319460-85-0Relevant articles and documents
Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor
Schmidt, Dorian,Rodat, Theo,Heintze, Linda,Weber, Jantje,Horbert, Rebecca,Girreser, Ulrich,Raeker, Tim,Bu?mann, Lara,Kriegs, Malte,Hartke, Bernd,Peifer, Christian
, p. 2415 - 2426 (2018)
The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned “on” and “off”, as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.
PROCESS FOR PREPARING AXITINIB, PROCESS FOR PURIFYING THE INTERMEDIATE 2-((3-IODO-1H-INDAZOL-6-YL)THIO)-N-METHYLBENZAMIDE, PROCESS FOR PURIFYING AXITINIB VIA THE AXITINIB HCL SALT, SOLID FORM OF THE AXITINIB HCL SALT
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Page/Page column 25-26, (2020/10/28)
1) A process for preparing Axitinib ( N-methyl-2-({3-[(E)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl}sulfanyl)benzamide; compound of formula (l)) 2) A process for purifying the intermediate 2-((3-iodo-lH-indazol-6- yl)thio)-N-methylbenzamide (compound of formula (lla)) 3) A process for purifying Axitinib using the Axitinib HCI salt (compound of formula (VIII)) as an intermediate 4) A solid form of the Axitinib HCI salt (form J) characterized by an XRPD pattern
CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PK PROPERTIES
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Page/Page column 265-266; 267, (2021/01/22)
The present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor ( TKI ) compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.
Photoswitchable azo‐ and diazocine‐functionalized derivatives of the vegfr‐2 inhibitor axitinib
Heintze, Linda,Schmidt, Dorian,Rodat, Theo,Witt, Lydia,Ewert, Julia,Kriegs, Malte,Herges, Rainer,Peifer, Christian
, p. 1 - 23 (2020/11/30)
In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)‐2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene‐like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]‐cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z‐isomer usually is bioinactive, and back isomerization from the bioactive E‐isomer occurs thermally. Here, we report on the development of different sulfur– diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR‐2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR‐2 kinase assay that the Z‐isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR‐2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40‐fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.
Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: Synthesis of axitinib
Yu, Jingbo,Hong, Zikun,Yang, Xinjie,Jiang, Yu,Jiang, Zhijiang,Su, Weike
supporting information, p. 786 - 795 (2018/04/16)
A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.
Method for preparing axitinib and intermediates thereof
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, (2018/05/30)
The invention discloses a method for preparing axitinib and intermediates thereof. A chemical name of the axitinib is N-methyl-2-[(3-(1E-2-(pyridine-2-yl)ethylene)-1H-indazole-6-yl)sulfur]benzamide, and a chemical formula of the axitinib is C22H18N4OS. The preparation process disclosed by the invention is simple in process, readily available in raw materials, economic, environmentally friendly, high in product yield and product purity, contributes to realizing industrialization, reduces the production cost and is suitable for mass production. The provided novel intermediates and the preparation method thereof have significance on the economic technology of the axitinib.
Preparation method of drug Axitinib for resisting kidney cancer
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, (2018/05/16)
The invention discloses a preparation method of the drug Axitinib for resisting the kidney cancer. The chemical name of the drug Axitinib for resisting the kidney cancer is N-methyl-2-[(3-(1E-2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)sulphur]benzamide, and the chemical formula of the Axitinib is C22H18N4OS. The preparation technology is simple in process, the raw materials are easy to obtain, the preparation method is economical, environmentally friendly, easy to industrialize, capable of promoting economic and technology development of raw materials of the drug Axitinib for resisting the kidneycancer and reducing the production cost, and suitable for large-scale production.
Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof
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Paragraph 0086; 0087, (2017/04/29)
The invention relates to the technical field of medical chemistry and particularly relates to Axitinib fumarate, a crystal form thereof and preparation methods for the Axitinib fumarate and the crystal form thereof. The prepared Axitinib fumarate and the crystal form thereof are high in Axitinib fumarate yield and high in purity. In addition, the Axitinib fumarate provided by the invention can further be used for preparing Axitinib after the Axitinib fumarate is dissociated. According to the preparation method for the Axitinib fumarate, disclosed by the invention, the Axitinib fumarate is prepared through subjecting the Axitinib and fumaric acid to a salt forming reaction. The Axitinib may be a direct crude product prepared by disclosures in the existing documents, or may also be pure Axitinib which is obtained through carrying out certain-aftertreatment impurity removal. Even if crude Axitinib and fumaric acid are subjected to salt forming, the Axitinib fumarate with high purity can be prepared through the salt forming reaction.
A process for the preparation of intermediates axi for Nepal the preparation and application of axi for Nepal
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, (2016/10/07)
The invention relates to a method for preparing an intermediate of axitinib and application of the intermediate in preparation of axitinib. The preparation method for the intermediate of axitinib 3-iodine-6-nitro-1-(teralin-2H-pyran-2-base)-1H-indazole comprises the following steps that 6-nitroindazole and 3,4-dihydro-2H-pyran react under the action of catalyst so as to protect perssad tetralin-2H-pyran-2-base at N-H site, and the key intermediate with high yield is obtained through iodination at site 3. The application of the intermediate in preparation of axitinib is as follows: Heck coupled reaction is carried out on the intermediate and 2-vinyl pyridine, then nitro reduction and diazo-reaction for iodination are sequentially carried out, finally, the axitinib is obtained after docking of 2-sulfydryl-N-methyl benzamide and deprotection. The related main initial raw materials are easy to purchase in markets, and the method has high yield and high molecule economic efficiency, is efficient and environment-friendly, and is suitable for industrial mass production.
Processes for the Preparation of Axitinib
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Paragraph 0054, (2016/11/17)
Processes for the preparation of Axitinib in good yield (generally greater than 80%) are provided that avoid the use of a palladium-catalyzed coupling reaction.