RU1780533C - Method for producing quinoline derivatives of their pharmaceutically acceptable salts or esters - Google Patents

Abstract

The invention relates to quinoline derivatives, in particular the preparation of compounds of the general form: CH2-CRz NRi-CH RVCbb-ft ZH CF-C-ClH-C CfCtOjOH CHN-cTl -CHa-CHz, where Z is NH2 or halogenTGNt- h - the same or different H or Ci-5-zlkil, or their pharmaceutically acceptable salts or complex zfirs with antibacterial activity, which can be used in medicine. The goal is the creation of new, more active substances of this class. The synthesis was carried out by the reaction of the compound of f-ly and with the compound of f-ly-II: ZC CFcl CH-c C gcc (o) -o H-rj-CH-CH2cTb 00 and ffRJ-CHR2-Crta-NPTCT-Ha-CPz (til ), where X is halogen; Y-H or CI-B-ELKIL, diacyloxyboryl or difluoroboryl, followed by hydrolysis or conversion to the desired salt if necessary. The new substances are low toxic (LD & about 2000 mg / kg) and have an antimicrobial effect of the best known analogues. 8 tab

Description

The invention relates to a method for producing new quinoline derivatives of the general formula (I)

o z °

1JL JL GLM

Wh-UUtt

R3a

where Z is an amino group or a halogen atom; Ri, Ra and Ra are the same or different, each represents a hydrogen atom or a lower alkyl group having 1-5 carbon atoms.

Known structural analogue with the same activity.

A known method for the formation of amines from amines and halogen-containing compounds.

The purpose of the invention is to provide new, more active quinoline derivatives using the known amine formation reaction.

The goal is achieved by the proposed method for producing compounds of formula (1), which consists in the interaction of the compounds of formula II

z o

wr

A I /

VI 00

o eat with

W

where X is a halogen atom, Y is a hydrogen atom of a lower alkyl group having 1-5 carbon atoms, a diacyloxyboryl or difluoroboryl group; 2 - indicated values with a pipeerein derivative of formula III

AND ,

Rl-NpNH

where Ri, R2 and Pz are previously defined values and, if necessary, hydrolyze the resulting compound and optionally convert the compound thus obtained into its pharmaceutically acceptable salt.

Example 1.1-Cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1). 38.8 g of 2,3,4,6-tetrafluorobenzoic acid are treated with thionyl chloride to give 36 g of 2,3,4,6-tetrafluorobenzoyl chloride as an oily substance. Mp 87-89 ° C (36mm Nd).

2). The resulting compound (36 g) was reacted with sodium diethyl malonate in anhydrous toluene to obtain diethyl 2,3,4,6-tetrafluorobenzoyl malonate as an oily substance. Then water and a catalytic amount of p-toluene sulfonic acid were added, the mixture was heated under reflux for 2.5 hours to obtain 28.4 g of ethyl 2,3,4,6-tetrafluoro-benzoyl acetate as an oil. Because 103-104 ° C (3 mm Nd).

3). The resulting compound (28.4 g) was treated with ethyl orthoformate and acetic anhydride to convert it to ethyl 3-ethoxy-2- (2,3,4, b-tetrafluorobenzoyl) acrylate. This compound is then treated with cyclopropylamine to obtain 32.8 g of ethyl 3-cyclopropylamino-2- (2,3,4,6-tetrafluorobenzoyl) acrylate. Because 107: 108 ° C.

4), A mixture of the resulting compound (33 g), 8.85 g of potassium fluoride and 100 ml of dimethylformamide is stirred at 150-160 ° C for 2 hours and then cooled at room temperature. Then water (300 ml) was added to the mixture and the crystalline material was collected by filtration. Then chloroform and water are added to this crystalline substance, the aqueous layer is made alkaline with a saturated aqueous solution of sodium carbonate. The chloroform layer is separated and dried to obtain anhydrous sodium sulfate. The solution is evaporated under reduced pressure, the residue is separated and purified by column chromatography to obtain the following compounds:

Ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2 g), mp 220-221 ° C.

Ethyl 1-cyclop ropil-5,7,8-trifluoro-1,

4-dihydro-4-oxoquinoline-3-carboxylate (27 g), mp 211-212 ° C.

5). A mixture of 1.54 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylase, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of concentrated sulfuric acid is mixed at 120 ° C for 1.5 hours. After cooling, the precipitated crystals are collected by filtration and washed thoroughly with water and

5 with ethanol to give the compound (1.34 g): 1-cyclopropyl-5, .6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needle crystals. T, pl. 295-297 ° C (decay).

0 PRI me R 2. 5-amino-1-cyclopropyl. 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1). A mixture of 2.57 g of ethyl-1-cyclopropyl-5,6.7-trifluoro-1,4-dihydro-4-oxoquinoline

5 -3-carboxylate, 1.8 ml of benzylamine and 180 ml of trichlorethylene are heated in a flask under reflux for 3 hours 40 minutes. Then, water and 10% hydrochloric acid were added to the reaction mixture to

0 acidification of the water layer. The trichlorethylene layer is separated and dried with anhydrous sodium sulfate. The solution was evaporated under reduced pressure, the precipitate was separated and purified by column chromatography on silica gel to

 2.78 g of ethyl 5-benzylamino-1-cyclopropyl-6, 7-difluoro-1,4-dihydro-4-oxo -

quinoline-3-carboxylate. Mp 144-145 ° C.

2). The resulting compound

0 (2.78 g) was dissolved in 100 ml of aqueous acetic acid and catalytically reduced at 60 ° C using 0.2 g of 5% palladium carbon as a catalyst. Then a theoretical amount of 5 is absorbed in hydrogen, the catalyst is removed by filtration, and the solution is evaporated under reduced pressure. The precipitate was recrystallized from acetonitrile to form 2.1 g of the compound: ethyl-5-amino 0 but-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless needle crystals. Mp 240-241 ° C.

3), A mixture of 2.09 g of the resulting compound 5, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of concentrated sulfuric acid was stirred at 110 ° C for 1.5 hours. Then, water was added to the reaction mixture ( 30 ml) and the precipitated crystals were collected by filtration and washed thoroughly with water and ethanol to obtain 1.71 g of the compound: 5-amino-1-cyclopropyl-6,7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid in the form of pale yellow needle crystals. T.p. more than 300 ° C,

Example 3, 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1). A mixture of 19.4 g of 2,3,4,6-tetrafluoro-benzoic acid, 200 ml of dioxane and 35.3 ml of benzylamine is heated under reflux for 3 hours. This reaction mixture is evaporated to dryness under reduced pressure. Water is then added to the precipitate and hydrochloric acid is added until the solution is at a pH of 3. The solution is then extracted with ethyl acetate. The extract is dried, treated with activated carbon and concentrated. Ether and n-hexane were added to the precipitate, and the resulting crystals were separated by filtration to obtain 20.2 g of 2-benzylamino-3,4,6-trifluorobenzoic acid. Mp 140-141 ° C.

2). A mixture of 21.7 g of the resulting compound, 16.8 ml of acetic anhydride and 200 ml of chloroform was heated under reflux for 9 hours. The reaction mixture was extracted with an aqueous solution of sodium hydroxide having a pH of 9-10. The extract is adjusted to a state in which the pH is 3-4 with hydrochloric acid and extracted with ethyl acetate. This extract is dried and concentrated under reduced pressure. Isopropyl ether is added to the residue and the precipitated crystals are separated by filtration. Thus, 17.6 g of the compound 2- (N-acetylbenzylamino) -3,4, b-trifluorobenzoic acid are obtained. Mp 150-153 ° C.

3). A mixture of 1.6 g of the resulting compound, 0.99 ml of triethylamine and 10 ml of toluene is ice-cooled, and then 3 ml of a toluene solution of 0.62 ml of ethyl chlorocarbonate are added dropwise over 10 minutes. The mixture was stirred for 1 h and the precipitate was removed by filtration (reaction mixture A). To the toluene solution of 1.67 ml of diethyl malonate was added 780 mg of 92% sodium ethoxyl, and this mixture was stirred at room temperature for 1 h. The resulting ethanol was evaporated, and reaction mixture A was added dropwise to this precipitate at room temperature. then the mixture is stirred for 2 hours. Then the reaction mixture is extracted with an aqueous solution of sodium hydroxide having

pH 9-10, the pH of the extract is adjusted to pH 3-4 with hydrochloric acid. and then extracted with ethyl acetate. The extract is dried and concentrated to dryness under reduced pressure. The precipitate was purified by silica gel chromatography (eluenge chloroform) to obtain 2.3 g of diethyl 3- (M-acetylbenzylamino) -3,4,6-trifluorobenzoyl malonate compound. Then, 10 ml of water and 480 ml of p-toluenesulfonic acid hydrate were added and the mixture was heated under reflux for 1 hour. After cooling, the mixture was extracted with ethyl acetate. The extract is dried and then concentrated under reduced pressure to obtain 1.9 g of ethyl 2- (M-acetylbenzylamino) -3,4,6-trifluorobenzoyl acetate compound.

4). A mixture of 1 g of the obtained compound, 0.6 g of acetic anhydride and 0.64 ml of ethyl orthoformate is heated in a flask under reflux for 1.5 h. The reaction mixture is concentrated to dryness under reduced pressure. The residue was dissolved in isopropyl ether under ice-cooling, then 0.2 ml of cyclopropylamine was added. This mixture was stirred for 1 hour. Then, 10 ml of p-hexane was added to the reaction mixture. Precipitated crystals were isolated by Filtration to give 993 ml of the compound ethyl-2- (M-acetyl-2-beneylamino-3.4,6-trifluorobenzoyl) -3-cyclopropylamino acrylate. Mp 119-12GS.

5). The resulting compound (26.3 g) was dissolved in 150 ml of tetrahydrofuran and then, after cooling with ice, 7.1 g of t-butoxy potassium was added little by little, and the resulting mixture was stirred for 30 minutes. The mixture was then stirred again at room temperature for 1.5 hours. Ice water was added and, using hydrochloric acid, the mixture was adjusted to a pH of 4-5, and then the mixture was extracted with chloroform. The extract is dried and evaporated to dryness under reduced pressure. Ether was added to the precipitate, and the crystals were separated by filtration to obtain 21.4 g of the ethyl 5- (M-acetylbenzylamino) -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3 compound carboxylate. Mp 147-150 ° C.

6). The resulting compound (1 g) is dissolved in ethanol and catalytically reduced at 50-55 ° C using palladium carbon as a catalyst. The catalyst is then removed by filtration and the filtrate is concentrated to dryness under reduced pressure.

10 ml of a mixed solution of concentrated sulfuric acid (glacial acetic acid) water (1: 8: 6) was added to the precipitate, and this mixture was refluxed for 2 hours. Water was added to the reaction mixture, and precipitated crystals were separated. by filtration and washed with ethanol to obtain 0.3 g of the compound 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp higher than 300 ° C.

Example 4. 5-amino-1-cyclopropyl-6-fluoro-7- (1-liperazinyl) -1,4-dihydro-4-hydroxyquinoline-3-carboxylic acid.

A mixture of 0.42 g of 5-amino-1-cyclopropyl-b, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.39 g of anhydrous piperazine and 10 ml of pyridine is heated in a flask under reflux for 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure, the precipitate is washed with ethanol and then dissolved in water 1n7 aq. rast. NaOH. The solution is neutralized with a 10% aqueous solution of acetic acid. The precipitated crystals were isolated by filtration, washed with water and dried to obtain 0.44 g of the compound 5-amino-1-cyclopropyl-6-fluoro-7- (1-pylerazinyl) -1,4-dihydro-4- oxoquinoline-3-carboxylic acid in the form of pale yellow needle crystals. Mp 214-216 ° C.

Example 5 5-amino-1-cyclopropyl-b-fluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

The compound 5-amino-1-cyclohophopyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid reacts with 1-methylpiperazine in dimethylformamide (room temperature, 24 hours), dioxane (reflux temperature, 5 h), acetonitrile (50 ° С, 1 h), water (60 ° С, 1 h), xylene (reflux temperature, 3 h) or dimethyl sulfoxide (150 ° С, 2 h), and then the reaction mixture processed by the method described in example 4 to give 5-amino-1-cyclopropyl-6-fluoro-7- (4-methyl-1-piperazinyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp 216-218 ° C.

Example 6. 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

A mixture of 1 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxosinolin-3-carboxylic acid, 1.18 g of 2-methylpiperazine and 10 ml of pyridine is heated in a flask with

reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 28% ammonia. The solution was neutralized with a 10% aqueous solution of acetic acid and cooled with ice. The crystals are collected by filtration, dissolved in a 10% aqueous solution of acetic acid, treated with activated carbon, the solution is brought into a state in which it has a pH of 8-9, with 29% ammonia and cooled with ice. The crystals were isolated by filtration and washed thoroughly with water and ethanol to give 0.8 g of the compound 5-amino-1-cyclopropyl-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro - 4-oxoquinoline-3-carboxylic acid. Mp 181-183 ° C

0 Example. 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its hydrochloride.

1). A mixture of 280 mg of 5-amino-15 cyclopropyl-6,7-difluoro- and 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 542 mg of cis-2,6-dimethylpiperazine and 10 ml of pyridine is heated in a flask with reflux for 2.5 hours. Solution

0 is evaporated under reduced pressure. A 1N aqueous solution of sodium hydroxide was added to the precipitate, and insoluble matter was removed by filtration. Then water is added to the filtrate.

5 Acetic acid solution in order to adjust the pH of the solution to 8. The solution is then extracted with chloroform. The chloroform layer is dried with sodium sulfate and concentrated under reduced

0 pressure. Acetonitrile was added to the residue and the mixture was cooled with ice. The crystals were separated by filtration and recrystallized from aqueous ammonia to give 250 mg of 5-amino-15 cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) 1,4-dihydro-compound 4-oxoquinoline-3-carboxylic acid. Mp 253-254 ° C.

2). The resulting compound was dissolved in 1N. aqueous solution of NaOH

0 and 10% hydrochloric acid was added to the solution to acidify it. Precipitated crystals were isolated by filtration and washed thoroughly with water and ethanol to give 5-amino-1-cyclopropyl-b5 fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline -3-carboxylic acids - and the acid is hydrochloride. T pl. above 300 ° C.

Example. 8, 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carbonic acid.

1). Ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and cis-3,5-dimethylpiperazine 5 interact with each other as described in Example 7, in resulting in the formation of ethyl 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-10 oxoquinoline-3- carboxylate. It is recrystallized from ethyl acetate. Mp 194-196 ° C.

2). A mixture of conc. 15 sulfuric acid, glacial acetic acid and water (1: 8: 6), then the mixture is heated in a flask under reflux. The reaction mixture was worked up by the method described in Example 7. to give 5-amino-1-cyclo-20 propyl-6-fluoro-7 (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro- 4-oxoquinolin-3-carboxylic acid. Mp 253-254 ° C,

Example 9.1-Cyclopropyl-5,6-difluoro-7- {4-methyl-1-piperazinyl) -1,4-dihydro-25 4-oxoquinoline-3-carboxylic acid.

1). A mixture of 0.41 g of boric acid and 5 ml of acetic anhydride is heated at 80 ° C for 1.5 hours, and then 1.25 g of 1-cyclopropyl-5, b, 7-triftbr-1,4-di- 30 hydro-4-oxoquinoline-3-carboxylic acid. The mixture was heated under reflux for 2 hours and then evaporated under reduced pressure. The precipitate was recrystallized from chloroform / ethyl acetate to give 1.62 g of 1-cyclopropyl-5, b, 7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH 3) 2 chelate. Mp above 300 ° C.

40

2). A mixture of 411 mg of the resulting compound, 0.11 ml of 1-methylpiperazinyl, 0.17 ml of triethylzmin and 4 ml of dimethylformamide was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated to dryness under reduced pressure. Residue dissolved in 2 ml of acetone, and then 1.5 ml of concentrated hydrochloric acid was added. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated to dryness under reduced pressure. The residue is soluble in water, neutralized with 1N. aqueous NaOH solution and then extracted with 55 chloroform. The solvent was evaporated under reduced pressure. The precipitate was recrystallized from ethyl acetate to give 320 mg of 1-cyclopropyl-5,6-difluoro-7- {4-methyl-1-piperazinyl) -1 4-dihydro-4-o-xochicholin-3- carboxylic acid. Mp 253-255 ° C (decomposition).

Example 10. 1-Cyclopropyl-5,6-difluoro-7- {1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1), A mixture of 1-cycloprepyl-5,6,7-trifluoro-1,4-digmdro-4-oxoquinoline-3-carboxylic acid-B (OCOCH3) 2 chelate. 1-formylpiperazine. triethylamine and this nola are stirred at room temperature for 1 hour. The reaction mixture is as described & Example 9 (2). used to prepare 1-cyclopropyl-5,6-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydoo-4-oxoquinoline-3-carboxylic acid mp. 297-299 ° C (decomp.).

2). A mixture of 120 mg of the resulting compound and 5 ml of 20% hydrochloric acid was stirred at 100-120 ° C for 1.5 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue is dissolved in water and treated with activated carbon. The solution is made basic with aqueous ammonia. The precipitated crystals are isolated by filtration, washed with water and dried to obtain 80 mg of 1-cyclopropyl-5,6-difluoro-7- (1-piperazinyl} -1,4 -dihydro-4-oxoquinoline-3-carboxylic acid, mp above 300 ° C.

Example 11, 1-Cyclopropyl-5,6-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

A mixture of 1-cyclopropyl-5,6,7-grifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid -B (OCOCH 3) 2 chelates, 2-methylpiperazine, triethylamine and dimethyl sulfoxide is stirred at room temperature in within 30 minutes Water was added to the reaction mixture and the precipitated crystals were separated by filtration. Then 1 N was added. aqueous NaOH solution and the mixture was stirred at 80 ° C for 10 minutes. The reaction mixture is then neutralized with acetic acid and the precipitated crystals are separated by filtration to obtain 1-cyclopropyl-5,6-difluoro-7- {3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Example 12. 1-Cyclopropyl-5,6-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

0.32 g of 1-cyclopropyl-5,6.7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-B (OCOCH 3) achelate is dissolved in 6 ml of dimethylformamide. While stirring this solution while cooling

with ice, a solution of 89 mg of cis-2,6-dimethyl-amiderazine and 0.13 ml of triethylamine in 2 ml of dimethylformamide was added thereto, this mixture was stirred for 30 minutes. The mixture was then stirred at room temperature for 40 minutes and 3 ml of conc / hydrochloric acid was added thereto. The mixture is then rapidly stirred at room temperature. The crystals are filtered off and dissolved in a 10% aqueous solution of acetic acid. The pH of the solution was adjusted to a value of 8 with 1N. aqueous NaOH solution. After cooling with ice, the crystals are separated by filtration. The crystals are then dissolved in 1N. aqueous NaOH solution, the pH of the solution was adjusted to 8 with a 10% aqueous solution of acetic acid and the solution was cooled with ice. The crystals were isolated by filtration and washed with water to give 80 mg of 1-cyclopropyl-5,6-difluoro-7- (cis-3.5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Mp 259-260 ° C.

Example 13 1-Cyclopropyl-5,6-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

A mixture of 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. yis-2.b-pimethylpiperazine, potassium carbonate and dimethylamide are stirred at room temperature for 7 hours. The reaction mixture is concentrated under reduced pressure. The residue was dissolved in 1N. aqueous sodium hydroxide solution. To obtain a pH of 8, a 10% aqueous solution of acetic acid was added to the filtrate, and the mixture was cooled with ice. The crystals are separated by filtration and washed with water to obtain 1-cyclopropyl-5, b-di-fluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1.4-DIGYDRO-4-oxoquinoline-3- carboxylic acid. Mp 259-260 ° C

The chemotherapeutic activity and some other properties of the compounds of this invention are illustrated in Examples 14-21 below. Compounds were tested.

Compound 1: 5-amino-1-cyclopropyl-b-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound 2: 5-amino-1-cyclopropyl-6-fluoro-7- (cis-3,5-dimethyl-1-piperaZinyl) -1,4-dihydro-4-oxoquinoline-3-carbonic acid.

Compound 3 5-amino-1-cyclopropyl-b-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Compound A. 1-cyclopropyl-b-fluoro-7- {1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic anhydride (does not have a substituent in the 5th position),

Compound B: 5-amino-1-cyclopropyl-b, 8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquino in-carboxylic acid.

P r igm-er p 14. In the table. Figure 1 shows ot5 data on the antibacterial activity of compounds in vitro. The table shows the minimum inhibitory concentration (MIC) mg / ml calculated for free

grounds. The maximum inhibitory concentrations were determined by double dilution in agar, which was recommended by the Japanese Society of Chemotherapy (Chemotherapy, 29 (1), 76 (1981) using Muller-Hlntow agar. One loop of the overnight culture of the test organisms in Muller-Hlntow-broth inoculated per 10 ml layer of drug-containing agar in Petri dishes.

lt contains approximately 106 colony forming units. Bacterial growth was observed after a 20-hour incubation at 37 ° C. was defined as the lowest drug concentration at which the apparent bacterial growth ceased.

Example 15. In vivo - the effectiveness of the drug against General infection when tested in mice is shown

in table 2.

Each compound was suspended in 0.4% carboxymethyl cellulose. Each of these suspensions was administered orally to mice infected with each of the tested microorganisms under the conditions described below, and the average effective dose (EDso) was calculated by the unit of probability analysis. Numbers

given in table. 2, mean LOso (mg / kg) calculated for the free bases.

Experimental conditions

Mice: males Std ddy, weight about 20 g.

Infection: Staphylococcus aureus - 50774

Intravenous infection of cl. per mouse suspended in saline,

Streptococcus pnenmonia 1 Nenfellel,

An intraperitoneal infection of 3 x 10 ° cells per mouse suspended in broth from a cardiac extract.

Streptococcus pyodenes A65

Intra-abdominal infection of cl. per mouse suspended in broth from a cardiac extract.

Pseudomonus agruginosa 12.

Intraperitoneal infection of cl. per mouse suspended in tryptosinized broth with 4% mucin.

Drug Therapy:

Four times: immediately after infection, b, 24, 30 hours after administration to Streptococcus puenmonfa 1

Twice: immediately after infection and 6 hours after the introduction of other microorganisms.

Observation: Observations were made within 14 days after the administration of Staphylococcus aureus 50775 and Streptococcus puenmdnlal I and within 7 days after the introduction of other microorganisms.

Example 16. In the table. Figure 3 shows the dyne activity against mycollasm. The table shows the minimum inhibitory concentrations (M1C) µg / ml calculated for the free bases.

MtC was determined by double dilution on agar. The following media were used in the tests: chanock broth and agar (PPLD broth and agar (Difco) supplemented with 20% horse serum and 10% fresh yeast extract. 2- 3-day microorganism culture broth was diluted with chanock broth to cell density of about 10 cells / ml One loop (about 1 μm) of the diluted medium of the organisms is dispersed in Petri dishes with 10 ml of chanock drug agar using a multi-point inoculator (Cathra International). Petri dishes are incubated at 37 ° C. for 7 days and 2 days for a friend of Mycoplasma pneumonia friend x Mycoplasma spp respectively. Incubation is carried out under anaerobic conditions using anaerobic Casprk system (BBL) flna microorganisms M. buccate, M formentas, M. homlnls, M. orale, and aerobically solivariufn environment for other Mycoplasma Spp

MIC was defined as the lowest drug concentration at which no microbial growth was observed.

Example 17. Table 4 presents the activity data of the compounds against Chlamydla bacteria. The table shows the minimum inhibitory concentrations (MIC) of μg / ml calculated for the free bases.

MICs were determined as follows. McCoy cells were freshly cultured in MI. The minimal nutrient medium Eagle (EMEM) containing 4% bovine embryo serum and 0.03% L-glutamine added to it. These cells are trypsinized and 5 are suspended in the same culture medium at a cell concentration of (1-2) x x 10 cells / ml. 1 ml of cell suspension is pipetted into flat-bottomed plastic tubes (14 mm in diameter),

0 containing a cover glass (12 mm in diameter). The tubes are placed in a 5% COa incubator and incubated at 3 ° C for 20 hours. Then, 0.5 ml of a suspension containing Chlamidia is added to each tube.

5 (approximately (1-4) 10 units forming body inclusions) and centrifuged at 1500 g for 60 minutes. The tubes are then incubated at 36 ° C for 1 h. Then the medium is replaced with 1 ml EMEM, which contains 8% serum of the cow embryo, 0.03% L-glutamine, 1 μg / ml cyclohexamide. 0.5% glucose, as well as drugs at various concentrations After incubation at 3 ° C for 40-48 hours

5 cells on coverslips were stained with Glemsa solution. Bodies included in cells on coverslips were examined with a microscope at 200-400 magnification. MIC was determined as the lowest

0 concentration of the drug at which no exception of the bodies was observed in all cells on coverslips.

Example 18 (acute toxicity).

5 A suspension containing each of the compounds of the present invention at various concentrations was administered orally to male mice (ddy) at a dose of 0.1 ml per 10 g body weight. amount

0 dead mice were counted for 7 days, and then the average lethal dose (LDso, mg / kg) was calculated using the Behrens-1 Caerber method. The results of these calculations are given in table. 5.

5 PRI me R 19. In the table. Figure 6 shows the photo-stability of compounds in aqueous solutions.

Each compound was dissolved in 0.1 N. hydrochloric acid to produce acidic

0 solution (0.3 mg / ml for compound 2; 0.5 mg / ml for other compounds) or in 0.1 N aqueous NaOH to give an alkaline solution (0.5 mg / ml for all compounds). The solution contained in 10 ml of colorless

5, the flask was exposed to light from a fluorescent lamp (6000 lux) for 100 h at 20 ° C. The concentration of the compound in the solution was determined before and after 100 h of irradiation using high-resolution liquid chromatography. The data in the table show the amount of compound remaining (%) after 100 hours irradiation.

Example 20. A suspension containing each of the compounds was administered orally to mice at a dose of 5 mg / kg. Urine was collected within 2 hours after administration of the suspension.

Compound levels in urine were determined by platelet culture of plate microbial cultures using E. schertchla Coll Kp. as an indicator of organisms.

Compound C: 5-amino-1-cyclopropyl-6,8-difluoro-7- (3,5-dimethyl-1-piperazinyl) 1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 21. The antimicrobial activity of n vitro compounds according to the invention, in which Z is a halogen atom, is shown in Table 8. The numbers in the table show the minimum inhibitory concentration (MIC) in μg / ml, which was determined by the method described in the example 14. Test compounds included:

Compound 4: 1-cyclopropyl-5, b-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

compound 5: 1-cyclopropyl-5,6-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

compound 6: 1-cyclopropyl-5,6-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound D: 1-cyclopropyl-5,6,8-trifluoro-7-4-methyl-1-piperazinyl} -1,4-di-hydro-4: oxoquinoline-3-carboxylic acid.

Claims (1)

SUMMARY OF THE INVENTION Method for the preparation of line derivatives of the general formula 2 About mm soon where 2 represents an amino group or a halogen atom; Ri. Ra and R3 are the same or different, each represents a hydrogen atom or a lower alkyl group having 1-5 carbon atoms, or their pharmaceutically acceptable salts or esters, characterized in that the compound of the formula Cool where X is a halogen atom; Y is a hydrogen atom, a lower alkyl group having 1-5 carbon atoms, a diacyloxyboryl group or a difluoroboryl group; Z has previously defined meanings, is reacted with a piperazine derivative of the formula bc where Ri, R2 and R3 are as defined, and if necessary, the resulting compound is hydrolyzed and optionally the compound thus obtained is converted into its pharmaceutically acceptable salt. Antibacterial activity in vitro Table 1 table 2 In vivo antibacterial activity in trials in mice with common infection Mycoplasma activity Activity against Chlamydla Table 5 Acute oral toxicity in mice Photo stability in aqueous solutions Table 3 Table 4 Table 6 nineteen Urination in mice Antimicrobial activity 1780533 20 table 7 Table 8