The discovery of high-ceiling natriuretic activity from a series of aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate prompted our continued investigation of this new class of (aryloxy)acetic acid diuretics. Systematic alteration of the oxyacetic side chain has shown that the carboxylic acid function is the active species in vivo and that the ethyl ester group serves as a prodrug to enhance oral absorption. Side-chain functional groups that are incapable of generating the carboxylic acid in vivo failed to impart diuretic activity to the target compounds. Additional side-chain modifications including homologation, methyl substitution, and heteroatom replacement are also described. Ring annelation of the oxyacetic side chain to a dihydrobenzofuran-2-carboxylic acid produced compound 32, which displayed the highest level of saluretic activity for this series.

Fluoroquinolones are synthetic antibacterials with potential use for treatment offish diseases. This study examined the comparative uptake of difloxacin, administered as a single oral gavage, by juvenile Atlantic salmon Salmo solar in freshwater and in seawater. In separate freshwater and seawater experiments with fish of the same spawning cohort, the concentration of difloxacin in plasma and fillets was determined at 1, 2, 4, 8, 12, 18, 24, and 48 h after the fish received the dose. Although plasma difloxacin concentration began to plateau in the freshwater fish at about 24 h, the highest average, 1,195 ng/mL, was in fish sampled at 48 h; thus, the plasma levels continued to rise through the end of the test. A similar pattern was observed in fillets from fish held in freshwater, but the peak average fillet concentration at 48 h was 4,737 ng/g. Contrastingly, in the seawater study, the average peak plasma concentration of 678 ng/mL was observed at 8 h after gavage and the peak average fillet concentration of 924 ng/g was observed at 18 h. Although difloxacin concentrations were higher in the freshwater-held fish than in the seawateradapted fish, the results suggest that difloxacin could be efficacious in treating bacterial diseases of Atlantic salmon in both freshwater and seawater.

Fluoroquinolones. such as difloxacin. have potential utility as therapcutants for bacterial diseases of farmed tish. Based on the previously determined hioavailahility of difloxacin in seawater, this study was performed to determine the dose efficacy of difloxacin for treating furunculosis of Atlantic salmon Salmo salar in seawater. A strain of the causative bacterium. Aeromonas salmonicida, sensitive to difloxacin was used. In two drug efficacy trials, each fish was challenged with an intramuscular injection of 300 pathogenic bacteria based on an injection model developed for these studies. Treatment groups, consisting of fish receiving different orally administered doses of difloxacin, untreated but pathogen-injected fish, and fish medicated with another fluoroquinolone (flumequine) were replicated four times. In the first trial, the cumulative mortalities of tish treated daily with difloxacin doses of 10.0 mg/kg. 5.0 mg/kg. and 2.5 mg/kg for 5 d were significantly lower than the mortality (38%) of untreated fish inoculated with the pathogen. In the second trial, administration of difloxacin daily for 5 or 10 d at 5.0 mg/kg and for 10 d at 2.5 mg/ kg and 1.25 mg/kg resulted in significantly lower cumulative mortality than suffered by untreated inoculated fish. Flumequine, administered daily at 25 mg/kg for 10 d, also significantly reduced cumulative mortality compared with untreated fish. The mortality rate of the 5-and 10-d treatments of difloxacin at 5 mg/kg daily were not significantly different from each other.

A series of substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazoles was prepared and evaluated for their saluretic and uricosuric properties. Pharmacological evaluation of the title compounds was carried out in mice, rats, dogs, and monkeys. The diuretic/saluretic nature of these compounds was observed in all species, whereas the uricosuric activity was best seen in the Cebus monkey. Evaluation of the enantiomers of 8-chloro-3-(o-fluorophenyl)-5,6-dihydrofuro [3,2-f]-1,2-benzisoxazole-6-carboxylic acid (15k) revealed that only the (+) enantiomer (29) displayed diuretic and saluretic activity, whereas both enantiomers possessed uricosuric activity. X-ray analysis showed that the (-) enantiomer (30) possesses the 2R configuration.

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