A novel disulfide biphenol ether compound and its preparation method and application

Abstract

A novel disulfide biphenol ether compound and its preparation method and application for treating inflammatory skin diseases, the structural formula of the disulfide biphenol ether compound is: biphenyl diester is first dissolved in anhydrous tetrahydrofuran solvent, lithium aluminum hydroxide is added, quenched, filtered, extracted with dichloromethane, water is added to quench the reaction, extracted with dichloromethane, the organic phases are combined, after removing residual moisture, the reduced pressure rotary evaporation and recrystallization are removed to obtain intermediate 2; intermediate 2 and potassium thioacetate are added to solvent N, N-dimethylformamide and extracted, the organic phases are combined, and the solvent is evaporated and concentrated to obtain a light intermediate 3; intermediate 3 is dissolved in anhydrous methanol, sodium methoxide is added, stirred, extracted with ethyl acetate, and the organic phases are combined to obtain. The disulfide biphenyl compound prepared by the present invention has good anti-inflammatory ability, can effectively reduce inflammatory infiltration in tissue, improve the inflammatory phenotype of animal models, and can prevent and treat inflammatory skin diseases.

Description

Technical Field

[0001] The present invention relates to a novel disulfide biphenol ether compound, a preparation method thereof and application thereof in treating inflammatory skin diseases. Background Art

[0002] Inflammatory skin diseases are common, including rosacea, psoriasis, atopic dermatitis, and alopecia areata. In recent years, their onset has become younger. These skin diseases are caused by a variety of internal and external factors, resulting in inflammation of the epidermis or dermis and manifesting in a variety of pathological manifestations. Rosacea and psoriasis are common chronic inflammatory skin diseases with high incidence, low clinical cure rates, and frequent recurrence, causing significant distress to patients.

[0003] Biphenol and its ether derivatives have a wide range of antioxidant, anti-inflammatory, and hepatoprotective activities and have attracted much attention. For example, schisandra chinensis A-isolated from the Chinese herbal medicine Schisandra chinensis has a good ability to reduce alanine aminotransferase activity. The biphenyl diester developed on this basis is clinically used as a hepatoprotective drug. The monoester reduction product of biphenyl diester, bicyclic alcohol, has a good free radical scavenging ability. In addition to its effect of reducing liver transaminase, bicyclic alcohol also has a good anti-hepatitis virus effect and is also used clinically as a hepatoprotective drug. The present invention innovatively introduced the important disulfide structure in the redox system of the living system based on the structure of schisandra chinensis A-isolated, and designed and synthesized a new type of disulfide biphenol ether compound. The compound exhibits certain anti-inflammatory and antioxidant abilities, and has good development and utilization prospects in terms of both activity and safety. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a novel disulfide biphenol ether compound and a pharmaceutically acceptable salt thereof, the structure of which is shown in Formula 1:

[0005]

[0006] A second object of the present invention is to provide a method for preparing the novel disulfide biphenol ether compound 1 (compound 1).

[0007] The technical route for the preparation of the novel disulfide biphenol ether compound 1 is as follows:

[0008]

[0009] (1) Preparation of intermediate 2

[0010] Bifendate is dissolved in anhydrous tetrahydrofuran. Lithium aluminum tetrahydrate is added portionwise in an ice bath. After stirring at room temperature for 10 minutes, the reaction is quenched by slowly adding water, and the residue is removed by filtration. The filtrate is extracted with dichloromethane, and the organic phases are combined. After removing residual water with anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure to obtain a concentrate. Dichloromethane, triethylamine, and methylsulfonyl chloride are added sequentially to the concentrate. The mixture is stirred overnight, quenched with water, extracted with dichloromethane, and the organic phases are combined. After removing residual water with anhydrous sodium sulfate, the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product is recrystallized from petroleum ether and ethyl acetate to remove impurities, yielding intermediate 2 as a white solid. The molar ratio of bifendate, lithium aluminum tetrahydrate, triethylamine, and methylsulfonyl chloride is 1:1-3:2-4:2-4. The amount of tetrahydrofuran and dichloromethane used is 5-100 ml per 1 gram of bifendate.

[0011] (2) Preparation of Intermediate 3

[0012] Intermediate 2 and potassium thioacetate are added to N,N-dimethylformamide solvent and stirred at room temperature for 10 minutes. The mixture is then poured into water and extracted with ethyl acetate. The organic phases are combined, and residual water is removed by anhydrous sodium sulfate. The solvent is then concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain a light yellow liquid intermediate 3. The molar ratio of intermediate 2 to potassium thioacetate is 1:1 to 6, and the amount of N,N-dimethylformamide solvent used is 10 to 100 ml per 1 gram of intermediate 2.

[0013] (3) Preparation of Compound 1

[0014] The intermediate 3 is dissolved in anhydrous methanol, sodium methoxide is added, and the mixture is stirred at room temperature. The mixture is then poured into water and extracted with ethyl acetate. The organic phases are combined, and residual water is removed by anhydrous sodium sulfate. The solvent is then concentrated by rotary evaporation under reduced pressure to remove the solvent, thereby obtaining compound 1. The molar ratio of the intermediate 3 to the sodium methoxide is 1:1 to 10, and the amount of the anhydrous methanol solvent used is 10 to 100 ml of anhydrous methanol per 1 gram of the intermediate 3.

[0015] A third object of the present invention is to provide the use of the novel disulfide biphenyl compound and its pharmaceutically acceptable salt in the treatment of inflammatory skin diseases.

[0016] The novel disulfide biphenyl compounds provided by the present invention have excellent anti-inflammatory properties, can effectively reduce inflammatory infiltration in tissues, improve the inflammatory phenotype in animal models, and can prevent and treat inflammatory skin diseases caused by various causes, including rosacea, psoriasis, atopic dermatitis, and alopecia areata. The novel disulfide biphenyl compounds provided by the present invention have excellent anti-inflammatory and antioxidant activities and good safety, and have great development and utilization value. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 1H-NMR spectrum of the novel disulfide biphenol ether compound 1 of the present invention;

[0018] Figure 2 13C-NMR spectrum of the novel disulfide biphenol ether compound 1 of the present invention;

[0019] Figure 3 This is the ESI-HRMS spectrum of the novel disulfide biphenol ether compound 1 of the present invention;

[0020] Figure 4 This is a cytotoxicity test diagram of the novel disulfide biphenol ether compound 1 of the present invention;

[0021] Figure 5 This is a graph showing the antioxidant activity of the novel disulfide biphenol ether compound 1 of the present invention;

[0022] Figure 6 This is a graph showing the anti-inflammatory activity of the novel disulfide biphenol ether compound 1 of the present invention;

[0023] Figure 7 This is the effect of the novel disulfide biphenol ether compound 1 of the present invention on erythema in the rosacea animal model;

[0024] Figure 8 The effect of the novel disulfide biphenol ether compound 1 of the present invention on the erythema score and skin lesion thickness of the rosacea animal model;

[0025] Figure 9 The effect of the novel disulfide biphenol ether compound 1 of the present invention on inflammatory infiltration in rosacea animal model tissues;

[0026] Figure 10 This is the effect of the novel disulfide biphenol ether compound 1 of the present invention on scales in psoriasis animal models;

[0027] Figure 11 This is the effect of the novel disulfide biphenol ether compound 1 of the present invention on inflammatory infiltration in psoriasis animal model tissues. DETAILED DESCRIPTION

[0028] Example 1

[0029] Preparation of 5,5'-bis(chloromethyl)-7,7'-dimethoxy-4,4'-bisbenzo[d][1,3]dioxazole (2)

[0030]

[0031] Bifendate (1.672 g, 4 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran. Lithium aluminum tetrahydride (456 mg, 12 mmol) was carefully added in portions under an ice bath. After stirring at room temperature for 10 min, the reaction was carefully quenched with water, the residue was filtered off, and the mixture was extracted three times with dichloromethane (20 ml x 3). The organic phases were combined, residual water was removed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. Dichloromethane (20 ml), triethylamine (2.24 ml, 16 mmol), and methanesulfonyl chloride (1.24 ml, 16 mmol) were added to the concentrate, and the mixture was stirred overnight and monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane (20 ml x 3). The organic phases were combined, residual water was removed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. After recrystallization from petroleum ether and ethyl acetate to remove impurities, a white solid 2 (802 mg, yield: 50%) was obtained. 1H NMR (500 MHz, CDCl3) δ 6.78 (s, 2H), 5.97 (s, 4H), 4.36 (s, 4H), 3.96 (s, 6H).

[0032] Example 2

[0033] Preparation of S,S'-((7,7'-dimethoxy-[4,4'-dibenzo[d][1,3]dioxazole]-5,5'-diyl)bis(methylene))diethylthioate (3)

[0034]

[0035] Intermediate 2 (802 mg, 2 mmol) and potassium thioacetate (684 mg, 6 mmol) were added to 5 ml of N,N-dimethylformamide and stirred at room temperature for 10 min. The mixture was then poured into water and extracted three times with ethyl acetate (20 ml x 3). The organic phases were combined, residual water was removed by addition of anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain 965 mg of a light yellow viscous liquid 3 in a 100% yield. 1H NMR (500 MHz, CDCl3) δ 6.68 (s, 2H), 5.98 (d, J = 1.2 Hz, 2H), 5.94 (d, J = 1.2 Hz, 2H), 4.00 (d, J = 13.9 Hz, 2H), 3.91 (s, 6H), 3.83 (d, J = 13.9 Hz, 2H), 2.28 (s, 6H).13C NMR (126MHz, CDCl3) δ195.11,147.07,143.61,134.29,131.25,109.38,108.60,101.74,5 6.59,31.11,30.24.HRMS(ESI)m / z[M+Na]+calcd.for[C22H22NaO8S2]+,501.0648; found 501.0653.

[0036] Example 3

[0037] Preparation of S,S'-((7,7'-dimethoxy-[4,4'-dibenzo[d][1,3]dioxazole]-5,5'-diyl)bis(methylene))diethylthioester (1) (Compound 1):

[0038]

[0039] The above-obtained 965 mg of light yellow viscous liquid 3 was dissolved in 20 ml of methanol, and sodium methoxide (324 mg, 6 mmol) was added, stirred at room temperature, and monitored by TLC. The mixture was then poured into water and extracted three times with ethyl acetate (20 ml x 3). The organic phases were combined, and after removing the residual water with anhydrous sodium sulfate, the solvent was concentrated by rotary evaporation under reduced pressure to obtain a white solid 1 (697 mg, yield: 89%). 1H NMR (500 MHz, CDCl3, Figure 1 ))δ6.46(s,2H),5.99(d,J=1.2Hz,2H),5.92(d,J=1.2Hz,2H),4.10(d,J=13.3Hz,2H),3.93(s,6H),3.46(d,J=13.5Hz,2H).13C NMR(126MHz, CDCl3, Figure 2)δ147.72,143.98,134.84,133.42,108.72,108.35,101.81,56.60,43.98.HRMS(ESI, Figure 3 )m / z[M+H]+calcd.for[C18H17O6S2]+,393.0467; found 393.0461,m / z[M+Na]+calcd.for[C18H16O6S2Na]+,415.0286; found415.0282

[0040] Example 4 Cytotoxicity Experiment

[0041] Plating: Digest and centrifuge the cultured HaCaT cells, collect the cell pellet, resuspend in DMEM containing 5% fetal bovine serum, and evenly plate 4,000 cells per well in a 96-well plate. Place in a cell incubator and culture for 24 hours.

[0042] Compound preparation: Weigh a certain amount of compound and prepare it into a 20 mM stock solution in DMSO in a clean bench under light-proof conditions. Dilute the 20 mM stock solution with culture medium to obtain solutions of 0.5, 1, 10, 20, 40, and 100 μM.

[0043] Drug Addition: Aspirate the culture medium from the 96-well plate and add various concentrations of drug solution for incubation. Set up five replicate wells for each drug concentration, five replicate wells for the control group (culture medium without the target drug), and three replicate wells for the blank group (culture medium only). Incubate the 96-well plate in a constant temperature incubator for 24 hours.

[0044] Activity Assay: Remove the 96-well plate and, in a clean bench under dark conditions, add 10 μL of CCK8 solution to each well at a ratio of 10:1 (well medium volume:CCK8 solution volume). Continue incubating in a cell incubator for 1 hour. After 1 hour, remove the 96-well plate and measure the absorbance of each well at 450 nm using a microplate reader. Record and calculate the cell viability (%). Calculate cell viability (%) as [(A sample - A blank) / (A control - A blank)] × 100%.

[0045] The results are as follows Figure 4 As shown, within the concentration range of 100 μM, Bifendate and compound 1 had no toxicity to cells.

[0046] Example 5 Cellular Antioxidant Experiment

[0047] (1) Plating: The cultured HaCaT cells were digested and centrifuged, the cell pellets were collected, resuspended in DMEM containing 5% fetal bovine serum, and plated at 4000 cells per well in a black 96-well plate. The plate was placed in a cell incubator and cultured statically until the cell density reached 50%.

[0048] (2) Compound preparation: Weigh a certain amount of compound and prepare it into a 20 mM stock solution using DMSO in a clean bench under light-proof conditions. Dilute the 20 mM stock solution of compound into a 20 μM solution using culture medium.

[0049] (3) Drug addition: After the cell density in the 96-well plate reaches 50%, starve the HaCaT cells with DMEM medium without fetal bovine serum for 12 hours, then remove the original medium, add medium containing 20 μM drug, and incubate in a cell constant temperature incubator for 12 hours.

[0050] (4) Hydrogen peroxide stimulation: Hydrogen peroxide was diluted to 800 μM in culture medium. After removing the medium containing or not containing the drug, culture medium containing 800 μM hydrogen peroxide was added and incubated for 8 hours.

[0051] Fluorescence Assay: Aspirate the medium containing 800 μM hydrogen peroxide and wash once with PBS. Dilute the DCFH-DA probe 1:1000 in DMEM without fetal bovine serum and incubate the cells. After incubation in a cell incubator for 30 minutes, remove the 96-well plate, discard the supernatant, and wash twice with PBS. Add 100 μL of PBS to each well and measure reactive oxygen species (ROS) production using a multi-functional fluorescence microplate reader with an excitation wavelength of 488 nm and an emission wavelength of 525 nm.

[0052] like Figure 5 The drug Bifendate was shown to reduce the increase in reactive oxygen species caused by hydrogen peroxide stimulation, while the drug compound 1 more significantly inhibited the increase in reactive oxygen species caused by hydrogen peroxide than the drug Bifendate. Therefore, the drug compound 1 exhibited better antioxidant capacity in HaCaT cells than the drug Bifendate.

[0053] Example 6 TNF-a induced inflammatory cell model

[0054] (1) Plating: Take the cultured HaCat cells, digest them, remove them and centrifuge them, add fresh culture medium and pipette them.

[0055] Mix thoroughly. Pipette 20 μl of cell suspension into an EP tube containing 180 μl of culture medium and pipette evenly. Measure the concentration of the cell suspension using a hemocytometer under a microscope. Then dilute the suspension to a concentration of 5 × 104 cells / ml, pipette evenly, and inoculate 1 ml of this suspension per well into a 6-well plate. Place the plate in a cell incubator for 12 hours.

[0056] (2) Compound preparation: Weigh a certain amount of target compound and add cell-grade DMSO solution to prepare a 20 mM stock solution.

[0057] (3) Starvation: Starve the cells with serum-free DMEM medium, 1 ml per well, and culture in a cell constant temperature incubator for 12 hours.

[0058] (4) Drug addition: The compound stock solutions were diluted with serum-free DMEM medium to prepare sample solutions with a concentration of 20 μM. Three groups were set up: Vehicle group, Bifendate group, and Compound 1 group, with three replicate wells in each group. 1 ml of serum-free DMEM medium was added to each well of the Vehicle group, and 1 ml of 20 μM Bifendate / Compound 1 sample solution was added to each well of the Bifendate group and Compound 1 group. The cells were then placed in a cell incubator and cultured for 12 h.

[0059] (5) Stimulation: Add 1 μl of TNF-α to each well and culture in a constant temperature incubator for 12 h.

[0060] (6) Anti-inflammatory activity detection: Cell RNA was extracted, reverse transcribed into cDNA, and the relative expression of inflammatory factor mRNA was detected by Q-PCR (such as Figure 6 ).

[0061] Results: We found that the Bifendate and compound 1 groups significantly reduced the mRNA expression of inflammatory factors TNF-α and IL-6 compared with the Vehicle group, among which compound 1 had a better effect. The results showed that compound 1 has stronger anti-inflammatory ability.

[0062] Example 7 LL37-induced rosacea animal model experiment

[0063] Experimental methods

[0064] Fifteen female BALB / c mice (18 g-20 g, 7 weeks old) were randomly divided into three groups (5 mice each): a control group, a bifendate group, and a compound 1 group. After acclimation in a constant temperature housing room for 2 days, mice in the control group were gavaged with 200 μl / mouse of 0.5% sodium carboxymethylcellulose (CMC) solution. Mice in the other groups were gavaged with 150 mg / kg of the corresponding drug suspension (drug suspension: 15 mg of drug suspended in 1 ml of 0.5% sodium carboxymethylcellulose solution, then ultrasonically ground). Dosage was repeated once daily on day 5. Two hours after drug administration, the dorsal hair of all mice in all groups was shaved. On day 6, LL37 modeling was initiated. All mice in all groups were intradermally injected with LL37 (640 μM) or PBS (50 μl / mouse) into the left and right control groups of the dorsal skin, once in the morning and evening, 12 hours apart. Dosage was repeated for two days after the mice regained consciousness. Twelve hours after the last intradermal injection, the gross images and local skin lesions of the mice were photographed, and the skin thickness was measured. The dorsal skin of the mice was taken for local modeling and then the mice were killed by dislocating the neck. The sections were stained with HE and immunofluorescence to detect inflammatory infiltration.

[0065] Compound 1 improves erythema in rosacea animal models

[0066] Rosacea erythema in BALB / c mice Figure 7 As shown in Figure 2, compared with the Control group, the erythema area of ​​the Bifendate group and the compound 1 group was significantly reduced, and the effect of the compound 1 group was better, and the score and lesion thickness were significantly reduced (e.g. Figure 8 ), indicating that compound 1 can improve rosacea-like symptoms.

[0067] 6.3 Compound 1 improves inflammatory infiltration in rosacea animal model tissues

[0068] The results of skin pathological sections of each group were as follows Figure 9 As shown. HE staining of the LL37-treated side of the control mice revealed significant inflammatory infiltration and thickening, and CD4 immunofluorescence staining revealed severe CD4+ T cell accumulation, indicating severe inflammatory infiltration. We found that inflammatory infiltration was reduced in the Bifendate- and Compound 1-treated groups, particularly in the Compound 1-treated group. Pathological sections revealed that Compound 1 significantly reduced inflammatory infiltration and CD4+ T cells, with a superior effect compared to Bifendate, indicating that Compound 1 can ameliorate inflammatory infiltration in the LL37-induced rosacea animal model.

[0069] Example 8 IMQ-induced psoriasis animal model experiment

[0070] 7.1 Experimental Methods

[0071] Fifteen female BALB / c mice (18 g-20 g, 7 weeks) were randomly divided into three groups (5 mice each): a control group, a bifendate group, and a compound 1 group. After acclimation for 2 days in a constant temperature housing room, mice in the control group were gavaged once daily with 200 μl / mouse of 0.5% sodium carboxymethylcellulose. Mice in the other groups were gavaged once daily with 150 mg / kg of the corresponding drug suspension (drug suspension: 15 mg of drug suspended in 1 ml of 0.5% sodium carboxymethylcellulose solution, homogenized using an ultrasonicator).

[0072] On the 4th day, IMQ-induced psoriasis modeling was started. Two hours after administration, an amount of IMQ the size of a rice grain was evenly applied to the left ears of mice in all groups. The body weight and ear thickness of the mice were recorded, and erythema and scaling were scored. This procedure was repeated once a day for 6 days.

[0073] 24 hours after the last application of IMQ, the gross and local ear images of the mice were photographed, and the weight, ear thickness, and erythema and scaling scores of the mice were recorded. The mice were killed by dislocating the neck after taking the ears, and the sections were used for HE staining and immunofluorescence staining to detect inflammatory infiltration.

[0074] 7.2 Compound 1 improves erythema and scaling in psoriasis animal models

[0075] Erythema and scales in the left ear of BALB / c mice psoriasis model Figure 10 As shown in the results, compared with the control group, the left ear erythema and scaling and ear thickness in the Bifendate group and compound 1 group were significantly reduced, and the effect of compound 1 group was better, indicating that compound 1 is more effective in improving the phenotype of psoriasis animal model and has better anti-inflammatory effect.

[0076] 7.3 Compound 1 improves inflammatory infiltration in tissues of psoriasis animal models

[0077] The results of skin pathological sections of each group were as follows Figure 11As shown. HE staining of the left ears of mice in the control group showed significant inflammatory infiltration and thickening of the stratum spinosum. Ki67 immunofluorescence staining showed a severe increase in Ki67-positive cells, indicating relatively active cell proliferation. We found that the inflammatory infiltration was reduced and the thickening of the stratum spinosum was significantly alleviated in the Bifendate and compound 1 treatment groups, especially in the compound 1 treatment group. Pathological section results showed that the inflammatory infiltration, thickening of the stratum spinosum, and Ki67-positive cells in the compound 1 group were significantly reduced, and the effect was better than that of Bifendate, indicating that compound 1 can improve the inflammatory infiltration in the tissues of the IMQ-induced psoriasis animal model.

Claims

1. A novel disulfide biphenol ether compound, characterized in that: The novel disulfide biphenol ether compound has a structure as follows: or a pharmaceutically acceptable salt of the above structural formula.

2. The method for preparing the novel disulfide biphenol ether compound according to claim 1, wherein: The steps include: (1) Preparation of intermediate 2 Dissolve biphenyl diester in anhydrous tetrahydrofuran as a solvent, add lithium aluminum tetrahydride in batches under ice bath conditions, stir at room temperature for 10 minutes, slowly add water to quench the reaction, and then filter to remove the residue; extract the filtrate with dichloromethane, combine the organic phases, remove residual water with anhydrous sodium sulfate, and then remove the solvent by rotary evaporation under reduced pressure to obtain a concentrate; add dichloromethane, triethylamine, and methylsulfonyl chloride as solvents in sequence to the concentrate, stir the mixture overnight, add water to quench the reaction, extract with dichloromethane, combine the organic phases, remove residual water with anhydrous sodium sulfate, and then remove the solvent by rotary evaporation under reduced pressure to obtain a crude product, which is recrystallized from petroleum ether and ethyl acetate to remove impurities to obtain a white solid intermediate 2; the molar ratio of biphenyl diester, lithium aluminum tetrahydride, triethylamine, and methylsulfonyl chloride used is 1:1-3:2-4:2-4, and the amount of tetrahydrofuran and dichloromethane used is 5-100 ml per 1 gram of biphenyl diester; (2) Preparation of Intermediate 3 Intermediate 2 and potassium thioacetate are added to N,N-dimethylformamide solvent, stirred at room temperature for 10 minutes, then poured into water, extracted with ethyl acetate, the organic phases are combined, residual water is removed by anhydrous sodium sulfate, and then concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain a light yellow liquid intermediate 3; the molar ratio of intermediate 2 to potassium thioacetate is 1:1-6, and the amount of solvent N,N-dimethylformamide used is 10-100 ml per 1 gram of intermediate 2; (3) Preparation of Compound 1 The intermediate 3 is dissolved in anhydrous methanol, sodium methoxide is added, and the mixture is stirred at room temperature. The mixture is then poured into water and extracted with ethyl acetate. The organic phases are combined, and residual water is removed by anhydrous sodium sulfate. The solvent is then concentrated by rotary evaporation under reduced pressure to remove the solvent, thereby obtaining compound 1. The molar ratio of the intermediate 3 to the sodium methoxide is 1:1 to 10, and the amount of the anhydrous methanol solvent used is 10 to 100 ml of anhydrous methanol per 1 gram of the intermediate 3.

3. Use of the novel disulfide biphenol ether compound according to claim 1 in the preparation of a drug for treating inflammatory skin diseases.

4. Use of the novel disulfide biphenol ether compound according to claim 3 in the preparation of a drug for treating inflammatory skin diseases, characterized in that: The inflammatory skin diseases include rosacea, psoriasis, atopic dermatitis, and alopecia areata.

5. Use of the novel disulfide biphenol ether compound according to claim 3 in the preparation of a drug for treating inflammatory skin diseases, characterized in that: The drug further includes a pharmaceutically acceptable carrier.

6. Use of the novel disulfide biphenol ether compound in the preparation of a drug for treating inflammatory skin diseases according to claim 5, wherein the carrier refers to the components other than the active molecule in the drug administration preparation, including pharmaceutical excipients.

7. Use of the novel disulfide biphenol ether compound in the preparation of a drug for treating inflammatory skin diseases according to claim 6, wherein the pharmaceutical excipients are excipients, buffers, absorption promoters, emulsifiers, thickeners, surfactants, antioxidants, preservatives and flavors.

8. Use of the novel disulfide biphenol ether compound according to claim 3 in the preparation of a drug for treating inflammatory skin diseases, characterized in that: The dosage forms of the drug for treating inflammatory skin diseases include tablets, injections, capsules, granules, pills, powders, oral liquids, sustained-release preparations, controlled-release preparations, creams, ointments, liniments, lotions or pharmaceutically acceptable dosage forms of nanoformulations.

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