Medicine for treating psoriasis

Abstract

The invention relates to a medicine for treating psoriasis. Specifically, the invention provides application of a compound shown in a formula I, the compound is used for preparing a composition, and the composition is used for preventing and / or treating psoriasis. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to a medicine for treating psoriasis. Background Art

[0002] Psoriasis is considered to be a genetically related inflammatory skin disease, manifested as scaly erythema or plaques, often accompanied by itching, and can be combined with multiple systemic diseases. The potential causes and mechanisms of psoriasis are not yet fully understood. Under the stimulation of genetic factors and the external environment, immune cells and the inflammatory cytokines they secrete accumulate in large numbers in the skin, thus forming an inflammatory environment. At the same time, the keratinocytes of the skin will also overproliferate and abnormally differentiate. Although psoriasis is not a fatal disease, it is prone to recurrence and cannot be completely cured, which has a great adverse effect on the patient's physiological and psychological state. Although the launch of a series of innovative drugs such as biologics in recent years has made breakthroughs in the treatment of psoriasis, its recurrence and heterogeneity of drug efficacy are still important clinical problems that need to be solved urgently. Psoriasis patients often have discontinuous sleep due to night itching problems, and the disorder of sleep rhythm is closely related to circadian rhythm genes. Therefore, small molecule drugs targeting circadian rhythm genes need to be urgently developed to treat psoriasis.

[0003] Therefore, there is a need in the art to develop a new and effective drug for treating psoriasis. Summary of the invention

[0004] The purpose of the present invention is to provide a small molecule targeted drug for treating psoriasis in view of the deficiencies in the prior art.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] In a first aspect, the present invention provides a use of a compound of formula I for preparing a composition for preventing and / or treating psoriasis.

[0007]

[0008] Preferably, the composition is a pharmaceutical composition.

[0009] Preferably, the composition further comprises a pharmaceutically acceptable carrier.

[0010] Preferably, the composition is in the form of a solid preparation, a liquid preparation or a semisolid preparation.

[0011] Preferably, the composition is in the form of an oral preparation, an external preparation or an injection preparation.

[0012] Preferably, the composition is in the form of a skin external preparation.

[0013] Preferably, the skin external preparation is a skin ointment or a skin cream.

[0014] Preferably, the composition is in the form of tablets, injections, infusions, ointments, creams, gels, solutions, microspheres or films.

[0015] Preferably, the content of the compound of formula I is 0.1-99.9wt%, preferably 1-99wt%, more preferably 10-90wt%, more preferably 20-80wt%, more preferably 30-70wt%, more preferably 30-60wt%, based on the weight of the composition.

[0016] Preferably, the compound of formula I is the only active ingredient in the composition.

[0017] Preferably, the composition further comprises other active ingredients for preventing and / or treating psoriasis.

[0018] Preferably, the psoriasis is human psoriasis.

[0019] Preferably, the prevention and / or treatment of psoriasis comprises one or more methods selected from the following group for prevention and / or treatment:

[0020] (1) Improve skin erythema, infiltration, and scaling;

[0021] (2) reduce epidermal thickness at the site of skin lesions; and / or

[0022] (3) Reduce the expression of pro-inflammatory and chemotactic cytokines IL-17A, IL-23 and / or CCL20.

[0023] The second aspect of the present invention provides a method for preventing and / or treating psoriasis, the method comprising the step of administering the compound of formula I as described in the first aspect of the present invention to a subject in need thereof, thereby preventing and / or treating psoriasis.

[0024] Preferably, the subject is a human.

[0025] Within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below can be combined with each other to form a new or preferred technical solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The psoriasis model and drug treatment scheme were designed for the experimental and control group mice.

[0027] Figure 2The therapeutic effect of compound KL001 on IMQ-induced psoriasis-like mice, in which DMSO administration was used as a control. (2A) is a photo of mouse skin lesions, showing that the application of compound KL001 in the IMQ-induced psoriasis-like mouse model significantly reduced the erythema, infiltration, and scaling of the skin of IMQ-induced psoriasis-like mice. (2B and 2C) are the results of Western Blot and immunofluorescence of CRY2, showing that the application of compound KL001 in the IMQ-induced psoriasis-like mouse model significantly increased the expression of IMQ-induced CRY2 protein, indicating that compound KL001, which inhibits the ubiquitination and degradation of CRY2 protein, has a significant stabilizing effect. (2D) is H&E staining, and the results show that the application of KL001 in the IMQ-induced psoriasis-like mouse model significantly reduced the epidermal thickness of IMQ-induced psoriasis-like mice and reduced inflammatory cell infiltration. (2E) is the measurement of epidermal thickness of mouse skin, showing that the application of compound KL001 in the IMQ-induced psoriasis-like mouse model significantly reduced the epidermal thickness of IMQ-induced mice, and there was a significant statistical difference (P<0.05). (2F) is the result of the weight measurement of mice on days 1-6, showing that the application of compound KL001 in the IMQ-induced psoriasis-like mouse model significantly improved the weight loss of IMQ-induced mice.

[0028] Figure 3 The qPCR results of inflammatory and chemokines IL-17A (interleukin-17A), IL-23 (interleukin-23) and CCL20 (chemokine ligand 20) showed that the application of KL001 in the IMQ-induced psoriasis-like mouse model significantly reduced IL-17A, IL-23 and CCL20, with DMSO administration as a control. DETAILED DESCRIPTION

[0029] The present invention unexpectedly discovered for the first time a compound of formula I for preventing and treating psoriasis.

[0030] the term

[0031] As used herein, the terms "include", "comprises", and "comprising" are used interchangeably, and include not only open definitions, but also semi-closed and closed definitions. In other words, the terms include "consisting of", "consisting essentially of".

[0032] As used herein, "DMSO" refers to dimethyl sulfoxide.

[0033] In the present invention, the term "prevention" means a method of preventing the onset of a disease and / or its attendant symptoms or protecting a subject from acquiring a disease. "Prevention" as used herein also includes delaying the onset of a disease and / or its attendant symptoms and reducing the risk of a subject acquiring a disease.

[0034] In the present invention, the term "treatment" includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination and reversal.

[0035] Compounds of formula I

[0036] The structure of the compound of formula I described in the present invention is as follows:

[0037]

[0038] use

[0039] The present invention provides a use of a compound of formula I for preparing a composition, wherein the composition is used for preventing and / or treating psoriasis.

[0040] In a preferred example of the present invention, the content of the compound of formula I is 0.1-99.9wt%, preferably 1-99wt%, more preferably 10-90wt%, more preferably 20-80wt%, more preferably 30-70wt%, more preferably 30-60wt%, based on the weight of the composition.

[0041] In a preferred embodiment of the present invention, the compound of formula I is the only active ingredient in the composition.

[0042] In a preferred embodiment of the present invention, the composition further comprises other active ingredients for preventing and / or treating psoriasis.

[0043] The present invention also provides a method for preventing and / or treating psoriasis, wherein the method comprises the step of administering the compound of formula I to a subject in need thereof, thereby preventing and / or treating psoriasis.

[0044] Preferably, the subject is a human.

[0045] Composition

[0046] The composition of the present invention is preferably a pharmaceutical composition, and the composition of the present invention may include a pharmaceutically acceptable carrier.

[0047] As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solid, semisolid, liquid or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the various components and active ingredients in the drug and their mutual blending without significantly reducing the efficacy.

[0048] It should be understood that in the present invention, the pharmaceutically acceptable carrier is not particularly limited, and can be selected from commonly used materials in the art, or prepared by conventional methods, or purchased from the market. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talcum powder, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickeners, pH regulators, transdermal enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-free water, etc.

[0049] In a preferred embodiment of the present invention, the dosage form of the composition is a solid preparation, a liquid preparation or a semisolid preparation.

[0050] In a preferred embodiment of the present invention, the composition is in the form of an oral preparation, an external preparation or an injection preparation.

[0051] In a preferred embodiment of the present invention, the composition is in the form of tablets, injections, infusions, ointments, gels, solutions, microspheres or films.

[0052] Preferably, the composition is in the form of a skin external preparation, for example, a skin ointment or a skin cream.

[0053] The pharmaceutical preparation should be matched with the mode of administration. The drug of the present invention can also be used with other synergistic therapeutic agents (including before, during or after use). When using a drug or a preparation, a safe and effective amount of the drug is applied to the desired object (such as a human or non-human mammal), and the safe and effective amount is usually at least about 10 micrograms / kg body weight, and in most cases does not exceed about 8 milligrams / kg body weight, preferably the dosage is about 10 micrograms / kg body weight-about 1 milligram / kg body weight. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0054] The main excellent technical effects of the present invention include:

[0055] The present invention unexpectedly discovered for the first time that the compound of formula I has an excellent therapeutic effect on psoriasis.

[0056] The present invention is further described below in conjunction with specific examples. It should be understood that the following specific examples are based on the technical solution and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to these examples.

[0057] Example 1 Investigation of the effect of compound KL001 on the treatment of psoriasis

[0058] The structure of compound KL001 is as follows:

[0059]

[0060] Experimental methods and results:

[0061] On day -4, the back of the mice was shaved, with an area of ​​about 2.5 cm × 2.0 cm. Before constructing the psoriasis-like mouse model induced by imiquimod (IMQ), the base cream (40 mg) mixed with compound KL001 (dose of 11 mg / kg.bw) and the base cream (40 mg) mixed with DMSO were applied to the shaved area on the back of the experimental group and the control group mice on day -3, day -2, and day -1, respectively, once a day, and the administration time was in the morning. Starting from day 0, an IMQ-induced psoriasis-like mouse model was established. Compound KL001 cream and DMSO (equal to compound KL001) cream were applied to the shaved areas on the backs of the experimental group and control group mice respectively in the morning. In the evening, 5% IMQ cream (dose of 62.5 mg) was applied once. The interval between the two drug applications was greater than 4 hours. The treatment was continued for 5 days. On the 6th day, the mice were killed and skin samples were collected (the psoriasis modeling and drug administration treatment schemes of the experimental group and control group mice are as shown in Figure 1 Then, Western blotting and immunofluorescence staining were used to detect the expression of Cryptochrome 2 (CRY2) protein in the lesions, H&E staining was used to measure the epidermal thickness, and fluorescence quantitative PCR was used to detect the expression of inflammatory factors such as IL-17A (interleukin-17A), IL-23 (interleukin-23) and CCL20 (chemokine ligand 20) in the lesions, which play a major role in the pathogenesis of psoriasis. The results are shown in Figure 2 and Figure 3 shown.

[0062] from Figure 2 and Figure 3It can be seen that in the IMQ-induced psoriasis model, compared with the DMSO group, the topical compound KL001 showed significant improvement in the psoriasis-like inflammation and disease severity of mice, mainly manifested in the significant improvement of the characteristic skin manifestations of psoriasis, erythema, infiltration, and scaling; the epidermal thickness of the lesions was significantly reduced, and the infiltration of inflammatory cells was reduced; the expression of inflammatory factors IL-17A, IL-23 and chemokine CCL20 was significantly reduced; the weight loss of mice was also significantly improved; thus indicating that compound KL001 has an excellent therapeutic effect on psoriasis-like inflammation in mice. Therefore, the topical compound KL001 can effectively treat psoriasis, effectively improve the epidermal thickness and immune cell infiltration of the lesions, reduce the erythema, infiltration, and scaling of the lesions, and effectively curb the expression of proinflammatory cytokines and chemokines that cause the occurrence and aggravation of the disease, thereby effectively preventing and treating psoriasis.

[0063] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the description and illustrations of the present invention should be included in the protection scope of the present invention.

Claims

1. A use of a compound of formula I, characterized in that: Used for preparing a composition for preventing and / or treating psoriasis; 2. The use according to claim 1, characterized in that The composition is a pharmaceutical composition.

3. The use according to claim 1, characterized in that The composition also includes a pharmaceutically acceptable carrier.

4. The use according to claim 1, characterized in that The dosage form of the composition is a solid preparation, a liquid preparation or a semisolid preparation.

5. The use according to claim 1, characterized in that The dosage form of the composition is oral preparation, external preparation or injection preparation.

6. The use according to claim 1, characterized in that The dosage form of the composition is a skin external preparation.

7. The use according to claim 6, characterized in that The skin external preparation is a skin ointment or a skin cream.

8. The use according to claim 1, characterized in that The dosage form of the composition is tablet, injection, infusion, ointment, cream, gel, solution, microsphere or film.

9. The use according to claim 1, characterized in that The composition also includes other active ingredients for preventing and / or treating psoriasis.

10. A method for preventing and / or treating psoriasis, characterized in that: The method comprises the step of administering the compound of formula I as claimed in claim 1 to a subject in need thereof, thereby preventing and / or treating psoriasis.

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