Application of FN-1501 and its pharmaceutical composition

Abstract

The present invention discloses an application of FN-1501 and its pharmaceutical composition in the preparation of drugs for preventing and / or treating liver injury, specifically including drugs for preventing and treating autoimmune hepatitis, viral hepatitis or drug-induced liver injury, especially drugs for preventing and treating autoimmune hepatitis. It can achieve multiple pharmacological effects of improving liver tissue structure damage, liver inflammation, reducing serum transaminase, serum lactate dehydrogenase and mRNA levels of inflammatory factors, and can play a therapeutic role at the gene level, molecular level and tissue level. There are no toxic side effects in the body, and the preparation form used is wide. The appropriate drug dosage form can be selected according to the clinical application scenario, which provides a new development strategy for targeted drugs for the prevention and treatment of liver injury.

Description

Technical Field

[0001] The present invention relates to an application of FN-1501 and a pharmaceutical composition thereof, and in particular to their application in preparing a drug for preventing and / or treating liver damage. Background Art

[0002] Liver injury refers to the damage of liver parenchymal and non-parenchymal cells caused by various factors such as viruses, alcohol, drugs, autoimmune disorders, genetic susceptibility, etc., which will eventually lead to cirrhosis, liver cancer and even death if not diagnosed and treated in time. Animal studies have shown that in the pathological development of various types of liver injury diseases, there are different degrees of immune liver injury, and it is generally believed that immune liver injury is the basic pathological change of various liver diseases. Therefore, targeting immune liver injury can be used as one of the prevention and treatment strategies for various liver injury diseases in clinical practice.

[0003] At present, the conventional use of broad-spectrum immunosuppressants such as corticosteroids, azathioprine, and mycophenolate mofetil for treatment is prone to nonspecific immunosuppression, drug tolerance, and recurrence after discontinuation of medication. In addition, there are no small molecule drugs that effectively target liver damage. Summary of the invention

[0004] Purpose of the invention: In view of the problems of nonspecific immunosuppression, drug tolerance and recurrence after drug withdrawal in existing drugs, the present invention aims to provide an FN-1501 that can effectively improve liver tissue structure and inflammation and its pharmaceutical composition for use in the preparation of drugs for preventing and / or treating liver injury.

[0005] Technical solution: As the first aspect of the present invention, the present invention applies FN-1501 or a pharmaceutically acceptable salt thereof to prepare a drug for preventing and / or treating liver injury, wherein the structural formula of FN-1501 is as follows:

[0006]

[0007] Specifically, the above-mentioned liver injury is autoimmune hepatitis, viral hepatitis or drug-induced liver injury.

[0008] More specifically, the above-mentioned drug can achieve multi-level pharmacological effects of improving liver tissue structure damage or liver inflammation, and reducing serum transaminase, serum lactate dehydrogenase and mRNA levels of inflammatory factors.

[0009] In the concanavalin A-induced liver injury model, FN-1501 can significantly improve liver tissue damage and liver inflammation in mice. At the same time, FN-1501 showed good safety in clinical phase I studies. Therefore, FN-1501 and its pharmaceutical composition can be prepared as a drug for treating or preventing liver injury, especially autoimmune hepatitis, viral hepatitis, drug-induced hepatitis and other diseases.

[0010] The pharmaceutically acceptable salt is a salt of FN-1501 and any of the following acids: hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, malic acid, oxalic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, salicylic acid, isobutyric acid, adipic acid, palmitic acid or tannic acid. Further, FN-1501 or its pharmaceutically acceptable salt includes its amorphous or crystalline form.

[0011] The preparation method of FN-1501 is described in CN103012428A, CN105189517A and CN107098903A. Further, FN-1501 is salified with any of the above acids to obtain its pharmaceutically acceptable salt. Further, by controlling the crystallization conditions, different solid forms of FN-1501 and its pharmaceutically acceptable salt are formed, and different crystal forms include its solvates.

[0012] As a second aspect of the present invention, the present invention applies a pharmaceutical composition containing FN-1501 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to the preparation of a drug for preventing and / or treating liver injury. FN-1501 and its pharmaceutically acceptable salts can be in an amorphous state or a crystalline state in the formulation composition, and different crystal forms also contain its solvates, and the solid state can be changed according to the formulation process and dosage form requirements, for example: a certain crystal form is prepared into an amorphous state by a hot melt extrusion process. It can also form a combined state with pharmaceutical excipients, for example: grinding is used to make the active ingredient fully contact and combine with the pharmaceutical excipient, and the excipient is used to encapsulate the active ingredient to form a complex, etc.

[0013] Among them, the above-mentioned pharmaceutically acceptable carrier is selected from one or more of starch, sucrose, cellulose derivatives, alginate, gelatin, polyvinyl pyrrolidone, glycerol, agar, calcium carbonate, sodium bicarbonate, quaternary ammonium compounds, hexadecanol, kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, flavoring agents, and sweeteners.

[0014] Specifically, the pharmaceutical composition is in the form of an injection, tablet, powder, granule, capsule or oral solution.

[0015] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0016] (1) Provides a new application of FN-1501 and its pharmaceutical composition for the prevention and treatment of targeted liver damage, especially autoimmune hepatitis; can achieve multiple pharmacological functions such as improving liver tissue structure damage, liver inflammation, and reducing serum transaminase, serum lactate dehydrogenase and mRNA levels of inflammatory factors, and exerts therapeutic effects at the gene level, molecular level and tissue level;

[0017] (2) It has a good therapeutic effect on the ConA-induced immune liver injury model in mice, has no toxic side effects, and has good clinical application prospects;

[0018] (3) The pharmaceutical composition is easy to prepare and has a wide range of application forms. The appropriate pharmaceutical dosage form can be selected according to the clinical application scenario. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The results of the effect of FN-1501 on improving ConA-induced liver congestion in mice;

[0020] Figure 2 This is the result of hematoxylin-eosin staining (HE staining) of mouse liver tissue sections;

[0021] Figure 3 The results of FN-1501 in alleviating ConA-induced increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels; **** P<0.0001 vs Control, #### P < 0.0001 vs Model (results are expressed as Mean & SEM, one-way ANOVA was used for variance analysis);

[0022] Figure 4 The results of FN-1501 improving the levels of cytokines related to ConA-induced liver inflammation in mice; * P<0.05, ** P<0.01, *** P<0.001 vs Control, # P<0.05, ## P<0.01, ### P<0.001 vs Model (the results are expressed as Mean & SEM, and variance analysis was performed by one-way ANOVA). DETAILED DESCRIPTION

[0023] The technical solution of the present invention is further described below in conjunction with embodiments and drawings.

[0024] Example 1: Pharmacological study of FN-1501 in ConA-induced immune liver injury model in mice

[0025] 1. Experimental methods

[0026] Female SPF clean grade C57BL / 6J mice, weighing 18-22g, were fed under specific pathogen-free conditions, with a 12h light-dark cycle at room temperature, free access to food and water, and were adaptively fed for 2 weeks before the start of the study. The mice were randomly divided into 3 groups: normal control group (Control), model control group (Model), and FN-1501 group (FN-1501). In the Model group and FN-1501 group, a mouse immune liver injury model was established by a single tail vein injection of 10mg / kg ConA; the Control group was injected with an equal amount of saline; the FN-1501 group was pre-administered with a single tail vein at a dose of 10mg / kg 1h before ConA injection; mice in each group were fasted 12h before injection and had free access to water. 8h after modeling, blood was collected from the orbits of mice in each group, and then euthanized and the whole liver was removed. Serum was used to detect ALT, AST and TBIL levels. After the whole liver was taken for photography, the fixed, dehydrated and embedded sections of the left lateral lobe of the liver were taken for HE staining to observe tissue damage. The remaining liver tissue was used for real-time fluorescence quantitative PCR (Real-time qPCR) technology to detect the mRNA levels of liver inflammation-related factors.

[0027] 2. Experimental results

[0028] Analysis of FN-1501 pharmacological results: FN-1501 improves the ConA-induced immune liver injury model in mice.

[0029] like Figure 1 As shown in the figure, compared with the Control group, the liver of the Model group mice was severely congested and dark red. Compared with the Model group, the liver congestion of the FN-1501 group mice was significantly reduced, and the liver color was close to that of the normal group. Therefore, FN-1501 can significantly improve ConA-induced liver congestion in mice.

[0030] like Figure 2 As shown in the figure, HE staining results showed that compared with the Control group, the Model group had obvious liver damage, patchy differences, disordered arrangement of liver cords, punctate necrosis of hepatocytes with inflammatory cell infiltration in the lobules, and severe red blood cell infiltration in the lobules. Compared with the Model group, the FN-1501-treated group had no obvious punctate necrosis and a significant reduction in inflammatory cell infiltration, and a significant reduction in red blood cell infiltration in the lobules. Therefore, FN-1501 can significantly improve ConA-induced liver tissue structural damage and inflammatory infiltration.

[0031] like Figure 3 As shown in the figure, compared with the Control group, the levels of liver function-related indicators ALT, AST, and TBIL in the Model group were significantly increased. The FN-1501-administered group significantly alleviated the increase in ALT, AST, and TBIL levels induced by ConA. Therefore, FN-1501 can significantly improve the abnormal liver function indicators induced by ConA.

[0032] like Figure 4 As shown in the figure, compared with the Control group, the pro-inflammatory cytokines IFN-γ, TNF-α, IL-1β, IL-6, and IL-17A in the liver of the Model group were significantly increased, and the anti-inflammatory cytokine IL-10 was also significantly increased. The FN-1501-administered group significantly reduced the increase in the levels of the above inflammatory cytokines, and the anti-inflammatory cytokines were increased compared with the Model. Therefore, FN-1501 can significantly improve the abnormal levels of inflammatory-related cytokines induced by ConA.

[0033] In summary, FN-1501 can achieve multiple pharmacological effects, including improving liver tissue structure damage, liver inflammation, and reducing serum transaminase, serum lactate dehydrogenase, and mRNA levels of inflammatory factors. It can exert therapeutic effects at the genetic level, molecular level, and tissue level, and has application prospects as a drug for the prevention and treatment of liver damage.

Claims

1. Use of FN-1501 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating autoimmune hepatitis, wherein: The structural formula of FN-1501 is as follows:

2. The use according to claim 1, characterized in that: The drug can improve liver tissue structure damage or liver inflammation.

3. The use according to claim 1, characterized in that: The drug is capable of lowering serum transaminase or serum lactate dehydrogenase levels.

4. The use according to claim 1, characterized in that: The drug can reduce the mRNA level of inflammatory factors.

5. The use according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by FN-1501 and any of the following acids: hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, malic acid, oxalic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, salicylic acid, isobutyric acid, adipic acid, palmitic acid or tannic acid.

6. The use according to claim 1, characterized in that: The FN-1501 or a pharmaceutically acceptable salt thereof includes an amorphous state or a crystalline state.

7. Use of a pharmaceutical composition comprising FN-1501 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for preventing and / or treating autoimmune hepatitis.

8. The use according to claim 7, characterized in that: The pharmaceutically acceptable carrier is selected from one or more of starch, sucrose, cellulose derivatives, alginate, gelatin, polyvinyl pyrrolidone, glycerol, agar, calcium carbonate, sodium bicarbonate, quaternary ammonium compounds, cetyl alcohol, kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, flavoring agents, and sweeteners.

9. The use according to claim 7 or 8, characterized in that: The pharmaceutical composition is in the form of an injection, tablet, powder, granule, capsule or oral solution.

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