Synthesis of N‐(Iodophenyl)‐amides via an Unprecedented Ullmann—Finkelstein Tandem Reaction.

Toto, Patrick; Gesquière, Jean‐Claude; Déprez, Benoît; Willand, Nicolas

doi:10.1002/chin.200621076

Cited by 1 publication

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“…An alternative approach was used for the synthesis of 50k ( Scheme 11 ). In this case, a Cu-catalyzed cross coupling N -arylation of O -Bn-protected bromo-nitrophenol 51b with 4-methylpiperazin-2-one afforded 52b in acceptable yield, 45 which upon standard reactions led to the benzoxazolone 50k .…”

Section: Chemistrymentioning

confidence: 99%

Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

Martino¹,

Tardia²,

Cilibrasi³

et al. 2020

J. Med. Chem.

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Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m , where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher’s and Krabbe’s diseases. After daily intraperitoneal administration at 90 mg kg –1 , 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.

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Section: Chemistrymentioning

confidence: 99%