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WO2019112381A1 - Composition comprising pi3 kinase inhibitor and bcl-2 inhibitor - Google Patents

Composition comprising pi3 kinase inhibitor and bcl-2 inhibitor Download PDF

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Publication number
WO2019112381A1
WO2019112381A1 PCT/KR2018/015549 KR2018015549W WO2019112381A1 WO 2019112381 A1 WO2019112381 A1 WO 2019112381A1 KR 2018015549 W KR2018015549 W KR 2018015549W WO 2019112381 A1 WO2019112381 A1 WO 2019112381A1
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Prior art keywords
group
inhibitor
bcl
lymphoma
formula
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French (fr)
Korean (ko)
Inventor
김남훈
왕진상
김백경
전병욱
이보람
손미권
최연서
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Boryung Pharmaceutical Co Ltd
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Boryung Pharmaceutical Co Ltd
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Priority to KR1020207012297A priority Critical patent/KR102436875B1/en
Publication of WO2019112381A1 publication Critical patent/WO2019112381A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical composition for the prophylaxis or treatment of lymphoma comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.
  • PI3K phosphatidylinositol 3-kinase
  • Cancer can pose a health threat to the world, due to a variety of causative factors that can be triggered individually or together to initiate or promote the onset of cancer. Therefore, it is important to develop a more effective approach, especially a combined approach, to improve cancer prevention and treatment.
  • the present invention has developed a composition for the prevention or treatment of lymphoma including PI3 kinase inhibitor and Bcl-2 (B-cell lymphoma 2) inhibitor.
  • the composition for preventing or treating lymphoma is PI3
  • the kinase inhibitor and the Bcl-2 inhibitor in combination, it was confirmed that the preventive and therapeutic activity of lymphoma was prominent due to the up-complementing effect of the combination of the kinase inhibitor and the Bcl-2 inhibitor.
  • composition for the prevention or treatment of lymphoma
  • the present invention provides a composition for the prevention or treatment of lymphoma comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.
  • the ratio of the PI3 kinase inhibitor to the Bcl-2 inhibitor may be 0.001: 1 to 20: 1.
  • the compound used as the PI3 kinase inhibitor is a compound represented by the following Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate 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; A halogen group; Or a pyridinyl group.
  • x represents the number of carbon atoms in the "number of carbon atoms x" of the functional group
  • the number of carbon atoms x to y represents a functional group having x or more and 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.
  • " halogen " in the present invention represents a halogen group element and includes, for example, F, Cl, Br or I.
  • the compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is a compound represented by Formula 2, a stereoisomer thereof, a pharmaceutical composition thereof, Or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in the manufacture of a medicament for the prophylaxis or treatment of lymphoma,
  • 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 &gt is a methyl group.
  • R 2 is a phenyl group or a pyridinyl group, and the phenyl group or the pyridinyl group is a halogen group; And a linear or branched alkyl group having 1 to 5 carbon atoms.
  • R 2 is a phenyl group.
  • R < 3 &gt is hydrogen; A halogen group; Or a pyridinyl group.
  • R 3 is a halogen group.
  • R < 3 > is chlorine.
  • R < 4 &gt is hydrogen; Or a halogen group.
  • R < 4 > is a halogen group.
  • R < 4 &gt is chlorine.
  • the compound represented by the general formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof may be 4 - ((1- (4,8-dichloro- 2,3-d] pyrimidin-5 (8H) -one (4 - ((1- (4,8 pyrido [2,3-d] pyrimidin-5 (8H) -one), its stereoisomers, its pharmacological Acceptable salt, hydrate thereof or solvate thereof.
  • the compound represented by the formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof can be prepared by reacting (S) -4 - ((1- (4,8- 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.
  • 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.
  • the term " salt " in the present invention means an acid addition salt formed by a pharmaceutically acceptable free acid
  • the pharmaceutically acceptable salt is a salt commonly used in the pharmaceutical industry Inorganic acid salts prepared by, for example, calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid;
  • " hydrate " in the present invention means that the compound represented by the formula (1) is bonded to water by a force between non-covalent molecules and includes stoichiometric or non-stoichiometric amounts of water.
  • the hydrate may comprise from about 0.25 mole to about 10 mole percent of water based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, about 5 moles, and the like.
  • " solvate " in the present invention means that the compound represented by the above formula (1) and the solvent are bonded by the force between the noncovalent molecules and include a stoichiometric or non-stoichiometric amount of the solvent.
  • Preferred solvents are volatile, non-toxic, and can be administered to humans in very small doses.
  • the solvate may comprise water in an amount of from about 0.25 mole to about 10 mole, more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 1 mole, about 1 mole, About 3 moles, about 5 moles, and the like.
  • the compound represented by the formula (I) according to the present invention may selectively inhibit PI3 kinase selected from the group consisting of PI3K ?, PI3K ?, PI3K? And PI3K? can do.
  • Bcl-2 is a protein that regulates apoptosis, induces pro-apoptosis, inhibits anti-apoptosis and regulates apoptosis.
  • the Bcl-2 inhibitor means a substance that inhibits the activity of Bcl-2 through inhibition of expression or the like.
  • the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.
  • Venetoclase a Bcl-2 inhibitor
  • a Bcl-2 inhibitor is a BH3-mimetic drug designed to block the function of protein Bcl-2.
  • Venetoclass was found to be useful in the treatment of multiple myeloma, chronic lymphocytic leukemia, systemic lupus erythematosus, Acute myeloid leukemia, and non-Hodgkin's lymphoma.
  • Bennett Clark was able to synthesize 4- (4- [2- (4-chlorophenyl) -4,4-dimethylcyclohex- 1-en-1-yl] methylpiperazin- Pyrrolo [2,3-b] pyridin-5-yloxy) benzamide was prepared from IUPAC Lt; / RTI >
  • the pharmaceutical composition of the present invention can be used in combination with a compound represented by the above-mentioned formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a Bcl-2 inhibitor
  • a compound represented by the above-mentioned formula (1) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a Bcl-2 inhibitor
  • the pharmaceutical composition of the present invention may be useful for the prevention or treatment of lymphoma.
  • lymphoid tumors include, for example, non-Hodgkin's lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, lymphoblastic leukemia, multiple myeloma, diffuse But not limited to, diffuse large B-cell lymphoma.
  • the pharmaceutical composition of the present invention may be prepared in unit dosage form by formulating it using a pharmaceutically acceptable carrier according to a method which can be easily carried out by a person skilled in the art to which the present invention belongs, Into the container.
  • Such pharmaceutically acceptable carriers are those conventionally used in the field of manufacture and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • 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 usual formulation.
  • composition of the present invention may be formulated into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • the pharmaceutical composition of the present invention may be used for oral administration, and non-limiting examples of such oral administration preparations include tablets, troches, lozenges, aqueous suspensions, oily suspensions, Emulsions, hard capsules, soft capsules, syrups or elixirs.
  • composition of the present invention may be used for parenteral administration.
  • parenteral preparation include injectable solutions, suppositories, respirable inhalation powders, aerosol preparations for spraying, ointment, powder for application, .
  • 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 suitably selected by those skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg / kg, but is not limited to this, and may be administered once a day or divided into several times a day.
  • the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the intended method.
  • composition of the present invention may comprise two separate preparations and may be composed of one formulation.
  • the compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be administered parenterally or orally, ≪ / RTI >
  • the Bcl-2 inhibitor may be administered parenterally or orally, preferably parenterally.
  • the pharmaceutically effective amount and the effective dose of the pharmaceutical composition of the present invention may be varied depending on the formulation method, administration method, administration time and / or administration route of the pharmaceutical composition, and those having ordinary skill in the art
  • the effective dosage for treatment of the < RTI ID 0.0 > metastatic < / RTI >
  • the administration of the pharmaceutical composition of the present invention may be administered once a day or divided into several doses.
  • the invention provides a method of preventing or treating a lymphoma comprising administering to a mammal, including a human, a therapeutically effective amount of a composition comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.
  • the compound used as the PI3 kinase inhibitor in the method for preventing or treating lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >
  • Mammals, including humans, include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats and mice.
  • " therapeutically effective amount &quot means an amount effective to treat a lymphoma, for example, an amount of a composition to be administered to a subject to be treated, to prevent the occurrence or recurrence of lymphoma, Or an amount of the composition that inhibits an indirect pathological outcome, prevents metastasis, decreases the rate of progress, alleviates or palliates the condition, or improves the prognosis. That is, the therapeutically effective amount can be interpreted as encompassing any dose at which the symptoms of the lymphoma are improved or cured by the composition.
  • the prophylactic or therapeutic method of the present invention comprises administering a compound represented by the above formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a Bcl-2 inhibitor, which function as the PI3 kinase inhibitor, Not only does it deal with the disease itself before the onset of the symptoms, but it also involves inhibiting or avoiding the signs of it.
  • 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.
  • the therapeutic method of the present invention can be carried out by administering a therapeutically effective amount of a compound represented by the above formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and the additional active agent may exhibit a synergistic or additive effect with the compound of formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or its solvate .
  • lymphoma For the prevention or treatment of lymphoma
  • the present invention provides a use of a composition comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor for the prevention or treatment of lymphoma.
  • a composition comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor for the prevention or treatment of lymphoma.
  • the compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >
  • the invention provides a use for the manufacture of a medicament for the prevention or treatment of lymphoma of a composition comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.
  • the compound used as the PI3 kinase inhibitor in the use for the manufacture of a medicament for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the above pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, Or a solvate thereof.
  • composition of the present invention for the preparation of a medicament may be admixed with an acceptable carrier or the like, and may further comprise other agonists.
  • composition for preventing or treating lymphoma Composition for preventing or treating lymphoma
  • the present invention provides a composition for preventing or treating lymphoma, comprising a PI3 kinase inhibitor, which is administered together with an effective amount of Bcl-2 (B-cell lymphoma 2) inhibitor.
  • the Bcl-2 inhibitor may be administered simultaneously or separately with the PI3 kinase inhibitor, and the effective dose may be varied depending on the formulation method, administration mode, administration time and / or route of administration of the pharmaceutical composition, One of ordinary skill in the art can readily determine and prescribe dosages effective for the desired treatment.
  • the compound used as the PI3 kinase inhibitor is a compound represented by the following Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate 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; A halogen group; Or a pyridinyl group.
  • the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.
  • Venetoclase a Bcl-2 inhibitor
  • a Bcl-2 inhibitor is a BH3-mimetic drug designed to block the function of protein Bcl-2.
  • Venetoclass was found to be useful in the treatment of multiple myeloma, chronic lymphocytic leukemia, systemic lupus erythematosus, Acute myeloid leukemia, and non-Hodgkin's lymphoma.
  • Bennett Clark was able to synthesize 4- (4- [2- (4-chlorophenyl) -4,4-dimethylcyclohex- 1-en-1-yl] methylpiperazin- Pyrrolo [2,3-b] pyridin-5-yloxy) benzamide was prepared from IUPAC Lt; / RTI >
  • the compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >
  • composition for co-administration for prevention or treatment of lymphoma Composition for co-administration for prevention or treatment of lymphoma
  • the present invention provides a composition for co-administration for prevention or treatment of a lymphoma comprising as an active ingredient a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.
  • the compound used as the PI3 kinase inhibitor is a compound represented by the following Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate 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; A halogen group; Or a pyridinyl group.
  • the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.
  • the compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >
  • composition according to the present invention is superior in the prophylactic or therapeutic activity of lymphoma tumors as compared with the case where the compound of formula (I) is administered alone. Therefore, the composition of the present invention can be usefully applied for the prevention, treatment or improvement of lymphoid tumor.
  • FIG. 1 shows inhibition of caspase 3 expression by the compound of Chemical Formula 1 in the SU-DHL-6 cell line.
  • FIG. 2 shows the cell cycle distribution by the compound of Chemical Formula 1 in the SU-DHL-6 cell line.
  • FIG. 5A shows the inhibitory activity of c-Myc on the expression of the compound of formula 1, the adelalysin, TGR-1202 and NU-7441 in the SU-DHL-4 cell line, b and SU-DHL- 1, the c-Myc expression-inhibiting activity of Veneto Clark, Adelalysin, and Ibutinib.
  • FIG. 6 shows Mcl-1 inhibitory activity according to the concentration of the compound of Formula 1 in SU-DHL-4, SU-DHL-6 and DOHH-2 cell lines.
  • FIG. 7 shows the inhibitory activities of c-Myc and phospho-GSK3? In the SU-DHL-4 cell line.
  • FIG. 8 shows the inhibitory activity of c-Myc on the expression of the compound of Chemical Formula 1 in the DOHH-2 cell line.
  • FIG. 9 shows the Mcl-1 expression-inducing activity of the SU-DHL-4 cell line and the DOHH-2 cell line when the Venetia clark was temporarily treated.
  • FIG. 10 shows the activity of inducing Mcl-1 expression when chronic treatment with Veneto clark was performed in the SU-DHL-6 cell line.
  • Fig. 11 shows the growth inhibitory activity of cells of Veneto clark in the resistant or non-resistant SU-DHL-6 cell line.
  • FIG. 12 shows the results of a single treatment of compound 1, Veneto Clark, Adelalysis, Iburutinib, and the compound of Formula 1, the drug of the Formula 1, the drug of the Formula 1, and the drug of the Formula 1 in the SU-DHL-
  • Mcl-1 alc c-Myc was observed when the combination of Venetia Clark and the selected one was used.
  • FIG. 13 shows the expression of c-Myc when the compound of Chemical Formula 1 was treated with tumor tissue of DOHH2 genograft mouse.
  • FIG. 14 shows changes in tumor size when DOHH2 genograft mice are administered with a combination of a compound of Formula 1, a Veneto Clark, a compound of Formula 1, and Veneto Clark.
  • caspase 3 The activity of caspase 3 was confirmed by treating the compound of formula 1 with the SU-DHL-6 cell line which is a diffuse large B-cell lymphoma (DLBCL) cell.
  • SU-DHL-6 cell line which is a diffuse large B-cell lymphoma (DLBCL) cell.
  • the caspase activity of the compound of Chemical Formula 1 was measured with dimethyl sulfoxide (DMSO), idelalisib, TGR-1202, NU-7441, and the results are shown in FIG.
  • DMSO dimethyl sulfoxide
  • idelalisib idelalisib
  • TGR-1202 TGR-1202
  • NU-7441 N-methyl sulfoxide
  • Example 1-2 confirmation of cell cycle arrest
  • the cells of the SU-DHL-6 and DOHH-2 cells which are DLBCL cells, were treated with the compound of Chemical Formula 1 at various concentrations to confirm cell cycle arrest. The results are shown in FIG. 2 and FIG.
  • Example 3 The method according to claim 1, wherein the c- Myc Confirmation of decomposition of protein
  • the DLBCL cell SU-DHL-4 cell line was treated with cycloheximide (CHX), and only a few cells were treated with the PI 3 kinase inhibitor of formula 1, 4 - ((1- (4,8-dichloro- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H)
  • CHX cycloheximide
  • the expression of phospho-GSK3? was confirmed, and the results are shown in Fig.
  • a PI3 kinase inhibitor 4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one; Ethyl) amino) pyrido [2,3-d] pyrimidine (prepared according to the procedure described for the synthesis of 4 - [(4,8-dichloro-1-oxo- -5 (8H) -one and cycloheximide; Ethyl) amino) pyrido [2,3-d] pyrimidine (prepared according to the procedure described for the synthesis of 4 - [(4,8-dichloro-1-oxo- -5 (8H) -one, cycloheximide, and MG132, a proteasome inhibitor, respectively
  • Mcl-1 was confirmed by transient treatment of the DLBCL cells SU-DHL-4 cell line and DOHH-2 cell line with the Bcl-2 inhibitor Veneto Clark for 18 hours. The results are shown in FIG. 9 .
  • Mcl-1 was confirmed by chronic treatment of DLBCL cell line SU-DHL-6 with Veneto Clark for 1 month, and the results are shown in FIG.
  • the inhibitory activity of the Bcl-2 inhibitor on the cell growth was confirmed by treating the resistant or non-resistant SU-DHL-6 cell line with the Bcl-2 inhibitor Veneto Clark, and the results are shown in FIG.
  • the growth inhibitory effect of the Bcl-2 inhibitor in the resistant SU-DHL-6 cells was significantly reduced.
  • Example 4-1 Check CI value
  • the cells were treated with the compound of formula (I) and the Bcl-2 inhibitor Venetoclase to the DLBCL cells SU-DHL-6, DOHH-2, U2932 and CLI-LY3, (CI) were measured.
  • (1) is a Chou-Talalay equation
  • a is the GI x value when the compound of formula (1) and Veneto clark are coadministered
  • b is the GI x value when administered alone
  • c represents the GI x value when administered with Veneto Clark alone.
  • the GI x value is a concentration at which x% inhibition of cell growth, for example, GI 50 means a concentration that inhibits cell growth by 50%.
  • the CI value is interpreted as synergism when 1 is less than 1, additive when 1, and antagonism when 1 is greater than 1 according to the Chou-Talalay equation.
  • Isobologram is a table comparing cell growth inhibition (%) and cell growth inhibition (%) at the time of combination treatment for each single drug, for example, in the case of DOHH-2 Isobologram 50, the calculated value is represented as 0.35 when substituted in Talal ray equation (Chou-Talalay equation) - to measure the GI 50 value at the GI 50, Veneto Clarks processed with GI 50 and the combination treatment of both drugs at the time of processing the Chow And it is confirmed that the combination treatment of the two drugs (compound of formula (I) and Veneto Clark) is synergistic.
  • the DLBCL cells SU-DHL-4 and SU-DHL-6 cell lines were treated with the test substances of the group shown in Table 2 below to confirm the expression of Mcl-1 and c-Myc, and the results are shown in FIG.
  • Veneto Clarks The compound of formula (1) Eidralis Ibrutinip Veneto Clark + Compound of Chemical Formula 1 Veneto Clark + Veneto Clark + Ibutorutinip
  • the concentration of the test substance shown in Table 2 is as follows.
  • Mcl-1 and c-Myc were greatly inhibited by the compound of formula (1). Mcl-1 and c-Myc Can be inhibited more effectively.
  • the combination of the compound of formula (I) and the Bcl-2 inhibitor shows synergistic effects on tumor growth inhibition.
  • the compound represented by the formula (1), 4 - ((1- (4,8-dichloro- Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one in combination with Bcl-2 inhibitor has synergistic effects in the treatment of lymphoma tumors.
  • the pharmaceutical composition according to the present invention can be usefully applied to prevent, treat or ameliorate lymphoma tumors, and the therapeutic method according to the present invention can also be effectively applied to the prevention or treatment of lymphoma tumors.
  • the present invention relates to a pharmaceutical composition for the prophylaxis or treatment of lymphoma comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor, wherein the composition according to the present invention is useful for the prophylaxis or treatment of lymphoma
  • the prophylactic or therapeutic activity is excellent. Therefore, the composition of the present invention can be usefully applied for the prevention, treatment or improvement of lymphoid tumor.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of a lymphoma comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor, a method for treating lymphoma by using the composition, and a use of the composition in the preparation of a medicament for the treatment of lymphoma. The PI3 kinase inhibitor according to the present invention is a compound represented by formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. The composition exhibits excellent effects on the prevention and treatment of lymphoma due to a synergistic effect of the combination PI3 kinase inhibitor and the Bcl-2 inhibitor.

Description

PI3 키나아제 억제제 및 BCL-2 억제제를 포함하는 조성물A composition comprising a PI3 kinase inhibitor and a BCL-2 inhibitor

본 발명은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 림프종의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of lymphoma comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.

c-Myc 및 Blc-2의 동시 재배열에 의한 더블 히트(double hit) 림프종뿐만 아니라 c-Myc 및 Bcl-2의 동시 과발현을 갖는 이중 발현체(double expressor)는 표준 R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine 및 prednisone) 요법에서 결과가 매우 낮고 임상 과정에서의 짧은 생존을 특징으로 한다. 그러나, 표준 화학 요법 이후에는 다른 치료법이 없다. Double expressors with simultaneous overexpression of c-Myc and Bcl-2, as well as double-hit lymphoma by c-Myc and Blc-2 co-rearrangement, are standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy is very low and is characterized by short survival in the clinical course. However, there is no other treatment after standard chemotherapy.

따라서, 보다 집중적인 처방이 사용되거나 다른 약물 조합이 사용될 수 있다. Bcl-2 (B-cell lymphoma 2) 억제제인 베네토클락스(Venetoclax) 단일 요법에 대한 1상 임상시험은 재발성/난치성 미만성 거대 B세포 림프종(diffuse large B-cell lymphoma, DLBCL) 환자에서 불충분한 결과를 나타냈다 (CR:4/34 (12%), PR:2/32(6%)). 이와 같은 결과에 대한 한가지 이유는, 베네토클락스가 Bcl-2만을 표적으로 하므로, 종양에서의 c-Myc 활성을 함께 억제하지 못하기 때문이다. 또한, Blc-2 표적화 전략은 Mcl-1과 같은 항-세포 사멸 단백질에 대한 활성을 보장하지 않는다. Mcl-1의 수준은 베네토클락스에 대한 1차 및 2차 내성 모두와 관련이 있기 때문에, Mcl-1 표적화 전략은 임상 환경에서 베네토클락스의 효능을 강화시키는 주된 치료법이 될 수 있다.Thus, more intensive prescriptions may be used or other drug combinations may be used. Phase I clinical trials for the Venetoclax monotherapy, a B-cell lymphoma 2 inhibitor, were inadequate for patients with relapsed / diffuse large B-cell lymphoma (DLBCL) (CR: 4/34 (12%), PR: 2/32 (6%)). One reason for such a result is that since Veneto Clark targets Bcl-2 only, it does not inhibit c-Myc activity in tumors at the same time. In addition, the Blc-2 targeting strategy does not guarantee activity against anti-apoptotic proteins such as Mcl-1. Since the level of Mcl-1 is related to both the primary and secondary resistance to Venetia Clark, the Mcl-1 targeting strategy can be the main therapy to enhance the efficacy of Veneto Clark in clinical settings.

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 발병을 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 be triggered individually or together to initiate or promote the onset of cancer. Therefore, it is important to develop a more effective approach, especially a combined approach, to improve cancer prevention and treatment.

[선행기술문헌][Prior Art Literature]

[특허문헌][Patent Literature]

국제 특허공개공보 WO 2016/204429호 International Patent Publication No. WO 2016/204429

본 발명의 목적은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 림프종의 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 lymphoma which comprises a PI3 kinase inhibitor and a Bcl-2 inhibitor.

본 발명의 다른 목적은 PI3 키나아제 억제제 및 Bcl-2 억제제를 를 포함하는 조성물을 치료학적으로 유효한 양으로 인간을 포함한 포유류에 투여하는 단계를 포함하는 림프종을 예방 또는 치료하는 방법을 제공하는 것이다.It is another object of the present invention to provide a method of preventing or treating lymphoma, comprising administering to a mammal, including a human, a therapeutically effective amount of a composition comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.

본 발명의 목적은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 조성물의 림프종 예방 또는 치료를 위한 용도를 제공하는 것이다.It is an object of the present invention to provide a use for the prevention or treatment of lymphoma of a composition comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.

본 발명의 목적은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 조성물의 림프종 예방 또는 치료용 약제의 제조를 위한 용도를 제공하는 것이다.It is an object of the present invention to provide a use for the preparation of a medicament for the prevention or treatment of lymphoma of a composition comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.

본 발명의 목적은 Bcl-2(B-cell lymphoma 2) 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 림프종 예방 또는 치료용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for the prevention or treatment of lymphoma, comprising a PI3 kinase inhibitor, which is administered in combination with an effective amount of Bcl-2 (B-cell lymphoma 2) inhibitor.

본 발명의 목적은 PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 유효성분으로 포함하는 림프종의 예방 또는 치료를 위한 병용 투여용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for concomitant administration for the prophylaxis or treatment of lymphoma including PI3 kinase inhibitor and Bcl-2 (B-cell lymphoma 2) inhibitor as an active ingredient.

상기 과제를 해결하기 위하여, 본 발명에서는 PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 림프종의 예방 또는 치료용 조성물을 개발하였으며, 상기 림프종의 예방 또는 치료용 조성물은 PI3 키나아제 억제제와 Bcl-2 억제제를 병용함으로써, 이들의 병용에 따른 상승 보완 효과로 인하여 림프종의 예방 및 치료 활성이 현저해짐을 확인하였다.In order to solve the above problems, the present invention has developed a composition for the prevention or treatment of lymphoma including PI3 kinase inhibitor and Bcl-2 (B-cell lymphoma 2) inhibitor. The composition for preventing or treating lymphoma is PI3 By using the kinase inhibitor and the Bcl-2 inhibitor in combination, it was confirmed that the preventive and therapeutic activity of lymphoma was prominent due to the up-complementing effect of the combination of the kinase inhibitor and the Bcl-2 inhibitor.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

림프종의 예방 또는 치료용 조성물Composition for the prevention or treatment of lymphoma

본 발명은 PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 림프종의 예방 또는 치료용 조성물을 제공한다.The present invention provides a composition for the prevention or treatment of lymphoma comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.

본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제와 Bcl-2 억제제의 함량비는 0.001:1 내지 20:1 일 수 있다.In one embodiment of the present invention, the ratio of the PI3 kinase inhibitor to the Bcl-2 inhibitor may be 0.001: 1 to 20: 1.

본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제로 사용된 화합물은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물이다: 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, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:

[화학식 1][Chemical Formula 1]

Figure PCTKR2018015549-appb-img-000001
Figure PCTKR2018015549-appb-img-000001

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; 할로겐기; 또는 피리디닐기이다. R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group.

본 발명에서 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, x represents the number of carbon atoms in the "number of carbon atoms x" of the functional group, and the number of carbon atoms x to y represents a functional group having x or more and x or more and y or less.

본 발명에서, 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 발명에서 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 발명에서 용어 「할로겐」은 할로겐족 원소를 나타내며, 예를 들어 F, Cl, Br 또는 I를 포함한다.The term " halogen " in the present invention represents a halogen group element and includes, for example, F, Cl, Br or I.

또 하나의 구현예에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종의 예방 또는 치료용 약학적 조성물이다: In another embodiment, the compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is a compound represented by Formula 2, a stereoisomer thereof, a pharmaceutical composition thereof, Or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, in the manufacture of a medicament for the prophylaxis or treatment of lymphoma,

[화학식 2](2)

Figure PCTKR2018015549-appb-img-000002
Figure PCTKR2018015549-appb-img-000002

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 하나의 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.

또 하나의 구현예에 있어서, 상기 R 1은 메틸기이다. In another embodiment, 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 또 하나의 구현예에 있어서, R 3는 수소; 할로겐기; 또는 피리디닐기이다. In another embodiment of the present invention R < 3 > is hydrogen; A halogen group; Or a pyridinyl group.

본 발명의 또 하나의 구현예에 있어서, R 3는 할로겐기이다. In another embodiment of the present invention, R 3 is a halogen group.

하나의 구현예에 있어서, 상기 R 3는 염소이다. In one embodiment, R < 3 > is chlorine.

본 발명의 다른 구현예에 있어서, R 4는 수소; 또는 할로겐기이다. In another embodiment of the present invention, R < 4 > is hydrogen; Or a halogen group.

본 발명의 다른 구현예에 있어서, R 4은 할로겐기이다. In another embodiment of the present invention, R < 4 > is a halogen group.

또 하나의 구현예에 있어서, 상기 R 4은 염소이다. In another embodiment, R < 4 > is chlorine.

본 발명에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 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, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물이다. 더욱 구체적으로 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 (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)이다. In the present invention, the compound represented by the general formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof may be 4 - ((1- (4,8-dichloro- 2,3-d] pyrimidin-5 (8H) -one (4 - ((1- (4,8 pyrido [2,3-d] pyrimidin-5 (8H) -one), its stereoisomers, its pharmacological Acceptable salt, hydrate thereof or solvate thereof. More specifically, the compound represented by the formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof can be prepared by reacting (S) -4 - ((1- (4,8- 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.

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, 본 발명에서 용어 「염」이란, 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염을 의미하고, 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, 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 " salt " in the present invention means an acid addition salt formed by a pharmaceutically acceptable free acid, and the pharmaceutically acceptable salt is a salt commonly used in the pharmaceutical industry Inorganic acid salts prepared by, for example, calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid; 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, 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 발명에서 용어 「수화물」이란, 상기 화학식 1로 표시되는 화합물과 물이 비공유 분자간의 힘에 의해 결합된 것으로, 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 것을 의미한다. 구체적으로는, 상기 수화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1목, 약 1.5몰, 약 2몰, 약 3몰, 약 5몰 등을 포함할 수 있다.The term " hydrate " in the present invention means that the compound represented by the formula (1) is bonded to water by a force between non-covalent molecules and includes stoichiometric or non-stoichiometric amounts of water. Specifically, the hydrate may comprise from about 0.25 mole to about 10 mole percent of water based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, about 5 moles, and the like.

본 발명에서 용어 「용매화물」은 상기 화학식 1로 표시되는 화합물과 용매가 비공유 분자간의 힘에 의해 결합된 것으로, 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 것을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다. 구체적으로는, 상기 용매화물은 활성성분 1 몰을 기준으로 물을 약 0.25몰 내지 약 10몰 비로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1목, 약 1.5몰, 약 2몰, 약 3몰, 약 5몰 등을 포함할 수 있다.The term " solvate " in the present invention means that the compound represented by the above formula (1) and the solvent are bonded by the force between the noncovalent molecules and include a stoichiometric or non-stoichiometric amount of the solvent. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small doses. Specifically, the solvate may comprise water in an amount of from about 0.25 mole to about 10 mole, more specifically about 0.5 mole, about 1 mole, about 1.5 moles, about 2 moles, about 1 mole, about 1 mole, About 3 moles, about 5 moles, and the like.

본 발명에 따른 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 PI3Kα, PI3Kβ, PI3Kδ 및 PI3Kγ로 이루어지는 군으로부터 선택되는 PI3 키나아제에 대하여 선택적으로 억제할 수 있다. 본 발명에 있어서, Bcl-2는 세포 사멸을 조절하는 단백질로, 프로-에이포토시스(pro-apoptosis)를 유도하고, 안티-에이포토시스(anti-apoptosis)를 억제하여 세포 사멸을 조절한다. 본 발명에 있어서, Bcl-2 억제제는 상기 Bcl-2의 활성을 발현 저해 등을 통하여 억제시키는 물질을 의미한다.The compound represented by the formula (I) according to the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof may selectively inhibit PI3 kinase selected from the group consisting of PI3K ?, PI3K ?, PI3K? And PI3K? can do. In the present invention, Bcl-2 is a protein that regulates apoptosis, induces pro-apoptosis, inhibits anti-apoptosis and regulates apoptosis. In the present invention, the Bcl-2 inhibitor means a substance that inhibits the activity of Bcl-2 through inhibition of expression or the like.

본 발명의 구체적인 구현예에서, Bcl-2 억제제는 베네토클락스(Venetoclax) 일 수 있으나, 이에 제한되는 것은 아니다.In a specific embodiment of the invention, the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.

Bcl-2 억제제인 베네토클락스는, 단백질 Bcl-2의 기능을 차단하도록 설계된 BH3-모방 약물이며, 제3상 임상 시험에서 다발성 골수종, 만성 림프구성 백혈병, 전신 홍반 루푸스, 광범위 거대 B-세포 림프종, 급성 골수세포 백혈병, 및 비-호지킨 림프종의 치료를 위한 것이다. 베네토클락스는 4-(4-[2-(4-클로로페닐)-4,4-다이메틸사이클로헥스-1-엔-1-일]메틸피페라진-1-일)-N-(3-나이트로-4-[(테트라하이드로-2H-피란-4-일메틸)아미노]페닐설폰일)-2-(1H-피롤로[2,3-b]피리딘-5-일옥시)벤즈아마이드의 IUPAC 명칭을 가진 유리염기이다.Venetoclase, a Bcl-2 inhibitor, is a BH3-mimetic drug designed to block the function of protein Bcl-2. In phase III clinical trials, Venetoclass was found to be useful in the treatment of multiple myeloma, chronic lymphocytic leukemia, systemic lupus erythematosus, Acute myeloid leukemia, and non-Hodgkin's lymphoma. Bennett Clark was able to synthesize 4- (4- [2- (4-chlorophenyl) -4,4-dimethylcyclohex- 1-en-1-yl] methylpiperazin- Pyrrolo [2,3-b] pyridin-5-yloxy) benzamide was prepared from IUPAC Lt; / RTI >

본 발명의 약학적 조성물은 전술한 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 Bcl-2 억제제를 병용함으로써, 이들의 병용에 따른 상승 보완 효과로 인하여 림프종의 예방 및 치료 활성이 현저해진다.The pharmaceutical composition of the present invention can be used in combination with a compound represented by the above-mentioned formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a Bcl-2 inhibitor The prophylactic and therapeutic activity of lymphoma is remarkable.

본 발명의 약학적 조성물은 림프계 종양 예방 또는 치료용으로 유용하게 사용될 수 있다. 상기 림프계 종양은 예를 들어, 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 pharmaceutical composition of the present invention may be useful for the prevention or treatment of lymphoma. Such lymphoid tumors include, for example, non-Hodgkin's lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, lymphoblastic leukemia, multiple myeloma, diffuse But not limited to, diffuse large B-cell lymphoma.

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.The pharmaceutical composition of the present invention may be prepared in unit dosage form by formulating it using a pharmaceutically acceptable carrier according to a method which can be easily carried out by a person skilled in the art to which the present invention belongs, Into the container.

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 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.Such pharmaceutically acceptable carriers are those conventionally used in the field of manufacture and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. 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 발명에 있어서, 상기 약학적 조성물에 포함되는 첨가제의 함량은 특별히 한정되는 것은 아니며 통상의 제제화에 사용되는 함량 범위 내에서 적절하게 조절될 수 있다.In 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 usual formulation.

본 발명의 조성물은 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.The composition of the present invention may be formulated into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.

본 발명의 약학적 조성물은 경구 투여용일 수 있으며, 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 엘릭시르제 등을 들 수 있다. The pharmaceutical composition of the present invention may be used for oral administration, and non-limiting examples of such oral administration preparations include tablets, troches, lozenges, aqueous suspensions, oily suspensions, Emulsions, hard capsules, soft capsules, syrups or elixirs.

또한, 본 발명의 약학적 조성물은 비경구 투여용일수 있으며, 비경구용 제제의 비제한적인 예로는, 주사액, 좌제, 호흡기 흡입용 분말, 스프레이용 에어로졸제, 연고, 도포용 파우더, 오일, 크림 등을 들 수 있다. In addition, the pharmaceutical composition of the present invention may be used for parenteral administration. Non-limiting examples of the parenteral preparation include injectable solutions, suppositories, respirable inhalation powders, aerosol preparations for spraying, ointment, powder for application, .

본 발명의 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 연령, 성별, 건강상태, 식이 체질 특이성, 제제의 성질, 질병의 정도, 조성물의 투여시간, 투여방법, 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 suitably 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 발명에 있어서, 상기 약학적 조성물은 목적하는 방법에 따라 경구 투여되거나 비경구 투여(예를 들면, 정맥 내, 피하 내, 복강 내 또는 국소에 적용)될 수 있다. In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the intended method.

본 발명의 조성물은, 2종의 별개의 제제를 포함하는 것일 수 있으며, 1개의 제제로 구성될 수도 있다.The composition of the present invention may comprise two separate preparations and may be composed of one formulation.

본 발명의 하나의 구현예에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 비경구 또는 경구 투여될 수 있으며, 바람직하게는 경구 투여될 수 있다.In one embodiment of the present invention, the compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be administered parenterally or orally, ≪ / RTI >

본 발명의 하나의 구현예에 있어서, 상기 Bcl-2 억제제는 비경구 또는 경구 투여될 수 있으며, 바람직하게는 비경구 투여될 수 있다.In one embodiment of the invention, the Bcl-2 inhibitor may be administered parenterally or orally, preferably parenterally.

본 발명의 약학적 조성물의 약학적 유효량, 유효 투여량은 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.The pharmaceutically effective amount and the effective dose of the pharmaceutical composition of the present invention may be varied depending on the formulation method, administration method, administration time and / or administration route of the pharmaceutical composition, and those having ordinary skill in the art The effective dosage for treatment of the < RTI ID = 0.0 > metastatic < / RTI >

본 발명의 약학적 조성물의 투여는 하루에 1회 투여될 수 있고, 수회에 나누어 투여될 수도 있다. The administration of the pharmaceutical composition of the present invention may be administered once a day or divided into several doses.

림프종을 예방 또는 치료하는 방법How to Prevent or Treat Lymphoma

본 발명은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 조성물을 치료학적으로 유효한 양으로 인간을 포함하는 포유류에게 투여하는 단계를 포함하는 림프종을 예방 또는 치료하는 방법을 제공한다.The invention provides a method of preventing or treating a lymphoma comprising administering to a mammal, including a human, a therapeutically effective amount of a composition comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor.

본 발명의 림프종을 예방 또는 치료하는 방법에서 상기 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 동일할 수 있다.The compound used as the PI3 kinase inhibitor in the method for preventing or treating lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >

인간을 포함하는 포유류는, 인간, 원숭이, 소, 말, 개, 고양이, 토끼, 레트, 마우스 등의 포유류를 포함한다.Mammals, including humans, include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats and mice.

본 발명에서 용어 「치료학적으로 유효한 양」이란, 림프종의 치료에 유효한 양으로, 예컨대 치료하고자 하는 대상에게 투여되는 조성물의 양으로, 림프종의 발생 또는 재발을 예방하거나, 증상을 완화시키거나, 직접 또는 간접적인 병리학적 결과를 저해시키거나, 전이를 예방하거나, 진행 속도를 감소시키거나, 상태를 경감 또는 일시적 완화시키거나, 예후를 개선시키는 조성물의 양을 모두 포함할 수 있다. 즉, 상기 치료학적 유효한 양은 상기 조성물에 의해 림프종의 증세가 호전되거나 완치되는 모든 용량을 포괄하는 것으로 해석될 수 있다.The term " therapeutically effective amount " as used herein means an amount effective to treat a lymphoma, for example, an amount of a composition to be administered to a subject to be treated, to prevent the occurrence or recurrence of lymphoma, Or an amount of the composition that inhibits an indirect pathological outcome, prevents metastasis, decreases the rate of progress, alleviates or palliates the condition, or improves the prognosis. That is, the therapeutically effective amount can be interpreted as encompassing any dose at which the symptoms of the lymphoma are improved or cured by the composition.

본 발명의 예방 또는 치료 방법은 상기 PI3 키나아제 억제제로 작용하는 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 Bcl-2 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 치료 방법은 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 함께 시너지 효과 또는 상가적 효과를 나타낼 수 있다.The prophylactic or therapeutic method of the present invention comprises administering a compound represented by the above formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a Bcl-2 inhibitor, which function as the PI3 kinase inhibitor, Not only does it deal with the disease itself before the onset of the symptoms, but it also involves inhibiting or avoiding the signs of it. 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 therapeutic method of the present invention can be carried out by administering a therapeutically effective amount of a compound represented by the above formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, And the additional active agent may exhibit a synergistic or additive effect with the compound of formula 1, its stereoisomer, its pharmaceutically acceptable salt, its hydrate or its solvate .

림프종 예방 또는 치료를 위한 용도For the prevention or treatment of lymphoma

본 발명은 PI3 키나아제 억제제 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 조성물의 림프종 예방 또는 치료를 위한 용도를 제공한다.The present invention provides a use of a composition comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor for the prevention or treatment of lymphoma.

본 발명의 림프종 예방 또는 치료를 위한 용도에서 상기 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 동일할 수 있다.The compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >

림프종 예방 또는 치료용 약제의 제조를 위한 용도For the manufacture of medicaments for the prophylaxis or treatment of lymphoma

본 발명은 PI3 키나아제 억제제 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 조성물의 림프종 예방 또는 치료용 약제의 제조를 위한 용도를 제공한다.The invention provides a use for the manufacture of a medicament for the prevention or treatment of lymphoma of a composition comprising a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.

본 발명의 림프종 예방 또는 치료용 약제의 제조를 위한 용도에서 상기 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 동일할 수 있다.The compound used as the PI3 kinase inhibitor in the use for the manufacture of a medicament for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the above pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, Or a solvate thereof.

약제의 제조를 위한 본 발명의 조성물은 허용되는 담체 등을 혼합할 수 있으며, 다른 작용제들을 추가로 더 포함할 수도 있다.The composition of the present invention for the preparation of a medicament may be admixed with an acceptable carrier or the like, and may further comprise other agonists.

림프종 예방 또는 치료용 조성물Composition for preventing or treating lymphoma

본 발명은 Bcl-2(B-cell lymphoma 2) 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 림프종 예방 또는 치료용 조성물을 제공한다.The present invention provides a composition for preventing or treating lymphoma, comprising a PI3 kinase inhibitor, which is administered together with an effective amount of Bcl-2 (B-cell lymphoma 2) inhibitor.

상기 Bcl-2 억제제는 PI3 키나아제 억제제와 동시에 투여되거나, 개별적으로 각각 투여될 수 있고, 유효 투여량은 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.The Bcl-2 inhibitor may be administered simultaneously or separately with the PI3 kinase inhibitor, and the effective dose may be varied depending on the formulation method, administration mode, administration time and / or route of administration of the pharmaceutical composition, One of ordinary skill in the art can readily determine and prescribe dosages effective for the desired treatment.

본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제로 사용된 화합물은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물이다.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, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[화학식 1][Chemical Formula 1]

Figure PCTKR2018015549-appb-img-000003
Figure PCTKR2018015549-appb-img-000003

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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group.

본 발명의 구체적인 구현예에서, Bcl-2 억제제는 베네토클락스(Venetoclax) 일 수 있으나, 이에 제한되는 것은 아니다.In a specific embodiment of the invention, the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.

Bcl-2 억제제인 베네토클락스는, 단백질 Bcl-2의 기능을 차단하도록 설계된 BH3-모방 약물이며, 제3상 임상 시험에서 다발성 골수종, 만성 림프구성 백혈병, 전신 홍반 루푸스, 광범위 거대 B-세포 림프종, 급성 골수세포 백혈병, 및 비-호지킨 림프종의 치료를 위한 것이다. 베네토클락스는 4-(4-[2-(4-클로로페닐)-4,4-다이메틸사이클로헥스-1-엔-1-일]메틸피페라진-1-일)-N-(3-나이트로-4-[(테트라하이드로-2H-피란-4-일메틸)아미노]페닐설폰일)-2-(1H-피롤로[2,3-b]피리딘-5-일옥시)벤즈아마이드의 IUPAC 명칭을 가진 유리염기이다.Venetoclase, a Bcl-2 inhibitor, is a BH3-mimetic drug designed to block the function of protein Bcl-2. In phase III clinical trials, Venetoclass was found to be useful in the treatment of multiple myeloma, chronic lymphocytic leukemia, systemic lupus erythematosus, Acute myeloid leukemia, and non-Hodgkin's lymphoma. Bennett Clark was able to synthesize 4- (4- [2- (4-chlorophenyl) -4,4-dimethylcyclohex- 1-en-1-yl] methylpiperazin- Pyrrolo [2,3-b] pyridin-5-yloxy) benzamide was prepared from IUPAC Lt; / RTI >

본 발명의 림프종 예방 또는 치료를 위한 용도에서 상기 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 동일할 수 있다.The compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >

림프종의 예방 또는 치료를 위한 병용 투여용 조성물Composition for co-administration for prevention or treatment of lymphoma

본 발명은 PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 유효성분으로 포함하는 림프종의 예방 또는 치료를 위한 병용 투여용 조성물을 제공한다.The present invention provides a composition for co-administration for prevention or treatment of a lymphoma comprising as an active ingredient a PI3 kinase inhibitor and a B-cell lymphoma 2 (Bcl-2) inhibitor.

본 발명의 일 구현예에 있어서, 상기 PI3 키나아제 억제제로 사용된 화합물은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물이다.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, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[화학식 1][Chemical Formula 1]

Figure PCTKR2018015549-appb-img-000004
Figure PCTKR2018015549-appb-img-000004

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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group.

본 발명의 구체적인 구현예에서, Bcl-2 억제제는 베네토클락스(Venetoclax) 일 수 있으나, 이에 제한되는 것은 아니다.In a specific embodiment of the invention, the Bcl-2 inhibitor may be, but is not limited to, Venetoclax.

본 발명의 림프종 예방 또는 치료를 위한 용도에서 상기 PI3 키나아제 억제제로 사용된 화합물은 상기 약학적 조성물의 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물과 동일할 수 있다.The compound used as the PI3 kinase inhibitor in the use of the present invention for the prevention or treatment of lymphoma of the present invention is a compound represented by the formula 1 of the pharmaceutical composition, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof . ≪ / RTI >

본 발명의 조성물, 치료 방법 및 용도에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters mentioned in the composition, the treatment method and the use of the present invention are applied equally as far as they are not mutually contradictory.

본 발명에 따른 조성물은 화학식 1의 화합물을 단독으로 투여한 경우와 비교하여, 림프계 종양의 예방 또는 치료 활성이 우수하다. 따라서, 본 발명의 조성물은 림프계 종양의 예방, 치료 또는 개선에 유용하게 적용될 수 있다. The composition according to the present invention is superior in the prophylactic or therapeutic activity of lymphoma tumors as compared with the case where the compound of formula (I) is administered alone. Therefore, the composition of the present invention can be usefully applied for the prevention, treatment or improvement of lymphoid tumor.

도 1은 SU-DHL-6 세포주에서 화학식 1의 화합물에 의한 카스파아제 3 발현 억제를 확인한 것이다.FIG. 1 shows inhibition of caspase 3 expression by the compound of Chemical Formula 1 in the SU-DHL-6 cell line.

도 2는 SU-DHL-6 세포주에서 화학식 1의 화합물에 의한 세포주기 분포를 확인한 것이다.FIG. 2 shows the cell cycle distribution by the compound of Chemical Formula 1 in the SU-DHL-6 cell line.

도 3은 DOHH-2 세포주에서 화학식 1의 화합물에 의한 세포주기 분포를 확인한 것이다.3 shows the cell cycle distribution by the compound of Chemical Formula 1 in the DOHH-2 cell line.

도 4는 SU-DHL-4 세포주, SU-DHL-6 세포주 및 DOHH-2 세포주에서 화학식 1의 화합물의 농도에 따른 c-Myc 발현 억제 활성을 확인한 것이다.4 shows the inhibitory activity of c-Myc expression on the SU-DHL-4, SU-DHL-6 and DOHH-2 cell lines according to the concentration of the compound of formula (1).

도 5의 a는 SU-DHL-4 세포주에서 화학식 1의 화합물, 이델랄리십, TGR-1202 및 NU-7441의 c-Myc 발현 억제 활성을 확인한 것이고, b는 및 SU-DHL-6 세포주에서 화학식 1의 화합물, 베네토클락스, 이델랄리십 및 이브루티닙의 c-Myc 발현 억제 활성을 확인한 것이다.FIG. 5A shows the inhibitory activity of c-Myc on the expression of the compound of formula 1, the adelalysin, TGR-1202 and NU-7441 in the SU-DHL-4 cell line, b and SU-DHL- 1, the c-Myc expression-inhibiting activity of Veneto Clark, Adelalysin, and Ibutinib.

도 6은 SU-DHL-4 세포주, SU-DHL-6 세포주 및 DOHH-2 세포주에서 화학식 1의 화합물의 농도에 따른 Mcl-1 억제 활성을 확인한 것이다.FIG. 6 shows Mcl-1 inhibitory activity according to the concentration of the compound of Formula 1 in SU-DHL-4, SU-DHL-6 and DOHH-2 cell lines.

도 7은 SU-DHL-4 세포주에서 화학식 1의 화합물의 c-Myc 및 포스포-GSK3β의 발현 억제 활성을 확인한 것이다.FIG. 7 shows the inhibitory activities of c-Myc and phospho-GSK3? In the SU-DHL-4 cell line.

도 8은 DOHH-2 세포주에서 화학식 1의 화합물의 c-Myc 발현 억제 활성을 확인한 것이다.FIG. 8 shows the inhibitory activity of c-Myc on the expression of the compound of Chemical Formula 1 in the DOHH-2 cell line.

도 9는 SU-DHL-4 세포주 및 DOHH-2 세포주에 베네토클락스를 일시적으로 처리하였을때의 Mcl-1 발현 유도 활성을 확인한 것이다.FIG. 9 shows the Mcl-1 expression-inducing activity of the SU-DHL-4 cell line and the DOHH-2 cell line when the Venetia clark was temporarily treated.

도 10은 SU-DHL-6 세포주에서 베네토클락스를 만성적으로 처리하였을 때의 Mcl-1 발현 유도 활성을 확인한 것이다.FIG. 10 shows the activity of inducing Mcl-1 expression when chronic treatment with Veneto clark was performed in the SU-DHL-6 cell line.

도 11은 내성 또는 비내성 SU-DHL-6 세포주에서 베네토클락스의 세포의 성장 저해 활성을 확인한 것이다.Fig. 11 shows the growth inhibitory activity of cells of Veneto clark in the resistant or non-resistant SU-DHL-6 cell line.

도 12은 SU-DHL-4 세포주 및 SU-DHL-6 세포주에서 화학식 1의 화합물, 베네토클락스, 이델랄리십, 이브루티닙 단일 처리, 및 화학식 1의 화합물, 이델랄리십 및 이브루티닙중 선택된 어느 하나와 베네토클락스의 병용 처리하였을 때의 Mcl-1 alc c-Myc 발현을 확인한 것이다.FIG. 12 shows the results of a single treatment of compound 1, Veneto Clark, Adelalysis, Iburutinib, and the compound of Formula 1, the drug of the Formula 1, the drug of the Formula 1, and the drug of the Formula 1 in the SU-DHL- The expression of Mcl-1 alc c-Myc was observed when the combination of Venetia Clark and the selected one was used.

도 13는 DOHH2 제노그래프트 마우스의 종양 조직에 화학식 1의 화합물을 처리하였을 때의 c-Myc 발현을 확인한 것이다.FIG. 13 shows the expression of c-Myc when the compound of Chemical Formula 1 was treated with tumor tissue of DOHH2 genograft mouse.

도 14는 DOHH2 제노그래프트 마우스에 화학식 1의 화합물, 베네토클락스, 그리고 화학식 1의 화합물 및 베네토클락스의 조합을 투여하였을 때의 종양 크기의 변화를 나타낸 것이다.14 shows changes in tumor size when DOHH2 genograft mice are administered with a combination of a compound of Formula 1, a Veneto Clark, a compound of Formula 1, and Veneto Clark.

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.

제조예Manufacturing example 1. 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  Amino) pyrido [2,3-d] pyrimidin-4-yl) Pyrimidin-5 (8H) -one

상기 화학식 1로 표시되는 화합물인 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.(1 - (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino) pyrido [ 2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) amino (2-oxo- ) 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.

실시예Example 1. 화학식 1의 화합물의 작용 기전 확인 1. Identification of the mechanism of action of the compound of formula

화학식 1의 PI3 키나아제 억제제로, 제조예 1에 따른 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 사용하여 화학식 1의 화합물의 작용기전을 확인하였다.( 4 - ((4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) ethyl) piperazine according to Preparation Example 1 as a PI3 kinase inhibitor of Formula Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one was used to confirm the mechanism of action of the compound of formula (I).

실시예Example 1-1:  1-1: 카스파아제Caspase 3 활성 확인 3 Verify Active

미만성 거대 B세포 림프종(diffuse large B-cell lymphoma, DLBCL) 세포인 SU-DHL-6 세포주에 화학식 1의 화합물을 처리하여 카스파아제 3(caspase 3) 활성을 확인하였다.The activity of caspase 3 was confirmed by treating the compound of formula 1 with the SU-DHL-6 cell line which is a diffuse large B-cell lymphoma (DLBCL) cell.

화학식 1의 화합물의 카스파아제 활성은 디메틸 설폭시드(dimethyl sulfoxide, DMSO), 이델랄리십(idelalisib), TGR-1202, NU-7441과 함께 측정하였으며, 그 결과는 도 1에 나타내었다. The caspase activity of the compound of Chemical Formula 1 was measured with dimethyl sulfoxide (DMSO), idelalisib, TGR-1202, NU-7441, and the results are shown in FIG.

도 1에 나타낸 바와 같이, 화학식 1의 화합물이 카스파아제 3을 유효하게 억제함을 알 수 있다.As shown in Fig. 1, it can be seen that the compound of Chemical Formula 1 effectively inhibits caspase 3.

실시예Example 1-2: 세포주기 정지 확인 1-2: confirmation of cell cycle arrest

DLBCL 세포인 SU-DHL-6 세포주 및 DOHH-2 세포주에 화학식 1의 화합물을 농도별로 처리하여 세포주기 정지(cell cycle arrest)를 확인하였으며, 그 결과는 도 2 및 도 3에 나타내었다.The cells of the SU-DHL-6 and DOHH-2 cells, which are DLBCL cells, were treated with the compound of Chemical Formula 1 at various concentrations to confirm cell cycle arrest. The results are shown in FIG. 2 and FIG.

도 2 및 도 3에 나타낸 바와 같이, 화학식 1의 화합물의 농도가 증가할수록 DLBCL 세포의 세포주기가 정지되는 것을 확인할 수 있다.As shown in FIG. 2 and FIG. 3, it can be confirmed that the cell cycle of DLBCL cells is stopped as the concentration of the compound of Chemical Formula 1 is increased.

실시예Example 2. 화학식 1의 화합물의 분자  2. The molecule of the compound of formula 1 타겟target 확인 Confirm

DLBCL 세포인 SU-DHL-4 세포주, SU-DHL-6 세포주 및 DOHH-2 세포주에 화학식 1의 PI3 키나아제 억제제인 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온, 다른 PI3 키나아제 억제제인 이델랄리십, TGR-1012 및 NU-7441, 그리고 Bcl-2 억제제인 베네토클락스(Venetoclax)와 브루톤 티로신 키니아제(Bruton's Tyrosine Kinase, BTK) 억제제인 이브루티닙(Ibrutinib)를 각각 처리하여 분자 타겟을 확인하였으며, 그 결과는 도 4 내지 6에 나타내었다.4 - ((1- (4,8-dichloro-1-oxo-2-phenyl) -1H-pyrazolo [3,4-d] pyrimidin- 2,3-d] pyrimidin-5 (8H) -one, the other PI3 kinase inhibitors, Adelalysin, TGR-1012, and NU-7441, and the Bcl-2 inhibitor Venetoclax and Bruton's Tyrosine Kinase (BTK) inhibitor, Ibrutinib, respectively, to identify the molecular target, 4 to 6.

도 4 내지 6에 나타낸 바와 같이, 화학식 1의 화합물이 농도 의존적으로 c-Myc 및 Mcl-1을 억제시키는 것을 확인할 수 있으며, 반면 다른 PI3 키나아제 억제제 및 Bcl-2 억제제 각각은 c-Myc 및 Mcl-1을 충분히 억제하지 못함을 알 수 있다.As shown in FIGS. 4 to 6, it can be confirmed that the compound of Chemical Formula 1 inhibits c-Myc and Mcl-1 in a concentration-dependent manner, while other PI3 kinase inhibitors and Bcl-2 inhibitors inhibit c-Myc and Mcl- 1 can not be sufficiently suppressed.

실시예Example 3. 화학식 1의 화합물에 의한 c- 3. The method according to claim 1, wherein the c- MycMyc 단백질의 분해 확인 Confirmation of decomposition of protein

DLBCL 세포인 SU-DHL-4 세포주에 사이클로헥시미드(Cycloheximide, CHX)를 처리하고, 일부 세포에만 화학식 1의 PI3 키나아제 억제제인 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 처리하여 시간에 따른 c-Myc 및 포스포-GSK3β의 발현을 확인하였으며, 그 결과를 도 7에 나타내었다.The DLBCL cell SU-DHL-4 cell line was treated with cycloheximide (CHX), and only a few cells were treated with the PI 3 kinase inhibitor of formula 1, 4 - ((1- (4,8-dichloro- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) The expression of phospho-GSK3? Was confirmed, and the results are shown in Fig.

또한, DLBCL 세포인 DOHH-2 세포주에 화학식 1의 PI3 키나아제 억제제인 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-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온 및 사이클로헥시미드; 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온, 사이클로헥시미드 및 프로테아좀 억제제인 MG132을 각각 처리하여 c-Myc의 발현을 확인하였으며, 그 결과를 도 8에 나타내었다.In addition, to the DOHH-2 cell line that is a DLBCL cell, a PI3 kinase inhibitor 4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-l, 2-dihydroisoquinolin- Yl) ethyl) amino) pyrido [2,3-d] pyrimidin-5 (8H) -one; Ethyl) amino) pyrido [2,3-d] pyrimidine (prepared according to the procedure described for the synthesis of 4 - [(4,8-dichloro-1-oxo- -5 (8H) -one and cycloheximide; Ethyl) amino) pyrido [2,3-d] pyrimidine (prepared according to the procedure described for the synthesis of 4 - [(4,8-dichloro-1-oxo- -5 (8H) -one, cycloheximide, and MG132, a proteasome inhibitor, respectively, to confirm the expression of c-Myc. The results are shown in FIG.

도 7 및 도 8에 나타낸 바와 같이, 화학식 1의 화합물이 c-Myc의 발현을 효과적으로 억제함을 확인할 수 있다.As shown in FIG. 7 and FIG. 8, it can be confirmed that the compound of Chemical Formula 1 effectively suppresses the expression of c-Myc.

비교예Comparative Example 1.  One. BclBcl -2 억제제에 의한 -2 inhibitor MclMcl -1 유도 확인-1 induction confirmation

DLBCL 세포인 SU-DHL-4 세포주 및 DOHH-2 세포주에 Bcl-2 억제제인 베네토클락스를 18시간 동안 일시적 처리(transient treatment)하여 Mcl-1의 발현을 확인하였으며, 그 결과를 도 9에 나타내었다.The expression of Mcl-1 was confirmed by transient treatment of the DLBCL cells SU-DHL-4 cell line and DOHH-2 cell line with the Bcl-2 inhibitor Veneto Clark for 18 hours. The results are shown in FIG. 9 .

또한, DLBCL 세포인 SU-DHL-6 세포주에 베네토클락스를 1달동안 만성적 처리(chronic treatment)하여 Mcl-1의 발현을 확인하였으며, 그 결과를 도 10에 나타내었다.In addition, the expression of Mcl-1 was confirmed by chronic treatment of DLBCL cell line SU-DHL-6 with Veneto Clark for 1 month, and the results are shown in FIG.

도 9에 나타낸 바와 같이, Bcl-2 억제제를 일시적으로 처리할 경우 Mcl-1의 발현을 농도의존적으로 증가시켰으며, 도 10에 나타낸 바와 같이, Bcl-2 억제제를 만성적으로 처리할 경우에도 Mcl-1의 발현이 크게 증가함을 확인할 수 있다.As shown in Fig. 9, when the Bcl-2 inhibitor was temporarily treated, the expression of Mcl-1 was increased in a concentration-dependent manner. As shown in Fig. 10, 1 expression was significantly increased.

비교예Comparative Example 2.  2. BclBcl -2 억제제의 내성 확인-2 inhibitor

내성 또는 비내성 SU-DHL-6 세포주에 Bcl-2 억제제인 베네토클락스를 처리하여, Bcl-2 억제제의 세포의 성장 저해 활성을 확인하였으며, 그 결과를 도 11에 나타내었다.The inhibitory activity of the Bcl-2 inhibitor on the cell growth was confirmed by treating the resistant or non-resistant SU-DHL-6 cell line with the Bcl-2 inhibitor Veneto Clark, and the results are shown in FIG.

도 11에 나타낸 바와 같이, Bcl-2 억제제는 내성 SU-DHL-6 세포에는 성장 저해 효과가 크게 감소하는 것을 확인할 수 있다.As shown in Fig. 11, the growth inhibitory effect of the Bcl-2 inhibitor in the resistant SU-DHL-6 cells was significantly reduced.

실시예Example 4. 화학식 1의 화합물 및  4. Compounds of formula (I) and BclBcl -2 억제제의 시너지 효과 확인Confirmation of synergistic effect of 2 inhibitor

화학식 1의 PI3 키나아제 억제제로 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 사용하고, Bcl-2 억제제로 베네토클락스를 사용하여 화학식 1의 화합물 및 Bcl-2 억제제의 시너지 효과를 확인하였다.A PI3 kinase inhibitor of formula (1) 4 - ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydro-isoquinolin-3-yl) ethyl) amino) pyrido [2 , 3-d] pyrimidin-5 (8H) -one was used as a Bcl-2 inhibitor and the Venetia Clark was used as a Bcl-2 inhibitor.

실시예Example 4-1: CI 값 확인 4-1: Check CI value

DLBCL 세포인 SU-DHL-6 세포주, DOHH-2 세포주, U2932 세포주 및 CLI-LY3 세포주에 화학식 1의 화합물 및 Bcl-2 억제제인 베네토클락스를 처리하고, 하기 식 1에 따라 세포의 성장 저해 정도(CI)를 측정하였다.The cells were treated with the compound of formula (I) and the Bcl-2 inhibitor Venetoclase to the DLBCL cells SU-DHL-6, DOHH-2, U2932 and CLI-LY3, (CI) were measured.

[식 1][Formula 1]

Figure PCTKR2018015549-appb-img-000005
Figure PCTKR2018015549-appb-img-000005

상기 식 1은 초우-탈랄레이 식(Chou-Talalay equation)으로서, a는 화학식 1의 화합물 및 베네토클락스를 병용 투여 시 GI x 값이고, b는 화학식 1의 화합물 단독 투여 시 GI x 값이며, c는 베네토클락스 단독 투여 시 GI x 값을 나타낸다.(1) is a Chou-Talalay equation, a is the GI x value when the compound of formula (1) and Veneto clark are coadministered, b is the GI x value when administered alone, c represents the GI x value when administered with Veneto Clark alone.

상기 GI x 값은 세포성장을 x %저해하는 농도로서, 예를 들면 GI 50은 세포성장을 50% 저해시키는 농도를 의미한다.The GI x value is a concentration at which x% inhibition of cell growth, for example, GI 50 means a concentration that inhibits cell growth by 50%.

상기 초우-탈랄레이 식(Chou-Talalay equation)에 따라 CI 값이 1보다 작으면 상승적(synergism), 1이면 상가적(additive), 1보다 크면 길항적(antagonism)으로 해석하였다.According to the Chou-Talalay equation, the CI value is interpreted as synergism when 1 is less than 1, additive when 1, and antagonism when 1 is greater than 1 according to the Chou-Talalay equation.

그 결과는 아래 표 1 과 같다.The results are shown in Table 1 below.

세포주Cell line Isobologram (GI)Isobologram (GI) CICI DOHH-2DOHH-2 4040 0.610.61 5050 0.350.35 6060 0.230.23 7070 0.210.21 8080 0.430.43 SU-DHL-6SU-DHL-6 8080 0.170.17 9090 0.080.08 U2932U2932 6060 0.910.91 7070 0.440.44

상기 표에서 Isobologram은 각각의 단독 약물 처리 시 세포 성장 저해도(%) 와 병용 처리 시의 세포 성장 저해도(%)를 비교한 표로서, 예를 들면 DOHH-2 Isobologram 50인 경우 화학식 1의 화합물 처리 시의 GI 50, 베네토클락스 처리 시 GI 50 및 두 약물의 병용 처리 시의 GI 50 값을 측정하여 상기 초우-탈랄레이 식(Chou-Talalay equation)에 대입하였을 때 산출된 값이 0.35로 나타났고, 이를 통해 두 약물 (화학식 1의 화합물과 베네토클락스)의 병용 처리가 상승적임을 확인할 수 있다.In the above table, Isobologram is a table comparing cell growth inhibition (%) and cell growth inhibition (%) at the time of combination treatment for each single drug, for example, in the case of DOHH-2 Isobologram 50, the calculated value is represented as 0.35 when substituted in Talal ray equation (Chou-Talalay equation) - to measure the GI 50 value at the GI 50, Veneto Clarks processed with GI 50 and the combination treatment of both drugs at the time of processing the Chow And it is confirmed that the combination treatment of the two drugs (compound of formula (I) and Veneto Clark) is synergistic.

실시예Example 4-2: 분자적 작용기전 확인 4-2: Identification of molecular mechanism

DLBCL 세포인 SU-DHL-4 세포주 및 SU-DHL-6 세포주에 아래 표 2의 그룹의 시험물질을 처리하여 Mcl-1 및 c-Myc의 발현을 확인하였으며, 그 결과를 도 12에 나타내었다.The DLBCL cells SU-DHL-4 and SU-DHL-6 cell lines were treated with the test substances of the group shown in Table 2 below to confirm the expression of Mcl-1 and c-Myc, and the results are shown in FIG.

베네토클락스Veneto Clarks 화학식 1의 화합물The compound of formula (1) 이델랄리십Eidralis 이브루티닙Ibrutinip 베네토클락스 + 화학식 1의 화합물Veneto Clark + Compound of Chemical Formula 1 베네토클락스 + 이델랄리십Veneto Clark + 베네토클락스 + 이브루티닙Veneto Clark + Ibutorutinip

이때, 상기 표 2에 나타낸 실험 물질의 농도는 다음과 같다.At this time, the concentration of the test substance shown in Table 2 is as follows.

-화학식 1의 화합물: 0.1 μM- Compound of formula 1: 0.1 [mu] M

-이델랄리십: 0.1 μM-Edelalysin: 0.1 μM

-이브루티닙: 0.1 μM- Iburutinib: 0.1 μM

-베네토클락스: SU-DHL-4 : 0.01 μM, SU-DHL-6 : 0.02 μM- Veneto Clark: SU-DHL-4: 0.01 μM, SU-DHL-6: 0.02 μM

도 12에 나타낸 바와 같이, 화학식 1의 화합물에 의하여 Mcl-1 및 c-Myc의 발현이 크게 억제됨을 확인할 수 있으며, 화학식 1의 화합물과 Bcl-2 억제제의 조합에 의하여 Mcl-1 및 c-Myc의 발현이 더욱 효과적으로 억제됨을 확인할 수 있다. As shown in FIG. 12, the expression of Mcl-1 and c-Myc was greatly inhibited by the compound of formula (1). Mcl-1 and c-Myc Can be inhibited more effectively.

실시예Example 5. 종양 조직에서의 c- 5. C- MycMyc 감소 확인 Confirm reduction

화학식 1의 PI3 키나아제 억제제로 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온을 사용하고, Bcl-2 억제제로 베네토클락스를 사용하여 화학식 1의 화합물 및 Bcl-2 억제제의 시너지 효과를 확인하였다.(1 - (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3- yl) ethyl) amino) pyrido [ , 3-d] pyrimidin-5 (8H) -one was used as a Bcl-2 inhibitor and the Venetia Clark was used as a Bcl-2 inhibitor.

실시예Example 5-1: 화학식 1 화합물의 종양 조직에서의 c- 5-1: The expression of the < RTI ID = 0.0 > c- MycMyc 억제 활성 확인 Identify inhibitory activity

DOHH2 제노그래프트 마우스의 종양 조직에 화학식 1의 화합물을 처리한 후 c-Myc의 발현을 확인하였으며, 그 결과를 도 13에 나타내었다.The expression of c-Myc was confirmed after treating the compound of Chemical Formula 1 with tumor tissue of DOHH2 genograft mouse, and the results are shown in FIG.

도 13에 나타낸 바와 같이, 화학식 1의 화합물을 투여할 경우 시간에 따라 c-Myc의 발현이 크게 감소함을 알 수 있다.As shown in FIG. 13, when the compound of Chemical Formula 1 is administered, the expression of c-Myc is greatly decreased with time.

실시예Example 5-2:  5-2: 제노그래프트Genograft 마우스에서의 종양 성장 억제 활성 확인 Identification of tumor growth inhibitory activity in mice

DOHH2 제노그래프트 마우스에 화학식 1의 화합물, Bcl-2 억제제인 베네토클락스 및 화학식 1의 화합물과 베네토클락스의 조합을 투여하고, 종양의 크기 변화를 관찰하였으며, 그 결과를 도 14에 나타내었다.In the DOHH2 genograft mouse, the combination of the compound of Formula 1, the Bcl-2 inhibitor Veneto Clark, and the compound of Formula 1 and Veneto Clark was administered to observe the change in tumor size. The results are shown in FIG.

도 14에서 확인할 수 있는 바와 같이, 화학식 1의 화합물과 Bcl-2 억제제의 조합에 의하여 종양의 성장 억제에 시너지 효과가 발생함을 알 수 있다.As can be seen from FIG. 14, the combination of the compound of formula (I) and the Bcl-2 inhibitor shows synergistic effects on tumor growth inhibition.

상기 실험 결과를 통하여, 화학식 1로 표시되는 화합물인 4-((1-(4,8-다이클로로-1-옥소-2-페닐-1,2-다이하이드로아이소퀴놀린-3-일)에틸)아미노)피리도[2,3-d]피리미딘-5(8H)-온과 Bcl-2 억제제의 병용 투여가 림프계 종양 치료에 시너지 효과를 가지는 것을 확인할 수 있었다. 따라서, 본 발명에 따른 약학적 조성물은 림프계 종양의 예방, 치료 또는 개선에 유용하게 적용될 수 있으며, 본 발명에 따른 치료방법 또한 림프계 종양의 예방 또는 치료에 효과적으로 적용될 수 있다.According to the results of the above experiment, the compound represented by the formula (1), 4 - ((1- (4,8-dichloro- Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one in combination with Bcl-2 inhibitor has synergistic effects in the treatment of lymphoma tumors. Accordingly, the pharmaceutical composition according to the present invention can be usefully applied to prevent, treat or ameliorate lymphoma tumors, and the therapeutic method according to the present invention can also be effectively applied to the prevention or treatment of lymphoma tumors.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

본 발명은 PI3 키나아제 억제제 및 Bcl-2 억제제를 포함하는 림프종의 예방 또는 치료용 약학적 조성물에 관한 것으로서, 본 발명에 따른 조성물은 화학식 1의 화합물을 단독으로 투여한 경우와 비교하여, 림프계 종양의 예방 또는 치료 활성이 우수하다. 따라서, 본 발명의 조성물은 림프계 종양의 예방, 치료 또는 개선에 유용하게 적용될 수 있다.The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of lymphoma comprising a PI3 kinase inhibitor and a Bcl-2 inhibitor, wherein the composition according to the present invention is useful for the prophylaxis or treatment of lymphoma The prophylactic or therapeutic activity is excellent. Therefore, the composition of the present invention can be usefully applied for the prevention, treatment or improvement of lymphoid tumor.

Claims (18)

PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 림프종의 예방 또는 치료용 약학적 조성물.A PI3 kinase inhibitor, and a B-cell lymphoma 2 (Bcl-2) inhibitor. 제1항에 있어서, The method according to claim 1, 상기 PI3 키나아제 억제제는 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종의 예방 또는 치료용 약학적 조성물:Wherein the PI3 kinase inhibitor is a compound represented by the following formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof: [화학식 1][Chemical Formula 1]
Figure PCTKR2018015549-appb-img-000006
Figure PCTKR2018015549-appb-img-000006
 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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group. 제2항에 있어서, 3. The method of claim 2, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종의 예방 또는 치료용 약학적 조성물:The compound represented by Formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be prepared by reacting a compound represented by Formula 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, ≪ / RTI > or a solvate thereof. [화학식 2](2)
Figure PCTKR2018015549-appb-img-000007
Figure PCTKR2018015549-appb-img-000007
 화학식 2에 있어서, In formula (2) 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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group. 제2항에 있어서, 3. The method of claim 2, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물은 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, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종의 예방 또는 치료용 약학적 조성물.The compound represented by the general formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be 4 - ((1- (4,8-dichloro- 2,3-d] pyrimidin-5 (8H) -one (4 - ((1- (4,8-dichloro- 1- 2,3-d] pyrimidin-5 (8H) -one), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, Or a hydrate thereof or a solvate thereof. 제1항에 있어서, The method according to claim 1, 상기 PI3 키나아제는 PI3Kα, PI3Kβ, PI3Kδ 및 PI3Kγ로 이루어지는 군으로부터 선택되는 하나 이상인 림프종의 예방 또는 치료용 약학적 조성물.Wherein the PI3 kinase is at least one selected from the group consisting of PI3K [alpha], PI3K [beta], PI3K [delta] and PI3K [gamma]. 제1항에 있어서, The method according to claim 1, 상기 림프종은 비호지킨림프종(non-Hodgkin's lymphoma), 엡스타인바 관련 림프종(Epstein-Barr related lymphoma), 호지킨림프종, 림프구성 백혈병(lymphoblastic leukemia), 다발성 골수종(multiple myeloma), 및 미만성 거대 B 세포 림프종(diffuse large B-cell lymphoma)으로 이루어진 군으로부터 선택되는 하나 이상인 림프종의 예방 또는 치료용 약학적 조성물.The lymphoma may be a non-Hodgkin's lymphoma, an Epstein-Barr related lymphoma, a Hodgkin's lymphoma, a lymphoblastic leukemia, multiple myeloma, and diffuse large B cell lymphoma (diffuse large B-cell lymphoma). < Desc / Clms Page number 19 > 제1항에 있어서, The method according to claim 1, 상기 Bcl-2 억제제는 베네토클락스(Venetoclax)인 것인 림프종의 예방 또는 치료용 약학적 조성물.Wherein said Bcl-2 inhibitor is Venetoclax. ≪ RTI ID = 0.0 > 11. < / RTI > 제1항에 있어서, The method according to claim 1, 상기 조성물은 경구 투여용인 것인 림프종의 예방 또는 치료용 약학적 조성물.Wherein said composition is for oral administration. PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 조성물을 치료학적으로 유효한 양으로 인간을 포함한 포유류에 투여하는 단계를 포함하는 림프종을 예방 또는 치료하는 방법.PI3 kinase inhibitor, and Bcl-2 (B-cell lymphoma 2) inhibitor to a mammal, including a human, in a therapeutically effective amount. PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 조성물의 림프종 예방 또는 치료를 위한 용도.PI3 kinase inhibitor, and Bcl-2 (B-cell lymphoma 2) inhibitor for the prevention or treatment of lymphoma. PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 포함하는 조성물의 림프종 예방 또는 치료용 약제의 제조를 위한 용도.PI3 kinase inhibitor, and Bcl-2 (B-cell lymphoma 2) inhibitor for the manufacture of a medicament for the prevention or treatment of lymphoma. Bcl-2(B-cell lymphoma 2) 억제제의 유효량과 함께 투여되는 것인, PI3 키나아제 억제제를 포함하는 림프종 예방 또는 치료용 조성물.Wherein the composition is administered in combination with an effective amount of Bcl-2 (B-cell lymphoma 2) inhibitor. 제12항에 있어서,13. The method of claim 12, Bcl-2 억제제는 PI3 키나아제 억제제와 동시에 투여되거나, 개별적으로 각각 투여되는 것인 림프종 예방 또는 치료용 조성물.Wherein the Bcl-2 inhibitor is administered simultaneously with the PI3 kinase inhibitor, or is administered separately, respectively. 제12항에 있어서,13. The method of claim 12, 상기 PI3 키나아제 억제제는 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종 예방 또는 치료용 조성물:Wherein the PI3 kinase inhibitor is a compound represented by the following formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof: [화학식 1][Chemical Formula 1]
Figure PCTKR2018015549-appb-img-000008
Figure PCTKR2018015549-appb-img-000008
 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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group. 제12항에 있어서,13. The method of claim 12, 상기 Bcl-2 억제제는 베네토클락스(Venetoclax)인 것인 림프종 예방 또는 치료용 조성물.Wherein the Bcl-2 inhibitor is Venetoclax. PI3 키나아제 억제제, 및 Bcl-2(B-cell lymphoma 2) 억제제를 유효성분으로 포함하는 림프종의 예방 또는 치료를 위한 병용 투여용 조성물.PI3 kinase inhibitor, and Bcl-2 (B-cell lymphoma 2) inhibitor as an active ingredient for the prevention or treatment of lymphoma. 제16항에 있어서, 17. The method of claim 16, 상기 PI3 키나아제 억제제는 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물인 것인 림프종의 예방 또는 치료를 위한 병용 투여용 조성물:Wherein the PI3 kinase inhibitor is a compound represented by the following formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof: [화학식 1][Chemical Formula 1]
Figure PCTKR2018015549-appb-img-000009
Figure PCTKR2018015549-appb-img-000009
 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; 할로겐기; 또는 피리디닐기이다.R 3 and R 4 are each independently hydrogen; A halogen group; Or a pyridinyl group. 제16항에 있어서,17. The method of claim 16, 상기 Bcl-2 억제제는 베네토클락스(Venetoclax)인 것인 림프종 예방 또는 치료용 조성물.Wherein the Bcl-2 inhibitor is Venetoclax.
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