- 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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scheme or table
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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- PROCESS FOR THE PREPARATION OF GEFITINIB
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There is provided a compound of formula (III), and a process for preparing a compound of formula (V) comprising converting a compound of formula (III) to the compound (V), wherein (X) is fluoro, chloro, bromo or iodo. There is also provided a process for preparing a compound of formula (Xl) comprising converting a compound of formula (X) to the compound (Xl). The compounds (V) and (Xl) so prepared may be used in a process for preparing gefitinib.
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Page/Page column 22-23
(2008/12/08)
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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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- QUINAZOLINE DERIVATIVES AS SRC TYROSINE KINASE INHIBITORS
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The invention concerns quinazoline derivatives of Formula (I): (A chemical formula should be inserted here - please see paper copy enclosed herewith) wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group wherein each R2 group is hydrogen or (1-8C) alkyl, m is 0, 1, 2 or 3, each R1 group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, n is 0, 1, 2 or 3, and each R3 group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, or pharmaceutically-acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
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