NZ222736A

NZ222736A - Process for the preparation of heterocyclically substituted quinoline or naphthyridine carboxylic acids or derivatives

Info

Publication number: NZ222736A
Application number: NZ222736A
Authority: NZ
Inventors: Michael Preiss
Original assignee: Bayer Ag
Priority date: 1986-12-03
Filing date: 1987-11-30
Publication date: 1990-08-28
Also published as: NO874788L; KR970005191B1; HU199823B; CN87107230A; IE64261B1; HUT45521A; AU8217787A; NO174199B; PT86252B; NO174199C; CS868887A2; PL269185A1; YU45049B; YU215687A; ATE73446T1; DK633187A; PT86252A; PL158614B1; IL84627A0; JPS63145268A

Abstract

A process for the preparation of quinolinecarboxylic acids of the formula (I) <IMAGE> in which R<1>, R<2> and R<3>, X and A have the meaning given in the description, which are used as such or in the form of their esters, salts, prodrugs etc. as antibacterial agents in human and veterinary medicine and as agents stimulating the immune defence.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £22736 2.2 2 7 3 6 NO DRAWINGS Priority Oate(s^. .. Complete Specification Filed3s-?.;1\'.W?-ci39* f^TIPSJft. c.oTl e.4A2/o^j L PuWrcation Date: . X $ ,$!••'.'?. !??9. °.0. Journal, No: \.c5$>v5* ,j. AMENDED under Section fJx of the -— Patents Act 1953 from —~L'„^ — ASSISTANT COMMISSIONER OF PATENTS NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION PROCESS FOR THE PREPARATION OF QUINOLINECARBOXYLIC ACIDS We, BAYER AKTIENGESELLSCHAFT, a Company registered under the laws of the Federal Republic of Germany of Leverkusen, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following s ta temen t - 1 - (Followed by 1A) ; 2 2 7 3 6 The invention relates to a new process for the preparation of quino IinecarboxyIic acids which are used as such or in the form of their esters, salts, prodrugs and the like as antibacterial agents in human and veterinary medicine and as agents which stimulate immune defence. The invention relates to a process for the preparation of compounds of the formula (I) (I ) 10 in which 15 wherein 20 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyI, 2-fIuoroethy I , methoxy, amino, methyI amino, dimethyI amino, ethylamino, phenyl, 4-fIuorophenyI or 2,4-di- fluorophenyl, 2 ? ' R represents CN or C00R , 2 • R denotes hydrogen, C — C4 — alkyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, or R^ represents CON(C1IkyI>2, represents a cyclic amino group, such as n- n- , h Rl n-, r4-n > r n- , n-, ^n- , r4-n^\^n- > r<-nt>, - 1 22 27 36 / \ N-, I I or where i n represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxo-propyl, 3-oxobutyl, phenacyl, formyl, CFClj-S-, CFCL2-SO2-, CH3O-CO-S-, benzyl, 4-aminobenzyI o r ch3 ch7- , R^ represents hydrogen or methyl, R^ represents hydrogen, alkyl with 1 to 4 carbon 10 atoms, phenyl or benzyI 0xymethyI, R^ represents hydrogen, amino, methylamino, ethylamino, ammomethyl, me t h y I am i nome t h y I , ethyI aminomethyI, d 1 methyI aminomethyI, hydroxyl or hydroxymethyI and g 15 R represents hydrogen, methyl, ethyl or chlorine, 0 r R^ represents the group R9 n-B10/ in which 9 10 20 R and R are identical or different and represent hydrogen or a branched or unbranched alkyl, alkenyl or alkynyl radical which has 1 to 12 carbon atoms and can optionally be substituted by hydroxyl groups, alkoxy, a IkyI mercap10 or 25 dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile group or the alkoxycarbonyI group with 1 to 4 carbon atoms in 22 2 7 3 6 the alcohol part, or an aryl or heteroaryl radical, or furthermore denotes Cj-C^-cycloalkyI, X represents halogen, in particular fluorine or chlorine, or nitro or C-j-C4-a I ky I suI phony I or C1-C4~aIkyIsulphonyloxy and wherein 11 A represents N or C-R , 11 R represents hydrogen, halogen, such as fluorine, bromine or chlorine, methyl or nitro 10 and R^, together with R^, can form a bridge of the structure -0-CH2-CH-CH3, -S-CH2-CH-CH3 or -CH2-CH2-CH-CH3 which is characterized in that compounds of the formula 15 (II) 0 (II) r1 wherein 1 2 R , R , A and X have the abovementioned meaning and 20 Y represents halogen, in particular fluorine or chlorine, or nitro or C1-C4-a IkyIsuI phony I or C-]-C4-alkylsulphonyloxy, are reacted with amines of the formulae r7 r* \l-h, \l-h, ho—<( n-h, r4-n n-h, r 8 R 9 <- ■isa or R9\ N-H rIO^- 5 wherein R4, R5, R6, R7, R8, R9, R10 and R11 have the abovementioned meaning, dispensing with the use of solvents, at temperatures between 20°C and 200°C, if appropriate under pressure, 10 preferably under 1 - 200 bar. The amines mentioned are the reactant and solvent at the same time in the process according to the invention. If the amines are solid at room temperature, they are melted and the reaction with (II) is then carried out 15 in the melt. It is to be described as decidedly surprising that a) the reaction of (II) with the amines proceeds at a very much higher rate than when an additional solvent is used, that b) the reaction proceeds at lower tempera-20 tures, which means fewer by-products are formed, and that c) in spite of the excess of amine no increased substitution of X takes place. The Last finding is all the more surprising, since in fact if (II) is metered into the amine, an 25 almost infinitely large excess of amine is present at least at the start. The advantages of the process according to the invention are accordingly: - a purer product (fewer by-products) due to the lower .12 7 3 6 reaction temperature - a saving in time due to the higher rate of reaction - economic advantage by dispensing with an additional solvent. 5 The ratio of the compounds (II) to the amines can be 1r1 to 1:50, preferably 1:2 to 1:10 and especially preferably 1:3 to 1:5. The reaction temperature is 20 to 200°C and the range is preferably 80 to 180°C, especially preferably 120 to 160°C. 10 Amines which are preferably used in the process according to the invention are those of the formula wherein R9 NH R10/ 9 10 R and R are identical or different and 15 represent hydrogen or a branched or unbranched alkyl, alkenyl or alkynyl radical which has 1 to 12 carbon atoms and can optionally be substituted by hydroxyl groups, alkoxy, a IkyI mercapto or dialkylamino groups with 1 to 3 carbon atoms in 20 each alkyl radical, the nitrile group, an alkoxy- carbonyl group with 1 to 4 carbon atoms in the alcohol part or an aryl or heteroaryl radical, or furthermore denote Cj-C^-cycIoaIkyI. Amines which are also particularly preferred for 25 the process according to the invention are cyclic amines, such as morpholine, piperidine, thiomorpholine, pyrrolidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)-piperazine, N-formylpiperazine, 2-methyIpiperazine, 1,2-dimethyIpiperazine, cis- and trans-30 2,5-dimethy I piperazine, cis- and trans-2,6-dimethy I-piperazine, 2-ethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine, 2-isobutylpiperazine, 2-piperazin-one, 1-methyI-2-piperazinone, 1-ethyl-2-piperazinone, - 5 - 22 2 7 3 6 2-cyc lohexylpiperazine, 2-phenyLpiperazine, 2-(4-chIoro-phenyL)-piperazine, 2-(4-fluorophenyl)-piperazine, 2 —(4 — bromophenyl)-piperazine, 2-(4-methylphenyl)-piperazine, 2-(4-biphenyl)-piperazine, 2-(4-methoxyphenyl)-piperazine, 5 2-(4-benzyLoxyphenyI)-piperazine, 2-(4-hydroxyphenyI )-piperazine, 2-(4-nitrophenyL)-piperazine, 2-(3-nitro-phenyl )-piperazine, 2-(4-piperidinophenyl)-piperaz ine, 2-(3,4-dimethoxyphenyl)-piperazine, 2-(3,4,5-trimethoxy-phenyl)-piperazine, 2-(3,4-dimethoxy-6-methyl)-piperazine, 10 2-(2-thienyI)-piperazine and 3-aminopyrroLidine and 3-aminomethylpyrrolidine. The quinoLinecarboxyIic acids of the formula (II) are prepared as described below: Example A 15 6-Chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quino I inecarboxyIic acid O 15.7 g (0.65 mol) of magnesium filings are stirred in 40 ml of ethanol and 2 ml of carbon tetra-20 chloride, and after the reaction has started, 103 g (0.64 mol) of diethyl malonate in 80 ml of ethanol and 250 ml of toluene are added dropwises at 50 to 60°. The mixture is subsequently stirred at this temperature for 1 hour and cooled to -5 to -10°, a solution of 138 g 25 (0.65 mol) of 5-chIoro-2 , 3 , 4-1rifIuorobenzcyI fluoride in 63 ml of toluene is added dropwise and the mixture is stirred at 0° for a further hour and left to stand overnight at room temperature. Thereafter, the mixture is warmed at 40 to 50° for a further 2 hours and cooled, 30 and 250 ml of ice-water and 38.5 ml of concentrated - 6 - 22 2 7 3 6 sulphuric acid are added. The organic phase is separated off, the aqueous phase is extracted with 2 portions of 150 ml of toluene and the combined organic phases are washed with saturated sodium chloride solution, dried 5 with sodium sulphate and concentrated. 200 ml of water are added to the residue (the addition of 0.4 g of 4-toluenesulphonic acid is advantageous here) and the mixture is heated under reflux for 5 hours for de-ethoxycarboxylation. It is extracted with 10 3 portions of 200 ml of methylene chloride, the extracts are washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated and the residue is distilled under a high vacuum. 103 g (56.5%) of ethyl (5-chI oro-2,3,4-trifIuoro-benzoyI)-acetate of boiling 15 point 110°/0.9 mm Hg are obtained. 103 g (0.37 mol) of the resulting ester and 83 g (0.56 mol) of triethyl orthoformate are heated at 150 to 160° with 95 g of acetic anhydride for 2 hours and the mixture is then concentrated at 120 to 130° under normal 20 pressure and then under a high vacuum. 115 g (92% of theory) of ethyl 2-(5-chIoro-2,3,4-trifIuoro-benzoyI)-3-ethoxy-acryI ate are obtained as an oil. 14.8 g (0.26 mol) of cycI opropyI amine are added dropwise to 84.1 g (0.25 mol) of this compound in 170 ml 25 of ethanol, while cooling with ice, and the mixture is stirred at room temperature for 2 hours. Thereafter, it is stirred with 170 ml of water and cooled in ice and the precipitate which has separated out is filtered off with suction, washed with water and a little methanol and 30 dried. 47 g (54%) of ethyl 2-(5-chI oro-2,3,4-1rifIuoro-benzoyI)-3-cyclopropyI amino-acryI ate of melting point 71 _ A to 73 are obtained. According to the H-NMR spectrum, a cis-trans mixture is present. 47 g (0.14 mol) of this compound are heated at 35 160 to 170° in 230 ml of dimethylformamide with 9.7 g (0.23 mol) of sodium fluoride for 2 hours. The reaction 22 2 7 3 6 mixture is poured into 400 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 44 g (99%) of ethyl 6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of 5 melting point 169 to 172° are isolated. 33 ml of concentrated sulphuric acid are added to 44 g (0.13 mol) of the quino IonecarboxyIic acid ester in 300 ml of glacial acetic acid and 179 ml of water and the mixture is heated at 150°C for 2 hours. The reac-10 tion mixture is stirred into 400 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 37 g (95% of theory) of 6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of melting point 200 to 204° are iso-15 I ated. Example B 8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quino Iinecarboxy I ic acid O 20 3-Chloro-2,4,5-trifluoro-benzoyl chloride is reacted analogously to Example A, the process passing through the following stages: ethyl (3-chIoro-2,4,5-1rifIuoro-benzoyI)-acetate as the enol (yield: 42%, melting poinc 72-7f), ethyl 2-(3- 25 chI oro-2,4,5-1rifIuoro-benzoyI-3-ethoxy-acryI ate (crude yield: 95% oil), ethyl 2-(3-chIoro-2,4,5-trifIuoro- benzyl)-3-cyclopropyl-aminoacrylate (yield: 67%, melting point 78-80°), ethyl 8-chIoro-1-cyclopropyI-6,7-di- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (yield: 30 85%, melting point 154-157°) and 8-chloro-1-cyclo- - 8 - '2 2 7 3 6 propyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acid (yield: 97.6%, Belting point 189-192°). Example C 6,8-Dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-5 quinolinecarboxylic acid reacted analogously to Example A, the process passing through the following stages: 10 ethyl (3,5-dichIoro-2,4-difIuoro-benzoyI)-acetate (yield: 43%, boiling point 133°/2.5 mm Hg), ethyl 2-(3,5-dichIoro-2,4-dif I uoro-benzoyI)-3-ethoxy-acry I ate (crude yield: 91% oil), ethyl 2-(3,5-dichIoro-2,4-dif I uoro-benzoyI)-3-cycIo-propyI-aminoacryl ate (yield: 96%, melting point 71-74°), 15 ethyl 6,8-dichIoro-1-cycI op ropy I-7-f I uoro-1,4-dihydro-4-oxo-3-quino Iinecarboxy I ate (yield: 97%, melting point 215-217°, with decomposition) and 6,8-dichIoro-1-cycI op ropy I-7-fluoro-1,4-dihydro-4-oxo-4-quinoline-carboxylic acid (yield: 93%, melting point 204-206°). 20 Other quino IinecarboxyIic acids, in particular cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quino-linecarboxy I ic acids, can be prepared in accordance with the following equation: 0 3,5-DichIoro-2,4-difIuoro-benzoyI fluoride is - 9 - 2 2 7 3 6 FVX^-^COCl PyC f ♦ CH- cooc2h5 cooc2h5 Mg(OEt)2 (1) 10 (2) 15 x^cooc2H5 \cooc2h5 II fs/vc " ch p c ooc ?h 5 xc (3) (4) 20 oc2h5 25 (5) 0 II "c-coocphe II — ch f hn (6) 30 cooc2h5 cooh (7) ( ii ) 35 'J<. ' Jf ■ - (-» - -c ^ / o o According to this equation, diethyl malonate (2) is acylated with 2,3,4,5-tetrafluorobenzoyl chloride (1) in the presence of magnesium ethylate to gjv.e, the aroyU- awllable on request). malonate (3) (Organ i cum, 3rd edition 1964, page 438, -copy / 5 Instead of (1), 2,3,4,5-tetrafluorobenzoyl fluoride can also be used. Partial hydrolysis and decarboxylation of (3) in an aqueous medium with catalytic amounts of sulphuric acid or p-toluenesulphonic acid gives a good yield of 10 the ethyl aroylacetate (4), which is converted into ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acryI ate (5) with triethyl o-formate/acetic anhydride. The reaction of (5) with cyclopropylamine in a solvent, such as, for example, methylene chloride, alcohol, chloroform, cyclohexane or 15 toluene, gives the desired intermediate product (6) in a slightly exothermic reaction. The cyclization reaction (6) —> (7) is carried out in a temperature range of about 60 to 300°C, preferably 80 to 180°C. 20 Diluents which can be used are dioxane, dimethyl- sulphoxide, N-methyIpyrroIidone, sulpholane, hexamethyl-phosphoric acid triaaide and, preferably, N,N-dimethyI-formamide. Possible acid-binding agents for this reaction 25 stage are potasium tert.-butanolate, butyl-lithium, Iithium-phenyI, phenyl-magnesium bromide, sodium methyl-ate, sodium hydride, sodium or potassium carbonate and, particularly preferably, potassium or sodium fluoride. It may be advantageous to use an excess of 10 mol % of 30 base. The ester hydrolysis of (7) which takes place in the last step under basic or acid conditions leads to 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylicacid. ^ 35 The 2,3,4,5-tetrafluorobenzoyl chloride^41) used as the starting material for this synthesis route iTa~s-. Iii /-V fi -11 - * a* 22 2 7 3 6 obtained in the customary manner from 2,3,4,5-tetra-fLuoro-benzoic acid, which is known from the Literature (G.G. Yakobson, V.N. Odinokov and N.N. Vorozhtsov Jr., Zh. Obsh. Khim. 36, 139 (1966)), with thionyl chloride. It has a boiling point of 75-80°C/17 mbar. 2,3,4,5-Tetrafluorobenzoyl fluoride has a boiling point of 46 to 47°C/20 mbar(np°: 1.4375). Other quinolinecarboxylic acids can be prepared as follows: - 12 - 22 2 7 3 6 cDCC cocl ^cooc2h5 ♦ ch 2 M<3°Et ^cooc2H5 » CI II x^COOC^H c-ch 2 5 ^OOCjHs iv vii viii 10 15 0 II :-cooc->hc II ii 25 cl^v^cl ch oc2H5 0 II ,IXjC ch2cooc2h5 U>™; IX 20 25 o IYK-coo* HN^ ch vi 30 CI oor 35 II 22S73G According to this equation, diethyl malonate (VII) is acylated with IV in the presence of magnesium alcoholate to give the acylmalonate VIII (Organicum, 3rd edition 1964, page 438. - copy available on request). 5 Partial hydrolysis and decarboxylation of VIII in an aqueous medium with catalytic amounts of p-toluene-sulphonic acid gives a good yield of the ethyl aroyl-acetate IX, which is converted into ethyl 2-(2,4-di-chloro-5-fluorobenzoyl)-3-ethoxy-acrylate X with tri-10 ethyl o-formate/acetic anhydride. The reaction of X with cyclopropylamine in a solvent, such as, for example, methylene chloride, alcohol, chloroform, cyclohexane or toluene, leads to the desired intermediate product VI in a slightly exothermic reaction. 15 The cyclization reaction VI —> II (R^ = alkyl) is carried out in a temperature range from about 60° to 280°C, preferably 80° to 180°C. Diluents which can be used are dioxane, dimethyl-sulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethyl-20 phosphoric acid triamide and, preferably, N,N-dimethyl-fornamide. Possible acid-binding agents for this reaction stage are potassium t-butanolate, butyIIithium, phenyl-lithium, phenyImagnesium bromide, sodium ethylate and, 25 particularly preferably, sodium hydride or potassium carbonate. It may be advantageous to use an excess of 10 aol X of base. The 2,4-dichloro-5-fluoro-benzoyl chloride IV used as the starting material for this synthesis route 30 and the corresponding carboxylic acid, and also the 3-n ioro-4 , 6 -d i c h I o r o t o I u jjge,^ i rfid^o r, frh e2(fer tfgf a -tion of IV are known from European Patent A2-0,078,362]. Preferred compounds which can be prepared by the process according to the invention are described in 35 European Patent A2-0,078,362, page 4, lines 10 to 16, European Patent A-1 0,049,355, Examples 1 to. . el * at 86d - 14 - * . ~ - ■ ^0 \ ■ - ( O b #nd from NZ Patent Specification No 212,272 and US Patent Specification No 4670444. 5 Other compounds which can be prepared by the process according to the invention are: 6-chLoro-1-cycLo-propyl-7-(1,4-diazabicycLoC3.2.1]-oct-4-yL)-1,4-dihydro-4-oxo-3-quino I inecarboxyLic acid, 1-cycLopropyL-7-(1,4-diazabicycLoC3.2.1]-oct-4-yl)-6-fluoro-1,4-dihydro-8-10 methyL-4-oxo-3-quinoLinecarboxyLic acid, 7-(1,4-diaza-bicycLo[3.2.1]oct-4-yL)-6-fLuoro-1-(2-fLuoroethyL)-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 7-(1 ,4-diaza-bicycLoC3.2.1]oct-4-yL)-6-fLuoro-1-(4-fLuorophenyL)-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 1-eyeLopropyL-15 7-(1,4-diazabicycLoC3.2.1]oct-4-yL)-6-fLuoro-1,4-dihydro-4-OXO-1,8-naphthyridine-3-carboxyLic acid, 7-(1 ,4-diaza-bicycloC3.2.1]oct-4-yL)-1-ethyL-6-fLuoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyLic acid, 7-(1 ,4-diaza-bicycLoC3.2.1]oct-4-yL)-1-ethyL-6-fLuoro-1,4-dihydro-4-20 oxo-3-quinoLinecarboxyLic acid, 7-(1,4-diazabicycLo- C3.2.1]oct-4-yL)-9-fLuoro-6,7-dihydro-5-methyL-1-oxo-1H, 5H-benzoCi,j]quinoLine-2-carboxyLic acid, 7-(1,4-diaza-bicycloC3.2.1Doct-4-yLD-6-fLuoro-1-(4-fLuorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyLic acid, ethyL 25 1-cycLopropyL-7-(1,4-diazabicycLoC3.2.1Doct-4-yL)-6-fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLate, 5-methyL-2-oxo-1,3-dioxoL-4-yL-methyL 1-cycLopropyL-7-(1, diazabicycloC3.2.1]oct-4-yL)-6-fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLate, 1-cycLopropyL-7-(1,4-diazabi-30 cycloC3.1.1]hept-4j-yL)-6--fLuoro-1,4-dihydro-4-oxo-3- quinoLinecarboxyLic acid, 1-cycLopropyL-7-(1,4-diazabi-cycLo[3.1.1]hept-4-yL)-6,8-difLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxylic acid, 8-chLoro-1-cycLopropyL-7-(1,4-diazabicycloC3.1.1]hept-4-yL)-6-fLuoro-1,4-dihydro-4-oxo-35 3-quinoL inecarboxyL ic acid, 1-cyc Lopropy L - 7-^74-_d i aza-bieye IoC3.1.1 ]hept-4-yL)-6-fLuoro-1,4-dihydro-8-methyT-~ - 15 Jc 2 2 7 3 6 4-oxo-3-quinolinecarboxyLic acid, 1-cyclopropyl-7-(1,4-diazabicycloC3.1.1]hept-4-yl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyLic acid, methyl 1-cycLo-propyl-7-(1,4-diazabicyclo[3.1.1]hept-4-yL)-6-fluoro-1,4-5 dihydro-4-oxo-3-quino IinecarboxyL ate, 1-cycI opropyI-6,8-difluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3.2.1]-oct-3-yL)-4-oxo-3-quinoLinecarboxyIic acid, 8-chLoro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diaza-bicycLoC3.2.1]oct-3-yl)-4-oxo-3-quinolinecarboxyLic acid, 10 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diaza-bicycloC3.2.1]oct-3-yL)-4-oxo-1,8-naphthyndine-3-carboxylic acid, 1-cycLopropyL-6-fLuoro-1,4-dihydro-7-(3-methyl-3,8-diazabicycloC3.2.1]oct-8-yl)-4-oxo-3-quinolinecarboxyLic acid, 1-cyclopropyL-6,8-difluoro-1,4-15 dihydro-7-(3-methyl-3,8-diazabicycloC3.2.1]oct-8-yL)-4-oxo-3-quinoLinecarboxyLic acid, 8-chIoro-1-cycI opropyI- 6-fluoro-1,4-dihydro-7-(3-methyl-3,8-diazabicyclo[3.2.1]-oct-8-yL)-4-oxo-3-quinoLinecarboxyLic acid, 1-cycLo-propyL-7-(2,5-diazabicycLoC2.2.1]hept-2-yL)-6-fLuoro-1,4- 20 dihydro-4-oxo-3-quinoLinecarboxyLic acid, 1-cyclopropyL- 7-(2,5-diazabicycLoC2.2.1]hept-2-yL)-6,8-difLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 8-chLoro-1-cycLopropyL-7-(2,5-diazabicycLo[2.2.1]-hept-2-yl)-7- fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 1-25 cycLopropyL-7-(2,5-diazabicycLoC2.2.1]hept-2-yL)-6- fLuoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyLic acid, 1-cycLopropyL-6-fLuoro-1,4-dihydro-7-C5-(2-hydroxy-ethyL)-2,5-diazabicycLo[2.2.1]hept-2-yL]-4-oxo-3-quino-LinecarboxyLic acid, 1 -cycLopropyL-6-fLuoro-1,4-dihydro-30 4-oxo-7-C5-(2-oxopropyl)-2,5-diazabicycLoC2.2.1]hept-2-yL]-3-quinoLinecarboxyLic acid, 1-cycLopropyL-6-fLuoro-1,4-dihydro-7-(5-methyL-2,5-diazabicycLoC2.2.1Dhept-2-yL)-4-oxo-3-quinoLinecarboxyLic acid, 1-cycLopropyL-6,8-difLuoro-1,4-dihydro-7-(5-methyL-2,5-diazabicycLoC2.2.1]-35 hept-2-yL)-4-oxo-3-quinoLinecarboxyLic acid, 8-chLoro-1-cyclopropyL-6-fluoro-1,4-dihydro-7-(5-methyL-2,5-diaza- - 16 - t 2 7 3 6 bicycloC2.2.1]hept-2-yl)-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7-(8-ethyl-3,8-diazabicyclo[3.2.1]-oct-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid, 1-cycI op ropyl-6-fIuoro-1,4-dihydro-4-oxo-7-C8-5 (3-oxobutyl)-3,8-diazabicycloH3.2.13oct-3-yl]-3-quino-l inecarboxyLic acid, 7-C8-(4-aminobenzyL)-3,8-diazabi-cycLo[3.2.1]oct-3-yL]-1-cyclopropyl-6-fLuoro-1,4-dihydro-4-oxo-3-quino IinecarboxyIic acid, 1-cycI op ropy I-7-(2,5-diazabicycloC2.2.2]oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo-10 3-quinoLinecarboxyLic acid, 1-cycLopropyL-7-(2,5-diaza-bicycLoC2.2.2]oct-2-yi)-6,8-difLuoro-1,4-dihydro-4-oxo- 3-quinolinecarboxyLic acid, 8-chIoro-1-cycI opropyI-7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-7-fluoro-1,4-dihydro- 4-oxo-3-quino IinecarboxyLic acid, 1 -cycI opropyI-7-(2,5 -15 diazabicyclo[2.2.23oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxyLic acid, 1 -cycI opropyI-6-fLuoro-1,4-dihydro-7-(5-methyl-2,5-diazabicycLo[2.2.2]-oct-2-yL)-4-oxo-3-quinoLinecarboxyLic acid, 1-cyclo-propyl-6,8-difluoro-1,4-dihydro-7-(5-methyl-2,5-diaza-20 bicycLoC2.2.2]oct-2-yL)-4-oxo-3-quinoLinecarboxyLic acid, 8-chLoro-1-cycLopropyl-6-fluoro-1,4-dihydro-7-(5-methyL-2,5-diazabicycLoC2.2.2]oct-2-yL)-4-oxo-3-quinolinecarboxyLic acid, 1-cycLopropyL-7-(3,9-diazabicycLoC3.3.1]-non-3-yl)-6-fLuoro-1,4-dihydro-4-oxo-3-quinolinecarboxy-25 lie acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(7- hydroxy-3,9-diazabicycloC3.3.1]non-3-yl)-4-oxo-3-quino-l inecarboxyLic acid, 1-cyrlopropyl-6-fluoro-1,4-dihydro-7-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yL)-4-oxo-3-quino-l inecarboxyLic acid, 7-(5-aLLyI-2,5-diazabicycIoC2.2.1]-30 hept-2-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cycLopropyL-6-fIuoro-1,4-dihydro-4-oxo-7-(5-propargyl-2,5-diazabicyclo[2.2.2]oct-2-yl)-3-quinolinecarboxyIic acid, 1 -cycI opropyL-7-( 1,4-diazabicycloC3.2.13oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-35 3-quinolinecarboxy I ic acid hydrochloride of melting point 322°C, 1-cycLopropyl-7-(1,4-diazabicycloC3.2.13oct-4-yl)- - 17 - 2 7 3 6 6-fluoro-1,.4-dihydro-4-oxo-3-quinolinecarboxylic acid hemiembonate of melting point from 271°C, 8-chloro-1-cyclopropyl-7-(1,4-diazabicycloC3.2.1]oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid hydro- 5 chloride hydrate of melting point 310°C, 1-cyc lopropyl- 7-(1,4-diazabicyclo[3.2.1]oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid of melting point 275-282°C, 1-cyclopropyl-7-(1,4-diazabicycloC3.2.1]oct-4-yl)-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxyL ic 10 acid hydrochloride of melting point 303-307°C/ 1-cyclo-propyl-7-(1,4-diazabicycloC3.2.1]oct-4-yl)-6-fLuoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxyIic acid hydrochloride of melting point >300°C/ 7-(1,4-diazabicycIo-C3.2.1]oct-4-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-15 3-quinolinecarboxylic acid hydrochloride of melting point 308-312°C, 10-(1,4-diazabicycIoC3.2.1]oct-4-yL)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxacine-6-carboxyIic acid hydrochloride of melting point 355°Cr 7-(1,4-diazabicyclo[3.2.1Joct-4-20 yl)-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 310-314°C/ 1-cyclopropyl-7-(1,4-diazabicycloC3.2. 1 ]-oct-4-yl)-6-fLuoro-1,4-dihydro-8-nitro-4-oxo-3-quinoL inecarboxyLic acid of melting point 215-232°C. 25 The 7-chIoro-1-cycI opropyl-6-fLuoro-1,4-dihydro- 8-nitro-4-oxo-3-quinoLinecarboxyIic acid required for this is obtained via the following stages: a) 2,4-Dichloro-5-fluoro-3-nitro-benzoic acid 30 40 ml of concentrated nitric acid are added drop- wise to 34 ml of concentrated sulphuric acid while cooling with ice and stirring. 20.9 g of 2,4-dichIoro-5- - 18 - 222736 fluorobenzoic acid are introduced in portions into this nitrating mixture, whereupon the temperature rises to 45 - 50°C. The mixture is then heated at 90 - 100°C for a further 3 hours, cooled to room temperature and 5 poured onto 350 ml of ice-water and the precipitate is filtered off with suction and washed with water. The moist crude product is dissolved in 30 ml of hot methanol and 150 ml of water are added to the solution. The precipitate is filtered off with suction in 10 the cold, washed with methanol/water and dried at 80°C in vacuo. 21.2 g of crude 2,4-dichIoro-5-fIuoro-3-nitrobe n z o i c acid are obtained. The product is sufficiently pure for further reactions. A sample recrysta 11ized from toluene/petroleum ether gives crystals of melting point 15 192°C. b) 2,4-DichIoro-5-fIuoro-3-nitro-benzoyI chloride no2 106.6 g of 2,4-dichloro-5-fluoro-3-nitro-benzoic 20 acid are heated at the boiling point under reflux with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then distilled off under normal pressure and the residue is fractionated under a fine vacuum. 104.7 g of 2,4-dichIoro-5-fIuoro-3-nitro-benzoyI 25 chloride pass over at 110 - 115°C/0.08-0.09 mbar. When left to stand, crystals of melting point 35 to 37°C form, c) Ethyl (2,4-dichIoro-5-fIuoro-3-nitro-benzoy I)-acetate - 19 - 22 2 7 3 6 2.1 g of carbon tetrachloride are added to 10.1 g of magnesium filings in 21 ml of ethanol and, when the evolution of hydrogen has started, a mixture of 66.6 g 5 of diethyl malonate, AO ml of ethanol and 150 ml of toluene are added dropwise at 50 - 60°C. The mixture is subsequently stirred at this temperature for 1 hour and cooled to -5 to -10°C, and a solution of 109.2 g of 2,A-dichIoro-5-fIuoro-3-nitro-benzoyI chloride in 50 ml 10 of toluene is slowly added dropwise. Thereafter, the mixture is stirred at 0°C for 1 hour, brought to room temperature overnight and warmed at AO - 50°C for a further 2 hours. A mixture of 160 ml of water and 10.A ml of concentrated sulphuric acid is added to the reaction 15 mixture, while cooling with ice, and the organic phase is separated off. The aqueous phase is extracted with toluene, the combined organic extract is washed with saturated sodium chloride solution and dried with sodium sulphate and the solvent is stripped off. 1AA.5 g of 20 diethyl (2,A-dichIoro-5-fIuoro-3-nitro-benzoyI)-ma Ionate are obtained as a crude product. After addition of 200 ml of water and 0.6 g of A-toluenesulphonic acid, this is heated under reflux for 3 hours, the mixture is extracted with methylene chloride, the extract is dried 25 with sodium sulphate and the solvent is distilled off in vacuo. 118 g of substituted benzoyl acetate are obtained as a crude product. This is sufficiently pure for the further react ions. d) 7-Chloro-1-cyclopropyl-6-fluoro-1,A-dihydro-8-nitro-30 A-oxo-3-quino IinecarboxyIic acid - 20 - } 2 2 7 3 6 o 244.8 g of ethyl (2,4-dichIoro-5-fIuoro-3-nitro-benzoyl)-acetate are heated at 150 - 160°C with 166 g of triethyl orthoformate and 185 g of acetic anhydride 5 for 3 hours. The mixture is concentrated in vacuo to give 270 g of ethyl 2-(2,4-dichIoro-5-fIuoro-3-nitro-benzoyI)-3-ethoxy-acryI ate as an oily residue. 5.9 g of cyclopropylamine are added dropwise to 38 g of this intermediate stage in 80 ml of ethanol while 10 cooling with ice and the mixture is stirred at 20°C for 1 hour. The product which has precipitated is filtered off with suction, after addition of 100 ml of water, and is washed with ethanol/HgO (1:1) and dried. 32.8 g of ethyl 2-(2,4-dichloro-5-fluoro-3-nitro-benzoyl)-3-cyclo-15 propylamino-acrylate of melting point 143 - 146°C are obtained. 3.1 g of 1,8-diazabicycIoC5.4.0]undec-7-ene (DBU) are added to 7.8 g of the abovementioned compound in 30 ml of anhydrous dioxane and the mixture is heated 20 at 100°C for 4 hours. The solvent is distilled off in vacuo, the residue is taken up in methylene chloride/ water, the methylene chloride phase is separated off and dried with sodium sulphate and the methylene chloride is distilled off. 7.2 g of ethyl 7-chloro-1-cyclopropyl-6-25 fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylate are obtained as a crude product. After recrystallization from ace tonitriIe, the pale brown crystals have a melting point of 174 - 175°C. Yield: 6 g . 30 7-(5-Benzyl-2,5-diazabicycloC2.2.1]hept-2-yl)-1- - 21 - 22 2 7 3 6 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of meLting point 205 - 214°C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicycloC3.2.1]oct-3-yl)-4-oxo-3-quinoline-5 carboxyLic acid of meLting point 273 - 278°C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-1,4-diazabicycloC3.2.1]oct-4-yl)-4-oxo-3-quinol inecarboxyLic acid hydrochLoride of meLting point >300°C. 1.1 g of ethyL 1-cyclopropyl-7-(1,4-diazabicyclo-10 C3.2.1]-oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLate of meLting point 196-199°C. 7-(1,4-DiazabicycloC3.2.1]oct-4-yl)-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinoline-carboxyLic acid hydrochloride of meLting point 329-15 3310 C. 7-(1, 4-D iazabi cycloC3.2.13oct-4-yl)-6,8-difluoro-1,4-dihydro-l-methylami no-4-oxo-3-qu inoL inecarboxyL ic acid hydrochLoride of melting point 300-305°C. Other active compounds which can be prepared 20 according to the invention are 6-chloro-7-[3-(4-chloro-phenyl)-1-piperazinyl]-1-cyclopropyl-8-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxyLic acid, 6-chloro-1-cyclo-propyl-8-fluoro-7-C3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinoLinecarboxyIic acid, 7-C3-C4-25 bromophenyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fIuoro-1,4-dihydro-4-oxo-3-quino IinecarboxyIic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-8-C3-(4-methyl-phenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 7-C3-(4-biphenylyl)-1-piperazinyl]-6-chloro-1-cyclo-30 propyl-8-fluoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 6-chloro-1-cyclopropyl-S-fluoro-1,4-dihydro-7-C3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-3-quinoline-carboxylic acid, 6-ch I oro-1-cycIopropyL-8-fluoro-1,4-dihydro-7-[3-(4-hydroxyphenyl)-1-piperazinyl]-4-oxo-3-35 quinolinecarboxylic acid, 8-chloro-1-cycLopropy1-6- fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3- - 22 - 22 2 7 3 6 quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[(4-nitrophenyl)-1-piperazin-yI]-3-quinolinecarboxyLic acid, 8-chloro-1-cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-7-C3-(4-piperidino-phenyl)-1-5 piperazinyL3-3-quinoLinecarboxyLic acid, 8-chloro-1- cycLopropyL-6-fLuoro-1,4-dihydro-4-oxo-7-C3-(3,4-dimeth-oxy-phenyl)-1-piperazinyl3-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4,5-trimethoxy-phenyl)-1-piperazinylD-3-quinoline-10 carboxylic acid, 8-chIoro-1-cycI op ropy I-6-fIuoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quino-LinecarboxyLic acid, 8-chLoro-1-cycLopropyL-6-fLuoro-1,4-dihydro-4-oxo-7-piperidino-3-quinolinecarboxyL ic ac id, 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-15 fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piper-azinyL)-3-quinoLinecarboxyLic acid, 7-(4-acetyL- 1-piper-azinyl)-6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, 7-(4-acetyL-1-piperazinyL)-6-20 chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chLoro-1-cycI op ropy I-8-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quino Iinecarboxy Iic acid, 6-chLoro-1-cycLop ropy I-8-■fluoro-1,4-dihydro-4-oxo-7-morphol ino-3-quinol ine-25 carboxylic acid, 6-chIoro-1-cycI op ropy I-8-fLuoro-1,4- dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxyLic acid and 8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxo-1-piperazin-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 30 According to the invention, the free carboxylic acids are as a rule initially obtained and are then converted into salts, esters, prodrugs and the like by known methods. The compounds which can especially preferably be 35 prepared by the process according to the invention are ciprofloxacin and the corresponding 1-ethyl-piperazine 22 2 7 3 6 derivative. Examples Example 1 606 parts by weight of 1-cyclopropyl-7-chloro-6-5 fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid and 575 parts by weight of piperazine are heated at 150 to 160°C in a suitable reactor for 30 minutes. The reaction mixture is diluted with water, 1-cycI opropyI-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-10 carboxylic acid being obtained in a yield of 71% with a content of about 98%. Example 2 133 parts by weight of 1-cycI opropyI-6,7-di-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid and 15 129 parts by weight of piperazine are reacted as in Example 1. 1-CycLopropyI-6-fIuoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyLic acid is obtained in a yield of 70% with a content of 98.5%. Example 3 20 143 parts by weight of piperazine are heated at 140 to 150°C. 94 parts by weight of 1-cycI opropyI-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyL ic acid are metered into this melt in the course of 20 minutes. The mixture is cooled to 100°C and water is 25 added. 1-CycI op ropy I-6-fLuoro-1,4-dihydro-4-oxo-7-(1-piperazinyI)-3-quinolinecarboxyIic acid thereby crystal-Lizes out in a yield of 78% with a purity of 97.2%. Example 4 150 parts by weight of piperazine are reacted 30 with 102 parts by weight of 1-cycLopropyL-6,7-difIuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxy Iic acid as in Example 3. 1-CycIopropyI-6-fIuoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyLic acid is obtained in a yield of 76% with a purity of 97.5%. 35 Example 5 60 parts by weight of 1 -cyc I opropyL-7-chIoro-6- - 24 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> .2 2 7 3 6 fLuoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid are added to 122 parts by weight of 1-ethyl-piperazine, which has been heated to 140 to 150°C, in the course of 30 minutes. After cooling to 100°C, water is added, 1-5 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1- piperazinyl)-3-quinolinecarboxylic acid crystallizing out in a yield of 76% and a purity of 96.2%. - 25 - 222736 WHAT l/WE CLAIMJS 1. Process for the preparation of compounds of the formula (I) (I) in which R^ represents methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fIuoroethy I , methoxy, amino, methylamino, dimethyl amino, ethylamino, phenyl, 4-fIuorophenyI or 2,4-di- fLuorophenyl, wherein 2 2 • R represents CN or COOR , 2 • R denotes hydrogen, C-| — C4—aLkyL or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, or 2 R represents CONCC-j-C^-alkyl >2/ R ^ represents a cyclic amino group, selected from R7 R6 N- , / <( , HO—^N~, R4-N N- , R8 R 0 N-, S N-, r4"nSn"' N-^N- / v N^^N- LJ • L—l - 26 - '/ f o 222736 wherein R4 represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyI, allyl, propargyl, 2-oxo-propyl, 3-oxobutyl, phenacyl, formyl, CFCI2-S-, CFCl2~S02-^ CH3O-CO-S-, benzyl, 4-aminobenzyl or represents hydrogen or methyl, R^ represents hydrogen, alkyl with 1 to 4 carbon atoms, phenyl or benzyloxymethyl, R^ represents hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyI, ethylaminomethyl, dimethy1 aminomethyI, hydroxyl or hydroxymethyI and Q R represents hydrogen, methyl, ethyl or chlorine, or R^ represents the group R9\ N- R10/ in which 9 10 R and R are identical or different and represent hydrogen or a branched or unbranched alkyl, alkenyl or alkynyl radical which has 1 to 12 carbon atous and can optionally be substituted by hydroxyl groups, alkoxy, alkylmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile group or the alkoxycarbonyl group with 1 to 4 carbon atoms in. the alcohol part, or an aryl or heteroaryl radical, or furthermore denotes Cj-C^-cycIoaIkyI, X represents halogen, 22273G C1-C4-alkylsul.phonyl.oxy and 11 A represents N or C-R , wherein R^ represents hydrogen, halogen, methyl or nitro and R^, together with R1, can form a bridge of the structure -0-CH2-CH-CH3, -S-CH2-CH-CH3 or -CH2-CH2-CH-CH3 characterized in that conpounds of the formula (II) (ii) wherein 1 2 R , R , A and X have the abovementioned meaning and Y represents halogen, or nitro or Ci-C4~alkylsulphonyl or Ci-C4-alkylsulphonyloxy, are reacted with amines of the formulae VH, O-H, HO-^N-H, r4-n n-h, r Vh, s' Vh, r<-n£n-,;, r4-n^^n-h, / \ Nj^N-H x^N-H N^N"H' Cj • f_ I - 28 - ? a r-.-. A,1 (, 'r ii I ;-; J"' >% i \r> *0£i! \ (- v 222736 or r9> N-H R1^ 10 and R 11 have the wherein R4, R5, R6, R7, R8, R9, R abovementioned meaning, dispensing with the use of solvents, at temperatures between 20°C and 200°C, if appropriate under pressure. 2. A process according to claim 1, wherein X represents fluorine or chlorine. 3. A process according to claim 1 or 2, wherein represents fluorine, chorine or bromine. 4. A process according to claim 1,2 or 3, wherein Y represents fluorine or chlorine. _ .. . »any one of claims 1 to.4, . Process according to J characterized in that the compounds of the formula (II) are reacted with the amines in a ratio of 1:1 to 1:50. r.1a,mQ 1 tQ 4> 6. Process according to any one of/characterized in that the compounds of the formula (II) are reacted with the amines in a ratio of 1:2 to 1:10.,, any one of 7. Process according tojClaims lto 6, characterized in that the compounds of the formula (II) are reacted with the amines at 80 to 180°C. c any one of 8. Process according to/Claims 1 to 6, characterized in that the compounds of the formula (II) are reacted with the amines at 120 to 160°C. _ any one of ,9. Process according to/Claims 1 to 8 , characterized in that 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with piperazine without a solvent. /any one of - Claims 1 to 8, characterized in that 1-cy c I opr opy I-6,7-d i f I uoro-1,4-d i hydr o-ks&xjo-Z- quinolinecarboxylic acid is reacted with p ip^rlz^i ne. //-> - 29 - tJL'Ll9?o3 - ft / V E I ■\ I V, <"fk 222736 now am:;oed any one of / 11. Process according to/Claims 1 to 8, characterized / in that 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4- , oxo-3-quinolinecarboxyLic acid is metered into,piperazine which has been heated to 140 to 150°C, the mixture is / cooled, water is added and the reaction product is crystallized out. 12. Process according to Claim H, characterized in that 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3- / / quinolinecarboxylic acid is used as the starting substance. any one of 13. Process according to/Claim's 1 to 8, characterized in that 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid 'is reacted with 1-ethyl-piperazine, B-hydroxyethylpiperazine or 1-methylpiperazine. 14. A process according to claim 1 substantially as herein described or exemplified. ,(D 15. A compound of the formulaJof claim 1, whenever nrepared by a process according to any one of claims 1 to 11. BAYER AKTIENGESELLSCHAFT /IBy Their Attorneys HENRY HUGHES LIMITED - 30 - AS AMENDED 22273G any one of 11. Process according to/Claims 1 to 8, characterized in that 1-cyclop ropyt-7-chLoro-6-fLuoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid is metered into piperazine which has been heated to 140 to 150°C, the mixture is cooled, water is added and the reaction product is crystallized out. 12. Process according to Claim characterized in that 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid is used as til e starting substance. any one of 13. Process according to/Claims 1 to 8, characterized in that 1-cycIopropyl-7-chIoro-6-fIuoro-1,4-dihydro-4-oxo-3-quinolinecarboxyLic acid is reacted with 1-ethyl-piperazine, b-hydroxyethylpiperazine or 1-methyLpiperazine. 14. A process according to claim 1 substantially as herein described or exemplified. BAYER AKTIENjE SELLS CHAFT HENRY HUi By: By Their At/uorneys TED - 30 - </div>