JP2005263761A - Gentisic acid derivative and external preparation for skin using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a gentisic acid derivative having excellent bleaching effects; and to provide an external preparation for the skin. <P>SOLUTION: The gentisic acid derivative is represented by general formulas (1) or (2) (in the formulas, n is an integer of 1-22). The external preparation for the skin contains one or more of the gentisic acid derivatives. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel and gentisic acid derivative useful as a medicinal agent, and a skin external preparation using the same.

  Conventionally, it is known that gentisic acid (2,5-dihydroxybenzoic acid) has a whitening effect. Moreover, the application to the skin external preparation is proposed also about the specific derivative of gentisic acid (patent documents 1-3). However, in recent years, external skin preparations are required to have a higher medicinal effect, and some conventional agents do not necessarily have sufficient medicinal effects to meet the requirements. In addition, a topical skin preparation that is applied directly to human skin is required to have high safety, and it is possible to provide a medicinal agent having a high medicinal effect at a lower concentration, or a medicinal agent excellent in safety as well as medicinal properties. It has been demanded.

Japanese Patent No. 3081030 Japanese Patent No. 2722309 WO97 / 41825

  This invention makes it a subject to provide the skin external preparation which was excellent in the medicinal effect, especially the whitening effect, and also excellent in safety. Another object of the present invention is to provide a novel gentisic acid derivative useful as a medicinal agent, particularly as a whitening agent. In particular, it is an object of the present invention to provide a gentisic acid derivative which has good safety and exhibits an excellent whitening effect at a low concentration.

又は、下記一般式（２）：

式中、ｎは１〜２２の整数である；で表されるゲンチシン酸誘導体に関する。また、本発明は、上記ゲンチシン酸誘導体の１種又は２種以上を含有する皮膚外用剤；及び上記ゲンチシン酸誘導体を美白剤として含有する皮膚外用剤にも関する。 The present invention provides the following general formula (1):

Or the following general formula (2):

In the formula, n is an integer of 1 to 22, and relates to a gentisic acid derivative represented by: The present invention also relates to a skin external preparation containing one or more of the gentisic acid derivatives; and a skin external preparation containing the gentisic acid derivative as a whitening agent.

  From another point of view, according to the present invention, a skin whitening method using one or more selected from gentisic acid derivatives represented by the general formula (1) or (2); A method of inhibiting pigmentation using one or more selected from gentisic acid derivatives represented by 1) or (2); selected from gentisic acid derivatives represented by the general formula (1) or (2) A method of improving pigmentation using one or more selected from the above, or a skin comprising adding one or more selected from gentisic acid derivatives represented by the general formula (1) or (2) A method for producing an external preparation (preferably whitening cosmetic) is provided.

  In this specification, the term “whitening” is used to include not only a positive effect of whitening the skin but also a preventive effect of suppressing skin blackening. For example, it includes not only the effect of improving pigmentation such as spots and freckles but also the effect of suppressing pigmentation.

  ADVANTAGE OF THE INVENTION According to this invention, while being excellent in a medicinal effect, especially a whitening effect, the skin external preparation excellent also in safety | security can be provided. Moreover, according to this invention, the novel gentisic acid derivative useful as a medicinal agent, especially a whitening agent can be provided.

Hereinafter, the present invention will be described in detail.
The skin external preparation of the present invention contains one or more compounds represented by the following general formula (1) or the following general formula (2) (hereinafter sometimes referred to as “gentisic acid derivatives”).

式中、ｎは１〜２２の整数であり、好ましくは１〜８であり、より好ましくは１〜３である。ｎが８以下であると、皮膚への浸透性がより高くなるので、皮膚外用剤中に用いる場合に特に好ましい。

In formula, n is an integer of 1-22, Preferably it is 1-8, More preferably, it is 1-3. When n is 8 or less, the permeability to the skin becomes higher, and therefore it is particularly preferred when used in a skin external preparation.

  The compound represented by the general formula (1) can be synthesized using a conventionally known esterification reaction. For example, it can be synthesized by reacting gentisic acid with acid chloride, acid anhydride or acid amide (preferably acid chloride). There is no restriction | limiting in particular about the reaction solvent, It is preferable to use the organic solvent which can melt | dissolve starting materials, such as a gentisic acid and a nicotinic acid chloride. In order to improve the solubility of the starting material, two or more organic solvents may be mixed and used. Examples of the organic solvent that can be used include pyridine, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, and a mixed solvent of two or more thereof.

  In the general formula (1), the substitution position of the ester group with respect to the pyridine ring is not particularly limited, but from the viewpoint of easy availability of the raw material, the ester group is preferably in the 2-position or 3-position of the pyridine ring. The 2nd position is particularly preferred. In addition, other substitutable sites of the pyridine ring may be substituted with a substituent. Examples of the substituent include a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, a triazinyl group, and a carboxyl group in these heterocyclic rings. Or an aromatic group with an amino group.

  The compound represented by the general formula (2) can be synthesized using a conventionally known esterification reaction. For example, it can be synthesized by reacting gentisic acid with picolyl alcohol. An acid is preferably present in the reaction system, and examples of the acid include hydrochloric acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid. There is no restriction | limiting in particular about the reaction solvent. The starting material may be dissolved in a solvent, or may be dispersed or suspended. Usable organic solvents include toluene, xylene, and mixed solvents thereof.

  In the general formula (2), the substitutable portion of the pyridine ring may be substituted with a substituent. Examples of the substituent include a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, a triazinyl group, and a complex thereof. The aromatic group which attached | subjected the carboxyl group or the amino group to the ring is mentioned.

  In the present invention, the range of the gentisic acid derivative represented by the general formula (1) or (2) includes salts and solvates (including hydrates) of the gentisic acid derivative having an equivalent medicinal effect. ).

  The content of the gentisic acid derivative in the external preparation for skin of the present invention is preferably 0.00001 to 10% by mass (hereinafter simply indicated as “%”), more preferably 0.0001 to 1%. Within this range, the gentisic acid derivative can be stably blended and can exhibit excellent medicinal effects. Moreover, the said gentisic acid derivative has low toxicity, The skin external preparation containing the said gentisic acid derivative with content of this range can be safely applied to skin.

  The gentisic acid derivative alone has an excellent whitening effect, but the whitening effect can be further enhanced by using it together with other various whitening agents. Other various whitening agents include vitamin C derivatives such as ascorbic acid, ascorbic acid phosphate magnesium salt, ascorbic acid phosphate sodium salt, ascorbyl palmitate, ascorbyl glucoside; arbutin, kojic acid, ellagic acid, Linoleic acid is mentioned. Among these, when used in combination with one or more selected from the group consisting of ascorbic acid glucoside, ascorbic acid phosphate magnesium salt, ascorbyl palmitate and arbutin, the whitening effect is further enhanced. In addition to the above-exemplified examples, placenta extract, chamomile extract, licorice extract, age extract, oxon extract, seaweed extract, cucumber extract, coconut extract, gokahi extract, rice bran extract, wheat germ Extract, Saisin extract, Hawthorn extract, Sunpens extract, Shirayuri extract, Peonies extract, Sempukuka extract, Soybean extract, Tea extract, Molasses extract, Byaclen extract, Grape extract, Hop extract , Micaika extract, mokka extract, saxifrage extract, yokuinin extract and the like.

  The preferable range of the content of the other whitening agent in the external preparation for skin of the present invention varies depending on the use, but is generally preferably 0.001 to 20%, preferably 0.01 to 20%. It is more preferable that

  In the external preparation for skin of the present invention, in addition to the above components, components that are usually used in preparations such as cosmetics, quasi-drugs, and external pharmaceuticals, water (purified water, Hot spring water, deep water, etc.), oil agent, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film-forming agent, resin, clathrate compound, antiseptic, antibacterial agent, fragrance, Deodorant, salt, pH adjuster, freshener, UV protection agent, plant / animal / microbe extract, anti-inflammatory agent, cell activator, active oxygen remover, blood circulation promoter, astringent, antiseborrhea Agents, moisturizers, chelating agents, keratolytic agents, enzymes, hormones, vitamins and the like can be added as necessary.

  The oil is used as a component of the base or for the purpose of improving usability or feeling of use. Any of those used in normal cosmetics can be used, such as whether it is a natural oil or a synthetic oil, or whether it is a solid, semi-solid, liquid, etc. It doesn't matter about the properties. In the present invention, hydrocarbons, waxes, fatty acids, higher alcohols, ester oils, silicone oils, fluorine oils and the like can be used. More specifically, hydrocarbons such as liquid paraffin, squalane and petrolatum, synthetic ester oils such as cetyl tri-2-ethylhexanoate and pentaerythritol tetra-2-ethylhexanoate, olive oil, castor oil, jojoba oil , Mink oil, macadamia nut oil, apricot oil, persic oil, safflower oil, sunflower oil, avocado oil, medhome oil, camellia oil, almond oil, egoma oil, sesame oil, borage oil, shea butter and other plants and animals Derived oils and fats, waxes such as beeswax, carnauba wax, candelilla wax, and gay wax can be used.

  Alcohol is used for the purpose of dissolution, refreshing feeling, antiseptic, moisturizing and the like. Examples of alcohols that can be used in the present invention include lower alcohols such as ethanol; and various alcohols such as glycerin, diglycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol. And the like.

  The water-soluble polymer is used for stabilizing the system, improving usability or feeling of use, and also for obtaining a moisturizing effect. Examples of water-soluble polymers that can be used include plant polymers such as carrageenan, pectin, agar, locust bean gum, microbial polymers such as xanthan gum, animal polymers such as gelatin, and starch-based polymers such as starch. Examples include molecules, cellulosic polymers such as methylcellulose, carboxymethylcellulose, and hydroxypropylcellulose, alginic acid polymers such as sodium alginate, vinyl polymers such as carboxyvinyl polymer, and the like.

  Examples of antiseptics and antibacterial agents include benzoic acid, sodium benzoate, paraoxybenzoic acid ester, benzalkonium chloride, phenoxyethanol, isopropylmethylphenol, and the like.

  Examples of UV protection agents that can be used include para-methoxycinnamate-2-ethylhexyl, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5 sodium sulfate, 4-butyl-4 ′ -Methoxydibenzoylmethane, 2-phenyl-benzimidazole-5-sulfuric acid, titanium oxide, zinc oxide and the like.

  Anti-inflammatory agents are used for the purpose of suppressing inflammation such as hot flashes and erythema after sunburn. Examples of anti-inflammatory agents that can be used in the present invention include sulfur and its derivatives, tranexamic acid, glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, aloe extract, artea extract, ashitaba extract, arnica extract, Ginseng extract, nettle extract, duckweed extract, hypericum extract, chamomile extract, goldfish extract, watercress extract, comfrey extract, salvia extract, lion extract, perilla extract, birch extract, gentian Extracts and the like are included.

  The cell activator is used for the purpose of improving rough skin. Examples of cell activators that can be used in the present invention include caffeine, chicken crown extract, shell extract, shell extract, royal jelly, silk protein and its degradation product or derivatives thereof, lactoferrin or its degradation product, chondroitin Mucopolysaccharides such as sulfuric acid and hyaluronic acid or salts thereof, collagen, yeast extract, lactic acid bacteria extract, bifidobacteria extract, fermentation metabolic extract, ginkgo biloba extract, barley extract, assembly extract, thymus extract, Examples include carrot extract, rosemary extract, organic acids such as glycolic acid, citric acid, lactic acid, malic acid, tartaric acid, succinic acid, and derivatives thereof.

  The active oxygen scavenger is used for the purpose of suppressing oxidative damage such as lipid peroxide production suppression. Examples of active oxygen scavengers that can be used in the present invention include superoxide dismutase, mannitol, quercetin, catechin and derivatives thereof, rutin and derivatives thereof, bopi extract, yashajitsu extract, melissa extract, rahan extract, retinol And derivatives thereof, vitamin A such as carotenoid, thiamine and derivative thereof, riboflavin and derivative thereof, pyridoxine and derivative thereof, vitamin B such as nicotinic acid and derivative thereof, vitamin E such as tocopherol and derivative thereof, dibutylhydroxytoluene And butylhydroxyanisole.

  Examples of humectants include proteins such as elastin and keratin or derivatives thereof, hydrolysates and salts thereof, amino acids such as glycine, serine, aspartic acid, glutamic acid, arginine and theanine and derivatives thereof, sorbitol, erythritol, Trehalose, inositol, glucose, sucrose and derivatives thereof, dextrin and derivatives thereof, saccharides such as honey, D-pantenol and derivatives thereof, urea, phospholipid, ceramide, lauren extract, ginger extract, diautum extract, senkyu extract Products, mallow extracts, gypsophila extracts, dodami extracts, hamamelis extracts, bodaige extracts, maronier extracts, quince extracts and the like.

  Examples of the formulation of the external preparation for skin of the present invention are not particularly limited. For example, emulsions, creams, lotions, cosmetics, packs, cleaning products, makeup cosmetics, dispersions, ointments, solutions, aerosols, patches Any form of cosmetics such as pills, poultices, liniments and the like may be external medicines.

EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to the following examples.
[Example 1: Synthesis of compound (1) (pyridine-2-carboxylic acid-3-carboxy-4-hydroxyphenyl ester)]
Compound (1) was synthesized by the following method.

In a nitrogen atmosphere, a dry dimethylformamide (50 mL) solution containing 10 g (64 mmol) of gentisic acid in a mixture of dry dimethylformamide (50 mL) and dry pyridine (20 mL) in which 11.4 g (64 mmol) of picolinic acid chloride was dissolved was required. The solution was added dropwise and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, and then the crude reaction oil was suspended in methanol and filtered. The obtained filtrate was evaporated, suspended in methanol, and filtered off until no crystals precipitated. The obtained oily solid was recrystallized from methanol to obtain 2.2 g (yield: 13.1%) of the desired compound (1).
Identification was performed by IR.
IRν _max (KBr) cm ⁻¹ : 3500, 1730, 1676, 1626, 1497, 1452.
The IR measurement results are shown in FIG.

[Example 2: Synthesis of compound (2) (pyridine-3-carboxylic acid-3-carboxy-4-hydroxyphenyl ester)]
Compound (2) was synthesized by the following method.

Under a nitrogen atmosphere, a solution of 10 g (64 mmol) of gentisic acid in 50 mL of dry dimethylformamide (50 mL) dissolved in 11.4 g (64 mmol) of nicotinic acid chloride hydrochloride was mixed with 30 g of dimethylformamide (50 mL). The mixture was added dropwise and stirred for 12 hours at room temperature. After completion of the reaction, the solvent was distilled off, and then the crude reaction oil was suspended in methanol and filtered. The obtained filtrate was evaporated, suspended in methanol, and filtered off until no crystals precipitated. The obtained oily solid was recrystallized from methanol to obtain 4.2 g (yield 25%) of the desired compound (2).
Identification was performed by IR.
IRν _max (KBr) cm ⁻¹ : 3485, 1731, 1591, 1491.
The IR measurement results are shown in FIG.

[Example 3: Synthesis of compound (3) (2,5-dihydroxybenzoic acid pyridin-3-ylmethyl ester)]
Compound (3) was synthesized by the following method.

2 g (12.8 mmol) of gentisic acid, 1.4 g (12.8 mmol) of picolyl alcohol, and 250 mg of p-toluenesulfonic acid were suspended in dry toluene (50 mL) and heated to reflux at 140 ° C. for 12 hours. After completion of the reaction, the temperature was returned to room temperature. The solvent was distilled off, and the resulting crude reaction oil was fractionated and purified by open column chromatography (mobile phase: chloroform: methanol = 95: 5) to obtain the target compound (3) as 1. 5 g (yield 42%) was obtained.
Identification was performed by IR.
IRν _max (KBr) cm ⁻¹ : 3500, 1691, 1641, 1596, 1482, 1442, 1407.
The IR measurement results are shown in FIG.

[Test Example 4: Melanin production inhibition test by cultured cells]
An appropriate amount of 10% FBS-containing MEM medium was taken in two 6-well plates, seeded with B16 melanoma cells, and allowed to stand at 37 ° C. in a carbon dioxide concentration of 5%. The next day, each of the dimethyl sulfoxide solutions of compounds (1) and (3) prepared in Examples 1 to 3 and only dimethyl sulfoxide were added to the medium. For compound (1), the sample preparation solution was added and mixed so that the final concentrations were 0 (control), 0.095, 0.19, and 0.38 μmol / mL. For compound (3), the sample preparation solution was added and mixed so that the final concentrations were 0 (control), 0.0016, and 0.004 μmol / mL. On day 5 of the culture, the medium was changed, and the sample preparation solution was added again. On the next day, the medium was removed and the cells were collected after washing with phosphate buffer on one plate, and the degree of whiteness of the cultured B16 melanoma cells was evaluated according to the following criteria. The results for compound (1) are shown in Table 1, and the results for compound (3) are shown in Table 2.

As a comparative example, the same test was conducted for gentisic acid, which is known to have a melanin production inhibitory effect, and the following compounds A, B and C. The compounds A and B were tested under the same concentration conditions as the compound (1), the compound C was tested under the same concentration conditions as the compound (3), and gentisic acid was tested under both concentration conditions. The respective results are shown in Table 1 or Table 2.
Compound A (compound described in Japanese Patent No. 2722309) was a commercially available product (manufactured by ACROS ORGANICS). Compound B was synthesized according to the method described in WO / 97/41825 and compound C was synthesized according to the method described in Japanese Patent No. 3081030.

(Criteria)
++: Clearly white relative to the control.
+: White relative to the control ±: Slightly white relative to the control
-: The same black color as the control.

ｎ．ｄ．：not detected(判定できず)。具体的には、化合物の毒性が高く、細胞生育率が低いので、回収できる細胞数が少なくなり、上記判定（対照と比較した色の評価）ができない場合である。

n. d. : Not detected (cannot be judged). Specifically, since the toxicity of the compound is high and the cell growth rate is low, the number of cells that can be collected decreases, and the above determination (evaluation of the color compared to the control) is not possible.

Further, for the remaining one plate, cells were fixed with formalin, added to a 1% crystal violet solution, and stained. The viable cell ratio with respect to each sample concentration was measured with a monocerator (manufactured by Olympus).
The results of cell growth rate at a concentration of 0.38 μmol / mL for compound (1), A, B and gentisic acid are shown below, and 0.004 μmol / mL for compound (3), C and gentisic acid. The results of cell growth rate at the concentration are shown in Table 3 and Table 4, respectively.

From the results shown in Tables 1 to 4, the following was shown.
First, from the results shown in Table 1, the compound (1) of the present invention had a melanin production inhibitory effect that was markedly superior to that of gentisic acid at the same concentration, and was excellent in the whitening effect. Further, the compound (1) had an excellent whitening effect even more than the known compounds A and B, which are known to have a whitening effect. Furthermore, from the results of Table 3, it was found that the cell growth rate of the compound (1) of the present invention was higher than the cell growth rates of the known compounds A and B of the same concentration. From these results, it was found that the compound (1) of the present invention has an excellent whitening effect and low toxicity to B16 melanoma cultured cells as compared with known gentisic acid derivatives A and B of the same concentration. .
On the other hand, from the results of Table 2, the compound (3) also showed an excellent whitening effect as compared with the known compound C, which is known for the whitening effect. Furthermore, from the results in Table 4, it was found that the cell growth rate of the compound (3) of the present invention was much higher than that of the known compound C having the same concentration. Compound C was highly cytotoxic in the range of 0.0014 to 0.004 μmol / mL, and the whitening effect could not be evaluated. When the concentration of Compound C was decreased from 0.0014 μmol / mL, the cell growth rate was sufficiently increased, but no whitening effect was observed in such a concentration range. From these results, it was found that the compound (3) of the present invention was superior in whitening effect and low in toxicity to B16 melanoma cultured cells as compared with the known gentisic acid derivative C of the same concentration.
Therefore, the skin external preparation of the present invention containing the compound (1) or (3) of the present invention can be safely applied to the skin, and exhibits an extremely excellent melanin production inhibitory effect when applied to the skin. In addition, it is possible to effectively suppress whitening of skin, spots, freckles, and the like caused by sunburn, thereby obtaining whitening and skin-beautifying effects.

Next, an example of a gentisic acid derivative to an external preparation for skin will be shown.
[Example 5: lotion]
The following components (3) to (5) and (9) to (11) were mixed and dissolved, and components (1), (2), (6) to (8) and (12) were mixed and dissolved. The solution was mixed and uniformed to obtain a skin lotion.
(Ingredient) (%)
(1) Glycerin 5.0
(2) 1,3-butylene glycol 6.5
(3) Polyoxyethylene (20E.O.) sorbitan 1.2
Monolaurate (4) Ethyl alcohol 8.0
(5) Compound (1) * 1 0.005
(6) Magnesium L-ascorbate phosphate * 2 0.5
(7) Lactic acid 0.05
(8) Sodium lactate 0.1
(9) Paramethoxycinnamic acid-2-ethylhexyl 3.0
(10) Preservative Appropriate amount (11) Fragrance Appropriate amount (12) Purified water Remaining amount * 1 Made in Example 1 * 2 Sigma

[Example 6: Latex]
The following components (13), (16) and (18) were heated and mixed, and the mixture A maintained at 70 ° C. was heated and mixed with the components (1) to (9), (12) and (15), and 70 ° C. The mixture B kept at 1 was added and mixed, and uniformly emulsified to obtain an emulsion C. After cooling this emulsion C, components (10) and (11) are added and mixed uniformly. Further, component (14) is added, and the mixture is sufficiently stirred. Further, (17) is added and mixed uniformly. An emulsion was obtained.
(Ingredient) (%)
(1) Polyoxyethylene (10E.O.) sorbitan 1.0
Monostearate (2) Polyoxyethylene (60EO) Sorbit 0.5
Tetraoleate (3) Glyceryl monostearate 1.0
(4) Stearic acid 0.5
(5) Behenyl alcohol 0.5
(6) Squalane 8.0
(7) Retinol palmitate * 1 0.002
(8) Dipotassium glycyrrhizinate * 2 0.3
(9) Compound (2) * 3 0.02
(10) Daylily extract * 4 0.1
(11) Hyaluronic acid 0.1
(12) Preservative 0.1
(13) Carboxyvinyl polymer 0.1
(14) Sodium hydroxide 0.05
(15) Ethyl alcohol 5.0
(16) Purified water remaining amount (17) Fragrance appropriate amount (18) Zinc oxide * 5 5.0
* 1 Nippon Roche * 2 Sigma * 3 Manufactured in Example 2 * 4 Maruzen Pharmaceutical * 5 Sigma

[Example 7: Cream]
The following components (1) to (12) were heated and mixed, and the mixture A maintained at 70 ° C. was heated and mixed with the following components (13) to (17) and (20) to (22) and maintained at 70 ° C. The mixture was mixed with the mixture B and uniformly emulsified to obtain an emulsion C. After cooling this emulsion C, components (18) and (19) were added and mixed uniformly to obtain a cream.
(Ingredient) (%)
(1) Cetostearyl alcohol 3.0
(2) Glycerin fatty acid ester 2.0
(3) Polyoxyethylene monooleate (20) sorbitan 1.0
(4) Sorbitan monostearate 1.0
(5) N-stearoyl-N-methyltaurine sodium 0.5
(6) Vaseline 5.0
(7) Dimethylpolysiloxane (100 mm ² / s) 3.0
(8) Glyceryl tri-2-ethylhexanoate 20.0
(9) dl-α-tocopherol * 1 1.0
(10) Compound (2) * 2 0.001
(11) Compound (3) * 3 0.05
(12) Ellagic acid * 4 0.05
(13) Lactic acid (50% aqueous solution) 1.0
(14) Dipropylene glycol 10.0
(15) Arbutin * 5 3.0
(16) Sodium citrate 0.5
(17) L-ascorbic acid-2-glucoside * 6 0.1
(18) Titanium oxide 0.1
(19) Perfume appropriate amount (20) Disodium edetate 0.03
(21) Preservative Appropriate amount (22) Remaining amount of purified water * 1 Eisai * 2 Manufactured in Example 2 * 3 Manufactured in Example 3 * 4 Manufactured by Sigma * 5 Manufactured by Wako Pure Chemicals * 6 Toyo Seika Made by company

  The cosmetics prepared in Examples 5, 6 and 7 had an extremely excellent whitening effect when applied to the skin, and also had good safety and stability.

  The gentisic acid derivative of the present invention is a component that exhibits an excellent melanin production inhibitory effect and is also excellent in safety. Therefore, it can be blended into a wide range of preparations for external preparations for skin such as cosmetics, quasi-drugs, and pharmaceuticals, and is useful as a whitening component for external preparations for skin. The external preparation for skin of the present invention containing such a gentisic acid derivative is excellent in whitening effect and excellent in safety.

Claims (3)

The following general formula (1):

Or the following general formula (2):

In the formula, n is an integer of 1 to 22; A skin external preparation containing one or more of the gentisic acid derivatives according to claim 1. The external preparation for skin according to claim 2, comprising the gentisic acid derivative according to claim 1 as a whitening agent.