4 -Quinolone-3-carboxylic acid derivatives

Yoshikazu A, Kazuhiko I, Fujio I, Masaki H, Takayoshi 1 (2005) Synthesis and antibacterial activity of l-(2-fluorovinyl)-7-substituted-4-quinolone-3-carboxylic acid derivatives, confor-mationaUy restricted analogues of fleroxacin. J Med Chem 48 3194-3202... 

Kim WJ, et al. Novel quinolone carboxylic acid derivatives and process for preparing the same. 1994. Korea Res. Inst. Chem. Technology EP 622 367. 

A related strategy was suggested in which one of the reactants is attached via a linker to tetrabenzo[a,c,g,i]fluorene (Tbf). The reaction product can now be purified by taking advantage of the high affinity of Tbf to charcoal in polar solvents (mixture of DCM and methanol). Desorption can be affected with non polar solvents such as toluene [144]. The method was exemplified by the synthesis of a quinolone carboxylic acid derivative (ciprofloxacin). 

Petersen U, et al. Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them. 1988. Bayer AG US 5 173 484. 

Pyridyl quinolone carboxylic acids, (V), and 7-piperazine quinazolin-2,4-dione derivatives, (VI), prepared by Park (5) and Domagala (6), respectively, exhibited broad-spectrum antibacterial activity with reduced cytotoxicity. 

Quinolone and fluoroquinolone antibiotics are a group of highly-potent, synthetic antibiotics, derived from 3-quinolone carboxylic acid They are used as broad-spectrum antibiotics in the treatment of both human and veterinary diseases. 

Prototropic tautomerism of 4(l//)-quinolone-3-carboxylic acid derivatives 25 has been studied with particular emphasis on the influence of the ring substituents on the equilibrium. The techniques used include UV, H-NMR, 13C-NMR (solution), and 13C-NMR CP/MAS (solid state) (92T6135). 

Many quinoline derivatives are important biologically active agents. 8-Hydroxyquinoline and some of its halogenated derivatives are used as antiseptics. Chloroquine 111 is one of the older but still important antimalarials. A -Alkyl-4-quinolone-3-carboxylic acid and systems derived therefrom are constituents of antibacterials (gyrase inhibitors [112]) such as nalidixic acid 112, ciprofloxazin 113 and moxifloxazin 114. The quinoline-8-carboxylic acid derivative 115 (quinmerac) is employed as a herbicide for Galium aparine and other broad-leaved weeds. Methoxatin 116, known as coenzyme PQQ is a heterotricyclic mammalian cofactor for lysyl oxidase and dopamine P-hydroxylase [113]. 

Petersen U, Schenke T, Saetsch T, Bartel S, Bremm K, Endermann R, Metzger K (1994) Preparation of quinolone and naphthyridine carboxylic acid-derivative antibiotics. DE Patent 4427530 4 Aug 1994... 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

Perhydro derivatives of pyrido[l,2-6][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and 4-(substituted amino)-5-fluoro-7-oxo derivatives of 3,7-dihydro-2//-pyrido[3,2,l-f7][2,l]benzoxazine- and l,2,3,7-tetrahydropyrido[3,2,l-//]cin-noline-8-carboxylic acids are considered as a subfamily of the third generation of antibacterial quinolones. 

Very few synthetic compounds other than the sulfa drugs have shown useful activity against systemic bacterial infections, particularly those due to Gram-negative bacteria. Activity of this kind was discovered in a series of l-alkyl-4-quinolones (60BRP830832), but the most active of these, l,2-dimethyl-6-nitro-4-quinolone and l-methyl-6-nitro-4-quin-olone-3-carboxylic acid, produced eye damage (opacity of the lens) that precluded clinical trial. A closely related 1,8-naphthyridine derivative, nalidixic acid (255), was later found to be effective, and it is largely used for urinary tract infections. The quinolone oxolinic acid (256) is also used for this purpose. These compounds inhibit enzymes concerned in DNA synthesis. 

The alternative Scheme B is based on A-nucleophilic attack. Thus, bubbling air through a boiling solution of ethyl 3-amino-2-(quinoxaline-2-carbonyl)crotonoate 66 in DMF furnishes pyrido[2,3-Zr]quinoxaline 67 (Scheme 20) (04RCB1267). The latter has a structural similarity to derivatives of 4-quinolone-3-carboxylic acid, well known because of their high antibacterial activity. 

This section reviews the results of investigations on other methods for the synthesis of 4-quinolinecarboxylic acid derivatives, including various 2-quinolone-4-carboxylic acids. The transformations were mostly based on various substituted hydroxyindoles or isatins. 

However, the ketols 166 and 167, which are similar to compounds 164 and are the products from the condensation of isatin 7 with malononitrile or phenylacetic ester respectively, were transformed into 2-quinolone-4-carboxylic acid 168 or its 3-phenyl derivative 169 [146],... 

Papers in which the reactions of isatins with various reagents leading mainly to derivatives of 2-quinolone-4-carboxylic acid were studied are discussed below. The condensation of isatins 180 with diketene gave quinolonecarboxylic acids 181 acylated at position 3 [152],... 

Features of antibacterial action of derivatives of 4-quinolone-3-carboxylic acid 93KFZ(5)4. 

Leysen DC, et al. Synthesis of antibacterial 4-quinolone-3-carboxylic acids and their derivatives. Part 1. Pharmazie,... 

The usual method for making quinolone antibiotics is possible because they all have a carboxylic acid in the 3-position. Disconnection suggests a rather unstable malonic ester derivative as starting material. 

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