IE53709B1 - 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, a process for their preparation and anti-bacterial agents containing these compounds - Google Patents
1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, a process for their preparation and anti-bacterial agents containing these compoundsInfo
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- IE53709B1 IE53709B1 IE1606/82A IE160682A IE53709B1 IE 53709 B1 IE53709 B1 IE 53709B1 IE 1606/82 A IE1606/82 A IE 1606/82A IE 160682 A IE160682 A IE 160682A IE 53709 B1 IE53709 B1 IE 53709B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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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
FEDERAL REPUBLIC OF GERMANY.
Price SOp 3 7 0 9 .-.202 The present invention relates to certain new 1cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acids, to a process for their production and to their :ise in feed additives and as antibacterial agents.
It has already been disclosed that l-ethyl-6fluoro-l,4-dihydro-4-oxo-7-piperazino-guinoline-3carboxylic acids possess antibacterial properties [J. Med. Chert. 21, 1358 (1980)].
According to the present invention we now provide, as new compounds, l-cyclopropyl-6-fluoro-l,4-dihydro-4oxo-7-piperazino-quinoline-3-carboxylic acids of the in which R denotes a hydrogen atom or a methyl, ethyl or βhydroxyethyl group, and their pharmaceutically usable acid addtion salts, alkali metal salts and hydrates, except l-cyclopropyl-6-fluoro-l,4-dihydro 4-oxo-7-piperazino-quinoline-3-carboxylic acid and 3 7 0 9 its hydrochloride, l-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-(4-methylpiperazino)-quinoline-3carboxylic acid and l-cyolopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(4-ethylpiperazino)quinoline-3-car5 boxylic acid hydriodide.
The compounds of the present invention have an antibacterial action superior to that of the known quinolone-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 provide a process for the production of l-cyclopropyl-615 fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3carboxylic acids of the formula (I,, in which 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of the formula (II) 3 7 0 9 in which R1 denotes a hydrogen atom, is reacted with piperazine or a piperazine derivative of the general formula (III) in which R-N^H >_f (III) R has the meaning given above .
Furthermore, a compound of the formula (II), as given above in which R1 denotes an alkyl group, can be reacted with a compound of formula (III) as defined above, if appropriate in the presence of an acid-binding agent (such as triethylamine, l,4-diaza-bicyclo[2. 2. 2]octane or l,8-diaza-bicyclo[5.4.0]undec-7~ene) and the 7piperazino-quinolone-3-carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (I).
The reaction of (II) (R1=H) with (III) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethylformamide, hexamethyl-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between 20 and 200°C, preferably between 80 and 18O°C.
The reaction 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.
In carrying out the reaction 1 to 5 mol of alkyl-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 Ii. 3 7 0 9 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 acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.
If, for exanple, 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4oxo-quinoline-3-carboxylic acid and methylpiperazine are 10 used as starting materials in the reaction of (II) with (III), the course of the reaction is illustrated by the following equation: CH3OHJ xHCl The following may be mentioned individually as active compounds according to the present invention: 7-(4- ethvlpiperazino )- and 7-(4-B-hydroxyethylpiperazino)-l-cyclopropyl-6-fluoro-l,4’ 53709 dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceutically tolerated acid addition salts or alkali metal salts of these compounds.
The starting compounds of formula (II) can be prepared via a malonic ester synthesis, according to the following equation: ΧΓ COOCjHj + cC 'V'C00C2H5 II C-CH A,' IV VII VIII COOCjHj C00C2H5 It C-C-COOC,Hs II CH he.
IX aHs C-CH2C00C2H5 Cl II According to this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (IV) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organicum, 3rd edition 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, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxyacrylate of formula (X). The reaction of the compound of formula (X) with cyclopropylamine in a solvent (such as methylene chloride, alcohol, chloroform, cyclohexane or 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 28O°C, preferably 80° to 18O°C.
Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphoric acid triamide and preferably N,N-dimethyIformamide can be used as diluents.
Potassium t-butanolate, butyl-lithium, lithiumphenyl, phenyl magnesium bromide, sodium ethanolate and 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 formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic acid, and the 3-fluoro4,6-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.
The equation below shows the preparation of these S 3 7.09 precursors or intermediate products, starting from 2,4dichloro-5-methyl-aniline of formula (XII).
Cl 1" F |xm Cl COOH Γ COCI (W) Cl Cl According to this equation, 2,4-dichloro~5methyl-aniline of formula (XII) is diazotised by means of NaN02, and the resulting diazonium salt is converted into the triazene of formula (Xlla), using dimethyl amine.
The triazene of formula (Xlla) 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 3fluoro-4,6-dichlorotoluene XI, Ng being split off (Yield: Π.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-ltrichloro-methylbenzene of formula (XIII).
The hydrolysis of the compound of formula (XIII) with 95 per cent sulphuric acid leads to 2,4-dichloro-5fluoro-benzoic acid of formula (XV), which is converted with thionyl chloride into the carboxylic acid-chloride 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 compounds of German Patent Application P 30 33 157.8 of 3.9.1980 and DE-OS (German Published Specification) 2,804,097, as can be seen from the table below. 53708 o P Φ Λ bOP C Ό OS £1 O * u o c o OK (fl Ή *-» P Ό G H G Φ 3 > Cd O G H ft«rt 3 ε ε ο Φ ο Λ Ο ^Ρ ft in x CN U ft CO ο ι -3 ω φ Q χ; <-* G-rt C •Η Η Ο <· ·Η S 3 p cr φ ft cd ο co ο · ο βτΐ«· Η cd ft Ο ο 6·Η0ό CO k Ο * •Η ο Φ (\| 3 α ft ''—'00 G Λ G ε Ο k ·Η ft Φ Ρ Ο Ο cd ο co ft-rt · Ο Η t-O ftlACO CJ ftrH · <3? o\ φ m · η p mm ft G S Φ O cd p m κ cd W ft a cn O I m KQ Ό KO m CJ o O O o in O o o o o o in CJ in ir ko ft CJ CJ o ft Q o O o ι—I in 00 (—1 ft ft O .sr in CO co 3 ft • O o KO ε co t— o CJ 3 ft co o m Φ cd O cd cd □ m 2 ft irt G co Ο H ft o cd ft •rt •rt Φ CO ε c >a ca (—t ft •rt 3 o «rt X3 3 O 0 03 Φ 3 bfl S4 ? O o XJ P 3 3 Cd Φ 0 Φ k P 3 • • ft ca Φ co cd ω ω W ft ft cd Φ P cd ft ft ε Φ bO m o ft CJ I ft 3 •rt 3 Φ ε P co Φ P >, P •rt > •rt P P •rt ca CO Φ G P Φ 03 G O Φ •rt CO P cd 3 XJ ft κ •rt φ 3 3 Sh cd bO CO Q As stated above, the compounds of the invention can be used in human and veterinary medicine as antibacterial agents.
The present invention provides a pharmaceutical 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 than 350) except in the presence 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.
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 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 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.
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.
The pharmaceutical composition according to the 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, 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, 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; (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 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 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.
The ingredient can also be made up in microencapsulated form together with one or several of the abovementioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene 537 0 9 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, 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.
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, 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 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 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 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, surfaceactive agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro14 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 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 to the invention can also contain other pharmaceutically 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 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 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 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 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).
This invention further provides a method of combating ι (including prevention, relief and cure of) the abovementioned 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 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 invention further. Example 1 CH, N~\COOH A mixture of 20 g of 7-chloro-l-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-quinoline-3~carboxylie acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to 14O°C for 1.5 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of H20. The suspension was filtered under suction, and the residue was rinsed with HgO, dried in a vacuum drying cabinet at 80°C over CaClj, and recrystallised from glycol monomethyl ether. 14.5 g of l-cyclopropyl-6-fluoro-l,4-dihydro7-(4-methylpiperazino)-4-oxo-quinoline~3-carboxylic acid which decomposes at 248 to 25O°C were obtained.
Example 2 F.
H0CHa CHa -iOi' OOH A suspension of 2.81 of 7-chloro-l-cyclopropyl16 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylie acid and 5.2 g of N-S-hydroxyethylpiperazine in 25 ml of dimethylsulphoxide was heated at 135 to 14O°C for 2 hours. The solvent was distilled off under a fine vacuum, the residue was boiled for a short time with 20 ml of HgO and left to stand overnight at room temperature, and the precipitate Vias filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaCl2 at 80°c. 2.1 g of l-cyclopropyl-6-fluoro10 l,4-dihydro-4-oxo-7-(4-S-hydroxyethylpiperazino)-quinoline-3-carboxylic acid which decomposed at 237 to 239°C were obtained.
Example 3 A mixture of 19.7 ε of 7-chloro-l-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylie acid, .1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide was heated at 135 to l40°C for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H20, 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 H20 and dried over CaClg in a vacuum drying cabinet at 100°C until its weight remained constant. 19.6 g of 1-oyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid which decomposed at 255 to 257°C were obtained.
The compound prepared according to Example 3 was dissolved in 5θ ml of hot 10 per cent hydrochloric acid. 150 ml of ethanol were added to the filtered solution, the 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 l-cyclopropyl-6-fluoro-l,4dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride were obtained as colourless crystals which decomposed at 308 to 310°C.
Example 4 COOH x Hi a) A mixture of 1,2 g of l-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-piperazipo-quinoline-3-carboxylie acid, 1.13 g of ethyl iodide, O.73 g of triethylamine and 20 ml of Ν,Ν-dimethyIformamide 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 off under suction, rinsed with H^O and pressed on clay. 1.15 g of l-cyclopropyl-6-fluoro-7-(ethylpiperazino)l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydroiodide which decomposes at 3O6°C were obtained. b) The 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro4-oxo-quinoline-3-carboxylic 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 of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was added dropwise, 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/aeetone at -5°C to -10°C and a solution of 227.5 g of 2,4-dichloro-553709 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 ml of ice-water and 25 ml of concentrated sulphuric acid v:as 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 NagSO^, and the solvent was stripped off in vacuo. 349.5 g of diethyl 2,4-dichloro-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 S of crude diethyl 2,4-dichloro-5-fluoro15 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 CH2C12 solutions were washed once with saturated NaCl solution and dried with Na2S0^, and 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 142°C/O.O9 mbar.
A mixture of 21.1 g of ethyl 2,4-diehloro-525 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 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-fluoro35 benzoyl)-3-ethoxy-acrylate in'80'ml of ethanol while 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/ petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 - C^H^) 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-dichloro5- fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 = ) 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 (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 H^O. The filtrate was then acidified to pH = 1 to 2 with semiconcentrated hydrochloric 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-ehloro-l-cyclopropyl6- fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (R^ - H) of melting point 234 to 237°C were obtained in this manner.
Claims (23)
1. A l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7piperazino-quinoline-3-oarboxylio acid of the general formula (I) (i) in which R denotes hydrogen, methyl, ethyl or -hydroxyethyl, or a pharmaceutically usable acid addition salt, alkali metal salt or hydrate thereof, except l-cyelopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-guinoline-3-carboxylic acid and its hydrochloride, l-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-(4-methylpiperazino)-quinoline-3carboxylic acid and l-oyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(4-ethylpiperazino)quinoline-3-oarboxylio acid hydriodide.
2. l-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4ethylpiperazino)-quinoline-3-carboxylio acid.
3. l-Cyolopropyl-6-fluoro-l,
4. -dihydro-4-oxo-7-(4- hydroxyethyl-piperazino)-quinoline-3-carboxylic acid. 20 4. A process for the production of a l-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-earboxylic acid of the general formula (I) given and defined in Claim 1 or an aoid addition salt, alkali metal salt or hydrate thereof, which comprises reacting piperazine or methyl-, ethyl-, or -hydroxyethyl piperazine with 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylio aoid of the formula (II) 5370$ (II) SI ο Cl COOH at a temperature between 20 and 200°C and, if desired, converting the compound of formula I thus obtained into an acid addition salt, alkali metal salt or hydrate thereof.
5. A process according to claim 4, wherein the reaction is carried out in the presence of a diluent.
6. A compound according to claim 1, which is any one of those specifically hereinbefore mentioned. 10
7. A process for the production of a compound according to claim 1, substantially as described in any of Examples 1 to 4.
8. A compound according to claim 1, whenever prepared by a process according to any one of claims 4, 5 or 7. 15
9. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims l to 3 and 6 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 except in 20 the presence of a surface-active agent.
10. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 3 and 6 in the form of a sterile or physiologically isotonic aqueous solution. 537 09
11. A medicament in dosage unit form comprising a compound according to any one of claims l to 3 and 6.
12. A medicament in the form of a tablet, pill, dragee, capsule, ampoule, or suppository comprising a compound according to any one of claims 1 to 3 and 6.
13. A compound according to claim 1 for use in combating bacterial diseases.
14. Use of a compound of the formula I according to claim 1 for the preparation of a medicament.
15. Use of a l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7piperazinoquinoline-3-carboxylic acid of the formula I in which R denotes hydrogen, methyl, ethyl or 6-hydroxyethyl, or a pharmaceutically usable acid addition salt, alkali metal salt or hydrate thereof, for the preparation of a medicament which is active against bacteria selected from Staphylococcus aureus 133, £. coli A 261, £. coll Neumann, Klebsiella 8085, Proteus 1017 and Pseudomonas aeruginosa W.
16. Use of a compound of the formula I according to claim 1 as an additive for animal feedstuffs.
17. An animal feed or animal feed premix containing a compound of the formula X according to claim l.
18. l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-chloroquinoline-3-carboxylic acid.
19. A pharmaceutical composition according to claim 9 or 10, substantially as hereinbefore described.
20. Use according to claim 14 of a compound of tbe formula (I) according to claim 1, substantially as hereinbefore described.
21. Use according to claim 16 of a compound of the formula (X) according to claim 1, substantially as hereinbefore described.
22. · An animal feed or animal feed premix according to claim 17, substantially as hereinbefore described.
23. Use of a compound according to any one of claims 1 to 3 and 6 either alone or in admixture with a diluent or in the form of a medicament according to claim 11 or 12 for combating bacterial diseases in a human or non-human animal.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813142854 DE3142854A1 (en) | 1981-10-29 | 1981-10-29 | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE821606L IE821606L (en) | 1983-04-29 |
| IE53709B1 true IE53709B1 (en) | 1989-01-18 |
Family
ID=6145081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1606/82A IE53709B1 (en) | 1981-10-29 | 1982-07-01 | 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, a process for their preparation and anti-bacterial agents containing these compounds |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0078362B1 (en) |
| JP (5) | JPS5874667A (en) |
| KR (1) | KR870000895B1 (en) |
| AT (1) | ATE23040T1 (en) |
| AU (3) | AU561103B2 (en) |
| CA (1) | CA1218067A (en) |
| DD (1) | DD202560A5 (en) |
| DE (2) | DE3142854A1 (en) |
| DK (2) | DK160491C (en) |
| ES (1) | ES516921A0 (en) |
| FI (1) | FI78689C (en) |
| GR (1) | GR77707B (en) |
| HU (1) | HU187580B (en) |
| IE (1) | IE53709B1 (en) |
| IL (1) | IL66243A (en) |
| LU (1) | LU88325I2 (en) |
| NO (2) | NO158018C (en) |
| NZ (1) | NZ202278A (en) |
| PH (1) | PH18803A (en) |
| ZA (1) | ZA824829B (en) |
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| DE3248505A1 (en) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7 (4- (OXOALKYL) -1-PIPERAZINYL / -3-QUINOLINE CARBONIC ACIDS AND THEIR DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND THEIR CONTAINERS |
| DE3306771A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| DE3306772A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| DE3318145A1 (en) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
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|---|---|---|---|---|
| JPS5188973A (en) * | 1975-01-29 | 1976-08-04 | SHINKINAKINORONKARUBONSAN JUDOTAINOSEIHO | |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| CA1175836A (en) * | 1977-09-20 | 1984-10-09 | Marcel Pesson | Production of 1,4-dihydroquinoline-3-carboxylic acid derivatives |
| JPS5466686A (en) * | 1977-09-20 | 1979-05-29 | Dainippon Pharmaceut Co Ltd | Quinoline-3-carboxylic acid derivative, its preparation, and pharmaceutical composition containig the same |
| DE2808070A1 (en) * | 1978-02-24 | 1979-08-30 | Bayer Ag | PROCESS FOR THE PRODUCTION OF 4-PYRIDONE-3-CARBONIC ACIDS AND / OR DERIVATIVES |
| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
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| IE52125B1 (en) * | 1980-10-02 | 1987-06-24 | Fox Charles L Jun | 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quino-line carboxylic acid and metal salts thereof useful in burn therapy |
| US4788320A (en) * | 1986-01-20 | 1988-11-29 | Kyorin Pharmaceutical Co., Ltd. | Benzoylacetic acid ester derivatives and process for their preparations |
| US4689423A (en) * | 1986-04-01 | 1987-08-25 | Warner-Lambert Company | Process for the preparation of 2,3,4,5-tetrafluorobenzoyl acetates |
| JPS6356224A (en) * | 1986-08-27 | 1988-03-10 | 株式会社クボタ | Soil covering apparatus of mulching work machine |
| CA2017090A1 (en) * | 1990-05-17 | 1991-11-17 | Stephen Dunn | Coating composition |
-
1981
- 1981-10-29 DE DE19813142854 patent/DE3142854A1/en not_active Withdrawn
-
1982
- 1982-07-01 IE IE1606/82A patent/IE53709B1/en not_active IP Right Cessation
- 1982-07-05 NO NO822346A patent/NO158018C/en not_active IP Right Cessation
- 1982-07-06 IL IL66243A patent/IL66243A/en not_active IP Right Cessation
- 1982-07-07 ZA ZA824829A patent/ZA824829B/en unknown
- 1982-07-07 DK DK306082A patent/DK160491C/en not_active IP Right Cessation
- 1982-07-08 FI FI822442A patent/FI78689C/en not_active IP Right Cessation
- 1982-07-09 AU AU85768/82A patent/AU561103B2/en not_active Expired
- 1982-07-16 DD DD82241728A patent/DD202560A5/en unknown
- 1982-07-19 KR KR8203203A patent/KR870000895B1/en active IP Right Grant
- 1982-07-19 EP EP82106472A patent/EP0078362B1/en not_active Expired
- 1982-07-19 DE DE8282106472T patent/DE3273892D1/en not_active Expired
- 1982-07-19 AT AT82106472T patent/ATE23040T1/en not_active IP Right Cessation
- 1982-07-29 JP JP57131346A patent/JPS5874667A/en active Granted
- 1982-08-13 CA CA000409435A patent/CA1218067A/en not_active Expired
- 1982-10-25 GR GR69612A patent/GR77707B/el unknown
- 1982-10-26 NZ NZ202278A patent/NZ202278A/en unknown
- 1982-10-28 HU HU823457A patent/HU187580B/en unknown
- 1982-10-28 PH PH28052A patent/PH18803A/en unknown
- 1982-10-28 ES ES516921A patent/ES516921A0/en active Granted
-
1987
- 1987-04-09 AU AU71405/87A patent/AU573125B2/en not_active Expired
- 1987-04-09 AU AU71406/87A patent/AU573126B2/en not_active Expired
- 1987-05-25 JP JP62127877A patent/JPS6322076A/en active Granted
- 1987-05-25 JP JP62127876A patent/JPS6322075A/en active Granted
- 1987-05-25 JP JP62127878A patent/JPS6322057A/en active Granted
-
1990
- 1990-08-10 DK DK190890A patent/DK162637C/en not_active IP Right Cessation
-
1991
- 1991-05-27 JP JP3151073A patent/JPH0824536B2/en not_active Expired - Lifetime
-
1993
- 1993-06-24 LU LU88325C patent/LU88325I2/en unknown
-
1994
- 1994-12-30 NO NO1994030C patent/NO1994030I1/en unknown
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| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |