Enoxacin

Eluoropyridine derivatives can be constmcted from fluoroaUphatic feedstocks. 5-Eluoro-2,6-dihydroxynicotinamide [655-15-OJ, a precursor to the anti-bacterial, enoxacin [74011-58-8] was prepared in 63% yield from ethyl fluoroacetate [459-72-3] ethyl formate [109-94-4], and malonamide [108-13-4] (394). 

The discovery of new broad spectmm antibiotics has been accompanied by the development of processes for fluorinated feedstocks ring-fluorinated aromatics for those quinolones containing a fluorobenzopyridone group, and fluorinated pyridine precursors for those antibiotics containing a naphthyridine nucleus (enoxacin, tosufloxacin) (see Table 14). 

The 8-position of the quinolone nucleus can often be advantageously substituted by fluorine (58) or chlorine (59) to give compounds with improved antibacterial potency over hydrogen in this position. With 1,8-naphthyridines, activity is reported to be approximately equivalent to the quinolone bearing a hydrogen in this position (60). As an example of this, see the data for norfloxacin (8) and enoxacin (7) in Table 2. 

The fluoroquinolones include ciprofloxacin (Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), lome-floxacin (Maxaquin), moxifloxacin (Avelox), ofloxacin (Floxin), and sparfloxacin (Zagain). 

C 2H]7FN402 75167-28-1) see Enoxacin 4-amino-5-fluoro-2-(methylthio)pyrimidine (C H FNjS) see Flucytosine a-aminoglutarimide... 

C2H5I 75-03-6) see Butibufen Cinoxacin Diethylstilbestrol Enoxacin Ethotoin Gallamine triethiodide Imiquimod Lomefloxacin Mosapride citrate Nalidixic acid Oxolinic acid Pefloxacin Pipemidic acid Tridihexethyl chloride Zaleplon... 

Quinolones Ciprofloxacin, enoxacin, and levofloxacin Urinary tract infections... 

On the other hand, the analgesic phenylbutazone, the antidepressant paroxetine, tetracycline antibiotics doxycycline and chlorotetracycline, the antibiotics tilmico-sin, danofloxacin, enoxacin, nifuroxazide, the (3-blockers betaxolol, carazolol, pindolol, the (3-agonist clenbuterol, barbiturates, the antihypertensive lisinopril, and the drug to treat cancer tamoxifen were never detected. 

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 first members of the new fluoroquinolone class (such as norfloxacin (2a), enoxacin (5), pefloxacin (6), ciprofloxacin (2b) and ofloxacin (7)), are generally somewhat less active versus Gram-positive species than Gram-negative... 

The data on the adverse reactions of the fluoroquinolones which have received the most extensive clinical evaluation (ciprofloxacin, ofloxacin, pefloxacin, norfloxacin and enoxacin), involving about 30,000 patients, have been the subject of a review [54a], An important point noted in this review involves the difficulty in detecting an important severe adverse reaction if it is of relatively low frequency, until there has been a very large patient exposure (some examples are provided in which at least 150,000-300,000 exposures would be required to observe the importance of side-effects, resulting in an alert, which have been discovered with specific drugs). However, the majority of side-effects observed thus far with the fluoroquinolones have been minor,... 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

The lack of direct proportionality between the MIC values and the gyrase inhibition values is suggested reasonably to be related to varying relative cell-penetrating properties of the different agents. Thus, enoxacin would appear... 

In 1984, the results of a study investigating amino-substituted alicyclic amino groups as replacements for the 7-piperazinyl group, common to many of the most potent quinolones, was reported [73], This comprehensive study systematically examined variations at the 7-position of the 1,8-naphthyridine nucleus. The in vitro antibacterial activities for several of these enoxacin analogues (19) are summarized in Table 6.6. The most noteworthy feature of these data is that replacement of the piperazin-l-yl group with a 3-aminopyr-rolidin-l-yl moiety (compound (19b)) results in an enhancement in potency... 

---