CA2073993A1 - 8-vinyl- and 8-ethinyl-quinolone-carboxylic acids - Google Patents

Abstract

B-Vinyl- and 8-ethinyl-quinolone-carboxylic acids Abstract of the disclosure The invention relates to new B-vinyl- and 8-ethinyl-quinolonecarboxylic acids, processes for their preparation, and antibacterial agents and feed additives containing them.

Description

The invention relates to new 8-vinyl- and 8-ethinyl-quinolonecarboxylic acids, processes for their prepara-tion, and antibacterial agents and feed additives con taining them.

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

It has now been found that the new compounds of the formula (I) xl o F ~ COO-R2 Y~NJI (1), in which R1 represents straight-chain or branched Cl-C~-alkyl which is optionally substituted by hydroxyl, halogen or Cl-C3-alkoxy, ox repre~ents optionally halogen- or Le A 28 391 - l -C1-C3 alkyl-substituted C3-C6-cycloalkyl, C2-C4-alk-enyl, furthermore represents Cl-C3-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, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -C-CH-R3, -C-C-R5 or -CH2-CH=CH2, where R3 represents hydrogen, Cl-C3-alkyl, C1-C3-alkoxy or alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, R4 represents hy~rogen or halogen and R5 represents hydrogen, Cl-C6-alkyl which is optionally monosubstituted to trisubstituted by halogen, or C2-C3-alkenyl, alkoxy having 1 to 3 C atoms, alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and Y represents Le A 28 391 - 2 -` ~ ~ r~ 3 R9 Rl R6 ~ R8_ N/~N--R8 N~N-- N N _ 0~;\ ~N-- ~N-- \~\N--Rl6 Rl5 o 1 8 R8 N CH2~CN- R~ N~

(CH~CN _ ~N R8--~ ~C

R~o R9 N--~CN-- N~\N-- [~N

Le A 28 391 - 3 -where R6 represents hydrogen, optionally hydroxyl- or meth-oxy-substituted straight chain or branched Cl-C4-alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having l to 3 C atoms, R7 represents hydrogen, methyl, phenyl, thienyl or pyridyl, RB represents hydrogen or methyl, R9 repre~ents hydrogen or methyl, R10 represents hydrogen or methyl, R11 represents hydrogen, methyl or -CH2-N
Rl R12 represents hydrogen, methyl, amino, optionally hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, aminomethyl, aminoethyl, optionally hydroxyl-6ubstituted alkyl-or dialkylaminomethyl having 1 or 2 C atoms in the alkyl moiety or l-imidazolyl, Le .A 28 391 - 4 -;~ ~ f .~ 3 c' Rl3 represents hydrogen, hydroxyl, methoxy, methylthio or halogen, methyl or hydrsxymethyl, R1~ represents hydrogen or methyl, R15 represents hydrogen, methyl or ethyl, R16 represents hydrogen, methyl or ethyl, Rl7 represents hydrogen, methyl or ethyl, R19 represents hydroxyl, N / or CH2-N \
\ Rl7 Rl7 Rl9 represents hydr~gen, optionally hydroxyl-substituted Cl-C3-alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or Cl-C3-acyl, Rl9 R2C xepresents hydrogen, hydroxyl, ~

Le A 28 391 - 5 -f ;~;` rJ ?

Rl9 hydroxymethYl or CH2- ~ , where R~l R2~ denotes hydrogen or methyl, A represents CH2, 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, alka-line earth metal salts, silver salts and guanidinium salts of the carboxylic acids on which they are based have a powerful antibacterial action.

They are therefore suitable as active compounds for human and veterinary medicine, veterinary medicine also includ~
ing the treatment of fish for the therapy or prophylaxis of bacterial infec~ions.

Preferred compounds of the formula (I) are those in which R' represents optionally hydroxyl-substituted C1-C2-alkyl, C3-C5-cycloalkyl, vinyl, amino, monoalkylamino Le A 28 391 - 6 -d ,~

having 1 to 2 C atoms, dialkylamino having 2 to 4 C
atoms, or phenyl which is optionally monosubstituted or disubstituted by halogen, R2 represents hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, Xl represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -C=CH-R3 -C-C-R5 or -CH2-CH=CH

where R3 represents hydrogen, C1-C2-alkyl, methoxy or methoxymethyl, R4 represents hydrogen and R5 represents hydrogen, C1-C4-alkyl which is optionally monosubsti~uted to trisubstituted by fluorine, or C2-C3-alkenyl, methoxy or trLmethylsilyl, and ., : Y represents Le A 28 391 - 7 -~ ~ 3 3 R6 N N R8 N$N ~8 N5~M
~~ , N~N O N ~CN
) / Rl3 Rll R~
R16 Rl5 0 I R8 - CH2t~N - ~ ~N-- XN
Rl8 RI3 ~CH~\N ~N R8- N~N

R~

Rl9 N - ~ N - N~

where R6 represents hydrogen, optionally hydroxyl-substituted straight-chain or branched Cl-C3-alkyl or oxoal~yl having 1 to 4 C atoms, 1e A 28 391 - 8 -~ J..~ 3 ~`

R7 represents hydrogen, methyl or phenyl, RB represents hydrogen or methyl, R9 represents hydrogen or methyl, Rll represents hydrogen, methyl or -CH2-NH2, Rl2 represents hydrogen, methyl, amino, methylamino, dimethyl~mino, aminomethyl, methylaminomethyl or ethylaminomethyl, R'3 represents hydrogen, hydroxyl; methoxy, fluorine, methyl or hydroxymethyl, R15 represents hydrogen or methyl, R1s represents hydrogen or methyl, R17 represents hydrogen or methyl, ~ Rl6~RI6 Rl9 represents ~ or CH2-N \
\ Rl7 Rl7 R19 represents hydrogen, methyl or ethyl, Le A 28 391 - 9 -`~ V .~ ',t '.: ~

Rl9 R20 represents N /
R~

where R21 denotes hydrogen or methyl, A represents CH2, 0 or a direct bond and n represents 1 or 2.

Particularly preferred compounds of the formula (I~ are those in which R1 represents methyl, ethyl, cyclopropyl or phenyl which is optionaily monosubstituted or disubstituted by fluorine, R2 represents hydrogen, methyl or ethyl, X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -CH=CH2 or -C-C-Rs Le A 28 391 - lO -,' ~! ,,. ' ~ ~ - f ', where Rs denotes hydrog~n, Cl-C4-alkyl, C2-C3-alkenyl or trimethylsilyl and Y represents 5R6- N N - , Rg- N ~ N - R8- N ~ N -)/ , , Rl2 - O N ~
~J Rl3 R"

Rl6 R15 0 I R8 N-cH2 ~ N- ~ ~ N - , Rl3 Rl3 (CH ~ N _ ~ N R8- ~XN

. R8 ,.

~C

where Le A 28 391 - 11 -jF ~ é~

R6 represents hydrogen, methyl, optionally hydroxyl-subskituted ethyl, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, Rll represents hydrogen or -CH2-NH2, Rl2 represents hydrogen, methyl, amino, methylamino, aminomethyl or ethylaminomethyl, Rl3 represents hydrogen, hydroxyl or methoxy, Rl5 represents hydrogen or methyl, Rl6 represents hydrogen or methyl, Rl' represents hydrogen or methyl, ~ Rl6 Rl9 represents N
Rl7 Rl9 represents hydrogen or methyl, Le A 28 391 - 12 -Rl9 R20 represents ~
\ R21 where R21 denotes hydrogen or methyl, A represents C~2, 0 or a direct bond and n represents 1.

Furthermore, it has been found that the compounds of the formula (I) are obtained when a compound of the formula (II) X o F ~ COO-R2 I 1I N ~ (Il), x2 in which Le A 28 391 - 13 -`J ~/ ~

R1~ R2, X1 and x2 have the abovementioned meaning and X3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula ~III) Y-H (III) in which Y has the abovementioned meaning, if appropriate in the presence of acid scavengers.

If, for example, 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methylpiperazine are used a~ starting compounds, the course of the reaction can be represented by the follow-ing equation:
O O
~ COOH F ~ COOH
F ~ + HN J ~-CH3 ~ ~ ~ N

CH CH3~T J CH

The 8-(1-chlorovinyl)-quinolonecarboxylic acids are also Le A 28 391 - 14 -~ ~v . 3,, ~

obtained by reacting the 8-ethinyl-quinolonecarbo~lic acids with hydrochloric acid at ~emperatures from 10C to lOODC, preferably 20C to 60C.

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 (IV) X O
F~,,COO-R2 in which lQ R1, R2, X1 and X3 have the abovementioned meaning and X~ represents halogen, in particular iodine, bromine or chlorine, with oxganometal vinyl or alkinyl compounds of the formula (V) M_x2 (V) in which Le A 28 391 - 15 -X~ has the abovementioned meaning and M represents SnR' 3 ~ Z nX I ~ B(OR") 2 /

where R' denotes Cl-C4-alkyl, R" denotes hydrogen or C1-C4-alkyl and X~ denotes bromine or chlorine, in the presence of transition metal cataly~ts and elimin-ating 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 ~he literature.
For example, vinyl-trialkyltin compounds can be prepared from the corresponding ~inyl iodides, vinyl bromides or vinyl chlorides by obtaining the ~inyl-Grignard compounds by reaction with magnesium and reacting these compounds with a trialkyltin chloride ~o give the desired vinyltin derivatives.

Organometal alkinyl compounds can be prepared in a known manner, for example by metallating the l-alkine with n-butyllithium, sec-butyllithium or tert.-butyllithium at temperatures between -20 and -78C in an aprotic solvent such as, for example, tetrahydrofuran, followed by reaction with a halometal compound such as, for example, ~inc chloride, magnesium bromide, copper iodide or Le A 28 391 16 -trialkyltin chloride. The reaction at 78C 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 ~oth the vinyl and the alkinyl derivatives. "Alkyl" in the trialkyltin compounds is understood as meaning C1~ to C
alkyl; methyl and n-butyl are preferred.

Trialkylvinyltin compounds can also be obtained by methods known from the literature, by hydrostannylation of alkines with trialkyltin hydrides in the presence of transition metal catalysts (J. Org. Chem. 55 (1990) 1857-18~7).

The organometal vinyl and alkinyl compounds are reactedwith 8-halogenoquinolonecarboxylic acid derivati~es of the general formula (IV) by process~s known in principle in the presence of a suitable catalyst. In this contex~, ~'halogen~ represents iodine, bromine or chlorine; bromine and chlorine being preferred, bromine being particularly preferred.

Examples of suitable catalysts are transition metal compounds of the metals cobalt, ruthenium, rhodium, iridium, nickel, palladium or platinum. Compounds of the me~als platinum, palladium and nickel are preferred, and palladium is particularly preferred. Such transition Le ~ 28 391 - 17 -, d `~: J , ) J . ~ ~ !
metals can be employed in ~he form of their salts such as, for example, in the form of NiCl2, PdCl2 or Pd(OAc)2, or in the form of complexes with suitable ligands. The use of complexes is preferred. Ligands which are pr~fer-5 red are phosphines such as, for example, triphenyl-phosphine, tri(o-tolyl~phosphine, trLmethylphosphine, tributylphosphine and tri(2-furyl)phosphine, triphenyl-phosphine being preferred. Preferred complex catalysts which may be mentioned are bis(triphenylpho~phine)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-lates employed; amounts of 0.5 to 10 mol % are preferred~
and amounts of 1 to 5 mol 4 are very particularly pre-ferred.

The coupling reactions are carried out in ~uitable inert solvents such as, for example, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, dimethoxyethane or mixtures of such solvents; dLmethylformamide 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 between 20 and 200C; temperatures between 50 and 180C
are preferred.

Le A 28 321 - ].8 -r ~ s The duration of the reaction depends on the reactivity of the educts and is generally between 2 and 40 hours;
reaction tLmes between 4 and 24 hours are preferred.

The reactions are carried out under a protective gas atmosphere. Suitable protective gases are inert gases such as, for example, helium, argon or nikrogen; 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.
Examples which may be mentioned are:
piperazine, l-methylpiperazine, 1-ethylpiperazine, 1-(2-hydroxyethyl)-piperazine, 3-methylpiperazine, cis~ -dLmethyl-piperazine, cis 2,3-dLmethyl-piperazine, 1,2-dimethylpiperazine, 1-cyclopropyl-piperazine, 2-phenyl-piperazine, 2-(4-pyridyl)-piperazine, 2-(2-thienyl)-piperazine, 1,4-diazabicyclo[3.2.1]octane, Le A 28 391 - 19 -8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, 3-methyl-3,8-diazabicyclo~3.2.1]octane dihydrochloride, 2,5-diazabicyclo[2.2.1]heptane dihydrochloride, 2-methyl-2,5-diazabicyclo~2.2.1]heptane dihydrochloride, 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 2-methyl-2,5-diazabicyclo~2.2.2]octane dihydrochloride, 1,4-diazabicyclo[3.1.1]heptane, morpholine, 2,6-dimethyl-morpholine, 2-aminomethyl-morpholine, 2-tert.-butoxycarbonylaminomethyl-morpholine, 2-methylaminomethyl-morpholine, 2-dimethylaminomethyl-morpholine, imidazole, 4-methyl imidazole, pyrrole, 3-aminomethyl-2,5-dihydro-pyrrole, 3-aminome~hyl-4-methyl-2,5-dihydro-pyrrole, 3-(1-aminoethyl)-2,5-dihydro-pyrrole, 3-amino-azetidine, 3-tert.-butoxycarbonylamino-azetidine, 3-tert.-butoxycarbonylamino-2-methyl-azetidine, 3 tert.-butoxycarbonylamino-3 methyl-azetidine, 3-tert.-butoxycaxbonylaminomethyl-azetidine, pyrrolidine, 3-methylpyrrolidine, 3-amino-pyrrolidine, 3-tert.-butoxycarbonylamino~pyrrolidine, 3-(2,2-dimethyl-propylideneamino)-pyrrolidine, 3-methylamino-pyrrolidine, Le A 28 391 - 20 -3-dLmethyl~mino-pyrrolidine, 3-aminomethyl-pyrrolidine, 3-tert.-butoxycarbonylaminomethyl-pyrrolidine, 4-chloro-3-tert.-b~toxycarbonylaminomethyl-pyrrolidine, 3-tert.-butoxycarbonylaminomethyl-3-methyl-pyrrolidine, 3-tert.-butoxycarbonylamino-4-methyl-pyrrolidine, 3-tert.-butoxycarbonylaminomethyl-3-methoxy pyrrolidine, 3-methylaminomethyl-pyrrolidine, 3-ethylaminomethyl-pyrrolidine, 4-tert.-butoxycarbonylamino-2-methyl-pyrrolidine, 2-methyl-3-methylamino-pyrrolidine, 2-methyl-4-methylamino-pyrrolidine, ~-(2-hydroxyethylamino)-pyrrolidine, 3-hydroxy-pyrrolidine, 3-hydroxymethyl-pyrrolidine, 4-amino-3-hydroxy-pyrrolidine, 3-hydroxy-4-~ethylamino-pyrrolidine, 3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine, 3-methylaminomethyl-3-hydroxy-pyrrolidine, 3-dimethylaminomethyl-3-hydroxy-pyrrolidine, 3-diethylaminomethyl-3-hydroxy-pyrrolidine, 3-tert.-butylaminomethyl-3-hydroxy-pyrrolidine, 3-methylamino-4-hydroxymethyl-pyrrolidine, 4-methoxy-3-methylamino-pyrrolidine, 3-methoxy-3-methylaminomethyl-pyrrolidine, 3-amino-4-methoxy-2-methyl-pyrrolidine, 3 tert.-butoxycarbonylamino-3-methyl-pyrrolidine, 3-methyl-4 tert.-butoxycarhonylaminomethyl-pyrrolidine, 3-methoxy-4-tert~-butoxycarbonylaminomethyl-pyrrolidine, 3-(1-imidazolyl)-pyrrolLdine, Le A 28 391 - 21 -6-hydroxy-3-azabicyclo[3.3.0]octane, 6-amino-3-azabicyclo[3.3.0]octane, l-amino-3-azabicyclo[3.3.0]octane, 1-aminomethyl-3-azabicyclo[3.3.0]octane, 1-ethylaminomethyl-3-azabicyclo[3.3.0]octane, 6-amino-3-azabicyclo[4.3.0]nonane, 3-amino-4-methylene-pyrrolidine, 7-amino-5-azaspiro[2.4]heptane~
3,7-diazabicyclo[3.3.0]octane, 3-methyl-3,7-diazabicyclo[3.3.0]octane, 2,8-diazabicyclo[4.3.0]nonane, 2-methyl-2,8-diazabicyclo[4.3.0]nonane, 3-methyl-3,8-diazabicyclo[4.3.0]nonane, 2-oxa-5,8-diazabicyclo[4.3.0]nonane, 5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 2,7~diazabicyclo[3.3.0]octane, 2-methyl-2,7-diazabicyclo[3.3.0]octane, 3-methyl-~,7-diazabicyclo[3.3.0]octane, 4-methyl-2,7-diazabicyclo[3.3.0]octane, tert.-butyl 5-methyl-2,7-diazabicyclo[3.3.0]octane, 7-methyl-2,7-diazabicyclo[3.3.0]octane, 8-methyl-2,7-diaz~bicyclo[3.3.0]octane, 7l8-dimethyl-2~7-diazabicyclo[3.3.o]octane~
2,3-dimethyl-2,7-diazabicyclo[3.3.0]octane, 2,8~dimethyl-2,7-diazabicyclo[3.3.0]octane, 1,4-diazatricyclo[6.2Ø o2,6 ]decane, 1,4-diazatricyclo[6.3Ø02~6]undecane, 2~7-diazaspiro[4.4]nonanel 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-hexahydroisoindole, 5-methyl-4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole, 6-methyl-4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole, 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-hexahydroiso-indole, 4-dimethylamino-1,3,3a,4,7,7a-hexahydroisoindole, 4-ethylamino-1,3,3a,4,7,7a-hexahydroisoindole, 4-aminomethyl-1,3,3a,4,7,7a-hexahydroisoindole, 4-methylaminomethyl-1,3,3a,4,7,7a-hexahydroisoindole, 4-hydroxy-1,3,3a,4,7,7a-hexahydroisoindole, 2,3,4,5,6,7-hexahydro-lH-pyrrolo[3,4-c]pyridine, 5-methyl-2,3,4,5,6,7-hexahydro-lH-pyrrolo[3,4-c]pyridine, 5-ethyl-2,3,4,5,6,7-hexahydro-lH-pyrrolo[3,4-c]pyridine, 5-(tart.-butoxycarbonyl)-2,3,4,5,6,7-hexahydro-lH
pyrrolo[3,4-c]pyridine.

Most of the substituted 1,3,3a,4,7,7a-hexahydro~iso-indoles are new. For example, they can be obtained by Diels-Alder reaction of dienes of the formula (1) (1), where R9 has the abovementioned meaning and RZ2 is either Le A 28 391 - 23 -!~.' ~,' i .' .' `
identical to R20 or is a functional group which can be converted into R20, with dienophiles of the formula (2) o N - R23 (2), o in which R23 denotes hydrogen or a pro~ective group such as tr~nethyl~ilyl, benzyl, Cl-C4-alkylphenylmethyl, methoxybenzyl or benzylhydryl, followed by reduction of the carbonyl groups and, if appropriate, elLmination of the protective ~roup.

Suitable diluents for the Diels-Alder reaction are all inert organic solvents. These preferably include ethers, such as diisopropyl ether, di-n-butyl ether, dimethoxy-ethane, 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 substan-tial range. In general, the process is carried out between approximately -20C and ~200C, preferably between ~20C and +150C. 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 S employed are lithium aluminium hydride, lithium boro-hydrides, lithium triethylborohydride, sodium-bis-[2-methoxyethoxy]-aluminium hydride or sodium borohydride in the presence of Lewis acid catalysts such as chlorotri-methylsilane, boron trifluoride etherate or aluminium chloride.

Diluents which can he 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 of these.

The reaction temperatures can be varied in the range between -40 and ~180C, preferably between 0~ and 140C.
The reduction is generally carried out under atmospheric pressure, but it can also be carried out under reduced pressure or under superatmospheric pressure.

The U52 of pressures between 100 and lO00 kPa is recommended so as to achieve higher reaction temperatures with low-boiling solvents.

The amount of complex hydrides employed in the reduction ~5 is at least stoichiometric. However, an excess of Le A 28 391 - 25 -preferably betw~en 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 (cf., for example, T.W. Greene, ~Protective Groups in Organic Synthesisl, John Wiley & Sons, New York 1981).

The starting substances of the formula (1) and (2) are known or can be prepared by generally known methods of organic chemistry [cf., for example, J. Am. Chem. Soc.
]00, 5179 (1978), J. Org. Chem. 43, 2164 (1978), DE 3,927,115, J. Org. Chem. 40, 24 (1975)].

If, for example, l-(tert.-butyloxycarbonylamino)-1,3-butadiene and maleimide are used as starting materials and lithium aluminium hydride as reducing agent, the course of the reaction can be represented by the follow-ing equa~ion~
O O
~ ~ NH ~ ~ NH 4 H~ C-O-C(c~3~3 O ¦ O
HN-C - O C(CH3)3 NH

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.-butylo~ycarbonylamino)-1,3-pentadiene and N-trimethyl-silyl-maleimide are used as starting materials, the course o~ the reaction can be represented by the follow-ing equation:

HN C-O-C(CH3)3 . 2 In this case, NMR spectroscopy demonstrates that all substituents on the 6-membered ring are in the cis-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 such as, for example, the hydrochlorides, is preferably carried out in a diluent such as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoric 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 -. ,'f ~ f ,f Acid binders which can be used are all customary inor-ganic and organic acid-binding agents. These preferably include the alkali metal hydroxides, alkali metal carbon-ates, organic amines and amidines. The following æubstan-ces which may be mentioned individu~lly are particularlysuitable: triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or exce~s amine (III).

The reaction temperatures can be varied within a substan-tial range. In general, the process is carried out a~
between approximately 20 and 200C, preferably between 80 and 180C.

~he reaction can be carried out under atmospheric pres-sure, but also under increased pressure. In ~eneral, the pressures used are between approximately l and 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the inven~ion, l to 15 moles, preferably l to 6 moles, of the compound (III) are employed per mole of the compound (II).

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 a~ hydrochloric acid or tri-fluoroacetic acid, when the reaction has ended (see Houben-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 the 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 sulph-oxide or tetramethylurea, at temperatures ofapproximately 0 to 100C, preferably 0 to 50C.

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 sufficient amount of aqueous acid and precipitatin~ the salt with an organic ~olvent, 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 and subsequently ~o evaporate the mixture to dryness or filter off the precipitated salt with suction. Pharma-ceutically acceptable salts are, for example, the salts of hydrochloric acid, sulphuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulphonic acid, 4-toluene~ulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

Le A 28 391 - 29 -The alXali metal salts or alkaline earth metal salts of the carboxylic acids according to the invention are cbtained, 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 examples, the active compounds listed in the table below can also be prepared, it being possible for these optio-nally chiral compounds to be present both as diastereomer mixtures or as the diastereomerically or enantiomerically pure compounds.

Le A 28 391 - 30 -F 1 ~COOR2 X2 Rl Rl R2 Xl x2 Y __ ~ H H HC_C- HN N--C~
~ H H HC_C- HN N--C~
H H HC_C- HN .~--~ H H HC_C- HN N--~ H H HC_C- N~N--[~ H H HC_C- HN~ --H H HC_C- y~--CH2-liH-CH3 Le A 28 391 - 31 -~ d ~ i i d ~ ~i J ~ -Rt R2 Xl x2 y > H H HC_C-H2N-CH

H H HC_iC- ,CN--H H HC_C- H~N-CH~

~ H H HC-C- CH~C

~ H H HC~C-H H HC~C- XJ

H H HC_C- HNIx~N--D-- H H HC_C- HNXN--H H HC_C- <~
H

Le A 28 391 - 32 -:

~J `3 ~

Rl R2 Xl x2 y H H HC=-C- HN~ XN--NHz H H HC-C- (~N--H H HC~C- ~CN--2H5 H H~=C- ~N--H F H~=C- [~N--H NH2 HC-C- ¢~N--C2H5 H H -C_CH H2N { J

~H H -C_CH ~

F -C=-CH ¢~ N--F ~ -C_C-CH3 HN~N--Le A 28 391 - 33 -'.3 ~ S ! 3 Rl R2 X XZ Y

D-- H H F-C_C- ¢~N--H H CH30-C_CCH3-N N--I> H H CH30-C--C-2 {

'' / \
H H CF3-C-C-C~3-N N--~ H H CF3-C=C-C2H5NH-CH2~

D-- H H CH30-CH2-C_C- CH3-N N--.. NH2 C~ H H CH30-CH2-C_C- ~N--Le A 28 391 - 34 --Rl R2 Xl X2 Y
-H H CH2=CH- HN N--> H H CH2=CH- CH3 >cJN-D-- H H CH2=CH- ~N-->-- H H CH30-CH=CH CH3-N N--H CH30-CH=CH- H2N CJ

H H CH30-CH2-CH=CH-CH3-N~ N--N-D-- H H CH30-CH2-CH=CH-H0{
.~ ~
H H CH2=CH-CH2-CH3-N N--H H CH2 CH CH2 H2N-CH2>~ N--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, aminoglyco-sides, sulphonamides or tetracyclins.

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

The compounds according to the invention are active towards a very broad range of microorganisms. With their aid, it is possible to combat Gram-negative and Gram-positive bacteria and bacteria-like microorganisms, and to prevent, alleviate and/or cure the diseases caused by these pathogens.

The compounds according to the invention are distin-guished by an improved action on resting and resistant microorganisms. In the case of quiescent bacteria, that is bacteria which do not show any detectable grow~h, 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 Gram-positive 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-like microorganisms, they are particularly suitable for the prophylaxis and chemotherapy of local ~nd systemic infections in human and veterinary medicine which ~re caused by these pa~hogens.

Furthermore, the compounds are suitable for combating pxotozoonoses and helminthoses.

The compounds acc~rding to the invention can be used in a range of pharmaceutical preparations. Preferred phanma-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 ,3 ~

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 incuba~ed at 37C, and growth of the pathogens was determined after approx. 20 hours.
The MIC value (~g/ml) indicates the lowest concentration of active compound where no growth was discernible to the naked eye.

The table below lists the MIC values of some of the compounds according to the invention compared with ciprofloxacin.

Le A 28 391 - 38 -__ __ _ _ __ __ O ~ o ~ c~ ~ In n ~s '~
c~o ~ ~ ~ o o l o o o ~u ~ ~
- - - - ~
~ w ~ ~ u~ ~n N O LnO _~ _1 ~1 t~l ~ O O ~ O O O O O
~ ~) ~ In U~ ~
C~ O _I .-1 ~ N O
_~ O _l ~ O ~ O O O
_ _ _ _ O O N O
U') O C~ ~ O O _l ~ O
_ _ _, U~ U~ ~ ~D ~ ~ ~r ~r _l ~ ~ o o ~ ~ _~
O O O O O O O O
_ __ _ _ o~ ~ ~ ~ n u~
O ~ ~ O O O _~ O
_ _ _. . _ __ _ ~ ~D ~D U~ U'~ U~
a~ ~ ,, o o ~ N
O ~~ O O O O O
-~, _ _ ~ ~ U~~O U~ ~ ~ r~
~D O ~IO O ~-1 _~
O O_l O O O O O
tl~ _ O In O r~ _~ r~ O
_O O ~_ O O O O O
~1r~ ~ ~1 Il~
~_~ _~ ~ ~
o~ C~ O O O
._ _ ___. _ _ ~ .
C~
l ~ U~ ~
:~ ~ _l ~D O O ~O
_ ~3 ~ ~4 U~ ~) _~ Cl~ O
l Z ~ ~ ~ ~1 ~ ~ ~
U u2 ~, ~ ~ ~ U ~.~
~h U O O u~ ,4 ~
. ~ .,1 O _~ U-~l O U
In - l ~ n ~ O--I ~ nJ
O O ~ .C ~:1 1~ ~ ~ O
J~ U h a~ P~ ~ ~u U ~:: u Iu~ t)~ a~ ~ ~
~ e~ ~,3 ~ ~ ~ ~ I ~I ~ ~ ~ ~

LeA_28 391 - 39 -J ~

PreParation of the intermediates Example Zl Ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate ~--3.72 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 4.4 g of tributyl-vinyl stannan and 0.46 g of tetrakis(triphenylphosphina)-palladium(0) are refluxed in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere. The mixture is flltered 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 l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylate are obtained (79~ of theory).Melting point: 178-179~C.

Example Z2 l-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid 0.9 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-S-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 temperatuxe, the reaction mixture i8 then treated with 10 ml of water. The solid is filtered off Le A 28 391 - 40 with suction at room temperature, washed with water and dried. 0.58 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (71% of theory) is obtained.
Melting point: 182-184~C.

ExamPle Z3 Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(tri-methylsilyl ethinyl)-4-oxo-3-quinolinecarboxylate 22.2 g of ethyl 8-bromo-l-cyclopropyl-6,7-difluoro~1,4-dihydro-4-oxo-3-quinolinecarboxylate, 30.2 g of tributyl-stannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis-(triphenylphosphine)palladium(0) are refluxed for 3 hours in 300 ml of absolute toluene under a nitrogen atmos-phere. After the reaction mixture has cooled to approx.
-18C, the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trLmethylsilylethinyl)-4-oxo-3-quinolinecarboxylate (~o~ of theory) are obtained.
Melting point: 171-172~C.

ExamPle Z4 Ethyl l-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-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 h mixture of 300 ml of dimethyl-formamide, 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 ~haking with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue obtained i~
recrystallised from methanol. In thi~ way, 9 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (59% of ~heory) are obtained.
Melting point: 186-187C.

Example Z5 1-Cyclopropyl-8 ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 10.3 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 4 hours in a mixture of 100 ml of glacial acetic acid, 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-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ~62~ of theory) are obtained.
Melting point: 233 C.

Le A 28 391 - 42 -Example Z6 Ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3 quinolinecarboxylate 1.9 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3.5 g of l-tri-butylstannyl-hex~1-ine and 0.29 g of tetrakis(triphenyl-pho~phine)palladium(0~ are refluxed for 8 hour~ in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue i8 ~tirred with 30 ml of hexane, and the resulting solid is recrys-tallised from cyclohexane. 0.7 g of ethyl l-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-~-oxo-3-quinoline-carboxylate is obtained (36% of theory).
lH NMR (200 MHz, CDCl3): ~ 0.95 (t; 3 H), 1.1-1.7 (m;
11 H), 2.50 (t; 2 H), 4.1-4.3 (m; 1 H), 4.38 (q; 2 H), 8.14 (dd; 1 H), 8.56 ~s; 1 H) ppm.

Example Z7 1-Cyclopropyl-6,7-difluoro-8~ hexinyl)-1,4-dihydro-4-oxo-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 concentra~ed sulphuric acid. The reaction mixture is treated with 100 ml of water, and the 601id i8 filtered off with ~uction and Le A 28 391 - 43 ~ I ~. 3 dried. 0.5 g of 1-cyclopropyl~6,7-difluoro-8-(l-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid i5 obtained (85~ of theory)~
lH NMR (200 MHz, CDCl3): ~ 0.96 (t; 3 H), 1.1-1.7 ~m;
8 H), 4.3-4.5 (m; 1 H), 8.20 (dd; 1 H), 8.85 (s; 1 H) ppm.
Melting point: 118-121C.

Example Z8 Ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dLmethylbutin-l-yl)-4-oxo-3-quinolinecarboxylate __ Analogously to Example Z6, l-tributylstannyl-3,3-di-methyl-but-l-ine gives 0.87 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dLmethylbutin-1-yl)-4-oxo-3-quinolinecarboxylate (46% of theory).
Melting point: 170-172C.

Exa~ple Z9 1-Cyclopropyl-6,7-difluoro-1,4-d~hydro-8-(3,3-dimethyl-butin-l-yl)-4-oxo-3-quinolinecarboxylic asid Hydrolysis of 0.75 g of the ester from ~xample Z8 analog-ously to Example Z7 qive~ 0.56 g of l-cyclopropyl-6,7-difluoro-8-(3,3-dimethylbutin-1-yl)-4-oxo-3-quinoline-carboxylic acid (81~ of theory).
Melting point: 199 201C.

Le A 28 391 - 44 -, ;~ , ' . t Example Z10 Ethyl l (2,4~difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trLmethylsilylethinyl) -4-oxo 3-guinolinecarboxylate ~___ _ 6.7 g o f ethyl 8-bromo-1-( 2,4-difluorophenyl)-6,7-di-fluoro-1,4-dihydro-4-oxo-3 -quinolinecarboxylate (Example Z20), 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 -18C. 4.8 g of ethyl l-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(tri-methylsilylethinyl)-4-oxo-3-quinolinecarboxylate are o~tained (69% of theory).
Melting point: 173-174C.

Example Zll Ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate A solution of 4.6 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl~ 4-oxo-3-quinolinecarboxylate in 20 ml of chloroform i8 added dropwise at room temperature to 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. 20C, the reaction mixture is then treated with more chloroform and Le A 28 391 - 45 -~ _ J :., J
extracted several times by shaking with water, and ~he organic phase is dried and concentrated. The residue obtained is recrystallised from methanol. 3.4 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylate are obtained (87% of theory).
Melting point: 189C.

Example Z12 1-(2,4-Difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-di-hydro-4 oxo-3-quinolinecarboxylic acid 1.17 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 9 ml of glacial acetic acid, 0.75 ml of water and 0.2 m~ of concentrated sulphuric acid. The solid which has crystalli~ed out at room temperature is filtered off with suction and dried.
0.98 g of 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of theory).
Melting point: 220C (decompo~ition).

Example Z 13 Ethyl 1 cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin l~yl)-3-quinolinecarboxylate 7O5 ~ of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-Le A 28 391 - 46 ~

dihydro-4-oxo-3-quinolinecarboxylate~ 9.1 g of 1-tri-butylstannyl-prop-l-ine and 1.16 g of tetrakis(~riphenyl phosphine)palladium(O) are refluxed for 8 hour~ in 80 ml of absolute toluene under a ni~rogen atmosphere. Th~
solid which crystallises out at -18C is filtered off with suction and dried. 2.05 g of ethyl l-cyclopropyl-6,7-difluoro 1,4-dihydro~4-oxo-8-(propin-1-yl)-3-quino-linecarboxylate are obtained (31% of theory).
lH NMR (200 MHz, CDC13): ~ 1.1-1.35 (m; 4 H), 1.40 (t;
3 H), 2.16 (d; 3 H), 4.1-4.3 (m; 1 H~, 4.35 (q; 2 H), 8.15 (dd; 1 H), 8.56 (s; 1 H) ppm.
Melting point: 180-182C.

Exam~le Z14 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-~propin-1-yl)-3-quinolinecarboxylic acid 1.4 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)~3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 20 ml of glacial ace~ic 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-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinoline-carboxylic acid are obtained (82% of theory).
H NMR (20G MHz, CDCl3): ~ 1.4 (m; 4 H), 2.26 (d; 3 H),4.4-4.6 (m; 1 H)~ 8.16 (dd; 1 H), 8.81 (s; 1 H) ppm.
Melting poin~: 212-213C.

Le A 28 391 - 47 -, ` ! , ~ ! 3 , . ~

Example Z15 Ethyl l-ethyl-6~7~difluoro-l~4-dihydro-8-(trimethylsi ethinyl)-4-oxo-3-quinolinecarboxylate _ _ 5.4 g of ethyl 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and O.B7 g of tetrakis(triphenylphosphine)palladium(0) are refluxed 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 result-ing solid is filtered off with suction and dried. 4.53 g of ethyl l-ethyl-6,7-difluoro-1,4-dihydro-8~(trimethyl-silylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (80~ of theory).
Melting point: 151-152 C.

Example Z16 Ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-8 (tri-methylsilylethinyl)-4-oxo-3-quinolinecarboxylate 1.64 g of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3 g of tributyl-stannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis-(triphenylphosphine)palladium(0) are refluxed for 42 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to approx.
18C and filtered. After the filter residue has been Le A 28 391 - 48 ~

/r J ~ ~ Ji ,~
dried, 0.74 g of ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinoline-carboxylate is obtained (38% of theory).

Example Z17 Ethyl 1-cyclopropyl-6,7-difluoro 1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate 1.86 g of ethyl 8-bromo-1-cyclopropyl-6l7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.8 g of 1-tri-butylstannyl-3-methyl-but-3-en-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 6 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture 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 1-cyclopropyl-6,7-difluoro-1,4-dihydro 8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate are obtained (80% of theory).
Melting point: 169-171C.

Exam~le Z18 l-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3 quinolinecarboxylic acid 0.715 g of ethyl l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylate is refluxed 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 precipi-tated is filtered off with suction, washed with water and 5 dried. 0.53 g of 1-cyclopropyl-~,7-difluoro-1,4-dihydro-8-(3-methyl~but-3-en-1-inyl)-4-oxo-3-quinolinecarboxy:Lic acid is obtained (80% of theory).
Melting point: 204-206 C.

Example Z19 Ethyl 2-(3-bromo-2,4,5-trifluo~o-benzoyl)-3-(2,4-difluorophenylamino)-acrylate .
40 g (0.1 mol) of ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-ethoxy-acrylate in 180 ml of ethanol are treated with 14.S g (0.11 mol) of 2,4-difluoro-aniline, with ice-cooling. The mixture is allowed to stand over~
night at 10C, and the precipitated solid is filtered off with suction, washed with cold ethanol and dried in vacuo.
Yield: 38 g (81% of theory).
Melting point~ 102-103~C (with decomposition) (from isopropanol).

Le A 28 391 - 50 -' j ~ I` ~ ~
Example Z20 E~18-~n~1-(2,4-diflu~r~Y~yl)-6,7-difluo ~ 1,4-d~ydn~4-o ~ 3-quinolinecarboxylate 38 g (82 mmol) of ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-(2,4-difluorophenylamino)-acrylate in 200 ml of dimethylformamide are treated with 7.6 g of sodium fluoride and the mixture is refluxed for 2 hours. The mixture is poured into ice-water, and the precipitate is filtered off with suction, washed thoroughly with ~ater and dried at 80C in a recirculation drying cabinet.
Yield: 34.7 g (95% of theory).
Melting point: 208-210C (with decomposition) (from glycol monomethyl ether).
Acid hydrolysis of this ester gives 8-bromo~1-(2,4-difluorophenyl)-6~7-difluoro-1,4-dih~ -o-4-oxo-3-quino-linecarboxylic acid of melting point 210-221C (with decomposition).

Example Z21 Ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-ethylamino-acrylate 20 g (0.05 mol~ of ethyl 2-(3-bromo-2,4,5-~rifluoro-benzoyl)-3-ethoxy-acrylate in 40 ml of ethanol are treated with 5.5 g of a 50% strength aqueous ethylamine solution, with ice-cooling. The mixture is allowed to stand overnight at 10C, the suspension is treated with Le A 28 391 -- 51 -' J ' ` ~

200 ml of water, and the precipitated solid is filtered off with suction, washed with water and dried in vacuo at 60C.
Yield: 17.3 g (91% of theory).
Melting point: 101--102C (with decomposition) (from isopropanol).

Example Z22 Ethyl 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 16 g (42 mmol) of ethyl 2-(3-bromo-2,4,5-trifluoro-benzoyl)-3-ethylaminoacrylate are reacted analogously to Example Z20.
; Yield: 14.6 g (96~ of theory).
lS Melting point: 172-173 C (with decomposition) (from glycol monomethyl ether).
Acid hydrolysis of this ester gives 8-bromo-l-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 215-217C (with decomposition).

Example Z23 4-Methylamino-1,3 3a,4,7,7a-hexahYdroisoindole Method I:

10.1 g (60 mmol) of N-trimethylsilylmaleimide [J.Org.
Chem. 40, 24 (1975)~ in 30 ml of absolute tetrahydrofuran Le A 28 391 - 52 -are introduced into a reaction vessel, and 14.4 g (60 mmol) of 70~ 1-(tert.-butyloxycarbonylamino)-1,3-butadiene [J.Org.Chem. 43, 2164 (1978)], dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise. When the exothermic reaction ha~ 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 succe6sion to the cold reaction mixture. The salts are filtered off and the filtrate is concentrated in vacuo. The residue (10.3 g) is distilled at 87C/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 -70C.
Yield: 3.3 g, melting point: 72-82C.

Treatment with an equimolar amount of 2N hydrochloric acid gives 4-methylamino-1,3,3a,4,7,7a-hexahydro-iso-indole dihydrochloride of melting point 265-268C (from methanol).

Le A 28 391 - 53 -r;~; -? ~ ri Method I I:

a) 4-(tert.-Butyloxysarbonylamino)-1,3 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. 70%
l-(tert.-butyloxycarbonylamino)-1,3-bu~adiene di~solved in 500 ml of absolute tetrahydrofuran are added dropwise, during which process the temperature is kept at 20 to 30C. Stirring is continued over-night at room temperature. The mixture is then concentrated, and the product is recrystallised from ethyl acetate. 57 g of product of a melting point of 177 to 182C are obtained. A further 13 g of a melting point of 158 to 160C are obtained from the mother liquor.

b) 4-Methylamino-1,3,3a,4,7,7a-hexahydroisoindole Under nitrosen, 27.1 g (0.71 mol) of lithium alumin-ium 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-l,3,3a,4,7,7a-hexahydroisoindole in 570 ml of abfiolute tetrahydrofuran is added dropwise. The mixture is then r0fluxed 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 ~etra-hydrofurar., and the filtrate is concentrated in vacuo. The residue is distilled off under a high vacuum.
Yield: 19.1 g.

Example Z24 4-AI[ ino-l, 3, 3a, 4, 7 . 7a-hexahYdro-isoindole 13.3 g (50 mmol) of 4-tert.-butyloxycarbonylamino-1,3-dioxo-1,3,3a,4,7,~a-hexahydro-isoindole ( f rom Example Z23, method II) are stirred overn~ght 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 50C. The residue is subsequently taken up in absolute tetrahydro-furan 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 (O.3 mol) of lithi~m aluminium hydride in 300 ml of absolute tetrahydrofuran. Ths mixture is then refluxed for 16 hours. 11.3 g of water in 34 ml of tetrahydro-furan, 11.3 ml of 10% strength sodium hydroxide solu~ion and 34 ml of water are added dropwise in succession to the cold mixture. Tha precipitate is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated, and the residue is distilled.
Yield: 2.2 g, content: 92~ (determination by gas Le A 28 391 - 55 -,;~, ; ~ 3 , ,~

chromatography) Boiling point: 70C/0.2 mbar.

Example Z25 7-Methyl-4-methYlamino-1 3 3a,4.7 7a-hexah~dro-isoindole Analogously to Example Z23, method I, 21.9 g (0.12 mol) of l-(tert.-butyloxycarbonylamino)-1,3~pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilyl-maleimide, and the product is subsequently reduced with 15.2 g (0.4 mol) of lithium aluminium hydride. The crude product is recrystallised from tetrahydrofuran.
Yield: 6.2 g, melting point: 105-108C.

Example Z26 l-CYcloproPYl-6.7-difluoro-1 4-dihvdro-8-(3-methoxy-propin-1-yl~-4-oxo-3-auinolinecarboxYlic acid A) 1.86 g (5 mmol) of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 20 ml of absolute toluene are treated with 2.5 g (7 mmol) of 1-tributyl-stannyl-3-methoxy-propine and 0.29 g (correspc-nding to 5 mol %) of tetrakis-(triphenylphosphine)-palladium(0), and the mixture is refluxed for 4 hours in a nitrogen atmosphere.
The reaction mixture is concentrated, the residue is stirred with hexane, 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-cyclo-propyl-6,7-difluoro-1,4-dihydro-8-(3-methoxy-propin-1 yl)-4-oxo-3-quinolinecarboxylate.
Melting point: 144-146C

B) 0.36 g (1 mmol) of the product of stage A is refluxed for 1 hour in a mixture of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concen-trated sulphuric acid. The mixture is poured into water, and the precipitate is filtered off and recrystallised from ethanol.
Yield: 153 mg (46% of theory) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methoxy-propin-1-yl)-4-oxo-3-guinolinecarboxylic acid.
lS Melting point: 170-172C
H NMR (270 MHz, CDCl3): ~ 1.24 m (2H), 1.4 m (2H), 3.45 s tOCH3), 4.35 m (lH), 4.41 s (O-CH2-), 8.27 "t"
(lH), 8.87 ppm s (lH).

Preparation of the active compounds Example 1 o F~C~I~ COOH
~ N ~ N
C~3 C
CH

Le A 28 391 - 57 -.

A) 2.32 g (8 mmol) of 1-cyclopropyl-8-e~hinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide are refluxed 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 suspen-sion 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 1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(4-methyl-l-piperaz-inyl)-4-oxo-3-quinolinecarboxylic acid.
Melting point: 228-230~C (with decomposition).
lH NMR (d5-DMF): ~ 4.95 ppm s (-C-C-H).

- 15 B) In an analogous manner, l-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid is obtained with 2-methylpiperazine.
lH NMR (d5-DMSO). ~ 5.03 ppm s (-C-C-H).
Mass spectrum: m~e 369 (M~), 325 (M'-CO2), 300, 293, 269, 243, 44 (CO2).

Using ~he products of Examples Z14, Z7 and Z9, the following are obtained analogously to Example 1:

Le A 28 391 - 58 -~J Z Jr ,~ t, "".

F ~ COOH

, N J C
C

Example 2 (R=CH3): 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(propin-1-yl)-3-guino-linecarboxylic acid.
5 Melting point: 246-249 C (with decomposition).

Exam~le 3 (R=CH2CH2CH2CH3): 1-Cyclopropyl-6-fluoro-8-(hexin-1-yl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
Melting point: 206-208~C (with decomposition).

Example 4 (R=C(CH3)3: 1-Cyclopropyl-8-(3,3-dimethylbutin-l-yl)-6-fluoro-1,4-dihydro 7-(4-m~thyl-l-piperazinyl)-4-oxo-3 quinolinecarboxylic acid.
Mel~ing point: 234-237C (with decomposition).

k~ - 59 -Example 5 o F ~ COOH

CH

Analogously to Example 1, the reaction is carried out with ci6-2,8-diazabicyclo[4.3.0]nonane to give l-cyclo-propyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 225-227C (with decomposition).
1H NMR (d6-DMF): ~ 4.9 s (-C-C-H~.

Example 6 o F ~ COOH

C ~ x H20 CH

3.2 g (12 mmol) of 1-cyclopropyl-8-ethinyl-6,7-dihydro-1,4-dihydro-4-oxo-3-quinolinecarboxylic 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 ~ (14 mmol3 of 1,4-diazabicyclo[2.2.2]octane and 2.75 g (18 mmol) of 3-(2/2-dimethylpropylideneamino)pyrrolidine. The solution is concentrated, the residue is stirred with approximately 100 ml of water (pH 7), the precipitate is filtered off with suction, wa~hed with wat~r 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 i~ then filtered off with suction, washed with water and dried in vacuo at 80C.
Yield: 3.8 g (82% of theory) of 7-(3-amino-1-pyrrolid-inyl)-l~cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrate.
Melting point: 193-196C (with decompo~3ition).

Example 7 O A:R=CO-O-C(CH3)3 F ~ COOH B:R=HxCF3COOH
CH3 ~ N ~ N
R-NH ~--~ C
CH

A) Analogously to Example 1, the reaction is carried out with 3-tert.-butoxycarbonylamino~3-methyl-pyrrolidine to give 7-(3-tert.-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclo-propyl-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid .

Le A 28 391 - 61 -! I ~. J ~

of melting point 244-246C (with decomposition).
1H NMR (d6-DMSO): ~ 4.92 ppm s (-C-C-H).

B) 500 mg of the product of stage A are dissolved in 5 ml of trifluoroacetic acid with ice-cooling, the solu~ion is conc~ntrated 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-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid trifluoroacetate.
Meltin~ point: 242-244C (with decomposition).

15 Exam~le 8 o F ~3~ COOH
~ C
CH

Analogously to Example 1, the reaction is carried out with 2-oxa-5,8-diazabicyclo[4.3.0]nonane to give 1 cyclopropyl-8-ethinyl-6-fluoro-1,4-dihy~ro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic ~e A 28 391 - 62 -acid of melting point 290C (with decomposition; sinter-ing starts at approximately 170C).
1H NMR (d6-DMSO): ~ 5.0 ppm s ~ C-C-H).

Example 9 o F ~ COOH

~ ~ ~ C
C

Analogously to Example 1, 2-oxa-5,8-diazabicyclo[4.3.0]-nonane are reacted with the product of Example Z14 to give l-cyclopxopyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0~non-8-yl)-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylic acid of melting point 241-242C ~with decomposition).

Le A 28 391 ~ 63 -~ J~

Exam~e 10 F ~ COOH A:~=(CH3)3C-O-CO-CH3 ~ ~ ~ N B:R=H
R-NH ~ C
C

A) 303 mg (1 mmol) of the product of Example Z14 in a mixture of 6 ml of acetonitrile and ~ ml of dimethylformamide are treated with 2~0 mg of 3-tert.-butoxycarbonylamino~3-methyl-pyrrolidine 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 re~idue is stirred with 30 ml of water, and the mixture is dried at 8 0 C in vacuo .
Yield. 420 my (87% of theory) of 7-(3-tert.-butoxy-carbonylamino-3-methyl-l-pyrrolidinyl)-l-cyclo-propyl-6-fluoro-l~4-dihydro-4-oxo-8-(propin-l~yl) 3-quinolinecarboxylic acid.
Melting point: 195-196C (with decomposition).
H NMR (d6-DMSO): ~ 1.42 s (CH3 on the pyrrolidine), 2.12 ppm s (CH3-C-C-).

B) 180 mg of the product of stage A are di6solved in 1.6 ml of trifluoroacetic acid at 0CI and, after Le A 28 391 64 -~ f~, r~

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-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylic acid of melting point 209-210C are isolated (with decom-position).
Mass spectrum: m/e 383 (Mt), 309, 298, 267 (100%), 133, 70.

Exam~le 11 o F ~ COOH
f ~ ~ N
CH3 C ~ F
CH
F

Analogously to Example l, the product of Example Zl2 is reacted with N-methylpiperazLne to give 8-ethinyl-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 193-l95~C (with decomposition).
H NMR (CDCl3): 3.35 s (-C-CH).

Le A 28 391 - 65 -~' J '~ ~f Exam~le 12 o F ~ ~ COOH

~ ~ ~ N~
CH3-N ~ C
CH

Analogously to Example 1, the reaction is carried out with 3-methyl-3,8-diazabicyclo[4.3.0]nonane, and 1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(3-methyl-3,8--diazabicyclo[4.3.0]non-8-yl)-4 oxo-3-quinoline-carboxylic acid, which is obtained as crude product, is purified by chromatography (silica gel; dichloromethane/
methane/20~ aqueous ammonia 2:4:1~.
1H NMR (CDCl3): 4.15 s (-C-C-H).

Example 13 o COO~I
~N ~f N
N ~
c~3 CH

Analogously to Example 1, the reaction is carried out Le A 28 391 - 66 -J

with 3-methyl-3,7-diazabicyclo[3.3.0]octane to give 1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-~7-methyl-3,7-diazabicyclo[3.3.0~oct-3-yl)-4-oxo-3 quinoline-carboxylic acid or melting point 212-216C ~with decom-position~.
1H NMR (d6-DMF): ~ 4.95 s (-C-C-H).

Example 14 F ~ ~ C~OH
CH3 - ~H ~ ~
~ Cj ~
CH

Analogously to Example 1, the reaction is carried out with 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole to give l-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(4-methylamino-1,3,3a,4,7,7a-hexahydroisoindol-2-yl)-4-OxO-3-quinolinecarboxylic acid of melting point 128-133C
(with decomposition).
1H NMR (d5-DMSO): 8 4.93 ppm s (-C=CH).

Le A 28 391 - 67 -Example 15 o F ~ COOH
f N ~ N
CH,NJ C
C

H2C~ ` CH3 164 mg (0.5 mmol) of the product of Example Z18 are reacted analogously to Example 1 with 1-methylpiperazine to give 120 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-(3-methyl-but-3-en 1-inyl)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 195-197C
(with decomposition) (recrystallised from glycol mono-methyl ether).
lH NMR (CDCl3): ~ 5.36 m (>C=CH~), 2.4 s (N-CH3), 2.0 t (C-CH3) Le A 28 391 - 68 Example 16 o F ~ COOH
H ~ ~ ~ N
~ Cl ~
C
H2C~ CH3 Analogously to Example 15, the reaction is carried out with 2,8-diazabicyclo[4.3.0]nonane to giYe 1-cyclopropyl-7-(2,8-diazabicyclo~4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyll-4-oxo-3-quinolinecarboxylic acid of melting poin~ 201-202~C (wi~h decomposition).

ExamPle 17 F ~ COOH A R= N ~
R N r ~ -C ~ B. R= H
C HN~
H2C~ ~ CH3 C. R= CH3 Le A 28 391 - 69 -Analogously to Example 15, the reaction is carried out with A. 1,4-Diazabicyclo[3.2.1]oc~ane B. 3-Hydroxypyrrolidine C. 2-Methylpiperazine to give the following compounds:

A. l-Cyclopropyl-7-(1,4-diazabicyclo[3.2.1]oct 4-yl)-6-fluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid, 0 B . l-cyclopropyl-6-fluoro-l~4-dihydro-7-(3-hydr pyrrolidinyl)-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid, melting point: 190-198C (with decomposition), C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.

Example 18 o F ~ COOH
~ N ~ N~ xHCI
CH' N J Cl C

Le A 28 391 - 70 -!,, f~ _ 100 mg of the product of Example l are dissolved in 40 ml of lN hydrochloric acid, and the solution is stirred for 2 hours at 30C. This gives a suspension which is concen-trated. The residue is stirred with a little isopropanol, and the precipitate is filtered off with suction, washed with isopropanol and dried in vacuo at 90C.
Yield: 0.1 g (83~ of theory) of 8-(1-chlorovinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-me~hyl-1-piperaz inyl)~4-oxo-3-quinolinecarboxylic acid hydrochloride.
Melting point: 251-252C (with decomposition).

1H N~R (d6-DMSO): ~ 6.0 ppm dd (- I=CH )~

Example 19 o F ~ ~ COOH

CH3 J il ~ x HCI

A) 100 mg of the product of Example 2 in 58 ml of 4N
hydrochloric acid are heated for S hours at 60C.
The mixture is concentrated, and the residue is stirred with diethyl ether and dried in vacuo at Le A 28 391 - 71 -J i ~ i e 70t~C ~
Yield: 90 mg of cis-trans-8-(1-chloro-1-propenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride.
Melting point: 236-237C (with decomposition).
Mass spectrum: m/e 419 (M+), 71.58 (100~), 43.36.

1H NMR (d6-DMSO): ~ 6.12 q and 6.35 q (-C=CH-CH3 ;
two si~nals for cis-trans forms).
B) Analogously, cis-trans-8-(l-chloro-l-hexenyl)-1-cyclopropyl-6-fluoro-1,4-dlhydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride i5 formed with the product of Example 3.
Mass spectrum: m/e 461 (M+), 425 (M-HCl), 71.58 (100%), 43.36.

Examcle 20 o F ~ COOH

CH3 N ~ N xHCI
>C Cl--C ~, CH

Le A 28 391 - 72 -370 mg of the product of Example lOA are dlssolved in 9 ml of half-concen~rated hydrochloric acid, and the solution is concentrated under a hiyh vacuum.
Yield: 340 mg of cis-trans-7-(3-amino-3-methyl-1-pyrroli~
dinyl)-8-(1-chloro-1-propenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro-chloride.
NMR (d6-DMSO): ~ 6.19 q and 6~36 q (~C=CH-CH3; 2 signals for cis-trans forms).

Example 21 o N J C~ ~HCI
~ F

10 mg of the product of Example 11 in 4.5 ml of 2.5N
hydrochloric acid are heated for 1 hour at 60C. The mixture is concentrated, and 8-(1-chlorovinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperaz-inyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride is obtained as residue.

Le A 28 391 73 -,$, i, "
, ~ ~ . ...

Mass spectrum: mie 477 (M~), 442 (M'-Cl), 36 (100%, HCl).

Example 22 o H2.~ ~ ~ ~ COOH

291 mg (1 mmol) of the product of Example Z2 in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide are treated with 240 mg (2.2 mmol) of 1,4-diazabicyclo-[2.2.2]octane and 360 mg (2.3 mmol) of 3-(2,2-dimethyl-propylideneamino)-pyrrolidine, and the mixture is refluxed for 32 hours. The mixture is concentrated, the dark oily residue is stirred with 1~ ml of water, and the solid which has precipitated (103 mg) is filt~red off 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-amino-1-pyrrolid-inyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3-~uinolinecarboxylic acid.

Melting point: 179-182 C (with decomposition).

CI mass spectrum: m/e 358 ([M+H]+), 340 ([M+H-H2O]~).

Example 23 Le A 28 391 - 74 -F ~ COOH
~ ~ N ~ N

145 mg (0.5 mmol) of the product of Example Z2 in a mixture of 10 ml of acetonitrile and 5 ml of dimethyl-formamide are treated with 60 mg (0.54 mmol) of 1, 4-diazabicyclo[2.2.2]octane and 140 mg (1.1 mmol) of cis-2,8-diazabicyclo-[4.3.0]nonane, and the mixture is refluxed for 4 hours. The solution is concentrated, the concentrate is stirred with approximately 5 ml of water, and the mixture is brouqht to pH 7 using dilute hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried in vacuo at 90C.
Yield: 120 m~ (61% of theory) of 1-cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo 8-vinyl-3-quinolinecarboxylic acid.
Melting point: 205-207C (with decomposition).
H NMR (CF3COOD): ~ 5.05 d (lH3, 5.7 d (lH), 7.55 dd (lH) (signal groups for ~C~=CH2).

Le A 28 391 - 75 Example 24 o F ~ COOH

C

Analogously to Example 1, the reaction is carried out with the product of Example Z26, and 1-cyclopropyl-6-S fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-8-(3-methoxy-propin-1-yl) 4-oxo-3-quinolinecarboxylic acid of melting point 187-189C is obtained.
lH NMR (CDC13): ~ 8.95 s (lH), 8 d (lH), 4.37 s (O-CH2), 4.35 m (lH), 3.58 m (4H), 3.43 s (O-CH3), 2.58 m ~4H), 2.38 s (N-CH3), l.33 m (2 H), 1.02 ppm m (2H).

Example 25 o F ~ COOH

H ~
CH

Le A 28 391 - 76 -Analogously to Example 1, the reaction is carried out with 3,7-diazabicyclo[3.3.0]octane, the reaction product is chromatographed on silica gel using dichloromethane/
methanol/17% strength ammonia (30:8:1~ as the eluent, and 1-cyclopropyl-7-(3,7-diazabicyclo~3.3.0]oct-3-yl)-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained as a "solidified foam".
H N~R (d6-DMSO): 8 4.9 s (-C~CH).

Le A_28 391 - 77 -

Claims (19)

1. Quinolonecarboxylic acid derivatives of the formula (I) (I).
in which R1 represents straight-chain or branched C1-C4-alkyl which is optionally substituted by hydroxyl, halogen or C1-C3-alkoxy, or represents optionally halogen- or C1-C3-alkyl-substituted C3-C6-cycloalkyl, C2-C4-alkenyl, furthermore represents C1-C3-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, R2 represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, Le A 28 391 - 78 -X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -?=CH-R3. -C=C-R5 or -CH2-CH=CH2, where R3 represents hydrogen, C1-C3-alkyl, C1-C3-alkoxy or alkoxymethyl having 1 to 3 C
atoms in the alkoxy moiety, R4 represents hydrogen or halogen and R5 represents hydrogen, C1-C6-alkyl which is optionally monosubstituted to trisubstituted by halogen, or C2-C3-alkenyl, alkoxy having 1 to 3 C atoms, alkoxymethyl having 1 to 3 C atoms in the alkoxy moiety, halogen or trimethylsilyl, and Y represents Le A 28 391 - 79 - Le A 28 391 - 80 -where R6 represents hydrogen, optionally hydroxyl- or methoxy-substituted straight-chain or branched C1-C4-alkyl, cyclopropyl, oxoalkyl having 1 to 4 C atoms or acyl having 1 to 3 C atoms, R7 represents hydrogen, methyl, phenyl, thienyl or pyridyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R10 represents hydrogen or methyl, R11 represents hydrogen, methyl or R12 represents hydrogen, methyl, amino, optionally hydroxyl-substituted alkyl- or dialkylamino having 1 or 2 C atoms in the alkyl moiety, aminomethyl, aminoethyl, optionally hydroxyl-substituted alkyl- or dialkylaminomethyl having 1 or 2 C atoms in the alkyl moiety or 1-imidazolyl, R13 represents hydrogen, hydroxyl, methoxy, Le A 28 391 - 81 -methylthio or halogen, methyl or hydroxymethyl, R14 represents hydrogen or methyl, R15 represents hydrogen, methyl or ethyl, R16 represents hydrogen, methyl or ethyl, R17 represents hydrogen, methyl or ethyl, R18 represents hydroxyl, or R19 represents hydrogen, optionally hydroxyl-substituted C1-C3-alkyl, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety or C1-C3-acyl, R20 represents hydrogen, hydroxyl, Le A 28 391 - 82 -hydroxymethyl or , where R21 denotes hydrogen or methyl, A represents CH2, 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 R1 represents optionally hydroxyl-substituted C1-C2-alkyl, C3-C5-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, R2 represents hydrogen, alkyl having 1 to 3 carbon Le A 28 391 - 83 -atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -?=CH-R3. -C=C-R5 or -CH2-CH=CH2, where R3 represents hydrogen, C1-C2-alkyl, methoxy or methoxymethyl, R4 represents hydrogen and R5 represents hydrogen, C1-C4-alkyl which is optionally monosubstituted to trisubstituted by fluorine, or C2-C3-alkenyl, methoxy or trimethylsilyl, and Y represents Le A 28 391 - 84 - where R6 represents hydrogen, optionally hydroxyl-sub-stituted straight-chain or branched C1-C3-alkyl, or oxoalkyl having l to 4 C atoms, Le A 28 391 - 85 -R7 represents hydrogen, methyl or phenyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R11 represents hydrogen, methyl or -CH2-NH2, R12 represents hydrogen, methyl, amino, methyl-amino, dimethylamino, aminomethyl, methylamino-methyl or ethylaminomethyl, R13 represents hydrogen, hydroxyl, methoxy, fluor-ine, methyl or hydroxymethyl, R15 represents hydrogen or methyl, R16 represents hydrogen or methyl, R17 represents hydrogen or methyl, R18 represents or R19 represents hydrogen, methyl or ethyl, Le A 28 391 - 86 -R20 represents where R21 denotes hydrogen or methyl, A represents CH2, 0 or a direct bond and n represents 1 or 2.

3. Quinolonecarboxylic acid derivatives according to Claim 1, where R1 represents methyl, ethyl, cyclopropyl or phenyl which is optionally monosubstituted or disub-stituted by fluorine, R2 represents hydrogen, methyl or ethyl, X1 represents hydrogen, fluorine, chlorine, amino or methyl, X2 represents -CH=CH2 or -C=C-R5 Le A 28 391 - 87 -where R5 denotes hydrogen, C1-C4-alkyl, C2-C3-alkenyl or trimethylsilyl and Y represents Le A 28 391 - 88 - where R6 represents hydrogen, methyl, optionally hydroxyl-substituted ethyl, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, R9 represents hydrogen or methyl, R11 represents hydrogen or -CH2-NH2, R12 represents hydrogen, methyl, amino, methyl-amino, aminomethyl or ethylaminomethyl, Le A 28 391 - 89 -R13 represents hydrogen, hydroxyl or methoxy, R15 represents hydrogen or methyl, R16 represents hydrogen or methyl, R17 represents hydrogen or methyl, R18 represents R19 represents hydrogen or methyl, R20 represents where R21 denotes hydrogen or methyl, A represents CH2, 0 or a direct bond and n represents 1.

Le A 28 391 90

4. Quinolonecarboxylic acid derivatives of the formula (II) (II).
in which R1, R2, X1 and x2 are as defined in Claim 1 and X3 represents halogen, in particular fluorine or chlorine.

5. Process for the preparation of quinolonecarboxylic acid derivatives according to Claim 1, characterised in that a compound of the formula (II) (II).
Le A 28 391 - 91 -in which R1, R2, X1 and X2 are as defined in Claim 1 and X3 represents halogen, in particular fluorine or chlorine, is reacted with compounds of the formula (III) Y-H (III) in which Y is as defined in Claim 1, if appropriate in the presence of acid scavengers.

6. 8-Bromo-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its pharrnaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

7. 8-Bromo-1-ethyl-6,7-difluoro-1,4-dihydro-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.

8. 1-Cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-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.

9. 1-Cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-8-ethinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its phannaceutically acceptable hydrates and acid addition salts as well as the alkali metal salts, alkaline earth rnetal salts, silver salts and guanidinium salts.

Le A 28 391 -92-

10. 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-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.

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

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

13. 1-Cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo-[4.30]non-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-1,4-dihydro-7-(7-methyl-3,7-diazabicyclo-[3.3.0]oct-3-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.

15. 1-Cyclopropyl-8-ethinyl-6-fluoro-1,4-dihydro-7-(4-methylamino-1,3,3a,4,7,7a-hexahydroisoindol-2-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 guanidiniumsalts.

16. 1-Cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-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.

17. Quinolonecarboxylic acid derivatives according to Claims 1 - 3 and 6 - 16 for combating diseases.

LeA28391 -93-

18. Medicament containing quinolonecarboxylic acid derivatives according to Claims 1 - 3 and 6 - 16.

19. Use of quinolonecarboxylic acid derivatives according to Claims 1 - 3 and 6 - 16 in the preparation of medicaments.

LeA28391 -94-