DD274029A5 - PROCESS FOR PREPARING 5-SUBSTITUTED CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

The invention relates to processes for preparing 5-substituted quinolone and naphthyridonecarboxylic acid derivatives of the formula (I) in which X, Y, R 1, R 2 and R 3 have the meaning given in the description. The novel process is characterized in that compounds of the formula (II) are reacted with compounds of the formula (III), if appropriate in the presence of acid scavengers. The process according to the invention is used in the pharmaceutical industry. Formula (I)

Description

Process for the preparation of 5-substituted quinolone and naphthyridonecarboxylic acid derivatives

Field of application of the invention

The method according to the invention is used in the pharmaceutical industry.

Characteristic of the known state of the art

A number of patent applications in which 5-aminoquinolonecarboxylic acids have been claimed as antibacterial agents have already become known. Japanese Patent Application 57 149 286 claims pyridobenzoxazine derivatives of the following structure (1),

HH ₂ O

COOH

(D

R '

in which

-2-

R for an Amincrost and

R ^{2 is} hydrogen or alkyl.

The introduction of the amino group takes place daduroh that the pyridobenzoxazine is nitrated and the nitro group is then reduced to the amino group.

The 5-aminoquinolonecarboxylic acids claimed in European patent application 172,651 to South African patent application 8,502,369 and Japanese patent application 58,174,367 are also prepared via 5-nitroquinolone carboxylic acids, which must first be synthesized from suitable bitroaromatics.

Object of the invention

The compounds prepared by the process according to the invention are useful as active ingredients for human and veterinary medicine, with the veterinary medicine also the treatment of fish for therapy or. Prevention of bacterial infections is counted.

Explanation of the essence of the invention

The object of the invention is to provide a process for preparing 5-substituted quinolone and naphthyridonecarboxylic acid derivatives. The invention relates to the preparation of 5-substituted quinolone and naphthyridonecarboxylic acid derivatives of the formula (I)

-2a "

Y o

COOR '

in which

X is fluorine or chlorine,

029

Y is amino, optionally substituted by amino, hydroxy or methoxy substituted alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, cycloalkylamino having 3 to 6 carbon atoms, alkoxyamino having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms , Mercapto, optionally substituted by ethoxycarbonyl, carboxy or hydroxy alkylthio having 1 to 4 carbon atoms, phenylthio, hydrazino, hydroxyamino, methoxyamino,

Chlorine, 15

R ¹ is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl, 20

R ^{2 is} hydrogen, alkyl having 1 to 4 carbon atoms or (S-methyl-2-oxo-l, 3-dioxol-4-yl) -methyl and

25 r3 is methyl or a cyclic amino group such as

, ^ H-, HO- ^ N-, R4-N N-, 30 r8 _r *

Le A 25 079

A Κ ^

O N, S N, R ^H -N TN,

he

H ₃ C

stands in which

R ^{4 is} hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, benzyl, 4-aminobenzyl or (5-methyl-2-oxo-l 3-dioxol-4: yl) -methyl,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen, alkyl having 1 to 4 carbon atoms, optionally substituted, in particular fluorine-substituted phenyl or benzyloxymethyl,

R ^{7 represents} hydrogen, amino, methylamines, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, isopropylaminomethyl, hydroxy or hydroxymethyl,

Le A 25 079

-5-

R ^{8 is} hydrogen, methyl, ethyl, fluorine or chlorine,

A is N or C-R ^ in which

R ^{9 is} hydrogen, halogen such as fluorine or chlorine, methyl, cyano or nitro or auoh together with R a bridge of the structure

-O-CH ₉ -CH-CH-, -S-CH ₉ -CH-CH- or -CH ₉ -CH ₉ -CH-CHo

can form

and their pharmaceutically usable hydrates and acid addition salts and the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids have a high antibacterial activity, in particular in the gram-positive region, with the exception of 8-mino-9-fluoro-3-niethyl-10- (4- methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido-1,2,3-de-7Z.i, 4-benzoxazine-o-carboxylic acid, 1-ethyl-5-amino-6,8 Difluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (4-methyl-1-piperazinyl) 4-oxo-1,4-dihydro-3-ohinolino-carboxylic acid and excluding 8-amino-9-fluoro-3-methyl-10- (heterocyclyl) -7-oxo-2,3-dihydro-7H-pyridol / ~ 1 , 2,3-de_7Z ~ 1,4_7-benzoxazine-6-carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heterocyclyl) -4-oxo-1,4-dihydroquinoline-3-ocarboxylic acids in which heterocyclyl is 3-amino-1-pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3- (ethylaminomethyl) -1-pyrrolidinyl, 2,7-diazaspiro ~~ A , 4_7non-2-yl and 7-methyl (or ethyl) -2,7-diazaspiro / ~ * 4,4_7no n-2-yl means, and

-6-

5-Amino-7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-oarbonsäure ·

Preference is given to 5-substituted ohinolone and naphthyridonecarboxylic acid derivatives of the formula (I)

^X IU GOOR ²

(D,

in which

X is fluorine or chlorine,

Y is amino, optionally substituted by amino, hydroxy or methoxy alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 bit carbon atoms per alkyl group, glycyl

274 O

alkylamino of 3 to 6 carbon atoms, alkoxyamino of 1 to 4 carbon atoms, hydroxy-substituted alkoxy of 1 to 4 carbon atoms, mercapto, ethoxycorbonyl, carboxy or hydroxy substituted alkylthio of 1 to 4 carbon atoms, phenylthio, hydrazino, hydroxyamines, methoxyamino, chloro,

R ^{1 represents} methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, dimethylamino, ethylamino,

Phenyl, 4-fluorophenyl or 2,4-difluorophenyl,

R ^{2 is} hydrogen, alkyl having 1 to 4 carbon atoms or <5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl and

r3 is methyl or a cyclic amino group such as

R ⁷ . R ⁶

/ θ nS

N, S N, R ⁴

-NV _n ^ N, R ⁴ -N <N-

Le A 25 079

^N ; j · LXi

LX_i 'LJ' LJ

H ₃ C

\ V stands in which

R ^{4 is} hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl propargyl,

2-oxopropyl, 3-oxobutyl, phenacyl, formyl, benzyl, 4-aminobenzyl or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl »

R ⁵ for heat or methyl,

R ^{6 is} hydrogen, alkyl having 1 to 4 carbon atoms, optionally substituted, in particular fluorine-substituted phenyl or benzyloxymethyl,

B ⁷ for hydrogen "amino, methylamines, ethylamino, aminomethyl, methylaminomethyl, ethyl

aminomethyl, dimethylaminomethyl, isopropylaminomethyl, hydroxy adder hydroxytnethyl,

R ^{8 is} hydrogen, methyl, ethyl, fluorine or chlorine,

Le A 25 079

A is N or CR ⁹ , in which

R ^{9 is} hydrogen, halogen such as fluorine or chlorine, methyl, cyano or nitro or together with R ^{1 is} a bridge of the structure

Can form -O-CH ₂ -CH-CH ₃ , -S-CH ₂ -CH-CH ₃ or -CH ₂ -CH ₂ -CH-CH ₃ ,

and their pharmaceutically usable hydrates and acid adipose salts, and the alkali, alkaline earth, silver and guanidinium salts of the basic carboxylic acids, with the exception of 8-amino-9-fluoro-3-methyl-10- (4-methyl-1-one) piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, 1-ethyl-5-amino-6,8-difluoro- 7- (1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (4-methyl-1-piperazinyl) -4-oxo 4-dihydro-3-quinolinecarbalcoic acid and excluding 8-amino-9-fluoro-3-methyl-10- (heterocyclyl) -7-oxo-2,3-dihydro-7H-pyridoCl ,, 2,3- de] [l, 4] benzoxazine-6-carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heterocyclyI) -4-oxo-1-dihydro-S-quinolinecarboxylic acids in which Hetiur ocyclyl 3-Amino-i-pyrrolidinyl, 3- (aminomethyl) -i-pyrrolidinyl, 3- (ethylaminomethyl) -l-pyrrolidinyl, 2,7-oiazcspiroC4.4-non-2-yl, and 7-methylbenz, ethyl> -2,7 = diazaspirot4 .4 3non-2-yl, and O-amino-7- (3-amino-1-pyrrolidinyl) i. ethyl-6-fluoro-1,4-dihydro-4- oxo-l, 8-naphthyridinecarboxylic acid, and other

Le A 25 07 9

3 4 '^

Compounds in which R represents the radical R -N N-

is with R ^4, R ⁵ and R ⁶ = H or C ₁ -C ₄ -AUyI when R ¹ Cyclopropyi, X is fluorine, Y is amino, hydroxy or C ₁ -C ₄ -alkoxy and AN, R is halogen or H stands,

R ^{2 is} H and their acid addition salts and compounds in which Y is amino or chlorine, R ^{1 is} cyclopropyl and X is fluorine, A is CF and R is

R ¹

10 R "-NV

R ¹ "

means

wherein R 'is H or CH ₀ , R "H, CH ₃ or C ₂ H ₅ , R" ¹

Mean H or methyl, and R ^? for H, CH ₃ or C ₂ H ₅

stands.

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

X for fluorine,

Y is amino, optionally substituted by amino, hydroxy or hethoxy alkyl with 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, cyclopropylmino, alkoxyamino having 1 to 3 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, optionally by ethoxycarbonyl, carboxy or

25 hydroxy-substituted alkylthio having 1 to 4 carbon atoms, phenylthio, hydroxyamines,

Le A 25 079

R ^{1 is} ethyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, phenyl, 4-fluorophenyl or 2,4-difluorophenyl,

R ² door hydrogen, alkyl having 1 to 3 carbon atoms, (5-methyl-2-oxo-l »3-dioxol-4-yl) methyl,

r3 represents a cyclic * amino group such as R ⁷ R ⁶

O N, S N-

K ₃ C Nji ^ N-, ^

L = J

N-, V ^ ^N "" ^H0 "\ ₇ N-, R ⁴ ~ N

stands, .worin

R ^{4 is} hydrogen, alkyl of 1 to 3 carbon atoms, 2-hydroxyethyl, allyl, 2-oxopropyl, 3-oxobutyl, phenacyl, benzyl, 4-aminobenzyl, (5-methyl-2-oxo-1,3-dioxole-4 -yl) methyl,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen, alkyl having 1 to 2 carbon atoms, phenyl, 4-fluorophenyl,

R 'is hydrogen, amino, aminomethyl, methylamine

methyl, ethylaminomethyl, dimethylaminomethyl, hydroxy or hydroxymethyl,

Le A 25 079

- 12- 274 O 29

R ^{8 is} hydrogen or methyl, 5

A is N or CR ⁹ , in which R ^{9 is} hydrogen, halogen such as fluorine or chlorine

stands or also together with F * a bridge of the structure

Can form -O-CH ₂ -CH-CH ₃ or -CH ₂ -CH ₂ -CH-CH ₃ »

and their pharmaceutically usable hydrates and acid *. additionsfaalze and the alkali, alkaline earth, silver and cusnidinium salts of the basic carboxylic acids, excluding 8-amino-7-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro- 7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (1-piperazinyl) -4-oxo-1 , 4-dihydro-3-quinolinecarboxylic acid, 1-ethyl-S-anrino-6,8-difluoro-7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, and except 8-amino-9-fluoro-3-methyl-10-

25 (heterocyclyl) -7-oxo-2,3-dihydro-7H-pyrido [l, 2,3-

de] [1,4] benzoxazine-6-carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heterocyclyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acids in which heterocyclyl 3-amino-1-pyrrolidinyl, 3- (aminomethyl) -l-pyrrolidinyl or 3- (ethylaminomethyl) -l-pyrrolidinyl, and 5-amino-7- (3-amino-1-pyrrolidinyl) -1-ethyl-6 "fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,

Le A 25 079

- 13 -

Particular preference is given to those compounds of the formula (I) in which

X for fluorine,

Y for amino ι optionally by amino ι hydroxyl or ^1ί? Methoxy-substituted alkylamino having 1 to 4 carbon atoms "Dialkylamino having 1 to 4 carbon atoms per Alkylgruppei cyclopropylamino, methoxyamino, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, optionally substituted by ethoxy, carbonyl, carboxy or hydroxyalkylthio having 1 to 4 carbon atoms, phenylthio .

R ^{1 is} ethyl, cyclopropyl, 2-hydroxyethyl, 4-fluoro. phenyl or 2,4-difluorophenyl,

R ^{2 is} hydrogen, alkyl having 1 to 2 carbon atoms

r3 is a cyclic amino group such as

PN, <N, HO-K N, R * -N N-,

Le A 25 079

- 14 -

LJ

H ₃ C

sees where

R ^{4 is} hydrogen, alkyl having 1 to 2 carbon atoms, 2-hydroxyethyl, 2-oxopropyl, 3-oxobutyl, phenacyl, 4-aminobenzyl,

R ^{5 is} hydrogen or methyl, 2Q R ⁶ is "" hydrogen, methyl, phenyl, 4-fluorophenyl,

R 'is hydrogen, amino, aminomethyl, methylaminomethyl, ethylaminomethyl, hydroxy or hydroxyrethyl,

R ^{8 is} hydrogen, A is N or CR ⁹ , in which

R ^{9 is} hydrogen, halogen, such as fluorine or chlorine, or together with R ¹ ine bridge of the structure

Can form -0-CH ₂ -CH-CH ₃ 25,

Le A 25 079

- 15 -

and their pharmaceutically usable hydrates and acid addition salts, and the alkali metal, alkaline earth metal, silver and guanidinium salts of the basic carboxylic acids except 8-amino-9-fluoro-3-methyl-10- (4-methyl-Ί-piperazinyl) -7-oxo -2,3-dihydro-7H-pyrido [l, 2,3-deHl, 4] -benzoxazine-6-carboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (1-piperazinyl) - 4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydroxy 3-quinolinecarboxylic acid and 8-amino-9-fluoro-3-methyl-10- (heterocyclyl) -7-oxo-2,3-dihydro-7H-pyrido [l, 2,3-deHl "4] benzoxazine-6 -carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heteroeyclyl) -4-oxo-1,4-dihydro-3-quinolinone carboxylic acids in which heterocyclyl is 3-amino-1-pyrrolidinyl, 3 (Aminomethyl) -1-pyrrolidinyl or 3- (ethylaminomethyl) -1-pyrrolidinyl, and 5-amino-7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid.

It has furthermore been found that the compounds of the formula (I) are obtained when compounds of the formula (II) 25

COOR ²

in which

X, R, R ² , R and A are as defined above

to have,

Le A 25 079

27 * O 29

- 16 - ⁷

with compounds of the formula (III)

Y-H (III),

in which IB Y has the meaning given above,

if appropriate in the presence of acid scavengers «

If, for example, 1-cyclopropyl-S, 6 _# 8-t-trifluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid and ammonia are used as starting materials Retention sequence can be represented by the following equation:

Le A 25 079

- 17 -

The compounds of the formula (II) used as starting materials are known or can be prepared by known processes

Methods are produced (European Patent Application 202 763 »German Patent Application 35 22 405)" Examples include:

7- [3- (Aminomethyl) -1-pyrrolidinyl] -1-cyclopropyl-S, 6,8-trifluoro-1 ', 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-Z-tS-t (methylamino3methyl3 1-pyrrolidinyl] -5,6, 8-trifluoro-1-dihydro-3-oxo-3-olcarboxylic acid,

1-Cyclopropyl -? - t3 - [(ethylamino) methyl] 1-pyrrolidinyl3-5 | 6 | 8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7- [3-amino-1-pyrrolidinyl3 -l-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- [3- (ethylamino) -l-pyrrolidinyl3-5 # 6.8 -

20 trifluoro-1 »4-dihydro-4-oxo-3-quinolinecarboxylic acid,

1-Cyclopropyl-5,6,8-trifluoro-1 ', 4-dihydro-7- [3 - [[(1-n-ethyl-1-ethyl) -amino-3-methyl-1-pyrrolidinyl] -4-oxo-3-quinolinecarboxylic acid; 7- [3- (aminomethyl) -l-cyclopropyl-l-pyrrolidinyl3-1, 4-

2- dihydro-5,6-difluoro-4-oxo-1-naphthyridine-S-carboxylic acid,

l-Cycloprepyl-7- [3 - [(ethylamino) methyl3-1-pyrrolidinyl3-1,4-dihydro-5,6-difluoro-4-oxo-l »8-naphthyridine-3-carboxylic acid,

^ O 7-C3-amino-1-pyrrolidinylS-l-cyclopropyl-l, 4-dihydro-5 16-difluoro-4-oxo-l »8-naphthyridine-3-carboxylic acid, 7- [3- (aminomethyl) ~ 1-pyrrolidinyl3-l-ethyl-5,6-difluoro-1,4-dihydro-4-oxo-l, e-naphthyridine-3-carboxylic acid,

Le A 25 079

- 18 -

7- [3- (aminomethyl) -l-pyrrolidinyl] -l-ethyl-5,6,8-5 trifluoro-1-dihydro-oxo-S-quinolinecarboxylic acid,

7- [3- (Aminomethyl) -l-pyrrolidinyl-3,5,6,8-trifluoro-1- (2-fluoroethyl) -l _f 4- * dihydro-4-oxo-3-quinocarboxylic acid 7-C3- (aminomethyl) 1-Pyrrolidinyl 3 -5 »6,8-trifluoro-1-ethenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ₍

* 0 l-ethyl-7- Z 3 - [(ethylamino-methyl] -l-pyrrolidinyl] -5,6-difluoro-1 ♦ 4-dihydro-4-oxo-1, e-naphthyridine-3-carboxylic acid,

1-ethyl-7-C3-C (ethylamino-methyl) -l-pyrrolidinyl-1-5,6,8-trifluoro-1-dihydro-oxo-S-quinolinecarboxylic acid, 7-C3 - [(ethyl-binomethyl) -methyl l-pyrrolidinyl] -5,6,8-trifluoro-1- (2-fluoroethyl) -l _f 4-dihydro-4-oxo-3-chinolincarbonsaure "

1-ethenyl-7- [3-C (ethylamino) -methyl-1-pyrrolidinyl] -5,6 "-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-ethyl-5, 6-difluoro-1,4-dihydro-7- [3-t C (1-methylethyl) amino] methyl] -1-pyrrolidinyl3-4-oxo-1,8-naphthyridine-3-carboxylic acid,

l-ethyl-7- [3 - [(l-methylethyl) aminomethyl] -l-pyrrolidinyl] -5 _{t 6,} # 8-trifluoro-l, 4-dihydro-4-oxo-3-quinoline

²⁵ carboxylic acid, 1-ethyl-5i6-difluoro-1,4-dihydro-7- (7-methyl-2,7-diazaspiro [4,4] non-2-yl) -4-oxo-1,8-naphthyridine -3-carboxylic acid, l-ethyl-5,6,8-trifluoro-1,4-dihydro-7- (7-ethyl-2,7-

diazaspiro [4,4] non-2-yl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (7-methyl-2,7- diazaspiro [4,4] non-2-yl] -4-oxo-3-quinolinecarboxylic acid, 7- (3-amino-1-pyrrolidinyl) -1-ethyl-5,6,8-trifluoro-1,4-

35 dihydro-4-oxo-3-quinolinecarboxylic acid,

Le A 25 079

- 19 -

1-Cyclopropyl-5,6-difluoro-1- _t 4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) J-oxo-S-quinolinecarboxylic acid, 1-cyclopropyl-sifefB-trifluoro-1,4-dihydro-? - (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-sife-difluoro-1-dihydro-3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl -7- (1,4-di-azabicyclo) -2,1] oct-4-yl> -5,6 »8 · trifluoro-1,4-dihydo-O-oxo-3-quinoline-acyl-β8-β, 1-cyclopropyl-7- ( l, 4-diazabicycloC3.2.13oci-4-yl) -5,6-difluoro-1,4-dihydro-4-oxo-l »8-naphthyridine-3-carboxylic acid,

l-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (2-methyl-1 _e-4 diazabicycloC3.2.1] oct-4-yl) -4-oxo-3-chinolincarbonsaure,

1-Cyclopropyl-S-trifluoro-1- _f 4-dihydro-7- (8-ethyl-3,8-diazabicyclo [3.2.1-oct-3-yl) -4-oxo-3-quinoline-carboxylic acid .

1-Cyclopropyl-5,6,8-trifluoro-1-chloro-4,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid, 1-cyclopropyl-S, 8-trifluoro-1 , 4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid, 1-cyclopropyl-S-tert-trifluoro-1,4-dihydro-4-oxo-7- (4- ethyl-1-piperζinyl) -3-quinolinecarboxylic acid, 1-cyclopropyl-5,6,8-trifluoro-l _# 4-dihydro-7-t4- (2-hydroxyethyl) -1-piperazinyl3-4-oxo-3-quinolinecarboxylic acid , 1-Cyclopropyl-Sjfeje-trifluoro-1,4-dihydro-4-oxo-7- (3-methyl-1-piperazinyl-3-quinolinecarboxylic acid, 1-cyclopropyl-5-trifluoro-1,4-dihydro 4-oxo-7- (3,5-dimethyl-1-piperazinyl) -3-ehinolinecarboxylic acid, 1-cyclopropyl-SiSi-trifluoro-1,4-dihydro-4-oxo-7- »orpholino-3-quinolinecarboxylic acid,

Le A 25 079

- 20 -

SifctB-trifluoro-l, 4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylic acid,

1-Cyclopropyl-S-trifluoro-1,4-dinydro-4-oxo-7- (4-isopropyl-1-piperazinyl) JS-quinolinecarboxylic acid, 7- (4-allyl-1-piperazinyl) -l-cyclopropyl -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-chinolincarbonsaure,

1-Cyclopropyl-5,6,8-trifluoro-1 _# 4-dihydro-4-oxo -? - [4- (2-oxopropyl-1-piperazinyl-1-quinolinecarboxylic acid) 1-cyclopropyl-Stois-trifluoro-1, 4-dihydro-4-oxo-7- [4- (3-oxobutyl) -l-piperazinyl] -3-quinolinecarboxylic acid, 1-cyclopropyl- _5f 6, 8-trifluoro-1, 4-dihydro-4-oxo 7 - (3

1-phenyl-1-piperazinyl) -3-quinolinecarboxylic acid ,

l-cyclopropyl-Siöie-trifluoro-1 _f 4-dihydro-7- (limidazolylJ-4-OXO-3-cninolincarbnnsaure, l-cyclopropyl-5,618-trifluoro-l> 4-dihydro-4-oxo-7- (1- pyrrolylJ S chinolincarbonsaMre,

S-8,9-difluoro-3-rnethyl ~ 30- (4-methyl-l-pipera2inyl) -7-oxo-7H-pyrido [1,2,3-de] [l, 4Dbenzoxazin-fc-carboxylic Baure.

The compounds of the formula (III) which are wounded as starting compounds are known

called: ammonia 1 methylamine, ethyl amiη, propylamine, isopropylumin, butylamine, dimethylamine, ethyl-methylamine, diethylamine, 2-hydroxyethylamine, ethylenediamine, 2- (tert-butoxycarbonylamino) -ethylamine, 2-methoxy (f thy 1 ami η, cyclopropylamine, methoxyamine, butoxyamine,

Methanol, methylmercaptan, thiophenol, mercaptoacetic acid ethyl ester, mercaptoacetic acid, hydrazine

The reaction of (II) with (III) is preferably carried out in a diluent such as dimethylsulfoxide, N, N-dimethylformamide, hexamethylphosphoric acid triamide,

Le A 25 079

- 21 -

Sulfolane, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether, acetonitrile or pyridine. "Mixtures of these diluents may also be used.

All common inorganic and organic acid binding agents can be used as acid binders. These include, preferably, the alkali metal hydroxides, alkali metal carbonates, sodium hydride, organic amines and amidines. Be particularly suitable in detail! Triethylamine, 1,4-diazB-bicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [S.3.0 "ndec-7-ene (DBU).

The reaction temperatures can be varied within a substantial range. In general, one works between about 70 and 200 ⁰ C, preferably between 100 and 180 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one works at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

In carrying out the erf indungsgemaß.en method is used for 1 mol of the carboxylic acid (II) λ bis 50 mol,

preferably 1 to 30 mol of the compound (III) a "30

In individual cases, it is also possible to use protective groups which are obtained after the reaction of (II) has ended

Le A 25 079

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(III) can subsequently be split off. For example, L-esters are hydrolytically cleaved to carboxylic acids by heating in the presence of sulfuric acid at 100 ° to 150 ° C. The tert -butoxycarbonyl radical is split off as the amino-protecting group in the presence of acids such as hydrochloric acid »hydrobromic acid (see Houben-Weyl, Methods of Organic Chemistry» Volume E4, page 144 (1983)).

Under the same acidic conditions, the elimination of the Tetrahydroxypyranylrestes takes place as a hydroxy protecting group (see J, F.W, McOmie, Protective Groups in Organic Chemistry (1973), page 104).

To prepare the esters according to the invention, the underlying carboxylic acid in excess Alko-hol in the presence of strong ι such as sulfuric acid, anhydrous hydrogen chloride ι methanesulfonic acid, p-toluenesulfonic acid or ion-exchangers, at temperatures of about 20 ° to 200 ⁰ C _1, preferably about 60 ° to 120 ⁰ C to be implemented. The resulting water of reaction can also be removed by szeotropic distillation with chloroform, toluene Totrachlormethant or toluene.

The (5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl) esters used as prodrugs can also be prepared by reacting an alkali metal of the underlying carboxylic acid with 4-bromomethyl- or 4-chloromethyl-5-methyl- l, 3-dioxol-2-one

35

L »A 25 079

can be obtained in a solvent such as dimethylformamide, dimethylacetamide), dimethyl sulphoxide or tetramethylurea at temperatures from about 0 ° to K) O ⁰ C, preferably 0 ° to 50 ⁰ C,

The introduction of an aminobenzyl radical R ⁴ can also be effected by reduction of a nitrobenzyl radical already introduced in the active compound of the formula I by catalytically excited hydrogen or chemically by reduction with iron or zinc,

The preparation of the acid addition salts by the compounds according to the invention is carried out in a customary manner, for example by dissolving the residue in excess aqueous acid and precipitating the salt with a water-miscible organic solvent, such as

Methanol, ethanol, acetone, acetonitrile. One can also

equivalents Mangen Betai.n and acid in water or an alcohol such as glycol monomethyl ether, then evaporate to dryness or vacuum the precipitated salt. Examples of suitable pharmaceutically usable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

30

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are prepared, for example, by batches of betaine in unierschüseiger alkali or alkaline earth liquor,

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27 4 0 2

Filtration of undissolved betaine and evaporation of the filtrate to dryness · Pharmaceutical

suitable are sodium »potassium or calcium salts. By reacting an alkali or alkaline earth metal salt with a suitable silver salt such as silver nitrate, the

corresponding silver salts. 10

The active compounds according to the invention having an asymmetric carbon atom in the radical R ³ can be used both as racemates and as enantiomerically pure compounds

be present · 15

Apart from the compounds listed in the examples, new active substances may be mentioned in detail «

5-amino-7-C3- (aminomethyl) -l-pyrrolidinyl3-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

S-amino-1-cyclopropyl-y-tS-C (methylamino) methyl 3-1-

pyrrolidinyl-3-8,8-difluoro-1- _t- 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-1-cyclopropyl-7- [3 - [(ethylamino) methyl-3-1-pyrrolidinyl] -6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ,

5-Amino-7-C3-amino-1-cyclopropyl-6,8-pyrrolidinyl3-1

difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ^^ 5-Amino-1-cyclopropyl-7- [3- (ethylamino) -l-pyrrolidinyl-3-8,8-difluoro-1,4-dihydro -4-oxo-3-chinolincarboneäure,

5-amino-1-cyclopropy1-6,8-difluoro-1 4 _t-dihydro-7- [3-

[[(1-methylethyl) amino-3-methyl-3-pyrrolidinyl-3,4-oxo-3-yl]

quinolinecarboneiure, 35

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5-Aynino-7- (3- (aminomethyl) -1-pyrrolidinyl) 3-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3

carboxylic acid, 5-amino-1-cyclopropyl-7- [3-C (ethylamino) methyl-3-pyrrolidinyl] -1,4-dihydro-6-fluoro-4-oxo-1, naphthyridine-3-carbonic acid .

5-Amino-7- [3-amino-1-pyrrolidinyll-l-cyclopropyl-l, 4-

dihydro-6-fluoro-4-oxo-l »e-naphthyridine-3-carboxylic

5-amino-7- [3- (eminomethyl) -l-pyrrolidinyl3-l-ethyl-6- (luor-1 _# 4-dihydro-4-oxo-lte-naphthyridine-3-carboxylic

15 acid ι

5-Amino-7-t3- (aminomethyl) -1-pyrrolidinyl-3-l-ethyl-6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-7- [3- (2-amino) aminomethyl) -l-pyrrolidinyl3-6,8-difluorl- (2-fluoroethyl) -l '4-dihydro-4-oxo-3-quinolinecarboxylic

20 acid,

5-Amino-7- [3- (aminomethyl) 1-pyrrole-idinyl-3-8,8-difluoro-1-ethenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-1-ethyl-7 - [3 - [(ethylamino) methyl] -1-pyrroloalpha inyl 3-6-fluoro-1,4-dihydro-4-oxo-l _# 8-naphthyridin-3

25% carboxylic acid,

5-amino-1-ethyl-7- [3-C (ethylamino) methy13-1-pyrrol i dinyl 3-6.8-di f luor-1 ^ -dihydrb ^ -oxo-S-chinolincar-

bonsaure,

5-amino-7-t3 - [(ethylamino) methyl] -1-pyrrole-idynyl-3-8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

5-Amino-1-ethenyl-7- [3-C (ethylamino) methyl-1-pyrrole [alpha] inyl3-6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid,

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5-amino-1-ethyl-6-fluoro-1,4-dihydro-7-t3-tl (1-methylethyl) amino] methyl] -1-pyrrolidinyl] -4-oxo-1,8-naphthyridine-3 -carboxylic acid ι

5-amino-1-ethyl-7-C3- [il-methylethyl) amino-ethyl-3-pyrrolidinyl] -6,8-difluoro-1,4-dihydro-oxo-S-quinolinecarboxylic acid,

5-amino-1-ethyl-6-fluoro-1,4-dihydro-7- (7-methyl-2,7-diazaspiro [4.4] non-2-yl) -4-oxo-1, e-n-Bpht. hyridin-3-carboxylic acid,

5-amino-1-ethyl-6,8-difluoro-1,4-dihydro-7- (7-ethyl-2,7-diazaspiroC4 _< 4) non-2-yl) -4-oxo-3-quinolinecarbon -

15 acid «

5-amino-l-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (7-

methyl-2,7-diaza6piro [4 '4] non-2-yl] -4-oxo-3-chinolinear-

bonsäure,

5-Amino-7- (3-amino-l-pyrrolidinyl) -l-ethyl-6,8-difluoro-

20 l -dihydro-oxo-S-quinolinecarboxylic acid »

5-Amino-1-eyero-propyl-6-fluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic, 5-amino-1-eyero-propyl-6-fluoro 1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-chinolincarbonsaure, 5-amino-1-eyelopropyl-7- (1,4-diazabicyclo [3 '2.l] oct -4-yl) -6-fluoro-1 '4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid,

5-Amino-1-eyepropropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-1,4-diazabic ylene 3,2,13oct-4-yl) -4-OXO-3-

30 quinolinecarboxylic acid,

5-amino-1-eyelopropyl-6,8-difluoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo [3 "2, l] oct-3-yl) -4-oxo- 3-chinolincarbonsaure,

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S-Amino-1-cyclopropyl-Fe | 8-difluoro-1,4-dihydro-4-oxo-7-S (1-piperazinyl) -3-quinolinecarboxylic acid, S-amino-1-cyclopropyl-Fe _# 8-difluoro -l _# 4-dihydro-4-oxo-7-thiomorpholino-3-chinolincarbonsaure, _5-amino-l-f cyclcpropyl-6 8-difluoro-1,4-dihydrp-4-oxo-7- <Λ- i ' , : -, jrcpyl-l-pipera2inyl) -3-quinolinecarboxylic acid,

* "5-A; rtino-7- (4-Blyl-1-piper-2-ylinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-1-ol cyclopropyl-6- | 8-difluoro ~ l _t 4-dihydro-4-oxo-7- [4- (2-oxopropyl) -l-piperazinyl l-.s-quinolinecarboxylic acid »S-amino-1-cyclopropyl-oxy-fluoro -1 _t 4-dihydro-4-oxo-7- [4-

^ 5 (3-oxobutyl) -1-piperazinyl] -3-quinolinecarboxylic acid,

6-Amino-1-cyclopropyl-Fe "8-fluoro-1 _# 4-dihydro-4-oxo-7- (1-pyrrolyl) -J-quinolinecarboxylic acid,

5-Amino-7- [4- (4-aminobenzyl) -l-piperazinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline af-bon

20 BBUre,

S-Amino-1-cyclopropyl-6- _t 8-difluoro-l, 4-dihydro-4-oxo-7- (4-phenacyl-1-piperazinyl) -3-quinolinecarboxylic, S-8-amino-9-fluoro 3-methyl-10- (4-methyl-1-piperazinyl) -7-CXO-7K-pyrido [l, 2, 3-de] ti, 4] benzoxazine-6-carboxylic acid.

5- (2-aminoethylamino) -l-cyclopropyl-6,8-difluoro-1- _t 4-dihydro-7- ( ^4- methyl-1-piperazinyl) -4-oxo-3-quinoline-carboxylic acid

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Example of an Inventive Tablet Each tablet contains:

Compound of Example 1 583.0 mg Microcrystalline cellulose 55.0 mg

¹⁰ corn starch 72.0 mg

Poly (1-vinyl-2-pyrrolidone) insoluble 30.0 mg Highly dispersed silica 5.0 mg

Magnesium stearate 5 _t 0 ntg

750.0 mg 15

The paint envelope contains:

Poly (0-hydroxypropyl-O-methyl) cellulose 15 cp

Kacrogol 4000 tec, INN

F'c lyethylenglykole (DAB) titanium (IV) oxide

6.0 mg 2.0 mg 2.0 mq 10.0 mg

Le A 25

The compounds of the present invention exhibit, at low toxicity, a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, especially against Enterobacteriaceae, especially those resistant to various antibiotics, e.g. Penicillins, cephalosporins, aminoglycosides, * 0 sulfonamides, tetracyclines.

These valuable properties enable their use as chemotherapeutic agents in medicine as well as materials for the preservation of inorganic and organic materials, especially organic materials of all kinds, e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds of the invention are effective against a very broad spectrum of microorganisms. With their help gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled and the diseases caused by these pathogens

²⁵ prevents, ameliorates and / or heals.

The compounds of the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and eystemisehen infections in human and veterinary medicine, which are caused by these pathogens «

For example, local and / or systemic diseases can be treated and / or prevented

Le A 25 079

be caused by the following pathogens or by mixtures of the following pathogens?

Gram-positive cocci, e.g. Staphylococci (staph, aureus, staph epidermidis) and streptococci (strepto agolactiae, strepto faecalis, strept pneumoniae, strepto pyogenes); gram-negative cocci (Neisseria

* ° gonorrhoeae) as well as Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrubacter (Citrob.friendii, Citrob

divernis) "Salmonella and Shigellaj also Klebsiella (Klebs pneumoniee, Klebs oxytoca), Enterobacter (Ent aerogenes, Entagglomerans), Hafnia, Serratia (Serr marcescens), Proteus (Pr Mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia _# and the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (Ps * aeruginosa »Ps.

^ ^ maltophilia) as well as strictly anaerobic bacteria such as e.g.

Bacteroides fragilis »representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; furthermore mycoplasmas (M. pneumoniae, M. hominie, M. urealyticum)

and mycobacteria, e.g. Mycobacterium tuberculosis, 25

The above listing of pathogens is merely exemplary and not restrictive to understand As diseases caused by the said pathogens or Mischimektionen and can be prevented, ameliorated or cured by the compounds of the invention, may be mentioned, for example:

Human infectious diseases such as otitis, pharyngitis, pneumonia, peritonitis,

Le A 25 079

Pyelonephritis, cystitis «endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, upper respiratory tract diseases, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, frcstatitis, epididymitin, gastrointestinal infections, bone and joint -infections, cyst.isr.he fibrosis, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth, infections after dental surgery, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intra-abdominal Abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, meningitis and nervous system infections, salpingitis, endometritis, genital infections, pelvic peritonitis and ocular

2Q infections «

Except for humans, bacterial infections can also

to be treated in other species

called: 25 pig: Coi diarrhea, enterotoxemia, sepsis,

Dysentery, salmonellosis, mastitis metritis agalactia Syndrome »Mastitisj Ruminants (cattle, sheep, goats): diarrhea, sepsis,

Bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis; Genital infections;

Horse: Bronchopneumonien, Fohlenlahme, puerperale and

postpuerperal infections, salmonellae;

Dog and cat: bronchopneumonia, diarrhea, dermatitis,

Otitis, urinary tract infections, prostatitis; 35

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Poultry (chicken, turkey »quail» pigeon, ornamental birds and others): mycoplasmosis, E.coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, pacificationacosis «

Likewise, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, the antibacterial spectrum on the aforementioned pathogens on other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, ¹ ^ Nocardia, Riketteien, Yersinia, expanded »

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more compounds according to the invention or which consist of one or more active substances according to the invention and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units "This means that dia preparations in the form of individual parts. e.g. Tablets, dragees, capsules, pills, suppositories and ampoules are present, whose active substance content corresponds to a fraction or a multiple of a single dose "The dosage units can eg" 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 ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

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By η * cht-toxic, inert pharmaceutically acceptable carriers are solid, semi-liquid or liquid diluents · fillers and formulation auxiliaries of any kind to understand ·

Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients, such as (a) fillers and extenders, e.g. Starches, lactose, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g., carboxymethyl cellulose,

Alginates »gelatine, polyvinylpyrrolidone, (c) moisturizing

preservative, eg, glycerol, (d) disintegrants, 2.B. Agar agar, calcium carbonate and sodium carbonate, (e) Losungsverzogerer, eg paraffin and (f) absorption accelerators, eg quaternary ammonium compounds, (g) NeIz- medium, eg cetyl alcohol, glycerol monostearet, (h) adsorbents, such as kaolin and bentonite and (i) lubricants, for example talcum, calcium and magnesium stearate, and solid felyethylene glycols or mixtures of (a)

to (i) listed substances. 30

The tablets, tablets, capsules, pills and granules may be provided with the usual coatings and sheaths optionally containing opacifying agents and may also be composed in such a way that they prefer the active ingredient (s) only in one certain part

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optionally delaying the intestinal tract, with all embedding masses e.g. Polymer substances and waxes can be used

The active substance (s) may optionally also be present in microcapsolated form with one or more of the abovementioned carrier substances. «

Suppositories may contain the usual water-soluble or water-insoluble carriers in addition to the active substance (s) "2 · Β. Polysthylenylykole, fats »eg cocoa fat and higher esters (eg C ₁₄ alcohol with C ₁₆ fatty acid) or mixtures of these substances.

Ointments, Pastes »Creams and gels may contain, in addition to the active substance (s), the usual excipients» e.g. Animal and vegetable fats »Waxes» Paraffins »Strong» Tragacanth »Cellulose derivatives» Polyethylene glycols »Silicones» Bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays may contain, in addition to the active substance (s), the usual excipients »e.g. Lactose «talc, silicic acid» aluminum hydroxide »calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain the usual propellants »e.g. Chlorine-

30 fluorohydrocarbon ₍ contain.

Solutions and emulsions may contain, in addition to the active substance (s), the usual excipients such as solvents.

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water, ethyl alcohol, ieopropyl alcohol, ethyl t.arbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil , Glycerol, glycerolformal, tetrahydrofurfurylalcohol, polyothylene glycols and fatty acid esters of sorbitan odoi · mixtures of these substances ·

For parenteral administration, the solutions and emulsions may also be present in sterile and blood isotonic form.

Suspensions may contain, in addition to the active substance (s), the usual excipients such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agent, 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 said formulations may also form colorants, preservatives and odor and flavor improving additives, for example peppermint oil and eucalyptus oil and sweeteners, 2.E. Saccharin, contain «

The therapeutically active compounds are intended in the. The above-listed pharmaceutical preparations may preferably be present in a concentration of from about 0.1 to 99.5, preferably from about 0.5 to 95,% by weight of the total mixture.

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The abovementioned pharmaceutical preparations may, in addition to the compounds according to the invention, also contain other active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in a customary manner by known methods, for example by mixing the active substance (s) with the trimer (s) »

The preparations mentioned can be administered either orally rectally in humans and animals parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for the treatment of infections in cavities and body cavities. Suitable formulations include injection solutions, solutions and suspensions for oral therapy, gels »infusion formulations, emulsions, ointments or drops. For local therapy, ophthalmic and dermatological formulations, silver and other salts, ear drops, eye washes, powders or solutions may be used "In animals, intake can also take place via feed or drinking water in suitable formulations. Furthermore, gels, powders, tablets, sustained release tablets, premixes, concentrates, granules, pellets, tablets, capsules, aerosols, sprays, inhalants can be used in humans and animals. Further, the compounds according to the invention can be used in other carrier materials such as, for example, plastics (Kunsfjitoff chains for local therapy), collagen or bone cement to be incorporated «

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274 ο 29

In general, it has proved advantageous in both human and veterinary medicine to obtain the active compound (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form several individual doses to achieve the desired results. A single dose contains the active compound (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight. However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object, the nature and severity of the disease, the method of preparation and administration of the drug, and the period or interval within which it is administered.

Thus, in some cases it may be sufficient to manage with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. The determination of the optimal dose and type of administration of the active ingredients required in each case can easily be carried out by any person skilled in the art on the basis of his specialist knowledge.

The new compounds can be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. This can cause an infection by gram-negative or

Le A 25 079

Gram-positive bacteria are prevented, ameliorated and / or cured, and thus a promotion of growth and an improvement in the pre-evaluation of the feed can be achieved.

embodiments

Table : Minimum inhibitory concentrations (mg / 1)

O uj test strain: 21 23 24 Be 25 »Ispiel 26 27 28 32 30 I E.coli Neumann 455/7 A261 <0.015 2 0.5 10.015 1 0.25 0.125 4 1 .0.125 1 0.125 0.03 16 4 0.125 16 2 <0.015 2 0.25 <0.015 1 0.06 0.03 16 2 IO I Klebsieila 63 8085 0.06 0.06 <0.015 0.03 0.125 0.125 0.03 0.06 0.06 0.06 0.125 0.125 <0.015 10.015 <0.015 0.03 0.06 0.03 Proteus to me "8223 8175 vulg. 1017 Morq, morg * 932 11006 0.5 0.125 <0.015 0.03 0.125 0.125 0.06 <0.015 <0.015 0.03 2 0.25 0.06 0.125 0.25 1 0.125 <0.015 <0.015 0.03 0.5 0.125 0.03 0.03 0.125 0.25 0.25 0.06 0.06 0.125 0.06 10.015 10.015 <0.015 10.015 0.5 0.06 <0.015 <0.015 0.03 2 0.06 <0.015 i.0.015 0.06 Providencia 12012 12052 0.06 2 <0.015 1 0.125 4 0.06 4 0.06 8 C, 06 8 <0.015 1 0.03 1 <0-015 4 Serratia 16040 4 2 8th 4 8th 16 1 4 8th StaDh. FK 422 1756 133 0.06 0.06 0.06 <0.015 <0.015 10.015 0.06 0.06 <0.015 10.015 10.015 0, G3 0.03 0.03 <0.015 10.015 10.015 <0> 015 <0.015 10.0t5 0.03 0.03 0.03 <0.015 <0.015 0.03 Enteroc »27101 9790 0.25 0.25 0.03 0.06 0.25 0.25 0.125 0.125 0.25 0.25 0.03 0.125 0, G3 0.03 0.03 0.03 0.25 0.25 Pseudomonas Walter Ellsworth 1 10,015 1 10,015 2 0.25 0.5 0.03 2 O, Q3 1 0.125 0.25 0.03 1 0.03 2 0.25

The MIC values were measured in the agar gradient. Agar plates with isosensitest agar (Oxoid) were inoculated with a multipoint inoculator. The inocuium was about 10 germs per inoculation point.

Table (Fort set zttng)

Test strain: 19 Beis] 20 > 17 22 E.coli Neumann 0.03 <0.015 <0.015 <0.015 455/7 Α261 1 0.25 2 0.25 0.5 0.125 0.5 0.125 Klebsiella 63 8085 0.03 0.03 0.03 0.06 <0.015 i.0.015 0.03 0.06 Proteus me · 822: 3 8175 vulg. 1017 Mora mora * 932 11006 0.25 0.125 0.06 0.03 0.06 0.25 0.125 i.0.015 0.03 x 0.06 0.25 0.06 <r, ois <0.015 i.0.015 0.50 0.06 <0.015 0.03 0.03 Providencia 12012 12052 0.06 i 0.06 1 <0.015 2 0.03 1 Serratia 16040 4 4 2 2 SLaoh. FK 422 1756 133 0.03 0.06 0.06 0.06 0.06 0.06 0.03 0.03 0.03 0.03 0.03 0.03 Enteroc. 27101 9790 0.25 0.25 0.25 0.25 0.125 0.125 0.125 0.25 Pseudomonas Walter Ellsworth 0.5 0.06 1 0.03 0.25 i.0.015 0.5 0.03

O I

Nd

ro

- 41 -

5 Example A

11 # 1 g of magnesium turnings are dissolved in 25 ml of anhydrous

Ethanol suspended. 2.5 g of carbon tetrachloride are added and, when the reaction has started, a mixture of 79 g of diethyl malonate, 50 ml of absolute ethanol and 200 ml of anhydrous diethyl ether is added dropwise. The reflux is then continued for a further 2 hours Cooled ice / methanol to ^{0 0} C and slowly added dropwise at this temperature, a solution of 106.3 g (0.5 mol) of pentafluorobenzoyl fluoride in 135 ml of diethyl ether. It is stirred for 1 hour at ^{0 0} C, allowed to come to room temperature overnight and allowed while cooling with ice, add a mixture of 200 ml of ice-water and 12.4 ml of concentrated sulfuric acid. The phases are separated and washed twice with ether. The combined ether solutions are washed with water, dried with Na ₂ SO ₄ and the solvent is stripped off in vacuo. 170.8 f of pentafluorobenzoyl malonic acid diethyl ester are obtained as crude product.

An emulsion of 170 g of crude diethyl pentafluorobenzoyl malonate in 335 ml of water is added to 0.7 g of p-toluenesulfonic acid

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Stir for 3.5 hours, the cooled emulsion repeatedly with methylene chloride, washed the combined Ch ₂ Cl ₂ solutions once with water »dried with Na ₂ SO ₄ and the solvent is distilled off in vacuo, the fractionation of the residue (125.3 g) in vacuo provides 79.5 g (56 X of theory) Pentafluorbenzoylessigsaureethylsster of boiling point 77-7V ⁰ C / 0.13 mbarj nS ° t 1.4608.

With Pentafluorbenzoylchlorid the reaction proceeds according to · 15

Ex iel B

246 g (0.87 mol) of pentafluorobenzoyl-acetic acid ethyl ester are refluxed for 2 hours with 189 g (1.25 mol) of ortho-formic acid and uretriethy) ester and 214 g (2.1 mol) of igeic anhydride. It is then concentrated to 140 ⁰ C bath temperature in vacuo and 196 g (£ 7 X derTheorie) of 3-ethoxy-2- (pentafluorobenzoyl) -acrylsa «resthyl ladder obtained as an oil.

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- 43 -

Example C 5

196 g (0.58 mol) of 3-ethoxy-2- (pentafluorobenzoyl) -acrylsäureethy? Ester in 750 ml of ethanol under cooling ge'iBsl and 34.2 g (0.6 mol) of cyclopropylamine are added dropwise, Man let nachrUhren 2 hours , let stand overnight, the precipitated crystals are filtered off with suction, washed

2 h with cold ethanol and dried (123.2 g, melting point 87-88 °). The mother liquor is concentrated by half and a further fraction (37.4 g, melting point 87-88 °) isolated. Total Construction: 160.6 g (79 X of theory) 3-Cyclopropylamino-2- (pentafluorobenzoyl) -acrylic ·

25 acid ethyl ether.

Ex iel D

30 y

JOOC ₂ H ₅

Le A 25 079

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160.6 g (0.46 mmol) of 3-cyclopropyl-2-amino (pantafluorobenzoate) acrylate are mixed in 700 ml of dimethylformamide with 33.4 g (0.8 mol) of sodium fluoride and refluxed for 3 hours 3 1 of water poured out, the precipitate was filtered off with suction, washed with water and dried. Yield: 144.6 g (96 × of theory) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4 oxo-3-quinolinecarboxylic acid ethyl ester of melting point 169-173 ° C

Example E 15

144.6 g (0.44 mol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are dissolved in a mixture of 854 ml of acetic acid, 612 ml Water and 97 ml of concentrated sulfuric acid for 3 hours under reflux. After cooling, poured into 3 1 of ice water, the precipitate is filtered off with suction, with water

3Q geweechon ijnH dried,

Yield: 117.9 g (89 X of theory) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 176-178 °; after recrystallization from ethanol: mp 178-180 ° x 35

Le A 25 079

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Example F

^C 2 ^H 5

OOH

3-Ethaxy-2- (pentafluorobenzoyl) -acrylate ethyl ester is reacted analogously to Example C with 50% aqueous ethylamine solution to give 3-ethylamino-2- (pentafluorobenzoyl) -acrylacureethyl ester (cis-trans mixture) of melting point 37-88 ° * analogously to Example D with sodium fluoride cyclized to l-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ether of melting point 216-221 ° (with decomposition) This is hydrolyzed analogously to Example E to give l-ethyl-5,6,7,8-tetrafluoro-1, 4-dihydro-4-oo-3-quinolinecarboxylic acid of melting point 223-225 ° (with decomposition).

25 Example G

F O

OOH

F is CH ₂ -CH ₂ -OH

Le A 25 079

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274 ö 29

If the reaction sequence described in Example F is carried out analogously with 2-aminoethanol, then excess 3- (2-hydroxyethylamino) -2- (p9ntafluoro-enzoyl) -acrylic acid ethyl ester (oil which crystallizes very slowly, R f value: 0, 7 [eluent S dichloromethane / MeUianol / 17 % aqueous ammonia solution 150: 20: 1; silica gel]) and 5,6,7,8-tetrafluoro-1,4-dihydro-1- (2-hydroxyethyl) -4-oxo S-quinolinecarboxylic acid ethyl ester (melting point: 200-203 ° with decomposition), the 5,6,7,8-tetrafluoro-1,4-dihydro-l- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid of

Melting point 192-194 ° (with decomposition) × 15

Example H

'COOH I' Il Il 20

10.1 g (0.032 mol) of ethyl 3-ethoxy-Z- (pentafluorobenzoyl) acrylate are initially charged in 12 ml of ethanol. Under ice-cooling, a solution of 2.5 g (0.033 mol) of 2-amino-1-propanol in 12 ml Ethanol added dropwise. The mixture is then allowed to stir for two hours at room temperature and then concentrated in vacuo. There are obtained 11.0 ς 2- (Pentafiuorbenzoyl) -3- (l-hydroxy-2-propylamino) -acrylic acid ethyl ester as a crude product (oil).

This crude product was heated to 140 ° C. with 5.8 g of potassium carbonate in 50 ml of dimethylformamide for four hours. After cooling to room temperature, water is added. The

Le A 25 079

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The precipitate is filtered off with suction, dried, stirred with acetonitrile and recrystallized from glycol monomethyl ether acetate,

Yield: 2.4 g (24.3 K) of 8,9,10-trifluoro-3-methyl-7-oxo-7H-pyridoCl, 2,3-deHl, 4] benzoxazine-6-carboxylic acid ethyl-

ester of melting point 251-2 ° (with decomposition). 10

2.0 g of this ester are heated together with 7 ml of acetic acid, 5 ml of water and 0.6 ml of sulfuric acid for four hours at 140 °. After cooling, it is mixed with water, the solid is isolated and dried. Yield: 1.5 g (91 X) 8,9,10-Trifluoro-3-methyl-7-oxo-7H-pyrido [l, 2,3-de] [1 _i 4] benzoxa7.in-6-carboxylic acid of melting point 300 ° (under Decomposition) «The recrystallization from dimethylformamide changes the

Decomposition point not »20

Le A 25 079

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example 1

F O

CHo-N N

30 g (0.1 mol) of 1-cyclopropyl-5,6,7,8-t * trafluoro-1-di-4-hydrox-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 200 ml of acetonitrile and 100 ml of dimethylformamide with 15 g (0.15 mol) of N-methylpiperazine and 16.5 g (0.165 mol) of 1,4-diazabicyclo [2 «2» 2] octane and heated under reflux for 3 hours. "The suspension is concentrated, the residue with Stirred water, the undissolved precipitate was filtered off with suction, washed with water and methanol and dried at 8J ¹ C / 12 mbar. Yield: 20.3 g (53.3 Ά of theory) of 1-cyclopropyl-5,6,8-trifluoro-l , 4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo · S-quinolinecarboxylic acid of melting point 210-220 ⁰ C (under Zeruetzung); after recrystallization from glycol monomethyl ether * Melting point 239-242 ° (with decomposition) «

Analogously to Example 1, the compounds of Examples 2 to 14 are obtained:

Le A 25 079

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274 O 29

Example 2 5

1-Cyclopropyl-7- (4-ethyl-1-piperrazinyl) -5-6 # 8-trifluoro-1-dihydro-oxo-S-quinolinecarboxylic acid of melting point 220-222 ° (with decomposition) ("us glycol monomethyl ether )

 10

Example 3

fluoro-1,4-dihydroc-7-C4- (2-hydroxyethyl) -1-piperazinyl] -4-0X0-3-quinolinecarbontonic acid of melting point 244-247 ° (with decomposition) (from glycol monomethyl ether)

Example 4

1-Cyclopropyl-5,6,8 "trifluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolecarboxylic acid of melting point 235-236 ° (with decomposition) (from glycol monomethyl ether) ,

25 Example S

fluor-1-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 257-258 ° (with decomposition) (from glycol monomethyl ether)

Example 6

SieiS-trifluoro-l, 4-dihydro-4-oxo-7- (lpiperazinyl) -3-quinolinecarboxylic & ur ·.

A 25 079

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Example 7 5

1-Cyclopropyl-5,6,8-trifluoro-1-dihydroM-oxo-3- (3-phenyl-1-piperazinyl) -3-quinolinecarboxylic acid of melting point 198-199 ° (with decomposition) (after purification by flash chromatography on silica gel with dichloromethane / methanol / 17 X ammonia [30: 8: 1] as eluant; R _f value: 0.7).

Example 8

1-Cyclopropyl-5,6,8-trifluoro-7- [3- (4-fluorophenyl) -l-piperazinyl] -l-4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 205-206 ° (with decomposition) ( from glycol monomethyl ether) «

²⁰ Example 9

1-Cyclopropyl-7- (1,4-diazabicycloC3.2.1] oct-4-yl) -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of

Melting point 319-321 ° (with decomposition). 25

Example 10

1-Cyclopropyl-5,6,8-trifluoro-l, 4-dihydro-7-morpholino-4-oxo-3-quinolinecarboxylic acid of melting point 296-300 ° (with decomposition) (purification by stirring with dichloromethane / methanol / 20 % Ammonia [2: 4: 1]).

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Example 11 5

1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-OX0-7- (1-pyrrolidinyl) -3-quinolinecarboxylic acid of melting point 314-316 ° (with decomposition) (from dimethylformamide).

¹⁰ Example 12

1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 281-282 ° (with decomposition) (from glycol monomethyl ether).

Example 13

1-Cyclopropyl-7- (3-ethylaminomethyl-1-pyrroleidinyl) -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate melting at about 260 ° (with decomposition).

Example 14

l-Cyclopropyl-S-trifluoro-1,4-dihydro-7- (1-imidazolyl) -4-oxo-3-quinolinecarboxylic acid of melting point 207-208 ° (with decomposition) (from glycolmethylmethyl ether).

Example 15 30

1.6 g (4.2 mmol) of the compound from Example 4 are dissolved in 5 ml of half-concentrated hydrochloric acid, the solution filtered and the filtrate with ethanol until precipitation

Le A 25 079

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of the hydrochlorides. The salt is filtered off with suction, washed with & ethanol and dried at 100 ° / 12. Yield: 1.1 g (63% of theory) of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7 (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 295 °

(with decomposition) «10

Example 16

Analogously to Example 15, the compound from Example 13 in 1-cyclopropyl ^ -O-ethylaminomethyl-l-pyrrolidinyl) -5,6,8-trifluoro-1 ^ -dihydro ^ -oxo-S-quinolinecarboxylic acid hydrochloride of melting point 298 ° converted (with decomposition),

Example 17 20

CH

13.2 g (34.6 mmol) of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid in 112 ml of pyridine with 56 ml of saturated ethanolic ammonia solution and heated for β hours at 120 ° in an autoclave. After cooling, the precipitated yellow crystallizate is filtered off with suction · washed with water and ethanol and dried.

Le A 25 079

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Yield: 9.3 g (71 S of theory) of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-β- (3-methyl-1-piperazinyl) -4-oxo. 3-quinolinecarboxylic acid of melting point 231-232 ° (with decomposition); after recrystallization, give glycol monomethyl ether melting point 239-242 ° (under

Decomposition). 10

If the reaction is carried out for 12 hours at 155 ° in an autoclave, then isolated the reaction product of melting point 231-233 ° (with decomposition) in 32 X yield

Mass Spectrum: m / e 378 (M ^4), 356, 343, 322 (100 K, MC ₃ H ₆ N), 278, 235, 180, 129, 70, 56, 41st

Example 18 a 20

₃ CH ₃ SO ₃ H

- ^ T ι

CH, F

300 mg (0.8 mmol) of the compound from Example 17 are suspended at 70 ° in 7 ml of ethanol and treated with 0.1 g of methanesulfonic acid. "The mixture is stirred without heating and allowed to cool overnight. The precipitate is filtered off with suction, washed with ethanol and dried at 80 ° / 0.1 mbar.

Le A 25 079

- 54 -

Yield: 260 mg (68.6 X of theory) of 5-amino-1-cyclopropyl-6,8-difluoro-1-dihydro-FO-diethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid. MethaneBuLfonate of melting point from 290 ° (with decomposition) «

C ₁₈ H ₂₀ F ₂ N ₄ O ₃ χ CH ₃ SO ₃ H (474)

calculated: C 48.1 H 5.1 NU ₁ BS 6.6 found! C 47.7 H 5.1 N 11.8 S 6.6

Example 18 b

HN N

COOH

χ HCl

29.5 g (78 mmol) of the compound from Example 17 are dissolved in about 700 ml of half-concentrated hydrochloric acid hot and filtered. The filtrate is cooled, the precipitated crystals are filtered off with suction, washed with ethanol and dried.

Yield: 26.9 g (83 % of theory) of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3- quinolinecarboxylic acid hydrochloride of melting point from 330 ° (with decomposition) «

Analogously to Example 17- the compounds of Examples 19 to 29 are obtained.

Le A 25 079

- 55 - 27402

Example 19 p

5-amino-1-cyclopropyl-6,8-difluoro-1-dihydro -? - (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 239-241 ° (with decomposition) (from glycolic

monomethyl ether) × 10

Example 20

5-Amino-1-cyclopropyl-7- (4-ethyl-1-piperazinyl) -6- 8-difluoro-1-dihydro-oxo-S-quinolinecarboxylic acid of melting point 220-222 ° (with decomposition) (from glycol monomethyl ether ) "

Example 21

S-Amino-l-cyclopropyl-6- »8-difluoro-l | 4-dihydro-7- [4- (2-hydroxyethyl) -4-oxo-3-quinolinecarboxylic acid of melting point 244-245 ° (with decomposition) (from glycol monomethyl ether).

25 Example 22

δ-Amino-1-cyclopropyl-Feie-difluoro-1,4-dihydro-7- (cis-3,5-dimethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 250-253 ° (with decomposition ) (from glycol monomethyl ether).

Le A 25 079

-56 -

Example 23 5

S-Amino-1-cyclopropyl-e1 -difluoro-1,4-dihydro-4-oxo-7- (3-phenyl-1-piperazinyl) -3-quinolinecarboxylic acid of melting point 242-243 ° (without decomposition) ( from glycol monomethyl ether) «10

Example 24

5-amino-1-eyelopropyl-6,8-UiFlUOr -? - [3- (4-fluorophenyl) -1-piperazinyl3-1,4-dihydro-4-oxo-3-chinolincarbonsaure ¹ ^ of melting point 252-255 ° (with decomposition) (from glycol monomethyl ether).

Example 25

² ^ ö-amino-1-cyclopropyl-? (1,4-diazabicycloC3.2.1] oct-4-yl) -6,8-difluoro-1 »4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 282-285 ° (with decomposition).

Example 26 25

5-Amino-1-cyclopropyl-6,8-d .1-fluoro-1,4-dihydro-7-morpholino-4-oxo-3-quinoi. »- carboxylic acid of melting point 287-290 ° (with decomposition ) (from glycol monomethyl ether)

 30

Lc A 25 079

Example 27 5

S-Amino-1-cyclopropyl-o, 8-difluoro-1,4-dihydro-4-oxo-7- (1-pyrrolidinyl) -3-quinolinecarboxylic acid of melting point 241-244 ° (with decomposition) ( from glycol monomethyl

ether). 10

Example 28

S-Amino-1-cyclopropyl-oiB-difluoro-1 »4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 258-259 ° (with decomposition) (from glycol monomethyl ether ).

Example 29

²⁰ 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1

imidazolyl) -4-oxo-3'-quinolinecarboxylic acid of melting point 268-270 ° (with decomposition) (from glycol monomethyl ether).

25 Example 3 0

NHp O

I * It

: οοΗ

X CHoSO-, Η

Le A 25 079

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0.9 g (2.6 mmol) of the compound from Example 29 are suspended in 10 ml of water and admixed slowly with 0.6 g (6.2 mmol) of methanesulfonic acid. After adding about 5/6 of the amount, the product is largely dissolved, then spontaneous crystallization occurs. The compact crystals are mixed with another 5 ml of water and brought into solution by heating. It is allowed to crystallize out slowly, stirred with 10 ml of ethanol, filtered off, washed with ethanol and dried at 100 ° / 0.1 rnbar. Yield: 0.87 g (75.7 X of theory) of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1-imidazolyl) -4-OXO-3 · quinolinecarboxylic acid. methanesulfonate of melting point 274-276 ° (with decomposition).

Example 31

NH ₂ 0

: oüh

₃ CH ₃ SO ₃ H χ 1.5 H ₂ O

0.3 g (0.76 mmol) of the product from Example 20 are suspended in 7 ml of ethanol at 70 ° and admixed with 0.1 g of methanesulfonic acid. The mixture is stirred without heating and allowed to stand for 2 days. The crystals are filtered off and dried at 80 ° / 1 mbar.

Yield! 0.38 g (97 X theory) of 5-amino-1-cyclopropyl-7- (4-ethyl-1-piperazinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. methanesulfonate hydrate

35 of melting point 271-273 ° (with decomposition).

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Example 32

C ₂ K ₅ -NH-CH ₂

NH-

0OH χ KCl χ 1.5 H ₂ O

11.1 g (27 mmol) of the compound from Example 13 are crosslinked in 70 ml of pyridine with 35 ml ethanolischsr ammonia solution and heated in an autoclave for 12 hours at 155 ° Kach cooling the precipitate is filtered off with suction, washed with water and 150 ml hydrochloric acid is dissolved. The solution is filtered, concentrated and the residue is diluted with ethanol. The undissolved hydrochloride is filtered off with suction, washed with ethanol and dried.

Yield: 5 g (39% of theory) of 5-amino-1-cyclopropyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. hydrochloride hydrate of melting point 225-229 ° (with decomposition); after recrystallization from glycol monomethyl ether: mp 245-250 ° (with decomposition).

30 C ₂₀ K _2A F ₂ N _{A O 3} χ HCl χ 1.5 H ^ C Calculated: C 51.1 H 5.9 N 11.9 Cl 7.6 Found: C 51.1 H 5.9 N 11, 8 Cl 7.6

Le A 25 079

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Example 33

CH ₃ -NN

COOH

2 # 5 g (65.5 mmol) of 1-cyclopropyl-5,6,8-trifluoro-1'-dihydro-? - (4-xnethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid are obtained in 15 ml of pyridine with 7.5 ml of saturated ethanolic Dimethylaminlosung and heated in an autoclave for 6 hours at 120 ° After cooling, is evaporated, stirred with about 25 ml of water and the precipitated product is filtered off, washed with water and dried.

Yields 0.8 g (30 * A of theory) of 1-cyclopropyl-5-dimethylamino-6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperrazinyl) -4-oxo-3-quinolinecarboxylic acid of Melting point 221-223 ° (with decomposition) «

Example '34

If the reaction is carried out with methylamine analogously to Example 33, l-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methylamino-7- (4-methyl-1-piperazinyl) -oxo-S is obtained. quinolinecarboxylic acid of melting point 226-229 ° (with decomposition) (from glycol monomethyl ether),

Le A 25 079

-i- 17 * 0 29

Example 35

If9 g (5 mmol) of 1-cyclopropyl-S, 8-trifluoro-1 ', 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid are dissolved in 20 ml of dimethyl sulfoxide with 0, 6 g of 1,4-diazabicycloC2 »2,2] octane and 370 mg (5.7 mmol) of 2-aminoethanol and heated to IfJO 140 ° for 2 hours. The mixture is evaporated, the residue is stirred with 20 ml of water, the precipitate is filtered off with suction and recrystallized from glycol monomethyl ether. Yield: 0.79 g (37.4 × of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro -S- (2-hydroxyethyltmino) -7- (4-methyl-1-piperazinyl) -4-oxo-3 "quinolinecarboxylic acid of melting point 189-190 ° ♦

Example 3 6

If, analogously to Example 35, cyclopropylamine is employed, the mixture is obtained in a thin manner and l-cyclopropyl-S-cyclopropylamino-fc, 8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-S carboxylic acid from Melting point 202-204 ° (with decomposition) «

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Example 37

If, analogously to Example 35, the starting compound is butylamine, »5-butylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3 is obtained quinolinecarboxylic acid of melting point 148-1490 (with decomposition),

Example 38

I O

'COOH

2.9 g (7.6 mmol) of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-0X0-3-quinolinecarboxylic acid.

acid in 30 ml of dimethyl sulfoxide with 1.7 g of 25

(15 mmol) of 1,4-diazabicycloC2 «2« 2] octyne and

While cooling with ice, about 450 mg of methylmercaptan are condensed in. The mixture is stirred without cooling and heated to 110 ° C. for 6 hours. After cooling, the suspension is poured into

Water added, the precipitate sucked off, with 30

Washed water and dried at 80 ° / 12 mbar «

Yield: 1.9 g (68 X of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methylmercapto-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid of Mp 225-235 ° (with decomposition); after Umkristalli-35

from dimethylformamide: mp 232-241 °

(with decomposition) «

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Example 39 5

1.9 g (5 nunol) l-cyclopropyl-5,6 _# 8-trifluoro-1,4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo-3-quinolinecarboxylic acid are dissolved in 15 ml of dimethyl sulfoxide with 1.1 g (10 nunol) of 1,4-diazabicyclo [2 «2« 2] octane and 660 mg (6 mmol) of thiophenol and heated to HO ⁰ C for 2 hours. The suspension is introduced into water, and the precipitate is filtered off with suction, washed with water and recrystallised from dimethylformamide.

Yield: 1.1 g (46.7 % of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-5-phenylthio 3-quinolinecarboxylic acid of melting point 234-236 ° (with decomposition) «

Example 40 30

The procedure according to Example 39 with Mercaptoessig-BBuremethylester as starting compound and receives 1-

Le A 25 079

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27402g

Cyclopropyl-6- | 8-difluoro-1,4-dihydro-5- (maihoxycarbonylmethylthio) -7- (4-methyl-1-piperazinyl) -4-OXO-3-quinolinecarboxylic acid of melting point 180-183 ° (with decomposition) ·

Example 41

HOOC-CH ₂ -S 0

CH ₃ -NN

0.4 g (0.86 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5- (methoxycarbonylmethylthio) -7- (4-methyl-1-piperazinyl) -4-oxo 3-quinolinecarboxylic acid are added in 2.7 ml of acetic acid and 1.5 ml of water with 0.3 ml of concentrated sulfuric acid and heated to 150 ° for 2 hours. The solution is introduced into ice-water, and the precipitate which has precipitated out is filtered off with suction, washed with water and dried at 80 ° C./12 mbar.

Yield: 390 mg (100 X of theory) of 5-carboxymethylthio-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid of Melting point from about 265 ° (with decomposition) ·

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Example 42

F O

CH ₃ -NN

Analogously to Example 1, N-methylpiperazine is reacted with 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 1-ethyl-5,6,8 -trifluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinoincarboxylic acid of melting point 214-216 ° (with decomposition).

Example 43

NH ₂ O

CH ₃ -N

Analogously to Example 17, the compound from Example 42 is reacted with ammonia to give 5-amino-1-ethyl-6 _# 8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3- quinolinecarboxylic acid of melting point 246-248 ° (with decomposition).

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Example 44

CH ₃ -NN

F O

COOH

F CH ₂ CH ₂ -OH

Analogously to Example 1, N-methylpiperazine is added

5,6,7,8-tetrafluoro-1,4-dihydro-l- (2-hydroxyethyl) -4-oxo ·

S-quinolinecarboxylic acid to yield S, 6,8-trifluoro-1 , A-

dihydro-1- (2-hydroxyethyl) -7- (4-methyl-1-piperazinyl) -4-oxo-S-quinolinecarboxylic acid of melting point 210-211 °

(with decomposition) ·

Example 45

NH ₂ Ο

CH ₃ -N

COOH

CH ₂ CH ₂ -OH

Analogously to Example 17, the compound from Example 44 with ammonia is converted into 5-amino-6,8-difluoro-1,4-dihydro-1- (2-hydroxyethyl) -7- (4-methyl-1-piperazinyl) -4- oxo-3-quinolinecarboxylic acid implemented «

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Example 46

F O

CH ₃ -NN

COOH

Analogously to Example 1, N-methylpiperazine is reacted with the precursor of Example 4 to obtain 8,9-difluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyridoCl, 2,3 -de] [l »4] benzoxazine-6-carboxylic acid.

Example 47

NH ₂ 0

CHo-N N

COOH

The product from Example 46 is reacted with ammonia analogously to Example 17 to give S-amino-9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,3,3-deHl, 4] benzoxazine-6-carboxylic acid of melting point 289-290 ° reacted (with decomposition)

Le A 25 079

Claims (5)

Y is amino, optionally substituted by amino, hydroxy or methoxy alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, Cyoloalkylamino having 3 to 6 carbon atoms, alkoxyamino having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 Carbon atoms, mercapto, optionally by. Ethoxycarbonyl, carboxy or hydroxy-substituted alkylthio having 1 to 4 carbon atoms, phenylthio, hydrazine *), hydroxyamino, methoxyamino, chlorine, R is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, Amino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- / 4- (2-oxopropyl) -1-piperazinyl _- 7 = "3 = O" inoline carboxylic acid, i-Oyolopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-2f "4- (3-oxobutyl) -1-piperazinyl _e 7-3-chlorolincarbonic acid. / i-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4 "OXo-7- (3-phenyl-1-piperazinyl) -3-quinolinoic acid, / i-Cyolopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1-imidazolyl) -4-oxo-3-ohinolincarboneäure, i -olopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- (1-pyrrolyl) -3-quinolinecarboxylic acid. 6. The method according to claim 1, characterized in that one comprises compounds auj the group consisting of 5-amino-7- / 3- (aminomethyl) -1-pyrrolidinyl _# _7-1-cyolopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-1-cyclopropyl-7- / 3- (3-methyl) -methyl-7-pyrrolidinyl-8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 5-amino-1-cyclopropyl-7- / 3-Z "(ethylamino) methyl_7-1-pyrrolidinyl_7-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-Amino-7 "/ ~ 3-amino-1-pyrrolidinyl__7-1-cyolopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, SH 5-amino-1-oxypropyl-7- / 3- (ethylamino) -1-pyrrolidinyl-7,6,8-difluoro-1, A- py / ZZ methyl thyl) amino-7-methyl-1-pyrrolidinyl-7-4-oxo-3-quinolinecarboxylic acid, 5-amino-7- / 3- (aminomethyl) -1-pyrrole-idinyl-7-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 5-Amino-1-cyolpropyl-7 - / "" 3- (- ethylamino) methyl_7-1-pyrrolidinyl_7-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine -3-carbon8äure, 5-Amino-7 - / "3-amino-1-pyrrolidinyl_7-1-oyclopropyl-1,4-dihydro-5-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 5-Amino-7- / ~ 3- (aminomethyl) -1-pyrrolidinyl_7-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 5-Araino-7- / ~ 3- (aminomethyl) -1-pyrrolidinyl_7-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-chinolinoarbonsäure, 5-amino-7- / 3- (aminomethyl) -1-pyrrolidinyl _- 7-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-ohi.nolincarboxylic acid, 5-amino-7 - /, "" 3- (aminomethyl) -1-pyrrolidinyl __7-6,8-difluoro-1-ethenyl-1,4-dihydro-4-oxo-3-quinoleacarbonyic acid, 5-Amino-1-ethyl-7 - / "" 3-Z "" (ethylamino) methyl-7-1-pyrrolidinyl _> _7-6-fluoro-1,4-dihydro-4-oxo-1, e -naphthyridine-3 carboxylic acid, 5-amino-1-e thyl-7 "/" 3 "* Z" ^(θ methylamino) me thyl__7-1 pyrrol id iny I _- / 6,8-difluoro-1,4-dihydroergotamine ^<: lro-4- oxo-3-quinolinecarboxylic acid, 5-amino-7- / ~ 3 - /. ~ "(Β-thylamino) ine-tyl_7-1 -pyrrolidinyl__7-6> 8-difluoro-i-C 1 -fluoroethyl-i-dihydro-oxo-o-amino-quinolone aäure, 5-amino-1-ethenyl-7- / 3-hydroxyethyl 1-6,8-difluoro-1,4-dihydro-4-oxo-3-ohinolinoic acid, 5-Amino-1-ethyl-6-fluoro-1,4-dihydro-7 ~ / ~ * 3- / ~ 2f "(1-methylethyl) -amino ^ / m®-thy 1 ^ 7-1 -pyrrolidinyl_7" -4-oxo-1,8-naphthyridine-3-carboneäure, 5-amino-1-ethyl-7 - /, * "3- / _l ~" d "^'me'''^{': l} yl ^e' ''^{': i} yl) aminomethyl ^ -ipyrrolidinyl_7-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-Amino-1-ethyl-6-fluoro-1,4-dihydro-7- (7-methyl-2,7-diazaspiro ι4_7non-2-yl) -4-OXO-1,8-naphthyridine-3-carboxylic acid . 5-amino-1-ethyl-6,8-difluoro-1,4-dihydro-7- (7-ethyl-2,7-diazaspiro / ~ 4,4_7non-2-yl) -4-oxo-3-quinolinecarboxylic acid . 5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (7-methyl-2,7-diaza8piro / ~ 4 »4_7non-2-yl_7" -4-oxo-3-chinolinoarbonBäure . 5-Amino-7- (3-amino-1-pyrrolidinyl) -1 ~ ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-i-cyclopropyl-6-fluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-ohinolinoärbonsäure, 5-amino-1-cyolopropyl-6-fluoro-1,4-dihydro-7- (3-b.ydroxy-1-pyrrolidinyl) -4-oxo-3-chinolinoarbonsäure, 5-Jtoino-1-oxypropyl-7- (1,4-diazabicyclo) -3,2,1_7-oot-4-yl] 1 -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine -3 "Carbonßä'ure, L-6,8-difluoro-1,4-dihydro-7- (2-methyl-J, 2.1 _- 7oot-4-yl) -4-oxo-3-chinolincarbonsaure, 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- (4-isopropyl-1-piperazinyl) -3-quinolinecarboxylic acid, 7- (4-allyl-1-pi. perazinyl) -1-cyolopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-chinolinoarbonsäure, 1-cyclopropyl-5 "6,8-trifluoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylic acid, 1-Oxypropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-morpholino-3-quinolinecarboxylic acid, 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- (3-niethyl-1-piperazinyl) -3-quinolinecarboxylic acid, i-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- (3,5-dimethyl-1-piperazinyl) -3-quinolinecarboxylic acid, 1-cyclopropyl-5 'b, 8-trifluoro-1,4-dihydro-4-oxo-7- (4-ethyl-1-piperazinyl) -3-quinolinecarboxylic acid, i-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (4- (2-hydroxyethyl) -1-piperazinyl-7-7-oxo-3-quinoline-carboxylic acid, 1-Oyclopropyl-5 "6,8-1rifluor-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-chinolincarbonaäure, i-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid, 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo / ~ 3,2,1_7oct "3-yl) -4-oxo-3-chinolinoarbonsäure 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7 ~ (2-methyl-1,4-diazabicyclo / "3" 2,1_7oct-4-yl) -4-oxo-3 chinolincarbonaäure, 1-Cyclopropyl-7- (1,4-diazabicyclo) -3- (2,1-octo-4-yl) -5,6-difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 carbonaäure, 1-Cyclopropyl-7- (1,4-diazabicyclo / ~ 3,2,1 __7oct ~ 4-yl) -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolino-carboxylic acid, 1-Cyölopropyl-5 '6-difluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-chinolinoarbonsäure, 1-ethyl-5-α-α-lacto-6,8-difluoro-7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-3-chitiolin ocarboxylic acid and also excluding 8-amino-9- f luor-3-methyl-10- (heterocyclyl) -7-oxo-2,3 -. ^ ihydro-TH-pyrido / fi, "carboxylic acids 4_7benzoxazin-6-2,3-άβ_7 /" 1 ₁ and 1-ethyl -5-amino-6,8-dichloro-7- (heterooyolyl) -4-oxD «Hi, 4-dihydro-3-quinolino-carboxylic acids in which hetero-o-ol-3-amino-i-pyrrolidinyl, 3- (amino-methyl) - 1-pyrrolidinyl, 3- (ethylaminomethyl) -1-pyrrolidinyl, 2,7-diazaspiro / 4,4_7non-2-yl and 7-methyl (or ethyl.) * "-2,7-diazaspiro / 4,4 ~ _- 7non-2-yl, and 5-amino-7- (3-amino-i-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridinecarboxylic acid, and excluding compounds in which R ^ for the remainder R ⁶ , R ⁴ -N ^{? K} N- R 1, R 1 and R 4 are H or C ¹ -C 4 -alkyl, when R ^{1 is} cyolpropyl, X is fluorine, Y is amino, hydroxy or C ¹ -C -alkoxy and AN, r 'is halogen or H, R is H and their acid addition salts and compounds in which Y is amino or fluoro, R is cyclopropyl and X is fluorine, A is OP and R ^ R ' N- RfI »RIMI means wherein R 'is H or OH ₃₁ R "H, OH, or O ₂ H ₅ , R"> and R "» are H or methyl, and R is H, CH ~ or CgH, -, consists. 2 * Process according to Claim 1, characterized in that 5-substituted quinolone- and naphthyridono-carboxylic acid derivatives of the formula (I) in which X is fluorine or chlorine, Y is amino, optionally substituted by amino, hydroxy or methoxy substituted alkylamino with 1 to 2,4'-ifluorphenyi, R ^{2 is} hydrogen, alkyl of 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl and R ^ is methyl or a cyclic amino group such as R ⁷ _R 6 R ⁴ stands in which R ^{4 is} hydrogen, alkyl of 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, pormyl, benzyl, 4-aminobenzyl or (5-methyl-2-oxo-1,3 -dioxol-4-yl) methyl, R ^{5 is} hydrogen or methyl, R ^{6 is} hydrogen, alkyl having 1 to 4 carbon atoms, optionally substituted, in particular fluorine-substituted phenyl or benzyloxymethyl, R? for hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylimidylthiol, isopropylaminomethyl, hydroxy or hydroxymethyl, R ^{8 is} hydrogen, methyl, ethyl, fluorine or chlorine, A is N or C-R ^ in which R ^ is hydrogen, halogen such as fluorine or Ohlor, methyl, cyano or nitro or together with R a bridge of the structure -O-CH ₂ -CH-CH ₃ , -S-CH ₂ -CH-CH ₃ or -CH ₂ -CH ₂ -CH-CH ₃ can form and their pharmaceutically usable hydrates and acid addition salts, and the alkali, alkaline earth, silver and guanidinium salts of the basic carboxylic acids, excluding 8-amino-9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7- oxo-2,3-dihydro-7H- -pyrido / ~ * 1,2,3-de _- 7/4 -7-benzoxazine-6-carboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7- (1-piperazinyl) -4-oxo -1,4 ~ dihyero-3-quino1.1-carboxylic acid, 1-ethyl-5-beta: ηη-6,8-difluoro-7- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro 3-quinolino-carboxylic acid and also excluding 8-amino-9-fluoro-3-methyl-10- (hetero-oxyl) -7-oxo-2,3-dihydro-7H-pyrido / 1,2,3-de _- 7 / 'i, 4 _- .7ben25Oxazin-6-carboxylic acid] n and 1-ethyl-5-amino-6,8-difluoro-7- (heterooyolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acids _> in which Hetsrooyolyl 3-Amino-i-pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3- (ethylaminomethyl) -1-pyrrolidinyl, 2,7-diazaspiro "" 4,4 _- 7non-2-yl and 7-methyl (or ethyl) -2,7-diazaspiro / ~ 4,4_7non-2-yl, and 5-amino-7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4 -dihydro-4-OXO-1,8-naphthyridino-arabic acid, characterized in that compounds of the formula (II) I " in which 12 1
X, R, R, R 'and A are as defined above to have, with compounds of the formula (III) Yr-H (III), 274 02o in v / elcher Y has the meaning given above, if appropriate in the presence of acid scavenger " ¹ converts * 3,8-diazabio-yl-ol / ~ 3 »2, 1 -7-o-3-yl) -4-oxo-3-quinolinecarboxylic acid, 3. Method according to Anspn ch 1, characterized ge characterized in that compounds of formula (I), in the X for fluorine, Y is amino, alkyl, optionally substituted by amino, hydroxy or methoxy, having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, cyclopropylamino, alkoxyamino having 1 to 3 carbon diseurate, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, optionally substituted by ethoxycarbonyl, carboxy or hydroxy alkylthio having 1 to 4 carbon atoms, phenylthio «hydroxyamino, R ^{1 is} ethyl, isopropyl, cyolpropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, phenyl, 4-chlorophenyl or 2,4-difluorophenyl, R ^{2 is} hydrogen, alkyl having 1 to 3 carbon atoms, (5-methyl-2-oxo-i, 3-dioxol-4-yl) -methyl, R- ^ for a cyclic amino group such as N-, ίN ₇ , HO \ N , -, R ⁴ -N p. R ° R O N, ^ - U stands in which R ^{4 is} Waaaerstoff, alkyl mib 1 to 3 carbon atoms, 2-hydroxyethyl _t allyl, 2-oxopropyl, 3 'oxobutyl. Phenaoyl 9 Benzyl _4, 4-aminobenzyl, (5 ~ methyl-2-oxo-1,3-dioxol-4-yl) methyl, R ^{5 is} hydrogen or methyl, R ^{6 is} hydrogen, alkyl having 1 to 2 carbon atoms, phenyl, 4-fluorophenyl, R 'is hydrogen, amino, aminomethyl, methylamino-methyl, ethylaminomethyl, dimethylaminomethyl, hydroxy or hydroxymethyl, _R 8 is hydrogen or methyl; A is N or CR ⁹ wherein 274 O for V / asaerstof.f, halogen such as fluorine or chlorine or ai
the structure stands or together with R e: ln bridge -CH-CHo or -CH ₀ -CH ₀ -CH-CHo cι3 ddt j can form and their pharmaceutically usable hydrates and acid addition salts, and the alkali, alkaline earth, silver and guanidinium salts of the basic carboxylic acids, with the exception of 8-amino-7-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo "£ i, 2,3-de_7" 2,3-dihydro-7H-pyrido / \, 4_7benzoxazin-6-oarbonsäure, 1-ethyl-5-amino-6,8-difluoro-7- (1-piperazinyl) - 4-oxo-1,4-dihydro-3-quinolino-carboxylic acid, 1-ethyl-5 · -amino-6,8-difluoro-7- (4-methyl-1- pipaxaxyl ) -4-cxo-i, 4 -dihydro-3-quinolino-carboxylic acid and excluding 8-amino-9-fluoro-3-methyl-10- (heterocycyl) -7-oxo-2,3-dihydro-7H-pyrido / 1,2,3-de_7 / ~ 1,4_7 benzoxazine-6-carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heterocyclyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acids in which heterooyolyl is 3-amino 1-pyrrolidinyl, 3- (aminomethyl) -1-pyrrolidinyl and 3- (ethylsminomethyl) -1-pyrrolidinyl, and 5-amino-7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. , 4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylic acid, -S, 8-difluoro-1,4-dlhydro-4-oxo-7- (4-i8opropyl-1-piperazinyl) -3-ohinolincarbon8äure, 5-amino-7 - »(4-allyl-1-piperazinyl) -1-oxypropyl-6,8-difluoro-1,4-d, yro-4-oxo-3-clolinequinonecarboxylic acid, -e, 8-difluoro-1,4-dihydro-4-oxo-7- ^ 4- (2-oxopropyl) -1-piperazinyl-7-3-oxyquinolinecarboxylic acid, -e, 8-fluoro-1,4-dihydro-4-oxo-7- / 4- (3-oxobutyl) -1-piperazinyl _t _7-3-quinolino-carboxylic acid, - 87 - -O, 8-fluoro-1,4-dihydro-4-oxo-7- (1-pyrrolyl) -3-ohinolinoarbonsäure, 5-amino-7 - / '' 4- (4-arainobenzyl) -1-piperazinyl-7-1-ethylolpropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-ohinoline carboxylic acid, , 4-dihydro-4-oxo-7- (1-piperazinyl) -3-chinolinoarbonsäure, 4 · Process according to Claim 1, characterized in that compounds of the formula (I) in which X for fluorine Y is amino, optionally amino, hydroxy or methoxy substituted alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, cyolopropylamino, methoxyamino, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, optionally by ethoxycarbony. ¹ , carboxy or hydroxy-substituted alkylthio having 1 to 4 carbon atoms, phenylthio, R is ethyl, cyolpropyl, 2-hydroxyethyl, 4-huorophenyl or 2,4-difluorophenyl, R ^{2 is} hydrogen, alkyl having 1 to 2 carbon atoms R ^ for a cyclic amino group such as _R 7. R ⁶ N-, ίN- , HO- / N-, R ⁴ -N ? - · 5? - · ¹¹ ^ Jr ' LJ L = ^ Z \ T ^ ^M - stands in which R ^{4 is} hydrogen, alkyl having 1 to 2 carbon atoms, 2-hydroxyethyl, 2-oxopropyl, 3-oxobutyl, Phena cy1, 4-aminobenzyl, R ^{5 is} hydrogen or methyl, R is hydrogen, methyl, phenyl, 4-ELuorphenyl, R 'is hydrogen, amino, aminomethyl, methylaminomethyl, ethylaminomethyl, hydroxy or hydroxymethyl, R ^{8 is} hydrogen, A is N or CR ^ wherein Br is hydrogen, halogen, such as fluorine or chlorine -j stands or together with R a bridge the structure -O-CH ₂ -CH-CH ₃ can form and their pharmaceutically usable hydrates and acid addition salts, and the alkali, alkaline earth, silver and guanidinium salts of the basic carboxylic acids, other than 8-amino-9-fluoro-3-niethyl-10- (4-methyl-1-piperazinyl) - 7-oxo-2,3-dihydro-7H-pyrido ~ 1,2,3-de__7 / ~~ 1,4_7-benzoxazine-6-carboxylic acid, 1-ethyl-5-amino-6,8-difluoro-7 (1-piperazinyl) -4-oxo-1,4-dihydro-3-ohinolino-carboxylic acid 1-ethyl-5-amino-6,8-difluoro-7- (4-niethyl-1-piperazinyl) -4-oxo 1,4-dihydro-3-quinolinecarboxylic acid and also excluding 8-amino-9-fluoro-3-niethyl-10- (heterocyclyl) -7-oxo-2,3-dihydro-7H-pyrido ["i, 2,3 -de_7Z ~ 1,4_7benzoxazin- 6-carboxylic acids and 1-ethyl-5-amino-6,8-difluoro-7- (heterocyclo) -4-oxo-1,4-dihydro-3-ohinolino-carbonic acids in which hetero-oxylyl is 3-amino-1-pyrrolidinyl , 3- (Am ± no-diethyl) -1-pyrrolidinyl or 3 ~ (ethylaminoethyl) -1-pyrrolidinyl, and 5-amino-7- (3-araino-1-pyrazole; 1-dinyl) -1 ethyl 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, Process according to Claim 1, characterized in that compounds from the group consisting of 1-cyclopropyl-5,6-difluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3- quinolinecarboxylic acid, i-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid, 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms per alkyl group, cycloalkylamino having 3 to 6 carbon atoms, alkoxyamino having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, mercapto, optionally substituted by ethoxycarbonyl, carboxy or hydroxy alkylthio with 1 to 4 Carbon atoms, phenylthio, hydrazino, hydroxyamino, methoxyamino, chloro, R is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl,  75- is hydrogen, alkyl of 1 to 4 carbon atoms or (5-methyl-2-OXO-1,3-dioxol-4-yl) -methyl and for methyl or an oyolisohe amino group such as R ¹ N-, N, HO R- stands in which is hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenoyl, pormyl, benzyl, 4-aminobenzyl or (5-methyl-2-oxo-1,3-dioxole -4-yl) · methyl, R ^{5 is} hydrogen or methyl, R ^{6 is} hydrogen, alkyl having 1 to 4 carbon atoms, optionally substituted, in particular fluorine-substituted phenyl or benzyloxymethyl, R 'is hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, isopropylaminomethyl, hydroxy or hydroxymethyl, R ^{8 is} hydrogen, methyl, ethyl, fluorine or chlorine, A is N or C-R ^ in which R ^ is hydrogen, halogen such as fluorine or chlorine. Methyl, cyano or nitro stands or together with R a bridge of the structure -0-CH ₉ -CH-CH-, -S-CH ₉ -CH-CHO or -CH can -CHO _0-CH-CH-, form, and their pharmaceutically usable hydrates and acid addition salts, and the alkali, alkaline earth, silver and guanidinium salts of the basic carboxylic acids, with the exception of 8-amino-S-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7- oxo-2,3-dihydro-7H-pyrido / "" i, 2, 3-aeJfi , 4_7-benzoxazine-6-carboxylic acid, 1-ethyl-S-amino-ö, 8-difluoro-7- (1-piperazinyl) -4-0x0-1,4-dihydro-3-ohinolino-carboxylic acid _y 27402ο -? s · ^y 5-Am: too-1-cyclopropyl ~ 6,8-difluoro-1,4-dihydro-4-oxo-7- (4-phenaoyl-1-piperazinyl) -3-chinolinoarbonsäure, S-8-amino-9-fluoro-3-methyl-10- (4-methyl-1-pipera-2-ynyl) -7-oxo-7H-pyrido / 1,2,3-de _- 7/1 4_7benzoxazine-6-carboxylic acid.