DE19651687A1 - 7- (3-Vinyl-1,4-piperazin-1-yl) substituted quinolonecarboxylic acids - Google Patents

Abstract

The invention concerns new quinolone carbonic acids substituted by 7-(3-vinyl-1,4-piperazine-1-yl) of general formula (I) in which R<1> stands for hydrogen or alkyl optionally substituted by hydroxy, methoxy, amino, methylamino or dimethylamino with 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl; R<2> stands for hydrogen or fluorine when at the same time R<4> is a different hydrogen or fluorine, or stands for amino, methyl or vinyl; R<3> stands for hydrogen, benzyl, alkyl with 1 to 3 carbon atoms, groups of -CH=CH-COOR<5>, -CH2CH2-COOR<5>, -CH2CH2CN, -CH2CH2COCH3, -CH2COCH3, in which R<5> stands for methyl or ethyl or stands for a group of the general structure R<6>-(NH-CHR<7>-CO)n- in which R<6> stands for hydrogen, alkyl with 1 to 3 carbon atoms or stands for the -COO-tertiary butyl group, R<7> stands for hydrogen, alkyl with 1 to 4 carbon atoms, hydroxyalkyl with 1 or 2 carbon atoms, CH2-phenyl, aminoalkyl or thioalkyl with 1 or 2 carbon atoms and n = 1 or 2; and R<4> stands for hydrogen or flourine when R<2> stands for amino, methyl or vinyl or stands for chlorine, methoxy, difluoromethoxy, CN or ethinyl. The invention also concerns a method for their use and their use in antibacterial substances.

Description

The invention relates to new 7- (3-vinyl-1,4-piperazin-1-yl) -substituted quinolones carboxylic acids, process for their preparation and antibak containing them material means.

EP-A 230 053 describes quinolonecarboxylic acids with a 3-vinyl-1,4-piperazine The rest in the 7 position became known.

New compounds of the general formula (I) have been found

in which
R¹ is hydrogen, optionally substituted by hydroxy, methoxy, amino, methyl amino or dimethylamino alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl,
R² represents hydrogen or fluorine if R⁴ is not hydrogen or fluorine at the same time, or represents amino, methyl or vinyl,
R³ represents hydrogen, benzyl, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-COOR⁵, -CH₂CH₂CN, -CH₂CH₂COCH₃, -CH₂COCH₃, in which R⁵ represents methyl or ethyl, or a radical of the general structure R⁶- (NH-CHR⁷-CO) _n - in which R⁶ represents hydrogen, alkyl having 1 to 3 carbon atoms or the rest -COO-tert. -Butyl, R⁷ is hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH₂- phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms and n = 1 or 2,
and
R⁴ represents hydrogen or fluorine if R² represents amino, methyl or vinyl, or represents chlorine, methoxy, difluoromethoxy, CN or ethinyl.

The compounds of formula (I) can be in the form of racemates or as enanes tiomerically pure compounds and in the form of their pharmaceutically usable Hydrates and acid addition salts as well as in the form of their alkali, alkaline earth, silver and guanidinium salts are present.

The compounds of the formula (I) are obtained if compounds of the formula (II)

in which
R¹, R² and R⁴ have the meaning given above and
X represents fluorine or chlorine,
with compounds of the formula (III)

in which R³ has the meaning given above, optionally in the presence of acid scavengers.  

The compounds of the invention have compared to known Vertre tter this structure type a higher antibacterial effect, especially against E. coli, staphylococci, streptococci, salmonella and mycoplasmas. she are therefore suitable as active ingredients for human and veterinary medicine Veterinary medicine also the treatment of fish for therapy or for pre prevention of bacterial infections.

Compounds of the formula (I) in which
R¹ represents hydrogen- optionally substituted by hydroxy, methoxy, amino, methyl amino or dimethylamino alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxo1-4-yl) methyl,
R² represents hydrogen or fluorine if R⁴ is not equal to hydrogen or fluorine, or represents amino or methyl,
R³ represents hydrogen, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-COOR⁵, -CH₂CH₂CN, -CH₂COCH₃, R⁶- (NH-CHR⁷-CO) _n -, in which R⁶ represents hydrogen , Alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R⁷ is hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH₂-phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms stands and n = 1 or 2,
and
R⁴ represents hydrogen or fluorine if R² represents amino or methyl, or represents chlorine, methoxy, difluoromethoxy or CN,
and their pharmaceutically usable hydrates and acid addition salts and the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying car bonic acids.

Compounds of the formula (I) in which
R¹ represents hydrogen, methyl or ethyl,
R² stands for hydrogen or fluorine if R⁴ is simultaneously not hydrogen or fluorine, or stands for amino,
R³ represents hydrogen, methyl, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-CN or -CH₂COCH₃, in which R⁵ represents methyl or ethyl, or a radical of the general structure R⁶- (NH-CHR⁷-CO) _n - is in which R⁶ is hydrogen or methyl, R⁷ is hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH₂-phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms, and n = 1 or 2 ,
and
R⁴ represents hydrogen or fluorine if R² represents amino, or represents chlorine, methoxy, difluoromethoxy or CN.

The following are examples of particularly preferred compounds of the formula (i):
8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-yl) -3-quinolinecarboxylic acid,
5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-p-iperazin-1-yl) -3-quinolinecarboxylic acid,
1-cyclopropyl-6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-yl) -3-quinolinecarboxylic acid,
8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-y1) -3-quinoline carboxylic acid.

Is used for example for the preparation of compounds of formula (I) 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carbonic acid and 2- Vinyl 1,4-piperazine, so the course of the reaction by the following formula Scheme are reproduced:

Compounds of the formula (I) can also be obtained by the reaction of a compound of formula (II) with 2-Viny1-1,4-piperazine (R³ = H in formula (III)) carries out a further reaction of the product obtained. So can compounds of formula (I) with R³ is a radical -CH = CH-COOEt can be obtained, for example, according to the following formula scheme:

Another example is the reaction of a compound of formula (I) with R³ = Hydrogen to a compound of formula (I) with R³ = methyl called:

The compounds of formula (II) used as starting compounds are known or can be prepared by known methods.

Examples include:
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarbonic acid,
1-cydopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarbonic acid,
7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-rbonic acid,
1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

The piperazines of the formula (III) used as starting compounds are knows.

An example is 2-vinyl-1,4-piperazine.

This connection is mentioned in EP-A 230 053.

The synthesis can be carried out, for example, by debenzylating 1-benzyl-3-vinyl piperazine or 1,4-dibenzyl-2-vinyl-piperazine take place:

1-Benzyl-3-vinyl-piperazine and 1,4-dibenzyl-2-vinyl-piperazine are known from the literature known connections.

The vinyl piperazines can be used both as racemates and as enantiomerically pure Connections are used.

The reaction of (II) with (III), in which the compounds (III) also in the form their salts, such as. B. the hydrochloride can be used is preferred wise in a diluent such as dimethyl sulfoxide, 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 pyridine. Mixtures of these can also Thinners are used.  

All common inorganic and organic acid bins can be used as acid binders be used. These preferably include the alkali metal hydroxides, Alkali carbonates, organic amines and amidines. Be particularly suitable in called individual: triethylamine, 1,4-diazabicydo [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 over a wide range. in the generally one works between about 20 and 200 ° C, preferably between 80 and 180 ° C.

The reaction can be carried out at normal pressure, but also at elevated pressure leads. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 mol of Compound (II) 1 to 15 mol, preferably 1 to 6 mol of compound (III).

Free amino groups can be replaced by a suitable amino during the reaction protecting group, e.g. B. protected by the tert-butoxycarbonyl radical and according to Be termination of the reaction by treatment with a suitable acid such as chlorine hydrochloric acid or trifluoroacetic acid are released again (see Houben- Weyl, Methods of Organic Chemistry, Volume E4, page 144 (1983); J.F.W. Mc Omie, Protective Groups in Organic Chemistry (1973), page 43).

The esters according to the invention are reacted with an alkali salt basic carboxylic acid, optionally on the N atom through protection group such as the tert-butoxycarbonyl group can be protected with suitable halo genalkyl derivatives in a solvent such as dimethylformamide, dimethyl acetamide, N-methylpyrrolidone, dimethyl sulfoxide or tetramethylurea Temperatures of about 0 to 100 ° C, preferably 0 to 50 ° C, obtained.

The preparation of the acid addition salts of the compounds according to the invention follows in the usual way z. B. by dissolving the betaine in sufficient quantity aqueous acid and precipitation of the salt with a water-miscible orga African solvents such as methanol, ethanol, acetone, acetonitrile. One can also equivalent amounts of betaine and acid in water or an alcohol such as glycol Heat the monoethyl ether and then evaporate to dryness or that  Vacuum out any salt that has fallen out. Examples of pharmaceutically usable salts are show the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, Succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, Galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid understand. Furthermore, the compounds of the invention can be acidic or bind basic ion exchangers.

The alkali or alkaline earth metal salts of the carboxylic acids according to the invention are used in for example, by dissolving the betaine in a deficient alkali or alkaline earth lye, filtration of undissolved betaine and evaporation of the filtrate to Get dry. Sodium, potassium or calcium are pharmaceutically suitable salts. By reacting an alkali or alkaline earth salt with a suitable one Silver salts such as silver nitrate give the corresponding silver salts.

The compounds according to the invention have a strong antibiotic effect and show low toxicity a broad antibacterial spectrum against gram positive and gram-negative germs, especially against those that are resistant to ver various antibiotics, such as B. penicillins, cephalosporins, aminoglycosides, sul fonamides, tetracyclines.

These valuable properties enable them to be used as chemotherapeu active ingredients in medicine and veterinary medicine as well as substances for consumer use vation of inorganic and organic materials, especially organi all types of materials, e.g. B. polymers, lubricants, paints, fibers, Leather, paper and wood, food and water.

The compounds according to the invention are against a very broad spectrum of Microorganisms effective. With their help, gram-negative and gram-positive Fights bacteria and bacterial-like microorganisms as well as through them Pathogens caused diseases prevented, improved and / or cured who the.

The compounds according to the invention are notable for enhanced activity especially resistant germs and mycoplasmas.

Compared to bacteria that compared to comparable substances as less em sensitive, especially resistant Staphylococcus aureus and E.  coli, the compounds of the invention show surprising activity wrestled.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly good for professionals phylaxis and chemotherapy of local and systemic infections in the Suitable for human and veterinary medicine, which are caused by these pathogens.

The compounds are also suitable for combating protozoonoses and Helmets.

The compounds of the invention can be used in various pharmaceutical Preparations are applied. As preferred pharmaceutical preparations be tablets, coated tablets, capsules, pills, granules, suppositories, injection and oral solutions, suspensions and emulsions, also pastes, Called ointments, gels, creams, lotions, powders and sprays.

The active ingredients are particularly suitable for use with favorable warm-blooded toxicity fighting bacterial diseases involved in animal husbandry and breeding Livestock, breeding, zoo, laboratory, experimental and hobby animals occur. they are against all or individual stages of development as well as against resistant and normally sensitive strains effective. By fighting the bacterial Er Diseases are said to be illness, deaths and reduced performance (e.g. in the case of Production of meat, milk, wool, skins, eggs, honey, etc.) decreased be, so that through the use of active ingredients a more economical and a more professional animal husbandry is possible.

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, Fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, Turkeys, ducks, pigeons, bird species for home and zoo keeping. It also includes Farm and ornamental fish.

Laboratory and experimental animals include mice, rats, guinea pigs, gold hamsters, dogs and cats.

The pets include dogs and cats.  

In general, it has been found advantageous to use amounts from about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day Deliver effective results.

The active ingredients can also be taken together with the feed or drinking water of the animals be administered.

Feed and food contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used both for medicinal purposes and for prophylactic purposes.

Such feed or food is produced by mixing a concentrate or premix containing 0.5 to 30%, preferably 1 to 20 wt .-% of an active ingredient in a mixture with an edible organic or contains inorganic carrier with common feed. Edible carriers are e.g. B. Corn meal or corn and soybean meal or mineral salts, which are preferred a small amount of an edible dust prevention oil, e.g. B. corn oil or soybean oil, contain. The premix obtained in this way can then be the complete feed medium before being fed to the animals.

The minimum inhibitory concentrations (MIC) of the compounds of the invention were diluted with Iso-Sensitest Agar (Oxoid) Right. A series of agar plates were prepared for each test substance decreasing concentrations of the active substance at twice the dilution contained. The agar plates were loaded with a multipoint inoculator (Denley) vaccinates. Overnight cultures of the pathogens were used for inoculation, the previous ones were diluted so that each vaccination point contained approximately 10⁴ colony-forming particles. The inoculated agar plates were incubated at 37 ° C, and the germ growth was read after about 20 hours. The MIC value (µg / ml) gives the lowest Active substance concentration at which no growth can be seen with the naked eye was. The MIC values for mycoplasmas were recorded microscopically after an incubation period of 5 to 7 days.

In the tables below, the MIC values of some of the invention appropriate connections listed.  

Table 1

MIC values (µl / ml)

Table 2

MIC values against mycoplasma (µg / ml)

The antibacterial activity of the compound according to the invention was in vivo determined as follows. Two to three week old chicken chicks (Lohmann Hybrids, Fa. Lohmann, Cuxhaven) were with 5 × 10⁶ CFU / ml of the E. coli strain mes 6200 Serovar 078 (Prof. Hinz, Hanover) infected intrathoracically. Right away after infection, groups of 10 to 20 chicks were given the active ingredient administered orally. 6 dilutions of a geometric dilution were tested series. The evaluation was carried out by recording the mortality rate of 48 hours after infection. The effectiveness of the compound in question is considered ED₉₀ given in mg / kg.

As a comparison, the compound 1-Cyciopro known from EP-A 230 053 pyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-yl) -3-quinononecarboxylic acid (Example 102).

Manufacture of active ingredients example 1 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4- piperazin-1-yl) -3-quinolinecarboxylic acid

2.4 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1.08 g of 2-vinylpiperazine and 1.12 g of DABCO are mixed in a mixture of 12 ml Acetonitrile and 4 ml of dimethylformamide heated at reflux temperature for 5 hours. The reaction mixture is concentrated in vacuo and the residue with water stirred. The solid obtained is filtered off, washed with water and ge dries. 1.64 g of solid (52% of theory) of melting point 154 are obtained up to 156 ° C.

1 H-NMR (400 MHz, CDCl₃): δ = 0.95 (m, 2H), 1.35 (m, 2H), 3.15 (m, 2H), 3.3 (m, 2H), 3.4 (m, 1H), 3.55 (m, 1H), 4.35 (m, 1H), 5.2 (d, 1H), 5.32 (d, 1H) , 5.8-5.9 (m, 1H), 8.03 (d, 1H), 8.9 (s, 1H) ppm.

Example 2 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4- piperazin-1-yl) -3-quinolinecarboxylic acid - hydrochloride

1 g 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-yl) - 3-Quinoline carboxylic acid is dissolved in 3 ml of concentrated aqueous hydrochloric acid. The solution is evaporated to dryness in vacuo. 1.09 g of solid are obtained from melting point 299 to 301 ° C.

Example 3 8-chloro-1-cyclopropyl-7- [4- (2-ethoxycarbonyl-vinyl) -3-vinyl-1,4- piperazin-1-yl] -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

0.392 g of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazine- 1-yl) -3-quinolinecarboxylic acid and 0.98 g of ethyl propiolate are dissolved in 7 ml Ethylene glycol monomethyl ether heated under reflux for 1 hour. The reaction ge Mix is concentrated in vacuo and the residue is dissolved in methylene chloride. It is shaken out with water and the organic phase is dried over sodium sulfate and constricts. The residue is chromatographed on silica gel. You get 0.3 g of solid (61% of theory) with a melting point of 128 to 130 ° C. (decomposition).

Example 4 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4- piperazin-1-yl) quinoline carboxylic acid

0.15 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carbon acid, 0.09 g of 2-vinylpiperazine and 0.09 g of DABCO are mixed out 2 ml of acetonitrile and 1 ml of dimethylformamide are heated at reflux for 4 hours. The The reaction mixture is concentrated in vacuo and the residue is mixed with water stirs. The solid obtained is filtered off, washed with water and dried net. 0.12 g of solid (62% of theory) of melting point 214 to is obtained 216 ° C.

Example 5 1-cyclopropyl-6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-7- (3- vinyl-1,4-piperazin-1-yl) -3-quinolinecarboxylic acid

0.17 g of 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-quinolino-ncar Bonic acid, 0.09 g of 3-vinylpiperazine and 0.067 g of DABCO are mixed from 1 ml of acetonitrile and 0.5 ml of dimethylformamide under reflux for 20 hours is heating. The reaction mixture is concentrated in vacuo and the residue with Water stirred. The solid obtained is filtered off with suction, washed with water and dried. 0.155 g of solid (73% of theory) is obtained from the enamel point 209 ° C.

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

0.285 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 0.17 g of 2-vinylpiperazine and 0.14 g of diazabicyclooctane (DABCO) are combined in one Mixture of 3 ml of acetonitrile and 1 ml of dimethylformamide under reflux for 4 hours river heated. The reaction mixture is concentrated in vacuo, the residue with Water is stirred and the solid obtained is suction filtered and dried. You get 0.349 g (93% of theory) solid, melting point 184-186 ° C.

Example 7 8-cyan-1-cydopropyl-6-fluoro-7- (3′-vinyl-piperazin-1-yl) -1,4-dihydro-- 4-oxo-3-quinoline carboxylic acid

150 mg of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carbonic acid are mixed with 66 mg of 2-vinyl-piperazine and 0.136 ml of triethylamine in 5 ml of acetonitrile 7 Stirred at 40 to 45 ° C for hours. All volatile components are removed in vacuo and the residue is recrystallized from ethanol.
Yield: 160 mg (85% of theory)
Melting point: 265 ° C (decomposition)

Example 8 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4- piperazin-1-yl) -3-quinolinecarboxylic acid methyl ester

100 mg of the compound from Example 1 are mixed in a mixture of 3 ml of 2,2- Dimethoxypropane, 0.26 ml 33% hydrochloric acid and 1 ml saturated with HCl gas Methanol stirred for 24 hours at room temperature. The reaction mixture is in Given 50 ml of water and extracted three times with 15 ml of ether. The watery The phase is then made alkaline with soda solution and three times with 20 ml each Chloroform shaken out. The organic phase is dried over sodium sulfate net and constricted. The residue is chromatographed on silica gel (vinegar ester / ethanol / ammonia 88: 10: 2) and crystallized by stirring with a little ether lized. 42 mg of solid (41% of theory) with a melting point of 148 ° C. are obtained.

Example 9 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-5-vinyl-7- (3-vinyl-1,4-piperazin-1-yl) -3- quinoline carboxylic acid

0.29 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.28 g of 2-vinyl-piperazine dihydrochloride and 0.34 g of DABCO are combined in one Mixture of 2 ml of acetonitrile and 1 ml of dimethylformamide under reflux for 4 hours  river heated. The reaction mixture is concentrated in vacuo and the residue mixed with water. The resulting solid is filtered off with water washed and dried. 0.20 g of beige solid are obtained (52% of theory) melting point 170 ° C (decomposition).

Example 10 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7- (3-vinyl-1,4-pipe-razin-1-yl) -3- quinoline carboxylic acid

0.28 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline carbon acid, 0.28 g of 2-vinylpiperazine dihydrochloride and 0.5 g of DABCO are combined in one Mixture of 3 ml of acetonitrile and 1 ml of dimethylformamide under reflux for 5 hours river heated. The reaction mixture is largely concentrated in vacuo and the residue is stirred with water. After filtration, the filtrate is used several times Chloroform extracted. The combined organic phases are over Dried sodium sulfate and concentrated in vacuo. The solid obtained is dried in vacuo. Yield: 0.243 g beige solid (65% of theory) melting point 110-112 ° C.  

Comparative compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazin-1-y-l) -3- quinoline carboxylic acid

0.53 g 1-cyclopropyl-6,7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.56 g 2- Vinylpiperazine dihydrochloride and 0.67 g DABCO are mixed 4 ml of acetonitrile and 2 ml of dimethylformamide are heated under reflux for 4 hours. The reaction mixture is filtered, the filtrate is concentrated in vacuo and the The residue is mixed with water. The solid obtained in this way is filtered off with Washed water and dried. 0.41 g of solid is obtained (57% of theory) from melting point <295 ° C.

Claims (10)

1. Compounds of the general formula (I) in which
R 1 represents hydrogen, optionally substituted by hydroxy, methoxy, amino, methylamino or dimethylamino alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl,
R² represents hydrogen or fluorine if R⁴ is not hydrogen or fluorine at the same time, or represents amino, methyl or vinyl,
R³ represents hydrogen, benzyl, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-COOR⁵, -CH₂CH₂CN, -CH₂CH₂COCH₃, -CH₂COCH₃, in which R⁵ represents methyl or ethyl, or a radical of the general structure R⁶- (NH-CHR⁷-CO) _n - in which R⁶ represents hydrogen, alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R⁷ represents hydrogen, alkyl having 1 to 4 carbon atoms, Hydroxyalkyl with 1 or 2 carbon atoms, CH₂-phenyl, aminoalkyl or thioalkyl with 1 or 2 carbon atoms and n = 1 or 2,
and
R⁴ represents hydrogen or fluorine if R² represents amino, methyl or vinyl, or represents chlorine, methoxy, difluoromethoxy, CN or ethinyl. 2. Compounds of formula (I) according to claim 1, in which
R1 is hydrogen; alkyl with 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl optionally substituted by hydroxy, methoxy, amino, methylamino or dimethylamino,
R² represents hydrogen or fluorine if R⁴ is not equal to hydrogen or fluorine, or represents amino or methyl,
R³ represents hydrogen, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-COOR⁵, -CH₂CH₂CN, -CH₂COCH₃, R⁶- (NH-CHR⁷-CO) _n -, in which R⁶ represents hydrogen , Alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R⁷ is hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH₂-phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms stands and n = 1 or 2,
and
R⁴ represents hydrogen or fluorine if R² represents amino or methyl, or represents chlorine, methoxy, di-fluoromethoxy or CN. 3. Compounds of formula (I) according to claim 1, in which
R¹ represents hydrogen, methyl or ethyl,
R² stands for hydrogen or fluorine if R⁴ is simultaneously not hydrogen or fluorine, or stands for amino,
R³ represents hydrogen, methyl, radicals of the structures -CH = CH-COOR⁵, -CH₂CH₂-CN or -CH₂COCH₃, in which R⁵ represents methyl or ethyl, or a radical of the general structure R⁶- (NH-CHR⁷- CO) _n - is in which R⁶ is hydrogen or methyl, R⁷ is hydrogen; Alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH₂-phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms, and n = 1 or 2,
and
R⁴ is hydrogen or fluorine when R² is amino; or represents chlorine, methoxy, difluoromethoxy or CN. 4. A process for the preparation of the compounds of formula (I) according to claim 1, characterized in that compounds of formula (II) in which
R¹, R² and R⁴ have the meaning given above and
X represents fluorine or chlorine,
with compounds of the formula (III) in which R³ has the meaning given above, if appropriate in the presence of acid scavengers. 5. 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-piperazine-1- yl) -3-quinoline carboxylic acid and its esters. 6. 5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-vinyl-1,4-p-ipera zin-1-yl) -3-quinolinecarboxylic acid and its esters. 7. 1-Cyclopropyl-6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-7- (3-vinyl - 1,4- piperazin-1-yl) -3-quinolinecarboxylic acid and its esters. 8. Medicament-containing compounds of formula (I) according to claim 1. 9. Use of compounds of formula (I) according to claim 1 for the preparation provision of medicines. 10. Use of compounds of formula (I) according to claim 1 in anti bacterial agents.