7-amino-1-cyclopropyl-4-oxo-1, 4-dihydro-quinoline-and naphthyridine-3-carboxylic acids and antibacterial agents containing these compounds

The invention relates to 7-amino-1-cyclo-propyl-4-oxo-1, 4-dihydro-naphthyridine (or quinoline)-3-carboxylic acids of Formula I as defined in the specification. Also included in the invention is a process for the preparation of said compounds of Formula I and Ia. Further, the invention includes compositions containing the compounds of Formula I or Ia and the use of said compounds and compositions as antibacterial agents.

The present invention relates to certain new 
7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline- and 
napthyridine-3-carboxylic acid compounds, to processes for their 
production, to their use as antibacterial agents, and to feed additives 
containing these compounds. 
It has already been disclosed that 
7-amino-1-ethyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids have 
antibacterial properties [see Eur. J. Med. Chem. 12, 541-547 (1977)]; and 
it has also been disclosed that 
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic 
acids possess antibacterial properties [J. Med. Chem. 23, 1358 (1980)]. 
According to the present invention there are provided compounds which are 
7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline- and 
naphthyridine-3-carboxylic acids of the formula 
##STR1## 
or a salt thereof, 
in which A represents a nitrogen atom or CR.sup.3, 
wherein R.sup.3 denotes a hydrogen, a nitro group or a halogen atom 
(preferably a fluorine or chlorine atom), or a nitrile, carboxamide, 
carboxyl or ester group, and 
Z represents a nitrogen atom or C--H, and A and Z cannot simultaneously be 
nitrogen atoms, and R.sup.1 and R.sup.2 are identical or different and 
represent a hydrogen atom or a straight-chain or branched alkyl, alkenyl 
or alkinyl radical which has up to 12 (preferably up to 6) carbon atoms 
and is optionally substituted by radical(s) selected from hydroxyl, 
alkoxy, alkylmercapto or dialkylamino with 1 to 3 carbon atoms in each 
alkyl radical, nitrile, alkoxycarbonyl with 1 to 4 carbon atoms in the 
alcohol part, aryl and hetaryl, or furthermore represent a cycloalkyl 
radical with 3 to 6 carbon atoms, or, together with the nitrogen atom 
which they substitute and, if appropriate, a further hetero-atom (such as 
oxygen or sulphur, or NR.sup.4) form a 3-membered to 7-membered ring which 
can be monosubstituted disubstituted or polysubstituted by radical(s) 
selected from alkyl or alkenyl with up to 6 carbon atoms, hydroxyl, alkoxy 
or alkyl-mercapto with 1 to 3 carbon atoms, alkoxycarbonyl with 1 to 4 
carbon atoms in the alcohol part, nitrile group and aryl, and which can 
furthermore possess a double bond, and R.sup.4 represents a hydrogen atom, 
or a branched or straight-chain alkyl, alkenyl or alkinyl group which has 
up to 6 carbon atoms and is optionally substituted by radical(s) selected 
from hydroxyl, alkoxy, alkylmercapto or dialkylamino with 1 to 3 carbon 
atoms per alkyl radical, and alkoxycarbonyl with 1 to 4 carbon atoms in 
the alcohol part, or represents an aralkyl group which is optionally 
substituted in the aryl radical by C.sub.1 -C.sub.2 -alkyl, halogen, 
preferably chlorine, NO.sub.2 and/or NH.sub.2 and has up to 4 (preferably 
1 2) carbon atoms in the aliphatic part, or an optionally substituted 
phenyl or naphthyl group or a heterocyclic radical (such as a radical of 
pyridine, pyrimidine, thiazole or benzothiazole), or R.sup.4 denotes an 
alkoxycarbonyl group which is optionally substituted by an aryl radical 
and has 1 to 4 carbon atoms in the alcohol part, an alkanoyl radical with 
1 to 6 carbon atoms, an aryl radical, an optionally substituted C.sub.1 
-C.sub.3 -alkyl- or aryl-(thio) carbamoyl radical, an C.sub.1 -C.sub.3 
-alkyl- or aryl-sulphonyl radical or an optionally substituted 
aminosulphonyl radical. 
As used herein and unless otherwise specified, the term "aryl" is 
preferably mono- or bi-cyclic carbocyclic aryl, such as phenyl or 
naphthyl; the term "aralkyl" is preferably mono- or bi-cyclic carboxylic 
aryl-C.sub.1 -C.sub.4 -alkyl, such as benzyl, phenethyl, naphthyl-methyl 
and naphthyl-ethyl; the term "hetaryl" is preferably mono- or bi-cyclic, 
N-, O- or S-heteroaryl, such as pyridine, thiophene and furane; and the 
term "aroyl" is preferably benzoyl or naphtyoyl. 
The compounds of the present invention have a superior antibacterial action 
against both gram positive and gram negative bacteria, including 
pseudomonas aerwginosa, to that of the known quinolone- and 
azaquinolone-carboxylic acids. 
The abovementioned aryl radicals, preferably the phenyl or naphthyl 
radical, are optionally monosubstitured di-substituted or polysubstituted 
by substituent(s) selected from halogen (preferably fluorine, chlorine 
and/or bromine), alkyl, alkoxy or alkylmercapto with 1 to 3 carbon atoms, 
aryloxy or arylmercapto, trifluoromethyl, nitro, nitrile and a carboxylic 
and ester group with 1 to 4 carbon atoms in the alcohol part. 
Further according to the present invention and within the scope of the 
compounds identified above under Formula (I) there are now provided, as 
new compounds, 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperzino-quinoline-3-carboxyli 
c acids of the general formula 
##STR2## 
or salts thereof, 
in which, R.sup.a denotes a hydrogen atom or a methyl, ethyl or 
.beta.-hydroxyethyl group. 
Suitable salts are those of inorganic or organic acids, p.e. hydrochloric 
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphonic acid, 
acetic acid, succinic acid, malic acid etc. Suitable salts are furthermore 
those of anorganic or organic bases, p.e. KOH, NaOH, 
Ca(OH).sub.2,Al(OH).sub.3, piperidine, morpholine, ethylamine, 
triethylamine etc. 
The compounds of the formula (I') may contain various amounts of water. 
According to the present invention, there is further provided a process for 
the production of a compound of the present invention characterized in 
that 
(a) a quinolone-carboxylic acid of the formula 
##STR3## 
in which 
R denotes a hydrogen atom, 
A and Z have the abovementioned meaning and 
X represents a halogen atom or an alkylsulphonyl group with 1 to 4 carbon 
atoms, 
is reacted with an amine of the formula 
##STR4## 
in which 
R.sup.1 and R.sup.2 have the abovementioned meanings or 
(b) a 7-halogeno-naphthyridine-3-carboxylic acid ester of a compound of 
formula (II), as given above, in which R denotes an alkyl radical and A, Z 
and X have the abovementioned meanings, is reacted with an amine of 
formula (II), as defined above, if appropriate in the presence of an 
acid-binding agent, (such as triethylamine or pyridine) and then the 
resulting 7-amino-naphthyridine-3-carboxylic acid ester is hydrolyzed 
under alkaline conditions. 
If, for example, 
7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid and N-methylpiperazine are used as reactants in the reaction, the 
course of the reaction variant (a) according to the present invention is 
illustrated by the following equation: 
##STR5## 
The starting compound of formula (II) can be prepared in the following 
manner (in which the formulae for the compounds concerned are given in the 
following reaction scheme): 
The starting substance used is, for example, a 
4-halogeno-pyridine-3-carboxylic acid ester of the formula (IV), which is 
substituted by a radical X in the 6-position, this ester is largely 
converted selectively into a monosubstitution product of the formula (IV), 
the halogen atom in the 4-position being replaced by the amine radical, 
with a .beta.-cyclopropylamino-propionic acid ester of the formula (V), 
preferably a methyl or ethyl ester, which is readily accessible by 
reaction of corresponding acrylic acid ester with cyclopropylamine. The 
monosubstitution product of the formula (VI) is converted into a 
tetrahydro-naphthyridine-3-carboxylic acid ester of the formula (VII) by 
Dieckmann cyclisation in the presence of a strong base (such as potassium 
t-butylate or sodium hydride). The carboxylic acid ester of the formula 
(VIII) is obtained from the ester of formula (VII) with bromine or 
sulphuryl chloride and triethylamine or pyridine as the 
dehydrohalogenating agent, and the compound of the formula (VIII) is 
saponified with an alkali to give the carboxylic acids of the formula (II) 
(in which R represents a hydrogen atom, A represents a nitrogen atom and Z 
represents CH). 
One version of the abovementioned process for the production of a starting 
substance of formula (II) is represented by the reaction scheme: 
##STR6## 
Preferred possible diluents for the reaction variant (a) or (b) are 
ethanol, dioxane, toluene, dimethylformamide and dimethylsulphoxide. 
Acid-binding agents which can be used in reaction variant (b) are, 
preferably, alkali carbonates, alkali metal hydroxides or tert.-organic 
bases (such as, preferably, triethylamine and pyridine). 
The reaction temperatures for reaction variants (a) or (b) can be varied 
within a substantial range. In general, the reaction is carried out at a 
temperature between 20.degree. and 180.degree. C., preferably between 
60.degree. and 140.degree. C. 
Both reaction variants can be carried out under normal pressure, but also 
under increased pressure, especially in the case of gaseous and 
low-boiling amines of the formula (III). In general, the reaction is 
carried out under pressures between 1 and 100 bars, preferably between 1 
and 10 bars. 
In carrying out reaction variant (a) or (b), 1 to 5 moles of amine, 
preferably 2 to 3 moles of amine, are employed per mole of carboxylic 
acid. 
The 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid used as a starting material can be prepared in a multi-stage reaction 
sequence, for example starting from 4,6-dichloro-nicotinic acid ethyl 
ester, which is known (see Recueil Trav. chim. Pays-bas. 69, 687 (1950). 
The methyl ester is known from U.S. Pat. Nos. 4,066,645 and 4,075,210. 
According to the present invention there is further provided a process for 
the production of a compound of the invention of Formula (I') in which 
(a') 
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic 
acid of the formula 
##STR7## 
in which R.sup.b denotes a hydrogen atom, is reacted with piperazine or a 
piperazine derivative of the formula 
##STR8## 
in which 
R.sup.a has the meaning given above, or 
(b') a compound of the formula (II'), as given in reaction variant (a) in 
which R.sup.b 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-binding 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, into a salt and/or a hydrate thereof. 
The reaction variant (a) is preferably carried out in a diluent (such as 
dimethylsulphoxide, N,N-dimethylformamide, hexamethyl-phosphoric acid 
trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature 
between 20.degree. and 200.degree. C., preferably between 80.degree. and 
180.degree. C. 
The reaction variants can be carried out under normal pressure, but also 
under elevated pressure, in particular 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'). 
Among the new 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazo-quinoline-3-carboxylic 
acid salts and hydrates of the invention those salts or hydrates that are 
pharmaceutically acceptable are particularly important and are preferred. 
The new free 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyl 
ic acids of the general formula (I) and their salts and hydrates can be 
interconverted in any suitable manner; 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, hydroiodic 
acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid. 
If 7-chloro-1-cyclopropyl-6-fluoro-1,4-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: 
##STR9## 
The following may be mentioned individually as active compounds according 
to the present invention: 7-piperazino-, 7-(4methylpiperazino)-, 
7-(4-ethylpiperazino)-, 
7-(4-.beta.-hydroxyethylpiperazino)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o 
xo-quinoline-3-carboxylic acid and pharmaceutically tolerated acid addition 
salts or alkali metal alkaline earth metal or ammonium salts of these 
compounds. 
The starting compounds of formula (II') can be prepared via a malonic ester 
synthesis, according to the following equation: 
##STR10## 
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 (Organicum, 3rd edition 1964, 
page 438). 
The ethyl aroylacetate of formula (IX') is obtained in good yield by 
partial hydrolysis and decarboxylation of the compound of formula (VIII') 
in an aqueous medium containing a catalytic amount of p-toluenesulphonic 
acid, and is converted with triethyl o-formate/acetic anhydride into the 
ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxyacrylate of formula (X'). 
The reaction of the compound of formula (X') with cyclopropylamine in a 
solvent (such as methylene chloride, alcohol, chloroform, cyclohexane or 
toluene) leads to the desired intermediate product of formula (VI) in a 
slightly exothermic reaction. 
The cyclisation reactin VI.fwdarw.II (R.sup.1 =alkyl) is carried out in a 
temperature range of 60.degree. to 280.degree. C., preferably 80.degree. 
to 180.degree. C. 
Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, 
hexamethylphosphoric 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 preferably sodium hydride or 
potassium carbonate are suitable acid-binding agents for this reaction 
stage. It can be advantageous to employ an excess of 10 mol% of base. 
The 2,4-dichloro-5-dichloro-5-fluoro-benzoyl chloride of formula (IV) used 
as a starting material for this synthesis route, the corresponding 
carboxylic acid, and the 3-fluoro-4,6-dichlorotoluene of formula (XI) 
required for the preparation of formula (IV) were not yet known in the 
literature and form a further subject of the present invention. 
The equation below shows the preparation of these precursors or 
intermediate products, starting from 2,4-dichloro-5-methyl-aniline of 
formula (XIII). 
##STR11## 
According to this equation, 2,4-dichloro-5-methyl-aniline of formula (XII') 
is diazotised by means of NaNO.sub.2, and the resulting diazonium salt is 
converted into the triazene of formula (XIIa'), using dimethylamine. 
Triazene of formula (XIIa') is dissolved in excess anhydrous HF. In 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.degree. to 140.degree. to give 
3-fluoro-4,6-dichlorotoluene XI', N.sub.2 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.degree. to 160.degree. C., under UV 
irradiation, to give 2,4-dichloro-5-fluoro-1-trichloro-methylbenzene of 
formula (XIII'). 
The hydrolysis of the compound of formula (XIII') with 95 percent sulphuric 
acid leads to 2,4-dichloro-5-fluoro-benzoic acid of formula (XV'), which 
is 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 No. P 30 33 157.8 of 3.9.1980 and DE-OS (German 
Published Specification) No. 2,804,097, as can be seen from the table 
below. 
__________________________________________________________________________ 
##STR12## 
##STR13## 
##STR14## 
Example 2 of German 
(disclosed in DE-OS (German 
(compound according to 
Patent Application Published Specification) 
the invention, of the 
P 30 33 157.8 of 3.9.80 
2,804,097) formula I (R 
__________________________________________________________________________ 
= H) 
Staphylo- 
8 1 0.25-0.5 
coccus 
aureus 133 
E. coli 
1 0.125 0.06 
A 261 
E. coli 
1 0.25 0.06 
Neum. 
Klebsiella 
1 0.25 0.06 
8085 
Proteus 
0.5 0.06 0.03 
1017 
Pseudo- 
4 1 0.5 
monas 
aeruginasa 
__________________________________________________________________________ 
Agar dilution test 
DST (dexhase sensitivity test) medium; 1-2 .times. 10.sup.3 germs/plate 
New antibacterial active compounds which may be mentioned specifically are: 
7-methylamino-, 7-benzylamino-, 7-pyrrolidino-, 7-morpholino-, 
7-piperidino-, 7-piperazino-, 7-(4-methylpiperazino)-, 
7-(4-benzylpiperazino)-, 7-(4-.beta.-hydroxyethylpiperazino)-, 
7-(4-.gamma.-hydroxypropyl-piperazino)-, 7-(4-formylpiperazino)- or 
7-(4-hydroxypiperidino)-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine- 
3-carboxylic acid and pharmaceutically acceptable acid addition salts or 
alkali or alkaline earth metal salts of these compounds. 
It has furthermore been found that the compounds according to the invention 
have outstanding antimicrobial properties. 
In particular, they have a broad bacteriostatic and bactericidal action 
against Gram-positive bacteria, such as Staphylococci and Streptococci, 
and Gram-negative bacteria, such as Escherichia, Proteus, Providencia, 
Enterobacter, Klebsiella, Salmonella and Pseudomonas. The list of 
sensitive bacteria is to be regarded as a list of examples and in no way 
restrictive. 
The improved broad antibacterial activity of the compounds according to the 
invention enable them to be used as active compounds both in medicine, in 
which they can be used both for preventing and for the treatment of 
systemic or local bacterial infections, in particular of the urinary 
tract. The compounds according to the invention can furthermore also be 
used as feed additives for promoting growth and for improving feed 
utilisation in livestock husbandry, in particular in the rearing of 
animals for fattening. The active compounds are then preferably 
administered via the feed and/or the drinking water. 
The present invention furthermore relates to agents which contain the new 
compounds according to the invention. These agents include, for example, 
feed concentrates, for livestock husbandry, which can also contain, as is 
customary, vitamins and/or mineral salts, in addition to the active 
compounds, and pharmaceutical formulations. 
Among the new 
7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid 
salts of the invention, those salts that are pharmaceutically acceptable 
are particularly important and are preferred, alkali metal salts and 
alkaline earth metal salts being particularly preferred. 
The new free 
7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-carboxylic acids of 
the general formula (I) and (I') and their salts can be interconverted in 
any suitable manner; methods for such interconversion are known in the 
art. 
As stated above, the invention also relates to the use in medicine 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 an inert 
pharmaceutical carrier, e.g. 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 of 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 physiologically 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. "Medicament 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 invention may, for example, 
take the form of ointments, gels, 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 particlar 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 microencapsulated 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 glycols and fats (e.g. cocoa oil and high esters 
(e.g. C.sub.14 -alcohol with C.sub.16 -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, tragacanth, cellulose 
derivatives, polyethylene 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 
sorbital 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), microcrystalline 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). 
The pharmaceutical compositions according to the invention generally 
contain from 0.1 to 99.5% usually from 0.5 to 95% of the active ingredient 
by weight of the total composition. 
In addition to a compound of the invention, the pharmaceutical 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 discrete 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 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 (e.g. tablets). 
This invention further provides a method of combating the above-mentioned 
diseases in warm-blooded animals, which comprises administering to the 
animals a compound of the invention alone or in admixture with a diluent 
or in the form of a medicament according to the invention. 
The provision of new bactericides for combating bacteria which are 
resistant to known bactericides as is the case with compounds of the 
present invention is an enrichment of the state of the art.

The following examples illustrated but do not limit the invention. 
EXAMPLE 1 
7-(4-Methylpiperazino)-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3- 
carboxylic acid (a compound of formula (I) in which R.sup.1 R.sup.2 
N=4-methylpiperazino, A=N and B=CH). 
A suspension of 2.64 g of 
7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid and 2.5 g of N-methylpiperazine in 30 ml of ethanol or DMSO 
(=Dimethylsulfoxide) was heated to the boiling point under reflux for 16 
hours or to 135.degree.-140.degree. C. for two hours. The diluent was 
distilled off in vacuo, the residue was dissolved in 30 ml of 1N NaOH, the 
solution was filtered and the filtrate was acidified with 10 strength 
hydrochloric acid. The precipitate was filtered off and washed with water 
and ethanol. It could be recrystallised from N-dimethylformamide/ethanol. 
3.1 g (94% of the theoretical yield) of 
7-(4-methylpiperazino)-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3 
-carboxylic acid of melting point 326.degree. C. (hydrochloride) 
(decomposition) were obtained. 
EXAMPLES 2 TO 10 
The carboxylic acids of Examples 2 to 19 were obtained by a procedure 
analogous to that in Example 1. They are summarised in Table 1. The 
labelling of the radicals R.sup.1 and R.sup.2 relates to the formula (I) 
of the description. 
TABLE 1 
______________________________________ 
Ex- 
ample Decomposition 
No. A B R.sup.1 R.sup.2 
Point (.degree.C.) 
______________________________________ 
2 N CH 
##STR15## (hydrochloride)322 
3 N CH (CH.sub.2).sub.2 O(CH.sub.2).sub.2 
286 
4 N CH (CH.sub.2).sub.2 CH.sub.2 (CH.sub.2) .sub.2 
297 
5 N CH CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 
330 
6 N CH 
##STR16## (hydrochloride)305 
7 N CH 
##STR17## (hydrochloride)306 
8 N CH 
##STR18## 300 
9 N CH 
##STR19## 302 
10 N CH 
##STR20## 279 
1 CF CH 
##STR21## (hydrochloride)306256 
2 CH N 
##STR22## 279 
3 CH N 
##STR23## 277 
4 CF CH 
##STR24## 249 
5 CF CH (CH.sub.2).sub.4 
323 
6 CCN N 
##STR25## (hydrochloride)335 
7 CCN N 
##STR26## (hydrochloride)295 
8 CCN N (CH.sub.2).sub.4 
290 
9 CF CH 
##STR27## (hydroiodide)306 
______________________________________ 
EXAMPLE 20 
Preparation of precursors 
(a) 
6-Chloro-4-(N-2-methoxycarbonylethyl-N-cyclopropyl)-amino-pyridine-3-carbo 
xylic acid methyl ester (a compound of formula (VI) in which R=methyl and 
X=chlorine). 
A mixture of 28.6 g of .beta.-cyclopropylamino-propionic acid methyl ester 
and 21 g of triethylamine was rapidly added dropwise to a solution of 41.2 
g of 4,6-dichloropyridine-3-carboxylic acid methyl ester in 150 ml of 
toluene at 10.degree. to 20.degree. C., whilst cooling with ice and 
stirring. The ice-bath was removed and the mixture was stirred at room 
temperature for 1/2 hour and heated to the boiling point under reflux for 
6 hours. The resulting suspension was washed with water and dried with 
Na.sub.2 SO.sub.4 and the solvent was distilled off in vacuo. 59 g of the 
title compound were obtained as a brown oil. 
(b) The .beta.-cyclopropylaminopropionic acid methyl ester 
This compound, used as a reactant in Example 20(a), was prepared as 
follows: 
86 g of freshly distilled methyl acrylate which had been cooled to 
-60.degree. C. was added dropwise to a solution, which had been cooled to 
-60.degree. C. to -70.degree. C., of 57 g of cyclopropylamine in 150 ml of 
ethanol in the course of about 3 hours. The mixture was then allowed to 
rise slowly to room temperature overnight, the solvent was distilled off 
in vacuo and the residue was then fractionated. 95 g of 
.beta.-cyclopropylamino-propionic acid methyl ester passed over at 
84.degree.-86.degree. C./22 mm Hg. 
(c) 
7-Chloro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbox 
ylic acid methyl ester (a compound of formula (VII) in which R=methyl and 
X=chlorine). 
59 g of crude 
6-chloro-4-(N-2-methoxycarbonylethyl-N-cyclopropyl)-amino-pyridine-3-carbo 
xylic acid methyl ester were dissolved in 240 ml of anhydrous toluene, and 
23 g of potassium t-butylate were rapidly added, whilst stirring. The 
mixture was left to stand overnight, 20 g of glacial acetic acid and 100 
ml of water were added, the phases were separated, the toluene solution 
was washed again with water and dried with Na.sub.2 SO.sub.4 and the 
toluene was stripped off in vacuo. After recrystallisation from methanol, 
18 g of the carboxylic acid ester of melting point 155.degree. to 
157.degree. C. were obtained. 
(d) 7-Chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid methyl ester (a compound of formula (VIII) in which R=methyl and 
X=chlorine). 
9.8 g of the tetrahydronaphthyridine-3-carboxylic acid methyl ester 
prepared according to Example 20(c) were dissolved in 200 ml of methylene 
chloride, and a solution of 5.9 g of bromine in 40 ml of CH.sub.2 Cl.sub.2 
was rapidly added dropwise at 10.degree. to 15.degree. C., whilst cooling 
with ice. The mixture is then stirred at .about.10.degree. C. for a 
further 10 minutes, 8 g of triethylamine were added and the ice-bath was 
removed. The mixture was subsequently stirred for 3 hours, washed twice 
with water and dried with Na.sub.2 SO.sub.4, the solvent was distilled off 
in vacuo and the residue was recrystallised from 
dimethylformamide/ethanol. 8.8 g of 
7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid 
methyl ester of melting point 272.degree. to 274.degree. C. 
(decomposition) were obtained. 
(e) 7-Chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid (a compound of formula (II) in which R=H, A=N, Z=CH and X=chlorine). 
A solution of 5.7 g of potassium hydroxide in 300 ml of water was added to 
27.85 g of the ester prepared according to Example 11(d). The mixture was 
heated to 85.degree. to 95.degree. C. for 30 minutes, whilst stirring, and 
the resulting solution was filtered at room temperature and acidified with 
glacial acetic acid. The precipitate was filtered off, washed with water 
and dried over calcium chloride in a vacuum drying cabinet. 20 g of pure 
7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic 
acid of melting point 226.degree. to 227.degree. C. were obtained. 
(including prevention, relief and cure of) the above-mentioned diseases in 
warm-blooded animals, which comprises administering to the animals a 
compound of the invention alone or in admixture 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 admixture with a feed 
additive-carrier. 
The Examples which follow illustrate the invention further. 
EXAMPLE 21 
##STR28## 
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-methylpiperazine and 120 ml of anhydrous 
dimethylsulphoxide was heated at 135.degree. to 140.degree. C. for 1.5 
hours. The solvent was distilled off under a fine vacuum, and the residue 
was suspended in approx. 50 ml of H.sub.2 O. The suspension was filtered 
under suction, and the residue was rinsed with H.sub.2 O, dried in a 
vacuum drying cabinet at 80.degree. C. over CaCl.sub.2, and recrystallised 
from glycol monomethyl ether. 14.5 g of 
1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylpiperazino)-4-oxo-quinoline- 
3-carboxylic acid which decomposes at 248.degree. to 250.degree. C. were 
obtained. 
EXAMPLE 22 
##STR29## 
A suspension of 2.81 of 
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic 
acid and 5.2 g of N-.beta.-hydroxyethylpiperazine in 25 ml of 
dimethylsulphoxide was heated at 135.degree. to 140.degree. C. for 2 
hours. The solvent was distilled off under a fine vacuum, the residue was 
boiled for a short time with 20 ml of H.sub.2 O and left to stand 
overnight at room temperature, and the precipitate was filtered off under 
suction, while cooling with ice, and was washed with water and dried in 
vacuo over CaCl.sub.2 at 80.degree. C. 2.1 g of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-.beta.-hydroxyethylpiperazin 
o)-quinoline-3-carboxylic acid which decomposed at 237.degree. to 
239.degree. C. were obtained. 
EXAMPLE 23 
##STR30## 
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 dimethylsulphoxide was 
heated at 135.degree. to 140.degree. C. for 2 hours. The solvent was 
distilled off under a fine vacuum, and the residue was suspended in 
H.sub.2 O, filtered off under suction and washed with water. For further 
purification, the moist crude product was boiled with 100 ml of water, 
filtered off under suction at room temperature, washed with H.sub.2 O and 
dried over CaCl.sub.2 in a vacuum drying cabinet at 100.degree. C. until 
its weight remained constant. 19.6 g of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyl 
ic acid which decomposed at 255.degree. to 257.degree. C. were obtained. 
The compound prepared according to Example 3 was dissolved in 50 of hot 10 
percent hydrochloric acid. 150 ml of ethanol were added to the filtered 
solution, the mixture was cooled with ice, and the product was filtered 
off under suction, washed with alcohol, and dried in vacuo at 100.degree. 
C. 18.5 g of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyl 
ic acid hydrochloric were obtained as colourless crystals which decomposed 
at 326.degree.-328.degree. C. The monohydrate of this hydrochloride has a 
m.p. 318.degree.-320.degree. C. 
EXAMPLE 24 
##STR31## 
(a) A mixture of 1.2 g of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyl 
ic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of 
N,N-dimethylformamide was heated at 70.degree. to 80.degree. C. 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 H.sub.2 O and pressed on clay. 1.15 g of 
1-cyclopropyl-6-fluoro-7-(ethylpiperazino)-1,4-dihydro-4-oxo-quinoline-3-c 
arboxylic acid hydroiodide which decomposes at 306.degree. C. 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 added dropwise, a vigorous 
reflux being observed. After the reaction had ceased, the mixture was 
heated at the boil for a further 2 hours and was cooled with dry 
ice/acetone at -5.degree. C. to -10.degree. C. and a solution of 227.5 g 
of 2,4-dichloro-5-fluoro-benzoyl chloride in 100 ml of absolute ether was 
slowly added dropwise at this temperature. The mixture was stirred for 1 
hour at 0.degree. C. to -5.degree. C. 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 with saturated NaCl solution and 
dried with Na.sub.2 SO.sub.4, and the solvent was stripped off in vacuo. 
349.5 g of diethyl 2,4-dichloro-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 CH.sub.2 Cl.sub.2 solutions were washed once with saturated NaCl 
solution and dried with Na.sub.2 SO.sub.4, 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.degree. to 142.degree. C./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 
150.degree. C. 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 120.degree. C. 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-benzoyl)-3-ethoxy-acrylate in 80 ml of 
ethanol while cooling with ice and stirring. When 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 (R.sup.1 
=C.sub.2 H.sub.5) of melting point 89.degree. to 90.degree. C. were 
obtained. 
3.44 g of 80 percent 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 (R.sup.1 
=C.sub.2 H.sub.5) 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 H.sub.2 O. 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 
100.degree. C. 27.7 g of 
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic 
acid (R.sup.1 =H) of melting point 234.degree. to 237.degree. C. were 
obtained in this manner. 
The present invention also comprises pharmaceutically acceptable 
bioprecursors of the active compounds of the present invention. 
The following example shows the recipe of a tablet according to the 
invention: 
______________________________________ 
1-Cyclopropyl-6-fluoro- 
277.5 mg (corresponding 
1,4-dihydro-4-oxo-7- to 250.0 mg Butain) 
piperazino-3-carboxylic 
acid HCl 
Avicel 49.0 mg 
Moist corn starch 
14.0 mg 
Pregelatiniged starch 
6.0 mg 
Magnesium stearate 
3.5 mg 
tablet without film coating 
350.0 mg 
Film coating 
HPM cellulose 15 cp 
3.0 mg 
Polyethylene glycol 4000 
1.0 mg 
Titanium dioxide 1.0 mg 
film coated tablet 
355.0 mg 
______________________________________ 
For the purpose 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 a warm-blooded animal is converted in 
the patient's body to the active compound. 
The improved bacterial action of the compounds of Example 1 according to 
the present invention is particularly clear in the following biotest 
Example, in which it was compared with 
2-piperazino-8-ethyl-5-oxo-5,8-dihydropyrido 2,3-d pyrimidine-6-carboxylic 
acid ("pipemidic acid") or the known compound 
1-ethyl-7-methyl-1,8-naphthyrid-4-one-3-carboxylic acid ["nalidixic acid"; 
Ehrhart/Ruschig, Arzneimittel (Medicaments), Volume 2: Chemotherapeutika 
(Chemotherapeutics), Verlag Chemie 1968, page 1,568]. The compounds of the 
invention have proved to be far superior in vitro and in vivo on bacteria 
such as Staphylococci, Escherichia coli, Proteus, Klebsiella and 
Pseudomonas than such known compounds. 
EXAMPLE 
The agar dilution test was carried out by the Denley multipoint inoculation 
method and the results were as shown in the following Table. 
______________________________________ 
Minimum inhibitory concentrations mog/ml 
in an agar dilution test.sup.x 
Compounds Nalidixic 
from Example 1 
Pipemidic acid 
acid 
______________________________________ 
Escherichia coli 
T 7 0.25 2 1 
455/7 128 128 256 
103400 0.25 1 2 
Salmonella 683 
0.5 2 4 
Klebsiella 63 
1 2 4 
Pseudomonas 7167 
8 16 64 
Proteus 8228 
2 4 8 
______________________________________ 
.sup.x Denley multipoint inoculation method 
The present invention also comprises pharmaceutically 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 a warmblooded animal is 
converted in the patient's body to the active compound.