AU658901B2 - 8-vinyl- and 8-ethinyl-quinolone-carboxylic acids - Google Patents

Abstract

The invention relates to novel 8-vinyl- and 8-ethynyl- quinolonecarboxylic acids, a process for their preparation and antibacterial agents and feed additives containing them.

Description

Our Ref: 432807 P/00/011 Regulation 3:2 65801

AUSTRALIA

Patents Act 1990

ORIGINAL.

COMPLETE SPECIFICATION STANDARD PATENT

S

S

C C

C

C

C.

C. he Applicant(s): Bayer Aktiengesellschaft D-5090 Leverkusen Bayerwerk

GERMANY

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 .61 Address for Service: Invention Title: 8-Vinyl- and 8-ethinyl--quinolone-carboxylic acids The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 The invention relates to new 8-vinyl- and 8-ethinylquinolonecarboxylic acids, processes for their preparation, and antibacterial agents and feed additives containing them.

It has already been disclosed that 8-alkyl-quinolonecarboxylic acids have antibacterial activity: 8-methylquinolonecarboxylic acids were described, for example, in EP 237,955 and JP 2,019,377, and 8-trifluoromethylquinolonecarboxylic acids were described in US 4,780,468, US 4,803,205 and 4,933,335.

It has now been found that the formula (I) new compounds of the

COO-R

2 o in which R' represents straight-chain or branched Ci-C 4 -alkyl which is optionally substituted by hydroxyl, halogen or C.-C 3 -alkoxy, or represents optionally halogen- or Le A 28 391 i

C-C

3 -alkyl-substituted C 3

-C

6 -CYCloalkyl, C 2

-C

4 -alkenyl, furthermore represents Cl-C 3 -alkoxy, amino, monoalkylamino, having 1 to 3 C atoms, dialkylamino having 2 to 6 C atoms, or phenyl which is optionally monosubstituted to trisubstituted by halogen, R 2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1, 3-dioxol-4-yl) -methyl,

X

1 represents hydrogen, fluorine, chlorine, amino or methyl, A_ 10 X 2 represents -C=CH-R 3

-C=EC-R

5 or -CH 2

-CH=CH

2 1 where R R represents hydrogen, Cl-C 3 -alkyl Cl-C 3 -alkoxy 15 or alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, R4 represents hydrogen or halogen and

R

5 represents hydrogen, Cl-C 6 -alkyl which is optionally monosubstituted to trisubstituted by halogen, or C 2

-C

3 -alkenyl, alkoxy having 1 to 3 C atoms, alko*ymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and Y represents Le A 28 391-2 2

R

9 Rio RL NRL N3N ,r RL NIN

R

7

R

8 N~JVN

RN-

N

R 1 3

R

1 4

H

2

C

R 12 R1 6 R'?L 0 N CH R17 (CHtQN R8

I

N

R 14 f

N

A

Rk- NJCN

R

19

R

9

II

I

I

*1II

I

Rs- NI

N

R1 6

R

9 t- l

IR

20 rv \N N

N-,

Le A28 391 3.where

R

6 represents hydrogen, optionally hydroxyl- or methoxy-substituted straight-chain or branched C,-C 4 alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having 1 to 3 C atoms,

R

7 represents hydrogen, methyl, phenyl, thienyl or pyridyl,

R

8 represents hydrogen or methyl, rie R 9 represents hydrogen or methyl, 10 R 10 represents hydrogen or methyl, R9

R

1 represents hydrogen, methyl or .CH2-N NR'o

R

12 represents hydrogen, methyl, amino, optionally .A hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, aminomethyl, 15 aminoet' yl, optionally hydroxyl-substituted alkylor dialkylaminomethyl having 1 or 2 C atoms in the alkyl moiety or 1-imidazolyl, Lw I, F' 9- 4

R

1 3 represents hydrogen, hydroxyl, methoxy, methylthio or halogen, methyl or hydroxymethyl, R1 4 represents hydrogen or methyl, R's represents hydrogen, methyl or ethyl, R 16 represents hydrogen, methyl or ethyl,

R

17 represents hydrogen, methyl or ethyl,

S

S.

S. 10 .9 Set...

R18 represents hydroxyl, N 7 R1 Or CIH-N \R1 R3, 9 represents hydrogen, optionally hydroxyl -substituted Cl-C 3 -alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or C-C 3 -acyl,

R

20 represents hydrogen, hydroxyl, R2 Le A 28 391-5 5

RI

9 hydroxymethyl or CHy where \R21

R

21 denotes hydrogen or methyl, A represents CH 2 0 or a direct bond and n represents 1 or 2, a4a 5 and their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts of the carbcxylic acids on which they are basc-', have a powerful antibacterial action.

10 They are therefore suitable as active compounds for human and -eterinary medicine, veterinary medicine also including the treatment of fish for the therapy or prophylaxis of bacterial infections.

Preferred compounds of the formula are those *t4..

in which

R

1 represents optionally hydroxyl-substituted Ci-C2alkyl, C 3

-C

5 -cyloalkyl, vinyl, amino, monoalkylamino Le A 28 391 6 having 1 to 2 C atoms, dialkylanino having 2 to 4 C atoms, or phenyl which is optionally monosubstituted or disubstituted by halogen, R 2 represents hydrogen, alkyl having 1 to 3 carbon atoms (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl, X3. represents hydrogen, fluorine, chlorine, amino or methyl,

X

2 represents -C=CH-R 3

-C=C-R

5 or -CH 2

-CHCH

2 where

W

3 represents hydrogen, Cl-C 2 -alkyl, methoxy or taethoxymethyl, R 4 vpresents hydrogen and R 5 represents hydrogen, Cl-C 4 -alkyl which is optionally monosubstituted to trisubstituted by 15 fluorine, or C 2

-C

3 -alkenyl, methoxy or trimethylsilyl, and Y represents Le A 28 391-- 7 NI N- R1 6 RIL o /NCHAi

N

(CH CN

R

8 3

R

8 0N

R

8

N

CNAZCN R8 R1 3

R

8 RL NJICN 9 9 9 j*99 9* 9 911*99* *9 9 S. .4 0949 9 %s NQCIN or where R 6 represents hydrogen,, optiona.lly hydroxyl-substituted straight-chain or branched Cl-C 3 -alkyl or oxoalkyl having 1. to 4 C atoms, Le A 28 391- 8

R

7 represents hydrogen, methyl or phenyl, R" represents hydrogen or methyl,

R

9 represents hydrogen or methyl,

R

1 represents hydrogen, methyl or -CH 2

-NH

2

R

12 represents hydrogen, methyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl or ethyl aminomethyl,

R

13 represents hydrogen, hydroxyl, methoxy, fluorine, methyl or hydroxymethyl,

R

15 represents hydrogen or methyl,

R

16 represents hydrogen or methyl,

R

17 represents hydrogen or methyl, *to

C..

C

Cr

C

R

18 represents

R

16 RI6 or CH2-N RI7

R

19 represents hydrogen, methyl or ethyl, Le A 28 391 9

R

2 0 represents

N

R21 where

R

21 denotes hydrogen or methyl, a A represents CH 2 0 or a direct bond and n represents 1 or 2.

Particularly preferred compounds of the fo:mula are those in which

R

1 represents methyl, .ethyl, cyclopropyl or phenyl 10 which is optionally monosubstituted or disubstituted S*Sg by fluorine,

R

2 represents hydrogen, methyl or ethyl,

X

1 represents hydrogen, fluorine, chlorine, amino or methyl,

X

2 represents -CH=CH 2 or -C=C-R Le A 28 391 10 where

R

5 denotes hydrogen, C.-C 4 -alkylI C 2

-C

3 -alkenyl or trimethylsilyl and Y represents 4* a. a 0eO* 0@*O 4 4* 4 a

R

4 N N-,

R

16

R

1 H2 N R1 8 (CHN R1 9 R8- N7N 0 N

$R

8

NN

R1 2 R1 3 4* a 4~

S

a RL N rN or N where L e A 2_8 391 11

R

6 represents hydrogen, methyl, optionally hydroxylsubstituted ethyl,

R

7 represents hydrogen or methyl,

R

8 represents hydrogen or methyl,

R

9 represents hydrogen or methyl,

R

11 represents hydrogen or -CH 2

-NH

2

R

12 represents hydrogen, methyl, amino, methylamino, aminomethyl or ethylaminomethyl,

R

13 represents hydrogen, hydroxyl or methoxy, 10 R represents hydrogen or methyl,

R

16 represents hydrogen or methyl,

R

16 represents hydrogen or methyl, *R represents

R

19 represents hydrogen or methyl, Le A 28 391 12

WO

0 represents R9 ~R21 *5 Sb *0 0000 0I 0* 0 0 *0 0*

S.

*0*e a.

*0 4**e 0 0000~0 where

R

2 1 denotes hydrogen or methyl, A represents CH 2 0 or a direct bond and n represents 1.

Furthezcxncre, it has been found that the compounds of the formula are obtained when a compound of the formula

(II)

X1 F COO-R 2 in which L9 A 28 391 13 R 2 X1 and X 2 have the abovementioned meaning and x 3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula (III)

Y-H

(III)

iJn which

OS

0 *0@S 0* 0~ 0 0**0 00 S

S

*5 0* 50 S. S 6**S

S

*4V*SV Y has the abovementioned meaning, if appropriate in the presence of acid scavengers.

If, for example, l-cyclopropyl-.8-ethinyl-6,7-difluoro- 10 1,,4-dihydro-4-oDxo-3-quinolinecarboxylic acid and 1methylpiperazi e are used as starting compounds, the course of the reaction can be represented by the following equation: 0 F COCH 1+ F N

C

COOH

FIN N-CH 3

CH

3 The 8-(l-chlorovinyl)-qnpinolo~necarboxylic acids are also Le 16 2 8 3 91 14 obtained by reacting the 8-ethinyl-quinolonecarboxylic acids with hydrochloric acid at temperatures from 10"C to 100°C, preferably 20'C to The compounds of the formula (II) which are used as starting compounds are new. They can be prepared by reacting quinolinecarboxylic acid derivatives of the formula (1'V) X1 O F

COO-R

2

'N

X

3

X

4

R

in which 10 R R 2

X

1 and X 3 have the abovementioned meaning and *a c r o c r

X

4 represents halogen, chlorine, with organometal vinyl formula (V) in particular iodine, bromine or or alkinyl compounds of the

M-X

2

(V)

in which Le A 28 391 15

X

2 has the abovementioned meaning and M represents SnR' 3 ZnX', B(OR") 2 where R' denotes Ci-C 4 -alkyl, R" denotes hydrogen or Ci-C 4 -alkyl and X' denotes bromine or chlorine, in the presence of transition metal catalysts and eliminating any protective groups which may be present.

The organometal vinyl and alkinyl compounds which are required for the coupling reaction are either known or can be synthesised by methods known from the literature.

For example, vinyl-trialkyltin compounds can be prepared *too.

from the corresponding vinyl iodides, vinyl bromides or vinyl chlorides by obtaining the vinyl-Grignard compounds 15 by reaction with magnesium and reacting these compounds with a trialkyltin chloride to give the desired vinyltin derivatives.

Organometal alkinyl compounds can be prepared in a known manner, for example by metallating the 1-alkine with n- 20 butyllithium, sec-butyllithium or tert.-butyllithium at temperatures between -20 and -78°C in an aprotic solvent such as, for example, tetrahydrofuran, followed by reaction with a halometal compound such as, for example, zinc chloride, magnesium bromide, copper iodide or Te A 28 391 16 trialkyltin chloride. The reaction at -78 0 C is preferred.

Other possible solvents, apart from the preferred solvent tetrahydrofuran, are other ethers such as diethyl ether, dipropyl ether or tert.-butyl methyl ether, or mixtures of such ethers with aprotic, aliphatic or aromatic solvents such as n-hexane or toluene. The zinc chloride and trialkyltin derivatives are preferred with both the vinyl and the alkinyl derivatives. "Alkyl" in the trialkyltin compounds is understood as meaning Ci- to C 6 alkyl; methyl and n-butyl are preferred.

r. Trialkylvinyltin compounds can also be obtained by 9 methods known from the literature, by hydrostannylation of alkines with trialkyltin hydrides in the presence of transition metal catalysts Org. Chem. 55 (1990) 1857- 1867).

The organometal vinyl and alkinyl compounds are reacted with 8-halogenoquinolonecarboxylic acid derivatives of the general formula (IV) by processes known in principle in the presence of a suitable catalyst. In this context, 20 "halogen" represents iodine, bromine or chlorine; bromine and chlorine being preferred, bromine being particularly preferred.

.0 Examples of suitable catalysts are transition metal compounds of the metals cobalt, ruthenium, rhodium, iridium, nickel, palladium or platinum. Compounds of the metals platinum, palladium and nickel are preferred, and palladium is particularly preferred. Such transition Le A 28 391 17 metals can be employed in the form of their salts such as, for example, in the form of NiC1 2 PdCl 2 or Pd(OAc),, or in the form of complexes with suitable ligands. The use of complexes is preferred. Ligands which are preferred are phosphines such as, for example, triphenylphosphine, tri(o-tolyl)phosphine, trimethylphosphine, tributylphosphine and tri(2-furyl)phosphine, triphenylphospiine being preferred. Preferred complex catalysts which may be mentioned are bis(triphenylphosphine)nickel- (II) chloride, bis(triphenylphosphine)palladium(II) chloride, tris(triphenylphosphine)palladium(0) and tetrakis(triphenylphosphine)palladium(0).

The complex catalysts are employed in amounts of 0.1 to 20 mol relative to the 8-halogeno-quinolonecarboxy- 15 lates employed; amounts ot 0.5 to 10 mol are preferred, and amounts of 1 to 5 mol are very particularly preferred.

The coupling reactions are carried out in suitable inert solvents such as, for example, benzene, toluene, xylene, 20 dimethylformamide, dimethylacetamide, dimethoxyethane or mixtures of such solvents; dimethylformamide and toluene are preferred. Before use, the solvents are dried and freed from air by known processes.

The coupling reactions are carried out at temperatures 25 between 20 and 200*C; temperatures between 50 and 180"C are preferred.

Le A 28 391 18 The duration of the reaction depends on the reactivity of the educts and is generally between 2 and 40 hours; reaction times between 4 and 24 hours are preferred.

The reactions are carried out under a protective gas 1 atmosphere. Suitable protective gases are inert gases such as, for example, helium, argon or nitrogen; nitrogen is preferred. The coupling reaction is generally carried out under atmospheric pressure. However, it is also possible, of course, to carry out the reaction under reduced or increased pressure.

Most of the amines of the formula (III) which are used as starting compounds are known. Chiral amines can be employed in the form of racemates as well as in the form of pure enantiomeric or pure diastereomeric compounds.

15 Examples which may be mentioned are: piperazine, 1-methylpiperazine, 1-ethylpiperazine, 1-(2-hydroxyethyl)-piperazine, 20 3-methylpiperazine, cis-2,6-dimathyl-piperazine, cis-2,3-dimethyl-piperazine, 1,2-dimethylpiperazine, 4 1-cyclopropyl-piperazine, 25 2-phenyl-piperazine, 2-(4-pyridyl)-piperazine, 2-(2t.hienyl)-piperazine, 1,4-diazabicyclo[3.2.1]octane, Le A 28 391 19 8-mothyl1-3, 8-diazabicyclo[ 3.2. 1] octane dihydirochloride, 3-methiyl-3, 8-diazabicyclo[3 1]octane dihydrochioride, 2, 5-diazabicyclo[2 1]heptane dihydrochioride, 2'-rnthyl-2 ,5-diazabicyclo(2 .2.11.heptane dijhydrochioride, 2 ,5-diazabicyclo[2 .2 .2Joctane dihydrochioride, 2.-m~ethyl-2, S-diazabicyclo[2 .2 .2]occane dihydrochioride, l,4-.diazabicyclo[3.1. 1]heptane, morphoiline, 2, 6-dimethyrl--morpholine, 2-aminomethy.1-morpholine, 2-tert butoxycarbonylamr,-kmethy-morphol~neI 2 -methylaminomethy'1-morphol.ine, VS 2 -dimethylamiinomethy1 -morpho line, ijridazole, 4-methyl-.tmidazole, 1 pyrrole, 0 3-aiuino~ethyl-2,5-dihydr )-pyrroleI 3-aminorethyl-4-methyl-2 3- -aminoethyl) 3-aiino-azetidine, 3-tert. -butoxycarbonylamino- azetidine, 3-tert. -butoxycarbony' amiipo-2-r,',thyl-azetidine, 3-et btxcabnlaio rity ze d e 3-tert. -butoxycarboniylmino-3-ithyl-azetidne, 3-et*btoyabiylmnmtylaeiie pyrrolid.4ne, 3 -mat-.hy1pyrrolidalne, 3-6mino-pyrrolidine, 3-tert -buto xyc ,r-oa~y 1,amino -pyrr'o 1,idine, (22 2-di imethyl -propyl ideneamino) ,-pyrro lL dine, 3-methylamrino-pyrro1lidine, Le A 28 391 20 3-dimethylamino-pyrrolidine, 3 -aminome~thy1-pyrro1 idine, 3-tert butoxycarbonylaninomethyl-pyrrolidine, 4-chloro-.3-tert. -butoxycarbonylaniinomethyl-pyrrolidine, 3-tert butoxycarbonylamninomethyl-3-methyl-pyrrolidine, 3-tert. -butoxycarbonylamino-4-methyl-pyrrolidine, 3-tert. -butoxycarbonylaminomethyl ,-3-methoxy-pyrrolidine, 3-methylaminomethyl-pyrrolidine, 3-ethylaniinomethy1-pyrrolidine, 4-tert. -butoxycarbonylam'ino-2-methyl-pyrrolidine, 2-methyl-3-methylainino-pyrrolidine, 2 -methyl-4-methylamino-pyrrolidine, 3- (2-hydroxyethylanino) -pyrrolidine, 3-yroypyrliie 3-hydroxymy-pyrrolidine, 4-,axuino-3-hydroxy-pyrrolidile, "A.hydroxy-4 -methylamino-pyrrolidine, $3-tert. -but;oxycarbonylaznino-4-methoxy-pyrrol.LdineI 3,*Tinthyaninomethy 3 -hyda, oxy-pyrrol idine 20 3-dixliethylaminomethyl-3-hydroxy-pyrrolidile, ~3.'diethylaininomethyl-3-hydrox&y-pyrrolidilC, 3-tert. -butylaminomethyl-3'-hydroxy-pyrrolidine, 3-rethylamino-4 -hydroxymethyl-pyrrolidine, 4 -methoxy- 3-melthylamino-pyrrolidine, 3-methoxy-3-methylaminomethyl-pyrrolidile, 3-amino-4-methoxy-2-methyl-pyrrolidile, 4 h 3-tert butoxycar ,onylamino-3-methyl-pyrroidile, 3 -methyN4 -tert -butoxyc arbonylaminomethyl-pyrrolidile, 3-methoxy-4-tert. ,,butoxyt.arbonyaiinomethyl-pyrrolidile, 3-.(-imidazo,'-y1)-pyrrolidine, Le A 28 391 21 6-hydroxy-3-azabicyclot 3.3. 0]octane, 6-axnino-3-azabicyclo[ 3.3.0] octane, I-aiio-3-azabicyclo octane, 1-aiinomethyl-3-azabicyclo octane, 1-ethylaminomethyl-3-azabicyclo[3.3.0 ]octane, 6-axnino-3-azabicyclo [4.3.0 ]nonanie, 3-amino-4-methylene-pyrrolidine, 7-amino-5-azaspiro[2 .4]heptane, 3,7-diazabicyclo[3 3-methyl-3,7-diazabicyclo[3 .0]octane, 2,8-diazabicyclo[4 .3 .0]nonane, 2-methyl-2 ,8-diazabicyclo [4 .3.0 jnonane, 3-methyl-3, 8-diazabicyclo[4 0]nonane, 2-oxa-5,8-diazabicyclo[4.3.0]naonane, 155-methyl-2-oxa-5,8-diazabicyc~o[4 2,7-diazabicyclo[3 2-methyl-2,7-diazabicyclo[3.3,,0]octane, 3-methyl-2, 7-diazabicyclo octane, 4-methyl-2, 7-diazabicyclo[3.3. 0]octane, tert.-butyl 5-methyl-2,7-diazabicyclo[3.3.0]octane, 7-methy'1-2, 7-diazabicyclo[3 .3.0 ]octane, 8-methyl-2. 7-diazabicyclo[3.3. 0]octane, 7, 8-dimethyl-2, 7-diazabicyvlo[ 3.3.0 Joctane, 2, 3-dimethyl-2 ,7-diazabicyclo octane, 2,8-dimnethyl-2,7-diazabicyclo[3.3.0]octane, 1,4-diazatricyclo[6.2 .0.0 2 6 )decane, 1,4-ciiazatricyclo[6.3 .0.0 2 6 ]undecane, 2,7-diazaspiro[4 .4]nonane, 2-methyl-2, 7-diazaspiro[4 .4 ]nonane, 4-amino-1,3,3a,4,7,7a-hexahydroisoindole, Le A 28 391 22 4-methylamino-1, 3, 3a, 4,7, 7a-hexahyvdroisoindole, 5-methyl-4-methylamino-1, 3, 3a, 4,7, 7a-hexahydroisoindole, 6-methyl-4-methylamino-1, 3,Za, 4,7, 7a-hexahyc ,roisoindole, 7-methyl-4-methylamino-1, 3, 3a,4,7 ,7a-hexahydroisoindole, 7a-methyl-4-methylamino-1, 3, 3a, 4,7 ,7a-hexahydroisoindole, 6, 7-dimethyl-4-methylamino-1, 3, 3a, 4,7, 7a-hexahydroisoindole, 4-dimethylamino-1, 3, 3a, 4,7, 7a-hexahydroisoindole, 4-ethylamino-1, 3,3a, 4,7, 7a-hexahy~iroisoindole, 4-aniinomethyl-1, 3, 3a,4,7 ,7a-hexahydroisoindole, 4-methylaminomethyl-1, 3, 3a, 4,7, 7a-hexahydroisoindole, 4-hydroxy-1, 3, 3a, 4,7, 7a-hexahydroisrindole, V ~2,3,4,.5,6,7-hexahydro-lH-pyrrolo[3,4-c]pyridine,

S

5-methyl-2 7-hexahydro-1H-pyrrolo[3,4-c]pyridine, 5-ethyl-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-c]pyridine, 5-(tert.-butoxycarbonyl)-2,3,4,5,6,7-hexahydro-1Hpyrrolo [3,4-c Jpyridine.

Most of the substituted 1,3,3a,4,7,7a-hexahydro-isoindoles ar~e new. For example, they can be obtained by Diels-Alder reaction of dienes of the fc~rmula (1)

R

22

R

9 where R 9 has the abovementioned meaning and R 1 2 is either Le A 28 391 23 identical to R 20 or is a functional group which can be converted into R 20 with dienophiles of the formula (2) 0 RN -R 23

O

in which R 23 denotes hydrogen or a protective group such as trimethylsilyl, benzyl, Ci-C 4 -alkylphenylmethyl, methoxybenzyl or benzylhydryl, followed by reduction of the carbonyl groups and, if appropriate, elimination of the protective group.

Suitable diluents for the Diels-Alder reaction are all 10 inert organic solvents. These preferably include ethers, such as diisopropyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and anisole, hydrocarbons such .as, for example, hexane, methylcyclohexane, toluene, xylene and mesitylene, and halogenated hydrocarbons such as, for example, chloroform, 1,2-dichloroethane and chlorobenzene. However, the Diels-Alder reaction can also be carried out without a solvent.

The reaction temperatures can be varied within a substantial range. In general, the process is carried out between approximately -20C and +200"C, preferably between -20 0 C and +150 0 C. The Diels-Alder reaction is usually carried out under atmospheric pressure. However, Le A 28 391 24 pressures of up to 1.5 GPa can also be used for accelerating the reaction.

Reduction of the carbonyl groups can be brought about using complex hydrides. Examples of hydrides which can be employed are lithium aluminium hydride, lithium borohydrides, lithium triethylborohydride, sodium-bis-[2methoxyethoxy]-aluminium hydride or sodium borohydride in the presence of Lewis acid catalysts such as chlorotrimethylsilane, boron trifluoride etherate or aluminium chloride.

Diluents which can be used are ethers such as, for example, diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, and hydrocarbons such as, for example, hexane, methylcyclohexane and toluene, and also mixtures 15 of these.

The reaction temperatures can be varied in the range between -40 and +180oC, preferably between 0" and 140*C.

The reduction is generally carried out under atmospheric pressure, but it can also be carried out under reduced pressure or under superatmospheric pressure.

The use of pressures between 100 and 1000 kPa is recommended so as to achieve higher reaction temperatures with low-boiling solvents.

The amount of complex hydrides employed in the reduction is at least stoichiometric. However, an excess of Le A 28 391 25 preferably between 30 and 300% is generally employed.

The elimination of a protective group which may be present is effected by the generally known methods of protective group chemistry for example, T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley Sons, New York 1981).

The starting substances of the formula and are known or can be prepared by generally known methods of organic chemistry for example, J. Am. Chem. Soc.

S 10 100, 5179 (1978), J. Org. Chem. 43, 2164 (1978), DE 3,927,115, J. Org. Chem. 40, 24 (1975)].

If, for example, l-(tert.-butyloxycarbonylamino)-1,3butadiene and maleimide are used as starting materials and lithium aluminium hydride as reducing agent, the course of the reaction can be represented by the following equation: 0* Q 0 NH NH LiAIH HN C C(CH3)3 I 0 HN- C C(CH 3 3 jNH

O

N CII NHCH3 Le A 28 391 26 In a preferred embodiment of the preparation process, all stages can be carried out without isolation of the intermediates if a suitable solvent such as, for example, tetrahydrofuran, is used. If, for example, l-(tert.butyloxycarbonylamino)-l,3-pentadiene and N-trimethylsilyl-maleimide are used as starting materials, the courz of the reaction can be represented by the following equation:

CH

3 O

CH

3

THF

N-SiMe 3 T b. j NH 1 2.LiA1H4 HN C-0 C(CH 3 3

II

HNCH3 10 In this case, NMR spectroscopy demonstrates that all substituents on the 6-membered ring are in the ci(j- 4 position relative to each other.

The reaction of (II) with (III), in which the compounds (III) can also be employed in the form of their salts S 15 such as, for example, the hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulpholane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine.

Mixtures of these diluents can also be used.

Le A 28 391 27 Acid binders which can be used are all customary inorganic and organic acid-binding agents. These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. The following substances which may be mentioned individually are particularly suitable: triethylamine, 1,4-diazabicyclo[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 substantial range. In general, the process is carried out at between approximately 20 and 200"C, preferably between a and 180°C.

The reaction can be carried out under atmospheric pressure, but also under increased pressure. In general, the pressures used are between approximately 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 S(III) are employed per mole of the compound (II).

20 Free amino groups can be protected during the reaction by a suitable amino protective group, for example by the tert.-butoxycarbonyl radical, and set free by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid, when the reaction has ended (see Houten-Weyl, Methoden der Organischen Chemie [Methods in Organic Chemistry], Volume E4, page 144 (1983); Le A 28 391 28 J.F.W. McOmie, Protective Groups in Organic Chemistry (1973), page 43).

The esters according to the invention are obtained by reaction of an alkali metal salt of the carboxylic acid on which they are based which, if appropriate, can be protected on 'he N atom by a protective group such as the .tert.-butoxycarbonyl radical, with suitable halogenoalkyl derivatives in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea, at temperatures of approximately 0 to 100"C, preferably 0 to 50 0

C.

The acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving the betaine in a iufficient amount 15 of aqueous acid and precipitating the salt with an organic solvent, which is miscible with water, such as methanol, ethanol, acetone or acetonitrile. It is also possible to heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether 20 and subsequently to evaporate the mixture to dryness or filter off the precipitated salt with suction. Pharmafes ceutically acceptable salts are, for example, the salts o"o of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

Le A 28 391 29 The alkali metal salts or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in a substoichiometric amount of alkali metal hydroxide solution or alkaline earth metal hydroxide solution, filtering off the undissolved betaine, and evaporating the filtrate to dryness. Pharmaceutically acceptable salts are sodium salts, potassium salts or calcium salts.

The corresponding silver salts are obtained by reacting 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 i;i* examples, the active compounds listed in the table below can also be prepared, it being possible for these optionally chiral compounds to be present both as diastereomer mixtures or as the diastereomerically or enantiomerically pure compounds.

0..

OC

Le A 28 391 30

,COOR

2

X

2

R'

X

2

R

2

X

S.

a ae a a H H HC-=C- H H a. a H H H

H

H H

HC-=C-

HC=5C-

HC-=C-

HC-=C-

HC=EC-

y RN N

CR

3 RN N-

CR

3 HN N-

CH

3 RN N-

CAH

RNlN 0 N

CH

2

-NH-CR

3 H H H H LeA 283 9 1, -31 Ri R2 x 1 H H HC-=C-

HC-=C-

H-

S.

S

S*

S S S S S. H H H Ti H H

S

Se

S.

S S S. S H H

HCE=C-

HC-=C-

HC=-C-

HC-=C-

HC-=C-

N

H

2

N-CH

2

(N-

H

2

N-CH

2

H

2

N

CH

3

H

2

N

CH

3

O

H

2

N-CH

2

HO

HN -2N-

N

H

H H H H H H H H HCmC- Le A 28 391 32 vo 0 op *Goo* ,00O* H H H H H H CAH H H F S. C S S 0* S. O~ 0 *5 9* 9 .4 9.9.

*05S

HC-=C-

HC=-C-

HC-=C-

HC-=C-

HC-=C-

HC=-C-

-C=ECH

-C-=CH

-C=-CH

-C=-C-CH

3

HN

NH

2 N

NH

2

OCN-

NH-CH

3

NH-CR

3

NH-

NH-CR

3

N-

I N- HN N H NH 2 CAH H H F\/QH l'

F

H

H

F

F\ H

HH

F

Le A 28 391 33 H H H H F-CmC-

F-C=EC-

CH

3 -N N-

CH

3 -N4-C 2 J

NH-CH

3

CH

3 -N a.

a .a*a a a 0e a a H H

HIIA

CH

3

O-C=C-

good 00a.

H H

H

2 N rNJ

CH

3 -N N H H H H H H

CF

2 -C=C

CF

3

C

2

H

5

NHCH

2

-K

,-H:5-CH 2 C8 3 -N N

NH

2 H H

CH

3 q-CoH 2

-CMC-

Le A U 391 -3 34 H H CHI=CH- HN N-

COH

3

S

S

S.

S.

See.

S S

S

1 H H H H H H H H H H H H H H 14f H

CH

2

=CH-

CH

2

=CH-

CH

3 O-CH=CH- CHi

CH

3 O-C~i-=CH-

CH

3

O-CH

2

-CH=CH-

CH

3

O-CH

2

-CH=CH-

CH

2

=CH-CH

2

CH

2 =CH-CH 2

H

NH

2 N N-

N

3

N-

H

2

N-<J

CH

3 -N

CH

3 -N N

CH

3

OK

Le A 28 391 35 The compounds according to the invention are powerful antibiotics and show a broad antibacterial spectrum against Gram-positive and Gram-negative pathogens, in particular against enterobacteria, while having a low toxicity; in particular, they also act against those which are resistant to a range of antibiotics such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides or tetracyclins.

These valuable properties allow them to be used as chemotherapeutic active comiounds in medicine as well as preservatives of inorganic and organic materials, in particular all types of organic materials such as polymers, lubricants, colours, fibres, leather, paper and wood, as well as foodstuffs, and water.

0*S* 15 The compounds according to the invention are active 0 towards a very broad range of microorganisms. With their aid, it is possible to combat Gram-negative and Grampositive bacteria and bacteria-like microorganisms, and

SS

to prevent, alleviate and/or cure the diseases caused by these pathogens.

The compounds accorc. ,to the invention are distinguished by an impro- ,tion on resting and resistant microorganisms. In t *ase of quiescent bacteria, that is bacteria which do not show any detectable growth, the compounds act in concentrations far below those of previously known substances. This relates not only to the amount to be employed, but also to the speed of Le A 28 391 36 destruction. Such results were found in the case of Grampositive and -negative bacteria, in particular in Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

Surprising improvements with regard to their action was also shown by the compounds according to the invention against bacteria which are classified as less sensitive to comparable substances, in particular resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.

By virtue of the powerful activity of the compounds according to the invention against bacteria and bacteria- .9 like microorganisms, they are particularly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine which are caused by these pathogens.

o. Furthermore, the compounds are suitable for combating protozoonoses and helminthoses.

oeae The compounds according to the invention can be used in a range of pharmaceutical preparations. Preferred pharma- S.ceutical 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.

The minimum inhibitory concentrations (MIC) were Le A 28 391 37 determined on Iso-Sensitest agar (Oxoid) using the serial dilution method. For each test substance, a series of agar plates was prepared which contained concentrations of the active compound which decreased as the dilution was doubled. The agar plates were inoculated using a multipoint inoculator (Denley). The inocula used were overnight cultures of the pathogens which had previously been diluted to such an extent that each inoculation point contained approx. 104 colony-forming units. The inoculated agar plates were incubated at 37"C, and growth of the pathogens was determined after approx. 20 hours.

The MIC value (ig/ml) indicates the lowest concentration of active compound where no growth was discernible to the naked eye.

15 The table below lists the MIC values of some of the *est: s compounds according to the invention compared with ciprofloxacin.

*.e ee pp p..

Le A 28 391 38 V~ T a b 1 e: 141C values Test strain: E x 5 am p 6 .1e f8 Ciprof loxacin B. coli Neumann 0.02 0.02 0.02 0.13 0.251 0.13 0.02 0.03 0.03 0.02 Micrococcus luteus 9341 0.5 0.25 1 2 0.25 8 1 0.5 2 Staphylococcus aureus ICH 25701 4 1 1 1 4 0.25 32 4 4 16 1756 0.13 0.03 0.06 0.06 0.13 0.06 0.02 0.13 0.06 0.25 133 0.13 0.13 0.06 0.06 0.13 0.06 0.02 0.13 0.13 0.25 Enterococcus faecalis 27101 0.25 0.13 0.13 0.25 0.5 0.13 1 0.25 0.13 9790 0.25 0.13 0.13 0.25 11 0.13 1 0.25 0.25 Acinetobacter calcoaceticus 14068 0.03 0.30.25 0.5 0.13 0.031 0.03, 0.25 10. Preparation of the intermediates Example Z1 Ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8vinyl-3-quinolinecarboxylate 3.72 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylate, 4.4 g of tributylvinyl stannan and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere. The mixture is filtered under hot conditions, and the product which has precipitated at room temperature is filtered off with suction, washed with toluene and dried. 2.55 g of ethyl 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3quinolinecarboxylate are obtained (79% of theory).

Melting point: 178-179"C.

Example Z2 l-Cyclopropyl-6,7-difluoro-l1,4-dihydro-4-oxo-8-vinyl-3quinolinecarboxylic acid 0.9 g of ethyl 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4oxo-8-vinyl-3-quinolinecarboxylate is refluxed for 4 hours in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0.2 ml of concentrated sulphuric acid. At reflux temperature, the reaction mixture is then treated with 10 ml of water. The solid is filtered off Le A 28 391 40 with suction at room tempe rature, washed 'with water an~d dried. 0.58 g of l-cyclopropyl-6 ,7-(ifluoro-l, 4-dihydro- 4 -oxo- 8-vinyl- 3-quinol1inec arboxyl ic acid (71% of theory) is obtained.

Melting point: 182-184 0

C.

Example Z3 Ethyl l-cyclo propyl-6,7-difluoro-l, 4-dihydro-8-(trimethylsilyl-ethinyl) -4-oxo-3-quinolinecarboxylate 22.2 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-l,4dihydro- 4-oxo 3-quinol1inec arboxyl ate, 30.2 g of tributyl- V stannyl-trimethylgilyl-acetylene and 3.48 g of tetrakis- ****(triphenylphosphit~e) palladium are ref luxed for 3 hours in 300 ml of absol~ite toluene under a nitrogen atmosphere. After the reaction mixture has cooled to approx.

-18*C, the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl 1-cyclopropyl- 6 ,7-difluoro-1, 4-dihydro-8- (trimethylsilylethinyl) -4-oxo- 3-quinolinecarboxylate (80% of theory) are obtained.

Melting point: 171-172 0

C.

Example Z4 Ethyl l-cyclopropyl-8-ethinyl-6, 7-difluoro-l, 4-dihydro-4oxo-3-quinolinecarboxylate 18. 8 g of ethyl 1-cyclopropyl-6,7-dif luoro-1, 4-dihydro-8- (trimethylsilylethinyl) -4-oxo-3-quinolinecarboxylate and Le A 28 391, 41 9.7 g of potassium fluoride are stirred for 3 hours at room temperature in a mixture of 300 ml of dimethylformamide, 200 ml of chloroform and 15 ml of water. The mixture is then filtered, the filtrate is treated with 120 ml of water, and the mixture is acidified with dilute aqueous hydrochloric acid. After extraction by shakLng with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue obtained is recrystallised from methanol. In this way, 9 g of ethyl l-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylate (59% of theory) are obtained.

V' Melting point: 186-187 0

C.

Example -Cyclopropyl-8-ethinyl-6,7-difluoro-l,4-, ro-4-oxo-3quinolinecarboxylic acid 10.3 g of ethyl l-cyclopropyl-8-ethinyl-6,7-diflubro-l,4dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 4 hours in a mixture of 100 ml of glacial acetic acid, 20 8 ml of water and 3 ml of concentrated sulphuric acid.

After cooling to room temperature, the solid is filtered off with suction, washed with water and dried. In this way, 5.7 g of 1-cyclopropyl-8-ethinyl-6,7-difluoro-l,4dihydro-4-oxo-3-quinolinecarboxylic acid (62% of theory) are obtained.

Melting point: 233°C.

Le A 28 391 42 Example Z6 Ethyl l-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4dihydro-4-oxo-3-quinolinecarboxylate 1.9 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluorto-1,4dihydro-4-oxo-3-quinolinecarboxylate, 3.5 g of 1-tnbutylstannyl-hex-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladim(O) are refluxed for 8 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 30 ml of hexane, aLid the resulting solid is recrystallised from cyclohexane. 0.7 g of ethyl 1-cyclopropyl- 6,7-difluoro-B-(l-hexinyl)-1,4-Q- hydro-4-oxo-3-quinolinecarboxylate is obtained (36% of theory).

is 1 H NNR (200 MHz, CDCl 3 6 0.95 3 1.1-1.7 (in; 11 2.50 2 4.1-4.3 1 4.38 2 H), 8.14 (dd; 1 8.56 1 H) ppm.

Example Z7 2-Cyclopropyl-6,7-difluoro-8- (-hexinyl)-1,4-dihydro-4oxo-3-quinolinecarboxylic acid 0.7 g of ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylate is refluxed for 3 hours in a mixture of 6 ml of glacial acetic acid, 0.5 ml of water and 0.1 ml of concentrated sulphuric acid. The reaction mixture is treated with 100 ml of water, and the solid is filtered off with suction and Le A 28 391 43 dried. C. 5 g of 1-cycloprcpyl-6,7-dif luoro-8- (1-hexinyl) 1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained of theory).

1H.{ NMR (200 MHz, CDCl 3 8 0.96 3 1.1-1.7 (in; 8 4.3-4.5 (in; 1 Hi), 8.20 (dd; 1 8.85 1 H)

PPM.-

Melting point: 118-121 0

C.

Examp~le Z8 Ethyl l-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-( 3,3dimethylbutin-1-yl) -4-oxo-3-quinolinecarboxylate

V.

C:Analogously to Example Z6, 1-tributylstannyl-3,3-dimethyl-but-1ime gives 0.87 g of ethyl 1-cyclopropyl-6,7difluoro-1, 4-dihydro-8- 3-dimethylbutin-1-yl) -4-oxo-3- 15 quinolinecarboxylate (46% of theory).

Melting point: 170-172 0

C.

Examp~le Z9 0 OV 1-Cyclopropyl-6, 7-di-fluoro-1, 4-dihydro-8- (3 ,3-dimethyl- :%**6butin-1-yl) -4-oxo-3-quinolinecarboxylic acid Hydrolysis of 0.75 g of the ester from Example Z8 analogously to Example V7 gives 0.56 g of 1-cyclopropyl-6p7difluoro-8- 3-dimethylbutin-1-yl) -4-oxo-3-quinolinecarboxylic acid (81% of theory).

Melting point: 199-201*C.

Le A 28 391 44 Example Ethyl 2 ,4-difluorophenyl) 7-difluoro-1,4-dihydro-8- (trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate 6.7 g of ethyl 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro- 1,4 -dihydro-4-oxo-3-quinoiinecarboxylate (Example 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The product crystallises from the reaction mixture! at -18 0 C. 4.8 g of ethyl 1,- (2,4-difluorophenyl)-6,7-difluoro-l,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (69% of theory).

15 Melting point: 173-174*C.

Example Zl1 Ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6 ,7-difluoro-1 ,4- 6 dihydro-4-oxo-3-quinolinecarbc xylate A solution of 4.6 g of ethyl 1-(2,4-difluorophenyl)-6,7difluoro-l,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3quinolinecarboxylate in 20 ml of chloroform is added dropwise at room temperate o a solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. The mixture is stirred for 1 hour at approx. 20*C, the reaction mixture is then treated with more chloroform and Le A 28 391 45 extracted several times by shaking with water, and the organic phase is dried and concentrated. The reviidue obtained is recrystallised from methanol. 3.4 g of ethyl hydro- 4-oxo- 3-quinolinecarboxyl ate are obtained (87% of theory).

Melting point: 189 0

C.

Example Z12 1-(2,4-Difluorophenyl)-S-ethinyl-6,7-difluoro-l,4-dihydro-4-oxo-3,-quinolinecarboxylic acid 1.17 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-617- :0difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate are *ref luxed for 1 hour in a mixture of 9 ml of glacial acetic acid, 0.75 ml of water and 0.2 mf of concentrated sulphuric acid. The solid wrhich has crystallised out at room temperature is filtered off with suction and dried.

.:0.98 g of 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro- 'GOV,1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of theory).

Melting point: 220*C (decomposition).

Example Z13 Ethyl 1-cyclopropyl-6 ,7-difluoro-1,4-dihydro-4-oxo-8- (propin--yl) -3-quinolinecarboxylate g of ethyl 8-bromno-1-cyclopropyl-6, 7-difluoro-1,4- Le A 28 391 46 dihydro- 4-oxo- 3 -quino 1inec arboxyl ate, 9.1 g of 1-tbutyl stannyl -prop- 1 -ine and 1. 16 g of tetraki~i(tripheny1phosphine)palladium(0) are refluxed for 8 hours in 80 ml of absol-ute toluena under a nitrogen atmosphere. The solid which crystallises out at -18*C is filtered of f with suctioa and dried. 2.05 g of ethyl 1-cyclopropyl- 6, 7-difluoro-1 ,4-dihydro-4-oxo-8- (propin-1-yl) -3-quinolinecarboxylate are obtained (31% of theory).

1H NMR (200 k'Hz, CDCl 3 8 1.1-1.35 (in; 4 1.40 (t; 3 2.16 3 4.1-4.3 (in; 1 4.35 2 H), 8.15 (dd; 1 8.56 1 H) ppm.

Melting point: 180-182 0

C.

*Example Z 14 1-Cyclopropyl-6, 7 -dif luoro- 1, 4-dihydro-4-oxo-6- (propin-.yl)-3-quinolinecarboxylic acid 1.4 g of ethyl l-cyclopropyl-6,7-di!luoro-1,4-dihydro-4oxo- 8 -(propin- 1-yl) -3 -quinolinecarboxyl ate are refluxed for 1 hour in a mixture of 20 ml of glacial acetic acid, 1.5 ml of water and 0.5 ml of concentrated sulphuric acid. The mixture is treated with. approx. 10 ml of water, and the solid which has precipitated is then isolated and dried. In this manner, 1.05 g of 1-cycJlopropyl-.6,7difluoro-1, 4-dihydro-4-oxo-B-(propin-1-y1)-3-quinolinecarboxylic acid are obtained (82% of theory).

1H1 NMR (200 Mflz, CDC1 3 8 1.4 4 2.26 3 Hi), 4.4-4.6 (in; 1 8,1L6 (dd; I 8.81 1 H) ppm.

Melting point: 212-213*C.

L

4 e A 28 391 47 Example Ethyl I-ethyl-6,7-difluoro-l, 4-dihydro-8- (trimethylsilylethinyl) -4-oxg-3-quinolineca-boxylate 5.4 g of ethyl 8-bromo-l-ethyl-.6,7-difluoro-l,4-dihydro- 4-oxo-3-quinolinecarboxylate (Example !322), 10.8 g of tributylotannyl-trimethylsilyl-acetyleae and 0.87 g of tetrakis (1toiphenylphosphine palladiumn( 0) are ref luxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 100 ml of hexane, and the resulting solid is filtered off with suction and dried. 4.53 g of ethyl 1 -ethyl- 6, 7 -dif luoro- 1, 4 -dihydro- 8 -(tri-methyl silylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).

Melting pQint: 151-152 0

C.

Example Z16 Ethyl 1-cyclopropyl-6, 7-dif luoro-l, 4-dihydro-8-(trimethylsilylethinyl) -4-oxo-3-quinolinecarboyylate 20 ,1.64 g of ethyl 8-.-->loro-l-cyclopropyl-6,7-&tfluoro-1,4dihydro-4-.oxo-3-quinolinecarboxylate, 3 g of tributylstannyl-trimethylsilyl-acetylenie and 0.29 g of tetrakis- (triphenylphosphine) palladium( 0) are ref luxed for 42 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to approx.

-18 0 C and filtered. After the filter residue has been Le A 28 391 48 dried, 0.74 g of ethy& i-cyclopropyl-6,7-difluoro-1,4dihydro-8- (trimethylslilylethinyl) -4-oxo-3-quinolinecarboxylate is obtaineid (38% of theory) Examle Z17 Ethyl 1-cyclopropyl-6, 7-difluoro-l, 4-dihydro-8- (3-methylbut-3-en-1-inyl )-4-,oxo-3-quinolinecarboxylate 1.86 g of et, I romo--cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo- .c,1inecarboxylate, 2.8 g of 1-tributylstannyl-3-mewthyl-but-3-en-1-ine and 0.29 g of tetrakis (triphenyiphoephine) palladium a 2e ref luxed for 6 hours in 20 ml of absol.,a toluene under a nitrogen 0046atmosphere. The reaction mixt'ire is filtered under hot conditions and concentrated, and the residue is stirred with hexane. After filtration with suction and drying, 1. 43 g of ethyl 'I-cyclopropyl-6,7-dif luoro-1, 4-dihydro-8- (3-methyl-but,--3-en-1-inyl>-4-oxo-3-guinolinecarboxylate are obtained (80% of theory).

Melting point: 169-1,71 0

C.

Example Z18 1-Cyclopropyl-6, 7-difluoro-1, 4-dihycdro-8- (3-methyl-but-3en-1-inyl) -4-oxo-3-quinolinecarboxylic acid 0.715 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro- 8- (3-methyl-but-3-en-1-inyl) -4-oxo-3-quinolinecarboxylata is ref luxed for 1.5 hours in a mixture of 10 ml of Le A 28 391 49 glacial acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulphuric acid. The reaction mixture is poured into 100 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-- ihydro- 8- 3-methyl -but- 3-en- 1 -inyl) -4 -oxo- 3-quinolinecarboxyl ic acid is obtained (80% of theory).

Melting point: 204-206*C.

3xample Z19 Ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-(2,4set*difluorophenylamino) -acrylate g (0.1 mol) of ethyl 2-(3-bromo-2,4,5-trifluoroto** benzoyl)-3-.ethoxy-acrylate in 180 ml of ethanol are treated with 14.5 g (0.11 mol) of 2,4-difluoro-aniline, with ice-cooling. The mixture ip allowed to stand overto 0. night at 10"C, and the precipitat d solid is filtered off with suction, washed with cold ethanol and dried in vacuo.

Yield: 38 g (81% of theory).

Melting point: 102-103 0 C (with decomposition) (from isopropanol).

Le A 28 391 50 Exampl1e Ethyrl 8-brnra-l- 4-dif luorcp1hnyl) 7-dif luoro-1, 4-dihydro-4-oo-3quinol inecarboxylate 38 g (82 mmol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl) -3-(2,4-difluorophenylanino)-acrylate in 200 ml of dimethylforn'amide are treated with 7.6 g of sodium fluoride and the mixture is ref luxed for 2 hours. The mixture is poured into ice-water, and the precipitate is filtered of f with suction, washed thiroughly with water and dried at 80*C in a recirculation drying cabinet.

Yield: 34.7 g (95% of theory).

*Melting point: 208-210 0 C (with decomposition) (from glycol monoinethyl ether).

,0:0.e 15 Acid hydrolysis of this ester gives 8-bromo-1-(2,4- 0 6 0difluorophenyl)-6,7-difluoro-l,4-dihI rc-4-oxo-3-quinolinecarboxylic acid of melting point 210-221 0 C (with decomposition).

Example Z21 Ethyl 2-(3-bromo-2,4,5--trifluoro-benzoyl)-3-ethylaminoacryl ate 20 g (0.05 mol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-ethoxy-acrylate in 40 ml of ethanol are treated with 5.5 g of a 50% strength aquieous ethylainine solution, with ice-cooling. The mixture is allowed to stand overnight at 10*C# the suspension is treated with Le A 28 391 31 200 ml of water, and the precipitated solid is filtered off with suction, washed with water and dried in, vacuo at 0

C.

Yield: 17.3 g (91% of theory).

Melting point: 101-102 0 C (with decomposition) (from isopropanol).

Example Zi22 Ethyl. 8-bromo-1-ethyl-6, 7-difluoro-l,4-dihydro-4-oxo-3quinol inec arboxylate 0010 UNA 16 g (42 mmol) of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-ethylaminoacrylate are reacted analogously to Example Yield: 14.6 g (96% of theory).

Melting point: 172-173 0 C (with decomposition) (from glycol monomethy. ether).

Acid hydrolysis of this ester g~ves 8-bromo-1-ethyl-6,7difluoro-l, 4-dihydro-4-.oxo-3-quinolinecarboxylic acid of melting point 215-217 0 C (with decomposition).

Example Z23 4-Methvlamino-1, 3,3a, 4,7,7a-hexahydroisoindole Method I: 10.1. g (60 mmxol) of N-trimethylsilylmaleimide [J.Org.

Chem. 40, 24 (1975) in 30 ml of absolute tetrahydrofuran Le A 28 391 52 are introduced it.i a reaction vessel, and 14.4 g mmol) of 70% 1-(tert.-butyloxycarbonylamino)-1,3butadiene [J.Org.Chem. 43, 2164 (1978)], dissolved in ml of absolute tetrahydrofuran, are added dropwise. When the exothermic reaction has subsided, the mixture is refluxed for a further hour.

7.6 g (0.2 mol) of lithium aluminium hydride in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and the cold reaction mixture is then added dropwise under nitrogen. The mixture is then refluxed for 14 hours. 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10% strength sodium hydroxide solution and 22.8 g of water are then added dropwise in succession to the cold reaction mixture. The salts are filtered off and 15 the filtrate is concentrated in vacuo. The residue (10.3 g) is distilled at 87 0 C/0.8 mbar.

The distillate is taken up in 80 ml of absolute pentane, the mixture is filtered, and the product is crystallised by cooling the filtrate to 20 Yield: 3.3 g, melting point: 72-82"C.

Treatment with an equimolar amount of 2N hydrochloric Sacid gives 4-methylamino-l,3,3a,4,7,7a-hexahydro-isoindole dihydrochloride of melting point 265-268"C (from methanol).

Le A 28 391 53 i Method II: a) 4-(tert.-Butyloxycarbonylamino)-l,3-dioxo- 1,3,3a,4,7,7a-hexahydroisoindole 48.0 g (0.5 mol) of maleimide dissolved in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and 120 g (0.5 mol) of approx. 1-(tert.-butyloxycarbonylamino)-1,3-butadiene dissolved in 500 ml of absolute tetrahydrofuran are added dropwise, during which process the temperature is kept at 20 to 30 0 C. Stirring is continued over- *night at room temperature. The mixture is then eo* concentrated, and the product is recrystallised from ethyl acetate. 57 g of product of a melting point of 177 to 182°C are obtained. A further 13 g of a melting point of 158 to 160 0 C are obtained from the mother liquor.

Be b) 4-Methylamino-1,3,3a,4,7,7a-hexahydroisoindole Under nitrogen, 27.1 g (0.71 mol) of lithium aluminium hydride are introduced into 300 ml of absolute tetrahydrofuran, and a solution of 57 g (0.21 mol) of 4-(tert.-butyloxycarbonylamino)-1,3-dioxo- S1,3,3a,4,7,7a-hexahydroisoindole in 570 ml of absolute tetrahydrofuran is added dropwise. The mixture is then refluxed overnight. 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% strength sodium hydroxide solution and 81.3 g of water are Le A 28 391 54 then added dropwise to the cold batch. The salts are filtered off with suction and washed with tetrahydrofuran, and the filtrate is concentrated in vacuo. The residue is distilled off under high vacuum.

Yield: 19.1 g.

Example Z24 4-Am no-1,3,3a,4,7,7a-hexahydro-isoindole 13.3 g (50 mmol) of 4-tert.-butyloxycarbonylamino-l,3y 10 dioxo-l,3,3a,4,7,7a-hexahydro-isoindole (from Example Z23, method II) are stirred overnight at room temperature in 166 ml of trifluoroacetic acid. The trifluoroacetic acid is then distilled off at 10 mbar, and the residue is freed from remaining acid in a high vacuum at 50"C. The residue is subsequently taken up in absolute tetrahydrofuran and concentrated in vacuo. The residue is taken up in 100 ml of absolute tetrahydrofuran and the mixture is added dropwise under nitrogen to a solution of 11.3 g (0.3 mol) of lithium aluminium hydride in 300 ml of 20 absolute tetrahydrofuran. The mixture is then refluxed for 16 hours. 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% strength sodium hydroxide solution and 34 ml of water are added dropwise in succession to the cold mixture. The precipitate is filtered off with suction and washed with tetrahydrofrran. The filtrate is concentrated, and the residue is distilled.

Yield: 2.2 g, content: 92% (determination by gas Le A 28 391 55 chromatography) Boiling point: 70*C/O.2 mbar.

Example 7-Methyl-4-methvlamino-1 3a.4,7. 7a-hexahydro-isoindole Analogously to Exaxn~le Z23, method 1, 21.9 g (0.12 mol) of 1 tert. -butyloxycarbonyl amino) -1,3 3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide, and the product is subsequently reduced with W 15.2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.

Yield: 6.2 g, melting point: 106-108 0

C.

Example Z26 1-Cvclopropvl-6 ,7-di:C'luoro-l, 4-dihvdro-8- (3-methoxyprop n-1yl) -4-oxo-3-Qruinolinecarboxylic acid A) 1.86 g (5 nimol) of ethyl 8-bromo-l-cyclopropyl-6,7difluoro-1, 4-dihydro-4-oxo-3.-quinolinecarboxylate in ml of absolute toluene are treated with 2.5 g (7 inmol) of l-tributyl-stannyl-3-methoxy--propine and 0.29 g (corresponding to 5 mol of tetrakis- (triphonyiphosphino) -palladium and the mixture is ref lvxed for 4 hours in a nitrogen atmosphere.

The reaction mixture is concentrated, the residue is stirred with he~xane, and the solid is filtered off with suction and purified by chromatography over a Le A 28 391 56 little silica gel.

Yield: 0.74 g (41% of theory) of ethyl 1-cyclopropyl-6, 7-difluoro-l, 4-dihydro-8- (3-methoxy-propinl-yl) -4-oxo-3-quinolinecarboxylate.

Melting point: 144-146 0

C

B) 0.36 g (1 mmol) of the produc)- of stage A is ref luxed for I hour in a mixtu~re of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concentrated sulphuric acid. The mixture is poured into 10 water, and the precipitate is filtered of f and of recrystallised from ethanol.

Yield: 153 mg (46% of theory) of 1-cyclopropyl-6,7difluoro-1, 4-dihydro-8- (3-methoxy-propin-l-yl) -4- S oxo-3-quinolinecarboxylic acid.

15 Melting point: 170-172*C 1H- NMR (270 M~Iz, CDCl 3 8 1.24 m 1A in (2H), 3H), 4.35 m 4.41 s -8.7 "t (111), 8.87 ppm s (1H).

Preparation of the active compounds N N'

CH

3

III

CH

Le A 28 391 57 A) 2.32 g (8 mmcl) of l-cyclopropyl-8-ethinyl-6,7difluoro-l, 4 -dihydro-4-oxo-3-guinolinecarboxylic acid in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide are ref luxed for 1 hour with 0.92 g (8 mmol) of 1, 4-diazabicyclo [2.2.2 ]octane and 1.2 g (12 mmol) of N-methylpiperazine. The suspension is concentrated, the residue is stirred with acetonitrile, and undissolved crystallisate is filtered off with suction and dried.

Yield: 1.83 g (62% of theory) of l-cyclopropyl-.8ethinyl-6-f lucre-i, 4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo-3-quinolinecarboxylic acid.

Melting point: 228-230*C (with decomposition) 1H NMR (d 6 -DMF) 8 4.95 ppm s 0 0000 00 0 I *000 0*SS S S S. S

S

0050*5

S

S

S S o 0* *9 S. 5

S

455

S

*SS.

15 B) In an analogou3 manner, 1-cyclopropyl-8-ethinyl-6f lucre-i, 4-dihydro-7-( 3-methyl-l-piperaziny,) -4-oxo- 3-quinolinecarboxylLe acid is obtained with 2methylpiperazine.

1H NMR (d 6 -DMSO): 8 5.03 ppm s Mass spectrum: m/e 369 325 (M"-CO 2 300, 293, 269, 243, 44 (C0 2 Using the products of Examples Z14, Z7 and, Z9, the following are obtained analogously to Example 1: Le A 28 391 58 0 F 1 COOH

N

C

CH

3

III

C

Example 2 (R=CH 3 1-Cyclopropyl-6-fluoro-1, 4-dihydro-7- 0 (4-methyl-l-piperazinyl)-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylic acid.

Melting point: 246-249 0 C (with decomposition).

*SExample 3 (R=CF'-CH 2

CH

2 CHA) l-Cyclopropyl-6-fltioro-8- (hexin-1-yl)-l,4-dihydro-7-(4-methyl-1-piperazinyl)-4oxo-3-quinolinecarboxylic acid.

Melting point: 206-208 0 C (with decomposition).

oe 10 Example 4 (R=C(CH 3 3 I-Cyclopropyl-8-(3,3-.dimethylbutin- 1-yl) -6-f luoro-1, 4-dihydro-7- (4-methyl-1-piperazinyl) -4oxo-3-quinolinecarboxylic acid.

Melting point: 234-2370C (with decomposition).

Le A 28 391 Exam]?le 0 F _q COOR N

N

CH

Analogously to Example 1, the' reaction is carried out with cis-2,8-diazabicvcloE4 .5.0]nonane to give 1-cyclopropyl-7- (cis 8-diazabicyclo 3.Q0 ]non-8-yl) -8-ethinyl- 6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 225-227*C (with decomposition).

1H1 NNR (d 6 -DMF): 6 4.9 s Example 6 0 *F COOH

H

2 N-j N x H 2 0 99999CH 3.2 g (12 mmol) of l-cyclopropyl-8-ethinyl-6,7-dihydro- 1, 4-dihydro-4-oxo-3-quinoltinecarboxylic acid in a mixture of 120 ml of acetonitrile and 60 ml of dimethylformamide Le A 28 391 60 are refluxed for 1 hour with 1.56 g (14 nimol) of 1,4diazabicyclo[2.2.2 )octane and 2.75 g (18 nimol) of 3-(2,2diiethylpropylideneamino )pyrrolidine. The solution is concentratedi, the residue is stirred with approximately 100 ml of water IpH the precipitate is filtered off with suction, waphed with water and subsequently suspended in 50 ml of water to completely eliminate the protective group, and the mixture is treated for 1 hour in an ultrasonic bath. Solid is then filtered off with suction, washed with' water and dried in vacuo at 80 0

C.

Yield: 3.8 g (82% of theory) of 7-(3-axnino-l-pyrrolidinyl cyclopropyl-8-ethinyl-6-fluoro-114-dihydro-4-oxo- 3-quinolinacarboxylic acid hydrate.

Meltin2 point: 193-196 0 C (with decomposition).

Example 7 0 A: R= C00-C(CH 3 3 F COOH B: R H xCF 3 C0E-

CH

3 N .R -N-H'

CC

A) Analogously to Example 1, the reaction is carried out with 3 -tert butoxyc arbonylamino -3-methyl pyrrolidine to give 7 (3 3-tert. -bvttoxycarbonyl amino- 3-niethyl-l-pyrro' 0.inyl)-l-cyclo-propyl-8-ethinyl-6fluc 4-dihydro-4-oxo-3-quinolinetuarboxylic acid Le A 28 391-63- 61 of melting point 244-246 0 C (with decomposition).

'H NMR (d'-DMSO): 8 4.92 ppm s B) 500 mg of the product of stage A are dissolved in Sml of trifluoroacetic acid with ice-co~oling, the solution is concentrated in vacuo, the residue is brought to crystallisation by stirring with three times approximately 1 ml portions of ethanol, and the salt is filtered off with suction, washed with ethanol and dried.

Yield; 270 mg (52% of theory) of 7-(3-amino-i- V methyl-1-pyrrolidinyl) -l-cyclopropyl-8-et'iinyl-6fluoro-l, 4-dihydro-4-oxo-3-quinolinecarbox-ylic acid trifluoroacetate.

Melting point: 242-244*C (with decomposition).

15 Example 8

C)

III C OI

CH

Analogously to Example 1, the reaction is carried out with 2-oxa-5,8-diazabicyclo[4.3.Ojnonane to give 1cyclopropyl-8-ethin-1-6-fluoro-l, 4-dihydro-7- (2-oxa-5, 8diazabicyclo C4 o.3. 0O]non- 8-yl) -4-oxo- 3-cl-inolinecarboxyl ic Le A 28 391 62 acid of melting point 290 0 C (with decomposition; sintering starts at approximately 170*C).

1H1 NMR (d 6 -DI4SO): 6 5.0 ppm s Example 9 0 F COOH H N N

C

CH

3 Anlgul toEape1 0oa0,-izbiyl[..1 non ar rece.ihtepouc fEapeZ4t AaoosytEapl1,2x-58diazabicyclo(4.3.0]no--l--x--poi--lquinolinecarboxylic acid of melting point 241-242 0 C (with decomposition).

Le A 28 391 63 Exampl.e 1Q 0 F COOH A: R= (CH 3 3

C-O-CQ-

IH B: R =H N3 I

C

CH

3 A) 303 mg (1 mmol) of the product of Example Z14 in a ****mixture of 6~ ml of acetonitrile and 3 ml of 5 dimethylformamide are treated with 240 mg of 3- 9 V tert. -b'utoxyc arbonyl amino -3 -methyl -pyrro 1idine and 134 mg (1.2 mmol) of 1, 4-diazabicyclo[2.2.2 ]octane and the mixture is refluxed for 2 hours. The mixture is concentrated in vacuo, the residue is stirred *:10 with 30 ml of water, and the mixture is dried at 80*C in vacuo.

Yield: 420 mg (87% of theory) of 7-(3-tert.-butoxy-, carbonylamino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-f luoro-1 4-dihydro-4-oxo-8- (propin-1-yl) -3qpainolinecarboxylic acid.

Melting point: 195-196 0 C (with decomposition).

'H NMR (d 5 -DMSO):- 8 1.42 s on the pyrrolidine), 2.12 ppm s (CH 3 B) 180 mg of the product of stage A are dissolved in 1.6 ml of trifluoroacetic acid at 0 0 C, and, after Le A 28 391 64 1.25 hours, the solution is concentrated. The residue is purified by chromatography (silica gel, dichloromethane/methanol/ 17% strength aqueous ammonia 30:8:1). 10 mg of 7-(3-amino-3-methyl-lpyrrolidinyl) -1-cyclopropyl-6-f luoro-1, 4-dihydro-4oxo-8-(propin-1-yl) -3-quinolinecarboxylic acid of melting point 209-210 0 C are isolated (with decomposition).

Mass spectrum: m/e 383 309, 298, 267 (100%), 133, Examtple 11 0 F COOH rN) N C F

CH

3

III

CH

F

Analogously to Example 1, tbos product of Examnple Z312 is reacted with N-methylpiperazine to give O-ethinyl-6- 15 fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1piperazinyl) -4-oxo-3-quinolinecarboxylic acid of melting point 193-195'C (with decomposition).

1H NMR (CDCl3): 3.35 s (-C=sCH).

Le A 28 391 65 Example 12

CH

.1W a *a a a a.

a. a Analogously to Exam~ple 1, the reaction is carried out with 3-methyl-3,8-diazabicyclo[4 0]nonane, and 1- 5 cvclopropyl-8-ethinyl-6-fluoro-1, 4-dihy-dro-7-( 3-methyl- 3, 8-diazabicyclo 3. 01'rion-8-yl) -4-oxo-3-quinolinecarboxylic acid, which is obtained as crude product, is purified by chromatography (silica gel; dichloromethane/ methane/20% aqueous ammonia 2:4:1).

1 H NMR (CDCl 3 4. 15 s (-C=RC-HI) Example 13 0 F, COOH N

NJ

CH

3

CH

Analogously to Example 1, the reaction is carried out Le A 28 391 66 with 3-methyl-3,7-diazabicyclo[33. 0]octane to give 1cyclopropyl-8-ethinyl-6-fluoro-1, 4-dihydro-7-( 7-methyl- 3, 7-diazabicyclo oct-3-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 212-216 0 C (with decomposition).

1 H NMR (d 6 -DMF): 8 4.95 s Example 14 0 k

COO

'W III

CH

.00 Analogously to Example 1, the reaction is carried out with 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole to give l-cyclopropyl-8-e hinyl-6-fluoro-1,A4-dhdr-7(4 'PS iiethylamino-.L,3,3a,4,7,7a-hexahydroisoindol-2.yl)-4-oxo- 3-quinolinecarboxylic acid of melting point 128-133*C V. (with decomposition).

1H NMR (d 6 -DMSO): 8 4.93 ppm s (-CsCH).

Le A 2B 391~ Example 0 NF

COCH

C

CH-

3 III L2

C

H

2 C~ CH 3 **164 mg (0.5 inmol) of tha pi!-duct ofExample Z18ar *..*reacted analogously to Example 1 with 1-methylpiperazine 5 to give 120 mg of 3,-cyclopropyl-6-fluoro-l,4-dihydro-8- (3-methyl-but-3-en,-l.4nyl )-7-(4-methyl-l-piperazinyl) -4oxo-3-quinolinecparboxylic acid of melting point 195-197 0

C

(with decomposition) (recrystallised from glycol monomethyl ether).

1H NMII (CDCl 3 8 5.36 m s (N-CH 3 2.0 t

(C-CH

3 Le A 28 391~ 68 Example 16

COOH

C

H

2 C CH 3 4*

S

S S

*SSS

S

S. 4 0e5.e 4 An-logously to Example 15, the reaction is carried out with 2, S-diazabicyclo[4 .3 .O]nonane to give 1-cyclopr/opyl- 5 7-(2,8-diazabicyclo[4.3.]non-8-yl)-.6-fluoro-1,4-dihydro- 8- (3-methyl-but-3-en-1-inyl) -4-oxo-3-.quinolinecarboxylic acid of melting point 201-202 0 C (with decomposition).

Example 17

S.

S**S

54..

S

0 F COOH R qN

C

C-

H

2 C~ CH 3 A. R= B. H{Qfj C. R= H-N N

CH

3 Le A 28 391 69 Analogously to Example 15, the reaction is carried out with

A.

B.

C.

1, 4-Diazabicyclo" 3.2. 1] octane 3 -Hydroxypyrrolidine 2 -Methylpiperazine t~o give the followii~g nompounds: A. 1-Cyclopropyl-7-(1,4,-diazabicyclo[3.2.ljoct-4-yl)-6fluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4oxo-3-quinoli~necarboxylic acid, 4O 4 4

S.

4O 4 Se*e S 4 .4 4 4

S

.4 *4 4 .4 10 B 1 -Cycl1o pr opy1- 6 flu o r o-1, 4- d ihyd co 7- 3 -hydro xy -l1pyrrolidinyl)-8.-(3-methyl-but-3-en-1-inyl)-4-oxo-3quinolinecarboxylic acid, melting point: 190-i98*C (with decomposition), 1 5 C. 1-Cyclopropyl-.6-fluoro-l, 4-dihydro-8-( 3-methyl-but- 3-en-1-inyl)-7-(3-methyl-1-piperazinyl) -4-oxo-3quinolinecarboxylic acid.

gcample 18 0 F COOH N ,cxHCI Cl- C

CR

3

CH

2 Le A 28 391 70 100 mg of the product of Example 1 are dissolved in 40 ml of 1N hydrochloric acid, and the solution is stirred for 2 hours at 30 0 C. This gives a suspension which is concentrated. The residue is stirred with a little isopropanol, and the precipitate is filtered off with suction, washed with isopropanol and dried in vacuo at Yield: 0.1 g (83% of theory) of 8-(l-chlorovinyl)-lcyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyi-1-piperazinyl) -4.-oxo-3-quinolinc,,carboxylic acid hydrochloride.

Melting point: 251-252 0 C (with decomposition).

:0 11 NWT (d -DMSO) 6 6. 0 ppm dd (.C--CH 2 F CO.

*q CC C

C

CC C3 EApl 10 go h rdc f2ape2i 8m f4 hyrcloi ci r hae fr5hor 0 0C Th mitr sconcnrtead h esdei stre wit dity ete nNdidi vcoa Le A 28 391 71 Yield: 90 mg of cis-.trans-8- -chloro-l-propenyl) -lcyclopropyl-6-fluoro-1,4-dihydro-; ,4-methyl-lpiperazinyl) -4-oxo-3-quinolinecarboxylic acid hydrochloride.

Melting point: 236-237 0 C (with decomposition).

mass spectrum: W/e 419 71.58 43.36.

lii NMR (d 6 -DMSO): 8 6.12 q and 6.35 q (-C--CH-CH 3 two signals for cis-trans forms).

10 B) Analogously, cis-trans-8-(l-chloro-l-hexenyl)-l- "060cyclopropyl-6-fluoro-1 ,4-dihydro-7- (4-methyl-i- '10:0 piperazinyl) -4-oxo-3-quinolinecarboxylic acid hydrochloride is formed with the product of Example 3.

Mass Pectrun: m/e 461 425 (14-HCl), 71.58 ole 1 0 il 4 6 0 (t00 4.6 e** 4.0 Example 0 F COOH 6*CH3 NI xHCL

H-

2 N 1

CH

IH

Le A 28 391 72 370 mg of the product of Example 10A are dissolved in 9 ml of half -concentrated hydrochloric acid, an(' the solution is concentrated under a high vacuum.

Yield: 340 mg of cis-trans-7- (3-amino-3-methyl-3.-pyrroli.

dinyl)-8-( 1-chloro-1-propenyl)-l-cyclopropyl6fluoro- 1, 4-dih.ydro-4-oxo-3-quiinolinecarboxylic acid hydrochloride.

'H NMR (d 6 _-MSO) 6 6.19 q and 6.36 q (>C=CH-CH 3 2 signals for cis-trans forms).

Example 21 re 0 F0 CQOH N I x H C I CH2

F

mgo*h rdc fEape1 n45m hyrchoi acdaehaedfrIhu a 0C h mitr iscnetaead*.lclrvnl--loo 1F24dfurpey)14dhyr-7(-ehllppr 0*l--x--unoieabxlcaidhdohoiei obandasrsde Le A 28 391 73 Mass spectrum: m/e 477 442 (14-Cl) 36 (100%, HCl).

Exampe 2 0 F COOR

NI

H

2

N

291 mg (1 inmol) of the product of Example Z2 in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformanide are treated with 240 mg (2.2 wraol) of 1,4-d1iazabicyclo- (2.2.2]octane and 360 mg (2.3 mmol) of 3-'2,2-dimethyl- **:.propylideneamino)-pyrrolidine, and the mixture is .9.9.:ref luxed for 32 hours. The mixture is concentrated, the dark oily residue is stirred with 10 ml of water, and the solid which has precipitated (103 mg) is filtered oif with suction and purified by chromatography (silica gel; **:*.dichloromethane/methanol/17% aqueous ammonia 30:8:1).

Yield: 58 mg (16% of theory) of 7-(3-amnino-1-pyrrolid- 15 irnyl) -1-oyclopropyl-6-f luoro-l, 4-dihydro-4 -oxo-8 -vinyl-3 quinolinecarboxylic acid.

Melting point: 179-3.32 0 C (with decomposition).

4 CI mass spectrum: m/e 358 340 ((M+H-H 2 0] 4 Example 23 74 F COOH

HN

N N N 145 mg (0.5 mmoll of the product of Example 72 in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformainide are treated with 60 mg (0.54 mmol) of 1,4- C diazabicyclo[2.2.2 ]octane and 140 mg (1.1 inmol) of cis-

V,

2,8-diazabicyclo-f4 .3.0]nonane, and the mixture is refl'ixed for 4 hours. The solution is concentrated, the concentrate is stirred with approximately 5 ml of water, So and the mixture is brought to pH 7 using dilute 0 10 hydrochloric acid. Thie precipitate is filtered off with suction, washed with water and dried in vacuo at 90 0

C.

Yied: 20 g (1%of theory) of 1-cyclopropyl-7- (cis- 2,-izbccl*.. y)6fur-14dhda4 0.0 oxo-8-vinyl-3-quinolinecarboxylic acid.

Melting point: 205-207 0 C (with decomposition).

'H NMR (CI 3 COOD): 8 5.05 d 5.7 d 7.55 dd (1H) (signal groups for -CH=CH 2 L~e A 28 391 75 Example 24 0 F COCH N cN

CH

3 III L2

C

CFT

2

-O-CH

3 vok Analogously to Example 1, the reaction is carried out with the product of Example Z26, and 1-cyclopropyl-6fluoro-l,4-dihydro-7-(4-rnethyl-1-piperazinyl)-8-(3methoxy-propin-1-yl) -4-oxo-3-quinolinecarboxylic acid of melting point 187-189 0 C is obtained.

1H NIAR (CDCl 3 6 8.95 s 8 d 4.37 s (O-CH 2 4.35 mn 3.58 mn 3.43 s (O-CH 3 2.58 m (4H), 2.38 s (N-CH3), 1.33 mn (2 1.02 ppm mn (2H) Example 0 F C C0 0 d Le A 28 391 76 Analogously to Example 1, the reaction is carried out with 3,7-diazabicyclo[3.3 .O3octane, the reaction product is chromatographed on silica gel, using dichioromethane/ methanol/17% strength ammonia (30:8:1) as the eluent, and l-cyclopropyl-7-(3,7-diazabicyclo[3.3.0]ct t-3..yl8...

ethinyl-6-fluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained as a "solidified foam" 1H1 NMR (d 6-DMSO): 8 4.9 s &too seatI 1 e A 28 391 -7 77

Claims (16)

1.Quinolonecarboxylic acid derivatives of the formula XI0 F COO-R 2 Y#N X 2 R' s ee 5 in which futhrmr rerset ClCloxaio Srepresen stavig-ai or brCanched or pheny **aywhich is optionally mnsubstituted by hydtroxyl halogenb haore-naoy, o sels: 0r~eet pinlyhlgn rC- 3 ak monopeenshrgealkylwnn having 1 to C aoms, dialkylorino having 2 to 6 C atoms, or pheny wehc sotinlymoousittdt Le A 28 391 -778 X 1 represents hydrogen, fluorine, chlorine, amino or methyl, X 2 represents -C=CH-R 3 -C=C-R 5 or -CH 2 -CH=CH 2 R 4 where R 3 represents hydrogen, C 1 -C 3 -alkyl, C-C 3 alkoxy or alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, R 4 represents hydrogen or halogen and R 5 represents hydrogen, Ci-C 6 -alkyl which is S: 10 optionally monosubstituted to *o trisubstituted by halogen, or C 2 -C 3 alkenyl, alkoxy having 1 to 3 C atoms, alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and Y Y represents Le A 28 391 79 R 9 Rio RLN N N RL NN R 7 R 8 NIN\ R 8 0ON- I N- R1 2 H- 2 C R 1 2 CN- 9* 9 .9*e *999 9 R 16 R 1 I-5 (CH2 N R 8 ~N N- R 20 RI+JQ )N R 8 RL NJCN R 9 Ra R1 6 R 9 N -CH--N< R1 RiN- C r \N N or N 80 where R 6 represents hydrogen, optionally hydroxyl- or methoxy-substituted straight-chain or branched C 1 -C 4 -alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having 1 to 3 C atoms, R 7 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R 8 represents hydrogen or methyl, R 9 represents hydrogen or methyl, R 0 represents hydrogen or methyl, R 9 R n represents hydrogen, methyl or -CH 2 -N R 2 represents hydrogen, methyl, amino, optionally hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, 15 aminomethyl, aminoethyl, optionally hydroxyl- substituted alkyl- or dialkylaminomethyl having 1 or 2 C atoms in the alkyl moiety or 1-imidazolyl, R 3 represents hydrogen, hydroxyl, methoxy, Le A 28 391 81 R 14 R' R 1 methylthio or halogen, methyl or hydroxymethyl, represents hydrogen or methyl, represents hydrogen, methyl or ethyl, represents hydrogen, methyl or ethyl, represents hydrogen, methyl or ethyl, a Rl6 R 1 represents hydroxyl, R17 RL6 or CH2-N R17 oo e "'l R 19 represents hydrogen, optionally hydroxyl- substituted Ci-C 3 -alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or Ci-C 3 -acyl, Rt 9 R 20 represents hydrogen, hydroxyl, R21 Le A 28 391 82 hydroxymeyl C hydroxymethyl or CH 2 where 9 R 21 denotes hydrogen or methyl, A represents CH 2 0 or a direct bond and n represents 1 or 2, and their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

2. Quinolonecarboxylic acid derivatives according to Claim 1, where R' represents optionally hydroxyl-substituted Cj- C 2 -alkyl, C 3 -C 5 -cycloalkyl, vinyl, amino, monoalkylamino having 1 to 2 C atoms, dialkyl- amino having 2 to 4 C atoms, or phenyl which is optionally monosubstituted or disubstituted by halogen, R 2 represents hydrogen, alkyl having 1 to 3 carbon Le A 28 391 83 atoms methyl, or (5-methyl-2-oxo-1, 3-dioxol-4-yl) e A 00* X 1 represents hydrogen, fluorine, chlorine, amino or methyl, x 2 represents -C=CH-R 3 -C=C-R 5 or -CH 2 -CH-=CH 2 where R 3 represents hydrogen, Cl-C 2 -alkyl, methoxy or methoxymethyl, R 4 represents hydrogen and R 5 represents hydrogen, C.-C 4 -alkyl which is optionally monosubstituted to trisubstituted by fluorine, or C2-C 3 alkenyl, methoxy or trimathylsilyl, and Y represents Lp A28 391 84- R 7 NIN R1 6 R-5 N CH 2 tN R17 (CH2CN R 8 N N RS 0 N-_ R 8 N RN3 R 8 R8 8NN R 12 )N R1 3 QrNCN 0e-N'IN S S S S. *SSSS* ses *0. NQCIN or where R 6 represents hydrogen, optionally hydroxyl-sub- stituted straight-chain or branched CI-C 3 alkyl, or oxoalkyl having 1 to 4 C atoms, Le A 28 391 85 R 7 represents hydrogen, methyl or phenyl, R 8 represents hydrogen or methyl, R 9 represents hydrogen or methyl, R 11 represents hydrogen, methyl or -CH2-NH 2 R 12 represents hydrogen, methyl, amino, methyl- amino, dimethylamino, aminomethyl, methylamino- methyl or ethylaminomethyl, 4e e R 13 represents hydrogen, hydroxyl, methoxy, fluor- ine, methyl or hydroxymethyl, 4 10 R 1 5 represents hydrogen or methyl, R 16 represents hydrogen or methyl, R 17 represents hydrogen or methyl, R 16 Rl 6 R 18 represents y or CH 2 -N e:.s \R7 17eR R 17 R 19 represents hydrogen, methyl or ethyl, 19 A 28 391 86 R l9 R 20 represents N/ R21 10 where R 21 denotes hydrogen or methyl, A represents CH 2 O or a direct bond and n represents 1 or 2.

3. Quinolonecarboxylic acid derivatives according to Claim 1, where R 1 represents methyl, ethyl, cyclopropyl or phenyl which is optionally monosubstituted or disub- stituted by fluorine, R 2 represents hydrogen, methyl or ethyl, X 1 represents hydrogen, fluorine, chlorine, amino or methyl, X 2 represents -CH=CH 2 or -CaC-R Le A 28 391 87 where R 5 denotes hydrogen, Cl-C 4 -aJlkyl, alkonyl or trixnethylsilyl and Y represents C 2 -C 3 S S o ao 5* S. S 55655e S 50 0 S *S 0SSS 0* *5 S 0S 0 R-N 16- N R 8 N N R 7 R8- R 12 N R13 R8 N NCCN Le A 2 8 391 88 R (CH JQN R1 3 N N R 8 RL NKN C C '%N0 OCN or IN- Nzz/ a* C C OC 5 CC*C C ow where R 6 represents hydrogen, methyl, optionally hydroxyl-substituted ethyl, R 7 represents hydrogen or methyl, Re representa hydirogen or methyl, R 9 represents hydrogen or methyl, R' 1 represents hydrogen or -CH 2 -N1 R 1 2 represents hydrogen, methyl, amino, methyl- amino, aminomethyl or ethyl aminomethyl Le A 28 391 m R 1 representi hydrogen, hydroxyl or methoxy, R's represents hydrogen or methyl, 16 represents hydrogen or methyl, *R1 represents hydrogen or methyl, R 18 represents N R1 VO.U", R 1 7 :R 19 represents hydrogen or methyl, N R19 R •R 20 represents o••:eN R21 where a 00 R: 21 denotes hydrogen or methyl, i0A represents CH2, 0 or a direct bond and n represents 1. Le A 28 391 :*too 0 0 a Soo*

4. Quinolonecarboxylic acid derivatives of the formula (II) X1 F COO-R 2 N x 3 X 2 R in which R X' and V 2 are as def ined in Claim 1 and x3 represents halogen, in particular fluorine or chlorine. Process for the preparation of quinolonecarboxylic acid derivatives according to Claim 1, characterised in that a compound of the formula (II) xi F ry ,COO-R 2 Le A 28 391 91 in which R 2 X1, and X 2 are as defined in Claim 1 and V 3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula (III) Y-H (III) e '4 in which :Y is as defined in Claim 1, if appropriate in the presence of acid scavengers.

6. C-rm--24dfurpey)6,-iloo14dhdo4oo3 6. 8-Bromo- 1-(-dfluohn-6,7-difluoro-I,4-dihydro-4-oxo-3-qioneabxlccd C:qunlncabxli cdand its pharmaceutically acceptable hydrates andacdditoslsaswl aiadiinslsawelas the alkali metal salts, alkaline earth metal salts, sle at n sivrssadguanidinium slts.

8. 8-Bylro- I-etyl--fluoro-,4-dihydro-7-34-quinolpieaoxyl ci 4-x,-unlncroyi cdand its pharmaceutically acceptable hdae n cdadto at swl asdrtes akaid metal salts alkaliel tatheal metal salts, lesalsand eat ea1sls ivrslsadguanidinium salts. 8. 1 -Cyclopropyl-8-etin-6-luo I,-di hydry o--myl- -iperazinyl)r- 1,-iro4-oxo--quinolinecarboxyli; acid and its pharmaceutically cpal acebehydrates and acid addition salts as well as the alkali metal salts, kln alaeearth metal salts, silver salts and guanidinium salts. Le A28 391 92 93 7-(3-Amnino- 1 -pyrrolidinyl)- 1 _cyclopropyl-8-ethinyl-6-fluoro- I ,4-dihydro-4- oxo-3--quivolinecarboxylic acid and its pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

11. 7-(3-Amino-3-methyl-lI-pyrrolidinyl)-l1-cyclopropyl-8-ethinyl-6-fl uoro- 1,4- dihydro-4oxo-3-quinolinecarboxylic acid trifluoroacetate.

12. 1 -Cyclopropyl-6-fluoro- 1,4-dihydro-8-(3-methyl-but-3-en-l1-iniyl)-7-(4-me- thly 1-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid and its pharmaceutical- ly acceptable hydrates and acid addition salts as well as the alk-ali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

13. 1 -Cyclopropyl-8-ethinyl-6-fluoro-1I,4-dihydro-7-(2-oxa-5,8-dia-zabicyclo- [4.3 fnon-8-yl)-4-oxo-3-quinolinecarboxylic acid and its pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

14. 1 -Cyclopropyl-8 -ethinyl-6-fluoro-1I,4-dihydro-7-(7-methyl-3,7-diazabicyclo- [3.3.0]oct-3-yl)-4-oxo-3-quinolinecarboxyli, acid and its pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidirilum salts.

15. 1 -Cyclopropyl-8-ethnyl-6-fluoro-l ,4-dihydro-7-(4-methylamino- 1 ,3,3a 1 4,7,7a-hexahydroisoindol-2-yl)-4-oxo-3-quinolinecarboxylic acid and 6 its pharmaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

16. 1 -Cyclopropyl-7-(cis-2,8-diazabicyclo non- 9-yl1)-6- fluoro-. I 4-dihydro-4 oxo-8-vinyl-3-quinolinecarboxylic acid and its pharmaceutically acceptable hydrates and acid addition salts as well as the aAl-ili metal salts, alkaline earth metal salts, silver salts and guanidiniumn salts. -94-

17. A method for the treatment (prevention, alleviation and/or cure) of diseases caused by gram-positive and gram-negative bacteria and bacteria-like microorganisms wherein there is administered, to a subject in need of such treatment, a compound as claimed in any one of claims 1-3, 8-16.

18. A medicament containing a compound according to any one of claims 1-3, 8-16 together with a pharmaceutically acceptable diluent or carrier.

19. A compound according to claim 1, substantially as herein described with reference to any one of the foregoing examples thereof. DATED this 15th day of February, 1995. BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys, DAVIES COLLISON CAVE 9O o* o eo *ooo** p:\wpdocs\grs\432801\jgs fl-Vinvl- and 8-ethinvl-qujnolone-carboxylic acids Abstract of the disclosure Seed 0 es:a es 60000 a. The invention relates to new B-vinyl- and 8-ethinyl-quinolonecarboxylic acids, processes for their prepax'ation, and antibacterial agents and feed additives containing \hemn. S. S@ S. SS S. S SO S

555. S SeeS .0* 55.55. S S