JP2005162715A - Skin whitening agent and external preparation for skin whitening containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a skin whitening agent that has excellent skin-whitening effect in high safety and provide an external skin composition that develops excellent skin-whitening effect. <P>SOLUTION: This whitening agent comprises a diterpene compound having the abietane skeleton as a basic structure. This whitening agent includes a diterpene compound bearing the abietane skeleton as a basic structure. This external skin composition that includes a diterpene compound bearing the abietane skeleton as a basic structure and develops excellent skin-whitening effect for preventing and ameliorating the pigmentation after sun-burn/spots/freckles/liver spots. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a whitening agent and a skin whitening external preparation containing the same. More specifically, it has a melanin production inhibitory action and a tyrosinase activity inhibitory action, and has an excellent whitening effect, as well as a skin whitening effect such as prevention and improvement of pigmentation / stain / freckle / liver spots after sunburn. The present invention relates to an external preparation for skin.

  Skin pigment abnormalities range from cosmetics such as spots and freckles to those seen in skin diseases such as liver spots and sparrow eggs. Although there are many unclear points in the mechanism of action of these pigment abnormalities, in general, melanin pigments are formed by stimulation of hormonal abnormalities, ultraviolet rays from sunlight, etc., which are abnormally deposited in the skin It is believed that.

  This melanin pigment is produced in melanin-producing granules (melanosomes) in melanocytes (melanocytes) existing in the basal layer at the bottom of the epidermis, and the produced melanin diffuses to adjacent cells by osmotic action. The biochemical reaction in this melanocyte is considered as follows.

  That is, tyrosine, an essential amino acid, is converted to dopaquinone by the action of the enzyme tyrosinase, which is converted to black melanin through red and colorless pigments by enzymatic or non-enzymatic oxidation is the melanin pigment production process. .

  Therefore, suppressing the action of tyrosinase, which is the first stage of the reaction, is important for suppressing melanin pigment production.

  For the prevention and improvement of pigment abnormalities as described above, a whitening agent, ie, a melanin production inhibitor, is used for the purpose of treatment. For example, a method of orally administering vitamin C in a large amount, a method of injecting glutathione, etc. Alternatively, kojic acid, vitamin C and its derivatives, cysteine and the like are locally applied in the form of an ointment, cream, lotion and the like.

  However, it is the actual situation that these conventional methods do not always have a sufficient effect.

  On the other hand, in Europe and the United States, hydroquinone and its derivatives, which are melanin production inhibitors, are used as whitening agents or pharmaceuticals for the purpose of depigmentation of pigment spots.

  However, hydroquinone derivatives have very slow effects, and the whitening effect may not always be sufficient. In addition, although hydroquinone itself has been recognized for its whitening effect, its use is restricted due to safety issues.

  Derivatives that reduce the side effects of this hydroquinone and have an excellent whitening effect have been studied, but no compound having sufficient effect and safety has yet been obtained.

  In addition, although the diterpene compound based on this invention is a known substance which exists in a plant (refer nonpatent literature 1-18), it is not known that it has a whitening effect | action.

MARIA C. CHAMY et al., Phytochemistry, 1987, 26, p. 1763-1765 ARTURO SAN FELICIANO et al., Journal of Natural Products, 1995, Vol. 58, p. 1059-1064 JOAQUIN DE PASCUAL et al., Phytochemistry, 1983, Vol. 22, p. 300-301 J. DE PASCUAL TERESA et al., Anales de Quimica, 1978, 74, p. 465-469 Helen D. Skaltsa et al., Planta Medica, 1999, 65, p. 255-256 M. KORAY SAKAR et al., Fitoterapia, 1999, 65, p. 304-306 Dimitra Angelopoulou et al., Biochemical Systematics and Ecology, 2001, 29, p. 405-415 A. ULUBELEN et al., Phytochemistry, 1992, 31, p. 3949-3951 ALEJANDRO F. BARRERO et al., Phytochemistry, 1994, 35, p. 1271-1274 BRAULIO M. FRAGA et al., Phytochemistry, 1994, 35, p. 1509-1512 TOSHIFUMI MINAMI, etc., Journal of Natural Products, 2002, 65, p. 1921 to 1923 MOHD ALI et al., Indian Journal of Pharmaceutical Science, 1996, Vol. 58, p. 243-245 Lai-King Sy et al., Journal of Natural Products, 1998, 61, p. 907-912 CHING-KUO LEE et al., Phytochemistry, 1994, 35, p. 983-986 Robert P. Adams et al., Journal of Essential Oil Reseach 1998, 10 volumes, p. 21-24 ANTHONY H. CONNER et al., Phytochemistry, 1977, 16, p. 1777-1781 J. L. BRETON et al., Anales de Quimica, 1970, 66, p. 293-301 A. H. CONNER et al., Journal of the American Oil Chemists' Society, 1975, 52, p. 334-338

  The present invention has been made in view of the above circumstances, and its purpose is to provide a highly safe whitening agent having an excellent whitening effect, and further to an external composition for skin that exhibits an excellent whitening effect on the skin. To provide things.

  As a result of intensive studies to solve the above problems, the present inventors have excellent melanin production inhibitory action and tyrosinase activity inhibitory action in the diterpene compound having a specific structure, and are excellent in whitening effect and useful as a whitening agent. In particular, the whitening agent, that is, a topical skin preparation containing the diterpene compound having the above-mentioned specific structure is safe and excellent for the skin such as prevention and improvement of pigmentation, stains, freckles, and liver spots after sunburn. The present inventors have found that a whitening effect is exhibited and have completed the present invention.

  That is, the present invention is a whitening agent composed of one or more compounds selected from diterpene compounds having an abietane skeleton represented by the following formulas (1) to (7) as a basic structure.

  Moreover, this invention is a whitening agent which uses as an active ingredient the compound of 1 type, or 2 or more types chosen from the diterpene compound which has the abietan frame | skeleton represented by said Formula (1)-(7) as a basic structure.

  Moreover, this invention is the skin external preparation for whitening containing the said whitening agent.

  Furthermore, the present invention is a skin whitening external preparation containing one or more compounds selected from diterpene compounds having a basic structure of the abietane skeleton represented by the above formulas (1) to (7).

  According to the present invention, a whitening agent having a melanin production inhibitory action and a tyrosinase activity inhibitory action and having an excellent whitening effect is obtained, and by adding the whitening agent to a skin external preparation, pigmentation / staining after sunburn is obtained. -A safe skin external preparation that exhibits an excellent whitening effect on the skin, such as the prevention and improvement of freckles and liver spots.

  Hereinafter, the present invention will be described in detail.

  In the present invention, the following formulas (1) to (7)

A diterpene compound having an abietane skeleton represented by the general structure is used.

  A diterpene compound having a basic structure of an abietane skeleton represented by the formula (1) (hereinafter simply referred to as a compound of the formula (1), also referred to as a compound 1) is 8,11,13-abietatrien-19- The diterpene compound (hereinafter simply referred to as the compound of the formula (2), also referred to as the compound 2), which is ol and has the abiethane skeleton represented by the formula (2) as a basic structure, is 8,11,13-abietatrien-18 a diterpene compound (hereinafter simply referred to as a compound of formula (3), also referred to as compound 3) having an abietane skeleton represented by formula (3) as a basic structure is 8,11,13-abietatrien- A diterpene compound (hereinafter simply referred to as a compound of formula (4), also referred to as compound 4), which is 1,18-diol and has a basic structure of an abiethane skeleton represented by the above formula (4) is 8,11,13. -abietatrien-15,18-diol, and the basic structure of the abietane skeleton represented by the above formula (5) The diterpene compound (hereinafter simply referred to as the compound of formula (5), also referred to as compound 5) is 7-hydroxy-8,11,13-abietatrien-19-al, and is abiethane represented by the formula (6). A diterpene compound having a skeleton as a basic structure (hereinafter simply referred to as a compound of formula (6), also referred to as compound 6) is 8,11,13-abietatrien-15,19-diol, and is represented by the formula (7). The diterpene compound (hereinafter, simply referred to as the compound of the formula (7), also referred to as the compound 7) having the abiethane skeleton shown as a basic structure is 8,11,13-abietatrien-19-al.

  The compounds of formulas (1) to (7) are known compounds, but are not known to have a whitening action.

  In preparing the compounds of the above formulas (1) to (7) in the present invention, for example, they can be prepared based on the methods described in the above-mentioned documents that are known to exist, but are not particularly limited thereto. It can be widely prepared by extraction from plants containing the compounds of formulas (1) to (7). Specific examples of the plant to be prepared from the above plant include, for example, cedar plant Calceolaria ascendens (preparation of compound 1), cypress plant Juniperus communis subsp. Hemisphaerica (preparation of compound 1), pine plant Picea obovata (compound 1), Labiatae Origanum majorana (Preparation of Compound 1), Lamiaceae Stachys candida (Preparation of Compound 1), Cypress Plant Juniperus foetidissima (Preparation of Compound 1), Citrus parviflorus (Compound 1) 2), Lamiaceae Salvia pomifera (Preparation of Compound 2), Pinaceae Abies macrocarpa (Preparation of Compound 2), Lamiaceae Nepeta teydea (Preparation of Compounds 2 and 3), Pinaceae Pinus luchuensis (Compound) 4), solanaceous plant Datura metel (preparation of compound 4), magnoliaceae plant Illicium angustisepalum (preparation of compound 6), cypress plant Juniperus chinensis ( Preparation of compounds 5 and 6), cypress plant Juniperus phoenicea (preparation of compound 1), cypress plant Juniperus recurva (preparation of compound 7), cypress plant Juniperus sabina (preparation of compounds 1 and 7), etc. These plants can be prepared by purification and isolation after solvent extraction or steam distillation.

  Examples of the extraction solvent include solvents usually used for plant extraction, such as ethanol, hydrous ethanol, methanol, hydrous methanol, ethyl acetate, acetone, chloroform, ether, hexane, heptane, etc., and these may be used alone or in combination. used. Extraction can be performed at room temperature, under heating, or under reflux with heating. As a purification method after extraction, for example, a conventional purification method, for example, concentration of a target compound by solvent partitioning or removal of unnecessary compounds, silica gel column chromatography, Alumina column chromatography, adsorption treatment with synthetic resin, activated carbon, or the like can be used alone or in combination. Preferred extraction solvents are methanol, ethanol, acetone or ether, and preferred purification methods include solvent partitioning and / or silica gel column chromatography, alumina column chromatography and the like, but are not limited thereto.

  In addition, the part of the plant used in preparing the compounds of the formulas (1) to (7) in the present invention is not particularly limited, but the above-ground part of the cedar plant Calceolaria ascendens is a cypress plant Juniperus communis subsp. Hemisphaerica leaves, cypress Juniperus Sabina berries, pines Picea obovata resin or bark, Lamiaceae Origanum majorana leaves or whole plants, Lamiaceae Stachys candida leaves, cypresses Juiperus foetidissima has berries, Citrus parviflorus has a terrestrial part, Lamiaceae plant Salvia pomifera has an aerial part, pine department Abies macrocarpa has a xylem part, Lamiaceae plant Nepeta teydea has an aerial part, Pinus luchuensis has cones, solanaceous plant Datura metel has trunk bark, magnolic plant Illicium angustisepalum has terrestrial parts, cypress family Juniperus Leaves are particularly preferred for phoenicea, leaves for the cypress Juniperus recurva, and leaves for the cypress Juniperus chinensis.

  Furthermore, the compounds of the above formulas (1) to (7) in the present invention can also be prepared by synthesis. In the synthesis, for example, Journal of Organic Chemistry, 1977, Vol. 42, p2879, Journal of Chemical Society, Section D, Chemical Communication, 1971, Vol. 1, p10, Recueil des Travaux Chimiques des Pays-Bas, 1996, Vol. 115, p77, Bulletin of the Academy of Sciences of USSR, Division of Chemical Science (English Translation), 1979, Vol. 28, p2490, Journal of Organic Chemistry, 1977, Vol. 42, p2769, Chemical and Pharmaceutical Bulletin, 1976 , Vol. 24, p1527, etc. can be used.

  The compounds of the formulas (1) to (7) have an excellent melanin production inhibitory action and tyrosinase activity inhibitory action, as will be described later. Accordingly, one or more compounds selected from the compounds of the formulas (1) to (7) (hereinafter, one or more compounds selected from the compounds of the formulas (1) to (7)) Simply referred to as “diterpene compound”) is useful as a whitening agent. Furthermore, it is useful as a whitening agent containing the diterpene compound as an active ingredient. These whitening agents are new and useful applications based on the discovery of the novel functions of the diterpene compounds according to the present invention.

  The whitening agent of the present invention has a very wide application range and can be applied to various fields. Examples of the field include cosmetics including quasi-drugs, pharmaceuticals, and foods, which are suitable.

  In applying the whitening agent of the present invention, the diterpene compound is used as a simple substance, contains the diterpene compound as an active ingredient, and effectively exhibits a melanin production inhibitory action or a tyrosinase activity inhibitory action. You may use in the form of the plant containing the said diterpene compound of the density | concentration made, or its extract. Whether the extract is in the form of a solvent extract, a concentrated solution thereof, or a solvent extract obtained by converting the solvent extract into any fraction containing the diterpene compound, the melanin production inhibitory action or tyrosinase activity inhibitor Any form may be used as long as the condition that the action is effectively exhibited can be satisfied. As a solvent in these cases, ethanol, 1,3-butylene glycol and the like are preferable.

  Moreover, it can be used as a solution dissolved in a cosmetic solvent other than the extraction solvent containing the diterpene compound. The cosmetic solvent is preferably a cosmetic oil such as hydrocarbon oil or ester oil. Examples of the solution dissolved in the cosmetic solvent include a solution prepared by dissolving an alcohol extract of the plant in a cosmetic solvent such as hydrocarbon oil or ester oil, the plant, etc. The alcohol extract was prepared by partitioning the solvent extract with an ester organic solvent or hydrocarbon organic solvent and water, and then transferring the organic solvent soluble part into a cosmetic solvent such as hydrocarbon oil or ester oil. Examples include solutions. Examples of the extraction solvent from the plant include alcohols such as ethanol and 1,3-butylene glycol, ester solvents such as hydrous alcohol and ethyl acetate, and hydrocarbon solvents such as hexane and heptane. Examples of the hydrocarbon oil include squalane and ester oils such as tetra-2-ethylhexanoic acid pentaerythritol, cetyl 2-ethylhexanoate, and glyceryl tri-2-ethylhexanoate.

  Further, the whitening agent or diterpene compound that is a whitening agent according to the present invention is blended in a composition for external use as a whitening component, and prevents or improves pigmentation / stain / freckle / liver spots etc. after sunburn on the skin. Prepared as a skin whitening external preparation that exhibits an excellent whitening effect.

  Therefore, the skin external composition containing the whitening agent or diterpene compound according to the present invention is useful as a skin whitening external preparation that exhibits a whitening effect.

  The whitening skin external preparation of the present invention can be suitably used for facial cosmetics, body skin external preparations and the like.

  When the whitening agent or diterpene compound according to the present invention is blended in the skin external preparation for whitening, the content of the whitening agent or diterpene compound varies depending on the use, dosage form, blending purpose, etc. The total amount of the external preparation for skin is preferably 0.0001 to 20% by mass, more preferably 0.001 to 10% by mass. If the content is less than 0.0001% by mass, the whitening effect is not sufficient, and if it exceeds 20% by mass, an increase in the whitening effect cannot be expected.

  The skin whitening preparation for whitening according to the present invention includes other components usually used in skin external preparations such as cosmetics and pharmaceuticals, for example, powder components, liquid fats and oils, waxes and waxes, as long as the effects of the present invention are not impaired. , Hydrocarbon oil, higher fatty acid, higher alcohol, synthetic ester oil, silicone oil, anionic surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickening Agent, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol, sugar, amino acid, organic amine, polymer emulsion, pH adjuster, skin nutrient, vitamins, antioxidant, antioxidant assistant An agent, a fragrance, water, or the like can be appropriately blended as necessary.

  The specific said arbitrary compounding component is enumerated below. One or more optional ingredients can be arbitrarily selected and blended.

  Examples of the powder component include inorganic powders (for example, talc, kaolin, mica, sericite (sericite), muscovite, phlogopite, synthetic mica, saucite, biotite, permiculite, magnesium carbonate, calcium carbonate, silicic acid. Aluminum, barium silicate, calcium silicate, magnesium silicate, strontium silicate, metal tungstate, magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate (baked gypsum), calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powder Metal soaps (eg, zinc myristate, calcium palmitate, aluminum stearate), boron nitride, etc.);

  Organic powder (for example, polyamide resin powder (nylon powder), polyethylene powder, polymethyl methacrylate powder, polystyrene powder, copolymer resin powder of styrene and acrylic acid, benzoguanamine resin powder, polytetrafluoroethylene powder, cellulose powder, etc. ); Inorganic white pigments (eg, titanium dioxide, zinc oxide, etc.); inorganic red pigments (eg, iron oxide (Bengara), iron titanate, etc.); inorganic brown pigments (eg, γ-iron oxide, etc.); inorganic Yellow pigments (eg, yellow iron oxide, ocher, etc.); inorganic black pigments (eg, black iron oxide, low-order titanium oxide, etc.); inorganic purple pigments (eg, mango violet, cobalt violet, etc.); inorganic green types Pigments (eg, chromium oxide, chromium hydroxide, cobalt titanate, etc.); inorganic blue pigments (eg, ultramarine blue, bitumen, etc.); pearl face (E.g., titanium oxide coated mica, titanium oxide coated bismuth oxychloride, titanium oxide coated talc, colored titanium oxide coated mica, bismuth oxychloride, fish scale foil);

  Metal powder pigments (eg, aluminum powder, copper powder, etc.); organic pigments such as zirconium, barium or aluminum lake (eg, red 201, red 202, red 204, red 205, red 220, red 226) Organic pigments such as red 228, red 405, orange 203, orange 204, yellow 205, yellow 401, and blue 404, red 3, red 104, red 106, red 227, Red 230, red 401, red 505, orange 205, yellow 4, yellow 5, yellow 202, yellow 203, green 3 and blue 1); natural pigments (eg, chlorophyll, β -Carotene and the like).

  Examples of liquid oils include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, southern castor oil, castor oil, linseed oil , Safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, cinnagiri oil, Japanese kiri oil, jojoba oil, germ oil, triglycerin and the like.

  Examples of the solid fat include cacao butter, palm oil, horse fat, hydrogenated palm oil, palm oil, beef tallow, sheep fat, hydrogenated beef tallow, palm kernel oil, pork fat, beef bone fat, owl kernel oil, hydrogenated oil, cattle Leg fats, moles, hydrogenated castor oil and the like.

  Examples of waxes include beeswax, candelilla wax, cotton wax, carnauba wax, bayberry wax, ibota wax, whale wax, montan wax, nuka wax, lanolin, kapok wax, lanolin acetate, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl, hexyl laurate, and reduced lanolin. Jojoba wax, hard lanolin, shellac wax, polyoxyethylene (hereinafter referred to as POE) lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether, and the like.

  Examples of the hydrocarbon oil include liquid paraffin, ozokerite, squalane, pristane, paraffin, ceresin, squalene, petrolatum, microcrystalline wax, and the like.

  Examples of the higher fatty acid include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecylenic acid, toluic acid, isostearic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid ( DHA) and the like.

  Examples of higher alcohols include linear alcohols (eg, lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol); branched chain alcohols (eg, monostearyl glycerin ether (batyl alcohol) ), 2-decyltetradecinol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol, isostearyl alcohol, octyldodecanol and the like.

  Synthetic ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate Lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di2-ethylhexanoate, dipentaerythritol fatty acid ester, monoisostearic acid N-alkyl glycol, dicapric acid neopentyl glycol, malic acid Diisostearyl, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, triisostearin Trimethylolpropane, tetra-2-ethylhexanoic acid pentaerythritol, tri-2-ethylhexanoic acid glycerin, trioctanoic acid glycerin, triisopalmitic acid glycerin, triisostearic acid trimethylolpropane, 2-ethylhexanoic acid cetyl, 2-ethylhexyl palmitate Glyceryl trimyristate, glyceride tri-2-heptylundecanoate, castor oil fatty acid methyl ester, oleyl oleate, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, 2-octyldodecyl N-lauroyl-L-glutamate Esters, di-2-heptylundecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, palmitic acid 2 Hexyl decyl, 2-hexyldecyl adipate, diisopropyl sebacate, 2-ethylhexyl succinate, and triethyl citrate.

  Examples of the silicone oil include linear polysiloxanes (for example, dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, etc.); cyclic polysiloxanes (for example, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexyl). And silicone resins that form a three-dimensional network structure, various modified polysiloxanes (amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, fluorine-modified polysiloxane, etc.) It is done.

  Anionic surfactants include, for example, fatty acid soaps (eg, sodium laurate, sodium palmitate, etc.); higher alkyl sulfates (eg, sodium lauryl sulfate, potassium lauryl sulfate, etc.); alkyl ether sulfates (eg, POE lauryl sulfate triethanolamine, POE sodium lauryl sulfate, etc.); N-acyl sarcosine acid (eg, sodium lauroyl sarcosine, etc.); higher fatty acid amide sulfonates (eg, N-myristoyl-N-methyl taurine sodium, coconut oil fatty acid) Methyl tauride sodium, lauryl methyl tauride sodium, etc.); Phosphate ester salts (POE oleyl ether sodium phosphate, POE stearyl ether phosphate, etc.); -Sodium ethylhexyl sulfosuccinate, sodium monolauroyl monoethanolamide polyoxyethylene sodium sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate, etc .; alkyl benzene sulfonates (eg, sodium linear dodecyl benzene sulfonate, triethanol amine linear dodecyl benzene sulfonate, Linear dodecyl benzene sulfonic acid, etc.); higher fatty acid ester sulfates (for example, hydrogenated coconut oil fatty acid sodium glycerol sulfate, etc.); N-acyl glutamate (for example, monosodium N-lauroyl glutamate, disodium N-stearoyl glutamate, N -Myristoyl-L-monosodium glutamate, etc.); sulfated oil (eg funnel oil); POE alkyl ester Tercarboxylic acid; POE alkyl allyl ether carboxylate; α-olefin sulfonate; higher fatty acid ester sulfonate; secondary alcohol sulfate ester; higher fatty acid alkylolamide sulfate ester; sodium lauroyl monoethanolamide succinate; N -Palmitoyl aspartate ditriethanolamine; sodium caseinate and the like.

  Examples of the cationic surfactant include alkyltrimethylammonium salts (eg, stearyltrimethylammonium chloride, lauryltrimethylammonium chloride, etc.); alkylpyridinium salts (eg, cetylpyridinium chloride, etc.); distearyldimethylammonium dialkyldimethylammonium chloride; Poly (N, N'-dimethyl-3,5-methylenepiperidinium chloride); alkyl quaternary ammonium salt; alkyldimethylbenzylammonium salt; alkylisoquinolinium salt; dialkyl morpholinium salt; POE alkylamine; Examples include amine salts; polyamine fatty acid derivatives; amyl alcohol fatty acid derivatives; benzalkonium chloride; benzethonium chloride and the like.

  Examples of amphoteric surfactants include imidazoline-based amphoteric surfactants (for example, 2-undecyl-N, N, N- (hydroxyethylcarboxymethyl) -2-imidazoline sodium, 2-cocoyl-2-imidazolinium Hydroxide-1-carboxyethyloxy disodium salt, etc.); betaine surfactants (for example, 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryldimethylaminoacetic acid betaine, alkylbetaine, amide) Betaine, sulfobetaine, etc.).

  Nonionic surfactants include, for example, sorbitan fatty acid esters (for example, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate). Glycerol, diglycerol sorbitan tetra-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate); glycerin polyglycerol fatty acids (for example, mono-cotton oil fatty acid glycerin, monoerucic acid glycerin, sesquioleate glycerin, monostearate glycerin, α , Α′-oleic acid pyroglutamate glycerin, monostearate glycerin malate, etc.); propylene glycol fatty acid esters (eg monostearate) Propylene glycol phosphate, etc.); hardened castor oil derivative; glycerin alkyl ether;

  POE sorbitan fatty acid esters (eg, POE sorbitan monooleate, POE sorbitan monostearate, POE sorbitan monooleate, POE sorbitan tetraoleate, etc.); POE sorbite fatty acid esters (eg, POE sorbite monolaurate, POE sorbite monolaurate) Oleate, POE sorbite pentaoleate, POE sorbite monostearate, etc.); POE glycerol fatty acid esters (for example, POE monooleate such as POE glycerol monostearate, POE glycerol monoisostearate, POE glycerol triisostearate, etc.) POE fatty acid esters (for example, POE distearate, POE monodiolate, ethylene glycol distearate, etc.); POE alkyl ester Tells (for example, POE lauryl ether, POE oleyl ether, POE stearyl ether, POE behenyl ether, POE2-octyldodecyl ether, POE cholestanol ether, etc.); Pluronic type (for example, Pluronic etc.); POE polyoxypropylene ( Hereinafter referred to as POP) -alkyl ethers (for example, POE · POP-cetyl ether, POE · POP-2-decyltetradecyl ether, POE · POP-monobutyl ether, POE · POP-hydrogenated lanolin, POE · POP- Glycerin ether, etc.); tetra-POE / tetra-POP-ethylenediamine condensates (eg, Tetronic); POE castor oil-hardened castor oil derivatives (eg, POE castor oil, POE-hardened castor oil, POE-hardened) Castor oil monoisostearate, POE hydrogenated castor oil triisostearate, POE hydrogenated castor oil monopyroglutamic acid monoisostearic acid diester, POE hydrogenated castor oil maleic acid, etc .; POE-beeswax lanolin derivatives (eg POE sorbite beeswax etc.) ); Alkanolamides (eg coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, etc.); POE-propylene glycol fatty acid ester; POE alkylamine; POE fatty acid amide; sucrose fatty acid ester; A trioleyl phosphate etc. are mentioned.

  Examples of the humectant include polyethylene glycol (hereinafter referred to as PEG), propylene glycol (hereinafter also referred to as PG), glycerin, 1,3-butylene glycol (hereinafter referred to as 1,3-BG), xylitol, Sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, cholesteryl-12-hydroxystearate, sodium lactate, bile salt, dl-pyrrolidone carboxylate, short chain soluble collagen, diglycerin (EO ) PO adduct, Izayoi rose extract, Achillea millefolium extract, Merirot extract and the like.

  Examples of natural water-soluble polymers include plant-based polymers (for example, arabia gum, tragacanth gum, galactan, guar gum, carob gum, caraya gum, carrageenan, pectin, agar, quince seed (malmello), algae colloid (gypsum extract), starch ( Rice, corn, potato, wheat), glycyrrhizic acid); microbial polymers (eg, xanthan gum, dextran, succinoglucan, bullulan, etc.); animal polymers (eg, collagen, casein, albumin, gelatin, etc.) Can be mentioned.

  Semi-synthetic water-soluble polymers include, for example, starch polymers (eg, carboxymethyl starch, methylhydroxypropyl starch, etc.); cellulose polymers (methylcellulose, ethylcellulose, methylhydroxypropylcellulose, hydroxyethylcellulose, sodium cellulose sulfate) , Hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, etc.); alginic acid polymers (for example, sodium alginate, propylene glycol alginate, etc.) and the like.

  Examples of the synthetic water-soluble polymer include vinyl polymers (for example, polyvinyl alcohol (hereinafter referred to as PVA), polyvinyl methyl ether (hereinafter referred to as PVM), polyvinyl pyrrolidone (hereinafter referred to as PVP), carboxy. Vinyl polymers, etc.); polyoxyethylene polymers (eg, PEG 20,000, 40,000, 60,000, POE / POP copolymers, etc.); acrylic polymers (eg, sodium polyacrylate, polyacrylamide, etc.) ); Polyethyleneimine; and cationic polymers.

  Examples of thickeners include gum arabic, carrageenan, caraya gum, gum tragacanth, carob gum, quince seed (quince), casein, dextrin, gelatin, sodium pectate, sodium alginate, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, Hydroxyethyl cellulose, hydroxypropyl cellulose, PVA, PVM, PVP, sodium polyacrylate, carboxyvinyl polymer, locust bean gum, guar gum, tamarind gum, cellulose dialkyldimethylammonium sulfate, xanthan gum, magnesium aluminum silicate, bentonite, hectorite, silicic acid A1Mg (bee gum), laponite, silicic anhydride, etc. It is.

  Examples of the ultraviolet absorber include benzoic acid-based ultraviolet absorbers (for example, paraaminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester. N, N-dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA ethyl ester, etc.); anthranilic acid ultraviolet absorbers (for example, homomenthyl-N-acetylanthranylate, etc.); Salicylic acid UV absorbers (eg, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate); (For example, octylcinnamate, ethyl-4-isopropylcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2,4-diisopropylcinnamate, methyl-2,4-diisopropylcinnamate, propyl-p-methoxy Cinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl -P-methoxycinnamate, ethyl-α-cyano-β-phenylcinnamate, 2-ethylhexyl-α-cyano-β-phenylcinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, trimeth Methyl bis (trimethylsiloxy) silylisopentyl xycinnamate); benzophenone ultraviolet absorbers (for example, 2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2′-dihydroxy-4, 4′-dimethoxybenzophenone, 2,2 ′, 4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4′-methylbenzophenone, 2-hydroxy-4-methoxy Benzophenone-5-sulfonate, 4-phenylbenzophenone, 2-ethylhexyl-4′-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone ); 3- (4′-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5-methylphenyl 2- (2′-hydroxy-5′-t-octylphenyl) benzotriazole; 2- (2′-hydroxy-5′-methylphenylbenzotriazole; dibenzalazine; dianisoylmethane; 4-methoxy-4 ′ -T-butyldibenzoylmethane; 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one and the like.

  Examples of the sequestering agent include 1-hydroxyethane-1,1-diphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid tetrasodium salt, disodium edetate, trisodium edetate, and tetrasodium edetate. Sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid, succinic acid, edetic acid, trisodium ethylenediaminehydroxyethyl triacetate and the like.

  Examples of the lower alcohol include ethanol, propanol, isopropanol, isobutyl alcohol, t-butyl alcohol and the like.

  Examples of the polyhydric alcohol include divalent alcohols (for example, ethylene glycol (hereinafter also referred to as EG), PG, trimethylene glycol, 1,2-butylene glycol, 1,3-BG, tetramethylene glycol, 2,3-butylene glycol, pentamethylene glycol, 2-butene-1,4-diol, hexylene glycol, octylene glycol, etc.); trivalent alcohol (for example, glycerin, trimethylolpropane, etc.); tetravalent Alcohol (eg, pentaerythritol such as 1,2,6-hexanetriol); pentahydric alcohol (eg, xylitol); hexavalent alcohol (eg, sorbitol, mannitol, etc.); polyhydric alcohol polymer (eg, diethylene glycol) , Dipropylene glycol, triethylene Glycol, polypropylene glycol, tetraethylene glycol, diglycerin, PEG, triglycerin, tetraglycerin, polyglycerin, etc.); divalent alcohol alkyl ethers (for example, EG monomethyl ether, EG monoethyl ether, EG monobutyl ether, EG mono) Phenyl ether, EG monohexyl ether, EG mono 2-methylhexyl ether, EG isoamyl ether, EG benzyl ether, EG isopropyl ether, EG dimethyl ether, EG diethyl ether, EG dibutyl ether, etc.);

  Dihydric alcohol alkyl ethers (for example, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol butyl ether, diethylene glycol methyl ethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, PG monomethyl ether, PG monoethyl ether, PG monobutyl ether, PG isopropyl ether, dipropylene glycol methyl ether, dipropylene glycol ethyl ether, dipropylene glycol butyl ether, etc.); dihydric alcohol ether esters (for example, EG monomethyl) Ether ether, EG monoethyl ether acetate, EG monobutyl ether acetate, EG monophenyl ether acetate, EG diadibate, EG disuccinate, diethylene glycol monoethyl ether acetate, diethylene glycol monobutyl ether acetate, PG monomethyl ether acetate, PG monoethyl ether acetate, PG Monopropyl ether acetate, PG monophenyl ether acetate, etc.); glycerin monoalkyl ether (eg, xyl alcohol, ceralkyl alcohol, batyl alcohol, etc.); sugar alcohol (eg, sorbitol, maltitol, maltotriose, mannitol, sucrose) , Erythritol, glucose, fructose, amylolytic sugar, maltose Glycyl solid; tetrahydrofurfuryl alcohol; POE-tetrahydrofurfuryl alcohol; POP-butyl ether; POP-POE-butyl ether; tripolyoxypropylene glycerin ether; POP-glycerin ether; POP -Glyceryl ether phosphoric acid; POP / POE-pentane erythritol ether, polyglycerin, etc. are mentioned.

  Examples of monosaccharides include tricarbon sugars (eg, D-glyceryl aldehyde, dihydroxyacetone, etc.); tetracarbon sugars (eg, D-erythrose, D-erythrulose, D-treose, erythritol, etc.); pentose sugars (eg, L-arabinose, D-xylose, L-lyxose, D-arabinose, D-ribose, D-ribulose, D-xylulose, L-xylulose, etc .; hexose (eg, D-glucose, D-talose, D) -Bucicose, D-galactose, D-fructose, L-galactose, L-mannose, D-tagatose, etc.); pentose sugar (eg, aldoheptose, heprose, etc.); octose sugar (eg, octulose, etc.); For example, 2-deoxy-D-ribose, 6-deoxy-L-galactose, 6-deoxy- -Mannose, etc.]; amino sugars (eg, D-glucosamine, D-galactosamine, sialic acid, aminouronic acid, muramic acid, etc.); uronic acids (eg, D-glucuronic acid, D-mannuronic acid, L-guluronic acid, D -Galacturonic acid, L-iduronic acid, etc.).

  Examples of the oligosaccharides include sucrose, gnocyanose, umbelliferose, lactose, planteose, isoliquinoses, α, α-trehalose, raffinose, lycnose, umbilicin, stachyose verbusose and the like.

  Examples of the polysaccharide include cellulose, quince seed, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, heparan sulfate, hyaluronic acid, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucoitin sulfate, guar gum, dextran, kerato sulfate. , Locust bingham, succinoglucan, caronic acid and the like.

  Examples of amino acids include neutral amino acids (eg, threonine, cysteine, etc.); basic amino acids (eg, hydroxylysine, etc.) and the like. Examples of the amino acid derivative include acyl sarcosine sodium (lauroyl sarcosine sodium), acyl glutamate, acyl β-alanine sodium, glutathione, and pyrrolidone carboxylic acid.

  Examples of the organic amine include monoethanolamine, diethanolamine, triethanolamine, morpholine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, and 2-amino-2-methyl-1-propanol. Is mentioned.

  Examples of the polymer emulsion include an acrylic resin emulsion, a polyethyl acrylate emulsion, an acrylic resin liquid, a polyacryl alkyl ester emulsion, a polyvinyl acetate resin emulsion, and a natural rubber latex.

  Examples of the pH adjusting agent include buffers such as lactic acid-sodium lactate and citric acid-sodium citrate.

Examples of vitamins include vitamins A, B ₁ , B ₂ , B ₆ , C, E and derivatives thereof, pantothenic acid and derivatives thereof, biotin and the like.

  Examples of the antioxidant include tocopherols, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid esters and the like.

  Examples of the antioxidant assistant include phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid, succinic acid, fumaric acid, kephalin, hexametaphosphate, phytic acid, and ethylenediaminetetraacetic acid.

  Other ingredients that can be blended include, for example, preservatives (ethyl paraben, butyl paraben, etc.); anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.); Agents (for example, vitamin C, magnesium ascorbate phosphate, ascorbic acid glucoside, arbutin, kojic acid, etc.); various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe, Mallow, Iris, Grape, Yokuinin, Loofah, Lily, Saffron, Senkyu, Pepper, Hypericum, Onionis, Garlic, Pepper, Chimpi, Toki, Seaweed, etc.), Activator (eg, Royal Jelly, Photosensitive Element, Cholesterol Derivative) ); Blood circulation promoter (for example, nonyl acid wallenyl amide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ectamol, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate Cyclandrate, cinnarizine, trazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc.); antiseborrheic agents (eg, sulfur, thianthol, etc.); Can be mentioned.

  The skin external preparation of the present invention can be prepared according to a conventional method by blending the above components.

  The external preparation for skin of the present invention can be used as products and forms such as creams, lotions, emulsions, ointments, gels, packs, foams, solutions, essences, sticks, and powders.

  The dosage form of the external preparation for skin of the present invention can be arbitrarily selected as long as the whitening effect can be sufficiently exhibited, and is a solution system, a solubilization system, an emulsification system, a powder dispersion system, a water-oil two-layer system, a water-oil- Any dosage form such as a powder three-layer system may be used. In addition, the product form of the external preparation for skin of the present invention is also arbitrary, such as facial cosmetics such as lotion, emulsion, cream, pack, makeup cosmetics such as foundation, lipstick, eye shadow, body cosmetics, aromatic cosmetics, It can be used for cleaning materials, ointments and the like.

  Next, the configuration of the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

  The following tests were conducted on the melanin production inhibitory effect, tyrosinase activity inhibitory effect and whitening effect of the compounds according to the present invention.

Preparation of Samples Preparation of Compounds of Formulas (1) to (7) The isolation methods common to each compound are basically as follows. The extract obtained by extracting from the dry bulk material (plant) for 1 week to 10 days at room temperature using an appropriate solvent is purified by repeated column chromatography or finally after column chromatography. Prepared by purification by HPLC or recrystallization. The preparation method of each compound is as follows.

Preparation of 8,11,13-abietatrien-19-ol (Compound 1) 1 kg of the above-ground part of the cedar plant Calceolaria ascendens was extracted with ether and purified by silica gel column chromatography to isolate 40 mg. Alternatively, 1.5 kg of a leaf of Origanum majorana was extracted with ethanol, and the ethyl acetate-soluble part obtained by solvent partitioning the extract with ethyl acetate and water was purified by silica gel column chromatography and HPLC to isolate 5 mg. .

Preparation of 8,11,13-abietatrien-18-ol (compound 2) 500 g of the above-ground part of the Labiatae plant Salvia pomifera was extracted with acetone, and the extract was purified by silica gel column chromatography and Sephadex LH-20 to give 10 mg. Was isolated. Alternatively, 5 kg of the above-ground part of the Labiatae plant Nepeta teydea was extracted with ethanol, and the extract was purified by silica gel column chromatography to isolate 10 mg.

Preparation of 8,11,13-abietatrien-1,18-diol (compound 3) 5 kg of the above-ground part of the family Lamiaceae Nepeta teydea was extracted with ethanol, and the extract was purified by silica gel column chromatography to isolate 50 mg. .

Preparation of 8,11,13-abietatrien-15,18-diol (compound 4) 800 g of pinus luchuensis cones were extracted with chloroform, and the extract was purified by silica gel column chromatography and HPLC to obtain 70 mg. Released.

Preparation of 7-hydroxy-8,11,13-abietatrien-19-al (compound 5) Soluble ethyl acetate extract 2 kg of the cypress family Juniperus chinensis extracted with acetone and the solvent was partitioned between ethyl acetate and water Part was purified by silica gel column chromatography to isolate 5 mg.

Preparation of 8,11,13-abietatrien-15,19-diol (Compound 6) 1.5 kg of the above-ground part of the magnolic plant Illicium angustisepalum was extracted with chloroform, and the extract was purified by silica gel column chromatography and HPLC to give 10 mg. Was isolated.

Preparation of 8,11,13-abietatrien-19-al (compound 7) The berries of Juniperus Sabina, a cypress family plant, were extracted with hexane, and the residue treated with dilute NaOH solution was purified by silica gel column chromatography. 300 mg was isolated.

  The preparation method of the compound containing solution of Formula (1)-(7) is as follows. In the following, a solution containing 8,11,13-abietatrien-19-ol (compound 1) was described, but other compounds 2 to 7 were prepared in the same manner.

Preparation of squalane solution (1) containing 8,11,13-abietatrien-19-ol (compound 1) 1.5 kg of leaves of Orchium majorana were extracted with ethanol, and the resulting extract was extracted with ethyl acetate and water The solvent-distributed ethyl acetate soluble part was dispersed in 5 times the amount of squalane and filtered to prepare the solution. The concentration of 8,11,13-abietatrien-19-ol was 0.06% by mass.

Preparation of tetra-ethylhexanoic acid pentaerythritol solution (1) containing 8,11,13-abietatrien-19-ol (compound 1) 1.5 kg of leaves of Lamiaceae Origanum majorana extracted with ethanol The ethyl acetate-soluble part obtained by partitioning the extract with ethyl acetate and water was dispersed in 5 times its amount of tetra-2-ethylhexanoic acid pentaerythritol and filtered to prepare the solution. The concentration of 8,11,13-abietatrien-19-ol was 0.10% by mass.

Preparation of 8,11,13-abietatrien-19-ol (compound 1) -containing cetyl 2-ethylhexanoate solution (1) Extract 1.5 kg of leaves from Orchidaceae Origanum majorana with ethanol. The ethyl acetate soluble part obtained by partitioning the solvent with ethyl acetate and water was dispersed in 5 times the amount of cetyl 2-ethylhexanoate and filtered to prepare the solution. The concentration of 8,11,13-abietatrien-19-ol was 0.17% by mass.

Preparation of squalane solution (2) containing 8,11,13-abietatrien-19-ol (compound 1) 1.5 kg of leaves of Origanum majorana were extracted with ethanol, and the resulting extract was 3.5 times its extract The solution was prepared by dispersing in an amount of squalane and filtering. The concentration of 8,11,13-abietatrien-19-ol was 0.02% by mass.

Preparation of tetra-ethylhexanoic acid pentaerythritol solution (2) containing 8,11,13-abietatrien-19-ol (compound 1) 1.5 kg of leaves of Lamiaceae Origanum majorana extracted with ethanol The extract was dispersed in 3.5 times its amount of tetra 2-ethylhexanoic acid pentaerythritol and filtered to prepare the solution. The concentration of 8,11,13-abietatrien-19-ol was 0.04% by mass.

Preparation of cetyl 2-ethylhexanoate solution (2) containing 8,11,13-abietatrien-19-ol (compound 1) Extract 1.5 kg of leaves from Orchidaceae Origanum majorana with ethanol. The solution was prepared by dispersing in 3.5 times the amount of cetyl 2-ethylhexanoate and filtering. The concentration of 8,11,13-abietatrien-19-ol was 0.10% by mass.

Test for inhibiting melanin production B16 melanoma cultured cells derived from mice were used. The cells were cultured in an Eagle's MEM medium containing 10% FBS and theophylline (0.09 mg / ml) in a CO ₂ incubator (95% air, 5% carbon dioxide) at 37 ° C. After 24 hours of culture, a sample solution (DMSO solution) containing the sample was added so that the sample concentration was 1.25 × 10 ^{−4 to} 5 × 10 ⁻⁴ mass%, and the culture was further continued for 3 days. Were used to measure the melanin production and the tyrosinase activity suppression effect.

Visibility determination of melanin production amount A diffusion plate was placed on the lid of the well plate, the amount of intracellular melanin was observed with an inverted microscope, and compared with the sample (reference) to which no sample was added. The results are shown in “Table 1”. In addition, as a comparative example, hydroquinone already known to have a melanin production inhibitory action is also shown in Table 1.

(Criteria)
○: White compared to the standard (the amount of melanin is small compared to the standard).
Δ: Slightly white compared to the standard (the amount of melanin is slightly small compared to the standard).
X: The same level as the standard (the amount of melanin is comparable to the standard).

Measurement of tyrosinase activity Before the measurement, the medium in the well was removed and washed twice with 100 μl of PBS. To each well was added 45 μl of PBS containing 1% Triton-X (Rohm and Haas brand name, surfactant). The plate was vibrated for 1 minute to thoroughly break the cell membrane, and the absorbance at 475 nm was measured with a microplate reader to obtain the absorbance at 0 minute. Thereafter, 5 μl of 10 mM L-DOPA solution was quickly added, transferred to a 37 ° C. incubator, and allowed to react for 60 minutes. The plate was shaken for 1 minute, and the absorbance (475 nm) at 60 minutes was measured. The absorbance difference of the sample to which the sample was added relative to the difference in absorbance at 0 minutes and 60 minutes in the case of the sample to which no sample was added (control) was defined as the tyrosinase activity rate. The results are shown in “Table 1”. In addition, as a comparative example, hydroquinone known to have a tyrosinase activity inhibitory action is also shown in “Table 1”.

  From the results in Table 1, it can be seen that the compound according to the present invention is extremely excellent in the melanin production inhibitory effect and the tyrosinase activity inhibitory effect as compared with hydroquinone.

Whitening effect test Preparation of external preparation for skin A lotion was prepared according to the following formulation. According to a conventional method, the alcohol phase and the aqueous phase were prepared and solubilized.

(lotion)
Ingredient Amount (% by mass)
(Alcohol phase)
95% ethanol 55.0
POE (40 mol) hydrogenated castor oil 2.0
Antioxidant Appropriate amount Preservative Appropriate amount Sample described in "Table 2" Amount described in "Table 2" (aqueous phase)
Dipropylene glycol 5.0
Sodium hexametaphosphate
Ion exchange water

Test Method Each lotion from the 5th day of the second day of exposure to sunlight, with the subjects exposed to the sunlight in the summer for 4 hours (2 hours a day for 2 days) and 80 inner skin of the upper arm Was applied once a morning and evening for 4 weeks. The panel was divided into 8 groups with 10 members per group. After the application, whether or not there was an inhibitory effect on pigmentation induced by ultraviolet irradiation was examined, and the degree was evaluated based on the following criteria. The results are shown in Table 2.

(Evaluation criteria)
◎: Eight or more subjects who were marked or effective ○: Five to seven subjects who were marked or effective △: Three to four subjects who were marked or effective ×: Subjects who were marked or effective 2 or less

  As is apparent from Table 2, the whitening effect on the subject exposed to sunlight is that the lotion to which the compound according to the present invention is added prevents the deposition of melanin pigment and prevents the darkness compared with the case of hydroquinone combination. An improvement was observed.

  Examples of the external preparation for skin containing the compound according to the present invention will be given below. The compound prepared was the one prepared above. A compounding quantity represents the mass%. The skin external preparations obtained in Examples 1 to 19 were all effective in the whitening effect test.

Example 1 Cream A cream was prepared according to the following formulation. In the preparation method, PG, caustic potash and ethylenediaminetetraacetic acid tetrasodium salt were added to ion-exchanged water and dissolved, and the mixture was kept at 70 ° C. (aqueous phase). Mix and dissolve the other ingredients, heat and maintain at 70 ° C (oil phase), gradually add the oil phase to the aqueous phase, pre-emulsify at 70 ° C, uniformly emulsify with a homomixer, and stir well While cooling to 30 ° C.

Ingredient Amount (% by mass)
Stearic acid 6.0
Stearyl alcohol 3.0
Isopropyl myristate 18.0
Glycerol monostearate 3.0
PG 10.0
8,11,13-abietatrien-19-ol (Compound 1) 0.01
Caustic potash 0.2
Ethylenediaminetetraacetic acid tetrasodium salt 0.01
Tocopherol acetate 0.1
Butylparaben Appropriate perfume Appropriate ion-exchange water Residual

Example 2 Cream A cream was prepared according to the following formulation. In the preparation method, PG and ethylenediaminetetraacetic acid disodium salt were added and dissolved in ion-exchanged water and kept at 70 ° C. (aqueous phase). Mix and dissolve the other ingredients, heat and maintain at 70 ° C (oil phase), gradually add the oil phase to the aqueous phase, pre-emulsify at 70 ° C, uniformly emulsify with a homomixer, and stir well While cooling to 30 ° C.

Ingredient Amount (% by mass)
Stearic acid 5.0
Sorbitan monostearate ester 2.5
POE (20 mol) sorbitan monostearate 1.5
Arbutin 7.0
Sodium bisulfite 0.03
PG 10.0
8,11,13-abietatrien-18-ol (compound 2) 0.0005
Glycerin trioctanoate 10.0
Squalene 5.0
Octyl paradimethylaminobenzoate 3.0
Ethylenediaminetetraacetic acid disodium salt 0.01
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

Example 3 Cream A cream was prepared in the same manner as in Example 2 with the following formulation.

Ingredient Amount (% by mass)
Stearyl alcohol 7.5
Stearic acid 1.5
Hydrogenated Lanolin 2.0
Squalane 5.0
2-Octyldodecyl alcohol 6.0
POE (25 mol) cetyl ether 3.0
Glycerin monostearate ester 2.0
PG 5.0
Placenta extract 0.1
Sodium hyaluronate 0.1
Octyl cinnamate 4.0
8,11,13-abietatrien-1,18-diol (Compound 3) 0.00001
Ethylenediaminetetraacetic acid disodium salt 0.03
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

Example 4 Cream A cream was prepared in the same manner as in Example 2 with the following formulation.

Ingredient Amount (% by mass)
Stearic acid 6.5
Sorbitan monostearate ester 2.0
POE (20 mol) sorbitan monostearate 1.5
PG 10.0
8,11,13-abietatrien-15,18-diol (compound 4) 0.007
Glycerin trioctanoate 10.0
Squalane 5.0
Sodium hyaluronate 1.0
Ethylenediaminetetraacetic acid trisodium salt 0.01
Glucose 0.5
Ascorbic acid glucoside 5.0
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

Example 5 Emulsion An emulsion was prepared according to the following formulation. In the preparation method, the carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A), PEG 1500, triethanolamine and sodium bisulfite were added to the remaining ion-exchanged water, and dissolved by heating and maintained at 70 ° C. (water phase). ). Mix other ingredients, heat and melt and keep at 70 ° C. (oil phase), add oil phase to water phase, pre-emulsify, add phase A and uniformly emulsify with homomixer, stirring well Cooled to 30 ° C.

Ingredient Amount (% by mass)
Stearic acid 2.0
Cetyl alcohol 1.5
Vaseline 5.0
Execol D-5 (decamethylcyclopentasiloxane) 1.0
Liquid paraffin 10.0
POE (10 mol) monooleate 2.0
PEG 1500 3.0
Triethanolamine 1.0
Sodium hyaluronate 0.05
7-hydroxy-8,11,13-abietatrien-19-al (compound 5) 0.05
Carboxyvinyl polymer 0.05
(Product name: Carbopol 941, BF Goodrich Chemical company)
Ascorbic acid glucoside 3.0
Sodium bisulfite 0.01
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

Example 6 Latex The placenta extract was heated and dissolved in ion-exchanged water and ethanol, and further water-soluble components below PG were dissolved and kept at 70 ° C. (aqueous phase). Other oil components were mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. while stirring well.

Ingredient Amount (% by mass)
POE (20 mol) · POP (2 mol) cetyl alcohol 1.0
Silicone oil 2.0
(Product name: Silicone KF96 (20cs), manufactured by Shin-Etsu Chemical Co., Ltd.)
Liquid paraffin (medium viscosity) 3.0
PG 5.0
Glycerin 2.0
4-Methoxy-4-tert-butylbenzoylmethane 3.5
Ethanol 15.0
Carboxyvinyl polymer 0.3
KOH appropriate amount preservative appropriate amount placental extract 5.0
8,11,13-abietatrien-15,19-diol (Compound 6) 0.0001
Ion exchange water

Example 7 Emulsion An emulsion was prepared in the same manner as in Example 5 with the following formulation.

Ingredient Amount (% by mass)
Stearic acid 2.5
Cetyl alcohol 1.0
Vaseline 5.0
Liquid paraffin 10.0
POE (10 mol) monooleate 2.0
PEG 1500 3.0
Triethanolamine 1.0
8,11,13-abietatrien-19-al (Compound 7) 0.01
Glycyrrhizic acid 0.5
Amino acid 0.3
Carboxyvinyl polymer 0.05
(Product name: Carbopol 941, BF Goodrich Chemical company)
Sodium bisulfite 0.01
Arbutin 3.0
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

Example 8 Emulsion An emulsion was prepared according to the following formulation. In the preparation method, the oil phase part and the water phase part were each dissolved at 70 ° C., the oil phase part was mixed with the water phase part, emulsified with an emulsifier, and then cooled to 30 ° C. with a heat exchanger.

Ingredient Amount (% by mass)
[Oil phase part]
Stearyl alcohol 2.0
Squalane 2.0
Vaseline 2.5
Deodorized liquid lanolin 1.5
Evening primrose oil 2.0
Isopropyl myristate 5.0
Glycerol monooleate 2.0
POE (60 mol) hydrogenated castor oil 2.0
Tocopherol acetate 0.05
8,11,13-abietatrien-19-ol (Compound 1) 0.1
Tranexamic acid 5.0
Ethylparaben 0.2
Butylparaben 0.1
Perfume appropriate amount (water phase part)
Glycerin 5.0
Sodium hyaluronate 0.01
Carboxyvinyl polymer 0.2
(Product name: Carbopol 941, BF Goodrich Chemical company)
Potassium hydroxide 0.2
Sodium bisulfite 0.01
Purified water residue

Example 9 Jelly A jelly was prepared according to the following formulation. In the preparation method, carbopol 940 was uniformly dissolved in ion-exchanged water (aqueous phase). POE (50 mol) oleyl ether was dissolved in 95% ethanol and added to the aqueous phase. Further, other components were added, and finally sodium hydroxide and L-arginine were added to neutralize and thicken.

Ingredient Amount (% by mass)
95% ethanol 10.0
Dipropylene glycol 12.5
POE (50 mol) oleyl ether 2.0
Carboxyvinyl polymer 1.0
(Product name: Carbopol 940, BF Goodrich Chemical company)
Arbutin 0.5
Sodium bisulfite 0.03
8,11,13-abietatrien-19-ol (compound 1) containing squalane solution (1)
(Concentration 0.06% by mass) 0.1
Caustic soda 0.15
L-Arginine 0.1
2-Hydroxy-4-methoxybenzophenone 0.05
Sodium methylparaben sulfonate 0.2
Ethylenediaminetetraacetate, 3 sodium, 2 water 0.05
Perfume Appropriate amount of ion-exchanged water

Example 10 Cosmetic liquid A cosmetic liquid was prepared according to the following formulation. In the preparation method, the A phase and the C phase were uniformly dissolved, and the A phase was added to the C phase and solubilized. Then phase B was added and dissolved.

Ingredient Amount (% by mass)
[Phase A]
95% ethanol 10.0
POE (20 mol) octyldodecanol 1.1
Methylparaben 0.2
Pantotenyl ethyl ether 0.1
8,11,13-abietatrien-19-ol (Compound 1) -containing tetra 2-ethylhexanoic acid pentaerythrit solution (1) (concentration 0.10% by mass) 0.1
[Phase B]
Potassium hydroxide 0.1
[Phase C]
Glycerin 5.0
Dipropylene glycol 10.0
Sodium bisulfite 0.03
Carboxyvinyl polymer 0.2
(Product name: Carbopol 940, BF Goodrich Chemical company)
Tranexamic acid 3.0
Purified water residue

Example 11 Pack A pack was prepared according to the following formulation. In the preparation method, the A phase, the B phase, and the C phase were uniformly dissolved, the B phase was added to the A phase, solubilized, and this was added to the C phase and filled.

Ingredient Amount (% by mass)
[Phase A]
Dipropylene glycol 6.0
POE (60 mol) hydrogenated castor oil 5.0
[Phase B]
Cetyl 2-ethylhexanoate solution (1) containing 8,11,13-abietatrien-19-ol (Compound 1)
(Concentration 0.17% by mass) 1.0
Olive oil 5.0
Tocopherol acetate 0.2
Ethylparaben 0.2
Perfume appropriate amount [Phase C]
Polyvinyl alcohol (degree of saponification 90, degree of polymerization 2,000) 13.0
Ethanol 7.0
Arbutin 3.0
Sodium bisulfite 0.03
Purified water residue

Example 12 Peel-off type pack An aqueous phase was prepared at 80 ° C and cooled to 50 ° C. Subsequently, the alcohol phase prepared at room temperature was added, mixed uniformly, and allowed to cool.

Ingredient Amount (% by mass)
(Alcohol phase)
95% ethanol 10.0
POE (15 mol) oleyl alcohol ether 2.0
2-Hydroxy-4-methoxybenzophenone 3.5
Antiseptic agent
8,11,13-abietatrien-19-ol (Compound 1) 1.0
8,11,13-abietatrien-15,19-diol (Compound 6) 1.0
(Water phase)
Tranexamic acid 2.0
Polyvinyl alcohol 12.0
Glycerin 3.0
PEG 1500 1.0
Ion exchange water

Example 13 Solid Foundation A solid foundation was prepared according to the following formulation. After thoroughly mixing the powder component of talc to black iron oxide with a blender, add the oily component of squalane to isocetyl octoate, 8,11,13-abietatrien-18-ol, preservative, flavor, and knead well. The container was filled and molded.

Ingredient Amount (% by mass)
Talc Residual Kaolin 15.0
Sericite 10.0
Zinc flower 7.0
Titanium dioxide 3.8
Yellow iron oxide 2.9
Black iron oxide 0.2
Squalane 8.0
Isostearic acid 4.0
Monooleic acid POE sorbitan 3.0
Isocetyl octoate 2.0
8,11,13-abietatrien-18-ol (Compound 2) 0.01
Antiseptic agent

Example 14 Emulsification Foundation (Cream Type)
An emulsified foundation was prepared according to the following formulation. After the aqueous phase was heated and stirred, the powder part sufficiently mixed and ground was added and homomixed. Furthermore, after adding the heat-mixed oil phase and carrying out a homomixer process, the fragrance | flavor was added while stirring and it cooled to room temperature.

Ingredient Amount (% by mass)
(Powder part)
Titanium dioxide 10.3
Sericite 5.4
Kaolin 3.0
Yellow iron oxide 0.8
Black iron oxide 0.2
(Oil phase)
Decamethylcyclopentasiloxane 11.5
POE-modified dimethylpolysiloxane 4.0
8,11,13-abietatrien-19-ol (compound 1) containing squalane solution (2)
(Concentration 0.02% by mass) 4.5
(Water phase)
Purified water Residual 1,3-BG 4.5
Tranexamic acid 2.0
Sorbitan sesquioleate 3.0
Antiseptic agent

Example 15 Lotion Toner lotion was obtained by stirring and mixing the following components.

Ingredient Amount (% by mass)
Ethanol 8.0
1,3-BG 5.0
POE (20 mol) oleyl alcohol ether 1.8
8,11,13-abietatrien-19-ol (Compound 1) -containing tetra 2-ethylhexanoic acid pentaerythrit solution (2) (concentration 0.04 mass%) 0.1
Magnesium ascorbate 3.0
2-hydroxy-4-methoxybenzophenone-5-sulfonic acid sodium salt
0.1
Sodium pyrrolidonecarboxylate 0.5
Pullulan 0.05
Jojoba oil 0.5
Caustic potash 0.015
EDTA-3Na 0.01
Fragrance 0.1
Ion exchange water

Example 16 Lotion A lotion was prepared according to the following formulation. POE (60) hydrogenated castor oil, octyl paramethoxycinnamate, compound 4, compound 7 and flavor were dissolved in ethyl alcohol (alcohol phase). On the other hand, arbutin was dissolved in purified water in advance, and other polyhydric alcohols were further added and dissolved sufficiently (aqueous phase). The alcohol phase was added to the aqueous phase and stirred thoroughly.

Ingredient Amount (% by mass)
Purified water Residual dipropylene glycol 5.0
1,3-BG 10.0
PEG400 10.0
Ethyl alcohol 20.0
POE (60) hydrogenated castor oil 3.0
Octyl paramethoxycinnamate 1.0
8,11,13-abietatrien-15,18-diol (compound 4) 0.00005
8,11,13-abietatrien-19-al (Compound 7) 0.00005
Arbutin 4.0
Sodium bisulfite 0.03
Ascorbic acid glucoside 5.0
Triethanolamine 5.0
Perfume

Example 17 Lotion Toner lotion was obtained by stirring and mixing the following components.

Ingredient Amount (% by mass)
7-hydroxy-8,11,13-abietatrien-19-al (Compound 5) 0.00001
Hydroquinone-β-D- (N-acetylglucosamine) 0.1
Dimethyl myristylamine oxide 0.01
Ethanol 9.0
POE (20) oleyl ether 1.0
Ascorbic acid glucoside 5.0
Preservative Appropriate amount of perfume Appropriate amount of purified water Residue

Example 18 Lotion A lotion was obtained by stirring and mixing the following components.

Ingredient Amount (% by mass)
Ethyl alcohol 55.0
POE (25 mol) hydrogenated castor oil ether 2.0
Antioxidants and antiseptics
8,11,13-abietatrien-19-ol (Compound 1) 0.01
Kojic acid 3.0
Sodium hexametaphosphate Appropriate amount of ion exchange water Residual

Example 19 Cold cream The following components were stirred and mixed to obtain a cold cream.

Ingredient Amount (% by mass)
Solid paraffin 5.0
Honey wax 10.0
Vaseline 15.0
Liquid paraffin 41.0
Glycerin monostearate ester 2.0
POE (20 mol) sorbitan monolaurate 2.0
Magnesium ascorbate phosphate 2.0
4-Methoxy-4-tert-butylbenzoylmethane 3.5
Soap powder 0.1
Borax 0.2
Cetyl 2-ethylhexanoate solution (2) containing 8,11,13-abietatrien-19-ol (Compound 1)
(Concentration 0.10% by mass) 0.1
Ion-exchanged water Residual fragrance

Claims (4)

A whitening agent comprising one or more compounds selected from diterpene compounds having a basic structure of an abietane skeleton represented by the following formulas (1) to (7).

  The whitening agent which uses as an active ingredient the compound of 1 type, or 2 or more types chosen from the diterpene compound which has an abietan skeleton shown by Formula (1)-(7) of Claim 1 as a basic structure.   The skin external preparation for whitening containing the whitening agent of Claim 1 or 2.   A skin whitening preparation for skin whitening comprising one or more compounds selected from diterpene compounds having a basic structure of an abietane skeleton represented by formulas (1) to (7) according to claim 1.