Synthesis, analgesic, and antibacterial activity of the products of interaction of hetereno[A]-dihydro-2,3-pyrrolediones with phenylhydrazines

In continuation of our investigation into the chemical properties and pharmacological activity of hetereno[a]-dihydro-2,3-pyrrolediones [1], we have studied the interactions of these substances with phenylhydrazine and 2,4-dinitrophenylhydrazine and characterized the reaction products with respect to antibacterial and analgesic activity. Both 1-unsubstituted and 1-phenyl-5,5-dimethyl2,3,5,6-tetrahydropyrrolo[5,1-a]isoquinoline-2,3-diones react with phenylhydrazine to form the corresponding 3-hydrazones existing in the form of Z-isomers [2, 3]. In contrast to these products, 2,3-dihydro-2,3-pyrrolediones I – VII (condensed with their [a]-side exposing 2-quinoxalone and 1,4-benzoxazin-2-one cycles) react with phenylhydrazine and 2,4-dinitrophenylhydrazine to form three series of products, corresponding to the possible reaction pathways. The primary nucleophilic attack of the reagents upon a diketone molecule (I – VII) takes place either at C (see scheme, pathway a) with the formation of addition products VIII – X or at C (pathway b ) followed either by opening of the dihydropyrroledione cycle at the C – N bond with the formation of compounds XI and XII (this process takes place at room temperature) or by closing of the pyridazine cycle with the formation of compounds XIII – XVIII. Compounds VIII – X appear as white (X = O, R = Ph) or yellow (X = NH, R = C 6 H 3 (NO 2 ) 2 ) crystalline substances. These compounds melt with decomposition and show a positive reaction (cherry-red coloration) with an ethanol solution of iron(III) chloride (a test reaction for enole hydroxy groups). The solutions of compounds VIII – X in acetone and chloroform exhibit a violet color; according to [4], this fact is indicative of the reversible character of phenylhydrazine addition to diketones I – VII. The IR spectra of compounds VIII – X contain absorption bands due to the stretching vibrations of NH and OH groups (3310 – 3150 cm – ), C=O group (1710 – 1720 cm – ), aroyl carbonyl (1640 – 1650 cm – ), lactam carbonyl in compounds X and XI (1680 – 1690 cm – ), or lactone carbonyl in VIII (1760 cm – ). Compounds XI and XII appear as yellow-orange crystalline substances. These compounds melt without decomposition and exhibit no positive color reaction when tested for the presence of enole hydroxy groups. The IR spectra of compounds XI and XII display absorption bands due to the stretching vibrations of NH groups (3110 – 3340 cm – ), amide carbonyl group (1680 – 1700 cm – ), aroyl carbonyl (1610 – 1630 cm – ), a broad band of carbonyls in position 2 (1580 – 1610 cm – ), and “Amide 2” band (1530 – 1540 cm – ). The H NMR spectrum of compound XII contains signals due to the protons of aromatic substituents, a singlet of the amide NH side-chain group (8.15 ppm), and a singlet of the NH group in the heterocycle (12.75 ppm). It should be noted that, judging by the TLC data, the products of opening of the dihydropyrroledione cycle at room temperature are present in all reaction mixtures. However, these products were isolated in individual form only for compounds XI and XII. The reactions of diketones I – VII with phenylhydrazine on heating in anhydrous dioxane lead to the formation of bright-red high-melting poorly soluble crystalline compounds XIII – XVIII. The IR spectra of these compounds display absorption bands due to the stretching vibrations of NH and OH groups (3340 – 3190 cm – ), ketone carbonyl group of pyridazine cycle (1690 – 1700 cm – ), and amide carbonyl groups (1670 – 1680 cm – ). The H NMR spec-