Central nervous system activity of new pyrimidine-8-on[2,1-f]theophylline-9-alkylcarboxylic acids derivatives

The appropriate esters 1-3 were synthesized by the alkylation of unsubstituted pyrimidin-8-on[2,1-f]theophylline I with ethyl-chloroacetate, ethyl-acrylate and ethyl-4-bromobutyrate. The acids 4-6 were obtained by hydrolysis of the esters 1-3, and transformed into Na salts 4a-6a. Amidation of the ester 1 with 25% ammonia and hydroxylamine led to amide 7 and N-hydroxyamide 8. The bromination of 1 gave 7-bromo intermediate 9 transformed to the 7-amino derivatives via nucleophilic substitution with phenylpiperazine for compound 10 and morpholine for compound 11. In the reaction of 9, 10 and 11 with sodium alcoholate, the corresponding Na salts 12a-14a were obtained. The pharmacological properties of the compounds were tested in CNS activity screening. It was found that all of the investigated compounds produced significant sedative effects in behavioral tests except weak activity of pyrimido[2,1-f]theophylline-9-sodium acetate 4a. The potent activity of pyrimido[2,1-f]theophylline-9-sodium butyrate 6a, pyrimido[2,1-f]theophylline-9-acetamide-7,7-N-phenylpiperazine-pyrimido[2,1-f]theophylline-9-sodium acetate 13a, and 7-N-morpholine-pyrimido[2,1-f]theophylline-9-sodium acetate 14a was observed. They inhibited spontaneous locomotor activity, potentiated sedation and prolonged duration of sleeping time after thiopental sodium administration. All compounds had no effects in the test of analgesia and they showed weak anti-convulsant properties. The results of this investigation may suggest hypnotic, sedative and/or tranquillizing properties of the tested compounds.