Aromatic Oxidation of Some Phenothiazines

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Abstract
1. 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-methylanilmo)-2-chlorophenothiazin-7-one are reported. 5. It is postulated that in metabolism one electron is transferred from a region of high electron availability (positions 3 and/or 7) in the molecule to activated oxygen to give the phenolic derivatives.