Compounds for treatment of liver cancer

Abstract

The invention discloses a compound for treating liver cancer. The compound is named as HCC-IN-919. The invention discloses the value of the compound HCC-IN-919 in the aspect of treating liver cancer for the first time, which not only provides a new thought for the research and development of anti-liver cancer drugs, but also lays a solid foundation for the new application of the compound HCC-IN-919 in the anti-cancer field, and provides reference for the research and development of new drugs in the future.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a compound for treating liver cancer. Background Technology

[0002] Liver cancer is one of the most common malignant tumors with high incidence and mortality rates worldwide. According to the International Agency for Research on Cancer's global cancer statistics report, liver cancer ranks among the top common malignant tumors in terms of incidence, and its mortality rate ranks third among cancer-related causes of death. Due to the high prevalence of hepatitis B virus and hepatitis C virus infection, as well as the combined effects of aflatoxin exposure, alcohol consumption, and obesity, the disease burden of liver cancer is particularly heavy.

[0003] Liver cancer has an insidious onset, with few or no early symptoms. Most patients are diagnosed at an advanced stage, missing the optimal window for radical treatment such as surgical resection or liver transplantation. For patients with unresectable advanced liver cancer, traditional treatments such as systemic chemotherapy have limited efficacy and significant side effects, failing to meet clinical needs. In recent years, the advent of molecularly targeted drugs and immune checkpoint inhibitors has brought new breakthroughs in the treatment of advanced liver cancer. Multi-kinase inhibitors, such as sorafenib and lenvatinib, and immunotherapy combinations such as atezolizumab combined with bevacizumab, have extended patient survival to some extent. However, these treatments still face many challenges, such as the increasing problem of drug resistance, making it difficult for most patients to obtain lasting benefits.

[0004] Given the high incidence and mortality rates of liver cancer, as well as the limitations of existing treatments in terms of efficacy, drug resistance, and safety, in-depth exploration of the molecular mechanisms of liver cancer development and the discovery of small molecule compounds with novel mechanisms of action and new chemical structures have become an urgent need and an important direction in the field of liver cancer drug development. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a novel compound for treating liver cancer.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: The first aspect of this invention provides a compound for treating liver cancer.

[0007] Furthermore, the structural formula of the compound is shown in formula (I): Formula (I).

[0008] In this invention, the compound represented by formula (I) is named HCC-IN-919, and its molecular formula is C1. 26 H 22N2O2, with a molecular weight of 394.47, has the compound name 13-(2-toluidinomethyl)-9,10-dihydro-9,10-[3,4]pyrrolidinoanthracene-12,14-dione.

[0009] Furthermore, the compound also includes its pharmaceutically acceptable salts, pharmaceutically acceptable esters, isomers, polymorphs, solvates, and prodrugs.

[0010] In this invention, the compound can be the compound itself or a pharmaceutically acceptable salt of the compound. The pharmaceutically acceptable salt refers to an acidic salt formed with inorganic and / or organic acids and a basic salt formed with inorganic and / or organic bases. Additionally, when the compound contains a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, carboxylic acid), an amphoteric ion can be formed, and the amphoteric ion is contained in the pharmaceutically acceptable salt described in this application. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, but other salts are also useful. The pharmaceutically acceptable salt of the compound can be formed, for example, by reacting the compound with a certain amount of acid or base in a medium, such as a medium in which salts precipitate or an aqueous medium (fly-dried after the reaction).

[0011] Specific pharmaceutically acceptable salts include those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit or risk. Pharmaceutically acceptable salts (pharmaceutically acceptable salts) are well known in the art. Pharmaceutically acceptable salts of the compounds described in this application include salts derived from suitable inorganic and organic acids and inorganic and organic bases.

[0012] In some embodiments, a pharmaceutically acceptable ester refers to an ester formed by a hydroxyl group present in the compound provided in this application and a suitable acid (e.g., a carboxylic acid or an oxy-containing inorganic acid). Suitable esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate, or palmitate.

[0013] In some embodiments, isomers refer to compounds of this application that can exist as racemic derivatives, racemic mixtures, single enantiomers, diastereomer mixtures, single diastereomers, geometric isomers, etc., when the compound contains one or more asymmetric centers and / or double bonds. These compounds may be represented by the symbols "R" or "S," depending on the configuration of the substituents surrounding the stereocarbon atom, and may also be represented by the symbols "Z" or "E," depending on the carbon atom. The arrangement of substituents around the carbon double bond, or the carbon Substituents around the carbon double bond may be referred to as "cis" or "trans". The compounds disclosed in this application may exist in tautomer forms, and both tautomer forms are intended to be included within the scope of this application, even if only one tautomer structure is described, such as keto-enol tautomer, phenol-keto tautomer, nitroso-oxime tautomer, imine-enamine tautomer, etc.

[0014] In some embodiments, polymorphs refer to compounds that can also exist in various crystalline forms, obtained by recrystallizing the compound or its pharmaceutically acceptable salt in a solvent to obtain their different single crystalline forms and mixtures of polymorphs.

[0015] In some embodiments, a solvate refers to a compound that can exist in the form of a solvate (such as a hydrate), wherein the compound contains a polar solvent, particularly such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0016] In some embodiments, a prodrug refers to a compound that may also be in the form of a prodrug or in a form that releases the active ingredient after metabolic changes in vivo. The selection and preparation of suitable prodrug derivatives are techniques well known to those skilled in the art.

[0017] The second aspect of this invention provides the use of the compound described in the first aspect of this invention in the preparation of a medicament for treating liver cancer.

[0018] Furthermore, the drug also includes a pharmaceutically acceptable carrier.

[0019] Furthermore, the pharmaceutically acceptable carriers include diluents, binders, surfactants, humectants, adsorbents, lubricants, fillers, and disintegrants.

[0020] In some implementations, the diluent includes, but is not limited to, lactose, sodium chloride, glucose, urea, starch, water, etc.

[0021] In some embodiments, the adhesive includes, but is not limited to: starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginate and alginate, xanthan gum, hydroxypropylcellulose and hydroxypropylmethylcellulose, etc.

[0022] In some embodiments, the surfactant includes, but is not limited to: polyethylene oxide sorbitan fatty acid ester, sodium lauryl sulfate, glyceryl monostearate, hexadecyl alcohol, etc.

[0023] In some embodiments, the humectant includes, but is not limited to, glycerin, starch, etc.

[0024] In some embodiments, the adsorbent carrier includes, but is not limited to, starch, lactose, bentonite, silica gel, kaolin, and soap clay.

[0025] In some embodiments, the lubricant includes, but is not limited to: zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium dodecyl sulfate, etc.

[0026] In some embodiments, the filler includes, but is not limited to: mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polysaccharides, coupled sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, kelp polysaccharide powder, agar powder, calcium carbonate, and sodium bicarbonate, etc.

[0027] In some embodiments, the disintegrant includes, but is not limited to: crosylvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylmethyl, crosylcarboxymethyl cellulose sodium, soybean polysaccharides, etc.

[0028] In some implementations, the pharmaceutically acceptable carrier may additionally contain liquids such as water, saline, glycerol, and ethanol.

[0029] Furthermore, the dosage form of the drug is selected from any one of the following: injectable drugs, sprays, capsules, tablets, pills, granules, powders, and oral liquids.

[0030] Furthermore, the administration methods of the drug include oral, subcutaneous, intravenous, intramuscular, intra-arterial, intrathecal, mucosal, and / or intraperitoneal injection.

[0031] In some embodiments, the dosage form of the drug includes, but is not limited to: tablets, pills, powders, granules, capsules, lozenges, syrups, solutions, emulsions, suspensions, controlled-release formulations, aerosols, films, injections, intravenous infusions, transdermal absorption formulations, ointments, lotions, adhesive formulations, nasal formulations, and pulmonary formulations, for patient ingestion.

[0032] In some embodiments, suitable routes of administration of the drug include any of a variety of methods and delivery systems known to those skilled in the art to physically introduce the drug of the present invention into a subject, including but not limited to: oral administration, non-gastrointestinal administration, administration via inhalation spray, topical administration, nasal administration, buccal administration, or administration via an implanted drug reservoir. When the drug is intended for injection, it may be in the form of a suspension, solution, or emulsion in an oily or aqueous medium and may contain formulation agents such as suspending agents, preservatives, stabilizers, and / or dispersants.

[0033] Furthermore, the drug also includes a second therapeutic agent.

[0034] Furthermore, the second therapeutic agent includes sorafenib, lenvatinib, regorafenib, cabozantinib, atezolizumab, bevacizumab, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, capecitabine, or paclitaxel.

[0035] In some embodiments, the compound of the present invention may also be used in combination with other drugs for treating liver cancer, including simultaneous or sequential use, such that a therapeutically effective amount of the compound of the present invention and one or more other drugs for treating liver cancer are present in the patient.

[0036] In some embodiments, the compound of the present invention is used in combination, including administering a unit dose of the compound before, after, or simultaneously with the administration of a unit dose of one or more other drugs for treating liver cancer. For example, the compound of the present invention may be administered within seconds, minutes, or hours after the administration of one or more other drugs for treating liver cancer; or, for example, a unit dose of the compound of the present invention may be administered within seconds, minutes, or hours after the administration of a unit dose of the compound of the present invention; or, for example, a unit dose of one or more other drugs for treating liver cancer and the compound of the present invention may be administered simultaneously.

[0037] The third aspect of this invention provides the use of the compounds described in the first aspect of this invention in the preparation of reagents for inhibiting the activity, proliferation, migration, invasion and / or promoting apoptosis of liver cancer cells in vitro.

[0038] Furthermore, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721.

[0039] Furthermore, the liver cancer cells are MHCC-97H.

[0040] The fourth aspect of the present invention provides a method for inhibiting the activity, proliferation, migration, invasion and / or promoting apoptosis of liver cancer cells in vitro for non-therapeutic purposes.

[0041] Furthermore, the method includes the following steps: treating liver cancer cells with an effective amount of the compound described in the first aspect of the present invention or a pharmaceutical composition comprising an effective amount of the compound described in the first aspect of the present invention.

[0042] Furthermore, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721.

[0043] Furthermore, the liver cancer cells are MHCC-97H.

[0044] In this invention, the term "effective amount" refers to the therapeutic amount required to alleviate at least one or more symptoms of a disease or condition, and relates to a sufficient amount of medicine to provide the desired effect. Therefore, the term "therapeutic effective amount" refers to a therapeutic amount sufficient to cause a specific effect when administered to a typical subject. In various contexts, the effective amount, as used herein, also includes amounts sufficient to delay the development of disease symptoms, alter the course of the disease (e.g., but not limited to, slowing the progression of disease symptoms), or reverse disease symptoms. It should be understood that many methods are known in the art for determining the effective amount for a given application. For example, pharmacological methods for dosage determination can be used in a therapeutic context. In the context of therapeutic or preventative applications, the amount of composition administered to a subject will depend on the type and severity of the disease and the characteristics of the individual, such as general health status, age, sex, weight, and tolerance to the drug. It also depends on the degree, severity, and type of the disease. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. Appropriate effective dosage also takes into account therapeutic factors such as the drug formulation, the individual's constitution, weight, age, disease progression, and administration site.

[0045] The fifth aspect of the present invention provides a system for inhibiting the activity, proliferation, migration, invasion and / or promoting apoptosis of liver cancer cells.

[0046] Furthermore, the system includes a treatment unit for treating liver cancer cells with an effective amount of the compound described in the first aspect of the present invention or a pharmaceutical composition comprising an effective amount of the compound described in the first aspect of the present invention.

[0047] Furthermore, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721.

[0048] Furthermore, the liver cancer cells are MHCC-97H.

[0049] In some specific embodiments, the system provided by the present invention includes a computer-readable storage medium for storing a computer-readable program or instructions, which, when executed by a processor, enable the therapeutic unit in the system of the present invention to perform its functions.

[0050] The sixth aspect of this invention provides the use of the compounds described in the first aspect of this invention in screening drugs for the treatment of liver cancer.

[0051] In some implementations, the compound described in the first aspect of the present invention can be used as a positive control to determine whether a drug to be screened has the effect of treating liver cancer.

[0052] The term "treatment" as used in this invention refers to medical management of a patient aimed at preventing, improving, stabilizing, or curing a disease, pathological state, or symptom. This term includes active therapy, i.e., treatment specifically aimed at improving a disease, pathological state, or symptom; etiological treatment, i.e., treatment aimed at eliminating the cause of a related disease, pathological state, or symptom; palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological state, or symptom; preventive treatment, i.e., treatment aimed at minimizing or partially or completely inhibiting the development of a related disease, pathological state, or symptom; and supportive treatment, i.e., treatment used to supplement another specific therapy aimed at improving a related disease, pathological state, or symptom.

[0053] The present invention also provides a method for treating liver cancer.

[0054] Furthermore, the method includes the following steps: administering the compound described in the first aspect of the present invention to a subject to treat liver cancer.

[0055] The term "subject" or "test animal" as used in this invention refers to any animal, including both human and non-human animals. The non-human animals include all vertebrates, such as mammals, including non-human primates (especially higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, bats, and any livestock or pets; as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0056] Advantages and beneficial effects of the present invention: This invention reveals for the first time the value of compound HCC-IN-919 in the treatment of liver cancer. This not only provides new ideas for the development of anti-liver cancer drugs, but also lays a solid foundation for new applications of compound HCC-IN-919 in the field of anti-cancer, and provides a reference for future drug development. Attached Figure Description

[0057] Figure 1 Here is a schematic diagram of the structure of compound HCC-IN-919; Figure 2 The image shows the results of mouse weight measurement. Figure 3 Image showing the results of tumor volume measurement; Figure 4 Image of the tumor tissue removed at the experimental endpoint. Detailed Implementation

[0058] The present invention will be further described below with reference to specific embodiments. However, the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention. Unless otherwise specified in the following embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments used, unless otherwise specified by the manufacturer, are all commercially available conventional products.

[0059] Example: Compound HCC-IN-919 for treating liver cancer 1. Experimental materials: Wild-type MHCC-97H cells were purchased from the National Model and Special Experimental Cell Resource Bank, catalog number SCSP-5092; NTG mice were purchased from Spiefol (Beijing) Biotechnology Co., Ltd.; corn oil was purchased from MedChemExpress, catalog number HY-Y1888; and the HCC-IN-919 compound was purchased from Taoshu Biotechnology Co., Ltd., catalog number ZINC000000701919, with the molecular structure as follows. Figure 1 As shown.

[0060] 2. Experimental methods: Six-week-old male NTG mice were selected and housed in an SPF-grade animal facility with free access to food and water. After one week of acclimatization, approximately 1×10⁻⁶ mice were... 6 Wild-type MHCC-97H cells were subcutaneously inoculated into the right abdomen of NTG mice to establish a liver cancer-bearing mouse model. Mice were randomly divided into a control group (corn oil) and a treatment group (HCC-IN-919), with 6 mice in each group. On day 3 and day 15, the control group received an intraperitoneal injection of a blank solvent (100 μL corn oil), while the treatment group received an intraperitoneal injection of HCC-IN-919 (100 μL corn oil containing 2 mg / mL HCC-IN-919, i.e., a total HCC-IN-919 concentration of 10 mg / kg). Tumor volume and body weight were measured every 3 days after injection, and tumor growth curves were plotted. At the experimental endpoint on day 27, all mice were sacrificed, the tumor tissue was completely dissected, and the tumor weight was measured and photographed.

[0061] 3. Experimental Results: Experimental results are as follows Figures 2-4As shown, compared with the control group, HCC-IN-919 treatment can significantly inhibit tumor growth without affecting the body weight of mice, indicating that the compound HCC-IN-919 has a good therapeutic effect on liver cancer.

[0062] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. A compound for treating liver cancer, characterized in that, The structural formula of the compound is shown in formula (I): Equation (I).

2. The compound according to claim 1, characterized in that, The compounds also include their pharmaceutically acceptable salts, pharmaceutically acceptable esters, isomers, polymorphs, solvates, and prodrugs.

3. The use of the compound according to claim 1 or 2 in the preparation of a medicament for treating liver cancer.

4. The application according to claim 3, characterized in that, The drug also includes a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier includes diluents, binders, surfactants, humectants, adsorbents, lubricants, fillers, and disintegrants.

5. The application according to claim 3, characterized in that, The dosage form of the drug is selected from any one of the following: injectable drugs, sprays, capsules, tablets, pills, granules, powders, and oral liquids; Preferably, the administration of the drug includes oral, subcutaneous, intravenous, intramuscular, intra-arterial, intrathecal, mucosal, and / or intraperitoneal injection.

6. The application according to claim 3, characterized in that, The drug also includes a second therapeutic agent; Preferably, the second therapeutic agent includes sorafenib, lenvatinib, regorafenib, cabozantinib, atezolizumab, bevacizumab, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, capecitabine, or paclitaxel.

7. The use of the compound of claim 1 or 2 in the preparation of a reagent for inhibiting the activity, proliferation, migration, invasion and / or promoting apoptosis of liver cancer cells in vitro; Preferably, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721; Preferably, the liver cancer cells are MHCC-97H.

8. A method for inhibiting the activity, proliferation, migration, invasion, and / or promoting apoptosis of liver cancer cells in vitro for non-therapeutic purposes, characterized in that, The method includes the following steps: treating liver cancer cells with an effective amount of the compound of claim 1 or 2 or a pharmaceutical composition comprising an effective amount of the compound of claim 1 or 2; Preferably, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721; Preferably, the liver cancer cells are MHCC-97H.

9. A system for inhibiting the activity, proliferation, migration, and invasion of liver cancer cells and / or promoting apoptosis of liver cancer cells, characterized in that, The system includes a treatment unit for treating liver cancer cells with an effective amount of the compound of claim 1 or 2 or a pharmaceutical composition comprising an effective amount of the compound of claim 1 or 2; Preferably, the liver cancer cells include MHCC-97H, MHCC-97L, HepG2, and SMMC-7721; Preferably, the liver cancer cells are MHCC-97H.

10. The use of the compound of claim 1 or 2 in screening drugs for the treatment of liver cancer.

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