Synthesis and Pharmacological Activity of Urea and Thiourea Derivatives of 4-Azatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione

Abstract

Thiourea and urea derivatives show a broad spectrum of biological activities as anti-HIV, antiviral, HDL-elevating, antibacterial, analgesic properties. [1][2][3][4] Numerous compounds containing thiourea group are selective ligands for 5-HT family receptors, including 5-HT 2A , 5-HT 2B and 5-HT 2C . [5][6][7][8][9] The drug-elicited head twitch response (HTR) 10,11) is a selective behavioral model for 5-HT 2 agonist activity in rodents, and several previous studies have established that direct and indirect 5-HT agonists induce this effect.12-19) Additionally, 5-HT 2 receptor antagonists selectively block HTR, [19][20][21] and their potency is highly correlated with the antagonist's affinity for 5-HT 2 receptors. 12,22)Here we report the synthesis of compounds h2, h2a, d2, d2a, k2, k2a-h4, h4a, d4, d4a, k4, k4a which composed of thiourea or urea system attached to policyclic imide.Chemistry The preparation of new nineteen thiourea and urea derivatives of 10-isopropyl-8-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3,5-dione, 1-isopropyl-7-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3, 5-dione and 1,7,8,9,10-pentamethyl-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione (Chart 1) is described.Imides obtained in Diels-Alder reaction were used as starting material. 10-Isopropyl-8-methyl-4-azatricyclo- ]-dec-8-ene-3,5-dione in reaction 1,2,3,4,5-pentamethylcyclopentadiene with pyrrole-2,5-dione. 24)The obtained tricyclic imides reacted with hydrazine (80% aqueous solution). Afterwards the compounds were subjected to the reaction with phenyl, 4-methoxyphenyl, cyclohexyl isocyanate or isothiocyanate in order to be transformed into the corresponding urea or thiourea derivatives.All final compounds were characterized by 1 H-NMR spectra which corresponded with the proposed structures.The general synthetic pathway is given in Chart 1. Pharmacology Acute toxicity of tested compound was lower than 2000 mg/kg i.p. and therefore LD 50 ϭ2000 mg/kg was accepted for the continuation of the studies. Spontaneous motor activity, amphetamine-induced hyperactivity, motor coordination and body temperature, were not changed by k1a. This compound did not protect from clonic seizures and tonic convulsions evoked by pentetrazole and from abdominal constriction induced by i.p. administration of the acetic acid solution.Only the head-twitch responses to 5-HTP were significantly decreased by 77.88% ( pϽ0.05), from 14.13Ϯ4.24 to 3.125Ϯ1.007, by k1a (Fig. 1). The result seems to point out some connection with 5-HT the system. Since it appears that head shakes induced by 5-HTP are mediated by 5-HT 2 recep- Chart 1. Synthesis of the Obtained Compounds h2, h2a, d2, d2a, k2, k2a-h4, h4a, d4, d4a, k4, k4a

Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives

“…Based on our previous research on central nervous system (CNS) for urea [43] and thiourea [44] derivatives of tricyclic imide and described in this paper for cyclic derivatives of thiourea (1,3-thiazepine system), we could conclude that this group of compounds possesses significant influence on CNS of laboratory animals.…”

“…Obtained tricyclic anhydrides were subjected to the reaction of hydrazine (80% aqueous solution), described previously [43,47].…”

“…In a previous study [43,44], we synthesized a series of urea and thiourea derivatives of tricyclic imide. Reported urea and thiourea derivatives exhibited activity on animal central nervous system (CNS) and characterized by low toxicity.…”

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro

“…Similarly, Szacon et al reported that urea derivatives with relatively low acute toxicity significantly influenced spontaneous locomotor activity and body temperature. Additionally, urea derivatives reduced the number of the ‘head‐twitch’ episodes .…”

“…The presence of semicarbazide/urea moieties in the newly synthesized molecules makes them good candidates for therapeutic agents to be administered in case of medical conditions with impacts on the CNS as well. Semicarbazide and urea derivatives show a broad spectrum of biological activities, such as antimicrobial, anticancer and central properties . Wujec et al showed that semicarbazide moieties exhibited strong antinociceptive activity organized by the CNS (at the ‘writhing’ test and that effect was reversed by opioid antagonist) and antiserotonergic effect in behavioural models.…”