WO2018170997A1 - Procédé de préparation d'un composé - Google Patents

Procédé de préparation d'un composé Download PDF

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Publication number
WO2018170997A1
WO2018170997A1 PCT/CN2017/081677 CN2017081677W WO2018170997A1 WO 2018170997 A1 WO2018170997 A1 WO 2018170997A1 CN 2017081677 W CN2017081677 W CN 2017081677W WO 2018170997 A1 WO2018170997 A1 WO 2018170997A1
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WO
WIPO (PCT)
Prior art keywords
compound
acid
reaction
group
formula
Prior art date
Application number
PCT/CN2017/081677
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English (en)
Chinese (zh)
Inventor
许军
彭红
张文燕
陶琳
张晓丽
赵银鹰
王晓霞
李永华
邹阳
Original Assignee
南昌弘益药业有限公司
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Application filed by 南昌弘益药业有限公司 filed Critical 南昌弘益药业有限公司
Publication of WO2018170997A1 publication Critical patent/WO2018170997A1/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

Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and in particular, the present invention relates to a process for synthesizing quinoline compounds.
  • Protein tyrosine kinase is a class of proteins with protein tyrosine kinase activity that catalyzes the transfer of phosphogenes on ATP to many protein tyrosine residues associated with cellular life activities, allowing them to undergo phosphoric acid Chemical.
  • the protein tyrosine kinase signaling pathway is involved in the regulation, signaling, transmission and development of normal cells, and is also closely related to the proliferation, differentiation, migration and apoptosis of tumor cells.
  • 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 binds to its ligand VEGF to produce 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 fine Cells, also found in endothelial cells, hepatocytes, nerve cells and hematopoietic cells, play an important role in embryonic 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.
  • novel quinoline compounds of the present invention require a synthetic process suitable for industrial production, high purity products, and multi-targeted tyrosine protein kinase inhibitors, whose main function is to inhibit Tyrosine protein kinase activity plays its role.
  • tyrosine protein kinase inhibitors whose main function is to inhibit Tyrosine protein kinase activity plays its role.
  • the possibility of such compounds inhibiting other disease-associated protein kinases is not excluded.
  • R 1 is selected from the group consisting of hydrogen, OH, NH 2 ;
  • R 2 is selected from the group consisting of ROH, RNH, wherein R is a C 1 -C 4 alkyl group, a halogenated C 1 -C 4 alkyl group; and
  • Ar is an aryl or heteroaryl group.
  • Y is 0, 1, 2;
  • X is 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, and other acids known to those skilled in the art;
  • Z is 0, 1, 2H 2 O.
  • the reaction temperature is from 0 ° C to 50 ° C, and the reaction time is from 1 to 12 hours.
  • the reaction in the step (2), is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.
  • an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.
  • the molar ratio of the compound of the formula I to the various acids is from 1/0.1 to 1/20.
  • the method optionally further comprises the step (1):
  • the reaction temperature is from 0 ° C to 50 ° C, and the reaction time is from 1 to 12 hours.
  • the reaction in the step (1), is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.
  • an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.
  • the reaction in the step (1), can be carried out in the presence or absence of a base; the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, or a combination thereof.
  • the molar ratio of the compound of the formula II to the compound A is from 1/0.1 to 1/100.
  • the temperature of the reaction system was lowered to 0 ° C, 1250 g of ethyl chloroacetate was added, and the reaction was carried out for 2 hours at room temperature; the temperature of the reaction system was lowered to 0 ° C, 8000 ml of ice water was slowly added, and a large amount of solid was precipitated and stirred for 1 hour. , to all precipitated, suction filtration, washed 3 times with water; the filter cake is further beaten twice with 2 times the amount of absolute ethanol, filtered, and the filter cake is dried at 40-70 ° C for 4-8 hours; 430 g of intermediate 1 is obtained. Light yellow powder. Yield: 80%.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 11 Inhibition of tyrosine kinase activity in vitro screening assay
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 ⁇ g/ml with potassium-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, each time for 10 minutes; 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 to make a stock solution of 10-2 M, and dispensed.
  • the reaction system was placed in a wet box, shaken at 37 ° C for 1 hour in the dark, and T-PBS was washed three times after the reaction; the antibody was added, shaken at 37 ° C for 30 minutes, and washed three times with T-PBS; horseradish was added.
  • Peroxidase-labeled goat anti-mouse IgG shaken at 37 ° C for 30 minutes, washed three times with T-PBS; add OPD color solution, avoid reaction at room temperature for 1-10 minutes; add 2M H 2 SO 4 50 ⁇ l to stop
  • the reaction was measured for AB 490 using a tunable wavelength microplate reader.
  • the proliferation inhibitory activity of the compound on the cells was investigated and expressed by IC 50 .
  • the cells in the logarithmic growth phase were removed from the culture medium in the culture flask, and the cells were washed once with PBS, collected by centrifugation, centrifuged, resuspended in a medium containing 10% fetal bovine serum, and counted and adjusted to an appropriate concentration.
  • the cell suspension was added to a 96-well plate at 100 ul per well, and the compound was formulated into a 20 mM solution in DMSO.
  • the compound solution and paclitaxel (reservoir 0.2 mM) were diluted with DMSO (10 concentrations), and 5 ul of the gradient-diluted compound were respectively taken.
  • the solution and the paclitaxel solution were added to 495 ul of a medium containing 10% FBS to prepare a test compound solution.
  • 100 ul of the test compound solution was added to the corresponding well of a 96-well plate, and cultured in a carbon dioxide cell incubator for 72 hours.
  • the medium was removed, 150 ul per well of XTT working solution was added, and the carbon dioxide incubator was placed for 2 hours, the microplate was shaken for 5 min, and the absorbance was read by a microplate reader at 450 nm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé représenté par la formule I au moyen d'un composé représenté par la formule (II), les définitions de chaque groupe étant telles que définies dans la description. Le procédé de préparation de la présente invention possède les caractéristiques d'être productible de manière industrielle, étant d'un rendement élevé, ayant un produit facilement séparé, et similaire; le composé représenté par la formule (I) est un inhibiteur de protéine tyrosine kinase multi-cibles ayant une bonne activité antitumorale.
PCT/CN2017/081677 2017-03-23 2017-04-24 Procédé de préparation d'un composé WO2018170997A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710176619.1 2017-03-23
CN201710176619.1A CN108623565A (zh) 2017-03-23 2017-03-23 一种化合物的制备方法

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WO2018170997A1 true WO2018170997A1 (fr) 2018-09-27

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111253385B (zh) * 2020-02-12 2023-11-24 遵义医科大学珠海校区 一种杂环类化合物、制备方法及应用

Citations (3)

* 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
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

Patent Citations (3)

* 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
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
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

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