A bibenzyl dimer compound, and a preparation method and application thereof

Abstract

The application discloses a kind of bibenzyl dimer compounds, the structural formula of the compound is as shown in the following formula I: this bibenzyl dimer compound is extracted from the stem and leaf of Alpinia oxyphylla Miq., it has significant inhibiting melanin production effect, can be used as melanin inhibitor or in the preparation of inhibiting melanin excessive production of drug or skin care product.

Description

Technical Field

[0001] This invention belongs to the field of natural medicine technology, specifically relating to a bibenzyl dimer compound, its preparation method and application, and in particular a bibenzyl dimer compound extracted from the stems and leaves of Alpinia oxyphylla, its preparation method and application. Background Technology

[0002] Melanin plays a vital role in protecting the skin and eyes, but excessive production can lead to darker skin, and in severe cases, cause skin diseases such as melasma and melanoma, seriously affecting people's physical and mental health. Furthermore, with rising living standards, people have increasingly higher demands for their appearance, making skin-whitening skincare products one of the best-selling products on the market. Currently, commonly used whitening agents include arbutin and kojic acid, but these substances all have certain safety concerns. Therefore, finding natural, safe, and effective melanin inhibitors has become a research hotspot.

[0003] Alpinia oxyphylla Miq., commonly known as Yizhi, is a perennial herb belonging to the genus Alpinia in the family Zingiberaceae. It is considered one of the "Four Great Southern Chinese Herbs" and is also a plant used for both food and medicine. According to the Chinese Pharmacopoeia, Yizhi is pungent and warm in nature, and enters the kidney and spleen meridians. Generally, its mature seeds or fruits are dried before being used medicinally, primarily for treating kidney deficiency with enuresis, cold-induced diarrhea, seminal emission, and abdominal pain due to cold. Studies have shown that the main components of Yizhi seeds are flavonoids, sesquiterpenes, diphenylheptane, sterols, and glycosides, possessing various pharmacological activities such as anti-aging, anti-tumor, neuroprotective, and treatment of Alzheimer's disease. The types and contents of chemical components vary in different parts of Yizhi, with the stems and leaves containing a higher content of flavonoids. These compounds have been reported to have strong hypoglycemic, antibacterial, anti-tumor, and neuroprotective activities.

[0004] Currently, no bibenzyl dimer compounds have been found that can be extracted from the stems and leaves of Alpinia oxyphylla and used to inhibit melanin production. Summary of the Invention

[0005] Therefore, the purpose of this invention is to provide a bibenzyl dimer compound that can significantly inhibit melanin production.

[0006] Another objective of this invention is to provide a method for preparing the above-mentioned bibenzyl dimer compounds.

[0007] The final object of the present invention is to provide the above-mentioned bibenzyl dimer compounds as melanin inhibitors and their use in the preparation of drugs or skin care products that inhibit excessive melanin production.

[0008] The first objective of this invention can be achieved by the following technical solution: a bibenzyl dimer compound, the structural formula of which is shown in Formula I below:

[0009]

[0010] The second objective of this invention can be achieved through the following technical solution: the preparation method of the bibenzyl dimer compound includes the following steps:

[0011] S1) After crushing the stems and leaves of Alpinia oxyphylla, extract them multiple times by heating and refluxing with ethanol. Combine the resulting extracts and concentrate them into an ethanol extract.

[0012] S2) Prepare a suspension by mixing the ethanol extract with an equal volume of water, and extract it sequentially with petroleum ether, ethyl acetate and n-butanol. Then concentrate each extract to prepare an extract.

[0013] S3) The ethyl acetate extract was subjected to gradient elution with chloroform-methanol through a normal-phase silica column under reduced pressure to obtain 20 fractions, denoted as Fr.1 to Fr.20. Liquid chromatography-mass spectrometry analysis of the fractions Fr.1 to Fr.20 revealed that Fr.15 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da.

[0014] S4) Fraction Fr.15 was subjected to gradient elution with chloroform-methanol on a silica gel column to obtain 20 fractions, denoted as Fr.15-1 to Fr.15-20. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-1 to Fr.15-20 revealed that Fr.15-3 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da.

[0015] S5) Fraction Fr.15-3 was eluted with methanol on a Sephadex LH-20 gel column to obtain 7 fractions, denoted as Fr.15-3-1 to Fr.15-3-7. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-3-1 to Fr.15-3-7 revealed that Fr.15-3-2 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da.

[0016] S6) Fraction Fr.15-3-2 was subjected to gradient elution with chloroform-methanol on a silica gel column to obtain 12 fractions, denoted as Fr.15-3-2-1 to Fr.15-3-2-12. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-3-2-1 to Fr.15-3-2-12 revealed that Fr.15-3-2-9 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da.

[0017] S7) The fraction Fr.15-3-2-9 was eluted by semi-preparative high performance liquid chromatography to obtain a bibenzyl dimer compound with a molecular weight between 800-900 Da as shown in Formula I.

[0018] In the above-mentioned methods for preparing bibenzyl dimer compounds:

[0019] Optionally, the volume percentage of ethanol in step S1) is 90% - anhydrous ethanol.

[0020] Optionally, the ratio of the amount of Alpinia oxyphylla stems and leaves to the amount of ethanol in step S1) is 1.5-2.0 kg: 1 L.

[0021] Optionally, in step S1), the extraction is performed by heating and reflux 3-5 times.

[0022] Optionally, in step S3), chloroform-methanol is eluted in a gradient ratio of 1:0 → 0:1, V / V, specifically in the ratios of 100:0, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, and 0:100. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 20 fractions.

[0023] Optionally, the reduced-pressure positive-phase silica column mentioned in step S3) is silica gel H.

[0024] Optionally, in step S4), chloroform-methanol is eluted in a gradient ratio of 40:1 to 10:1, V / V, specifically in the ratios of 40:1, 30:1, 20:1, and 10:1. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 20 fractions.

[0025] Optionally, the silicone column described in steps S4) and S6) is filled with 200-300 mesh silicone.

[0026] Optionally, in step S6), chloroform-methanol is eluted in a gradient ratio of 40:1 to 10:1, V / V, specifically in the ratios of 40:1, 30:1, 20:1, and 10:1. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 12 fractions.

[0027] Optionally, the conditions for the semi-preparative high-performance liquid chromatography described in step S7) include: C18 column; methanol / water, 45:55, V / V; flow rate 4.0 mL / min; UV detection wavelength 210 / 254 nm.

[0028] The third objective of the present invention can be achieved through the following technical solutions: the application of the above-mentioned bibenzyl dimer compounds as melanin production inhibitors and the application of the above-mentioned bibenzyl dimer compounds in the preparation of drugs or skin care products that inhibit excessive melanin production.

[0029] Preferably, the bibenzyl dimer compounds of the present invention are used as melanin production inhibitors and in the preparation of drugs or skin care products that inhibit excessive melanin production, especially for diseases related to excessive melanin production. These diseases can be treated with one or more skin problems such as freckles, age spots, melanoma, etc., caused by excessive melanin production.

[0030] The present invention also provides a drug or skin care product for inhibiting excessive melanin production, comprising the aforementioned bibenzyl dimer compound and pharmaceutically or skin care-acceptable excipients.

[0031] Preferably, the dosage form of the drug of the present invention is a tablet, capsule, powder for injection or suspension.

[0032] Preferably, the dosage form of the skin care product of the present invention is a spray, lotion, cream, or lotion.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] (1) The bibenzyl dimer compounds in this invention are novel bibenzyl dimers with significant inhibitory effects on melanin production. They can be used as melanin inhibitors or in the preparation of drugs or skin care products that inhibit melanin production.

[0035] (2) The bibenzyl dimer compounds in this invention were evaluated for inhibiting melanin production using mouse melanoma (B16) cells as a model. They were able to inhibit melanin production and could be used in the preparation of drugs or skin care products for treating and / or alleviating melanin overproduction. They have broad development and application prospects in the preparation of drugs or skin care products for inhibiting melanin overproduction-related (diseases). Attached Figure Description

[0036] Figure 1 It is the compound of formula I prepared in Example 1. 1 H NMR spectrum;

[0037] Figure 2 It is the compound of formula I prepared in Example 1. 13 C NMR spectrum;

[0038] Figure 3 This is the HSQC spectrum of the compound with structure I prepared in Example 1;

[0039] Figure 4It is the compound of formula I prepared in Example 1. 1 H- 1 H COSY spectrum;

[0040] Figure 5 This is the HMBC spectrum of the compound with structure I prepared in Example 1;

[0041] Figure 6 This is the ROESY spectrum of the compound with structure I prepared in Example 1;

[0042] Figure 7 This is the HRESIMS spectrum of the compound with structure I prepared in Example 1. Detailed Implementation

[0043] This invention provides a compound that inhibits melanin production. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0044] The experimental materials used in the following embodiments of the present invention are all commercially available products that can be purchased on the market.

[0045] The present invention will be further illustrated below with reference to the embodiments:

[0046] Example 1

[0047] 1.1 Instruments and reagents, including but not limited to:

[0048] Bruker AV-500 superconducting nuclear magnetic resonance spectrometer (Bruker GmbH, Switzerland); Autospec 300 mass spectrometer (VG Corporation, UK); analytical high-performance liquid chromatograph (Agilent Technologies, USA); semi-preparative high-performance liquid chromatograph (Dionex Corporation, USA); N-1000 (2L) vertical rotary evaporator and CA-1111 cooling water circulation system (Shanghai Ailang Instrument Co., Ltd.); SHZ-D (Ⅲ) circulating vacuum pump (Shanghai Longtuo Instrument Equipment Co., Ltd.); AS220.R2 0.001 g electronic balance (RADWAG Wagi Elektroniczne); Sephadex LH-20 gel (Merck) Co., Ltd.; silica gel H, 200-300 mesh silica gel for column chromatography and thin-layer chromatography silica gel plates (Qingdao Ocean Chemical Plant); deuterated reagents and chromatographic methanol (Merck, Germany); 95% ethanol, redistilled methanol, ethyl acetate, chloroform, petroleum ether and other commonly used organic reagents (Tianjin Kemeio, Tianjin Fuchen, Guangzhou Guanghua and other companies).

[0049] 1.2 Preparation and structural identification of compounds

[0050] The stem and leaf samples of Alpinia oxyphylla were collected in Danzhou City, Hainan Province in June 2020. Dr. Liu Shoubai of the Institute of Tropical Biotechnology, Chinese Academy of Tropical Agricultural Sciences, identified the original plant as Alpinia oxyphylla Miq. of the Zingiberaceae family. The specimen (YZ202006) is currently stored at the Institute of Tropical Biotechnology.

[0051] S1) After crushing the stem and leaf sample of Alpinia oxyphylla (95.5 kg), it was extracted three times by heating (slight boiling) and refluxing with 50 L of 95% ethanol aqueous solution. The resulting extracts were filtered and combined, and concentrated at 45 °C to obtain ethanol extract paste (925.8 g).

[0052] S2) Dilute the extract into a suspension with about 1.0L of water, and extract it three times in sequence with petroleum ether (5.0L each time), ethyl acetate (5.0L each time), and n-butanol (5.0L each time). The extract layers are evaporated and concentrated at 45°C to prepare petroleum ether phase extract, ethyl acetate phase extract, and n-butanol phase extract, respectively.

[0053] S3) Take 150.1 g of ethyl acetate extract (i.e., ethyl acetate phase extract) and elute it with a gradient of chloroform:methanol (1:0→0:1, V / V) through a normal-phase silica gel H column under reduced pressure. Specifically, the gradient elution was performed at ratios of 100:0, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, and 0:1. The obtained fractions were detected by thin-layer chromatography spotting plate. Based on the color development, similar fractions were combined to obtain 20 fractions, which were designated as Fr.1 to Fr.20. Liquid chromatography-mass spectrometry analysis of fractions Fr.1 to Fr.20 revealed that Fr.15 contained bibenzyl dimers with a molecular weight between 800-900 Da.

[0054] S4) Fraction Fr.15 (4.11 g) was subjected to normal-phase silica gel column chromatography (200-300 mesh) with gradient elution of chloroform-methanol (40:1→10:1, V / V), specifically at ratios of 40:1, 30:1, 20:1, and 10:1. The resulting fractions were detected by thin-layer chromatography spotting. Based on the color development, similar fractions were combined to obtain 20 fractions, designated Fr.15-1 to Fr.15-20. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-1 to Fr.15-20 revealed that Fr.15-3 contained bibenzyl dimers with a molecular weight between 800-900 Da.

[0055] S5) The fraction Fr.15-3 (830.0 mg) was eluted with 95% methanol and water (V / V) on a Sephadex LH-20 gel column to obtain 7 fractions, denoted as Fr.15-3-1 to Fr.15-3-7; by liquid chromatography-mass spectrometry analysis of the fractions Fr.15-3-1 to Fr.15-3-7, it was found that Fr.15-3-2 contained bibenzyl dimer with a molecular weight between 800-900 Da.

[0056] S6) Fraction Fr.15-3-2 (243.2 mg) was eluted with chloroform-methanol (50:1→40:1, V / V) on a normal-phase silica gel column (200-300 mesh), specifically in gradient elution ratios of 40:1, 30:1, 20:1, and 10:1. The resulting fractions were analyzed by thin-layer chromatography spotting. Based on the color development, similar fractions were combined to obtain 12 fractions, designated Fr.15-3-2-1 to Fr.15-3-2-12. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-3-2-1 to Fr.15-3-2-12 revealed that Fr.15-3-2-9 contained bibenzyl dimers with a molecular weight between 800-900 Da.

[0057] S7) The fraction Fr.15-3-2-9 (21.2 mg) was eluted by semi-preparative high-performance liquid chromatography (C18 column; methanol / water, 45:55, V / V; flow rate 4.0 mL / min; UV detection wavelength 210 / 254 nm) to obtain a compound with a molecular weight between 800-900 Da (t R 22.2 min; 8.5 mg).

[0058] The obtained compound was subjected to nuclear magnetic resonance spectroscopy using a deuterated reagent solvent.

[0059] The compound with the structure of Formula I obtained from nuclear magnetic resonance spectroscopy is shown below:

[0060]

[0061] The structure of the compound with formula I prepared in Example 1 was identified. 1 H NMR spectrum as follows Figure 1 As shown, 13 C NMR spectra as follows Figure 2 As shown, the HSQC spectrum is as follows: Figure 3 As shown, 1 H- 1 H COSY spectrum as follows Figure 4 As shown, the HMBC map is as follows: Figure 5 As shown, the ROESY map is as follows: Figure 6 As shown, the HRESIMS map is as follows: Figure 7 As shown, the high-resolution mass spectrum of the compound is m / z 861.3341 [M+Na]. + The molecular formula is C 44 H 54 O 16 ; compounds 1 H (500MHz) and 13 The C NMR (125MHz) data are shown in Table 1:

[0062] Table 1 Compounds 1 H and 13 C NMR data (δin ppm, J in Hz, in CD3OD)

[0063] 1,1” 5.09,d(6.0) 81.5,CH 2,2” 3.31,q(5.9,5.4) 58.6, CH 3,3” 4.71, td(7.0, 2.9) 79.9, CH 4,4” 2.05, dt(13.9, 8.0) <![CDATA[36.6,CH2]]> 1.82, ddd(13.9, 8.0, 4.0) 5,5” 3.24, dt(7.8, 3.5) 72.7,CH 6,6” 3.45, dt(8.2, 4.0) 76.1,CH 7,7” 2.49,m <![CDATA[40.5,CH2]]> 8,8” 132.1,C 9,9” 6.69,d(1.8) 114.0,CH 10,10” 148.7,C 11,11” 145.7,C 12,12” 6.63,d(8.0) 116.0,CH 13,13” 6.53,dd(8.0,1.8) 122.8,CH 1',1”' 135.0,C 2',2”' 6.67,s 105.4,CH 3',3”' 149.4,C 4',4”' 136.3,C 5',5”' 149.4,C 6',6”' 6.67,s 105.4,CH <![CDATA[10,10”-OCH3]]> 3.73,s <![CDATA[56.3,CH3]]> <![CDATA[3',5',3”',5”'-OCH3]]> 3.77,s <![CDATA[56.9,CH3]]>

[0064] Example 2: Activity assay of the compound in inhibiting melanin production

[0065] B16 cells (mouse melanoma cells) were cultured in DMEM high-glucose complete medium containing 10% fetal bovine serum at 37°C in a 5% CO2 saturated humidity incubator. Cells in the logarithmic growth phase were seeded into 96-well plates (5 × 10⁻⁶ cells / well).3 Cells were cultured for 24 hours with 100 μL / well of L-DOPA. The experiment included a control group, sample groups with different concentrations (compounds of Formula I prepared in Example 1, at concentrations of 150, 100, 50, and 25 μM), and a positive control group. The control group was replaced with fresh culture medium, the experimental groups with culture medium containing different concentrations of the sample, and the positive control group with culture medium containing different concentrations of kojic acid (150, 100, 50, and 25 μM). After 48 hours of culture, the cells were washed once with PBS, and 50 μL of PBS containing 1% Ttriton X-100 was added to each well. The cells were incubated at -80°C for 30 minutes, then incubated at 37°C to completely lyse the cells. This process was repeated three times. L-DOPA (4 mmol / L, 50 μL / well) was then added, and the cells were incubated at 37°C for 1 hour. The absorbance (A) of each well was measured at 475 nm using a microplate reader. The inhibition rate of melanin production was calculated using the following formula:

[0066] Melanin production inhibition rate = A 试验组 / A 对照组 ×100%

[0067] In the formula: A 试验组 and A 对照组 The absorbance values ​​of the experimental group and the control group were measured at 475 nm, respectively. The inhibition rate at each concentration was calculated. The detection results are shown in Table 2.

[0068] Table 2 Results of the compounds' activity in inhibiting melanin production

[0069]

[0070] a Positive control, *P<0.05 vs positive control group, **P<0.01 vs positive control group

[0071] As can be seen from Examples 1-2 above, this invention has discovered a novel bibenzyl dimer compound with melanin-inhibiting activity. This compound is derived from the stems and leaves of Alpinia oxyphylla and can be used to prepare drugs or skin care products that inhibit melanin production. These include the bibenzyl dimer compound and pharmaceutically or skin care excipients. The dosage form of the drug can be tablets, capsules, powder for injection, or suspension, etc., and the skin care product can be a spray, ointment, lotion, cream, etc. It is used to treat and / or alleviate skin diseases caused by excessive melanin production, such as freckles, age spots, and melanoma. Therefore, the bibenzyl dimer compound provided by this invention has good application prospects in the development of drugs or skin care products for treating skin problems caused by excessive melanin production.

[0072] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A bibenzyl dimer compound, characterized in that... The structural formula of the compound is shown in Formula I below: Formula I.

2. The method for preparing the bibenzyl dimer compound according to claim 1, characterized in that... Includes the following steps: S1) After crushing the stems and leaves of Alpinia oxyphylla, extract them multiple times by heating and refluxing with ethanol. Combine the resulting extracts and concentrate them into an ethanol extract. S2) Prepare a suspension by mixing the ethanol extract with an equal volume of water, and extract it sequentially with petroleum ether, ethyl acetate and n-butanol. Then concentrate each extract to prepare an extract. S3) The ethyl acetate extract was subjected to gradient elution with chloroform-methanol through a normal-phase silica column under reduced pressure to obtain 20 fractions, denoted as Fr.1 ~ Fr.

20. Liquid chromatography-mass spectrometry analysis of the Fr.1 ~ Fr.20 fractions revealed that Fr.15 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da. S4) Fraction Fr.15 was subjected to gradient elution with chloroform-methanol on a silica gel column to obtain 20 fractions, denoted as Fr.15-1 to Fr.15-20. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-1 to Fr.15-20 revealed that Fr.15-3 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da. S5) Fraction Fr.15-3 was eluted with methanol on a Sephadex LH-20 gel column to obtain 7 fractions, denoted as Fr.15-3-1 to Fr.15-3-7. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-3-1 to Fr.15-3-7 revealed that Fr.15-3-2 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da. S6) Fraction Fr.15-3-2 was subjected to gradient elution with chloroform-methanol on a silica gel column to obtain 12 fractions, denoted as Fr.15-3-2-1 to Fr.15-3-2-12. Liquid chromatography-mass spectrometry analysis of fractions Fr.15-3-2-1 to Fr.15-3-2-12 revealed that Fr.15-3-2-9 contained bibenzyl dimer compounds with a molecular weight between 800 and 900 Da. S7) The fraction Fr.15-3-2-9 was eluted by semi-preparative high performance liquid chromatography to obtain a bibenzyl dimer compound with a molecular weight between 800-900 Da as shown in Formula I.

3. The method for preparing the bibenzyl dimer compound according to claim 2, characterized in that: In step S1), the ratio of Alpinia oxyphylla stems and leaves to ethanol is 1.5-2.0 kg: 1 L, and the extraction is carried out by heating and reflux 3-5 times.

4. The method for preparing the bibenzyl dimer compound according to claim 2, characterized in that: In step S3), chloroform-methanol is specifically eluted in gradient proportions of 100:0, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, and 0:

100. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 20 fractions.

5. The method for preparing the bibenzyl dimer compound according to claim 2, characterized in that: In step S4), chloroform-methanol is specifically eluted in a gradient ratio of 40:1, 30:1, 20:1, and 10:

1. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 20 fractions.

6. The method for preparing the bibenzyl dimer compound according to claim 2, characterized in that: In step S6), chloroform-methanol is specifically eluted in a gradient ratio of 40:1, 30:1, 20:1, and 10:

1. The resulting fractions are detected by thin-layer chromatography spot plate, and similar fractions are combined based on color development to finally obtain 12 fractions.

7. The method for preparing the bibenzyl dimer compound according to claim 2, characterized in that: The reduced-pressure normal-phase silica column mentioned in step S3) is silica gel H; the silica column mentioned in steps S4) and S6) is filled with 200-300 mesh silica gel; the semi-preparative high-performance liquid chromatography conditions mentioned in step S7) include: C18 column; methanol / water volume ratio of 45:55; flow rate of 4.0 mL / min; and UV detection wavelength of 210 / 254 nm.

8. The use of the bibenzyl dimer compound of claim 1 in the preparation of melanin production inhibitors.

9. The use of the bibenzyl dimer compound of claim 1 in the preparation of drugs or skin care products that inhibit excessive melanin production.

10. A drug or skincare product for inhibiting excessive melanin production, characterized in that: This includes the bibenzyl dimer compounds of claim 1 and pharmaceutically or skincare-acceptable excipients.

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