[go: up one dir, main page]

WO2021066443A1 - Composition pharmaceutique pour le traitement de la leucémie aiguë myéloïde contenant un inhibiteur de flt3 et un inhibiteur de mdm2 - Google Patents

Composition pharmaceutique pour le traitement de la leucémie aiguë myéloïde contenant un inhibiteur de flt3 et un inhibiteur de mdm2 Download PDF

Info

Publication number
WO2021066443A1
WO2021066443A1 PCT/KR2020/013188 KR2020013188W WO2021066443A1 WO 2021066443 A1 WO2021066443 A1 WO 2021066443A1 KR 2020013188 W KR2020013188 W KR 2020013188W WO 2021066443 A1 WO2021066443 A1 WO 2021066443A1
Authority
WO
WIPO (PCT)
Prior art keywords
flt3
inhibitor
pharmaceutically acceptable
chloro
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2020/013188
Other languages
English (en)
Korean (ko)
Inventor
배인환
송지영
최재율
김민정
안영길
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Publication of WO2021066443A1 publication Critical patent/WO2021066443A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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 myelogenous leukemia comprising a therapeutically effective combination of an Fms-Like Tyrosine kinase-3 (FLT3) inhibitor and a Murine double minute 2: MDM2 inhibitor, and
  • FLT3 Fms-Like Tyrosine kinase-3
  • MDM2 inhibitor Murine double minute 2
  • 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 acute myelogenous leukemia (AML) standard chemotherapy 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 have poor prognosis even with chemotherapy treatment with cytarabine (AraC) and anthracycline (such as daunorubicin (DNR) or idarubicin (IDR)). Shows (Patent Document 1). 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.
  • MDM2 is a tumor protein, a key negative regulatory protein for p53, a tumor suppressor protein.
  • the main function of MDM2 is to degrade p53 protein and inhibit p53 activity.
  • By inhibiting MDM2 it is possible to induce apoptosis by activating the function of p53 (Non-Patent Document 3).
  • a treatment method for acute myeloid leukemia (AML) and hematologic malignancies in combination with such an MDM2 inhibitor and an FLT3 inhibitor has been studied (Non-Patent Document 4).
  • WT-p53 wild-type p53
  • p53 is a tumor suppressor protein that plays a central role in preventing tumor formation.
  • the p53 transcription factor prevents leukocyte formation in AML by playing a critical role in tumor suppression by various mechanisms regulating apoptosis, DNA repair, maintenance of normal stem cells, and self-renewal.
  • MDM2 forms a self-regulating feedback loop with p53.
  • MDM2 is an oncogene that has both p53-dependent and non-p53-dependent oncogenic activity. Many human tumors have high MDM2 protein levels, which can inactivate p53 function. Therefore, a treatment strategy targeting MDM2 inhibitors has been studied (Non-Patent Document 5).
  • Non-Patent Document 4 a therapeutically effective combination of an FLT3 inhibitor and an MDM2 inhibitor is presented.
  • an FLT3 inhibitor the trade name Jostapine Gilteritinib ("6-ethyl-3-( ⁇ 3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1) -Yl]phenyl ⁇ amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide”), Quizartinib (“1-(5- ( t -butyl)isooxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[ d ]imidazo[2,1-b]thiazol-2-yl ) Phenyl) urea”), the brand name of Lydapt, Midostaurin (Midostaurin) and an MDM2 inhibitor were used in combination.
  • Patent Document 1 Korean Patent Laid-Open Patent No. 10-2018-0124055
  • Patent Document 2 Korean Laid-Open Patent No. 10-2009-0087094
  • Non-Patent Document 2 J Natl Cancer Inst. 2014, 106(2), djt440
  • Non-Patent Document 3 Acta Biochimica et Biophysica Sinica, 2014, 46(3), 180189
  • Non-Patent Document 4 Haematologica, 2018, 103(11), 1862-1872
  • 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 (FLT3) inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, a murine double minute 2 (MDM2) inhibitor, a pharmaceutically acceptable thereof
  • FLT3 Fms-like tyrosine kinase
  • MDM2 murine double minute 2
  • AML acute myelogenous leukemia
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a murine double minute 2 (MDM2) inhibitor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a combination thereof, an Fms-like tyrosine kinase (FLT3) inhibitor, It provides a pharmaceutical composition for the treatment of acute myeloid leukemia (AML) used in combination with a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • MDM2 murine double minute 2
  • FLT3 Fms-like tyrosine kinase
  • One aspect of the present invention provides a pharmaceutical composition or a pharmaceutical combination comprising an Fms-like tyrosine kinase (FLT3) inhibitor and a murine double minute 2 (MDM2) inhibitor, or a kit comprising the same.
  • FLT3 Fms-like tyrosine kinase
  • MDM2 murine double minute 2
  • One aspect of the present invention provides a method for treating hematologic malignancies including acute myeloid leukemia (AML) using the pharmaceutical composition, a pharmaceutical combination, or a kit comprising the same, and a use for the treatment of acute myeloid leukemia. do.
  • AML acute myeloid leukemia
  • One aspect of the present invention can increase the therapeutic effect of AML, including patients with FLT3 mutations, by providing the pharmaceutical composition, the pharmaceutical combination, or a kit including the same.
  • Figure 2 shows the antitumor effect when administered in combination with a FLT3 inhibitor and an MDM2 inhibitor in NOD/SCID mice subcutaneously implanted with MOLM-13 cell line.
  • the Y-axis represents the tumor volume (mm 3 ) of the surviving mice in each group, and the X-axis represents the number of days of administration.
  • FLT3 Fms-like tyrosine kinase
  • MDM2 murine double minute 2
  • AML acute myelogenous leukemia
  • Acute myelogenous leukemia as used herein includes acute myelogenous leukemia with the FLT3 mutation.
  • the acute myelogenous leukemia comprises 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.
  • FLT3 is a member of the class III receptor tyrosine kinase (TK) family, which 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%. These activated mutations in FLT3 are tumorigenic and exhibit modifying activity in cells.
  • the FLT3 inhibitor is 4'-N-benzoylstaurosporine (ingredient name: midostaurin), 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1] -Piperazinyl)-1-piperidinyl]phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]-2-pyrazinecarboxamide (ingredient names: gilteritinib, gilteritinib) , 1-(2- ⁇ 5-[(3-methoxacene-3-l)methoxy]-1H-benzimidazol-1-yl ⁇ quinolin-8-yl)piperidin-4-amine (ingredient name : Crenolanib, Crenolanib), 1-(5-(tert-butyl)isooxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)
  • a pharmaceutically acceptable salt thereof, or a solvate (including a hydrate) form of an FLT3 inhibitor thereof is not limited to these substances.
  • the FLT3 inhibitor is a compound having a kinase inhibitory activity described in International Patent Application Publication No. WO2018-139903 or a FLT3 inhibitory activity described in Korean Patent Application Application No. 10-2018-0086768 (Registration No. 10-1954370).
  • 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, a stereoisomer thereof, a tautomer thereof, and a combination thereof described herein. .
  • the compound having FLT3 inhibitory activity described in Korean Patent Application No. 10-2018-0086768 is a compound of Formula 3 described herein, a stereoisomer thereof, a tautomer thereof, and It may be a compound selected from a combination thereof.
  • One aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an Fms-like tyrosine kinase (FLT3) inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • FLT3 Fms-like tyrosine kinase
  • MDM2 murine double minute 2
  • the FLT3 inhibitor provides a pharmaceutical composition for the treatment of acute myelogenous leukemia (AML), which is any one selected from a compound of Formula 1, a stereoisomer thereof, a tautomer thereof, and a combination 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 from 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 from 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.
  • the solvate includes a hydrate.
  • 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. Is denatured.
  • the FLT3 inhibitor may be a compound selected from the group consisting of a compound represented by Formula 3 below, a stereoisomer thereof, a tautomer thereof, 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. , It may be a compound selected from the group consisting of a pharmaceutically acceptable salt thereof, and a solvate including a hydrate.
  • 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 compounds listed in Nos. 1 to 32 of Table 2 below. It may be a compound selected from selected compounds, any pharmaceutically acceptable salts thereof, or solvates (including hydrates).
  • the FLT3 inhibitor may be any one selected from the group consisting of the compounds shown in Table 2 above.
  • 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 thereof, or a solvate thereof.
  • the MDM2 inhibitor activates p53 by inhibiting the binding of the MDM2 protein to the p53 protein.
  • Activated p53 plays a critical role in tumor suppression by various mechanisms regulating apoptosis, DNA repair, maintenance of normal stem cells, and self-renewal.
  • the MDM2 inhibitor is, for example, 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluoro Phenyl)-4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid (ingredient name: idasanutlin, idasanutlin), ( 3'R,4'S,5'R)-N-((3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl)-6''-chloro-4'-(2-chloro- 3-Fluoropyridin-4-yl)-4,4-dimethyl-2''-oxodisspiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, a solvent thereof, And it may be any one selected from the group consisting of a combination thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and ,
  • the FLT3 inhibitor may be any one selected from the group consisting of the compound of Formula 1, a stereoisomer thereof, and a tautomer.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and ,
  • the FLT3 inhibitor may be any one selected from the group consisting of the compound of Formula 3, a stereoisomer thereof, and a tautomer thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and ,
  • 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, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, a solvate thereof, And any one selected from the group consisting of a combination thereof,
  • the FLT3 inhibitor may be any one selected from the group consisting of the compound of Formula 1, a stereoisomer thereof, and a tautomer thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, a solvent thereof, And any one selected from the group consisting of a combination thereof,
  • the FLT3 inhibitor may be any one selected from the group consisting of the compound of Formula 3, a stereoisomer thereof, and a tautomer thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, a solvate thereof, And any one selected from the group consisting of a combination thereof,
  • 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, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt thereof, a solvate thereof, And any one selected from the group consisting of a combination thereof,
  • 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, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, a pharmaceutically acceptable salt or hydrate thereof,
  • 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, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • FLT3 inhibitor As the FLT3 inhibitor according to an embodiment, 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 bone marrow dysplasia induced by FLT3-ITD, 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 the treatment of AML patients.
  • the FLT3 inhibitor has a high risk of recurrence after treatment, has a poor prognosis, and reduces overall survival, against acute myelogenous leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation.
  • AML acute myelogenous leukemia
  • FLT3 FMS-like tyrosine kinase 3
  • the FLT3 inhibitor according to the above embodiment exhibits clinical benefits in patients with acute myelogenous leukemia (AML) who are resistant to conventional treatments.
  • AML acute myelogenous leukemia
  • activated mutations within FLT3's internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations are reported as oncogenic driver mutations.
  • the mutation of TKD may further include internal tandem duplication (ITD).
  • 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 having a FLT3 point mutation.
  • ITD internal tandem duplication
  • composition for the treatment of acute myeloid leukemia comprising the FLT3 inhibitor of any one of the compound of Formula 1, a pharmaceutically acceptable salt thereof, or a 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 FLT3(D835V), FLT3(D835Y), FLT3(D835H), FLT3(D835E), FLT3(D835N), FLT3(F691L), FLT3(F691L/D835YLT), ITD/D835Y), FLT3 (ITD/F691L), and the like, and may include any one selected from a combination thereof, but is not limited thereto.
  • the compound having kinase inhibitory activity described in International Patent Application Publication No. WO2018-139903, Fms-like tyrosine kinase-3 described in Korean Patent Application Application No. 10-2018-0086768: FLT3) provides a pharmaceutical composition for the treatment of acute myelogenous leukemia (AML) comprising any one FLT3 inhibitor selected from compounds having inhibitory activity, pharmaceutically acceptable salts or hydrates thereof, and combinations thereof.
  • AML acute myelogenous leukemia
  • 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 or hydrate thereof.
  • AML acute myelogenous leukemia having a FLT3 mutation, such as internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations of FLT3, such as FLT3 (ITD/D835Y).
  • FLT3 FLT3
  • IMD/F691L FLT3 inhibitor for the treatment of acute myelogenous leukemia (AML)
  • AML acute myelogenous leukemia
  • the mutation of FLT3-TKD may include one or more amino acid mutations in the region of positions 823 to 861 of the FLT3 amino acid sequence.
  • the mutation of TKD may include a mutation of at least one amino acid selected from the group consisting of Nos. 835, 836, and 842 of the FLT3 amino acid sequence.
  • the amino acid mutation is glycine, alanine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, proline, histidine, serine, threonine, asparagine, glutamine, cysteine, lysine, arginine, aspartic acid, glutamine, and methionine. It may be substituted with one or more other amino acids selected from the group consisting of.
  • the mutation of TKD may include a mutation of amino acid No. 835 of the FLT3 amino acid sequence.
  • the mutation of TKD may be one in which aspartic acid No. 835 of the FLT3 amino acid sequence is substituted with valine, tyrosine, histidine, glutamic acid, or asparagine.
  • the mutation of TKD may be that isoleucine at No. 836 of the FLT3 amino acid sequence is substituted with leucine or aspartic acid.
  • the mutation of TKD may be a substitution of cysteine or histidine for tyrosine 842 of the FLT3 amino acid sequence.
  • the mutation may be FLT3 (D835Y).
  • the mutation of FLT3-TKD may have a mutation of at least one amino acid selected from the group consisting of Nos. 621, 627, 676, 691, and 697 of the FLT3 amino acid sequence.
  • the amino acid mutation is glycine, alanine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, proline, histidine, serine, threonine, asparagine, glutamine, cysteine, lysine, arginine, aspartic acid, glutamine, and methionine. It may be substituted with one or more other amino acids selected from the group consisting of.
  • the mutation of TKD may be a substitution of leucine for phenylalanine 691 of the FLT3 amino acid sequence.
  • the mutation may be FLT3 (F691L).
  • the mutation of the TKD may further include internal tandem duplication (ITD).
  • ITD internal tandem duplication
  • the mutation may be FLT3 (ITD/D835Y) or FLT3 (ITD/F691L).
  • FLT3 inhibitor As the FLT3 inhibitor according to an embodiment, 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 is caused by the FLT3 mutation in an in vivo study using Ba/F3 cells expressed in the FLT3 ITD/F691L or FLT3 ITD/D835Y xenograft mouse model. Resistance overcoming and treatment effects are verified.
  • the FLT3 inhibitor exhibits an effect of overcoming the resistance of acute myelogenous leukemia (AML) treatment.
  • the FLT3 inhibitor exhibits inhibitory activity against drug-resistant point mutant species (D835Y, F691L, or F691L/D835Y) of FLT3 due to the D835Y and F691L point mutations obtained in FLT3-TKD.
  • the mutation of TKD may be that aspartic acid No. 835 of the FLT3 amino acid sequence is substituted with tyrosine.
  • the mutation may be FLT3 (D835Y), or FLT3 (ITD/D835Y).
  • the mutation of TKD may be that phenylalanine No. 691 of the FLT3 amino acid sequence is substituted with leucine.
  • the mutation may be FLT3 (F691L) or FLT3 (ITD/F691L).
  • the FLT3 inhibitor according to the above embodiment is a result of performing an in vitro site-directed competition binding assay using an AML-resistant cell line, standard proliferation assay, immunoblotting, and apoptosis analysis. Through this, the effect of treatment and overcoming resistance due to the FLT3 mutation is verified.
  • the FLT3 inhibitor according to the above embodiment strongly inhibits the FLT3 (ITD/D835Y) and FLT3 (ITD/F691L) mutations in preclinical evaluation.
  • the FLT3 inhibitor according to the above embodiment exhibits high in vitro binding affinity in both mutations, in vitro and in vivo using Ba/F3 cell lines expressing FLT3 (ITD/D835Y) or FLT3 (ITD/F691L). Shows strong inhibitory activity.
  • the FLT3 inhibitor according to the above embodiment can exhibit high cytotoxic efficacy in MOLM-14 cell lines containing FLT3 ITD and overcome FL-induced drug resistance.
  • the FLT3 inhibitor according to the above embodiment can strongly inhibit the phosphorylation of SYK, STAT3 and STAT5 in KG-la cells.
  • the FLT3 inhibitor according to the above embodiment may exhibit a synergistic effect in combination with one or more leukemia treatment drugs such as an MDM2 inhibitor or a combination therapy.
  • the MDM2 inhibitor is 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl) -4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid, or (3'R,4'S,5'R) -N-((3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl) -4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide, or a pharmaceutical thereof It may be an acceptable salt, solvate, or hydrate.
  • the term “combination” refers to the use of two or more active ingredients together.
  • the term “combination therapy” refers to a combination of active ingredients contained in a single or multiple compositions. The active ingredients may be administered simultaneously, sequentially or separately.
  • each of the active ingredients may be administered “simultaneously”, that is, simultaneously or essentially simultaneously, or administered in a “sequential” manner prescribed by a healthcare practitioner, or “individually” in each or any combination (eg For example, at intervals of 10 to 60 minutes).
  • the FLT3 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof is combined with the MDM2 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, simultaneously, sequentially, or separately. Can be administered.
  • an FLT3 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and an MDM2 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate thereof may be included in a therapeutically effective amount, respectively.
  • the route of administration includes, but is not limited to, oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous and rectal administration. Does not.
  • 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 thereof, a solvate or hydrate thereof can be administered orally.
  • MDM2 inhibitor 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl )-4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid (ingredient name: idasanutlin, idasanutlin), its drug A scientifically acceptable salt, solvate or hydrate thereof may be administered orally.
  • the pharmaceutical combination according to one embodiment comprises a FLT3 inhibitor and an MDM2 inhibitor in a therapeutically effective amount.
  • the FLT3 inhibitor and the MDM2 inhibitor may be administered at a dose of about 0.001 mg per kg of patient weight to about 100 mg per kg of patient weight.
  • the FLT3 inhibitor may be administered in an amount of 6 mg to 600 mg.
  • the FLT3 inhibitor may be administered in an amount of 0.1 mg to 30 mg/kg body weight/day.
  • the FLT3 inhibitor may be administered in an amount of a body surface area of 3.8 mg/m 2 to 375 mg/m 2.
  • the MDM2 inhibitor may be administered in an amount of 50 mg to 1000 mg. Alternatively, the MDM2 inhibitor may be administered in an amount of 1 mg/kg to 50 mg/kg body weight/day. Alternatively, the MDM2 inhibitor may be administered in an amount of 1 mg/kg to 17 mg/kg body weight/day. Alternatively, the MDM2 inhibitor may be administered in an amount of 30 mg/m 2 to 617 mg/m 2 of a body surface area.
  • the amount of the two drugs in combination 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 reactions; 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 10 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 preparation is administered at a dose of about 0.001 to about 100 mg/kg per body weight, and may be administered once a day or dividedly administered several times a day.
  • Idasanutlin can be administered in an amount of about 400 to about 1200 mg per day.
  • idasanutlin is the patient's body In a dose of about 30 mg per m 2 of surface area to about 617 mg per m 2 of patient body surface area, e.g., about 90 mg/m 2 to about 370 mg/m 2 , e.g., about 185 mg/m It can be administered in an amount of 2.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a murine double minute 2 (MDM2) inhibitor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a combination thereof, an Fms-like tyrosine kinase (FLT3) inhibitor, It provides a pharmaceutical composition for the treatment of acute myeloid leukemia (AML) used in combination with a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • MDM2 murine double minute 2
  • FLT3 Fms-like tyrosine kinase
  • the pharmaceutical composition according to an embodiment may further include one or more optional pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, lubricants, and any combination thereof.
  • the additives are any substances known to those skilled in the art to be useful in the preparation of formulations, and can be adjusted as needed, for example, according to the mode of administration of the drug.
  • Another aspect is a FLT3 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, and an MDM2 inhibitor, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient, wherein The two active ingredients are administered simultaneously, sequentially or separately, to provide a pharmaceutical combination for the treatment of acute myelogenous leukemia (AML).
  • AML acute myelogenous leukemia
  • the dosage of the pharmaceutical combination according to one embodiment, or the dosage or therapeutically effective amount of the FLT3 inhibitor and the MDM2 inhibitor in the combination 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 dosage may be administered as a single dose or divided doses, or, in the case of parenteral administration, may be given as continuous infusion.
  • the FLT3 inhibitor and the MDM2 inhibitor 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 if necessary.
  • Another aspect provides a pharmaceutical kit, wherein the pharmaceutical composition or combination is administered simultaneously, sequentially or separately.
  • the two active ingredients may be included in any amount for use simultaneously, sequentially, or separately.
  • Another aspect provides a pharmaceutical combination comprising an FLT3 inhibitor, or any pharmaceutically acceptable salt or hydrate thereof, and an MDM2 inhibitor, or any pharmaceutically acceptable salt or hydrate thereof.
  • the combination includes the FLT3 inhibitor and the MDM2 inhibitor in the form of a salt or hydrate formed from two components. For example, the formation of the salt can be partially or completely.
  • compositions comprising a FLT3 inhibitor, or a pharmaceutically acceptable salt, or a solvate or hydrate thereof, and an MDM2 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, as an active ingredient.
  • a method of treating a subject suffering from acute myeloid leukemia (AML) is provided.
  • the two active ingredients may be administered simultaneously, sequentially or separately.
  • the treatment method according to an embodiment provides a treatment method for acute myeloid leukemia having FLT3 mutation using the composition.
  • 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.
  • ITD FLT3 gene
  • FLT3 inhibitor or any pharmaceutically acceptable salt or hydrate thereof, used in the manufacture of a drug for treating acute myelogenous leukemia (AML), and an MDM2 inhibitor, or any pharmaceutically acceptable salt thereof. Or a combination comprising a hydrate as an active ingredient.
  • AML acute myelogenous leukemia
  • MDM2 inhibitor or any pharmaceutically acceptable salt thereof.
  • a combination comprising a hydrate as an active ingredient.
  • the combination therapy of the FLT3 inhibitor and the MDM2 inhibitor using the composition, combination, or kit according to an embodiment has an improved therapeutic effect compared to the effect of administering the FLT3 inhibitor or the MDM2 inhibitor alone.
  • the therapeutic effect according to one embodiment shows a synergistic therapeutic effect of more than the arithmetic sum of two or more drugs in combination.
  • therapeutically effective amount is an amount of a compound that, when administered in combination to a subject or patient, treats acute myeloid leukemia.
  • 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 therapeutically effective amount may be a combination amount of one or both of the FLT3 inhibitor or the MDM2 inhibitor administered as a sub-therapeutic effective amount or dose, but to treat acute myelogenous leukemia.
  • a sub-therapeutic effective amount, when administered to a patient alone, is an amount of a compound that does not completely inhibit the biological activity of the intended target over time.
  • 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 that begins when one of the compounds is administered to a patient and ends at the limit of administration of the other compound, where the benefit of co-administration of the two compounds is 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.
  • combination refers to a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.
  • “Fixed combination” herein is used as known to those skilled in the art, for example, the first active ingredient, such as the FLT3 inhibitor and the additional active ingredient, the MDM2 inhibitor is administered in one unit It is defined as a combination that exists together in quantities or as a single entity.
  • a “fixed combination” is a pharmaceutical composition in which the first active ingredient and the additional active ingredient are present in a mixture for simultaneous administration, such as as a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination in which the first active ingredient and the additional active ingredient are not present as a mixture, but as a unit.
  • a fixed combination means that any compound as an active ingredient and its combination partner are both administered to a patient simultaneously in the form of a single entity or dosage.
  • Non-fixed combination herein is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the additional active ingredient are present in more than one unit.
  • an unfixed combination is a combination in which the first active ingredient and the additional active ingredient are present separately. It is possible for the components of the non-fixed combination to be administered individually, sequentially, simultaneously, jointly or at a staggered time.
  • a non-fixed combination means that any compound as an active ingredient and a combination partner are both administered to a patient at the same time as separate individuals, in combination, or sequentially without specific time restrictions.
  • the active ingredients or compounds included in the combination may be formulated in two, three, or more separate pharmaceutical compositions.
  • one or more active ingredients in the combination may be independently formulated as a composition for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous or rectal administration.
  • one or more other active ingredients in the combination are independently formulated into a composition for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous or rectal administration.
  • composition often refers to a pharmaceutical product comprising a therapeutically effective amount of a particular ingredient, as well as any product that results directly or indirectly from a combination of certain ingredients in a certain amount.
  • a composition or pharmaceutical composition means a mixture comprising at least one compound and at least one, pharmaceutically acceptable component, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, or excipient.
  • subject encompasses mammals and non-mammals, including humans.
  • mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs; Includes, but is not limited to, rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • salt refers to a pharmaceutically acceptable derivative of the disclosed compound, wherein the parent compound is modified by converting an acid or base moiety present into its salt form.
  • solvent compound as used herein is used to describe a molecular complex, and may exist as a compound according to the present invention and one or more pharmaceutically acceptable solvent molecules, for example ethanol Contains the stoichiometric amount of.
  • solvent molecules for example ethanol Contains the stoichiometric amount of.
  • hydrate is used when the solvent is water.
  • treating include limiting, delaying, arresting, reducing or reversing the progression or severity of an existing symptom, disease, condition or disease. do.
  • 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 (hereinafter Compound A) and 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4- (4-Chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-benzoic acid (hereinafter It was confirmed whether the combined effect of the two drugs by inhibiting the growth of the MOLM-13 (DSMZ no.
  • MOLM-13 cells were diluted with a culture medium to 30 nM, which is a concentration (GI 40 ) that inhibits the growth of about 40%, and then cultured for 3 days after simultaneous treatment with Compound A or treatment alone.
  • CCG CellTiter-Glo® test was performed to measure the viability of cells, and a 50% growth inhibition value (GI 50 ) for cell growth was calculated using GraphPad Prism software for analysis of the results. The results are shown in Table 3 and FIG. 1.
  • Table 3 below shows the data on the MOLM-13 cell growth inhibitory effect by treatment with Compound A alone or in combination with Idasanutlin.
  • MOLM-13 cell line subcutaneously transplanted mouse model
  • MOLM-13 cell line was inoculated subcutaneously into NOD/SCID mice with 5 ⁇ 10 6 cells/0.1 mL/mouse and allowed to grow.
  • Idasanutlin group, an MDM2 inhibitor was administered orally once a day at a dose of 30 mg/kg/day.
  • Compound A was administered orally once a day at a dose of 15 mg/kg/day, and the MDM2 inhibitor was orally administered once a day at a dose of 30 mg/kg/day.
  • Each group received individual medications for 28 days.
  • FIG. 2 shows the antitumor effect when a combination of a FLT3 inhibitor and an MDM2 inhibitor was administered in NOD/SCID mice xenografted with MOLM-13 cell line.
  • the Y-axis represents the tumor volume (mm 3 ) of the surviving mice in each group, and the X-axis represents the number of days of administration.
  • the result of complete response (CR) in which the tumor was completely disappeared was confirmed.
  • Figure 2 as a result of measuring and confirming the tumor volume according to the drug administration, a complete response in the combination group appeared on the 7th day.
  • the result showed a more excellent anti-tumor efficacy by significantly reducing the tumor volume in the group administered with the MDM2 inhibitor alone, the Idasanutlin group and the group administered with the compound A alone.
  • the FLT3 inhibitor 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4- It can be seen that the combination of (6-methyl-1H-indol-3-yl)pyrimidin-2-amine and Idasanutlin, an MDM2 inhibitor, shows an improved antitumor effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne : une composition pharmaceutique pour le traitement De la leucémie aiguë myéloïde (LAM), la composition pharmaceutique contenant une combinaison thérapeutiquement efficace d'un inhibiteur de la tyrosine kinase-3 de type FMS (FLT-3), d'un sel pharmaceutiquement acceptable de celui-ci ou d'un solvate de celui-ci, et d'un inhibiteur double de murine double minute 2 (MDM2), d'un sel pharmaceutiquement acceptable de celui-ci ou d'un solvate de celui-ci ; et un procédé de traitement de la leucémie aiguë myéloïde mettant en œuvre ladite composition.
PCT/KR2020/013188 2019-09-30 2020-09-28 Composition pharmaceutique pour le traitement de la leucémie aiguë myéloïde contenant un inhibiteur de flt3 et un inhibiteur de mdm2 Ceased WO2021066443A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20190120540 2019-09-30
KR10-2019-0120540 2019-09-30

Publications (1)

Publication Number Publication Date
WO2021066443A1 true WO2021066443A1 (fr) 2021-04-08

Family

ID=75338305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/013188 Ceased WO2021066443A1 (fr) 2019-09-30 2020-09-28 Composition pharmaceutique pour le traitement de la leucémie aiguë myéloïde contenant un inhibiteur de flt3 et un inhibiteur de mdm2

Country Status (2)

Country Link
KR (1) KR20210038366A (fr)
WO (1) WO2021066443A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116583275A (zh) * 2020-09-21 2023-08-11 诺华股份有限公司 用于治疗或预防造血细胞移植后血液肿瘤复发的mdm2抑制剂
US12325698B2 (en) 2018-07-25 2025-06-10 Hanmi Pharm. Co., Ltd. Pyrimidine compounds and pharmaceutical compositions for preventing or treating cancers including the same
US12350265B2 (en) 2019-06-27 2025-07-08 Hanmi Pharm. Co., Ltd. Pharmaceutical composition for treating acute myeloid leukemia, containing FLT3 inhibitor and chemotherapeutic agents
US12433867B2 (en) 2019-02-22 2025-10-07 Hanmi Pharm. Co., Ltd. Pharmaceutical composition comprising FLT3 inhibitor and hypomethylating agent for treating acute myeloid leukemia

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006075152A1 (fr) * 2005-01-11 2006-07-20 Cyclacel Limited Derives de 4-(1h-indol-3-yl)-pyrimidin-2-ylamine et leur utilisation a des fins therapeutiques
KR20170101908A (ko) * 2014-11-05 2017-09-06 인벤티스바이오 상하이 리미티드 피리미딘 또는 피리딘계 화합물, 이의 제조방법 및 약학적 용도
KR20170123602A (ko) * 2015-02-20 2017-11-08 다이이찌 산쿄 가부시키가이샤 암의 병용 치료법
KR20180117710A (ko) * 2016-03-15 2018-10-29 오리존 지노믹스 에스.에이. 혈액 악성 종양의 치료를 위한 lsd1 억제제의 조합물
KR101954370B1 (ko) * 2018-07-25 2019-03-05 한미약품 주식회사 피리미딘 화합물 및 이를 포함하는 암의 예방 또는 치료용 약학 조성물
KR20190084292A (ko) * 2016-11-15 2019-07-16 노파르티스 아게 HDM2-p53 상호작용 억제제에 대한 용량 및 요법

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006075152A1 (fr) * 2005-01-11 2006-07-20 Cyclacel Limited Derives de 4-(1h-indol-3-yl)-pyrimidin-2-ylamine et leur utilisation a des fins therapeutiques
KR20170101908A (ko) * 2014-11-05 2017-09-06 인벤티스바이오 상하이 리미티드 피리미딘 또는 피리딘계 화합물, 이의 제조방법 및 약학적 용도
KR20170123602A (ko) * 2015-02-20 2017-11-08 다이이찌 산쿄 가부시키가이샤 암의 병용 치료법
KR20180117710A (ko) * 2016-03-15 2018-10-29 오리존 지노믹스 에스.에이. 혈액 악성 종양의 치료를 위한 lsd1 억제제의 조합물
KR20190084292A (ko) * 2016-11-15 2019-07-16 노파르티스 아게 HDM2-p53 상호작용 억제제에 대한 용량 및 요법
KR101954370B1 (ko) * 2018-07-25 2019-03-05 한미약품 주식회사 피리미딘 화합물 및 이를 포함하는 암의 예방 또는 치료용 약학 조성물

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12325698B2 (en) 2018-07-25 2025-06-10 Hanmi Pharm. Co., Ltd. Pyrimidine compounds and pharmaceutical compositions for preventing or treating cancers including the same
US12433867B2 (en) 2019-02-22 2025-10-07 Hanmi Pharm. Co., Ltd. Pharmaceutical composition comprising FLT3 inhibitor and hypomethylating agent for treating acute myeloid leukemia
US12350265B2 (en) 2019-06-27 2025-07-08 Hanmi Pharm. Co., Ltd. Pharmaceutical composition for treating acute myeloid leukemia, containing FLT3 inhibitor and chemotherapeutic agents
CN116583275A (zh) * 2020-09-21 2023-08-11 诺华股份有限公司 用于治疗或预防造血细胞移植后血液肿瘤复发的mdm2抑制剂

Also Published As

Publication number Publication date
KR20210038366A (ko) 2021-04-07

Similar Documents

Publication Publication Date Title
WO2021066443A1 (fr) Composition pharmaceutique pour le traitement de la leucémie aiguë myéloïde contenant un inhibiteur de flt3 et un inhibiteur de mdm2
WO2020171646A1 (fr) Composition pharmaceutique comprenant un inhibiteur flt3 et un agent hypométhylant pour le traitement de la leucémie myéloïde aiguë
WO2020171649A1 (fr) Combinaison pharmaceutique comprenant un inhibiteur flt3 et un antagoniste iap pour le traitement de la leucémie myéloïde aiguë
WO2020262974A1 (fr) Composition pharmaceutique pour le traitement de la leucémie myéloïde aiguë contenant un inhibiteur de flt3 et des agents de chimiothérapie
WO2021177721A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer présentant une mutation kras et l'activation de ron
CN1165482A (zh) 用作蛋白激酶抑制剂的吡唑药物组合物
CN107428729A (zh) 用于治疗癌症的化合物
JP2005511540A (ja) インドリノン化合物を用いる急性骨髄性白血病の治療
CN101522026A (zh) 蛋白激酶抑制剂及其应用方法
WO2022098083A1 (fr) Composition pharmaceutique pour le traitement de la leucémie comprenant un inhibiteur de flt3
TW200529846A (en) 3-quinolinecarbonitrile protein kinase inhibitors
WO2023068858A1 (fr) Combinaison thérapeutiquement efficace d'un inhibiteur de flt3 et d'un inhibiteur de bcl-2 pour le traitement de la leucémie aiguë myéloïde
NO325454B1 (no) Anvendelse av N-{5-[4-(4-metyl-piperazino-metyl)-benzoylamido]-2-metylfenyl}-4-(3-pyridyl)-2-pyrimidin-amin.
US20170007615A1 (en) Antibacterial Compounds
WO2020141828A2 (fr) Compositions anticancéreuses comprenant des inhibiteurs de points de contrôle immunitaires
CN105793421A (zh) 耐性突变型90kDa热休克蛋白质
WO2017023047A1 (fr) Composition pour la prévention ou le traitement d'une maladie inflammatoire ou du cancer contenant de l'aripiprazole en tant qu'ingrédient actif
WO2016159575A9 (fr) Composition pour inhiber la croissance ou la prolifération de cellules souches cancéreuses de la leucémie myélogène chronique, et procédé de criblage associé
WO2019035522A1 (fr) Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de triazolopyridine comme principe actif
WO2023063751A1 (fr) Composés inhibant les kinases de mutation alk et/ou egfr et leur utilisation médicale
WO2021182903A1 (fr) Composition comprenant un inhibiteur de kinase pi3 et un inhibiteur de btk
WO2021085888A1 (fr) Nouveau dérivé de pyrimidine à substitution hétérocyclique présentant un effet inhibiteur de la croissance des cellules cancéreuses, et composition pharmaceutique le contenant
WO2020111325A1 (fr) Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de l'activation de plk1 en tant que principe actif
WO2019112381A1 (fr) Composition comprenant un inhibiteur de kinase pi3 et un inhibiteur de bcl-2
WO2024242360A1 (fr) Agent thérapeutique contre le cancer à médiation par alk

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20872356

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20872356

Country of ref document: EP

Kind code of ref document: A1