WO2010041417A1 - External preparation for skin - Google Patents

Abstract

An external preparation for the skin which can be easily applied to various cosmetic preparations by being improved in solubility in low-polarity solvents.  The external preparation for the skin also has excellent skin whitening effect, antibacterial effect, acne preventing/improving effect and deodorizing effect. The external preparation for the skin is characterized by containing a rhododendrol derivative represented by general formula (1). (In the formula, R1 represents an acyl group having 2-20 carbon atoms, and R2 represents a hydrogen atom or an acyl group having 2-20 carbon atoms.)

Description

Topical skin preparation

The present invention relates to an external preparation for skin.

Blots and freckles are those in which the balance between production and excretion of melanin is lost and melanin is excessively accumulated in epidermal cells. These causes are various, such as inflammation, hormonal balance, genetic factors, etc., but are promoted by the influence of ultraviolet rays. A whitening agent relieves increased pigmentation. Among these, kojic acid, arbutin, hydroquinone monobenzyl ether, hydrogen peroxide, etc. are known to be applied to whitening cosmetics to prevent skin darkening, spots and freckles, and to maintain the original white skin. It has been. However, when these whitening agents are blended, although there is an effect of lightening the skin of dark black slightly, a sufficiently satisfactory effect as a whitening cosmetic has not been obtained, and further, there is no inflammation suppression effect due to ultraviolet rays, Many things left problems in terms of safety. Vitamin C and its derivatives are known as whitening agents that suppress inflammation caused by ultraviolet rays. However, these were not satisfactory in terms of the degree of whitening effect and the stability in the preparation.

Conventionally, parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben have been frequently used as an antiseptic disinfectant in cosmetics, quasi drugs, and pharmaceuticals. In recent years, cosmetics appealing for low irritation and sensitive skin have been put on the market, and reductions in the amount of parabens used, alternative methods, etc. are desired. Various methods such as blending plant extracts and blending alkanediols such as 1,2-pentanediol and 1,2-hexanediol have been proposed (Patent Documents 1 to 5). However, it has been a problem that the amount of these components to be used is limited from the viewpoint of the texture and stability of the preparation when blended in cosmetics and the like, and the taste such as odor.

The pathological conditions of acne (acne vulgaris) are broadly divided into 1) comedones that are non-inflammatory skin rashes, 2) inflammatory papules such as red papules, 3) scars, and 4) post-inflammation pigmentation. Depending on the pathological condition, the treatment is performed by one or a combination of the following three treatment methods: 1) topical external therapy, 2) systemic internal use therapy, and 3) physical therapy. Among these, topical external therapy is considered to be an effective treatment method for symptoms other than scarring, and external preparations containing various active ingredients have been developed so far (Non-patent Document 1). The pathogenesis of acne is divided into two major stages. The first stage is comedone formation and the second stage is inflammation. The comedones are formed when the pores are blocked and sebum is stored in the hair follicles due to excessive sebum secretion and increased keratinization of the pores. Since comedones are a habitat suitable for the anaerobic bacterium Propionibacterium acnes, which is a skin-resident bacterium, in the comedones, the number of bacteria increases and extracellular inflammation-inducing substances are produced. Therefore, inflammatory papules such as red papules are induced (Non-patent Document 2). Such acne prevention and improvement measures include sebum (triglyceride) and facial cleansing to prevent keratin thickening that cause pore closure, the use of antiseborrheic agents such as vitamin B6, and the early use of unnecessary keratin due to resorcin and salicylic acid. Exfoliation, P.I. Prevention of deterioration by an antibacterial substance having a high bactericidal effect such as isopropylmethylphenol that inhibits the growth of acnes, and the use of anti-inflammatory agents are known (Non-patent Document 3). Also, for pigmentation after inflammation, topical topical therapy with vitamin C (ascorbic acid) derivatives has attracted attention (Non-Patent Document 1), and further, a tyrosinase activity inhibitor and an antibacterial or anti-acne agent are combined. Thus, methods for preventing or improving the darkening of acne scars have been reported (Patent Documents 6 and 7).

In addition, odor, which is a unique odor among human body odors, is caused by glycoproteins and lipids secreted by the apocrine sweat glands in the axilla, which are decomposed by enzymes produced by skin bacteria, resulting in the removal of volatile and off-flavor fatty acids. It is caused by production (Non-patent Document 4). As a causative bacterium that generates a particularly strong and unpleasant odor, there is Corynebacterium xerosis, and since it is a lipophilic bacterium, it is detected in the buttocks where there are many sebaceous glands and sweat glands. Antibacterial agents effective against bacteria belonging to the genus Corynebacterium, compositions for odors, sucrose esters of fatty acids that have been used conventionally as preservatives and preservatives for foods and cosmetics (Patent Document 8), disinfection and sterilization Ingredients such as triclosan and isopropylmethylphenol (patent document 9), edible flower extract of licorice (patent document 10), alkanediol and lysozyme (patent document 11) for enhancing antibacterial activity have been proposed. In order to prevent the bad smell, two functions of antiperspirant and sterilization are necessary. Conventionally, an aluminum salt such as hydroxyaluminum chloride (aluminum chloride hydrate) has been used as an astringent as an example of antiperspirant. In addition, as an example of sterilization, a substance having a wide bactericidal activity such as benzalkonium chloride has been used as an antibacterial agent (Non-patent Document 3). However, no deodorant active agent having a sufficient effect has been found yet.

As mentioned above, many studies have been conducted on skin external preparations for the purpose of whitening, antiseptic antibacterial, acne prevention / improvement and deodorization. Was difficult.

On the other hand, rhododendrol and some of its derivatives have an excellent whitening action, and exhibit antibacterial effects against specific bacteria, so that application to an external preparation for skin has been proposed (Patent Document 12). To 14). In addition, phenylbutanoids containing rhododendrol have been reported to exhibit antibacterial activity against several types of bacteria (Non-patent Document 5).

JP-A-8-73364 JP-A-8-73368 Japanese Patent Laid-Open No. 10-182333 JP-A-10-203955 Japanese Patent Laid-Open No. 11-322591 JP 2002-145802 A Japanese Patent No. 2883368 JP 2002-255775 A JP 2006-96719 A JP 2007-1948 A JP 2007-145750 A Japanese Patent No. 3340935 JP 2008-7432 A International Publication No. 09-084200 Pamphlet

FRAGRANCE JOURNAL, 2007, Vol. 35, No. 5, p. 12-17 COSMETIC STAGE, 2007, Vol. 1, No. 5, p. 23-27 FRAGRANCE JOURNAL, 2003, Vol. 31, No. 3, p. 23-28 Ikumon Junhisa, “All of sweat, Apocrine sweat gland disease” Mon Book Derma, March 2007, p. 45-47 P. Srinivasa Reddy, Kaiser Jamil et al., Pharmaceutical Biology, 39, 236-238, 2001

However, these rhododendrol and derivatives thereof have a problem in solubility in a low-polar solvent widely used as a cosmetic base, and are difficult to apply to various cosmetic preparations. In addition, for the same reason, there has been a current situation that studies on preparations that sufficiently exhibit their effectiveness are limited.

The present invention is a novel rhododendrol derivative with improved solubility in low-polarity solvents and easy application to various cosmetic preparations, and whitening effect, antiseptic antibacterial effect, acne prevention / improvement effect containing this It is another object of the present invention to provide an external preparation for skin having excellent deodorizing effects.

As a result of intensive studies to solve the above-mentioned circumstances, the present inventors have found that a novel rhododendrol derivative in which the hydroxyl group on the butyl group of rhododendrol represented by the following general formula (1) is acylated is It has been found that it has superior solubility in low-polar solvents widely used as cosmetic bases, compared to rhododendrol and rhododendrol derivatives acylated with phenolic hydroxyl groups. As a result, application to various cosmetic preparations is facilitated, and further, whitening effect, antibacterial effect against bacteria, P. acnes causing bacteria. The present invention was completed by confirming that the growth inhibitory effect against acnes, the effect of preventing and improving acne scars, and the bactericidal effect against Corynebacterium Xerosis, which is a causative bacterium that generates an unpleasant odor, can be sufficiently exhibited.

That is, this invention provides the skin external preparation containing the rhododendrol derivative represented by following General formula (1).

(In the formula, R ¹ represents an acyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or an acyl group having 2 to 20 carbon atoms.)

The present invention also provides a rhododendrol derivative represented by the following general formula (1b).

(In the formula, R ^1b and R ^2b each represents an acyl group having 3 to 20 carbon atoms.)

The present invention also provides a whitening agent, antiseptic fungicide, anti-acne agent and deodorant containing a rhododendrol derivative represented by the following general formula (1a) as an active ingredient.

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.)

Further, the present invention provides use of the rhododendrol derivative represented by the above general formula (1a) for producing a whitening agent, antiseptic / antibacterial agent, anti-acne agent or deodorant.

Further, the present invention provides a whitening method, antiseptic sterilization method, acne treatment method or deodorization method characterized by applying a rhododendrol derivative represented by the above general formula (1a).

The rhododendrol derivative of the present invention has high solubility in a low-polarity solvent, can be easily applied to various cosmetic preparations, and also has a whitening effect, antiseptic antibacterial effect, acne prevention / improvement effect, and deodorant effect. An excellent skin external preparation can be provided.

Hereinafter, embodiments of the present invention will be described in detail.

The rhododendrol derivative used in the present invention is a compound represented by the general formula (1). In the formula (1), R ¹ is an acyl group having 2 to 20 carbon atoms, and R ² is a hydrogen atom. Or an acyl group having 2 to 20 carbon atoms. R ¹ and R ² may be both acyl groups having the same carbon number, or may be acyl groups having different carbon numbers. The acyl groups of R ¹ and R ² may be saturated or unsaturated, and may have a functional group such as an amino group. Of these, a saturated alkanoyl group is more preferred. Specific examples include an acetyl group, a propionyl group, a butyroyl group, an isobutyroyl group, a valeryl group, a hexanoyl group, an octanoyl group, a lauroyl group, a palmitoyl group, and a stearoyl group. Of these, an alkanoyl group having 2 to 18 carbon atoms is preferable, an alkanoyl group having 2 to 8 carbon atoms is more preferable, and in the case of an acetyl group, propionyl group, butyroyl group, or isobutyroyl group having 2 to 4 carbon atoms, It is particularly preferable because it can be easily applied to a preparation.

Among the rhododendrol derivatives represented by the general formula (1), the compound represented by the following general formula (1b) is a novel compound.

(In the formula, R ^1b and R ^2b each represents an acyl group having 3 to 20 carbon atoms.)

Further, in general formula (1), R ¹ is an acyl group having 2 to 8 carbon atoms (particularly having 2 to 4 carbon atoms) from the viewpoint of applicability to whitening agents, antiseptics, anti-acne agents, deodorants, and the like. A compound in which R ² is a hydrogen atom or an acyl group having 2 to 8 carbon atoms (particularly a hydrogen atom or an acyl group having 2 to 4 carbon atoms) is preferable, and is particularly represented by the following general formula (1a). Are preferred.

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.)

The production method of the rhododendrol derivative used in the present invention is obtained by separating and purifying from a rhododendrol obtained by a known synthesis method or an extract of a plant containing rhododendrol such as muslinoki or birch. And can be produced using known acylation reactions. For example, there is a method of reacting rhododendrol and acid chloride or acid anhydride in a pyridine solvent. It can also be obtained by acylating a plant extract such as a medulinary tree by an appropriate method and then separating and purifying the target rhododendrol derivative.

The rhododendrol derivative obtained by the above method has optical isomers, but the (+) isomer, the (−) isomer alone, or a mixture thereof can also be used.

The rhododendrol derivative represented by the general formula (1) has excellent whitening action, antiseptic sterilization action, acne prevention improvement action, deodorization action and solubility in a low-polarity solvent as shown in Examples below. Since it is excellent, it is useful as a whitening agent, whitening cosmetic, anti-acne agent, acne skin external preparation, antiseptic disinfectant, deodorant, and deodorant skin external preparation.

Moreover, the rhododendrol derivative used in the present invention may be any one of the rhododendrol derivatives represented by the above general formula (1), or a mixture of two or more thereof. It may be used as

The content of the rhododendrol derivative of the present invention cannot be defined unconditionally depending on the purpose of blending and what is to be blended, but is usually 0.00001% by mass to 10.0% by mass based on the total amount of the external preparation for skin, The amount is preferably 0.001% by mass to 5.0% by mass, more preferably 0.01% by mass to 3.0% by mass.

In addition to the rhododendrol derivative of the present invention, the skin external preparation of the present invention includes hydroquinone, arbutin, ellagic acid, vitamin C and derivatives thereof (for example, ascorbic acid glucoside, ascorbic acid phosphate ester) which are already known whitening agents. Sodium, ascorbic acid sulfate disodium, ascorbic acid phosphate magnesium, etc.), biphenyl derivatives (eg, dehydrodicreol, 2,2′-dihydroxy-5,5′-dipropylbiphenyl, etc.), and Japanese Patent No. 3340935 Melanin inhibitors such as raspberry ketone, hexanoyl raspberry ketone, octanoyl raspberry ketone, rhododendrol, 4- (3-hydroxybutyl) phenyl acetate, fire thorn extract, geoscorea compositor extract, Iwashiro Extract, chamomile extract, adenosine 5'-monophosphate and a salt thereof, linoleic acid derivatives, tranexamic acid and tranexamic acid salts, can be used in combination whitening agent suitable such tranexamic acid derivative.

In addition, when used in combination with chelating agents such as alcohols, phenoxyethanol, dipropylene glycol, butylene glycol, alkanediol, sodium edetacetate, etc. The bactericidal effect can be improved. Particularly in combination with phenoxyethanol, it is more preferable in terms of antiseptic sterilization effect.

In addition to the above, the external preparation for skin of the present invention includes moisturizers such as hyaluronic acid, polyhydric alcohols, sugar alcohols, tar pigments, colored pigments such as iron oxide, preservatives such as parabens, fatty acid soap, sodium cetyl sulfate Non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyhydric alcohol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyhydric alcohol fatty acid ester, polyglycerin fatty acid ester Ionic surfactants, cationic surfactants such as tetraalkylammonium salts, betaine type, sulfobetaine type, sulfoamino acid type, amphoteric surfactants such as sodium N-stearoyl-L-glutamate, lecithin, lyso Natural surface activity such as phosphatidylcholine Natural polymers such as gelatin, casein, starch, gum arabic, karaya gum, guar gum, locust bean gum, dragagacanto gum, quince seed, pectin, carrageenan, sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, ethylcellulose, etc. Semi-synthetic polymers, polyvinyl alcohol, polyvinyl methyl ether and copolymer, synthetic polymers such as polyvinylpyrrolidone, sodium polyacrylate, carboxyvinyl polymer, polyethylene oxide polymer, thickeners such as xanthene gum, pigments such as titanium oxide Antioxidants such as dibutylhydroxytoluene can be appropriately blended within a range not impairing the object of the present invention.

The form of the external preparation for skin of the present invention is not particularly limited because the rhododendrol derivative is dissolved in a low-polarity solvent, but forms such as an ointment, cream, lotion, sunscreen, cosmetic liquid, emulsion, pack, bath preparation, etc. It can be.

Hereinafter, although this invention is demonstrated in detail based on a manufacture example, a test example, and an Example, this invention is not limited to these. The rhododendrol described below was prepared by reducing commercially available 4- (p-hydroxyphenyl) -2-butanone (raspberry ketone) with sodium borohydride by a conventional method. . The structure of each compound was confirmed by NMR measurement (JEOL JNM-LA400 (manufactured by JEOL Ltd.), ¹ H; 400 MHz, ¹³ C; 100 MHz, CDCl ₃ ).

Production Example 1: 4- (3-acetoxybutyl) phenylacetate rhododendrol (5.0 g) was placed in a 200 mL eggplant-shaped flask, dissolved in pyridine (1 mL), and reacted with acetic anhydride (8.0 g). . After 4 hours, the mixture was worked up according to a conventional method, and the resulting crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.), and ethyl acetate / n-hexane (1/5) was added. Purification as a mobile phase gave the desired rhododendrol derivative (5.4 g) as a colorless and transparent oil. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 170.8, 169.7, 148.9, 139.1, 129.2, 121.4, 70.4, 37.4, 31.1 21.2, 21.0, 19.9

Production Example 2: 4- (4-Hydroxyphenyl) -2-butanyl acetate Rhododendrol (5.0 g) was placed in a 200 mL eggplant-shaped flask, and pyridine (1.0 mL) and acetic anhydride (8.0 g) were sequentially added. In addition, after 4 hours, it was worked up according to a conventional method to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.), and fractionated and purified using ethyl acetate / n-hexane (1/5) as a mobile phase. The obtained purified product (3.0 g) was placed in a 200 mL eggplant-shaped flask, 80 vol% aqueous methanol solution (120 mL) was added, and the mixture was stirred. Further, ammonium acetate (7.5 g) was added and reacted at 40 ° C. for 48 hours, followed by post-treatment according to a conventional method to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) and purified with ethyl acetate / n-hexane (1/4) as a mobile phase to obtain the target rhododene. A drole derivative (1.1 g) was obtained as a colorless oil. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 171.7, 154.2, 133.1, 129.3, 115.3, 70.9, 37.6, 30.7, 21.2 19.8

Production Example 3: 4- (3-propanoyloxybutyl) phenylpropanoate Rhododendrol (2.5 g) was placed in a 200 mL eggplant-shaped flask, dissolved in pyridine (5 mL) and tetrahydrofuran (50 mL), and ice-cooled. Then, propionyl chloride (5.0 g) was added dropwise, and after 24 hours, post-treatment was performed according to a conventional method. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) and purified with ethyl acetate / n-hexane (1/5) as a mobile phase to obtain the desired rhododene. A drole derivative (3.3 g) was obtained as a colorless and transparent oily substance. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 173.9, 172.8, 148.8, 138.8, 129.0, 121.2, 69.9, 37.3, 30.9 27.5, 27.4, 19.7, 8.9, 8.7

Production Example 4: 4- (3-Octanoyloxybutyl) phenyloctanoate Rhododendrol (5.0 g) was placed in a 200 mL eggplant-shaped flask and dissolved in pyridine (7.5 mL) and tetrahydrofuran (92.5 mL). Then, octyl chloride (12.5 g) was added dropwise with stirring under ice cooling, and after 4 hours, the mixture was post-treated according to a conventional method. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) and purified using n-hexane as a mobile phase to obtain the target rhododendrol derivative (11.3 g). Obtained as a colorless and transparent oil. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 173.5, 172.5, 148.9, 139.0, 129.2, 121.4, 70.1, 37.6, 34.7 34.4, 31.7, 31.7, 31.2, 29.1, 29.0, 28.9, 28.9, 25.1, 25.0, 22.6, 22.6, 20 .1, 14.0, 14.0

Production Example 5: 4- (4-Hydroxyphenyl) -2-butanyloctanoate Rhododendrol (5.0 g) was placed in a 200 mL eggplant-shaped flask and poured into pyridine (7.5 mL) and tetrahydrofuran (92.5 mL). After dissolution, octyl chloride (12.5 g) was added dropwise with stirring under ice cooling. After 4 hours, the reaction product was worked up according to a conventional method to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.), and fractionated and purified using n-hexane as a mobile phase. The obtained purified product (5.0 g) was placed in a 200 mL eggplant-shaped flask, and 80 vol% acetonitrile aqueous solution (100 mL) was added and stirred. Further, ammonium acetate (6.0 g) was added and reacted at 50 ° C. for 96 hours, followed by post-treatment according to a conventional method to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) and purified with ethyl acetate / n-hexane (1/4) as a mobile phase to obtain the target rhododene. A drole derivative (1.3 g) was obtained as a colorless and transparent oily substance. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 174.0, 154.0, 133.5, 129.4, 115.3, 70.3, 37.8, 34.7, 31.6 30.8, 29.0, 28.8, 25.0, 22.5, 19.9, 13.9

Production Example 6: 4- (3-palmitoyloxybutyl) phenyl palmitate Rhododendrol (1.7 g) was placed in a 200 mL eggplant-shaped flask, dissolved in pyridine (2 mL) and tetrahydrofuran (50 mL), and chlorinated under ice-cooling. Palmitoyl (9.5 g) was added dropwise, and after 24 hours, post-treatment was performed according to a conventional method. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.), fractionated and purified using n-hexane as a mobile phase, and the desired rhododendrol derivative (3. 7 g) was obtained as white crystals. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 173.1, 172.0, 148.8, 138.8, 128.9, 121.3, 69.9, 37.5, 34.4 34.2, 31.8, 31.1, 29.6, 29.6, 29.5, 29.4, 29.4, 29.3, 29.2, 29.2, 29.1, 29 0.0, 29.0, 25.0, 24.8, 22.6, 19.9, 14.0

Production Example 7: 4- (4-Hydroxyphenyl) -2-butanyl palmitate Rhododendrol (1.7 g) was placed in a 200 mL eggplant-shaped flask, dissolved in pyridine (2 mL) and tetrahydrofuran (50 mL), and cooled on ice. Under the conditions, palmitoyl chloride (9.5 g) was added dropwise, and after 24 hours, post-treatment was performed according to a conventional method. The obtained crude product was subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) and purified using n-hexane as a mobile phase. The obtained purified product (1.0 g) was placed in a 200 mL eggplant-shaped flask, dissolved in 100 mL of THF, and 1N NaOH aqueous solution was added dropwise. After confirming the disappearance of the reaction product by TLC, it was worked up according to a conventional method. The crude product was dissolved in 0.1N KOH aqueous solution, stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and then subjected to silica gel column chromatography (silica gel 60N: 100-210 μm; manufactured by Kanto Chemical Co., Inc.) to purify ethyl acetate / n-hexane (1/9) as a mobile phase to obtain the desired rhododene. A drole derivative (0.5 g) was obtained as white crystals. The results of ¹³ C-NMR are shown below.

¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 174.0, 154.2, 133.8, 129.6, 115.5, 70.6, 38.0, 35.0, 32.1 31.1, 29.9, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 25.3, 22.9, 20.2, 14.3

Test Example 1 (Solubility test)
Using the rhododendrol derivatives obtained in Production Examples 1 to 4, the following solubility test was performed. As comparative controls, rhododendrol and 4- (3-hydroxybutyl) phenyl acetate were used as Comparative Examples 1 and 2.

Test Method To each compound (0.1 g) of Production Examples 1 to 4 and Comparative Examples 1 and 2, the solvent (1 mL) shown in Table 1 below was added, heated at 40 ° C. for 10 minutes, and then returned to room temperature. The supernatant of each solution was collected, and each solubility was evaluated by gas chromatography using a sample diluted 50-fold with ethyl acetate as a sample. Evaluation was performed in the range of 10 to 100 mg / mL.
Analysis conditions: Column: DB-1 (manufactured by Agilent Technologies, 30 m × 0.25 mm × 0.25 mm)
Oven: 130 ° C. for 5 min, 130 ° C. to 260 ° C. at 10 ° C./min
Detector: FID, 250 ° C
Sample introduction: Split, 250 ° C., Split racio 1:50, 1 μL

The results are shown in Table 1 below.

From Table 1, the rhododendrol derivative of the present invention has improved solubility in a low-polarity solvent as compared with Comparative Example 1 (Rhodendrol) and Comparative Example 2 (4- (3-hydroxybutyl) phenyl acetate). I understand that. Further, from the comparison between Production Example 2 and Comparative Example 2, when an acyl group is added to rhododendrol, the solubility differs depending on the position of addition, and the product of the present invention has a significantly improved solubility compared to Comparative Example 2. It was confirmed that Further, it was confirmed that the solubility in Production Examples 1 to 4 in DPG and ethanol was maintained in the same manner as in Comparative Examples 1 and 2, and the product of the present invention has a broad solubility spectrum for general-purpose cosmetic bases. It was confirmed.

Test example 2 (antibacterial activity test against general bacteria and fungi)
Using the rhododendrol derivative obtained in Production Example 2, the antibacterial activity test shown below was performed. As comparative objects, rhododendrol (Comparative Example 1) and phenoxyethanol (Comparative Example 3) were used.

Test Method Antibacterial activity was evaluated by measuring the minimum growth inhibitory concentration (MIC, unit: μg / mL) of various microorganisms shown in Table 2 according to the agar plate dilution method of the Japanese Society of Chemotherapy Standard Method. That is, a medium was prepared by adding evaluation samples (Production Example 2 and Comparative Examples 1 and 3) to a concentration in the range of 625 to 10000 μg / mL, and the growth properties of various microorganisms shown in Table 2 were determined. Was used to evaluate. The medium and culture conditions are as follows. For Candida albicans of (3), glucose peptone agar medium is used for 72 hours under an aerobic condition at 25 ° C., and for others, soybean casein digest agar medium is used for 30 ° C. aerobic condition. After 48 hours of culturing, their proliferation was confirmed.

The results are shown in Table 3.

From the results in Table 3, the rhododendrol derivative of Production Example 2 has an excellent antiseptic sterilization having a very high antibacterial activity because the MIC value is low in all strains as compared with the rhododendrol of Comparative Example 2. It was confirmed to be an agent. Moreover, compared with the phenoxyethanol of the comparative example 3, since it showed the same MIC value, it was shown that it is a useful antiseptic antibacterial agent similarly to the phenoxyethanol known as a general antiseptic antibacterial agent. .

Test example 3 (antibacterial activity test for acne prevention and improvement)
Using the rhododendrol derivative obtained in Production Example 2, the antibacterial activity test shown below was performed. As comparative objects, rhododendrol (Comparative Example 1) and resorcin (Comparative Example 4) were used.

-Test method The test was conducted in the same manner as in Test Example 2. That is, a medium was prepared by adding evaluation samples (Production Example 2 and Comparative Examples 1 and 4) to a concentration in the range of 625 to 10000 μg / mL, and the growth of Propionibacterium acnes was evaluated using these media. did. A brain heart infusion agar medium was used as the medium, and the cells were cultured under anaerobic conditions at 37 ° C. for 72 hours, and then their growth properties were confirmed.

The results are shown in Table 4.

From the results in Table 4, it can be seen that the rhododendrol derivative of Production Example 2 has much higher antibacterial activity against Propionibacterium acnes than Comparative Example 1 and Comparative Example 4.

Test example 4 (external preparation for acne skin)
According to the formulation shown in Table 5 below, acne skin external preparation (skin lotion) was prepared, and its anti-acne effect was evaluated according to the following evaluation method.

・ Evaluation method (acne improvement effect)
Each evaluation sample was evaluated by taking 10 adults (5 men and 5 women) from 18 to 30 years old who have acne on their face as one group. After washing with the same face washing soap twice a day in the morning and evening, each evaluation sample was used blindly. Compare the appearance of acne on the face before use and one week after use by visual inspection and photography, and change the symptoms in five stages: "Improved""Slightlyimproved""Nochange""Slightlyworsened""Worse" evaluated.

・ Evaluation method (acne scar improvement effect)
The evaluator of the above-mentioned “acne improvement effect” had the sample continuously used, and the condition of acne scars on the face 4 weeks after the start of use was compared with the state after 1 week by visual inspection and photography. The change was evaluated in five stages: “improvement”, “slight improvement”, “no change”, “slight deterioration”, and “deterioration”.

The results are shown in Table 5.

From the results of Table 5, Example 1 was superior to Comparative Example 5 in acne improvement effect and acne scar improvement effect.

Test Example 5 (Example of antibacterial activity test regarding deodorization action)
Using the rhododendrol derivative obtained in Production Example 2, the antibacterial activity test shown below was performed. As a comparison object, rhododendrol (Comparative Example 1) was used.

-Test method The test was conducted in the same manner as in Test Example 2. That is, a medium to which evaluation samples (Production Example 2 and Comparative Example 1) were added so as to have a concentration in the range of 625 to 10000 μg / mL was prepared, and the growth of Corynebacterium xerosis was evaluated using these media. As the medium and culture conditions, a soy bean / casein / digest agar medium was used and cultured for 30 hours under aerobic conditions at 30 ° C., and their growth was confirmed.

The results are shown in Table 6.

From the results of Table 6, the rhododendrol derivative of Production Example 2 is an excellent deodorizing active agent having a very high antibacterial activity because it has a low MIC value as compared with the rhododendrol of Comparative Example 1. Indicated.

Test Example 6 (Melanin production inhibition test)
Using the rhododendrol derivative obtained in Production Example 1 and Production Example 2 and rhododendrol (Comparative Example 1), the following melanin production inhibition test was performed.

Test Method B16 melanoma cells were seeded in a 12-well culture plate at a volume of 1 × 10 ⁴ cells / well in a 10 vol% fetal bovine serum-containing MEM medium, and precultured for 24 hours in a conventional manner. After the pre-culture, the medium was replaced with the test medium to which the sample (Production Example 1 and Comparative Example 1) was added, and cultured for 72 hours. As the test medium, a medium obtained by adding theophylline to the above-mentioned pre-culture medium so as to be 2 mmol / L was used. After culturing, it was dissolved in a 1 mol / L sodium hydroxide aqueous solution containing 10 vol% dimethyl sulfoxide, and the OD475 value was measured to obtain the amount of melanin. At the same time, using the Coomasie Plus Protein Assay Reagent Kit (manufactured by PIERCE), the total amount of protein in the lysate was quantified, and the amount of melanin per amount of protein was calculated.
IC ₅₀ calculation formula Melanin production inhibition rate (%) = (AB) / A × 100
(However, A: Amount of melanin per amount of protein when sample is not added, B: Amount of melanin per amount of protein when sample is added)
A graph was prepared by plotting the concentration on the horizontal axis and the inhibition rate of melanin production on the vertical axis, and the concentration (IC ₅₀ ) for inhibiting melanin production by 50% was determined from this graph.

The results are shown in Table 7.

From the results in Table 7, it can be seen that the rhododendrol derivative of the present invention exhibits an equivalent melanin production inhibitory effect as compared with the rhododendrol of Comparative Example 1.

Test Example 7 (Whitening practical test)
Using the rhododendrol derivative obtained in Production Examples 1 and 2 above and a skin cream blended with rhododendrol, the following whitening practical test was conducted.

Test Method Summer sun light was exposed to the skin of the forearm bent side of 20 subjects for 3 hours (1.5 hours per day for 2 consecutive days). After exposure, skin creams of Example 2 and Example 3 in Table 8 below were applied to the subject's left forearm flexion side skin once a day in the morning and evening for 13 consecutive weeks. The skin cream of Comparative Example 6 in Table 8 below was applied to the subject's right forearm bent side skin under the same conditions. At the end of the final application, the degree of whitening before and after continuous use of the left and right forearm skin was evaluated by a specialist judge. In the evaluation, subjects who were confirmed to have a whitening effect were considered to have “whitening effect” and the number of subjects was shown.

The results are shown in Table 9 below. From this result, since the skin cream containing the rhododendrol derivative of the present invention has improved solubility in oil compared with the skin cream containing the rhododendrol of Comparative Example 6, it is very useful as a whitening cosmetic. It turns out that it is excellent. During the test period, there was no subject who had a skin irritation reaction or a skin sensitization reaction at the site where the skin creams of Example 2 and Example 3 were applied, and the product of the present invention is safe even in the form of a preparation. I was able to confirm.

Next, using the compounds of Production Examples 1 to 7, each cosmetic was produced according to a conventional method according to the following ingredients.

Example 4 (skin lotion)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Ethanol 10.0
Monolauric acid POE (20) sorbitan 5.0
Phenoxyethanol 0.1
Fragrance 0.05
Compound of Production Example 2 2.0
Glycerin 5.0
Xanthan gum 0.1
Hydroxyethyl cellulose 0.1
Purified water balance
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　

Example 5 (skin cream)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Glycerol monostearate 2.0
Beeswax 1.0
Monooleic acid POE (20) sorbitan 6.0
Vaseline 4.0
Liquid paraffin 12.0
Compound of Production Example 1 2.0
N-stearoyl-L-glutamate sodium 1.0
Carrageenan 0.3
Methylparaben 0.1
Purified water balance
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　

Examples 6 to 7 (cream)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
Example 6 Example 7
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Stearic acid 1.0 1.0
Glycerol monoisostearate 2.0 2.0
Behenyl alcohol 2.0 2.0
White beeswax 1.0 1.0
Isocetyl myristate 1.0 1.0
Sorbitan isostearate 1.0 1.0
Retinyl palmitate 0.1 0.1
Hydrogenated lecithin 0.1 0.1
Ubidecarenone 0.03 0.03
Phytosterol 0.1 0.1
Plant squalane 5.0 5.0
Hydrogenated polydecene 5.0 5.0
Dicapryl carbonate 5.0 5.0
1,3-butylene glycol 5.0 5.0
Concentrated glycerin 5.0 5.0
N-acetylglucosamine 0.1 0.1
Ascorbic acid sulfate disodium salt 0.2 0.2
γ-aminobutyric acid 0.1 0.1
Sodium N-stearoyl glutamate 0.2 0.2
Monoammonium glycyrrhizinate 0.1 0.1
Edelweiss extract (Note 3) 0.2 0.2
Yeast extract (Note 4) 0.2 0.2
Acrylic acid / alkyl methacrylate copolymer (Note 5) 0.05 0.05
Nicotinamide 0.1 0.1
Creatine 0.2 0.2
Carnitine chloride 0.1 0.1
Fire thorns (Note 6) 0.1 0.1
Compound of Production Example 4 3.0 −
Compound of Production Example 7-1.0
Purified water residual amount Residual amount
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 3) Edelweiss Extract GC (Penta Farm)
(Note 4) Dismutin BTJ (Penta Farm)
(Note 5) PEMULEN TR-1 (manufactured by Lubrizol Advanced Materials)
(Note 6) Fire thorn extract (manufactured by Suntory)

Example 8 (cream)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Isostearic acid 1.0
Glycerol monoisostearate 2.0
Behenyl alcohol 2.0
Sara honey bee 1.0
Isocetyl myristate 1.0
Sorbitan isostearate 1.0
Retinyl palmitate 0.1
Hydrogenated lecithin 0.1
Ubidecarenone 0.03
Phytosterol 0.1
Plant Squalane 5.0
Dicapryl carbonate 5.0
Methyl paraoxybenzoate 0.2
1,3-butylene glycol 10.0
Concentrated glycerin 5.0
N-acetylglucosamine 0.1
Ascorbic acid sulfate disodium salt 0.2
γ-aminobutyric acid 0.1
Sodium N-stearoyl glutamate 0.2
Monoammonium glycyrrhizinate 0.1
Edelweiss extract (Note 3) 0.2
Yeast extract (Note 4) 0.2
Acrylic acid / alkyl methacrylate copolymer 0.05
Nicotinamide 0.1
Creatine 0.2
Carnitine chloride 0.1
Ascorbic acid phosphate magnesium 0.1
Dioscorea compositor extract (Note 7) 0.1
Elderberry extract (Note 8) 0.1
Compound of Production Example 6 1.0
Purified water balance
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 7) Dioscorea compositor root extract (Mitsui Chemicals)
(Note 8) Elder extract BG (manufactured by Maruzen Pharmaceutical Co., Ltd.)

Examples 9 to 11 (sunscreen)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
Example 9 Example 10 Example 11
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Dioctyl ether 22.0 15.0 10.0
Co-modified silicone (Note 9) 2.0 2.0 2.0
Glyceryl tri-2-ethylhexanoate--0.5
Hardened oil--0.1
Methylphenylpolysiloxane-3.0-
Macadamia nut fatty acid phytosteryl--2.0
Titanium oxide 5.0-4.0
Zinc oxide 5.0-4.0
Ethoxyhexyl methoxycinnamate 10.0 10.0 10.0
Compound of Production Example 0.5 0.5 0.5 0.5
Phenoxyethanol 0.3 0.3 0.3
Magnesium chloride 1.0 1.0 1.0
1,3-butylene glycol 5.0 5.0 5.0
Royal Jelly Extract (Note 10) 1.0 1.0 1.0
Aloe extract (Note 11) 0.1 0.1 0.1
Oat extract (Note 12) 0.5 0.5 0.5
Yeast extract (Note 4) 1.0 1.0 1.0
Purified water remaining amount remaining amount remaining amount
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 9) ABIL EM90 (Gold Schmidt)
(Note 10) Royal jelly (Api)
(Note 11) Aloe extract gel BG (Maruzen Pharmaceutical Co., Ltd.)
(Note 12) Alum extract J (Maruzen Pharmaceutical Co., Ltd.)

Examples 12 to 14 (Cosmetic liquid)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
Example 12 Example 13 Example 14
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Co-modified silicone (Note 9) 2.0 2.0 2.0
POE modified silicon dispersion (Note 13)-2.0-
Squalane--10.0
Decamethylcyclopentasiloxane 15.0 20.0 10.0
Methyl polysiloxane (100 cs) 5.0 2.0 3.0
Long-chain branched fatty acid cholesteryl (Note 14)--2.0
Silicon elastomer dispersion (Note 15) 5.0 2.0-
Compound of Production Example 3 0.01 0.1 0.5
P-Hydroxybenzoic acid methyl ester 0.05 0.05 0.05
Sodium chloride 1.0 1.0 1.0
Dipropylene glycol 5.0 5.0 5.0
Concentrated glycerin 5.0 5.0 5.0
Raffinose 1.0 1.0 1.0
Mixed isomerized sugar (Note 16) 1.0 1.0 1.0
Licorice extract (Note 17) 0.1 0.1 0.1
N-methyl-L-serine 0.5 0.5 0.5
Purified water remaining amount remaining amount remaining amount
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 13) Silicon BY22-008 (Toray Dow Corning Silicone)
(Note 14) YOFCO CLE-NH (Nippon Seika Co., Ltd.)
(Note 15) Trefill (Toray Dow Corning Silicone)
(Note 16) PENTAVITIN (Penta Farm)
(Note 17) Licorice extract (Maruzen Pharmaceutical Co., Ltd.)

Examples 15 to 17 (lotion)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
Example 15 Example 16 Example 17
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Compound of Production Example 2 1.0 0.1 0.01
Phenoxyethanol 0.2 0.2 0.2
1,3-butylene glycol 0.1 0.3 0.3
Dipropylene glycol 5.0-5.0
Raffinose-5.0 5.0
Dimethyl hyaluronate Silanol solution (Note 18) 0.1 0.1 0.1
MPC polymer (Note 19) 0.1 0.1 0.1
Ethanol--1.0
Pectin--0.05
Xanthan gum--0.01
Sodium citrate 0.05 0.05 0.05
Horsetail extract (Note 20) 0.1 0.1 0.1
Diisopropylamine dichloroacetate 0.2 0.2 0.2
Dl-α-tocopherol acetate 0.1 0.1 0.1
γ-amino-β-
Hydroxybutyric acid 0.2 0.2 0.2
Sodium hyaluronate 0.001 0.001 0.001
Dipotassium glycyrrhizinate 0.2 0.2 0.2
Pentapeptide-3 (Note 21) 0.05 0.05 0.05
Decarboxycarnosine hydrochloride 0.05 0.05 0.05
Perfume 0.02 0.02 0.02
Purified water remaining amount remaining amount remaining amount
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 18) DSHC-N (manufactured by EXYMOL)
(Note 19) Lipidur PMB (manufactured by NOF Corporation)
(Note 20) Horsetail extract (manufactured by Maruzen Pharmaceutical Co., Ltd.)
(Note 21) MATRIXYL (manufactured by Croda Japan)

Example 18 (Emulsion)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Raw material component amount (% by mass)
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
Methylphenyl polysiloxane (Note 22) 3.0
Dicapryl carbonate 1.0
Olive oil 1.0
Medfoam oil 0.1
Monolauric acid POE (20) sorbitan 0.5
Nicotinic acid dl-α-tocopherol 0.01
POE (60) hydrogenated castor oil 2.0
Shea fat (Note 23) 0.01
Ascorbyl tetraisopalmitate 0.1
N-acetylglucosamine 0.02
Yeast extract (Note 4) 3.0
1,3-butylene glycol 3.0
Sorbitol solution 3.0
Polyethylene glycol 1000 1.0
Carboxyvinyl polymer 0.1
Compound of Production Example 5 0.01
Methyl paraoxybenzoate 0.2
White jellyfish polysaccharide (Note 24) 0.05
Sodium edetate 0.02
Potassium hydroxide 0.05
Xanthan gum 0.05
Polyacrylamide (Note 25) 0.01
Purified water balance
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
(Note 22) Cosmeserve WP-58MP (Dainippon Kasei Co., Ltd.)
(Note 23) Cropure SB (manufactured by Croda Japan)
(Note 24) Tremoist-TP (Nippon Seika Co., Ltd.)
(Note 25) Kosmedia SP (manufactured by Cognis)

The rhododendrol derivative of the present invention can be applied to the cosmetic preparations of Examples 4 to 18, and by using these, it has excellent whitening action, antiseptic antibacterial action, acne prevention / amelioration action and deodorization action. Expressed.

The rhododendrol derivative of the present invention can be applied to a wide range of dosage forms, for example, cosmetics such as lotions, emulsions, creams, packs, bathing agents, etc. due to improved solubility. In addition, since the rhododendrol derivative of the present invention has excellent whitening action, antiseptic antibacterial action, acne prevention / amelioration action and deodorization action, the use of a skin external preparation containing the rhododendrol derivative of the present invention makes it possible to Very useful in terms of beauty.

Claims (8)

A skin external preparation containing a rhododendrol derivative represented by the following general formula (1).

(In the formula, R ¹ represents an acyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or an acyl group having 2 to 20 carbon atoms.) A whitening cosmetic containing a rhododendrol derivative represented by the following general formula (1).

(In the formula, R ¹ represents an acyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or an acyl group having 2 to 20 carbon atoms.) A whitening agent comprising a rhododendrol derivative represented by the following general formula (1) as an active ingredient.

(In the formula, R ¹ represents an acyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or an acyl group having 2 to 20 carbon atoms.) An antiseptic fungicide containing a rhododendrol derivative represented by the following general formula (1a) as an active ingredient.

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.) A skin external preparation for acne skin containing a rhododendrol derivative represented by the following general formula (1a).

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.) A skin deodorizing agent for deodorization containing a rhododendrol derivative represented by the following general formula (1a).

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.) A deodorizing agent comprising a rhododendrol derivative represented by the following general formula (1a) as an active ingredient.

(In the formula, R ^1a represents an acyl group having 2 to 4 carbon atoms.) A rhododendrol derivative represented by the following general formula (1b).

(In the formula, R ^1b and R ^2b each represents an acyl group having 3 to 20 carbon atoms.)