7-Substituted quinolone- and naphthyridinecarboxylic acid derivatives.

0001The invention relates to 7-aryl- and 7-hetaryl-substituted quinolone and naphthyridonecarboxylic acid derivatives, processes for their preparation and antibacterial agents containing them.

0002The good antibacterial activity of 7-aryl- or 7-hetaryl-substituted quinolonecarboxylic acid derivatives is known in principle. For example, the compound 1-ethyl-1,4-dihydro-4-oxo-7- (4-pyridyl) -3-quinolinecarboxylic acid (rosoxacin) is known from US Pat. No. 3,753,993. US Pat. No. 4,636,506 describes, inter alia, the preparation of 1-ethyl-6,8-difluoro-7- (4-pyridyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Finally, EP-PS 184 384 describes the synthesis of 1-alkyl-6, (8) - (di) fluoro-7-aryl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

0003The decisive CC linking step for the aryl substituents in the 7-position in the process of the last-mentioned application consists in the coupling reaction between an aryl bromide and an aryl zinc chloride catalyzed by a palladium complex.

0004The 7-bromo-quinolonecarboxylic acid ester or a correspondingly substituted bromobenzene, which is then converted to 7-arylquinolonecarboxylic acid in further reaction steps, can serve as the aryl bromide.

0005The disadvantages of this process are the restriction to the reactive iodine and bromoaryl compounds, the use of relatively large amounts (6-12 mol%) of an expensive palladium catalyst such as tetrakis (triphenylphosphine) palladium (O) and the preparation of the aryl zinc chlorides from an aryl bromide, lithium alkyl and anhydrous zinc chloride required to see the required low reaction temperatures of -78 to -50 ° C.

0006It has now been found that, surprisingly, 7-haloquinolonecarboxylic acid esters in general, but especially 7-chloroquinolonecarboxylic acid esters, which are easier to prepare than the corresponding iodine or bromine compounds, can be converted directly to 7-arylquinolonecarboxylic acid esters in the presence of a simple and inexpensive nickel catalyst using aryl halides.

0007The invention accordingly relates to a new process for the preparation of quinolonecarboxylic acid derivatives of the general formula (I)<chemistry id="chem0001" num="0001"><img file="EP0343398A2_D0001.tif" /></chemistry>in the<ul id="ul0001" list-style="none"><li>R 'is hydrogen, optionally mono- to trisubstituted by halogen₁-C₆-Alkyl or cycloalkyl, vinyl, allyl, benzyl or for optionally one to three times by C₁-C₆-Alkyl or halogen, especially fluorine-substituted C₆-C₁₀-Aryl stands,</li><li>R² for aryl with 6 to 10 carbon atoms or heteroaryl with 3 to 9 carbon atoms, substituted one or more times by C₁-C₄-Alkyl, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkyl with 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkoxy with 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylthio with 1 or 2 carbon atoms and 1 to 5 halogen atoms, optionally by C₁-C₃-Alkyl and / or fluorine-substituted phenyl, for optionally by C₁-C₃-Alkyl and / or fluorine-substituted phenoxy, dialkylamino, diarylamino, carboxyalkyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, formyl, cyano, acetoxy or a group<chemistry id="chem0002" num="0002"><img file="EP0343398A2_D0002.tif" /></chemistry></li><li>X² for hydrogen, C₁-C₃Alkyl or halogen,</li><li>X³ for hydrogen, C₁-C₃Alkyl, alkoxy having 1 to 3 carbon atoms or halogen,</li><li>A represents nitrogen or a radical CX °, in which</li><li>X⁴ Can be hydrogen, halogen or cyano, or together with R 'a bridge of the structure<chemistry id="chem0003" num="0003"><img file="EP0343398A2_D0003.tif" /></chemistry></li><li>can form</li><li>and</li><li>Y is a nitrile group, an ester group -COOR³ or an acid amide group -CONR⁴R⁵ represents</li><li>in which</li><li>R³ for C₁-C₄-Alkyl stands and</li><li>R⁴ and R⁵ can be the same or different and for C₁-C₃-Alkyl stand and R⁴ optionally substituted phenyl,</li><li>characterized in that 7-haloquinolonecarboxylic acid derivatives of the formula II<chemistry id="chem0004" num="0004"><img file="EP0343398A2_D0004.tif" /></chemistry></li><li>in the</li><li>R ', X², X³, A and Y have the meaning given above and</li><li>X 'represents halogen, preferably chlorine, bromine and iodine, particularly preferably chlorine,</li><li>in the presence of a nickel catalyst with aryl halides or hetaryl halides of the formula III<chemistry id="chem0005" num="0005"><img file="EP0343398A2_D0005.tif" /></chemistry></li><li>in the</li><li>R² the meaning given above and</li><li>X⁵ represents halogen other than fluorine, preferably chlorine and bromine,</li><li>implements.</li></ul>

0008The process is preferably suitable for the preparation of quinolonecarboxylic acid derivatives of the formula I in which

0009R¹ for C optionally substituted by halogen, preferably fluorine₁-C₃Alkyl or cycloalkyl, vinyl, alkyl or represents phenyl which is optionally mono- to trisubstituted by halogen, in particular fluorine,

0010R² for aryl with 6 to 10 carbon atoms or hetaryl with 3 to 9 carbon atoms, substituted one or more times by C₁-C₄-Alkyl, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkyl with 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkoxy with 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylthio with 1 or 2 carbon atoms and 1 to 5 halogen atoms, optionally by C₁-C₃-Alkyl and / or fluorine substituted phenyl, for optionally by C₁-C₃-Alkyl and / or fluorine-substituted phenoxy, dialkylamino, diarylamino, carboxyalkyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, formyl, cyano, acetoxy or a group<chemistry id="chem0006" num="0006"><img file="EP0343398A2_D0006.tif" /></chemistry><ul id="ul0002" list-style="none"><li>X² represents hydrogen or halogen, preferably fluorine,</li><li>X³ Hydrogen means</li><li>A for nitrogen or a residue CX⁴ stands,</li><li>in which</li><li>X⁴ represents hydrogen, halogen, preferably fluorine and chlorine, or together with R¹ a bridge of structure<chemistry id="chem0007" num="0007"><img file="EP0343398A2_D0007.tif" /></chemistry></li><li>can form, and</li><li>Y is a nitrile group, an ester group -COOR³ or an acid amide group -CONR⁴R⁵ represents</li><li>in which</li><li>R³ for C_l-C₄-Alkyl stands and</li><li>R⁴ and R⁵ can be the same or different and for C₁-C₃-Alkyl stand and R⁴ optionally substituted phenyl.</li></ul>

0011In this preferred embodiment, the process is characterized in that 7-haloquinolonecarboxylic acid derivatives of the formula (II) in which<ul id="ul0003" list-style="none"><li>R ', X², X³, A and Y have the meaning given above and</li><li>X 'represents halogen, preferably chlorine, bromine, particularly preferably chlorine,</li><li>in the presence of a nickel catalyst with aryl halides or hetaryl halides of the formula III</li><li>in the</li><li>X⁵ represents chlorine or bromine and</li><li>R² has the meaning given above,</li><li>implements.</li></ul>

0012For example, the reaction of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with chlorobenzene in the presence of nickel (II) chloride, metallic zinc and triphenylphosphine 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid ethyl ester:<chemistry id="chem0008" num="0008"><img file="EP0343398A2_D0008.tif" /></chemistry>

0013The catalyst used in the process according to the invention contains a preferably anhydrous nickel compound, a ligand from the group of the triarylphosphines with 6 to 10 carbon atoms in each aryl unit, a promoter from the group of the alkali metal, alkaline earth metal, manganese and zinc halides, sulfates or phosphates and a metal such as zinc, manganese or magnesium. Optionally, a polycyclic aromatic compound with at least 2 nitrogen atoms in various aromatic rings and 10 to 18 carbon atoms can be added as a further component .

0014Suitable anhydrous nickel compounds are those which can be reduced by the metals mentioned or are already in such a reduced form. Without claiming to be complete, the following may be mentioned: nickel (II) halides such as nickel (II) chloride, bromide and iodide, nickel (II) complexes such as nickel acetylacetonate and dichlorobis (triphenylphosphine) nickel (II) and nickel ( 0) complexes such as bis (cycloocta-1,5-diene) nickel (0) and tetrakis (triphenylphosphine) nickel (0), which can be prepared by processes known from the literature. The nickel (II) halides mentioned are preferred; nickel (II) chloride, which is known in a known manner, for example, is particularly preferred obtained from the hexahydrate with thionyl chloride in anhydrous form.

0015The nickel catalyst is used in an amount of 0.1 to 25 mol%, based on the 7-haloquinolonecarboxylic acid compound, preferably 1 to 20 mol% and particularly preferably 5 to 15 mol%.

0016Suitable triarylphosphines are, for example, triphenylphosphine, the tritolylphosphines and trinaphthylphosphines. Triphenylphosphine is particularly preferred.

0017The triarylphosphine is used in a molar ratio to the nickel compound of 2 to 100, preferably 4 to 50 and particularly preferably 5 to 10.

0018Alkali, alkaline earth, zinc, magnesium and manganese halides are preferred as promoters. The iodides are particularly preferred.

0019The amount of promoter can be 0.1 to 1000 mol%, based on the nickel catalyst used; 0.1 to 700 mol% are preferred and 10 to 500 mol% are particularly preferred.

00202,2'-Bipyridyl and 1,10-phenanthroline may be mentioned as preferred polycyclic aromatic compounds with at least 2 nitrogen atoms, which are preferably added in proportions of 50 to 500 mol%, based on the nickel catalyst used.

0021For example, zinc, manganese or magnesium can be used as the metal. Zinc is preferred. The zinc is used, for example, as so-called zinc dust, which, if desired, can be pretreated beforehand by washing with glacial acetic acid, water and acetone and then drying in vacuo.

0022The metal used is used in an amount of at least half a molar equivalent, based on the 7-haloquinolonecarboxylic acid derivative of the general formula (11), but preferably in an excess of 10 to 1000 mol%, particularly preferably 100-500 mol% %, based on the compound of general formula (II).

0023The quinolonecarboxylic acid derivatives of the formula II used are known.

0024Examples include:<ul id="ul0004" list-style="none"><li>7-chloro-1-cyciopropyl-6-fiuor-1,4-dihydro-4-oxo-3-quinoinocarboxylic acid,</li><li>7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methyl ester,</li><li>7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid n-propyl ester,</li><li>7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-chloro-6-fluoro-1- (p-fluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-bromo-1-cyciopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,</li><li>1-cyclopropyl-6-fluoro-1,4-dihydro-7-iodo-4-oxo-3-quinolinecarboxylic acid,</li><li>7-chloro-1-cyclopropyl-1,4-dihydro-6-methyl-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinolinecarboxylic acid ethyl ester,</li><li>1-allyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>1-benzyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-chloro-8-cyano-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7,8-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,</li><li>7-chloro-1-cyciopropyl-6-fiuor-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester,</li><li>7-chloro-1-cyciopropyl-6-fiuor-1,4-dihydro-4-oxo-3-quinoline carbonitrite,</li><li>7-chloro-1-cyciopropyl-6-fiuor-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid dimethylamide.</li></ul>

0025Suitable solvents for the process according to the invention are, for example, aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methyl-caprolactam, N-methyl-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfone etc. The solvents can be dried in a known manner before use and under a protective gas such as nitrogen be distilled.

0026The reaction can be carried out at temperatures between 0 and 250 C, preferably at 20-200 C, particularly preferably at 50 to 150 C.

0027The coupling reaction is advantageously carried out in an inert protective gas atmosphere such as helium, argon or nitrogen.

0028The reaction is normally carried out under normal pressure, but can also take place under increased or reduced pressure.

0029The reaction time is between 0.05 and 24 hours, preferably 0.1 and 10 hours and particularly preferably 0.5 and 6 hours.

0030The invention also relates to compounds of the formula IV<chemistry id="chem0009" num="0009"><img file="EP0343398A2_D0009.tif" /></chemistry>in the<ul id="ul0005" list-style="none"><li>R² for C₆-C₁₀Aryl or C₃-C₉Heteroaryl, mono- or polysubstituted by C₁-C₄-Alkyl, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogen, C₁-C₂-Halogenalkyl with 1 to 5 halogen atoms, optionally one to two times by halogen or C₁-C₃-Alkyt substituted phenyl, optionally one to two times by halogen or C₁-C₃-Alkyl substituted phenoxy, nitro, amino, alkylamino with 1 to 3 carbon atoms, dialkylamino with 2 to 6 carbon atoms, aminomethyl, methylamino, dimethylaminomethyl, formylamino, acetylamino, acetyloxy, formyl, acetyl, carboxyalkyl with 1 to 3 carbon atoms in the acid radical, alkoxycarbamoyl with 1 to 3 carbon atoms in alkoxy part, cyano, alkylsulfinyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, arylsulfinyl, arylsulfonyl, sulfamoyl, Alkylsulfamoyl with 1-3 carbon atoms or dialkylsulfamoyl with 2 to 6 carbon atoms,</li><li>X² for hydrogen, C₁-C₃Alkyl, nitro or halogen,</li><li>X³ Hydrogen, C₁-C₃-Alkyl, nitro, C₁-C₃-Alkoxy or halogen means</li><li>A for nitrogen or a residue CX⁴ where X⁴ for hydrogen, C₁-C₃-Alkyl, halogen, nitro or cyano and</li><li>Y a nitrile group, a COOR group³ or an acid amide group CONR⁴R⁵ represents, where R³ for hydrogen or for C₁-C₄-Alkyl stands and R⁴ and R⁵ can be the same or different and for C_i-C₃-Alkyl stand and R⁴ optionally substituted phenyl.</li></ul>

0031Compounds of the formula IV in which R.² for the following aryl or hetaryl residues<chemistry id="chem0010" num="0010"><img file="EP0343398A2_D0010.tif" /></chemistry><chemistry id="chem0011" num="0011"><img file="EP0343398A2_D0011.tif" /></chemistry><chemistry id="chem0012" num="0012"><img file="EP0343398A2_D0012.tif" /></chemistry>substituted one or more times by C_l-C₄-Alkyl, alkoxy with 1 to 3 carbon atoms, alkyl mercapto with 1 to 3 carbon atoms, halogen, optionally one to two times by halogen, preferably fluorine, or Ci-C₃-Alkyl substituted phenyl, nitro, amino, alkylamino with 1 to 3 carbon atoms, dialkylamino with 2 to 6 carbon atoms, aminomethyl, methylaminomethyl, dimethylaminomethyl, formylamino, acetylamino, acetyloxy, alkoxycarbonyl with 1 to 3 carbon atoms in the alkoxy part, cyano, sulfamoyl, alkylsulfamoyl 1 to 3 carbon atoms or dialkylsulfamoyl with 2 to 6 carbon atoms,<ul id="ul0006" list-style="none"><li>X² represents hydrogen or halogen,</li><li>X³ Means hydrogen or halogen,</li><li>A nitrogen or a residue CX⁴ in which X⁴ represents hydrogen, halogen or cyano and</li><li>Y is a nitrile group or a COOR group³ means, where R³ for hydrogen or for C, to C₄-Alkyl stands.</li></ul>

0032Compounds of the formula IV in which R.² for the following aryl or hetaryl residues<chemistry id="chem0013" num="0013"><img file="EP0343398A2_D0013.tif" /></chemistry><chemistry id="chem0014" num="0014"><img file="EP0343398A2_D0014.tif" /></chemistry>

0033one or more substituted by C, -C₃-Alkyl, alkoxy with 1 to 3 carbon atoms, methyl mercapto, halogen, optionally phenyl, nitro, amino, amino, alkylamino with 1 to 3 carbon atoms, substituted once or twice by halogen, in particular fluorine, or methyl, dialkylamino with 2 to 4 carbon atoms, aminomethyl, methylaminomethyl , Dimethylaminomethyl, sulfamoyl, alkylsulfamoyl with 1-3 carbon atoms or dialkylsulfamoyl with 2-4 carbon atoms,<ul id="ul0007" list-style="none"><li>X² represents fluorine,</li><li>X³ Hydrogen means</li><li>A nitrogen or a residue CX⁴ in which X⁴ represents hydrogen, fluorine or chlorine,</li><li>and</li><li>Y a group COOR³ means, where R³ represents hydrogen, methyl or ethyl.</li></ul>

0034The compounds of the formula IV according to the invention are largely obtainable by the process described above.

0035In the preparation of the compounds according to the invention, however, it may also be necessary to introduce some groups only after the decisive CC linking step, because their presence in compounds of the formula II or compounds of the formula III would prevent the CC linking step.

0036Such groups such as amino, nitro etc. can be introduced by known methods of preparative organic chemistry.

0037This is exemplified by the following formula scheme:<chemistry id="chem0015" num="0015"><img file="EP0343398A2_D0015.tif" /></chemistry>

0038It may also be necessary to provide more reactive centers on the compounds II and III with protective groups in order to be able to carry out the CC linking step. The compounds of the formula IV according to the invention can be obtained by the processes known in organic chemistry for removing these protective groups.

0039In addition to the compounds listed in the examples, the compounds listed in Table 1 are to be mentioned as further active ingredients of the invention.<tables id="tabl0001" num="0001"><img file="EP0343398A2_D0016.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0343398A2_D0017.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0343398A2_D0018.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0343398A2_D0019.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0343398A2_D0020.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0343398A2_D0021.tif" /></tables>

0040With low toxicity, the compounds according to the invention show a broad antibacterial spectrum against gram-positive and gram-negative germs, in particular against enterobacteriaceae; especially against those that are resistant to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

0041These valuable properties enable them to be used as chemotherapeutic agents in medicine and as substances for the preservation of inorganic and organic materials, in particular organic materials of all kinds, for example polymers, lubricants, paints, fibers, leather, paper and wood, food and water .

0042The compounds according to the invention are active against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

0043The compounds according to the invention are particularly effective against bacteria and bacterial-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

0044For example, local and / or systemic diseases can be treated and / or prevented that are caused by the following pathogens or by mixtures of the following pathogens: Gram-positive cocci, e.g. staphylococci (Staph. Aureus, Staph. Epidermidis) and streptococci (strept. agalactiae, strept.faecalis, strept.pneumoniae, strept.pyogenes); gram-negative cocci (Neisseria gonorrhoeae) and gram-negative rods such as enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. Freundii, Citrob. Divernis), Salmonella and Shigella; further Klebsiell (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (Ps. Aeruginosa, Ps. maltophilia) and strictly anaerobic bacteria such as Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and mycobacteria, for example Mycobacterium tuberculosis.

0045The above list of pathogens is only an example and is in no way to be interpreted as limiting. Examples of diseases which can be caused by the pathogens mentioned or mixed infections and which can be prevented, improved or cured by the compounds according to the invention are:<ul id="ul0008" list-style="none"><li>Infectious diseases in humans such as otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, system infections, bronchitis (acute, chronic), septic infections, diseases of the upper airways, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscess , Prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, post-operative wound infections, Abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth area, infections after dental surgery, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intra-abdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis and infections, tonsillitis, typhoiditis, typhoiditis, Ty of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections.</li></ul>

0046In addition to humans, bacterial infections can also be treated in other species. Examples include:<ul id="ul0009" list-style="none"><li>Pig: coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, mastitis-metritis-agalactia syndrome, mastitis;</li><li>Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;</li><li>Horse: bronchopneumonia, foal paralysis, puerperal and postpuerperal infections, salmonellosis;</li><li>Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;</li></ul>

0047Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

0048Bacterial diseases in the rearing and keeping of commercial and ornamental fish can also be treated, the antibacterial spectrum extending beyond the previously mentioned pathogens to other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rikettsien, Yersinia, expanded.

0049The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.

0050The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, for example tablets, dragées, capsules, pills, suppositories and ampoules, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can contain, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

0051Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

0052Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

0053Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethyl cellulose, Alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the (a) to (i ) listed substances.

0054The tablets, dragées, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, where polymer substances and waxes, for example, can be used as embedding compounds.

0055The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.

0056In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example cit alcohol with C,₆Fatty acid) or mixtures of these substances.

0057In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

0058In addition to the active ingredient (s), powders and sprays can contain the usual carriers, for example milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these. Sprays can also contain the usual blowing agents, such as chlorofluorocarbons.

0059In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, for example Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formaldehyde, tetrahydrofuran fatty acid, tetrahydrofuran fatty acid, tetrahydrofuran fatty acid, tetrahydrofuran fatty acid, tetrahydrofuran fatty acid, tetrahydrofuran or mixtures of these substances.

0060For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

0061In addition to the active ingredient (s), suspensions can include the customary carriers such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures of these contain.

0062The formulation forms mentioned can also contain colorants, preservatives and odorless. and taste-improving additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.

0063The therapeutically active compounds should preferably be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.

0064In addition to the compounds according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

0065The pharmaceutical preparations listed above are prepared in a customary manner by known methods, for example by mixing the active ingredient (s) with the carrier (s).

0066The preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the therapy of infections in cavities, body cavities. Suitable solutions are injection solutions, solutions and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used. In animals, the feed can also be taken in suitable formulations via feed or drinking water. Furthermore, gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, boluses, capsules, aerosols, sprays, inhalants can be used in humans and animals. Furthermore, the compounds according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.

0067In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.

0068In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

0069The new compounds can be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. This can prevent, ameliorate and / or cure infection by gram-negative or gram-positive bacteria, thereby promoting growth and improving the utilization of the feed.

0070The table below shows the MIC values ​​of some of the compounds according to the invention compared to ciprofloxacin.<tables id="tabl0007" num="0007"><img file="EP0343398A2_D0022.tif" /></tables>

example 1

1 -Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid ethyl ester

00716.7 g of zinc powder, 6.7 g of triphenylphosphine, 1 g of sodium iodide, 0.435 g of nickel (II) chloride and 50 ml of dimethylformamide are placed in a nitrogen atmosphere. After half an hour at 50-60 C there is a deep red-brown suspension. A warm solution of 7.75 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and 5.65 g of chlorobenzene in 50 ml of dimethylformamide is added. After half an hour at 80 ° C under nitrogen, the reaction mixture is filtered hot. After the filtrate has cooled, the mixture is filtered again and the residue is washed with dimethylformamide and methylene chloride / n-hexane. After drying, 4 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid ethyl ester (45.5%) of theory are obtained; Melting point: 262-263 ° C.¹H-NMR (200 MHz, CDCl₃): 1.1-1.5 (m; 7H), 3.55 (m; 1H), 4.4 (q; 2H), 7.45-7.7 (m; 5H), 7.95 (i.e. , J 6 Hz; 1 H), 8.09 (d, J 11 Hz; 1 H), 8.56 (s; 1 H) ppm.<chemistry id="chem0016" num="0016"><img file="EP0343398A2_D0023.tif" /></chemistry>

Example 2

1 -Cylopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid

00723.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid ethyl ester are refluxed in 60 ml of glacial acetic acid, 20 ml of water and 2 ml of concentrated sulfuric acid for 4 hours . After the reaction mixture has cooled, the mixture is filtered, the residue is washed with glacial acetic acid and water and dried. 2.86 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid are obtained (88.8% of theory); Melting point: 268 ° C.<chemistry id="chem0017" num="0017"><img file="EP0343398A2_D0024.tif" /></chemistry>The compounds listed in Table 2 were obtained in a corresponding manner.<tables id="tabl0008" num="0008"><img file="EP0343398A2_D0025.tif" /></tables><tables id="tabl0009" num="0009"><img file="EP0343398A2_D0026.tif" /></tables>

Example 19

7- (4-Aminomethylphenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester

00732nd g 7- (4-Cyanophenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are added in 130 ml tetrahydrofuran in the presence of 20 ml ammonia and 2 g Raney cobalt Hydrogen pressure 140-150 bar hydrogen.

0074The reaction mixture is filtered, the solvent is stripped off and the residue is dissolved in chloroform. This solution is shaken out with dilute aqueous hydrochloric acid. The aqueous phase is diluted, made alkaline with aqueous sodium hydroxide solution and extracted with chloroform. After drying the organic phase and stripping off the solvent, 1 g of ethyl 7- (4-aminomethylphenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (49.5 % of theory).

0075'H NMR (200 MHz, CDCl₃): 1.1-1.5 (m; 7H), 1.7 (s, br; 2H), 3.5 (m; 1H), 3.95 (s; 2H), 4.39 (q; 2H), 7.55-7.65 (m; 4H), 7.95 (d, J - 6 Hz; 1 H), 8.15 (d, J-11 Hz; 1 H), 8.85 ( s; 1 H) ppm.

0076<chemistry id="chem0018" num="0018"><img file="EP0343398A2_D0027.tif" /></chemistry>

Example 20

7- (4-aminomethylphenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

00770.5 g of 7- (4-aminomethylphenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are dissolved in 2 ml of glacial acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulfuric acid boiled under reflux for 4 hours. After cooling, the reaction mixture is filtered, the residue was washed with glacial acetic acid and water and dried. This gives 0.22 g of 7- (4-aminomethylphenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (27.5% of theory). Melting point: 285 C (dec.).<chemistry id="chem0019" num="0019"><img file="EP0343398A2_D0028.tif" /></chemistry>

Example 21

0078<chemistry id="chem0020" num="0020"><img file="EP0343398A2_D0029.tif" /></chemistry>

00791.0 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-phenyl-3-quinolinecarboxylic acid are placed in 10 ml of sulfuric acid. 0.47 g of potassium nitrate are added in portions with ice cooling. The mixture is then slowly brought to room temperature and then heated to 50 ° for 3 hours. After adding ice, the solid formed is isolated, washed, dried and recrystallized from dimethylformamide. Yield: 0.3 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-nitro-phenyl) -4-oxo-3-quinolinecarboxylic acid. Melting point 304-5 °.

Example 22

0080<chemistry id="chem0021" num="0021"><img file="EP0343398A2_D0030.tif" /></chemistry>

00811 g 1-Cyclopro_Pyl-6-fluoro-1,4-dihydro-7- (4-nitro-phenyl) -4-oxo-3-quinolinecarboxylic acid are hydrogenated in 50 ml of dimethylformamide with the addition of 1 g of Raney nickel. After the hydrogen uptake has ended, the catalyst is filtered off. The filtrate is concentrated and the residue is stirred with dilute hydrochloric acid. The solid formed is isolated, washed with ethanol and dried. Yield 0.8 g of 7- (4-aminophenyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as the hydrochloride. Melting point> 270 °.