WO2019139388A1 - Pharmaceutical composition comprising pi3 kinase inhibitor and immune checkpoint inhibitor for preventing or treating cancer - Google Patents

Abstract

Provided is a pharmaceutical composition comprising a PI3 kinase inhibitor and an immune checkpoint inhibitor for preventing or treating cancer. The composition according to the present invention exhibits excellent cancer treatment effects compared to administration solely of a cytotoxic anti-cancer agent or a compound expressed by chemical formula 1 which has been used as a PI3 kinase inhibitor. Therefore, the composition according to the present invention can be effectively utilized to prevent, treat or ameliorate cancer.

Description

Pharmaceutical composition for preventing or treating cancer comprising PI3 kinase inhibitor and immunostimulatory agent

Mutual citation with related application

This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0003401, filed on Jan. 10, 2018, the entire contents of which are incorporated herein by reference.

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

Immunotherapy has recently been developed as a result of the development of the field of immunology and the understanding of the immune system of the human body has been developed as a new tumor treatment method, using the patient's own immune system to obtain long-term anti-tumor immunity with few side effects There are advantages.

The goal of immunotherapy is to generate tumor-specific cytotoxic T lymphocytes (CTLs) that can recognize tumor cells or tumor antigens and remove tumor cells. In other words, tumor antigen peptides are loaded on the major histocompatibility complex (MHC) and presented on T lymphocytes by tumor cells or antigen presenting cells to activate T lymphocytes, inducing differentiation into CTLs and increasing CTLs.

However, most human tumors are difficult to treat due to the immunological monitoring of individuals. 1) Tumor antigens are mostly expressed during the birth or are part of the self-antigen that is expressed in normal cells, 2) MHC expression by tumor cells is poor, tumor antigen is incompletely treated in tumor cells, and 3) most tumor cells are not stimulated with auxiliary stimulating molecules necessary for antigen presentation And 4) it is possible to avoid immunosurveillance by the inhibitory cytokine secreted by the tumor.

In addition, phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates lipid molecules instead of proteins. It is known to inhibit cell survival, signal transduction, control of membrane trafficking, and so on. If there is a problem with these controls, cancer, inflammatory diseases, autoimmune diseases and the like occur.

Cancer can pose a health threat to the world, due to a variety of causative factors that can individually or collectively trigger or promote the invention of cancer. Therefore, it is important to develop a more effective approach, especially a combined approach, to improve cancer prevention and treatment.

Accordingly, the present inventors have conducted various studies to provide a pharmaceutical composition for preventing or treating cancer that can maximize the advantages of the immunotherapeutic agent using the immunotherapy together with the PI3 kinase inhibitor.

[Prior Art Literature]

[Patent Literature]

(Patent Document 1) 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 an immunostimulant inhibitor.

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

It is another object of the present invention to provide a pharmaceutical composition for the combined administration for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.

Another object of the present invention is to provide a method of preventing or treating cancer, comprising administering a PI3 kinase inhibitor and an immunostimulatory agent to a subject in need thereof.

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

In order to achieve the above object, the present invention has developed a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor, wherein the pharmaceutical composition for preventing or treating cancer is a PI3 kinase inhibitor, It was confirmed that the preventive or curative activity of cancer was improved because of the upward complementary effect according to the combination thereof.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for preventing or treating cancer

The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.

By using the PI3 kinase inhibitor and the immunostimulant inhibitor in combination, the pharmaceutical composition of the present invention is remarkably effective for the prevention and treatment of cancer due to the synergistic complementary effect of the combined use of the PI3 kinase inhibitor and the immunostimulant inhibitor.

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

[Chemical Formula 1]

In formula (1)

R ₁ is hydrogen; Or a straight 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 the pyridinyl group is a halogen group; And a linear or branched alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted with one or more substituents selected from the group consisting of

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

In the present invention, in the expression "number of carbon atoms x" of the functional group, x represents the number of carbon atoms, and the number of carbon atoms x to y represents a functional group having a carbon number of x or more and y or less.

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 straight or branched alkyl group having 1 to 5 carbon atoms, such as methyl , Ethyl, propyl, isobutyl, pentyl, and the like.

In the present invention, the term "substituted with a substituent" is replaced with a substituent whose 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 the substitution. Also, unless expressly stated to be "unsubstituted ", all functional groups should be interpreted as being able to be substituted or unsubstituted.

In the present invention, the term " halogen " represents 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.

(2)

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

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

In one embodiment of the present 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 the pyridinyl group is a halogen group; And a linear or branched alkyl group 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 present invention, R ₃ is a halogen group.

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

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

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

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

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

(3)

In the present invention, the compound represented by the formula (1) can be produced by, for example, but not limited to, the process described in International Patent Publication No. WO 2016/204429.

In the present invention, the term " pharmaceutically acceptable " means physiologically acceptable and when administered to humans, does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness or the like, Means an acid addition salt formed by a pharmaceutically acceptable free acid. Accordingly, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, and includes inorganic ion salts such as calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, , Inorganic acid salts prepared from perchloric acid, sulfuric acid, and the like; There may be mentioned acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic 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, Organic acid salts prepared from acids, ascorbic acid, carbonic acid, or vanillyric acid; Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid; Amino acid salts prepared with glycine, arginine, lysine and the like; Or an amine salt prepared by using trimethylamine, triethylamine, ammonia, pyridine, picoline, or the like. However, the types of salts defined in the present invention are not limited by the listed salts.

In one embodiment of the invention, the compound represented by Formula 1, its stereoisomer or pharmaceutically acceptable salt thereof is selectively inhibited against a PI3 kinase inhibitor selected from the group consisting of PI3K [alpha], PI3K [beta], PI3K [ can do.

In the present invention, the term " immune checkpoint inhibitor " refers to any nucleic acid or protein that prevents inhibition of any component in the immune system, such as MHC class presentations, T cell presentation and / or differentiation, And / or differentiation, and signal transduction for cytokine, chemokine, or immune cell proliferation and / or differentiation. By blocking the immune gating that prevents the progress of the immune response in cancer with high immunosuppressive ability, Lt; / RTI >

The immunostimulant inhibitor of the present invention has been widely used for anticancer strategies as a new tumor treatment agent developed according to the result of the understanding of the human immune system as the development of immunology field. There is a PD-1 / PD-L1 mechanism that inhibits T-lymphocyte inhibition by CTLA-4 and activated T-lymphocyte. However, current immunostimulatory agents have been reported to have limitations such as low therapeutic efficacy and low efficacy.

However, the pharmaceutical composition for preventing or treating cancer according to the present invention has a remarkable up-regulating effect compared with the case of using the anti-cancer drug PI3 kinase inhibitor and the immunostimulant inhibitor alone, It helps prevent and treat cancer.

In one embodiment of the invention, the immunostimulatory agent may be an antibody, a fusion protein, an aptamer or an immunoglobulin protein-binding fragment thereof. For example, the immunostimulatory agent is an anti-immunoglobulin protein antibody or antigen-binding fragment thereof. In a specific example, the anti-CTLA4 antibody, derivatives thereof or antigen-binding fragments thereof; An anti-PD-L1 antibody, a derivative thereof or an antigen-binding fragment thereof; And anti-PD-1 antibodies, derivatives thereof, or antigen-binding fragments thereof. For example, the immunostimulant inhibitor may be selected from the group consisting of ipilimumab, derivatives thereof or antigen-binding fragments thereof; Atezolizumab, derivatives thereof or antigen-binding fragments thereof; Nivolumab, derivatives thereof or antigen-binding fragments thereof; And Pembrolizumab, derivatives thereof, or antigen-binding fragments thereof, and may be used without limitation as long as it is an antibody or other type of immunostimulatory agent that can be used as an immunostimulatory agent.

The immunostimulant inhibitor may exhibit the preventive or therapeutic effect of cancer according to the combination therapy with other therapeutic methods other than the PI3 kinase inhibitor.

In one embodiment of the present invention, the immunostimulatory agent is preferably at least one selected from anti-CTLA4 antibody, anti-PD-1 antibody and anti-PD-L1 antibody. The antibody may be purchased from, for example, a conventional antibody manufacturer, or may be prepared according to a known method for producing an antibody.

In one embodiment of the invention, the ratio of the PI3 kinase inhibitor to the immunostimulant inhibitor may be 1: 1 to 50: 1, but is not limited thereto.

The pharmaceutical composition of the present invention is remarkably effective for preventing and treating cancers due to the combination of the above-mentioned PI3 kinase inhibitor, compound of formula (1) and an immunostimulant inhibitor.

In a specific embodiment of the present invention, it was confirmed that the combination of the compound represented by the formula (1), which is the PI3 kinase inhibitor, and the anti-PD-1 antibody showed an increased cancer therapeutic effect as compared with the single administration ), The pharmaceutical composition of the present invention can be usefully used for prevention or treatment of cancer.

In the present invention, the term " cancer " as used herein refers to a disease caused by a disorder in the function of regulating normal division, differentiation or death of cells, resulting in abnormally excessive proliferation and invasion into surrounding tissues or organs to form lumps, Or transforming a state. Cancer is largely divided into primary carcinoma in the affected area and metastatic cancer that has spread to other parts of the body from the site of development.

The cancer may be, for example, various cancers of the human body, gynecologic tumors, endocrine system cancers, central nervous system tumors, urothelial carcinomas, pancreatic cancer, Cancer cells such as lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar lung cancer, gastric 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 Cancer of the endometrium, vulvar carcinoma, vulvar carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small bowel cancer, thyroid cancer, prostate cancer, soft tissue sarcoma, urethral cancer, penile cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, Cancer of the prostate, multiple myeloma, chronic or acute leukemia, childhood solid tumor, lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, axillary neoplasm, brainstem glioma, or pituitary adenoma And, without being limited thereto. More specifically, in the present invention, the cancer may be non-small cell lung cancer, bladder cancer, head and neck cancer, or lymphoma. For example, lymphoma can be classified as non-Hodgkin's lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, lymphoblastic leukemia, multiple myeloma, diffuse large B Cell lymphoma (diffuse large B-cell lymphoma).

In the present invention, the term " prevention " means delaying the onset of a disease, disorder or disease. If the onset of a disease, disorder or disease is delayed for a predetermined period of time, prevention may be considered complete.

In the present invention, the term " treatment " refers to a treatment that partially or completely alleviates, ameliorates, alleviates, inhibits or slows the onset of a particular disease, disorder and / or disease, decreases severity, . ≪ / RTI >

In one embodiment of the present invention, the pharmaceutical composition of the present invention may be formulated using a pharmaceutically acceptable carrier according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs May be prepared in unit dosage form or may be manufactured by intrusion into a multi-dose container.

In the present invention, the term " carrier " means a compound that facilitates addition of a compound into a cell or tissue. The term " pharmaceutically acceptable " means physiologically acceptable, Refers to compositions that do not cause an allergic reaction such as gastrointestinal disorders, dizziness, or similar reactions.

In one embodiment of the present invention, the pharmaceutically acceptable carriers are those conventionally used in the field of the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, But is not limited to. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, 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 additive contained in the pharmaceutical composition is not particularly limited and may be appropriately controlled within the range of contents used for conventional formulation.

In one embodiment of the present invention, the composition of the present invention may be formulated into a liquid, a suspension, a powder, a granule, a tablet, a capsule, a pill, an extract, an emulsion, a syrup, Or oral administration of a sterile injectable solution and may be administered orally or intravenously, intraperitoneally, subcutaneously, intradermally, intramuscularly, spinally, spinally or rectally, including topical administration or infusion. Can be administered parenterally through various routes.

In the present invention, the term " liquid preparation " means a drug that consumes the medicament in the form of a potion dissolved in water or an organic solvent. The liquid agent has a more advantageous effect of absorbing the drug into the systemic circulation system in the intestinal tract as compared with the suspension or solid agent, and the liquid agent can include an additional solute in addition to the medicines. The liquid agent can provide color, odor, Additives may also be included.

In the context of the present invention, the term " suspension " refers to any agent capable of providing the desired solubility and / or dispersion of the alginate containing composition, i. E., Providing substantially clear, precipitated and lump- ≪ / RTI >

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

In the present invention, the term " granule " means a granule made of granules or a mixture of medicines, usually in a range of 4.76 to 20 mm through a sieve. Granules are generally produced by wetting a powder, or a powder mixture, and passing the granules through a suitable mesh size sieve or granulator depending on the size of the granules that need it. As with granules, granules are also in a particulate state, so the degree of contact of the drug with the tongue is so great that if a bitter taste drug is used in the granule form, it may cause discomfort to the patient, especially to the young or elderly.

In the present invention, the term " tablet " means that a powdered medicament is compressed into a small disc shape and made easy to take. Tablets may include tablets, film-coated tablets, dragees, multi-layer tablets, tablets, core tablets, oral tablets, chewable tablets, effervescent tablets, dispersions, dissolving tablets and the like.

In the present invention, the term " capsule preparation " means a preparation made by filling a capsule into a capsule in the form of a liquid, a suspension, a tablet, a powder, a granule, a mini tablet or a pellet or a capsule base.

For the purposes of the present invention, the term " pills " is meant to encompass small, round solid dosage forms comprising multiparticulates mixed with binders and other excipients.

In the present invention, the term " extract " is intended to mean that the active ingredient in vegetable or animal herbal medicines is leached out using a suitable precipitant and the solvent is evaporated to a predetermined concentration. In the case where the main ingredient content is specified, Means a semi-solid or solid preparation made by adjusting the content.

In the present invention, the term " syrup agent " means a thickened hand made of sugar or sugar substitute. In the present invention, the above-mentioned syrup agent is an easy-to-take pharmaceutical agent having an unpleasant taste, for example, a bitter taste, and is particularly suitable for use by children. In the present invention, the above-mentioned syrup may include, but is not limited to, a substitute for sardine used in order to impart sweetness or sweetness and viscosity in addition to purified water and extract, antimicrobial preservative, flavor or colorant. Examples of the sweetening agent that can be included in such a syrup 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 " injectable preparation " means a sterile preparation which is usually applied to the body through a skin or mucous membrane, As for the subcutaneous injection and the intramuscular injection, any dosage form can be used, and the dosage form is selected depending on the characteristics of each pharmacologically active substance.

In one embodiment of the invention, the pharmaceutical composition of the present invention may be for oral administration. For the purposes of the present invention, the term " oral administration " means that the active substance is administered to a material prepared to digest, i.e., to the gastrointestinal tract for absorption. Non-limiting examples of such oral dosage forms include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, . 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; Excipients such as dicalcium phosphate and the like; Disintegrating agents such as corn starch or sweet potato starch; Magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, and the like, and sweeteners, fragrances, syrups, and the like may be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, liquid carriers such as fatty oils can be further used.

The term " excipient " in the present invention means any substance other than a therapeutic agent, means to be used as a carrier or medium for delivery of a therapeutic agent or added to a pharmaceutical composition. Thereby improving handling and storage characteristics, or allowing and promoting the formation of unit dosage forms of the composition.

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

The preferred dosage of the pharmaceutical composition of the present invention may vary depending on the condition and body weight of the patient, age, sex, health status, dietary sperm specificity, the nature of the preparation, the degree of the disease, the administration time, administration method, Rate, and type of drug, 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 to this, and may be administered once a day or divided into several times a day.

The composition of the present invention may comprise two separate preparations, and may be composed of one formulation, but is not limited thereto.

In one embodiment of the present invention, the pharmaceutical composition may be formulated as a solution, a suspension, a powder, a granule, a tablet, a capsule, a pill, an extract, an emulsion, a syrup, an aerosol Or intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, vertebral, vertebral, or rectal topical administration or infusion, and the like can be administered orally, The dosage may vary depending on the patient's body weight, age, sex, health condition, diet, time of administration, administration method, administration period or interval, excretion rate, sickness specificity, The severity of the disease, and the like.

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

In one embodiment of the present invention, the immunostimulatory agent may be administered parenterally or orally, preferably parenterally. The content of parenteral administration is the same as described above.

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, which is administered together with an effective amount of an immunostimulatory agent.

In one embodiment of the present invention, the immunostimulant inhibitor may be administered simultaneously with the PI3 kinase inhibitor, or may be separately administered separately, and the effective amount may vary depending on the formulation method, administration route, administration time, and / , And those skilled in the art will readily determine and prescribe dosages that are 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 the formula (1) of the pharmaceutical composition, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, Specifically, it may be a compound represented by the general formula (2) or (3), and the immunostimulant inhibitor is applicable in the same manner as described above.

A pharmaceutical composition for co-administration for prevention or treatment of cancer

The present invention provides a pharmaceutical composition for the combined administration for prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.

The compound used as a PI3 kinase inhibitor in a pharmaceutical composition for coadministration of the present invention for the prophylaxis or treatment of cancer is the same as the compound represented by the formula (1) of the above pharmaceutical composition, its stereoisomer or pharmaceutically acceptable salt thereof Specifically, a compound represented by the general formula (2) or (3), and the immunostimulant inhibitor is applicable in the same manner as described above.

Prevention or Treatment of Cancer

The present invention provides a method of preventing or treating cancer, comprising administering to a subject in need thereof a PI3 kinase inhibitor and an immunostimulatory agent.

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. Such prophylactic or therapeutic methods include administration of a therapeutically effective amount.

In the present invention, the term "therapeutically effective amount" refers to the amount of PI3 kinase inhibitor and immunostimulant inhibitor 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 immunostimulant inhibitor may be administered sequentially or simultaneously in any order. When the PI3 kinase inhibitor and the immunostimulant inhibitor are administered simultaneously in the prophylactic or therapeutic method of the present invention, the agent comprising the PI3 kinase inhibitor and the agent comprising the immunostimulant inhibitor may be formulated and administered in one preparation They may be separately formulated into separate preparations and administered simultaneously.

The prophylactic or therapeutic method of the present invention not only treats the disease itself prior to the manifestation of the symptoms, but also inhibits or avoids its manifestations, by administering PI3 kinase inhibitors and immunostimulatory agents. In the management of 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 by which the active ingredient is to be administered. The frequency of dose and dose will vary with the age, weight and response of the individual patient. Appropriate dosing regimens can be readily selected by those of ordinary skill in the art which will of course consider these factors. In addition, the prophylactic or therapeutic method of the present invention may further comprise administration of a therapeutically effective amount of an additional active agent that is useful in treating a disease together with a PI3 kinase inhibitor and an immunostimulatory agent, wherein the additional active agent is a PI3 kinase inhibitor ≪ / RTI > and immunostimulatory < RTI ID = 0.0 > inhibitors. ≪ / RTI >

The compound used as a PI3 kinase inhibitor in the method for the prevention or treatment of cancer of the present invention may be the same as the compound represented by the formula (1) of the above pharmaceutical composition, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, The compound represented by the general formula (2) or (3), and the immunostimulant inhibitor is applicable in the same manner as described above.

For the manufacture of medicaments for the prophylaxis or treatment of cancer

It is an object of the present invention to provide a use of a pharmaceutical composition comprising a PI3 kinase inhibitor and an immunostimulatory agent for the manufacture of a medicament for the prophylaxis or treatment of cancer.

In one embodiment of the invention, the pharmaceutical composition comprising the PI3 kinase inhibitor and the immunostimulant inhibitor of the present invention for the manufacture of a medicament may be admixed with an acceptable carrier and the like, have.

The compound used as a PI3 kinase inhibitor in the use for the manufacture of a medicament for the prophylactic or therapeutic treatment of cancer of the present invention is the same as the compound represented by the general formula (1) of the above pharmaceutical composition, a stereoisomer thereof or a pharmaceutically acceptable salt thereof Specifically, it may be a compound represented by the general formula (2) or (3), and the immune gate inhibitor may be applied in the same manner as described above.

The matters mentioned in the use, composition and treatment method of the present invention are applied equally unless they are mutually contradictory.

The composition according to the present invention is superior in the prevention or treatment of cancer when the PI3 kinase inhibitor and the immunostimulant inhibitor are administered in combination as compared with the case where the PI3 kinase inhibitor is administered alone. Therefore, the pharmaceutical composition of the present invention can be usefully applied for prevention or improvement of cancer.

FIG. 1 is a graph showing the effect of PI3 kinase inhibitor (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- (Tumor necrosis factor-α), which is a tumor caused by a single or concomitant administration of an anti-inflammatory agent, such as 1-ethylamino) pyrido [2,3-d] pyrimidin-5 (8H) FIG. 4 is a graph showing the volume of a cell. FIG.

FIG. 2 is a graph showing the effect of the PI3 kinase inhibitor (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- 1-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one (designated as "PI3K inhibitor") and immunostimulatory (anti- FIG. 4 is a graph showing the volume of tumor cells. FIG.

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

(S) -4 - ((1- (4,8-Dichloro-1 -oxo-2-phenyl-1,2- dihydroisoquinolin-3- yl) ethyl) amino) (4 - ((4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) -pyrido [ ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one) was prepared in the same manner as described in Example 10 of International Patent Publication No. WO2016 / 204429.

(3)

Example  2. in vivo  exam

4T1 mouse-derived breast cancer cells were collected using 0.25% Trypsin. Balb-c / cAnNCrljOri 6-week-old females were supplied from Charles River, Japan and subjected to a 2-week purification procedure. Donated. Temperature 23.0 ± 1.0 ° C, relative humidity 50.0 ± 5.0%, illumination cycle 12 hours, and free animal test rats and drinking water. Also, the PI3 kinase inhibitor of the formula (1) was the same as that of Example 1 except that (S) -4 - ((1- (4,8-dichloro- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one.

By counting the cells in 5 × 10 ^4/100 μL in PBS using a 1 mL syringe into the abdominal region of Balb / c mice were implanted SC (subcutaneous). (S) -4 - ((1- (4-hydroxyphenyl) -1- (4-methylpiperidin-4-yl) Pyrido [2,3-d] pyrimidin-5 (8H) -one To a solution of 50 mg / kg group, the PI3 kinase inhibitor of Formula 1, (S) -4 - ((1- (4,8-Dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- (S) -4 - ((1- (4,8-dihydroxyphenyl) ethyl) amino) pyrido [2,3- d] pyrimidin- Pyrido [2,3-d] pyrimidin-5 (8H) -one in an amount of 50 mg / kg + anti-PD-1 10 mg / kg.

(S) -4 - ((1- (4,8-Dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) Pyrido [2,3-d] pyrimidin-5 (8H) -one was administered at 50 mg / kg daily (DMSO: PEG 400: water 1: 5: 4 ) And PD-1 and Isotype (IgG 2A, BioXcell) were administered intraperitoneally from 1 day after transplantation to 10 mg / kg (saline) every 3 days until the end of the treatment.

Body weights and tumor size were measured three times a week from the time when the tumor size was measurable to the end of the day after the start of the administration, and the volume of the tumor was calculated by applying the long axis and short axis to the second decimal place using a vernier caliper. The following formula 1 was used as a calculation formula.

[Formula 1]

FIG. 1 is a graph showing the effect of PI3 kinase inhibitor (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- 1) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one and anti-PD-1 alone or in combination.

In the following, FIG. 1 shows a method of producing the (S) -4 - ((1- (4,8-dichloro-1-oxo- [2,3-d] pyrimidin-5 (8H) -one was designated "PI3K inhibitor".

1, the PI3 kinase inhibitor, (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2- dihydroisoquinolin- (S) -4 - ((1 - ((S) -4-hydroxypyridazinone), which is a PI3 kinase inhibitor, Dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) And anti-PD-1 were administered in combination, a statistically significant tumor volume was observed.

In addition, when the anti-PD-1 was administered alone, the rebound phenomenon that appeared after 27 days was inhibited by the PI3 kinase inhibitor (S) -4 - ((1- (4,8-dichloro- (2-phenyl-l, 2-dihydroisoquinolin-3yl) ethyl) amino) pyrido [2,3- d] pyrimidin-5 (8H) It was confirmed that it was inhibited in the administration group.

Table 1 below shows the data of Fig. 1 in numerical values.

[Table 1]

As shown in Table 1, 45.0% of the PI3 kinase inhibitor group, 37.2% of the anti-PD-1 group, and 58.9% of the PI3 kinase inhibitor and anti-PD- %, Respectively.

From the above experimental results, it was found that the PI3 kinase inhibitor, (S) -4 - ((1- (4,8-dichloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin- ) Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one in combination with an immunostimulant inhibitor (anti-PD-1) exhibit a remarkably excellent anticancer effect I could confirm.

Accordingly, the pharmaceutical composition according to the present invention can be effectively applied to prevent or ameliorate cancer, and the therapeutic method according to the present invention can also be effectively applied to prevent or treat cancer.

Example  3. in vivo  exam

CT26 mouse colon cancer cells were collected using 0.25% trypsin. The test animals were a Balb-c / cAnNCrljOri 6-week-old female from Charles River, Japan and subjected to a 2-week purification procedure Respectively. Temperature 23.0 ± 1.0 ° C, relative humidity 50.0 ± 5.0%, illumination cycle 12 hours, and free animal test rats and drinking water. Also, the PI3 kinase inhibitor of the formula (1) was the same as that of Example 1 except that (S) -4 - ((1- (4,8-dichloro- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one.

And counting the cells with ⁵ × 10 5/100 μL in PBS using a 1 mL syringe into the abdominal region of the mice were implanted SC (subcutaneous). (S) -4 - ((1- (4-hydroxyphenyl) -1- (4-methylpiperidin-4-yl) Pyrido [2,3-d] pyrimidin-5 (8H) -one To a solution of 50 mg / kg group, the PI3 kinase inhibitor of Formula 1, (S) -4 - ((1- (4,8-Dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- (S) -4 - ((1- (4,8-dihydroxyphenyl) ethyl) amino) pyrido [2,3- d] pyrimidin- Pyrido [2,3-d] pyrimidin-5 (8H) -one in an amount of 50 mg / kg + anti-PD-1 10 mg / kg group.

(S) -4 - ((1- (4,8-Dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin-3- yl) ethyl) amino) Pyrido [2,3-d] pyrimidin-5 (8H) -one was administered at 50 mg / kg daily (DMSO: PEG 400: water 1: 5: 4 ) And PD-1 and Isotype (IgG 2A, BioXcell) were administered intraperitoneally from 1 day after transplantation to 10 mg / kg (saline) every 3 days until the end of the treatment.

The weight and size of the tumor were measured three times a week from the time when the tumor size was measurable to the end of the day after the start of administration and the volume of the tumor was applied to the second decimal place using a vernier caliper in the order of major axis and minor axis, Respectively.

FIG. 2 is a graph showing the effect of the PI3 kinase inhibitor (S) -4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin- 1-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one and anti-PD-1 alone or in combination.

In the following, FIG. 2 shows an example of the preparation of the 4 - ((1- (4,8-dichloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin- -d] pyrimidin-5 (8H) -one was designated as "PI3K inhibitor ".

Referring to FIG. 2, when compared with the case of administration of the immunostimulants (anti-PD-1) alone, the PI3 kinase inhibitor, (S) -4 - ((1- (4,8-dichloro- (2-phenyl-l, 2-dihydroisoquinolin-3yl) ethyl) amino) pyrido [2,3- d] pyrimidin-5 (8H) -one and anti- The tumor volume was observed to be statistically significant.

Table 2 below shows the data of FIG. 2 in numerical values.

[Table 2]

As shown in Table 2, 54.4% of the PI3 kinase inhibitor group, 43.4% of the anti-PD-1 group, and 70.9% of the PI3 kinase inhibitor and anti-PD- %, Respectively.

From the above experimental results, it was found that the PI3 kinase inhibitor, (S) -4 - ((1- (4,8-dichloro-1 -oxo-2-phenyl-1,2-dihydroisoquinolin- ) Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one in combination with an immunostimulant inhibitor (anti-PD-1) exhibit a remarkably excellent anticancer effect I could confirm. Accordingly, the pharmaceutical composition according to the present invention can be effectively applied to prevent or ameliorate cancer, and the therapeutic method according to the present invention can also be effectively applied to prevent or treat cancer.

The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor, wherein the composition according to the present invention is administered alone or in combination with a compound of Formula 1 or an immunostimulant inhibitor used as a PI3 kinase inhibitor Compared with one case, the activity of preventing or treating cancer is excellent. Therefore, the composition of the present invention can be usefully applied for prevention, treatment or improvement of cancer.

Claims (19)

1. A pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulatory agent.
2. 2. The pharmaceutical composition according to claim 1, wherein the PI3 kinase inhibitor is a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

   [Chemical Formula 1]

   

   In formula (1)

   R ₁ is hydrogen; Or a straight 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 the pyridinyl group is a halogen group; And a linear or branched alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted with one or more substituents selected from the group consisting of

   R ₃ and R ₄ are each independently hydrogen or a halogen group.
3. 3. The method of claim 2,

   The compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is a compound represented by Formula 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, :

   (2)

   

   In formula (2), R ₁ to R ₄ are the same as defined in formula (1).
4. 3. The method of claim 2,

   And R ₃ is hydrogen or a halogen group.
5. 3. The method of claim 2,

   R ₄ is hydrogen; Or a halogen group.
6. 3. The method of claim 2,

   The compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof can be prepared by reacting 4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) (2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one), a stereoisomer thereof or a pharmaceutically acceptable salt thereof A pharmaceutical composition.
7. 3. The method of claim 2,

   The compound represented by the general formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is (S) -4 - ((1- (4,8-dichloro- Dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) 2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating.
8. The method according to claim 1,

   Wherein said immunostimulatory agent is at least one selected from the group consisting of an antibody, a fusion protein, an aptamer, and an immunoglobulin protein-binding fragment thereof.
9. The method according to claim 1,

   Said anti-CTLA4 antibody, derivative or antigen-binding fragment thereof; An anti-PD-L1 antibody, a derivative thereof or an antigen-binding fragment thereof; And an anti-PD-1 antibody, a derivative thereof, or an antigen-binding fragment thereof.
10. The method according to claim 1,

    Wherein said immunostimulatory agent is an anti-PD-1 antibody.
11. The method according to claim 1,

    Wherein said PI3 kinase inhibitor is orally administered.
12. The method according to claim 1,

    Wherein said immunostimulatory agent is parenterally administered.
13. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the composition is any one of a liquid preparation, a suspension, a powder, a granule, a tablet, a capsule, a pill, an extract, an emulsion, a syrup, an aerosol or an injection .
14. The method of claim 1, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCL), bronchogenic lung cell lung cancer, gastric cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, , Cancer of the rectum, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, laryngeal cancer, small bowel cancer, thyroid cancer, Wherein the cancer is any one of cancer, prostate cancer, multiple myeloma, chronic or acute leukemia, childhood solid tumor, lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, axillary neoplasm, brainstem glioma, or pituitary adenoma A pharmaceutical composition for preventing or treating cancer.
15. 15. The pharmaceutical composition according to claim 14, wherein the cancer is non-small cell lung cancer, bladder cancer, head and neck cancer, or lymphoma.
16. Wherein the compound is administered in combination with an effective amount of an immunostimulant inhibitor.
17. A pharmaceutical composition for the combined administration for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.
18. A method of preventing or treating cancer, comprising administering to a subject in need thereof a PI3 kinase inhibitor and an immunostimulatory agent.
19. Use of a pharmaceutical composition comprising a PI3 kinase inhibitor and an immunostimulatory agent for the manufacture of a medicament for the prophylaxis or treatment of cancer.

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