O. M. Chasovskikh

Synthesis and Antituberculous Activity of Fluorinated 3-R-Hydrazino-2-benzoylacrylates and Their Cyclization Products

In recent years, there has been considerable increase in the incidence of tuberculosis, which now ranks first with respect to lethality among patients with infectious diseases [1]. The rapid development of drug resistance in microbes, the toxicity and side effects of existing antituberculous drugs, and the lack of bactericidal preparations effective against stable mycobacteria are factors stimulating the effort directed toward the creation of new antituberculous drugs. The main directions in the search for effective tuberculostatic agents were recently reviewed in [1]. In particular, it was pointed out that a promising group of compounds showing pronounced antibacterial activity with respect to both sensitive and resistant strains of M. tuberculosis, in combination with low toxicity, is fluorinated quinolonecarboxylic acids. Synthetic fluoroquinolones (pefloxacin, ofloxacin, ciprofloxacin, etc.) are among the widely used antibacterial drugs with a broad spectrum of activity [2]. In one of the wellknown synthetic pathways to fluoroquinolones, key intermediates represent ethyl esters of 3-amino-2-poly(fluorobenzoylacrylic) acid [3]. Previously [4, 5], we have studied the conversions of 3-R-hydrazinobenzoylacrylates I and II. It was shown that these compounds can be involved in intramolecular cyclization processes of two types, leading to either quinolones III or pyrazoles IV, followed by the formation of derivatives belonging to the condensed system V. In particular, the cyclization of (benzazol-2-yl)hydrazinoacrylates I in acetonitrile (in the presence of diazabicycloundecene (DBU) or in dioxane (in the presence of NaH) yields a series of derivatives of 4-oxo-1,2-difluoro-4H-benzazolo[2 ,3 :3,4]-[1,2,4]triazino[5,6,1-i,j]quinolino-5-carboxylic acid (III). These compounds are the first representatives of a new pentacyclic system containing the fluoroquinolone fragment [4]. By heating acrylates I in acetonitrile or in some other solvent, it is possible to obtain substituted pyrazoles IV. Compounds IV with Y = NH can be subjected to further cyclization (in the presence of an HF acceptor) with the formation of a heterocyclic system of benzimidazo[1,2-a] pyrazolo[1,5-c]quinazoline (V) [5]. Acrylates II can be converted into derivatives of 1,3,4-oxadiazino[6,5,4-i,j]quinoline [6].

Synthesis of Fluorinated 1,3,4-Oxadiazino[6,5,4-i,j]quinolines

Abstract3-(2-Acylhydrazino)-2-tetra(penta)fluorobenzoylacrylates are readily converted to acylamino-substituted quinolones and, under more forcing conditions, annelation of oxadiazine ring occurs. We have identified the possible cyclization of the mentioned acrylates to 4,5-substituted pyrazoles.

Fluorine-Containing Heterocycles: VIII. Transformations of 2-Polyfluorobenzoylacrylates Having a Thiosemicarbazide Fragment

Depending on the conditions, 3-(4-R-thiosemicarbazido)-2-polyfluorobenzoylacrylates can be converted into the corresponding potassium salts, [1,3,4]thiadiazino[6,5,4-ij]quinolines, and pyrazole or 1,3,4-thiadiazole derivatives.

Fluorinated quinolones possessing antituberculous activity

In recent years, statistics have shown a considerable increase in the incidence of tuberculosis, which has reached one of the first places with respect to lethality among patients with infectious diseases [1]. The rapid development of drug resistance in microbes, the toxicity and side effects of the existing antituberculous agents, and the lack of bactericidal preparations effective against stable mycobacteria – all these factors stimulate the effort directed toward the search for and development of new drugs. An important group of modern antibacterial drugs, so-called fluoroquinolones, is represented by synthetic derivatives of 4-oxo-6-fluoro-1,4-dihydroquinoline-3carboxylic acid [2 – 4]. Thorough investigation into the properties of fluoroquinolones, especially those with polycyclic structures, revealed some new features of their biological activity spectrum such as antitumor and antiviral properties, including activity with respect to hepatitis C and HIV infection [5 – 7]. Since some derivatives of ofloxacin and ciprofloxacin have demonstrated high tuberculostatic properties [8, 9], it would be expedient to continue the search for new antituberculous agents in this group of compounds. Previously, we have developed methods for the synthesis of fluoroquinolonecarboxylic acid derivatives of types I – III [10 – 12]. This paper presents the results of characterization of a series of such compounds with respect to their tuberculostatic activity. (R, R, R, R, and X are specified in Tables 1 and 2). Quinolones I were obtained using a scheme analogous to that of pefloxacin synthesis, via modification of the initial structure at positions 1, 3, and 7. In particular, quinolonecarboxylic acid Ia, containing the (7-fluoroquinoxalin-6-yl)amino group in position 1, was obtained by heating 3-ethoxy-2-tetrafluorobenzoylacrylic acid ethyl ester with a hydrazine derivative of quinoxaline in toluene, followed by hydrolysis of the ester group on heating in a mixture of hydrochloric and acetic acids, and by substitution of the pyrrolidine residue for the fluorine atom at position 7. Compounds Ih, Ii, Ik, and Il were synthesized in the same way proceeding from the corresponding acrylates. 3-(4-Dimethylaminophenylmethinimino)carbamoyl derivative Ib was obtained via interaction of 7-morpholino-6-fluoro-1-ethyl4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrazide with p-dimethylaminobenzaldehyde. 6-Fluoroquinolone Ic (containing the 1,2,3-triazoline fragment in position 7) was obtained via the reaction of 1,3-dipolar cycloaddition of cyclopentanone enamine to 7-azido-6-fluoro-4-oxoquinoline-3-carboxylic acid ethyl ester (see experimental part below). 7-Isoxazolidinyl-substituted 4-oxo-6-fluoro-1,4-dihydroquinoline-3-carboxylic acids (Id – Ig) were synthesized via the reactions of 1,3-dipolar cycloaddition of 4-oxo-6-fluoro1-ethyl-1,4-dihydroquinoline-3-carboxylic acid 7-azomethinoxide with various unsaturated compounds as described in [11]. The synthesis of annelated 1,3,4-thia(oxa)diazino[6,5,4i, j ]quinolones (II, III) was based on the intramolecular cyclization of 2-poly(fluorobenzoylacrylates) containing (thio)semicarbazide residues in position 3 [10, 13]. We have also substituted amine residues for fluorine atoms in thiadiazinoquinoline derivatives. Thiadiazinoquinolones IIa – IIg were obtained as described in [12]; the synthesis of oxadiazinoquinolones IIIa – IIIc and compounds Ih and Ii was described in [13, 14]. 7-Pyrrolidino-4-oxo-6-fluoro-1,4-dihydroquinoline-