A. V. Milyutin

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, 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].

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 and biological activity of 3-aroylmethylene-substituted 1-methyl(phenyl)-piperazin-2-ones

It was demonstrated that 3-aroylmethylenepiperazin-2ones exhibit antiinflammatory, anticonvulsive, and analgetic activity on a background of rather low toxicity [1 ]. It was established that one of the factors determining the activity is the character of acylmethylene derivative in position 3 of the piperazinone cycle. At the same time, arylamides ofaroylpyroracemic acids (noncyclic analogs of piperazinones) are known to exhibit antimicrobial effect with respect to Staphylococcus aureus [2]. In this connection, it was of interest to study the effect of substituents in position 1 of the piperazinone cycle on the biological activity. To this end, we have synthesized lmethyl(phenyl)-3-aroylmethylenepiperazin-2-ones and characterized their biological activity. The target products were obtained by interaction Of methyl esters of 4-aryl-2-hydroxy4-oxo-2-butenoic acids (1) with N-methyland Nphenylethylenediamines (II, III). It was reported that the ester of aroylpyroracemic acid (a ketone form of I) reacts with amines at the a-ketone carbonyl [4, 5]. In the case of nonsymmetric ethylenediamines, the reaction may lead to two products (A and B, see the scheme below). Taking into account the electronic effects of the methyl group and benzene ring, we may expect that the reactions of N-methylethytenediamine and N-phenylethylenediamine would lead to compounds of the B and A type, respectively. However, the steric effect of the methyl group in N-methylethylenediamines also favors the formation of compound A. The reaction proceeds smoothly with a good yield in an alcohol medium (boiling for I 1.5 h) in the presence of catalytic amounts of glacial acetic acid [2].

Interaction of 5-aryl-2,3-dihydrofuran-2,3-diones with 4-amino-3-R-1,2,4,-(4H)-triazoles and antimicrobial activity of the reaction products

As is known, aroylpyruvic acid amides formed upon decyclization of 5-aryl-2,3-dihydrofuran-2,3-diones under the action of aliphatic and aromatic amines [1] and heterylamines [2], or as a result of hydrolysis of N-substituted 2-imino-5aryl-2,3-dihydrofuran-3-ones [3], exhibit spasmolytic [4 6], analgetic, antiflammatory [7], and antimicrobial[8] activity, while being extremely low-toxicity compounds. In order to obtain new promising biologically active heterylamines of aroylpyruvic acids, we have studied the interaction of 5-aryl-2,3-dihydrofuran-2,3-diones with 4-amino3-R-1,2,4,-(4H)-triazole [9]. It is known that acylated derivatives of the latter compounds exhibit high antiflammatory and analgetie activity [10, 11], and their furfurylidene derivatives also offer bactericidal activity [12]. We have established that 5-aryl-2,3-dihydrofuran-2,3diones react at room temperature with 4-amino-l,2,4-(4H)triazoles in the course of 6 h with the formation of N-[4-1,2,4(4H)-triazolyl]amides ofaroylpyruvic acids (I IV, Table 1). The synthesized amides appear as white, creamy-tinted substances, which develop a cherry-red color on adding a FeCI3 solution in ethanol as a result of ct-carbonyl enolization [13]. The IH NMlK spectra of compounds I IV show, besides the signals of substituents in the aromatic core and the aromatic protons, a singlet due to the methyl proton of aroylpyruvoyl fragment at 7 .087.11 ppm (indicative of ct-carbonyl enolization in I IV similarly to other aroylpyruvic acid amides [1, 2, 7, 14]) and a singlet due to the two methine protons of the triazole fragment at 8.68 8.71 ppm. The signal of the proton of the amino group is not observed, probably because of the strong broadening caused by the proton exchange with solvent. The IiK absorption spectra show bands due to the stretching vibrations of N-H bonds (3100 3150 cm1), am_

Amides and hydrazides of acylpyruvic acids. 4. Synthesis and pharmacological activity of some aroyl- and pivaloylpyruvic acids

It is known that substituted amides and hydrazides of aroylpyruvic acids exhibit a broad spectrum of biological activity [ 1 4]. A bacteriostatic activity with respect to Staphylococcus aureus and Escherichia coli was reported in amides [5 13], acylhydrazides [2, 14, 15], and various arylidenehydrazides [3] of aroylpyruvic acids. The most pronounced bacteriostatic effect was observed for arylamides and adamantylamides of aroylpyruvic acids [5, 8], which showed a specific antistaphylococcal action comparable to that of the known antibacterial agents such as oxolinic acid, nalydixic acid, and flumequin [16, 17]. A transition from amides to 13-acyland substituted arylidenehydrazides of aroylpyruvic acids is usually accompanied by a significant decrease in the antimicrobial activity [2, 14]. An exception was reported for trifluoroacetylhydrazides [15], which produced a pronounced bacteriostatic action that was probably related to the toxicogenic effect of the trifluoroacetyl fragment [ 18]. A significant antiviral activity was observed in some I]-acyl-[2, 19] and arylidenehydrazides ofaroylpyruvic acids [3]. An antiinflammatory activity was observed in substituted aryiand hetarylamides [9, 12, 20-22] , hetarylhydrazides [23], and (to a lower extent) diarylmethylenehydrazides of aroylpyruvic acids [3]. Of these, the most promising antiphlogistic properties can be probably expected in some hetarylamides of aroylpyruvic acids [ 11 ]. An analgesic activity was observed in alkyland benzylamides [5, 6, 24] and in some hetarylamides of aroylpyruvic acids [I 1, 21, 22]. At the same time, it was reported that adamantylamides [8] and some hetarylhydrazides of aroylpyruvic acids [1] were inactive. We expect that a promising search for analgesic agents is possible among the alkyland benzylamides, because some preliminary results show that these derivatives have the most pronounced effect [5].

Synthesis and biological activity of substituted pyridyl amides of aroylpyruvic acid

2-Aroylpyridyl amides of aroylpyruvic acids were found to exhibit the antiinflammatory and analgesic activity at rather low toxicity [I ]. Of interest is the study of pharmacological effect of 2�9 pyridyl amides as a function of the substituent nature in the pyridine moiety. Thus we synthesized 2-(6-methyl)- and 2(5-bromo)pyridyl amides of aroylpyruvic acids (IV- XXVI) and studied their acute toxicity and antiinflammatory, sic, and antimicrobial activity. Compounds IV- XXVI were obtained by the reaction of 5-aryl-2~3-dihydrofuran-2,3-diones (1) with 6-methyl- and 5-bromo-2-aminopyridines (II and Ill) carried out in anhydrous dioxane at room temperature.

Amides and hydrazides of aroylpyruvic acids. 2. Synthesis and biological activity of some arylidenehydrazides of aroylpyruvic acids

As shown in the previous communication [12], substituted amides and/3-acylhydrazides of aroylpyruvic acids are characterized by a wide spectrum of biological activity. These compounds possess antimicrobial [6, 12], antiviral [12], antiinflammatory, analgetic [4, 12], and antispasmodic [7] activity, and also may be used in the synthesis of dyestuffs, pesticides, and a variety of nitrogen-containing biologically active compounds [5]. While amides [2, 3] and acylhydrazides of the aroylpyruvic acids [12, 14] are sufficiently well known, the structurally-related methylenehydrazides have practically not been studied. We are aware of only a limited number of works [9, 11, 15, 20] containing fragmentary information on the synthesis of some compounds of this series. Biological activity of the methylenehydrazides of aroylpyruvic acids has not been reported before. In a search for biologically active compounds among the substituted hydrazides of the aroylpyrivic acids, we prepared the arylidenehydrazides of aroylpyrivic acids (I-XII) by the reaction of 5-aryl-2,3-dihydro-2,3-furandiones with the hydrazones of aromatic aldehydes and ketones in tetrahydrofuran or dioxane at room temperature. The constants and spectral characteristics of compounds I-XII are given in Table 1. Judging by the presence in the IR spectra of I-XII of a low-frequency band at 1590-1636 cm- 1, corresponding to the carbonyl groups of the/3-diketone fragment, these compounds exist in the form of the H-chelate with the stable intramolecularly hydrogen bond (IHB) of the type OH-.-O=C [18]. This fact agrees well with literature data indicating that/3-aroylhydrazides of aroylpyruvic acids are found in the enol chelate form of the carbonyl in position 2 [12, 14, 15].