2. Description of Prior Art A color of human skin is determined by various factors such as red blood corpuscles, carotene, melanin, et al, however the racial color difference or hyperpigmentation, for example mole and freckles is influenced by melanin. Melanin exists in the outermost layer of the epidermis, i. e., stratum corneum, and blocks ultraviolet to protect skin tissues under the inner skin and captures free radicals to protect skin proteins and genes. However, the melanin that formed by inner or outer stress and is very stable compound and is not removed from the

human body until discharged by corneous tissue. This melanin is formed by oxidative polymerization of tyrosine or DOPA with the catalytic action of tyrosinase, further it may be increased by free radicals of the skin, inflammation or ultraviolet. Particularly, ultraviolet accelerates the formation of melanin, which partially grows into moles having bad affect on the skin beauty.

Unfortunately, it may grow into dangerous cutaneous cancer.

Tyrosinase is a very important enzyme involved in the formation of melanin and many researchers have made efforts to find materials inhibiting the action of tyrosinase. In results, it has been reported that kojic acid has a strong activity of inhibiting the action of tyrosinase. In order to increase the activity of kojic acid, many derivatives, especially, substituted with hydrophobic groups at 7-hydroxymethyl position have been synthesized. Mostly, these derivatives have increased activities for inhibiting the action of tyrosinase, but have poor stability in comparison with that of kojic acid itself. Therefore, these derivatives could not be widely applied.

In order to solve the above problem of kojic acid derivatives and to find new derivatives having improved stability, the present inventors have conducted extensive studies for kojic acid derivatives. As a result thereof, we found that kojic acid derivatives substituted at 7-hydroxy position with other kojic acid by using connecting group exhibit improved tyrosinase-inhibiting activity and have better stability than that of kojic acid itself, as well as decreased side effects to human skin.

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a new kojic acid derivative represented by the following formula 1 and a preparation method thereof : [Formula 1]

(I) (wherein, R is an alkyl group having 2-10 of carbon number substituted by a lower alkyl group having 1-6 of carbon number or not substituted; an alkenyl group having 2-10 of carbon number; a benzyl group substituted or not substituted; or a pyridine group substituted or not substituted).

DETAILED DESCRIPTION OF THE INVENTION Hereinafter, the present invention is described in detail.

The present invention provides a kojic acid derivative represented by the following formula 1: [Formula 1] (I) (wherein, R is an alkyl group having 2-10 of carbon number substituted by a lower alkyl group having 1-6 of carbon number or not substituted; an alkenyl group having 2-10 of carbon number; a benzyl group substituted or not substituted; or a pyridine group substituted or not substituted).

Preferably, said benzyl group may be C6H4-1, 4-, C6H4-1, 3-, etc., and said pyridine group may be C5H3N-2, 5-, CsH3N-3, 5-, etc.

The present kojic acid derivative may be prepared by either of the following two processes according to R of said formula 1. One is employing dicarboxylic anhydride, and the other is employing chloride such as thionyl chloride.

The first method for preparing the present kojic acid derivative comprises the following steps. The first method may be preferably applied to a preparation of the derivatives of which R is an alkyl group having 2-10 of carbon number, an alkyl group having 2-10 of carbon number substituted by a lower alkyl group having 1-6 of carbon number or an alkenyl group having 2-10 of carbon number.

Step (A): reacting kojic acid with dicarboxylic anhydride in an organic solvent, in the presence of an organic base, to produce kojyl dicarboxylic compound represented by the following formula 2 (compound (II)) ; [Formula 2] Step (B): condensing the kojyl dicarboxylic compound II (formula 2) with other kojic acid in an organic solvent in the presence of an acid catalyst, to produce kojic dimer.

The above method of the present invention may be schematized by the following reaction scheme 1: [Reaction Scheme 1]

(wherein, R has the same meaning as defined in the formula 1).

The first method for preparing the present kojic acid derivatives will be described hereinafter in more detail.

Step (A) of reacting kojic acid with dicarboxylic anhydride in an organic solvent in the presence of an organic base, to produce kojyl dicarboxylic compound (II) represented by formula 2: An organic base employed in the above step comprises triethylamine, pyridine, sodium, sodium hydroxide, potassium hydroxide, etc., and preferably triethylamine.

And, an organic solvent employed in the above step comprises an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether and dioxane; and a polar solvent such as methanol, ethanol and propanol. Preferably, it may be dioxane.

Further, a dicarboxylic anhydride employed in the present invention comprises, but not limited to the following specific examples, dicarboxylic anhydride having 2-10 of carbon number, dicarboxylic anhydride having 2-10 of carbon number substituted by a lower alkyl group having 1-6 of carbon number.

Preferably, it comprises succinic anhydride, maleinic anhydride, glutaric anhydride, 3-methylglutaric anhydride and 3,3-dimethylglutaric anhydride.

In the above step, it is preferable to react 1-1. 3 equivalent of dicarboxylic anhydride per 1 equivalent of kojic acid. If the amount of dicarboxylic

anhydride is lower than 1 equivalent, the aimed product may not be obtained, and, if the amount of dicarboxylic anhydride is more than 1.3 equivalent, by-product, in addition to the aimed product is produced.

Further, the reaction may be preferably performed at a temperature of 0-50 °C, more preferably of 25 °C, for one day.

Step (B) of condensing the kojyl dicarboxylic compound (II) obtained in the above step (A) with other kojic acid in an organic solvent in the presence of an acid catalyst, to produce kojic dimer of the formula 1: An acid catalyst employed in the above step comprises sulfuric acid, hydrochloric acid, p-toluene sulfonic acid, etc., and an organic solvent comprises may be toluene, benzene, etc.

Further, the second method for preparing the present kojic acid derivatives may comprise the following steps. The second method may be preferably applied to a preparation of the derivatives of which R is a benzyl group substituted or not substituted; or a pyridine group substituted or not substituted.

More preferably, said benzyl group may be C6H4-1,4- or C6H4-1,3- and said pyridine group may be CsH3N-2, 5-or CsH3N-3, 5-. And, R may be - CH=CHCH=CH-.

Step (A) of reacting kojic acid with chloride such as thionyl chloride in an organic solvent, to produce kojyl chloride; Step (B) of reacting dicarboxylic acid such as terephthalic acid, pyridinedicarboxylic acid or 2,4-hexadienedioic acid with hydroxide in an organic solvent, to produce dicarboxylic salt such as terephthalic salt, pyridinedicarboxylic salt or 2,4-hexadienedioic salt; and Step (C) of reacting kojyl chloride obtained in said step (A) with dicarboxylic salt such as terephthalic salt, pyridinedicarboxylic salt and 2,4-hexadienedioic salt in an organic solvent obtained in said step (B), to produce kojic dimer.

The above method of the present invention may be schematized by the following reaction scheme 2: [Reaction Scheme 2] ouzo<BR> HO#R#OH (B) #K#O#R#O#K#<BR> (IV)<BR> <BR> (no

m (wherein, R has the same meaning as defined in the formula 1).

The second method for a preparing the present kojic acid derivatives will be described hereinafter in more detail.

Step (A) of reacting kojic acid with chloride such as thionyl chloride in an organic solvent, to produce kojyl chloride represented by the above compound (ici) : In the above step, it is preferable to react 1-1. 3 equivalent of thionyl chloride per 1 equivalent of kojic acid. If the amount of thionyl chloride is lower than 1 equivalent, the aimed product may not be obtained. And, if the amount of thionyl chloride is more than 1. 3 equivalent, excessive by-product in addition to the aimed product is produced.

A chloride employed in the step (A) comprises thionyl chloride, oxalic chloride, phosphorus trichloride, phosphorus oxychloride, etc., and, an organic solvent employed in the above step comprises chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, toluene, benzene, etc.

Further, the reaction may be preferably performed at a temperature of

0-80 °C, more preferably of 10-40 °C.

Step (B) of reacting dicarboxylic acid such as terephthalic acid, pyridinedicarboxylic acid or 2,4-hexadienedioic acid with hydroxide in an organic solvent, to produce dicarboxylic salt such as terephthalic salt, pyridinedicarboxylic salt or 2,4-hexadienedioic salt represented by the above compound (IV) : A hydroxide employed in said step (B) may be sodium hydroxide, potassium hydroxide, etc., and, an organic solvent may be ethanol, methanol, butanol, isopropyl alcohol, etc.

Step (C) of reacting kojyl chloride obtained in said step (A) with dicarboxylic salt obtained in said step (B) such as terephthalic salt, pyridinedicarboxylic salt or 2,4-hexadienedioic salt in an organic solvent, to produce kojic dimer: An organic solvent employed in said step (C) may be dimethyl formamide.

The kojic acid derivatives of the formula 1 obtained in the above methods may include, but not limited thereto, di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl butan-1, 4-dioate, di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl-2 (E)-butan-1,4-dioate, di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl pentan-1, 5-dioate, di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl 3-methylpentan-1,5-dioate, di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl 3,3-dimethylpentan-1,5-dioate, terephthalic acid bis (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, isophthalic acid bis (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, 2,4-hexadienedioic acid bis (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, 2,5-pyridinedicarboxylic acid bis (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, 3,5-pyridinedicarboxylic acid bis (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, etc.

The present kojic acid derivatives of the formula (I) obtained in said methods may be used as a whitening agent.

PREFERRED EMBODIMENT OF THE INVENTION The present invention will be described in more detail with reference to the following examples, which should not be considered to limit the scope of the present invention.

[The first method] <Reference Example 1> Preparation of kojyl succinic acid 50g of kojic acid was dissolved in 500mQ of dioxane in a 500mt round flask.

35.2g of succinic anhydride and 35. 6g of triethylamine were added thereto at a temperature of 25°C, and stirred for 4 hours at that temperature. After the reaction was terminated, the mixture was concentrated, of which the residue was dissolved in ethyl acetate. The organic layer was washed with dilute hydrochloric acid twice and with distilled water 3 times, and then separated.

The resultant was dried and concentrated under reduced pressure. Petroleum ether was added thereto, and then standed for one night. The resulting solution was filtrated and dried to obtain 68. 4g (yield: 80%) of kojyl succinic acid as white solid state.

<Reference Example 2> Preparation of kojyl maleinic acid The same procedure as described in Reference Example 1 was followed by employing maleinic anhydride instead of succinic anhydride, to obtain 66.7g (yield: 79%) of kojyl maleinic acid as white solid.

<Reference Example 3> Preparation of kojyl glutaric acid

The same procedure as described in Reference Example 1 was followed by employing glutaric anhydride instead of succinic anhydride, to obtain 69. Og (yield: 77%) of kojyl glutaric acid as white solid.

<Reference Example 4> Preparation of kojyl 3-methylglutaric acid The same procedure as described in Reference Example 1 was followed by employing 3-methylglutaric anhydride instead of succinic anhydride, to obtain 75.7g (yield: 80%) of kojyl 3-methylglutaric acid as white solid.

<Reference Example 5> Preparation of kojyl 3,3-dimethylglutaric acid The same procedure as described in Reference Example 1 was followed by employing 3,3-dimethylglutaric anhydride instead of succinic anhydride, to obtain 99.5g (yield: 80%) of kojyl 3,3-dimethylglutaric acid as white solid <Example 1> Preparation of di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl butan- 1,4-dioate 10b of kojic acid and 17g of kojyl succinic acid obtained in Reference Example 1 was dissolved in ZOOm. of toluene. p-toluene sulfonic acid was added thereto in an amount of catalyst, and then the mixture was refluxed for 5 hours. After the reaction was terminated, the reacting solution was concentrated, and of which the residue was dissolved in 500mQ of ethyl acetate. The resulting solution was washed with distilled water twice, dried over sodium sulfate anhydride, then filtrated and concentrated to obtain 15. 5g (yield: 60%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 62 'H-NMR (DMSO-d6, S) : 9.18 (s, 2H), 8. 07 (s, 2H), 6.46 (s, 2H), 4.96 (s, 4H), 2.70 (s, 4H).

<Example 2> Preparation of di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl 2 (E)-butan-1, 4-dioate The same procedure as described in Example 1 was followed by employing kojyl maleinic acid obtained in Reference Example 2 instead of kojyl succinic acid, to obtain 16.6g (yield: 65%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 58 'H-NMR (DMSO-d6,6) : 9.19 (s, 2H), 8.05 (s, 2H), 6.43 (s 2H), 6.12 (s, 2H), 4.96 (s, 4H).

<Example 3> Preparation of di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl pentan- 1,5-dioate The same procedure as described in Example 1 was followed by employing kojyl glutaric acid obtained in Reference Example 3 instead of kojyl succinic acid, to obtain 18.7g (yield: 70%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 60 1H-NMR (DMSO-d6,6) : 9.16 (s, 2H), 8.05 (s, 2H), 6.44 (s 2H), 4.95 (s, 4H), 2.50 (s, 4H), 1.60 (s, 2H).

<Example 4> Preparation of di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl 3- methylpentan-1, 5-dioate The same procedure as described in Example 1 was followed by employing kojyl 3-methylglutaric acid obtained in Reference Example 4 instead of kojyl succinic acid, to obtain 17.7g (yield: 64%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf = 0.56 'H-NMR (DMSO-d6, S) : 9.19 (s, 2H), 8.04 (d, 4H, J=7.8Hz), 6.47 (s 2H), 2.45 (m, 4H), 1.0 (s, 3H).

<Example 5> Preparation of di (5-hydroxy-4-oxo (4H-pyran-2-yl) methyl 3,3-dimethylpentan-1,5-dioate The same procedure as described in Example 1 was followed by employing kojyl 3,3-dimethylglutaric acid obtained in Reference Example 5 instead of kojyl succinic acid, to obtain 21. 5g (yield: 75%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 63 1H-NMR (DMSO-d6,6) : 9.18 (s, 2H), 8.06 (s, 2H), 6.45 (s, 2H), 4.94 (s, 4H), 2.20 (s, 4H), 1.10 (s, 6H).

[The second method] Preparation of kojyl chloride 50g of kojic acid was dissolved in 300mQ of chloroform in a 500mQ round flask. 50.2g of thionyl chloride was added thereto at a temperature of 25 °C, and stirred for 4 hours at that temperature. After the reaction was terminated, the mixture was concentrated, of which the residue was dissolved in ethyl acetate.

The organic layer was washed with dilute hydrochloric acid twice and with distilled water 3 times, and then separated. The resultant was dried and concentrated under reduced pressure. Petroleum ether was added thereto, and then standed for one night. The resulting solution was filtrated and dried to obtain 46.7g (yield: 83%) of kojyl chloride as light brown solid.

<Reference Example 6> Preparation of terephthalic salt 20g of terephthalic acid and 13.5g of potassium hydroxide were dissolved in 400mQ of ethanol anhydride in a 500mQ round flask. The mixture was stirred for 2 hours at a temperature 25°C, and then filtrated. The resulting solid was dried to obtain 27.7g (yield: 95%) of white terephthalic salt.

<Reference Example 7> Preparation of isophthalic salt The same procedure as described in Reference Example 6 was followed by employing isophthalic acid instead of terephthalic acid, to obtain 28.3g (yield : 97%) of white isophthalic salt.

<Reference Example 8> Preparation of 2, 4-hexadienedioic salt The same procedure as described in Reference Example 6 was followed by employing 2,4-hexadienedioic acid instead of terephthalic acid, to obtain 29.1g (yield: 95%) of white 2,4-hexadienedioic salt.

<Reference Example 9> Preparation of 2, 5-pyridinedicarboxylic salt The same procedure as described in Reference Example 6 was followed by employing 2,5-pyridinedicarboxylic acid instead of terephthalic acid, to obtain 28. 5g (yield: 98%) of white 2,5-pyridinedicarboxylic salt.

<Reference Example 10> Preparation of 3,5-pyridinedicarboxylic salt The same procedure as described in Reference Example 6 was followed by employing 3,5-pyridinedicarboxylic acid instead of terephthalic acid, to obtain 27.3g (yield: 94%) of white 3,5-pyridinedicarboxylic salt.

Example 6> Preparation of terephthalic acid bis (5-hydroxy-4-oxo-4H-pyran- 2-ylmethyl) ester lOg of terephthalic salt and 7.9g of kojyl chloride prepared above was dissolved in 150mQ of dimethyl formamide and refluxed for 5 hours. After the reaction was terminated, the reacting solution was filtrated and concentrated, of which the residue was dissolved in 500mQ of chloroform. The resulting solution was washed with 0. 1N of hydrochloric acid twice, dried over sodium sulfate anhydride, filtrated and then concentrated. Ethyl acetate was added

thereto, and then standed for one night. The resulting solution was filtrated and dried to obtain 10.7g (yield: 60%) of the title compound as light yellow solid.

TLC (in ethyl acetate) Rf= 0. 62 'H-NMR (DMSO-d6,6) : 9.18 (s, 2H), 8.14 (d, 4H, J=7.8Hz), 8.07 (s 2H), 6.46 (s, 2H), 4.96 (s, 4H).

<Example 7> Preparation of isophthalic acid bis (5-hydroxy-4-oxo-4H-pyran-2-yl methyl) ester The same procedure as described in Example 6 was followed by employing isophthalic salt instead of terephthalic salt, to obtain ll. lg (yield: 65%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 58 lH-NM : R (DMSO-d6, # ): 9.19 (s, 2H), 8.68 (s, 1H), 8.18 (d, 2H, J=7.6Hz), 8.05 (s 2H), 7.48 (d, 1H, J=7.8Hz), 6.43 (s, 2H), 4.96 (s, 4H).

<Example 8> Preparation of 2,4-hexadienedioic acid bis (5-hydroxy-4-oxo- 4H-pyran-2-ylmethyl) ester The same procedure as described in Example 6 was followed by employing 2,4-hexadienedioic salt instead of terephthalic salt, to obtain 12. 5g (yield: 70%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf = 0.60 lH-NM : R (DMSO-d6, 6) : 9.16 (s, 2H), 8.05 (s 2H), 7.50 (d, 2H, J=7. 2Hz), 6.44 (s, 2H), 6.05 (d, 2H, 7.2Hz), 4.95 (s, 4H).

<Example 9> Preparation of 2,5-pyridinedicarboxylic acid bis (5-hydroxy-4-oxo -4H-pyran-2-ylmethyl) ester The same procedure as described in Example 6 was followed by employing 2,5-pyridinedicarboxylic salt instead of terephthalic salt, to obtain 10.9g (yield:

64%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0.56 H-NMR (DMSO-d6, 0) : 9.63 (s, 1H), 9.19 (s, 2H), 8.78 (d, 1H, J=7. 6Hz), 8.58 (d, 1H, J=7.6Hz), 8.04 (s 2H), 6.47 (s, 2H), 4.96 (s, 4H).

<Example 10> Preparation of 3,5-pyridinedicarboxylic acid bis (5-hydroxy-4- oxo-4H-pyran-2-ylmethyl) ester The same procedure as described in Example 6 was followed by employing 3,5-pyridinedicarboxylic salt, instead of terephthalic salt, to obtain 12.8g (yield : 75%) of the title compound as yellow solid.

TLC (in ethyl acetate) Rf= 0. 63 1H-NMR (DMSO-d6,6) : 9.55 (s, 2H), 9.18 (s, 2H), 8.95 (s, 1H), 8.06 (s 2H), 6.45 (s, 2H), 4.94 (s, 4H).

<Experimental example 1> Melanin-inhibiting activity evaluated by mouse's pigment cell In order to evaluate whitening effect on the skin, melanin-inhibiting activity was measured by employing mouse's pigment cell. Mel-Ab cell of C57BL/6 mouse was cultured in Dulbecco's modified Eagle's media (DMEM) in which 10% of fetal bovine serum, 100nM of 12-O-tetradecanoyl phorbol-13-acetate and InM of cholera toxin were added at a temperature of 37C with 5% CO2. The cultured Mel-Ab cell was detached with 0.25% of trypsin-EDTA, and then cultured in a concentration of 105 cells/well in 24-well plate. From the second day, lOppm of test compounds (kojic acid and products of Examples 1-10) were added for 3 consecutive days. Then, the media was removed and the cell was washed with PBS. And, the cell was dissolved in IN of sodium hydroxide and the absorbance was measured at 400nm. Melanin-inhibiting activity was calculated by means of the following equation 1 (Dooley's method):

[Equation 1] 100-[{(Absorbance of the test compound)/ (Absorbance of the control)} XI 00] The results are shown in Table 1.

[Table 1] Melanin-inhibiting activity of the kojic acid derivative Test compounds Melanin-inhibiting activity (% control) Kojic acid 25.0 Compd of Ex. 1 52.3 Compd of Ex. 2 45. 5 Compd of Ex. 3 40.5 Compd of Ex. 4 42. 8 Compd of Ex. 5 45. 7 Compd of Ex. 6 52. 3 Compd of Ex. 7 35. 5 Compd of Ex. 8 40.5 Compd of Ex. 9 39. 8 Compd of Ex. 10 45. 7

As shown in Table 1, the kojic acid derivatives of the present invention exhibit a strong activity of inhibiting melanin formation.

<Experimental example 2> Whitening effect on the skin The brachium of twelve (12) healthy volunteers (males) were attached with opaque tape having 1. 5cm-diameter hole, and then irradiated by UVB in 1.5-2 times of minimum amount to form erythema for each volunteer, to induce pigmentation.

Thereafter, 1% solution of each compound of Examples 1,3,5,7 and 9 (solvent: 1,3-butyleneglycol: ethanol = 7: 3), 3% solution of kojic acid as control and solvent were applied for ten (10) weeks. Every one (1) week, the color of the skin was measured by means of Chromameter CR 2002 (Japan, Minolta Co.).

The whitening effect was evaluated by measuring the increase of"L"value, i. e.

"A L". The results are shown in Table 2.

[Table 2] Whitening effect on the skin of the kojic acid derivative Test compounds Skin luminosity (A L) Solvent (Vehicle) 0.50+ 0.15 Kojic acid 0.99 0.11 Compd of Ex. 1 0.58 0.21 Compd of Ex. 3 1. 51+ 0.13 Compd of Ex. 5 1.22 0.18 Compd of Ex. 71. 71 0.25 Compd of Ex. 9 1.38 0.11

As shown in Table 2, the kojic acid derivatives of the present invention exhibit a strong whitening effect.

<Experimental example 3> Safety on the skin In order to evaluate the safety of the kojic acid derivative provided in the present invention, the patch test was carried out by employing the conventional nutrition creams containing the compounds of Examples 1-10 in amount of 5 wt%.

The brachium of thirty (30) healthy volunteers (15 males and 15 females) was thoroughly washed with 70% of ethanol and applied with a finn chamber

containing 20, c of a cream formulation containing 5 wt% of each of the compounds of Examples 1-10. The finn chamber was thoroughly attached to the brachium using an adhesive tape for 24 hours. As a control, a chamber containing only cream base was attached. 24 Hours later, the adhesive tape and the finn chamber were removed, and the adherent site of the arm was wiped with a qauze to remove the remaining preparation and observed skin irritation, for example, erythma, edema, papule, etc. Another 24 hours later, the site was reexamined. The results are shown in Table 3.

[Table 3]

Test preparations 24 hours later 48 hours later Control (Cream base) 0/30 0/30 Cream containing compd of Ex. 1 0/30 0/30 Cream containing compd of Ex. 2 0/30 0/30 Cream containing compd of Ex. 3 0/30 0/30 Cream containing compd of Ex. 4 1/30 0/30 Cream containing compd of Ex. 5 2/30 0/30 Cream containing compd of Ex. 6 0/30 0/30 Cream containing compd of Ex. 7 0/30 0/30 Cream containing compd of Ex. 8 1/30 0/30 Cream containing compd of Ex. 9 0/30 0/30 Cream containing compd of Ex. 10 1/30 0/30

(Note) The results are shown in terms of the number of positive subjects/the number of total subjects.

As shown in Table 3, although 1 or 2 volunteers showed a positive response in the experiment with the creams containing the compounds of Examples 1-10, these skin irritations were disappeared after 48 hours. Accordingly, it is

confirmed that the compounds of the present invention are safe to human skin.

As above described, the kojic acid derivatives of the present invention can exhibit a strong activity of inhibiting melanin formation and cure pigmentation of the skin, and therefore, can be incorporated as a whitening agent.

Although preferred embodiments of the present invention have been described in detail hereinabove, it should be clearly understood that many variations or modifications of the basic inventive concepts herein taught, which may appear to those skilled in the art, will still fall within the spirit and scope of the present invention as defined in the appended claims.