WO2019139388A1 - Pharmaceutical composition comprising pi3 kinase inhibitor and immune checkpoint inhibitor for preventing or treating cancer - Google Patents
Pharmaceutical composition comprising pi3 kinase inhibitor and immune checkpoint inhibitor for preventing or treating cancer Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- pharmaceutical composition
- kinase inhibitor
- present
- group
- Prior art date
Links
Images
Classifications
-
- 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.
- " 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 > is hydrogen; Or a halogen group.
- R 3 is a halogen group.
- R < 3 > is chlorine.
- R < 4 > is hydrogen; Or a halogen group.
- R 4 is a halogen group.
- R < 4 > 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.
- " pharmaceutically acceptable "
- 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.
- 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 " 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.
- " 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.
- " 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.
- " 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.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
관련 출원과의 상호 인용Mutual citation with related application
본 출원은 2018년 01월 10일자 한국 특허 출원 제10-2018-0003401호에 기초한 우선권의 이익을 주장하며, 해당 한국 특허 출원의 문헌에 개시된 모든 내용은 본 명세서의 일부로서 포함된다.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.
본 발명은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.
면역요법은 최근 면역학 분야의 발전으로 인체 면역 체계에 대한 많은 이해가 이루어짐에 따라 개발된 새로운 종양 치료법으로서, 환자 자신의 면역 체계를 이용하여 부작용이 적으면서 장기간의 항-종양 면역을 획득할 수 있는 장점이 있다.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.
면역요법의 목표는 종양세포 또는 종양항원을 인식하여 종양세포를 제거할 수 있는 종양-특이 세포살해 T 림프구(cytotoxic T lymphocytes, CTL)를 생성시키는 데 있다. 즉, 종양항원 펩티드가 주조직적합체(major histocompatibility complex, MHC)에 탑재되어 종양세포 자체 또는 항원제시세포에 의해 T 림프구에 제시되어 T 림프구를 활성화시키고 CTL로의 분화 및 CTL의 증가를 유도한다.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.
다만, 대부분의 인체 종양은 개체의 면역 감시를 피해 치료에 어려움이 있는데, 그 원인으로 1) 종양항원은 대부분 태생기 동안 표현되거나, 정상세포에서 발현되기도 하는 자가 항원의 일부이거나, 면역 유발 정도가 매우 약해 항원으로 인지되지 못하고, 2) 종양세포에 의한 MHC 발현이 저조하거나, 종양항원이 종양세포 내에서 불완전하게 처리되어 아예 제시되지 못하고, 3) 대부분의 종양세포는 항원제시에 필수적인 보조자극 분자를 표현하지 못하며, 4) 종양이 분비하는 억제성 사이토카인에 의해 면역 감시를 피해갈 수 있음을 들 수 있다.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.
한편, 포스파티딜이노시톨 3-키나아제(PI3 kinase; PI3K)는 단백질 대신 지질 분자를 인산화하는 지질 키나아제(lipid kinase)이며, 세포생존(cell survival), 신호전달(signal transduction), 세포막 투과조절(control of membrane trafficking)등에서 중요한 역할을 한다. 이들 조절에 문제가 생기면, 암, 염증성 질환, 자가면역 질환 등이 발생한다.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.
암의 발명을 개시 또는 촉진시키는 개별적 또는 종합적으로 작용할 수 있는 다양한 원인 인자에 기인하여 암은 전 세계적으로 건강에 위협이 될 수 있다. 따라서, 암을 예방 및 치료의 향상을 위하여 보다 효과적인 접근법 특히 병용 접근법의 개발이 중요하다.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.
이에 본 발명자들은 PI3 키나아제 억제제와 함께 면역 요법을 이용한 면역 치료제의 장점을 최대한 살릴 수 있는 신규의 암의 예방 또는 치료용 약학적 조성물을 제공하기 위하여 다양한 연구를 시도하였다.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.
[선행기술문헌][Prior Art Literature]
[특허문헌][Patent Literature]
(특허문헌 1) 국제 특허공개공보 WO 2016/204429호(Patent Document 1) International Patent Publication No. WO 2016/204429
본 발명의 목적은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 면역관문 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료를 위한 병용 투여용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 필요로 하는 개체에게 PI3 키나아제 억제제 및 면역관문 억제제를 투여하는 것을 포함하는 암의 예방 또는 치료방법을 제공하는 것이다.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.
마지막으로, 본 발명의 목적은 암의 예방 또는 치료용 약제의 제조를 위한 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 약학적 조성물의 용도를 제공하는 것이다.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.
상기의 목적을 달성하기 위하여 본 발명에서는 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물을 개발하였으며, 상기 암의 예방 또는 치료용 약학적 조성물은 PI3 키나아제 억제제와 면역관문 억제제를 병용함으로써 이들의 병용에 따른 상승 보완 효과로 인하여 암의 예방 또는 치료 활성이 우수해짐을 확인하였다.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.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
암의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cancer
본 발명은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.
본 발명의 약학적 조성물은 PI3 키나아제 억제제와 면역관문 억제제를 병용함으로써, 이들의 병용에 따른 상승 보완 효과로 인하여 암의 예방 및 치료 활성이 현저해진다.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.
본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제로 사용된 화합물은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용 가능한 염이다. 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.
[화학식 1][Chemical Formula 1]
화학식 1에 있어서, In formula (1)
R
1은 수소; 또는 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기이고, R 1 is hydrogen; Or a straight or branched alkyl group having 1 to 5 carbon atoms,
R
2는 페닐기 또는 피리디닐기이고, 상기 페닐기 또는 피리디닐기는 할로겐기; 및 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기로 이루어진 군에서 선택되는 1 이상의 치환기로 치환 또는 비치환되며, 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 및 R
4는 각각 독립적으로 수소 또는 할로겐기이다. R 3 and R 4 are each independently hydrogen or a halogen group.
본 발명에 있어서, 작용기의 「탄소수 x」의 표시에서 x는 탄소의 개수를 나타내고, 탄소수 x 내지 y는 탄소수가 x 이상 y 이하를 갖는 작용기를 의미하는 것으로 한다.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.
본 발명에 있어서, 용어 「알킬기」는 직쇄(linear) 포화탄화수소기 또는 분지쇄(branched) 포화탄화수소기를 의미하며, 이때 알킬기는 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기이며, 예를 들면, 메틸, 에틸, 프로필, 이소부틸 또는 펜틸 등을 포함한다.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.
본 발명에 있어서, 용어 「치환기로 치환」은, 수소원자가 비-수소원자인 치환기로 대체된 것이다. 이때, 원자가(valence) 요구조건이 만족되어야 하고 화학적으로 안정한 화합물이 치환으로부터 발생되어야 한다. 또한, 명시적으로 "비치환된"이라고 기재되지 않는 한, 모든 작용기는 치환 또는 비치환될 수 있는 것으로 해석되어야 한다.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.
본 발명에 있어서, 용어 「할로겐」은 할로겐족 원소를 나타내며, 예를 들어 F, Cl, Br 또는 I를 포함한다.In the present invention, the term " halogen " represents a halogen group element and includes, for example, F, Cl, Br or I.
본 발명의 일 구현예에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염 일 수 있다.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.
[화학식 2](2)
화학식 2에 있어서, R
1 내지 R
4는 상기 화학식 1에서 정의한 바와 동일하다. In Formula (2), R 1 to R 4 are the same as defined in Formula (1).
본 발명의 일 구현예에 있어서, 상기 R
1은 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기이다. In one embodiment of the present invention, R 1 is a linear or branched alkyl group having 1 to 5 carbon atoms.
본 발명의 일 구현예에 있어서, 상기 R
1은 메틸기이다.In one embodiment of the present invention, R 1 is a methyl group.
본 발명의 일 구현예에 있어서, R
2는 페닐기 또는 피리디닐기이고, 상기 페닐기 또는 피리디닐기는 할로겐기; 및 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기로 이루어진 군에서 선택되는 1 이상의 치환기로 치환 또는 비치환된다.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.
본 발명의 일 구현예에 있어서, 상기 R
2는 페닐기이다.In one embodiment of the present invention, R 2 is a phenyl group.
본 발명의 일 구현예에 있어서, R
3는 수소; 또는 할로겐기이다.In one embodiment of the invention, R < 3 > is hydrogen; Or a halogen group.
본 발명의 일 구현예에 있어서, R
3는 할로겐기이다.In one embodiment of the present invention, R 3 is a halogen group.
본 발명의 일 구현예에 있어서, 상기 R
3는 염소이다.In one embodiment of the present invention, R < 3 > is chlorine.
본 발명의 일 구현예에 있어서, R
4는 수소; 또는 할로겐기이다. In one embodiment of the invention, R < 4 > is hydrogen; Or a halogen group.
본 발명의 일 구현예에 있어서, R
4은 할로겐기이다. In one embodiment of the present invention, R 4 is a halogen group.
본 발명의 일 구현예에 있어서, 상기 R
4은 염소이다.In one embodiment of the present invention, R < 4 > is chlorine.
본 발명에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 (4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one), 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염이다. 더욱 구체적으로 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 ((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)이며, 하기 화학식 3으로 표시된다.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.
[화학식 3](3)
본 발명에 있어서, 상기 화학식 1로 표시되는 화합물은 예컨대, 국제 특허공개공보 WO 2016/204429호에 개시된 제법에 의해 제조될 수 있으나, 이에 제한되는 것은 아니다.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.
본 발명에 있어서, 용어 「약학적으로 허용되는」 이란, 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 말하며, 용어 「염」이란, 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염을 의미한다. 따라서, 약학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 포타슘, 소듐 또는 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 또는 황산 등으로 제조된 무기산염; 아세트산, 트라이플루오로아세트산, 시트르산, 말레산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만델산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산 또는, 바닐릭산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, 살리실산, p-톨루엔설폰산 또는 나프탈렌설폰산 등으로 제조된 설폰산염; 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염; 또는 트라이메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.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.
본 발명의 일 구현예에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 PI3Kα, PI3Kβ, PI3Kδ 및 PI3Kγ로 이루어지는 군으로부터 선택되는 PI3 키나아제 억제제에 대하여 선택적으로 억제할 수 있다.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.
본 발명에 있어서, 용어 「면역관문 억제제(immune checkpoint inhibitor)」는 면역계 내 임의의 성분의 억제를 방지하는 임의의 핵산 또는 단백질, 예컨대 MHC 부류 제시, T 세포 제시 및/또는 분화, B 세포 제시 및/또는 분화, 및 사이토카인, 케모카인 또는 면역 세포 증식 및/또는 분화를 위한 신호전달을 지칭하며, 면역억제력이 높은 암에서 면역반응의 진행을 막는 면역관문을 차단하여 암의 면역 회피를 억제함으로서 암을 치료할 수 있다.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 >
본 발명의 면역관문 억제제는 면역학 분야의 발전으로 인체 면역 체계에 대한 많은 이해가 이루어진 결과에 따라 개발된 새로운 종양 치료제로서 항암 전략에 많이 사용되고 있다. 상기 면역관문 억제제를 사용하여 항암 효과를 나타내기 위해 대표적으로 주목 받고 있는 기전으로 CTLA-4에 의한 T 림프구 억제 기전과 기활성화된 T 림프구를 억제하는 PD-1/PD-L1 기전이 있다. 그러나, 현재의 면역관문 억제제는 치료 효율이 낮고 효과가 미비하다는 등의 한계가 보고되고 있다.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.
그러나, 본 발명의 암의 예방 또는 치료용 약학적 조성물은 다른 치료기전의 항암제인 PI3 키나아제 억제제와 상기 면역관문 억제제를 병용 투여하여 단독으로 사용하는 경우에 비하여 현저한 상승 보완 효과로 인하여 면역 요법을 통해 암의 예방 및 치료에 도움을 준다.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.
본 발명의 일 구현예에 있어서, 상기 면역관문 억제제는 항체, 융합 단백질, 압타머 또는 이의 면역관문 단백질-결합 단편일 수 있다. 예를 들어, 면역관문 억제제는 항-면역관문 단백질 항체 또는 이의 항원-결합 단편이다. 특정 예에서, 항-CTLA4 항체, 이의 유도체 또는 이의 항원-결합 단편; 항-PD-L1 항체, 이의 유도체 또는 이의 항원-결합 단편; 및 항-PD-1 항체, 이의 유도체 또는 이의 항원-결합 단편 중에서 선택된다. 예를 들어, 면역관문 억제제는 이필리무맙(Ipilimumab), 이의 유도체 또는 이의 항원-결합 단편; 아테졸리주맙(atezolizumab), 이의 유도체 또는 이의 항원-결합 단편; 니볼루맙(Nivolumab), 이의 유도체 또는 이의 항원-결합 단편; 및 펨브롤리주맙(Pembrolizumab), 이의 유도체 또는 이의 항원-결합 단편 중에서 선택될 수 있으며, 면역관문 억제제로 사용될 수 있는 항체 또는 다른 형태의 면역관문 억제제라면 제한 없이 사용될 수 있다.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.
상기 면역관문 억제제는 PI3 키나아제 억제제 이외의 다른 치료법과의 병용 투여에 따른 암의 예방 또는 치료 효과를 나타낼 수 있다.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.
본 발명의 일 구현예에 있어서, 상기 면역관문 억제제는 항-CTLA4 항체, 항-PD-1 항체 및 항-PD-L1 항체로부터 선택되는 어느 하나 이상이 바람직하다. 상기 항체는 예컨대, 통상의 항체 제조 업체 등으로부터 구입하여 사용하거나 알려진 항체의 제조방법에 따라 제조하여 사용할 수도 있다.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.
본 발명의 일 구현예에 있어서, PI3 키나아제 억제제와 면역관문 억제제의 함량비는 1:1 ~ 50:1 일 수 있으며 이에 제한되는 것은 아니다.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.
본 발명의 약학적 조성물은 전술한 PI3 키나아제 억제제인 화학식 1로 표시되는 화합물과 면역관문 억제제를 병용함으로써, 이들의 병용에 따른 상승 보완 효과로 인하여 암의 예방 및 치료 활성이 현저해진다.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.
본 발명의 구체적인 구현예에서, 상기 PI3 키나아제 억제제인 화학식 1로 표시되는 화합물과 항-PD-1 항체를 병용 투여시 단독 투여에 비해 상승된 암 치료 효과를 나타냄을 확인하였고 (도 1 및 도 2), 본 발명의 약학적 조성물은 암의 예방 또는 치료용으로 유용하게 사용될 수 있다.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.
본 발명에 있어서, 용어 「암」이란, 의학적으로 세포의 정상적인 분열, 분화 또는 사멸의 조절 기능에 문제가 발생하여 비정상적으로 과다 증식하여 주위 조직 또는 장기에 침윤하여 덩어리를 형성하고 기존의 구조를 파괴하거나 변형시키는 모든 상태를 의미한다. 암은 크게, 발생한 부위에 존재하는 원발암과 발생 부위로부터 신체의 다른 부위로 퍼져나간 전이암으로 구분된다. 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.
상기 암은 예를 들어, 펨브롤리주맙, 니볼루맙, 아테졸리주맙, 이필리무맙 등의 면역관문 억제제가 면역항암제로서 사용되는 인체의 각종 암, 부인과 종양, 내분비계 암, 중추신경계 종양, 수뇨관 암 등이 있으며, 구체적으로는 폐암, 비-소세포 폐암(NSCL), 기관지 폐포 세포 폐암, 위암, 위장관암, 간암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 난소암, 직장암, 대장암, 결장암, 유방암, 자궁 육종, 나팔관 암종, 내궁내막 암종, 자궁경부 암종, 질 암종, 외음부 암종, 식도암, 후두암, 소장암, 갑상선암, 부감상선암, 연조직의 육종, 요도암, 음경암, 전립선암, 다발성 골수종, 만성 또는 급성 백혈병, 유년기의 고상종양, 림프종, 방광암, 신장암, 신장세포 암종, 신장 골반 암종, 축수축 종양, 뇌간 신경교종 또는 뇌하수체 아데노마를 포함하며, 이에 제한되는 것은 아니다. 보다 구체적으로는, 본 발명에 있어서 암은 비소세포폐암, 방광암, 두경부암 또는 림프종 일 수 있고. 예를 들어, 림프종은 비호지킨림프종(non-Hodgkin's lymphoma), 엡스타인바 관련 림프종(Epstein-Barr related lymphoma), 호지킨림프종, 림프구성 백혈병(lymphoblastic leukemia), 다발성 골수종(multiple myeloma), 미만성 거대 B 세포 림프종(diffuse large B-cell lymphoma)을 들 수 있으나 이에 제한되는 것은 아니다.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).
본 발명에 있어서, 용어 「예방」은, 질병, 장애 또는 질환의 발병의 지연을 의미한다. 질병, 장애 또는 질환의 발병이 예정된 기간 동안 지연된 경우 예방은 완전한 것으로 간주될 수 있다.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.
본 발명에 있어서, 용어 「치료」란, 특정 질병, 장애 및/또는 질환의 발병을 부분적으로 또는 완전히 경감, 개선, 완화, 저해 또는 지연시키며, 중증도를 감소시키거나, 하나 이상의 증상 또는 특징의 발생을 감소시키는 것을 의미한다.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 >
본 발명의 일 구현예에 있어서, 본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다.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.
본 발명에 있어서, 용어 「담체」란, 세포 또는 조직 내로의 화합물의 부가를 용이하게 하는 화합물을 의미하고, 용어 「약학적으로 허용되는」 이란, 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다.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.
본 발명의 일 구현예에 있어서, 상기 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸 히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 제한되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.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.
본 발명의 일 구현예에 있어서, 상기 약학적 조성물에 포함되는 첨가제의 함량은 특별히 제한되는 것은 아니며 통상의 제제화에 사용되는 함량 범위 내에서 적절하게 조절될 수 있다.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.
본 발명의 일 구현예에 있어서, 본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 액제, 현탁제, 산제, 과립제, 정제, 캡슐제, 환제, 엑스제, 에멀젼, 시럽제, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥 내, 복강 내, 피하, 피내, 근육 내, 척추, 척추강 또는 직장 내 국소 투여 또는 주입 등을 포함한 다양한 경로를 통해 비경구 투여될 수 있다.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.
본 발명에 있어서, 용어 「액제」는, 의약품을 물 또는 유기 용매에 용해한 물약 상태로 먹는 약을 의미한다. 상기 액제는 현탁제 또는 고형제에 비하여 장관에서의 전신 순환계로의 약물 흡수가 보다 효과적인 이점을 지니며, 상기 액제는 의약품 외에도 부가적인 용질도 포함할 수 있으며, 색깔, 냄새, 감미 혹은 안정성을 주는 첨가제도 포함할 수 있다.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.
본 발명에 있어서, 용어 「현탁제」는, 알기네이트 함유 조성물의 요망되는 용해도 및/또는 분산도를 제공할 수 있는, 즉, 실질적으로 투명하며 침강 및 덩어리가 없는 수성 제제를 제공할 수 있는 어떠한 작용제를 의미한다.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 >
본 발명에 있어서, 용어 「산제」는, 잘게 분할된 약물, 화학물질 또는 양자의 건조상태의 혼합물을 의미한다.In the present invention, the term " powder " means a finely divided drug, chemical or a mixture of both in a dry state.
본 발명에 있어서, 용어 「과립제」는, 의약용 또는 의약품의 혼합물을 입상으로 한 것으로, 보통 4.76 내지 20 ㎜의 체를 통과하는 범위의 것을 말한다. 과립은 일반적으로 분말, 또는 분말 혼합물을 적셔서 그 덩어리를 필요로 하는 과립의 크기에 따라 적당한 메쉬 사이즈의 체 또는 과립기를 통과시킴으로써 생성한다. 과립제 역시 산제와 마찬가지로, 입자 상태이기 때문에 약물이 혀에 닿는 정도가 커서, 쓴맛을 가지는 약물을 과립제 형태로 사용할 경우에는, 환자, 특히 어린이나 노약자에게는 불편함을 야기할 수 있다.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.
본 발명에 있어서, 용어 「정제」는, 분말상의 의약품을 작은 원판 모양으로 압축하여 복용하기 쉽게 만든 것을 의미한다. 정제는 나정, 필름 코팅정, 당의정, 다층정, 유핵정, 내핵정, 구강붕해정, 츄어블정, 발포정, 분산정, 용해정 등이 포함될 수 있다.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.
본 발명에 있어서, 용어 「캡슐제」는, 의약품을 액상, 현탁상, 물상, 분말상, 과립상, 미니정제 또는 펠렛 등의 형태로 캡슐에 충전하거나 캡슐기제로 피포 성형하여 만든 것을 의미한다.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.
본 발명에 있어서, 용어 「환제」는, 결합제 및 기타 부형제와 혼합된 복합입자를 포함하는 작고 둥근 고체 투여형을 포괄하는 의미이다.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.
본 발명에 있어서, 용어 「엑스제」는, 식물성 또는 동물성 생약 중의 약효성분을 적당한 침출제를 사용해서 침출하고 용매를 증발시켜 규정된 농도로까지 농축하고 주성분함량의 규정이 있는 것에서는 부형제를 가해 함량을 조절해서 만든 반고형 또는 고형의 제제를 의미한다.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.
본 발명에 있어서, 용어 「시럽제」는, 설탕 또는 설탕대용제의 농조한 수제를 의미한다. 본 발명에서 상기 시럽제는, 불쾌한 맛, 예컨대 쓴맛이 있는 의약품을 액제로 하여 복용하기 쉽게 한 것으로, 특히 어린이들이 복용하기에 적합한 제형이다. 본 발명에서 상기 시럽제는 정제수 및 추출물 외에 사당 또는 감미와 점성을 주기 위하여 쓰이는 사당의 대용약품, 항균성 보존제, 착미제 향료(flavor), 또는 착색제 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. 이러한 시럽제에 포함될 수 있는 감미제의 예로는 백당, 만니톨, 소르비톨, 자일리톨, 아스파탐, 스테비오사이드, 과당, 유당, 수크랄로스, 사카린 또는 멘톨 등이 있으나, 이에 제한되는 것은 아니다.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.
본 발명에 있어서, 용어 「주사제」는, 보통 약품의 용액 또는 현탄액, 혹은 사용할 때 녹여 쓰는 약품으로, 피부 내 또는 피부 혹은 점막을 통하여 체내에 적용하는 무균의 제제를 의미하며, 특히 주사제 투여 경로로는 피하 주사, 근육 주사 중 어느 투여 형태도 가능하고, 투여 형태는 각각의 약리활성 물질의 특성에 의해서 선택된다.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.
본 발명의 일 구현예에 있어서, 본 발명의 약학적 조성물은 경구 투여용일 수 있다. 본 발명에 있어서, 용어 「경구 투여」는, 활성물질이 소화되도록 제조된 물질, 즉 흡수를 위한 위장기관으로 투여되는 것을 의미한다. 상기 경구 투여용 제제의 비제한적인 예로는, 정제, 트로키제 (troches), 로젠지 (lozenge), 수용성 현탁액, 유성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭실제 등을 들 수 있다. 본 발명의 약학적 조성물을 경구 투여용으로 제제화하기 위하여, 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴 등과 같은 결합제; 디칼슘 포스페이트 등과 같은 부형제; 옥수수 전분 또는 고구마 전분 등과 같은 붕해제; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴 푸마르산 나트륨 또는 폴리에틸렌 글리콜 등과 같은 윤활유 등을 사용할 수 있으며, 감미제, 방향제, 시럽제 등도 사용할 수 있다. 나아가 캡슐제의 경우에는 상기 언급한 물질 외에도 지방유와 같은 액체 담체 등을 추가로 사용할 수 있다.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.
본 발명에서 용어 「부형제」는, 치료제가 아닌, 어느 물질을 의미하며, 치료제의 전달을 위한 담체 또는 매체로 이용되거나 또는 약학적 조성물에 추가되는 것을 의미한다. 이에 의해, 취급 및 저장 특성을 개선하거나 또는 조성물의 단위 투여량 형성을 허용 및 촉진시키게 된다.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.
본 발명의 일 구현예에 있어서, 본 발명의 약학적 조성물은 비경구 투여용일 수 있다. 본 발명에 있어서, 용어 「비경구 투여」는, 정맥 내, 복강 내, 피하, 피내, 근육 내, 척추, 척추강 또는 직장 내 국소 투여 또는 주입하는 것을 의미한다. 비경구 투여는 좌약기제, 피하주사제, 정맥 주사제, 근육 내 주사제 또는 흉부 내 주사제를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 조성물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알의 단위 투여형으로 제조할 수 있다.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.
본 발명의 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 연령, 성별, 건강상태, 식이 체질 특이성, 제제의 성질, 질병의 정도, 조성물의 투여 시간, 투여 방법, 투여기간 또는 간격, 배설율, 및 약물 형태에 따라 그 범위가 다양할 수 있으며 이 분야 통상의 기술자에 의해 적절하게 선택될 수 있다. 예컨대, 약 0.1 내지 10,000 mg/kg의 범위일 수 있으나 이제 제한되지 않으며, 하루 일회 내지 수회에 나누어 투여될 수 있다.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.
본 발명의 조성물은, 2종의 별개의 제제를 포함하는 것일 수 있으며, 1개의 제제로 구성될 수도 있고, 이에 한정되는 것은 아니다. The composition of the present invention may comprise two separate preparations, and may be composed of one formulation, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 약학적 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 액제, 현탁제, 산제, 과립제, 정제, 캡슐제, 환제, 엑스제, 에멀젼, 시럽제, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여되거나, 정맥 내, 복강 내, 피하, 피내, 근육 내, 척추, 척추강 또는 직장 내 국소 투여 또는 주입 등을 포함한 다양한 경로를 통해 비경구 투여 될 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여 시간, 투여 방법, 투여 기간 또는 간격, 배설율, 체질 특이성, 제제의 성질, 질환의 중증 등에 따라 그 범위가 다양할 수 있다.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.
본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제는 비경구 또는 경구 투여될 수 있으며, 바람직하게는 경구 투여될 수 있다. 경구 투여에 대한 내용은 상기와 동일하다.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.
본 발명의 일 구현예에 있어서, 상기 면역관문 억제제는 비경구 또는 경구 투여될 수 있으며, 바람직하게는 비경구 투여될 수 있다. 비경구 투여에 대한 내용은 상기와 동일하다.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.
암의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating cancer
본 발명은 면역관문 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.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.
본 발명의 일 구현예에 있어서, 면역관문 억제제는 PI3 키나아제 억제제와 동시에 투여되거나, 개별적으로 각각 투여될 수 있고, 상기 유효량은 약학적 조성물의 제제화 방법, 투여 방식, 투여 시간 및/또는 투여 경로 등에 의해 다양해질 수 있으며, 당해 기술 분야에서 통상의 지식을 가진 자는 목적하는 치료에 효과적인 투여량을 용이하게 결정하고 처방할 수 있다.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.
본 발명의 암의 예방 또는 치료용 약학적 조성물에서 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용 가능한 염과 동일할 수 있으며, 구체적으로는 화학식 2 또는 3으로 표시되는 화합물일 수 있고, 면역관문 억제제는 상기 기재된 내용과 동일하게 적용 가능하다.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.
암의 예방 또는 치료를 위한 병용 투여용 약학적 조성물A pharmaceutical composition for co-administration for prevention or treatment of cancer
본 발명은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료를 위한 병용 투여용 약학적 조성물을 제공한다.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.
본 발명의 암의 예방 또는 치료를 위한 병용 투여용 약학적 조성물에서 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용 가능한 염과 동일할 수 있으며, 구체적으로는 화학식 2 또는 3으로 표시되는 화합물일 수 있고, 면역관문 억제제는 상기 기재된 내용과 동일하게 적용 가능하다.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.
암의 예방 또는 치료방법Prevention or Treatment of Cancer
본 발명은 필요로 하는 개체에게 PI3 키나아제 억제제 및 면역관문 억제제를 투여하는 것을 포함하는 암의 예방 또는 치료방법을 제공한다.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.
본 발명에 있어서, 용어 「개체」란, 원숭이, 소, 말, 개, 고양이, 토끼, 레트, 마우스 등의 포유 동물을 의미하며, 특히 인간을 포함한다. 상기 예방 또는 치료 방법은 치료학적으로 유효한 양의 투여를 포함한다.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.
본 발명에 있어서, 용어 「치료학적으로 유효한 양」이란, 암의 예방 또는 치료에 유효한 본 발명의 PI3 키나아제 억제제 및 면역관문 억제제의 양을 나타낸다.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.
본 발명의 예방 또는 치료방법에서, PI3 키나아제 억제제 및 면역관문 억제제는 임의의 순서로 순차적으로 또는 동시에 투여될 수 있다. 본 발명의 예방 또는 치료방법에서 PI3 키나아제 억제제 및 면역관문 억제제가 동시에 투여될 경우, 하나의 제제로 제형화되어 투여될 수도 있고, PI3 키나아제 억제제를 포함하는 제제, 및 면역관문 억제제를 포함하는 제제가 각각 별개의 제제로 제형화되어 동시에 투여될 수도 있다.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.
본 발명의 예방 또는 치료방법은 PI3 키나아제 억제제와 면역관문 억제제를 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 예방 또는 치료방법은 PI3 키나아제 억제제 및 면역관문 억제제와 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 PI3 키나아제 억제제 및 면역관문 억제제와 함께 시너지 효과 또는 상가적 효과를 나타낼 수 있다.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 >
본 발명의 암의 예방 또는 치료방법에서 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용 가능한 염과 동일할 수 있으며, 구체적으로는 화학식 2 또는 3으로 표시되는 화합물일 수 있고, 면역관문 억제제는 상기 기재된 내용과 동일하게 적용 가능하다.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.
암의 예방 또는 치료용 약제의 제조를 위한 용도For the manufacture of medicaments for the prophylaxis or treatment of cancer
본 발명의 목적은 암의 예방 또는 치료용 약제의 제조를 위한 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 약학적 조성물의 용도를 제공한다.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.
본 발명의 일 구현예에 있어서, 약제의 제조를 위한 본 발명의 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 약학적 조성물은 허용되는 담체 등을 혼합할 수 있으며, 다른 작용제들을 추가로 더 포함할 수도 있다.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.
본 발명의 암의 예방 또는 치료용 약제의 제조를 위한 용도에서 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약제학적으로 허용 가능한 염과 동일할 수 있으며, 구체적으로는 화학식 2 또는 3으로 표시되는 화합물일 수 있고, 면역관문 억제제는 상기 기재된 내용과 동일하게 적용 가능하다.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.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters mentioned in the use, composition and treatment method of the present invention are applied equally unless they are mutually contradictory.
본 발명에 따른 조성물은 PI3 키나아제 억제제를 단독으로 투여한 경우와 비교하여, PI3 키나아제 억제제와 면역관문 억제제의 병용 투여 시 암의 예방 또는 치료 활성이 우수하다. 따라서, 본 발명의 약학적 조성물은 암의 예방 또는 개선에 유용하게 적용될 수 있다.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.
도 1은 4T1 마우스 유래 유방암 세포에 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 (“PI3K inhibitor”로 표시) 및 면역관문 억제제 (항 PD-1)의 단독 또는 병용 투여에 따른 종양 세포의 부피를 나타낸 도이다.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.
도 2는 CT26 마우스 유래 대장암 세포에 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 (“PI3K inhibitor”로 표시) 및 면역관문 억제제 (항 PD-1)의 단독 또는 병용 투여에 따른 종양 세포의 부피를 나타낸 도이다.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.
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다.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.
실시예Example
1. (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온의 제조 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
상기 하기 화학식 3으로 표시되는 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 (4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one)은 국제 공개특허공보 WO2016/204429의 실시예 10에 기재된 방법과 동일한 방법으로 제조하였다. (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.
[화학식 3](3)
실시예Example
2. 2.
in in
vivovivo
시험 exam
4T1 마우스 유래 유방암 세포를 0.25% Trypsin을 사용하여 수거하여 사용하였으며, 시험 동물로는 Balb-c/cAnNCrljOri 6주령 암컷을 오리엔트바이오 (Charles river, Japan)로부터 공급받아 2주간의 순화과정을 거쳐 시험에 공여하였다. 온도 23.0 ± 1.0℃, 상대습도 50.0 ± 5.0 %, 조명주기 12시간, 자유로운 시험동물용 쥐 사료와 음용수 섭취의 환경에서 사육하면서 시험에 사용하였다. 또한, 화학식 1의 PI3 키나아제 억제제로는 상기 실시예 1에 따른 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 사용하였다.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.
세포를 PBS에 5 × 10
4/100 μL로 계수하여 Balb/c 마우스의 복부 부위에 1 mL 주사기를 이용하여 SC (subcutaneous)로 이식하였다. 이식 후 비히클(vehicle, PBS) + IgG 아이소타입 (Isotype) 10 mg/kg 군, 항 PD-1 10 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg + 항 PD-1 10 mg/kg 군을 투여하였다.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.
화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온은 세포 이식 12시간, 1시간 전, 이식 후 7시간 후부터 매일 50 mg/kg (DMSO:PEG 400:water 1:5:4)로 투여 종료 시점 까지 경구 투여 하였고, 항 PD-1과 Isotype (IgG 2A, BioXcell)은 이식 후 1일 뒤부터 10 mg/kg (saline), 3일 간격으로 투여종료 시점 까지 복강 투여 하였다.(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.
체중 및 종양의 크기는 투여 개시일 이후 종양크기 측정이 가능한 시점부터 종료일까지 주 3회 측정하였으며, 종양의 부피는 장축, 단축의 순으로 버니어 캘리퍼를 이용해 소수점 둘째 자리까지 적용하여 계산하였다. 계산식으로는 하기 [식 1]을 사용하였다.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.
[식 1][Formula 1]
도 1은 4T1 마우스 유래 유방암 세포에 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 항 PD-1의 단독 또는 병용 투여에 따른 종양 세포의 부피를 나타낸 도이다.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.
이하 도 1에서는 상기 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온는 "PI3K inhibitor"로 표시하였다.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".
상기 도 1을 참조하면 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 항 PD-1을 단독으로 투여하는 경우에 비하여, PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 항 PD-1을 병용 투여하는 경우에 통계적으로 유의한 종양 부피가 관찰되는 것을 확인할 수 있었다. 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.
또한, 항 PD-1을 단독으로 투여하는 경우, 27일 이후 나타나는 반동(rebound) 현상이 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온과 면역관문 억제제 (항 PD-1)의 병용 투여군에서는 억제되는 것을 확인할 수 있었다.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.
하기 표 1은 도 1의 데이터를 수치로 기재한 것이다.Table 1 below shows the data of Fig. 1 in numerical values.
[표 1][Table 1]
상기 표 1에서 보는 바와 같이, 대조군 대비 종양 억제율이 화학식 1의 PI3 키나아제 억제제 군은 45.0%, 항 PD-1 군은 37.2%, 화학식 1의 PI3 키나아제 억제제와 항 PD-1의 병용 투여 군은 58.9%로 각각 나타남을 알 수 있었다. 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.
상기 실험 결과를 통하여, PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온과 면역관문 억제제 (항 PD-1)의 병용 투여가 암 치료에 시너지 효과를 가지면서 현저히 우수한 항암 효과를 보이는 것을 확인할 수 있었다. 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.
따라서, 본 발명에 따른 약학적 조성물은 암의 예방 또는 개선에 유용하게 적용될 수 있으며, 본 발명에 따른 치료방법 또한 암의 예방 또는 치료에 효과적으로 적용될 수 있다.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.
실시예Example
3. 3.
in in
vivovivo
시험 exam
CT26 마우스 유래 대장암 세포를 0.25% Trypsin을 사용하여 수거하여 사용하였으며, 시험 동물로는 Balb-c/cAnNCrljOri 6주령 암컷을 오리엔트바이오(Charles river, Japan)로부터 공급받아 2주간의 순화과정을 거쳐 시험에 공여하였다. 온도 23.0 ± 1.0℃, 상대습도 50.0 ± 5.0 %, 조명주기 12시간, 자유로운 시험동물용 쥐 사료와 음용수 섭취의 환경에서 사육하면서 시험에 사용하였다. 또한, 화학식 1의 PI3 키나아제 억제제로는 상기 실시예 1에 따른 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 사용하였다.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.
세포를 PBS에 5 × 10
5/100 μL로 계수하여 마우스의 복부 부위에 1 mL 주사기를 이용하여 SC (subcutaneous)로 이식하였다. 이식 후 비히클(vehicle, PBS) + IgG 아이소타입 (Isotype) 10 mg/kg 군, 항 PD-1 10 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg 군, 화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 50 mg/kg + 항 PD-1 10 mg/kg 군으로 투여하였다.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.
화학식 1의 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온은 세포 이식 12시간, 1시간 전, 이식 후 7시간 후부터 매일 50 mg/kg (DMSO:PEG 400:water 1:5:4)로 투여 종료 시점 까지 경구 투여 하였고, 항 PD-1과 Isotype (IgG 2A, BioXcell)은 이식 후 1일 뒤부터 10 mg/kg (saline), 3일 간격으로 투여종료 시점 까지 복강 투여 하였다.(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.
체중 및 종양의 크기는 투여 개시일 이후 종양크기 측정이 가능한 시점부터 종료일까지 주 3회 측정하였으며, 종양의 부피는 장축, 단축의 순으로 버니어 캘리퍼를 이용해 소수점 둘째 자리까지 적용하여 상기 식 1을 통해 계산하였다. 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.
도 2는 CT26 마우스 유래 대장암 세포에 PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 항 PD-1의 단독 또는 병용 투여에 따른 종양 세포의 부피를 나타낸 도이다. 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.
이하 도 2에서는 상기 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온는 "PI3K inhibitor"로 표시하였다.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 ".
상기 도 2를 참조하면, 면역관문 억제제 (항 PD-1)를 단독으로 투여하는 경우에 비하여, PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 면역관문 억제제 (항 PD-1)를 병용 투여하는 경우에 통계적으로 유의한 종양 부피가 관찰되는 것을 확인할 수 있었다.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.
하기 표 2는 도 2의 데이터를 수치로 기재한 것이다.Table 2 below shows the data of FIG. 2 in numerical values.
[표 2][Table 2]
상기 표 2에서 보는 바와 같이, 대조군 대비 종양 억제율이 화학식 1의 PI3 키나아제 억제제 군은 54.4%, 항 PD-1 군은 43.4%, 화학식 1의 PI3 키나아제 억제제와 항 PD-1의 병용 투여 군은 70.9%로 각각 나타남을 알 수 있었다. 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.
상기 실험 결과를 통하여, PI3 키나아제 억제제인 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온과 면역관문 억제제 (항 PD-1)의 병용 투여가 암 치료에 시너지 효과를 가지면서 현저히 우수한 항암 효과를 보이는 것을 확인할 수 있었다. 따라서, 본 발명에 따른 약학적 조성물은 암의 예방 또는 개선에 유용하게 적용될 수 있으며, 본 발명에 따른 치료방법 또한 암의 예방 또는 치료에 효과적으로 적용될 수 있다.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.
본 발명은 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것으로서, 본 발명에 따른 조성물은 PI3 키나아제 억제제로 사용된 화학식 1의 화합물 또는 면역관문 억제제를 단독으로 투여한 경우와 비교하여, 암의 예방 또는 치료 활성이 우수하다. 따라서, 본 발명의 조성물은 암의 예방, 치료 또는 개선에 유용하게 적용될 수 있다.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)
- PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulatory agent.
- 제1항에 있어서, 상기 PI3 키나아제 억제제는 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염인 것인 암의 예방 또는 치료용 약학적 조성물: 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:[화학식 1][Chemical Formula 1]화학식 1에 있어서, In formula (1)R 1은 수소; 또는 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기이고, R 1 is hydrogen; Or a straight or branched alkyl group having 1 to 5 carbon atoms,R 2는 페닐기 또는 피리디닐기이고, 상기 페닐기 또는 피리디닐기는 할로겐기; 및 탄소수 1 내지 5의 직쇄 또는 분지쇄의 알킬기로 이루어진 군에서 선택되는 1 이상의 치환기로 치환 또는 비치환되며, 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 ofR 3 및 R 4는 각각 독립적으로 수소 또는 할로겐기이다. R 3 and R 4 are each independently hydrogen or a halogen group.
- 제2항에 있어서, 3. The method of claim 2,상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염인 것인 암의 예방 또는 치료용 약학적 조성물: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, :[화학식 2](2)화학식 2에 있어서, R 1 내지 R 4는 화학식 1에서 정의한 바와 동일하다. In formula (2), R 1 to R 4 are the same as defined in formula (1).
- 제2항에 있어서, 3. The method of claim 2,R 3는 수소 또는 할로겐기인 것인 암의 예방 또는 치료용 약학적 조성물. And R 3 is hydrogen or a halogen group.
- 제2항에 있어서, 3. The method of claim 2,R 4는 수소; 또는 할로겐기인 것인 암의 예방 또는 치료용 약학적 조성물. R 4 is hydrogen; Or a halogen group.
- 제2항에 있어서, 3. The method of claim 2,상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 (4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one), 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염인 것인 암의 예방 또는 치료용 약학적 조성물. 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.
- 제2항에 있어서, 3. The method of claim 2,상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염은 (S)-4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 ((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) 또는 이의 약학적으로 허용가능한 염인 것인 암의 예방 또는 치료용 약학적 조성물. 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.
- 제1항에 있어서, The method according to claim 1,상기 면역관문 억제제는 항체, 융합 단백질, 압타머 및 이의 면역관문 단백질-결합 단편으로부터 선택되는 1 이상인 것인 암의 예방 또는 치료용 약학적 조성물.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.
- 제1항에 있어서, The method according to claim 1,상기 면역관문 억제제는 항-CTLA4 항체, 이의 유도체 또는 이의 항원-결합 단편; 항-PD-L1 항체, 이의 유도체 또는 이의 항원-결합 단편; 및 항-PD-1 항체, 이의 유도체 또는 이의 항원-결합 단편으로부터 선택되는 1 이상인 것인 암의 예방 또는 치료용 약학적 조성물.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.
- 제1항에 있어서, The method according to claim 1,상기 면역관문 억제제는 항-PD-1 항체인 것인 암의 예방 또는 치료용 약학적 조성물. Wherein said immunostimulatory agent is an anti-PD-1 antibody.
- 제1항에 있어서, The method according to claim 1,상기 PI3 키나아제 억제제는 경구 투여되는 것인 암의 예방 또는 치료용 약학적 조성물. Wherein said PI3 kinase inhibitor is orally administered.
- 제1항에 있어서, The method according to claim 1,상기 면역관문 억제제는 비경구 투여되는 것인 암의 예방 또는 치료용 약학적 조성물. Wherein said immunostimulatory agent is parenterally administered.
- 제1항에 있어서, 상기 조성물은 액제, 현탁제, 산제, 과립제, 정제, 캡슐제, 환제, 엑스제, 에멀젼, 시럽제, 에어로졸 또는 주사제 중 어느 하나인 것인 암의 예방 또는 치료용 약학적 조성물.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 .
- 제1항에 있어서, 상기 암은 폐암, 비-소세포 폐암(NSCL), 기관지 폐포 세포 폐암, 위암, 위장관암, 간암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 난소암, 직장암, 대장암, 결장암, 유방암, 자궁 육종, 나팔관 암종, 내궁내막 암종, 자궁경부 암종, 질 암종, 외음부 암종, 식도암, 후두암, 소장암, 갑상선암, 부감상선암, 연조직의 육종, 요도암, 음경암, 전립선암, 다발성 골수종, 만성 또는 급성 백혈병, 유년기의 고상종양, 림프종, 방광암, 신장암, 신장세포 암종, 신장 골반 암종, 축수축 종양, 뇌간 신경교종 또는 뇌하수체 아데노마 중 어느 하나인 것인 암의 예방 또는 치료용 약학적 조성물.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.
- 제14항에 있어서, 상기 암은 비소세포폐암, 방광암, 두경부암 또는 림프종인 것인 암의 예방 또는 치료용 약학적 조성물.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.
- 면역관문 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물.Wherein the compound is administered in combination with an effective amount of an immunostimulant inhibitor.
- PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 암의 예방 또는 치료를 위한 병용 투여용 약학적 조성물.A pharmaceutical composition for the combined administration for the prevention or treatment of cancer comprising a PI3 kinase inhibitor and an immunostimulant inhibitor.
- 필요로 하는 개체에게 PI3 키나아제 억제제 및 면역관문 억제제를 투여하는 것을 포함하는 암의 예방 또는 치료방법.A method of preventing or treating cancer, comprising administering to a subject in need thereof a PI3 kinase inhibitor and an immunostimulatory agent.
- 암의 예방 또는 치료용 약제의 제조를 위한 PI3 키나아제 억제제 및 면역관문 억제제를 포함하는 약학적 조성물의 용도.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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020207012298A KR20200055116A (en) | 2018-01-10 | 2019-01-10 | Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and immune checkpoint inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20180003401 | 2018-01-10 | ||
KR10-2018-0003401 | 2018-01-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019139388A1 true WO2019139388A1 (en) | 2019-07-18 |
Family
ID=67219813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2019/000420 WO2019139388A1 (en) | 2018-01-10 | 2019-01-10 | Pharmaceutical composition comprising pi3 kinase inhibitor and immune checkpoint inhibitor for preventing or treating cancer |
Country Status (3)
Country | Link |
---|---|
KR (1) | KR20200055116A (en) |
TW (1) | TW201938168A (en) |
WO (1) | WO2019139388A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115671289A (en) * | 2021-07-27 | 2023-02-03 | 广州嘉越医药科技有限公司 | Pharmaceutical composition and application thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115803060A (en) | 2020-07-10 | 2023-03-14 | (株) 娜迪安生物公司 | Pharmaceutical composition for preventing or treating cancer comprising naphthoquinone-based compound and immune checkpoint inhibitor as active ingredients |
KR20230017753A (en) | 2021-07-28 | 2023-02-06 | 성균관대학교산학협력단 | Combination therapy using exosome secretion inhibitor and immune checkpoint inhibitor |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150290207A1 (en) * | 2014-03-19 | 2015-10-15 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
KR20160150006A (en) * | 2015-06-18 | 2016-12-28 | 한국화학연구원 | Heteroaryl derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases |
US20170007587A1 (en) * | 2015-06-29 | 2017-01-12 | Biomed Valley Discoveries, Inc. | Lpt-723 and immune checkpoint inhibitor cominations and methods of treatment |
KR20170069257A (en) * | 2014-10-14 | 2017-06-20 | 노파르티스 아게 | Antibody molecules to pd-l1 and uses thereof |
KR20170074381A (en) * | 2015-12-22 | 2017-06-30 | 한국화학연구원 | Pyrimido oxazine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016204429A1 (en) | 2015-06-18 | 2016-12-22 | 한국화학연구원 | Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient |
-
2019
- 2019-01-10 KR KR1020207012298A patent/KR20200055116A/en not_active Application Discontinuation
- 2019-01-10 TW TW108101074A patent/TW201938168A/en unknown
- 2019-01-10 WO PCT/KR2019/000420 patent/WO2019139388A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150290207A1 (en) * | 2014-03-19 | 2015-10-15 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
KR20170069257A (en) * | 2014-10-14 | 2017-06-20 | 노파르티스 아게 | Antibody molecules to pd-l1 and uses thereof |
KR20160150006A (en) * | 2015-06-18 | 2016-12-28 | 한국화학연구원 | Heteroaryl derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases |
US20170007587A1 (en) * | 2015-06-29 | 2017-01-12 | Biomed Valley Discoveries, Inc. | Lpt-723 and immune checkpoint inhibitor cominations and methods of treatment |
KR20170074381A (en) * | 2015-12-22 | 2017-06-30 | 한국화학연구원 | Pyrimido oxazine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating PI3 kinase related diseases |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115671289A (en) * | 2021-07-27 | 2023-02-03 | 广州嘉越医药科技有限公司 | Pharmaceutical composition and application thereof |
CN115671289B (en) * | 2021-07-27 | 2024-04-26 | 广州嘉越医药科技有限公司 | Pharmaceutical composition and application thereof |
Also Published As
Publication number | Publication date |
---|---|
KR20200055116A (en) | 2020-05-20 |
TW201938168A (en) | 2019-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2019139388A1 (en) | Pharmaceutical composition comprising pi3 kinase inhibitor and immune checkpoint inhibitor for preventing or treating cancer | |
JP2016535756A (en) | Combination therapy for cancer using bromodomain and extra terminal (BET) protein inhibitors | |
EP3054952A1 (en) | Combinations of histone deacetylase inhibitors and either her2 inhibitors or pi3k inhibitors | |
US9364459B2 (en) | 3-(indolyl)- or 3-(azaindolyl)- 4-arylmaleimide derivatives for use in the treatment of colon and gastric adenocarcinoma | |
US20220354846A1 (en) | Pharmaceutical combinations comprising a histone deacetylase inhibitor and a cd38 inhibitor and methods of use thereof | |
TW202120500A (en) | Sting agonist compounds and methods of use | |
JP2015536986A (en) | Combination therapy | |
WO2017155234A1 (en) | Peptide for preventing or treating inflammatory diseases and use thereof | |
JP5599519B2 (en) | Quinoline derivative compound, process for producing the same and pharmaceutical composition containing the same | |
EP1293213A1 (en) | Preventives/remedies for postoperative stress | |
CN114929225A (en) | Quinoline derivatives for the treatment of rheumatoid arthritis | |
WO2019139399A1 (en) | Pharmaceutical composition comprising pi3 kinase inhibitor and cytotoxic anti-cancer agent for preventing or treating cancer | |
WO2020071795A1 (en) | Anticancer pharmaceutical composition containing if1 as active ingredient | |
CN118382459A (en) | Combination therapy of KRAS G12D inhibitors with SOS1 inhibitors | |
CA3188003A1 (en) | Use of btk inhibitors in the treatment of diseases | |
CN101903027B (en) | Preventive or therapeutic agent for inflammatory bowel disease | |
WO2022025709A1 (en) | Preventive, relief or therapeutic use of 2,3,5-substituted thiophene compound against gastrointestinal stromal tumor | |
WO2023277514A1 (en) | Peptide having anticancer activity, and use thereof | |
WO2023195798A1 (en) | Composition for preventing or treating pulmonary fibrosis, comprising taurodeoxycholic acid or pharmaceutically acceptable salt thereof as active ingredient | |
WO2022019583A1 (en) | Therapeutic agent for exosome-mediated disease | |
EP3967693A1 (en) | Amorphous pi3k inhibitor and pharmaceutical composition comprising same | |
EP1667719A1 (en) | Treatment of gastrointestinal stromal tumors with imatinib and midostaurin | |
KR101168235B1 (en) | COMPOSITION FOR PREVENTING AND TREATING OF ALLERGIC DISEASES COMPRISING 4-CHLOROTETRAZOLO[1,5-a]QUINOXALINE AND DERIVATIVES | |
WO2021246666A1 (en) | Anticancer drug composition comprising as active ingredient tlr5 agonist derived from flagellin | |
US20230312588A1 (en) | Imidazopiperazine inhibitors of transcription activating proteins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19738471 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 20207012298 Country of ref document: KR Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19738471 Country of ref document: EP Kind code of ref document: A1 |