KR20170069133A - Novel phenolic acid derivatives, and uses of the same - Google Patents

Abstract

여기서, n은 0, 또는 1; X는 NH, 또는 S; Y는 탄소수 C₁ 내지 C₂의 알킬; R₁는 벤질, 탄소수 C₁ 내지 C₈의 히드록시알킬, 히드록시아릴, 히드록시알킬아릴, 아미노기, 또는 아마이드기; R₂는 H, 또는 탄소수 C₁ 내지 C₃의 알킬; 및 R₃는 H, 또는 메틸이다.The present invention relates to a novel phenolic acid derivative compound having a whitening and antioxidative activity, and a use thereof, and more particularly, to a compound represented by the following formula (1), an isomer thereof, or a salt thereof. Since the compounds according to the present invention have a skin whitening activity inhibiting tyrosinase, they can be usefully used in a pharmaceutical composition for skin whitening or cosmetics, and also have an antioxidative activity. Therefore, they are useful for preventing or treating skin aging and the like .
[Chemical Formula 1]

Wherein n is 0, or 1; X is NH, or S; Y is C ₁ -C ₂ alkyl; R ₁ is benzyl, hydroxyalkyl of C ₁ to C ₈ , hydroxyaryl, hydroxyalkylaryl, amino, or amido group; R ₂ is H, or C ₁ -C ₃ alkyl; And R < ₃ > is H, or methyl.

Description

NOVEL PHENOLIC ACID DERIVATIVES AND USES OF THE SAME [0001] The present invention relates to novel phenolic acid derivative compounds,

The present invention relates to novel phenolic acid derivative compounds having whitening and antioxidative activity, and their use.

Women prefer white, clean skin like white whiting, and since they use it as an important criterion of beauty, they are actively developing whitening agents to treat skin pigmentation abnormalities and meet beauty needs.

The skin color of a person is determined by the amount of melanin pigment, carotene and hemoglobin. Among them, melanin pigment has the greatest influence on the skin color. Therefore, control of melanin pigment formation is a key task of developing a whitening agent.

The melanin pigment is a phenolic high molecular substance having a complex form of black pigment and protein. It is produced through a complex process from tyrosine by the action of tyrosinase present in the pigment cells, and acts as an ultraviolet shielding It is an important and essential material.

However, when the skin responds to external stimuli such as ultraviolet rays, environmental pollution, or stress, melanin is excessively produced and is not discharged out of the skin, is transferred to keratinocyte, accumulated in the skin surface layer, Not only cause serious cosmetic problems such as aging, but also promotes skin aging and skin cancer.

Methods for controlling melanin pigment formation include a method of decolorizing melanin pigments by reducing them and a method of inhibiting the activity of tyrosinase, an enzyme that forms a melanin pigment. Tocopherol, which is used for reducing melanin pigment, Or vitamins, it is known that the decolorizing effect of the melanin pigment is very small. Thus, an inhibitor that inhibits the activity of tyrosinase has been attracting attention.

As a whitening ingredient in the conventional cosmetics field, for example, substances inhibiting tyrosinase enzyme activity such as kojic acid and arbutin, hydroquinone, L-ascorbic acid, And derivatives thereof and various plant extracts have been used. However, the use thereof is limited due to poor stability in the prescription system and coloration, generation of odor, efficacy at a living body level, unclear effects, and safety problems. In addition, koji acid adsorbs copper ions present in the active site of tyrosinase to inhibit the enzyme activity, but there is a problem such as instability when it is added to cosmetics. Vitamin C and its derivatives are difficult to use as raw materials for cosmetics because of their good oxidative instability. Hydroquinone has excellent whitening effect on the skin, but it does not cause skin irritation such as allergenicity, toxicity to melanocytes, It is highly irritating to the public and is recently prohibited to use as a carcinogen. In addition, arbutin is a derivative in which hydroquinone is conjugated with glucopyranoside. As a result, hydroquinone is less toxic to human body, and inhibits the synthesis of melanin pigment, resulting in an increase in melanin pigmentation However, it has a disadvantage in that it is partially decomposed by skin enzymes. Therefore, it is urgent to develop a safe alternative whitening agent which has excellent efficacy and few side effects even in small amounts.

On the other hand, the skin is damaged due to the collapse of enzymatic and non-enzymatic antioxidant defenses of the skin caused by active oxygen, resulting in damage of cellular components such as proteins, lipids and DNA ( Kor . J. Biotechnol. Bioeng . 1), 40 ~ 45). Such cellular damage refers to the generation of oxidative related diseases, namely, skin aging, wrinkles, pigmentation, and the like.

Since the antioxidant activity is the key to preventing the oxidation or aging of cells in the body by removing the active oxygen, the ability of the active oxygen scavenging by a substance having an antioxidant activity may be related to the skin protection ability. In addition, melanin is synthesized by melanocytes in the underlying layer of the epidermis. It is known that inflammatory substances caused by active oxygen and the like induce and promote the melanin production in the blackening cells. Thus, the antioxidant has a direct whitening effect , But it can be related to the inhibitory effect of pigmentation.

From this perspective, antioxidants are used for the purpose of preventing oxidative cell damage by free radicals by reacting with free radicals. Synthetic antioxidants commonly used in foods or pharmaceuticals include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tertiary butyl hydro- Quinone (TBHQ, Teritiarybutyl hydroquinone). However, when they are administered to experimental animals at a high concentration, it is known that hepatic hypertrophy is induced or carcinogenic. In particular, butylated hydroxytoluene has been known to increase microsomal enzyme activity in the liver of experimental animals through various studies, and the safety of these phenolic synthetic antioxidants has been controversial. It is well known that the use is legally regulated (Brannen AL, J. Amer. Oil Chem. Soc., 52, pp 59-63, 1975; Ito N et al., J. Natl. Cancer Inst., 70, p343, 1983; KM et al., J. Food. Sci., 58, pp. 1-4, 1993). Therefore, many studies have been made in anticipation of developing a safe and economical natural antioxidant with high antioxidant effect (Larson RA, Phytochemistry, 27, pp969-978, 1988). Recently, studies on natural products have been actively carried out, and secondary metabolites contained in natural products have become a major concern as physiologically active substances. Particularly, studies on antioxidative substances have been actively carried out. Examples thereof include tocopherols, flavonoids, gossypol, sesamol, oryzanol, and vitamin C (Huson B et al., Food Chem., 19 , Pszcczola DE, Food Tech., 55, pp 51-59, 2001), pp. 537-541, 1987; Frankel, EN Food Chem., 57, p 51, 1996; Giese J, Food Technol., 5, pp 73-81, . Among them, tocopherol and L-ascorbic acid are preferred as natural antioxidants. Among them, tocopherol has high safety but low oxidation inhibition ability alone (Halliwell B et al., FASEB J., 2, pp2867-2870, 1988) is disadvantageous in that it is expensive.

Therefore, it is necessary to develop alternative antioxidants to prevent various symptoms and diseases including aging caused by oxidative damage.

It is an object of the present invention to provide novel compounds having skin whitening activity.

Another object of the present invention is to provide a novel compound having an antioxidative activity.

In order to solve the above-described problems of the prior art of the present invention,

Claims 1. A compound represented by the following formula (1), an isomer thereof, or a salt thereof:

[Chemical Formula 1]

here,

n is 0, or 1;

X is NH, or S;

Y is C ₁ -C ₂ alkyl;

R ₁ is benzyl, hydroxyalkyl of C ₁ to C ₈ , hydroxyaryl, hydroxyalkylaryl, amino, or amido group;

R ₂ is H, or C ₁ -C ₃ alkyl; And

R ₃ is H, or methyl.

The present invention also provides a compound represented by the following general formula (2), an isomer thereof, or a salt thereof.

(2)

here,

R ₂ is H, or C ₁ -C ₃ alkyl;

R ₃ is H, or methyl; And

R < ₄ > is benzyl, hydroxymethyl, or hydroxyethyl.

The present invention also provides a compound represented by the following general formula (3), an isomer thereof, or a salt thereof.

(3)

here,

R ₂ is H, or C ₁ -C ₃ alkyl;

R ₃ is H, or methyl; And

R ₅ is an amino group or an amide group having ₁ to ₃ carbon atoms.

In the present invention, ( S ) -ethyl-3-phenyl-2- (3,4,5-trihydroxybenzamido) propanoate; ( R ) -ethyl-2-amino-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( R ) -methyl-2-acetamido-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( S ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; Or ( 2S, 3R ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) butanoate, an isomer thereof or a salt thereof to provide.

Also provided is a composition for skin whitening comprising the compound of the present invention, an isomer thereof, or a salt thereof as an active ingredient.

The present invention also provides an antioxidant composition for preventing or treating an oxidation-related symptom or disease containing the compound of the present invention, an isomer thereof, or a salt thereof as an active ingredient.

In addition, in the present invention, the above-mentioned oxidation-related symptom or disease is at least one selected from aging of skin, wrinkle formation, and skin pigmentation.

Also provided is a cosmetic composition comprising the compound of the present invention, an isomer thereof, or a salt thereof, in an amount of 0.01 to 10% by weight based on the total weight of the composition.

Since the compounds according to the present invention have a skin whitening activity inhibiting tyrosinase and melanin production, they can be usefully used in pharmaceutical compositions or cosmetics for skin whitening, and also have antioxidative activity, . ≪ / RTI >

FIG. 1 is a graph showing the antioxidative effects of the compounds of the present invention.
FIG. 2 is a graph showing the results of measurement of thyrosinase activity inhibitory effects of the compounds of the examples of the present invention.
FIG. 3 is a graph showing the results of measuring melanin production inhibitory effects of the compounds of the examples of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention is a compound represented by the following general formula (1), an isomer thereof, or a salt thereof.

[Chemical Formula 1]

here,

n is 0, or 1;

X is NH, or S;

Y is C ₁ -C ₂ alkyl;

R ₁ is benzyl, hydroxyalkyl of C ₁ to C ₈ , hydroxyaryl, hydroxyalkylaryl, amino, or amido group;

R ₂ is H, or C ₁ -C ₃ alkyl; And

R ₃ is H, or methyl.

The compound of the formula (1) is a derivative compound obtained by reacting gallic acid and syringic acid in the main skeleton of naturally occurring phenolic acids and reacting with amino acids. The pharmacological and toxic mechanism of the degradation products produced when the synthesized phenolic acid derivative compounds are separated by metabolism or decomposition activity since the substances which are present in nature and whose toxicity of substances are well known are designed and synthesized as synthetic main materials. Is well known, and it is advantageous in that safety can be secured easily in using synthetic derivative compounds.

From this viewpoint, it is preferable to use amino acids or essential amino acids which are metabolized or used in the human body. Examples of such amino acids are alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, And the like. Examples of the compound include cysteine (an acetyl group substituted with an acetyl group substituted with an acetyl group), a thiol group, a thiol group, a thiol group, ), Phenylalanine, serine, and threonine.

The compound of formula 1 may be synthesized by way of example as illustrated in the following scheme.

[Reaction Scheme]

1) is a step of replacing a hydroxy group with a protecting group for the next reaction, 2) activating a carboxylic acid moiety of benzoic acid to react with an amino acid to synthesize a binding compound, and 3) Followed by deprotection with a hydroxy group to synthesize a phenolic acid derivative compound.

Usually, an amino acid residue refers to a portion excluding H ₂ O generated by H of an amino group of a peptide bond and OH of a carboxy group, but an amino acid residue in the present invention is an amino acid residue Residue structure resulting from the reaction of a reactive functional group of the amino acid with a gallic acid or a sialic acid and remaining structure derived from an amino acid. Depending on the type of the amino acid, various structures may be formed, and unreacted reactive functional groups may be contained. Accordingly, depending on the kind of the amino acid, various substances can be produced by a combination of an amino acid and a gallic acid or a sialic acid. In particular, it may contain sulfur or an amine depending on the nucleophilic substitution reactor of the amino acid in which the synthesis takes place.

Specifically, the compound represented by Formula 1 may be an isomer thereof, or a salt thereof, a compound represented by Formula 2 or 3, an isomer thereof, or a salt thereof.

(2)

here,

R ₂ is H, or C ₁ -C ₃ alkyl;

R ₃ is H, or methyl; And

R < ₄ > is benzyl, hydroxymethyl, or hydroxyethyl.

(3)

here,

R ₂ is H, or C ₁ -C ₃ alkyl;

R ₃ is H, or methyl; And

R ₅ is an amino group or an amide group having ₁ to ₃ carbon atoms.

More specifically, the compound represented by Formula 2 or Formula 3, an isomer thereof, or a salt thereof is ( S ) -ethyl-3-phenyl-2- (3,4,5-trihydroxybenzamido Propanoate; ( R ) -ethyl-2-amino-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( R ) -methyl-2-acetamido-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( S ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; Or (2 S, 3 R) - it may be mentioned that methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxy-benzoyl thio) butanoate aeyi open.

The compound of the present invention, its isomer or its salt can be used for skin whitening by inhibiting melanin production and tyrosinase, has excellent antioxidative effect and can also be used for prevention or treatment of oxidation-related symptoms or diseases have. The oxidation-related symptom or disease may be skin aging, wrinkle formation, skin pigmentation, various inflammatory diseases, geriatric degenerative diseases, psoriasis, eczema and the like, but may be skin aging, wrinkles or skin pigmentation, in particular.

The compound of the present invention, an isomer thereof or a salt thereof is preferably a cosmetic composition, but may be a pharmaceutical composition or a health functional food, but does not exclude it.

In the case of a cosmetic composition, it may be prepared in any form conventionally produced in the art, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation , A wax foundation, and a spray, but the present invention is not limited thereto. More specifically, it can be prepared in the form of a sun cream, a softener, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder, The salt thereof may be contained in an amount of 0.01 to 10% by weight based on the total weight of the composition. When it is less than 0.01% by weight, it may be insufficient to exhibit the effect, and when it is more than 10% by weight, it may not be good in terms of formulation stability and storage stability.

In the case of a pharmaceutical composition, it may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions according to conventional methods. It may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions. Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

In the case of a health functional food, it may be provided in the form of powder, granule, tablet, capsule, syrup or beverage. The health food may be used together with food or food additives other than the compound according to the present invention, And the like. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood, however, that these embodiments are for the purpose of further illustrating the present invention and are not intended to limit the scope of the present invention.

Example

Example  One

Preparation of ( S ) -ethyl-3-phenyl-2- (3,4,5-trihydroxybenzamido) propanoate

(1) Preparation of ( S ) -ethyl-3-phenyl-2- (3,4,5-triacetoxybenzamido) propanoate

3,4,5-Triacetoxybenzoic acid (3.55 g) is added to a 100 mL flask, and dichloromethane (12 mL) and DME (0.1 mL) are added thereto, followed by stirring at low temperature (5 degrees). To this was added oxalyl chloride (1.7 mL) dropwise. The mixture was stirred at room temperature for 6 hours and the solution was concentrated under reduced pressure to obtain 3,4,5-triacetoxybenzoyl chloride.

Add ( S ) -phenylalanine ethyl ester hydrochloride (2.75 g), dichloromethane (12 mL) and diisopropylethylamine (6.2 mL) into a 100 mL flask and stir at low temperature (5 degrees). To this is added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (10 mL). The mixture was stirred at room temperature for 3 hours and the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (50 mL) and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic solution layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain 4.43 g (78%) of a white solid.

(2) Preparation of ( S ) -ethyl-3-phenyl-2- (3,4,5-trihydroxybenzamido) propanoate

(2.83 g) of ( S ) -ethyl-3-phenyl-2- (3,4,5-triacetoxybenzamido) propanoate obtained in the above (1) was dissolved in ethanol (6 mL) , 4-dioxane 4M solution, 10 mL). The mixture was stirred at room temperature for 8 hours, concentrated under reduced pressure and then purified by column chromatography to obtain 1.9 g (92%) of the target compound.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.35 (t, J = 6.8 Hz, 3H), 3.10-3.17 (m, 2H), 4.07-4.13 (m, 2H), 4.90-4.95 (m, 2H), 6.83 (s, 2H), 7.01-7.20 (m, 5H), 7.14 (d, J = 7.2 Hz, 1H), 7.65-7.25 (br, 3H); _{^{[α] 20.0 D = -42.97 (}} c = 1, CH 3 OH); FT-IR (Neat) 3358.43 ㎝ -1, 2983.34㎝ -1, 1728.87㎝ -1, 1601.59㎝ -1, 1514.81㎝ -1, 1444.42㎝ -1, 1324.86㎝ -1, 1274.72㎝ -1, 1203.36㎝ -1 ^{, 1092.48㎝ -1, 1034.62㎝ -1, 862.99㎝} -1, 748.25㎝ -1, 701.96㎝ -1; MS (ESI): m / z = 346.1 [M + H] < ^{+ &}

Example  2

( R ) -ethyl-2-amino-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

(1) Preparation of ( R ) -ethyl-2-amino-3- (4-acetoxy-3,5-dimethoxybenzoylthio) propanoate

4-Acetoxy-3,5-dimethoxybenzoic acid (4.8 g) was added to a 100 mL flask, and dichloromethane (20 mL) and DMEF (0.1 mL) were added and stirred at a low temperature (5 degrees). To this was added dropwise oxalyl chloride (2.4 mL). The mixture was stirred at room temperature for 6 hours and the solution was concentrated under reduced pressure to obtain 4-acetoxy-3,5-dimethoxybenzoyl chloride.

To a 100 mL flask was added 3.6 g of ( R ) -N-acetylcysteine ethyl ester, 20 mL of dichloromethane and 10 mL of diisopropylethylamine, and the mixture was stirred at a low temperature (5 ° C). To this was added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (20 mL). The mixture was stirred at room temperature for 3 hours and the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (150 mL) and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic solution layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 6.8 g (87%) of a white solid.

(2) Preparation of ( R ) -ethyl-2-amino-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

Obtained in (1) (R) - ethyl 2-amino-3- (4-acetoxy-3,5-dimethoxy-benzoyl thio) propanoate aeyi dissolved agent (3.0g) in ethanol (7mL), hydrazine hydrate ( 0.8 mL) is added. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (50 mL) and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic solution layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 2.0 g (83%) of the target product.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.35 (t, J = 6.8 Hz, 3H), 3.09-3.22 (m, 2H), 3.96 (s, 6H), 4.25-4.37 (m, 2H), 5.03-5.05 (m, 1 H), 5.86 (s, 1 H), 6.95 (d, J = 6.4 Hz , 1 H), 7.09 (s, 2H); _{^{[α] 22.3 D = -4.80 (}} c = 1, CH 3 OH); ^{FT-IR (KBr) 3364.21㎝ -1} , 3302.5㎝ -1, 2996.84㎝ -1 2977.55㎝ -1, 2963.09㎝ -1, 2931.27㎝ -1, 2834.85㎝ -1, 2570.65㎝ -1, 1724.05㎝ -1, ^{1648.84㎝ -1, 1609.31㎝ -1, 1509.03㎝ -1} , 1458.89㎝ -1, 1421.28㎝ -1, 1368.25㎝ -1, 1347.03㎝ -1, 1322.93㎝ -1, 1304.61㎝ -1, 1284.36㎝ -1, ^{1245.79㎝ -1, 1224.58㎝ -1, 1213.97㎝ -1} , 1193.72㎝ -1, 1120.44㎝ -1, 764.64㎝ -1, 752.10㎝ -1, 720.28㎝ - 1; MS (ESI): m / z = 329.9 [M + H] < ^{+ &}

Example  3

( R ) -methyl-2-acetamido-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

(1) Preparation of ( R ) -methyl-2-acetamido-3- (4-acetoxy-3,5-dimethoxybenzoylthio) propanoate

4-Acetoxy-3,5-dimethoxybenzoic acid (3.6 g) was added to a 100 mL flask, and dichloromethane (15 mL) and DMEF (0.1 mL) were added and stirred at low temperature (5 degrees). Add oxalyl chloride (1.6 mL) dropwise thereto. The mixture was stirred at room temperature for 6 hours and the solution was concentrated under reduced pressure to obtain 4-acetoxy-3,5-dimethoxybenzoyl chloride.

To a 100 mL flask was added 2.7 g of ( R ) -N-acetylcysteine methyl ester, 15 mL of dichloromethane and 4 mL of diisopropylethylamine, and the mixture was stirred at a low temperature (5 ° C). To this was added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (15 mL). The mixture was stirred at room temperature for 3 hours and the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (100 mL), and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic solution layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 4.4 g (73%) of a white solid.

(2) Preparation of ( R ) -methyl-2-acetamido-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

Obtained in (1) (R) - methyl-2-amino-3- (4-acetoxy-3,5-dimethoxy-benzoyl thio) propanoate aeyi dissolved agent (2.4g) in methanol (10mL), hydrazine hydrate ( 0.7 mL) is added. The mixture was stirred at room temperature for 8 hours and concentrated under reduced pressure. The resulting solid was washed with water and hexane and separated to obtain 1.4 g (74%) of the target compound.

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.84 (s, 3H), 3.21 (dd, J = 8.4, 13.6 Hz, 1H), 3.48 (dd, J = 4.8, 13.6 Hz, 1H), 3.64 (s 2H), 8.47 (d, J = 8.0 Hz, 1H), 9.57 (s, 1H); 3.81 (s, 6H), 4.43-4. _{^{[α] 20 .2 D = -4.39}} (c = 1, CH 3 OH); ^{FT-IR (KBr) 3497.27㎝ -1} , 3285.14㎝ -1, 3068.19㎝ -1, 2958.27㎝ -1, 2934.16㎝ -1, 2837.74㎝ -1, 1749.12㎝ -1, 1641.13㎝ -1, 1614.13㎝ -1 ^{, 1541.81㎝ -1, 1511.92㎝ -1, 1457.92㎝} -1, 1421.28㎝ -1, 1402.0㎝ -1, 1378.85㎝ -1, 1326.79㎝ -1, 1311.36㎝ -1, 1282.43㎝ -1, 1255.43㎝ -1 ^{, 1223.61㎝ -1, 1189.86㎝ -1, 1143.58㎝} -1, 1106.94㎝ -1, 998.95㎝ -1, 851.42㎝ -1, 834.06㎝ -1, 772.35㎝ -1, 690.39㎝ - 1; MS (ESI): m / z = 357.8 [M + H] < ^{+ &}

Example  4

( S ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

(1) Preparation of ( S ) -methyl-3-hydroxy-2- (4-acetoxy-3,5-dimethoxybenzoylthio) propanoate

4-Acetoxy-3,5-dimethoxybenzoic acid (2.4 g) was added to a 100 mL flask, and dichloromethane (10 mL) and DMEF (0.1 mL) were added thereto, followed by stirring at low temperature (5 degrees). Add oxalyl chloride (1.2 mL) dropwise thereto. The mixture was stirred at room temperature for 6 hours and the solution was concentrated under reduced pressure to obtain 4-acetoxy-3,5-dimethoxybenzoyl chloride.

Add ( S ) -serinyl methyl ester (1.55 g), dichloromethane (15 mL) and triethylamine (2.8 mL) into a 100 mL flask and stir at low temperature (5 degrees). To this is added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (10 mL). The mixture was stirred at room temperature for 3 hours and the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (100 mL) and washed with water, a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic solution layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 2.5 g (73%) of a white solid.

(2) Preparation of ( S ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate

( S ) -methyl-3-hydroxy-2- (4-acetoxy-3,5-dimethoxybenzoylthio) propanoate (1.4 g) obtained in the above (1) was dissolved in methanol (8 mL), hydrazine hydrate (0.4 mL) is added. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resulting solid was washed with water and hexane to obtain 0.85 g (69%) of the target compound.

^{1 H NMR (400MHz, DMSO-} d 6) δ 3.65 (s, 3H), 3.77-3.82 (m, 8H), 4.50-4.54 (m, 1H), 5.07 (t, J = 6.0 Hz, 1H), 7.22 (s, 2 H), 8.44 (d, J = 6.8 Hz, 1 H), 8.99 (s, 1 H); _{^{[α] 20.2 D = -4.39 (}} c = 1, CH 3 OH); ^{FT-IR (KBr) 3472.20㎝ -1} , 3281.29㎝ -1, 3172.33㎝ -1, 3034.44㎝ -1, 3017.09㎝ -1, 3001.66㎝ -1, 2975.62㎝ -1, 2948.63㎝ -1, 2907.16㎝ -1 ^{, 2844.49㎝ -1, 1749.12㎝ -1, 1634.38㎝} -1, 1606.41㎝ -1, 1536.99㎝ -1, 1509.99㎝ -1, 1470.46㎝ -1, 1451.17㎝ -1, 1424.17㎝ -1, 1375.0㎝ -1 ^{, 1348.0㎝ -1, 1314.25㎝ -1, 1294.0㎝} -1, 1241.93㎝ -1, 1227.47㎝ -1, 1187.94㎝ -1, 1141.65㎝ -1, 1120.44㎝ -1, 1059.69㎝ -1, 1027.87㎝ -1 ^{, 972.91㎝ -1, 849.49㎝ -1, 777.17㎝} - 1; MS (ESI): m / z = 299.9 [M + H] < ^{+ &}

Example  5

( 2S, 3R ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) butanoate

(1) Preparation of (2S , 3R ) -methyl-3-hydroxy-2- (4-acetoxy-3,5-dimethoxybenzoylthio) butanoate

4-Acetoxy-3,5-dimethoxybenzoic acid (2.64 g) was added to a 100 mL flask, and dichloromethane (11 mL) and DMEF (0.1 mL) were added thereto, followed by stirring at low temperature (5 degrees). Add oxalyl chloride (1.2 mL) dropwise thereto. The mixture was stirred at room temperature for 6 hours and the solution was concentrated under reduced pressure to obtain 4-acetoxy-3,5-dimethoxybenzoyl chloride.

Add ( S ) -threonine methyl ester (1.87 g), dichloromethane (10 mL), tetrahydrofuran (10 mL) and triethylamine (3.2 mL) into a 100 mL flask and stir at low temperature (5 degrees). To this is added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (11 mL). The mixture was stirred at room temperature for 3 hours and the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (100 mL) and washed with water, a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 2.45 g (66%) of a white solid.

(2) (2 S, 3 R) - Preparation of methyl 3-hydroxy-2- (4-hydroxy-3,5-dimethoxy-benzoyl thio) butanoate aeyi agent

Methyl-3-hydroxy-2- (4-acetoxy-3,5-dimethoxy-benzoyl thio) butanoate aeyi bit methanol (10mL) to (2.1g) - (1) ( 2 S, 3 R) obtained in And hydrazine hydrate (0.6 mL) was added thereto. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate (50 mL) and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.4 g (76%) of the desired product.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.30 (d, J = 6.4Hz, 3H), 2.50-3.00 (br, 1H), 3.80 (s, 3H), 3.91 (s, 6H), 4.44-4.46 (m 1H), 4.82 (d, J = 9.2, 1H), 5.98-6.03 (br, 1H), 7.01 (d, J = 9.2 Hz, 1H), 7.11 _{^{[α] 21.2 D = -4.45 (}} c = 1, CH 3 OH); ^{FT-IR (Neat) 3366.14㎝ -1} , 2975.62㎝ -1, 2844.49㎝ -1, 1742.37㎝ -1, 1640.16㎝ -1, 1604.48㎝ -1, 1542.7㎝ -1 7, 1508.06㎝ -1, 1459.85㎝ - ^{1, 1423.21㎝ -1, 1339.32㎝ -1,} 1214.93㎝ -1, 1158.04㎝ -1, 1116.58㎝ -1, 1014.37㎝ -1, 912.17㎝ -1, 863.95㎝ -1, 758.85㎝ -1, 696.18㎝ - ¹ ; MS (ESI): m / z = 313.9 [M + H] < ^{+ &}

[ Test Example  1] - Antioxidative Effects of Phenolic Acid Derivatives

The DPPH radical scavenging activity of the phenolic acid derivatives described in the above examples was measured, and the antioxidant activity against free radicals was measured. Ascorbic acid was used as a positive control.

The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical required for the test was purchased from Sigma Chemical Co. L-ascorbic acid was used as a control in Sigma (USA).

100 μl of a 0.2 mM DPPH solution dissolved in methanol in a 96-well culture vessel and 100 μl of a synthetic compound at various concentrations were dispensed, respectively, and incubated at room temperature for 10 min, and the absorbance was measured at 517 nm.

The absorbance from the measurement is related to the concentration of the compound, and is shown in Fig. 1.

As can be seen from Fig. 1, the activity of the compound of Example 1 was higher than that of the control group, ascorbic acid, although the activity of most of the compounds of the Examples was less than that of ascorbic acid.

Therefore, the phenolic acid derivatives according to the present invention have a strong antioxidant ability, and thus they have shown potential for use in applications such as oxidation-related diseases, such as skin aging, wrinkles and skin pigmentation inhibition.

[ Test Example  2] -Phenolic Acids Derivative Compounds Tyrosine  Active inhibitory effect

The inhibitory effect on tyrosinase production in cells was measured for the compounds synthesized in the above examples.

Fetal bovine serum (FBS) and Dulbecco's Modified Eagle Medium (DMEM) used in the cell experiments were purchased from Gibco (USA), and the cell line used was mouse-derived B16F10 (melanoma cell) purchased from Korean Cell Line Bank. The cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco) and 1% antibiotic-antimycotic (Gibco) at 37 ° C in a 5% CO ₂ incubator and subcultured at 3 to 4 days intervals. The cultured B16F10 cells were detached with 0.05% trypsin-EDTA, inoculated in the same number (1.0 × 10 ⁵ cells / well) to a 24-well plate, and then replaced with serum-free medium for 16 hours. After additional incubation for 6 hours, α-MSH (100 nM) and test drug were treated and cultured for 3 days. After 3 days of incubation, the cells were washed twice with cold PBS (phosphate buffered saline) and then treated with RIPA buffer (50 nM Tris-HCl, 150 nM NaCl, 2% NP-40, 0.5% sodium dexo- ycholate, 0.1% SDS, pH 7.4) was treated with 200 쨉 l to disrupt the cells. The recovered pulverized solution was centrifuged at 4 ° C for 30 minutes at a rate of 13,000 rpm to recover only the supernatant containing the protein. The recovered supernatant was quantified by bradford assay. 198 200 of protein at 200 / / ml and 2 2 of 2 ㎎ / ㎖ L-DOPA, and incubated in a 37 ° C CO2 incubator for 1 hour. The absorbance was then measured at 405 nm

The intracellular tyrosinase activity rate (%) = sample group / control group (melanin biosynthesis participant factor treatment) * 100 was calculated and arbutin was used as a control group. The results are shown in Fig.

As can be seen from FIG. 2, the compounds of the Examples show a higher inhibitory effect on tyrosinase activity than do arbutin. Therefore, in order to investigate whether the phenolic acid derivatives inhibit tyrosinase activity and also affect melanogenesis, an additional experiment was conducted to confirm the production of melanin in the cells.

[ Test Example  3] - Effect of Phenolic Acid Derivatives on Melanin Production

The inhibitory effect on melanogenesis in cells was measured by Chang and Chen (Chang and Chen, "Inhibitory effect of homochlorcyclizine on melanogenesis in α-melanocyte-stimulating hormone-stimulated mouse B16 melanoma cells Archives of Pharmacal Research January 2012, Volume 35, Issue 1, pp 119-127).

Fetal bovine serum (FBS) and Dulbeccos Modified Eagle Medium (DMEM) used in cell experiments were purchased from Gibco (USA). B16F10 (melanoma cells) derived from mouse purchased from Korean Cell Line Bank was used. The cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco) and 1% antibiotic-antimycotic (Gibco) at 37 ° C in a 5% CO ₂ incubator and subcultured at 3 to 4 days intervals. The cultured B16F10 cells were removed with 0.05% trypsin-EDTA and inoculated in the same number of cells (2.0 x 10 ⁴ cells / well) in a 24-well plate. After 24 hours, α-MSH ) And the test drug were treated and cultured for 3 days. After 3 days of incubation, the cells were treated with 1N NaOH for 1 hour at 80 ° C to dissolve the melanin contained in the cells. The amount of melanin was measured by measuring the absorbance at 405 nm. Kojic acid and arbutin were used as positive control. The results are shown in Fig.

As can be seen from FIG. 3, the compounds of the Examples show a higher inhibitory effect on melanin formation than do arbutin. And an example compound showing higher activity than kojic acid was also confirmed. Therefore, it can be seen that the phenolic acid derivative compound described in the present invention inhibits melanin production and has a whitening effect.

Claims (8)

A compound represented by the following formula (1), an isomer thereof, or a salt thereof.
[Chemical Formula 1]

here,
n is 0, or 1;
X is NH, or S;
Y is C ₁ -C ₂ alkyl;
R ₁ is benzyl, hydroxyalkyl of C ₁ to C ₈ , hydroxyaryl, hydroxyalkylaryl, amino, or amido group;
R ₂ is H, or C ₁ -C ₃ alkyl; And
R ₃ is H, or methyl. The compound according to claim 1, represented by the following formula (2), an isomer thereof, or a salt thereof.
(2)

here,
R ₂ is H, or C ₁ -C ₃ alkyl;
R ₃ is H, or methyl; And
R < ₄ > is benzyl, hydroxymethyl, or hydroxyethyl. The compound according to claim 1, represented by the following formula (3), an isomer thereof, or a salt thereof.
(3)

here,
R ₂ is H, or C ₁ -C ₃ alkyl;
R ₃ is H, or methyl; And
R ₅ is an amino group or an amide group having ₁ to ₃ carbon atoms. 4. The compound according to claim 1, which is ( S ) -ethyl-3-phenyl-2- (3,4,5-trihydroxybenzamido) propanoate; ( R ) -ethyl-2-amino-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( R ) -methyl-2-acetamido-3- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; ( S ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) propanoate; Or ( 2S, 3R ) -methyl-3-hydroxy-2- (4-hydroxy-3,5-dimethoxybenzoylthio) butanoate, an isomer thereof, or a salt thereof. A skin whitening composition comprising the compound of any one of claims 1 to 4, an isomer thereof, or a salt thereof as an active ingredient. An antioxidant composition for preventing or treating an oxidation-related symptom or disease containing the compound of any one of claims 1 to 4, an isomer thereof or a salt thereof as an active ingredient. The composition according to claim 6, wherein the oxidation-related symptom or disease is at least one selected from skin aging, wrinkle formation, and skin pigmentation. A cosmetic composition comprising the compound of any one of claims 1 to 4, an isomer thereof or a salt thereof in an amount of 0.01 to 10% by weight based on the total weight of the composition.

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