WO2005070915A1

WO2005070915A1 - 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, preparation method thereof and whitening composition containing the same

Info

Publication number: WO2005070915A1
Application number: PCT/KR2005/000215
Authority: WO
Inventors: Won Chul Choi
Original assignee: Han, Sang Min; Lee, Myung Hee
Priority date: 2004-01-26
Filing date: 2005-01-26
Publication date: 2005-08-04
Also published as: KR100632794B1; KR20050076912A

Abstract

The present invention relates to novel compounds, 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives and to preparation method thereof. In detail, 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives have strong tyrosinase inhibitory activity and thereby can inhibit melanin biosynthesis and exhibit skin-whitening effect. Further, the present invention relates to skin-whitening compositions containing 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient.

Description

1.3-BENZODIOXOL-5-YLMETHYL METHYL SULFONE AND ITS DERIVATIVES, PREPARATION METHOD THEREOF AND WHITENING COMPOSITION CONTAINING THE SAME

BACKGROUD OF THE INVENTION

.1. Field of the Invention The present invention relates to novel compounds, l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, and to a preparation method thereof. More particularly, the present invention relates to l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives represented by the following chemical formula 1, which have a strong tyrosinase inhibitory activity and thereby can inhibit melanin biosynthesis and exhibit a skin- whitening effect. [Chemical Formula 1]

wherein R is an alkyl group having 1 to 4 carbon atoms. Further, the present invention relates to skin-whitening compositions containing l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient. 2. Description of Prior Art Human skin produces melanin in order to scavenge active oxygen or free radicals spontaneously generated or to prevent UN-transmission, hi the process of melanogenesis, the starting substance is tyrosine, as species of amino acid normally existing in our body. Tyrosine is oxidized by tyrosinase in a melanocyte, to 3,4-dihydroxyphenylalanine (hereinafter, "DOPA"), followed by further oxidation to DOPA quinone. Later, DOPA quinone goes tlirough spontaneous oxidation to 5,6-dihydroxyindole, converted to indole-5,6-quinone and final dark brown melanin. {Goldsmith, L. A., Physiology, Biochemistry, and Molecular Biology of the Skin, Oxford University Press (1991)} . Thus, the best way to prevent melanin hyperpigmentation is to block each step of melanogenesis. For example, there are several ways ( i ) to block exposure to ultraviolet rays, ( ii) to use tyrosinase inhibitor, (iii) to administer substances exhibiting toxicity specifically to melanocyte and (iv) to accelerate melanin excretion. Substances for preventing hyperpigmentation on the skin can be classified, according to their mechanisms-of-action, into ultraviolet absorbent agents or ultraviolet scattering agents such as inorganic pigments for blocking out ultraviolet rays; tyrosinase inhibitors such as vitamin C or kojic acid; substances such as hydroqumone exhibiting toxicity to melanocyte; tocopherols to scavenge active oxygen or free radicals accelerating melanin biosynthesis; and AHA (alpha-hydroxyl acid) to accelerate melanin excretion by removing old horny layers. In particular, arbutin obtained by combining glucose with hydroqumone exhibiting toxicity only to melanocyte has been well known as a tyrosinase inhibitor, like kojic acid, and widely used in functional cosmetics for the purpose of skin whitening and anti-aging. Besides, retinal or ascorbic acid known to control skin aging are gathering interest from both inside and outside of Korea and are already available on the market. Their mechanisms-of-action have not been clarified yet, but many studies have reported that tyrosinase inhibitory action is related to a whitening effect, further then the anti-aging effect. {Curto, E. N. et al., Biochemical Pharmacology, 57, 663-672 (1999); Cabanes, J. et al, J. Pharm. Pharmacol, 46, 982-985 (1994)}. As mentioned above, tyrosinase inhibitors have been conventionally used as a whitening agent up to the present. However, they showed some problems at the same time, hi practice, 4-hydroxyanisol and hydroquinone have strong inhibitory activity on melanin biosynthesis and thereby were topically used for treatment of hyperpigmentation such as melasma, freckles, age spots and chloasma that appears during pregnancy. However, at the same time, they have side effects of inducing cell death or morphological change in melanocyte cells, and of damaging cellular intrinsic functions. Particularly, hydroquinone compounds were used as whitening agent for melanogenesis inhibitory creams, but lαiown to cause skin irritation or cutaneous diseases due to cytotoxicity. For this reason, their use is permitted only in some countries.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors have conducted extensive studies in order to develop a novel substance having strong tyrosinase inhibitory activity and no side effect. As a result thereof, a novel substance having tyrosinase inhibitory activity was developed, and confirmed that it could inliibit melanin biosynthesis. Thus, the present invention was completed. Therefore, an object of the present invention is to provide novel compounds having strong tyrosinase inhibitory activity, l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, and a preparation method thereof. Further, another object of the present invention is to provide skin- whitening compositions containing said l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows graphically the results of a cytotoxicity assay for the compounds provided by the present invention. Figure 2 shows graphically the inhibitory activity on melanin secretion of the compounds provided by the present invention. Figure 3 shows graphically the inhibitory activity on tyrosinase of the compounds provided by the present invention.

DETAILED DESCRIPTION OF THE INVENTION In order to accomplish said objects, the present invention provides l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives represented by the following chemical formula 1 : [Chemical Formula 1]

wherein, R is an alkyl group having 1 to 4 carbon atoms. A preferable example of said compounds of chemical foraiula 1 may include the following compounds : l,3-benzodioxol-5-ylmethyl methyl sulfone represented by the following chemical formula la ; [Chemical Foraiula la]

l,3-benzodioxol-5-ylmethyl ethyl sulfone represented by the following chemical formula lb ; [Chemical Foraiula lb]

l,3-benzodioxol-5-ylmethyl propyl sulfone represented by the following chemical formula lc ; [Chemical Foraiula lc]

l,3-benzodioxol-5-ylmethyl isopropyl sulfone represented by the following chemical foraiula Id ; [Chemical Formula Id]

l,3-benzodioxol-5-ylmethyl butyl sulfone represented by the following chemical formula le ; [Chemical Foraiula le]

Further, the present invention provides a method for preparing said 1 ,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives. The method for preparing said l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives comprises the following steps and is schematized by the following reaction scheme 1 : Step (1) of reacting l,3-benzodioxol-5-yl methanol of the following chemical foraiula 2, in the presence of thionyl chloride, to give 5-(chloromethyl)-l,3-benzodioxol of the following chemical foraiula 3; and [Chemical Foraiula 2]

[Chemical Foraiula 3]

step (2) of reacting 5-(chloromethyl)-l,3-benzodioxol of said chemical formula 3 with alkyl sulfonyl chloride of the following chemical formula 4, in the presence of magnesium and [l,3-bis(diρhenylphosρhino)propane] nickel(II) dichloride, to give l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives of said chemical formula

1

[Chemical Formula 4]

wherein R is alkyl group. hi said step (2), the reaction may take place in an organic solvent such as diethyl ether; tetrahydrofuran or their mixture, at a temperature of 0°C to 50°C, for 1 hour. [Reaction Scheme 1] _Mgcl

Further, l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives of the present invention have strong tyrosinase inhibitory activity and thereby can inhibit melanin biosynthesis, to be used as a whitening agent. Therefore, the present invention provides skin-whitening compositions containing l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient. The present whitening compositions may be provided in the form of solution, suspension or emulsion in oily or aqueous medium; provided as skin-care external composition or oral administration, in a form such as dried powder to be dissolved in sterile water without pyrogen, just before use; or formulated for parenteral administration such as hypodermic injection, intravenous injection or intramuscular injection. In the case of a skin-care external composition, it may be provided as a conventional formulation to be applied onto the skin. For example, it may be formulated into cosmetic products such as skin softeners, astringents, nutrient toilet water, nutrient creams, massage creams, essences, eye creams, eye essences, cleansing creams, cleansing foams, cleansing water, packs, powders, body lotions, body creams, body oils, body essences, make-up bases, foundations, body cleansers, tooth pastes and oral cleaning fluid; or into body cleansing products such as liquid soap, solid soaps and washing foams. These formulations may comprise all sorts of suitable substrates and additives necessary for the preparation thereof, whose kinds and amounts can be easily selected by one skilled in the ait. h the case of oral administration, it may be formulated into general oral formulations such as tablet, troche, lozenge, aqueous or oily suspension, dispersive powder or particle, emulsion, soft or hard capsule, syrup, elixir, etc. by conventional methods using pharmaceutically acceptable carriers or excipients. It may be prepared suitably according to unit dose or formulation. In the case of parenteral administration, it may be provided as sterile injection or suspension in which the active substance is suspended in a non-toxic diluent or in a solvent such as 1,3-butandiol. An excipient or solvent to be used, may be sterile water, Ringer's solution, isotomc saline, etc., which may also be used as a co-solvent with ethanol, polyethylene glycol or polypropylene glycol. Further, sterilized non-volatile oil may be conventionally used as a solvent or suspension solvent. Further, the parenteral administration may be provided in the form of a suppository in which the active substance is mixed with a non-irritative excipient such as cocoa butter, polyethylene glycol, etc. It may be suitable to use an excipient that is solid at room temperature but turns to liquid at a rectum temperature, to be dissolved within a rectum and thereby to release the active substance. In the case that the present composition is used for the treatment of hyperpigmentation, the dose of the compound of said chemical foraiula 1, as an active ingredient, may be controlled depending on the patient's condition such as age, weight, common health condition, sex, diet, administration time, defecation interval, drug to be combined, disease symptoms during treatment period, etc. hi detail, it may be administered daily within a range of 0.01 to 140 mg per kg weight and within a range of 0.5 mg to 7g per day, depending on disease. In addition, for the preparation of formulation, the amount of the present compound to be mixed with a carrier may be controlled depending on administration route and patient's condition. For example, in the case of topical application or oral administration, its formulation may comprise 0.5 mg to 5g of the present compound as an active ingredient and carriers of 5 to 95% by weight based on the total weight of the formulation. And, in case of parenteral administration, its formulation may comprise 0.1 mg to 2.5g of the present compound as an active ingredient and earners of 5% to 99% by weight based on the total weight of the formulation. PREFERRED EMBODIMENT OF THE INVENTION

The present invention will be described in more detail by way of the following examples. However, these examples are provided for the purpose of illustration only and should not be construed as limiting the scope of the invention, which will be apparent to one skilled in the art.

<Example 1> Preparation of l,3-benzodioxol-5-ylmethyl methyl sulfone Step (1): Preparation of 5-(chloromethyl)-l,3-benzodioxol 20 g of l,3-benzodioxol-5-yl methanol was dissolved in 50 ml of thionyl chloride at 0°C and stirred for 30 minutes, then reacted at 30°C for 2 hours. The reaction mixture was dried under reduced pressure, and then fractionated by column chromatography using ethyl acetate: n-hexane (1:3), to give 19 g of the title compound of the following chemical foraiula 3 (R_f: 0.55, Yield: 86%). [Chemical Foraiula 3]

The compound was dissolved in CDC1₃ and TMS and then characterized by H NMR spectroscopy. The result is as follows; 1H NMR δ: 4.53(s, 2H), 5.98(s, 2H), 6.75-6.88(m, 3H).

Step (2): Preparation of 3-benzodioxol-5-ylmethyl methyl sulfone 9.7 g of 5-(chloromethyι)-l,3-benzodioxol was dissolved in 20 ml of anliydrous tetrahydrofuran and 20 ml of diethyl ether and then added to magnesium at 0°C, and reacted for 10 minutes. The reactant was then heated to 50°C and reacted for 1 hour. The reaction mixture was cooled to 0°C and then slowly added to a flask containing [l,3-bis(diphenylphosphino)propane] nickel(II) dichloride as a catalyst. After the addition of 5 ml methane sulfonyl chloride, the mixture was reacted for 30 minutes, and the reactant was heated to 50°C and reacted for 1 hour. Then, its pH was adjusted to 7 with dilute hydrochloric acid. The resulting mixture was extracted with diethyl ether and distilled water, dried over anliydrous magnesium sulfate and the solvent was removed. The residue was fractionated by column chromatography using ethyl acetate: n-hexane (1 :3), to give 0.75 g of the title compound of the following foraiula la (R_f-: 0.35, Yield: 5%). [Chemical Formula la]

The compound was dissolved in CDC1 and TMS and then characterized by 1H NMR spectroscopy. The result is as follows; 1H NMR δ: 2.75(s, 3H), 4.14(s, 2H), 5.97(s, 2H), 6.81-6.88(m, 3H).

<Example 2> Preparation of l,3-benzodioxol-5-ylmethyl ethyl sulfone 8.6 g of 5-(chloromethyl)-l,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether and then added to magnesium at 0°C. The reaction was done for 10 minutes and then for 1 hour at 50°C. The reaction mixture was cooled to 0°C and then slowly added to the flask containing [1,3 -bis (diphenylphosphino)propane] nickel(II) dichloride as a catalyst. After the addition of 3.7 ml ethane sulfonyl chloride, the mixture was reacted for 30 minutes. The reactant was then heated to 50°C and reacted for 1 hour. Then, its pH was adjusted to 7 with dilute hydrochloric acid. The resulting mixture was extracted with diethyl ether and distilled water, dried over anliydrous magnesium sulfate and the solvent was removed. The residue was fractionated by column chromatography using ethyl acetate: n-hexane (1 :3), to give 0.3 g of the title compound of the following foraiula lb (R_f: 0.35, Yield: 3%). [Chemical Foraiula lb]

The compound was dissolved in CDC1 and TMS and then characterized by Η

NMR spectroscopy. The result is as follows;

1H NMR δ: 1.57-1.64(t, 3H, J=7.3Hz), 2.78(s, 2H), 3.60-3.78(q, 2H, J=7.3Hz), 5.90(s, 2H), 6.56-6.79(m, 3H).

<Example 3> Preparation of l,3-benzodioxol-5-ylmethyl propyl sulfone 5.0 g of 5-(chloromethyl)-l,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether and then added to magnesium at 0°C, and reacted for 10 minutes. The reactant was heated to 50°C and reacted for 1 hour. The reaction mixture was cooled to 0°C and then slowly added to a flask containing [l,3-bis(diphenylphosphmo)propane] nickel(II) dichloride as a catalyst. After the addition of 2.8 ml propane sulfonyl chloride, the mixture was reacted for 30 minutes, then the reactant was heated to 50°C and reacted for 1 hour. Then, its pH was adjusted to 7 with dilute hydrochloric acid. The resulting mixture was extracted with diethyl ether and distilled water, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was fractionated by column chromatography using ethyl acetate: n-hexane (1 :3), to give 0.8 g of the title compound of the following foraiula lc (R_f: 0.35, Yield: 7%). [Chemical Foraiula lc]

The compound was dissolved in CDC1₃ and TMS and then characterized by 1H NMR spectroscopy. The result is as follows; 1H NMR δ: 1.16-1.19(t, 3H, JY.OHz), 2.10-2.15(q, 2H, 7.4Hz), 2.81(s, 2H), 3.66-3.69(1, 2H, J=7.8Hz), 5.94(s, 2H), 6.61-6.63(d of d, 1H), 6.68(s, 1H), 7.28(d, 1H, J=0.8).

<Example 4> Preparation of l,3-benzodioxol-5-ylmethyl isopropyl sulfone 7.8 g of 5-(chloromethyl)-l,3-benzodioxol was dissolved in 20 ml of anliydrous tetrahydrofuran and 20 ml of diethyl ether and then added to magnesium at 0°C, and reacted for 10 minutes. The reactant was heated to 50°C and reacted for 1 hour. The reaction mixture was cooled to 0°C and then slowly added to a flask containing [l,3-bis(diphenylphosphino)propane] nickel(II) dichloride as a catalyst. After the addition of 3.9 ml isopropane sulfonyl chloride, the mixture was reacted for 30 minutes and the reactant was heated to 50°C and reacted for 1 hour. Then, its pH was adjusted to 7 with dilute hydrochloric acid. The resulting mixture was extracted with diethyl ether and distilled water, dried over anliydrous magnesium sulfate and the solvent was removed. The residue was fractionated by column chromatography using ethyl acetate: n-hexane (1 :3), to give 0.6 g of the title compound of the following foraiula Id (R_f: 0.35, Yield: 5%). [Chemical Formula Id]

The compound was dissolved in CDC1₃ and TMS and then characterized by H NMR spectroscopy. The result is as follows;

1H NMR δ: 1.60-1.62(d, 6H, Y6.7Hz), 2.79(s, 2H), 3.75-3.78(m, 1H), 5.91(s, 2H), 6.66(m, 3H)

<Example 5> Preparation of l,3-benzodioxol-5-ylmethyl butyl sulfone 7.1 g of 5-(chloromethyl)-l,3-benzodioxol was dissolved in 20 ml of anliydrous tetraliydrofuran and 20 ml of diethyl ether and then added to magnesium at 0°C and reacted for 10 minutes. The reactant was then heated to 50°C and reacted for 1 hour. The reaction mixture was cooled to 0°C and then slowly added to the flask containing [l,3-bis(diphenylphosphino)propane] nickel(II) dichloride as a catalyst. After the addition of 4.1 ml butane sulfonyl chloride, the reaction was done for 30 minutes and then for 1 hour at 50°C. Then, its pH was adjusted to 7 with dilute hydrochloric acid. The resulting mixture was extracted with diethyl ether and distilled water, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was fractionated by column chromatography using ethyl acetate: n-hexane (1 :3), to give 0.2 g of the title compound of the following formula le (R_f: 0.35, Yield: 2%). [Chemical Formula le]

The compound was dissolved in CDC1₃ and TMS and then characterized by ^!H NMR spectroscopy. The result is as follows;

'H NMR δ: 1.16-1.18(t, 3H, JY.OHz), 2.09-2.19(m, 4H), 2.81(s, 2H), 3.69-3.73(t, 2H), 5.94(s, 2H), 6.50-6.68(m, 3H), Experimental Example 1> Cytotoxicity Assay hi order to assay the cytotoxicities of the compounds prepared in said Examples 1 to 5, toxicity to melanocytes was tested according to the procedure described by Mosmami (Mosmaim, T.: J. Immunol Methods 65, 55-63, (1983)) using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (hereinafter, "MTT"). The toxic effects of the chemicals were examined by MTT assay. This assay is based on the cellular MTT reduction due to the decomposition of tetrazolium salts by viable cells. 5 mg/ml MTT solution was dissolved in phosphate buffer saline (hereinafter, "PBS") and filtered through a 0.22 μm filter to remove formazan crystals, and then was stored at room temperature in the dark. For this assay, B16 melanoma cells were seeded into 96-well microplates to a density of 10,000 cells/well, and the B 16 melanoma cells in each microplate were treated with 10 μg/ml of one of the compounds of Examples 1-5, arbutin, vitamin C or hydroqumone (Sigma). After incubation for a predetermined time, 10-fold dilution of MTT solution was added to each well and incubation was continued for a further 4 hours. The plates were centrifuged at 3,000 rpm for 1 minute, to remove 100 μl of supernatant. In order to remove formazan crystals, DMSO was added and the mixture was shaked in a microplate shaker to completely dissolve DMSO. The optical density at 560 nm was measured using microplate ELISA reader (El 312e, Bio-Tek). The cell viability in each test group treated with chemicals was evaluated as a relative value, considering the viability of a control group with no treatment as 100. The results are shown in Figure 1. As shown in Figure 1, arbutin and vitamin C, lαiown for their whitening effects, showed almost 100% of cell viability to a concentration of 10 μg/ml, but hydroqumone showed high cytotoxicity as lαiown. On the other hand, the compounds prepared in said Examples 1 to 5 showed very high viability. All the compounds of Examples 1-5 showed almost 100% of cell viability, indicating that the compounds of Examples 1-5 are very safe for the skin cells. Experimental Example 2> Inhibitory activity on melanin secretion in B16 melanoma cells In order to evaluate the whitening effect of the compounds provided by the present invention, this experiment was perfomied using decolorized B16 mouse melanoma cells, modifying the procedure described by Waiter Siegrist (Waiter Siegrist et al., Analytical

Biochemistry 159, 191-197, 1986). B16 cells were cultured on Dulbecco's Modified Eagle's Medium (DMEM, INBIS logenin) supplemented with 10% thermally inactivated fetal bovine serum (hereinafter, "FBS"), 100 mg/ml, streptomycin and 100 U/ml penicillin. The cultured B16 cells were detached with trypsin, and then seeded into 96-well microplates to a density of 1 X10⁴ cells/well. After 24 hr incubation, the culture medium was refreshed with phenol red-free DMEM containing 2 μM α-melanocyte stimulating hormone and 2 mM theophylline, and to each microplate, was added one of the compounds of Examples 1-5, arbutin, vitamin C or hydroqumone to a final concentration of 10 μg/ml.

Iincubation was then continued for a further 7 days. The whitening effects of the active substances added were evaluated by melanin contents secreted by B16 cells. After a lapse of 7 days after the treatment of the chemicals, the culture medium of each well was centrifuged to remove the cells. The optical density at 405 nm was measured using ELISA reader, to detemiine the melanin content secreted. The results are shown in Figure 2. The inhibitory activity of each chemical was calculated by means of the following equation:

[Equation 1]

Inhibitory activity (%) = (1 - OD of the test group treated with the chemical/OD of the control group) x 100

The results demonstrated that arbutin, vitamin C and hydroqumone had a tendency to inliibit melanin secretion in B16 melanoma cells in a dose-dependent manner. Further, some of the compounds prepared in Examples 1 to 5 showed inhibitory activity similar to or stronger than arbutin. Putting together the results of cytotoxicity by MTT assay, it was confirmed that some of the compounds of Examples 1-5 provided by the present invention inhibited melanin secretion by 80% or higher, without cytotoxicity, at a concentration of 0.1 to 10 μg/ml.

Experimental Example 3> Tyrosinase inhibitory activity In order to evaluate the inhibitory activity of the compounds of Examples 1 to 5 against tyrosinase that plays an important role in melanin biosynthesis, this experiment was performed modifying the procedure described by Nho et al. (Li/e Science, 65, 21, pi

241-246, 1999). Inhibitory activity on mushroom tyrosinase was assayed using commercially purified mushroom tyrosinase (Sigma). The compounds of Examples 1-5, arbutin, vitamin C and hydroquinone were each diluted to final concentrations of 10 μg/ml, and then 20 μl of each were added to 96-well microplates. L-tyrosine, as a substrate, was added to a final concentration of

1 10^"3M, and then 50 μl of tyrosinase solution (100 unit/ml) was added. As a buffer solution, phosphate buffer (pH 7.4) was used. After incubation at 37°C for 1 hour, the optical density at 490 nm was measured using ELISA reader, to determine the degree of pigmentation. The results are shown in Figure 3. In general, arbutin or hydroquinone have been reported to inliibit tyrosinase activity in several steps of melanogenesis and thereby to exhibit a skin- whitening effect.

This experiment demonstrated also that these two materials exhibited 60% or higher inhibition on tyrosinase activity, to be worthy as tyrosinase inhibitors. As demonstrated in said results, the compounds prepared in Examples 1 to 5 have stronger inhibitory activity against tyrosinase than arbutin, and thereby exhibit excellent whitening effects.

Although preferred embodiments of the present invention have been described in detail hereinabove, it should be clearly understood that many variations 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. INDUSTRIAL APPLICATION OF THE INVENTION

As above described, the novel compounds provided by the present invention have strong tyrosinase inhibitory activity, so to effectively inliibit melanin biosynthesis, and are safe for the skin without cytotoxicity and effective in skin whitening, so to be incorporated into whitening compositions as an active ingredient.

Claims

1. l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives represented by the following chemical foraiula 1 : [Chemical Foraiula 1]

wherein R is an alkyl group having 1 to 4 carbon atoms.

2. l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives according to Claim 1, which is selected from the group consisting of l,3-benzodioxol-5-ylmethyl methyl sulfone; l,3-benzodioxol-5-ylmethyl ethyl sulfone; l,3-benzodioxol-5-ylmethyl propyl sulfone; l,3-benzodioxol-5-ylmethyl isopropyl sulfone; and 1 ,3-benzodioxol-5-ylmethyl butyl sulfone.

3. A method for preparing l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, comprising the steps of (1) reacting l,3-benzodioxol-5-yl methanol of the following chemical foraiula 2, in the presence of thionyl chloride, to give 5-(chloiOinethyl)-l,3-benzodioxol of the following chemical foraiula 3; and [Chemical Foraiula 2]

[Chemical Foraiula 3]

(2) reacting 5-(chloromethyl)-l,3-benzodioxol of said chemical foraiula 3 with alkyl sulfonyl chloride of the following chemical formula 4, in the presence of magnesium and [l,3-bis(diphenylphosphino)propane] nickel(]I ) dichloride, to give l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives: [Chemical Formula 4]

wherein R is alkyl group.

4. The method according to Claim 3, wherein the reaction in said step (2) is perfoπned in an organic solvent such as diethyl ether, tetrahydrofuran or their mixture.

5. A whitening composition containing at least one of l,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives according to Claim 1, as an active ingredient.