Abstract:
New compounds effective as antibacterial agent are disclosed. These new compounds include 8-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, hydrates and acid addition salts thereof, and possess superior activities against gram-negative and gram-positive of aerobicbacteria.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to new and useful benzoquinolizine carboxylic acid derivatives, useful as antibacterial agent and preparation process therefor. 
     2. Description of the Prior Art 
     Nalidixic acid, developed by Lesser et al. in 1962, has been widely known as antibacterial agent having potent activities against gram-negative of aerobicbacteria. Many new quinolone compounds related to nalidixic acid have been developed during the last few years. And, norfloxacin, one of these derivatives, possessing superior activities not only to gram-negative but also to gram-positive of aerobicbacteria has been developed. 
     The present inventors have made extensive studies earnestly to develop compounds having potent antibacterial activity not only against aerobicbacteria but also against obligate anaerobicbacteria, and invented new compounds having greater potencies and a broader antibacterial spectrum against both aerobicbacteria and obligate anaerobicbacteria than the prior art compounds, such as nalidixic acid and norflaxacin. 
     SUMMARY OF THE INVENTION 
     Namely, the new compounds according to the present invention firstly include 8-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (hereinafter abbreviated as Compound [I]), hydrates and acid addition salts thereof, having the formula; ##STR1## 
     DETAILED DESCRIPTION OF THE INVENTION 
     The Compound [I] of the present invention shows a striking broad spectrum in antibacterial activity against both of gram-negative and gram-positive aerobicbacteria, and gram-negative and gram-positive obligate anaerobicbacteria. Therefore, the Compound [I] is practically effective as antibacterial agent, applicable to new medicines to be administered for treatment of human deseases and also applicable to drugs for fishes and animals, and agricultural chemicals. The compounds of the present invention are prepared from 8-[4-(4-nitrobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (hereinafter abbreviated as Compound [II]) by reduction, such as, for example, catalytic reduction by hydrogen in the presence of catalysts, such as, palladium, nickel and platinum, or reduction by metals such as zinc, tin, iron and aluminum amalgam, or reduction by metal ions, such as stannous ion and ferrous ion, for example, in the form of salts, and preferably, catalytic reduction, for example, by hydrogen in the presence of palladium on charcoal in acetic acid under normal pressure at room temperature. ##STR2## 
     In addition, the Compound [II], the starting material, is also a novel compound, and is prepared, for example, by the following method. The Compound [II] is prepared by reaction of 9-fluoro-6,7-dihydro-5-methyl-1-oxo-8-(1-piperazinyl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (hereinafter abbreviated as Compound [III]), or its acid addition salts with p-nitrobenzyl halide (preferably bromide or chloride) (hereinafter abbreviated as Compound [IV]) in an appropriate solvent, such as, for example, N,N-dimethylformamide, at a temperature range from room temperature to boiling points of solvents used, preferably, in the presence of an acid acceptor, such as triethylamine. ##STR3## 
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
     The present invention will be better understood from the following description of preferred embodiments. 
     EXAMPLE 1 
     Preparation of 8-[4-(4-nitrobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [II]) 
     A mixture of 9-fluoro-6,7-dihydro-5-methyl-8-(1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [III]), hydrochloride (1.1 g), p-nitrobenzyl bromide (Compound [IV]) (1.87 g) and triethylamine (1.46 g) in N,N-dimethylformamide (50 ml) was heated with stirring at 80°-90° C. for 10 hr. After evaporation of the solvent, water was added to the residue, and the aqueous mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from a mixture of N,N-dimethylformamide and ethanol (2:1) to give 0.83 g (yield: 60%) of 8-[4-(4-nitrobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [II]) as pale yellow needles, m.p. 230°-233° C. (decompd.). 
     
         ______________________________________            C      H      N______________________________________Anal. Calcd. for C.sub.25 H.sub.25 FN.sub.4 O.sub.5              62.49    5.24   11.66Found              62.59    5.11   11.82______________________________________ 
    
     EXAMPLE 2 
     Preparation of 8-[4-(4-aminobenzyl)-1-piperazinyl-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [I]) 
     The Compound [II] (0.71 g), mixed with 10% palladium on charcoal (0.2 g) and acetic acid (25 ml), was hydrogenated with the calculated volume of hydrogen under normal pressure at room temperature. After the calculated volume of hydrogen was taken up, palladium on charcoal was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in a small amount of water, and neutralized with 10% sodium hydroxide solution. The resulting precipitate was collected, dried, and purified by column chromatography on silicagel using a mixture of chloroform and ethanol (10:1) as the developing solvent. The purified product was recrystallized from ethanol to give 0.25 g (yield: 37.1%) of 8-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [I]) as pale yellow needles, m.p. 215.5°-217.5° C. (decompd.). 
     
         ______________________________________              C     H      N______________________________________Anal. Calcd. for C.sub.25 H.sub.27 FN.sub.4 O.sub.3.1/3H.sub.2 O                65.77   6.11   12.27Found                65.92   5.93   12.21______________________________________ 
    
     EXPERIMENT 1 
     The antibacterial activity of the Compound [I] of the present invention was assayed by the standard agar dilution streak method against aerobicbacteria and obligate anaerobicbacteria (Chemotherapy Vol.22, No.6, pp.1126-1128 (1974): Vo.27, No.3, pp.559-560 (1979). The results are shown in Table 1 and Table 2. 
     
                       TABLE 1______________________________________Antibacterial Activity Against Aerobicbacteria             Minimum Inhibitory             Concentration (μg/ml)                   Com-Organisms       Gram    pound (I)                            NA    NFLX______________________________________Bacillus subtilis PCI219           +       0.05     6.25  0.20Staphylococcus aureus 209P           +       0.05      100  0.78Streptococcus pyogenes           +       0.20     &gt;100  3.13IID692Streptococcus pyogenes S-8           +       0.10     &gt;100  1.56Streptococcus faecalis           +       0.39     &gt;100  3.13IID682Escherichia coli NIHJ JC-2           -       0.20     3.13  0.05Escherichia coli ATCC10536           -       0.20     3.13  0.05Proteus vulgaris IFO3167           -       0.78     3.13  0.05Salmonella enteritidis           -       1.56     12.5  0.10IID604Shigella sonnei IID969           -       0.39     1.56  0.05Pseudomonas aeruginosa V-1           -       12.5      100  0.78Pseudomonas aeruginosa           -       25       &gt;100  1.56IFO12689______________________________________ NA: Nalidixic acid NFLX: Norfloxacin 
    
     
                       TABLE 2______________________________________Antibacterial Activity Against Anaerobicbacteria             Minimum Inhibitory             Concentration (μg/ml)                   Com-                   poundOrganisms       Gram    (I)     NA    NFLX______________________________________Bacteroides fragilis GM7000           -       1.56    &gt;25   &gt;25Bacteroides fragilis 0558           -       0.78    &gt;25   &gt;25Bacteroides distasonis 8503           -       3.13    &gt;25   12.5Bacteroides thetaiotaomicron           -       6.25    &gt;25   &gt;250661Bacteroides vulgatus           -       0.78    &gt;25   &gt;25Bacteroides bivius           -       1.56    &gt;25   &gt;25Bacteroides melaninogenicus           -       0.78    &gt;25   6.25GAI0410Fusobacterium necrophorum           -       0.20    &gt;25   3.13S-45Fusobacterium varium           -       12.5    &gt;25   &gt;25Fusobacterium nucleatum           -       1.56    &gt;25   25Eubacterium limosum           +       3.13     25   6.25Propionibacterium acnes           +       3.13    &gt;25   1.5611828Peptococcus maggnus           +       0.20    &gt;25   1.56Clostridium difficile           +       12.5    &gt;25   &gt;25Clostridium perfringens           +       0.39    12.5  1.56Clostridium ramosum           +       1.56    &gt; 25  &gt;25______________________________________ NA: Nalidixic acid NFLX: Norfloxacin 
    
     As shown in Table 1 and Table 2, the Compound [I] is more active than nalidixic acid and norfloxacin against obligate anaerobicbacteria (both gram-negative and gram-positive bacteria) and gram-positive of aerobicbacteria, and nalidixic acid against gram-positive of aerobicbacteria. As illustrated above, the present compounds possess greatly broader potent antibacterial spectrums against both aerobic and obligate anaerobicbacteria and are particularly effective as antibacterial agent.