56177-76-5Relevant academic research and scientific papers
Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin
Oboh, Edmund,Schubert, Tanner J.,Teixeira, Jose E.,Stebbins, Erin E.,Miller, Peter,Philo, Emily,Thakellapalli, Haresh,Campbell, Scott D.,Griggs, David W.,Huston, Christopher D.,Meyers, Marvin J.
, p. 11729 - 11745 (2021/08/24)
Cryptosporidiosis is caused by infection of the small intestine by Cryptosporidium parasites, resulting in severe diarrhea, dehydration, malabsorption, and potentially death. The only FDA-approved therapeutic is only partially effective in young children and ineffective for immunocompromised patients. Triazolopyridazine MMV665917 is a previously reported anti-Cryptosporidium screening hit with in vivo efficacy but suffers from modest inhibition of the hERG ion channel, which could portend cardiotoxicity. Herein, we describe our initial development of structure-activity relationships of this novel lead series with a particular focus on optimization of the piperazine-urea linker. We have discovered that piperazine-acetamide is a superior linker resulting in identification of SLU-2633, which has an EC50 of 0.17 μM, an improved projected margin versus hERG, prolonged pharmacokinetic exposure in small intestine, and oral efficacy in vivo with minimal systemic exposure. SLU-2633 represents a significant advancement toward the identification of a new effective and safe treatment for cryptosporidiosis.
Synthetic method of aromatic ring group or aromatic heterocyclic tetrazole
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Paragraph 0036-0042; 0044, (2020/12/30)
The synthetic method comprises the following steps: (1) reacting 1.0 eq of ArI or HArI with 1.2 eq of ethyl 2, 2-difluoroacetate in the presence of DMSO as a solvent and 4.0 eq of Cu under the protection of nitrogen at 30 DEG C and 50 DEG C, and purifying to obtain a first intermediate compound; (2) dissolving 1.0 eq of the first intermediate compound in a mixed solvent of THF and water, adding 2.0 eq of LiOH, reacting at room temperature for 2 hours, spin-drying the solvent, adding HCl until the pH value is equal to 3, and filtering to obtain a second intermediate compound; and (3) reacting 1.0 eq of the second intermediate compound with 2.0 eq of diphenyl azide phosphate in the presence of 2.5 eq of triethylamine by taking tert-butyl alcohol as a solvent to generate aromatic ring group or aromatic heterocyclic tetrazole. The invention provides a novel synthetic method of aromatic ring group or aromatic heterocyclic tetrazole, wherein a target compound can be more conveniently obtained, and reagents participating in the reaction are low in toxicity, mild in reaction condition, simple and safe in aftertreatment, good in product quality and suitable for large-scale production.
A new method for aromatic difluoromethylation: Copper-catalyzed cross-coupling and decarboxylation sequence from aryl iodides
Fujikawa, Kenichi,Fujioka, Yasutaka,Kobayashi, Akira,Amii, Hideki
supporting information; experimental part, p. 5560 - 5563 (2011/12/05)
A new methodology for aromatic difluoromethylation is described. Aryl iodides reacted with α-silyldifluoroacetates upon treatment with copper catalyst in DMSO or DME to give the corresponding aryldifluoroacetates in moderate to good yields. The subsequent hydrolysis of aryldifluoroacetates and KF-promoted decarboxylation afforded a variety of difluoromethyl aromatics.
