DD265401A5 - PROCESS FOR THE PREPARATION OF 7- (AZABICYCLOACYL) -QUINOLINE CARBOXYLIC ACID AND NAPHTHYDRIDE CARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

According to the invention, novel 7- (azabicycloalkyl) -quinolonecarboxylic acid and naphthyridonecarboxylic acid derivatives of the general formula (I) are prepared in which, for example: R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl and the like. ae .; R 2 is hydrogen, alkyl having 1 to 4 carbon atoms and the like ae .; R3 is a radical of the formula N (CH 2) n N u. ae; X1 fluorine, chlorine or nitro; A N or C-R6; R6 is hydrogen, fluorine, methyl, nitro and the like. a. Formula (I)

Description

Y N

ZN

in which

Y for R ⁴ -N, O, S,

Z is - (CH ₂ ) _n -, - CH ₂ -O-CH ₂ -, - CH ₂ -S-CH ₂ -, - CH ₂ -S-,

-CH ₂ -N-CH ₂ -,

η for 1,2 or 3,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms, optionally substituted by nitro or amino-substituted benzyl,

Oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl and R ^{6 is} hydrogen or methyl, X ^{1 is} fluorine, chlorine or nitro and A is N or CR ⁶ is in which

R ^{8 represents} hydrogen, fluorine, chlorine, methyl or nitro or together with R ^{1 represents} 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 underlying carboxylic acids.

Field of application of the invention

The present invention relates to a process for the preparation of novel 7- (A2abicycloalky)) -quinolonecarboxylic acid and -naphthyrldonecarboxylic acid derivatives as well as antibacterial agents and feed additives containing them.

Characteristics of the known state animal technology

It has already been disclosed that i-ethyl-e-fluoro-M-dihydro ^ -oxo ^ -d-piperazinyl-S-quinolinecarboxylic acids (German Pat. Nos. 2084097 and 2939786), 1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acids (EP-PS 49355, DE-PS 3142854), 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- ( 1-piperazinyl) -1,8-naphthyridine-3-carboxylic acids (Japanese Patent Publication No. 60032790), g-fluoro-S-dihydro-S-methyl-o-oxo-IO-d-piperazinyl-D-H-pyridolino-1,3-delli ^ lbenzoxacin-e-carboxylic acids (EP-PS 47005), i-aryl-efluoro-IAdihydro ^ -oxo ^ -d-piperazinyO-S-quinolinecarboxylic acids (EP-PS 131839) and Azabicycloalkylchinoloncarbonsäuren (EP-PS 159174) are antibacterially effective.

Object of the invention

Ziol of the invention is the provision of new compounds with high anti-microbial activity, especially in the gram-positive area.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired property and process for their preparation.

It has been found that the novel 7- (azabicycloalkyl) -quinonecarboxylic acid or -naphthyridonecarboxylic acid derivatives of the formula (I)

COOF ²

(D,

in which

R ^{1 is} methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamines), dimethylamines phenyl, 4-fluorophenyl, 2,4-difluorophenyl,

R ^{2 is} hydrogen, alkyl of 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, R ^{3 is} a radical of the formula

N- (CHO-N-, YZN-, YZN-,

in which

Y for R ⁴ -N, O, S,

Z represents - (CH j) _n -, -CHH) -CH ;, -CH ₇ -S-CH ₇ -, -CH ₇ -S-,

T is -CH ₂ -N-CH ₂ -,

η for 1,2 or 3,

R ^{4 is} hydrogen, optionally substituted by hydroxy alkyl, alkenyl or alkynyl with 1 to 4 carbon atoms, optionally substituted by nitro or amino-substituted benzyl, oxoalkyl having 2 to 4 carbon atoms or

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, R * is hydrogen or methyl, X ^{1 is} fluoro, chloro or nitro "A is N or CR ^e , in which

R ^{6 is} hydrogen, fluorine, chlorine, methyl or nitro or together with R 'is a bridge of the structure -0-CH ₇ -CH-OH ₃ , -S-CH ₇ -CH-CH ₃ or -CH ₇ -CH ₇ -CH-CH ₃

can form

with the proviso Diss for the case that X 'represents fluorine, R ² and H and A is CF or N, and R' is ethyl, cyclopropyl, fluoroethyl or Vi nyl ste ht Odir R ^e where R ¹ a bridge of the structure -O-CH ₇ -CH-CH ₃ , η is not equal to 2 and R ^{3 is} not the radical R ⁴ - N ^ Λ N - 'tenone, and 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 have a high antibacterial effect especially in the gram-positive region.

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

The invention further provides 7- (azabicycloalkyl) -quininocarboxylic acid or -naphthyridonecarboxylic acid derivatives of the formula (I)

COOR ²

(D,

in which

R ^{1 is} methyl, ethyl, propyl. Isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, Dimethylamines, phenyl, fluorophenyl, 2,4-difluorophenyl,

R ^{2 is} hydrogen, alkyl having 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, R ^{3 is} a radical in the ring system by hydroxy or methyl mono- or polysubstituted radical the formula

N- (CHO) -N-, YZN-, YZN-, YZN-,

in which

Y for R ⁴ -N, O, S,

Z represents - (CHj) _n -, -CHt-O-CHt-, -CHi-S-CH ₂ -, -CH ₇ -S-,

R ⁵ -CH ₂ -N-CH ₂ - *

η for 1,2 or 3,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl with ibis 4 carbon atoms,

optionally substituted by nitro or amino-substituted benzyl, oxoalkyl having 2 to 4 carbon atoms or

(5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl and R ⁵ isWaeserstoffoder methyl, X ^{1 is} fluorine, chlorine or nitro and A is N or CR *, wherein

R ^{6 represents} hydrogen, fluorine, chlorine, methyl or nitro or together with R 'a bridge of the structure

-O-CH ₇ -CH- ^ H ₃ , -S-CH ₇ -CH-CH ₃ or -CH ₇ -CH ₇ -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 underlying carboxylic acids

 Preference is given to those compounds of the formula (I) in which R 'is methyl, ethyl, cyclopropyl, 2-hydroxyethyl, vinyl, 2-fluoroethyl, methoxy, methylamino, phenyl, 4-fluorophenyl,

2,4-difluorophenyl, R ^{7 is} hydrogen, methyl, ethyl, R ^{3 is} a radical of the formula

Y ^ N-.

in which

Y for R ⁴ -N, O,

F ^{5 represents} - (CH ₂ J _n -, -CH ₂ -O-CH ₂ -, -CH ₂ -N-CH ₂ -,

η for 1,2 or 3,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms,

optionally substituted by nitro or amino substituted benzyl or oxoalkyl having 2 to 4 carbon atoms and R ^{5 is} hydrogen or methyl, X 'is fluorine, chlorine or nitro and A is N or CR *, wherein

R ^v "stands for hydrogen, fluorine, chlorine, methyl or nitro or you share with R 'olna bridge of the structure

-O-CH ₇ -CH-CH ₃ OdOr-CH ₇ -CH ₇ -CH-CH ₃

can form

with the proviso that in the event that X ^{1 is} fluorine, R * and H and A is CF or N and R ^{1 is} ethyl, cyclopropyl, fluoroethyl or vinyl or R * with R 'is a bridge of SImICtUr-O -CH ₇ -CH-CH ₃ forms, η not equal to 2 hit and R ¹ not for the rest

R ^ - N ^ \ N - and 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 and the alkali, alkaline earth, silver and

Guanidinium salts of the underlying carboxylic acids. Particular preference is given to those compounds of the formula (I) in which R 'is ethyl, cyclopropyl, 2-fluoroethyl, vinyl, methylamines, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R ^{2 is} hydrogen, methyl, ethyl, R ^{3 is} a radical of the formula

J, T N, YZ

in which

Y for R ⁴ -N,

Z Wr- (CH ₂ I _n -,

n for 1 or 2,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms,

optionally substituted by nitro or amino benzyl or oxoalkyl having 2 to 4 carbon atoms and R ^{5 is} hydrogen or methyl, X 'is fluorine, chlorine or nitro and A is N or CR ", wherein

R * represents hydrogen, fluorine, chlorine or nitro or together with R ^{1 represents} a bridge of the structure

-O-CHj-CH-CH ₃ or -CH ₂ -CHHpH-CH ₃

can form

with the proviso that in the event that X 'is fluorine, R ^{2 is} H and A is CF or N, and R ^{1 is} ethyl, cyclopropyl, fluoroethyl or vinyl, then R ^{e is} a bridge of structure -0-CH ₂ -CH-CH ₃ forms, η is not equal to 2 and R ³ nichi for the rust

& ^R \ T ^s

R ^ -N \ N - may stand, 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 and the alkali, alkaline earth, silver and

Guanidinium salts of the underlying carboxylic acids. Preference is also given to those compounds of the formula (I) in which R ^{1 represents} methyl, ethyl, cyclopropyl, 2-hydroxyethyl, vinyl, 2-fluoroethyl, methoxy, methylamines, phenyl, 4-fluorophenyl,

2,4-difluorophenyl, R ^{7 is} hydrogen, methyl, ethyl, R ^{3 is} a mono- or polysubstituted, preferably 2-fold, methyl-substituted radical of the formula

Y Z N, Y Z N, YZN

in which

Y for R ⁴ -N, O,

Z I

for - <CH ₂ ) _n -, -CH ₂ -O-CH ₂ -, -CH ₂ -N-CH ₂ -,

η for 1,2 or 3,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms,

optionally substituted by nitro or amino-substituted benzyl or oxoalkyl having 2 to 4 carbon atoms and R ⁶ stands for hydrogen or methyl, X 'is fluorine, chlorine or nitro and A is N or CR ", wherein

R ^{6 is} hydrogen, fluorine, chlorine, methyl or nitro or together with R 'is a bridge of the structure. -O-CH ₂ -CH-CHL-S-CH ₂ -CH-CH ₃ OdOr-CH ₂ -CH ₂ -CH-CH ₃

can form

with the proviso that in the event that X 'is fluorine, R ² and H and A is CF or N and R ^{1 is} ethyl, cyclopropyl, fluoroethyl or vinyl or II * with R ^{1 is} a bridge of structure -0 -CH ₂ -CH-CH ₃ forms, η is not equal to 2 and R ^{3 is} not the radical and its pharmaceutically usable hydrates and acid addition salts and the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids. Also particularly preferred are those compounds of the formula (I) in which R 'is ethyl, cyclopropyl, 2-fluoroethyl, vinyl, methylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R ^{2 is} hydrogen, methyl, ethyl, R ^{3 is} a one or more times in the ring system, preferably 2 times, substituted by methyl radical of the formula

N - (CH ₂ ) WW-, Y.Z N-, YZ ^ N-,

in which

Y for R ⁴ -N,

Z is - (CH ₂ ) _n -,

η for 1 or 2,

R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms,

optionally substituted by nitro or amino benzyl or oxoalkyl having 2 to 4 carbon atoms and R ^{5 is} Wassbrstoff or 'methyl, X' is fluorine, chlorine or nitro and A is N or CR ⁶ , wherein

R ^{6 represents} hydrogen, fluorine, chlorine or nitro or together with R ¹ a bridge of the structure

-O-CHHfH-CH ₃ OdOr-CH ₇ -CHi-CH-CH ₃

can form

and their pharmaceutically usable hydrates and acid addition salts and the alkali, alkaline earth, silver and guamdinium salts of the underlying carboxylic acids. Furthermore, it has been found that the compounds of the formula (I) are obtained when compounds of the formula (II)

COOR ²

in which R ¹ , R ² , X 'and A have the abovementioned meaning and X ^{2 is} halogen, in particular fluorine or chlorine, with azabicycloalkanes of the formula (III)

R ³ -H (III),

in which R ^{3 has} the abovementioned meaning, if appropriate in the presence of acid-binding agents

(Method A).

Compounds of the formula (I) according to the invention

COOR ²

(D,

in which

R ¹ , R ^? , A and X ^{1 have} the abovementioned meaning and

R ^{3 is} a radical in the ring system optionally one or more times, preferably 2 times, substituted by hydroxy or methyl radical of the formula

A ^ _Λ / TN _Λ ry \

F ⁴ -l

in which

Z and R ^{4 have} the abovementioned meaning, can also be obtained by reacting a compound of the formula (IV)

COOR ²

(IV),

in which

R ¹ , R ² , A and X ^{1 have} the abovementioned meaning and R ^{7 is} a radical of the formula

T T HN Z N, HN Z N or HN Z N-V ^f V-Λ / V /

in which

Z has the abovementioned meaning, with compounds of the formula (V)

R ⁴ -X ³

in which

R ^{4 has} the abovementioned meaning, but can not stand for hydrogen, and X ^{3 is} halogen, in particular chlorine, bromine or iodine, optionally in the presence of acid-binding agents

(Method B).

Compounds of the formula (I) according to the invention in which R ^{4 is} CH ₃ -CO-CH ₂ CH _{2 are} also obtained by reacting a compound of the 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 [3.2.1] octane are used as starting materials, the course of the reaction can be represented by the following formula scheme:

COOH base

RF

COOH

Is used in the implementation of the method B i-cyclopcopyl-7 (2,5-diazabicyclo | 2.2.2loct-2-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and ethyl iodide as starting materials, the course of the reaction can be represented by the following formula scheme:

COOH

BAEE

♦ C ₂ H ₅ -J

-HJ

COOH

If, in the reaction according to method C1, cyclopropyl-7- (3,8-diazabicyclo (3.2.1) oct-3-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and methyl vinyl ketone are used as starting compounds, the reaction sequence can be represented by the following formula scheme:

COOH

♦ CH ₃ -CO-CH = CH ₂

CH ₂ -COCH ₂ CH ₂

COOH

The compounds of the formula (II) used as starting materials are known or can be prepared by known methods. Examples include:

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3142L54), 1-cyclopropyl-6,7-fluoro-1,4-dihydro-4-oxo 3-chinoicarboxylic acid (European Patent Application 113091), 6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Doutchche Patent Application 3420743), 8-chloro-1-cyclopropyl-6,7-dichlorofluoro 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3420743), 1-cyclopropyl-6,7, (IIrifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3318145),

ee-dichloro-i-cyclopropyl-fluoro-M-dihydro-oxo-S-quinolinecarboxylic acid (German Patent Application 3420743), 7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo 3-quinolinecarboxylic acid (European Patent Application 113091), 6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 113091), i-cyclopropyl-ej-difluoro-IAdihydro- e-methyl ^ -oxo-a-quinolinecarboxylic acid, i-cyclopropyl ^ -chloro-ö-fluoro-IAdihydro-e-nitro ^ oxo-S-quinolinecarboxylic acid, ej-difluoro-i-ethyl-i ^ -dihydro ^ -oxo S-chinolincarbonsä'jre, 7-chloro · 6 · fluoro-1-ethyl-1,4-dίhydro-4-oxo-3-chίnolincarbo.1säure, 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 · chinolincarbon8äure, ej-difluoro-IAdihydro ^ -oxo-i-phenyl-S-quinolinecarboxylic acid, y-chloro-i-cyclopropyl-e-fluoro-i ^ -dihydro ^ -oxo-ie-naphthyridine din-S-carboxylic acid, 6,7-di-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-1, e-naphthyridine-S-carboxylic acid, 1-cyclopropyl-6,7,8-trifluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (German Patent Application 3318145), 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3- del (1) benzoxazine-e-carboxylic acid (European Patent Application

8,9-Difluoro-6,7-dihydro-5-methyl-1-oxo-1 H.SH-benzoli.jl-quinolicin -carboxylic acid, 7-chloro-6-fluoro-1-phenyl-1,4 dihydro-4-oxo-1, e-naphthyridine-S-carboxylic acid (European Patent Application 153580), 7-chloro-e-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1, 8-naphthydrin-3-carboxylic acid (European Patent Application 153580),

GJ.e -trifluoro-IAdihydro-i-methylamino ^ -oxo-S-quinolinecarboxylic acid (German Patent Application 3403922),

i-Amino-ej.e-trifluoro-IAdihydro ^ -oxo-S-quinolinecarboxylic acid (German Patent Application 3409922), 6,7,8 trifluoro-IAdihydro-i-dimethylamino ^ -oxo-S-quinolinecarboxylic acid German Patent Application 3409922), 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, ej-difluoro-i-li-fluorphenyO-IAdihydro-e-methyl ^ -oxo-S-quinolinecarboxylic acid, 6-chloro-7-fluoro-1- (4'fluorphenyl) - 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 131839), 6-chloro-7-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 131839), 6,7,8-trifluoro-1 - (4-fluorophenyl) -1-dihydro-oxo-S-quinolinecarboxylic acid (European Patent Application 154780), 6,7,8-trifluoro-1- (2 , 4-difluorophenyl) -1,4-dihydro-4-oxo-3-ninolinecarboxylic acid (European Patent Application 154780), ej.e-trifluoro-i-dihydro-oxo-i-phenyl-S-quinolinecarboxylic acid (European Patent Application 154780) , 7-chloro-1-et hyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, SSJ-difluoro-'i ^ -dihydro ^ -oxo-i-vinyl-S-chinolincarbonsöure.

The azabicycloalkanes of the formula (III) used as starting compounds are known in some cases or can be

confessed procedures are produced. The compounds can be used as racemates or after separation into the enantiomeric enantiomers-pure azabicycloalkanes. Examples include:

1,4-O-azabicyclo (3.2.1! Octane (US Pat. No. 3281423, J. Med. Chem., 20, 1333 [1977]), 8-methyl-3,8-diazabicyclo | 3.2.1-joctane dihydrochloride (J. Med. Chem. 17,481 [1974]), 3-methyl-3,8-diazabicyclo [3.2.1] octane dihydrochloride (J.Med.Chem., 17.48111974), 2,5-diazabicyclo [2.2.1] heptane Dihydrochloride (J. Org. Chem., 31, 1059 [1966]), 2-methyl-2,5-dia / abicyclo | 2.2.1 heptane dihydrochloride (J. Org. Chem., 31, 1059 [1966]; J. Med. Chem., 17, 481 [1974]), 2-benzyl-2,5-diazabicyclo [2 → 1] hepta.-i-dihydrochloride (J. Org. Chem., 31, 1059 [1966]),

8-ethyl-3,8-diazabicyclo (3.2.1 octane,

8-benzyl-3,8-diazabicyclo [3.2.1! Octane,

8- (4-nitrobenzyl) -3,8-diaubicyclo [3.2.1! Octane,

8- (4-nitrobenzyl) -3,8-diazabicyclo [3.2.1 joctane,

3-ethyl-3,8-diazabicyclo | 3.2.1! Octane,

3-Benzyl-3,8-dia; abicyclo [3.2.1! Octane,

3- (4-aminobenzyl) -3,8-diazabicyclo [3.2.1] octane, 2,5-dia-bicyclo [2.2.2] octane dihydrochloride (J. Med. Chem., 17, 481 (1974)), 2- Methyl 2,5-diazabicyclo [2.2.2] octane dihydrochloride (J. Med. Chem. 17,481 [1974]), 2-ethyl-2,5-diazabicyclo [2.2.2] octane,

2-benzyl-2,5-diazabicyclo [2.2.2) octane,

2- (4-aminobenzyl) -2,5-diazabicyclo [2.2.2] octane, 8-propyl-3,8-diazabicyclo [3.2.1! Octane,

3-isopropyl-3,8-diazabicyclo [3.2.1! Octane,

2-butyl-2,5-diazabicyclo | 2.2.1! Heptane,

2-isobutyl-2,5diazabicyclo | 2.2.2] octane,

8- (2-hydroxyethyl) -3,8-diazablcyclo | 3.2.1! Octane, 3- (2-hydroxyethyl) -3,8-diazabicyclo [3.2.1] octane, 2- (2-hydroxyethyl) -2,5-diazabicyclo 2.2.1] heptane, 2- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.2loctane, 1 ^ -diazabicycloO. 1.1! Heptan,

3,9-diazabicyclo [3.3.1] nonane,

7-hydroxy-3,9-diazabicyclo (3.3.1) nonane (Chem. Heterocyclic Compounds USSR 1,195 (19651), 7-hydroxy-9-methyl-3,9-diazabicyclo [3.3.1] nonane,

3-oxa-7,9-diazabicyclo [3.3.1] nonane, 3-oxa-9-8zabicyclo (3.3.1inonane, 2,5-diazabicyclo | 3.1.1! Heptane, 1,4-diazabicyclo [3.3.1 inonane, 2,5,9-triazabicyclo3.2.2] nonane,

Did starting compounds of formula IV are unknown. They correspond to the compounds of the formula of the invention I, in which the radical R ^{4 is} hydrogen. The starting compounds of the formula V are known. Examples include: Methyl iodide. Methyl bromide, mothyl chloride, ethyl iodide, ethyl bromide, benzyl bromide, benzyl chloride, n-nitrobenzyl bromide,

2-chloroethanol, 2-bromoethanol, 2-iodoethanol, 3-bromopropanol, 4-iodobutanol, chloroacetone, 1-chloro-butanone, 1-bromo-3-butanone, allyl bromide, propargyl bromide. Methyl vinyl ketone is also known.

The reaction of (II) with (III) according to method A, in which the diazabicycloalkanes (III) are also used in the form of their hydrochlorides

can be, preferably, in a diluent such as dimethyl sulfoxide, N ₁ N dimethylformamide, hexamethylphosphoramide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol

Glycolmonomethylether odor pyridine made. Likewise, mixtures of these diluents may be used

become.

As acid binders, all ut borrowed inorganic and organic acid binding agents have been used. These include

preferably the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specifically, triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), diazabicyclic BAOlundec-T-ene (DBU) or excess amine (III) are particularly suitable.

The reaction temperatures can be varied over a wider range. In general, you work between about 20

and 200 ⁰ C, preferably between 80 and 180 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one works at Printing between about 1 and 100 bar, preferably between 1 and 10 bar. When carrying out the process according to the invention, 1 to 15 mol, preferably 1, are employed per mole of the carboxylic acid (II)

to 6 moles of the compound (III).

Free hydroxy groups may be added during the reaction by a suitable hydroxy protecting group, for example by the Tetrahydropyranylrest, protected and released after completing the reaction. The reaction of (IV) with (V) according to method B is preferably carried out in a diluent such as dimethyl sulphoxide, Dioxane, Ν, Ν-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 are used. As acid binder, it is possible to use all customary inorganic and organic acid binders. These include

preferably the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specifically, triethylamine, 1,4-diazabicyclo | 2.2.2) octane (DABCO) or delta-diazabicyclol0A1-olundecene (DBU) are particularly suitable.

To speed up the reaction, phase transfer catalysts such as tetrabutylammonium bromide, Tetrabutylammonium chloride or benzyl-triethyl-ammonium chloride are added. The reaction temperatures can be varied within a wide range. In general, you work between about 20

and about 18O ⁰ C, preferably between 40 and 1 ^{0 0} C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, one works at Printing between about 1 and about 100 bar, preferably between 1 and 10 bar. When carrying out the process according to Method B according to the invention, 1 to 4 moles are added to 1 mole of compound (IV),

preferably 1 to 1.5 moles of the compound (V).

The reaction of (IV) with methyl vinyl ketone (Method C) is preferably carried out in a diluent such as dioxane, Dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, isopropanol, n-propanol, glycol monomethyl ether or else in Mixtures of these diluents performed. The reaction temperatures can be varied within a substantial range. In general, it works between about 2O ⁰ C.

and about 150 ° C, preferably between 5O ⁰ C and 100 ⁰ C.

The reaction can be carried out at Normaldru ''!:, But also at elevated pressure Printing between about 1 and about 100 bar, preferably between 1 and 10 bar. When carrying out the process according to the invention, 1 to 5 mol, preferably 1, of 1 to 1 mol of the compound (IV) are used

to 2 moles of methyl vinyl ketone.

To prepare the esters of the invention, the underlying carboxylic acid is preferably in excess Alcohol in Ger ^ η were strong acids, such as sulfuric acid, anhydrous hydrogen chloride, methanesulfonic acid,

p-toluenesulfonic acid or acidic ion exchangers, reacted at temperatures of about 2O ⁰ C to 200 ⁰ C, preferably about 60 ⁰ C to 120 ° C. The resulting water of reaction can also by azeotropic distillation with chloroform, carbon tetrachloride,

Benzene or toluene are removed. The wounded as a prodrug (5-methyl-2-oxo-1,3-dioxol-4-yl-methyl) ester by reacting an alkali metal salt of the

underlying carboxylic acid with 4-bromomethyl- or 4-chloromethyl-5-methyl-1,3-dioxol-2-one in a solvent such as

Dimethylformamide, dimethylacetamide, dimethyl sulfoxide or tetramethylurea at temperatures of about ⁰ ° C. to 100 ^° C.,

preferably from 0 ° C to 5O ⁰ C, was obtained.

The introduction of an aminobenzyl radical R ⁴ is carried out by reduction of an already introduced in the active ingredient of the formula I. Nitrobenzylrostes by catalytically excited hydrogen or chemically by reduction with iron or zinc. The preparation of the acid addition salts of the compounds according to the invention is carried out in the usual way, for example by Dissolving the betaine in excess aqueous acid and precipitating the salt with a water-miscible organic Solvents such as methanol, ethanol, acetone, acetonitrile. You can also use equivalent amounts of betaine and acid in water or

Heat an alcohol such as glycol monomethyl ether and then evaporate to dryness or the precipitated salt

aspirate. Examples of suitable pharmaceutically acceptable 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. The alkali metal or alkaline earth metal salts of the inventive carboxylic acids are dissolved, for example, by dissolving the betaine in

of undiluted alkali or alkaline earth liquor, filtration of undissolved betaine and evaporation of the filtrate to dryness. Pharmaceutically suitable are sodium, potassium or calcium salts. By reaction of an alkali or

Frdalkalisalzes with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained. Active ingredients according to the invention can be present both as racemates and as onantiomerically pure compounds. Apart from the compounds listed in the examples, new active substances may be mentioned in detail:

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 [3.2.1) oct-4-yl) -6-fluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid, 7- (1,4-DiazabicycloI3.2.1 ) oct-4-yl) -6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7- (1,4-diazabicyclo [3.2.1 | oct-4-yl ) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 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, 7- (1,4 · diazabicyclo [3.2.1] OCl • 4-yl) -1-θthyl-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonsäurβ, 7- (1,4-diazabicyclo (3.2.1] oct-4-yl) -1-ethyl-6-tiuor- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -9-fluoro-6,7-dihytiro-5-methyl-1- oxo-1H, 5H-benzo | i, j) quinoline-2-carboxylic acid, 7- (1,4-diazabicyclo | 3.2.1) oct-4-yl) -6-fluoro-1- (4-fluorophenyl) - 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-7- (1,4-diazabicyclo (3.2.1Ioct-4-yl) -6-fluoro 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 1-cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinoline carboxylic acid- (5-methyl-2-oxo-1,3-dioxol-4-yl-methyl) esters,

i-Cyclopropyl-7- (1,4-diazabicyclo | 3.1.1] hept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl -? -! 1,4-diazabicydo [3.1.1] hept-4-yl) -6,8-difluoro-1/1-dihydro ^ -oxo-S-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-7- (1,4 -diazabicyclo [3.1.1lhept-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- (1,4-diazabicyclo [3.1.1] hept-4 -yl) -6-fl "or-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- (1,4-diazabicyclo [3.1.1 | hept-4-yl ) -6-fljor-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-7- (1,4-diazabicyclo [3.1.1] hept-4-yl) - Methyl 4-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7'8-methyl-3,8-diazabicyclo | 3.2.1 ] oct-3-yl) -4-oxo-S-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (8-rriethyl-3,8-diazabicyclo [3.2.1 | oct-3- yl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, ^1- cyclopropyl-6-fluoro-1,4-dihydro-7-; 3-methyl-3,8-aiezabicyclo | 3.2.1] octane 8-yl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-d ifluor-1,4-dihydro-7- (3-methyl-3,8-diazabicyclo [3.2.1] oct-8-yl) -4-oxo-3-ch: nolincarbonsäure, 8-chloro-1-cyclopropyl 6-Fluoro-1,4-dihydro-7- (3-methyl-3,8-diazabinyclo [3.2.1loct-8-yl) -4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- (2.5 -diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-1-dihydro-1-oxo-S-quinolinecarboxylic acid, 1-cyclopropyl-7- (2,5-diazabicyclo [2.2.1lhept-2-yl ) -6,8-difluoro-1,4-dihydro-4-oxo-3-chinolincarbon8äure, 8-chloro-1-cyclopropyl-7- (2,5-diazabicyclo | 2.2.1] hept-2-y ' ) -7-fluoro-1,4-dihydro-4-oxo-3-chinolincarbons8ure, 1-cyclopropyl-7- (2,5-diazabicyclo (2.2.1 | hept-2-yl) -6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carbo'söure, 1-cyclopropyl-6-fluoro-1,4-fJihydro-7- | 5- (2-hydroxyethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -4-oxo-3-diolcarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-I5- (2-oxopropyl) -2,5- diazabicyclo [2.2.1 ihept- ⁰ -yl-S-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.1] hopt-2-yl) - 4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-dIfL fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo! 2.2.1] hept-2-yl) -4-oxo-3-quinoline-carboxylic acid, 8Chlor-1-cyclopropyl-6- fluoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo- 2.2.1-hept-2-yl) -4-oxo S-quinonocarboxylic acid, 1-cyclopropyl-7- (8 -ethyl-3,8-diazabicyclol3.2.1] oct-3-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, i-cyclopropyl-B-fluoro-i ^ -dihydro ^ -oxo ^ -le-O-oxo-butyD-Se ^ diazabicycloO .Doct-S-yll-S-quinolinecarboxylic acid, 7-I8- (4-aminobenzyl) -3,8-diazabicycloi3.2.1] oct-3- yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -6fluor-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

I-cyclopropyl '' '2,5-diazabicyclo [2.2.2] oct-2-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,

8-chloro-1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -7-fluoro-1-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7- (2,5-diazabicyclo [2.2.2loct-2-yl) -6-fluoro-1,4-dihydru-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1, 4-dihydro-7- (5-inethyl-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-diazabicyclo [2.2.2 | oct-2-yl)! -4-oxo-3-quino incarbonsäure, 8-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-7- (5-methyl-2,5-diazablcyclo [2.2.2) oct-2-yl) -4-oxo-3-quinolinecarboxylic acid, 1-Cyc! opropyl-7- {3,9-diazabicyclo [3.3.1 | non-3-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (7-hydroxy 3,9-diazabicyclo [3.3.1] non-3-yl) -4-oxo-3-quinolinecarboxylic acid, f-cyclopropyl-1,3-fluoro-1,4-dihydro-7- (3-oxa-7,9-diazabicyclo) 3.3.1 (non-7-yl) -4-oxo-3-chlorolincarboxylic acid, 7- (5-allyl-2,5-diazabicyclo (2.2.1lhept-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-propargyl-2,5-diazabicyclo [2.2.2) oct-2-yl) -3-quinolinecarboxylic acid.

Example of a tablet according to the invention 583.0 mg Each tablet contains: 55.0 mg Compound of Example 1 72.0 mg Microcrystalline cellulose 30.0 mg corn starch 5.0 mg Poly (I-vinyl-2-pyrrolidone) insoluble 5.0 mg Highly disperse silica magnesium stearate

750.0 mg

The paint cover contains:

Poly (O-hydroxypropyl-O-methyl) -cellulose 15cp 6.0 mg

MacrogoUOOOrec. INN 2.0 mg polyethylene glycols (DAB)

Titanium (IV) oxide 2.0 mg

10.0 mg

The orformungsgemäßen compounds show low toxicity a broad antibacterial spectrum against gram-positive and gram-negative bacteria, especially against Enterobakteriaceen; especially against those that are resistant to various antibiotics, such. Penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties enable their use as chemotherapeutic agents in medicine as well as substances for the preservation of inorganic and organic materials, especially organic materials of all kinds,

z. As 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 agents can be prevented, treated 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 the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by these pathogens.

For example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

Gram-positive cocci, z. Staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept.

faecalis, Strept. pneumoniae, Strept. pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.friendii, Citrob. Divernis), Salmonella and Shigella; Klebsiella (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) and sirikt anaerobic bacteria such. B. Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, e.g. B.

Mycobacterium tuberculosis.

The above enumeration of pathogens is merely exemplary and by no means limiting. Examples of diseases which are caused by the named pathogens or mixed infections and which can be prevented, improved or cured by the compounds according to the invention are mentioned;

Infectious diseases in humans such as otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, upper respiratory tract diseases, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis , Prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses. nlegmone, wound infections, infected burns, burn wounds, infections in the mouth, infections after dental operations osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastitis, mastitis, tonsillitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelvic peritonitis and eye infections.

Apart from humans, bacterial infections can also be treated in other species. Examples include:

Pig: Coiliarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalact-ae-syndrome, mastitis; Ruminants (bovine, ovine, caprine): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

Horse: bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonellosis; Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis; Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Likewise, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, with the antibacterial spectrum on the aforementioned pathogens on other pathogens such as Pasteurella, Bruceila, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsien, Yersmia, expanded.

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

The present invention also includes pharmaceutical preparations in dosage unit. This means that the preparation in the form of individual parts, for. As tablets, dragees, capsules, pills, suppositories and ampoules are present, the active substance content corresponding to a fraction or a multiple of a single dose. The dosage units can z. B. 1, 2, 3 or 4 single doses or ^y h, '/ 3 or Ί * 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.

Non-toxic carriers which are suitable pharmaceutically suitable in-plants include solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all types.

Preferred pharmaceutical preparations which may be mentioned are 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 substance (s) in addition to (a) fillers and extenders, ζ. Starches, lactose, cane sugar, glucose, mannitol, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, ζ agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, e.g. Paraffin quaternary ammonium compounds, (g) wetting agents, e.g. Alcohol, glycerol monostyrene and bentonite; and (i) lubricants e.g. Talc, calcium and magnesium stearate and test F

substances removed under (a) to (i).

The tablets, dragees, capsules, pills and granules may be provided with the usual coagulant-containing coatings and hullers, and may also be compounded so that they may be preferentially used in a particular portion of the intestinal tract, optionally retarded polymeric substances and waxes.

The active ingredient (s) may optionally be selected from one or more of those listed above

mikroverkapseltei Fo ^r m are present.

Suppositories may contain the usual water-soluble Tr; Polyethylene glycols, fats, for example cocoa fat and higher esters (eg C ₁ -C 4 alcohol with C ₆ fatty alcohols, pastes, cements and gels may contain, in addition to the active substance (s) the usual powdered vegetable fats, wax, paraffins, starch, Tragacanth, cellulose derivatives, polyethylene glycol <talc and zinc oxide or mixtures of these substances.

Powders and sprays can, in addition to the odei the active ingredients, the usual carriers enl silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these conventional blowing agents, /.B. Chlorofluorohydrocarbons.

Solutions and emulsions may contain, in addition to the active substance (s), the usual 1-solution solubilizers and emulsifiers, ζ. b. Water, Ethyhlkohoi, isopropyl alcohol, Ethylc Benzylbunzoat, propylene glycol, 1,3-Butylonglykol, dimethylformamide, oils, in particular corn oil, Oüvonöl castor oil and sesame oil, glycerol, glycerol formal, Tetrahydofurfur fatty acid esters of scriban or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be used in sterile and suspension in addition to dom or don drugs, the usual Trägerstoffo such as ethyl alcohol, P; opylo iglykol, suspending, ζ. B. ethoxylated Isostoarylalkoholo, PoI ^ microcrystalline cellulose, Aluminiummetahydroxid, bentonite, agar-agar and tragacanth The FormiJierungsformen can also colorants, preservatives so taste-improving additives, eg. B. Pfefforminzöl and eucalyptus oil and sweetener, ι.

The therapeutically effective Vorbindungen should be in the above pharmazouli a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95GgW- ⁰ O, the above pharmaceutical preparations may aor the Orfindungsji

contain active pharmaceutical ingredients.

The preparation of the pharmaceutical preparations listed above takes place in ublicl

z. B. by mixing dos or dor agents with the don or donors.

The genannton preparations can be used in humans and animals either orally, rectally, parontc iiibkutan), intracisternal, intravaginal, intraperitoneal, local (powders, salbo, drops) and <cavities, body cavities.

Suitable preparations are injection solution, solutions and suspensions, infusion formulations, emulsions, ointments or drops. For local therapy dermatological formulations, silver and other salts, ear drops, eye salve will be. In animals k.inn dio intake also via the Futtor or drinking water in geoi; ₍ n <!

Furthermore, gels, powders, powders, tablets, sustained-release tablets, Promixo, concentrates, G aerosols, sprays, inhalants can be used in humans and animals. Furthermore, dio <other support materials such as, for example, plastics, (Kunsistoffkotten to local TIu

be incorporated.

In general, in both human and veterinary medicine, it has as active ingredients in total amounts of about 0.5 to about 500, before / about 24 hours, optionally in the form of monoruclear monoline, to achieve the desired single dose contains don or the active substances according to the invention preferably in Monger 3 to 30 mg / kg of body weight. However, it may orfordorlich no, of don gonannlon Dosi dependence on the type and body weight dos object to be treated, the type of preparation and the application of Arznoimittols and Dom Zoitraum or Inte

Administration takes place.

Thus, in some cases, it may be sufficient to pass the above-mentioned drug mongoose sufficiently with less than the obongonannton mong other cases. Dio Fos!

optimal dosage and Anwendungsari the VVirkstoffo can aul by any specialist

respectively.

The new compounds may have been fermented in don ublichon concentrations and preparations to feed power lines or with dom drinking water. Thus, oino info gram-positivo bacteria can be prevented, gobossert and / or goheiit and thereby an improvement in the voiwortung the feed achieved wordon.

In the TaboMo below, all of the MIC values are given in comparison to i-cyclopropyl G-tide 3-chlorobenzobutyric acid (ciprofloxacin):

Tablets, dragees, capsules, pills and granules may contain the active substance (s) in addition to the usual excipients, such as (a) fillers and extenders, 2. B. starches, lactose, cane sugar, glucose, minnin and silica, (b) Binders, e.g. B.

Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, eg glycerol, (d) disintegrants, 1. B.

Agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, e.g. Paraffin and (f) resorption accelerators, e.g. B.

quaternary ammonium compounds, (g) wetting agents, i. Cotyl alcohol, glycerol monostearate, (h) adsorbent, e.g. Kaolin and bentonite and (i) lubricants e.g. As talc, calcium and magnesium stearate and solid Polyethylopglykole or mixtures of substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules may be provided with the usual, optionally Opakisierungsmittoln containing coatings and shells and also be composed so that they give the active substance or only preferably in a bestimmton part of the intestinal tract delay 1, being used as embedding masses z. B.

Polymorsubstanzep and waxes vei can be used.

The active ingredient (s) may optionally be in microencapsulated form with one or more of the excipients listed above.

Suppositories may contain the usual water-soluble excipients in addition to the active substance or substances, for. B.

Polyethylene glycols, fats, z. As cocoa and higher esters (eg, C, ₄ -alcohol with Ci ₆ fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels, in addition to the active ingredient or the usual Trägerstoffo contain, z. As animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances

Powders and sprays may in addition to the odei the active ingredients contain the usual carriers, eg. As lactose, talc, silica, aluminum hydroxide, calcium sulfate and polyamide powder or mixtures of these substances. Sprays may additionally contain the usual propellants, eg. For example, chlorofluorocarbons.

Solutions and emulsions may comprise the customary Λ r.igerstoffe such as solvents, solubilizing agents and emulsifiers, eg water, Ethylilkohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzylbonzoat, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils in addition to the odor do drugs, especially Cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycorine, glycerol formal, tetrahydofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.

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

Suspensions may be dom or the active ingredients dio standard carriers where liquid diluents, eg. For example, water, ethyl alcohol, propylene glycol, Siispendiermittol, z. Example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these Stoffo included.

The formulation forms mentioned can also colorants, Konservierungsstofto and odor and flavor-improving additives, eg. Peppermint oil and eucalyptus oil and sweeteners, e.g. For example, saccharin.

The therapeutically active compounds should preferably be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95,% by weight of the mixture of the gosad.

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

The preparation of the abovementioned pharmaceutical preparations is carried out in the usual way according to bokannton methods,

z. B. by mixing the active substance or substances with the carrier or excipients.

The preparations mentioned can be applied orally, rectally, parenterally (intravenously, intramuscularly, sibkutan), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) in humans and animals, and for the treatment of infections in cavities, body cavities.

Suitable preparations are 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 salves, powders or solutions may be used. In animals, uptake can also take place via the feed or drinking water in suitable formulations.

Fernor gels, powders, powders, tablets, sustained-release tablets, Promixo, concentrates, granules, Pollets, BoIi, capsules, aerosols, sprays, inhalants in humans and animals are used. In addition, compounds can be incorporated in other carrier materials such as, for example, plastics (plastic core for local therapy), collagen or bone cement.

In general, it has proven to be advantageous both in human and in veterinary medicine, the active ingredient according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100mg / kg body weight per 24 hours, optionally in the form of several Single dues, to the Erziolung the desired results to vorabroichon. 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 of body weight. However, it may be necessary to deviate from dosages mentioned above, depending on the type and body weight of the object to be treated, the nature and severity of the disease, the nature of the preparation and application of the drug, and the interval or interval within which administration takes place.

So it may be sufficient in oinigen cases, with less than the above-mentioned mongo drug from / ukommon, whnond in other cases the above-mentioned amount of active ingredient wordon muston exceeded. The Fostlegung of the respectively required optimal dosage and mode of administration of the active ingredients can be done by iodine specialist due to his expertise loiclv.

The new compounds may have been used in don common concentrations and preparations along with the feed or with feed preparations or with the drinking water. As a result, infection by grarn-negative or gram-positive bacteria can be prevented, ameliorated and / or cured, thereby achieving promotion of growth and improvement of utilization of the feed.

The following table gives some MIC values as compared to 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1 -piporezinyl) -3-quinolinecarboxylic acid (ciprofloxacin):

Example 3

OOH

HCl 'H ₂ O

8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is prepared analogously to Example 1um, giving 8-chloro

cyclopropyl-7- (1,4-diazabicyclo (3.2.1) oct-4-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride hydrate from the melting point 310 ° C (under Decomposition).

C ₁₉ H ₁ UCIFN ₃ O ₃ · HCl H ₂ O (440.3) Calculated = C 51.1 H 4.96 N 0.41 Cl 15.9 Bound = C 51.2 H 4.6 N 9,! I Cl 15.6 Example 4

OOH

χ HCl

1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 to give 1-cyclopropyl-7- (1,4-diazabicyclo (3.2.1) oct-4-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 275-282 ° C (under Zervjizung) and therefrom the hydrochloride of melting point> 310 ⁰ C under Zenieretzung ( already from about 26O ⁰ C the substance slowly becomes dark).

Examples

OOH

χ HCl

Analogously to Example 1, 7-chloro-cyclopropyl-1-adihydro-e-nitro-o-oxo-S-n-butylcarboxylic acid is reacted to give 1-cyclopropyl-7- (1-diazabicyclo) -1-oct-4-yl. 1,4-dihydro-6-nitro-4-oxo-3- chinolinorbonväure-Hydrochlorld of melting point 303-307 ⁰ C (with decomposition).

Examples

OOH

χ HCl

Analogously to Example 1, 7-chloro-cyclopropyl-e-fluoro-i, 4-dihydro-4-oxo-1, e-naphthyridine-S-carboxylic acid is reacted to give 1-cyclopropyl-7- (1,4- di.izabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-4-uxo-1,8-naphtho-tridine-3-carbonyl 9 "e-hydrochloride of melting point> 30 ° C Decomposition.

Example 7

OOH

κ HCl

1-Ethyl-e1.-trifluoro-1-dihydro-3-oxo-S-quinolinecarboxylic acid is prepared analogously to Example 1, giving 7- (1,4-diazabicyclo-3.2.1-oct-4-yl) -1-ethyl-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 308-312 ° C with decomposition.

Example 8

OOH

χ HCl

A mix of

and 1.2 g (10,7mmol) of 1,4-diazabicyclo | 3.2.1) octane in 25 ml Oimethylsulfoxid is reacted with 2.2 g (20 mmol) of 1,4-diazabicyclo | 2.2.2 | octane added and the mixture 5 hours at 120 ⁰ C heated. The mixture is concentrated under reduced pressure, the residue is stirred with 40 ml of acetonitrile, the undissolved residue is removed and purified by chromatography on silica gel with dichloromethane / methanol / 20% aqueous ammonia solution (2: 4: 1 as eluent, 1.2 g of solid product are isolated which is converted into the hydrochloride by dissolving in 8 ml of half-concentrated hydrochloric acid and precipitating with 30 ml of ethanol. Yield: 1.1 g of IC-i ^ ADiazabicycloSi, .siloct ^ -d-S-fluoro-.s-dihydro-S-methyl ^ - Oxo ^ H-pyridoli ^ carboxylic acid hydrochloride of melting point 355 ° C with decomposition (becomes dark from about 290 "C).

Example 9

OOH

x HCl

6,7,8-trifluoro-1- (4-fluorophenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are reacted analogously to Example 1, giving 7 (1,4-diazabicyclo [3.2.1] oct-4-yl). -6,8-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 310-314 ⁰ C with decomposition.

Example 10

OOH

2.0 g (6 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of

-16- 26S401

10 ml of acetonitrile and 25 ml of dimethylformamide with 0.7 g (6 mmol) of 1,4-oiazabicyclo [2.2.2] octane and 0.7 g (6 mmol) of 1,4-diazabicyclo [3.2.1! Octane and heated under reflux for 2 hours. It is then concentrated and treated with water. It is allowed to crystallize out with ice cooling, filtered off, washed with water and dried.

Yield: 1 g (41% of the theory) of 1-cyclopropyl-7- (1,4-diazabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro-8-nitro-4- oxo-3-

quinolinecarboxylic acid of melting point 215-232 ⁰ C (with decomposition). After recrystallization from glycol monomethyl ether /

Ethanol is the melting point 224-232 ° C (with decomposition). The required for this 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolir.carboxylic acid is the following steps

receive:

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

OOH

Under ice-cooling and stirring, 34 ml of concentrated sulfuric acid are added dropwise with 40 ml of concentrated nitric acid. In this nitration mixture carries portionwise a 20,9g 2,4-dichloro-5-fluoro-benzoesäuro, whereby the temperature rises to 45- 50 ⁰ C. Then it is heated for 3 hours to 90-100 ⁰ C, poured the cooled to room temperature mixture to 350ml of ice water, the precipitate was filtered off with suction and washed with water. The moist crude product is dissolved in 30 ml of hot methanol and the solution is mixed with 150 ml of water.

The precipitate is filtered off with suction, washed with methanol / water and dried at 80 ^° C. under reduced pressure. There are obtained 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitrobenzoic acid. It is sufficiently pure for the further implementations. A sample of toluene / Potrolether recrystallized yields crystals of melting point 192 ⁰ C. b) 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride

OCl

Cl j Cl NO ₂

106.6 g of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid are refluxed with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then distilled off at normal pressure and the residue is fractionated in a fine vacuum. At 110-115 ° C / 0.08-O, 09mbar go 104.7 g of 2,4-dichloro-5fluor-3nitro-banzoy! Chloride over. On standing, crystals of melting point 35-37 ⁰ C are formed

 c) (2,4-dichloro-5-fluoro-3-nitro-benzoyl) -acetic acid ethyl ester

OCH ₂ COOC ₂ H ₅

10.1 g of magnesium turnings are placed in 21 ml of ethanol with 2.1 g of carbon tetrachloride and after the onset of hydrogen evolution, a mixture of 66,6g diethyl malonate, 40 ml of ethanol and 150 ml of toluene at 50-60 ⁰ C was added dropwise. The mixture is stirred for 1 hour at this temperature, cooled to -5 to - 1O ⁰ C and slowly added dropwise a solution of 109.2g 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride in 50 ml of toluene. Then 1 hour at ⁰ ° C is quilted brought overnight to room temperature and heated for 2 Stundon at 40-5O ⁰ C. The reaction mixture is added under Eiskühlur.g with a mixture of 160ml of water and 10.4ml concentrated sulfuric acid and the organic phase separated. The aqueous phase is extracted with toluene and the combined organic extract washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent removed. 144.5 g (2,4-dichloro-5-fluoro-3-nitrobenzyld-malonic acid diethyl ester as crude product are obtained, which, after addition of 200 ml of water and 0.6 g of 4-toluenesulphonic acid, is refluxed for 3 hours, the mixture is extracted with methylene chloride, The extract is dried with sodium sulfate and the solvent is distilled off in vacuo, giving 118 g of substituted benzoylacetic ester as crude product and having a purity which is sufficient for the further reactions, d) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydroxypropyl- 8-nitro-4-oxo-3-chinolincarbonsnure

OOH

244.8 g (2,4-dichloro-5-fluoro-3-nitrobenzoyl) -e3-acetic acid ethyl ester are heated to 150-160 ° C. with 166 g of triethyl orthoformate and 185 g of acetic anhydride for 3 hours. Put in a vacuum and get 270g. (2,4-dichloro-5-fluoro-3-nitro-benzoyl) -3-ethoxy-acrylic acid ethoxylate as an oily residue.

38 g of this intermediate are added dropwise in 80 ml of ethanol with ice cooling with 5.9 g of cyclopropylamine and stirred at 20 ° C for 1 hour. The precipitated product is filtered off with suction after addition of 100 ml of water, washed with ethanol / H ₂ O (1: 1) and dried. This gives 32.8 g of 2- (2,4-dichloro-5-fluoro-3-nitro-benzoyl) -3-cyclopropylaminoacrylsäureethylester of melting point 143-146 ⁰ C.

7.8 g of the abovementioned compound are mixed in 30 ml of anhydrous dioxane with 3.1 g of (1,8-diazabicyclo-I5.4.0! Undec-7-ene (DBU) and heated for 4 hours to 100 ° C. The solvent is distilled off in vacuo the residue is taken up in methylene chloride / water, the methylene chloride phase is separated off, dried with sodium sulfate and the methylene chloride is distilled off to give 7.2 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydroc-8-nitrobenzene. After recrystallization from acetonitrile, the light brown crystals melt at 174-175X. Yield: 6g.

35,4g of this ester are heated in a mixture of 195ml acetic acid, 142ml of water and 22ml of concentrated sulfuric acid 1.6 hours at 15O ⁰ C. The solution is poured into 500 ml of ice water, the precipitate is filtered off with suction, gewiischen with water and dried in vacuo. Yield: 31.8 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid of melting point 260-261 ° C.

Example 11

O Il

: ooh

530 mg (2 mmol) of i-cyclopropyl-ej-difluoro-M-dihydro ^ -oxo-S-quinolinecarboxylic acid are dissolved in 4 ml of acetonitrile and 6 ml of dimethylformamide with 530 mg (2 mmol) of 2-benzyl-2,5-diazabicyclo [2.2.1] heptane Dihydrochloride and 880 mg (7.9 mmol) of 1,4-diazabicyclo [2.2.2] octane were refluxed for 6 hours. The reaction mixture is concentrated, the residue is stirred with water, the precipitate is filtered off with suction, washed with water and dried. The crude product obtained (0.8 g of the melting point 194-205X and decomposition) is purified by chromatography on dichloromethane / methanol / 17% aqueous ammonium hydroxide solution (150: 40: 1) as eluant on 60 g of silica gel. This gives 0.57 g (66% of theory) 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 melting point 205-214X (with decomposition).

Example 12

O Il

: ooh

HoC-N J N

Analogously to Example 11 is reacted with 8Methyl-3,8-diazabicyclo- | 3.2.1] octane dihydrochloride and recrystallized the crude product from glycol monomethyl ether. This gives 1-cyclopropyl-6-fluoro-1-adihydio ^ -i.e-methyl-S.e-diazabicyclolS ^. 1-oct-3-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 273-278X (with decomposition).

Example 13

OOH

HCl

The reaction is carried out analogously to Example 1 with 5-methyl-1,4-diazabicyclo [3.2.1] ontan to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (5-

methyl-1,4-diazabicyclo [3.2.1] gct-4-yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point> 300X (under

Decomposition). The S-methyl-M-diazabicycloO ^ .H-octane used for this purpose is obtained via the following steps:

a) 3-methyl-3-methoxycarbonylmethylpiporazin-2-one

^H 3

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

Yield: 125 g (67% of theory) Melting point: 135-145 "C (from dioxane)

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

To a suspension of 30.4 g (0.8 mol) of lithium aluminum hydride in 300 ml of absolute tetrahydrofuran is added dropwise a hot solution of 74.6 g (0.4 mol) of 3-methyl-3-methoxycarbonylmethylpiperazin-2-one in 300 ml of absolute dioxane. Then it is stirred for 16 hours under reflux.

Then it is cooled, with 30 ml of water, 30 ml of 15% aqueous potassium hydroxide solution and again 30 ml of water, the excess LiAIH ₄ destroyed and the inorganic salts are filtered off with suction. These are thoroughly stirred five more times with chloroform. The organic phases were dried over potassium carbonate, concentrated and distilled.

Yield: 45g (78% of theory) Boiling point: 78 ° C / 0.05mbar.

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

2HCl

To 363 g (3 mol) of thionyl chloride in 500 ml of chloroform is added dropwise with heating to reflux and stirring 110 g (0.76 mol)

2- (2-hydroxyethyl) -2-methylpiperazole in 600 ml of chloroform. Then, until the end of SO _r, development is refluxed.

It is cooled, 500 ml of water are added dropwise, the aqueous phase is separated off and the chloroform phase is washed twice with 200 ml Water. The aqueous phases are evaporated to dryness, taken up in 11 water and activated charcoal for 30 minutes

iwt reflux heated.

It is filtered, concentrated to dryness, the crystals are washed with cold methanol, filtered off with suction and dried in Vakuumoxikkator over Phosphorus pentoxide. Yield: 160 g (89.4% of theory)

Melting point:> 300 ° C

 d) 5-methyl-1,4-diazabicyclo (3.2.1! octane

Dissolve 100 g (0.42 mol) of 2- (2-chloroethyl) -2-methylplperazine.2 HCl in 100 ml of water and, with ice-cooling, add a solution of 70 g (1.75 mol) of sodium hydroxide in 70 ml of water. The temperature is kept below 4O ⁰ C. Then heated for 1 hour at 80 ° C. Water is added to the solution to dissolve excreted sodium chloride and saturated with potassium carbonate. Then it is extracted several times with chloroform, the organic phases dried over potassium carbonate, eingenngt and distilled.

Yield: boiling point:

Example 14

45 g (85% of theory) 60 ° C / 6mbar.

0OC ₂ H ₅

suspended in 80 ml of ethanol and introduced at reflux temperature, a dry hydrogen chloride stream. After completion of the reaction, the mixture is concentrated, the residue dissolved in water, adjusted with sodium carbonate solution to pH 8, extracted with dichloromethane, dried with sodium sulfate and the filtrate was concentrated. The residue is recrystallized from ethanol / water. This gives 1.1 g of quinolinecarboxylic acid ethyl ester of melting point 196-199T.

Example 15

0OH

x HCl

6,7,8-Trifluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 to obtain 7- (1,4-diazabicyclo (3.2. 1] oct-4-yl) - 6,8-difluoro-1- (2,4-f-5-fluorophenyl) -1,4dihydro-4-oxo-3-cinolincarbonsaure hydrochloride of melting point 329-331 ⁰ C with decomposition.

Example 16

OOH

κ HCl

The procedure is analogous to Example 1 GJ.e-trifluoro-M-dihydro-i-methylarr.ino ^ -oxo-S-quinolincarbonsäuro to obtain 7-0 4-diazabicyclo | 3.2.1] oct-4-yl) -6, 8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 300-305 ° C with decomposition.

Example 17

Il

COOH

CH,

2.6b g of dmmol) i-cyclopropyl-BJ-difluoro-1-dihydro-oxo-S-quinolinecarboxylic acid are dissolved in 20 ml of acetonitrile and 10 ml of dimethylformamide with 2.7 g (24 mmol) of 1,4-diazabicyclo | 2.2.2) octane and 2 , 1g (17 mmol) of 2-methyl-1,4-diozabicyclo [3.2.1] octane and heated under reflux for 6 hours. The mixture evaporated wild, the residue with water (pH 7), the undissolved crystals filtered off, washed water and recrystallized from Giykoimonomethylether. You get 1.4g

1-cyclopropyl-6-fluoro-1,4-dihydro-7- (2-methyl-1,4-diazabicyclo [3.2.1l-oct-4-yl) -oxo-3-quinolinecarboxylic acid of melting point 255-257 ⁰ C. (with decomposition).

The required 2-methyl-1,4-diazabicyclo [3.2.1] octane is obtained in the following way:

ö-methyl ^ -methoxycarbonylmethylpiporazin-S-on

"'COOCH ₃

0 H

81 g (1.1 mol) of 1,2-propylenediamine, 144 g (1 mol) of dimethyl maleate and 250 ml of absolute ether are mixed. The mixture comes to reflux and is occasionally cooled with ice water.

Then it is stirred overnight at room temperature. It is suctioned off, washed with a little ice-cold isopropanol and dried in air. The mother liquors are concentrated and the residue is recrystallized from ethyl acetate.

Yield: 95 g (51% of theory)

Melting point: 102-105 ⁰ C

2- (2-hydroxyethyl) -5-methylpiperazine

OH

H ₃ C ^ NIH

To a suspension of 30.4 g (0.8 mol) LiAlH ₄ in 300 ml abs. Tetrahydrofuran is added dropwise to a solution of 74.5 g (0.4 mol) of 5-methyl-2-methoxycarbonylmethylpiperaz! N-3-one in 300 ml abs. Tetrahydrofuran. Then heated for 16 hrs. Under reflux. Then, excess LiAlH _{4 is} decomposed successively with 30 ml of water, 30 ml of 1.'i% potassium hydroxide solution and 30 ml of water, the inorganic salts are filtered off with suction and stirred several times with dichloromethane. The organic phases are dried over K ₂ CCj, concentrated and distilled.

Yield: 31.8 g (65.1% of theory)

Boiling point: 85-87 ° C / 0.07mbar 2- (2-chloroethyl) -5-methylpipera * in dihydrochloride

f ^N Y ^^ · HCl

H ₃ C- iT

I H

To 95 g (0.79 mol) of thionyl chloride in 125 ml of methylene chloride is added dropwise with heating to reflux 28g (0.208 mol) of 2 (2-hydroxyethyl) -5-methylpiperazine in 125 ml of dichloromethane. Then it is stirred for 5h. under reflux. Then added dropwise 200 ml of water carefully and separates the aqueous Phaso. The organic phase is washed twice with water and discarded. The aqueous phases are concentrated, taken up again in 200 ml of water and with 3 g of active charcoal 30 min. heated to reflux. It is filtered, concentrated to dryness, mixed with methanol, filtered off and dried in a vacuum desiccator P ₄ Oi ₀ . Yield: 23.5 g (48% of theory) of 2-methyl-1,4-diazabicyclo | 3.2.1] octane

I H

Dissolve 23.5 g (0.1 mol) of 2- (2-chloroethyl) -6-methylplperazln dihydrochloride in 20 ml of water and added dropwise at a maximum of 40 ° C 32g (0.4 mol) of 50% sodium hydroxide solution. Then it is stirred for 1 hr. At 75 ° C, cooled, saturated with potassium carbonate and extracted ten times with 50ml dichloromethane. The organic phases are dried over potassium carbonate, concentrated and distilled.

Yield: 9.7 g (76.8% of theory)

Boiling point: 60-6 (> ° C / 0.8mbar

Example 18 8-Oxa-3-azabicyclo [3.2.1] octane hydrochloride is reacted analogously to Example 17 to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (8-

oxa-3-aza-bicycloI3.2.11oct-3-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 272-275 ° C (with decomposition) (from

Glycol monomethyl ether). The required 8-oxa-3-aza bicyclo [3.2.1 joctan-hydrochlo-id is obtained in the following way:

3-Benzyl-8-oxa-3-azabicyclo [3.3.1] octane

61.2 g (0.15 mol) of 2,5-bis- (tosyloxymethyl) -tetrahydrofuran (FHNev. ,::, LFWiggins, J. Chem.Soc 155 (1948)) 300 ml of toluene and 54 g (0.5 mol) benzylamine are allowed to stand for 20h. heated to reflux. It is filtered, washed with toluene, concentrated and distilled.

Yield: 21.5 g (70.5% of theory) Boiling point: 140 ° C / 9mbar

8-oxa-3-azabicyclo | 3.2.1) octane hydrochloride

Dissolve 20 g (0.098 mol) of S-benzyl-e-oxa-S-azabicyclo- s ^ .Hooctane in 150m! Methanol and add 8.5ml of concentrated hydrochloric acid. It is hydrogenated on 5 g Pd coal (10%) at 50 ° C and 50 bar. The catalyst is filtered off with suction, the solution is concentrated, the residue triturated with acetone, filtered off and dried over P4O10.

Expansion: 12.5g (85.3% of the tenth)

M .: 202-204 ⁰ C

Example 19 3-Oxa-8-azabicyclo (3,2,1-octane hydrochloride is reacted analogously to Example 17 to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (3

oxo-8-aza-bicycloI3,2,1) oct-8-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 283-284 ⁰ C (with decomposition) (from

Glycol monomethyl ether). The required 3-oxa-8-aza-bicyclo | 3.2.1 (octane is obtained in the following way:

3-oxa-8-azabicyclo [3.2.1] octane hydrochloride

22.7 g (0.104 mol) of e-benzyl-S-oxa-e-azabicyclophenol octane are dissolved (J. von Braun, J. Seemann, Ber. Deutsch. Chem. Ges. 56,

1840 (1923)) in 140ml of methanol and added 9.3ml of concentrated hydrochloric acid. Then hydrogenated on 5 g of Pd-carbon (5%) at 6O ⁰ C and 60 bar. The catalyst is filtered off with suction, the solution is concentrated by evaporation, the residue is triturated with acetone, filtered off with suction and concentrated by evaporation in a vacuum

Desiccator over P ₄ O ₁₀ dried. Yield: 13.7 g (88.7% of theory)

M.p .: 236 ⁰ C

Example 20 2,2-Dimethyl-1,4-diazabicyclo (3.2.1) octane is reacted analogously to Example 17 to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (2,2-)

dimethyl-1,4-diazabicyclo | 3.2.1 | oct-4-yl) -4-oxo-3-quinoline-carboxylic acid of melting point 242-246 ⁰ C (with decomposition) is irhalten.

The required Z ^ -dimethyl-IAdiazabicycloß ^ .iloctan is obtained in the following way:

ö.ö-dimethyl ^ -methoxycarbonylmethylpiperazin-S-on

H ι

H ₃ C

OOCHa

80 g (0.91 mol) of 1,2-diamino-2-methylpropane, 127 g (0.88 ml) of dimethyl maleate and 200 ml of absolute ether are mixed. After the exothermic reaction, the mixture is stirred for a further 16 hours, filtered off with suction, the mother liquor is concentrated and recrystallized from diisopropyl ether.

Example 22

χ HCL

3.5 g (10 mmol) of 6,7,8-trifluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxo-3-quinolonecarboxylic acid are dissolved 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) of 2-methyl-1,4-diazabicyclo | 3.2.1 | octone are heated to 14O ⁰ C for 2 hours. The work-up is carried out as in Example 21. After recrystallization from water, 1.1 g of 6,8-difluoro-1 - (2,4-difluorophenyl) -1,4-dihydro-7- (2-methyl-1,4- diazabicyclo [3.2.1loct-4-yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 278-28O ⁰ C (dec.).

Example 23

COOH

2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-c'- ^lr > olincarbons6ure be implemented analogously to Example 17. This gives 1.3 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (2-methyl-1,4-diazabicyclo [C! .2.1) oct-4-yl) -4-oxo-3- quinolinecarboxylic acid of melting point 239-242 ° (with decomposition) (recrystallized from glycol monomethyl ether). Mass spectrum: "Ve 389 (M +), 325.276, 247, 111 97 (98%), 69.56 (98%), 32, 28 (10 (1%).

Example 22

3.5g (10mmol) of 6,7,8-trifluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinolonecarbony with 2.7g (24mmol) of 1,4- Diazabicyclo | 2.2.2 | octane and 2,) g (17mmol) of 2-methyl-1,4-diazabi heated. The work-up is carried out as in Example 21. After recrystallization from water W <phenyl) -1,4-dihydro-7- (2-methyl-1,4-diazabicyclo | 3.2.1] oct-4-yl) -4oxo-3 -quinolincarbons 278-280 'C (Zers.) obtained.

Example 23

• v ^ Γ '

N

/ CU ₀

2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxa are obtained analogously to Example 17, giving 1.3 g of 1-Ον (ΙορΓοργΙ · 6.8 ^ ίίΙυοΜ, 4- αίΙιναΓο-7- (2-ΓηβΙην! · 1.4 · αίθΖ8 ^ ϋνϋΙο | 3.2.1 of melting point 2: 19-242 "(subject to decomposition) (umkristellisicrt from glycol monomethyl mass spectrum:" 7.389 (Mf), 325, 276 , 247, 1 Ί, 97 (98%), 69, 56 (98%), 32, 28 (100%).

Claims (2)

1. A process for preparing 7- (azabicycloalkyl) -quinolonecarboxylic acid or -naphthyridonecarboxylic acid derivatives of the general formula (I) COOR ² (0, in which R ^{1 is} methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, Methoxy, amino, methylamino, dimethylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R ^{2 is} hydrogen, alkyl having 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxole) 4-yl) -methyl, R ^{3 is} a radical of the formula N- (CH ₉ ) N-, Y ^X Z N-, YZN-, YZ ^ N-. in which Y for R ⁴ -N, O, S, Z is - (CH ₂ ) n -, -CH ₂ -O-CH ₂ -, -CH ₂ -S-CH ₂ -, -CH ₂ -S-, R ^{5 is} -CH ₂ -N-CH ₂ -, η for 1,2 or 3, R ^{4 is} hydrogen, optionally hydroxy-substituted alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms, optionally substituted by nitro or amino-substituted benzyl, Oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, R ^{5 is} hydrogen or methyl,
X ¹ for fluorine, chlorine or nitro and
A is N or CR ⁶ , in which R ^{6 is} hydrogen, fluorine, chlorine, methyl or nitro or together with R ¹ a Bridge of the structure -O-CH ₂ -CH-CH ₃ , -S-CH ₂ -CH-CH ₃ or CH-CH ₃ , -S-CH ₂ -Cl ·
CH- -CH ₂ -CH ₂ -CH-CH ₃ can form with the proviso that in the event that X ^{1 is} fluorine, R ^{2 is} H and A is CF or N and R 'is ethyl, cyclopropyl, fluoroethyl or vinyl, or R ^e with R ^{1 is} a structure-0 bridge -CH ₂ -CH-CH ₃ forms, η is not equal to 2 and R ^{3 is} not the radical and excluding the compound 7- (2,5-diazabicyclo (2.2.2) oct-2-yl) -1-ethyl-6-fluoro-1-dihydro-oxo-quinolinecarboxylic acid, and their pharmaceutically usable hydrates and acid addition salts, and their alkali metal, alkaline earth metal, silver and guanidinium salts of the basic carboxylic acids, characterized in that compounds of the formula (II) COOR ' (ID, in which R ¹ , R ² , X ¹ and A have the abovementioned meaning and X ^{2 represents} halogen, in particular fluorine or chlorine, with azabicycloalkanes of the formula (III) R ³ -H, in which R ^{3 has} the abovementioned meaning, if appropriate in the presence of acid-binding agents. 2. The method according to claim 1, characterized in that compounds of the formula I are prepared according to claim 1, wherein
R ^{1 is} methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamines, phenyl, fluorophenyl, 2,4-difluorophenyl stands,
R ^{2 is} hydrogen, alkyl of 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl stands,
R ^{3 is} a mono- or polysubstituted in the ring system by hydroxy or methyl radical of the formula