AU638005B2 - 5-alkylquinolonecarboxylic acids - Google Patents

Description

Jr Ou*R'ef: 311352 63005

AUSTRALIA

Patents Act FORM COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: 000 0 Applicant(s): BAYER AKTIENGESELLSCHAFT D-5090 Leverkusen, Bayerwerk, Germany ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Address for Service: *0 *0 0 S 0 00 5

S

@0 5 00 00 Complete specification for the invention entitled acids".

The following statement is a full description of this invention, including the best method of performing it known to me:- 1 4024U/gs The invention relates to new quinolonecarboxylic acid derivatives which carry an alkyl, to processes for their preparation and to antibacterial agents and food additives containing them.

It has been found that quinolonecarboxylic acid derivatives of the formula (I)

R

3 0 f Iv cOOR 2 R4 'N' A

R

1 in which S.'0 R 1 represents straight-chain or branched Ci-C 4 -alkyl which is optionally substituted by hydroxyl, halogen, Ci-C 3 -alkoxy or Ci-C 3 -alkylthio, C 3 -C6-cycloalkyl which is optionally substituted by halogen or Ci-C 3 -alkyl, Ci-C 4 -alkenyl, and in addition Ci-C 3 alkoxy, amino, monoalkylamino having 1-3 C atoms, dialkylmunino having 2-6 C atoms or phenyl which is optiona.lly substituted by halogen,

R

2 represes ts hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, .'2D R 3 denotes C 1 -C.-alkyl,

R

4 represents a radical, which is optionally substituted in the ring system by hydroxyl or methyl, of Le A 26 756 la-

T

the formula

N-(CH

2 )I E G N-, E G N-, EG7 Nin which E represents R 5 0 or S, G represents -(CH 21

-CH

2

-O-CH

2

-CH

2

-S-CH

2

-CH

2 00 0 000 0 0000 *~fl *0 00 00 0 0 0 0 00 0 0 000 0 0000 0 0000 0000 0 0 00 0 00 00 0 0 0 00 00 0 0 0 00 j

R

6

-CH

2

-N-CH-

2 -p represents 1, 2 or 3, represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 4 carbon atoms which is optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino, oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, represents hydrogen or methyl, in addition represents a radical of the formula (CH2 P-(CH 2 )n -W

N-(CH

2

)M

0 (CH2)p- N-CH 2)mr

X

2 (C2 KNC 3 in which, P represents 0,1 or 2, in represents 1 or 2, where p m together can be 1, Le A 26 756-2 2 r 7 2 or 3, n represents 1 or 2, W represents N, ,g OR halogen or hydrogen, X represents N R7, OR 9

SR

9 halogen, CN, CONH 2 or or C I- C 4 akyl,

X

2 and X3 can be identical or different and represent oxygen or N-CH 3 R7 represents hydrogen, CI-C 3 -alkyl, allyl or propargyl and R 8 represents hydrogen, Cl-C 3 -alkyl or C 3

-C

6 -CYCloalkyl, where 887 04: R 7

R

8 together can also represent the groups 0:696:-CH 2 CHi 2

-O-CH

2

CH

2 or -(CH2)k-,I in which k can represent' :0,6003, 4 or 5, and R 9 represents hydrogen, Cl-C 3 -alkyl or Cl-C 3 -acyl, R1 represents hydrogen or Cl-C 3 -alkyl,

R

4 also denotes a radical of the structure *-N12

/Y-

16.

N

'N ~R 16

I

*.P1 6 R13 1 in which R1 can represent H, C-C 3 -alkyl Or Cl-C 2 -acyl, R 12 can represent H, Cl-C-alkyl,, OH or OCH 3 where R 1 1 0*'*and W' 2 together can also denote a C 1

C

2 -alkylene bridge which is optionally monosubstituted or Le A 26 756-3 3 disubstituted by methyl,

R

1 can represent H, or C 1

-C

3 -alkyl, aryl, heteroaryl, benzyl, C 1

-C

4 -alkoxycarbonyl, C 1

-C

4 -acyl or 2-oxo-1,3-dioxol-4)-methyl,

R

1 4

R

15

R

16

R

17

Y

can represent H or C 1

-C

4 -alkyl, can represent H or CH 3 or phenyl, can represent H or CH 3 or phenyl, can represent H or CH 3 can represent 0, CH 2

CH

2

CH

2 or CH 2 where the linking of the CH 2 -O group to the nitrogen can be both via 0 and via CH 2 can represent 0 or S, represents hydrogen, halogen, methyl, cyano or nitro or, together with R 1 can also form a bridge of the structure

CH

3 or -CH2CH2-

-O-CH

2

CH-CH

3

-S-CH

2 -CH-CH or LH 2

CH

2

-CH-CH

3 I I IFHCH

C

0*

C.

S..

C

C

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.

35 They are therefore suitable as active compounds for human and veterinary medicine, where veterinary medicine also includes the treatment of fish for the S therapy or prevention of bacterial infections.

i Preferred compounds of the formula are those Le A 26 756 4 t 'u in which

R

1 represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-fluoroethyl, amino, methylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl,

R

2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,

R

3 represents Cl-C 3 -alkyl,

R

4 represents a substituted radical, which is optionally substituted in the ring system by methyl, of the formula N (CH2) E G E E N- in which E represents

R

5 -N or 0, e

R

6 S. 5 G represents -(CH 2

-CH

2

-O-CH

2 or -CH2-N-CH 2 j represents 1, 2 or 3,

R

5 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 .6 to 4 carbon atoms and

R

6 represents hydrogen or methyl,

R

4 in addition represents a radical of the formula (CH2 -(CH 2 (CH2)- 0

N/(CH

2 )m N(CH2m 0 Le A 26 756 5 I (NC(CX 2 3 P

-I

in which P represents 0, 1 or 2, m represents 1 or 2, where -p m together can be 1, 2 or 3, n represents 1 or 2, w represents ,j OR" or hydrogen,

,R

7 X~ represents "R OR 9 fluorine, chlorine or Cl-C 2 -alkyl,

SX

2 and X3 can be identical or different and represent oxygen, sulphur or N-CH 3 1 R 7 represents hydrogen, C.,-C7-alkyl or acetyl, R 8 represents hydrogen or CI-C 2 -alkyl, where R 7 Ra together also denote the groups -CH 2

CH,-O-,

-CH

2

CH

2 or -(CH2)k-O' in which k can represent 3, 4 or

R

9 represents~ hydrogen, C.-C 2 -alkyl or acetyl, R1 0 represents hydrogen or CI-C 2 -alkyl, R' also represents a radical of the structure Le A 2 6 756 -6 6 t 4, f

R

15 Z-RllR15zR 1 1 -N 12 NIii R14 -N1 R16 R1 1 R6 1 in which R" can represent H, C 1

-C

3 -alkyI. or Cl-C-acyl, R 12 can represent H, C 1

,-C

3 -alkyl, OH or OCH 3 1 where R" and R 12 together can also denote a C-C 2 -alkylene bridge which is optionally monosubstituted or disubstituted by methyl,

R

13 can represent H, C-C 3 -alkyl, phenyl, benzyl, C 1

-C

4 alkoxycarbonyl, C 1

-C

2 -acyl or (5-methyl-2-oxo-1, 3-' dioxol-4-yl) -methyl, *R 2 l 14 can represent H or Cl-C 2 -alkyl, R1 a epeetH rC3 00 R 1 6 can represent H or CH 3 R 7 can represent H or CH,,

R

7 can represent H0o CH2 H wer h Y canreprsent CH 2

CH

2 or C 2 hr1h 14 linking of the CH 2 O-group to the nitrogen can be 0000 both via 0 and via CH 2 0 z can represent 0, A represents H, fluorine, chlorine, methyl, cyano or 0 0 nitro or together with R1 can also f orm a bridge of the structure '000, -0-CH 2

-CH-CH

3 having the R- or S-configuration.

Le A 26 756 7 Particularly preferred compounds of the formula are those in which

R

i represents ethyl, vinyl, t-butyl, cyclopropyl, 2hydroxyethyl, 2-fluoroethyl, methylamino, 4-fluorophenyl or 2,4-difluorophenyl,

R

2 represents hydrogen or alkyl having 1 to 2 carbon atoms,

R

3 represents Ci-C 3 -alkyl, R4 represents a radical, which is optionally substituted in the ring system by methyl, of the formula

N-(CH

2 )j EG EG EG N- 2\L 9.

in which E represents R 5

-N,

G represents -(CH 2 9 j represents 1 or 2,

R

5 represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 3 carbon atoms and optionally substituted by hydroxyl, benzyl which is optionally substituted by nitro or amino, or oxoalkyl having 2 to 4 carbon atoms and

R

6 represents hydrogen or methyl, .s R in addition represents a radical of the formula (CH W 0 (CH) 3 9N9(CHZ)m N(CH 2 )m S X21

-N/(CH

2 )m

I

Le A 26 756 8 in which P represents 0, 1 or 2, in represents 1 or 2, where p in together can be 1, 2 or 3, n represents 1, 'W represents N 8, OR9 or hydrogen,

~R

8 X 2 and X 3 can be identical or different and represents oxygen or N-CH, lb) R.

7 represents hydrogen or methyl, R ersnt yrgnormty n R9 represents hydrogen or methylan R 10 represents hydrogen or methyl, R R 4 additionally denotes a radical of the structure z 1 1R-NR1 12 i N 16 16 1 ER 313 001~5 in which R" can represoiit H, Cl.-C 2 -alkyl or acetyl, R2 can represent H or C 1

C

2 -alkcyl, where R" and R 1 2 together can also denote a Cl-C 2 -alkylene bridge SC which is optionally substituted by methyl, R. '3 can represent H, Cl-C 2 -alkyl, hydroxyethyl, ben-%yl, Le A 26-756k9 9 R 1 5

R

1 6 R1 y z

A

Cl-C 4 -alkoxycarbonyl or C,-C 2 -acyl, can represent H or CH 3 can represent H or CH 3 1 can represent H or CH 3 1 can represent H or CH 3 1 can represent 0, CH 2

CH

2

CH

2 or CH 2 where the linking c-f the CH 2 -0-groups to the nitrogen can be both via 0 and via CH 2 can represent 0, represents H, fluorine or chlorine, or together with Rcan also form a bridge of the structure -0-CH 2

-CH-CH

3 having the R- or S-configuration.

e a o *j~ .ao 4q.,

A

4' 45 ft I A ft I? ~I 5 4 Sb a, S I I~.t of the f ormula It has furthermore been found that the compounds.

formula are obtained when compounds of the

(II)

;OOR2

(II)

I I A

R

1 44 016 in which

R

1

R

2 R 3 and A have the abovementioned meaning and x4 represents halogen, in particular fluorine or chlorine, are reacted with compo~unds of the formula (III) R'-H (III) in which R4 has the abovementioned meaning, Le A_26 i756 -110 if appropriate in the presence of acid scavengers and if appropriate protective groups contained in R 4 are removed.

If, for example, l-cyclopropyl-6,7,8-trifluoro- 1, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and l-methyl-octahydropyrrolo[3,4-bjpyridine are used as starting substances, the course of the reaction can be represented by the following equation:

CH

3 0 COOK CD Base N NH HF

CH

3 0

COOH

3 Le A_26_ U5 11 11 6 If, for example, 8-chloro-l-cyclopropyl-6,7dif luoro-1, 4-dihydro-5-methyl-4-oxo-3-quiniolinecarboxylic 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:

CH

3 0 F N COOH C 2

H

5 -NH-CHj-NH Base F) I H -HF

CH

3 0

COOH

C2H5-NH-CH2 N *0 *6*

:HO

If, for example, l-cyclopropyl-7-(2 ,7-diazabicy- *i do 3.3.0 ]oct-7-yl) -6-fluoro-l, 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: CH, 0 Sose COOH HC1

C

2

H

5 0H

CH

3 0 00C 2

H

x HC1 Le A 26 756 12 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-l-cyclopropyl-6, 7-difluoro-1, 4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-5, 8-dimethyl-4oxo-3-quinolinecarboxylic acid, 1-ethyl-6,7,8-trifluoro-1,4-dihydro--s-methyl-4-oxo-3quinolinecarboxylic acid Ethyl l-cyclopropyl-6, 7, 8-trifluoro-l, 4-oxo-3-quinolinecarboxylate, Ethyl 8-chloro-1-cyclopropyl-6 ,7-difluoro-1, 0* 060:6 ,7-difluoro-1- (4-f luoro-phenyl 4-dihydro-5-methyl-4- :0044, oxo-3-guinolinecarboxylic acid, 0 0 "See 6, 7-difluoro-1- 4-difluoro-phenyl ZO methyl-4-oxo-3-quinolinecarboxylic acid.

7-Chorol-ccloropl-68-difluoro-1,4-dihydro- 5-methyl-4-oxo-3-quinolinecarboxyvlic acid is not known.

It can be prepared according to the following scheme.

*Gee FCOO F 0 COH 1. SOC1 2 F- C00E L N 2. ELCH C F0 00 Le A 26 756 13

N

C CH 2 NaH EL0C, ,CN CH 0 I)COOEt C1 CH3 0

DABCO

OOH

Ci

COOH

CH

2 j~

COOH

C1 0*

S

5.55 DABCO 1,4-Diazabicyclo[2,2,2]octane The compounds of the formula III having the structures N-(CH2)j E G EGN- EG N-

\L-I

are known (EP-PS 230,274).

5 Some of the compounds of the formula III rsed as starting compounds and having the structures X1 (CH (CH 2 )n-y R10

S

o so 5 S 0O S (CH2 f N CH 2

)M

(CH 2 x 3 2)1-1Z~ Le A 26 756 14 are new.

They can be prepared by various methods: 1. By reaction of the spiro-oxiranes protected on the nitrogen atom Med. Chem. 30, 222 (1987); Us-p 4,508,724; EP-PS 189,370] with amines ring opening to give the hydroxylainines occurs.

Removal of the protective group yields starting compounds of the formula (Mia):

NCH)

1 CR-N KN CH2)M

RB

0:00 R ILOO-alkyl or CH 2

CH

00* 0 H .0

(CR

2 1

CH

2

_-R

KN-(CTI H (IIla) 2. The cyclization of the succinic acid ester (4) '0000,[Tetrahedron Letters 46, 4561 (1973)] with ben- 5:5zylamine yields the alkyl 00 pyrrolidin-3-carboxylate which, by reaction with :0"00,an amine reacts to give the amide Sub- 0 15sequent reduction with LiAIH 4 and hycirogenolytic cleavage of the benzyl group yields starting comnpounds of the formula (MXb): 00 (4) Le A 26 756 15

OH

COO-Alkyl (21 :0-N

H

0*

S

o so.

S

So S5 5 5 S. S S 55 0* S S

S

IlIb) 3. Reaction of (l-benzyl-3-hydroxy-2,5-dioxo-pyrrolidin-3-yl) -acetic acid [Gazz. Chim. Ital. 24, 226 (1894)] to give the amide and subsequent reduction with LiAlH 4 and removal of the benzyl group yields starting compounds of the formula (IIc): see* 0 0 0 *o

COOH

'0-N 8

S.

S 5 55 55 5

S.

S.

(8) OH

,,R

7

N-R

H

(IIIC)

Le A-26 756 16 4. 3 -Hydroxy-3-methyl pyrrolidine can be prepared by LiAlH 4 reduction of 4 -hydroxy-4-metylpyrrolidin-2 one [Zh. Org. Khim. 14, 7, p. 1420 (1978)] or by debenzylation of l-benzyl-3-hydroxy-3-methylpyr.

rolidine (EP 132,845).

Starting from cyclic oxo-amines which are blocked on the nitrogen by a protective group, starting compounds of the formulae (IIId), (Mhle), (IIIf) can be synthesized [Acta Chem. Scand. B 34, 319 (1980)].

*0 00 "0 0 *a 0 00 S 0 0 00 *a 0 *r 0 h(CH2)

M

CI

H

18 (9) R18= COO-Alkyl,

CH

2

-C

6

H

5

NH

2 (CH2 N

RI

H ,2 CH 2 1 S 2 R18 (10)

CH

(CH) HH /(CH2)M

H

(IIId) HCN or

(CH

3 3 SiCN

OH/

N-(CH

2 )m 18 0000 0 *000 0000 0 0

NH

2

(CH

2 1

OOH

r 7KW(CH2)m

(CH

2

'(CH

2 )n *0 00 0 00 00 0 00 00 (13) (12) (IMle) H2 (C (1CH 1 m

H

UIII!)

Le A 26 756 17 6. Th.- hydroxyl group of the hydroxylamines (Ila) (IIle) can be alkylated or halogenated.

7. Ketals, thioketals or aminals can be prepared from the cyclic oxamines [Helv. Chim. Acta 50, 1289 (1967)].

By reaction of the spiro oxiranes protected on the nitrogen atom with trimethylsilyl cyanide (J Amer. Chem. Soc. 104, 5849 (1982)], the isonitriles (14) can be prepared which, by hydrolysing and removing the protective group, can be reacted to give the starting compounds of the formula (lug):

(CH

3 3 SiCN

N-'(CH

2 mr se I0 0 0

NH

2 CH) NC -"S(H)3(CH 2 1-1- H 0 C H 2i C H 3 N C H

'--CH

2

N(H

2 )mr 0000 (14) (lg Examples of starting compounds of the formula 0 4.00 (111) which may be mentioned are the following compounds, a it being possible to employ chiral compounds both as racemates and as enantiomerically pure substances: '0000 3 -Aminomethyl-3 -hydroxy-pyrrolidine, a: 6% 3-Acetylaminomethyl-3-hydroxy-pyrrolidine, Le A 26 756 -118 3-tert.-Butoxycarbonyaninomethy-3.hydroxy..pyrrolidine, 3-Hydroxy-3-methylaminomethyl-pyrrolidinie, 3-Ethylalninomethyl-3-hydroxy-pyrrolidine, 3 -Hydroxy-3-propylam..inomethyl-pyrrolidine, 3 -Ethylazninomethyl-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-Ethylazninomethyl-3-methylthio-pyrrolidine, 3-Acetoxy-3-ethylaminomethyl-pyrrolidine, 3-Diriethylaminomethyl-3-hydroxy-pyrrolidine, 3-yrx--yrld.oehlproiie 9 3-Hydroxy-3-pyrrolinomethyl-pyrrolidine, 3-Hydrox-3-morphoinomethyl-pyrrolidine, 3-Actmino-3-ethylaminomethyl-pyrrolidi 3-tyaioehy -ehlmnoproiie 3-Acetylamino-3-ethylaminomethyl-prrolidine, 3-Ethyo-3-minoethy -tyrroliney,~iie S 3-Diehya-3 -ethylaminomethl- yl-pyroliin 3-Amino-3-hydrcaxymethyl-pyrrolidine, 3-Act oylamino me".',y-3-hydroxy -pyrrolidine, 3-Amino- 3 -methoxmethyl-3hdypyrrolidine, 3 -ox-tet -utxyasproyla no-3-methxmty-proii 3-.xam-3-methyltiomethylpyrroidi 31 4-Dioxal-7-azasp7iaz(4 o,4]nonane, 6. 0-x-4 -izsio(44 oae Le A 26 756 19 1-Thia-4 ,7-diazaspiro [4,4 ]nonane, 1,4 ,7-Triazaspiro[4,4]nonane, 1, 4-Dixnethyl-l 7-triazaspiro [4 nonane.

Some of the compounds of the formula III used as a starting material and having the structures R-'7 -E1= z 1 12NN FRI 91316R 16

R

13 6 960* 04 *4 6 9 0 a 4 *9 6 I 6 .69 S 66 9 9 0* S *6 69 6 6 S I

S.

4* 6 S I 6 6* are also new. They can be prepared by the following methods.

1. Starting from the N-protected 3,4-epoxypyrrolidine (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.

12 t;O Removal of FT'~R 13protective groups KN) N -'3 P.0 H3

R

11

X

5 Base R1 10 11 2 Reoa o p II1h) R110 l 2 1NR 3 (liii) Le A 26 756 -2 20 R 18 benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or suiphonyl (examples of protective groups), X leaving group such as halogen, alkyl- or ary-Lulphonyloxy

N

3 R1 8

RIIX

Base

R

1 1 0

R'

1 0~ 02 zrCOOC(CH 3 3 4.

4 404 tee...

4 co *0 4 *4 I I C 4 a.

a~4 4 0 R 0 R 0

H

N

.4,3 o a COO ~I Jo 4 44 04 44 4

S

4.

6 4 4~ 84 4 1) 4* pl2

N-

Le A 26 756i 21 1I 2 1,-R1 -I o 4 R 1 R 11 1 13

H

H

2 /Fd (I I11) I H 2 /pd I (111k)

H

2. Starting compounds of the formula (IIIm) are obtained from 2-(l,2-dichloroethyl)-oxirane via the following reaction sequence: :eg 0 Go* 0 e 00 0 C1 HO C1 1r ~1 1g..

Goes 0 S R110 OH

RP

1 0O 0

CIJ

OS

*5 5* S S 5* Le A 26 756 22 R 1 1 ~12

N

13

H

2 R110 N 1 H3 (U I) 3. By addition of azides to N-benzylmaleimides optionally substituted with one or two methyl or phenyl radicals, starting compounds of the formula (III n) can be prepared: 0 00S a* 0 0 0 00 00.0 06 a

-'I

N: N.,N -Ra v5N 0

R

9

N

0- Reduction 00S

R

4 0 00 0 0 00 00 0 00 00 R 0HR

H

(IIn) Le A 26 756 23 R 4.

H, alkyl or benzyl.

From the 3,4-epoxypyrrolidines via a cyclization with thionyl chloride, the starting compounds of the formula (III o) are obtained: H H 2 1 1 8 HO H-CO-R 1 4 H N SOC12 R18

R

14

I

1 R 1 8 *0 0 *0 S 011.5 000

H

(III o) 5. By reacting the 3,4-epoxypyrrolidines with ethanolamines by intramolecular etherification, the starting compounds of the formula (III p) are obtained: 0000 0 0000 *000 0S 00 0 00 00 0 0 00 00 0 00 00 0 00o *0

NH-R

6

HO

(1) R13 HO N

R

1 8 e 0 N-R 1 3

R

1 8 0 N-R 1 3

I,

(III p).

Le A 26 756 24 6. The starting compounds of the formula (III q) are obtained from amino acetaldehyde dimethy. acetal via an intramolecular 1,3-dipolar cycloaddition.

o 0 0 *0 00 0 0 0 *0 0 0@ *0 o *00 0 *000 0 0S00 000* .5

S

*e 0* 0 0

OCH

3 x2' 0

R

1 8 N 1 CH3 R15

N

R

1 8 R1 18-

OCH

3 Base H 0R 1 3 N H- )H

R

1 8

-N

1 CH 2 1 R 5

E

-4 P 1

-R

13 (III q) 7. Starting from N-benzyl-pyridine-2, 3-dicarboximide, starting compounds (III r) or (111 1) are prepared via the reaction steps indicated.

50 0

S*

*0 0 S 00 00 Le A 2675 25 alkyl iodide

-CH

2

-C

6

H

5 0 000 0 000000 0 0S 0 0 0 *0 0 0*

S.

5* 0 0 000 0 @005 0

SOS,

55.5 0 S S. S 55 5 5

S

S.

5 0 55 5* 5 S S 55 alkyl jH 2 IptO 2 0 N1-CH 2

-C

6

H

5 alkyl I LiAlH4 Q2~ N-CH 2 alkyl

I

N-CH-

2

-C

6

H

0 or 0 CT N-CH 2 -C 6

H

H

0 LiA1H 4 or NaBH

BF

3 l2520 Q2: N-CH 2

-C

6

H

H

I H 2 /Pd

-C

QCNH

H

INS.

Le-A Z6 756i 26 ~H 2 /Pd-C

NH

alkyl III r 8. N -benzyl -male imide adds 2-chioroethylamine to give the 3- (2-chloroethylainino) -succinir- ides, which are reacted to give the starting compounds of the formula (III t):

S

S..

OSSS@S

0e o 0

S

0* S 0 S 0@

SS

S S 500 6 0 ~NCH2

-C

6

H

5 +C1-CH 2

CH

2

-NH-R

1 3 0 C1 r'2 NCH2

_C

6

H

5 a

CH

2 -N 0 1

S..

S

*505 5500 S S S. S *0 00 0 0

N_CH

2 C6 H5 R13 LiAlH 4

*S

S S *0 SS S S 0 0 5* qI N-CH 2

-C

6

H

R13 Le A 26 756 27

N~H

R13 (III L) 9. 2-Meithyl-2-propenal dimethyihydrazone reacts with N-benzylmaleimide to give a cycloadduct which can be converted into the starting compound (III u) by the reaction sequence indicated.

0*

S

OS

S

S

0S S *Oa S 55 55 5 050 CH 3 H 2

CH

3 CH3 0 N H-CH 2 -Ph 0

CH

3 CH 3

(C

3 2

NH

0 2 cata-CH3 -4 CH P lyst

H

S

*SS5 5555 o 5

J

iUAIH 4 CH3N'y"'N H 2 IPd-C CH',,y NC2Ph H H (III U) According to this general reaction scheme, for example, the following starting compounds can be prepared. They can be prepared and employed as diastereomer Le A 26 756 28 mixtures, in diastereomerically pure and also in enantiomerically pure form.

4-Amino-3-hydroxypyrrolidine, 3-Hydroxy-4-methylaminopyrrolidine, 4-Diniethylamino-3-hydroxypyrrolidine, 4-Ethylamino-3-hydroxypyrrolidine, 3-Amino-4-methoxypyrrolidine, 4 -!ethoxy-3-methylaminopyrrolidine, 3 -Dimethylamino-4 -nethoxypyrrol idine, 3-Ethylamino-4-methoxypyrrolidine, 3-Amino-4-ethoxypyrrolidine, 4 -Ethoxy-3-methylaminopyrrolidine, 3-Dimethylamino-4-ethoxypyrrolidine, 4-Ethoxy-3-ethylaminopyrrolidine, 3 -Hydroxy-4-hydroxyamirlopyrrolidine, 3 -Hydroxy- 4-methoxyaminopyrrol idine, 3-Iydroxyamino-4-methoxy-pyrrolidine, 4 -Methoxy-3-methoxyaminopyrrolidine, 3-Benzylamino-4-methoxyi,.yrrolidine, 204-!4ethoxy-3-( (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl- *,oo amino) pyrrolidine, 3-Amino-4-methylmercapt-opyrrolidine, 3 -Acetoxy-4 -dimethylaminopyrrolidine, 3-Acetamido-4-methoxypyrrolidine, 4-Methoxy-3-methoxycarbonylaminopyrrolidile, 3-Formamido-4-methoxypyrrolidine, 3-mn--mtoy2-ehly4oiie 0 3 -Amino-4-methoxy-2-methylpyrrolidine, 4 -lethoxy-2 -methyl- 3 -methylaminopyrrolidine, 4-Methoxy-5-methyl-3-methylaminopyrrolidine, Le A 26-756 29 l6 3-Axnino-4-mrethoxcy-2 -phenylpyrrolidine, 4-Methoxy-3-methylamino-5-phenylpyrrolidine, 3-Methyl-2, 7-diazabicyclo [3.3.0 ]octane, 4-M~ethy-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-Dixnethyl-2,7-diazabicyclo[3.3.O]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.Ojoctane, 1, 2-Diznethyl-3-oxa-2 ,7-diazabicyclo 0l3octane, 2, 5-Dimethyl-3-oxa-2, 7-diazabicyclo[ 3.3.0 ]octane, seem"2,8-Diinethyl-3-oxa-2,7-diazabicyclo[3.3 .0]octane, 5-Methyl-3-oxa-2, 7-diazabicyclo octane, 15*oa47daaiyco330ot3ee 3-Oeh--xa-4,7-diazabicyclo[3 .3,0)oct-3-ene, 3-Mehyl-2-oxa-4, 7-diazabicyclo oct-3-ene, 6-ehl2ox-,-iz0iyl[..0ot3ee 8-Pehy2.-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene, 6-Iethyl-2-oa- -diazabicyclo[ 3.3.0 oct--ene 8-Methyl-2,-x a-4,b.iazabiycl 3.3.0 oct--ene 3-Methy1-2,8-diazabicyco[4~.3.0]nonane, C '80 -Methyl-2,8-diazabicyclo[4.3.0]nonane, V8 3 -Methyl-2-ox58-diazabicyclo[4 3.0]no non, -Methyl-2, x58-diazabicyclo 4..0]nonn, ne a 31-Methyl-2-oxa-5,8-dia±zabicyclo[4 O]nonane, 4-Dmethyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 8-diazabicyclo[4.3. Inonne 5-ehl2tha58dazbcco4...oae 3,5-Dimethyl-2-oxa-5,8-diazabicyclo[4 Le A 26 756 30 3-Oxa-2,8-diazabicyclo[4 2-Methyl-9-oxa-2, 8-diazabicyclo nonane, 4-Methyl-3-oxa-2,8-diazabicyclo[4 2, 5-Dimethyl-3-oxa-2,8-diazabicyclo [4 nonane, 3-Oxa-5,8-diazabicyclo[4.3.0]nonane, 5-methyl-3-oxa-5,8-diazabicyclo[4 .3 .0]nonane, l,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-dimethylformamide, 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 customary inorganic and organic acid-binding agents. These preferably include the alkali metal hydroxides, alkali 0* metal carbonates, organic amines and amidines. Those which may be mentioned as being particularly suitable are: triethylanine, 1,4-diazabicyclot2.2.2)]octane (DABCO), l,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 00. carried out between about 20 and 200*C, preferably between 80 and 1800C.

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), *e page 104).

Free amino functions can be protected during the 5 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 0. or acidic ion exchangers, at temperatures from about 6 to 200*C, preferably about 60o to 120"C. The resultant water of reaction can also be removed by azeotropic Le A 26 756 32 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-l,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 1,3-dioxol-2-one in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea at temperatures from about 0° 0 to 100 0 C, preferably 0" to L. 5 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, 20 acetone or acetonitrile. Equivalent amounts of betaine 0000 .oo oand 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, *00" citric acid, tartaric acid, methanesulphonic acid, i 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

The alkali metal or alkaline earth metal salts of Le A 26 756 33 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. Pharmaceutically 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 .15 also as diastereomerically pure or enantiomerically pure compounds.

The compounds according to the invention show, combined with low toxicity, a broad antibacterial spectrum 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, fibres, 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 bacterialike 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 prophylaxis and chemotherapy of local and systemic infections which are produced by these pathogens.

a 01.: For example, local and/or systemic diseases which are caused by the following pathogens or by mixtures of a. I5 the following pathogens can be treated and/or prevented: gram-positive cocci, for example staphylococci (Staph.

S aureus, Staph. epidermidis) and streptococci (Strept.

agalactiae, Strept. faecalis, Strept. pneumoniae, Strept.

pyogenes); gram-negative cocci (Neisseria gonorrhoeae) and also gram-negative rods such as Enterobacteriaceae, for example Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella; furthermore Klebsiella (Klebs.

Spneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), 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 Le A 26 756 35 as, for example, Bacteroides fragilis, representatives of the order Peptococcus, Peptostreptococcus and also the order Clostridium; furthermore mycoplasma 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, pyelonephritis, cystitis, endocarditis, systcmic infections, 15 bronchitis (acute, chronic), septic infections, diseases 0 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, abscesses, phlegmone, wound infections, infected burns, scalds, infections in the oral region, infections after dental operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intra-abdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections.

In addition to humans, bacterial infections can Le A 26 -"U5 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, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections; horse: bronchopneumonias, joint-ill, puerperal and postpuerperal infections, salmonellosis; dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections, prostatitis; *.e poultry (hen, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic 1* 5 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, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.

The present invention includes pharmaceutical preparations which contain one or more compounds according 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 t and processes for the production of these preparations.

The present invention also includes Le A 26 756 37 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 administered 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, o* pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

0 Tablets, coated tablets, capsules, pills and granules may contain the customary excipients, such as fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, humectants, for example glycerol, disintegrants, for example agar-agar, calcium carbonate and sodium carbonate, solution retardants, for example paraffin and absorption accelerators, for example quaternary ammonium compounds, wetting agents, for example cetyl alcohol, glycerol Le A 26 756 38 monostearate, adsorption agents, for example kaolin and bentonite and lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols or mixtures of the substances mentioned under to 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 compound(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.

S, If appropriate, the active compound(s) may also 15 be present in micro-encapsulated form with one or more of a 0 the abovementioned excipients.

Suppositories may contain the customary watersoluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C 14 -alcohol with C 1 -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 vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, S'0" bentonites, silica, talc and zinc oxide or mixtures of o* these substances in addition to the active compound(s).

Powders and sprays may contain the customary excipients, for example lactose, talc, silica, aluminium Le A 26 756 39 hydroxide, calcium silicate and polyamide powder or mixtures of these substances in addition to the active compound(s). Sprays may additionally contain the customary propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions may contain the customary excipients, such as solvents, solubilizers and emulsifiers, 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, maize germ oil, olive oil, castor oil and o, sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl S alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances in addition to the active compound(s).

S*For parenteral administration, the solutions and emulsions may also be present in sterile and bloodisotonic form.

Suspensions may contain the customary excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium 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 odour-improving and S flavour-improving additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.

Le A 26 756 40 The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical 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 pharmaceutical preparations takes place in a customary manner by *known methods, for example by mixing the active compound(s) with the excipient(s).

The preparations mentioned may be used in humans and animals either orally, rectally, parenterally (intra- *5 venously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, 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 *0 0 and dermatological formulations, silver salts and other 0 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, delayedrelease tablets, premixes, 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 Le A 26 756 41 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 compound(s) 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 compound(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, wherveas in other cases the abovementioned as* 0 amount of acLive compound must be exceeded. The optimum dosage required in each case and the type of administration of the active compounds can easily be established by any person skilled in the art on the basis of his expert knowledge.

0 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 A 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 multipoint 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- 0o6ooo tained about 104 colony-forming particles. The inoculated 0* agar plates were incubated at 37°C and the bacterial *.35 growth was read off after about 20 hours. The MIC value (pg/ml) indicates the lowest active compound concentration with which no bacterial growth could be detected with the naked eye.

0* o* e Le A 26 756 43

HA

H

H noH N~ CH: -N I a a 0 0 aa e 00 0 0

S

0 C C TABLE 1 (contiflU~&iOfl) 0 C e 0 5 C C. C C 000 Ce C e CC* 0 C*O C C C CC C CC C C C C C C C C S C C C C C C CCC C C*C C 1

F

-CH=CH

2

HO-CHZCH

2 N _IN- NT:: N-

NF\N-

CH

3

CH

3

CH

3

CH-

3 Cl-k C 211

CH

3 0 0 0 0*0 SO TABLE 1 (continUation) 000 S S 0 0 0 0 0000 00 C 0 0 *0 0 00 0 000 5 000 0 600 o 0 0 0 00 0 *0 0 0 0 0 0 6 0 0 0 6e 00 0 0 605 0 000 0

O

I i I I

H

C$L

H

H

CH

3 NN CHaNI__

HNZIN-

C

2

C

3

C

3

C

2

CH

3 a a *a 0 a a a a a. a TABLE 1 (continuation)

S

~x1~

CH

3

C"

3 H NJN H -N\Z/N cl-I C 2H5

C

2

H

5

A

C N

F

C 1 C I 0 0 0 0 0 00 0@ 000 0 TABLE 1 (continuatiOn) 000 0 0 0 0 0 0 0* @0 *0 0 0 00 0 00 0 .0 0. 0 00 00 0

F-CH

2

-CH

2 N N-

CH

3 N'T\N

CH

3 O-

CH

3

CH

3

C

2 5 c'- 3

CH

3

F

C"

3 N02 CH3 4 4 S

S

9 5 TABLE 1 (continuation) *St S S S 59 0* S S S 4 *3 S fOS uSC o 4 5 9 Ct C SC C 9 5 C 9 C 0 40e C 4 5 4 SS3 5 545 1. 4 I t

CH

3

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CH

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HNZN-

HNZN

CH

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CH

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CH

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F

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C

2 1 8*.

4 4 4 4 4 0w0 4 0.4 4 4..

*4 8 4 8.

.4 *0 .04 0 944 8 0 08 8 4 4 S 4 9 0 4 494 .4 0 0 6.4 4 TABLE 1 (continuation) I 4- -4 4.

H

C

2

H

5

H

H

IN

H

oc>1

H

CH

3

CH-

3

CH

3

CH

3

H

ff a TABLE 1 (continuation) SOS 0 S S S S S S S. S S S S

S

55* S S 550 S S S 55 S. 5 S S 5 5 55 55 5 *se 5 05. 0 I i I-

C

2 5

C

2

H.

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F

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H

OC>-

H

H

C"

3

CH

3

C

2 11 C1.' 3 0 0 0 0 C S 0 0 0 0e 000 S TABLE 1 (contInuation) 000 0 0 0 0 S 0 0 0 0* C 0 0 0 0 0 00 0 00. 0 0. 0: 6 0 L 4-

JIO-CH

2

CH

2

H

H

H

CH2)y

O

CH

3 CH

ON-

H

CH

3

H

H

N

H

H

£113 Cl- 3 CH~3 Cl- 3

CH-

3 o 0 C C 0 0 0* C C *o

C

CC, 0. CCC 0 I TABLE 1 (continuation)

HN

H

HN

H

H

C 2145 C2

F

CZH

CH-

3 C14 3 N0 2 0% 00 00 .0 00: 0 000 0 0 Do 0 0 0 0 0 0 0 0 0 000 0 0 0 0 0.0 0% 0 TABLE 1 (continuation) R R2 R4 R A H C C> -CH 3 Cl-Ia

H

H H3 H H- C 3

H

7 F1

H

u' H

C!

3

F

IH33j

H

SHN

CH

3

C

H

CH

3

F-CH

2

CH

2 H N- Cl-I 3

F

S

0*S S S S S S S S S S S 55 B S S S S S S. S U 555 5 555 S S S @5 55 5 5 0 9 5 5 C S S S 55 5 5 5 5*5 5 050 0 OI TABLE 1 (continuation) t I I

H

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H

H

H

Cl-I 3

CH

3

CH-

3 Cl! 3

CH

3

CH

3

Q-

CH

3

-NH-

S 0. 5: 'e TABLE 1 (continuation) H ICH3 if fri

C

3

N-

H CH3 F

H

CH

3

N-

H

CH

3

F

H

CH

3

CH

3 0 H CH 3

F

H

2

N

00: .0.0 0 0 0 0 0 0 0 00 0 0.0 0 0 0 0 0 0.0 00 STABLE 1 (continuation) r

H-

4 f CH3 H

H

CH-

3 0 N- H ICM 3

F

H

H C~~IN- CH 3

F

H [j 10 CH 3

CH

3

H

2 113 !Iqz.

V

o 0 0 OS.

0 0 0 0 0 0 0 S S 0 0 (u 0

B

0*5 0 0 0 0 0 0 ~iOz,) 0 0 0 5 0 I- S 0 0 0 0

OS@

0 0 0@ 5O #00 0 0 0 o 000.

4040 o *0 0 0 0 0* S 0. 0 *00 0 000 0 000 C S S 55 0 *0 0 0 5 0 5 5 0 0 0 0e S 0 0 0 00) 0 500 0 zrm I (continuation) jn RZ v

CH

3 i t I

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2

H

5

H

2 t4

H

2

N

HO% jN

H

2

N

H

2

N

CH

3

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CH-

3 Cl- 3

CH

3

CH

3

CH

3 0. 0 0 0 0 wo C C C IALE- (continuation) F? 2 4 fR 3

A

J~ H)iIi]

C

3

F

CI-

3

-NH

H CH30Onl(-

C

2

H

5

F

CH-

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NH

UH

CH

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H

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H CH j 30.nH 3

F

CH

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CHO

H

CHO

0

SHZO

H

H

H

CHZ3

OH

Z~HDHN-

HD

to

U,

-K1l 4 1~~ (@9 0 0~ 0 0 9 00 0' 0 4' 0 000 0 000 00.

00 3 0 00 00 00~ 00 a 00 q~ U- 00 0

A

H

H

H

A

CHO

SHZ3J

H

.4

H

H

H

H

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A

~c~I

SH~-J

-K

A

I

-OH

rN:OH JDZHHN.cHO

CHO

CHO

v a a a a a a a a a a S a a a a a a. a a a a aa. a aaa a aaa a. a a a a *a a a a a a C. C a a aaa a a a a a a

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42 D4ZHHN

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CHO

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SHZO

CHO

CHO

CHO

3

CHO

CHO3

H

H

H

H

H

CHO

Ji0-

ZHD-

0 SHZ:3

-K

V I c 8 I Fe 0C* o *0 0 0 0 0 0 S 00 0 0 0 0 0 S 0 0 0 000 000 0 0 0 00 0 0 0 0 0 0 0 0 0 A EHHZ H HJ CHO H A SHZO H

A

A HNGZ EHO H -N

HO

C C C CH H C4 C C CND ZD C CC C CC CC CV Ed Cit] C C C C C No

ZON

A

To

A

H

OH

H

N

CHO

CHO.

LHC.J..U

SHZO

CHO

CHO

%Sc

U,

C CC. C C CC C C C U C C C C C C CC CC C C C C CCC C CCC C CCC CC C C C C C C CC C C C C C C C C C C C*C C CCC C C C C C C C C C C C Ot 00 0 00 a 0a .00 0-

CH

3

CH

3 1

(CH

3 2NCH2>KI- 1710CN Examp~leA 7-Chloro-l-cyclopropyl-6, 8-difluoro-1, 4-oxo-3-quinolinecarboxylic acid a) F 0 COOEt

I

8.0 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid and 7.9 ml of thionyl chloride are boiled until gas no longer escapes.

Goo**: The mixture is then concentrated in vacuo. 50 ml of ethanol are added to the residue and the mixture is *ao boiled for two hours. It is then cooled to room temperao:*ture and the solid precipitated is isolated.

Yield: 8.6 g of ethyl 7-chloro-1-cyclopropyl-5,6,8trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxyl ate Melting point: 166-1680 b) CH 0 "006 IT COOE.

S.,

Le A 26 756 67 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 0 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 methyl) -l-cyclopropyl-6,8-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylate Melting point: 156-57".

o r* c)

COOH

a

I

CO

OH

ClN a 0 a 1 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 and diluted with water. The solid is isolated, washed with water and dried.

Yield: 1.6 g of 5-carboxymethyl-7-chloro-l-cyclopropyl- 6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid Le A 26 756 68 Yield: 236-8* Analysis: calculated: f ound: C 50.3 50.5 50.6 Hi 3.0 3.2 3.2 N 3.9 Cl 3.7 3.8 9.9 10.0 9.9

:OOH

Sb

S

S. a a a

S.

1 0 a.

PS 0

S

S S S 1' S o es 0 0 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 1400 for 3 hours in 20 ml, of dimethyl suiphoxide. 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-1,4dihydxo-5-methyl-4-oxo-3-guinolinecarboxylic acid Melting point: 195-70 Example 1 .c~ 0 0' S. S

SO

CH3

O

F

CO

COO

Le A 26 756 69 0 0.56 g (2 mmol) of l-cyclopropyl-6,7-difluoro- 1, 4 -dihydro-5-methyl-4-oxo- 3 -quinolinecarboxylic acid are heated at 140 0 C for 2 hours with 0.384 g (3 mmol) of 2,8diazabicyclo[4.3.0]nonane and 0.672 g (6 mmol) of 1,4diazabicyclo[2 .2 ]octane in 3.5 ml of dimethyl sulphoxide. 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 60-800.

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

CH

3 O0 F COOH *0 N0i

HH

**915 0.28 g (1 mmol) of 1-cycrlopropyl-6,7-difluoro- 1, 4 -dihydro-5-methyl-4-oxo-3-quinlinecarboxylate are heated at 140 0 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 suiphoxide. The dimethyl suiphoxide is distilled off in a high vacuum. The residue is stirred with acetonitrile and the solid is isolated.

0. e.

Le A 26 756 70 Yield: 0.27 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-5methyl-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)- 4-oxo-3-quinolinecarboxylic acid Melting point: 273-50 Example 3

CH-

3 0 F COOH 0.14 g (0.5 inmol) of 1-cyclopropyl-6,7-difluoro- 1, ,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are so. heated at 1400 for 2 hours with 0.084 g (0.75 mnmol) of 1* 2,7-diazabicyclo[ 3.3.O0joctane and 0.17 g (1.5 mmol) of :1.6 1,4-diazabicyclo[2.2.2Joctane in 3.5 ml of dimnethyl suiphoxide. Dimethyl suiphoxide is then distilled off in a high vacuum. Acetonitrile is added to the residue, 0000 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: 232-40 with decomposition Example 4

CH

3 O0 F COOH CH3-I Le A 26 756 71 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 methyl-3-oxo-5,8-diazabicyclo[4.3.0]nonane and 0.34 g (3 mmol) of l,4-diazabicyclo[2.2.2]octane in 3.5 mil of dimethy. suiphoxide. The solvent is then removed in a high vacuum. After stirring the residue with acetonitrile, 0.22 g of 1-cyclopropyl-6-fluoro-l,4-dihydro-5methyl-7- (5-methyl-3-oxo-5, 8-diazabicyclo [4 non-8yl)-4-oxo-3-quinolinecarboxylic acid are obtained.

Melting point: 208-10* with decomposition Example

CH

3 0

COOH

0.28 g (1 mnmol) of 1-cyclopropyl-6,7-difluoro- 1, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid are heated at 1400 for 2 hours with 0.17 g (1.5 nimol) of 1,4diazabicyclo[ 3.2.l 1]octane and 0.34 g (3 mnmol) of 1,4diazabicyclo[ 2.2.2 ]octane in 3.5 ml of dimethyl suiphoxide. After removing the solvent in a high vacuum, the residue is stirred with acetonitrile and the solid is isolated.

Yield: 0.24 g of 1-cyclopropyl-7-(1,4-diazabicyclo- 13.2. 1)oct-4-yl) -6-f luoro-l, 4-cxo-3-quinolinecarboxylic acid Melting point: 274-76* with decomposition Le A.2 757 Example B

CH

3 0 I COOH

FF

6, 7-Difluoro-l- 4-difluoro-phenyl) xethyl-4-oxo-3-quinolonecarboxylic acid a) 0* 0

OH

3 11 ~COOEt I C- C F I CH -NH F 00 0 F F 21 g of ethyl 3-ethoxy-2-(2,4,5-trifluoro-6rethyl-benzoyi)acrylate are initially introduced into ml of ethanol. 9.4 g of 2,4-difluoroaniline are added 0000 dropwise with cooling. The mixture is then stirred at 25 0 C for one hour. 55 ml of water are then added and the A solid which precipitates is isolated.

e~gYield: 25 g of ethyl 3- (2,4-difluorophenylamino)-2-(2,4,5trifluoro-6-methyl-benzoyl )-acrylate Melting point 109-10 0

C.

SoC Le A 26 756 73

CR

3 0 F~-c 0 Et 12.5 g.of substance from a) and 5.1 g of potassium carbonate are heated at 140 0 C for 4 hours in 60 ml VO of dimethylfornaiide. After cooling to room temperature, F) the mixture is diluted with water. The solid which precipitates is isolated and dried.

0 Yield: 11.3 g of ethyl 6,7-difluoro-l-(2,4-difluoro- .00. :phenyl) 4-dihydro-5-methyl-4-oxo-3-qvinoline- *6 carboxylate **Ole Melting point: 157-9* C)

OH

3 0 11.2~ g fsbtneI rmb,7 m faei acid 70 l o watr ad 3. mCof upuicaiRr 0 00 hetda240Cfr4hur.Atrcoln oro is islt1.2 did1. g of substacetlro bcom7omuno ae Le A 26 756 74 obtained. Melting point: 277-8*C Example 6

CH

3 0 1 11

CN

H

0.6 g of substance from Example B, 0.57 g of 1,4diazabicyclo[2.2.2 ]-octane and 0.25 g of 2,8-diazabicyclo[4.3.0]-nonar-tare stirred at room temperature in 6 ml of dimethyl sulphox- 1 Je until starting material is no longer detectable 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 cf 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-l- 4-difluorophenyl)-6-fluoro-l,4-dihydro-5-methyl-4-oxo- 3 -guinolinecarboxylic acid.

Melting point: 247-8*C.

00 Le A 2621_j 75

Claims (3)

1. Quinolonecarboxylic acid derivatives of the formula (I) R 3 0(I in which R represents straight-chain or branched C 1 -C 4 -alkyl which is optionally substituted by hydroxyl, halogen, Cl-C 3 -alkoxy or C 1 ,-C 3 -alkylthio, C3-CG-CYC'o- alkyl which is optionally substituted by-halogen or C-C 3 -alkyl, C,-C-alkenyl, and in addition C 1 -C 3 alkoxy, amino, monoalkylamino having 1-3 C atoms, dialkylanino having 2-6 C atoms or phenyl which is optionally substituted by halogen, R 2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1, 3-dioxol-4-yl )-methyl, R 3 denot .es Cl-C-alkyl, R4 represents a radical, which is optionally substi- tuted in the ring system by hydroxyl or methyl, of ri the formula nwih (CH 2 )j .E G3 E G E G N- in whc E represents R 5 -N or 0, G represents C8-CH- *.H2 j- 0*20-H Le A 26 75 76 -CH 2 -N-CH 2 represents 1 or 2, represents hydrogen, alkyl, alkenyl or alkinyl having 1 to 4 carbon atoms which is optionally substitutei by hydroxyl, benzyl which is optionally substituted by nitro or amino, oxoalkyl having 2 to 4 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)- methyl, represents hydrogen or methyl, in addition represents a radical of the formula xi KN-1CH 2 rn .4 a *a a. a a a. a a a a. a a. a a a a a. a. a a in which, P' represents 1 or m represents 1 or 2, 2 or 3, n represents 1 or 2, W represents N A7 c Le A26-75-6 2, where p m together can be r 0119 77 X1 represents OR, R 7 represents hydrogen, Cl-C 3 -alkyl, acetyl, allyl or' propargyl and R8 represents hydrogen, CI-C 3 -alkyl or C 3 -C 6 -CYCloalkyl, where R+ RO together can also represent the groups -CH 2 CH 2 -Q-CH 2 CH 2 or -(CH 2 in which k can represent 3, 4 or 5, and R 9 represents hydrogen, Cl-C 3 -alkyl or C,-C-acyl, R4 also denotes a radical of the structure R 1 12 -NR1 R 16 i13 R 16 in which R1 can represent H, Cl-C.-alkyl or C 1 -C..-acyl, R 1 2 can represent H, or C 1 C 3 -alkyl, where R1 and R12 together can also denote a Cl-C-alkylene ~bridge which is optionally substituted by methyl, R R 13 can represent Cl-C 3 alkyl or hydroxyalkyl, C 1 C4-alkoxycatrbony1 or C-C 4 cl C1 -a Y Le. A 6767 can represent H or CH 3 4 can represent H or CH 3 can represent H or CH 3 can represent 0, CH 2 CH 2 CH 2 or CH 2 O, where the linking of the CH 2 -0 group to the nitrogen can be both via 0 and via CH 2 1 can represent 0, represents hydrogen, halogen, methyl, or nitro, 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.

2. Compounds of the formula according to Claim 1, in which Ri represents ethyl, isopropyl, cyclopropyl, vinyl, t-butyl, 2-hydroxyethyl, 2-f luoroethyl, amino, methylamino, phenyl, 4-f luorophenyl or 2, 4-dif luoro- phenyl, *9 9 9 99 9 9

9. 9 99 9 9 9 9 9 99 99 9 9 9 9999 9. 9 9 99 *9 9 9 9999 9 9 9999 .99999 9 999999 f p b Le A 256 79 R 2 represents hydrogen, alkyl heiving 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yI)-methyl, R 3 represents Cl-C 3 -alkyl, R4 represents a substituted radical, which is option- ally substituted in the ring system by methyl, of the formula N-(CH 2 )I N-P E G E G E G N- in which E represents R 5 -N or 0, R 6 G represents -(CH 2 -CH 2 -Q-CH 2 or -CH 2 -N-CH 2 j represents 1. or 2, R 5 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, R4 in addition represents a radical of -the formula xi (CH 2 )P (H K"N-(CH 2 0 S. 0 0S Le A 6568 represents 1 or 2, where p mn together can be 2 or 3, represents 1 or 2, R 7 9 represents~ N or OR R8 represents OR C, represents hydrogen, Cl-C 2 -alkyl or acetyl, represents hydrogen or C,-C 2 -alkyl, where R+ Ra together also denote the groups -CH 2 CH 2 or -(CH2a)k-, in which k can represent 3, 4 or represents hydrogen, C,-C 2 -alkyl or acetyl, also represents a radical of the struct ure C C C. C C C CC C C C CC C C C C. C C CC., C CC C S C C CC.. C C *CCCCC C NJ Q <S ~NT C) ,R12 1R 1 3 R 16 I R 13 in which R1can represent H, Cl-C-alkyl or C 1 -C 2 -acyl, Le A 26756 81 R 12 can represent H or Cl- C 3 alkyl1, where 3,'1 and R 12 together can also denote a C-C 2 alkylene bridge which is optionally substituted by methyl, R 13 can represent H, C 1 -C 3 alkyl or hyc2roxyalkyl, CI-C 4 -alkoxycarbonyl or cC- acyl, R 15 an epreentH orCM2 R 15 can represent H or CM 3 R 6 can represent H or CM 3 Y can represent 0, CM 2 CHCH 2 or CH 2 where the linking of the '.CH 2 -0-group to the nitrogen can be both via 0 and via CM., Z represents 0, A represents H, fluorine, chlorine, methyl, or nitro. 3. Compounds of the formula according to Claim 1, in which Ri represents ethyl, vinyl, t-butyl, cyclopropyl, 2-hydroxyethyl, 2-.fluoroethyl, methylamino, 4-f luorophenyl or 2, 4-dif luorophenyl, R represents hydrogen or alkyl having 1 to 2 carbon **atoms, R 3 represents Cl-C 3 -alkyl, R represents a radical, which is optionally substi- *9 99 9 9 flee 44 49 69 9* 9 9 I 9*99 9 9 .9.9 4944*I 4 Le A 26 756 82 tuted in the ring system by methyl, of the formula N-(CH 2 )j E G E G E G N- in which E represents Rs 5 N G represents -(CH 2 j represents 1 or 2, R 5 represents hydrogen, alkyl, alkenyl 'or alkinyl having 1 to 3 carbon atoms and optionally substi- tuted by hydroxyl, benzy. which is optionally substituted by nitro or amino, or oxoalkyl. having 2 to 4 carbon atoms and R 6 represents hydrogen or methyl, R in addition represents a radical of the form~ula xi (H2p 4 4CH 2 )n-W V4K N(H: o: Vooin which P represents 1 or 2, m represents 1 or 2, where m together can be 2 lime kor 3, a9 0* I S V '.6 fee# too*.: **se Ar 2 568 n represents 1, w represents N> or Or X1 represents. OR, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, where R 7+ R8 together can also denote the groups -CH 2 CH 2 O-CH 2 CH2- or in which k can represent 3, 4 or 5, and R9 represents hydrogen, Cl-C 3 -alkyl or Cl-C 3 -acyl, R 4 also denotes a radical of the structure 12 P 1 R 1 3 S.. S S S S 1 3 in wh ich R1can represent H, C 1 -C 2 -alkyl. or acetyl, R 1 2 can represent H or C,-C 2 -alkyl,, where R' 1 and R 1 2 together can also denote a Cl-C-alkylene bridge which is optionally substituted by methyl, R 1 3 can represent H, Cl-C 2 -alkyl, hydroxyethyl, Cl-C-alkoxycarbonyl or Cl-C 2 -acyl, 26 756- 84 f 4 Le A rw R 15 can represent H or CH, R 1 6 can represent H or CH 3 R 1 7 can represent H or CH 3 Y can represent 0, CH 2 CH 2 CH 2 or CH 2 where the linking of the CH 2 -O-groups to the nitrogen can be both via 0 and via CH 2 Z can represent 0, A represents H, fluorine or chlorine. 4. Process for the preparation of compounds of the formula according to Claim 1, characterized in that. compounds of the formula (II) R3 O oo (II) F 2vi~s^ ^OORZ I I A Ri in which R 1 R 2 R 3 and A have the meaning indicated in Claim 1 and X' represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) R-H (III) in which R' has the meaning indicated in Claim 1, LJ' e A 26 756 *T 0355s:AB 86 if appropriate in the presence of acid scavengers and if appropriate protective groups contained in R 4 are removed. A medicament, containing at least one compound according to Claim 1, together with a non-toxic, inert pharmaceutically acceptable excipient. 6. A method for the prophylaxis and chemotherapy of local and systemic infections or diseases produced, in humans and animals, by gram-negative and gram-positive bacteria and bacteria-like microorganisms, wherein there is administered, to a human or animal in need of such prophylactic and chemotherapeutic treatment, at least one compound according to claim 1. 7. 7-Chloro-l-cyclopropyl-6,8-difluoro-1,4-dihydro-5- methyl-4-oxo-3-quinolinecarboxylic acid. DATED this llth day of March, 1993. BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE a* 0