Studies on the stability and decomposition of the Hagedorn-oxime HLö 7 in aqueous solution.
HLö 7, (pyridinium, 1-[[[4-(aminoarbonyl)pyridinio]methoxy]methyl] -2,4-bis- [(hydroxyimino)methyl] diiodide) has been shown to be efficacious in soman poisoning of mice even in the absence of atropine. To assess possible risks involved in the administration of HLö 7 its degradation products were analyzed at pH 2.5 and pH 7.4, respectively. At pH 2.5, where HLö 7 in aqueous solution was assumed to possess maximal stability, the predicted shelf life (10% decomposition) was about 8 years for 10 mM solutions at 8 degrees C. The apparent energy of activation was 117 kJ/mol. At pH 2.5, attack on the aminal-acetal bond predominated with formation of pyridine-2,4-dialdoxime, 2-cyanopyridine-4-aldoxime, isonicotinamide, and formaldehyde. At pH 7.4, primary attack on the 2-aldoxime group resulted in formation of an intermediate 2-cyano-4-aldoxime derivative which mainly decomposed into cyanide and the corresponding 2-pyridinone, 1-[[[4-(aminocarbonyl)-pyridinio]methoxy]methyl]-4- [(hydroxyimino)methyl] diiodide. In addition, liberated cyanide reacted with the intermediate 2-cyano-4-aldoxime derivative with formation of 2-pyridinone, 1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]methyl]-6-cyano-4- [(hydroxyimino)methyl] diiodide. This cyanide sequestering pathway became significant only at high concentrations (10 mM) of HLö 7, and was marginal at 1 mM HLö 7.
Eyer
P
P
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Federal Republic of Germany.
Ladstetter
B
B
Schäfer
W
W
Sonnenbichler
J
J
D002851:Chromatography, High Pressure Liquid; D003486:Cyanides; D003512:Cyclohexanones; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011725:Pyridines / Q000032:analysis*; D011726:Pyridinium Compounds / Q000032:analysis*; D012996:Solutions; D013055:Spectrophotometry, Infrared
D003486:Cyanides; D003512:Cyclohexanones; D011725:Pyridines; D011726:Pyridinium Compounds; D012996:Solutions; C058577:HLo 7; C004774:dimedone