SK396692A3 - Quinolone- and naphthyridone carboxylic acid derivatives - Google Patents

Abstract

Disclosed are quinolone- and naphthyridone carboxylic acid derivatives of the formula (I). Their preparation method and antibacterial compositions and feed additives containing these.

Description

Ί?

DERIVATIVES OF QUINOLONE CARBOXYLIC ACID AND NAPHTHYRIDONE CARBOX, METHODS OF MANUFACTURING;

NA4GHÄROBU E ^ £ 1VÁcT1E TQ: L & HM ^^^

Technical field

The present invention relates to quinoline carboxylic acid and naphthyridone carboxylic acid derivatives, processes for their preparation, antibacterial agents and feed additives containing said substances and intermediates for the production of these compounds.

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 relates to quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula I

in which

A is CH, CF, CCI, C-OCH _3, C-CH ₃ or N,

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

V290 / 93H -12.11.2001 group,

R ¹ represents an alkyl group having 1 to 3 carbon atoms, an FGH 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-1,3-dioxol-4-yl-methyl,

B represents the remainder of the formula

in which

Y represents a methylene group 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 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 3 carbon atoms, and their pharmaceutically usable hydrates and acid addition salts, as well as the corresponding alkali metal, alkaline earth metal salts of the corresponding acids,

V230 / 93H -12.11.2001 silver and guanidine.

Said compounds have a high antibacterial effect. Their special feature is a strong effect on calm and resistant strains.

Preferred are compounds of formula I wherein:

A is CH, CF, CCl, C-OCH 3 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-1,3-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

I

5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, 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.

Particularly preferred is a compound of formula I which is 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4 - dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmaceutically usable hydrates and acid addition salts as well as the corresponding carboxylic acid salts with alkali metals, alkaline earth metals, silver and guanidine.

Further preferred is a derivative of the general formula I, which is 1V230 / 93H -12.11.2001

cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-8-methoxy-7-oxo-3-quinolinecarboxylic acid.

Other preferred derivatives of formula I are 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid and 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid and salts thereof.

Compounds of formula I wherein

A is CH, CF, CCI, C-OCH 3, 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-1,3-dioxol-4-yl- methyl;

B represents the remainder of the formula

H

V230 / 93H -12.11.2001 in which

Y represents a methyl group 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 ₅ , 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 a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, is prepared by reacting a compound of formula V

in which A, R ¹ , R ² and X ^{1 are} as defined above and X ² represents a halogen atom, in particular fluorine or chlorine atom, with enantiomerically pure compounds of the general formula VI

H (VI).

V230 / 93K-12.11.2001 in which:

Y represents a methylene group and

R ⁴ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, optionally in the presence of acid binders, and the reaction product is optionally reacted further with a compound of formula IIIa

R ⁴ -X ³ (IIIa) wherein X ^{3 is} as defined above and 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 ₂ R 'or CN.

For example, when 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and [S, S] -2,8-diazabicyclo [4.3.0] nonane are used as starting compounds , the reaction may be illustrated by the following reaction scheme:

V230 / 93H-12.11.2001 · · · · · · · · · · · · · · · · · · · · ·

Racemic compounds used as starting materials are for the most part known. The enantiomeric compounds are novel and can be obtained in various ways:

1. The racemic compound is reacted with an enantiomerically pure adjuvant, the resulting diastereomers are separated, for example, chromatographically, and the chiral auxiliary is separated again from the desired diastereomers.

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

N.

NH (a).

in which it means

^R4 hydrogen or alkyl having 1 to 3 carbon atoms,

V230 / 93H -12.11.2001 can be reacted with enantiomerically pure acids such as carboxylic or sulfonic acids such as N-acetyl-L-glutamic acid , N-benzoyl-L-alanine, 3-bromo-camphor-9-sulfonic acid, camphor-3-carboxylic acid, cis-camphoric acid, camphor-10-sulfonic acid, Ο, Ο'-dibenzoyltartaric acid, D-tartaric acid, L-tartaric acid, mandelic acid, α-methoxyphenylacetic acid, 1-phenylethanesulfonic acid and afenylsuccinic acid, to a mixture of diastereomeric salts which can be separated into diastereomerically 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 metal or alkaline earth metal hydroxides can liberate enantiomerically pure amines.

2.2 In a similar manner to that described in 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 using the enantiomerically pure acids mentioned above. Examples of such basic intermediate steps include the following compounds (b) to (e).

V230 / 93H -12.11.2001

In the following reaction scheme, an example of resolution of racemates is shown by separating 8-benzyl-cis-2,8-diazabicyclo [4.3.0] nonane through the tartates into enantiomers and converting them into enantiomerically pure cis-2,8-diazabicyclo [4.3.0] nonanes:

L (+) - tartaric acid crystallization

1) 1 x recryst.

2) NaOH

T • crystallization ^x recrystallization.

Ί i

mother liquor

1) NaOH

2) D (-) tartaric acid, _{I '}

NaOH

H ₂ / Pd-C

H ₂ / Pd-C

H

> 99% R, R-Configuration

> 99% S, S-Configuration

V230 / 93H -12.11.2001

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

2.4 Both racemic amines (a) and basic intermediates (b), (c), (e) can be converted by chemical bonding with chiral esters into 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 binding with chiral alkyl esters include methoxy-α-trifluoromethylpentacetyl chloride, methyl isocyanate, D-α-phenylethyl isocyanate, L-α-phenylethyl isocyanate, methyl chloroformate and camphor-10sulfonyl chloride.

2.5. During the synthesis of bicyclic amines (a), chiral protecting groups may also be introduced instead of achiral. In this way diastereomers can be separated 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 The 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 protected on a nitrogen atom.

As an example for the synthesis of enantiomerically pure amine, starting from enantiomerically pure 1-benzyl-3,4-dihydroxypyrrolidine, mention may be made of:

V230 / 93H -12.11.2001 • · • 9 the following reaction scheme:

a, b

WHAT

WHAT

R = for example a group (CH 2 CO a: H ₂ Pd / activated carbon b: acylation of c: NaH, BrCH ₂ COOC ₂ H 5 or c:

d: LiBH ₄ de: tosyl chloride, Ne 3 f: benzylamine, xylene, reflux g: hydrolysis h: H ₂ , Pd / act. coal.

_CH2 = _CH-CH2 Br, NaH O _3, NaBH ₄

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,

V230 / 93H -12.11.2001

trans-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

S, S-2,8-diazabicyclo [4.3.0.] Nonane,

IR, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

R, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane a

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

The reaction of the compounds of the formula V with the compounds of the formula VI, in which the compounds of the formula VI can also be used in the form of their salts, for example the hydrochlorides, is preferably carried out in a diluent such as dimethylsulfoxide, NN-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 the remaining amine of general formula VI.

The reaction temperatures can be varied within a wide range, but are usually 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 in the range from 0.1 to 10 MPa, preferably from 0.1 to 1 MPa.

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

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 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, emonic 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 the remaining 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. Treatment 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 can also be prepared by the processes described.

V230 / 93H -12.11.2001 ············

COOH

R ³ x ¹ A c ₂ h ₅ o ₂ c-ch ₂ -ch ₂ - H C-F ch ₃ o ₂ c-ch = ch- H C-F nc-ch ₂ -ch ₂ - H C-F 5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl- H C-F CH ₃ -CO-CH ₂ - H C-Cl 5-Methyl-2-oxo-l, 3-dioxol-4-yl-methyl H C-Cl CH ₃ -CO-CH ₂ -CH ₂ - H C-H ch ₃ -co-ch ₂ - H C-H c ₂ h ₅ o ₂ c-ch ₂ -ch ₂ H C-H c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ H C-H ch ₃ o ₂ c-ch = ch- H C-H c ₂ h ₅ o ₂ c-ch = ch- F C-F ch ₃ -co-ch ₂ ch ₂ - nh ₂ C-F c ₂ h ₅ o ₂ c-ch ₂ ch ₂ - nh ₂ C-F ch ₃ o ₂ c-ch = c-co ₂ ch ₃ 1 NHO C-F C ₂ H ₅ O ₂ C-CH = C-CO ₂ C ₂ H ₅ nh ₂ C-F

V230 / 93H-12.11.2001

• ·· ·

C ₂ H ₅ O ₂ C-CH = CH- NH; ch ₃ -co-ch ₂ ch ₂ - H c ₂ h ₅ o ₂ c-ch ₂ -ch ₂ - H nc-ch ₂ ch ₂ - H c ₂ h ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ l H ch ₃ o ₂ c-ch = ch- H ch ₃ -co-ch ₂ ch ₂ - ch ₃ ch ₃ -co-ch ₂ - ch ₃ c ₂ h ₅ o ₂ c-ch ₂ ch ₂ - ch ₃ C ₂ H _with O ₂ C-CH = C-CO ₂ C ₂ H ₅ ch ₃ ch ₃ o ₂ c-ch = c-co ₂ ch ₃ | ch ₃ c ₂ h ₅ o ₂ c-ch = ch- ch ₃ ch ₃ o ₂ c-ch = ch- ch ₃ c ₂ u ₅ o ₂ c-ch = c-co ₂ c ₂ h ₅ ch ₃

A

C-F

N

N _t N

N

N

C-H

C-H

C-H

C-H

C-H

C-H

C-F

N

V230 / 93H-12.11.2001 ·····

The compounds of the present invention act strongly antibiotic and exhibit a broad antibacterial spectrum with low toxicity against gram-positive and gram-negative germs, particularly against enterobacteria, particularly those resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and sulfonamides.

These valuable properties allow their use as chemotherapeutic active ingredients 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 inhibit gram-negative and gram-positive bacteria and bacteria-like microorganisms, as well as control, ameliorate and / or treat diseases caused by these agents.

The compounds of the present invention exhibit an enhanced effect on resting and resistant germs. In resting bacteria, i.e. bacteria which show no detectable growth, these compounds act well below the concentration of the 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, in particular Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

In particular, the compounds of the present invention exhibit a surprising spectrum of activity against bacteria which are classified as being less sensitive to comparable substances, particularly 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.

V230 / 93H -12.11.2001

The compounds are also suitable for the control of 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 infections in mice (mg / kg)

substance after. sc ciprofoxacin 80 80 Example 14 10 2.5 Example 16A 5 5 Example 18 10 5 Example 20 2.5 2.5

^CI Á

Example 2 compound: A

CH ₃

R = Ň - known from EP-A-0 350 733: B coV230 / 93H -12.11.2001 • ··· · · · · · · · · · · · · · · · · · ··· ···························

ciprofloxacin:

table

microorganism tribe compound A B C Bacteroides fragilis EC 25 0.25 1 8 DSM 2151 0.25 0.5 4 Clostridium perfringens 1024027 0,125 0.5 0.5 Bact. thetaiotaomicron DSM 2079 0.5 2 8

(MHK-values in μ9 / ιτιΙ; agar dilution test in a multi-point inoculator (Denley); Isosensites-agar)

DETAILED DESCRIPTION OF THE INVENTION

Production of pre-products

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

H

1) [S, S] -8-Benzyl-2,8-diazabicyclo [4.3.0] nonane

Method I

a) Separation of diastereomeric salts

V230 / 93H-12.11.2001

D (-) - tartaric acid (3.0 g, 20 mmol) was dissolved in dimethylformamide (10 ml) with heating at 80 ° C and treated with a solution of cis-8-benzyl-2,8 (2,16 g, 10 mmol). -diazabicyclo [4.3.0] nonane in 3 ml of dimethylformamide. The reaction mixture is stirred for 1 hour at 0 ° C, then the product is filtered off with suction and washed with diethylformamide and methoxyethanol.

Yield: 1.93 g, m.p .: 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.

[α] ²³ = -22.7 '(c = 1, H ₂ O).

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] nonane, boiling point: 107-109 ° C / 10 Pa, [α] ²⁴ = 17.3 ° (not inherited).

Method II

Dissolve 75.0 g (0.5 mol) of L (+) - tartaric acid at 80 ° C in 250 ml of dimethylformamide and add 54,1 g (0,25 mol) of cis-8-benzyl-2,8V230 dropwise. Diazabicyclo [4.3.0] nonane as a solution in 75 ml of dimethylformamide. The reaction mixture was slowly cooled to 20 ° C and the formed slurry of crystals was stirred for 1 hour. The formed crystals of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartrate are aspirated and the filtrate is concentrated on a rotary evaporator. The residue was dissolved in 500 ml of water and treated with 63 g of 45% sodium hydroxide as described in Method I.

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 chloroformate as determined by gas chromatography).

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

Method III

To a solution of 102.9 g (0.685 mol) of L - (+) - tartaric acid in 343 ml of dimethylformamide was added dropwise at a temperature ranging from 80 ° C to 90 ° C 73.6 g (0.34 mol) of cis-8-benzyl -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] nonane-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] nonane-L-tartate, and the mixture is stirred until crystallization is complete. (From the mother liquor, after concentration and liberation of the bases, can be obtained according to Method I by purification with D - (-) - tartaric acid [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-D-tartate). 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] nonane-L-tartrate trihydrate are obtained.

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

V230 / 93H -12.11.2001 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The salt can be worked up 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 enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane 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 II / 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] nonane-L-tartate (from Example B, method 11 / a) are concentrated together, taken up into 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 initially charged cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] -nonane), [α] _D ²³ = -4.5 ° (c = 5, ethanol).

The 14.4 g (59 mmol) of D (-) - tartaric acid is crystallized from 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] nonane-D-tartate, [α] _D ²³ = - 46.2 ° (c = 0.5, 1n HCl).

after crystallization from a mixture of ethanol 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) diastereomerically obtained

V230 / 93H -12.11.2001

The pure tartrate was 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. 60-61 [deg.] C, [ct] [ _Α ] ²³ _D = 22.2 ° (c = 5, ethanol).

An excess of enantiomers of 96.6% were found by gas chromatography after derivatization with methyl 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 11 / 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 was shown to be [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane by derivatization with methyl chloroformate. 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 methanol in the presence of 5.8 g of palladium on activated carbon (5%) at temperature 90 ° C and pressure 9 MPa for 5 hours. The catalyst is then filtered off, washed with methanol and the filtrate is concentrated on a rotary evaporator. 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

V230 / 93H-12.11.2001 ··· (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 [4.3. 0] nonane as a solution in 15 ml of dimethylformamide. It is then seeded with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-L-tartate and stirred for 1 hour at a temperature of about 72 ° C until seed formation is complete. The mixture was 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. Warm to 119 ° C until a clear solution is formed and cool again slowly to room temperature while seeding with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane-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, mp 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] nonane-L-tartrate trihydrate (76% of theory) which The mixture is melted while foaming at a temperature in the range of 112-118 ° C, then solidifies again and melts again at a temperature in the range of 199-101 ° C.

[α] _D ²³ = 4.5 ° (c = 1, H ₂ O).

ee: 98.0% (determined by gas chromatography after derivatization with methyl chloroformate).

Example B [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane

V230 / 93H -12.11.2001 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Η

1) [S, S] -8-Benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane

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 acid. 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 [4.3.0] nonane

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 on a rotary evaporator 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 C cis-7,9-dioxo-8 - ([1S] -1-phenylethyl-2,8-diazabicyclo [4.3.0] nonane

V230 / 93H -12.11.2001

1) Pyridine-2,3-dicarboxylic acid ([1S] -1-phenylethyl) 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-phenylethylamine are added dropwise. thus increasing the temperature to 33 ° C. The reaction mixture was stirred for an additional 1 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 1 liter of ice-water with good stirring, filtered off with suction, 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-phenylethyl) -2,8-diazabicyclo [4.3.0] nonane

Pyridine-2,3-dicarboxylic acid ([1S] -1-phenylethyl) imide (79.7 g, 0.316 mol) was hydrogenated in 600 mL of tetrahydrofuran at 90 ° C / 10 MPa using 10 g of palladium on charcoal (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

V230 / 93H -12.11.2001 (m. 1H); 2.28 (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 D cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane

H

1) trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) pyrrolidine

Dissolve 95 g (0.55 mol) of 1-benzoyl-3-pyrrolidine in 380 g of ethylene glycol and add 101 g (0.57 mol) of N-bromosuccinimide in 5-gram portions at room temperature over 2 hours. 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 60 g (0) are added dropwise. (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 are washed with 10% hydrochloric acid,

V230 / 93H-12.11.2001 are dried over anhydrous magnesium sulphate 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

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 are heated with 200 ml of concentrated hydrochloric acid and 140 ml of water at reflux overnight. After cooling, the benzoic acid is filtered off with suction, the solution is concentrated to half the volume, made alkaline 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

Hydrogenated 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 charcoal (10% Pd) at 100 ° C and a hydrogen pressure of 10 bar. The catalyst is then filtered off with suction, the filtrate is filtered off

V230 / 93H -12.11.2001

it 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 E

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- oxa5,8-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, and seeded with the crystals obtained from the previous experiment, 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-D- tartrate and stirred for 30 minutes at this temperature until the seed crystals formed, then slowly cooled to 0-3 ° C. After suctioning off the crystals, they are washed with a mixture of 200 ml of ethyl alcohol 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] nonane tartate melting point: 174-176.5 ° C, ee> 97 % (after derivatization with 1-phenyl-ethylisocyanate and HPLC evaluation) [α] ^D = + 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).

V230 / 93H -12.11.2001 ·· · · · ··· ··

The methanolic mother liquor from the first crystallization is concentrated on a rotary evaporator. The resulting syrupy residue (236 g) is dissolved in 500 ml of water and the pH is adjusted to 12-13 with 250 ml of 6 N sodium hydroxide solution. This solution is extracted three times with 350 ml of toluene each time, dried over sodium carbonate and vacuum. concentrated. 113.1 g of residue are obtained in the form of a brown oil which, according to a gas-chromatographic test, shows 97% of cis-5-benzyl-2-oxa-5,8-diazabicyclo [14.3.0] nonane which is used without purification for 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 155 ml of methanol and add dropwise to boiling solution 77.8 g (0.518 mol) of L - (+) - tartaric acid in 363 ml of methanol. Already during the dripping, a crystal slurry forms freely. The mixture was allowed to stir for 1 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 mixture of ethyl alcohol and methanol (2; 1), 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] nonane-L-tartrate, 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) of 6N are added. 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 are dried over sodium carbonate, filtered and

V230 / 93H -12.11.2001 • · 4 • 4 • ·· The filtrate is 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] ²³ = - 60.9 ° (undiluted).

Distillation residue: 0.12 g.

In the same way 76.0 g (93% of theory) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane tartate are obtained from 139.2 g (0.376 mol). 5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0], [.alpha.] D @ ²³ = + 61.2 DEG (undiluted).

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

Example F

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 1 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 removed on a rotary evaporator, diluted in 230 / 93H -12.11.2001. · · ·········· · · · · 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] ²³ D = -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-hydroxy-pyrrolidine-1-carboxylic acid in 250 ml of methanol, cool the solution to 0 ° C and introduce ozone into the mixture until it is added. the potassium iodide solution washer does not indicate the occurrence of ozone and thus the reaction is complete. 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, 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-3V230 / 93H-12.11.2001 hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester in 30 ml of ethyl acetate are added. ml of methylene chloride, mixed with 6 ml of 45% 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 1 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] nonane-8-carboxylic acid tert-butyl ester

Heat 87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl-3-tosyl-4- (2-tosylethoxy) pyrrolidine with 58 g (0.54 mol) of benzylamine in refluxing overnight in 1 x xylene. 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) The product was 67% according to gas chromatography.

5) 1S, 6R-5-benzyl-5,8-diazabicyclo [4.3.0] nonane (90 mmol) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo tert -butyl ester [4.3.0] of nonan-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. 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),

V230 / 93H -12.11.2001

boiling point: 108-115 ° C / 0.07 mbar, [α] D ²⁶ = -58.3 ° (undiluted).

Example G

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

COOH

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 l of thionyl chloride and the mixture is refluxed for 11 hours until evolution is complete. gas. The remaining 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, stirring is continued at 0 DEG C. for 1 hour at 0 DEG C. and the mixture is left overnight. warm to room temperature. It is then treated with 100 ml of 5 N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulfate and concentrated by evaporation in a vacuum.

Crude yield: 62.7 g.

3) (2-Bromo-3,4,5,6-tetrafluorobenzoyl) acetic acid ethyl ester

600 g of crude diethyl ester of (2-bromo-3,4,5,6-tetrafluorobenzoyl) malonic acid is added to 150 ml of water, mixed with 0.6 g of 4-toluenesulfonic acid and heated at reflux for 6 hours. It is then extracted with methylene chloride, the extract is washed with water, dried over anhydrous sodium sulphate and concentrated.

Crude yield: 46 g, boiling point (bead distillation test): 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) Ethyl 2- (2-bromo-3,4,5,6-tetrafluorobenzoyl) -3-ethoxyacrylic acid ethyl ester g of crude (2-bromo-3,4,5,6-tetrafluorobenzoyl) acetic acid ethyl ester is 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 is heated under reflux for 2 hours. The remaining reagent is 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-tetrafluorobenzoyl) -3-cyclopropylaminoacrylic acid ethyl ester

V230 / 93H -12.11.2001

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-3,4,5) ethyl ester 6-Tetrafluorobenzoyl) 3-cyclopropylaminoacrylic acid was heated at reflux for 6 hours in 88 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride. 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-6,7,8,7-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, and 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.

V230 / 93H -12.11.2001

Yield: 19.7 g (80% of theory), melting point: 208-210 ° C (dec.), Melting point after crystallization from glycol monomethyl ether: 212-214 ° C (dec.), ¹ H-NMR (DMSO): δ, 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

ABOUT

COOH

A. 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

141.5 g (0.5 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 1500 ml of acetonitrile and 750 ml for 1 hour. dimethylformamide in the presence of 55 g (0.5 mol) of 1,4-diazabicyclo [2.2.2] octane, 69.25 g (0.55 mol) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] ] nonane (ee 99.5%, GC 99.8%). The suspension is then cooled, the precipitate is filtered off with suction, washed with water and then stirred with 1 l of water (pH 7). Finally, it is suctioned off and dried in a circulating oven at 60 ° C.

Yield: 163.4 g (84% of theory), melting point: 249 DEG-251 DEG C. (decomposition).

V230 / 93H-12.11.2001

B. (-) - Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] n-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid

6.0 g (15.4 mmol) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0-yn-8-yl) -6,8-difluoro-1,4-dihydro 4-Oxo-3-quinolinecarboxylic acid is dissolved in 40 ml of semi-concentrated hydrochloric acid at 60 ° C and the hydrochloride solution is filtered off. The filtrate is concentrated in half, cooled with ice and treated with 40 ml of ethyl alcohol. The yellow crystallizate is filtered off with suction, washed with ethyl alcohol and dried at 60 [deg.] C. under high vacuum, the color being lightened. 5.51 g (84% of theory) of hydrochloride are obtained, which is already very pure.

For further purification, the compound is dissolved in 50 ml of water while warm. The yellow solution is mixed with 5 ml of semi-concentrated hydrochloric acid, cooled with ice, the precipitated crystallizate is filtered off with suction, washed well with ethyl alcohol and dried first at room temperature and then under high vacuum at 100 ° C.

Yield: 4.64 g (70% of theory), melting point: 324 DEG-325 DEG C. (decomposition),

TLC (silica gel, dichloromethane / methanol / 17% aqueous ammonia = 30: 8: 1) uniform product, Rf = 0.3, rotation: [α] ²⁵ = -256 ° (c = 0.5, H ₂ O) , HPLC content: 99.4%.

C ₂ N 30 ₂ oH2iF _third HCl (425.5) calculated C 56.4 H 5.2 N 9.9 Cl 8.3 found C 56.3 H 5.4 N 9.8 Cl 8.3

V230 / 93H -12.11.2001 · · · · · · · · · · ···

Example 2

A. 8-Chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 quinoline carboxylic

Two batches of the following sizes are run in parallel and processed together:

180 g (0.6 mol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 1.8 l of acetonitrile and 900 ml of dimethylformamide for 1 hour. hours at reflux (internal temperature 90.5 ° C) in the presence of 99 g (0.88 mol) 1,4-diazabicyclo [2.2.2] octane (DABCO) with 84 g (0.67 mol) (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane. The yellow solution thus obtained is cooled and mixed with the seed crystals obtained from a 5 ml sample which is concentrated and the residue is triturated with acetonitrile. The mixture is stirred for 2 hours at a temperature of about 3 [deg.] C., the precipitated precipitate from both batches is drained vigorously, washed with acetonitrile and poured into 1.5 l of ice-water. The slurry, which is first sparse and well miscible, is after 10 minutes turned into a hardly miscible mass which is diluted with an additional 150 ml of water. It is then filtered off with suction, washed with water and dried at 80 [deg.] C. in a circulating oven.

Yield: 402 g (82.7% of theory), light yellow product, melting point: 193-196 DEG C. (decomposition),

R f (silica gel, methylene chloride / methanol / 17% aq _NH3 = 30: 8: 1) 0.4.

V230 / 93H -12.11.2001 ·

········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

B The hydrochloride of 8-chloro-1-cyclopropyl-7 - ([S, S] _-2 '8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4 oxo-3-quinolinecarboxylic acid

13.1 g (32 mmol) of 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro The 4-oxo-3-quinolinecarboxylic acid is suspended in 50 ml of water and brought into solution by the addition of 50 ml of semi-concentrated hydrochloric acid. It is filtered through a sintered glass, concentrated in vacuo and the residue is stirred with about 300 ml of absolute ethyl alcohol. The suspension is cooled with ice, the precipitate is filtered off with suction, washed with ethyl alcohol and dried first at room temperature and then under vacuum at 100 ° C.

Yield: 13.4 g (93.8% of theory), melting point: 328 DEG-330 DEG C. (decomposition),

Rf (silica gel; methylene chloride / methanol / 17% aqueous NH3 = 30: 8: 1) = 0.4; content (HPLC): 99% rotation: [.alpha.] D @ ²⁴ = -164.4 DEG (c = 0.45) H ₂ O).

C20H21CIFN3O3. HCl (442.3) calculated C 54.3 H 5.0 N 5.0 Cl 16.0 found C 54.3 H 5.0 N 9.5 Cl 16.0

C. For example, the following salts can be prepared analogously:

8-Chloro-1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methanesulfonate, 8-chloro-1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid toluenesulfonate, 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sulfate, acetate 8-Chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) V230 / 93H -12.11.2001

6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) lactate 6- Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) 6-fluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 8-chloro-1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8yl) -6-fluoro-1,4-carbonate dihydro-4-oxo-3-quinolinecarboxylic acid.

Example 3

Analogously to Example 2, it is obtained with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. 1-Cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 258 ° C (dec.),

B. 1-Cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p. 320 ° C (decomposition), rotation: [α] D ²⁶ = -90.6 ° (c = 0.48, H 2 O).

V230 / 93H -12.11.2001

A. 6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was heated under reflux in 40 ml of acetonitrile and 20 ml of N for 1 hour. -methylpyrrolidone in the presence of 2.2 g (20 mmol) of 1,4-diazabicyclo [2.2.2] octane with 2.7 g (21.4 mmol) of (+) - [S, S] -2,8-diazabicyclo [4.3. 0] nonane. The suspension thus obtained is cooled, the precipitate is filtered off with suction, washed with acetonitrile and dried at 100 DEG C. mbar.

Yield: 6.7 g (82.3% of theory) of 1-cyclopropyl-7 - ([S, S] -diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 257-259 ° C (decomposition; after recrystallization from glycol monomethyl ether: mp 260-265 ° C (decomposition)).

B. 1.5 g (3.7 mmol) of the product from Step A are taken up in 6 ml of 1 N hydrochloric acid and after a short time the hydrochloride precipitates and is filtered off with suction, washed twice with 5 ml of ethanol each time and dried at room temperature. 100 ° C / 12 mbar.

Yield: 1.4 g (85.7% of theory) of 1-cyclopropyl-7 - ([S, S] diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1 hydrochloride, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. > 310 DEG C. (decomposition),

V230 / 93H -12.11.2001 Rotation: [α] _D ²⁶ = -272 ° (c = 0.5, H ₂ O).

Example 5

5.2 g (13 mmol) of the product of Example 4A in 80 ml of pyridine are mixed with 15 ml of liquid ammonia in an autoclave and heated at 130 ° C for 12 hours. It is then cooled, the autoclave is depressurized and the reaction mixture is concentrated. The residue is treated with acetonitrile in an ultrasonic bath. The undissolved precipitate is filtered off with suction, the residue is dissolved in hot in about 150 ml of water, the solution is filtered and the hydrochloride is precipitated by adding 10 ml of semi-concentrated hydrochloric acid. The precipitate is filtered off with suction and dried at 100 ° C in a hot-air circulation drier. The product thus obtained is suspended at 110 DEG-115 DEG C. in 100 ml of glycol monomethyl ether and brought into solution by the addition of 38 ml of semi-concentrated hydrochloric acid. The solution is filtered hot through a glass frit, cooled and the precipitated yellow crystallizate is filtered off with suction, washed with ethyl alcohol and dried at 120 ° C / 12 mbar.

Yield: 2.5 g (44% of theory) of 5-amino-1-cyclopropyl-7 ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1 hydrochloride, 4-dihydro-4-oxo-3-quinolinecarboxylic acid melting point:> 335 ° C (decomposition, already below 335 ° C brown color), rotation: [α] _D ²⁸ = -280.8 ° (c = 0.53) H ₂ O).

V230 / 93H -12.11.2001

1.4 g (5 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are stirred in 1.3 ml of acetonitrile in 15 ml ( 10.3 mmol) of (+) - [S, S] -2,8-diazabicyclo [4.3.0] nonane, avoiding moisture ingress for 1 hour at room temperature. After standing overnight, the mixture is filtered off with suction, washed with acetonitrile and chromatographed on silica gel (mobile phase: methylene chloride / methanol / 17% aqueous ammonia 30: 8: 1; Rf = 0.4) for purification. The obtained 1-cyclopropyl-7 ([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid Dissolve in 15 ml of semi-concentrated hydrochloric acid, evaporate and stir the residue with ethyl alcohol. The precipitate is filtered off with suction, washed with ethyl alcohol and dried at 120 ° C / 12 mbar.

Yield: 960 mg (47% of theory) of 1-cyclopropyl-7 - ([S, S, 2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4- acid hydrochloride oxo-1,8-naphthyridine-3-carboxylate, m.p .: 345-346 ° C (dec.), [α] _D ³⁰ = + 5.4 ° (c = 0.5, H ₂ O).

V230 / 93H -12.11.2001 * · 2 2 2 2 2 2 2 · · · · · · ·

1.52 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 30 ml of acetonitrile was treated with 550 mg (5 mmol) of 1,4 -diazabicyclo [2.2.2] octane and 760 mg (6 mmol) of (+) - [S, S] 2,8-diazabicyclo [4.3.0] nonane for 2 hours at 50 ° C and for 2 hours at 60 ° C . After cooling, the suspension thus obtained is filtered off with suction, the precipitate is washed with water and dried at 90 DEG C. in vacuo.

Yield: 0.99 g (47.5% of theory), 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] n-8-yl) -6,8-difluoro-, ethyl ester 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p .: 194-195 ° C (from acetonitrile), [α] _D ²³ = -272 ° (c = 0.51, CHCl ₃ ).

Example 8

1.4 g (5 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxacin-6-carboxylic acid reacted in 15 ml of acetonitrile and 7.5 ml of dimethylformamide with 0.85 g (7.7 mmol) of 1,4-diazabicyclo [2.2.2] octane and 0.7 g (5.6 mmol) of (+) - [ S, S] -2,8-diazabicyclo [4.3.0] nonane

V230 / 93H -12.11.2001

9 9 analogously to Example 1.

Yield: 1.24 g (64% of theory) of 10 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido [1,2,3-de] - [1,4] benzoxacin-6-carboxylic acid, m.p .: 265-268 ° C (dec.), [Α] _D ²⁵ = -232.2 ° ( c = 0.58, CHCl ₃ ).

Similarly, 3S-10 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo is also obtained. -7 H -pyrido [1,2,3- de] [1,4] benzoxacín6-carboxylic acid.

Example 9

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 and the reaction product is purified by chromatography (silica gel, mobile phase: methylene chloride / methanol / 17% aqueous ammonia 30: 8: 1). 1-Cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxo- 3-quinolinecarboxylic acid.

mp: 203-208 ° C (dec.), [α] _D ²³ = -193 ° (c = 0.4, CHCl ₃ ).

V230 / 93H -12.11.2001

• · · · · · · · · · · · · · · · · · · ·

It is reacted analogously to Example 1A with 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 1-ethyl-7 - ([S , S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

mp: 236-239 ° C (decomp.) (crystallized from glycol monomethyl ether), [α] _D ²³ = -186.3 ° (c = 0.3, CHCl ₃ ).

Example 11

A. 7 - ([S, S] -2,8-Diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4- acid ethyl ester 1,8-oxo-naphthyridine-3-carboxylic acid

1.9 g (5 mmol) of 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 20 ml of acetonitrile Stir in the presence of 560 mg (5 mmol) of 1,4-diazabicyclo [2.2.2] octane with 680 mg (5.4

V230 / 93H (12.11.2001 mmol) [S, S] -2,8-diazabicyclo [4.3.0] nonane for 3 hours at 10 ° C. The suspension formed is filtered off with suction, washed with water and filtered off with suction. 0.35 g of product is obtained. Concentration of the mother liquor, stirring of the residue with water, isolation of the insoluble product and chromatographic purification (silica gel, eluent: dichloromethane / methanol / 17% aqueous ammonia) yielded an additional 0.7 g of product.

Total yield: 1.05 g (44% of theory), Melting point: 184-185 DEG C. (dec), [a] _D ²³ = + 6.8 ° (c = 0.46, CHCl _3).

B. 7 - ([S, S] -2,8-Diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4- acid hydrochloride oxo-1,8-naphthyridine-3-carboxylic acid

The product from Step A (0.8 g, 1.7 mmol) was heated under reflux in a mixture of 10 ml of acetic acid and 8 ml of semi-diluted hydrochloric acid for 4 hours. The reaction mixture is then concentrated, the residue is stirred with a small amount of water, the precipitate formed is filtered off with suction, washed with ice-cold ethanol and dried.

Yield: 0.67 g (83% of theory), melting point: 324-326 DEG C. (decomposition), [.alpha.] _D @ ²⁵ = + 10.8 DEG (c = 0.37, DMF).

Example 12

V230 / 93H -12.11.2001 · · ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid was heated with 0.38 g (3 mmol) of [S, S] -2,8-diazabicyclo [4.3.0] nonane and 0.45 g (4 mmol) of 1,4-diazabicyclo [2.2.2] octane in

3.5 ml of dimethylsulfoxide for 2 hours at 120 ° C. After cooling, the solvent was removed under high vacuum. The residue is taken up in acetonitrile, the solid is collected, washed with acetonitrile and dried at 60-80 ° C.

Yield: 0.5 g (65% of theory) of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4- dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, m.p. 217-219 ° C (dec.), [α] _D ²⁵ = -119 ° (c = 0.5, DMF).

Analogously to Example 1, [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane is obtained:

A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7 - ([S, S] -2-methyl-2,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo acid -3-quinolinecarboxylic acid;

Melting point: 230-233 ° C (decomposition) (crystallized from glycol monomethyl ether).

B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7 - ([S, S] -2-methyl acid) hydrochloride230 / 93H -12.11.2001

2,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid; mp: 258-260 ° C (dec.), [α] _D ²⁵ = -216.3 ° (c = 1, H ₂ O).

Example 14

COOH

1.95 g (5 mmol) of the product of Example 1A 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 stirred with water, the precipitate formed is filtered off with suction, washed with ethyl alcohol and dried at 100 ° C / 12 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) -3-quinolinecarboxylic acid, melting point: 181-183 ° C (decomp.) (crystallized from glycol monomethyl ether), [α] d ²⁴ = -120.7 ° (c = 0.57, CH ₂ Cl ₂ ).

Example 15

V230 / 93H -12.11.2001

1.95 g (5 mmol) of the product of Example 1A is heated in 30 ml of dimethylformamide for 3 hours at 50-80 ° C with 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol). ) 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). Recrystallize 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-quinolinecarboxylate melting point: 181-184 ° C (dec.), [α] _D ²³ = -72 ° (c = 0.55, CHCl ₃ ).

Example 16

A. The product of Example 2A is reacted to give 8-chloro-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7 - ([S, S] -2- [3-oxo-1] acid). -butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 107-109 ° C, [α] _D ²³ = -53 ° (c = 0.67, CHCl 3) ), content: 99.2% (HPLC).

V230 / 93H-12.11.2001

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 rac. 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 17

ABOUT

COOH

1.95 g (4.8 mmol) of the product of Example 2A was heated in 30 ml of glycol monomethyl ether for 2 hours under reflux with 3 g (30 mmol) of ethyl acrylate. 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). Recrystallize from glycol monomethyl ether.

Yield: 1.45 g (60% of theory) of 8-chloro-1-cyclopropyl-7 - ([S, S] -2- [2-ethoxycarbonylethyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 117-118 ° C (dec.), [Α] _D ²⁸ = -103.5 ° (c = 0.49, DMF), content: 99.6% (HPLC).

V230 / 93H -12.11.2001

Example 18

1.95 g (4.8 mmol) of the product of Example 2A 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, mp: 153-155 ° C (dec.), [α] _D ²⁷ = -98.6 ° (c = 0.53, DMF), content: 96% (HPLC), mass spectrum: m / e 458 (M < ^{+ >} ), 250, 149 (100%, C8H11N3), 110, 49.

Example 19 ch ₃ ooc

V230 / 93H-12.11.2001

1.95 g (5 mmol) of the product of Example 1A was heated in 60 ml of ethanol for 2 hours under reflux with 1.2 g (8 mmol) of dimethyl acetylenedicarboxylate. 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-methoxycarbonylvinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl] - 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 262-264 ° C (dec.), [Α] _D ²⁴ = + 28.8 ° (c = 0.24, CH ₂₎ CI ₂ ).

Example 20

Analogously to Example 9, the product of Example 2A is reacted with dimethyl acetylenedicarboxylic acid ester. In 87% yield, 8-chloro-1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonylvinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl) - was obtained. 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) .

By analogy, the following compounds are obtained from the corresponding intermediates:

V230 / 93H-12.11.2001 · · 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

COOH

II u

u fS o

CM

ABOUT

- *

Ό

C

CB>

ABOUT

N

K / 3

xz <u c

V230 / 93H -12.11.2001

Analogous to that described above, 8-chloro-1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro is reacted Of 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-methoxycarbonylvinyl) - [S, S ] -2,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic.

mp: 220-222 ° C (dec.), [α] _D ²⁴ = + 8.2 ° (c = 0.5, CHCl ₃ ).

V230 / 93H -12.11.2001

Claims (12)

7? 590e '72. PATENT CLAIMS Quinolone carboxylic acid and naphthyridone carboxylic acid derivatives of the general formula I (I) in which: A is CH, CF, CCI, C-OCH 3, 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-1,3-dioxol-4-yl- methyl; B represents the remainder of the formula V230 / 93H -12.11.2001 in which Y represents a methylene group 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 ₅ , 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 a hydrogen atom or an alkyl group having 1 to 3 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. 2. A compound according to claim 1, wherein the compound according to claim 1, wherein: A is CH, CF, CCl, C-OCH ₃ 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-1,3-dioxol-4-yl-methyl, and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, v230 / 93H -12.11.2001 of the group CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H _{5 I} 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 I 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, 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. 3. A compound according to claim 1, which is 8-chloro-1-cyclopropyl-7 ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl). 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharmaceutically acceptable hydrates and acid addition salts as well as the corresponding alkali metal, alkaline earth metal, silver and guanidine salts of the corresponding carboxylic acids. 4. A compound according to claim 1, which is 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro- 1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. 5. A compound according to claim 1, which is 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6, 8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro 4-dihydro-4-oxo-3-quinolinecarboxylic acid a V230 / 93H -12.11.2001 • 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acids and their salts. A process for the preparation of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1, of the general formula I in which: A is CH, CF, CCI, C-OCH 3, 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-1,3-dioxol-4-yl- methyl; B represents the remainder of the formula V230 / 93H -12.11.2001 in which Y represents a methylene group 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 ₅ , CH ₂ CH ₂ CO ₂ R 6, RO ₂ C-CH = C-CO ₂ R ', I -CH = CH-C ₂ O 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 the general formula V is reacted in which A, R ¹ , R ² and X ^{1 are} as defined above and X ² represents a halogen atom, especially fluorine or chlorine, with enantiomerically pure compounds of formula VI (VI), V230 / 93H -12.11.2001 in which Y represents a methylene group and R ⁴ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, C-1 ····· * ·! or in the presence of acid binders, and the reaction product is optionally reacted further 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 ₂ R 'or CN. Enantiomerically pure compounds of formula VI (VI), wherein: Y represents a methylene group and R ⁴ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms V230 / 93H -12.11.2001 atoms as intermediates for the production of derivatives of formula (I). The quinolonecarboxylic acid and naphthyridonecarboxylic acid derivatives according to claim 1 for use in the treatment of diseases. The quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1 for use in the treatment of infectious diseases. Medicaments, characterized in that they contain, as active ingredient, the quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1. Medicaments having an antibacterial action, characterized in that they contain the quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1. Use of quinolone carboxylic acid and naphthyridone carboxylic acid derivatives according to claim 1 in the manufacture of medicaments for controlling infectious diseases.