JPH06256353A - Glabridin derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound excellent in safety to the skin, capable of rapidly making the dark skin into the pale-colored skin, thus useful for cosmetics or medicines. CONSTITUTION:A compound of formula I or II (R is 2-20C aliphatic hydrocarbon), e.g. 4'-O-ethylglabridin or 2'-O-ethylglabridin. This compound of formula I or II can be obtained by the following process: glabridin of formula III is made to react with a halide of the formula R-X (X is Cl, Br or I) in a solvent (e.g. DMF) in the presence of a base (e.g. potassium carbonate) at room temperature to 200 deg.C, and the product is extracted with ethyl acetate, concentrated under reduced pressures and then purified. The compound of formula I or II as active ingredient is formulated at 0.001-10wt.% in a cosmetic or medicine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a glabridin derivative which is excellent in skin safety and has an effect of rapidly lightening dark skin.

[0002]

BACKGROUND OF THE INVENTION Glabridin is already known as one of the compounds having a strong antibacterial property contained in licorice (Journal of Natural Products, p. 259, vol. 43, vol. No. 2 and 1
980). Also, there is a report that it has a strong melanin production inhibitory effect (JP-A 1-311011). However, since it is easily deteriorated by heat, light, etc. and there is a problem in safety, the amount and range of use have been limited.

As the derivative of glabridin, only its diacetyl form and dimethyl ether form have been already reported (Chemical Pharmaceutical Bulletin, 99).
1, p. 24, No. 5, 1976), these derivatives do not have the effect of suppressing melanin production or the effect of rapidly lightening dark skin. Therefore, the development of new derivatives has been desired.

[0004]

Means for Solving the Problems The present inventors have conducted diligent research in view of such circumstances, and as a result, it has been found that the specific compounds described below are highly safe and have the effect of rapidly lightening dark skin. Heading, completed the present invention.

That is, an object of the present invention is to provide a glabridine derivative which is excellent in safety and has an effect of rapidly lightening dark skin.

This object is achieved by the glabridin derivatives characterized by being represented by the general formulas (I) and (II).

[Chemical 3]

[Chemical 4] (However, R is a linear or branched aliphatic hydrocarbon group having 2 to 20 carbon atoms.)

The structure of the present invention will be described in detail below. In the glabridin derivative represented by the above general formulas (I) and (II) of the present invention, the linear or branched aliphatic hydrocarbon group having 2 to 20 carbon atoms represented by R is, for example, ethyl. Group, propyl group, isopropyl group, butyl group, t-
Examples thereof include a butyl group, an octyl group, a 2-ethylhexyl group, a dodecyl group, a tetradecyl group and an octadecyl group.

The glabridin derivative represented by the general formulas (I) and (II) of the present invention can be produced, for example, by the following method.

[0009]

[Chemical 5]

In a solvent such as acetone, N, N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO), a base catalyst (KOH, NaOH, K ₂ CO ₃ , Na) is used.
H) and the like, glabridin (1) and halide (2) (R represents a linear or branched aliphatic hydrocarbon group having 2 to 20 carbon atoms. X represents Br, Cl, I. .) At room temperature to 200 ° C. for 30 minutes to 100 hours. After the reaction, the raw product is extracted with ethyl acetate, and the extract is washed with water. The extract was concentrated under reduced pressure and then purified by silica gel column chromatography to give the compound of the general formula
The glabridin derivative of the present invention represented by (I) and (II) is obtained.

The glabridin derivative according to the present invention is
It can be used for commonly used cosmetics and pharmaceuticals. The blending amount is preferably 0.001% to 10%,
More preferably, it is 0.1% to 3%.

[0012]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 4'-O-ethyl glabridin (I-1) and 2'-O-
Synthesis of ethyl glabridin (II-1) 3.24 g (10 mmol) DMF (3
0 ml) solution with 1.09 g (10 mmol) of ethyl bromide
And 1.38 g (10 mmol) of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was dosed in water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography. Hexane: ethyl acetate = 9: 1 The solvent was distilled off, and isolation was carried out while confirming by thin-layer chromatography, I -1 (1.06 g, yield 30.0%) and II-1.
(1.12 g, yield 31.9%) was obtained. These were identified by the following NMR (JNM FX-270, manufactured by JEOL Ltd.) and MS (JMS DX-303, manufactured by JEOL Ltd.). [I -1]: NMR data ¹ H-NMR (solvent: CDCl ₃ , tetramethylsilane (TMS) standard): 1.38 (t, J = 7.1 Hz, 3H), 1.41
(s, 3H), 1.43 (s, 3H), 2.81-2.89 (m, 1H), 2.99 (dd, J = 10.7 a
nd 15.7Hz, 1H), 3.43-3.54 (m, 1H), 3.97 (q, J = 7.1Hz, 2H),
4.02 (t, J = 10.1Hz, 1H), 4.35-4.41 (m, 1H), 5.12 (s, 1H), 5.5
6 (d, J = 9.9Hz, 1H), 6.33 (d, J = 2.5Hz, 1H), 6.37 (d, J = 8.2Hz,
1H), 6.46 (dd, J = 8.5 and 2.5Hz, 1H), 6.65 (d, J = 9.9Hz, 1
H), 6.82 (d, J = 8.2Hz, 1H), 6.99 (d, J = 8.5Hz, 1H) MS data M / Z 352 (M ⁺ ). [II-1]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 1.41
(t, J = 7.1Hz, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 2.78-2.86 (m, 1
H), 2.95 (dd, J = 10.7 and 15.7z, 1H), 3.51-3.62 (m, 1H), 4.
00 (t, J = 10.1Hz, 1H), 4.01 (q, J = 7.1Hz, 2H), 4.30-4.36 (m, 1
H), 5.56 (d, J = 9.9Hz, 1H), 6.36 (dd, J = 8.2 and 2.5Hz, 1H),
6.37 (d, J = 8.2Hz, 1H), 6.42 (d, J = 2.5Hz, 1H), 6.66 (d, J = 9.9
Hz, 1H), 6.82 (d, J = 8.2Hz, 1H), 6.94 (d, J = 8.2Hz, 1H) .MS data M / Z 352 (M ⁺ ).

Example 2 4'-O-octylgrabrizine (I-2) and 2'-
Synthesis of O-octyl glabridin (II-2) Glabridin 1.62 g (5 mmol) DMF (15
ml) solution, 0.97 g (5 mmol) of octyl bromide and 0.69 g (5 mmol) of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was dosed in water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained oil was treated in the same manner as in Example 1 to give I-2 (0.58 g,
Yield 26.8%) and II-2 (0.65 g, yield 30.
0%). These were identified by the following NMR and MS analysis values. [I-2]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 0.87
(t, J = 6.9Hz, 3H), 1.28 (br.s, 10H), 1.40 (s, 3H), 1.42 (s, 3
H), 1.69-1.77 (m, 2H), 2.81-2.88 (m, 1H), 2.98 (dd, J = 10.7
and 15.4Hz, 1H), 3.45-3.51 (m, 1H), 3.89 (t, J = 6.6Hz, 2H),
4.01 (t, J = 10.2Hz, 1H), 4.34-4.40 (m, 1H), 4.79 (s, 1H), 5.5
4 (d, J = 10.2Hz, 1H), 6.33 (d, J = 2.5Hz, 1H), 6.35 (d, J = 8.2H
z, 1H), 6.46 (dd, J = 8.5 and 2.5Hz, 1H), 6.64 (d, J = 10.2Hz,
1H), 6.81 (d, J = 8.2Hz, 1H), 6.98 (d, J = 8.5Hz, 1H). MS data M / Z 436 (M ⁺ ) [II-2]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 0.87
(t, J = 7.1Hz, 3H), 1.27 (br.s, 10H), 1.42 (s, 3H), 1.43 (s, 3
H), 1.72-1.83 (m, 2H), 2.79-2.86 (m, 1H), 2.94 (dd, J = 10.7
and 15.7Hz, 1H), 3.51-3.60 (m, 1H), 3.92 (t, J = 6.6Hz, 2H),
4.00 (t, J = 10.0Hz, 1H), 4.30-4.36 (m, 1H), 4.85 (s, 1H), 5.5
5 (d, J = 9.9Hz, 1H), 6.35 (dd, J = 8.2 and 2.5Hz, 1H), 6.36
(d, J = 8.2Hz, 1H), 6.41 (d, J = 2.5Hz, 1H), 6.66 (d, J = 9.9Hz, 1
H), 6.82 (d, J = 8.2Hz, 1H), 6.94 (d, J = 8.2Hz, 1H). MS data M / Z 436 (M ⁺ )

Example 3 4'-O-dodecyl glabridin (I-3) and 2'-
Synthesis of O-dodecyl glabridin (II-3) Glabridine 0.97 g (3 mmol) of DMF (9 m
l) To the solution, 0.75 g (3 mmol) of dodecyl bromide and 0.41 g (3 mmol) of anhydrous potassium carbonate were added and stirred at room temperature for 48 hours. The reaction mixture was dosed in water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained oil was treated in the same manner as in Example 1 to give I-3 (0.38 g, yield 26.0%) and II-3 (0.42 g, yield 30.6).
%) Was obtained. These were identified by the following NMR and MS analysis values. [I-3]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 0.88
(t, J = 6.6Hz, 3H), 1.26 (br.s, 18H), 1.41 (s, 3H), 1.42 (s, 3
H), 1.72-1.78 (m, 2H), 2.81-2.89 (m, 1H), 3.00 (dd, J = 10.7
and 15.4Hz, 1H), 3.47-3.50 (m, 1H), 3.90 (t, J = 6.6Hz, 2H),
4.02 (t, J = 10.2Hz, 1H), 4.35-4.41 (m, 1H), 4.82 (s, 1H), 5.5
6 (d, J = 9.9Hz, 1H), 6.34 (d, J = 2.5Hz, 1H), 6.37 (d, J = 8.2Hz,
1H), 6.47 (dd, J = 8.5 and 2.5Hz, 1H), 6.65 (d, J = 9.9Hz, 1
H), 6.82 (d, J = 8.2Hz, 1H), 7.00 (d, J = 8.5Hz, 1H). MS data M / Z 492 (M ⁺ ) [II-3]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 0.88
(t, J = 6.6Hz, 3H), 1.25 (br.s, 18H), 1.42 (s, 3H), 1.43 (s, 3
H), 1.72-1.80 (m, 2H), 2.78-2.86 (m, 1H), 2.94 (dd, J = 10.4
and 15.7Hz, 1H), 3.47-3.58 (m, 1H), 3.91 (t, J = 6.5Hz, 2H),
3.99 (t, J = 10.2Hz, 1H), 4.30-4.36 (m, 1H), 5.34 (s, 1H), 5.5
5 (d, J = 9.9Hz, 1H), 6.35 (dd, J = 8.2 and 2.5Hz, 1H), 6.37
(d, J = 8.2Hz, 1H), 6.41 (d, J = 2.5Hz, 1H), 6.66 (d, J = 9.9Hz, 1
H), 6.82 (d, J = 8.2Hz, 1H), 6.93 (d, J = 8.2Hz, 1H). MS data M / Z 492 (M ⁺ )

Example 4 Synthesis of 4'-O-octadecyl glabridin (I-4) and 2'-O-octadecyl glabridin (II-4) 1.62 g (5 mmol) of glabridine in DMF (15)
ml) solution with stearyl bromide 1.67 g (5 mmol)
And 0.69 g (5 mmol) of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 48 hours. Administering the reaction mixture in water,
It was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained oily product was treated in the same manner as in Example 1 to give I-4 (0.82).
g, yield 28.4%) and II-4 (0.87 g, yield 3)
0.2%) was obtained. These were identified by the following NMR and MS analysis values. [I-4]: NMR data ¹ H-NMR (CDCl ₃ , TMS): 0.88
(t, J = 6.6Hz, 3H), 1.25 (br.s, 30H), 1.41 (s, 3H), 1.43 (s, 3
H), 1.72-1.78 (m, 2H), 2.82-2.89 (m, 1H), 2.99 (dd, J = 11.0
and 15.4Hz, 1H), 3.45-3.53 (m, 1H), 3.90 (t, J = 6.5Hz, 2H),
4.02 (t, J = 10.2Hz, 1H), 4.34-4.41 (m, 1H), 4.83 (s, 1H), 5.5
6 (d, J = 9.9Hz, 1H), 6.34 (d, J = 2.5Hz, 1H), 6.37 (d, J = 8.2Hz,
1H), 6.47 (dd, J = 8.5 and 2.5Hz, 1H), 6.65 (d, J = 9.9Hz, 1
H), 6.82 (d, J = 8.2Hz, 1H), 6.99 (d, J = 8.5Hz, 1H) MS data M / Z 576 (M ⁺ ) [II-4]: NMR data ¹ H-NMR ( CDCl ₃ ,, TMS): 0.88
(t, J = 6.6Hz, 3H), 1.25 (br.s, 30H), 1.42 (s, 3H), 1.43 (s, 3
H), 1.74-1.79 (m, 2H), 2.79-2.86 (m, 1H), 2.96 (dd, J = 10.4
and 15.4Hz, 1H), 3.53-3.56 (m, 1H), 3.90 (t, J = 6.5Hz, 2H),
3.99 (t, J = 10.2Hz, 1H), 4.31-4.35 (m, 1H), 5.04 (s, 1H), 5.5
5 (d, J = 9.9Hz, 1H), 6.35 (dd, J = 8.2 and 2.5Hz, 1H), 6.37
(d, J = 8.2Hz, 1H), 6.40 (d, J = 2.5Hz, 1H), 6.66 (d, J = 9.9Hz, 1
H), 6.81 (d, J = 8.2Hz, 1H), 6.93 (d, J = 8.2Hz, 1H) .MS data M / Z 576 (M ⁺ )

With respect to the glabridin derivative of the present invention, each test of (1) tyrosinase activity inhibition test (2) skin color lightness recovery test (3) optical patch test was conducted. Each test method is as follows.

(1) Tyrosinase activity inhibition test 0.3 ml per 1 ml of McClubain buffer (pH 6.8)
1 ml of a tyrosine solution having a concentration of g / ml and 0.9 ml of a sample solution having each concentration were added, and pre-incubation was performed at 37 ° C for 10 minutes. 0.1 ml of tyrosinase (manufactured by Sigma) having a concentration of 1 mg / ml was added thereto, and the mixture was heated at 37 ° C. for 15 minutes, and then the absorbance (A) was measured at a wavelength of 475 nm using a spectrophotometer. On the other hand, the absorbance (B) of 0.1 ml buffer solution added instead of tyrosinase, the absorbance (C) of 0.9 ml buffer solution instead of the sample solution, and 1 ml buffer solution instead of the sample solution and tyrosinase. The absorbance (D) of each of the samples to which was added was measured, and the inhibition rate (%) was calculated according to the following formula.

Inhibition rate (%) = {1- (AB) / (C-
D)} × 100

(2) Skin color brightness recovery test UVA and UV were applied to two skins on the inner part of the upper arm of 20 test subjects.
The minimum erythema dose of ultraviolet rays in the B region was continuously irradiated for 3 days. 7 days after the end of irradiation, the standard lightness (V0 value, V0
Value) was measured. The sample was applied to one side and the base to the other side three times a day for 4 consecutive weeks, and the skin lightness (Vn
Value, Vn 'value) was measured and the recovery of skin color was evaluated according to the criteria shown in Table 1.

The brightness of the skin (V value of Munsell display system)
Is obtained by measurement with a high-speed spectrocolorimeter and calculated from X, Y, and Z values. The evaluation is shown by the average value of the evaluation points of 20 test subjects after 4 weeks.

[0022]

[Table 1]

(3) Optical Patch Test After performing a closed patch for 24 hours using a patch test adhesive bandage having a diameter of 1.0 cm, which was prepared by applying 0.05 g of the sample to the skin of the flexor side of the forearm of 25 test subjects, the summer season Of sunlight for 6 hours (3 hours a day for 2 days).

In the evaluation, the skin condition of 25 test subjects was evaluated according to the criteria shown in Table 2. The determination results are shown by the number of people (±) or more 24 hours after irradiation.

[0025]

[Table 2]

Application Examples 1 to 4 and Comparative Examples 1 to 3 Skin Cream A skin cream was prepared by blending the compounds of the present invention as shown in Table 4 according to the raw material composition of Table 3. The blending amount is% by weight.

[0027]

[Table 3]

The results of various tests are shown in Table 4.

[0029]

[Table 4]

As shown in Table 4, Application Examples 1 to 4 clearly showed good results in all of the tests, and no skin irritation occurred in the tests on human skin.

[Stability Test] A stability test was conducted on the glabridin derivative of the present invention. The glabridin derivative of the present invention and the comparative compound were dissolved in ethanol to a concentration of 2 mmol / l. This solution was allowed to stand for one month under irradiation with sunlight (room temperature), and the remaining amount of the glabridin derivative and the comparative compound was quantified to evaluate the stability. The results are shown in Table 5.

[0032]

[Table 5] Comparative compound A: glabridin Comparative compound B: glabridin diethyl ether

As shown in Table 5, it is clear that the glabridin derivative of the present invention is more stable than glabridin.

[0034]

INDUSTRIAL APPLICABILITY As described above, it is apparent that the present invention provides a glabridine derivative having excellent stability and skin safety, and having an effect of rapidly lightening dark skin.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/35 ADZ 7431-4C

Claims (1)

[Claims] 1. A glabridin derivative represented by the following general formulas (I) and (II). [Chemical 1] [Chemical 2] (However, R is a linear or branched aliphatic hydrocarbon group having 2 to 20 carbon atoms.)