WO2018035950A1 - Composé en tant qu'inhibiteur de tyrosine kinase - Google Patents

Composé en tant qu'inhibiteur de tyrosine kinase Download PDF

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Publication number
WO2018035950A1
WO2018035950A1 PCT/CN2016/102411 CN2016102411W WO2018035950A1 WO 2018035950 A1 WO2018035950 A1 WO 2018035950A1 CN 2016102411 W CN2016102411 W CN 2016102411W WO 2018035950 A1 WO2018035950 A1 WO 2018035950A1
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Prior art keywords
methoxy
amide
fluoro
piperidin
quinoline
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PCT/CN2016/102411
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English (en)
Chinese (zh)
Inventor
许军
彭红
张文燕
陶琳
张晓丽
赵岩
赵银鹰
王晓霞
李永华
邹阳
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南昌弘益药业有限公司
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Publication of WO2018035950A1 publication Critical patent/WO2018035950A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a class of compounds of tyrosine protein kinase inhibitors, including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, which are useful for modulating protein kinase activity in order to modulate cellular activity such as Signal transduction, proliferation and cytokine secretion. Furthermore, the present invention relates to a pharmaceutical composition comprising the compound, which can be used for preventing or treating tyrosine protein kinase receptors, especially diseases related to c-Met, VEGFR, Ret, etc., and can be applied in medicine, pharmacy, biology. , physiology, biochemistry and other experiments.
  • vascular endothelial growth factor receptor VEGFR is activated during many cancer developments leading to angiogenesis.
  • Vascular endothelial growth factor-A VEGF-A
  • VEGF-A vascular endothelial growth factor-A
  • VEGFR-1 and VERFR-2 vascular endothelial growth factor receptors
  • Vascular endothelial growth factor receptors further activate downstream signaling pathways in the network, including the phosphatidylinositol-3-kinase/protein kinase B signaling pathway.
  • Immunohistochemistry experiments showed that VEGF and VEGFR were over-expressed in tumor patients, suggesting that vascular endothelial growth factor receptor activation plays an important role in tumor growth.
  • Angiogenesis plays an important role in the growth, development, reproduction, and wound healing of the organism.
  • the growth and metastasis of the primary tumor also depends on angiogenesis.
  • New tumors require more blood vessels to meet their metabolic and proliferation needs.
  • the blood circulation spreads to other tissues and organs.
  • Angiogenesis is a key factor in tumor growth, providing not only nutrition and oxygen to the tumor, but also the pathway through which tumor cells enter the system's circulation and metastasis.
  • a variety of angiogenic factors secreted by tumor cells are interconnected and regulated.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • VEGF receplor vascular endothelial growth factor receptor
  • VEGF also known as vascular permeability factor
  • Ferrarra was a kind of glycoprotein isolated and purified from bovine pituitary follicular stellate cell culture medium.
  • a member of the Platelet derived growth factor (PDGF) family with a molecular weight of 34-45KD, is highly conserved and widely distributed in tissues such as brain, kidney, spleen, pancreas and bone in humans and animals.
  • Factor extracellular factor, hypoxia, regulation of P53 gene.
  • VEGFR and Ligand binding to VEGF produces a range of physiological and biochemical processes that ultimately promote neovascularization. In normal blood vessels, angiogenic factors and angiogenesis inhibitors maintain a relatively balanced level, and during tumor growth, high expression of VEGFR and VEGF disrupts this balance and promotes tumor angiogenesis.
  • c-Met also known as MET or HGFR, is a protein product encoded by the MET proto-oncogene (mainly present in stem cells, progenitor cells), a hepatocyte growth factor transmembrane receptor with tyrosine kinase activity.
  • c-Met is mainly expressed in epithelial cells, but also in endothelial cells, hepatocytes, nerve cells and hematopoietic cells, and plays an important role in embryo development and wound healing.
  • Hepatocyte growth factor (HGF) is the only ligand of c-Met receptor secreted by mesenchymal cells.
  • the c-Met receptor plays an important role in the cell metabolism, differentiation and signal transduction of cell apoptosis. It binds to the ligand and activates five downstream signal transduction pathways, such as RAS/RAF and phosphatidylcholine. Alcohol 3 kinase (PI3K), signal transduction and transcriptional activator (STAT), Notch and Beta-catenin promote cell mitosis, morphogenesis and other biological reactions, thereby participating in embryonic development, tissue damage repair, liver regeneration and tumor invasion. And transfer.
  • PI3K Alcohol 3 kinase
  • STAT signal transduction and transcriptional activator
  • Notch Notch
  • Beta-catenin promote cell mitosis, morphogenesis and other biological reactions, thereby participating in embryonic development, tissue damage repair, liver regeneration and tumor invasion. And transfer.
  • Hepatocyte growth factor also known as a dispersing factor, is a ligand for the tyrosine kinase variant c-Met and acts as a derivative of fibroblasts that induce epithelial cell dispersion, contributing to many epithelial cells. Mitosis, the role of induced morphological changes.
  • HGF stimulates vascular endothelial growth factor and upregulates the expression of molecules and their receptors involved in extracellular matrix proteolysis. In order to produce an effect (biological effect), HGF must bind to its receptor c-Met, the receptor tyrosine kinase.
  • the specific membrane receptor for HGF is the expression product of the proto-oncogene c-Met, which is located on chromosome 7q31 and has a size of 110 kb containing 21 exons. Its promoter domain includes many regulatory sequences such as AP1, AP2, NF2JB, and SP1.
  • HGF specifically binds to the c-Met receptor protein, induces a conformational change in the C-Met receptor protein, and activates the tyrosine protein kinase (PTK) in the receptor's intracellular protein kinase domain, which is HGF/c- The primary link of the Met signal transduction pathway.
  • PTK tyrosine protein kinase
  • the tyrosine residue of the 4-phosphorylation site near c-Met near the intracellular region undergoes autophosphorylation, followed by a series of phosphorylation reactions to activate phospholipase (PLC ⁇ ), phosphoinositide 3 Tyrosine phosphorylation of proteins such as kinase (PI3K), Ras protein, S ⁇ C protein, adaptor protein Gabl and growth factor receptor binding protein 2 (G ⁇ b2).
  • PLC ⁇ phospholipase
  • PI3K phosphoinositide 3 Tyrosine phosphorylation of proteins such as kinase (PI3K), Ras protein, S ⁇ C protein, adaptor protein Gabl and growth factor receptor binding protein 2 (G ⁇ b2).
  • HGF and c-Met regulate growth, angiogenesis, invasiveness and metastasis in many human cancers and promote tumors.
  • Activation of c-Met expression is caused by hypoxia-induced hypoxia induced by factor-1 ⁇ (HIF-1 ⁇ ) and leads to invasion of hypoxic tumors.
  • HIF-1 ⁇ reduces the expression of c-Met, which can be triggered by vascular puncture caused by VEGF inhibitors, and is selective for migration, invasive tumor cells, and propensity for metastasis through metastasis.
  • the RET proto-oncogene encodes a cellular transmembrane glycoprotein, Ret, a member of the receptor tyrosine kinase (RTK) family.
  • the Ret protein is a member of the receptor tyrosine kinase protein family, a protein polymer that is a cell surface molecule that signals the growth and differentiation of cells.
  • the Ret protein includes a cysteine-rich extracellular region, a transmembrane region, and an intracellular region portion containing a tyrosine kinase (TK). Like many single transmembrane receptors, Ret regulates cell growth and differentiation.
  • RET gene mutation enhances the function of RET tyrosine kinase signal transduction in many aspects, promotes the activation of kinase and the transformation of proto-oncogene. RET gene mutation is closely related to the occurrence of various diseases, including MEN2, PTC, congenital giant Colon and lung adenocarcinoma, etc.
  • novel quinoline compounds according to the present invention are selective tyrosine protein kinase inhibitors, and their main function is to exert their effects by inhibiting tyrosine protein kinase activity.
  • the major tyrosine protein kinases inhibited by such compounds are C-met, VEGFR, Ret, and the like. Of course, the possibility of such compounds inhibiting other disease-associated protein kinases is not excluded.
  • the present invention relates to a novel class of compounds which are tyrosine kinase inhibitors, which are compounds of formula (I), and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and
  • the pharmaceutical composition of the compound which can be used for preventing or treating, treating, controlling, delaying or preventing one or more selected from the group consisting of protein tyrosine kinase receptors, especially c-Met, VEGFR in human patients, mammalian patients And a method for the disease state of related diseases and diseases such as Ret; and it can be used as a protein tyrosine kinase receptor inhibitor in medical, pharmaceutical, biological, physiological, biochemical and the like experiments.
  • Ring A is H, CH 3 , NH 2 ,
  • R 1 is H, OH, NO 2 , NR 2 R 3 , CF 3 , COOH, OR 2 , OR 3 , halogen, C 1-8 alkyl, wherein the C 1-8 alkyl group is optionally the same by one or more Or different R 3 substitutions;
  • R 2 is H, C 1-8 alkyl
  • R 3 is H, halogen, C 3-7 cycloalkyl, C 5-7 aromatic ring group, C 5-7 aromatic heterocyclic group, C 7-11 aromatic bicyclic group, C 7-11 aromatic heterobicyclic group, wherein These rings are optionally substituted by one or more of the same or different R 4 ;
  • R 4 is H, C 1-8 alkyl.
  • Halogen means F, Cl, Br, I, At.
  • C 3-7 cycloalkyl refers to a cycloalkyl chain having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of the cycloalkyl carbon can be replaced by a further defined substituent.
  • the "C 5-7 aromatic heterocyclic group” means an aromatic heterocyclic group having 5 to 7 carbon atoms, such as imidazole, thiazole, pyrazole, pyridine, pyrimidine or the like. Each hydrogen of the aromatic heterocyclic group may be replaced by a further defined substituent.
  • C 7-11 aromatic bicyclic group means an aromatic bicyclic group having 7 to 11 carbon atoms, such as naphthalene, anthracene or the like. Each hydrogen of the aromatic bicyclic group can be replaced by a further defined substituent.
  • C 7-11 aromatic heterobicyclic group means an aromatic heterobicyclic group having 7 to 11 carbon atoms, such as quinoline, isoquinoline, benzothiazole or the like. Each hydrogen of the aromatic heterobicyclic group can be replaced by a further defined substituent.
  • C l-8 alkyl means an alkyl chain having from 1 to 8 carbon atoms, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl.
  • Each hydrogen of the Cl-8 alkyl carbon can be replaced by a further defined substituent.
  • the "prodrug” means a derivative which is converted into a compound of the present invention by a reaction with an enzyme, a gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like which is each carried out under an enzyme catalysis.
  • metabolite refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.
  • Isotopic derivative means a compound which contains an isotope in an unnatural ratio to one or more of the constituent compounds. For example, hydrazine (2H or D), carbon-13 (13C), nitrogen-15 (15N), and the like.
  • Solidvate means a form of the compound which is usually physically associated with a solvent by a solvolysis reaction. This physical bond involves hydrogen bonding.
  • Conventional solvents include water, ethanol, methanol, acetic acid, and the like.
  • the compound of formula (I) can be crystallized It is prepared in the form of a solvate (for example, in hydrated form).
  • Suitable solvates comprise pharmaceutically acceptable solvates (e.g., hydrates), and further comprise stoichiometric solvates and non-stoichiometric solvates. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of dissociating.
  • “Solvate” encompasses both solution and dissociable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • the invention also includes all tautomeric and stereoisomeric forms in all ratios together with mixtures thereof in any ratio, and pharmaceutically acceptable salts, prodrugs, metabolites thereof, Isotopic derivatives and solvates, and pharmaceutical compositions comprising the compounds.
  • the isomers can be separated by methods well known in the art, for example by liquid chromatography. Suitable for use by the use of, for example, the chiral stationary phase of the enantiomer.
  • the enantiomers can be separated by conversion to the diastereomers, i.e., coupled to the enantiomerically pure auxiliary compound, followed by isolation of the resulting diastereomer and cleavage of the auxiliary residue.
  • any enantiomer of a compound of formula (I) can be obtained from stereoselective synthesis using optically pure starting materials.
  • the compound of formula (I) may exist in crystalline or amorphous form. Furthermore, certain crystalline forms of the compounds of formula (I) may exist in polymorphic form and are included within the scope of the invention.
  • Many conventional analytical techniques can be used including, but not limited to, single crystal X-ray powder diffraction (XRPD) patterns, infrared (IR) spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solids.
  • XRPD single crystal X-ray powder diffraction
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • solidssNMR Nuclear magnetic resonance
  • a pharmaceutically acceptable salt of a compound of formula (I), which comprises one or more basic or acidic groups also includes its corresponding pharmaceutically or toxicologically acceptable salts, in particular pharmaceutically acceptable salt.
  • compounds of the formula (I) which comprise an acidic group can be used according to the invention, for example as an alkali metal salt, an alkaline earth metal salt or as an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the formula (I) which comprise one or more basic groups, ie groups which can be protonated, can be used in the form of their addition salts with inorganic or organic acids according to the invention.
  • suitable acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, as well as other acids known to those skilled in the art.
  • the compound of the formula (I) contains both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned.
  • the individual salts of formula (I) can be obtained by conventional methods known to those skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. obtain.
  • the invention also includes all salts of the compounds of formula (I) which are not directly applicable to the drug due to low physiological compatibility. However, it can be used, for example, as an intermediate in a chemical reaction or in the preparation of a pharmaceutically acceptable salt.
  • the term "pharmaceutically acceptable” means that the corresponding compound, carrier or molecule is suitable for administration to a human.
  • the term refers to a mammalian preferred person certified by a regulatory agency such as CFDA (China), EMEA (Europe), FDA (United States), and the like.
  • “Pharmaceutical composition” when used as a medicament, a salt, an isotopic derivative, a metabolite, a prodrug, a solvate of the compound of the formula (I) and a compound of the formula (I) of the present invention and having biological activity and or no biological activity
  • a composition of a composition of matter as a JAK inhibitor for use in the treatment or prevention of an immune, autoimmune or allergic condition, a proliferative or proliferative disease, inflammation, an allergic condition, transplant rejection, immune mediated.
  • the pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable carriers for use as pharmaceutical formulations and pharmaceutical dosage forms for administration by injection and non-injection.
  • the carrier includes all pharmaceutical preparations which can be used in the pharmaceutical field for the preparation of injection and non-injection routes, such as diluents, wetting agents, fillers, binders, slip agents, disintegrating agents, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculating agents, emulsifiers, common substrates, solubilizers, solubilizers, latent solvents, preservatives, flavoring agents, colorants, antioxidants A buffer, a bacteriostatic agent, an isotonicity adjusting agent, a pH adjusting agent, a metal ion complexing agent, a hardening agent, a thickening agent, an absorption enhancer, and the like.
  • the compounds of the formula (I) and pharmaceutical compositions of the invention may be formulated into pharmaceutical preparations and pharmaceutical dosage forms for administration by injection or non-injection. Suitable for subcutaneous injection, intramuscular injection, intravenous injection, oral administration, pulmonary (nasal or oral inhalation), rectal, topical, parenteral, intra-articular, ocular, nasal administration, etc., although most appropriate in any given case
  • the route will depend on the nature and severity of the disease state being treated and the nature of the active ingredient. They can conveniently be presented in a single dosage form and are prepared by any methods known in the art of pharmacy.
  • the diseases and conditions associated with tyrosine kinase inhibitors in the present invention are proliferative diseases such as cancer and the like.
  • the compounds of the present invention and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and pharmaceutical compositions comprising the same, are useful for preventing or treating proliferative diseases such as cancer Methods.
  • the results show that the compound of the present invention (I) has good tyrosine kinase activity and no cytotoxicity.
  • Example 5 1-(2-Fluoro-acetyl)-cyclopropene ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidine-4-methoxy )-quinoline-4-oxy]-phenyl ⁇ -amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 9 cyclopropane-1,1-dicarboxylic acid ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidin-4-methoxy)-quin Phenyl-4-oxy]-phenyl ⁇ -amide (1-methyl-1,6-dihydro-pyridin-3-yl)-amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 12 cyclopropane-1,1-dicarboxylic acid (1-ethyl-piperidin-3-yl)-amide ⁇ 3-fluoro-4-[6-methoxy-7-(1-carboxamide) -piperidin-4-methoxy)-quinoline-4-oxy]-phenyl ⁇ -amide
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 13 Cyclopropane-1,1-dicarboxylic acid cyclopentadienyl-1,3-amido ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl- Piperidine-4-methoxy)-quinoline-4-oxo]-phenyl ⁇ -amide
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 14 cyclopropane-1,1-dicarboxylic acid ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidin-4-methoxy)-quin Phenyl-4-oxy]-phenyl ⁇ -amide (4H-pyrazol-3-yl)-amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 15 cyclopropane-1,1-dicarboxylic acid ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidin-4-methoxy)-quinaline Phenyl-4-oxy]-phenyl ⁇ -amide (1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 16 Cyclopropane-1,1-dicarboxylic acid ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidin-4-methoxy)-quinaline Phenyl-4-oxy]-phenyl ⁇ -amide (1-methyl-4,5-dihydro-1H-pyrrol-3-yl)-amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 17 Cyclopropane-1,1-dicarboxylic acid benzyl ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidine-4-methoxy) -quinoline-4-oxy]-phenyl ⁇ -amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 20 cyclopropane-1,1-dicarboxylic acid ⁇ 3-fluoro-4-[6-methoxy-7-(1-methylcarbamoyl-piperidin-4-methoxy)-quinaline Phenyl-4-oxy]-phenyl ⁇ -amide (4H-pyrazole-3-methyl)-amide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 21 Inhibition of tyrosine kinase activity in vitro screening assay
  • the enzyme reaction substrate PolyB 4:1 was diluted to 20 ⁇ g/ml with potassium ion-free PBS, coated with an enzyme plate at 37 ° C for 12-16 hours, and the liquid in the well was discarded; T-PBS was washed three times. 10 minutes each time; the enzyme plate was dried in an oven at 37 ° C; the test sample was added to the wells of the coated enzyme plate (the test sample was first prepared with DMSO in a stock solution of 10-2 M, and stored after dispensing.
  • Example 22 Inhibition of proliferation of human tumor cells in vitro
  • 100 ⁇ l of the compound containing 2X and paclitaxel were added to the corresponding wells of a 96-well plate, and cultured in a carbon dioxide cell incubator for 72 hours.
  • the medium was removed, 150 ⁇ l of XTT working solution (0.3 mg/ml XTT; 0.00265 mg/ml PMS) was added to each well, and placed in a carbon dioxide incubator for 2 hours, the microplate oscillator was shaken for 5 minutes, and the absorbance was read by a microplate reader at 450 nm. The inhibition rate (%) of the compound against human tumor cells was calculated, and the IC 50 value ( ⁇ M) was determined. The results are shown in Table 2.
  • Wst-8 in CCK8 can be reduced by dehydrogenase in mitochondria to form a highly water-soluble orange-yellow formazan product (formazan) in the presence of an electron coupling reagent.
  • the depth of color and the proliferation of cells In proportion, it is inversely proportional to cytotoxicity.
  • the OD value was measured at a wavelength of 450 nm using a microplate reader, indirectly reflecting the number of viable cells, and was used to determine the cytotoxicity of the compound.

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Abstract

La présente invention concerne un composé d'un inhibiteur de tyrosine kinase, le composé étant un composé de formule (I), un sel pharmaceutiquement acceptable, un promédicament, un métabolite, un dérivé d'isotope ou un solvate de celui-ci. La présente invention concerne en outre une composition pharmaceutique comprenant le composé, la composition pharmaceutique pouvant prévenir ou traiter une maladie ou un trouble lié à un récepteur de tyrosine kinase. La présente invention concerne en outre une application de celui-ci en tant qu'inhibiteur de tyrosine kinase dans des expériences médicales, pharmaceutiques, biologiques, physiologiques et biochimiques.
PCT/CN2016/102411 2016-08-26 2016-10-18 Composé en tant qu'inhibiteur de tyrosine kinase WO2018035950A1 (fr)

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WO2012171487A1 (fr) * 2011-06-17 2012-12-20 天津隆博基因药物科技有限公司 Dérivés d'aryloxy quinolines et leur utilisation thérapeutique

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WO2012171487A1 (fr) * 2011-06-17 2012-12-20 天津隆博基因药物科技有限公司 Dérivés d'aryloxy quinolines et leur utilisation thérapeutique

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DATABASE REGISTRY 10 January 2013 (2013-01-10), retrieved from STN Database accession no. 1416321-45-3 *

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