Small molecule compound and application thereof in preparation of medicine for treating 24p3R-mediated diseases

Abstract

The invention relates to a small molecule compound and application thereof in preparation of a medicine for treating 24p3R-mediated diseases. The invention relates to an application of small molecule compounds 5509605 and 5318411 or pharmaceutically acceptable salts thereof in preparation of medicines for treating diseases mediated by 24p3R (24p3R), in particular to an application of the small molecule compounds 5509605 and 5318411 in preparation of medicines for treating diseases mediated by 24p3R. According to the technical scheme, the core mechanism of the compound in treatment of 24p3R-mediated skin inflammatory diseases is disclosed for the first time by screening and verifying the targeted regulation effect of a specific small molecule compound on a 24p3R receptor. The small molecule drug can be specifically combined with an active site of a 24p3R receptor protein, and by blocking the combination of 24p3R and LCN2, the activation of an LCN2-SREBP2-NLRC4 signal axis is inhibited, and the expression of proinflammatory factors such as IL1beta, CXCL1 and CCL20 is reduced, so that the pathological proliferation and immune cell infiltration of psoriasis characteristic epidermal keratinocytes are blocked at the molecular level.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the application of small molecule compounds in the preparation of drugs for treating diseases mediated by 24p3R. Background Art

[0002] Psoriasis, as an immune-mediated chronic inflammatory skin disease, its pathological mechanism is closely related to genetic background, environmental triggers and immune microenvironment disorders. The clinical manifestations are typical skin lesion characteristics such as skin erythema, scales and thickening. Some patients are accompanied by systemic diseases such as joint inflammation or metabolic syndrome, and the disease burden is significant. At the molecular mechanism level, abnormal proliferation and differentiation imbalance of keratinocytes, infiltration of immune cells in the dermis layer and activation of the pro-inflammatory cytokine network are the core pathological links.

[0003] In recent years, further research has revealed that the interaction between lipocalin LCN2 and its receptor 24p3R plays a key role in the occurrence and development of psoriasis: the LCN2 / 24p3R axis induces abnormal cholesterol metabolism in keratinocytes by activating the SREBP2 pathway, and at the same time cooperates with the NLRC4 inflammasome to trigger the release of inflammatory mediators such as IL-1β and IL-18, forming a continuously amplified inflammatory cycle. Animal model studies have shown that by gene knockout or pharmacological means to inhibit 24p3R signaling, it can significantly improve imiquimod-induced epidermal hyperplasia, inflammatory cell infiltration and Th17-related cytokine expression in mice, suggesting the regulatory status of this receptor in the disease process.

[0004] Currently, the clinical treatment strategies for psoriasis mainly focus on immune regulation and anti-inflammatory pathways, such as biological agents targeting IL-17A, IL-23 or TNF-α, and small molecule drugs that inhibit signal nodes such as JAK-STAT or PDE4. Although these therapies have alleviated symptoms to a certain extent, long-term use may lead to problems such as increased infection risk, reduced efficacy or drug resistance. In addition, existing drugs mostly target downstream inflammatory factors or broad-spectrum immune pathways, and it is difficult to accurately intervene in the upstream pathogenic mechanisms, such as the metabolic-inflammatory cross-regulation network mediated by LCN2 / 24p3R. Particularly worthy of attention is that direct inhibitors or antagonists of the 24p3R receptor have not been fully developed in the prior art, and there are few reports on the structure, selectivity and drugability of related compounds. Most studies still remain in the preliminary exploration stage of gene intervention or antibody blockade, lacking molecular entities that can be translated into clinical applications. This technical gap limits the possibility of achieving source intervention for psoriasis by targeting 24p3R, and at the same time also makes it difficult for the existing treatment system to take into account the dual pathological characteristics of metabolic abnormalities and inflammatory responses. Therefore, the development of small molecule compounds with high selectivity and high activity for psoriasis is expected to provide a solution with both mechanism innovation and clinical feasibility for psoriasis treatment.

[0005] In addition, on the one hand, there are differences in the understanding of those skilled in the art; on the other hand, when the inventor made this invention, a large number of documents and patents were studied, but due to space limitations, all details and content were not listed in detail. However, this by no means means that this invention does not possess the features of these prior arts. On the contrary, this invention already possesses all the features of the prior arts, and the applicant reserves the right to add relevant prior arts in the background art. Summary of the Invention

[0006] Based on the above technical problems, one object of the present invention is to provide a pharmaceutical composition, which comprises a compound and a pharmaceutically acceptable carrier, and the compound is selected from the following groups:

[0007] (1) The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] (2) The compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] The pharmaceutically acceptable carrier can be an excipient, a disintegrant (solubilizer), a flavoring agent (coloring agent), an antioxidant. Preferably, the excipient is, for example, microcrystalline cellulose, lactose or starch, which is used to stabilize the active ingredient and regulate the formulation form. The disintegrant (solubilizer) is, for example, sodium carboxymethylcellulose, polysorbate, which is used to improve the dissolution rate or bioavailability. The flavoring agent (coloring agent) is, for example, a natural plant extract, stevioside, which is used to improve palatability. The antioxidant is, for example, ascorbic acid, which is used to maintain product stability.

[0012] Another object of the present invention is to provide the use of the small molecule compound 5509605 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases mediated by 24p3R, wherein the small molecule compound 5509605 is the compound represented by formula (I).

[0013] Another object of the present invention is to provide the use of the small molecule compound 5318411 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases mediated by 24p3R, wherein the small molecule compound 5318411 is the compound represented by formula (II).

[0014] According to a preferred embodiment, the dosage form of the drug includes tablets, capsules, granules, pills, powders, powders for external use, ointments, suspensions, oral liquids or injections.

[0015] According to a preferred embodiment, the oral dose of the small molecule compound 5509605 is: ≥2 mg / kg; the external application dose of the drug is: ≥1 mM. Preferably, the oral dose of the small molecule compound 5509605 is 2 mg / kg. The external application dose of the small molecule compound 5509605 is 1 mM.

[0016] According to a preferred embodiment, the oral dose of the small molecule compound 5318411 is: ≥2 mg / kg; the external application dose of the drug is: ≥5 mM. Preferably, the oral dose of the small molecule compound 5318411 is 2 mg / kg. The external application dose of the small molecule compound 5318411 is 5 mM.

[0017] According to a preferred embodiment, the disease mediated by 24p3R is erythrodermic and scaly dermatosis, and the erythrodermic and scaly dermatosis is preferably psoriasis.

[0018] According to a preferred embodiment, the application includes reducing skin inflammation, skin hyperplasia and in vivo inflammation caused by erythrodermic and scaly dermatosis. Preferably, the erythrodermic and scaly dermatosis includes psoriasis. Skin inflammation is preferably manifested as the growth of erythema and / or an increase in T cell infiltration. Skin hyperplasia is preferably manifested as an increase in scales and / or an increase in epidermal thickness. In vivo inflammation is preferably manifested as an increase in the transcriptional levels of the inflammatory factors IL1B and the chemokines CXCL1 and CCL20.

[0019] The beneficial effects of this technical solution are as follows:

[0020] The technical solution involved in this application reveals for the first time the core mechanism of such compounds in the treatment of 24p3R-mediated skin inflammatory diseases by screening and verifying the targeted regulatory effect of specific small molecule compounds on the 24p3R receptor. This small molecule drug can specifically bind to the active site of the 24p3R receptor protein, block the binding of 24p3R to LCN2, and then inhibit the activation of the LCN2-SREBP2-NLRC4 signaling axis, reducing the expression of pro-inflammatory factors such as IL1β, CXCL1, and CCL20, thereby blocking the pathological proliferation and immune cell infiltration of characteristic epidermal keratinocytes in psoriasis at the molecular level.

[0021] Compared with existing biological agents, this small molecule drug can achieve an effective drug concentration in the target tissue through systemic or local administration, with simple operation and easy implementation, and no risk of bone marrow suppression or liver and kidney function damage related to immunosuppressants is observed. Its technical effect is particularly reflected in the promotion of the repair of skin barrier damage in psoriasis and the potential therapeutic value of preventing complications such as psoriatic arthritis, providing a new molecular entity option for the development of new anti-psoriasis drugs with both high efficiency and safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Distribution setting diagram of cell plates for cell cultivation of the compounds involved in the present invention. Among them, A is the distribution diagram of the cytotoxicity test of small molecule drugs on HaCaT cells detected by CCK8, B is the distribution diagram of screening the optimal concentration of drugs using HaCaT cells; C is the cell survival rate;

[0023] Figure 2 Detection result diagram of inflammatory factors in the cells of the compounds involved in the present invention. Among them, A is the detection result of inflammatory factor IL1B; B is the detection result of chemokine CXCL1; C is the detection result of chemokine CCL20;

[0024] Figure 3 Detection result diagram of the external application of compound 5509605 involved in the present invention on the ear tissues of IMQ mice. Among them, A is the ear phenotype of the mouse; B is the statistical chart of the epidermal thickness of the ear tissues of the mouse; C is the HE staining of the ear tissues of the mouse;

[0025] Figure 4 Immunofluorescence staining of the ear tissues of IMQ mice externally applied with compound 5509605 involved in the present invention;

[0026] Figure 5 qRT-PCR detection results of downstream inflammatory factors and chemokines in the ear tissues of IMQ mice externally applied with compound 5509605 involved in the present invention;

[0027] Figure 6 Detection result diagram of the external application of compound 5318411 involved in the present invention on the ear tissues of IMQ mice. Among them, A is the ear phenotype of the mouse; B is the statistical chart of the epidermal thickness of the ear tissues of the mouse; C is the HE staining of the ear tissues of the mouse;

[0028] Figure 7 Immunofluorescence staining of the ear tissues of IMQ mice externally applied with compound 5318411 involved in the present invention;

[0029] Figure 8 qRT-PCR detection results of downstream inflammatory factors and chemokines in the ear tissues of IMQ mice externally applied with compound 5318411 involved in the present invention;

[0030] Figure 9 Back phenotype of IMQ mice after intragastric administration of the compounds involved in the present invention;

[0031] Figure 10Detection results of inflammatory factors in mice intragastrically administered with the compounds involved in the present invention. Among them, A is the detection result of IL1B inflammatory factor of 5509605; B is the detection result of CXCL1 chemokine of 5509605; C is the detection result of IL1B inflammatory factor of 5318411; D is the detection result of CXCL1 chemokine of 5318411;

[0032] Figure 11 Effect diagrams of the compound 5509605 involved in the present invention and MTX in treating IMQ mice after intragastric administration. Among them, A is the phenotype of the mouse back; B is the detection result diagram of IL1B inflammatory factor; C is the detection result diagram of CXCL1 chemokine. Detailed implementation manners

[0033] In the description of the present invention, the terms are only for the purpose of description and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. In the description of the present invention, "a plurality of" means two or more unless otherwise specifically defined.

[0034] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier of the compounds of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound, such as salts. Such salts include: acid addition salts formed with inorganic acids or with organic acids, such as nitric acid, phosphoric acid, carbonic acid, etc. for inorganic acids; propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc. for organic acids; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compounds containing acid radicals or basic groups. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of both, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to the salt form, prodrug forms of the compounds provided by the present invention also exist. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to convert into the compounds of the present invention. In addition, the prodrug can be converted into the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0035] The compounds shown by formulas (I) and (II) of the present invention can be prepared by using synthetic methods known in the art or by combining methods known in the art with the methods described in the present invention. The solvents, temperatures, and other reaction conditions given in the present invention are all exemplary and can be varied according to methods well-known in the art. The example compounds described in the present invention can be synthesized according to their specific structures using appropriate starting materials according to the methods described in the examples, or can also be synthesized using methods similar to those described in the examples. The starting materials used for synthesizing the example compounds of the present invention can be prepared by known synthetic methods or methods similar to those described in the literature, or obtained from commercial sources. The compounds can be further resolved into their stereoisomers by methods well-known in the art, such as crystallization, chromatography, etc., and the resolution conditions can be easily obtained by those skilled in the art through conventional means or limited experiments. As a further illustration, the compounds of formulas (I) and (II) of the present invention can be synthesized by the following methods, wherein the solvents, temperatures, and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art can be used.

[0036] The classical animal model of psoriasis involved in this application is the imiquimod (IMQ)-induced psoriasis model.

[0037] In the following examples, Vehicle indicates that this group is the animal control group using media such as cream matrix and 90% corn oil for uniformly dispersing drug components. WT in the figures indicates non-diseased mice (wild-type mice). The present invention has conducted cell experiments, topical animal experiments, and intragastric animal experiments based on the screened small molecule compound 5509605 and small molecule compound 5318411.

[0038] The present invention provides a treatment method for psoriasis and other erythrodermic and scaly skin diseases, and the treatment methods are selected from the following groups:

[0039] Using a topical dose of: small molecule compound 5509605 or a pharmaceutically acceptable salt thereof with a concentration ≥ 1 mM;

[0040] Using an oral dose of: small molecule compound 5509605 or a pharmaceutically acceptable salt thereof ≥ 2 mg / kg;

[0041] Using a topical dose of: small molecule compound 5318411 or a pharmaceutically acceptable salt thereof with a concentration ≥ 5 mM; and / or

[0042] Using an oral dose of: small molecule compound 5318411 or a pharmaceutically acceptable salt thereof ≥ 2 mg / kg.

[0043] The present invention provides a treatment method for diseases mediated by 24p3R, and the treatment methods are selected from the following groups:

[0044] The externally applied dose used is: a small molecule compound 5509605 with a concentration ≥ 1 mM or a pharmaceutically acceptable salt thereof;

[0045] The oral dose used is: a small molecule compound 5509605 ≥ 2 mg / kg or a pharmaceutically acceptable salt thereof;

[0046] The externally applied dose used is: a small molecule compound 5318411 with a concentration ≥ 5 mM or a pharmaceutically acceptable salt thereof; and / or

[0047] The oral dose used is: a small molecule compound 5318411 ≥ 2 mg / kg or a pharmaceutically acceptable salt thereof.

[0048] I. CCK8 experiment

[0049] 1. Experimental design

[0050] (1) Preliminary screening of CCK8 toxicity detection

[0051] Select HaCaT cells in the logarithmic growth phase, digest and prepare a single-cell suspension; use an automatic cell counter to accurately count, and adjust the cell concentration to 5×10 4 cells / mL, add 100 μL of cell suspension (5×10 3 cells / well) to each well of a 96-well plate, fill the edge wells with sterile PBS to prevent evaporation, and pre-incubate in a 37°C incubator for 12 hours;

[0052] Observe the cell status under a microscope. When the adherent growth fusion reaches 30 ± 5%, change the medium. Gently aspirate the old medium, and add fresh complete medium pre-warmed to 37°C and different concentrations of the drug solution (the final concentration refers to the dose design Figure 1 A, the drug concentration gradients are 0.1 μM, 1 μM, 10 μM, 50 μM, and 100 μM), set up a blank control group (only medium) and a negative control group (cells + medium), gently shake horizontally to mix well and continue to culture for 24 hours;

[0053] After the drug stimulation is completed, gently aspirate the old medium, add CCK-8 solution (the volume ratio of CCK-8 solution to the total solution is 1:10) to each experimental well under light-proof conditions, and detect the absorbance after incubating at 37°C in the dark for 30 minutes.

[0054] (2) Concentration gradient screening

[0055] Take HaCaT cells in the logarithmic growth phase, digest and prepare a single-cell suspension, and adjust the cell concentration to 5×10 4 cells / mL, add 2 mL of cell suspension (1×10 5Cells / well), gently shake horizontally to evenly distribute the cells, and then place them in an incubator at 37°C for 12 hours;

[0056] When the cells adhere and grow to a confluence of 30±5%, gently aspirate and discard the old medium, and add fresh complete medium and different concentrations of the drug solution ( Figure 1 B, the drug concentration screening gradient is 1 μM, 5 μM, 10 μM, 20 μM) according to the experimental design concentration gradient in each well. Set up a blank control group and a negative control group, gently mix, and continue to culture for 8 hours;

[0057] After the drug stimulation is completed, add 10 μl of cytokine M5 (concentration: OSM 10 ng / mL, TNF-α 10 ng / mL, IL-22 10 ng / mL, IL-17α 10 ng / mL, IL-1α 10 ng / mL) to each well, gently mix, and continue to culture for 24 hours to simulate the psoriasis microenvironment;

[0058] After the M5 stimulation is completed, discard the medium, gently wash the cells 3 times with pre-cooled PBS, add 1 mL of Trizol to each well to lyse the cells, let it stand at room temperature for 15 minutes, then collect the lysate, store it at -80°C or immediately perform RNA extraction for subsequent qRT-PCR experimental analysis of the target gene expression changes.

[0059] As Figure 1 C and Figure 2 shown by the cell experiment results, the drug 5509605 has a better inhibitory effect at a concentration of 1 μM, and the drug 5318411 has a better inhibitory effect at a concentration of 5 μM.

[0060] II. Zoological experiments of drug 5509605 and drug 5318411

[0061] The animal experiments of 24p3R small molecule drugs (mouse ear external application experiment) were carried out on mice at a 1000-fold concentration, that is, the concentration of drug 5509605 was 1 mM and the concentration of drug 5318411 was 5 mM.

[0062] The experimental mice included four groups.

[0063] The first group: WT+Vehicle group. Cream matrix, applied externally at 10:00 every day, and the external application dose was 2 mg / ear / time / day.

[0064] The second group: WT+drug group. 24p3R small molecule drug + cream matrix, 1 mM drug 5509605 / 5 mM drug 5318411 was mixed in 1 mg of cream matrix, applied externally at 10:00 every day, and the external application dose was 2 mg / ear / time / day.

[0065] Group 3: IMQ + Vehicle group. Imiquimod + cream base was topically applied at 16:00 every day, and the topical application dose was 2 mg / ear / time / day.

[0066] Group 4: IMQ + drug group. The 24p3R small molecule drug + cream base was topically applied to mice at 10:00 every day, and imiquimod cream was applied to mice at 16:00 every day. The topical application dose was 2 mg / ear / time / day for both.

[0067] It was continuously applied for 6 days, and the ear skin lesions of mice were collected on the 7th day for subsequent RT and section observation.

[0068] As Figure 3 shown in A, compared with the Vehicle group, a reduction in erythema and scales was observed in the ears of mice treated with 5509605 in the IMQ group. As Figure 3 shown in B and 3C, a significant decrease in epidermal thickness was observed by HE staining. CD3 is a T cell marker, and it Figure 4 was found that the infiltration of T cells decreased after treatment. As Figure 5 shown, from the results of RT (mRNA expression level), the downstream inflammatory factors and chemokines (IL1B, CXCL1, CCL20) were significantly inhibited.

[0069] As Figure 6 shown in A, compared with the Vehicle group, a reduction in erythema and scales was observed in the ears of mice treated with 5318411 in the IMQ group. As Figure 6 shown in B and 6C, a significant decrease in epidermal thickness was observed by HE staining. CD3 is a T cell marker, and it Figure 7 was found that the infiltration of T cells decreased after treatment. As Figure 8 shown, from the results of RT (mRNA expression level), the downstream inflammatory factors and chemokines (IL1B, CXCL1, CCL20) were significantly inhibited.

[0070] 2. Animal experiments (mouse gavage experiments) of the drug 5509605 and the drug 5318411 as 24p3R small molecule drugs were carried out.

[0071] The experimental mice included four groups.

[0072] Group 1: WT + Vehicle group. 10% DMSO + 90% corn oil was gavaged at 10:00 every day, and the gavage dose was 200 μl / day.

[0073] Group 2: WT + drug group. The 24p3R small molecule drug (5509605 / 5318411) was dissolved in 10% DMSO + 90% corn oil, and the drug concentration was 2 mg / kg. It was gavaged at 10:00 every day, and the gavage dose was 200 μl / day.

[0074] Group 3: IMQ + Vehicle group. Imiquimod was topically applied at 16:00 every day, and the topical application dose was 62.5 mg / rat / day (on the back).

[0075] Group 4: IMQ + Drug group. The mice were gavaged with the 24p3R small molecule drug (5509605 / 5318411) at 10:00 every day, and imiquimod cream was applied to the mice at 16:00 every day. The topical application and gavage doses were the same as above.

[0076] Group 5: IMQ + MTX group. The mice were gavaged with MTX at 10:00 every day, and imiquimod cream was applied to the mice at 16:00 every day. The topical application and gavage doses were the same as above.

[0077] It was continuously applied for 5 days, and on the 6th day, the skin lesions on the backs of the mice were collected for subsequent RT and section observation.

[0078] As Figure 9 shown, compared with the Vehicle group, in the IMQ group, it was observed that the erythema and scales were reduced in the mice gavaged with 5509605 and 5318411. Among them, the effect of 5509605 was particularly obvious. As Figure 10 shown, it can be seen from the RT (mRNA expression level) results that the downstream inflammatory factors and chemokines (IL1B, CXCL1) were significantly inhibited.

[0079] As Figure 11 shown, taking the changes in the backs of the mice gavaged with the classical psoriasis treatment drug MTX (methotrexate) as a reference, it can be seen that the drug 5509605 involved in the present application has a particularly obvious effect on psoriasis, and 5318411 also has a certain therapeutic effect. It can be seen from the RT (mRNA expression level) results that the drugs 5509605 and 5318411 as well as MTX have a significant inhibitory effect on the downstream inflammatory factors and chemokines (IL1B, CXCL1).

[0080] It should be noted that the above specific embodiments are exemplary. Those skilled in the art can come up with various solutions inspired by the disclosure content of the present invention, and these solutions also belong to the disclosure scope of the present invention and fall within the protection scope of the present invention. Those skilled in the art should understand that the description and drawings of the present invention are illustrative and do not constitute a limitation to the claims. The protection scope of the present invention is defined by the claims and their equivalents.

Claims

1. A pharmaceutical composition, characterized in that, Comprising a compound and a pharmaceutically acceptable carrier, the compound being selected from the following group: (1) A compound of formula (I) or a pharmaceutically acceptable salt thereof, or (2) A compound of formula (II) or a pharmaceutically acceptable salt thereof, 2. Use of the small molecule compound 5509605 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a 24p3R-mediated disease, characterized in that, The small molecule compound 5509605 is the compound of formula (I) in the pharmaceutical composition according to claim 1.

3. The application according to claim 2, wherein The dosage forms of the drug include tablets, capsules, granules, pills, powders, powders for external use, ointments, suspensions, oral liquids or injections.

4. The application according to claim 2 or 3, characterized in that, The oral dose of the drug is: ≥ 2 mg / kg; the external application dose of the drug is: ≥ 1 mM.

5. The application according to any one of claims 2 to 4, characterized in that, The 24p3R-mediated disease is an erythrodermic and scaly skin disease, and the erythrodermic and scaly skin disease is preferably psoriasis.

6. The application according to any one of claims 2 to 4, characterized in that, The application comprises reducing skin inflammation, skin hyperplasia and in vivo inflammation caused by the erythrodermic and scaly skin disease.

7. Use of the small molecule compound 5318411 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease mediated by 24p3R, characterized in that, The small molecule compound 5318411 is the compound of formula (II) in the pharmaceutical composition according to claim 1.

8. The application according to claim 7, wherein The oral dose of the drug is: ≥ 2 mg / kg; the external application dose of the drug is: ≥ 5 mM.

9. The application according to claim 7 or 8, characterized in that, The 24p3R-mediated disease is an erythrodermic and scaly skin disease, and the erythrodermic and scaly skin disease is preferably psoriasis.

10. The application according to any one of claims 7 to 9, characterized in that, The application comprises reducing skin inflammation, skin hyperplasia and in vivo inflammation caused by the erythrodermic and scaly skin disease.

Images