SK285155B6 - Enantiomer-pure quinoline and naphthyridone carboxylic acid derivatives, a method of their production, pharmaceuticals containing these substances and their use - Google Patents

Abstract

The solution involves the enantiomeric pure derivatives of quinoline and naphtyridone carboxyl acid of general formula (I), where the substituents are given in the description, a process of their preparation, pharmaceuticals containing these substances and their use for producing of antibacterial agents and feed additives.

Description

Technical field

The invention relates to enantiomerically pure quinolone carboxylic acid and naphthyridone carboxylic acid derivatives, a process for their preparation and 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.

SUMMARY OF THE INVENTION

The present invention provides enantiomerically pure 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‘ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, optionally substituted by a halogen atom or an amino group, or a 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl group,

B represents the remainder of the formula

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 the enantiomerically pure quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (I) in which:

A is CH, CF, CCl, 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 a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, and

R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, 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, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, 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 enantiomerically pure 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 a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl,

B is a radical of the formula wherein

Y represents an oxygen atom and

R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms,

CH ₂ -CO-C ₆ H ₃ , CH ₂ CH ₂ CO ₂ R ', RO ₂ C-CH = C-CO ₂ R',

I

-CH = CH-CO ₂ R or CH ₂ CH ₂ -CH, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein:

R 'is hydrogen or C skupi \ / I / ^H / - \ .......... ..... ^h of ^h-s

R 'N Y R Y in which

Y represents an oxygen atom and

R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms or groups

CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', RO ₂ C-CH = C-CO ₂ R',

I

-CH = CH-CO ₂ R or CH ₂ CH ₂ -CN, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein:

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

COOR ² (V), wherein A, R ¹ , R ² and X ^{1 are} as defined above and X ² is a halogen atom, especially fluorine or chlorine, with enantiomerically pure compounds of formula (VI)

in which

Y represents an oxygen atom and

R ⁴ represents a hydrogen atom or an alkyl group having 1 to C atoms, optionally in the presence of acid binders, and the reaction product is optionally reacted further with a compound of formula (111a)

R ⁴ -X ³ (IIIa), wherein X ^{3 is} as defined above a

R ⁴ represents an oxoalkyl group having 2 to 5 carbon atoms, or the group CH ₂ -CO-C _D H _5, CH ₂ CH ₂ CO ₂ R, and CH ₂ CH ₂ -CN, wherein

R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or with a Michael acceptor, such as a dialkyl acetylenedicarboxylic acid ester, an alkyl ester of propiolic acid or a compound of formula (IV)

CH ₂ = CH-R ⁵ (IV) wherein

R ⁵ is COCH ₃ , CO ₂ R 'or CN.

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 reactions of compounds of formula (V) with compounds of formula (VI), wherein the compounds of formula (VI) may also be used in the form of their salts, for example in the form of hydrochlorides, are preferably carried out in a diluent such as dimethyl sulfoxide. Ν, Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfolane, acetonitrile, water, or in alcohols such as methyl alcohol, 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 the general 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 both as racemates and as diastereomerically pure or enantiomerically pure compounds are:

F 1 ⁰ "COOR- R ¹ R, R ² AN 1 R - X ¹ (H) Y A cyclopropyl c ₂ h ₅ H ch ₂ C-H F-CH ₂ CH ₂ H H ch ₂ C-F cyclopropyl c ₂ h ₅ H ch ₂ C-Cl cyclopropyl H H ch ₂ C-OCH cyclopropyl H H ch ₂ C-CH cyclopropyl c ₂ h ₅ H ch ₂ N cyclopropyl H br ch ₂ C-F cyclopropyl H Cl ch ₂ C-F cyclopropyl H ch ₃ ch ₂ C-F cyclopropyl C ₂ H ₅ nh ₂ ch ₂ C-F cyclopropyl H H 0 C-H cyclopropyl C ₂ H ₅ H 0 C-F c ₂ h ₅ H H 0 C-Cl CH 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 cyclopropyl H nh ₂ 0 C-F

R ¹ ¾ ° 11 H ^AN n Ας R ¹ R ² XOOR ² J l x ¹ (11) Y A cyclopropyl ch ₃ H ch ₂ C-H cyclopropyl ch ₂ ch ₂ oh H ch ₂ C-F cyclopropyl ch ₂ ch ₂ oh H ch ₂ C-Cl cyclopropyl H H ch ₂ C-OCH cyclopropyl H H ch ₂ C-CH cyclopropyl H H ch ₂ N cyclopropyl H br ch ₂ C-F cyclopropyl H F ch ₂ C-F cyclopropyl H CH ₃ ch ₂ C-F cyclopropyl H nh ₂ ch ₂ C-F cyclopropyl H H 0 C-H cyclopropyl CH H 0 C-F C ₂ H ₅ H H 0 C-Cl cyclopropyl 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 Cl 0 C-F cyclopropyl H CH ₃ 0 C-F c ₂ h ₅ H nh ₂ 0 C-F

COOR ²

H

R ¹ R ² X ¹ Y A cyclopropyl H H ch ₂ C-H cyclopropyl H H ch ₂ C-F cyclopropyl H H ch ₂ C-Cl cyclopropyl H H ch ₂ c-och ₃ cyclopropyl H H ch ₂ C-CH cyclopropyl H H ch ₂ N cyclopropyl H br ch ₂ C-F cyclopropyl H F ch ₂ C-F cyclopropyl H CH ch ₂ C-F cyclopropyl H nh ₂ ch ₂ 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 ₃ 0 C-F cyclopropyl H nh ₂ 0 C-F

R ¹ R ² X ¹ Y A R ¹ R ² X ¹ Y A cyclopropyl H H ch ₂ C-H 2,4-difluorophenyl H Cl ch ₂ C-F cyclopropyl H H ch ₂ C-F 2,4-difluorophenyl H ch ₃ ch ₂ C-F cyclopropyl H H ch ₂ C-Cl 2,4-difluorophenyl H H ch _{2 C-CH3} cyclopropyl H H ch ₂ c-och ₃ 2,4-difluorophenyl H H 0 C-F cyclopropyl H H ch ₂ c-ch ₃ 2,4-difluorophenyl H H 0 C-Cl cyclopropyl H H ch ₂ n 4-fluorophenyl H H 0 CH cyclopropyl H br ch ₂ C-F 2,4-difluorophenyl H H 0 N cyclopropyl H F ch ₂ C-F 2,4-difluorophenyl H H 0 C-OCH ₃ cyclopropyl H ch ₃ ch ₂ C-F 2,4-difluorophenyl H H 0 _C-CH3 cyclopropyl H nh ₂ ch ₂ C-F 2,4-difluorophenyl H H ch ₂ C-F cyclopropyl H H 0 C-H 2,4-difluorophenyl H F ch ₂ C-F cyclopropyl H H 0 C-F 2,4-difluorophenyl H H ch ₂ C-Cl cyclopropyl H H 0 C-Cl 2,4-difluorophenyl H H 0 C-Cl cyclopropyl H H 0 C-OCH ₃ 2,4-difluorophenyl H H ch ₂ N cyclopropyl H H 0 c-ch ₃ 2,4-difluorophenyl H H 0 N cyclopropyl H H 0 N 2,4-difluorophenyl H H 0 C-H cyclopropyl H br 0 C-F 2,4-difluorophenyl c ₂ h ₅ H 0 C-F cyclopropyl H F 0 C-F

Starting compounds of formula (II) a

cyclopropyl H ch ₃ 0 C-F (IV) are known. Examples include: chloroacetone, 4-chloro-2-butanone, 5-chloro-2-pentanone, 1- cyclopropyl H nh ₂ 0 C-F -bromo-2-butanone, phenacyl chloride, methyl acrylate, ethyl acrylate, acrylonitrile, methylv-

nylketone, acetylenedicarboxylic acid dimethyl ester, acetylenedicarboxylic acid diethyl ester, propiolic acid methyl ester and propiolic acid ethyl ester.

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 ester 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. 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. 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) is preferably carried out in a diluent such as acetonitrile, dimethylsulfoxide, Ν, Ν-dimethylformamide, alcohols such as methanol, ethyl alcohol, 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 salt 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 can also be heated and then evaporated to dryness or suctioned off. 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.

vi

R ³ x ¹ A C ₂ H ₅ O ₂ C-CH = CH- nh ₂ C-F ch ₃ -co-ch ₂ ch ₂ - H N c ₂ h ₅ o ₂ c-ch ₂ -ch ₂ - H N nc-ch ₂ ch ₂ - H N c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ H N 1 CH ₃ O ₂ C-CH = CH- H N CH ₃ -CO-CH ₂ CH ₂ - ch ₃ C-H ch ₃ -co-ch ₂ - ch ₃ C-H c ₂ h ₅ o ₂ c-ch ₂ ch ₂ - ch ₃ C-H C ₂ H ₅ O ₂ C-CH = C-CO ₂ C ₂ H ₅ 1 ch ₃ C-H 1 CH ₃ O ₂ C-CH = C-CO ₂ CH ₃ ch ₃ C-H 1 C ₂ H ₅ O ₂ C-CH = CH- ch ₃ C-H ch ₃ o ₂ c-ch = ch- CH C-F C ₂ H ₅ O ₂ C-CH = C-CO ₂ C ₂ H _s ch ₃ N

COOH

R ³ x ' A CH ₃ -CO-CH ₂ CH ₂ - H C-F CH 3 -CO-CH ₂ - H C-F c ₂ h ₅ o ₂ c-ch ₂ ch ₂ - H C-F nc-ch ₂ ch ₂ - H C-F ch ₃ o ₂ c-ch = ch- H C-F CH, O ₂ C-CH-C-CO-CH, H C-F c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ H C-F 1 5-methyl-2-oxo-l, 3-dioxol-4-yl-rnetyl- H C-F CH-CO ₂ CH ₂ CII - H C-Cl ch ₃ -co-ch ₂ - H C-Cl C ₂ H _with O ₂ C-CH ₂ CH ₂ - H C-Cl NC-CH ₂ CH ₂ - H C-Cl CH ₃ O ₂ C-CH = CH- H C-Cl ch ₃ o ₂ c-ch = c-co ₂ ch ₃ H C-Cl 1 c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ H C-Cl 1 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl H C-Cl

R ' x ¹ A c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ l H C-H 1 C ₂ H ₅ O ₂ C-CH = CH- H C-H ch ₃ o ₂ c-ch = ch- F C-F c ₂ h ₅ o ₂ c-ch ₂ -ch ₂ - F C-F c ₂ h ₅ o ₂ c-ch = c- nh ₂ C-F c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ nh ₂ C-F 1 CH ₃ -CO-CH ₂ CH ₂ - ch ₃ C-H c ₂ h ₅ o ₂ c-ch = ch- ch ₃ C-H C ₂ H ₅ O ₂ C-CH = C-CO ₂ C ₂ H _s ch ₃ C-H 1 CH ₃ O ₂ C-CH = C-CO ₂ C ₂ H ₅ ch ₃ N 1 CH-CO-CH ₂ CH ₂ - H C-OCH C ₂ H ₁₀ O ₂ C-CH = CH- H C-OCH c ₂ h ₅ o ₂ c-ch = ch H N nc-ch ₂ ch ₂ H N ch ₃ -co-ch ₂ ch ₂ - H N

The compounds of the present invention act strongly antibiotic and exhibit 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 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 to say bacteria that show no detectable growth, these compounds act well below the concentration of known substances. This concerns not only the amount used, but also the killing rate. Such results have been observed in Gram-positive and Gram-negative bacteria, in particular Staphylococcus aurcus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

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

DETAILED DESCRIPTION OF THE INVENTION

Production of pre-products

Example A cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane

H

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 triethylamine 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 is dissolved in ethyl acetate, filtered through silica gel, and the filtrate is concentrated. 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] -nonane

124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4- (2-tosyloxy-ethoxy) -pyrrolidine were heated with 86 g (0.8 mol) of benzylamine in 1.5 l of xylene overnight under 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, the benzoic acid is filtered off with suction, the solution is concentrated to half the 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. 244-255 ° C.

Example B 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, 1 R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] of nonan-D-tartrate and stirred for 30 minutes at this temperature 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 ethyl alcohol 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 oily liquid containing by gas-chromatographic test 97% of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, which is used without purification for the preparation of 1S. , 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 J 55 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 derivatisation 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, Μι / ³ = - 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] nonan-tartate. 5-benzyl-2-oxa-5,8 ~ diazabicyclo [4.3.0] nonane.

[.alpha.] _D @ ²³ = + 61.2 DEG (undiluted).

The enantiomer resolution described for cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane can be analogously carried out also 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 C

1. 3S, 4S-4-Allyloxy-3-hydroxy-pyrrolidine-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. 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 45% hydroxide. sodium chloride 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), the product is uniform by thin layer chromatography.

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

87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl- were heated under reflux overnight in one liter of xylene.

Of 3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine with 58 g (0.54 mol) of 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] nonane g (90 mmol) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [t] -butyl ester 4.3.0] N-8-carboxylic acid in 35 ml of concentrated hydrochloric acid and 35 ml of water are heated to reflux until the evolution of carbon dioxide is complete. The reaction mixture was basified with potassium carbonate, extracted with chloroform, the organic extract was dried over anhydrous magnesium sulfate, 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, [α] _D ²⁶ = - 58.3 "(undiluted).

Example D

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 tert-butyl 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) -pyrrolodine-1-carboxylic acid tert-butyl ester

The reaction is carried out analogously to Example H2) tert-Butyl 3R, 4R-4-allyloxy-3-hydroxypyrrolidine-1-carboxylate: Yield: 99% of theory (0.175 molar batch) [a] _D ²⁰ = + 16.5 ° (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] nonan-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 [4.3.0] nonan-8-carboxylic acid tert-butyl ester:

Yield: 63% of theory (40 mol batch), boiling point: 120 ° C / 0.06 mbar, 95% by gas chromatography, [α] _D ²³ = + 58.5 "(undiluted)

Example E

1) 1S, 6R-2-Oxa-5,8-diazabicyclo [4.3.0] nonanedihydrochloride

7.5 g (34.4 mmol) of 1 S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are hydrogenated 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: [α] _D ²⁸ = + 8.2 "(undiluted), ee> 99.5% (derivatized with Mosher's reagent).

Example F

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 molar 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 G 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 overnight at reflux 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 in 900 ml xylene. The cooled solution was washed with 2N sodium hydroxide, dried over potassium carbonate, the desiccant was removed and the solution was concentrated. Upon cooling, crystals are separated from the residue which are suctioned off 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 DEG C., rotation: [.alpha.] _D @ ²⁸ = + 103.7 DEG (c = 1, CHCl3).

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 of ethyl alcohol using 2.5 g of 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 H 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic 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) is 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: 81-895 ° 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 malonic acid dictyl 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. The (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetic acid ethyl ester of crude (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonic acid diethyl ester is added to 150 ml of water. It is treated with 0.6 g of 4-toluenesulphonic acid and heated at reflux for 6 hours, then extracted with methylene chloride, the extract is washed with water, dried over anhydrous sodium sulphate and concentrated. (bead column distillation test): 150-160 ° C / 3 mbar, mass spectrum: m / e 3342 (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) -ethyl ester Acetic acid was added to 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate and the reaction mixture was heated under reflux for 2 hours. Excess reagents are stripped off first under vacuum 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-cyclopropylamino-acrylic acid ethyl ester

50.7 g of the crude product from step 4) are mixed dropwise with 90 ml of ethyl alcohol 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-quinoline-carboxylic 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 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 p (H on C-2), 4.16 m (H, cyclopropyl), 1.2 m (4H, cyclopropyl) / ppm / MS: m / e 361 (m ⁺ -H ₂ O) 3 17 (M-CO ₂ ), 41 (100%, C ₃ H ₃ ).

Production of final compounds

Example 1

1-Cyclopropyl-7- (2-oxa-cis-2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3 COOH mmol 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 25 ml of ethyl alcohol and dried at 80 DEG C. under high vacuum.

Yield: 880 mg (90% of theory) of 1-cyclopropyl-7- [2-oxa-5- (trans-2-ethoxycarbonyl-vinyl) -cis-2,8-diazabicyclo [4.3.0] non-8-yl M.p. 208-209 ° C] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. [.alpha.] _D = + 24 DEG (c = 0.5, CHCl3).

Analogously to Example 1, the following compounds are obtained from the corresponding intermediates:

Example A X ' Y melting point [° C] [a] _D 2 CC1 H ABOUT 197-199 ° C - 46 ° (c = 0.5, CHCl ₃ ) 3 CF F about Mp 230-232 ° C -5 ° (c = 0.25, CHCl 3)

Example 4

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) -yl) -4-oxo-3-quinolinecarboxylic acid (from Example 13B) is mixed in 15 ml of ethyl alcohol 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] none -8-yl] -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 220-222 ° C (decomp.) (Crystallized from glycol monomethyl ether), [a ] _D ²⁵ = - 57 ° (c 0.5, CHC1 _3).

Claims (8)

Enantiomerically pure quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula (f) (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 the remainder of the formula H in which Y represents an oxygen atom and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms, II CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH = C-CO ₂ R', -CH = CH-CO ₂ R ₁ or CH ₂ CH ₂ -CH, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein: R 'represents a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; And their pharmaceutically usable hydrates and acid addition salts, as well as the corresponding acid salts with alkali metals, alkaline earth metals, silver and guanidine. Enantiomerically pure 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 a 5-methyl-2-oxo-l, 3-dioxol-4-yl-methyl, and R ⁴ represents a hydrogen atom, a C 1 -C 3 alkyl group, 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', I - CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, 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 production of enantiomerically pure quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1, of the general formula (1) 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 is a radical of the formula wherein Y represents an oxygen atom and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an oxoalkyl group having 2 to 5 carbon atoms or groups CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', RO _; C-CH-C-CO ₂ R ', -CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein: R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, characterized in that a compound of formula (V) (V) in which A, R ¹ , R ² and X ^{1 are} as defined above and X is reacted; ² represents a halogen atom, in particular fluorine or chlorine, with enantiomerically pure compounds of the general formula (VI) in which: Y represents an oxygen atom and R ⁴ represents a hydrogen atom or an alkyl group having from 1 to ⁵ carbon atoms; 3 carbon atoms, optionally in the presence of acid binders, and optionally reacting the reaction product with a compound of formula (IIIa) R ⁴ -X ³ (IIIa), wherein X ^{3 is} as defined above a R ⁴ 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 or a Michael acceptor, such as a dialkyl ester of acetylenedicarboxylic acid, an alkyl ester of propiolic acid or a compound of formula (IV) CH ₂ = CH-R ⁵ (IV) wherein R ⁵ is COCH ₃ , CO ₃ R ₈ 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. Compounds of 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. Medicaments having a santibacterial action, characterized in that they contain, as active principle, quinolone carboxylic acid and naphthyridone 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.