Biotransformation of aliphatic formamides: Metabolites of (±)-N-methyl-N-(1-methyl-3,3-diphenylpropyl) formamide in rats

Abstract

The in vivo biliary and urinary metabolites of (+-)-N-methyl-N-(1-methyl-3,3-diphenylpropyl) formamide (1) from male Wistar rats have been characterized by gas chromatography/mass spectrometry. In urine, non-conjugated metabolites included 1,1-diphenyl-3-butanone (4) and 3-methylamino-1,1,diphenylbutane (7). beta-Glucuronidase liberated 4, 1,1-diphenyl-3-butanol (5), 1,1-diphenyl-3-butanone oxime (6), N-hydroxymethyl-N-(1-methyl-3, 3-diphenylpropyl) formamide (3), 1-(4-hydroxyphenyl)-1-phenyl-3-butanone (11), 1-(4-hydroxyphenyl)-1-phenyl-3-butanone oxime (12), N-methyl-N-(1-methyl-3-(4-hydroxyphenyl)-3-phenylpropyl) formamide (8), 1-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-butanone (16); 1-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-butanol (17), 1-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-butanone oxime (18), N-(1-methyl-3-(4-hydroxy-3-methoxyphenyl)-3-phenylpropyl) formamide (14) and N-methyl-N-(1-methyl-3-(4-hydroxy-3-methoxyphenyl)-3-phenylpropyl) formamide (13). Most of the carbinolamide (3) decomposed in the gas chromatograph inlet to N-(1-methyl-3,3-diphenylpropyl) formamide (2) unless stabilized as a trimethylsilyl (TMS) derivative. In bile, compounds 1, 2, 3, 5, 6, 11, 12 and 16 were present as non-conjugated metabolites. beta-Glucuronidase also liberated N-(1-methyl-3-(4-hydroxyphenyl-3-phenylpropyl) formamide (9), and all of the previously listed compounds except 7. Trimethylsilylation of the conjugated bile fraction revealed the presence of an additional two compounds: N-hydroxymethyl-N-(1-methyl-3-(4-hydroxyphenyl)-3-phenylpropyl) formamide (10) and N-hydroxymethyl-N-(1-methyl-3-(4-hydroxy-3-methoxyphenyl)-3-phenylpropyl ) formamide (15). A stable carbinolamide metabolite standard was synthesized and the mass spectral fragmentations of its TMS derivative studied by tandem mass spectroscopy. This is the first report on stable carbinolamide metabolites of high-molecular-weight formamides.

Characterization of Novel Isocyanate-Derived Metabolites of the Formamide N-Formylamphetamine with the Combined Use of Electrospray Mass Spectrometry and Stable Isotope Methodology

“…GC/MS: m/z 168 (1) (M)+, 123 (80), 96 (30), 72 (100), 44 (55). -NMR (CDC13): ó 1.10 (d, J = 8 Hz, 2H, CH3), 1.30 (d, J = 8 Hz, 1H, CH3), 2.65-2.90 (m, 2H, CH2), 3.70 (m, 0.2H, CH2C ), 4.30 (m, 0.8H, CH2CU), 5.60 (bs, 1H, NH), 7.10-7.30 (m, 0.02H, Ar-H), 7.60 (d, J = 10 Hz, 0.2H, CHO), 8.10 (d, J = 2 Hz, 0.8H, CHO). Isotopic purity was 99 atom % D based on -NMR integration of the aromatic protons and >96 atom % D based on MS analysis.…”

“…Despite the interest shown in the metabolism of NMF and low molecular weight formamides, few studies in the literature have focused on high molecular weight formamides (7,8). Notwithstanding, large formamides are toxicologically relevant as evidenced by the occurrence of IV-formyl derivatives as contaminants in illicit preparations of amphetamine analogues (9)(10)(11).…”