Application of N-substituted phenyl-2-pyridone compounds in treatment of cancers

Abstract

The invention discloses application of N-substituted phenyl-2-pyridone compounds in treatment of cancers, and belongs to the technical field of medicines. The compound is an N-substituted phenyl-2-pyridone compound or a medicinal derivative or a preparation thereof. The cancers comprise one or more of common cancers such as lung cancer, breast cancer, liver cancer, prostatic cancer and pancreatic cancer. The medicine can be combined with one or more medicinal carriers to form a medicinal composition. The medicine or the pharmaceutical composition thereof can be used independently or combined with other medicines. The N-substituted phenyl-2-pyridone compound has an anti-cancer curative effect, is relatively good in safety and is expected to be developed into a clinical first-line drug.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and relates to application of a class of N-substituted phenyl-2-pyridone compounds in treatment of cancer. BACKGROUND

[0002] Pirfenidone, 5-methyl-1-phenyl-2-pyridone, is an oral anti-pulmonary fibrosis drug. It has anti-inflammatory, antioxidant and anti-fibrosis effects. Since its launch, pirfenidone can delay pulmonary function failure and reduce disease exacerbation. In addition, studies have shown that pirfenidone has certain anti-cancer effect and can alleviate liver fibrosis, kidney fibrosis and the like. However, pirfenidone has low efficacy, often requires a high dose, and easily causes adverse reactions in the gastrointestinal tract and skin, and has certain phototoxicity. Through modification and improvement of the structure of pirfenidone, it has important practical application value to develop a new type of anti-cancer and fibrosis relieving drug. The inventors disclosed a class of N-substituted phenyl-2-pyridone compounds with excellent anti-pulmonary fibrosis effect in the previous patent (publication number: CN114716365A), but the efficacy of the above-mentioned compounds in anti-cancer and relieving other types of fibrosis diseases needs to be studied. SUMMARY

[0003] The present application is a divisional application of the patent application with application number 202410337916.X, application date 2024-03-25, and name Application of a class of N-substituted phenyl-2-pyridone compounds in treatment of cancer and alleviation of fibrosis.

[0004] In the above background, the technical problem to be solved by the present application is to provide application of a class of N-substituted phenyl-2-pyridone compounds in treatment of cancer and alleviation of fibrosis in view of the lack of effective anti-cancer and fibrosis disease relieving drugs.

[0005] Application of the compound of formula I in preparation of a drug for treating liver fibrosis, a drug for treating kidney fibrosis, and a drug for treating myocardial fibrosis.

[0006] Application of the compound of formula I in preparation of a drug for treating lung cancer, a drug for treating breast cancer, a drug for treating liver cancer, a drug for treating prostate cancer, and a drug for treating pancreatic cancer.

[0007]

[0008] wherein R 1 , R 2 , R 3 , R 4 , R 5each independently is a hydrogen atom, a deuterated methyl group, a halogen, a hydroxyl group, a cyano group, an amino group, a nitro group, a trifluoromethyl group, a carboxyl group, an amide group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a thioether group having 1 to 6 carbon atoms, or the like.

[0009] Some specific compounds, R 1 , R 2 , R 3 , R 4 , R 5 each independently is a hydrogen atom, a methyl group, an ethyl group, a deuterated methyl group, a trifluoromethyl group, a butyl group, a halogen, a hydroxyl group, a cyano group, an amino group, a carboxyl group, a methoxy group, an ethoxy group, a methylthio group.

[0010] Some specific compounds, R 1 , R 2 , R 3 , R 4 , R 5 each independently is a hydrogen atom, a methyl group, an ethyl group, a deuterated methyl group, or a trifluoromethyl group.

[0011] Specifically, the compound is selected from the following structures:

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

[0013] The pharmaceutical dosage form is a tablet, a capsule, a granule, a powder, an oral preparation, an injection, a microcapsule preparation, a suppository, and can also be prepared into a liposome or a micelle for administration. The medicine can be used alone or in combination with other medicines.

[0014] The medicine is administered orally, intravenously, by respiratory inhalation, topically, sublingually, and the like.

[0015] The cancer treated by the medicine includes one or more of lung cancer, breast cancer, liver cancer, prostate cancer, pancreatic cancer, and the like.

[0016] The medicine can alleviate one or more of pulmonary fibrosis, liver fibrosis, kidney fibrosis, myocardial fibrosis, and the like, or diseases induced by fibrosis, and in addition, has a therapeutic effect on kidney injury diseases including acute kidney injury, chronic kidney disease, and end-stage kidney disease.

[0017] The medicine can alleviate nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, and diseases such as inflammation, vacuolization, and necrosis of the liver.

[0018] The present application studies N-substituted phenyl-2-pyridone compounds with different substituents on the benzene ring, and in particular, the effects of a series of compounds without substituents on the pyridone structure but with substituents on the benzene ring in treating cancer and relieving fibrosis diseases. The anti-pulmonary fibrosis effect of the compounds has been reported in the patent previously applied by the inventors, and the present patent discloses the related results of the compounds in treating cancer, in particular, lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer, and relieving fibrosis diseases such as liver fibrosis, kidney fibrosis, and myocardial fibrosis.

[0019] The present application relates to the application of a class of N-substituted phenyl-2-pyridone compounds in treating cancer and relieving fibrosis, including a class of N-substituted phenyl-2-pyridone compounds and their medically acceptable salts, which can also be added with conventional adjuvants in the preparation field to form tablets, capsules, granules, powders, oral liquids, injection preparations, and other conventional dosage forms. It can also include pharmaceutically acceptable adjuvants, auxiliary components, or other carriers such as solvents, diluents, binders, disintegrants, lubricants, glidants, flavoring agents, coating agents, gelatin capsule shells, latent solvents, propellants, surfactants, preservatives, lyophilization protectants, etc. In addition, it can also be prepared into liposomes or micelles for administration.

[0020] The present application has the following beneficial effects: the present application provides a new therapeutic application of a class of N-substituted phenyl-2-pyridone compounds, which proves that the compounds without substituents on the pyridone structure but with methyl substituents on the benzene ring can effectively treat cancer, in particular, lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer, and relieve fibrosis, in particular, liver fibrosis, kidney fibrosis, and myocardial fibrosis. In addition, the safety evaluation proves that the developed drug also has good safety, and plays a curative effect without obvious damage to other organs. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is the tumor volume change curve of mice during the treatment process.

[0022] Figure 2 is the tumor picture of mice after the treatment.

[0023] Figure 3 is the tumor volume of mice after the treatment.

[0024] Figure 4 is the HE staining picture of mice after the treatment.

[0025] Figure 5 is the TUNLE staining picture of mice after the treatment.

[0026] Figure 6 is the HE staining picture of other organs of mice after the treatment.

[0027] Figure 7Figure 1 is the ALT, AST, BUN and SCr content graph in the serum of mice after treatment.

[0028] Figure 8 Figure 2 is the body weight change curve of mice during treatment. DETAILED DESCRIPTION

[0029] The present application is illustrated by the following examples but is not limited thereto. Example 1

[0030] The synthesis of the series of compounds refers to the patent document CN114716365A: Example 2

[0031] Anti-cancer experiment: A549 cell suspension (1 x 10 7 cells / mL) was inoculated subcutaneously in the right front armpit of each 6-8 week old Balb / c male nude mouse to establish a mouse lung cancer model. The A549 tumor-bearing mice were randomly divided into two groups, namely the 0.5% carboxymethylcellulose sodium group (control group) and the drug treatment group, with a dosage of 300 mg / kg. The long diameter (L, mm) and short diameter (W, mm) of the tumors of each experimental group were measured and recorded daily, and the tumor volume (Vt, mm 3 ) was calculated according to the following formula: Vt = L x W 2 / 2. The Vt data within 14 days of administration were recorded, and the tumor growth curve was plotted with time (d) as the horizontal coordinate and Vt as the vertical coordinate. The state of the mice was observed, and the body weight of the mice was measured and recorded daily. After 14 days of administration, the tumor-bearing mice were sacrificed by taking the eyeball blood, the tumor mass was carefully peeled off and washed with normal saline, excess water was absorbed with absorbent paper, and the remaining water was weighed on a balance and photographed with a camera. The main organs (heart, liver, spleen, lung, kidney, etc.) of the mice were removed and fixed in 4% paraformaldehyde, then paraffin sectioned, hematoxylin-eosin (H&E) stained, and observed under a microscope and photographed. In addition, the tumor was further subjected to immunofluorescence (TUNEL) staining and photographed.

[0032] Analysis of anti-lung cancer results of representative compound P1

[0033] The A549 non-small cell lung cancer mouse model was selected to determine the effect of the series of compounds on inhibiting tumor growth in vivo. The tumor changes in the mice models after receiving 0.5% carboxymethylcellulose sodium (blank control group, control) and P1 treatment were as follows Figure 1 . The results showed that the volume of the mice in both groups showed a growth trend, with the P1 administration group growing slowly. As Figure 2 , Figure 3, the growth of tumors in the treatment group mice was significantly inhibited, proving that the drug P1 can alleviate the growth of tumors and has an anticancer effect. As shown in the tumor tissue pathological H&E section Figure 4 , compared with the control group, the tumor tissue of the drug administration group showed obvious necrosis, verifying the anticancer efficacy of compound P1. In addition, the antitumor effect of compound P1 was further verified by Tunel immunofluorescence staining Figure 5 ).

[0034] Safety evaluation of representative compound P1

[0035] a. HE staining of heart, liver, lung, spleen and kidney tissues The heart, liver, lung, spleen and kidney tissues of the blank group and P1 treatment group mice were respectively subjected to HE staining to evaluate the effect of the drug on other organs and prove the safety of the drug. As shown in Figure 6 , compared with the blank group, continuous use of P1 did not cause obvious damage to other organs of the mice, proving that P1 has good safety.

[0036] b. Evaluation of liver and kidney functions As shown in Figure 7 , there was no significant difference in the contents of AST, ALT, BUN and SCR in the plasma of the treatment group mice and the blank group, proving that the drug P1 has good safety.

[0037] c. Body weight of mice The change in the body weight of mice in the experiment can be used to evaluate the effect of the drug on the mice. As shown in Figure 8 , compared with the blank group, the P1 treatment group did not have obvious weight loss, further indicating the excellent safety of the new drug P1. Example 3

[0038] The anti-lung cancer test data of other compounds are given in the form of the following table, wherein the test process and method refer to Example 2, and breast cancer cells MCF7, liver cancer cells HepG2, prostate cancer cells LNCap and pancreatic cancer cells PANC-1 are respectively used to construct the corresponding cancer models to evaluate the universality of the anticancer effect of the series of compounds.

[0039] Table 1 Anti-cancer data table of series of compounds

[0040]

[0041] In the anticancer experiment, “yes” means that the drug can inhibit the growth of tumors, and “no” means that it cannot inhibit the growth of tumors. Example 4

[0042] Treatment of liver fibrosis experiment The therapeutic effect of compound P1 on liver fibrosis was evaluated using carbon tetrachloride (CCl4) to induce liver fibrosis in mice, and the specific method was as follows: male mice were randomly divided into 3 groups, 10 in each group, namely: blank group, CCl4 model group, and P1 treatment group. The CCl4 model group and P1 treatment group were modeled for 4 weeks using CCl4 (3 mL / kg, twice a week, for 4 weeks) to establish a liver fibrosis model. During the treatment period, the P1 treatment group was administered a 5% carboxymethylcellulose sodium (CMC-Na) solution of P1 (400 mg / kg), and the blank group and CCl4 model group were administered the same dose of CMC-Na solution by gavage. The body weight and survival of the mice were monitored during the gavage period, and the mice were sacrificed 14 days after administration. The mice were enucleated to collect blood and separate serum, and the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicators were detected to determine the degree of liver damage. The LN (laminin) and total bilirubin (TBIL) indicators were detected to evaluate the degree of liver fibrosis, and the mouse liver was removed to detect the content of hydroxyproline (HYP).

[0043] Analysis of the results of treating liver fibrosis

[0044] As shown in Table 2, the ALT and AST levels in the serum of the P1 treatment group mice were significantly lower than those in the CCl4 model group, and P1 could significantly inhibit the increase of ALT and AST induced by CCl4 in mice, and reduce the damage to liver function. The LN (laminin) and total bilirubin (TBIL) in the treatment group were significantly reduced. Compared with the blank control group, the content of hydroxyproline in the liver of the CCl4 model group mice was significantly increased, and after administration of P1, the content of hydroxyproline was significantly reduced, indicating that P1 could reduce the content of hydroxyproline in liver tissue and inhibit the generation of collagen fibers in the liver of mice, thereby inhibiting liver fibrosis.

[0045] Table 2: Data table of representative compound P1 for relieving liver fibrosis Example 5

[0046] The test data of other compounds for treating liver fibrosis are given in the form of the following table, where the test process and method refer to Example 4.

[0047] Table 3: Data table of other compounds for treating liver fibrosis

[0048] In the liver fibrosis experiment, "yes" indicates that the drug can inhibit liver fibrosis, and "no" indicates that it cannot inhibit liver fibrosis. Example 6

[0049] Treatment of kidney fibrosis experiment and result analysis The rats were randomly divided into 3 groups, 10 rats in each group, namely: blank group, model group, P1 treatment group. The model group and P1 treatment group used the unilateral ureter ligation method to model: the rats were anesthetized, the abdomen was disinfected and shaved, the skin was exposed, and the left abdominal kidney area was incised to enter the abdominal cavity, the lower edge of the kidney was exposed, and the ureter was found. After ligation of the ureter at the proximal and distal ends of the kidney, the wound was sutured, and a renal fibrosis model was constructed after three weeks. During the treatment, the P1 treatment group was given P1 5% carboxymethyl cellulose sodium (CMC-Na) solution (400 mg / kg), and the blank group and model group were given the same dose of CMC-Na solution. During the gavage, the body weight and survival of the mice were detected, and the mice were sacrificed after 14 days of medication. The mice were enucleated to take blood and separate serum, and the urea nitrogen (BUN) and creatinine (Scr) contents were detected to analyze the degree of renal fibrosis. As shown in Table 4, the BUN and Scr levels of the P1 treatment group mice were significantly lower than those of the model group, indicating that P1 can improve the damage of glomerulus and renal tubule, reduce renal fibrosis and infiltration of inflammatory cells.

[0050] Table 4 Data table of representative compound P1 for relieving renal fibrosis

[0051] Example 7 The test data of other compounds for relieving renal fibrosis are given in the form of the following table, wherein the test process and method refer to Example 6.

[0052] Table 5 Data table of other compounds for relieving renal fibrosis

[0053] In the renal fibrosis experiment, "yes" means that the drug can reduce renal fibrosis and infiltration of inflammatory cells, and "no" means that it cannot reduce renal fibrosis and infiltration of inflammatory cells. Example 8

[0054] Treatment of myocardial fibrosis experiment and result analysis Mouse myocardial fibroblasts were induced using TGF-β1 to construct an in vitro myocardial fibrosis model. The experiment was divided into a control group, a model group, and a P1 treatment group. The model group cells were incubated with TGF-β1 (10 ng / ml), and the P1 treatment group cells were incubated with TGF-β1 (10 ng / ml) and compound P1 at the same time. After the experiment, RNA was extracted for reverse transcription and amplification to determine the a-SMA and collagen I and collagen III mRNA expression levels.

[0055] As shown in the results of Table 6, a-SMA, collagen I and collagen III in the myocardial fibroblasts treated by TGF-β1 were significantly increased, which proved the establishment of the myocardial fibrosis model. The above factors in the treatment group were significantly inhibited, close to the normal level, which proved that the compound P1 could inhibit the expression of myocardial fibrosis biomarkers and had the effect of anti-myocardial fibrosis.

[0056] Table 6 Data table of myocardial fibrosis alleviation of representative compound P1 Example 9

[0057] The test data of other compounds for treating myocardial fibrosis are given in the form of the following table, wherein the test process and method refer to Example 8.

[0058] Table 7 Data table of other compounds for treating myocardial fibrosis

[0059] In the myocardial fibrosis experiment, "yes" means that the drug can inhibit the expression of myocardial fibrosis biomarkers and has the effect of anti-myocardial fibrosis, and "no" means that it has the effect of anti-myocardial fibrosis.

Claims

1. Application of compounds of formula I in the preparation of drugs for treating lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer: ； The compounds of formula I are selected from the following structures: 。 2. The application according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: 。 3. The application according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: .

4. The application according to claim 1, characterized in that, The compounds of Formula I are selected from the following structures: 。 5. A drug for treating lung cancer, breast cancer, liver cancer, prostate cancer, and pancreatic cancer, characterized in that, It contains at least one of the compounds of any one of claims 1-4 or their pharmaceutically acceptable salts.

6. The drug according to claim 5, characterized in that, The dosage form of the drug is tablets, capsules, granules, powders, oral preparations, injections, microcapsules, or suppositories.

7. The drug according to claim 5, characterized in that, The drug can be administered orally, intravenously, via inhalation, topically, or sublingually.

8. The drug according to claim 5, characterized in that, The drug is prepared in liposome or micelle form.

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