JPH07291989A - Hydroquinonehydroxyalkyl ether glycoside - Google Patents

Abstract

PURPOSE:To obtain the novel compound glycoside being a specific hydroquinonehydroxyalkyl ether glycoside, having excellent skin-beautifying effect, free from sensitizing property and useful as a skin external preparation for cosmetics, medicines, etc. CONSTITUTION:A novel hydroquinonehydroxyalkyl ether glycoside expressed by the formula I [G1c is a group expressed by the formula II; R1 and R2 are each H, OH, a 1-10C alkyl or a hydroxyalkyl; (n) is an integer of 0-10], having excellent skin beautifying effect, free from sensitizing property and useful as an active ingredient for skin external preparation for cosmetics, medicines, etc. [e.g., 4-beta-D-glucopyranosyloxy-l-(4-hydroxyphenoxy)butane[. This compound is obtained by glycosylating hydroquinonehydroxyalkyl ether prepared by reacting hydroquinone with a halohydrin, an alkylepoxide, etc., using a glycosylating agent such as an acetylated sugar or halogenated sugar.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel hydroquinone hydroxyalkyl ether glycoside having a skin whitening effect.

[0002]

BACKGROUND OF THE INVENTION Although there are some unclear points about the mechanism of skin spots and the like, in general, melanin pigments are formed due to hormonal abnormalities and irritation of ultraviolet rays from the sun, and this is the skin. It is thought to be abnormally deposited inside. Such treatments for blemishes and bruises include substances that suppress the production of melanin, for example, a method of administering a large amount of vitamin C, a method of injecting glutathione or the like, or kojic acid,
Methods such as topical application of cysteine or the like in the form of an ointment, cream, lotion or the like are used. In Europe and America, hydroquinone preparations are used as medicines.

[0003]

However, these compounds, except for hydroquinone, show a very slow effect, so that the whitening effect is not sufficient, while hydroquinone has been confirmed to have an effect. Due to its sensitizing properties, its use is generally restricted.

In view of such circumstances, the inventors of the present invention have conducted extensive studies and, as a result, have found that the novel hydroquinone hydroxyalkyl ether glycoside exerts a whitening effect more than hydroquinone, and completes the present invention. Came to.

[0005]

That is, claim 1 of the present invention is a glycoside of hydroquinone hydroxyalkyl ether represented by the following general formula (4). In addition, claim 2
Is a hydroquinone hydroxyalkyl ether glycoside, which is a hydroquinone hydroxyalkyl ether glycoside represented by the following general formula 5. The hydroquinone hydroxyalkyl ether glycoside according to claim 1, wherein Claim 3 is a hydroquinone hydroxyalkyl ether glycoside, wherein the hydroquinone hydroxyalkyl ether glycoside is a hydroquinone hydroxyalkyl ether glycoside represented by the following general formula 6. is there.

[0006]

[Chemical 4]

[0007]

[Chemical 5]

[0008]

[Chemical 6]

The structure of the present invention will be described in detail below. The glycoside of hydroquinone hydroxyalkyl ether according to the present invention is a novel compound and can be synthesized, for example, by the following method.

That is, halohydrin is added to hydroquinone,
Hydroquinone hydroxyalkyl ether is produced by reacting with an alkyl epoxide. The reaction is performed in a solvent that does not participate in the reaction, for example, a solvent of dimethyl sulfoxide or water, for 6 to 20 hours at 80 ° C to 120 ° C.
It is preferable to react at C. Then, a glycoside of hydroquinone hydroxyalkyl ether is produced by subsequently performing glycosylation using an appropriate glycoside, such as acetylated sugar and halogenated sugar. Here, one of the phenolic hydroxyl groups of hydroquinone is a suitable protecting group,
For example, it may be protected with a benzyl group or the like, and after glycosylation, the protective group may be eliminated by catalytic reduction or the like. Also,
The hydroxyl group of glucose may be protected by a suitable protecting group such as an acetyl group, and the protecting group may be removed by hydrolysis after glycosylation.

Specific examples of substance names include 4-β-D
-Glucopyranosyloxy-1- (4-hydroxyphenoxy) butane, 5-β-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) pentane, 6-β
-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) hexane, 2-β-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) propane,
2-β-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) butane, 2-β-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) propan-3-ol and the like can be mentioned. To be

When the glycoside of the hydroquinone hydroxyalkyl ether of the present invention is used as an external preparation such as cosmetics and pharmaceuticals, the compounding amount is 0.001 to 20% by weight, preferably 0.01 to 7% by weight based on the total amount of the external preparation. If it is less than 0.001% by weight, the skin whitening effect is poor, and if it exceeds 20% by weight, the effect cannot be expected to increase.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential constituents, other components usually used in external preparations for skin such as cosmetics and pharmaceuticals, for example, oils, ultraviolet absorbers, antioxidants and surfactants. , Moisturizers, fragrances, water, alcohols, thickeners, coloring materials, skin nutrients (tocopherol acetate, pantotenyl ethyl ether, glycyrrhizinate) and the like can be appropriately added as necessary.

[0014]

EXAMPLES Next, the present invention will be described in more detail with reference to examples. The present invention is not limited to this. First, a synthesis example of a hydroquinone hydroxyalkyl ether glycoside according to the present invention will be described in detail.

Synthesis Example 1 1- (4-Benzyloxyphenoxy) propan-2-ol Hydroquinone benzyl ether (10 g, 50 mmol) was dissolved in 100 ml of dimethyl sulfoxide and 10 ml of pyridine, and the reaction solution was kept at 120 ° C. -Epoxy propane (7 ml,
100 ml of a 0.1 mol) solution of dimethyl sulfoxide was added dropwise. After the completion of dropping, the mixture was stirred at 120 ° C for 20 hours. The reaction solution is concentrated under reduced pressure, separated and purified by a silica gel column,
1- (4-benzyloxyphenoxy) propane-2-
All (8.7 g, yield 68%) was obtained as a racemate. Melting point 104.2-105.0 ° C

Synthesis Example 2 1- (4-benzyloxyphenoxy) -2- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) propane 1- (4-benzyl Oxyphenoxy) propane-2-
All (1.0 g, 3.9 mmol), pentaacetyl glucose
(2.0 g, 5.1 mmol) was dissolved in 20 ml of dichloroethane, and trimethylsilyl trifluoromenthanesulfonate (0.9 m
(1, 5.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate and distilled water, and concentrated under reduced pressure. The residue is separated and purified with a silica gel column, 1-
(4-benzyloxyphenoxy) -2- (2,3,
4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) propane (1.4 g, yield 60%) was obtained. Melting point 105.2-117.5 ° C

Synthesis Example 3 1- (4-benzyloxyphenoxy) -2-β-D-glucopyranosyloxypropane 1- (4-benzyloxyphenoxy) -2- (2,2
3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) propane (1.2 g, 2.1 mmol) was dissolved in 60 ml of a 10% sodium methylate methanol solution and the mixture was heated to 60 °.
Reaction was carried out at C for 1 hour. The reaction solution was neutralized with an acidic resin and concentrated under reduced pressure to give 1- (4-benzyloxyphenoxy) -2-β-D-glucopyranosyloxypropane.
(0.8 g, yield 94%) was obtained.

Synthesis Example 4 2-β-D-Glucopyranosyloxy-1- (4-hydroxyphenoxy) propane 1- (4-benzyloxyphenoxy) -2-β-D-
Glucopyranosyloxypropane (4.4 g, 10.4 mmol) was dissolved in 130 ml of methanol, and the debenzylation reaction was carried out for 3 hours in a hydrogen atmosphere using 10% palladium carbon as a catalyst. After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure, separated and purified by a silica gel column, and 2-β-D-glucopyranosyloxy-1- (4-hydroxyphenoxy) propane.
(3.0 g, yield 86%) was obtained. ¹ H-NMR (DMSO-d _6, TMS, ppm) δ1.21 to 1.25 (m, 3H, —C H ₃ ) δ 2.91 to 2.98 (m, 1H, derived from glucose) δ 3.02 3.19 (m, 3H, -C H O-) δ3.41~3.48 (m, 1H, derived glucose) δ3.63~4.11 (m, 4H, -C H 2 O-, derived glucose ) Δ 4.26 to 4.38 (m, 2H, derived from glucose) δ 4.69 to 4.85 (m, 3H, derived from glucose) δ 6.63 to 6.79 (m, 4H, derived from benzene ring) δ 8.79 , 8.82 (s, 1H, derived from phenolic hydroxyl group) ¹³ C-NMR (DMSO-d _6, TMS, ppm) δ17.2, 18.7 ( -C H ₃ ) δ71.8, 71.9, 72. .3, 72.4 ( -C HO
_{-, - C H 2 O-)} δ61.1,70.1,73.4,73.6,76.
8,101.6,102.2 (derived from glucose) δ115.5, 115.6, 151.2, 151.3
(Derived from benzene ring) Elemental analysis value Calculated value as C ₁₅ H ₂₂ O ₈ (%) C: 62.85, H: 6.71 Measured value (%) C: 62.84, H: 6.72

Synthesis Example 5 1- (4-benzyloxyphenoxy) -6-hexanol hydroquinone benzyl ether (25 g, 126 mmol) in water
250 ml and sodium hydroxide (5 g, 126 mmol) were added, and the reaction solution was kept at 120 ° C and dissolved. 6-Chloro-1-hexanol (25 ml, 190 mmol) was added dropwise, and after completion of the addition, 120
The mixture was stirred at 20 ° C for 20 hours. When the reaction solution was cooled to room temperature, a product started to precipitate, so the precipitate was filtered off and recrystallized with a mixed solvent of benzene and hexane to give 1- (4-benzyloxyphenoxy) -6-hexanol (23.7 g, yield
63%). Melting point 96.3-97.4 ° C

Synthesis Example 6 1- (4-benzyloxyphenoxy) -6-β-D-glucopyranosyloxyhexane 1- (4-benzyloxyphenoxy) -6-hexanol (8.1 g, 27.3 mmol), penta Acetyl glucose (11
g, 27.3 mmol) was added with 8 ml of dibutyl cellosolve and dissolved at 80 ° C under reduced pressure (6 mmHg). Phosphomolybdic acid (80 mg) was added and the pressure was reduced to 1 mm at 80 ° C (6 mmHg).
Reacted for hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and distilled water, and concentrated under reduced pressure. The residue was dissolved in 60 ml of 10% sodium methylate methanol solution,
The reaction was carried out at ° C for 1 hour. The reaction solution was neutralized with an acidic resin and concentrated under reduced pressure to give 1- (4-benzyloxyphenoxy) -6-β-D-glucopyranosyloxyhexane.
(6.6 g, yield 50%) was obtained. Melting point 135.3-137.6 ° C

Synthesis Example 7 6-β-D-Glucopyranosyloxy-1- (4-hydroxyphenoxy) hexane 1- (4-benzyloxyphenoxy) -6-β-D-
Glucopyranosyloxyhexane (2.6 g, 5.1 mmol) was dissolved in 50 ml of methanol, and the debenzylation reaction was carried out for 3 hours in a hydrogen atmosphere using 10% palladium carbon as a catalyst. The reaction solution was concentrated under reduced pressure and recrystallized from chloroform-methanol to give 6-β-D-glucopyranosyloxy-
1- (4-hydroxyphenoxy) hexane (2.0 g, yield 98%) was obtained. Melting point 118.6 to 119.5 ° C ¹ H-NMR (DMSO-d _6, TMS, ppm) δ 1.38, 1.54, 1.66 (m, total 8 H, -C
H ₂ −) δ2.95 (ddd, 1H, derived from glucose) δ3.02 to 3.29 (derived from m, 3H, glucose) δ 3.44 (m, 2H, —CH ₂ O—) δ 3.67 (ddd) , 1H, glucose derived) δ3.76 (ddd, 1H, glucose derived) δ3.84 (t, 2H, —CH ₂ O—) δ 4.11 (d, 1H, glucose derived) δ 4.37 (dd, 1H , Glucose derived) δ4.78, 4.80, 4.84 (eachd, 3H, glucose derived) δ6.66, 6.72 (eachd, 4H, derived from benzene ring) δ8.78 (s, 1H, phenolic hydroxyl group ^{derived) 13 C-NMR (DMSO-} d 6, TMS, ppm) δ25.2,25.3,28.7,29.2 (- C H 2
−) Δ67.9,68.4 ( −C H ₂ O−) δ61.1,70.1,73.4,76.7,76.
8,102.8 (from glucose) δ115.4, 115.6, 151.0, 151.5
(Derived from benzene ring) Elemental analysis value Calculated value as C ₁₈ H ₂₈ O ₈ (%) C: 58.05, H: 7.58 Measured value (%) C: 58.03, H: 7.58

Next, the effect test method and evaluation method of the present invention will be described.

(1) Whitening effect test Test method 50 subjects exposed to the sunlight in the summer for 4 hours (2 hours a day for 2 days) 5 skins exposed to the sunlight From the day after, each sample was applied once in the morning and evening for 8 weeks. The panel was divided into 10 groups per group and divided into 5 groups, and the test was conducted according to the following formulation.

Samples of Examples 1 to 2 and Comparative Examples 1 and 2 (alcohol phase) wt% 95% ethyl alcohol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 antioxidant / preservative proper amount perfume proper amount drug ( Table 1) 1.0 (Aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Suitable amount Ion-exchanged water Residual (Production method) The aqueous phase and alcohol phase are prepared and solubilized.

(Evaluation method) The lightening effect after use was judged based on the following judgment criteria. (Judgment) ⊚: When the rate of marked efficacy and efficacy among the subjects is 80% or more ◯: The rate of marked efficacy and efficacy among the subjects is 50 to 8
In the case of 0% Δ: The ratio of markedly effective and effective in the subjects is 30 to 5
0% ×: When the ratio of markedly effective or effective in subjects is 30% or less

[0026]

[Table 1]

As is clear from Table 1, the effect after exposure to sunlight is that in Examples, as compared with Comparative Examples, excessive deposition of melanin pigment can be prevented and darkening can be prevented. Admitted.

[0028]

The glycoside of hydroquinone hydroxyalkyl ether according to the present invention is a novel compound having an excellent skin whitening effect.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Rumiko Kaku 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Stock company Shiseido Daiichi Research Center

Claims (3)

[Claims] 1. A hydroquinone hydroxyalkyl ether glycoside represented by the following general formula 1. [Chemical 1] 2. A hydroquinone hydroxyalkyl ether glycoside according to claim 1, wherein the hydroquinone hydroxyalkyl ether glycoside is a hydroquinone hydroxyalkyl ether glycoside represented by the following general formula 2. [Chemical 2] 3. The hydroquinone hydroxyalkyl ether glycoside according to claim 1, wherein the hydroquinone hydroxyalkyl ether glycoside is a hydroquinone hydroxyalkyl ether glycoside represented by the following general formula 3. [Chemical 3]