Is ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] unusually reactive for an imide?
The hydrolysis of ICRF-187 and two model compounds, 4-methylpiperazine-2,6-dione (4-MP) and 3-methylglutarimide (3-MG), was investigated over the neutral to alkaline pH range at 25 degrees C and an ionic strength of 0.5 (sodium chloride). The purpose of the study was to correlate the influence of molecular changes to the reactivity of these imides. Additionally, an improved chromatographic resolution of all the components of the degradation and NMR confirmation of the identity of the degradation products are presented. Based on the study of 4-MP, which is essentially half of an ICRF-187 molecule, and 3-MG, which has a carbon in place of the piperazine nitrogen, several conclusions can be drawn with regard to the stability of ICRF-187. The tertiary piperazine nitrogen/s of 4-MP and ICRF-187 contributed to the base-catalyzed hydrolysis of these compounds above pH 7 and caused a significant decrease in the pKa values of the imide moiety of ICRF-187 and 4-MP compared with 3-MG. One 2,6-piperazinedione ring of ICRF-187 was shown to affect only minimally the rate of hydrolysis of the second ring. ICRF-187 hydrolyzes by parallel consecutive pathways forming two monoacids with one ring opened and, subsequently, the diacid with both rings hydrolyzed.
Sisco
J M
JM
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Stella
V J
VJ
D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007094:Imides / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011929:Razoxane / Q000737:chemistry* / Q000378:metabolism
D007094:Imides; D010879:Piperazines; D010880:Piperidines; C077250:3-methylglutarimide; D011929:Razoxane; C077079:4-methylpiperazine-2,6-dione