- Anti-cancer drug gefitinib and analog intermediate electro-reduction preparation method thereof
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The invention relates to an electroreduction preparation method of a 2-amino-4-methoxybenzoic acid derivative represented by a formula I, wherein the preparation reaction is defined in the specification, n is selected from 1, 2 and 3, X is selected from C
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Paragraph 0076-0079; 0080-0083
(2021/05/08)
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- Four-membered heterocycles-containing 4-anilino-quinazoline derivatives as epidermal growth factor receptor (EGFR) kinase inhibitors
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We report herein the design and synthesis of novel azaspirocycle or azetidine substituted 4-anilinoquinazoline derivatives. The EGFR inhibitory activities and in vitro antitumor potency of these newly synthesized compounds against two lung cancer cell lines HCC827 and A549 were evaluated. Most of the target compounds possess good inhibitory potency. In particular, compounds 21g with 2-oxa-6-azaspiro[3.4]octane substituent was found to possess higher EGFR inhibitory activities and similar antitumor potency comparing to the lead compound gefitinib with improved water solubility.
- Zhao, Feng,Lin, Zhaohu,Wang, Feng,Zhao, Weili,Dong, Xiaochun
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p. 5385 - 5388
(2013/09/23)
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- Novel EGFR inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines
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On the basis of combination strategy, a novel series of EGFR inhibitors were designed and synthesized by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay in three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Two compounds (11d and 11f) were found more potent against all three cell lines and five compounds (11a, 11d-11g) were found more potent against both MDA-MB-468 and SK-BR-3 than Lapatinib. SAR studies revealed that the substituents on C6 and C7 positions of quinazoline, the amine component of dithiocarbamate moiety and the linker greatly affected the activity. This work provides a promising new strategy for the preparation of potent tyrosine kinase inhibitors.
- Li, Ri-Dong,Zhang, Xin,Li, Qiao-Yan,Ge, Ze-Mei,Li, Run-Tao
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p. 3637 - 3640
(2011/08/06)
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- 4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors
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Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy) phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
- Holladay, Mark W.,Campbell, Brian T.,Rowbottom, Martin W.,Chao, Qi,Sprankle, Kelly G.,Lai, Andiliy G.,Abraham, Sunny,Setti, Eduardo,Faraoni, Raffaella,Tran, Lan,Armstrong, Robert C.,Gunawardane, Ruwanthi N.,Gardner, Michael F.,Cramer, Merryl D.,Gitnick, Dana,Ator, Mark A.,Dorsey, Bruce D.,Ruggeri, Bruce R.,Williams, Michael,Bhagwat, Shripad S.,James, Joyce
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p. 5342 - 5346
(2011/10/09)
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- Design, synthesis, and in vitro antitumor activity evaluation of novel 4-pyrrylamino quinazoline derivatives
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Here, we describe the design and synthesis of two series of 4-pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI-6, GII-4, GII-6, GII-8, and GII-9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure-activity relationship to provide information for designing and developing more potent antitumor agents.
- Wu, Xiaoqing,Li, Mingdong,Tang, Wenhua,Zheng, Youguang,Lian, Jiqin,Xu, Liang,Ji, Min
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p. 932 - 940
(2012/03/11)
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- Design, synthesis of novel quinazolone alkaloids derivatives as potential antitumor agents
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Several novel quinazolone alkaloids derivatives were synthesized. Some of the target compounds were determined against human prostate cancer DU145 and pancreatic cancer Miacapa2 cells in vitro. The entire compounds had been identified by 1HNMR, 13CNMR, IR, MS and EA.
- Zheng, Youguang,Sun, Min,Liu, Yi,Li, Mingdong,Ji, Min
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p. 295 - 300
(2012/06/01)
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- Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity
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There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefiti
- Wu, Xiaoqing,Li, Mingdong,Qu, Yang,Tang, Wenhua,Zheng, Youguang,Lian, Jiqin,Ji, Min,Xu, Liang
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experimental part
p. 3812 - 3822
(2010/08/06)
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- Design, synthesis, docking and antitumor activity of quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one derivatives
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Several novel quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one derivatives were synthesized. All of the compounds were determined against MiaPaCa2 and DU145 cells in vitro, and the crystal structures of analog 8 and 20 in the active site of the EGFR c
- Zheng, Youguang,Wu, Xiaoqing,Xue, Bai,Li, Mingdong,Ji, Min
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experimental part
p. 285 - 290
(2010/12/19)
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- QUINAZOLINE DERIVATIVES AS RAF KINASE MODULATORS AND METHODS OF USE THEREOF
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Compounds according to formula (I), compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases. Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate of hydrate thereof, wherein X is O or S(O)t; Ra is O or S.
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Page/Page column 185
(2009/10/22)
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- Synthesis of gefitinib from methyl 3-hydroxy-4-methoxy-benzoate
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This paper reports a novel synthesis of gefitinib starting from methyl 3-hydroxy-4-methoxybenzoate. The process starts with alkylation of the starting material, followed by nitration, reduction, cyclization, chlorination and two successive amination reactions. The intermediates and target molecule were characterized by 1H-NMR, 13C-NMR, MS and the purities of all these compounds were determined by HPLC. This novel synthetic route produced overall yields as high as 37.4%.
- Ming, Dong Li,You, Guang Zheng,Ji, Min
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p. 673 - 678
(2008/02/01)
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- PROCESS FOR PRODUCING QUINAZOLIN-4-ONE DERIVATIVE
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A process for producing a quinazolin-4-one compound having the formula: [wherein R1, R2, R3 and R4 each represents a group not participating in the below-mentioned reaction, and R1, R2, R3 and R4 can be combined together to form a ring] which comprises reacting an anthranilic acid derivative having the formula: [wherein R5 is a hydrogen atom or a hydrocarbyl group] with a formic acid derivative in the presence of an ammonium carboxylate.
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- Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity
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Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino] -6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM) several additional analogues were prepared. Optimization of the C-4 anilino group of la led to lc which contains a 2,4-dichloro-5-methoxy- substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors and the propoxy group of 2c was preferred over ethoxy butoxy or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a which had an IC50 of 1.2 nM in the Src enzymatic assay an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a which had higher 1 and 4 h plasma levels than 2c effectively inhibited tumor growth in xenograft models.
- Boschelli,Ye,Wang,Dutia,Johnson,Wu,Miller,Powell,Yaczko,Young,Tischler,Arndt,Discafani,Etienne,Gibbons,Grod,Lucas,Weber,Boschelli
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p. 3965 - 3977
(2007/10/03)
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