JPH1121225A - Ingredient for beautifying and whitening and skin preparation for external use for beautifying and whitening containing the same ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an ingredient for beautifying and whitening useful for skin preparation for external use for beautifying and whitening capable of suppressing melanin production and having excellent beautifying and whitening effect by including an anilide derivative, phenol derivative, (benzo)imidazole derivative, etc., having a specific structure. SOLUTION: This ingredient for beautifying and whitening is obtained by including one or more kinds of compounds among an anilide derivative of formula I, etc., a phenol derivative of formula II, etc., a benzoimidazole derivative of formula III, etc., an imidazole derivative of formula IV, etc., benzenesulfonamide derivative of formula V, etc., a naphthalene derivative and/or their salts exhibiting beautifying and whitening action. This skin preparation for external use for beautifying and whitening is obtained by formulating the above ingredient for beautifying and whitening in an amount of 0.0001-10 wt.%, preferably 0.001-3 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an anilide derivative and a phenol derivative having a specific structure exhibiting a whitening effect.
The present invention relates to a whitening ingredient containing a benzimidazole derivative, an imidazole derivative, a benzenesulfonamide derivative or a naphthalene derivative and / or a salt thereof as an active ingredient, and a skin whitening external preparation containing the ingredient as an active ingredient.

[0002]

2. Description of the Related Art Pigmentation on spots, freckles, and skin after sunburn occurs, increases or hardly disappears with aging, and is a problem for middle-aged and elderly people. Although the mechanism of the onset of these pigmentation diseases has not been clarified yet, it is considered that the mechanism of melanin synthesis in epidermal melanocytes has been enhanced by the action of sunlight, particularly ultraviolet rays, and melanocyte stimulating hormone.

[0003] Further, it is considered that the keratinization delay associated with the aging of epidermal keratinocytes (keratinocytes) also causes a clinical symptom in which the density of melanin granules in the epidermis increases, that is, pigmentation increases. These pigmentations are localized and their color may be distinctly different from the surrounding normal skin color.

Therefore, there is a strong 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. . In recent years, for example, cosmetics containing a vitamin C (L-ascorbic acid) derivative having excellent reducing ability have been developed. However, this also has the drawbacks that it has difficulty in stability and that the effect is hardly recognized when used externally.

On the other hand, in the United States and Europe, hydroquinone is used as a treatment for spots and as a drug for whitening black skin. However, these also have problems with the safety (irritative and allergic) of the substance itself, and also have vitiligo. There is a problem in formulating it as a drug, for example, in that it may cause In addition, various skin whitening external preparations such as isoflavone derivatives (JP-A-58-22504)
Japanese Patent Application Laid-Open (JP-A) No. 195/1989) and a p-hydroxycinnamic acid derivative as a cinnamic acid derivative (JP-A-59-196813) are known.

However, at present, there is no known substance which has a substantial effect of preventing and improving pigmentation and excellent incorporation into a base for a skin whitening preparation.

[0007] Therefore, there is a demand for the development of a whitening ingredient which has a skin whitening effect and is capable of preventing and treating spots and freckles caused by sunburn and the like, and a skin whitening skin external preparation containing the same as an active ingredient. .

On the other hand, formula (II):

[0009]

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The anilide derivative represented by
Although it is known that it is useful as an active ingredient of a bactericide as described in JP-A-7936, it is not known about a whitening effect.

Formula (XX):

[0012]

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[0013] (wherein, R ⁴ is 6-methoxy-2-pyridyl group, or R ⁵ represents a 2-morpholinophenyl group, R ⁴
Represents a 3-hydroxy-2-pyridyl group, R ⁵ represents a 2-dimethylaminophenyl group, R ⁴ represents a 3-isopropoxy-2-pyridyl group, R ⁵ represents a 2-dimethylaminophenyl group, or R ⁴ represents a 5-amino-2-pyridyl group, and R ⁵ represents a 2-morpholinophenyl group).
As described in Japanese Patent Application Laid-Open Publication No. H10-209, it is known that it is useful as a synthetic intermediate of a pharmaceutical compound having an excellent gastric acid secretion inhibitory action, but its whitening effect is not known.

Formula (XXI):

[0015]

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Wherein R ⁶ is a hydrogen atom, R ⁷ is a 4-methylphenyl group, and R ⁸ is 5- (2-furyl) pyrimidine-2
Or R ⁶ represents a morpholino group, R ⁷ represents a 2-methoxyphenoxy group, and R ⁸ represents 5-bromopyrimidine-2.
Represents an -yl group, R ⁶ represents a hydrogen atom, R ⁷ represents a 3-methoxyphenoxy group, R ⁸ represents a 4-pyridyl group, or R ⁶ represents an n-propyl group, and R ⁷ represents a 2-methoxyphenoxy group. , R ⁸ represents a 5-bromopyrimidin-2-yl group), as described in JP-A-8-99961, which is known to be a substance which strongly antagonizes endothelin. But no known whitening effect.

Formula (XXII):

[0018]

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(Wherein R ⁹ is an ethyl group, R ¹⁰ is a hydrogen atom, R ¹¹ is an aldehyde group, R ¹² is a methoxy group, R ¹³ is a hydroxyl group, or R ⁹ , R ¹¹ and R ¹³ are all hydrogen. An atom, R ¹⁰ represents a methoxy group, R ¹² represents a carboxymethyl group, or R ⁹ , R ¹¹ and R ¹³ are all hydrogen atoms, R ¹⁰ is a hydroxyl group, and R ¹² is a carboxymethyl group. The derivative is EP 37
No. 6288, German Patent Publication No. 200500544 and European Patent Publication No. 372385. However, these naphthalene derivatives are effective, for example, in treating pathological conditions of autoimmune diseases, ie rheumatoid arthritis, arthritis, or inflammatory conditions, have anti-inflammatory, antipyretic and analgesic effects, and have myeloperoxidase accumulation. It is described that it can be used as a starting material when synthesizing an inhibitor of the above, but its whitening effect is not known.

Formula (VII):

[0021]

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The 4-phenyl-2-aminophenol represented by the formula (1) is known to be used, for example, in the synthesis of a copper complex compound of an azomethine dye, as described in DE-A-2539608. However, no whitening effect is known.

[0023]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and not only has an excellent effect of suppressing the synthesis of melanin that is newly formed in melanosomes, but also has a low irritancy. It is an object of the present invention to provide a whitening component and a skin whitening agent excellent in stability.

[0024]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have developed an anilide derivative represented by the following formula (I) or (II), the following formulas (III), (IV), (V), (V
A phenol derivative represented by I) or (VII) or a salt thereof, a benzimidazole derivative represented by the following formula (VIII), a following formula (IX), (X), (XI) or (XII)
An imidazole derivative represented by the following formula (XIII), (XI
V), (XV) or (XVI), a benzenesulfonamide derivative represented by the following formula (XVII), (XVIII) or (XI
The naphthalene derivative represented by X) and a salt thereof are
The present inventors have found that they exhibit an action of suppressing the synthesis of melanin that is newly formed in melanosomes, and have completed the present invention.

That is, the present invention provides a skin-whitening ingredient containing any of the following compounds and / or salts thereof as an active ingredient and a skin-whitening skin external preparation containing the ingredient as an active ingredient (hereinafter referred to as skin-whitening skin external preparation). About.

[0026]

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[0027]

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[0028]

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[0029]

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[0030]

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[0031]

BEST MODE FOR CARRYING OUT THE INVENTION The skin whitening preparation of the present invention contains any of the compounds represented by the formulas (I) to (XIX) and / or their salts as active ingredients. Seeds or two or more kinds are appropriately selected and blended. The amount of the whitening skin external preparation varies depending on the type of the target whitening component and the like, and cannot be unconditionally determined. However, in order to sufficiently obtain a whitening effect, 0.0001 to 10 is required.
% By weight (hereinafter simply indicated as%), preferably 0.001
It is desirable to mix 3%.

The whitening component of the present invention may be, for example, a component known as a whitening component generally used in cosmetics, such as arbutin, placental extract, ascorbic acid, and L-ascorbyl phosphate, in addition to the above compounds. Ascorbic acid derivatives such as magnesium, and salts thereof, mulberry bark extract, liquiritin, isoliquiritin, glabridine, flavonoids such as glabrene, and licorice extract containing these flavonoids, pantethein-
Calcium S-sulfonate and the like can be appropriately compounded as long as the effects of the present invention are not impaired.

Furthermore, in the skin whitening agent for external use of the present invention, besides the above, oils and fats, surfactants, water, humectants, pH adjusters, thickeners, preservatives, antioxidants, ultraviolet absorbers Agents, pigments, animal and plant-derived components, anti-inflammatory agents, vitamins, amino acids, and various other skin whitening agent components can be appropriately blended within a range that does not impair the effects of the present invention.

Examples of the fats and oils include vegetable fats and oils commonly used in cosmetics, such as liquid paraffin, paraffin, cetanol, avocado oil, olive oil, jojoba oil, and coconut oil; Animal fats and oils such as turtle oil, mink oil, parserine oil, squalane;
Synthetic oils and fats such as behenyl alcohol, glyceryl tricaprylcaprate, glyceryl trioctanoate, glycerin triisopalmitate, silicone oil, and fluorine-based oils are exemplified.

Examples of the surfactant include anionic surfactants such as sodium lauryl sulfate, triethanolamine lauryl sulfate, and diethanolamide laurate; and positive surfactants such as stearyltrimethylammonium chloride, cetyltrimethylammonium chloride, and benzalkonium chloride. Nonionic surfactants such as glyceryl monostearate, sorbitan monostearate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene hydrogenated castor oil, sucrose ester, and fatty acid amide; can give.

Examples of the humectant include synthetic humectants such as glycerin, propylene glycol, 1,3-butylene glycol and sodium pyrrolidone carboxylate; hyaluronic acid, collagen, elastin, royal jelly, and fermented liquid of microorganisms such as chitin, chitosan and pectin. And other natural moisturizing liquids such as extracts derived from plants and animals.

Examples of the pH adjuster include citric acid,
Organic acids such as sodium citrate and salts thereof can be mentioned.

Examples of the thickener include carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, tragacanth gum, sodium alginate, carrageenan and the like.

Examples of preservatives include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben and butylparaben, phenoxyethanol, ethanol, dehydroacetic acid and the like.

Examples of the antioxidant include vitamin E, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and the like.

Examples of the ultraviolet absorber include octyl paramethoxycinnamate, 2-hydroxy-4-methoxybenzophenone, 4-t-4'-methoxy-benzoylmethane, paraaminobenzoic acid and the like.

Examples of the pigment include red iron oxide, yellow iron oxide, black iron oxide, titanium oxide, nylon powder, sericite, mica, and talc.

Examples of the anti-inflammatory agent include glycyrrhizic acid, glycyrrhizic acid salts such as dipotassium glycyrrhizinate, glycyrrhizic acid derivatives, allantoin, indomethacin and the like, and these can be used alone or in combination of two or more. .

The form of the whitening skin external preparation of the present invention is optional and not particularly limited. The whitening skin external preparation of the present invention prevents the appearance of dull skin, spots and freckles, It has excellent properties such as maintaining youthful, healthy, moist white and beautiful skin condition, for example, creams, emulsions, lotions, essences, facial cleansers, basic cosmetics such as packs, lipsticks, foundations, white powder, etc. Cosmetics, ointments, gel ointments and other skin whitening external preparations, body soaps, soaps and other toiletry products.

The skin whitening agent for external use of the present invention may be prepared in various forms using a usual production method.

Formulas (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (X
V), (XVI), (XVII), (XVIII) or (XIX), the external preparation for whitening skin of the present invention, which contains the compound represented by (XIX), suppresses the expression of spots, freckles, etc. due to enhanced melanin production. In addition to the effect of maintaining moist, white and beautiful skin, the skin is characterized by low irritation.

Hereinafter, the skin whitening agent of the present invention will be described in more detail with reference to Test Examples, Production Examples and Examples, but the present invention is not limited thereto.

Test Example 1 Inhibitory effect of melanin production in a cell culture system using B-16 melanoma cells (a) Culture conditions B-16 melanoma cells were obtained from 10% fetal bovine serum (FB).
Using an Eagle medium containing S), the cells were cultured in a CO ₂ incubator (5% by volume CO ₂ , 95% by volume air) at 37 ° C. as follows. Cells of 1.2 × 10 ⁴ cells / 2 ml medium were placed in a 6-well plate having a diameter of 35 mm. After culturing for 24 hours under the above conditions, samples containing each compound produced in Production Examples 1 to 19 were added to each well. Each compound was dissolved in DMSO and the final concentration in the medium was 1-1.
A sample prepared to be 00 μg / ml was added to 20 μl /
Each well was added. As a control, B-16 melanoma cells to which no sample was added were used, and as a positive control, a placenta extract prepared by adding 100 μl of a placenta extract prepared to a final concentration of 1000 μg / ml was used. After further culturing for 3 days, the medium was replaced, and at that time, a sample was further added.

On the next day (day 6), the cells were collected, and the inhibitory effect on the synthesis of melanin, which is newly formed in melanosomes, was determined as follows based on the color tone of the cell pellet.

(B) Evaluation of melanin production inhibitory action The melanin production inhibitory action was evaluated by evaluating the score based on the color tone of the cell pellet. Medium in well
After washing with (-), the cells were detached with a microscrubber, collected with PBS (-), centrifuged (1000 rpm).
, 10 minutes, 5 ° C.), the supernatant was discarded, and the color tone of the precipitated cell pellet was evaluated in four steps based on the following criteria.

Color tone of cell pellet-: Same black as control ±: Black slightly lighter than control +: Grayish white equivalent to positive control ++: White (c) Toxicity test Cell viability (number of viable cells) (ratio to control) was measured to evaluate toxicity.

For each well, after fixing the cells with formalin, a 1% crystal violet solution was added and stained. The number of surviving cells (A) and the number of control cells (B) for each sample concentration were measured, and the cell growth rate was calculated by equation (1).

[0053]

(Equation 1)

Table 1 shows the results.

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

As is clear from the results in Table 1, each of the compounds (Compound Nos. I to XIX) which are the active ingredients of the skin whitening preparation of the present invention has low cytotoxicity and high melanin activity for B-16 melanoma. It was confirmed that it had the ability to suppress production. This indicates that the compound has a high whitening effect on the skin.

Production Example 1 Production of 2'-hydroxy-3'-methoxycarbonyl-4-methoxy-benzanilide (Compound No. I) (1) 670 ml of an acetic acid solution of 250 g of 5-chloro-2-hydroxybenzoic acid was cooled, After 71 ml of fuming nitric acid (94%, specific gravity 1.52) was added over 40 minutes, the mixture was stirred at room temperature for 1 hour with occasional cooling. The mixture was poured into 2.5 liters of water and the entire mixture was
Heated briefly until the precipitate was collected. A mixture of the precipitate and 300 ml of water was evaporated and then cooled. The obtained yellow crystals were collected, washed with cold water, and dried to obtain 256.1 g of crude 5-chloro-2-hydroxy-3-nitrobenzoic acid yellow powder (crude substance A).

(2) 256.1 g of the unpurified product A was added at room temperature to a sulfonyl chloride or thionyl chloride (600 m).
and the resulting mixture was refluxed for 3 hours.
The residue was added to 1.0 liter of cold methanol, and the precipitated crystals were collected by filtration to obtain 200 g of yellow powder of methyl 5-chloro-2-hydroxy-3-nitro-benzoate (unpurified product B).

(3) One out of 200 g of the unpurified product B
00 g was suspended in a THF (1 liter) -methanol (1.2 liter) solution, and 20 g of a 10% palladium catalyst was added, followed by catalytic reduction at normal pressure. After 6 hours, the resulting mixture was filtered through celite and the filtrate was evaporated. The precipitate was made basic by adding a saturated sodium hydrogen carbonate solution, and extracted with about 2 liters of ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The remaining 100 g of crude B were treated similarly. The obtained crystals were combined and recrystallized from an ethyl acetate-n-hexane mixed solution to give 2-amino-1
-Hydroxy-methyl benzoate as the first crystal 109.
10 g (yield: 75.6%), 20.30 as a second crystal
g (yield: 14.1%).

(4) Crystal 1 of the first and second crystals combined with methyl 2-amino-1-hydroxy-benzoate 1
TH of 23.7 g and 134.5 g of dimethylaniline
The acid chloride 138.8 was added to the F (1 liter) solution under ice cooling.
6 g were added dropwise over 15 minutes. After completion of the dropwise addition, the reaction solution was returned to room temperature, stirred for 30 minutes, and then 0.5 liter of water was added. The mixture was treated with THF-ethyl acetate (1: 1, v
/ V) The mixture was extracted with 2 liters, washed with 10% hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and dried under reduced pressure. The residue was crystallized from ethyl acetate to give 198.6 g of the desired compound 2'-hydroxy-3'-methoxycarbonyl-4-methoxy-benzanilide represented by the following formula (I) (melting point:
136-139 ° C).

[0063]

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Production Example 2 2-hydroxy-3-methyl-5-bromobenzoyl-
Production of 2'-hydroxyanilide (Compound No. II) According to Example 1 of JP-B-43-7936, the target compound 2-hydroxy-3 represented by the following formula (II)
-Methyl-5-bromobenzoyl-2'-hydroxyanilide was obtained.

[0065]

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Production Example 3 2- [3- (2-hydroxy-5-methoxy-3-te)
rt-butylphenyl) ureido] -4-methoxy-6
Production of -tert-butylphenol (Compound No. III) (1) 257 g of p-anisidine was dissolved in 514 ml of concentrated hydrochloric acid, and 158 g of sodium nitrite and 1530 g of water were added under ice-cooling.
ml solution was added dropwise. This mixture was added dropwise to a solution of 356 g of 4-methoxy-2-tert-butylphenol, 416 g of sodium hydroxide and 3000 ml of water under ice-cooling, followed by stirring at the same temperature for 15 minutes. Concentrated hydrochloric acid (about 400ml)
Was adjusted to pH 3, and the precipitated crystals were collected by filtration, washed, dried, and then recrystallized from a mixed solution of chloroform and ethanol to give 400 g of 2- (4-methoxyphenylazo) -4-methoxy-6-tert-butylphenol. (Yield: 6
4%, melting point: 125-127 ° C, IR: 1600c
m ^-1 ).

(2) 63 g of 62.5% sodium hydride
And 2,500 ml of dimethylformamide (DMF), a solution of 400 g of 2- (4-methoxyphenylazo) -4-methoxy-6-tert-butylphenol in 3000 ml of tetrahydrofuran (THF) was added dropwise under ice cooling. After the temperature was raised to room temperature, the mixture was ice-cooled again, and 113 g of methoxymethyl chloride was added dropwise. After stirring at room temperature for 2 hours, 300 ml of a saturated aqueous solution of ammonium chloride was gradually added dropwise.
THF was distilled off under reduced pressure, and a saturated saline solution was added to the residue, followed by extraction with ethyl acetate. After the extract was washed and dried, the solvent was distilled off.
The precipitated crystals were recrystallized from a hexane-ethyl acetate mixed solution to give {2- (4-methoxyphenylazo) -4-methoxy-6-tert-butylphenoxy} methoxymethane 4
41 g (yield: 97%, melting point: 102-103 ° C, I
R: 1610 cm ^-1 ).

(3) 180 g of main crystals of methanol 1200
10% palladium-carbon (Pd-C) 3
g was added thereto, and the mixture was subjected to a medium pressure catalytic reduction at room temperature for 30 minutes using a Parr reducing apparatus. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was distilled under reduced pressure to give (2-amino-4-methoxy-6-tert-butylphenoxy) methoxymethane 1
09 g (yield: 91%, boiling point: 125 to 130 ° C. (1 m
mHg), IR: 3480, 3390, 1630, 16
00 cm ^-1 ).

(4) A mixed solution of 3.62 ml of a 2.901 M phosgene-dichloromethane solution and 30 ml of dichloromethane was cooled to -78 ° C, and (2-amino-4-methoxy-6-tert-butylphenoxy) methoxymethane was added. After dropwise adding a solution of 58 g and 2.93 ml of triethylamine in 30 ml of dichloromethane, the temperature was raised to 0 ° C., and the solvent was distilled off under reduced pressure. 30m dichloromethane in the residue
l and adding (2-amino-4-methoxy-6-t) at room temperature.
tert-butylphenoxy) methoxymethane 1.68 g
Then, a solution of 1.46 ml of triethylamine in 30 ml of dichloromethane was added dropwise, and the mixture was further stirred for 1 hour. After washing and drying the reaction solution, the solvent was distilled off under reduced pressure, and the residue was crystallized from n-hexane to give {2- [3- (3-tert-butyl-2-methoxymethoxy-5-methoxyphenyl)}.
2.32 g of ureido] -4-methoxy-6-tert-butylphenoxydimethoxymethane (yield: 65%, melting point: 115 to 116 ° C.) were obtained.

(5) 2.28 g of the main crystal in 40 m of methanol
2 ml of concentrated hydrochloric acid was added to the 1 solution, and the mixture was stirred at room temperature for 1 hour.
After evaporating the solvent under reduced pressure, water was added to the residue and extracted with ethyl acetate. After washing and drying, the solvent is distilled off under reduced pressure, and the residue is crystallized from isopropyl ether to give the following formula (II)
1.35 g of the target compound 2- [3- (2-hydroxy-5-methoxy-3-tert-butylphenyl) ureido] -4-methoxy-6-tert-butylphenol represented by I) (yield: 71%, Melting point: 153-154
° C).

[0071]

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Production Example 4 2- [3- (2-hydroxy-5-methoxyphenyl)
Ureido] -4-methoxyphenol (Compound No. IV)
Production of (1) 4.22 g of 62% sodium hydride in DMF10
11. 4-methoxyphenol was added to the 0 ml suspension under ice-cooling.
20 ml of a 41 g DMF solution was added dropwise. After stirring at room temperature for 30 minutes, the mixture was ice-cooled again, and 8.86 g of methoxymethane chloride was added.
Was added dropwise. After further stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was extracted with ether, washed and dried, and then the solvent was distilled off. The residue is subjected to silica gel column chromatography (solvent; methyl acetate: hexane = 1: 20).
Then, 13.57 g (yield: 81%) of O-methoxymethyl-4-methoxyphenol was obtained.

(2) A solution of 11.86 g of O-methoxymethyl-4-methoxyphenol in 50 ml of THF was added to -78.
It cooled to ° C and 91 ml of 1Msec-butyllithium hexane solutions was dripped. After stirring for further 15 minutes, a solution of 15 g of p-toluenesulfonyl azide in 30 ml of THF was added dropwise, and the mixture was further stirred for 2 hours. The reaction solution was poured into 253 ml of a 0.3 M aqueous solution of sodium pyrophosphate (Na ₄ P ₂ O ₇ ) under ice cooling, stirred for 1 hour, added with water, extracted with ether, washed, dried, and evaporated. did. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1), and the eluate was concentrated to obtain 13.75 g of a residue. This was dissolved in 100 ml of THF and added dropwise to 150 ml of a THF suspension of 5 g of lithium aluminum hydride under ice cooling. After stirring for 2 hours,
5 ml of water, 5 ml of a 15% aqueous sodium hydroxide solution and 15 ml of water were sequentially added, insolubles were filtered off, the filtrate was concentrated, extracted with ether, washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give (2-
Amino-4-methoxyphenoxy) methoxymethane 1.
80 g (yield: 14%) was obtained as a colorless syrup.

(3) 6.3 ml of a 3.1 M phosgene-dichloromethane solution was cooled to -78 ° C.
-Methoxyphenoxy) methoxymethane 2.4 g and triethylamine 2.7 ml dichloromethane 10 ml
After the solution was added dropwise, the temperature was raised to 0 ° C., and the solvent was distilled off under reduced pressure. 10 ml of dichloromethane was added to the residue to form a solution,
At room temperature, a solution of 2.4 g of (2-amino-4-methoxyphenoxy) methoxymethane and 2.7 ml of triethylamine in 10 ml of dichloromethane was added dropwise.
Stirred for hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the crystals were collected by filtration, washed, dried, recrystallized from ethyl acetate to give 3,3'-bis (2-methoxymethoxy-5-methoxyphenyl) urea 3 0.4 g (yield: 67%, melting point: 18)
3-185 ° C).

(4) 3.0 g of the main crystals in 20 ml of methanol
Then, 2 ml of concentrated hydrochloric acid was added to a solution of 20 ml of acetone, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 20: 1),
By recrystallization from ethyl acetate, the following formula (IV)
The target compound 2- [3- (2-hydroxy-5) represented by
-Methoxyphenyl) ureido] -4-methoxyphenol 1.5 g (yield: 65%, melting point: 164-166)
° C).

[0076]

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Production Example 5 2- [3-phenyl-3- (3-carboxypropyl)
Production of ureido] -4-methoxy-6-tert-butylphenol (Compound No. V) (1) N-benzyloxycarbonylaniline 27.7
g of dimethylformamide (DMF) (150 ml) was added with 62% sodium hydride (5.4 g) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl 4-bromobutanoate 2 under ice cooling
A solution of 5.0 g of dimethylformamide (DMF) in 80 ml was added dropwise, and the mixture was stirred at room temperature overnight. DMF was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was concentrated. The residue was purified by silica gel chromatography (solvent; hexane: ethyl acetate = 5: 1) to give N. 19.6 g of -benzyloxycarbonyl-N-ethoxycarbonylpropylaniline was obtained as an oil. Dissolve 19.6 g of this product in 200 ml of ethanol, and add 10%
3.0 g of palladium-carbon (Pd-C) was added, and the mixture was subjected to catalytic reduction at room temperature and pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated to quantitatively obtain N-ethoxycarbonylpropyl-N-phenylamine as a powder.

(2) A mixed solution of 9.4 ml of a 2.464 M phosgene-dichloromethane solution and 75 ml of dichloromethane was cooled to −78 ° C., and the mixture was treated with (2-amino-4-methoxy-dichloromethane).
6-tert-butylphenoxy) methoxymethane
After dropwise adding a mixed solution of 69 g, 6.5 ml of triethylamine and 50 ml of dichloromethane, the temperature was raised to 0 ° C., and the solvent was distilled off under reduced pressure. 75m dichloromethane in the residue
l-N-ethoxycarbonylpropyl-N at room temperature.
-Phenylamine 3.20 g, triethylamine 3.2
A mixed solution of 50 ml of the mixture and 75 ml of dichloromethane was added dropwise, and the mixture was further stirred at room temperature for 1 hour and then refluxed for 6 hours.
After washing and drying the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 20: 1) to give {2- [3-phenyl-3- (3- Ethoxycarbonylpropyl) ureido] -4-83-methoxy-6-tert-butylphenoxydimethoxymethane (yield: 66%, properties:
An oil, IR: 1735, 1680, 1610) was obtained.

(3) 4.61 g of the main crystal in 46 m of ethanol
To the solution was added 9.8 ml of a 10% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. After distilling off ethanol under reduced pressure, the reaction solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate. After washing and drying the extract, the solvent was distilled off, and the crystalline residue was recrystallized from an isopropyl ether-ethyl acetate solution to give {2- [3-phenyl-3- (3-carboxypropyl) ureido] -4-. Methoxy-6-tert-
3.34 g of butylphenoxydimethoxymethane (yield:
77%, melting point: 147-150 ° C (decomposition)).

(4) 3.23 g of the main crystal in 32 ml of THF
1 ml of concentrated hydrochloric acid was added to the solution, and the mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed and dried, and the solvent is distilled off. The residue is recrystallized from a solution of isopropyl ether-ethyl acetate to give the target compound 2- [3-phenyl-3] represented by the following formula (V).
-(3-Carboxypropyl) ureido] -4-72-tert-butylphenol (1.72 g, yield: 59%, melting point: 118 to 120 ° C) was obtained.

[0081]

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Production Example 6 2- {3- [2- (diphenylmethylamino) ethyl]
Ureido} -4-methoxyphenol (Compound No. VI)
(1) N-benzyloxycarbonyl-2-ethylamine 30.5 g, diphenylmethylamine 18.0
g, 69.0 g of potassium carbonate and 200 ml of hexamethylphosphamide were stirred at room temperature for 3 days. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed, and dried,
28.4 g of N-benzyloxycarbonyl-2- (diphenylmethylamino) ethylamine were obtained. This product 9.0
g of ethanol 150 ml, water 150 ml, concentrated hydrochloric acid 4.
The mixture was dissolved in 2 ml of a mixed solution, and 2.0% of 10% palladium-carbon (Pd-C) was added thereto, followed by catalytic reduction at room temperature and pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain 3.9 g of 2- (diphenylmethylamino) ethylamine hydrochloride.

(2) A solution of phosgene in dichloromethane (3.1 M) A solution of 4.75 ml of dichloromethane in 30 ml of dichloromethane was cooled to -78 ° C., and 1.8 g of (2-amino-4-methoxyphenoxy) methoxymethane and 3 ml of triethylamine in dichloromethane were added. After dropping a 10 ml solution, the temperature was raised to 0 ° C., and the solvent was distilled off under reduced pressure. 30 ml of tetrahydrofuran was added to the residue to form a solution,
2.3 g of (diphenylmethylamino) ethylamine and 3 ml of triethylamine in 10 m of tetrahydrofuran
The solution was added dropwise, and the mixture was further stirred for 4 hours. After washing and drying the reaction solution, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; chloroform: ethanol = 25: 1) to give {2- [3- [2- (diphenylmethylamino)]. Ethyl] ureido] -4-methoxyphenoxydimethoxymethane 2.0 g (yield: 47%,
Melting point: 132-134 ° C).

(3) Main crystal 2.0 g methanol 50 ml
5 ml of concentrated hydrochloric acid was added to the solution, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous potassium carbonate solution was added to the reaction solution, methanol was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with water. This was further washed with a mixed solution of ethanol and ether, and dried to obtain the target compound 2- represented by the following formula (VI).
{3- [2- (diphenylmethylamino) ethyl] ureide} -4-methoxyphenol 1.4 g (yield: 78)
%, Melting point: 198-201 ° C).

[0085]

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Production Example 7 4-Phenyl-2-aminophenol (Compound No. VI
Production of I) L. C. Rayford
And J. C. Colbert (JC Colbe)
rt), Journal of American Chemical Society (J. Am. Chem. Soc.) 47 , 14
According to page 54 (1925), the target compound 4-phenyl-2-aminophenol represented by the following formula (VII) was obtained.

[0087]

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Production Example 8 1- (2-pyridyl) -2- (4-methoxy-3,5-
Preparation of dimethyl-2-pyridylmethylenethio) benzimidazole (Compound No. VIII) (1) 107.16 g of p-toluidine in DMSO 50
80 ml of carbon disulfide was added to the 0 ml solution, and 60 ml of an aqueous solution of 49.48 g of sodium hydroxide was added dropwise at room temperature. 800 ml of DMSO was further added to the mixture,
The reaction was performed for 30 minutes. Then, under ice cooling, methyl iodide 17
0.34 g was added dropwise. After stirring at room temperature for 3 hours, the reaction solution was distilled off under reduced pressure and poured into 6 liters of water. The precipitated crystals were collected by filtration and recrystallized from chloroform-n-hexane to give methyl p-toluidine carbodithioate 8
6.85 g (Yield: 44.0%, melting point: 79-81 ° C)
I got

(2) o-phenylenediamine 21.63
g, 2-bromopyridine 15.8 g, copper sulfate · 5H ₂ O
A mixture of 1.50 g and 100 ml of water was heated under reflux for 3 days. After cooling, the mixture was made alkaline by adding 30% aqueous ammonia, extracted with diethyl ether, and the diethyl ether layer was washed three times with water and dried over sodium sulfate. The solvent was evaporated to dryness under reduced pressure and recrystallized from methanol-isopropyl ether to give 8.03 g of N- (2-pyridyl) -o-phenylenediamine (yield: 43.4%, melting point: 129 to
131 ° C.).

(3) 100 ml of a mixture of 7.89 g of methyl p-toluidine carbodithioate obtained in (1) and 7.89 g of N- (2-pyridyl) -o-phenylenediamine obtained in (2) The solution was heated at reflux for 19 hours. The reaction solution was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1- (2-pyridyl) -2-.
6.95 g of mercaptobenzimidazole (yield: 7
6.4%, melting point: 233-234 ° C).

(4) 0.84 g of sodium hydroxide was added to a solution of 2.27 g of 1- (2-pyridyl) -2-mercaptobenzimidazole obtained in (3) in 20 ml of DMF.
A solution of 5 ml of water was added, and a solution of 2.44 g of 1-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 6 ml of DMF-water (2: 1, v / v) was added dropwise under ice cooling.
After returning to room temperature and stirring for 1 hour, the mixture was diluted with 10 ml of water, and the precipitated crystals were collected by filtration. Then, by recrystallization from chloroform-isopropyl ether, the following formula (VI
The target compound 1- (2-pyridyl) -2- represented by II)
2.62 g of (4-methoxy-3,5-dimethyl-2-pyridylmethylenethio) benzimidazole (yield: 6
9.7%, melting point: 145.5-147 ° C).

[0092]

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Preparation Example 9 Preparation of 1- (6-methoxy-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole (Compound No. IX) According to Example 35 of JP-B-6-55737,
The target compound 1- (6-methoxy-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole represented by the following formula (IX) was obtained.

[0094]

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Production Example 10 Production of 1- (3-hydroxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole (Compound No. X) In accordance with Example 6 of JP-B-6-55737, The target compound 1- (3-hydroxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole represented by the following formula (X) was obtained.

[0096]

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Production Example 11 1- (3-Isopropoxy-2-pyridyl) -2- (2
Preparation of -Dimethylaminobenzylthio) imidazole (Compound No. XI) According to Example 100 of JP-B-6-55737, the target compound 1- (3-isopropoxy-2-pyridyl) represented by the following formula (XI) ) -2- (2-Dimethylaminobenzylthio) imidazole was obtained.

[0098]

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Production Example 12 Production of 1- (5-amino-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole (Compound No. XII) Example 85- (2) of JP-B-6-55737 The target compound 1- represented by the following formula (XII)
(5-Amino-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole was obtained.

[0100]

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Production Example 13 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5- (2-furyl) pyrimidine-2]
Preparation of [-yloxy) ethoxy {pyrimidin-4-yl] benzenesulfonamide (Compound No. XIII) In accordance with Example 97 of JP-A-8-99961,
The target compound 4-tert- represented by the following formula (XIII)
Butyl-N- [5- (4-methylphenyl) -6- {2
-(5- (2-furyl) pyrimidin-2-yloxy)
[Ethoxydipyrimidin-4-yl] benzenesulfonamide was obtained as crystals.

[0102]

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Production Example 14 4-tert-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (2-
Methoxyphenoxy) -2-morpholinopyrimidine-4
Preparation of -yl] benzenesulfonamide (Compound No. XIV) According to Example 164 of JP-A-8-99961, the target compound 4-ter represented by the following formula (XIV)
t-Butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (2-methoxyphenoxy) -2-morpholinopyrimidin-4-yl] benzenesulfonamide is obtained as crystals. Was.

[0104]

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Production Example 15 N- [6- {2- (pyrimidin-4-yloxy) ethoxy} -5- (3-methoxyphenoxy) pyrimidine-
Preparation of 4-yl] -4-tert-butylbenzenesulfonamide (Compound No. XV) In accordance with Example 29 of JP-A-8-99961,
The target compound N- [6- {2-} represented by the following formula (XV)
(Pyrimidin-4-yloxy) ethoxy} -5- (3
-Methoxyphenoxy) pyrimidin-4-yl] -4-
Tert-butylbenzenesulfonamide was obtained as crystals.

[0106]

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Production Example 16 4-tert-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (2-
Methoxyphenoxy) -2-n-propylpyrimidine-
4-yl] benzenesulfonamide (Compound No. XVI)
According to Example 153 of JP-A-8-99961, the target compound 4-ter represented by the following formula (XVI)
t-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-n-propylpyrimidin-4-yl]
Benzenesulfonamide was obtained as crystals.

[0108]

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Production Example 17 Production of 4-hydroxy-3-methoxy-5-ethyl-naphthalenecarbaldehyde (Compound No. XVII) M. Tanaka, et al., Journal of Medical Chemistry (J. Med. Che
m) According to 35 (25), p. 4665 (1992), the target compound 4-hydroxy-3-methoxy-5-ethyl-naphthalenecarbaldehyde represented by the following formula (XVII) was obtained.

[0110]

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Production Example 18 2- (6-methoxy-2-naphthyl) acetic acid (Compound No.
XVIII) Production of A. Ormancy and A.
A. Horeau, Birce de la Sociét Cimique de France (Bull. Soc. Chi)
m. Fr. 1955 , p. 962, the desired compound 2- (6-methoxy-) represented by the following formula (XVIII).
2-Naphthyl) acetic acid was obtained.

[0112]

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Production Example 19 Production of 2- (6-hydroxy-2-naphthyl) acetic acid (Compound No. XIX) A. Ormancy and A.
A. Horeau, Birce de la Sociét Cimique de France (Bull. Soc. Chi)
m. Fr. 1955 , p. 962, the desired compound 2- (6-hydroxy-) represented by the following formula (XIX).
2-Naphthyl) acetic acid was obtained.

[0114]

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Various skin whitening preparations for whitening were prepared according to the following formulation and production method.

Example 1 Cream: (Formulation) (%) (1) Beeswax 6.0 (2) Cetanol 5.0 (3) Reduced Lanolin 5.0 (4) Squalane 30.0 (5) Glycerin Monostearate 4.0 (6) Lipophilic glyceryl monostearate 2.0 (7) Polyoxyethylene (20EO) sorbitan 2.0 monolaurate (8) Compound (I) ^{* 1} 0.1 (9) Magnesium phosphate-L-ascorbyl ^{* 2} 0.1 (10) Butyl paraben (preservative) Suitable amount (11) Perfume suitable amount (12) Remaining purified water * 1 Produced according to Production Example 1 * 2 Produced by Sigma (Method) A . Components (1)-(8), (10) and (11) were mixed and heated to 70 ° C.

B. Mixing components (9) and (12),
Heated and maintained at 70 ° C.

C. B was added to A, mixed, and then cooled to obtain a cream.

Example 2 Lotion: (Formulation) (%) (1) Glycerin 5.0 (2) 1,3-butylene glycol 6.5 (3) Polyoxyethylene (20EO) Sorbitan 1.2 Monolauric acid ester (4) Ethyl alcohol 8.0 (5) Compound (II) ^{* 1} 1.0 (6) Butylparaben (preservative) suitable amount (7) Perfume suitable amount (8) Purified water balance * 1 Production example 2 (Production method) A. Components (3), (4), (5), (6) and (7)
Was mixed and dissolved.

B. Components (1), (2) and (8) were mixed and dissolved.

C. A and B were mixed and made uniform to obtain a lotion.

Example 3 Emulsion: (Formulation) (%) (1) Polyoxyethylene (10EO) Sorbitan 1.0 Monostearate (2) Polyoxyethylene (60EO) Sorbit 0.5 Tetra Oleate (3) Glycerin monostearate 1.0 (4) Stearic acid 0.5 (5) Behenyl alcohol 0.5 (6) Squalane 8.0 (7) Compound (III) ^{* 1} 3.0 (8) Compound (IX) ^{* 2} 0.1 (9) Compound (XIX) ^{* 3} 0.2 (10) Phenoxyethanol (preservative) 0.1 (11) Carboxyvinyl polymer 0.1 (12) Sodium hydroxide 0.05 ( 13) Ethyl alcohol 5.0 (14) Remaining purified water (15) Appropriate amount of perfume * 1 Produced by Production Example 3 * 2 Produced by Production Example 9 * 3 Produced by Production Example 19 Components (10) to (14) were mixed by heating and maintained at 70 ° C.

B. The components (1) to (9) are mixed by heating.
It was kept at 0 ° C.

C. A was added to B, mixed, and uniformly emulsified.

D. After cooling C, (15) was added and mixed uniformly to obtain an emulsion.

Example 4 Ointment: (Formulation) (%) (1) Stearic acid 18.0 (2) Cetanol 4.0 (3) Triethanolamine 2.0 (4) Glycerin 5.0 (5) Compound ( IV) ^{* 1} 1.0 (6) Compound (X) ^{* 2} 0.1 (7) Compound (XVII) ^{* 3} 0.5 (8) Compound (XVIII) ^{* 4} 0.01 (9) Remaining purified water * 1 Manufactured according to Production Example 4 * 2 Manufactured according to Production Example 10 * 3 Manufactured according to Production Example 17 * 4 Manufactured according to Production Example 18 (Production method) A part of the components (3), (4) and (9) was mixed by heating and kept at 75 ° C.

B. Components (1), (2), (5),
(6), (7) and (8) were mixed by heating and kept at 75 ° C.

C. A was gradually added to B.

D. While cooling C, the rest of (9) was added to obtain an ointment.

Example 5 Pack: (Formulation) (%) (1) Polyvinyl alcohol 20.0 (2) Ethyl alcohol 20.0 (3) Glycerin 5.0 (4) Kaolin 6.0 (5) Compound (V) ) ^{* 1} 0.05 (6) Compound (XI) ^{* 2} 0.2 (7) Methylparaben (preservative) 0.2 (8) Perfume 0.1 (9) Remaining amount of purified water * 1 Prepared according to Production Example 5 * 2 Manufactured by Production Example 11 (Production method) Components (1), (3), (4) and (9) were mixed, heated to 70 ° C. and stirred.

B. Component (2), (5), (6), (7)
And (8) were mixed.

C. The above B was added to the above A, mixed, and then cooled to obtain a pack.

Example 6 Detergent: (Formulation) (%) (1) Stearic acid 10.0 (2) Palmitic acid 8.0 (3) Myristic acid 12.0 (4) Lauric acid 4.0 (5) Oleyl alcohol 1.5 (6) Purified lanolin 1.0 (7) Fragrance 0.1 (8) Butylparaben (preservative) 0.2 (9) Glycerin 18.0 (10) Potassium hydroxide 6.0 (11) ) Compound (VI) ^{* 1} 0.5 (12) Compound (XII) ^{* 2} 0.05 (13) Remaining amount of purified water * 1 Manufactured by Production Example 6 * 2 Manufactured by Production Example 12 (Production method) Mix components (9), (10) and (13) and mix
Heated to 0 ° C.

B. Components (1) to (6) and (8),
(11) and (12) were mixed and heated to 70 ° C.

C. Add B to A above
After the completion of the reaction, the mixture was cooled to 50 ° C., and the component (7) was added.

Example 7 Gel Ointment: (Formulation) (%) (1) Carboxyvinyl polymer 1.0 (2) Triethanolamine 1.0 (3) 1,3-butylene glycol 10.0 (4) Compound ( VII) ^{* 1} 0.01 (5) Compound (XIII) ^{* 2} 0.002 (6) Remaining amount of purified water * 1 Produced according to Production Example 7 ^{* 2} Produced according to Production Example 13 (Production method) Components (1) and (3) to (6) were mixed and dissolved.

B. Component (2) was added to A and mixed to make a uniform, and a gel ointment was obtained.

Example 8 Cream: A cream was prepared by the following formulation and the following method.

(Formulation) (%) (1) Polyoxyethylene (40EO) monostearate 2.0 (2) Glycerin monostearate (self-emulsifying type) 5.0 (3) Stearic acid 5.0 ( 4) behenyl alcohol 0.5 (5) squalane 15.0 (6) cetyl isooctanoate 5.0 (7) 2-ethylhexyl paramethoxycinnamate 5.0 (8) methyl paraben 0.1 (9) 1,3 -Butylene glycol 5.0 (10) Compound (VIII) ^{* 1} 0.2 (11) Compound (XIV) ^{* 2} 0.05 (12) Compound (XV) ^{* 3} 0.01 (13) Compound (XVI) ^{* 4} 0.1 (14) Remaining amount of purified water (15) Appropriate amount of fragrance * 1 Manufactured by Production Example 8 * 2 Manufactured by Production Example 14 * 3 Manufactured by Production Example 15 * 4 Manufactured by Production Example 16 Components (1) to (7) and (10) to (13)
The mixture was dissolved by heating at 0 ° C.

B. Components (8), (9) and (14) were heated to 70 ° C.

C. A was added to B and cooled to obtain a cream.

D. Component (15) was added to C, and the mixture was cooled to obtain a cream.

[0143]

The formulas (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (X
V), (XVI), (XVII), (XVIII) or (XIX), and / or a salt thereof, as an active ingredient, the external preparation for whitening skin of the present invention suppresses melanin production of melanocytes. Thus, a melanin pigmentation-preventing / improving effect is excellent, and a skin whitening preparation containing the compound exhibits an excellent skin-whitening effect, and is extremely useful for prevention and treatment of spots and freckles caused by sunburn.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/11 A61K 31/11 31/135 31/135 31/165 31/165 31/17 31/17 31/19 31/19 31/24 ADA 31/24 ADA 31/44 31/44 31/505 31/505 31/535 31/535 C07D 239/34 C07D 239/34 // C07D 401/04 233 401/04 233 401/12 239 401 / 12 239 401/14 235 401/14 235 405/14 239 405/14 239 (72) Inventor Hiroshi Omizu 5 Matsugasaki Unkujicho, Sakyo-ku, Kyoto 5 Matsugasaki Parkhomes 505 (72) Inventor Taku Hoshino Sakaemachi, Kita-ku, Tokyo 48-18 Kose Research Institute Co., Ltd. (72) Eiji Nari, Inventor 48-18 Sakaemachi, Kita-ku, Tokyo 48-18 Kose Research Institute, Inc. (72) Inventor Mikimasa Takisada 48-18, Sakaemachi, Kita-ku, Tokyo Kose Research Institute, Inc.

Claims (2)

[Claims] 1. A whitening ingredient comprising any one of the following compounds and / or salts thereof as an active ingredient: Embedded image Embedded image Embedded image Embedded image Embedded image 2. An external preparation for skin whitening comprising the whitening ingredient according to claim 1 as an active ingredient.