GB2057440A

GB2057440A - Quinoline carboxylic acid derivatives

Info

Publication number: GB2057440A
Application number: GB8027372A
Authority: GB
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Kyorin Pharmaceutical Co Ltd
Priority date: 1979-08-22
Filing date: 1980-08-22
Publication date: 1981-04-01
Also published as: SE8005534L; BE884824A; IT1132392B; CH645641A5; MY8700155A; DE3031767C3; SU978727A3; FR2463771B1; ES494352A0; DE3031767A1; HK98486A; JPS5630964A; BE887574R; GB2057440B; CA1159454A; IT8024111A0; HU184817B; DE3031767C2; SU1015827A3; FR2463771A1

Abstract

Certain novel quinoline carboxylic acid derivatives, being the compounds of the general formula: <IMAGE> (wherein R2 is halogen; R3 is a 1- piperazinyl or 4-(C1-C5)alkyl- piperazinyl; and either R1 is (C1-C5) alkyl and R4 is halogen or (C1-C5) alkyl, or R1 and R4 are each alkylene and together form a 5 or 6 membered ring which may be substituted by a (C1-C5) alkyl radical) and the hydrates and salts thereof, possess good anti-bacterial activity against both gram-negative and gram-positive bacteria. They may be prepared by reacting a corresponding 7-halo quinoline carboxylic acid derivative with a compound of formula R3H. The 7-halo quinoline carboxylic acid derivatives employed as starting materials are novel compounds which may be prepared by processes analogous to known processes.

Description

SPECIFICATION Quinoline carboxylic acid derivatives This invention relates to quinoline carboxylic acid derivatives which are believed to be useful as anti-bacterial agents.

In the past, anti-bacterial agents such as nalidixic acid, piromidic acid, and pipemidic acid have proved highly effective in the therapy of infections caused by gram-negative bacteria, but these agents suffer the serious disadvantage of having only weak activity against most gram-positive bacteria and especially Pseudomonas aeruginosa.

Accordingly, attempts have been made to produce anti-bacterial agents having a wider spectrum of activity, and indeed the Applicants themselves have reported (c.f. the 98th Annual Meeting of Pharmaceutical Society of Japan, April, 1978, Abstract p. 233; Japan Kokai Sho 53-65887, Sho 53-141 286) that 1-ethyl, 1-vinyl or 1 -(2-fluoroethyl)-1 ,4-dihydro-4-oxo-7-( 1 -piperazinyl or 4substituted-1-piperazinyl)quinoline-3-carboxylic acids substituted in the 6 position or the 8 position by a fluorine or chlorine atom have potent anti-bacterial activity against both gram-positive and gramnegative bacteria, including Pseudomonas aeruginosa.

As a result of further structure-activity studies on quinoline carboxylic acid derivatives, it has now been found that certain 1 ,6,7,8-tetrasubstituted-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acids have still greater activity against gram-negative bacteria, including Pseudomonas aeruginosa, than the above-mentioned compounds, whilst still having potent anti-bacterial activity against gram-positive bacteria and other micro-organisms.

Accordingly, this invention provides quinoline carboxylic acid derivatives, being the compounds of the general formula

(wherein R2 is a halogen atom; R3 is a 1-piperazinyl radical which may optionally be substituted at the 4-position by an alkyl radical of from 1 to 5 carbon atoms; and either R, is an alkyl radical of from 1 to 5 carbon atoms and R4 is a halogen atom or an alkyl radical of from 1 to 5 carbon atoms, or R1 and R4 each represent an alkylene radical and together with the intervening nitrogen atom and carbon atoms form a 5 or 6 membered ring which may optionally be substituted by an alkyl radical of from 1 to 5 carbon atoms) and the hydrates and salts thereof.

Where a derivative of the invention is a salt of a compound of general formula I, it is preferably a pharmaceutically acceptable salt, as defined hereinafter.

The substituent R2 in general formula I is preferably a fluorine or chlorine atom. Where the substituent R4 is a halogen atom it is preferably a fluorine, chlorine or bromine atom, and where an alkyl radical it is preferably a methyl radical.

In the case where R1 and R4 together form a 5 or 6 membered ring, this is preferably a 6 membered ring.

The following groups of derivatives of the invention are especially preferred: those wherein R2 represents a fluorine atom; - those wherein R, represents an ethyl radical; - those wherein R4 represents a fluorine or chlorine atom; and - those wherein R4 and R1 together represent a 6 membered ring substituted by a methyl radical.

The following specific derivatives of the invention viz.

1 -Ethyl-6,8-difluoro-1 ,4-dihydro-4-oxo-7-( 1 -piperazinyl)-quinoline-3-carboxylic acid, 1 -Ethyl-6,8-difluoro- 1 ,4-dihydro-4-oxo-7-(4-methyl-1 -piperazinyl)quinoline-3-carboxylic acid, 9-Fluoro-6,7-dihydro-5-methyl-1 -oxo-8-(1 -piperazinyl)-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9-Fluoro-6,7-dihydro-5-methyl-1 -oxo-8-(4-methyl-1 -piperazinyl)-1 H,5H-benzo[ij]quinolizine-2carboxylic acid, 8-Chloro-1 -ethyl-6-fluoro-l ,4-dihydro-4-oxo-7-( 1 -piperazinyl)quinoline-3-carboxylic acid, and 8-Chloro- 1 -ethyl-6-fluoro-l ,4-dihydro-4-oxo-7-(4-methyl-1 -piperazinyl)quinoline-3-carboxylic acid, their hydrates and their pharmaceutically acceptable salts, are particularly indicated for use as anti-bacterial agents.

The invention also provides a process for preparing the derivatives of the invention, in which process a compound of the general formula:

(wherein R1, R2 and R4 are as defined above and X is a halogen atom) is reacted with a compound of the general formula: R3H (111) (wherein R3 is as defined hereinbefore) in order to obtain the desired derivative.

The reaction is preferably carried out at a temperature of from 600C to 1 800C, in the presence of a dehydrohalogenating agent. The dehydrohalogenating agent may be a base such as an alkali hydroxide, alkali carbonate, or an amine.

The reaction may be carried out either in the presence of an inert solvent or without a solvent.

Where an inert solvent is employed this may be a polar solvent such as water, an alcohol, pyridine, picoline, N,N-dimethyl formamide or dimethylsulphoxide.

The starting materials of general formula II are believed to be novel compounds, and this invention provides them per se. Nevertheless, the compounds of general formula II may be prepared by processes that are analogous to known processes, and processes for preparing certain compounds of general formula II are set out by way of illustration in the Examples hereinbelow.

Derivatives of the invention wherein R3 represents a 1-piperazinyl radical substituted at the 4position by an alkyl radical of from 1 to 5 carbon atoms may alternatively be prepared by a process in which a compound of general formula I wherein R3 represents an unsubstituted 1-piperazinyl radical that is a compound of general formula:

wherein R1, R2 and R4 are as defined above-is reacted with a compound of the general formula: Fl6-CO-Fl7 (IV) (wherein R6 and R7, which may be the same or different, are each a hydrogen atom or a lower alkyl radical of from 1 to 4 carbon atoms) in order to obtain the desired derivative.

The reaction is preferably carried out in the presence of a reducing agent such as formic acid, sodium borohydride or a catalytic hydrogenating agent The reaction may also be carried out in the presence of a polar solvent such as water, an alcohol, an ether or a dipolar aprotic solvent.

The anti-bacterial activity of the derivatives of the invention indicates their employment in human or veterinary medicine.

Before using them in medicine however, it is preferred to form the derivatives of the invention into pharmaceutical compositions, by association with suitable pharmaceutical vehicles.

Accordingly, this invention further provides compositions suitable for use in the chemotherapy of infections caused by bacteria or other micro-organisms, which compositions comprise a compound of general formula I and/or a pharmaceutically acceptable salt and/or a hydrate thereof, in association with a pharmaceutically acceptable vehicle.

The compositions of the invention preferably comprise those derivatives mentioned hereinbefore as being preferred.

The description "pharmaceutically acceptable" is used herein to exclude any possibility that the nature of the vehicle or salt, considered of course in relation to the route by which the composition is to be administered, should be harmful to the patient to be treated. The choice of a suitable vehicle or salt is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

The derivatives of the invention may also be used to combat micro-organisms at a locus, and the invention provides a method of combatting micro-organisms at a locus in which a derivative of the invention is applied to the locus in an amount sufficient to inhibit the growth of the micro-organisms.

The derivative is preferably applied to the locus in association with an inert diluent.

Finally, this invention provides the derivatives of the invention for use in a method of treating the human or animal body by therapy.

The following Examples are now given, though only by way of illustration, to show certain aspects of the invention in detail.

EXAMPLE 1 I -Ethyl-6,8-difluoro- 1,4-dihydro-4-oxo-7-(I -pipe/azinyllguinoline-3-carboxylic acid hydrochloride Stage A 1 -Ethyl- 1,4-dihydro-4-oxo-6, 7,8-trifluoroquinoline-3-carboxylic acid A mixture of 3-ethoxycarbonyl-4-hydroxy-6,7,8-trifluoroquinoline (3.0 g), anhydrous potassium carbonate (7.6 g), ethyl iodide (8.8 ml) and N,N-dimethyl formamide (100 ml) was heated with stirring at 90 ~ 000C for 10 hours. The reaction mixture was evaporated to dryness, water added, the resulting solid was collected, washed with water, and dried. The solid was dissolved in dichloromethane, and the solution filtered and evaporated. To the residue were added 18% hydrochloric acid (50 ml) and ethanol (25 ml) and the mixture was refluxed for 2.5 hours.After cooling, the precipitate was filtered off, washed with water and dried. The solid was recrystallised from a mixture of N,Ndimethyl formamide and ethanol to give 2.1 g of 1-ethyl-i ,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3- carboxylic acid as colourless needles, mp: 259 - 261 C.

C H N Anal. Calcd. for C,2H803NF3: 53.15 2.97 5.16 Found: 53.30 2.88 5.24 The starting material, 3-ethoxycarbonyl-4-hydroxy-6,7 ,8-trif luoroquinoline was prepared by the following method.

A mixture of 2,3,4-trifluoroaniline (4.9 g) and ethoxymethylene malonic acid diethyl ester (7.2 g) was heated at 1 20 ~ 1400C for 1 hour. After the mixture had cooled, diphenylether (50 ml) was added and the mixture was refluxed for 30 minutes. Again after the mixture had cooled, benzene was added and the formed precipitate was filtered, washed with benzene, dried, and recrystallised from N,Ndimethyl formamide to give 5.7 g of 3-ethoxycarbonyl-4-hydroxy-6,7,8-trifluoroquinoline as a colourless powder, mp: 280 - 2830C (decomp.).

C H N Anal. Calcd. for C,2H803NF3: 53.15 2.97 5.16 Found: 52.83 2.84 5.10 Stage B 1 -Ethyl-6,8-difluoro- 1,4-dihydro-4-oxo-7-( 1 -piperazinyl)quinollne-3-carboxylic acid hydrochloride A mixture of 1-ethyl-i ,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid (1.35 g), piperazine (2.2 g) and pyridine (10 ml) was refluxed for 6 hours. The reaction mixture was evaporated to dryness. To the residue was added dilute hydrochloric acid so as to adjust the pH to below 1. The formed precipitate was filtered and recrystallised from water to give 1.45 g of 1 -ethyl-6,8-difluoro-1 ,4 dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride as colourless crystals, mp.

3000 C.

C H N Anal.Calcd.forC,6H,703N3F2-HCI: 51.41 4.85 11.24 Found: 51.07 4.79 11.18 EXAMPLE 2 1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-94-methyl-1-piperazinyl)quinoline-3-carboxylic acid.

1 -Ethyl-6,8-difluoro- 1 ,4-dihyd?o-4-oxo-7-( 1 -piperazinyl)-quinoline-3-carboxylic acid hydrochloride (0.75 g), sodium formate (0.27 g), 87% formic acid (4 ml) and 37% formaldehyde solution (4 ml) were mixed and refluxed for 5 hours. The reaction mixture was evaporated. To the residue was added water (10 ml), and the resulting solution was adjusted to pH 7 by the addition of 10% sodium hydroxide solution, and was then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, and evaporated. The residue was recrystallised from a mixture of N,N-dimethyl formamide and ethanol to give 0.45 g of 1-ethyl-6,8difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)quinoline-3-carboxylic acid as colourless crystals, mp: 245 ~ 2460C.

C H N Anal. Caled. for C17H19O3N3F2 : 58.11 5.45 11.96 Found: 57.97 5.48 12.02 EXAMPLE 3 9-Fluoro-6, 7-dihydro-5-methyl- 1 -oxo-8-( 1 -piperazinyl)- 1 H,5H-benzo[ij]quinoline-2-carboxylic acid hydrochloride Stage A 8,9-Difluoro-6, 7-dihydro-5-methyl- 1 -oxo -1 H,SH-benzo[ij]quinolizine-2-carboxylic acid A mixture of 5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (5.0 g) and ethoxymethylene malonic acid diethyl ester (5.9 g) was heated at 120 ~ 1300C for 5 hours. After cooling, polyphosphoric acid (40 g) was added to the mixture, and the resulting mixture was heated with stirring at 120 N 1300C for 20 minutes.

Again after cooling, water (80 ml) and concentrated hydrochloric acid (30 ml) were added to the mixture and the resulting mixture was refluxed for 3 hours. The mixture was cooled and diluted with water. The formed precipitate was filtered, washed with water, and dried to give a solid. This was recrystallised from a mixture of N,N-dimethyl formamide and ethanol to give 4.5 g of 8,9-difluoro-6,7dihydro-5-methyl-1 -oxo-l H,5H-benzo[ij]quinolizine-2-carboxylic acid as colourless needles, mp: 287 ~ 2880C.

C H N Anal. Calcd. for C,4H"03NF2: 60.22 3.97 5.02 Found: 60.38 3.84 4.94 The starting material, 5,6-difluoro-2-methyl-1,2,3,4-tetrahydroqunoline was prepared by the following method.

To a stirred mixture of 1-bromo-3,4-difluorobenzene (27 g) and concentrated sulphuric acid (30 ml) at 20 ~ 300C was added dropwise 90% nitric acid (11.2 g). The stirring was continued, at 50 ~ 600C for 2 hours. The mixture was poured onto ice and extracted with benzene, and after washing with water, drying over anhydrous sodium sulphate and evaporating, 323 g of 2-bromo-4,5difluoro-1-nitrobenzene were obtained as a yellow oil.

The 2-bromo-4,5-difluoro-1-nitrobenzene (32.7 g) was added to a stirred mixture of iron powder (69 g), concentrated hydrochloric acid (6.8 ml), and water (500 ml) at 80 ~ 900C. The stirring was continued, at 85 ~ 900 C, for 2 hours. After cooling, the mixture was made basic with potassium carbonate and extracted with benzene, and after washing with water, drying over anhydrous sodium sulphate and evaporating, a residual oil was obtained. This was distilled to give 19.6 g of 2-bromo-4,5 difluoro-aniline as an oil, bp: 120 1 1250C (27 mmHg).

To a stirred mixture of the 2-bromo-4,5-difluoroaniline (19.5 g) and polyphosphoric acid (100 g) was added acetoacetic acid ethyl ester (13 g), and the stirring was continued at 1400C for 2 hours. The mixture was cooled and neutralised with 10% sodium hydroxide solution. The formed precipitate was filtered, washed with water and dried. After recrystallisation from N,N-dimethyl formamide, 11.3 g of 8bromo-5,6-difluoro-4-hydroxy-2-methylquinoline obtained as colourless needles, mp: 278 ~ 2790C.

A mixture of the 8-bromo-5,6-difluoro-4-hydroxy-2-methylquinoline (11.3 g) and phosphorus oxychloride (100 ml) was refluxed for 5 hours. The excess phosphorus oxychloride was evaporated, and the residue of the mixture was neutralised with aqueous potassium carbonate solution, with ice-cooling.

The formed precipitate was extracted with dichloromethane, and after washing with water, drying over an hydros sodium sulphate and evaporating, a residue was obtained. This was recrystallised from ethanol to give 9.3 g of 8-bromo-4-chloro-5,6-difluoro-2-methylquinoline as colourless needles, mp: 140 - 1420C.

A mixture of the 8-bromo-4-chloro-5,6-difluoro-2-methylquinoline (9.3 g) sodium acetate (5.2 g), acetic acid (100 ml) and 10% palladium on charcoal (3.0 g) was hydrogenated at room temperature until hydrogen uptake ceased. The mixture was filtered, concentrated, and made basic with aqueous potassium carbonate. After extracting with dichloromethane, washing with water, drying over anhydrous sodium sulphate and evaporating, 5.3 g of 5,6-difluoro-2-methylquinoline were obtained.

Finally, a mixture of the 5,6-difluoro-2-methylquinoline (5.3 g), platinum dioxide (0.3 g), and methanol (1 50 ml) was hydrogenated at room temperature at a pressure of 40 atm. until hydrogen uptake ceased. The mixture was filtered and concentrated to give 5.0 g of the desired 5,6-difluoro 1 ,2,3,4-tetra hydro-2-m ethyl qui noline.

Stage B 9-Fluoro-6, 7-dihydro-5-methyl- 1 -oxo-8-' 1 -piperazin yl)- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride A mixture of 8,9-difluoro 6,7-dihydro-5-methyl-1-oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid (1.4 g), piperazine (2.2 g), and p-picoline (5 ml) was refluxed for 7.5 hours. The mixture was evaporated to dryness and acidified with hydrochloric acid. The resulting precipitate was filtered and recrystallised from a mixture of water and ethanol to give 1.0 g of 9-fluoro-6,7-dihydro-5-methyl-1 -oxo- 8-(1-piperazinyl)-1H, 5H-benzo# quionliaine-2-carboxylic acid hydrochloride as colourless needles, mp > 3000C.

C H N Anal. Calcd. for C18H2003N3F.HCl.i-43H20: 52.30 5.97 10.17 Found: 52.25 5.64 10.43 EXAMPLE 4 9-Fluoro-6, 7-dihydro-5-methyl- 1 -oxo-8-(4-methyl- 1 -piperazinyl)- 1 H,5H-benzo[ij]quinolizine-2 carboxylic acid A mixture of 9-fl uoro-6,7-dihydro-5-methyl- 1 -oxo-8-(1 -piperazinyl)-l H,5 H-benzo[ij]quinolizine)2-carboxylic acid hydrochloride (0.9 g), sodium formate (0.64 g) 87% formic acid (5 ml), and 37% formaldehyde solution (5 ml) was refluxed for 5 hours. The mixture was evaporated to dryness and an aqueous sodium hydroxide solution was added. The formed basic solution was neutralised with acetic acid and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, and evaporated.The formed residual solid was recrystallised from a mixture of N,N-dimethyl formamide and ethanol to give 0.70 g of 9-fluoro-6,7-dihydro-5-methyl-1-oxo- 8-(4-methyl-1 -piperazinyl)-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as colourless needles, mp: 261 ~ 263aC.

C H N Anal. Calcd. for C1gH2203N3F 63.50 6.1 7 11.69 Found: 63.45 6.20 11.65 EXAMPLE 5 8-Chloro- 1 -ethyl-6-fluoro- 1 ,4-dihydro-4-oxo- 7-( 1 -piperazin yl)quinoline-3-carboxylic acid hydrochloride Stage A 8-Chloro- 1 -ethyl-6, 7-difluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 3-Ethoxycarbonyl-8-chloro-6,7-difluoro-1 ,4-dihydro-4-oxoquinoline (12.0 g), anhydrous potassium carbonate (29) g), ethyl iodide (33.6 ml), and N,N-dimethyl formamide (300 ml) were mixed and stirred at 90 ~ 1000C for 12 hours. To the mixture were added anhydrous potassium carbonate (14.5 g) and ethyl iodide (16.8 ml), and the formed mixture was heated with stirring at 90 ~ 1000C for 9.5 hours.The mixture was concentrated to dryness and water was added. After extracting with dichloromethane and evaporating, a residue was formed, to which was added 18% hydrochloric acid (100 ml). After refluxing for 4 hours, water (200 ml) was added to the formed aqueous solution, and the thus-formed mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and evaporated. The residue was recrystallised from a mixture of N,N-dimethyl formamide and ethanol to give 5.7 g of 8-chloro-l -ethyl-6,7-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid as colourless needles, mp: 215 21 2170C.

C H N Anal. Calcd. for Cr2H803N F2CI: 50.11 2.80 4.87 Found: 50.40 2.72 4.93 The starting material, 3-ethoxycarbonyl-8-chloro-6,7-dif luoro-1,4-di hydro4-oxoquinoline was prepared by the following method.

2-Chloro-3,4-difluoroaniline (9.6 g) and ethoxymethylene malonic acid diethyl ester (12.8 g) were mixed and heated at 120 1 1300C for 2 hours. After cooling, diphenylether (100 ml) was added, and the mixture was refluxed for 30 minutes. The reaction mixture was cooled, and benzene (100 ml) added.

The formed precipitate was collected, washed with benzene and dried to give a solid, which was recrystallised from N,N-dimethyl formamide. 13.3 g of 3-ethoxycarbonyl-8-chloro-6,7-dif luoro-1,4- dihydro-4-oxoquinoline were obtained as a colourless powder, mp: 292 - 2930C (decomp.).

Stage B 8-Chloro- 1 -ethyl-6-fluoro- 1,4-dihydro-4-oxo-7-( 1 -piperazinyl)quinoline-3-carboxylic acid hydrochloride A mixture of 8-chloro-1 -ethyl-6,7-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.65 g), piperazine (1.0 g) and pyridine (5 ml) was refluxed for 30 minutes. The reaction mixture was evaporated and acidified with hydrochloric acid. The precipitate was collected and recrystallised from a mixture of water and ethanol to afford 0.60 g of 8-chloro-1 -ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1 piperazinyl)quinoline-3-carboxylic acid hydrochloride as a colourless powder, mp > 3000C.

C H N Anal. Calcd. for C16H1703N3F Cl.HCI-41QH50H: 49.33 4.89 10.46 Found: 49.30 4.59 10.25 EXAMPLE 6 8-Chloro- 1 -ethyl-6-fluoro- 1,4-dEhydro-4-oxo-7-(4-methyl- 1 -piperazin yl)quinollne-3-carboxyllc acid 8-chloro-1-ethyl-6-fluoro-1.4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid hydrochloride (0.25 g), sodium formate (0.5 g), 87% formic acid (5 ml), and a 37% formaldehyde solution (5 ml) were mixed and refluxed for 6.5 hours. The solution was evaporated and made basic with an aqueous sodium hydroxide solution. The basic solution was neutralised with acetic acid, and extracted with dichloromethane. After evaporating, the residue was recrystallised from ethanol to give 0.21 g of 8-chloro-l -ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1 -piperazinyl)quinoline-3 carboxylic acid as a colourless powder, mp: 213 21 2160C.

C H N Anal. Calcd. for C17H19O3N3FCl.+ H2O 54.84 5.28 11.29 Found: 54.98 5.20 11.14 The anti-bacterial activity of various derivatives of the invention was investigated as follows: Anti-bacterialActivity in vitro The in vitro anti-bacterial activities of derivatives of the invention were assayed by the standard agar dilution streak method against gram-positive and gram-negative bacteria [Chemotherapy, 22, 1126 (1974)]. The results are shown in Table 1, together with results obtained with known agents. The compounds of Examples 1, 2, 3, 4, 5 and 6 were more active than nalidixic acid (NA) and pipemidic acid (PPA) against gram-positive and gram-negative bacteria.

Anti-bacterialActivity in vivo The in vivo anti-bacterial activity of the derivatives of Examples 1, 2 and 4 were determined in systemic infections, and the results are shown in Table 2, together with results obtained with 1 -ethyl-6 fluoro-1 ,4-dihydrn-7-(1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid (AM-71 5) nalidixic acid (NA), pipemidic acid (PPA) and miloxacin (MLX). Systemic infections were produced by inoculating male mice (weighing 20 + 2 g) intraperitoneally with the following test strains suspended in 0.5 ml of brain heart infusion containing 5% mucin: Pseudomonas aeruginosa GN1 1187,3.3 x x 105 cells, Serratia marcescens GN7577 2.2 x 105 cells, and Staphylococcus aereus Smith, 3.0 x 105 cells.The drugs were administered orally to the mice twice a day, beginning immediately after and 4 hours after infection, and the therapeutic effect of the drugs was judged from the survival rate. A comparison of in vivo anti-bacterial activity was made on the basis of the mean effective dose (ED50) calculated by probit analysis. The in vivo anti-bacterial activities of the compounds of Examples 1, 2 and 4 against systemic infections of the mice with each bacteria were clearly higher than those of AM-7 1 5, NA, PPA and MLX.

TABLE 1 Antibacterial Actlvity in vitro

Minimum inhibitory concentration ( g/ml) The compound of Orgenisms Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex.5 Ex. 6 NA PPA Bacillus subtilis PC1219 0.10 0.20 0.10 1.10 0.20 0.20 6.25 6.25 Staphylococcus aureus 209P 0.39 0.39 0.78 0.20 0.78 0.78 100 25 S. aureus ATCC14775 1.56 0.78 3.13 0.39 1.56 1.56 > 100 100 Escherichia coli NiHj 0.05 0.05 0.025 0.10 0.05 0.05 3.13 1.56 E. Coli ATCc10536 0.05 0.05 0.05 0.05 0.05 0.05 3.13 3.13 Proteus vulgaris 3167 0.025 0.05 0.025 0.05 0.05 0.05 3.13 6.25 P. vulgaris XK Denken 0.05 0.10 0.20 0.20 0.10 0.39 1.56 1.56 Klebsiella pneumoniae IFO 3512 0.025 0.025 0.025 0.025 0.05 0.05 100 12.5 Pseudomonas aeruginosa v-1 0.39 1.56 6.25 3.13 1.56 6.25 > 200 25 P. aeruginosa IFO12689 0.78 3.13 6.25 6.25 3.13 12.5 > 200 50 P. aeruginosa 11D11210 3.13 12.5 > 200 25 P. aeruginosa 11D1130 0.78 3.13 Salmonella enteritidis 11D604 0.20 0.39 0.39 1.56 12.5 12.5 TABLE 1 (Continued) Antibacterial Activity in vitro

Minimum inhibitory concentration ( g/ml) The compound of Organisms Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 NA PPA Shlgella sonnel 11D969 0.05 0.05 #0.05 # 0.05 1.56 1.56 Serratia marcescens 11D6.8 0.10 0.20 S. marcescens 11D619 0.20 0.39 S. marcescens 11D620 0.10 0.20 Yersinia enterocolitica 11D981 0.10 0.20 0.39 0.39 0.20 0.39 Acinetobacteranitratus 11D 876 0.78 0.20 0.78 0.20 0.39 0.39 Staphylococcus epldermidis 11D 866 0.78 0.78 1.56 0.39 1.56 1.56 Streptococcus pyogenes 11D692 3.13 6.25 > 100 > 100 S. pyogen es S-8 12.5 12.5 > 100 > 100 S. faecalis 11D682 6.25 6.25 Diplococcus pneumoniae 11D552 6.25 6.25 > 100 > 100 Coryneba cterium pyogenes 11D548 3.13 6.25 100 TABLE 2 Anti-bacterial Activity in vivo

ED50 (mg/kg) P. aeruginosa S. marcescens S. aureus Compound GN11187 GN7577 Smith EX. 1 11.2 14.5 < 17.5 EX. 2 9.2 21.3 < 17.5 EX. 4 24.5 - - AM-715 38.0 44.9 38.0 NA > 400 > 400- > 400 PPA 280 > 400 183 MLX 150 78.6 98.4

Claims

1. Quinoline carboxylic acid derivatives, being the compounds of the general formula:

(wherein R2 is a halogen atom; R3 is a 1 -piperazinyl radical which may optionally be substituted at the 4position by an alkyl radical of from 1 to 5 carbon atoms; and either R1 is an alkyl radical of from 1 to 5 carbon atoms and R4 is a halogen atom or an alkyl radical of from 1 to 5 carbon atoms, or R1 and R4 each represent an alkylene radical and together with the intervening nitrogen atom and carbon atoms form a 5 or 6 membered ring which may optionally be substituted by an alkyl radical of from 1 to 5 carbon atoms) and the hydrates and salts thereof.

2. 1 -Ethyl-6,8-difluoro- 1 ,4-dihydro-4-oxo-7-( 1 -piperazinyl)-quinoline-3-carboxylic acid.

3.1 -Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)quinoline-3-carboxylc acid.

4. 9-Fluoro-6,7-dihydro-5-methyl-l -oxo-8-( 1 -piperazinyl)-1 H,5H-benzo[ij]quinolizine-2- carboxylic acid.

5. 9-Fluoro-6,7-dihydro-5-methyl-1 -oxo-8-(4-methyl- 1 -piperazinyl)-1 H,5H-benzoijjquinoIizine-2- carboxylic acid.

6. 8-Chloro-l -ethyl-6-fluoro-l ,4-dihydro-4-oxo-7-(1 -piperazinyl)quinoline-3-carboxylic acid.

7.8-Chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-emthyl-1-piperazinyl)quinoline-3-carboxylic acid.

8. A hydrate or a pharmaceutically acceptable salt of a compound as claimed in any one of claims 2 to 7.

9. A process for preparing a derivative as claimed in claim 1, in which process a compound of the general formula:

(wherein R,, R2 and R4 are as defined in claim 1 and X is a halogen atom) is reacted with a compound of the general formula: R3H (Ill) (wherein R3 is as defined in claim 1) in order to obtain the desired derivative.

1 0. A process as claimed in claim 9 and substantially as hereinbefore described with reference to any one of Examples 1,3 and 5.

11. A process for preparing a derivative as claimed in claim 1 wherein R3 represents a 1 piperazinyl radical substituted at the 4-position by an alkyl radical of from 1 to 5 carbon atoms, in which process a compound of general formula:

wherein R1, R2 and R4 are as defined in claim 1 is reacted with a compound of the general formula: R6COR7 (IV) (wherein R6 and R,, which may be the same or different, are each a hydrogen atom or a lower alkyl radical of from 1 to 4 carbon atoms) in order to obtain the desired derivative.

12. A process as claimed in claim 11, carried out in the presence of a reducing agent.

13. A process as claimed in claim 11 and substantially as hereinbefore described with reference to any one of Examples 2, 3 and 6.

14. A process as claimed in any of claims 11 to 13, in which the starting material of general formula la is prepared by a process as claimed in claim 9 or claim 10.

1 5. Compositions suitable for use in the chemotherapy of infections caused by bacteria or other microorganisms, which compositions comprise a compound of general formula I (as defined in claim 1) and/or a pharmaceutically acceptable salt and/or a hydrate thereof, in association with a pharmaceutically acceptable vehicle.

1 6. A composition as claimed in claim 15, which comprises a derivative as claimed in any one of claims 2 to 8.

1 7. A method of combatting micro-organisms at a locus in which a derivative as claimed in claim 1 is applied to the locus in an amount sufficient to inhibit the growth of the micro-organisms.

1 8. A method as claimed in claim 17, in which the derivative is applied to the locus in association with an inert diluent.

19. A derivative as claimed in claim 1 for use in a method of treating the human or animal body by therapy.

20. A compound of general formula 11, as defined in claim 9.

21. 1 -Ethyl-1 ,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid.

22. 8,9-Difluoro-6,7-dihydro-5-methyl-1 -oxo-1 H,5H-benzo[ijjquinolizine-2-carboxylic acid.

23.8-Chloro-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.