E.B. Levandovskaya, N.L. Fedorova, V.L. Gein, B.Ya. Syropyatov, M.Yu. Kovaleva

Due to structural similarities with some analgesics-antipyretics (analgin, antipyrine) and antichloristic preparations (butadione), pyrazolone derivatives, as well as, in view of recent publications about the presence of analgesic activity in 1-alkoxyarylderivatives pyrroline-2-ones, research of antipyretic activity of 1-alkoxyarylderivatives 3-hydroxy-3-pyrroline-2-ones is relevant. In continue of researching with purpose of studying the antipyretic action and establishing the dependence of biological activity on the structure a series of 1-(ortho-, meta- and para-methoxyphenyl)derivatives 5-aryl-4-acetyl (benzoyl)-3-hydroxy-3-pyrroline-2-ones were synthesized by reaction of methyl esters of acyl pyruvic acids with a mixture of aromatic aldehyde and methoxyphenylamine. Amino derivatives were obtained by the interaction of three-product synthesis with p-toluidine and excess of hydrazine hydrate. The structure of compounds was proved by methods of IR and 1H NMR spectroscopy. Determination of antipyretic activity was carried out on outbred albino rats of both sexes, weighing 220 - 280 g, on the model of fever caused by intramuscular pyrogenal 400 mg / kg. Test compounds and reference drug (acetylsalicylic acid) were injected intraperitoneally at a dose of 50 mg / kg after 3 h following pyrogenal, ie at the peak of hyperthermia. Antipyretic effect was evaluated by reduction of hyperthermia after 30 min, 1, 2 and 3 h following by introduction of test substances. Initial 4-acetyl (benzoyl) pyrrolinones, which contain methoxy group in ortho- and para-positions, have antipyretic activity at the standard level of comparison or surpass it. Tested amino derivatives showed no activity. 1-(3-Methoxyphenyl)-4-acetylderivatives pyrrolinone also showed no antipyretic action, in addition, its synthesis is difficult due to the deterioration the crystallization of the product. Conducted research have shown that under the influence of compounds, which contain acetyl fragment in the 4-position of heterocycle, body temperature decreased sharply during the first hour, and below the original. Compounds with the benzoyl residue at C4, in general, have antipyretic activity comparable to that of acetylsalicylic acid and, consequently, opportunistic substances with acetyl fragment. Reduce the temperature of these compounds, in contrast to 4-acetylcontain pyrroline-2-ones were not observed below the original. Conclusions 1. Researched 4-acyl-1-(2 - and 4-methoxyphenyl)derivatives 5-aryl-3-hydroxy-3-pyrroline-2-ones, in contrast to their amino derivatives showed an antipyretic activity, which is probably more dependent on the substituents at the first and fourth positions of the heterocycle. 2. Fundamental influence affects by residue of acylpyruvic acids: 4-acetyl-5-aryl-3-hydroxy-3-pyrroline-2-ones, which is considerably more active than 4-benzoylderivatives on the strength and duration of the antipyretic activity. 3. According to the experiment revealed that 2-methoxyphenyl substituent, which is in first position of the heterocyclic molecules, provides a strong, but gradual decrease of body temperature with reaching a maximum after 1 h, in contrast to 4-methoxyphenylderivatives pyrroledione, the marginal temperature decrease of which observed within the first hour. 4. Due to this we can assume the effect of ortho-methoxy group on the speed of onset of antipyretic action. Thus, further search for compounds with antipyretic activity among the 4-acetyl-5-aryl-1-(4-methoxyphenyl)-3-hydroxy-3-pyrroline-2-ones is perspective.