JPH05213857A - Melanin inhibitor - Google Patents

Abstract

PURPOSE:To obtain a melanin inhibitor, containing an aryl sulfide derivative as an active ingredient and excellent in improving effects on pigmentation and blending properties in cosmetic bases. CONSTITUTION:The objective melanin inhibitor is obtained by including a compound of the formula [R<1> to R<5> are H, OH or acetoxyl; X is lower alkyl, lower acyl, hydroxyphenyl, hydroxyphenylthio or CH2COCH2COR substituted with OH, carboxyl or lower alkoxy)], e.g. 2-(p-hydroxyphenylthio)ethanol as an active ingredient in an amount of 0.01-50wt.% in the total composition. The inhibitor can locally be applied to dermal stains, ephelides or sunburned pigmented parts of the skin to treat and improve the parts and return the skin to its normal color. This inhibitor can be prepared as a cosmetic in the form of a lotion, a milky lotion, a cream, an ointment, a stick, a pack, a get, etc. In the case of the cosmetic in the form of the cream or ointment, it is applied in an amount of 1-20mg per cm<2> skin surface. In the case of the cosmetic in the form of the liquid formulation, it is similarly applied in an amount of 1-10mg per cm<2> skin surface.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a melanin inhibitor containing an aryl sulfide derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Stain, freckles and pigmentation after sunburn are less likely to occur, increase or disappear with age.
It is a problem for the skin of middle-aged and older people. Although the pathogenic mechanism of these pigmentation disorders has not been clarified yet, it is considered that the melanin synthesis function in epidermal melanocytes is enhanced by the action of sunlight, especially ultraviolet rays, and melanocyte-stimulating hormone. In addition, it is considered that the delayed keratinization with aging of epidermal keratinocytes (keratinocytes) also causes an increase in the density of melanin granules in the epidermis, that is, a clinically symptomatic increase in pigmentation. In addition, these pigmented areas are localized and may be clearly different from the surrounding normal skin color.

There is a strong demand for a drug that restores these acquired pigments, that is, the melanin deposits to a normal skin color, and many drugs have been developed and commercialized. For example, in recent years, cosmetics using a vitamin C (L-ascorbic acid) derivative having an excellent reducing ability have been used, but it is difficult to be stable and almost no effect is observed when used externally. Met.

On the other hand, in Europe and America, hydroquinone is used as a drug for treating spots and whitening black skin, but this also has a problem in the safety (irritation and allergenicity) of the substance itself, and vitiligo. In some cases, there is a problem in that it is compounded as a drug. Other various melanin inhibitors have been reported, but isoflavone derivatives (JP-A-58-225004)
Or p-hydroxycinnamic acid as a cinnamic acid derivative (JP-A-59
-196813), p-hydroxycinnamic acid amide derivative (JP-A-62-56459), and the like. However, at present, no substance is known that has both an excellent pigmentation improving effect and an excellent blending property with a cosmetic base.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a melanin inhibitor having an effect of improving pigmentation and having excellent performance in terms of mixability with a cosmetic base.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to obtain a substance that reduces or eliminates pigmentation through research on the mechanism of melanin production. As a result, a specific aryl sulfide derivative has a melanin production inhibitory action. It was found that the present invention has been completed.

That is, the present invention has the following general formula (1)

[0008]

[Chemical 3]

[Wherein R ^{1 to} R ⁵ represent a hydrogen atom, a hydroxyl group or an acetoxyl group, and X represents a lower alkyl group, a lower acyl group, a hydroxyphenyl group, a hydroxy group substituted by a hydroxyl group, a carboxyl group or a lower alkoxy group. A phenylthio group or -CH ₂ COCH ₂ COR (wherein R represents a lower alkoxy group) is shown. ] A melanin inhibitor containing an aryl sulfide derivative represented by the following as an active ingredient. In the above general formula (1), the lower alkoxy group is an alkoxy group having 1 to 5 carbon atoms, for example, a methoxy group,
Examples thereof include ethoxy group, n-propoxy group, isopropoxy group, isobutoxy group, sec-butoxy group and the like. Examples of the lower alkyl group include an alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group and an isopropyl group. Examples of the lower acyl group include an acyl group having 1 to 5 carbon atoms, such as a formyl group, an acetyl group, a propionyl group and a butyryl group.

Examples of the aryl sulfide derivative (1) used in the present invention include 2- (p-hydroxyphenylthio) ethanol, p-hydroxyphenylthioacetic acid, 3- (p-hydroxyphenylthio) propionic acid, 3 -(p
-Hydroxyphenylthio) -1-propanol, 3- (o, p-dihydroxyphenylthio) -1-propanol, 1- (p-hydroxyphenylthio) -3-methoxy-2-propanol, 4-
Ethyl (p-hydroxyphenylthio) acetoacetate, 1- (p-
Hydroxyphenylthio) -2,5-pentanedione, O, S-diacetyl-p-hydroxythiophenol, 2- (m, p-dihydroxyphenylthio) ethanol, 3- (p-hydroxyphenylthio) -1,2 -Propanediol, bis (p-hydroxyphenyl) disulfide, bis (p-hydroxyphenyl)
Preferred are sulfide and the like. A particularly suitable compound may be 3- (o, p-dihydroxyphenylthio) -1-propanol.

The aryl sulfide derivative (1) can be synthesized according to the method described in the literature (for example, DE3207064 etc.) or in accordance with it. For example, according to the following reaction formula, the aryl sulfide derivative (1) is produced by reacting 1 equivalent of a halide with 1 equivalent of a thiophenol derivative in an alcohol in the presence of a base.

[0012]

[Chemical 4]

(R ^{1 to} R ⁵ and X have the same meanings as described above, and Y represents a chlorine atom, a bromine atom or an iodine atom.)

Among the aryl sulfide derivatives (1) thus obtained, a compound in which X is a lower alkyl group simultaneously substituted with a hydroxyl group and a lower alkoxy group, or --CH ₂ COCH ₂ COR is a novel compound not described in the literature. is there.

The above-mentioned aryl sulfide derivative (1) can be blended in the melanin inhibitor of the present invention alone or in combination of two or more thereof, and the blending amount thereof is 0.01 to 50% by weight in the whole composition. %, Especially 0.1 to 20% by weight is preferred.

The melanin inhibitor of the present invention can be in various forms, but in general, it is generally a lotion, an emulsion, a cream, an ointment, a stick, a solution with an organic solvent, a pack, or a gel. It is preferable to use such cosmetics.

The melanin inhibitor of the present invention may contain any component other than the aryl sulfide derivative (1) within a range that does not impair the effects of the present invention. Ingredients such as purified water, ethanol, oily substances, moisturizers, thickeners, preservatives, emulsifiers,
Medicinal ingredients, powders, fragrances, emulsion stabilizers, pH adjusters and the like can be added.

Specific examples of the oily component include liquid paraffin, petrolatum, paraffin wax, squalane, beeswax, carnauba wax, olive oil, lanolin, higher alcohols, fatty acids, synthetic ester oils of higher alcohols and fatty acids, silicone oils and the like. , As humectants sorbitol, xylitol, glycerin, maltitol, propylene glycol, 1,3-butylene glycol,
1,4-butylene glycol, sodium pyrrolidonecarboxylate, lactic acid, sodium lactate, polyoxypropylene fatty acid ester, polyethylene glycol and the like,
Examples of the thickener include carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl alcohol, carrageenan, water-soluble polymers such as gelatin, electrolytes such as sodium chloride and potassium chloride, and preservatives such as urea, methylparaben, ethylparaben and propyl. Paraben, butyl paraben, sodium benzoate and the like can be mentioned. As the emulsifier, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester. , Polyoxyethylene hydrogenated castor oil, nonionic surfactants such as polyoxyethylene sorbitol fatty acid ester, and powders such as talc and serisa. Door, mica, kaolin, silica,
Examples include bentonite, vermiculite, zinc white, mica, titanium mica, titanium oxide, magnesium oxide, zirconium oxide, barium sulfate, red iron oxide, iron oxide, ultramarine blue, and the like, and lactic acid-sodium lactate, citric acid-citric acid as pH adjusters. Examples include buffering agents such as sodium. In addition, as various active ingredients, allantoin, vitamin E derivative, glycyrrhizin, ascorbic acid derivative, kojic acid, arbutin, pantethenic acid derivative, placenta extract, anti-inflammatory agent, yoquinin, various plant extracts, etc. are added to suppress melanin. The effect can be improved. Further, by adding various ultraviolet absorbing substances, it is possible to obtain a cosmetic having both a sunburn preventing effect and a sunburn preventing effect.

The melanin inhibitor of the present invention is applied to the affected area such as skin inflammation caused by ultraviolet rays, stains, freckles, and pigmented area after sunburn to treat the area.
Can improve and return to normal skin color. In general, the dose is preferably 1 to 20 mg per 1 cm ^{2 of} the skin surface in the case of a cream or ointment-like preparation, and 1 to 10 mg in the case of a liquid preparation, but it is not limited to this. Absent.

[0020]

The present invention will be described below with reference to synthesis examples and formulation examples.

Synthesis Example 1 Synthesis of 3- (o, p-dihydroxyphenylthio) -1-propanol: (a) Synthesis of 6-hydroxy-1,3-benzoxathiol-2-one Resorcinol (11.0 g, 100 mmol ), Copper sulfate pentahydrate (74.9 g, 300 mmol) and 150 ml of water in a 500 ml flask containing ammonium thiocyanate (31.0 g, 407.5 mmol).
/ 60 ml of water was added dropwise at room temperature. The aqueous solution turned black from blue immediately. After reacting at room temperature for 8 hours, the mixture was filtered, and 24.8 g of the obtained brown solid was purified by silica gel chromatography (hexane / ethyl acetate = 5/1) to give 6-hydroxy-1,3-benzoxathiol-2- ON (10.1g, 60.1mmo
l) got. Yield 60.1%. Light yellow crystal mp 156.7-157.6 ° C ¹ H-NMR (200MHz, DMSO-d ₆ , TMS) δ: 6.8 (1H, d, J = 8.5Hz),
6.9 (1H, bs), 7.5 (1H, m), 10.0 (1H, bs) IR (cm ^-1 ,, KBr): 3400 (s), 1710 (s), 1620 (m), 1600 (w),
1460 (m) (b) 3- (o, p-dihydroxyphenylthio) -1-propanol synthesis In a 50 ml flask, under nitrogen atmosphere, 6-hydroxy-1,3-benzoxathiol obtained in (a) -2-on (2.5g, 14.9mmo
l) and 10 ml of water. 20 ml of 2N sodium hydroxide was added dropwise to this suspension solution, and the mixture was stirred at room temperature for 1 hour. After adding 3-chloro-1-propanol (1.4g, 14.9mmol),
The reaction was carried out at 50 ° C for 4 hours. After neutralization with 1.2N hydrochloric acid and extraction with ethyl acetate, 3.3 g of the residue obtained after distilling off the solvent was subjected to silica gel chromatography (hexane / ethyl acetate = 10/1 to 1/1 /).
Purified by 1), 3- (o, p-dihydroxyphenylthio)
-1-Propanol (2.6g, 12.9mmol) was obtained. Yield 86.5
%. Light yellow oily ¹ H-NMR (200 MHz, DMSO-d ₆ , TMS) δ: 1.6 (2H, m), 2.7 (2H, t,
J = 7.0Hz), 3.4 (2H, m), 4.4 (1H, bs), 6.2 (1H, s) IR (cm ^-1 ,, KBr): 3400 (s), 1710 (s), 1620 (m), 1600 (w),
1460 (m)

Synthesis Example 2 Synthesis of 2- (p-hydroxyphenylthio) ethanol: 50 ml
Add 10 ml of methanol and sodium hydroxide (0.8
g, 20.0mmol) and p-hydroxythiophenol (2.5g, 2
(0.0 mmol) was added, ethylene chlorohydrin (1.6 g, 20.0 mmol) was added at room temperature with stirring, and the mixture was reacted at 60 ° C. for 3 hours. Recrystallization (diethyl ether / hexane = 2 /
1) was carried out to obtain 2- (p-hydroxyphenylthio) ethanol (2.5 g, 14.9 mmol). Yield 74.5%. Colorless crystal mp 68.5 ~ 70.3 ℃ ¹ H-NMR (200MHz, CDCl ₃ , TMS) δ: 1.7 (1H, bs), 3.0 (2H, t, J
= 5.9Hz), 3.7 (2H, t, J = 5.9Hz), 5.3 (1H, bs), 6.8 (2H, d, J =
8.5Hz), 7.4 (2H, d, J = 8.6Hz) IR (cm ^-1 , KBr): 3400 (br), 3200 (br), 1600 (m), 1510
(s), 1250 (s)

Synthesis Example 3 Synthesis of 1- (p-hydroxyphenylthio) -3-methoxy-2-propanol: Methanol 10 ml, sodium hydroxide (0.8
g, 20.0 mmol), p-hydroxythiophenol (2.5 g, 20.
0mmol) and 3-methoxy-1,2-epoxypropane (1.8g, 2
0.0 mmol) was used and the reaction was carried out at room temperature for 4 hours in the same manner as in Synthesis Example 2. Silica gel chromatography (hexane / ethyl acetate = 2/1) was performed to give 1- (p-hydroxyphenylthio) -3-methoxy-2-propanol (3.7
g, 17.3 mmol) was obtained. Yield 86.5%. Colorless oil ¹ H-NMR (200MHz, CDCl ₃ , TMS) δ: 2.9 (1H, dd, J = 7.4Hz, J = 1
3.8Hz), 3.0 (1H, dd, J = 5.7Hz, J = 13.8Hz), 3.0-3.1 (1H, m),
3.36 (3H, s), 3.4 (1H, dd, J = 6.0Hz, J = 9.8Hz), 6.4 (1H, b
s), 6.7 (1H, d, J = 8.7Hz), 7.3 (1H, d, J = 8.7Hz) IR (cm ^-1 ,, NaCl): 3350 (br), 2950 (w), 1600 (m), 1510 (s)

Synthesis Example 4 Synthesis of p-hydroxyphenylthioacetic acid: Methanol 10 m
l, sodium hydroxide (1.6g, 40.0mmol), p-hydroxythiophenol (2.5g, 20.0mmol) and bromoacetic acid (2.8
g, 20.0 mmol) by the same procedure as in Synthesis Example 2
The reaction was carried out at ℃ for 3 hours. Recrystallize (ethyl acetate)
p-Hydroxyphenylthioacetic acid (2.4 g, 13.2 mmol) was obtained. Yield 66.0%. Colorless crystals mp 143.7-144.6 ° C ¹ H-NMR (200MHz, MeOH-d ₄ , TMS) δ: 3.5 (2H, s), 6.7 (2H, d,
J = 8.8Hz), 7.3 (2H, d, J = 8.7Hz) IR (cm ^-1 , KBr): 3200 (br), 1700 (s), 1600 (m), 1520 (m),
1240 (s)

Synthesis Example 5 Synthesis of 3- (p-hydroxyphenylthio) -1-propanol: Methanol 10 ml, sodium hydroxide (0.8 g, 20.0 mmo)
l), p-hydroxythiophenol (2.5 g, 20.0 mmol) and 3-chloro-1-propanol (1.9 g, 20.0 mmol) were used and the reaction was carried out at 60 ° C. for 4 hours in the same manner as in Synthesis Example 2. .. Recrystallization (CHCl ₃ ) was performed to obtain 3- (p-hydroxyphenylthio) -1-propanol (2.0 g, 10.9 mmol). Yield 5
4.5%. Colorless crystal mp 62.1-63.1 ° C ¹ H-NMR (200MHz, DMSO-d ₆ , TMS) δ: 1.6 (2H, m), 2.8 (2H, t,
J = 7.2Hz), 3.4 (2H, m), 4.5 (1H, t, J = 5.2Hz), 6.7 (2H, d, J =
8.6Hz), 7.2 (2H, d, J = 8.5Hz), 9.5 (1H, br) IR (cm ^-1 ,, KBr): 3250 (br), 1600 (w), 1500 (s)

Synthesis Example 6 Synthesis of ethyl 4- (p-hydroxyphenylthio) acetoacetate: Methanol 10 ml, sodium hydroxide (0.8 g, 20.0 mmo)
l), p-hydroxythiophenol (2.5 g, 20.0 mmol) and ethyl 4-chloroacetoacetate (3.3 g, 20.0 mmol) were used and the reaction was carried out at 50 ° C. for 4 hours in the same manner as in Synthesis Example 2. Purification by silica gel chromatography (hexane / ethyl acetate = 8/1) gave ethyl 4- (p-hydroxyphenylthio) acetoacetate (4.6 g, 18.0 mmol).
Yield 90.0%. Light yellow oily crystal ¹ H-NMR (200MHz, CDCl ₃ , TMS) δ: 1.3 (3H, t, J = 7.1Hz), 3.6
(2H, s), 3.7 (2H, s), 4.2 (2H, p, J = 7.1Hz), 6.2 (1H, bs),
6.7 (2H, d, J = 8.5Hz), 7.3 (2H, d, J = 8.5Hz) IR (cm ^-1 , KBr): 3450 (br), 3020 (w), 1750 (s), 1720 (s ),
1600 (m), 1520 (s)

Synthesis Example 7 Synthesis of O, S-diacetyl-p-hydroxythiophenol: 5
In a 0 ml flask, p-hydroxythiophenol (2.5 g,
20.0 mmol), sodium acetate (328 mg, 4.0 mmol) and 10 ml of chloroform were added, and acetic anhydride (2.0 g, 20.0 m) was added at room temperature.
mol) was added dropwise. After reacting at 50 ° C. for 4 hours, the mixture was neutralized with 1.2N hydrochloric acid, extracted with ether and the solvent was distilled off. Silica gel chromatography (hexane / ethyl acetate = 20 /
After purification by 1), recrystallization (diethyl ether / hexane) was performed to obtain O, S-diacetyl-p-hydroxythiophenol (1.6 g, 7.6 mmol). Yield 38.0%. Colorless crystals mp 63.9-65.5 ° C ¹ H-NMR (200MHz, CDCl ₃ , TMS) δ: 2.3 (3H, s), 2.4 (3H, s),
7.2 (2H, d, J = 8.6Hz), 7.4 (2H, d, J = 8.6Hz) IR (cm ^-1 ,, KBr): 1780 (s), 1720 (s), 1600 (w), 1520 (s )

Synthesis Example 8 Synthesis of 2- (m, p-dihydroxyphenylthio) ethanol: (a) S- (m, p-dihydroxyphenyl) isothiuronium acetate In a 300 ml flask, catechol (13.0 g, 118 mm) was added.
ol), thiourea (9.9g, 130mmol), sodium acetate (10
0 g, 1.2 mol) and 150 ml of water were added, and potassium hexacyanoferrate (III) (65 g, 197 mmol) / 100 ml of water was added dropwise at room temperature over 40 minutes. The reaction mixture turned brown. After reacting for 6 hours, the mixture was filtered, and the obtained off-white solid was dissolved in 1.2N hydrochloric acid. When sodium acetate was gradually added to this, crystals began to precipitate. After filtration and washing with methanol, S- (m, p-dihydroxyphenyl) isothiuronium acetate (18.9 g, 77.3 mmol) was obtained. Yield 66%. Brown crystals (b) 2- (m, p-dihydroxyphenylthio) ethanol under a nitrogen gas atmosphere, S- (m, obtained in (a) in a 30 ml flask.
p-Dihydroxyphenyl) isothiuronium acetate (2.0 g, 8.2 mmol) was added, 6N aqueous sodium hydroxide solution was added at room temperature, and the mixture was stirred at 80 ° C for 2 hr. After cooling to 50 ° C., ethylene chlorohydrin (1.4 g, 17.2 mmol) was added, and the mixture was reacted for 2 hours. After acidification, extraction with ethyl acetate and evaporation of the solvent gave 1.7 g of a brown oily residue. This oily substance was purified by silica gel chromatography (hexane / ethyl acetate = 1/1 to 1/10) to give 2- (m, p-dihydroxyphenylthio) ethanol (0.56 g, 3.0 mmol). Yield 36.6%. Colorless oily ¹ H-NMR (200 MHz, DMSO-d ₆ , TMS) δ: 2.8 (2 H, t, J = 7.0 Hz),
3.5 (2H, t, J = 7.0Hz), 6.7 (2H, s), 6.8 (1H, s), 9.0 (2H, br) IR (cm ^-1 ,, NaCl): 3400 (br), 1620 (m) , 1530 (s), 1300 (s)

Test Example 1 Evaluation by tyrosinase activity in organ-cultured mouse dorsal skin hair follicles or guinea pig dorsal skin: Dorsal hair follicles of C57BL mice aged 8 to 11 days, which are actively performing melanin synthesis, for 3 to 4 days Cultured. During the culture, an evaluation sample was added to the culture medium (final concentration 5 mM). After culturing, the activity of tyrosinase, an enzyme responsible for melanin synthesis, was measured by the amount of free tritium from ³ H-tyrosine, and compared with a control for evaluation. The results are shown in Table 1.

[0030]

[Table 1]

Test Example 2 A brown guinea pig having an acquired ability to form melanin pigment spots was used as an experimental animal, and after the formation of pigmentation, the effect of improving fading on pigmentation was examined. Test method: Using a brown guinea pig (a guinea pig whose skin color is similar to that of a yellow race, pigmented spots start to appear about 4 days after irradiation of ultraviolet rays like humans, and turn black most about 8 days later).
The back hair of each guinea pig was shaved with a hair clipper and further shaved with an electric razor. After intraperitoneal administration of 8-methoxypsoralen (PUVA) to this guinea pig, UVA (BLB lamp, 3.1 m
W / cm ² ) was irradiated for 5 minutes. PUV generated from 15 days after irradiation
A 5% solution of the evaluation sample (ethanol 80
%, Water 20%) was applied twice a day for a total of 24 days. The degree of blackening of the skin color was visually evaluated according to the following criteria, and the evaluation points were averaged to measure the effect. The results are shown in Table 2. Criteria: 0: No pigmentation is observed. 1: A slight pigmentation with unclear boundaries is observed. 2: Medium pigmentation with clear boundaries is recognized. 3: Clearly marked strong pigmentation is observed. result:

[0032]

[Table 2]

Formulation Example 1 Lotion type melanin inhibitor: (Composition) 3- (o, p-dihydroxyphenylthio) -1-propanol 5 (wt%) Glycerin 4 Polyoxyethylene hydrogenated castor oil 1.5 Ethanol 10 Pyrrolidonecarboxylic acid Sodium 2 Fragrance Micro purified water Remaining amount 100

Formulation Example 2 Oil essence type melanin inhibitor: (Composition) 3- (o, p-dihydroxyphenylthio) -1-propanol 5 (wt%) Mink oil 55 Wheat germ oil 40 100

Formulation Example 3 Powder Essence Type Melanin Inhibitor: (Composition) Ethyl 4- (p-hydroxyphenylthio) acetoacetate 5 (wt%) Mannitol 95 100

Formulation Example 4 W / O type moisturizing cream type melanin inhibitor: (Composition) Bis (p-hydroxyphenyl) disulfide 5 (wt%) Vaseline 4 Cholesterol 0.6 Cetanol 0.5 Sorbitane sesquioleate 2 Liquid lanolin 4 Isopropyl palmitate 8 Squalane 10 Solid paraffin 4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Perfume 0.2 Purified water balance 100

Formulation Example 5 O / W type moisture cream type melanin inhibitor: (Composition) Bis (p-hydroxyphenyl) disulfide 5 (wt%) Stearic acid 2 Cetanol 4 Vaseline 5 Squalane 8 Hardened palm oil 4 Polyoxyethylene ( 20) Sorbitan monostearate 1.4 Lipophilic glycerin monostearate 2.4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Dipropylene glycol 3 Potassium hydroxide 0.2 Perfume 0.2 Purified water balance 100

Formulation Example 6 Emulsion type melanin inhibitor: (Composition) 3- (o, p-hydroxyphenylthio) -1-propanol 5 (% by weight) Stearic acid 1 Cetanol 2 Vaseline 2.5 Squalane 4 Hardened palm oil 2 Polyoxy Ethylene (20) sorbitan monostearate 1.4 Lipophilic glycerin monostearate 1.2 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Dipropylene glycol 3 Potassium hydroxide 0.2 Carboxyvinyl polymer 0.2 Perfume 0.2 Purified water balance 100

Formulation Example 7 Pack type (paste peel-off type) melanin inhibitor: (Composition) Bis (p-hydroxyphenyl) sulfide 10 (wt%) Polyvinyl alcohol 12 Sodium carboxymethyl cellulose 3 Dipropylene glycol 2 Glycerin 2 Ethanol 5 Olive oil 3 Polyoxyethylene hydrogenated castor oil (30E.O.) 0.5 Titanium oxide 8 Kaolin 6 Perfume 0.1 Methylparaben 0.1 Purified water balance 100

Prescription Example 8 Ointment type melanin inhibitor: (Composition) Bis (p-hydroxyphenyl) sulfide 10 (wt%) White petrolatum 90 100

Formulation Example 9 Lotion-type melanin inhibitor: (Composition) Bis (p-hydroxyphenyl) sulfide 10 (wt%) Ethanol 90 100

[0042]

EFFECTS OF THE INVENTION The melanin inhibitor of the present invention has an excellent effect of improving pigmentation, and is applied locally to spots on the skin, freckles, and pigmented areas after sunburn to treat the area.
It is possible to improve and restore the normal skin color.
The aryl sulfide derivative (1), which is the active ingredient, is
It is excellent in compoundability with cosmetic bases.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] February 19, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

Test Example 1 Evaluation by tyrosinase activity in mouse dorsal skin hair follicles that had been organ-cultured: The dorsal hair follicles of 8 to 11-day-old C57BL mice that were actively performing melanin synthesis were cultured for 3 to 4 days. During the culture, an evaluation sample was added to the culture medium (final concentration 5 mM). After culturing, the activity of tyrosinase, an enzyme responsible for melanin synthesis, was measured by the amount of free tritium from ³ H-tyrosine, and compared with a control for evaluation. The results are shown in Table 1.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroko Shirokura 561-10 Yamamoto-cho, Utsunomiya City, Tochigi Prefecture (72) Inventor Tsuyoshi Kobayashi 4954 Kao-cho, Haga-gun, Tochigi Prefecture Kao Castle Dormitory E-101

Claims (2)

[Claims] 1. A general formula (1): [Wherein R ^{1 to} R ⁵ represent a hydrogen atom, a hydroxyl group or an acetoxyl group, and X represents a lower alkyl group substituted by a hydroxyl group, a carboxyl group or a lower alkoxy group, a lower acyl group,
Hydroxyphenyl group, hydroxyphenylthio group or
-CH ₂ COCH ₂ COR (where R represents a lower alkoxy group)
Indicates. ] A melanin inhibitor comprising an aryl sulfide derivative represented by the following as an active ingredient. 2. A compound represented by the general formula (1a): [Wherein R ^{1 to} R ⁵ are a hydrogen atom, a hydroxyl group or an acetoxyl group, X ′ is a lower alkyl group simultaneously substituted with a hydroxyl group and a lower alkoxy group, or —CH ₂ COCH ₂ COR (here,
R represents a lower alkoxy group). ] The aryl sulfide derivative represented by these.