Note: Descriptions are shown in the official language in which they were submitted.
~5~4
This invention relates to new and useful quinoline
carboxylic acid derivatives having potent antibacterial
ac-tivities.
Antibacterial agents such as nalidixic acid,
piromidic acid, and pipemidic acid have proved to be highly
effective in the therapy of infections due to gram-negative
bacteria. However, such agents suffer the serious disadvan-
tage of having only weak activities against most gram-posi-
tive bacteria and Pseudomonas aeruginosa.
The compounds of the present invention are par-
ticularly useful in that they possess potent antibacterial
activity against both gram-positive and gram-negative
bacteria, including Pseudomonas aeruginosa~
We reported previously (The 98th Annual Meeting
of Pharmaceutical Society of Japan, April 1978, Abstract
p. 233, Japan Kokai Sho 53-65887, Sho 53-141286) that the
l-ethyl, l-vinyl or l-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-
(l-piperazinyl or 4-substituted-1-piperazinyl)quinoline-3-
carboxylic acids having fluorine or chlorine in the 6 or 8-
position have potent antibacterial activity against both gram-
positive and gram-negative bacteria including Pseudomonas
aeruginosa. As a result of a continuous study on structure-
activity relationships on the related compounds, we have
found that 1,6,7,8-tetrasubstituted-1,4-dihydro-4-oxoquinoline-
3-carboxylic acids having fluorine or chlorine in the 6-posi-
tion, a substituent other than hydrogen in the 7-position, and
fluorine, chlorine, bromine, methyl, or alkyl in the 8-posi-
tion, which together with a substituent in the l-position can
form a 5 or 6-membered ring had more potent antibacterial
activities against gram-negative bacteria than the above
compounds.
The new compounds of the present invention are
quinoline carboxylic acid derivatives having the formula: ~,
~LX~
R2~ ~ COOH (I)
R3
R4 Rl
[wherein Rl is lower alkyl, R2 is halogen, preferably fluor-
ine or chlorine, R3 is piperazinyl or N-lower alkyl pipera-
zinyl, and R4 is halogen, preferably fluorine, chlorine, or
bromine, lower alkyl, preferably methyl or Rl and R4 are
alkylene which can together form a 6-membered ring], the
hydrates, or the pharmaceiutically acceptable salts thereof.
The preferred compounds of formula (I) which can
be used as antibacterial agents are the following:
1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-quinoline-3-carboxylic aeid,
l-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-
methyl-l-piperazinyl~quinoline-3-.earboxylie aeid,
9-Fluoro-6,7-dihydro-5-methyl-1-oxo-8-(1-pipera-
zinyl)-lH,5H-benzoCij3quinolizine-2=earboxylie aeid,
9-Fluoro-6,7-dihydro-5-methyl-1-oxo-8-(4-methyl-1-
piperazinyl)-lH,5H-benzo[ij]quinolizine-3-earboxylic aeid,
8-Chloro-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-
(l-piperazinyl)quinoline-3-earboxylie aeid,
8-Chloro-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-
methyl-l-piperazinyl)quinoline-3-earboxylie acid,
the hydrates, and the pharmaeeutieally aeeeptable salts of
these eompounds.
The compounds of the present invention are prepar-
ed by the methods A and B.
Method A:
The compound (I) is prepared by the reaction of a
compound of formula (II~:
-- 2
~ 5~! 4~,f~
R2`~COOH
X ~ N
R4
~wherein Rl, R2 and R4 are the same as described above and
X is halogen] with a compound of formula (III):
R5- N NH (III)
[wherein R5 is hydrogen or lower alkyl group] in an inert
solvent such as, for example, water, alcohols, pyridine,
picoline, N,N-dimethyl formamide, dimethylsulfoxide, or the
like, or in the absence of a solvent, at a temperature in
the range of 60C to 180C. The reaction is preferably
carried out in the presence of a base, which will serve as
a dehydrohalogenating agent, such as an alkali hydroxide,
an alkali carbonate, or amines.
Method B:
The compounds of the formula (I) are obtained by
the reaction of a comp~und of the formula (IV):
R2 ~ ~ COOH
HN ~ ~ (IV)
R4 Rl
[wherein Rl, R2 and R4 are the same as mentioned above] with
a compound of the formula (V)
R -CO-R7 (V)
[wherein R6 and R7 are hydrogen or lower alkyl] in the
presence of a reducing agent such as, for example, formic
acid, sodium borohydride, a catalytic hydrogenating agent,
or the like. E~amples of the solvent used in the reaction
~ ` - 3 -
~s~ c~'~
are water, alcohols, ethers, dipolar aprotic solvent, or the
like .
The following examples serve to illustrate the
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-
trifluoroquinoline (3.0 g), anhydrous potassium car~onate
(7.6 g), ethyl iodide (8.8 ml) and N,N-dimethylformamide
(DMF) (100 ml) was heated with stirring at 90 ,v 100C for
10 hours. The reaction mixture was evaporated to dryness,
water was added, the resulting solid was collected, washed
with water, and dried. The solid was dissolved in dichloro-
methane, filtered and evaporated. To the residue there 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 recrystallized from a mixture of DMF and~
ethanol to give 2.1 g of 1-ethyl-1,4-dihydro-4-oxo-6,7,8-
trifluoroquinoline-3-carboxylic acid as colorless needles,
mp : 259,v 261C.
C H N
Anal. CalCd. for C12H803~F3 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 method.
A mixture of 2,3,4-trifluoroaniline (4.9 g) and
ethoxymethylene malonic acid diethyl ester (7.2 g) was heated
at 120~- 140C for 1 hour. After cooling, diphenylether
(50 ml) was added to the mixture which was refluxed for 30
min. After cooling, benzene was added to the mixture, the
precipitate was filtered, washed with benzene, dried, and
recrystallized from DMF to give 5.7 g of 3-ethoxycarbonyl-4-
-- 4 --
~ ....
~ r ~
hydroxy-6,7,8-trifluoroquinoline as colorless powder, mp :
280 -J283C (decomp.)
C H N
Anal. Calcd. for C12H803NF3: 53.15 2.97 5.16
Found 52.83 2.84 5.10
EX~MPLE 2 1-Ethyl-6,8-dlfluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)quinoline-3-carboxylic acid hydro-
chloride
A mixture of l-ethyl-1,4-dihydro-4-oxo-6,7,8-tri-
fluoroquinoline-3-carboxylic acid (1.35 g), piperazine (2.2 g)
and pyridine (10 ml) was ~efluxed for 6 hours. The reaction
mixture was evaporated to dryness. Diluted hydrochloric
acid was added to the residue to adjust the pH below 1 and
the precipitate was filtered. The solid was recrystallized
from water to give 1.45 g of 1-ethyl-6,8-difluoro-1,4-di-
hydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid
hydrochloride as colorless crystals, mp ~ 300C.
C H N
Anal. Calcd. for C16H17O3N3F2-HCl 51-41 4.85 11.24
Found 51.07 4.79 11.18
EXAMPLE 3 1-Ethyl-~,8-difluoro-1,4-dihydro-4-oxo-7-(4-
methyl-l-piperazinyl)quinoline-3-carboxylic acid
l-Ethyl-6,8-~ifluoro-1,4-dihydro-4-oxo-7 (1-
piperazinyl)-quinoli~e-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. Water (10 ml)
was added to the residue, the pH of the solution was adjust-
ed to 7 by the addition of 10% sodium hydroxide solution,
and was extracted with dichloromethane. The organic layer
was washed with water, dried over anhydrous sodium sulfate,
and evaporated. The residue was recrystallized from a
~ 5 ~
,4
mixture of DMF and ~-thanol to give 0.45 g of l-ethyl-6,8-
difluoro-1,4-dihydro-4-oxo-7-(4-methyl-l-piperazinyl)quino-
line-3-carboxylic acid as colorless crystals, mp : 245~ 246C.
C H N
Anal. Calcd. for Cl7Hl903N3F2 11.96
Found : 57.97 5.48 12.02
EXAMPLE 4 8,9-Difluoro-6,7-dihydro-5-methyl-l-oxo-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid
A mixture of 5,6-difluoro-2-methyl-1,2,3,4-tetra-
hydroquinoline (5.0 g) was heated at 120 -'130C for 5 hours.
After cooling polyphosphoric acid (40 g) was added to the
mixture and the latter was heated with stirring at 120~130C
for 20 min. After cooling, water (80 ml) and concentrated
hydrochloric acid (30 ml) were added to the mixture and the
latter was refluxed for 3 hours. The reaction mixture was
cooled and dilute~ wi~h water. The precipitate was filtered,
washed with water, and dried. The solid was recrystallized
from a mixture of DMF and ethanol to give 4.5 g of 8,9-di-
fluoro-6,7-di-hydro~ ~thyl-l-oxo-lH,5H-benzo~ij]quinolizine-
2-carboxylic acid as colorless needles, mp : 287-~ 288C.
C ~ N
Anal,Calcd. for C14Hll03NF2 : 60.22 3,97 5.02
Found : 60.38 3.84 4.94
The starting material of the above process, 5,6-
difluoro-2-methyl-1,2,3,4-tetrahydroquinoline was obtained by
the following method.
To a stirred mixture of l-bromo-3,4-difluoro-
benzene (27 g) and concentrated sulfuric acid (30 ml) there
was added dropwise 90% nitric acid (11.2 g~ at 20 ~30C and
stirred at 50 ,v 60C for 2 hrs. The mixture was poured onto
ice, extracted with benzene, washed with water, dried over
anhydrous sodium sulfate, and evaporated to give 32.7 g of
,
6 --
2-brorno-4,5-difluoro-1-nitrobenzene as yellow oil.
2-~romo-4,5-difluoro-1-nitrobenzene (32.7 g) was
added to a stirred mixture of iron powder (69 g), concen-
trated hydrochloric acid ~6.8 ml), and water (500 ml) at
80,v 90~C and the mixture was stirred at 85,v 90C for 2 hrs.
After cooling, the mixture was made basic with potassium car-
bonate, extracted with benzene, washed with water, dried aver
anhydrous sodium sulfate, and evaporated. The residual
oil was distilled to give 19.5 g of 2-bromo-4,5-difluoro-
aniline as oil, bp : 120-V 125C (27 mmHg).
To a stirred mixture of 2-bromo-4,5-difluoroaniline
(19.5 g) and polyphosphoric acid (100 g) acetoacetic acid
ethyl ester (13 g) was added and the mixture was stirred at
140C for 2 hours. The mixture was cooled and neutralized
with 10% sodium hydroxide solution. The precipitate was
filtered, washed with water and dried. The solid was recrys-
tallized from DMF to afford 11.3 g of 8-bromo-5,6-difluoro-
4-hydroxy-2-methylquinoline as colorless needles, mp : 278
278 ~v 279C.
A mixture of 8-bromo-5,6-difluoro-4-hydroxy-2-
methylquinoline (11.3 g) and phosphorus oxychloride (100 ml)
was refluxed for 5 hrs. The excess phosphorus oxychloride
was evaporated and the residue was neutralized with an
aqueous potassium carbonate solution while cooling 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-bromo-4-chloro-5,6-difluoro-2-methylquinoline
as colorless needles, mp : 140 GV 142C.
A mixture of 8-bromo-4-chloro-5,6-difluoro-2-methyl-
quinoline (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
carbcnate. The mixture was extracted with dichloromethane,
washed with water, dried over anhydrous sodium sulfate, and
evaporated to give 5.3 g of 5,6-difluoro-2-methylquinoline.
A mixture of 5,6-difluoro-2-methylquinoline (5.3 g)
platinum dioxide (0.3 g), and methanol (150 ml) was hydro-
genated at room temperature at a pressure of 40 atm, until
the hydrogen uptake had ceased. The mixture was filtered
and concentrated to give 5.0 g of 5,6-difluoro-1,2,3,4-
tetrahydro-2-methylquinoline.
EXAMPLE 5 9-Fluoro-6,7-dihydro-5-methyl-1-oxo-8-(1-
piperazinyl)-lH,SH-benzo[ij]quinolizine-2-
carboxylic acid hydrochloride
A mixture of 8,9-difluoro-6,7-dihydro-5-methyl-1-
oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (1.4 g),
piperazine ~2.2 g), and ~-p~oline (5 ml) was refluxed for
7.5 hour~. The mixture-w~ evaporated to dryness and acidi-
fied with hydrochloric aci~. The resulting precipitate was
filtered and recrystallized 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)-lH,5H-benzo~ij]quinolizine-2-carboxyl-
ic acid hydrochloride as colorless crystals, mp > 300C.
18 20 3 3 H 1-1 3/4 H20
C H ~
: 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-
methyl-l-piperazinyl)-lH,5H-benzo[ij]quinoli-
zine-2-carboxylic acid
A mixture of 9-fluoro-6,7-dihydro-5-methyl-1-oxo-8-
(l-piperazinyl)-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
"
. ~ - 8 -
hydrochloride (0.9 g), sodilDn formate (0.64 g), 87% formic
acid (5 ml), and a 37% formaldehyde solution (5 ml) was re
fluxed for S hours. The mixture was evaporated to dryness
after which an aqueous sodium hydroxide solution was added.
The basic solution was neutralized with acetic acid and
extracted with dichloromethane. The organic layer was
washed with water, dried over anhydrous sodium sulfate, and
evaporated. The residual solid was recrystallized from a
mixture of DMF and ethanol to give 0.70 g of 9-fluoro-6,7-
dihydro-5-methyl-1-oxo-8-(4-methyl-1-piperazinyl)-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid as colorless needles,
mp : 261 -'263C.
C H N
Anal. Calcd. for C19~2203~3F : 63.50 6.17 11.69
Found : 63.45 6.20 11.65
EXAMæLE 7 8-Chloro-l-ethyl-6,7-difluoro-1,4-dihydro-4-
oxo-quinoline-3-carboxylic acid
8-Chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ~hyl ester (12.0 g), anhydrous potassium
carbonate (29 g), ~thyl iodide (33.6 ml), and DMF (300 ml)
were mixed and the mixture was stirred at 90-- 100C for 12
hours. To the mixture there were added anhydrous potassium
carbonate (14.5 g) and ethyl iodide (16.8 ml) and the mix-
ture was heated with stirring at 90-v 100C for 9.5 hours.
The mixture was concentrated to dryness, water was added, it
was extracted with dichloromethane and evaporated. 18%
~ydrochloric acid (100 ml) was added to the residue and it
was refluxed for 4 hours. To the aqueous solution there
was added water (200 ml) and the mixture was 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 5O7 g of 8-chloro-1-ethyl-
~L~S~4~
6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as
colorless needles, m.p. : 215 -~217C.
C ~ N
1. Calcd. for C12H803N3 ~Cl : S0.11 2.80 4.87
Found : 50.40 2.72 4.93
The starting material, 8-chloro-6,7-difluoro-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was
obtained by the following method.
2-Chloro-3,4-difluoroaniline (9.6 g) and ethoxy-
methylenemalonic acid diethyl ester (12.8 g) were mixed and
heated at 120-v 130C for 2 hours. After cooling, diphenyl-
ether (100 ml) was added to the mixture which was refluxed
for 30 min. The reaction mixture was cooled, and benzene
(100 ml) added. The precipitate was collected, washed with
benzene, and dried. The solid was recrystallized from DMF
to give 13.3 g of 8-chloro-6,7-difluoro-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid ethyl ester as colorless pow-
der, mp : 292 _v 293C (decomp.).
EXAMPLE 8 8-Chloro-l-ethyl-6-fluo~-1,4-dihydro-4-oxo-7-
(l-piperazinyl)quinoline-~-carboxylic acid
hydrochloride
A mixture ~f 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 min. The
reaction mixture was evaporated and acidified with hydrochlor-
ic acid. The precipitate was collected and recrystallized
from a mixture of water and ethanol to give 0.60 g of 8-
chloro-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)
quinoline-3-carboxylic acid hydrochloride as coIorless powder,
mp > 300~C.
' 7~ .,
-- 10 --
~ lS~
Anal,Calcd. for C16H1703N3F Cl.HCL.1/4 C2~150H
C ~ N
: 49,33 4.89 10.46
Found: : 49.30 4.59 10.25
EXAMPLE 9 8-Chloro-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-
(4-methyl-1-piperazinyl)quinoline-3-carboxylic
acid
8-Chloro-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7~
piperazinyl)-quinoline-3-carboxylic acid hydrochloride (0.25
g), sodium formate ~0.5 g), 87% formic acid (5 ml), and 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 neutralized with acetic acid, extracted with dichloro-
methane, and evaporated. '~he re6idue was recrystallized
from ethanol to give 0.21 g of 8-chloro-1-ethyl-6-fluoro-
1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)quinoline-3-
carboxylic acid as colorless powder,~mp : 213 ~v 216C.
17 19 3 3 1/ 2
C w 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
this invention were assayed by the standard agar dilution
streak method against gram-positive and gram-negative bact-
eria [Chemotherapy, 22, 1126 (1974)]. The result is shown
in Table 1 together with some of the known agents. The com-
pounds of EXAMPLES 2, 3, 5, 6, 8 and 9 were more active than
nalidixic acid and pipemidic acid against gram-positive and
gram-negative bacteria.
Experiment 2 Antibacterial Activity (in vivo)
, , ,
-- 11 -- -
~ ~5~3434
The in vivo antibacterial activity of the compounds
of ~XAMPLE 2, 3 and 6 were determined in systemic infections,
and the results were shown in Table 2, compared with those of
AM-715, nalidixic acid ( NA ), pipemidic acid ( PPA ) and
miloxacin ( MLX). Systemic infections were produced by
inoculating male mice (weighing 20 i 2 g) intraperitoneally
with the following test strains suspended in 0.5 ml of brain
heart infusion containing 5% mucin: Pseudomonas aeruginosa
GN11187, 3.3 x 10 cells, Serratia marcescens GN7577,
2.2 x 105 cells, and Staphylococcus aureus Smith, 3.0 x 105
cells. The drugs were administered orally to mice twice a
day, immediately after and 4 hours after infection, the
therapeutic effect of drugs was judged from the survival rate.
A comparison of in vivo antibacterial activity was made on
the basis of the mean ef~ective dose ( ED50 ) calculated by
probit analysis. The in vivo antibacterial activities of
the compounds of EXAMPLE 2, 3 and 6 were~clearly more effect-
ive than those of AM-71S, NA, PPA and m~loxacin against
systemic infections of mice ~ith each b~cteria.
- 12 -
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TABLE 2
Comparative activities of the compounds of
EXAMPLE 2, 3 and 6, AM-715, NA, PPA and MLX
against systemic infections
_ _ _ ED50 (mgjkg)
Compound ~
P aeruginosa S. marcescens S. aureus
GN11187 GN7577 Smith
.
EX. 211.2 14.5 ~17.5
EX. 39.2 21.3 ~17.5
EX. 624.5 - _
AM-71538.0 ~ 44.9 38.0
NA >400 i400 >400
PPA 280 ~4~00 183
150 -~8.6 98.4
....
AM-715 : 1-Ethyl-6-fluoro-1,4-dihydro 7-~1-piperazinyl)-4-
oxo-quinoline-3-car~oxylic `aeid
