50.6 N-butyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 6) 66.6 N-amyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 7) 71.4 N-hexyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 8) 83.3 N-heptyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 9) 84.7 N-octyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 10) 83.9 N-phenyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 11) 43.0 N-benzyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 12) 45.6 N- (2-phenyl) ethyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 13) 52.7 N- (3-phenyl) propyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 14) 42.5 N-allyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 15) 52.8 N-methyl-3-propyloxy-4,5-dihydroxy benzamide (Preparation 16) 36.1 N-methyl-3-isopropyloxy-4,5-dihydroxy benzamide 39.3 N-methyl-3-butyloxy-4,5-dihydroxy benzamide 29.5 N-methyl-3-pentyloxy-4,5-dihydroxy benzamide 28.7 4,5-dihydroxy-3-hydroxy benzoic acid N-acetylaminoethyl thioether (Preparation 17) 69.5 4,5-dihydroxy-3-hydroxy benzoic acid phenyl thioether (Preparation 18) 41.3

[Test Example 2]: melanin production inhibitory ability

While melanin-producing skin pigment cells were cultured, the melancholine derivatives, melancholyza, kojic acid, and methyl 3,4,5-trihydroxy benzoate were treated to measure melanin production, and the results are shown in Table 2. .

Experimental Method: Melanin activity inhibition was measured by Dooley's method. That is, Mel-Ab cell line derived from C57BL / 6 skin pigment cells was used. The culture was performed at 37 ° C., 5 in DMEM medium containing 10% bovine placenta serum, 100 nM of 12- o -tetradecanoyl phobol-13-acetate and 1 nM of Cholera Toxin. Under conditions of% CO ₂ .

The cultured Mel-Ab cells were detached with 0.25% trypsin-EDTA, and we spread them in 24-well plates with the same number (1 × 10 ⁵ cells / well) and then in a medium containing samples for two consecutive days from the second day. Substance treatment was carried out in a replacement manner. After 5 days, melanin was dissolved by treating with 1N NaOH, and the amount of melanin was measured by measuring absorbance at 400 nm.

Test Results: The results in Table 2 show the relative activity of the inhibitors when the effect of the vesicles, which dissolved the inhibitors, ie, the substances listed in Table 2 below, was 100% of the control group.

Compound name (10 ppm) Melanin production (%) Kojisan 84.7 Informal assets 78.9 3,4,5-tribenzyloxy benzoic acid 82.5 Methyl 3,4,5-trihydroxy benzoate 65.0 N-methyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 1) 96.2 N-ethyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 2) 84.9 N-isopropyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 3) 92.4 N-propyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 4) 86.9 N-butyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 6) 67.4 N-amyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 7) 28.6 N-hexyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 8) 37.6 N-heptyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 9) 21.3 N-octyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 10) 19.1 N-phenyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 11) 20.3 N-benzyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 12) 57.0 N- (2-phenyl) ethyl-3-methoxy-4,5-dihydroxy benzamide (Preparation Example 13) 46.5 N- (3-phenyl) propyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 14) 23.1 N-allyl-3-methoxy-4,5-dihydroxy benzamide (Preparation 15) 70.1 N-methyl-3-propyloxy-4,5-dihydroxy benzamide (Preparation 16) 60.7 N-methyl-3-isopropyloxy-4,5-dihydroxy benzamide 43.9 N-methyl-3-butyloxy-4,5-dihydroxy benzamide 37.2 N-methyl-3-pentyloxy-4,5-dihydroxy benzamide 34.8 4,5-dihydroxy-3-hydroxy benzoic acid N-acetylaminoethyl thioether (Preparation 17) 63.2 4,5-dihydroxy-3-hydroxy benzoic acid phenyl thioether (Preparation 18) 47.5

It can be seen from Tables 1 and 2 that the derivatives of the present invention have similar or improved tyrosinase activity inhibition and melanin production inhibitory effects as compared to kojic acid and the molar asset known as the whitening agent.

[Test Example 3]: whitening effect

Twelve healthy men were attached with an opaque tape with 6 holes of 1.5 cm diameter on the upper forearm of the subject, and then irradiated with UVB (1.5-2 times the minimum amount of erythema) of each subject. Induced.

After irradiation, 1% of each of the following test materials ① ~ ③ (solvent is 1,3-butylene glycol: ethanol = 7: 3), 3% koji acid, a solvent was applied for 10 weeks (one place without applying anything) Skin color was measured on a weekly basis with Chromameter CR2002 (Minolta, Japan). Evaluation was determined by the degree of increase ("ΔL") of the "L" value, the results are shown in Figure 1.

Test substance

① Methyl 3,4,5-trihydroxy benzoate

② N-amyl-4,5-dihydroxy-3-methoxy benzamide (production example 7)

③ N- (3-phenyl) propyl-4,5-dihydroxy-3-methoxy benzamide (production example 14)

1, it can be seen that the molar asset derivative of the present invention has a superior whitening effect compared to koji acid, which is a known whitening agent, and also shows an excellent whitening effect even when compared with the molar alkyl ester known as an antioxidant.

Hereinafter, after preparing the whitening cosmetics of Examples 1 and 2 containing Preparation Examples 7 and 14 and methyl 3,4,5-trihydroxy benzoate, kojic acid, and arbutin, A whitening efficacy test was performed.

[Examples 1-2 and Comparative Examples 1-3]

ingredient Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 (A) Stearyl alcohol 10.0 10.0 10.0 10.0 10.0 Polysorbate 60 1.2 1.2 1.2 1.2 1.2 Sorbitan sesquioleate 0.6 0.6 0.6 0.6 0.6 Liquid paraffin 10.0 10.0 10.0 10.0 10.0 Squalane 5.0 5.0 5.0 5.0 5.0 antiseptic 0.2 0.2 0.2 0.2 0.2 Triethanolamine 0.2 0.2 0.2 0.2 0.2 (B) glycerin 5.0 5.0 5.0 5.0 5.0 ethanol 2.0 2.0 2.0 2.0 2.0 Purified water to 100 to 100 to 100 to 100 to 100 (C) Carboxy Vinyl Polymer 0.2 0.2 0.2 0.2 0.2 Preparation Example 7 1.0 - - - - Preparation Example 14 - 1.0 - - - Methyl 3,4,5-trihydroxy benzoate - - 1.0 - - Kojisan - - - 1.0 - Arbutin - - - - 1.0 Spices Quantity Quantity Quantity Quantity Quantity

[Production method]

After A, B and C were weighed, A was added to B and emulsified first using a homomixer. Then, C was slowly added thereto, followed by secondary emulsification, followed by stirring and cooling to form a product.

[Test Example 4]: Skin irritation test

In order to test the skin irritation degree of the whitening cosmetics of Examples 1 and 2, the CTFA guidelines for 30 healthy women aged 20 to 30 years (The Cosmetic, Toiletry and Fragrance Association. Inc. Washington, DC, 20036, 1991) Was carried out according to. 20 μl of the test substance (10% in Patch base) prepared in the Finn Chamber was added dropwise, washed with 70% ethanol, and placed on the back of the dried test site and fixed with a micropore tape. The patch is applied for 24 hours. After removing the patch, mark the test site with a marking pen. After 30 minutes and 24 hours, the skin reaction of each test site is observed. The International Contact Dermatitis Research Group: ICDRG). After calculating the average reactivity using Equation 1 shown in Table 3 below. Also, based on the average reactivity, the degree of skin irritation was classified into the following four grades.

Skin irritation determination criteria:

Class I… … MS <1 (non-irritating) Class II. … 1≤MS <3 (light stimulus)

Class III… … 3≤MS <5 (medium stimulus) Grade IV … MS≥5 (strong stimulus)

Test substance (concentration: 2% saline) 24 hours 48 hours Average reactivity (n = 30) Judgment grade ± + ++ +++ ± + ++ +++ Example 1 One - - - - - - - 0.42 I Example 2 One - - - - - - - 0.42 I

As can be seen in Table 3, the cosmetic composition containing the molar derivatives of the present invention was confirmed that there is no skin irritation.

[Test Example 5]: Whitening efficacy test

In order to test the whitening efficacy of the cosmetic of the present invention, a healthy adult man and woman 40 people 2x2cm2 site was set in the lower arm hips. The aluminum foil was put on the arm so that the ultraviolet ray was irradiated only on the test subject, and the test subject was washed well with 70% isopropyl alcohol solution before irradiation. At a distance of 10 cm, the FL 20S BLB lamps and the FL 20S E-30 lamps of Japan were simultaneously irradiated three times in succession once a day at 0.8 × 10 ⁻⁷ erg / cm 3. After ultraviolet irradiation, the products of Examples 1 and 2 and Comparative Examples 1 to 3 were applied three times a day for three weeks. After 3 weeks of application, the degree of pigmentation was visually determined according to the following evaluation criteria. The results are shown in Table 4 below.

[Evaluation standard]

Excellent effect: Pigmentation is hardly noticeable.

· Effective: Pigmentation is very soft.

Slightly effective: Pigmentation is softened.

No effect: no change

* Effectiveness Criteria

◎: 80% or more of the subjects indicate "excellent" or "effective"

○: 50% to 80% of the subjects showed "excellent" or "effective"

(Triangle | delta): The ratio which shows the "excellent effect" or "effective" among the subjects is 30-50%.

×: Less than 30% of the subjects showed "excellent" or "effective"

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Whitening effect ◎ ◎ ○ ○ ×

As described above, the molar derivatives of the present invention are not only tyrosinase inhibitory activity but also very excellent melanin production inhibitory effect, when it is contained as an active ingredient of the whitening cosmetics can provide an excellent whitening effect.

Claims (2)

A molar asset derivative represented by the following general formula (I). (Ⅰ) Wherein R 1 is a C _1-16 alkoxy group, R 2 is a C _1-16 alkyl, alkenyl, C _1-16 alkyl group substituted with an aromatic ring, X is NH or S. A whitening cosmetic comprising the molar asset derivative (I) according to claim 1 in an amount of 0.01 to 20.0% by weight based on the total weight of the composition.