SALICYLIC ACID DERIVATIVE, METHOD FOR PREPARING SAME, AND COSMETIC COMPOSITION FOR WHITENING COMPRISING SAME

Abstract

The present invention relates to a novel salicylic acid derivative, a method for preparing the same, and a cosmetic composition for whitening having the same. The compound exhibits a skin whitening effect by acting on tyrosinase, which is a melanin producing enzyme, to inhibit the production of melanin, and exhibits an improved skin whitening effect compared with kojic acid, alkyl salicylic acid, or alkoxy salicylic acid, which is previously known as a skin whitening agent. Therefore, the compound can be variously applied to cosmetics, preparations for external use, and the like.

Claims

1. A salicylic acid derivative represented by the following Chemical Formula 1: ##STR00011## wherein R is a C1 to C4 alkyl group or a C1 to C4 alkoxy group.

2. The salicylic acid derivative according to claim 1, wherein R is a methyl group or a methoxy group.

3. The salicylic acid derivative according to claim 1, wherein the salicylic acid derivative is, 2-hydroxy-3-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester, 2-hydroxy-4-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester, 2-hydroxy-5-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester, 2-hydroxy-3-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester, 2-hydroxy-4-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester, or 2-hydroxy-5-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester.

4. A method for preparing a salicylic acid derivative, characterized by reacting the compound of Chemical Formula 2 with the compound of Chemical Formula 3 to produce the compound of Chemical Formula 1 as shown in the following Reaction Scheme 1: ##STR00012## wherein, R is a C1 to C4 alkyl group or a C1 to C4 alkoxy group, X and Y are OH, OM or a leaving group, provided that at least one of X and Y is the leaving group, and M is Li, Na, or K.

5. The method for preparing the salicylic acid derivative according to claim 4, wherein R is a methyl group or a methoxy group, X is Cl, and Y is ONa.

6. A cosmetic composition for whitening comprising the salicylic acid derivative according to claim 1 as an effective component.

Description

BEST MODE

[0029] Hereinafter, the present invention will be described in detail.

[0030] The present invention provides a salicylic acid derivative represented by the following Chemical Formula 1:

##STR00003##

[0031] wherein R is a C1 to C4 alkyl group or a C1 to C4 alkoxy group.

[0032] The C1 to C4 alkyl group referred to herein may be a linear or branched, saturated or unsaturated alkyl group. The alkyl group may be, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, preferably a methyl group.

[0033] In addition, the C1 to C4 alkoxy group referred to in the present specification may be a linear or branched, saturated or unsaturated alkoxy group. The alkoxy group may be, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a butoxy group, preferably a methoxy group.

[0034] Non-limiting examples of the compounds represented by Chemical Formula 1 include the following compounds: [0035] (1) 2-hydroxy-3-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 2),

##STR00004## [0036] (2) 2-hydroxy-4-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 3),

##STR00005## [0037] (3) 2-hydroxy-5-methyl-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 4),

##STR00006## [0038] (4) 2-hydroxy-3-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 5),

##STR00007## [0039] (5) 2-hydroxy-4-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 6),

##STR00008## [0040] (6) 2-Hydroxy-5-methoxy-benzoic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester (Chemical Formula 7),

##STR00009##

[0041] The compound of Chemical Formula 1 according to the present invention has excellent tyrosinase activity and thus can be used as a raw material for a cosmetic composition for whitening.

[0042] The compounds of Chemical Formula 1 of the present invention include all isomers unless otherwise specified.

[0043] Meanwhile, the present invention provides a method for preparing the compound of Chemical Formula 1 above.

[0044] Specifically, the compound of Chemical Formula 1 can be prepared by the esterification reaction of the compound of Chemical Formula 2 with the compound of Chemical Formula 3 as shown in the following Reaction Scheme 1:

##STR00010##

[0045] wherein,

[0046] R is a C1 to C4 alkyl group or a C1 to C4 alkoxy group,

[0047] X and Y are OH, OM or a leaving group, provided that at least one of X and Y is a leaving group, and

[0048] M is Li, Na, or K.

[0049] The leaving group may be, but is not limited to, halogen such as F, Cl, Br, and I, a C1-C4 alkoxy group, a substituted or unsubstituted (C1-C6) alkanesulfonyloxy group (e.g., a methanesulfonyloxy group, an ethanesulfonyloxy group or a trifluoromethanesulfonyloxy group), or a substituted or unsubstituted (C6-C12) arylsulfonyloxy group (e.g., a benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-bromophenylsulfonyloxy group, p-nitrobenzenesulfonyloxy group)

[0050] In the above Reaction Scheme 1, the compound of Chemical Formula 2 and the compound of Chemical Formula 3, which are reaction materials, can be purchased, or can be directly prepared by methods known in the art.

[0051] Specifically, the alkali metal salt of the compound of Chemical Formula 2 or Chemical Formula 3 can be prepared by reacting commercially available kojic acid or salicylic acid with an alkali metal hydroxide (LiOH, NaOH, or KOH).

[0052] In addition, the compound of Chemical Formula 2 or Chemical Formula 3 including the leaving group can be respectively prepared by reacting commercially available kojic acid or salicylic acid with an appropriate reaction reagent according to methods known in the art.

[0053] According to an embodiment of the present invention, the salicylic acid derivative may be prepared by reacting kojic acid with thionyl chloride to produce 5-hydroxy-2-(chloromethyl)-4H-pyran-4-one and reacting it with the alkali metal salt of alkyl or alkoxy salicylic acid. At this time, the alkali metal salt of the alkyl or alkoxy salicylic acid may be prepared by reacting alkyl or alkoxy salicylic acid with the inorganic base of LiOH, NaOH, or KOH in a polar solvent.

[0054] The reaction conditions of the reaction are not particularly limited and can be appropriately adjusted as necessary. Specifically, according to an embodiment of the present invention, the reaction temperature may be in the range of 10 to 200 C., preferably 50 to 150 C., and the reaction time may be in the range of 0.5 to 72 hours, preferably from 0.5 to 24 hours.

[0055] The solvent used in the reaction is not particularly limited, but the solvent is preferably an organic solvent, and specifically may be, but is not limited to, at least one selected from the group consisting of tetrahydrofuran (THF), acetone, di methyl formamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO) and mixed solvents thereof.

[0056] The salicylic acid derivative of Chemical Formula 1 according to the present invention can be applied to various fields and is preferably used as an effective component for a cosmetic composition.

[0057] As shown in Experimental Example 1, the salicylic acid derivative of Chemical Formula 1 exhibits excellent skin whitening effect by significantly inhibiting the activity of tyrosinase, which is a major enzyme for the production of melanin, even at a concentration significantly lower than that of the known whitening components such as kojic acid, 3-methyl salicylic acid and 3-methoxy salicylic acid. Thus, the salicylic acid derivative of Chemical Formula 1 can be used as an effective component for cosmetic composition for whitening.

[0058] At this time, the content of the salicylic acid derivative of Chemical Formula 1 varies depending on the formulations, and as an example, may be 0.01 to 20 wt. %. If the effective component is contained in the above range, it is not only suitable for exhibiting the intended effect of the present invention but also can satisfy both stability and solubility of the composition, and it may also be appropriate to include in the above range in terms of cost-effectiveness.

[0059] The cosmetic composition may be prepared as any formulation conventionally prepared in the art, and for example, can be formulated, but is not limited thereto, into solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation, wax foundation and spray, etc. More preferably, the cosmetic composition may be prepared as a formulations of sun cream, softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence, eye cream, pack, spray or powder.

[0060] In addition, the cosmetic composition according to the present invention may contain adjuvants conventionally used in the field of cosmetics or dermatology, such as fatty substances, organic solvent, solubilizers, thickeners, gelling agents, softener, antioxidants, suspending agents, stabilizers, foaming agent, perfumes, surfactants, water, ionic or nonionic type emulsifiers, fillers, metal ion sequestrants, chelating agents, preservatives, vitamin, blocking agents, wetting agents, essential oil, dye, pigment, hydrophilic or lipophilic active agents, lipid vesicle or any other ingredient commonly used in cosmetics. Such adjuvants are introduced in amounts commonly used in the field of cosmetics or dermatology.

[0061] When the formulation is a paste, a cream or a gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide or the like may be used as a carrier component.

[0062] When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, Particularly, in the case of the spray, it may further comprise propellants such as chlorofluorohydrocarbons, propane/butane or dimethyl ether.

[0063] When the formulation is a solution or an emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as the carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, and fatty acid esters of polyethylene glycol or sorbitan.

[0064] When the formulation is a suspension, liquid diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, etc., can be used as a carrier component.

[0065] Hereinafter, the present invention will be described in more detail by the following examples. It is to be understood, however, that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention.

EXAMPLE 1: PREPARATION OF 2-HYDROXY-3-METHYL-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0066] 50 g (0.35 mmol) of 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one was dissolved in 250 ml of N, N-dimethylformamide, cooled in an iced water bath at 10 C., and then 50 g (0.42 mol) of thionyl chloride was added dropwise for 30 minutes. After stirring at room temperature for 2 hours, the reaction solution was added to 2000 ml of ice water. The resulting solid was filtered, and the solid (filtered substance) was dissolved in 1000 ml of ethyl acetate. Magnesium sulfate and activated carbon were added, dried, discolored and filtered, and then the filtrate was concentrated and nucleic acid was added to obtain crystals. The crystals were dried in vacuo to obtain 39.5 g (70%) of the reaction product, 5-hydroxy-2-(chloromethyl)-4H-pyran-4-one as a yellow solid.

[0067] 4.4 g (0.026 mol) of 3-methylsalicylic acid and 1.3 g (0.031 mol) of sodium hydroxide was dissolved in 40 ml of methanol. Methanol was distilled off and the residue was dissolved in 70 ml of N,N-dimethylformamide. 4.2 g (0.026 mol) of 5-hydroxy-2-(chloromethyl)-4H-pyran-4-one was added thereto and the mixture was heated and stirred in an oil bath at 110 C. for 2 hours. The solvent was distilled off and the residue was dissolved in 300 ml of ethyl acetate, and then the ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, and dried and discolored by adding magnesium sulfate and activated carbon.

[0068] Insolubles were filtered off and the filtrate was evaporated under reduced pressure to give 5.5 g (73% yield) of the reaction product as an off-white solid.

[0069] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.45

[0070] .sup.1H NMR (DMSO-d.sub.6) 10.60 (s, 1H), 9.22 (s, 1H), 8.12 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=8.1 Hz), 6.88 (m, 1H), 6.58 (s, 1H), 5.27 (s, 2H), 2.20 (s, 3H).

EXAMPLE 2: PREPARATION OF 2-HYDROXY-4-METHYL-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0071] The target substance (5.3 g, 70%) was obtained as an off-white solid in substantially the same manner as in Example 1, except that 4-methylsalicylic acid was used instead of 3-methylsalicylic acid.

[0072] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.44

[0073] .sup.1H NMR (DMSO-d.sub.6) 10.00 (s, 1H), 9.23 (s, 1H), 8.12 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.80 (d, 1H, J=8.1 Hz), 6.57 (s, 1H), 5.22 (s, 2H), 2.31 (s, 3H).

EXAMPLE 3: PREPARATION OF 2-HYDROXY-5-METHYL-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0074] The target substance (5.9 g, 78%) was obtained as an off-white solid in substantially the same manner as in Example 1, except that 5-methylsalicylic acid was used instead of 3-methylsalicylic acid.

[0075] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.45

[0076] .sup.1H NMR (DMSO-d.sub.6) 10.10 (s, 1H), 9.24 (s, 1H), 8.12 (s, 1H), 7.60 (s, 1H), 7.36 (d, 1H, J=8.1 Hz), 6.90 (d, 1H, J=8.1 Hz), 6.59 (s, 1H), 5.21 (s, 2H), 2.24 (s, 3H).

EXAMPLE 4: PREPARATION OF 2-HYDROXY-3-METHOXY-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0077] The target substance (4.9 g, 65%) was obtained as an off-white solid in substantially the same manner as in Example 1, except that 3-methoxysalicylic acid was used instead of 3-methylsalicylic acid.

[0078] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.43

[0079] .sup.1H NMR (DMSO-d.sub.6) 10.19 (s, 1H), 9.26 (s, 1H), 8.11 (s, 1H), 7.41 (d, 1H, J=8.1 Hz), 7.20 (d, 1H, J=8.1 Hz), 6.57 (s, 1H), 5.23 (s, 2H), 3.81 (s, 3H).

EXAMPLE 5: PREPARATION OF 2-HYDROXY-4-METHOXY-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0080] The target substance (6.0 g, 80%) was obtained as an off-white solid in substantially the same manner as in Example 1, except that 4-methoxysalicylic acid was used instead of 3-methylsalicylic acid.

[0081] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.42

[0082] .sup.1H NMR (DMSO-d.sub.6) 10.60 (s, 1H), 9.20 (s, 1H), 8.06 (s, 1H), 7.78 (d, 1H, J=8.1 Hz), 6.56 (s, 1H), 6.53 (s, 1H), 6.52 (s, 1H), 5.21 (s, 2H), 3.80 (s, 3H).

EXAMPLE 6: PREPARATION OF 2-HYDROXY-5-METHOXY-BENZOIC ACID 5-HYDROXY-4-OXO-4H-PYRAN-2-YLMETHYL ESTER

[0083] The target substance (5.7 g, 76%) was obtained as an off-white solid in substantially the same manner as in Example 1, except that 5-methoxysalicylic acid was used instead of 3-methylsalicylic acid.

[0084] TLC (ethyl acetate:hexane=1:1, v/v) R.sub.f=0.45

[0085] .sup.1H NMR (DMSO-d.sub.6) 9.92 (s, 1H), 9.22 (s, 1H), 8.08 (s, 1H), 7.24 (s, 1H), 7.18 (d, 1H, J=8.1 Hz), 6.94 (d, 1H, J=8.1 Hz), 6.60 (s, 1H), 5.29 (s, 2H), 3.72 (s, 3H).

EXPERIMENTAL EXAMPLE 1: DETERMINATION OF THE INHIBITORY EFFECT ON TYROSINASE ACTIVITY

[0086] In order to investigate the tyrosinase activity inhibitory effect of the salicylic acid derivatives prepared in Examples 1 to 6, the following experiment was conducted.

[0087] Mushroom-derived tyrosinase and tyrosine were purchased from Sigma Chemical. Each sample was treated with 150 microliters of 0.1 M phosphate buffer (pH 6.5), 8 microliters of mushroom tyrosinase (2,100 units/ml, 0.05 M phosphate buffer, pH 6.5) and 36 microliters of 1.5 mM L-tyrosine by concentration. After the enzymatic reaction was carried out at 37 C. for 20 minutes, the activity of tyrosinase was measured by measuring the absorbance at 490 nm using a microplate reader (Bio-Rad 3550, Richmond, Calif., U.S.A.). The inhibitory effect of tyrosinase of the salicylic acid derivatives prepared in Examples 1 to 6 was determined based on the following Equation (1).

Tyrosinase inhibition ratio (%)=100((Reaction absorbance of each sample/reaction absorbance of the control group)100)[Equation 1]

[0088] The concentration of each test substance which decreased the activity of tyrosinase by 50% was determined by the above Equation, and the obtained results are shown in Table 1.

TABLE-US-00001 TABLE 1 The inhibitory effect on tyrosinase activity Inhibition of tyrosinase activity Test substance (IC.sub.50) Kojic acid 40.97 M 3-Methylsalicylic acid >200 M 3-Methoxysalicylic acid >200 M Compound of Example 1 3.20 M Compound of Example 2 1.51 M Compound of Example 3 5.30 M Compound of Example 4 4.21 M Compound of Example 5 4.20 M Compound of Example 6 3.29 M

[0089] As shown in Table 1, It can be seen that 3-methylsalicylic acid and 3-methoxysalicylic acid at a concentration of 200 M or less do not exhibit the inhibitory effect on tyrosinase activity, and the compounds of Examples 1 to 6 exhibit a greatly enhanced inhibitory effect on tyrosinase activity as compared to starting compounds, methylsalicylic acid, methoxysalicylic acid, and kojic acid. Thus, it can be seen that the salicylic acid derivatives according to the present invention inhibit melanin production and have an excellent skin whitening effect.

[0090] Hereinafter, Formulation Examples of the present invention will be described. However, the cosmetic formulation containing the salicylic acid derivative according to the present invention is not limited to these examples.

FORMULATION EXAMPLE 1: LOTION

[0091] The lotion was prepared according to the conventional method with the composition shown in the following table.

TABLE-US-00002 2 Component Content (wt. %) Compound of Example 1 0.1 Glycerine 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 PEG 12 nonylphenyl ether 0.2 Polysorbate 80 0.4 Ethanol 10.0 Triethanolamine 0.1 preservative, Coloring, Perfume Appropriate amount Purified water Remainder

FORMULATION EXAMPLE 2: NOURISHING CREAM

[0092] The nourishing cream was prepared according to the conventional method with the composition shown in the following table.

TABLE-US-00003 TABLE 3 Component Content (wt. %) Compound of Example 1 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 Hydrogenated castor oil 2.0 Liquid paraffin 10. Squalane 5.0 Caprylic/capric triglyceride 5.0 Glycerine 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, Coloring, Perfume Appropriate amount Purified water Remainder

FORMULATION EXAMPLE 3: MASSAGE CREAM

[0093] The massage cream was prepared according to the conventional method with the composition shown in the following table.

TABLE-US-00004 TABLE 4 Component Content (wt. %) Compound of Example 1 1.0 Beewax 10.0 Polysorbate 60 1.5 PEG 60 Hydrogenated castor oil 2.0 Sorbitan sesquioleate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprylic/capric triglyceride 4.0 Glycerine 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, Coloring, Perfume Appropriate amount Purified water Remainder

FORMULATION EXAMPLE 4: PACK

[0094] The pack was prepared according to the conventional method with the composition shown in the following table.

TABLE-US-00005 TABLE 5 Component Content (wt. %) Compound of Example 1 0.2 Polyvinyl alcohol 13.0 Sodium carboxymethylcellulose 0.2 Glycerine 5.0 Allantoin 0.1 Ethanol 6.0 PEG 12 nonylphenyl ether 0.3 polysorbate 60 0.3 Preservative, Coloring, Perfume Appropriate amount Purified water Remainder