SK285223B6 - Quinolone and naphthyridone carboxylic acid derivatives, a method of their production, pharmaceuticals containing these substances and their use - Google Patents

Abstract

Quinolone and naphthyridone carboxylic acid derivatives of the general formula (I), in which the substituents are explained in the description, a method of their production, pharmaceuticals containing these substances and their use for production of antibacterial agents.

Description

The present invention relates to novel quinolone carboxylic acid derivatives of anaphthyridone carboxylic acid, to a process for their preparation and to antibacterial agents and feed additives containing said substances.

BACKGROUND OF THE INVENTION

EP-A-0 350 733 discloses quinolone carboxylic acids and naphthyridone carboxylic acids which are substituted at the 7-position with a bicyclic amine residue.

Certain derivatives of 7- (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxoquinoline are known from JP 3,188,080. 3-carboxylic acid and naphthyridine-3-carboxylic acid whose bicycloclonyl at the 5-position nitrogen atom carries a hydrogen atom or a lower alkyl group.

EP 350 733 discloses, inter alia, certain derivatives of 7- (2,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and naphthyridine-3. -carboxylic acid whose bicycloclonyl on the nitrogen atom in the 2-position carries a hydrogen atom or a hydroxy-substituted alkyl group having 1 to 4 carbon atoms, an aryl group, a heteroaryl group, a benzyl group, a C1-4 alkoxycarbonyl group, an acyl group having 1 or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl or cycloalkyl of 3 to 6 carbon atoms.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula (I)

in which

A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N,

X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group,

R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or

R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -,

R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl,

B represents a mixture of enantiomers and / or diastereomers of the radical of formula wherein:

Y represents an oxygen atom or a methylene group and R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', r ₂ c-ch = c-co ₂ · r,

-CH = CH-CO ₂ R ₁ or CH ₂ CH ₂ -CN wherein

R 'represents a hydrogen atom or an alkyl group having 1 to carbon atoms, with the exception of the quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) in which B represents exclusively the radical of the formula

wherein Y is CH ₂ and R ³ is as defined herein, and their pharmaceutically usable hydrates and acid addition salts, as well as the corresponding alkali metal, alkaline earth metal, silver and guanidine salts of the corresponding acids.

Preferred are quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1, in which:

A is CH, CF, CC1, _C-OCH3 or N,

X ¹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an amino group or a methyl group,

R ¹ is ethyl, 2,4-difluorophenyl, or

R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -,

R ² represents hydrogen, methyl, ethyl or 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, and

R ³ is CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R' O ₂ C-CH = C -CO ₂ R ',

-CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, wherein

R 'represents an alkyl group having 1 to 2 carbon atoms, and the pharmaceutically usable hydrates and acid addition salts thereof, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine.

The present invention further provides a process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I), in which:

A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N,

X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group,

R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopiopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or

R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -,

R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl,

B represents a mixture of enantiomers and / or diastereomers of the radical of the formula

in which

Y represents an oxygen atom or a methylene group,

R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R 'or CH ₂ CH ₂ -CN, wherein:

R 'represents a hydrogen atom or an alkyl group having 1 to carbon atoms, characterized in that a compound of formula (II) is reacted

wherein A, Y, X ¹ , R ¹ and R ^{2 are} as defined above, with a compound of formula (III)

R ³ - X ³ (III) in which

R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO ₂ R 'and CH ₂ CH ₂ -CN, wherein:

R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and

X ³ represents a halogen atom, in particular chlorine, bromine or iodine, optionally in the presence of acid binders.

The present invention also relates to a process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) in which:

A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N,

X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group,

R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or

R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -,

R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or

5-methyl-2-oxo-1,3-dioxol-4-ylmethyl,

B represents a mixture of enantiomers and / or diastereomers of the radical of the formula

in which

Y represents an oxygen atom or a methylene group,

R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R 'or CH ₂ CH ₂ -CN, wherein:

R 'represents a hydrogen atom or an alkyl group having 1 to carbon atoms, characterized in that a compound of formula (II) is reacted

in which A, Y, X ¹ , R ¹ and R ^{2 are} as defined above, with a Michael acceptor, such as a dialkyl ester of acetylndicarboxylic acid, an alkyl ester of propionic acid or a compound of formula (IV)

CH ₂ = CH-R ⁵ (IV) wherein

R ⁵ is COCH ₃ , CO ₂ R 'or CN.

For example, when starting from 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and [S, S] -2,8-diazabicyclo- [4.3] .0] -nononate, the reaction may be illustrated by the following reaction scheme:

When, for example, 6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7 - ([1S, 6R] -2-oxa-5,8-diazabicyclo [4.3.1] c) is used as starting material. .0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid and acetylenedicarboxylic acid diethyl ester, the reaction may be illustrated by the following reaction scheme:

COOH + c _; h ₃ o ₂ cc = c-co, c, h ₃

The racemic compounds of formula (II) used as starting materials are largely known. The enantiomeric compounds of formula (II) are novel and can be obtained by a variety of methods:

1. The racemic compound of formula (II) is reacted with an enantiomerically pure adjuvant, the resulting diastereomers are separated, for example, by chromatography, and the chiral auxiliary group is separated again from the desired diastereomers. An example is the following reaction.

COOH

2. The bicyclic amines of formula (VI) are novel as enantiomerically pure compounds. They can be produced by the following procedure.

2.1. Racemic bicyclic amines of general formula (a)

R ⁴

in which it means

R ^{4, a} hydrogen atom or an alkyl group having 1 to 3 carbon atoms, can be reacted with enantiomerically pure acids such as carboxylic or sulfonic acids such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine, acid 3 -bromocamer-9-sulfonic acid, camper-3-carboxylic acid, cis-camperic acid, camper-10-sulfonic acid, 0,0'-dibenzoyltartaric acid, D-tartaric acid, L-tartaric acid, mandelic acid, α- methoxy-phenylacetic acid, 1-phenylethanesulfonic acid and α-phenyl-succinic acid, to a mixture of diastereomeric salts which can be separated into diastereomeric pure salts by fractional crystallization (see P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1). The molar ratio between amine and enantiomerically pure acid can be varied within a wide range. Treatment of this salt with alkali or alkaline earth metal hydroxides can liberate the enantiomerically pure amines.

2.2 In a manner similar to that described in paragraph 2.1, the resolution of the racemates of the basic intermediate steps which occur in the production of racemic bicyclic amines can be carried out by means of the enantiomerically pure acids mentioned above. Examples of such basic intermediate steps include the following compounds (b) to (e).

about

In the following reaction scheme, an example of the resolution of the racemate is shown to separate 8-benzyl-cis-2,8-diazabicyclo [4.3.0] nonane via the tartates into the enantiomers and to carry out the enantiomerically pure cis-2,8-di-azabicyclo [4.3. 0] nonane

H

N-Ph CH -.-

H- / Pd-C

H / Pd-C

H

e.e.> 99%

R, R-configuration

IN

H

H

e.e.> 99%

5, S-configuration

2.3 Both racemic amines (a) and basic intermediates (bv) - (e) can be chromatographically separated over chiral supports (see, for example, G. Blaschke, Angew. Chem. 92, 14 (1980)).

2.4 Both racemic amines (a) and basic intermediates (b), (c), (e) can be carried out by chemical bonding with chiral acyl esters to diastereomeric mixtures which can be separated into diastereomerically pure acyl derivatives by distillation, crystallization or chromatography and of these, the enantiomerically pure amines can be isolated by saponification. Examples of reagents for coupling with chiral acyl esters include methoxy- [alpha] -trifluoromethylpentacetylchoride, menthyl isocyanate, D-[alpha] -phenyl-ethyl isocyanate, L-[alpha] -phenyl-ethyl-isocyanate, chloroformic acid menthyl ester and camphor chloride 10.

2.5 During the synthesis of bicyclic amines (a), chiral protecting groups may also be introduced instead of achiral. In this way diastereomers are obtained which can be separated. For example, in the synthesis of cis-2,8-diazabicyclo [4.3.0] nonane, the benzyl radical can be replaced by an R-configured or S-configured α-phenyl residue:

2.6 Enantiomerically pure amines of formula (VI) may also be formed from enantiomerically pure precursors, such as [R, R] -3,4-dihydroxypyrrolidine or [S, S] -3,4-dihydroxypyrrolidine, which must be on a nitrogen protecting group.

As an example for the synthesis of the enantiomerically pure amine, starting from the enantiomerically pure 1-benzyl-3,4-dihydroxy-pyrrolidine, the following reaction scheme is given:

c, d o N-Bzl

/ --- K

WHAT

I

R

HO OCH, CH, OH

ζ)

I

WHAT

I

R = - O N-H

H

R =, for example, (CH ₃ ) ₃ CO a: H ₂ , Pd / act. charcoal b: acylation c: NaH, BrCH ₂ COOC ₂ H ₅ or c: CH ₂ = CH-CH ₂ Br, NaH d: LiBH ₄ d: O ₃ , NaBH ₄ e: tosyl chloride, NEt ₃ f: benzylamine, xylene, reflux g: hydrolysis h: H ₂ , Pd / act. coal.

Examples of compounds of formula (VI) include: cis-2,8-diazabicyclo [4.3.0] nonane, cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane, trans-2-oxa -5,8-diazabicyclo [4.3.0] nonane, S, S-2,8-diazabicyclo [4.3.0] nonane, 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane, 1S 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane, 1R, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane and 1S, 6S-2-oxa-5,8 diazabicyclo [4.3.0] nonane.

The reaction of compounds of formula (V) with compounds of formula (VI), in which compounds of formula (VI) may also be used in the form of their salts, for example in the form of hydrochlorides, is preferably carried out in a diluent such as dimethylsulfoxide. , Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, or in alcohols such as methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, or in glycol monomethyl ether or pyridine. Mixtures of these diluents may also be used.

All conventional inorganic and organic acid binding agents can be used as acid binders. These preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and organic amidines. Particularly preferred are triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or excess amine of formula VI ).

The reaction temperatures can be varied within a wide range, but are generally carried out at a temperature in the range of 20 to 200 ° C, preferably 80 to 180 ° C.

The reaction can be carried out at normal pressure but also at elevated pressure. In general, the process is carried out at a pressure of from 1 to 10 MPa, preferably from 1 to 10 MPa.

In carrying out the process, 1 to 15 mol, preferably 1 to 6 mol, of the compound of formula (VI) is used per mole of the compound of formula (V).

Examples of compounds of formula (II) which can be used as racemates, as well as diastereomerically pure or enantiomerically pure compounds are:

R ¹ R ² x ' Y A cyclopropyl c, h ₃ H CH ₂ C-H F-CH ₂ CH ₂ H H ch. C-F cyclopropyl c ₂ h ₃ H ch. C-Cl cyclopropyl H H ch. C-OCH-j cyclopropyl H H CH, _C-CH3 cyclopropyl c ₂ h, H CH, N cyclopropyl H br CH, C-F cyclopropyl H C! CH, C-F cyclopropyl H CH ₃ Ch ' C-F cyclopropyl C _; H ₅ NH, CH, C-F cyclopropyl H H ABOUT C-H cyclopropyl C ₂ Hj H ABOUT C-F C, _Hj H H 0 C-Cl CH, H H 0 C-OCH ₃ cyclopropyl H H 0 c-ch ₃ cyclopropyl H H 0 N cyclopropyl H br 0 C-F cyclopropyl H C1 0 C-F cyclopropyl H CH, about C-F cyclopropyl H NH, 0 C-F

cyclopropyl ch ₃ H ch. C-H Cyc'opropyl ch ₂ ch ₂ oh H ch ₂ C-F cyclopropyl ch ₂ ch, oh H ch ₃ C-Cl cyclopropyl H H Ch- ₂ C-Ochi cyclopropyl H H CH, c-ch ₃ cyclopropyl H H CH, N cyclopropyl H br CH, C-F cyclopropyl H F CH, C-F cyclopropyl H ch ₃ CH, C-F cyclopropyl H nh. CH, C-F cyclopropyl H H 0 C-H cyclopropyl CH H 0 C-F H H 0 C-Cl cyclopropyl H H 0 C-OCH cyclopropyl H H 0 c-ch ₃ cyclopropyl H H 0 N cyclopropyl H br 0 C-F cyclopropyl H Cl 0 C-F cyclopropyl H ch ₃ 0 C-F C, H _S H nh. 0 C-F

R ¹ R ² x ¹ Y A cyclopropyl H H CH, C-H cyclopropyl H H CH. C-F cyclopropyl H H CH, C-Cl cyclopropyl H H CH. c-och ₃ cyclopropyl H H CH. C-CH cyclopropyl H H CH, N cyclopropyl H br CH. C-F cyclopropyl H F CH, C-F cyclopropyl H CH; CH, C-F cyclopropyl H NH, CH, C-F cyclopropyl H H 0 C-H cyclopropyl H H 0 C-F cyclopropyl H H 0 C-Cl cyclopropyl H H 0 C-OCH cyclopropyl H H 0 _C-CH3 cyclopropyl H H 0 N cyclopropyl H br 0 C-F cyclopropyl H F 0 C-F cyclopropyl H CH ₌ 0 C-F cyclopropyl H NH- 0 C-F

R ¹ R ² x ' Y A cyclopropyl H H ch ₂ C-H cyclopropyl H H CH, C-F cyclopropyl H H CH. C-Cl cyclopropyl H H CH, C-OCH cyclopropyl H H CH; _C-CH3 cyclopropyl H H CH; N cyclopropyl H br CH. C-F cyclopropyl H F CH, C-F cyclopropyl H ch ₃ CH. C-F cyclopropyl H NH, CH, C-F cyclopropyl H H 0 C-H Cyc.'opropyí H H 0 C-F cyclopropyl H H 0 C-Cl cyclopropyl H H 0 C-OCH cyclopropyl H H 0 C-CH cyclopropyl H H 0 N cyclopropyl H br C C-F cyclopropyl H F 0 C-F cyclopropyl H CH, 0 C-F cyclopropyl H NH, 0 C-F

R · R ² x ¹ Y A 2,4-Dinuorphenyl H Cl CH, C-F 2.4-Dinuorphenyl H CH ₃ CH, CF 2.4-Difluorphenyl H H CH, C-CH 2.4-Din.uorphenyl H H 0 C-F 2.4-Dtŕluorphenyl H H 0 C-Cl 4-Fiuorphenyl H H 0 CH 2,4-difluoropyridin; er.yl H H 0 N 2.4-Difjuorpiienyl H H 0 C-OCH, 2.4-Difluorphenyl H H C-CH ₃ 2.4-Difluorplienyl H H CH, C-F 2,4-Dinuorphenyl H F CH, C-F 2.4-Difluorphenyl H H CH, C-Cl 2.4-Dínuorphenyl H H 0 C-Cl 2.4-DinLjorpheny! H H CH, N 2.4-Dinuarpheíiyl H H 0 N 2.4-DíHuorpheny! H H 0 C-H 2.4-Difluorphenyl C, H _; H 0 C-F

SK 285223 Β6

The starting compounds of the formulas (III) and (IV) are known. Examples include: chloroacetone, 4-chloro-2-butanone, 5-chloro-2-pentanone, 1-bromo-2-butanone, phenacyl chloride, methyl acrylate, ethyl acrylate, acrylonitrile, methyl vinyl ketone, dimethyl acetylenedicarboxylic acid dimethyl ester, diethyl acetylenedicarboxylate, methyl propionate and ethyl propionate.

The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out in a diluent such as dimethylsulfoxide, Ν, Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, alcohols, such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine, in the presence of an acid binder. It is also possible to use mixtures of the solvents mentioned.

All conventional inorganic and organic acid-binding agents can be used as acid-binding agents. These preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particular preference is given in particular to triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or an excess amine of formula (VI) ).

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at a temperature in the range of about 20 to 200 ° C, preferably in the range of 60 to 130 ° C.

The reaction can be carried out at normal pressure but also at elevated pressure. Usually, the pressure is in the range of about 0.1 to 10 MPa, preferably 0.1 to 1.0 MPa.

In carrying out the process, 1 to 15 mol, preferably 1 to 6 mol, of the compound of formula (III) is used per mole of the compound of formula (II).

The reaction of the compound of formula (II) with the Michael acceptor of formula (IV) according to Method B is preferably carried out in a diluent such as acetonitrile, dimethylsulfoxide, Ν, Ν-dimethylformamide, alcohols such as methanol, ethanol, propyl alcohol or isopropyl alcohol, or glycol monomethyl ether.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at a temperature in the range of about 20 to 150 ° C, preferably 40 to 100 ° C.

The reaction can be carried out at normal pressure but also at elevated pressure. Usually, the pressure is in the range of about 0.1 to 10 MPa, preferably 0.1 to 1.0 MPa.

In carrying out the process, 1 to 5 mol, preferably 1 to 2 mol, of a compound of formula (IV) is used per mole of the compound of formula (II).

The acid addition salts of the compounds of the present invention are prepared in a conventional manner, for example by dissolving betaine in aqueous acid and precipitating the salts with a water-miscible organic solvent, such as methanol, ethyl alcohol, acetone or acetonitrile. Equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether may also be heated and then evaporated to dryness or the precipitated salt aspirated. Pharmaceutically useful salts are, for example, salts with hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

For example, the alkali metal or alkaline earth metal salts of the carboxylic acids of the present invention are obtained by dissolving betaine in excess alkali metal or alkaline earth metal hydroxide, filtering the undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are the sodium, potassium and calcium salts. Reaction of the alkali metal or alkaline earth metal salts with a suitable silver salt, such as silver nitrate, yields the corresponding silver salts.

In addition to the active compounds mentioned in the Examples section, the compounds described in the following table (optionally in cis or trans form) can be prepared by the processes described.

R ³

X ¹ A

C.H 3 OC-CH.-CH; · CH; OC-CH = CHNC-CH.-CH.5-Methyl · 2-oxo-1,3-diosol-4-yl-methoxyCH 3 -CO-CH 5 -M5: hyi-2-oxo-3- <fíoxol-4-yl -methylCH - CO-CH _r CH _r

CH-CO-CH-CHjC.KjOjC-CH

C, HO-C-CH = C-CO-CaH _s

CH ₃ O ₂ C-CH = CHCl ₂ H ₃ O; C-CH = CHCH 3 -CO-CH 2 CH; C ₃ H ₃ O ₃ -C-CH 3 CH 2 O, O, C-CH = C-CO _: CH ₃

I

C.HjO.C-CH-C-H-CC.C <

'' I

HC-F

HC-F

HC-F

HC-F

R. C.-Cl

HC-Cl

HC-H

HC-H

HC-H

KC-H

HC-H

FC-F

NH, C-F

S'H, C-F

NHjC-F

NH _; CF

COOH

R ³ x ¹ A c _; h _} o ₂ c-ch = ch- NH ₃ C-F CH _r CO-CH ₂ CH ₂ - H N C.HjOjOCHj-chi- H N NC-CH-CH, - H N C _; H <0 ₂ C-CH = C-CO ₂ C ₂ H _; H N CH-O _: C-CH = CH- H N CH-CO-CHjCHj ' CH C-H CH - CO-CH, - ch ₃ C-H CHíOjC-CHjCHj- CH, C-H c ₂ h ₂ o ₂ c-ch = c-co ₂ c ₂ h _j ^CH 3 C-H CH ₂ O ₂ C-CH = C-CO ₂ CH ₃ CH, C-H C, HjOjC-CH = CH- CH, C-H CH ₃ O ₂ C-CH = CH- CHy C-F C ₂ H _} O ₂ C-CH = C-CO2C ₂ H ₅ CH ₃ N

R ³ x ¹ A CH ₃ -CO-CH ₂ CH ₂ - H C-F ch ₃ -co-ch ₂ - H C-F c ₂ h ₃ o _: c-ch _: ch ₂ - H C-F NC-CH ₂ CH _; - H C-F CH ₃ O ₂ C-CK = CH- H C-F ch, o, c-ch = c-co, ch ₂ H C-F GHjOpCH ^ C-COjG.Hf H C-F S-oxo-Meihyl ^ L. S-dioxo-yl-nethyl- H C-F CH ₃ -CO-CH ₂ CH ₂ - H C-Cl ch ₃ -co-ch ₂ - H C-Cl C ₂ H ₂ C-CE ₂ CH _; - H C-Cl N'C-CHiCHj- H C-Cl CH ₃ OC = CH · H C-Cl

CH ₃ O ₂ C-CH = C-CO ₂ CH ₃

C _: H ₅ OC.CH = C-CO ₂ C ₂ Hj

5-Meihyl-2-oxo-1,3-dioxol-4-yl-methyl ·

H, C-Cl

H, C-Cl

H C-C:

R ¹ x ¹ A C _! H ₂ O ₂ C-CH = C-CO ₂ C _: H ₅ H C-H c ₂ h ₃ o ₂ c-ch = ch- H C-H CH ₂ O ₂ C-CH = CH- F C-F C _: H ₃ O ₂ C-CH ₂ -CH.- F C-F c _: h ₃ o ₂ c-ch = ch- NH ₂ C-F C _: H ₃ O ₂ C-CH = C-CO _; C, H ₃ nh ₂ C-F CW ₃ -CD-CH _; CH ₂ - ch ₃ C-H C ₂ H? O _; C = CH · ch ₃ C-H C ₂ H ₃ C ₂ C-CH = C-CO ₂ C ₂ Hj ch ₃ C-H CH _{3 O-C-T} C = _CH-CO; C ₂ H ₃ CH ₃ \ _{CH3 -CO-CH.CH;} - H C-OCH, C ₂ H ₃ O _: C-Cb> CH- E c-och ₃ C ₂ H 10 -C-CH = CH H N nc-ch _: ch ₂ H N ch ₃ -co-ch, ch ₂ H N

The compounds of the present invention act strongly antibiotic and have a broad antibacterial spectrum against gram-positive and gram-negative germs, in particular against enterobacteria, in particular against those which are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and sulfonamides.

These valuable properties make them useful as chemotherapeutic active substances in medicine, as well as for the preservation of inorganic and organic materials, in particular organic materials of all kinds, for example polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds of the present invention are active against a very wide range of microorganisms. They can be used to combat gram-negative and gram-positive bacteria and bacteria-like microorganisms, as well as to suppress, ameliorate and / or treat diseases caused by these agents.

The compounds of the present invention exhibit an enhanced effect on calm and resistant germs. In calm bacteria, that is, bacteria that have no detectable growth, these compounds act well below the concentration of substances known so far. This applies not only to the amount used but also to the killing rate. Such results have been observed in Gram-positive and Gram-negative bacteria, particularly in Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

In particular, the bacteria according to the invention have a surprising spectrum of activity against bacteria which are classified as being less sensitive against comparable substances, in particular resistant strains of Staphylococus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococus faecalis.

The compounds of the present invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by these agents.

The compounds are also suitable for combating protozoonoses and helminths.

The compounds of the present invention can be used in various pharmaceutical compositions. Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, jellies, creams, skin preparations, powders and sprays.

The following table demonstrates the surprising advantages of the compounds of the present invention over Ciprofloxacin in a model of Staphylococcus aureus infected mice.

table

Efficacy in Staphylococcus aureus infection in mice (mgfcg) ____________, __________________,

substance after. sc ciprofloxacin 80 80 Example 2 10 2.5 Example 4A 5 5 Example 6 10 10 Example 8 10 5 Example 10 2.5 2.5

DETAILED DESCRIPTION OF THE INVENTION

Production of pre-products

Example A [S, S] -2,8-Diazabicyclo [4.3.0] nonane

NH

H

1. [S, S] -8-Benzyl-2,8-diazabicyclo [4.3.0] nonane Method I

a) Separation of diastereomeric salts

D - (-) - tartaric acid (3.0 g, 20 mmol) was dissolved in dimethylformamide (10 ml) while warming to 80 ° C and stirred with a solution of cis-8-benzyl-2,8 (2,16 g, 10 mmol). -diazabicyclo [4.3.0] nonane in 3 ml dimethylformamide. The reaction mixture is stirred for one hour at 0 ° C, then the product is filtered off with suction and washed with dimethylformamide and methoxyethanol.

Yield: 1.93 g Melting point: 146-151 ° C [α] _D ²³ = -19.3 ° (c = 1, H ₂ O).

Simple crystallization from methoxyethanol gives diastereomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

^ = -22.7 ^ = 1, ^ 0). mp 148-154 ° C.

(b) Base release g [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is dissolved in 250 ml of water and mixed with 32 g of 45% sodium hydroxide. The precipitated oily liquid is taken up in 150 ml of tert-butyl methyl ether, the aqueous phase is extracted once more with 150 ml of tert-butyl methyl ether, and the combined organic phases are dried after drying over anhydrous sodium sulphate. Then the residue is distilled under vacuum.

Yield: 18.5 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -onane, boiling point: 107-109 ° C / 10 Pa, [α] _D ²⁴ = 17.3 ° (undiluted).

Method II

Dissolve 75.0 g (0.5 mol) of L - (+) - tartaric acid at 80 ° C in 250 ml of dimethylformamide and add dropwise

54.1 g (0.25 mol) of cis-8-benzyl-2,8-diazabicyclo [4.3.0] -onane as a solution in 75 ml of dimethylformamide. The reaction mixture was slowly cooled to 20 ° C and the formed crystal slurry was stirred for an additional hour. The formed crystals of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonan-L-tartate are filtered off with suction and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 500 ml of water and treated with 63 g of 45% sodium hydroxide as described in Method 1. Yield: 25.2 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane;

The product contains 3.6% of the R, R-enantiomer (after derivatization with methyl ester of chloroformic acid as determined by gas chromatography).

The compound can be reacted with D - (-) - tartaric acid on diastereomeric pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartate according to Method I. Crystallization is not necessary here.

Method III

73.6 g (0.34 mol) of cis-8-benzyl are added dropwise to a solution of 102.9 g (0.685 mol) of L - (+) - tartaric acid in 343 ml of dimethylformamide at a temperature between 80 ° C and 90 ° C. -2,8-diazabicyclo [4.3.0] nonane as a solution in 111 ml of dimethylformamide. Inoculate with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate and slowly cool to an internal temperature of 18 ° C. The formed crystals are aspirated, the filtrate is seeded with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate, and the mixture is stirred until crystallization is complete. (After concentration and liberation of the base, method D can be obtained by purification with D - (-) - tartaric acid [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-D from the mother liquor -Tartu). The crystals are then filtered off with suction, washed with dimethylformamide and isopropyl alcohol and air-dried. The crystals were recrystallized from 88% ethyl alcohol. 52 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartrate trihydrate are obtained.

Melting point: 201-204 ° C, [α] _D ²³ = + 5.2 ° (c = 1, H ₂ O).

The salt can be treated as described in Method I (base release) to enantiomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

Method IV

a) Separation of the enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] -onane into [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane

The procedure is analogous to that described in Example B (method ΙΙ / a) using D - (-) - tartaric acid as the chiral auxiliary, or as follows:

The mother liquor and the wash liquor from [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonan-L-tartate (from Example B, method ΙΙ / a) are concentrated together They are taken up in water and extracted three times with toluene. The toluene phase is removed and the aqueous phase is mixed with sodium bicarbonate solution to adjust the pH to 7-8. Then it is extracted four times with methylene chloride, the combined methylene chloride phases are dried over anhydrous magnesium sulphate and concentrated.

Yield: 14.4 g (60% of theory of the initially charged cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] mononate), [α] _D ²³ = - 4.5 ° ( c = 5, ethanol).

The 14.4 g (59 mmol) of D - (-) - tartaric acid was crystallized with 120 ml of ethyl alcohol analogously to Example B (Method II / a).

Yield: 8.9 g (77% of theory) of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonan-D-tartate, [a] _D ²³ - 46.2 ° (c = 0.5, 1N HCl);

after crystallization with a mixture of ethyl alcohol and glycol monomethyl ether, the following are obtained without further purification: [α] _D ²³ = - 59.3 ° (c = 0.5, 1n HCl).

5.0 g (12.7 mmol) of the diastereomerically pure tartrate obtained above were converted to the free amine by the procedure described in Example B, Method II / a. Yield: 3.0 g (96% of theory) of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, m.p. [ _Α ] ²³ _D = 22.2 ° (c = 5, ethanol).

An excess of enantiomers of 96.6% were found by gas chromatography after derivatization with mentyl chloroformate.

b) Reduction of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane to [S, S] -8-benzyl-2,8-diazabicyclo [4.3] .0] nonane

The procedure is analogous to Example B (Method II / b), but using [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane as the starting material.

The crude product obtained after work-up showed to be derivatized with methyl chloroformate as [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane. Racemization was not observed in the reduction.

2. [S, S] -2,8-Diazabicyclo [4.3.0] nonane

28.4 g (0.131 mol) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are hydrogenated in 190 ml of methyl alcohol in the presence of 5.8 g of palladium on activated carbon (5%) at 90 ° C and 9 MPa for 5 hours. The catalyst is then filtered off, washed with methanol and the filtrate is concentrated by rotary evaporation. The residue was distilled without fractionation. Yield: 15.0 g (90.5% of theory) of [S, S] -2,8-diazabicyclo [4.3.0] nonane boiling point: 44-59 ° C / 0.18 mbar [α] _D ²² = - 2.29 "(undiluted), ee> 99% (ascertained by gas chromatography after derivatization with Mosher's reagent).

Method

3.75 g (25 mmol) of L - (+) - tartaric acid are dissolved in 50 ml of dimethylformamide at 80 ° C and 10.82 g (50 mmol) of cis-8-benzyl-2,8-diazabicyclo [dropwise] are added. 4.3.0] -nonane as a solution in 15 ml of dimethylformamide. Subsequently, seed with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate and stir for one hour at about 72 ° C until the formation of seed crystals is complete. The mixture was then cooled slowly to 15 ° C, filtered off with suction and washed twice with 13 ml of dimethylformamide each time. The combined filtrates were heated to 80 ° C and treated with an additional 3.75 g (25 mmol) of L - (+) - tartaric acid. Heat to 119 ° C until a clear solution is formed and slowly cool again to room temperature while seeding with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate. The crystals formed are filtered off with suction, washed successively with dimethylformamide, 2-methoxyethanol and ethyl alcohol and dried.

Yield: 9.59 g Melting point: 188-192 ° C

The crystals were recrystallized from 95 ml of 80% ethyl alcohol to give 8.0 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate trihydrate (7% of theory), which melts with foaming at a temperature in the range 112 to 118 ° C, then solidifies again and melts again at a temperature in the range 199 to 201 ° C.

[α] _D ²³ = 4.5 "(c = 1, water), ee: 98.0% (determined by gas chromatography after derivatization with menthyl chloroformate).

Example B [R, R] -2,8-Diazabicyclo [4.3.0] nonane

NH

H

1. [R, R] -8-Benzyl-2,8-diazabicyclo [4.3.0] nonane Method I

The [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane crystals obtained according to Example A, Method II are washed with dimethylformamide and methoxyethanol (49.2 g) and recrystallized from 300 ml of methoxyethanol. 45.6 g of enantiomerically pure [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonan-L-tartate are obtained by purification of the enantiomers as determined by gas chromatography after derivatisation with menthyl chloroformate).

mp: 121-124 ° C, [α] _D ²³ = + 22.3 ° (c = 1, H ₂ O).

The obtained salt (44.5 g) was converted to the free base as described in Example A, Method Ib. 20.2 g of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are obtained. Boiling point: 107-111 ° C / 0.04 mbar, [α] _D ²⁴ = - 17.5 "(undiluted).

Method II

a) Separation of the enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] -onane into [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane

24.1 g (98.8 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane are heated in a three-necked flask in a mixture of 410 ml of ethanol and 25 ml of acetonitrile to reflux. Then 14.8 g (98.8 mmol) of L - (+) - tartaric acid are added in one portion. After all the amount of tartaric acid has completely dissolved, heating is first removed, but the flask is left in an oil bath. When the system has cooled so far that the solution no longer boils, stirring is discontinued. At 50 ° C crystallization occurs after the addition of seed crystals. The mixture is allowed to stand overnight, cooled to room temperature, the precipitated crystals are filtered off with suction, washed with a small amount of a mixture of petroleum ether and ethyl alcohol (1: 1) and dried for 2 hours at 80 ° C.

Yield: 9.8 g (50% of theory) of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonan-L-tartate, [α] _D ²³ = + 47.7 "(c = 0.5, 1N HCl).

Recrystallization from ethanol / glycol monomethyl ether can be further purified by double recrystallization.

[α] _D ²³ = + 58.6 "(C = 0.5, 1N HCl).

1 H-NMR (DMSO): 7.22-7.35 (2m, 2H, aryl-H); 4.55 (s, 2 H, benzyl _CH2);

4.28 (s, 2H, tartaric acid-CH); 3.91 (d, 1H, 1H); 2.97 (dd, 1H, 6CH); 2.53 to 2.66 (m, 2H, _3-CH2); 1.78 and 1.68 (2m, 2H, _5-CH2); 1.42 and 1.28 ppm (2m, 2H, _4-CH2).

C ₁₈ H ₂₂ N ₂ O ₈ (394) calculated C 54.4 H 5.6 N 7.1 O 32.5 found C 54.7 H 5.8 N 7.1 0 32.4

The absolute configuration is determined by X-ray structure analysis:

CO, H

CO ₂ H

3.6 g (9.1 mmol) of the diastereomerically pure tartrate thus obtained are dissolved in water to liberate the base and mixed with saturated sodium bicarbonate solution until a pH of 7-8 is reached. The aqueous solution is extracted four times with 20 ml of methylene chloride each time. and the combined methylene chloride phases are dried over anhydrous magnesium sulfate and dried.

Yield: 2.2 g (99% of theory) of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, [α] _D ²³ - + 21.8 " (c = 5, ethanol).

Excess of one enantiomer of 93.8% is determined by gas chromatography after derivatization with menthyl chloroformate.

b) Reduction of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane to [R, R] -8-benzyl-2,8-diazabicyclo [4.3] .0] nonane

0.34 g (9 mmol) of lithium aluminum hydride in 18 ml of anhydrous tetrahydrofuran was added to a heated flask under nitrogen and 0.73 g (3 mol) of [1R, 6S] -8-benzyl-7,9-dioxo-2 was added dropwise. 8-diazabicyclo [4.3.0] nonane as a solution in 3 mL of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 16 hours. Work-up is carried out dropwise with 0.34 ml of water in 10 ml of tetrahydrofuran, 0.34 ml of 10% sodium hydroxide and 1.02 ml of water. The precipitate formed is filtered off with suction, washed with tetrahydrofuran and the filtrate is concentrated. 0.7 g of crude [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane is obtained as a residue.

No racemization was observed when determining the purity of the enantiomers with methyl chloroformate by gas chromatrography.

2. [R, R] -2,8-Diazabicyclo [4.3.0] nonane

Following the procedure of Example A, 2, 19.4 g (0.09 mol) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane was hydrogenated. Yield: 9.61 g (85% of theory) of [R, R &lt; 2 &gt; -2,8-diazabicyclo [4.3.0] nonane, boiling point: 45-48 [deg.] C / 0.08 mbar, [ _{α D} ²³ = + 2] , 30 ° (undiluted).

Example C [S, S] -2-Methyl-2,8-diazabicyclo [4.3.1] gononate

CH ₃

H

1. [S, S] -8-Benzyl-2-methyl-2,8-diazabicyclo [4.3.

43.2 g (0.2 mmol) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane are mixed with 20 ml of 37% formaldehyde solution, 40 ml of water and 24 g of glacial acetic acid. and hydrogenated for 10 hours at 20 ° C and 2.0 MPa using 2 g of palladium on charcoal (5%). It is then filtered off with suction, the filtrate is made alkaline with potassium carbonate and the product is extracted with tert-butyl methyl ether. After drying over anhydrous sodium sulfate, the solution is concentrated and the residue is distilled under vacuum.

Yield: 14.8 g, boiling point: 114-124 ° C / 0.14 mbar.

2. [S, S] -2-Methyl-2,8-diazabicyclo [4.3.-iodonate

12.9 g (56 mmol) of [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane are hydrogenated in 90 ml of methanol at 90 ° C and 9.0 MPa using palladium on activated carbon (5%). The mixture is then filtered, the filtrate is concentrated by rotary evaporation and the residue is distilled under vacuum. Yield: 5.5 g of enantiomerically pure [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane (proof by derivatization with Mosher's reagent), boiling point: 78-81 ° C / 14 mbar.

Example D [R.R] -2-Methyl-2,8-diazabicyclo [4.3.0]

CH

The title compound was prepared according to the procedure for EXAMPLE C starting from 43.2 g (0.2 mol) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

Yield: 4.9 g of [R, R &lt; 2 &gt; -2-methyl-2,8-diazabicyclo [4.3.0] naphthane, boiling point: 30-33 [deg.] C. / 0.12 mbar.

Example E cis-7,9-Dioxo-8 - ([1S] -1-phenyl-ethyl-2,8-diazabicyclo [4.3.0] -nonane

1. Pyridine-2,3-dicarboxylic acid ([1S] -1-phenyl-ethyl) imide

74.5 g (0.5 mol) of pyridine-2,3-dicarboxylic acid anhydride are dissolved in 500 ml of dioxane at 20 ° C and 60.5 g (0.5 mol) of S - (-) - 1 are added dropwise. -phenyl-ethylamine, thereby increasing the temperature to 33 ° C. The reaction mixture was stirred for one more hour, then concentrated on a rotary evaporator and the remaining solvent was removed at 40 ° C / 0.1 mbar. The residue is taken up in 245 g (2.4 mol) of acetic anhydride, mixed with 4.9 g (0.06 mol) of anhydrous sodium acetate and stirred for 1 hour at 100 ° C. After cooling, it is poured into one liter of ice water with good stirring, suctioned off, washed with cold water and hexane and air-dried.

The crude product (114 g, mp 112-114 ° C) was recrystallized from 285 ml of methanol. Yield: 96.3 g (76% of theory), melting point: 115 DEG -117 DEG C., [.alpha.] _D @ ²² = -46.9 DEG (c = 2, ethanol).

2. cis-7,9-Dioxo-8 - ([1S] -1-phenyl-ethyl) -2,8-diazabicyclo [4.3.-iodonate]

79.7 g (0.316 mol) of pyridine-2,3-dicarboxylic acid ([1S] -1-phenyl-ethyl) -imide is hydrogenated in 600 ml of tetrahydrofuran at 90 ° C / 10 MPa using 10 g of palladium on active coal (5%). After the uptake of hydrogen was complete, the catalyst was filtered off and the filtrate was completely concentrated. 83.7 g of a viscous residue are obtained.

Content: 95%, 1 H-NMR (CDCl ₃ , 200 MHz): 1.4-1.7 (m, 3H); 1.82 and 1.83 (2d, 3H); 1.9 - 2.05 (m, 1H); 2.88 (broad S, 1H); 2.54 - 2.86 (m, 3H); 3.77 (d, IH); 5.39 (q, IH); 7.24-7.48 ppm (m, 5H).

Example F cis-2-Oxa-5,8-diazabicyclo [4.3.-iodonate

H

I.

NH I NH

1. trans-1-Benzoyl-3-bromo-4- (2-hydroxyethoxy) pyrrolidine

95 g (0.55 mol) of 1-benzoyl-3-pyrrolidine are dissolved in 380 g of ethylene glycol and, at room temperature, 101 g (0.57 mol) of N-bromosuccinimide are added to this solution over 2 hours in portions. The reaction mixture was then stirred overnight at room temperature, poured into water, extracted with methylene chloride, dried over anhydrous magnesium sulfate and the resulting solution was concentrated. The residue (188 g) is chromatographed on silica gel using ethyl acetate.

Yield: 136.5 g (78% of theory); content after GC: 99%.

2. trans-1-Benzoyl-3-bromo-4- (2-tosyloxyethoxy) pyrrolidine

92 g (0.239 mol) of trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) pyrrolidine, 32 g (0.316 mol) of trictylamine and 1 g of 4-dimethylaminopyridine are dissolved in 750 ml of toluene and this solution is added dropwise. 60 g (0.31 mol) of tosyl chloride in 450 ml of toluene. The reaction mixture is stirred for 2 days at room temperature, water is added and the aqueous phase is separated and extracted with toluene. The combined toluene solutions were washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated. The residue obtained is dissolved in ethyl acetate, filtered through silica gel and concentrated by filtration. Yield: 125 g (91% of theory).

Thin layer chromatography indicated a uniform compound.

3. cis-8-Benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] -nononate

Heat 124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy) pyrrolidine with 86 g (0.8 mol) of benzylamine in 1.5 L of xylene overnight at reflux. The benzylamine salts are aspirated and the filtrate is concentrated.

Crude yield: 91.2 g.

4. cis-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

91 g (0.265 mol) of cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane with 200 ml of concentrated hydrochloric acid and 140 ml of water are refluxed overnight. After cooling, benzoic acid is filtered off with suction, the solution is concentrated to half its volume, basified with potassium carbonate, extracted with chloroform, dried with potassium carbonate, concentrated and distilled.

Yield: 30.7 g (48.8% of theory), boiling point: 134-142 ° C / 0.6 mbar, GC content: 92%.

5. cis-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

Hydrogenate 26 g (0.11 mol, 92%) of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 180 ml of ethyl alcohol and 19 ml of concentrated hydrochloric acid using 3 g of palladium on activated carbon (10% Pd) at a temperature of 100 ° C and a hydrogen pressure of 10 bar. The catalyst is then filtered off with suction, the filtrate is concentrated and the precipitated crystals are dried in a desiccator over phosphorus pentoxide.

Yield: 17.1 g (77% of theory), m.p. 244-250 ° C.

Example G Separation of enantiomers of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

Dissolve 150.1 g (1 mol) of D - (-) - tartaric acid at 700 to 65 ° C in 700 ml of methyl alcohol and add 218,3 g (1 mol) of cis-5-benzyl-2- oxa-5,8-diazabicyclo [4.3.0] nonane as a solution in 300 ml of methanol. The mixture is then allowed to slowly cool to 49 ° C when the solution becomes cloudy, seeded with the crystals obtained from the previous experiment, 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane Of D-tartrate and stirred at this temperature for 30 minutes to form seed crystals, then slowly cooled to 0-3 ° C. After suctioning off the crystals, they are washed with a mixture of 200 ml of ethanol and 100 ml of ethanol, cooled to 0 [deg.] C. and then three times with 300 ml of ethanol each time. Finally, the product is air dried.

Yield: 160.3 g (87% of theory) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan-tartate melting point: 174.5-176.5 ° C ee> 97% (after derivatization with 1-phenyl-ethylisocyanate and HPLC evaluation) [α] _D ²³ = + 24.0 ° (c = 1, methanol).

156.9 g of the first crystallizate are recrystallized from 1500 ml of methanol.

Yield: 140.0 g (89% recovered), melting point: 176-177 ° C, [α] _D ²³ = + 25.2 ° (c = 1, methanol).

The methanolic mother liquor from the first crystallization is concentrated on a rotary evaporator. The resulting syrupy residue (236g) is dissolved in 500 ml of water and the pH is adjusted to 12-13 with 250 ml of 6N sodium hydroxide solution. This solution is extracted three times with 350 ml of toluene each time, dried over sodium carbonate and concentrated in vacuo. . 113.1 g of residue are obtained in the form of a brown oil which, according to the gas chromatography test, shows 97% of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, which is used without purification for the manufacture of 16S. , 6R enantiomers.

Dissolve 113.1 g (0.518 mol) of crude enriched 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 155 ml of methanol and add dropwise to the boiling solution 77.8 g ( 0.518 mol) of L - (+) - tartaric acid in 363 ml of methanol. Already during the dripping, a crystal slurry slowly forms. The resulting mixture was allowed to stir for one hour at 60 ° C and then slowly cooled to 0 ° C over 2 hours. The crystals are then filtered off with suction, washed with a 2: 1 mixture of ethyl alcohol and methanol, cooled to 0 [deg.] C. and then three times with ethyl alcohol, then air dried.

Yield: 145.5 g (79% of theory) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan-L-tartate, m.p. 174.5-176.5 °. C ee> 97% (after derivatization with 1-phenyl-ethylisocyanate and HPLC evaluation), [α] _D ²³ = - 24.0 ° (c = 1, methanol).

Release of enantiomerically pure bases:

144 g (0.39 mol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan-tartrate are dissolved in 250 ml of water and 175 ml (1.05 mol) are added. 6 n sodium hydroxide. The oily liquid obtained is taken up in 500 ml of toluene, the organic phase is separated and the aqueous phase is extracted three more times with 250 ml of toluene each time. The combined organic phases were dried over sodium carbonate, filtered and the filtrate evaporated on a rotary evaporator. The residue is distilled under a high vacuum through a 20 cm Vigreux column.

Yield: 81.6 g (96% of theory) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, boiling point: 120-139 ° C / 0.04-0, 07 mbar, content: 100% (determined by gas chromatography), density: δ = 1,113 g / ml, [α] _D ²³ = - 60.9 ° (undiluted), distillation residue: 0.12 g.

In the same way 76.0 g (93% of theory) of 1R, 6S are obtained from 139.2 g (0.376 mol) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonate tartrate. 5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

[a] r? ³ = + 61.2 ° (unedited).

The enantiomeric separation described for cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] mononate can also be carried out analogously with trans-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] ] nonane to R, R- and S, S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

Example H

1. 3S, 4S-4-Allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

16.5 g (0.55 mol) of 80% sodium hydride are introduced into 500 ml of absolute dioxane and a solution of 107.5 g (0.53 mol) of tert.-butyl ester of S, S-3 is added dropwise at 60 ° C. 4-dihydroxypyrrolidine-1-carboxylic acid (DE-A-3 403 194) in hot absolute dioxane. The reaction mixture was stirred for one hour at 60 ° C and then 64 g (0.53 mol) of allyl bromide was added dropwise, followed by stirring at 60 ° C for 3 hours. The reaction mixture is concentrated and the residue is dissolved in 200 ml of water and 600 ml of methanol. The solution is extracted three times with 200 ml of pentane each, the methanol is stripped off on a rotary evaporator, diluted with 200 ml of water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, concentrated, and the residue was dissolved in tert-butyl methyl ether (200 mL). 9 g of starting material (44 mol) crystallized overnight. The ether solution was concentrated and distilled.

Yield: 83 g (80% of theory, based on recovered starting material and dialyl ether), boiling point: 149 ° C / 0.7 mbar to 159 ° C / 0.9 mbar. The distillate contains 5% of starting material and 4% of dialyl ether.

The pentane extract provides 17 g of a mixture of 15% of the desired product and 84% of dialyl ether.

[α] _D ²³ = -10.5 "(c = 1, methanol).

2. 3S, 4S-3-Hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid tert-butyl ester

Dissolve 64 g (0.24 mol, 91%) of 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid in 250 ml of methanol, cool the solution to 0 ° C and introduce ozone into it until a subsequent potassium iodide solution washer does not indicate the occurrence of ozone and thus complete reaction. The ozone residue is then displaced by a stream of nitrogen and the resulting ozonide is reduced by 18 g of sodium borohydride, which is added in one-gram portions. After stirring overnight at room temperature, the batch is concentrated, diluted with water and treated with 20 g of potassium carbonate and extracted five times with 100 ml of methylene chloride each time. The organic extracts were dried over anhydrous magnesium sulfate and concentrated.

Yield: 65.8 g (100% of theory), the product is 91% (determined by gas chromatography), [.alpha.] _D @ ²⁰ = -15.2 DEG (c = 0.97, methanol). ^{3 * * * * * * * * * * * * * *}

3. 3S, 4S-1-tert-Butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine

2.7 g (10 mmol, 91%) of 3S, 4S-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid tert.-butyl ester in 30 ml of methylene chloride are added, mixed with 6 ml of%. sodium hydroxide and 0.1 g of benzyltriethylammonium chloride and then a solution of 2.86 g (20 mmol) of tosyl chloride in 10 ml of methylene chloride is added dropwise with cooling. The reaction mixture is stirred for an additional hour at room temperature, poured into 20 ml of water, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried over anhydrous magnesium sulphate and concentrated.

Yield: 5 g (90% of theory); product is uniform by thin layer chromatography.

4. 1S, 6R-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.1] -non-8-carboxylic acid tert-butyl ester

87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine with 58 g (0.54 mol) were heated under reflux overnight in one liter of xylene. benzylamine. The reaction mixture is cooled, the precipitated benzylamine salts are filtered off with suction and the residue is concentrated. Yield: 43 g (58% of theory);

5. 1S, 6R-5-Benzyl-5,8-diazabicyclo [4.3.0] nonan-g (90 mmol) tert-butyl ester of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] 0-N-8-carboxylic acid in 35 ml of concentrated hydrochloric acid and 35 ml of water are refluxed until the evolution of carbon dioxide is complete. Then, the reaction mixture is basified with potassium carbonate, extracted with chloroform, the organic extract is dried over anhydrous magnesium sulphate, concentrated and distilled twice through a 20 cm Vigreux column.

Yield: 11.1 g (55% of theory), boiling point: 108-115 ° C / 0.07 mbar, [.alpha.] _D @ ²⁶ = -58.3 '(not inherited).

Example I

1. 3R, 4R-4-Allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

The reaction is carried out analogously to Example H1) with R, R-3,4-dihydroxypyrrolidine-1-carboxylic acid stereobutyl ester: boiling point: 145 ° C / 0.1 mbar, [ _α ] _D ²³ = + 9, 5 '(c = 1.0, methanol), 95% by gas chromatography.

2. 3R, 4R-3-Hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction is carried out analogously to Example H2) with 3R, 4R-4-allyloxy-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester:

Yield: 99% of theory (0.175 mole feed) [.alpha.] _D @ ²⁰ = + 16.5 DEG (c = 0.94, methanol).

3. 3R, 4R-1-tert-Butoxycarbonyl-3-toloxyloxy-4- (2-tosyloxyethoxy) -pyrrolidine

The reaction is carried out analogously to Example H3) with 3R, 4R-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylic acid tert-butyl ester: Yield: quantitative (0.11 mole yield).

4. 1R, 6S-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] -non-8-carboxylic acid tert-butyl ester

The reaction is carried out analogously to Example H4) with 3R, 4R-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine:

Yield: 40% of theory (0.1 molar charge).

5. 1R, 6S-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

The reaction is carried out analogously to Example H5) with 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.1] mono-8-carboxylic acid stereobutyl ester: Yield: 63% of theory (40 mol%) boiling point: 120 ° C / 0.06 mbar, the product is 95% by gas chromatography, [α] D ²³ = + 58.5 "(undiluted)

Example J

1. 1S, 6R-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochioride

Hydrogenate 7.5 g (34.4 mmol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 200 ml of ethyl alcohol with the addition of 7 ml of concentrated hydrochloric acid using 1 g of palladium on activated carbon (10% Pd) at 100 ° C and 10 MPa. The catalyst is then filtered off and washed several times with water, the combined filtrates are concentrated and the residue is crystallized. The crystals are triturated with ethyl alcohol, suctioned off and air-dried. Yield: 4.6 g (66.5% of theory), melting point: 233-235 ° C.

2. 1S, 6R-2-Oxa-5,8-diazabicyclo [4.3.0] nonane

59 g (0.27 mol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are hydrogenated in 500 ml of ethyl alcohol using 5 g of palladium on charcoal (10% Pd) at a temperature of 120 ° C and a pressure of 12 MPa. The catalyst is then filtered off with suction, the filtrate is concentrated and the residue is distilled. Yield: 32.9 g (95% of theory), boiling point: 65 ° C / 0.03 mbar, rotation: [cc] _D ²⁸ = + 8.2 "(undiluted), ee> 99.5% (derivatization with Mosher's reagent).

Example K

1. 1R, 6S-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

The reaction is carried out analogously to Example J1) with 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane:

Yield: 77% of theory (23.8 mol% batch), m.p. 230-232 ° C.

2. 1R, 6S-2-Oxa-5,8-diazabicyclo [4.3.0] nonane

The reaction is carried out analogously to Example J2) with 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane:

Yield: 93.3% of theory (1.58 moles charge), boiling point: 63-65 ° C / 0.03 mbar, rotation: [α] _D ²³ = - 8.4 "(undiluted), ee value:> 99.5% (derivatization with Mosher's reagent).

Analogously, 1R, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane and 1S, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane can be obtained.

Example L 1R, 6S-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrobromide

1. 1R, 6S-5- (1R-Phenethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

Heat 101.8 g (0.196 mol) of trans-3-bromo-1-tosyl-4- (2-tosyloxyethoxy) pyrrolidine and 72 g (0.584 mol) of R - (+) - 1-phenylethylamine overnight at reflux. in 900 ml xylene. The cooled solution was washed with 2N sodium hydroxide, dried. The mixture is dried over potassium carbonate, the drying agent is removed and the solution is concentrated. Upon cooling, crystals precipitated from the residue, which were filtered off with suction and crystallized from a mixture of 750 ml of petroleum spirit and 200 ml of n-butanol.

Yield: 15 g (39.6% of theory of optically pure material) Melting point: 188 "C, Rotation: [a] _D ²⁸ = + 103.7 ° (c = 1, CHC1 _3).

2. 1R, 6S-8-Tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

13 g (33.6 mmol) of 1R, 6S-5- (1R-phenethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are hydrogenated at 100 ° C and 10 MPa. in 200 ml ethyl alcohol using

2.5 g palladium on charcoal (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is crystallized from 30 ml of toluene.

Yield: 7.5 g (79% of theory), Melting point: 160 -161 "C, Rotation: [a] _D ²³ = + 17.5 ° (C = 1.21, _CHCl3).

3. 1R, 6S-2-Oxa-5,8-diazabicyclo [4.3.0] nonane dihydrobromide

Dissolve 7 g (24.8 mmol) of 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 25 ml of 33% hydrogen bromide in glacial acetic acid, add 5 g of phenol and the reaction mixture is stirred overnight at room temperature, then diluted with diisopropyl ether, the crystallized salt is filtered off with suction and air-dried.

Yield: 5.5 g.

Derivatization with Mosher's reagent and gas chromatography analysis gave only one detectable enantiomer (ee> 99.5%).

Example M

5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid

1. 2-Bromo-3,4,5,6-tetrafluoro-benzoyl chloride

365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid (Tetrahedron 23, 4719/1967) are added to 2 liters of thionyl chloride and the mixture is refluxed for 11 hours until evolution is complete. gas. The excess thionyl chloride is then stripped off in vacuo and the residue is distilled.

Yield: 330 g (85% of theory), boiling point: 81-85 ° C / 3-5 mbar.

2. (2-Bromo-3,4,5,6-tetrafluorobenzoyl) -malonic acid dimethyl ester

15.9 g (0.167 mol) of magnesium chloride are introduced into 150 ml of anhydrous acetonitrile (dried with zeolite) and 26.9 g (0.167 mol) of diethyl malonic ester are added dropwise with cooling. The reaction mixture was then cooled to 0 ° C, 46 ml (33.7 g = 0.33 mol) triethylamine was added dropwise and stirred for a further 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise, stirred for one hour at 0 DEG C. and the mixture is allowed to warm to room temperature overnight. It is then treated with 100 ml of 5N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulphate and concentrated in vacuo. Crude yield: 62.7 g.

3. Charge the (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetic acid crude diethyl ester (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonate into 150 ml. water, treated with 0.6 g of 4-toluenesulfonic acid and heated at reflux for 6 hours, then extracted with methylene chloride, washed with water, dried over anhydrous sodium sulphate and concentrated.

Crude yield: 46 g, boiling point (bead column distillation): 150-160 ° C / 3 mbar, mass spectrum: m / e 342 (M ⁺ ), 297 (M ⁺ -OC 2 H 5), 263 (M ⁺ -) Br), 257, 255 (M ⁺ -CH ₂ CO ₂ C ₂ H ₅ ), 235 (263-28).

4. 2- (2-Bromo-3,4,5,6-tetrafluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester g of crude (2-bromo-3,4,5,6-tetrafluoro-benzoyl) - of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate are added and the reaction mixture is heated under reflux for 2 hours. and then under high vacuum (bath temperature up to 120-130 ° C) and the crude product obtained is reacted in the next step Crude yield: 50.7 g.

5. 2- (2-Bromo-3,4,5,6-tetrafluoro-benzoyl) -3-cyclopropyl-amino-acrylic acid ethyl ester

50.7 g of the crude product from step 4) are mixed dropwise in 90 ml of ethanol with ice-cooling with 8.6 g (0.15 mol) of cyclopropylamine, allowed to stir at room temperature and then allowed to stand overnight. It is further cooled well once again, the crystallizate is filtered off with suction, washed with cold ethyl alcohol and dried.

Yield: 29 g (42% over 4 steps), melting point: 103-105 ° C (from ethanol).

6. 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester g (68 mmol) of 2- (2-bromo-3,4) -ethyl ester 5,6-Tetrafluoro-benzoyl) -3-cyclopropylamino-acrylic was heated at reflux in 6 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride for 6 hours. After cooling, the reaction mixture is poured into water, the precipitated precipitate (red) is filtered off with suction, washed with more water and dried in a hot-air circulation oven at 80 ° C.

Crude yield: 27.3 g, melting point: 150-175 ° C, melting point after recrystallization from glycol monomethyl ether: 187-191 ° C.

7. 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

26.7 g (68 mmol) of crude 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was added to a mixture of 165 ml of acetic acid, 110 ml of water and 18 ml of concentrated sulfuric acid, the reaction mixture is refluxed for 2 hours. The cooled reaction mixture was then poured into ice water, the precipitated precipitate was filtered off with suction, washed with more water and dried in a circulating oven at 80 ° C.

Yield: 19.7 g (80% of theory), melting point: 208-210 DEG C. (decomposition), melting point after crystallization from glycol monomethyl ether: 211-214 DEG C. (decomposition), @ 1 H-NMR (DMSO): .delta. 73 s (1H on C-2), 4.16 m (1H, cyclopropyl), 1.2 m (4H, cyclopropyl) (ppm), mass spectrum: m / e 361 (M ⁺ -H ₂ O) 3 17 (M-CO ₂ ), 41 (100%, C ₃ H ₅ ).

Production of final compounds

Example 1 o

390 mg (1 mmol) of 1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid Dissolve 40 mg of sodium hydroxide in 3 ml of water at room temperature in an ultrasonic bath and mix this solution with 160 mg (1.1 mmol) of R - (+) -. alpha.-methylbenzyl isocyanate under ice-cooling. The precipitate is filtered off with suction, washed with dioxane and dried at 100 ° C under high vacuum. Yield: 530 mg (99% of theory), 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (2- [1R-phenyl-ethyl-aminocarbonyl] -2, -, 8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p .: 208-210 ° C (dec.), [Α] _D ²⁵ = - 23.2 ° C (c = 0.5 , DMF).

The reaction product can be separated into the diastereomers by chromatography and the carbamoyl residue can be removed again by acid hydrolysis.

Example 2

1.95 g (5 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro The 4-oxo-3-quinolinecarboxylic acid was heated in 50 ml of ethyl alcohol for 4 hours under reflux with 2.1 g (30 mmol) of methyl vinyl ketone. The reaction mixture is then concentrated, the residue is taken up with water, the precipitate formed is filtered off with suction, washed with ethyl alcohol and dried at 100 DEG C./1 mbar.

Yield: 2.1 g (91.5% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [3-oxo- 1-butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) quinolinecarboxylic acid, melting point: 181-193 ° C (decomp.) (crystallized from glycomonomethyl ether), [ct] _D ²⁴ = - 120 7 ° (c = 0.57, CH ₂ Cl ₂ ).

Example 3

1.95 g (5 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro The 4-oxo-3-quinolinecarboxylic acid is heated in 30 ml of dimethylformamide for 3 hours to a temperature between 50 ° C and 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol) of triethylamine. The solution obtained is concentrated, the residue is stirred with water (pH 6), the insoluble precipitate is filtered off with suction, washed with water and dried at 100 ° C in a hot-air circulating oven (crude yield: 1.3 g). It is recrystallized from glycol monomethyl ether.

Yield: 1.12 g (50% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [2-oxopropyl] - 2,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 181-184 ° C (dec.), [Α] _D ²³ = -72 ° (c = 0.55, CHCl 3) ₃ ).

Example 4

A. 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1 acid is reacted analogously to Example 2, 4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [3] l-oxo-butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, melting point: 107-109 DEG C., _[a] ^23-53 ° (c = 0 , 67, CHC1 _3), content: 99.2% (HPLC).

B. Analogously with 8-chloro-1-cyclopropyl-7-cis-2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo- 3-Quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (cis-2- [3-oxo-1-butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 124-125 ° C

Example 5

COOH

1.56 g (4 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) Of 4-oxo-3-quinolinecarboxylic acid is mixed in 30 ml of dimethylformamide with 0.82 g (8.8 mmol) of chloroacetone and 1.05 g (10.4 mmol) of triethylamine and the reaction mixture is heated at a temperature ranging for 3 hours. Mp 50-80 ° C. The yellow solution obtained is concentrated at 80 ° C / 1.5 kPa and the oily residue is stirred with water until it solidifies. The solid product is filtered off with suction, washed with water and recrystallized from glycol monomethyl ether.

Yield: 830 mg (47% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [2-oxopropyl] -2-oxa-5,8) diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 192-193 ° C (dec.).

Example 6

CH ₃ -CO-CH ₂ CH ₂

COOH

1.56 g (4 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) The 4-oxo-3-quinolinecarboxylic acid was heated to 50 ml of ethyl alcohol for 3 hours under reflux with 1.8 g (25.6 mmol) of methyl vinyl ketone. The suspension obtained is concentrated at 70 ° C / 1.2 kPa, the residue is stirred with water and recrystallized from glycol monomethyl ether.

Yield: 1.33 g (72% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [3-oxo-1-butyl] -2 Oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 188-189 ° C (dec.).

Example 7

1.95 (4.8 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4- of dihydro-4-oxo-3-quinolinecarboxylic acid was heated in 30 ml of glycol monomethyl ether for 2 hours under reflux with 3 g (30 mmol) of ethyl acrylic acid ester. The reaction mixture is then evaporated, the residue is stirred with water, the precipitate obtained is filtered off with suction and dried (crude yield: 1.9 g). It is recrystallized from glycol monomethyl ether.

Yield: 1.45 g (60% of theory) of 8-chloro-1-cyclopropyl-7 - ([S, S] -2- [2-ethoxycarbonyl-ethyl] -2,8-diazabicyclo [4.3.0] non 8-yl) -6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

mp: 117-118 ° C (dec.), [α] _D ²⁸ - 103.5 ° (c = 0.49, DMF), content: 99.6% (HPLC).

Example 8

NC-CH ₂ -CH ₂

COOH

1.95 g (4.8 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4 of dihydro-4-oxo-3-quinolinecarboxylic acid was heated under reflux for 30 hours in 30 ml of ethyl alcohol with 0.8 g (15 mmol) of acrylonitrile. The reaction mixture is then evaporated, the residue is stirred with water, dried (crude yield 1.9 g) and recrystallized from glycol monomethyl ether.

Yield: 1.6 g (73% of theory) of 8-chloro-7 - ([S, S] -2- [2-cyanoethyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 153-155 ° C (dec.), [α] _D ²⁷ = -98.6 ° (c = 0) , 53, DMF), content of 96% (HPLC); MS: m / e 458 (m ^+), 250, 149 (100%, C ₉ H, _I3 N _2), 110, 49th

Example 9

CHjOOC

1.95 g (5 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro The 4-oxo-3-quinolinecarboxylic acid was heated in 60 ml of ethyl alcohol for 2 hours under reflux with 1.2 g (8 mmol) of acetylenedicarboxylic acid dimethyl ester. The suspension obtained is concentrated, the residue is stirred with water and the precipitate is filtered off with suction and dried. The crude product (2.3 g) was recrystallized from a mixture of glycol monomethyl ether and dimethylformamide.

Yield: 2 g (74% of theory) of 1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonyl-vinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8- yl] -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 262-264 DEG C. (dec), [ajo ²⁴ = + 28.8 ° (c = 0.24 , CH _{2 (} C ₁₂ ).

Example 10

COOH

In analogy to Example 9, the starting product is reacted with dimethyl acetylenedicarboxylic acid dimethyl ester. In 87% yield 8-chloro-1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonyl-vinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8- was obtained. yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 210-212 ° C (dec.), [α] _D ²⁴ = + 16.6 ° (c = 0.5 , DMF).

Example 11

780 mg (2 mmol) of 1-cyclopropyl-7- (cis-2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3 of quinolinecarboxylic acid in 15 ml of ethanol is refluxed for one hour with 500 mg (5 mmol) of ethyl propiolate. The resulting suspension is cooled, the precipitate is filtered off with suction, washed with ml of ethanol and dried at 80 DEG C. under high vacuum.

Yield: 880 mg (90% of theory) of 1-cyclopropyl-7- [2- (trans-2-ethoxyacarbonyl-vinyl) -cis-2,8-diazabicyclo [4.3.0] non-8-yl] -6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 244-246 ° C.

Analogously to Example 11, the following compounds are obtained from the corresponding intermediates:

Example A X ' Y melting point [O> 1d 12 CC1 H CH; 211-213 + 6.3 "(c = 0.5, CHCl 3) 13 CH CH, CH, 199-201 - 205 ° (c = 0.5, CHCl 3) 14 CH H CH, 284-286 -231 ° (c = 0.5, CHCl 3) 15 CF nh ₂ CH, 246-248 -14 ° (c = 0.5, CHCl 3) 16 N H CH, 219-221 -162 ° (c = 0.25, CHCl 3) 17 C-OCH, H CH, -23 ° (c = 0.25, CHCl 3) 18 CF F ABOUT 232-233 + 8 ° (c = 0.25, CHCl 3) 19 CF H CH, 225-227 *)

*) uncrystallized

Example A X ¹ Y melting point [° C] Wd 20 CF H 0 208-209 + 24 ° (c = 0.5, CHCl 3) 21 CCI H 0 197-199 -46 "(c = 0.5, CHCl 3) 22 CF F 0 230-232 -5 ° (c = 0.25, CHCl 3)

Example 23

Analogously to Example 11, 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1 is reacted. 4-dihydro-4-oxo-3-quinolinecarboxylic acid with methyl propiolate in ethyl alcohol or methyl alcohol to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [2-trans-2] (methoxycarbonyl-vinyl) - [S, S] -2,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid. mp: 220-222 ° C (dec.), [α] _D ²⁴ = + 8.2 ° (c = 0.5, CHCl 3).

SK 28S223 B6

Example 24

Example 27

CH ₃ O ₂ C ^ </

H

COOH

407.5 g (1 mmol) of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid in 10 ml of methanol was heated under reflux for 1 hour with 210 mg (2.5 mmol) of ethyl propiolate. The reaction mixture was then concentrated and the isolated crude product (450 mg) was crystallized from 4 ml of acetonitrile. Yield: 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5-trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diazabicyclo [4.3] .0] non-8-yl] -4-oxo-3-quinolinecarboxylic m.p. 153-156 ° C (dec.), [Α] _D ²⁸ = + 36 ° (c = 0.5, CHCl 3).

Example 25

COOH

Analogously to Example 24, 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl) -4-oxo-3-quinolinecarboxylic acid to give 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) ) -cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid.

Melting point: 169-170 ° C (decomposition) (crystallized from glycol monomethyl ether).

Example 26

COOH

Analogously to Example 24, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl) -4-oxo-3-quinolinecarboxylic acid to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diaza-bicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid.

Melting point: 230 - 234 ° C (decomposition) (crystallized from glycol monomethyl ether).

[α] _D ²⁸ = - 27 ° (c = 0.5, CHCl 3)

Analogously to Example 24, 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] is reacted) non-8-yl) -4-oxo-3-quinolinecarboxylic acid to give 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [5- (trans-2- methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid.

Melting point: 158 - 160 ° C (decomposition) (isopropyl alcohol crystals).

[α] _D ²⁸ = + 8 ° (c = 0.27, CHCl ₃ ).

Example 28

Analogously to Example 11, 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1, ethyl ester was reacted. 4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonyl-vinyl) -1,6,6-2,8-diazabicyclo [4.3.0] non-ethyl ester 8-yl] -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 168-169 ° C.

Example 29

818 mg (2 mmol) of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] -non-8) of ethyl-4-oxo-3-quinolinecarboxylic acid in 15 ml of ethanol is mixed with 680 mg (4 mmol) of acetylenedicarboxylic acid diethyl ester and the mixture is treated for one hour at 30 ° C in an ultrasonic bath. The suspension is filtered off with suction, washed with ethyl alcohol and dried at 70 ° C under high vacuum.

Yield: 890 mg (77% of theory) of 1-cyclopropyl-7- [5- (1,2-bis-ethoxycarbonyl-vinyl) -1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non 8-yl] -5,6,8-trifluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 220 - 222 ° C (decomposition) (crystallized from glycol monomethyl ether), [α] _D ²⁵ - 57 ° (c = 0.5, CHCl 3).

Example 30

C ₂ H ₅ O ₂ C

COOH

B represents a mixture of enantiomers and / or diastereomers of the radical of the formula

Analogously to Example 11, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-) was reacted. yl) -4-oxo-3-quinolinecarboxylic acid to give 1-cyclopropyl-7- [5-trans-2-ethoxycarbonyl-vinyl) -trans-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl] -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 266-268 ° C (decomposition) (crystallized from glycol monomethyl ether).

Example 31

Analogously to Example 11, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-) was reacted. yl) -4-oxo-3-quinolinecarboxylic acid with methyl propiolate to give 1-cyclopropyl-7- [5- (trans-2-methoxycarbonyl-vinyl) -trans-2-oxa-5,8-diazabicyclo [4.3] .0] non-8-yl] -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. Melting point: 275 - 277 ° C (decomposition).

Claims (9)

Quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) in which: A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N, X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group, R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or R ¹ and A may together represent a bridge of the structure C-O-CH ₂ -CH (CH ₃ ) -, R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl group, wherein Y represents an oxygen atom or a methylene group and R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ groups, CH ₂ CH ₂ CO ₂ R ', RO ₂ C-CH = C-CO ₂ R', I -CH = CH-COjR'alebo CH ₂ CH ₂ -CN, wherein R 'represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 3 carbon atoms, with the exception of derivatives of quinolone and naphthyridonecarboxylic acids of the formula (I) wherein B is meant the residue of formula wherein Y is _CH2 and ^R3 is as defined above, and pharmaceutically usable hydrates and acid addition salts, as well as salts of the corresponding acids with alkali metals, alkaline earth metals, silver and guanidine. 2. A compound according to claim 1, wherein the compound of formula (I): A is CH, CF, CC1, _C-OCH3 or N, X ¹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an amino group or a methyl group, R ¹ is ethyl, 2,4-difluorophenyl, or R ¹ and A may together represent a bridge of the structure C-O-CH ₂ -CH (CH ₃ ) -, R ² represents hydrogen, methyl, ethyl or 5-methyl-2-oxo-l, 3-dioxol-4-yl group and metyIovú R ³ is CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', RO ₂ C-CH = C-CO ₂ R', CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, wherein R 'represents an alkyl group having 1 to 2 carbon atoms, and the pharmaceutically usable hydrates and acid addition salts thereof, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine. A process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) according to claim 1 or 2, wherein: A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N, X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group, R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -, R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, B represents a mixture of enantiomers and / or diastereomers of the radical of formula wherein: Y represents an oxygen atom or a methylene group, R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H 5, CH ₂ CH ₂ CO ₂ R 'or CH ₂ CH ₂ -CN, wherein: R 'represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 3 carbon atoms, characterized in that a compound of formula (II) in which A, Y, X ¹ , R ¹ and R ^{2 are} as defined above, is reacted with a compound of formula (III) R ³ - X ³ (III) in which R ³ represents an oxoalkyl group having 2 to 5 carbon atoms or CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO ₂ R 'and CH ₂ CH ₂ -CN, wherein: R 'represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; 3 carbon atoms and X ³ represents a halogen atom, in particular chlorine, bromine or iodine, optionally in the presence of acid binders. A process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1 or 2, in which: A is CH, CF, CC1, _C-OCH3, C-CH ₃ or N, X ¹ represents a hydrogen atom, a halogen atom, an amino group or a methyl group, R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FCH ₂ CH ₂ - group, a cyclopropyl group, a phenyl group, optionally substituted one to three times with a halogen atom, or R ¹ and A may together represent a bridge of the structure CO-CH ₂ -CH (CH ₃ ) -, R ² represents hydrogen, alkyl having 1 to 3 carbon atoms, optionally substituted by halogen or amino, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, B represents a mixture of enantiomers and / or diastereomers of the radical of formula wherein: Y represents an oxygen atom or a methylene group, R ³ represents the groups CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', r ₂ c-ch = c-co ₂ r; -ch-ch-co ₂ R 5 or CH ₂ CH ₂ -CN, wherein R 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, characterized in that a compound of formula (II) (II) is reacted. in which A, Y, X ¹ , R ¹ and R ^{2 are} as defined above, with a Michael acceptor, such as a dialkyl acetylenedicarboxylic acid ester, an alkyl propionate or a compound of formula (IV) CH ₂ = CH-R ⁵ (IV) wherein R ⁵ is COCH ₃ , CO ₂ R 'or CN. The quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) according to claim 1 for use in the treatment of diseases. The quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) according to claim 1 for use in the treatment of infectious diseases. Medicaments, characterized in that they contain, as active ingredient, quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) according to claim 1. SK 285223 Β6 Medicaments having an antibacterial action, characterized in that they contain, as active principle, quinolone carboxylic acid and naphlyridone carboxylic acid derivatives of the general formula (I) according to claim 1. Use of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) according to claim 1 in the manufacture of medicaments for combating infectious diseases.