Benvitimod derivative as well as preparation method and application thereof

Abstract

The invention discloses a benvitimod derivative as well as a preparation method and application thereof, and belongs to the technical field of skin medicines. Comprising 3, 5-diphenol tretinoin ester-4-isopropyl stilbene, 3, 5-diphenol isotretinoin ester-4-isopropyl stilbene, 3, 5-diphenol tretinoin ester-4-isopropyl diphenylethane, 3, 5-diphenol tretinoin ester-4-isopropyl diphenylethane, 3, 5-diphenol tretinoin ester-4-isopropyl diphenylethane, 3, 5-diphenol tretinoin ester-4-isopropyl diphenylethane, 3 The composition is prepared from the following raw materials: 3-diphenol isotretinoic acid ester-4-isopropyl diphenylethane, 3-tretinoic acid ester-4-isopropyl-5-hydroxyl-stilbene, 3-isotretinoic acid ester-4-isopropyl-5-hydroxyl-stilbene, 3-tretinoic acid ester-4-isopropyl-5-hydroxyl-stilbene, 3-tretinoic acid ester-4-isopropyl-5-hydroxyl-diphenylethane, 3-tretinoic acid ester-4-isopropyl-5-hydroxyl-diphenylethane and 3-tretinoic acid ester-4-isopropyl-5-hydroxyl-diphenylethane. According to the present invention, by using the characteristic that the phenolic hydroxyl group and the carboxylic acid can form the ester, the benvitimod and the benalkanmod are respectively esterified and combined with the tretinoin and the isotretinoin to form the new compound molecule, and the excellent drug activity is represented in the treatment of the skin diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of skin medicines, and particularly relates to a benzenemod derivative and a preparation method and application thereof. Background Art

[0002] Benzenemod, i.e. 3,5-dihydroxy-4-isopropyl trans-stilbene, is the world's first aromatic hydrocarbon receptor agonist drug, belonging to the diphenylene or stilbene compounds. Benzenemod, i.e. 3,5-dihydroxy-4-isopropyl diphenylethane and related compounds are a new class of drugs pioneered by Wuhan Inna, showing great prospects in immune system diseases and inflammation (CN201310477097.0, Li Jianxiong, a diphenylethane derivative and its application). Retinoic acid and isotretinoin can promote epithelial cell proliferation, differentiation, keratolysis and other metabolic effects, and are used to treat diseases such as acne vulgaris, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, follicular keratosis, squamous cell carcinoma and melanoma. The application of single acid itself is limited.

[0003] The applicant discovered that the new compound molecule formed by creatively esterifying benzophenone (alkane) mod and retinoic acid (isotretinoin) exhibits a synergistic effect in the treatment of skin diseases and has unexpected therapeutic effects. Summary of the invention

[0004] Those skilled in the art know that benzenetide, benzanemod, tretinoin and isotretinoin are all active in the treatment of skin diseases, but they have different focuses. For example, if they are physically mixed together alone, although it makes sense, the effect is not obvious, especially the use of tretinoin and isotretinoin has many limitations. The present invention creatively utilizes the property that phenolic hydroxyl and carboxylic acid can form esters, and esterifies benzenetide and benzanemod with tretinoin and isotretinoin to form new compound molecules, which show excellent drug activity in the treatment of skin diseases. What is even more surprising is that the combined use of benzenetide diester (or monoester) and benzanemod diester (or monoester) has a synergistic effect, which is significantly better than the effect of each used alone. The technical scheme is as follows: On the one hand, an embodiment of the present invention provides a benzenemod derivative, including 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene, and 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene. Among them, 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene and 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene are benzene-modified diesters; 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethane and 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethane are benzane-modified diesters; 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene are benzene-modified monoesters; 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane are benzane-modified monoesters. Preferably, the benzenemod derivatives in the embodiments of the present invention include 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene, and 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene.

[0005] Among them, the structural formula of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene is as follows: .

[0006] The structural formula of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane is as follows: .

[0007] The structural formula of 3,5-diphenol isotretinoin-4-isopropylstilbene is as follows: .

[0008] The structural formula of 3,5-diphenol isotretinoin ester-4-isopropyldiphenylethane is as follows: .

[0009] The structure of 3,5-diphenol vitamin E succinate-4-isopropylstilbene is as follows: .

[0010] The structure of 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethane is as follows: .

[0011] On the other hand, an embodiment of the present invention further provides a method for preparing a benzenemod derivative, the method comprising: Raw material A, raw material B, organic base and condensing agent are reacted in a solvent at 0-50°C (preferably room temperature) to obtain a benzenemod derivative. Raw material A is selected from E-4-isopropyl-3,5-dihydroxy-stilbene or 4-isopropyl-3,5-dihydroxy-diphenylethane, and raw material B is selected from retinoic acid, isotretinoin or vitamin E succinic acid. Organic base is selected from DMAP or diisopropylethylamine, etc., and the amount used is a catalytic amount.

[0012] Among them, raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, raw material B is retinoic acid, and the molar ratio of raw material A to raw material B is 1:2.1-5.0; then the product is 3,5-diphenol retinoic acid ester-4-isopropylstilbene.

[0013] Among them, raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, raw material B is isotretinoin, and the molar ratio of raw material A to raw material B is 1:2.1-5.0; the product is 3,5-diphenolisoretinoic acid ester-4-isopropylstilbene.

[0014] Among them, raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, raw material B is retinoic acid, and the molar ratio of raw material A to raw material B is 1:2.1-5.0; then the product is 3,5-diphenol retinoic acid ester-4-isopropyldiphenylethane.

[0015] Among them, raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, raw material B is isotretinoin, and the molar ratio of raw material A to raw material B is 1:2.1-5.0; the product is 3,5-diphenolisoretinoic acid ester-4-isopropyldiphenylethane.

[0016] Among them, raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, raw material B is retinoic acid, and the molar ratio of raw material A to raw material B is 1:0.9-1.2; then the product is 3-retinoic acid ester-4-isopropyl-5-hydroxy-stilbene.

[0017] Among them, raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, raw material B is isotretinoin, and the molar ratio of raw material A to raw material B is 1:0.9-1.2; the product is 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-stilbene.

[0018] Among them, raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, raw material B is retinoic acid, and the molar ratio of raw material A to raw material B is 1:0.9-1.2; then the product is 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane.

[0019] Wherein, when the raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane and the raw material B is isotretinoin, the molar ratio of the raw material A to the raw material B is 1:0.9-1.2; the product is 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane; Wherein, the raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is vitamin E succinic acid, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol vitamin E succinate-4-isopropylstilbene; Among them, raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, raw material B is vitamin E succinic acid, and the molar ratio of raw material A to raw material B is 1:2.1-5.0; the product is 3,5-diphenol vitamin E succinate-4-isopropyldiphenylethane.

[0020] Wherein, the condensing agent is selected from EDC hydrochloride or DCC, etc. Preferably, the condensing agent is selected from EDC hydrochloride, and the mass ratio of raw material A to the condensing agent (EDC hydrochloride) is 1:2-6.

[0021] The solvent is selected from dichloromethane or chloroform, and is preferably dichloromethane.

[0022] Further, after the reaction is completed, the mixture is washed with water, separated, decolorized with activated carbon and a small amount of silica gel, filtered to remove the activated carbon and silica gel, and a light yellow solution is obtained. After distillation under reduced pressure to recover dichloromethane, the mixture is recrystallized and filtered to obtain the product. The recrystallization solvent is selected from methanol, ethanol or isopropanol, and methanol is preferred.

[0023] In another aspect, an embodiment of the present invention provides a pharmaceutical composition, comprising one or more of the aforementioned benzenemod derivatives and a pharmaceutically acceptable diluent or / and carrier (such as vaseline, etc.). Specifically, the pharmaceutical composition contains one or more of the benzenemod derivatives and vaseline, etc., and the content of the benzenemod derivative is 0.4-3.0wt%.

[0024] Preferably, the applicant unexpectedly found that the combined use of benzanemod diester (or monoester) and benzenemod diester (or monoester) has a synergistic effect, which is significantly better than the effect of each used alone. Then the composition includes one or more of benzanemod diester or benzanemod monoester and one or more of benzenemod diester or benzenemod monoester.

[0025] Specifically, the composition includes 3,5-diphenol retinoic acid ester-4-isopropyl diphenyl ethane and 3,5-diphenol retinoic acid ester-4-isopropyl diphenyl ethane; or 3,5-diphenol retinoic acid ester-4-isopropyl diphenyl ethane and 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane; or 3,5-diphenol retinoic acid ester-4-isopropyl diphenyl ethane and 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenyl ethane; or 3,5-diphenol retinoic acid ester-4-isopropyl diphenyl ethane and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenyl ethane.

[0026] Specifically, the composition includes 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane and 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane; or 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane and 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane; or 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane and 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenyl ethane; or 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenyl ethane and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenyl ethane.

[0027] Specifically, the composition includes 3-vitamin A ester-4-isopropyl-5-hydroxy-stilbene and 3-vitamin A ester-4-isopropyl-5-hydroxy-diphenylethane, or 3-vitamin A ester-4-isopropyl-5-hydroxy-stilbene and 3-isovitamin A ester-4-isopropyl-5-hydroxy-diphenylethane, or 3-isovitamin A ester-4-isopropyl-5-hydroxy-stilbene and 3-vitamin A ester-4-isopropyl-5-hydroxy-diphenylethane, or 3-isovitamin A ester-4-isopropyl-5-hydroxy-stilbene and 3-isovitamin A ester-4-isopropyl-5-hydroxy-diphenylethane. The pharmaceutical composition provided by the embodiment of the present invention includes: More specifically, the composition includes 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane in a mass ratio of 0.2-10.0:1; Or 3,5-diphenol isotretinoin ester-4-isopropyl diphenylethylene and 3,5-diphenol isotretinoin ester-4-isopropyl diphenylethane in a mass ratio of 0.2-10.0:1; Or 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene and 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane in a mass ratio of 0.2-10.0:1; Or 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane in a mass ratio of 0.2-10.0:1.

[0028] More preferably, the pharmaceutical composition provided by the embodiment of the present invention comprises 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane in a mass ratio of 1-10:1.

[0029] In another aspect, the present invention provides the use of the above-mentioned benzenemod derivatives in drugs for treating inflammation and relieving itching, and in particular in drugs for treating acne, psoriasis, eczema, etc.

[0030] Among them, the benzenemod derivatives in the present invention are used in skin topical preparations, which are a type of preparations that act on the skin to exert local or systemic therapeutic effects, and the dosage forms include ointments, creams, gels, powders, aqueous solutions and lotions, etc. Topical preparations have many advantages, such as preventing drugs from being affected by the acidic environment in the stomach and gastrointestinal mucus after oral administration; reducing the peak and valley changes in blood drug concentration, thereby reducing the adverse reactions of drugs; facilitating patients to take drugs independently, and having a high compliance rate; and at the same time, during use, if adverse reactions occur, patients can interrupt the medication at any time. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the mass spectrum of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene; Figure 2 This is the mass spectrum of 3,5-diphenol retinoic acid ester-4-isopropyldiphenylethane. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in further detail below.

[0033] Example 1 Preparation of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene In a 10L reactor, 500g of 4-isopropyl-3,5-dihydroxy-stilbene (benzenemod), 3L of dichloromethane, 2200g of EDC hydrochloride, 2000g of retinoic acid, and 200ml of diisopropylethylamine were added. The mixture was stirred at 20-30°C for 8h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, and filtered to remove the activated carbon and silica gel to obtain a light yellow solution. After recovering the dichloromethane, the solution was recrystallized with methanol and filtered to obtain 1145g of a yellow solid powder with a yield of 71%.

[0034] Embodiment 2 In a 10L reactor, 500 g of 4-isopropyl-3,5-dihydroxy-diphenylethane (benzenemod), 3 L of dichloromethane, 2200 g of EDC hydrochloride, 2000 g of retinoic acid, and 200 ml of diisopropylethylamine were added, stirred at 20-30 ° C for 8 h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, filtered to remove activated carbon and silica gel, and a light yellow solution was obtained. After recovering dichloromethane, it was recrystallized with methanol and filtered to obtain 1015 g of yellow solid powder with a yield of 63%.

[0035] Embodiment 3 In a 10L reactor, 500g of 4-isopropyl-3,5-dihydroxy-stilbene (benzenemod), 3L of dichloromethane, 2200g of EDC hydrochloride, 2000g of isotretinoin, and 200ml of diisopropylethylamine were added, stirred at 20-30°C for 8h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, filtered to remove the activated carbon and silica gel, and a light yellow solution was obtained. After recovering the dichloromethane, the solution was recrystallized with methanol and filtered to obtain 1189g of a yellow solid powder with a yield of 73%.

[0036] Embodiment 4 In a 10L reactor, 500 g of 4-isopropyl-3,5-dihydroxy-diphenylethane (benzenemod), 3 L of dichloromethane, 2200 g of EDC hydrochloride, 2000 g of isotretinoin, and 200 ml of diisopropylethylamine were added, stirred at 20-30 ° C for 8 h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, and filtered to remove the activated carbon and silica gel to obtain a light yellow solution. After recovering dichloromethane, the solution was recrystallized with methanol and filtered to obtain 966 g of a yellow solid powder with a yield of 61%.

[0037] Embodiment 5 Add 10 grams of 3,5-diphenol retinoic acid ester-based 4-isopropyl diphenylethylene (i.e., benzenemod retinoic acid ester) to 990 grams of yellow vaseline, and stir repeatedly under warm conditions until all the mixture is evenly dissolved to obtain a 1wt% benzenemod retinoic acid ester ointment.

[0038] Embodiment 6 Add 10 grams of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane (i.e., benzyl alcohol bisretinoic acid ester) to 990 grams of yellow vaseline, and stir repeatedly under warm conditions until all the mixture is evenly dissolved to obtain a 1wt% benzyl alcohol bisretinoic acid ester ointment.

[0039] Embodiment 7 500 g of 1 wt% benzenemod bisretinoic acid ester ointment and 500 g of 1 wt% benzenemod bisretinoic acid ester ointment were repeatedly stirred under warm conditions to obtain a benzenemod and benzenemod mixed ointment.

[0040] No adverse reactions were observed when the ointments of Examples 5 to 7 were repeatedly applied to sensitive areas of human skin, which was similar to the situation with yellow vaseline.

[0041] Embodiment 8 In a 10L reactor, 500g of 4-isopropyl-3,5-dihydroxy-stilbene (benzenemod), 3L of dichloromethane, 2200g of EDC hydrochloride, 2600g of vitamin E succinate, and 200ml of diisopropylethylamine were added, stirred at 20-30°C for 8h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, filtered to remove the activated carbon and silica gel, and a light yellow solution was obtained. After recovering the dichloromethane, the solution was recrystallized with methanol and filtered to obtain 1563g of a yellow solid powder with a yield of 62%.

[0042] Embodiment 9 In a 10L reactor, 500 g of 4-isopropyl-3,5-dihydroxy-diphenylethane (phenylethane), 3 L of dichloromethane, 2200 g of EDC hydrochloride, 2600 g of vitamin E succinate, and 200 ml of diisopropylethylamine were added, stirred at 20-30 ° C for 8 h, washed with water, separated, decolorized with activated carbon and a small amount of silica gel, filtered to remove activated carbon and silica gel, and a light yellow solution was obtained. After recovering dichloromethane, it was recrystallized with methanol and filtered to obtain 1651 g of yellow solid powder with a yield of 66%.

[0043] Testing for pharmacological activity Effectiveness against TPA-induced edema Female mice (Balb / c) aged 10-12 weeks were used, and phorbol-12 myristate-13-acetate (TPA) was used as an edema inducing agent. TPA and the test compound were dissolved in 100% ethanol, and 20 μl was applied to the right ear of the mouse, with six mice in a group. The concentration of TPA was 0.01% (w / v). The thickness of the mouse ears was measured 6 hours after TPA treatment to determine whether the edema was reduced. In each experiment, parallel groups of mice treated with TPA were treated with the samples respectively, and the level of edema inhibition was obtained by measuring the thickness of the ears, and the difference in thickness from the ears treated with ethanol was expressed as a percentage.

[0044] Among them, sample 1 is 1wt% benzene mod; Sample 2 is 1wt% benzanemod; Sample 5 is 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene 1wt%; Sample 6 is 3,5-diphenol isotretinoin-4-isopropylstilbene 1wt%; Sample 7 is 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane 1wt%; Sample 8 is 3,5-diphenol isotretinoin ester-4-isopropyl diphenylethane 1wt%; Sample 9 is 3-retinoic acid ester-4-isopropyl-5-hydroxy-stilbene 1wt%; Sample 10 is 0.5 wt% of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 0.5 wt% of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane; Sample 11 is 0.7 wt% of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 0.3 wt% of 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane; Sample 12 is 0.5 wt % of 3-retinoic acid ester-4-isopropyl-5-hydroxy-stilbene and 0.5 wt % of 3-retinoic acid ester-4-isopropyl-5-hydroxy-stilbene.

[0045] The results are shown in Table 1: Table 1

[0046] As can be seen from Table 1, the ester products of benzenmod and retinoic acid or isotretinoin have a significant edema inhibition rate. The combination of ene ester and alkyl ester has a better effect.

[0047] The same mice were used and randomly divided into 7 groups, namely, blank group (control group), model group, positive drug group, sample group 1, sample group 5, sample group 7 and sample group 10, with 6 mice in each group. After one week of adaptive feeding, the mice were shaved on the back, and 100 μL of 1% dinitrochlorophenylacetone-olive oil solution (4:1) was applied to the shaved area continuously on the first and second days (first prepare an acetone olive oil solution with a volume ratio of 4:1, then weigh 200 mg of dinitrochlorophenylacetone powder and dissolve it in 20 mL of acetone-olive oil (4:1, v / v) solution to obtain 1% dinitrochlorophenylacetone-olive oil solution), and the blank group was not applied. The appearance of scabs, tissue fluid exudation, redness and swelling at the applied area indicates that the model is successfully established. On the 5th day, 20 μL of 0.5% dinitrochlorophenylacetone-olive oil solution (4:1) was applied to the inside and outside of the right ear of each group of mice for stimulation once. On the 5th to 8th days, drug treatment was given respectively, 0.01 g for sample group 1, sample group 5, sample group 7 and sample group 10, 0.01 g of hydrocortisone butyrate cream was applied to the positive group, and no treatment was given to the model group and the blank group. Subsequently (starting from the 9th day), stimulation was continued once, and the drug was administered four times (on the day of stimulation and the following three days). These 4 days were one enhanced stimulation cycle, and a total of 4 cycles were performed. The samples were collected on the day when the 4th cycle ended. After the 4th enhanced stimulation, the number of times the mice in each group scratched the skin of the right ear, neck, and back within 10 minutes was recorded, and continuous scratching was counted as 1 time. The results are shown in Table 2: Table 2

[0048] As can be seen from Table 2, benzenemod has a certain effect. After benzenemod is made into an ester of retinoic acid or isotretinoin, the number of scratching is slightly reduced, which is also effective. The combination of benzenemod and benzenemod has the best effect and the least number of scratching.

[0049] Simple human experiment Four patients with eczema were confirmed, all male, aged 35, 27, 31 and 45 years old respectively. The time was July 2023 and the location was Wuhan.

[0050] 1wt% benzadimethoxine bisretinoate ointment, 1wt% benzadimethoxine bisretinoate ointment, 0.5wt% benzadimethoxine bisretinoate and 0.5wt% benzadimethoxine bisretinoate mixed ointment, and a blank control (yellow vaseline ointment); four different ointments were used on eczema patients who had no effective drugs, and the patients gave feedback on their experience: Blank users felt their skin was slightly more comfortable, but it was still itchy and uncomfortable, and the symptom improvement was limited.

[0051] Users of 1wt% benzyl alcohol bisretinoate cream felt that the itching and discomfort was significantly improved after using the cream, and the effect was very fast, with obvious improvement within three days; they continued to use it for seven days. However, the improvement became slower and slower as time went on.

[0052] The users of 1wt% benzenemod bisretinoate cream felt that the itching and discomfort was improved after using the cream. The improvement was not obvious after one day, but it was improved after three days. They continued to use it for seven days. However, the improvement became more and more obvious as time went by. In general, the effect was a bit slow, but the effect was obvious.

[0053] The users of the mixed ointment had the best overall feeling and were most satisfied with the product. They felt that the itching and discomfort after using the ointment was significantly improved within one day; they continued to use it for seven days. Moreover, the improvement became more and more obvious as time went by. In general, they were satisfied with the use of the product.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A benzene derivative, characterized in that: Including 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene, 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene, 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene.

2. The benzene derivative according to claim 1, characterized in that Including 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethylene, 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane, 3,5-diphenol isotretinoic acid ester-4-isopropyl diphenylethane, 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethylene, and 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethane.

3. A method for preparing a benzene derivative, characterized in that: The method comprises: Raw material A, raw material B, an organic base and a condensing agent are reacted in a solvent at 0-50° C. to obtain a benzenemod derivative, wherein the raw material A is selected from E-4-isopropyl-3,5-dihydroxy-stilbene or 4-isopropyl-3,5-dihydroxy-diphenylethane, and the raw material B is selected from retinoic acid, isotretinoin or vitamin E succinate; The raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is retinoic acid, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol retinoic acid ester-4-isopropylstilbene; The raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is isotretinoin, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol isotretinoin ester-4-isopropylstilbene; The raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, the raw material B is retinoic acid, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane; The raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, the raw material B is isotretinoin, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol isotretinoin ester-4-isopropyldiphenylethane; The raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is retinoic acid, and the molar ratio of the raw material A to the raw material B is 1:0.9-1.2; the product is 3-retinoic acid ester-4-isopropyl-5-hydroxy-stilbene; The raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is isotretinoin, and the molar ratio of the raw material A to the raw material B is 1:0.9-1.2; the product is 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-stilbene; The raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, the raw material B is retinoic acid, and the molar ratio of the raw material A to the raw material B is 1:0.9-1.2; the product is 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane; When the raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane and the raw material B is isotretinoin, the molar ratio of the raw material A to the raw material B is 1:0.9-1.2; the product is 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane; The raw material A is E-4-isopropyl-3,5-dihydroxy-stilbene, the raw material B is vitamin E succinic acid, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol vitamin E succinate-4-isopropylstilbene; The raw material A is 4-isopropyl-3,5-dihydroxy-diphenylethane, the raw material B is vitamin E succinic acid, and the molar ratio of the raw material A to the raw material B is 1:2.1-5.0; the product is 3,5-diphenol vitamin E succinate-4-isopropyl diphenylethane.

4. The preparation method according to claim 3, characterized in that: The condensing agent is selected from EDC hydrochloride or DCC.

5. The preparation method according to claim 3, characterized in that: The condensing agent is selected from EDC hydrochloride, and the mass ratio of the raw material A to the condensing agent is 1:2-6.

6. The preparation method according to claim 3, characterized in that: The solvent is selected from dichloromethane or chloroform.

7. A pharmaceutical composition, characterized in that It comprises one or more of the benzenemod derivatives as claimed in claim 1 and a pharmaceutically acceptable diluent and / or carrier.

8. The pharmaceutical composition according to claim 7, characterized in that include: 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane in a mass ratio of 0.2-10.0:1; Or 3,5-diphenol isotretinoin ester-4-isopropyl diphenylethylene and 3,5-diphenol isotretinoin ester-4-isopropyl diphenylethane in a mass ratio of 0.2-10.0:1; Or 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene and 3-retinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane in a mass ratio of 0.2-10.0:1; Or 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethylene and 3-isoretinoic acid ester-4-isopropyl-5-hydroxy-diphenylethane in a mass ratio of 0.2-10.0:

1.

9. The pharmaceutical composition according to claim 7, characterized in that The invention comprises 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethylene and 3,5-diphenol retinoic acid ester-4-isopropyl diphenylethane in a mass ratio of 1-10:

1.

10. Use of the benzenemod derivatives as claimed in claim 1 in drugs for treating inflammation and relieving itching.

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