WO2021112626A1 - Nouveau dérivé d'indirubine et son utilisation - Google Patents
Nouveau dérivé d'indirubine et son utilisation Download PDFInfo
- Publication number
- WO2021112626A1 WO2021112626A1 PCT/KR2020/017666 KR2020017666W WO2021112626A1 WO 2021112626 A1 WO2021112626 A1 WO 2021112626A1 KR 2020017666 W KR2020017666 W KR 2020017666W WO 2021112626 A1 WO2021112626 A1 WO 2021112626A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- biindolinylidene
- oxo
- imino
- amino
- acetamide
- Prior art date
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- CRDNMYFJWFXOCH-YPKPFQOOSA-N (3z)-3-(3-oxo-1h-indol-2-ylidene)-1h-indol-2-one Chemical class N/1C2=CC=CC=C2C(=O)C\1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-YPKPFQOOSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 66
- -1 cyano, hydroxy Chemical group 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 17
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the present invention relates to novel indirubin derivatives and their use as inhibitors of fms-like tyrosine kinase 3 (FLT3).
- FLT3 fms-like tyrosine kinase 3
- Fms-like tyrosine kinase 3 (fms-like tyrosine kinase 3; FLT3) is a protein belonging to class III of receptor-type tyrosine kinases, has five immnunoglobulin-like motifs in the N-terminal extracellular domain, and two kinases at the C-terminus. have a domain FLT3 is expressed on normal CD34-positive human bone marrow progenitor cells and dendritic progenitor cells, and plays an important role in proliferation and differentiation of these cells (Brown P et al., European Journal of Cancer, 40th, pp.707-721). , 2004).
- the ligand (FL) of FLT3 is expressed in bone marrow stromal cells and T cells, affects the cell development of a number of hematopoietic lines, and interacts with other growth factors such as hepatocytes, progenitor cells, dendritic cells and natural killer cells.
- FL ligand
- FLT3 is also known to be an acute myeloid leukemia (AML) target antigen, is overexpressed in blasts of AML patients when compared to healthy cells, and is expressed in the majority of patient cells (Carow et al, Feb 2, 1996 Blood: 87(3); Birg et al Nov 1992 Blood: 80(10))
- FLT3 is a frequently mutated gene in AML patients, and the mutation is associated with a poor prognosis (Abu-Duhier et al Br J Haematol 2000 Oct;111(1):190).
- Yamamoto et al April 15, 2001;Blood: 97 (8) small molecule FLT3 inhibitors showed activity in clinical trials; The response is usually transient due to the acquisition of resistance.
- kinase inhibitors are only effective in a subset of patients expressing a mutated form of FLT3, so there is still a need for improved therapeutic agents.
- novel indirubin derivative compounds can effectively inhibit FLT3, in particular, mutant FLT3, the present invention has been completed.
- An object of the present invention is to provide a novel indirubin derivative compound having FLT3 inhibitory ability, and a pharmaceutically acceptable salt thereof.
- the present invention also provides a pharmaceutical composition for preventing or treating FLT3-related diseases, including a novel indirubin derivative compound, use of the novel compound for preventing or treating FLT3-related diseases, and administering the novel compound to a subject in need thereof It is intended to provide a method for preventing or treating FLT3-related diseases, including the steps of:
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
- Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
- R5 and R6 are each independently hydrogen or C1-C6 alkyl
- Re and Rf is each independently hydrogen or C1-C6 alkyl.
- the compounds disclosed herein have high inhibitory activity against FLT3, particularly mutant FLT3.
- the compounds and pharmaceutical compositions disclosed herein are useful, for example, in preventing or treating FLT3-related diseases by administering the compounds or compositions to a subject.
- the indirubin derivative compound of the present invention is a novel compound that has not been previously known, and effectively inhibits the activity of FLT3, in particular, mutant FLT3, and thus can be usefully used for the prevention or treatment of mutant FLT3-associated diseases, particularly acute myeloid leukemia. .
- n-member typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n.
- pyridine is an example of a 6-membered heteroaryl ring
- thiophene is an example of a 5-membered heteroaryl ring.
- substituents are intended to include both substituted and unsubstituted instances.
- halo refers to bromo, chloro, fluoro, or iodo.
- alkyl is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms and includes saturated aliphatic groups, which may be straight chain, branched, or cyclic, or combinations thereof. do.
- an alkyl group may have 1 to 20 carbon atoms (ie, C1-C20 alkyl), 1 to 10 carbon atoms (ie, C1-C10 alkyl), or 1 to 6 carbon atoms (ie, C1-C6 alkyl).
- alkyl can have examples of suitable alkyl include methyl (Me, —CH 3 ), ethyl (Et, —C 2 H 5 ), 1-propyl (n-Pr, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, -CH 2 CH(CH 3 ) 2 ) , 2-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-Butyl (-CH(CH
- alkoxy refers to a group having -OR, wherein an alkyl group as defined above is attached to the parent compound through an oxygen atom.
- Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
- alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula -R-O-R'. wherein R and R' are each independently an alkyl group as defined above.
- the oxygen atom may be bonded to any carbon atom in the alkyl radical.
- amine refers to a substituted or unsubstituted group represented by the form -NRR'.
- Substituted amino wherein R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl groups.
- amino also includes the corresponding quaternary ammonium salts of any amino group, for example -[N(Rl)(Rm)(Rn)]+.
- amino groups include aminoalkyl groups in which at least one of Rl, Rm, or Rn is an alkyl group. In certain embodiments, R1 and Rm are hydrogen or alkyl.
- aryl includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic, or polycyclic.
- the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring.
- An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are aromatic, e.g., the other cyclic rings are cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
- Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.
- heteroaryl refers to a monocyclic, bicyclic or polycyclic, substituted or unsubstituted monovalent or divalent aromatic group containing one or more heteroatoms in the ring.
- suitable heteroatoms include oxygen, sulfur and nitrogen.
- the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
- a heteroaryl group is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like, each of which may be substituted or unsubstituted.
- cycloalkyl refers to a non-aromatic saturated or unsaturated, monovalent or divalent ring, which may be monocyclic, bicyclic or polycyclic and wherein each atom of the ring is carbon.
- a cycloalkyl group can have 3 to 7 carbon atoms as a monocyclo, 7 to 12 carbon atoms as a bicyclo, and up to about 20 carbon atoms as a polycyclo.
- Maternalcyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms.
- Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused ring systems, spirocyclic ring systems or bridged ring systems.
- the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], [6,6] system.
- the cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms.
- Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
- heterocycloalkyl As used herein, the terms “heterocycloalkyl”, “heterocyclyl”, “heterocycle” and “heterocyclic” are used interchangeably and the ring structure contains one or more heteroatoms, preferably 1 to 4 A monovalent or divalent, saturated or partially saturated non-aromatic ring structure comprising two heteroatoms, more preferably 1 to 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably 3- to 7-membered ring.
- suitable heteroatoms include oxygen, sulfur and nitrogen.
- heterocycloalkyl also refers to polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings. wherein at least one of the rings is heterocyclic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
- Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems.
- heterocycloalkyls include azetidinyl, dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidi nyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroiso Quinolinyl, 6H-1,2,5-thiadiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, a
- ester refers to —C(O)R 9 , wherein R 9 represents a hydrocarbyl group.
- cyano refers to the —CN radical.
- hydroxy refers to the —OH radical.
- substituted as used herein for alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, etc. means alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heteroaryl , heterocycloalkyl, or one or more hydrogen atoms of cycloalkyl are each independently replaced by a non-hydrogen substituent.
- Substituents are any of the substituents described herein, for example halogen, hydroxyl, amino, nitro, alkyl, alkoxy, carbonyl (eg, carboxyl, alkoxycarbonyl, formyl, or acyl), phosphoryl, phosphate , phosphonate, phosphinate, amido, amidine, imine, cyano, azido, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or hetero aromatic moieties. It will be understood by those skilled in the art that a substituted moiety on the hydrocarbon chain may itself be optionally substituted.
- pyridinyl is 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl) ) can be
- adjacent groups combine with each other to form a ring means to form a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or condensed ring thereof by combining adjacent groups with each other do.
- phrases “pharmaceutically acceptable” is an art-used expression that indicates that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal to be treated therewith. indicates.
- “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient.
- exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
- Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid.
- Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form.
- acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form.
- the selection of an appropriate salt is known to the person skilled in the art.
- Other non-pharmaceutically acceptable salts, such as oxalates, can be used in the isolation of compounds of the present invention, for example, for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.
- Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
- Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
- contemplated salts of the present invention include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
- contemplated salts of the invention include L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, theanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol; Ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
- contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
- Pharmaceutically acceptable acid addition salts may also exist in various solvates, such as solvates with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared.
- the source of such a solvate may be from the solvent of crystallization, native to the solvent of manufacture or crystallization, or adventitious to such solvent.
- IC 50 refers to the concentration of an inhibitor or compound that produces 50% inhibition.
- GI 50 refers to a concentration of an inhibitor or compound that produces 50% inhibition to maximal inhibition of cell proliferation.
- the terms “subject”, “subject”, “patient” refer to warm-blooded animals such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
- the terms “treat”, “treating”, “treatment” in addition to “ameliorate” and “ameliorate” refer to any objective or subjective parameter, eg, reduction; driveway; reduce symptoms or make the symptoms, injury, pathology or condition better tolerated by the patient; reduce the frequency or duration of a symptom or condition; In some contexts, refers to any indication of success in the treatment or amelioration of an injury, pathology, condition, or symptom (eg, pain), including preventing the onset of the symptom or condition. Treatment or amelioration of symptoms may be based on any objective or subjective parameter, including, for example, the results of a physical examination.
- the present invention provides novel indirubin derivative compounds.
- the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
- Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a heteroaryl or heterocycloalkyl
- R5 and R6 are each independently hydrogen or alkyl
- Re and Rf is each independently hydrogen or alkyl.
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, provided that Rc and Rd is not hydrogen at the same time; or
- Rc and Rd together with the nitrogen atom to which they are attached at -NRcRd form a 5- to 10-membered heteroaryl or 3- to 10-membered heterocycloalkyl;
- R5 and R6 are each independently hydrogen or C1-C6 alkyl
- Re and Rf is each independently hydrogen or C1-C6 alkyl.
- the heteroaryl or heterocycloalkyl includes one or more of N, O, or S atoms.
- R1 and R3 can each independently be hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy.
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl, provided that Rc and Rd are not simultaneously hydrogen; or
- Rc and Rd may be taken together with the nitrogen atom to which they are attached at -NRcRd to form a 5- to 6-membered heteroaryl or 3- to 7-membered heterocycloalkyl.
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
- Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
- R5 and R6 can each independently be hydrogen or methyl.
- R2 is
- the present invention provides a compound represented by Formula 1a or a pharmaceutically acceptable salt thereof.
- R1, R2, and R3 are as defined above.
- R 1 is halogen; or C1-C6 alkoxy unsubstituted or substituted with halogen.
- R 3 may be hydrogen
- R2 is or ego
- R4 is -NRcRd
- Rc and Rd are each independently hydrogen, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, provided that Rc and Rd are not simultaneously hydrogen; or
- Rc and Rd may be such that together with the nitrogen atom to which they are attached at -NRcRd form azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
- Representative compounds of Formula 1 or 1a include, but are not limited to, compounds selected from compounds 1) to 35).
- novel indirubin derivative compound or a pharmaceutically acceptable salt thereof according to the present invention inhibits the activity of FLT3, particularly mutant FLT3, and exhibits a preventive or therapeutic effect on diseases related to these activities.
- the mutant FLT3 may have a mutation in a tyrosine kinase domain (TKD) (FLT3-TKD) of the FLT3 amino acid sequence.
- the mutant FLT3 may further include an internal tandem duplication (ITD).
- ITD internal tandem duplication
- Examples of the mutant FLT3 include, but are not limited to, one or more of FLT3-ITD, FLT3-D835Y, FLT3-F691L, FLT3-F691L/D835Y, FLT3-ITD/D835Y, or FLT3-ITD/F691L.
- the compounds of the present invention may be used to treat FLT3-related diseases.
- the FLT3-associated disease comprises malignant cells expressing FLT3, eg, cancer.
- the cancer is a cancer of hematopoietic origin, such as lymphoma or leukemia.
- the cancer is multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, Caller's disease and myeloma, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia , Hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), follicular lymphoma, Burkitt Lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, progenitor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphom
- AML acute myeloid leukemia
- the compound of the present invention has a mutant FLT3 inhibitory ability, and it was confirmed that it can be used as an AML therapeutic agent by confirming strong antiproliferative activity in the FLT3-ITD-expressing MV4-11 cell line, the FLT3/D835Y-expressing MOLM14-FLT3/D835Y cell line, and the like.
- the present invention provides a pharmaceutical composition for inhibiting FLT3 comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition is for preventing or treating a FLT3-associated disease, more specifically, for preventing or treating AML.
- the present invention provides a method for preventing or treating FLT3-associated diseases, comprising administering a compound according to the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need thereof.
- the present invention comprises the step of administering the compound according to the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in a pharmaceutically effective amount to a subject having AML or a subject at risk of developing, Methods for inhibiting FLT3 are provided.
- the present invention provides a method for inhibiting FLT3, wherein the pharmaceutical composition has potent antiproliferative activity in FLT3-ITD expressing MV4-11 cell line and FLT3/D835Y expressing MOLM14-FLT3/D835Y cell line.
- the present invention provides the use of the compound according to the present invention or a pharmaceutically acceptable salt thereof for inhibiting FLT3 or preventing or treating FLT3-associated diseases.
- the present invention also provides the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of AML.
- the indirubin derivative compound of the present invention may have an IC 50 value of 100 nM or less for FLT3 inhibition. More specifically, the compound represented by Formula 1 may have an IC 50 value for FLT3 inhibition of 50 nM or less, more specifically 40 nM or less, still more specifically 35 nM or less, and even more specifically may be 30 nM or less, more specifically 25 nM or less, still more specifically 20 nM or less, still more specifically 15 nM or less, and even more specifically 10 nM or less.
- Intermediate 3 of a compound of the present invention can be prepared according to Scheme 1 below.
- the compound of the present invention can be prepared according to Scheme 2 below.
- a suitable compound eg, 1-Boc-piperazine, etc.
- glycolic acid 4 is added, stirred, and the product 5 is obtained through neutralization, extraction, concentration and purification.
- the obtained product 5 is dissolved in an appropriate solvent, MsCl and TEA are added and stirred, followed by neutralization, extraction, concentration and purification to obtain product 6 .
- stirring, adding TEA and stirring again the mixture is cooled, neutralized, extracted and concentrated.
- TFA is added, followed by stirring, followed by neutralization, extraction, concentration and purification to obtain product 7 .
- the compounds of the present invention may be prepared according to Scheme 3 below.
- Diiodomethane is dissolved in an appropriate solvent, refluxed by adding Na 2 SO 3 , and the mixture is concentrated and recrystallized to obtain product 10.
- the obtained product 10 was dissolved in a solvent, refluxed and neutralized, followed by extraction and concentration again. It is dissolved in a solvent, an appropriate reagent (eg 1-Boc-piperazine) and TEA are added, stirred, and then neutralized, extracted, concentrated and purified to obtain the product 11 .
- the obtained product 11 is added to product 3 dissolved in a suitable solvent and stirred, followed by addition of K 2 CO 3 and stirring again.
- the mixture is cooled, neutralized, extracted and concentrated.
- the resulting mixture is dissolved in an appropriate solvent, stirred with TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 12.
- the compounds of the present invention can be prepared according to Scheme 4 below.
- the product 14 After dissolving 2-chloroacetyl chloride 13 in an appropriate solvent and stirring, the product 14 is obtained through neutralization, extraction, concentration, and purification processes.
- the obtained product 14 is dissolved in a suitable solvent, NaOAc is added and stirred, then cooled and neutralized.
- KOH is added, stirred, and concentrated and neutralized, and this is again extracted, concentrated and purified to obtain product 15.
- the obtained product 15 is dissolved in a solvent, and MsCl and TEA are added thereto and stirred, followed by neutralization, extraction, concentration, and purification to obtain product 16.
- the obtained product 16 was added to the product 3 dissolved in a solvent, stirred, and K 2 CO 3 was It is added and stirred again, then cooled and neutralized.
- the neutralized product is extracted and concentrated, and the resulting mixture is dissolved in a solvent, stirred by adding TFA, and then subjected to neutralization, extraction, concentration and purification to obtain product 17.
- the obtained product 5 was dissolved in DCM, and MsCl (1.5eq) and TEA (1.5eq) were added thereto and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 6 .
- the obtained product 6 was added to Indirubin-3'-oxime 3a-g dissolved in DMF and stirred for 5 minutes. TEA (2eq) was then added and stirred at 60° C. overnight. The mixture was cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 7a-g .
- the obtained product 10 was dissolved in DCM and PCl 5 was added and refluxed for 1 hour. Then, the mixture was cooled , neutralized with an aqueous NaHCO 3 solution, extracted using EA, and concentrated by rotary evaporation. The obtained extract was dissolved in DCM, 1-Boc-piperazine (1.5eq) and TEA (2eq) were added and stirred at -20°C for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain product 11 .
- the obtained product 11 was added to Indirubin-3'-oxime 3a-b dissolved in DMF and stirred for 5 minutes. Then K 2 CO 3 (5eq) was added and stirred at 60° C. overnight. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product is extracted using EA and concentrated by rotary evaporation. The resulting mixture was dissolved in DCM and TFA was added and stirred for 2 hours. Then, the mixture was neutralized with 1N aqueous NaOH solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 12a-b .
- the obtained product 14a-d was dissolved in DMF, and NaOAc (2eq) was added and stirred at 80° C. for 1 hour. The mixture was then cooled and neutralized with aqueous NH 4 Cl solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The obtained extract was dissolved in MeOH, and 10% KOH was added and stirred for 1 hour. Then, MeOH in the mixture was removed by rotary evaporation and neutralized with 1N HCl aqueous solution. The neutralized product was extracted using EA and concentrated by rotary evaporation. The extract was purified by column chromatography to obtain products 15a-d .
- the obtained product 15a-d was dissolved in DCM, MsCl (1.5eq) and TEA (1.5eq) were added and stirred for 1 hour. Then, the mixture was neutralized with an aqueous NH 4 Cl solution, extracted using EA, and concentrated by rotary evaporation. This extract was purified by column chromatography to obtain products 16a-d .
- the FLT3 inhibitory effect of the compound of the present invention was confirmed through the FLT enzyme inhibition test and the leukemia cell proliferation inhibition test in cancer cell lines.
- Inhibition of FLT3 activity was measured using a homogeneous, time-resolved fluorescence (HTRF) assay.
- HTRF time-resolved fluorescence
- Recombinant protein containing the FLT3 domain was purchased from Carna biosciences (Japan). Optimal enzyme, ATP and substrate concentrations were established using the HTRF KinEASE kit (Cisbio, France) according to the manufacturer's instructions.
- FLT3 enzyme or FLT3/D835Y enzyme in kinase reaction buffer 50 mM HEPES (pH 7.0), 500 ⁇ M ATP, 0.1 mM sodium orthovanadate, 5 mM MgCl 2 , 1 mM DTT, 0.01% bovine serum albumin (BSA), 0.02% NaN3 ), the diluted compounds of the present invention and peptide substrates were mixed in sequence.
- IC 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad).
- MV4-11 is an FLT3-ITD expressing AML cell line
- MOLM-14/D835Y is an FLT3/D835Y expressing AML cell line
- MOLM-14 is a FLT3-ITD expressing AML cell line.
- MV4-11 human AML cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA, CRL-9591) and cells were cultured with 10% fetal bovine serum, 1% penicillin/streptomycin and 4 mM L-glutamine (Life Technology). , Grand Island, NY) supplemented with IMDM medium (Sigma Co., St. Louis, MO, USA).
- MOLM14-FLT3/D835Y is produced by transfecting MOLM14 with the pLKO.1 blast lentiviral expression vector containing the genetic information of FLT3-ITD-D835Y. MOLM14 expressing FLT3-ITD-D835Y was selected and maintained through puromycin selection.
- EZ-Cytox Cell Viability Assay kit (DaeilLab, Korea). Specifically, 2,000 - 15,000 cells were plated in a 96-well plate in 100 ⁇ l of medium. The next day, cells were treated with compounds with dimethyl sulfoxide (DMSO) as a negative control. 3 days (72 hours) after compound addition, 10 ⁇ l of EZ-Cytox kit reagent was placed in each well of a 96-well plate and incubated at 37° C. in a humidified CO 2 incubator for 4 hours.
- DMSO dimethyl sulfoxide
- GI 50 was calculated by nonlinear regression using Prism version 5.01 (GraphPad, LaJolla, CA, USA).
- the compounds of the present invention exhibited FLT3 or FLT3 mutagenesis inhibitory activity, and in particular FLT3/D835Y mutation inhibitory activity was excellent*.
- the compound of the present invention exhibits potent antiproliferative activity in acute leukemia cell lines.
- FLT3-ITD expressing MV4-11 and MOLM14 cell lines expressing mutant kinases
- FLT3/D835Y expressing MOLM14-FLT3/D835Y cell lines expressing potent antiproliferative activity It was confirmed that the proliferation activity was shown.
- the compound of the present invention has excellent FTL3, particularly FLT3 mutation inhibitory activity.
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Abstract
La présente invention concerne un nouveau dérivé d'indirubine et son utilisation en tant qu'inhibiteur de la tyrosine kinase 3 de type fms (FLT3).
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WO2000061555A1 (fr) * | 1999-04-12 | 2000-10-19 | Gerhard Eisenbrand | Derives bisindoliques d'indigoides |
WO2002100401A1 (fr) * | 2001-06-11 | 2002-12-19 | Schering Aktiengesellschafat | Derives d'indirubine inhibiteurs de cdk solubles |
WO2007099402A2 (fr) * | 2005-12-23 | 2007-09-07 | Centre National De La Recherche Scientifique (Cnrs) | Nouvelles indirubines substituees en 3' et 7 et leurs applications |
US20140275168A1 (en) * | 2013-03-14 | 2014-09-18 | City Of Hope | Indirubin derivatives, and uses thereof |
KR20190049584A (ko) * | 2017-10-31 | 2019-05-09 | 광주과학기술원 | 급성 골수성 백혈병 또는 전이성 유방암의 예방 또는 치료용 약제학적 조성물 |
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WO2000061555A1 (fr) * | 1999-04-12 | 2000-10-19 | Gerhard Eisenbrand | Derives bisindoliques d'indigoides |
WO2002100401A1 (fr) * | 2001-06-11 | 2002-12-19 | Schering Aktiengesellschafat | Derives d'indirubine inhibiteurs de cdk solubles |
WO2007099402A2 (fr) * | 2005-12-23 | 2007-09-07 | Centre National De La Recherche Scientifique (Cnrs) | Nouvelles indirubines substituees en 3' et 7 et leurs applications |
US20140275168A1 (en) * | 2013-03-14 | 2014-09-18 | City Of Hope | Indirubin derivatives, and uses thereof |
KR20190049584A (ko) * | 2017-10-31 | 2019-05-09 | 광주과학기술원 | 급성 골수성 백혈병 또는 전이성 유방암의 예방 또는 치료용 약제학적 조성물 |
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