Human moricizine metabolism. I. Isolation and identification of metabolites in human urine

Abstract

1. Using synthetic standards and/or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholino-propionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl ¿10-[N-(2'-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl¿ carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl ¿10-[N-(2'-hydroxyethyl) 3-aminopropionyl]phenothiazin-2-yl¿ carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.

Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

“…The carbamic acid intermediate is generally unstable and will tend to dissociate to yield CO 2 and the amine [12] upon isolation, but exceptions have been described in the literature (see below, as well as [17][18][19]). Direct evidence for the carbamate product in solution has, however, been obtained using NMR.…”

BIOTRANSFORMATION OF A GABAARECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUEN-CARBAMOYL METABOLITES

“…In these in vitro studies, the carbamic acid was never detected, although the N-carbamoyl glucuronide was generated readily, consistent with our experience with 1. Although the proposed structure of M7 may be considered instinctively speculative due to the anticipated instability of such a molecule during sample work-up, in acidic mobile phase and under high-temperature MS conditions, similar carbamic acid metabolites have been observed under analogous conditions by LC-MS (Beloborodov et al, 1989;Wang et al, 1991), and some were stable enough to be isolated for 1 H NMR analysis Richards et al, 1997;Pothuluri et al, 2000).…”

A new synthetic approach to phenothiazine-2-amines

“…19,20 The key to this simplified synthesis is that phenothiazine amides 4d,e can be hydrolyzed to the desired primary amine as reported earlier. 19 In our hands, hydrolysis of these amides was accomplished in 1,4-dioxane with 10% hydrochloric acid (4d at rt for 1 h, 4e at 100°C for 30 min) to give phenothiazine-2-amine hydrochloride (12) in 80% yield.…”