Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~L2593~S
. 23189-6009D
Our Patent Application Serial No. 482,912 relates to
new 1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids,
process for their preparation and antibacterial agents and feed
additives containing them. This application is divided out of
Application Serial No. 482,912.
Application Serial No. 482,912 discloses new 1-cyclopro-
pyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecar-
boxylic acids of the formula (I)
F ~ COOH
1 ~ -'' ~ N (I)
R - N y N X1 ~
R2
in which
R1 denotes hydrogen, straight-chain or branched alkyl
which has 1 to 4 carbon atoms and is optionally substituted by hy-
droxyl, methoxy, amino, dimethylamino, halogen, such as, for ex-
ample, fluorine or chlorine, cyano or alkoxycarbonyl having 1 or 2
carbon atoms in the alkyl moiety, oxoalkyl having up to 4 carbon
atoms, phenacyl, or acyl having 1 to 4 carbon atoms,
R denotes phenyl and cyclohexyl which are optionally
singly to triply substituted by halogen, such as, for example,
chlorine, bromine or fluorine, methyl, phenyl, cyano, hydroxyl,
methoxy, benzyloxy, amino, methylamino, dimethylamino, piperidino
or nitro, methylenedioxyphenyl, methylenedioxycyclohexyl, furyl,
tetrahydrofuryl or thienyl, and
~L2~i~3~i
- la - 23189-6009D
xl denotes hydrogen or fluorine,
and their pharmaceutically utilisable hydrates, acid
addition salts, alkali metal and alkaline earth metal salts
-- 2 --
have high antibacterial activity.
Preferred compounds of the formula (I) are those in
~hich
R1 denotes hydrogen, straight-chain or branched
alkyl which has 1 to 4 carbon atoms and is option-
ally substituted by hydroxyl, methoxy, halogen,
such as, for example, fluorine or chlorine, cyano
or alkoxycarbonyL having 1 or 2 carbon atoms in
the alkyl moiety, oxoalkyl having up to 4 carbon
atoms, phenacyl, formyl or acetyL,
R2 denotes phenyl and cyclohexyl which are optionally
singly to tr;ply substituted by chlorine, bromine,
fluorine, methyl, phenyl, cyano, hydroxyl, methoxy,
benzyloxy, amino, piperidino or nitro, and thienyl,
and
x1 denotes hydrogen or fluorine~
Particularly preferred compounds of the formula tI)
are those in which
R1 denotes hydrogen, straight-chain or branched alkyl
~hich has 1 to 3 carbon atoms and is optionally
substituted by hydroxyl, methoxy, cyano or alkoxy
carbonyl having 1 or 2 carbon atoms in the alkyl
moiety, oxoalkyl having up to 4 carbon atoms,
phenacyl, formyl or acetyl,
25 R2 denotes phenyl and cyclohexyl which are optionally
s;ngly to triply substituted by chlorine, bromine,
fluorine, methyl, phenyl, hydroxyl, methoxy, ben~yl~
oxy, amino, piperidino or nitro, and thienyl, and
x1 denotes hydrogen or fluorine.
3~ It has also been found that the compounds of the
formula (I~ are obtained when 1-cyclopropyl-7-fluoro-1,~-
dihydro-4-oxo-3-quinolinecarboxylic acids of the formula
(II)
Le A ~3 081
__
~L25i~3~5
F ~,~ COOH ( I I )
X1 ~
in which
x1 has the abovement;oned meaning, and
x2 represents halogen~ ;n particular fluorine or
chlorine,
are reacted with piperazines of the formula (III)
R1-N ~ NH
~ (II I)
in which
R1 and R2 have the abovementioned meaning,
~here appropriate ;n the presence of acid-binding agents
(method A).
The compounds according to the invention, of the
formula (I), can also be obtained by reacting a 7-(1-
piperazinyl)-3-qu;nolonecarboxylic acid of the formula (IV)
o
F ~I~COOH
1 5 H~--~N~ ( I V )
R2 X1 ~
in which R2 and X1 have the abovementioned meaning,
with compounds of the formula (V)
R1 -X (V ~
in ~hich0 R1 has the abovementioned meaning but cannot be
hydrogen, and
Le_A 23 081
~25~3~5
-- 4 --
X denotes fluorine, bromine, lodine, hydroxyl, acyl-
oxy, phenoxy or 4-nitrophenoxy, ~here appropriate
in the presence of acid-binding agents tmethod a)~
The compounds according to the invention, of the
formula (I), are also obtained when a 7-(1-piperazinyl)-
3-qu~nolonecarboxylic acid of the formula (IV) is reacted
with a Michael-acceptor of the formula (VI)
R -C}I=CH2 tVI)
in which
R3 represents CN, CH3Co or CooR4,
R4 denotlng methyl or ethyl ~method C).
If, tn the reactlon by method A, 2-phenylpiperazine
and 1-cyclopropyl-6,7-dif1uoro-l,4-dihydro-4-oxo-3-
quinol1necarboxylic acid are used as the starting materials,
then the course of the reaction can be represented by the
equat~on below:
F ~ COOH
~ Nl! ~ --- ~ ~ N ~
If, in the reaction by method B, ethyl lodide and 1-cyclo-
propyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piper-
az1nyl)-3-qu1nolinecarboxylic acid are used as the starting
materials, then the course of the reaction can be represen-
ted by the equation belou.
Le A 23 081
.,
~Z~i~3~L5
~ 5 --
F ~J COOH
H~CN ~ N ~ 2 5
F~ COOH
C H N/~
~ . Hl
If, ;n the reaction by method C, for example
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-
p;peraz;nyl~3-quinolinecarboxylic acid and methyl vinyl
ketone are used as the starting compounds, then the course
of the reaction can be represented by the equation below:
F ~ COOH
H ~ ~ N~ +CH3-CO-CH=
CH3-CO-CU2CH2-N~N ~f
Some of the quinolonecarboxylic acids (II) used as
starting compounds are known (see DE-OS (German Published
Specification) 3,14Z,854: 7-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxyL;c acid), or they can
be prepared by the follo~;ng route:
Le A Z3 081
~.2S93~a5
-- 6 --
x2 ~C20- Zl "COOC2H5 Mg (OEt) 2
Xl ~ ~, z2=cl ,E'
2 )
~`~ 2--COOC2H5 - 3 ~C-CH2COOC H
(3~ X ~4
O
OC2H, X
(:~) (6)
O O
x2 ~ C2H5 x2 ~ COOH
(II)
According to this, diethyL malonate ~2) is acyl-
ated with the appropr;ate benzoyl fluoride or chloride (1)
in the presence of magnesium ethyla~e to give the aroyl-
malonate (3) (Organicum, 3rd edition,1964 page 438~.
By partial hydrolysis and decarboxylation of (3)
in aqueous medium with catalytic amounts of sulphuric ac;d
or p-toluenesulphonic acid, the ethyl aroylacetate (~) is
obtained in good yield, and this is converted into the
Le A 23 081
~LZSi93~
-- 7 --
corresponding ethyl 2-benzoyl-3-ethoxyacrylate (5) using
triethyl orthoformate/acetic anhydride. The reaction of
(5) with cyclopropylamine in a solvent, such as, for example,
methylene chloride, alcohol, chloroform, cyclohexane or
5 toluehe leads, in a slightLy exothermic reaction, to the
desired intermediate (6).
The cyclisation reaction (6) -~7) is carried
out in a temperature range from about 6û to 300C, prefer-
ably 80 to 1 80C~
The diluents which can be used are dioxane, di-
methyl sulphoxide~ N-methylpyrrolidone, sulpholane, hexa-
methylphosphoric triamide and, preferably, N,N-dimethyl-
formamide.
Suitable acid-binding agents for this reaction step
15 are potassium tert.-butanolate, butyllithium, lithiumphenyl,
phenyl magnesium bromide, sodium methylate, sodium hydride
sodium or potassium carbonate. When the intention is to
eliminate hydrogen fluoride (Z2=F~, potassium or sodium
fluor;de has also proved to be particularly suitable. It
20 may be advantageous to use an excess of 10 mol-% of base.
The ester hydrolysis of (7) under basic or acid
conditions, uhich is carried out in the last step, leads to
the appropriate cyclopropyl-6-fluoro~1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid (II).
Z5 The 2,3,4,5-tetrafluorobenzoyl chloride (1)
(X1=x2=zz~F~ z1 = Cl), which is used as starting material
for this synthetic route, was obtained from 2,3,4,5-tetra-
fluorobenzoic acid which is known from the literature ~G.G.
Yakobson, V.N. Odinokov and N.N. Vorozhtsov Jr., Zh. Obsh.
30 Khim. 36, 139 (1966)) using thionyl chloride in the custo-
mary manner. It has a boiling point of 75-80C/17 mbar~
2,3,4,5-tetrafluorobenzoyl f luoride has a boiling point of
46 to 47C/20 mbar (n2D0: 1.4375).
2,4,5-trifluoroben~oyl f luoride (1)
35 ~X1=H, X2=71=~2=F) which is used as a starting material was
prepared analogously from Z,~,5-trifluorobenzoic acid which
Le A 23 081
.
'- '
:~L2593~S
- 8 - 23189-6009D
is known from the literature (I.J. DeGraw, M. Corey and
W.A. Skinner, J. Chem. Eng. Datal3,587 (1968)). It has a boiling
point of 53-56 /18 mbar (nD:1.4546).
The compound of formula II in which X1 is hydrogen and
X is fluorine, l.e. the compound 1-cyclopropyl-6,7-difluoro,1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid is novel and is the
subject of this divisional application.
The 2-substituted piperazines (III) which are used as
starting materials are known or can be obtained from processes
known from the literature (for example: United States Patent
4,166,180; J. Med. Chem. 26, 1116 (1983)). The following may be
mentioned as examples: 2-phenylpiperazine, 2-(4-chlorophenyl)
piperazine, 2-(4-fluorophenyl)piperazine, 2-(4-bromophenyl)piper-
azine, 2-(4-methylphenyl)piperazine, 2-(4-biphenylyl)piperazine,
2-(4-methoxyphenyl)piperazine, 2-(4-benzyloxyphenyl)-piperazine,
2-(4-hydroxyphenyl)piperazine, 2-(3-hydroxyphenyl)piperazine, 2-
(2-hydroxyphenyl)piperazine, 2-(4-nitrophenyl)piperazine, 2-(3-
nitrophenyl)piperazine, 2-(4-aminophenyl)piperazine, 2-(4-piper-
idinophenyl)piperazine,2-(3,4-dimethoxyphenyl)piperazine, 2-(3,4,
5-trimethoxyphenyl)piperazine, 2-(3,4-dimethoxy-6-methyl)pipera-
zine, 2-(3,4-methylenedioxyphenyl)piperazine, 2-(4-cyanophenyl)-
piperazine, 2-(2-thienyl)piperazine or 2-(2-furyl)piperazine. In
accordance with our own proposal of the same date (Le A 23 097),
2-cyclohexylpiperazines are obtained by catalytic hydrogenation of
corresponding 2-arylpiperazines; for example 2-cyclohexylpiperazine
(melting point 82-83C).
9 ~ 231 89-6009D
~25~31~
The reaction of tII) with (III) by method A is
preferably carried out in a diluent such as dimethyl sul-
phoxide, N,N-dimethylformamide, hexamethylphosphoric tris-
amide, sulpholane, water, an alcohol, such as methanol,
ethanol, n-propanol, isopropanol or glycol monomethyl ether,
or pyridine. It is likewise possible to use mixtures of
these diluents.
All customary inorganic and organic acid-binding
agents can be used as the acid-binding agent. These
preferably include the alkali metal hydroxides, alkaline
metal carbonates, organic amines and amidines. The fol-
loning may be specifically mentioned as particularlysuitable: triethylamine, 1,4-diazabicycloC2.2~2]octane
(DABC0), excess amine (III) or 1,8-diazabicycloC5.4.0]undec-
7-ene (D~U).
The reaction temperatures can be varied within a
uide range. In general, the reaction is carried out between
about 20 and 200C, preferably between 80 and 1~0C.
The reaction can be carried out under atmospheric
pressure but also under elevated pressure. In general, it
is carried out under pressures between about 1 and about
100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the in-
vention, 1 to 5 moles, preferably 1 to 3 moles, of the pipe-
razine (III) are used for 1 mole of the carboxylic acid (II).
The reaction of (IV) with (V) is preferably carried
out in a d;luent such as dimethyl sulphoxide, dioxane, N,N-
dimethylformamide, hexamethylphosphoric trisamide, sulpholane,
uater, an alcohol, such as methanol, ethanol, n-propanol,
isopropanolO glycol monomethyl ether or pyridine. It is
likewise possible to use mixtures of these diluents.
All customary inorganic and organic acid-binding
agents can be used as the acid-binding agent. These
iL2~93~5
- 10 -
preferably include the alkaline metal hydroxides, alkaline
metal carbonates, or~anic amines and amid;nes. The follow-
ing may be specifically mentioned as particularly suitable:
triethylamine, 1,4-diazabicyclo~2.2.2]octane (DA~C0) or
1,8~d~azabicycloC5.4.0~undec-7-ene (D~U).
~ he reaction temperatures can be varied within a
wlde range. In general, the reaction is carried out bet-
ween about 20 and about 180C, preferably between 40 and
1 1 0 C .
The reaction can be carried out under atmospheric
pressure but also under elevated pressure. In general, it
is carried out under pressures between about 1 and about
100 bar, preferably between 1 and 10 bar.
When carrying out the process accord;ng to the in-
vention by method ~, 1 to 4 moles, preferably 1 to 1.5 mole,of the compound (V) are used for 1 mole of compr,und (IV).
The react~on of (I) with ~VI) (method C) is carried
out in a diLuent such as N,N-dimethylformamide, dioxane,
tetrahydrofuran, pyridine, water or in mixtures of these
dlluents. The reaction temperatures can be varied uithin
a ~ide range. In general, the reaction is carr;ed out bet-
ueen about oC and about 140C, preferably between 10
and 100C.
The reaction can be carried out under atmos,oheric
pressure but also under elevated pressure. In general, it
is carried out under pressures between about 1 and about 1Q0
bar, preferably betueen 1 and 10 bar.
When carrying out the process according to the ;n-
vention, 1 to 5 moles, preferably 1 to 2 moles, of compound
~VI) are used for 1 mole of compound (I).
Apart from the compounds detailed in the Examples,
the following may be specifically mentioned as new active
compounds of formula (I),
1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-3-phenyl-
1-piperazinyl)-~-oxo-3-quinolinecarboxylic acid,
7-(4-butyl-3-phenyl-1-p;perazinyl)-1-cyclopropyl-6-fluoro-
Le A 23 081
1~19~5
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1-cyclopropyl-6-fluoro-1~4-dihydro-7-c4-(2-hydroxyethyl)
3-phenyl-1-p;peraz;nyl~-4-oxo-3-qu;nol;necarboxyl;c ac;d,
1-cyclopropyl 6-fluoro-1,4-d;hydro-7-C4-t2-methoxyethyl)-
3-phe~yl-1-piperazinyl]-4-oxo-3-qulnolinecarboxylic acid,
7-[4-(2-aminoethyl)-3-phenyl 1-piperazinyl]-1-cyclopropyl-
6-fluoro-1,4-d;hydro-4-oxo-3-qu;nolinecarboxylic acid,
1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(2-dimethylamino-
ethyl)-3-phenyl-1-piperaz;nyl]-4-oxo-3-qu;nolinecarboxylic
acid,
1-cyclopropyl-6-fluoro-7-[4-(2-fluoroethyl)-3-phenyl-1-
p;peraz;nyl]-1,4-d;hydro-4-oxo-3-qu;nolinecarboxylic acid,
7-C4-(2-cyanoethyl)-3-phenyl-1-piperazinyl]-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-3-qu;nol;necarboxylic acid,
1-cyclopropyl-6-fluoro-1,4-d;hydro-7-[4-~2-methoxycarbonyl-
ethyl)-3-phenyl-1-piperaz;nyl]-4-oxo-3-quinolinecarboxyl;c
ac;d,
1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-7-(4-phenacyl-3-
phenyl-1-piperazinyl]-3-qu;nol;necarboxylic acid,
1-cyclopropyl-6-fluoro-7-(4-formyl-3-phenyl-1-piperazinyl)-
1,4-dihydro-4-oxo-3-quinolineocarboxylic acid,
7-(4-acetyl-3-phenyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinol;necarboxylic acid,
1-cyclopropyl-6-fluoro-1,4-d;hydro-7-C3-(4-methylcyclohexyl)-
1-piperaz;nyl]-4-oxo-3-qu;nolinecarboxylic acid,
1-cyclopropyl-6-fluoro-1,4-d;hydro-7-C3-(3,4,5-tr;methoxy-
phenyl)-1-p;perazinyl]-4-oxo-3-qu;nolinecarboxylic acid,
1-cyclopropyl-6-fluoro-1,4-d;hydro-7-[3-(3,4-methylenedioxy-
phenyl)-1-p;peraz;nyl]-4-oxo-3-qu;nolinecarboxylic acid,
7-C3-(4-cyanophenyl)-1-piperazinyl~-1-cyclopropyl-6-fluoro-
1,4-d;hydro-4-oxo-3-qu;nol;necarboxylic acid,
7-C3-(3-am;nophenyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-
1,4-d;hydro-4-oxo-3-quinolinecarboxylic acid,
1-cyclopropyl-6-fluoro-7-C3-t2-furyl)-1-piperazinyl~-1,4-
dihydro-4-oxo-3-quinolinecarboxyL;c ac;d,
1-cyclopropyl-6-fluoro-1,4-d;hydro-7-C3-(2-tetrahydrofuryl)-
Le A 23 081
____
:~L2593~
- 12 - 23189-6009D
1-p;peraz1nyl~-b-oxo-3-quinolinecarboxyl;c acid,
1-cyclopropyl-6-fluoro-1,4-dihydro-7-~3-~4-hydroxycyclo-
hexyl)-1-p;perazinyl]-4-oxo-3-qu;nolinecarboxylic acid,
7-~3-t3-aminocyclohexyl)-1-pipera~inyl]-1-cyclopropyl-6-
fluoro-1,4-dihydro-4-oxo-3-qu~nolinecarboxyl;c acid,
1-cyclopropyl-7-t4-ethyl-3-phenyl-1-piperazinyl)-6,8-
difluoro-1,4~diilydro-4-oxo-3-quinolinecarboxyl;c acid,
1-cyclopropyl-6,~-di~luoro-7-~3-t4-fluorophenyl)-4-(3-oxo-
butyl)-1-p1perazinyl-1,4-dihydro-4-oxo-3-quinolinecarboxy-
lic acid, and1-cyclopropyl-6,8-difluoro-7-~4-formyl-3-(2-thienyl)-1-
piperazinyl~-1,4-dihydro-l-oxo-3-qu1nolinecarboxylic ac;d.
The compounds according to formula (I) are of
low toxicity and exhibit a broad antibacterial spectrum
to~ard Gram-pos1tive and Gram-negat;ve organisms, ~ par-
ticular toward Enterobacter~aceae, especially includ;ng
those wh;ch are res;stant to various ant;biotics, such as,
for example, penicillins, cephalosporins, aminoglycosides,
sulphonamides and tetracyclines.
These valuable propert;es make ;t possible to use
them as chemotherapeutic act;ve compounds in medicine and
as substances for the preservation of inorganic and organic
mater;als, especially of organ;c materials of every type,
for example polymers, lubricants, dyes, fibres, leather,
paper and wood, of foodstuffs and of water.
The compounds according to formula (I) arc activeaga~nst a very broad spectrum of microorganisms. It ;s
possible with their aid to combat Gram-negative and Gram-
positive bacteria and bacterold microorgan;sms, and to
prevent, ameliorate and/or cure illnesses caused by these
pathogens.
The compounds according to formula (I) ar~ parti-
cularly active against bacteria and bactero;d microorgan;sms.
Thus they are particularly ~ell suited for the prophylaxis
and chemotherapy of local and systemic infections wh;ch are
raused by these pathogens in human and veter;nary med;cine.
Le A 23 081
~25~3~5 23189-6009D
- 13 -
For example, local and/or systemic illnesses which
are caused by the following pathogens or by mixtures of
tne following pathogens can be treated and/or prevented:
Micrococcaceae, such as Staphylococci, for example Staph.
aureus, Staph. Epidermidis (Staph. = Staphylococcus);
Lactobacteriaceae~ such as Streptococci, for example
Streptococcus pyogenes,~ - and~ -haemolytic Streptococci,
non-~ -haemolytic Streptococci, Enterococci and Diplococcus
pneumoniae ~Pneumococci),Enterobacteriaceae, such as
Escherichiae-bacterla of the Col; group: Escher;ch;a-
bacter;a, for example Escherich;a coli, Enterobacter bac-
teria, for example E. aerogenes, E. cloacae, (E. ~ Entero-
bacter), Klebsiella bacteria, for example K. pneumoniae
(K. = Klebsiella),Serrat;a, for example Serratia marcescens,
Proteae bacteria of the proteus group: Proteus, for example
Pr. vulgaris, Pr~ morgan;i, Pr. rettgeri, Pr. mirabilis
(Pr. = Proteus); Pseudomonadaceae, such as Pseudomonas
bacteria, for example Ps. aeruginosa (Ps. = Pseudomonas);
Bacteroidaceae, such as Bacteroides bacteria, for example
Z0 Bacteroides fragilis; Mycoplasma, for example Mycoplasma
pneumonia; also Mycobacteria, for example Mycobacterium
tuberculosis, Mycobacterium leprae and atypical Mycobacter;a.
The above list of pathogens is purely illustrative
and is in no ~ay to be interpreted as restrictive.
The following may be mentioned as examples of
illnesses which can be prevented ameliorated and/or healed
by the compounds according to formula (I):
otitis; pharyngitis; pneumonia; peritonitis; pyelone-
phritisj cystitis; endocarditis; systemic infections;
bronchitis; arthritis; local infections and septic ill-
nesses.
The invention of the parent application includes pharmaceutical
preparations which, in addition to non-toxic, inert pharma-
3~ ceutically sui~able vehicles, contain one or more compoun,dsaccording to formula (I) or which consist of one or more
3~5
- 14 23189 6009D
active compounds according to formula (I), and processes
for the production of these preparations.
~ he invention of the parent application also includes pharma-
ceutical preparations in dosage units. ~his means that the pre-
preparations are in the form o~ individual parts, for example
tablets, coated tablets, capsules, pills, suppositories and
ampoules, of which the content of active compound corres-
ponds to a function or a multiple of an individual dose.
The dosage units can contain, for example, 1, 2, 3 or 4
;ndiv;dual doses or 1/2, 1/3 or 1/4 of an indiv;dual
dose. An ;ndiv;dual dose preferably contains the amount of
active compound which is g;ven in one administration and
which usually corresponds to a whole, a half or a third or
a quarter of a daily dose.
ay non-toxic, inert pharmaceutically suitable
vehicles there are to be understood solid, semi-solid or
l;qu;d diluents, fillers and formulation auxil;aries of all
kinds.
Tablets, coated tablets, capsules, pills, granules,
suppos;tor;es, solutions, suspensions and emulsions, pastes,
ointments, gels, creams, lotions, powders and sprays may be
mentioned as preferred pharmaceutical preparations.
Tablets, coated tablets, capsules, pills and gran-
ules can contain the active compound or compounds alongside
the customary vehicles, such as (a) fillers and extenders,
for example starches, lactose, sucrose, glucose, mannitol
and silica, tb) binders, for example carboxymethylcellulose,
alginates, gelatin and polyvinylpyrrolidone, tc) humec-
tants, for example glycerol, (d) disintegrants, for example
agar-agar, calciumcarbonate and sodium bicarbonate, (e)
solution retarders, for example paraffin and (f) absorption
acceleratorsr for example quaternary ammonium compounds,
(g) wetting agents, for example cetyl alcohol or glycerol
monostearate, (h) adsorbents, for example kaolin and ben-
tonite and (i) lubricants, for example talc, calcium andmagnesium stearate and solid polyethylene glycols, or
- 12593~5
mixtures of the substances listed under (a) to (i).
The tablets, coated tablets~ capsules, pills and
granules can be provided with the customary coatings and
shells, optionally containing opacifying agents, and can
also be of such composition that they release the active
compound or compounds only, or preferentially, in a certain
part of the intestinal tract, optionally in a delayed
manner, examples of embedding compositions which can be
used be;ng polymeric substances and waxes.
The active compound or compounds, optionally
together with one or more of the abovementioned vehicles,
can also be in a microencapsulated form.
Suppositories can contain, in addition to the active
compound or compounds, the customary uater-soluble or water-
insoluble vehicles, for example polyethylene glycols, fats,for example cacao fat, and higher esters (for example C14-
alcohol with C16-fa~ty acid) or mixtures of these
substances.
Ointments, pastes, creams and gels can contain the
ZO customary vehicles in addition to the active compound or
compounds, for example animal and vegetable fats, waxes,
parafflns, starch, tragocants, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silica, talc
and z;nc oxide or mixtures of these substances.
Powders and sprays can contain the customary
vehicles, in addition to the act;ve compound or compounds,
for example lactose, talc, silica, aluminium hydroxide,
calcium silicate and polyam;de powders or mixtures of
these substances. Sprays can additionally contain the
customary propellants, for example chlorofluorohydro-
carbons~
Solutions and emulsions can contain the customary
vehicles in addition to the active compound or compounds
such as solvents, solublising agents and emulsifiers, for
example ~ater, ethyl alcohol, isopropyl alcohol, ethyl carbo-
nate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
Le A _3 081
~L25~3~L5
- 10 -
glycol, 1,3-butylene glycol, dimethylforma0ide, oils,
especia-ly cottonseed oil, groundnut oil, maize germ oi~,
olive oil, castor oil and sesame oil, glycerol, glycerol-
formal, tetrahydrofurfuryl alcohol, polyethylene glycols
and fatty acid esters of sorbitan, or mixtures of these
substances.
For parenteral administration, the solutions and
emulsions can also be in a sterile form which is ;sotonic
uith blood.
Suspensions can contain the customary vehicles in
addition to the active compound or compounds, such as
li~uld diluents, for example water, ethyl alcohol or pro-
pylene glycol, suspending agents, for example ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan
esters, microcrystalline cellulose, aluminium metahydroxide,
benton;te, agar-agar and tragacanth, or mixtures of these
substances.
The formulation forms mentioned can also contain
colorants, preservatives and additives which improve the
odour and flavour, for example peppermint oil and eucalyptus
oil, and s~eeteners, for example saccharin.
The therapeutically active compounds should prefer-
ably be present in the abovementioned pharmaceutical prep-
arations in a concentrat;on of about 0.1 to 99.5, preferably
Z5 of about 0.5 to 95, X by weight of the total mixture.
The abovementioned pharmaceutical preparations can
also contain other pharmaceutical active compounds in addi-
tion to the compounds according to the invention.
The abovementioned pharmaceutical preparations are
produced in the usual manner according to known methods,
for example by mixing the active compound or compounds uith
the vehicle or vehicles.
The active compounds or the pharmaceuticaL prepara-
tions can be admin;stered locally, orally, parenterally,
intraperitoneally and/or rectally, preferably orally or
parenterally, such as intravenously or intramuscularly.
Le A 23 081
3LZ5~313~5
- 17 -
In general, ;t has proved advantageous both in
human medicine and in veterinary medicine to administer
the active compound or compounds in total amounts of about
0.5 to about 500, preferably 1 to 50, mg/kg of body weigh~
every Z4 hours, optionaLly in the form of several indivi-
dual administrations, in order to achieve the desired
results. An ind;vidual administration contains the active
compound or compounds preferably in amounts of about 0.5
to about ZS0, in particular 1 ~D bn~ mg/kg of body weight.
Ho~ever, it can be necessary to deviate from the dosages
mentioned and ;n part;cular to do so as a function of the
nature and body we19ht of the subject to be treated, the
nature and severity of the illness, the nature of the pre-
paration and of the administration of the medicine, and the
time or interval over wh;ch administration takes place.
Thus, ;t can suffice ;n some cases to manage ~ith
less than the abovementioned amount of active compound,
whilst in other cases the abovementioned amount of active
compound must be exceeded. The particular required opti-
mum dosage and the type of administration of the activecompounds can easily be decided by anyone skilled ln the
art on the basis of his expert knowledge.
The ne~ compounds can be administered in the custo-
mary concentrations and preparations together ~ith the feed
or uith feed preparations or ~ith the drlnk;ng water. By
this means, it is possible to prevent, ameliorate andlor
heal an infection by Gram-negative or Gram-positive bac-
teria, and by this means to achieve promotion of growth
and improvement in the utilisation of the feed.
The compounds accord1ng to formula (I) are like-
wise sultable for the prevent~on and treatment of bacterial
lnfection in fish.
It has already been disclosed in J. Med. ~hem. 23,
135~ t1980) that 1-ethyl-6-fluoro-1,4-dihydro-l~-oxo-7-
51-piperazinyl)-3-quinoLinecarboxylic acid (norfloxacin)
has antibacterial properties. However, the compounds
Le A 23 081
~L2~i913~S
according to the invention are superior ~o norfloxacin, as
is evident from the table below, which indicates the MIC
values of some of the compounds according to the invention
and that of norfloxacin.
Le A 23 081
~L~5939~S
1~ ~ oo-.c~
U~
~D O O O . OO O
Ç~ c~ o ~r ~ o o o
u~ ~n ~
o o ~
~r ~ ~ ~ ~ co oo o
In U~ U~
N O O ~ U~ oo o
~_ C:~ Q O O ~ . OO O
rO O
4-~ _ ~ O 00
O C~ ~ ~ ~ ~~ ~ .
O .0 ~ U~ O O O
U~ O O O t~ O O O
C . O O ~ 11') 0 0 0
.~ ~ O O O O ~ ~ OO O
J U) U~
O O O ~ OO O
. ~ O~ O O O CO ~ OO O
f~l 1
O O O O OO 0
~_ O o c~ o ~ OO
' ~ _ _ - -- ~
t_l E / Ul
~;
DI --
Le A 23 081
~Z5~1L5
~ 20 -
Prepar~
Preparation of the starting materials (II)
Example A
1-Cyclopropyl-6,7,~-trifluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid
~COO~
F ~
24.3 9 of magnesium turnings are suspended in 50 ml
of anhydrous ethanol. 5 ml of carbon tetrachloride are added
and, ~Ihen the reaction has started, a mixture of 160 g of
diethyl malonate, 1ûO ml of absolute ethanol and 400 ml of
anhydrous toluene are added dropwise at 50-60C. The mix-
ture is then heated at 50-60C for a further 1 hour, cooled
with dry ;ce/acetone to -5C to -10C and a solution of
212~5 g of 2,3,4,5-tetrafluorobenzoyl chloride in 80 ml of
absolute toluene is slowly added dropwise at this temperature.
The mixture ;s stirred at 0 to -5C for 1 hour, allowed to
reach room temperature overnight, and is then run into a
mixture of 400 ml of ;ce-water and 25 ml of concentrated
sulphuric acid while cooling in ice. The phases are sepa-
rated and two further extractions w;th toluene are carried
out. The combined toluene solutions are washed with satu
rated NaCl solution, dried with Na2S04, and the solvent
is removed in vacuo. 335 g of diethyl 2,3,4,5-tetrafluoro-
benzoylmalonate are obtained as a crude product.
0.3 9 of p-toluenesulphonic acid is added to an
emuls;on of 234.8 g of crude diethyl 2,3,4,5-tetrafluoro-
benzoylmalonate in 300 ml of water. This mixture is
heated to boiling, stirring vigorously for 5 hours, the
cooled emulsion is extracted several times with methylene
chloride, the combined methylene chloride solutions are
uashed once with saturated NaCl solution, dried uith
Le A Z3 0~11
2~33~
- 21 -
Na2S04 and the solvent is removed by distillation in
vacuo. Fractionation of the residue under high vacuum pro-
v;des 160.2 g of ethyl 2,3,4,5-tetrafluoroben~oylacetate of
boil;ng po;nt 100-110~C/0.09-0.1 mbar. Melting point
47-49C.
A mixture of 110.7 g of ethyl 2,3,4,5-tetrafluoro-
ben~oyl ace~ate, 93.5 g of ethyl orthoformate and 107 g of
acetic anhydride ;s heated at 150C for 2 hours. The
volatile const;tuents are then removed by distillat;on
under water pump vacuum and finaLly under high vacuum at a
bath temperature of 120C. 123.9 g of crude ethyl
2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate remain.
Thls is suffic;ently pure for the subsequent reactions.
23~2 g of cyclopropylam;ne are added dropwise,
with stirring and cooling in ;ce, to a solution of 123.9 g
of ethyl Z-(2,3,4,5-tetrafluorobenzoyl~-3-ethoxyacrylate
in 250 ml of ethanol. When the exothermic reaction has
subsided, the mixture is st;rred for a further 1 hour at
room temperature, the solvent is removed in vacuo, and the
2D residue is recrystall;sed from cyclohexanetpetroleum ether.
115 g of ethyl Z-~2,3,4,5-tetrafluorobenzoyl)-3-cyclo-
propyLam;noacrylate of melt;ng po;nt 63-65C are obtained.
21.2 9 of sod;um fluoride are added to a solut;on
of 107.8 9 of ethyl 2-t2,3,4,5-tetrafluorobenzoyl)-3-cyclo-
propylaminoacrylate in 400 ml of anhydrous dimethylformamide.The reaction mixture is then stirred under reflux for Z
hours and poured hot onto ice. The precipitate is filtered
off wi~h suction, thoroughly washed with water, and dried
over calcium chloride at 100C in vacuo. 91.2 9 of ethyl
1-cyclopropyl-6,7,8-tri~luoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylate of melting point 167-168C are obtained.
A mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-
tr;fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 600 ml
of glacial acetic acid, 450 ml of water and 70 ml of con-
centrated sulphur;c acid is heated to reflux for 105 hoursOThe hot suspension is then poured onto ice, and the
Le A 23 081
~2sg3~5
-- 22 --
precip;tate ;s filtered off with suction, thoroughly washed
w;th water, and dried ;n vacuo at 100C. In th;s manner,
88.9 9 of pure 1-cyclopropyl-6,7,8-tr;fluoro-1,4-dihydro-
4 oxo-3-qu;nol;necarboxylic ac;d II tX1=X2=F) of melt;ng
po;nt 228-230C (decompos;tion) are obta;ned.
Example P
1-Cyclopropyl-6,7 difluoro-1,4-d;hydro-4-oxo-3-
qu;nol;necarboxylic ac;d
o
~3~:oo~
'
The process ;s carr;ed out ;n analogy to Example A,
start;ng from 2,4,5-tr;fluorobenzoyl fluor;de and passing
through the follow;ng stages: diethyl 2,4,5-trifLuoro-
benzoylacetate (bo;ling po;nt: 92-95/o 5 mbar; melting
po;nt: 53-55) - ~ ; ethyl 2-(2,4,5-trifluoro-
benzoyl)-3-ethoxyacrylate (o;l) - ----------, ethyl 2-
(2,4,5-tr;fluorobenzoyl)-3-cyclopropylam;noacrylate (o;l)
--- ethyl 1-cyclopropyl-6,7-difluoro-1,4-
d;hydro-4-oxo-3-quinol;necarboxylate (melting point 230-
233) _~ 1-cyclopropyl-6,7-difluoro-1,4-
dihydro-4-oxo-3-quinol;necarboxylic acid (melting po;nt:
302-303 ~;th decomposition)~
Preparation of the active compounds (I)
Example 1
o
F COOH
}~7~NJ
Le A 23 081
~ 2~;93~5
- ~3 -
A mixture of 2.8 9 (0.01 mols) of 7-chloro-1-
cyclopropyl-6-fluoro-1~4-dihydro-4-oxo-3-quinolinecarboxy-
lic acid, 1.8 g (0.011 mole) of 2-phenylpiperazine and
2.2 9 (0.02 mole) of 1,4-diazabicycloC2.2.2]octane in 6 ml
of dimethyL sulphoxide is heated at 140C for 4 hours.
The solution is concentrated under high vacuum, and the
residue is stirred with 20 ml of water and the pH is
adjusted to 7 ~ith 2N hydrochloric acid. The precipitate
;s filtered off with suction, washed with water and methanol,
and bo;led in 30 ml of methanol. 1.3 9 (32X of theory) of
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-
piperazinyl) 3-quinolinecarboxylic acid of melting point
Z18-220 (with decomposition) is obtained (recrystall;sed
from glycol monomethyl ether).
The same product is obtained when 1-cyclopropyl-
6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
is reacted correspondingly with 2-phenylpiperazine.
The follouing compounds are obtained in analogy to
Example 1 using the appropriate piperazines:
o
F ~J COO~I
~N~J
R2 A
Example R2 Melting point (with
decomposition)
_
2 F ~ - 198-203
3 ~ 207-209 (Trom mathanol)
4 Br ~ - 252-255
Le A 23 081
~"2~;~13~5
- 2~ -
Example R2 Melting point (with
_ der,omposit;on
CH30 ~ 208-211D ~frorn etrlanoL)
6 ~ CH2-o~ 3 - 208-211 ( I rom
metllanol)
_ rH3
t~H30 ~ 233-237 (-fro~ glycol
monometnyl
CH30 eth~r)
8 - CN ~ 156 - 1610
9 ~3C~ - 258 - 261
~ 278 -281
~ 247-2500 (-frc~
~ metllanol
N02
12 l~ 218-222 (from aceto-
nitrile)
O 316-320 ttrom
methanol)
.~Cl
Le A 23 081
.
~S~3~L~
- 25 -
Example 14
t)
F ~ COOH
~ ~N~
OH .~Br
60 ml of 48% strength hydrobromic acid are added
to 2,5 9 (4.9 mmol) of the product from Example 6 in 30 ml
of ethanol, and the mixture is stirred at 55 for 1 hour.
It is concentrated in vacuo~ the residue ;s stirred with
50 ml of water, and the precipitate is filtered off with
suct;on and ~ashed with methanol. 1.5 9 (66X of theory)
of 1-cyclopropyl-6~fluoro-1,4-dihydro-7-[3-(4-hydroxyphenyl)-
1-piperazinyl~-4-oxo-3-quinolinecarboxylic acid hydrobromide
of melting point 295-298 (with decomposition~ is obtained.
Example 15
~C~O~
~ F
2~8 9 (0.01 mole) of 1-cyclopropyl-6,7,8-tr1fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example A)
are heated to 140C together with 1.8 9 (0.011 mole) of
2-t2-thienyl)piperazine and 2.2 9 (0.02 mole) of 1,4-diazo-
bicyclo~2.2.Z]octane in 6 mL of DMS0 for 2 hours. The mix-
ture is concentrated under high vacuum, the residue is
stirred with 20 ml of uater, and the precipitate is filtered
off w;th suction and boiled in 20 ml of methanol. 2.4 9
t56X of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-
4-oxo-7-C3~t2-thienyl)-1-piperazinyl~-3-quinolinecarboxylic
acid of melting point 252-254C (with decomposition) are
Le A 23 081
~:25~3~5
- 2b -
obtained. The melting point remains unchanged after re
crystallisation from glycol monomethyl ether.
The following compounds are obtained in analogy to
Example 15:
F ~ ~ COOH
~2 F
Example R2 Melting point (with
decomposition~
16 ~3- 245-247
17 F-~-- 244--245
18. Br-~ 242-245
Example 19
F ~ COOH
C2H5-N ~ ~ N ~
.HI
Le A 23 081
~25~3~5
- 27 -
1.1 9 (2.7 mmole) of the product from Example 1 in
10 ml of dimethyl formamide are heated at ao with 0.6 9
of triethylamineand 0,9 9 of ethyl iodide for 3 hours. The
reaction mixture is concentrated in vacuo, and the residue
is stirred with 10 ml of water and recrystalLised from
glycol monomethyl ether. D.75 9 (49% of theory) of 1-
cyclopropyl-7-4-ethyl-3-phenyl-1-piperazinyl)-6-fluoro-
1,4-dihydro-t4-oxo-3-quinolinecarboxylic acid hydroiodide
of melting point 240-243 (with decomposition) is
obta;ned.
Example 20
O
E` ~,~ COOH
CH3 -co-cH2cH2 -N N J~; ~N ~J
~' .
1.1 9 (2.7 mmol) of the product from Example 1 in
15 ml of ethanol is heated under reflux with 1.05 9 of
methyl vinyl ketone for 8 hours . The precipitate is
filtered off with suction and washed with ethanol. 0.9 9
~70% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-7-~4-(3-oxobutyl)-3~phenyl-1-piperazinyl~-3-quinoline-
carboxylic acid of melting point 224-226 (with decomposi-
t;on) is obtained.
Example 21
F ~ COOH
OC~- ~ ~ N
F
.
Le A 23 D81
-
~259~3~i
- Z8 -
0.8 9 ~1.9 mmol) of the compound from Example 16
in 6 ml of dimethylformamide are heated under reflux ~ith
0.6 ml of 98-1û0% strength formic acid for 8 hours~ The
reaction mixture is concentrated ;n vacuo, and the residue
is stirred wi~h 20 ml of ~ater and the pH is adjusted to
5 with 5% strength sodium bicarbonate solution. The pre-
c;pitate which has separated out is filtered off with suc-
tion, ~ashed with uater and methanol and recrystallised
from glycol monomethyl ether. 0.6 9 (70X of theory) of
1-cyclopropyl-6,8-difluoro-7-~4-formyl-3-phenyl-1-pipera-
2inyl)-1~4-dihydro-4-oxo-3-quinolinecarboxylic acid of
melting point Z42-245 (with decomposition) is obtained.
~xample for a tablet _according to the invention
~ .. . . . _. __
Each tabletcontains:
15 Compound of the example Z91.5 mg
MicrocrystaLline cellulose 27.5 mg
Maize starch 36.0 mg
Poly(1-vinyL-Z-pyrrolidone) insoluble 15.0 mg
Highly disperse silica 2.5 mg
Magnesium stearate _ 2.5 mg
375.0 mg
The lacquer coating contains:
Poly(o-hydroxypropyl-o-methyl)celLulose
15 cp (hydroxypropylmethylcellulose USP) 3.9 mg
Macrogol 40ûO rec. INN
25 (polyethylene glycols DAB) 1.3 mg
Titanium(IY~ oxide
~titanium dioxide ~P) 1.3 m~
6.5 mg
Le A 23 081
