Norfloxacin derivative

Fang KC, Chen YL, Sheu JY, Wang TC, Tzeng CC (2000) Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J Med Chem 43 3809-3812... 

This class of compounds comprises a series of synthetic agents patterned after nalidixic acid, a naphthyridine derivative introduced in 1963 for the treatment of urinary tract infections. Isosteric heterocyclic groupings in this category include the quinolones (e.g., norfloxacin, ciprofloxacin, lome-floxacin, gatifloxacin, sparfloxacin, moxifloxacin, and ofloxacin), the naph-thyridones (e.g., nalidixic acid, enoxacin, and trovafloxacin), and the cin-nolones (e.g., cinnoxacin) [2] (Fig. 1). 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

A-56620) and (21 c) (difloxacin) were compared with the corresponding 1 -ethyl derivatives, norfloxacin and pefloxacin in mouse protection tests versus E. coli Juhl (Table 6.8). The two 7-(4-methylpiperazin-l-yl)quinolone derivatives, difloxacin and pefloxacin show enhanced oral activity relative to the 7-(piperazin-l-yl)quinolones, A-56620 and norfloxacin, respectively the absolute improvement in ED50 values in the 1-phenyl series is less dramatic. However, it should be noted that difloxacin, the more active agent in vivo, is 2 log2 dilutions less active in vitro. 

The related derivative (79), obtained by thermal rearrangement of the /V-oxide of (78), also exhibits excellent prodrug properties [110], This compound, when administered orally to mice, liberates excellent levels of norfloxacin and is slightly more effective in mouse protection tests than (78) and significantly better than norfloxacin. 

Upon chemical oxidation, the AT-(5-methyl-2-oxo-l,3-dioxol-4-yl)meth-yl derivative of norfloxacin (8.65, R = H, R = 8.191 with R" =Me) discussed above yielded an oxodioxolane derivative, i.e., /V-[(4-mclhyl-5-meth-ylidene-2-oxo-l,3-dioxolan-4-yl)oxy]norfloxacin (8.65, R = H, R = 8.192) [252], This compound had modest activity in vitro as an antibacterial agent. 

The quinolone antibiotics feature as the one main gronp of antibacterial agents that is totally synthetic, and not derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid more recent drugs in current use include ciprofloxacin, norfloxacin, and ofloxacin... 

Norfloxacin Norfloxacin, l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolincarboxylic acid (33.2.18), is the first representative of a series of fluorinated qninolones as well as the first drug of the quinolone derivatives used in medicine that contains a piperazine snbstituent. The method of synthesis is basically the same as that suggested for synthesizing nalidixic and oxolinic acids. 

The quinolone derivative that is most effective against Pseudomonas aeruginosa is Norfloxacin Ciprofloxacin... 

It is a methyl derivative of norfloxacin which penetrates tissues better and attains higher plasma concentration. Concentration... 

Composite MIP membranes can also be obtained by incorporation of MIP particles into the membrane polymer matrix by mixing the particles in an appropriate solvent with the membrane-forming polymer that is then solidified by the phase inversion process. Membranes thus prepared were used for separation, with targets such as tetracycline [257], theophylline [255], methylphosphonic acid [258], bisphenol [259], indole derivatives [260], propanolol [261], luteolin [262] and norfloxacin... 

Amines are particularly prone to reaction with excipients and salt counterions, as shown in Figure 45 for tartaric acid. The potential for a reaction with magnesium stearate or stearic acid is particularly of concern with an API containing a primary amine. In the case of norfloxacin, formation of a stearoyl derivative was observed in tablets containing magnesium stearate after prolonged storage at 60°C (Fig. 46) (81). 

The API norfloxacin contains a piperazine ring. This undergoes degradation under light conditions in the solution and solid state to form the ring-opened ethylene diamine derivative and amino derivative (Fig. 117). Additional degradants observed in the solid state include the amino and formyl derivatives (167). 

Scheme 135 Preparation of a prodrug derived from Norfloxacin.

Fig. 10.21 Quinolone and antibacterial 4-quinolones. Note that the newer fluoroquine derivatives (e.g. norfloxacin, ciprofloxacin, ofloxacin) have a 6-fluoro and a 7-piperazino substituent. Drugs marked with an asterisk are difluorinated quinolones, with a second fluorine atom at C-8.

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterial agents have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nalidixic acid therapy may be sensitive to the newer derivatives. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic acid. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 10.21). 

However, the newer fluoroquinolone derivatives show superior activity against Enterobacteriaceae and Ps. aeruginosa, and their spectrum also includes staphylococci but not streptococci. Extensive studies with norfloxacin have demonstrated that its broad spectrum, high urine concentration and oral administration make it a useful drug in the treatment of urinary infections. Ciprofloxacin may be used in the treatment of organisms resistant to other antibiotics it can also be used in conjunction with a p-lactam or aminoglycoside antibiotic, e.g. when severe neutropenia is present. 

More recently Brochot et al. [89] reported an extension of the isobolographic approach to interaction studies for convulsant interaction among pelloxacin, norfloxacin, and theophylline in rats. Their contribution is unique in that they started out by explaining pharmacodynamic interactions for two drugs, but then extended the approach to derive an isobol for three drug interaction. In addition they included Bayesian analysis and developed a population model with Markov chain Monte Carlo methods. 

The synthesis of fluoroquinoline antibacterials almost invariably involves substitution of the chlorofluoroquinolone with an amine as the final step (Scheme 1). Thus, the above model studies indicate excellent potential for the palladium-catalyzed amination reaction to succeed. However, initial attempts to couple the chlorofluoroquinolone derivative 2 with piperazine using the Pd2dba3/binap catalyst system and NaOtBu in toluene solvent resulted only in the recovery of unreacted starting material. Changing to more polar solvents (DMSO, DMF) or the addition of iodide salts (in an attempt to generate the iodo derivative) had no effect. It was believed that the insolubility of the carboxylic acid 2 played a role in its failure to react and that the ethyl ester would be a more productive substrate. Conveniently, the ethyl ester of 2 is an intermediate in the standard synthesis of Norfloxacin, thus, the synthesis of 13 was readily accomplished (eq 2). ... 

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