Pharmaceutical composition for preventing, alleviating or treating cancers, containing as active ingredient 2, 6-dichloro-4 - (4 - (4-hydroxycyclohexylamino) - 7h - pyrrolo [2, 3-d] pyrimidin-5-yl) phenol

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancers, which contains 2, 6-dichloro-4 - (4 - (4-hydroxycyclohexylamino) -7H - pynolo [2, 3-D] pyrimidin-5-yl) phenol as an active ingredient.SOLUTION: The present invention inhibits the formation of mammospheres in breast cancer cell lines, and when compared with the anticancer drugs sorafenib and etoposide, which are widely used topoisomerase inhibitors in lung cancer, ovarian cancer, colon cancer, melanoma and the like, it has been found to exhibit an effect more marked than or equal to the anticancer drugs sorafenib and etoposide. In addition, the compound of Example 1, according to the present invention, exhibits synergistic anticancer effects when combined with radiotherapy or other anticancer drugs in breast cancer cell lines and liver cancer cell lines, and thus can be developed as an anticancer drug or food exhibiting excellent effects in the treatment of cancer.SELECTED DRAWING: Figure 12

Description

[Technical Field]

[0001] Background of the Invention 1. Field of the Invention The present invention relates to a pharmaceutical composition for preventing or treating cancer, which contains 2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-D]pyrimidin-5-yl)phenol as an active ingredient. [Background technology]

[0002] 2. Description of Related Art Although the incidence of cancer is increasing with the development of civilization, the treatment of cancer patients still relies on surgery, radiation therapy, and chemotherapy by administering highly cytotoxic anticancer drugs.However, these treatments are generally limited to patients with early stage cancer or certain types of cancer, and cause various side effects, so there is a need to develop effective anticancer drugs with safety profiles and fewer side effects.

[0003] In particular, the breast cancer market is known to be an area of ​​unmet medical need lacking high anti-cancer efficacy and safety.

[0004] Regarding breast cancer treatment, various therapies have been introduced to target patients with different disease characteristics, such as hormonal therapy, chemotherapy, and targeted therapy, but there is a certain clinical need for treatments with excellent anti-cancer efficacy and safety. Among these, triple-negative breast cancer (TNBC), which accounts for 16% of all breast cancers, is difficult to treat due to poor prognosis after treatment, and there are insufficient available treatments targeting TNBC (Non-Patent Document 1, Rev Peru Med Exp Salud Publica. Oct-Dec 2013;30(4):649-56).

[0005] Currently, treatments for breast cancer include therapies that inhibit the human epidermal growth factor receptor 2 (hereinafter referred to as "HER2") gene, which is involved in tumor growth, and antihormonal drugs are widely used. However, in the case of TNBC, HER2 receptors, estrogen receptors, and progesterone receptors are all negative, and therefore do not respond to existing anticancer drugs. Consequently, new targeted treatments that can be safely and effectively administered are urgently needed.

[0006] Therefore, the present inventors have studied and completed the pharmaceutical composition of the present invention, which can be used as a safe and effective anticancer drug, using various cancer cell lines. Summary of the Invention

[0007] SUMMARY OF THE INVENTION It is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer. It is an object of the present invention to provide a health functional food composition for preventing or treating cancer.

[0008] It is an object of the present invention to provide a pharmaceutical kit for preventing or treating cancer. It is an object of the present invention to provide a combination of radiation and an anti-cancer agent for preventing or treating cancer.

[0009] It is another object of the present invention to provide a method for treating cancer, said method comprising the step of administering to a subject in need thereof. It is another object of the present invention to provide compounds for preventing or treating cancer. It is another object of the present invention to provide the use of a compound for the preparation of a medicament for use in the prevention or treatment of cancer.

[0010] In order to achieve the above object, in an aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In another aspect, the present invention provides a health functional food composition for preventing or ameliorating cancer, comprising a compound represented by formula 1 described herein as an active ingredient.

[0011] In another aspect of the present invention, there is provided a pharmaceutical kit for preventing or treating cancer, comprising: a first component containing a pharmaceutically effective amount of an anticancer agent; and a second component containing, as an active ingredient, a compound represented by Formula 1 as described herein, its stereoisomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a combination of radiation and an anti-cancer agent for preventing or treating cancer.

[0012] In another aspect, the present invention provides a method for treating cancer, said method comprising administering a compound represented by formula 1 described herein to a subject in need thereof. In another aspect of the present invention, the present invention provides a compound represented by Formula 1 described herein for use in the prevention or treatment of cancer. In another aspect of the present invention, the present invention provides the use of a compound represented by Formula 1 described herein for the preparation of a medicament for use in the prevention or treatment of cancer.

[0013] beneficial effects It has been found that the compound of Example 1 of the present invention inhibits the formation of tumor-like masses in breast cancer cell lines, and when compared with the anticancer drugs sorafenib and etoposide, which are topoisomerase inhibitors widely used in lung cancer, ovarian cancer, colon cancer, melanoma, etc., it exhibits effects that are significantly greater than or equal to the anticancer drugs sorafenib and etoposide. In addition, according to the present invention, the compound of Example 1 exhibits a synergistic anticancer effect when combined with radiation therapy or other anticancer drugs in breast cancer cell lines and liver cancer cell lines, and therefore can be developed as an anticancer drug or food that exhibits excellent effects in cancer treatment. [Brief explanation of the drawings]

[0014] Brief description of the drawings [Figure 1] FIG. 1 is a diagram showing the evaluation of the ability to inhibit the expression of major proteins. [Figure 2] FIG. 2 is a series of graphs showing cell viability of the human-derived breast cancer cell line BT20 after 48 hours of treatment with the compound of Example 1 in culture. [Figure 3] FIG. 3 is a series of graphs showing cell viability of the TNBC cell line MDA-MB-231 after 48 hours of treatment with the compound of Example 1 in culture.

[0015] [Figure 4] FIG. 4 is a series of graphs showing cell viability of MDA-MB-231, MDA-MB-453, and BT-20 after 24 hours of treatment with the compound of Example 1. [Figure 5] FIG. 5 is a graph confirming that treatment with the compound of Example 1 can significantly inhibit tumor growth. [Figure 6] FIG. 6 is a series of photographs showing apoptotic bodies undergoing the apoptotic process.

[0016] [Figure 7] FIG. 7 is a series of graphs showing cell viability of the liver cancer cell line Hep3B after treatment with the compound of Example 1. [Figure 8]FIG. 8 is a series of graphs showing cell viability of the liver cancer cell line HepG2 after treatment with the compound of Example 1. [Figure 9] FIG. 9 is a series of photographs showing the results of treating the liver cancer cell line Hep3B with the compound of Example 1.

[0017] [Figure 10] FIG. 10 is a series of photographs showing the results of treating the liver cancer cell line HepG2 with the compound of Example 1. [Figure 11] FIG. 11 is a series of graphs showing the results of confirming the toxicity of the compound of Example 1 of the present invention against various cancer cell lines. [Figure 12] FIG. 12 is a graph showing the change in tumor size in a triple-negative breast cancer allograft mouse model according to treatment regimen.

[0018] [Figure 13] FIG. 13 is a series of photographs showing the lungs and a graph showing the number of tumor nodules in a triple-negative breast cancer allograft mouse model according to treatment regimen. [Figure 14] FIG. 14 is a series of graphs showing the results of observing changes in immune cells according to treatment methods in tumor cells through flow cytometry. [Figure 15] FIG. 15 is a series of graphs showing changes in immune cells following treatment regimens in the tumor cells of FIG. 14 via flow cytometry.

[0019] [Figure 16] FIG. 16 is a series of photographs showing the results of observing protein expression and immune cell changes in tumor cells through immunocytochemical assays. [Figure 17] FIG. 17 is a series of graphs showing changes in protein expression and immune cells in the tumor cells of FIG. 16 through immunocytochemistry assays. [Figure 18] FIG. 18 is a series of graphs showing cell viability of tumor cells (SKOV-3 and OVCAR-3) upon administration of the compound of Example 1 and cisplatin, alone and in combination. [Figure 19] FIG. 19 is a series of graphs showing cell viability of tumor cells (SK Hep1 and Huh-7) upon administration of the compound of Example 1 and sorafenib alone and in combination. DETAILED DESCRIPTION OF THE INVENTION

[0020] Description of the Preferred Embodiments In the following the present invention will be described in detail. The embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. It is well understood by those skilled in the art who have average knowledge in this field that the embodiments of the present invention are provided to more accurately interpret the present invention.

[0021] Additionally, the "comprising" of an element throughout this specification does not exclude other elements and may include other elements, unless specifically stated otherwise.

[0022] In an aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by the following formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 1] [ka]

[0023] In another aspect of the present invention, the compound represented by Formula 1 above can be (trans)-2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-D]pyrimidin-5-yl)phenol. In another aspect of the present invention, the pharmaceutical composition may be used in combination treatment with radiation or anti-cancer agents.

[0024] The anticancer drug can be at least one selected from the group consisting of cisplatin, sorafenib, OKN-007, gefitinib, doxorubicin, vinblastine, taxol, etoposide, 5-FU, and ifosfamide.

[0025] In another aspect of the present invention, the pharmaceutical composition can enhance immunity. In Experimental Example 9 below, changes in immune cells in the tumor microenvironment were evaluated. As a result, it was confirmed that when the compound of Example 1 was administered alone or in combination with radiation, the proportion of CD8-positive T cells increased, M1 TAM also increased, and M2 TAM decreased.

[0026] In the present invention, the term "pharmaceutically acceptable salt" refers to salts commonly used in the pharmaceutical industry, such as inorganic ionic salts made from calcium, potassium, sodium, and magnesium; inorganic acid salts made from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, and sulfuric acid; acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, and glutamic acid. The term "salts" refers to organic acid salts made from carboxylic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonate salts made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; amino acid salts made from glycine, arginine, lysine, etc.; and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but these salts do not limit the types of salts of the present invention.

[0027] In the present invention, the term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. Isomers include structural isomers such as tautomers and stereoisomers, and stereoisomers include both R isomers and S isomers (optical isomers, enantiomers) with asymmetric carbon centers and geometric isomers (trans, cis). In the present invention, all stereoisomers of the compound represented by Formula 1 and their mixtures are also included in the scope of the present invention.

[0028] In the present invention, the term "hydrate" refers to a compound represented by Formula 1 above and water bound by non-covalent intermolecular forces, and may include stoichiometric or non-stoichiometric amounts of water. Specifically, the hydrate may contain water in a ratio of about 0.25 moles to about 10 moles based on 1 mole of active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.

[0029] In the present invention, the term "solvate" refers to a compound represented by Formula 1 above and a solvent other than water bound by non-covalent intermolecular forces, which may include stoichiometric or non-stoichiometric amounts of water. Preferred solvents are volatile, non-toxic, and can be administered to humans in minute amounts. Specifically, the solvate may contain water in a ratio of about 0.25 moles to about 10 moles per mole of active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc.

[0030] In the present invention, the term "about" refers to a numerical value that is ±10% of the preceding value.

[0031] In the present invention, the term "containing as an active ingredient" means containing in a dosage range that produces the effect of preventing, ameliorating, or treating cancer, and the dosage range may vary depending on the severity and formulation, and the number of applications may also vary depending on the age, weight, and physique of the subject. In one embodiment of the present invention, the compound represented by Formula 1 is contained in the pharmaceutical composition of the present invention in an amount of, for example, 0.001 mg / kg or more, preferably 0.1 mg / kg or more, more preferably 10 mg / kg or more, more preferably 100 mg / kg or more, more preferably 250 mg / kg or more, and most preferably 0.1 g / kg or more. The upper limit of the amount of the compound represented by Formula 1 contained in the pharmaceutical composition of the present invention may be selected within an appropriate range by those skilled in the art.

[0032] Pharmaceutical compositions according to the present invention may comprise an effective amount of a compound represented by Formula 1 alone, or may also include one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0033] Pharmaceutically acceptable carriers, excipients, or diluents refer to physiologically acceptable substances, and typically do not cause allergic reactions such as gastrointestinal upset, dizziness, or similar reactions when administered to humans. Examples of carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, and preservatives may also be included.

[0034] The pharmaceutical compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject.The pharmaceutical compositions can be formulated in the form of oral preparations, injectable preparations, or topical preparations.Oral preparations can be selected from, but are not necessarily limited to, tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, and lyophilized preparations.In addition, topical preparations can be selected from, but are not necessarily limited to, creams, gels, ointments, emulsions, suspensions, sprays, and transdermal patches.

[0035] The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, transdermal, subcutaneous, intravenous, or intramuscular administration. In the present invention, the term "amelioration" refers to the alleviation, prevention, or treatment of cancer symptoms by administering, ingesting, or applying the pharmaceutical or food composition of the present invention to a subject suffering from cancer.

[0036] In the present invention, the term "prevention" refers to inhibiting or blocking cancer symptoms by administering, ingesting, or applying the pharmaceutical or food composition of the present invention to a subject not suffering from cancer. In the present invention, the term "treatment" refers to complete cure of cancer symptoms, as well as partial cure, improvement, and alleviation of cancer symptoms as a result of administering the pharmaceutical composition of the present invention to a subject suffering from cancer.

[0037] In the present invention, the term "subject" refers to any animal, including a human, that already has or may develop cancer. The pharmaceutical compositions of the present invention are administered in pharmaceutically effective amounts.

[0038] In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment or improvement. Effective dose levels depend on factors including the type and severity of the disease, age, sex, drug activity, drug sensitivity, time of administration, route of administration and rate of excretion, duration of treatment, concomitant drugs, and other factors well known in the medical field.

[0039] In the present invention, the term "administration" means providing a substance to a subject or patient by any appropriate method. The substance can be administered parenterally (for example, intravenous injection, subcutaneous injection, intraperitoneal injection, or local injection) or orally according to the desired method. The dosage range varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. Specifically, in the present invention, the term "parenteral administration" refers to a method of administration using a tube subcutaneously, intramuscularly, intravenously, or intraperitoneally, but excludes oral administration. In addition, in the present invention, the term "oral administration" refers to a method of administering an injection into the mouth to ameliorate pathological symptoms.

[0040] For parenteral administration, topical preparations such as sterile suspensions, liquids, water-insoluble excipients, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, and aerosols, as well as sterile injectable solutions, can be prepared by conventional methods, preferably, but not necessarily, in the form of creams, gels, patches, sprays, ointments, plasters, lotions, liniments, eye ointments, eye drops, pastes, or poultices. Water-insoluble excipients and suspensions may contain, in addition to the active compound(s), propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethylolate, and the like. Suppositories may contain, in addition to the active compound(s), witepsol, macrogol, Tween 61, cocoa butter, lauric butter, glycerogelatin, and the like.

[0041] In the present invention, the cancer may be any one selected from the group consisting of lung cancer, non-small cell lung cancer (NSCL), bronchioalveolar cell lung cancer, ovarian cancer, colon cancer, melanoma, gastric cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or ocular melanoma, uterine cancer, rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, multiple myeloma, and chronic or acute leukemia. Preferably, the cancer may be liver cancer, lung cancer, ovarian cancer, colon cancer, melanoma, or breast cancer.

[0042] In another aspect, the present invention provides a health functional food composition for preventing or ameliorating cancer, comprising a compound represented by the following formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 1] [ka]

[0043] The food compositions according to the present invention can be formulated in the same manner as pharmaceutical compositions and can be used as functional foods or added to a variety of foods, including beverages, alcoholic drinks, confectioneries, diet bars, dairy products, meats, chocolate, pizza, ramen, other noodles, gum, ice cream, and hangover relievers (drinks, low-viscosity gels, pills, tablets, capsules, etc.), vitamin complexes, health supplements, etc.

[0044] The food compositions of the present invention contain a compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient, and may also include ingredients commonly added during food manufacturing, such as proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents. Examples of the carbohydrates mentioned above include common sugars, including monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides such as dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural sweeteners (thaumatin, stevia extract, e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic sweeteners (saccharin, aspartame, etc.) may be included as sweeteners. When the food compositions of the present invention are formulated as drinks and beverages, they may additionally include citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts in addition to the compound represented by Formula 1 or 2, its pharmaceutically acceptable salt, its hydrate, or its solvate.

[0045] The present invention provides a health functional food or health supplement food containing a food composition comprising the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient. In the present invention, the term "health functional food or health supplement food" refers to a food manufactured and processed using raw materials or ingredients with functional properties beneficial to the human body in accordance with the Act on Health Functional Food. The term "functional" food refers to a food consumed for the purpose of obtaining beneficial health effects (such as regulating nutrients for the structure and function or physiological effects of the human body). In the present invention, a functional food is a food product prepared by adding the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate to food materials such as beverages, tea, spices, gum, and confectionery, or by encapsulating, powdering, or suspending it. The functional foods described above have specific health benefits when consumed. However, because they are produced using food as raw materials, they have the advantage of being free of any side effects that may occur with long-term drug intake, unlike common drugs. The functional health foods or dietary supplements of the present invention thus obtained can be taken daily and are therefore extremely useful. The amount of the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate in such functional health foods or dietary supplements depends on the type of functional health food being used. It is added within a range that does not impair the original taste of the food, generally ranging from 0.01 to 50 wt%, preferably 0.1 to 20 wt%, of the target food, and therefore cannot be uniformly formulated. Additionally, in the case of functional health foods or dietary supplements in the form of pills, granules, tablets, or capsules, the amount added is usually in the range of 0.1 to 100 wt%, preferably 0.5 to 80 wt%. In one embodiment of the present invention, the health functional food or dietary supplement of the present invention may be in the form of a pill, tablet, capsule, or drink.

[0046] The food compositions of the present invention may contain conventional food additives. Qualification as a "food additive" is determined by the specifications and standards for the product in question, in accordance with the General Rules and General Test Methods for Food Additives approved by the Ministry of Food and Drug Safety, unless otherwise specified.

[0047] The items listed in the Korean Food Additives Code include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon color, licorice extract, crystalline cellulose, sorghum color, and guar gum; and mixed preparations such as monosodium L-glutamate preparations, alkali agents for noodles, preservative preparations, and tar color preparations.

[0048] In addition, the food compositions of the present invention can be prepared and processed into the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing and / or ameliorating cancer.

[0049] For example, a health functional food in tablet form can be prepared by conventionally granulating a mixture of a food composition containing the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient, and an excipient, a binder, a disintegrant, and other additives, and then compressing the mixture with a lubricant or the like, or directly compressing the mixture. In addition, the health functional food in tablet form can optionally contain a flavor enhancer or the like, and can also be optionally coated with a suitable coating agent.

[0050] Among the health functional foods in capsule form, hard capsules can be prepared by filling a conventional hard capsule with a mixture of a food composition containing the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient, and additives such as excipients, or a granular product thereof or a coated granular product thereof. Soft capsules can be prepared by filling a capsule base such as gelatin with a mixture of a food composition containing the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient, and additives such as excipients. Soft capsules can contain plasticizers such as glycerin or sorbitol, colorants, preservatives, etc., as necessary.

[0051] The health functional food in pill form can be prepared by molding a mixture of a food composition containing the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient, and an excipient, a binder, a disintegrant, etc. in any suitable manner, and if necessary, can be coated with white sugar or another suitable coating agent, or can be coated with starch, talc, or other suitable substance.

[0052] The health functional food in granule form can be prepared by using a mixture of a food composition containing the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient, and excipients, binders, disintegrants, etc. in any suitable manner, and may contain flavorings, flavor enhancers, etc., if necessary. When particle size tests were conducted using No. 12 (1680 μm), No. 14 (1410 μm), and No. 45 (350 μm) sieves, the entire amount of the health functional food in granule form passed through the No. 12 sieve, less than 5.0% of the total amount remained on the No. 14 sieve, and less than 15.0% of the total amount passed through the No. 45 sieve.

[0053] There are no specific limitations on the type of food, and all health functional foods in the conventional sense are included. The matters referred to in the pharmaceutical composition and food composition of the present invention are applied in the same manner unless they are mutually contradictory.

[0054] In another aspect, the present invention provides a pharmaceutical kit for preventing or treating cancer, comprising: a first component containing a pharmaceutically effective amount of an anticancer agent; and a second component containing, as an active ingredient, a compound represented by Formula 1 below, its stereoisomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof. [Formula 1] [ka]

[0055] In another aspect of the present invention, the compound represented by Formula 1 above can be (trans)-2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-D]pyrimidin-5-yl)phenol.

[0056] In another aspect of the present invention, the cancer may be any one selected from the group consisting of lung cancer, non-small cell lung cancer (NSCL), bronchioloalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, gastric cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or ocular melanoma, uterine cancer, rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, multiple myeloma, and chronic or acute leukemia.

[0057] In another aspect of the present invention, the anticancer agent can be at least one selected from the group consisting of cisplatin, sorafenib, OKN-007, gefitinib, doxorubicin, vinblastine, taxol, etoposide, 5-FU, and ifosfamide.

[0058] In another aspect, the present invention provides a method for preventing or treating cancer, comprising the step of administering to a subject in need thereof a compound represented by Formula 1 as described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, the present invention provides a method for preventing or treating cancer, comprising the step of co-administering a compound represented by Formula 1 as described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and radiation or an anticancer agent to a subject in need thereof.

[0060] In another aspect of the present invention, the present invention provides the use of a compound represented by Formula 1 as described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in the prevention or treatment of cancer.

[0061] In another aspect of the present invention, the present invention provides the use of a compound represented by Formula 1 as described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, administered in combination with radiation or an anticancer agent, for the preparation of a medicament for use in the prevention or treatment of cancer. The above detailed description of the pharmaceutical composition may be applied to the above method or use.

[0062] Hereinafter, the present invention will be described in detail by the following examples and experimental examples. However, the following examples and experimental examples are only intended to illustrate the present invention, and the contents of the present invention are not limited thereto.

[0063] Example 1: Preparation of (trans)-2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol [Reaction Scheme 1] [ka]

[0064] Step 1 DMF (30 mL) was added to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol), and NBS (2.52 g, 14.24 mmol) was added thereto at 0° C. The mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the solvent was removed under high pressure, and the resulting mixture was mixed with water, filtered, washed with hexane, and dried to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.66 g, 88%). 1 H NMR (DMSO, 300MHz): δ7.81(s,1H),8.76(s,1H),5.02(br s,1H).

[0065] Step 2 NaH (0.41 g, 10.3 mmol) was added to 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 5.16 mmol) dissolved in DMF (10 mL), followed by stirring at 0 °C for 30 min. p-Tosyl chloride (1.36 g, 7.16 mmol) was added, and the mixture was stirred at room temperature for 6 h. Upon completion of the reaction, water was added and stirred for 10 min. The resulting product was collected by filtration and dried to give 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.79 g, 90%). 1 H NMR (CDCl3,300MHz): δ8.76(s,1H),8.09(d,2H,J=8.1Hz),7.54(s,1H),7.34(d,2H,J=8.1Hz),2.41(s,3H).

[0066] Step 3 N-BuOH (10 mL) was added to 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.29 mmol), and to this was added trans-4-aminocyclohexan-1-ol (223 mg, 1.94 mmol) and DIPEA (2.58 mmol). The mixture was heated at 110° C. for 3 hours. The solvent was removed under high pressure, and the residue was purified by chromatography to give (trans)-4-((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexan-1-ol (540 mg, 90%). 1 H NMR(CDCl3,300MHz):δ8.37(s,1H),8.06(d,2H,J=8.3Hz),7.45(s,1H),7.31(d,2H,J=8.2Hz),5.87 (d,1H),4.12(m,1H),3.70(m,1H),2.40(s,3H),2.16(m,2H),2.03(m,2H),1.54(m,2H),1.31(m,2H).

[0067] Step 4 (Trans)-4-((5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexan-1-ol (200 mg, 0.43 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.86 mmol), Na2CO3 (0.86 mmol), dioxane (4 mL), and water (1 mL) were placed in a microwave vial. The solvent was degassed for 15 min, and Pd(PPh3)2Cl2 (10 mol%) was added. The mixture was then irradiated in a microwave oven at 80 °C for 30 min. The solution was filtered through a pad of Celite, the filtrate was washed with brine (10 mL x 5), and the organic layer was concentrated and chromatographed (10% methanol:dichloromethane) to give (trans)-2,6-dichloro-4-(4-((-4-hydroxycyclohexyl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (40%). 1H NMR(CDCl3,300MHz):δ8.46(s,1H),8.11(d,2H,J=8.36Hz),7.41(s,1H),7.36(s,2H),7.31(d,2H,J=8.13Hz),6.0 3(m,1H),4.71(d,1H),4.09(m,1H),3.63(m,1H),2.41(s,3H),2.05(m,2H),1.89(m,2H),1.40(m,2H),1.10(m,2H).

[0068] Step 5 1M TBAF (in THF) was added to the above intermediate (trans)-2,6-dichloro-4-(4-((-4-hydroxycyclohexyl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol and stirred at room temperature for 20 hours. The reaction was purified by chromatography (15% methanol:dichloromethane + 0.1% aqueous ammonia) under reduced pressure to give the title compound (40%). 1 H NMR(DMSO-d6,300MHz):δ11.82(br s,1H),10.16(br s,1H),8.17(s,1H),7.42(s,2H),7.29(s,1H),5.27(d,1H),4.54(m,1H),4. 01(m,1H),3.43(m,1H),1.95(m,2H),1.76(m,2H),1.40(m,2H),1.20(m,4H).

[0069] Experimental example 1: Evaluation of inhibition of key protein expression An experiment was carried out to confirm the inhibitory effect of the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, on the expression of key proteins during cancer cell growth through Western blotting.

[0070] Specifically, MDA-MB-231 cells, a TNBC cell line, were cultured in a 37°C, 5% CO2 incubator using RPMI-1640 medium supplemented with 10% FBS. BALB / c nude mice (five mice each in the control and treatment groups) were subcutaneously injected with 5x10 mAbs into the right neck. 6Tumors were induced by injecting 100 μl of MDA-MB-231 cells per head, and tumors were grown to a size of 200 mm. 3 The experiment was carried out when the tumor tissue count reached 100 mg / kg. The compound of Example 1, the active ingredient of the pharmaceutical composition of the present invention, was administered once by intravenous injection at concentrations of 5, 10, and 20 mg / kg (T4, T5, and T6). The mice were then euthanized using CO2, and the resulting tumor tissues from the control and treatment groups were collected and subjected to Western blotting. Proteins were isolated from the tumor tissues, and the results of Western blotting were confirmed using antibodies against BRD4, c-myc, PD-L1, and actin, respectively.

[0071] When the expression of BRD4, c-myc, and PD-L1 in groups T4, 5, and 6 treated with the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, was compared with that of the untreated negative control (NC), it was confirmed that the expression of proteins important for cancer formation in groups T4, 5, and 6 was reduced.

[0072] Experimental example 2: Evaluation of breast cancer cell line inhibition An experiment was carried out to confirm the growth inhibitory effect of the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, on breast cancer cell lines through a cell viability assay.

[0073] Specifically, a cell viability assay was performed as follows: 5 × 10 human-derived breast cancer cell line BT20 and TNBC cell line MDA-MB-231 were each placed in a 96-well plate. 3 The cells were seeded at a density of 100 cells / well and cultured for 24 hours. Then, I-bet 762 and the compound of Example 1 were treated at various concentrations and cultured for 48 hours. At the end of the culture, 100 μl of WST-8 solution was added to each well of the plate, and the absorbance was measured using a microplate reader with a 450 nm optical filter to measure formazan produced by the reducing factor in live cells.

[0074] As shown in Figures 2 and 3, the formation of tumor-like masses was analyzed by culturing the human-derived breast cancer cell line BT20 and the TNBC cell line MDA-MB-231. As a result, it was confirmed that the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, dose-dependently inhibited cell viability not only in common breast cancer cell lines but also in TNBC cell lines.

[0075] Figure 4 shows the cell viability of MDA-MB-231, MDA-MB-453, and BT-20 cells 24 hours after treatment with the compound of Example 1. As shown in Figure 4, it was confirmed that cell viability was suppressed in a dose-dependent manner not only in common breast cancer cell lines but also in TNBC cell lines.

[0076] Experimental Example 3: Evaluation of breast cancer growth inhibition An experiment was carried out to confirm the tumor inhibition of the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, against xenograft tumor samples of breast cancer cells (MBA-MB-231), a human-derived TNBC cell line.

[0077] Specifically, an experiment was conducted to confirm the in vitro inhibitory effect of the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, on breast cancer cell viability using 80 female 5-week-old xenograft Balb / c nude mice, the mice being approximately 8 weeks old at the start of administration.

[0078] Balb / c nude mice lack immune T cells and were selected as an animal model suitable for transplanting human cancer cells. Animals within ±20% of the total mean body weight at the time of administration were selected, and tumor growth was monitored twice a week. Tumor size was measured with a caliper for 3 weeks.

[0079] As shown in FIG. 5, it was confirmed that the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, was able to significantly inhibit tumor growth.

[0080] Experimental Example 4: Comparison of apoptotic body frequency An experiment was conducted to confirm the tumor necrosis effect of the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, by measuring the number of apoptotic bodies in tumors and H&E staining of tumor tissues in BALB / c-nude mice injected with cancer cell lines.

[0081] Specifically, to measure the number of apoptotic bodies in tumor tissues from groups T4, T5, and T6 in Experimental Example 1, five areas where tumor tissues had grown were randomly selected, and the number of apoptotic bodies was measured at a magnification of x400. The measured values ​​were summed and expressed as individual values, and statistically compared using GraphPad Prism 5.

[0082] Apoptotic bodies were observed to be shrunk and divided (blebs) and surrounded by hollow spaces. In addition, the cytoplasm was observed to be more eosinophilic, and the nuclei were small, condensed, or fragmented, and phagocytosed by surrounding cells.

[0083] According to the number of measured apoptotic bodies in Table 1, the number was dose-dependently higher in the T4, T5, and T6 groups treated with the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, compared to NC (negative control), confirming that the compound of Example 1 of the present invention has a tumor-suppressing effect by increasing apoptosis of cancer cells.

[0084] The central area was excised, and a paraffin block was prepared through a general tissue processing process. The tissue was then sectioned at a thickness of 3 μm using a microtome. The sections were then stained with hematoxylin and eosin to observe the cell necrosis area, as shown in Figure 6.

[0085] When comparing the stained tissues of the NC group with those of the T4, T5, and T6 groups treated with the compound of Example 1, there were more areas of tissue necrosis in the groups treated with the compound of Example 1, which confirmed that the compound of Example 1 caused necrosis of tumor tissue and had a tumor-suppressing effect.

[0086] [Table 1]

[0087] Experimental Example 5: Evaluation of inhibition of liver cancer cell lines It was confirmed whether the compound of Example 1, which is the active ingredient of the pharmaceutical composition of the present invention, also has a growth inhibitory effect on cancer cell lines other than TNBC.

[0088] Specifically, the WST-8 assay to check the cell viability of the hepatocellular carcinoma cell lines HepG2 and Hep3B shown in Figures 7 and 8 was performed as follows: 5 × 10 HepG2 and Hep3B cells were each placed in a 96-well plate. 3 Cells were seeded at a density of 1000 cells / well and cultured for 24 hours. Sorafenib and OPT-0139 were then serially diluted at 2-fold concentrations and applied to the plate at various concentrations, followed by 24, 48, and 72 hours of culture. 100 μl of WST-8 solution was added to each well of the plate, and absorbance was measured using a microplate reader with a 450 nm optical filter to measure formazan produced by reducing factors in live cells.

[0089] Cells that were not treated with sorafenib and the compound of Example 1 exhibited a deep orange color, while cells that were treated with sorafenib and the compound of Example 1 exhibited a light pink color, which is the color of the cell line's culture medium. Therefore, the number of viable cells can be determined by measuring the absorbance.

[0090] As shown in Figures 9 and 10, clonogenic assays were performed as follows: 3 x 10 HepG2 and Hep3B cells were each placed in a 12-well plate. 3The cells were seeded at a density of 1000 cells / well and cultured for 24 hours. Then, sorafenib and the compound of Example 1 were treated at 2.5 μM and 5 μM, respectively, and cultured for 10 days. After the culture was completed, the cells were washed with PBS, fixed with 37% formaldehyde, and stained with 0.01% crystal violet. After staining, the cells were washed with distilled water, and the colonies of stained cells were photographed.

[0091] As a result of observing the colonies of stained cells, there was a clear difference in the number of colonies, indicating cell viability, between the areas not treated with sorafenib and the compound of Example 1 and the areas treated.

[0092] As shown in Figures 7 to 10, cell viability was confirmed using WST-8 in liver cancer cell lines Hep3B cells and HepG2 cells. As a result, it was found that treatment with the compound of Example 1 and sorafenib reduced cell viability in a dose-dependent and time-dependent manner, demonstrating a significant effect compared to sorafenib, an existing targeted anticancer drug.

[0093] Experimental Example 6: Evaluation of cytotoxicity against various cancer cell lines The cytotoxicity of the compound of Example 1 against various cancer cell lines was evaluated through a process similar to that described above for evaluating liver cancer cell line inhibition. Etoposide, a commercially available anticancer drug, was used as a control drug.

[0094] The results are shown in Figure 11. FIG. 11 is a series of graphs showing the results of confirming the toxicity of the compound of Example 1 of the present invention against various cancer cell lines.

[0095] As shown in Figure 11, the compound of Example 1 according to the present invention exhibited excellent toxicity to cancer cell lines A549, SK-OV-3, SK-MEL-2, and HCT15 in a dose-dependent manner, and therefore can be effectively used as an active ingredient in anticancer drugs.

[0096] Experimental Example 7: Evaluation of changes in tumor size following treatment regimens in a triple-negative breast cancer allograft mouse model 4T1 mouse triple-negative breast cancer cells (6x105 Cells) were injected into the hind limbs of immunocompetent 6-week-old BALB / c mice. After confirming steady tumor growth 7 days after injection, 10 mice were selected from each group and used for subsequent experiments.

[0097] The experimental groups consisted of a control group (no treatment), a radiotherapy group, a group treated with the compound of Example 1, and a group treated with the compound of Example 1 in combination with radiotherapy. Each treatment was performed 31 days after tumor implantation.

[0098] Radiation treatment was performed using an electron beam, with three doses of 24 Gy administered once every two days for one week (days 10, 12, and 14) (8 Gy x 3). The compound of Example 1 was administered intravenously at a dose of 10 mg / kg once every two or three days (days 10, 12, 14, 17, 19, and 21) for a total of six doses over two weeks. On days when radiation treatment and drug administration were performed simultaneously, the compound of Example 1 was administered 4 hours after radiation treatment, after confirming that the mice had woken up from anesthesia.

[0099] Tumor length and width were measured on each treatment day using calipers, and tumor volume (mm) was calculated using the formula 1 below. 3 ) was calculated. [Formula 1] Volume (mm 3 ) = length (mm) x {width (mm)} 2 x 0.5

[0100] In the same manner as above, tumors were injected into 10 mice for each treatment method, and tumor growth was observed for 31 days. The results are shown in Figure 12. As a result, it was confirmed that the single administration of the compound of Example 1 significantly delayed tumor growth compared with the control group. In addition, it was also confirmed that the combined administration of the compound of Example 1 and radiation had a superior inhibitory effect on tumor growth compared with the single administration of each compound.

[0101] Experimental Example 8: Evaluation of lung metastases according to treatment regimen in a triple-negative breast cancer allograft mouse model Mice were prepared in the same manner as in Experimental Example 7, and the lungs of the mice were removed 31 days after tumor injection, and the results of observing lung metastasis are shown in Figure 13. As a result, it was confirmed that single administration of the compound of Example 1 significantly reduced metastasis compared to the control group. In addition, it was also confirmed that combined administration of the compound of Example 1 and radiation significantly (P<0.05) reduced lung metastasis compared to each single administration.

[0102] Experimental Example 9: Evaluation of immune cell changes in the tumor microenvironment following treatment regimens in a triple-negative breast cancer allograft mouse model Tumor tissue from each mouse was subjected to single cell isolation followed by flow cytometry analysis (FACS) to confirm the immunomodulatory effect.

[0103] Specifically, 31 days after tumor cell injection, mouse spleens and tumors were extracted in the same manner as in Experiment 7. After excision, tumor tissues were mechanically minced using a sterilized razor blade, then treated with DNase (0.1 mg / ml) and collagenase (1 mg / ml), respectively, and incubated at 36°C for 30 minutes to obtain single-cell suspensions. After single-cell isolation from tumor tissues, 1 × 10 cells per FACS tube were stained with FITC, PE, PerCP / Cy5.5, and APC fluorescence using antibodies against CD3, CD8b, CD4, CD11b, F4 / 80, and CD206 to analyze infiltrating leukocytes. For each stained sample, the fraction of CD8+ cytotoxic T cells was calculated using a BD Bioscience FACSCalibur instrument. FACS results were analyzed using FlowJo software (version 10).

[0104] The observed changes in immune cells in the tumor microenvironment following the treatment regimen as described above are shown in Figures 14 and 15.

[0105] CD8+ T cells are known to be cytotoxic T cells that can destroy tumor cells. As a result of the above experiment, it was confirmed that the percentage of CD8+ T cells increased when the compound of Example 1 was administered alone. In addition, it was confirmed that the percentage of CD8+ T cells also increased significantly when the compound of Example 1 was administered in combination with radiation compared to the administration of either compound alone.

[0106] When the compound of Example 1 was administered alone, M1 TAM, which has an antitumor effect, significantly increased (P<0.01), and M2 TAM, which has an immunosuppressive effect, significantly decreased (P<0.01). In addition, when the compound of Example 1 was administered in combination with radiation, an increase in M1 TAM and a decrease in M2 TAM were also confirmed.

[0107] Experimental Example 10: Evaluation of protein expression changes in the tumor microenvironment following treatment regimens in a triple-negative breast cancer allograft mouse model Bromodomain and extraterminal domain (BET) family proteins have recently become important targets for cancer treatment, and one BET family member, BRD4, is commonly found in hematological and solid tumors. Therefore, in addition to down-regulating oncogenes, BRD4 inhibitors inhibit tumor growth by directly suppressing tumor cell proliferation. Additionally, hypoxia-inducible factor 1α (HIF-1α) protein is a key factor in the tumor microenvironment that regulates tumor cell division, angiogenesis, invasion, and metastasis.

[0108] To assess changes in the expression of proteins such as BRD4 and HIF-1α, tumor cells isolated in Example 9 were subjected to immunocytochemistry (IHC) analysis to assess protein expression in the tumor microenvironment following treatment. The results are shown in Figures 16 and 17.

[0109] Specifically, tumor tissue was extracted, fixed in 4% paraformaldehyde, and embedded in paraffin to create blocks. The paraffin blocks containing the tissue were sliced ​​transversely to a thickness of 4 μm, and slides were attached. The paraffin was removed from the attached tissue using xylene and ethanol, and endogenous peroxidase was removed from the tissue by immersing the slides in a solution of 3% H2O2 in methanol at room temperature for 10 minutes. For antigen retrieval, the slides were then boiled in 0.01 M sodium citrate buffer (pH 6.0). To exclude nonspecific binding, FcR on the cell surface was blocked using 5% normal goat serum. Slides were then incubated overnight at 4°C with primary antibodies (HIF-1α (SantaCruz, sc-13515), PD-L1 (Abcam, ab2025921), CD8 (Abcam, ab203035), and CD68 (CellSignaling, 97778)). Secondary antibodies were attached and chromogenic development was induced using the ImmPRESS Goat Anti-Rat IgG (Mouse Adsorbed) Polymer Kit (Vector Laboratories), Abcam (ab150165, ab150081), and the REAL EnVision detection system (Dako). Stained tissues were observed under an Axioskop40 light microscope (Carl Zeiss) at 40x magnification, and images were captured using AxioVision 4.7 software. Expression levels were measured by measuring the area of ​​the stained region in the photograph using Image J software (NIH, Bethesda, MD). The average density value was calculated from at least three slides per sample.

[0110] As a result, Brd4 expression was significantly (P<0.001) reduced by treatment with the compound of Example 1, and HIF-1α expression, which is known to be associated with Brd4, was also significantly (P<0.05) reduced in tumor tissues. In addition, it was confirmed that the compound of Example 1 also significantly (P<0.01) reduced the expression of PD-L1, which is expressed by cancer cells to induce immune evasion.

[0111] Consistent with the flow cytometry results of Experimental Example 9, it was observed that the population of CD8+ T cells increased due to both radiation and administration of the compound of Example 1. In addition, it was confirmed that when the compound of Example 1 was administered in combination with radiation, the population of CD8+ T cells further increased (synergistic effect). Furthermore, the population of CD68+ macrophages in tumor tissues was significantly (P<0.01) reduced by the compound of Example 1.

[0112] Experimental Example 11: Evaluation of efficacy in combination with other anticancer drugs <11-1>Evaluation of efficacy in combination with cisplatin Human ovarian cancer cell lines (SKOV-3 and OVCAR-3) were treated with a control (no treatment), 0.1 μM of the compound of Example 1, 1 μM of cisplatin, and 0.1 μM of the compound of Example 1 / 1 μM of cisplatin, and the cell viability of SKOV-3 and OVCAR-3 was determined. The results are shown in Figure 18.

[0113] It was confirmed that when 0.1 μM of the compound of Example 1 or 1 μM of cisplatin was administered to SKOV-3 cell line and OVCAR-3 cell line, cell viability was inhibited. In addition, it was also confirmed that when 0.1 μM of the compound of Example 1 and 1 μM of cisplatin were administered in combination, cell viability was further inhibited (synergistic effect).

[0114] <11-2>Evaluation of efficacy in combination with sorafenib Human liver cancer cell lines (SK Hep1 and Huh-7) were treated with a control (no treatment), 0.1 μM of the compound of Example 1, 1 μM of sorafenib, and 0.1 μM of the compound of Example 1 / 1 μM of sorafenib, and the cell viability of SK Hep1 and Huh-7 was examined. The results are shown in Figure 19.

[0115] When 0.1 μM of the compound of Example 1 or 1 μM of sorafenib was administered to SK Hep1 cell line and Huh-7 cell line, it was confirmed that cell viability was inhibited. In addition, when 0.1 μM of the compound of Example 1 and 1 μM of sorafenib were administered in combination, it was confirmed that cell viability was further inhibited (synergistic effect).

[0116] From the above results, it was confirmed that the compound of Example 1 according to the present invention inhibits the formation of tumor-like masses in breast cancer cell lines, and exhibits effects that are significantly greater than or equal to the anticancer drugs sorafenib and etoposide, which are topoisomerase inhibitors widely used in lung cancer, ovarian cancer, colon cancer, melanoma, etc. In addition, the compound of Example 1 according to the present invention exhibits synergistic anticancer effects when combined with radiation therapy or other anticancer drugs in breast cancer cell lines and liver cancer cell lines, and therefore can be developed as an anticancer drug or food that exhibits excellent effects in cancer treatment.

Claims

1. Equation 1 below: [Formula 1] 【Chemistry 1】 A pharmaceutical composition for use in the prevention or treatment of cancer, comprising as an active ingredient a compound represented by the formula:

2. 2. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 1, wherein the compound represented by the above formula 1 is (trans)-2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-D]pyrimidin-5-yl)phenol.

3. 2. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 1, wherein the cancer is any one selected from the group consisting of lung cancer, non-small cell lung cancer (NSCL), bronchioloalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, gastric cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or ocular melanoma, uterine cancer, rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, multiple myeloma, and chronic or acute leukemia.

4. 4. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 3, wherein the cancer is breast cancer or liver cancer.

5. 10. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 1, wherein the pharmaceutical composition is used for treatment in combination with radiation or an anticancer agent.

6. 6. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 5, wherein the anticancer drug is at least one selected from the group consisting of cisplatin, sorafenib, Opdivo, Tecentriq, Keytruda, Imfinzi, OKN-007 (Oklahoma nitrone-007), gefitinib, doxorubicin, vinblastine, taxol, etoposide, 5-FU (5-fluorouracil), and ifosfamide.

7. 2. The pharmaceutical composition for use in the prevention or treatment of cancer according to claim 1, wherein the pharmaceutical composition enhances immunity.

8. Equation 1 below: [Formula 1] 【Chemistry 2】 A health functional food composition for use in preventing or recovering cancer, comprising as an active ingredient a compound represented by the formula:

9. a first component containing a pharmaceutically effective amount of an anti-cancer drug; and Equation 1 below: [Formula 1] 【Transformation 3】 a compound represented by the formula: A pharmaceutical kit for preventing or treating cancer, comprising:

10. 10. The pharmaceutical kit for preventing or treating cancer according to claim 9, wherein the compound represented by the above formula 1 is (trans)-2,6-dichloro-4-(4-(4-hydroxycyclohexylamino)-7H-pyrrolo[2,3-D]pyrimidin-5-yl)phenol.

11. 10. The pharmaceutical kit for preventing or treating cancer according to claim 9, wherein the cancer is any one selected from the group consisting of lung cancer, non-small cell lung cancer (NSCL), bronchioloalveolar cell lung cancer, ovarian cancer, colon cancer, melanoma, gastric cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or ocular melanoma, uterine cancer, rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, multiple myeloma, and chronic or acute leukemia.

12. 10. The pharmaceutical kit for preventing or treating cancer according to claim 9, wherein the anticancer drug is at least one selected from the group consisting of cisplatin, sorafenib, Opdivo, Tecentriq, Keytruda, Imfinzi, OKN-007 (Oklahoma nitrone-007), gefitinib, doxorubicin, vinblastine, taxol, etoposide, 5-FU (5-fluorouracil), and ifosfamide.

13. A method for preventing or treating cancer, comprising administering to a subject in need thereof a compound represented by formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

14. A method for preventing or treating cancer, comprising the step of co-administering a compound represented by formula 1 of claim 1, its stereoisomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof, and radiation or an anticancer agent to a subject in need thereof.

15. Use of a compound represented by formula 1 according to claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt for the preparation of a medicament for use in the prevention or treatment of cancer.

16. 10. Use of a compound represented by formula 1 according to claim 1, its stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, administered in combination with radiation or an anticancer agent, for the preparation of a medicament for use in the prevention or treatment of cancer.

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