Chromone dimer having melanin production inhibitory activity, and preparation method and use thereof

Abstract

The application discloses a chromone dimer with melanin production inhibition, a preparation method and application thereof, and belongs to the technical field of natural products. The chromone dimer with melanin production inhibition has a structure shown in formula I. The chromone dimer with melanin production inhibition is evaluated by taking the melanin production of mouse melanoma (B16) cells as a model. The results show that the chromone dimer with melanin production inhibition can significantly inhibit the production of melanin, and has a good application prospect in the preparation of drugs or skin care products for treating and / or relieving excessive melanin production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of natural products, and particularly relates to a chromone dimer for inhibiting melanin production and a preparation method and application thereof. BACKGROUND

[0002] Melanin plays an important role in protecting skin and eyes, but excessive production of melanin can cause skin color to darken, and can even cause skin diseases such as chloasma and melanoma, which seriously affect people's physical and mental health. Moreover, with the improvement of living standards, people's requirements for appearance are also getting higher and higher, and whitening skin care products have become one of the hot-selling products in the market. At present, the whitening agents commonly used mainly include arbutin and kojic acid, but these substances all have certain safety problems. Therefore, searching for natural, safe and efficient melanin inhibitors has become one of the research hotspots. SUMMARY

[0003] Therefore, the technical problem to be solved by the present application is to provide a chromone dimer for inhibiting melanin production and a preparation method and application thereof. The chromone dimer for inhibiting melanin production can effectively inhibit the production of melanin, and has good application in the preparation of drugs or skin care products for treating and / or relieving excessive production of melanin.

[0004] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0005] The present application provides a chromone dimer for inhibiting melanin production, which has the structure shown in formula I:

[0006]

[0007] wherein R1 is hydrogen, R2 is hydrogen, R3 is hydroxyl, and R4 is methoxyl;

[0008] or R1 is hydrogen, R2 is methoxyl, R3 is hydroxyl, and R4 is methoxyl;

[0009] or R1 is hydroxyl, R2 is methoxyl, R3 is methoxyl, and R4 is hydroxyl.

[0010] The chromone dimer for inhibiting melanin production has any one of the structures shown in formulae 1-3:

[0011]

[0012]

[0013]

[0014] In the present application, the compounds shown in the above formulae 1-3 are proved to have the effect of inhibiting the melanin production of mouse melanoma cells B16 by activity test, and the half inhibitory concentration (IC 50 value) of the melanin production of B16 cells is 23-43 μM.

[0015] Specifically, the IC 50 value of the compound shown in formula 1 is 33.06±1.56, the IC 50 value of the compound shown in formula 2 is 24.86±1.20, and the IC 50 value of the compound shown in formula 3 is 40.09±2.96, which is obviously better than the inhibitory effect of kojic acid (IC 50 value of 275.00±13.03) on the melanin production of mouse melanoma cells B16.

[0016] The preparation method of the above chromone dimer having the effect of inhibiting melanin production comprises the following steps:

[0017] 1) The different flow parts are obtained by heating reflux extraction, extraction and normal phase silica gel column separation of Aquilaria sinensis, and then liquid chromatography-mass spectrometry analysis is performed to determine the flow part containing the chromone dimer with a molecular weight of 600-700 Da, which is called L flow part;

[0018] 2) The above L flow part is sequentially subjected to C18 reverse phase silica gel column, Sephadex LH-20 gel column and silica gel column separation and elution to obtain a mixed system S;

[0019] 3) The above mixed system S is eluted by semi-preparative high performance liquid chromatography to obtain the chromone dimer with a molecular weight of 600-700 Da having the effect of inhibiting melanin production.

[0020] Preferably, after the heating reflux extraction of step 1), the solvent is removed to obtain an extract, the extract is mixed with water to obtain a suspension, and then the suspension is extracted.

[0021] Preferably, the volume ratio of the extract to water is 1:(1-5); more preferably 1:(1-2). In some embodiments of the present application, the volume ratio of the extract to water is preferably 1:1.

[0022] Preferably, the solvent used in the heating reflux extraction in step 1) is selected from ethanol.

[0023] Preferably, the volume fraction of the ethanol is 95%.

[0024] Preferably, the solvent used in the extraction is selected from one or more of petroleum ether, ethyl acetate and n-butanol; more preferably ethyl acetate.

[0025] In some embodiments of the present application, the extract after extraction with ethyl acetate is further separated.

[0026] The extract after extraction with ethyl acetate is sequentially separated and eluted by a normal pressure silica gel column, a C18 reversed-phase silica gel column, a Sephadex LH-20 gel column, and a silica gel column.

[0027] Preferably, the solvent for separation by the normal pressure silica gel column in step 1) is a mixed solvent of chloroform and methanol.

[0028] Preferably, the separation by the normal pressure silica gel column in step 1) is gradient elution using a mixed solvent of chloroform and methanol at a volume ratio of 200:1→5:1 to obtain 11 fractions, denoted as Fr.1-Fr.11, and the component Fr.5 is taken as the L fraction.

[0029] Since liquid chromatography-mass spectrometry analysis of the components Fr.1-Fr.11 shows that the L fraction (Fr.5) contains chromone dimers with a molecular weight of 600-700 Da, the L fraction is further separated to obtain the chromone dimers with melanin production inhibiting activity according to the present application.

[0030] Preferably, the separation and elution by the C18 (ODS) reversed-phase silica gel column in step 2) is performed using a mixed solvent of methanol and water as the eluent.

[0031] Preferably, the separation and elution by the C18 reversed-phase silica gel column in step 2) is gradient elution of the L fraction (Fr.5) using a mixed solvent of methanol and water at a volume ratio of 3:7→8:2 to obtain 15 fractions, denoted as Fr.5-1-Fr.5-15.

[0032] Liquid chromatography-mass spectrometry analysis of the components Fr.5-1-Fr.5-15 shows that Fr.5-8 contains chromone dimers with a molecular weight of 600-700 Da, and therefore the Fr.5-8 fraction is further separated.

[0033] Preferably, the separation and elution by the Sephadex LH-20 gel column in step 2) is elution of the Fr.5-8 fraction using methanol to obtain 5 fractions, denoted as Fr.5-8-1-Fr.5-8-5.

[0034] The volume concentration of the methanol is preferably 95%.

[0035] The liquid phase mass spectrometry analysis of the components of Fr.5-8-1 to Fr.5-8-5 shows that the component Fr.5-8-4 contains a chrysin dimer with a molecular weight of 600-700 Da, and therefore the component Fr.5-8-4 is further separated.

[0036] Preferably, the separation and elution of the silica gel column in step 2) is performed by using chloroform and methanol mixed solvent as the eluent.

[0037] Preferably, the separation and elution of the silica gel column in step 2) is performed by using chloroform and methanol mixed solvent with a volume ratio of 30:1 to 10:1 to elute the component Fr.5-8-4 to obtain five components, which are denoted as Fr.5-8-4-1 to Fr.5-8-4-5; more preferably, the separation and elution of the silica gel column in step 2) is performed by using chloroform and methanol mixed solvent with a volume ratio of 20:1 to elute the component Fr.5-8-4.

[0038] The liquid phase mass spectrometry analysis of the components of Fr.5-8-4-1 to Fr.5-8-4-5 shows that the component Fr.5-8-4-4 contains a chrysin dimer with a molecular weight of 600-700 Da, and therefore the component Fr.5-8-4-4 is further separated.

[0039] In the preparation method of the present application, the mixed system S in step 2) is the component Fr.5-8-4-4 obtained after the above-mentioned different separation operations, which contains less impurities.

[0040] The component Fr.5-8-4-4 is eluted by semi-preparative high performance liquid chromatography to obtain the chrysin dimer with melanin production inhibition effect according to the present application. Preferably, the elution solvent of the semi-preparative high performance liquid chromatography in step 3) is selected from acetonitrile and water mixed solvent.

[0041] Preferably, the elution of the semi-preparative high performance liquid chromatography in step 3) is performed by using acetonitrile and water mixed solvent with a volume ratio of 23:87 to 40:60 to elute the component Fr.5-8-4-4 to obtain the chrysin dimer with a molecular weight of 600-700 Da; more preferably, the elution of the semi-preparative high performance liquid chromatography in step 3) is performed by using acetonitrile and water mixed solvent with a volume ratio of 33:67 to elute the component Fr.5-8-4-4.

[0042] In some specific embodiments of the present application, the semi-preparative high performance liquid chromatography preferably uses a C18 column.

[0043] The flow rate of the elution solvent of the semi-preparative high performance liquid chromatography is preferably 4.0 mL / min.

[0044] The UV detection wavelength of the semi-preparative high performance liquid chromatography is 210 nm or 254 nm.

[0045] The above "→" in the present application represents the volume ratio gradient of the elution solvent.

[0046] The present application also provides the use of the above-mentioned color ketone dimer with inhibiting melanin production or the above-mentioned color ketone dimer prepared by the preparation method in the preparation of a drug or a skin care product for treating and / or relieving excessive production of melanin.

[0047] The above-mentioned excessive production of melanin can cause one or more of the skin problems including freckles, yellow spots, age spots, melanoma, etc.

[0048] The present application also provides a drug for inhibiting melanin production, which comprises the above-mentioned color ketone dimer or the color ketone dimer prepared by the above-mentioned preparation method and a pharmaceutically acceptable excipient.

[0049] Preferably, the dosage form of the drug for inhibiting melanin production is selected from tablets, capsules, powder injections or suspensions.

[0050] The present application does not limit the above-mentioned pharmaceutically acceptable excipient, which can be a filler, a binder, etc.

[0051] The present application also provides a skin care product for inhibiting melanin production, which comprises the above-mentioned color ketone dimer or the color ketone dimer prepared by the above-mentioned preparation method and a skin care product acceptable excipient.

[0052] The present application does not limit the above-mentioned skin care product acceptable excipient, which can be a humectant, an antioxidant, a surfactant, a thickening agent, etc.

[0053] Compared with the prior art, the color ketone dimer with inhibiting melanin production provided by the present application has the structure shown in formula I. The color ketone dimer with inhibiting melanin production is evaluated by the model of melanin production by mouse melanoma (B16) cells, and the results show that the color ketone dimer with inhibiting melanin production of the present application can significantly inhibit the production of melanin, and has good application prospect in the preparation of a drug or a skin care product for treating and / or relieving excessive production of melanin. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 The H NMR spectrum of the compound 1 prepared in Example 1 is shown in Figure 1. 1 The H NMR spectrum of the compound 1 prepared in Example 1 is shown in Figure 1.

[0055] Figure 2 The H NMR spectrum of the compound 1 prepared in Example 1 is shown in Figure 1. 13C NMR spectrum;

[0056] Figure 3 HSQC spectrum of compound 1 prepared for Example 1;

[0057] Figure 4 HMBC spectrum of compound 1 prepared for Example 1; 1 H- 1 H COSY spectrum;

[0058] Figure 5 HMBC spectrum of compound 1 prepared for Example 1;

[0059] Figure 6 ROESY spectrum of compound 1 prepared for Example 1;

[0060] Figure 7 HRESIMS spectrum of compound 1 prepared for Example 1;

[0061] Figure 8 HSQC spectrum of compound 2 prepared for Example 1; 1 H NMR spectrum;

[0062] Figure 9 HMBC spectrum of compound 2 prepared for Example 1; 13 C NMR spectrum;

[0063] Figure 10 HSQC spectrum of compound 2 prepared for Example 1;

[0064] Figure 11 HMBC spectrum of compound 2 prepared for Example 1; 1 H- 1 H COSY spectrum;

[0065] Figure 12 HMBC spectrum of compound 2 prepared for Example 1;

[0066] Figure 13 ROESY spectrum of compound 2 prepared for Example 1;

[0067] Figure 14 HRESIMS spectrum of compound 3 prepared for Example 1;

[0068] Figure 15 HSQC spectrum of compound 3 prepared for Example 1; 1 H NMR spectrum;

[0069] Figure 16 HMBC spectrum of compound 3 prepared for Example 1; 13 C NMR spectrum;

[0070] Figure 17HSQC spectrum of compound 3 prepared in Example 1;

[0071] Figure 18 HMBC spectrum of compound 3 prepared in Example 1; 1 H- 1 H COSY spectrum of compound 3 prepared in Example 1;

[0072] Figure 19 HMBC spectrum of compound 3 prepared in Example 1;

[0073] Figure 20 ROESY spectrum of compound 3 prepared in Example 1;

[0074] Figure 21 HRESIMS spectrum of compound 3 prepared in Example 1. DETAILED DESCRIPTION

[0075] In order to further illustrate the present application, the diketone dimers with melanin production inhibiting activity provided by the present application, the preparation method and application thereof are described in detail below with reference to the examples.

[0076] The experimental materials used in the following examples are all commercially available and can be purchased in the market. The "-" in the elution solvent indicates a mixture of two solvents.

[0077] Example 1

[0078] 1.1 Instruments and reagents

[0079] Bruker AV-500 superconducting nuclear magnetic resonance spectrometer (Bruker Co., Ltd., Switzerland); Autospec 300 mass spectrometer (VG Co., Ltd., UK); analytical high performance liquid chromatograph (Agilent Co., Ltd., USA); semi-preparative high performance liquid chromatograph (Dionex Co., Ltd., USA); N-1000 (2L) vertical rotary evaporator and CA-1111 cooling water circulating device (Ailang Instrument Co., Ltd., Shanghai); SHZ-D (III) circulating vacuum pump (Longtuo Instrument Equipment Co., Ltd., Shanghai); AS220.R2 one-millionth electronic scale (RADWAG Wagi Elektroniczne); Sephadex LH-20 gel (Merck Co., Ltd.); C18 reversed-phase silica gel (20-45 μm, Fuji Silysia Chemical Ltd, Japan); silica gel for column chromatography and thin-layer chromatography silica gel plate (Qingdao Marine Chemical Plant); deuterated reagents and chromatographic methanol (Merck Co., Ltd., Germany); 95% ethanol, heavy distilled methanol, ethyl acetate, chloroform, petroleum ether, acetone and other commonly used organic reagents (Kemio, Fuchan, Guanghua, etc. companies in Tianjin).

[0080] The agarwood sample used in the present application was produced in Sri Lanka and purchased in Bangkok, Thailand.

[0081] 1.2 Preparation and structural identification of the compound

[0082] The agarwood sample was purchased in Bangkok, Thailand in August 2014. It was identified by Dr. Dai Haofu of the Institute of Tropical Biosciences, Chinese Academy of Tropical Agricultural Sciences, as being derived from Aquilaria walla (Gaertn.) Hallier f. of the family Thymelaeaceae. The specimen (201408SLLK) is now kept in the Institute of Tropical Biosciences.

[0083] The Sri Lankan A. walla agarwood sample (384.0 g) was pulverized and extracted with 95% ethanol aqueous solution (2.5 L each time) by heating (micro-boiling state) for 5 times. The obtained extract was filtered and combined, and concentrated at 45°C to obtain an ethanol extract (129.0 g). The extract was diluted with 1.0 L of water to form a suspension, and extracted with ethyl acetate (1.0 L each time) for 3 times. The extract was concentrated at 45°C to obtain an ethyl acetate extract.

[0084] The ethyl acetate extract (75.0 g) was subjected to gradient elution with chloroform:methanol (200:1→5:1, V / V) by reduced pressure normal phase silica gel column (silica gel H) to obtain 11 fractions, denoted as Fr.1-Fr.11. The components of Fr.1-Fr.11 were analyzed by liquid chromatography-mass spectrometry, and it was found that Fr.5 contained chromone dimers with a molecular weight of 600-700 Da.

[0085] The fraction Fr.5 (3.2 g) was subjected to gradient elution with methanol-water (3:7→8:2, V / V) by ODS reverse phase silica gel column chromatography to obtain 15 fractions, denoted as Fr.5-1-Fr.5-15. The components of Fr.5-1-Fr.5-15 were analyzed by liquid chromatography-mass spectrometry, and it was found that Fr.5-8 contained chromone dimers with a molecular weight of 600-700 Da.

[0086] The fraction Fr.5-8 (218.5 mg) was subjected to elution with 95% methanol and water (V / V) by Sephadex LH-20 gel column to obtain 5 fractions, denoted as Fr.5-8-1-Fr.5-8-5. The components of Fr.5-8-1-Fr.5-8-5 were analyzed by liquid chromatography-mass spectrometry, and it was found that Fr.5-8-4 contained chromone dimers with a molecular weight of 600-700 Da.

[0087] The fraction Fr.5-8-4 (130.0 mg) was subjected to column chromatography on normal silica gel (silica gel H) eluted with chloroform-methanol (20:1, V / V) to give five fractions, denoted as Fr.5-8-4-1~Fr.5-8-4-5. The components of Fr.5-8-4-1~Fr.5-8-4-5 were subjected to liquid chromatography-mass spectrometry analysis, and it was found that Fr.5-8-4-4 contained a chrysin dimer with a molecular weight of 600~700 Da.

[0088] The fraction Fr.5-8-4-4 (55.0 mg) containing compounds 1, 2, 3 was subjected to semi-preparative high performance liquid chromatography (C18 column; acetonitrile / water, 33:67, V / V; flow rate 4.0 mL / min; ultraviolet detection wavelength 210 / 254 nm) to give compound 1 (t R 27.2 min; 5.4 mg), compound 2 (t R 25.0 min; 5.8 mg) and compound 3 (t R 13.0 min; 3.0 mg).

[0089] The structural formulas of the compounds 1, 2 and 3 are shown in formulas 1, 2 and 3, respectively:

[0090]

[0091]

[0092]

[0093] The compounds 1, 2 and 3 prepared in Example 1 were subjected to structural identification, and the detection results are shown in Table 1. Figures 1-21 The high resolution mass spectrum of compound 1 is m / z 665.1990 [M+Na] + The molecular formula of compound 1 is C 36 H 34 O 11 The high resolution mass spectrum of compound 2 is m / z 695.2117 [M+Na] + The molecular formula of compound 2 is C 37 H 36 O 12 The high resolution mass spectrum of compound 3 is m / z 711.2046 [M+Na] + The molecular formula of compound 3 is C 37 H 36 O 13 .

[0094] The physical properties of the compounds 1, 2 and 3 are shown in Table 2. 1 H NMR (500 MHz) and 13C NMR (125 MHz) data are shown in Table 1, and specific spectra are shown in Figures 1-21 :

[0095] Table 1. C NMR (125 MHz) data of compounds 1, 2 and 3 1 H NMR data (δ in ppm, J in Hz, in CD3OD)

[0096]

[0097]

[0098] Example 1

[0099] Activity determination of compounds 1, 2 and 3 in inhibiting melanin production

[0100] B16 cells (mouse melanoma cells) were cultured in DMEM high glucose complete medium with 10% fetal bovine serum, and the culture conditions were 37°C, 5% CO2 saturated humidity incubator. Cells in logarithmic growth phase were inoculated in 96-well plates (5 x 10 3 cells / 100 μL / well), and cultured for 24 h. The experiment was set up with a control group, different concentrations of sample groups and a positive control group. The control group was replaced with fresh culture medium, the test group was replaced with culture medium containing different concentrations of samples, and the positive control group was different concentrations of kojic acid culture medium. After 48 h of culture, they were washed once with PBS, 50 μL of PBS containing 1% Ttriton X-100 was added to each well, and they were placed at -80°C for 30 min, then incubated at 37°C to completely rupture the cells. After repeated 3 times, L-dopa (4 mmol / L, 50 μL / well) was added, and incubated at 37°C for 1 h. The absorbance (A) of each well was measured at 475 nm by a microplate reader. The inhibition rate of melanin production was calculated according to the following formula:

[0101] Inhibition rate of melanin production = A 试验组 / A 对照组 x 100%

[0102] In the formula, A 试验组 and A 对照组 are the absorbance values of the test group and the control group measured at 475 nm, respectively. The inhibition rate at each concentration was calculated and the compound concentration-inhibition rate curve was plotted, and the half-inhibitory concentration (IC 50 value) of the compound in inhibiting B16 cell melanin production was calculated, and the test results are shown in Table 2.

[0103] Table 2. Activity results of compounds 1, 2 and 3 in inhibiting melanin production

[0104] Compound IC 50 ± SD (μM) Compound 1 33.06±1.56* Compound 2 24.86±1.20* Compound 3 40.09±2.96* Kojic acid a ]]> 275.00±13.03

[0105] Note: a positive control, *P <0.05 vs. positive control group.

[0106] From the above examples and application examples, it can be seen that the present application provides a chromone dimer with melanin production inhibition. The chromone dimer with melanin production inhibition is derived from Aquilaria sinensis, which has a good application prospect in the preparation of drugs or skin care products for treating and / or relieving excessive production of melanin.

[0107] The above examples are only used to help understand the method of the present application and its core idea. It should be pointed out that for those skilled in the art, without departing from the principles of the present application, the present application can be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present application.

Claims

1. A chromone dimer that inhibits melanin production, characterized in that, having the structure of Formula I: wherein R1 is hydrogen, R2 is hydrogen, R3 is hydroxyl, and R4 is methoxyl; or R1 is hydrogen, R2 is methoxyl, R3 is hydroxyl, and R4 is methoxyl; or R1 is hydroxyl, R2 is methoxyl, R3 is methoxyl, and R4 is hydroxyl.

2. The method for preparing a dimer of chromones having a melanin production inhibitory effect according to claim 1, characterized by, comprising the following steps: 1) obtaining different flow fractions by heating reflux extraction, extraction, and normal phase silica gel column separation of Aquilaria sinensis, then performing liquid chromatography-mass spectrometry analysis to determine the flow fraction containing chromone dimers with molecular weights between 600-700 Da, referred to as L flow fraction; 2) sequentially performing C18 reverse phase silica gel column, Sephadex LH-20 gel column, and silica gel column separation and elution on the L flow fraction to obtain a mixed system S; 3) eluting the mixed system S by semi-preparative high performance liquid chromatography to obtain chromone dimers with molecular weights between 600-700 Da that inhibit melanin production.

3. The method for preparing a colorant having a colorant dimer of a chromone having a melanin production inhibitory effect according to claim 2, characterized by, The heating reflux extraction of step 1) further comprises removing the solvent to obtain an extract, mixing the extract with water to obtain a suspension, and then extracting the suspension.

4. The method for preparing a colorant having a colorant dimer of a chromone having a melanin production inhibitory effect according to claim 2, characterized by, The solvent used in the heating reflux extraction of step 1) is selected from ethanol; The solvent used in the extraction of step 1) is selected from one or more of petroleum ether, ethyl acetate, and n-butanol; The gradient elution of the normal phase silica gel column separation of step 1) uses a chloroform and methanol mixed solvent with a volume ratio of 200:1→5:1 to obtain 11 flow fractions, referred to as Fr.1-Fr.11, and the component Fr.5 is the L flow fraction.

5. The method for preparing a colorant having a colorant dimer of a colorant having an inhibitory effect on melanin production according to claim 2, wherein The gradient elution of the C18 reverse phase silica gel column of step 2) uses a methanol and water mixed solvent with a volume ratio of 3:7→8:2 to elute the L flow fraction to obtain 15 flow fractions, referred to as Fr.5-1-Fr.5-15.

6. The method for preparing a colorant having a colorant dimer of a chromone having a melanin production inhibitory effect according to claim 2, wherein The elution of the Sephadex LH-20 gel column of step 2) uses methanol to elute the flow fraction Fr.5-8 to obtain 5 flow fractions, referred to as Fr.5-8-1-Fr.5-8-5; The elution of the silica gel column of step 2) uses a chloroform and methanol mixed solvent with a volume ratio of 30:1→10:1 to elute the flow fraction Fr.5-8-4 to obtain 5 flow fractions, referred to as Fr.5-8-4-1-Fr.5-8-4-5.

7. The method for preparing a colorant having a colorant dimer of a chromone having an inhibitory effect on melanin production according to claim 2, wherein The elution of the semi-preparative high performance liquid chromatography of step 3) uses an acetonitrile and water mixed solvent with a volume ratio of 23:87→40:60 to elute the flow fraction Fr.5-8-4-4 to obtain chromone dimers with molecular weights between 600-700 Da that inhibit melanin production.

8. Use of the chromone dimers that inhibit melanin production of claim 1 or prepared by the method of any one of claims 2-7 in the preparation of a medicament or skin care product for treating and / or alleviating excessive melanin production.

9. A medicament for inhibiting melanin production, characterized by comprising a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof. The chromone dimers of claim 1 or prepared by the method of any one of claims 2-7 and a pharmaceutically acceptable excipient.

10. A skin care product for inhibiting melanin production, characterized by, The chromonyl dimer of claim 1 or the chromonyl dimer prepared by the method of any one of claims 2 to 7, together with a cosmetically acceptable adjuvant.

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