JPH11255637A - Tyrosinase activity inhibitor and cosmetic - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor highly inhibiting tyrosinase activity involved in melanogenesis and usable in e.g. bleaching cosmetics, by including one or more kinds of specific flavonoids as active ingredient. SOLUTION: This tyrosinase activity inhibitor is obtained by including (A) as active ingredient, >=0.0001 wt.% of one or more kinds of flavonoids of formula I to formula V (R is OH, carbonyl, a 1-9C alkyl, alkenyl- or alkoxy; (n) is 0-3) or the like and (B) as necessary, another tyrosinase activity inhibitor. To prepare the component A, flavonoids or isoflavonoids afforded by e.g. extraction from natural plants are nitrated and then aminated by conventional means fallowed by addition of hydroxyl groups. The other objective cosmetic is obtained by including >=0.0001 wt.%, pref. 0.0001-20 wt.%, more pref. 0.0001-10 wt.% of the flavonoids.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tyrosinase activity inhibitor which can be used as an active ingredient for preventing or treating skin spots and freckles, as well as a whitening cosmetic and the like, and a cosmetic using the inhibitor.

[0002]

2. Description of the Related Art Conventionally, various substances have been proposed for inhibiting melanin production by inhibiting tyrosinase activity for the purpose of preventing or treating skin spots and freckles and for whitening effects. Specifically, vitamin C, hydroquinone, kojic acid, thiol-based compounds, and various animal and plant extracts are known, and cosmetics containing these have been developed and commercialized. It has also been proposed to apply a specific compound having a 4-substituted resorcinol skeleton or a specific flavonoid compound to a whitening agent (for example, JP-A-2-49715, JP-A-55-111411, JP-A-57-35506, JP-A-6-16
No. 531). However, since vitamin C, hydroquinone, and kojic acid have high polarity, it is necessary to consider this point when blending as cosmetics. Further, the thiol-based compound has a problem in stability when blended into cosmetics. On the other hand, a compound having a 4-substituted resorcinol skeleton or a flavonoid compound containing the 4-substituted resorcinol skeleton does not necessarily have a tyrosinase inhibitory activity that can be expected to have a whitening effect. Are also known in the same manner.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a tyrosinase activity inhibitor which strongly suppresses tyrosinase activity involved in melanin production and can be used for whitening cosmetics and the like. Another object of the present invention is to provide a cosmetic that suppresses tyrosinase activity to suppress melanin production and is expected to have a whitening effect and the like.

[0004]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have paid attention to compounds having a tyrosinase inhibitory activity and compounds not having a tyrosinase inhibitory activity among compounds having a 4-substituted resorcinol skeleton. There are many flavonoids having no tyrosinase inhibitory activity among flavonoids having a 4-substituted resorcinol skeleton. However, this 4-substituted resorcinol skeleton is also important in a substance having a tyrosinase inhibitory activity. In the following formulas (1) to (9), those having a carbonyl group at the position indicated by an arrow have no such inhibitory activity, and those having an azo group or chlorine element at this position also have a lower inhibitory activity. I understood. Therefore, it was found that the structure at the position indicated by the arrow also greatly contributed to the tyrosinase inhibitory activity. From the results, the present inventors have found that among the existing flavonoids, those having a 4-substituted resorcinol skeleton and having a specific structure at the position indicated by the arrow show excellent tyrosinase inhibitory activity. completed.

[0005]

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That is, according to the present invention, formulas (1) to (1)
(9) (wherein R is the same or different and represents a hydroxyl group, a carbonyl group, an alkyl group, an alkenyl group, or an alkoxy group having 1 to 9 carbon atoms, and n is an integer of 0 to 3). The present invention provides a tyrosinase activity inhibitor containing at least one flavonoid to be used as an active ingredient.

[0007]

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Further, according to the present invention, there is provided a cosmetic comprising the tyrosinase activity inhibitor.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The tyrosinase activity inhibitor of the present invention is represented by the formula (1):
One or more of the flavonoids represented by (9) to (9) may be contained as an active ingredient, and may be used in combination with a known tyrosinase activity inhibitor, if desired. Equation (1)
In (9), R is the same or different and represents a hydroxyl group, a carbonyl group, an alkyl group having 1 to 9 carbon atoms, an alkenyl group or an alkoxy group, and n represents an integer of 0 to 3. Since these substituents do not affect the structure at the position indicated by the arrow in the above formula,
Regardless of the substitution structure within the range of R, and even when R is not contained (n = 0), the same tyrosinase activity inhibiting ability is exhibited. Therefore, specific flavonoids that can be used in the present invention can be easily designed and synthesized within the range of R by a known method.

To prepare these flavonoids,
It can be easily obtained by a method of adding a hydroxyl group to flavonoids or isoflavonoids obtained by extraction from nature or the like through nitration and amination by a conventional method. In order to extract flavonoids or isoflavonoids from nature, for example, first, a higher plant is finely pulverized with a pulverizer, immersed in ether, and kept at room temperature for 24 hours. Then, after stirring, filtration was performed to obtain an ether extract, and the solvent was distilled off from the obtained ether extract. The mixture was subjected to silica gel chromatography and two silica gel MPLC treatments to separate the fraction of each flavonoid and isoflavonoid. Get a minute. The obtained fraction was subjected to LC-HRFABMS (liqu
id chromatography-high re
solution fast atom bombbar
The target flavonoids and isoflavonoids can be purified and isolated by analysis by NMR (dment mass spectrometry) and NMR.

The tyrosinase activity inhibitor of the present invention may contain the above-mentioned active ingredient.
0001% by weight or more.

The cosmetic of the present invention contains the tyrosinase activity inhibitor as an essential component, and preferably exhibits a melanin production inhibitory action based on the tyrosinase activity inhibitory action,
It can be used as a whitening cosmetic or the like. The compounding ratio of the tyrosinase activity inhibitor to cosmetics is such that the flavonoids as an active ingredient is 0.0001% by weight or more, particularly 0.0
001 to 20% by weight, further 0.0001 to 10% by weight
It is desirable that

[0013] In addition to the tyrosinase activity inhibitor, various materials can be added to the cosmetic of the present invention according to the purpose. Particularly conventionally known whitening agents, wrinkle preventives,
By blending a humectant or a mixture thereof, the desired effect can be synergistically improved.

The whitening agents include, for example, kojic acid, ascorbic acid, hydroquinone, thiol compounds, compounds having a 4-substituted resorcinol skeleton exhibiting a tyrosinase activity inhibitory action other than the flavonoids, derivatives thereof, and the like. An extract of animals and plants or a mixture thereof is mentioned. Examples of the humectant include polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, mannitol, polyethylene glycol, and dipropylene glycol; NMF components such as amino acids, sodium lactate, and sodium pyrrolidonecarboxylate; Hyaluronic acid; collagen; elastin; chondroitin sulfate; fibronectin; ceramides; heparin-like substances; water-soluble high-molecular substances such as chitosan or mixtures thereof.
The mixing ratio of the whitening agent, anti-wrinkle agent or humectant is preferably 0.001 to 1000 times, more preferably 0.1 to 1000 times the active ingredient of the tyrosinase activity inhibitor.
It is desirable to mix in the range of 005 to 500 times.

The cosmetics of the present invention include fats and oils, surfactants, alcohols, and the like which are generally blended according to the type of cosmetics.
Fatty acids, preservatives, bactericides, thickeners, anti-inflammatory agents, antioxidants, pigments, fragrances, water-soluble polymers, ultraviolet absorbers, chelating agents, pH adjusters, buffers, purified water, etc. Components can be appropriately blended.

Examples of the thickening agents include sodium alginate, xanthan gum, aluminum silicate, quince seed extract, tragacanth gum, starch and other natural polymer substances; methyl cellulose, soluble starch, hydroxyethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose, soluble starch, cationized Semi-synthetic polymer substances such as cellulose; synthetic polymer substances such as carboxyvinyl polymer and polyvinyl alcohol; and mixtures thereof. As the preservative, benzoate, sorbate,
Dihydroacetate, p-hydroxybenzoate, 2,
2,4'-Trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide, benzalkonium chloride, ethanol and the like. Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, vitamin E, propyl gallate and the like. As the ultraviolet absorber, 4-methoxybenzophenone, octyldimethylparaaminobenzoate, ethylhexylparamethoxycinnamate,
Examples include titanium oxide, kaolin, and talc. Examples of the chelating agent include ethylenediaminetetraacetate, pyrophosphate, hexametaphosphate, citrate, tartaric acid, gluconic acid and the like. As the pH adjuster, sodium hydroxide, potassium hydrogen phosphate, potassium carbonate,
Citric acid and the like.

The cosmetics of the present invention can be prepared as pharmaceuticals, quasi-drugs or cosmetics by blending the above-mentioned active ingredients and other ingredients as required for various purposes. Specifically, lotions, emulsions, creams,
Packing agents, skin cleansing agents, haptics, plasters, pastes, ointments, essences, gels, shampoos, rinses, powders, foundations, lotions, facial cleansers, hair tonics, hair tonics, bath preparations, etc. it can. In this case, as the other components, in addition to the above-described components, components conventionally used for such applications can be appropriately selected and blended.

[0018]

Since the tyrosinase activity inhibitor of the present invention contains the above-mentioned flavonoids as an active ingredient, the tyrosinase activity involved in melanin production can be strongly suppressed. In addition, the cosmetic of the present invention contains the tyrosinase activity inhibitor as an essential component, and thus suppresses tyrosinase activity to suppress melanin production, can be expected to have a whitening effect, and the active ingredient is contained in the cosmetic. Can be stably compounded, so that various cosmetics can be obtained over a wide range.

[0019]

The present invention will be described in more detail with reference to the following examples.
The present invention is not limited to these. Example 1 A tyrosinase activity inhibition test shown below was performed using a flavonoid represented by the following formula, wherein n of the formula (1) was 0, prepared by a conventional method.

[0020]

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Tyrosinase activity inhibition test To 2.0 ml of a 0.1% L-tyrosine solution (Mcilvaine buffer, pH 6.8), 0.2 ml of a dimethyl sulfoxide solution containing a sample is added and incubated at 37 ° C. for 10 minutes. did. Next, 0.1 ml of 1250 unit / ml tyrosinase solution (Mcilvaine buffer, pH 6.8)
Were mixed and incubated at 37 ° C. for 10 minutes. The absorbance at 475 nm after incubation was measured using a spectrophotometer to determine the IC ₅₀ for the control. As a result, the IC ₅₀ was 13.2 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 2 Anthocyanins extracted from nature by a conventional method were converted into nitric acid:
The sulfuric acid mixture was slowly added dropwise while cooling in an ice bath.
After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. After the reaction, 2 ', 4'-dinitroanthocyanin was obtained by chloroform extraction. The obtained 2 ', 4'-dinitroanthocyanin and tin chloride were put in ethanol, and hydrochloric acid was added dropwise in an ice bath so as not to exceed 0 ° C. After dropping, add 2
After stirring for an hour, the mixture was concentrated under reduced pressure, and the crystals were washed with water to give 2 ',
4′-Diaminoanthocyanin was obtained. These 2 ', 4'
-A mixture of nitrous acid and hydrochloric acid was slowly added dropwise to diaminoanthocyanin in an ice bath. After completion of the dropwise addition, the mixture was stirred while being kept at 0 to 5 ° C., and heated to 30 ° C. after 2 hours. After 3 hours, water was added and extracted with chloroform. When the obtained compound was analyzed by NMR spectrum, it was 2 ', 4'-dihydroxyanthocyanin represented by the following formula, wherein n in the formula (2) was 0.

[0023]

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Using the obtained 2 ', 4'-dihydroxyanthocyanin as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ was 2.8 μM.
It was found to have excellent tyrosinase inhibitory activity.

Example 3 Example 2 was carried out using flavan extracted from nature by a conventional method.
2 ′, 4′-dihydroxyflavan represented by the following formula, wherein n of the formula (5) is 0, was prepared according to the following formula.

[0026]

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Using the obtained 2 ′, 4′-dihydroxyflavan as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ was 2.1 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 4 2 ', 4'-Dihydroxyisoflavan represented by the following formula wherein n in the above formula (6) is 0 is prepared according to Example 2, using isoflavane extracted from nature by a conventional method. did.

[0029]

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Using the obtained 2 ', 4'-dihydroxyisoflavan as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ was 2.4 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 5 Using isoflavanone extracted from nature by a conventional method, 2 ', 4'-dihydroxyisoflavanone represented by the following formula wherein n in the above formula (7) is 0 was obtained in accordance with Example 2. Prepared.

[0032]

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Using the obtained 2 ', 4'-dihydroxyisoflavanone as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ was 23.1 μm.
M, and was found to have excellent tyrosinase inhibitory activity.

Example 6 Using isoflavanol extracted from nature by a conventional method,
According to Example 2, 2 ′, 4′-dihydroxyisoflavanol represented by the following formula wherein n in the formula (8) was 0 was prepared.

[0035]

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Using the obtained 2 ', 4'-dihydroxyisoflavanol as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ was 22.3.
μM, which proved to have excellent tyrosinase inhibitory activity.

Example 7 Using isoflav-3-ene extracted from nature by a conventional method, 2 ', 4'-dihydroxy represented by the following formula wherein n of the formula (9) is 0 according to Example 2 Isoflava-3
-An ene was prepared.

[0038]

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Using the obtained 2 ', 4'-dihydroxyisoflava-3-ene as a sample, a tyrosinase activity inhibition test was carried out in the same manner as in Example 1. As a result, the IC ₅₀ becomes 1
5.8 μM, which proved to have excellent tyrosinase inhibitory activity.

Example 8 4.0 parts by weight of stearic acid, 3.0 parts by weight of cetyl alcohol, 1.0 part by weight of stearyl alcohol, 6.5 parts by weight of liquid paraffin, 10.0 parts by weight of petrolatum, sorbitan monostearate 1 0.5 parts by weight, 3.0 parts by weight of polyoxyethylene monostearate (25EO) and 2 ′, 4 ′ represented by the following formula wherein n in the above formula (3) is 0.
-1.0 parts by weight of dihydroxyaron was dissolved by heating.
Next, 5.0 parts by weight of 1,3-butylene glycol, 0.1 part by weight of potassium hydroxide, and 64.9 parts by weight of purified water were mixed with the heat-dissolved solution, followed by cooling to prepare a cream.

[0041]

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Example 9 4.0 parts by weight of stearic acid, 3.0 parts by weight of cetyl alcohol, 1.0 part by weight of stearyl alcohol, 6.5 parts by weight of liquid paraffin, 10.0 parts by weight of petrolatum, sorbitan monostearate 1 0.5 parts by weight, 3.0 parts by weight of polyoxyethylene monostearate (25EO), 2 ′, 4′- represented by the following formula wherein n in the above formula (4) is 0
0.1 parts by weight of dihydroxybiflavanone and 0.4 parts by weight of 2 ′, 4′-dihydroxyflavanone where n in the formula (7) is 0 were dissolved by heating. Next, 5.0 parts by weight of 1,3-butylene glycol was added to the heat-dissolved solution.
After mixing 0.1 part by weight of potassium hydroxide, 0.2 part by weight of arbutin and 65.2 parts by weight of purified water, the mixture was cooled to prepare a cream.

[0043]

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Example 10 0.5 parts by weight of 2 ', 4'-dihydroxyisoflavanol where n in the formula (8) is 0, 5.0 parts by weight of polyoxyethylene cetyl ether, and propylene glycol 2.
0 parts by weight, 0.1 part by weight of l-menthol, ethanol 1
5.0 parts by weight and 77.4 parts by weight of purified water were stirred until uniform to prepare a lotion.

Example 11 0.5 parts by weight of 2 ', 4'-dihydroxyflavan wherein n in the formula (5) is 0, 2.0 parts by weight of polyoxyethylene hydrogenated castor oil (60EO), ethanol 15.0
By weight, 4.0 parts by weight of 1,3-butylene glycol and 78.5 parts by weight of purified water were stirred until uniform to prepare a lotion.

Example 12 8.0 parts by weight of squalane, 2.0 parts by weight of petrolatum, 0.5 parts by weight of beeswax, 0.8 parts by weight of sorbitan sesquiolate and polyoxyethylene oleyl ether (20
E. FIG. O. ) 1.2 parts by weight and 0.5 parts by weight of 2 ', 4'-dihydroxyflavan wherein n in the formula (5) is 0 were dissolved by heating. 0.2 part by weight of the carboxyvinyl polymer and 5.0 parts of propylene glycol were added to the obtained heat-dissolved solution.
1. parts by weight, 0.1 parts by weight of potassium hydroxide, ethanol
After mixing 0 parts by weight and 79.7 parts by weight of purified water, the mixture was cooled to prepare an emulsion.

Example 13 8.0 parts by weight of squalane, 2.0 parts by weight of petrolatum, 0.5 parts by weight of beeswax, 0.8 parts by weight of sorbitan sesquiolate, polyoxyethylene oleyl ether (20E.
O. ) 1.2 parts by weight and 0.5 parts by weight of 2 ', 4'-dihydroxyisoflavan wherein n in the formula (6) is 0 were dissolved by heating. To the obtained heat-dissolved solution, 0.2 parts by weight of carboxyvinyl polymer and propylene glycol5.
0 parts by weight, 0.1 part by weight of potassium hydroxide, 2.0 parts by weight of ethanol, 1.0 part by weight of kojic acid and 78.000 parts of purified water.
After mixing 7 parts by weight, the mixture was cooled to prepare an emulsion.

Example 14 1.0 part by weight of polyethylene glycol monostearate, 2.0 parts by weight of lipophilic glyceryl monostearate
5.0 parts by weight of olive oil, 2.0 parts by weight of oleic acid, 0.2 part by weight of 2 ', 4'-dihydroxyisoflavan wherein n in the above formula (6) is 0, and n is 0 in the above formula (7) Was heated and dissolved in 0.3 part by weight of 2 ′, 4′-dihydroxyisoflavanone. 0.2 parts by weight of hydroxyethyl cellulose, 2.0 parts by weight of propylene glycol, 0.1 parts by weight of dipotassium glycyrrhizinate and 87.2 parts by weight of purified water were mixed with the obtained heat-dissolved solution, and then cooled to obtain an emulsion. Prepared.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/12 A61K 31/12 31/34 31/34 31/35 ADA 31/35 ADA // C07D 311/36 C07D 311/36 311/38 311/38 311/58 311/58 311/60 311/60 (72) Inventor Hiroaki Sato 3-12-13 Wing 102, Shimootari, Onojo-shi, Fukuoka

Claims (2)

[Claims] 1. A compound of the formula (1) to (9) wherein R is the same or different and is a hydroxyl group, a carbonyl group,
-9 represents an alkyl group, an alkenyl group or an alkoxy group, and n is an integer of 0 to 3). Embedded image 2. A cosmetic comprising the tyrosinase activity inhibitor according to claim 1.