JPH0128002B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel cosmetics, more specifically reduced α
- This relates to cosmetics containing a derivative of lipoic acid (dihydrolipoic acid). Conventionally, α-lipoic acid itself has been widely distributed in the animal and plant kingdom in a state bound to proteins, and has been qualitatively detected. In terms of quantity, for example, 3.2 μg/g in animal liver.
(dry weight). When pyruvate enters the TCA cycle in the mitochondrial fraction of mammalian cells, α-lipoic acid is oxidized to acetyl-CoA, carbon dioxide gas, and two hydrogen atoms with the involvement of coenzyme A (hereinafter abbreviated as CoA). In one step, the acyl group is involved in the rearrangement of the acyl group. After the acyl group of α-lipoic acid present in the body is transferred to CoASH, reduced dihydrolipoic acid is formed, but it is reoxidized by lipoic acid dehydrogenase and returns to α-lipoic acid. In this way, α-lipoic acid is a substance that undergoes reversible redox in the living body, and plays an important role in energy production within cells. It can be said that there are no known examples of its application. The reason is,
α-lipoic acid itself is relatively stable in solid form, but when heated above its melting point or in the presence of acid, light, etc., the S-S bond tends to cleave and polymerize, resulting in its stability. This was due to sexual difficulties. As a result of intensive research on the effective use of α-lipoic acid, the present inventor solved the above-mentioned difficulties by derivatizing its reduced form (dihydrolipoic acid), and in addition, when incorporated into a cosmetic base. We have now discovered a cosmetic that has significantly improved effects when applied to the skin, ie, prevents skin darkening, age spots, and freckles due to the inhibition of tyrosinase activity, compared to α-lipoic acid. Generally, when the skin is irradiated with ultraviolet rays from sunlight, tyrosinase activity in the skin causes
Melanin is produced significantly and the skin tends to darken. Ascorbic acids, hydrogen peroxide, glutathione, goroid sulfur, and various other natural products have long been known as substances that prevent this skin blackening phenomenon. In systems containing a large amount, it is easily oxidized and unstable, which tends to cause discoloration and odor. As for hydrogen peroxide, it is difficult to say that it is sufficient in terms of storage and stability due to its characteristics as a peroxide. Glutathione and colloidal sulfur are avoided in cosmetics because they emit a distinct odor. Moreover, there are almost no natural products whose effects have been confirmed, and like the above-mentioned substances, their effects on the skin are not fully satisfactory. That is, the main object of the present invention is to provide a novel cosmetic product that has extremely excellent properties and effects that cannot be obtained with conventionally known substances by incorporating a dihydrolipoic acid derivative into a cosmetic base material. The dihydrolipoic acid derivative applied to the present invention is represented by the following general formula (), in which the 6th and 8th positions are
The mercapto group at position is substituted with various acyl groups, and the carboxyl group is unsubstituted or esterified with various alkyl groups. General formula () (In the formula, R is a linear or branched fatty acid acyl residue, and R' represents either a hydrogen atom or a linear or branched alcohol alkyl residue.) S.S-diacyllipoic acid, which is the dihydrolipoic acid derivative mentioned above. Specific examples of ester derivatives thereof include S.S.-dibutanoyllipoic acid, S.S.-dioctanoyllipoic acid, S.S.-dilauroyllipoic acid, S.S.-dipalmitoyllipoic acid, and S.S.-dibutanoyllipoic acid. -2-ethylhexanoyl lipoic acid, S・S-di-
2-hexyldecanoyllipoic acid, S.S.dioctanoyllipoic acid ethyl ester, S.S.dipalmitoyllipoic acid ethyl ester, S.S.-di-2
-Ethylhexanoyllipoic acid-2-ethylhexyl ester, S.S.-di-2-hexyldecanoyllipoic acid octyldodecyl ester, S.S.-dilauroyllipoic acid cetyl ester, S.S.-dibutanoyllipoic acid 2-hexyldecyl ester Ester, etc., in which the acyl group represented by R in the general formula () has 2 to 20 carbon atoms, and the alkyl group represented by R' has 1 to 20 carbon atoms, are stable and easy to handle in cosmetics. These are listed in terms of ease of application, and are appropriately selected depending on the type of cosmetic preparation. S・S is particularly excellent in terms of stability and effectiveness.
-Dioctanoyllipoic acid ethyl ester, S.S.
- dipalmitoyllipoic acid ethyl ester, etc. There are various methods for synthesizing S.S.-diacyllipoic acid and its alkyl ester derivatives that are applicable to the present invention. For example, in the case of S.S.-diacyllipoic acid, α-lipoic acid is hydrogenated in an appropriate solvent such as ethanol. The disulfide bond is cleaved with a reducing agent such as sodium boron to form dihydrolipoic acid, which is then treated in a non-polar solvent such as tetrahydrofuran.
It is advantageous to obtain the desired product by reacting a desired fatty acid chloride in the presence of a base such as triethylamine, and in the case of S.S-diacyllipoic acid alkyl ester derivatives, α-lipoic acid is first reacted with triethylamine or the like in an appropriate solvent such as chloroform. A chlorinating agent such as thionyl chloride is reacted in the presence of a base to produce α-lipoyl chloride, which is then treated with ethanol,
It is also advantageous to react a desired alcohol such as cetanol in the presence of a base such as triethylamine to form an α-lipoic acid alkyl ester, and then perform disulfide cleavage and acylation to obtain the desired product according to the above-mentioned method. Next, a synthesis example of S.S-diacyllipoic acid and its alkyl ester derivatives will be shown. Synthesis example 1 S.S-dipalmitoyllipoic acid 16g of sodium borohydride and 200ml of ethanol
Dissolve 20.6g of α-lipoic acid in ethanol.
The solution dissolved in 100 ml was stirred and reacted for 1 hour while being added dropwise under ice-cooling. Then, the excess sodium borohydride was neutralized with 5% hydrochloric acid, and the resulting crude product was extracted with ethyl acetate. After washing with water, Solvent at 40℃
Dihydrolipoic acid is obtained by distillation under reduced pressure. This was dissolved in 200 ml of tetrahydrofuran, and 32 g of triethylamine was added thereto. 60 g of palmitic acid chloride was added dropwise under ice-cooling and stirred for 1 hour. Then, after stirring at room temperature for 2 hours, unreacted palmitic acid chloride and triethylamine were added. After treating with ethanol and 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off to obtain a crude reaction product. For purification, use a column and elute with hexane/ether (98/2) solvent.
45 g of white crystalline S.S-dipalmitoyllipoic acid was obtained. Yield 66% Elemental analysis Actual values C: 70.56% H: 11.02% O: 9.08% (Calculated values C: 70.18% H: 11.11% O: 9.36%) Synthesis example 2 S.S-dioctanoyllipoate ethyl α -To a mixture of 20.6 g of lipoic acid and 10.1 g of triethylamine dissolved in 100 ml of chloroform, separately add 11.9 g of freshly distilled thionyl chloride to 30 g of chloroform.
ml, stirred and reacted for 1 hour while dripping under ice-cooling, 32 g of ethanol was added without taking out the α-lipoyl chloride produced, and 10.1 g of triethylamine was added to 30 ml of chloroform.
The solution dissolved in the solution was further added dropwise under ice-cooling and reacted for 3 hours, and then the triethylamine hydrochloride produced was separated and distilled off at below 40°C. Next, the obtained ethyl lipoate was dissolved in 200 ml of ethanol, and while cooling on ice, a solution of 16 g of sodium borohydride dissolved in 100 ml of ethanol was added dropwise.
The reaction mixture is stirred for a period of time, then neutralized with dilute acetic acid, extracted with ethyl acetate, washed with water, and the solvent is distilled off under reduced pressure to obtain dihydrolipoic acid ethyl ester. Dissolve this in 200ml of benzene and add triethylamine.
36g of octylic acid chloride to the mixture of 32g of
was added dropwise under ice-cooling while stirring for 1 hour, and after stirring at room temperature for 2 hours, the reaction was stopped.
After treating unreacted triethylamine with 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off to obtain a crude reaction product. Purification was carried out using a column and eluting with hexane/ether (98/2) solvent to obtain colorless liquid S.S-dioctanoyllipoic acid ethyl ester.
Get 30g. Yield 61% Elemental analysis Actual values C: 64.35% H: 9.28% O: 12.96% (Calculated values C: 63.93% H: 9.84% O: 13.11%) Synthesis example 3 S・S-di-2-ethylhexanoyl Lipoic acid-2-ethylhexyl ester To a mixture of 20.6 g of α-lipoic acid and 10.1 g of triethylamine dissolved in 100 ml of benzene, 11.9 g of freshly distilled thione chloride dissolved in 30 ml of benzene was added dropwise under ice cooling. 2-ethylhexyl alcohol without removing the produced α-lipoyl chloride.
A mixture of 12 g of triethylamine and 10.1 g of triethylamine dissolved in 30 ml of benzene was further added dropwise under ice cooling and reacted for 3 hours. The triethylamine hydrochloride formed was separated and the solvent was distilled off at below 40°C. Next, the obtained lipoic acid-2-ethylhexyl ester was dissolved in 200 ml of tetrahydrofuran, and a solution of 16 g of sodium borohydride dispersed in tetrahydrofuran was added dropwise thereto while stirring for 1 hour, followed by dilute acetic acid. After neutralization, the mixture was extracted with ethyl acetate, washed with water, and the solvent was distilled off under reduced pressure to obtain dihydrolipoic acid α-ethylhexyl ester. Dissolve this in 200ml of benzene and add triethylamine.
32g of 2-ethylhexanoyl chloride was added dropwise to the mixture, and 36g of 2-ethylhexanoyl chloride was added dropwise under ice cooling while stirring for 1 hour, followed by stirring at room temperature for 2 hours, and refluxing at the boiling point of benzene for 1 hour. After stopping the reaction and treating unreacted triethylamine with 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off to obtain a crude reaction product. Purification was carried out using a column and eluting with hexane/ether (98/2) solvent to obtain colorless liquid S.S.-di-2-ethylhexanoyllipoic acid-2-ethylhexyl ester.
Get 28g. Yield 49% Elemental analysis Actual values C: 67.95% H: 10.43% O: 10.84% (Calculated values C: 67.13% H: 10.49% O: 11.19%) S-S-diacyllipoic acid blended into the cosmetic of the present invention The blending amount of the cosmetic composition and its alkyl ester derivative is 0.01 to 5% by weight, preferably 0.1 to 1% by weight, based on the total weight of the cosmetic ingredients. If the amount is less than 0.01% by weight, even if the cosmetic of the present invention is applied to the skin, the amount of transdermal absorption will not be the optimum amount to prevent skin darkening, and if it is more than 5% by weight, there may be problems due to excessive inhibition of tyrosinase activity. These ranges should be avoided as they tend to give the skin a natural bleaching effect. When the dihydrolipoic acid derivatives according to the present invention are incorporated into a cosmetic base, they may be used alone or in combination, or together with other reducing substances. However, this substance itself is oil-soluble and has much better solubility in oils and other organic solvents than the tyrosinase inhibitors provided so far, so it is used more advantageously than these conventional substances. That is, one of the main points of the present invention is to derivatize dihydrolipoic acid in order to fully exhibit the effects derived from dihydrolipoic acid, keeping in mind the improvement of solubility and stability in actual systems. That's what I was trying to do. The tyrosinase inhibitory effect of S.S.-diacyllipoic acid and S.S.-dioctanoyllipoic acid ethyl ester, one of its alkyl ester derivatives, was investigated by Harding-Putsey.
-Passay) Using the enzyme tyrosinase extracted from mouse melanoma, the enzyme activity was measured using a photometry method that measures the absorbance of doperchrome at 475 nm. When a reaction solution prepared by incubating guinea pig skin homogenate with 1×10 ^-4 mol of the test substance dihydrolipoic acid derivative was reacted as a control, the reaction rate showed that lipoic acid inhibited the initial reaction rate by 9%. In contrast, dihydrolipoic acid derivatives showed 30% inhibition. From this, it was demonstrated that the dihydrolipoic acid derivative, which is an applicable substance of the present invention, inhibits tyrosinase activity and reduces the production of dopachrome. Next, the test results for the whitening effect of the products of the present invention and the control products are shown in the table. For the test, 48 women between the ages of 28 and 52 who suffer from dark skin, age spots, and freckles were divided into four groups: A, B, C, and D.
Group A contained the cream according to Example 3 described below, which is a product of the present invention, and Group B contained α-lipoic acid instead of S.S.-dioctanoyllipoic acid ethyl ester in the formulation of Example 3 described later. The cream obtained by adding oxidized glutathione instead of S.S.-dioctanoyllipoic acid ethyl ester in the formulation of Example 3 described later was added to Group D. A cream obtained by adding the same amount of water except for S.S.-dioctanoyllipoic acid ethyl ester in the formulation of Example 3 below was applied twice a day, once in the morning and once in the evening, for one month. After continuous use, a questionnaire survey was conducted to evaluate the improvement of dark skin, age spots, and freckles.

[Table] According to the evaluation shown in the table, it was demonstrated that the improvement effect in Group A using the product of the present invention was significantly superior to Groups B, C, and D using comparative products. As detailed above, the present invention relates to cosmetics that effectively contain dihydrolipoic acid derivatives with excellent biological activity, and includes various conventionally known ascorbic acids, hydrogen peroxide, glutathione, colloidal sulfur, etc. Compared to cosmetics containing glutathione, which has similar effects in terms of inhibiting tyrosinase activity and depigmenting melanin pigments, it is far more effective at preventing skin darkening caused by ultraviolet rays from sunlight. It can prevent dark skin pigmentation, dark spots, and freckles,
It has excellent effects such as beautifying the skin and can be used safely without any harm. Next, examples of the cosmetics of the present invention will be shown. The blending ratio is in parts by weight. Example 1 Packed polyvinyl alcohol 20.0 Ethanol 20.0 S・S-dipalmitoyl lipoic acid ethyl ester
1.0 Glycerin 5.0 Fragrance Appropriate amount of water 53.5 Example 2 Cosmetic oil squalane 49.9 Castor oil 49.9 S・S-dipalmitoyllipoic acid 0.5 S・S-dipalmitoyllipoic acid ethyl ester
0.5 Butylated hydroxytoluene 0.01 Fragrance Appropriate amount Example 3 Cream stearic acid 8.0 spermaceti 4.0 cetanol 4.0 lanolin 2.0 isopropyl myristate 6.0 squalane 7.0 olive oil 2.0 polyoxyethylene sorbitan monostearate 5.0 sorbitan monostearate 1.0 propylene glycol 5.0 butyl paraben 0 .1 Methylparaben 0.1 Butylated hydroxytoluene 0.05 Fragrance Appropriate amount of water 54.5 S・S-dioctanoyl lipoic acid ethyl ester
1.0 Example 4 Lotion ethanol 10.0 Propylene glycol 5.0 Polyoxyethylene (50) Hydrogenated castor oil 0.5 Citric acid 0.015 Sodium citrate 0.1 Methylparaben 0.05 S・S-dibutanoyllipoic acid 1.0 Fragrance Appropriate amount of water 83.0

Claims (1)

[Claims] 1 General formula () (In the formula, R is a straight chain or branched fatty acid acyl residue, and R' represents either a hydrogen atom or a straight chain or branched alcohol alkyl residue.) A cosmetic comprising at least one or two or more ester derivatives.