Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.

Metabolism of imipramine in vitro: synthesis and characterization of N-hydroxydesmethylimipramine.

The synthesis of N-hydroxydesmethylimipramine via the corresponding primary hydroxylamine and oxime is described. The N-oxygenated products are unstable to g.l.c. analysis without prior derivatization; the decomposition products are identified by g.l.c.-mass spectrometry. N-Hydroxydesmethylimipramine is shown to be a metabolite of imipramine and desmethylimipramine on incubation of either with fortified 9000 g liver homogenates of male New Zealand white rabbits. The metabolic product is characterized by mass spectrometry and n.m.r. Didesmethylimipramine is shown to undergo metabolic alpha-C-oxidation, to yield the carboxylic acid, 3-(10,11-dihydro-5H-dibenz[b, f]azepin-5-yl)propionic acid, but not N-oxidation. N-Hydroxydesmethylimipramine is metabolically reduced to desmethylimipramine and metabolized further to 10-hydroxydesmethylimipramine, 2-hydroxydesmethylimipramine and the carboxylic acid. The possible role of N-hydroxydesmethylimipramine and 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propionic acid in the formation of iminodibenzyl is discussed.

Metabolic oxidation of desmethylchlorimipramine in vitro by 9000 g rabbit-liver preparations.

1. The metabolism of desmethylchlorimipramine (I) has been investigated in vitro using fortified 9000 g liver homogenates of male rabbits. 2. Four metabolic products: N-hydroxydesmethylchlorimipramine (II), 3-(3-chloro-10, 11-dihydro-5H-dibenz[b,f]azepin-5-yl)propanoic acid (III), 10/11-hydroxydesmethylchlorimipramine (IV) and 2/8-hydroxydesmethylchlorimipramine (V) were isolated and identified by electron-impact mass spectrometry and n.m.r. spectroscopy. 3. Desmethylchlorimipramine (I) undergoes both N- and alpha-carbon oxidation in addition to aromatic and alicyclic carbon oxidation.

Aromatic oxidation of some phenothiazines.

The previously reported N-oxidation products phenothiazine-N-OH, N-O. and -NOOH obtained upon chemical and metabolic oxidation of phenothiazine nuclei are now shown to be the C-oxidation products, 7-hydroxyphenothiazines, phenothiazin-3-ones and phenothiazin-7-ones which have the para-hydroquinoneimino and para-quinoneimino type systems. 2. The metabolism of various 2-substituted phenothiazines in vitro gave mainly ring-hydroxylated metabolites and sulphoxides. The phenolic metabolites were further oxidized to phenothiazones either as metabolites or as 'metabonates'. 3. After metabolism of chlorpromazine, nor1-chlorpromazine and nor2-chlorpromazine in vitro, phenothiazones ('pink compounds') were obtained as N-dealkylated products of the phenolic derivatives 7- or 3-hydroxy compounds. 4. The synthesis and physicochemical characteristics including t.l.c., u.v., g.l.c. and mass spectra of the oxidized phenothiazine nuclei and of 8-(N-methyl-anilino)-2-chlorophenothiazin-7-one are reported.