JP3071990B2 - External preparation for skin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a chromone derivative and an external preparation for skin containing the compound.

[0002]

2. Description of the Related Art Blots, freckles and pigmentation on skin after sunburn occur with the aging, increase and become difficult to disappear, which is a problem for middle-aged and elderly people. The mechanism of the onset of these pigmentation diseases has not been elucidated yet, but it is considered that the action of sun rays, particularly ultraviolet rays, melanocyte stimulating hormone, and the like has enhanced the melanin synthesis function in epidermal melanocytes.

[0003] Further, it is considered that the keratinization delay associated with the aging of epidermal keratinocytes (keratinocytes) also causes an increase in the density of melanin granules in the epidermis, that is, a symptom of clinically increasing pigmentation. These pigmentations are localized and may cause a clear difference from the surrounding normal skin color.

[0004] There is a strong demand for the development of a drug capable of restoring such acquired pigment (ie, melanin) deposits to a normal skin color, and many drugs have been commercialized so far.

For example, in recent years, cosmetics containing a vitamin C (L-ascorbic acid) derivative having excellent reducing ability have been used. However, this also has difficulty in stability, and almost no effect is observed in external use. On the other hand, in the United States and Europe, hydroquinone is used as a drug for treating spots and whitening black skin. However, there are also problems with the safety (irritant and allergic) of the substance itself, and cases that cause vitiligo There is a problem in formulating it as a drug from the viewpoint of the presence of some drugs. In addition, various skin external preparations such as isoflavone derivatives (JP-A-5
No. 8-225004) and p as cinnamic acid derivatives
-Hydroxycinnamic acid derivatives (JP-A-59-196813)
Is known.

[0006] However, at present, there is no substance which has a substantial pigmentation improving effect and is excellent in incorporation into a cosmetic base. Under such circumstances, the present inventors have found that chromone derivatives are safe and have an excellent pigmentation-improving effect, and have previously filed a patent application (JP-A-5-301813).

[0007]

However, as a result of further studies, the present inventors have found that most of the chromone derivatives disclosed in the above specification have poor light stability. Accordingly, an object of the present invention is to provide a compound which is excellent in safety and pigmentation-improving effect and has good stability to light.

[0008]

Means for Solving the Problems Accordingly, the present inventors have:
As a result of conducting various studies to solve the above problems, the present inventors have found that a specific chromone derivative represented by the following general formula (1), which is not specifically disclosed in the above specification, satisfies the above conditions. Was completed.

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

[0010]

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Wherein R ¹ represents a linear or branched alkyl group having 4 to 15 carbon atoms and R ² represents a methoxy group, a skin external preparation containing the chromone derivative as an active ingredient, And a melanin inhibitor.

[0012]

[0013]

[0014]

Specific examples of the chromone derivative of the general formula (1) in the present invention include, for example, 2-butylchromone,
-Pentylchromone, 2-heptylchromone, 2-nonylchromone, 2-hexadecylchromone, 2- (1-ethylpentyl) chromone, 2-butyl-7-methoxychromone, 2-pentyl-7-methoxychromone, 2-heptyl -7-methoxychromone, 2-nonyl-7-methoxychromone, 2-pentadecyl-7-methoxychromone, 2- (1-ethylpentyl) -7-methoxychromone, 7-hydroxy-2-methylchromone, 7-hydroxy -2-butylchromone, 7-hydroxy-2-pentylchromone, 7-hydroxy-2-heptylchromone, 7-hydroxy-2-nonylchromone, 7-hydroxy-2-pentadecylchromone, 7-hydroxy-2
-(1-ethylpentyl) chromone and the like are preferred. Particularly preferred compounds are those in which R ¹ is a linear or branched alkyl group having 4 to 9 carbon atoms and R ² is a hydrogen atom, a hydroxy group, or a methoxy group. -Pentylchromone, 2-heptylchromone, 2-nonylchromone, 2-
(1-ethylpentyl) chromone, 2-butyl-7-methoxychromone, 2-pentyl-7-methoxychromone, 2-heptyl-7-methoxychromone, 2-nonyl-7-methoxychromone, 2- (1-ethyl Pentyl)
-7-methoxychromone, 7-hydroxy-2-butylchromone, 7-hydroxy-2-pentylchromone, 7
-Hydroxy-2-heptylchromone, 7-hydroxy-2-nonylchromone, 7-hydroxy-2- (1-ethylpentyl) chromone and the like.

The chromone derivative (1) of the present invention can be synthesized, for example, according to the following method.

[0017]

Embedded image

(Wherein R ¹ and R ² have the same meanings as described above, and R ³ represents a methyl group or an ethyl group). That is, the compound (2) and the compound (3) are reacted in the presence of a base such as sodium hydride. The compound can be easily obtained by a method of dehydrating by heating in the presence of an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like (for example, Lindeman et al: 304, 456 (1927). ), VV, irk
ar et la: Indian.Acad.Sci., 30A, 57 (1949), JHRicha
rds et al: 1610 (1948)).

In the skin external preparation of the present invention, these chromone derivatives (1) can be used alone or in combination of two or more, and 0.01 to 50% by weight (hereinafter simply referred to as%) in the total amount of the skin external preparation. Preferably 0.1 to 20)
%, More preferably 0.1 to 5%.

The external preparation for skin of the present invention can be prepared into various forms by a conventional method, and is generally a lotion, an emulsion, a cream, an ointment, a stick, a solution with an organic solvent, a pack, etc. And a gel.

The external preparation for skin of the present invention can contain any component other than the chromone derivative (1) as long as the effect of the present invention is not impaired. Components used, for example, purified water, ethanol, oily substances, humectants, thickeners, preservatives, emulsifiers, medicinal ingredients, powders, fragrances, emulsion stabilizers, pH adjusters and the like can be used.

Specific examples of the oily component include liquid paraffin, vaseline, paraffin wax, squalane, beeswax, carnauba wax, olive oil, lanolin, higher alcohols, fatty acids, synthetic ester oils of higher alcohols and fatty acids, and silicone oils. As the agent, sorbitol, xylitol, glycerin, maltitol, propylene glycol, 1,3-butylene glycol, 1,4
-Butylene glycol, pyrrolidone carboxylate, lactic acid, sodium lactate, polyoxypropylene fatty acid ester, polyethylene glycol and the like; water-soluble polymers such as carboxyvinyl polymer, carboxymethylcellulose, polyvinyl alcohol, carrageenan and gelatin as the thickener; Electrolytes such as sodium chloride and potassium chloride; urea, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium benzoate, etc. as preservatives; polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene as emulsifier Oxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene Non-ionic surfactants such as hydrogenated castor oil and polyoxyethylene sorbitol fatty acid ester; powders include talc, sericite, mica, kaolin, silica, bentonite, vermiculite, zinc white, mica, mica titanium, titanium oxide, Magnesium oxide, zirconium oxide, barium sulfate, red iron oxide, iron oxide, ultramarine and the like; pH adjusters include buffers such as lactic acid-sodium lactate and citric acid-sodium citrate.

As the various active ingredients, allantoin, a vitamin E derivative, a glycyrrhizin, an ascorbic acid derivative, a codic acid, an arbutin, a pantethic acid derivative, a placenta extract, an anti-inflammatory agent, yoquinin, and various plant extracts are added. Thereby, the melanin suppressing effect can be further improved. Furthermore, by adding various ultraviolet absorbing substances, it can be used as a skin external preparation having both the effect of preventing and treating sunburn.

The external preparation for skin of the present invention thus obtained is applied topically to affected areas such as skin spots, freckles, and pigmented areas after tanning.
In the case of an ointment-like preparation, the amount is preferably 1 to 20 mg per cm ² of the skin surface, and in the case of a liquid preparation, it is preferably 1 to 10 mg.

[0025]

The external preparation for skin of the present invention suppresses the production of melanin in artificially formed pigment spots, exhibits an excellent effect of preventing melanin deposition with almost no side effects, and is extremely stable to light. It is.

[0026]

The present invention will be described in more detail with reference to Synthesis Examples, Test Examples and Examples, which should not be construed as limiting the invention thereto.

Synthesis Example 1 [Synthesis of 2-alkylchromone]

Synthesis of butylchromone In a nitrogen atmosphere, 17.7 g (0.46 mol) of 60% sodium hydride and dry TH were placed in a 1000 ml three-necked flask.
350 ml of F was added. After drying at room temperature, 2 in 50 ml of THF
-26.1 g (192 mmol) of hydroxyacetophenone
Was added and stirred at 60 ° C. for 30 minutes. Thereafter, 25.0 g (192 mmol) of ethyl valerate was added dropwise, and the mixture was refluxed for about 2 hours. After the reaction, return to room temperature and add concentrated hydrochloric acid 2
00 g (167 mmol) were added, which was refluxed for 30 minutes and then poured into 150 ml of water at room temperature. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated. The residue was distilled to obtain 32.4 g (83.3%) of 2-butylchromone.

Table 1 shows the physical properties of the obtained compound.

Table 1 bp. 150 to 153 ° C./0.35 mmHg white crystal mp. 32.0 to 33.0 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.97 (t, 3H, J = 7.3 Hz), 1.35 1.53 (m, 2H), 1.66-1.80 (m, 2
H), 2.63 (t, 2H, J = 7.7Hz), 6.18 (s, 1H), 7.33-7.45 (m, 2H),
7.64 (ddd, 1H, J = 7.8,7.8,1.6Hz), 8.18 (dd, 1H, J = 7.8,1.6H
z). IR (KBr): 2956, 1644, 1574, 1464, 1380cm ^-1 .

Similarly, by changing the chain length of the corresponding ester, the following 2-alkylchromone was obtained. The yield and physical properties of the obtained 2-alkylchromone are shown below.

2-pentylchromone (yield 92.5)
%)

Table 2 bp. 173 to 175 ° C./1.5 mmHg white crystal mp. 27.8 to 28.3 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.92 (t, 3H, J = 6.6 Hz), 1.26 1.43 (m, 4H), 1.67-1.82 (m, 2
H), 2.62 (t, 2H, J = 7.8Hz), 6.18 (s, 1H), 7.34-7.45 (m, 2H),
7.64 (ddd, 1H, J = 7.8,7.8,1.7Hz), 8.19 (dd, 1H, J = 7.8,1.7H
z). IR (KBr): 2960, 1662, 1614, 1468, 1386cm ^-1 .

2-heptylchromone (yield 85.7)
%) Purification was performed using silica gel column chromatography. Solvent: hexane / ethyl acetate (15/1).

Table 3 White crystals mp. 30.0-31.0 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.89 (t, 3H, J = 6.4 Hz), 1.20-1.50 (br, 8H), 1.60-1.90 (br, 2
H), 2.62 (t, 2H, J = 7.8Hz), 6.18 (s, 1H), 7.30-7.50 (m, 2H),
7.60-7.80 (m, 1H), 8.19 (dd, 1H, J = 6.2,1.8Hz). IR (KBr): 2932,1660,1614,1576,1468,1384cm- ¹ .

.2-nonylchromone (yield 64.1%)

Table 4 White crystals mp. 31.0-32.0 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.89 (t, 3H, J = 6.7 Hz), 1.27-1.35 (br, 12H), 1.67-1.77 (br,
2H), 2.62 (t, 2H, J = 7.8Hz), 6.18 (s, 1H), 7.33-7.44 (m, 2H),
7.64 (ddd, 1H, J = 7.7,7.0,1.6Hz), 8.18 (dd, 1H, J = 7.9,1.6H
z). IR (KBr): 2932, 1662, 1468, 1384cm ^-1 .

2-pentadecyl chromone (yield: 83.
6%)

Table 5 White crystals mp. 54.5-55.5 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.88 (t, 3H, J = 6.7 Hz), 1.20-1.50 (br, 24H), 1.60-1.90 (br,
2H), 2.62 (t, 2H, J = 7.8Hz), 6.18 (s, 1H), 7.30-7.45 (m, 2H),
7.60-7.80 (m, 1H), 8.19 (dd, 1H, J = 6.3,1.6Hz). IR (KBr): 2916, 1640, 1466, 1380cm ^-1 .

2- (1-ethylpentyl) chromone (yield 38.6%)

[Table 6] Light yellow oil bp.
mmHg ¹ H-NMR (CDCl ₃ : δppm) 0.83 (m, 6H), 1.18-1.46 (br, 4H), 1.54-1.83 (br, 4H), 2.37-
2.52 (m, 1H), 6.18 (s, 1H), 7.35-7.44 (m, 2H), 7.65 (ddd, 1H,
J = 7.3,7.9,1.5Hz), 8.20 (dd, 1H, J = 7.9,1.5Hz). IR (NaCl): 2964, 1658, 1468, 1386cm ^-1 .

Synthesis Example 2 [Synthesis of 7-methoxy-2-alkylchromone]

Synthesis of 2-butyl-7-methoxychromone Under a nitrogen atmosphere, 14.2 g (354 mmol) of 60% sodium hydride and 250 ml of dry THF were added to a 500 ml three-necked flask. 25.5 g (154 g) of 2-hydroxy-4-methoxyacetophenone in 50 ml of dry THF at room temperature.
(mmol) was added and stirred at 60 ° C. for 30 minutes. Thereafter, 20.0 g (154 mmol) of ethyl valerate was added dropwise, and the mixture was refluxed for about 2 hours. After the reaction, the temperature was returned to room temperature, 100 g (83.3 mmol) of concentrated hydrochloric acid was added, and the mixture was refluxed for 30 minutes and poured into 150 ml of water at room temperature. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and hexane / ethyl acetate (8/1) was used as a developing solution to obtain 29.1 g (81.3%) of 2-butyl-7-methoxychromone.

Table 7 shows the physical properties of the obtained compound.

Table 7 White crystals mp. 63.4-64.4 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.96 (t, 3H, J = 7.4 Hz), 1.37-1.48 (m, 2H), 1.64-1.79 (m, 2
H), 2.59 (t, 2H, J = 7.6Hz), 3.90 (s, 3H), 6.11 (s, 1H), 6.93
(d, 1H, J = 2.3Hz), 6.94 (dd, 1H, J = 8.9,2.3Hz), 8.08 (d, 1H, J
= 8.9Hz). IR (KBr): 2952, 1624, 1554, 1456, 1334cm ^-1 .

Similarly, the following 2-alkyl-7-methoxychromone or a derivative thereof was obtained by changing the corresponding acetophenone or carboxylic acid ester.
The yield and physical properties of the obtained 2-alkyl-7-methoxychromone are shown below.

.2-pentyl-7-methoxychromone (45.3% yield)

Table 8 White crystals mp. 43.3-44.2 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.92 (t, 3H, J = 7.2 Hz), 1.35-1.42 (m, 4H), 1.69-1.77 (m, 2
H), 2.59 (t, 2H, J = 7.8Hz), 3.90 (s, 3H), 6.11 (s, 1H), 6.83
(d, 1H, J = 2.4Hz), 6.94 (dd, 1H, J = 8.8,2.4Hz), 8.18 (d, 1H, J
IR (KBr): 2936, 1654, 1616, 1440, 1382cm ^-1 .

2-heptyl-7-methoxychromone (yield 75.2%)

Table 9 White crystals mp. 53.6-55.0 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.89 (t, 3H, J = 6.8 Hz), 1.29-1.34 (br, 8H), 1.72 (dt) , 2H, J = 1
1.1,7.5Hz), 2.58 (t, 2H, J = 7.5Hz), 3.90 (s, 3H), 6.11 (s, 1
H), 6.82 (d, 1H, J = 2.4Hz), 6.93 (dd, 1H, J = 8.9,2.4Hz), 8.08
(d, 1H, J = 8.9Hz). IR (KBr): 2920, 1602, 1434, 1386, 1334cm ^-1 .

· 2-nonyl-7-methoxychromone (47.8% yield)

Table 10 White crystals mp. 51.2-52.0 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.88 (t, 3H, J = 6.7 Hz), 1.27-1.34 (br, 12H), 1.65-1.75 (br,
2H), 2.58 (t, 2H, J = 7.8Hz), 3.90 (s, 3H), 6.10 (s, 1H), 6.82
(d, 1H, J = 2.4Hz), 6.94 (dd, 1H, J = 8.9,2.4Hz), 8.08 (d, 1H, J
IR (KBr): 2928, 1648, 1610, 1434, 1390cm ^-1 .

· 2-pentadecyl-7-methoxychromone (97.7% yield)

Table 11 White crystals mp. 64.6-66.5 ° C ¹ H-NMR (CDCl ₃ : δ ppm) 0.88 (t, 3H, J = 6.8 Hz), 1.25 (br, 24H), 1.65-1.76 (br , 2H),
2.58 (t, 2H, J = 7.4Hz), 3.90 (s, 3H), 6.11 (s, 1H), 6.82 (d, 1
H, J = 2.4Hz), 6.94 (dd, 1H, J = 8.8,2.4Hz), 8.19 (d, 1H, J = 8.8
Hz). IR (KBr): 2920, 2848, 1606, 1436, 1352cm ^-1 .

2- (1-ethylpentyl) -7-methoxychromone (71.2% yield)

Table 12 White crystals mp. 64.6-66.5 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.83-0.94 (m, 6H), 1.12-1.45 (br, 4H), 1.51-1.83 (br, 4H),
2.34-2.48 (m, 1H), 3.91 (s, 3H), 6.11 (s, 1H), 6.83 (d, 1H, J =
2.4Hz), 6.95 (dd, 1H, J = 8.9,2.4Hz), 8.09 (d, 1H, J = 8.9Hz). IR (KBr): 2964, 2940, 1642, 1608, 1442, 1384cm ^-1 .

Synthesis Example 3 [Demethylation]

Synthesis of 2-butyl-7-hydroxychromone 12.6 g of 2-butyl-7-methoxychromone (54.
(2 mmol) was added with 40 ml of 47% hydrobromic acid, and the mixture was refluxed for 48 hours. After the reaction, the mixture was poured into 150 ml of water, extracted with ethyl acetate, washed with saturated saline, and concentrated to obtain crystals. 50 ml of ethyl acetate and 10 ml of hexane were added thereto, and the mixture was washed twice to obtain 10.8 g of 2-butyl-7-hydroxychromone (yield from 2-butyl-7-methoxychromone: 91.3%). .

Table 13 shows the physical properties of the obtained compound.

Table 13 White crystals mp. 121.7-123.2 ° C. ¹ H-NMR (DMSO-d ₆ : δ ppm) 0.95 (t, 3H, J = 7.2 Hz), 1.25-1.51 (m, 2H), 1.63 -1.78 (m, 2
H), 2.61 (t, 2H, J = 7.8Hz), 6.17 (s, 1H), 6.94 (d, 1H, J = 2.0H
z), 6.96 (dd, 1H, J = 8.2,2.0Hz), 8.06 (d, 1H, J = 8.8Hz), 10.5
(s, 1H). IR (KBr): 2951, 1624, 1554, 1456, 1334cm ^-1 .

Similarly, other chromones were demethylated. The yield and physical properties are shown below.

2-pentyl-7-hydroxychromone (yield from 2-pentyl-7-methoxychromone: 9
5.7%)

Table 14 White crystals mp. 132.9-133.7 ° C. ¹ H-NMR (DMSO-d ₆ : δ ppm) 0.90 (t, 3H, J = 6.9 Hz), 1.34-1.42 (m, 4H), 1.65 -1.76 (m, 2
H), 2.58 (t, 2H, J = 7.5Hz), 6.04 (s, 1H), 6.81 (d, 1H, J = 2.2H
z), 6.88 (dd, 1H, J = 8.7,2.2Hz), 7.96 (d, 1H, J = 8.7Hz), 10.1
(s, 1H). IR (KBr): 3092, 2964, 1632, 1570, 1460, 1334cm ^-1 .

2-heptyl-7-hydroxychromone (yield from 2-heptyl-7-methoxychromone: 8
9.3%)

Table 15 White crystals mp. 131.9-133.8 ° C. ¹ H-NMR (DMSO-d ₆ : δ ppm) 0.89 (t, 3H, J = 6.8 Hz), 1.28-1.34 (br, 8H), 1.68 -1.75 (br, 2
H), 2.58 (t, 2H, J = 7.7Hz), 6.04 (s, 1H), 6.82 (d, 1H, J = 2.2H
z), 6.89 (dd, 1H, J = 8.7, 2.2Hz), 7.95 (d, 1H, J = 8.7Hz). IR (KBr): 3094, 2926, 1566, 1452, 1302cm ^-1 .

2-nonyl-7-hydroxychromone (yield from 2-nonyl-7-methoxychromone: 75.
9%)

Table 16 White crystals mp. 127.9 to 129.2 ° C. ¹ H-NMR (DMSO-d ₆ : δ ppm) 0.88 (br, 3H), 1.27-1.34 (br, 12H), 1.68-1.71 (br, 2H), 2.5
8 (t, 2H, J = 7.7Hz), 6.03 (s, 1H), 6.81 (d, 1H, J = 2.2Hz), 6.88
(dd, 1H, J = 8.7,2.2Hz), 7.95 (d, 1H, J = 8.7Hz), 8.62 (s, 1H). IR (KBr): 3140,2928,1638,1458,1336cm- ¹ .

2-pentadecyl-7-hydroxychromone (yield from 2-pentadecyl-7-methoxychromone 23.2%)

Table 17 White crystals mp. 112.8-114.5 ° C. ¹ H-NMR (DMSO-d ₆ : δ ppm) 0.87 (t, 3H, J = 6.8 Hz), 1.25-1.34 (br, 24H), 1.71 (br, 2H),
2.53-2.61 (m, 2H), 6.02 (s, 1H), 6.80 (d, 1H, J = 2.2Hz), 6.87
(dd, 1H, J = 8.7,2.2Hz), 7.93 (d, 1H, J = 8.7Hz), 8.59 (s, 1H). IR (KBr): 3472,2920,1575,1455,1395cm- ¹ .

2- (1-ethylpentyl) -7-hydroxychromone (87.1% yield from 2- (1-ethylpentyl) -7-methoxychromone)

Table 18 White crystals mp. 125.8-126.7 ° C. ¹ H-NMR (CDCl ₃ : δ ppm) 0.82-0.92 (m, 6H), 1.14-1.38 (br, 4H), 1.51-1.81 (br, 4H),
2.35-2.49 (m, 1H), 6.15 (s, 1H), 6.95 (d, 1H, J = 2.2Hz), 7.01
(dd, 1H, J = 8.7,2.2Hz), 8.08 (d, 1H, J = 8.7Hz), 8.99 (s, 1H) .IR (KBr): 3100,2936,1640,1554,1390cm- ¹ .

Test Example 1 The photostability tests of Compounds 1 to 15 of the present invention and Comparative Compounds 1 to 10 were carried out using a solar simulator. That is, a test sample prepared as a 1% ethanol solution was placed in a quartz cell, and a solar simulator (SUNSET manufactured by Heraeus) was used.
The photostability was tested by irradiating for 2 hours in CPS).
As an evaluation standard, a test sample in a solution 2 hours after light irradiation was quantified by liquid chromatography and expressed as follows.

[0055]

[Table 19] 0-5% decomposition ◎ 5-10% decomposition ○ 10-30% decomposition △ 30% or more decomposition ×

Table 20 shows the results.

[0057]

[Table 20]

Evaluation of the whitening effect in Examples 1 to 5
The improvement was performed on the UVB-induced pigment spots as described below.

[Effect test on UVB pigment spots] Irradiation of UV light in the UVB region with twice the minimum erythemal dose (MED) once a day for 2 days was performed on the inner upper arm of 10 subjects. The amount of pigment spot disappearance by continuously applying the sample to the test site twice a day for one month was examined. The evaluation was performed using a color difference meter, and the L * value was calculated from the obtained Munsell value.
The value (ΔΔL *) was obtained by subtracting ΔL ′ * (temporal change) of the uncoated portion from the sample. ΔΔL * is represented by the following equation.

[0060]

ΔΔL * = (L * ₁ −L * ₀ ) − (L ′ * ₁ −L ′ * ₀ ) L * ₀ ; sample application test site before application L ′ * ₀ ; sample not applied before application Test site L * ₁ ; Sample application test site one month after continuous application L '* ₁ ; Sample non-application site one month after continuous application

The evaluation was shown by the average of the evaluation points of 10 subjects.

[0062]

[Table 21]

Example 1 (Cream) A cream having the composition shown in Table 22 was prepared according to the following production method, and the whitening effect by continuous application was evaluated according to the above criteria. The results are shown in Table 22. (Manufacturing method) The oil phase components (1) to (6) were heated and mixed at 80 ° C, and the aqueous phase components (7) to (1) heated to 80 ° C under stirring.
After adding 0) and emulsifying, add (11) and then cool to room temperature with stirring.

[0064]

[Table 22]

Example 2 (Cream) In the same manner as in Example 1, a cream having the composition shown in Table 23 was prepared.
The whitening effect by continuous application was evaluated, and the results are also shown.

[0066]

[Table 23]

Example 3 (Emulsion) An emulsion having the composition shown in Table 24 was prepared according to the following method.
The whitening effect of the continuous application was evaluated according to the same standard as in Example 1. (Preparation method) The oil phase components (1) to (7) were heated and mixed at 80 ° C, and the aqueous phase components (8) to (1) heated to 80 ° C under stirring.
After adding 2) and emulsifying, add (13) and then cool to room temperature with stirring.

[0068]

[Table 24]

Example 4 (Lotion) A lotion having the composition shown in Table 25 was prepared according to the following production method, and the whitening effect by continuous application was evaluated according to the same standard as in Example 1. (Production method) After the components of (1) to (3) and (6) are dispersed by stirring, A is added by adding 60% of purified water. On the other hand, after stirring and dissolving the components (4), (5), (8) and (9), the remaining amount of purified water is added to B, and while A is being stirred, B is added and stirred.

[0070]

[Table 25]

Example 5 (Essence Beauty Essence) Essences (beauty essence) having the composition shown in Table 26 were prepared according to the following production method, and the whitening effect by continuous application was evaluated according to the same criteria as in Example 1. (Preparation method) After the components (1) to (5) and (8) were stirred and dispersed, 65% of purified water was added thereto to obtain A. On the other hand, after stirring and dissolving the components (6), (7), (10), and (11), the remaining amount of purified water is added to B, and while B is added, B is added and stirred.

[0072]

[Table 26]

Continued on the front page (72) Inventor Yoshinori Nishizawa 251-233 Karinuma-cho, Utsunomiya-city, Tochigi Prefecture (72) Inventor Mitsutoshi Kimura 2606-6, Kabashi-cho, Kaiga-cho, Haga-gun, Tochigi Prefecture 3-405 Kao Ichikai Company House 3-405 (72) Inventor Yada Yukihiro 1-15-1 Kunishida Nishi, Ninomiya-cho, Haga-gun, Tochigi Prefecture (72) Inventor Genji Imokawa 1022-89, Himuro-cho, Utsunomiya-shi, Tochigi Prefecture (56) References JP-A-5-301813 (JP, A) 2-227483 (JP, A) JP-A-55-111410 (JP, A) JP-A-55-143908 (JP, A) JP-A-5-505641 (JP, A) Helv. Chim. Acta, Vol. 64, no. 8 (1981), p. 2654-2664 J.P. Heterocycl. Chem. , Vol. 19, No. 6 (1982), p. 1281-1283 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/00-311/74 A61K ^7/ 00-7/48 A61K 31/33-61/655 REGISTRY (STN) CA (STN )

Claims (3)

(57) [Claims] [Claim 1] The following general formula (1) (Wherein R ¹ represents a straight-chain or branched-chain alkyl group having 4 to 15 carbon atoms, and R ² represents a methoxy group). 2. The following general formula (1): (Wherein, R ¹ represents a straight-chain or branched-chain alkyl group having 4 to 15 carbon atoms, and R ² represents a methoxy group). 3. The following general formula (1): (Wherein, R ¹ represents a linear or branched alkyl group having 4 to 15 carbon atoms, and R ² represents a methoxy group).