Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: Part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1 H)dioxo-2,3-dihydroimidazo[1,2- a][1,3,5]triazines

Abstract

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1 H)dioxo-2,3-dihydroimidazo-[1,2- a][1,3,5]triazines ( C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents—phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1 H)-dioxo-2,3-dihydroimidazo[1,2- a][1,3,5]triazine ( C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD 50>2000 mg kg −1 i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg −1) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid μ receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT 2 and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar′) at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT 2 expressed in the binding assay test.