JPH08283119A - Skin lightener - Google Patents

Abstract

PURPOSE: To obtain a skin lightener and a skin cosmetic which have excellent skin-lightening effect and can prevent and treat skin spots and ephelis caused by sun burn by using a specific sulfonamide. CONSTITUTION: A sulfonamide of formula I [R<1> is H, an alkyl, an alkoxy, an alkylthio; R<2> is H, a halogen, an alkoxy, CF3 ; R<3> is H, OH, a halogen, an alkylthio, a cycloalkyl, CF3 , an alkoxy where R<2> and R<3> may form butadienyl; R<4> is H, an alkyl, an aryl; R<5> is H, an alkanoyl, benzoyl; R<6> is formula II (R<7> is H, an alkoxy; R<8> is H, a halogen, an alkyl where R<7> and R<8> may form butadienyl), formula III (R<9> is H, a halogen, an alkyl; R<10> is H, an alkyl, an alkoxy); X, Y are each O, S, NH; (n) is 2-4] is used. The skin cosmetic contains the sulfonamide of formula I in an amount of 0.0001-10wt.%. The skin lightener inhibits the melanin formation in melanocytes.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a whitening agent and a skin cosmetic, and more particularly to a whitening cosmetic having an excellent skin whitening effect and capable of preventing and treating spots and freckles caused by sunburn and the like.

[0002]

2. Description of the Related Art Pigments, freckles, and pigmentation on the skin after sunburn are less likely to occur, increase, or disappear with age, which is a problem for middle-aged and older people. Although the pathogenic mechanism of these pigmentation diseases has not been clarified yet,
It is considered that the mechanism of melanin synthesis in epidermal melanocytes was enhanced by the action of sunlight, especially ultraviolet rays, and melanocyte-stimulating hormone.

Further, it is considered that the delay of keratinization of epidermal keratinocytes (keratinocytes) with aging causes an increase in the density of melanin granules in the epidermis, that is, a clinically symptomatic increase in pigmentation. These pigmented areas are localized and may be distinctly different from the surrounding normal skin color.

Therefore, there is a strong demand for the development of a drug capable of recovering such an acquired pigment (ie, melanin) deposit to a normal skin color, and many drugs have been commercialized so far. For example, in recent years, cosmetics containing a vitamin C (L-ascorbic acid) derivative having excellent reducing ability have been used. However, this also has a drawback in that the stability is difficult and the effect is hardly recognized when used externally.

On the other hand, in Europe and America, hydroquinone is used as a medicine for treating spots and whitening black skin, but these also have a problem in safety (irritation, allergy) of the substance itself, Further, there is a problem in compounding it as a drug in that it may cause vitiligo. In addition, various external skin preparations such as isoflavone derivatives (Japanese Patent Laid-Open No. 58-225004) and
A p-hydroxycinnamic acid derivative as a cinnamic acid derivative (JP-A-59-196813) and the like are known.

[0006]

However, at present, no substance has been known which has a substantial effect of preventing / improving pigmentation and an excellent compoundability with a cosmetic base.

Therefore, it has been desired to develop a whitening agent having a skin whitening effect and capable of preventing and treating spots and freckles caused by sunburn and the like.

[0008]

Under these circumstances, the present inventors have conducted extensive studies to obtain a substance that reduces or eliminates pigmentation through research on the mechanism of melanin production, and as a result, it is represented by the following general formula (1). The present inventors have completed the present invention by discovering that sulfonamide has a substantial skin pigmentation preventing / ameliorating effect and an excellent skin whitening effect.

That is, the present invention is represented by the following general formula (1):

[0010]

Embedded image

[Wherein R¹Is a hydrogen atom, lower alkyl,
Lower alkoxy, lower alkylthio, halogen atom or
Indicates trifluoromethyl, R²Is hydrogen atom, halogen
Atom, lower alkoxy, hydroxy lower alkoxy or
Indicates trifluoromethyl, R ³Is a hydrogen atom,
Si, halogen atom, alkylthio, cycloalkyl,
Droxy lower alkyl, hydroxy lower alkoxy,
Droxymino lower alkyl, lower alkenyl, oxo low
Grade alkyl, trifluoromethyl, trifluoromethoxy
Si, lower alkoxy, lower alkoxy lower alkoxy or
Represents aryl lower alkoxy, or R²
And R³Together represent butadienyl, R
^FourIs a hydrogen atom, lower alkyl, aryl or heteroari
R,^FiveIs a hydrogen atom, lower alkanoyl, benzene
Zoyl, heterocyclylcarbonyl or tetrahydropyro
Rani-2-l, R⁶Is the formula (2) or (3):

[0012]

[Chemical 4]

Is a residue of R⁷Is a hydrogen atom,
Indicates Coxy or Nitro, R⁸Is hydrogen atom, halogen atom
Child, lower alkyl, lower alkoxy, lower alkyl
O, nitro, hydroxy, amino or trifluoroethyl
Showing R or R⁷And R⁸Together
Represents butadienyl, R⁹Is a hydrogen atom, halogen, lower
Alkyl, lower alkoxy, lower alkylthio or tri
Represents fluoromethyl, R ^TenIs hydrogen atom, halogen atom
Child, lower alkyl, lower alkoxy or lower alkyl group
And X and Y are each independently O, S or NH.
And n is 2, 3 or 4. ]

The present invention provides a whitening agent comprising a sulfonamide represented by and a skin cosmetic containing the compound.

Sulfonamide (1) used in the present invention
Is a known compound (Japanese Unexamined Patent Publication No. 5-155864), but nothing was known about its inhibition of melanin production.

The term "lower" as used herein means a group having 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Alkyl, alkoxy, alkylthio and alkenyl groups, and alkyl groups as a constituent of alkanoyl groups can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary butyl are examples of such alkyl groups. Vinyl and allyl are examples of alkenyl groups. Aryl lower alkoxy is, for example, benzyloxy. Halogen represents fluorine, chlorine, bromine and iodine,
Chlorine is preferred. Examples of aryl residues are phenyl and substituted phenyl residues, halogen, alkyl and alkoxy being especially considered as substituents. Examples of heteroaryl residues are in particular monocyclic 5- and 6-membered heteroaromatic residues having nitrogen or sulfur as heteroatoms, such as pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl and thienyl. Heterocyclyl-carbonyl residues are, for example, 2-, 3- or 4-pyridylcarbonyl, 3-methylisoxazol-5-ol-carbonyl, 2- or 3-furoyl, and 2- or 3-
It's Tenoil.

In the present invention, among the sulfonamides represented by the general formula (1), N- [5- (p-
Chlorophenyl) -6- (2-hydroxyethoxy)-
4-Pyrimidinyl] -α, α, α-trifluoro-p-
Toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5. -(O
-Methoxybenzyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, pt-butyl-N
-[6- (2-Hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-
(O- (methylthio) benzyl) -4-pyrimidinyl]
-P-isopropylbenzenesulfonamide, N- [6
-Hydroxyethoxy-5-p-tolyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide and pt-butyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] Benzenesulfonamide is preferred.

In the skin cosmetic of the present invention, the sulfonamide (1) is 0.0001 to 10% by weight, and particularly 0.001 to
It is preferable to add 5% by weight.

Further, in the skin cosmetic of the present invention, in addition to the sulfonamide (1), various optional components used in ordinary cosmetics, quasi drugs, pharmaceuticals, etc., such as oils, moisturizers, thickeners, etc. Agents, preservatives, emulsifiers, pigments, powders, pH adjusters,
Antioxidants, fragrances, emulsion stabilizers and the like can be appropriately added.

Specific examples of the oil agent 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. Moisturizers include sorbitol, xylitol, glycerin, maltitol, propylene glycol, sodium pyrrolidone carboxylic acid, polyoxypropylene fatty acid ester, polyethylene glycol, and the like, and thickeners include carboxyvinyl polymer, carboxymethylcellulose, polyvinyl alcohol, carrageenan. , Water-soluble polymers such as gelatin, electrolytes such as sodium chloride and potassium chloride, and preservatives such as methylparaben, ethylparaben, propylpa Ben, 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. , Nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol fatty acid ester, etc., powders such as talc, sericite, mica, kaolin, silica, bentonite, vermiculite, zinc white, mica, mica. Examples include titanium, titanium oxide, magnesium oxide, zirconium oxide, barium sulfate, red iron oxide, iron oxide, ultramarine blue, and the like, and examples of pH adjusters include buffering agents such as citric acid-sodium citrate. To be

Also, 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. should be added. Thereby, the melanin suppressing effect can be improved. Furthermore, the addition of various ultraviolet absorbing substances can improve the sunburn preventing effect.

The skin cosmetics to which the present invention is applied are not limited to general skin cosmetics, but include medicated cosmetics and the like. The skin cosmetics of the present invention can be prepared in various forms by conventional methods, but generally they are lotions, emulsions, creams, ointments, sticks, solutions with organic solvents, packs, gels. It is preferable to have a shape.

[0023]

The whitening agent of the present invention comprising sulfonamide (1) exhibits excellent melanin pigmentation preventing / ameliorating effect by suppressing melanin production of melanocytes,
Skin cosmetics containing the compound exhibit an excellent skin whitening effect and are extremely useful for the prevention and treatment of spots and freckles due to sunburn and the like.

[0024]

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. The following samples were used as the samples in the following examples. Compound-a: N- [5- (p-chlorophenyl) -6-
(2-Hydroxyethoxy) -4-pyrimidinyl]-
α, α, α-trifluoro-p-toluenesulfonamide. Compound-b: N- [6- (2-hydroxyethoxy)-
5- (p-methoxyphenyl) -4-pyrimidinyl]-
p-isopropylbenzenesulfonamide. Compound-c: N- [6- (2-hydroxyethoxy)-
5- (o-methoxybenzyl) -4-pyrimidinyl]-
p-isopropylbenzenesulfonamide. Compound-d: pt-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-
Pyrimidinyl] benzenesulfonamide. Compound-e: N- [6- (2-hydroxyethoxy)-
5- (o- (methylthio) benzyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide. Compound-f: N- [6-hydroxyethoxy-5-p-
Tolyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide. Compound-g: pt-butyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl]
Benzenesulfonamide.

Example 1 Effect of Cultured Human Melanocytes on Melanin Production: According to the following test method, samples of various concentrations were added to a culture plate of normal human melanocytes to examine the effect on cell melanin production. The results are shown in Table 2.

[Test Method] Normal human melanocytes commercially available from Clontakes were subcultured according to a conventional method and subjected to the present test. A sample was added to this cell culture plate so that the final concentration was 0.00001 to 100 μM, and the effect of melanocytes on melanin production after a certain period was examined. The effect on melanin production was evaluated by collecting cells at a sample concentration of 10 μM, visually observing the color tone of the cell pellet, and assigning evaluation points of 1 to 4. The color tone was determined according to the criteria shown in Table 1 below. The evaluation was shown by the average of the evaluation points of 10 culture plates. Further, in the determination of the color tone, as a control, the solvent used for dissolving the sample was added to the culture solution so as to have the same concentration, and this was used.

[0027]

[Table 1]

[Results] As shown in Table 2, by visual inspection of the color tone of the cell pellet, clear whitening of cells was observed at a concentration of 0.01 μM or more. From the above results, an inhibitory effect on the melanin production of cultured human melanocyte-producing cells was confirmed.

[0029]

[Table 2]

Example 2 Extinction effect of UV-B pigment spots on the back of brown guinea pigs: The extinction effect on UV-B pigment spots was examined according to the following test method. The results are shown in Table 4.

[Test method] The back hair of 20 brown guinea pigs was carefully shaved with a hair clipper and a shaver, and then U
Double the amount of UV rays in the VB region to the minimum erythema dose (MED)
Irradiate once a day for 3 days to induce pigment spots 2 times a day
Once, the amount of pigment spot extinction was examined by continuously applying a 1 wt% concentration sample to the test site for 1 month. For evaluation, the L * value was calculated from the Munsell value obtained by measuring with a color difference meter, and the ΔL * (change with time) of the sample-coated portion was changed to the ΔL * (change with time of the sample) where the sample was not applied (solvent only = control). )
The value (ΔΔL *) obtained by subtracting In addition, ΔΔL * is expressed by the following formula, and the result is shown as an average value of the evaluation points of 20 test animals.

ΔΔL * = (L * ₁ −L * ₀ ) − (L ′ * ₁ −L ′ * ₀ ) L * ₀ : sample application test site before application L ′ * ₀ : sample unapplication test before application Site L * ₁ : Sample application test site 1 month after continuous application L '* ₁ : Sample non-application test site 1 month after continuous application

[0033]

[Table 3]

[Results] As shown in Table 4 below, clear discoloration of pigment spots was observed by application of this sample as compared with the control.

[0035]

[Table 4]

From the above results, it was revealed that this sample has a melanin production and a fading effect on UV-B-induced pigment spots, suggesting its usefulness as a whitening agent.

[0037]

Table 3 Example 3 (Emulsion) (Composition) (wt%) (1) Polyoxyethylene sorbitan tristearate 1.0 (2) Glycerol oleate 1.0 (3) Glycerin monostearate 0.5 ( 4) Squalane 5.0 (5) Glyceryl trioctanoate 2.0 (6) Dimethylpolysiloxane (50cs) 0.2 (7) Cetyl octanoate 1.5 (8) Stearyl alcohol 2.0 (9) Methoxycinnamate Octyl acid 2.0 (10) Butyl paraoxybenzoate 0.1 (11) 1,3-Butylene glycol 5.0 (12) Glycerin 3.0 (13) Xanthan gum 0.2 (14) Tetrasodium edetate 0. 1 (15) Sodium citrate 1.0 (16) Compound-e 1.0 (17) Glycine 0.5 (18) Methyl paraoxybenzoate 0.1 (19) Ion-exchanged water Part

(Preparation Method) The oil phase components (1) to (10) heated and dissolved at 80 ° C. were added to the aqueous phase components (11) to (19) heated to 80 ° C. with stirring to emulsify. Then, cool to room temperature with stirring.

[0039]

Table 6 Example 4 (lotion) (composition) (wt%) (1) 1,3-butylene glycol 8.0 (2) glycerin 4.0 (3) xanthan gum 0.1 (4) sodium chondroitate 0.1 (5) Sodium hyaluronate 0.1 (6) Ethanol 3.0 (7) Methyl paraoxybenzoate 0.1 (8) Polyoxyethylene-oleyl ether (20E.O.) 0.5 (9) Tetrasodium edetate 0.1 (10) Sodium citrate 1.0 (11) Compound-f 0.01 (12) Arbutin 0.01 (13) Ion-exchanged water The balance

(Preparation method) After stirring and dispersing the components (1) to (5), 65 parts of ion-exchanged water (13) is added to make A. After stirring and dissolving (6) to (8), the remaining amount of ion-exchanged water (13) is added and designated as B. After stirring A and adding B to make the mixture uniform, components (9) to (12) are added and dissolved by stirring.

[0041]

Table 7 Example 5 (Cream foundation) (Composition) (wt%) (1) Methylpolysiloxane (6cs) 10.0 (2) Methylphenylpolysiloxane 3.0 (3) Octamethylcyclotetrasiloxane 10 0.0 (4) Polyoxyalkylene-modified silicone 5.0 (5) Titanium oxide 5.0 (6) Sericite 2.0 (7) Talc 3.0 (8) Red iron oxide 0.4 (9) Iron oxide yellow 0 .7 (10) Iron oxide black 0.1 (11) Butylparaben 0.1 (12) Glycerin 5.0 (13) Edetate disodium 0.1 (14) Compound-a 0.5 (15) Citric acid Sodium 1.0 (16) Methylparaben 0.1 (17) Ion-exchanged water balance

(Preparation method) The components (1) to (11) are added in 8 parts.
While heating and dissolving at 0 ° C and stirring, an aqueous phase in which the components (12) to (17) were dissolved and heated at 80 ° C was added and uniformly emulsified.

[0043]

Table 8 Example 6 (pack) (Composition) (wt%) (1) Dipropylene glycol 3.0 (2) Polyethylene glycol 3.0 (3) 1,3-Butylene glycol 1.0 (4) Glycerin 2.0 (5) Sodium pyrrolidonecarboxylate 1.0 (6) Sodium citrate 1.0 (7) Disodium edetate 0.1 (8) Lactic acid 0.5 (9) Polyvinyl alcohol 12.0 (10) Kojic acid 0.05 (11) Compound-c 0.05 (12) Ethanol 5.0 (13) Methyl paraoxybenzoate 0.1 (14) Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.3 (15) Purified water balance

(Preparation Method) The components (1) to (8) were dissolved by stirring with 50 parts of ion-exchanged water (15) to give A.
After stirring and dissolving the components (12) to (14), the remaining amount of ion-exchanged water (15) is added to homogenize the mixture to give B. (9) to (11) were added to A while stirring, and the mixture was uniformly dispersed, and then heated and dissolved at 70 ° C. This is cooled to 45 ° C., B
Add to homogenize and cool to room temperature.

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Claims (2)

[Claims] 1. The following general formula (1):[In the formula, R¹Is a hydrogen atom, lower alkyl, lower alkoxy
Ci, lower alkylthio, halogen atom or trifluoro
Indicates methyl, R²Is a hydrogen atom, halogen atom,
Lucoxy, hydroxy lower alkoxy or trifluoro
Indicates methyl, R ³Is hydrogen atom, hydroxy, halogen
Atom, alkylthio, cycloalkyl, lower hydroxy
Alkyl, hydroxy lower alkoxy, hydroxymino
Lower alkyl, lower alkenyl, oxo lower alkyl,
Trifluoromethyl, trifluoromethoxy, lower alcohol
Coxy, lower alkoxy lower alkoxy or aryl low
Indicates a primary alkoxy, or R²And R³Is one
Showing butadienyl,^FourIs hydrogen
Child, lower alkyl, aryl or heteroaryl
Then R^FiveIs a hydrogen atom, lower alkanoyl, benzoyl,
Heterocyclylcarbonyl or tetrahydropyrani-2
-Represents R⁶Is the formula (2) or (3):The residue of R,⁷Is a hydrogen atom, lower alkoxy or
Show Toro, R⁸Is a hydrogen atom, a halogen atom, a lower alkyl
Kill, lower alkoxy, lower alkylthio, nitro, high
Indicates droxy, amino or trifluoroethyl
Or R⁷And R⁸Together with butadienyl
Show, R⁹Is a hydrogen atom, halogen, lower alkyl, lower
Alkoxy, lower alkylthio or trifluoromethyl
Indicates R ^TenIs hydrogen atom, halogen atom, lower alkyl
R, lower alkoxy or lower alkylthio, X and
And Y each independently represent O, S or NH, and n is
Indicates 2, 3, or 4. ] Sulfonamide represented by
Whitening agent. 2. A skin cosmetic containing the sulfonamide according to claim 1.