CA2086914C - Quinolone-and naphthyridone-carboxylic acid derivatives - Google Patents

Abstract

The invention relates to new quinolone- and naphthyridone carboxylic acid derivatives, processes for their preparation and also antibacterial agents and feed additives containing them.

Description

The invention relates to new quinolone- and naphthyridonecarboxylic acid derivatives, processes for their preparation and also antibacterial agents and feed additives containing them.
Quinolone- and naphthyridonecarboxylic acids which are substituted in the 7-position by a bicyclic amine radical have already been disclosed in EP-A-0,350,733.
The present invention relates to new compounds of the formula (I) F ( y in which A represents CH, CF, CC1, C-OCH3, C-CH3 or N, X1 represents H, halogen, NHZ or CH3, R1 represents C1-C3-a13cy1, FCHZCHZ-, cyclopropyl or phenyl which is optionally monosubstituted to trisubstituted by halogen, or A and R1 together can denote a bridge of the structure C-0-CHz-CH ( CH3 ) -, xl O
C
~N~
A
L~e A 28 100 - 1 -RZ represents H, C1-C3-alkyl which is optionally substituted by hydroxyl, halogen or amino or 5-methyl-2-oxo-1,3-dioxol-4-y1-methyl, B represents a radical of the formulae N N N N N
R3N Y R~ N Y R4 N Y R4 N Y R4 N Y
U a U
in which Y represents 0 or CH2, R3 represents C2-CS-oxoalkyl, CHZ-CO-C6H5, CHZCHZCOZR°, R' OZC-CH= ~-COZR' , -CH=CH-CO2R' or CHZCHZ-C1N, in which R' denotes hydrogen or C1-C3-alkyl, R4 represents H, C1-C~-alkyl, CZ-CS-oxoalkyl, CHZ-CO-C6H5, CHZCH2CO2R' , R' 0zC-CH=C~-(:OZR' , -CH=CH-COzR ° or CHZCHZ-CN or represents 5-methyl-2-oxo-1, 3-dioxol-4-~1-methyl, in which R' denotes hydrogen or Cl-C3-alkyl, Le A 28 x.00 - 2 -and to pharmaceutically utilisable hydrates and acid addition salts thereof as well as the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids. These compounds have a high antibacterial activity. The compounds according to the invention are particularly distinguished in that they have a high activity on dormant and resistant microorganisms.
Preferred compounds of the formula (I) are those in which A represents CH, CF, CC1, C-0CH3 or N, X1 represents H, F, Cl, Br, NHZ or CH3, R1 represents CZHS, cyclopropyl or 2,4-difluorophenyl, or A and R1 together can denote a bridge of the structure C-0-CHZ-CH ( CH3 ) -, RZ represents H, CH3, CZHS or 5-methyl-2-oxo-1, 3-dioxol-4-yl-methyl, B represents a radical of the formulae H--~~H H 4 .
.. ..., ""~~ H H ""... ~ H H

U ~ U
in which Le A 28 100 - 3 -s ~~°s~
Y represents 0 or CHZ and R3 represents CHz-C0-CH3, CHZ-CO-CsHS, GHzCH2-C0-CH3, CHZCHZCOZR' , R ° 02C-CH=C-COzR' , -CH=CH-COZR' Or i CH2CH2-CN, S in which R' denotes Ci-CZ-alkyl.
R° represents H, C1-C3-alkyl, 5-methyl-2-oaco-1, 3-dioxol-4-yl-methyl, CHz-CO-CH3, CHZ-CO~C6H5, CHZCHz-C0-CHa, CHZCHzCOzR' , R' 02C-CH=C-COZR' , -CH=CH-COzR ° Or CHZCHZ
-CN, in which R' denotes C1-CZ-alkyl.
Particularly preferred compounds of the formula (I) are those in which A represents CH, CF, CC1, C-OC',H~ or Id, Xl represents H, F, C1, Hr, NHz or CH3o R1 represents CZHS, cyclopropyl or 2,4-difluorophenyl, or A and R1 together can denote a bridge of the structure C-0-CHZ-CH ( CH3 ) -, Le A 28 100 - 4 -R2 represents H, CH3 or C2H5, B represents a radical of the formulae N N N N
H H H ~,~~,.. "~~~ H H ~~~".. H H ~ H
R4N~Y R4N~Y R4N~Y R4N~Y
in which Y represents O or CH2 and R4 represents H, C1-C3-alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH2-CO-CH3, CH2-CO-C6H5, CH2CH2-CO-CH3, CH2CH2C02R', R~OzC-CH=i-COZR'~ -CH=CH-C02R' OR CH2CH2-CN, in which R' denotes C1-C2-alkyl.
Specific compounds of the invention include:
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;
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;
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;

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;
or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.
The compounds of the formula (I) in which A, X1, R1 and R2 have the abovementioned meaning, and B represents a radical of the formula - 5a -N
R~~'~ \y U
in which R3 and Y have the abovementioned meaning, are obtained by reacting a compound of the formula (II) F , OOR2 N sA~N~
I (zz) HN Ri in which A, Y, Xl, R' and RZ have the abovernentioned meaning, with a compound of the formula (I2I) R3~~3 t z z z ) in which a Le A 28 100 - 6 -R3 represents Cz-CS-oxoalkyl, CHz-CO-CsHS, CHzCHz-COzR' or CHZCHz-CN, in which R' denotes hydrogen or C1-C3-alkyl, and X3 represents halogen, in particular chlorine, bromine or iodine, if appropriate in the presence of acid binders . [Method A]
Compounds according to the invention of the formula (I) in which A, X1, R' and Rz have the abovementioned meaning, and B represents a radical of the formula N

in which Y has the abovementioned meaning and R3 represents CHZCHx-CO-CH3, CHZCHz-COZR ° , Le A 28 100 - 7 -~~~if.~
R' OzC-CH=C-COzR' , -CH-CH-C02R' or CHZCHZ-CN, in which R' denotes hydrogen or C1-C3-alkyl, can be obtained by reacting a compound of the formula (II) Xl O
F , OOR2 N A"N-HN~ ~I (II) with a Michael acceptor such as dialkyl acetylenedi-carboxylate, alkyl propiolate or a compound of the formula (IV) CHZ=CH-R~ ( IV) in which RS represents COCH3, COZR' or CN. [Method H]
To prepare enantiomerically pure compounds of the formula (I), a compound of the formula (V) Le A 28 100 - 8 XI
O

A~N
X
I

in which A, R1, RZ and X1 have the abovementioned meaning and XZ represents halogen, in particular fluorine or chlorine, is reacted with enantiomerically pure compounds of the formulae (DTI ) H H H H
N N N N

~/ ~J ~J ~J
in which Y represents O or CHZ and R4 represents H or C1-C3-alkyl, Le A 28 100 - 9 -

2~~ ~.~t~
if appropriate in the presence of acid scavengers, and the reaction product is optionally further reacted with a compound of the formula (IIIa) R''-X3 ( 2I I a ) in which X3 has the abovementioned meaning and R'' represents C2-C5-oxoalkyl, CHZ-CO-CsHs, CHZCH2COZR' or CHZCHZ-CN, in which R' denotes hydrogen or C1-C3-alkyl, or with a Michael acceptor such as dialkyl acetylene-diearboxylate, alkyl propiolate or a compound of the formula (IV) CHZ=CH-RS ( IV) in which R5 represents COCH3, COzR' or CN [Method C] .
If, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-~-oxo-3-quinolinecarboxylic acid and [S,S]-2,8-he A 28 100 - 10 -diazabicyclo[4.3.0]nonane are used as starting compounds, the course of the reaction can be represented by the following reaction schemes F COOH H H
N
~~N NH
F
Cl H
O
F ~ COOH
y H N \ N
HN C!
'H
If, for example, 6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-([15,6R)-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)--4~-oxo-3-quinolinecarboxylic acid and diethyl acetylenedicarboxylate are used as starting substances, the course of the reaction can be represented by the following reaction scheme:
O
F ~ COOH
N \ I N fJ
-f- C2HSOZC-C=C-CO2CZH5 HN~~ F i F
~O H ~
F
Le A 28 100 - 11 -2~~~~.~

F , COOH

H~ N ~ N
CZHSOZC-CH=C
N ~H F ~ F
~O
F
The racemic compounds of the formula (II) used as starting compounds are mainly known. Enantiomerically pure compounds of the formula ( TI ) are new and can be obtained in various ways.
1. A racemic intermediate of the formula (II) is reacted with an enantiomerically pure auxiliary reagent, the resulting diastereomers are separated, for example by chromatography and the chiral auxi-liary group is removed again from the desired diastereomer. The following reaction may be shown as an example:

F , COOH
IJ *
N ~ N + ~ ~ CH-NCO ---HN* F ~ CH3 *cis Le A 2~ 100 - 12 -~~~1~~~
O
F , COOH D~astere~r separation CH- NH-CO * N F N
\N

O
F ~ COOH
_ (R> ~. ~ J H~
CH- NH-CO H N F N -I ~N
CH3 ' H
O
F ~ COOH
N ~' N
HN F
'H
2. The bicyclic amines (VI) are, as enantiomerically pure compounds, new. They can be prepared by the following processes:
2.1. The racemic bicyclic amines (~a) N ~a~
~NH
Y
in vahich R° represents H Or C1-C3-alkyl, Le A 28 100 - 13 ~~~~v~e can be reacted with enantiomerically pure acids, for example carboxylic acids or sulphonic acids such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine, 3-bromocamphor-9-sulphonic acid, camphor-3-carboxylic acid, cis-camphoric acid, camphor-10-sulphonic acid, O,0'-dibenzoyl-tartaric acid, D- or L-tartaric acid, mandelic acid, «-methoxy-phenylacetic acid, 1-phenyl-ethanesulphonic acid or «-phenyl-succinic acid, to give a mixture of the diastereomeric salts, which can be separated by fractional crystallisation to give the diastereomerically pure salts (see P.
Newman, Optical Resolution Procedures for Chemical Compounds, Volume 1). The molar ratio between amine arid enantiomerically pure acid can be varied in a relatively wide range. By treatment of these salts with alkali metal or alkaline earth metal hydroxides, the enantiomerically pure amines can be liberated.
2.2. In a similar manner, as described in 2.1., resolution of the basic intermediates which occur during the preparation of the racemic bicyclic amines can be carried out using the abovementioned enantiomerically pure acids. Examples of basic intermediates of this type are:
Le A 28 100 - 14 -~~c~~~l H H
I
N N
N CE-IZ \ / (b) ~ ~N - CHZ (e) Y Y
O
CHz \ i Ha \
I
C N ~d) N (e) ~N - CO ~ / ~ NH
O ~/
In the following reaction scheme, the separation of 8-benzyl-cis-2,8-diazabicyclo[4.3,0)nonane into the enantiomers via the tartrates and conversion thereof into the enantiomerically pure cis-2,8-diazabicyclo[4.3.0]nonanes may be shown as an example of a resolution:
Le A 28 100 - 15 -~~a~~~.
H
N
N-CHZ-Ph L(+)-tartaric acid l.Crystallisation 2. Crystallisation Plother liquor 1 ) NaOH
1) 1 x recrystallisation 1 x recryst. 2) D(-)-2) NaOH tartaric acid NaOH
H ~ ~ H H
N-CHZ-Ph N-CH.,-Ph HZ/ Pd-C
HZ/ pd-C
H H H H
N
N-H ~N-H
e.e.> 99 % e.e.> 99 %
R,R-Configuration S,S-Configuration Le A 28 100 .- 16 -~~~~3~i~~
2.3. Both the racemic amines (a) and the basic intermediates (b) - (e) can be separated by chromatography, if appropriate after acylation, by means of chiral support materials (see, for example, G. Blaschke, Angew. Chem. 92, 14r19~0]).
2.4. Both the racemic amines (a) and the basic intermediates (b), (c), (e) can be converted by chemical linkage with chiral acyl radicals into diastereomer mixtures which can be separated by distillation, crystallisation or chromatography into the diastereomerically pure acyl derivatives, from which the enantiomerically pure amines can be isolated by hydrolysis. Examples of reagents for linkage to chiral acyl radicals are: a-methoxy-a-trifluoromethyl-phenylacetyl chloride, menthyl isocyanate, D- or L-a-phenyl-ethyl isocyanate, menthyl chloroformate or camphor-10-sulphonyl chloride.
2.5. Tn the course of the synthesis of the bicyclic amines (a), instead of achiral protective groups chiral protective groups care also be introduced. In this manner, diastereomers axe obtained which can be separated. For example, in the synthesis of cis-2, ~-diazabicyclo[4.3.0]nonane, the benzyl radical can be replaced by the R- or S-a-phenylethyl radical:
Le A 2B 100 - 17 -~~~ L
H

~N ~ ~N-CH ~ ~ ---.- N N-CH

2.6. The enantiomerically pure amines (VT) can also be synthesised from enantiomerically pure precursors, such as, for example, [R,R]- or [S, S]-3,4-dihydroxy-pyrrolidine, which should be protected on the nitrogen by a protective group.
An example of the synthesis of an enantiomerically pure amine, starting from enantiomerically pure 1-benzyl-3,4-dihydroxy-pyrrolidine, which may be given is the following reaction schemes a,b ~~ c,d a N N N
I I I
Bzl CO CO
R R
TosO OCHZCH20Tos ~ /~
0 N-BzI O N_H
N f ~ a.h t N ~ N
CO
CO H
R
R
Le A 28 100 - 18 -~~V~~~~.~
R = for example, ( CH3 ) 3C-O, a: H2, Pd/A-carbon b: acylation c : NaH, HrCHZCOOC2H5 or c : CHz=CH-CH2Br, NaH, d: LiBH4 d: 03, NaBH4, a : tosyl chloride, NEt3, f: benzylamine, xylene, reflex g: hydrolysis h: H2, PdJA-carbon Examples of compounds of the formula (VI) which may be mentioned are:
cis-2,8-diazabicycla[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, IR,6S-2-oxa-5,8~-diazabicyclo(4.3.0]nonane, IS,6R-2-oxa-5,8-diazabicyclo(4.3.0]nonane, IR,6R-2-oxa-5,8-diazabicyclo[4.3.0]nonane, IS,6S-2-oxa-5,8-diazabicyclo[4.3.0]nonane, The reaction of (V) with (VI), in which the compounds (VI) can also be employed in the farm of their salts, such as, for example, the hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoramide, sulpholane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol or isopropanol, glycol monomethyl ether or pyridine.
Mixtures of these diluents can also be used.
Le A 28 100 .- 19 --~c~~3~i.Lt.~
Acid binders which can be used are all the customary inorganic and organic acid binding agents, These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Those which may be mentioned specifically as being particularly suitable are: triethylamine, 1,4-diazabicyclo-[2.2.2]octane(DABCO),1,8-diazabicyclo[5.4.0]under-7-ene (DEU) or excess amine {vI).
The reaction temperatures can be varied within a relatively wide range. In general the reaction is carried out between about 20 and 200°C, preferably between 80 and 180°C.
The reaction can be carried out at normal pressure, but also at elevated pressure. In general, it is carried out at pressures between about 1. and 100 bar, preferably between 1 and 10 bar.
When carrying out this process, 1 to 15 mol, preferably 1 to 6 mol of the compound (VI) are employed per mol of the compound (V).
Examples of compounds of the formula (II) which can be used both as race~mates and as enantiomerically pure or diastereomerically pure compounds which may be mentioned are:
Le A 28 100 - 20 -XI
O

F / COORZ

H N ~,\ ~N~ (II) I.I\ ~y~
,~ R i N \

~ H
~Y

Ri R2 X1 Y A

Cyclopropyl CZHS H CH2 C-H

F-CHzCH2 H H CHZ C-F

Cyclopropyl C2H5 H CH, C-Cl Cyclopropyl H H CH2 C-OCI-I3 .

Cyclopropyl H H CHZ C-CH3 Cyclopropyl CZHS H CHZ N

Cyclopropyl H Br CHZ C-F

Cyclopropyl H CI CHZ C-F

Cyclopropyl H CH3 CH2 C-F

Cyclopropyl C2H5 NHZ CHZ C-F

Cyclopropyl H H O C-H

Cyclopropyl C2HS H O C_F

Cyclopropyl H H O C-CH3 Cyclopropy H H O ' N
l Cyclopropyl H Br O C-F

Cyclopropyl H Cl O C-F

Cyclopropyl H CH3 O C-F

Cyclopropyl H NHZ O C-F

Le A 28 100 - 21 -~~~~~~1~
Xl F / COORZ
N \p ~ N ~ (II) H H' I
\ N '''~ .:/"" R 1 ~y H
RZ X1 y p Cyclopropyl CH3 H CH2 C_H
Cyclopropyl CHZCH20H H CH2 C-F
cyclopropyl CHZCH20H H Cl-i2 C-Cl Cyclopropyl H H CH2 C-OCH3 Cyclopropyl H H CH2 C-CH3 Cyelopropyl H H CH2 N
Cyclopropyl H gr CH2 C-F
Cyclopropyl H F CH2 C-F
Cyclopropyl H CH3 CH2 C-F
Cyclopropyl H NH2 CH2 C_I~
Cyclopropyl H 1-1 ~ C-H
Cy~lopropyl CH3 H O C-F
C2H5 H H ' p C-Cl Cyclopropyl H H 0 C-OCH3 Cycloprop~'1 H ' ~-I- a' C-CH3 Cyclopropyl H H O ' N
Cy~lopropyl H Br 0 C-F
Cyclopropyl H Cl O C-F
Cyclopropyl 1-1 CH3 O C-F , C2H5 H NHZ Q C_F
Le A 28 100 _ 22 _ ~7 ~ .r ~Oc~~~i~.
xl F , COOR2 H N ~A ~ N ~ (II) H\ ,,, ~Y-~H

Cyclopropyl H H Cl-I2C-H

Cyclopropyl H H CHZ C-F

Cyclopropyl H H CHZ C-Cl Cyclopropyl H H CHZ C-OCH3 Cyclopropyl H H CH2 C-CH3 Cyclopropyl H H CH2 N

Cyclopropyl H Br CHZ C-F

Cyclopropyl H F CH2 C-F

Cyclopropyl H CH3 CHZ C-F

Cyclopropyl H NHZ CHZ C-F

Cyclopropyl H H O C-H

Cyclopropyi H H O C-F

:;:"
Cyclopropyl H H O C-Cl Cyclopropyl H H O C-OCH3 Cyclopropyl H H O C-CH3 Cyclopropyl H H O N

Cyclopropyl H Br O C-F

Cyclopropyl H F O C-F

Cyclopropyl H CH3 O C-F

Cyclopropyl H NHZ O C-F

Le A 28 100 - 23 -~~~~~1~
xl F / COORZ
H N \A ~ N ~ (ii) H\ N~~ R t ~Y ,H
Rt RZ xl Y A
Cyclopropyl H H CH2 C-H
Cyclopropyl H H CHZ C-F
Cyclopropyl H H CH2 C-Cl Cyclopropyl H H CHZ C-OCH3 Cyclopropyl H H CHZ C-CH3 Cyclopropyl H H CHZ N
Cyclopropyl H Br CH2 C-F
Cyclopropyl H F CI-i2 C-F
Cyclopropyl H CH3 C:H2 C-F
Cyclopropyl I-1 NH2 C:HZ C-F
Cyclopropyl H H O C-H
Cyclopropyl H H O C_F
Cy~lop~opyl H H O C-Cl Cyclopropyl H H O C-OCH3 Cy~lopropyl H H O C-CH3 Cyclopropyl H H O N
Cyclopropyl H ~r O C-F
Cyclopropyl H F O C-F
Cyclopropyl H CH3 O C-F
Cyclopropyl H NH2 O C-F
Le A 28 100 - 2~

F COORZ
N A N

~Y
R1 RZ ~C1 Y A
2,4-DifluorophenylH Cl CH2C-F

2,4-DifluorophenylH CH3 CH2C-F

2,4-Difluo=ophenylH H CH2C-CII~

2,4-DifluorophenylH H O C-F

2,4-DifluorophenylH H O C-CI

4-Fluorophenyl H H 0 CH

2,4 DifluorophenylH H O N

2,4-DifluorophenylI-I H O C-OCH3 2,4-DifluorophenylH H O C-CHg 2,4-Difluorophenyll-i H CHZC-F

2,4-DifluorophenylH F CH2C-F

..>.~
?,4-Difluorophenyll-I H CHzC-Cl ~,4-Difluorophenyll-~ H O C-Cl 2,4-Difluo=ophenylH H CHZN

2,4-Difluorophenyll--I H O N

2,4-DifluorophenylH H O C-H

2,4-DiflucrophenylC2~--15 H O C-F

Le A 28 100 - 25 -The starting compounds of the structures (III) and (IV) are known. Examples which may be mentioned are:
chloroacetone,4-chloro-2-butanone,5-chloro-2-pentanone, 1-bromo-2-butanone, phenacyl chloride, methyl acrylates, ethyl acrylates, acrylonitrile, methyl vinyl ketone, dimethyl acetylenedicarboxylate, diethyl acetylene-dicarboxylate, methyl propiolate and ethyl propiolate.
The reaction of (II) with (III) is preferably carried out in a diluent such as dimethyl sulphoxide, N,P7-dimethyl-formamide, N-methylpyrrolidone, hexamethylphosphoramide, sulpholane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol or isor.wopa.nol, glycol monomethyl ether or pyridine in the presence of an acid binder. Mixtures of these compounds can also be used.
Acid binders which can be used are all the customary inorganic and organic acid binders, These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and am:idines. Those which may be specifically mentioned as being particularly suitable are: triethylamfne, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU) or excess amine (VI).
The reaction temperatures can be varied within a relatively wide range. In general the reaction is carried out between about 20 and 200°C, preferably between 60 and 130°C.
Le A 28 100 - 26 -~~~~~i.r~
The reaction can be carried out at normal pressure, but also at elevated pressure. In general, it is carried out at pressures between about 1 and 100 bar, preferably between 1 and 10 bar.
When carrying out this process, 1 to 15 mol, preferably 1 to 6 mol, of the compound (III) are employed per mol of the compound (II).
The reaction of (II) with the Michael acceptors (IV) according to method ~ is preferably carried out in a diluent such as acetonitrile, dimethyl sulphoxide,. N,A1-dzmethylformamide, an alcohol such as methanol, ethanol, propanol or isopropanol, or glycol monomethyl ether.
The reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out between about 20°C and about 150°C, preferably between 40°C and 100°C.
The reaction can be carried out at normal pressure, but also at elevated pressure. In general, the reaction is carried out at pressures between 1 and 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention, 1 to 5 mol, preferably 1 to 2 mol, of the compound (IV) are employed per mol of the compound (II).
Le A 28 100 - 27 -2~~~~~.~
The preparation of the acid addition salts of the compounds according to the invention is carried out in a customary manner, for example by dissolving the betaine in aqueous acid and precipitating the salt with a water-s miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent amounts of betaine and acid can also be heated in water or an alcohol such as glycol monomethyl ether and then evaporated to dryness or the precipitated salt filtered off with suction.
Pharmaceutically utilisable salts are understood as meaning, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.
The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in excess alkali metal or alkaline earth metal hydroxide solution, filtering off undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable salts are sodium, potassium or calcium salts. Py reacting an alkali metal or alkaline earth metal salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.
Apart from the active substances mentioned in the examples, for example, the compounds listed in the Le A 28 100 - 28 -following tables (optionally in the cis- or traps-form) can also be prepared by the processes describeda X~
O
F / COOH
H N ~p~N~
R~
N
-H
lZ3 - X 1 A

CH302C-CH=CH- H C-F

5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl- H C-F

5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl- H C-Cl CH3-CO-CHz- H C-H
C2H502C-CH2-CI-Iz H C-H
C2Hs02C-CH=C_COZCZHs H C-H
CH30zC-CH=CF-I- H C-H
CaHsO2C-CH=CH- F C-F
CH3-CO-CH2CHz- NHZ C-F
CZHSOzC-CHzCH2- NHz C-F
CH3OZC-CH=C-CO2CH3 NHZ C-F
C2HSOZC-CH=C-COzC2Hs ~THZ C_F
i Le A 28 100 - 29 -O
F / COON
H N \A' _NJ

~N
'H

C2HSp2C_CH=CH- NH~ C-F

CZH502C_CH2-CH2- H N

NC-CH2CHz- H N

C2HSOZC-CH=C-COZCZHS H N

CH302C-CH=CH- H N

CH3-CO-CHzCH2- CH3 C_H

CH3-CO-CH2_ CHI3 C-H

C2HSO2C-CH=C-CO2CZH5 CH3 C_H

CH30zC-CH=C-COZCH3 CI-I3 C_H

C2HSO2C-CH=CH- CH3 C-H

CH302C-CH=CH- CH3 C-F

C2HSOZC-CH=C-COZC2H5 CH3 N

Le A 28 100 - 30 -C~ ~ e) .~
Xt O
F / COOH
H N ~A~y~
R \ N''l,I , "r~~ H

CH3-CO-CI-i2CHz- H C-F

CH302C-CH=CH- H C-F

CH302C-CH=C-COzCH~ H C-F

C2HSO2C-CH=C-CO2C2H5 H C-F

5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl- H C-F

CH3-CO-CHZ- H C-Cl - C2H5O2C-CH2CH2- H C-Cl CH30zC-CH=CH- H C-CI

CH3O2C-CH=C-CO2CH3 H C-Cl C2Hs02C-CH=C-CO2C2E15 H C-C1 5-Methyl-2-oxo-1,3-dioxol-4-yl-methyl- H C-Cl )Je A 2>3 100 - 31 -XI

F / COOH
N A~N
H
N~~~" H
R3 Xl A

C2H502C-CH=CH- H C-H

CH302C-CH=CH- F C-F

C2I-ISOZC-CH2-CH2_ F C-F

C2HSOZC-CH=CH- NHZ C-F

CZHSO~C-CH=C-COZCZHS NHZ C-F

C2HSOZC-CH=CH- CH3 C-H

(.zH5O2C-CH=C-CO2C2H5 CH3 C-H
I

CH3O2C-CH=C-CO2C2H5 CH3 N

C~I3:C0-CH2CH2- H C-OCH3 C2H502C-CH=CH- H C-OCH3 C2Hg02C-CH=CH H N

Le A 28 100 - 32 -A specific process of the invention is a process for preparing 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 which comprises reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid with (+)-[S,S]-2,8-diazabicyclo[4.3.0]-nonane, followed, if required, by converting the obtained compound into a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.
The invention also provides pharmaceutical and antibacterial compositions comprising a quinolone- or naphthyridone-carboxylic acid compound of the invention or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid; and a pharmaceutically acceptable carrier, diluent or excipient.
The invention also provides uses of the compounds and compositions of the invention for: preventing, controlling or curing an infectious disease; as an additive for the preservation of an organic or inorganic material; or for the preparation of a medicament for the prevention, control or cure of an infectious disease.
The invention also provides a commercial package comprising a compound or composition of the invention together with instructions for use thereof in the treatment of an infectious disease.
- 32a -The compounds according to the invention have potent antibiotic activity and exhibit, together with low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative microorganisms, in particular against enterobacteria; especially even against those which are resistant to various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.
These useful properties make possible their use as chemotherapeutic active substances in medicine and also as substances for the preservation of inorganic and organic materials, in particular of organic materials of all types, for example polymers, lubricants, dyes, fibres, leather, paper and wood, of foodstuffs and of water.
The compounds according to the invention are active against a very broad spectrum of mircoorganisms. With their aid, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled and the diseases produced by these pathogens can be prevented, ameliorated and/or cured.
The compounds according to the invention are distinguished by increased activity on dormant and resistant microorganisms. In the case of dormant bacteria, e.g. bacteria which show no detectable growth, the compounds act at concentrations which are far below those of substances known hitherto. This relates not only Le A 28 100 - 33 -to the amount to be employed, but also to the rate of destruction. It was possible to observe results of this type with gram-positive and gram-negative bacteria, in particular with Staphylococcus aureus, Pseudomonas aeruginosa, Enterocaccus faecalis and Escherichia coli.
The compounds according to the invention also show surprising increases in activity against bacteria which are classified as less sensitive to comparable substances, in particular resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.
The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms.
They are therefore particularly highly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine which axe caused by these pathogens.
The compounds are also suitable for controlling protozoonoses and helminthoses.
The compounds according to the invention can be used in various pharmaceutical preparations. Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
Le A 28 100 - 3~ -The table below confirms the surprising advantages of the compounds according to the invention compared with ciprofloxacin in the Staphylococcus aureus-infected mouse models Tablet Activity in Staph. aureus infection in the mouse (mg/kg) Substance p.o. s.c.

Ciprofloxacin 80 80 Example 27 10 2.5 Example 29A 5 5 Example 31 10 10 Example 33 10 5 Example 35 2.5 2.5 The compounds according to the invention, compared to known structurally similar compounds, show an improved antibacterial action, in particular with anaerobic microorganisms. O
F COOH
I
N
CI
Component according to the invention as in Ex.ampls 2Bs A

R = N , disclosed in EP-A-0,350,733s B
~~N -Ciprofloxacin C
Le A 28 100 - 35 -~~~~~:~.<.~
'1'F3D1 -~

Compound Species Strain A B C

Bacteroides ES 25 0,25 1 8 fragilis DSM 2151 0.25 0.5 4 Clostridium 1024027 0.125 0.5 0.5 perfringens Bact. DSM 2079 0.5 2 $

thetaiotaomicron ~

(MIC values in ~sg/ml~ agar dilution test ir. the multipoint inoculator (Denley); isosensitest agar).
Preparation of the.precursors Example A
[S:S]I-2,8-Diazabicycloj4.3.Olnonane H
H
N
NH
H
1) [S,S]-8-Benzyl-2,8-diazabicyclo[4.3.0]nonane Method T:
a) Separation of the diastereomeric salts:
Le A 28 100 - 36 -

3.0 g (20 mmol) of D-(-)-tartaric acid are dissolved in 10 ml of dimethylformamide by heating to 80°C and the solution is treated with a solution of 2.16 g (10 mmol) of cis-8-benzyl-2,8-diazabicyclo[4.3.0]-nonane in 3 ml of dimethylformamide. The mixture is stirred at 0°C for 1 hour, and the product is filtered off with suction and washed with dimethylformamide and methoxyethanol.
Yield: 1.93 g, Melting point: 146-151°C, [a]D3 = -19.3° (c = 1, 1H20) . .
Diastereomerically pure [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate is obtained by a single recrystallisation from methoxyethanol.
[«]p3 = -22.7° (c = 1, HZO) .
Melting point: 148-154°C.
b) Liberation of the base:
40 g of [S,S[-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate are dissolved ire 250 ml of water and treated with 32 g of 45 ~ strength sodium hydroxide solution. The precipitated oil is taken up in 150 ml of tart-butyl methyl ether, the aqueous phase is extracted again with 150 ml of tent-butyl methyl ether and the comba.ned organic phases are concentrated after drying over sodium sulphate. The Le A 28 100 - 37 -residue is then distilled in vacuo.
Yield: 18.5 g of [S,S]-8-Benzyl-2,8-diazabicyclo-[4.3.0]nonane, Boiling point: 107-109°C/0.1 mbar, [~]o° = 17.3° (undiluted).
Method 3I:
75.0 g (0.5 mol) of L-(°~)-tartaric acid are dissolved in 250 ml of di.methylformamide at 80°C and 54.1 g (0.25 mol) of cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane are added dropwise as a solution in 75 ml of dimethylformamide. The mixture is slowly cooled to 20°C and the crystal suspension is stirred for 1 hour. The crystals ([R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate) are filtered off with suction and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 500 m1 of mater and wor3ced up as described in Method I using 63 g of 45 ~ strength sodium hydroxide solution.
Yield: 25.2 g of [S,S]-8-benzyl-2,8-diazabieyclo[4.3.0]-nonane;
the product contains 3.6 ~ of the R,R-enantiomer (determined by gas chromatography after derivatisation with menthyl chloroformate).
The compound can be reacted with D-(-)-tartaric acid Le A 28 100 - 38 -according to Method I to give diastereomerically pure [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate.
Recrystallisation in this case is not necessary.
Method III:
73.6 g (0.34 mol) of cis-8-benzyl-2,8-diazabicyclo-[4.3.0]nonane are added dropwise at 80 to 90°C as a solution in 111 ml of dimethylformamide to a solution of 102 . 9 g ( 0 . 685 mol ) of L ( * ) -tartaric aeid in 343 ml of dimethylformamide. The mixture is seeded with [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate and slowly cooled to an internal temperature of 18°C. The crystals are filtered off with suction, and the filtrate is seeded with [S,S]-8-benzyl-2,8-diazabicyelo[4.3.0]-nonane L-tartrate and stirred until it has crystallised completely. (After concentration and liberation of the base as described in Method :C, [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate can be obtained from the mother liquor by purification with D-tartaric acid).
The product is then filtered off with suction, washed 20. with dimethylformamide and isopropanol and dried in air.
The crystals are recrystallisecl from 88 ~ strength ethanol. 52 g of [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]-nonane L-tartrate trihydrate are obtained.
Melting points 201-204°C, [«]D3 = +5.2° (c = 1, Hz0) .
The salt can be processed as described in Method I
Le A 28 100 -'39 -(liberation of the base) to give enantiomerica~.ly pure [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]n~anane.
Method IV:
a) Separation of enantiomers of cis-8-benzyl-7,9-dioxo 2,8-diazabicyclo[4.3.0]nonane to give jlS,GR]-$
benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane.
The procedure is analogous to Example H (Method II/a), using I~-(-)-tartaric acid as the chiral auxiliary reagent, or the procedure is as follows:
Mother liquor and washing liquor from [1R,6S]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane L-tartrate (from Example B, Method IT/a) are con-centrated together, the residue is taken up in water and the solution is extracted three times with toluene. The toluene phases are discarded. The aqueous phase is treated with saturated sodium hydrogen carbonate solution until a pH of 7 to 8 is obtained, then extracted four times with methylene chloride. The combined methylene chloride phases are dried over magnesium sulphate and concentrated.
Yield: 14.4 g (60 ~ of theory of the originally employed racemic cis-8-benzyl-7,9-dioxo-2,8-diaza-bicyclo[4.3.0]nonane).
ja]D3 = -4.5° (c = 5, ethanol).
Le A 28 100 - 40 -These 14.4 g (59 mmol) axe crystallised from 120 ml of ethanol analogously to Example B (Method II/a) using 8.6 g (57 mmol) of D-(-)-tartaric acid. .
Yield: 8.9 g (77 ~ of theory) of [1S,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane D-tartrate.
[c~JD3 = _46.2° (c = 0.5, 1N HC1);
after recrystallisation from an ethanol/glycol monomethyl ether mixture a further purification is carried out:
[a]D3 = -59.3° (c = 0.5, aP1 HC1) .
5.0 g (12.7 mmol) of the diastereomerically pure tartrate obtained in this manner were converted, as described in Example B, Method II/a, into the free amine:
Yield: 3.0 g (96 ~ of theory) of [1S,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, Melting point: 60-61°C, [a]n3 = _22.2° (c = 5, ethanol).
An enantiomer excess of 96.6 ~ ee was determined by gas chromatography after derivatisation with menthyl chloroforxnate.
b) Reduction of[1S,6R]-8-benzyl-7,9-dioxo-2,8-diazabi-cyclo[4.3.0]nonane to [S,S]-8~benzyl-2,8-diazabi-cyclo[4.3.0]nonane.
Le A 28 100 -- 41 -~Q~~a~
The procedure is analogous ~to Example s (Method zx, b), [1S,6R]-8-benzyl-7,9-dioxo-2,8-diazabicyclo-[4.3.0]nonane being, however, employed as the starting material.
The crude product obtained after working up proved to be [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane on derivatisation with menthyl chloroformate.
Racemisation was thus observed during 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-diazabi-cyclo[4.3.0]nonane are hydrogenated at 90°C and 90 bar in the course of 5 hours over 5.8 g of palladium on active carbon (5$) in 190 ml of methanol. The catalyst is then filtered off with suction and washed with methanol, and the filtrate is concentrated on a rotary evaporator. The residue is 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, [«]DZ = _2.29° (undiluted), ee > 99 $ ( determined by gas chromatography after derivatisation with Mosher's reagent).
Method V:
3.75 g (25 mmol) of Z-(+)-tartaric acid are Le A 28 100 - 42 -~~lor~~~.~~.
initially introduced in solution in 50 ml of dimethylformamide at 80C and 10.82 g (50 mmol) of cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane are added dropwise as a solution in 15 ml of dimethylformamide.

The mixture is seeded with [R,R]-8-benzyl-2,8-diaza-bicyclo[4.3.0]-nonane L-tartrate and stirred for one hour at about 72 C to complete seed crystal formation.

This is then slowly cooled to 15C, and the crystals are filtered off with suction and washed twice with 13 ml of dimethylformamide in each case. The combined filtrates are heated to 80C and treated with a further 3.75 g (25 mmol) of L-(+)-tartaric acid. The mixture is additionally heated to 119 C

until a clear solution is formed, and again slowly cooled to room temperature with seeding with [S,S]-_ 8-benzyl-2,8-diazabicyclo[4.3.0]-nonane L-tartrate.

The crystals are filtered off with suction, washed successively with dimethyl-formamide, 2-methoxy-ethanol and ethanol and dried in air.

Yield: 9.59 g Melting point: 188 to 192C.

The crystals are recrystallised from 95 ml of 80 strength ethanol. 8.00 g of [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartratetrihydrate(76 of theory) are obtained which melts at 112 to 118C

with foaming, then resolidifies and melts again at 199 to 201C.

[ a ] D3 4 . 5 ( c = 1, water ) ee: 98.0 ~ (determined by gas chromatography after derivatisation with menthyl Le A 28 100 - 43 -2~~~~~~.~
chloroformate).
Example B
[R,R1-2.8-Diazabicycloj4.3.OLnonane H
H
N
NH
H
1) [R,R]-8-Benzyl-2,8-diazabicyclo[4.3.0]nonane Method I:
The crystals of [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]-nonane obtained according to Example A, Method II
(4~.2 g) are washed with dimethylformamide and_ methoxyethanol and recrystallised from 300 ml of methoxyethanol. 45.6 g of enantiomerically pure [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate are obtained (enantiomer purity determined by gas chromatography after derivatisation with menthgl chloroformate).
I5 Melting point: 121-I24°C, [a]D~ = +22.3° (c = 1, Ha0) .
The salt (44.5 g) is converted into the free base as described in Example A, Method Ib. 20.2 g of [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane are obtained.
Boiling point: 107-111°C/0.04 mbar, Le A 28 100 - 44 -[a]D° _ _17.5° (undiluted).
Method II
a) Separation of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane to give [1~t,6S]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane 24.1 g (98.8 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4:3.0]nonane are heated to reflux with stirring in a mixture of 410 ml of ethanol and 25 m1 of acetonitrile in a three-necked flask. 14.8 g (98.8 mmol) of L-(+)-tartaric acid are then added at once. After all the tartaric acid has completely dissolved, the heating is first turned off, but the flask is left in the oil bath. When the system has cooled until the solution no longer boils, the stirrer is turned off. Crystallisation and addition of seed crystals takes place at a temperature of 50°C. After standing overnight and cooling to room temperature, the precipitated crystals are filtered off with suction and washed with a little ethanol/petroleum ether (1:1) and dried at 80°C for 2 hours.
Yields 9.8 g (50 ~k of theory) of [1~,6S]-8-benzyl-7,9-dioxo-2,8-dl.azabicyclo[4.3.0]nbnane L-fiaxtrate, [«]p3 = +47.7° (c = 0.5, lId HCl).
the compound can be further purified by Le A 28 100 - 45 -recrystallising twice from a mixture of ethanol and glycol monomethyl ethers _ +58.6° (c = 0.5, 1N HC1).
1H-NMR (DMSO): 7.22-7.35 (2m, 2H, aryl-H); 4.55 (s, 2H, benzyl-CHZ); 4.28 (s, 2H, tartaric acid-CH); 3.91 (d, 1H, 1-CH); 2.97 (dd, 1H, 6-CH); 2.53-2.66 (m, 2H, 3-cH2) ;, 1. 78 and 1. 68 ( 2m, 2H, 5-CHZ) ; 1.42 and 1.28 ppm (2m, 2H, 4-CHZ).
C18H22N2~8 ( 394 ) Calculated: C 54.4 H 5.6 N 7.1 0 32.5 Found: C 54.7 H 5.8 N 7.1 0 32.4 The determination of the absolute configuration was carried out by means of an X-ray structural.
analysis:
H
H O HOw'C02H
HO'~ COZH
H O
3.6 g (9.1 mmol) of the diastereomerically pure tartrate obtained in this manner are dissolved in water to liberate the base and treated with saturated sodium hydrogen carbonate solution until a pH of 7 to 8 is obtained. The aqueous solutzon is extracted four times with 20 ml of methylene chloride each time. The combined methylene chloride phases are dried over magnesium sulphate and Le A 28 100 - 46 -~~ ~~:~~.
Concentrated.
Yield 2.2 g (99 ~ of theory) of jlR,6S]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane Melting points 60-61°C, [ « ] D3 = +21. 8 ° ( c = 5 , ethanol ).
An enantiomer excess of 93.8 ~ ee was determined by gas chromatography after derivatisation with menthyl chloroformate.
b) Reduction of [18,65]-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane to jR,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane In a heated flask, 0.34 g (9 mmol) of lithium aluminium hydride is introduced under NZ in 18 ml of anhydrous tetrahydrofuran and 0.73 g (3 mmol) of jlR,6S]-8-benzyl-?,9-dioxo-2,8-diazabicyclo[4.3.0]-nonane is added drnpwise as a solution in 3 ml of anhydrous tetrahydrofuran. The mixture is then boiled for 16 hours with reflux condensation.
Woxking up is carried out by dropwise edition of 0.34 ml of water in 10 m~ of tetrahydrofuran, 0.34 ml of 10 ~S strength sodium hydroxide solution and 1.02 ml of water. The precipitate is filtered off with suction and washed with tetrahydrofuran, and the filtrate is concentrated. 0.? g of crude [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane remains (GC purity: 99 ~k).
Le A 28 100 - 47 -~i~~ ~r~
It was not possible to determine any racemisation during the gas chromatographic determination of the enantiamer purity using menthyl chloroformate.
2) [R,R]-2,8-diazabicyclo[4.3.0]nonane 19.4 g (0.09 mol) of [R,R]-8-benzyl-2,8-diaza-bicyclo[4.3.0]nonane are hydrogenated according to the procedure of E~cample A, 2.
Yield: 9.61 g (85 ~ of [R,R]-2,8-diazabicyclo-[4.3.0]nonane, Boiling point: 45-58°C/0.08 mbar, [,a]D3 = +2.30° (undiluted).
Example C
iS.S]I-2-Methyl-2.8-diazabicyclo~4.3.0]nonane IH
N
C~NH
H
1) [S,S]-8-Benzyl-2-methyl-2,8-diazabicyclo[4.3.0]-nonane X3.2 g (0.2 mmol) of [S,S]-8-benzyl-2,8-diazabi-cycla [ 4 : 3 . 0 ] nonane are treated with 20 ml of 37 ~
formaldehyde solution, 40 ml of water and 24 g of acetic acid and the mixture is hydrogenated over Le A 28 100 - 48 -2 g of palladium on active carbon (5 $) at 20°C and 20 bar fox 10 hours. The catalyst is then filtered off with suction, the filtrate is rendered alkaline with potassium carbonate and the product is extracted with tart-butyl methyl ether. After drying over sodium sulphate, the mixture is concentrated and the residue is distilled in vacuo.
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 over 1.1 g of palladium on active carbon (5 ~) at 90°C
and 90 bar in 90 ml of methanol. The mixture is then filtered, the filtrate is concentrated on a rotary evaporator and the residue is distilled in vacuo.
Yield: 5.5 g of enantiomeyically pure [S,S]-2-methyl-2,8-diazabicyclo[4.3.0]nonane (detection by derivatisation with Mosher's reagent), Boiling point: 78-81°C/14 mbar.
Le A 28 100 - 49 -Example D
jR.Rl1-2-Methyl-2r8-diazabicvcloj4.3.0],nonane IH
N.
C~NH
H
The compound is prepared by the v~~orking instructions described in Example C, starting from 43.2 g (0.2 mol) of [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane.
Yield: 4.9 g of [R,R]-2-methyl-2,8-diazabicyclo[4.3.0]-nonane.
Boiling point: 30-33°C/0.12 mbar.
Example E
cis-7 , 9-nioxo-8-t j 1S,L-~-_phenyl-ethyl l-2~, 8-diazabicyclo~4.3.0]nonane O
~N - CI-I- Ph H
1) N-([1S]-1-Rhenyl-ethyl)pyridine-2,3-diearboximide 74.5 g (0.5 mol) of pyridine-2,3-dicarboxylic anhydride are initially introduced at 20°C in solution in 500 ml of dioxane and 60.5 g (0.5 mol) T.e A 28 100 - 50 -~0~~~1~
of S-(-)-1-phenyl-ethylamine are added dropwise, whereupon the temperature rises to 33 ° C . The mixture is stirred for a further 1 hour and then concentrated on a rotary evaporator, and residual solvent is removed at 40°C10.1 mbar. The residue is taken up in 245 g (2.4 mot) of acetic anhydride, and the solution is treated with 4.9 g (0.06 mol) of anhydrous sodium acetate and stirred at 100°C for 1 hour. After cooling, the mixture is poured onto 1 1 of ice-water while stirring well, and the precipitate is filtered off with suction, washed with cold water and hexane and dried in air.
The crude product (114 g, Melting points 112-114°C) is recrystallised from 285 ml of methanol.
Yields 96.3 g (76 ~), Melting point: 115-117°C, [a]p2 - _46.9° (c = 2, ethanol).
2) cis-7,9-Dioxo-8-([1S]-1-phenyl-ethyl)-2,8-diazabicyclo[4.3.0]nonane 79.7 g (0.316 mol) of N-([1S]-1-phenylethyl)-pyridine-2,3-dicarboximide are hydrogenated over l0 g of palladium on active carbon (5 $ strength) at 90°C/100 bar in 600 ml of tetrahydrofuran. The catalyst is filtered off after completion of the absorption of hydrogen and the filtrate is completely concentrated. 83.7 g of a viscose residue are obtained. v Le A 28 100 - 51 -,t ~~~u i.~~~
Puritys 95 ~ strength, 1H-~tMR (CDC13, 200 MHz ) : 1. 4-1. 7 (m, 3H) ; 1. 82 and 1.83 (2d, 3H); 1.9-2.05 (m, 1H); 2.28 (broad s, 1H);
2.54-2.86 (m, 3H); 3.77 (d, 1H); 5.39 (q. 1H); 7.24 7.48 ppm (m, 5H).
Example F
cis-2-Oxa-5,8-diazabicvclof4.3.Olnonane H
I
N cis 1) trans-1-Benzoyl-3-bromo-4-(2-hydroxyethoxy)-pyrrolidine 95 g (0.55 mol) of 1-benzoyl-3-pyrroline are dissolved in 380 g of ethylene glycol and 101 g (0.57 mal) of N-bromosuccinimide are added in 5 g portions in the course of 2 hours. The mixture is then stirred overnight at room temperature, poured into water and extracted with methylene chloride, and the solution is dried over. magnesium sulphate and concentrated. The residue (188 g) was chromatographed on silica gel using ethyl acetate.
Yields 136.5 g (78 ~ of theory), Purity by GCs 99 ~.
Le A 28 100 - 52 -2) traps-1-~enzoyl-3-bromo-4-(2-tosyloxyethoxy)-pyrrolidine 92 g (0.239 mol) of traps-1-benzoyl-3-bromo-4-(2-hydroxyethoxy)-pyrrolidine, 32 g (0.316 mol) of triethylamine and 1 g of ~-dimethylaminopyridine are dissolved in 750 ml of toluene and 60 g (0.31 mol) of tosyl chloride in 450 ml of toluene are added dropwise. The mixture is stirred at room temperature for two days, water is added, and the aqueous phase is separated off and extracted with toluene. The toluene solutions are washed with 10 ~S strength hydrochloric acid, dried over magnesium sulphate and concentrated, the residue is dissolved in ethyl acetate and the solution is filtered through silica gel. The filtrate is concentrated.
Yield: 125 g (91 ~ of theory).
The thin layer chromatogram shows a homogeneous compound.
3) cis-8-Benzoyl-5-benzyl-2-oxa-5,8-diazabi-cyclo(4.3.0]nonane 124 g (0.265 mol) of traps-1-benzoyl-3-bromo-4-(2-tosyloxyethoxy)-pyrrolidine are heated under reflux overnight with 86 g (0.8 mot) of benzylamine in 1.5 1 of xylene, the salts of benzylamine are filtered off with suction and the filtrate is concentrated.
Le A 28 100 - 53 -~~s~~l.~~
Crude yield: 91.2 g.

4) cis-5-~enzyl-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 under reflux overnight with 200 ml of concentrated hydrochloric acid and 140 ml of water. After cooling, the benzoic acid is filtered off with suction, the filtrate is concentrated to half the volume, the solution .is rendered alkaline with ZO potassium carbonte and extracted with chloroform, the extract is dried over potassium carbonate and concentrated, and the residue is distilled.
Yield: 30.7 g (48.8 ~ of theory), foiling point: 134-142°C/0.6 mbar, Purity by GC: 92 ~.
5) cis-2-Oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride 26 g (0.11 mal, 92 ~ strength) of cis-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane in 180 ml of ethanol and 19 ml of cancentrated hydrochloric acid are hydrogenated in 3 g of palladium/active carbon (10 ~ Pd) at 100°C and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the separated crystals are dried in a dessicator over phosphorus pentoxide.
Le A 28 100 - 54 -Yield: 17.1 g {77 ~ of theory), Melting point: 244-250°C.
Example G
Separation of enantiomers of cis-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane 150.1 g (1 mol) of D-(-)-tartaric acid are initially introduced into 700 ml of methanol at 60 to 65°C and 218.3 g (1 mol) of cis-5-benzyl-2-oxa-5,8-diazabicyclo-[4.3.0]nonane are added dropwise as a solution in 300 ml ZO of methanol. The mixture is then slowly allowed to cool to about 49°C until the solution becomes cloudy, and is seeded with crystals of 1R,6S-5-benzyl-2-oxa-5,8-diaza-bicyclo[4.3.0]nonane D-tartrate obtained in a prior ex-periment, stirred for 30 minutes at this temperature for seed crystal formation and then slowly cooled down to 0 to 3°C. After filtering off with suction, the solid is washed with ~ mixture of 200 m1 of-_ ethanol and 100 ml of methanol cooled to 0°C and then 3 times with 300 ml of ethanol in each case and the product is then dried in air.
Yield: 160.3 g of 1R,6S-5-benzyl-2-oxa-5,8-diazabicyclo-[4.3.0]nonane tartrate (87 ~ of theory) Melting point: 174.5 to 176.5°C
ee > 97 ~ (after derivatisation with 1-phenyl-ethyl isocyanate and HPLC analysis).
Le A 28 100 - 55 -[ cx ] D3 = +24 . 0 ° ( c = 1, methanol ) .
156.9 g of the 1st crystallisate are recrystallised from 1,500 ml of methanol.
Yield: 140.0 g (89 ~ recovered) Melting point: 1?6 to 177°C
[«]D3 = +25.2° (c = 1, methanol).
The methanolic mother liquor from the 1st crystallisation is concentrated on a rotary evaporator. The syrupy residue (236 g) is dissolved in 500 ml of water, adjusted to pFi 12 to 13 with 250 ml of 6N sodium hydroxide solution, extracted 3 times with 350 ml of toluene each time, and the extracts are dried over sodium carbonate and concentrated in vacuo. The residue, 113.1 g of a brown oil which, according to gas chromatographic investigation, contains 97 ~ of cis-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, is employed without purifica-tion for the preparation of the 1S,6R-enantiomer.
113.1 g (0.518 mol) of crude concentrated 1S,6R-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane axe dissolved in 155 ml of methanol and added dropwise to a boiling solution of 77.8 g (0.518 mol) of L-(+)-tartaric acid in 363 m1 of methanol. A crystal magma is gradually formed during the dropwise addition. The mixture is stirred at 60°C for 1 hour and then slowly cooled to 0°C in the course of 2 hours. The crystals are filtered off with suction and washed with a 2:1 mixture of ethanol and methanol cooled to 0°C and then 3 times with ethanol. The Le A 28 100 - 56 -product is then dried in air.
Yield: 145.5 g of 1S,6R-5-benzyl-2-oxa-5,8-diazabi-cyclo[4.3.0]nanane L-tartrate (79 ~ of theory) Melting point: 174.5 to 176.5°C
ee > 97 ~ (after derivatisation with 1-phenyl-ethyl isocyanate and ~IPLC analysis) [a]D3 ~ -24.0° (c = 1, methanol).
Liberation of the enantiomerically pure bases:
144 g (0.39 mol) of 1S,6R-5-benzyl-2-oxa-5,8-diazabi cyclo[4.3.0]nonane tartrate are dissolved in 250 ml of water and 175 ml (1.05 mol) of 6 N sodium hydroxide solu tion are added. The deposited oil is taken up in 500 ml of toluene, the organic phase is separated off and the ac;ueous phase is extracted a further 3 times with 250 ml of toluene in each case. The combined organic phases are dried over sodium carbonate, filtered and cancentxated on a rotary evaporator. The residue is distilled through a cm Vigreux column under a high vacuum.
Yield: 81.6 g (96 ~ of theory) of 1S,6R-5-benzyl-2-oxa-20 5,8-diazabicyclo[4.3.0]nonane Boiling point: 120 to 139°C/0.04 to 0.07 mbar Purity: 100 ~ determined by gas chromatography Density: b "' 1.113 g/ml - _60,9° (undiluted).
Distillation residue: 0.12 g In the same manner, 76.0 g (93 ~ of theory) of 1R,6S-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane are obtained from 139.2 g (0.37b mot) of IR,6S-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane tartrate.
Le A 28 100 - 57 -[a]D3 = +61.2° (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 traps-5-benzyl-2-oxa- 5,8-diazabicyclo[4.3.O~nonane to give R,R- and S,S-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane.
Example H
1) tart-Butyl 3S,4S-4-allylnxy-3-hydroxypyrrolidine-1-carboxylate 16.5 g (0.55 mol) of 80 ~ strength I~aH are initially introduced into 500 ml of absolute dioxane and a solution of 107,5 g (0.53 mol) of tart-butyl S,S-3,4-dihydroxypyrrolidine-1-carboxylate (DE-A-3,403,194) dissolved hot in absolute dioxane is added dropwise at 60C. The mixture is stirred at 60C for 1 hour and 64 g (0.53 mol) of allyl bromide are then added dropwise . The mixture is then stirred at 60C for three haurs. It is concentrated and the residue is dissolved in 200 ml of water and 600 ml of methanal. The solution is extracted three times with 200 mi ~f pentane each time, the methanol is stripped off on a rotary evaporator, the residue is diluted with 200 ml of water and the mixture is extracted with methylene chloride. The methylene chloride solution is dried over MgSC74 and concentrated, and the residue is dissolved in Le A 28 100 - 58 -tent-butyl methyl ether (200 ml). 9 g of starting material (44 mmol) crystallised out overnight. The ether solution is concentrated and distilled.
Yield: 83 g ( 80 ~ of theory relative to recovered starting material and diallyl ether) Boiling point: 149°C10.7 mbar to 159°C/0.9 mbar.
The distillate contains 5 ~ of the starting material and 4 ~ of diallyl ether.
The pentane extract yielded 17 g of a mixture of 15 $ desired product and 84 ~ of diallyl ether.
(a]D3 - -10.5° (c = i, methanol).
2) tart-Butyl 3S,4S-3-hydroxy-4-(2-hydroxyethoxy)-pyrrolidine-1-carboxylate 64 g (0.24 mol, 91 ~ strength) of tart-butyl 3S,4S-4-allyloxy-3-hydraxypyrrolid9_ne-~.-carboxylate are dissolved in 250 ml of methanol and cooled to 0°C, and ozone is passed through the solution until a washing bottle containing potassium iodide solution and connected in series indicates the emergence of ozone and thus complete reaction. Residues of ozone are carried out by means of a stream of nitrogen, then the resulting ozonide is reduced at 0°C using 18 g of sodium borohydride, which is added in 1 g portions. The mixture is then stirred overnight at room temperature and concentrated, the residue is diluted with water, and the mixture is treated with Le A 28 100 - 59 -~~t~~~~~
20 g of potassium carbonate and extracted five times with 100 ml of methylene chloride each time. The organic solutions are dried over magnesium sulphate and concentrated.
Yields 65.8 g (100 ~ of theory) The product is 91 ~ strength by gas chromatography.
[«]D~ - _15.2° (c = 0.97, methanol).
3) 35,48-1-tent-Butoxycarbonyl-3-tosyloxy-4-(2-tosyloxyethaxy)-pyrrolidine 2.7 g (10 mmol, 91 ~ strength) of tent-butyl 35,48-3-hydroxy-4-(2-hydroxyethoxy)-pyrrolidine-1-carboxylate axe initially introduced into 30 ml of methylene chloride, 6 ml of 45 ~ strength radium hydroxide solution and 0.1 g of benzyltriethyl-ammonium chloride are added and a solution of 2.86 g (20 moral) of tosyl chloride in 10 ml of methylene chloride are then added dropwise with cooling. The mixture is then stirred for a further hour at room temperature and poured into 20 ml of water, the organic phase is separated of:~ and the aqueous phase is extracted with methylene chloride. The organic phases are dried over magnesium sulphate and concentrated.

Yielda 5 g (90 ~ of theory).

The product is homogenous by thin layer chromatography.

Le A 28 100 - 60 -4) tert-Butyl 1S,6R-5-benzyl-2-oxa-5,8-diazabicyclo-[4.3.0]nonane-8-carboxylate 87 g (156 mmol) of 3S,4S-1-tert-butoxycarbonyl-3-tosyloxy-4-(2-tosyloxyethoxy)-pyrrolidine are heated under reflex overnight with 58 g (0.54 mol) of benzylamine in 1 1 of xylene. The mixture is cooled, precipitated salts of benzylamine are filtered off with suction and the residue is concentrated.
Xield: 43 g (58 ~ of theory).
The product is 67 ~ strength by gas chromatography.
5) 1S,6R-5-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane 43 g (90 mmol) of tert-butyl 1S,6R-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane-8-carboxylate are heated under reflex in 35 ml of concentrated hydrochloric acid and 35 ml_ of water until the evolution of carbon dioxide is complete. The mixture is rendered alkaline with pcatassium carbonate and extracted with chloroforrn, the: organic solutions are dried over MgS04 and concentrated, and the residue is distilled twice through a 20 cm 'Vigreux column.
Yield: 11.1 g (55 ~ of theory) Boiling point: 108 - 115°C/0:07 mbar [«]D6 = ~58.3° (undiluted).
Le A 2s loo - sl -Example T
1) tart-Butyl 3R,4R-4-allyloxy-~-hydroxypyrrolidine-1-carboxylat~:
The reaction is carried out analogously to Example H1) using tart-butyl R,R-3,4-dihydroxypyrrolidine-1-carboxylate:
Boiling point: 145°C/0.1 mbar [«]D3 = +9.5° (c = 1.0, methanol).
The product is 95 ~ strength by gas chromatography.
ZO 2) tart--Butyl 3R,4R-3-hydroxy-4-(2-hydroxyethoxy)-pyrrolidine-1-carboxylate The reaction is carried out analogously to Example H2) using tart-butyl 3R,4R-4-allyloxy-3-hydraxy-pyrrolidine-1-carboxylate:
Yield: 99 ~ of theory (0.175 molar batch) [«]D -- +16.5° (c = 0.94, methanol).
3) 3R,4R-1-tart-Butoxycarbonyl-3-tosyloxy-4-(2-tosyloxyethoxy)-pyrrolidine The reaction is carried out analogously to Example H3) using tart-butyl 3R,4R-3-hydroxy-4-(2--hydroxyethoxy)-pyrrolidine-l~.carboxylate Yield: quantitative (0.11 molar batch).
4) tart-Butyl 1R,6S-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane-8-carboxylate Le A 28 100 - 62 -The reaction is carried out analogously to Example H4) using 3R,4R-1-tert-butoxy-carbonyl-3-tosyloxy-4-{2-tosyloxyethoxy)-pyrrolidine:
Yield: 40 ~ of theory (0./1 molar batch).
5) 1R,6S-5-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane The reaction is carried out analogously to Example H5) using tent-butyl 1R,6S-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane-8-carboxylate:
Yield: 63 ~ of theory (40 mmolar batch) Roiling point: 120°C/0.06 mbar The product is 95 ~ strength by gas chromatography (a]D3 = +58.5° (undiluted).
Example J
1) 1S,6R-2-Oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride 7.5 g (34.4 mmol) of 1S,6R-5-benzyl-2-oxa-5,8-diazabicyclo(4.3.0]nonane arse hydrogenated at 100°C
and 100 bar on 1 g of palladium/active carbon (10 Pd) in 200 ml of ethanol with the addition of 7 m1 of concentrated hydrochloric acid. The catalyst is filtered off with suction and washed sevezal times with water. The aqueous filtrate is concentrated, whereupon the residue crystallises. The crystals are thoroughly saturated with ethanol, filtered off with suction and dried in air.
Le A 28 100 - 63 -~J~~~.~~
Yield: 4.6 g (66.5 ~ of theory) Melting point: 233-235°C.
2) 1S,6R-2-Oxa-5,8-diazabacyclo[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 at 120°C
and 120 bar on 5 g of palladium/active carbon (10 Pd) in 500 m1 of ethanol. The catalyst is faltered 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 : [a]De = +8.2° (undiluted).
ee values >_ 99.5 ~ (by derivatisation with Mosher reagent).
Exam lp a K
1) 1R,6S-2-Cxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride The reaction is carried out analogously to Example J1) using 1R,68-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0]nonane:
Yield: 77 ~ of theory (23.8 mmolar batch) Melting point: 230-232°C.
2) 1R,6S-2-Uxa-5,8-diazabicyclo[4.3.0]nonane Le .A 28 100 - 64 -The reaction is carried out analogously to Example J2) using 1R,6S-5-benzyl-2-oxa-5,8-diazabicyclo-[4.3.0]nonane:
Yield: 93.3 ~ of theory (1.58 molar batch) Boiling point: 63 - 65°x/0.03 mbar Rotation: [oc]p~ = -8.4° (undiluted).
ee value: >_ 99.5 ~ (by derivatisation with Mosher reagent).
1R,6R- or 1S,6S-2-Oxa-5,8-diazabicyclo[4.3.0]nonane can be obtained analogously.
Example L
1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydro-bramide 1) 1R,6S-5-(1R-Phenylethyl)-8-tosyl-2-oxa-5,8-diaza-bicyclo[4.3.0]nonane 101.8 g (0.196 mol) of traps-3-brom-1-tosyl-4-(2-tosyloxyethoxy)-pyrrolidine and 72 g (0.584 mol) of R-(+)-1-phenylethylamine in 900 ml of xylene are heated under reflux overnight. The cooled solution is washed with 2N sodium hydroxide solution and dried over potassium carbonate, the drying agent is removed and the solvent is concentrated. Qn cooling, crystals are deposited from the residue which are filtered off with suction and recrystallised from a mixture of 750 ml of petroleum ether and 200 ml of Le A 28 100 - 65 - -~)a.~~l n-butanol.
Yields 15 g (39.6 $ of theory of optically pure material.
Melting point: 188°C, Rotation : [a]oe = +103.7° (c = 1, CHC13) .
2) 1R,6S-8-Tosyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane 13 g (33.6 mmol) of 1R,6S-5-(1R-phenylethyl)-8-tosyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane are hydro-genated at 100°C and 100 bar on 2.5 g of palladium/
active carbon (10 ~ Pd) in 200 ml of ethanol. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is recrystallised from 30 ml of toluene.
Yield: 7.5 g (79 ~ of theory), Melting point: 160-161°C, Rotation: [«]03 = +17.5° (c = 1.21, CHC13).
3) 1R,6S-2-Oxa-5,8-diazabicyclo[4.3.0]nonane dihydro-bromide 7 g (24.8 mmol) of 1R,6S-8--tosyl-2-oxa-5,8-diaza-bicyclo[4.3.0]nonane axe dissolved in 25 ml of 33 ~
strength hydrogen bromide solution in glac~.al acetic ;..,..~
acid, 5 g of phenol are added and the mixture is stirred overnight at room temperature. It is diluted with diisopropyl ether, and the crystallised salt is filtered off with suction and dried in air.
Yield: 5.5 g.
Le A 28 100 - 66 -U ZA 'v Derivatisation with Mosher reagent and gas chromatographic analysis shows only one detectable enantiomer (ee > 99.5 ~).
Example M
5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinalinecarboxylic acid Br O
F ~ COOH
J
F ~ ~:I
F
1) 2-Bramo-3,4,5,6-tetrafluoro-benzoyl chloride 365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluoro-benzoic acid [Tetrahedron 23, 4719 (1967)] are introduced into 2 1 of thionyl chloride and the mixture is heated under refl.ux for 11 hours until the evolution of gas stops. F;xcess thionyl chloride is stripped off in vacuo and the residue is distilled.
Yield: 330 g (85 ~ of theory), Boiling point: 81-85°C/3-5 mbar.
2) Diethyl (2-broma-3,4,5,6-tetrafluoro-benzoyl)-malonate 15.9 g (0.167 mol) of magnesium chloride are Le A ?.8 100 - 67 -introduced into 150 ml of anhydrous acetonitrile (dried over zeolite) and 26.9 g (0.167 mol) of diethyl malonate are allowed to drop in with cooling. The mixture is cooled to 0°C, 46~ ml (33.7 g - 0.33 mol) of triethylamine are added dropwise and the mixture is stirred for 30 minutes.
48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluoro-benzoyl chloride are then added dropwise, and the mixture is stirred for a further 1 hour at 0°C and brought to room temperature overnight. It is treated with 100 ml of 5 N hydrochloric acid and extracted three times with methylene chloride, and the extracts are dried with NaZSOa and concentrated in vacuo.
Crude yield: 62.7 g.
3) Ethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl)-acetate 60 g of crude diethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl)-malonate are introduced into 150 m1 of water and treated with 0.6 g of 4-toluenesulphonic acid, and the mixture is heated under reflex for 6 hours. It is extracted with methylene chloride, and the extract is washed with water, dried with Na2S04 ' a and concentrated.
Crude yields 46 g, Boiling point (sample distillation in a bulb tube):
150-160°C(oven)/3 mbara Mass spectrum: m/B 342 (M+) , 297 (M+-OCZHS) , 263 (M+-Br), 257, 255 (M+-CHzCO2C2HS), 235 (263-28) .
Le A 28 100 - 68 -4) Ethyl 2-(2-bromo-3,4,5,6-tetrafluoro-benzoyl)-3-ethoxy-acrylate 45 g of crude ethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl)-acetate are introduced into 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate and the mixture is heated under reflux for 2 hours. Excess reagent is first stripped off in vacuo, then under a high vacuum (bath up to 120-130°C) and the crude product is reacted to the next step.
Crude yield: 50.7 g 5) Ethyl 2-(2-bromo-3,4,5,6-tetrafluoro-benzoyl)-3-cyclopropylamino-acrylate 50.7 g of crude product from Step 4) axe treated dropwise with 8.6 g (0.15 mot) of cyclopropylamine in 90 ml of ethanol with ice-cooling, the mixture is stirred at room temperature, allowed to stand overnight and again well cooled, and the cry5tallisate is filtered of;f with suction, washed with cold ethanol and dried.
Yield: 29 g (42 ~ over 4 steps), Melting point: 103-105°C (from ethanol).

6) Ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluora-1,4-dihydro-4-oxo-3-quinolinecarboxylate Le A 28 100 - 69 -L3 =I .~. ~~
28 g (68 mmol) of ethyl 2-(2-bromo-3,4,5,6-tetrafluoro-benzoyl)-3-cyclopropylaminoacrylate axe heated under reflux for 6 hours with 6.9 g (164 mmol) of sodium fluoride in 88 ml of DMF. The mixture is poured into water after cooling, and the deposited precipitate (red) is filtered off with suction, washed with plenty of water and dried at 80°C in a recirculating air oven.
Crude yield: 27.3 g, Melting point: 150-175°C;
after recrystallisation from glycol monomethyl ether:
Melting point: 187-191°C.

7) 5-Bromo-1-cycloprnpyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 26.7 g (68 mmol) of crude ethyl 5-bromo-1-cycloprapyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are introduced into a mixture of 165 ml of acetic acid, 110 ml of water and 18 ml of concentrated sulphuric ~~cid and heated under reflux for 2 hours: The cooled xeaction mixture is poured into ice-water, and the deposited precipitate is filtered off with suction, washed with plenty of water and dried in a recirculating air oven at 80°C.
Yield: 19.7 g (80 ~ of theary), Melting point: 208-210°C (with decomposition);
after recrystallisationfrom glycol monomethyl ether:
Melting points 212-214°C (with decomposition);
Le A 28 100 - 70 -,~ n :~~.az~~~
NMR, li-I (DMSO) : 8. 73 s ( 1H at C-2 ) , 4, 10' m ( 1H, cyclo-propyl), 1,2 m (4H, cyclopropyl) [ppm].
Mass spectrum: '°/e 361 (M''-H20) , 317 (M-COZ) , 41 ( 100 ~, C3H5) .
preparation of the final compounds Examt~le 1 O
F , COOH
J
N ~ N
F
N
H
A. 1-~clopropyl-7- ~[l S . S ] -2 . 8-diazabic~,rclo [ 4 . 3 . 0~ non-8-~1L 6,8-difluoro-1.4-dihydro-4-oxo-3-guinolinecarboxylic ac id 141.5 g (0.5 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-duinolinecarboxylic acid are heated under reflux for 1 houx with 69.25 g (0.55 mol) of (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane (ee> 99.5 ~, GC 99.8 strength) in a mixture of 1500 ml of acetonitrile and 750 ml of dimethylforariamide in the presence of 55 g (0.5 mol) of 1,4-diazabicyclo-[2.2.2]octane. The suspension is cooled, and the precipitate is filtered off with suction, washed with water and then additionally stirred with 1 1 of water (pH 7). The product is filtered off with suction and dried at 60°C in a recirculating air Le A 28 100 - 71 -~J~J1~
oven, Yield: 163.4 g (84 ~ of theory), Melting point: 249-251°C (with decomposition) B. (-)-1-Cyc.loproPyl-7-~.IS.S]-2.8-diazabicycloj4.3.0]non=

8-yl)-6,8-difluoro-1.4-dihydro-4-oxo-3-quinoline-carboxylic acid hydrochloride 6.0 g (15.4 mmol) of 1-cyclopropyl-7-([S,S]-2,8-diaza-bicyclo[4.3.O~non-8-yl)-6,8-difluoro-1,4-dihyriro-4-oxo-3-quinolinecarboxylic acid are dissolved in 40 ml of half-concentrated hydrochloric acid at 60°C and the solution of the hydrochloride is filtered. The filtrate is concentrated to one half, cooled in ice and treated with 40 ml of ethanol. The yellow crystallisate is filtered off with suction, washed with ethanol and dried at 60°C in a high vacuum, where the colour lightens.
5.51 g (84 $ of theory) of the hydrochloride are obtained, which is already very gore.
For further purification, it is dissolved in 50 ml of water in the presence of heat. 'The yellow solution is treated with 5 ml of half-concent:cated hydrochloric acid and cooled in ice, and the deposited crystallisate is filtered oft with suctian, washed well with ethanol and dried first at room temperature and then under a high vacuum at 100°C.
Yield: 4.64 g (70.8 ~ of theory), Le A 28 lU0 - 72 -~~~u~~.~
Melting point: 324--325°C (with decomposition), TLC (silica gel, dichloromethane/methanol/17 ~ strength aqueous ammonia = 30:8:1): homogeneous, Rf value: 0.3, [«]D5: -256° (c = 0.5, H20), Purity (HPLC): 99.4 ~ strength, G20H21~2N3~3 ~ HC1 ( 425 . 5 ) Calculated: C 56.4 H 5.2 N 9.9 G1 8.3 Found: C 56.3 H 5.4 N 9.8 C1 8.3 Example 2 O
F , COOH
i J
H N ~' N
~ Cl N[ J'H
A. 8-Chloro-1-cyclopropyl-7-(fS,S~ -2,8-diazabicyclo-L4.3.Olnon-8-vl~-6-fluoro-1.4-dihydro-4-oxo-3-guinoline-carboxylic acid 2 batches of the following size are run in parallel and worked up together:
180 g (0.6 mol) of 8-chloro-1-cycloprapyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid axe heated under reflux for 1 hour with 84 g (0.67 mol) of (+)-(S,S]-2,8-diazabicyclo(4.3.0]nonane in a mixture of 1.8 1 of acetonitrile/900 ml of dimethylformamide in the Le A 28 100 - 73 -presence of 99 g (0.88 mol) of 1,4-diazabicyclo[2.2.2]-octane (DABCO) (internal temperature: 90.5°C). The yellow solution is cooled and treated with seed crystals (obtained from a 5 ml sample which was concentrated;
residue stirred with acetronitrile). The mixture is stirred far 2 hours at about 3°C, and the deposited precipitate from both batches is rapidly filtered off with suction, washed with acetronitrile and introduced into 1.5 1 of ice-water. The initially thin, well-stirrable suspension after about 10 minutes becomes a poorly stirrable mass, which is diluted with a further 150 ml of water. The precipitate is filtered off with suction, washed with water and dried at 80°C in a recirculating air drying oven.
Yield: 402 g (82.7 ~ of theory), faintly yellow product;
Melting point: 193-196°C (with decomposition), Rf value (silica gel; methylene chloride/methanol/17 strength aqueous NH3 = 30:8:1): 0.4.
B 8-Chloro-1-cyclogro~~yl-7- ( j S , S ] -2 , 8-diazabicyclo _P 4 . 3 . 0 )non-8-yl ~ 6-fluoro-1, 4-dihvdro-4-oxo-3-quinolinecarboxvlic acid h~yidrochloride 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-4-oxo-3-quinolinecarboxylic acid are suspended in 50 ml of water and brought into solution by addition of 50 ml of half-concentrated hydrochloric acid. The mixture is filtered through a glass frit, the filtrate is Le A 28 100 - 74 -i ~1~~~_~~
concentrated in vacuo and the residue is stirred with about 300 ml of abs. ethanol. The suspension is cooled in ice, the precipitate is filtered off with suction,, washed with ethanol and dried first at room temperature and then at 100°C in vacuo.
Yield: 13.4 g (93.8 ~ of theory);
Melting point: 328-330°C (with decomposition);
Rf value (silica gel, methylene chloride/methanol/17 strength aqueous NH3 = 30:8:1): 0.4;
Purity (HPLC): 99.9 ~ strength, [a]D4: -164.4° (c = 0.45, H20), C20H21C1FN3o3. HC1 ( 442 . 3 ) Calculated: C 54.3 H 5.0 N 9.5 C1 16.0 Found: C 54.3 H 5.0 N 9.5 C1 16.0 C. The following salts, for example, can also be prepared analogously:
8-chloro-1-cyclopropyl-_7-([~i,S]-2,8-diazabicyclo-[4.3.0]non-8-yl),-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid methanesulphonate - 20 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 acid toluenesulphonate 8-chloro-1-cyclopropyl-7-([S,S]-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-Le A 28 100 - 75 -quinoline carboxylic acid sulphate 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 acid acetate 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 acid lactate 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 acid citrate 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 acid embonate Example 3 O
COOH
J
y ~
H
N' H
25 Analogously to Example 1, the following are obtained with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids T~e A 28 100 - 76 -A. 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4~-dihydro-4-oxo-3-quinoline-carboxylic acid Melting point: 256-258°C (with decomposition).
B. 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid hydrochloride, Melting point: > 320°C (with decomposition), [a]D6: -90.6° (c = 0.48, H20) .
Example 4 F O
F , COOH
J
N \ N
H N
'H
A. 6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for 1 hour with 2.7 g (21.4 mmol) of (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane in 40 ml of acetonitrile/20 ml of I~-methylpyrrolidone in the presence of 2.2 g (20 mmol) of 1,4 diazabicyclo[2.2.2]octane. 2'he suspension obtained is cooled, and the precipitate is filtered off with suction, washed with acetonitrile and dried at 100°C/12 mbar.
Le A 28 100 - 77 -~t,1?~~...~ ~'~.
Yield: 6.7 g (82.3 ~ of theory) of 1-cyclopropyl-7-([S,5]-2,8-diazabicyclo(4.3.0]non-8-y1)-5,6,8-tri-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, Melting point: 257-259°C (with decomposition); after recrystallisation from glycol monomethyl ether:
Melting point: 260-265°C (with decomposition).
B. 1.5 g (3.7 mmol) of the product from Step A are introduced into 6 ml of 1 N hydrochloric acid. After a short time, the hydrochloride deposits, and is filtered off with suction, washed twice with 5 ml of ethanol each time and dried at 100°C/12 mbar.
Yield: 1.4 g (85.7 ~ of theory) of 1-cyclopropyl-7 ([5,5]-2,8-diazabicyclo[4.3.0]non-8-yl)-5,6,8 trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, Melting point: > 310°C (with decomposition), [a]D6: -272° (c = 0.5, H20) .
Example 5 F , COOH
~J
N ~ N
H~N F ~ x HCl 'H
5.2 g (13 mmol) of the product from Example 4A are treated with 15 ml of liquid ammonia in 80 ml of pyridine in an autoclave and heated at 130 °C for 12 hours . The Le A 28 100 - 78 -mixture is then cooled, the autoclave is let down, the mixture is concentrated and the residue is treated with acetonitrile in an ultrasonic bath. The undissolved precipitate is filtered off with suction, the residue is dissolved in about 150 ml of water in the presence of heat, the solution is filtered and the hydrochloride is precipitated using 10 ml of half-concentrated hydro-chloric acid, filtered off with suction and dried at 100°C in a recirculating air drying oven. The product obtained is suspended in 100 ml of glycol monomethyl ether at 110-115°C and brought into solution by addition . . of 38 ml of half-concentrated hydrochloric acid. The solution is filtered hot through a glass frit, cooled and the cooled yellow crystallisate is filtered off with suction, washed with ethanol and dried at 120°C~12 mbar.
Yield: 2.5 g (44 ~ of theory) of 5-amino-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 hydro-chloride, Melting point: > 335°C (with decomposition; dark colouring already below 335°C), [a]De: -2$0.8° (c = 0.53, H20) .
Exam~gle 6 O
COOH
Ha/-'N N N
x HCl N
J H
Le A 28 100 - 79 -~fl ~~~.i~:~.
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 at room temperature for 1 hour with 1.3 g (10.3 mmol) of (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane with exclusion of water in 15 ml of acetonitrile. After standing overnight, the precipitate is filtered of.f with suction, washed with acetonitrile and chromatographed on silica gel for purification (eluent: methylene chloride/-methanol/17 ~ strength aqueous ammonia 30x8:1; Rf value:
0.4). The 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 obtained is dissolved in 15 ml of half-concentrated hydrochloric acid, the solution is evaporated and the residue is stirred with ethanol. The precipitate is filtered off with suction, washed with ethanol 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-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride Melting point: 345-346°C (with decomposition), [a]p°: +5.4° (c = 0.5, H20).
Example 7 O
COOH
~J
H, N ~ N
..", H
H\N//'.
Le A 28 100 - 80 -Analogously to Example 1, the fallowing are obtained using-(~)-[R,R]-2,8-diazabicyclo[4.3.0]nonane:
A. 1-Cyclopropyl-7-([R,R]-2,8-diazabicyclo[4.3.0]non 8-yl)-6,8-difluoro-i,4-dihydro-4-oxo-3-quinoline carboxylic acid Melting point: 247-249°C (with decomposition).
H. 1-Cyclopropyl-7-([R,R]-2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-guinoline-carboxylic acid hydrochloride, Melting point: 322-326°C (with decomposition), Purity (HPLC): 99.4 ~ strength, ee: 98.6 $, [«]D4: +250° (c = 0.5, H20) .
Example 8 O
F ~ COOH
H ,,, N w N
Cl N .. ..." H
Analogously to Example 2, the following are obtained ~,5 using (-)-[R,R]-2,8-diazabicyclo[4.3.0]nonane:
A. 8-Chloro-1-cyclopropyl-7-([R,R]-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-quinolinecarlaoxylic acid, Le A 28 100 - 81 -~ a W' '1:5 a .:. ~,;r.
Melting point: 192-195°C (with decomposition).
B. 8-Chloro-1-cyclopropyl-7-([R,R]-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid hydrochloride, Melting point: 323-324°C (with decomposition).
Purity (HPLC): 99.9 ~ strength, [a)D°: +164.5° (c = 0.53, HZa).
CzDHzIC1FN303. HC1 ( 442 . 3 ) Calculated: C 54.3 H 5.0 N 9.5 C1 16.0 Found: C 54.2 H 5.0 N 9.5 C1 16.1 Example 9 O _ F ~ COOH
J
H F.i ,,,.
N ~ N
N . ..,, 'H
Analogously to Example 1, the following are obtained from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid and (-)-[R, R]-2,8-diazabicyclo [4.3.0)nonane:
A. 1-Cyclopropyl-7-([R,R)-2,8-diazabicyclo[4.3.0]non-$-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, Melting point: 25~-258°C (with decomposition).
Le A 28 100 - 82 -~~~~~1~~
B. 1-Cyclopropyl-7-([R,R]-2,8-diazabicyclo[4.3.0]non-$-yl)-6-fluoro-1.,4-dihydro-4-oxo-3-quinoline-carboxylic acid, Melting point: decomposition above 320°C, [a]p°: +92.5° (c = 0.53, HZO) .
Example 10 O
F , COOH
J
H
cis ~O
A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid:
1.43 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for :1 hour with 0.74 g (5.4 mmol) of 93 ~ strength cis-2-oxa-5,8-diaza-bicyclo[4.3.0]nonane in the presence of 0.67 g (6 mmol) of 1,4-.diazabicyclo[2.2.2]octane in a mixture of 15 ml of acetonitrile/75 ml of dimethylformamide.
The suspension is concentrated, the residue is stirred with water, and the precipitate is filtered off with suction and dried in vacuo at 80°C.
Yield: 1.67 g (85.4 ~ of theory), Melting point: 210-212°C (with decomposition).
Le A 28 100 - 83 -B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid hydrochloride: .
1.6 g (4 mmol) of the product from Step A are dissolved in 120 m1 of half-concentrated hydro-chloric acid at 60°C, the solution is concentrated, the residue is stirred with ethanol and the preci-pitate is filtered off with suction and dried at 90°C iri vacuo.
Yield: 1.57 g, Melting points 300-303°C (with decomposition), Purity (FiPLC): 97 ~ strength.
C. Analogously to Example 10A, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid of melting point 204-206°C (with decomposition) is obtained 'using 1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]nonane.
D, Analogously to Example 10B, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid hydrochloride of melting point 324-325°C (with decomposition) is obtained using the betaine from Example lOC.
[a]o°: -241° (c = 0.59, H20) .
Le A 28 100 - 84 -E. Analogously to Example 10A, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid of melting point 204-206°C (with decomposition) is obtained using 1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]nonane.
[a]D5; +248° (c = 0.57, DMF).
F. Analagously to Example IOB, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid hydrochloride of melting point 323°C
(with decomposition) is obtained using betaine from Example 10E.
[a]DSt +238° (c = 0.5, HZO) .
Example 11 O
F , CO03-I
y w y H~N~ C!
cis ~O
Analogously to Example l0, the following are obtained using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids Le A 28 100 - g5 -A. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl-4-oxo-3-quinolinecarboxylic acid, Melting point: 180-185°C (with decomposition), B. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, Melting point: 227-232°C (with decomposition).
C. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 186-188°C (with decomposition).
[«]D6: -269° (c = 0.5, DMF).
D. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride Melting point: 278-280°C (with decomposition), [«]D4: -208° (c = 0.5, HZ~) .
E. 8-Chloxo-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]nori-8-yl)-4-oxo-3-quinolinecarboxylic acid Melting point: 188-190°C (with decomposition).
+270° (c = 0.5, DMF).
Le A 28 100 - 86 -A (.1 n F. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diazabicycla[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, Melting point: 292-294°C (with decomposition).
[a]D': +193° (c = 0.5, H20) .
Example 12 O
F ~ COOH
J
N \ N
cis H\
~O
Analogously to Example 10A, the following are obtained using 1-cyclopropyl-6,?-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
ZO A. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid, Melting point: 246-249°C (with decomposition) (from glycol monomethyl ether).
B. 1-Cyclopropyl-6-fluoro-1,4-dihydro-?-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid, Melting point: 243-245°C (with decomposition) Le A 28 100 - 8? -2~~~a.~:~
C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid hydrochloride, Melting point: 300°C (decomposition) [a]p3: -99° (c = 0.5, Hz0) .
Example 13 F O
COOH
J
N ~ N
~y~s F
~o Analogously to Example 10A, the following are obtained using 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid:
A. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7-(cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 210-216°C (with decomposition).
B. 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, Melting point: 234-237°C (with decomposition).
[a]D4: -287° (c = 0.5, DMF).
Le A 28 100 - 88 -C. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 236-237°C (with decomposition).
[«]D°: +282° (c = 0.5, DMF) .
Examlale 14 NHZ O
COON
J
-N ~ N
H\N
~'~s O
A. 4.1 g (10 znmol) of the product from Example 13A are treated with 5 ml of liquid ammonia in 40 ml of pyridime and heated at 130°C for 10 hours in an autoclave. After cooling, the precipitate is filtered off with suction, washed with water and dried at 100°C in a recirculating air drying oven.
The crude product (2 g) is purified by recrystalli sation from glycol monomethyl ether: yellow crystallisate.
Yields 1.3 g (31 ~ of theory) of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-2-oxa-S,8-diazabicyclo[4.3.0]non-8-y1)-4-oxo-3-quinoline-carboxylic acid, Melting point: 233-240°C (with decomposition).
Le A 28 100 - 89 °

2~~~~~.~.~
B. 5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained analogously using the product from Example 13C, Melting point: 212-214°C (with decomposition), [a]D5: -260° (c = 0.5, DMA') .
C. 5-Amino-1-cyclopropyl-6,8-difhuoro-1,4-dihydro-7-(1S,6Ft-2-oxa-5,8-diazabicyclo(4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained analogously using the product from Example 13C, Melting point: 213-215°C (with decomposition), (a]D6: +261° (c = 0.5, D1H:F') .
Mass spectrum: m/e 406 (M+,95 ~), 346, 249, 98, 41, 28 (100 ~).
Example 15 O (S) F ~ COO- CHZ- CH- CHZ CI-I3 cH3 cis xCF3COOH
H\N F
A. 7-(2-tart-Butoxycarbonyl-2,8-diazabicyclo(4.3.0]non-8-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid L,e A 28 100 - 90 -~fl 7.8 g (20 mmol) of 1-cyclopropyl-7-(2,8-diaza-bicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in a mixture of 60 ml of dioxane/water (2:1) and 20 ml of 1 N sodium hydroxide solution and the mixture is treated with ice-cooling and stirring with 5.24 g (24 mmol) of di-tart-butyl pyro-carbonate. The mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The deposited precipitate is filtered off with suction, washed with 250 ml of water and dried overnight at 50°C in a recirculating air drying oven.
Yield: 9.34 g (95.5 ~ of theory), Melting point: 216-219°C {with decomposition).
B. 2S-Methyl-1-butyl 7-(2-tart-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-8-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 2 .15 g ( 4 . 4 mmol ) of the product from Step A are susper:ded. in 60 ml of tetrahyctrofuran/water ( 1:1 ) at room temperature and 1.65 g (5 mmol) of cesium carbonate are added. The mixture is allowed to react at about 40°C in an ultrasonic bath for 20 minutes, about 40 ml of the solvent are distilled off at 40°C/12 mbar) and the solution which remains is lyophilised, the slightly soluble crude caesium salt being obtained. 3.3 g of this crude salt are dissolved in 40 ml of dimethylformamide and treated with 1.4 g of S(+)-1-bromo-2-methyl-butane and Le A 28 100 ° 91 -p n ~;~~;.~~:~
reacted overnight in the ultrasonic bath at 40-50°C.
The suspension obtained is concentrated, and the residue is treated with water and extracted with methylene chloride. After drying with sodium sulphate, the solution is concentrated and the residue is purified by chromatography (silica gel, eluent: methylene chlaride/methanol 95:5).
Yield: 950 mg (38 ~ of theory), Melting point: 72-83°C (with decomposition).
C. 2S-Methyl-1-butyl 1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxa-3-quinolinecarboxylate trifluoroacetate 570 mg (1 mmol) of the product of Step D are dissolved in 3 ml of trifluoroacetic acid at roam temperature and the solution is concentrated at 60°C/12 mr..r. The viscous oil obtained is stirred with 5 ml of ether, a solid product being obtained.
This is filtered off with suction, washed with ether and dried at 80°C in a high vacuum.
Yield: 450 mg (78 ~ of theory), Melting point: 214-216°C (with decomposition), [oc]D5: +2.8° (C = 0.5, DMF).
Example 16 O
F ~. COOH
cR) I J
/ \ N \ N
CH- NH- CO F
N cis Le A 28 100 - 92 -390 mg (1 mmol) of 1-cyclapropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are dissolved in a solution of 40 mg of sodium hydroxide in 3 ml of water at room temperature in an ultrasonic bath and the solution is treated with ice-cooling with a solution of 160 mg (1.1 mmol) of R-(+)-a-methyl-benzyl isocyanate. The deposited precipitate is filtered off with suction, washed with dioxane and dried at 100°C in a high vacuum.
Yield: 530 mg (99 ~ of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2-[1R-phenyl-ethyl-amino-carbonyl]-2,8-diazabicyclo[4.3.0]non-8-yl)-3-quinoline-carboxylate, Melting points 208-210°C (with decomposition), [a]D5: -23.2° (c = 0.5, DMF).
The reaction product can be separated into the diastereomers by chromatography and the carbamoyl radical removed again by acidic hydrolysis, the compounds of Examples 1 and 7 being obtained.
Example 17 O
F ~ COzC2H5 H N ~ N
H~ F
N~ H
Le A 28 100 - 93 -~~ y~~~~
1.52 g (5 mmol) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are reacted 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 in 30 ml of acetonitrile for 2 hours at 50°C and for 2 hours at 60°C. After cooling, the suspension obtained is filtered off with suction, and the precipitate is washed with water and dried at 90°C in vacuo.
Yields 0.99 g (47.5 ~ of theory) of ethyl 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, Melting points 194-195°C (from acetonitrile), [a]D~s -188.9° (c = 0.51, CHC13) .
Example 18 O
F , COOH
J
H N ~ N
H .. O
N H ~ CHs 1.4 g (5 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxacine-6-carboxylic acid are reacted 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 in 15 ml of acetonitrile/7.5 m1 of dimethylformamide 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-Le A 28 100 - 94 -s~9 ~ L~ ?' ~.: .:i ~t~~ti~.:;.v methyl-7-oxo-7H-pyr5.do[1,2,3-de][1,4]benzoxacine-6-carboxylic acid, Melting point: 265-268°C (with decomposition), [a]D: -232,2° (c = 0.58, CHC13) 3S-10-([S,S]-2,8-~7iazabicyclo[4.x.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxacine-6-carboxylic acid is also obtained analogously.
Example 19 O
COOH
~ ~~ NJ
H
H~N _ 'H

ZO 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, eluent: methylene chloride/me~thanol/17 ~ strength aqueous ammonia 30:8:1).
1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-tluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid of melting point 203--208°C (with decomposition) is obtained.
[a]D3: -193° (c = 0.4, CHC13) .
Le A 28 100 - 95 -Example 20 O
F ~ COOH
J
H N ~ N
H~ F
N ~H C2Hs The reaction is carried out analogously to Example lA
using 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-ethyl-7-(jS,S]-2,8-diazabicyclo[4.3.0]-non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 236-239°C (with decomposition) is obtained (recrystallised from glycol monomethyl ether);
[«]D3c -186.3° (c = 0.3, CHC13) .
ZO Example 21 O
F ~ COOH
~ N N N
H .F
N~H I \
x HCl F
A. Ethyl 7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbo~cylate 1.9 g (5 mmol) of ethyl 7-chloro-1-(2,4-difluoro-phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate are stirred at 10°C for Le A 28 100 - 96 -~~~~~.~
3 hours with 680 mg (5.4 mmol) of [S,S]-2,8-diazabicyclo[4.3.0]nonane in the presence of 560 mg (5 mmol) of 1,4-diazabicyclo[2.2.2]octane in 20 m1 of acetonitrile. The suspension is filtered oft with suction, washed with water and dried. 0.35 g of product is obtained. By concentrating the mother liquors, stirring the residue with water, isolating the undissolved product and purifing by chromatography (silica gel, eluent: dichloro-methane/methanol/17 ~ strength aqueous ammonia), a further 0.7 g of product is isolated.
Total yield: 1.05 g (44 $ of theory), Melting point: 184-185°C (with decomposition) [a]D3; +6.8° (c = 0.46, CHC13) .
B. 7-([S,S]-2,8-Diazabicyclo[4.3.0]non-8-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,S-naphthyridine-3-carboxylic acid hydrochloride 0.8 g (1.7 mmol) of the product from Step A are heated under reflux for 4 hours in a mixture of 10 ml of acetic acid and 8 ml of half-diluted hydrochloric acid. The mixture is concentrated, the residue is stirred with a little water, and the precipitate is filtered off with suction, washed with ice-sold ethanol and dried.
Yield: 0.67 g (83 $ of theory), P3el.ting point: 324-326°C (with decomposition), [a]D5: +10.8° (c = 0.37, 17MF') .
Le A 28 100 - 97 -Example 22 CH3 O
F ~ COOH
H N \ N
I-IN H
0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate are heated at 120°C for 2 hours with 0.38 g (3 mmol) of [S,S]-2,8-diazabicyclo[4.3.0]nonane and 0.45 g (4 mmal) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. After cooling, the solvent is removed in a high vacuum. The residue is taken up with acetonitrile.
The solid is separated off, washed with acetonitrile and dried at 60 to 80°C.
Yield: 0.5 g (65 ~ of theory) of 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-fi-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate Melting point: 217-219°C (with dec:omposition), [a]D: -119° (c = 0.5, DMF) Example 23 F , COOH
y N ~ N
NN
Le A 28 100 - 98 -~~~i A. 837 mg (3 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated under reflex for 2 hours with 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 665 mg (3.3 mmol) of 1R,6S-2-oxa-5,8-diazabi-cyclo(4.3.0]nonane-dihydrochloride in a mixture of m1 of acetonitrile and 5 ml of dimethylformamide.
The mixture is evaporated, the residue is stirred with 30 ml of water, and the precipitate is filtered 10 off with suction and dried at 80°C in vacuo.
Yield: 400 mg (34 ~ of theory of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid, Melting point: 213-214°C (with decomposition).
$. 0.4 g of the betaine from Step A is dissolved in 5 ml of half-concentrated hydrochloric acid at room temperature, the solution is concentrated and the residue is stirred with about 3 ml of ethanol. The precipitate is filtered off with suction and dried at 80°C/12 mbar.
Yield: 290 mg (66 ~ of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(1R,6S-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinoline-carboxylic acid hydrochloride, Melting point: 305-308°C (with decomposition), [~]D3: -79° (c = 0.52, H20) Le A 28 loo - 99 -Example 24 Br O
F , COOH
J
H N W N
F , IAN H
~0 362 mg (1 mmol) of 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for 1.5 hours with 220 mg (2 mmol) of 1,4-diazabicyclo[2.2.2]octane and 220 mg (1.1 mmol) of 1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride in a mixture of 3 ml of acetonitrile and 2.5 m1 of dimethyl-formamide. The suspension is cooled, and the precipitate is filtered off with suction, stirred with 30 ml of water and dried at 90°C in a high vacuum.
Yield: 320 mg (68 ~ of theory) of 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1S,6R-2-oxa-5,8-diaza-bicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 263-264°C (with decomposition), [a]n~: -t~251° (c = 0.3, CHZC12].
Example 25 O
F ~ COOH
H N \ N
CHS\N F
Le A 28 100 - 100 -Analogously to Example 1, the following are obtained using [S,S]-2-methyl-2,8-diazobicyclo[4.3.0]nonane:
A: 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([S,S]-2 methyl-2,8-diazobicyclo[4.3.0]non-8-yl)-4-oxo-3 quinolinecarboxylic acid, melting point: 230-233°C (with decomposition) (recrystallised from glycol monomethyl ether);
B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([S,S]-2-methyl-2,8-diazobicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 258-260°C (with decomposition), [«]D5: -216.3° (c=1, x2o) .
Example 26 o -F , COOH
H N ~ N
CHI \ F
N~~~" H
Analogously to Example 1, the following are obtained using [R,R]-2-methyl-2,8-diazabieyclo[4.3.0]nonane:
A: 1-Cycopropyl-6,8-difluoro-1,4-dihydro-7-([R,R]-2-methyl-2,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 228-230°C (with decomposition) (recrystallised from glycol monomethyl ether):
B: 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([R,R]-2-methyl-2,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-Le A 28 100 - 101 -qu:inolinecarboxylic acid hydrochloride, melting point: 258-260°C (with decomposition), [alDS: +213.8° (c=1, Hz0) .
Example 27 O
F , COOIi ~J
N ~ N
CH3-CO-CH2CH2 ~ F
N~ H
1.95 g (5 mmol) of the product from Example lA are heated under reflux for 4 hours with 2.1 g (30 mmol) of methyl vinyl ketone in 50 ml of ethanol. The mixture is concentrated, the residue is stirred with water, and the precipitate is filtered off with suction, washed with ethanol and dried at 100°C/12 mbar.
yield: 2.1 g (91.5 ~ of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-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 (with decomp~sition) (recrystallised from glycol monomethyl ether, [a]D°:-120.7° (c = 0.57, CHZCIz) Le A 28 100 - 102 -Example 28 O
COOH
y N w N

N H F
1.95 g (5 mmol) of the product from Example 1A are heated at 50-80°C for 3 hours with 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol) of triethylamine in 30 ml of dimethylformamide. The solution is concentrated, the residue is stirred with water (pH 6), and the undissolved precipitate is filtered off with suction, washed with water and dried at 100°C in a recirculat.ing air drying oven (crude yields 1.3 g) and recrystallised from glycol monomethyl ether:
Yield: 1.12 g (50 ~ of theory) of 1-cyclopropyl-6,8-difluoropl,4-dihydro-4-oxo-?-([S,5]-2-(2-oxopropyl]-2,8-diazabicyclo[4.3.0]]non-8-yl)-3-quinolinecarboxylic acid, Me~.ting point: 181-184°C (with decomposition), [«]pie-72° (c -- 0.55, CHC13) .
Example 29 F , COOH
H N ~ N
C~-f3-CO-CH2CH2 ~ ~,l H
Le A 28 100 - 103 -A. The product from Example 2A is reacted analogously to Example 27 and 8-chloro-1-cyclopropyl-6-fluoro-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 of melting point 107-109°C is obtained.
[rx]D3: -53° (c = 0.67, CHC13), purity: 99.2 ~ strength (HPLCj.
B. Rac. 8-chloro-1-cyclopropyl-6-fluoro-I,4-dihydro-4--oxo-7-cis-2-[3-oxo-1-butyl]-2,8-diazabicyclo[4.3.0]-non-8-ylj-3-quinolinecarboxylic acid of melting point 224-125°C is obtained analogously using 8-chloro-1-cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]-non-B-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid.
Example 30 O
F , COOH
N w CH3-CO-CHz ~ F

~O
I.56 g (4 mmol) of the product from Example l0A are treated with 0 . 82 g ( 8 . 8 mol ) of chloroacetone and 1 . 05 g (10.4 mmol) of triethylamine in 30 ml of dirnethyl-formamide and the mixture is heated at 50-80°C fox 3 hours. The yellow solution obtained is concentrated at Le A 28 100 - 104 -80°C/15 mbar, and the oily residue is stirrad with water until it solidifies. The solid product is filtered off with suction, washed with water and recrystallised from glycol monomethyl ether.
Yield: 830 mg (47 ~ of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(cis-5-[2-oxopropyl]-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-3-quinolinecarboxylic acid, Melting points 192-193°C (with decomposition).
Example 31 O
F s COOH
-N ~ N
CH3-CO-CHZCHZ ~ F
N cis ~O
7..56 g (4 mmol) of the product from Example l0A are heated under reflux fox 3 hours with 1.8 g (25.6 mmol) of methyl vinyl ketone in 50 ml of ethanol. The suspension is concentrated at 70°C/12 mbar, and the residue is stirred with water and recrystallised from glycol monomethyl ether.
Yield: 1.33 g (72 $ of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(cis-5-[3-oxo-1-butyl]-2-Le A 28 100 - 105 -oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-3-quinolinecarboxylic acid, Melting point: 188-189°C (with decomposition).
Example 32 O
F ~ COOH
J
H N w N
CZHSOZC-CHz-CHZ ~ C1 N~ H
1.95 g (4.8 mmol) of the product from Example 2A are heated under reflux for 2 hours with 3 g ( 30 mmol ) of ethyl acrylate in 30 ml of glycol monomethyl ether. The mixture is evaporated, the residue is stirred with water, and the precipitate is filtered off with suction, dried (Crude yield: 1.9 g) and recrystallised from glycol monomethyl ether.
Yield: 1.45 g (60 ~ of theory) of 8-chloro-1-cyclopropyl 7-([S,S]-2-[2-ethoxy-carbonyl-ethyl]-2,8 diazabicyclo[4.3.0]non--8-yl)-6-flL~oro-1,4-dihydro-4-oxo 3-duinolinecarboxylic acid, Melting point: 117-118°C (with decomposition), [a]pe: °103.5° (c = 0.49, DMF), Purity: 99.6 ~ strength (HPbC).
Le 1~ 28 100 - 106 -fi, Example 33 U
COOH
N w I v~
H
NC-CHI-CHZ ~ C
H
1.95 g (4.8 mmol) of the product from Example 2A are heated under reflux for 5 hours with 0.8 g (15 mmol) of acrylonitrile in 30 ml of ethanol. ~'he mixture is evaporated, and the residue is stirred with water, dried (crude yield: 1.9 g) and recrystallised 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-quinoline-carboxylic acid, Melting point: 153-255°C (with dec:omposition), [a]D': -98.6° (c = 0.53, DMF), Purity: 96 ~ strength (HPLC), Mays spectrum: m/e 458 (M'') , 250, 149 ( 100 ~, C9H13~2) , llQ~ 49.
he A 28 100 - 107 -Example 34 O
F ~. COOH

H N w N
CH=C, .
N~ H
CH300 '~/C
1.95 g (5 mmol) of the product from Example lA are heated under reflux for 2 hours with 1.2 g (8 mmol) of dimethyl ~cetylenedicarboxylate in 60 ml of ethanol. The suspension is concentrated, the residue is stirred with water, and 'the precipitate is filtered off with suction and dried. the crude product (2.3 g) is recrystallised from glycol monomethy~l etherldimethylformamide.
Yield: 2 g (74 ~ of theory) of 1-cyclopropyl-7-[2-(1,2-me~thoxycarbonyl-vinyl)-1S,65-2,8-diazabicyclo[4,3.0]non-8-yl]-6,8-difluoro-1,4-dihydrc~-4-oxo-3-quinoline-carboxylic acid, Melting point: 262--264°C (with decomposition);
[«]pG: +28.8° (c = 0.24, CH~Clz) .
Fxam~le 35 O
F ~ COOI-I

I ~-I N ~ N
CH=C~N CI
H
cH3ooc be A 28 100 - 108 -~~~~"~ j;~
The product from Example 2A is reacted with dimethyl acetylenedicarboxylate analogously to Example 34. 8-Chloro-1-cyclopropyl-7-(2-(1,2-bis-methoxycarbonyl-vinyl)-1S,6S-2,8-diazabicyclo(4.3.0]non-8-yl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 210-212°C (with decomposition) is obtained in 87 yield;
[cx]D'': +16.6° (c = 0.5, DMF).
Example 36 O
F , COOH
J
N ~ N
CZHSOzC - CH= CH
,N
~~cis ?80 mg (2 mmol) of 1-cyclopropyl-7-(cis-2,8-diazabicyclo-[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-oxo-3-quino-linecarboxylic acid are heated under reflux for 1 hour with 500 mg (5 mmol) of ethyl propiolate in 15 ml of ethanol. The suspension is cooled, and the precipitate is filtered off with suction, washed with 25 ml of ethanol and dried at 80°C in a high vacuum.
Yield: 880 mg (90 ~ of theory) of 1-cyclopropyl-7-[2 (traps-2-ethoxycarbonylvinyl)-cis-2,8-diazabicyclo [4.3.0]non-8-yl]-6,8-difluoro-1,4-dihydro-4-oxo-3 quinolinecarboxylic acid, Le A 28 100 - 109 -Melting goint: 244-246°C.
analogously to Examgle 36, the following are obtained from the corresgonding starting materials:
Le A 28 100 - 110 -~M

M _M M ~ _C~1 U T U ~"' .T. ~ U . U U
, U U U U ~

U

~i W Ui ~n vi 0 0 0 '~?o ~' J O O
O

a ~ U

J U
~ ~
' O O O ' o -O M V'1~ o N o _ 0 O M d'w0 M

L3 + CV N N

a a ~

U o ~J 00 .--. M (~

O 00 V (V M N
O ~ ~ .,~ ('7N N N N C'1(V

~ C W ~J O N V'1 1' ~

-I ~W 00 V' _ M ('7 U

~ N r~ c'JN N N N

J

N N N N N N N

Tr ~,~

"'"' ~ U U U U U U O U

~,, X ~ U x Z .:4~ ra..~

U M

U

U
Q U U V Z O U U

~ w U

~, ~

y .,.1 N Id r1 a ~ (d a, ,~,1 ~

.; U ~
a, Q N Q ~ M Q

ro N N M tI J ,-...~,-.U

~ N
+~

-- H

O

r~I

pa O

~

M M V ~ d' ~

~e A 28 100 - 111 -~

+
b .,., b a~

a~

.'., b a c~ ~ -~., U U

U U U

U ~i vi vi O Q N
p ~d-~ A o ~

~.70 ~ 2~ + et'V ;
i ~

~ ~

_---~ b~
p ~ M
- C

O p - \ ~N N N
~

i~

S-I ~

/
Id O
,' ~

ri ~.~, '' ~ r~ ,.i.'.:..
,-~-~

'?; i ~ ~U

~~ U U

~ U
U

+? ~

w a N

~ ,~

N -e-.N d~
~ U ~

a ~ o U a ~

ro ~
~ x N
~

~ ~

~ ..

V

O ~

ri '~

t0 O

Qt Le A 28 100 - 112 -~n r, .a Example 48 O
F ~ COOH
CHOC
2 ~ / H N \ N
C=C\ CI
H '~I~ H
8-Chloro-1-cyclopropyl-7-([S,S]-2,8 diazabicyclo(4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3--quinolznecarboxylic acid is reacted with methyl propiolate in ethanol or methanol analogously to Example 36 and 8--chloro-l~cyclapropyl-6-fluoro-1,4-dihydro-7-[2-(trans-2-methoxycarbonyl-vinyl)-[S,S]-2,8-diazabicyclo-[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid of melting point 220-222°C (with decomposition) is obtained, (a]D4: +8.2° (c = 0.5; CHC13).
Exa.m~le 49 F , COOH
H ~ ~
N N
C = C\ o~~CI
H ~'~~O'~'~
407:5 g (1 mmol') of 8-chlorc~-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(15,6R-2-oxa-5,8-diazabicyclo[4.3.0]npn~8-yl)-Le A 28 100 - 113 -4-oxo-3-quinolinecarboxylic acid (from Example 11E) are heated under reflux for 1 hour with 210 mg (2.5 mmol) of methyl propiolate in 10 ml of methanol. The mixture is concentrated and the isolated crude product (450 mg) is recrystallised from 4 ml of acetonitrile.
Xielde 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[5-(traps-2-methoxycarbonyl-vinyl)-15,68-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl]-4-oxo-3-quinolinecarboxylic acid, Melting point: 153-156°C (with decomposition), L«]D8o +36° (c = 0.5, CHC13).
Example 50 F O
F , COOH
H \~ J _ cH3o2c ~ ~ ~ N
C-C~ ~ F
N
H ~ O cis Reaction with the compound of Example 13A is carried out analogously to Example 49 and 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7-[5-(traps-2-methoxycarbonyl-vinyl)-cis-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl]-4-oxo-3-quinolinecarboxylic acid of melting point 169~170°C
(with decomposition) is obtained (from glycol monomethyl ether).
Le A 28 100 - 114 -Example 51 O
F COOH
i H
CH j02C, / H
C C\ ~~ p H ~O H
Reaction is carried out with the compound from Example 10E analogously to Example 49 and 1-cyclopropyl-6,8-difluoro--1,4-dihydro-7-[5-(traps-2-methoxycarbonyl-vinyl)-1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl]-4-oxo-3-quinolinecarboxylic acid of melting paint 230-234°C
(with decomposition) i obtained (from glycol monomethyl ether); _ [«]~e= -27° (c = 0.5, CHC13) .
Example 52 L~r O
F COOI-~
CH30zC\ HH N ~ ~
C-C\ F
H~ ~ O N
Reaction is carried out with the compound from Example 24 analogously ~o Example 49 apd 5~bro~o-l~cyclopropyl-6,8-difluoro-1,4-dihydro-7-[5-(traps--2-methoxycarbonyl-~e A 28 100 - 115 -v vinyl)-1S,6R-2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl]-4-oxo-?-quinolinecarboxylic acid of melting point 158-160°C
(with decomposition) is obtained (from isopropanol):
(a]De: +8° (c = 0.27, CHC13) .
Example 53 O
F C02CzHs H
CH302C ~ / H N ~ ~ N
C = C \ ~~~ F
N H
H ~O
Reaction is carried out with the compound from Example 17 analogously to Example 36 and methyl 1-cyclopropyl-7-[2-(trans-2-ethoxycarbonyl-vinyl)-1S,6S-2,8-diazabicyclo(4.3.0]non-8-yl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 168-169°C is obtained.
Example 54 F O
F COOH
i CO2C~H5 H N N
C.,H502C - CH= C\ ~) F
N ,H
O
Le A 28 100 - 116 -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) are treated with 680 mg (4 mmol) of diethyl acetylene-dicarboxylate in 15 ml of ethanol and the mixture is treated in an ultrasonic bath at 30°C for 1 hour. The suspension is filtered off with suction, and the precipitate is washed with ethanol and dried at 70°C in a high vacuum.
Yield: Bg0 mg (77 ~ of theory) of 1-cyclopropyl-7-(5-(1,2-bis-ethoxycarbonyl-vinyl)-1R,6S-2-oxa-5,8-diazabicyclo(4.3.0]non-8-yl]-5;6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, Melting points 220-222°C (with decomposition) (tram glycol monomethyl ether) (a]a5: -57° (c=0.5, CHC13). _ Example 55 O
COOH
N \ ~N~
CaHsO2C~
~N~ F
traps, rac.
O
The reaction is carried out with 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(traps-2-oxa-5,8-diaza[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid analogously to Le A 28 100 - 117 -Example 36 and 1-cyclopropyl-7-[5-(traps-2-ethoxy-carbonyl-vinyl]-traps-2-oxa-5,8-diaza[4.3.0]non-8-yl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.
Melting point: 266-268°C (with decomposition) (from glycol monomethyl ether).
EXample 56 O
F ~ COOH
J
CH300C ~ N
F
N ~rans rac.
t , O
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(traps-2-oxa-5,8-diaza[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is reacted with methyl propiolate analogously to Example 36 and 1-cyclopropyl-7-[5-(traps-2-methoxy-carbonyl-vinyl)-traps-2-oxa-5,8-diaza[4.3.0]non-8-yl]-~,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.
Melting point: 275-277°C (with decomposition).
he A 28 100 - 118 -

Claims (28)

CLAIMS:

1. Quinolone- and naphthyridone-carboxylic acid compounds of the formula (I) in which A represents CH, CF, CCl, C-OCH3, C-CH3 or N, X1 represents H, halogen, NH2 or CH3, R1 represents C1-C3-alkyl, FCH2CH2-, cyclopropyl or phenyl which is optionally monosubstituted to trisubstituted by halogen, or A and R1 together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, C1-C3-alkyl which is optionally substituted by hydroxyl, halogen or amino or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, B represents a radical of the formulae in which Y represents O or CH2, R3 represents C2-C5-oxoalkyl, CH2-CO-C6H5, CH2CH2CO2R', -CH=CH-CO2R' or CH2CH2-CN, and R4 represents H, C1-C3-alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, C2-C5-oxoalkyl, CH2-CO-C6H5, CH2CH2CO2R', -CH=CH-CO2R' or CH2CH2-CN, in which R' denotes hydrogen or C1-C3-alkyl and pharmaceutically utilisable hydrates and acid addition salts thereof and the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids.

2. Quinolone- and naphthyridone-carboxylic acid compounds of the formula (I) according to claim 1, in which A represents CH, CF, CCl, C-OCH3 or N, X1 represents H, F, Cl, Br, NH2 or CH3, R1 represents C2H5, cyclopropyl or 2,4-difluorophenyl, or A and R1 together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, CH3, C2H5 or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, B represents a radical of the formulae in which Y represents O or CH2, R3 represents CH2-CO-CH3, CH2-CO-C6H5, CH2CH2-CO-CH3, CH2CH2CO2R', -CH=CH-CO2R' or CH2CH2-CN, and R4 represents, H, C1-C3-alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH2-CO-CH3, CH2-CO-C6H5, CH2CH2-CO-CH3, CH2CH2CO2R', -CH=CH-CO2R' or CH2CH2-CN, in which R' denotes C1-C2-alkyl, and pharmaceutically utilisable hydrates and acid addition salts thereof and the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids.

3. Quinolone- and naphthyridone-carboxylic acid compounds of the formula (I) according to claim 1, in which A represents CH, CF, CCl, C-OCH3 or N, X1 represents H, F, Cl, Br, NH2 or CH3, R1 represents C2H5, cyclopropyl or 2,4-difluorophenyl, or A and R1 together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, CH3 or C2H5, B represents a radical of the formulae in which Y represents O or CH2, and R4 represents H, C1-C3-alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH2-CO-CH3, CH2-CO-C6H5, CH2CH2-CO-CH3, CH2CH2CO2R', -CH=CH-CO2R' or CH2CH2-CN, in which R' denotes C1-C2-alkyl, and pharmaceutically utilisable hydrates and acid addition salts thereof and the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids.

4. A compound 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 or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.

5. A compound 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 or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.

6. A compound which is a quinolonecarboxylic acid of the group consisting of 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, 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, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.

7. Process for the preparation of a quinolone- or naphthyridone-carboxylic acid compound according to claim 1 of the formula (I) in which A represents CH, CF, CCl, C-OCH3, C-CH3 or N, X1 represents H, halogen, NH2 or CH3, R1 represents C1-C3-alkyl, FCH2CH2-, cyclopropyl or phenyl which is optionally monosubstituted to trisubstituted by halogen, or A and R' together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, C1-C3-alkyl which is optionally substituted by hydroxyl, halogen or amino or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, and B represents a radical of the formula in which Y represents O or CH2,and R3 represents C2-C5-oxoalkyl, CH2-CO-C6H5, CH2CH2-CO2R' or CH2CH2-CN, in which R' denotes hydrogen or C1-C3-alkyl, comprising reacting a compound of the formula (II) in which g, Y, X1; R1 and R2 have the abovementioned meanings, with a compound of the formula (III) R3-X3 (III) in which R3 has the abovementioned meaning, and X3 represents halogen, if appropriate in the presence of an acid binder.

Process for the preparation of a quinolone- or naphthyridone-carboxylic acid compound. according to claim 1 of the formula (I) in which A represents CH, CF, CCl, C-OCH3, C-CH3 or N, X1 represents H, halogen, NH2 or CH3, R1 represents C1-C3-alkyl, FCH2CH2-, cyclopropyl or phenyl which is optionally monosubstituted to trisubstituted by halogen, or A and R1 together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, C1-C3-alkyl which is optionally substituted by hydroxyl, halogen or amino or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, and B represents a radical of the formula in which Y represents 0 or CH2, and R3 represents CH2CH2-CO-CH3, CH2CH2-CO2R', , -CH=CH-CO2R' or CH2CH2-CN, in which R' denotes hydrogen ar C1-C3-alkyl, comprising reacting a compound of the formula (II) in which A, y, X1, R1 and R2 have the abovementioned meanings, with a Michael acceptor.

9. Process for the preparation of a quinolone- or naphthyridone-carboxylic acid compound according to claim 1 of the formula (I) in which A represents CH, CF, CCl, C-OCH3, C-CH3 or N, X1 represents H, halogen, NH2 or CH3 R1 represents C1-C3-alkyl, FCH2CH2-, cyclopropyl or phenyl which is optionally monosubstituted to trisubstituted by halogen, or A and R1 together can denote a bridge of the structure C-O-CH2-CH(CH3)-, R2 represents H, C1-C3-alkyl which is optionally substituted by hydroxyl, halogen or amino or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, B represents a radical of the formulae, in which Y represents O or CH2, and R4 represents H, C1-C3-alkyl, C2-C5-oxoalkyl, CH2-CO-C6H5 , CH2CH2CO2R', , -CH=CH-CO2R' or CH2CH2-CN or represents 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, in which R' denotes hydrogen or C1-C3-alkyl, comprising reacting a compound of the formula (V) in which A, R1, R2 and X1 have the abovementioned meanings and X2 represents halogen, with an enantiomerically pure compound of the formulae (VI) in which Y represents O or CH2, and R4 represents H or C1-C3-alkyl, if appropriate in the presence of an acid scavenger, and optionally further reacting the product with a compound of the formula (IIIa) R4-X3 (IIIa) in which X3 is a halogen, and R4 represents C2-C5-oxoalkyl, CH2-CO-C6H3, CH2CH2CO2R' or CH2CH2-CN, in which R' denotes hydrogen or C1-C3-alkyl, or with a Michael acceptor.

10. A process according to claim 7, wherein X3 is chlorine, bromine or iodine.

11. A process according to claim 8, wherein the Michael acceptor is dialkyl acetylene-dicarboxylate, alkyl propiolate or a compound of the formula (IV) CH2=CH-R5 (IV) in which R5 represents COCH3, CO2R' or CN
in which R' is as defined in claim 8.

12. A process according to claim 9, wherein X2 is fluorine or chlorine, X3 is as defined in claim 9, and the Michael acceptor is as defined in claim 11.

13. A process for preparing 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 which comprises reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid with (+)-[S,S]-2,8-diazabicyclo[4.3.0]-nonane, followed, if required, by converting the obtained compound into a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid.

14. A process according to claim 13 wherein the (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane is of enantiomeric excess greater than 99%.

15. A process according to claim 13 wherein the (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane is of 99.5%
enantiomeric excess.

16. A pharmaceutical composition, comprising a quinolone- or naphthyridone-carboxylic acid compound according to any one of claims 1 to 6, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid; and a pharmaceutically acceptable carrier, diluent or excipient.

17. An antibacterial composition, comprising a quinolone- or naphthyridone-carboxylic acid compound according to any one of claims 1 to 6, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acid; and a pharmaceutically acceptable carrier, diluent or excipient.

18. Use of a quinolone- or naphthyridone-carboxylic acid compound according to any one of claims 1 to 6, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acids for preventing, controlling or curing an infectious disease caused by bacteria or bacteria-like microorganisms.

19. Use of the composition of claim 16 for preventing, controlling or curing an infectious disease caused by bacteria or bacteria-like microorganisms.

20. Use according to claim 18 or 19, wherein the bacteria are enterobacteria.

21. Use according to claim 18 or 19, wherein the bacteria are selected from the group consisting of Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

22. Use according to claim 18 or 19, wherein the bacteria-like microorganisms are protozoonoses or helminthoses.

23. Use of a quinolone- or naphthyridone-carboxylic acid compound according to any one of claims 1 to 6, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acids as an additive for the preservation of an organic or inorganic material.

24. Use according to claim 23, wherein the material is selected from the group consisting of polymers, lubricants, dyes, fibres, leather, paper, wood, foodstuffs and water.

25. Use of a quinolone- or naphthyridone-carboxylic acid compound according to any one of claims 1 to 6, or a pharmaceutically utilisable hydrate or acid addition salt thereof or an alkali metal, alkaline earth metal, silver or guanidinium salt of the underlying carboxylic acids for the preparation of a medicament for the prevention, control or cure of an infectious disease caused by bacteria or bacteria-like microorganisms.

26. Use according to claim 25, wherein the infectious disease is caused by a microorganism as defined in any one of claims 20 to 22.

27. A commercial package comprising a compound according to any one of claims 1 to 6, or composition according to claim 16 or 17 together with instructions for the use thereof in the treatment of an infectious disease caused by bacteria or bacteria-like microorganisms.

28. A commercial package according to claim 27, wherein the infectious disease is caused by a microorganism as defined in any one of claims 20 to 22.