WO2022245121A1 - Composition for preventing, relieving or treating cancer - Google Patents

Composition for preventing, relieving or treating cancer Download PDF

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Publication number
WO2022245121A1
WO2022245121A1 PCT/KR2022/007095 KR2022007095W WO2022245121A1 WO 2022245121 A1 WO2022245121 A1 WO 2022245121A1 KR 2022007095 W KR2022007095 W KR 2022007095W WO 2022245121 A1 WO2022245121 A1 WO 2022245121A1
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Prior art keywords
cancer
fluorouracil
pharmaceutical composition
present
leucovorin
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PCT/KR2022/007095
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French (fr)
Korean (ko)
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정재호
박기청
Original Assignee
연세대학교 산학협력단
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Publication of WO2022245121A1 publication Critical patent/WO2022245121A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a composition for preventing, improving or treating cancer.
  • Cancer is a disease that contributes to a significant number of deaths worldwide, with 9.6 million deaths due to cancer worldwide in 2018. In 1990, cancer was the third leading cause of death, but in 2018 it became the second leading cause of death after heart disease. Despite the increase in the progression rate and overall average survival rate due to the continuation of research on cancer, complete treatment of cancer is still impossible due to drug resistance to anticancer drugs.
  • Anticancer drugs used in chemotherapy are drugs that inhibit the growth or proliferation of cancer cells. It is largely classified as a cytotoxic anticancer agent, a targeted anticancer agent, and an immunotherapeutic agent. In order to select an anticancer agent according to the type of cancer, the degree of progression, and the condition of the patient, and to increase the effect, combination anticancer chemotherapy using two or more drugs at the same time is sometimes used. . Cytotoxic anti-cancer agents, known as first-generation anti-cancer agents, have anti-cancer effects by directly attacking indiscriminate and rapidly differentiating cells.
  • Targeted anti-cancer drugs act on specific proteins or specific genetic changes in cancer cells to block signal transduction involved in cancer growth and differentiation. Unlike cytotoxic anti-cancer drugs, it does not act on normal cells and acts specifically only on cancer cells, so there are few side effects.
  • cancer cells In order for chemotherapy for cancer patients to be successful, cancer cells must be killed at a blood concentration at which normal tissue can survive. refers to cases in which cancer cells do not die despite Anticancer drug resistance may vary from patient to patient and may even be caused by various factors including genetic differences between tumors derived from the same tissue. Each cancer cell derived from a patient can acquire different genetic characteristics, and shows diversity in gene expression as well as activation of tumor-inducing factors and inactivation of tumor suppressors by 'mutation'. As a result, all cancers express anticancer drug resistance genes in different patterns, and cells within a single cancer mass acquire diversity for drug resistance.
  • MDR multi-drug resistance
  • One object of the present invention is to provide a composition for combined administration for the prevention, improvement or treatment of cancer.
  • Another object of the present invention is to provide a composition for preventing, improving or treating cancer.
  • Another object of the present invention is to provide a method for preventing, improving or treating cancer.
  • One embodiment of the present invention provides a pharmaceutical composition for concomitant administration for the prevention or treatment of cancer.
  • the pharmaceutical composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S )-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[ a] phenanthrene-3,5,6,15-tetraol; MarinLit-13631 [Chemical ID]) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • the pharmaceutically acceptable salt is a salt generally regarded by those skilled in the art as being suitable for medical applications (eg, because such a salt is not harmful to a subject that can be treated with the salt), or each salts that cause acceptable side effects within the treatment of
  • the pharmaceutically acceptable salt is a salt that is considered acceptable by regulatory authorities such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare.
  • FDA US Food and Drug Administration
  • EMA European Medicines Agency
  • PMDA Pharmaceuticals and Medical Devices Agency
  • the present invention in principle relates to, for example, an intermediate in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof.
  • salts of the compounds according to the invention which are not pharmaceutically acceptable per se are also included.
  • the salts include water-insoluble salts and, in particular, water-soluble
  • the person skilled in the art can determine whether a particular compound according to the present invention or a physiologically functional derivative thereof can form a salt, i.e., whether said compound according to the present invention or a physiologically functional derivative thereof
  • it can be easily determined whether or not it has a group capable of carrying an electric charge, such as an amino group, a carboxylic acid group, and the like.
  • Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceutics, which are water insoluble or particularly water soluble acid addition salts. It is salt. Depending on the substituents of the compounds of this invention, salts with bases may also be suitable. Acid addition salts are formed, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be formed by mixing.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be
  • pharmaceutically acceptable base addition salts include alkali metal salts (eg sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included.
  • alkali metal salts eg sodium or potassium salts
  • alkaline earth metal salts eg, calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulf
  • Illustrative examples of pharmaceutically acceptable salts include acetates, adipates, alginates, arginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxyna
  • Salts which are not pharmaceutically acceptable in the present invention and which can be obtained, for example, as process products during the preparation of the compounds according to the present invention on an industrial scale, are also included in the present invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by the method.
  • the cancer of the present invention may be resistant, recurrent or metastatic cancer.
  • the cancer may be resistant to anticancer drug treatment, or metastasis or recurrence after treatment.
  • the type of the anticancer agent is not particularly limited and may be any type of anticancer agent, but, for example, nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib , vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept
  • the cancer of the present invention is colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, bladder cancer, blood cancer, pancreatic cancer , It may be any one or more selected from the group consisting of prostate cancer, thyroid cancer, endocrine cancer, oral cancer and liver cancer, for example, it may be colorectal cancer, but is not limited thereto.
  • the compound represented by Formula 1 of the present invention may be administered in combination with an anticancer agent to enhance the activity of the anticancer agent.
  • an anticancer agent to enhance the activity of the anticancer agent.
  • oxalaplatin which is a type of anticancer agent
  • the activity of the anticancer agent can be effectively enhanced in drug-resistant, recurrent or metastatic cancer, thereby reducing the size and weight of the tumor very effectively. confirmed what was possible.
  • the anticancer agent of the present invention may include any drug capable of preventing or treating cancer by enhancing its activity by the compound represented by Formula 1 of the present invention, wherein the type of the drug is not particularly limited and all types of anticancer agent can be For example, nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib , cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, afliber sept, regorafenib, viscum album, asparaginase,
  • prevention of the present invention means any action that suppresses or delays the onset of a disease or condition.
  • the composition is used together with an anticancer agent to delay the onset of cancer or to inhibit the onset of cancer.
  • treatment of the present invention refers to any action that delays, stops, or reverses the progression of a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to stop, reduce, alleviate or reverse the progression of cancer. It means to eliminate or reverse.
  • the pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.
  • the pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc.
  • a buffer, a preservative, A pain reliever, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used.
  • the formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above.
  • the pharmaceutically acceptable carrier for example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have.
  • it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
  • Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, This includes sublingual or rectal. Oral or parenteral administration is preferred.
  • the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition may be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may be variously varied, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug type, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg.
  • Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
  • Another embodiment of the present invention provides a food composition for concomitant intake for the prevention or improvement of cancer.
  • the food composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S )-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[ a] phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • the contents related to the compound represented by Formula 1, pharmaceutically acceptable salt, cancer, anticancer agent, etc. are the same as described above, and thus the description thereof is omitted.
  • the "improvement" of the present invention refers to any action that improves or beneficially changes a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to improve symptoms of cancer.
  • the food composition of the present invention may be prepared in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread.
  • the amount may be added in an amount of 0.1 to 50% of the total weight, but is not limited thereto.
  • the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except that the food composition is included in the indicated ratio, and as in conventional beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients.
  • natural carbohydrates common sugars such as monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol, etc.
  • the flavoring agent may include natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • natural flavoring agents taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjusting agent, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like may be further included.
  • Components included in the food composition of the present invention may be used independently or in combination.
  • the ratio of the additives does not correspond to the core elements of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
  • Another embodiment of the present invention provides a composition for preventing, improving or treating cancer.
  • composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S) -6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • the composition may further include an anticancer agent whose activity is enhanced by the compound represented by Formula 1 of the present invention and which can prevent or treat cancer
  • the anticancer agent is, for example, nitrogen mustard, Imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, lestaurtinib, Trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept, regorafenib, viscum albumin, asparaginase, tretinoin, hydroxycarbamide,
  • the compound and the anticancer agent may be used in a ratio of 1:0.001 to 1:1000, preferably 1:0.01 to 1:100, and more preferably 1:0.1 to 1:10, but are limited thereto It is not.
  • the ratio may be a molar concentration ratio or a weight ratio, but is not limited thereto.
  • composition for preventing, improving or treating cancer of the present invention descriptions of the compounds represented by Formula 1, pharmaceutically acceptable salts, and cancers overlap with those described above, so detailed descriptions thereof are omitted.
  • prevention of the present invention means any action that suppresses or delays the onset of a disease or condition.
  • the composition is used together with an anticancer agent to delay the onset of cancer or to inhibit the onset of cancer.
  • the "improvement" of the present invention refers to any action that improves or beneficially changes a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to improve symptoms of cancer.
  • treatment of the present invention refers to any action that delays, stops, or reverses the progression of a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to stop, reduce, alleviate or reverse the progression of cancer. It means to eliminate or reverse.
  • composition of the present invention may be used as a pharmaceutical composition or a food composition, and the form is not particularly limited.
  • the pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.
  • the pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc.
  • a buffer, a preservative, A pain reliever, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used.
  • the formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above.
  • the pharmaceutically acceptable carrier for example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have.
  • it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
  • Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, This includes sublingual or rectal. Oral or parenteral administration is preferred.
  • the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition may be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may be variously varied, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug type, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg.
  • Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
  • the food composition of the present invention may be prepared in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread.
  • the amount may be added in an amount of 0.1 to 50% of the total weight, but is not limited thereto.
  • the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except that the food composition is included in the indicated ratio, and as in conventional beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients.
  • natural carbohydrates common sugars such as monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol, etc.
  • the flavoring agent may include natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • natural flavoring agents taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjusting agent, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like may be further included.
  • Components included in the food composition of the present invention may be used independently or in combination.
  • the ratio of the additives does not correspond to the core elements of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
  • the compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17 to a subject in need of administration -((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)
  • a method for preventing or treating cancer comprising administering an effective amount of hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof:
  • the contents of the compound represented by Formula 1, the pharmaceutically acceptable salt, and the cancer are the same as described above, and thus are omitted to avoid excessive complexity in the present specification.
  • the "administration" means providing a given compound of the present invention to a subject by any suitable method.
  • the "subject" in need of the administration may include both mammals and non-mammals.
  • the mammal include humans, non-human primates such as chimpanzees, other apes or monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domesticated animals such as rabbits, dogs or cats; Laboratory animals, such as rodents, such as rats, mice, or guinea pigs may be included, but are not limited thereto.
  • examples of the non-mammals in the present invention may include birds or fish, but are not limited thereto.
  • the formulation of the compound administered as described above is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and a liquid formulation for oral or parenteral administration immediately before use. It can be administered in solid form preparations intended to be converted into, for example, oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions. However, it is not limited thereto.
  • a pharmaceutically acceptable carrier may be additionally administered together with the compound of the present invention during the administration.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffer, Preservatives, analgesics, solubilizers, tonicity agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used.
  • Formulations of the compound of the present invention can be variously prepared by mixing with the pharmaceutically acceptable carriers described above.
  • it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have.
  • it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, and the like can be used.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
  • Routes of administration of the compounds according to the present invention are, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work included. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • “pharmaceutically effective amount” refers to a sufficient amount of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in a biological system.
  • an “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease.
  • An “effective” amount suitable in any individual case can be determined by one skilled in the art using routine experimentation.
  • the expression “effective amount” generally refers to an amount of an active substance that has a therapeutic effect.
  • the active substance is a growth inhibitor of cancer cells, and a preventive, ameliorative or therapeutic agent for cancer.
  • the compounds of the present invention vary depending on a number of factors, including the activity of the specific compound used, age, body weight, general health, sex, dosage, time of administration, route of administration, excretion rate, drug formulation, and severity of the specific disease to be prevented or treated.
  • the dosage of the compound may vary, depending on the patient's condition, body weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 100 mg/kg or 0.001 to 0.001 mg/kg per day. It can be administered at 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
  • the compounds according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries and suspensions.
  • the compounds of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
  • the compound of the present invention may be further used in combination with other anticancer agents, wherein the anticancer agents include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, and bande Tanib, Nirotinib, Semasanib, Bosutinib, Axitinib, Cediranib, Lestaurtinib, Trastuzumab, Gefitinib, Bortezomib, Sunitinib, Carboplatin, Sorafenib, Bevacizumab, Cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumabozogamicin, ibritumomabtucetan, heptaplatin, methylamino
  • the anticancer effect can be significantly improved, as well as in a significantly smaller amount than the amount of the previously used anticancer drug. It can also induce the same anticancer effect, reducing side effects caused by taking anticancer drugs. Furthermore, anticancer drug-resistant cancer, or recurrence or metastasis after anticancer drug treatment can be effectively prevented, improved, or treated.
  • Figure 1 shows the results of confirming the gene expression changes of HT29, YUMC-C1 and YUMC-C2 cell lines according to an embodiment of the present invention through microarray analysis.
  • Figure 2 is a graph showing the results of measuring the size change of tumors according to drug administration according to an embodiment of the present invention.
  • Figure 3 is a graph showing the results of measuring the change in pure tumor weight according to drug administration according to an embodiment of the present invention.
  • One embodiment of the present invention relates to a pharmaceutical composition for combined administration comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another embodiment of the present invention relates to a food composition for concomitant consumption comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another embodiment of the present invention relates to a composition for preventing, improving or treating cancer, comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another embodiment of the present invention relates to a method for preventing, improving or treating cancer, comprising administering an effective amount of a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof to a subject in need of administration. .
  • the cells were resuspended in RPMI-1640 (UTC, UT, South Logan, UT) medium with 10% fetal bovine serum (Hyclone) and 2% penicillin/streptomycin solution (Gibco, Grand Island, NY, USA), and It was cultured using ⁇ 15% Fetal Bovine Serum RPMI-1640 medium.
  • Patient 1 (YUMC-C1 cell line)
  • Patient 2 (YUMC-C2 cell line) age 71 63 gender female male primary disease location colon colon step IVc IVc primary pathology
  • Colorectal cancer (recurrence and metastasis after FOLFOX*)
  • Colorectal cancer (recurrence and metastasis after FOLFOX) Classification of Specimens Used for Culture fresh tumor fresh tumor where you got it Severance Hospital (Seoul, Korea) Severance Hospital (Seoul, Korea) * FOLFOX: triple combination administration of Folinic acid, Fluorouracil (5-FU) and Oxaliplatin in colorectal cancer
  • the expression of genes expressed in the YUMC-C1 cell line and YUMC-C2 cell line of Example 1 was compared with that of the colorectal cancer cell line HT29 cell line.
  • RNA purity and integrity were measured using an ND-1000 spectrophotometer (NanoDrop) and an Agilent 2100 Bioanalyzer (Agilent Technologies).
  • RNA labeling and hybridization were performed using the Agilent One-Color Microarray-Based Gene Expression Analysis protocol (Agilent Technology, V 6.5, 2010).
  • 100 ng of total RNA from each sample was linearly amplified and labeled with Cy3-dCTP, and the labeled cRNA was purified using RNAeasy Mini Kit (Qiagen).
  • the concentration and specific activity of the labeled cRNA was measured using a NanoDrop ND-1000.
  • each labeled cRNA was fragmented by adding 5 ⁇ l 10x blocking agent and 1 ⁇ l of 25X fragmentation buffer, followed by heating at 60° C. for 30 minutes. Finally, 25 ⁇ l of 2X GE Hybridization Buffer was added to dilute the labeled cRNA. 40 ⁇ l of the hybridization solution was dispensed on a gasket slide and processed on Agilent SurePrint G3 Human GE 8X60K, V3 Microarrays (Agilent®). Raw data was obtained using Agilent Feature Extraction Software (v11.0.1.1), and then a file was created using the Agilent feature extraction protocol to obtain raw data for each gene. expression information was available.
  • the YUMC-C1 and YUMC-C2 cell lines of the present invention have the characteristics of recurrent and metastatic colorectal cancer cell lines.
  • Example 1 After culturing YUMC-C1 and YUMC-C2 cell lines (4.5 X 10 6 cells/mouse) of Example 1 in vitro, 6-week-old female BALB/c nude, NOD/Shi-scid, IL-2R ⁇ KOJic (NOG) The mouse was injected subcutaneously in the upper left flank region.
  • the results are shown in FIG. 3 .
  • the control group Control
  • the anticancer effect can be significantly improved, and the amount of the previously used anticancer drug is higher than that of the anticancer drug.
  • the same anticancer effect can be induced even in a remarkably small amount, so side effects caused by taking anticancer drugs can be reduced.
  • composition according to the present invention can not only inhibit the growth of cancer cells, but also can remarkably improve the anticancer effect when used in combination with the anticancer drug when resistant to an anticancer drug, so it is very effective in preventing, improving or treating cancer. can be used

Abstract

A compound represented by formula 1 according to the present invention can not only significantly improve anticancer effects when used in combination with an anticancer drug when resistance to the anticancer drug is exhibited, but can also induce the same anticancer effects even when used in a significantly smaller amount than conventional anticancer drugs, and thus can reduce side effects caused by the administration of anticancer drugs.

Description

암의 예방, 개선 또는 치료용 조성물Composition for preventing, improving or treating cancer
본 발명은 암의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating cancer.
암은 전 세계적으로 상당한 수의 사망에 기여하는 질환으로서, 2018년 전 세계적으로 암에 인한 사망은 960만명에 해당하였다. 1990년에는 암이 사망의 원인으로 3번째에 해당하였으나, 2018년에는 심장 질환 다음으로 가장 높은 사망 원인으로 등극하였다. 암에 대한 연구의 지속으로 인하여 진행률 및 전체 평균 생존율이 증가하였음에도 불구하고, 항암제에 대한 약물 내성으로 인하여 아직까지도 암은 완전한 치료가 불가능한 상황이다.Cancer is a disease that contributes to a significant number of deaths worldwide, with 9.6 million deaths due to cancer worldwide in 2018. In 1990, cancer was the third leading cause of death, but in 2018 it became the second leading cause of death after heart disease. Despite the increase in the progression rate and overall average survival rate due to the continuation of research on cancer, complete treatment of cancer is still impossible due to drug resistance to anticancer drugs.
항암 화학 요법에 사용되는 항암제는 암세포의 발육이나 증식을 억제하는 약물이다. 크게 세포독성항암제, 표적항암제, 면역항암제로 분류되며, 암의 종류나 진행 정도, 환자의 상태 등에 따라 항암제를 선택하고 효과를 높이기 위해 2가지 이상의 약제를 동시에 사용하는 복합 항암 화학 요법이 사용되기도 한다. 1세대 항암제로 알려져 있는 세포독성항암제는 무분별하고 빠르게 분화하는 세포를 직접 공격하여 항암효과를 가진다. 다만, 모근세포와 같이 빠르게 분화하는 특성을 가진 정상세포들도 세포독성항암제에 의해 공격받기 때문에 백혈구 감소, 탈모, 구토, 설사 등의 부작용을 일으키는 단점이 있다. 2세대 항암제로 알려져 있는 표적항암제는 암세포에 나타나는 특정 단백질이나 특정 유전자 변화에 작용하여 암의 성장과 분화에 관여하는 신호전달을 차단한다. 세포독성항암제와는 달리 정상세포에는 작용하지 않으며 암세포에만 특이적으로 작용하여 부작용이 적은 편이다.Anticancer drugs used in chemotherapy are drugs that inhibit the growth or proliferation of cancer cells. It is largely classified as a cytotoxic anticancer agent, a targeted anticancer agent, and an immunotherapeutic agent. In order to select an anticancer agent according to the type of cancer, the degree of progression, and the condition of the patient, and to increase the effect, combination anticancer chemotherapy using two or more drugs at the same time is sometimes used. . Cytotoxic anti-cancer agents, known as first-generation anti-cancer agents, have anti-cancer effects by directly attacking indiscriminate and rapidly differentiating cells. However, since normal cells with rapidly differentiating characteristics, such as hair follicle cells, are also attacked by cytotoxic anticancer agents, there are disadvantages of causing side effects such as leukocyte reduction, hair loss, vomiting, and diarrhea. Targeted anti-cancer drugs, known as second-generation anti-cancer drugs, act on specific proteins or specific genetic changes in cancer cells to block signal transduction involved in cancer growth and differentiation. Unlike cytotoxic anti-cancer drugs, it does not act on normal cells and acts specifically only on cancer cells, so there are few side effects.
그러나 항암 화학 요법을 사용하는데 장애가 되는 요소 중 하나는 항암제 내성을 일으킨다는 점이다. 암환자에 대한 항암 화학 요법이 성공하기 위해서는 정상조직이 살아남을 수 있는 혈중농도에서 암세포가 살해되어야 하는데, 항암제에 대한 약제 내성은 암세포를 죽일 수 있는 혈중농도에 도달할 수 있는 양의 항암제를 투여했음에도 불구하고 암세포가 죽지 않는 경우를 말한다. 항암제 내성은 환자 개개인에 따라 다를 수 있으며 심지어 같은 조직으로부터 유래된 종양들 사이의 유전적 차이 등을 포함한 다양한 인자들에 의해 유발될 수 있다. 한 환자로부터 유래된 각각의 암세포들은 다른 유전적 특성을 획득할 수 있으며 '돌연변이현상'에 의해 유전자 발현의 다양성뿐만 아니라 종양유발인자의 활성화와 종양억제인자의 불활성화 등을 보이게 된다. 그 결과 모든 암은 다른 패턴으로 항암제 내성 유전자를 발현하며, 하나의 암 덩어리 안에 있는 세포들은 약제 내성에 대한 다양성을 획득하게 된다. 또한 종양들이 특정 항암치료에 기본적으로 내성을 가지고 있지 않더라도 일단 항암제에 노출되면 이런 다양성을 바탕으로 선별적으로 내성 세포들이 자라나게 되고 결국 많은 암세포들이 빠르게 항암제 내성을 가지게 된다. 이러한 경우에 세포내 또 다른 표적물질들을 갖는 다수의 약제들을 사용하면 효과적으로 치료할 수 있고 완치율을 높일 수 있다. 그러나 많은 경우에 있어서 세포들은 구조적으로나 기능적으로 완전히 다른 약제들에 대해서 동시에 내성을 보이곤 한다. 이러한 현상을 다중 약물 내성(MDR, multi drug resistance)이라고 하며 항암제의 제한적인 흡수, 증가된 방출 또는 세라마이드와 같은 막 지질들의 변화 등을 통해 세포내 약제의 축적을 제한함으로써 유발된다. 다중 약물 내성은 대부분의 항암제에 의해 유도되는 세포 사멸(apoptosis)을 저해하고, DNA 손상의 복구와 약제의 비독성화를 유발시키며 세포주기를 변화시킴으로서 세포에 항암제에 대한 내성을 추가로 부여할 수 있다.However, one of the obstacles to the use of chemotherapy is that it causes resistance to chemotherapy. In order for chemotherapy for cancer patients to be successful, cancer cells must be killed at a blood concentration at which normal tissue can survive. refers to cases in which cancer cells do not die despite Anticancer drug resistance may vary from patient to patient and may even be caused by various factors including genetic differences between tumors derived from the same tissue. Each cancer cell derived from a patient can acquire different genetic characteristics, and shows diversity in gene expression as well as activation of tumor-inducing factors and inactivation of tumor suppressors by 'mutation'. As a result, all cancers express anticancer drug resistance genes in different patterns, and cells within a single cancer mass acquire diversity for drug resistance. In addition, even if tumors are not basically resistant to a specific anticancer treatment, once exposed to an anticancer drug, resistant cells selectively grow based on this diversity, and eventually many cancer cells quickly develop anticancer drug resistance. In this case, the use of multiple drugs having other intracellular target substances can effectively treat and increase the cure rate. In many cases, however, cells are simultaneously resistant to drugs that are structurally and functionally completely different. This phenomenon is called multi-drug resistance (MDR) and is caused by limiting the accumulation of intracellular drugs through limited uptake of anticancer drugs, increased release, or changes in membrane lipids such as ceramide. Multi-drug resistance inhibits cell death (apoptosis) induced by most anticancer drugs, induces DNA damage repair and drug detoxification, and alters the cell cycle, thereby conferring additional resistance to anticancer drugs to cells. .
암세포를 사멸시킬 수 있을 뿐만 아니라, 항암제 내성을 갖는 암세포의 사멸을 유도할 수 있는 새로운 항암제의 개발이 요구된다.There is a need for the development of new anticancer agents capable of inducing the death of cancer cells having anticancer drug resistance as well as killing cancer cells.
본 발명의 일 목적은 암의 예방, 개선 또는 치료를 위한 병용 투여용 조성물을 제공하는 것이다.One object of the present invention is to provide a composition for combined administration for the prevention, improvement or treatment of cancer.
본 발명의 다른 목적은 암의 예방, 개선 또는 치료를 위한 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for preventing, improving or treating cancer.
본 발명의 또 다른 목적은 암의 예방, 개선 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing, improving or treating cancer.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명의 일 구현 예에서는 암의 예방 또는 치료를 위한 병용 투여용 약학 조성물을 제공한다.One embodiment of the present invention provides a pharmaceutical composition for concomitant administration for the prevention or treatment of cancer.
본 발명의 상기 약학 조성물은 하기 화학식 1로 표시되는 화합물((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol; MarinLit-13631[Chemical ID]) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함한다:The pharmaceutical composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S )-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[ a] phenanthrene-3,5,6,15-tetraol; MarinLit-13631 [Chemical ID]) or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Formula 1]
Figure PCTKR2022007095-appb-img-000001
Figure PCTKR2022007095-appb-img-000001
본 발명에서 상기 약학적으로 허용되는 염은, 의학적 적용에 적합한 것으로 당업자에 의해 일반적으로 간주되는 염(예를 들어 이러한 염이 상기 염으로 치료될 수 있는 대상체에게 유해하지 않기 때문임), 또는 각각의 치료 내에서 허용 가능한 부작용을 야기하는 염이다. 일반적으로, 상기 약학적으로 허용되는 염은 미국 식품 의약국(FDA), 유럽 의약청(EMA), 또는 일본 후생성의 의약품 의료기기 종합기구(PMDA)와 같은 규제 당국에 의해 허용되는 것으로 간주되는 염이다. 그러나, 본 발명은 원칙적으로, 예를 들어 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체, 또는 본 발명에 따른 화합물의 약학적으로 허용되는 염 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체로서, 그 자체로는 약학적으로 허용되지 않는 본 발명에 따른 화합물의 염을 또한 포함한다. 상기 염은 수불용성 염을 포함하고, 특히, 수용성 염을 포함한다.In the present invention, the pharmaceutically acceptable salt is a salt generally regarded by those skilled in the art as being suitable for medical applications (eg, because such a salt is not harmful to a subject that can be treated with the salt), or each salts that cause acceptable side effects within the treatment of Generally, the pharmaceutically acceptable salt is a salt that is considered acceptable by regulatory authorities such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare. . However, the present invention in principle relates to, for example, an intermediate in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof. As intermediates in the preparation of derivatives, salts of the compounds according to the invention which are not pharmaceutically acceptable per se are also included. The salts include water-insoluble salts and, in particular, water-soluble salts.
각각의 경우에, 당업자는 본 발명에 따른 특정 화합물 또는 그의 생리학적으로 작용성인 유도체가 염을 형성할 수 있는지 여부, 즉, 상기 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체가, 예를 들어 아미노 기, 카르복실산 기 등과 같은 전하를 띨 수 있는 기를 가지는지 여부를 쉽게 결정할 수 있다.In each case, the person skilled in the art can determine whether a particular compound according to the present invention or a physiologically functional derivative thereof can form a salt, i.e., whether said compound according to the present invention or a physiologically functional derivative thereof For example, it can be easily determined whether or not it has a group capable of carrying an electric charge, such as an amino group, a carboxylic acid group, and the like.
본 발명의 화합물의 예시적인 염은 산 부가 염 또는 염기와의 염, 특히 약학적으로 허용되는 무기산 및 유기산 부가 염 및 약학에서 통상적으로 사용되는 염기와의 염이며, 이는 수불용성 또는 특히 수용성 산 부가 염이다. 본 발명의 화합물의 치환기에 따라 염기와의 염이 또한 적합할 수 있다. 산 부가 염은, 예를 들어, 본 발명의 화합물의 용액을 염산, 황산, 푸마르산, 말레산, 석신산, 아세트산, 벤조산, 시트르산, 타르타르산, 탄산 또는 인산과 같은 약학적으로 허용되는 산의 용액과 혼합함으로써 형성될 수 있다. 마찬가지로, 약학적으로 허용되는 염기 부가 염은 알칼리 금속염(예를 들어, 나트륨 또는 칼륨 염); 알칼리 토금속 염(예를 들어, 칼슘 또는 마그네슘 염); 및 적합한 유기 리간드로 형성된 염(예를 들어, 할라이드, 하이드록사이드, 카복실레이트, 설페이트, 포스페이트, 니트레이트, 알킬 설포네이트 및 아릴 설포네이트와 같은 반대 음이온을 사용하여 형성된 암모늄, 4차 암모늄 및 아민 양이온)을 포함할 수 있다. 약학적으로 허용되는 염의 예시적인 예로는 아세테이트, 아디페이트, 알기네이트, 아르기네이트, 아스코르베이트, 아스파테이트, 벤젠설포네이트, 벤조에이트, 바이카르보네이트, 바이설페이트, 바이타르트레이트, 보레이트, 브로마이드, 부티레이트, 칼슘 에데테이트, 캄포레이트, 캄포설포네이트, 캄실레이트, 카르보네이트, 클로라이드, 시트레이트, 디글루코네이트, 디하이드로클로라이드, 도데실설페이트, 에데테이트, 에디실레이트, 에탄설포네이트, 포르메이트, 푸마레이트, 갈락테이트, 갈락투로네이트, 글루코네이트, 글루타메이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 헥실레소르시네이트, 하이드로브로마이드, 하이드로클로라이드, 하이드로요오다이드, 2-하이드록시-에탄설포네이트, 하이드록시나프토에이트, 요오다이드, 이소부티레이트, 이소티오네이트, 락테이트, 라우레이트, 라우릴 설페이트, 말레이트, 말레에이트, 말로네이트, 만델레이트, 메탄설포네이트(메실레이트), 메틸설페이트, 2-나프탈렌설포네이트, 니코티네이트, 니트레이트, 올레에이트, 옥살레이트, 팔미테이트, 판토테네이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 포스페이트/디포스페이트, 프탈레이트, 피크레이트, 피발레이트, 폴리갈락투로네이트, 프로피오네이트, 살리실레이트, 스테아레이트, 설페이트, 수베레이트, 석시네이트, 탄네이트, 타르트레이트, 토실레이트, 운데카노에이트, 발레레이트 등이 포함되지만 이로 한정되지 않는다.Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceutics, which are water insoluble or particularly water soluble acid addition salts. It is salt. Depending on the substituents of the compounds of this invention, salts with bases may also be suitable. Acid addition salts are formed, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included. Illustrative examples of pharmaceutically acceptable salts include acetates, adipates, alginates, arginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methane Sulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate and the like, but are not limited thereto.
본 발명에서 약학적으로 허용되지 않으며, 예를 들어, 산업적 규모로 본 발명에 따른 화합물을 제조하는 동안 공정 생성물로서 수득될 수 있는 염이 또한 본 발명에 포함되고, 요망되는 경우, 이는 당업자에게 알려진 방법에 의해 약학적으로 허용되는 염으로 전환될 수 있다.Salts which are not pharmaceutically acceptable in the present invention and which can be obtained, for example, as process products during the preparation of the compounds according to the present invention on an industrial scale, are also included in the present invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by the method.
본 발명의 상기 암은 내성, 재발성 또는 전이성을 갖는 암일 수 있다. 본 발명의 목적상 상기 암은 항암제 치료에 대하여 내성을 갖거나, 치료 이후 전이 또는 재발된 암일 수 있다. 여기서 상기 항암제의 종류는 특별히 제한하지 않으며 모든 종류의 항암제일 수 있으나, 예를 들면, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상일 수 있고, 바람직하게는 세툭시맙, 파니투무맙, 이리노테칸, 비노렐빈, 카페시타빈, 류코보린, 옥살리플라틴, 시스플라틴, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 아플리베르셉트 및 레고라페닙으로 이루어지는 군에서 선택된 1종 이상의 항암제일 수 있고, 보다 바람직하게는 5-플루오로우라실 (5-FU), 류코보린 (폴리닌산) 및 옥살리플라틴을 포함하는 FOLFOX 체제; 폴리닌산 (류코보린), 플루오로우라실 (5-FU) 및 이리노테칸을 포함하는 FOLFIRI 체제; 또는 카페시타빈 및 옥살리플라틴을 포함하는 CAPOX 체제일 수 있으나, 이에 제한되는 것은 아니다.The cancer of the present invention may be resistant, recurrent or metastatic cancer. For the purpose of the present invention, the cancer may be resistant to anticancer drug treatment, or metastasis or recurrence after treatment. Here, the type of the anticancer agent is not particularly limited and may be any type of anticancer agent, but, for example, nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib , vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept, regorafenib, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumabozo Gamycin, ibritumomabtusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed , tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, Thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferonalpha-2a, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, tenipo Seed, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolo amide, 5-fluorouracil, busulfan, ifosfamide, cyclophosphamide, melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemestane, aminoglutesimide, anagrelide, navelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, and carmustine It may be one or more selected from the group consisting of, preferably cetuximab, panitumumab, irinotecan, vinorelbine, capecitabine, leucovorin, oxaliplatin, cisplatin, carboplatin, 5-fluoroura It may be at least one anticancer agent selected from the group consisting of sil (5-FU), bevacizumab, aflibercept, and regorafenib, more preferably 5-fluorouracil (5-FU), leucovorin (poly FOLFOX system, including ninic acid) and oxaliplatin; the FOLFIRI regime, which includes polyninic acid (leucovorin), fluorouracil (5-FU) and irinotecan; or a CAPOX system including, but not limited to, capecitabine and oxaliplatin.
본 발명의 상기 암은 대장암, 유방암, 자궁암, 나팔관암, 난소암, 위암, 뇌암, 직장암, 소장암, 직장암, 식도암, 임파선암, 담낭암, 폐암, 피부암, 신장암, 방광암, 혈액암, 췌장암, 전립선암, 갑상선암, 내분비선암, 구강암 및 간암으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것일 수 있고, 예를 들면, 대장암일 수 있으나, 이에 제한되는 것은 아니다.The cancer of the present invention is colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, bladder cancer, blood cancer, pancreatic cancer , It may be any one or more selected from the group consisting of prostate cancer, thyroid cancer, endocrine cancer, oral cancer and liver cancer, for example, it may be colorectal cancer, but is not limited thereto.
본 발명의 상기 화학식 1로 표시되는 화합물은 항암제와 병용 투여되어 항암제의 활성을 증진시키는 것일 수 있다. 본 발명의 일 실시예에서는 항암제의 한 종류인 옥살라플라틴과 병용하여 투여함으로써, 약물 내성, 재발성 또는 전이성을 갖는 암에서 항암제의 활성을 효과적으로 증진시켜 종양의 크기 및 무게를 매우 효과적으로 감소시킬 수 있는 것을 확인하였다.The compound represented by Formula 1 of the present invention may be administered in combination with an anticancer agent to enhance the activity of the anticancer agent. In one embodiment of the present invention, by administering in combination with oxalaplatin, which is a type of anticancer agent, the activity of the anticancer agent can be effectively enhanced in drug-resistant, recurrent or metastatic cancer, thereby reducing the size and weight of the tumor very effectively. confirmed what was possible.
본 발명의 상기 항암제는 본 발명의 상기 화학식 1로 표시되는 화합물에 의해 활성이 증진되어 암을 예방 또는 치료할 수 있는 약물이라면 모두 포함될 수 있고, 여기서 상기 약물의 종류는 특별히 제한하지 않으며 모든 종류의 항암제일 수 있다. 예를 들면, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상일 수 있고, 바람직하게는 파클리탁셀, 인터페론알파-2a, 카보플라틴, 독소루비신, 시스플라틴, 젬시타빈, 5-플루오로우라실, 세툭시맙, 류코보린, 이리노테칸, 옥살라플라틴, 카페시타빈, 도세탁셀 및 이의 혼합물로 이루어진 군으로부터 선택되는 어느 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.The anticancer agent of the present invention may include any drug capable of preventing or treating cancer by enhancing its activity by the compound represented by Formula 1 of the present invention, wherein the type of the drug is not particularly limited and all types of anticancer agent can be For example, nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib , cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, afliber sept, regorafenib, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtucetan, heptaplatin, methylaminolevulinic acid , Amsacrine, Alemtuzumab, Procarbazine, Alprostadil, Holmium Nitrate Chitosan, Gemcitabine, Doxifluridine, Pemetrexed, Tegapur, Capecitabine, Gimeracin, Oteracil, Azacity Dean, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferon Alpha-2a, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin , bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, 5-fluorouracil, busulfan, ifosfamide, cyclophospha Mead, melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutecimide, anagrelide, navelbine, It may be at least one selected from the group consisting of fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine and carmustine, preferably paclitaxel and interferon alpha -2a, carboplatin, doxorubicin, cisplatin, gemcitabine, 5-fluorouracil, cetuximab, leucovorin, irinotecan, oxalaplatin, capecitabine, docetaxel and mixtures thereof It may be any one selected, but is not limited thereto.
본 발명의 상기 "예방"은 질병 또는 병증의 발병을 억제하거나 지연시키는 모든 행위를 의미한다. 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 발병 시기를 지연시키거나, 발병을 억제하는 것을 의미한다.The above "prevention" of the present invention means any action that suppresses or delays the onset of a disease or condition. For the purpose of the present invention, the composition is used together with an anticancer agent to delay the onset of cancer or to inhibit the onset of cancer.
본 발명의 상기 "치료"는 질병 또는 병증의 진행을 지연, 중단 또는 역전시키는 모든 행위를 의미하는 것으로서, 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 진행을 중단, 경감, 완화 또는 없애거나 역전시키는 것을 의미한다.The "treatment" of the present invention refers to any action that delays, stops, or reverses the progression of a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to stop, reduce, alleviate or reverse the progression of cancer. It means to eliminate or reverse.
본 발명의 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. The pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.
본 발명의 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있고, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다.The pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffer, a preservative, A pain reliever, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used.
본 발명의 상기 약학 조성물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(Elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화 할 수 있다.The formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have. In addition, it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
본 발명의 상기 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
본 발명의 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. 본 발명에서 상기 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입 기술을 포함한다. 또한, 상기 약학 조성물은 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, This includes sublingual or rectal. Oral or parenteral administration is preferred. In the present invention, the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In addition, the pharmaceutical composition may be administered in the form of a suppository for rectal administration.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may be variously varied, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug type, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
본 발명의 다른 구현 예에서는 암의 예방 또는 개선을 위한 병용 섭취용 식품 조성물을 제공한다.Another embodiment of the present invention provides a food composition for concomitant intake for the prevention or improvement of cancer.
본 발명의 상기 식품 조성물은 하기 화학식 1로 표시되는 화합물((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함한다:The food composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S )-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[ a] phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Formula 1]
Figure PCTKR2022007095-appb-img-000002
Figure PCTKR2022007095-appb-img-000002
본 발명의 상기 식품 조성물에서, 화학식 1로 표시되는 화합물, 약학적으로 허용 가능한 염, 암, 항암제 등과 관련된 내용은 앞서 기재된 바와 동일하여 그 기재를 생략한다.In the food composition of the present invention, the contents related to the compound represented by Formula 1, pharmaceutically acceptable salt, cancer, anticancer agent, etc. are the same as described above, and thus the description thereof is omitted.
본 발명의 상기 "개선"은 질병 또는 병증 상태를 호전 또는 이롭게 변경하는 모든 행위를 의미하는 것으로, 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 증상을 호전시키는 것을 의미한다.The "improvement" of the present invention refers to any action that improves or beneficially changes a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to improve symptoms of cancer.
본 발명의 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. The food composition of the present invention may be prepared in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread.
본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염이 유효성분으로 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is included in a food composition as an active ingredient, the amount may be added in an amount of 0.1 to 50% of the total weight, but is not limited thereto.
본 발명의 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다. When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except that the food composition is included in the indicated ratio, and as in conventional beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients. . Specifically, as natural carbohydrates, common sugars such as monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol, etc. can include Examples of the flavoring agent may include natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등이 더 포함될 수 있다.The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjusting agent, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like may be further included.
본 발명의 상기 식품 조성물에 포함되는 성분들은 독립적으로 또는 조합하여 사용될 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.Components included in the food composition of the present invention may be used independently or in combination. The ratio of the additives does not correspond to the core elements of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 또 다른 구현 예에서는 암의 예방, 개선 또는 치료를 위한 조성물을 제공한다.Another embodiment of the present invention provides a composition for preventing, improving or treating cancer.
본 발명의 상기 조성물은 하기 화학식 1로 표시되는 화합물((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함한다:The composition of the present invention is a compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S) -6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Formula 1]
Figure PCTKR2022007095-appb-img-000003
Figure PCTKR2022007095-appb-img-000003
본 발명에서 상기 조성물은 본 발명의 상기 화학식 1로 표시되는 화합물에 의해 활성이 증진되어 암을 예방 또는 치료할 수 있는 항암제를 추가로 더 포함할 수 있고, 상기 항암제는 예를 들면, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상일 수 있고, 바람직하게는 세툭시맙, 파니투무맙, 이리노테칸, 비노렐빈, 카페시타빈, 류코보린, 옥살리플라틴, 시스플라틴, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 아플리베르셉트 및 레고라페닙으로 이루어진 군에서 선택된 1종 이상일 수 있고, 바람직하게는 파클리탁셀, 인터페론알파-2a, 카보플라틴, 독소루비신, 시스플라틴, 젬시타빈, 5-플루오로우라실, 세툭시맙, 류코보린, 이리노테칸, 옥살리플라틴, 카페시타빈, 도세탁셀 및 이의 혼합물로 이루어진 군으로부터 선택되는 어느 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the composition may further include an anticancer agent whose activity is enhanced by the compound represented by Formula 1 of the present invention and which can prevent or treat cancer, and the anticancer agent is, for example, nitrogen mustard, Imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, lestaurtinib, Trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept, regorafenib, viscum albumin, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumabozogamicin, ibritumomabtusetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, Procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine , fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferonalpha-2a, docetaxel, paclitaxel, Irinotecan, Belotecan, Topotecan, Vinorelbine, Etoposide, Vincristine, Vinblastine, Teniposide, Doxorubicin, Idarubicin, Epirubicin, Mitoxantrone, Mitomycin, Bleromycin, Daunorubicin , dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, 5-fluorouracil, busulfan, ifosfamide, cyclophosphamide, melpharan, altretmin , dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutesimide, anagrelide, navelbine, fadrazole, tamoxifen, toremifene , testolactone, anastrozole, letrozole, vorozole, bicalutamide, may be one or more selected from the group consisting of lomustine and carmustine, preferably cetuximab, panitumumab, irinote At least one selected from the group consisting of khan, vinorelbine, capecitabine, leucovorin, oxaliplatin, cisplatin, carboplatin, 5-fluorouracil (5-FU), bevacizumab, aflibercept, and regorafenib Paclitaxel, interferon alpha-2a, carboplatin, doxorubicin, cisplatin, gemcitabine, 5-fluorouracil, cetuximab, leucovorin, irinotecan, oxaliplatin, capecitabine, docetaxel, and mixtures thereof It may be any one selected from the group consisting of, but is not limited thereto.
본 발명의 조성물에서 상기 화합물 및 항암제는 1:0.001 내지 1:1000, 바람직하게는 1:0.01 내지 1:100, 더욱 바람직하게는 1:0.1 내지 1:10의 비율로 사용될 수 있으나, 이에 제한되는 것은 아니다. 여기서, 상기 비율은 몰 농도비 또는 중량비일 수 있으나, 이에 제한되는 것은 아니다. In the composition of the present invention, the compound and the anticancer agent may be used in a ratio of 1:0.001 to 1:1000, preferably 1:0.01 to 1:100, and more preferably 1:0.1 to 1:10, but are limited thereto It is not. Here, the ratio may be a molar concentration ratio or a weight ratio, but is not limited thereto.
본 발명의 암의 예방, 개선 또는 치료를 위한 조성물에서 상기 화학식 1로 표시되는 화합물, 약학적으로 허용 가능한 염 및 암에 관한 기재는 앞서 기재된 바와 중복되어 이하 자세한 기재를 생략한다. In the composition for preventing, improving or treating cancer of the present invention, descriptions of the compounds represented by Formula 1, pharmaceutically acceptable salts, and cancers overlap with those described above, so detailed descriptions thereof are omitted.
본 발명의 상기 "예방"은 질병 또는 병증의 발병을 억제하거나 지연시키는 모든 행위를 의미한다. 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 발병 시기를 지연시키거나, 발병을 억제하는 것을 의미한다.The above "prevention" of the present invention means any action that suppresses or delays the onset of a disease or condition. For the purpose of the present invention, the composition is used together with an anticancer agent to delay the onset of cancer or to inhibit the onset of cancer.
본 발명의 상기 "개선"은 질병 또는 병증 상태를 호전 또는 이롭게 변경하는 모든 행위를 의미하는 것으로, 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 증상을 호전시키는 것을 의미한다.The "improvement" of the present invention refers to any action that improves or beneficially changes a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to improve symptoms of cancer.
본 발명의 상기 "치료"는 질병 또는 병증의 진행을 지연, 중단 또는 역전시키는 모든 행위를 의미하는 것으로서, 본 발명의 목적상 상기 조성물은 항암제와 함께 사용되어 암의 진행을 중단, 경감, 완화 또는 없애거나 역전시키는 것을 의미한다.The "treatment" of the present invention refers to any action that delays, stops, or reverses the progression of a disease or condition, and for the purpose of the present invention, the composition is used together with an anticancer agent to stop, reduce, alleviate or reverse the progression of cancer. It means to eliminate or reverse.
본 발명의 조성물은 약학 조성물 또는 식품 조성물로 사용될 수 있으며, 그 형태를 특별히 제한하지 않는다. The composition of the present invention may be used as a pharmaceutical composition or a food composition, and the form is not particularly limited.
본 발명의 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. The pharmaceutical composition of the present invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be intended for humans.
본 발명의 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있고, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다.The pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffer, a preservative, A pain reliever, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used.
본 발명의 상기 약학 조성물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(Elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화 할 수 있다.The formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have. In addition, it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
본 발명의 상기 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
본 발명의 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. 본 발명에서 상기 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입 기술을 포함한다. 또한, 상기 약학 조성물은 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, This includes sublingual or rectal. Oral or parenteral administration is preferred. In the present invention, the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In addition, the pharmaceutical composition may be administered in the form of a suppository for rectal administration.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may be variously varied, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, disease severity, drug type, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 50 mg/day. kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
본 발명의 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. The food composition of the present invention may be prepared in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread.
본 발명의 상기 화학식 1로 표시되는 화합물이 유효성분으로 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.When the compound represented by Formula 1 of the present invention is included in a food composition as an active ingredient, the amount may be added in an amount of 0.1 to 50% of the total weight, but is not limited thereto.
본 발명의 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다. When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except that the food composition is included in the indicated ratio, and as in conventional beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients. . Specifically, as natural carbohydrates, common sugars such as monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol, etc. can include Examples of the flavoring agent may include natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등이 더 포함될 수 있다.The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjusting agent, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like may be further included.
본 발명의 상기 식품 조성물에 포함되는 성분들은 독립적으로 또는 조합하여 사용될 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.Components included in the food composition of the present invention may be used independently or in combination. The ratio of the additives does not correspond to the core elements of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 또 다른 구현 예에서는 투여가 필요한 대상체에게 하기 화학식 1로 표시되는 화합물((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17-((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol) 또는 이의 약학적으로 허용 가능한 염을 유효한 양으로 투여하는 단계를 포함하는 암의 예방 또는 치료 방법을 제공한다:In another embodiment of the present invention, the compound represented by Formula 1 ((3S,5R,6R,8S,9R,10R,13R,14S,15S,17R)-10,13-dimethyl-17 to a subject in need of administration -((2R,5S)-6-methyl-5-(((2S,3R,4S,5S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)heptan-2-yl) Provided is a method for preventing or treating cancer comprising administering an effective amount of hexadecahydro-1H-cyclopenta[a]phenanthrene-3,5,6,15-tetraol) or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022007095-appb-img-000004
Figure PCTKR2022007095-appb-img-000004
본 발명의 상기 암의 예방 또는 치료 방법에서, 화학식 1로 표시되는 화합물, 약학적으로 허용 가능한 염 및 암에 관한 내용은 앞서 기재된 바와 동일하여, 본 명세서의 과도한 복잡성을 피하기 위하여 생략한다.In the method for preventing or treating cancer of the present invention, the contents of the compound represented by Formula 1, the pharmaceutically acceptable salt, and the cancer are the same as described above, and thus are omitted to avoid excessive complexity in the present specification.
본 발명에서 상기 "투여"는 임의의 적절한 방법으로 대상체에 소정의 본 발명의 화합물을 제공하는 것을 의미한다. In the present invention, the "administration" means providing a given compound of the present invention to a subject by any suitable method.
본 발명에서 상기 투여가 필요한 "대상체"는 포유동물 및 비-포유동물을 모두 포함할 수 있다. 여기서, 상기 포유동물의 예로는 인간, 비-인간 영장류, 예컨대 침팬지, 다른 유인원 또는 원숭이 종; 축산 동물, 예컨대 소, 말, 양, 염소, 돼지; 사육 동물, 예컨대 토끼, 개 또는 고양이; 실험 동물, 예를 들어 설치류, 예컨대 래트, 마우스 또는 기니아 피그 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. 또한, 본 발명에서 상기 비-포유동물의 예로는 조류 또는 어류 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "subject" in need of the administration may include both mammals and non-mammals. Here, examples of the mammal include humans, non-human primates such as chimpanzees, other apes or monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domesticated animals such as rabbits, dogs or cats; Laboratory animals, such as rodents, such as rats, mice, or guinea pigs may be included, but are not limited thereto. In addition, examples of the non-mammals in the present invention may include birds or fish, but are not limited thereto.
본 발명에서 상기와 같이 투여되는 화합물의 제제는 특별히 제한하지 않으며, 고체 형태의 제제, 액체 형태의 제제 또는 흡인용 에어로졸 제제로 투여될 수 있으며, 사용하기 바로 전에 경구 또는 비경구 투여용 액체 형태 제제로 전환되도록 의도되는 고체 형태 제제로 투여될 수 있고, 예를 들면, 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 투여될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the formulation of the compound administered as described above is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and a liquid formulation for oral or parenteral administration immediately before use. It can be administered in solid form preparations intended to be converted into, for example, oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions. However, it is not limited thereto.
또한, 본 발명에서 상기 투여 시 본 발명의 화합물과 함께 약학적으로 허용 가능한 담체를 추가로 투여할 수 있다. 여기서, 상기 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 화합물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.In addition, in the present invention, a pharmaceutically acceptable carrier may be additionally administered together with the compound of the present invention during the administration. Here, the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffer, Preservatives, analgesics, solubilizers, tonicity agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used. Formulations of the compound of the present invention can be variously prepared by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have. In addition, it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.On the other hand, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.
본 발명에 따른 화합물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥 내, 근육 내, 동맥 내, 골수 내, 경막 내, 심장 내, 경피, 피하, 복강 내, 비강 내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. Routes of administration of the compounds according to the present invention are, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work included. Oral or parenteral administration is preferred.
본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
본 발명에서, "약학적으로 유효한 양"은 바람직한 생물학적 결과를 제공하기 위한 작용제의 충분한 양을 지칭한다. 상기 결과는 질환의 징후, 증상 또는 원인의 감소 및/또는 완화, 또는 생물계의 임의의 다른 바람직한 변화일 수 있다. 예를 들어, 치료 용도를 위한 "유효량"은 질환에서 임상적으로 유의한 감소를 제공하는데 요구되는, 본 발명에 개시된 화합물의 양이다. 임의의 개별적인 경우에서 적절한 "효과적인" 양은 일상적인 실험을 사용하여 당업자에 의해 결정될 수 있다. 따라서, 표현 "유효량"은 일반적으로 활성 물질이 치료 효과를 갖는 양을 지칭한다. 본 발명의 경우에, 활성 물질은 암 세포의 성장 억제제이자, 암의 예방, 개선 또는 치료제이다.In the present invention, "pharmaceutically effective amount" refers to a sufficient amount of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in a biological system. For example, an “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease. An "effective" amount suitable in any individual case can be determined by one skilled in the art using routine experimentation. Thus, the expression “effective amount” generally refers to an amount of an active substance that has a therapeutic effect. In the case of the present invention, the active substance is a growth inhibitor of cancer cells, and a preventive, ameliorative or therapeutic agent for cancer.
본 발명의 화합물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 화합물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 100mg/kg 또는 0.001 내지 100mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 화합물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The compounds of the present invention vary depending on a number of factors, including the activity of the specific compound used, age, body weight, general health, sex, dosage, time of administration, route of administration, excretion rate, drug formulation, and severity of the specific disease to be prevented or treated. The dosage of the compound may vary, depending on the patient's condition, body weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and is 0.0001 to 100 mg/kg or 0.001 to 0.001 mg/kg per day. It can be administered at 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way. The compounds according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries and suspensions.
본 발명의 화합물은 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The compounds of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
또한, 본 발명의 화합물은 다른 항암제와도 추가로 병용하여 사용될 수 있으며, 이때 상기 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 케페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 보리노스텟, 엔티노스텟, 펜포민, 메트포민, 탈라조파립 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상을 사용할 수 있으나, 이에 제한되는 것은 아니다.In addition, the compound of the present invention may be further used in combination with other anticancer agents, wherein the anticancer agents include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, and bande Tanib, Nirotinib, Semasanib, Bosutinib, Axitinib, Cediranib, Lestaurtinib, Trastuzumab, Gefitinib, Bortezomib, Sunitinib, Carboplatin, Sorafenib, Bevacizumab, Cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumabozogamicin, ibritumomabtucetan, heptaplatin, methylaminolevulinic acid , Amsacrine, Alemtuzumab, Procarbazine, Alprostadil, Holmium Nitrate Chitosan, Gemcitabine, Doxifluridine, Pemetrexed, Tegapur, Capecitabine, Gimeracin, Oteracil, Azacity Dean, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, kefecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, Docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin , daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melpharan, altretmin, daka bazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutesimide, anagrelide, olaparib, navelbine, fadrazole, tamoxifen, toremy At least one selected from the group consisting of pen, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat, phenformin, metformin, thalazoparib, and carmustine Can be used, but is not limited thereto.
본 발명에 따른 화학식 1로 표시되는 화합물은 항암제 저항성을 보이는 경우, 해당 항암제와 병용하여 사용하였을 때 항암 효과를 현저하게 향상시킬 수 있을 뿐만 아니라, 기존에 사용되던 항암제의 양보다 현저하게 적은 양으로도 동일한 항암 효과를 유도할 수 있어 항암제 복용으로 인한 부작용을 감소시킬 수 있다. 더 나아가 항암제 내성 암이나, 항암제 치료 후 재발 또는 전이된 암도 효과적으로 예방, 개선 또는 치료할 수 있다.When the compound represented by Formula 1 according to the present invention exhibits resistance to an anticancer drug, when used in combination with the corresponding anticancer drug, the anticancer effect can be significantly improved, as well as in a significantly smaller amount than the amount of the previously used anticancer drug. It can also induce the same anticancer effect, reducing side effects caused by taking anticancer drugs. Furthermore, anticancer drug-resistant cancer, or recurrence or metastasis after anticancer drug treatment can be effectively prevented, improved, or treated.
도 1은 본 발명의 일 실시예에 따른 HT29, YUMC-C1 및 YUMC-C2 세포주의 유전자 발현 변화를 마이크로 어레이 분석을 통해 확인한 결과를 나타낸 것이다.Figure 1 shows the results of confirming the gene expression changes of HT29, YUMC-C1 and YUMC-C2 cell lines according to an embodiment of the present invention through microarray analysis.
도 2는 본 발명의 일 실시예에 따른 약물 투여에 따른 종양의 크기 변화를 측정한 결과를 그래프로 나타낸 것이다.Figure 2 is a graph showing the results of measuring the size change of tumors according to drug administration according to an embodiment of the present invention.
도 3은 본 발명의 일 실시예에 따른 약물 투여에 따른 순수 종양 무게의 변화를 측정한 결과를 그래프로 나타낸 것이다.Figure 3 is a graph showing the results of measuring the change in pure tumor weight according to drug administration according to an embodiment of the present invention.
본 발명의 일 구현 예에서는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 병용 투여용 약학 조성물에 관한 것이다.One embodiment of the present invention relates to a pharmaceutical composition for combined administration comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 구현 예에서는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 병용 섭취용 식품 조성물에 관한 것이다.Another embodiment of the present invention relates to a food composition for concomitant consumption comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 구현 예에서는 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암의 예방, 개선 또는 치료용 조성물에 관한 것이다.Another embodiment of the present invention relates to a composition for preventing, improving or treating cancer, comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 구현 예에서는 투여가 필요한 대상체에게 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효한 양으로 투여하는 단계를 포함하는, 암의 예방, 개선 또는 치료 방법에 관한 것이다.Another embodiment of the present invention relates to a method for preventing, improving or treating cancer, comprising administering an effective amount of a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof to a subject in need of administration. .
[화학식 1][Formula 1]
Figure PCTKR2022007095-appb-img-000005
Figure PCTKR2022007095-appb-img-000005
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are only to illustrate the present invention, and the content of the present invention is not limited by the following examples.
실시예Example
[실시예 1] [Example 1] 종양 세포 분리 및 1차 배양Tumor cell isolation and primary culture
하기 표 1에 기재되어 있는 환자의 절제된 대장 조직으로부터, 정상 조직 및 지방이 제거된 종양 조직을 분리하여, 분리된 종양 조직을 1X 한스 밸런스 솔트 용액(1X Hank 's Balanced Salt Solution)으로 수회 세척하였다. 이후, 1 mg/ml 콜라게나아제 타입 IV 형(Sigma, St. Louis, MO; C5138)이 포함된 20 % 우 태아 혈청을 갖는 DMEM/F12를 함유하는 해리 배지의 튜브에서 종양을 분쇄하였다. 70-마이크론 폴(70-micron pores, BD Falcon) 갖는 멸균 나일론 세포 스트레이너를 이용하여 상기에서 분쇄하여 현탁된 종양 세포를 여과하고, 50 ml의 1X 행크 밸런스드 염 용액 (Hank's Balanced Salt Solution)으로 헹구고, 5분 동안 200 g에서 원심 분리하였다. 세포를 10% 소 태아 혈청 (Hyclone) 및 2% 페니실린/스트렙토 마이신 용액(Gibco, Grand Island, NY, USA)과 함께 RPMI-1640(UTC, UT, South Logan, UT) 배지에 재현탁 시키고, 10~15% 우태아 혈청 RPMI-1640 배지를 이용하여 배양하였다.Normal tissues and tumor tissues from which fat was removed were separated from the resected colon tissues of patients listed in Table 1 below, and the separated tumor tissues were washed several times with 1X Hank's Balanced Salt Solution. . Tumors were then ground in a tube of dissociation medium containing DMEM/F12 with 20% fetal bovine serum containing 1 mg/ml collagenase type IV (Sigma, St. Louis, MO; C5138). Filter the suspended tumor cells by crushing above using a sterile nylon cell strainer with 70-micron pores (BD Falcon), rinse with 50 ml of 1X Hank's Balanced Salt Solution, Centrifuged at 200 g for 5 minutes. The cells were resuspended in RPMI-1640 (UTC, UT, South Logan, UT) medium with 10% fetal bovine serum (Hyclone) and 2% penicillin/streptomycin solution (Gibco, Grand Island, NY, USA), and It was cultured using ~15% Fetal Bovine Serum RPMI-1640 medium.
환자 1 (YUMC-C1 세포주)Patient 1 (YUMC-C1 cell line) 환자 2 (YUMC-C2 세포주)Patient 2 (YUMC-C2 cell line)
나이age 7171 6363
성별gender 여성female 남성male
일차 질환 위치primary disease location 대장(colon)colon 대장(colon)colon
단계step IVcIVc IVcIVc
일차 병리primary pathology 대장암(FOLFOX* 후 재발 및 전이)Colorectal cancer (recurrence and metastasis after FOLFOX*) 대장암(FOLFOX 후 재발 및 전이)Colorectal cancer (recurrence and metastasis after FOLFOX)
배양에 사용되는 표본의 분류Classification of Specimens Used for Culture 신선한 종양fresh tumor 신선한 종양fresh tumor
얻은 곳where you got it 세브란스 병원(서울, 한국)Severance Hospital (Seoul, Korea) 세브란스 병원(서울, 한국)Severance Hospital (Seoul, Korea)
* FOLFOX: 대장암에서 폴린산(Folinic acid), 플루오라실(Fluorouracil; 5-FU) 및 옥살리플라틴(Oxaliplatin) 삼중 병용투여* FOLFOX: triple combination administration of Folinic acid, Fluorouracil (5-FU) and Oxaliplatin in colorectal cancer
[실시예 2] [Example 2] 마이크로 어레이(Microarray)를 이용한 유전자 발현 분석Gene expression analysis using microarray
마이크로 어레이 분석 방법을 이용하여, 상기 실시예 1의 YUMC-C1 세포주 및 YUMC-C2 세포주에서 발현되는 유전자의 발현을 대장암 세포주인 HT29 세포주와 비교하였다.Using the microarray analysis method, the expression of genes expressed in the YUMC-C1 cell line and YUMC-C2 cell line of Example 1 was compared with that of the colorectal cancer cell line HT29 cell line.
구체적으로, RNA 순도 및 무결성은 ND-1000 분광 광도계 (NanoDrop) 및 Agilent 2100 Bioanalyzer (Agilent Technologies)를 사용하여 측정되었다. RNA 표지 및 하이브리드화는 Agilent 1색 마이크로어레이에 기초한 유전자 발현 분석 프로토콜(Agilent One-Color Microarray-Based Gene Expression Analysis protocol, Agilent Technology, V 6.5, 2010)을 사용하여 수행되었다. 각 샘플로부터 100 ng의 토탈 RNA를 선형으로 증폭시키고 Cy3-dCTP로 표지하였고, 표지된 cRNA를 RNAeasy Mini Kit(Qiagen)를 사용하여 정제하였다. 표지된 cRNA (pmol Cy3/μg cRNA)의 농도 및 특이적 활성은 NanoDrop ND-1000을 사용하여 측정되었다. 이어, 5μl 10x 블로킹 에이전트(blocking agent) 및 1μl의 25X 단편화 버퍼(fragmentation buffer)를 첨가하여 각각의 표지된 cRNA 600 ng을 단편화한 다음, 60 ℃에서 30분 동안 가열하였다. 마지막으로, 25μl의 2X GE 하이브리드화 버퍼를 첨가하여 표지된 cRNA를 희석시켰다. 하이브리드화 용액(Hybridization solution) 40 μl를 슬라이드(gasket slide)에 분배하고 Agilent SurePrint G3 Human GE 8X60K, V3 Microarrays (Agilent®)에 처리하였다. 로데이터(raw data)는 Agilent Feature Extraction Software (v11.0.1.1)를 이용하여 확보하였고, 그 후 각 유전자에 대한 로데이터를 Agilent 추출 프로토콜(Agilent feature extraction protocol)로 파일을 생성하여 각 유전자에 대한 발현 정보를 확인할 수 있었다. 중요한 프로브 목록에 대한 유전자 및 기능 분석은 온톨로지 및 유전자 게놈에 대한 교토 백과사전(KEGG) 분석을 이용하여 수행되었으며, 차등 발현된 유전자의 모든 정보에 대한 분석 및 시각화는 R 3.1.2을 통해 수행되었다. 이렇게 분석된 차등 발현된 유전자에 대한 결과를 도 1에 나타내었다.Specifically, RNA purity and integrity were measured using an ND-1000 spectrophotometer (NanoDrop) and an Agilent 2100 Bioanalyzer (Agilent Technologies). RNA labeling and hybridization were performed using the Agilent One-Color Microarray-Based Gene Expression Analysis protocol (Agilent Technology, V 6.5, 2010). 100 ng of total RNA from each sample was linearly amplified and labeled with Cy3-dCTP, and the labeled cRNA was purified using RNAeasy Mini Kit (Qiagen). The concentration and specific activity of the labeled cRNA (pmol Cy3/μg cRNA) was measured using a NanoDrop ND-1000. Then, 600 ng of each labeled cRNA was fragmented by adding 5 μl 10x blocking agent and 1 μl of 25X fragmentation buffer, followed by heating at 60° C. for 30 minutes. Finally, 25 μl of 2X GE Hybridization Buffer was added to dilute the labeled cRNA. 40 μl of the hybridization solution was dispensed on a gasket slide and processed on Agilent SurePrint G3 Human GE 8X60K, V3 Microarrays (Agilent®). Raw data was obtained using Agilent Feature Extraction Software (v11.0.1.1), and then a file was created using the Agilent feature extraction protocol to obtain raw data for each gene. expression information was available. Gene and functional analysis for the list of important probes was performed using Ontology and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis, and analysis and visualization of all information of differentially expressed genes was performed through R 3.1.2 . The results of the differentially expressed genes thus analyzed are shown in FIG. 1 .
도 1에서 보는 바와 같이, YUMC-C1 및 YUMC-C2 세포주의 경우, 전이성 유전자와 줄기세포 마커에 해당하는 유전자의 발현 수준이 현저하게 증가되었다.As shown in FIG. 1, in the case of YUMC-C1 and YUMC-C2 cell lines, the expression levels of metastatic genes and genes corresponding to stem cell markers were significantly increased.
이와 같은 결과를 통해, 본 발명의 상기 YUMC-C1 및 YUMC-C2 세포주는 재발 및 전이성 대장암 세포주의 특성을 가지는 것임을 알 수 있다.Through these results, it can be seen that the YUMC-C1 and YUMC-C2 cell lines of the present invention have the characteristics of recurrent and metastatic colorectal cancer cell lines.
[실시예 3] [Example 3] 이종 이식 마우스 모델에서 치료 효과 확인 결과Result of confirming treatment effect in xenotransplantation mouse model
상기 실시예 1의 YUMC-C1 및 YUMC-C2 세포주(4.5 X 106 cells/mouse)를 시험관에서 배양한 뒤, 6주령 암컷 BALB/c 누드, NOD/Shi-scid, IL-2Rγ KOJic (NOG)마우스의 왼쪽 상단 옆구리 영역에 피하 주사하였다. 세포주를 주사한 지 15일 후, 종양의 크기가 약 100 내지 200 mm3에 도달하였을 때, 해당 크기의 종양을 갖는 마우스를 무작위로 그룹화(n=10/그룹)한 뒤, 옥살리플라틴 단독(17 mg/kg, Oxaliplatin), 화학식 1로 표시되는 화합물 단독(25 mg/kg, candidate 7)과, 화학식 1로 표시되는 화합물(25 mg/kg) 및 옥살리플리틴(8.5mg/kg)을 병용(Oxaliplatin+C7)하여 각각의 그룹에 이틀에 한번씩 경구투여하면서, 총 41일간 종양의 크기 변화를 측정하여 그 결과를 도 2에 나타내었다. 또한, 상기 종양을 적출하여 순수한 종양의 무게를 측정한 뒤, 그 결과를 도 3에 나타내었다. 여기서, 대조군(Control)의 경우에는 아무것도 투여하지 않았다.After culturing YUMC-C1 and YUMC-C2 cell lines (4.5 X 10 6 cells/mouse) of Example 1 in vitro, 6-week-old female BALB/c nude, NOD/Shi-scid, IL-2Rγ KOJic (NOG) The mouse was injected subcutaneously in the upper left flank region. Fifteen days after the injection of the cell line, when the size of the tumor reached about 100 to 200 mm3, mice with tumors of that size were randomly grouped (n = 10/group), and oxaliplatin alone (17 mg/group) kg, Oxaliplatin), the compound represented by Formula 1 alone (25 mg/kg, candidate 7), and the compound represented by Formula 1 (25 mg/kg) and oxaliplatin (8.5 mg/kg) in combination (Oxaliplatin+ C7) was administered orally to each group once every two days, and the change in tumor size was measured for a total of 41 days, and the results are shown in FIG. 2 . In addition, after removing the tumor and measuring the weight of the pure tumor, the results are shown in FIG. 3 . Here, in the case of the control group (Control), nothing was administered.
도 2 및 3에서 보는 바와 같이, 대조군과 비교하여 옥살리플라틴을 단독으로 경구투여한 경우(Oxaliplatin) 해당 약물에 대한 저항성을 보이며 종양의 크기 및 무게가 감소되지 않았으나, 옥살리플라틴 및 화학식 1로 표시되는 화합물을 병용하여 투여하였을 때, 종양의 크기 및 무게가 매우 효과적으로 감소되었다.As shown in Figures 2 and 3, when oxaliplatin was administered orally alone compared to the control group (Oxaliplatin), resistance to the drug was shown and the size and weight of the tumor were not reduced, but oxaliplatin and the compound represented by Formula 1 When administered in combination, tumor size and weight were very effectively reduced.
상기 결과를 통해, 본 발명에 따른 화학식 1로 표시되는 화합물은 항암제 저항성을 보이는 경우, 해당 항암제와 병용하여 사용하였을 때 항암 효과를 현저하게 향상시킬 수 있을 뿐만 아니라, 기존에 사용되던 항암제의 양보다 현저하게 적은 양으로도 동일한 항암 효과를 유도할 수 있어 항암제 복용으로 인한 부작용을 감소시킬 수 있다.Through the above results, when the compound represented by Formula 1 according to the present invention exhibits anticancer drug resistance, when used in combination with the corresponding anticancer drug, the anticancer effect can be significantly improved, and the amount of the previously used anticancer drug is higher than that of the anticancer drug. The same anticancer effect can be induced even in a remarkably small amount, so side effects caused by taking anticancer drugs can be reduced.
본 발명에 따른 조성물은 암 세포의 성장을 억제할 수 있을 뿐만 아니라, 항암제 저항성을 보이는 경우 해당 항암제와 병용하여 사용하였을 때 항암 효과를 현저하게 향상시킬 수 있어 암의 예방, 개선 또는 치료에 매우 효과적으로 사용될 수 있다.The composition according to the present invention can not only inhibit the growth of cancer cells, but also can remarkably improve the anticancer effect when used in combination with the anticancer drug when resistant to an anticancer drug, so it is very effective in preventing, improving or treating cancer. can be used

Claims (18)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암의 예방 또는 치료를 위한 병용 투여용 약학 조성물:A pharmaceutical composition for concomitant administration for the prevention or treatment of cancer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Formula 1]
    Figure PCTKR2022007095-appb-img-000006
    Figure PCTKR2022007095-appb-img-000006
  2. 제1항에 있어서,According to claim 1,
    상기 암은 내성, 재발성 또는 전이성을 갖는 암인, 약학 조성물.The cancer is resistant, recurrent or metastatic cancer, the pharmaceutical composition.
  3. 제1항에 있어서,According to claim 1,
    상기 암은 대장암, 유방암, 자궁암, 나팔관암, 난소암, 위암, 뇌암, 직장암, 소장암, 직장암, 식도암, 임파선암, 담낭암, 폐암, 피부암, 신장암, 방광암, 혈액암, 췌장암, 전립선암, 갑상선암, 내분비선암, 구강암 및 간암으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 약학 조성물.The cancer is colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, bladder cancer, blood cancer, pancreatic cancer, prostate cancer , Thyroid cancer, endocrine adenocarcinoma, oral cancer, and at least one selected from the group consisting of liver cancer, the pharmaceutical composition.
  4. 제1항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물은 항암제와 병용 투여되어 항암제의 활성을 증진시키는 것인, 약학 조성물.The compound represented by Formula 1 is administered in combination with an anticancer agent to enhance the activity of the anticancer agent, a pharmaceutical composition.
  5. 제4항에 있어서,According to claim 4,
    상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상인, 약학 조성물.The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, Cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept , regorafenib, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtusetan, heptaplatin, methylaminolevulinic acid, Amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine , methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferonalpha -2a, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, Bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, 5-fluorouracil, busulfan, ifosfamide, cyclophosphamide , melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutecimide, anagrelide, navelbine, par A pharmaceutical composition comprising at least one selected from the group consisting of drazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, and carmustine.
  6. 제5항에 있어서,According to claim 5,
    상기 항암제는 파클리탁셀, 인터페론알파-2a, 카보플라틴, 독소루비신, 시스플라틴, 젬시타빈, 5-플루오로우라실, 세툭시맙, 류코보린, 이리노테칸, 옥살리플라틴, 카페시타빈, 도세탁셀 및 이의 혼합물로 이루어진 군으로부터 선택되는 어느 하나인 것인, 약학 조성물.The anticancer agent is selected from the group consisting of paclitaxel, interferonalpha-2a, carboplatin, doxorubicin, cisplatin, gemcitabine, 5-fluorouracil, cetuximab, leucovorin, irinotecan, oxaliplatin, capecitabine, docetaxel and mixtures thereof Whichever one is selected, the pharmaceutical composition.
  7. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암의 예방 또는 개선을 위한 병용 섭취용 식품 조성물:A food composition for concomitant intake for the prevention or improvement of cancer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Formula 1]
    Figure PCTKR2022007095-appb-img-000007
    Figure PCTKR2022007095-appb-img-000007
  8. 제7항에 있어서,According to claim 7,
    상기 암은 내성, 재발성 또는 전이성을 갖는 암인, 식품 조성물.The cancer is a cancer having resistance, recurrence or metastasis, food composition.
  9. 제7항에 있어서,According to claim 7,
    상기 암은 대장암, 유방암, 자궁암, 나팔관암, 난소암, 위암, 뇌암, 직장암, 소장암, 직장암, 식도암, 임파선암, 담낭암, 폐암, 피부암, 신장암, 방광암, 혈액암, 췌장암, 전립선암, 갑상선암, 내분비선암, 구강암 및 간암으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 식품 조성물.The cancer is colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, bladder cancer, blood cancer, pancreatic cancer, prostate cancer , Thyroid cancer, endocrine adenocarcinoma, oral cancer, and at least one selected from the group consisting of liver cancer, food composition.
  10. 제7항에 있어서,According to claim 7,
    상기 화학식 1로 표시되는 화합물은 항암제와 병용으로 섭취되어 항암제의 활성을 증진시키는 것인, 식품 조성물.The compound represented by Formula 1 is taken in combination with an anticancer agent to enhance the activity of the anticancer agent, a food composition.
  11. 제10항에 있어서,According to claim 10,
    상기 항암제는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상인, 식품 조성물.The anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, Cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept , regorafenib, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtusetan, heptaplatin, methylaminolevulinic acid, Amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine , methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferonalpha -2a, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, Bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, 5-fluorouracil, busulfan, ifosfamide, cyclophosphamide , melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutecimide, anagrelide, navelbine, par A food composition comprising at least one selected from the group consisting of drazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, and carmustine.
  12. 제11항에 있어서,According to claim 11,
    상기 항암제는 파클리탁셀, 인터페론알파-2a, 카보플라틴, 독소루비신, 시스플라틴, 젬시타빈, 5-플루오로우라실, 세툭시맙, 류코보린, 이리노테칸, 옥살리플라틴, 카페시타빈, 도세탁셀 및 이의 혼합물로 이루어진 군으로부터 선택되는 어느 하나인 것인, 식품 조성물.The anticancer agent is selected from the group consisting of paclitaxel, interferonalpha-2a, carboplatin, doxorubicin, cisplatin, gemcitabine, 5-fluorouracil, cetuximab, leucovorin, irinotecan, oxaliplatin, capecitabine, docetaxel and mixtures thereof Whichever one is selected, the food composition.
  13. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물:A pharmaceutical composition for preventing or treating cancer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Formula 1]
    Figure PCTKR2022007095-appb-img-000008
    Figure PCTKR2022007095-appb-img-000008
  14. 제13항에 있어서,According to claim 13,
    상기 조성물은 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 파니투무맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 시스플라틴, 세툭시맙, 아플리베르셉트, 레고라페닙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 류코보린, 카르모퍼, 랄티트렉세드, 인터페론알파-2a, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 5-플루오로우라실, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상의 항암제를 추가로 포함하는, 약학 조성물.The composition includes nitrogen mustard, imatinib, oxaliplatin, rituximab, panitumumab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, Cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, 5-fluorouracil (5-FU), bevacizumab, cisplatin, cetuximab, aflibercept , regorafenib, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtusetan, heptaplatin, methylaminolevulinic acid, Amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine , methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, leucovorin, carmophor, raltitrexed, interferonalpha -2a, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, Bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, 5-fluorouracil, busulfan, ifosfamide, cyclophosphamide , melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exmestane, aminoglutecimide, anagrelide, navelbine, par A pharmaceutical composition further comprising at least one anticancer agent selected from the group consisting of drazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine and carmustine.
  15. 제14항에 있어서,According to claim 14,
    상기 항암제는 파클리탁셀, 인터페론알파-2a, 카보플라틴, 독소루비신(doxorubicin), 시스플라틴(cisplatin), 젬시타빈(gemcitabine), 5-플루오로우라실, 세툭시맙, 류코보린, 이리노테칸, 옥살리플라틴, 카페시타빈, 도세탁셀 및 이의 혼합물로 이루어진 군으로부터 선택되는 어느 하나인 것인, 약학 조성물.The anticancer agent is paclitaxel, interferon alpha-2a, carboplatin, doxorubicin, cisplatin, gemcitabine, 5-fluorouracil, cetuximab, leucovorin, irinotecan, oxaliplatin, capecitabine , Docetaxel, and any one selected from the group consisting of mixtures thereof, the pharmaceutical composition.
  16. 제13항에 있어서,According to claim 13,
    상기 암은 내성, 재발성 또는 전이성을 갖는 암인, 약학 조성물.The cancer is a cancer having resistance, recurrence or metastasis, the pharmaceutical composition.
  17. 제16항에 있어서,According to claim 16,
    상기 암은 세툭시맙, 파니투무맙, 이리노테칸, 비노렐빈, 카페시타빈, 류코보린, 옥살리플라틴, 시스플라틴, 카보플라틴, 5-플루오로우라실 (5-FU), 베바시주맙, 아플리베르셉트 및 레고라페닙으로 이루어지는 군에서 선택된 1종 이상의 항암제에 대하여 내성을 가지는 것인, 약학 조성물. The cancer is cetuximab, panitumumab, irinotecan, vinorelbine, capecitabine, leucovorin, oxaliplatin, cisplatin, carboplatin, 5-fluorouracil (5-FU), bevacizumab, aflibercept and Having resistance to one or more anticancer agents selected from the group consisting of regorafenib, the pharmaceutical composition.
  18. 제16항에 있어서,According to claim 16,
    상기 암은 대장암, 유방암, 자궁암, 나팔관암, 난소암, 위암, 뇌암, 직장암, 소장암, 직장암, 식도암, 임파선암, 담낭암, 폐암, 피부암, 신장암, 방광암, 혈액암, 췌장암, 전립선암, 갑상선암, 내분비선암, 구강암 및 간암으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 약학 조성물.The cancer is colorectal cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, brain cancer, rectal cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph gland cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, bladder cancer, blood cancer, pancreatic cancer, prostate cancer , Thyroid cancer, endocrine adenocarcinoma, oral cancer, and at least one selected from the group consisting of liver cancer, the pharmaceutical composition.
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