NO870126L - 7- (AZABICYCLOALKYL) -CHINOLONCARBOXYLIC ACID AND NAFTYRIDON CARBOXYLIC ACID DERIVATIVES. - Google Patents

Description

The invention relates to the new 7-(azabicycloalkyl)-quinolone carboxylic acid and -naphthyridone carboxylic acid derivatives, methods for their preparation, as well as antibacterial agents and additives containing these.

It is already known that 1-ethyl-6-fluoro-1,4-didhydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acids (German patent applications 2 084 097 and 2 939 786), l- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acids (European patent application 49 355, German patent application 3 142 854), 1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acids (Japanese Application No. 60 032-790), 9-fluoro-2,3-dihydro-3- methyl-7-oxo-10-(1-piperazinyl)-7H-pyrido^~1,2,3-de7/~1,4/benzoxazine-6-carboxylic acids (European patent application 47 005) , l-ary.l- 6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (European patent application 131 839) and azabicycloalkyl-quinolone carboxylic acid (European patent application 159 174) are antibacterially active.

It was found that the new 7-(azabicycloalkyl)-quinolinecarboxylic acid resp. 1-Naphthyridonecarboxylic acid derivatives of formula

(IN)

in which

R<1> means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl,

2-hydroxyethyl, 2-fluoroethyl, methoxy/amino, methylamino, dimethylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl,

R<2> means hydrogen, alkyl of 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

3

R means a residue with formula

in which

Y means R<4->N, 0, S,

Z means -(CH ) -, -CH -O-CH , -CH -S-CH -, -CH„-S-,

n means 1, 2 or 3, ■ \• *

R 4 means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

R 5 means hydrogen or methyl,

X<1> means fluorine, chlorine or nitro, and

A means N or C-R^, in which R6 means hydrogen, fluorine, chlorine,

methyl or nitro, or also together with R^ can form a bridge with structure

-0-CH_-CH-CH^, -S-CH_-CH-CH„ or -CH„-CH„-CH-CH_

2\3 2. \2.2 2%o

with the precaution that for the case that X1 means fluorine, R means H and A means CF or N, and R<1> means ethyl, cyclopropyl, fluoroethyl or vinyl, or R^ with R<1> forms a bridge of structure - O-CH<^£ -Ci H-CH - i is n different from 2 and R 3 cannot mean the rest

as well as excluding the compound 7-(2,5-diazabicyclo[2,2,2-7oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid,

and their pharmaceutically acceptable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts

ter of the underlying carboxylic acids have a high antibacterial effect, especially in the Gram-positive area.

They are therefore suitable as active substances for human and veterinary medicine, as the treatment of fish for therapy or prevention of bacterial infections is also suitable for veterinary medicine.

A further object of the invention is 7-(azabicycloalkyl)-quinolinecarboxylic acid or -naphthyridone carboxylic acid derivatives of formula (I)

in which

means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl,

2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, fluorophenyl, 2,4-difluorophenyl,

R 2 means hydrogen, alkyl of 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

R 3 means one in the ring system with hydroxy or methyl one- or

multiply substituted residue with formula

in which

Y means R<4->N, 0, S,

Z means -(CH2)n<«->, -CH2~0-CH2-, -CH2-S-CH2-, -CH2~S-,

n means 1, 2 or 3,

r<4> means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and

R means hydrogen or methyl,

X"'" means fluorine, chlorine or nitro, and

A means N or C-R^, where R^ means hydrogen, fluorine, chlorine,

methyl or nitro, or also together with R"<*>" can form a bridge of structure

-O-CH -CH-CH-, -S-CH_-CH-CH,. or

-CH2-CH2-CH-CH3

and their pharmaceutically acceptable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids.

Preferred are the compounds of formula (I), in which

R"1" means methyl, ethyl, cyclopropyl, 2-hydroxyethyl, vinyl, 2-fluoroethyl, methoxy, methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl,

2

R means hydrogen, methyl, ethyl,

3

R means a residue with formula

in which

Y means R<4->N, 0,

Z means"(CH2)-, -CH2-0-CH2-,

n means 1, 2 or 3,

R<4> means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl with 1 to 3 carbon atoms, optionally with nitro or amino substituted benzyl or oxoalkyl with 2 to 4 carbon atoms, and

R^ means hydrogen or methyl,

X<1> means fluorine, chlorine or nitro, and

A means N or C-R<6>, where R<6> means hydrogen, fluorine, chlorine,

methyl or nitro, or together with R<1> can form a bridge with the structure

-O-CH2-CH-CH3 or -CH2-CH2-CH-CH3

with the precaution that for the case that X<1>means fluorine,

R<2> means H and A means CF or N and R<1> means ethyl, cyclopropyl, fluoroethyl or vinyl, or R^ forms with R<1> a bridge of structure -0-CH--CH-CH-, is n different from 2, and R<3> cannot mean the remainder

as well as excluding the connection

7-(2,5-diazabicyclo[2,2,27oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid,

and their pharmaceutically acceptable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts

of the underlying carboxylic acids.

Particularly preferred are the compounds of formula (I), in which

R<1> means methyl, ethyl, cyclopropyl, 2-fluoroethyl, vinyl,

methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl,,

2

R means hydrogen, methyl, ethyl,

3

R means a residue with formula

in which

Y means R<4->N, 0,

Z means"(CH2)-,

n means 1 or 2,

R<4> means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl with 1 to 3 carbon atoms, optionally with nitro or amino substituted benzyl or oxoalkyl with 2 to 4 carbon atoms, and

5

R means hydrogen or methyl,

X"<1>"means fluorine, chlorine or nitro, and

A means N or C-R , in which R<b>means hydrogen, fluorine, chlorine or nitro, or together with R^" can form a bridge of the structure

-O-CH2-CH-CH3 or -CH2-CH2-CH-CH3

with the precaution that for the case that X1 means fluorine,

2 1

R means H and A means CF or N, and R means ethyl, cyclopro-C-i

pyl, fluoroethyl or vinyl, or R forms with Rx a bridge of the structure -0-CH2-CH-CH3 n is different from 2 and R<3> cannot mean the residue

as well as excluding the connections

7-(2,5-diazabicyclo</~2,2,27oct-2-yl)-1-ethy 1-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid, and their pharmaceutically useful hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids.

Also preferred are the compounds of formula (I) in which

R<1>means methyl, ethyl, cyclopropyl, 2-hydroxyethyl, vinyl, 2-fluoroethyl, methoxy, methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl,

R 2 means hydrogen, methyl, ethyl,

R<3> means one or more times, preferably twice, with methyl

substituted residue with formula

in which

Y means R<4->N, 0,

Z means -(CH2)n"~'-CH2-0-CH2~,

t

n means 1, 2 or 3,

R 4 means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl with 1 to 3 carbon atoms, optionally with nitro or amino substituted benzyl or oxoalkyl with 2 to 4 carbon atoms, and

5

R means hydrogen or methyl,

X<1> means fluorine, chlorine or nitro, and

fi fi

A means N or C-R, where R means hydrogen, fluorine, chlorine,

methyl or nitro or also together with R"*" can form a bridge with the structure

-0-CH2-CH-CH3-, -S-CH2-CH-CH3 or -CH2-CH2-CH-CH3

with the precaution that for the case that X<1>is fluorine, R is H and A is CF or N, and R<1>is ethyl, cyclopropyl, fluoroethyl or vinyl, or R<6>forms together with R<1 >en b3 ro of the structure -0-CH9-C1H-CH is n different from

2 and R do not mean the rest

and their pharmaceutically usable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids.

Particularly preferred are the compounds of formula (I), in which

R<1> means ethyl, cyclopropyl, 2-fluoroethyl, vinyl, methylamino,

phenyl, 4-fluorophenyl, 2,4-difluorophenyl,

R 2 means hydrogen, methyl, ethyl,

R 3 means a residue of formula substituted in the ring system once or more preferably twice with methyl

in which

Y means R<4->N,

Z means"(CH2)n-f

n means 1 or 2,

R 4 means hydrogen, optionally with hydroxy substituted alkyl,

alkenyl or alkynyl of 1 to 3 carbon atoms, optionally with nitro or amino substituted benzyl or oxoalkyl of 2 to 4 carbon atoms, and

R 5 means hydrogen or methyl,

X<1> means fluorine, chlorine or nitro, and

A means N or C-R^, in which R^ means hydrogen, fluorine, chlorine or nitro, or also together with R"<*>" can form a bridge of structure

-O-CH -CH-CH- or -CH_-CH -CH-CH-

and their pharmaceutically acceptable hydrates and acid addition salts, as well as the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids.

Furthermore, it was found that the compounds of formula (I) are obtained when the compounds of formula (II)

12 1

wherein R , R , X have the above meanings, and

2

X means halogen, especially fluorine or chlorine,

reacted with azabicycloalkanes of formula (III)

in which R 3 has the above meaning, possibly in the presence of an acid binder (method A).

Compounds according to the invention with formula (I)

in which

R 1 , R 2, A and x<l>have the above meaning, and

R 3 means a radical substituted in the ring system optionally one or more times, preferably twice with hydroxy or methyl, with the formula

in which

Z and R 4 have the above meaning,

can also be obtained as a compound of formula (IV)

in which

2 2 1

R , R , A and X have the above meaning, and

R<7>means a residue of formula

in which

Z has the above meaning, is traded in connection with

formula (V)

in which

R 4 has the above meaning, but cannot mean hydrogen, and

means halogen, especially chlorine, bromine or iodine, optionally

in the presence of acid binders (method B).

Compounds according to the invention with formula (I), in which R<4> means CH3-CO-CH2CH2, are also obtained by reacting a compound of formula (IV) with methyl vinyl ketone (method C).

If, in the reaction according to method A, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1,4-diazabicyclo^3,2,17octane are used as starting materials, then the course of the reaction is given by the following > nth formula kernel: n v.

Used in the reaction according to method B 1-cyclopropyl-7-(2,5-diazabicyclo[2,2,27oct-2-yl)-6,8-difluoro-1,4-dihydro-4-oxo-2-quinolinecarboxylic acid and ethyl iodide as starting materials, the course of the reaction can be reproduced by the following formula: Used, in the reaction according to method C 1-cyclopropyl-7-(3,8-diazabicyclo/3,2,1/oct-3-y1)-6-fluoro- 1,4-dihydro-4-oxo-3-quinoline carboxylic acid and methyl vinyl ketone as starting compounds, the course of the reaction can be reproduced by the following formula core:

The compounds of formula (II) used as starting materials

are known and can be produced by known methods. Examples include: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 142 854),

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 113 091),

6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 420 743),

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 420 743),

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 318 145),

6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 420 743),

7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid (European patent application 113 091),

6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 113 091),

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1,,4-dihydro-1-methoxy-4-oxo-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid,

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-triaphthyridine-3-carboxylic acid,

6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

1-cyclopropyl-6,7-8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester (German patent application 3 318 145),

8,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[1,2,3-de7^1,4_7benzoxazine-6-carboxylic acid (European patent application 47 005) ,

8,9-difluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[i,j]quinoline-2-carboxylic acid,

7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (European patent application 153 580),

7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (European patent application 153 580),

6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (German patent application 3 409 92 2), l-amino-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (German patent application 3 409 922),

6,7,8-trifluoro-1,4-dihydro-1-dimethylamino-4-oxo-3-quinolinecarboxylic acid (German patent application 3 409 922),

7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-1-phenyl-3-quinolinecarboxylic acid,

7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid,

6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid,

6-chloro-7-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 131 839),

6-chloro-7-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 131 8 39),

6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 154 780),

6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European patent application 154 780),

6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylic acid (European patent application 154 780),

7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

6,7-difluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinolinecarboxylic acid.

The azabicycloalkanes of formula (III) used as starting compounds are partially known or can be prepared according to known methods. The compounds can be used as racemates or after cleavage into the enantiomers as the enantiomeric azabicycloalkanes. Examples should be mentioned: 1,4-diazabicyclo/~3,2,1/octane /US patent 3,281,423, J. Med. Chem. 20 , 1333 (1977)./ 8-methyl-3,8-diazabicyclo/~3,2,17octane-dihydrochloride. Med. Chem. 17, 481 (1974}/,

3-methyl-3,8-diazabicyclo/~3,2,17octane dihydrochloride / J.

With.' Chem. 17 , 481 (1974)/,

2,5-diazabicyclo^~2,2,17heptane dihydrochloride (J. Org. Chem.

31 , 1059 (1966)/,

2-methyl-2,5-diazabicyclO/</>~2,2,17heptane-dihydrochloride / J. Org. Chem. 31 , 1059 (1966), J. Med. Chem. 17, 481 (1974}/,!

2- benzyl-2,5-diazabicyclo/~2,2,17heptane-dihydrochloride £~ J. Org. Chem. 31 , 1059 (1966}/,

5-methyl-1,4-diazabicyclo/3,2,3/octane,

8-ethyl-3,8-diazabicyclo/ 3,2,3/octane,

8-benzyl-3,8-diazabicyclo/3,2,1/octane,

8-(4-nitrobenzyl)-3,8-diazabicyclo/3,2,3/octane,

8-(4-aminobenzyl)-3,8-diazabicyclo/3,2,1/octane,

3- ethyl-4,8-diazabicyclo/~3.2, l/octane,

3-benzyl-3,8-diazabicyclo/3,2,l?octane,

3-(4-aminobenzyl)-3,8-diazabicyclo/3,2,17octane,

2,5-diazabicyclo/ 2 > 2 , 2/octane-dihydrochloride / J. Med. Chem. 17, 481 (1974}/,

2-methyl-2,5-diazabicyclo/ 2,2, 2/octane dihydrochloride /~J. With. Chem. 17, 481 (19'74)/,

2-ethyl-2,5-diazabicyclo/~2,2, 2/octane,

2-benzyl-2, 5-diazabicyclo/ 2,2,2/octane,

2-(4-aminob:enzyl)-2,5-diazabicyclo/2,2,2/octane,

8-propyl-3,8-diazabicyclo/3,2,l/octane,

3-isopropyl-3,8-diazabicyclo/3,2,17octane,

2-butyl-2,5-diazabicyclo/2,2,17heptane,

2- isobutyl-2,5-diazabicyclo/ 2,2,2/octane,

8-(2-Hydroxyethyl)-3,8-diazabicyclo/3,2,1/octane,

3-(2-Hydroxyethyl)-3,8-diazabicyclo/3,2,3/octane,

2-(2-Hydroxyethyl)-2,5-diazabicyclo[2,2,]/heptane,

2-(2-hydroxyethyl)-2,5-diazabicyclo/~2,2,2/octane,

1.4-diazabicyclo/~3,1,17heptane,

3,9-diazabicyclo/ 3,3,17nonane,

7-hydroxy-3,9-diazabicyclo/ 3,3,1/nonane / Chem. heterocyclic/. composition USSR 1, 195 (19651/,

7-hydroxy-9-methyl-3,9-diazabicyclo/3,3,1/nonane,

3-oxa-7,9-diazabicyclo/ 3,3,17nonane,

3-oxa-9-azabicyclo/ 3,3,l/nonane,

2.5- diazabicyclo/ 3,1,Vheptane,

1,4-diazabicyclo/' 3,3,17nonane,

2,5,9-triazabicyclo/3,2,1/nonane,

7-thia-3,8-diazabicyclo/ 3,2,l/octane.

The starting compounds of formula IV are not known. They correspond to the compounds according to the invention with formula (I),

4

wherein the residue R means hydrogen.

The starting compounds of formula (V) are known. Examples include: Methyl iodide, methyl bromide, methyl chloride, ethyl iodide, ethyl bromide, benzyl bromide, benzyl chloride, 4-nitrobenzyl bromide, 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, 3-bromopropanol, 4-iodobutanol, chloroacetone, l-chloro -2-butanone, l-bromo-3-butanone, allyl bromide, propargyl bromide. Methyl vinyl ketone is also known.

The reaction of (II) with (III) according to method A where diazabi-cycloalkanes (III) can also be used in the form of their hydrochlorides is preferably carried out in a diluent such as dimethylsulfoxide, N,N-dimethylformamide, hexamethyl-prophosphoric trisamide, sulfolane , acetonitrile, water, an alcohol such as methanol ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Likewise, mixtures of these diluents can be used.

As acid binders, all common, inorganic and organic acid binders can be used. These preferably include alkali hydroxide with alkali carbonates, organic amines and amidines. As particularly suitable, the following should be mentioned in detail: Triethylamine, 1,4-diaza-bicyclo/~2,2, 2/octane (DABCO) , 1,8-d:Lazabicyclo/~5 , 4 , p_7undec-7-ene ( DBU) or excess amine (III) •

The reaction temperatures can be varied over a large range. Usually work between approx. 20 and 200°C, preferably between 80

and 180°C.

The turnover can be carried out at normal pressure but also at elevated pressure. Usually work is done at a pressure between approx. 1 and 100 bar, preferably between 1 and 10 bar.

When carrying out the method according to the invention, 1 to 15 mol, preferably 1 to 6 mol, of the compound (III) are used for 1 mol of the carboxylic acid (II).

Free hydroxyl groups can be protected during the reaction by a suitable hydroxy protecting group, for example with the tetrahydro-pyranyl residue, and released again after completion of the reaction.

The reaction of (IV) with (V) according to method B is preferably carried out in a diluent such as dimethyl sulfoxide, dioxane, N,N-dimethylformamide, hexamethylphosphoric acid trisamide, sulfolane, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine . Likewise, mixtures of these diluents can be used.

All common inorganic acid binders can be used

and organic acid binders. These preferably include the alkali-potassium hydroxides, alkali carbonates, organic amines and amidines. As particularly suitable, the following should be mentioned in detail: Triethylamine, 1, 4-diazabicyclo/~2 , 2 , 2_7octane (DABCO) or 1,8-diazabicyclo/ 5 , 4 , 0_7undec-7-ene (DBU) .

To accelerate the reaction, phase transfer catalysts such as tetrabutylammonium bromide, tetrabutylammonium chloride or benzyltriethylammonium chloride can be added.

The reaction temperatures can be varied over a large range. Usually you work between approx. 20 and approx. 180°C, preferably between 40 and 110°C.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually, you work at a pressure between approx.

1 and approx. 100 bar, preferably between 1 and 10 bar.

When carrying out the method according to the compound

according to method B, one uses 1 mol of the compound (IV)

1 to 4 mol, preferably 1 to 1.5 mol of the compound (V).

The reaction of (IV) with methyl vinyl ketone (method C) is preferably carried out in a diluent such as dioxane, dimethylsulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, n-propanol, glycol monomethyl ether or also mixtures of these diluents.

The reaction temperatures can be varied over a large range. Usually you work between approx. 20° and approx. 150°C, preferably between 50°C and 100°C.

The turnover can be carried out at normal pressure, but also at elevated pressure. Usually, you work under pressure between approx. 1 and approx. 100 bar, preferably between 1 and 10 bar.

When carrying out the method according to the invention, 1 to 5 mol, preferably 1 to 2 mol, of methyl vinyl ketone is used for 1 mol of compound (IV).

To produce the ester according to the invention, basic carboxyl groups are preferably reacted in excess alcohol in the presence of strong acids, such as sulfuric acid, anhydrous hydrogen chloride, methanesulfonic acid, p-toluenesulfonic acid, or acidic ion exchangers at temperatures of approx. 20° to 200°C, preferably approx. 60 to 110°C. The reaction water formed can also be removed by azeotropic distillation with chloroform, tetrachloromethane, benzene or toluene.

The (5-methyl-2-oxo-1,3-dioxol-4-yl-methyl)-esters used as prodrugs are obtained by reacting an alkali salt of the to*: basic carboxylic acid with 4-bromomethyl- or 4-chloro- methyl-5-methyl-1,3-dioxol-2-one in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or tetramethylurea at temperatures of approx. 0° to 100°C, preferably 0° to 50°C.

The introduction of an aminobenzyl residue R<4>prior reduction

of a nitrobenzyl residue already introduced into the active substance of formula (I) by means of catalytically energized hydrogen or chemically by reduction with iron or zinc.

The preparation of the acid addition salts of the compounds according to the invention takes place in the usual way, for example by dissolving betaine in excess aqueous acid and precipitation of the salt with a water-miscible organic solvent, such as methanol, ethanol, acetone, acetonitrile. You can also heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether and then evaporate to dryness or suck off the precipitated salt. Pharmaceutically applicable salts include, for example, the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, ethanesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

Alkali or alkaline earth salts of carboxylic acid according to the invention are obtained, for example, by dissolving betaine in deficit alkaline or alkaline earth solution, filtering from undissolved betaine, and evaporating the filtrate to dryness. Pharmaceutically suitable are sodium, potassium or calcium salts. By reacting an alkali or alkaline earth salt with a suitable silver sieve such as silver nitrate, corresponding silver salts are obtained.

The active substances according to the invention can exist both as racemates and also as enantiomeric compounds.

Because without the compounds listed in the exeimols, the following should be mentioned in detail as new active substances: 6-chloro-1-cyclopropyl-7-(1,4-diazabicyclo/~3,2,1/-oct-4-yl) - 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7-('1,4-diazabicyclo/3,2,17-oct-4-yl)-6-fluoro-1,4-dihydro -8-methyl-4-oxo-3-quinolinecarboxylic acid,

7-(1,4-diazabicyclo[3,2,1]oct-4-yl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-(1,4-diazabicyclo[3,2,17oct-4-yl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

7-(1,4-diazabicyclo([3,2,17oct-4-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid,

7-(1,4-diazabicyclo[3,2,17octo-4-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

7-(1,4-diazabicyclo[3,2,17octo-4-yl)-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[1,1] quinoline-2-carboxylic acid,

7-(1,4-diazabicyclo[3,2,17octo-4-yl)-6-fluoro-1-(4-fluoro-phenyl)-1,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid,

1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17octo-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester,

1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17octo-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-(5-methyl-2- oxo-1,3-dioxol-4-yl-methyl) ester,

1-Cyclopropyl-7-(1,4-diazabicyclo[3,2,17hept-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17hept-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17hept-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ,

1-cyclopropyl-7-(1,4-diazabicyclo[3,2,1]hept-4-yl)-6-fluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(1,4-diazabicyclo/3,2,17hept-4-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

1-cyclopropyl-7-(1,4-diazabicyclo/3,2,1/hept-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methyl ester,

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(8-methyl-3,8-diaza-bicyclo/3,2,17oct-3-yl)-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diaza-bicyclo[3,2,17octo-3-yl)-4-oxo-3 -quinoline carboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3,2,17octo-3-yl)-4-oxo-1,8-naphthyridine-3 -carboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-3,8-diazabicyclo Z~3,2,1/octo-8-yl)-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3,8-diaza-bicyclo[3,2,17oct-8-yl)-4-oxo-3-quinolinecarboxylic acid ,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-3,8-diazabicyclo/3,2,17oct-8-yl)-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(2,5-diazabicyclo[2,2,17hept-2-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(2,5-diazabicyclo[2,2,17hept-2-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-7-(2,5-diazabicyclo[-2,2,17-hept-2-yl)-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(2,5-diazabicyclo[2,2,17hept-2-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[5-(2-hydroxyethyl)-2,5-diazabicyclo[2,2,1]hept-2-yl7-4-oxo-3- quinoline carboxylic acid,

1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-/ 5-(2-oxo-propyl)-2,5-diazabicyclo/~2,2,1/hept-2-yl73- quinoline carboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2,2,17hept-2-yl)-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(5-methyl-2,5-diaza-bicyclo/2,2,17hept-2-yl)-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)-4-oxo-3 -quinoline carboxylic acid,

1-cyclopropyl-7-(8-ethyl-3,8-diazabicyclo[3,2,1/oct-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(8-(3-oxobutyl)-3,8-diazabicyclo[3,2,1]oct-3-yl7-3- quinoline carboxylic acid,

7- /~8-(4-aminobenzyl)-3,8-diazabicyclo/~3,2,17oct-3-yl7-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ,

1-cyclopropyl-7-(2,5-diazabicyclo[2,2,2-7oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-(2,5-diazabicyclo[2,2,27oct-2-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-7-(2,5-diazabicyclo[-2,2,27oct-2-yl)-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-7-('2,5-diazabicyclo[2,2,2-7oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2,2,2]oct-2-yl)-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(5-methyl-2,5-diaza-bicyclo[2,2,2-7oct-2-yl)-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2,2,2-7oct-2-yl)-4-oxo-3-quinolinecarboxylic acid ,

1-cyclopropyl-7-(3,9-diazabicyclo[3,3,17non-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(7-hydroxy-3,9-diaza-bicyclo/3,3,17non-3-yl)-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-oxa-7,9-diazabicyclo-[3,3,17non-7-yl)-4-oxo-3-quinolinecarboxylic acid,

7-(5-ally1-2,5-diazabicyclo[2,2,17hept-2-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(5-propargy1-2,5-diazabicyclo/2,2,2_7oct-2-yl)-3-quinolinecarboxylic acid,

Example of a tablet according to the invention

Each tablet contains:

The lacquer sleeve contains:

With low toxicity, the compounds according to the invention show a broad antibacterial spectrum against gram-positive and gram-negative germs, especially against: enterobacteriaceae, above all also against those that are resistant to various antibiotics, such as e.g. penicillin, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties enable their use as chemotherapeutic active substances in medicine as well as substances for the preservation of inorganic and organic materials, especially of organic materials of any type, e.g. polymeric lubricants, paints, fibres, leather, paper and wood from foodstuffs and from water.

The invention according to the invention is effective against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be fought, and the diseases caused by these organisms can be prevented, improved and/or cured.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for prophylaxis and chemotherapy of local and systemic infections in human and animal medicine, and which are produced by these producers.

For example, local and/or systemic diseases can be treated and/or prevented, which are caused by the following agents or with mixtures of the following agents: Gram-positive come, e.g. staphylococci (Staph. aureus, Staph. epidermidis) and streptococci (Strept. agalactiae, Strept. faecalis, Strept pneumoniae, Strept pyogenes), gram-negative bacteria (Neisseria gonorrhoeae), as well as gram-negative rods such as enterobacteriaceae, e.g. Escherichia coli, Hemo-philus influenzae, citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella, further klebsiella (Klebs. pneumoniae, Klebs. oxytoca), enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, serratia ( Serr. marcescens), Pro-teus (Pr. mirabilis, Pr. rettgeri. Pr. vulgaris) , Providencia, Yresinia, as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudominas (Ps. aeru-ginosa, Ps. maltophilia), as well as strictly anaerobic bacteria,

like for example. Baceteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus, as well as the genus Clostridium, further mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum), as well as mycobacteria, e.g. mycobacterium tuberculosis.

The above list of producers is just an example

and in no way to be perceived as limiting. As diseases caused by the aforementioned agents or mixed infections, which can be prevented, improved or cured by the compound according to the invention, the following should be mentioned, for example: Infectious diseases in humans such as otitis,

Pharyngitis, Pneumonia, Peritonitis, Pyelonephritis, Cys-titis, Endocarditis, Systemic infections, Bronchitis (acute, chronic), Septic infections, Diseases of the upper respiratory tract, Diffuse Panbroncholitis, Pulmonary emphysema, Dysentery, Enteritis, Liver abscesses, Urethritis, Prostatitis, Epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, post-operative wound infections, abscesses, phlegmons, wound infections, infected burns, burns, infections in the mouth area, infections after dental surgery, Osteomyelitis, septic arthritis. Cholecystitis, Peritonitis with Appendicitis, Cholangitis, intra-abdominal abscesses, Pancreatitis, Sinusitis, Mastoiditis, Mastitis, Tonsillitis, typhus, Meningitis and infections of the nervous system, Salpingitis, Endometritis, genital infections, Pelveoperitonitis and eye infections.

Because apart from humans, bacterial infections can also be treated by other species. Examples should be mentioned: Pigs: Coli diarrhea, Enterotoxemia, Sepsis, Dysentery, Salmonellosis, Metritis-Mastitis-Agalactia syndrome, Mastitis, Ruminants: (cattle, sheep, goat): diarrhoea, sepsis, Bronchopneumonia, Salmonellosis, Pasteuerellosis, Mycoplasmosis, Geni-tal inf ex ions ,

Horse: Bronchopneumonia, foal paralysis, pueroeral oq post-puerperalé infections, Salmonellosis,

Dog and cat: Bronchopneumonia, diarrhoea, Dermatitis, Otitis, urinary tract infections, Prostatitis,

Poultry: (hen, turkey, quail, pigeon, farmed birds and others): Mycoplasmosis, E. coli infections, chronic respiratory diseases, Salmonellosis, Pasteurellosis, Psittacosis.

Likewise, bacterial diseases can be treated when breeding and keeping commercial and ornamental fish, as the antibacterial spectrum extends beyond the previously mentioned pathogens to further pathogens such as Pasteurella, Bru-cella, Campylobacter, Listeria, Erysipelothrix, Corynobacteria, Borellia , Treponema, Nocardia, Rickettsiae, Yersinia.

Pharmaceutical preparations contain, in addition to non-toxic inert pharmaceutical suitable carriers, one or more of the compounds according to the invention or consist of one or more active substances according to the invention, the method being carried out in a manner known per se.

The pharmaceutical preparations may be available in dosage units. This means that the preparations are in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, whose active substance content corresponds to a fraction or a multiple of single doses. The dosing units can e.g. contain 1, 2, :3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active substance that is administered in one application and which usually corresponds to a whole,

half or a third or a quarter of a daily dose.

As non-toxic, inert pharmaceutical suitable carriers

is to understand solid, semi-solid or liquid diluents, fillers and formulation aids of any type.

As preferred pharmaceutical preparations it should be mentioned

tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, oils, creams, lotions, powders and sprays. Tablets, dragees, capsules, pills and granules may contain the active substance(s) in addition to the usual carriers such as ('a) bulking and thickening agents, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b), binders, e.g. carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidone, (c) humectants,

e.g. glycerol, (d) explosives, e.g. agar agar, calcium carbonate and sodium carbonate, (e) dissolution retarders,

e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents,

e.g. kaolin and bentonite, and (i) lubricants, e.g.

talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be equipped with the usual coating, optionally containing an opacifying agent, sleeves and can be composed so that they release the active substance(s) only or preferentially in a specific part of the digestive tract in a delayed manner,

since as an embedding mass e.g. polymer substances and wax can be used.

The active substance(s) may optionally be present with one or more of the above-mentioned carriers also in micro-encapsulated form.

Suppositories can contain the usual water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa fat and higher esters, (e.g. C-^-alcohol with C^g-fat-

acid) or mixtures of these substances.

Ointments, pastes, creams and gels can next to it or

the active substances contain the usual carriers, for example animal or vegetable fat, wax, paraffin, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.*

Powders and sprays can contain the usual carrier substances in addition to the active substance(s), e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these substances, sprays can also contain the usual propellants, e.g. chlorofluorocarbons.

Solutions and emulsions can contain, in addition to the active substance(s), the usual carriers such as solvents, dissolution mediators and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol , polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral application, the solutions and emulsions can also be available in sterile and blood isotonic form.

Suspensions can contain, in addition to the active substance(s), the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The aforementioned formulation forms can also contain coloring agents, preservatives, as well as odor and taste-improving additives, e.g. peppermint oil and eucalyptus oil and sweeteners, e.g. saccharin.

Therapeutically active compounds must be present in the pharmaceutical preparations listed above, preferably in a concentration from approx. 0.1 to 99.5, preferably from 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparation listed above may, without the compounds according to the invention, also contain additional pharmaceutical active substances.

The production of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. by mixing the active substance(s), carrier substances or substances.

The aforementioned preparations can be used in humans and animals either orally, rectally, parenterally (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, local (powders, ointments, drops) and for the therapy of infections in cavities, the body cavity . Suitable preparations include injection solutions, solutions and suspensions, for oral therapy, gel, casting formulations, emulsions, ointments or drops. For local therapy, ophthalmological and dermatological formulations can be used,

silver and other salts, ear drops, eye ointment, powders or solutions. In the case of animals, uptake can also take place in the feed or drinking water in suitable formulations. Furthermore, gels, powders, powders, tablets, retard tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays, inhalations in humans and animals can be used. Furthermore, the compound according to the invention can be incorporated into other carrier materials, such as, for example, artificial victims (plastic chains for local therapy), collagen or bone cement.

In general, both in human and also in veterinary medicine it has been shown to be advantageous to administer the active substance(s) according to the invention in total amounts of approx.

0.5 to approx. 500, preferably 5 to 100 mg/kg body weight per

24 hours in the form of several individual submissions, to achieve the desired result. A single administration contains the active substance(s) according to the invention, preferably in amounts of approx. 1 to approx. 80, especially 3' to 30 mg/kg body weight. However, it may be necessary to deviate from the aforementioned dosages, namely depending on the type and body weight of the object being treated, the type and severity of the disease, the type and preparation q.g. the application of the drug as well as the time period resp. intervals within which no administration takes place.

Thus, in some cases it may be sufficient to come

out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amounts of active substance must be exceeded. The determination of the resp. necessary optimal dosage and method of application of the active substances, can easily be carried out by any expert due to his professional knowledge.

The new compounds can be given in the usual concentrations and preparations together with for, resp. with the pre-preparation or with the drinking water. In this way, an infection with gram-negative or gram-positive bacteria can be prevented, improved and/or cured, thereby achieving a promotion of growth and an improvement in the utilization of the forage.

In the following table, some MHK values are indicated compared to 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo"-7-(1-piperazinyl)-3-quinolinecarboxylic acid (citrofloxacin):

The invention will be explained in more detail with the help of some examples. Example 1 8.1 g (30 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 60 ml of acetonitrile and 90 ml of dimethylformamide are mixed with 3.4 g (30 mmol ) 1,4-diazabicyclo/~3,2,1/octane and 6.6 g (59 mmol) 1,4-diazabicyclo-/ 2 , 2 , 2/octane and heated for 6 hours under reflux. After cooling, the mixture is evaporated, the residue is stirred with water and the undissolved betaine is sucked off (m.p. from approx. 258oC during decomposition). This is dissolved hot in 5 ml of semi-concentrated hydrochloric acid, filtered, mixed with 40 ml of ethanol and filled with ice. The precipitated hydrochloride is suctioned off, washed with ethanol and dried. 5.3 g (45% of the theoretical) of 1-cyclopropyl-7-(1,4-diazabicyclo/3,2,17oct-4-yl)-6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 322°C (during decomposition) . Example 2

3.3 g (9.2 mmol) 1-cyclopropyl-7-(1,4-diazabicyclo/~3,2,17~

octan-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (betaine from example 1) and 1.8 g (4.6 mmol) of benzoic acid are heated in 35 ml of glycol monomethyl ether for 4 hours under backflow. The suspension is cooled, the crystallisate is suctioned off, washed with ethanol and dried at 120°C in a vacuum. 4.7 g of 1-cyclopropyl-7-(1,4-diazabicycl/~3,2,17oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hemienbonate are obtained of sm.p. from 271°C (under decomposition.

Example 3

One reacts 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid analogously to example 1, and obtains 8-chloro-1-cyclopropyl-7-(1,4- diazabicyclo(3,2,1(oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride hydrate of m.p. 310°C (during decomposition).

C19<H>19<C>1FN3°3' HC1 * H2° (446'3)

Example 4

One reacts l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid analogously to example 1 and obtains l-cyclopropyl-7-(1,4-diazabicyclo/~3.2, 1/oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of m.p. 275-282°C during decomposition and from this the hydrochloride of m.p. above 310°C during decomposition (already from approx. 260°C the material slowly turns dark).

Example 5

Analogous example 17-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid qg is reacted to obtain 1-cyclopropyl-7-(1,4-diazabicyclo/ 3,2,17 oct -4-yl)-1,4-dihydro-6-nitro-3-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 30-3-307°C (during decomposition) .

Example 6

Analogous to example 1, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is reacted and 1-cyclopropyl-7-(1,4-diazabicyclo (<->3,2,1/oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride of m.p. above 30 0.°C during decomposition.

Example 7

One reacts analogously to example 1 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and obtains 7-(1,4-diaza-bicyclo/~3,2,17oct- 4-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 308-312°C during decomposition.

Example 8

A mixture of 2.8 g (10 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido/1,2,3-de//~l,4_7benzoxacin-6 -carboxylic acid and 1.2 g (10.7 mmol) 1,4-diazabicyclo/~3,2,17 octane in 25 ml of dimethyl sulfoxide are mixed with 2.2 g (20 mmol) 1,4-diazabicyclo/ 2,2, 2/octane dg is heated for 5 hours at 120°C. The mixture is evaporated in vacuo, the residue is stirred in 40 ml of acetonitrile, the undissolved residue is suctioned off and purified by chromatography on silica gel with dichloromethane/methanol/20% aqueous ammonia solution (2:4: 1) as eluent. One isolates 1.2 g of a solid which, by dissolving in 8 ml of semi-concentrated hydrochloric acid and precipitation with 30 ml of ethanol, is transferred to the hydrochloride.

Yield: 1.1 g of 10-(1,4-diazabicyclo[3,2,17oct-4-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido] 1,2,3-de7/~l, i?~ Benzoxacin-6-carboxylic acid hydrochloride of m.p. 355°C during decomposition (turns dark from about 290°C).

Example 9

One reacts analogously to example 1 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and obtains 7-(1,4-diazabicyclo/"3,2, 17oct-4-yl)-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 310-314°C with decomposition.

Example 10

2.0 g (6 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid are mixed in a mixture of 10 ml of acetonitrile and 25 ml of dimethylformamide with 0.7 g (6 mmol) 1,4-diazabicyclo/2,2,2_7octane and 0.7 g (6 mmol) 1,4-diazabicyclo/~3,2,17octane and heated for 2 hours under reflux. It is then inhaled and mixed with water. It is allowed to crystallize under ice cooling, suctioned off and washed

with water and dried.

Yield: 1g (41% of theory) 1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17oct-4-yl)-6-fluoro-1,4-dihydro-8-nitro-4 -oxo-3-quinolinecarboxylic acid of m.p. 215-232°C (under decomposition). After recrystallization from glycol monomethyl ether/ethanol, m.p. 224-232°C (during cleavage)

The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid required for this is obtained in the following steps:

a) 2,4-dichloro-5-fluoro-3-nitro-benzoic acid

During ice-cooling and stirring, mix 34 ml conc. sulfuric acid dropwise with 40 ml conc. nitric acid. Into this nitration mixture, 20.9 g of 2,4-dichloro-5-fluorobenzoic acid are introduced in portions, the temperature increasing to 45-50°C. It is then heated for a further 3 hours at 90-100°C, the mixture cooled to room temperature is poured into 350 ml of ice water, the precipitate is suctioned off and washed with water. The moist crude product is dissolved hot in 30 ml of methanol and the solution is mixed with 150 ml of water.

The precipitate is filtered off cold, washed with methanol/water and dried in a vacuum at 80°C. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are obtained. It is sufficiently clean for further sales. A sample recrystallized from toluene/petroleum ether gives crystals of m.p. 192°C.

b) 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride

106.6 g (2,4-dichloro-5-fluoro-3-nitro-benzoic acid is heated with 250 ml of thionyl chloride for 2 hours under reflux. The excess thionyl chloride is then distilled off at normal pressure and the residue is fractionated in a fine vacuum. At 110-150°C / 0.08-0.09 mbar over 104.7 g of 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride is obtained. On standing, crystals of m.p. 35-37°C are formed. c) (2,4-Dichloro-5-fluoro-3-nitro-benzoyl)-acetic acid ethyl ester

10.1 g of magnesium shavings are mixed in 21 ml of ethanol with 2.1 g of tetrachloromethane and after the beginning of hydrogen evolution, a mixture of 6 6.6 g of malonic acid diethyl ester, 40 ml of ethanol and 150 ml of toluene is added dropwise at 50-60°C. It is stirred for 1 hour at this temperature, cooled to; -5 to -10°C, and slowly add dropwise a solution of 109.2 g of 2,4-dichloro-5-fluoro-3-nitrobenzyl chloride in 50 ml of toluene. It is then stirred for 1 hour at 0°C, brought to room temperature overnight, and heated for a further 2 hours at 40-50°C. The reaction mixture is mixed by ice-cooling with a mixture of 160 ml of water and 10.4 ml of conc. sulfuric acid, and the organic phase is separated. The aqueous phase is extracted with toluene, and the combined organic extracts are washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent is removed. 144.5 g of (2,4-dichloro-5-fluoro-3-nitro-benzoyl)-malonic acid diethyl ester is obtained as crude product. This is heated after adding 200 ml of water and 0.6 g of 4-toluenesulfonic acid for 3 hours under

reflux, the mixture is extracted with methylene chloride, the extract is dried over sodium sulphate and the solvent is distilled off in vacuo. 118 g of substituted benzoyl acetic acid are obtained as crude product. It has sufficient purity for further sales.

d) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid

244.8 g of (2,4-dichloro-5-fluoro-3-nitrobenzoyl)-acetic acid ethyl ester is heated with 166 g of triethyl orthoformic acid and 185 g of acetic anhydride for 3 hours at 150-160°C. Evaporation in vacuo gives 270 g of 2-(2,5-dichloro-5-fluoro-3-nitro-benzoyl)-3-ethoxy-acrylic acid ethyl ester as an oily residue.

38 g of this intermediate product are mixed in 80 ml of ethanol under ice-

in

cooling dropwise with 5.9 g of cyclopropylamine and stirring for 1 hour at 20°C. The precipitated product is suctioned off after adding 100 ml of water, washed with ethanol/I 2 O (1:1) and dried. 32.8 g of 2-(2,4-dichloro-5-fluoro-3-nitro-benzoyl)-3-cyclopropylamino-acrylic acid ethyl ester of m.p. 143-146°C.

7.8 g of the above compound are mixed in 30 ml of anhydrous dioxane with 3.1 g of (1,8-diazabicyclo-/5,4,0_7undec-7-ene (DBU)

and heated for 4 hours at 100°C. The solvent is distilled off in vacuo, the residue is taken up in methylene chloride/water. The ethylene chloride phase is separated, dried with sodium sulphate and the methylene chloride is distilled off. 7.2 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained as crude product. After recrystallization from aceto-

nitrile melts the light brown crystals at 174-175°C. Yield: 6 g.

35.4 g of this ester is heated in a mixture of 195 ml of acetic acid, 142 ml of water and 2 2 ml of conc. sulfuric acid 1.5 hours at 150°C. The solution is poured into 500 ml of ice water, the precipitate is suctioned off, washed with water, dried in a vacuum. Yield 31.8 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid of m.p. 260-261°C.

Example 11

530 mg (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in 4 ml of acetonitrile and 6 ml of dimethylformamide with 530 mg (2 mmol) of 2-benzyl-2 ,5-diazabicyclo/2,2,17heptane dihydrochloride and 880 mg (7.9 mmol) 1,4-diazabicyclo/~2,2,27octane for 6 hours under reflux. The reaction mixture is evaporated, the residue is stirred with water, the precipitate is filtered off with suction, washed with water and dried. The crude product formed (0.8 g of m.p. 194-205°C during cleavage) is purified chromatographically with dichloromethane/methanol/17% aqueous ammonium hydroxide solution (15 0:40:1) as eluent on 60 g of silica gel. 0.57 g (66% of the theoretical) of 7-(5-benzyl-2,5-diazabicyclo/2,2,1/hept-2-yl)-1-cyclopropyl-6-fluoro-1,4 -dihydro-4-oxo-3-quinolinecarboxylic acid of m.p. 205-214°C (under decomposition). Example 12

Analogous example 11 is reacted with 8-methyl-3,8-diazabicyclo-/3,2,17-octane dihydrochloride and the crude product is recrystallized from glycol monomethyl ether. One obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3,2,1]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid of sm.p. 273-278°C (under decomposition).

Example 13

One reacts analogously to example 1 with 5-methyl-1,4-diazabicyclo-/~3,2,1/octane and obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-1, 4-diazabicyclo(3,2,1(oct-4-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. above 300°C (during decomposition).

The 5-methyl-1,4-diazabicyclo/3,2,1/-octane used for this purpose is obtained in the following steps:

a) 3-methyl-3-methoxycarbonylmethylpiperazin-2-one

While stirring, 160 g (1 mol) of citraconic acid dimethyl ester are dissolved in 300 ml of abs. ether, and adds 66 g (1.1 mol) of ethylenediamine. The solution comes to reflux after a short time, stirred overnight at room temperature. The precipitated product is suctioned off and recrystallized from dioxane.

Yield: 125 g (67% of the theoretical)

Melting point: 135-145°C (from dioxane).

b) 2-(2-hydroxyethyl)-2-methylpiperazine

To a suspension of 30.4 g (0.8 mol) of lithium aluminum hydride in 300 ml of abs. tetrahydrofuran, a hot solution of 7 4.6 g (0.4 mol) 3-methyl-3-methoxycarbonylmethy1-piperazin-2-one in 300 ml abs. dioxane. It is then stirred for 16 hours under reflux.

It is then cooled with 30 ml of water, 30 ml of 15% aqueous potassium hydroxide and again 30 ml of water, the excess LiAlH^ is split and the organic salts are sucked off. These are thoroughly stirred a further 5 times with chloroform. The organic phase is dried over potassium carbonate, evaporated and distilled.

Yield: 45 g (78% of theoretical)

Boiling point: 78°C/0.05 mbar.

c) 2-(2-chloroethyl)-2methylpiperazine dihydrochloride

Add 363 g (3 mol) of thionyl chloride in 500 ml of chloroform drop by drop

while heating to reflux and stirring 110 g (0.76 mol) 2-(2-hydroxyethyl)-2-methylpiperazine in 600 ml chloroform. It is then heated to the end of SC^ development to return flow.

It is cooled, 500 ml of water are added dropwise, the aqueous phase is separated, and the chloroform phase is washed twice with 200 ml of water. The aqueous phase is evaporated to dryness, taken up in 1 liter of water and heated with activated carbon for 30 minutes to reflux.

Filter, evaporate to dryness, wash the crystals

with cold methanol, suction off and dry in a vacuum desiccator over phosphorus pentoxide.

Yield: 160 g (89.4% of the theoretical),

Melting point: above 300°C.

d) 5-methyl-1,4-diazabicyclo/3,2,1/octane

100 g (0.42 mol) of 2-(2-chloroethyl)-2-methylpiperazine are dissolved. 2HC1 in 100 ml of water and, under ice-cooling, add dropwise a solution of 70 g (1.75 mol) of sodium hydroxide in 70 ml of water. The temperature is kept below 40°C. Then heat for 1 hour at 80°C. The solution is mixed with water to dissolve excreted sodium chloride and saturated with potassium carbonate. It is then extracted several times with chloroform, the organic phases are dried over potassium carbonate and evaporated and distilled.

Yield: 45 g (85% of the theoretical)

Boiling point: 60°C/6 mbar.

Example 14

3.75 g (10 mmol) 1-cyclopropyl-7-(1,4-diazabicyclo/3,2,17-oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo- 3-quinoline carboxylic acid is suspended in 80 ml of ethanol, and at reflux temperature a dry chlorine hydrogen stream is introduced. After completion of the reaction, the residue is evaporated, dissolved in water, adjusted with sodium carbonate solution to pH 8, extracted with dichloromethane, dried with sodium sulfate and the filtrate evaporated. The residue is recrystallized from ethanol/water. 1.1 g of 1-cyclopropyl-7-(1,4-diazabicyclo[3,2,17-oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid ethyl ester of m.p. 196-199°C. Example 15

One reacts analogously to example 1 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and obtains 7-(1,4-diazabicyclo/~3, 2,17oct-4-yl)-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 329-331°C during decomposition.

Example 16

One reacts analogously to example 1 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid and obtains 7-(1,4-diazabicyclo/~3,2,1/oct- 4-yl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 300-305°C during decomposition.

Example 17

2.65 g (10 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are mixed in 20 ml of acetonitrile and 10 ml of dimethylformamide with 2.7 g (24 mmol) 1 ,4-diazabicyclo/2,2,2_7octane and 2.1 g (17 mmol) of 2-methyl-1,4-diazabicyclo/_3,2,17octane are heated for 6 hours under reflux. The mixture is evaporated, the residue is mixed with water (pH 7), the undissolved crystallisate is suctioned off, washed with water and recrystallized from glycol monomethyl ether. 1.4 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-1,4-diazabicyclo[3,2,17-oct-4-yl)-4-oxo- 3-quinolinecarboxylic acid of m.p. 255-257°C (under decomposition).

The necessary 2-methyl-1,4-diazabicyclo/3,2,17octane is obtained in the following way:

5-methyl-2-methoxycarbonylmethylpiperazin-3-one

81 g (1.1 mol) of 1,2-propylenediamine, 144 g (1 mol) of maleic acid dimethyl ester and 2 50 ml of abs. ether. The mixture comes to reflux, and is cooled in the meantime with ice water. Then stir overnight at room temperature. Vacuum off and wash with ice-cold isopropanol and dry in the air. The mother liquor is evaporated and the residue is recrystallized from acetic ester.

Yield: 95 g (51% of theoretical).

Sm.p. 102-105°C.

2-(2-hydroxyethyl)-5-methylpiperazine

To a suspension of 30.4 g (0.8 mol) LiAlH^ in 300 ml abs. tetrahydrofuran, a solution of 7 4.5 g (0.4 mol) 5-methyl-2-methoxycarbonylmethylpiperazin-3-one in 300 ml abs. tetrahydrofuran. It is then heated for 16 hours during the return run. The excess LiAlH2 is then split in order with 30 ml of water, 30 ml of 15% potassium hydroxide and 30 ml of water, the inorganic salts are filtered off and they are stirred several times with dichloromethane. The organic phases are dried over K^CO^, evaporated and distilled.

Yield: 31.8 g (55.1% of the theoretical),

Boiling point: 85-87°C/0.07 mbar.

2-(2-Chloroethyl)-5-methylpiperazine dihydrochloride

To 95 g (0.79 mol) of thionyl chloride in 125 ml of methylene chloride, 28 g (0.208 mol) of 2-(2-hydroxyethyl)-5-methylpiperazine in 125 ml of dichloromethane are added dropwise while heating to reflux. It is then stirred for 5 hours under reflux. 200 ml of water are then carefully added dropwise, and the aqueous phase is separated. The organic phase is washed twice with water and discarded.

The aqueous phases are evaporated, taken up again in 200 ml of water and heated with 3 g of activated carbon for 30 minutes to reflux. It is filtered, evaporated to dryness, mixed with methanol, sucked off and dried in a vacuum desiccator P^O-^q .

Yield: 23.5 g (48% of theoretical).

2-methyl-1,4-diazabicyclo/3,2,1/octane.

23.5 g (0.1 mol) of 2-(2-chloroethyl)-5-methylpiperazine dihydrochloride are dissolved in 20 ml of water and added dropwise at a maximum of 40°C 32 g (0.4 mol) of 50% ig sodium lye. The mixture is stirred for 1 hour at 75°C, cooled, saturated with potassium carbonate and extracted ten times with 50 ml of dichloromethane each time. The organic phases are dried over potassium carbonate, evaporated and distilled.

Yield: 9.7 g (76.8% of theoretical).

Boiling point: 60-65°C/0.8 mbar

Example 18

Analogously to example 17, 8-oxa-3-aza-bicyclo/3,2,1/octane hydrochloride is reacted, obtaining 1-cyclopropyl 1-6-fluoro-1,4-dihydro-7-(8-oxa- 3-aza-bicyclo(~3,2,1/oct-3-yl)-4-oxo-3-quinolinecarboxylic acid of m.p. 272-275°C (during decomposition)

(from glycol monomethyl ether).

The necessary 8-oxa-3-aza-bicyclo/3,2,1/octane hydrochloride is obtained in the following way:

3-Benzyl-8-oxa-3-azabicyclo/3,2,17octane

61.2 g (0.15 mol) 2,5-bis-(tosyloxymethyl)-tetrahydrofuran (F.H. Nezth. L.F. Wiggins. J. Chem. Soc. 155 (1948))

300 ml of toluene and 54 g of 0.5 mol benzylamine are heated for 20 hours under reflux. Filter, wash with toluene, evaporate and distill.

Yield: 21.5 g (70.5% of the theoretical)

Boiling point: 140°C/9mbar)

8-oxa-3-azabicyclo/3,2,1/octane hydrochloride

Dissolve 20 g (0.098 mol) of 3-benzyl-8-oxa-3-azabicyclo/~3,2,17 octane in 150 ml of methanol and add 8.5 ml of conc. hydrochloric acid. 5 g of Pd-charcoal (10% strength) is hydrolysed at 50oC and 50 bar. The catalyst is sucked off, the solution is evaporated, the residue is expelled with acetone, filtered off and dried over<P>4°10-

Yield: 12.5 g (83.5% of the theoretical),

Melting point: 202-204°C.

Example 19

Analogously to example 17, 3-oxa-8-aza-bicyclo/3,2,1/octane hydrochloride is reacted, obtaining 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-oxo-8- aza-bicyclo(~3,2,17oct-8-yl)-4-oxo-3-quinolinecarboxylic acid of m.p. 283-284°C (under decomposition)

(from glycol monomethyl ether).

The necessary 3-oxa-8-aza-bicyclo/3,2,1/octane is obtained in the following way:

3-oxa-8-azabicyclo/~3,2,17octane hydrochloride.

One dissolves 22.7 g (0.104 mol) of 8-benzyl-3-oxa-8-azabicyclo/3,2,17-octane (J. von Braun, J. Seemann, Ber. Deutsch. Chem. Ges. 56, 1840 (1923)) in 140 ml of methanol and add 9.3 ml of conc. hydrochloric acid. Next, hydrogenation is carried out on 5 g of Pd-charcoal (5%) at 60°C and 60 bar. The catalyst is sucked off, the solution is evaporated, the residue is expelled with acetone, sucked off and dried in a desiccator at P.O,n.

4 10

Yield: 13.7 g (88.7% of theory).

Melting point: 236°C.

Example 20

Analogous to example 17, 2,2-dimethyl-1,4-diazabicyclo</>3,2,17octane is reacted, obtaining 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2,2- dimethyl-1,4-diazabicyclo(3,2,1(oct-4-yl)-4-oxo-3-quinolinecarboxylic acid of m.p. 242-246°C (under decomposition).

The necessary 2,2-dimethyl-1,4-diazabicyclo/3,2,1/ octane is obtained in the following way:

5,5-dimethyl-2-methoxycarbonylmethylpiperazin-3-one

80 g (0.91 mol) of 1,2-diamino-2-methylpropane, 127

g (0.88 ml) maleic acid dimethyl ester and 200 ml abs. ether. After the exothermic reaction, the mixture is stirred for a further 16 hours, the mother liquor is sucked off and evaporated, and recrystallized from diisopropyl ether.

Yield: 154 g (87% of theoretical).

Melting point: 76-78°C.

5,5-dimethyl-2-(2-hydroxyethyl)-piperazine

A hot solution of 80 g (0.4 mol) 5,5-dimethyl-2-methoxycarbonylmethylpiperazine-3- on in 300 ml of tetrahydrofuran. It is then boiled for 16 hours under reflux. After cooling, excess LiAlH3 is decomposed in order with 30 ml of water, 30 ml of 15% potassium hydroxide and 30 ml of water. The inorganic salts are sucked off, stirred several times with dichloromethane, and the organic phases are dried over potassium carbonate. It is then evaporated and distilled.

Yield: 31.6 g (49.9% of theory)

Boiling point: 114°C/0.1 mbar.

2-(2-Chloroethyl)-5,5-dimethylpiperazine dihydrochloride

20 g (0.126 mol) of 5,5-dimethyl-2-(2-hydroxyethyl)-piperazine in 100 ml of dichloromethane are added dropwise under reflux heated 60 g (0.5 mol) of thionyl chloride in 100 ml of dichloromethane. The stirring is then continued for 2 hours under reflux. One hydrolyzes with 100 ml of water, separating the aqueous phase. The organic phase is washed twice with water and discarded. The aqueous phase is evaporated to dryness, taken up in 200 ml of water and heated with 3 g of activated carbon for 30 minutes under reflux. It is filtered, evaporated, the crystalline residue is washed with a little cold methanol, and dried in a desiccator over P4°]_o* Yield: 21 g (66.8% of the theoretical) 2,2-dimethyl-1,4-diazabicyclo/~ 3,2,17 octane

To 20 g (0.08 mol) of 2-(2-chloroethyl)-5,5-dimethylpiperazine dihydrochloride in 20 ml of water, at a maximum of 40°C, 30 g of 50% caustic soda are added dropwise. It is then heated for a further 1 hour at 80°C. Then cool, saturate with potassium carbonate, i. extract 10 times with each time 50 ml of dichloromethane, dry over potassium carbonate, evaporate and distill.

Yield: 7.9 g (70.5% of theoretical)

Boiling point: 65°C/4 mbar.

Example 21

3.37 g (10 mmol) of 6,7,8-trifluoro-1-(4-fluoro-phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are mixed in 30 ml of dimethyl sulfoxide with 2.7 g £ 24 mmol) 1,4-diazabicyclo/2,2,2/octane and 2.1 g (17 mmol) 2-methyl-1,4-diazabicyclo/3,2,1/octane and heated for 2 hours at 140°C . The solvent is distilled off under high vacuum and the residue is mixed with water (pH 7). It is then adjusted to pH 1 with half-concentrated hydrochloric acid, mixed with the same volume of ethanol, and the hydrochloride is sucked off cold. After

recrystallization from water/ethanol gives 2.5 g of 6,8-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-7-(2-methyl-1,4-diazabicyclo /~3.2, 17-oct-4-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 325-330°C (during decomposition).

Example 22

3.5 g (10 mmol) of 6,7,8-trifluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in 30 ml of dimethylsulfoxide with 2 .7 g (24 mmol) 1,4-diazabicyclo/2,2,2/ octane and 2.1 g (17 mmol) 2-methyl-1,4-diazabicyclo/ 3,2,1/ octane for 2 hours at 140°C. Processing takes place as in example 21. After recrystallization from water, 1.1 g of 6,8-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-7-(2-methyl-1,4 -diazabicyclo(~3,2,1/oct-4-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. 278-280°C during decomposition. Example 23

Analogous to example 17, 2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are reacted. 1.3 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-methyl-1,4-diazabicyclo[3,2,1]oct-4-yl)-4 is obtained -oxo-3-quinolinecarboxylic acid of m.p. 239-242°C (under decomposition) (recrystallized from glycol monomethyl ether).

Mass spectrum: m/e 389 (M+), 325, 276, 247, 111, 97 (98%), 69, 56 (98%), 32, 28 (100%).

Claims (9)

1. 7-(azabicycloalkyl)-quinolinecarboxylic acid or naphthyridonecarboxylic acid derivatives with formula I in which R"<*>" means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, fluorophenyl, 2,4-difluorophenyl, R 2 means hydrogen, alkyl with 1 to 4 carbon atoms, (5-methyl- 2-oxo-1,3-dioxol-4-yl)-methyl, R 3 means a residue with fo±'mel in which Y means R <4-> N, 0, S, Z means -(CHJ -, -CH -0-CH -, -CH -S-CH„-, -CH_-S-, R5 2 n ' 2 2' 2 2' 2 n means 1, 2 or 3, R 4 means hydrogen, optionally;. with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms or 5-(methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and R"<*> means hydrogen or methyl, X^" means fluorine, chlorine or nitro, and A means N or C-R <6> , wherein R^ means hydrogen, fluorine, chlorine, methyl or nitro, also together with R" '" can form a bridge with structure -O-CH -CH-CH-, -S-CH„-CH-CH or -CH2 -CH2 -CH-CH3 with the precaution that for the case thatX<1> means 2 1 fluorine, R means H and A means CF or N and R means ethyl, cyclopropyl, fluoroethyl or vinyl, or R^ forms with R- <1-> a bridge of the structure -O-CH -CH-CH-. is n different from 2, and R cannot mean the remainder as well as excluding the connection 7-(2,5-diazabicyclo[2,2,2]oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinolinecarboxylic acid, and their pharmaceutically acceptable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids. 2. 7-{azabicycloalkyl)-quinolinecarboxylic acid- resp. -naphthyridone carboxylic acid derivatives of formula (I) in which R" <*> " means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, fluorophenyl, 2,4-difluorophenyl, R 2 means hydrogen, alkyl with 1 to 4 carbon atoms, (5- methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R 3 means one in the ring system with Lydroxy or methyl en- or multiply substituted residues of formula in which Y means R <4-> N, 0, S, Z means -(CH )n~, -CH2 -0-CH2" , -CH2 -S-CH2" , -CH2~ S-, n means 1, 2 or 3, R 4 means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and R 5 means hydrogen or methyl, X1 means fluorine, chlorine or nitro, and A means N or C-R <6> , wherein R <6> means hydrogen, fluorine, chlorine, methyl or nitro, or also together with R"*" can form a bridge with structure -O-CH_-CH-CH_, -S-CH0 -CH-CH_. or 2 \ j 2 \ S -CH-CH-CH-CH. 2 2 \ j and their pharmaceutically useful hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids. 3. 7-(azabicycloalkyl)-quinolonecarboxylic acid- or -naphthyridone carboxylic acid derivatives of formula (I) according to claim 1, wherein R <1> means methyl, ethyl, cyclopropyl, 2-hydroxyethyl, vinyl, 2-fluoroethyl, methoxy, methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R 2 means hydrogen, methyl, ethyl, R means a residue with formula where Y means R <4-> N, 0, Z means -(CH2 )n -, -CH2 0-CH2 -, n means 1, 2 or 3, R <4> means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 3 carbon atoms, optionally with nitro or amino substituted benzyl or oxoalkyl with 2 to 4 carbon atoms, and R<5> means hydrogen or methyl, X^" means fluorine, chlorine or nitro, and A means N or C-R6, wherein. R <6> means hydrogen, fluorine, chlorine, methyl, or nitro, or together with R can form a bridge with structure -O-CH2 -CH-CH3 or -CH2 -CH2 -CH-CH3 with the precaution that for the case that X means fluorine, 2 1 R means H, and A means CF or N, and R means ethyl, cyclopropyl, fluoroethyl or vinyl, or R6 with R <1> forms a bridge of structure -O-CH 2. -Ci H-CH j, n is different from 2 and R 3 cannot mean the rest as well as excluding the compounds 7-(2,5-diazabicyclo[2,2,2]oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid, and their pharmaceutically acceptable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids. 4. 7-(azabicycloalkyl)-quinolone carboxylic acid- resp. -naphthyridone carboxylic acid derivatives of formula (I) according to claim 1, wherein R <1> means ethyl, cyclopropyl, 2-fluoroethyl, methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2 R means hydrogen, methyl, ethyl, R 3 means a residue of formula in which Y means R <4-> N, Z means" (CH^-, n means 1 or 2, R 4 means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 3 carbon atoms optionally with nitro or amino substituted benzyl or oxoalkyl with 2 to 4 carbon atoms, and R^ means hydrogen or methyl, X"*" means fluorine, chlorine or nitro, and A means N or C-R <6> , wherein R<6> means hydrogen, fluorine, chlorine, or nitro, and also together with R can form a bridge with structure -O-CH2 -CH-CH-, or -CH_-CH -CH-CH. , 3 2 2 in 3 with the precaution that for the case that X <1> means fluorine, R means H and A means CF or N, and Rx means ethyl, cyclopropyl, fluoroethyl or vinyl, or R <6> forms with R^- a bridge of the structure -O-CH -CH-CH is n different from 2 and R ■ cannot mean the remainder as well as excluding the compound 7-(2,5-diazabicyclo/2,2,2/oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid, and their pharmaceutically usable hydrates and acid addition salts as well as the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids. 5. Process for the production of 7-(azabicycloalkyl)-quinolone carboxylic acid- resp. -naphthyridone carboxylic acid derivatives of the general formula (I) in which R"*" means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R means hydrogen, alkyl of 1 to 4 carbon atoms, (5- methyl-2-oxo-1,3-dioxol-4-yl)-methyl, 3 R means a residue with formula in which Y means R <4-> N, 0, S, Z means -(CH^-, -CH2 -0-CH2~ , -CH2 -S-CH2 -, -CI^ -S-, R<5> n means 1, 2 or 3, R 4 means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbene atoms, or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R means hydrogen or methyl, X <1> means fluorine, chlorine or nitro, and A means N or C-R <6> , wherein R means hydrogen, fluorine, chlorine, methyl or nitro, or together with R"1" can form a bridge of structure -O-CH -CH-CH_, -S-CH -CH-CH- or 2 \ -J 2 \ J> -CH.-CH -CH-CH_ 2 2 in 3 with the precaution that for the case that X^" means fluorine, 2 1 R means H and A means CF or N and R means ethyl, cyclopropyl, fluoroethyl or vinyl or R forms with R a bridge of the structure -0-CH--CH-CH , n is different from 2 and R <3> cannot mean the rest as well as excluding the connection 7-(2,5-diazabicyclo/2,2,2_7oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid and their pharmaceutically usable hydrates and acid addition salts, as well as their alkaline, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids, characterized in that compounds of formula (II) in which R <1> , R 0 , X 1 and A have the above meaning, and X means halogen, especially fluorine or chlorine, possibly reacted in the presence of the acid binder with azabicycloalkanes of formula (III) 3 in which ;.R has the above meaning. 6. Process for the production of 7-(azabicycloalkyl)-quinolone carboxylic acid or -naphthyridone carboxylic acid derivatives of the general formula (I) in which R"*" means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 3-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, fluorophenyl, 2,4-difluorophenyl, r <2> means hydrogen, alkyl of 1 to 4 carbon atoms, (5-methyl- 2-oxo-1,3-dioxol-4-yl)-methyl, R 3 means that in the ring system with hydroxy or methyl en- or multiple substituted residue with formula in which Y means R <4-> N, 0, S, Z means -(CH^-, -CH2 0-CH2 -, -CH2~S-CH2-, -CI^-S-, n means 1, 2 or 3, R 4 means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 4 carbon atoms optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms, or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and R means hydrogen or methyl, X" <*> " means fluorine, chlorine or nitro, and A means N or C-R <6> , wherein R <6> means hydrogen, fluorine, chloromethyl or nitro, or together with R"1" can form a bridge with structure -O-CH--CH-CH-, -S-CH -CH-CH- or -CH2 -CH2 -CH-CH3 and their pharmaceutically usable hydrates and acid addition salts, as well as alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids, characterized by compounds of formula (II) 12 1 in which R , R , X and A have the above meaning, and X<2> means halogen, especially fluorine or chlorine, optionally reacted in the presence of acid binders with azabicycloalkanes of formula (III) 3 in which R has the above meaning. 7. Process for the production of 7-(azabicycloalkyl)-quinolone carboxylic acid or -naphthyridone carboxylic acid derivatives of the general formula (I) in which 12 1 R , R , A and X have the meaning referred to in claim 4, and R 3 means a in the ring system optionally with hydroxy or methyl substituted residue of formula 4 in which Z and R have the meaning specified in claim 4, characterized in that a compound of formula (IV) in which 12 1 R , R , A and X - have the meaning stated in claim 5, and R 7 means a residue with formula in which Z has the above-mentioned meaning, is possibly translated into presence of acid binders with compounds of formula (V) in which R 4 has the meaning indicated above but cannot mean hydrogen, X 3 means halogen, especially chlorine, bromine or iodine. 8. Process for the production of 7-(azabicycloalkyl)-quinolone carboxylic acid or -naphthyridone carboxylic acid derivatives with the general formula (I) according to claim 4, wherein R <4> means CH^-CO-d^-CH.^-, by reacting a compound of formula (IV) according to claim 7 with methyl vinyl ketone. 9. Animal feed or animal additives containing 7-(azabicycloalkyl)-quinolinecarboxylic acid- or -naphthyridone carboxylic acid derivatives of formula (I) in which R <1> means methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, phenyl, fluorophenyl, 2,4-difluorophenyl, R<2> means hydrogen, alkyl with 1 to 4 carbon atoms, (5-methyl- 2-oxo-1,3-dioxol-4-yl)-methyl, R<3> means one in the ring system optionally with hydroxy or methyl one or more substituted residue of formula in which Y means R <4-> N, 0, S, Z means -(CH^-, -CH2 -0-CH2 -, -CH2 -S-CH2 -, -CI^-S-, n means 1, 2 or 3, R <4> means hydrogen, optionally with hydroxy substituted alkyl, alkenyl or alkynyl with 1 to 4 carbon atoms, optionally with nitro or amino substituted benzyl, oxoalkyl with 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and R means hydrogen or methyl, X <1> means fluorine, chlorine or nitro, and A means N or C-R c, wherein R <6> means hydrogen, fluorine, chlorine,, methyl or nitro, or also together with R <1> can form a bridge of structure -O-CH2 -CH-CH3 -, -S-CH2 -CH-CH3 or -CH--CH -CH-CH and their pharmaceutically acceptable hydrates and acid addition salts, as well as the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids.