V. N. Charushin

Synthesis and Antibacterial Activity of 1,3,4-Thia(oxa)diazino[6,5,4-i,j]quinoline Derivatives

Synthetic compounds of the fluoroquinolone group, representing derivatives of 4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, are widely used as antibacterial drugs (pefloxacin, norfloxacin, ciprofloxacin, etc.) [1 – 3]. Besides the therapeutic breadth and high level of activity, an important advantage of fluoroquinolones in comparison to -lactams (penicillins, cephalosporins), aminoglycosides, and some other antibiotics is their high chemical stability. Experiments on the chimeric modification of fluoroquinolones have been conducted for more than a decade [3 – 5]. In recent years, considerable attention of researchers has been devoted to the condensed fluoroquinolones, the most widely known representatives of which are ofloxacin and marbofloxacin [6, 7]. We have developed new approaches to the synthesis of annelated fluoroquinolones [8, 9] based on the intramolecular cyclization of ethyl esters of 3-[R-carbonyl(thiocarbonyl)hydrazino]-2-tetra(penta)fluorobenzoylacrylic acid. Using this method, we obtained ethyl esters of 1,3,4-thia(oxa)diazino[6,5,4-i,j]quinoline-6-carboxylic acids and determined the conditions for hydrolysis of the ester groups and for replacement of the fluorine atoms in positions 8 and 10. This allowed us to synthesize a series of modified fluoroquinolones Ia – Ik and IIa – IIe. The synthesis of ethyl esters of 1,3,4-thia(oxa)diazino[6,5,4-i,j]quinoline-6-carboxylic acid was described in detail in [9, 10] and the synthesis of compounds Ia – Ik was reported in [11]. For this reason, below we describe only the synthesis of previously unreported 1,3,4-oxadiazino[6,5,4-i,j]quinolines (IIa – IIe). Since compounds Ia – Ik are representatives of a new heterocyclic system containing fluoroquinolone fragments and compounds IIa – IIe are the analogs of marbofloxacin, it was interesting to evaluate the antimicrobial activity of these substances. EXPERIMENTAL CHEMICAL PART

Fluorocontaining Heterocycles: IX. Derivatives of Imidazo[2,1-b][1,3]benzothiazine

The heating of derivatives of benzimidazole-2-thione and imidazolidine-2-thione with tetra(penta)fluorobenzoyl chlorides in toluene or pyridine gave rise to fluorocontaining derivatives of imidazo[2,1-b][1,3]benzothiazine. The latter were studied in reactions of nucleophilic substitution of fluorine for amino groups.

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].

Fluoro-containing Heterocycles. IV. Synthesis of Benzimidazole Derivatives

Abstract2-Mercapto-5,6-difluorobenzimidazole reacts with aliphatic and alicyclic ketones in acetic acid in the presence of catalytic amount of sulfuric acid to afford fluorinated derivatives of 2,3-disubstituted benz[4,5]imidazo[2,1-b][1,3]thiazoles. Reaction with aromatic α-haloketones occurs in another way: to furnish 2-phenylacylthio-5,6-difluorobenzimidazoles that in the system acetic anhydride-pyridine undergo cyclization into the corresponding fluorinated derivatives of benz[4,5]imidazo[2,1-b][1,3]thiazoles.

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.

Fluoro-containing Heterocycles: VI. New Derivatives of 1,3,4-Thiadiazino[6,5,4-i,j]quinoline

A series of new tricyclic fluoroquinolones was prepared by replacing fluorine atoms in derivatives of 2-R-8-Y-7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic acids. In acids and esters containing a hydrogen atom in position 8 occurred replacement of F10 by amine rests, and in compounds with a fluorine in position 8 was substituted either F8or F10 and F8depending on the amine character.

Improved method for the synthesis of norfloxacin

In recent years, a number of important antibacterial drugs for clinical use have appeared under the common name of fluoroquinolones, which are essentially the fluorine derivatives of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The first fluoroquinolone drug launched into the pharmaceutical market in 1983 was norfloxacin, namely, l-ethyl-6-fluoro-7(piperazinl-yl)-4-oxo1,4-dihydro-3-quinolinecarboxylic acid (I) [ 1]. Norfloxacin, albeit less active with respect to anaerobic microorganisms as compared to other modern fluoroquinolones, is highly efficient in the therapy of acute and chronic infections of the urinary tract and is therefore still among the best-selling preparations of the fluoroquinolone series. Moreover, only norfloxacin was certified with respect to possible application to infant therapy with no risk of negative side reactions. In most of the synthetic pathways described in the literature, norfloxacin is obtained by displacing the chlorine atom in l-ethyl-6-fluoro-7-chloro-4-oxo1,4-dihydro-3-quinolinecarboxylic acid (II) under the action of anhydrous piperazine [I 5 ] or piperazine hexahydrate [5]. The quality of norfloxacin can be improved by using N-ethoxycarbonylpiperazine instead of piperazine, followed by saponification of the resulting I -ethyl-6-fluoro-7-(4-ethoxycarbonylpiperazinl-yl)4-oxo-l,4-dihydro-3-quinolinecarboxylic acid with an alkali [6, 7]. It was also reported that norfloxacin can be obtained by interaction of the ethyl ester of I-ethyl-6-fluoro-7-chloro4-oxo-l,4-dihydro-3-quinolinecarboxylic acid (III) with anhydrous piperazine, followed by hydrolysis of the ester to acid. The reaction can be performed in boiling pyridine, picoline, pyridine toluene mixture, or triethylamine [5]. However, the above approaches to the synthesis of norfloxacin cannot be considered as perfect from the standpoint of chemistry because the relatively low mobility of the chlorine atom in position 7 of acid II or its ester III allows a competitive process of fluorine substitution in position 6. Indeed, the reaction of acid I1 with excess piperazine (in the absence of solvent) gave, in addition to norfloxacin with a 25% yield,

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-

Relationship between structure and antibacterial activity in the fluoroquinolone series of compounds

ConclusionConsidering the great number of publications related to fluoroquinolones, it is quite natural that this review cannot exhaustively summarize information on the biological activity of these compounds. This article is directed primarily at specialists in organic chemistry to acquaint them with the general laws and trends governing the relationship between the structure and biological activity of derivatives of 4-hydroxo-3-quinolinecarboxylic acid. The current interest in this promising class of compounds and the fact that other kinds of biological activity, in addition to the antibacterial action, have been discovered give us hope that new preparations of this series will be synthesized and used in practice, which would offer a wide spectrum and high level of biological activity.