CA2013449C - Antibacterial 5-alkylquinolonecarboxylic acids - Google Patents

Abstract

Antibacterial 5-alkylquinolonecarboxylic acids of the formula in which R3 is C1-C4-alkyl, R1 is optionally substituted alkyl or cycloalkyl, alkenyl, alkoxy, amino or alkylamino or optionally substituted phenyl, R2 is hydrogen or optionally substituted alkyl, R4 is a nitrogen-containing heterocyclic radical, and A is hydrogen, halogen, methyl, cyano or nitro, or forms a bridge with R1.
and hydrates and salts thereof.

Description

The invention relates to new quinolonecarboxylic acid derivatives which carry an alkyl, to processes for their preparation and to antibacterial agents and food addi tives containing them.
It has been found that quinolonecarboxylic acid derivatives of the formula (I) (I) I ~COOR2 R ~N~
I

in which R1 represents straight-chain or branched Cl-C,-alkyl which is optionally substituted by hydroxyl, halogen, Cl-C3-alkoxy or C1-C~-alkylthio, C3-C6-cyclo-alkyl which is optionally substituted by halogen or C~-C3-alkyl, C1-C,-alkenyl, and in addition C1-C3-alkoxy, amino, monoalkylamino having 1-3 C atoms, dialkylamino having 2-6 C atoms or phenyl which is optionally substituted by halogen, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R' denotes Ci-C,-alkyl, R' represents a radical, which is optionally substi-tuted in the ring system by hydroxyl or methyl, of t~ A 26 756 2p13449 the formula N\(CH2)j ESN- , N-, ESN-, ESN-, ~

in which E represents RS-N, 0 or S, G represents -(Cu2)j_~ -CH2-0-CH2-, -CH2-S-CH2-, or -CH2-N-CH2-, j represents 1, 2 or 3, RS represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 4 carbon atoms which is optionally substituted by hydroxyl, benzyl which is optionally substituted by vitro or amino, oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-1,3-di oxol-4-yl)-methyl, ' R6 represents hydrogen or methyl, R' in addition represents a radical of the formula XI
~i~2)~(CH2ln-W (io2) p--R ~' ~N~(CH ) ~ ~N~(CHZ)m or I 2 m ( . R10'2'')~ ~3 ~N~(CH2)m in which, p represents 0,1 or 2, m represents 1 or 2, where p + m together can be 1, Ire A 26 756 _ 2 2 or 3, n represents 1 or 2, R~
w represents N ~ R ,, OR°, SR°, halogen or hydrogen, R~
X1 represents N ~ R , OR°, SR°, halogen, CN, CONHZ
COOH or Cl--C4-afkyl, XZ and X3 can be identical or different and represent oxygen, su=Lphur, NH or N-CH3, R' represents hydrogen, Cl-C~-alkyl, allyl or propargyl and R° represents hydrogen, Cl-C~-alkyl or C3-Cs-cycloalkyl, where R' + R° together can also represent the groups -CH2CH2-0-CH2CH2- or - ( CH2 ) k-, in which k can represent -3, 4 or 5, and R9 represents hydrogen, C1-C3-alkyl or C1-C'-acyl, R1° represents hydrogen or C1-C~-alkyl, R' also denotes a radical of the structure R:5 Z_R11 R15 R15 N 12 ' N .~R 14 or_ N~~Y
Rlb N R16 in which R11 can represent H, C1-C~-alkyl or C1-Cz-acyl, R12 can represent 8, Cl-C~-alkyl, OH or OC8" where Rll and R~ together can also denote a Cl-CZ-alkylene bridge which i: optionally monosubetituted or Le A 26 756 - 3 -2p~.344p disubstituted by methyl, R'3 can represent H, or C1-C3-alkyl, aryl, heteroaryl, benzyl, C1-C4-alkoxycarbonyl, C1-C4-acyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R" can represent H or C1-C'-alkyl, R15 can represent H or CH3 or phenyl, R16 can represent H or CH3 or phenyl, R1' can represent H or CH3, Y can represent 0, CHZ, CH2CH2 or CH2-0, where the linking of the CH2-0 group to the nitrogen can be both via 0 and via CH2, Z can represent 0 or S, A represents hydrogen, halogen, methyl, cyano or nitro or, together with R1, can alsa form a bridge of the structure -C-CH2iH-CH3 , -S-CH2-iH-CH3 or -CHZCH2-iH-CH3 having the R- or S-configuration, and their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acids on which they are based,have a high antibacterial action, in particular in the gram-positive region.
They are therefore suitable as active compounds for human and veterinary medicine, where veterinary medicine also includes the treatment of fish for the therapy or prevention of bacterial infections.
Preferred compounds of the formula (I) are those ~ A 26 756 _ 2fl134~~
in which R1 represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, phenyl, 4-fluorophenyl or 2,4-difluoro-phenyl, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R3 represents Cl-C3-alkyl, R' represents a substituted radical, which is option ally substituted in the ring system by methyl, of the formula n N\ ( CH2 ) j' N- , ESN- , E_ CL N- , E ~ N- , a in which E represents RS-N or 0, R°
G represents - ( CH2 ) ~-, -CH2-0-CH2- or -CH2-N-CH2-, j represents 1, 2 or 3, Rs represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 3 carbon atoms, which is optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino or oxoalkyl having 2 to 4 carbon atoms and R6 represents hydrogen or methyl, R' in addition represents a radical of the formula xi R~~2)p~(CH2)n-i~
~''~ I R
~N~(CH ) 2 m , i (CH2)m or Le A 26 756 XZ
i ,.3 ~N-~~(CH2)m in which p represents 0, 1 or 2, m represents 1 or 2, where p + m together can be l, 2 or 3, n represents 1 or 2, R~
w represents t~ \ R , OR° or hydrogen, ~ R~
X1 represents N ~ R8, OR°, fluorine, chlorine or C1-C2-alkyl , XZ and X3 can be identical or different and represent oxygen, sulphur or N-CH3, R' represents hydrogen, C1-C2-alkyl or acetyl, Re represents hydrogen or Cl-C2-alkyl, where R' + R° together also denote the groups -CH2CH2-0-, -CHZCH2- or - ( CH2 ) r-, in Which k can represent 3 , 4 or 5, R° represents hydrogen, Cl-CZ-alkyl or acetyl, R'° represents hydrogen or Ci-Ci-alkyl, R' also represents a radical of the structure Le A 26 75y - 6 -R15Z_Ril R15 R15 ' 12 ~ _ N~~ 14 or_ N
~',T'~1'~.!' H16 ~ R15 Rib in which R11 can represent H, Cl-C3-alkyl or C1-C2-acyl, R12 can represent H, Ci-C3-alkyl, OH or OCH3, where Rli and R12 together can ~ also denote a C1-CZ-alkylene bridge which is optionally monosubstituted or disubstituted by methyl, Ris can represent H, C1-C3-alkyl, hydroxyalkyl, phenyl, benzyl, C1-C4-alkoxycarbony:l, C1-C2-acyl or (5-methyl-2-oxo-1., 3-dioxol-~~-yl) -methyl, R" can represent H or C1-C2-alkyl, R15 can represent H or CH3, R'6 can represent H or CH3, Rl' can represent H or CH3, Y can represent 0 r CH2, CH2CH2 or CHZ-0, where the linking of the CH2-0-group to the nitrogen can be both via 0 and via CH2, Z can repreae.nt 0, A represents H, fluorine, chlorine, methyl, cyano or vitro or together with R1 can also form a bridge of 2 0 the structuace -0-CHZ-jH-CH3 having the R- or S-configuration.
Le A 26 756 - 7 -- . 201344 Particularly preferred compounds of the formula (I) are those in which R1 represents ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methylamino, 4-fluoro-phenyl or 2,4-difluorophenyl, RZ represents hydrogen or alkyl having 1 to 2 carbon atoms, R3 represents C1-C3-alkyl, R' represents a radical, which is optionally substi-tuted in the ring system by methyl, of the formula N\ ( CH2 )~ N-, E~N- , ESN- , ESN-, in which E represents Rs-N, G represents - ( CHZ ) ~-, j represents 1 or 2, R5 represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 3 carbon atoms and optionally substi-tuted by hydroxyl, benzyl which is optionally substituted by nitro or amino, or oxoalkyl having to 4 carbon atoms and R6 represents hydrogen or methyl, R' in addition represents a radical of the formula Rip2)~(CH2)n-W (i02)__ /0 ~N~(CH ) 2 m ~ ~N~(CH2)m or Rio2)~3 ~N~(CH2)m I~ A 26 756 _ g r in which p represents 0, 1 or 2, 2 ~ ~ 3 4 4 9 m represents 1 or 2, where p + m together can be 1,2 or 3, n represents 1, R~
W represents N , OR9 or hydrogen, \R8 R~
X1 represents N , ORg, chlorine or alkyl, preferably methyl, R8 X2 and X3 can be identical or different and represent oxygen or N-CH3, R~ represents hydrogen or methyl, R8 represents hydrogen or methyl, where R~ + R8 together can also denote the groups -CH CH -O-CH2CH2- or -(CH2)k-, in which k can represent 3, 4 or 5, Rg represents hydrogen, Cl-C3-alkyl, preferably methyl, or Cl-C3-acyl, represents hydrogen or methyl, R4 additionally denotes a radical of the structure _g_ ... ~~ ~, ~ ~t RI5 .Rly R15 R15 2 H1~
-N 1~
-~ 12 ' N~ ~~R or N
R16~ R~N R16 in which R11 can represent H, C1-C2-alkyl or acetyl, R12 can represent H or C1-C2-alkyl, where R11 and R12 together can also denote a Cl-C2-alkylene bridge which is optionally substituted by methyl, R13 can represent H, C1-C2-alkyl, hydroxyethyl, benzyl, - 9a -w 2013440 C1-C~-alkoxycarbonyl or C1-CZ-acyl, R" can represent H or CH3, R'S can represent H or CH3, R16 can represent H or CH3, R1' can represent H or CH3, Y can represent 0, CH2, CHZCHZ or CHZ-0, where the linking of the CH2-0-groups to the nitrogen can be both via 0 and via CH2, Z can represent 0, A represents H, fluorine or chlorine, or together with R1 can also form a bridge of the structure -0-CH2-iH-CH3 having the R- or S-configuration.
It has furthenaore been found that the compounds-of the formula (I) are obtained when compounds of the formula (II) CCOR2 (II) X~~IJ

in which R1, R2, R' and A have the abovementioned meanings and X' represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) R~-H ( I I I ) in which R' has the abovementioned meaning, Iae A 26 755 - 10 -if appropriate in the presence of acid scavengers and if appropriate protective groups contained in R' are removed.
If, for example, 1-cyclopropyl-6,7,8-trifluoro 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and 1-methyl-octahydropyrrolo[3,4-b]pyridine are used as starting substances, the course of the reaction can be represented by the following equation:
COON Ease 'NH -~N
-HF
~H

~ ~ ~ cooH
/~ ~ N
F

~'~' F
I~ A 26 756 - 11 --- ~ 2013449 If, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and 3-ethylaminomethyl-3-hydroxy-pyrrolidone are used as starting substances, then the course of the reaction can be represented by the following equation:
~H3 0 YCOOH C2H5-NH-CH~~H Sace F w NJ ~ H _ H-.-i ' ~COOH
~'JIN
CZHS-NH_CH2 N
H0~ C1~
If, for example, 1-cyclopropyl-7-(2,7-diazabicy-clo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and ethanol/hydrogen chloride are used as starting substances, then the course of the reaction can be represented by the following equation:

~ V COON HC1 ~ C2HSpH --.
/~/~N
HN

x HCl Le A 26 756 - 12 -- 2~~~~~~
The compounds of the formula II used as starting substances are known or can be prepared by known methods.
Examples which may be mentioned are:
1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid, 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, Ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 6,7-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 6,7-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
7-Chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is not known.
It can be prepared according to the following scheme.

COOH 1. SOC12 ~ COOEt ~''= J '-' J
F I N 2. EtOH C1~N
F ~ F
Le A 26 756 - 13 -Ecooc~
C' H
NaH
COOS:
C00~:
~~~~J
F
COON

'' DABCO
w ( COOH ----~ I ~ ~ COON
C 1 ~NJ C 1 ~ NJ
F
DABCO a 1,4-Diazabicyclo[2,2,2]octane The compounds of the formula III having the structures N\ ( CH' ) jVN- , ESN- . E
~~ ' ~ G '.s' r are known (EP-PS 230,274).
Some of the compounds of the formula III used as starting compounds and having the structures Rio2)p~(CH2)n-Y
~N~(ICH2 ),~ ~N~( CH
~ 2)m and 8102 ) PT~3 ~N~(CH2)m he A 26 756 - 14 -are new.
They can be prepared by various methods:
1. Hy reaction of the spiro-oxiranes protected on the nitrogen atom (1) [J. Med. Chem. ~0, 222 (1987);
US-P 4,508,724; EP-PS 189,370] with amines (2), ring opening to give the hydroxylamines (3) occurs.
Removal of the protective group yields starting compounds of the formula (Ills):
~ H H » ,.
C:'. ; ~R~ ( CHZ )p !'~tCH2).n ~8 j~(C'.'.~)n a1? R:B
(1) (2) t3) R18 = C00-alkyl or CH2C6Hs OH ~R~
(CH2)p~CHZ-N
l ~8 ~N~(CH2)m H
(Ills) 2. The cyclization of the succinic acid ester (4) [Tetrahedron Letters !~,, 4561 (1973)] with ben-zylamine yields the alkyl 1-benzyl-3-hydroxy-5-oxo-pyrrolidin-3-carboxylate (5) which, by reaction with an amine (2), reacts to give the amide (6). Sub-sequent reduction with LiAlH, and hydrogenolytic cleavage of the benzyl Qroup yields :tatting com-pounds of the formula (IIIb)s A:Ky:-0-CO C00-Alkyl (4) Le A 26 756 - 15 -i.~.C00-Alkyl t :.:r-N
~J
1.y (6) (iiIS) 3. Reaction of (1-benzyl-3-hydroxy-2,5-dioxo-pyr-rolidin-3-yl)-acetic acid (7) [Gazz. Chim. Ital. 24, 226 (1894)] to give the amide (8) and subsequent reduction with LiAlH, and removal of the benzyl group yields starting compounds of the formula (IIIc):
c:; eH

!~COOH ~ ~'RB
~N~ _. ~N~O

(7) te) OH ~.R~
J
N
H
tIIIc) ~,e~ 26 756 - 16 -.. 201349 4. 3-Hydroxy-3-methyl-pyrrolidine can be prepared by LiAlH, reduction of 4-hydroxy-4-methyl-pyrrolidin-2 one [Zh. Org. Rhim. ~, 7, p. 1420 (1978)] or by debenzylation of 1-benzyl-3-hydroxy-3-methylpyr rolidine (EP 132,845).
5. Starting from cyclic oxo-amines (9) which are blocked on the nitrogen by a protective group, starting compounds of the formulae (IIId), (IIIe), (IIIf) can be synthesized [Acts Chem. Scand. B ~, 319 (1980)].
(C-')p~ C~:2N02 ~t~:2) O~r:~2 tC::2)p ~~NH2 -,., ~ F~ __. -.
~?:~; CH2 )~ ~)'~IO~'Z ).:~ ~~t CH2 )s, l, H
Rlg ~:e _ (9) (lu) (IIid) HCN Or (CH~)~ :,:CN
:~1'~= C00-hlkyl, C_2_C6H5 n tLH2 r ./
h (CH2)T

NHZ

( CH2 )p~00H ( CH2 >p H
NH 2 -. .._. ~
(CHZ) N ~(CH2)~ ~(CH2)~
~ H
,18 ~(CHZ)m R
R18 t13) tIIIe) 12) t ~2 tCH2 2 ~tCH2)~
H
tIIIf) Le A 26 756 - 17 -~01~449 6. The hydroxyl group of the hydroxylamines (Ills) -(IIIe) can be alkylated or halogenated.
7. Ketals, thioketals or aminals can be prepared from the cyclic oxamines (9) [Helv. Chim. Acts ~0_, 1289 (1967)].
By reaction of the spiro oxiranes protected on the nitrogen atom (1) with trimethylsilyl cyanide [J.
Amer. Chem. Soc. 104, 5849 (1982)], the isonitriles (14) can be prepared which, by hydrolyzing and removing the protective group, can be reacted to give the starting compounds of the formula (IIIg):
;~HZ) l ~ (CH3)3 SiCN
~N~(CH2)m (1) NHZ
NC ( CH2 ~~OH
(CH2)~OSi(CH3)3 -- l ~N~'(CH2)m ~N~(CHZ)m (14) (IIIg) Examples of starting compounds of the formula ( III ) which may be mentioned are the following compounds, it being possible to employ chiral compounds both as racemates and as enantiomerically pure substancess 3-Aminomethyl-3-hydroxy-pyrrolidine, 3-Acetylaminomethyl-3-hydroxy-pyrrolidine, Le A 26 756 - 18 -3-tert.-Butoxycarbonylaminomethyl-3-hydroxy-pyrrolidine, 3-Hydroxy-3-methylaminomethyl-pyrrolidine, 3-Ethylaminomethyl-3-hydroxy-pyrrolidine, 3-Hydroxy-3-propylaminomethyl-pyrrolidine, 3-Ethylaminomethyl-3-methoxy-pyrrolidine, 3-Ethoxy-3-ethylaminomethyl-pyrrolidine, 3-Chloro-3-ethylaminomethyl-pyrrolidine, 3-Ethylaminomethyl-3-fluoro-pyrrolidine, 3-Ethylaminomethyl-3-methyl-pyrrolidine, 3-Ethylaminomethyl-3-mercapto-pyrrolidine, 3-Ethylaminomethyl-3-methylthio-pyrrolidine, 3-Acetoxy-3-ethylaminomethyl-pyrrolidine, 3-Dimethylaminomethyl-3-hydroxy-pyrrolidine, 3-Hydroxy-3-pyrrolidinomethyl-pyrrolidine, 3-Hydroxy-3-morpholinomethyl-pyrrolidine, 3-Amino-3-ethylaminomethyl-pyrrolidine, 3-Acetylamino-3-ethylaminomethyl-pyrrolidine, 3-Ethylaminomethyl-3-methylamino-pyrrolidine, 3-Dimethylamino-3-ethylaminomethyl-pyrrolidine, 3-Amino-3-hydroxymethyl-pyrrolidine, 3-Acetylamino-3-hydroxymethyl-pyrrolidine, 3-Amino-3-methoxymethyl-pyrrolidine, 3-tert.-Butoxycarbonylamino-3-methoxymethyl-pyrrolidine, 3-Amino-3-methylthiomethyl-pyrrolidine, 3-Amino-3-mercaptomethyl-pyrrolidine, 3-Cyclopropylaminomethyl-3-hydroxy-pyrrolidine, 3-Isopropylaminomethyl-3-hydroxy-pyrrolidine, 1,4-Dioxa-7-azaapiro[4,4]nonane, 1-Oxa-4,7-diazaspiro[4,4]nonane, 4-Methyl-1-oxa-4,7-diazaspiro(4,4]nonane, Le A 26 756 - 1g --- ~ 201340 1-Thia-4,7-diazaspiro(4,4]nonane, 1,4,7-Triazaspiro[4,4]nonane, 1,4-Dimethyl-1,4,7-triazaspiro[4,4]nonane.
Some of the compounds of the formula III used as a starting material and having the structures ~~---Z ~ 15 2 ' _ N~ ~~~~and -N I ~fR: _ f . ~y R '\ - , ~i 6 R1 6 R " R13 are also new. They can be prepared by the following methods;
1. Starting from the N-protected 3,4-epoxypyrrolidine (1) (German Offenlegungsschrift 1,929,237, US Patent 4 , 254,135 ) , which can optionally carry a further one or two methyl or phenyl radicals, the starting compounds of the formula (IIIa)-(IIIe) are prepared.
'' H 3 ~ 12 . ~ 2 Removal of I i ~ H'~ -.. ' \R13 p~tective proupe '''~
\H 13 ~ _""'-""' \~ : 3 R'g X18 H
(1) (IIIh) RllXS Base ~ R11~ ~R12 R 1 1 ~ dal of r ~R 12 proteetih 9roupe \R 13 ~~\R 13 H
R18 tIIIiI
Le A 26 756 - 20 -R18 = benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protec-tive groups), x - leaving group such as halogen, alkyl- or arylsul-phonyloxy Q%;
N30 3 RllXS 3 ( 1 ) ----. _ R18 Ba a R11~ RIlOd ' ~NH-COOC(CH3)3 -.-...._, H
(IIIj) c,~~H

( 1 ', ----~ N
i R 1 10 -. --»
Le A 26 756 - 21 ~il~, H-R12 R11 , R11 \R13 \~:3 h' N H2 I Pd NJ
---~ -H
(III1) H2/Pd R11 H_R12 N
(IIIk) H
2. Starting compounds of the formula (IIIm) are ob-tained from 2-(1,2-dichloroethyl)-oxirane via the following reaction sequence:
HO CI

N

NJ
,~
Le A 26 756 - 22 -~R13 ~R13 NJ Z -~ NJ
i I H
(III:n) 3. By addition of azides to N-benzylmaleimides opti-onally substituted with one or two methyl or phenyl radicals, starting compounds of the formula (III n) can be prepareds N NwN_R18 N
'~~0 N
0 N~0 i i R~O~'~" H_R18 R4p~/i~ . H-R19 Reduction N~0 Rllp/ii. H_R19 H
fIIIn) I~e A 26 756 - 23 -R=9 = H, alkyl or benzyl.
4. From the 3,4-epoxypyrrolidines (1) via a cyclization with thionyl chloride, the starting compounds of the formula (III o) are obtained:
1'1 v./rl~~v }"t 2 .Z'~ .~ /~~~/ ~"~ - C' C1 - C~ . a ----r ~~N J -.-. ~50C 1 O~N p/ \N
N
NJ
N
r~ 1 8 H
(III o) 5. By reacting the 3,4-epoxypyrrolidines (1) with ethanolamines by intramolecular etherification, the starting compounds of the formula (III p) are obtained:

_ i /'~.~-off HO~H R6 HO N
1 ) _-------.. ~ H
N

0 N- R 13 --------. p -R 13 (III p).
I~ A 26 756 - 24 20.3449 6. The starting compounds of the formula (III q) are obtained from amino acetaldehyde dimethyl acetal via an intramolecular 1,3-dipolar cycloaddition.

C'~',~OCH3 --~ R18_NH~OCH3 H2C~/X
Base ~OCH3 Ht ~CHO R13-NH-C:', R18_N /CH2 -. R18_N /CH2 ~R 15 ~-'-~R 15 R 13 s H
N_R13 N_R13 R 15 --., R 15 Ni Ni RIS H
(III q) 7. Starting from N-benzyl-pyridine-2,3-dicarboximide, starting compounds (III r) or (III 1) are prepared via the reaction steps indicated.
Le A 26 756 - 25 -alkyl i odi de 0 H 2 I ?~ a - C or w w a I N-CH2-C6H5 N-CH2-C6H~
H

W
LiAlH4 (H2IPt02 NaBH~C H ) 0 l Br3~ 2 5 2 H

alkyl LiAlH4 H2IPd-C
N-.CH2-C~HS NH
I H
alkyl IIIs Le A 26 756 - 26 -1:~2~Pa-C
m cam -8. N-benzyl-maleimide adds 2-chloroethylamine to give the 3-(2-chloroethylamino)-succinimides, which are reacted to give the starting compounds of the formula (III t):

I N-CH2-C6H5 ~ CI-CH2CH2-NH-R13 --I NaH
iH2 N-CH2-C6H5 N-CH2-C6H5 Li111HQ N-CHZ-C6H5 R13 Ri3 Le A 26 756 _ 27 I
c::f :~

9. 2-Methyl-2-propenal dimethylhydrazone reacts with N-benzylmaleimide to give a cycloadduct which can be converted into the starting compound (III u) by the reaction sequence indicated.

Cv3~~H2 CH

I N-CH2-Ph ---~ I N-CHZ-Ph ( I
/N\ 0 /N\ 0 _ c CH3 ) 2NH CH3 H2 ~ cata~H3 '~' I I N-CHZ-Ph --~ 'N-CH2-Ph N lye H H

Li1~1H4» CH3 H2/pd-C CH3 N-CHZ-Ph ---r NH
H H
IIII u) According to this general reaction scheme, for example, the following starting compounds can be pre-pared. They can be prepared and employed as diastereomer Le A 26 756 - 2g mixtures, in diastereomerically pure and also in enanti-omerically pure form.
4-Amino-3-hydroxypyrrolidine, 3-Hydroxy-4-methylaminopyrrolidine, 4-Dimethylamino-3-hydroxypyrrolidine, 4-Ethylamino-3-hydroxypyrrolidine, 3-Amino-4-methoxypyrrolidine, 4-Methoxy-3-methylaminopyrrolidine, 3-Dimethylamino-4-methoxypyrrolidine, 3-Ethylamino-4-methoxypyrrolidine, 3-Amino-4-ethoxypyrrolidine, 4-Ethoxy-3-methylaminopyrrolidine, 3-Dimethylamino-4-ethoxypyrrolidine, 4-Ethoxy-3-ethylaminopyrrolidine, 3-Hydroxy-4-hydroxyaminopyrrolidine, 3-Hydroxy-4-methoxyaminopyrrolidine, 3-Hydroxyamino-4-methoxypyrrolidine, 4-Methoxy-3-methoxyaminopyrrolidine, 3-Benzylamino-4-methoxypyrrolidine, 4-Methoxy-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl-amino)pyrrolidine, 3-Amino-4-methylmercaptopyrrolidine, 3-Acetoxy-4-dimethylaminopyrrolidine, 3-Acetamido-4-methoxypyrrolidine, 4-Methoxy-3-methoxycarbonylaminopyrrolidine, 3-Formamido-4-methoxypyrrolidine, 3-Amino-4-methoxy-2-methylpyrrolidine, 3-Amino-4-methoxy-5-methylpyrrolidine, 4-Methoxy-2-methyl-3-methylaminopyrrolidine, 4-Methoxy-5-methyl-3-methylaminopyrrolidine, Le A 26 756 - 2g -3-Amino-4-methoxy-2-phenylpyrrolidine, 4-Methoxy-3-methylamino-5-phenylpyrrolidine, 3-Methyl-2,?-diazabicyclo[3.3.0]octane, 4-Methyl-2,7-diazabicyclo[3.3.0]octane, 5-Methyl-2,7-diazabicyclo[3.3.0]octane, 3,5-Dimethyl-2,7-diazabicyclo[3.3.0]octane, 1,5-Dimethyl-2,7-diazabicyclo[3.3.0]octane, 2-Oxa-4,7-diazabicyclo[3.3.0]octane, 3,3-Dimethyl-2-oxa-4,7-diazabicyclo[3.3.0]octane, 3-Oxa-2,7-diazabicyclo[3.3.0]octane, 1,2-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 2,5-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 2,8-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 5-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane, 2-Oxa-4,7-diazabicyclo[3,3,0]oct-3-ene, 3-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 3-Phenyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 6-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 8-Methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 3-Methyl-2,8-diazabicyclo[4.3.0]nonane, 4-Methyl-2,8-diazabicyclo[4.3.0]nonane, 5-Methyl-2,8-diazabicyclo[4.3.0]nonane, 6-Methyl-2,8-diazabicyclo[4.3.0]nonane, 3-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 4-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 1-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 3,5-Dimethyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 2-Thia-5,8-diazabicyclo[4.3.0]nonane, 5-Methyl-2-this-5,8-diazabicyclo[4.3.0]nonane, 3,5-Dimethyl-2-this-5,8-diazabicyclo[4.3.0]nonane, he A 26 75~ - 30 -3-Oxa-2,8-diazabicyclo[4.3.0]nonane, 2-Methyl-9-oxa-2,8-diazabicyclo[4.3.0]nonane, 4-Methyl-3-oxa-2,8-diazabicyclo[4.3.0]nonane, 2,5-Dimethyl-3-oxa-2,8-diazabicyclo[4.3.0]nonane, 3-Oxa-5,8-diazabicyclo[4.3.0]nonane, 5-Methyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane, 1,5-Dimethyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane, 4,4-Dimethyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane.
The reaction of (II) with (III), in which the compounds (III) can also be employed in the form of their hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N,N-dimethylforniamide, N-methylpyrrolidone,hexamethylphosphoramide,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.
Acid scavengers which can be used are all cus-tomary 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 as being particularly suitable are: triethylamine, 1,4-diazabi cyclo[2.2.2]octane(DABCO),1,8-diazabicyclo[5.4.0]undec 7-ene (DBU) or excess amine (III).
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 pres-]Le A 26 756 - 31 -sure, but also at elevated pressure. In general, the reaction is carried out at pressures between about 1 and 100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention, 1 to 15 moles, preferably 1 to 6 moles, of the compound (III) are employed per mole of the carboxylic acid (II).
Free hydroxyl groups can be protected during the reaction by a.suitable hydroxyl protective group, for example by the tetrahydropyranyl radical, and after completion of the reaction are set free again (see J.F.W.
McOmie, Protective Groups in Organic Chemistry (1973), page 104).
Free amino functions can be protected during the reaction by a suitable amino protective group, for example by the ethoxycarbonyl or the tert.-butoxycarbonyl radical, and after completion of the reaction are released again by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], volume E4, page 144 (1983); J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 43).
To prepare the ester according to the invention, the carboxylic acid on which they are based is preferably reacted in excess alcohol in the presence of strong acids, such as sulphuric acid, anhydrous hydrogen chloride, methanesulphonic acid, p-toluenesulphonic acid or acidic ion exchangers, at temperatures from about 20' to 200'C, preferably about 60' to 120'C. The resultant water of reaction can also be removed by azeotropic Le A 26 756 - 32 -,.. 2013449 distillation using chloroform, tetrachloromethane, benzene or toluene.
The preparation of esters is also advantageously carried out by heating the acid on which they are based with dimethylformamide dialkyl acetal in a solvent such as dimethylformamide.
The (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl esters used as a prodrug are obtained by reaction of an alkali metal salt of the carboxylic acid on which they are based with 4-bromomethyl or 4-chloromethyl-5-methyl-1,3-dioxol-2-one in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulph-oxide or tetramethylurea at temperatures from about 0°
to 100°C, preferably 0° to 50°C.
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 excess aqueous acid and precipitating the salt with a water-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 utilizable salts are taken to mean, for example, the salt of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methaneaulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic ncid, qlutamic acid or aspartic acid.
The alkali metal or alkaline earth metal salts of ~e A 26 756 - 33 -~Oi344~
the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in a subequivalent amount of alkali metal or alkaline earth metal hydroxide solution. filtering off undissolved betaine and evaporating the filtrate to dryness. Pharma ceutically suitable salts are those of sodium, potassium or calcium. The corresponding silver salts are obtained by reaction of an alkali metal salt or alkaline earth metal salt with a suitable silver salt such as silver nitrate.
In addition to the active compounds mentioned in the examples, the compounds shown by way of example in Table 1 can .also be prepared, it being possible for these compounds to be present both as diastereomer mixtures and also as diastereomerically pure or enantiomerically pure compounds.
The compounds according to the invention show, combined with low toxicity, a broad antibacterial spec-trum against gram-positive and gram-negative bacteria, in particular against Enterobacteriaceae; above all also against those which are resistant to various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.
These useful properties facilitate their use as chemotherapeutic active compounds 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, fibers, leather, paper and wood, and of foodstuffs and water.
Le A 26 756 - 34 -The compounds according to the invention are active against a very wide spectrum of microorganisms.
Gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled with their aid, and the diseases produced by these pathogens can also be prevented, improved and/or cured.
The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly well suited in human and veterinary medicine for the prophy-laxis and chemotherapy of local and systemic infections which are produced by these pathogens.
For example, local and/or systemic diseases which are caused by the following pathogens or by mixtures of the following pathogens can be treated and/or prevented:
gram-positive cocci, for example staphylococci (Staph.
aureus, Staph. epidermidis) and streptococci (Strept.
agalactise, Strept. faecalis, Strept. pneumoniae, Strept.
pyogenes); gram-negative cocci (Neisseria gonorrhoeae) and also gram-negative rods such as Enterobacteriaceae, for example Escherichia cola, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Sal-monella and Shigella; furthermore Rlebsiella (Blebs.
pneumoniae, Blebs. oxytoca), Enterobacter (Eat. aero-genes, Ent. agglomerans), iiafnia, Serratia (Serr. mar-cescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr.
vulgaris), Providencia, Yersinia, and also the order Acinetobacter. Moreover, the antibacterial spectrum comprises the order Pseudomonas (Ps. aeruginosa, Ps.
maltophilia) and also strictly anaerobic bacteria such ~013~43 as, for example, Bacteroides fragilis, representatives of the order Peptococcus, Peptostreptococcus and also the order Clostridium; furthermore mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and also mycobacteria, for example Mycobacterium tuberculosis.
The above enumeration of pathogens is merely by way of example and in no way to be conceived as limiting.
Examples of diseases which may be caused by the said pathogens or mixed infections and which may be prevented, improved or cured by the compounds according to the invention, which may be mentioned are:
infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelone-phritis, cystitis, endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, diseases of the upper airways, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, hepatic abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, post-operative wound infections, absces-ses, phlegmone, wound infections, infected burns, scalds, infections in the oral region, infections after dental operations, osteomyelitis, septic arthritis, chole-cystitis, peritonitis With appendicitis, cholangitis, intra-abdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis and infections of the nervous system, :alpingitis, endo-metritis, genital infections, pelveoperitonitis and eye infections.
In addition to humans, bacterial infections can Le A 26 756 - 36 -also be treated in other species. Examples which may be mentioned are:
pig: coli-diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, mastitis-metritis-agalactia syndrome, mastitis;
ruminants (cow, sheep, goat): diarrhoea, sepsis, broncho-pneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
horse: broncho~neumonias, joint-ill, puerperal and post-puerperal infections, 8almonellosis;
dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections, prostatitis;
poultry (hen, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic airway diseases, salmonellosis, pasteurellosis, psittacosis.
Bacterial diseases in the rearing and keeping of productive and ornamental fish can likewise be treated, the antibacterial spectrum being widened beyond the previously mentioned pathogens to further pathogens such as, for example, Pasteurella, Hrucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.
The present invention includes pharmaceutical preparations which contain one or more compounds accord ing to the invention or which consist of one or more active compounds according to the invention in addition to non-toxic, inert pharmaceutically suitable excipients and processes for the production of these preparations.
The present invention also includes j~e A 26 756 _ 37 2~1344~
pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual portions, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, whose active compound content corresponds to a fraction or a multiple of an individual dose. The dosage units may contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is admin-istered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose.
Non-toxic, inert pharmaceutically suitable excipients are taken to mean solid, semi-solid or liquid diluents, fillers or formulation auxiliaries of any type.
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.
Tablets, coated tablets, capsules, pills and granules may contain the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrants, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retardants, for example paraffin and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol I~ A 26 756 - 38 -monostearate, (h) adsorption agents, for example kaolin and bentonite and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid poly-ethylene glycols or mixtures of the substances mentioned under (a) to (i) in addition to the active compound(s).
The tablets, coated tablets, capsules, pills and granules may be provided with the customary coatings and shells containing, if appropriate, opacifying agents and can be so composed that they release the active com-pound ( s ) , if appropriate with a delay, only or preferably in a certain part of the intestinal tract, it being possible, for example, to use polymeric substances and waxes as embedding materials.
If appropriate, the active compounds) may also be present in micro-encapsulated form with one or more of the abovementioned excipients.
Suppositories may contain the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C1,-alcohol with ClB-fatty acid) or mixtures of these substances in addition to the active compound(s).
Ointments, pastes, creams and gels may contain the customary excipients, for example animal and vege table fats, waxes, paraffins, starch, tragacanth, cel lulose derivatives, polyethylene glycola, silicones, bentonitea, silica, talc and sinc oxide or mixtures of these substances in addition to the active compound(s).
Powders and sprays may contain the customary excipients, for example lactose, talc, silica, aluminum Le~A 26_Z"56 _ 3g hydroxide, calcium silicate and polyamide powder or mixtures of these substances in addition to the active compound(s). Sprays may additionally contain the cus-tomary propellants, for example chlorofluorohydrocarbons.
Solutions and emulsions may contain the customary excipients, such as solvents, solubilizers and emul-sifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances in addition to the active compound(s).
For parenteral administration, the solutions and emulsions may also be present in sterile and blood-isotonic form.
Suspensions may contain the customary excipients, such as liquid diluents, for example water, ethyl alco-hol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, alu-min um metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances in addition to the active compound(s).
The said formulation forms may also contain colorants, preservatives and also odor-improving and flavour-improving additives, for example peppermint oil and eucalyptus oil and sw~~tenera, for example saccharin.
Le A 26 756 - 40 -The therapeutically active compounds should preferably be present in the abovementioned pharmaceuti-cal preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight, of the total mixture.
The abovementioned pharmaceutical preparations may also contain further pharmaceutical active compounds in addition to the compounds according to the invention.
The preparation of the abovementioned pharmaceu tical preparations takes place in a customary manner by known methods, for example by mixing the active com pound s) with the excipient(s).
The preparations mentioned may be used in humans and animals either orally, rectally, parenterally (intra venously, intramuscularly, subcutaneously), intracister nally, intravaginally, intraperitoneally, locally (pow-der, ointment, drops) and for the therapy of infections in hollow spaces and body cavities . Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmological and dermatological formulations, silver salts and other salts, ear drops, eye ointments, powders or solutions may be used. In animals, the administration may also take place in suitable formulations via the feed or drinking water. Furthermore, gels, powders, tablets, delayed-release tablets, premises, concentrates, granules, pellets, boll, capsules, aerosols, sprays and inhalants may be used in humans and animals. Furthermore, the compounds according to the invention may be incorporated L~e A 26 756 - 41 -~01~449 into other excipient materials such as, for example, plastics, (plastic chains for local therapy) , collagen or bone cement.
In general, it has proved advantageous both in human and veterinary medicine to administer the active compounds) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to attain the desired results.
An individual dose preferably contains the active com-pound(s) according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to depart from the dosages mentioned, depending on the type and the body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the administration of the medicament and also the time period or interval within which the administration takes place.
Thus in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, whereas in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage required in each case and the type of administra tion of the active compounds can easily be established by any person skilled in the art on the basis of his expert knowledge.
The new compounds may be given in the customary concentrations and preparations together with the feed or feed preparations or with the drinking water. Infection by gram-negative or gram-positive bacteria can thus be Le ,~, 26 '756 - 42 -prevented, improved and/or cured and promotion of growth and an improvement in the utilization of the feed can thus be achieved.
The minimum inhibitory concentrations (MIC) were determined by the serial dilution method on iso-sensitest agar (Oxoid). A series of agar plates which contained concentrations of the active compound decreasing in double dilutions in each case were prepared for each test substance. The agar plates were inoculated using a multi-point inoculator (Denley). For the inoculation, overnight cultures of the pathogens were used which were previously diluted in such a way that each inoculation point con-tained about 10' colony-forming particles. The inoculated agar plates were incubated at 37'C and the bacterial growth was read off after about 20 hours. The MIC value-(~g/ml) indicates the lowest active compound concentra-tion with which no bacterial growth could be detected with the naked eye.
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S
S I ~ s : s s = s t s i I~e A 26 7y6 - 65 - Example A
7-Chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid a) OOEt C
8.0 g of 1-cyclopropyl-5,6,?,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and ?.9 ml of thionyl chloride are boiled until gas no longer escapes.
The mixture is then concentrated in vacuo. 50 ml of ethanol are added to the residue and the mixture is boiled for two hours. It is then cooled to room tempera-ture and the solid precipitated is isolated.
Yield: 8.6 g of ethyl ?-chloro-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarb-oxylate Melting points 166-168' b) Et00C~ ~.CN
OOEt C
I~e A 26 956 - 6? _ 1.6 ml (0.015 mol) of ethyl cyanoacetate are initially introduced into 50 ml of absolute dioxane and 0.58 g of sodium hydride (as the 80% strength material) are added at 20°C. After 30 minutes, 3.45 g (0.01 mol) of substance from a) are added. The mixture is then boiled under reflux for 6 hours. After cooling to 20°, the mixture is diluted with water and rendered acidic with hydrochloric acid. The solid is isolated, dried and recrystallized from isopropanol.
Yield: 2.3 g of ethyl 7-chloro-5-(cyano-ethoxycarbonyl-methyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-guinolinecarboxylate Melting point: 156-57'.
c) COON

~COOH

F
2.3 g of substance from b) are heated at 140° for 4 hours together with 6 ml of acetic acid, 5 ml of water and 0.5 ml of sulphuric acid. The mixture is cooled to 20° and diluted with water. The solid is isolated, washed with water and dried.
Yields 1.6 g of 5-carboxymethyl-7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acid I~e A 26 756 - 68 -Yleld: 236-8° (d.) Analysis:
calculated: C 50.3 H 3.0 N 3.9 C1 9.9 found: 50.5 3.2 3.7 10.0 50.6 3.2 3.8 9.9 d) COOH
C 1 ~N
F
1.0 g (2.8 mmol) of substance from c) and 0.9 g (8.4 mmol) of 1,4-diazabicyclo[2.2.2]octane are heated at 140° for 3 hours in 20 ml of dimethyl sulphoxide. The solvent is then removed in a high vacuum and the residue is chromatographed on silica gel (eluent: methylene chloride/methanol 99/1).
Yield: 0.2 g of 7-chloro-1-cyclopropyl-6,8-difluoro-1,4 dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Melting point: 195-7°
example 1 ' COOH
H ~~ I
I~e A 26 756 _ 0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 140°C for 2 hours with 0.384 g (3 mmol) of 2,8-diazabicyclo[4.3.0]nonane and 0.672 g (6 mmol) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sul-phoxide. After cooling, the DMSO is removed in a high vacuum. The residue is taken up using acetonitrile. The solid is separated off, washed with acetonitrile and dried at 60-80°.
Yield: 0.7 g of 1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate Melting point: 174-6° with decomposition Example 2 F COOH
O _N N
H
0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate are heated at 140°C for 2 hours with 0.19 g (1.5 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.34 g (3 mmol) of 1,4-diazabicyclo-[2.2.2.]octane in 3.5 ml of dimethyl sulphoxide. The dimethyl sulphoaide is distilled off in a high vacuum. The residue is stirred with acetonitrile and the solid is isolated.
Ire A 26 75,~ - 70 Yield: 0.27 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid Melting point: 273-5°
Example 3 F COOH
HN ~ ~~ !
~1 0.14 g (0.5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 140° for 2 hours with 0.084 g (0.75 mmol) of 2,7-diazabicyclo[3.3.0]octane and 0.17 g (1.5 mmol) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. Dimethyl sulphoxide is then distilled off in a high vacuum. Acetonitrile is added to the residue, whereupon a solid forms.
Yield: 0.15 g of 1-cyclopropyl-7-(2,7-diazabicyclo [3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl 4-oxo-3-quinolinecarboxylic acid Melting point: 232-4' with decomposition example 4 COOH
CH3.~'~
~" 0 I~ A 26 756 0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated to 140' for 2 hours with 0.213 g (1.5 mmol) of 5-methyl-3-oxo-5,8-diazabicyclo[4.3.0]nonane and 0.34 g (3 mmol) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulphoxide. The solvent is then removed in a high vacuum. After stirring t;he residue with aceto-nitrile, 0.22 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(5-met:hyl-3-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid are obtained.
Melting point: 208-10' with decomposition Example 5 Cli3 0 COON
.N
F~ \~N N
0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 140' for 2 hours with 0.17 g (1.5 mmol) of 1,4-diazabicyclo[3.2.1]octane and 0.34 g (3 mmol) of 1,4-diazabicyclo[2.2.2]octane in 3.5 ml of dimethyl sulph-oxide. After removing the solvent in a high vacuum, the residue is stixred with acetonitrile and the solid is isolated.
Yields 0.24 g of 1-cyclopropyl-7-(1,4-diazabicyclo-[3.2.1]oct-4-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oao-3-quinolinscarboxylic acid Melting points ;274-76' with decoanpoaition ?~e A 26 756 - 72 -Example B

COOH
F~N
I
i F
6,7-Difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolonecarboxylic acid a) CH3 II iC00Et I C- C F
I ~ I I C) H-NH ~ F
F F
21 g of ethyl 3-ethoxy-2-(2,4,5-trifluoro-6-methyl-benzoyl)acrylate are initially introduced into 55 ml of ethanol. 9.4 g of 2,4-difluoroaniline are added dropwise with cooling. The mixture is then stirred at 25°C for one hour. 55 ml of water are then added and the solid which precipitates is isolated.
Yield: 25 g of ethyl 3-(2,4-difluorophenyl amino)-2-(2,9,5-trifluoro-6-methyl-benzoyl)-acrylate Melting point 109-10°C.
Le A 26 756 _ 73 _ . _ X013449 b) COOEt FAN
F
12.5 g.of substance from a) and 5.1 g of potas-sium carbonate are heated at 140'C for 4 hours in 60 ml of dimethylformamide. After cooling to room temperature, the mixture is diluted with water. The solid which precipitates is isolated and dried.
Yield: 11.3 g of ethyl 6,7-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylate Melting point: 157-9' OOH
FAN
r F
11.2 g of substance from b), 70 ml of acetic acid, 70 ml of water and 3.5 ml of sulphuric acid are heated at 140'C for 4 hours. After cooling to room temperature, the mixture is diluted with water. The solid is isolated and dried. 10.3 g of the title compound are ~e A 26 756 - 74 -.. 2013449 obtained. Melting point: 277-8°C
Example 6 COOH
N I~N
I
N
H I
F
0.6 g of substance from Example B, 0.57 g of 1,4-diazabicyclo[2.2.2]-octane and 0.25 g of 2,8-diaza-bicyclo[4.3.0]-nonane are stirred at room temperature in 6 m1 of dimethyl sulphoxide until starting material is no longer detect-able in the thin layer chromatogram. The mixture is then concentrated in vacuo. Water is added to the residue and the solid is isolated.
Yield: 0.6 g of 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
Melting point: 247-8°C.
It is understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
~ A 26 756 _ ~5

Claims (12)

1. A quinolonecarboxylic acid derivative of the formula in which R1 represents straight-chain or branched C1-C4-alkyl which is optionally substituted by hydroxyl, halogen, C1-C3-alkoxy or C1-C3-alkylthio, C3-C6-cycloalkyl which is optionally substituted by halogen or C1-C3-alkyl, C2-C4-alkenyl, and in addition C1-C3-alkoxy, amino, monoalkylamino having 1-3 C atoms, dialkylamino having 2-6 C atoms or phenyl which is optionally substituted by halogen, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl), R3 denotes C1-C4-alkyl R4 represents a radical of the structure in which R11 and R12 together denote a C1-C3-alkylene bridge which is optionally monosubstituted or disubstituted by methyl, R13 represents H, C1-C3-alkyl, hydroxyalkyl, aryl, heteroaryl, benzyl, C1-C4-alkoxycarbonyl, C1-C4-acyl or (5-methyl-2-oxo-1,3-dioxol.-4-yl)-methyl, R15 represents H or CH3 or phenyl, R16 represents H or CH3 or phenyl, R17 represents H or CH3, Y represents O, CH2, CH2CH2 or CH2-O, where the linking of the CH2-O group to the nitrogen can be either via O or via CH2, Z represents O or S, A represents hydrogen, halogen, methyl, cyano or nitro or a pharmaceutically utilizable hydrate or acid addition salt or an alkali metal, alkaline earth metal, silver or guanidinium salt of the carboxylic acid.

2. A compound, hydrate or salt according to claim 1, in which R1 represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, phenyl, 4-fluorophenyl, or 2,4-difluorophenyl, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, and R3 represents C1-C3-alkyl, R4 represents a radical of the structure in which R11 and R12 together denote a C1-C2-alkylene bridge which is optionally monosubstituted or disubstituted by methyl, R13 represents H, C1-C3-alkyl, hydroxyalkyl, phenyl, benzyl, C1-C4-alkoxycarbonyl, C1-C2-acyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R15 represents H or CH3, R16 represents H or CH3, R17 represents H or CH3, Y represents O, CH2, CH2CH2 or CH2-O, where the linking of the CH2-O-group to the nitrogen can be either via O or via CH2, Z represents O, A represents H, fluorine, chlorine, methyl, cyano or nitro.

3. A compound, hydrate or salt thereof according to claim 1, in which R1 represents ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methylamino, 4-fluorophenyl or 2,4-difluorophenyl, R2 represents hydrogen or alkyl having 1 to 2 carbon atoms, R3 represents C1-C3-alkyl, R4 denotes a radical of the structure in which R11 and R12 together denote a C1-C2-alkylene bridge which is optionally substituted by methyl, R13 represents H, C1-C2-alkyl, hydroxyethyl, benzyl, C1-C4-alkoxycarbonyl or C1-C2-acyl, R15 represents H or CH3, R16 represents H or CH3, R17 represents H or CH3, Y represents O, CH2, CH2CH2 or CH2-O, where the linking of the CH2-O-groups to the nitrogen can be either via O or via CH2, Z represents O, A represents H, fluorine or chlorine.

4. The compound 1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate of the formula

5. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid of the formula

6. The compound 1-cyclopropyl-7-(2,7-diazabicyclo-[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid of the formula

7. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(5-methyl-3-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid of the formula

8. The compound 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-1-(2,4-difluorophenvl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid of the formula 81a

9. A process for preparing a compound of formula I as defined in claim 1 or a pharmaceutically utilizable hydrate or acid addition salt or an alkali metal, alkaline earth metal, silver or guanidinium salt of the carboxylic acid, wherein R1, R2, R3, R4 and A are as defined in claim 1, which process comprises reacting a compound of the formula (II) in which R1, R2, R3 and A have the abovementioned meanings and X4 represents halogen, with a compound of the formula (III) R4-H (III) in which R4 has the abovementioned meaning, and where required forming a pharmaceutically utilizable hydrate or acid addition salt or an alkali metal, alkaline earth metal, silver or guanidinium salt of the carboxylic acid thereof.

10. An antibacterially active composition comprising an antibacaterially effective amount of a compound, hydrate or salt thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable diluent or carrier.

11. The use for combating bacteria of an antibacterially effective amount of a compound, hydrate or salt thereof according to any one of claims 1 to 8.

12. 7-Chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.