JP4879344B1 - Antioxidant polyhydroxybenzene derivative and anti-inflammatory skin external preparation - Google Patents

Abstract

[PROBLEMS] To stabilize against heat and light, to have good storage stability, to have high skin permeability, to be rapidly hydrolyzed by phosphatase widely distributed in the living body, and to exhibit the useful physiological activity inherent in hydroxyphenol. A new polyhydroxybenzene derivative that is safe and has low skin irritation due to the anti-inflammatory effect of a predetermined hydrolyzed antioxidant substance, or an anti-inflammatory skin external preparation or whitening using the same It is to make cosmetics.
[Solution]
Antioxidant comprising polyhydroxyphenyl phosphate or a salt thereof in which phosphoric acid is ester-bonded to a hydroxyl group of an antioxidant substance comprising astaxanthin, tocopherol or tocotrienol, and this phosphate ester is diester-bonded to one or more hydroxyl groups of polyhydroxybenzene. An oxidizing polyhydroxybenzene derivative is used. Antioxidant polyhydroxybenzene derivatives have moderate fat solubility, are easily taken into cells, and have properties suitable for skin permeability. The antioxidant polyhydroxybenzene derivative taken up into cells is hydrolyzed into hydroxyphenol, astaxanthin, tocopherol or tocotrienol by phosphatase and other enzymes distributed in tissues in the living body, and has a useful effect on the living body.
[Selection figure] None

Description

  The present invention relates to a polyhydroxybenzene derivative, an anti-inflammatory skin external preparation containing the same, and a whitening cosmetic.

  In general, polyhydroxybenzene (also referred to as hydroxyphenol) includes compounds such as catechol, resorcin, and hydroquinone depending on the arrangement of the hydroxyl groups, and each is known to have an antioxidant effect.

  Such polyhydroxybenzene is also known to suppress biosynthesis from dopaquinone, which is a metabolic intermediate in the melanin production process, to dopachrome, and to reduce and bleach black melanin. It is well known as a component of whitening cosmetics that can be expected to treat skin whitening, blemishes, freckles, melanosis, hepatic lesions, etc. by inhibiting melanin synthesis and reducing melanin.

  However, since hydroxyphenol is very unstable with respect to heat and oxidation and is easily inactivated or decomposed, sufficient physiological action may not always be obtained stably.

  In order to improve the instability in hydroquinone, which is such a dihydroxyphenol, arbutin is known as a derivative obtained by glucosidation of a hydroxyl group that is easily oxidized (Patent Document 1).

  However, since arbutin and other polyhydroxybenzene derivatives have high hydrophilicity, they have a drawback of poor skin permeability.

In addition, hydroxyphenol derivatives other than hydroquinone, which are used as pharmaceuticals in Europe and the United States, are very slow in their effects as whitening preparations and are not sufficient.
Furthermore, hydroquinone, which has a whitening effect, has sensitization properties such as the occurrence of erythema on the skin, and therefore is generally limited in use and cannot be said to be sufficiently safe.

  Therefore, in order to improve the safety of hydroquinone, attempts have been made to convert it into an alkyl monoether of a higher alcohol. However, ethers are not fully satisfactory in terms of safety. In addition, monoquinone hydropyranyl ether derivatives of hydroquinone are known (Patent Document 2).

  By the way, a hydroxyalkyl ether glycoside is known as a hydroquinone derivative improved in both stability and skin permeability (Patent Document 3).

  However, in order to improve the liposolubility of hydroxyphenol in this way, the hydroxyl group of hydroxyphenol acylated with a fatty acid has no stability over time with respect to heat and light in a stored state, and the hydroxyl group is not a fatty acid. In the case of acyl esterification, there is not enough esterase or lipase to decompose it in the epidermis, so it was difficult to quickly and sufficiently convert it into hydroxyphenol in the body such as the skin. .

  In addition, those obtained by acyl esterifying the hydroxyl group of hydroxyphenol or glycosylated do not have sufficient esterase, lipase, and glucosidase in the epidermis in the same manner as above, so conversion to hydroxyphenol is not sufficient. There wasn't.

  The inventors of the present application have stabilized hydroxyphenol with respect to heat and light as a means of improving the stability and skin permeability of the above-mentioned hydroxyphenol derivative when the application was made earlier, and the storage stability is improved. An invention relating to a hydroxyphenol phosphate ester having an alkyl group in the phosphate ester portion so that the skin permeability is good and can be hydrolyzed by phosphatase widely distributed in the living body and exhibit the physiological activity inherent in hydroxyphenol. (Patent Document 4).

Japanese Patent Laid-Open No. 60-016906 Japanese Patent Laid-Open No. 06-192062 Japanese Patent Application Laid-Open No. 07-291989 JP 2010-105958 A

  However, even in the above-mentioned hydroxyphenol phosphates having an alkyl group, the problem of skin irritation in hydroxyphenols including hydroquinone cannot be said to be sufficiently solved.

  Therefore, the present invention solves the above problems of hydroxyphenol derivatives at once, stabilizes against heat and light, has good storage stability, has high skin permeability and is widely distributed in the living body. It is hydrolyzed quickly and can exhibit the useful physiological activity inherent in hydroxyphenol, and is highly safe to the skin due to the anti-inflammatory effect of the hydrolyzed antioxidant, and has low skin irritation It is an object to make a polyhydroxybenzene derivative or an anti-inflammatory skin external preparation using the same.

  In addition, the invention of the present application solves the problem of the whitening component of conventional cosmetics, in particular, stabilizes hydroxyphenol against heat and light, enhances skin permeability, and improves skin safety. Another object of the present invention is to provide a whitening cosmetic that is rapidly decomposed by enzymes widely distributed in the living body and that has a physiological activity of hydroxyphenol and a predetermined antioxidant substance.

In order to solve the above problems, in the present invention, astaxanthin, a hydroxyl group and phosphoric acid antioxidant comprising a tocopherol or tocotrienol is an ester bond, the phosphoric acid ester and one or more hydroxyl groups of the polyhydroxy benzene by an ester bond, it was an antioxidant polyhydroxy benzene derivatives consisting of those polyhydroxy phenyl phosphate or a salt thereof.

The antioxidant polyhydroxybenzene derivative of the present invention is obtained by using astaxanthin (3,3′-dihydroxy-β, β-carotene-4,4′-dione) via phosphoric acid to the hydroxyl group of polyhydroxybenzene having two or more hydroxyl groups. ) residue, is an ester bond tocopherol residue or tocotrienol residue.
Therefore, the antioxidant polyhydroxybenzene derivative of the present invention having these groups has appropriate lipid solubility, is easily taken into cells, and has characteristics suitable for skin permeability.

  The antioxidant polyhydroxybenzene derivative of the present invention that penetrates into the skin and is taken up by the cells is hydroxylated by phosphatase and other enzymes that are distributed in almost all living tissues without esterase and lipase. It is hydrolyzed to phenol, astaxanthin, tocopherol or tocotrienol, and has a useful effect on the living body.

  The burden on the living body due to such enzymatic degradation is small, and since the anti-inflammatory effect is exhibited by the decomposed astaxanthin, tocopherol or tocotrienol, the skin irritation of hydroxyphenol is reduced.

  Antioxidant polyhydroxybenzene derivatives that are decomposed in vivo by phosphatase and other enzymes exhibit relatively stable physical properties against heat and light.

Examples of the polyhydroxybenzene include dihydroxybenzene, trihydroxybenzene, tetrahydroxybenzene, pentahydroxybenzene, and hexahydroxybenzene. Among these, dihydroxybenzene includes catechol, resorcin, or hydroquinone.
The antioxidant polyhydroxybenzene derivative of the present invention using these polyhydroxybenzenes can sufficiently obtain the above-described effects.

  By making such an anti-inflammatory skin external preparation or whitening cosmetic containing such an oxidizable polyhydroxybenzene derivative as an active ingredient, it is stable against heat and light, has good preservation, and has high skin permeability. In addition, the anti-inflammatory skin external preparation with high safety to the skin, which is rapidly decomposed by enzymes widely distributed in the living body, etc., and has high originally useful physiological activity of hydroxyphenol and astaxanthin, tocopherol, or tocotrienol, or It becomes a whitening cosmetic.

The present invention, a hydroxyl group and phosphoric acid of a given antioxidant is an ester bond, and one or more hydroxyl groups and an ester bond is a polyhydroxy phenyl phosphate or a salt thereof was of the phosphoric acid ester polyhydroxy benzene This makes it possible to stabilize hydroxyphenol, which is unstable to heat and oxidation, and to suppress the degradation of hydroxyphenol in the storage state before use, and when used further, it can be quickly absorbed by phosphatase widely distributed in the living body. A polyhydroxybenzene derivative that is decomposed into hydroxyphenol and exhibits the original useful physiological activity of hydroxyphenol, and astaxanthin, tocopherol, and tocotrienol exhibit the original anti-inflammatory effect, or anti-inflammation that exhibits the above effect as an active ingredient For skin external use There is the advantage.

  In addition, in whitening cosmetics containing the same polyhydroxybenzene derivative as an active ingredient, hydroxyphenol is stabilized against heat and oxidation, and hydroxyphenol is decomposed in the storage state before use of the whitening cosmetic. Furthermore, when these cosmetics are used, they are rapidly decomposed into hydroxyphenol and astaxanthin, tocopherol, or tocotrienol by phosphatase and other enzymes present in the skin, and the original skin of hydroxyphenol Physiological activity useful for whitening, that is, there is an advantage that whitening of skin, spots, freckles, melanosis, liver spots, etc. can be treated.

  The polyhydroxybenzene used in the present invention is represented by the following formula 1.

(Wherein, R ₁ to R ₅ represents a hydrogen (H) or hydroxyl (OH), number of hydrogen (H) is 0-4.)

The polyhydroxybenzene represented by the above chemical formula 1 includes compounds 1 to 10 shown in Table 1 depending on the combination of hydrogen (H) or hydroxyl group (OH) of R _{1 to} R ₅ .

The predetermined phosphorus San'e ester group of phosphoric acid is ester bonded to a hydroxyl group of the antioxidant used in this invention are those represented by the following Formula 2.

(In the formula, R ₆ and R ₇ represent hydrogen (H) or an astaxanthin residue, a tocopherol residue, or a tocotrienol residue, except when R ₆ = R ₇ = hydrogen (H).)

Then, one or more hydroxyl groups and certain phosphate esters by an ester bond, a polyhydroxy phenyl phosphate or antioxidant polyhydroxy benzene derivatives according to the present invention as a salt thereof of the above-described polyhydroxy benzene, following reduction 3 is shown.

_(Wherein one or more R 8 _{to R 13} is a phosphorus San'e ester group having astaxanthin residues, tocopherol residue or tocotrienol residues, other _R 8 _{to R 13} are hydrogen (H) or hydroxyl group ( OH) provided that the number of hydrogen (H) is 0 to 4 in R _{8 to} R _13. )

  Moreover, as a salt of an antioxidant polyhydroxybenzene derivative, hydroxyphenol phosphorus having an ester moiety bound with astaxanthin 3,3′-dihydroxy-β, β-carotene-4,4′-dione, tocopherol or tocotrienol Examples thereof include inorganic salts such as sodium, potassium, magnesium and calcium salts of acid esters, organic amine salts such as monoethanolamine and diethanolamine, and basic amino acid salts such as L-arginine and L-lysine.

Production of the antioxidant polyhydroxybenzene derivative is carried out as follows.
First, using a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene and the like, in the presence of a base selected from trimethylamine, triethylamine, N, N-dimethylaniline and the like, astaxanthin represented by Chemical Formula 4, ie 3, 3 Reaction of phosphorous oxychloride at −20 to 20 ° C. with respect to “-dihydroxy-β, β-carotene-4,4′-dione, tocopherol represented by Chemical Formula 5 or tocotrienol represented by Chemical Formula 6 at −20 to 20 ° C. A dichlorophosphate having one molecule of an astaxanthin residue, a tocopherol residue or a tocotrienol residue represented by the formula, or a monochlorophos having two molecules of an astaxanthin residue, a tocopherol residue or a tocotrienol residue represented by the formula Manufacture fate.
When it is necessary to take these out, they can be isolated by distillation, but may proceed to the next step as a solution of the above nonpolar solvent.

(In the formula, R represents hydrogen (H) or a methyl group (CH ₃ ).)

(In the formula, R represents hydrogen (H) or a methyl group (CH ₃ ).)

(In the formula, R represents an astaxanthin residue, a tocopherol residue or a tocotrienol residue.)

(In the formula, R ¹ and R ² represent hydrogen (H) or an astaxanthin residue, a tocopherol residue or a tocotrienol residue, except when R ¹ = R ² = hydrogen (H)).

  Next, separately, a predetermined number of 1 to 5 phenolic hydroxyl groups of polyhydroxybenzene is protected with a suitable protecting group such as a benzyl group.

  Benzylhydroxyphenol in which a phenolic hydroxyl group is protected with a benzyl group is reacted with phenylacetic acid at −30 ° C. to 20 ° C. in the presence of a dehydrating agent such as benzyl chloride or fuming sulfuric acid, and is simply obtained by a method such as filtration. Can be separated.

  In addition, the benzylhydroxyphenol obtained as described above is formed in the presence of a base selected from trimethylamine, triethylamine, N, N-dimethylaniline, etc. in a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene and the like. Dichlorophosphate having one molecule of astaxanthin residue, tocopherol residue or tocotrienol residue represented by formula 7 or two molecules of astaxanthin residue, tocopherol residue or tocotrienol residue represented by formula 8 After reacting with monochlorophosphate at −20 ° C. to 20 ° C., hydrolysis is carried out at −10 to 50 ° C. with an acid selected from hydrochloric acid, sulfuric acid, acetic acid and the like.

  The benzylhydroxyphenol thus protected with a benzyl group or the like is reacted with the above-described dichlorophosphate or monochlorophosphate, and after esterification with phosphoric acid, the protecting group is eliminated by catalytic reduction or the like and purified by a conventional method. Thus, an antioxidant polyhydroxybenzene derivative composed of polyhydroxyphenyl phosphate represented by the above formula 3 or a salt thereof can be produced.

  At this time, in order to remove the remaining base, it is washed with an aqueous solution of an acid such as hydrochloric acid, sulfuric acid or acetic acid or an inorganic salt such as sodium chloride, potassium chloride, ammonium chloride, sodium carbonate, potassium carbonate or sodium hydrogen carbonate, and is nonpolar. Although the solvent is distilled off, when higher quality is required, the hydroxyphenol phosphate ester represented by the above formula 3 is isolated by column chromatography or the like.

  Or you may take out with solutions, such as ethanol and glycerol. As described above, the method for isolating and purifying the antioxidant polyhydroxybenzene derivative of the present invention may follow a general method and is not particularly limited.

  Specific examples of the antioxidant polyhydroxybenzene derivative of the present invention represented by the above formula 3 include 2-astaxanthin-hydroxyphenyl phosphate, 2-diaxanthanthine-hydroxyphenyl phosphate, 2- Astaxanthin-dihydroxyphenyl phosphate, 2-tocopherol-hydroxyphenyl phosphate, 2-ditocopherol hydroxyphenyl phosphate, 2-tocopherol-dihydroxyphenyl phosphate, 2-tocotrienol hydroxyphenyl phosphate, 2-ditocotrienol hydroxyphenyl phosphate 2-tocotrienol dihydroxyphenyl phosphate, 3-astaxanthin-hydroxyphenyl phosphate, 3-di Staxanthin-hydroxyphenyl phosphate, 3-astaxanthin-dihydroxyphenyl phosphate, 3-tocopherol-hydroxyphenyl phosphate, 2-ditocopherol hydroxyphenyl phosphate, 3-tocopherol-dihydroxyphenyl phosphate, 3-tocotrienol hydroxyphenyl phosphate Fate, 3-ditocotrienol hydroxyphenyl phosphate, 3-tocotrienol dihydroxyphenyl phosphate, 4-astaxanthin-hydroxyphenyl phosphate, 4-diastaxanthin-hydroxyphenyl phosphate, 4-astaxanthin-dihydroxyphenyl phosphate, 4-tocopherol -Hydroxyphenyl phosphate, - di tocopherol hydroxyphenyl phosphate, 4-tocopherol - dihydroxyphenyl phosphate, 4-tocotrienol-hydroxyphenyl phosphate, 4-di-tocotrienol-hydroxyphenyl phosphate, and 4-tocotrienol dihydroxyphenyl phosphate.

  Further, in the antioxidant polyhydroxybenzene derivative of the present invention, salts of these antioxidant polyhydroxybenzene derivatives can also be used, for example, alkali metal salts such as sodium salt and potassium salt, calcium salt, magnesium salt and the like. Alkaline earth metal salts, basic amino acids such as arginine, and organic amines such as triethanolamine can be used.

  And the content of the salt of the antioxidant polyhydroxybenzene derivative blended in the anti-inflammatory skin external preparation or whitening cosmetic containing the antioxidant polyhydroxybenzene derivative of the present invention as an active ingredient is 0.05 wt. % Or more is preferable in order to sufficiently exert an anti-inflammatory effect or a whitening effect. If the content is less than 0.05% by weight, an anti-inflammatory effect or a whitening effect cannot be expected or cannot be reliably obtained.

  The pH of the whitening cosmetic of the present invention is not particularly limited, but is preferably 4.0 to 9.0 in order to increase the stability of the cosmetic in a general storage state. In the pH range, ester hydrolysis is likely to occur, and a stable preparation may not be obtained.

  In addition to the above essential components, the whitening cosmetic composition of the present invention includes various components used in normal cosmetics, quasi-drugs, pharmaceuticals, etc., such as oily components, emulsifiers, moisturizers, thickeners, medicinal components, preservatives Pigments, powders, pH adjusters, ultraviolet absorbers, antioxidants, fragrances, and the like can be appropriately blended.

  Specific examples of the oil component described above include liquid paraffin, petrolatum, microcrystalline wax, squalane, jojoba oil, beeswax, carnauba wax, lanolin, olive oil, coconut oil, higher alcohol, fatty acid, ester of higher alcohol and fatty acid, silicone oil, etc. Is mentioned. Examples of the emulsifier include polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyglycerin alkyl ether, and polyoxyethylene hydrogenated castor oil. Nonionic surfactant, anionic surfactant such as sodium stearoyl lactate, amphoteric surfactant such as soybean phospholipid, and cationic surfactant such as alkyltrimethylammonium chloride. Examples of the humectant include glycerin, sorbitol, xylitol, maltitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, and 1,2-pentanediol. Examples of the thickening agent include clay minerals such as carboxyvinyl polymer, xanthan gum, methyl cellulose, polyvinyl pyrrolidone, gelatin, and bentonite. Examples of medicinal ingredients include various vitamins and derivatives thereof, allantoin, glycyrrhizic acid and derivatives thereof, and various animal and plant extracts.

  The whitening cosmetic of the present invention is not particularly limited, in addition to blending the above-mentioned predetermined antioxidant polyhydroxybenzene derivative and its salt as a whitening active ingredient, and is manufactured by a well-known cosmetic manufacturing method. It is not limited to general skin cosmetics, but can also be applied to quasi drugs, topical medicines, etc., and their dosage forms are creamy, emulsion, liquid, gel, ointment according to the purpose. A form such as a pack, a stick, or a powder can be selectively employed.

[Production Example 1 of Antioxidant Polyhydroxybenzene Derivative]
Astaxanthin and phosphorus oxychloride were reacted to synthesize astaxanthin dichlorophosphate, which is a dichlorophosphate having one molecule of astaxanthin residue.

Separately, this was reacted with phenylacetic acid phenol obtained by reacting p-hydroxyphenol and phenylacetic acid, and the resulting astaxanthin-phenylacetic acid phenol phosphate was hydrolyzed with hydrochloric acid, washed, isolated and purified, and Astaxanthin-p-hydroxyphenyl phosphate shown in Chemical Formula 9 was produced. In Chemical Formula 9, the assignment numbers of peaks in ¹ H-NMR described later are also shown.
Below, a manufacturing method is demonstrated in detail for every the synthetic | combination process.

(1) Synthesis of phenylacetic acid phenol Under nitrogen substitution, 1307.1 g (9.6 mol) of phenylacetic acid was cooled to −5 ° C., 54.3 g (0.2 mol) of 28% fuming sulfuric acid was added dropwise, and p- Charge 110.1 g (1.0 mol) of hydroxyphenol. The mixture was reacted at the same temperature for 17 hours, filtered and washed with cold acetone to obtain 210.5 g of p-phenylacetic acid phenol (purity: 85.4%) as a wet cake.

(2) Synthesis of astaxanthin dichlorophosphate Under nitrogen substitution, 540 mL of toluene and 138.0 g (0.9 mol) of phosphorus oxychloride are charged and cooled to −10 ° C. Thereto, a solution of 537.1 g (0.9 mol, 1.0 mol ratio) of astaxanthin and 91.1 g (0.9 mol) of triethylamine was dropped and reacted at 0 ° C. for 12 hours. After raising the temperature to 25 ° C., the triethylamine hydrochloride was removed by filtration to obtain 116.8 g of a toluene solution of astaxanthin dichlorophosphate (concentration 34.7%).

(3) Synthesis of astaxanthin-p-hydroxyphenyl phosphate Under nitrogen substitution, 198.4 g (1.0 mol) of the above p-phenylacetic acid phenol was charged into 2000 mL of toluene, and 202.4 g of triethylamine was added dropwise at room temperature. Stir for hours. Then, it cools to -10 degreeC and the toluene solution 1945.5g (0.9 mol) of said astaxanthin dichlorophosphate is dripped over 1 hour, It stirred at the same temperature for 14 hours. To the obtained reaction mass, 15047 g of a 6.7% hydrochloric acid aqueous solution was added, hydrolysis was performed at 35 ° C. for 4 hours, and the toluene layer was washed twice with 1000 g of 10% hydrochloric acid / 7.1% aqueous sodium chloride solution. Washed once with 20% aqueous sodium chloride solution.

  The toluene layer was subjected to column chromatography, and the fraction collected was concentrated under reduced pressure (35 ° C., 2 Torr) to distill off the toluene, and 368.7 g of astaxanthin-p-hydroxyphenyl phosphate (purity 95.2%). Got. The yield was 54.6% (vs. p-hydroxyphenol).

The molecular structure of the astaxanthin-p-hydroxyphenyl phosphate obtained was identified by infrared absorption spectrum (IR) and nuclear magnetic structure spectrum ( ¹ H-NMR), and these results (the position of the peak and the corresponding group or carbon atom) ) Are summarized in Tables 2 and 3, respectively.
The compound thus obtained is a [2- (1,3,3-trimethyl-n-butyl) -5,7,7-octyl] -p-hydroxyphenyl which is a polyhydroxybenzene derivative having the expected molecular structure. It was confirmed to be phosphate.

[Production Example 2 of polyhydroxybenzene derivative]
In Example 1, a compound was obtained in the same manner as in Example 1 except that α-tocopherol was used instead of astaxanthin.

The molecular structure of the obtained compound is shown in the following formula ( ¹⁰ ), the molecular structure is identified by infrared absorption spectrum (IR) and nuclear magnetic structure spectrum ( ¹ H-NMR), and the expected molecular structure It was confirmed that it was α-tocopherol-p-hydroxyphenyl phosphate which is a polyhydroxybenzene derivative. Moreover, about the identification by the result of the group corresponding to the position of a peak, or a hydrogen atom, Example 1 was made into the representative example and the description was abbreviate | omitted.

  It was confirmed that the compound thus obtained was α-tocopherol-p-hydroxyphenyl phosphate (purity 91.7%), which is a polyhydroxybenzene derivative having the expected molecular structure. The yield was 52.9% (vs. p-hydroxyphenol).

[Production Example 3 of Polyhydroxybenzene Derivative]
The sodium salt of α-tocotrienol-p-hydroxyphenyl phosphate was prepared by the following method.

  A reaction mass of α-tocotrienol-p-hydroxyphenyl phosphate was obtained in the same manner as in Example 1, 15047 g of a 6.7% aqueous hydrochloric acid solution was added to the reaction mass, and hydrolysis was performed at 35 ° C. for 4 hours. The toluene layer was washed twice with 1000 g of 10% hydrochloric acid / 7.1% aqueous sodium chloride solution and then once with a 20% aqueous sodium chloride solution.

  And 30% NaOH aqueous solution is added to a toluene layer, and pH is adjusted to seven. Ethanol was added to the aqueous layer after separation, and water and ethanol were distilled off by concentration under reduced pressure. The precipitated crystals were filtered and dried, and α-tocotrienol-p-hydroxyphenyl phosphate sodium salt (purity 94.2%) Got. The yield was 73.6% (vs. p-hydroxyphenol).

The molecular structure of the obtained compound is shown in the following chemical formula 11, and the molecular structure of the obtained compound is identified by infrared absorption spectrum (IR) and nuclear magnetic structure spectrum ( ¹ H-NMR). It was confirmed that it was α-tocotrienol-p-hydroxyphenyl phosphate disodium salt, which is a polyhydroxybenzene derivative having the molecular structure. In addition, about identification by the result of the group or hydrogen atom corresponding to the position of a peak, Example 1 was made into the representative example and the description was abbreviate | omitted.

  Using the polyhydroxybenzene derivatives obtained in Production Examples 1, 2, and 3 as active ingredients as described above, the cosmetic compositions (skin lotions) of Examples 4 to 12 were prepared at the blending ratios shown in Table 4 below. The whitening effect and the anti-inflammatory effect were determined.

[Judgment of whitening effect]
A group of 20 subjects with worries such as stains, buckwheat, and dark-skinned groups. Each cosmetic was applied daily and morning and night for 3 months. After 3 months, the cumulative application effect was determined according to the following criteria. The determination results were evaluated according to the following criteria, and the results are shown in Table 5.

Remarkable: Pigmentation is almost inconspicuous.
Effective: Thinned.
Slightly effective: Slightly thinner.
Invalid: No change.

[Evaluation]
(Double-circle): The ratio (effective rate) which shows remarkable effect and effectiveness among test subjects is 80% or more.
○: The ratio (effective rate) showing the effectiveness and effectiveness among the subjects is 60% or more and less than 80%.
(Triangle | delta): The ratio (effective rate) which shows remarkable and effective among test subjects is 40% or more and less than 60%.
X: The ratio (effective rate) which shows remarkable and effective among test subjects is less than 40%.

[Determination of inflammation relieving effect]
A group of 20 subjects with worries such as stains, buckwheat, and dark-skinned groups. Each cosmetic is applied daily for 3 months in the morning and at night, and after 3 months, the cumulative application effect is self-determined according to the following criteria. Further, the determination results were evaluated according to the following criteria and are shown in Table 5.

Remarkable: No erythema due to the drug was confirmed.
Effective: Only a few erythema due to the drug was confirmed.
Slightly effective: Some erythema due to the drug was confirmed.
Invalid: Erythema due to drug was confirmed.

[Evaluation]
(Double-circle): The ratio (effective rate) which shows remarkable effect and effectiveness among test subjects is 80% or more.
○: The ratio (effective rate) showing the effectiveness and effectiveness among the subjects is 60% or more and less than 80%.
(Triangle | delta): The ratio (effective rate) which shows remarkable and effective among test subjects is 40% or more and less than 60%.
X: The ratio (effective rate) which shows remarkable and effective among test subjects is less than 40%.

  As is clear from the results in Table 5, in Examples in which a predetermined amount (0.05% by weight or more) of the polyhydroxybenzene derivative was blended, at least 40%, 60% or 80% of the subjects were effective or effective. It was confirmed that the whitening cosmetic was able to exert physiological activity useful for the skin whitening of the original skin of hydroxyphenol. Furthermore, it was confirmed that erythema caused by a drug as confirmed with p-dihydroxybenzene can be alleviated in Examples in which a predetermined amount (0.05% by weight or more) of a polyhydroxybenzene derivative was blended.

  In the following, representative examples of cosmetic preparations are shown as examples using a predetermined polyhydroxybenzene derivative as an active ingredient. The numerical value at the right end of each row is the blending ratio (wt%).

[Example 13] (Gel cream)
Astaxanthin-p-hydroxyphenyl phosphate sodium salt 1.0
Glycerin 10.0
Ethanol 5.0
Sodium hydroxide 0.5
Carboxyvinyl polymer 0.8
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue

[Example 14] (Emulsion)
α-tocopherol-p-hydroxyphenyl phosphate 2.0
1,3-butylene glycol 10.0
Carboxyvinyl polymer 0.3
Squalane 5.0
Cetanol 0.8
L-Arginine 0.3
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue

Example 15 (Cream)
α-Tocotrienol-p-dihydroxyphenyl phosphate 5.0
1,3-butylene glycol 10.0
Carboxyvinyl polymer 0.3
Squalane 5.0
Cetanol 2.0
Beeslow 3.0
L-Arginine 0.3
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue

Claims (5)

Astaxanthin, is an ester bond between hydroxyl group and phosphoric acid antioxidant comprising a tocopherol or tocotrienol, by the phosphoric acid ester is 1 or more hydroxyl groups and an ester bond polyhydroxy benzene, poly-hydroxyphenyl phosphate or Antioxidant polyhydroxybenzene derivative consisting of a salt.   The antioxidant polyhydroxybenzene derivative according to claim 1, wherein the polyhydroxybenzene is dihydroxybenzene, trihydroxybenzene, tetrahydroxybenzene, pentahydroxybenzene or hexahydroxybenzene.   The antioxidant polyhydroxybenzene derivative according to claim 2, wherein the dihydroxybenzene is catechol, resorcin or hydroquinone.   The anti-inflammatory skin external preparation which contains the antioxidant polyhydroxybenzene derivative in any one of Claims 1-3 as an active ingredient.   A whitening cosmetic comprising the antioxidant polyhydroxybenzene derivative according to any one of claims 1 to 3 as an active ingredient.