NO302886B1 - Quinolone carboxylic acid derivatives with anti-bacterial action, intermediates for the preparation thereof, drugs containing the compounds and the use of the compounds in the manufacture of drugs - 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

The present invention relates to quinolone carboxylic acid derivatives with anti-bacterial action.

The invention further relates to intermediate products for the production of these derivatives, pharmaceuticals containing the derivatives as well as the use of the derivatives in the production of pharmaceuticals with antibacterial action.

It is already known that 8-alkyl-quinolone carboxylic acids have antibacterial activity; thus 8-methyl quinolone carboxylic acids are described for example in EP 237 955 and JP 2 019 377 while 8-trifluoromethyl quinolone carboxylic acids are described in US-PS 4 780 468, 4 803 205 and 4 933 335.

From GB-A 2,188,317, US 4,123,536-A as well as from "J.Clin. Pharmacol.", 28, 156 (1988) and "Antibicrob Agents Chemother."

33, 131 (1989), antimicrobially active quinolone derivatives have already been made known, but their effectiveness is not satisfactory.

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

there

R<1> means cyclopropyl or optionally with halogen, one more

triply substituted phenyl,

R<2> means hydrogen,

X<1> means hydrogen,

X<2>means

ten

or -CEC-R<5>

there

r<3> means hydrogen,

R<4> means hydrogen or halogen and

R<5>means hydrogen, C^^-alkyl, C2-3~alkenyl or alkoxymethyl with 1 to 3 C atoms in the alkoxy part, and Y means

there

R^ means hydrogen, optionally with hydroxy or methoxy substituted straight or branched C1-4 alkyl, cyclopropyl, oxoalkyl with 1 to 4 C atoms, acyl with 1 to 3 C atoms,

R<7> represents hydrogen, methyl, phenyl, thienyl or pyridyl,

R<8> means hydrogen or methyl,

R^ means hydrogen or methyl,

RIO means hydrogen or methyl,

R<12>means hydrogen, methyl, amino, optionally with hydroxy substituted alkyl- or dialkylamino with 1 or 2 C atoms in the alkyl part, aminomethyl, aminoethyl, optionally 3

with hydroxy substituted alkyl or dialkylaminomethyl with 1 or 2 C atoms in the alkyl part or 1-imidazolyl,

R<13> means hydrogen, hydroxy, methoxy, methylthio or

halogen, methyl, hydroxymethyl,

R-1-4 means hydrogen or methyl,

R<20> means hydrogen, hydroxy,

hydroxymethyl or

r<!9>means hydrogen, optionally with hydroxy substituted C^_3~alkyl, alkoxycarbonyl with 1 to 4 C atoms in the alkoxy part or C^_g-acyl,

R<21> means hydrogen or methyl,

A means CH2, 0 or a direct bond and

n means 1 or 2, and

their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids exhibit a high anti-bacterial effect.

They are therefore suitable as an active ingredient in human and animal medicine, whereby the treatment of fish for therapy or prophylaxis of bacterial infections is also counted under veterinary medicine.

Preferred are compounds of formula (I), where:

R<1> means cyclopropyl or optionally with one or two halogens

multiply substituted phenyl,

R 2 means hydrogen,

X<1> means hydrogen,

X<2> means -

or -C=C-R5

there

r<3> means hydrogen,

R<4> means hydrogen and

R<5> means hydrogen C1_4~alkyl or C2_g-alkenyl Y means

there

R<k>means hydrogen, optionally with hydroxy substituted straight or branched C1_3~alkyl, oxoalkyl with 1 to 4

C atoms,

R<7> means hydrogen, methyl or phenyl,

R^ means hydrogen or methyl,

R^ means hydrogen or methyl,

R<12> means hydrogen, methyl, amino, methylamino, dimethylamino,

aminomethyl, methylaminomethyl or ethylaminomethyl,

R<13> means hydrogen, hydroxy, methoxy, fluorine, methyl or hydroxymethyl,

R<l>9

R2<0>means N , where

<X>R21

R<19> means hydrogen, methyl or ethyl,

R<21> means hydrogen or methyl,

Å means CH2, 0 or a direct bond and

n means 1 or 2.

Particularly preferred are compounds of formula (I) where:

R<1> means cyclopropyl or optionally with one or two fluorines

multiply substituted phenyl,

R<2> means hydrogen,

X<1> means hydrogen,

X2 means -C=CE-R3 or -C=C-R5

R4

there

R<5>means hydrogen,<C>1-4-alkyl or C2-3<a>alkenyl, and

Y means

there

R<6> means hydrogen, methyl, optionally substituted with hydroxy

ethyl,

R<7> means hydrogen or methyl,

R* means hydrogen or methyl, ;R<9>means hydrogen or methyl, ;R<12>means hydrogen, methyl, amino, methylamino, aminomethyl ;or ethylaminomethyl, ;R<13>means hydrogen, hydroxy or methoxy, ;R <20> means ; ; R<19> means hydrogen or methyl, ;R<21> means hydrogen or methyl, ;A means CHg, 0 or a direct bond and ;n means 1. ;The invention further relates to quinolone carboxylic acid derivatives which are valuable as intermediates in the preparation of the above described compounds, and these derivatives are characterized by formula (II); where ;R1,R2,X<1>and X<2>have the above meaning, and ;X<3>means halogen and especially fluorine or chlorine. ;Finally, the invention relates to medicinal products which are characterized by the fact that they contain a quinolone carboxylic acid derivative as described above. The invention also relates to the use of such quinolone carboxylic acid derivatives as described above in the production of medicinal products with antibacterial action. ;The compounds of formula (I) are obtained when a compound of formula (II) ; ; where ;Ri,R<2>,X<1>and X<2>have the above meaning and X<3>means halogen and especially fluorine or chlorine, ;reacted with compounds of formula (III) ;Y-H (III) ;where ;Y has the above meaning, ;possibly in the presence of acid scavengers. If, for example, 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methylpiperazine are used as starting compounds, the course of the reaction can be reproduced by the following reaction scheme: ; The 8-(1-chlorovinyl)-quinolone carboxylic acids can also be obtained by reacting the 8-ethynyl-quinolone carboxylic acids with hydrochloric acid at temperatures from 10 to 100°C and preferably 20 to 60°C. The compounds of formula (II) used as starting compounds are, as mentioned, new. These can be prepared by quinoline carboxylic acid derivatives with formula (IV); where ;R1,R2,X<1>and X<3>have the above meaning and ;X<4>means halogen, especially iodine, bromine or chlorine, ;is reacted with organometallic vinyl or alkynyl compounds of formula (V); ; where ;X<2> has the meaning given above and ;M means SnR'3, ZnX<*>, B(0R")2,

there

R' means C 1 -alkyl,

R" means hydrogen or C1_4~alkyl and

X' means bromine or chlorine,

in the presence of transition metal catalysts, and cleavage of any protective groups present.

The organometallic vinyl and alkynyl compounds required for the coupling reaction are either known or can be synthesized according to methods known in the literature. Thus, for example, vinyl-trialkyltin compounds can be prepared from the corresponding vinyl iodides, bromides or chlorides by reacting with magnesium to obtain the vinyl Grignard compound and allowing this to react with a trialkyltin chloride to form the desired vinyltin derivatives.

Organometallic alkynyl compounds can be prepared in a manner known per se, for example by metallating 1-alkyne at temperatures between -20°C and -78°C in an aprotic solvent such as tetrahydrofuran with n-butyl-, sec-butyl- or tert-butyllithium and then reacts with a metal halide compound such as zinc chloride, magnesium bromide, copper iodide or trialkyltin chloride. The reaction is preferably carried out at -78°C. In addition to the preferred solvent tetrahydrofuran, 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, can also be used. For both the vinyl and the alkynyl derivatives, the zinc chloride and trialkyltin derivative is preferred. By "alkyl" is meant the trialkyltin compounds C1-4-alkyl, methyl and n-butyl are preferred.

The trialkylvinyltin compounds can be obtained according to literature-known methods also by hydrostannylation of alkynes with trialkyltin hydrides in the presence of transition metal catalysts ("J. Org. Chem.", 55 (1990) 1857-1867).

The organometallic vinyl and alkynyl compounds are reacted with 8-haloquinolone carboxylic acid derivatives of the general formula (IV) in the presence of a suitable catalyst according to methods known in principle, "halogen" here means iodine, bromine or chlorine; preferred are bromine and chlorine and particularly preferred is bromine.

As catalysts, mention may be made of 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 metals can be used in the form of their salts such as NiCl2»PdCl2 or Pd(0Ac)2» or in the form of complexes with suitable ligands. The use of the complexes is preferred. Phosphines such as triphenylphosphine, tri(o-tolyl)phosphine, trimethylphosphine, tributylphosphine and tri(2-furyl)phosphine are preferably used as ligands, triphenylphosphine being preferred. Preferred complex catalysts should be mentioned bis(triphenylphosphine)nickel(II) chloride, bis(triphenylphosphine)palladium(II)chloride, tris(triphenylphosphine)-palladium(O) and tetrakis(triphenylphosphine)palladium(0).

The complex catalysts are used in proportions of 0.1 to 20 mol-#, calculated on the 8-halo-quinolonecarboxylic acid ester used, proportions of 0.5 to 10 mol-% are preferred and proportions of 1 to 5 mol-% are particularly preferred.

The coupling reaction is carried out in suitable inert solvents such as benzene, toluene, xylene, dimethylformamide, dimethylacetamide or mixtures thereof, preferably dimethylformamide and toluene. Before use, the solvents are dried and made air-free in a manner known per se. The coupling reaction is carried out at temperatures between 20 and 200°C, preferably between 50 and 180°C.

The duration of the reaction depends on the reactivity of the educts and is generally between 2 and 40 hours, preferably between 4 and 24 hours.

The turnover is carried out under a protective gas atmosphere. Inert gases such as helium, argon or nitrogen can be mentioned as protective gas, nitrogen is preferred. The coupling reaction is generally carried out at normal pressure. However, it is of course also possible to carry out the reaction at reduced or increased pressure.

The amines of formula (III) used as starting compounds are mostly known. Chiral amines can be used both as racemates or as enantiomeric or diastereomeric compounds. Examples include:

piperazine,

1-methylpiperazine,

1-ethylpiperazine,

1-(2-hydroxyethyl)-piperazine,

3-methylpiperazine,

cis-2,6-dimethyl-piperazine,

cis-2,3-dimethyl-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,

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-methyl-2,5-diazabicyclo[2.2.2]octane dihydrochloride.

The substituted 1,3,3a,4,7,7a-hexahydro-isoindoles are predominantly new. They can, for example, be obtained by Diels-Alder reaction between dienes of formula (1)

whereby R<9> has the meaning given above and R<22> is either identical to R<20> or is a functional group which can be converted to R<20>, with dienophiles of formula (2)

where R<23> is hydrogen or a protecting group such as trimethylsilyl, benzyl, C1_4~alkylphenylmethyl, methoxybenzyl or benzhydryl and subsequent reduction of the carbonyl group and possibly removal of the protecting group.

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

The reaction temperature can vary within a large range. In general, you work between approx. -20°C and +200°C, preferably between -20°C and +150°C. The Diels-Alder reaction can be carried out at normal pressure. The reaction can also be carried out at pressures of up to 1.5 GPa.

The reduction of the carbonyl group can be achieved by means of complex hydrides. As hydrides, one can use, for example, lithium aluminum hydride, lithium borohydride, 1 lithium triethylborohydride, sodium bis-[2-methoxyethoxy] aluminum hydride or sodium borohydride in the presence of Lewis acid catalysts such as chlorotrimethylsilane, boron trifluoride etherate or aluminum chloride.

As a diluent, ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane and hydrocarbons such as hexane, methylcyclohexane or toluene, or mixtures thereof, can be used.

The reaction temperatures can be varied within the range -40°C to +180°C, preferably between 0°C and 140°C. The reduction is usually carried out under normal pressure, but can also be carried out under reduced or increased pressure.

The use of pressure between 100 and 1000 kPa is recommended in order to achieve higher reaction temperatures with easily boiling solvents.

The complex hydrides are used at least in an amount corresponding to the stoichiometry of the reduction. In general, however, a surplus is used, preferably between 30 and 300%.

The removal of any protective group takes place according to the generally known methods of protective group chemistry (see for example T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981).

The starting substances with formulas (1) and (2) are known or can be prepared according to per se known methods in organic chemistry, see for example "J. Am. Chem. Soc", 100, 5179 (1978), " J. Org. Chem.", 43. 2164 (1978), DE 39 27 115, "J. Org. Chem.", 40» 24 (1975).

If, for example, l-(tert-butyloxycarbonylamino)-1,3-butadiene and maleimide are used as starting materials and lithium aluminum hydride as reducing agent, the course of the reaction can be reproduced using the following reaction scheme:

In a particular embodiment of the production method, all steps can be carried out using a suitable solvent, for example tetrahydrofuran, without isolating the intermediate products. If, for example, l-(tert-butyl-oxycarbonylamino)-l,3-pentadiene and N-trimethylsilylmaleimide are used as starting material, the course of the reaction can also be reproduced by the following reaction scheme:

In this case, NMR spectroscopy can demonstrate that all substituents on the 6-ring exhibit a cis arrangement in relation to each other.

The reaction between (II) and (III), where the compounds (III) can also be used in the form of their salts such as hydrochloride, is preferably carried out in a diluent such as dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoric acid trisamide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or in pyridine. Mixtures of these diluents can also be used.

As an acid-binding agent, all common organic or inorganic acid-binding agents can be used. These preferably include alkali hydroxides, alkali carbonates, organic amines and amidines. Particularly suitable are 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 wide ranges. In general, you work between 20 and 200°C and preferably between 80 and 180°C.

The turnover can be carried out at normal pressure, but also at higher pressure. In general, you work at a pressure between approx. 1 and 100 bar, preferably between 1 and 10 bar.

When carrying out the method of the invention, one uses per 1 mol of compound (II) 1 to 15 mol and preferably 1 to 6 mol of compound (III).

During the reaction, free amino groups can be protected with a suitable amino protecting group, for example with the tert-butoxycarbonyl residue, and after completion of the reaction set free again by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, "Methoden der Organischen Chemie", vol. E4, page 144 (1983); J. F. W. McOmie, "Protective Groups in Organic Chemistry" (1973), page 43). The preparation of the acid addition salts of the compounds of the invention takes place in the usual way, for example by dissolving betaine in sufficient quantities in aqueous acid and precipitation of the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile. One can also heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether and then evaporate the whole to a dry state or suck off the precipitated salt. As pharmaceutically acceptable salts, mention should be made, for example, of salts of salt, sulphur, vinegar, glycol, milk, amber, lemon, wine, methanesulfone, 4-toluenesulfone, galacturon, glucone, embon- , glutamic or aspartic acid.

The alkali or alkaline earth salts of the carboxylic acids of the invention are obtained, for example, by dissolving the betaine in excess alkali or alkaline earth liquor, from filtering undissolved betaine and evaporating the filtrate to a dry state. Pharmaceutically suitable are the sodium, potassium or calcium salts. By reacting an alkali or alkaline earth salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.

As far as chiral compounds are concerned, these can be prepared and used both as diastereomeric mixtures or as diastereomers or enantiomeric compounds.

The compounds of the invention have a strong antibiotic effect and, at low toxicity, show a broad antibacterial spectrum against gram-positive and gram-negative germs, especially enterobacteria; above all, however, also against those that are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides or tetracyclines.

These valuable properties enable their use as chemotherapeutically active ingredients in medicine as well as substances for the preservation of inorganic and organic materials, especially organic materials of any type such as polymers, lubricants, paints, fibers, leather, paper and wood or of foodstuffs and water.

The compounds of the invention are effective against a very broad spectrum of microorganisms. With the help of the compounds, one can fight gram-negative and gram-positive bacteria and inhibit, cure or alleviate diseases caused by these.

The compounds of the invention are distinguished by an enhanced effect on dormant and resistant germs. When it comes to dormant bacteria, i.e. bacteria that do not show any detectable growth, the compounds work far below the concentrations of the currently known substances. This applies not only to the amount used, but also to the rate of eradication. Such results can be noted with gram-positive and -negative bacteria, particularly with Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.

The compounds of the invention also show surprising levels of effectiveness against bacteria which are considered to be less sensitive in relation to comparable substances, particularly resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.

Due to the high activity of the compounds of the invention against bacteria and bacteria-like microorganisms, they are particularly suitable for prophylaxis and chemotherapy of local and systemic infections in human and animal medicine caused by these sources.

The compounds are also suitable for combating proto-zoonoses and helminthoses.

The compounds of the invention can also be used in various pharmaceutical preparation forms. Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

The minimum inhibitory concentration, MIK, is determined per serial dilution samples on iso-sensite agar (Oxoid). For each test substance, a series of agar plates containing decreasing concentrations in a series of double dilutions is prepared. The agar plates are inoculated with a multipoint inoculator (Denley). For inoculation, overnight cultures of the germs of the disease are used, which were previously diluted in such a way that each inoculation point contains approx. IO<4>colony-forming particles. The inoculated agar plates are incubated at 37°C and the germ growth is read after approx. 20 hours. The MIC value in µg/ml gives the lowest concentration of active ingredient at which growth could not be detected with the naked eye.

The following table shows the MIK values for some of the compounds of the invention compared to Ciprofloxacin.

In the table below, the MIC values for compounds with the formula are reproduced with two selected values for the substituent Y.

Furthermore, a comparison has been made between selected compounds according to the invention and two compounds obtained from the initially mentioned GB 2,188,317.

These connections are as follows:

I) 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piper-azinyl)-4-oxo-8-vinyl-3-quinolinecarboxylic acid (according to the present application)

II) 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Example 1 according to the present application)

III) 1-cyclopropyl-8-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Otsuka, GB 2,188,317, example 10, no. 43).

IV) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (Example 22 according to the present application).

V) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 6 according to the present application).

VI) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Otsuka, GB 2,188,317, example 10, no. 45).

MANUFACTURE OF INTERMEDIATE PRODUCTS.

Example Zl

1- cyclopropyl- 6, 7- difluoro- 1. 4- dihydro- 4- oxo- 8- vinyl- 3-quinolinecarboxylic acid- ethyl ester

3.72 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 4.4 g of tributylvinylstannane and 0.46 g of tetrakis(triphenylphosphine)palladium( 0) is heated in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere and to reflux.

The whole is filtered hot, the product precipitated at room temperature is sucked off, washed once more with toluene and dried. 2.55 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester are obtained (79% of the theoretical).

Melting point: 178-179°C.

Example Z2

l- cvclopropvl- 6, 7- difluoro- l. 4- dihydro- 4- oxo- 8- vinyl- 3-quinolinecarboxylic acid

0.9 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0. 2 ml of concentrated sulfuric acid for 4 hours to reflux. The reaction mixture is then split at reflux temperature with 10 ml of water. The solid substance is sucked off 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 is obtained (71% of the theoretical).

Melting point: 182-184°C.

Example Z3 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilyl-ethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester 22.2 g 8-bromo-1-cyclopropyl-6,7 -difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis(triphenylphosphine )-palladium(O) are heated for 3 hours in 300 ml absolute toluene under a nitrogen atmosphere. After cooling the reaction mixture to approx. -18° C, the whole thing is washed with toluene and dried. 18.8 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (80$ of the theoretical).

Melting point: 171-172°C.

Example Z4

1- c. vclopropyl- 8- ethynyl- 6. 7- difluoro- 1. 4- dihydro- 4- oxo- 3-quinolinecarboxylic acid- ethyl ester

18.8 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethyl-silylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester and 9.7 g

potassium fluoride is stirred in a mixture of 300 ml dimethylformamide, 200 ml chloroform and 15 ml water for 3 hours at room temperature. The whole is then filtered, 120 ml of water is added and acidified with dilute aqueous hydrochloric acid. After shaking out with chloroform, the organic phase is dried over sodium sulfate and evaporated. The obtained residue is recrystallized from methanol. 9 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (59$ of the theoretical).

Melting point: 186-187°C

Example Z5

l- cyclopropvl- 8- ethynyl- 6. 7- difluoro- l. 4- dihydro- 4- oxo- 3-quinolinecarboxylic acid

10.3 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are heated in a mixture of 100 ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulfuric acid for 4 hours under reflux. After cooling to room temperature, the solid is sucked off, washed with water and dried. 5.7 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained in this way (6256 of the theoretical).

Melting point: 233°C

Example Z6

l-cyclopropyl-6. 7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

1.9 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3.5 g of 1-tributylstannyl-hex-l-yne and 0, 29 g of tetrakis(triphenylphosphine)palladium(0) are heated in 20 ml of absolute toluene for 8 hours under a nitrogen atmosphere to reflux. The reaction mixture is evaporated and the residue is recrystallized with 30 ml of hexane, after which the solid thus obtained is recrystallized from cyclohexane. 0.7 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (36$ of the theoretical) is obtained.

<i>fl-NMR (200 MHz, CDC13): § 0.95 (t, 3H), 1.1-1.7 (m, 11E),

2.50 (t, 2E), 4.1-4.3 (m, 1H), 4.38 (q, 2E),

8.14 (dd, 1E), 8.56 (s, 1E) ppm.

Example Z7

1- cyclopropyl- 6. 7- difluoro- 8-( 1- hexynyl)- 1. 4- dihydro- 4- oxo-3- quinolinic acid

0.7 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 6 ml of glacial acetic acid, 0.5 ml water and 0.1 ml concentrated sulfuric acid for 3 hours to reflux. After adding 100 ml of water, the solid is sucked off and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (85% of the theoretical).

<i>fl-NMR (200 MEz, CDCl3): S 0.96 (t, 3E), 1.1-1.7 (m, 8E),

4.3-4.5 (m, 1E), 8.20 (dd, 1E), 8.85 (s, 1E) ppm. Melting point: 118-121°C.

Example Z8

1- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 8-(3, 3- dimethylbutyn- 1-yl)- 4- oxo- 3- quinoline carboxylic acid ethyl ester

Corresponding to example Z6, 0.87 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dimethylbutyn- 1-yl)-4-oxo-3-quinolinecarboxylic acid ethyl ester (46% of theory).

Melting point: 170-172°C

Example Z9

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dimethylbutyn-1-yl)-4-oxo-3-quinolinecarboxylic acid

Saponification of 0.75 g of the ester from example Z8 corresponding to example Z7 gives 0.56 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-dimethylbutyn-1-yl)-4-oxo -3-quinoline carboxylic acid (81% of theory).

Melting point: 199-201°C

Example Z10 1-(2.4- dl fluorophenyl)- 6.7- dl fluoro- 1.4- dihydro- 8-(trimethyl-sylylethylenyl)- 4-oxo- 3- quinolinecarboxylic acid ethyl ester 6.7 g 8-bromo -1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z20), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis-(triphenylphosphine)-palladium(0) is heated in 50 ml of absolute toluene for 24 hours under a nitrogen atmosphere to reflux. At -18°C, the product crystallizes from the reaction mixture. 4.8 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (69% of the theoretical).

Melting point: 173-174°C

Example Zll

l-(2.4-difluorophenyl)-8-ethynyl-6.7-difluoro-1.4-dihydro-4-oxo-3- quinolinecarboxylic acid ethyl ester

A solution of 4.6 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester in 20 ml of chloroform is 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. Stir for one hour at approx. 20° C, further chloroform is added to the reaction mixture, the whole is shaken out several times with water, the organic phase is dried and evaporated. The obtained residue is recrystallized from methanol. 3.4 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (87% of the theoretical).

Melting point: 189°C

Example Z12

1-(2.4-difluorophenyl)-8-ethynyl-6.7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

1.17 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a

mixture of 9 ml glacial acetic acid, 0.75 ml water and 0.2 ml concentrated sulfuric acid for one hour under reflux. The solid that has crystallized at room temperature is sucked off and dried. 0.98 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of the theoretical).

Melting point: 220°C (decomposition).

Example Z13

l- c. ycloprop. yl-6,7-difluoro-l. 4-Dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester

7.5 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 9.1 g of 1-tributylstannyl-prop-1-yne and 1, 16 g of tetrakis(triphenylphosphine)palladium(0) are heated in 80 ml of absolute toluene for 8 hours under a nitrogen atmosphere to reflux. The solid crystallized at -18°C is sucked off and dried. 2.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester are obtained (31% of the theoretical).

<1->H-NMR (200 MHz, CDCl3): S 1.1-1.35 (m, 4H), 1.40 (t, 3H),

2.16 (d, 3E), 4.1-4.3 (m, 1H), 4.35 (q, 2H),

8.15 (dd, 1E), 8.56 (s, 1E) ppm.

Melting point: 180-182°C

Example Z14

l- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 4- oxo- 8-( propyn- l- yl)-3- quinoline carboxylic acid

1.4 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester is boiled in a mixture of 20 ml of glacial acetic acid, 1, 5 ml of water and 0.5 ml of concentrated sulfuric acid for one hour under reflux. After adding approx. 10 ml of water, the precipitated solid is isolated and dried. In this way, 1.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid is obtained (82% of the theoretical).

<i>H-NMR (200 MHz, CDCl 3 ): S 1.4 (m, 4H), 2.26 (d, 3H),

4.4-4.6 (m, 1H), 8.16 (dd, 1H), 8.81 (s, 1H) ppm.

Melting point: 212-213°C

Example Z15

1- ethyl- 6, 7- difluoro- 1. 4- dihydro- 8-( trimethylsilylethylenyl-4-oxo- 3- quinolinecarboxylic acid- ethyl ester

5.4 g of 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0. 87 g of tetrakis-(triphenylphosphine)palladium(0) are heated in 50 ml of absolute toluene under a nitrogen atmosphere for 24 hours under reflux. The reaction mixture is evaporated, the residue is stirred in 100 ml of hexane, the resulting solid is sucked off and dried. 4.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-(trimethyl-silylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester (80% of the theoretical) is obtained.

Melting point: 151-152°C.

Example Z16

l-cyclopropyl-6. 7- difluoro- l. 4- dihydro- 8- (trimethylsilyl- ethynyl)- 4- oxo- 3- quinoline carboxylic acid ethyl ester

1.64 g 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3 g tributylstannyl-trimethylsilyl-acetylene and 0.29 g tetrakis(triphenylphosphine) palladium(0) is heated in 20 ml of absolute toluene for 24 hours under nitrogen to reflux. The reaction mixture is cooled to approx. -18°C and filtered. After drying the residue, 0.74 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained (38% of the theoretical).

Example Z17

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester 1.86 g 8-bromo -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 2.8 g l-tributylstannyl-3-

methyl-but-3-en-l-yne and 0.29 g of tetrakis(triphenylphosphine)-palladium(O) are heated in 20 ml of absolute toluene for 6 hours under a nitrogen atmosphere to reflux. The reaction mixture is filtered hot, evaporated and the residue is stirred with hexane. After suction and drying, 1.43 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3- quinoline carboxylic acid ethyl ester (80% of theory).

Melting point: 169-171°C.

Example Z18

1- cyclopropyl- 6. 7- difluoro- 1. 4- dihydro- 8-( 3- methyl- but- 3- en- 1-invl)- 4- oxo- 3- quinoline carboxylic acid

0.715 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 10 ml glacial acetic acid, 0.5 ml water and 0.2 ml concentrated sulfuric acid in VA - hour under reflux. Add 100 ml of water to the reaction mixture. The precipitated solid is sucked off, washed afterwards with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid is obtained (80% of the theoretical).

Melting point: 204-206°C.

Example Z19

2-(3-bromo-2.4.5-trifluoro-benzoyl)-3-(2.4-difluorophenylamino)-acrylic acid ethyl ester

14.5 g (0.11 mol) 2,4-difluoroaniline. The mixture is allowed to stand overnight at 10°C, the precipitate that has formed is sucked off, washed with cold ethanol and dried under vacuum.

Yield: 38 g (81% of the theoretical).

Melting point: 102-103°C (under decomposition) (from isopropanol).

Example Z20

8-bromo-1-(2.4-difluorophenyl1-6.7-difluoro-1.4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 38 g (82 mmol) 2-(3-bromo-2,4 ,5-trifluoro-benzoyl)-3-(2,4-difluorophenylamino)acrylic acid ethyl ester is heated in 200 ml of dimethylformamide with 7.6 g of sodium fluoride for 2 hours under reflux. The mixture is poured into ice water, the precipitate is suctioned off, washed well with water and dried at 80 °C in an air circulation cabinet.

Yield: 34.7 g (95% of the theoretical).

Melting point: 208-210"C (under decomposition) (from glycol monomethyl ether).

By acid saponification of this ester, 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid is obtained with melting point 210-221°C (during cleavage).

Example Z21

2-( 3- bromo- 2. 4. 5- trifluoro- benzoyl)- 3- ethylamino- acrylic acid- ethyl ester

5.5 g of a 50% -ig aqueous ethylamine solution. The mixture is allowed to stand overnight at 10°C, 200 ml of water is added to the suspension, the precipitate that has formed is sucked off, washed with water and dried at 60°C under vacuum.

Yield: 17.3 g (91% of theoretical).

Melting point: 101-102°C (under decomposition) (from isopropanol).

Example Z22

8- bromo- 1- ethyl- 6, 7- difluoro- 1. 4- dihydro- 4- oxo- 3- quinoline carboxylic acid ethyl ester 16 g (42 mmol) 2-(3-bromo-2,4,5-trifluoro- benzoyl)-3-ethylamino-acrylic acid ethyl ester is prepared analogously to example Z20.

Yield: 14.6 g (96% of theoretical).

Melting point: 172-173" C (under decomposition) (from glycol monomethyl ether).

By acid saponification, 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 215-217°C (with cleavage) is obtained from this ester.

Example Z23

4-methylamino-l. 3. 3a. 4, 7. 7a-hexahydroisoindole

Method I:

14.4 g (60 mmol) of 70% 1-(tert-butyloxycarbonylamino)-1,3-butadiene ["J. Org. Chem.", 43»2164 (1978)] are added dropwise as a solution in 30 ml of absolute tetrahydrofuran to the present 10.1 g (60 mmol) of N-trimethylsilylmaleimide ["J. Org. Chem.", 40»24 (1975)] in 30 ml of absolute tetrahydrofuran. After the exothermic reaction has taken place, it is boiled for another hour under reflux cooling.

The cooled reaction mixture is then added dropwise under nitrogen to the present 7.6 g (0.2 mol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran. The whole thing is then boiled for 14 hours under reflux cooling. 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10% caustic soda and 22.8 g of water are then successively added dropwise to the cooled reaction mixture. The salts are filtered off and evaporated under vacuum. The residue of 10.3 g is distilled at 87°C/0.8 mbar.

The distillate is taken up in 80 ml of absolute pentane, filtered and the product crystallized by cooling to -70°C.

Yield: 3.3 g

Melting point: 72-82°C.

By treatment with equimolar amounts of 2N hydrochloric acid, 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole dihydrochloride is obtained with a melting point of 265-268°C (from methanol).

Method II:

a) 4-(tert-butyloxycarbonylamino)-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole.

48.0 g (0.5 mol) of maleimide is introduced into 200 ml of absolute tetrahydrofuran and 120 g (0.5 mol) of approx. 70% 1-(tert-butyloxycarbonylamino)-1,3-butadiene is added dropwise as a solution in 500 ml of absolute tetrahydrofuran, whereby the temperature is maintained at 20 to 30°C. The mixture is stirred overnight at room temperature. The whole is then evaporated and recrystallized from ethyl acetate. 57 g of a product with a melting point of 177 to 182° are obtained C. A further 13 g with a melting point of 158 to 160°C are obtained from the mother liquor.

b) 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole.

The starting point is 27.1 g (0.71 mol) 1 lithium aluminum hydride

under nitrogen in 300 ml absolute tetrahydrofuran and dropwise to a solution of 57 g (0.21 mol) 4-(tert-butyloxycarbonylamino)-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole in 570 ml of absolute tetrahydrofuran. It is then boiled overnight under reflux cooling. After cooling, 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% caustic soda and 81.3 g of water are added successively. The salts are sucked off, washed with tetrahydrofuran and the filtrate is evaporated under vacuum. The remainder is distilled in high vacuum.

Yield: 19.1 g.

Example Z24

4-amino-l. 3. 3a. 4. 7. 7a- hexahydro-isoindole

13.3 g (50 mmol) 4-tert-butyloxycarbonylamino-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-isoindole (from example Z23, method

II) is stirred in 166 ml of trifluoroacetic acid overnight at room temperature. The trifluoroacetic acid is then distilled off at 10 mbar and the residue is freed from acid residues at 50°C under high vacuum. The whole is then taken up in absolute tetrahydrofuran and evaporated under vacuum. The residue is taken up in 100 ml of absolute tetrahydrofuran and added dropwise under nitrogen to a solution of 11.3 g (0.3 mol) of lithium aluminum hydride in 300 ml of absolute tetrahydrofuran. It is then boiled for 16 hours under reflux. After cooling, 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% caustic soda and 34 ml of water are added successively. The residue is sucked off and washed with tetrahydrofuran. The filtrate is evaporated and the residue is distilled.

"Yield: 2.2 g

Content: 92% (determined gas chromatographically)

Boiling point: 70"C/0.2 mbar.

Example Z25

7-methyl-4-methylamino-1.3.3a,4,7.7a-hexahydro-isoindole In analogy with example Z23, method I, 21.9 g (0.12 mol) of 1-(tert-butyloxycarbonylamino )-1,3-pentadiene with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide and then reducing with 15.2 g (0.4 mol) of lithium aluminum hydride. The crude product is recrystallized from tetrahydrofuran.

Yield: 6.2 g

Melting point: 106-108°C.

Example Z26

1- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 8-( 3- methoxy- propyn- 1-yl)- 4- oxo- 3- quinoline carboxylic acid A) To 1.86 g (5 mmol) 8- bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is added to 20 ml of absolute toluene to 2.5 g (7 mmol) of 1-tributyl-stannyl-3 -methoxy-propyne and 0.29 g (corresponding to 5 mol-%) tetrakis-(triphenylphosphine)-palladium(0) and the whole is heated for 15 hours under nitrogen. The reaction mixture is evaporated, the residue is stirred with hexane, the solid is sucked off and purified chromatographically over some silica gel.

Yield: 0.74 g (41% of theory) 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methoxy-propyn-1-yl)-4-oxo-3-quinolinecarboxylic acid -ethyl ester.

Melting point: 144-146°C.

B) 0.36 g (1 mmol) of the product from step A is heated in a mixture of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concentrated sulfuric acid for one hour under reflux. The mixture is poured onto water, the precipitate is filtered off and recrystallized from ethanol.

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

Melting point: 170-172°C.

<i>H-NMR (200 MHz, CDCl 3 ): S 1.24 (m, 2H), 1.4 (m, 2H),

3.45 (s, OCH3), 4.35 (m, 1H), 4.41 (s, 0-CH2-),

8.27 ("t", 1H), 8.87 (s, 1E) ppm.

MANUFACTURE OF ACTIVE SUBSTANCES

Example 1

A) 2.32 g (8 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide with 0.92 g (8 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.2 g (12 mmol) of N-methylpiperazine for one hour under reflux. The suspension is evaporated, the residue is stirred with acetonitrile and the undissolved crystallisate is sucked off and dried.

Yield: 1.83 g (62% of theory) 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinoline carboxylic acid.

Melting point: 228-230°C (under decomposition).

<i>H-NMR (d<6->DMF): S 4.95 (s, -C<=>C-H) ppm.

B) With 2-methylpiperazine, 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid is obtained in an analogous manner .

1 H-NMR (d<6->DMS0): S 5.03 (s, -C<=>C-H) ppm.

Mass spectrum: m/e 369 (M<+>), 325 (M<+->CO 2 ), 300, 293, 269,

243, 44 (CO2).

Analogous to example 1, one obtains with the products from examples Z14, Z7 and Z9:

Example 2 (R=CH3: 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(propyn-1-yl)-3- quinoline carboxylic acid.

Melting point: 246-249"C (under cleavage).

Example 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 (under decomposition).

Example 4 (R=C(CH3)3: 1-cyclopropyl-8-(3,3-dimethylbutyn-1-yl)-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl )-4-oxo-3-quinolinecarboxylic acid.

Melting point: 234-237°C (under decomposition).

Example 5

Analogously to example 1, one reacts with cis-2,8-diazabicyclo[4.3.0]nonane to 1-cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-8- ethynyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 225-227°C (under decomposition).

<1->H-NMR (d<6->DMF): S 4.9 (s, -CEC-H) ppm.

Example 6

3.6 g (12 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 120 ml of acetonitrile and 60 ml of dimethylformamide with 1, 56 g (14 mmol) of 1,4-diazabicyclo[2.2.2]octane and 2.75 g (18 mmol) of 3-(2,2-dimethylpropylideneamino)pyrrolidine for one hour under reflux. The solution is evaporated, the residue is stirred with approx. 100 ml of water (pH 7), the precipitate is suctioned off, washed with water and then suspended for complete deprotection in 50 ml of water and treated for one hour in an ultrasonic bath. The whole thing is then sucked off, washed with water and dried at 80°C under vacuum.

Yield: 3.8 g (82% of the theoretical 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid hydrate.

Melting point: 193-196°C (under decomposition).

Example 7

A) Analogously to example 1, one reacts with 3-tert-butoxy-carbonylamino-3-methyl-pyrrolidine to 7-(3-tert-butoxy-carbonyl-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl- 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 244-246°C (under decomposition).

%-NMR (d<6->DMS0): δ 4.92 (s, -C<=>C-H) ppm.

B) 500 mg of the product from step A is dissolved in 5 ml of trifluoroacetic acid under ice-cooling, the solution is evaporated under vacuum, the residue is crystallized by stirring three times with approx. 1 ml of ethanol, the salt is sucked off, washed with ethanol and dried.

Yield: 270 mg (52% of theoretical) 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid trifluoroacetate. Melting point: 242-244°C (under decomposition).

Example 8

Analogous example 1 is reacted with 2.oxa-5,8-diazabicyclo-[4.3.0]nonane to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8 -diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 290°C (during cleavage; already sintering from about 170°C).

<1->H-NMR (d<6->DMS0): S 5.0 (s, -CEC-H) ppm.

Example 9

Analogous to example 1, 2-oxa-5,8-diazabicyclo[4.3.0]-nonane is reacted with the product from example Z13 to 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8 -diazabicyclo[4.3.0]non-8-yl)-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid with melting point 241-242°C (under decomposition).

Example 10

A) To 303 mg (1 mmol) of the product from example Z14 is added to a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide to 240 mg of 3-tert-butoxycarbonylamino-3-methyl-pyrrolidine and 134 mg (1.2 mmol) 1,4-diazabicyclo[2.2.2]-octane, after which the whole is stirred for 2 hours under reflux. The whole is evaporated under vacuum, stirred with 30 ml of water and dried at 80°C under vacuum.

Yield: 420 mg (87% of theoretical) 7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-( propyn-1-yl)-3-quinolinecarboxylic acid.

Melting point: 195-196°C (under cleavage).

-^H-NMR (d<6->DMS0): S 1.42 (s, CE3 on pyrrolidine),

2.12 (s, CH3-C<=>C-) ppm.

B) 180 mg of the product from step A is dissolved at 0°C in 1.6 ml of trifluoroacetic acid and the solution is evaporated after 1.25 hours. The residue is purified chromatographically (silica gel; dichloromethane.methanol: 17% 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-(propyn-1-yl)-

3-quinoline carboxylic acid with melting point 209-210°C (under decomposition).

Mass spectrum: m/e 383 (M<+>), 309, 298, 267 (100%), 133, 70.

Example 11

Analogous to example 1, the product from example Z12 is converted with N-methylpiperazine to 8-ethynyl-6-fluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl) )-4-oxo-3-quinolinecarboxylic acid with melting point 193-195°C (under decomposition).

<1>H-NMR (CDCl 3 ): δ 3.35 (s, -C<=>CH).

Example 12

Analogous to example 1, one reacts with 3-methyl-3,8-diazabicyclo-[4.3.0]nonane and purifies the 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-( 3-methyl-3,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid chromatographically (silica gel; dichloromethane:methanol:20% aqueous ammonia 2:4:1).

1 H-NMR (CDCl 3 ): δ 4.15 (s, -C<=>CH).

Example 13

Analogously to example 1, one reacts with 3-methyl-3,7-diazabicyclo-[3.3.0]octane to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(7-methyl-3, 7-diazabicyclo[3.3.0]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 212-216°C (under decomposition).

<1->NMR (d<6->DMF): S 4.95 (s, -CEC-H).

Example 14

Analogous example 1 is reacted with 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methylamino- 1,3,3a,4,7,7a-hexahydroisoindol-2-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 128-133°C (under decomposition).

<1>H-NMR (d<6->DMSO): S 4.93 (s, -C<=>CE) ppm.

Example 15

164 mg (0.5 mmol) of product from example Z18 is reacted analogously to example 1 with 1-methylpiperazine to 120 mg 1-cyclopropyl 1-6-fluoro-1,4-dihydro-8-(3-methyl-but-3 -en-1-ynyl)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid m.p. 195-19 VC (under cleavage) (recrystallized from glycol monomethyl ether).

■^E-NMR (CDC13): § 5.36 (m, >C=CE2), 2.4 (s, N-CE3),

3.0 (h, C-CE3)

Example 16

O

Analogous example 15 is reacted with 2,8-diazabicyclo[4.3.0]nonane to 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4- dihydro-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylic acid with melting point 201-202°C (under decomposition).

Example 17

Analogous example 15 is reacted with

B. 3-Hydroxypyrrolidine

to the following compounds:

B. 1 - cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-1- pyrrolidinyl)-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylic acid,

Melting point 190-198°C (under decomposition),

Example 18

100 mg of the product from example 1 is dissolved in 40 ml IN hydrochloric acid and stirred for 2 hours at 30° C. A suspension is obtained which is evaporated. The residue is stirred with a little isopropanol, the residue is sucked off, washed with isopropanol and dried at 90°C under vacuum.

Yield: 0.1 g (83% of theory) 8-(1-chlorovinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo -3-quinolinecarboxylic acid hydrochloride.

Melting point: 251-252°C (under decomposition).

<1>H-NMR (d<6->DMSO): S 6.0 (dd, -C=CH2) ppm.

Example 19

A) 100 mg of the product from example 2 is heated in 58 ml of 4N hydrochloric acid for 5 hours to 60°C. The mixture is evaporated, the residue is stirred with diethyl ether and dried at 70°C under vacuum.

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: 236-237°C (under decomposition).

Mass spectrum: m/e 419 (M<+>), 71.58 (100%), 43.36.

■^H-NMR (d<6->DMS0): δ 6.12 and 6.35 (q, -C=CH-CH3;

two signals for cis-trans forms).

B) Analogously, one obtains with the product from example 3 cis-trans-8-(1-k1or-1-hexenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1 -piperazinyl)-4-oxo~3-quinolinecarboxylic acid hydrochloride. Mass spectrum: m/e 461 (M<+>), 425 (M-HCl), 71.58 (100%), 43.36. Example 20

370 mg of the product from example 10A are dissolved in 9 ml of semi-concentrated hydrochloric acid and the solution is evaporated under high vacuum.

Yield: 340 mg of cis-trans-7-(3-amino-3-methyl-1-pyrrolidinyl)-8-(1-chloro-1-propenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid hydrochloride.

1-H-NMR (d<6->DMS0): S 6.19 and 6.36 (q, >C=CH-CH3; two signals

for cis-trans forms).

Example 21

10 mg of the product from example 11 is heated in 4.5 ml of 2.5N hydrochloric acid for one hour to 60° C. The mixture is evaporated and as a residue 8-(1-chlorovinyl)-6-fluoro-1-(2, 4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride.

Mass spectrum: m/e 477 (M<+>), 442 (M<+->C1), 36 (100%, HC1).

Example 22

To 291 mg (1 mmol) of the product from example Z2 is added to a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide, 240 mg (2.2 mmol) of 1,4-diazabicyclo[2.2.2]octane and 360 mg (2 .3 mmol) 3-(2,2-dimethyl-propylideneamino)-pyrrolidine and the mixture is heated for 32 hours under reflux. The whole is evaporated, after which the dark oil-like residue is stirred with 10 ml of water and the 103 mg of solid formed is sucked off and purified chromatographically (silica gel: dichloromethane/methanol: 17% aqueous ammonia 30:8:1).

Yield: 58 mg (16% of theoretical) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3- quinoline carboxylic acid.

Melting point: 179-182"C (under cleavage).

CI mass spectrum: m/e 358 ([M+H]<+>), 340 ([M+H-H 2 O]<+>).

Example 23

To 145 mg (0.5 mmol) of the product from example Z2, 60 mg (0.54 mmol) 1,4-diazabicyclo[2.2.2]octane and 140 mg are added to a mixture of 10 ml acetonitrile and 5 ml dimethylformamide (1.1 mmol) of cis-2,8-diazabicyclo[4.3.0]nonane and heated for 4 hours to reflux. The mixture is steamed in, stirred with 5 ml of water and adjusted to pH 7 with dilute hydrochloric acid. The precipitate is sucked off, washed with water and dried at 90°C under vacuum.

Yield: 120 mg (61% of theoretical) 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: 205-207°C (under decomposition).

<1->H-NMR (CF3COOD): δ 5.05 (d, 1H), 5.7 (d, 1H), 7.55 (dd,

1H), (signal groups for -CH=CH2)•

Example 24

Analogously to example 1, one reacts with the product from example Z26 and obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-8-(3-methoxy-propyn-1-yl) )-4-oxo-3-quinolinecarboxylic acid with melting point 187-189°C.

^H-NMS (CDCI3): § 8.95 (s, 1E), 8 (d, 1E),

4.37 (s, 0-CE2), 4.35 (m, 1E), 3.58 (m, 4E),

3.43 (s, O-CE3), 2.58 (m, 4H), 2.38 (s, N-CE3), 1.33 (m, 2E), 1.02 (m, 2E) ppm.

Example 25

Analogously to example 1, one reacts with 3,7-diazabicyclo[3.3.0]-octane, the reaction product is chromatographed on silica gel with dichloromethane:methanol:17% ammonia (30:8:1) as eluent and obtains l-cyclopropyl 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as "solidified foam".

1 H-NMR (d<6->DMS0): S 4.9 (s, -C<=>CH).

Claims (6)

1. Quinolone carboxylic acid derivatives characterized by formula (I) there R<1> means cyclopropyl or optionally with halogen, one more triply substituted phenyl, R<2>means hydrogen, X<*>means hydrogen, X<2>means -C=CE-R<3>or -C<=>C-R<5> R4 there R<3> means hydrogen, R<4> means hydrogen or halogen and R<5> means hydrogen, C 3 -alkyl, C 2 -3 -alkenyl or alkoxymethyl with 1 to 3 C atoms in the alkoxy part, and Y means there R<6> means hydrogen, optionally with hydroxy or methoxy substituted straight or branched C 2 -alkyl, cyclopropyl, oxoalkyl with 1 to 4 C atoms, acyl with 1 to 3 C atoms, R<7> represents hydrogen, methyl, phenyl, thienyl or pyridyl, R" means hydrogen or methyl, R<9>means hydrogen or methyl, R<*0>means hydrogen or methyl, R<12> means hydrogen, methyl, amino, optionally with hydroxy substituted alkyl- or dialkylamino with 1 or 2 C atoms in the alkyl part, aminomethyl, aminoethyl, optionally with hydroxy substituted alkyl- or dialkylaminomethyl with 1 or 2 C atoms in the alkyl part or 1-imidazolyl, R<*3>means hydrogen, hydroxy , methoxy, methylthio or halogen, methyl, hydroxymethyl, r<!4>means hydrogen or methyl, R20 means hydrogen, hydroxy, hydroxymethyl or R<19> means hydrogen, optionally with hydroxy substituted C-1-6-alkyl, alkoxycarbonyl with 1 to 4 C atoms in the alkoxy part or C1-6-acyl, R<21> means hydrogen or methyl, A means CEtø, 0 or a direct bond and n means 1 or 2, and their pharmaceutically acceptable hydrates and acid addition salts as well as alkali, alkaline earth, silver and guanidinium salts. 2. Compounds with formula (I) according to claim 1, characterized in that: R<*>means cyclopropyl or optionally with one or two halogens multiply substituted phenyl, R 2 means hydrogen, X<1> means hydrogen, X<2> means -C=CH-R3 or -C=C-R<5>i. there R<3> means hydrogen, R<4> means hydrogen and R<5> means hydrogen C1-4-alkyl or C2-3-alkenyl Y means r<6> means hydrogen, optionally with hydroxy substituted directly or branched C 1-6 alkyl, oxoalkyl with 1 to 4 C atoms, R<7> means hydrogen, methyl or phenyl, R^ means hydrogen or methyl, R<9>means hydrogen or methyl, R<*2>means hydrogen, methyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl or ethylaminomethyl, R<13> means hydrogen, hydroxy, methoxy, fluorine, methyl or hydroxymethyl, R<20>means where r<!9> means hydrogen, methyl or ethyl, R<21> means hydrogen or methyl, A means CH2, 0 or a direct bond and n means 1 or 2. 3. Compounds with formula (I) according to claim 1, characterized in that: Ri means cyclopropyl or optionally with fluorine one or two times substituted phenyl, R<2> means hydrogen, X<1> means hydrogen, X2 means or -C=C-R5 where R<5> means hydrogen, C-4-alkyl or C2-3-alkenyl, and Y means where R 1 means hydrogen, methyl, optionally substituted with hydroxy ethyl, R<7> means hydrogen or methyl, r<8> represents hydrogen or methyl, R<9> means hydrogen or methyl, R<l2> means hydrogen, methyl, amino, methylamino, aminomethyl or ethylaminomethyl, R<13> means hydrogen, hydroxy or methoxy, R<20>means where R<19> is hydrogen or methyl, R<21> means hydrogen or methyl, A means CH2, 0 or a direct bond and n means 1. 4. Quinolone carboxylic acid derivatives, characterized by formula (II) there R<1>, R<2>, X<1> and X<2> have the meaning given above, and X<3> means halogen and especially fluorine or chlorine. 5. Medicines, characterized in that they contain a quinolone carboxylic acid derivative according to claim 1. 6. Use of quinolone carboxylic acid derivatives according to claim 1 in the production of medicinal products with antibacterial action.