- Preparation method of erlotinib (by machine translation)
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2 -4 Difluoro 5 - 2 -dihydroquinazoline -4 ketone and a chlorination reagent are subjected to a condensation reaction in a solvent system; and the obtained 5 - [(6 ethynylphenyl) amino] 7 -3 difluoro quinazoline and diethylene glycol are subjected to an etherification reaction in a base reagent and a solvent system to obtain the erlotinib diecainide obtained by carrying out a cyclization 4 - reaction -4 - in an alkali reagent and a solvent system at a high temperature and carrying 4 - out -6 a 7 - cyclization reaction 3 - in a solvent system at a high temperature and carrying out a cyclization reaction in a 4 - solvent system 3 - at a high temperature.6 7 . The impurity is less and controllable, the next reaction can be directly carried out, the operation is simplified, the good yield can be obtained in each step, the process flow is simplified, and the safety and the environment protection are guaranteed. (by machine translation)
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- Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors
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In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potent anticancer compound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
- Chang, Chun-Feng,Chen, Chun-Hwa,Chen, Pei-Yi,Coumar, Mohane Selvaraj,Hsieh, Hsing-Pang,Hsu, John T. A.,Kuo, Fu-Ming,Kuo, Po-Chu,Li, An-Siou,Li, Mu-Chun,Lin, Chin-Yu,Lin, Shu-Yu,Lin, Wen-Hsing,Song, Jen-Shin,Wang, Sing-Yi,Yang, Chen-Ming,Yeh, Teng-Kuang
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- Enrichment of novel quinazoline derivatives with high antitumor activity in mitochondria tracked by its self-fluorescence
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In novel synthetic 28 4-arylamino-6-fluoro quinazoline derivatives, compound 3a displayed the most remarkable inhibitory activities against tumor cells (IC50 values ranging between 0.71 and 2.30 μM) in vitro. Importantly, 3a obviously inhibited the proliferation and metastasis of A549 cells in a zebrafish xenograft model, while also mediated cell apoptosis and G0/G1-phase cell cycle arrest in A549 cells. Interestingly, 3a had excellent fluorescence at 439 nm (λex = 375 nm) in DMSO and at 428 nm (λex = 372 nm) in 0.5% DMSO-phosphate buffer, and the self-fluorescent characteristic revealed 3a itself accumulates in the mitochondria of A549 cells, which suggested the antitumor process of 3a may involve the mitochondrial apoptotic pathway. The hypothesis was verified by the increase of the intracellular reactive oxygen species, the decrease of mitochondrial membrane potential, the release of cytochrome C from the mitochondria into the cytoplasm, and the cascade activation of caspase-9 and caspase-3 when A549 cells were treated with 3a. This work has great implications for further development of anticancer agents that can be enriched in mitochondria and can be tracked in real-time in biological systems due to the ideal fluorescence.
- Zhang, Yaling,Hou, Qiaoli,Li, Xiabing,Zhu, Jiuling,Wang, Wei,Li, Baolin,Zhao, Lijun,Xia, Haibin
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p. 417 - 432
(2019/06/18)
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- Quinazoline derivative and application of quinazoline derivative to preparation of anti-tumor medicine
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The invention discloses a quinazoline derivative and application of the quinazoline derivative to preparation of anti-tumor medicine. The chemical structure of the derivative is shown as the formula in the specification; in the formula, the R1 and the R2 respectively and independently represent hydrogen, halogen, ethynyl, propylene-1-yl or halogenated benzyloxy; R3 represents fluorine, piperazinyl, 1-methyl piperazine, morpholinyl, 1-(2-methoxy ethyl) piperazinyl, 1-(2-diethylaminoethyl) piperazinyl or 1-acryloyl piperazinyl. The compound provided by the invention has the obvious proliferation inhibition effects on human colon cancer cells, human non-small cell lung cancer cells, human skin squamous carcinoma cells and EGFR T790M/L858R double mutation containing human lung cancer cells, and can be used for preparing anti-tumor medicine.
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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 165
(2009/10/22)
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- ALKYLQUINOLINE AND ALKYLQUINAZOLINE KINASE MODULATORS
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The invention is directed to alkylquinoline and alkylquinazoline compounds of Formula I: wherein R1, R2, R3, B, Z, G, Q and X are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 131
(2010/11/25)
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- COMPOUNDS USEFUL AS CHEMOKINE RECEPTOR ANTAGONISTS
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The present invention relates to compounds useful as Chemokine Receptor antagonists. Compounds of general formula (I) are provided or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compounds and compositions for the inhibition of Chemokine Receptors and also for the treatment of various diseases, conditions, or disorders, including acute or chronic inflammatory disease, cancer, and osteolytic bone disorders.
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Page/Page column 133
(2008/06/13)
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- Structure-activity relationships of 6-fluoroquinazolines: Dual-Acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized various 6-fluoro-7-(1-piperazino)quinazolines based on the structure of 1 and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Among these compounds, 7a, having the 3,4-(methylenedioxy)phenyl moiety at the C(4)-position of the quinazoline ring, showed both inhibitory activities. Furthermore, the oral treatment with 7a exhibited an anti-inflammatory effect in rats with adjuvant arthritis as well as an inhibitory activity toward LPS-induced TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Obara, Fumihiro,Hayashi, Hideya
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p. 609 - 616
(2007/10/03)
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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
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p. 545 - 548
(2007/10/03)
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