- Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors
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Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.
- Zhang, Bin,Liu, Zhikun,Xia, Shengjin,Liu, Qingqing,Gou, Shaohua
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- Synthesis, crystal structure and anticancer activity of substituted quinazoline derivatives
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News series of substituted quinazoline derivatives has been synthesized from 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-yl acetate (1) by five-step procedures including chlorination, amination, hydrolysis and etherification. The structures of target compounds were confirmed by IR, 1H-NMR, element analysis and single-crystal X-ray diffraction. The results showed that the compound 8c exhibited remarkable inhibitory activity against MCF-7 cell lines with inhibition rate value of 38.45 %, which was comparable to that of the positive control Gefitinib (inhibition rate = 13.25 % for MCF-7). The initial relationship between structure and activity was worth further exploration.
- Cai, Zhi-Qiang,Li, Ji-Xin,Li, Shuai,Li, Xiang,Shi, Xiao-Yu,Wang, Bo
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p. 466 - 474
(2021/08/21)
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- Compound used as kinase inhibitor, and application thereof
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The invention relates to a compound used as a kinase inhibitor, and application thereof. The structure of the compound is shown as a formula I in the specification. The compound used as the kinase inhibitor provided by the invention has good inhibitory activity on EGFR and Her2 exon 20 insertion mutation, and has great potential to be developed into drugs for treating related diseases.
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Paragraph 0076; 0079-0083
(2021/08/21)
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- Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer
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Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.
- Zhang, Wanheng,Zhang, Kuojun,Yao, Yiwu,Liu, Yunyao,Ni, Yong,Liao, Chenzhong,Tu, Zhengchao,Qiu, Yatao,Wang, Dexiang,Chen, Dong,Qiang, Lei,Li, Zheng,Jiang, Sheng
-
supporting information
(2020/11/27)
-
- IMINO SULFANONE INHIBITORS OF ENPP1
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The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine- based inhibitors of ENPP1 of Formula (I) and methods of their use for treating disease mediated by ENPP1.
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Paragraph 0330
(2021/11/13)
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- Polysubstituted quinazoline compound and application thereof
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The invention discloses a polysubstituted quinazoline compound and an application thereof, and belongs to the field of chemical medicines. The substituted quinazoline compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof have excellent brain barrier permeability, enhanced metabolic stability and longer metabolic half-life period, show higher inhibitory activity on an activated or drug-resistant mutant form EGFR than a wild type EGFR, and can effectively reduce side effects.
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Paragraph 0099; 0102-0103
(2020/11/12)
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- Preparation method of tyrosine kinase inhibitor AZD3759
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The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, and relates to the field of medicinal chemistry. The preparation method comprises the following steps: by taking 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate as a raw material, carrying out a chlorination reaction and a hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-alcohol (a compound 3); taking (R)-(-)-2-methylpiperazine as a raw material, and obtaining (R)-4-chlorocarbonyl-3-tert-butyl formate (compound 6) through a nucleophilic addition-elimination reaction and a chloroformylation reaction; carrying out an esterification reaction on the compound 3 and the compound 6 to obtain a compound 7; carrying out a Boc removal reaction and a methylation reaction on the compound 7 to obtain a compound 9; and carrying out alkylation reaction on the compound 9 and 2-fluoro-3-chloroaniline to obtain AZD3759. The method has the advantages of cheap and accessible raw materials and lower cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly and is beneficial to industrial large-scale production.
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Paragraph 0041; 0072-0074; 0082-0084
(2020/09/23)
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- QUINOLINE AND QUINAZOLINE COMPOUNDS AND METHODS OF USE THEREOF
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Compounds and methods for their preparation and use as therapeutic or prophylactic agents, fo example for treatment of cancer, bacterial or viral diseases by targeting Ectonucleotide Pyrophosphatase/Phosphodiesterase- 1 (ENPP1).
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- COMPOSITIONS AND METHODS FOR TREATING CANCER
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The present disclosure relates to compounds that are capable penetrating to the blood brain barrier to modulate the activity of EGFR tyrosine kinase. The disclosure further relates to methods of treating Glioblastoma and other EGFR mediated cancers. The disclosure further relates to methods of treating Glioblastoma and other EGFR mediated cancers that have been determined to have altered glucose metabolism in the presence of inhibitors. The present disclosure also provides methods of administering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.
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Page/Page column 51; 68
(2020/10/09)
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- As Aurora kinase inhibitors of the substituted quinazoline derivatives
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The invention relates to a substituted quinazoline derivative as an aurora kinase inhibitor, which is shown as structural formula (I) or (Ia), tautomers, hydrates, solvates or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the tautomers, hydrates, solvates and pharmaceutically acceptable salts as drug active ingredients, and application of the compounds and the pharmaceutical compositions in preparation of medicines for protection, treatment, curing or alleviation of proliferative diseases of patients.
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Paragraph 0336; 0339-0341
(2019/04/04)
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- Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10
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Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC50 = 0.87 nM, ~2000-fold improvement in potency) with cocrystal confirmation.
- Li, Zhe,Huang, Yiyou,Wu, Yinuo,Chen, Jingyi,Wu, Deyan,Zhan, Chang-Guo,Luo, Hai-Bin
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p. 2099 - 2111
(2019/02/26)
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- A preparation method of gefitinib (by machine translation)
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The present invention relates to organic chemical and medical technology field, in particular relates to a preparation method of gefitinib. The present invention provides a preparation method of gefitinib, obtained by formula I compounds, the formula I compound preparation method comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, a cyclization reaction, phenolic hydroxyl acetylation reaction. The present invention provides a preparation method can at the same time reducing the cost, it is easy for the refined purification, easy preparation and control of related impurities, the overall preparation process routes are greatly optimized, is suitable for industrial scale production. (by machine translation)
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Paragraph 0110-0112
(2019/05/16)
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- Novel method of synthetic process of lung cancer targeted compound AZD-3759
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The invention discloses a novel method of a synthetic process of a lung cancer targeted compound AZD-3759. The novel method comprises the following specific steps: carrying out chlorination on 3,4-dihydro-7-methoxyl-4-oxyquinazoline-6-farnesyl acetate to obtain a compound 2; reacting the compound 2, a compound 3 and an organic solvent to obtain a compound 4, and carrying out hydrolysis reaction toobtain a compound 5; reacting a compound 6, dichloromethane and Boc-anhydride to obtain a compound 7; reacting the compound 7 and pyridine with triphosgene by taking dichloromethane as a solvent to obtain a compound 8; and reacting the compound 5, the compound 8, organic alkali and DMF to obtain a compound 9, desorbing Boc from an acidic system, regulating pH to obtain a compound 10, carrying outmethylation, adjusting pH and separating out, and refining to obtain AZD-3759. The novel method of the synthetic process of the lung cancer targeted compound AZD-3759 has the beneficial effects thatthe raw materials for the novel method are easily obtained, the price is low, the yield is high, the cost is low, the method is environmentally friendly, and industrialized enlarged production can berealized.
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Paragraph 0034; 0036; 0044; 0048; 0061
(2019/04/09)
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- Synthesis and evaluation of some novel 6-substituted quinazoline derivatives as antitumor agents
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Summry: A series of novel 6-substituted quinazoline derivatives were synthesised as epidermal growth factor receptor(EGFR) and Human epidermal growth factor receptor 2 (HER2)inhibitors in our lab. The novel compounds were measured for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results revealed that all the compounds showed inhibition of both enzymes. Compound 5c showed the best inhibitory activity against both enzymes and IC50 of its was 2.6 nM against EGFR kinases and 4.3 nM against HER2 kinases, respectively. Most of the measured compounds showed to antitumor activity on MCF7.
- Ding, Hai-guan,Cai, Zhi-qiang,Hou, Ling,Hu, Zhi-quan,Jin, Zheng-sheng,Xu, Di,Cao, Hui,Meng, Miao-miao,Xie, Yu-Hui,Zheng, De-qiang
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p. 186 - 190
(2019/05/01)
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- Quinazoline derivatives and its preparation method and application
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The invention relates to quinazoline derivatives and its preparation method and application. The quinazoline derivatives with The structural formula, the quinazoline derivative to gefitinib for the positive control, the result shows that compared with the gefitinib has good activity; and lead compound OTS514 compared, equivalent activity, PBK/TOPK inhibitors for further transformation and the discovery of new anti-tumor medicine phenological shopping has higher learning with the reference value. The invention also provides a preparation method of the quinazoline derivatives and the preparation of PBK/TOPK inhibitor and an anticancer drug.
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Paragraph 0038-0040
(2019/07/08)
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- Substituted aminoquinazoline compounds and pharmaceutical compositions and uses thereof (by machine translation)
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The amino quinazoline compound is a compound shown as a formula (I), or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvent compound, a crystal form, a stereoisomer or an isotopic variant. The compounds and compositions of the present invention may be used to treat and/or prevent ErbbB family tyrosine kinase mediated diseases. (by machine translation)
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Paragraph 0188; 0191-0193
(2019/08/07)
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- Hetero-aromatic compound and its use in medicine
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The invention provides a hetero-aromatic compound or a stereisomer, geometric isomer, tautomer, despinner, nitrogen oxide, hydrate, solvate, metabolite, metabolism precursor and pharmaceutically acceptable salt or prodrug thereof, which is used for treating proliferative diseases. The invention also discloses a pharmaceutical composition containing the compound and an application of the compound or pharmaceutical composition thereof in preparation of a medicine for treating proliferative diseases.
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Paragraph 1489; 1500-1502; 1572; 1575-1577
(2019/07/04)
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- Aminoquinazoline derivatives and their use in medicine
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The invention provides aminoquinazoline derivatives, or their stereoisomers, geometric isomers, tautomers, despinners, nitrogen oxides, hydrates, solvates, metabolites, metabolism precursors and pharmaceutically acceptable salts or prodrugs. The above compounds can be used for treating proliferative diseases. The invention also discloses a pharmaceutical composition containing the above compounds and a use of the above compounds or their pharmaceutical composition in preparation of drugs for treating proliferative diseases.
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Paragraph 0541; 0544-0546
(2019/11/29)
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- COMPOSITIONS AND METHODS FOR TREATING CANCER
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The present disclosure relates to compounds that are capable penetrating to the blood brain barrier to modulate the activity of EGFR tyrosine kinase. The disclosure further relates to methods of treating Glioblastoma and other EGFR mediated cancers. The disclosure further relates to methods of treating Glioblastoma and other EGFR mediated cancers that have been determined to have altered glucose metabolism in the presence of inhibitors. The present dislcsoure also provides methods oadministering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.
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Page/Page column 82; 94
(2019/04/26)
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- Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold
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Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.
- Ju, Yilan,Wu, Jintao,Yuan, Xi,Zhao, Luqing,Zhang, Ganlin,Li, Chao,Qiao, Renzhong
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p. 11372 - 11383
(2019/01/04)
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- Method for synthesizing quinazoline antitumor drug intermediate
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The invention discloses a method for synthesizing a quinazoline antitumor drug intermediate, wherein the intermediate is a 4-chloroquinazoline compound; and the method comprises the following steps: sealing and reacting 6,7-disubstituted quinazolinone of formula (II) with a chlorinating reagent at 70-80 DEG C for 4-5 hours in an inert gas protection atmosphere in the case of using macroporous resin and triethylenediamine as catalysts in an organic solvent; and after reaction, naturally cooling, concentrating in vacuum, recrystallizing and purifying to obtain the 4-chloroquinazoline compound offormula (I), wherein R1 and R2 are independently selected from methoxyl, nitro, amino, 2-methoxyethoxy, halogen and acetoxy. The method provided by the invention has advantages of mild reaction conditions, short reaction time, low cost, high purity, economy and environmental protection, easy preparation of intermediates of pharmaceutical raw materials, remarkable industrial advantages, and broadmarket prospect and application potential.
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Paragraph 0036-0037; 0038-0039; 0041; 0043
(2018/08/03)
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- Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof
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The invention belongs to the field of chemical medicine, and discloses a benzo nitrogen hetero-aromatic ring compound represented by formula I, or pharmaceutically acceptable salts, stereisomers, racemic compounds, prodrugs, or solvates thereof. The invention also discloses applications of the benzo nitrogen hetero-aromatic ring compound in preparation of drugs used for treating diseases caused byprotein kinase and/or nicotinamide phosphoribosyltransferase abnormal activity. The benzo nitrogen hetero-aromatic ring compound represented by formula I or the salts thereof possess tyrosine kinaseand Nampt double inhibition effects, can be taken as effective components in treatment or prevention of tumor, are excellent in curative effect, and low in toxic or side effect.
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Paragraph 0136; 0137; 0138; 0139
(2018/03/01)
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- Novel tinib-type compound, preparation method and application thereof
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The invention provides a novel tinib-type compound shown as a structural formula (I), wherein R1 is selected from aryl or ceteroary the aryl or ceteroary is substituted by one or more of alkyl, halogen, aryl, alkynyl, cyano, trifluoromethyl, methoxy and halogenated benzyl; R2 is 1,4,7,10-tetraazacyclododecane or 1,4,7-triazacyclononane. The invention also provides application of the compound in preparation of antitumor medicines. The novel tinib-type compound has an obvious inhibiting effect for A549 cell lines, apoptosis of A549 cells can be obviously enhanced, and the effect is obviously superior to that of gefitinib. (The structural formula is shown in the specification).
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Paragraph 0041; 0045; 0046
(2018/07/03)
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- Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1
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The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have Ki 105 nM against human NPP1.
- Forcellini, Elsa,Boutin, Sophie,Lefebvre, Carole-Anne,Shayhidin, Elnur Elyar,Boulanger, Marie-Chloé,Rhéaume, Gabrielle,Barbeau, Xavier,Lagüe, Patrick,Mathieu, Patrick,Paquin, Jean-Fran?ois
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p. 130 - 149
(2018/02/14)
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- EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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- Novel quinazoline inhibitor
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The present invention relates to a novel quinazoline inhibitor, and disclose a compound represented by a formula (I) and a pharmaceutically acceptable salt thereof, a method for preparing the compoundrepresented by the formula (I) and the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the formula(I) or the pharmaceutically acceptable salt thereof, and uses of the compound represented by the formula (I) and the pharmaceutically acceptable salt thereof. The formula (I) is defined in the specification.
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- Facile Synthesis of Novel Perfluorocarbon-Modulated 4-Anilinoquinazoline Analogues
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4-Anilinoquinazoline analogues stand out among many kinds of small molecules that inhibit the tyrosine kinase activities of epidermal growth factor receptor (EGFR), thus serving as significant molecular targets for anticancer drug design. Herein, a series of novel perfluorocarbon (PFC) modulated 4-anilinoquinazolines were designed and prepared straightforwardly by nucleophilic substitution reaction of various anilinoquinazolines and PFC-derived methanesulfonate. In the presence of base, the reaction proceeded smoothly to afford a wide range of 4-anilinoquinazolines with different substituents on aniline moiety in good to high yields. Furthermore, the PFC-modified analogues of gefitinib and erlotinib were also obtained in 93% and 90% respectively, which may have potential for developing new inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and fluorinated contrast agents (CA) for 19F MRI.
- Shi, Huiping,Lai, Bonan,Chen, Shizhen,Zhou, Xin,Nie, Jing,Ma, Jun-An
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p. 1693 - 1700
(2017/09/06)
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- A class of methods for quinoline compound and its preparation method and application (by machine translation)
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The invention discloses a quinazolinone quinoline compound and its preparation method and application, the states kuikui zuo lin the apperception compound of formula (I) has a structure shown in, wherein R is a cyclic or non-cyclic aliphatic amine, aromatic or heterocyclic amine, acyl-containing groups, containing a hydroxy group, mercapto-containing group; R1 For hydrogen or methoxy, methyl, ethyl, halogen, trifluoromethyl, ethoxy, acetyl, cyano, nitro, N, N - dimethyl, methyl, benzyloxy, non-substituted or substituted amino, substituted guanidino, substituted or non-substituted phosphate group, substituted or non-substituted sulfonic acid group, heterocyclic substituted the end is fragrant or the end of a long chain aliphatic alkane groups and bases. The invention provides a quinazoline compound is a kind of structure of novel compound, and the compound to phosphodiesterase 10 type good inhibition effect, while at the same time to phosphodiesterase 3 type has an excellent selectivity, can be used as a phosphodiesterase 10 type of selective inhibitor. In addition, the quinazoline compounds of the invention of the preparation method with quick, simple, low cost and the like. (by machine translation)
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Paragraph 0081; 0082; 0083
(2017/07/08)
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- Novel molecular design method for EGFR (epidermal growth factor receptor) and DNA (deoxyribonucleic acid) double-target ruthenium anti-tumor complex
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The invention discloses a novel molecular design method for an EGFR (epidermal growth factor receptor) and DNA (deoxyribonucleic acid) double-target ruthenium anti-tumor complex. The novel molecular design method includes the steps: S1 designing a ligand and synthesizing a ruthenium (II) complex; S2 determining a structure according to the synthesized ruthenium (II) complex, measuring a single-crystal structure of a compound, measuring an ultraviolet absorption curve of the compound by ultraviolet spectrometry and measuring the purity of the compound by high-performance liquid chromatography; S3 targeting ability evaluation and biological activity testing: performing research on effects of DNA, EGFR inhibitory activity experiment and in vitro anti-tumor activity testing. The molecular design method effectively overcomes the steric hindrance of a quinazoline matrix, conducts research on EGFR and DNA double-target ruthenium (II) complex preparation in order to prepare and screen efficient low-toxicity anti-tumor drugs, and is of great significance in research on in vivo activity, and the formed complex is stable.
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Page/Page column 8
(2017/12/28)
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- Kuikui zuo lin kind of target anti- tumor compound and its preparation method and application (by machine translation)
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The present invention provides a chemical formula (I) indicated by the kuikui zuo lin kind of target anti- tumor compound and its preparation method, in particular to EGFR, HER - 2 and DNA multi-target anti- tumor compounds, also provides a method for preparing the same and in the application of the anti-tumor medicament. Studies show that the compounds of the invention have significant anti-tumor activity, metabolic stability relative to the reference substance EMB - 3 is improved notably. (by machine translation)
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Paragraph 0073; 0074
(2017/08/31)
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- Preparation method of gefitinib intermediate
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The invention discloses a preparation method of a gefitinib intermediate. The preparation method comprises steps as follows: 1) in the presence of anion exchange resin, 6-acetoxyl-7-methoxy-3,4-dihydroquinazoline-4-ketone and sulfonyl chloride are subjected to a contact reaction in acetonitrile, after the reaction ends, ice water quenching, dichloromethane extraction and concentration under the reduced pressure are performed, and 6-acetoxyl-4-chloro-7-methoxyquinazoline is obtained, wherein the temperature for the contact reaction ranges from 65 DEG C to 75 DEG C; 2) in the presence of AuCl, 6-acetoxyl-4-chloro-7-methoxyquinazoline obtained in the step 1) and 3-chloro-4-fluoroaniline are subjected to a substitution reaction at the temperature of 55-65 DEG C, and the gefitinib intermediate is obtained. By means of the method, the product yield can be greatly increased, the conditions are mild, and few by-products are produced.
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Paragraph 0032
(2016/10/08)
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- Quinazoline derivative and preparation method thereof
-
The invention relates to a quinazoline derivative and a preparation method thereof. 4-(3-amino)phenyl-6-aminoethoxy-7-methoxyquinazoline and 1,2,3-triazole-4-aldehyde are added to a reactor, a reaction solvent and a catalyst are added, and the mixture is evenly stirred and is subjected to a reaction at 80-120 DEG C; after the reaction is completed, a product is cooled to the room temperature, the solvent is removed through reduced pressure distillation, an obtained solid is recrystallized with ethanol, and an off-white solid is obtained through vacuum drying. According to the quinazoline derivative, quinazoline, Schiff base and a triazole group are organically combined, so that the derivative has a certain anti-tumor effect and is also beneficial to reducing the possibility of drug resistance of tumor cells. The synthetic route has the advantages that raw materials are easy to obtain, operation is simple, the solvent is saved, pollution is reduced and the like, and industrial production is facilitated.
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Paragraph 0021; 0022; 0023
(2016/12/26)
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- Model 18 F mark 4-amino-quinazoline derivatives and its preparation method and tumor PET imaging applications
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The invention provides novel F marked 4-aminoquinazoline compounds. The novel F marked 4-aminoquinazoline compounds are characterized in that one end of each of the novel F marked 4-aminoquinazoline compounds has a F substituted alkyloxy structure; the other end of each of the compounds has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 3 position of a 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, I, a trifluoromethyl group or an acetenyl group; a substituent R2 is positioned in the 4 position of the 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, a methyl group, a methoxy group, a 3-fluorophenoxyl group, or a 2-pyridyloxy group; and n is 1-5. The structural formula of the compounds is shown as A in the specification. Results of experiments show that the precursor of the marker of the compounds is easy to synthesize, marks through using a two-step method and has a high marking rate. The compounds have a good bioactivity, for example, the compounds have high absorption and slow removal in tumor tissues and low intake and fast removal in normal tissues and blood, so the compounds have a high tumor/background ratio, and especially have a high tumor/blood ratio, a high tumor/flesh ratio and a high tumor/brain ration, are in favor of the PET tumor development, and perform a huge potential as a brain tumor developer.
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Paragraph 0101-0103
(2016/11/28)
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- Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC
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A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching.
- Peng, Fan-Wei,Xuan, Ji,Wu, Ting-Ting,Xue, Jia-Yu,Ren, Zi-Wei,Liu, Da-Ke,Wang, Xiu-Qi,Chen, Xin-Hang,Zhang, Jia-Wei,Xu, Yun-Gen,Shi, Lei
-
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- Novel quinazoline derivative LU1501, as well as preparation method and application thereof
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The invention discloses a novel quinazoline derivative LU1501, as well as a preparation method and application thereof. The chemical name of the novel quinazoline derivative LU1501 is N-[(4-fluorophenyl)-methyl]-4-N-{7-methoxy-6-[(2-pyrrolidine-1-yl)-ethoxy]quinazoline-4-yl}benzene-1,4-diamine. The quinazoline derivative as well as pharmaceutically acceptable salts, solvates and hydrates thereof have excellent anti-tumor in-vitro and in-vivo activities on MCF-7, SK-BR-3, A549, HCT 116, U-118MG, U-87MG and MDA-MB-468, and have a relatively good application prospect in preparation of anti-tumor medicines.
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Paragraph 0030; 0031
(2016/10/07)
-
- A novel quinazoline derivative LU1509 and its preparation method and application (by machine translation)
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The invention discloses a novel quinazoline derivative LU1509 and its preparation method, its chemical named N-4 - [(4-aminophenyl) methoxy] phenyl-7-methoxy-6 - [(2-pyrrolidin-1-yl) ethoxyl] quinazolin-4-amine. Quinazoline derivatives of the present invention and its pharmaceutically acceptable salts, solvates, and hydrate the MCF-7, SK-BR-3, A549, HCT? 116, MDA-MB-468 has outstanding kilograms of in vivo anti-tumor, anti-tumor drug in the preparation has better application prospect. (by machine translation)
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Paragraph 0026; 0028; 0029
(2016/10/10)
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- Novel quinazoline derivative LU1507 as well as preparation method and application thereof
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The invention discloses a novel quinazoline derivative LU1507 as well as a preparation method thereof. The quinazoline derivative LU1507 is chemically named 4-{4-[(7-methoxy)-6-[2-pyrrrolidine-1-yl)hydroxyethyl]quinazoline-4-yl}aminophenyl amino methylphenol. The quinazoline derivative as well as pharmaceutically acceptable salts, solvates and hydrates thereof has excellent in-vitro and in-vivo anti-tumor activity for MCF-7, SK-BR-3, A549, HCT 116, A172 and U-87 MG and has brighter application prospect in preparation of anti-tumor drugs.
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Paragraph 0030; 0031
(2016/10/10)
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- A novel quinazoline derivative LU1505 and its preparation method and application (by machine translation)
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The invention discloses a novel quinazoline derivative LU1505 and its preparation method, its chemical named N-{ [(4-dimethylamino) phenyl] methyl} - 4-N - [7-methoxy-6 - (2-pyrrolidin-1-yl) ethoxyl] quinazolin -4 yl} benzene -1,4-diamine. Quinazoline derivatives of the present invention and its pharmaceutically acceptable salts, solvates, and hydrate the MCF-7, SK-BR-3, A172, HCT? 116, U -118 mg, U -87 mg, MDA-MB-468 has outstanding kilograms of in vivo anti-tumor, anti-tumor drug in the preparation has better application prospect. (by machine translation)
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Paragraph 0026; 0027
(2016/11/21)
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- Novel quinazoline derivative LU1503 and preparing method and application thereof
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The invention discloses a novel quinazoline derivative LU1503 and a preparing method thereof. The chemical name of the derivative is N-{7-methoxy-6-[(2-pyrrolidine-1-base) ethoxy] quinazoline-4 base}-4-N-[(4-nitrobenzophenone) methyl] benzene-1,4-diamine. The quinazoline derivative and pharmaceutically acceptable salt, solvate and aquo-complex thereof have excellent anti-tumor in vitro and in vivo activity on MCF-7, SK-BR-3, A549, HCT 116, U-118 MG, U-87 MG and A172 and have broad application prospects in preparing anti-tumor drugs.
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Paragraph 0027; 0028
(2016/11/24)
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- Synthesis of several new quinazolin-4-amines containing p-toluenesulfonate moiety
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A series of novel quinazolin-4-amine derivatives containing p-toluenesulfonate moiety have been synthesised through the reaction of 4-chloro-7-methoxyquinazolin-6-yl acetate with substituted anilines in toluene solution at 90°C. Further treatment of the synthesised compound with ammonium hydroxide gave the corresponding substituted quinazoline derivatives which were subsequently processed through the sulfonyl reaction into quinazolin-4-amines containing p-toluenesulfonate moiety in DMF. Their structures were established by elemental analysis, IR and 1H NMR spectra.
- Cai, Zhi-Qiang,Jin, Zheng-Sheng,Zheng, De-Qiang,Hou, Ling,Huang, Guan-Wang,Tian, Jun-Qiang,Wang, Guo-Jiang
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p. 573 - 575
(2016/10/05)
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- Artemisin derivative and its preparation and use
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Provided are artemisinin derivatives of formula (I) or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, and racemic bodies thereof, and a pharmaceutical composition of the compounds, the preparation process and uses thereof. Artemisinin derivatives of formula (I) have excellent effects in the treatment of tumours.
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Paragraph 0319; 0320; 0324
(2016/10/08)
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- Preparation method of gefitinib
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The invention discloses a preparation method of gefitinib. The preparation method comprises steps as follows: 1) on the presence of anion exchange resin, 6-(2-morpholino ethyoxyl)-7-methoxy-3,4-dihydroquinazolin-4-ketone and sulfonyl chloride have a contact reaction in acetonitrile, quenching is performed through ice water after the reaction ends, dichloromethane extraction and reduced pressure concentration are performed, and 6-(2-morpholino ethyoxyl)-4-chloro-7-methoxyquinazoline is obtained, wherein the temperature of a contact reaction is 55-60 DEG C; 2) 6-(2-morpholino ethyoxyl)-4-chloro-7-methoxyquinazoline obtained in the step 1), nickel chloride and TMEDA (tetramethylethylenediamine) are added to a reaction container and stirred for 20-30 min, 3-chloro-4-fluoroaniline is added and has a substitution reaction in THF (tetrahydrofuran) at the temperature of 50-55 DEG C, and gefitinib is obtained. By means of the method for preparing gefitinib, the product yield can be greatly improved, the steps are reasonable, the conditions are mild, and fewer byproducts are produced.
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Paragraph 0026; 0034
(2016/10/10)
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- Dual-targeting organometallic ruthenium(ii) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands
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We have recently demonstrated that complexation with (η6-arene)RuII fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η6-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)RuII fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η6-arene)Ru(N,N-L13)Cl]PF6 (4, IC50 = 1.36 μM, L13 = 4-(3′-chloro-4′-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η6-arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules.
- Zhang, Yang,Zheng, Wei,Luo, Qun,Zhao, Yao,Zhang, Erlong,Liu, Suyan,Wang, Fuyi
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supporting information
p. 13100 - 13111
(2016/01/09)
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- The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling
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The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [11C]CO2and decay corrected to end of bombardment (EOB) with 370-1110 GBq/μmol specific activity at EOB.
- Wang, Min,Gao, Mingzhang,Zheng, Qi-Huang
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p. 4455 - 4459
(2014/12/11)
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- Heterocycle Amido Alkyloxy Substituted Quinazoline Derivative and Use Thereof
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Heterocycle amino alkyloxy substituted quinazoline derivatives as represented by the structural Formula (I) and pharmaceutically acceptable salts thereof, capable of inhibiting the activity of receptor tyrosine kinase EGFR, and being used to treat cancers related to the expression of the receptor tyrosine kinase of the ErbB family are provided.
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Paragraph 0225
(2014/08/06)
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- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
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The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0271-0272
(2014/08/19)
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- HETEROCYCLE AMIDO ALKYLOXY SUBSTITUTED QUINAZOLINE DERIVATIVE AND USE THEREOF
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Heterocycle amino alkyloxy substituted quinazoline derivatives as represented by the structural Formula (I) and pharmaceutically acceptable salts thereof, capable of inhibiting the activity of receptor tyrosine kinase EGFR, and being used to treat cancers related to the expression of the receptor tyrosine kinase of the ErbB family are provided.
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Paragraph 0079
(2014/11/13)
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- QUINAZOLINE INHIBITORS OF ACTIVATING MUTANT FORMS OF EPIDERMAL GROWTH FACTOR RECEPTOR
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The invention relates to compounds of formula(I), or a pharmaceutically acceptable salt thereof: Formula (I) which possess inhibitory activity against activating mutant forms of EGFR,and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti- cancer effect in a warm-blooded animal such as man.
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- Quinazoline Inhibitors of activating mutant forms of Epidermal Growth Factor Receptor
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The invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof: which possess inhibitory activity against activating mutant forms of EGFR, and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.
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- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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supporting information
p. 8551 - 8556
(2013/09/12)
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