1-CYCLOPROPYL-6-FLUORO-1,4-DIHYDRO-4-OXO-7-PIPERAZINO- QUINOLINE-3-CARBOXYLIC ACIDS, A PROCESS FOR THEIR PREPARATION AND ANTIBACTERIAL AGENTS CONTAINING THESE COMPOUNDS

ACIDES 1-CYCLOPROPYL-6-FLUORO-1,4-DIHYDRO-4-OXO-7- PIPERAZINE-QUINOLINE-3-CARBOXYLIQUES; PREPARATION ET AGENTS ANTIBACTERIENS RENFERMANT CES ACIDES

English Abstract

A b s t r a c t
The invention relates to 1-cyclo-propyl-6-fluoro-1,4-
dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acids, a
process for their production, compositions containing them and
methods for the use of said compounds and compositions. The
compounds of the invention are useful as agents against bacteria.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid of the
general formula
<IMG> (I)
or a salt or hydrate thereof, in which
R denotes hydrogen, methyl, ethyl or .beta.-hydroxy-ethyl
which comprises,
(a) reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid of the formula
<IMG> (II)
in which
R1 denotes a hydrogen atom,
with a piperazine or a piperazine derivative of the general formula
<IMG> (III)
18

in which
R has the meaning given above, or
(b) reacting an alkyl ester of the compound of formula (II)
above, in which R1 denotes an alkyl group, with a compound of
formula (III) above and hydrolysing the obtained 7-piperazo-
quinolone-3-carboxylic acid ester under alkaline conditions to
give a compound of formula (I),
and if required, converting the compound of formula (I), obtained
by reaction variant (a) or (b) into a pharmaceutically acceptable
salt or hydrate thereof.
2. A process according to claim 1 (a), wherein the re-
action is carried out in the presence of a diluent.
3. A process according to claim 1 (a) or 2, wherein the
reaction is carried out at a temperature between 20 and 200°C.
4. A process according to claim 1 (b), wherein the re-
action is carried out in the presence of an acid-binding agent.
5. A process according to claim 1, wherein the compound
of formula II is obtained by cyclizing a compound of formula VI
<IMG> VI
wherein R1 is as defined in claim 1.
19

6. A process according to claim 5 wherein the compound of
formula VI is obtained by reacting a compound of formula X
<IMG> X
wherein R1 is as defined in claim 1, with cyclopropylamine.
7. A process according to claim 6 wherein the compound of
formula X is obtained by reacting a compound of formula IX
<IMG> IX
wherein R1 is as defined in claim 1, with triethyl o-formate/
acetic anhydride.
8. A 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-
quinoline-3-carboxylic acid of formula I as defined in claim 1 or
a pharmaceutically acceptable salt or hydrate thereof when pre-
pared by a process according to claim 1 or an obvious chemical
equivalent thereof.
9. A process according to claim 1, 5 or 6 wherein R is
hydrogen.
10. A process for preparing 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which

comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid with piperazine.
11. A process according to claim 10 wherein the 7-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-
benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium
hydride in anhydrous dioxane.
12. A process according to claim 11 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is
obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-
ethoxy-acrylate with cyclopropylamine.
13. A process according to claim 12 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy acrylate is obtained
reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl
o-formate and acetic anhydride.
14. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-7-piperazino-quinoline-3-carboxylic acid when prepared by
a process according to claim 10, 11 or 12 or an obvious chemical
equivalent thereof.
15. A process according to claim 1, 5 or 6 wherein R is
methyl.
16. A process for preparing 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-(4-methylpiperazino)-quinoline-3-carboxylic
acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with methylpip-
21

erazine.
17. A process according to claim 16 wherein the 7-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro
benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium
hydride in anhydrous dioxane.
18. A process according to claim 17 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is
obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-
ethoxy-acrylate with cyclopropylamine.
19. A process according to claim 18 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained
reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl
o-formate and acetic anhydride.
20. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-7-(4-methylpiperazino)-quinoline-3-carboxylic acid when pre-
pared by a process according to claim 16, 17 or 18 or an obvious
chemical equivalent thereof.
21. A process according to claim 1, 5 or 6 wherein R is
ethyl.
22. A process for preparing 1-cyclo-6-fluoro-1,4-dihydro-
4-oxo-7-(4-ethylpiperazino)-quinoline-3-carboxylic acid which
comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid with ethylpiperazine.
22

23. A process according to claim 22 wherein the 7-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-
benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium
hydride in anhydrous dioxane.
24. A process according to claim 23 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is
obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-
ethoxy-acrylate with cyclopropylamine.
25. A process according to claim 24 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained
reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl
o-formate and acetic anhydride.
26. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-7-(4-ethylpiperazino)-quinoline-3-carboxylic acid when pre-
pared by a process according to claim 22, 23 or 24 or an obvious
chemical equivalent thereof.
27. A process according to claim 1, 5 or 6 wherein R is
.beta.-hydroxyethyl.
28. A process for preparing 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-(4,.beta.-hydroxyethyl-piperazino)quinoline-3-carboxylic
acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with .beta.-hydroxy-
ethylpiperazine.
23

29. A process according to claim 28 wherein the 7-chloro-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-
benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium
hydride in anhydrous dioxane.
30. A process according to claim 29 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is
obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-
ethoxy acrylate with cyclopropylamine.
31. A process according to claim 30 wherein the ethyl 2-
(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained
reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl
o-formate and acetic anhydride.
32. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-7-(4-.beta.-hydroxyethyl-piperazino)-quinoline-3-carboxylic acid
when prepared by a process according to claim 28, 29 or 30 or
an obvious chemical equivalent thereof.
24

Description

t?~
-- 1 --
The present invention rela-tes to certain new l-cyclo
propyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-car-
boxylic acids, to a process for their production and to their use
in feed additives and as antibacterial agents.
A first divisional application, divided out of this ap-
plication, has been filed which relates to compounds of formula
II which are intermediates useful in the preparation of compounds
of the present invention and further relates to a process for
preparing a compound of formula II
F =~COOR ( I I )
Cl N
wherein Rl is hydrogen or an alkyl group which process comprises
cyclizing a compound of formula VI
11
F~ ~-COOR
Cl J~C1 CH (VI)
HN
wherein Rl is as defined above.
A second divisional application, divided out of this
application, has been filed which relates to compounds of formula
, . , ~ ,

- la -
IX which are intermediates useful in the preparation of compounds
of the present inven-tion and further relates to a process for
preparing a compound of formula IX
F ~ C ~ ( I X )
lC Cl
wherein R is hydrogen or alkyl, which process comprises partial
hydrolysis and decarbo~ylation of a compound of formula VIII
Il /COORl
F ~ C-ÇH (VIII)
Cl ~'~ Cl
wherein Rl is as defined above
A third divisional application, divided out of this ap-
plication, has been filed which relates -to compounds of formula
X which are intermediates useful in the preparati.on of compounds
of the present invention and further relates to a process for
preparing a compound of formula X
o
F ~ ~ - COOR (X)
C Cl CH
OC2H5
wherein R is hydrogen or alkyl, which comprises reacting a
compound of formula IX

- lb - ~q~
o
Il
, ~ CH -COoR1 (IX)
Cl Cl
wherein Rl is as defined above, with triethyl o-formate/acetic
anhydride.
It has already been disclosed ~hat l-ethyl-6-fluoro-1,4-
dihydro-4-oxo-7-piperazino-quinoline-3-carboxyllc acids possess
antibacterial properties rJ. Med. Chem. 23, 1358 (1380)] .
According to the present invention we now provide, as
new compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piper-
azino-quinoline-3-carboxylic acids of the general formula
E' ~ ~ , COOH
R- ~ ~ N
or salts or hydrates thereof,
in which
R denotes a hydrogen atom or a methyl, ethyl or ~-
hydroxyethyl group.
The compounds of the present invention have an antibac-
terial action superior to that of the known quinolone-carboxylic
acids and azaquinolone-carboxylic acids. The compounds according
to the invention exhibit their superior antibacterial activity
against both gram positive and gram negative bacteria, including

- lc-
Pseudomonas aeruginosa.
According to -the present invention we further provide a
process for the producti.on of a compound of the invention in which
(a) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-
3-carboxylic acid of the formula
o
F ~ ~\ J ~ ~ COOR (II)
Cl
,, .
,

-- 2
in which
Rl denotes a hydrogen atom,
is reacted T~ith piperazine or a piperazine derivative of
the general formula
r~
R~N~_,NH (III)
in which
R has the meaning given above, or
(b) a compound of the formula (II), as given in reaction
variant (a) in which Rl denotes an alkyl group, is reacted
with a compound of formula (III) as defined in reaction
variant (a), if appropriate in the presence of an acid-bind-
ing agent (such as triethylamine, 1~4-diaza--bicyclo[2,2,2]-
octane or 1,8-diaza-bicyclo[5,4,0~undec-7-ene) and the 7-
piperazino-quinolone-3-carboxylic acid ester obtained is
hydrolysed under alkaline conditions to give a compound of
formula (I),
and the compound of formula (I) obtained by reaction
variant (a) or (b) is converted, if desired, lnto a salt or
hydrate thereof.
The reaction variant (a) is preferably carried out
in a diluent (such as dimethylsulphoxide, N,N-dimethyl-
formamide, hexamethyl-phosphoric acid trisamide, sulpholane,
water, an alcohol or pyridine) and at a temperature between
20 and 200C, preferably between 80 and 180C.
The reaction variants can be carried out under
normal pressure, but also under elevated pressure, in partic-
ular in the case of a low-boiling solvent. In general,
the reaction is carried out under pressures between about 1
and about 100 bar, preferably between 1 and 10 bar.
In carrying out reaction variants 1 to 5 mol of
alkyl-piperazine (in the case of piperazine 1 to 15 mol),
preferably 2 to 3 mol of alkylpiperazine (in the case of
piperazine 5 to 10 mol), are employed per mol of carboxylic
acid, or carboxylic acid ester of formula (II).
Le A 21 353

967
Among the new l-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-7-piperazo-quinoline-3-carboxylic acid salts and
hydrates of the invention those sal~s or hydrate that are
pharmaceutically acceptable are particular~ important and
are preferred.
The new free l-cyclopropy1-6-fluoro-1,4-dihydro-
4-oxo-7-piperazino-quinoline-3-carboxylic acids of the
general formula (I) and their salts and hydrates can be
interconverted in any suitable ~.anner; methods for such
interconversion are known in the art.
Thus the 7-piperazino-quinolone-3-carboxylic acids
of formula (I) obtained can, if required, be converted into
a salt using an organic or inorganic acid. Examples of
acids which are suitable for salt formation are hydrohalic
acids, such as hydrochloric acid, hydrobromic acid, hydro-
iodic acid, sulphuric acid, acetic acid, citric acid and
benzenesulphonic acid.
If 7-chloro-l-cyclopropyl-6-fluoro l,4-dihydro-4-
oxo-quinoline-3-carboxylic acid and methylpiperazine are
used as starting materials in reaction variant (a), the course
of the reaction is illustrated by the following equation:
F~ ~ COOH r~~
C1 ~ 2c~3N~_JNH -~
CH3-N ~ + ~C~3N ~ ~] x~Cl
The following may be mentioned individually as
active compounds according to the present invention:
7-piperazino-, 7-(4-methylpiperazino)-, 7-(4-ethylpiperazino~,
7-(4-~-hydroxyethylpiperazino)-l-cyclopropyl-6-fluoro-1,4-
Le A 21 353

~8
dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceuti-
cally tolerated acid addition salts or alkali metal salts
of these compounds.
The starting compounds of formula (II) can be
prepared -~ia a malonic ester synthesis, according to the
following equation:
F~ ~ ,COC1 ~ COOC2H5 1 l _ C O O C 2 H5
Cl ~ ~ COOC2H5 C ~ ~ COOC2~5
I~ VII VIII
1~ O
F ~ C~C~COOC2Hg F C-CH2COOC2H~
Cl ~ C ~~~ Cl ~ C1
X I~
~D-~2
F ~ ~ C-COOR~
C 1 FrN ~
¦ ~I
~3,C O O
II
Le A 21 353

According to -this equation, diethyl malonate of
formula (VII) is acylated with a compound of formula (IV) in the
presence of magnesium alcoholate to give the acylmalonate of
formula (VIII) (Organieum, 3rd edition 1964, page 438).
The ethyl aroylaeetate of formula (IX) is obtained in
good yield by partial hydrolysis and deearboxylation of the eom-
pound of formula (VIII) in an aqueous medium eontaining a eata-
lytic amount of p-toluenesulphonic acid, and is converted with
triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-diehloro-
5-fluoro-benzoyl)-3-ethoxy-acrylate of formula (X). The reaetion
of the eompound of formula (X) with eyelopropylamine in a solvent
(sueh as methylene chloride, alcohol, ehloroform, cyclohexane or
toluene) leads to the desired intermediate product of formula (VI)
in a slightly exothermic reaction.
The cyclisation reaetion VI~ II (Rl = alkyl) is
carried out in a temperature range from 60 to 280C, preferably
~0 to 180C.
Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone,
sulpholane, hexamethylphosphorie acid triamide and preferably
N,N-dimethylformamide can be used as diluents.
Potassium t-butanolate, butyl-lithium, lithium-phenyl,
phenyl magnesium bromide, sodium ethylate and particularly pre-
ferably sodium hydride or po-tassium carbonate are suitable acid-
binding agents for this reaetion stage. It can be advantageous
to employ an excess of 10 mol% of base.
The 2,4-dichloro-5 fluoro-benzoyl chloride of formula
(IV) used as a starting material for this synthesis route, the
corresponding carboxylic aeid, and the 3-fluoro-4,6-diehloro-

-5a-
toluene of formula (XI) required for the preparation of formula
(IV) were not yet known i.n the literature.
The equation below shows the preparation of these

L80~
precursor~ or intermediate products~ starting from 2,4-
dic~lloro-5-methyl-aniline of formula (,~II).
Cl ~ 1. NaNO2, ~3o C1
I I _~
NH2 HN(cH3)2 Cl ~=N-N(CH3)2
XIIa
XII
¦ H~
XI
CC13
F
C1
XIII
COOH
C1 ~
F
COCl
(IV) Cl
Le A 21 353

67
According to this equation, 2,4-dichloro-5-
methyl-aniline of formula (XII) is diazotised by means of
NaN02, and the resulting diazonium salt is converted into
the triazene o~ ~ormula (XIIa~, using dimethylamine.
The triazene of formula (XIIa) is dissolved in
excess anhydrous HF. I~ this step, the triazene is cleaved
to give 2,4-dichloro-5-methyl-diazonium fluoride and
dimethylamine. Without intermediate isolation, this
solution is cleaved thermally at 130 to 140 to give 3-
fluoro-4,6-dichlorotoluene XI3 N2 being split off
(Yield: 77.7% of theory).
The 3-fluoro-4,6-dichlorotoluene of formula (XI)
is chlorinated in a temperature range from 110 to 160C,
under W irradiation, to give 2,4-dichloro-5-fluoro-1-
trichloro-methylbenzene of formula (XIII).
The hydrolysis of the compound of formula (XIII)
with 95 per cent sulphuric acid leads to 2,4-dichloro-5-
fluoro-benzoic acid of formula (X~)s which i5 converted
with thionyl chloride into the carboxylic acid-chloride
of formula (IV).
The compounds according to the invention are
distinguished by a particularly good antibacterial action
against gram positive and gram negative bacteria, in
particular in comparison with the compounds of German
Patent Application P 30 33 157.8 of 3.9.1980 and DE-OS
(German Published Specification) 2,804,097, as can be seen
from the table below.
Le A 21 353

6~7
- 8
o
1, o ~
=~ ~ C ~ IA ~.D ~D ~ ~\
z ~; ~ a) ~I O O O O h'~
O O O O O O
~>
.
O ~ ` hO
r! _ .h--~.
~rl r-l O--~ ~\Jh'~ h'~ ~D
// ,~-rl 1~ rl (~I ~ O O
~ ~ . . . . ~_1
05-C~3~ rl. O O O O rl X
~J r~ ~o . . ~
. . r~
, ~ ~ . . ; e
e.o ~ :
~\ C,) CO ; . h'~
0=( 7 ~-r! ~ . U~
N Gr CO ~--I ~1 r-l O 3 1~
,-1 ~ r~ ~\ r!
X ~ I~ r!
h'~ ~ (D
5r-! . (~0 5
C~~O ~ COC~ ~ O ~
C)i \1 5 rl u~ ~r! ~q
o ,~ a) ~ o td ~ J~ ~d
O -I ¢ Z ,-1 ,-1 _ 5
r-lr!r! ~u~ 5 r!
~ U)r-l r-!r! 5 O --1 ~ ~
5~ 5O Ou~ a) ~ hO `_
(I)V C)(' J~ ~ 5
~ ~ O a.
J~ :5 . . rl ~1 u~ ~ h3 C/~
u2 ~L~ ~1~: P,l ~ ~ ¢
Le A 21 353

g
As stated above, the invention also relates to
the use in human and veterinary medicine as antibacterial
agents of the compounds of the invention.
The present invention provides a pharmaceutical
composition containing as active ingredient a compound
of the invention in admixture with a solid or liquefied
gaseous diluent, or in admixture with a liquid diluent
other than a solvent of a molecular weight less than
200 (preferably less than 350) except in the presence
f a surface active agent.
The invention further provides a pharmaceutical
composition containing as active ingredient a compound
of the invention in the form of a sterile and/or physio-
logically isotonic aqueous solution.
The invention also provides a medicament in dosage
unit form comprising a compound of the invention.
The invention also provides a medicament in the
form of tablets (including lozenges and granules)~
dragees, capsules, pills, ampoules or suppositories
comprising a compound of the invention.
"Medicament" as used in this Specification means
physically discrete coherent portions suitable for
medical administration. 'IMedicament in dosage unit
form" as used in this Specification means physically
discrete coherent units suitable for medical administration
each containing a daily dose or a multiple (up to four
times) or submultiple (down to a fortieth) of a daily
dose of the compound of the invention in association
with a carrier and/or enclosed within an envelope.
Whether the medicament contains a daily dose or, for
example, a half, a third or a quarter of a daily dose
will depend on whether the medicament is to be administered
once or, for example, twice, three times or four times
a day respectively.
The pharmaceutical composition according to the
Le A 21 353

~8~
-- 10 --
invention may, for example~ take the form of ointments,
geis, pastes, creams, sprays (including aerosols),
lotions, suspensions, solutions and emulsions of the
active ingredient in aqueous or non-aqueous diluents,
syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions
(e.g. granulates) adapted to be formed into tablets,
dragees, capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol,
and silicic acid; (b) binding agents, e.g. carboxymethyl
cellulose and other cellulose derivatives, alginates,
gelatine and polyvinyl pyrrolidone; (c) moisturizing
agents, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators, e.g. quaternary ammonium
compounds; (g) surface active agents, e.g. cetyl alcohol,
glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; (i) lubricants, e.g. talc, calcium
and magnesium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed
from the pharmaceutical compositions of the invention
can have the customary coatings, envelopes and protective
matrices~ which may contain opacifiers. They can be
so constituted that they release the active ingredient
only or preferably in a particular part of the intestinal
tract, possibly over a period of time. The coatings,
envelopes and protective matrices may be made, for
example, of polymeric substances or waxes.
The ingredient can also be made up in microencap~
sulated form together with one or several of the above-
mentioned diluents.
The diluents to be used in pharmaceutical compositions
adapted to be formed into suppositories can, for example,
be the usual water-soluble diluents, such as polyethylene
Le A 21 353

67
glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these
diluents.
The pharmaceutical compositions which are ointments,
pastes, creams and gels can, for example, contain the
usual diluents, e.g. animal and vegetable fats, waxes,
paraffins, starch, tragacarlth, cellulose derivatives,
polyetnylene glycols, silicones, bentonites, silicic
acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders
and sprays can, for example, contain the usual diluents,
e.g. lactose, talc, silicic acid, aluminium hydroxide,
calcium silicate, and polyamide powder or mixtures
of these substances. Aerosol sprays can, for example,
contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions
and emulsions can, for example, contain the customary
diluents (with, of course, the above-mentioned exclusion
of solvents having a molecular weight below 200 except
in the presence of a surface-active agent), such as
solvents, dissolving agents and emulsifiers; specific
examples of such diluents are water, ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethylformamide, oils (for example ground
nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitol or mixtures
thereof.
For parenteral administration, solutions and emulsions
should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions
can contain the usual diluents, such as liquid diluents~
e.g. water, ethyl alcohol, propylene glycol, surface-
active agents (e.g. ethoxylated isostearyl alcohols,
polyoxyethylene sorbite and sorbitane esters), micro-
Le A 21_353

- 12 -
crystalline cellulose, aluminium metahydroxide, bentonite,
agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical compositions according
to the invention can also contain colouring agents
and preservatives as well as perfumes and flavouring
additions (e.g. peppermint oil and eucalyptus oil)
and sweetening agents (e.g. saccharin).
In addition to a compound of the invention, the
pharmaceu~ical compositions and medicaments according
to the invention can also contain other pharmaceutically
active compounds. They may also contain a plurality
of compounds of the invention.
Any diluent in the medicaments of the present
invention may be any of those mentioned above in relation
to the pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular
weight less than 200 as sole diluent.
The dlscrete coherent portions constituting the
medicament according to the invention will generally
be adapted by virtue of their shape or packaging for
medical administration and may be, for example, any
of the following: tablets (including lozenges and
granulates), pills, dragees, capsules, suppositories
and ampoules. Some of these forms may be made up
for delayed release of the active ingredient. Some,
such as capsules, include a protective envelope which
renders the portions of the medicament physically discrete
and coherent.
The production of the above-mentioned pharmaceutical
3 compositions and medicaments is carried out by any
method known in the art, for example, by mixing the
active ingredient(s) with the diluent(s) to form a
pharmaceutical composition (e.g. a granulate) and then
forming the composition into the medicament (eOg. tablets).
This invention further provides a method of combating
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- 13 - ~8~6~
(including prevention, relief and cure of) the above-mentioned
diseases in human and non-human animals which comprises adminis-
tering to the animals a compound of the invention alone or in ad-
mixture with a diluent or in the form of a medicament according to
the invention.
The present invention further provides a feed additive
comprising an active compound of the present invention in admix-
ture with a feed additive-carrier.
The Examples which follow further illustrate the inven-
tion of the parent application and of the three divisionalapplications.
Example 1
3 ~ ~ ~ ~COOH
A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-quinoline 3-carboxylic acid, 28.5 g of N-methyl-
piperazine and 120 ml of anhydrous dimethylsulphoxide was heated
at 135 to 140C for 1.5 hours. The solvent was distilled off
under a fine vacuum, and the residue was suspended in approx. 50
ml of H2O. T~e suspension was filtered under suction, and the
residue was rinsed with H2O, dried in a vacuum drying cabinet at
80C over CaC12, and recrystallised from glycol monomethyl ether.
1~.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylpiper-
aZino)-4-oxo-quinoline-3-carboxylic acid which decomposes at 248
,., . .~,

- 13a
to 250 C were obtained.
Example 2
~ O
HOCH2CH2~ COOH
A suspension of 2.81 of 7-chloro-1-cyclopropyl-

8~7
- ~4 -
6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid
and 5.2 g of N-~-hydroxyethylpiperazine in 25 ml of di
methylsulphoxide was heated at 135 to 140C for 2 hours.
The solvent was distilled off under a fine vacuum, the
residue was boiled for a short time with 20 ml of H20 and
left to stand overnight at room temperature, and the pre-
cipitate was filtered off under suction, while cooling
with ice, and was washed with water and dried in vacuo
over CaC12 at 80C. 2.1 g of 1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-7-(4-~-hydroxyethylpiperazino)-quino-
line-3-carboxylic acid which decomposed at 237 to 239C
were obtained.
Example 3
~-N
~J ~
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
30.1 g of anhydrous piperazine and 100 ml of dimethyl-
sulphoxide was heated at 135 to 140C for 2 hours. The
solvent was distilled off under a fine vacuum, and the
residue was suspended in H20, filtered off under suction
and washed with water. ~or further purification, the
moist crude product was boiled with 100 ml of water, fil-
tered off under suction at room temperature, washed with
H20 and dried over CaC12 in a Yacuum drying cabinet at
100 C until its weight remained constant. 19.6 g of
l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-
quinoline-3-carboxylic acid which decomposed at 255 to
257C were obtained.
The compound prepared according to Example 3 was
dissolved in 50 ml of hot 10 per cent hydrochloric acid.
150 ml of ethanol were added to the filtered solution, the
Le A 21 353

mixture was cooled with ice, and the product was filtered
off under suction, washed with alcohol, and dried in
vacuo at 100C. i8.5 g of 1-cyclopropyl-6-fluoro-1,4-
dihydro-4 oxo-7-piperazino-quinoline-3-carboxylic acid
hydrochloride were obtained as colourless crystals which
dècomposed at 308 to 310C.
xample 4
~_~ ~ C~OH
H5C ~ -L~
a) A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-piperazi~o-quinoline-3-carboxylic acid,
1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml
of N,M-dimethylformamide was heated at 70 to 80C for 2.5
hours. The solvent was distilled off in vacuo, and the
residue was suspended in water. The product was filtered
off under suction, rinsed with H20 and pressed on clay.
1.15 g of 1-cyclopropyl-6-fluoro-7-(ethylpiperazino)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydro-
iodide which decomposes at 306C were obtained.
b) The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid used as the starting
material was prepared as follows:
24.3 g of magnesium turnings were suspended in 50
ml of anhydrous ethanol. 5 ml of carbon tetrachloride
were added and, when the reaction had started, a mixture
of 160 g of diethyl malonate, 100 ml of absolute
ethanol and 400 ml of anhydrous ether was addeddropwise,
a vigorous reflux being observed~ After the reaction
had ceased, the mixture was heated at the boil for a fur-
ther 2 hours and was cooled with dry ice/acetone at -5C
to -10C and a solution of 227.5 g of 2,4-dichloro-5-
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~ 7- 16 -
fluoro-benzoyl chloride in 100 ml of absolute ether was
slowly added dropwise at this temperature. The mix-
ture was s~irred for 1 hour at 0C to -5C and was allowed
to reach room temperature overnight, and a mixture of 400
ml of ice-water and 25 ml of concentrated sulphuric acid
was allowed to run in while cooling with ice. The
phases were separated and were extracted twice with ether.
The combined ether solutions were washed wlth saturated
NaCl solution and dried with Na2SC4, and the solvent was
stripped off in vacuo. 349.5 g of diethyl 2,4-di-
chloro~5-fluoro-benzoyl-malonate were obtained as the
crude product.
0.15 g of p-toluenesulphonic acid was added to an
emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-
benzoyl-malonate in 50 ml of water. The emulsion was
heated at the boil for 3 hours while stirring thoroughly,
and, when cold, was extracted several times with methylene
chloride, the combined CH2C12 solu-tions were washed once
with saturated NaCl solution and dried with Na2S04, and
the solvent was distilled off in vacuo. Fractionation
of the residue under a fine vacuum gave 21.8 g of ethyl
2,4-dichloro-5-fluoro-benzoyl acetate IX of boiling point
127 to 142C/0.09 mbar.
A mixture of 21.1 g of ethyl 2,4-dichloro-5-
fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and
18.55 g of acetic anhydride was heated at 150C for 2
hours. The volatile constituents were then distilled
off under a waterjet vacuum and finally under a fine
vacuum, at a bath temperature of 120C. 25.2 g of crude
ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate
remained. It was sufficiently pure for the further
reactions.
4.3 g of cyclopropylamine were added dropwise to a
solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluoro-
}5 benzoyl)-3-ethoxy-acrylate in 80 ml of ethanol while
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cooling with ice and stirring. ~Ihen the exothermic
reaction had ceased, the mixture was stirred for another
hour at room temperature, the solvent was stripped off in
vacuo, and the residue was recrystallised from cyclohexane/
.
petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-
fluoro-benzoyl)-3-cyclopropylamino-acrylate (Rl = C2H5)
of melting point 89 to 90C were obtained.
3.44 g of 80 per cent sodium hydride were added in
portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-
5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (Rl = C2H5)
in 100 ml of anhydrous dioxane while cooling with ice
and stirring. The mixture was then stirred at room
temperature for 30 minutes and under reflux for 2 hours,
and the dioxane was stripped off in vacuo. The residue
(40.3 g) was suspended in 150 ml of water, 6.65 g of
caustic potash were added, and the mixture was refluxed
for 1.5 hours. The warm solution was filtered and the
residue was rinsed with H20. The filtrate was then
acidified to pH = 1 to 2 with semiconcentrated hydrochloric
acid, while cooling with ice, and the precipitate was
filtered off under suction, washed with water and dried
in vacuo at 100C. 27.7 g of 7~chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid
(R1 = H) of melting point 234 to 237C were obtained in
this manner
The present invention also comprises pharmaceutic-
ally acceptable bioprecursors of the active compounds of
the present invention.
For the purposes of this specification the term
'pharmaceutically acceptable bioprecursor' of an active
compound of the invention means a compound having a
structural formula different from the active compound but
which nonetheless, upon administration to an animal or
human being is converted in the patient's body to the
active compound.
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