KR20200055117A - Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and cytotoxic anticancer agent - Google Patents

Abstract

The present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent. The composition according to the present invention exhibits an excellent cancer treatment effect compared to when the compound of Formula 1 or a cytotoxic anticancer agent used as a PI3 kinase inhibitor is administered alone. Therefore, the composition of the present invention can be usefully applied to the prevention, treatment or improvement of cancer.

Description

Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and cytotoxic anticancer agent

Mutual citations with related applications

This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0004210 filed on January 12, 2018, and all contents disclosed in the literature of the Korean patent application are incorporated as part of this specification.

The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent.

Cancer is characterized by the growth of cells uncontrolled in a part of the body, and by such abnormal cell growth, a cell mass called a tumor is formed, which infiltrates into surrounding normal tissues or organs and destroys them, thereby creating a new growth site. Generic term for a group of diseases that can take the life of an individual. Cancer is one of the most deadly diseases, and despite the enormous amount of capital invested in developing it to cure it worldwide, and the medical technology is also developing innovatively, the incidence of cancer and death from cancer continue to increase. Is in trend.

Cancer treatment methods are largely classified into three types: surgical surgery therapy, anticancer drug therapy, and radiation therapy. Most of anticancer drugs currently used in anticancer drug therapy occupy cytotoxic anticancer drugs. Advances in cytotoxic anti-cancer agents have been made steadily, but unfortunately, many cancer patients do not respond to initial treatment or experience relapse after initial response to treatment and eventually die from progressive metastatic disease. Therefore, a constant focus on the design and discovery of new anticancer drugs is still very important.

On the other hand, phosphatidyl inositol 3-kinase (PI3 kinase; PI3K) is a lipid kinase that phosphorylates lipid molecules instead of proteins, cell survival, signal transduction, and control of membrane control. trafficking). When these control problems occur, cancer, inflammatory diseases, autoimmune diseases, and the like occur.

Cancer can be a global health threat due to various factors that can act individually or collectively to initiate or promote the onset of cancer. Therefore, it is important to develop a more effective approach, particularly a combination approach, for the prevention and treatment of cancer.

Accordingly, the present inventors tried various studies to provide a novel pharmaceutical composition for preventing or treating cancer, which can maximize the therapeutic effect of cancer by using a cytotoxic anticancer agent together with a PI3 kinase inhibitor.

International Patent Publication No. WO 2016/204429

It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor, which is administered together with an effective amount of a cytotoxic anticancer agent.

Another object of the present invention is to provide a pharmaceutical composition for combination administration for the prevention or treatment of cancer, including a PI3 kinase inhibitor and a cytotoxic anticancer agent.

Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering a PI3 kinase inhibitor and a cytotoxic anticancer agent to an individual in need.

Finally, it is an object of the present invention to provide the use of a pharmaceutical composition comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent for the manufacture of a medicament for the prevention or treatment of cancer.

In order to achieve the above object, in the present invention, a pharmaceutical composition for preventing or treating cancer comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent, and the pharmaceutical composition for preventing or treating cancer is a PI3 kinase inhibitor and cells It was confirmed that the combination of toxic anti-cancer agents improves the prophylactic or therapeutic activity of cancer due to the synergistic complementary effect of the combination.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for preventing or treating cancer

The present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent.

The pharmaceutical composition of the present invention is a combination of a PI3 kinase inhibitor and a cytotoxic anti-cancer agent, and thus preventive and therapeutic activity of cancer is remarkable due to the synergistic complement effect of the combination.

In one embodiment of the present invention, the compound used as the PI3 kinase inhibitor is a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is hydrogen; Or a linear or branched alkyl group having 1 to 5 carbon atoms,

R ₂ is a phenyl group or a pyridinyl group, and the phenyl group or pyridinyl group is a halogen group; And one or more substituents selected from the group consisting of straight or branched alkyl groups having 1 to 5 carbon atoms, or unsubstituted,

R ₃ and R ₄ are each independently hydrogen or a halogen group.

In the present invention, in the display of the "carbon number x" of the functional group, x represents the number of carbons, and the number of carbons x to y refers to a functional group having x to y carbons.

In the present invention, the term "alkyl group" means a linear saturated hydrocarbon group or a branched saturated hydrocarbon group, wherein the alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl , Ethyl, propyl, isobutyl or pentyl.

In the present invention, the term "substitution with a substituent" is replaced by a substituent in which the hydrogen atom is a non-hydrogen atom. At this time, the valence requirement must be satisfied and a chemically stable compound must be generated from substitution. Also, all functional groups should be construed as being substituted or unsubstituted, unless explicitly stated as "unsubstituted."

In the present invention, the term "halogen" refers to a halogen group element, and includes, for example, F, Cl, Br or I.

In one embodiment of the present invention, the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be a compound represented by Formula 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof have.

[Formula 2]

In Formula 2, R ₁ to R ₄ are the same as defined in Formula 1 above.

In one embodiment of the present invention, R ₁ is a straight or branched alkyl group having 1 to 5 carbon atoms.

In one embodiment of the invention, R ₁ is a methyl group.

In one embodiment of the present invention, R ₂ is a phenyl group or a pyridinyl group, and the phenyl group or pyridinyl group is a halogen group; And one or more substituents selected from the group consisting of straight or branched chain alkyl groups having 1 to 5 carbon atoms.

In one embodiment of the present invention, R ₂ is a phenyl group.

In one embodiment of the invention, R ₃ is hydrogen; Or a halogen group.

In one embodiment of the invention, R ₃ is a halogen group.

In one embodiment of the invention, R ₃ is chlorine.

In one embodiment of the invention, R ₄ is hydrogen; Or a halogen group.

In one embodiment of the invention, R ₄ is a halogen group.

In one embodiment of the invention, R ₄ is chlorine.

In one embodiment of the present invention, the compound represented by Formula 1, the stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 4-((1- (4,8-dichloro-1-oxo-2-phenyl -1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one (4-((1- (4,8-dichloro- 1-oxo-2-phenyl-1,2-dihydroisoquinolin -3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one), its stereoisomer or a pharmaceutically acceptable thereof Salt. More specifically, the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1) , 2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one ((S) -4-((1- (4,8- dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one), which is represented by Formula 3 below.

[Formula 3]

In one embodiment of the present invention, the compound represented by Formula 1 may be prepared by, for example, the manufacturing method disclosed in International Patent Publication No. WO 2016/204429, but is not limited thereto.

In the present invention, the term "pharmaceutically acceptable" means a physiologically acceptable, when administered to humans, that usually does not cause allergic reactions such as gastrointestinal disorders, dizziness or similar reactions, and the term "salt" Iran means an acid addition salt formed by a pharmaceutically acceptable free acid. Accordingly, a pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid , Inorganic acid salts made of perchloric acid or 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, glutaric acid, glucuronic acid, aspartic acid Organic acid salts made of acid, ascorbic acid, carbonic acid, or vanic acid; Sulfonic acid salts made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid; Amino acid salts made of glycine, arginine, lysine, etc .; Or there are amine salts made of trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the types of salts in the present invention are not limited by the salts listed.

In one embodiment of the present invention, the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selectively inhibited against PI3 kinase selected from the group consisting of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Can be.

In the present invention, the term "cytotoxic anticancer agents (cytotoxic anticancer agents)" is an anticancer agent that inhibits the synthesis and division of DNA or RNA by intervening in the metabolic pathway of cancer cells, or damages the DNA itself to induce cell death. Meaning, also called chemotherapeutic agents.

In one embodiment of the present invention, the cytotoxic anticancer agent is an alkylating agent, platinum compounds, antimetabolites, antineoplastic antibiotics, plant-derived alkaloids. ) And hormones (hormones) may be one or more selected from the group consisting of, but is not limited thereto.

In the present invention, the term "alkylating agent" is a highly reactive substance having the ability to introduce an alkyl group R-CH ₂ into a compound, and acts on a cell to modify the DNA structure and cause a chain break, thereby causing an anticancer effect and a cell. It has a poison effect and is also called a DNA-damaging agent. The alkylating agent is, for example, bendamustine, chlorambucil, melphalan, busulfan, cyclophosphamide, ifosfamide, carmustine (carmustine), lomustine, nimustine, ranimustine, dacarbaxine, temozolomide, thiotepa or combinations thereof It is not limited.

In the present invention, the term "platinum compound" means a compound containing platinum, which forms oxides and chlorides or complexes. The platinum compound may be, for example, carboplatin, cisplatin, heptaplatin, oxaliplatin, or a combination thereof, but is not limited thereto.

In the present invention, the term "metabolic antagonist" means a substance that inhibits the growth and proliferation of cells by antagonizing with the indispensable essential metabolites for metabolism or growth of microorganisms or tumor cells. The metabolic antagonists, for example, methotrexate, pemetrexed, cladribine, fludarabine, mercaptopurine, 6-thioguanine , Clofarabine, 5-azacytidine, cytarabine, decitabine, enocitabine, gimeracil, oteracil ), Capecitabine, carmofur, doxyfluridine, gemcitabine, tegafur, 5-fluorouracil or combinations thereof It may be, but is not limited thereto.

In the present invention, the term "anti-neoplastic antibiotic" refers to an antibiotic that exhibits a proliferation-inhibiting effect on animal tumor cells and a life-spanning effect on bile cancer animals. The anti-tumor antibiotics include, for example, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitoxanthrone, Pirarubicin, bleomycin, ixabepilone, mitomycin C, or a combination thereof, but is not limited thereto.

In the present invention, the term "plant-derived alkaloid" means an organic compound containing a basic nitrogen having a specific and strong physiological action to animals among plant extracts. The plant-derived alkaloids are, for example, etoposide, docetaxel, paclitaxel, cabazitaxel, vinblastine, vincristine, vinorelbine , Teniposide, trabectedin, or a combination thereof, but is not limited thereto.

In the present invention, the term "hormone preparation" means to regulate, reduce, block or inhibit the hormonal effect that can promote the growth of cancer. The hormonal preparations include diethylstilbestrol, medroxyprorogesterone, megestol, megesterol, fulvestrant, tamoxifen, toremifene, and bicalutamide ), Flutamide, anastrozole, exemestane, letrozole, buserelin, gosereline, leuprorelin, trypto It may be a retorlin (triptorelin), aminoglutethimide (aminoglutethimide) or a combination thereof, but is not limited thereto.

In one embodiment of the present invention, the cytotoxic anti-cancer agent included in the pharmaceutical composition of the present invention may be one or more selected from the group consisting of alkylating agents, anti-tumor antibiotics and plant-derived alkaloids, preferably bendamu. It may be one or more selected from the group consisting of stin, doxorubicin and etoposide.

In one embodiment of the present invention, the content ratio of the PI3 kinase inhibitor and the cytotoxic anticancer agent may be 0.2 to 1: 20 to 1, but is not limited thereto.

The pharmaceutical composition of the present invention is a combination of a compound represented by Chemical Formula 1, a PI3 kinase inhibitor, and a cytotoxic anticancer agent, and thus prevents and treats cancer due to synergistic complementary effects.

In a specific embodiment of the present invention, it was confirmed that the compound represented by Chemical Formula 1, which is the PI3 kinase inhibitor and the cytotoxic anticancer agent, exhibits an increased cancer cell killing effect compared to single administration (Table 1 and FIG. 1). The pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of cancer.

In the present invention, the term "cancer" refers to a problem in the regulation function of normal division, differentiation or death of cells, which causes abnormally excessive proliferation and infiltration into surrounding tissues or organs to form lumps and destroy existing structures. It means any state that transforms or transforms. Cancer is largely divided into primary cancer existing at the site of development and metastatic cancer spreading from the site of development to other parts of the body. The cancers include, for example, gynecological tumors, endocrine cancers, central nervous system tumors, and urinary tract cancers, and diseases to be prevented, improved or treated according to the present invention are interpreted to be included as long as they fall within the category of cancer medically. The specific disease name is not particularly limited, but specifically, lung cancer, non-small cell lung cancer (NSCL), bronchial alveolar cell lung cancer, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine cancer , Ovarian cancer, rectal cancer, colon cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, larynx cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethra Cancer, penile cancer, prostate cancer, multiple myeloma, chronic or acute leukemia, childhood solid tumor, lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, contractile tumor, brain stem Glioma or pituitary adenomas. More specifically, in the present invention, the cancer may be lymphoma. For example, lymphomas are non-Hodgkin's lymphoma, Epstein-Barr related lymphoma, Hodgkin lymphoma, lymphocytic leukemia, multiple myeloma, diffuse giant B Diffuse lymphoma (diffuse large B-cell lymphoma).

In the present invention, the term "prevention" means a delay in the development of a disease, disorder or disease. Prevention may be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period of time.

In the present invention, the term "treatment" refers to partially or completely alleviating, improving, alleviating, inhibiting or delaying the onset of a specific disease, disorder and / or disease, reducing the severity, or developing one or more symptoms or characteristics It means reducing.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is formulated by using a pharmaceutically acceptable carrier according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. It can be manufactured in unit dose form or can be prepared by incorporating into a multi-dose container.

In the present invention, the term "carrier" means a compound that facilitates the addition of a compound into cells or tissues, and the term "pharmaceutically acceptable" means physiologically acceptable and when administered to humans, It refers to a composition that does not cause allergic reactions or similar reactions such as gastrointestinal disorders and dizziness.

In one embodiment of the present invention, the pharmaceutically acceptable carrier is commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not limited. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.

In one embodiment of the present invention, the content of the additives contained in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within a content range used in conventional formulation.

In one embodiment of the present invention, the composition of the present invention is a liquid, suspension, powder, granule, tablet, capsule, pill, ex-emulsion, emulsion, syrup, aerosol, etc. It can be formulated and used in various forms such as oral formulations, injections of sterile injectable solutions, or by intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, spinal, spinal or rectal topical administration or injection. It can be administered parenterally through a variety of routes, the dosage of the patient's body weight, age, sex, health status, diet, time of administration, method of administration, duration or interval, excretion rate, constitution specificity, the nature of the agent, the disease The range may vary depending on the severity.

In the present invention, the term "liquid" means a medicine taken in the form of a medicine dissolved in water or an organic solvent. The liquid formulation has a more effective advantage of drug absorption into the systemic circulatory system in the intestinal tract than the suspension or solid formulation, and the liquid formulation may contain additional solutes in addition to pharmaceuticals and give color, odor, sweetness or stability. Additives may also be included.

In the present invention, the term "suspension agent" is any that can provide the desired solubility and / or dispersibility of the alginate-containing composition, that is, to provide an aqueous formulation that is substantially transparent and free of sedimentation and lumps. Means an agonist.

In the present invention, the term "powder" means a finely divided drug, a chemical, or a mixture of both.

In the present invention, the term "granule" means a mixture of pharmaceutical or pharmaceutical products in the form of granules, and generally refers to a range that passes through a sieve of 4.76 to 20 mm. Granules are generally produced by wetting the powder, or powder mixture, and passing the mass through a sieve or granulator of suitable mesh size, depending on the size of the granules required. Since granules, like powders, are in a particle state, the degree to which the drug touches the tongue is large, and when a drug having a bitter taste is used in the form of granules, it may cause discomfort to patients, especially children or the elderly.

In the present invention, the term "tablet" means that the powdered medicine is compressed into a small disk shape and is easily taken. Tablets may include uncoated tablets, film coated tablets, dragee tablets, multilayer tablets, nucleated tablets, inner core tablets, oral disintegrating tablets, chewable tablets, foamed tablets, dispersed tablets, dissolved tablets, and the like.

In the present invention, the term "capsule" means that the medicine is filled into capsules in the form of liquid, suspension, water, powder, granule, minitablet or pellet, or encapsulated with a capsule base.

In the present invention, the term "pill" is meant to encompass a small, round solid dosage form comprising composite particles mixed with a binder and other excipients.

In the present invention, the term "ex-agent", a pharmaceutical ingredient in a vegetable or animal herbal medicine is leached with a suitable leaching agent, the solvent is evaporated, concentrated to a prescribed concentration, and the excipient is added in the case where the main ingredient content is specified. It means a semi-solid or solid preparation made by adjusting the content.

In the present invention, the term "syrup agent" means a thick, sugar-made substitute of sugar or a sugar substitute. In the present invention, the syrup agent is a medicine that has an unpleasant taste, such as a bitter taste, as a liquid and is easy to take, and is particularly suitable for children to take. In the present invention, the syrup may include, but not limited to, purified water and extracts, sugar substitutes, antimicrobial preservatives, flavoring agents, flavoring agents, or colorants used to give sweetness and sweetness and viscosity. Examples of sweeteners that may be included in such syrup agents include, but are not limited to, white sugar, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin or menthol.

In the present invention, the term "injection agent" refers to a sterile preparation that is applied to the body through the skin or through the skin or mucous membranes, usually as a solution or suspension of a drug, or as a drug to be dissolved when used, and in particular, the route of administration of the injection. Either a subcutaneous injection or an intramuscular injection may be used, and the dosage form is selected by the properties of each pharmacologically active substance.

In one embodiment of the present invention, the pharmaceutical composition of the present invention may be for oral administration. In the present invention, the term "oral administration" means that the active substance is administered to a substance prepared to be digested, that is, to the gastrointestinal tract for absorption. Non-limiting examples of the formulation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, preparation powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, etc. Can be heard. In order to formulate the pharmaceutical composition of the present invention for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, etc .; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol can be used, and sweeteners, fragrances, syrups, and the like can also be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be additionally used.

In the present invention, the term "excipient" means any substance that is not a therapeutic agent, and is used as a carrier or medium for delivery of the therapeutic agent or means added to a pharmaceutical composition. This will improve handling and storage properties or allow and promote the formation of unit doses of the composition.

In one embodiment of the present invention, the pharmaceutical composition of the present invention may be for parenteral administration. In the present invention, the term "parenteral administration" means intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, spinal, vertebral cavity or rectal topical administration or infusion. Parenteral administration is by injection of suppositories, subcutaneous injections, intravenous injections, intramuscular injections or intrathoracic injections. At this time, in order to formulate a formulation for parenteral administration, the composition may be mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and may be prepared as a unit dosage form of an ampoule or vial.

Preferred dosages of the pharmaceutical compositions of the present invention are the patient's condition and weight, age, sex, health status, dietary constitution specificity, the nature of the agent, the extent of the disease, the time of administration of the composition, the method of administration, the duration or interval of excretion, excretion The range may vary depending on the rate and the drug form, and may be appropriately selected by those skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg / kg, but is not limited now, and may be administered once or several times a day.

In one embodiment of the present invention, the pharmaceutical composition of the present invention may include two separate agents, may be composed of one agent, but is not limited thereto.

In one embodiment of the present invention, the PI3 kinase inhibitor may be administered parenterally or orally, preferably orally. The contents of oral administration are the same as above.

In one embodiment of the present invention, the cytotoxic anti-cancer agent may be administered parenterally or orally, preferably parenterally. The contents for parenteral administration are the same as above.

Pharmaceutical composition for preventing or treating cancer

The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a PI3 kinase inhibitor, which is administered together with an effective amount of a cytotoxic anticancer agent.

In one embodiment of the present invention, the cytotoxic anti-cancer agent may be administered simultaneously with the PI3 kinase inhibitor or separately, and the effective amount may be a method for formulating a pharmaceutical composition, a mode of administration, a time of administration and / or a route of administration, etc. It can be varied, and those of ordinary skill in the art can easily determine and prescribe a dose effective for the desired treatment.

The compound used as a PI3 kinase inhibitor in the pharmaceutical composition for preventing or treating cancer of the present invention may be the same as the compound represented by Formula 1 of the pharmaceutical composition, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Specifically, it may be a compound represented by Formula 2 or 3, and the cytotoxic anticancer agent is applicable in the same manner as described above.

Pharmaceutical composition for combination administration for prevention or treatment of cancer

The present invention provides a pharmaceutical composition for combination administration for the prevention or treatment of cancer, including a PI3 kinase inhibitor and a cytotoxic anticancer agent.

The compound used as a PI3 kinase inhibitor in the pharmaceutical composition for combination administration for the prevention or treatment of cancer of the present invention is the same as the compound represented by Formula 1 of the pharmaceutical composition, its stereoisomer or its pharmaceutically acceptable salt It may be, specifically, may be a compound represented by the formula (2) or (3), and the cytotoxic anticancer agent is applicable in the same manner as described above.

Prevention or treatment of cancer

The present invention provides a method for preventing or treating cancer, including administering a PI3 kinase inhibitor and a cytotoxic anticancer agent to an individual in need.

In the present invention, the term "individual" means a mammal such as a monkey, a cow, a horse, a dog, a cat, a rabbit, a rat, and a mouse, and particularly includes humans. The prophylactic or therapeutic method includes administration of a therapeutically effective amount.

In the present invention, the term "therapeutically effective amount" refers to the amount of the PI3 kinase inhibitor and cytotoxic anticancer agent of the present invention effective for the prevention or treatment of cancer.

In the prophylactic or therapeutic method of the present invention, the PI3 kinase inhibitor and the cytotoxic anticancer agent may be administered sequentially or simultaneously in any order. When the PI3 kinase inhibitor and the cytotoxic anticancer agent are administered simultaneously in the prophylactic or therapeutic method of the present invention, they may be formulated and administered as a single agent, and the agent containing the PI3 kinase inhibitor and the agent containing the cytotoxic anticancer agent Each may be formulated in separate formulations and administered simultaneously.

The prophylactic or therapeutic methods of the present invention include not only treating the disease itself prior to the onset of symptoms, but also inhibiting or avoiding the symptoms thereof, by administering a PI3 kinase inhibitor and a cytotoxic anticancer agent. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Suitable dosage regimens can be readily selected by those of ordinary skill in the art taking these factors into account. In addition, the prophylactic or therapeutic methods of the present invention may further include the administration of a therapeutically effective amount of an additional active agent conducive to the treatment of a disease together with a PI3 kinase inhibitor and a cytotoxic anticancer agent, and the additional active agent is a PI3 kinase inhibitor And it may exhibit a synergistic or additive effect with the cytotoxic anticancer agent.

The compound used as a PI3 kinase inhibitor in the method for preventing or treating cancer of the present invention may be the same as the compound represented by Formula 1 of the pharmaceutical composition, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, specifically It may be a compound represented by the formula (2) or (3), and the cytotoxic anticancer agent is applicable in the same manner as described above.

Use for the manufacture of drugs for the prevention or treatment of cancer

The present invention provides the use of a pharmaceutical composition comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent for the manufacture of a medicament for the prevention or treatment of cancer.

In one embodiment of the present invention, the PI3 kinase inhibitor and the cytotoxic anticancer agent of the present invention for the manufacture of a medicament may be mixed with an acceptable carrier, and may further include other agents.

The compound used as a PI3 kinase inhibitor in the use for the preparation of a medicament for the prevention or treatment of cancer of the present invention may be the same as the compound represented by Formula 1 of the pharmaceutical composition, its stereoisomer, or a pharmaceutically acceptable salt thereof It may be, specifically, may be a compound represented by the formula (2) or (3), and the cytotoxic anticancer agent is applicable in the same manner as described above.

The matters mentioned in the compositions, treatment methods and uses of the present invention apply equally unless contradictory to each other.

The composition according to the present invention is excellent in preventing or treating cancer when the PI3 kinase inhibitor and the cytotoxic anticancer agent are administered in combination, compared to the case where the PI3 kinase inhibitor is administered alone. Therefore, the pharmaceutical composition of the present invention can be usefully applied to the prevention, treatment or improvement of cancer.

1 is a PI3 kinase inhibitor (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3) in the SU-DHL-10 cell line. Tumors following single or combined administration of -yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one (labeled "PI3K inhibitor") and cytotoxic anticancer agent (bendamustine) It is a diagram showing the volume of cells.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example 1. (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [ Preparation of 2,3-d] pyrimidin-5 (8H) -one

(S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) represented by the following Chemical Formula 3 Pyrido [2,3-d] pyrimidin-5 (8H) -one (4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin -3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one) was prepared by the same method as described in Example 10 of International Patent Publication WO2016 / 204429.

[Formula 3]

Example 2. Confirmation of synergistic effect of PI3 kinase inhibitor and cytotoxic anticancer agent

DLBCL GCB (SU-DHL-10, ATCC) cells were cultured in 10% fetal calf serum RPMI (Gibco) medium in a 37 ° C, 5% CO ₂ incubator, and the cell growth was measured using the WST-8 kit (Cyto X, LPSsolution). As a PI3 kinase inhibitor of Formula 1, (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3) according to Example 1 above -Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was used.

Cells were inoculated into 96-well plates at 5 × 10 ³ cells / well, and the cytotoxic anticancer drugs Vendamustine (Selleckchem), Doxorubicin, and Etoposide (Sigma Aldrich) were prepared for each concentration, followed by the PI3 kinase inhibitor of Formula 1 (S ) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] Dilution with pyrimidine-5 (8H) -one to half log level was treated to a final 0.2% DMSO. After 72 hours, WST-8 was treated with 10 μL / well, and the change in cell growth was analyzed by measuring the absorbance at 450 nm using Flexation 3 (Molecular Devices). The GI (growth inhibition) value was calculated by the following [Equation 1], and the GI ₅₀ value was calculated by nonlinear regression analysis using GraphPad Prism.

[Equation 1]

In addition, the CI (combinational index) value was calculated using a CompuSyn software program based on the Chou-Talalay equation, and if the CI value is less than 1, synergism, 1 It was interpreted as additive on the back side and antagonism on a scale greater than 1.

The results are shown in Table 1 below.

[Table 1]

As a result of Table 1, the PI3 kinase inhibitor of Formula 1 (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3 It can be confirmed that a significant synergistic effect occurs in the prevention or treatment of cancer by the combination of -yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one and a cytotoxic anticancer agent. .

Example 3. in vivo  exam

Human-derived lymphoma cells SU-DHL-10 cells (American Type Culture Collection, ATCC) were used, and CB 17 SCID mice were 6-week-old females that were supplied from Hallym experimental animals (Charles river, Japan) and purified for 1 week. After the process, it was used in a test while breeding in a thermo-hygrostat. In addition, as a PI3 kinase inhibitor of Formula 1, (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline) according to Example 1 above -3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was used.

After counting the cells, 100 μL of 2 × 10 ⁶ cells and 100 μL of Matrigel (Corning, NY) were mixed, and a total of 200 μL were transplanted into the abdominal region of a CB 17 SCID mouse by SC (subcutaneous). When the tumor size after transplantation is about 80 to 120 mm 2, the control (Control), the PI3 kinase inhibitor of Formula 1 (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl) -1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one 50 mg / kg group, bendamustine 25 mg / kg group , PI3 kinase inhibitor of formula 1 (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino ) Pyrido [2,3-d] pyrimidine-5 (8H) -one 50 mg / kg + bendamustine 25 mg / kg group was administered. (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline), a PI3 kinase inhibitor of Formula 1, for preparing drugs for administration to animals. After measuring 50 mg / kg of -3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one, 0.5 mL of DMSO (Sigma, USA) as an excipient, PEG400 (Dae- jung Co.) 5.5 mL and 4 mL of distilled water were added, and Bendamustine (Eisai Co.) was dissolved in 10 mL of physiological saline after measuring 25 mg / kg. The dose of the drug was calculated at 10 mL / kg based on the most recently measured body weight, and the PI3 kinase inhibitor of Formula 1 (S) -4-((1- (4,8-dichloro-1-oxo) -2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was administered once / day by oral administration. , Bendamustine was administered once / week by intravenous administration. Cancer transplanted mice were tumor sized for all subjects 3 times a week from the start of the administration to the end of the administration, and the tumor volume was calculated by applying to the second decimal place using vernier calipers in the order of long axis and short axis. The following [Equation 2] was used as the calculation formula.

[Equation 2]

1 is a PI3 kinase inhibitor of Formula 1 (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroiso) in the SU-DHL-10 cell line. Quinoline-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one compound and the volume of tumor cells following administration alone or in combination with a cytotoxic anticancer agent (bendamustine) It is shown.

Hereinafter, in FIG. 1, (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was designated as "PI3K inhibitor".

As a result of FIG. 1, (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) belonging to the category of Chemical Formula 1 ) Ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one and the cytotoxic anticancer agent (bendamustine) alone, the PI3 kinase inhibitor (S) -4 -((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine- It was confirmed that a statistically significant difference in tumor volume was observed when the 5 (8H) -on and cytotoxic anticancer agent (bendamustine) was administered in combination.

Table 2 below shows the data in FIG. 1 numerically.

[Table 2]

As shown in Table 2, the tumor inhibition rate compared to the control group was 40.8% for the PI3 kinase inhibitor group of Formula 1, 53.5% for the bendamustine group, and 66.1% for the combination administration group of the PI3 kinase inhibitor of Formula 1 and bendamustine. It appeared that it appeared.

Through the above experimental results, PI3 kinase inhibitor (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl It was confirmed that the combination administration of amino) pyrido [2,3-d] pyrimidine-5 (8H) -one and the cytotoxic anticancer agent (bendamustine) has a synergistic effect in the treatment of cancer and shows a remarkably excellent anticancer effect. Could. Therefore, the pharmaceutical composition according to the present invention can be usefully applied to the prevention, treatment or improvement of cancer, and the treatment method according to the present invention can also be effectively applied to the prevention or treatment of cancer.

The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and a cytotoxic anti-cancer agent, wherein the composition according to the present invention alone administers a compound of Formula 1 or a cytotoxic anti-cancer agent used as a PI3 kinase inhibitor Compared with one case, the prevention or treatment activity of cancer is excellent. Therefore, the composition of the present invention can be usefully applied to the prevention, treatment or improvement of cancer.

Claims (19)

A pharmaceutical composition for the prevention or treatment of cancer, comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the PI3 kinase inhibitor is a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is hydrogen; Or a linear or branched alkyl group having 1 to 5 carbon atoms,
R ₂ is a phenyl group or a pyridinyl group, and the phenyl group or pyridinyl group is a halogen group; And one or more substituents selected from the group consisting of straight or branched alkyl groups having 1 to 5 carbon atoms, or unsubstituted,
R ₃ and R ₄ are each independently hydrogen or a halogen group. According to claim 2,
The compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is a compound represented by Formula 2 below, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating cancer :
[Formula 2]

In Formula 2,
R ₁ is hydrogen; Or a linear or branched alkyl group having 1 to 5 carbon atoms,
R ₂ is a phenyl group or a pyridinyl group, and the phenyl group or pyridinyl group is a halogen group; And one or more substituents selected from the group consisting of straight or branched alkyl groups having 1 to 5 carbon atoms, or unsubstituted,
R ₃ and R ₄ are each independently hydrogen or a halogen group. According to claim 2,
R ₃ is a hydrogen or halogen group, a pharmaceutical composition for the prevention or treatment of cancer. According to claim 2,
R ₄ is hydrogen; Or a pharmaceutical composition for preventing or treating cancer that is a halogen group. According to claim 2,
The compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline -3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one (4-((1- (4,8-dichloro-1-oxo-2-phenyl-1) , 2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer Pharmaceutical composition. According to claim 2,
The compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is (S) -4-((1- (4,8-dichloro-1-oxo-2-phenyl-1,2- Dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidine-5 (8H) -one ((S) -4-((1- (4,8-dichloro-1) -oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one) or a pharmaceutically acceptable salt thereof Pharmaceutical composition for prevention or treatment. According to claim 1,
The cytotoxic anticancer agent is a pharmaceutical composition for the prevention or treatment of cancer that is at least one selected from the group consisting of alkylating agents, platinum compounds, metabolic antagonists, anti-tumor antibiotics, plant-derived alkaloids and hormones. According to claim 1,
The cytotoxic anti-cancer agent is a pharmaceutical composition for preventing or treating cancer that is one or more selected from alkylating agents, anti-tumor antibiotics and plant-derived alkaloids. According to claim 1,
The cytotoxic anticancer agent is a pharmaceutical composition for preventing or treating cancer that is at least one selected from the group consisting of bendamustine, doxorubicin and etoposide. According to claim 1,
The PI3 kinase inhibitor is a pharmaceutical composition for preventing or treating cancer, which is administered orally. According to claim 1,
The cytotoxic anti-cancer agent is a pharmaceutical composition for the prevention or treatment of cancer that is administered parenterally. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the composition is any one of a liquid, a suspension, a powder, a granule, a tablet, a capsule, a pill, an ex, an emulsion, a syrup, an aerosol, or an injection. . The method of claim 1, wherein the cancer is lung cancer, non-small cell lung cancer (NSCL), bronchial alveolar cell lung cancer, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine cancer, ovarian cancer. , Rectal cancer, colon cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penis Cancer, prostate cancer, multiple myeloma, chronic or acute leukemia, childhood solid tumor, lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, contractile tumor, brainstem glioma or pituitary adenomas Pharmaceutical composition for the prevention or treatment of cancer. The pharmaceutical composition for preventing or treating cancer according to claim 14, wherein the cancer is lymphoma. A pharmaceutical composition for the prophylaxis or treatment of cancer comprising a PI3 kinase inhibitor, which is administered together with an effective amount of a cytotoxic anticancer agent. A pharmaceutical composition for combination administration for the prevention or treatment of cancer, including a PI3 kinase inhibitor and a cytotoxic anticancer agent. A method for preventing or treating cancer, comprising administering a PI3 kinase inhibitor and a cytotoxic anticancer agent to an individual in need. Use of a pharmaceutical composition comprising a PI3 kinase inhibitor and a cytotoxic anticancer agent for the manufacture of a medicament for the prevention or treatment of cancer.

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