WO2012171487A1 - Dérivés d'aryloxy quinolines et leur utilisation thérapeutique - Google Patents

Dérivés d'aryloxy quinolines et leur utilisation thérapeutique Download PDF

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Publication number
WO2012171487A1
WO2012171487A1 PCT/CN2012/077016 CN2012077016W WO2012171487A1 WO 2012171487 A1 WO2012171487 A1 WO 2012171487A1 CN 2012077016 W CN2012077016 W CN 2012077016W WO 2012171487 A1 WO2012171487 A1 WO 2012171487A1
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Prior art keywords
decyloxy
yloxy
phenyl
piperidin
cyclopropane
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PCT/CN2012/077016
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English (en)
Chinese (zh)
Inventor
陈从喜
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天津隆博基因药物科技有限公司
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Priority to CN201280028921.8A priority Critical patent/CN103748074B8/zh
Publication of WO2012171487A1 publication Critical patent/WO2012171487A1/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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly to a class of aryloxyquinoline derivatives, salts of the compounds, and medicaments using the compounds or salts thereof as active ingredients, mainly for treating tyrosine with protein Acid kinase receptors are especially diseases associated with c-Met, VEGFR and the like. Background technique
  • Protein kinases represent a large family of proteins that play a key role in the regulation of cellular function processes. Protein kinases can cause a variety of tumors due to mutations or rearrangements that can cause signals to go to process disorders or abnormalities, leading to abnormal cell growth, differentiation, metabolism, and biological behavior. Protein kinases mainly include serine/threonine kinases and tyrosine kinases, in which protein tyrosine kinases play an important role in the signaling pathways of tumor cells, transmitting extracellular signals into cells and amplifying and regulating them. A series of physiological processes such as tumor cell proliferation, differentiation and apoptosis are the centers of cell signal transduction mechanisms.
  • c-Met kinase is a hepatocyte growth factor receptor and is a member of the tyrosine kinase receptor family. c-Met kinase is widely present in epithelial tissues and plays an important role in embryo development and wound healing. Recent studies have shown that c-Met kinase exhibits abnormally high expression in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, and prostate cancer. Mutation or activity changes. c-Met kinase can promote the proliferation of tumor cells, regulate the migration of tumor cells, enhance the invasive ability of tumor cells and induce the formation of tumor blood vessels. At present, c-Met kinase has become an important target for anti-tumor drug research.
  • c-Met is the intersection of many pathways leading to tumor formation and metastasis. It plays an important role in the formation and metastasis of primary tumors. Simultaneous interference with many pathways can be achieved with c-Met as a target. Therefore, c-Met is a promising target for anti-tumor metastasis treatment and has become one of the hotspots of anti-tumor drug research.
  • Hepatocyte growth factor also known as the dispersing factor, is a ligand for the tyrosine kinase receptor c-Met and As a fibroblast-derived factor that induces the dispersion of epithelial cells, it has a mitogenic and induced morphogenesis effect on many epithelial cells.
  • HGF stimulates vascular endothelial growth factor and up-regulates the expression of molecules and their receptors involved in extracellular matrix proteolysis. In order to produce a biological effect, HGF must bind to its receptor c-Met, the receptor tyrosine kinase.
  • the specific membrane receptor of HGF is the expression product of the protooncogene c-Met, and its gene is located on chromosome 7q31, and the size of 110Kb contains 21 exons. Its promoter domain contains a number of regulatory sequences, including AP1, AP2, NF2JB, and SP1.
  • the HGF/c-Met signaling pathway plays an important role in the development of tumors. Specific binding of HGF to the c-Met receptor protein induces a conformational change in the c-Met receptor protein, activating 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 present invention provides a class of aryloxyquinoline derivatives having selective tyrosine protein kinase inhibitors whose main function is to exert anticancer effects by inhibiting tyrosine protein kinase activity.
  • the major tyrosine protein kinases inhibited by such compounds are c-Met, Abl, P38 ⁇ , PDGF-R and the like. Of course, such compounds may also inhibit other disease-associated protein kinases.
  • An object of the present invention is to provide an aryloxyquinoline derivative and a salt thereof or a solvate thereof.
  • a second object of the present invention is to provide a process for producing the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above aryloxyquinoline derivative and a salt thereof or a solvate thereof.
  • a fourth object of the present invention is to provide the use of the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
  • the present invention provides an aryloxyquinoline derivative having the structure of formula (I), Oen
  • R 2 , R 3 , R4 are each independently selected from hydrogen, C r C 3 alkyl; optionally, R 2 , R 3 may form a 3-6 membered carbocyclic ring with the carbon atom to which it is attached, or R 2 , R 3, wherein one of R4 may be connected to form a 4-8 membered azacyclic ring.
  • X is hydrogen or a halogen atom
  • Ar is an aryl or heteroaryl group, and may be substituted by halogen, C r C 4 alkyl, halogenated C r C 4 alkyl, C r C 4 alkoxy, - alkoxy;
  • R 5 and R 6 are each independently selected from hydrogen, dC 4 alkyl, and may be optionally substituted by dC 4 alkoxy, 5-10 membered heterocyclic ring or 3-10 membered carbocyclic group;
  • R 7 is dC 4 alkyl, which may be optionally substituted by a 5-10 membered heterocyclic ring or a 3-10 membered carbocyclic group;
  • n 0, 1, 2 or 3;
  • n 1, 2 or 3;
  • G is 3-10 yuan containing N heterocyclic ring, and can be optionally substituted
  • Ri , R 5 , Ar, m and X are as defined by the structure of formula (I);
  • the invention provides a preferred compound of the formula (II): N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
  • R 7 , Ar, X, m are as defined by the structure of formula (I);
  • the invention provides preferred compounds of the structure of formula (III):
  • the compounds provided herein have the structure of formula (IV):
  • R 7 , Ar, X, m are as defined by the structure of formula (I);
  • the invention provides a preferred compound of the formula (IV): ⁇ (3-fluoro-4-(6-decyloxy-7-((1-(2-( ⁇ )) Sulfo)ethyl)piperidin-4-yl)nonyloxy)quinoline-4-yloxy) Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diphthalamide;
  • a pharmaceutically acceptable salt thereof can form a salt with an acid, and a salt of a quinoline derivative can be produced by a method well known to those skilled in the art.
  • the common salts include organic acid salts, inorganic acid salts, and the like.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, camphor sulfonate, p-toluene, barium salt, etc.; Salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
  • a lower alkyl acid such as sulfonic acid, trifluorosulfonium sulfonic acid, etc.
  • it can form an oxime sulfonate, a trifluorosulfonium sulfonate; and an aryl sulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid.
  • an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc.
  • the -C 4 alkyl group includes a decyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group.
  • the halogen includes fluorine, chlorine, bromine and iodine.
  • the halogenated C r C 4 alkyl group means having one or more surface groups on the dC 4 carbon chain, such as a trifluoromethyl group.
  • the invention provides a process for the preparation of the above compounds:
  • each of the above compounds in the above-mentioned production method is as defined in the compound of the formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above aryloxyquinoline derivative or a salt or solvate of the compound as an active ingredient.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers including conventional diluents in the pharmaceutical field, excipients, fillers, binders, wetting agents, disintegrants, absorption promotion Agent, surfactant, adsorption carrier, lubricant, etc., if necessary To add flavoring agents, sweeteners, and the like.
  • the pharmaceutical composition of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
  • the present invention provides the use of an aryloxyquinoline derivative of the present invention or a salt or solvate of the compound for treating a human or animal disease associated with a tyrosine kinase, particularly c-Met, VEGFR, including treatment of hyperplasia Sexual diseases such as cancer, or inflammatory diseases.
  • the inventors of the present invention confirmed by experiments that the compound of the present invention has an anti-value-inhibiting action against a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with human or animal cell proliferation.
  • MMC-803 human gastric cancer cell line
  • Step 8 Synthesis of 4-(4-(2-fluoro-4-nitrophenoxy)-6-methoxyoxyquinolin-7-yloxy)piperidine-1-indolyl tert-butyl ester
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 53 Compound of the present invention is swollen; i cell proliferation inhibition test
  • the tumor cells were trypsinized, they were seeded in a 96-well microplate at a density of 3,000 per well. Incubate for 24 hours in 10% FBS in complete medium. Add the test compound and solvent control, the final compound concentration is 10nmol / L to 5 ( ⁇ mol / L. Then cultured in complete medium for 72 hours. Add MTS reagent (Promega) according to the instructions, at 37 °C C0 2 The culture was incubated for 2 hours in an incubator, and then the absorbance at 490 nm was read on an ELISA plate reader, and the inhibition rate and IC 5 value were calculated.
  • MTS reagent Promega
  • XL-184 is N-(4-((6,7-dimethoxyoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl) Cyclopropane-1, 1-diamide.
  • the target compound has a high inhibitory effect on proliferation of MGC-803 (stomach cancer cells). Most of the compounds are superior to the positive drug Cabozantinib, which is equivalent to the activity of doxorubicin. In addition, the target compound has a higher affinity for BGC-823 (stomach cancer cells). High in vitro proliferation inhibition is superior to the positive drug Cabozantinib.
  • Example 54 Enzyme inhibition assay of the compounds of the invention c-Met and VEGFR2
  • the tyrosine kinase c-Met was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements;
  • the kinase reaction substrate Poly(Glu, Tyr)B 4:1 was purchased from Sigma;
  • Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
  • Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
  • ATP, DTT, OPD were purchased from Amresco;
  • the ELISA plate was purchased from Corning; PF2341066 was purchased from LC LabORATORIES;
  • the enzyme reaction substrate Poly(Glu, Tyr)B 4:1 was diluted to 20 g/ml with PBS without potassium ions, coated with the enzyme plate, and reacted at 37 °C for 12-16 h, and discarded in the well. liquid.
  • test sample was first prepared in DMSO with 10 - 2 M stock solution, and stored at -20 ° C after being dispensed. Dilute to the desired concentration with reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 ⁇ reaction system. A positive control well was also established and the positive control compound PF2341066 was added.
  • ATP solution diluted with the reaction buffer (ATP final concentration of 5 ⁇ ) was added, and finally, the test tyrosine kinase diluted with the reaction buffer was added.
  • the total volume of the reaction system is 100 ⁇ l. Negative control wells and enzyme-free control wells were also established.
  • Horseradish peroxidase-labeled goat anti-mouse IgG 100 ⁇ /well was added and shaken at 37 ° C for 30 min. The plate was washed three times with T-PBS.
  • the tyrosine kinase VEGFR2 was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements; the kinase reaction substrate Poly(Glu, Tyr) 4:1 was purchased from Sigma Corporation;
  • Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
  • Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
  • ATP, DTT, OPD were purchased from Amresco;
  • the ELISA plate was purchased from Corning;
  • Sul l248 was purchased from LC LabORATORIES
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 g/ml with PBS without potassium ion, coated with the enzyme plate, and reacted at 37 ° C for 12-16 h, discarding the liquid in the well. .
  • test sample was first prepared into 10 - 2 M stock solution in DMSO, and stored at - 20 ° C after being dispensed. Dilute to the desired concentration with the reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 ⁇ reaction system. A positive control well was also established and the positive control compound SU11248 was added.
  • Horseradish peroxidase-labeled goat anti-mouse IgG 100 ⁇ /well was added and shaken at 37 °C for 30 min. The plate was washed three times with T-PBS.
  • the aryloxyquinoline derivative compound of the present invention has an anti-inhibitory inhibitory effect on a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with cell proliferation of human or animal cells.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des dérivés d'aryloxy quinolines, qui sont des composés de formule (I), ou des sels ou solvates pharmaceutiquement acceptables de ceux-ci. Dans ladite formule, R1, R2, R3, R4, m, n, X, Z, Ar sont tels que définis dans la description. L'invention concerne également des médicaments contenant ces composés ou sels comme principes actifs, ainsi que leur utilisation dans le traitement d'affections ou de troubles associés aux récepteurs de la protéine tyrosine kinase, en particulier c-Met et VEGFR.
PCT/CN2012/077016 2011-06-17 2012-06-15 Dérivés d'aryloxy quinolines et leur utilisation thérapeutique WO2012171487A1 (fr)

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Application Number Priority Date Filing Date Title
CN201280028921.8A CN103748074B8 (zh) 2011-06-17 2012-06-15 芳氧基喹啉类衍生物及其治疗用途

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CN201110163215 2011-06-17
CN201110163215.1 2011-06-17
CN201110252035.0 2011-08-30
CN201110252035 2011-08-30
CN201110397142 2011-12-05
CN201110397142.2 2011-12-05

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018035950A1 (fr) * 2016-08-26 2018-03-01 南昌弘益药业有限公司 Composé en tant qu'inhibiteur de tyrosine kinase
WO2018035951A1 (fr) * 2016-08-24 2018-03-01 南昌弘益药业有限公司 Nouveau composé de quinoléine
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
WO2018133159A1 (fr) * 2017-01-17 2018-07-26 南昌弘益药业有限公司 Méthode de préparation d'un nouveau composé de quinoléine
WO2018170997A1 (fr) * 2017-03-23 2018-09-27 南昌弘益药业有限公司 Procédé de préparation d'un composé
CN109824587A (zh) * 2017-11-23 2019-05-31 上海翔锦生物科技有限公司 酪氨酸激酶抑制剂xjf007及其中间体的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093421A (zh) * 2011-01-28 2011-06-15 广州盈升生物科技有限公司 一种含磷取代基的喹啉类化合物及其制备方法、以及含有该化合物的药物组合物及其应用
CN102408411A (zh) * 2011-09-19 2012-04-11 广州盈升生物科技有限公司 一种含喹啉基的羟肟酸类化合物及其制备方法、以及含有该化合物的药物组合物及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2408300B1 (fr) * 2009-03-21 2016-05-11 Sunshine Lake Pharma Co., Ltd. Dérivés d'ester d'amino, sels de ceux-ci et procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093421A (zh) * 2011-01-28 2011-06-15 广州盈升生物科技有限公司 一种含磷取代基的喹啉类化合物及其制备方法、以及含有该化合物的药物组合物及其应用
CN102408411A (zh) * 2011-09-19 2012-04-11 广州盈升生物科技有限公司 一种含喹啉基的羟肟酸类化合物及其制备方法、以及含有该化合物的药物组合物及其应用

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
WO2018035951A1 (fr) * 2016-08-24 2018-03-01 南昌弘益药业有限公司 Nouveau composé de quinoléine
CN107778285A (zh) * 2016-08-24 2018-03-09 南昌弘益药业有限公司 一类喹啉类新化合物
WO2018035950A1 (fr) * 2016-08-26 2018-03-01 南昌弘益药业有限公司 Composé en tant qu'inhibiteur de tyrosine kinase
CN107778287A (zh) * 2016-08-26 2018-03-09 南昌弘益药业有限公司 作为酪氨酸蛋白激酶抑制剂的一类化合物
WO2018133159A1 (fr) * 2017-01-17 2018-07-26 南昌弘益药业有限公司 Méthode de préparation d'un nouveau composé de quinoléine
CN108329298A (zh) * 2017-01-17 2018-07-27 南昌弘益药业有限公司 一类喹啉类新化合物制备方法
WO2018170997A1 (fr) * 2017-03-23 2018-09-27 南昌弘益药业有限公司 Procédé de préparation d'un composé
CN108623565A (zh) * 2017-03-23 2018-10-09 南昌弘益药业有限公司 一种化合物的制备方法
CN109824587A (zh) * 2017-11-23 2019-05-31 上海翔锦生物科技有限公司 酪氨酸激酶抑制剂xjf007及其中间体的制备方法

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