KR100760288B1 - Novel oxyresveratrol derivative and a composition comprising the same showing skin whitening activity - Google Patents

Abstract

A composition comprising are provided to whiten and protect skin by containing oxyresveratrol derivatives having improved tyrosinase-inhibiting activity and stability in liquid due to different structure from the conventional oxyresveratrol. A skin external composition for skin whitening and skin protection comprises the novel oxyresveratrol derivative, 4-(6-hydroxy-2-naphtyl)-1,3-benzenediol, represented by the formula(1) and its pharmaceutically acceptable salt, and is a pharmaceutical composition having a formulation selected from cream, gel, patch, spray, ointment, plaster, lotion, liniment, pasta and cataplasma, or a cosmetic composition having a formulation selected from skin lotion, skin softener, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, foundation, essence, nutrition essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion and body cleanser.

Description

Novel oxyresveratrol derivative and a composition comprising the same showing skin whitening activity}

      The present invention relates to a oxyresveratrol derivative having a novel structure having an inhibitory effect on tyrosinase activity and a whitening effect and skin protection pharmaceutical composition and cosmetic composition containing the same as an active ingredient.

Melanin pigment produced by the melanocytes of the skin of the body is a phenolic polymer material having a complex form of a black pigment and protein, and plays an important role in inhibiting skin damage by ultraviolet radiation from the sun. However, excessive synthesis and accumulation of melanin not only causes severe aesthetic problems such as blemishes, freckles, and senile lentigo, but also promotes skin aging and causes skin cancer (Hearing VJ et al., FASEB J. , 5 , pp. 2902-2909, 1991).

It is known that the action of tyrosinase present in melanocytes is the most important for melanin biosynthesis. Tyrosinase is an enzyme that contains copper as a coenzyme. It is widely distributed in various animals, plants, and microorganisms, including humans, and it is possible to hydrate L-tyrosine (L-DOPA; dihydroxy-phenylalanine) among amino acids. It is a type of polyphenol oxidase that is oxylated and in turn oxidizes L-dopa to dopaquinone, a component of the melanin polymer (Korner A. et al., Science 217 :, pp. 1163-1165 , 1982). Dopaquinone is oxidized back to leucochrome, and dopachrome produced by oxidation of leucochrome is either 5,6-dehydroxy indole (DHI) or 5,6-dihydroxy. It is converted into indole carboxylic acid (5,6-dehydroxyindole carboxylic acid) and DHI and the like are combined with proteins to form melanin through polymerization (Pavel S., J. Invest . Dermatol , 100 (2 suppl): 162S -165S, 1993 Feb).

       Therefore, most studies for skin whitening and skin cancer prevention through melanin overproduction and deposition inhibition focus on the inhibition of tyrosinase activity.

      As tyrosinase activity inhibitors that have been developed to date, kojic acid, arbutin, licorice extract, and mulberry extract, which inhibit melanin production by inhibiting tyrosinase activity catalyzing the oxidation of tyrosine, are known.

  In addition, 4-hydroxyanisole, 4-hydroanione, hydroquinone, retinol, or hydrocortisole, etc., are known to have a whitening effect by inhibiting tyrosinase activity.

       Among them, hydroquinone is a representative whitening agent active ingredient and shows a strong inhibitory effect on tyrosinase, but not only causes skin irritation or dermatitis due to cytotoxicity such as degeneration or lethality of melanocytes, but also strong against mammalian cells. It is known to act as a mutagen. Therefore, as part of efforts to find low cytotoxic tyrosinase inhibitors, the search for alternatives to hydroquinone, such as arbutin, has been conducted. Recently, Schisandra chinensis (Patent No. 10-228741) and grape seed (Patent application publication 2000-34037), mugwort (patent application No. 97-64450), whitening cosmetics containing Ho Jang-geun extract (patent registration No. 10-0084763-0000), and also extract of lettuce extract (patent registration No. 10-0122094-0000) Attempts have been made to find substances with tyrosinase inhibitory activity from natural products.

      However, these substances are known to have low cytotoxicity but inferior tyrosinase inhibitory ability to hydroquinone, and thus no effective tyrosinase inhibitors have been developed to replace hydroquinone.

       Therefore, a new whitening agent excellent in inhibiting the tyrosinase activity of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol as a compound of the present invention was selected.

The present inventors have found that the inhibitory effect was continued a study to explore the excellent material, of the natural vegetable banyan (Moraceae) Mulberry plant for tyrosinase (Mours Oxyresveratrol among various stilbene compounds obtained by separating and purifying the extract fraction of alba L.), the root skin of alba l., strongly inhibits the activity of tyrosinase, an enzyme associated with whitening, and is widely used in cosmetics. It is known in the literature that it is better than kojic acid (Shin MH et al., Biochem . Biophys . Res . Commun ., 243, 801-3 , 1998).

      However, the amount of oxyresveratrol component present in the baekryepi skin is not so much and effective synthetic methods have not been established yet, it is currently used in the manufacture of whitening cosmetics containing the extract of baekryepimus root containing oxyresveratrol.

      Therefore, the present inventors have synthesized a derivative which has a stronger tyrosinase inhibitory ability than the known oxresveratrol and is stable and mass-synthesizable in the liquid phase and uses the present invention as a material that inhibits the optimal tyrosinase enzyme in a whitening cosmetic composition. It was completed.

It is an object of the present invention to provide a oxyresveratrol derivative having a novel structure having an inhibitory effect on tyrosinase activity and a whitening effect and skin protection pharmaceutical composition and cosmetic composition containing the same as an active ingredient.

      In order to achieve the above object, the present invention provides a oxyresveratrol derivative having a novel structure having an inhibitory effect on tyrosinase activity and a whitening effect and skin protection pharmaceutical composition and cosmetic composition containing the same as an active ingredient.

      Specifically, the present invention provides 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and a pharmaceutically acceptable salt thereof of the novel structure represented by the following structural formula (1):

                          (One)

     4- (6-hydroxy-2-naphthyl) -1,3-benzenediol of the present invention represented by the above formula (1) may be prepared as a pharmaceutically acceptable salt according to a conventional method in the art. Can be.

As salts are acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol of formula (1) above, unless otherwise indicated, are present in the compound of formula (1) Salts of acidic or basic groups which may be present. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, which are known in the art. It can be prepared through.

       Another object of the present invention is to provide a method for preparing the compound of formula (1), which may be chemically synthesized by the method shown in the following schemes, but is not limited thereto.

The following reaction schemes represent the preparation method of the compound of the present invention in stages of manufacture, and may be prepared with small modifications such as changing the reagents, solvents, and reaction sequences used in the synthesis of Scheme 1 of the present invention. Described in the examples.

        Scheme (1) shows the process for preparing the oxyresveratrol derivative.

       To the 2-bromonaphthalene compound of formula (2), a metal condensing agent such as magnesium is slowly added dropwise at low temperature under an inert solvent such as THF, and 30 minutes to a reaction temperature of 40 to 100 ° C, preferably about 60 ° C. After heating and stirring for 24 hours, preferably 1 to 3 hours, to which a bromobenzene compound of formula (3) is added, it is 6 to 24 hours at a reaction temperature of 40 to 100 ° C, preferably about 60 ° C. The novel oxyresveratrol derivative of formula (1) can be synthesized through a condensation reaction heated for a period of time, preferably about 12 hours, but the present invention is not intended to limit the preparation method to the preparation method described in Scheme 1.

      Another object of the present invention is to provide a novel oxyresveratrol derivative of formula (1) comprising a condensation step of reacting the 2-bromonaphthalene compound of formula (2) with a bromobenzene compound of formula (3) in the presence of a condensing agent. It provides a manufacturing method for manufacturing.

     Compound of the formula (1) obtained by the production method of the present invention by confirming the inhibitory effect on tyrosinase, a whitening-related enzyme, the oxyresveratrol derivative compounds of the present invention have a whitening effect and skin protection function And it can be usefully used as a cosmetic composition.

       The present invention provides a whitening effect and skin containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and a pharmaceutically acceptable salt thereof having a novel structure obtained by the above method as an active ingredient. It provides a skin external pharmaceutical composition having a protective function.

The external skin pharmaceutical composition having a whitening effect and skin protection function of the present invention is included in an amount of 0.1 to 50% by weight based on the total weight of the composition.

The external dermal pharmaceutical composition comprising 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and a pharmaceutically acceptable salt thereof of the novel structure of the present invention is commonly used in the preparation of pharmaceutical compositions. Suitable carriers, excipients and diluents may further be used.

     The pharmaceutical composition comprising 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and its pharmaceutically acceptable salts of the novel structure according to the present invention may be prepared according to conventional methods, respectively, It can be used in the form of external preparations such as granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and sterile injectable solutions, preferably creams, gels, patches, sprays, ointments, warnings, lotions, Provided is an external skin pharmaceutical composition of linen, pasta, or cataplasma.

     Carriers, excipients and diluents that may be included in the composition comprising the novel structure of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and pharmaceutically acceptable salts thereof include lactose, dex Rhodes, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, Methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil are mentioned. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspending agents, liquid solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

     A composition having a whitening effect and skin protection function containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and a pharmaceutically acceptable salt thereof of the novel structure of the present invention is applied to the skin As an external preparation for skin, it may be prepared as a pharmaceutical composition in the form of an external preparation for cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasm, but is not limited thereto. It is not.

Preferred dosages of the composition containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and its pharmaceutically acceptable salts of the novel structures of the invention are determined by the condition and weight, Depending on the degree, drug form, route of administration, and duration, it may be appropriately selected by those skilled in the art. However, for the preferred effect, the composition of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg per day. Topical administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

      In addition, the present invention has a whitening effect and skin protection function containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol of the novel structure represented by the formula (1) as an active ingredient. It provides a cosmetic composition.

      4- (6-hydroxy-2-naphthyl) -1,3-benzenediol of the present invention can be used in a variety of applications such as cosmetics and face washes for the whitening effect and skin protection function. Examples of products to which the present composition can be added include cosmetics such as various creams, lotions, skins, and the like, cleansing agents, face washes, soaps, treatments, and essences.

     Cosmetics of the present invention comprises a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids and seaweed extract.

The water-soluble vitamins may be any compound that can be incorporated into cosmetics, but preferably vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, vitamin H, and the like. Their salts (thiamine hydrochloride, sodium ascorbate salt, etc.) and derivatives (ascorbic acid-2-sodium phosphate salt, ascorbic acid-2-magnesium phosphate salt, etc.) may also be used in the water-soluble vitamins that can be used in the present invention. Included. The water-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microorganism culture, enzyme or chemical synthesis.

     The oil-soluble vitamin may be any compound that can be incorporated into cosmetics, but preferably vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), and the like. And derivatives thereof (ascorbic palmitate, ascorbic stearate, ascorbic acid dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherolvitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenyl ethyl) Ethers, etc.) are also included in the oil-soluble vitamins used in the present invention. Oil-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification of microorganism culture, enzyme or chemical synthesis.

      The polymer peptide may be any compound as long as it can be incorporated into cosmetics. Preferably, collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, keratin, and the like can be given. Polymeric peptides can be purified and obtained by conventional methods such as purification from microbial cultures, enzymatic methods or chemical synthesis methods, or can be purified and used from natural products such as dermis and pig silk such as pigs and cattle.

      The polymer polysaccharide may be any compound as long as it can be blended into cosmetics. Preferably, hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate or a salt thereof (sodium salt, etc.) may be mentioned. For example, chondroitin sulfate or its salt, etc. can be normally purified from a mammal or fish.

      The sphingolipid may be any compound as long as it can be blended into cosmetics. Preferably, ceramide, phytosphingosine, sphingosaccharide lipid, etc. may be mentioned. Sphingo lipids can usually be purified from mammals, fish, shellfish, yeasts or plants by conventional methods or obtained by chemical synthesis.

     The seaweed extract may be any compound as long as it can be blended into cosmetics. Preferably, the seaweed extract may include brown algae extract, red algae extract, green algae extract, and the like. Also, calginine, arginic acid, sodium arginate, Potassium arginate and the like are also included in the seaweed extract used in the present invention. Seaweed extract can be obtained by purification from seaweed by conventional methods.

     In addition to the said essential component, you may mix | blend the cosmetics of this invention with the other components normally mix | blended with cosmetics as needed.

     Other components that may be added include fats and oils, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, Blood circulation accelerators, cooling agents, restriction agents, purified water and the like.

      Examples of the fat or oil component include ester fats, hydrocarbon fats, silicone fats, fluorine fats, animal fats, and vegetable fats and oils.

      As ester fats and oils, glyceryl tri2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl mystinate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, and stearic acid Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl acid isocetyl, isostyl acid isostearyl, isostaryl palmitate, octylate acid octyldodecyl, isostearic acid isetyl, diethyl sebacate, adipine Acid isopropyl, isoalkyl neopentane, tri (capryl, capric acid) glyceryl, trimethyl ethyl trimethylol propane, triisostearic acid trimethylol propane, tetra 2-ethylhexanoic penta erythritol Cetyl caprylate, lauric acid decyl, hexyl laurate, decyl myristin, myristin acid myristyl, myritic acid cetyl, stearyl stearate, decyl oleate, rininooleic acid , Isostearyl laurate, isotridecyl myristin, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecate oleate, octylate decyl oleate, octyl dodecyl linoleate, isopropyl isopropyl acid, 2 -Cetostearyl ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicapric acid, propylene glycol dicacapate, capric acid Propylene glycol, dicapric acid neopentyl glycol, dioctanoate neopentyl glycol, tricaprylic acid glyceryl, triundecyl glyceryl, triisopalmitinate glyceryl, triisostearate glyceryl, neopentane dodecyl Isostearyl octanoate, octyl isononate, hexyl decyl neodecanoate, octyl dodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, Sothete octylate, polyglycerol oleate, polyglycerine isostearate, triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myritic lactate, octyl lactate, octyl lactate Ethyl, acetyl triethyl citrate, acetyl tributyl citrate, trioctyl citrate, diisostearyl malic acid, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipicate, diisopropyl sebacinate, Dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, physteryl isostearate, phytic oleate, 12-Steloylhydroxystearate isocetyl, 12-Steloylhydroxystearate stearyl, 12-stealo Esters such as monohydroxystearic acid isostearyl; and the like.

        Hydrocarbon-based fats and oils, such as squalene, a liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, a liquid isoparaffin, polybutene, microcrystal wax, and a vaseline, etc. are mentioned as a hydrocarbon-type fats and oils.

       Examples of the silicone-based oils and fats include polymethylsilicone, methylphenylsilicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane, methylcetyloxysiloxane copolymer, dimethylsiloxane and methylsteoxysiloxane copolymer, and alkyl. Modified silicone oil, amino modified silicone oil and the like.

Perfluoro polyether etc. are mentioned as fluorine-based fats and oils.

Animal or vegetable oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, soybean oil, soybean oil, corn oil, rapeseed oil, almond oil, palm kernel oil, palm oil, castor oil, sunflower oil, grape seed oil. , Cottonseed oil, Palm oil, Cucumber nut oil, Wheat germ oil, Rice germ oil, Shea butter, Walnut colostrum oil, Marker demia nut oil, Meadow home oil, Egg yolk oil, Uji, Horse oil, Mink oil, Orange rape oil, Jojoba oil And animal or plant fats and oils such as candeler wax, carnava wax, liquid lanolin and hardened castor oil.

      Examples of the moisturizing agent include a water-soluble low molecular moisturizer, a fat-soluble molecular moisturizer, a water-soluble polymer, and a fat-soluble polymer.

      Water-soluble low molecular humectants include serine, glutamine, sorbitol, mannitol, pyrrolidone-sodium carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (polymerization degree n = 2 or more), polypropylene Glycol (polymerization degree n = 2 or more), polyglycerol B (polymerization degree n = 2 or more), lactic acid, lactic acid salt, etc. are mentioned.

     Examples of the fat-soluble low molecular humectants include cholesterol and cholesterol esters.

     Examples of the water-soluble polymer include carboxyvinyl polymer, polyasparaginate, tragacanth, xanthan gum, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, water soluble chitin, chitosan, and dextrin. Can be.

     Examples of the fat-soluble polymers include polyvinylpyrrolidone-eicosene copolymers, polyvinylpyrrolidone-hexadecene copolymers, nitrocellulose, dextrin fatty acid esters, polymer silicones, and the like.

     Examples of the emollient include long-chain acyl glutamic acid cholesteryl esters, hydroxy stearic acid cholesterol, 12-hydroxystearic acid, stearic acid, rosin acid, lanolin fatty acid cholesteryl esters, and the like.

     As surfactant, nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant, etc. are mentioned.

     As the nonionic surfactant, self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerol fatty acid ester, sorbitan fatty acid ester, POE (polyoxyethylene) sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE Glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hardened castor oil, POE castor oil, POE / POP (polyoxyethylene / polyoxypropylene) copolymer, POE / POP alkyl ether, polyether modified silicone, lauric acid Alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid, etc. are mentioned.

     Anionic surfactants include fatty acid soaps, alpha-acyl sulfonates, alkyl sulfonates, alkyl allyl sulfonates, alkyl naphthalene sulfonates, alkyl sulfates, POE alkyl ether sulfates, alkylamide sulfates, alkyl phosphates, POE alkylphosphates, and alkylamides. Phosphates, alkyloylalkyltaurine salts, N-acylamino acid salts, POE alkyl ether carboxylate salts, alkyl sulfosuccinate salts, sodium alkyl sulfo acetates, acylated hydrolyzed collagen peptide salts, perfluoroalkyl phosphate esters, and the like. have.

     As cationic surfactant, alkyl trimethylammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, cetostearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium bromide, behenyl trimethyl ammonium chloride, chloride Benzalkonium, diethylaminoethyl stearate, dimethylaminopropyl stearate, lanolin derivatives, quaternary ammonium salts, and the like.

      Examples of amphoteric surfactants include the carboxybetaine type, the amide betain type, the sulfobetain type, the hydroxysulfobetain type, the amide sulfobetain type, the phosphobetaine type, the aminocarboxylate type, the imidazoline derivative type, and the amideamine type. An amphoteric surfactant etc. are mentioned.

Organic and inorganic pigments include silicic acid, silicic anhydride, magnesium silicate, talc, sericite, mica, kaolin, bengala, clay, bentonite, titanium film mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, aluminum oxide Inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, ultramarine blue, chromium oxide, chromium hydroxide, calamine and composites thereof; Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenol resin, fluorine resin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene, styrene copolymer, Organic pigments such as silk powder, cellulose, CI pigment yellow, CI pigment orange, and composite pigments of these inorganic pigments and organic pigments;

As organic powder, Metal soaps, such as a calcium stearate; Alkyl phosphate metal salts such as sodium cetylinate, zinc lauryl acid and calcium laurate; Acylamino acid polyvalent metal salts such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroylglycine calcium; Amide sulfonic acid polyvalent metal salts, such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N-epsilon-lauroyl-L-lysine, N-epsilon-palmitolyzine, N-alpha-paratoylol nitin, N-alpha-lauroyl arginine, N-alpha-cured fatty acid acyl arginine -Acyl basic amino acid; N-acyl polypeptides, such as N-lauroyl glycyl glycine; Alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid; Polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, divinylbenzene-styrene copolymer, ethylene tetrafluoride and the like.

Examples of the ultraviolet absorber include paraaminobenzoic acid, ethyl paraaminobenzoate, amyl paraaminobenzoic acid, octyl paraaminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomentyl salicylic acid and benzyl cinnamic acid. , Paramethoxy cinnamic acid-2-ethoxyethyl, paramethoxy cinnamic acid octyl, diparamethoxy cinnamic acid mono-2-ethylhexaneglyceryl, paramethoxy cinnamic acid isopropyl, diisopropyl diisopropyl cinnamic acid ester mixture, wuro Canonic acid, ethyl urokanoate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and salts thereof, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium sulfonate, dihydroxybenzophenone , Tetrahydroxybenzophenone, 4- tert -butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino- p- (carbo-2'-ethylhexyl-1'-oxy) -1 , 3,5-triazine, 2- (2-hi And the like can be mentioned hydroxy-5-methylphenyl) benzotriazole.

      As fungicides, hinokithiol, trichloric acid, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, ginxitlionone, benzalkonium chloride, photosensitive Sodium No. 301, sodium mononitroguicol, undecylenic acid, and the like.

      Examples of the antioxidant include butylhydroxyanisole, propyl gallic acid, and erythorbic acid.

      Examples of the pH adjuster include citric acid, sodium citrate, malic acid, sodium malate, fmaric acid, sodium pmarate, succinic acid, sodium succinate, sodium hydroxide, sodium dihydrogen phosphate, and the like.

      Examples of the alcohol include higher alcohols such as cetyl alcohol.

     Moreover, the compounding component which may be added other than this is not limited to this, Moreover, Although all said components can be mix | blended within the range which does not impair the objective and effect of this invention, Preferably it is 0.01-5% weight percentage with respect to a total weight, More preferably 0.01-3% by weight.

     The cosmetic of the present invention may take the form of a solution, an emulsion, a viscous mixture, or the like.

    Ingredients included in the cosmetic composition of the present invention may include components commonly used in cosmetic compositions in addition to the compound as an active ingredient, for example, conventional auxiliary agents such as stabilizers, solubilizers, vitamins, pigments and flavorings. And carriers.

    The cosmetic composition of the present invention may be prepared in any formulation commonly prepared in the art, and includes, for example, milky lotion, cream, lotion, pack, foundation, lotion, essence, hair cosmetic, and the like.

    Specifically, the cosmetic composition of the present invention skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, Formulations of packs, soaps, cleansing foams, cleansing lotions, cleansing creams, body lotions and body cleansers.

    When the formulation of the present invention is a paste, cream or gel, animal carriers, vegetable fibers, waxes, paraffins, starches, tracantes, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide, etc. may be used as carrier components. Can be.

    When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.

    When the formulation of the present invention is a solution or emulsion, a solvent, solvating or emulsifying agent is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

    When the dosage form of the present invention is a suspension, liquid carrier 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 metahydroxy, bentonite, agar or tracant and the like can be used.

    When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

     Hereinafter, the present invention will be described in detail by the following Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

Example  One. 4- (6-hydroxy-2- Naphthyl ) -1,3- Benzenediol  Produce

Step 1. 2- (2,4- Dimethoxyphenyl ) -6- Methoxy  Preparation of Naphthalene

   Tetrahydrofuran was added to 0.4 g of completely dried magnesium, and 3.66 g of 1-bromo-2,4-dimethoxy benzene was dissolved in THF and slowly added at 0 ° C. After heating to 60 ℃ stirred for 2 hours. After cooling to room temperature again, the mixture was slowly added to a flask containing a nickel catalyst and 2-bromo-6-methoxy naphthalene (2 g). After heating to 60 ° C., the mixture was stirred for about 12 hours. After the reaction was completed, the mixture was diluted with ice water and neutralized to pH 7 using hydrochloric acid. Extracted with ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and then separated by column chromatography using ethyl acetate: hexane = 1: 50 as eluent to obtain 2- (2,4-dimethoxyphenyl having the following physical properties. ) -6-methoxy naphthalene (1.05 g) was obtained. (Yield 41%)

R _f : 0.33, ethyl acetate: hexane (1: 50);

m.p: 99 ° C .;

¹ H-NMR (Benzene-D ₆ ): δ ppm 3.255 (s, 3H), 3.388 (s, 3H), 3.412 (s, 3H), 6.465-6.512 (d, 1H, J = 8.4 Hz), 6.580 ( s, 1H), 6.986 (s, 1H), 7.185-7.234 (d, 1H, J = 9 Hz), 7.359-7.399 (d of d, 1H, J = 3.6 Hz, 8.4 Hz), 7.574-7.614 (d of d, 1H, J = 3 Hz, 9 Hz), 7.702-7.740 (d, 1H, J = 8.4 Hz), 7.862-7.901 (d, 1H, J = 8.7 Hz), 8.003 (s, 1H);

¹³ C-NMR (Benzene-D ₆ ): δ ppm 55.12, 55.33, 55.43, 100.03, 105.38, 106.25, 119.49, 124.75, 126.79, 129.71, 130.04, 130.33, 132.27, 134.34, 135.03, 158.43, 158.62, 161.26.

Step 2. 4- (6-hydroxy-2- Naphthyl ) -1,3- Benzenediol  Produce

    500 mg of 2- (2,4-dimethoxyphenyl) -6-methoxy naphthalene obtained in step 1 was dissolved in 30 mL of completely dry methylene chloride, and then 5.1 mL of boron trifluoride was slowly added at 0 ° C. After stirring for 30 minutes, the temperature was raised to 50 ℃, and then stirred for 4 hours. After the reaction was completed, the temperature was lowered to 0 ° C., and a saturated aqueous sodium hydrogen carbonate solution was slowly added until the pH was about 6, extracted with ethyl acetate and water, dried over anhydrous magnesium sulfate, and the solvent was removed. Eluent was separated by column chromatography using ethyl acetate: hexane = 1: 50 to obtain 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol (366.5 mg) having the following physical properties. Got it. (Yield 86%)

R _f : 0.32, ethyl acetate: hexanes (1: 50);

m.p: 186 ° C;

¹ H-NMR (Benzene-D ₆ ): δ ppm 6.700-6.736 (d of d, 1H, J = 2.1 Hz, 8.1 Hz), 6.859-6.867 (d, 1H, J = 2.4 Hz), 7.230-7.267 ( d of d, 1H, J = 2.4 Hz, 8.7 Hz), 7.270-7.298 (d, 1H, J = 8.4 Hz), 7.366-7.374 (d, 1H, J = 2.4 Hz), 7.592-7.611 (d, 1H , J = 5.7 Hz), 7.621-7.640 (d, 1H, J = 5.7 Hz), 7.760-7.793 (d of d, 1H, J = 1.5 Hz, 8.4 Hz), 7.977 (s, 1H);

¹³ C-NMR (Benzene-D ₆ ): δ ppm 103.99, 108.142, 109.79, 119.07, 121.86, 126.66, 127.36, 129.33, 130.43, 132.47, 134.55, 134.69, 155.85, 156.08, 158.53.

 name rescue 4- (6-hydroxy-2-naphtyl) -1,3-benzendiol

Experimental Example  1. Measurement of Inhibitory Effect on Tyrosinase

In order to confirm the whitening activity of the compounds described in the above examples, tyrosinase inhibition experiments described in the literature were carried out as follows. (No J. K et al , Life Sci . , 65 , PL241246,1999).

      A 20 μl aqueous solution of mushroom tyrosinase (1000 units, Sigma) was added to the 96-well microplate, followed by the addition of 1 mM L-tyrosine solution and 50 mM buffer (pH 6.5) to a total volume of 200 μl.

The assay mixture was incubated at 25 ° C. for 30 minutes. Thereafter, the dopachrome number generated in the reaction mixture was spectrophotometrically measured at 492 nm (OD 492) in a microplate reader, with IC ₅₀ representing the concentration of substrate corresponding to 50% inhibition of activity.

IC ₅₀ based on the control without the sample using Equation 1 described in the literature The tyrosinase enzyme inhibition effect by the value was calculated. (Hewlett Packa et al ., Biol . Pharm . Bull . 19 (1) , pp. 153-156,1996)

% Tyrosinase inhibition rate = (reaction absorbance of 100-test sample / reaction absorbance of control) × 100

      As a result, 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol showed stronger inhibitory effect than the existing strong tyrosinase inhibitors, especially about 985 times stronger than the inhibitory effect of hydroquinone. It was confirmed to have inhibitory ability.

       Tyrosinase inhibitory effects on 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol were investigated by hydroquinone (H9003, Sigma), kojic acid (K3125, Sigma) and resveratrol (R5010, Sigma). It is shown in Table 2 in comparison with 4). (Each number is the average of three experiments.)

             sample IC ₅₀ (μM)           Hydroquinone                33.48             Kojic acid                38.24           Resveratrol                55.61   4- (6-hydroxy-2-naphthyl) -1,3-benzenediol                0.034

Experimental Example  2. Cell viability measurement

The experiment as described below to proliferate the cells using the test method of the ride (Tada) described in the literature in order to determine the cell viability of the compounds described in this Example was carried out. (H Tada et al ., J. Immunol . Methods , 93 , pp. 157-165, 1986)

This method used 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium brimide (MTT; M2128, Sigma) and B16 cells (B16F10 murine melanoma cells, Korea Cell Line Bank) were used. 4 hours in DMEM with 10% fetal bovine serum (FBS; Gibco) and penicillin / streptomycin (100 IU / 50 μg / ml) under humid atmospheric conditions containing 5% CO ₂ . Incubated at 37 ° C.

The cultured cells were added to a 24-well plate at a concentration of 5 × 10 ⁴ , and the cells were then concentrated for 24 hours at the concentration of drug [4- (6-hydroxy-2-naphthyl) -1,3-benzenediol]. After much exposure, 5 mg / ml of MTT solution was added thereto. Insoluble derivatives formed by cytoplasmic dehydrogenase in this reaction were dissolved by EtOH-DMSO (1: 1 mixed solution). Each well was measured using a microplate reader (fluorescence / phosphorescence / absorption analyzer, GreenMake ZIOTECH Co., Ltd.) at an absorption wavelength of 560 nm.

      As a result of the experiment, it was confirmed that 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol of the present invention showed cell viability as shown in FIG. 4 (see FIG. 4).

      In other words, 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol showed a survival rate of 96.60% at 20 μM, 93.86% at 50 μM, and 87.36% at 100 μM.

Experimental Example  3. Determination of melanin content

In order to determine the melanin content of the compounds described in the above examples, experiments were carried out as follows using the method of Bilodeeau described in the literature. (Bilodeau M. L et al ., Pigmen . Cell Res . , 14, pp. 328-336, 2001)

In the melanin production test, 5 × 10 ⁴ B16 cells (B16F10 murine melanoma cells, Korea Cell Line Bank) were used in a 24-well multi-dish culture.

       After addition of the α-MSH in the comparative group and the addition of 22μl of 100μM α-MSH, the drug was added by concentration (10-200㎛) and incubated for 24 hours. After washing twice with PBS, the samples were dissolved in 100 μl of 1N NaOH, incubated at 60 ° C. for 1 hour, and then thoroughly mixed to dissolve melanin. Then absorbance was measured at 405 nm.

       As a result of the experiment, 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol showed a cell survival rate of 96.60% at 20μM, 93.86% at 50μM, and 87.36% at 100μM. In contrast, melanin production was strongly inhibited to 95.94% at 20μM, 92.71% at 50μM and 35.94% at 100μM (see Figure 4).

    density     One     2     3   AvG (%) *   S.E ** 100 μ M   86.17   79.41   96.50   87.36   4.97 50 μ M   96.44   91.29   93.85   93.86   1.49 20 μ M   96.12   97.55   96.12   96.60   0.48 * AvG (%): Average ** S.E: Standard Deviation

Examples of the formulation of the composition are described below, but are not intended to limit the present invention but to explain in detail only.

Formulation example  1. Flexible Lotion

  number          Raw material Content (% by weight)     One Compound of Example 1    0.5     2 Butylene Glycol    4.0     3 glycerin    8.0     4 Carboxy Vinyl Polymer    0.06     5 Disodium ethylenediamineteracetic acid    0.01     6 ethanol    7.0     7 Triethanolamine    0.2     8 Sorbitan monostearate    0.8     9 Hydrogenated Castor Oil    0.4    10 Phenyltrimethicone    3.5    11 Paraoxybenzoic acid propyl    0.2    12 Methyl paraoxybenzoate    0.2    13 Purified water    Remaining amount    system    100.0

Formulation example  2. Nutritional Cosmetics

  number       Raw material Content (% by weight)     One Compound of Example 1     0.5     2 Stearic acid     1.0     3 Cetyl alcohol     1.0     4 Glyceryl Monostearate     1.0     5 Polyoxyethylene sorbitan monostearate     1.0     6 Sorbitan sesquioleate     1.0     7 Liquid paraffin     4.0     8 Carlylic / Capric Triglycerides     4.0     9 Squalane     3.0    10 Carboxy Vinyl Polymer     0.1    11 Butylene glycol     5.0    12 Triethanolamine     0.2    13 Paraoxybenzoic acid propyl     0.2    14 Methyl paraoxybenzoate     0.2    15 Purified water    Remaining amount    system   100.0

Formulation example  3. Nutrition Cream

number ingredient Content (unit: weight%)    One Compound of Example 1   1.00    2 Propylene glycol   4.00    3 Triethanolamine   0.65    4 glycerin   6.00    5 Glycerin Monostearate   2.00    6 Cetearyl Alcohol   2.50    7 Beeswax   1.00    8 Stearic acid   2.00    9 Squalane   4.00    10 silicon   3.00    11 Seesaw oil   0.50    12 Spices   Quantity    13 antiseptic   Quantity    14 Purified water  To 100 Sum Sum    100

Formulation example  4. Essence

  number ingredient Content (unit: weight%)    One Compound of Example 1     1.00    2 Allantoin     0.02    3 Sodium Hyaluronate (1%)     8.00    4 glycerin    10.00    5 Witch hazel     2.00    6 Carbomer     0.40    7 Triethanolamine     0.40    8 Ethyl alcohol     2.00    9 Carboxy Vinyl Polymer     0.20   10 Benzophenone-9     0.04   11 antiseptic     Quantity   12 Spices     Quantity   13 Purified water    To 100  Sum Sum     100

Formulation example  5. Preparation of Hydrophilic Ointment

number Raw material Content (% by weight) Content (% by weight)   One   Compound of Example 1 0.5 -   2   Compound of Example 1 - 0.5   3   White vaseline 250 250   4   Stearyl alcohol 220 220   5   Ethyl (or methyl) p-oxybenzoate 0.25 0.25   6   Propylene glycol 120 120   7   Sodium lauryl sulfate 15 15   8   Propyl p-oxybenzoate 0.15 0.15

The present invention provides a oxyresveratrol derivative of a novel structure, these compounds inhibit the tyrosinase activity, useful as a skin external pharmaceutical composition and cosmetic composition having a whitening effect and skin protection function through inhibition of melanin production Can be used.

       1 is a diagram comparing the inhibitory effect on tyrosinase activity against 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol using L-tyrosine as a substrate of tyrosinase. ,

       2 is a diagram comparing the inhibitory effect on tyrosinase activity of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol with hydroquinone, kojic acid and resveratrol.

       FIG. 3 is a graph showing the mechanism of inhibition of tyrosinase activity of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol by kinetic assay (Lineweaver-Burk plot) ego,

       Figure 4 is a diagram showing the effect of inhibiting cell viability and melanin synthesis to determine the toxicity of 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol.

Claims (5)

4- (6-hydroxy-2-naphthyl) -1,3-benzenediol and a pharmaceutically acceptable salt thereof of the novel structure represented by the following structural formula (1):                                         (One) Skin whitening and skin protection skin containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol or its pharmaceutically acceptable salt thereof as an active ingredient represented by formula (1) of claim 1 External pharmaceutical composition. According to claim 2, wherein the composition is an external skin pharmaceutical composition is a cream, gel, patch, spray, ointment, warning, lotion, linen, pasta or cataplasma formulation.  Whitening effect and skin protection agent containing 4- (6-hydroxy-2-naphthyl) -1,3-benzenediol or its pharmaceutically acceptable salt thereof as an active ingredient represented by formula (1) of claim 1 Enteric composition.  The composition of claim 4, wherein the composition comprises skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, Cosmetic composition characterized in that it has one or more formulations selected from the group consisting of packs, soaps, cleansing foams, cleansing lotions, cleansing creams, body lotions and body cleansers.