FR2463771A1 - PROCESS FOR THE PREPARATION OF QUINOLINECARBOXYLIC ACID DERIVATIVES AND NOVEL PRODUCTS OBTAINED WITH ANTIBACTERIAL ACTIVITY - Google Patents

Abstract

DERIVATIVES OF QUINOLEINECARBOXYLIC ACID HAVING THE FORMULA: (CF DRAWING IN BOPI) OR R IS A LOWER ALKYL GROUP, R IS A HALOGEN, R IS THE PIPERAZINYL GROUP OR A N-ALKYL GROUP (LOWER ALKYL (INFERIOR) AND PIPERAZINYL (LOWER) AND RIPERAZINYL HALOGEN A LOWER ALKYL GROUP, OR R AND R REPRESENT ALKYL GROUPS AND MAY TOGETHER COMPLETE A HEXAGONAL CORE WHICH MAY OR NOT BE SUBSTITUTED BY LOWER ALKYL RADICALS, AS WELL AS THEIR HYDRACES OR THEIR SOUNDS OF ACDITION ACDITION ANTIBACTERIAL AGENTS WITH POWERFUL ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA, INCLUDING PSEUDOMONAS AERUGINOSA.

Description

1. The present invention relates to new

  quinoline-carboxylic acid derivatives having

  powerful antibacterial properties. Anti-bacterial agents

  such as nalidixic acid, piromidic acid and pipemidic acid have been shown to be highly effective in the treatment of infections caused by gram-negative bacteria, but these agents have the serious disadvantage of

  have only weak activities against most

  gram-positive series and against Pseudomonas aeruginosa.

  The compounds of the present invention are particularly

  useful because they have antibacterial activity

  not powerful at the same time against Gram-positive bacteria

  and gram-negative, including Pseudomonas aeruginosa.

  The Applicant has previously indicated (98th Annual Meeting of the Japan Pharmaceutical Society, April

  1978, Abstract p. 233rd Japan Kokai Sho 53-65887, Sho 53-

  141286) that 1-ethyl, 1-vinyl or 1- (2-fluoroethyl) -

  1,4-Dihydro-4-oxo-7- (-piperazinyl or 4-substituted-1-piperazinyl)

  zinyl) quinoline-3-carboxylic acids, having fluorine or chlorine

  in position 6 or 8, have potent antibacterial activity against both gram-positive and gram-negative bacteria including Pseudomonas aeruginosa. By

  following on-going studies of the structure-activity relationship

  For the related compounds, we have found that 1,6,7,8-tetrasubstituted 1,4-dihydro-4-oxoquinoline-3-carboxylic acids having fluorine or chlorine at the 6-position, a substituent other than in the 7-position, and in the 8-position of fluorine, chlorine, bromine, the methyl group, or another alkyl group, which may together form a

  pentagonal or hexagonal ring with the substituent in position

  tion 1, have stronger antibacterial activities

  gram-negative bacteria that the compounds indi-

above.

  The novel compounds of the present invention are quinolinecarboxylic acid derivatives having the formula:

R2 COOH

R

4 R1

  R1 is a lower alkyl group, R2 is a halogen,

  preferably fluorine or chlorine; R3 is the piper group

  razinyl or N-lower alkyl piperazinyl and R4 is halogen, preferably fluorine, chlorine or bromine, lower alkyl, preferably methyl, or R1 and R4 are alkylene groups and all two can together complete a hexagonal nucleus,

  as well as the hydrates or the pharmaceutically acceptable salts

ceptables of these products.

  The preferred compounds of (I) as antibacterial agents are as follows:

  1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-

  (1-piperazinyl) quinoline-3-carboxylic acid,

  11-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-

  (4-methyl-l-piperazinyl) quinoline-3-carboxylic acid,

  9-fluoro-6,7-dihydro-5-methyl-1-oxo-8-

  (1-piperazinyl) -LH, 5H-benzo [ij] quinolizine-2-carboxylic acid,

  9-fluoro-6,7-dihydro-5-methyl-1-oxo-8- (4-

  methyl-l-piperazinyl) -LH, 5H-benzo [ij] quinolizine-2-carboxylic

3. lique,

  8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4- acid

  oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid,

  8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4- acid

  oxo-7- (4-methyl-l-piperazinyl) quinoline-3-carboxylic acid,

  as well as the hydrates and pharmaceutically acceptable salts

tables of these compounds.

  The compounds of the present invention are prepa-

  by Method A and B. Method A: The compound (I) is prepared by the reaction of a compound having the formula (II):

R COO

R2X

X

  ## STR2 ## R 1, R 1, R 2 and R 4 are as indicated above and X is halogen, with a compound having the formula (III)

R5 ... N NH (III)

  R 5 is hydrogen or lower alkyl, in

  an inert solvent such as, for example, water,

  cools, pyridine, picoline, N, N-dimethylformamide,

  dimethylsulfoxide, or the like, or in the absence of

  at a temperature in the range 60 C to 180 C.

  It is preferred to carry out the reaction in the presence of a base, such as a hydrohalic acid removal agent, such as a

  alkali hydroxide, alkali carbonate or amines.

  Process B: The compounds having formula (I) are obtained by reacting a compound of formula (IV) 4.

R2 COOH

HN N (IV)

R4

  R4, R1, R1, R2 and R4 are as mentioned above, with a compound of formula (V)

R6-CO-R7 (V)

  R 6 and R 7 represent hydrogen or a lower alkyl group, in the presence of a reducing agent such as, for example,

  formic acid, sodium borohydride, a catalytic

  hydrogenation, or the like. Examples of the solvent used in the reaction are water, alcohols, ethers,

  a dipolar neutral solvent or the like.

  The following examples serve to illustrate the

this invention.

EXAMPLE 1

  1-ethyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-

quinoline-3-carboxylic acid

  A mixture of 3-ethoxycarbonyl-4-hydroxy-6,7,8-tri-

  fluoroquinoline (3.0 g), anhydrous potassium carbonate

  (7.6 g) of ethyl iodide (8.8 ml) and N, N-dimethylformamide were

  (DMF) (100 mL) was heated with stirring at 90-100C for 10 hours. The reaction mixture was evaporated to dryness, water added, the resulting solid was collected, washed with water and dried. The solid has been dissolved in

  dichloromethane, filtered and evaporated. In the residue, we added

  18% hydrochloric acid (50 ml) and ethanol (25 ml) were added and the mixture was refluxed for 2 1/2 hours. After cooling, the precipitate was separated by

  filtration, washed with water and dried. The solid has been re-

  crystallized in a mixture of DMF and ethanol to give 2.1

  1-Ethyl-11,4-dihydro-4-oxo-6,7,8-trifluoroquinoline

  3-carboxylic acid in the form of colorless needles.

m.p .: 259 - 261 C.

5.

C H N

  Calcd for C12H803NF3: 53.15 2.97 5.16 Found: 53.30 2.88 5.24

  The starting material, 3-ethoxycarbonyl-4-hydroxy-

  6,7,8-trifluoroquinoline was provided by the following procedure. A mixture of 2,3,4-trifluoroaniline (4.9 g) and diethyl ester of ethoxymethylenemalonic acid (7.2 g)

  was heated at 120-140 ° C for 1 hour. After cooling

  Finally, diphenyl ether (50 ml) was added to the mixture, and the mixture was refluxed for 30 minutes. After cooling, in the mixture was added benzene, the precipitate was filtered, washed with benzene,

  dried and recrystallized from DMF to give 5.7 g of 3-

  ethoxycarbonyl-4-hydroxy-6,7,8-trifluoroquinoline in the form

  of colorless powder. m.p .: 280-283 ° C (decomposition).

C H N

  Analysis calculated for C12H803NF3: 53.15 2.97 5.16 Found: 52.83 2.84 5.10

EXAMPLE 2

  1-Ethyl-6,8-difluoro-1,4-dihydroxychloride

  hydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid

  A mixture of 1-ethyl-11,4-dihydro-4-bxo-6,7,8-

  trifluoroquinoline-3-carboxylic acid (1.35 g), piperazine

  (2.2 g) and pyridine (10 ml) was refluxed

  6 hours. The reaction mixture was evaporated to dryness.

  In the residue, dilute hydrochloric acid was added so that the residue was adjusted to a pH below 1 and the precipitate

  been filtered. The solid was recrystallized from water to give

  1.45 g of 1-ethyl-6,8-difluoro-1,4-hydrochloride

  dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid under

  form of colorless crystals. m.p. > 300 C.

C H N

  Analysis calculated for C16H1703N3F2HCl: 51.41 4.85 11.24 Found 51.07 4.79 11.18 6.

EXAMPLE 3

  1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (4-) -acetate

  methyl-l-piperazinyl) quinoline-3-carboxylic acid

  1-Ethyl-6,8-difluoro-1,4-acid hydrochloride

  dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid

  (0.75 g), sodium formate (0.27 g), formic acid and

  than 87% (4 ml) and a 37% formaldehyde solution

  (4 ml) were mixed and refluxed for 5 hours.

  res. The reaction mixture was evaporated. In the residue, water (10 ml) was added; the solution was adjusted to pH 7 by addition of 10% sodium hydroxide solution and extracted with dichloromethane. The organic layer has been washed

  with water, dried over anhydrous sodium sulphate and

  porated. The residue was recrystallized from a DMF mixture

  and ethanol to give 0.45 g of 1-ethyl-6,8-difluorinated

  ro-l1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) quinoline

  3-carboxylic acid in the form of colorless crystals; m.p. 245 -

246 C.

C H N

  Calcd for C17H19O3N3F2: 58.11 5.45 11.96 Found: 57.97 5.48 12.02

EXAMPLE 4

  8,9-Difluoro-6,7-dihydro-5-methyl-1-oxo-1H, H-benzo [i] quinolizine-2-carboxylic acid

  A 5,6-difluoro-2-methyl-1,1,2,3,4-tetrahydro-

  droquinoline (5.0 g) and diethyl ester of ethoxymethyl

  Thylenemalonic (5.9 g) was heated at 120-130 ° C for 5 hours. After cooling, polyphosphoric acid (40 g) was added to the mixture with stirring at 120-130 ° C for 20 minutes. After cooling, in the mixture

  water (80 ml) and hydrochloric acid were added.

  centered (30 ml) and refluxed for 3 hours.

  The reaction mixture was cooled and diluted with water.

  The precipitate was filtered, washed with water and dried. The O-

  lide was recrystallized from a mixture of DMF and ethanol

  to give 4.5 g of 8,9-difluoro-6,7-dihydro-5-methyl-

  1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid in form

  colorless needles; m.p .: 287-288 C.

C H N

  Analysis calculated for C14H11O3NF2: 60.22 3.97 5.02 Found: 60.38 3.84 4.94 Starting material of the above-mentioned process, 5,6-difluoro-2-methyl-1,2,3,3 4-Tetrahydroquinoline

  was obtained by the following method.

  In a stirred mixture of 1-bromo-3,4-difluorobenzene

  zene (17 g) and concentrated sulfuric acid (30 ml), 90% nitric acid (11.2 g) was added dropwise.

  at 20-30 ° C and stirred at 50-60 ° C for 2 hours. The melange

  The gel was spilled on ice, extracted with benzene, washed with water, dried over anhydrous sodium sulphate and

  evaporated to give 32.7 g of 2-bromo-4,5-difluoro-1-nitro-

benzene as a yellow oil.

  2-Bromo-4,5-difluoro-1-nitrobenzene (32.7 g) a

  added to a stirred mixture of iron powder (69 g),

  concentrated hydrochloric acid (6.8 ml) and water (500 ml) at 80-

   C and stirred at 85-90 ° C for 2 hours. After cooling

  the mixture was made basic with carbonate

  of potassium, extracted with benzene, washed with water,

  on anhydrous sodium sulphate and evaporated. The oil remains

  duel was distilled to give 19.5 g of 2-bromo-4,5-di-

  fluoroaniline in the form of an oil; p.e .: 120-125 ° C (27 mm Hg).

  In a stirred mixture of 2-bromo-4,5-difluoroaniline

  ne (19.5 g) and polyphosphoric acid (100 g), we added

  acetoacetic acid ethyl ester (13 g) and stirred at 140 ° C. for two hours. The mixture has been cooled

  and neutralized with 10% sodium hydroxide solution. The precipitate

  This was filtered, washed with water and dried. The solid has been

  recrystallized from DMF to provide 11.3 g of 8-bromo-5,6-

  difluoro-4-hydroxy-2-methylquinoline in the form of needles

colorless, m.p .: 278 - 279 C.

  A mixture of 8-bromo-5,6-difluoro-4-hydroxy-2-methyl

  thylquinoline (11.3 g) and phosphorus oxychloride (100

  ml) was refluxed for 5 hours. The excess of oxy-

  phosphorus chloride was evaporated and the residue was neutralized

  8. Washed with an aqueous solution of potassium carbonate and cooled with ice. The precipitate was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethanol to give 9.3 g of 8-bromine.

  4-chloro-5,6-difluoro-2-methylquinoline as a needle

colorless; m.p .: 140 - 142 C.

  A mixture of 8-bromo-4-chloro-5,6-difluoro-2-methyl

  Thylquinoline (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

  the absorption of hydrogen ceases. The mixture was filtered,

  centered and made basic with an aqueous solution of carbon

  potassium nate. The mixture was extracted with dichloromethane

  methane, washed with water, dried over sodium sulphate

  anhydrous and evaporated to give 5.3 g of 5,6-difluoro-2-methyl

  thylquinoléine. A mixture of 5,6-difluoro-2-methylquinoline (5.3 g), platinum dioxide (0.3 g) and methanol (150 g)

  ml) was hydrogenated at room temperature under

  40 atmospheres until the absorption of hydro-

  gene stops. The mixture was filtered and concentrated to give 0 g of 5,6-difluoro-1,1,2,3,4-tetrahydro-2-methylquinoline.

EXAMPLE 5

  9-Fluoro-6,7-dihydro-5-methylhydrochloride

  l-oxo-8- (1-piperazinyl) -LH, 5H-benzo [ij] quinolizine-2-carboxylic

lic

  A mixture of 8,9-difluoro-6,7-dihydro-5-methyl-1

  oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid (1.4g), piperazine (2.2g) and p-picoline (5ml) was refluxed for 7 1/2 hours. The mixture was evaporated to dryness and acidified with hydrochloric acid. The resulting precipitate was filtered and recrystallized from a mixture of water and ethanol to give 1.0 g of acid hydrochloride.

  9-fluoro-6,7-dihydro-5-methyl-1-oxo-8- (1-piperazinyl) -1H, 5H-

  Benzo [ij] quinolizine-2-carboxylic acid in the form of crystals

colorless. m.p .:> 300 C.

  9. Analysis calculated for C18H2003N3F.HCl.1.75 H20

C H N

: 52.30 5.97 10.17

Found: 52.25 5.64 10.43

EXAMPLE 6

  9-Fluoro-6,7-dihydro-5-methyl-1-oxo-8- (4-) -acetate

  methyl-1-piperazinyl) -1H, 5H-benzo [i] quinolizine-2-carboxylic acid

lic

  A mixture of 9-fluoro-6,7-dihydro-5-methyl-

  1-oxo-8- (1-piperazinyl) -lHv5H-benzo [ij] quinolizine-2-carboxylic

  Xyl (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 and the basic solution was neutralized with acid.

  acetic acid and extracted with dichloromethane. The organic layer

  was washed with water, dried over

  anhydrous sodium and evaporated. The residual solid has been recreated

  tallied in a mixture of DMP and ethanol to give 0.70

  9-Fluoro-6,7-dihydro-5-methyl-1-oxo-8- (4-methyl-1) -acetate

  piperazinyl) -1H, 5H-benzo [ij] quinolizine-2-carboxylic acid under

  form of colorless needles; m.p .: 261 - 263 C.

C H N

  Analysis calculated for C19H2203N3F: 63.50 6.17 11.69 Found: 63.45 6.20 11.65

EXAMPLE 7

  8-chloro-1-ethyl-6,7-difluoro-1,4-dihydro-4- acid

oxoquinoline-3-carboxylic acid

  8-chloro-6,7-difluoro- ethyl acid ester

  1,4-dihydro-4-oxoquinoline-3-carboxylic acid (12.0 g), car-

  Anhydrous potassium bonate (29 g), ethyl iodide (33.6 ml) and DMF (300 ml) were mixed and stirred at 90-100 ° C for 12 hours. In the mixture, anhydrous potassium carbonate (14.5 g) and iodide were added.

  of ethyl (16.8 ml) and the mixture was heated with stirring.

  at 90-100 C for 9 hours and a half. The mixture has been

  concentrated to dry, water added, extracted with dichloromethane

  10. methane and evaporated. In the residue, we added

  18% hydrochloric acid (100 ml) and heated with

  flow for 4 hours. In the aqueous solution, water (200 ml) was added and extracted with dichloromethane. The dichloromethane layer was washed with water and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 7 g of 8-chloro-l-ethyl-6,7-difluoro acid. -1,4-dihydro-4-oxoquinoléi-ne-

  3-carboxylic acid in the form of colorless needles; m.p .: 215-217 C.

C H N

  Analysis calculated for C12H803NF2Cl: 50.11 2.80 4.87 Found: 50.40 2.72 4, 93

  Starting material, ethyl acid ester 8-

  chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic

  that was obtained by the following method.

  2-chloro-3,4-difluoroaniline (9.6 g) and diethyl ester of ethoxymethylenemalonic acid (12.8

  g) were mixed and heated at 120-130 C for 2 hours.

  After cooling, diphenyl ether (100 ml) was added to the mixture and refluxed for 30 minutes. The reaction mixture was cooled and benzene (100 ml) was added.

  been added. The precipitate was collected, washed with benzene

  ne and dried. The solid was recrystallized from DMF to

  give 13.3 g of 8-chloro-6,7-difluorinated ethyl ether

  α-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in the form of

  colorless powder: mp: 292-293 ° C (decomposition).

EXAMPLE 8

  8-chloro-1-ethyl-6-fluoro-1,4-acid hydrochloride

  dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid

  A mixture of 8-chloro-1-ethyl-6,7-difluoro-1,4-

* dihydro-4-oxoquinoline-3-carboxylic acid (0.65 g), piperine

  Zine (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 recrystallized from a mixture of water and ethanol

  to give 0.60 g of 8-chloro-1-ethyl acid hydrochloride

  6-fluoro-l1,4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-car-

  boxylic acid in the form of a colorless powder, m.p.

  11. Analysis calculated for C16H1703N3F.HCl. 2H5OH

C H N

49.33 3.89 10.46

Found: 49.30 4.59 10.25

EXAMPLE 9

  8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoacid

  7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid

  8-chloro-1-methyl-6-fluorohydrochloride

  1,4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid

  (0.25 g), sodium formate (0.5 g), formic acid,

  than 87% (5 ml) and 37% formaldehyde solution (5 ml)

  ml) were mixed and refluxed for 6 hours.

  one and a half times. The solution was evaporated and basified with aqueous sodium hydroxide solution. The basic solution has been

  neutralized with acetic acid, extracted with dichlo-

  romethane and evaporated. The residue was recrystallized from

  ethanol to give 0.21 g of 8-chloro-1-ethyl-6-fluo-

  ro-l1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) quinoline-3-

  carboxylic acid in the form of a colorless powder; mp: 213 -

216 C.

  Analysis calculated for C17H1903N3FCl.T H20

C H N

54.84 5.28 11.29

  Found: 54.98 5.20 11.14 Experiment 1 - Antibacterial activity (in vitro) The antibacterial activities of the compounds of the present invention were evaluated by the standard method

  streak development with agar dilution, vis-à-

  gram-positive and gram-negative bacteria [Chemothe-

  rapy, 22, 1126 (1974)]. The result has been indicated in the

  I with some of the known agents. The compounds of Examples 2, 3, 5, 6, 8 and 9 were more active than nalidixic acid and that pipemidic acid against bacteria

gram-positive and gram-negative.

  Experiment 2 - Antibacterial activity (in vivo) The in vivo antibacterial activity of the compounds of Examples 2, 3 and 6 was determined in infections of 12.

  the organization, and the results were presented in the table.

  In comparison with those of AM-715, nalidixic acid (NA), pipemidic acid (PPA) and miloxacin (MLX). Infections of the organism were produced by inoculation of male mice (weighing 2 g) intraperitoneally with experimental strains.

  suspended in 0.5 ml of infusion of

  calf-heart containing 5% mucin: Pseudomonas aeruginosa GN11187, 3.3 x 105 cells, Serratia marcescens GN7577, 2.2 x 10 cells, and Staphylococcus aureus Smith, 3.0 x

  cells. Pharmaceuticals were administered

  orally to the mice twice a day, immediately

  after and 4 hours after infection, and the therapeutic effect

  pharmacy was judged by survival rate. A comparison of antibacterial activity

  in vivo was made on the basis of the average effective dose.

  this (DE50) calculated by the so-called probit analysis. The in vivo antibacterial activities of the compounds of Examples 2, 3 and 6 were clearly more effective than those of AM-715, NA, PPA and miloxacin against infections.

  of the body of the mice with each bacterium.

TABLE I

  Antibacterial Activity Minimum Inhibition Concentration (μg / ml) Organisms The compound of - - - Ex.2 Ex.3 | Ex.5 Ex.86 Ex.8Ex. NA PPA Bacillus subtilis PCI219 0.10 0.20 0.10 0.10 0.20 0.20 6.25 6.25 Staphylococcus aureus 209P 0.39 0.39 0.78 0.20 0.78 0.78 100 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 1.56 Proteus vulgaris 3167 0.025 0.05 0.025 0.05 0.05 0.05 3.13 3.13 P. vulgaris XK Denken 0.05 0.10 0.20 0.20 0.10 0.39 3.13 6.25 Klebsiella pneumoniae IFO 3512 0.025 0.025 0.025 0.025 0.05 0.05 1.56 1 , 56 Pseudomonas aeruginosa V-1 0.39 1.56 6.25 3.13 1.56 6.25 100 12.5 P. aeruginosa IF012689 0.78 3.13 6.25 6.25 3.13 12, P. aeruginosa IID1210 3.13 12.5> 200 50 P. aeruginosa IID1130 0.78 3.13> 200 Salmonella enteritidis IID604 0.20 0.39 0.39 1.56 12.5 12 Shigella sonnei IID969 0.05 0.05 <0.0 5 1.56 1.56 Serratia marcescens IID6.8 0.10 0.20 S marcescens IID619 0.20 0.39 S. marcescens IID620 0.10 0, Yersinia enterocolitica IID981 0.10 0.20 0.39 0.39 0.20 0.39 Aci netobacter anitratus IID876 0.78 0.20 0.78 0.20 0.39 0.39 Staphylococcus epidermidis IID866 0.78 0.78 1.56 0.39 1.56 1.56 w Streptococcus pyogenes IID692 3.13 6 , 25> 100> 100 TABLE I (Continued) S. pyogenes S-8 S. faecalis IID682 Diplococcus pneumoniae

IID552

Corynebacterium pyogenes

IID548

12.5 6.25 6.25 12.5 6.25 6.25

3.13 6.25

  > 100> 100> 100> 100 NA: Nalidixic acid PPA: Piperidic acid.% 1% 4 N "Ns 15.

TABLE II

  Comparative Activities of the Compounds of Examples 2, 3 and 6, and AM-715, NA, PPA and MLX Products Against Infections of the Body

  AM-715: 1-Ethyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -acid

4-oxoquinoline-3-carboxylic acid

  The present invention is not limited to the examples

  These embodiments, which have just been described, are, on the contrary, susceptible of variations and modifications which

  will appear to those skilled in the art. -

I '

DE50 compound (mg / kg)

  _ _ _ _ _ _ _ _ _ _ _ _ 5 0_ _ _ _ _ _ _ _ _

  P. aeruginosa S.marcescens S.aureus Smith

GN11187 GN 7577

EX. 2 11.2 14.5 <17.5

EX. 3 9.2 21.3 <17.5

EX. 6 24.5

AM-715 38.0 44.9 38.0

NA> 400> 400> 400

PPA 280> 400 183

MLX 150 78.6 98.4

16.

Claims (4)

  1 - Compound, characterized in that it has the formula: O R4 R1   R1 is a lower alkyl group, R2 is a halogen, R3   is a piperazinyl group or a N-lower alkyl group   peroxinyl, and R4 is a halogen or lower alkyl group.   or R1 and R4 represent alkylene groups and may together complete a hexagonal ring, which may or may not be substituted by lower alkyl radicals,   as well as their hydrates or their pharmaceutically acceptable salts.   Ceptables of addition with acids.   2 - Compound according to claim 1, characterized in that it is chosen from a group consisting of:   of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-   (1-piperazinyl) quinoline-3-carboxylic acid, its hydrates or its salts,   1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-   (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid, from its draits or its salts,   9-fluoro-6,7-dihydro-5-methyl-1-oxo-8- (1-   piperazinyl) -1H, 5H-benzo [i] quinolizine-2-carboxylic acid, its hydrates or its salts,   of 9-fluoro-6,7-dihydro-5-methyl-1-oxo-8- (4-   methyl-1-piperazinyl) -1H, 5H-benzo [i] quinolizine -2-carboxylic acid   that of its hydrates or its salts,   8-chloro-1-ethyl-6-fluoro-11,4-dihydro-4-acid   oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid, its hydra- or its salts, and   of 8-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-acid   oxo-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid, its hydrates or its salts. 17.   3 - Process for the preparation of acid derivatives which   carboxylic compound, characterized in that it consists of   reacting a compound having the formula: R 2 X, R 4 COOH R 1, R 1, R 2 and R 4 are as defined in claim 1 and X is halogen, with a compound having the formula: r - N R5-N NH   R 5 is hydrogen or lower alkyl, to produce a compound having the formula: R 2 COOH N I I R4 R1   R1, R2, R4 and R5 are as defined above, its   hydrates or its pharmaceutically acceptable salts.   4 - Process for preparing a compound having the formula: COOH R I 4 R1   R 1, R 2 and R 4 are as defined in claim 1 and R 6 and R 7 represent hydrogen or a lower alkyl group, its hydrates or its pharmaceutically acceptable salts, characterized in that it consists in react a compound having the formula: R2 COOH HN N R4 R1   R1, R2 and R4 are as defined above, with a compound having the formula: R6-CO-R7   R6 and R7 are as defined above, in the presence of a reducing agent. Pharmaceutical composition with antibacterial activity, characterized in that it contains, as active ingredient, at least one of the compounds indicated in claim 1.