WO2020262974A1 - Flt3 저해제 및 화학치료제를 포함하는 급성 골수성 백혈병 치료용 약학적 조성물 - Google Patents

Flt3 저해제 및 화학치료제를 포함하는 급성 골수성 백혈병 치료용 약학적 조성물 Download PDF

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WO2020262974A1
WO2020262974A1 PCT/KR2020/008258 KR2020008258W WO2020262974A1 WO 2020262974 A1 WO2020262974 A1 WO 2020262974A1 KR 2020008258 W KR2020008258 W KR 2020008258W WO 2020262974 A1 WO2020262974 A1 WO 2020262974A1
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flt3
pharmaceutical composition
amino
pharmaceutically acceptable
methyl
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English (en)
French (fr)
Korean (ko)
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배인환
송지영
최재율
안영길
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Priority to US17/622,389 priority Critical patent/US12350265B2/en
Priority to EP20833623.0A priority patent/EP3991733A4/en
Priority to MX2021015724A priority patent/MX2021015724A/es
Priority to AU2020308814A priority patent/AU2020308814A1/en
Priority to EA202290154A priority patent/EA202290154A1/ru
Priority to JP2021576034A priority patent/JP2022538817A/ja
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Priority to CA3145391A priority patent/CA3145391A1/en
Priority to CN202080058522.0A priority patent/CN114650823A/zh
Publication of WO2020262974A1 publication Critical patent/WO2020262974A1/ko
Priority to IL289366A priority patent/IL289366A/en
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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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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

  • a pharmaceutical composition for the treatment of acute myeloid leukemia comprising a therapeutically effective combination of an Fms-Like Tyrosine kinase-3 (FLT3) inhibitor and chemotherapeutic agents, and a treatment method using the same .
  • FLT3 Fms-Like Tyrosine kinase-3
  • Fms-Like Tyrosine kinase-3 is one of the most frequently mutated genes in acute myeloid leukemia (AML).
  • Mutant FLT3 refers to a mutation expressed in leukemia cells in a subpopulation of patients with acute myelogenous leukemia (AML).
  • Activation mutations in FLT3 such as internal tandem duplication (ITD) in the membranous domain appear in about 25 to 30% in newly diagnosed AML cases (Patent Document 1). It is known that the FLT3 mutation occurs in about one third of patients with acute myeloid leukemia (AML) (Non-Patent Document 1).
  • Non-Patent Document 1 There are several FLT3 inhibitors that can be used clinically, but drug-resistant leukocyte cells were observed in AML patients treated with these FLT3 inhibitors and showed drug resistance (Non-Patent Document 1).
  • conventional standard chemotherapy for acute myelogenous leukemia (AML) cannot target AML stem/progenitor cells, so the disease frequently recurs in patients, thereby limiting long-term efficacy.
  • AML patients with the FLT3-ITD mutation are treated with either cytarabine (AraC) and anthracycline (such as daunorubicin (DNR) or idarubicin (IDR)) alone or in combination chemotherapy. Also shows a poor prognosis (Non-Patent Document 4). Therefore, there is a need for a method capable of solving drug resistance due to mutations to tyrosine kinase and effectively treating mutant acute leukemia patients.
  • Non-Patent Documents 3,4,5 As an attempt to resolve the resistance to FLT3 inhibitors, the administration of PI3K/Akt, MAPK, and JAK/STAT signaling pathway inhibitors and FLT3 inhibitors according to the combination use of various FLT3 inhibitors and chemotherapeutic agents was studied ( Non-Patent Documents 3,4,5).
  • Chemotherapeutic agents refer to drugs used in chemotherapy, cytarabine (AraC), daunorubicin (DNR), idarubicin (IDR), doxorubicin. Etc.
  • cytarabine is "4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- It is a drug referred to as "2-on” and is clinically applied to acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and non-Hodgkin's lymphoma.
  • Daunorubicin is "((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy- It is a drug referred to by the chemical name of "6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione", and under the trade name of cerubidine It is commercially available and is clinically used for acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and Kaposi's sarcoma. Idarubicin is “(1S).
  • Doxorubicin is “(7S,9S)-7- [(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl) It is a drug referred to by the chemical name of "-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione” and is marketed under the brand name of Adriamycin, breast cancer, bladder cancer, acute lymphoid composition It is clinically used for acute lymphocytic leukemia, etc.
  • Gilteritinib is "6-ethyl-3-( ⁇ 3-methoxy-4-[4-(4-methylpiperazin-1-yl)).
  • Piperidin-1-yl]phenyl ⁇ amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide” is a drug referred to by the chemical name of "Xospata” It is marketed under the trade name, and may exist as, for example, a hemifumarate salt
  • Non-Patent Document 4 is effective in the treatment of guilteritinib or a salt thereof and chemotherapeutic agents or salts thereof for the treatment of acute myelogenous leukemia (AML). Present combination .
  • Patent Document 1 Korean Patent Application Publication No. 10-2018-0124055
  • Non-Patent Document 2 J Natl Cancer Inst. Vol. 106, Issue 2, djt440, Feb 5, 2014
  • the present invention can lead to better therapeutic outcomes by providing an alternative therapy for the treatment of AML, including patients with FLT3 mutations.
  • FLT3 is a promising therapeutic target for leukemia and is mutated in approximately 30% or more of AML patients.
  • AML patients there is increasing interest in the occurrence and refractory of drug resistance resulting from the appearance of point mutations in targeted tyrosine kinases used for the treatment of patients with acute leukemia.
  • One approach to overcoming this resistance is confirmed by determining whether the efficacy and therapeutic effect are enhanced by combining inhibitors that are not structurally related and/or inhibitors of different signaling pathways.
  • One aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, chemotherapeutic agents ), a pharmaceutically acceptable salt, or solvate thereof, wherein the FLT3 inhibitor is a compound selected from a compound of Formula 1, a stereoisomer thereof, a tautomer, and a combination thereof, acute myelogenous leukemia ( AML) provides a therapeutic pharmaceutical composition.
  • FLT3 Fms-like tyrosine kinase-3
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a chemotherapeutic agent, or a pharmaceutically acceptable salt or solvate thereof, an Fms-like tyrosine kinase (FLT3) inhibitor, or a pharmaceutically acceptable salt or solvent thereof It provides a pharmaceutical composition for the treatment of acute myeloid leukemia (AML) that is administered in combination with cargo.
  • FLT3 Fms-like tyrosine kinase
  • AML acute myeloid leukemia
  • Another aspect of the present invention includes an FLT3 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a chemotherapeutic agent, a pharmaceutically acceptable salt, or solvate thereof, wherein the FLT3 inhibitor is represented by Formula 1 It provides a pharmaceutical combination for the treatment of acute myelogenous leukemia (AML), which is a compound selected from a compound, a stereoisomer, a tautomer, and a combination thereof.
  • AML acute myelogenous leukemia
  • Another aspect of the present invention provides a pharmaceutical kit comprising instructions for administering the pharmaceutical composition or pharmaceutical combination simultaneously, sequentially or separately.
  • Another aspect of the present invention provides a treatment method for treating acute myelogenous leukemia (AML) using the pharmaceutical composition, pharmaceutical combination, or kit.
  • AML acute myelogenous leukemia
  • One aspect of the present invention is a pharmaceutical comprising a therapeutically effective combination of an Fms-like tyrosine kinase inhibitor, a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • Another aspect of the present invention provides a method for treating acute myeloid leukemia (AML) using the pharmaceutical composition, the pharmaceutical composition, a pharmaceutical combination, and a kit using the same for treating acute myelogenous leukemia.
  • AML acute myeloid leukemia
  • compositions, pharmaceutical combinations, methods of treatment, and kits can enhance the therapeutic effect of AML in subjects suffering from acute myelogenous leukemia (AML), including individuals with FLT3 mutations.
  • AML acute myelogenous leukemia
  • Figure 1 shows the FLT3 inhibitor 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1) in nude mice xenografted with the MV-4-11 cell line.
  • -Yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine and chemotherapeutic agents cytarabine (AraC), anthracycline ) (E.g., daunorubicin (DNR)) alone or in combination shows the result of measuring the average tumor volume.
  • the Y-axis represents the average tumor volume
  • the X-axis represents the number of days of administration.
  • FLT3 Fms-like tyrosine kinase
  • FLT3 Fms-like tyrosine kinase
  • chemotherapeutic agent or any pharmaceutically acceptable salt thereof, or a solvent thereof. It provides a pharmaceutical composition, combination, kit or AML treatment method using the same for the treatment of acute myeloid leukemia (AML), including cargo, in a combination effective for the treatment of acute myelogenous leukemia.
  • acute myeloid leukemia is a disease in which hematopoietic stem cells change into malignant cells, proliferate in the bone marrow, spread out to peripheral blood and spread throughout the body, and invade the liver, spleen, lymph glands, etc., FLT3 mutation Acute myelogenous leukemia.
  • the acute myeloid leukemia may include a mutant FLT3 polynucleotide-positive myeloid leukemia, a columnar overlap in the FLT3 gene (ITD) positive acute myelogenous leukemia, or an acute myelogenous leukemia with a FLT3 point mutation.
  • Fms-Like Tyrosine kinase-3 is a member of the class III receptor tyrosine kinase (TK) family that is normally expressed on the surface of hematopoietic stem cells.
  • FLT3 and its ligands play an important role in the proliferation, survival and differentiation of pluripotent stem cells.
  • FLT3 is expressed in a number of AML cases.
  • activated FLT3 with intragene columnar overlap (ITD) in and around the membranous domain and tyrosine kinase domain (TKD) mutations near D835 in the activation loop were between 28% and 34% and 11% of AML cases, respectively. It is present at 14%.
  • the FLT3 inhibitor is 4'-N-benzoylstaurosporine (ingredient name: midostaurin), 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-pi] Perazinyl)-1-piperidinyl]phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]-2-pyrazinecarboxamide (ingredient name: gilteritinib, gilteritinib), 1 -(2- ⁇ 5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl ⁇ quinolin-8-yl)piperidin-4-amine (ingredient name: cre Noranib, Crenolanib), 1-(5-(tert-butyl)isooxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d
  • WO2018-139903 Or a compound having FLT3 inhibitory activity described in Korean Patent Application No. 10-2018-0086768 (Registration No. 10-1954370), or any pharmaceutically acceptable salt or solvate thereof, such as a hydrate. Including inhibitors, but not limited to these substances.
  • the FLT3 inhibitor is a compound having kinase inhibitory activity described in International Patent Application Publication No. WO2018-139903 or a compound having FLT3 inhibitory activity described in Korean Patent Application Application No. 10-2018-0086768 (Registration No. 10-1954370), Or a compound selected from stereoisomers, tautomers, and combinations thereof, or any pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound having kinase inhibitory activity described in International Patent Application Publication No. WO2018-139903 may be a compound selected from the compound of Formula 1, its stereoisomer, tautomer, and combinations thereof described in the present specification.
  • the compound having FLT3 inhibitory activity described in Korean Patent Application No. 10-2018-0086768 is the compound of Formula 3 described herein, its stereoisomer, tautomer, and these It may be a compound selected from a combination of.
  • One aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • FLT3 Fms-like tyrosine kinase-3
  • the FLT3 inhibitor provides a pharmaceutical composition for the treatment of acute myelogenous leukemia (AML), which is a compound selected from the compound of Formula 1, its stereoisomer, tautomer, and combinations thereof.
  • AML acute myelogenous leukemia
  • E a is hydrogen, hydroxy or C 1-4 alkoxy
  • E b is hydrogen, halogen, C 1-4 alkyl or C 1-4 fluoroalkyl
  • E c and E d are independently of each other hydrogen or hydroxy
  • X' is hydrogen or hydroxy
  • k is an integer from 1 to 2;
  • Each Q is independently of each other hydroxy, halogen, C 1-4 alkyl, hydroxyC 1-4 alkyl or C 1-4 alkoxy;
  • Z' is a monovalent functional group shown in Formula 2;
  • n is an integer of 1 to 2;
  • Each A is independently of each other a functional group selected from hydroxy, C 1-4 alkyl and hydroxyC 1-4 alkyl, wherein at least one A is C 1-4 alkyl;
  • L is hydrogen, C 1-4 alkyl, hydroxy or hydroxyC 1-4 alkyl.
  • solvate refers to a molecular complex of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and one or more solvent molecules.
  • solvent molecules may be those known or commonly used in the pharmaceutical art, such as water, ethanol, and the like.
  • solvate includes hydrates.
  • hydrate refers to a complex in which the solvent molecule is water.
  • salt or “pharmaceutically acceptable salt” as used herein refers to a pharmaceutically acceptable derivative of the disclosed compound, wherein the parent compound is by converting an acid or base moiety present into its salt form Denatured.
  • the FLT3 inhibitor may be a compound selected from a compound represented by Formula 3 below, a stereoisomer thereof, a tautomer, and a combination thereof.
  • E f is fluorine, chlorine, bromine or iodine
  • Q o is hydroxy, halogen, C 1-4 alkyl, hydroxyC 1-4 alkyl or C 1-4 alkoxy;
  • s is an integer from 1 to 2;
  • a o is a functional group selected from hydroxy, C 1-4 alkyl and hydroxyC 1-4 alkyl;
  • t is an integer of 1 to 2.
  • the FLT3 inhibitor may be a compound having kinase inhibitory activity described in International Patent Application Publication No. WO2018-139903, for example, a compound selected from the group consisting of compounds listed in Nos. 1 to 55 of Table 1 below.
  • Any pharmaceutically acceptable salt thereof, and a solvate including a hydrate may be a compound selected from the group consisting of
  • the FLT3 inhibitor may be a compound having FLT3 inhibitory activity described in Korean Patent Application No. 10-2018-0086768, for example, in the group consisting of the compounds listed in Table 2 below. It may be a compound selected from the group consisting of a selected compound, any pharmaceutically acceptable salt thereof, and a solvate including a hydrate.
  • the FLT3 inhibitor may be any one selected from the group consisting of the compounds shown in Table 2.
  • the FLT3 inhibitor is 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-( 6-methyl-1H-indol-3-yl)pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • FLT3 inhibitor 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl -1H-indol-3-yl)pyrimidin-2-amine inhibits kinases such as SYK, which are known to be associated with AML resistance.
  • SYK kinase transcribed FLT3 by direct physical interaction is important for the development of FLT3-ITD-induced bone marrow dysplasia, and is primarily activated more in FLT3-ITD positive AML. Therefore, activation of other signaling pathways of kinases such as SYK may cause resistance in the treatment of AML patients, and a combination of a FLT3 inhibitor and SYK inhibitor may be a more effective strategy for treating AML patients.
  • chemotherapeutic agents refer to drugs used for chemotherapy, and include biological (large molecule) or chemical (small molecule) compounds useful for the treatment of cancer regardless of the mechanism of action, and chemotherapy It is also called an anti-tumor agent.
  • chemotherapeutic agents are well known from those skilled in the art, and may be a compound selected from the group consisting of the following substances, or any pharmaceutically acceptable salts or hydrates thereof.
  • Mustard nitrogen such as cyclophosphamide, ifosfamide, mechlorethamine, chlorambucil, and melphalan; Ethyleneamines and methylmelamines such as thiotepa; Methylhydrazine derivatives such as procarbazine; Alkylsulfonates such as busulfan; Nitrosoureas such as carmustine or lomustine; Triazenes such as dacarbazine and temozolomide; Alkylating agents, including platinum coordination complexes such as cisplatin, carboplatin and oxaliplatin; Folic acid analogs such as methotrexate; Pyrimidine analogs such as fluorouracil, cytarabine, gemcitabine and capecitabine; Antimetabolites, including purine analogs such as mercaptopurine, pentostatin, cladribine and fludarabine; Vinca alkaloids such as vinblastine, vinorelbine
  • the chemotherapeutic agent may be 1 or more, such as 2, 3, 4, 5, 6 or 7 or more.
  • the chemotherapeutic agent may be two or more, for example, two chemotherapeutic agents may be used in combination.
  • the chemotherapeutic agent may be an anti-metabolite product, an anti-cancer antibiotic, or a combination thereof.
  • the anti-metabolite product may be a pyrimidine analog.
  • the pyrimidine analog may be fluorouracil, cytarabine, gemcitabine or capecitabine, or any pharmaceutically acceptable salt or hydrate thereof. have.
  • the anticancer antibiotic may be an anthracycline antibiotic.
  • Anthracycline anticancer substances have a structural feature of having one or more deoxy sugars in aglycon consisting of four rings.
  • Representative anthracyclines series anticancer substances are known as daunorubicin and doxorubicin.
  • the anticancer antibiotics are dactinomycin, daunorubicin, idarubicin, doxorubicin, plicomycin or epirubicin, or any drugs thereof It may be an academically acceptable salt or hydrate.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl]pyrimidin-2-one ( Ingredient name: cytarabine, cytarabine, AraC), ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxane-2 -Yl]oxy-6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione (ingredient name: daunorubicin, daunorubicin: DNR), ( 1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino- 2,3,6-trideoxo-
  • chemotherapeutic agent may be two or more, and the chemotherapeutic agent may be a combination of cytarabine and daunorubicin.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one, ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, pharmaceutically acceptable salts thereof, and solvates thereof It may be any one or more selected.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one, ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, pharmaceutically acceptable salts thereof, and hydrates thereof Is any one or more,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 1, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one, ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, pharmaceutically acceptable salts thereof, and hydrates thereof Is any one or more,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 3, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one, ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, and pharmaceutically acceptable salts thereof, and hydrates thereof Is any one or more selected,
  • FLT3 inhibitors are 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H -Indol-3-yl)pyrimidin-2-amine.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, or a pharmaceutically acceptable salt thereof, or a hydrate thereof,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 1, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione, or a pharmaceutically acceptable salt thereof, or a hydrate thereof,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 3, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 1, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione,
  • the FLT3 inhibitor may be any one selected from the compound of Formula 3, a stereoisomer thereof, and a tautomer.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine- 2-one and ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl]oxy-6 ,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione,
  • FLT3 inhibitors are 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H -Indol-3-yl)pyrimidin-2-amine.
  • the acute myelogenous leukemia may be an acute myelogenous leukemia having a FLT3 mutation.
  • the acute myelogenous leukemia may be a mutant FLT3 polynucleotide-positive acute myelogenous leukemia, an internal tandem duplication (ITD) positive acute myelogenous leukemia, or an acute myelogenous leukemia with a FLT3 point mutation.
  • ITD internal tandem duplication
  • compositions for the treatment of acute myeloid leukemia comprising the FLT3 inhibitor of any one of the compound of Formula 1, or a pharmaceutically acceptable salt, or solvate thereof,
  • the acute myelogenous leukemia may have a mutation in the tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence.
  • TKD tyrosine kinase domain
  • the FLT3-TKD mutation may further include internal tandem duplication (ITD).
  • ITD internal tandem duplication
  • the FLT3-TKD mutation is any selected from FLT3 (D835Y), FLT3 (F691L), FLT3 (F691L/D835Y), FLT3 (ITD/D835Y), FLT3 (ITD/F691L), and combinations thereof It can contain one.
  • the FLT3 inhibitor is 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1) -Yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the FLT3 inhibitor in the pharmaceutical composition for treating acute myelogenous leukemia according to one embodiment, is a chemotherapeutic agent, or a pharmaceutically acceptable salt or solvate thereof, and at the same time, sequentially They can be administered in reverse order, or individually.
  • a FLT3 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and a chemotherapeutic agent, or a pharmaceutically acceptable salt or solvate thereof are respectively therapeutic.
  • terapéuticaally effective amount is an amount of a compound that treats acute myelogenous leukemia when administered to a subject or patient in combination with an FLT3 inhibitor and a chemotherapeutic agent.
  • the therapeutically effective amount is the amount of a compound that does not completely inhibit the biological activity of the intended target over time when administered to a patient, and may vary within a wide tolerance, in a manner known in the art. Can be determined.
  • the dosage will be tailored to the individual requirements of each particular case, including the patient to be treated as well as the specific compound to be administered, the route of administration (oral, parenteral), and the condition to be treated.
  • An amount that proves to be a therapeutically effective amount at a given moment for a particular subject may not be effective for 100% of subjects similarly treated for the disease, even if the clinician considers such a dose to be a therapeutically effective amount.
  • the amount of the compound corresponding to a therapeutically effective amount may depend on the specific type of cancer, stage of cancer, age of the patient being treated, and other factors. In general, therapeutically effective amounts of these compounds are well known in the art.
  • the route of administration of the pharmaceutical composition according to an embodiment includes oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous and rectal administration. However, it is not limited thereto.
  • the FLT3 inhibitor is 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-( 6-methyl-1H-indol-3-yl)pyrimidin-2-amine, a pharmaceutically acceptable salt, or solvate thereof, for example, the FLT3 inhibitor may be administered orally.
  • the chemotherapeutic agent is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl]pyrimidine- 2-one (ingredient name: cytarabine, AraC), a pharmaceutically acceptable salt, or solvate thereof, for example, the chemotherapeutic agent may be administered by intravenous injection, intraperitoneal injection, or subcutaneous injection. have.
  • the chemotherapeutic agent in the pharmaceutical composition is ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-oxan-2-yl ]Oxy-6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione (ingredient name: daunorubicin, daunorubicin: DNR), its pharmaceutical It may be an acceptable salt or solvate, for example, the chemotherapeutic agent may be administered by intravenous injection, intraperitoneal injection, or subcutaneous injection.
  • the chemotherapeutic agent is (1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetra Sen-1-yl 3-amino-2,3,6-trideoxo- ⁇ -L-ylso-hexopyranoside (ingredient name: idarubicin, idarubicin: IDR), a pharmaceutically acceptable salt thereof, or It may be a solvate, for example, the chemotherapeutic agent may be administered by intravenous injection, intraperitoneal injection, or subcutaneous injection.
  • the FLT3 inhibitor may be administered in an amount of 6 mg to 600 mg. Alternatively, the FLT3 inhibitor may be administered in an amount of 0.1 mg to 10 mg/kg body weight/day. Alternatively, the FLT3 inhibitor may be administered in an amount of 3.7 mg/m 2 to 370 mg/m 2 of a body surface area.
  • the amount of combined drug administered to a patient can be determined by the attending diagnostician as a person skilled in the art using known techniques and by observing the results obtained under similar circumstances.
  • the effective amount or dose of the compound to be administered the species of the mammal; Its size, age and overall health; Specific neoplasms involved; The degree or involvement or severity of the neoplasm; Individual patient response; The specific compound being administered; Mode of administration; Bioavailability characteristics of the administered formulation; The usage chosen; The use of concomitant drugs; And other relevant circumstances, a number of factors are considered by the attending diagnostician.
  • the daily dose when administered orally, may be about 0.001 to about 100 mg/kg, for example about 0.005 to about 30 mg/kg, for example about 0.01 to about 10 mg/kg per patient's body weight. have.
  • the daily dose When administered intravenously, may suitably be about 0.0001 to about 81 mg/kg per body weight of the patient, and the whole is administered in divided doses of one or more doses per day.
  • the transmucosal oil formulation is administered at a dose of about 0.001 to about 81 mg/kg per body weight, and may be administered once a day or dividedly administered several times a day.
  • cytarabine can be administered in an amount of about 27 to about 81 mg per day.
  • the daily dose of the chemotherapeutic agent is about 0.001 to about 100 mg/kg, for example, about 0.01 to about 90 mg/kg, for example, about 0.1 to about 80 mg/kg per body weight of the patient, Alternatively, it may be administered orally, intravenously, or intraperitoneally in an amount of about 1 to about 50 mg/kg.
  • the daily dose of the chemotherapeutic agent according to an embodiment may be 1 to 500 mg/m2, 10 to 200 mg/m2, or 30 to 45 mg/m2 based on the body surface area of the patient.
  • the daily dose may be administered once a day or may be administered in divided doses.
  • the daily dose according to one embodiment may be adjusted according to the number and type of concomitant drugs.
  • 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxoran-2-yl] pyrimidine 2-one is a dose of about 100 mg per 1 m 2 of a patient's body surface area to about 200 mg per 1 m 2 of a patient's body surface, for example, about 100 mg/m 2 To about 200 mg/m 2 .
  • the recommended starting dose as monotherapy is for all patients, irrespective of baseline hematologic values, by subcutaneous (SC) injection of cytarabine 200 mg/m 2 per day for 5 days (120 hours) or intravenous (IV). It is administered by injection.
  • SC subcutaneous
  • IV intravenous
  • the treatment cycle can be repeated every two weeks.
  • the recommended dose for combination therapy is for all patients, regardless of the baseline hematologic value, for 7 days (Day 1- Day 7)
  • Daily cytarabine 100 mg/m 2 was administered by subcutaneous (SC) injection or intravenous (IV) infusion, and daunorubicin 45 mg/m 2 was administered for 3 days (day 1 to day 3). It is administered by subcutaneous (SC) injection or intravenous (IV) infusion If the disease persists, the above combination therapy may be repeated at intervals of 2 to 4 weeks.
  • the dosage of the pharmaceutical composition according to one embodiment, or the dosage or therapeutically effective amount of the FLT3 inhibitor and the chemotherapeutic agent in the composition may vary within wide tolerances and may be determined in a manner known in the art.
  • the dosage will be tailored to the individual requirements of each particular case, including the patient to be treated as well as the specific compound to be administered, the route of administration (oral, parenteral), and the condition to be treated.
  • the daily dose may be administered as a single dose or divided doses, or may be given as a continuous infusion for parenteral administration.
  • the FLT3 inhibitor and the chemotherapeutic agent may be administered simultaneously, sequentially or separately without a specific time limit.
  • This administration here is meant to provide a therapeutically effective level of the two compounds in the patient's body.
  • the inter-administration interval may be several seconds, several minutes, several hours, or days of a predetermined interval, and may have a pause as necessary.
  • One aspect of the invention includes the administration or use of the combination at therapeutically effective intervals.
  • the therapeutically effective interval is a period of time starting when one of the compounds is administered to a patient and ending at the limit of administration of the other compound while the benefits of co-administration of the two compounds are maintained.
  • co-administration can be simultaneous or sequential or in any order.
  • the time period or cycle of co-administration may be a total of 1 week, 28 days, 1 month, 2 months, 3 months, or 4 months, or more.
  • Individual drugs may be administered daily for the entire duration of each period or cycle, or only a portion thereof.
  • the FLT3 inhibitor or a pharmaceutically acceptable salt or hydrate thereof may be administered daily in the cycle, whereas the chemotherapeutic agent or a pharmaceutically acceptable salt or hydrate thereof is 5 consecutive days, 7 consecutive days, Or for a portion thereof, such as for 10 consecutive days, and 5, 7, and 10 consecutive days may be the first 5, 7, or 10 days of a period or cycle, respectively.
  • the FLT3 inhibitor may be administered once a day on 21 consecutive days, and the chemotherapeutic agent may be administered three times a week or five times a week for the same period.
  • each chemotherapeutic agent may have a different administration cycle.
  • the FLT3 inhibitor when administering a combination of cytarabine and daunorubicin together with FLT3 inhibition, the FLT3 inhibitor is administered once a day for a total of 21 days, and during the same period, cytarabine is administered 5 times a week, and daunorubicin is administered for a week. It can be administered three times.
  • the pharmaceutical composition according to one embodiment is the FLT3 inhibitor, or any pharmaceutically acceptable salt or hydrate thereof, and a chemotherapeutic agent, or any pharmaceutically acceptable salt or hydrate thereof, for the treatment of acute myelogenous leukemia (AML).
  • AML acute myelogenous leukemia
  • it may be included in any pharmaceutically acceptable amount for use simultaneously, sequentially or separately.
  • the pharmaceutical composition may further include one or more optional pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, lubricants, and any combination thereof.
  • optional pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, lubricants, and any combination thereof.
  • the above additives are any substances known to those skilled in the art to be useful in the preparation of formulations, and can be adjusted as necessary, for example, according to the mode of administration of the drug.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a chemotherapeutic agent, or a pharmaceutically acceptable salt or solvate thereof, an Fms-like tyrosine kinase (FLT3) inhibitor, or a pharmaceutically acceptable salt or solvent thereof It provides a pharmaceutical composition for the treatment of acute myeloid leukemia (AML) that is administered in combination with cargo.
  • FLT3 Fms-like tyrosine kinase
  • AML acute myeloid leukemia
  • the FLT3 inhibitor may be a compound selected from the compound of Formula 1, a stereoisomer thereof, a tautomer, and a combination thereof.
  • Another aspect of the present invention includes an FLT3 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a chemotherapeutic agent, a pharmaceutically acceptable salt, or solvate thereof, wherein the FLT3 inhibitor is represented by Formula 1 It provides a pharmaceutical combination (or combination) for the treatment of acute myelogenous leukemia (AML), which is a compound selected from a compound, a stereoisomer, a tautomer, and a combination thereof.
  • AML acute myelogenous leukemia
  • solvate including an FLT3 inhibitor, or a pharmaceutically acceptable salt or hydrate thereof and a solvate including a chemotherapeutic agent, or a pharmaceutically acceptable salt or hydrate thereof, in the pharmaceutical combination.
  • the active ingredients may be administered simultaneously, sequentially or individually.
  • the term “combination” or “pharmaceutical combination” as used herein refers to a product produced from mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” means that the active ingredient, eg, a compound disclosed herein and one or more additional therapeutic agents, are administered to a subject simultaneously in the form of a single aggregate or dosage.
  • the term “unfixed combination” means that the active ingredient, eg, a compound disclosed herein and one or more additional therapeutic agents, are administered to a subject as separate aggregates simultaneously, simultaneously or sequentially without specific time limitations, Here, such administration provides a therapeutically effective level of the active ingredient in the body of the subject.
  • cocktail therapy for example the administration of three or more active ingredients.
  • Another aspect of the present invention provides a pharmaceutical kit comprising instructions for administering the pharmaceutical composition or pharmaceutical combination simultaneously, sequentially or separately.
  • the kit optionally has a schedule of administration, e.g., to allow a practitioner (e.g., doctor, nurse) or patient to administer the composition or combination contained therein to a patient with cancer such as acute myeloid leukemia (AML) Included instructions may also be included.
  • the kit can also include a syringe.
  • Another aspect of the present invention provides a treatment method for treating acute myelogenous leukemia (AML) using the pharmaceutical composition, pharmaceutical combination, or kit.
  • the active ingredients may be administered simultaneously, sequentially or individually.
  • the FLT3 inhibitor, or a pharmaceutically acceptable salt or hydrate thereof, and a chemotherapeutic agent, or a composition containing a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, etc., suffering from acute myelogenous leukemia (AML) Subjects can be treated.
  • Subjects to be treated according to the above treatment method include subjects suffering from acute myelogenous leukemia having the FLT3 mutation.
  • the acute myelogenous leukemia includes mutant FLT3 polynucleotide-positive myeloid leukemia, columnar overlap in the FLT3 gene (ITD) positive acute myelogenous leukemia, or acute myelogenous leukemia with a FLT3 point mutation.
  • subject encompasses mammals and non-mammals, including humans
  • mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs; rabbits, dogs , Cats, rats, mice, guinea pigs, etc.
  • non-mammals include, but are not limited to, birds, fish, etc.
  • treating include limiting, delaying, arresting, reducing or reversing the progression or severity of an existing symptom, disease, condition or disease. do.
  • One aspect of the present invention is a FLT3 inhibitor, or a pharmaceutically acceptable salt, or solvate, and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, used in the manufacture of a drug for treating acute myelogenous leukemia (AML). , Or a solvate as an active ingredient.
  • AML acute myelogenous leukemia
  • the pharmaceutical composition, pharmaceutical combination, pharmaceutical kit, and method of treatment include components of the chemotherapeutic agent, FLT3 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and the dosage thereof described above.
  • the method of administration can be used.
  • the combination therapy of an FLT3 inhibitor and a chemotherapeutic agent using a pharmaceutical composition, a pharmaceutical combination, a pharmaceutical kit, and a treatment method according to the present invention is improved compared to the effect of each single administration of the FLT3 inhibitor or chemotherapeutic agent.
  • the therapeutic effect according to an embodiment shows a synergistic therapeutic effect of more than the arithmetic sum of two or more drugs in combination.
  • the MV-4-11 cell line was purchased from the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • Nude mice 5-week-old female CAnN.Cg-Foxn1nu/Crljbgi mice (hereinafter, Nude mice) were purchased from Charles River Laboratories Japan, Inc.
  • the MV-4-11 cell line was inoculated subcutaneously in the flank with 5 x 10 6 cells/10 ml/mouse and allowed to grow. Mice with a tumor volume of 100 to 300 mm 3 (length x width 2 x 0.5) were selected 1 day before administration, and the average tumor volume in each group was divided into 4 groups (5 mice/group) so that the total Each dose was administered over a period of 21 days.
  • Compound A was administered orally once a day at a dose of 3 mg/kg/day from 1 to 21 days, and in the CTx (cytarabine + daunorubicin) group, 50 mg of cytarabine from 1 to 21 days. /kg/day dose 5 times a week (every day 1-5 days: cytarabine) intraperitoneally, and daunorubicin at 2 mg/kg/day dose 3 times a week (every day 1-3 days: Daunoru Bicine) received intravenous infusion.
  • CTx cytarabine + daunorubicin
  • Fig. 1 shows the experimental results. 1 shows the tumor volume (mm 3 ) measured after treatment alone or in combination with each treatment solution or drug in nude mice xenografted with the MV-4-11 cell line. From the results of Fig. 1, it can be seen the anti-tumor effect when the FLT3 inhibitor and the chemotherapeutic agent are administered in combination.
  • the Y-axis represents the mean tumor volume (mm 3 ) and the X-axis represents the number of days of administration.
  • Tumor growth inhibition (TGI) was calculated from "(1-(mean tumor volume of drug-treated group)/(mean tumor volume of control group)) ⁇ 100%".
  • TGI Tumor growth inhibition
  • the average tumor volume was measured for a total of 21 days of drug administration in each treatment group, and the effect of tumor growth inhibition (TGI) was obtained from this.
  • TGI tumor growth inhibition
  • the average tumor volume in the combination group was significantly reduced.

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PCT/KR2020/008258 2019-06-27 2020-06-25 Flt3 저해제 및 화학치료제를 포함하는 급성 골수성 백혈병 치료용 약학적 조성물 Ceased WO2020262974A1 (ko)

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EP20833623.0A EP3991733A4 (en) 2019-06-27 2020-06-25 Pharmaceutical composition for treating acute myeloid leukemia, containing flt3 inhibitor and chemotherapeutic agents
MX2021015724A MX2021015724A (es) 2019-06-27 2020-06-25 Composición farmacéutica para el tratamiento de la leucemia mieloide aguda, que contiene inhibidores de flt3 y agentes quimioterapéuticos.
AU2020308814A AU2020308814A1 (en) 2019-06-27 2020-06-25 Pharmaceutical composition for treating acute myeloid leukemia, containing FLT3 inhibitor and chemotherapeutic agents
EA202290154A EA202290154A1 (ru) 2019-06-27 2020-06-25 Фармацевтическая композиция для лечения острого миелоидного лейкоза, содержащая ингибитор flt3 и химиотерапевтические агенты
JP2021576034A JP2022538817A (ja) 2019-06-27 2020-06-25 Ｆｌｔ３阻害剤および化学療法剤を含む急性骨髄白血病を治療するための薬学的組成物
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CN202080058522.0A CN114650823A (zh) 2019-06-27 2020-06-25 用于治疗急性髓系白血病的含有flt3抑制剂和化疗剂的药物组合物
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