Preparation and pharmacological evaluation of N3-substituted thymidine derivatives as central depressants

Central depressant effects in mice of N3-substituted thymidines (Td) (1) were examined by intracerebroventricular (i.c.v.) injection. Nine derivatives including the methyl, ethyl, propyl, allyl, benzyl, xylyl and alpha-phenylethyl derivatives at the N3-position of 1 were synthesized and their pharmacological effects were evaluated by using hypnotic activity, pentobarbital-induced sleep prolongation and locomotor activity as indices for central depressant effects. At a dose of 2.0 mumol/mouse, the values of mean sleeping time induced by N3-benzylthymidine (6), N3-o-xylylthymidine (7), N3-m-xylylthymidine (8), N3-p-xylylthymidine (9) and N3-alpha-phenylethylthymidine (10) were 61, 30, 48, 45 and 23 min, respectively. These derivatives (2.0 mumol/mouse) prolonged pentobarbital-induced (40 mg/kg, i.p.) sleeping time. None of the alkyl (2-4) or allyl (5) derivatives exerted hypnotic activity, although the derivatives tested (2-10) significantly prolonged the pentobarbital-induced sleeping time. Compound 1 and its xylyl derivatives tested (0.25 mumol/mouse, i.c.v.) decreased locomotor activity. These results indicate that thymidine derivatives have central depressant activity, and the benzyl derivatives but not alkyl derivatives possess a hypnotic activity.