Synthesis of Thiazolotriazine Derivatives and Their Antinociceptive Effects in Mice

Abstract

Ans raci A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro -thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg(-1). Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg(-1), also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg(-1). Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of micro-receptors in the antinociceptive effects of this drug. In addition, a nonopioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.

Synthesis of N-substituted 4,6-dioxo-imidazo[3,4-c] thiazoles and their analgesic activity in mice

“…The introduction of (4-aryl-piperazin-1-yl)alkyl moieties on various heterocyclic nuclei such as benzoxazolinones (Erdogan et al 1991 ;Palaska et al 1993 ;Go$ khan et al 1996), oxazolopyridine (Flouzat et al 1993 ;Viaud et al 1995), pyridazine (Moreau et al 1996 ;Rohet et al 1997) and pyrazolotriazine (Mavel et al 1993) led to favourable antinociceptive compounds. On this basis we decided to synthesize new N-substituted dioxo-imidazo [3,4-c]thiazoles, which share structural similarities with analgesic thiazolotriazine derivatives of the arylpiperazine class (Issartel et al 1998). We have described their analgesic activity in the phenylbenzoquinone-induced abdominal constriction test in mice and have studied their structure-activity relationships.…”