NZ202278A

NZ202278A - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid derivatives

Info

Publication number: NZ202278A
Application number: NZ202278A
Authority: NZ
Inventors: K Grohe; H-J Zeiler; K G Metzger
Original assignee: Bayer Ag
Priority date: 1981-10-29
Filing date: 1982-10-26
Publication date: 1985-02-28
Also published as: JPS6322075A; FI822442A0; NO158018B; FI78689C; NO158018C; JPH04253963A; AU573126B2; JPS6322076A; EP0078362B1; KR840000525A; DK160491C; PH18803A; AU7140587A; JPH0824536B2; IL66243A; AU8576882A; ZA824829B; FI822442L; JPS6362510B2; AU7140687A

Abstract

1. Claims (for the Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, NL, SE) Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids of the formula I see diagramm : EP0078362,P10,F3 in which R denotes hydrogen, methyl, ethyl or beta-hydroxyethyl, and their pharmaceutically usable acid addition salts, alkali metal salts and hydrates, except 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acid and its hydrochloride, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-methylpiperazino)-quinoline-3-carboxylic acid and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-ethylpiperazino)-quinoline-3-carboxylic acid hydroiodide. 1. Claims (for the Contracting State LU) 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids of the formula I see diagramm : EP0078362,P11,F3 in which R denotes hydrogen, methyl, ethyl or beta-hydroxyethyl, and their pharmaceutically usable acid addition salts and hydrates.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £02278 202278 j PrirtvCM* ComataSo Cpectfcatson Filed. ....... Cte- s; C0l3>- W> f.W.'* J . . 2 8 FEB 1985 Pufciicsruon Seta: #••••• P.O. Journal Mo: «•■■■• -?^*7 II ||gl I6S N.Z. NO. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION 25 0CTS982 \ v^AT^ac-tCWS^- " it -JC-T - " l-Cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazino- ,* quinoline-3-carboxylie acids, a process for their preparation and antibacterial agents containing these compounds S 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 statement:- 1 (Followed by 1A.) 7 - itf- The present invention relates to certain new 1-cycl propy1-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, to a process for their production and to their use in feed additives and as antibacterial agents. 5 It has already been disclosed that l-ethyl-6- fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids possess antibacterial properties [J. Med. Chem. 23, 1358 (1980)]. According to the present invention we now provide, 10 as new compounds, 1-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylie acids of the general formula R-N(i) or salts or hydrates thereof, 15 in which R denotes a hydrogen atom or a methyl, ethyl or 8- hydroxyethyl group. The compounds of the present invention have an antibacterial action superior to that of the known quinolone 20 carboxylic acids and azaquinolone-carboxylic acids. The . compounds according to the invention exhibit their superior antibacterial activity against both gram positive and gram negative bacteria, including Pseudomonas aeruginosa. According to the present invention we further 25 provide a process for the production of a compound of the invention in which (a) 7-chloro-l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-quino line-3-carboxylie acid of the formula coor1 , s (II) Ltt=±=23=553- <L ^ c '— a . - 2 - in which R1 denotes a hydrogen atom, is reacted with piperazine or a piperazine derivative of the general formula 5 H0 (III) in which R has the meaning given above, or (b) a compound of the formula (II), as given in reaction variant (a) in which R^" denotes an alkyl group, is reacted 10 with a compound of formula (III) as defined in reaction variant (a), if appropriate in the presence of an acid-binding agent (such as triethylamine, 1,4-diaza-bicyclo[2,2,2]-octane or 1,8-diaza-bicyclo[5,4,0]undec-7-ene) and the 7-piperazino-quinolone-3-carboxylic acid ester obtained is 15 hydrolysed under alkaline conditions to give a compound of formula (I), and the compound of formula (I) obtained by reaction variant (a) or (b) is converted, if desired, into a salt or hydrate thereof. 20 The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethyl-formamide, hexamethy1-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between 20 and 200°C, preferably between 80 and l80°C. 25 The reaction variants can be carried out under normal pressure, but also under elevated pressure, in particular in the case of a low-boiling solvent. In general, the reaction is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar. 30 In carrying out reaction variants 1 to 5 mol of alky1-piperazine (in the case of piperazine 1 to 15 mol), preferably 2 to 3 mol of alkylpiperazine (in the case of piperazine 5 to 10 mol), are employed per mol of carboxylic acid, or carboxylic acid ester of formula (II). Lo A 21 355 (7)!'■ . .. ;? -7 o - 3 - Among the new l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7~piperazo-quinoline-3-carboxylic acid salts and hydrates of the invention those salts or hydrate that are pharmaceutical^ acceptable are particular^ important and 5 are preferred. The new free l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-piperazino-quinoline-3~carboxylic acids of the general formula (I) and their salts and hydrates can be interconverted in any suitable manner; methods for such 10 interconversion are known in the art. Thus the 7-piperazino-quinolone-3~carboxylic acids of formula (I) obtained can, if required, be converted into a salt using an organic or inorganic acid. Examples of acids which are suitable for salt formation are hydrohalic 15 acids, such as hydrochloric acid, hydrobromic acid, hydro-iodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid. If 7-chloro-l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are 20 used as starting materials in reaction variant (a), the course of the reaction is illustrated by the following equation: 0 F^^X^COOH + 2CH3NWNH ch3-N^J 0 cooh ch n xHCl The following may be mentioned individually as active compounds according to the present invention : 25 7-piperazino-, 7-(4-methylpiperazino)~, 7-(4-ethylpiperazino)~, 7-(4-g-hydroxyethylpiperazino)-1-cyclopropy1-6-fluoro-1,4- -lu a 21 202278 - 4 - dihydro-4-oxo-quinoline-3~carboxylie acid and pharmaceutical^ tolerated acid addition salts or alkali metal salts of these compounds. The starting compounds of formula (II) can be 5 prepared via a malonic ester synthesis, according to the following equation: ^cooc2h5 f^lr000^ ci^Xi ♦ » cl3SCcl ^ooc2a5 ^cooc2h5 iv vii viii F CI 0 )1 c-c-COOC2H5 (I 3 ch 1 ic< '2H5 x o- nh- V :i ci 0 11 c-ch2 cooc2 h5 ix f CI o II ^C-COOR1 II -1 ^CH hn' vi 0 f il ^coor1 U- II 2022 78 _ - 5 - According to this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (XV) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organicum, 3rd edition 5 1964, page 438). The ethyl aroylacetate of formula (IX) is obtained in good yield by partial hydrolysis and decarboxylation of the compound of formula (VIII) in an aqueous medium containing a catalytic amount of p-toluenesulphonic acid, 10 and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-dichloro-5~fluoro-benzoyl)-3~ethoxy- acrylate of formula (X). The reaction of the compound * of formula (X) with cyclopropylamine in a solvent (such as methylene chloride, alcohol, chloroform, cyclohexane or 15 toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction. The cyclisation reaction VI II (R1 = alkyl) is carried out in a temperature range from 60° to 280°C, preferably 80° to l80°C. 20 Dioxane, dimethylsulphoxide, N-methy1-pyrrolidone, sulpholane, hexamethyIphosphoric acid triamide and preferably N,N-dimethylformamide can be used as diluents. Potassium t-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium ethylate and 25 particularly preferably sodium hydride or potassium carbonate are suitable acid-binding agents for this reaction stage. It can be advantageous to employ an excess of 10 mol$ of base. The 2,4-dichloro-5~fluoro-benzoyl chloride of 30 formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic acid, and the 3-fluoro-4,6-dichlorotoluene of formula (XI) required for the preparation of formula (IV) were not yet known in the literature and form a further subject of the present invention. 35 The equation below shows the preparation of these "Le a il 3 [j$ 2022 7« - 6 - precursors or intermediate products, starting from 2,4-dichloro-5-methyl-aniline of formula (XII). CI a NH, CI XII 1. NaN02, H30 hn(ch3)2 N=N-N(CH3)2 HF CHn CI xi cc1, I lci xiii CI cooh CI I xv coci (IV) CI CI j> i\ ?r zm 202278 - 7 - According to this equation, 2,4-dichloro~5-methyl-aniline of formula (XII) is diazotised by means of NaNO^j and the resulting diazonium salt is converted into the triazene of formula (X11 a ) , using dimethyl amine. 5 The triazene of formula (X11 a) is dissolved in excess anhydrous HF. In this step, the triazene is cleaved to give 2,4-dichloro-5~methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is cleaved thermally at 130 to 140° to give 3" 10 fluoro-4,6-dichlorotoluene XI, being split off (Yield: 11.1% of theory). The 3-fluoro-4,6-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to l60°C, under UV irradiation, to give 2,4-dichloro-5-fluoro-1-15 trichloro-methylbenzene of formula (XIII). The hydrolysis of the compound of formula (XIII) with 95 per cent sulphuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid of formula (XV), which is converted with thionyl chloride into the carboxylic acid-chloride 20 of formula (IV). The compounds according to the invention are distinguished by a particularly good antibacterial action against gram positive and gram negative bacteria, in 'particular in comparison with the known compounds 25 as can be seen from the table/below. o a- ri> V.J \n * ^ i ^ vi o < erf *v/. o/' o FD1_/ cooh f UN ^ :ooh N C2H5 (disclosed in U.S. Patent No. 4,146,719) joooh HN N (compound according to the invention, of the formula I (R = H) Staphylococcus 8 1 0.25 - 0.5 aureus 133 E. coli A 26l " . 1 0.125 0.06 E. coli Neum. . . 1 0.2b 0.06 Klebsiella 8085 1 O.25 0.06 Proteus 1017 0.5 0.06 0.03 Pseudomonas 4 1 0.5 aeruginasa W i co I Agar dilution test DST (dexhase sensitivity test) medium; 1-2 x 10^ germs/plate lO to to *"v7 00 202278 - 9 - As stated above, the invention also relates to the use in human and veterinary medicine as antibacterial agents of the compounds of the invention. The present invention provides a pharmaceutical 5 composition containing as active ingredient a compound of. the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less tha!n 350) except in the presence 10 of a surface active agent. The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or physiologically isotonic aqueous solution. 15 The invention also provides a medicament in dosage unit form comprising a compound of the invention. The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories 20 comprising a compound of the invention. "Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically 25 discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. 30 Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively. 35 The pharmaceutical composition according to the Liu A 21 353 ^ tf]"!) r! ^ - 10 - invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, 5 syrups, granulates or powders. 'The. diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, 10 and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; 15 (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium 20 and magnesium stearate and solid polyethyl glycols. The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be 25 so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes. 30 The ingredient can also be made up in microencap sulated form together with one or several of the above-mentioned diluents. The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, 35 be the usual water-soluble diluents, such as polyethylene A 21 123 M 2 ^ <. -o ( - 11 - glycols and fats (e.g. cocoa oil and high esters (e.g. C-^-alcohol with C^g-fatty acid)) or mixtures of these diluents. The pharmaceutical compositions which are ointments, 5 pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. 10 The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, 15 contain the usual propellants, e.g. chlorofluorohydrocarbons. The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except 20 in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene 25 glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof. For parenteral administration, solutions and emulsions 30 should be sterile, and, if appropriate, blood-isotonic. The pharmaceutical compositions which are.suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, 35 polyoxyethylene sorbite and sorbitane esters), micro- Lu1 A 21 £5^= 2022 78 crystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof. All the pharmaceutical compositions according to the invention can also contain colouring agents 5 and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin). In addition to a compound of the invention, the pharmaceutical compositions and medicaments according 10 to the invention can also contain other pharmaceutical^ active compounds. They may also contain a plurality of compounds of the invention. Any diluent in the medicaments of the present invention may be any of those mentioned above in relation 15 to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of molecular weight less than 200 as sole diluent. The discrete coherent portions constituting the medicament according to the invention will generally 20 be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may -be made up 25 for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent. The production of the above-mentioned pharmaceutical 30 compositions and medicaments is carried out by any method known in the art, for example, by mixing.the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into, the medicament (e.g. tablets). 35 This invention further provides a method of combating 202278 (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent 5 or in the form of a medicament according to the invention. The present invention further provides a feed additive comprising an active compound of the present invention in admixture with a feed additive-carrier. The Examples which follow illustrate the inven-10 tion further. Example 1 0 ch3 n~V cooh A mixture of 20 g of 7-chloro-l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 15 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to l40°C for 1.5 hours The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of 1^0, The suspension was filtered under suction, and the residue was 20 rinsed with HgO, dried in a vacuum drying cabinet at 80°C over CaClg, and recrystallised from glycol monomethyl ether. 14.5 g of 1-cyclopropy1-6-fluoro-1,4-dihydro-7-(4-methylpiperazino)-4-oxo-quinoline-3_carboxylic acid which decomposes at 248 to 250°C were obtained. 25 Example 2 :ooh ■ hoch2 ch, -n A suspension of 2.81 of 7-chloro-l-cyclopropyl- lm a- 2t 355 202278 - 14 - 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5-2 g of N-0-hydroxyethylpiperazine in 25 ml of di-raethylsulphoxide was heated at 135 to l40°C for 2 hours. The solvent was distilled off under a fine vacuum, the 5 residue was boiled for a short time with 20 ml of and left to stand overnight at room temperature, and the precipitate was filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaC^ at 80°C . 2.1 g of 1-cyclopropy1-6-fluoro-10 1,4-dihydro-4-oxo-7-(4-3-hydroxyethylpiperazino)-quino-line-3-carboxylic acid which decomposed at 237 to 239°C were obtained. Example 5 0 :ooh h-n v 15 A mixture of 19.7 g of 7-chloro-l-cyclopropy1-6- fluoro-1,4-dihydro-4-oxo-quinoline-3~carboxylie acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl-sulphoxide was heated at 135 to 140°C for 2 hours. The solvent was distilled off under a fine vacuum, and the 20 residue was suspended in H^O, filtered off under suction and washed with water. For further purification, the moist crude product was boiled with 100 ml of water, filtered off under suction at room temperature, washed with HgO and dried over CaC^ in a vacuum drying cabinet at 25 100°C until its weight remained constant. 19.6 g of 1-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7_piperazino-quinoline-3-carboxylic acid which decomposed at 255 to 257°C were obtained. The compound prepared according to Example 3 was 30 dissolved in 50 ml of hot 10 per cent hydrochloric acid. 150 ml of ethanol were added to the filtered solution, the L u a 21 J&Z 2 78' - 15 - mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100°C. 18.5 g of 1-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid 5 hydrochloride were obtained as colourless crystals which decomposed at 308 to 310°C. Example 4 a) A mixture of 1.2 g of l-cyclopropyl-6-fluoro-1,4-10 dihydro-4-oxo-7-piperazipo-quinolihe-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N,N-dimethylformamide was heated at 70 to 80°C for 2.5 hours. The solvent was distilled off in vacuo, and the residue was suspended in water. The product was filtered 15 off under suction, rinsed with 1^0 and pressed on clay. 1.15 g of l-cyclopropyl-6-fluoro-7-(ethylpiperazino)-1,4-dihydro-4-oxo-quinoline~3-carboxylic acid hydro-iodide which'decomposes at 306°C were obtained. b) The 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-20 4-oxo-quinoline-3~carboxylie acid used as the starting material was prepared as follows: '24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture 25 of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was added ci1 op wise, a vigorous reflux being observed. After the reaction had ceased, the mixture was heated at the boil for a further 2 hours and was cooled with dry ice/acetone at -5°C 30 to -10°C and a solution of 227.5 g of 2,4-dichloro-5- La A 21 353, 202278 - 16 - fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mixture was stirred for 1 hour at 0°C to -5°C and was allowed to reach room temperature overnight, and a mixture of 400 5 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while cooling with ice. The phases were separated and were extracted twice with ether. The combined ether solutions were washed with saturated NaCl solution and dried with Na2S0^, and the solvent was 10 stripped off in vacuo. 349-5 g of diethyl 2,4-di-chloro-5-fluoro-benzoyl-malonate were obtained as the crude product. 0.15 g of p-toluenesulphonic acid was added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-15 benzoyl-malonate in 50 ml of water. The emulsion was heated at the boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride, the combined solutions were washed once with saturated NaCl solution and dried with Na2S0^, and 20 the solvent was distilled off in vacuo. Fractionation of the residue under a fine vacuum gave 21.8 g of ethyl 2,4-dichloro-5~fluoro-benzoyl acetate IX of boiling point 127 to 142oC/0.09 mbar. A mixture of 21.1 g of ethyl 2,4-dichloro-5~ 25 fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150°C for 2 hours. The volatile constituents were then distilled off under a waterjet vacuum and finally under a fine vacuum, at a bath temperature of 120°C. 25.2 g of crude 30 ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate remained. It was sufficiently pure for the further reactions. 4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluoro-35 benzoyl)-3-ethoxy-acrylate in "80"ml of ethanol while </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 20227t - 17 - cooling with ice and stirring. When the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/ 5 petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 = C2H5^ of melting point 89 to 90°C were obtained. 3.44 g of 80 per cent sodium hydride were added in portions to a solution of 31*9 g of ethyl 2-(2,4-dichloro-10 5~fluoro-benzoyl)-3-cyclopropylamino-acrylate (R"'" = C^H^) in 100 ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue 15 (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H20. The filtrate was then acidified to pH = 1 to 2 with semiconcentrated hydrochloric 20 acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in vacuo at 100°C. 27.7 g of 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (R1 = H) of melting point 234 to 237°C were obtained in 25 this manner. The present invention also comprises pharmaceutic-ally acceptable bioprecursors of the active compounds of the present invention. For the purposes of this specification the term 30 'pharmaceutical^ acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the 35 active compound. , o ^ 7 T7 - 18 - WHAT WE CLAIM IS: 1. Compounds which are l-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of the general formula in which R denotes hydrogen, methyl, ethyl or j3-hydroxy-ethyl. 10 2. 1-Cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7~ piperazino-quinoline-3-carboxylic acid. 3. l-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7~(4-methylpiperazino)-quinoline-3-carboxylie acid. 4. l-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7~(4-15 ethylpiperazino)-quinoline-3-carboxylie acid. 5. 1-Cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7-(4-6-hydroxyethyl-piperazino)-quinoline~3-carboxylie acid. 6. A process for the production of a compound according to claim 1, in which 20 (a) 7--chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-quinoline-3-carboxylie acid of the formula (II) derivative of COOR1 in which R"^ denotes a hydrogen atom, 25 is reacted with piperazine or a piperazine the general formula Be A 11 ^4- - 202278 - 19 - R-i/ "j>TH (III) in which R has the same meaning as in claim 1, or (b) a compound of formula (II), as given, in reaction 5 variant (a), in which R1 denotes an alkyl group, is reacted with a compound of formula (III), as defined in reaction variant (a), and the 7-piperazo-auinclone-3-carboxylie acid ester obtained is hydrolysed under alkaline conditions to give a compound cf formula (I), 10 and the compound of formula (I), obtained by reaction variant (a) or (b) is converted, if desired, into a salt or hydrate thereof. 7. A process according to claim 6 (a), characterised in that the reaction is carried out in the presence of a 15 diluent. 8. A process according to claim 6 (a) or 7, characterised in that the reaction is carried out at a temperature between 20 and 200°C. 9. . A process according to claim 6 (b), characterised 20 in that the reaction is carried out in the presence of an acid-binding agent. •' 10. A process for the production of a compound according I to claim 1, substantially as described in any of Examples ' 1 to 4. 25 11. Compounds according to claim 1 whenever prepared by a process according to any of claims 6 to 10. 12. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 5 and 11 in admixture with a solid or liquefied 30 gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. 13. A pharmaceutical composition containing as an active \ i V - 20 - 202278 ingredient a compound according to any one of claims 1 to 5 and 11 in the form of a sterile or physiologically isotonic aqueous solution. 14. A medicament in dosage unit form comprising a compound according to any one of claims 1 to 5 and 11. 15. A medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a compound according to any one of claims 1 to 5 and 11. 16. A feed additive comprising an active compound according to claim 1 in admixture with a feed additive-carrier. 17. A compound according to claim 1 for use in combating bacterial diseases. BAYER AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By: t v, I </div>