Scheme 27

Insertion of a nitro substituent, as in the anticonvulsant nitrazepam (79), changes the photochemistry, that is now dominated by reaction at that group (compare Scheme 1, b). As expected, this abstracts hydrogen and is reduced to the azoxy, azo, and amino functions by irradiation in organic solvents under nitrogen (Scheme 27).85 In the presence of oxygen the molecule is rather photostable, but produces singlet oxygen.86 Analogously, the hypnotic flunitrazepam (80) undergoes a multistep reduction finally leading to the 7-amino derivative under anaerobic conditions,87' 88 while it is JV-demethylated to give (81) in the presence of oxygen (Scheme 27).87

When a iV-oxide function is present, as in the sedative chlordiazepoxide (82), this is the photochemically active moiety. As it is usual with nitrones,89 rearrangement to the oxaziridine (83) takes place (compare Scheme 1, c), and this compound further reacts to give compounds (84) and (85) through ring contraction and ring expansion respectively (Scheme 28) 90, 91 jn tjje presence of a reducing agent such as glutathione (GSH) the main process is TV-deoxygenation to (86), occurring in part from the oxaziridine, in part directly from the excited state of the jV-oxide.92 Irradiation in the solid state leads again to the quinazoline (84), but a ring-opened imine (87) and a diazepinone (88) are also obtained, independent of whether the free base or the hydrochloride are irradiated (Scheme 28).93

2.2.3 Thioxcmthine and Phenothiazine Psychotherapeutic Agents. Many derivatives of these two heterocycles are largely used in therapy, mainly as antipsychotic agents. The alkylenethioxanthines flupenthixol (89), clopenthixol (90), thiotixene (91) and chlorprothixene (92) are used as E/Z isomeric mixtures. The E/Z ratio changes upon irradiation (>300 nm, see

Scheme 29) and, as it has been pointed out, this may affect the potency of such drugs.94 Furthermore, a slow oxidation to thioxanthone derivatives (93) occurs.94




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