JPH05139946A - Melanin inhibitor - Google Patents

Abstract

PURPOSE:To obtain a melanin inhibitor strongly suppressing enzyme activity related to melanin synthesis, having excellently improving effects on melanization, comprising a benzyl phenyl, ketone derivative as an active ingredient. CONSTITUTION:A melanin inhibitor comprising 0.01-50wt.%, preferably 0.1-20wt.% compound of the formula (R<1> to R<10> are H, OH or lower alkoxy; R<11> is H, OH or cyano) such as 3,4-dihydroxyphenyl-p-hydroxybenzyl ketone as an active ingredient. The inhibitor can be prepared into a form such as lotion, milky lotion, pack or gel. The inhibitor is locally applied to an affected part such as stain of skin, freckle, chromatosis after suntan. The amount of the inhibitor used is 1-20mg based on 1cm<2> skin face in the case of cream or ointment and 1-10mg in the case of liquid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin inhibitor, and more particularly to a melanin inhibitor containing a benzyl phenyl ketone derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Problems to be Solved by the Invention
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 melanin synthesis 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 delay 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 cause a clear difference from the surrounding normal skin color.

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.

For example, in recent years, cosmetics containing a vitamin C (L-ascorbic acid) derivative having an excellent reducing ability have also 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 with the safety of the substance itself (irritation, allergenicity), and also cause vitiligo. In some cases, there is a problem in that it is mixed as a drug. In addition, various melanin inhibitors such as isoflavone derivatives (JP-A-58-225004) and p-hydroxycinnamic acid as a cinnamic acid derivative (JP-A-59-19).
6813), p-hydroxycinnamic acid amide derivatives (JP-A-62-56459), and the like.

However, at present, no substance is known that has a substantial effect of improving pigmentation and is excellent in compoundability with a cosmetic base.

[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, and as a result, a specific benzyl phenyl ketone derivative was identified. The inventors have found that they have a melanin production inhibitory effect and have completed the present invention.

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

[0009]

[Chemical 2]

(In the formula, R ^{1 to} R ¹⁰ are each a hydrogen atom,
A hydroxyl group or a lower alkoxy group, R ¹¹ is a hydrogen atom,
The present invention provides a melanin inhibitor containing a benzyl phenyl ketone derivative represented by a hydroxyl group or a cyano group) as an active ingredient.

In the above general formula (1), the lower alkoxy group is an alkoxy group having 1 to 5 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group and the like. Is mentioned.

The benzyl phenyl ketone derivative (1) used in the present invention is preferably one in which at least one of the substituents R ^{1 to} R ¹¹ is a hydroxyl group. In particular, R ¹ ~
It is preferable that three of R ¹¹ are hydroxyl groups and at least one of R ^{5 to} R ¹⁰ is a hydroxyl group.

For example, 3,4-dihydroxyphenyl
p-hydroxybenzyl ketone, 2,4-dihydroxyphenyl m-hydroxybenzyl ketone, 2,4-
Dihydroxyphenyl p-methoxybenzyl ketone, 2,4,6-trihydroxyphenyl p-hydroxybenzyl ketone, 2,3,4-trihydroxyphenyl p-hydroxybenzyl ketone, 2,4,6
-Trihydroxyphenyl-p-hydroxy-m-methoxybenzyl ketone, 2,4,6-trihydroxyphenyl 2,4-dihydroxybenzyl ketone, 2,
4,6-Trihydroxyphenyl 2,4-dimethoxybenzyl ketone, 2-hydroxy-4-methoxyphenyl p-hydroxybenzyl ketone, 4-hydroxyphenyl p-hydroxybenzyl ketone, phenyl p-hydroxybenzyl ketone, phenyl α-cyano -P-hydroxybenzyl ketone, phenyl benzyl ketone, 4,4'-dihydroxybenzoin and the like can be mentioned. Particularly suitable compounds include 2,4-dihydroxyphenyl p-hydroxybenzyl ketone.

The benzyl phenyl ketone derivative (1) used in the present invention can be synthesized according to the method described in the literature or according to it. For example, catechol and p
-A method of condensing hydroxyphenylacetic acid in the presence of polyphosphoric acid (Agric. Biol. Chem., 32.
Vol., Pp. 769-772 (1968)), or a method of condensing phloroglucin and p-hydroxyphenylacetonitrile in the presence of hydrogen chloride gas (Angew. Ch.
em. Int. Ed. Engl. , 20 volumes, 102-1
03 (1981)) and the like. It should be noted that some of the benzyl phenyl ketone derivatives used in the present invention are known as rejection reaction inhibitors and immunostimulatory anti-inflammatory reagents.

In the melanin inhibitor of the present invention, these benzyl phenyl ketone derivatives (1) can be used alone or in combination of two or more, and preferably 0.01 to 50% by weight, particularly preferably 50% by weight based on the total amount of the melanin inhibitor. Is 0.1
It is produced by blending ˜20% by weight.

As the optional components which can be added to the melanin inhibitor of the present invention, those components which are commonly used in cosmetics and external preparations for skin, such as oily substances, humectants, thickeners, preservatives, emulsifiers, Medicinal ingredients, fragrances, emulsion stabilizers and the like can be used. In addition, as various active ingredients, allantoin, vitamin E derivative, glycyrrhizin, ascorbic acid derivative, kojic acid, arbutin, pantothenic acid derivative, placenta extract, anti-inflammatory agent, yoquinin, various plant extracts, and the like to give melanin. The suppression effect can be improved. Furthermore, by adding various ultraviolet absorbing substances, a melanin inhibitor having both preventive and therapeutic effects on sunburn can be obtained.

The melanin inhibitor of the present invention can be prepared in various forms by conventional methods. Generally, it is in the form of lotion, emulsion, cream, ointment, stick, solution with an organic solvent, or pack. Preferably, it is in the form of gel.

The melanin inhibitor of the present invention thus obtained is topically applied to affected areas such as skin spots, freckles, and pigmented areas after sunburn. In general, the dose is 1 cm on the skin surface for cream or ointment preparations.
^{1 to 20} mg per ² ; 1 to 10 for liquid formulations
It is preferably mg.

[0019]

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

[0020]

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 2,4-dihydroxyphenyl p-hydroxybenzyl ketone (a): 30
90.0 g of 85% phosphoric acid (7.
60.0 g of diphosphorus pentoxide (4.2x) in 8x10 ^-1 mol)
10 ^-1 mol) was added, and the mixture was vigorously stirred. After the dissolution of diphosphorus pentoxide, 6.0 g (54.0) of resorcin at 90 ° C.
mmol) and p-hydroxyphenylacetic acid 7.3 g (48.
(0 mmol) was added at the same time, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into 3000 ml of ice water, stirred overnight, extracted with ethyl acetate, washed with water and saturated brine,
The solvent was distilled off. 7.7 g (67.0) of the obtained crude product.
%) In ethyl acetate and column chromatography (Wak) using hexane: ethyl acetate (1: 1).
ogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., 60.0
Purified according to g). 3.22 g (yield 28.0%) of the obtained yellow crystals were recrystallized from ethyl acetate and hexane to obtain 2.0 g of compound (a) (colorless crystals, yield 17.4).
%) Was obtained.

With respect to the compound (a), the melanin suppressing effect was determined by the following method. The suppressive effect was ++. Evaluation of tyrosinase activity in mouse dorsal skin hair follicle organ culture system: The dorsal hair follicles of 8 to 11-day-old C57BL mice that actively perform melanin synthesis were cultured for 3 to 4 days.
The evaluation sample was added to the culture solution to a final concentration of 5 mM, and the enzyme responsible for melanin synthesis, tyrosinase activity, was added to ³ H.
-It was measured by the amount of tritium released from tyrosine, compared with the control, and evaluated according to the following criteria. Criteria: No suppressive effect (equivalent to control): 0 to 5%: ± 5 to 35%: + 35% or more: ++

Example 2 4-hydroxyphenyl p-
Synthesis of hydroxybenzyl ketone (b): 60.0 g (5.2 x 1) of 85% phosphoric acid in a 300 ml four-necked flask.
0 ^-1 mol) in phosphorus pentoxide 60.0g (4.2 × 10 ^-1
mol) was added and stirred vigorously. After diphosphorus pentoxide was dissolved, at 90 ° C. resorcin 4.7 g (42.7 mmol)
And p-hydroxyphenylacetic acid 7.6g (50.0mmo
l) was added at the same time and stirred at the same temperature for 2 hours. The reaction mixture was poured into 200 ml of ice water and stirred overnight, then extracted with ethyl acetate, washed with water, washed with saturated sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained crude product was dissolved in ethyl acetate and subjected to column chromatography (Wakogel C) using hexane: ethyl acetate (10: 3).
-200, 20.0 g) to give compound (b)
1.5 g (colorless crystals, yield 13.2%) was obtained.

The compound (b) was evaluated for its melanin suppressing effect in the same manner as in Example 1, and the result was ++.

Example 3 Synthesis of 2,4-dihydroxyphenyl m-hydroxybenzyl ketone (c): 10
In a 0 ml four-necked flask, 18.0 g of 85% phosphoric acid (15
Diphosphorus pentoxide 12.0 g (84.5 mmo) in 6.1 mmol)
l) was added and stirred vigorously. After diphosphorus pentoxide was dissolved, 1.1 g (10.0 mmol) of resorcinol and 1.0 g (6.6 mmol) of m-hydroxyphenylacetic acid were added simultaneously at 90 ° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into 200 ml of ice water, stirred overnight, and then neutralized with sodium carbonate. Then, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated. The obtained crude product was dissolved in ethyl acetate and subjected to column chromatography (Wak) using hexane: ethyl acetate (3: 1).
Ogel C-200, 20.0 g) to obtain 170 mg of compound (c) (yellow crystals, yield 10.5%).

The compound (c) was evaluated for melanin suppressing effect in the same manner as in Example 1, and the result was ++.

Example 4 Synthesis of 3,4-dihydroxyphenyl p-hydroxybenzyl ketone (d): 30
60.0 g of 85% phosphoric acid (5.
2 × 10 ^-1 mol) in phosphorus pentoxide 60.0 g (4.2 ×
10 ^-1 mol) was added, and the mixture was vigorously stirred. After the dissolution of diphosphorus pentoxide, 5.5 g of catechol (50.0
mmol) and 7.6 g of p-hydroxyphenylacetic acid (50.
(0 mmol) was added at the same time, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into 200 ml of ice water, stirred overnight, extracted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated. The obtained crude product was dissolved in ethyl acetate and subjected to column chromatography (Wakogel C-200,2) using hexane: ethyl acetate (10: 3).
The compound (d) (600 mg, colorless crystals, yield 4.9%) was obtained after purification by 0.0 g).

When the compound (d) was evaluated for its melanin suppressing effect in the same manner as in Example 1, the result was ++.

Example 5 Synthesis of 2-hydroxy-4-methoxyphenyl p-hydroxybenzyl ketone (e): 85% phosphoric acid 225% in a 300 ml four-necked flask.
172.0 g of diphosphorus pentoxide to 0 g (1.95 mol)
(1.1 mol) was added and the mixture was vigorously stirred. After diphosphorus pentoxide was dissolved, m-methoxyphenol 1 was added at 90 ° C.
5.0 g (0.12 mol) and 16.5 g (0.11 mol) of p-hydroxyphenylacetic acid were added simultaneously, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into 1000 ml of ice water and stirred overnight, and the crude product obtained by filtration was dissolved in ethyl acetate and subjected to column chromatography (Wakogel C- using hexane: ethyl acetate (1: 1)).
200,60.0 g) to give compound (e) 1
0.4 g (colorless crystals, yield 36.6%) was obtained. The crystals were recrystallized from ethyl acetate and hexane to obtain 6.1 g of the desired product.

Example 6 Synthesis of 2,4,6-trihydroxyphenyl p-hydroxybenzyl ketone (f): Phloroglucin 4.7 in a 300 ml four-necked flask.
75 g of dry ether was added to g (38.0 mmol) and 5.0 g (38.0 mmol) of p-hydroxybenzyl cyanide, and the mixture was stirred at 0 ° C. Hydrogen chloride gas was passed for 6 hours while maintaining the same temperature, and then left at room temperature for 24 hours.
The suspended reaction solution was poured into 150 ml of water and refluxed for 2 hours. The precipitate formed by cooling was filtered and recrystallized from methanol to obtain 4.8 g of compound (f) (colorless crystals, yield 48.6%).

When the compound (f) was evaluated for its melanin suppressing effect in the same manner as in Example 1, the result was ++.

Example 7 Synthesis of 2,3,4-trihydroxyphenyl p-hydroxybenzyl ketone (g): 0.95 pyrogallol in a 300 ml four-necked flask.
50 g of dry ether was added to 1.0 g (7.5 mmol) of p-hydroxybenzyl cyanide.
Stirred at 0 ° C. Hydrogen chloride gas was passed for 6 hours while maintaining the same temperature, and then left at room temperature for 24 hours. The suspended reaction solution was poured into 20 ml of water and refluxed for 2 hours. The precipitate formed by cooling was filtered and recrystallized twice with methanol to obtain 140 mg of compound (g) (colorless crystals, yield: 7.2%).

The compound (g) was evaluated for melanin-inhibiting effect in the same manner as in Example 1, and the result was ++.

Example 8 Synthesis of 2,4,5-trihydroxyphenyl p-hydroxybenzyl ketone (h): 1.90 g (15.0 mmol) 1,3,4-trihydroxybenzene in a 300 ml four-necked flask. 50 ml of dry ether was added to 2.0 g (15.0 mmol) of p-hydroxybenzyl cyanide, and the mixture was stirred at 0 ° C. Hydrogen chloride gas was passed for 6 hours while maintaining the same temperature, and then left at room temperature for 24 hours. The bluish black precipitate was filtered and recrystallized from water to obtain 500 mg of compound (h) (black crystals, yield 12.8%).

Example 9 Synthesis of p-hydroxybenzyl phenyl ketone (i): (1) 41.5 g of potassium carbonate in a 1 l four-necked flask.
(0.30 mol), p-hydroxyacetonitrile 2
0.0 g (0.15 mol) and 300 ml of acetone were added, and the mixture was stirred at room temperature. 31.1 g (0.23 mol) of benzyl bromide in 30 ml of acetone was added dropwise over 15 minutes,
The mixture was stirred at 50 ° C for 4 hours. Excess potassium carbonate was filtered off, the solvent was distilled off, and the residue was crystallized to obtain 29.4 g of p-benzyloxyphenylacetonitrile (ocherous crystals, yield 87.8%).

(2) 0.35 g (14.5 mmol) of sodium hydride and dry THF in a 200 ml four-necked flask.
20 ml was added, and 2.0 g (8.6 mmol) of p-benzyloxyphenylacetonitrile dissolved in 5 ml of THF was added at room temperature. Then, when refluxing, 1.42 g (9.5 mmol) of ethyl benzoate dissolved in 5 ml of THF was added dropwise, and the mixture was further refluxed for 1 hour. After completion of the reaction, 100 ml of water was added, and the mixture was concentrated, extracted with ethyl acetate, washed with saturated saline, and dried with sodium sulfate. 4.0 g of the residue obtained by distilling off the solvent was dissolved in ethyl acetate and subjected to column chromatography (W with hexane: ethyl acetate (4: 1)).
akogel C-200, 60.0 g), and 1.18 g of phenyl α-cyano-p-hydroxybenzyloxybenzyl ketone (colorless crystals, yield 40.
7%).

Next, in a 100 ml flask, 15 ml of concentrated sulfuric acid was added.
1, and further at −10 ° C., 0.7 g of phenyl α-cyano-p-hydroxybenzyloxybenzyl ketone (2.1
mmol) was added and the temperature was raised to dissolve. After the temperature was lowered to 0 ° C. again, 50 ml of water was quickly added and the mixture was refluxed for 2 hours. After completion of the reaction, the solution was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was evaporated and the obtained residue was dissolved in ethyl acetate and purified by column chromatography (Wakogel C-200, 60.0 g) using hexane: ethyl acetate (2: 1) to give compound (i) 80 mg ( Yellow crystals, yield 18.1
%) Was obtained.

Example 10 Phenyl α-cyano-p-
Synthesis of hydroxybenzyl ketone (j): 5% Pd / C 200 mg in a nitrogen atmosphere in a 100 ml three-necked flask,
And 200 mg of phenyl α-cyano-p-hydroxybenzyloxybenzyl ketone were added, and further 15 ml of ethanol was added. Hydrogen gas was passed through for 48 hours while stirring at room temperature. After the reaction, the mixture was filtered through Celite, washed with ethanol, and the solvent was distilled off. The residue was dissolved in ethyl acetate and column chromatography (Wakogel C-200,6) using hexane: ethyl acetate (2: 1).
0.0 g) to obtain 96 mg of compound (j) (colorless crystals, yield 71.6%).

Example 11 2,4,6-Trihydroxyphenyl 2,4-dimethoxybenzyl ketone (k)
Synthesis of 2,4-dimethoxyphenylacetonitrile [J. Indian Chem. Soc. , Volume 13, 2
Page 36 (1936)] 2.72 g (15.35 mmo)
l), 2.73 g of phloroglucinol dihydrate (16.
84 mmol) and 1.21 g (8.9) of anhydrous zinc (II) chloride.
mmol) was dissolved in 40 ml of ether, and hydrochloric acid was continuously blown therein for 50 minutes, followed by stirring for 18 hours. After adding 40 ml of water in an ice bath, the orange solid precipitated was repeatedly recrystallized from ethanol to give 2.84 g of compound (k) (pale yellow crystal, yield 6).
0.8%) was obtained.

Example 12 Synthesis of 2,4,6-trihydroxyphenyl 2,4-dihydroxybenzyl ketone (l): 0.43 g of 2,4,6-trihydroxyphenyl 2,4-dimethoxybenzyl ketone (1.
(43 mmol) was dissolved in 40 ml of methylene chloride, and a 1.0 M solution of boron tribromide in methylene chloride was added dropwise in an ice bath. After that, liquid separation operation was performed to separate the aqueous layer, 1N sodium hydroxide was added to the aqueous layer, neutralized, and then concentrated under reduced pressure at 20 ° C. The obtained residue was washed with ethanol, salts were removed by filtration, and the ethanol washing solution was concentrated. The washing residue was subjected to preparative thin layer chromatography (Merck 5717, Merc).
CK, 2 sheets hexane: ethyl acetate: methanol = 1
0: 10: 1 double development) and gel filtration column (LH-2
0, sequentially separated with Pharmacia, MeOH), and 0.13 g of compound (l) (pale yellow crystal, yield 33.5%)
Got

The compound (l) was evaluated for its melanin suppressing effect in the same manner as in Example 1, and the result was ++.

Example 13 Synthesis of 4,4'-dihydroxybenzoin (m): 1.45 g of potassium cyanide (2
2.3 mmol) was dissolved in 15 ml of distilled water and p-anisaldehyde 15.01 g (110.2 mmol) / ethanol 3
After dropping 0 ml, the mixture was heated under reflux for 27 hours. After adding 30 ml of water to the reaction system, extraction was carried out with ether, and the obtained ether layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was separated by a flash column (450 g of silica gel, hexane / ethyl acetate = 20: 1 to 7: 1) to collect 5.91 g (39.4 mmol) of p-anisaldehyde and 5.58 g of a yellow solid. Got The yellow solid was recrystallized from ethanol to obtain 5.05 g of 4,4'-dimethoxybenzoin (pale yellow crystal, yield 33.6%).

Next, 1.30 g (4.77 mmol) of 4,4'-dimethoxybenzoin was dissolved in 20 ml of methylene chloride, and 1.0 M boron tribromide methylene chloride solution 1 was prepared in an ice bath.
After dropwise adding 9.01 ml (19.01 mmol), 5 in an ice bath
Stir for hours. In an ice bath, 50 ml of water was added dropwise to the reaction system, and then liquid separation operation was performed to separate a methylene chloride layer and an aqueous layer,
Further, the aqueous layer was extracted with ether. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was flash column (silica gel 150 g, hexane / ethyl acetate = 4:
1-3: 2) and preparative thin layer chromatography (Me
rck 5717, 2 sheets hexane: ethyl acetate: methanol = 10: 10: 1 double development) were sequentially performed to obtain 0.13 g of compound (m) (pale yellow crystal, yield 11.3%).

Example 14 Synthesis of 2,4,6-trihydroxyphenyl-p-hydroxy-m-methoxybenzyl ketone (n): 2.51 g (15.35 mmol) of 4-hydroxy-3-methoxyphenylacetonitrile, flo 2.73 g (16.84 mmol) of loglucinol dihydrate
And 1.21 g (8.9 mmol) of anhydrous zinc (II) chloride were dissolved in 40 ml of ether, and hydrochloric acid was continuously blown therein for 50 minutes, followed by stirring for 18 hours. After adding 40 ml of water in an ice bath, the precipitated orange solid was repeatedly recrystallized from ethanol to obtain 2.72 g of compound (n) (pale yellow crystal, yield 60.8%).

When the compound (n) was evaluated for its melanin suppressing effect in the same manner as in Example 1, the result was ++.

Example 15 Using a brown guinea pig having an acquired ability to form melanin pigment spots as an experimental animal, the effect of improving fading on pigmentation was investigated after pigmentation.

Test method: Using a brown guinea pig (a guinea pig whose skin color is similar to that of a yellow race, pigmented spots start to appear about 4 days after the irradiation of ultraviolet rays like humans, and become the blackest after about 8 days) The back hair of each guinea pig was shaved with a hair clipper and further shaved with an electric razor. After administration of 8-methoxypsoralen (PUVA) to this guinea pig intraperitoneally, U
Irradiation with VA (BLB lamp, 3.1 mW / cm ² ) for 5 minutes. 15 days after irradiation, a 5% solution of the evaluation sample compound (a) (ethanol 80
%, 20% water) were applied twice a day for a total of 24 days. The degree of blackening of the skin color was visually evaluated according to the following criteria, and the evaluation points were averaged to measure the effect. The results are shown in Table 1.

Criteria:-: 0: No pigmentation is observed. ±: 1: A slight pigmentation with unclear boundaries is recognized. +: 2: Medium pigmentation with clear boundaries is recognized. ++: 3: Intense pigmentation with clear boundaries is recognized.

[0049]

[Table 1]

Example 16 Preparation of lotion type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (a) 5 Glycerin 4 Polyoxyethylene (30 E.O.) Hydrogenated castor oil 1.5 Ethanol 10 Sodium pyrrolidonecarboxylate 2 Perfume Micro purified water balance 100

Example 17 Preparation of oil essence type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (c) 5 Mink oil 55 Wheat germ oil 40 100

Example 18 Preparation of powder essence type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (b) 5 Mannitol 95 100

Example 19 Preparation of W / O type moisture cream type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (a) 5 Vaseline 4 Cholesterol 0.6 Cetanol 0.5 Sorbitan sesquioleate 2 Liquid lanolin 4 Isopropyl palmitate 8 Squalane 10 Solid paraffin 4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Perfume 0.2 Purified water Balance 100

Example 20 Preparation of O / W type moisture cream type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (g) 5 Stearic acid 2 Cetanol 4 Vaseline 5 Squalane 8 Hardened palm oil 4 Polyoxyethylene (20) sorbitan mono stearate 1.4 Lipophilic glyceryl monostearate 2.4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Dipropylene glycol 3 Potassium hydroxide 0.2 Perfume 0.2 Purified water Balance 100

Example 21 Preparation of emulsion type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (a) 5 Stearic acid 1 Cetanol 2 Vaseline 2.5 Squalane 4 Hardened palm oil 2 Polyoxyethylene (20) sorbitan mono stearate 1.4 Lipophilic glyceryl monostearate 1.2 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3 Dipropylene glycol 3 Potassium hydroxide 0.2 Carboxyvinyl polymer 0.2 Perfume 0.2 Purified water Balance 100

Example 22 Preparation of pack type (paste peel-off type) melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (d) 10 Polyvinyl alcohol 12 Sodium carboxymethyl cellulose 3 Dipropylene glycol 2 Glycerin 2 Ethanol 5 Olive oil 3 Polyoxyethylene hydrogenated castor oil (30 E.O.) 0.5 Titanium oxide 8 Kaolin 6 Perfume 0.1 Methylparaben 0.1 Purified water Balance 100

Example 23 Preparation of ointment type melanin inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) 2,4,6-trihydroxyphenyl-p-hydroxy-m-methoxybenzyl ketone 10 White petrolatum 90 100

Example 24 Preparation of Solvent-Type Melanin Inhibitor: A melanin inhibitor having the following composition was prepared. (Composition) (% by weight) Compound (f) 10 Ethanol 90 100

The melanin inhibitors of the present invention obtained in Examples 16 to 24 all had a good feeling in use and had almost no side effects.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Genji Imokawa 1022-89 Himurocho, Utsunomiya City, Tochigi Prefecture 72-89 (72) Hiroko Shirokura 561 Yamamoto-cho, Utsunomiya City, Tochigi Prefecture 10 (72) Inventor Go Kobayashi Haga, Tochigi Prefecture 4954 Kaoru-shi, Kaori-cho Kaori Castle Dormitory E-101

Claims (1)

[Claims] 1. The following general formula (1): (In the formula, R ^{1 to} R ¹⁰ each represent a hydrogen atom, a hydroxyl group or a lower alkoxy group, and R ¹¹ represents a hydrogen atom, a hydroxyl group or a cyano group), and a melanin inhibitor containing the benzyl phenyl ketone derivative as an active ingredient. ..