JPH11255638A - 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 useful in e.g. bleaching cosmetics, by including specific compound(s) having 4-substituted resorcinol skeleton. SOLUTION: This tyrosinase activity inhibitor is obtained by including, as active ingredient, at least one kind of compound having 4-substituted resorcinol skeleton and shown by formula I to formula IV (R is H, OH, a 1-9C alkylalkenyl-or the like; (n) is 1-5) (e.g. 2,4-dihydroxybiphenyl). It is preferable that the above compound is prepared, for example, by the following procedure: a mixture of nitric acid and sulfuric acid, under chilling in an ice bath, is dripped onto 2-hydroxybiphenyl to carry out a reaction at room temperature for one hour to form 4-nitro-2-hydroxybiphenyl, and hydrochloric acid is then dripped, so as not to exceed 0 deg.C, onto the 4-nitro-2-hydroxybiphenyl in the presence of tin chloride in ethanol and also in an ice bath followed by agitation at room temperature for 2 h to afford 4-amino-2-hydroxybiphenyl, onto which a mixed solution of nitrous acid and hydrochloric acid is then dripped, followed by agitation at 0-5 deg.C for 2 h and then warming the system to 30 deg.C.

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 to a whitening agent (for example, JP-A-2-49715). 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, if the compound has a 4-substituted resorcinol skeleton, it does not necessarily have tyrosinase inhibitory activity for which whitening effect can be expected. Various are also known.

[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 compounds having no tyrosinase inhibitory activity among compounds having a 4-substituted resorcinol skeleton.
The position-substituted resorcinol skeleton is also important in a substance exhibiting tyrosinase inhibitory activity, and in addition, it has been found that the structure of the benzyl position of the 4-substituted resorcinol skeleton also greatly contributes to the tyrosinase inhibitory activity. From these results, the present inventors have identified a compound having an existing 4-position-substituted resorcinol skeleton and having a structure having an excellent tyrosinase inhibitory activity at the benzyl position, and completed the present invention. That is, according to the present invention, formulas (1) to (4)
(R in the formula is the same or different and represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 9 carbon atoms, an alkenyl group, or an alkoxy group, which may have a cyclic structure. A tyrosinase activity inhibitor comprising, as an active ingredient, at least one compound having a 4-substituted resorcinol skeleton represented by the following formula:

[0005]

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

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail. The tyrosinase activity inhibitor of the present invention is represented by the formula (1):
Containing, as an active ingredient, one or more compounds having a 4-substituted resorcinol skeleton represented by-(4);
If desired, it may be used in combination with a known tyrosinase activity inhibitor. In the formulas (1) to (4), R is the same or different and represents a hydroxyl group, an alkyl group having 1 to 9 carbon atoms, an alkenyl group, or an alkoxy group, which may have a cyclic structure. Among these, the substituent is a substituent that does not affect the structure at the benzyl position following the 4-substituted resorcinol skeleton, and therefore exhibits excellent tyrosinase activity inhibitory ability regardless of the structure within the range of R. . Therefore, a specific compound having a 4-substituted resorcinol skeleton that can be used in the present invention is:
It can be easily designed and synthesized within the range of R by a known method.

[0008] These compounds having a 4-substituted resorcinol skeleton can be easily synthesized according to known methods.
For example, to prepare 2,4-dihydroxybiphenyl in which R is a hydrogen atom among the compounds corresponding to the formula (1), first, a mixed solution of nitric acid and sulfuric acid is cooled in an ice bath while a commercially available θ is used. Slowly dropping into the hydroxybiphenyl; After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, and after completion of the reaction, 4-nitro-2-hydroxybiphenyl is obtained by extracting with chloroform. The obtained 4-nitro-2-hydroxybiphenyl and tin chloride are put in ethanol, and hydrochloric acid is added dropwise in an ice bath so as not to exceed 0 ° C. After dropping,
After stirring at room temperature for 2 hours, the mixture is concentrated under reduced pressure, and the crystals are washed with water to give 4-amino-2-hydroxybiphenyl. A mixture of nitrous acid and hydrochloric acid is slowly added dropwise to the 4-amino-2-hydroxybiphenyl in an ice bath. After completion of the dropwise addition, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 5 ° C.
Warm at 0 ° C. After 3 hours, water is added, and the mixture is extracted with chloroform to obtain the desired 2,4-dihydroxybiphenyl.

In order to prepare 2,4-dihydroxybenzyl acetic acid in which R is a hydroxyl group among the compounds corresponding to the formula (2), first, a mixture of nitric acid and sulfuric acid is cooled in an ice bath while a commercially available mixture is prepared. Slowly add dropwise to benzyl acetic acid. After completion of the dropwise addition, the mixture is stirred at room temperature for 3 hours, and after completion of the reaction, 2,4-nitrobenzylacetic acid is obtained by extraction with chloroform. The obtained 2,4-nitrobenzylacetic acid and tin chloride are put in ethanol, and hydrochloric acid is added dropwise in an ice bath so as not to exceed 0 ° C. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 hours, concentrated under reduced pressure, and washed with water to obtain 2,4-diaminobenzylacetic acid. A mixture of nitrous acid and hydrochloric acid is slowly added dropwise to the 2,4-diaminobenzylacetic acid in an ice bath.
After completion of the dropwise addition, the mixture is stirred while maintaining the temperature at 0 to 5 ° C.
Warm at 0 ° C. After 3 hours from the heating, water is added and the mixture is extracted with chloroform to obtain the desired 2,4-dihydroxybenzylacetic acid.

To prepare a compound corresponding to the formula (3) wherein R is a phenyl group, first, aqueous ammonia is added to chlorobenzylformic acid and stirred. After 3 hours, the mixture was concentrated under reduced pressure, and the crystals were washed with water to obtain aminobenzyl formic acid. The obtained aminobenzyl formic acid and 2,4
- Put the dihydroxy benzaldehyde in methanol, was added NaBH ₃ CN portionwise and stirred at room temperature for 50 hours. Next, 18% hydrochloric acid is added until HCN is no longer generated, and the mixture is concentrated under reduced pressure. The target compound can be obtained by adding sodium chloride thereto to make it saturated and extracting it with chloroform. Further, by substituting a phenyl group with a hydroxyl group from this compound according to a conventional method, a compound in which R in Formula (3) is a hydroxyl group can be easily obtained.

To prepare 2-hydroxytyrosine in which R is a hydroxyl group among the compounds corresponding to the above formula (4),
First, tyrosine is put in ethanol to obtain tyrosine ethyl ester with thionyl chloride. A mixed solution of sulfuric acid and hydrochloric acid is slowly added dropwise to the obtained tyrosine ethyl ester in an ice bath. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, and after completion of the reaction, extracted with chloroform to obtain 2-nitrotyrosine ethyl ester. The obtained 2-nitrotyrosine ethyl ester and tin chloride are put in ethanol, and hydrochloric acid is added dropwise in an ice bath so as not to exceed 0 ° C. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 hours, concentrated under reduced pressure, and washed with water to obtain 2-aminotyrosine ethyl ester. This 2-aminotyrosine ethyl ester is added with nitrous acid,
The hydrochloric acid mixture is slowly added dropwise in an ice bath. After dropping,
Stir while maintaining the temperature at 0-5 ° C, and warm at 30 ° C after 2 hours. After 3 hours from the warming, water is added and extracted with chloroform to give 2-hydroxytyrosine ethyl ester. The obtained 2-hydroxytyrosine ethyl ester is placed in 1 N (N) NaOH and stirred at room temperature. After 2 hours, add hydrochloric acid until the pH reaches 7, and further add n.
Add hexane and stir. Then, the mixture is allowed to stand until the aqueous layer and the n-hexane layer are separated, and only the aqueous layer is separated and dried under reduced pressure to obtain the desired 2-hydroxytyrosine.

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. The mixing ratio of the tyrosinase activity inhibitor to the cosmetic is determined according to the aforementioned 4
0.000 of the compound having the resorcinol skeleton
It is desirable that the content be 1% by weight or more, particularly 0.0001 to 20% by weight, more preferably 0.0001 to 10% by weight.

[0014] In addition to the tyrosinase activity inhibitor, various materials can be added to the cosmetic of the present invention depending on the purpose. Particularly conventionally known whitening agents, wrinkle preventives,
By blending a humectant or a mixture thereof, the desired effect can be synergistically improved.

Examples of the whitening agent include kojic acid, ascorbic acid, hydroquinone, thiol compounds, derivatives thereof, extracts of animals and plants containing these, and mixtures thereof. 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 blending ratio when blending the whitening agent, anti-wrinkle agent or humectant is preferably in the range of 0.001 to 1000 times, more preferably 0.005 to 500 times the active ingredient of the tyrosinase activity inhibitor. It is desirable to mix them.

The cosmetics of the present invention contain fats and oils, surfactants, alcohols, and the like generally incorporated 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 agent include natural polymer substances such as sodium alginate, xanthan gum, aluminum silicate, quince seed extract, tragacanth gum, starch; methyl cellulose, soluble starch, hydroxyethyl 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 necessary for various purposes. Specifically, lotions, emulsions, creams,
Packs, skin cleansers, cataplasms, plasters, pastes, ointments, essences, gels, shampoos, rinses, powders, foundations, lotions, facial cleansers, hair tonics, hair tonics, bath preparations and the like can be prepared. 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.

[0019]

Since the tyrosinase activity inhibitor of the present invention comprises the above-mentioned compound having a 4-substituted resorcinol skeleton as an active ingredient, 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, so that by suppressing tyrosinase activity, melanin production can be suppressed and a whitening effect can be expected, and the active ingredient is contained in the cosmetic. Can be stably compounded, so that various cosmetics can be obtained over a wide range.

[0020]

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 According to a conventional method, 2,4-dihydroxybiphenyl represented by the following formula was prepared.

[0021]

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Using the obtained 2,4-dihydroxybiphenyl as a sample, the following tyrosinase activity inhibition test was performed. Tyrosinase activity inhibition test 2.0 ml of 0.1% L-tyrosine solution (Mcilvai
ne buffer (pH 6.8), 0.2 ml of a dimethyl sulfoxide solution containing the sample was added, and the mixture was incubated at 37 ° C. for 10 minutes. Next, 1250 unit / m
1 Tyrosinase solution (Mcilvaine buffer, pH 6.8)
0.1 ml was mixed and incubated at 37 ° C. for 10 minutes. 475n after incubation using a spectrophotometer
The absorbance at m was measured to determine the IC ₅₀ for the control. As a result, the IC ₅₀ was 9.7 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 2 According to a conventional method, 2,4-dihydroxybenzyl acetic acid represented by the following formula was prepared.

[0024]

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Using the obtained 2,4-dihydroxybenzylacetic acid 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 25.8 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 3 A compound represented by the following formula (3a) was prepared according to a conventional method.

[0027]

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Using the obtained compound represented by the formula (3a) 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 30.6 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 4 According to a conventional method, 2-hydroxytyrosine represented by the following formula was prepared.

[0030]

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Using the obtained 2-hydroxytyrosine 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 1.5 μM, indicating that the compound had excellent tyrosinase inhibitory activity.

Example 5 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 1.0 part by weight of 2,4-dihydroxybiphenyl were 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.

Example 6 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 and 3.0 parts by weight of polyoxyethylene monostearate (25EO) were dissolved by heating. Then, 0.5 parts by weight of 2,4-dihydroxybenzyl acetic acid, 5.0 parts by weight of 1,3-butylene glycol, 0.1 parts by weight of potassium hydroxide, 0.2 parts by weight of arbutin, and After mixing 65.2 parts by weight of water, the mixture was cooled to prepare a cream.

Example 7 0.5 part by weight of the compound represented by the formula (3a), 5.0 parts by weight of polyoxyethylene cetyl ether, 2.0 parts by weight of propylene glycol, 0.1 part by weight of l-menthol, ethanol 15.0 parts by weight and purified water 77.4 parts by weight were stirred until uniform to prepare a lotion.

Example 8 0.5 parts by weight of 2-hydroxytyrosine, 2.0 parts by weight of polyoxyethylene hydrogenated castor oil (60 EO), 15.0 parts by weight of ethanol, and 1,3-butylene glycol 4.0 A lotion was prepared by stirring parts by weight and 78.5 parts by weight of purified water until uniform.

Example 9 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 were dissolved by heating. 0.5 g of 2,4-dihydroxybenzylacetic acid was added to the resulting heat-dissolved solution.
Parts by weight, carboxyvinyl polymer 0.2 parts by weight, propylene glycol 5.0 parts by weight, potassium hydroxide 0.1
After mixing 2.0 parts by weight of ethanol, 2.0 parts by weight of ethanol and 79.7 parts by weight of purified water, the mixture was cooled to prepare an emulsion.

Example 10 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 parts by weight)
E. FIG. O. ) 1.2 parts by weight were dissolved by heating. 0.5 parts by weight of 2,4-dihydroxybiphenyl, 0.2 parts by weight of carboxyvinyl polymer, 5.0 parts by weight of propylene glycol, 0.1 parts by weight of potassium hydroxide, 2.0 parts by weight of ethanol After mixing 1.0 parts by weight of kojic acid and 78.7 parts by weight of purified water, the mixture was cooled to prepare an emulsion.

Example 11 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 and 2.0 parts by weight of oleic acid were dissolved by heating. The obtained formula (3a)
0.2 part by weight of the compound represented by the formula, 0.3 part by weight of 2-hydroxytyrosine, 0.2 part by weight of hydroxyethyl cellulose, 2.0 parts by weight of propylene glycol, 0.1 part by weight of dipotassium glycyrrhizinate and 87.2 purified water After mixing by weight, the emulsion was cooled to prepare an emulsion.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/12 A61K 31/12 31/135 31/135 31/165 31/165 31/19 31/19 31/235 31/235 (72) Inventor Hiroaki Sato 3-12-13 Wing 102, Shimootari, Onojo-shi, Fukuoka

Claims (2)

[Claims] 1. Formulas (1) to (4) (wherein R is the same or different group, and includes a hydrogen atom, a hydroxyl group,
9 represents an alkyl group, an alkenyl group or an alkoxy group,
These may have a ring structure. And n is an integer of 1 to 5). A tyrosinase activity inhibitor comprising, as an active ingredient, at least one compound having a 4-substituted resorcinol skeleton represented by the following formula: Embedded image 2. A cosmetic comprising the tyrosinase activity inhibitor according to claim 1.