JPH0655747B2 - Kojic acid phosphate compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel kojic acid compound.

More specifically, the present invention does not provide a novel kojic acid phosphoric acid ester compound having extremely excellent stability against heat, light, pH, etc., and having a remarkable effect on melanin suppression effect derived from kojic acid and pigmentation disease. It is what

Conventionally, kojic acid is, for example, a substance produced by statically culturing or shaking culturing strains having a kojic acid-producing ability such as Aspergillus, Penicillium, and Acetobacter in a liquid medium containing glucose as a carbon source. Was known as. And, as for this kojic acid, its pharmacological research and safety were also evaluated, and as a result, kojic acid had an excellent anti-ultraviolet effect, melanin production inhibitory action and antioxidative activity and tyrosinase activity based on inhibition. It has been clarified that it has an effect of improving pigmentation and has almost no side effects on the skin (JP-A-53-3).
No. 538, JP-A-53-6432, and JP-A-53-18.
739, JP-A-55-157509, etc.).

However, the substance itself of kojic acid is weakly resistant to heat, light, pH, etc., causing coloration due to decomposition and diminishing the effect, and kojic acid forms a complex with many metal ions such as iron and copper (mainly kojic acid). There are many problems in terms of preservability and practical use, such as coloring due to the involvement of the hydroxyl group at the 5-position of the acid).

On the other hand, it has also been attempted to acylate either or both of the hydroxyl groups at the 5-position to the 7-position of kojic acid to improve its storage stability (JP-A-54-92632).
JP-A-56-7710, JP-A-56-7776
JP-A-56-77272, JP-A-56-7961
No. 6, etc.). The purpose of these kojic acid acyl ester compounds is to make the kojic acid, which is originally water-soluble, lipophilic, and to block the hydroxyl groups at the 5th to 7th positions that affect storage stability. However, in the case of the 7-position monoacylated product of kojic acid, not only the formation of chelate by the 5-position hydroxyl group cannot be prevented (coloring), but also the formation of chelate in the 5-position-monoacylated product and even in the 5,7-position-diacylated product. However, the storage stability under various pH was still unsatisfactory, and it was colored and decomposed, so that it was still unsatisfactory in actual use.

Therefore, the present inventors focused their attention on the industrially useful kojic acid having such a rare activity, and carried out various experimental studies to solve the above conventional problems and obtain a valuable kojic acid compound. As a result of repeating the above, a derivative obtained by converting at least the 5-hydroxyl group into a phosphoric ester can solve the above problems.
If necessary, various functional groups may be introduced into the hydroxyl group of the position to further improve storage stability and widen the solubility, and in vivo, the activity derived from kojic acid is also sufficient. The inventors have found that they can be exhibited, and have completed the present invention.

That is, the present invention provides the following general formula (I) (In the formula, R is hydrogen or one or two kinds selected from a linear or branched alkyl group having 1 to 32 carbon atoms, an alkenyl group, an aryl group, and an alkali metal or an alkaline earth metal;
X is hydrogen or a saturated / unsaturated acyl group having 2 to 22 carbon atoms,
It represents a phosphoric acid group and its alkali metal salt or alkaline earth metal salt. ) Relating to a kojic acid phosphoric acid ester compound.

Hereinafter, the present invention will be described in detail.

The kojic acid phosphoric acid ester compound of the present invention has, as a general skeleton, a phosphoric acid monoester compound in which a phosphoric acid group is introduced into the hydroxyl group at the 5-position of kojic acid, as shown in the general formula (I). Accordingly, the phosphoric acid group moiety is further alkyl or alkenyl, aryl esterified, or in salt form. On the other hand, the oxymethyl group at the 2-position, in other words, the hydroxyl group at the 7-position, may be left as it is, or may be acyl esterified, phosphoric esterified, and salts thereof. Specific examples of these kojic acid phosphoric acid ester compounds include kojic acid-5-O-phosphoric acid, kojic acid-5-O-phosphate disodium, kojic acid-5-O-monophosphate potassium, and kojic acid. -5-O-magnesium phosphate, kojic acid-5,
7-O, O-diphosphoric acid, kojic acid-5,7-O, O-diphosphate tetranatourim, kojic acid-5,7-O, O-
Tetrapotassium diphosphate, kojic acid-5,7-O, O-
Dicalcium diphosphate, Kojic acid-7-O-acetyl-
5-O-phosphoric acid, kojic acid-7-O-palmitoyl-5
-O-phosphoric acid, kojic acid-7-O-oleoyl-5-O
-Phosphoric acid, kojic acid-7-O-2-ethylhexanoyl-5-O-phosphoric acid, kojic acid-7-O-palmitoyl-
5-O-monosodium phosphate, kojic acid-7-O-oleoyl-5-O-magnesium phosphate, kojic acid-5
-O-dimethyl dimethyl phosphate, kojic acid-5-O-diphenyl phosphate, kojic acid-5-O-methyl sodium phosphate,
Kojic acid-5-O-monooctyl phosphate, kojic acid-5
-O-octyl magnesium phosphate, kojic acid-7-O
-Lauroyl-5-O-diethyl phosphate, kojic acid-7
-O-myristoyl-5-O-ethyl sodium phosphate, kojic acid-7-O-oleoyl-5-O-magnesium oleyl phosphate, kojic acid-5-O-oleyl phosphate, etc. R is hydrogen or has 1 to 3 carbon atoms
2 linear or branched alkyl groups, alkenyl groups, aryl groups, and alkali metals such as sodium and potassium,
Examples thereof include one or two selected from alkaline earth metals such as calcium and magnesium. Among them, those in which R is hydrogen, a lower alkyl group, an alkali metal, or an alkaline earth metal are used alone or in combination. More preferable. On the other hand, examples of X include hydrogen or a saturated / unsaturated acyl group having 2 to 22 carbon atoms, a phosphoric acid group and its alkali metal salts, alkaline earth metal salts, and the like. The part may be an alkyl or alkenyl or aryl phosphate group.

As described above, these kojic acid phosphoric acid ester compounds of the present invention are novel compounds which have not been known at all until now, and moreover, compared with the conventional kojic acid and kojic acid acylated compounds, they have no chelate formation even in the presence of metal ions. It has excellent storage stability that is stable and extremely resistant to heat and light. Further, even when considering formulation, it has excellent properties such as hardly causing deterioration with time such as decomposition and coloring particularly in an acidic to neutral region, and that it can be easily incorporated into various external bases. There is. On the other hand, it is also safe without toxicity and side effects on the skin.

The general properties of these kojic acid phosphoric acid ester compounds of the present invention take various aspects depending on the type and size of the functional group to be introduced, but the properties are colorless to slightly yellow liquid to viscous liquid. Many of them are crystallized in the form of salt. On the other hand, regarding solubility, some of them are water-soluble in the state of the basic skeleton, but some of them exhibit oil-soluble or surfactant-like behavior when a functional group having high fat-solubility is introduced.

As a compound similar to the kojic acid phosphate compound of the present invention, a compound in which the hydroxyl group at the 7-position is converted to a phosphoric ester and the hydroxyl group at the 5-position is as it is or is acylated, for example, kojic acid-7-O-phosphate And kojic acid-5-O-palmitoyl-7-O-phosphoric acid were also investigated. In these cases, stability, especially in chelate formation with metal ions,
It was inferior to that of the present invention.

Next, a method for producing the kojic acid phosphate compound of the present invention will be described.

In the method for producing a kojic acid phosphoric acid ester compound of the present invention, first, a phosphoric acid halide is allowed to act on kojic acid or kojic acid in which the hydroxyl group at the 7-position is protected. Examples of the protective group for the 7-position hydroxyl group include, but are not limited to, trityl group, acetyl group, propionyl group, acryl group, valyl group, capryl group, lauryl group, palmitoyl group, oleyl group and stearyl group. Not a thing. As the method, for example, for trityl group, trityl chloride is allowed to act in a pyridine solution, for various acyl groups, the method of JP-A-54-92632 is used, and for other protecting groups, the kind of protecting group is used. It may be carried out by a known method described in literatures or the like.

On the other hand, as the phosphoric acid halide, specifically, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyfluoride,
Tetrachloropyrophosphate, methyl phosphate dichloride,
Dimethyl phosphate chloride, ethyl phosphate dichloride, diethyl phosphate chloride, ethyl phosphate dibromide, allyl phosphate dichloride, diphenyl phosphate chloride, oleyl phosphate dichloride, stearyl phosphate dichloride, dioctyl phosphate chloride, etc. However, any of those generally applicable to the phosphoric acid esterification reaction can be used. In the case of an alkylphosphoric acid dichloride, etc., it can be obtained by reacting a sufficiently dehydrated alcohol with an organic base such as 2,6-lutidine at a low temperature and phosphorus oxychloride, etc. It can also be used for a phosphoric acid esterification reaction of an acid.

Regarding the phosphoric acid esterification reaction of kojic acid, the target compound such as 5-O-monophosphoric acid or 5,7
The presence or absence of a protecting group may be appropriately selected depending on the difference between —O and O-diphosphoric acid. The amount of the phosphoric acid halide used cannot be unconditionally specified because it varies depending on the type of solvent, the reaction temperature, the type of phosphoric acid halide, etc., but is usually equimolar to kojic acid having a protecting group, for example. Is more, preferably about equimolar to twice the molar amount. In addition, using kojic acid having no protecting group, 5,7-
Needless to say, when the O, O-diphosphoric acid esterification is intended, a double molar amount or more of phosphoric acid halide is used.

The phosphoric acid esterification reaction easily proceeds in an organic solvent in the presence of an organic base under temperature conditions of room temperature or lower to give a kojic acid phosphoric acid ester derivative. Specific examples of the organic solvent used at this time include benzene, toluene, tetrahydrofuran, acetone, trimethyl phosphate, triethyl phosphate, and the like, and these may be used alone or in combination. However, pyridine and dimethylformamide react with phosphoric acid halide,
It should be avoided as it gives a complex product and reduces the yield. On the other hand, as the organic base, for example, aliphatic amines such as triethylamine and trioctylamine, aromatic amines such as dimethylaniline, pyridine, N-methylmorpholine, N-ethylpiperidine, lutidine, collidine and quinoline are used. Further, the amount used should be equimolar to the kojic acid used in the monophosphoric acid esterification and double the molar amount in the diphosphoric acid esterification. In this case, since the final yield of the kojic acid phosphoric acid ester compound decreases when the excess organic base remains during the subsequent hydrolysis, use of an equimolar (mono) or double molar (di) organic base is used. Should be avoided. Further, the reaction temperature is relatively low, specifically, room temperature or lower, preferably 0 ° C. or lower, and the reaction is completed in a short time of 30 minutes to several hours. It should be avoided because high temperature or heating not only induces an extra side reaction but also causes decomposition and alteration of kojic acid itself.

Next, the obtained kojic acid phosphoric acid ester derivative is hydrolyzed under neutral or acidic conditions to obtain the desired kojic acid phosphoric acid ester compound. However, when the kojic acid phosphoric acid ester derivative is, for example, kojic acid-5-O-dialkyl phosphate, the subsequent hydrolysis step is unnecessary. However, the kojic acid phosphoric acid ester derivative is usually a kojic acid halophosphoric acid ester, and in such a case, the hydrolysis reaction is generally a reaction involving the kojic acid phosphoric acid ester derivative obtained by the above reaction. Just add water to the solution to proceed rapidly. Hydrolysis proceeds even under acidic conditions other than water, hydrochloric acid,
An aqueous solution of an inorganic acid such as sulfuric acid or phosphoric acid, an organic acid such as formic acid or acetic acid, or a hydroalcoholic solution can be used. However, hydrolysis under alkaline conditions may be accompanied by dissociation of the phosphate bond, so it should be avoided.

When the kojic acid phosphoric acid ester compound is taken out in the form of a salt, the kojic acid phosphoric acid ester in the form of a free acid is neutralized with an alkali hydroxide or an alkaline earth hydroxide, or more. Preferably, it is advantageous to add an organic salt such as sodium acetate or magnesium acetate and then add alcohol or the like to precipitate the salt.

Examples will be shown below to further describe the kojic acid phosphoric acid ester compound of the present invention and the method for producing the same.

Example 1. Kojic acid-5-O-phosphoric acid 1.53 g (0.01 mol) of phosphorus oxychloride was dissolved in a mixed solvent of 10 ml of benzene / 40 ml of THF, and 1.42 g (0.01 mol) of kojic acid, 2,6- Lutidine 1.
07 g (0.01 mol) of triethyl phosphate 5
What was dissolved in a mixed solvent of 50 ml of THF / mL of -2
The reaction is carried out dropwise at 0 ° C. for about 1 hour. After the dropping is completed,
Further, the reaction is carried out at 0 ° C. or lower for 2 hours. 2,6-precipitated
After filtering out lutidine hydrochloride, 0.72 g (0.04 mol)
Add water to hydrolyze. After 2 hours, the solvent is distilled off to obtain a viscous pale yellow liquid. Put on a silica gel column,
Elute triethyl phosphate with chloroform, unreacted kojic acid with chloroform / acetone (8/2), and kojic acid-5-O-phosphate with water. Then 40
Water was distilled off at a temperature of not more than 0 ° C. to obtain 1.3 g (yield 60%) as a slightly yellow liquid.

○ Elemental analysis value ○ Infrared absorption spectrum (see Fig. 1) ○ NMRδ value (CDCl ₃ -CD ₃ OD) (see Fig. 2) 4.4 (s) -CH ₂ OH, Example 2. Kojic acid-5-O-magnesium phosphate 1.53 g (0.01 mol) phosphorus oxychloride in THF5
Dissolve and cool in 0 ml of 7-trityl kojic acid.
68 g (0.01 mol), pyridine 0.79 g (0.0
1 mol) and a mixed solution of 50 ml of THF are reacted dropwise at -10 ° C over about 1 hour. After completion of dropping, the mixture is further reacted with stirring at 0 ° C. or lower for 2 hours. After filtering off the precipitated pyridine hydrochloride, about 1 g of water is added to hydrolyze the trityl group and phosphoric acid chloride. After distilling off the solvent at 40 ° C or lower, the product is purified by a silica gel column. The obtained kojic acid-5-O-phosphoric acid is dissolved in water, an equal amount of magnesium acetate aqueous solution is added, and then ethanol is added to precipitate kojic acid-5-O-phosphate magnesium salt. After filtration, washing with ethinol, and drying, 2.2 g of white crystals (yield 72
%) Was obtained.

○ Melting point 205 ° C (decomposition) ○ Elemental analysis value (C ₄ H ₅ O ₇ PM _g · 4H ₂ O) ○ NMR .delta. Value (D ₂ O) (see FIG. _{3) 4.6 (s) -C H 2} OH, Example 3. Kojic acid-5-O-ethyl phosphate Absolute ethanol 0.42 g (0.01 mol) and phosphorus oxychloride 1.53 g (0.01 mol) were dissolved in 50 ml of THF and cooled to -20 ° C for 2,6 -Lutidine 1.0
10 g of a benzene solution containing 7 g (0.01 mol) was reacted dropwise to form ethylphosphorodichloridate. Next, 7-trityl kojic acid 3.6 was added to the reaction solution.
8 g (0.01 mol), 2,6-lutidine 1.07 g
(0.01 mol) dissolved in 20 ml of THF
The reaction is carried out dropwise at 20 ° C or lower. Then, about 1 g of water was added for hydrolysis, followed by silica gel column purification to obtain 2.0 g of ethyl kojic acid-5-O-phosphate as a slightly yellow liquid (yield 80%).

○ Elemental analysis value O NMRδ value (CDCl ₃ -CD ₃ OD) _{4.5 (d) - CH 2 -OH} , Example 4. Kojic Acid-5-O-Ethyl Phosphate Potassium The kojic acid-5-O-ethyl phosphate obtained in Example 3 was dissolved in ethanol, and an ethanol solution of potassium hydroxide was gradually added to adjust the pH of the solution to medium. When it is added dropwise until it becomes acidic, a faintly yellowish white crystal is deposited. This was filtered and recrystallized from water-ethanol-acetone to obtain white powder crystals.

○ Melting point 195 ° C (decomposition) ○ Elemental analysis value (C ₈ H ₁₀ O ₇ PK · H ₂ O) Example 5. 2.69 g (0.01 mol) of kojic acid-5-O-phosphate diphenyldiphenyl chloride chloride was dissolved in 20 ml of toluene, and 3.68 g (0.01 mol) of trityl kojic acid and 2,6-lutidine were dissolved therein. 1.
20 ml of a solution of 07 g (0.01 mol) in THF was added to -10
The reaction is performed dropwise while cooling to -20 to -20 ° C. After completion of the dropping, stirring is continued for 2 hours while maintaining the temperature at -10 ° C or lower. After the precipitated 2,6-lutidine hydrochloride was filtered off, 10 ml of 0.05N hydrochloric acid ethanol solution was added to remove the hydrolyzed trityl group. After the solvent was distilled off, the residue was applied to a silica gel column and eluted with chloroform and then with chloroform / methanol to obtain 3.3 g (yield 87%) of pale yellow transparent crystals of 5-phenyl-5-O-diphenylphosphate.

○ Melting point 74.5 ℃ ○ Elemental analysis value ○ NMR .delta. Value _{(CDCl 3) 4.4 (s)} -C H 2 OH, Example 6. Kojic acid 7-O-acetyl-5-O-diphenyl phosphate 1.87 g (0.005 mol) of 5-phenyl kojic acid-5-O-phosphate obtained in Example 5 was dissolved in 50 ml of benzene. After acetylation with 0.05 mol acetic anhydride-pyridine, the solvent was distilled off, and this was put into a silica gel column and eluted with chloroform / methanol (9/1) to give kojic acid-7-O-acetyl-5. 1.97 g (yield 95%) of white crystals of -O-diphenyl phosphate were obtained.

○ Melting point 76.0 ° C ○ Elemental analysis value ○ NMR .delta. Value (CDCl ₃₎ (FIG. 4 _{refer) 2.2 (s) -CH 2 OCO} CH 3, 5.0 (s) - CH 2 OAc Example 7. Kojic acid-7-O-oleyl-5-O-ethyl sodium phosphate Kojic acid-7-O-oleate 4.0 was added to ethyl phosphorodichloridate produced as in Example 3.
6 g (0.01 mol), N-ethylmorpholine 1.15
20 ml of a toluene solution of g (0.01 mol) was added at -10 ° C.
Under cooling, the reaction is carried out dropwise. After reacting for another 2 hours with stirring, water is added for hydrolysis. After the solvent is distilled off, the residue is dissolved in ethanol, and an ethanol solution of sodium hydroxide is gradually added dropwise to the solution until the pH of the solution becomes neutral, whereby white crystals with a slight yellowish color are deposited. This is filtered off,
Recrystallization from water-ethanol-acetone gave 3.0 g of white powder crystals (yield 55%).

○ Melting point Gradually carbonization decomposition above 210 ℃ ○ Elemental analysis value (C ₂₆ H ₄₂ O ₈ PNa ・ H ₂ O) ○ NMRδ value (CDCl ₃ −CD ₃ OD) 0.90 (t) CH ₃ − _{4.9 (s) -C H 2 O} -COC 17 H 33 5.3 (t) -C H = C H - Example 8. Kojic acid-7-O-octanoyl-5-O-
50 ml of a THF solution containing 1.53 g (0.01 mol) of magnesium phosphate phosphate (0.01 mol) was cooled to -10 ° C, and kojic acid-7-O was added thereto.
-A mixed solution of 2.68 g (0.01 mol) of octanate, 1.01 g (0.01 mol) of triethylamine and 20 ml of THF is reacted dropwise. After adding water to this and hydrolyzing it, the solvent was distilled off and the residue was dissolved in a water-ethanol mixed solvent,
An aqueous magnesium acetate solution was added, and ethanol was further added to precipitate a precipitate. Kojic acid-7-O-octanoyl-
2.2 g (yield 49%) of white crystals of 5-O-magnesium phosphate were obtained.

○ Melting point 200 ° C (decomposition) ○ Elemental analysis value (C ₁₄ H ₁₉ O ₈ PMg ・ 4H ₂ O) ○ NMR .delta. Value _{(CD 3 OD-D 2 O} ) 0.9 (t) C H 3 -, 1.3 (m) -COCH 2 (C
_{H 2) 5 CH 3 2.2 (} t) -CO CH 2 (CH 2) 5 CH 3 4.9 (s) -C H 2 OCO- Example 9. Kojic acid-5,7-O, O-dimagnesium diphosphate 3.06 g (0.02 mol) phosphorus oxychloride was added to THF5.
To a solution dissolved in 0 ml, 1.42 g of kojic acid (0.01
Mol), quinoline 2.58 g (0.02 mol) and trimethyl phosphate 50 ml mixed solution on dry ice /
The reaction is performed dropwise with acetone under cooling to -20 to -30 ° C. After completion of the dropping, the mixture is further reacted under stirring at the same temperature for 2 hours. The precipitated quinoline hydrochloride was filtered off under reduced pressure to give 1.44
Hydrolysis is carried out by adding g (0.08 mol) of water. 40 ° C
After distilling off the solvent, the residue was purified using a hydrogen ion type strongly acidic cation exchange resin. The obtained kojic acid-5,7-O,
After dissolving O-diphosphoric acid in water and adding an equal amount of an aqueous solution of magnesium acetate, ethanol was added to give kojic acid-5,
The 7-O, O-diphosphoric acid dimagnesium salt is precipitated.
After filtration, washing with ethanol, and drying, 1.1 g of white crystals (yield 32%) was obtained.

○ Melting point: Decomposition above 250 ℃ ○ Elemental analysis value ○ NMR .delta. Value _{(D 2 O) 5.1 (d} ) -C H 2 -O-P- Next, the results of evaluation of how excellent the storage stability of the kojic acid phosphoric acid ester compound of the present invention obtained as described above will be shown.

It has been known in the literature so far that kojic acid forms a chelate compound with many metal ions such as iron and copper, and in particular, it forms a reddish brown color even at about 5 ppm in the case of forming a chelate with iron ions. For this reason, kojic acid is used as a hot water reagent for detecting iron (III) ions. Therefore, when this kojic acid is expected to have pharmacological activity and is to be used for a skin external preparation, especially a cosmetic, an essential raw material in the formulation base, such as water,
Iron ions mixed in kaolin, mica, dyes, pigments and the like cause coloring over time, which causes a problem of significantly impairing the commercial value. Then, the kojic acid phosphoric acid ester compound of the present invention and a conventional kojic acid and a kojic acid acyl ester were used as comparative products to carry out a comparative experiment of the degree of coloring with iron ions over time.
As a method, each sample was dissolved in a water / ethanol = 1/1 mixed solution, one drop of a 10% Fecl ₃ solution was dropped with a bipet, and a color change was observed with time at room temperature. The results are shown in Table-1.

As is clear from the results in Table 1, none of the kojic acid phosphoric acid ester compounds of the present invention showed any coloration due to iron ions, as compared with the conventional kojic acid or kojic acid acyl ester. Was done. This is extremely useful in view of the fact that it is practically impossible to eliminate a trace amount of iron ions in the production of external preparations for skin, cosmetics and the like.

Furthermore, in order to confirm the storage stability of the kojic acid phosphoric acid ester compound of the present invention, the present inventors have selected kojic acid-5-O-magnesium phosphate which is one of the kojic acid phosphoric acid ester compounds of the present invention. Then, kojic acid was evaluated as a control product for its stability against heat and light. The method is to add each sample material to a predetermined M / 10 citrate buffer solution at 0.
After dissolution to a concentration of 5%, 1M citric acid or 1M
The pH was adjusted again with N sodium hydroxide solution. The pH value after pH adjustment is 4.17, 5.0 for the product of the present invention.
8, 5.91, 6.97, 7.47, and the comparative products were 4.11, 5.06, 5.99, 6.94,
It was 7.47. Next, these sample solutions are mixed with 100
After treatment at ℃ for 3 hours (heat stability) or after being exposed to sunlight for 5 hours (light stability), the absorbance at 400 nm of the light yellow to yellow-brown sample solution was measured, The degree of alteration was evaluated. The results are shown in FIG.

As shown in FIG. 5, the kojic acid-5-O-magnesium phosphate of the present invention, as compared with the kojic acid of the control product, first shows that in the range of neutral to weak alkaline to heat, On the other hand, it was proved that the pigment was suppressed from being colored (altered) in all pH regions with respect to light, and had excellent chemical storage stability.

Next, the case of using the kojic acid phosphoric acid ester compound of the present invention as an external preparation for skin will be described.

The kojic acid phosphoric acid ester compound of the present invention basically has a water-soluble compound as described above.
It is formulated into a cream, lotion, powder, ointment or the like together with other excipients, diluents, adjuvants and the like. These pharmaceutical and cosmetic external preparations for skin can be produced by a conventional method using techniques such as emulsification, dispersion, dissolution and mixing.

The content of the kojic acid phosphate compound in the external preparation for skin is approximately 0.01 to 5% by weight,
Among them, in the case of external preparations for skin such as cosmetics for the purpose of preventing skin blackening, the range of 0.1 to 1% by weight is preferably selected, and the purpose is to decolorize melanin pigments. In the case of an external preparation for skin such as a therapeutic agent, the range of 1% by weight or more is preferably selected. When the content is less than the above range, for example, when a formulation having poor transdermal absorbability is used, even if a skin external preparation is applied, the transdermal absorption of the kojic acid phosphate compound is It may not reach the optimum amount to prevent blackening, and on the contrary, if it becomes too large, the effect itself may be expressed, but it may give the skin an unnatural bleaching effect due to excessive inhibition of tyrosinase activity. .

When these kojic acid phosphoric acid ester compounds are contained in the external preparation for skin, they may be used alone or in combination, or may be used together with other reducing substances, ultraviolet absorbing / scattering agents and the like.

Here, the external preparation for skin according to the present invention, in order to improve the melanin suppressing effect and pigmentation of the skin which is the object of the present invention, the kojic acid phosphate compound in the external preparation for skin is percutaneously absorbed through the skin. Release of kojic acid by the action of an enzyme or the like after it is taken in is a technical point in exhibiting the action and effect. In other words, the previously known effect of kojic acid is expected to be remarkable because it can produce free kojic acid.

Therefore, the present inventors have investigated whether or not free kojic acid is produced by liver homogenate by using kojic acid-5-O-magnesium phosphate which is one of the kojic acid phosphate compounds of the present invention. The experiment was conducted by using rat liver, and the conversion rate to kojic acid and tyrosinase inhibition were examined as Mercumar.

A rat liver homogenate was added to 2.0 ml of kojic acid-5-O-magnesium phosphate solution (5 mg / ml).
After adding 0 ml and 2.0 ml of 0.1 M acetate buffer (pH 4.7), the mixture was reacted at 37 ° C. for 1 hour. Next, 0.2 ml of the reaction solution was sampled, and a 0.5% FeCl ₃ solution was added to this sample.
After adding 0 ml, the absorbance at 500 nm was measured. On the other hand, the absorbance of the rat liver homogenate was similarly developed, the absorbance was measured, and the above measurement values were corrected using this as a blank. Then, the amount of kojic acid was determined from the calibration curve of kojic acid alone, and kojic acid-5-O was obtained. -The conversion of magnesium phosphate to kojic acid was calculated.

The tyrosinase inhibitory activity was examined by using a tyrosinase enzyme extracted from Harding-Passay mouse melanoma, and the enzyme activity was examined by a photometric method in which the absorbance at 475 nm of doperchrome was measured.

0.2 ml of the above homogenate reaction solution was collected, and 1 ml of dopa solution (mg / ml) and 0.1M phosphate buffer solution (pH 6.8)
After adding 1.6 ml, 0.2 ml of thyrodinase enzyme solution is added to start the reaction. After incubating at 37 ° C. for 10 minutes, the absorbance at 475 nm was measured (D ₁ ). On the other hand, after the liver homogenate was reacted in the same manner and the absorbance was measured as a control (D ₂ ), the tyrosinase activity inhibition rate was calculated from the following formula ¹⁾ .

As a result, when kojic acid-5-O-magnesium phosphate was reacted with rat liver homogenate, 58.4% had already been converted to kojic acid at 1 hour, and only liver homogenate was added. It was found that the tyrosinase activity at that time was inhibited by 68% (71.5% for the non-addition system). From these things, the kojic acid phosphoric acid ester compound, after being taken into the living body,
It was demonstrated that the action of an enzyme rapidly hydrolyzes to produce kojic acid, which can strongly exert an effect such as inhibition of tyrosinase activity.

Furthermore, in order to confirm the evaluation of the external preparation for skin according to the present invention in an actual use system, the present inventors have used the cream according to the present invention (Usage Example 1 below) and conventionally known kojic acid or kojic acid diacetate. Comparative cream containing (the kojic acid-5-O-magnesium phosphate in Use Example 1 described later was replaced with kojic acid or kojic acid diacetate, respectively)
Using and, a use test for preventing dark skin, stains, and freckles on the skin (one-month long-term continuous use test by 30 female panelists) was carried out, and the external preparation for skin according to the present invention is also effective here. It was confirmed to be equal to or higher than that of the comparative cream. Further, the cream of the comparative product had a markedly low commercial value due to the progress of yellowing during the test period, whereas the cream according to the present invention shows no change even at the end of the test. However, even if it was present, it was only slightly yellowish, and the superiority of the external preparation for skin according to the present invention was proved.

As described above in detail, the present invention maintains the pharmacological effects such as suppressing melanin production of kojic acid to prevent skin darkening and dark spots, freckles, and improving pigmentation. However, a novel kojic acid phosphoric acid ester compound having excellent properties such as stability and no complex formation with metal ions such as iron ions has been obtained.

Hereinafter, examples of use of the external preparation for skin according to the present invention will be shown. still,
The mixing ratio is parts by weight.

Example of use 1. Cream (A) Cetanol 7.0 Whale wax 3.0 Lanolin 2.0 Liquid paraffin 20.0 Antioxidant 0.1 Sorbitan monooleate 2.0 Polyoxyethylene monooleate 3.5 (B) Glycerin 5.0 Koji Acid-5-O-magnesium phosphate 1.0 Purified water 56.2 (C) Perfume 0.2 (Method) Dissolve (A) and (B) separately at 80 ° C., emulsify both, and cool. Then, (C) was added to obtain a cream.

Example of use 2. Cream (A) Cetanol 5.0 Beeswax 5.0 Microcrystalline wax 5.0 Vaseline 5.0 Squalane 10.0 Glyceryl monostearate 2.0 POE (20) Sorbitan monostearate 2.0 (B) 1,3 -Butylene glycol 5.0 Glycerin 4.0 Ethylparaben 0.1 Kojic acid-5,7-O, O-diphosphoric acid 1.5 Purified water 55.2 (C) Perfume 0.2 (Method) Use Example 1 and A cream was obtained in the same manner.

Example of use 3. Emulsion (A) Cetanol 1.5 Vaseline 2.0 Beeswax 2.5 Squalane 10.0 POE (20) Sorbitan monostearate 3.0 Sorbitan monostearate 1.5 (B) 1,3-Butylene glycol 8.0 Methylparaben 0.1 Kojic acid-5,7-O, O-magnesium diphosphate 0.5 Magnesium ascorbyl phosphate 1.0 Purified water 69.6 (C) Perfume 0.2 (Method) Same as in Example 1. To obtain an emulsion.

Example of use 4. Emulsion (A) POE (50) hydrogenated castor oil 1.5 coconut oil fatty acid monoglyceride 1.0 oleic acid triglyceride 8.0 (B) glycerin 2.5 kojic acid-5-O-diethyl phosphate 1.0 purified water 85 .8 (C) Perfume 0.2 (Method) An emulsion was obtained in the same manner as in Use Example 1.

Example of use 5. Lotion (A) Ethanol 10.0 Propylene glycol 5.0 POE (50) Hydrogenated castor oil 0.5 Perfume 0.2 (B) Citric acid 0.15 Sodium citrate 0.1 Methylparaben 0.05 Kojic acid-5- O-Ethyl phosphate 0.1 2-Hydroxybenzophenone-4-diglyceryl ether 3.0 Purified water 80.9 (Method) (A) and (B) are dissolved at room temperature, and (A) is added to (B). It was solubilized and a lotion was obtained.

Example of use 6. Lotion (A) Ethanol 7.0 1,3-Butylene glycol 3.0 Glycerin 2.0 POE (40) Hydrogenated castor oil 0.5 Perfume 0.1 (B) Citric acid 0.01 Sodium citrate 0.1 Methylparaben 0.05 Kojic acid-5-O-phosphoric acid 0.5 Purified water 86.74 (Method) In the same manner as in Use Example 5, a lotion was obtained.

Example of use 7. Ointment (A) Beeswax 2.5 Squalane 7.5 Solid paraffin 7.5 Liquid paraffin 10.0 Vaseline 22.5 Kojic acid-7-0-palmitoyl-5-O-sodium phosphate 1.5 Sorbitan monooleate 3. 5 POE sorbitan monooleate 1.5 (B) Methylparaben 0.1 Purified water 43.4 (Method) (A) was dissolved by heating at 70 ° C, (B) dissolved at 70 ° C was added separately, and mixed and stirred. After cooling, an ointment was obtained.

Example of use 8. Ointment (A) POE (30) Cetyl ether 2.0 Glyceryl monostearate 10.0 Liquid paraffin 10.0 Cetanol 7.0 Vaseline 6.0 Butylparaben 0.1 (B) Propylene glycol 10.0 Methylparaben 0.1 Kojic acid-5,7-O, O-tetraethyl diphosphate 1.8 Kojic acid-5-O-disodium phosphate 3.0 Purified water 50.0 (Method) An ointment was obtained in the same manner as in Use Example 7. .

Example of use 9. Powder (A) Sodium ascorbate 10.0 Kojic acid-5-O-magnesium phosphate 5.0 (B) D-glucose 83.5 (C) Squalane 1.5 (Method) Mix (B) with Henschel Then, (C) was added to and mixed with this, and then (A) was added and mixed, and then pulverized with a pulverizer to obtain a powder.

Example of use 10. Powder (A) Talc 73.0 Kaolin 8.0 Fine particle titanium oxide 5.0 Spherical polyethylene 5.0 Zinc stearate 4.5 Kojic acid-5-O-ethyl potassium phosphate 1.0 (B) Dimethylpolysiloxane 2 .0 Liquid paraffin 1.3 Fragrance 0.2 (Method) After mixing (A) with Henschel and pulverizing with a pulsarizer, transfer to Henschel and adding (B) and mixing, pulverizing with a pulsarizer to obtain powder. It was

[Brief description of drawings]

FIG. 1 is an infrared absorption spectrum of kojic acid-5-O-phosphoric acid obtained in Example 1. 2, FIG. 3 and FIG. 4 show kojic acid obtained in Examples 1, 2 and 6, respectively.
It is a nuclear magnetic resonance absorption (NMR) spectrum of 5-O-phosphoric acid, kojic acid-5-O-magnesium phosphate, and kojic acid-7-O-acetyl-5-O-diphenyl phosphate.
Fig. 5 shows the thermal stability test (100 ° C-
The results of the degree of coloring after 3 hours) and the light stability test (sunlight-5 hours) are shown. In the figure, (A) is kojic acid after the heat stability test, and (B) is light stability. After the sex test, (C) is kojic acid-5-O-magnesium phosphate after the heat stability test, and (D) is kojic acid after the light stability test.
It is 5-O-magnesium phosphate.

Claims (1)

[Claims] 1. A general formula (I) (In the formula, R is hydrogen or one or two kinds selected from a linear or branched alkyl group having 1 to 32 carbon atoms, an alkenyl group, an aryl group, and an alkali metal or an alkaline earth metal;
X is hydrogen or a saturated / unsaturated acyl group having 2 to 22 carbon atoms,
It represents a phosphoric acid group and its alkali metal salt or alkaline earth metal salt. ) A kojic acid phosphoric acid ester compound represented by: