Search

1. A series of 1-(2-chloroacyl)ureas, related to the sedative-hypnotic drugs bromvaletone and carbromal, was synthesized and tested in mice to determine central depressant and acute toxic effects. Four 1-(2-bromoacyl)ureas and two 3-halo compounds were included for comparison. 2. Large variations in potency were seen between the compounds. Much of this can be ascribed to differences in lipophilicity. Among homologous 1-(2-chloroacyl)ureas, those with 6 acyl carbons had maximal potency. Among groups of structural isomers, the most potent were 2-halo, 3-alkyl substituted compounds. 3. The most potent compounds were also those with the largest ratios of hypnotic to lethal activity. 4. The variation in the onset and duration of action of these compounds enables a choice to be made for a compound with a particular set of characteristics.

1. The central depressant effects of bromvaletone, carbromal and six non-bromo analogues were compared in mice. 2. The chloro analogues of bromvaletone and carbromal were slightly less potent as central depressant agents than the bromo compounds. 3. The chloro analogue of bromvaletone had the greatest margin between central depressant and lethal doses. 4. Lipophilicity (octanol-water partition coefficient) did not provide a unifying relationship for potency within this group of eight acylureas. However, within each of the two subsets of compounds, a linear relationship was found between relative potency and lipophilicity.

In the rabbit the application of a non-lethal, sleep-inducing dose of bromisovalerianyl carbamide (0.5 g/kg body weight) causes an activation of the coagulation system. This activation is manifested by shortened thrombin and partial thromboplastin times and a decrease of fibrinogen concentration and Factor V activity. In contrast, pentobarbital sodium at a dose (62.5 mg/kg) which causes the same changes in arterial partial oxygen pressure and arterial pH does not influence the coagulation system. The bromocarbamide-induced changes in the coagulation system are not to be considered as a result of hypoxia and acidosis but seem to be caused by early endothelial and tissue lesions which result in the release of procoagulatory substances. In healthy test persons a single dose of 1.5 g bromisovalerianyl carbamide has no demonstrable influence on the system of hemostasis.