Yu. S. Andreichikov

Amides and hydrazides of aroylpyrivic acids. Part 6 Synthesis and study of antiinflammatory and analgesic activity of β-aroylpyruvoyl hydrazides of 2-methyl(phenyl)-4-quinolinecarboxylic acids

Previously we have demonstrated that 4-quinolinecarboxylic acid amides and hydrazides, substituted at position 2, exhibit pronounced antiinflammatory and analgesic activity at a quite low toxicity [1 5]. It was established that the charaeter and strength of the pharmacological action depend on the type of substituents at positions 2 and 4 of the quinoline cycle. As is known, introduction of the aroylpyruvoyl fragment into amides and hydrazides imparts to them a high antiinflammatory and analgesic activity [6, 7]. In this connection, we have synthesized cinehoninie acid hydrazides containing aroylpyruvoyl fragments at the 15-nitrogen atom. The new compounds, namely, 13-aroylpyruvoyl hydrazides of 2methyl(I) and 2-phenyl-4-quinolinecarboxylic (II) acids were obtained using a reaction of 5-aryl-2,3-dihydro-2,3furandiones with 2-methyland 2-phenyl-4-quinolinecarboxylic acids according to the scheme. Compounds I and II appear as white crystalline substances (except for Ih) poorly soluble in ethanol, benzene, chloroform, and acetonitrile, and soluble in DMSO and DMF. Their structures were established using the data of elemental analyses and the results of IR and IH NMR spectroscopic measurements. Similarly to the other pyruvic acid derivatives, the synthesized compounds provide red coloration of an ethanol solution of iron(Ill) chloride, which is evidence for the presence ofenolic hydroxyl [9, 10]. The IH NMR spectra of compounds I a Ih, IIb, and IIe contain signals attributed to the protons of methyl group (2.28-2.71 ppm), methoxy group (3.65-3.75ppm), and methine group (6.83-7.21 ppm), and a group of signals belonging to the protons of benzene ring and quinoline cycle

Synthesis and molecular structure of 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines

EthylZ-5-aryl-2-diazo-5-hydroxy-3-oxopent-4-enoates interact with triphenylphosphine to give 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines (Ar=Ph, 4-MeC6H4, 4-ClC6H4). Quantum-chemical calculations (MNDO) were performed to estimate the tautomeric equilibrium in the latter using a 6-phenyl-substituted derivative as an example. Acetylation of the 4-hydroxypyridazines led to 4-acetoxy-6-aryl-3-ethoxycarbonylpyridazines. The structure of the latter was confirmed by an X-ray diffraction analysis of 4-acetoxy-3-ethoxycarbonyl-6-(p-tolyl)pyridazine.

Synthesis and pharmacological activity of bis(O,O′-aroylpyruvoyl) and bis(O,O′-aroylacetyl) 1,2-dioximes

In this work we have extended the reactions of 5-aryl2,3-dihydrofuran-2,3-diones ( I a Id) with oximes [13] to 1,2-dioximes. The interest in this interaction was stimulated by the possibility of synthesizing compounds possessing biological activity due to the simultaneous introduction of two aroylpyruvoyl or aroylacetyl pharmacophore fragments. Previously, oximes containing these substituents were reported to possess antiinflammatory, analgesic, and antimicrobial activity [2, 3]. It was therefore of interest to study the new derivatives with respect to the same types of biological activity. The 1,2-dioximes were represented by the readily available dimethyl-(IIa), diphenyl-(IIb), and diaminoglyoximes (IIc), and 1,2-cyclohexanedione dioxime (lid).

Synthesis, properties, and biological activity of β-aroylpyruvoyl hydrazides oF N-methyl- and N-phenylanthranilic acid

Anthranilic acid hydrazides exhibit antistaphylococcus [ I ] and antiaggregation activity with respect to blood plasma thrombocytes [2]. They also can be used for the syntheses of nitrogen-containing heterocycles exhibiting various pharmacological effects [3]. Aroylpyruvic acid hydrazides exhibit a bacteriostatic effect against Staphylococcus aureus and Escherichia coli [4], inhibit the growth of A and B influenza viruses, and exhibit an antiinflammatory effect [5]. In searching for novel biologically active compounds we synthesized 13-aroylpyruvoyl hydrazides of N-methyland Nphenylanthranilic acids ( IVXVI) and studied their antiinflammatory and antimicrobial activity. The target products were obtained by the reaction of 5aryl-2,3-dihydrofuran-2,3-diones (I) with hydrazides of Nmethyland N-phenylanthranilic acids (I1 and III) in an inert solvent at room temperature. Compounds I1 and III qualify as binucleohilic reagents. The nucleophilic centers are the !3amino group ofhydrazide moiety and the aromatic N-methyland N-phenyl amino groups. The nucleophilic properties of the hydrazide 13-amino group are most pronounced, because nucleophilicity of the aromatic amino group is reduced due to the positive mesomeric effect. In addition, the steric effects can also affect the reactivity of this group [6]. It is well known that in the case of nonequivalent nucleophilic centers the furandione ring is opened under the action of the strongest nucleophilic agent [7]. The synthesized compounds are yellow solids, almost insoluble in water, and give like other ariylpyruvic acid derivatives a cherry color when reacted with an ethanol solution of FeCI3. This indicates that the compounds exist in the enol. The previous studies have established that cc-carbonyl of aroylpyruvic moiety undergoes enolization in any case [8].

Reactions of aroylpyruvic acids withS-methylisothiosemicarbazide hydroiodide and studies of the crystal structures of the reaction products

The reactions ofp-chlorobenzoyl- and benzoylpyruvic acids withS-methylisothiosemicarbazide hydroiodide gave 3-methylthio-6-(p-chlorophenacyl)-2,5-dihydro-1,2,4-triazin-5-one and 6-phenacyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5,-dione, respectively. The molecular and crystal structures of the compounds synthesized were studied by X-ray diffraction analysis.

SYNTHESIS AND STUDY OF ANTIINFLAMMATORY AND ANALGESIC ACTIVITY OF 6-METHYL(PHENYL)-3-AROYLMETHYLENE-PIPERAZIN-2-ONES

Previously we have demonstrated that 3-phenacylmethylenepiperazin-2-ones possess antiinflammatory and analgesic properties in combination with low toxicity [1, 2]. In order to search for a relationship between the structure of piperazin-2-ones and their antiinflammatory and analgesic effects, it would be of interest to introduce a substituent in position 5 or 6 of the piperazinone cycle. For this purpose, we have studied reactions of the methyl esters of aroylpyruvic acids (I) with 1,2-diaminopropane (II) and 1,2-diaminophenylethane (III). Because compounds II and III are nonsymmewically substituted, the reactions may proceed in two pathways with the formation of isomeric piperazinones A and B:

Synthesis of N-aroylpyruvoyl- and N-aroylacetyl-hetarylaminonitriles

Abstract5-Aryl-2,3-dihydrofuran-2,3-diones react with five-membered hetarylaminonitriles to give N-aroytpyruvoyl and N-aroylacetyt derivatives of the latter. The reaction of 2,2-dimethyl-6-aryl-1,3dioxin-4-ones with these hetarylaminonitriles leads solety to the N-aroylacetyl derivatives.

Synthesis and crystal structure of ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate

Reaction of 5-phenyl-2,3-dihydro-2,3-furandione with ethyl 3-benzylamino-2-butenoate, resulting in ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate and benzylamide ofN-benzoylpyruvic acid, was studied. The structure of the pyrrole derivative was confirmed by X-ray analysis.

Reaction of 5-aryl-2-tosylmethylimino-2,3-dihydro-3-furanones with substitutedN-(benzylidene)benzylamines. Crystal structure of 1-benzyl-5-p-methoxyphenyl-2-(p-chlorobenzoyl)acetylimidazole

Abstract5-Aryl-2-aroylacetyl-1-benzylimidazoles were synthesized by treatment of 5-aryl-2-tosylmethylimino-2, 3-dihydro-3-furanones withN-(benzylidene)benzylamines containing electron-donating substitutents in the benzylidene moiety. The structure of 1-benzyl-5-p)-methoxyphenyl-2-(p-chlorobenzoyl)acetylimidazole was studied by X-ray diffraction.

O-aroylpyruvoyl- and O-aroylacetyloximes: Synthesis and study of biological activity

We have previously synthesized O-aroylpyruvoyland O-aroylacetyloximes of aldehydes of the furan series; these showed pronounced antimicrobial activity [3]. We are interested in continuing our studies on the synthesis of new compounds, i.e., the corresponding O-substituted oximes, for studies of the effects on biological activity not only of the aroylpyruvoyl and aroylacetyl fragments, but also of substituents in the oxime part of the molecule. 5-Aryl-2,3-dihydrofuran-2,3-diones were reacted with the oximes of acetophenone, salicylaldehyde, acetyladamantane, and camphor. When reactions were carried out at 25-60~ the O-aroylpyruvoyloximes (compounds I-XV) were formed with almost quantitative yield. An increase in the reaction temperature to 100-110~ led to the formation of O-aroytacetyloximes (XVI-XXIII) with yields of 65-75 %. The IR spectra of aroylpyruvoyloximes I-XV contained a wide intense absorption band in the region 1580-1630 cm -s, due to superimposition of the valent vibrations of the C C bonds of the aromatic ring on vibrations of the H-chelate ring of the B-diketone fragment of the molecule, as well as the absorption band of -OC(~-O) in the region 1740-1770 cmt. Similar results were obtained for the alkyl esters of aroylpyruvic acids [5]. Shifts in the positions of the absorption bands of the complex carbonyl ester in oximes I-XV by 15-30 cm-1 to the higher-frequency region, as compared with the esters mentioned above, is probably associated with the electron-acceptor property of the -N~--~-CR2R 3 group. The IR spectra of the aroylacetyloximes XVI-XXIII contained bands corresponding to two carbonyls (1658-1680 cm t , the ketone carbonyl, and 1748-1775 cmt , the complex ester carbonyl). The same positioning of the corresponding absorption bands in the structurally similar phenyl esters of aroylacetic acids should also be noted [6, 7]. In this case, shifting of the band for the complex ester carbonyl did not occur, which is presumably due to the identical effects on its absorption of the aryl and oxime fragments.