Piperazine Norfloxacin

A lot of studies have been directed to the synthesis of fluoroquinolones, bearing a variety of piperazinyl substituents, since this part of quinolone molecule is of significant importance. Indeed, some representatives of 6-fluoroquinolones bearing at C(7) piperazine (norfloxacin, ciprofloxacin), 4-methylpiperazine (pefloxacin), 3-methylpiperazin (lomefloxacin, temafloxacin) proved to possess a much broader range of antibacterial activity, than those without the piperazine moiety, such as nalidixic and oxolinic acids. 

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. 

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. 

Reacting 3-chloro-4-fluoroaniline and ethyl ethoxymethylenmalonate gives the snbsti-tntion prodnct (33.2.15), which upon heating in diphenyl ester cyclizes into ethyl ester of 6-flnoro-7-chloro-l,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.16). Direct treatment of the prodnct with ethyl iodide in the presence of triethylamine and snbseqnent hydrolysis with a base gives l-ethyl-6-flnoro-7-chloro-l,4-dihydro-3-qninolin-4-on-carboxylic acid (33.2.17). Reacting this with piperazine gives norfloxacin (33.2.18) [70-75]. 

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). 

The breakthrough in the development of quinolones came with the appearance of norfloxacin 6 [19], a second-generation quinolone which combined a 6-fluorine substituent with a piperazine ring in the 7-position of the basic compound. Additional quinolones then followed in rapid succession pefloxacin [20], enoxacin [21] and fleroxacin [22] (Fig. 14.5). Particular mention must be made of ciprofloxacin 8 [23-25], ofloxacin 5 [26,27] and its active enantiomer levofloxacin 7 [28]. These quinolones have a broad spectrum of activity, which also includes Gram-positive bacteria and Pseudomonas aeruginosa, as well as favorable pharmacokinetics. The rapid absorption of these compounds from the gastrointestinal tract and their effective tissue penetration also allows them to be used for the treatment of systemic infections. 

The quinolone class of drugs were discovered in the 1960s when Lesher et al. isolated nalidixic acid as a by-product of chloroquine synthesis (2). More than a thousand quinolones and analogs have since been synthesized and evaluated in an attempt to reduce toxicity and increase antimicrobial potency. The attachment of a fluorine to C-6 and a piperazine or methylpiperazine to C-7 has led to more active agents such as norfloxacin, ciprofloxacin, ofloxacin and lomefloxacin (3). 

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). ... 

Catalytic synthesis of l-ethyl>6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid ethyl ester (Norfloxacin ethyl ester) (15a). To a dry 15 mL recovery flask equipped with a reflux condenser was added 13 (150 mg, 0.5 mmole), (R)-binap (10 mg, 0.017 mmole), cesium carbonate (360 mg, 0.950 mmole), piperazine (215 mg, 2.5 mmole), Pd2(dba)3 (10 mg, 0.010 mmole), and 1.5 mL of DMF. The reaction vessel was purged with nitrogen and heated to reflux. After three hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography on a 500 micron silica gel preparative plate with an elution mixture of chloroform methanol water ammonia (80 20 2 0.2) to give 101 mg of 15a as an off-white solid in 58% yield and, separately, 29 mg of 17 as a light brown solid in 22% yield. Using this procedure, the yield of 15a... 

The pXa values for norfloxacin were determined by dissolution of the compound in dilute aqueous sodium hydroxide or hydrochloric acid solution and potentiometric titrations of Bie solutions at 25 C wiBi O.IN HCl or O.IN sodium hydroxide. The pKai (carboxylic acid) and pXa2 (protonated piperazine nitrogen) are respectively 6.34 0.06 and 8.75 0.07 (21). 

The difference in activity for R- and -enantiomers of 7-(3-methylpiperazin-l-yl)quinolones, obtained from the corresponding (R)- and (5)-f-butyl-2-methylpiperazin-l-carboxylates, proved to be in the range from 2 to 64 folds in 52 % of cases [95]. In order to improve transport through biological membranes the piperazine moiety in norfloxacin was modified considerably and compound 26 was obtained [96]. To clarify the mechanism of antibacterial action of fluoroquinolones at the cellular level, two regioisomeric citrate-functionalized derivatives of ciprofloxacin 27a,b [97] (Scheme 14) have been obtained and studied. 

The fluorinated quinolones are generally more potent and less toxic than the first-generation agents. Agents containing a piperazine group at the C-7 position, such as ciprofloxacin and norfloxacin, are useiul in the treatment of pseudomonal infections. The fluoroquinolones inhibit bacterial topoisomerase II (predominantly) and topoisomerase IV. 

---