Application of isoalantolactone derivative in preparation of medicine for treating and / or preventing liver cancer

Abstract

The invention relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicine for treating and / or preventing liver cancer. The structure of the compound shown in the formula (I) is shown in the specification.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to the use of isocarboxylic acid lactone derivatives in the preparation of drugs for the treatment and / or prevention of liver cancer. Background Technology

[0002] Cancer has become a major threat to human health. Cancer recurrence and metastasis are among the leading causes of death in cancer patients and represent the greatest challenge in current cancer treatment. Liver cancer ranks among the most prevalent cancers in terms of incidence and mortality. Improving treatment efficacy and survival rates for liver cancer patients, while reducing drug toxicity and resistance, are key challenges for researchers.

[0003] Isotricholactone possesses certain anti-inflammatory, antiviral, and antitumor activities, but its water solubility and plasma stability are relatively poor. Therefore, structural modification is needed to further develop its pharmaceutical applications. Previous research by the inventors has developed a series of isotricholactone derivative structures, which can improve the water solubility of isotricholactone while maintaining its activity against leukemia stem cells, thus effectively treating leukemia. Recent findings indicate that isotricholactone derivatives show broad pharmaceutical potential in the treatment of liver cancer. Summary of the Invention

[0004] This invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing liver cancer:

[0005]

[0006] According to embodiments of the present invention, the pharmaceutically acceptable salt comprises an acid addition salt formed by the compound of formula (I) with an inorganic acid: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate; or an acid addition salt formed with an organic acid: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy- 2-Naphthoic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervaline, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid or thiocyanate.

[0007] According to embodiments of the present invention, those skilled in the art will understand that when the compound of formula I forms a salt with an acid, the molar ratio of the acid to the compound of formula I can be 5:1 to 1:5, for example 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5.

[0008] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the structure of formula (Ia):

[0009]

[0010] According to embodiments of the present invention, the liver cancer may be selected from primary liver cancer or secondary liver cancer. The primary liver cancer may be selected from one of hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, and hepatoblastoma; the secondary liver cancer may be selected from the following cancers: colon cancer, lung cancer, gastric cancer, pancreatic cancer, breast cancer, cholangiocarcinoma, esophageal cancer, ovarian cancer, prostate cancer, kidney cancer, and melanoma.

[0011] In some implementations, the drug can inhibit liver cancer metastasis or liver cancer cell migration.

[0012] In some embodiments, the drug contains 0.1 wt% to 99 wt%, preferably 0.5 wt% to 90 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the drug further includes a pharmaceutically acceptable carrier and / or excipient.

[0014] In some embodiments, the drug may also contain one or more additional preventive and / or therapeutic agents.

[0015] In some embodiments, the drug can be administered via both injection and oral administration, with injection including intravenous injection and intramuscular injection; the drug can be prepared as oral formulations, injectable formulations, topical formulations, etc., such as injection solutions, tablets, pills, capsules, etc.

[0016] According to an embodiment of the present invention, the drug can be prepared as a single-dose dosage form or a multi-dose dosage form.

[0017] The present invention also provides a method for treating and / or preventing liver cancer, comprising administering to a patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] According to embodiments of the present invention, the liver cancer may be selected from primary liver cancer or secondary liver cancer. The primary liver cancer may be selected from one of hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, and hepatoblastoma; the secondary liver cancer may be selected from the following cancers: colon cancer, lung cancer, gastric cancer, pancreatic cancer, breast cancer, cholangiocarcinoma, esophageal cancer, ovarian cancer, prostate cancer, kidney cancer, and melanoma.

[0019] When used as a drug, the compounds of the present invention can be used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1% to 99%, preferably 0.5% to 90%, of the compounds of the present invention, with the remainder being pharmaceutically acceptable, non-toxic, and inert pharmaceutically acceptable carriers and / or excipients for human and animal use, or in combination with other drugs for the prevention, treatment, or adjuvant treatment of liver cancer. The compositions of the present invention can be prepared as injections, tablets, and capsules, etc.

[0020] Beneficial effects

[0021] This invention provides the use of (I) a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of liver cancer, and experimental verification shows that the compound of this invention can inhibit the proliferation of liver cancer cells and inhibit tumor growth in a liver cancer PDX model mouse. Attached Figure Description

[0022] Figure 1 The cell proliferation curves of compound (Ia) inhibiting HCCLM3, Huh-7 and SK-hep1 liver cancer cells are shown.

[0023] Figure 2 (A) Photograph of the tumor in a PDX model mouse with liver cancer after oral administration of compound (Ia); (B) Tumor volume in a PDX model mouse with liver cancer after oral administration of compound (Ia); (C) Body weight in a PDX model mouse with liver cancer after oral administration of compound (Ia); (D) Tumor weight in a PDX model mouse with liver cancer after oral administration of compound (Ia); (E) Photograph of the spleen in a PDX model mouse with liver cancer after oral administration of compound (Ia); (F) Spleen weight in a PDX model mouse with liver cancer after oral administration of compound (Ia). Detailed Implementation

[0024] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0025] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0026] Example 1: Preparation of isocarboxylic acid lactone derivatives

[0027]

[0028] Compound M (498.2 mg, 1.4 mmol) was dissolved in dichloromethane (60 mL), and dimethylamine hydrochloride (1.69 g, 20.7 mmol) and anhydrous potassium carbonate (5.76 g, 41.7 mmol) were added. The mixture was heated to reflux and the reaction was completed by TLC after 2 hours and 40 minutes. The solid was filtered off using a funnel, and the resulting reaction solution was washed three times with water. The organic phase was dried over anhydrous magnesium sulfate and purified by column chromatography (ethyl acetate) to give compound (white solid, 361.7 mg). This product was dissolved in anhydrous methanol, and fumaric acid (105 mg, 0.9 mmol) was added to dissolve it. The solution was then directly evaporated to dryness to give compound (Ia) (white solid, 466.7 mg, 0.9 mmol, two-step yield: 65.4%).

[0029] l H NMR (400MHz, MeOD) δ8.04-7.95 (m, 2H), 7.60 (t, J = 7.4Hz, 1H), 7.48 (t, J = 7.7Hz,

[0030] 2H),6.68(s,2H),5.60(s,1H),5.26(s,1H),4.97(s,1H),4.70(s,1H),3.58-3.48(m,2 H),3.43(dd,J=11.2,6.0Hz,1H),3.35(s,1H),3.31(dt,J=3.2,1.6Hz,1H),2.92(s,6H) ,2.79(dd,J=11.0,5.1Hz,1H),2.42(d,J=12.1Hz,1H),2.20(d,J=15.5Hz,1H),2.02-1 .90(m,2H),1.84-1.63(m,3H),1.50(d,J=13.1Hz,1H),1.23-1.13(m,1H),0.86(s,3H);

[0031] 13 C NMR(100MHz,MeOD)δ176.6,169.4,165.5,145.9,134.6,132.9,130.5,129.1,128.3,112.2,7 8.8,75.9,53.1,42.9,42.7,41.8,40.4,39.0,36.3,34.0,26.9,20.6,16.2; HRMS(ESI)calcd for C 24 H 31NO4[M+H] + 398.2331, found 398.2328.

[0032] Example 2: Determination of the anti-hepatocellular carcinoma cell activity of isocarboxylic acid lactone derivatives by MTT assay

[0033] The experimental method is as follows:

[0034] (1) The HCCLM3, Huh-7 and SK-hep1 cells in the logarithmic growth phase were digested, centrifuged, washed with PBS, and resuspended in an appropriate amount of complete culture medium.

[0035] (2) Count the cells using a hemocytometer, adjust the cell concentration, and seed the cells at 3000 cells / well / 200μL into each well of a 96-well plate and incubate them in a cell culture incubator at 37°C and 5% carbon dioxide.

[0036] (3) After the cells adhered, the compound of formula (Ia) was serially diluted and then added to each well according to the corresponding concentration. The 96-well plate was placed in a cell culture incubator at 37°C and 5% CO2 and cultured for 72 hours.

[0037] (4) Add 20 μL of MTT solution (5 mg / mL) to each cell well and continue to incubate in a cell culture incubator for 3-5 hours.

[0038] (5) Discard the supernatant and add 150-200 μL of DMSO to the precipitate to completely dissolve the formazan precipitate.

[0039] (6) Place the 96-well plate to be tested flat in the microplate reader and measure the absorbance of each well at 570 nm.

[0040] Experimental results (e.g.) Figure 1 The results showed that isocarboxylic acid lactone derivative (Ia) inhibited the proliferation of HCCLM3, Huh-7 and SK-hep1 hepatocellular carcinoma cells in a gradient-dependent manner.

[0041] Example 3: Inhibition of tumor growth in a liver cancer PDX model mouse by isocarboxylic acid lactone derivative.

[0042] The experimental method is as follows:

[0043] (1) Collect liver cancer tissue, cut the tumor tissue into small pieces of 2-3 mm with scissors, and subcutaneously inoculate it into the armpit of Barb / c mice with a puncture needle.

[0044] (2) When the tumor grows to 50mm 3Around 10:00 AM, the tumor-bearing mice were randomly divided into two groups: a treatment group (BIAL) and a control group (Control). The treatment group received 50 mg / kg of compound (Ia) orally once daily, while the control group received an equal volume of PBS orally (solvent control).

[0045] (3) Measure the length and width of the tumors of each group of mice and the weight of the mice using vernier calipers, and record the measurements. Measure every 2 days. The tumor volume is calculated as a×b. 2 / 2 calculation.

[0046] (4) At the end of the experiment, the mice were euthanized, the tumor and spleen were removed, and the tumor weight and spleen weight were measured.

[0047] Experimental results show (e.g.) Figure 2 After oral administration of 50 mg / kg of isothomylene lactone derivative (Ia) (once daily), tumor volume significantly decreased, while mouse body weight was not significantly affected. Therefore, the isothomylene lactone derivative of this invention can significantly inhibit the growth of hepatocellular carcinoma PDX tumors without significant toxicity. Further observation of the spleen of PDX mice after administration showed that isothomylene lactone could reduce splenomegaly caused by tumor metastasis, indicating that the isothomylene lactone derivative can inhibit tumor metastasis in vivo.

[0048] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and / or prevention of liver cancer:

2. The application according to claim 1, characterized in that, The pharmaceutically acceptable salts include acid addition salts formed by compounds of formula (I) with inorganic acids: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate; or acid addition salts formed by compounds of formula (I) with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2- Naphthoic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, tervaline, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid or thiocyanate.

3. The application according to claim 1, characterized in that, The compound represented by formula (I) is selected from the structure of formula (Ia):

4. The application according to any one of claims 1-3, characterized in that, The liver cancer may be selected from primary liver cancer or secondary liver cancer; the primary liver cancer may be selected from one of hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, and hepatoblastoma; the secondary liver cancer may be selected from the following cancers: colon cancer, lung cancer, gastric cancer, pancreatic cancer, breast cancer, cholangiocarcinoma, esophageal cancer, ovarian cancer, prostate cancer, kidney cancer, and melanoma.

5. The application according to any one of claims 1-4, characterized in that, The drug can inhibit liver cancer metastasis or liver cancer cell migration.

6. The application according to any one of claims 1-5, characterized in that, The drug contains 0.1 wt% to 99 wt%, preferably 0.5 wt% to 90 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

7. The application according to any one of claims 1-6, characterized in that, The drug further includes pharmaceutically acceptable carriers and / or excipients.

8. The application according to any one of claims 1-7, characterized in that, The drug may also contain one or more other preventive and / or therapeutic agents.

9. The application according to any one of claims 1-8, characterized in that, The drug can be administered via injection and oral administration. Injection methods include intravenous injection and intramuscular injection. The drug can be prepared into oral preparations, injectable preparations, and topical preparations, such as injection solutions, tablets, pills, and capsules.

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