7682-18-0Relevant articles and documents
Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a sulfonyl moiety as potent dual inhibitors of PLK1 and BRD4
Chen, Fei,Cui, Xinhua,Gao, Zhanfeng,Gong, Ping,Hou, Yunlei,Li, Zhiwei,Liu, Jiuyu,Liu, Yajing,Qin, Mingze,Wang, Shihui,Wang, Yu,Wang, Yuehan,Zhao, Yanfang
, p. 1246 - 1259 (2022/02/07)
The simultaneous inhibition of PLK1 and BRD4 by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Herein, two series of novel pteridinone derivatives possessing a sulfonyl moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against HCT116, PC3 and BT474 cell lines. Among them, the most promising compound B2 showed high antiproliferative effects on the three cell lines with IC50 values of 0.30 μM, 1.82 μM and 1.69 μM, respectively. In the enzymatic assay, B2 was identified as a potent PLK1 and BRD4 dual inhibitor (PLK1 IC50 = 6.3 nM, BRD4 IC50 = 179 nM). Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound B2. The results showed that compound B2 obviously inhibited the proliferation of HCT116 cell lines, induced a great decrease in the mitochondrial membrane potential leading to apoptosis of HCT116 cells and arrested the G2 phase of HCT116 cells.
Expanding the Protecting Group Scope for the Carbonyl Olefin Metathesis Approach to 2,5-Dihydropyrroles
Catti, Lorenzo,Huck, Fabian,Reber, Gian Lino,Tiefenbacher, Konrad
supporting information, p. 419 - 428 (2022/01/03)
Chiral pyrrolidine derivatives are important building blocks for natural product synthesis. Carbonyl olefin metathesis has recently emerged as a powerful tool for the construction of such building blocks from chiral amino acid derivatives. Here, we demons
Preparation method of (S)-(+)-2-aminobutanamide hydrochloride
-
Paragraph 0043-0048; 0054-0059; 0065-0070; 0076-0081, (2020/08/02)
The invention discloses a preparation method of (S)-(+)-2-aminobutanamide hydrochloride, and relates to a preparation method of a levetiracetam key intermediate, and the method comprises the followingspecific steps: carrying out esterification reaction on L-2-aminobutyric acid serving as a starting material and thionyl chloride, and concentrating part of solvent after the reaction is finished; introducing ammonia gas to neutralize generated hydrogen chloride and residual thionyl chloride; and filtering, introducing ammonia gas, and carrying out an ammonolysis reaction to obtain the (S)-2-aminobutanamide hydrochloride after the treating is finished. According to the preparation method, the starting material is simple and easy to obtain, the one-pot method is adopted, the atom utilization rate is high, operation is easy and convenient, and the obtained product quality is high.
Method for preparing levetiracetam
-
Paragraph 0075; 0080-0082; 0087; 0088; 0093-0094; 0099; 0100, (2020/02/14)
The invention relates to a method for preparing levetiracetam. The method comprises the following steps: reacting aminobutyric acid in lower alcohol and thionyl chloride to obtain an intermediate I; adding ammonia water to continue the reaction, and adding hydrochloric acid to adjust the pH value to about 3 to salify to obtain a salified intermediate II refined product; reacting the intermediate II in the presence of KOH in the presence of a catalyst and dichloromethane, and then adding 4-chlorobutyryl chloride to continuously react; adding water to hydrolyze, adjusting the pH to be weakly alkaline by using diluted hydrochloric acid, and crystallizing to obtain a levetiracetam crude product; decolorizing and crystallizing in ethyl acetate to obtain a refined product of levetiracetam. The invention also relates to the levetiracetam prepared by the method and pharmaceutical application thereof, for example, the levetiracetam can be used for treating or preventing epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, idiopathic tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic diseases.
Method for preparing levetiracetam
-
Paragraph 0112-0116; 0129-0132, (2019/01/23)
The invention relates to the technical field of drug synthesis, and provides a method for preparing levetiracetam. The method includes the following steps: taking L-2-aminobutyric acid as a starting material, and preforming esterification with thionyl chloride to obtain (S)-2-methyl aminobutyrate hydrochloride; performing aminolysis reaction between the (S)-2-methyl aminobutyrate hydrochloride andammonia water to generate (S)-2-aminobutylamine hydrochloride; preforming acylation reaction between the(S)-2-aminobutylamine hydrochloride and the mixed solution of 4-chlorobutyryl chloride and dichloromethane; directly performing cyclization reaction between the intermediate product with the dichloromethane and tetrabutyl ammonium bromide to obtain a crude product of levetiracetam; and recrystallizing the crude product to generate the levetiracetam. The preparation method uses the easily-obtained starting material to ensure good reproducibility of the synthesis route, simple unit operationand economic accounting. The reaction in each step is easy to purify, the quality is controllable, and the reaction yield is greatly improved.
Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
supporting information, p. 7549 - 7553 (2019/10/02)
The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
N-1 BRANCHED CYCLOALKYL SUBSTITUTED IMIDAZO[4,5-C]QUINOLINE COMPOUNDS, COMPOSITIONS, AND METHODS
-
Page/Page column 44, (2019/12/15)
lmidazo[4,5-c]quinoline compounds of formula (II) having a substituent that is attached at the N-l position by a branched group, single enantiomers of the compounds, pharmaceutical compositions containing the compounds, and methods of making the compounds
Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate
Zhang, Yong-Kang,Plattner, Jacob J.,Easom, Eric E.,Jacobs, Robert T.,Guo, Denghui,Freund, Yvonne R.,Berry, Pamela,Ciaravino, Vic,Erve, John C. L.,Rosenthal, Philip J.,Campo, Brice,Gamo, Francisco-Javier,Sanz, Laura M.,Cao, Jianxin
, p. 5889 - 5908 (2017/07/22)
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.
THERAPEUTIC COMPOUNDS AS INHIBITORS OF THE OREXIN-1 RECEPTOR
-
Page/Page column 105, (2016/03/19)
The present invention relates to compounds that are inhibitors of the orexin-1 receptor. The compounds have the structural formula I defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with orexin-1 receptor activity.
BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536
Chen, Lijia,Yap, Jeremy L.,Yoshioka, Makoto,Lanning, Maryanna E.,Fountain, Rachel N.,Raje, Mithun,Scheenstra, Jacob A.,Strovel, Jeffrey W.,Fletcher, Steven
supporting information, p. 764 - 769 (2015/08/06)
A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a Ki = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.
