Submission Details

Design Rationale:

Inspired by X1334_0 and following the series of chloroacetamides. Chloroacetamide is replaced by fluormethanesulfonammide, which could be considered a bioequivalent for that regarding lypophilicity. Moreover, it has not strong electrophilic properties if compared to primary chloride, decreasing the potential of genotoxicity of the whole molecule. Moreover, this fragment is similar to that of fluticasone propionate and fluticasone furoate, which are a respiratory corticosteorids. Compared to the original chlrooacetamide series, the isonipecotic acid will have a reverse way of binding (halogen on the carboxylic side of the isonipecotic acid; while alkylamide on the aminic side). This modfiication makes synthesis more simple and gives the possibility to explore also aromatic rings as lypophylic substituents instead of isopropyl. Fluorine on aromatic ring could change electronic state of benzene without any great steric hindrance. This is particular important because eventual methabolism will produce benzoic acid, instead of genotoxic anilines.

Other Notes:

Easy synthesis (4 or 5 steps) is supposed. Ethylisonipecotate (fully commercial available) + alkyl or alry carboxylic acid (amidathion, carboxylic acids are fully commercially available) (1st step). Then hydrolysis of the ester (2nd step), formation of thioamide (2 or 3 steps involved, reactants are fully commercially available). No special catalyst needed

Inspired By:

AAR-POS-0daf6b7e-2