- Harnessing affinity-based protein profiling to reveal a novel target of nintedanib
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Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.
- Chen, Xiong,Li, Manru,Li, Menglin,Wang, Dongmei,Zhang, Jinlan
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supporting information
p. 3139 - 3142
(2021/04/02)
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- ALK5 INHIBITOR CONJUGATES AND USES THEREOF
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The present disclosure relates to targeted drug conjugates comprising ALK5 inhibitors and targeting moieties that direct the ALK5 inhibitors to cells involved in fibrosis and cancer, for example myofibroblasts, activated fibroblasts and transitioning fibr
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Paragraph 0191-0193
(2021/07/17)
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- Method for preparing nintedanib ethanesulfonate
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The invention discloses a method for preparing nintedanib ethanesulfonate. The method comprises the following steps: carrying out acylation reaction on 2-oxoindole-6-methyl formate and acetic anhydride to obtain 1-acetyl-2-oxoindoline -6-methyl formate; condensing with trimethyl orthobenzoate to generate 1-acetyl-3-(methoxyphenyl methylene)-2-oxoindoline-6-methyl formate, and finally reacting withN-(4-aminophenyl)-N, 4-dimethyl-1-piperazinecarboxamide; under the condition of not separating a main product, adding an alkali for deprotection to generate nintedanib, and finally salifying with ethanesulfonic acid to generate the nintedanib ethanesulfonate. The method has the advantages of mild reaction conditions, simple process operation and high yield, can obtain the nintedanib ethanesulfonate with the purity of 100% without refining, and is suitable for industrial production.
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Paragraph 0021; 0040-0042; 0049-0051; 0058-0060
(2020/11/12)
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- Preparation method of dihydroindolone derivative and intermediate thereof
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The invention provides a dihydroindolone derivative represented by a formula I, and a preparation method of an intermediate of the dihydroindolone derivative. The preparation method of the dihydroindole derivative intermediate comprises the following steps: enabling 2-oxoindole-6-methyl formate and acetic anhydride to react in methylbenzene under the heating condition of 100 DEG C to 110 DEG C toobtain 1-acetyl-2-oxodihydroindolone-6-methyl formate. The preparation method of the indolinone derivative comprises the following steps: (1) carrying out a condensation reaction on 1-acetyl-2-oxodihydroindolone-6-methyl formate and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound represented by a formula IV; (2) enabling the compound represented by the formula IV to react with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) acetamide to obtain a compound represented by a formula V; and (3) deprotecting the compound represented by the formula V to obtain the compound represented by the formula I.
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Paragraph 0071-0095
(2020/09/23)
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- ANTIBODY-ALK5 INHIBITOR CONJUGATES AND THEIR USES
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The present disclosure relates to antibody-drug conjugates comprising ALK5 inhibitors and their uses.
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Paragraph 0183-0185
(2020/02/06)
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- ANTIBODY-ALK5 INHIBITOR CONJUGATES AND THEIR USES
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The present disclosure relates to antibody-drug conjugates comprising ALK5 inhibitors and their uses.
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Paragraph 0199-0201
(2020/06/07)
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- ANTIB0DY-ALK5 INHIBITOR CONJUGATES AND THEIR USES
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The present disclosure relates to antibody-drug conjugates comprising ALK5 inhibitors and their uses.
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Paragraph 0188-0190
(2021/01/21)
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- SYNTHESIS OF A 2-INDOLINONE DERIVATIVE KNOWN AS INTERMEDIATE FOR PREPARING NINTEDANIB
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The invention discloses the preparation method of methyl (E)-1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylatefrom methyl 2-oxoindoline-6-carboxylate using high reaction temperatures and a reaction solvent enabling azeotropic removal of acetic acid during the reaction.
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Page/Page column 4; 6-8
(2019/06/13)
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- A METHOD FOR PREPARING METHYL (Z)-3-[[4-[METHYL[2-(4-METHYL-1-PIPERAZINYL)ACETYL] AMINO]PHENYL]AMINO]PHENYLMETHYLENE)-OXINDOLE-6-CARBOXYLATE (INTEDANIB, NINTEDANIB)
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The invention relates to a method of synthesizing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate of formula (1), known under the generic name of intedanib or nintedanib. The present method comprises a) a reaction of methyl oxindole-6-carboxylate with acetic anhydride at a temperature of 130 - 140°C, providing methyl 1-acetyl-oxindole-6-carboxylate; b) a reaction of methyl 1-acetyl-oxindole-6-carboxylate of with trimethyl orthobenzoate and acetic anhydride in the presence of toluene, providing methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate; c) a reaction (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and subsequently with an alkali hydroxide or alkali alkoxide in methanol or ethanol without isolation of the intermediate, providing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate, wherein the reaction is conducted at a temperature of 50 to 100°C. (1)
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Page/Page column 7
(2017/02/24)
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- Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth
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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.
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p. 2609 - 2616
(2017/04/06)
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- Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)
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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
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experimental part
p. 4466 - 4480
(2010/03/02)
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- HETEROCYCLICALLY SUBSTITUTED INDOLINONES, THEIR PRODUCTION AND USE AS MEDICAMENTS
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The invention relates to heterocyclically substituted indolinones of general formula (I), in which R1 to R5 and X are defined as cited in claim 1, to their tautomers, diastereomers, enantiomers and to their mixtures, prodrugs and salts, in particular their physiologically compatible salts. Said compounds exhibit valuable pharmacological characteristics, in particular an inhibiting action on various receptor tyrosine kinases and cyclin-CDK complexes and on the proliferation of endothelial cells and various tumour cells. The invention also relates to medicaments containing said compounds, to the use of the latter and to a method for producing the same.
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Page/Page column 81
(2008/06/13)
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