1421372-66-8Relevant articles and documents
Design, synthesis, SAR discussion, in?vitro and in?vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants
Zhang, Haoyang,Wu, Wenkui,Feng, Chao,Liu, Zhaogang,Bai, Enhe,Wang, Xueyuan,Lei, Meng,Cheng, Hao,Feng, Huayun,Shi, Jingmiao,Wang, Jia,Zhang, Zhao,Jin, Tao,Chen, Shanshan,Hu, Shihe,Zhu, Yongqiang
, p. 12 - 23 (2017)
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in?vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.
Preparation method of osimertinib mesylate
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, (2021/11/19)
The invention discloses a preparation method of osimertinib mesylate. 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole are subjected to a condensation reaction and then subjected to a nucleophilic substitution reaction with N, N-dimethylethylenediamine, a high-purity compound shown in the formula (6) is obtained through Eschweiler-Clarke amine reductive alkylation, water serves as a solvent, acetic acid and the like serve as a cosolvent, catalytic hydrogenation is performed, amidation reaction with acryloyl chloride is carried out to obtain high-purity osimertinib and salifying with methanesulfonic acid is carried out to obtain osimertinib mesylate, and compared with the patent CN103702990B, the method is simple and convenient to operate, less in environmental pollution, high in yield, low in cost, good in product quality and more suitable for industrial production.
Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury
Chen, Tianpeng,Wei, Yingying,Zhang, Xingxian,Zhao, Huajun,Zhu, Gaoyang
, (2021/08/25)
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti-ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro. The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo, which was expected to become a leading compound for the treatment of ALI.
