- Isolation and structural characterization of degradation products of afatinib dimaleate by LC-Q-TOF/MS/MS and NMR: cytotoxicity evaluation of afatinib and isolated degradation products
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Afatinib is an irreversible tyrosine kinase receptor inhibitor which was approved lately by USFDA for the treatment of metastatic non-small cell lung cancer (NSCLC). AFT was subjected to stress degradation studies under hydrolytic (acid, base and neutral), oxidative, thermal and photolytic conditions to investigate the inherent stability of the drug. The present study describes the simple and rapid HPLC method development for the selective separation of the AFT and its degradation products. The drug and degradation products were separated on Agilent Eclipse plus C18 (150 × 4.6 mm, 5 μ) column with ammonium acetate buffer (10 mM, pH 6.7) in gradient elution mode. The drug was found to be unstable in all the conditions studied. The developed chromatographic method was extended to tandem mass spectrometry (QTOF-MS) for the characterization of the degradation products. A total of 11 unknown degradation products were characterized using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS/MS). Two major degradation products (DP2 and DP3) were isolated using preparative HPLC and their structures were confirmed by conducting 1H and 13C NMR experiments. The isolated DPs were evaluated for their anticancer potential using non small cell lung cancer cell line A549. The IC50 values for AFT, DP2 and DP3 were found to be 15.02 ± 1.49, 25.00 ± 1.26 and 32.56 ± 0.11 respectively. The in silico toxicity studies were performed employing ProTox-II software for the assessment of toxicity potential of drug and its degradation products. Finally, the developed chromatographic method was validated as per the International Conference on Harmonization guideline Q2 (R1).
- Chavan, Balasaheb B.,Sawant, Vitthal,Borkar, Roshan M.,Ragampeta, Srinivas,Talluri, M.V.N. Kumar
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Read Online
- Industrial Cunninghamia lanceolata carbon supported FeO(OH) nanoparticles-catalyzed hydrogenation of nitroarenes
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The development of green and efficient methods for hydrogenation of nitroarenes is still highly demanding in organic synthesis. Herein, we report an industrial Cunninghamia lanceolata carbon supported FeO(OH) nanoparticles process for the synthesis of aryl amines with good yields via hydrogenation of nitroarenes. Nine key anti-cancer drug intermediates were successfully achieved with protocol. And Osimertinib intermediate 4m can be smoothly synthesized at a 2.67 kg-scale with >99.5% HPLC purity. This protocol features cheap carbon source, highly catalytic activity, simple operation, kilogram-scalable and recyclable catalysts (eight times without observable losing activity).
- Fu, Lihua,Li, Dingzhong,Lu, Hao,Qiu, Renhua,Sun, Tulai,Xing, Chen,Yang, Tianbao
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- Preparation method of afatinib intermediate
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The invention discloses an afatinib intermediate preparation method, which comprises: (1) adding a compound represented by a formula II, sodium thiosulfate, sodium bicarbonate and N, N-dimethylformamide into a reaction device, heating, completely reacting
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Paragraph 0055-0069
(2021/06/06)
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- Synthetic method of afatinib intermediate
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The invention discloses a synthesis method of an afatinib intermediate, which comprises the following steps: adopting a compound (I), by using hydrazine hydrate as a reducing agent, FeCl3. 6H2O as a catalyst, activated carbon as a carrier and a THF/MeOH s
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Paragraph 0020-0021
(2020/07/15)
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- Preparation method and application of aniline quinazoline intermediate
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The invention discloses a preparation method and application of an aniline quinazoline intermediate. The preparation method comprises the following steps: with N-(3-chloro-4-fluorophenyl)-7-[(S)-tetrahydro-3-furyl-oxy]-6-nitro-4-quinazolinamine as a raw m
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Paragraph 0035-0046
(2020/08/30)
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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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- 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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- 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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- 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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- A preparation method of the midbody arab league law for nepal
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The invention provides a preparation method of an Afatinib intermediate and particularly provides a preparation method of N-(3-chloro-4- fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine. According to the method, 4-[(3-chloro-4-flu
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Paragraph 0016-0028
(2018/04/21)
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- 4 - (Substituted phenylamino) aminoquin oxazolines, preparation method and application thereof
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The invention specifically relates to novel 4-(substituted phenylamino)quinazoline compounds with antineoplastic activity and a preparation method thereof, belonging to the field of pharmaceutical chemical engineering. The 4-(substituted phenylamino)quinazoline compounds have an effective irreversible inhibiting effect on tyrosine kinase and/or good in-vivo pharmacokinetic behavior and are an effective tyrosine kinase irreversible inhibitor.
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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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p. 3148 - 3157
(2017/05/29)
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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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- Improving method of afatinib synthesis technology
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The invention discloses an improving method of an afatinib synthesis technology, and belongs to the technical field of organic synthesis. Chlorination, amination, etherification and reduction reactions in the afatinib synthesis technology are improved and optimized, so the method improves the yield and the purity of a product, simplifies technology operation, reduces the production cost, realizes convenient and clean post-treatment, and has high practicality. Compared with the prior art, the improving method of the afatinib preparation technology overcomes many shortages, has a high yield, has simple steps, and allows the total yield to be about 71% and the purity to be 98%. The method has the main advantages of simplified steps, mild reaction conditions, simplicity in operation, high yield, high purity, and facilitation of industrial production.
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- Compound, and preparation method and application thereof
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The invention relates to a compound, and a preparation method and application thereof. Specifically, the compound is as shown in a formula 1 which is described in the specification. The invention also provides the preparation method for the compound as shown in the formula 1. The preparation method comprises a step of contacting N-[4-[(3-chloro-4-fluorophenyl)amino]-7[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butyleneamide with an alkaline aqueous solution in an organic solvent so as to obtain the compound as shown in the formula 1. The preparation method is simple to operate; a white powder product can be obtained through direct filtering after post-treatment; and the prepared compound has high purity, as high as 99% or above, and can be directly used as an impurity control substance for research on the quality of an afatinib bulk drug.
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- Containing zinc binding moiety based EGFR tyrosine kinase inhibitors
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Belonging to the technical field of medicine, the invention in particular relates to a zinc binding group-containing quinazolinyl EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor shown as general formula (I), its deuterated compounds, pha
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Paragraph 0208; 0213-0215
(2016/10/17)
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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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- Synthesis method of anti-tumor medicine afatinib
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The invention discloses a synthesis method of an anti-tumor medicine afatinib and belongs to the technical field of pharmaceutical chemistry. The method takes 2-nitryl-5-bromophenol as a raw material and obtains the afatinib through a five-step chemical reaction. The raw material of a synthesis route is easy to obtain, a process route is shortened, the operation is simple and the yield of products is high; and industrial production is easy to realize.
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- Preparing method of Afatinib
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The invention relates to a preparing method of Afatinib. The preparing method includes the steps that 6-nitro-7-fluoro-3,4-dihydro quinazoline-4-ketone is used as a raw material and is subjected to etherification reaction with S-3-hydroxy-tetrahydrofuran; obtained 6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl]-3,4-dihydro quinazoline-4-ketone is subjected to chlorination reaction; obtained 4-chloro-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to condensation reaction; obtained 4-[(3-chloro-4-fluoro-phenyl)amino]-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to reduction reaction; E-4-dimethyl amido crotonic acid is subjected to chloroformylation reaction, and E-4-dimethyl amido crotonyl chloride and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline are subjected to amidation reaction to obtain the finished product.
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- Quinoline and quinazoline derivatives, preparation method, intermediate, composition and use thereof (by machine translation)
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The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.
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- Synthetic method for afatinib intermediate
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The invention relates to a synthetic method for an afatinib intermediate. The method comprises the step of: carrying out a reaction on (S)-N-(3-floro-4-fluorophenyl)-6-nitryl-7-[(tetrahydrofuran-3-yl)oxy]quinazoline-4-amine and sodium hydrosulfite. The me
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Paragraph 0031; 0032; 0033; 0034
(2016/11/14)
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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 0303; 0305; 0312
(2016/10/08)
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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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Paragraph 0084; 0102
(2016/08/17)
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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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- CRYSTALLINE FORMS OF AFATINIB DI-MALEATE
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The present disclosure encompasses crystalline forms of Afatininb di-maleate and methods of their use.
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- Aminoquinazoline Derivative And Use Thereof In Preparing Anti-Malignant Tumor Medicament
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The invention discloses a new amino-quinazoline derivative and its use in preparing drugs for preventing and/or treating malignancies. The amino-quinazoline derivative of the invention is an ideal, high effective, dual and irreversible EGFR and HER2 kinas
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Paragraph 0031; 0032
(2015/03/16)
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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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- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
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Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug ther
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- A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles
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Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFRWT, EGFRT790M as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFRL858R/T790M driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
- Xia, Guangxin,Chen, Wenteng,Zhang, Jing,Shao, Jiaan,Zhang, Yong,Huang, Wei,Zhang, Leduo,Qi, Weixing,Sun, Xing,Li, Bojun,Xiang, Zhixiong,Ma, Chen,Xu, Jia,Deng, Hailin,Li, Yufeng,Li, Ping,Miao, Hong,Han, Jiansheng,Liu, Yanjun,Shen, Jingkang,Yu, Yongping
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p. 9889 - 9900
(2015/02/02)
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- Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor
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A novel series of anilinoquinazoline compounds with C-6 urea-linked side chains was designed and synthesized as reversible inhibitors of epidermal growth factor receptor (EGFR) based on the structure-activity relationships (SARs) of anilinoquinazoline inhibitors. All compounds demonstrated good inhibition of EGFR wild type (EGFR wt) (IC50 = 0.024-1.715 μM) and inhibited proliferation of A431cell line (IC50 = 0.116-22.008 μM). The binding mode of compounds 8a, 8d, 8k and 8o was consistent with the biological results. Moreover, compounds 8k and 8l almost completely blocked the phosphorylation of EGFR in A431 cell line at 0.01 μM. Interestingly, all of the compounds also demonstrated moderate inhibition of EGFR/T790M/L858R (IC 50 = 0.049-5.578 μM). In addition, compounds 8f and 8h blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (10 μM), and compound 8f was confirmed to be an irreversible inhibitor through the dilution method. Importantly, the compounds with C-6 urea-linked side chains which did not contain Michael acceptors demonstrated moderate to strong irreversible EGFR inhibition.
- Zhang, Xu,Peng, Ting,Ji, Xun,Li, Jian,Tong, Linjiang,Li, Zeng,Yang, Wei,Xu, Yungen,Li, Mengyuan,Ding, Jian,Jiang, Hualiang,Xie, Hua,Liu, Hong
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p. 7988 - 7998
(2014/01/06)
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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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- PROCESS FOR PREPARING AMINOCROTONYLAMINO-SUBSTITUTED QUINAZOLINE DERIVATIVES
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The invention relates to an improved process for preparing aminocrotonylamino-substituted quinazoline derivatives of general formula (I) wherein the groups Ra, Rb, Rc and Rd have the meanings given in the claims, as well as sulphonyl derivatives of formula (XIII) and the use thereof as synthesis components for preparing quinazolines of formula (I). The quinazoline derivatives of formula (I) are inhibitors of signal transduction mediated by tyrosinekinases and by the Epidermal Growth Factor-Receptor (EGF-R) and are therefore particularly suitable for the treatment of tumoral diseases.
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Page/Page column 22
(2008/06/13)
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- Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
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A compound of formula (I) wherein: Ra is a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, wherein: R1 is a hydrogen, fluorine, chlorine, or bromine atom, or a methyl, triflu
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- Quinazoline derivatives and phamaceutical compositions containing them
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A compound of general formula I wherein: Ra is a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group; Rb is a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino, or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and Rc is a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group, or a tautomer, stereoisomer, or salt thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and airways, and the preparation thereof.
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