AU720322B2 - 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

f, WO 98/00421 PCT/EP97/03116 -1- 7-(3-Vinyl-1 ,4-i:razin-1 -vl)-substituted guinolonecarboxnlic acids The invention relates to new 7-(3-vinyl- 1,4-piperazin- 1 -yl)-substituted quinolonecarboxylic acids, processes for their preparation, and antibacterial agents containing them.

EP-A 230 053 disclosed quinolonecarboxylic acids having a 3-vinyl-1,4-piperazine radical in the 7-position.

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

.COOR

1 in which R' represents hydrogen, optionally hydroxyl-, methoxy-, amino-, methylamino- or dimethylamino-substituted alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo- 1,3-dioxol-4-yl)-methyl,

R

2 represents hydrogen or fluorine if R 4 is simultaneously unequal to hydrogen or fluorine, or represents amino, methyl or vinyl,

R

3 represents hydrogen, benzyl, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH=CH-COOR 5

-CH

2

CH

2

-COOR

5

-CH

2

CH

2 CN, -CH 2

CH

2

COCH

3

-CH

2

COCH

3 in which R 5 represents methyl or ethyl, or a radical of the general structure R 6

-(NH-CHR

7 in which R 6 represents hydrogen, alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R 7 represents hydrogen, alkyl ,O0 having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH 2 -2phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms and n 1 or 2, and

R

4 represents hydrogen or fluorine if R 2 represents amino, methyl or vinyl, or represents chlorine, methoxy, difluoromethoxy, CN or ethinyl.

The compounds of the formula can be present in the form of racemates or as enantiomerically pure compounds, and in the form of their pharmaceutically utilizable hydrates and acid addition salts, and in the form of their alkali metal, alkaline earth metal, silver and guanidinium salts.

The compounds of the formula are obtained when compounds of the formula (II)

COOR

1

(II),

R4 in which

R

2 and R 4 have the meaning indicated above and X represents fluorine or chlorine, are reacted with compounds of the formula (III) r N R 3.,

(III),

-3in which R 3 has the meaning indicated above, if appropriate in the presence of acid scavengers.

In comparison with known representatives of this type of structure, the compounds according to the invention have a higher antibacterial action, in particular against E. coli, staphylococci, streptococci, salmonellae and mycoplasmae. They are therefore suitable as active compounds for human and veterinary medicine, where for veterinary medicine the treatment of fish for the therapy or for the prevention of bacterial infections is also to be included.

Preferred compounds of the formula are those in which R' represents hydrogen, optionally hydroxyl-, methoxy-, amino-, methylamino- or dimethylamino-substituted alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo- 1,3-dioxol-4-yl)-methyl,

R

2 represents hydrogen or fluorine when R 4 is simultaneously unequal to hydrogen or fluorine, or represents amino or methyl,

R

3 represents hydrogen, alkyl having 1 to 3 carbon atoms, radicals of the structures

-CH=CH-COOR

5

-CH

2

CH

2

-COOR

5

-CH

2

CH

2 CN, -CH2COCH 3 [lacuna]

R

6

-(NH-CHR

7 in which R 6 represents hydrogen, alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R 7 represents hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms,

CH

2 -phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms and n 1 or 2, and

R

4 represents hydrogen or fluorine if R 2 represents amino or methyl, or represents chlorine, methoxy, difluoromethoxy or CN, -4and their pharmaceutically utilizable hydrates and acid addition salts, and the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids.

Particularly preferred compounds of the formula are those in which R' represents hydrogen, methyl or ethyl,

R

2 represents hydrogen or fluorine if R 4 is simultaneously unequal to hydrogen or fluorine, or represents amino,

R

3 represents hydrogen, methyl, radicals of the structures -CH=CH-COOR 5

-CH

2

CH

2 -CN or -CH 2

COCH

3 in which R 5 represents methyl or ethyl, or a radical of the general structure R 6

-(NH-CHR

7 in which R 6 represents hydrogen or methyl, R 7 represents hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH 2 -phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms, and n 1 or 2, and

R

4 represents hydrogen or fluorine if R 2 represents amino, or represents chlorine, methoxy, difluoromethoxy or CN.

Particularly preferred compounds of the formula which may be mentioned are, for example, the following: 8-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-vinyl-1,4-piperazin-1-yl)-3quinolinecarboxylic acid, 5-amino-1 -cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxo-7-(3-vinyl- 1,4-piperazin- -yl)-3quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-7-(3-vinyl-1,4-piperazin-1yl)-3-quinolinecarboxylic acid, 8-cyano-1 -cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7-(3 -vinyl- 1,4-piperazin-1 -yl)-3quinolinecarboxylic acid.

If, for the preparation of compounds of the formula for example, 8-chloro-1cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and2-vinyl- 1,4piperazine are used, the course of the reaction can be represented by the following equation: 0 H j 0 F CO 2 H F CO 2

H

I I I F NH N N C1 H N I Compounds of the formula can also be obtained by carrying out, after the reaction of a compound of the formula (II) with 2-vinyl-1,4-piperazine (R 3 H in formula (III)), a further reaction of the product obtained. Thus compounds of the formula with R 3 equal to a radical -CH=CH-COOEt can be obtained, for example, according to the following equation:

R

2 O R 2 F CO 2 H F CO 2

H

I I I I N N HCEC-CO 2 Et N N HN R A CH=CHN R4 COOEt As a further example, the reaction of a compound of the formula with R 3 hydrogen to give a compound of the formula with R 3 methyl may be mentioned: -6- F C0 2 H F C0 2

H

I I I I N N NN 4 ~HCHOI/HCOOHO4 The compounds of the formula (II) used as starting compounds are known or can be prepared by known processes.

Examples which may be mentioned are: 8-chioro-l1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, -cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1 -cyclopropyl-8-ethinyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-chloro-8-cyano- 1 -cyclopropyl-6-fluoro- I ,4-dihydro-4-oxo-3-quinolinecarboxylicacid, I -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 known.

An example which may be mentioned is 2-vinyl-i ,4-piperazine.

This compound is mentioned in EP-A 230 053.

The synthesis can be carried out, for example, by debenzylation of I1-benzyl-3 -vinylpiperazine or 1 ,4-dibenzyl-2-vinyl-piperazine: -7- I H I S1. CICOOCHCICH 3

N

Jx 2 HC

I

N 2. MeOH N I N

CH

2 Ph

H

R H, CH 2 Ph I-Benzyl-3-vinyl-piperazine and 1,4-dibenzyl-2-vinyl-piperazine are compounds which are known from the literature.

The vinylpiperazines can be employed either as racemates, or as enantiomerically pure compounds.

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 sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoramide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, or isopropanol, glycol monomethyl ether or pyridine. Mixtures of these diluents can also be used.

Acid binders which can be used are all customary inorganic and organic acid binding agents. These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. The following may be specifically mentioned as particularly suitable: triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) or excess amine (III).

The reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out between approximately 20 and 200 0 C, preferably between 80 and 180 0

C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, it is carried out at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.

-8- When carrying out the process according to the invention, 1 to 15 mol, preferably 1 to 6 mol of the compound (III) are employed relative to 1 mol of the compound (II).

Free amino groups can be protected during the reaction by a suitable amino protective group, e.g. by the tert-butoxycarbonyl radical, and liberated again after completion of the reaction by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume E4, page 144 (1983); J.F.W. Mc Omie, 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 underlying carboxylic acid, which can optionally 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 sulfoxide or tetramethylurea at temperatures from approximately 0 to 100 0 C, preferably 0 to 50 0

C.

The preparation of the acid addition salts of the compounds according to the invention is carried out in a customary manner, e.g. by dissolving the betaine in an adequate amount of aqueous acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent amounts of betaine and acid can also be heated in water or an alcohol such as glycol monoethyl ether and then evaporated to dryness, or the precipitated salt can be filtered off with suction.

Pharmaceutically utilizable salts are, for example, 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. The compounds according to the invention can furthermore bind to acidic or basic ion exchangers.

The alkali metal or alkaline earth metal salts of the carboxylic acids according to the invention are obtained, for example, by dissolving the betaine in insufficient alkali metal or alkaline earth metal hydroxide solution, filtering undissolved betaine and -9evaporating the filtrate to dryness. Pharmaceutically suitable salts are sodium, potassium or calcium salts. By reaction of an alkali metal or alkaline earth metal salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.

The compounds according to the invention have strong antibiotic activity and, combined with low toxicity, exhibit a broad antibacterial spectrum against grampositive and gram-negative bacteria, in particular also against those which are resistant to various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulfonamides and tetracycline.

These useful properties make possible their use as chemotherapeutic active compounds in medicine and veterinary medicine, and as substances for the preservation of inorganic and organic materials, in particular of organic materials of all types, e.g. of polymers, lubricants, dyes, fibers, leather, paper and wood, of foodstuffs and of water.

The compounds according to the invention are active against a very broad spectrum of microorganisms. With their aid, gram-negative and gram-positive bacteria and bacterialike microorganisms can be controlled, and the disorders caused by these pathogens can be prevented, ameliorated and/or cured.

The compounds according to the invention are distinguished by increased activity, especially to resistant bacteria and mycoplasmae.

Against bacteria which are classified as less sensitive to comparable substances, in particular resistant Staphylococcus aureus and E. E. coli, the compounds according to the invention show surprising activity increases.

The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly highly suitable for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine which are caused by these pathogens.

The compounds are furthermore suitable for the control of protozoonoses and helminthoses.

The compounds according to the invention can be administered in various pharmaceutical preparations. Preferred pharmaceutical preparations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, injection and orally administrable solutions, suspensions and emulsions, and furthermore pastes, ointments, gels, creams, lotions, powders and sprays.

Combined with favorable toxicity to warm-blooded animals, the active compounds are preferably suitable for the control of bacterial disorders which occur in animal keeping and animal breeding with productive, breeding, zoo, laboratory and experimental animals and pets. They are active here against all or individual stages of development, and against resistant and normally sensitive strains. By controlling the bacterial disorders, disease, cases of death and yield reductions in the production of meat, milk, wool, hides, eggs, honey, etc.) should be decreased, so that more economical and simpler animal keeping is possible due to the use of the active compounds.

The productive and breeding animals include acid animals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, animals having a valuable coat such as, for example, mink, chinchilla and racoons, birds such as, for example, chickens, geese, turkeys, ducks, doves and species of birds for keeping at home and in zoos. They further include productive and ornamental fish.

The laboratory and experimental animals include mice, rats, guinea-pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

In general, it has proven advantageous to administer amounts of approximately 0.5 to approximately 50 mg, preferably 1 to 20 nig, of active compound per kg of body weight per day to achieve effective results.

11- The active compounds can also be administered together with the feed or drinking water of the animals.

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

Such a feed or foodstuff can be used both for healing purposes and for prophylactic purposes.

The preparation of such a feed or foodstuff is carried out by mixing a concentrate or a premixture which contains 0.5 to 30%, preferably 1 to 20%, by weight of an active compound in a mixture with an edible organic or inorganic carrier with customary feeds. Edible carriers are, for example, cornflour or corn and soybean flour or mineral salts which preferably contain a small amount of an edible dust-preventing oil, e.g. corn oil or soybean oil. The premixture obtained in this way can then be added to the complete feed before feeding it to the animals.

The minimum inhibitory concentrations (MIC) of the compounds according to the invention were determined by serial dilution methods on Iso-Sensitest agar (Oxoid). For each test substance, a number of agar plates were prepared which, each with a doubled dilution, contained decreasing concentrations of the active compound. The agar plates were inoculated using a multipoint inoculator (Denley). For inoculation, overnight cultures of the pathogens were used which had previously been diluted such that each inoculation point contained about 104 colony-forming particles. The inoculated agar plates were incubated at 37C, and the bacterial growth was read off after about hours. The MIC value (ptg/ml) indicates the lowest active compound concentration at which no growth could be detected with the naked eye. The determination of the MIC values for mycoplasmae were carried out microscopically after an incubation time of 5 to 7 days.

The MIC values of some of the compounds according to the invention are shown in the tables below.

12 Table 1: MIC values (jil/ml) Ex. 1 Ex. 2 Ex. 3 Ex. 4 E. coli G 293 LH 8 4 16 32 3614 GE 4 4 8 16 21lBui 8 4 8 16 9430 LH 16 16 32 64 Ec 9675 1 n.d. n.d. Stap~h. s121.

2706 0.06 0.06 0.25 0.125 3781 GE 1 1 2 4 G 600 LH 1 1 2 4 BS5520 TGD 1 1 2 4 ST 9616 n.d. n.d. 0.008 ST 9631 n.d. n.d. n.d. 0.008 ST 9638 n.d. n.d. n.d. 0.125 ST 9640 n.d. n.d. n.d. 0.06 Salmonella snn.

5S9602 n.d. n.d. n.d. 0.008 S 9606 n.d. n.d. n.d. 0.008 S 9623 n.d. n.d. n.d. 0.008 -13 Ex.1I Ex. 2 Ex. 3 Ex.4 S 9624 n.d. n.d. n.d. 0.008 S 9651 n.d. n.d. n.d. 0.004 S 9656 0.5 n.d. n.d. S 9657 0.5 n.d. n.d. Bordetella 9213 GE 8 8 16 n.d.

B. bronchiseptica B 9601 0.25 n.d. n.d. 0.25 B 9610 0.25 n.d. n.d. 0.25 B 9613 0.25 n.d. n.d. 0.25 B 9618 0.25 n.d. n.d. 0.25 Pseudomonas spp.

P 9510 0.5 n.d. n.d. n.d.

Streptococcus S. ap-alactiae Scc 9513 0.5 n.d. n.d. n.d.

Scc 9514 0.5 n.d. n.d. n.d.

Scc 9515 0.5 n.d. n.d. n.d.

Scc 9520 0.5 n.d. n.d. n.d.

14- Ex. 1 Ex. 2 Ex. 3 Ex. 4 Scc 9524 0.5 n.d. n.d. n.d.

S. suis Scc 9588 0.06 n.d. n.d. 0.004 Sec 9591 0.03 n.d. n.d. 0.004 Scc 9592 0.25 n.d. n.d. 0.015 Scc 9595 0.03 n.d. n.d. 0.004 Scc 95102 0.125 n.d. n.d. 0.015 Scc 9603 0.03 n.d. n.d. 0.004 Table 2 MIC values against mycoplasmae (pg/ml) Ex. 1 Ex.4 M. agalactiae PG 2 0.06 0.03 M. bovis "Donetta" 0.06 0.125 M. bovirhinis PG 43 0.06 0.25 M. gallisepticum PG 31 0.03 0.03 M. iowae 695 0.03 0.06 The antibacterial activity of the compound according to the invention in vivo was determined in the following way. Two- to three-week-old hen chicks (Lohmann hybrids, Lohmann, Cuxhaven) were infected intrathoracically with 5 x 106 CFU/ml of the E. coli strain 6200 Serovar 078 (Prof. Hinz, Hanover). Immediately after infection, groups of 10 to 20 chicks in each case received the active compound administered orally. 6 dilutions of a geometric dilution series were tested. Assessment was carried out by recording the mortality rate 48 hours after infection. The activity of the compound concerned is indicated as the ED 9 0 in mg/kg.

The comparison used was the compound disclosed in EP-A 230 053 1-cyclopropyl-6fluoro- 1,4-dihydro-4-oxo-7-(3-vinyl- 1,4-piperazin- -yl)-3-quinolonecarboxylic acid (Example 102).

Ex. 1 Ex. 102 from EP-A 230 053

ED

90 1.25 5 16 Pimpamtion of the active commounds ExaMle 1 8-Chioro- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(3 -vinyl- 1 ,4-piperazin- 1 -yl)-3-quinolinecarboxylic acid 0 F CO 2

H

I I N H C1 2.4 g of 8-chioro-l1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.08 g of 2-vinylpiperazine and 1.12 g of DABCO are heated at reflux temperature for 5 hours in a mixture of 12 ml of acetonitrile and 4 ml of dimethylformnamide. The reaction mixture is concentrated in vacuo and the residue is stirred with water. The solid obtained is filtered off with suction, washed with water and dried. 1.64 g of solid (52 of theory) of melting point 154 to 1 56'C are obtained.

'H-NMR (400 MHz, CDCl 3 8 0.95 1.35 3.15 3.3 (m,2H), 3.4 (m,1IH), 3.5 5 (m,1IH), 4.3 5 (in, I1H), 5.2 (d,1IH), 5.3 2 (d,1IH), 5.8 5.9 (in, IH), 8.03 (d,1IH), 8.9 (s,1IH) ppmn.

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

F

N

x HCI -17 1 g of 8-chloro- 1 -cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7-(3 -vinyl-i ,4-piperazin- 1yl)-3-quinolinecarboxylic acid are dissolved in 3 ml of concentrated aqueous hydrochloric acid. The solution is concentrated to dryness in vacuo. 1.09 g of solid of melting point 299 to 301 0 C are obtained.

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 F CO 2

H

N:P6 N N N CI EtOOC 0.392 g of 8-chloro- 1 -cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7-(3 -vinyl-i ,4-piperazin- 1-yl)-3-quinolinecarboxylic acid and 0.98 g of ethyl propiolate are heated under reflux for 1 hour in 7 ml of ethylene glycol monomethyl ether. The reaction mixture is concentrated in vacuo and the residue is dissolved in methylene chloride. The mixture is extracted by shaking with water, and the organic phase is dried over sodium sulfate and concentrated. The residue is chromrnatographed on silica gel. 0.3 g of solid (61 of theory) of melting point 128 to 130 0 C (decomposition) is obtained.

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

F.

N

H

N

-18 0.15 g of 5-amino- -cyclopropyl-6,7,8-trifluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.09 g of 2-vinylpiperazine and 0.09 g of DABCO are heated at reflux for 4 hours in a mixture of 2 ml of acetonitrile and 1 ml of dimethylformamide. The reaction mixture is concentrated in vacuo and the residue is stirred with water. The solid obtained is filtered off with suction, washed with water and dried. 0.12 g of solid (62% of theory) of melting point 214 to 216 0 C is obtained.

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

O

F C02H I I

H

CF 2

H

0.17 g of 1 -cyclopropyl-6,7-difluoro-8-difluoromethoxy- 1,4-dihydro-4-oxoquinolinecarboxylic acid, 0.09 g of 3-vinylpiperazine and 0.067 g of DABCO are heated under reflux for 20 hours in a mixture of I ml of acetonitrile and 0.5 ml of dimethylformamide. The reaction mixture is concentrated in vacuo and the residue is stirred with water. The solid obtained is filtered off with suction, washed with water and dried. 0.155 g of solid (73% of theory) of melting point 209 0 C is obtained.

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

O

F CO 2

H

I I N N

F

H, 19 0.285 g of 1 -cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.17 g of 2-vinylpiperazine and 0.14 g of diazabicyclooctane (DABCO) are heated under reflux. for 4 hours in a mixture of 3 ml of acetonitrile and 1 ml of dimethylformamide. The reaction mixture is concentrated in vacuo, the residue is stirred with water and the solid obtained is filtered off with suction and dried. 0.349 g (93% of theory) of solid of melting point 184 to 1 86'C is obtained.

ExgMle 7 8-Cyano-l1-cyclopropyl-6-fluoro-7-(3'-vinyl-piperazin- l-yl)-l ,4-dihydro-4oxo-3 -quinolinecarboxylic acid 0 F C0 2

H

I I

NN

H NN 150 mg of 7-chloro-8-cyano- 1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-3 quinolinecarboxylic acid are stirred at 40 to 45'C for 7 hours with 66 mg of 2-vinylpiperazine and 0.136 ml of triethylarnine in 5 ml of acetonitrile. 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) ExgMle 8 Methyl 8-chloro- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(3 -vinyl- 1,4piperazin- I -yl)-3-quinolinecarboxylate N N HN Cl N 100 mg of the compound from Example 1 are stirred at room temperature for 24 hours in a mixture of 3 ml of 2,2-dimethoxypropane, 0.26 ml of 33% strength hydrochloric acid and 1 ml of methanol saturated with HC1 gas. The reaction mixture is added to 50 ml of water and extracted three times by shaking with 15 ml of ether each time. The aqueous phase is then rendered alkaline with sodium carbonate solution and extracted three times by shaking with 20 ml of chloroform each time. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel (ethyl acetate/ethanol/ammonia 88:10:2) and crystallized by stirring with a little ether.

42 mg of solid (41% of theory) of melting point 148 0 C are obtained.

Example 9 1 -Cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-5-vinyl-7-(3-vinyl- 1,3-piperazin-1 -yl)-3 quinolinecarboxylic acid F CO 2

H

N N

HN

0.29 g of 1-cyclopropyl-6,7-dilfuoro-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 heated -21 under reflux for 4 hours in a mixture of 2 ml of autonitrile and 1 ml of dimethylformamide. The reaction mixture is concentrated in vacuo and the residue is stirred with water. The resulting solid is filtered off with suction, washed with water and dried. 0.20 g of beige dye (52% of theory) of melting point 170 0 C (decomposition) is obtained.

Example 1 -Cyclopropyl-6-fluoro- 1,4-dihydro-5-methyl-4-oxo-7-(3-vinyl-1 ,4-piperazin- -yl)-3quinolinecarboxylic acid CH, O F

CO

2

H

N N HN J 0.28 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.28 g of 2-vinylpiperazine dihydrochloride and 0.5 g of DABCO are heated under reflux for 5 hours in a mixture of 3 ml of acetonitrile and 1 ml of dimethylformamide. The reaction mixture is largely concentrated in vacuo and the residue is stirred with water. After filtration, the filtrate is extracted several times with chloroform. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The solid obtained is dried in vacuo. Yield: 0.243 g of beige solid (65 of theory) of melting point 110-112 0

C.

-22- Comarison compound 1 -Cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-7-(3-vinyl- 1,4-piperazin-1 -yl)-3quinolinecarboxylic acid 0 F CO 2

H

I

I

0.53 g of I -cyclopropyl-6,7-fluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.56 g of 2-vinylpiperazine dihydrochloride and 0.67 g of DABCO are heated under reflux for 4 hours in a mixture of 4 ml of acetonitrile and 2 ml of dimethylformamide. The reaction mixture is filtered, the filtrate is concentrated in vacuo and the residue is stirred with water. The solid thus obtained is filtered off with suction, washed with 10 water and dried. 0.41 g of solid (57% of theory) of melting point 295°C is obtained.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or ;oo* "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (7)

1. Compounds of the general formula (I) .COOR 1 in which R' represents hydrogen, optionally hydroxyl-, methoxy-, amino-, methylamino- or dimethylamino-substituted alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R 2 represents hydrogen or fluorine if R 4 is simultaneously unequal to hydrogen or fluorine, or represents amino, methyl or vinyl, R 3 represents hydrogen, benzyl, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH=CH-COOR 5 -CH 2 CH 2 -COOR 5 -CH 2 CH 2 CN, -CH 2 CH 2 COCH 3 -CH 2 COCH 3 in which R 5 represents methyl or ethyl, or a radical of the general structure R 6 -(NH-CHR 7 in which R 6 represents hydrogen, alkyl having 1 to 3 carbon atoms or the radical -COO- tert-butyl, R 7 represents hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH 2 -phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms and n 1 or 2, and R 4 represents hydrogen or fluorine if R 2 represents amino, methyl or vinyl, or represents chlorine, methoxy, difluoromethoxy, CN or ethinyl. -24-

2. Compounds of the formula according to Claim 1, in which R' represents hydrogen, optionally hydroxyl-, methoxy-, amino-, methylamino- or dimethylamino-substituted alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl, R 2 represents hydrogen or fluorine when R' is simultaneously unequal to hydrogen or fluorine, or represents amino or methyl, R 3 represents hydrogen, alkyl having 1 to 3 carbon atoms, radicals of the structures -CH=CH-COOR 5 -CH 2 CH 2 -COOR 5 -CH 2 CH 2 CN, -CH 2 COCH 3 in which R represents methyl or ethyl or a radical of the general structure R 6 -(NH-CHR 7 CO)n- in which R 6 represents hydrogen, alkyl having 1 to 3 carbon atoms or the radical -COO-tert-butyl, R 7 represents hydrogen, alkyl having 1 to 4 carbon atoms, :hydroxyalkyl having 1 or 2 carbon atoms, CH 2 -phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms and n 1 or 2, and R' represents hydrogen or fluorine if R represents amino or methyl, or represents chlorine, methoxy, difluoremethoxy or CN. o a

3. Compounds of the formula according to Claim 1, in which R' represents hydrogen, methyl or ethyl, R 2 represents hydrogen or fluorine ifR 4 is simultaneously unequal to hydrogen or fluorine, or represents amino, R represents hydrogen, methyl, radicals of the structures -CH--CH-COOR 5 -CH 2 CH 2 -CN or -CH 2 COCH 3 in which R' represents methyl or ethyl, or a radical of the general structure R'-(NH-CHR 7 in which R 6 represents hydrogen or methyl, R 7 represents hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 or 2 carbon atoms, CH 2 -phenyl, aminoalkyl or thioalkyl having 1 or 2 carbon atoms, and n 1 or 2, R 4 represents hydrogen or fluorine if R 2 represents amino, or represents chlorine, methoxy, difluoromethoxy or CN.

4. Process for the preparation of the compounds of the formula according to Claim 1, characterized in that compounds of the formula (II) -COOR 1 (II), in which R 2 and R 4 have the meaning indicated above and X represents fluorine or chlorine, are reacted with compounds of the formula (III) N H (III), in which R 3 has the meaning indicated above, if appropriate in the presence of 26 acid scavengers.

8-Chloro-1 -cyclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-7-(3 -vinyl-i ,4-piperazin-1- yl)-3-quinolinecarboxylic acid and its esters. 6. 5-Amino-l-cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxo-7-(3-vinyl-1I,4-pipefazin- l-yl)-3-quinolinecarboxylic acid and its esters. 7. 1 -Cyclopropyl-6-fluoro-S-difluoromethoxy- 1,4-dihydro-4-oxo-7-(3-vinyl-1 ,4- piperzin-1-yI)-3-quinolinecarboxylic acid and its esters. 8. Compounds of the formula. according to Claim 1 comprising medicaments.

9. Use of compounds of the formula according to Claim 1 for the production 0 of medicaments.. Use. of compounds of the formula according to Claim 1 in antibacterial compositions.

11. Compounds of the general formula (Ia process for the preparation thereof, use of compounds of the general formula, 8-Chloro-lI-cyclopropyl-6-fluoro- 1, 4-dihydro-4-oxo-7-(3 -vinyl- 1, 4-piperazin-1I-yl)-3-quinolinecarboxylic acid and its esters, 5-Amino-l-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4- oxo-7-(3 -vinyl- 1, 4-piperazin-l-yl)-3-quinolinecarboxylic acid and its esters or I -Cyclopropyl-6-fluoro-8-difluoromethoxy- 1, 4-dihydro-4-oxo-7-(3 vinyl-i1, 4-piperazn-1I -yl)-3 -quinolinecarboxylic acid and its esters substantially as herein described with reference to the examples and to the exclusion of the comparative examples. DATED this third day of April, 2000. BAYER AG By Its Patent Attorneys DAVIES COLLISON CAVE