59379-02-1Relevant articles and documents
Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia
Zhang, Dongfeng,Li, Peng,Gao, Yongxin,Song, Yaoyao,Zhu, Yaqin,Su, Hong,Yang, Beibei,Li, Li,Li, Gang,Gong, Ningbo,Lu, Yang,Shao, Huanjie,Yu, Chunrong,Huang, Haihong
, p. 7434 - 7452 (2021/06/25)
BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.
A process for preparing N - Boc - 3 - pyrrolidine of formaldehyde (by machine translation)
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Paragraph 0045; 0049; 0050; 0054, (2019/02/04)
The invention discloses a method for preparing N - Boc - 3 - pyrrolidine of formaldehyde, comprising the following steps: (1) in the solvent is added in chloromethane-based [...] and triphenyl phosphate reaction, to obtain the benzyloxy methyl trityl chloride; (2) the benzyloxy methyl trityl chloride by adding solvent, under alkaline conditions, adding N - Boc - 3 - pyrrolidone reaction, to obtain compound N - Boc - 3 - benzyloxy methylene pyrrolidine; (3) high-pressure container for adding a solvent, N - Boc - 3 - benzyloxy methylene pyrrolidine and catalyst, hydrogenation reaction to obtain N - Boc - 3 - pyrrolidine methanol; (4) will be N - Boc - 3 - pyrrolidine methanol dissolved in dichloromethane solvent, adding Dess - Martin oxidizer to carry out oxidizing, get N - Boc - 3 - pyrrolidine formaldehyde. The method of the invention has the following advantages: the used raw materials low toxicity, easy, low cost, consumption, high yield, few by-products, easy large-scale production. (by machine translation)
Boosting the hydrolytic stability of phosphite ligand in hydroformylation by the construction of superhydrophobic porous framework
Tang, Yongquan,Dong, Ke,Wang, Sai,Sun, Qi,Meng, Xiangju,Xiao, Feng-Shou
, (2019/06/05)
The development of a catalyst that delivers high activities and selectivities with excellent durability is of great importance. Numerous efficient catalysts suffer from the inherent hydrolysis liabilities, plaguing their practical applications. Herein, we show that this challenge can be tackled by constructing them into superhydrophobic porous frameworks, as exemplified by a water-sensitive phosphite ligand, tris(2-tert-butylphenyl) phosphite. The efficiency and long-term stability of the developed system are remarkably high in the hydroformylation of internal olefins after metalation with Rh species, superior to the corresponding homogeneous analogues. The significantly boosted hydrolytic stability allows for catalytic transformations using water as a green solvent, which not only facilitates the isolation of the products, but also furnishes the aldehydes with higher regioselectivities for the desired linear form in comparison with that operated under benchmark conditions using toluene as a reaction medium. Given these promising results, we anticipate the strategy advanced herein will form the basis for constructive perspectives in the enhancement of the water resistance of catalysts and the development of high performance hydroformylation catalysts.
