cas 162012-69-3, 7-Fluoro-6-nitro-4-hydroxyquinazoline

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Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing oxazole or imidazole as potential EGFR inhibitors
Six series of quinazoline derivatives bearing oxazole or imidazole (8a-f, 9a-f, 10a-d, 11a-f, 12a-d and 13a-i) were designed, synthesized and their IC50 values evaluated against three cancer cell lines (A549, MCF-7 and PC-3). Most of the thirty-five target compounds showed excellent antiproliferative activity against one or several cancer cell lines. Compound 12a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with IC50 values of 1.90 ± 0.13 μM, 2.23 ± 0.28 μM and 2.03 ± 0.14 μM, respectively. Four selected compounds (8a, 9d, 10a and 12a) were further evaluated for the inhibitory activity against EGFR kinase. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that compound 12a could induce apoptosis of human lung cancer A549 cells.
OuYang, Yiqiang,Wang, Caolin,Zhao, Bingbing,Xiong, Hehua,Xiao, Zhen,Zhang, Bingliang,Zheng, Pengwu,Hu, Jiayi,Gao, Yanli,Zhang, Manli,Zhu, Wufu,Xu, Shan
p. 17203 - 17215
(2018)
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Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor-Based Spin Labeling
The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof-of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available.
Yin, Dongsheng M.,Hannam, Jeffrey S.,Schmitz, Anton,Schiemann, Olav,Hagelueken, Gregor,Famulok, Michael
p. 8417 - 8421
(2017)
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Structure-based virtual screening of Src kinase inhibitors
Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC50 value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quin azolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC50 ratio > 80-fold) and VEGFR-2 (IC50 ratio > 110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC50 values of 1.52 and 0.78 μM, respectively. Moreover, compound 43 (0.1 μM) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization.
Lee, Kyungik,Kim, Jongwoo,Jeong, Ki-Woong,Lee, Ki Won,Lee, Yeonjoo,Song, Ji Yeon,Kim, Maeng Sup,Lee, Gwan Sun,Kim, Yangmee
p. 3152 - 3161
(2009)
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Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists
We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.
Bae, Inhwan,Kim, Daejin,Choi, Jaeyul,Kim, Jisook,Kim, Minjeong,Park, Bokyung,Kim, Young Hoon,Ahn, Young Gil,Hyung Kim, Ha,Kim, Dae Kyong
supporting information

(2021/01/26)

Afatinib refined product synthetic method
The invention discloses an afatinib refined product synthetic method, and belongs to the technical field of organic synthesis. The method particularly comprises the following steps that 4-fluoro-2-aminobenzoic acid and formamidine acetate are subjected to a ring-closure reaction to synthesize a compound of the formula I; the compound of the formula I is subjected to a nitration reaction to synthesize a compound of the formul II; the compound of the formula II and 3-chloro-4-fluoroaniline are subjected to dehydration to synthesize a compound of the formula III, the compound of the formula III and 3-hydroxy-tetrahydrofuran synthesize a compound of a formula IV through a nucleophilic substitution reaction; the compound of the formula IV is reduced to generate a compound of the formula V underthe Pd/C catalysis; the compound of the formula V and crotonic acid synthesizes a compound of the formula VI through a dehydration condensation reaction; the compound of the formula VI and dimethylamine finally synthesize the compound of the formula VII, that is to say, an afatinib refined product is obtained. According to the afatinib refined product synthetic method, the reaction process condition is mild, the corrosion risk to reaction equipment is lowered, the reaction process is simplified, operation is easy, the purity of the product is high, and the yield is increased conveniently.
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(2019/06/12)

Novel protein inhibitor and preparation method and application thereof
The invention provides a novel protein inhibitor and a preparation method and application thereof, and specifically provides a compound as shown in a formula I, wherein definitions of all groups are described in the specification. The compound has good Bcl-2 family protein inhibition activity and can be used for preparing a series of medicines for treating diseases related to Bcl-2 family proteinactivity.
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(2019/11/12)

STEFs: Activated Vinylogous Protein-Reactive Electrophiles
Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.
Hansen, Bente K.,Loveridge, Christopher J.,Thyssen, Stine,W?rmer, Gustav J.,Nielsen, Andreas D.,Palmfeldt, Johan,Johannsen, Mogens,Poulsen, Thomas B.
supporting information
p. 3533 - 3537
(2019/02/14)

Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 μM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.
Wang, Caolin,Xu, Shan,Peng, Liang,Zhang, Bingliang,Zhang, Hong,Hu, Yingying,Zheng, Pengwu,Zhu, Wufu
p. 204 - 218
(2019/01/03)

A high-purity arab league law for nepal intermediate preparation method
The present invention provides a high purity arab league law for nepal preparation method of the midbody. The method comprises: the 2 - amino - 4 - fluorobenzoic acid cyclization, nitration, [...] 3, - chloro - 4 - fluoro aniline, the reaction route shown in the following chart: . The invention material price is cheap, simple operation, high purity of the product, but also easy to industrial production.
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Paragraph 0022; 0030; 0031; 0032

(2019/05/11)

Design, synthesis and antitumor activity of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline
Background: Cancer continues to pose a great problem and burden on society despite new treatment options. While surgery, radiotherapy, and chemotherapy have led to major improvements in patient prognosis, newer treatments are needed to more effectively manage this disease in its advanced stage. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. The family of EGFR has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma. Thus, it is a good strategy that design anticancer agents by inhibiting the EGFR pathway. Methods: We group to obtain the six series compounds (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d). Hence we disclosed the design, synthesis and antitumor activity of novel quinazoline analogues against EGFR overexpression cancer cells A549 (human lung cancer), HepG-2 (human liver cancer), MCF-7 (human breast cancer) and PC-3 (human prostate cancer) and as well as the inhibitory on EGFR kinase. Moreover, apoptosis by acridine orange single staining and docking studies were presented in this paper as well. Results: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the half maximal inhibitory concentration (IC50) values against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty target compounds showed moderate to excellent (1.49 - 50 μM) cytotoxicity activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.49 ± 0.17 μM, 2.90 ± 0.24 μM, 1.85 ± 0.19 μM, 3.30 ± 0.22 μM, respectively. What’s more, the secondary amines were introduced to the target compounds to improve the water-soluble. The results showed that the compounds were beneficial to the cytotoxicity activity. Furthermore, the results prompted us that this series of compounds may be a kind of potential epidermal growth factor receptor (EGFR) kinase inhibitors. Conclusion: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4tetrahydroquinoline moiety (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the IC50 values of cytotoxicity against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty synthesized compounds showed moderate to excellent cytotoxicity activity against the different cancer cells. Especially, the compound 13a exerted antitumor effects in a dosage-dependent manner and the IC50 values of compound 13a were 1.49 μM, 2.90 μM, 1.85 μM and 3.30 μM against A549, HepG-2, MCF-7 and PC-3, respectively. From the antitumor activity data show that the compounds possessed selectivity for A549 and MCF-7 cancer cell lines. It meant that the compounds had better treatment effect on lung cancer and breast cancer. On the whole, the compounds substituted by 1,2,3,4-tetrahydroquinoline at C-4 position of quinazoline and (S)-tetrahydrofuran-3-ol at C-8 position of quinazoline were beneficial to the cytotoxicity activity. From the result of acridine orange (AO) single staining which indicated the compound 13a could induce apoptosis of A549 cells. From the result of Docking Studies, we hypothesized that the C-4 position of quinazoline were substituted by 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline with the equal influence of the cytotoxicity activity. Overall, the results prompted us that this series of compounds may be a kind of potential EGFR kinase inhibitors.
Ou Yang, Yiqiang,Zhao, Bingbing,Chen, Xiuying,Wang, Caolin,Zhang, Hong,Jia, Shuang,Zhu, Wufu,Zheng, Pengwu
p. 533 - 546
(2019/06/20)

Having inhibitory anti-apoptosis protein active compound and its preparation and use (by machine translation)
The present invention has offered a kind of inhibiting anti-apoptosis protein active compound and its preparation and use. In particular, the invention provides a compound of formula I the following; wherein the definition of each group as described in the specification. The compounds of the invention has very good Bcl - 2 family protein inhibitory activity, can be used for preparing a series of treating Bcl - 2 family protein activity associated with the disease. (by machine translation)
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(2018/10/19)

Quinazoline compound containing oxazole or imidazole structure and application thereof
The invention discloses a quinazoline compound containing an oxazole or imidazole structure, as well as geometrical isomers and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. The quinazoline compound containing the oxazole or imidazole structure as well as the pharmaceutically acceptable salts, hydrates and solvates thereof serving as active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare compositions and prepared into clinically acceptable dosage forms. The invention further discloses application of the compounds in preparation of medicines for treating and/or preventing hyperplastic diseases, application in preparation of medicines for treating and/or preventing cancers, and application in preparation of medicines for treating and/or prostatic cancer, lung cancer and cervical cancer.
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Paragraph 0082; 0085; 0086

(2018/09/14)

Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors
Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0.09 μM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells.
OuYang, Yiqiang,Zou, Wensheng,Peng, Liang,Yang, Zunhua,Tang, Qidong,Chen, Mengzi,Jia, Shuang,Zhang, Hong,Lan, Zhou,Zheng, Pengwu,Zhu, Wufu
p. 29 - 43
(2018/05/24)

Quinazoline compound containing acylhydrazone structure and application thereof
The invention discloses a quinazoline compound containing an acylhydrazone structure. The quinazoline compound is as shown in a formula I in the description. The invention relates to the quinazoline compound comprising the acylhydrazone structure, a pharmaceutically acceptable salt, a hydrate or a solvate as active ingredients, and the active ingredients are mixed with a pharmaceutically acceptable carrier or an excipient to prepare a composition and prepare a clinically acceptable dosage. The compound disclosed by the invention can treat and/or prevent proliferative diseases and prostatic cancer, lung cancer and cervical cancer.
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Paragraph 0078; 0079; 0080

(2017/07/22)

Quinazoline compound containing aroyl hydrazine structure and application of quinazoline compound
The invention discloses a quinazoline compound containing an aroyl hydrazine structure. The structure of the quinazoline compound is shown as a formula I (shown in the description). The quinazoline compound containing dihydroindoline and a similar structure, disclosed by the invention, as well as pharmaceutically-acceptable salts, hydrate or a solvent compound are used as active components, are mixed with a pharmaceutically-acceptable carrier or an excipient to obtain a composition and a clinically-acceptable dosage form. The compound disclosed by the invention can be used for treating and/or preventing proliferous diseases, and treating and/or preventing prostatic cancer, lung cancer and cervical cancer.
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Paragraph 0096; 0097; 0098

(2017/07/20)

Quinazoline compound containing dihydroindoline and similar structure and application thereof
The invention discloses a quinazoline compound containing dihydroindoline and a similar structure. The quinazoline compound is as shown in a general formula I, wherein the general formula I is shown in the description. The quinazoline compound containing the dihydroindoline and the similar structure, and pharmaceutically acceptable salts, hydrates or solvates thereof are used as active components, and are mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition; and the composition is prepared into clinically acceptable preparations. The compound provided by the invention can be used for treating and/or preventing proliferative diseases, and treating and/or preventing prostate cancer, lung cancer and cervical cancer.
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Paragraph 0053; 0055; 0057; 0084-0086

(2017/07/22)

Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors
Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a–o and 10a–o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32?±?0.38?μM, 0.07?±?0.01?μM, 0.91?±?0.29?μM and 4.89?±?0.69?μM, which were equal to more active than afatinib (1.40?±?0.83?μM, 1.33?±?1.28?μM, 2.63?±?1.06?μM and 3.96?±?0.59?μM), respectively. Activity of the most promising compound 9o (IC50 56?nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6?nM) but more active than reference staurosporine (IC50 238?nM). The result of flow cytometry, with the dose of compound 9o increasing, which indicated the compound 9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure–activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.
Tu, Yuanbiao,Wang, Caolin,Xu, Shan,Lan, Zhou,Li, Wei,Han, Jiaqian,Zhou, Yuanzhang,Zheng, Pengwu,Zhu, Wufu
p. 3148 - 3157
(2017/05/29)

Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors
Two series of afatinib derivatives bearing cinnamamide moiety (10a-n and 11a-h) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC50 values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC50 9.1 nM) and 10k (IC50 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC50 1.6 nM). Structure-activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn't decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.
Tu, Yuanbiao,Ouyang, Yiqiang,Xu, Shan,Zhu, Yan,Li, Gen,Sun, Chao,Zheng, Pengwu,Zhu, Wufu
p. 1495 - 1503
(2016/03/15)

Quinazoline compound containing cinnamamide structure and preparation method and application thereof
The invention discloses a quinazoline compound containing cinnamamide structure, geometric isomers of the quinazoline compound, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the quinazoline compound, as well as a preparation method of the quinazoline compound. The invention also discloses application in the preparation of drugs for treating and/or preventing proliferative diseases, application in the preparation of drugs for treating and/or preventing cancers, and application in the preparation of drugs for treating and/or preventing prostate cancer, lung cancer and cervical cancer. Cyano groups are removed, side chains such as S-tetrahydrofuran-3-oxy, and activity for A549 has a significant increase. In-vitro antitumor activity screening for various EGFR (epidermal growth factor receptor) inhibitor highly-expressed cell strains shows high antitumor activity and selectivity, some compounds good in in-vitro antitumor activity are also selected for in-vivo activity testing of EGFR and VEGFR2/KDR. Experiments show that some compounds have efficient antitumor activity.
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Paragraph 0073; 0074; 0075

(2016/12/22)

6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR
Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFRT790Mand EGFRL858Rkinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants.
Shao, Jiaan,Chen, En,Shu, Ke,Chen, Wenteng,Zhang, Guolin,Yu, Yongping
p. 3359 - 3370
(2016/07/20)

4-quinazoline amine derivatives and their use
A 4-quinazoline amine derivative as represented by formula (1), a pharmaceutical composition comprising the derivative, and an application thereof in preparing medicine for curing cancer. The cancer is a drug-resistant cancer, preferably a cancer resisting an EGFR reversible inhibitor, and more preferably, a cancer resisting gefitinib, erlotinib or lapatinib; alternatively, the cancer carries EGFR mutation.
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Paragraph 0171-0173

(2017/01/31)

Synthesis of quinazoline analogues with differential activity for HER2-overexpressing breast cancer cells
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Jang, Sun-Young,Lee, Seul,Kim, Mira,Ham, Young Jin,Cha, Mi Young,Suh, Kwee Hyun,Kim, Young Hoon,Kwon, Ara,Kang, Hae Ju,Min, Kyung Hoon,Lee, Kwang-Ok
p. 1933 - 1935
(2015/07/15)

QUINAZOLINE DERIVATIVES, COMPOSITIONS THEREOF, AND USE AS PHARMACEUTICALS
Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof,and method of use thereof.
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(2015/02/02)

TARGETED COVALENT PROBES AND INHIBITORS OF PROTEINS CONTAINING REDOX-SENSITIVE CYSTEINES
Covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR'2) of therapeutically important proteins (particularly kinases and phosphatases) are disclosed, where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein. Methods for synthesizing these compounds are also disclosed, as well as methods of using them for determining the bioactivity of a chemical composition comprising an active compound toward a specific protein and for determining the potency of an inhibitor against a specific protein.
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(2014/06/24)

Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR
This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity against A431WT,overexpression and H1975 [L858R/T790M] cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
Wu, Jianwei,Chen, Wenteng,Xia, Guangxin,Zhang, Jing,Shao, Jiaan,Tan, Biqin,Zhang, Chunchun,Yu, Wanwan,Weng, Qinjie,Liu, Haiyan,Hu, Miao,Deng, Hailin,Hao, Yu,Shen, Jingkang,Yu, Yongping
p. 974 - 978
(2013/10/22)

QUINAZOLINE DERIVATIVES SUBSTITUTED BY ANILINE, PREPARATION METHOD AND USE THEREOF
The invention relates to quinazoline derivatives substituted by aniline which are represented by the below formula (I), pharmaceutical acceptable salts and stereoisomer thereof, wherein these groups of R1, R2, R3, R4, R5, R6, L and n have the meanings given in the specification. The invention also relates to preparation methods, pharmaceutical compositions, pharmaceutical preparation and the use for preparation of medicine of treating excessive hyperplasia and chronic obstructive pulmonary disease and uses for treating excessive hyperplasia and chronic obstructive pulmonary disease thereof.
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Paragraph 0063; 0064

(2013/07/25)

QUINAZOLINE DERIVATIVES SUBSTITUTED BY ANILINE, PREPARATION METHOD AND USE THEREOF
The invention relates to quinazoline derivatives substituted by aniline which are represented by the below formula (I), pharmaceutical acceptable salts and stereoisomer thereof, wherein these groups of R1, R2, R3, R4, R5, R6, L and n have the meanings given in the specification. The invention also relates to preparation methods, pharmaceutical compositions, pharmaceutical preparation and the use for preparation of medicine of treating excessive hyperplasia and chronic obstructive pulmonary disease and uses for treating excessive hyperplasia and chronic obstructive pulmonary disease thereof.
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Paragraph 0065; 0066

(2013/07/25)

QUINAZOLINE COMPOUNDS
Provided are certain quinazoline compounds, compositions thereof and methods of use thereof. These quinazoline compound can effectively inhibit the overexpression and/or overactivity of epidermal growth factor receptor (EGFR).
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Page/Page column 12

(2012/01/14)

QUINAZOLINE COMPOUNDS
Provided are certain quinazoline compounds, compositions thereof and methods of use thereof. These quinazoline compounds can effectively inhibit the overexpression and/or overactivity of epidermal growth factor receptor (EGFR).
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Page/Page column 12

(2012/01/14)

QUINOLINE OR QUINAZOLINE DERIVATIVES WITH APOPTOSIS INDUCING ACTIVITY ON CELLS
Provided is a pharmaceutical composition comprising, as an active ingredient, a quinoline or quinazoline derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate, and a solvate thereof, which is effective in the prevention and treatment of a cancer, inflammation, autoimmune diseases or neurodegenerative disorders which are induced by the overexpression of inhibitor of apoptosis proteins (IAPs).
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Page/Page column 25

(2012/03/26)

QUINAZOLINE DERIVATIVES
Quinazoline derivatives of the following formula: wherein R1, R2, R3, R4, R5, X, Y, and Z are defined herein. It also discloses a method of treating cancer with one of these compounds.
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Page/Page column 23

(2010/02/17)

Modified PEG-anilinoquinazoline derivatives as potential EGFR PET agents
Inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) has emerged as a major approach for cancer-targeted therapy. Consequently, there has been a great interest in the use of labeled EGFR-TK inhibitors as positron emission tomography (P
Dissoki, Samar,Eshet, Renana,Billauer, Hana,Mishani, Eyal
scheme or table
p. 41 - 52
(2009/12/01)

Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer
A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6- yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhi
Mi, Young Cha,Lee, Kwang-Ok,Jong, Woo Kim,Chang, Gon Lee,Ji, Yeon Song,Young, Hoon Kim,Gwan, Sun Lee,Seung, Bum Park,Maeng, Sup Kim
scheme or table
p. 6880 - 6888
(2010/04/24)

BICYCLIC LACTAM FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS
The present invention provides novel bicyclic lactams derivatives, and analogues thereof, of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables A, B, C, W, Y, Z1, Z2, Z3, Z4, R8, and R9 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.
-
Page/Page column 156

(2008/12/07)

MACROCYCLIC FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS
The present invention relates generally to novel macrocycles of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the variables A, B, C, D, L, M, W, Z1, Z2, Z3, Z4, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.
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Page/Page column 102

(2008/12/07)

Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.
Hur, Wooyoung,Velentza, Anastasia,Kim, Sungjoon,Flatauer, Laura,Jiang, Xinnong,Valente, David,Mason, Daniel E.,Suzuki, Melissa,Larson, Brad,Zhang, Jianming,Zagorska, Anna,DiDonato, Michael,Nagle, Advait,Warmuth, Markus,Balk, Steven P.,Peters, Eric C.,Gray, Nathanael S.
supporting information; experimental part
p. 5916 - 5919
(2009/06/25)

POLYALKYLENE GLYCOL DERIVATIVES OF IRREVERSIBLE INHIBITORS OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE
Novel epidermal growth factor receptor tyrosine kinase (EGFR-TK) irreversible inhibitors, pharmaceutical compositions including same and their use in the treatment of EGFR-TK related diseases or disorders are disclosed. Novel radiolabeled EGFR-TK irrevers
-
Page/Page column 55; Figure 3

(2010/11/26)

QUINAZOLINE DERIVATIVES AS A MULTIPLEX INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof as a multiplex inhibitor, a method for the preparation thereof, and a pharmaceutical composition and a therapeutic composition comprising same as an active ingredient. The inventive quinazoline derivative as a multiplex inhibitor can selectively and effectively inhibit diseases caused by the overactivity of a tyrosine kinase.
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Page/Page column 30

(2008/06/13)

QUINAZOLINE DERIVATIVES AS A SIGNAL TRANSDUCTION INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof as a signal transduction inhibitor, a method for the preparation thereof, and a pharmaceutical composition and a therapeutic composition comprising same as an active ingredient. The inventive quinazoline derivative as a signal transduction inhibitor can selectively and effectively inhibit diseases caused by the overactivity of a tyrosine kinase.
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Page/Page column 20

(2010/11/27)

Tyrosine kinase inhibitors. 9. Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor
Following the discovery of 4-[(3-bromophenyl)amino]-6,7- dimethoxyquinazoline (4; PD 153035) as an extremely patent (IC50 0.025 nM) inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), several fused tricyclic quinazoline analogues have been prepared and evaluated for their ability to inhibit the enzyme. The most potent compound was the linear imidazo[4,5-g]quinazoline (8), which exhibited an IC50 of 0.008 nM for inhibition of phosphorylation of a fragment of phospholipase C-γ1 as substrate. While N-methyl analogues of 8 showed similar potency, analogous N-[2-(dimethylamino)ethyl] derivatives were less effective. The next most potent compounds were the linear pyrazoloquinazolines (19 and 20) (IC50s 0.34 and 0.44 nM) and pyrroloquinazoline (21) (IC50 0.44 nM), while several other linear tricyclic ring systems of similar geometry to 8 (triazolo-, thiazolo-, and pyrazinoquinazolines) were less effective. In the imidazo[4,5-g]quinazoline and pyrroloquinazoline series, the corresponding angular isomers were also much less effective than the linear ones. These results are consistent with structure-activity relationship studies previously developed for the 4-[(3- bromophenyl)amino]quinazolines, which suggested that small electron-donating substituents at the 6- and 7-positions were desirable for high potency. Cellular studies of the linear imidazoloquinazoline 8 show that it can enter cells and rapidly and very selectively shut down EGF-stimulated signal transmission by binding competitively at the ATP site of the EGFR.
Rewcastle, Gordon W.,Palmer, Brian D.,Bridges, Alexander J.,Showalter, H.D. Hollis,Sun, Li,Nelson, James,McMichael, Amy,Kraker, Alan J.,Fry, David W.,Denny, William A.
p. 918 - 928
(2007/10/03)

Chemical Properties

Melting Point: 282-285 °C(Solv: acetic acid (64-19-7))
Boiling Point: 407.6 °C at 760 mmHg
Flash Point:200.3 °C
Density: 1.75 g/cm³
Storage Temp.:Sealed in dry,Room Temperature
Vapor Pressure: 7.46E-07mmHg at 25°C
Refractive Index: 1.713
PKA: -2.69±0.20(Predicted)
PSA: 91.57000
LogP: 1.49360

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Chemical Properties

Melting Point: 282-285 °C(Solv: acetic acid (64-19-7))

Boiling Point: 407.6 °C at 760 mmHg

Flash Point:200.3 °C

Density: 1.75 g/cm³

Storage Temp.:Sealed in dry,Room Temperature

Vapor Pressure: 7.46E-07mmHg at 25°C

Refractive Index: 1.713

PKA: -2.69±0.20(Predicted)

PSA: 91.57000

LogP: 1.49360

Global suppliers and manufacturers of 162012-69-3total 164 suppliers on LookChem

Article Database

162012-69-3

Articles about 162012-69-3Total 40 be found

More Articles about upstream products of 162012-69-3

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Chemical Properties

Melting Point: 282-285 °C(Solv: acetic acid (64-19-7))

Boiling Point: 407.6 °C at 760 mmHg

Flash Point:200.3 °C

Density: 1.75 g/cm3

Storage Temp.:Sealed in dry,Room Temperature

Vapor Pressure: 7.46E-07mmHg at 25°C

Refractive Index: 1.713

PKA: -2.69±0.20(Predicted)

PSA: 91.57000

LogP: 1.49360

Global suppliers and manufacturers of 162012-69-3total 164 suppliers on LookChem

Density: 1.75 g/cm³