cas 262368-30-9, N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide

Articles about 262368-30-9Total 19 be found

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Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction
A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitor
Hanusek, Ji?í,Marek, Luká?,Svoboda, Jan,Váňa, Ji?í
p. 10621 - 10629
(2021/07/31)

Refining method of amino intermediate
The invention relates to a tefining method of an amino intermediate represented by formula (I). Through the refining method, the concentrations of a genotoxic impurity 1 (N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide) and an impurity 2 (N-(4-(hydroxyamino) phenyl)-N-methyl-2- (4-methylpiperazin-1-yl) acetamide) can be controlled to 4 ppm or less. According to the present invention, the contents of the genotoxic impurity 1 and the genotoxic impurity 2 in the formula (I) are significantly reduced, such that the process guarantee is provided for the industrial preparation of high-quality nintedanib ethanesulfonate, and the medication safety is ensured.
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(2021/03/03)

Preparation method of nintedanib key intermediate
The invention provides a preparation method of a nintedanib key intermediate, and belongs to the technical field of synthesis of medical intermediates. The first preparation method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking an alcohol reagent or tetrahydrofuran as a solvent, taking hydrazine hydrate as a reducing agent and taking palladium carbon (Pd/C) as a catalyst until the nitro reduction reaction is complete, performing filtering to remove the catalyst under the protection of nitrogen, performing desolventizing to remove the solvent, performing dissolving by using dichloromethane, performing filtering to remove impurities, and performing desolventizing to obtain a compound I; the second method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking hydrazine hydrate as a reducing agent and anhydrous ferric trichloride and activated carbon as catalysts until the nitro reduction reaction is complete, performing performing filtering to remove the catalyst, performing desolventizing to remove the solvent, dissolving dichloromethane, drying anhydrous sodium sulfate, performing filtering, and performing desolventizing to obtain a compound I. The preparation method provided by the invention is high in yield, strong in operability and high in safety, belongs to an environment-friendly process, and is suitable for industrial large-scale production.
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Paragraph 0005; 0026-0039; 0045

(2021/09/08)

Preparation method of amino intermediate (by machine translation)
Compared with an existing preparation method, the method for preparing. the amine-based (I) intermediate disclosed by the invention comprises the following, steps: carrying (III) out condensation, reduction and the like of the compound of. the formula I to obtain, the target compound (I), and 1 remarkably reducing the, content of the impurities in the obtained compound according to the, invention as compared with the existing preparation. method. (by machine translation)
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(2020/02/20)

INDOLINONE COMPOUNDS FOR USE AS MAP4K1 INHIBITORS
The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring C, X1, X2, L1, R1, R2, R3, R4, R5, R6, R7, m and n are as defined herein, which are useful as MAP4K1 inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by MAP4K1.
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Page/Page column 66-67

(2020/05/15)

Preparation method of nintedanib key intermediate
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib key intermediate compound II. A compound IV is reduced by adopting a common reaction reagent under the conditions of normal temperature and normal pressure, so that a high-purity compound II can be conveniently obtained. The adopted reaction conditions are mild, high-pressure equipment is avoided, the technical operation is simple, the conditions are mild, the process is safer and more environmentally friendly, and the feasibility of large-scale productionof nintedanib is greatly improved.
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Paragraph 0052-0068

(2020/10/27)

INDOLINONE DERIVATIVES AS INHIBITORS OF MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
The present disclosure relates to indolinone compounds, compositions, and methods for the inhibition of maternal embryonic leucine zipper kinase (MELK). The present disclosure further relates to indolinone compounds, compositions, and methods for the treatment or prevention of a cancer (for example, triple negative breast cancer).
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(2018/09/20)

Method for preparing Nintedanib,I intermediate through one-pot method
The invention relates to a method for preparing Nintedanib,I key intermediate N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-group)acetamide through a one-pot method. The method comprises the steps that according to the technical scheme, N-methyl-4-nitroaniline is dissolved in an aqueous solution of an organic solvent and alkali, mixing is carried out, then chloroacetyl chloride or bromoacetyl bromide is dropwise added, and a first-stage reaction is carried out for 0.1-3 hours at the temperature of 0-70 DEG C; a water layer is removed, N-methyl piperazine is added, a second-stage reactionis carried out, and reacting is carried out for 2-10 hours at the temperature of 0-75 DEG C; then a reducing reagent is added, a third-stage reaction is carried out for 8-36 hours at the temperatureof 0-75 DEG C and the pressure of 15-100 psi. After the reaction is finished, filtering is carried out to remove the reducing reagent, the reaction liquid is condensed, a reverse phase solvent is added, crystallization is carried out, and the Nintedanib,I key intermediate N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-group)acetamide (formula B) is obtained. According to the preparation method, the raw materials are easy to obtain, the process is simple, and the method is economical, environmentally friendly and suitable for industrial production.
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(2018/10/19)

Novel method for synthesizing nintedanib key intermediate through one pot method
The invention relates to a novel method for synthesizing a nintedanib key intermediate through a one pot method. The method employs the one pot method, N-methyl-4-amino nitrobenzene and chloroacetyl chloride are subjected to a reaction, a reactant and N-methyl piperazine are subjected to the reaction, sodium hydrosulfite is reduced for synthesis of N-(4-amino phenyl)-N,4-dimethyl-1-piperazine acetylamine, wherein, no intermediate purifying or separating operation is generated during the processes, an organic solvent used for the solvent as a single solvent system, and a reaction equation is shown in a specification. The method greatly shortens the reaction time, simplifies reaction operation, has the advantages of mild reaction condition, simple operation, low production cost, and environment friendness, and is suitable for industrial production.
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Paragraph 0034; 0036; 0037; 0038

(2017/04/19)

Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.
Huang, Zhenhua,Li, Heran,Zhang, Qian,Lu, Fangzheng,Hong, Mei,Zhang, Zhigang,Guo, Xiaocui,Zhu, Yuanju,Li, Sanming,Liu, Hongzhuo
supporting information
p. 1142 - 1147
(2017/11/15)

Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth
Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.
Edupuganti, Ramakrishna,Taliaferro, Juliana M.,Wang, Qiantao,Xie, Xuemei,Cho, Eun Jeong,Vidhu, Fnu,Ren, Pengyu,Anslyn, Eric V.,Bartholomeusz, Chandra,Dalby, Kevin N.
p. 2609 - 2616
(2017/04/06)

Indole ketone compound or its derivatives and their use
The present invention relates to indolone compounds shown by general formula (a) or derivatives thereof, and uses thereof. The technical problem solved by the present invention is to provide indolone compounds or derivatives thereof, and uses thereof. The present invention uses a deuterium-enriched indolone compound obtained from a deuterium-substituted indolone compound. The above-mentioned indolone compounds can simultaneously effect on three key receptor families involved in the process of blood vessel formation, i.e., vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR), and inhibit the formation of blood vessel, thereby achieving the effect of treating cancers. The above-mentioned deuterium-substituted indolone compounds or derivatives thereof have the advantage of high efficiency as medicaments.
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Paragraph 0125; 0146; 0150; 0151

(2017/02/02)

Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties
Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. Deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. Further research is underway.
Xu, Ruixue,Zhan, Miao,Peng, Lingling,Pang, Xuehai,Yang, Jun,Zhang, Tao,Jiang, Hongxia,Zhao, Lifeng,Chen, Yuanwei
p. 308 - 312
(2015/06/25)

OXINDOLE INHIBITORS OF TYROSINE KINASE
The present invention relates to new oxindole inhibitors of tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
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(2015/11/02)

INTEDANIB SALTS AND SOLID STATE FORMS THEREOF
The present invention provides salts of Intedanib, crystalline forms of the salts of Intedanib, processes for their manufacture and their use in pharmaceutical compositions.
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Page/Page column 13; 14

(2012/06/01)

Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a newtreatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
Roth, Gerald J.,Heckel, Armin,Colbatzky, Florian,Handschuh, Sandra,Kley, J?rg,Lehmann-Lintz, Thorsten,Lotz, Ralf,Tontsch-Grunt, Ulrike,Walter, Rainer,Hilberg, Frank
experimental part
p. 4466 - 4480
(2010/03/02)

INDOLINONE DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE
The present invention relates to specific indolinone derivatives, namely the compounds of formula, in which R1 represents an hydrogen atom or a group, and R2 and R3 each represent an hydrogen atom or R2 and R3 taken together represent a group, with the proviso that when R1 represents an hydrogen atom R2 and R3 taken together represent a group, and to a process for their manufacture.
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Page/Page column 21-22; 13

(2009/07/17)

PROCESS FOR THE MANUFACTURE OF AN INDOLINONE DERIVATIVE
The present invention relates to a process for the manufacture of a specific indolinone derivative and a pharmaceutically acceptable salt thereof, namely 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate, to new manufacturing steps and to new intermediates of this process.
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Page/Page column 4; 23-24

(2009/07/17)

Substituted indolines which inhibit receptor tyrosine kinases
Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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Page column 52

(2008/06/13)