WO2019139388A1 - Pi3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물 - Google Patents

Pi3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물 Download PDF

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WO2019139388A1
WO2019139388A1 PCT/KR2019/000420 KR2019000420W WO2019139388A1 WO 2019139388 A1 WO2019139388 A1 WO 2019139388A1 KR 2019000420 W KR2019000420 W KR 2019000420W WO 2019139388 A1 WO2019139388 A1 WO 2019139388A1
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cancer
pharmaceutical composition
kinase inhibitor
present
group
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PCT/KR2019/000420
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English (en)
French (fr)
Korean (ko)
Inventor
김남훈
왕진상
손미권
최연서
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보령제약 주식회사
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Priority to KR1020207012298A priority Critical patent/KR20200055116A/ko
Publication of WO2019139388A1 publication Critical patent/WO2019139388A1/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a 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.
  • CTLs tumor-specific cytotoxic T lymphocytes
  • MHC major histocompatibility complex
  • 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.
  • PI3K phosphatidylinositol 3-kinase
  • 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.
  • 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.
  • Patent Document 1 International Patent Publication No. WO 2016/204429
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.
  • 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.
  • 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.
  • 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.
  • x represents the number of carbon atoms
  • the number of carbon atoms x to y represents a functional group having a carbon number of x or more and y or less.
  • 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.
  • substituted with a substituent is replaced with a substituent whose hydrogen atom is a non-hydrogen atom.
  • the valence requirement must be satisfied and a chemically stable compound must be generated from the substitution.
  • all functional groups should be interpreted as being able to be substituted or unsubstituted.
  • &quot represents a halogen group element and includes, for example, F, Cl, Br or I.
  • 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.
  • R 1 to R 4 are the same as defined in Formula (1).
  • R 1 is a linear or branched alkyl group having 1 to 5 carbon atoms.
  • R 1 is a methyl group.
  • 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.
  • R 2 is a phenyl group.
  • R < 3 &gt is hydrogen; Or a halogen group.
  • R 3 is a halogen group.
  • R < 3 > is chlorine.
  • R < 4 &gt is hydrogen; Or a halogen group.
  • R 4 is a halogen group.
  • R < 4 &gt is chlorine.
  • 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.
  • 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.
  • 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.
  • &quot pharmaceutically acceptable &quot
  • pharmaceutically acceptable &quot 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.
  • 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;
  • 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
  • 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.
  • a PI3 kinase inhibitor selected from the group consisting of PI3K [alpha], PI3K [beta], PI3K [ can do.
  • the term " immune checkpoint inhibitor &quot 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.
  • 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.
  • current immunostimulatory agents have been reported to have limitations such as low therapeutic efficacy and low efficacy.
  • 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.
  • the immunostimulatory agent may be an antibody, a fusion protein, an aptamer or an immunoglobulin protein-binding fragment thereof.
  • the immunostimulatory agent is an anti-immunoglobulin protein antibody or antigen-binding fragment thereof.
  • 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;
  • anti-PD-1 antibodies derivatives thereof, or antigen-binding fragments thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the cancer may be non-small cell lung cancer, bladder cancer, head and neck cancer, or lymphoma.
  • 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).
  • 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.
  • &quot 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 >
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • &quot 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 >
  • the term " powder " means a finely divided drug, chemical or a mixture of both in a dry state.
  • 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.
  • 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.
  • &quot 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.
  • 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.
  • the term " pills " is meant to encompass small, round solid dosage forms comprising multiparticulates mixed with binders and other excipients.
  • 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.
  • the main ingredient content Means a semi-solid or solid preparation made by adjusting the content.
  • the term " syrup agent " means a thickened hand made of sugar or sugar substitute.
  • 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.
  • 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.
  • sweetening agent examples include, but are not limited to, white sugar, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin or menthol.
  • the term " injectable preparation " means a sterile preparation which is usually applied to the body through a skin or mucous membrane
  • any dosage form can be used, and the dosage form is selected depending on the characteristics of each pharmacologically active substance.
  • the pharmaceutical composition of the present invention may be for oral administration.
  • 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, .
  • 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.
  • liquid carriers such as fatty oils can be further used.
  • " 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.
  • the pharmaceutical composition of the invention may be for parenteral administration.
  • 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.
  • 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.
  • composition of the present invention may comprise two separate preparations, and may be composed of one formulation, but is not limited thereto.
  • 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.
  • the PI3 kinase inhibitor may be administered parenterally or orally, preferably orally.
  • the contents of oral administration are the same as described above.
  • the immunostimulatory agent may be administered parenterally or orally, preferably parenterally.
  • the content of parenteral administration is the same as described above.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • prophylactic or therapeutic methods include administration of a therapeutically effective amount.
  • 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.
  • the PI3 kinase inhibitor and the immunostimulant inhibitor may be administered sequentially or simultaneously in any order.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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- ⁇ ), 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. 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.
  • 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.
  • 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.
  • S PI3 kinase inhibitor
  • 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".
  • Table 1 shows the data of Fig. 1 in numerical values.
  • 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.
  • 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.
  • 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.
  • 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.
  • S PI3 kinase inhibitor
  • 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 ".
  • Table 2 below shows the data of FIG. 2 in numerical values.
  • 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.
PCT/KR2019/000420 2018-01-10 2019-01-10 Pi3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물 WO2019139388A1 (ko)

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CN115803060A (zh) 2020-07-10 2023-03-14 (株) 娜迪安生物公司 包含作为活性成分的萘醌基化合物和免疫检查点抑制剂的用于预防或治疗癌症的药物组合物
WO2023008924A1 (ko) 2021-07-28 2023-02-02 성균관대학교산학협력단 엑소좀 분비 억제제와 면역관문 억제제를 이용한 병용 치료 요법

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