Syntheses and central depressant activity in mice of uracil derivatives. Studies on development of new sedative-hypnotics. II

Abstract

Fifteen kinds of uracil derivatives, which were substituted with functional groups such as benzyl (Bn), methoxymethyl (MOM), n-propyl (Pr) or allyl (A) group at the N1 and/or N3 position of uracil, were synthesized. Sedative-hypnotic activity, pentobarbital (PB)-induced sleep prolongation and acute toxicity as indices of their pharmacological activities were evaluated using mice. Spontaneous activities of mice treated with N1-benzyluracil (N1-BnU, 7), N3-benzyluracil (N3-BnU, 8), N1,N3-dibenzyluracil (DBnU, 9), N1-benzyl-N3-allyluracil (BnAU, 14) and N1-allyl-N3-benzyluracil (ABnU, 15) were measured. Ten kinds of uracil derivatives showed hypnotic activity. ED50's values of ABnU (15) and N1-propyl-N3-benzyluracil (PrBnU, 13) were 155 and 172 mg/kg, i.p., respectively. Those effects were more potent than that of barbital (179 mg/kg, i.p.) Ten kinds of uracil derivatives tested significantly prolonged the PB-induced sleeping time. N3-BnU (8) increased the spontaneous activity of mice at a dose of 80 mg/kg, i.p., while ABnU (15) depressed the spontaneous activity at a dose of 160 mg/kg, i.p. The other compounds did not show any significant effect on the spontaneous activity of mice. LD50's values of ABnU (15), PrBnU (13) and N1-methoxy-methyl-N3-benzyluracil (MOMBnU, 11) were 199, 229 and 363 mg/kg, i.p., respectively. LD50's values of the other derivatives were more than 480 mg/kg, i.p. These results indicate that the benzyl group at the N3 position of uracil is important for exhibiting sedative-hypnotic activity of uracil derivatives, and that ABnU (15) has the most potent central depressant activity among the uracil derivatives tested.