N-hydroxybenzenecarboximidic acid derivatives: A new class of nitroxyl-generating prodrugs

On the basis of the propensity of Piloty's acid to generate nitroxyl (HNO), we previously prepared a number of N,O-bisacylated Piloty's acid derivativ es and showed that such prodrugs underwent a disproportionation reaction fo llowing ester hydrolysis to give an unstable intermediate that hydrolyzed t o nitroxyl, To expand the versatility of this series, we desired some mixed N,O-diacylated Piloty's acid derivatives and devised a synthetic route to them. Such efforts led us, serendipitously, to a new series of heretofore u nreported nitroxyl-generating compounds. Thus, benzohydroxamic acid was acy lated on the hydroxylamino oxygen and the resulting product converted to it s sodium salt. Treatment of this salt with arenesulfonyl chorides would be expected to give the mixed N,O-diacylated derivatives of Piloty's acid. How ever, the products obtained were the isomeric carboximidic acid derivatives whose structures were deduced from the IR and C-13 NMR spectral frequencie s associated with the sp(2) carbons. The structures were verified by analys is of the X-ray crystal structure of a prototype compound of this series. W hen incubated with porcine liver esterase or mouse plasma, these N-acyloxy- O-arenesulfonylated benzenecarboximidic acid derivatives liberated HNO, mea sured as N2O, as well as the expected arenesulfinic acid and benzoic acid. Alkaline hydrolysis also produced N2O, but the major products were the aren esulfonic acid and benzohydroxamic acid. Thus, these N-hydroxybenzenecarbox imidic acid derivatives represent a new series of nitroxyl prodrugs that re quire enzymatic bioactivation before nitroxyl can be liberated. (C) 2001 Ac ademic Press