Oximes prodrugs

Schiff Bases and Oximes Schiff bases and oximes formed from ketones or aldehydes with amines or hydroxyl amines are chemically reversible under acidic or basic conditions. They could be used as prodrugs of compounds containing either an amine or carbonyl functionality. 

Oximes of enones (98, 100, and 101) have been used as prodrugs of contraceptive norethindrone (97) and levonorgestrel (99). The oximes are highly bioavailable and are converted in vivo through chemical hydrolysis to their corresponding active drugs.56 57... 

A more recent application of oxime derivatives as prodrugs is the design of cascade prodmgs of dopamine agonists for the treatment of Parkinson s disease. As shown in Scheme 16, enones such as S-(-)-6-(Af,Af-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2//-naphthalen-l-one (103) can be oxidized in vivo to catecholamines... 

Oximes can be acylated to make prodrugs, as in the above example and in the case of FLM 5011, which is a strongly lipophilic, poorly water-soluble, lipoxygenase inhibitor. The water solubility was mproved by using the succinate monoester prodrug. The bioavailability of FLM 5011 in rabbits after oral administration was markedly increased by its prodrug.60... 

Simple and snbstituted oximes are biostable unless intramolecular assistance is provided. This is the case for the oximes derived from oxyamino acetic acid that are possible water-soluble prodrugs of ketones and aldehydes (See Chapter 38). 

The oxyacetic acid residue of the monoxacetams is bioisosteric with the sulfate moiety of the monosulfactams. In addition, the presence of the carboxylate moiety provided opportunity for the preparation of esters that could act as orally absorbed prodrugs. Based on structure-activity relationships, SQ 82,291 (45) [90898-90-1]y C12H15N506S, the nonacidic methoxime side chain of which was necessary to maintain oral absorption of the prodrugs, was prepared. SQ 82,291 has a high, specific affinity for the PBP-3 transpeptidase of gram-negative bacteria. However, it lacks the isobutyric acid moiety of aztreonam (17) on the oxime residue and whereas the activity of SQ 82,291 vs the Enterobacteriaceae was maintained, antipseudomonal activity was significandy diminished (37). 

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