Novel disulfide diphenol ether compound as well as preparation method and application thereof

Abstract

The invention relates to a novel disulfide diphenol ether compound and a preparation method and application thereof in the aspect of treating inflammatory dermatosis, the structural formula of the disulfide diphenol ether compound is # imgabs0, bifendate is dissolved in a solvent anhydrous tetrahydrofuran, lithium aluminum hydride is added, quenching, suction filtration, dichloromethane extraction, water addition quenching reaction and dichloromethane extraction are carried out, and the disulfide diphenol ether compound is obtained. Combining organic phases, removing residual moisture, and performing reduced pressure rotary evaporation recrystallization to obtain an intermediate 2; adding the intermediate 2 and potassium thioacetate into a solvent N, N-dimethylformamide for extraction, combining organic phases, and carrying out evaporation and concentration to remove the solvent so as to obtain a light intermediate 3; and dissolving the intermediate 3 with absolute methanol, adding sodium methoxide, stirring, extracting with ethyl acetate, and combining organic phases. The disulfide biphenyl compound prepared in the invention has good anti-inflammatory ability, can effectively reduce inflammation infiltration in tissues, improves the inflammation phenotype of an animal model, and can prevent and treat inflammatory skin diseases.

Description

Technical Field

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

[0002] Inflammatory skin diseases are common skin diseases in life, including rosacea, psoriasis, atopic dermatitis, alopecia areata, etc., and the incidence has tended to be younger in recent years. It is a type of skin disease caused by various internal and external factors that causes inflammation of the epidermis or dermis and manifests in various pathological manifestations. Rosacea and psoriasis are relatively common chronic inflammatory skin diseases with a high incidence rate, but low clinical cure rate, easy to relapse, causing great pain 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, Schisandrin A isolated from the Chinese medicine Schisandrae 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 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 introduces an important disulfide structure in the redox system of the life system based on the structure of Schisandrae Chinensis A, and designs and synthesizes 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] The 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 of the preparation method of the novel disulfide biphenol ether compound 1 is as follows:

[0008]

[0009] (1) Preparation of intermediate 2

[0010] Dissolve bifendate in anhydrous tetrahydrofuran, 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 remove the residue by suction filtration. The filtrate is extracted with dichloromethane, the organic phases are combined, the residual water is removed by anhydrous sodium sulfate, and the solvent is removed by reduced pressure rotary evaporation to obtain a concentrated solution. Solvent dichloromethane, triethylamine and methylsulfonyl chloride are added to the concentrated solution in sequence, the mixed solution is stirred overnight, water is added to quench the reaction, extracted with dichloromethane, the organic phases are combined, the residual water is removed by anhydrous sodium sulfate, and the solvent is removed by reduced pressure rotary evaporation to obtain a crude product, and the crude product is recrystallized with petroleum ether and ethyl acetate to remove impurities to obtain a white solid intermediate 2; the molar ratio of bifendate, lithium aluminum tetrahydride, triethylamine and methylsulfonyl chloride used is 1:1-3:2-4:2-4, and the amount of solvent tetrahydrofuran and dichloromethane used is 5-100 ml per 1 gram of bifendate.

[0011] (2) Preparation of Intermediate 3

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

[0013] (3) Preparation of compound 1

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

[0015] The 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 compound provided by the present invention has good anti-inflammatory ability, can effectively reduce inflammatory infiltration in tissues, improve the inflammatory phenotype of animal models, and can prevent and treat inflammatory skin diseases caused by various reasons, including rosacea, psoriasis, atopic dermatitis, and alopecia areata. The novel disulfide biphenyl compound provided by the present invention has excellent anti-inflammatory and antioxidant activities and good safety, and has good 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 detection 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 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 rosacea animal model;

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

[0026] Fig.10 The effect of the novel disulfide biphenol ether compound 1 of the present invention on the scales of psoriasis animal model;

[0027] Fig.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'-dibenzo[d][1,3]dioxazole (2)

[0030]

[0031] After dissolving bifendate (1.672g, 4mmol) in 10ml of anhydrous tetrahydrofuran, lithium aluminum tetrahydride (456mg, 12mmol) was carefully added in batches under ice bath conditions. After stirring at room temperature for 10min, water was carefully added to quench the reaction, the residue was filtered out, and dichloromethane (20ml×3) was added to extract three times. The organic phases were combined, and the residual water was removed by anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. Dichloromethane (20ml), triethylamine (2.24ml, 16mmol) and methanesulfonyl chloride (1.24ml, 16mmol) were added to the concentrated solution, and the mixed solution was stirred overnight and monitored by TLC. After the reaction was completed, water was added to quench the reaction, and dichloromethane (20ml×3) was extracted three times. The organic phases were combined, and the residual water was removed by anhydrous sodium sulfate, and the solvent was removed by reduced pressure and rotary evaporation to obtain a 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))diethylthioester (3)

[0034]

[0035] Intermediate 2 (802 mg, 2 mmol) and potassium thioacetate (684 mg, 6 mmol) were added to 5 ml 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×3). The organic phases were combined, and the residual water was removed by anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain 965 mg of light yellow viscous liquid 3, with a yield of 100%. 1H NMR (500 MHz, CDCl3) δ6.68 (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 light yellow viscous liquid 3 was dissolved in 20 ml methanol, 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×3). The organic phases were combined, and the residual water was removed by anhydrous sodium sulfate, and then 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: The cultured HaCaT cells were digested and centrifuged, the cell pellets were collected, resuspended in DMEM medium containing 5% fetal bovine serum, and evenly plated in a 96-well plate at 4,000 cells per well. The plates were placed in a cell thermostatic incubator for 24 hours.

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

[0043] Adding drugs: remove the original culture medium in the 96-well plate, and then add different concentrations of drug solutions for incubation. Set up 5 replicates for each drug concentration, 5 replicates for the control group (culture medium without target drug), and 3 replicates for the blank group (culture medium only). Place the 96-well plate in a cell thermostatic incubator for 24 hours.

[0044] Activity assay: Take out the 96-well plate, add 10 μL CCK8 solution to each well in a clean bench under light-proof conditions at a ratio of 10:1 (well medium volume: CCK8 solution volume), and continue to culture in a cell constant temperature incubator for 1 hour. Take out the 96-well plate after 1 hour, measure the absorbance value of each well at 450nm under an ELISA reader, record and calculate. Calculate cell viability (%) = [(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, both Bifendate and compound 1 were not toxic 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 medium containing 5% fetal bovine serum, and plated in a black 96-well plate at 4000 cells per well. 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 with DMSO in a clean bench under light-proof conditions. Dilute the 20 mM stock solution of the compound into a 20 μM solution with culture medium.

[0049] (3) Adding drugs: 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 incubator for 12 hours.

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

[0051] Fluorescence measurement: Remove the medium containing 800 μM hydrogen peroxide and wash once with PBS. Dilute the DCFH-DA probe at a ratio of 1:1000 with DMEM without fetal bovine serum and then use it to incubate cells. After incubation in the cell incubator for 30 minutes, remove the 96-well plate, discard the supernatant, and wash twice with PBS. Then add 100 μL PBS to each well, set the excitation wavelength to 488 nm and the emission wavelength to 525 nm under the multi-functional fluorescence microplate reader, and measure the generation of reactive oxygen species.

[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) Plate laying: Take the cultured HaCat cells, digest them, and centrifuge them. Then add fresh culture medium and pipette them.

[0055] Mix well. Pipette 20 μl of cell solution into an EP tube containing 180 μl of culture medium and mix well. Test the concentration of the cell solution with a hemocytometer under a microscope, then dilute it according to a cell concentration of 5×104 cells / ml, mix well, and inoculate 1 ml of the cell solution into a 6-well plate per well, and place it 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 h.

[0058] (4) Drug addition: The compound mother solutions were diluted with serum-free DMEM medium to prepare sample solutions with a concentration of 20 μM. Three groups were set up, namely, 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 the Compound 1 group. The cells were cultured in a cell constant temperature incubator for 12 h.

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

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

[0061] Results: We found that Bifendate and compound 1 groups significantly reduced the mRNA expression of cellular 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 a stronger anti-inflammatory ability.

[0062] Example 7 Experiment on LL37-induced rosacea animal model

[0063] Experimental methods

[0064] Fifteen female BALB / c mice (18g-20g, 7w) were randomly divided into three groups: Control group, Bifendate group and Compound 1 group, with 5 mice in each group. After the animals were adapted to the environment in the constant temperature breeding room for 2 days, the mice in the Control group were gavaged with 0.5% (m) sodium carboxymethyl cellulose at a dose of 200μl / mouse, and the mice in the other groups were gavaged with the corresponding drug suspension at a dose of 150mg / kg (drug suspension: each 15mg drug was suspended in 1ml 0.5% CMC-Na solution, and the ultrasound instrument was used to grind evenly), and the drug was administered once a day. On the 5th day, the back skin of all groups of mice was shaved 2h after the drug administration. On the 6th day, LL37 modeling was started, and LL37 (640μM) or PBS 50μl / mouse was intradermally injected into the left and right control of the back skin of all groups of mice, once in the morning and evening, with an interval of 12h. The mice were administered after waking up during the interval, and the intradermal injection was repeated for 2 days. 12 hours after the last intradermal injection, the mouse's gross image and local skin lesion image were taken, and the skin thickness was measured. The mouse's dorsal skin was taken for local modeling and then the mouse was killed by dislocating the neck for HE staining and immunofluorescence staining to detect inflammatory infiltration.

[0065] Compound 1 improves erythema in animal models of rosacea

[0066] Rosacea erythema in BALB / c mice Figure 7 As shown in the figure, compared with the Control group, the erythema area of ​​the Bifendate group and the Compound 1 group was significantly reduced, and the Compound 1 group had a better effect, and the score and skin lesion thickness were significantly reduced (such as 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 pathology sections of each group are as follows Fig. 9 As shown. HE staining of the LL37-treated side of the control group mice showed significant inflammatory infiltration and thickening, and CD4 immunofluorescence staining showed severe CD4+T cell accumulation, indicating severe inflammatory infiltration. We found that the inflammatory infiltration was reduced in the Bifendate and compound 1 treatment groups, especially in the compound 1 treatment group. Pathological section results showed that the inflammatory infiltration and CD4+T cells in the compound 1 group were significantly reduced, and the effect was better than Bifendate, indicating that compound 1 can improve the inflammatory infiltration in the LL37-induced rosacea animal model tissue.

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

[0070] 7.1 Experimental methods

[0071] Fifteen female BALB / c mice (18g-20g, 7w) were randomly divided into three groups: Control group, Bifendate group and Compound 1 group, with 5 mice in each group. After the animals were adapted to the environment in the constant temperature breeding room for 2 days, the mice in the Control group were gavaged with 0.5% (m) sodium carboxymethyl cellulose at a dose of 200μl / mouse, and the mice in the other groups were gavaged with the corresponding drug suspension at a dose of 150mg / kg (drug suspension: each 15mg drug was suspended in 1ml 0.5% CMC-Na solution and ground evenly by ultrasonic instrument), and the drug was administered once a day.

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

[0073] 24 hours after the last application of IMQ, the general and local ear images of the mice were taken, 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 scaling in the left ear of BALB / c mice Fig.10 As shown, compared with the Control group, the left ear erythema and scaling and ear thickness in the Bifendate group and the compound 1 group were significantly reduced, and the effect of the compound 1 group was better, indicating that compound 1 is more effective in improving the phenotype of the psoriasis animal model and has a better anti-inflammatory effect.

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

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

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, characterized in that: The steps include: (1) Preparation of intermediate 2 Dissolve biphenyl diester in anhydrous tetrahydrofuran 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 the residual water with anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to obtain a concentrated solution; add dichloromethane solvent, triethylamine and methylsulfonyl chloride to the concentrated solution in sequence, stir the mixed solution overnight, add water to quench the reaction, extract with dichloromethane, combine the organic phases, remove the residual water with anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to obtain a crude product, and the crude product is recrystallized with 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 solvent used is 5-100 ml per 1 gram of biphenyl diester; (2) Preparation of Intermediate 3 The intermediate 2 and potassium thioacetate are added to the solvent N,N-dimethylformamide, stirred at room temperature for 10 minutes, then the mixture is poured into water, extracted with ethyl acetate, the organic phases are combined, residual water is removed by anhydrous sodium sulfate, and then the solvent is removed by rotary evaporation under reduced pressure to obtain a light yellow liquid intermediate 3; the molar ratio of the intermediate 2 and potassium thioacetate is 1:1-6, and the amount of the solvent N,N-dimethylformamide is 10-100 ml per 1 gram of the intermediate 2; (3) Preparation of Compound 1 The intermediate 3 is dissolved in anhydrous methanol solvent, sodium methoxide is added, and the mixture is stirred at room temperature. Then, the mixture is poured into water, extracted with ethyl acetate, the organic phases are combined, and the residual water is removed by anhydrous sodium sulfate. The solvent is concentrated by rotary evaporation under reduced pressure to remove the solvent to obtain compound 1; the molar ratio of the intermediate 3 and the sodium methoxide is 1:1-10, and the amount of the solvent anhydrous methanol is 10-100 ml of anhydrous methanol per 1 gram of intermediate 3.

3. Use of the novel disulfide biphenol ether compound as claimed in claim 1 in the preparation of a drug for treating inflammatory skin diseases, for preventing and treating inflammatory skin diseases.

4. The 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: Also included are pharmaceutically acceptable carriers.

6. According to claim 5, the use of the novel disulfide biphenol ether compound in the preparation of a drug for treating inflammatory skin diseases, wherein the carrier refers to the ingredients other than the active molecule in the drug administration preparation, including pharmaceutical excipients such as excipients, buffers, absorption promoters, emulsifiers, thickeners, surfactants, antioxidants, preservatives and flavors.

7. 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 form of the drug for treating inflammatory skin diseases includes tablets, injections, capsules, granules, pills, powders, oral liquids, sustained-release preparations, controlled-release preparations, creams, ointments, liniments, lotions or pharmaceutically acceptable dosage forms of nano preparations.

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