JPH05345713A - External preparation for skin - Google Patents

Abstract

PURPOSE:To provide hydantoin derivatives (including new compounds) having pigmentation preventing and improving effects and excellent safety and stability and easily miscible to a cosmetic base, etc. CONSTITUTION:The objective melanogenesis suppressing agent is composed of a compound of formula I [R<1> is H, lower alkyl or aralkyl; R<2> is H, alkyl (which may contain epoxy group or ketone group), lower alkoxycarbonyl or lower alkoxycarbonylalkyl; dotted line represents the presence or absence of double bond], e.g. 5-(p-methoxybenzylidene)hydantoin. Compounds of formula wherein R<1> is not aralkyl and R<2> is not H are new compounds. The compound strongly inhibits the activity of tyrosinase which is an essential enzyme for melanin synthesis and suppresses the melanogenesis in the artificially formed pigment freckle. The amount of the compound to be compounded to the total external agent is 0.01-50wt.%, especially 0.1-20wt.%.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hydantoin derivative having an excellent melanin production inhibitory action and a skin external preparation containing the same.

[0002]

2. Description of the Related Art Stain, freckles, and pigmentation on the skin after sunburn are less likely to occur, increase, or disappear with age, which is a great concern for middle-aged and older people. Although the onset mechanism of these pigmentation has not been clarified yet, it is considered that the melanin biosynthesis function in epidermal melanocytes is enhanced by the action of sunlight, particularly ultraviolet rays, and melanocyte-stimulating hormone.

It is also considered that the aging-induced keratinization of epidermal keratinocytes (keratinocytes) 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 clearly different from the surrounding normal skin color.

There is a demand for the development of a drug capable of restoring 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 an excellent reducing ability have been used. However, this also has a difficulty in stability, and almost no effect is observed for external use. On the other hand, in Europe and the United States, hydroquinone is used as a medicine for treating spots and whitening black skin, but these also have problems in the safety of the substance itself (irritation, allergenicity), and may cause vitiligo. There is a problem in compounding it as a drug because of the fact that it is also present. In addition, various skin external preparations such as isoflavone derivatives (JP-A-58-225004) and p-hydroxycinnamic acid derivatives as cinnamic acid derivatives (JP-A-59-19681)
No. 3, etc.) are known.

[0006]

However, at present, no substance is known that has a substantial effect of improving pigmentation and is excellent in compoundability with cosmetic bases and the like. Therefore, an object of the present invention is to prevent and improve pigmentation and to have excellent safety and stability, and a compound having a good compounding property in a cosmetic base, an external drug base, etc., and a compound thereof. It is to provide a skin external preparation.

[0007]

In view of such circumstances, the inventors of the present invention have earnestly studied to obtain a substance that reduces or eliminates pigmentation through research on the mechanism of melanin production. As a result, the specific hydantoin derivative was superior. They have found that they have an action of suppressing melanin production and an action of reducing pigmentation, and have completed the present invention.

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

[0009]

[Chemical 3]

[Wherein R ¹ represents a hydrogen atom, a lower alkyl group or an aralkyl group, and R ² represents a hydrogen atom, an alkyl group which may contain an epoxy or a ketone, a lower alkoxycarbonyl group or a lower alkoxycarbonylalkyl group. Group and a broken line indicates that a double bond may be present], and a melanin production inhibitor comprising a hydantoin derivative and a skin external preparation containing the same.

Further, among the compounds of the general formula (1),
The following general formula (2)

[0012]

[Chemical 4]

[In the formula, R ^1a represents a hydrogen atom or a lower alkyl group, R ^2a represents an alkyl group which may contain an epoxy or a ketone, a lower alkoxycarbonyl group or a lower alkoxycarbonylalkyl group, and a broken line indicates Indicates that a double bond may be present. ] The hydantoin derivative represented by the above is a novel compound, and the present invention provides the compound.

In the above general formulas (1) and (2), the lower alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group and isopropyl group. , N-butyl group, sec-butyl group, te
Examples include rt-butyl group and n-pentyl group. Moreover, examples of the aralkyl group include a phenylalkyl group such as a benzyl group, a phenethyl group, and a biphenylmethyl group. Examples of the alkyl group which may contain an epoxy or a ketone include an alkyl group having 1 to 16 carbon atoms or a group containing an epoxy or a ketone in the alkyl group, specifically, a methyl group, an ethyl group. , N-
Propyl group, isopropyl group, n-butyl group, sec-
Butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, n-dodecyl group, n-tetradecyl group, n-hexadecyl group Etc., 3-epihydryl group,
Examples thereof include a 3-acetonyl group. Examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and a butoxycarbonyl group. Examples of the lower alkoxycarbonylalkyl group include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, methoxycarbonylpropyl group and ethoxycarbonylpropyl group.

Specific examples of the hydantoin derivative (1) include 5- (p-methoxybenzylidene) hydantoin, 3-ethoxycarbonyl-5- (p-methoxybenzylidene) hydantoin, 3-acetonyl-5- (p).
-Methoxybenzylidene) hydantoin, 3- (1-ethoxycarbonyl) propyl-5- (p-methoxybenzylidene) hydantoin, 3-epihydryl-5- (p
-Methoxybenzylidene) hydantoin, 3- (3-ethoxycarbonyl) propyl-5- (p-methoxybenzylidene) hydantoin, 5- (p-hydroxybenzyl) hydantoin, 3-octyl-5- (p-hydroxybenzyl) hydantoin, 5- (p-hydroxybenzylidene) hydantoin and the like can be mentioned, especially 5-
(P-Methoxybenzylidene) hydantoin is preferred.

The hydantoin derivative (1) can be produced, for example, according to the following reaction formula.

[0017]

[Chemical 5]

[In the formula, R ^2b represents an alkyl group which may contain an epoxy or a ketone, a lower alkoxycarbonyl group or a lower alkoxycarbonylalkyl group, X represents a halogen atom, and R ¹ is the same as the above]

That is, when a benzaldehyde (3) is reacted with a hydantoin (4), a 5-benzylidenehydantoin derivative (1-a) is obtained. By reacting this with a halide (5), 5-benzylidene- Three
A substituted hydantoin derivative (1-b) is produced. In addition, these benzylidene hydantoin derivatives (1-a)
Alternatively, the benzylhydantoin derivative (1-c) or (1-d) is produced by catalytically reducing (1-b). The benzylhydantoin derivative (1-c) or (1-d) in which R ¹ is a hydrogen atom is catalytically reduced to the benzylidene hydantoin derivative (1-a) or (1-b) in which R ¹ is a benzyl group. It can also be obtained.

The reaction of benzaldehydes (3) with hydantoin (4) can be carried out, for example, in Org. Syn. , Col
l. Vol. It may be heated to about 70 ° C. in water in the presence of glycine and sodium hydroxide as described in 5,627. The reaction of the compound (1-a) with the halide (5) is preferably carried out by heating to 90 to 100 ° C. in a polar solvent such as dimethylformamide in the presence of a base such as potassium carbonate. Furthermore, the reduction reaction of the benzylidene hydantoin derivatives (1-a) and (1-b) is
It is carried out by hydrogenation using a catalyst such as palladium-carbon.

The hydantoin derivative (1) thus obtained strongly inhibits the activity of tyrosinase, which is an enzyme required for melanin synthesis, and also suppresses the production of melanin in artificially formed pigment spots. Can be incorporated into various external skin preparations and internal preparations.

In the external preparation for skin of the present invention, these hydantoin derivatives (1) can be used singly or in combination of two or more kinds, and preferably 0.0% in the total amount of external preparation for skin.
It is produced by blending 1 to 50% by weight, particularly preferably 0.1 to 20% by weight.

As an optional component which can be added to the external preparation for skin of the present invention, components which are usually used in cosmetics and external medicines, such as oily substances, moisturizers, thickeners, preservatives, emulsifiers, fragrances, An emulsion stabilizer or the like can be used. In addition, by adding allantoin, vitamin E derivative, glycyrrhizin, ascorbic acid derivative, kojic acid, arbutin, pantethenic acid derivative, placenta extract, anti-inflammatory agent, yoquinin, various plant extracts, etc. as other medicinal properties, melanin The suppression effect can be improved. Furthermore, by adding various ultraviolet absorbing substances, a skin external preparation having both preventive and therapeutic effects on sunburn can be obtained.

The external preparation for skin of the present invention can be prepared into various forms which are usually applied to external medicines, quasi-drugs and cosmetics by a conventional method, but it is generally in the form of lotion, emulsion or cream. , Ointment, stick, solution with organic solvent, pack, and gel are preferable.

The thus-obtained external preparation for skin of the present invention is topically applied to affected areas such as skin spots, freckles, and pigmented areas after sunburn. In general, the dosage is preferably 1 to 20 mg per 1 cm ^{2 of} skin surface in the case of cream or ointment preparation, and 1 to 10 mg in the case of liquid preparation.

[0026]

The external preparation for skin of the present invention strongly suppresses the activity of tyrosinase, which is an enzyme required for melanin synthesis, and also suppresses the production of melanin in artificially formed pigment spots. Moreover, it has an excellent melanin deposition-preventing effect with almost no side effects.

[0027]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 Synthesis of 5- (p-methoxybenzylidene) hydantoin (A): In a 300 ml flask,
Hydantoin 20.0 g (0.20 mol) and p-methoxybenzaldehyde 25.0 ml (0.20 mol) were added to water 1
It was added to 00 ml. Furthermore, 11.4 g of glycine was added to this solution.
(0.15 mol) and sodium hydroxide 3.10 g (7
(7.0 mmol) was added and the mixture was stirred at 70 ° C. for 4 hours. Water (50 ml) was added to the reaction solution, and the mixture was washed with water and filtered to obtain 4- (p-methoxybenzylidene) hydantoin (43.6 g, 100%).

[0029]

Table 1 Light yellow crystal mp 271.6-272.4 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 3.80 (s, 3H), 6.38
(s, 1H), 6.95 (d, 2H, J = 8.6Hz), 7.57 (d, 2H, J = 8.6Hz) .IR (KBr): 1750, 1712, 1652, 1600cm ^-1 .

Example 2 3-Ethoxycarbonyl-5-
Synthesis of (p-methoxybenzylidene) hydantoin (B): DM in 3.00 g (13.7 mmol) of 5- (p-methoxybenzylidene) hydantoin in a 100 ml flask.
F50 ml was added. Ethyl bromoacetate 2.3 in this solution
0 g (13.7 mmol) was added dropwise and potassium carbonate 1.10
After adding g (8.20 mmol), it stirred at 90-100 degreeC all day and night. The reaction solution was filtered under reduced pressure, and the residue was washed 5 times with 10 ml of ethyl acetate to obtain 2.90 g (69.6%) of 3-ethoxycarbonyl-5- (p-methoxybenzylidene) hydantoin.

[0031]

[Table 2] White crystals mp 174.3-176.6 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (t, 3H, J = 7.0H
z), 3.82 (s, 3H), 4.17 (q, 2H, J = 7.0Hz), 4.30 (s, 2H), 6.9
8 (d, 2H, J = 8.6Hz), 7.64 (d, 2H, J = 8.6Hz) .IR (KBr): 3300, 1744, 1712, 1656, 1600cm ^-1 .

Example 3 Synthesis of 3-acetonyl-5- (p-methoxybenzylidene) hydantoin (C): 10
In a 0 ml flask, 3.00 g (13.7 mmol) of 5- (p-methoxybenzylidene) hydantoin was added to 50 ml of DMF.
Was added. 1.88 g of bromoacetone (1
3.7 mmol) was added dropwise, and 1.10 g (8.
(20 mmol) was added and the mixture was stirred at 90 to 100 ° C for 24 hours. The reaction solution was filtered under reduced pressure and the residue was washed with ethyl acetate 10
3-acetonyl-5- (p-
2.90 g (7) of methoxybenzylidene) hydantoin
7.2%) was obtained.

[0033]

Table 3 White crystals mp 175.6-177.9 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (s, 3H), 3.81
(s, 3H), 4.43 (s, 2H), 6.51 (s, 1H), 6.95 (d, 2H, J = 8.7Hz),
7.62 (d, 2H, J = 8.7Hz). IR (KBr): 3232, 1758, 1708, 1658, 1602cm ^-1 .

Example 4 Synthesis of 3- (1-ethoxycarbonyl) propyl-5- (p-methoxybenzylidene) hydantoin (D): 5- (p
-Methoxybenzylidene) hydantoin 3.00 g (1
50 ml of DMF was added to (3.7 mmol). 2-in this solution
2.67 g (13.7 mmol) of ethyl bromobutanoate was added dropwise, 1.10 g (8.20 mmol) of potassium carbonate was added, and the mixture was stirred at 90 to 100 ° C for one day. The reaction solution was filtered under reduced pressure, and the residue was washed 5 times with 10 ml of ethyl acetate to give 3- (1-ethoxycarbonyl) propyl-5.
-(P-methoxybenzylidene) hydantoin 1.5
0 g (32.9%) was obtained.

[0035]

[Table 4] White crystals mp 125.1-128.4 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.85 (t, 3H, J = 7.5H
z), 1.18 (t, 3H, J = 7.1Hz), 2.06 (dq, 2H, J = 7.5,6.9Hz), 3.
80 (s, 3H), 4.12 (q, 2H, J = 7.1Hz), 4.54 (t, 1H, J = 6.9Hz),
6.36 (s, 1H), 6.92 (d, 2H, J = 8.6Hz), 7.70 (d, 2H, J = 8.6Hz) .IR (KBr): 3212, 1754, 1708, 1660, 1602cm ^-1 .

Example 5 3-Epihydryl-5- (p-
Synthesis of (methoxybenzylidene) hydantoin (E): 1
5- (p-methoxybenzylidene) in a 00 ml flask
Hydantoin 3.00g (13.7mmol) to DMF50
ml was added. 1.88 g of epibromohydrin in this solution
(13.7 mmol) was added dropwise, and potassium carbonate 1.10 g
After (8.20 mmol) was added, the mixture was stirred at 90 to 100 ° C for 24 hours. The reaction solution was filtered under reduced pressure, and the residue was washed 5 times with 10 ml of ethyl acetate to give 3-epihydryl-5.
1.7% of-(p-methoxybenzylidene) hydantoin
0 g (45.2%) was obtained.

[0037]

Table 5 White crystals mp 215.6-217.1 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 3.35 (br, 2H), 3.80.
(s, 3H), 4.40-4.51 (m, 2H), 5.67 (br, 1H), 6.76 (s, 1H),
6.96 (d, 2H, J = 8.8Hz), 8.03 (d, 2H, J = 8.8Hz). IR (KBr): 1778, 1647, 1600cm ^-1 .

Example 6 Synthesis of 3- (3-ethoxycarbonyl) propyl-5- (p-methoxybenzylidene) hydantoin (F): 5- (p
-Methoxybenzylidene) hydantoin 3.00 g (1
50 ml of DMF was added to (3.7 mmol). 4-in this solution
2.70 g (13.7 mmol) of ethyl bromobutanoate was added dropwise, and 1.10 g (8.20 mmol) of potassium carbonate was added, followed by stirring at 90 to 100 ° C. for a whole day and night. The reaction solution was filtered under reduced pressure, and the residue was washed 5 times with 10 ml of ethyl acetate to give 3- (3-ethoxycarbonyl) propyl-5.
3.4- (p-methoxybenzylidene) hydantoin
0 g (74.7%) was obtained.

[0039]

Table 6 White crystals mp 127.5-129.0 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (t, 3H, J = 7.3H).
z), 1.84 (dq, 2H, J = 7.0,10.5Hz), 2.32 (t, 2H, J = 7.2Hz),
3.52 (t, 2H, J = 6.7Hz), 3.80 (s, 3H), 4.40 (q, 2H, J = 7.0Hz),
6.43 (s, 1H), 6.93 (d, 2H, J = 8.6Hz), 7.62 (d, 2H, J = 8.6H
z). IR (KBr): 3212, 1710, 1656, 1604cm ^-1 .

Example 7 Synthesis of 5- (p-hydroxybenzyl) hydantoin (G): 1.50 g (5.00 mmo) of 5- (p-benzyloxybenzylidene) hydantoin in 400 mg of 5% Pd / C in a 100 ml three-necked flask.
l) was added, and 30 ml of DMF was poured into this. Hydrogen gas was passed for 92 hours with slight pressure. After the reaction, the mixture was filtered on Celite and concentrated to obtain 0.79 g (76.1%) of 5- (p-hydroxybenzyl) hydantoin.

[0041]

Table 7 White crystals mp 256.7-258.1 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.82 (d, 2H, J = 4.7H
z), 4.21 (t, 1H, J = 4.7Hz), 6.35 (s, 1H), 6.78 (d, 2H, J = 8.5
Hz), 7.45 (d, 2H, J = 8.3Hz). IR (KBr): 3304, 1710, 1653, 1605cm ^-1 .

Example 8 Synthesis of 3-octyl-5- (p-hydroxybenzyl) hydantoin (H): 100 ml
In a three-neck flask, 1.50 g (3.70 mmol) of 3-octyl-5- (p-benzyloxybenzylidene) hydantoin was added to 400 mg of 5% Pd / C, and DMF3 was added thereto.
0 ml was poured. Hydrogen gas was passed for 63 hours with slight pressure. After the reaction, the mixture was filtered on Celite and concentrated to obtain 0.56 g (47.6%) of 3-octyl-5- (p-hydroxybenzyl) hydantoin.

[0043]

Table 8 Light yellow crystals mp 291.5-292.4 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83-0.86 (br, 3H),
1.26-1.56 (m, 12H), 3.45 (blind, 2H), 4.22 (1H), 6.77 (d,
2H, J = 8.3Hz), 7.48 (d, 2H, J = 7.7Hz). IR (KBr): 3250, 1698, 1647, 1602cm ^-1 .

Example 9 Synthesis of 5- (p-hydroxybenzylidene) hydantoin (I): Hydantoin 10.0 g (0.10 mol) and p-hydroxybenzaldehyde 12.2 g (0.10 mol) in a 300 ml flask.
Was added to 100 ml of water. Glycine 5.6 was added to this solution.
0 g (75.0 mmol) and sodium hydroxide 1.50 g
(37.5 mmol) was added, and the mixture was stirred at 70 ° C. for 5 hours. 50 ml of water was added to this reaction solution, and the mixture was filtered while washing with water to obtain 13.8 g (71.1%) of 5- (p-hydroxybenzylidene) hydantoin.

[0045]

Table 9 Light yellow crystals mp> 300 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 6.35 (s, 1H), 6.78
(d, 2H, J = 8.4Hz), 7.45 (d, 2H, J = 8.4Hz). IR (KBr): 3372, 1748, 1710, 1652, 1604cm ^-1 .

Example 10 A cream having the composition shown in Table 11 was prepared according to the following method, and its whitening effect was evaluated by its improving effect on UVB-induced pigment spots. (1) Test method The upper arm inner part of 10 subjects was irradiated with ultraviolet rays in the UVB region (double the minimum erythema dose (MED)) once a day for 2 days, and the induced pigment spots were twice a day. The amount of pigment spot extinction caused by continuously applying the sample to the test site for one month was examined. Color difference meter (Murakami Color, CMS-1200)
The L ^* value was calculated from the obtained Munsell value, and the value (ΔΔ) was obtained by subtracting ΔL ^* (change with time) of the sample-uncoated part from ΔL ^* (change with time) of the sample-coated part.
L ^* ). ΔΔL ^* is represented by the following formula.

[0047]

[Formula 1] ΔΔL ^* = (L ^* _1- L ^* ₀ )-(L ^'* _1- L ^{' *} ₀ ) L ^* ₀ ; test sample application before application L ^'* ₀ ; sample before application not applied Test site L ^* ₁ ; Sample application after 1 month of continuous application Test site L ^'* ₁ ; Sample unapplication after 1 month of continuous application Test site Evaluation was shown as the average value of the evaluation points of 10 subjects according to Table 10 below. ..

[0048]

[Table 10]

(2) Cream preparation method The oil phase components (1) to (6) in Table 11 were heated and mixed at 80 ° C., and the aqueous phase components (7) to (1) were heated to 80 ° C. with stirring.
After 0) is added and emulsified, (11) is added and then cooled to room temperature with stirring.

(3) Test Results Table 11 shows the improving effect on the obtained UVB-induced pigment spots.
As a result, it was found that the cream containing the hydantoin derivative (1) of the present invention has an excellent pigmentation improving effect. During the test, allergies did not occur and the cream was stable.

[0051]

[Table 11]

Example 11 (cream)

[0053]

Table 12 (% by weight) (1) Decaglyceryl stearate 1.8 (2) Polyoxyethylene cetyl ether 1.2 (3) Squalane 12.0 (4) Cetanol 6.0 (5) Cetyl palmitate 3 0.0 (6) 1,3-butylene glycol 6.0 (7) Glycerin 3.0 (8) 5- (p-methoxybenzylidene) hydantoin 1.0 (9) Purified water residual amount (10) Preservative proper amount ( 11) Suitable amount of fragrance

(Production method) Oil phase components (1) to (6) were added at 80 ° C.
The mixture is heated and mixed with, and the aqueous phase components (7) to (10) heated to 80 ° C. with stirring are added to emulsify, then (11) is added and then cooled to room temperature with stirring.

Example 12 (milky lotion)

Table 13 (% by weight) (1) Polyoxyethylene sorbitan stearate 1.0 (2) Glycerol oleate 1.0 (3) Glycerin monostearate 0.5 (4) Squalane 6.0 (5) Trioctane Glyceryl acidate 2.0 (6) Cetyl octanoate 2.0 (7) Stearyl alcohol 2.0 (8) 1,3-butylene glycol 5.0 (9) Glycerin 3.0 (10) 5- (p-methoxy) Benzylidene) Hydantoin 1.0 (11) Purified water Remaining amount (12) Preservative Suitable amount (13) Perfume Suitable amount

(Production method) Oil phase components (1) to (7) were added at 80 ° C.
The mixture is heated and mixed with, and the aqueous phase components (8) to (12) heated to 80 ° C. with stirring are added to emulsify, then (13) is added, and then the mixture is cooled to room temperature with stirring.

Example 13 (lotion)

[0058]

Table 14 (% by weight) (1) 1,3-butylene glycol 8.0 (2) glycerin 4.0 (3) sodium hyaluronate 0.1 (4) ethanol 3.0 (5) polyoxyethylene poly Oxypropylene decyl tetradecyl ether 0.3 (6) 5- (p-methoxybenzylidene) hydantoin 1.0 (7) Purified water remaining (8) Preservative proper amount (9) Perfume proper amount

(Production method) After stirring and dispersing the components (1) to (3) and (6), 60% of purified water is added to the mixture to give A. On the other hand, the components (4), (5), (8), and (9) are dissolved by stirring, and the remaining amount of purified water is added to the mixture to give B. While stirring A, add B and stir.

Example 14 Essence (beauty essence)

[0061]

Table 15 (% by weight) (1) 1,3-butylene glycol 8.0 (2) glycerin 4.0 (3) xanthan gum 0.3 (4) sodium chondroitin sulfate 0.1 (5) sodium hyaluronate 0 .05 (6) Ethanol 3.0 (7) Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.3 (8) 5- (p-methoxybenzylidene) hydantoin 1.0 (9) Purified water balance (10) Preservative Suitable amount (11) Perfume Suitable amount

(Production method) After stirring and dispersing the components (1) to (5) and (8), purified water (65%) is added to the mixture to give A. On the other hand, the components (6), (7), (10), and (11) are dissolved by stirring, and the remaining amount of purified water is added to the mixture to give B.
While stirring A, add B and stir.

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

[Procedure amendment]

[Submission date] September 17, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0023

[Correction method] Change

[Correction content]

The external preparation for skin according to the present invention can be applied to an external medicine by a conventional method.
A variety of drugs usually applied to medicines, quasi-drugs and cosmetics.
Can be prepared in the form of a lotion
, Emulsion, cream, ointment, stick, organic
It is preferable to use a solvent solution, pack, or gel.
Yes.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0024

[Correction method] Change

[Correction content]

The external preparation for skin of the present invention impairs the effects of the present invention.
Any range other than hydantoin derivative (1)
Ingredients can be added to cosmetics depending on the dosage form.
Ingredients that are normally used in combination, such as purified water and ethanol
Nole, oily substance, moisturizer, thickener, preservative, emulsifier,
Uses medicinal ingredients, powders, fragrances, emulsion stabilizers, pH adjusters, etc.
can do. Specifically, it is fluid as an oily component
Paraffin, Vaseline, Paraffin wax, Squirrel
, Beeswax, carnauba wax, olive oil, lanolin
, Higher alcohols, fatty acids, higher alcohols and fatty acids
Synthetic ester oil, silicone oil, etc.
As sorbitol, xylitol, glycerin,
Rutitol, propylene glycol, 1,3-butylene
Glycol, 1,4-butylene glycol, pyrrolidone
Sodium carboxylate, lactic acid, sodium lactate, polio
Xypropylene fatty acid ester, polyethylene glycol
And the like, and as a thickener, carboxyvinyl poly
Mar, carboxymethyl cellulose, polyvinyl alcohol
Water-soluble polymer such as sugar, carrageenan, gelatin, chloride
Electrolytes such as sodium and potassium chloride are listed,
As preservatives, urea, methylparaben, ethylparabe
Benzene, propylparaben, butylparaben, sodium benzoate
Examples of the emulsifier include polyoxyethylene.
Alkyl ether, polyoxyethylene fatty acid ester
Polyoxyethylene sorbitan fatty acid ester,
Lyserine fatty acid ester, polyglycerin fatty acid ester
Polyoxyethylene glycerin fatty acid ester,
Rioxyethylene hydrogenated castor oil, polyoxyethylene so
Nonionic surfactants such as rubitol fatty acid ester are listed.
As powder, talc, sericite, mica, mosquito
Olin, silica, bentonite, vermiculite, sub
Lead flower, mica, titanium mica, titanium oxide, magnesium oxide
Aluminum, zirconium oxide, barium sulfate, red iron oxide, oxidation
Iron, ultramarine, etc. are listed, and as a pH adjusting agent, lactic acid-lactic acid
Buffers such as thorium, citric acid-sodium citrate
Can be mentioned. In addition, as various active ingredients, allantoi
, Vitamin E derivative, glycyrrhizin, ascorbine
Acid derivative, kojic acid, alptin, pantethenic acid derivative
Body, placenta extract, anti-inflammatory agent, yokinin, various plants
The effect of suppressing melanin by adding extract
Can be improved. Furthermore, various UV absorption
By adding substances, preventive and therapeutic effects of sunburn
It can be a combined external preparation for the skin.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location C07D 233/78 (72) Inventor Mitsutoshi Kimura 2606-6 Akabane, Kai-cho, Haga-gun, Tochigi Kai-shi Kai Company housing 3 405

Claims (3)

[Claims] 1. A compound represented by the general formula (1): [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or an aralkyl group, and R ² represents a hydrogen atom, an alkyl group which may contain an epoxy or a ketone, a lower alkoxycarbonyl group or a lower alkoxycarbonylalkyl group. , A broken line indicates that a double bond may be present]. A melanogenesis inhibitor comprising a hydantoin derivative. 2. A skin external preparation containing the hydantoin derivative according to claim 1. 3. A compound represented by the general formula (2): [In the formula, R ^1a represents a hydrogen atom or a lower alkyl group;
^2a represents an alkyl group which may contain an epoxy or a ketone, a lower alkoxycarbonyl group or a lower alkoxycarbonylalkyl group, and a broken line indicates that a double bond may be present. ] The hydantoin derivative represented by these.