- STEFs: Activated Vinylogous Protein-Reactive Electrophiles
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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.
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- Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors
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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
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- Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
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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.
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- In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models
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Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts.
- Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Shi, Jingli,Hong, Jian
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- Tyrosine kinase inhibitor and pharmaceutical application thereof
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The invention relates to a tyrosine kinase inhibitor containing a quinazoline derivative in the fields of tumor treatment medicines and the like, and application of the tyrosine kinase inhibitor in treatment medicines for inhibiting and treating diseases caused by overexpression of tyrosine kinase. The active ingredient of the tyrosine kinase inhibitor is a quinazoline derivative with a structure shown in the following formula: a functional group containing XCH2 (CH2) nC = O is introduced on the basis of a quinazoline structure, and the functional group is easily combined with cysteine sulfydryl through nucleophilic reaction to form a covalent bond so that the activity of tyrosine kinase is irreversibly inhibited.
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- Preparation method of dcotinib
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The invention discloses a preparation method of Dacomitinib. The preparation method comprises the following steps: methyl oxidation, reduction and condensation reaction. The preparation method disclosed by the invention is simple and effective in process, simple and reliable to operate, high in economic benefit and more suitable for industrial production; the prepared Dacomitinib is high in purity and high in overall yield.
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Paragraph 0056-0059
(2021/04/17)
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- Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
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Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
- Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
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- Production method of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine
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The invention discloses a production method of a targeted anti-tumor drug afatinib intermediate namely N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine. The preparation method comprises the following steps: in a non-proton organic solvent environment; carrying out chlorination reaction on a Vislmeier reagent prepared from a non-phosphorus reagent and 4-hydroxy-5-fluoro-6-nitro-quinazoline; after the reaction is finished, adding a 3-chloro-4-fluorine-aniline solution taking the non-proton organic solvent as a solvent to carry out a coupling reaction; after the coupling reactionis finished, adding water, uniformly mixing, standing for layering; sequentially washing, concentrating under reduced pressure, and drying to obtain a final product. No waste is generated in the wholeproduction process, and the used non-proton organic solvent can be recycled, so that the production method has the advantages that the production process is environment-friendly and conforms to cleanproduction, the yield of the finally obtained N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazoline amine can reach 83-89%, and the purity reaches 98% or above.
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Paragraph 0018-0062
(2020/08/27)
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- Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities – Part 1
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Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC50 values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.
- Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Xu, Xin,Zhang, Zonghua,Shi, Jingli,Le, Xiaoyong,Hong, Jian
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p. 591 - 596
(2019/01/04)
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- Afatinib refined product synthetic method
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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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- Novel method for preparing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine
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The invention discloses a novel method for preparing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine. The method comprises the following steps: with 2-bromo-4-fluoro-5-nitrobenzonitrileas a starting material, subjecting 2-bromo-4-fluoro-5-nitrobenzonitrile and 3-chloro-4-fluoroaniline to addition under the promotion of a catalyst and microwaves; and then subjecting an addition product and methanamide to cascaded amination and condensation cyclization reactions to synthesize the key intermediate N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine used for the anticancer drugs, i.e., afatinib and dacomitinib, wherein overall yield is 90%. The method of the invention has the advantages of short synthetic route, mild reaction conditions, short reaction time, high product yield, no usage of highly-contaminating thionyl chloride and phosphorus oxychloride, and friendliness to environment; and the method provides a highly-efficient simple method approach for synthesis of 4-quinazolinamine compounds and has potential industrial application prospects.
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Paragraph 0019-0024
(2019/01/24)
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- Method for preparing afatinib impurities and prepared impurities
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The invention belongs to the field of medicinal chemistry, and particularly relates to a method for preparing afatinib impurities and the prepared impurities. The method can directionally synthesize aplurality of impurities of afatinib, and has fewer steps, mild conditions, simple purification, and high purity. The prepared impurities are high in purity, and can be used as impurity references foranalysis of afatinib related substances, and the afatinib quality monitoring level is improved. The impurities are shown by a formula (I) in the specification, wherein X is selected from OH or (R)-tetrahydrofuran-3-oxy.
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Paragraph 0019-0021
(2020/01/03)
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- 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
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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
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p. 204 - 218
(2019/01/03)
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- A high-purity arab league law for nepal intermediate preparation method
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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; 0033; 0034; 0035
(2019/05/11)
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- Arab league law for nepal intermediate high purity preparation method
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The present invention relates to a high purity preparation method of Afatinib intermediate, and particularly relates to a high purity preparation method of an antineoplastic treatment medicine maleate Afatinib intermediate (II) compound, the method comprises the following steps: an objective product is obtained sequentially through substitution in two steps, reduction reaction and the like of 6-amino-7-fluoro-3,4-dihydro-quinazolin-4-one. The method is simple in process, economic and environmental-friendly, and suitable for industrial amplification requirements, and the manufactured finished product is high in purity.
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Paragraph 0029; 0030
(2019/06/26)
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- PROCESS FOR THE PREPARATION OF N-[4-[(3-CHLORO-4-FLUORO PHENYL) AMINO]-7-[[(3s-TETRAHYDRO-3-FURANYL]OXY]-6-QUINAZOLINYL]-4-(DIMETHYL AMINO)-(2E)-2-BUTENAMIDE (2Z)-2-BUTENEDIOATE (1 :2) AND ITS POLYMORPHS THEREOF
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The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:
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Paragraph 0235
(2018/11/21)
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- Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors
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A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
- Hou, Weijie,Ren, Yan,Zhang, Zhenhua,Sun, Huan,Ma, Yongfen,Yan, Bo
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p. 1740 - 1750
(2018/03/12)
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- QUINAZOLINE DERIVATIVE, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
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Disclosed are a quinazoline derivative, a preparation method therefor, and a pharmaceutical composition and an application thereof. The present invention provides a compound represented by general formula I, a stereoisomer thereof and a pharmaceutical acceptable salt or a solvate thereof. The quinazoline derivative of the present invention has a unique chemical structure, is characterized by irreversibly inhibiting EGFR tyrosine kinase, has high biological activity, apparently improves the inhibiting effect on the EGFR tyrosine kinase, has quite strong tumor inhibiting effect on tumor cells and a transplantation tumor pathological model of animal tumors, and has good market developing prospects.
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Paragraph 0129
(2017/07/14)
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- Quinazoline compound containing acylhydrazone structure and application thereof
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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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- NOVEL FLUORINATED QUINAZOLINE DERIVATIVES AS EGFR INHIBITORS
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A novel class of fluorinated derivatives of Formula (I) have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders. (I)
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Paragraph 00196
(2017/08/01)
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- Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors
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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
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p. 1495 - 1503
(2016/03/15)
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- 6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR
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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
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p. 3359 - 3370
(2016/07/20)
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- Quinazoline compound containing cinnamamide structure and preparation method and application thereof
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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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- 4-quinazoline amine derivatives and their use
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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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- QUINAZOLINE DERIVATIVE AND PREPARATION METHOD THEREFOR
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The present invention relates to a quinazoline derivative shown in formula (I) and a preparation method therefor, a pharmaceutical composition comprising the compound shown in formula (I), and an application of the compound in preparing drugs for curing and preventing tumors. The compound of the present invention can irreversibly prevent EGFR phosphorylation, and effectively depress signal transduction of cancer cells, and accordingly has higher anti-tumor activity in vitro and in vivo,
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- QUINAZOLINE DERIVATIVES, COMPOSITIONS THEREOF, AND USE AS PHARMACEUTICALS
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Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof,and method of use thereof.
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- Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors
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We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
- Zhang, Long,Yang, Yingying,Zhou, Haojie,Zheng, Qingmei,Li, Yuhao,Zheng, Shansong,Zhao, Shuyong,Chen, Dong,Fan, Chuanwen
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p. 445 - 463
(2015/09/01)
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- TARGETED COVALENT PROBES AND INHIBITORS OF PROTEINS CONTAINING REDOX-SENSITIVE CYSTEINES
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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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- QUINAZOLINE DERIVATIVES SUBSTITUTED BY ANILINE, PREPARATION METHOD AND USE THEREOF
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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)
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- QUINAZOLINE DERIVATIVES SUBSTITUTED BY ANILINE, PREPARATION METHOD AND USE THEREOF
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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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- Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR
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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
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p. 974 - 978
(2013/10/22)
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- NOVEL QUINAZOLINE DERIVATIVES
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This disclosure concerns novel quinazoline compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful anticancer agents, especially in inhibiting the function of the EGF receptor tyrosine kinases, HERl tyrosine kinase, and HER2 tyrosine kinase. Thus, the disclosure also concerns a method of treating hyperproliferative diseases or conditions, such as various cancers and benign prostate hyperplasia (BPH), by use of these novel compounds or a composition comprising such novel compounds.
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Page/Page column 55-56
(2011/08/03)
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- 4-Phenylamino-quinazolin-6-yl-amides
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This invention provides quinazoline compounds of the formula: wherein: R1 is halo; R2 is H or halo; R3 is a) C1-C3 alkyl, optionally substituted by halo; or b) —(CH2)n-morpholino, —(CH2)n-piperidine, —(CH2)n-piperazine, —(CH2)n—-piperazine-N(C1-C3 alkyl), —(CH2)n-pyrrolidine, or —(CH2)n-imidazole; n is 1 to 4; R4 is —(CH2)m-Het; Het is morpholine, piperidine, piperazine, piperazine-N(C1-C3 alkyl), imidazole, pyrrolidine, azepane, 3,4-dihydro-2H-pyridine, or 3,6-dihydro-2H-pyridine, each optionally substituted by alkyl, halo, OH, NH2, NH(C1-C3 alkyl) or N (C1-C3 alkyl)2; m is 1-3; and X is O, S or NH; or a pharmaceutically acceptable salt thereof, as well as processes and intermediate compounds for making them, useful pharmaceutical compositions and methods of using the compounds in the treatment of proliferative diseases.
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Page/Page column 13-14
(2010/02/14)
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- Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4- (phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions
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4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6- fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium-(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC50([app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7- alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2- d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7- propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6- acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.
- Smaill, Jeff B.,Rewcastle, Gordon W.,Loo, Joseph A.,Greis, Kenneth D.,Chan, O. Helen,Reyner, Eric L.,Lipka, Elke,Showalter, H. D. Hollis,Vincent, Patrick W.,Elliott, William L.,Denny, William A.
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p. 1380 - 1397
(2007/10/03)
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