TWI400094B - Skin external preparations - Google Patents

Description

Skin external preparation

The present invention relates to a skin external preparation.

Black spots and freckles are caused by excessive accumulation of melanin in epidermal cells due to the collapse of the formation and excretion of melanin. These reasons are due to various factors such as inflammation, hormonal balance, and hereditary factors, but they are also affected by ultraviolet light. The whitening agent is added to alleviate the pigmentation added. Among them, tannin, arbutin, hydroquinone monobenzyl ether, hydrogen peroxide, and the like are known as whitening cosmetics for preventing skin blackening, dark spots, and freckles, and maintaining the original whitening skin. However, the blending of these whitening agents has the effect of lightening the skin of the blackened skin, but it is not sufficiently satisfactory as a whitening cosmetic, and further, it does not inhibit the inflammatory effect caused by ultraviolet rays. Most of the remaining aspects of the safety surface remain. Further, as a whitening agent which suppresses inflammation caused by ultraviolet rays, vitamin C and its derivatives are known. However, these are not satisfactory in terms of the degree of whitening effect and the stability in the preparation.

In addition, in conventional cosmetics, medical external products, and pharmaceuticals, p-hydroxybenzoic acid such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben is frequently used. In recent years, it has been marketed as a preservative and bactericidal agent, and it has been proposed to use a cosmetic material which is low in irritant or sensitive skin, and it is desired to reduce or replace the use amount of p-hydroxybenzoic acid. Various methods such as blending of plant extracts or blending of alkanediols such as 1,2-pentanediol or 1,2-hexanediol have been proposed as such a method (Patent Documents 1 to 5). However, from the viewpoint of the texture of the preparation when formulated in cosmetics or the like, the influence on stability, or the taste, etc., there is a problem that the amount of use of these components is limited.

In addition, the condition of acne (acne acne) is roughly classified into 1) non-inflammatory rash blister, 2) inflammatory papules such as red papules, 3) scar, and 4) post-inflammatory pigmentation. The treatment is combined with the condition, and the three treatments of 1) topical topical therapy, 2) systemic internal therapy, and 3) physiotherapy are administered separately or in combination. Among them, the topical topical therapy is considered to be an effective treatment for symptoms other than scars, and an external preparation formulated with various active ingredients has been developed so far (Non-Patent Document 1). The procedure for acne is roughly divided into two stages. The first stage is the formation of blister, and the second stage is caused by inflammation. The blister is formed by excess sebum secretion and keratinization of the pores, which clog the pores and store sebum in the hair follicles. The acne-like skin is often used in the growth environment suitable for the anaerobic bacteria of the bacteria, propionibacterium acnes. Therefore, in the blister, the number of bacteria increases and extracellular inflammatory-inducing substances are generated, thereby causing inflammatory papules such as red papules. (Non-Patent Document 2). As a precaution against such acne and measures for improvement, it is known that sebum (triglyceride) or keratotrophy is used as a cause of pore blockage, and the use of anti-lipid leakage agents such as face wash and vitamin B6 is known, and resorcin or Early peeling of unwanted keratin by salicylic acid or the like, prevention of deterioration by an antibacterial substance having a high bactericidal effect like isopropylmethylphenol which inhibits the growth of P. acnes, use of an anti-inflammatory agent, etc. Non-patent document 3). In addition, topical topical therapy with vitamin C (ascorbic acid) derivatives is attracting attention for pigmentation after inflammation (Non-Patent Document 1). Furthermore, it has been reported that by combining tyrosinase activity inhibitors with An antibacterial or anti-acne agent for preventing or improving black spots of acne marks (Patent Documents 6 and 7).

In addition, in the body odor, the stench of a unique odor is caused by the decomposition of the enzymes produced by the skin bacteria, such as glycoproteins and lipids secreted by the apocrine sweat glands of the lower part of the crotch, to produce volatile, odorous fatty acids. The result is (Non-Patent Document 4). As a causative agent which causes a particularly strong and unpleasant odor, for example, Corynebacterium xerosis, which is a good-fat bacteria, is detected in many crotch glands and sweat glands. As a composition for an antibacterial agent or a deodorant which is effective against bacteria belonging to the genus Corynebacterium, a sucrose ester of a fatty acid which is conventionally used as a preservative or preservative for foods and cosmetics has been proposed (Patent Document 8). Sterilization and disinfection components of triclosan and isopropylmethylphenol (Patent Document 9), edible calendula flower bud extract (Patent Document 10), alkanediol and lysozyme for improving antibacterial activity (Patent Document 11). In order to prevent odor, it is necessary to have two functions of sweating and sterilization. Conventionally, as an example of sweating, an aluminum salt such as aluminum hydroxychloride (aluminum chloride hydrate) is used as an astringent. Moreover, as an example of sterilization, a substance having a wide spectrum of bactericidal activity such as alginate is used as an antibacterial agent (Non-Patent Document 3). However, an anti-odor active agent having sufficient effects has not been found so far.

As described above, in the past, many skin external preparations for whitening, antiseptic, antibacterial, acne prevention, and anti-odor have been studied, but it is difficult to simultaneously achieve sufficient effects and preparations.

On the other hand, Rhododendrol and a part of its derivatives have a superior whitening effect and exhibit an antibacterial effect against specific bacteria, and therefore have been proposed to be applied to external preparations for skin (Patent Documents 12 to 14). Further, it has been reported that a phenylbutyric acid-containing phenolic acid-containing strain exhibits an antibacterial action (Non-Patent Document 5).

[Patent Document 1] Japanese Patent Laid-Open No. Hei 8-73364

[Patent Document 2] Japanese Patent Laid-Open No. Hei 8-73368

[Patent Document 3] Japanese Patent Laid-Open No. Hei 10-182333

[Patent Document 4] Japanese Patent Laid-Open No. Hei 10-203955

[Patent Document 5] Japanese Patent Laid-Open No. Hei 11-322591

[Patent Document 6] Japanese Patent Laid-Open Publication No. 2002-145802

[Patent Document 7] Japanese Patent No. 2883368

[Patent Document 8] Japanese Patent Laid-Open Publication No. 2002-255775

[Patent Document 9] Japanese Patent Laid-Open Publication No. 2006-96719

[Patent Document 10] Japanese Patent Laid-Open Publication No. 2007-1948

[Patent Document 11] Japanese Patent Laid-Open Publication No. 2007-145750

[Patent Document 12] Japanese Patent No. 3340935

[Patent Document 13] Japanese Patent Laid-Open Publication No. 2008-7432

[Patent Document 14] International Publication No. 09-084200

[Non-Patent Document 1] FRAGRANCE JOURNAL, 2007, Vol. 35, No. 5, p. 12-17

[Non-Patent Document 2] COSMETIC STAGE, 2007, Vol. 1, No. 5, p. 23-27

[Non-Patent Document 3] FRAGRANCE JOURNAL, 2003, Vol. 31, No. 3, p. 23-28

[Non-Patent Document 4] This is a long time, "All sweating gland disease of sweat" Mon Book Derma, March 2007, p.45-47

[Non-Patent Document 5] P. Srinivasa Reddy, Kaiser Jamil et al., Pharmaceutical Biology, 39, 236-238, 2001

However, these rhododendrols and their derivatives are problematic in solubility for a low-polarity solvent which is widely used as a cosmetic base, and are difficult to apply to various cosmetic preparations. Moreover, for the same reason, the current situation is limited in the research that can fully exert the effectiveness of the preparation.

An object of the present invention is to provide a novel rhododendine derivative which can be easily applied to various cosmetic preparations, and which has a whitening effect, an antiseptic effect, an acne prevention, an improvement effect, and an anti-corrosion effect. A skin external preparation with superior odor effect.

The inventors of the present invention conducted intensive studies to solve the above problems, and as a result, found that the novel rhododendron derivative in which the hydroxyl group on the butyl group of the rhododendrol represented by the following general formula (1) is thiolated is compared with The rhododendrol derivative in which the rhododendrol or the phenolic hydroxyl group is thiolated is superior to the low-polarity solvent widely used as a cosmetic base. As a result, it has been easy to apply to various cosmetic preparations, and further, it has been confirmed that it can fully evaporate whitening effect, antibacterial effect against bacteria, proliferation inhibition effect of P. acnes against acne bacteria, prevention of acne marks ‧ Improved effect and bactericidal effect against bacteria causing poor odor, Corynebacterium xerosis, and the present invention has been completed.

That is, the present invention provides a skin external preparation comprising the rhododendrol derivative represented by the following general formula (1).

[Chemical 1]

(wherein R ¹ represents a fluorenyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or a fluorenyl group having 2 to 20 carbon atoms.)

Further, the present invention provides a rhodolacol derivative represented by the following general formula (1b).

[Chemical 2]

(wherein R ^1b and R ^2b represent a fluorenyl group having 3 to 20 carbon atoms, respectively.)

Further, the present invention provides a whitening agent, an antiseptic antibacterial agent, an anti-acne agent and an anti-odor agent, which are obtained by using a rhododendamine derivative represented by the following general formula (1a) as an active ingredient.

[Chemical 3]

(wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms.)

Further, the present invention provides a use of the above-described general formula (1a) of a rhodamine derivative for producing a whitening agent, an antiseptic antibacterial agent, an anti-acne agent and an anti-odor agent.

Further, the present invention provides a whitening method, an antiseptic antibacterial method, an acne treatment method or an anti-odor method, which is characterized by using the rhododendrol derivative represented by the above general formula (1a).

The allopurinol-derived alcohol of the present invention has high solubility in a low-polarity solvent, is easily applied to various cosmetic preparations, and can provide a skin external preparation excellent in whitening effect, antiseptic and antibacterial effect, acne prevention, and improvement effect.

Embodiments of the present invention will be described in detail below.

The rhododendol derivative used in the present invention is a compound represented by the above general formula (1). In the formula (1), R ¹ represents a fluorenyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or a carbon number 2~ 20 base. R ¹ and R ² may be a fluorenyl group of the same carbon number at the same time, or may be a fluorenyl group having a different carbon number. The thiol group of R ¹ and R ² may be saturated or unsaturated, and may have a functional group such as an amine group. Among them, a saturated alkane group is more preferred. Specific examples thereof include an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentamidine group, a hexyl group, a octyl group, a lauryl group, a decyl group, a stearyl group, and the like. Among them, alkane fluorenyl group having 2 to 18 carbon atoms, more preferably an alkyl fluorenyl group having 2 to 8 carbon atoms, in the case of an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group or an isobutyl fluorenyl group having a carbon number of 2 to 4 It is particularly easy to apply to cosmetic preparations.

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

[Chemical 4]

(wherein R ^1b and R ^2b represent a fluorenyl group having 3 to 20 carbon atoms, respectively.)

Further, in the general formula (1), from the viewpoints of application to a whitening agent, an antiseptic antibacterial agent, an anti-acne agent, and an anti-odor agent, R ¹ is preferably a fluorenyl group having 2 to 8 carbon atoms (especially a compound having a carbon number of 2 to 4, and R ² being a hydrogen atom or a fluorenyl group having 2 to 8 carbon atoms (particularly a hydrogen atom or a fluorenyl group having 2 to 4 carbon atoms), particularly preferably the following general formula ( Compound shown in 1a).

[Chemical 5]

(wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms.)

The method for producing a rhododendrol derivative used in the present invention is prepared by using a rhododendrol obtained by a known synthesis method or an extract obtained from a plant containing a rhododendron such as mascarpone or white birch as a starting material. It can be produced by using a known thiolation reaction. For example, there is a method of reacting rhododendrol with an acid chloride or an acid anhydride in a pyridine solvent. Further, a plant extract such as mascarpa can be obtained by subjecting the plant extract to a thiol group by an appropriate method, and then separating and purifying the target sterol derivative.

Although the optically active isomer is present in the azathiol derivative obtained by the above method, the (+) and the (-) may be used singly or as a mixture thereof.

The rhododendrol derivative represented by the general formula (1) has whitening action, antiseptic and antibacterial action, anti-acne prevention and anti-odor effect, and excellent solubility in a low-polarity solvent, as shown in the examples below. It is used as a whitening agent, a whitening cosmetic, an anti-acne agent, an external preparation for skin for acne skin, an antiseptic antibacterial agent, an anti-odor agent, and an external preparation for anti-odor skin.

In addition, the azaleafol derivative to be used in the present invention may be used alone or in combination of two or more of them.

The content of the azathiol derivative of the present invention cannot be uniformly determined depending on the purpose of the preparation and the target of the preparation, and is usually 0.00001% by mass to 10.0% by mass, preferably 0.001% by mass based on the total amount of the external preparation for skin. ~5.0% by mass, more preferably 0.01% by mass to 3.0% by mass.

The external preparation for skin of the present invention may contain hydroquinone, arbutin, citric acid, vitamin C and its derivatives (for example, ascorbyl glucoside, sodium ascorbyl phosphate, etc.) of the known whitening agent in addition to the toluene alcohol derivative of the present invention. Ascorbic acid sulfate 2 sodium, ascorbyl phosphate magnesium, etc.), biphenyl derivatives (such as dehydroxylenol, 2,2'-dihydroxy-5,5'-dipropylbiphenyl, etc.), and Japanese patents Melanin production inhibitors such as raspberry ketone, hexyl ketene ketone, octyl ketene ketone, rhododendrol, and 4-(3-hydroxybutyl) phenyl acetate described in 3340935, Pyracantha Extract, extract of Chinese yam, extract of Chinese cabbage, chamomile extract, adenosine 5'-1 phosphate and its salt, linoleic acid derivative, tranexamic acid and tranexamic acid, tranexamic acid derivative, etc. The agents are used in appropriate combination.

Further, when used together with a skin external preparation or the like, a preservative-containing alcohol, a polyhydric alcohol such as phenoxyethanol, dipropylene glycol or butylene glycol, or a chimeric agent such as sodium alkanediol or sodium ethylenediaminetetraacetate may be used in combination. By means of the multiplication effect, the antiseptic and bactericidal effect can be enhanced. In particular, if phenoxyethanol is used in combination, it is more preferable in terms of antiseptic and bactericidal effects.

Further, in addition to the above, the skin external preparation of the present invention may suitably contain a moisturizing agent such as hyaluronic acid, a polyhydric alcohol or a sugar alcohol, a coloring pigment such as a tar pigment or an iron oxide, within a range not impairing the object of the present invention. , an anti-corrosive agent such as paraben, a fatty acid soap, an anionic surfactant such as sodium cetyl sulfate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyol fatty acid ester , non-ionic surfactants such as polyoxyethylene hardened castor oil, polyol fatty acid esters, polyglycerin fatty acid esters, cationic surfactants such as tetraalkylammonium salts, and beets Sulfonic acid beet Type, sulfonic acid amino acid type, N-stearyl sulfhydryl-L-glutamate sodium and other two ionic surfactants, lecithin, lysophospholipid Natural surfactants, gelatin, casein, starch, gum arabic, karaya gum, Guanya gum, locust bean gum, gum tragacanth, medlar seed, pectin, red algae, sodium sulphate, etc. Natural polymer, semi-synthetic polymer such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinyl methyl ether and Synthetic polymer such as copolymer, polyvinylpyrrolidone, sodium polyacrylate, carboxyvinyl polymer, polyethylene oxide polymer, tackifier such as Sanxian gum, pigment such as titanium oxide, dibutyl An antioxidant such as hydroxytoluene.

The form of the external preparation for skin of the present invention is not particularly limited because it dissolves the rhododendine derivative in a solvent having a low polarity, and can be used as an ointment, a cream, a lotion, a sunscreen, a beauty lotion, an emulsion, a mask, and a bath. The form of the agent.

[Examples]

Hereinafter, the present invention will be described in detail based on production examples, test examples and examples, but the present invention is not limited thereto. Further, the rhododendol described below is produced by reducing a commercially available 4-(p-hydroxyphenyl)-2-butanol (enketoxin) by sodium borohydride by a usual method. Further, 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-Ethyloxybutyl)phenylacetate

The rhododendrol (5.0 g) was placed in a 200 mL eggplant type flask, dissolved in pyridine (1 mL), and acetic anhydride (8.0 g) was added to cause a reaction. After 4 hours, the obtained crude product was subjected to post-treatment by a usual method, and the obtained crude product was subjected to a silica gel column chromatography (silicone 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was set to ethyl acetate/n-hexane. (1/5), it was purified, and the desired rhododendrol derivative (5.4 g) was obtained as a colorless, transparent oily substance. 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-butyl acetate

Toxic alcohol (5.0 g) was placed in a 200 mL eggplant type flask, and pyridine (1.0 mL) and acetic anhydride (8.0 g) were added in this order, and after 4 hours, it was post-treated by a usual method to obtain a crude product. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was separated and purified by using ethyl acetate/n-hexane (1/5). The obtained purified product (3.0 g) was placed in a 200 mL eggplant type flask, and 80 vol% aqueous methanol solution (120 mL) was added and stirred. Further, ammonium acetate (7.5 g) was added and the mixture was reacted at 40 ° C for 48 hours, and then worked up in a usual manner to give a crude product. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was made into ethyl acetate/n-hexane (1/4) to be purified as a colorless oil. The form of the substance gave the target of the rhododendrol derivative (1.1 g). 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-propenyloxybutyl)phenylpropionate

The rhododendrol (2.5 g) was placed in a 200 mL eggplant flask, dissolved in pyridine (5 mL) and tetrahydrofuran (50 mL), and propionyl chloride (5.0 g) was added dropwise under ice cooling, and after 24 hours, it was post-treated according to the usual method. The obtained crude product was subjected to silica gel column chromatography (silicone 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was purified by using ethyl acetate/n-hexane (1/5) to be colorless. The clear oily material form gave the target of the rhododendrol derivative (3.3 g). 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-octyloxybutyl)phenyl octanoate

The rhododendrol (5.0 g) was placed in a 200 mL eggplant type flask, dissolved in pyridine (7.5 mL) and tetrahydrofuran (92.5 mL), and octoberidine chloride (12.5 g) was added dropwise while stirring under ice cooling, and after 4 hours, The crude product was subjected to post-treatment, and the obtained crude product was subjected to silica gel column chromatography (silicone 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was refined to n-hexane to obtain a colorless transparent oil. The substance form gave the target of the rhododendrol derivative (11.3 g). 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-butyloctanoate

The rhododendrol (5.0 g) was placed in a 200 mL eggplant type flask, dissolved in pyridine (7.5 mL) and tetrahydrofuran (92.5 mL), and octoberidine chloride (12.5 g) was added dropwise while stirring under ice cooling, and after 4 hours, The conventional method is post-treated to obtain a crude product. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was separated into n-hexane to be separated and purified. The obtained purified product (5.0 g) was placed in a 200 mL eggplant type flask, and 80 vol% aqueous acetonitrile solution (100 mL) was added and stirred. Further, ammonium acetate (6.0 g) was added thereto, and the mixture was reacted at 50 ° C for 96 hours, and then worked up in a usual manner to give a crude product. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was made into ethyl acetate/n-hexane (1/4) to be purified as a colorless oil. The form of the substance was obtained as a target of a rhododendrol derivative (1.3 g). 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-lipoxymethoxybutyl)phenyl palmitate

The rhododendrol (1.7 g) was placed in a 200 mL eggplant type flask, dissolved in pyridine (2 mL) and tetrahydrofuran (50 mL), and the lipid bismuth chloride (9.5 g) was added dropwise under ice cooling, and after 24 hours, it was carried out according to the usual method. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was separated into n-hexane to be separated and purified to obtain a target in a white crystal form. A tolitol derivative (3.7 g). 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, 29.0, 25.0, 24.8, 22.6, 19.9, 14.0

Production Example 7: 4-(4-hydroxyphenyl)-2-butyl palmitate

The rhododendrol (1.7 g) was placed in a 200 mL eggplant type flask, dissolved in pyridine (2 mL) and tetrahydrofuran (50 mL), and the lipid bismuth chloride (9.5 g) was added dropwise under ice cooling, and after 24 hours, it was carried out according to the usual method. deal with. The obtained crude product was subjected to a gel column chromatography (tank 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was purified by using n-hexane. The obtained purified product (1.0 g) was placed in a 200 mL eggplant type flask, dissolved in 100 mL of THF, and a 1N aqueous NaOH solution was added dropwise. After confirming the disappearance of the reactants by TLC, post-treatment was carried out according to a usual method. The crude product was dissolved in a 0.1N aqueous KOH solution, stirred at room temperature for 30 min and then extracted with ethyl acetate. After concentrating the ethyl acetate layer, it was subjected to silica gel column chromatography (silicone 60N: 100-210 μm; manufactured by Kanto Chemical Co., Ltd.), and the mobile phase was purified by using ethyl acetate/n-hexane (1/9). The white crystalline form gave the desired dodecanol derivative (0.5 g). 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)

The solubility test shown below was carried out using the azathiol derivative obtained in the above Production Examples 1 to 4. The rhodamine and 4-(3-hydroxybutyl)phenyl acetate were used as Comparative Comparative Examples 1 and 2.

To each of the compounds (0.1 g) of Production Examples 1 to 4 and Comparative Examples 1 and 2, a solvent (1 mL) shown in Table 1 below was added, and the mixture was heated at 40 ° C for 10 minutes, and then returned to room temperature. The supernatant solution of each solution was fractionated, and 50-fold dilution with ethyl acetate was used as a sample, and each solubility was evaluated by gas chromatography. The evaluation was carried out in the range of 10 to 100 mg/mL.

Analysis conditions:

Column: DB-1 (made by Agilent Technologies, 30m × 0.25mm × 0.25mm)

Oven: 130 ° C for 5 minutes, from 10 ° C / min from 130 ° C to 260 ° C

Detector: FID, 250 ° C

Sample introduction: Split, 250 ° C, Split racio 1:50, 1 μL

The results are shown in Table 1 below.

As is apparent from Table 1, the azaleafene derivative of the present invention is soluble in a low-polarity solvent as compared with Comparative Example 1 (duricol) and Comparative Example 2 (4-(3-hydroxybutyl)phenyl acetate). Sexual improvement. Further, from the comparison between Production Example 2 and Comparative Example 2, it was confirmed that when the sulfhydryl group was added to the rhododendron, the solubility was different depending on the addition position, and the present invention was more excellent in solubility than Comparative Example 2. In addition, it was confirmed that the solubility of DPG or ethanol in the production examples 1 to 4 was the same as in Comparative Examples 1 and 2, and it was confirmed that the present invention has a broad dissolution range for the general cosmetic base.

Test Example 2 (antibacterial test for general bacteria and fungi)

The antibacterial force test shown below was carried out using the retinol derivative obtained in the above Production Example 2. Tocopherol (Comparative Example 1) and phenoxyethanol (Comparative Example 3) were used as comparison targets.

‧experiment method

The antibacterial property was evaluated by measuring the minimum development inhibitory concentration (MIC, unit μg/mL) of various microorganisms shown in Table 2 according to the method of the Japanese Society of Chemotherapy Society Standard Method. In other words, the culture medium of the evaluation sample (Production Example 2 and Comparative Examples 1 and 3) was added so as to have a concentration in the range of 625 to 10000 μg/mL, and the proliferation of various microorganisms shown in Table 2 was evaluated using the medium. . In the medium and culture conditions, the Candida albicans of (3) is cultured under aerobic conditions at 25 ° C for 72 hours, and the soybean meal digestive juice is used for other conditions. After 48 hours of culture under the conditions, the proliferation of the cells was confirmed.

The results are shown in Table 3.

From the results of Table 3, it was confirmed that the allopurinol derivative of Production Example 2 has a lower MIC value than that of Comparative Example 2, and therefore all of the strains have a very high antibacterial activity. Further, compared with the phenoxyethanol of Comparative Example 3, the MIC value of the same degree was exhibited, and it was shown to be an antiseptic antibacterial agent which is as effective as the phenoxyethanol known from the general antiseptic antibacterial agent.

Test Example 3 (antibacterial test for acne prevention and improvement)

The antibacterial force test shown below was carried out using the retinol derivative obtained in the above Production Example 2. Tocopherol (Comparative Example 1) and resorcinol (Comparative Example 4) were used as comparison targets.

‧experiment method

The same test as in Test Example 2 was carried out. In other words, the culture medium of the evaluation sample (Production Example 2 and Comparative Examples 1 and 4) was added so as to have a concentration in the range of 625 to 10000 μg/mL, and the proliferation of Propionibacterium acnes was evaluated using these media. After the brain culture was cultured for 72 hours under anaerobic conditions at 37 ° C using the brain heart extract, the proliferative properties were confirmed.

The results are shown in Table 4.

As is clear from the results of Table 4, the retinol derivative of Production Example 2 has a very high antibacterial activity against Propionibacterium acnes as compared with Comparative Example 1 and Comparative Example 4.

Test Example 4 (external preparation for skin for acne skin)

The anti-acne effect was evaluated according to the evaluation method shown below according to the formulation shown in the following Table 5 to prepare an external preparation for skin for acne skin (mother lotion).

‧ Evaluation method (acne improvement effect)

Each of the 10 adults (5 males and 5 females) having acne on the face was set as one group, and each evaluation test was evaluated. Two times a day, morning and evening, after washing the face with the same face soap, blindly use each evaluation sample. The acne condition before the start of use and the use of the facial acne after 1 week will be compared with the visually identical photo photography, with "improvement", "slight improvement", "no change", "slightly worse", "deterioration" for symptom changes. The five stages were evaluated.

‧ Evaluation method (acne lesion improvement effect)

The evaluator of the above-mentioned "acne improvement effect" continued to use the sample continuously, and the state of the acne on the face after the start of the use was photographed in the same manner as the visual observation, and the state after one week was compared, and the change was "improved". The five stages of "slight improvement", "no change", "slightly worse" and "deterioration" were evaluated.

The results are shown in Table 5.

As is clear from the results of Table 5, the acne-improving effect and the acne-staining-improving effect of Example 1 were superior to those of Comparative Example 5.

Test Example 5 (Example of antibacterial force test for deodorizing action)

Using the rhododendhol derivative obtained in the above Production Example 2, the antibacterial force test shown below was carried out. Dophorenol (Comparative Example 1) was used as a comparison object.

‧experiment method

The same test as in Test Example 2 was carried out. In other words, the culture medium of the evaluation samples (Production Example 2 and Comparative Example 1) was added so as to have a concentration in the range of 625 to 10000 μg/mL, and the proliferation of Corynebacterium xerosis was evaluated using these media. The culture medium and the culture conditions were cultured under a good air condition at 30 ° C for 48 hours using a soybean casein digestive solution, and the proliferation was confirmed.

The results are shown in Table 6.

From the results of Table 6, it was revealed that the retinol derivative of Production Example 2 has a lower MIC value than the retinol of Comparative Example 1, and is therefore a superior anti-odor active agent having a very high antibacterial activity.

‧Test 6 (melanin production inhibition test)

Using the rhododendine derivative obtained in the above Production Example 1 and Production Example 2 and the rhododendrol (Comparative Example 1), the melanin production inhibition test shown below was carried out.

‧experiment method

B16 melanoma cells were seeded in 10 vol% of calf serum-containing MEM medium in a 12-well culture dish at 1 × 10 ⁴ /well, and cultured for 24 hours in a usual manner. After the preculture, the test medium to which the samples (Production Example 1 and Comparative Example 1) were added was exchanged, and culture was carried out for 72 hours. As the test medium, those who added theophylline to the above-mentioned pre-culture medium in an amount of 2 mmol/L were used. After the cultivation, it was dissolved in a 1 mol/L sodium hydroxide aqueous solution containing 10 vol% of dimethylhydrazine, and the OD475 value was measured as the amount of melanin. In addition, the total protein amount of the solution was quantified using a Coomasie Plus Protein Assay Reagent Kit (manufactured by PIERCE Co., Ltd.), and the amount of melanin per protein amount was calculated.

‧IC ₅₀ calculation

Melanin production inhibition rate (%) = (A-B) / A × 100

(Where, A: the amount of melanin per protein amount when no sample is added, and B: the amount of melanin per protein amount when the sample is added)

The concentration on the horizontal axis and the inhibition rate of the melanin production on the vertical axis were plotted, and the concentration (IC ₅₀ ) at which 50% of melanin was suppressed was determined from the graph.

The results are shown in Table 7.

As is clear from the results of Table 7, the allopurinol derivative of the present invention exhibited an equivalent melanin production inhibitory effect as compared with the terpene alcohol of Comparative Example 1.

Test 7 (whitening practical test)

The whitening practical test shown below was carried out using the azathiol derivative obtained in the above Production Examples 1 and 2 and the skin cream prepared with dobutyl alcohol.

‧experiment method

Sunlight was exposed to the summer sun for 3 hours (1 day, 1.5 hours, 2 consecutive days) on the skin of the wrist before the testee. After exposure to the skin of the left front wrist of the subject, the skin creams of Example 2 and Example 3 of Table 8 below were applied one by one for 13 consecutive days. Further, the skin cream of Comparative Example 6 of the following Table 8 was applied to the skin of the right front wrist of the subject in the same condition. At the end of the final application, the professional judges evaluated the degree of whitening before and after the use of the left and right front wrists. In addition, the evaluation department will recognize the person who has the whitening effect as "whitening effect" and indicate the number of people.

The results are shown in Table 9 below. From this result, it was found that the skin cream formulated with the azathiol derivative of the present invention is superior to the skin cream prepared with the antifungal alcohol of Comparative Example 6 in that the solubility in the oil agent is further improved, so that it is excellent. Whitening cosmetic. In the test period, the subjects who applied the skin cream in Examples 2 and 3 confirmed that the skin irritation reaction and the skin-sensing reaction did not occur, and it was confirmed that the present invention was even a preparation. The form is still safe.

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

(Note 10) Royal Jelly (manufactured by API company)

(Note 11) Aloe extract gel BG (made by Maruzen Pharmaceutical Co., Ltd.)

(Note 12) Cork Extract J (made by Maruzen Pharmaceutical Co., Ltd.)

The azathiol derivative of the present invention can be applied to the cosmetic preparations of Examples 4 to 18, and further, by using these, it can exhibit superior whitening action, antiseptic and antibacterial action, acne prevention, improvement and anti-odor action.

(industrial availability)

The azathiol derivative of the present invention can be applied to a wide range of dosage forms, such as lotions, lotions, creams, masks, bathing agents, and the like, by improving solubility. Further, since the rhododendrol derivative of the present invention has excellent whitening action, antiseptic and antibacterial action, acne prevention, improvement and odor resistance, by using a skin external preparation formulated with the azathiol derivative of the present invention, Very useful for skin beauty.

Claims (8)

A skin external preparation comprising a Rhododendrol derivative represented by the following general formula (1); (wherein R ¹ represents a fluorenyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or a fluorenyl group having 2 to 20 carbon atoms). A whitening cosmetic containing a rhodolacol derivative represented by the following general formula (1); (wherein R ¹ represents a fluorenyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or a fluorenyl group having 2 to 20 carbon atoms). A whitening agent containing as an active ingredient a toluene alcohol derivative represented by the following general formula (1); (wherein R ¹ represents a fluorenyl group having 2 to 20 carbon atoms, and R ² represents a hydrogen atom or a fluorenyl group having 2 to 20 carbon atoms). An antiseptic bactericidal agent comprising as an active ingredient a rhododendrol derivative represented by the following general formula (1a); (wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms). An external preparation for skin for acne skin, which comprises a rhododendamine derivative represented by the following general formula (1a); (wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms). An anti-odor external preparation for skin containing a rhodolacol derivative represented by the following general formula (1a); (wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms). An anti-odor agent containing as an active ingredient a rhododendamine derivative represented by the following general formula (1a); (wherein R ^1a represents a fluorenyl group having 2 to 4 carbon atoms). a rhododol derivative represented by the following general formula (1b); (wherein R ^1b and R ^2b each represent a fluorenyl group having 3 to 20 carbon atoms).