IE80557B1 - 8-vinyl- and 8-ethinyl-quinolone-carboxylic acids - Google Patents

Abstract

The invention relates to novel 8-vinyl- and 8-ethynyl- quinolonecarboxylic acids, a process for their preparation and antibacterial agents and feed additives containing them.

Description

The invention relates to new 8-vinyl- and 8-ethinylquinolonecarboxylic acids, processes for their preparation, and antibacterial agents and feed additives containing them.

It has already been disclosed that 8-alkyl-quinolonecarboxylic acids have antibacterial activity: 8-methylquinolonecarboxylic acids were described, for example, in EP 237,955 and JP 2,019,377, and 8-trifluoromethylquinolonecarboxylic acids were described in US 4,780,468, US 4,803,205 and 4,933,335.

Also, GB-A-2,188,317, US Patent Specification 4,123,536 and J. Clin. Pharmacol. 28, 156 (1988) and antimicrob. Agents Chemother. 33., 131 (1989) have already disclosed quinolone derivatives having antimicrobial activity but their potency is unsatisfactory.

It has now been found that the new compounds of the formula (I) (I). in which R1 represents straight-chain or branched C1-C4-alkyl which is optionally substituted by hydroxyl, halogen or C1-C3-alkoxy, or represents optionally halogenor Cx - C3 - alkyl-substituted C3-C6-cycloalkyl, C2-C4alkenyl, furthermore represents C1-C3-alkoxy, amino, monoalkylamino having 1 to 3 C atoms, dialkylamino having 2 to 6 C atoms, or phenyl which is optionally monosubstituted to trisubstituted by halogen, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, X1 represents hydrogen, fluorine, chlorine, amino or 5 methyl, X2 represents -C=CH-R3, -C=C-R5 or -CH2-CH=CH2, *4 where R3 represents hydrogen, C1-C3-alkyl, Cx-C3-alkoxy or alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, R4 represents hydrogen or halogen and R5 represents hydrogen, Cx-C6-alkyl which is optionally monosubstituted to trisubstituted by halogen, or C2-C3-alkenyl, alkoxy having 1 to 3 C atoms, alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and represents R9 R10 R — J- , R-N^^N- ^Ι-ι/Υ^Ι NXN R7 R8 R8 K Ο N — R11 R12 Xn-, Rll N3 R16 R1— 0 >CH>KR17 RR8 I .N ,£WR8 where R6 represents hydrogen, optionally hydroxyl- or methoxy- substituted straight-chain or branched Cx-C4alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having 1 to 3 C atoms, R7 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R10 represents hydrogen or methyl, R9 R11 represents hydrogen, methyl or -ch2-n RlO R12 represents hydrogen, methyl, amino, optionally hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, aminomethyl, aminoethyl, optionally hydroxyl-substituted alkylor di alkyl aminomethyl having 1 or 2 C atoms in the alkyl moiety or 1-imidazolyl, R13 represents hydrogen, hydroxyl, methoxy, methylthio or halogen, methyl or hydroxymethyl, R14 represents hydrogen or methyl, R15 represents hydrogen, methyl or ethyl, R16 represents hydrogen, methyl or ethyl, R17 represents hydrogen, methyl or ethyl, R16 R16 1 fi z z R18 represents hydroxyl, N or CH,-N \ ,, R17 R17 R19 represents hydrogen, optionally hydroxyl-substituted Cx-C3-alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or Cx-C3-acyl.

R19 Ο R represents hydrogen, hydroxyl R21 hydroxymethyl or where R21 denotes hydrogen or methyl, A represents CH2, 0 or a direct bond and n represents 1 or 2, and their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts of the carboxylic acids on which they are based have a powerful antibacterial action.

They are therefore suitable as active compounds for human and veterinary medicine, -veterinary medicine also including the treatment of fish for the therapy or prophylaxis of bacterial infections.

Preferred compounds of the formula (I) are those in which R1 represents optionally hydroxyl-substituted C^-C^alkyl, C3-C5-cycloalkyl, vinyl, amino, monoalkylamino having 1 to 2 C atoms, dialkylamino having 2 to 4 C atoms, or phenyl which is optionally monosubstituted or disubstituted by halogen, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, X1 represents hydrogen, fluorine, chlorine, amino or 5 methyl, -C=CH-R3, -C=C-R5 X represents I or -CH2-CH=CH2 > R4 where R3 represents hydrogen, C^-02-alkyl, methoxy or me thoxyme thy1, R4 represents hydrogen and R5 represents hydrogen, C1-C4-alkyl which is optionally monosubstituted to trisubstituted by fluorine, or C2-C3-alkenyl, methoxy or trimethylsilyl, and Ί R8 R19 R8 where R6 represents hydrogen, optionally hydroxyl-substituted straight-chain or branched C^-C^-alkyl or oxoalkyl having 1 to 4 C atoms, R7 represents hydrogen, methyl or phenyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R11 represents hydrogen, methyl or -CH2-NH2, R12 represents hydrogen, methyl, amino, methylamino, dime thy lamino, aminomethyl, methyl aminomethyl or ethylaminomethyl, R13 represents hydrogen, hydroxyl, methoxy, fluorine, methyl or hydroxymethyl, R15 represents hydrogen or methyl, R16 represents hydrogen or methyl, R17 represents hydrogen or methyl, r16 R18 represents R17 or CH2-N, r16 R17 R19 represents hydrogen, methyl or ethyl.

· R represents f/ R19 R21 where R21 denotes hydrogen or methyl, A represents CH2, 0 or a direct bond and n represents 1 or 2.

Particularly preferred compounds of the formula (I) are those in which R1 represents methyl, ethyl, cyclopropyl or phenyl which is optionally monosubstituted or disubstituted by fluorine, R2 represents hydrogen, methyl or ethyl, X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -CH=CH2 or -C=C-R5 where R5 denotes hydrogen, C^C*-alkyl, C2-C3-alkenyl or trimethylsilyl and Y represents R96 VR6- N N — , R7 R8- j/'Sn - R8— N — \_V ’ \ \z wRk Ο N — R11 R8 Rp N — R13 R-N R8 R8 ι\τΖ\Λ UCNR19 ‘N N — N — or NNv where R6 represents hydrogen, methyl, optionally hydroxylsubstituted ethyl, represents hydrogen or methyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R11 represents hydrogen or -CH2-NH2, R12 represents hydrogen, methyl, amino, methylamino 5 aminomethyl or ethyl aminomethyl, R13 represents hydrogen, hydroxyl or methoxy, R15 represents hydrogen or methyl, R16 represents hydrogen or methyl, R17 represents hydrogen or methyl, r!6 ,18 represents N R17 ,19 represents hydrogen or methyl. ,20 represents z R19 R21 where R21 denotes hydrogen or methyl, A represents CH2, O or a direct bond and n represents 1.

Furthermore, it has been found that the compounds of the formula (I) are obtained when a compound of the formula (II) in which R1, R2, X1 and X2 have the abovementioned meaning and X3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula (III) Y-H (III) in which Y has the abovementioned meaning, if appropriate in the presence of acid scavengers.

If, for example, l-cyclopropyl-8-ethinyl-6,7-difluoro15 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1methylpiperazine are used as starting compounds, the course of the reaction can be represented by the following equation: The 8-(1-chlorovinyl)-quinolonecarboxylic acids are also obtained by reacting the 8-ethinyl-quinolonecarboxylic acids with hydrochloric acid at temperatures from 10°C to 100°C, preferably 20°C to 60°C.

The compounds of the formula (II) which are used as starting compounds are new. They can be prepared by reacting guinolinecarboxylic acid derivatives of the formula (IV) in which R1, R2, X1 and X3 have the abovementioned meaning and X4 represents halogen, in particular iodine, bromine or chlorine, with organometal vinyl or alkinyl compounds of the formula (V) M-X2 (V) in which X2 has the abovementioned meaning and M represents SnR'3, ZnX', B(OR)2, where R' denotes C^-C^-alkyl, R denotes hydrogen or Cx-C4-alkyl and X' denotes bromine or chlorine, in the presence of transition metal catalysts and eliminatingany protective groups which may be present.

The organometal vinyl and alkinyl compounds which are required for the coupling reaction are either known or can be synthesised by methods known from the literature. For example, vinyl-trialkyltin compounds can be prepared from the corresponding vinyl iodides, vinyl bromides or vinyl chlorides by obtaining the vinyl-Grignard compounds by reaction with magnesium and reacting these compounds with a trialkyltin chloride to give the desired vinyltin derivatives.

Organometal alkinyl compounds can be prepared in a known manner, for example by metallating the 1-alkine with nbutyllithium, sec-butyllithium or tert.-butyllithium at temperatures between -20 and -78°C in an aprotic solvent such as, for example, tetrahydrofuran, followed by reaction with a halometal compound such as, for example, zinc chloride, magnesium bromide, copper iodide or trialkyltin chloride. The reaction at -78°C is preferred. Other possible solvents, apart from the preferred solvent tetrahydrofuran, are other ethers such as diethyl ether, dipropyl ether or tert.-butyl methyl ether, or mixtures of such ethers with aprotic, aliphatic or aromatic solvents such as n-hexane or toluene. The zinc chloride and trialkyltin derivatives are preferred with both the vinyl and the alkinyl derivatives. Alkyl in the trialkyltin compounds is understood as meaning Cj- to C6alkyl; methyl and n-butyl are preferred.

Trialkylvinyltin compounds can also be obtained by methods known from the literature, by hydrostannylation of alkines with trialkyltin hydrides in the presence of transition metal catalysts (J. Org. Chem. 55 (1990) 18571867).

The organometal vinyl and alkinyl compounds are reacted with 8-halogenoquinolonecarboxylic acid derivatives of the general formula (IV) by processes known in principle in th6 presence of a suitable catalyst. In this context, halogen represents iodine, bromine or chlorine; bromine and chlorine being preferred, bromine being particularly preferred.

Examples of suitable catalysts are transition metal compounds of the metals cobalt, ruthenium, rhodium, iridium, nickel, palladium or platinum. Compounds of the metals platinum, palladium and nickel are preferred, and palladium is particularly preferred. Such transition metals can be employed in the form of their salts such as, for example, in the form of NiCl2, PdCl2 or Pd(OAc)2, or in the form of complexes with suitable ligands. The use of complexes is preferred. Ligands which are preferred are phosphines such as, for example,- triphenylphosphine, tri(o-tolyl)phosphine, trimethylphosphine, tributylphosphine and tri(2-furyl)phosphine, triphenylphosphine being preferred. Preferred complex catalysts which may be mentioned are bis (triphenylphosphine) nickelill) chloride, bis(triphenylphosphine)palladium(II) chloride, tris(triphenylphosphine)palladium(0) and tetrakis(triphenylphosphine)palladium(0).

The complex catalysts are employed in amounts of 0.1 to 20 mol %, relative to the 8-halogeno-quinolonecarboxylates employed; amounts of 0.5 to 10 mol % are preferred. and amounts of 1 to 5 mol % are very particularly preferred.

The coupling reactions are carried out in suitable inert solvents such as, for example, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, dimethoxyethane or mixtures of such solvents; dimethylformamide and toluene are preferred. Before use, . the solvents are dried and freed from air by known processes.

The coupling reactions are carried out at temperatures between 20 and 200°C; temperatures between 50 and 180°C are preferred.

The duration of the reaction depends on the reactivity of the educts and is generally between 2 and 40 hours; reaction times between 4 and 24 hours are preferred.

The reactions are carried out under a protective gas atmosphere. Suitable protective gases are inert gases such as, for example, helium, argon or nitrogen; nitrogen is preferred. The coupling reaction is generally carried out under atmospheric pressure. However, it is also possible, of course, to carry out the reaction under reduced or increased pressure.

Most of the amines of the formula (III) which are used as starting compounds are known. Chiral amines can be employed in the form of racemates as well as in the form of pure enantiomeric or pure diastereomeric compounds. Examples which may be mentioned are: piperazine, 1-methylpiperazine, 1-ethylpiperazine, 1-(2-hydroxyethyl)-piperazine, 3-methylpiperazine, cis-2,6-dimethyl-piperazine, cis-2,3-dimethyl-piperazine, 1,2-dimethylpiperazine. 1- cyclopropyl-piperazine, 2- phenyl-piperazine, 2-(4-pyridyl)-piperazine, 2- (2-thienyl)-piperazine, 1.4- diazabicyclo[3.2.1]octane, 8-methyl-3,8-diazabicyclo [3.2.1] octane dihydrochloride, 3- methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, 2.5- diazabicyclo[2.2.1]heptane dihydrochloride, 2-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrochloride, 2.5- diazabicyclo[2.2.2]octane dihydrochloride, 2-methyl-2,5-diazabicyclo[2.2.2]octane dihydrochloride, 1,4-diazabicyclo[3.1.1]heptane, morpholine, 2,6 -dimethyl -morpholine, - aminome thy 1 -morphol ine, 2- tert.-butoxycarbonylaminomethyl-morpholine, -me thylaminome thyl -morpholine, - dime thylaminome thyl-morpholine, imidazole, 4- methyl-imidazole, pyrrole, - aminome thyl - 2,5 - dihydro - pyrrol e, - aminomethyl - 4 -methyl - 2,5 - dihydro-pyrrole, 3- (1-aminoethyl)-2,5-dihydro-pyrrole, 3-amino-azetidine, 3-tert.-butoxycarbonylamino-azetidine, 3-tert.-butoxycarbonylamino-2-methyl-azetidine, -tert.-butoxycarbonylamino-3-methyl-azetidine, 3-tert.-butoxycarbonylaminomethyl-azetidine, pyrrolidine, 3-methylpyrrolidine, 3-amino-pyrrolidine, 3-tert.-butoxycarbonylamino-pyrrolidine, 3-(2,2-dimethyl-propylideneamino)-pyrrolidine, -methylamino-pyrrolidine, 3- dime thylamino-pyrrolidine, - aminome thyl - pyrro 1 i dine, - tert. -butoxycarbonylaminomethyl-pyrrolidine, 4- chloro-3-tert.-butoxycarbonylaminomethyl-pyrrolidine, 3-tert.-butoxycarbonylaminomethyl-3-methyl-pyrrolidine, 3-tert.-butoxycarbonylamino-4-methyl-pyrrolidine, - tert. -butoxycarbonylaminomethyl - 3 -methoxy-pyrrolidine, 3 -me thylaminomethyl -pyrrolidine, 3- ethylaminomethyl-pyrrolidine, 4- tert.-butoxycarbonylamino-2-methyl-pyrrolidine, 2- methyl-3-methylamino-pyrrolidine, -methyl -4 -me thylamino-pyrrolidine, 3- (2-hydroxyethylamino)-pyrrolidine, 3-hydroxy-pyrrolidine, 3- hydroxymethyl-pyrrolidine, 4- amino-3-hydroxy-pyrrolidine, -hydroxy-4-methylamino-pyrrο1idine, 3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine, -me thyl aminomethyl - 3 -hydroxy-pyrrolidine, -dime thylaminome thyl-3 -hydroxy-pyrrolidine, 3-diethylaminomethyl-3-hydroxy-pyrrolidine, 3-1ert. -butylaminomethyl-3 -hydroxy-pyrrο1idine, 3- methylamino-4-hydroxymethyl-pyrrο1idine, 4- methoxy-3-methylamino-pyrrolidine, 3-methoxy-3-methylaminomethyl-pyrrolidine, 3- amino-4-methoxy-2-methyl-pyrrolidine, 3-tert.-butoxycarbonylamino-3-methyl-pyrrolidine, 3-methyl-4 -tert.-butoxycarbonylaminomethyl-pyrrolidine, 3-methoxy-4-tert.-butoxycarbonylaminomethyl-pyrrolidine, 3-(1-imidazolyl)-pyrrolidine, 6-hydroxy-3-azabicyclo[3.3.0]octane, 6-amino-3-azabicyclo[3.3.0]octane, 1-amino-3-azabicyclo[3.3.0]octane, 1-aminomethyl-3-azabicyclo[3.3.0]octane, 1- ethylaminomethyl-3-azabicyclo[3.3.0]octane, 6- amino-3-azabicyclo[4.3.0]nonane, 3-amino-4-methylene-pyrrolidine, 7- amino-5-azaspiro[2.4]heptane, 3.7- diazabicyclo[3.3.0]octane, 3-methyl-3,7-diazabicyclo[3.3.0]octane, 2.8- diazabicyclo[4.3.0]nonane, 2- methyl-2,8-diazabicyclo[4.3.0]nonane, 3- methyl-3,8-diazabicyclo[4.3.0]nonane. 2-oxa-5, 8-diazabicyclo [4.3.0] nonane, -methyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, 2.7- diazabicyclo [3.3.0] octane, 2- methyl-2,7-diazabicyclo [3.3.0] octane, 3- methyl-2,7-diazabicyclo[3.3.0]octane, 4- methyl-2,7-diazabicyclo[3.3.0]octane, tert.-butyl 5-methyl-2,7-diazabicyclo[3.3.0]octane, 7- methyl-2, 7-diazabicyclo[3.3.0]octane, 8- methyl-2,7-diazabicyclo[3.3.0]octane, 7.8- dimethyl-2,7-diazabicyclo[3.3.0]octane, 2.3- dimethyl-2,7-diazabicyclo[3.3.0]octane, 2.8- dimethyl-2,7-diazabicyclo[3.3.0]octane, 1.4- diazatricyclo [6.2.0.02'6] decane, 1,4-diazatricyclo [6.3.0.02,6]undecane, 2.7- diazaspiro [4.4] nonane, 2-methyl-2,7-diazaspiro [4.4] nonane, 4-amino-1,3,3a,4,7,7 a-hexahydroi soindole, 4- methylamino-1,3,3a,4,7,7a-hexahydroisoindole, - methyl-4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole, 6- methyl-4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole, 7- methyl-4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole, 7 a -methyl - 4 -methylamino-1,3,3a,4,7,7a-hexahydroi soindole, 6.7- dime thy1-4-me thylamino-1,3,3a,4,7,7a-hexahydroi soindole, 4-dimethy1amino-1,3,3a,4,7,7a-hexahydroisoindole, 4-ethylamino-1,3,3a,4,7,7a-hexahydroisoindole, 4-aminomethyl-1,3,3a,4,7,7a-hexahydroisoindole, 4-methylaminomethyl-l,3,3a,4,7,7a-hexahydroisoindole, 4- hydroxy-1,3,3a,4,7,7a-hexahydroisoindole, 2.3.4.5.6.7- hexahydro-lH-pyrrolo[3,4-c]pyridine, -methyl - 2,3,4,5,6,7 -hexahydro- ΙΗ-pyrrolo [3,4 - c] pyridine, - ethyl-2,3,4,5,6,7-hexahydro-ΙΗ-pyrrolo[3,4-c]pyridine, -(tert.-butoxycarbonyl)-2,3,4,5,6,7-hexahydro-1Hpyrrolo[3,4-c]pyridine.

Most of the substituted 1,3,3a,4,7,7a-hexahydro-isoindoles are new. For example, they can be obtained by Diels-Alder reaction of dienes of the formula (1) (1), where R9 has the abovementioned meaning and R22 is either identical to R20 or is a functional group which can be converted into R20, with dienophiles of the formula (2) in which R23 denotes hydrogen or a protective group such as trimethylsilyl, benzyl, Cx - C4-alky lphenylme thy 1, methoxybenzyl or benzylhydryl, followed by reduction of the carbonyl groups and, if appropriate, elimination of the protective group.

Suitable diluents for the Diels-Alder reaction are all inert organic solvents. These preferably include ethers, such as diisopropyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and anisole, hydrocarbons such as, for example, hexane, methylcyclohexane, toluene, xylene and mesitylene, and halogenated hydrocarbons such as, for example, chloroform, 1,2-dichloroethane and chlorobenzene. However, the Diels-Alder reaction can also be carried out without a solvent.

The reaction temperatures can be varied within a substantial range. In general, the process is carried out between approximately -20°C and +200°C, preferably between -20°C and +150°C. The Diels-Alder reaction is usually carried out under atmospheric pressure. However, pressures of up to 1.5 GPa can also be used for accelerating the reaction.

Reduction of the carbonyl groups can be brought about using complex hydrides. Examples of hydrides which can be employed are lithium aluminium hydride, lithium borohydrides, lithium triethylborohydride, sodium-bis-[2methoxyethoxy] -aluminium hydride or sodium borohydride in the presence of Lewis acid catalysts such as chlorotrimethylsilane, boron trifluoride etherate or aluminium chloride.

Diluents which can be used are ethers such as, for example, diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, and hydrocarbons such as, for example, hexane, methylcyclohexane and toluene, and also mixtures of these.

The reaction temperatures can be varied in the range between -40 and +180°C, preferably between 0° and 140°C. The reduction is generally carried out under atmospheric pressure, but it can also be carried out under reduced pressure or under superatmospheric pressure.

The use of pressures between 100 and 1000 kPa is recommended so as to achieve higher reaction temperatures with low-boiling solvents.

The amount of complex hydrides employed in the reduction is at least stoichiometric. However, an excess of preferably between 30 and 300% is generally employed.

The elimination of a protective group which may be present is effected by the generally known methods of protective group chemistry (cf., for example, T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1981).

The starting substances of the formula (1) and (2) are known or can be prepared by generally known methods of organic chemistry [cf., for example, J. Am. Chem. Soc. 100, 5179 (1978), J. Org. Chem. 43, 2164 (1978), DE 3,927,115, J. Org. Chem. 40, 24 (1975)].

If, for example, 1-(tert.-butyloxycarbonylamino)-1,3butadiene and maleimide are. used as starting materials and lithium aluminium hydride as reducing agent, the course of the reaction can be represented by the follow10 ing equation: nhch3 NH LiAIH4 ► O HN- C - O — C(CH3)3 II In a preferred embodiment of the preparation process, all stages can be carried out without isolation of the intermediates if a suitable solvent such as, for example, tetrahydrofuran, is used. If, for example, l-(tert.butyloxycarbonylamino)-1,3-pentadiene and N-trimethylsilyl-maleimide are used as starting materials, the course of the reaction can be represented by the following equation: I N-SiMe3 THF HN - C - O - C(CH3)30 O 2. LiAlH4 3. H2O In this case, NMR spectroscopy demonstrates that all substituents on the 6-membered ring are in the cisposition relative to each other.

The reaction of (II) with (III) , in which the compounds (III) can also be employed in the form of their salts such as, for example, the hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulpholane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used.

Acid binders which can be used are all customary inorganic and organic acid-binding agents. These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. The following substances which may be mentioned individually are particularly suitable: triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a substantial range. In general, the process is carried out at between approximately 20 and 200°C, preferably between 80 and 180°C.

The reaction can be carried out under atmospheric pres23 sure, but also under increased pressure. In general, the pressures used are between approximately 1 and 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 to 15 moles, preferably 1 to 6 moles, of the compound (III) are employed per mole of the compound (II).

Free amino groups can be protected during the reaction by a suitable amino protective group, for example by the tert.-butoxycarbonyl radical, and set free by treatment with a suitable acid such as hydrochloric acid or trifluoroace tic acid, when the reaction has ended (see Houberi-Weyl, Methoden der Organischen Chemie [Methods in Organic Chemistry], Volume E4, page 144 (1983); J.F.W. McOmie, Protective Groups in Organic Chemistry (1973) , page 43).

The esters according to the invention are obtained by reaction of an alkali metal salt of the carboxylic acid on which they are based which, if appropriate, can be protected on the N atom by a protective group such as the tert.-butoxycarbonyl radical, with suitable halogenoalkyl derivatives in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea, at temperatures of approximately 0 to 100°C, preferably 0 to 50°C.

The acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving the betaine in a sufficient amount of aqueous acid and precipitating the salt with an organic solvent, which is miscible with water, such as methanol, ethanol, acetone or acetonitrile. It is also possible to heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether and subsequently to evaporate the mixture to dryness or filter off the precipitated salt with suction. Pharmaceutically acceptable salts are, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid> methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

The alkali metal salts or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in a substoichiometrie amount of alkali metal hydroxide solution or alkaline earth metal hydroxide solution, filtering off the undissolved betaine, and evaporating the filtrate to dryness. Pharmaceutically acceptable salts'are sodium salts, potassium salts or calcium salts. The corresponding silver salts are obtained by reacting an alkali metal salt or alkaline earth metal salt with a suitable silver salt such as silver nitrate.

In addition to the active compounds mentioned in the examples, the active compounds listed in the table below can also be prepared.

In the case of chiral compounds, these can be prepared and used as diastereomeric mixtures or in each case as diastereomerically or enantiomerically pure compounds.

R1 R2 [>— Η H |>— Η H [>- Η H [>— Η H [>— Η H >— Η H 10 t>— Η H HOCHCsCHOCHC=CHCsCHOCHCsCCH3 HN^ CH3 HN N)—' CH3 HN N )—f c6h5 )—f ch2-nh-ch3 >- Η Η HOC- χ> h2n-ch2 Η Η HOC- O'- ch3-nh5 [>- Η Η HOC- J^N h2n-ch2 Η Η HOC- h2n O ch3 Η Η HOC- h2n O ch3o [>— Η Η HCsC- H2N-CH2 ,-N HO 1 [>- Η Η HOC- HNa /-n DC10 >— Η Η HOC-hnDC/n ry ι>- Η Η HC=C- NJ Η >- H H HCsC- [>— H H HCbC- H H HCsC- C2H5 H HCsC- i>-'; H F HCsC- H nh2 HC=C- CjH5 H H -CsCH F h2nZj NH, hO R1 R2 X1 Ο- Η H [>— Η H >- Η H >— Η H t>— Η H [>— Η H C>— Η H O— Η H O- Η H X2 F-CsCF-OCF-C=CCH30-C=CCH30-CsCCF3-OCCF3-CsCCH3O-CH2-CsCch3o-ch2-c=cCHvN N · ch3-n *N H/—\ CH,-N N C2H5NH-CH2-^j [>— Η Η [>- Η Η >- Η Η >— Η η t>—... Η Η Ο— Η Η |>— Η Η 10 ο— Η Η [>— Η η ch2=chch2=chch2=chch3o-ch=chch3o-ch=chch3o-ch2-ch=chch3o-ch2-ch=chch2=ch-ch2ch2=ch-ch2- ch3*n ch3 h2n-ch ch3o The compounds according to the invention are powerful antibiotics and show a broad antibacterial spectrum against Gram-positive and Gram-negative pathogens, in particular against enterobacteria, while having a low toxicity; in particular, they also act against those which are resistant to a range of antibiotics such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides or tetracycline.

These valuable properties allow them to be used as chemotherapeutic active compounds in medicine as well as preservatives of inorganic and organic materials, in particular all types of organic materials such as polymers, ‘ lubricants, colours, fibres, leather, paper and wood, as well as foodstuffs, and water.

The compounds according to the invention are active towards a very broad range of microorganisms. With their aid, it is possible to combat Gram-negative and Grampositive bacteria and bacteria-like microorganisms, and to prevent, alleviate and/or cure the diseases caused by these pathogens.

The compounds according to the invention are distinguished by an improved action on resting and resistant microorganisms. In the case of quiescent bacteria, that is bacteria which do not show any detectable growth, the compounds act in concentrations far below those of previously known substances. This relates not only to the amount to be employed, but also to the speed of destruction. Such results were found in the case of Grampositive and -negative bacteria, in particular in Staphylococcus aureus. Pseudomonas aeruginosa. Enterococcus faecalis and Escherichia coli.

Surprising improvements with regard to their action was also shown by the compounds according to the invention against bacteria which are classified as less sensitive to comparable substances, in particular resistant Staphylococcus aureus, Escherichia coli. Pseudomonas aeruginosa and Enterococcus faecalis.

By virtue of the powerful activity of the compounds according to the invention against bacteria and bacteria5 like microorganisms, they are particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine which are caused by these pathogens.

Furthermore, the compounds are suitable for combating 10 protozoonoses and helminthoses.

The compounds according to the invention can be used in a range of pharmaceutical preparations. Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

The minimum inhibitory concentrations (MIC) were determined on Iso-Sensitest agar (Oxoid) using the serial dilution method. For each test substance, a series of agar plates was prepared which contained concentrations of the active compound which decreased as the dilution was doubled. The agar plates were inoculated using a multipoint inoculator (Denley). The inocula used were overnight cultures of the pathogens which had previously been diluted to such an extent that each inoculation point contained approx. 104 colony-forming units. The inoculated agar plates were incubated at 37 °C, and growth of the pathogens was determined after approx. 20 hours. The MIC value (gg/ml) indicates the lowest concentration of active compound where no growth was discernible to the naked eye.

The table below lists the MIC values of some of the compounds according to the invention compared with ciprofloxacin.

Tab 1 e: MIC values Test strain: la Example .15 18 22 Cipro- floxacin 5 6 8 9 14 E. coll Neumann 0.02 0.02 0.02 0.13 0.25 0.13 0.02 0.03 0.03 0.02 Micrococcus luteus 9341 0.5 0.25 1 2 0.25 8 1 0.5 2 S taphylococcus aureus ICB 25701 4 1 1 1 4 0.25 32 4 4 16 1756 0.13 0.03 0.06 0.06 0.13 0.06 0.02 0.13 0.06 0.25 133 0.13 0.13 0.06 0.06 0.13 0i06 0.02 0.13 0.13 0.25 Enterococcus faecalis 27101 0.25 0.13 0.13 0.25 0.5 0.13 1 0.25 0.13 0.5 9790 0.25 0.13 0.13 0.25 1 0.13 1 0.25 0.25 0.5 Acinetobacter calcoaceticus 14068 0.03 0.13 0.25 0.5 0.13 0.03 0.03 0.25 0.25 Preparation of the intermediates Example Z1 E thy 1 1-cyclopropyl-6,7-di fluoro-1,4-dihydro-4-oxo-8vinyl-3 -quinolinecarboxylate 3.72 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate, 4.4 g of tributylvinyl stannan and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere. The mixture is filtered under hot conditions, and the product which has precipitated at room temperature is filtered off with suction, washed with toluene and dried. 2.55 g of ethyl 1 - eye 1 opr opy 1 - 6,7 - di f luoro -1,4 - dihydro - 4 - oxo - 8 - vinyl - 3 quinolinecarboxylate are obtained (79% of theory). Melting point: 178-179°C.

Example Z2 - Cy c 1 opr opy 1 - 6,7 - di f luoro -1,4 - dihydro - 4 - oxo - 8 - vinyl - 3 quinolinecarboxylic acid 0.9 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4oxo-8-vinyl-3-quinolinecarboxylate is refluxed for 4 hours in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0.2 ml of concentrated sulphuric acid. At reflux tesqperature, the reaction mixture is then treated with 10 ml of water. The solid is filtered off with suction at room temperature, washed with water and dried. 0.58 g of l-cyclopropyl-6,7-difluoro-l,4-dihydro4-oxo-8-vinyl-3-quinolinecarboxylic acid (71% of theory) is obtained.

Melting point: 182-184°C.

Example Z3 Ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-(trinethylsllyl-ethinyl)-4-oxo-3-quinolinecarboxylate 22.2 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 3 hours in 300 ml of absolute toluene under a nitrogen atmosphere. After the reaction mixture has cooled to approx. -18°C, the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl 1-cyclopropyl6,7-difluoro-1,4-dihydro-8- (trimethylsilylethinyl) -4-oxo3-quinolinecarboxylate (80% of theory) are obtained. Melting point: 171-172°C.

Example Z4 Ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylate 18.8 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-8(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate and 9.7 g of potassium fluoride are stirred for 3 hours at room temperature in a mixture of 300 ml of dimethylformamide, 200 ml of. chloroform and 15 ml of water. The mixture is then filtered, the filtrate is treated with 120 ml of water, and the mixture is acidified with dilute aqueous hydrochloric acid. After extraction by shaking with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue obtained is recrystallised from methanol. In this way, 9 g of ethyl 1 - cyclopropyl - 8 - ethinyl- 6,7 -dif luoro-1,4 -dihydro-4 -oxo- 3 quinolinecarboxylate (59% of theory) are obtained. Melting point: 186-187°C.

Example Z5 - Cyclopropyl - 8 - e thiny1 - 6,7 - di f luor o -1,4 - dihydro - 4 - oxo - 3 quinolinecarboxylic acid .3 g of ethyl l-cyclopropyl-8-ethinyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 4 hours in a mixture of 100. ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulphuric acid. After cooling to room temperature, the solid is filtered off with suction, washed with water and dried. In this way, 5.7 g of l-cyclopropyl-8-ethinyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylic acid (62% of theory) are obtained.

Melting point: 233°C.

Example Z6 Ethyl l-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4dihydro-4-oxo-3-quinolinecarboxylate 1.9 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylate, 3.5 g of 1-tributylstannyl-hex-l-ine and 0.29 g of tetrakis(triphenylphosphine) palladium (0) are refluxed for 8 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 30 ml of hexane, and the resulting solid is recrystallised from cyclohexane. 0.7 g of ethyl 1-cyclopropyl6,7-difluoro-8- (1-hexinyl) -l,4-dihydro-4-oxo-3-quinolinecarboxylate is obtained (36% of theory). 1H NMR (200 MHz, CDCl3) : δ 0.95 (t; 3 Η) , 1.1-1.7 (null H), 2.50 (t; 2 Η) , 4.1-4.3 (m; 1 Η), 4.38 (q; 2 Η), 8.14 (dd; 1 Η), 8.56 (s; 1 H) ppm.

Example Z7 1-Cyclopropyl-6,7-difluoro-8- (1-hexinyl) -1,4-dihydro-4oxo-3-quinolinecarboxylic acid 0.7 g of ethyl l-cyclopropyl-6,7-difluoro-8-(l-hexinyl)1.4- dihydro-4-oxo-3-quinolinecarboxylate is refluxed for 3 hours in a mixture of 6 ml of glacial acetic acid, 0.5 ml of water and 0.1 ml of concentrated sulphuric acid. The reaction mixture is treated with 100 ml of water, and the solid is filtered off with suction and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)1.4- dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (85% 6f theory). 1H NMR (200 MHz, CDC13) s 6 0.96 (t; 3 H) , 1.1-1.7 (m; H) , 4.3-4.5 (m; 1 H) , 8.20 (dd; 1 H) , 8.85 (s; 1 H) ppm.

Melting point: 118-121°C.

Example Z8 Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3dimethylbutin-l-yl)-4-oxo-3-quinolinecarboxylate Analogously to Example Z6, 1-tributylstannyl-3,3-dimethyl -but- 1- ine gives 0.87 g of ethyl l-cyclopropyl-6,7di fluoro-1,4-dihydro-8-(3,3-dimethylbutin-l-yl)-4-oxo-3quinolinecarboxylate (46% of theory).

Melting point: 170-172°C.

Example Z9 - Cyclopropyl - 6,7 - dif luoro -1,4 - dihydro - 8-(3,3 - dimethyl butin-l-yl)-4-oxo-3-quinolinecarboxylic acid Hydrolysis of 0.75 g of the ester from Example Z8 analogously to Example Z7 gives 0.56 g of 1-cyclopropyl-6,7difluoro-8-(3,3-dimethylbutin-l-yl)-4-oxo-3-quinolinecarboxylic acid (81% of theory).

Melting point: 199-201°C.

Example ZIP Ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8(trimethyls ilylethinyl)-4-oxo-3-quinolinecarboxylate 6.7 g of ethyl 8-bromo-l-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z20), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The product crystallises from the reaction mixture at -18°C. 4.8 g of ethyl 1(2,4 - di f luorophenyl) - 6,7 - di f luoro -1,4 - dihydro - 8 - (trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (69% of theory).

Melting point: 173-174°C.

Example Zll Ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate A solution of 4.6 g of ethyl 1-(2,4-difluorophenyl)-6,7difluoro-1,4-dihydro-8- (trimethylsilylethinyl) -4-oxo-3quinolinecarboxylate. in 20 ml of chloroform is added dropwise at room temperature to a solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. The mixture is stirred for 1 hour at approx. 20°C, the reaction mixture is then treated with more chloroform and extracted several times by shaking with water, and the organic phase is dried and concentrated. The residue obtained is recrystallised from methanol. 3.4 g of ethyl 1-(2,4-difluorophenyl) -8-ethinyl-6,7-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are obtained (87% of theory).

Melting point: 189°C.

Example Z12 1-(2,4-Dif luoropheny 1) - 8 - e thiny 1 -6,7 -di fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1.17 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 9 ml of glacial acetic acid, 0.75 ml of water and 0.2 ml of concentrated sulphuric acid. The solid which has crystallised out at room temperature is filtered off with suction and dried. 0.98 g of 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of theory).

Melting point: 220°C (decomposition).

Example Z13 Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8(propin-l-yl)-3-quinolinecarboxylate 7.5 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate, 9.1 g of 1-tributylstannyl-prop-l-ine and 1.16 g of tetrakis(triphenylphosphine ) palladium (0) are refluxed for 8 hours in 80 ml of absolute toluene under a nitrogen atmosphere. The solid which crystallises out at -18°C is filtered off with suction and dried. 2.05 g of ethyl 1-cyclopropyl6,7-difluoro-l,4 - dihydro - 4 - oxo - 8 - (propin-1 - yl) - 3 - quino linecarboxylate are obtained (31% of theory).

XH NMR (200 MHz, CDC13) : δ 1.1-1.35 (m; 4 Η) , 1.40 (t; 3 Η) , 2.16 (d; 3 Η), 4.1-4.3 (m; 1 Η) , 4.35 (q; 2 Η) , 8.15 (dd; 1 Η), 8.56 (s; 1 H) ppm.

Melting point: 180-182°C.

Example Z14 - Cy c 1 opropy1 - 6,7 - di f luor o -1,4 - dihydro - 4 - oxo - 8 - (prop in -1 yl)-3-quinolinecarboxylic acid 1.4 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4oxo-8-(propin-l-yl)-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 20 ml of glacial acetic acid, 1.5 ml of water and 0.5 ml of concentrated sulphuric acid. The mixture is treated with approx. 10 ml of water, and the solid which has precipitated is then isolated and dried. In this manner, 1.05 g of 1-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-8- (propin-l-yl)-3-quinolinecarboxylic acid are obtained (82% of theory).

TH NMR (200 MHz, CDC13) : δ 1.4 (m; 4 H), 2.26 (d; 3 H), 4.4-4.6 (m; 1 H), 8.16 (dd; 1 H), 8.81 (s; 1 H) ppm. Melting point: 212-213°C.

Example Z15 Ethyl l-ethyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl) -4-oxo-3-quinolinecarboxylate .4 g of ethyl 8-bromo-l-ethyl-6,7-difluoro-l,4-dihydro4-oxo-3-quinolinecarboxylate (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 100 ml of hexane, and the resulting solid is filtered off with suction and dried. 4.53 g of ethyl l-ethyl-6,7-difluoro-l,4-dihydro-8-(trimethylsilylethinyl)-4-OXO-3-quinolinecarboxylate are obtained (80% of theory).

Melting point: 151-152°C.

Example Z16 Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl) -4-oxo-3-quinolinecarboxylate 1.64 g of ethyl 8-chloro-l-cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylate, 3 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis(triphenylphosphine)palladium (0) are refluxed for 42 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to approx. -18°C and filtered. After the filter residue has been dried, 0.74 g of ethyl l-cyclopropyl-6,7-difluoro-l,4dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate is obtained (38% of theory).

Example Z17 Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methylbut-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate 1.86 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate, 2.8 g of 1-tributylstannyl-3-methyl-but-3-en-l-ine and 0.29 g of tetrakis (triphenylphosphine) palladium(0) are refluxed for 6 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered under hot conditions and concentrated, and the residue is stirred with hexane. After filtration with suction and drying, 1.43 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-8(3 -me thyl -but-3-en-l - inyl )-4- oxo - 3 - quinolinecarboxylate are obtained (80% of theory).

Melting point: 169-171°C.

Example Z18 - Cyclopropyl - 6,7 -dif luoro-1,4 - dihydro- 8 - (3 -methyl -but- 3 en-l-inyl)-4-oxo-3-quinolinecarboxylic acid 0.715 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro8- (3-methyl-but-3-en-l-inyl) -4-oxo-3-quinolinecarboxylate is refluxed for 1.5 hours in a mixture of 10 ml of glacial acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulphuric acid. The reaction mixture is poured into 100 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried. 0.53 g of l-cyclopropyl-6,7-difluoro-l,4-dihydro8- (3-niethyl-but-3-en-l-inyl) -4-oxo-3-quinolinecarboxylic acid is obtained (80% of theory).

Melting point: 204-206°C.

Example Z19 Ethyl 2- (3-bromo-2,4,5-trifluoro-benzoyl)-3-(2,4difluorophenylamino)-acrylate g (0.1 mol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl) -3-ethoxy-acrylate in 180 ml of ethanol are treated with 14.5 g (0.11 mol) of 2,4-difluoro-aniline, with ice-cooling. The mixture is allowed to stand overnight at 10°C, and the precipitated solid is filtered off with suction, washed with cold ethanol and dried in vacuo.

Yield: 38 g (81% of theory).

Melting point: 102-103 °C (with decomposition) (from isopropanol).

Example Z20 Ethyl 8-bromo-l-(2,4-difluorophenyl)-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylate g (82 mmol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-(2,4-difluorophenylamino)-acrylate in 200 ml of dimethylformamide are treated with 7.6 g of sodium fluoride and the mixture is refluxed for 2 hours. The mixture is poured into ice-water, and the precipitate is filtered off with suction, washed thoroughly with water and dried at 80°C in a recirculation drying cabinet. Yield: 34.7 g (95% of theory).

Melting point: 208-210°C (with decomposition) (from glycol monomethyl ether).

Acid hydrolysis of this ester gives 8-bromo-l-(2,4di f luoropheny 1 )-6,7-dif luoro -1,4 - dihydro - 4 - oxo - 3 - quino linecarboxylic acid of melting point 210-221°C (with decomposition).

Example Z21 Ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-ethylaminoacrylate g (0.05 mol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl) -3-ethoxy-acrylate in 40 ml of ethanol are treated with 5.5 g of a 50% strength aqueous ethylamine solution, with ice-cooling. The mixture is allowed to stand overnight at 10°C, the suspension is treated with 200 ml of water, and the precipitated solid is filtered off with suction, washed with water and dried in vacuo at 60°C.

Yield: 17.3 g (91% of theory).

Melting point: 101-102°C (with decomposition) (from isopropanol).

Example Z22 Ethyl 8-bromo-l-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3 quinolinecarboxylate g (42 mmol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl) -3-ethylaminoacrylate are reacted analogously to Example Z20.

Yield: 14.6 g (96% of theory).

Melting point: 172-173 °C (with decomposition) (from glycol monomethyl ether).

Acid hydrolysis of this ester gives 8-bromo-l-ethyl-6,7difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 215-217°C (with decomposition).

Example Z23 4-Methylamino-1,3,3a,4,7,7a-hexahydroisoindole Method I: .1 g (60 mmol) of N-trimethylsilylmaleimide [J.Org. Chem. 40, 24 (1975)] in 30 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and 14.4 g (60 mmol) of 70% 1-(tert.-butyloxycarbonylamino)-1,3butadiene [J.Org.Chem. 43, 2164 (1978)], dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise. When the - exothermic reaction has subsided, the mixture is refluxed for a further hour. 7.6 g (0.2 mol) of lithium aluminium hydride in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and the cold reaction mixture is then added dropwise under nitrogen. The mixture is then refluxed for 14 hours. 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10% strength sodium hydroxide solution and 22.8 g of water are then added dropwise in succession to the cold reaction mixture. The salts are filtered off and the filtrate is concentrated in vacuo. The residue (10.3 g) is distilled at 87°C/0.8 mbar.

The distillate is taken up in 80 ml of absolute pentane, the mixture is filtered, and the product is crystallised by cooling the filtrate to -70°C.

Yield: 3.3 g, melting point: 72-82°C.

Treatment with an equimolar amount of 2N hydrochloric acid gives 4-methylamino-l,3,3a,4,7,7a-hexahydro-isoindole dihydrochloride of melting point 265-268°C (from methanol).

Method II: a) 4-(tert.-Butyloxycarbonylamino)-1,3-dioxo1,3,3a,4,7,7a-hexahydroisoindole 48.0 g (0.5 mol) of maleimide dissolved in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and 120 g (0.5 mol) of approx. 70% 1-(tert.-butyloxycarbonylamino)-1,3-butadiene dissolved in 500 ml of absolute tetrahydrofuran are added dropwise, during which process the temperature is kept at 20 to 30°C. Stirring is continued overnight at room temperature. The mixture is then concentrated, and the product is recrystallised from ethyl acetate. 57 g of product of a melting point of 177 to 182°C are obtained. A further 13 g of a melting point of 158 to 160°C are obtained from the mother liquor. b) 4-Methylamino-1,3,3a,4,7,7a-hexahydroisoindole Under nitrogen, 27.1 g (0.71 mol) of lithium aluminium hydride are introduced into 300 ml of absolute tetrahydrofuran, and a solution of 57 g (0.21 mol) of 4-(tert.-butyloxycarbonylamino)-1,3-dioxo1,3,3a,4,7,7a-hexahydroisoindole in 570 ml of absolute tetrahydrofuran is added dropwise. The mixture is then refluxed overnight. 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% strength sodium hydroxide solution and 81.3 g of water are then added dropwise to the cold batch. The salts are filtered off with suction and washed with tetrahydrofuran, and the filtrate is concentrated in vacuo. The residue is distilled off under a high vacuum.

Yield: 19.1 g.

Example Z24 4-Amino-l,3,3a,4,7,7a-hexahvdro-isoindole 13.3 g (50 mmol) of 4-tert.-butyloxycarbonylamino-1,3dioxo-1,3,3a,4,7,7a-hexahydro-isoindole (from Example Z23, method II) are stirred overnight at room temperature in 166 ml of trifluoroacetic acid. The trifluoroacetic acid is then distilled off at 10 mbar, and the residue is freed from remaining acid in a high vacuum at 50°C. The residue is subsequently taken up in absolute tetrahydrofuran and concentrated in vacuo. The residue is taken up in 100 ml of absolute tetrahydrofuran and the mixture is added dropwise under nitrogen to a solution of 11.3 g (0.3 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran. The mixture is then refluxed for 16 hours. 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% strength sodium hydroxide solution and 34 ml of water are added dropwise in succession to the cold mixture. The precipitate is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated, and the residue is distilled.

Yield: 2.2 g, content: 92% (determination by gas chromatography) Boiling point: 70°C/0.2 mbar.

B) Example Z25 7-Methvl-4-methvlamino-l,3,3a,4.7,7a-hexahydro-isoindole Analogously to Example Z23, method I, 21.9 g (0.12 mol) of 1-(tert.-butyloxycarbonylamino)-1,3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide, and the product is subsequently reduced with .2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.

Yield: 6.2 g, melting point: 106-108°C.

Example Z26 1-Cvclopropyl-6,7-difluoro-1.4-dihvdro-8 -(3-methoxypropin-l-vl)-4-oxo-3-quinolinecarboxvlic acid A) 1.86 g (5 mmol) of ethyl 8-bromo-1-cyclopropyl-6,7difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 20 ml of absolute toluene are treated with 2.5 g (7 mmol) of 1-tributyl - s tannyl-3-methoxy-propine and 0.29 g (corresponding to 5 mol %) of tetrakis(triphenylphosphine) -palladium(0) , and the mixture is refluxed for 4 hours in a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with hexane, and the solid is filtered off with suction and purified by chromatography over a little silica gel.

Yield: 0.74 g (41% of theory) of ethyl 1-cyclopropyl-6,7 -dif luoro-1,4-dihydro-8- (3-me thoxy-prop in1-yl)-4-oxo-3-quinolinecarboxylate.

Melting point: 144-146°C 0.36 g (1 mmol) of the product of stage A is refluxed for 1 hour in a mixture of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concentrated sulphuric acid. The mixture is poured into water, and the precipitate is filtered off and recrystallised from ethanol.

Yield: 153 mg (46% of theory) of 1-cyclopropyl-6,7difluoro-1,4-dihydro-8-(3-methoxy-propin-1-yl)-4oxo-3-quinolinecarboxylic acid.

Melting point: 170-172°C XH NMR (270 MHz, CDC13): δ 1.24 m (2H), 1.4 m (2H) , 3.45 s (OCH3), 4.35 m (1H) , 4.41 s (O-CH2-) , 8.27 t (1H), 8.87 ppm s (1H).

Preparation of the active compounds Example 1 A) 2.32 g (8 mmol) of l-cyclopropyl-8-ethinyl-6,7difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide are refluxed for 1 hour with 0.92 g (8 mmol) of 1,4-diazabicyclo [2.2.2] octane and 1.2 g (12 mmol) of N-methylpiperazine. The suspension is concentrated, the residue is stirred with acetonitrile, and undissolved crystallisate is filtered off with suction and dried.

Yield: 1.83 g (62% of theory) of 1-cyclopropyl-8ethinyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.

Melting point: 228-230°C (with decomposition).

*H NMR (d6-DMF) : δ 4.95 ppm s (-CsC-H) .

B) In an analogous manner, 1-cyclopropyl-8-ethinyl-6fluoro-1,4-dihydro-7- (3-methyl-l-piperazinyl)-4-oxo3-quinolinecarboxylic acid is obtained with 2methylpiperazine. 2H NMR (d6-DMSO) : δ 5.03 ppm s (-C=C-H) .

Mass spectrum: m/e 369 (M+) , 325 (M+-CO2), 300, 293, 269, 243, 44 (CO2).

Using the products of Examples Z14, Z7 and Z9, the following are obtained analogously to Example 1: COOH III c Example 2 (R=CH3) : l-Cyclopropyl-6-fluoro-l,4-dihydro-7(4-methyl-1-piperazinyl) -4-oxo-8- (propin-l-yl) - 3-quinolinecarboxylic acid.

Melting point: 246-249°C (with decomposition).

Example 3 (R=CH2CH2CH2CH3) : 1-Cyclopropyl-6-fluoro-8(hexin-l-yl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4oxo-3-quinolinecarboxylic acid.

Melting point: 206-208°C (with decomposition).

Example 4 (R=C(CH3) 3 : 1-Cyclopropyl-8-(3,3-dimethylbutin1-yl)-6-fluoro-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4oxo-3-quinolinecarboxylic acid.

Melting point: 234-237°C (with decomposition).

Example 5 III CH COOH Analogously to Example 1, the reaction is carried out with cis-2,8-diazabicyclo[4.3.0]nonane to give 1-cyclopropy 1 -7-(cis-2,8 -diazabicyclo [4.3.0] non- 8 -yl )-8- ethinyl 6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 225-227°C (with decomposition).

’•H NMR (d6-DMF) : δ 4.9 s (-CsC-H) . 3.2 g (12 mmol) of l-cyclopropyl-8-ethinyl-6,7-dihydro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 120 ml of acetonitrile and 60 ml of dimethylformamide are refluxed for 1 hour with 1.56 g (14 mmol) of 1,4diazabicyclo [2.2.2] octane and 2.75 g (18 mmol) of 3-(2,2dimethylpropylideneamino)pyrrolidine. The solution is concentrated, the residue is stirred with approximately 100 ml of water (pH 7), the precipitate is filtered off with suction, washed with water and subsequently suspended in 50 ml of water to completely eliminate the protective group, and the mixture is treated for 1 hour in an ultrasonic bath. Solid is then filtered off with suction, washed with water and dried in vacuo at 80°C. Yield: 3.8 g (82% of theory) of 7-(3-amino-1-pyrrolidinyl )-1- cyclopropyl - 8 -ethinyl - 6 - fluoro-1,4 -dihydro-4 -oxo3-quinolinecarhoxylic acid hydrate.

Melting point: 193-196°C (with decomposition).

COOH Example 7 CH A: R= CO-O-C(CH3)3 B: R = H x CF3COOH A) Analogously to Example 1, the reaction is carried out with 3-tert. -butoxycarbonylamino-3-methyl 5 pyrrolidine to give 7-(3-tert.-butoxycarbonylamino3 -methyl -1 -pyrrolidinyl )-1- cyclo-propyl - 8 - ethinyl - 6 fluoro-1,4-dihydro-4-oxo-3-guinolinecarboxylic acid of melting point 244-246°C (with decomposition).

XH NMR (d6-DMSO) : δ 4.92 ppm s (-CsC-H) .

B) 500 mg of the product of stage A are dissolved in 5 ml of trifluoroacetic acid with ice-cooling, the solution is concentrated in vacuo, the residue is brought to crystallisation by stirring with three times approximately 1 ml portions of ethanol, and the salt is filtered off with suction, washed with ethanol and dried.

Yield: 270 mg (52% of theory) of 7-(3-amino-3methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethinyl-6fluoro-1,4-dihydro-4-oxo-3 -quinolinecarboxylic acid trifluoroacetate.

Melting point: 242-244°C (with decomposition).

Example 8 O COOH CH Analogously to Example 1, the reaction is carried out with 2-oxa-5,8-diazabicyclo[4.3.0]nonane to give 1cyclopropy1-8-ethiny1-6-fluoro-1,4-dihydro-7- (2-oxa-5,8diazabicyclo[4.3.0] non-8-yl)-4-oxo-3-quinolinecarboxylic acid of melting point 290°C (with decomposition; sintering starts at approximately 170°C).

XH NMR (d6-DMSO) : δ 5.0 ppm s (-C=C-H) .

Example 9 COOH CH3 Analogously to Example 1, 2-oxa-5,8-diazabicyclo[4.3.0]nonane are reacted with the product of Example Z14 to give l-cyclopropyl-6-fluoro-l,4-dihydro-7-(2-oxa-5,8diazabicyclo [4.3.0] non-8-yl) - 4-oxo-8- (propin-l-yl) - 3 quinolinecarboxylic acid of melting point 241-242 °C (with decomposition).

Example 10 O ι CH3 COOH A: R= (CH3)3C-O-COB:R = H A) 303 mg (1 mmol) of the product of Example Z14 in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide are treated with 240 mg of 3tert.-butoxycarbonylamino-3-methyl-pyrrolidine and 134 mg (1.2 mmol) of 1,4-diazabicyclo [2.2.2] octane and the mixture is refluxed for 2 hours. The mixture is concentrated in vacuo, the residue is stirred with 30 ml of water, and the mixture is dried at 80°C in vacuo.

Yield: 420 mg (87% of theory) of 7-(3-tert.-butoxycarbonylamino- 3 -methyl-1-pyrrolidinyl)-1-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-8- (propin-l-yl) -3quinolinecarboxylic acid.

Melting point: 195-196°C (with decomposition).

NMR (d6-DMSO) : δ 1.42 s (CH3 on the pyrrolidine), 2.12 ppm s (CH3-C=C-).

B) 180 mg of the product of stage A are dissolved in 1.6 ml of trifluoroacetic acid at 0°C, and, after 1.25 hours, the solution is concentrated. The residue is purified by chromatography (silica gel, dichloromethane/methanol/17% strength aqueous ammonia = 30:8:1). 10 mg of 7-(3-amino-3-methyl-lpyrrolidinyl )-1- cyclopropyl - 6 - fluoro -1,4-dihydro-4oxo-8-(propin-l-yl)-3-quinolinecarboxylic acid of melting point 209-210°C are isolated (with decomposition) .

Mass spectrum: m/e 383 (M+), 309, 298, 267 (100%), 133, 70.

Example 11 COOH CH Analogously to Example 1, the product of Example Z12 is reacted with N-methylpiperazine to give 8-ethinyl-6fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1piperazinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 193-195’C (with decomposition).

XH NMR (CDC13)ϊ 3.35 s (-CsCH).

Example 12 CH COOH Analogously to Example 1, the reaction is carried out 10 with 3-methyl-3,8-diazabicyclo[4.3.0]nonane, and 1cy c 1 opr opy 1 -8-e thiny1-6-f luoro -1,4 - dihydro - 7 - (3 -me thyl 3,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, which is obtained as crude product, is purified by chromatography (silica gel; dichloromethane/ methane/20% aqueous ammonia 2:4:1). 1H NMR (CDC13): 4.15 s (-CsC-H).

Analogously to Example 1, the reaction is carried out with 3-methyl-3,7-diazabicyclo [3.3.0] octane to give 120 cyclopropyl - 8 - e thiny1 - 6 - f luoro -1,4 - dihydro - 7 - (7 -me thy 1 3,7-diazabicyclo[3.3.0]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid of melting point 212-216°C (with decomposition) . s (-C=C-H).

COOH Analogously to Example 1, the reaction is carried out with 4-methylamino-l,3,3a,4,7,7a-hexahydroisoindole to give l-cyclopropyl-8-ethinyl-6-fluoro-l,4-dihydro-7-(4methylamino-1,3,3a,4,7,7a-hexahydroisoindol-2-yl)-4-oxo3-quinolinecarboxylic acid of melting point 128-133°C (with decomposition).

XH NMR (d6-DMSO) : δ 4.93 ppm s (-C=CH) .

Example 15 COOH C H2C CH3 164 mg- (0.5 mmol) of the product of Example Z18 are reacted analogously to Example 1 with 1-methylpiperazine to give 120 mg of l-cyclopropyl-6-fluoro-1,4-dihydro-8(3-methyl-but-3-en-l-inyl)-7-(4-methyl-l-piperazinyl)-4oxo-3-quinolinecarboxylic acid of melting point 195-197°C (with decomposition) (recrystallised from glycol monomethyl ether).

XH NMR (CDC13) : δ 5.36 m (>C=CH2) , 2.4 s (N-CH3) , 2.0 t (C-CH3) .

Example 16 COOH Analogously to Example 15, the reaction is carried out 15 with 2,8-diazabicyclo[4.3.0]nonane to give 1-cyclopropyl7- (2,8-diazabicyclo[4.3.0]non-8-yl) -6-fluoro-1,4-dihydro8- (3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylic acid of melting point 201-202°C (with decomposition).

Example 17 A.

B.

R = N^N- HN C. ch3 Analogously to Example 15, the reaction is carried out with A. 1,4-Diazabicyclo[3.2.1]octane B. 3-Hydroxypyrrolidine C. 2-Methylpiperazine to give the following compounds: A. 1-Cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -610 fluoro-1,4-dihydro-8- (3-methyl-but-3-en-l-inyl) -4oxo-3-quinolinecarboxylic acid, Β. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3-hydroxy-1pyrrolidinyl)-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3quinolinecarboxylic acid, melting point: 190-198°C (with decomposition), C. l-Cyclopropyl-6-fluoro-l,4-dihydro-8- (3-methyl-but3-en-l-inyl)-7-(3-methyl-1-piperazinyl)-4-oxo-3quinolinecarboxylic acid.

Example 18 Ο COOH xHCl 100 mg of the product of Example 1 are dissolved in 40 ml of IN hydrochloric acid, and the solution is stirred for 2 hours at 30°C. This gives a suspension which is concentrated. The residue is stirred with a little isopropanol, and the precipitate is filtered off with suction, washed with isopropanol and dried in vacuo at 90°C.

Yield: 0.1 g (83% of theory) of 8-(1-chlorovinyl)-1cyclopropyl-6-f luoro-1,4-dihydro-7- (4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride. Melting point: 251-252°C (with decomposition).

XH NMR (ds-DMSO) : δ 6.0 ppm dd (_c=ch2) Example 19 CH O COOH CH CH3 A) 100 mg of the product of Example 2 in 58 ml of 4N hydrochloric acid are heated for 5 hours at 60°C.

The mixture is concentrated, and the residue is stirred with diethyl ether and dried in vacuo at 70°C.

Yield: 90 mg of cis-trans-8-(l-chloro-l-propenyl)-lcyclopropyl-6 -f luoro-1,4-dihydro-7 - (4-methyl-1piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride.

Melting point: 236-237°C (with decomposition).

Mass spectrum: m/e 419 (M+) , 71.58 (100%), 43.36.

XH NMR (d6-DMSO) : δ 6.12 q and 6.35 q -C=CH-CH3 ' two signals for cis-trans forms).

B) Analogously, cis-trans-8-(1-chloro-l-hexenyl)-1cyclopropyl- 6 - fluoro-1,4-dihydro-7 - (4-methyl-1piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride is formed with the product of Example 3.

Mass spectrum: m/e 461 (M+) , 425 (Μ-HCl) , 71.58 (100%), 43.36.

Example 2 0 I CH3 370 mg of the product of Example 10A are dissolved in 9 ml of half-concentrated hydrochloric acid, and the solution is concentrated under a high vacuum.

Yield: 340 mg of cis-trans-7-(3-amino-3-methyl-1-pyrrolidinyl) -8-(1-chloro-l-propenyl)-l-cyclopropyl-6-fluoro59 l,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride .

NMR (d6-DMSO) : δ 6.19 q and 6.36 q (>C=CH-CH3; 2 signals for cis-trans forms).

Example 21 mg of the product of Example 11 in 4.5 ml of 2.5N hydrochloric acid are heated for 1 hour at 60°C. The mixture is concentrated, and 8-(1-chlorovinyl)-6-fluoro10 1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride is obtained as residue.

Mass spectrum: m/e 477 (M+) , 442 (M+-C1) , 36 (100%, HCl). 291 mg (1 mmol) of the product of Example Z2 in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide are treated with 240 mg (2.2 mmol) of 1,4-diazabicyclo60 [2.2.2]octane and 360 mg (2.3 mmol) of 3-(2,2-dimethylpropylideneamino)-pyrrolidine, and the mixture is refluxed for 32 hours. The mixture is concentrated, the dark oily residue is stirred with 10 ml of water, and the solid which has precipitated (103 mg) is filtered off with suction and purified by chromatography (silica gel; dichloromethane/methanol/17% aqueous ammonia 30:8:1). Yield: 58 mg (16% of theory) of 7-(3-amino-l-pyrrolidinyl )-1- cyclopropyl - 6 - fluoro-1,4 -dihydro-4 -oxo- 8 -vinyl - 3 quinolinecarboxylic acid.

Melting point: 179-182°C (with decomposition).

CI mass spectrum: m/e 358 ([M+H]*), 340 ([M+H-H2O] *) .

Example 23 O COOH 145 mg (0.5 mmol) of the product of Example Z2 in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide are treated with 60 mg (0.54 mmol) of 1,4diazabicyclo [2.2.2] octane and 140 mg (1.1 mmol) of cis2.8- diazabicyclo-[4.3.0]nonane, and the mixture is refluxed for 4 hours. The solution is concentrated, the concentrate is stirred with approximately 5 ml of water, and the mixture is . brought to pH 7 using dilute hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried in vacuo at 90°C. Yield: 120 mg (61% of theory) of l-cyclopropyl-7-(cis2.8- diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4oxo-8-vinyl-3-quinolinecarboxylic acid.

Melting point: 205-207°C (with decomposition).

XH NMR (CF3COOD): δ 5.05 d (1H), 5.7 d (1H), 7.55 dd (1H) (signal groups for -CH=CH2) .

Example 24 Analogously to Example 1, the reaction is carried out with the product of Example Z26, and l-cyclopropyl-6fluoro-1,4-dihydro-7-(4-methyl-l-piperazinyl)-8- (3methoxy-propin-l-yl)-4-oxo-3-guinolinecarboxylic acid of melting point 187-189°C is obtained.

XH NMR (CDC13) : δ 8.95 s (1H), 8 d (1H), 4.37 s (O-CH2) . 4.35 m (1H) , 3.58 m (4H) , 3.43 s (O-CH3) , 2.58 m (4H) , 2.38 s (N-CH3), 1.33 m (2 H) , 1.02 ppm m (2H) .

Analogously to Example 1, the reaction is carried out with 3,7-diazabicyclo[3.3.0]octane, the reaction product is chromatographed on silica gel using dichloromethane/ methanol/17% strength ammonia (30:8:1) as the eluent, and 1-cyclopropyl-7-(3,7-diazabicyclo[3.3.0]oct-3-yl) - 8e thinyl-6-fluoro-l,4-dihydro-4-oxo-3-quino1inecarboxy1ic acid is obtained as a solidified foam XH NMR (ds-DMSO) : δ 4.9 s (-CsCH).

Claims (16)

1. 1. Quinolonecarboxylic acid derivatives of the formula COO-R 2 (I). in which R 1 represents straight-chain or branched C^C*alkyl which is optionally substituted by hydroxyl, halogen or C 1 -C 3 -alkoxy, or represents 10 optionally halogen- or C 1 -C 3 -alkyl-substituted C 3 -Cg-cycloalkyl, C 2 -C 4 -alkenyl, furthermore represents C-^Cj-alkoxy, amino, monoalkylamino having 1 to 3 C atoms, dialkylamino having 2 to 6 C atoms, or phenyl which is optionally 15 monosubstituted to trisubstituted by halogen, R 2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, X 1 represents hydrogen, fluorine, chlorine, amino 20 or methyl, represents -C=CH-R 3 · -CsC-R 5 or -CH 2 -CH=CH 2 , R 4 where R 3 represents hydrogen, C 1 -C 3 -alkyl, alkoxy or alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, R 4 represents hydrogen or halogen and R 5 represents hydrogen, C^-Cg-alkyl which is optionally monosubstituted to trisubstituted by halogen, or C 2 -C 3 alkenyl, alkoxy having 1 to 3 C atoms, alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and represents R 9 RlO r 6 -J 4- , r’-n^n- , r 8 -n^\- , n^QnR 7 R 8 R 8 Ο N — R 11 r16^ R 1 1q Z R 17 R 12 R 14 R 13 R 8 N - CH >b- z'Z'nR 12 where R 6 represents hydrogen, optionally hydroxyl- or methoxy-substituted straight-chain or branched C 1 -C 4 -alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having 1 to 3 C atoms, R 7 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R 8 represents hydrogen or methyl, R 9 represents hydrogen or methyl, R 10 represents hydrogen or methyl, R 9 »11 represents hydrogen, methyl or -CH?-N .10 R 12 represents hydrogen, methyl, amino, optionally hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, aminomethyl, aminoethyl, optionally hydroxylsubstituted alkyl- or dialkylaminomethyl having 1 or 2 C atoms in the alkyl moiety or 1-imidazolyl, R 13 represents hydrogen, hydroxyl, methoxy, methylthio or halogen, methyl or hydroxymethyl, >14 represents hydrogen or methyl, R 15 represents hydrogen, methyl or ethyl, >16 represents hydrogen, methyl or ethyl, R 17 represents hydrogen, methyl or ethyl, R 16 R 16 R 18 represents hydroxyl, or CH 2 -N. R 17 R 17 R 19 represents hydrogen, optionally hydroxylsubstituted C x -C 3 -alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or C 2 -C 3 -acyl, r 20 represents hydrogen, hydroxyl, R 19 R 21 hydroxymethyl or where R 21 denotes hydrogen or methyl, A represents CH 2 , O or a direct bond and n represents 1 or 2, and their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

2. Quinolonecarboxylic acid derivatives according to 5 Claim 1, where R 1 represents optionally hydroxyl-substituted C x C 2 -alkyl, C 3 -C 5 -cycloalkyl, vinyl, amino, monoalkylamino having 1 to 2 C atoms, dialkylamino having 2 to 4 C atoms, or phenyl which is optionally monosubstituted or disubstituted by halogen, R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, X 1 represents hydrogen, fluorine, chlorine, amino or methyl, X 2 represents -C=CH-R 3 · -C=C-R 5 or -CH 2 -CH=CH 2 , i 4 R 4 where R 3 represents hydrogen, C x -C 2 -alkyl, methoxy or methoxymethyl, R 4 represents hydrogen and R 5 represents hydrogen, C x -C 4 -alkyl which is optionally monosubstituted to trisubstituted by fluorine, or C 2 -C 3 alkenyl, methoxy or trimethylsilyl, and Y represents rI6 R 1 ! o >' ch 2V n R> 7 where R 6 represents hydrogen, optionally hydroxyl-substituted straight-chain or branched Cj-Cjalkyl, or oxoalkyl having 1 to 4 C atoms, R 7 represents hydrogen, methyl or phenyl, R 8 represents hydrogen or methyl, R 9 represents hydrogen or methyl, R 11 represents hydrogen, methyl or -CH 2 -NH 2 , R 12 represents hydrogen, methyl, amino, methyl amino, dime thy lamino, aminomethyl, methylamino methyl or ethylaminomethyl, R 13 represents hydrogen, hydroxyl, methoxy, fluor ine, methyl or hydroxymethyl, R 15 represents hydrogen or methyl, R 16 represents hydrogen or methyl, R 17 represents hydrogen or methyl, »18 represents z \ R 16 ,R 16 or ch 2 -n R 17 R 17 R 19 represents hydrogen, methyl or ethyl, ,20 represents Ν' R” R 21 where R 21 denotes hydrogen or methyl. A represents CH 2 , O or a direct bond and n represents 1 or 2.

3. Quinolonecarboxylic acid derivatives according to Claim 1, where J· R 1 represents methyl, ethyl, cyclopropyl or phenyl which is optionally monosubstituted or disubstituted by fluorine, R 2 represents hydrogen, methyl or ethyl, X 1 represents hydrogen, fluorine, chlorine, amino or methyl, X 2 represents -CH=CH 2 or -C=C-R 5 where R 5 denotes hydrogen, C 1 -C 4 -alkyl, C 2 -C 3 alkenyl or trimethylsilyl and Y represents R 9 15 R 6 -N n_ , R 7 R k Ο N — R! 2 Yn R 13 R 11 - 71 Rl<5 R^O >- CH 2R R 17 R 8 where R 6 represents hydrogen, methyl, optionally hydroxyl-substituted ethyl, R 7 represents hydrogen or methyl, R 8 represents hydrogen or methyl, R 9 represents hydrogen or methyl, R 11 represents hydrogen or -CH 2 -NH 2 , R 12 represents hydrogen, methyl, amino, methylamino, aminomethyl or ethyl aminomethyl, R 13 represents hydrogen, hydroxyl or methoxy, - 72 R 15 represents hydrogen or methyl, R 16 represents hydrogen or methyl, R 17 represents hydrogen or methyl, >18 represents r!6 R 17 4. Q R represents hydrogen or methyl. »20 represents R 19 R 21 where R 21 denotes hydrogen or methyl, A represents CH 2 , O or a direct bond and n represents 1.

4. Quinolonecarboxylic acid derivatives of the formula (ID, in which R 1 , R 2 , X 1 and X 2 are as defined in Claim 1 and X 3 represents halogen, in particular fluorine or chlorine.

5. Quinolinecarboxylic acid derivatives of the group consisting of 1- cyclopropyl- 8 -ethinyl -6-fluoro-1,4-dihydro-7-(4methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7-(cis-2,8-diazabicylco[4.3.0]-non-8yl) - 8 - ethinyl-6-fluoro-l,4-dihydro-4-oxo-3 quinolinecarboxylic acid, 7- (3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethinyl6- fluoro-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid, 7- (3- amino - 3 -methyl -1 -pyrrol idinyl )-1- cyclopropyl - 8 ethinyl - 6 -fluoro - 1, 4 - dihydro-4-oxo-3 quinolinecarboxylic acid trifluoroacetate, 1-cyclopropyl- 6- fluoro-1,4-dihydro-8-(3-methyl-but3-en-l-inyl)-7-(4-methyl-l-piperazinyl)-4-oxo-3quinolinecarboxylic acid, 1 - cyclopropyl - 8 - ethinyl - 6 - fluoro -1,4 - dihydro - 7 - (2 oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3quinoline- carboxylic acid, 1 - eye 1 op ropy 1 - 8 - e thiny 1 - 6 - f luoro -1,4 - dihydro - 7 - (7 methyl-3,7-diazabicyclo[3.3.0]oct-3-yl)-4-oxo-3quinolinecarboxylic acid, 1 - eye 1 opr opy 1 - 8 - e thiny 1 - 6 - f luoro -1,4 - dihydro - 7 - (4 - 74 methylamino-1,3,3a, 4,7,7a-hexahydroisoindol-2-yl) -4oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-7- (cis-2,8-diazabicylco [4.3.0]non-8yl-6 -fluoro-1,4- dihydro - 4 - oxo - 8 - vinyl - 3 - quinoline 5 carboxylic acid and their pharmacologically acceptable hydrates and acid addition salts and also the alkali metal, alkaline earth metal, silver and guanidinium salts.

6. Quinolinecarboxylic acid derivatives from the group 10 consisting of 8-bromo-1-(2,4-difluorophenyl)- 6,7-difluoro-1,4 dihydro-4-oxo-3-quinolinecarboxylic acid and 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3chinolinecarboxylic acid and their hydrates and acid 15 addition salts and also the alkali metal, alkaline earth metal, silver and guanidinium salts.

7. Process for the preparation of quinolonecarboxylic acid derivatives according to Claim 1, characterised in that a compound of the formula (II) in which R 1 , R 2 , X 1 and X 2 are as defined in Claim 1 and - 75 X 3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula (III) Y-H (III) in which Y is as defined in Claim 1, if appropriate in the presence of acid scavengers.

8. Quinolonecarboxylic acid derivatives according to Claims 1 to 5 for treating diseases.

9. Medicament containing quinolonecarboxylic acid derivatives according to Claims 1 to 5.

10. Use of quinolonecarboxylic acid derivatives according to Claims 1 to 5 in the preparation of medicaments.

11. . A compound according to Claim 1, substantially as hereinbefore described and exemplified.

12. A compound according to Claim 4, substantially as hereinbefore described and exemplified.

13. A process for the preparation of a compound according to Claim 1, substantially as hereinbefore described and exemplified.

14. A compound according to Claim 1, whenever prepared by a process claimed in Claim 7 or 13.

15. A medicament according to Claim 9, substantially as hereinbefore described.

16. Use according to Claim 10, substantially as hereinbefore described.