WO2017148440A1 - Dérivé de ptéridinone servant d'inhibiteur de flt3, et utilisations - Google Patents

Dérivé de ptéridinone servant d'inhibiteur de flt3, et utilisations Download PDF

Info

Publication number
WO2017148440A1
WO2017148440A1 PCT/CN2017/075628 CN2017075628W WO2017148440A1 WO 2017148440 A1 WO2017148440 A1 WO 2017148440A1 CN 2017075628 W CN2017075628 W CN 2017075628W WO 2017148440 A1 WO2017148440 A1 WO 2017148440A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
group
alkyl
hydrogen
disease
Prior art date
Application number
PCT/CN2017/075628
Other languages
English (en)
Chinese (zh)
Inventor
李洪林
徐玉芳
陈卓
孙德恒
吕剑昆
赵振江
宋文琳
周伟
杨宇
Original Assignee
华东理工大学
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 华东理工大学 filed Critical 华东理工大学
Publication of WO2017148440A1 publication Critical patent/WO2017148440A1/fr

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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to novel pteridine derivatives, methods for their synthesis and their use as FLT3 inhibitors in the preparation of medicaments for tumors and immune diseases.
  • Protein tyrosine kinase (protein tyrosine kinase) is a class of proteins that catalyze the transfer of ⁇ -phosphate on ATP to specific amino acid residues of proteins. It plays a very important role in the signal transduction pathway in cells and regulates cell growth. A series of physiological processes such as differentiation and death. It has been shown that more than 50% of protooncogenes and their products have protein tyrosine kinase activity, and their abnormal expression will lead to cell cycle life disorder, leading to tumorigenesis. In addition, the abnormal expression of tyrosine kinase is also closely related to tumor metastasis, chemotherapy resistance and the like.
  • FMS-like tyrosine kinase 3 belongs to the family of type III receptor tyrosine kinases. FLT3 plays an important role in the proliferation, differentiation and apoptosis of hematopoietic cells (Oncogene, 1993, 8,815-822). Upon binding to FLT3 ligand, FLT3 activates multiple downstream signaling pathways, including STAT5, Ras/MAPK, and PI3K/AKT pathways.
  • FLT3 mutation in approximately one-third of patients with acute myeloid leukemia (AML) (Blood, 2002, 100, 1532-1542), including the proximal membrane domain 14 and/or exon 15
  • FLT3-ITD an internal tandem repeat
  • FLT3-TKD amino acid deletion or insertion
  • the present invention relates to a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:
  • X is selected from: N, CH;
  • Y is selected from the group consisting of: O, S, and Se;
  • A is selected from various substituted benzene rings, nitrogen-containing five-membered rings, nitrogen-containing six-membered rings, for example
  • R 1 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, fluorine-containing C 1 -C 8 alkyl, optionally substituted phenyl;
  • R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, halogen, optionally substituted C 1 -C 6 alkoxy, amino, -NR a R b , carboxyl, optionally substituted alkoxy Formyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted morpholin-4-yl, optionally substituted piperidin-1-yl, optionally substituted pyrrol-1-yl, Optionally substituted pyrrolidin-1-yl, optionally substituted aryl or optionally substituted arylmethyl, optionally substituted piperidinyloxy, optionally substituted N,N',N'-three Alkyl ethylenediamine;
  • R a and R b are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, -NR c R d , C 1 -C 2 acylamino, optionally substituted C 1 -C 6 alkyl, C 1 -C 3 sulfonylamino, CN, carbamoyl, carboxyl, C1-C6 alkoxycarbonyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted morpholin-4-yl, optionally substituted pyrrol-1- Base, optionally substituted pyrrolidin-1-yl;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is not an amino group.
  • the compound has the structure shown in Formula II:
  • A is selected from various substituted benzene rings
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, halogen, amino, -NR a R b , optionally substituted piperazinyl, optionally Substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R a and R b are each independently selected from the group consisting of: hydrogen, C1-C6 alkyl and alkenyl;
  • n 1, 2, or 3;
  • R 3 is each independently selected from the group consisting of: hydrogen, halogen, C1-C2 acylamino, hydroxy, amino, -NR c R d , methanesulfonylamino, optionally substituted C 1 -C 6 alkyl, optionally substituted piperazine base;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 3 alkyl and alkenyl;
  • n 1, 2, or 3.
  • the compound has the structure shown in Formula III:
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of: an optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R 6 is selected from the group consisting of: an amino group, an optionally substituted piperazinyl group, -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl.
  • R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group; and R 5 is selected from an optionally substituted N-alkylpiperazin-1-yl group.
  • R 6 is selected from an amino group, or -NR e R f ; and R e and R f are each independently selected from hydrogen, and a C 1 -C 3 alkyl group.
  • the invention provides a specific compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or Shape agent.
  • the invention provides the use of a compound of the first or second aspect of the invention for the manufacture of a medicament for the treatment of a FLT3-mediated disease, or for the inhibition of FLT3.
  • the FLT3 mediated disease is a blood disorder, such as a myeloproliferative disorder, a cancer, an immune disease, and a skin disorder such as psoriasis and atopic dermatitis.
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), mixed line leukemia (MLL), T-cell acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic Bone marrow monocytic leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia.
  • AML acute myeloid leukemia
  • MML mixed line leukemia
  • T-ALL T-cell acute leukemia
  • B-ALL B-cell acute leukemia
  • CMML chronic Bone marrow monocytic leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • chronic neutrophilic leukemia chronic neutrophilic leukemia.
  • the immune disease is selected from the group consisting of arthritis, lupus, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis , diabetes, myasthenia gravis, Hashimoto's thyroiditis, Odd thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acutely transmitted encephalomyelitis, Dyson disease, aplastic anemia, autoimmune hepatitis, optic neuritis, silvery disease, graft versus host disease, transplantation, blood transfusion allergy, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis Atopic dermatitis.
  • Figure 1A shows that Western blot analysis determined that compound F-8 autophosphorylates FLT3 and inhibits phosphorylation of downstream signaling pathways;
  • Figure 1B shows compound 20 induction at various concentrations over 48 hours of cell culture. MV4-11 cell apoptosis;
  • Figure 1C shows inhibition of G1 phase cell growth with a specific concentration of compound 20 after 48 hours of culture;
  • Figure 2 shows tumor volume changes in the MV4-11 xenograft model
  • Figure 3 shows tumor weight changes in the MV4-11 xenograft model.
  • the present inventors synthesized a series of pteridinone derivatives which have not been reported in the literature with FLT3 inhibitory activity, and structurally characterized these compounds.
  • a series of compounds were tested for activity at the molecular and cellular levels to obtain a batch of compounds having FLT3 inhibition activity.
  • a plurality of compounds, such as F-8 and F-16 have an inhibitory activity against FLT3 with an IC 50 value of less than 10 nM, which is far superior to the positive control MLN 518.
  • alkyl refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include from 2 to 8 carbon atoms, from 1 to 6, and from 1 to 4 carbon atoms.
  • Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • the alkyl group of the present invention may be substituted with one or more substituents, for example, by halogen or haloalkyl.
  • an alkyl group can be 1-4
  • the fluorine atom-substituted alkyl group or the alkyl group may be an alkyl group substituted by a fluoroalkyl group.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • alkenyl generally denotes a monovalent hydrocarbon radical having at least one double bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, and may be straight or branched.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • halogen atom or halogen means fluoro, chloro, bromo and iodo.
  • Aryl means a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, tetrahydronaphthyl, Indane or the like.
  • the aryl group may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxy a formyl group, a N(CH 3 ) group, a C1-4 acyl group or the like, a heterocyclic group or a heteroaryl group.
  • substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4
  • aralkyl refers to an alkyl group substituted with an aryl group, such as a C1-C6 alkyl group substituted with a phenyl group.
  • aryl groups include, but are not limited to, arylmethyl, arylethyl, and the like, such as benzyl, phenethyl, and the like.
  • an aryl group may be substituted with from 1 to 3 groups selected from the group consisting of halogen, -OH, C1-4 alkoxy, C1-4 alkyl, -NO 2 , -NH 2 , -N(CH 3 ) 2 , carboxyl and ethoxylated groups.
  • 5- or 6-membered heterocyclic ring as used herein includes, but is not limited to, a heterocyclic group containing 1-3 heteroatoms selected from O, S and N, including but not limited to furyl, thienyl, pyrrolyl, Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl and the like.
  • heteroaryl refers to 5-14 ring atoms and 6, 10 or 14 electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur. Heteroaryl groups useful in the present invention include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but It is not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.
  • the heteroaryl or 5- or 6-membered heterocyclic ring may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen, C1-4 aldehyde, C1-6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy) Base), carboxyl group, C1-4 alkoxy group, ethoxylated group, N(CH 3 ) and C1-4 acyl group.
  • 1 to 5 eg, 1, 2, 3, 4 or 5
  • substituents selected from halogen, C1-4 aldehyde, C1-6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy) Base), carboxyl
  • acyloxy refers to a radical of the formula "-O-C(O)-R", wherein R may be selected from alkyl, alkenyl and alkynyl. The R can be optionally substituted.
  • amido refers to a group of the formula "-R'-NH-C(O)-R", wherein R' may be selected from a bond or an alkyl group, and R may be selected from an alkyl group, an alkenyl group. , an alkynyl group, NR a R b is a substituted alkyl group, NR a R b is a substituted alkenyl and NR a R b substituted alkynyl, halogen substituted alkyl, alkenyl substituted with cyano group, Wherein R a and R b may be selected from the group consisting of alkyl and alkenyl.
  • substituent to which it is modified may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a halogen-substituted alkyl group (for example, a trifluoromethyl group), a halogen-substituted alkoxy group ( For example, trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxycarbonyl, N(CH 3 ), and C1-4 acyl.
  • substituents selected from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group,
  • the compound of the present invention is a compound having the structure of the formula I or a pharmaceutically acceptable salt thereof:
  • X is selected from N, CH;
  • Y is selected from the group consisting of O, S and Se;
  • A is selected from various substituted benzene rings, nitrogen-containing five-membered rings, nitrogen-containing six-membered rings, for example
  • R 1 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, fluoro C 1 -C 8 alkyl, optionally substituted phenyl;
  • R 2 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, halogen, optionally substituted C 1 -C 6 alkoxy, amino, —NR a R b , carboxy, optionally substituted alkoxylate Acyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted morpholin-4-yl, optionally substituted piperidin-1-yl (preferably piperazine substituted piperidin-1-yl) , optionally substituted pyrrol-1-yl, optionally substituted pyrrolidin-1-yl, optionally substituted aryl or optionally substituted arylmethyl, optionally substituted piperidinyloxy, any Substituted substituted N,N',N'-trialkylethylenediamine;
  • R a and R b are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, -NR c R d , C1-C2 acylamino, optionally substituted C 1 -C 6 alkyl, C 1 -C 3 sulfonylamino, CN, amino Formyl, carboxyl, C1-C6 alkoxycarbonyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted morpholin-4-yl, optionally substituted pyrrol-1-yl, any Substituted pyrrolidin-1-yl;
  • R c and R d are each independently selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and alkenyl;
  • n 0, 1, 2, 3 or 4;
  • R 3 is not an amino group.
  • the compound has the structure shown in Formula II:
  • A is selected from various substituted benzene rings
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, halogen, amino, -NR a R b , optionally substituted piperazinyl, optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R a and R b are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and alkenyl;
  • n 1, 2, or 3;
  • R 3 is each independently selected from the group consisting of hydrogen, halogen, C1-C2 acylamino, hydroxy, amino, -NR c R d , C1-C3 sulfonylamino (preferably methanesulfonylamino), optionally substituted C 1 -C 6 alkane , optionally substituted piperazinyl, optionally substituted N-alkylpiperazin-1-yl;
  • R c and R d are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl;
  • n 1, 2, or 3.
  • the compound has the structure shown in Formula III:
  • R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of an optionally substituted N-alkylpiperazin-1-yl, optionally substituted piperidinyloxy;
  • R 6 is selected from the group consisting of amino, optionally substituted piperazinyl, -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and alkenyl.
  • R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, preferably a C 1 -C 3 alkyl group;
  • R 5 is selected from the group consisting of an optionally substituted N-alkylpiperazin-1-yl
  • R 6 is selected from amino, or -NR e R f ;
  • R e and R f are each independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl.
  • the present inventors synthesized a series of pteridine ketone compounds which have not been reported in the literature; specifically, the present inventors synthesized a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
  • the inventors synthesize a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:
  • the inventors synthesize a compound selected from the group consisting of or a pharmaceutically acceptable salt:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient .
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg per kilogram of oral administration.
  • a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial A form of administration, intranasal or topical, for the treatment of tumors and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals is humans.
  • the compounds of the invention or pharmaceutical compositions thereof are useful in the treatment of a variety of diseases mediated by FMS-like tyrosine kinase 3 (FLT3).
  • FLT3-mediated diseases are blood diseases such as myeloproliferative diseases, cancers, immune diseases, and skin diseases such as psoriasis and atopic dermatitis.
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), mixed line leukemia (MLL), T-cell acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic bone marrow Single cell leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia.
  • AML acute myeloid leukemia
  • MML mixed line leukemia
  • T-ALL T-cell acute leukemia
  • B-ALL B-cell acute leukemia
  • CMML chronic bone marrow Single cell leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • chronic neutrophilic leukemia chronic neutrophilic leukemia
  • the immune disease is selected from the group consisting of arthritis, lupus, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes , myasthenia gravis, Hashimoto's thyroiditis, Odd thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acutely transmitted encephalomyelitis, Addison Disease, aplastic anemia, autoimmune hepatitis, optic neuritis, silver disease, graft versus host disease, transplantation, blood transfusion allergy, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, special Shoulder dermatitis.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl
  • disintegrants such as the starch mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Adjuvants especially flow regulators and Lubricants, for example, silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • the invention further provides a method of treating a FLT3-mediated disease comprising administering to a subject in need thereof a compound or pharmaceutical composition of the invention.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the invention also encompasses the use of a compound of the invention in the manufacture of a medicament for the treatment of a FLT3-mediated disease, or inhibition of FLT3.
  • the compound provided by the present invention is a novel pteridine derivative
  • the compound provided by the present invention has excellent inhibitory activity against FLT3;
  • the compound provided by the invention lays a foundation for developing a targeted drug capable of inhibiting FLT3, and has great industrialization and commercialization prospects as well as market value, and the economic benefit is remarkable.
  • R 1 - R 4 are as defined above.
  • One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.
  • P-phenylenediamine (890 mg, 8.23 mmol) was weighed into a 100 mL round bottom flask, 40 mL of dichloromethane was added, and the mixture was stirred in an ice bath, and di-tert-butyl dicarbonate (449 mg, 2.06 mmol) was dissolved in dichloromethane. Among them, it was added dropwise to the above reaction liquid, and then the mixture was further stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness eluted eluted eluted elut elut elut elut elut elut %.
  • the synthesis method is referred to as F-1 to obtain a yellow solid, the yield is 52%, mp 228.9-229.4 ° C.
  • the synthesis method is referred to as F-1, and a yellow solid is obtained in a yield of 70%, mp 262.5-262.9 ° C.
  • the raw material 1 was placed in a 250 ml round bottom flask, dissolved in DCM and MeOH, 100 mg of palladium carbon (10% Pd) was weighed, hydrogen gas was introduced, and the reaction was carried out for about 10 hours at room temperature, followed by suction filtration, and the filtrate was evaporated under reduced pressure to give a solvent. It was used directly in the next step without purification.
  • kinase buffer 50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 2 mM DTT
  • stop buffer 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2
  • %Coating Reagent#3 50 mM EDTA.
  • the compound was diluted to the desired concentration with 100% DMSO, and the formulated compound was transferred to a 96-well plate at a concentration ranging from 20 ⁇ l to 60 ⁇ l and equilibrated to 10 concentrations with a concentration gradient. A 100 ⁇ l concentration of 100% DMSO was used as a blank control.
  • Cell culture Cell lines were obtained from the American Type Culture Collection. The cells were cultured in RPMI-1640 or MEM medium containing 10% fetal bovine serum in 5% CO 2 at 37 °C. MV4-11 cells were cultured in IMDM medium.
  • the activity test of suspension cells is mainly determined by the MTT test method, and the test of adherent cells is mainly the SRB test method.
  • the suspension cells were cultured in 96-well plates of 3-8 x 10 3 cells per well, 100 ⁇ L of the medium was added to each well, and then 10 ⁇ L of the compound (in triplicate) was added, and cultured at 37 ° C for 72 hours. After the cells were cultured, 20 ⁇ L of 5 mg/mL MTT reagent was added to each well plate for further 4 hours, and 50 ⁇ L of three mixed solvents (5% isopropanol-10% SDS-12 mmol/L HCl) were added to dissolve the oxidation product. .
  • the OD value was measured at 570 nm using a multifunction detector Synergy2.
  • the adherent cells were cultured in 96-well plates of 2-7 x 10 3 cells per well for 24 h, and the same equivalent of the compound was also added to the medium. After 72 h of culture, the culture solution was removed, and the strain was fixed with TCA for 1 h. The dried well plates were stained with sulforhodamine B and then 150 ⁇ L of 10 mM Tris-HCl was added. Finally, the light absorption of the lysed cells was detected at 560 nm using a Synergy 2 differential spectrophotometer. All experiments were performed in triplicate.
  • Immunoprecipitation and Western blotting experiments Cells were incubated with different concentrations of compounds for 2 h, then the cells were further solubilized with RIPA lysis buffer, then centrifuged at 4 ° C, and the supernatant was taken for relevant experiments. The protein was separated by SDS-PAGE and then transferred to a nitrocellulose membrane for antibody detection. The primary antibodies act on FLT3, AKT, p-AKT, STAT5, p-STAT5 and p44/42 MAPK, and anti-GAPDH is cultured at the recommended concentrations. The visualized signal was used to detect the elevated ECL matrix using the Tanon 5200 capture system after HRP copolymerization with the antibody.
  • the cell lysate was immunoprecipitated with FLT3 antibody and protein A gel, and the cooked sample was electrophoretically polarized with 6% gel, and then labeled with 4G10 antibody, and the FLT3 phosphorylation level was detected by this method.
  • Flow cytometry Cells were stained with Annexin V and propidium iodide for the detection of apoptotic activity of the compounds.
  • MV4-11 cells were cultured in a 6-well plate at a density of 1 ⁇ 10 5 cells/mL, and then cultured at different concentrations for 48 hours. The cells were divided and washed twice with cold PBS buffer solution. The sample was resuspended in binding buffer and incubated with annexin V and propidium iodide under the protection of light.
  • the cell cycle assay was performed according to the PI/Rnase staining solvent product specification. The dividing cells were fixed in 70% ethanol for 1 h. All cells were then stained with propidium iodide for 30 min under non-illuminated room temperature conditions. Apoptosis and cell cycle were detected by FACS flow cytometry.
  • test results of the compounds are shown in the following table, and the results of the cell test are shown in the attached drawings.
  • the inventors further tested the inhibitory activity of the compounds of the present invention on tumors in the MV4-11 xenograft model.
  • the inventors designed and synthesized a series of pteridinone derivatives that have not been reported in the literature.
  • the obtained compounds were tested at the molecular and cellular levels to obtain a batch of compounds capable of inhibiting FLT3. .
  • the IC 50 value of the inhibitory activity of these compounds on FLT3 reached nM level; the IC 50 value of inhibitory activity against related cells reached the ⁇ M level.
  • a plurality of compounds, such as F-8 and F-16 have an inhibitory activity against FLT3 with an IC 50 value of less than 10 nM, which is far superior to the positive control MLN 518.
  • Further tumor model tests have shown that the compounds of the invention also have excellent tumor suppressor activity in vivo.
  • the non-compounds of the invention may be the target drug for inhibiting FLT3, or the basis for further modification to give compounds that are more active and/or less toxic.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de ptéridinone utilisé comme inhibiteur de FLT3 et ses utilisations. Plus particulièrement, la présente invention concerne un composé représenté par la formule (I), une composition pharmaceutique contenant le composé de formule (I) et des utilisations du composé dans la préparation de médicaments pour le traitement de maladies médiées par FLT3 ou pour l'inhibition du FLT3: (I).
PCT/CN2017/075628 2016-03-04 2017-03-03 Dérivé de ptéridinone servant d'inhibiteur de flt3, et utilisations WO2017148440A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610125930.9 2016-03-04
CN201610125930.9A CN107151249B (zh) 2016-03-04 2016-03-04 作为flt3抑制剂的蝶啶酮衍生物及应用

Publications (1)

Publication Number Publication Date
WO2017148440A1 true WO2017148440A1 (fr) 2017-09-08

Family

ID=59743510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/075628 WO2017148440A1 (fr) 2016-03-04 2017-03-03 Dérivé de ptéridinone servant d'inhibiteur de flt3, et utilisations

Country Status (2)

Country Link
CN (1) CN107151249B (fr)
WO (1) WO2017148440A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
CN115197099A (zh) * 2022-05-30 2022-10-18 安徽昊帆生物有限公司 N-Boc-1，4-苯二胺的制备方法
US11697648B2 (en) 2019-11-26 2023-07-11 Theravance Biopharma R&D Ip, Llc Fused pyrimidine pyridinone compounds as JAK inhibitors

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用
CN110833554B (zh) * 2018-08-15 2022-03-08 广西梧州制药（集团）股份有限公司 吡唑并嘧啶衍生物在治疗自身免疫性甲状腺疾病的用途
CN110357885A (zh) * 2019-07-24 2019-10-22 江南大学 一种蝶啶类化合物及其在药学上的应用
CN113801118A (zh) * 2020-06-12 2021-12-17 华东理工大学 作为rsk抑制剂的蝶啶酮衍生物及其应用
CN115504980A (zh) * 2021-06-23 2022-12-23 石药集团中奇制药技术（石家庄）有限公司 嘧啶并含氮六元芳香杂环类化合物及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
CN101031568A (zh) * 2004-06-23 2007-09-05 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN103421010A (zh) * 2012-05-14 2013-12-04 华东理工大学 作为egfr抑制剂的蝶啶酮衍生物及其应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103833759A (zh) * 2012-11-23 2014-06-04 华东理工大学 作为blk、flt3抑制剂的蝶啶酮衍生物及其应用
CN106467540B (zh) * 2015-08-21 2021-03-16 华东理工大学 蝶啶酮衍生物作为flt3抑制剂的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
CN101031568A (zh) * 2004-06-23 2007-09-05 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN103421010A (zh) * 2012-05-14 2013-12-04 华东理工大学 作为egfr抑制剂的蝶啶酮衍生物及其应用

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
US11697648B2 (en) 2019-11-26 2023-07-11 Theravance Biopharma R&D Ip, Llc Fused pyrimidine pyridinone compounds as JAK inhibitors
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
CN115197099A (zh) * 2022-05-30 2022-10-18 安徽昊帆生物有限公司 N-Boc-1，4-苯二胺的制备方法

Also Published As

Publication number Publication date
CN107151249A (zh) 2017-09-12
CN107151249B (zh) 2020-08-14

Similar Documents

Publication Publication Date Title
WO2017148440A1 (fr) Dérivé de ptéridinone servant d'inhibiteur de flt3, et utilisations
JP7356546B2 (ja) タンパク質キナーゼのモジュレータとしてのジアリール大環状化合物
CN113651814B (zh) Kras突变蛋白抑制剂
AU2005332339B2 (en) Furanopyridine derivatives as ACK1 and Lck modulators
JP2022506887A (ja) 窒素含有縮合複素環系ｓｈｐ２阻害剤化合物、製造方法及び使用
JP6457623B2 (ja) ２，４−二置換７Ｈ−ピロロ［２，３−ｄ］ピリミジン誘導体、その製造方法および医薬における使用
CN112552295A (zh) Kras突变蛋白抑制剂
CN107922417B (zh) 蝶啶酮衍生物作为egfr抑制剂的应用
CN103930425A (zh) 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用
WO2018192536A1 (fr) Composé pyrimido-hétérocyclique servant d'inhibiteur de la tyrosine kinase de bruton et ses applications
JP2022517723A (ja) Ｃｄｋ阻害剤としての大環状化合物、その製造方法及びその医薬品における応用
CN106467540B (zh) 蝶啶酮衍生物作为flt3抑制剂的应用
US10807983B2 (en) Imidazo-fused heterocycles and uses thereof
WO2023036252A1 (fr) Dérivé de pyrrolopyrimidine ou de pyrrolopyridine et son utilisation médicale
JP2021515768A (ja) オキサジノキナゾリンおよびオキサジノキノリン系化合物、ならびに調製方法およびその使用
WO2022095960A1 (fr) Inhibiteurs de kras pour le traitement de cancers
JP7110335B2 (ja) プロテインキナーゼ阻害剤として有用なピリドキナゾリン誘導体
US20230133169A1 (en) Egfr inhibitor, composition, and method for preparation thereof
CA3156625A1 (fr) Compose imidazolidinone, son procede de preparation et son utilisation
CN112004809A (zh) 作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物
WO2023046114A1 (fr) Dérivé de ptéridinone et son utilisation
TW202406542A (zh) Kif18a抑制劑及其用途
TW202413377A (zh) 吲唑巨環化合物及其用途
CN112707905A (zh) 一种三并杂环化合物及其制备方法和用途
CN113024544A (zh) 一种含氰基并杂环化合物及其用途

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17759291

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17759291

Country of ref document: EP

Kind code of ref document: A1