Use of a class of n-substituted phenyl-2-pyridinone compounds in the treatment of cancer and alleviation of fibrosis

Abstract

The application of a class of N-substituted phenyl-2-pyridone compounds in treating cancer and relieving fibrosis belongs to the technical field of medicine. The compound is an N-substituted phenyl-2-pyridone compound or a pharmaceutical derivative or preparation thereof. The cancer includes one or more of common cancers such as lung cancer, breast cancer, liver cancer, prostate cancer, pancreatic cancer and the like. The fibrosis disease includes one or more of diseases such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, myocardial fibrosis and the like or diseases induced by fibrosis. The drug can be combined with one or more pharmaceutical carriers to form a drug combination. The drug or the pharmaceutical composition thereof can be used alone or in combination with other drugs. The class of N-substituted phenyl-2-pyridone compounds has anticancer efficacy and presents excellent ability to relieve organ and tissue fibrosis, has good safety, and is expected to be developed into a clinical first-line drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the application of a class of N-substituted phenyl-2-pyridone compounds in the treatment of cancer and the relief of fibrosis. Background Technology

[0002] Pirfenidone, 5-methyl-1-phenyl-2-pyridone, is an oral anti-pulmonary fibrosis drug. It possesses anti-inflammatory, antioxidant, and anti-fibrotic effects. Since its market launch, pirfenidone has been shown to delay lung function failure and mitigate disease progression. Furthermore, studies have shown that pirfenidone has certain anti-cancer effects and can slow the progression of liver and kidney fibrosis. However, pirfenidone has relatively low efficacy, often requiring high doses, and is prone to causing gastrointestinal and skin adverse reactions, while also exhibiting some phototoxicity. Developing novel anti-cancer and fibrosis-relieving drugs by modifying and improving the structure of pirfenidone has significant practical application value. The inventors previously disclosed a class of N-substituted phenyl-2-pyridone compounds with excellent anti-pulmonary fibrosis effects in a patent (publication number: CN114716365A), but the efficacy of these compounds in anti-cancer and fibrosis-relieving remains to be studied. Summary of the Invention

[0003] Against the above background, the technical problem to be solved by the present invention is to address the lack of effective anti-cancer and fibrotic disease drugs by providing a class of N-substituted phenyl-2-pyridone compounds for the treatment of cancer and the relief of fibrosis.

[0004] The application of compounds of Formula I in the preparation of drugs for treating liver fibrosis, kidney fibrosis, and myocardial fibrosis.

[0005] The application of compounds of Formula I in the preparation of drugs for treating lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer.

[0006]

[0007] Among them, R 1 R 2 R 3 R 4 R 5 Each of these can be a hydrogen atom, deuterated methyl group, halogen, hydroxyl group, cyano group, amino group, nitro group, trifluoromethyl group, carboxyl group, amide group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms, alkoxy group with 1-6 carbon atoms, thioether group with 1-6 carbon atoms, etc.

[0008] Some specific compounds, R 1 R 2 R 3 R 4 R5 Each of these groups is independent of the following: hydrogen atom, methyl, ethyl, deuterated methyl, trifluoromethyl, butyl, halogen, hydroxyl, cyano, amino, carboxyl, methoxy, ethoxy, and methylthio.

[0009] Some specific compounds, R 1 R 2 R 3 R 4 R 5 Each can be a hydrogen atom, methyl, ethyl, deuterated methyl, or trifluoromethyl.

[0010] Specifically, the compound is selected from the following structures:

[0011]

[0012] A drug for treating liver fibrosis, kidney fibrosis, myocardial fibrosis, lung cancer, breast cancer, liver cancer, prostate cancer, or pancreatic cancer, comprising at least one of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] The drug dosage forms include tablets, capsules, granules, powders, oral preparations, injections, microcapsules, and suppositories. It can also be prepared as liposomes or micelles for administration. The drug can be used alone or in combination with other drugs.

[0014] The drug can be administered orally, intravenously, via inhalation, topically, or sublingually.

[0015] The cancers treated with the drug include one or more diseases such as lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer.

[0016] The drug can alleviate one or more diseases such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, and myocardial fibrosis, or diseases induced by fibrosis. In addition, it also has therapeutic effects on kidney injury diseases, including acute kidney injury, chronic kidney disease, and end-stage renal disease.

[0017] The drug described can alleviate non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, and liver inflammation, cavitation, and necrosis.

[0018] This invention investigates N-substituted phenyl-2-pyridone compounds with different substituents on the benzene ring, particularly a series of compounds with no substituents on the pyridone structure but with substituents on the benzene ring, focusing on their effects in treating cancer and alleviating fibrotic diseases. The anti-pulmonary fibrosis effects of these compounds have been reported in previous patent applications filed by the inventors. This patent discloses the relevant results of these compounds in treating cancers, particularly lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer, as well as in alleviating fibrotic diseases such as liver fibrosis, kidney fibrosis, and myocardial fibrosis.

[0019] This invention relates to the application of a class of N-substituted phenyl-2-pyridone compounds in the treatment of cancer and the relief of fibrosis, including a class of N-substituted phenyl-2-pyridone compounds and their medically acceptable salts. These compounds can also be formulated into conventional dosage forms such as tablets, capsules, granules, powders, oral liquids, and injections by incorporating conventional excipients in the pharmaceutical field. They may also include pharmaceutically acceptable excipients, auxiliary components, or other carriers such as solvents, diluents, binders, disintegrants, lubricants, flow aids, flavoring agents, coating agents, gelatin capsule shells, cosolvents, propellants, surfactants, preservatives, and lyophilization protectants. Furthermore, they can also be prepared into liposomes or micelles for drug delivery.

[0020] The beneficial effects of this invention are as follows: This invention provides a new therapeutic application for a class of N-substituted phenyl-2-pyridone compounds, demonstrating that compounds without substituents on the pyridone ring but with methyl substituents on the benzene ring can effectively treat cancers, especially lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer, and alleviate fibrosis, especially liver fibrosis, kidney fibrosis, and myocardial fibrosis. Furthermore, safety assessments have demonstrated that the developed drug also has good safety, exerting therapeutic effects without significant harm to other organs. Attached Figure Description

[0021] Figure 1 This is a curve showing the change in tumor volume in mice during the treatment process.

[0022] Figure 2 These are images of tumors in mice after treatment.

[0023] Figure 3 This refers to the size of the tumor in the mouse after treatment.

[0024] Figure 4 These are HE-stained images of mouse tumors after treatment.

[0025] Figure 5 These are images of tumors stained with TUNLE in mice after treatment.

[0026] Figure 6 These are HE staining images of other organs of the mice after treatment.

[0027] Figure 7 This is a graph showing the levels of ALT, AST, BUN, and SCr in mouse serum after treatment.

[0028] Figure 8 This is a curve showing the change in mouse body weight during the treatment process. Detailed Implementation

[0029] The present invention is illustrated by the following embodiments, but is not limited thereto.

[0030] Example 1

[0031] The synthesis of the series of compounds was performed with reference to patent document CN114716365A:

[0032]

[0033] Example 2

[0034] Anti-cancer experiment:

[0035] To establish a mouse lung cancer model, 6-8 week old male Balb / c nude mice were subcutaneously inoculated with A549 cell suspension (1×10⁻⁶ cells per mouse) in the axilla of the right forelimb. 7 A549 tumor-bearing mice were randomly divided into two groups: a 0.5% sodium carboxymethyl cellulose group (control group) and a drug treatment group, with a dosage of 300 mg / kg. The long diameter (L, mm) and short diameter (W, mm) of the tumor were measured and recorded daily for each experimental group, and the tumor volume (Vt, mm) was calculated according to the following formula. 3 ):Vt=L×W 2 / 2. Record Vt data for 14 days after drug administration and plot tumor growth curves with time (d) on the x-axis and Vt on the y-axis. Observe the condition of mice, weigh and record their weight daily. After 14 days of drug administration, euthanize the tumor-bearing mice by exsanguination of the eyeballs, collect blood, carefully dissect the tumor, wash with physiological saline, absorb excess water with absorbent paper, weigh on a balance, and photograph. Remove the tumor and the mouse's major organs (heart, liver, spleen, lung, kidney, etc.), fix them with 4% paraformaldehyde, section them in paraffin, stain with hematoxylin and eosin (H&E), observe the sections under a microscope, and photograph them. In addition, the tumors were further stained with immunofluorescence (TUNEL) and photographed.

[0036] Analysis of the anti-lung cancer results of representative compound P1

[0037] The A549 non-small cell lung cancer mouse model was used to determine the in vivo inhibitory effects of a series of compounds on tumor growth. Tumor changes in the mouse model after treatment with 0.5% sodium carboxymethyl cellulose (blank control) and P1 are shown below. Figure 1 The results showed that both groups of mice exhibited an increasing volume trend, with the P1-treated group showing a slower growth rate. Figure 2 , Figure 3 The growth of tumors in the treatment group mice was significantly inhibited, demonstrating that drug P1 can alleviate tumor growth and has anti-cancer efficacy. Tumor tissue pathology H&E sections are shown below. Figure 4 As shown, compared to the control group, the tumor tissue in the treatment group exhibited significant necrosis, validating the anticancer efficacy of compound P1. Furthermore, the tumor-suppressing effect of compound P1 was further verified by TUNEL immunofluorescence staining. Figure 5 ).

[0038] Safety assessment of representative compound P1

[0039] a. HE staining of heart, liver, spleen, lung, and kidney tissues

[0040] HE staining was performed on the heart, liver, lung, spleen, and kidney tissues of mice in both the blank control group and the P1 treatment group to assess the drug's effects on other organs and demonstrate its safety. Figure 6 It is evident that, compared to the control group, continuous use of P1 did not cause significant damage to other organs in mice, demonstrating that P1 has good safety.

[0041] b. Evaluation of liver and kidney function

[0042] like Figure 7 As shown, there was no significant difference in the levels of AST, ALT, BUN, and SCR in the plasma between the treated group and the blank group, demonstrating that drug P1 has good safety.

[0043] c. Mouse weight

[0044] Changes in mouse body weight during experiments can assess the effects of drug use on mice. For example... Figure 8 As shown, compared with the blank group, there was no significant weight loss in the P1 treatment group, further demonstrating the excellent safety of the new drug P1.

[0045] Example 3

[0046] The anti-lung cancer test data of other compounds are given in the following table. The test process and methods are as described in Example 2. Corresponding cancer models were constructed using breast cancer cells MCF7, liver cancer cells HepG2, prostate cancer cells LNCap, and pancreatic cancer cells PANC-1 to evaluate the universality of the anti-cancer properties of the series of compounds.

[0047] Table 1. Anticancer data of a series of compounds.

[0048]

[0049]

[0050] In anti-cancer experiments, "yes" indicates that the drug can inhibit tumor growth, while "no" indicates that it cannot inhibit tumor growth.

[0051] Example 4

[0052] Treatment of liver fibrosis experiment

[0053] The therapeutic effect of compound P1 on liver fibrosis was evaluated by inducing liver fibrosis in mice using carbon tetrachloride (CCl4). The specific methods were as follows: Male mice were randomly divided into three groups of 10 mice each: a control group, a CCl4 model group, and a P1 treatment group. The CCl4 model group and the P1 treatment group were treated with CCl4 (3 mL / kg, twice a week for 4 weeks) to establish a liver fibrosis model for 4 weeks. During treatment, the P1 treatment group was administered P1 in a 5% carboxymethyl cellulose sodium (CMC-Na) solution (400 mg / kg), while the control group and the CCl4 model group were administered the same dose of CMC-Na solution by gavage. Mouse weight and survival were monitored during gavage. Fourteen days after treatment, the mice were sacrificed, and blood was collected from the eyes and serum was separated. ALT and AST levels were measured to assess the degree of liver damage, and LN (laminarin) and total bilirubin (TBIL) levels were measured to assess the degree of liver fibrosis. The livers of the mice were removed, and the hydroxyproline (HYP) content was measured.

[0054] Analysis of the results of treatment for liver fibrosis

[0055] As shown in Table 2, the serum ALT and AST levels in the P1 treatment group were significantly lower than those in the CCl4 model group. P1 significantly inhibited the CCl4-induced increase in ALT and AST in mice and alleviated liver function damage. The levels of LN (laminusoidal globulin) and total bilirubin (TBIL) were significantly reduced in the treatment group. Compared with the blank control group, the hydroxyproline content in the liver of mice in the CCl4 model group was significantly increased. After P1 administration, the hydroxyproline content was significantly reduced, indicating that P1 can reduce the hydroxyproline content in liver tissue, inhibit the formation of collagen fibers in the mouse liver, and thus inhibit liver fibrosis.

[0056] Table 2. Data on the relief of liver fibrosis by representative compound P1.

[0057]

[0058]

[0059] Example 5

[0060] Test data for the treatment of liver fibrosis with other compounds are presented in the following table, wherein the test procedures and methods are as described in Example 4.

[0061] Table 3. Data on the treatment of liver fibrosis with other compounds.

[0062]

[0063] In liver fibrosis experiments, "yes" indicates that the drug can inhibit liver fibrosis, while "no" indicates that it cannot inhibit liver fibrosis.

[0064] Example 6

[0065] Experimental Study and Results Analysis of Treatment for Renal Fibrosis

[0066] Rats were randomly divided into three groups of 10 rats each: a control group, a model group, and a P1 treatment group. The model group and the P1 treatment group used a unilateral ureteral ligation method to establish the renal fibrosis model: rats were anesthetized, their abdomens were disinfected and shaved to expose the skin. An incision was made in the left abdominal region of the kidney in the lateral decubitus position to enter the abdominal cavity, exposing the lower edge of the kidney. The ureter was located, and ligated at both the proximal and distal ends of the ureter, followed by suturing the wound. A renal fibrosis model was established three weeks later. During treatment, the P1 treatment group was administered a 5% carboxymethyl cellulose sodium (CMC-Na) solution (400 mg / kg), while the control group and the model group were administered the same dose of CMC-Na solution by gavage. Mouse weight and survival were monitored during gavage. Fourteen days after administration, the mice were sacrificed, and blood was collected from the eyes and serum was separated to detect blood urea nitrogen (BUN) and creatinine (Scr) levels, analyzing the degree of renal fibrosis. As shown in Table 4, the serum levels of BUN and Scr in mice in the P1 treatment group were significantly lower than those in the model group, demonstrating that P1 can improve glomerular and tubular damage and reduce renal fibrosis and inflammatory cell infiltration.

[0067] Table 4. Data on the alleviation of renal fibrosis by representative compound P1.

[0068]

[0069] Example 7

[0070] Data on the relief of renal fibrosis by other compounds are presented in the following table, wherein the testing procedures and methods are described in Example 6.

[0071] Table 5. Data on the relief of renal fibrosis by other compounds.

[0072]

[0073]

[0074] In the renal fibrosis experiment, "yes" indicates that the drug can reduce renal fibrosis and the infiltration of inflammatory cells, while "no" indicates that it cannot reduce renal fibrosis and the infiltration of inflammatory cells.

[0075] Example 8

[0076] Experimental Study and Results Analysis of Treatment for Myocardial Fibrosis

[0077] A myocardial fibrosis model was established in vitro by inducing mouse cardiomyocytes with TGF-β1. The experiment consisted of a control group, a model group, and a P1 treatment group. Cells in the model group were incubated with TGF-β1 (10 ng / ml), while cells in the P1 treatment group were incubated with both TGF-β1 (10 ng / ml) and compound P1. RNA was extracted after the experiment for reverse transcription and amplification, and the expression levels of α-SMA, collagen I, and collagen III mRNA were measured.

[0078] As shown in Table 6, the levels of α-SMA, collagen I, and collagen III were significantly increased in TGF-β1-treated myocardial fibroblasts, confirming the establishment of the myocardial fibrosis model. In the treatment group, these factors were significantly inhibited, approaching normal levels, demonstrating that compound P1 can inhibit the expression of myocardial fibrosis biomarkers and has an anti-myocardial fibrosis effect.

[0079] Table 6. Data on the relief of myocardial fibrosis by representative compound P1.

[0080]

[0081]

[0082] Example 9

[0083] Data from other compound treatments for myocardial fibrosis are presented in the table below, with the testing procedures and methods described in Example 8.

[0084] Table 7 Data on the treatment of myocardial fibrosis with other compounds

[0085]

[0086] In the myocardial fibrosis experiment, "yes" indicates that the drug can inhibit the expression of myocardial fibrosis biomarkers and has an anti-myocardial fibrosis effect, while "no" indicates that it has an anti-myocardial fibrosis effect.

Claims

1. The use of compounds of formula I in the preparation of drugs for treating liver fibrosis, kidney fibrosis, or myocardial fibrosis: ； The compounds of formula I are selected from the following structures: 。 2. Use according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: 。 3. Use according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: 。 4. Use according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: 。 5. The use according to claim 1, characterized in that, The liver fibrosis drug, kidney fibrosis drug, or myocardial fibrosis drug comprises at least one of the compounds of claim 1 or their pharmaceutically acceptable salts.

6. Use according to claim 5, characterized in that, The dosage forms of the liver fibrosis drugs, kidney fibrosis drugs, or myocardial fibrosis drugs are tablets, capsules, granules, powders, injections, microcapsules, or suppositories.

7. Use according to claim 5, characterized in that, The dosage form of the liver fibrosis drugs, kidney fibrosis drugs, or myocardial fibrosis drugs mentioned is an oral preparation.

8. Use according to claim 5, characterized in that, The aforementioned drugs for liver fibrosis, kidney fibrosis, or myocardial fibrosis are administered orally, intravenously, via inhalation, topically, or sublingually.

9. Use according to claim 5, characterized in that, The aforementioned liver fibrosis drugs, kidney fibrosis drugs, or myocardial fibrosis drugs are prepared into liposome or micelle forms.

Images