WO2022098083A1 - Flt3 억제제를 포함하는 백혈병 치료용 약학적 조성물 - Google Patents

Flt3 억제제를 포함하는 백혈병 치료용 약학적 조성물 Download PDF

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WO2022098083A1
WO2022098083A1 PCT/KR2021/015794 KR2021015794W WO2022098083A1 WO 2022098083 A1 WO2022098083 A1 WO 2022098083A1 KR 2021015794 W KR2021015794 W KR 2021015794W WO 2022098083 A1 WO2022098083 A1 WO 2022098083A1
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flt3
pharmaceutical composition
methyl
leukemia
compound
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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 US18/251,827 priority Critical patent/US20260102397A1/en
Priority to EP21889548.0A priority patent/EP4241773A4/en
Priority to CA3197836A priority patent/CA3197836A1/en
Priority to CN202180084028.6A priority patent/CN116583284A/zh
Priority to JP2023527016A priority patent/JP7842752B2/ja
Publication of WO2022098083A1 publication Critical patent/WO2022098083A1/ko
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a pharmaceutical composition for the treatment of leukemia comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor and a pharmaceutically acceptable excipient.
  • FLT3 Fms-like tyrosine kinase-3
  • Kinases mediate the transfer of phosphate groups of high-energy molecules, particularly ATP, to substrates. Kinases are responsible for stabilizing phosphate anhydride bonds and increasing the reaction rate by locating substrates and phosphate groups at specific positions. In most cases, the transition state resulting from interaction with a negatively charged phosphate group is electrostatically stabilized through positively charged surrounding amino acids, and some kinases use metal cofactors to coordinate with a phosphate group.
  • Kinases can be divided into various groups, such as protein kinases, lipid kinases, and carbohydrate kinases, according to their substrates and properties. Proteins, lipids, or carbohydrates may change their activity, reactivity, and ability to bind other molecules depending on their phosphorylation state. Kinases have a wide range of effects on intracellular signal transduction and regulate complex biological mechanisms inside cells. The activity of some molecules may be enhanced or inhibited through phosphorylation, and their ability to interact with other molecules may be modulated. Because many kinases respond to environmental conditions or signals, cells can control molecules within the cell depending on context through kinases. Therefore, kinases play a very important role in cell growth, differentiation, proliferation, survival, metabolism, signal transduction, cell transport, secretion, and numerous other cellular response pathways.
  • kinases are found in a variety of species from bacteria to fungi, insects and mammals, and more than 500 kinases have been discovered in humans to date.
  • Protein kinases can increase or decrease the activity of proteins, stabilize them or mark them for degradation, localize them in specific cellular compartments, and initiate or disrupt interactions with other proteins. Protein kinases are known to account for most of the total kinases, and have been an important research subject. Protein kinases, together with phosphatase, play a role in regulating proteins and enzymes as well as in cell signaling. Cellular proteins are subjected to numerous covalent bonds, but there are not many reversible covalent bonds like phosphorylation, so protein phosphorylation plays a regulatory role. It can be described as having Protein kinases often have multiple substrates, and sometimes a specific protein may act as a substrate for more than one kinase.
  • protein kinases are named using factors that regulate their own activity. For example, calmodulin-dependent protein kinases are regulated by calmodulin. Sometimes kinases are divided into subgroups. For example, type 1 and type 2 cyclic AMP-dependent protein kinases are composed of the same enzymatic subunit, but different regulatory subunits are regulated by binding to cyclic AMP.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups located at tyrosine, serine, and threonine residues of proteins, and play an important role in growth factor signaling leading to cell growth, differentiation and proliferation (Melnikova, I. et al . al ., Nature Reviews Drug Discovery, 3 (2004), 993), it has been reported that abnormal expression or mutation of specific kinases in cancer cells is frequent.
  • RTK Receptor tyrosine kinase
  • the extracellular part of the receptor is a part to which a specific ligand binds, and the intracellular part performs the function of transmitting the activation signal of the receptor activated by the ligand into the cell.
  • Receptor tyrosine kinase has a domain having tyrosine kinase activity at the C-terminal portion exposed in the cell, and when a specific ligand is attached to the extra-longitudinal portion, it is a kinase enzyme of the C-terminal tyrosine kinase domain exposed to the cytoplasmic portion of the receptor protein. is activated, and phosphorylates tyrosine at the C-terminus of each other on the duplex. The phosphorylation process of tyrosine is the most important process in which a signal for extracellular stimuli is transmitted into the cell. Receptors having tyrosine kinase activity to deliver extracellular stimuli into cells with such a mechanism are well known. Representative examples include FLT3, VEGFR, SYK, and the like.
  • the receptor tyrosine kinase FMS-like tyrosine kinase FMS-like tyrosine kinase (Fms-like tyrosine kinase 3: FLT3) is normally expressed in hematopoietic progenitor cells by hematopoietic cells, and plays an important role in the expression of normal stem cells and the immune system. .
  • FLT3 the receptor tyrosine kinase FMS-like tyrosine kinase FMS-like tyrosine kinase
  • FLT3 the receptor tyrosine kinase FMS-like tyrosine kinase
  • AML Acute myeloid leukemia
  • FLT3 has recently been considered as one of the most important targets from the therapeutic point of view of AML.
  • FLT3 gene mutations are found in approximately 30% of adult AML.
  • the most representative problem in AML is that mutations in FLT3 that cause a poor prognosis are activated.
  • FLT3 mutations are largely classified into two types. One is internal tandem duplications (ITD) in the juxtamembrane region, and the other is a point mutation in the tyrosine kinase domain (TKD).
  • ITD internal tandem duplications
  • TKD tyrosine kinase domain
  • FLT3-ITD the most frequently detected mutation, is activated in about 23% of patients with early AML. Patients with ITD mutations have a poor prognosis and a high recurrence rate.
  • FLT3 TKD FLT3 TKD mutation
  • the point mutation in the residue of aspartate 835 (D835), which is replaced by various amino acids, is one of the most common mutations, although less common than the ITD mutation.
  • another major activation method of FLT3 in AML is overexpression of wild type FLT3 protein.
  • FLT3-ITD is a driver lesion that plays a causative role in malignancy, and can be an effective therapeutic target in human AML (Non-Patent Document 1).
  • Mutation of the FLT3 gene is a frequent phenomenon in AML, and usually involves point mutation of the juxtamembrane domain coding region (ITD) or tyrosine kinase domain (TKD).
  • FLT3-ITD mutations and FLT3-TKD mutations cause ligand-independent proliferation due to component dimerization and activation of the FLT3 receptor.
  • a high mutation rate compared to the wild-type allele of FLT3-ITD is associated with a very poor prognosis in both adults and children (Non-Patent Document 2).
  • Other types of leukemia such as chronic myelomonocytic leukemia (CMML), may also carry activating mutations in FLT3. Therefore, FLT3 having an activating mutation is an important target for several cancer types (Non-Patent Document 3 and Non-Patent Document 4).
  • TKD mutations have been reported as various acquired resistances in the analysis of patients with refractory/relapsed acute myeloid leukemia to already approved drugs or FLT3 inhibitors under development.
  • Representative examples include K429A mutation in receptor domain (RD), Y572C in JM domain, A627P, N676K/D/I/S, F691L in TK1 domain, and D835Y/F/I/H/V/A, Y842C/ in TK2 domain. H/N, etc.
  • F691L is the most important acquired resistance in the analysis of resistance patients in FLT3 inhibitor clinical trials, and in the case of F691L, it is a gatekeeper mutation that can inhibit drug activity. Therefore, the development of a drug that can target F691L alone or a double mutation of ITD-F691L is considered unmet medical care (Non-Patent Document 6).
  • Spleen tyrosine kinase which is mainly expressed in blood cells, plays an important role in signaling pathways of B-cell receptors and other immune receptors such as mast cells. Splenic tyrosine kinase is also expressed in non-hematopoietic cells such as neurons and vascular endothelial cells. Recent studies have demonstrated that IL-1, TNF- ⁇ , and ITGB1 play an important role in the oxidation of various cellular stimuli including ITGB1. SYK is known as a potentially good target in various hematologic malignancies, autoimmune diseases, and other inflammatory reactions (Non-Patent Document 7 and Non-Patent Document 8).
  • Non-Patent Document 1 Catherine et al ., Nature, 2012, 485, 260-263
  • Non-Patent Document 2 AS Moore et al ., Leukemia, 2012, 26, 1462-1470
  • Non-Patent Document 3 Cancer Cell, (2007), 12: 367-380
  • Non-Patent Document 4 Current Pharmaceutical Design (2005), 11, 3449-3457
  • Non-Patent Document 5 H Kiyoi et al ., Cancer Science (2020), 111, 312
  • Non-Patent Document 6 Christine et al ., Cancer Discovery , 9, (2019), 1050
  • Non-Patent Document 7 Liu et al ., Journal of Hematology & Oncology (2017), 10, 145
  • Non-Patent Document 8 Yamada T et al ., J. Immunol., (2001) 167, 283-288
  • One aspect of the present invention is to provide a pharmaceutical composition for the treatment of leukemia comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor and a pharmaceutically acceptable excipient.
  • FLT3 Fms-like tyrosine kinase-3
  • Another aspect of the present invention is to provide a pharmaceutical use for the treatment of cancer having an F691L acquisition mutation according to the aspect.
  • One aspect of the present invention provides a pharmaceutical composition for the treatment of leukemia comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor and a pharmaceutically acceptable excipient.
  • FLT3 Fms-like tyrosine kinase-3
  • Another aspect of the present invention provides a pharmaceutical use for the treatment of cancer having an F691L acquisition mutation according to the above aspect.
  • One embodiment is a pharmaceutical composition
  • a pharmaceutical composition comprising an Fms-like tyrosine kinase-3 (FLT3) inhibitor and a pharmaceutically acceptable excipient,
  • the FLT3 inhibitor is at least one compound selected from the group consisting of a compound of Formula 1 below, a stereoisomer thereof, a tautomer thereof, and a combination thereof;
  • the pharmaceutical composition is a pharmaceutical composition for the treatment of leukemia, wherein the leukemia cancer cells have an internal tandem duplication (ITD) mutation in the FLT3 gene,
  • composition further comprising at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V and D835A.
  • the leukemia is acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the pharmaceutical composition may be administered concurrently or sequentially with the SYK inhibitor.
  • the term “simultaneous” administration refers to the administration of two or more components simultaneously or substantially simultaneously by the same route, and when administered substantially simultaneously, the route of administration may be the same or different.
  • the term “sequential” administration refers to administration of two or more components at different times, and the administration route may be the same or different.
  • Another embodiment of the pharmaceutical composition comprising the FLT3 inhibitor is as follows.
  • R 1 is hydrogen, halogen, hydroxy, C 1-4 alkoxy or —NR a R b ego,
  • R a and R b are each independently hydrogen or C 1-4 alkyl
  • R 2 is hydrogen, halogen, cyano, nitro, amino, carboxamide, formyl, haloC 1-4 alkyl or C 1-4 alkyl;
  • R 3 is hydrogen, halogen, hydroxy, haloC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • R c is C 1-4 alkyl or —NR d R e ,
  • R d and R e is each independently hydrogen or C 1-4 alkyl
  • l is an integer from 0 to 2;
  • k is an integer from 0 to 4.
  • R 5 and each R 6 is independently hydrogen, halogen, hydroxy, nitro, amino, C 1-4 alkoxy or C 1-4 alkyl;
  • R 7 is hydroxyC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl or C 3-9 heterocycloalkyl;
  • C 3-7 cycloalkyl or C 3-9 heterocycloalkyl may be unsubstituted or substituted with halogen, C 1-4 alkyl or haloC 1-4 alkyl;
  • X is H or OH
  • the compound of formula (A) may comprise a tautomeric structure such as the following formula (B),
  • R 3 , R 4 , and k are as defined in formula (A);
  • Y is -(CH 2 ) m -, -(CH 2 ) m -O-(CH 2 ) n -, -(CH 2 ) m -CO-(CH 2 ) n -, -(CH 2 ) m -NR 8 -(CH 2 ) n - or -(CH 2 ) m -SO 2 -(CH 2 ) n -;
  • R 8 is hydrogen or C 1-4 alkyl
  • n are each independently an integer from 0 to 2;
  • Z is a structure of formula (C);
  • R 9 is halogen, hydroxy, cyano, nitro, amino, thiol, formyl, haloC 1-4 alkyl, C 1-4 alkoxy, straight-chain or branched hydroxyC 1-4 alkyl, straight-chain or branched C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, hydroxyC 2-9 heterocycloalkyl, straight chain or branched hydroxyC 1-4 alkylcarbonyl, -NR 10 R 11 , -COR 12 , -COOR 12 or -SO 2 R 13 ,
  • q is an integer from 0 to 5
  • step, q is not 0 when is piperazinyl or piperidine;
  • R 9 are connected to each other or can be fused with 7 to 12 membered bicycloalkyl, heterobicycloalkyl, spirocycloalkyl, or spiroheterocycloalkyl;
  • R 10 and R 11 are each independently hydrogen, hydroxy C 1-4 Alkyl, HaloC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl or C 2-4 is alkynyl;
  • R 12 is hydrogen, hydroxy, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl or C 2-9 heterocycloalkyl;
  • R 13 is hydroxy, haloC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, aryl or -NR f R g ,
  • R f and each R g is independently hydrogen or C 1-4 alkyl.
  • a compound of the following formula (D), a stereoisomer, a tautomer, a solvate, and a pharmaceutically acceptable salt thereof may be included as an active ingredient.
  • 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 0 to 4.
  • each Q is independently of the 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 (E);
  • n is an integer of 1 to 8.
  • Each substituent A is independently a functional group selected from hydroxy, C 1-4 alkyl and hydroxyC 1-4 alkyl, wherein, when n is 2 or more, two A of n are linked to each other to form an alkyl group
  • Z' forms a 7 to 12 membered bridged heterobicycloalkyl ring, or two A's are linked by spiro to form a 7 to 12 membered spiroheterocycloalkyl ring can form;
  • L is hydrogen, C 1-4 alkyl, hydroxy or hydroxyC 1-4 alkyl.
  • a pharmaceutical composition comprising the compound in (2) above, wherein E b is halogen, n is 2, and A is methyl.
  • a pharmaceutical composition comprising a compound in (2) above, wherein E b is chlorine or fluoro.
  • the compound of formula A is a pharmaceutical composition comprising a compound selected from the group consisting of:
  • the pharmaceutical composition further comprising a pharmaceutically acceptable additive.
  • the pharmaceutical composition according to (8), wherein the leukemia is acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.
  • a pharmaceutical composition for the treatment of cancer having a mutation in the tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence In (1) or (2) above, a pharmaceutical composition for the treatment of cancer having a mutation in the tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence.
  • TKD tyrosine kinase domain
  • composition according to (14), wherein the cancer is acute myeloid leukemia (AML) having F691L alone or ITD-F691L double mutation.
  • AML acute myeloid leukemia
  • FLT3 herein is a member of the class III receptor tyrosine kinase (TK) family that is commonly expressed on the surface of hematopoietic stem cells. FLT3 and its ligands play important roles in proliferation, survival and differentiation of pluripotent stem cells. FLT3 is expressed in many AML cases.
  • activated FLT3 with intragenic tandem duplication (ITD) in and around the proximal domain and tyrosine kinase domain (TKD) mutations near D835 in the activation loop are 28% to 34% and 11% to 11% of AML cases, respectively. present at 14%. These activating mutations in FLT3 are tumorigenic and exhibit transforming activity in cells.
  • cancer is a leukemia such as acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), and the like.
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • APL acute promyelocytic leukemia
  • hairy cell leukemia chronic neutrophilic leukemia
  • CCL chronic neutrophilic leukemia
  • the cancer may be leukemia.
  • the leukemia may include acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.
  • Acute myeloid leukemia herein includes acute myeloid leukemia with a FLT3 mutation.
  • the acute myeloid leukemia comprises a mutant FLT3 polynucleotide-positive myeloid leukemia, a longitudinal duplication (ITD) positive acute myeloid leukemia in the FLT3 gene, or an acute myeloid leukemia having a FLT3 point mutation.
  • the FLT3 point mutation may be a mutation in a tyrosine kinase domain (TKD) (FLT3-TKD) region of the FLT3 amino acid sequence.
  • TKD tyrosine kinase domain
  • “Pharmaceutically acceptable” as used herein generally refers to a composition or component of a composition that is non-toxic, inert, and/or physiologically compatible.
  • “Pharmaceutical excipient” or “excipient” includes substances such as adjuvants, carriers, pH-adjusting and buffering agents, isotonicity adjusting agents, wetting agents, preservatives, and the like.
  • “Pharmaceutical excipient” is a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may include conventional pharmaceutically acceptable excipients or additives.
  • the pharmaceutical composition of the present invention can be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral administration such as intramuscular, intravenous or subcutaneous administration can be prepared in dosage form.
  • examples of carriers, additives, and excipients used include diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers.
  • the carrier or additive or excipient includes water, saline, aqueous glucose solution, similar sugar solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, and fatty acid esters, glycerides, surfactants, suspending agents, or emulsifiers.
  • Such formulation methods are well known to those skilled in the art of pharmaceuticals.
  • the compound of Formula A or Formula 1 is an effective amount for treatment or prevention of an individual or patient, and may be administered orally or parenterally as desired, and when administered orally, the active ingredient For parenteral administration, 1 body weight per day based on the active ingredient so as to be administered in an amount of, for example, 0.01 to 1000 mg, 0.01 to 500 mg, 0.1 to 300 mg, or 0.1 to 100 mg per 1 kg of body weight per day as a standard
  • the composition may be administered in 1 to several divided doses.
  • the dose to be administered to a specific individual or patient should be determined in light of several related factors such as the patient's weight, age, sex, health condition, diet, administration time, administration method, and disease severity, and can be appropriately adjusted or decreased by a specialist. It should be understood that the above dosage is not intended to limit the scope of the present invention in any way.
  • Another aspect of the present invention provides a method for preventing or treating cancer using the pharmaceutical composition.
  • the dosage, the frequency of administration, or the administration method of the compound used in the treatment method may vary depending on the subject to be treated, the severity of the disease or condition, the rate of administration, and the judgment of the prescribing physician.
  • the dosage for a person weighing 70 kg may be administered in an amount of 0.1 to 2,000 mg, for example, 1 to 1,000 mg or 10 to 2,000 mg per day.
  • the frequency of administration may be 1 to several times, for example, 1 to 4 times, or an on/off schedule may be administered, and the administration method may be administered through an oral or parenteral route.
  • dosages lower than the aforementioned ranges may be more suitable, higher dosages may be used without producing deleterious side effects, and higher dosages may be divided into several smaller dosages throughout the day.
  • a physician having ordinary skill in the related art can easily determine and prescribe the dosage of the compound to be used as needed. For example, a physician may start a dose of a compound of the present invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.
  • the method of treatment may use the compound according to an aspect of the present invention as an active ingredient alone or in combination with one or more other agents or pharmaceutical carriers known for treating cancer, tumor or leukemia.
  • the compound of Formula A or Formula 1, a compound selected from stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof is an agent for inhibiting other FLT3 kinase activity or efficacy of inhibiting FLT3 kinase activity
  • co-administering it with other drugs with various mechanisms that increase or decrease the level of synergism it is possible to decrease FLT3 activity or enhance the therapeutic effect of FLT3-mediated diseases.
  • treatment is used as a concept including all treatment, improvement, amelioration, or management of a disease.
  • treating or “treatment” refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, pathology. and/or preventing further occurrence of symptoms, ameliorating the disease, or reversing the pathology and/or symptoms, such as reducing disease severity.
  • preventing refers to preventing a disease, e.g., a disease in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease; To prevent a condition or disorder.
  • the term “subject” or “patient” refers to any animal, including mammals, eg, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. .
  • the terms “have”, “may have”, “comprises”, or “may include” indicate the presence of a corresponding characteristic (eg, a numerical value or a component such as a component), The presence of additional features is not excluded.
  • the pharmaceutical composition according to an aspect of the present invention has excellent FLT3 inhibitory activity, it can be effectively used for the prevention or treatment of cell proliferative diseases caused by abnormal FLT3 activity, such as cancer, eg, leukemia.
  • the pharmaceutical composition may be used for the treatment of cancer, including leukemia having an F691L acquisition mutation.
  • 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) was measured for inhibitory activity against wild-type or mutant FLT3 and SYK.
  • LanthaScreen test method wild-type and mutant FLT3 or Z'-LYTE test method (SYK) developed by Thermo Fisher Scientific.
  • LanthaScreen assay is based on the binding of Alexa Fluor 647-labeled, ATP-competitive kinase inhibitor (kinase tracer-236) to kinase, europium-conjugated antibody It is a method of measuring the activity of a protein by measuring a fluorescence resonance energy transfer (FRET) signal in the presence.
  • FRET fluorescence resonance energy transfer
  • the Z'-LYTE test method uses an enzyme capable of cleaving a non-phosphorylated substrate, and is a method to measure the activity of a kinase protein by measuring two fluorescence FRET signals attached to each end of a peptide substrate. Both experiments were performed in a 384 well plate under the conditions of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA, and 1% DMSO. A background signal is measured in the absence of each kinase, and after measuring by adding only a solvent (1% DMSO) as a non-inhibitory signal, the compound A to be evaluated is added at a set concentration (eg, 50 to 0.05 nM). . The results are shown in Table 1 below.
  • the binding ability of compound A to wild-type or mutant FLT3 was measured using DiscoverX's KINOMEscan screening platform.
  • the KINOMEscan test method is a method of quantitatively measuring the binding between a substance to be tested and a kinase using a competitive binding assay for the active site of a DNA-linked kinase enzyme using quantitative PCR. am.
  • the test was commissioned by DiscoverX, and the binding ability of the inhibitor to each wild-type or mutant FLT3 was calculated as the Kd value. The results are shown in Table 2 below.
  • the MOLM-14 FLT3-ITD/F691L cell line was subcutaneously injected into nude mice at 3 ⁇ 10 ⁇ 6 cells/0.15 mL/mouse and allowed to grow.
  • the gilteritinib group was orally administered once a day at a dose of 30 mg/kg/day.
  • the control group received individual drugs for 13 days, and the drug administration group received individual drugs for 18 days.
  • FIG. 1 shows the anti-tumor effect when the control group, Compound A and gilteritinib were administered to nude mice xenografted with MOLM-14 FLT3-ITD/F691L cell line.
  • the Y-axis represents the tumor volume (mm 3 ) of surviving mice in each group, and the X-axis represents the dosing days.
  • the result of complete response (CR) in which the tumor completely disappeared was confirmed.
  • FIG. 1 as a result of measuring and confirming the tumor volume according to drug administration, a complete response of Compound A appeared on the 12th day of administration.
  • FIG. 1 shows the anti-tumor effect when the control group, Compound A and gilteritinib were administered to nude mice xenografted with MOLM-14 FLT3-ITD/F691L cell line.
  • the Y-axis represents the tumor volume (mm 3 ) of surviving mice in each group
  • the X-axis represents the dosing days.

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PCT/KR2021/015794 2020-11-05 2021-11-03 Flt3 억제제를 포함하는 백혈병 치료용 약학적 조성물 Ceased WO2022098083A1 (ko)

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US18/251,827 US20260102397A1 (en) 2020-11-05 2021-11-03 Pharmaceutical composition for treating leukemia comprising flt3 inhibitor
EP21889548.0A EP4241773A4 (en) 2020-11-05 2021-11-03 PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF LEUKEMIA WITH FLT3 INHIBITOR
CA3197836A CA3197836A1 (en) 2020-11-05 2021-11-03 Pharmaceutical composition comprising for the treatment of myeloid leukemiea
CN202180084028.6A CN116583284A (zh) 2020-11-05 2021-11-03 用于治疗髓性白血病的包括flt3抑制剂的药物组合物
JP2023527016A JP7842752B2 (ja) 2020-11-05 2021-11-03 骨髄性白血病の治療のためのｆｌｔ３阻害剤を含む医薬組成物

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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

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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

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