A series of both symmetrical and unsymmetrical dibenzoyl guanidines containing a p-aminobenzamide moiety was studied for the reversal of cognition deficits in rats and mice.Dibenzoylguanidine la1 was identified in our laboratories as a potential agent for the improvement of cognition deficits as determined by activity in previously reported Hypoxic Survival and Anoxic Amnesia screens,2 as well as in a passive avoidance paradigm employing aged rats. We are now disclosing a series of p-aminobenzamide analogs related to la since the synthesis of a large number of dibenzoyl guanidines showed that this substitution in many of the congeners gave compounds that were active in reversing cognition deficits in rats and mice. The general synthesis of dibenzoyl guanidines has been reported in the patent literature.1Diaroyl-S-methyl thioureas, 4a-d were the starting materials for symmetrical analogs. Reaction of compounds 4 with p-aminobenzamide gave the desired dibenzoyl guanidines. The preparation of N-alkyl congeners of la was impeded by the low nucleophilicity of N-alkylamino benzamides. p-Methylaminobenzamide derivative 7, however, was obtained via the reaction of S-ethyl compound 53 with the N-methylaniline derivative 64. Compound 7 was inactive in all screens.Unsymmetrical derivatives were prepared by reacting aroyl chlorides 3 with ammonium thiocyanate in acetone to yield the aroyl isothiocyanates 8 which were then reacted in situ with ammonium hydroxide to give aroyl thioureas 95 (1.12 mol NH4NCS. 1.0 mol of 3, 400 mL acetone, refluxed 15 min. then 200 mL cont. NH4OH added at a rate to maintain reflux, quenched in ice water, solid collected). Methylation of N-aroyl thioureas 9 with methyl iodide in acetone gave the S-methyl hydroiodides 10. The second aroyl group was then attached to 10 by the addition of a different acid chloride to the S-methyl hydroiodide in pyridine. Conversion of 11 to le-12, laa. lab was then carried out in the usual manner.One of the problems in this series of analogs was their poor solubility, thus producing potential problems for drug development. Compound 1s (Table l), with a dimethylaminoethoxy group, was synthesized to impart aqueous solubility to this class of compound. Although solubility of the compound was enhanced, it had a half-life of 15 minutes6 in acidic solution. It hydrolyzed to inactive dibenzoyl urea 13. Thus, this chemical modification was abandoned.A radiolabelled sample of la (specific activity = 16.7pCi/mg) was prepared from 14C-2 methyl-2-thiopseudourea sulphate (obtained from *4C-thioureas and dimethyl sulphate).