WO2021182903A1 - Composition comprenant un inhibiteur de kinase pi3 et un inhibiteur de btk - Google Patents

Composition comprenant un inhibiteur de kinase pi3 et un inhibiteur de btk Download PDF

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WO2021182903A1
WO2021182903A1 PCT/KR2021/003058 KR2021003058W WO2021182903A1 WO 2021182903 A1 WO2021182903 A1 WO 2021182903A1 KR 2021003058 W KR2021003058 W KR 2021003058W WO 2021182903 A1 WO2021182903 A1 WO 2021182903A1
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group
inhibitor
formula
pharmaceutical composition
phenyl
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PCT/KR2021/003058
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Korean (ko)
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이주한
왕승호
양은희
박민
전병욱
이보람
손미권
김수정
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보령제약 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a composition for preventing or treating cancer comprising a PI3 kinase inhibitor and a BTK inhibitor.
  • Cancers including hematologic malignancies such as lymphoma and leukemia, may have a variety of causative factors that may act individually or collectively related to initiation and/or promotion of onset, and cancer may pose a global health threat. Therefore, it is important to develop more effective approaches, especially combination approaches, for improving the prevention and treatment of cancer.
  • lymphomas such as diffuse large B-cell lymphoma (DLBCL)
  • LLBCL diffuse large B-cell lymphoma
  • R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone
  • the present invention provides a pharmaceutical composition for preventing or treating hematologic cancer comprising a PI3 kinase inhibitor and a BTK (Bruton's tyrosine kinase) inhibitor.
  • a PI3 kinase inhibitor and a BTK (Bruton's tyrosine kinase) inhibitor.
  • BTK Brunauer's tyrosine kinase
  • the present invention provides a pharmaceutical composition for preventing or treating hematologic cancer comprising a PI3 kinase (PI3K) inhibitor, which is administered together with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor.
  • PI3K PI3 kinase
  • BTK Bruton's tyrosine kinase
  • the present invention provides a pharmaceutical composition for co-administration for the prevention or treatment of hematologic cancer comprising a PI3 kinase inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor.
  • a pharmaceutical composition for co-administration for the prevention or treatment of hematologic cancer comprising a PI3 kinase inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor.
  • the present invention provides a method for preventing or treating hematologic cancer, comprising administering to an individual in need of a PI3 kinase inhibitor and a BTK inhibitor.
  • the present invention provides the use of a pharmaceutical composition comprising a PI3 kinase inhibitor and a BTK inhibitor for preventing or treating hematologic cancer.
  • the present invention provides the use of a pharmaceutical composition comprising a PI3 kinase inhibitor and a BTK inhibitor for the preparation of a medicament for the prevention or treatment of hematologic cancer.
  • a pharmaceutical composition for preventing or treating hematologic cancer comprising a PI3 kinase inhibitor and a BTK inhibitor has been developed. It was confirmed that the preventive and therapeutic activity of blood cancer became remarkable due to the synergistic effect.
  • the present invention relates to a composition for preventing or treating hematologic cancer comprising a PI3 kinase inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor.
  • a composition for preventing or treating hematologic cancer comprising a PI3 kinase inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor.
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a composition for preventing or treating hematologic cancer comprising a PI3 kinase inhibitor used in combination with a BTK inhibitor.
  • the present invention relates to a PI3 kinase (PI3K) inhibitor, which is a compound represented by Formula 1 below, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
  • BTK Brunton's tyrosine kinase
  • R1 is hydrogen; Or a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
  • R2 is a phenyl group; or a pyridinyl group, and the phenyl group or pyridinyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group and a linear or branched alkyl group having 1 to 5 carbon atoms,
  • R3 and R4 are each independently hydrogen; halogen group; or a pyridinyl group.
  • x represents the number of carbons
  • the number of carbons x to y means a functional group having x or more and y or less of carbon.
  • alkyl group refers to a linear saturated hydrocarbon group or a branched saturated hydrocarbon group, wherein the alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl , propyl, isobutyl or pentyl and the like.
  • substituent means that a hydrogen atom is replaced by a substituent that is a non-hydrogen atom. In this case, the valence requirement must be satisfied and a chemically stable compound must result from the substitution. Also, unless explicitly stated as “unsubstituted”, all functional groups should be construed as being capable of being substituted or unsubstituted.
  • halogen refers to a halogen element, and includes, for example, F, Cl, Br, or I.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below.
  • R1 to R4 are the same as defined in Formula 1 above.
  • R1 is a linear or branched alkyl group having 1 to 5 carbon atoms.
  • R1 is a methyl group.
  • R2 is a phenyl group; or a pyridinyl group, and the phenyl group or pyridinyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group and a linear or branched alkyl group having 1 to 5 carbon atoms.
  • R2 is a phenyl group.
  • R 3 is hydrogen; halogen group; or a pyridinyl group.
  • R3 is a halogen group.
  • R3 is chlorine
  • R4 is hydrogen; or a halogen group.
  • R4 is a halogen group.
  • R4 is chlorine
  • the BTK inhibitor may be ibrutinib, zanubrutinib, or acalabrutinib, but is not limited thereto.
  • the pharmaceutical composition is a compound represented by Formula 1, a compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-) 1,2-Dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8) -dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, their PI3 kinase (PI3K) inhibitors, which are optical isomers, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and ibrutinib, zanubrutinib, and acalabrutinib ) may include at least one BTK inhibitor selected from among.
  • PI3K PI
  • the pharmaceutical composition is 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl) Amino) pyrido [2,3-d] pyrimidin-5 (8H) -one (4- ((1- (4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin -3- yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one), its optical isomer, its pharmaceutically acceptable salt, its hydrate or its solvate, which is a PI3 kinase (PI3K) inhibitor; and a BTK inhibitor that is ibrutinib.
  • PI3K PI3 kinase
  • the pharmaceutical composition is (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3- yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one ((S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl) -1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one) and ibrutinib.
  • the compound represented by Formula 1 according to the present invention the compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline) -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8-dichloro-1-oxo-) 2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, their optical isomers, and their pharmaceutically
  • a pharmaceutical composition comprising an acceptable salt, a hydrate or solvate thereof, a PI3 kinase (PI3K) inhibitor, and at least one BTK inhibitor selected from ibrutinib, janubrutinib, and acalabrutinib is a hematologic
  • the pharmaceutical composition according to the present invention may exhibit a significant synergistic effect by using the two components in combination than when each component is treated alone, in terms of the therapeutic effect on cancer including blood cancer, as a result, patients with cancer including hematologic cancer It can prolong the survival rate and duration of the drug and significantly reduce side effects.
  • the pharmaceutical composition of the present invention can exhibit a significantly superior effect in the prevention or treatment of cancer, such as blood cancer, compared to a PI3K inhibitor having a different structure or a combination composition of a DNA-PK inhibitor and ibrutinib, and without side effects. It is possible to more effectively inhibit, delay or stop the growth of tumors.
  • the duration of the drug effect is extended, the administration interval of the drug is extended, or the total dose or number of administrations of the drug compared to the case where the two components are used respectively.
  • the pharmaceutical composition of the present invention has a synergistic effect by using the two components in combination, and has significantly better synergy with fewer side effects than when other PI3K inhibitors or other DNA-PK inhibitors and BTK inhibitors such as ibrutinib are used in combination. effect can be shown.
  • the compound represented by Formula 1 may be prepared by, for example, the method disclosed in International Patent Publication No. WO 2016/204429, but is not limited thereto.
  • the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium or magnesium, hydrochloric acid, nitric acid, phosphoric acid, and hydrobromic acid.
  • inorganic acid salts prepared with iodic acid, perchloric acid or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, organic acid salts prepared from aspartic acid, ascorbic acid, carbonic acid, or vanillic acid; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid; amino acid salts prepared from glycine, arginine, lysine and the like; or amine salts prepared from trimethylamine, triethylamine, ammonia
  • the term "hydrate” refers to a compound represented by Formula 1 and water combined by a non-covalent intermolecular force, and includes a stoichiometric or non-stoichiometric amount of water.
  • the hydrate may contain water in a ratio of about 0.25 mole to about 10 moles based on 1 mole of the active ingredient, and more specifically, about 0.5 mole, about 1 mole, about 1.5 mole, about 2 mole, about 3 moles, about 5 moles, and the like.
  • the term "solvate” refers to a compound represented by Formula 1 and a solvent combined by a non-covalent intermolecular force, and includes a stoichiometric or non-stoichiometric amount of the solvent.
  • Preferred solvents are volatile, non-toxic, and can be administered in trace amounts to humans.
  • the solvate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 moles, about 5 moles, and the like.
  • a compound represented by Formula 1 according to the present invention a compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3) -yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8-dichloro-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, their optical isomers, and their pharmaceutically acceptable
  • the salts, hydrates thereof or solvates thereof can selectively inhibit one or more PI3 kinases selected from the group consisting of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ , and can simultaneously function as a DNA-PK inhibitor.
  • BTK is an enzyme involved in the survival of cancer cells, and is an enzyme that is activated in the process of B cells becoming cancer cells, and is often observed in B cells converted into cancer cells.
  • the BTK inhibitor refers to a substance that kills cancer cells by inhibiting the expression of the BTK activity.
  • BTK inhibitor is 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1 H-pyrazolo [3,4-d] pyrimidine - 1-yl]piperidin-1-yl]prop-2-en-1-one (1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3] ,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), which may be ibrutinib, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be usefully used for the prevention or treatment of hematologic cancer.
  • the hematologic cancer may be lymphoma or leukemia.
  • the hematological cancer is, for example, non-Hodgkin's lymphoma, Epstein Barr virus associated lymphoma, Hodgkin lymphoma (HL), lymphoblastic leukemia, multiple Multiple myeloma, diffuse large B-cell lymphoma, Burkitt's lymphoma (BL), Follicular lymphoma (FL), Mantle cell lymphoma (MCL), Peripheral T-cell lymphoma (PTCL), Acute Lymphoblastic Leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia At least one selected from (T-cell acute lymphoblastic leukemia, T-ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML
  • the pharmaceutical composition is a compound represented by Formula 1, a compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-) 1,2-Dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8) -dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, their
  • An optical isomer, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, which is a PI3K inhibitor, and at least one selected from the BTK inhibitors ibrutinib, janubrutinib and acalabrutinib are administered respectively may be a combination of
  • the pharmaceutical composition is represented by Formula 1, which is used in combination with a BTK inhibitor (eg, at least one BTK inhibitor selected from ibrutinib, janubrutinib, and acalabrutinib)
  • BTK inhibitor eg, at least one BTK inhibitor selected from ibrutinib, janubrutinib, and acalabrutinib
  • a compound represented by Formula 2 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyri Do[2,3-d]pyrimidin-5(8H)-one, (S)-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
  • the PI3K inhibitor and the BTK inhibitor may be a pharmaceutical composition administered simultaneously or sequentially.
  • the combination is 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2, 3-d]pyrimidin-5(8H)-one, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, a PI3 K inhibitor, and a combination comprising ibrutinib;
  • the two components may be separately administered simultaneously or sequentially to prevent or treat the hematologic cancer.
  • the combination is (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino )
  • the two components may be administered separately simultaneously or sequentially to prevent or treat the hematologic cancer.
  • the pharmaceutical composition may be for oral administration.
  • the present invention is to be administered together with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, a compound represented by the following formula (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, PI3 kinase (PI3K) ) relates to a pharmaceutical composition for the prevention or treatment of blood cancer comprising an inhibitor.
  • BTK Bruton's tyrosine kinase
  • PI3K PI3 kinase
  • R1 is hydrogen; Or a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
  • R2 is a phenyl group; or a pyridinyl group, and the phenyl group or pyridinyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group and a linear or branched alkyl group having 1 to 5 carbon atoms,
  • R3 and R4 are each independently hydrogen; halogen group; or a pyridinyl group.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below.
  • R1 to R4 are the same as defined in Formula 1 above.
  • the PI3 kinase inhibitor may be administered simultaneously or sequentially with the BTK inhibitor.
  • the BTK inhibitor may be at least one selected from ibrutinib, janubrutinib, and acalabrutinib.
  • the pharmaceutical composition is a compound represented by Formula 1, which is administered together with an effective amount of at least one BTK inhibitor selected from ibrutinib, janubrutinib and acalabrutinib , a compound represented by formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[ 2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline) -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, their optical isomers, their pharmaceutically acceptable salts, their hydrates or their solvates It may be a pharmaceutical composition for preventing or treating hematologic cancer
  • the pharmaceutical composition is administered together with an effective amount of the BTK inhibitor ibrutinib, 4-((1-(4,8-dichloro-1-oxo- 2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, its optical isomer, its pharmaceutically acceptable
  • the BTK inhibitor ibrutinib 4-((1-(4,8-dichloro-1-oxo- 2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, its optical isomer, its pharmaceutically acceptable
  • It may be a pharmaceutical composition for preventing or treating hematologic cancer, including a salt, a hydrate thereof, or a solvate thereof.
  • the pharmaceutical composition is administered together with an effective amount of the BTK inhibitor ibrutinib, (S)-4-((1-(4,8-dichloro- Prevention of hematologic cancer including 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one Or it provides a pharmaceutical composition for treatment.
  • the BTK inhibitor ibrutinib (S)-4-((1-(4,8-dichloro- Prevention of hematologic cancer including 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered together with an effective amount of the BTK inhibitor, ibrutinib, the therapeutic effect on cancer including hematologic cancer is significantly synergistic compared to when the compound of Formula 1 is administered alone. , and as a result, the survival rate and survival period of patients for cancer including blood cancer can be extended, and side effects can be significantly reduced.
  • the pharmaceutical composition of the present invention when the pharmaceutical composition of the present invention is administered together with an effective amount of ibrutinib, it has a significantly superior effect in the prevention or treatment of cancers such as hematologic cancer compared to PIK 3 inhibitors or DNA-PK inhibitors having other structures. , and it can inhibit the growth of tumors more effectively, and side effects such as weight loss can be significantly reduced.
  • the hematologic cancer is as described above.
  • the present invention relates to a PI3 kinase (PI3K) inhibitor, which is a compound represented by Formula 1 below, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof;
  • PI3K PI3 kinase
  • BTK Brunton's tyrosine kinase
  • R1 is hydrogen; Or a straight-chain or branched alkyl group having 1 to 5 carbon atoms,
  • R2 is a phenyl group; or a pyridinyl group, and the phenyl group or pyridinyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen group and a linear or branched alkyl group having 1 to 5 carbon atoms,
  • R3 and R4 are each independently hydrogen; halogen group; or a pyridinyl group.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below.
  • R1 to R4 are the same as defined in Formula 1 above.
  • the BTK inhibitor may be ibrutinib, zanubrutinib, or acalabrutinib, but is not limited thereto.
  • the PI3 kinase inhibitor and the BTK inhibitor may be administered simultaneously or sequentially.
  • the pharmaceutical composition for combined administration is a compound represented by Formula 1, a compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2) -Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-( 4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one , their optical isomers, their pharmaceutically acceptable salts, hydrates or solvates thereof, PI3 kinase (PI3K) inhibitors, and at least one selected from ibrunitib, janubrutinib and acalabrutinib BTK inhibitors may be included.
  • the pharmaceutical composition for combined administration is 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl) )ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one (4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin) -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one), an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, a PI3K inhibitor, and; It may include the BTK inhibitor ibrutinib.
  • the pharmaceutical composition for combined administration is (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinoline) -3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one and the BTK inhibitor ibrutinib.
  • the composition for combined administration can exhibit a significant synergistic effect by using the two components in combination than when each component is treated alone, as a result of which the patient's survival rate for cancer including hematologic cancer and It can prolong survival and significantly reduce side effects.
  • the pharmaceutical composition of the present invention has a significantly superior effect in the prevention or treatment of cancers, including hematologic cancers such as lymphoma and leukemia, compared to a combination composition of a PI3K inhibitor or a DNA-PK inhibitor and ibrutinib having a different structure. and can more effectively inhibit the growth of tumors.
  • the hematologic cancer is as described above.
  • the pharmaceutical composition of the present invention may be prepared in unit dosage form or multiple doses by formulating using a pharmaceutically acceptable carrier according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. It can be prepared by introducing into a container.
  • the pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • the content of the additive included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range used for conventional formulation.
  • the pharmaceutical composition of the present invention may be formulated as an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
  • the pharmaceutical composition of the present invention may be for oral administration, and non-limiting examples of the preparation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like.
  • composition of the present invention may be for parenteral administration, and non-limiting examples of parenteral preparations include injections, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, etc. can be heard
  • Preferred dosage of the pharmaceutical composition of the present invention is the patient's condition and weight, age, sex, health status, dietary constitution specificity, properties of the preparation, degree of disease, administration time of the composition, administration method, administration period or interval, excretion
  • the range may vary depending on the rate and drug form, and may be appropriately selected by those skilled in the art.
  • the PI3K inhibitor may be administered at about 1-400 mg/kg per day, and the BTK inhibitor may be administered at about 1-300 mg/kg per day.
  • the number of times of administration of the pharmaceutical composition is the patient's condition and weight, age, sex, health status, dietary constitution specificity, properties of the preparation, the degree of disease, administration time of the composition, administration method, administration period or interval, excretion rate, and It may be appropriately adjusted depending on the drug form, and may be administered 1 to 3 times a day.
  • the pharmaceutical composition may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or locally applied) according to a desired method, and specifically may be administered orally. have.
  • the composition of the present invention may include two separate agents, or may consist of one agent.
  • the pharmaceutical composition of the present invention may include a compound represented by Formula 1, a compound represented by Formula 2, 4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2) -dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4,8-dichloro) -1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, optical isomers thereof; It may be a kit including a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof and a BTK inhibitor such as ibrutinib separately.
  • the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof may be administered parenterally or orally, specifically, orally.
  • the BTK inhibitor such as ibrutinib, janubrutinib, or acalabrutinib may be administered parenterally or orally, specifically, it may be administered orally.
  • the present invention provides a compound represented by Formula 1, a compound represented by Formula 2, and 4-((1-(4,8-dichloro-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S)-4-((1-(4) ,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, Administering at least one of an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, and a BTK inhibitor, for example, ibrutinib, janubrutinib and acalabrutinib It provides a cancer treatment method, including hematologic cancers such as lympho
  • the present invention relates to a compound represented by Formula 1, a compound represented by Formula 2, 4-((1-(4,8-) Dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one, (S) -4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyri
  • a pharmaceutical composition comprising midin-5(8H)-one, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, and a BTK inhibitor.
  • composition of the present invention for the preparation of the drug may be mixed with a pharmaceutically acceptable carrier and the like, and may further include other agents.
  • the pharmaceutical composition according to the present invention has significantly superior prophylactic or therapeutic activity for hematologic cancers such as lymphoid tumors and leukemia, as well as significantly reduced side effects. Therefore, the composition of the present invention can be usefully applied to the prevention, treatment or improvement of lymphoid tumors.
  • FIG. 1 is a diagram showing the activity of the compound of Formula 1 on molecules related to apoptosis in a SU-DHL-6 cell line.
  • FIG. 2 is a diagram showing the cell cycle distribution according to the treatment concentration of the compound of Formula 1 in the DOHH-2 cell line.
  • FIG. 3 is a diagram showing c-Myc expression inhibitory activity when the compound of Formula 1, ibrutinib, and the compound of Formula 1 and ibrutinib are treated in combination in the RL cell line.
  • FIG. 4 is a diagram showing tumor growth inhibitory activity and changes in mouse body weight when a combination of the compound of Formula 1 and ibrutinib is administered to DOHH2 xenograft mice.
  • Example 1-1 Confirmation of apoptosis activity
  • the SU-DHL-6 cell line a diffuse large B-cell lymphoma (DLBCL) cell line
  • DLBCL diffuse large B-cell lymphoma
  • ATCC American Type Culture Collection
  • RPMI-1640 Roswell Park Memorial Institute medium-1640, Life technologies
  • FBS heat-inactivated fetal bovine serum, Life technologies
  • the DOHH-2 cell line which is a DLBCL-FL cell, was purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen) and placed in RPMI-1640 (Roswell Park Memorial Institute medium-1640, Life technologies) medium with 10% FBS (heat-inactivated fetal bovine). serum, Life technologies) and subcultured. 1 X 10 6 cells/ml was added to 1 ml in a 12 well plate, and the cells were added so that the total number of cells was 1 X 10 6 cells/well.
  • BR101801 is diluted in DMSO to 10mM, and then diluted with RPMI-1640 (10% FBS) medium so that it becomes 0.002, 0.01, 0.02, 0.1, 0.2, 0.4, 1, 2, 10 ⁇ M, which is twice the final concentration, 1 ml was put in the cell medium to make the final concentrations 0.001, 0.005, 0.01, 0.05, 0.1 0.2 0.5, 1, 5 ⁇ M, respectively. After culturing for 24 hours, the cells were harvested, centrifuged, the supernatant was discarded, and 70% ethanol (sigma) was added thereto and fixed.
  • PI Propidium iodide
  • Example 2-1 Check the GI50 (Half maximal growth inhibition concentration) value of the compound of Formula 1
  • the GI50 values of the PI3 kinase inhibitor of Formula 1, the compound of Preparation Example 1, and ibrutinib were measured.
  • a stock containing the compound at 10 uM was prepared by diluting the compounds in a medium at 10 mM. Using a pre-prepared 0.1% DMSO medium, the stock was diluted 10 0.5 times at 10 uM to prepare a 2X working solution. In a 96-well plate, 5X10 3 cells/well were placed in 50 uL medium. 50 uL of diluted 2X working solution was added to the cell cultured wells. After 72 hours of incubation, 10 uL of WST-8 was added to each well, and incubation was continued at 37° C. in an incubator for 4 hours. Then, the absorbance was analyzed with the Flex equipment for the culture medium. Using the obtained absorbance value, a GI50 value, which is a concentration that inhibits cell growth by 50%, was obtained using the prism program, and the results are shown in Table 1 below.
  • Example 2-2 CI value check
  • the PI3 kinase inhibitor of Formula 1, the compound of Preparation Example 1 (BR101801) and the BTK inhibitor, ibrutinib, were added to the SU-DHL-6 cell line and U2932 cell line, which are DLBCL cells, and the JVM-3 cell line and MEC-1 cell line, which are CLL cells. The combined treatment was performed, and the degree of inhibition of cell growth was measured.
  • CI combinational index
  • the Chou-Talalay equation is as follows.
  • a is the GIx value when the compound of Preparation Example 1 and ibrutinib are administered in combination
  • b is the GIx value when the compound of Preparation Example 1 is administered alone
  • c is the GIx value when ibrutinib is administered alone.
  • the GIx value is a concentration that inhibits cell growth by x%, for example, GI50 means a concentration that inhibits cell growth by 50%.
  • PF potentialiation factor
  • GI50 value of ibrutinib alone treatment is a value calculated by dividing the GI50 value of ibrutinib alone treatment by the GI50 value of ibrutinib when ibrutinib and the compound of Preparation Example 1 at a specific concentration are used in combination. It is a value that compares how high the magnification effect is.
  • the combination mechanism was confirmed by using the BTK inhibitor ibrutinib in combination with the compound of Preparation Example 1 (BR101801), which is a PI3 kinase inhibitor of Formula 1 having a mechanism of action of a PI3K inhibitor in the RL cell line, which is a DLBCL cell, and the results are shown in FIG. .
  • DOHH2 xenograft mice were administered with a combination of the compound of Preparation Example 1 and ibrutinib, which is the compound of Formula 1, and the tumor size change was observed, and the results are shown in FIG. 4 .
  • DOHH-2 a human follicular lymphoma cell line
  • DSMZ Germany
  • RPMI1640 Gibco, USA
  • penicillin/streptomycin Gibco, USA
  • DOHH-2 cells were counted at 5x10 6 cells/head, suspended in PBS, diluted 1:1 with Matrigel (50% Matrigel), and subcutaneously implanted in the abdomen of the mouse. After 2 weeks, when the tumor size reached 145-150 mm 3 , the mice were grouped.
  • the compound of Preparation Example 1 was orally administered at a dose of 50 mg/kg and ibrutinib at a dose of 30 mg/kg at the time of day 32 from the start date of the experiment, and the results were It is shown in Figure 4b.
  • the pharmaceutical composition according to the present invention can be usefully applied to the prevention, treatment or improvement of lymphoid tumors, and the treatment method according to the present invention can also be effectively applied to the prevention or treatment of lymphatic tumors.

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Abstract

La présente invention concerne une composition comprenant : un composé représenté par la formule chimique 1, un isomère optique de celui-ci ou un sel de qualité pharmaceutique de celui-ci. La composition de la présente invention présente un excellent effet de traitement de tumeurs lymphatiques.
PCT/KR2021/003058 2020-03-12 2021-03-11 Composition comprenant un inhibiteur de kinase pi3 et un inhibiteur de btk WO2021182903A1 (fr)

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CN118201617A (zh) * 2021-11-03 2024-06-14 株式会社保宁 包含pi3k及dna-pk双重抑制剂的外周t细胞淋巴瘤的预防或治疗用组合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160093062A (ko) * 2013-12-05 2016-08-05 아세르타 파마. 비.브이. Pi3k 억제제 및 btk 억제제의 치료적 조합
KR20160150006A (ko) * 2015-06-18 2016-12-28 한국화학연구원 헤테로아릴 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
WO2016209961A1 (fr) * 2015-06-23 2016-12-29 Gilead Sciences, Inc. Polythérapie pour traiter des tumeurs à cellules b
KR20170074381A (ko) * 2015-12-22 2017-06-30 한국화학연구원 피리미도 옥사진 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
WO2019183226A1 (fr) * 2018-03-21 2019-09-26 Mei Pharma, Inc. Polythérapie

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204429A1 (fr) 2015-06-18 2016-12-22 한국화학연구원 Dérivé hétéroaryle ou sel pharmaceutiquement acceptable de ce dernier, son procédé de préparation et composition pharmaceutique destinée à prévenir ou à traiter des maladies associées à des pi3 kinases, le contenant en tant que principe actif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160093062A (ko) * 2013-12-05 2016-08-05 아세르타 파마. 비.브이. Pi3k 억제제 및 btk 억제제의 치료적 조합
KR20160150006A (ko) * 2015-06-18 2016-12-28 한국화학연구원 헤테로아릴 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
WO2016209961A1 (fr) * 2015-06-23 2016-12-29 Gilead Sciences, Inc. Polythérapie pour traiter des tumeurs à cellules b
KR20170074381A (ko) * 2015-12-22 2017-06-30 한국화학연구원 피리미도 옥사진 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
WO2019183226A1 (fr) * 2018-03-21 2019-09-26 Mei Pharma, Inc. Polythérapie

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