Solid-phase synthesis of disubstituted N-acylureas from resin-bound ureas and acyl chlorides.

Acylureas (ureides) are valued for their important biological activities. Whereas cyclic acylureas have frequently been the object of solid-phase chemistry, only few reports have focused on the solid-supported preparation of acyclic representatives. We have prepared different types of acylureas on Rink amide resin in three or four steps. The products are either N-acylated (9, 18), N-acylated-N'-alkylated (10, 19), or N-acylated-N-alkylated (22). Characteristic NMR parameters of isomeric acylureas 10, 19, and 22 are discussed.

Evaluation of anticonvulsant and analgesic effects of benzyl- and benzhydryl ureides.

The anticonvulsant effects of benzyl- and benzhydryl ureides in mice models of seizures (maximal electroshock seizure test, pentylenetetrazol test, picrotoxin-induced seizure test) and the influence on spontaneous locomotor activity has been assessed. Furthermore, the analgesic effect of ureide derivatives was studied in the hot-plate test in mice. Selected compounds were investigated for their in vitro interaction with adenosine receptors as well as the benzodiazepine binding site of GABA(A) receptors. This study demonstrated the strong anticonvulsant activity of several ureides in electrically or chemically induced seizure models, and structure-activity relationships were discussed. 1-Benzyl-3-butyrylurea (9) was found to be equipotent to ethosuximide in the pentylenetetrazol test with regard to the number of attacks as well as the time of the onset of seizures. The ureide 9 also revealed the highest protective activity against seizures in the other models, maximal electroshock seizure and picrotoxin test. Moreover, 1-benzyl-3-butyrylurea was not neurotoxic at doses up to 200 mg/kg. Benzylureides 8-10 showed affinity to the adenosine A1 receptors at low micromolar concentrations. However, the apparent anticonvulsant activity in different seizure models does not appear to result from direct activation of adenosine A1 receptors or GABA(A) receptors, respectively. In the hot-plate test, the majority of investigated compounds exhibited analgesic activity. Again, compound 9 was superior to the other substances investigated, suggesting a potential therapeutic value of that ureide derivative.

A new objective method to compare different color reactions for the detection of cyclic ureides.

Modifications of the Zwikker- and Parri color detection tests were examined and compared according to their ability to distinguish between nine different barbituric acids and hydantoins. These tests comprised the formation of complexes with cobalt(II) and copper(II) salts and organic amines. Using the color palette introduced herein, the evaluation of the tests could be reduced to a simple yes/no decision on the basis of only seven defined colors. Suitable components for the color tests could be selected from the thirty six modifications.

The aminobarbituric acid-hydantoin rearrangement.

A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins is described. Starting from barbituric acids and following bromination and reaction with primary amines, 5-aminobarbituric acids 3a-s and 8 were prepared. Compounds 3 and 8 were subjected to different conditions of a base-catalyzed rearrangement reaction to yield the 1,5,5-trisubstituted hydantoins 4a-s and the 1,3,5,5-tetrasubstituted hydantoin 5c, respectively. Alkylation of 4a-s afforded 1,3,5,5-tetrasubstituted hydantoins 5a-h. Mechanisms that explain the transformation of corresponding aminobarbituric acids to hydantoins 4a-s and 5c were discussed in terms of the formation of ring-opened intermediates. Aminobarbituric acids 3a-s unsubstituted at position 3 underwent a ring contraction via intermediate isocyanates which were trapped by the amino function. A different mechanism involving a carbamate intermediate was concluded for conversion of the 1,3,5,5-tetrasubstituted aminobarbituric acid 8.