Synthesis of thiazolotriazine derivatives and their antinociceptive effects in mice

A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahy dro-thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinocice ptive 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 resul ting in half the maximum effect) ranged from 10 to 87 mg kg(-1). Derivative s with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-p osition of the bicyclic system were, when administered intraperitoneally at doses greater than 25mg kg(-1), also effective in the hot-plate test witho ut associated sedative effects. The compounds have a large therapeutic inde x; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg(-1) Naloxone attenuated the analgesic activity o f the 3-chloro derivative, suggesting the participation of CL-receptors in the antinociceptive effects of this drug. In addition, a nonopioid mechanis m, probably related to enhancement of the release of 5-hydroxytryptamine an d 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-h ydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazin ylmethyl derivatives might be suitable for treatment of a wide variety of p ainful conditions and could be attractive reserve agents for patients dissa tisfied with opioids.