Derivatives hinolincarbonova acids or their pharmaceutically acceptable salts

 

(57) Abstract:

The invention relates to new derivatives hinolincarbonova acids of the formula I, their pharmaceutically acceptable salts and their hydrates. In the formula I, X is a hydrocarbon group, a fluorocarbon group, or a nitrogen atom; Y is a hydrogen atom or a methyl group; R1is a hydrogen atom or a C1- C5is an alkyl group; R2is a group of formula (a) (where A and B - fluorocarbon group or a nitrogen atom, provided that when A = CF, B = N, and when A = N, B = CF), R3is a group of formula (b) (where the substituent R4the amino groups with the formation of the racemate or the (S)-enantiomer), or a group of the formula (I) where the substituents R5, R6and R7is a hydrogen atom or a C1- C3is an alkyl group). Derived hinolincarbonova acid of formula I is produced by condensation of compounds of formula II and compounds of formula HR3in a solvent in the presence of an acid acceptor and an excess of the compounds of formula HR3that is one of the reagents. The solvent is selected from the group comprising pyridine, acetonitrile, N,N - dimethylformamide. In the compound of formula II and compounds of formula HR3the substituents X, Y, Z, R1, R2and R3accept the values, oprep.f-crystals, 6 table.

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about

The invention relates to new derivatives hinolincarbonova acids, their esters, their pharmaceutically acceptable salts and their hydrates, which are represented by the formula (I), as well as to a method for producing these compounds. Some of the claimed derivatives hinolincarbonova acids represented by the formula (I) possess a wide spectrum of pharmacological properties, high efficiency and low toxicity

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where

X represents a hydrocarbon group, a fluorocarbon group, or a nitrogen atom;

Y represents a hydrogen atom or methyl group;

R1represents a hydrogen atom or a C1-C5is an alkyl group;

R2represents a group of the formula

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where

A and B represent a fluorocarbon group or a nitrogen atom, provided that when A=CF, B=N, and when A=N, B=CF;

R3represents a group of the formula

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where

Deputy R4represents an amino group with the formation of the racemate or the (S)-enantiomer, or a group of the formula

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where

the substituents R5, R6and R7represent a hydrogen atom or a C1-C3-alteredstates other quinolones, containing a small alkyl or cycloalkyl group at position N-1 [e.g., Norfloxacin: U.S. patent 4146719, Ciprofloxacin: U.S. patent 46200071] or contains an aromatic group at position N-1 [e.g., Temafloxacin: L. Med. Chem., 34, 168 (1991), Tosufloxacin: U.S. patent 4704459].

However worthy the attention of antibiotics from the class of quinolones, containing heteroaromatic group at position N-1, up to the present time have not been found. Otsuka, Toyama and others reported their studies on the introduction of a heteroaromatic group such as furyl, thienyl, thiazole, imidazole, pyridyl, pyrimidine at position N-1, but connections available in vivo, have not been received (RK 61-251667, 62-174053, 02-85255-A).

In particular, compounds developed to date tend to have good activity in vitro, but such activity does not provide activity in vivo due to poor pharmacokinetics, including half-life (t1/2), maximum blood levels (Cmax), bioavailability (DB), the area bounded by the curve (BOCOG) and others, which are important characteristics of compounds with good activity in vitro, which is stored and in vivo.

Thus, alteration, by introducing ftorpirimidinu group, which represents a heteroaromatic group, in position N-1, whereby formed compounds which are good antibiotics in vivo and has a long half-life, which provides the possibility of taking one dose per day. Therefore, the present invention offers a number of compounds, which have even more excellent pharmacokinetic properties than conventional quinolone antibiotics, with the introduction of 5-fluoro-2-peredelnoj group in the main molecule quinolone and naphthiridine.

Brief description of the invention.

The present invention relates to new derivatives hinolincarbonova acids in position N-1 contain perpillou group.

The purpose of the present invention is to create a new hinolincarbonova acids, their esters, their pharmaceutically acceptable salts and their hydrates, some of which possess a wide spectrum of activity, excellent pharmacokinetic properties and low toxicity, which is a significant factor for medications that must be entered and function in the living organism, as well as the method of obtaining the more prolonged half-life (t1/2), a higher maximum blood levels (Cmax), a higher bioavailability (DB) and a large area bounded by the curve (BOCOG). In addition, they have a longer half-life and a large area bounded by the curve, in comparison with ooxacin, which is known to be characterized by excellent pharmacokinetics. For example, the pharmacokinetic characteristics of one of the compounds obtained in accordance with the present invention, show that the half-life time of 8.07 h, Cmax- 11.46 mg/ml, POK at 41.05 μg h/ml, bioavailability 73.95% when administered orally (mouse).

On the other hand, for ciprofloxacin half life is 0.92 h, Cmax- 1.71 µg/ml, POK 2.27 µg/ml, bioavailability 14.60%. Therefore, due to such excellent pharmacokinetic properties of the compounds of the present invention have a significantly increased activity in vivo.

Average values U50(mg/kg) of this compound and ciprofloxacin, respectively 25 and > 50 against systemic infection of mice, caused by microorganisms S. aureus giorgio. Minimum inhibitory concentration (MIC, μg/ml) in vitro for the above-mentioned compounds sostavlyayuscyeye should have a significantly higher activity

Detailed description of the invention.

The compounds of formula (I)

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where

X represents a hydrocarbon group, a fluorocarbon group, or a nitrogen atom;

Y represents a hydrogen atom or methyl group;

R1represents a hydrogen atom or a C1-C5is an alkyl group,

R2represents a group of the formula

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where

A and B represents a fluorocarbon group or a nitrogen atom, provided that when A=CF, B=N, and when A=N, B=CF;

R3represents a group of the formula

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where

Deputy R4represents an amino group with the formation of the racemate or the (S)-enantiomer, or a group of the formula

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where

the substituents R5, R6and R7represents a C1-C3is an alkyl group.

The compounds of formula (I) can be obtained as follows. Each compound of formula (I), regardless of the type of substituents X, Y, Z in the compound of formula (II) where the substituents X, Y, Z in the compound of formula (II) where the substituents X, Y, Z, R1, R2and R3take the values described above, you will get almost the same way, except the reaction temperature

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This tragedian, dioxane, 1,2-dimethoxyethane, diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, and inert solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, pyridine, etc. at a temperature from 0 to 150owithin 5 minutes - 48 hours. In addition, the above reaction is usually carried out in the presence of an acid acceptor, required quantity is 1 to 3 equivalents of compound (II). On the other hand, as the acid acceptor can be used an excess of the compound (VI) or tertiary amines, such as pyridine, triethylamine or 1,8-diazabicyclo [5.4.0] Indes-7-ene, or carbonates of alkali metals, for example sodium bicarbonate, sodium carbonate or potassium.

The compounds of formula (I), where the substituent R1represents a hydrogen atom, get in the interaction of the compounds of formula (II') (where the substituent R1represents a hydrogen atom) and HR3formula (VI) (where the substituent R3takes the values defined above); or, otherwise, first by reaction of the compound of formula (II') (where the substituent R1represents an alkyl group) and HR3formula (VI) (where the substituent R3takes the values defined above), and then check the lots, as hydrochloric or sulfuric acid, and alkaline hydrolysis can be used alkali such as sodium hydroxide and potassium hydroxide. Acid or alkali can be used in the form of aqueous or aqueous-ethanol solution.

The compound of formula (II) can be obtained in the following way (P=P' + P")

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The substituents X, Y, Z, R1and R2take the values defined above.

The compound of formula (III) are obtained in the usual way [(Ger. Offen. DE 3142854; Ger. Offen. 3318145; J. Med.Chem., 29, 2363 (1986)] and then the obtained compound of the formula (III) reacts with the compound of the formula (IV) obtained in the usual way [Rocz. Chem., 38, 777-783 (1964); Synthesis, 12, 905-908 (1989)] , in an alcohol solvent such as methanol and ethanol, or californina solvent, such as methylene chloride or chloroform, at temperatures from -10 to -30oC with the formation of the compounds of formula (V). The compound (V) is further subjected to a cyclization reaction using potassium carbonate and 18-crown-6 in acetonitrile or using sodium hydride in N, N-dimethylformamide. Get the compound (II'). The temperature of the reaction should be in the range of 0oC to the boiling point. The compound of formula (II') is subjected to hydrolysis in the processing of sour (II). Acid hydrolysis can be used such acids as hydrochloric or sulfuric acid, and alkaline hydrolysis can be used alkali such as sodium hydroxide and potassium hydroxide. Acid or alkali can be used in the form of aqueous or aqueous-ethanol solution.

Specific examples of new derivatives hinolincarbonova acids of the present invention are the following compounds:

1. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

2. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

3. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

4. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

5. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

6. 1-(3-fluoro-4-pyridyl)-6-fluoro-7[(3S)-3-amino-1-pyrrolidinyl) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

7. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinil)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

8. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-PIP is piperazinyl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

10. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinil)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

11. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

12. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinil)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

13. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinil)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

14. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinil)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

15. 1-(5-fluoro-2-pyridinyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinil) -1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

16. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

17. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinil)-1,4 - dihydro-4-oxoindole-3-carboxylic acid.

18. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinil) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

19. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinil) - 1,4-dihydro-4-oxoindole-3-carboxylic acid.

20. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinil) - 1,4-dihydro-4-oxoindole-3-carboxylic celata.

22. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl) - 1,4-dihydro-4-oxoindole-3-carboxylic acid.

23. 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(1-piperazinil) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

24. 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(4-methyl-1-piperazinil) -1,4-dihydro-4-oxoindole-3 - carboxylic acid.

25. 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(3-methyl-1-piperazinil) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

26. 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(3,5-dimethyl-1-piperazinil) -1,4-dihydro-4-oxoindole-3-carboxylic acid.

27. 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(3-amino-1-pyrrolidinyl)- 1,4-dihydro-4-oxoindole-3-carboxylic acid.

28. 5-methyl-7-(4-methyl-1-piperazinil)-1-(5-fluoro-2-pyridyl) -6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid.

29. 5-methyl-7-(3-methyl-1-piperazinil)-1-(5-fluoro-2-pyridyl) - 6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid.

New derivatives of hinolincarbonova acids in accordance with the present invention can be used in the form of free compounds, acid additive salts or their salts at the carboxyl group. Acceptable acids to obtain salts are inorganic acids such as hydrochloric acid, FOSFA malonic and gluconic acid.

Pharmaceutically acceptable basic salts of the above compounds of formula (I) are formed with alkali metals such as sodium and potassium, or alkaline earth metals such as magnesium and potassium. Free compounds of the present invention, the acid additive salts and salts of carboxyl groups derived pyridineboronic acids may exist as hydrates.

The following examples are provided to illustrate how the compounds of the present invention.

An example of obtaining 1.

Getting ethyl-3-(3-fluoro-4-pyridyl)amino-2-(2,4,5-triterpenoid) acrylate.

Mix 2.5 g ethyl-1,4,5-tripersonality, 2.55 ml of triethyl-o-foliata, 12 ml of acetic anhydride and the resulting mixture is refluxed for 3-5 hours, cooled to room temperature and distilled in vacuum. The obtained product is dissolved in 50 ml of anhydrous methylene chloride and added 1.26 g of 4-amino-3-herperidin and stirred at room temperature for 5 hours and then concentrated in vacuo. The product is used in the next reaction without further purification.

Example of receipt 2.

Getting ethyl-3-(fluoro-4-pyridyl)amino-2-(2,6-dichloro-is of 1.

Example for the preparation of 3.

Getting ethyl-3-(5-fluoro-2-pyridyl)amino-2-(2,6-dichloro - 5-fornicating)acrylate.

A named connection receive according to the method similar to the method of example obtaining 1.

Example 4.

Getting ethyl-3-(5-fluoro-2-pyridyl) amino-2-(2,3,4,5-tetrafluorobenzoyl) acrylate.

A named connection receive according to the method similar to the method of example obtaining 1.

Example of getting a 5.

Getting ethyl-3-(5-fluoro-2-pyridyl) amino-2-(2,4,5-triterpenoid) acrylate.

A named connection receive according to the method similar to the method of example obtaining 1.

Example of getting a 6.

Getting ethyl-3-(5-fluoro-2-pyridyl) amino-2-(3-methyl-2,4,5-triterpenoid) acrylate.

A named connection receive according to the method similar to the method of example obtaining 1.

Example of getting a 7.

Obtaining the ethyl ester of 1-(3-fluoro-4-pyridyl)-6,7-debtor-1, 4-dihydro-4-oxoindole-3-carboxylic acid.

In 40 ml of anhydrous Acrylonitrile mix 2.0 g ethyl-3- (3-fluoro-4-pyridyl)amino-2-(2,4,5-triterpenoid) acrylate, 1.50 g of potassium carbonate and 0.43 g of 18-crown-6. The resulting mixture was refluxed in melt 1.3 g of the named compound. So pl. 212oC.

Range 1H-NMR (CDCl3, M. D.) : of 1.26 (t, 3H, J=7,20 Hz), 4.40 (q, 2H, J= 7.20 Hz), 6,50-to 6.80 (m, 1H), 7,40-of 7.60 (m, 1H), they were 8.22-8,42 (m, 2H), 8,68-8,96 (m, 2H).

Example receipt 8.

Obtaining the ethyl ester of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthiridine - 3-carboxylic acid.

A named connection receive according to the method similar to the method of example getting 7. So pl. 226oC.

Range 1H-NMR (CDCl3, M. D.): to 1.42 (t, 3H, J=7,20 Hz), 4,42 (q, 2H, J= 7,20 Hz), 7,46 is 7.50 (m, 1H), 8,48-8,54 (m, 2H), 8,70-8,82 (m, 2H).

Example of receipt 9.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6 - fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

A named connection receive according to the method similar to the method of example getting 7. So pl. 230oC.

Range1H-NMR (CDCl3, M. D.) : of 1.36 (t, 3H, J=7,20 Hz), to 4.38 (q, 2H, J= 7,20 Hz), 7,60-7,80 (m, 2H), at 8.36-8,54 (m, 2H), 8,94 (c, 1H), (m, 2H).

Example 10.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,7-debtor-1,4 - dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example obtaining 7, get a named connection. So pl. 210-213oC.

Range1H-NMR (CDCl3, mny 11.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,7,8-Cryptor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

A named connection receive according to the method similar to the method of example getting 7. So pl. 203-205oC.

Range1H-NMR (CDCl3, M. D.) : to 1.32 (t, 3H, J=7,20 Hz), 4,32 (q, 2H, J= 7,20 Hz), of 7.36-7,72 (m, 2H), 8,00 is 8.22 (m, 1H), 8.30 to-8,50 (m, 2H).

Example 12.

Obtain 1-(3-fluoro-4-pyridyl)-6,7-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

To 5 g of the ethyl ester of 1-(3-fluoro-4-pyridyl)-6,7-debtor - 1,4-dihydro-4-oxoindole-3-carboxylic acid, add 20 ml of water, 30 ml of ethanol and 15 ml conc. hydrochloric acid and refluxed for 8 hours. After cooling to room temperature and keeping at this temperature for 2 hours the reaction mass is filtered and dried. Gain of 4.2 g of the named product. So pl. 271 - 273oC.

Range1H-NMR (CF3COOD, M. D.): 7,28 - 7,58 (m, 1H), compared to 8.26 - 8,88 (m, 1H), which 9.22 - 9,62 (m, 3H).

Example of getting a 13.

Obtain 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

A named connection receive according to the method similar to the method of example 12. So pl. 228 - 230oCptx2">

Obtaining 1-(5-fluoro-2-pyridyl)-6,7-debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid.

A named connection receive according to the method similar to the method of example 12. So pl. 275-280oC.

Range 1H-NMR (CF3COOD, M. D.): 7,40 (DD, 1H, J=3,02 Hz, J = 10,06 Hz), 7,92-8,18 (m, 2H), 8,39-8,78 (m, 2H), 9,50 (s, 1H).

Example of receipt 15.

Obtaining 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naftalin-3-carboxylic acid.

By the method similar to the method of example 12, get a named connection. So pl. 234 - 238oC.

Range1H-NMR (CDCl3, M. D.): 8,58 - 8,84 (m, 2H), 9,18 - 9,42 (m, 3H).

Example 16.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinil)-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid.

To 45 ml of pyridine, add 0.5 g of ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid and 0.35 g of piperazine. The resulting mixture was stirred at 10oC for 1 hour, then concentrated in vacuo and subjected to column chromatography (eluent acetone/BC-hexane, 5: 2). Get to 0.47 g of the named compound, which is then subjected to further transformation of DL the th ether 1-(5-fluoro-2-pyridyl)- 6-fluoro-7-(4-methyl-1-piperazinil)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 85,0%.

An example of obtaining 18.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3 methyl-1-piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 91,5%.

Example obtain 19.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 84,1%. So pl. 165oC.

Range1H-NMR (CDCl3, M. D.): 0,94 (s, 3H), and 1.00 (s, 3H), of 1.35 (t, 3H, J= 6,40 Hz), 2,24 - of 3.06 (m, 4H), 4,00 was 4.42 (m, 4H), 7,44 - 8,24 (m, 3H), scored 8.38 - 5,52 (m, 1H), 8,76 (s, 1H).

An example of obtaining 20.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 90.3 per cent. So pl. 200 - 202oC.

Range1H-NMR (CDCl3, M. D.): of 1.30 (t, 3H, J=6,40 Hz), 1,90 - of 2.16 (m, 5H), 3,40 - of 3.94 (m, 4H), new ether 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 90.3 per cent.

Example of getting a 22.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (4-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 91.3% of

An example of retrieving 23.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (3-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 87,5%.

An example of obtaining 24.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (3,5-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 89.3 per cent.

An example of obtaining 25.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 90,3%.<)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 84,5%.

Example of getting 27.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7- (1-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 88.7 per cent.

An example of retrieving 28.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7- (3-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 83,7%.

An example of obtaining 29.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7- (3,5-dimethyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Yield: 88.7 per cent.

Example 30.

Obtaining the ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7- (3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 92,7%.

To 12 ml of pyridine added to 0.22 g of 1-(3-fluoro-4-pyridyl)-6,7 - debtor-1,4-dihydro-4-oxoindole-3-carboxylic acid and 0.11 g of 3-acetaminophenodeine, and then add 0,13 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene. The resulting mixture was stirred at room temperature for 24 hours and then evaporated in vacuum to remove the solvent. To the residue is added 20 ml of acetone and stirred at room temperature for 1 hour. Get the product, which is then filtered off, dried and used in the next reaction (the following reaction: example 5).

An example of obtaining 32.

Obtaining the ethyl ester of 5-methyl-7-(4-methyl-1-piperazinil)-1- (5-fluoro-2-pyridyl)-6-fluoro - 1,4-dihydro-4-oxoindole - 3-carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 82,5%.

An example of obtaining 33.

Obtaining the ethyl ester of 5-methyl-7-(3-methyl-1-piperazinil)-1- (5-fluoro-2-pyridyl)-6-fluoro - 1,4-dihydro-4-oxoindole-3 - carboxylic acid.

By the method similar to the method of example 16, get a named connection. Output: 85,0%.

Example 1.

Obtain hydrochloride of 1-(3-fluorescent-4-pyridyl)-6-fluorescent-7-(1 - piperazinil)-1,4-di is ro-1,4-dihydro-4-oxoindole-3-carboxylic acid and 0.22 mg piperazine. To the mixture of 0.39 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene, stirred at room temperature for 24 hours and concentrated under reduced pressure. Concentrate chromatographic in column (eluent chloroform/methanol/ammonia water, 15/12/1) to separate the desired product, which is then concentrated under reduced pressure. Then to the residue was added 15 ml of ethanol, 10 ml of water and 5 ml of concentrated hydrochloric acid and stirred at room temperature for 3 hours, then filtered and evaporated. The resulting product is recrystallized from a mixture of methanol, ethanol and water, get to 0.47 g of the desired compound. So pl. 284-286oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,26-4,24 (m, 8H), at 6.84 (d, 1H, J = 4,82 Hz), scored 8.38 (d, 1H, J = 12,82 Hz), 8,70-of 9.02 (m, 1H), 9,20-9,62 (m, 3H).

Example 2.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl - 1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 274-276oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,12 (s, 3H), 3,28-4,32 (m, 8H), to 6.88 (d, 1H, J = 4,80 Hz), scored 8.38 (d, 1H, J = 12,80 Hz), 8,68-8,98 (m, 1H), 9,20-9,62 (m, 3H).

Example 3.

Receiving

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 270-272oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): of 1.52 (d, 3H, J = 5,62 Hz), 3,36-4,24 (m, 7H), 6,86 (d, 1H, J = 4,80 Hz), at 8.36 (d, 1H, J=12,80 Hz), 8,70-of 8.92 (m, 1H), 9,20-9,60 (m, 3H).

Example 4.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5 - dimethyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 285-287oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 1,38-of 1.62 (m, 6H), 3,20-to 4.28 (m, 6H), 6.90 to (d, 1H, J = 4,80 Hz), scored 8.38 (d, 1H, J = 12,80 Hz), 8,68 - 9,00 (m, 1H), 9,20-9,56 (m, 3H).

Example 5.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3 - amino-1-pyridinyl)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

To 15 ml of ethanol, 10 ml of water and 5 ml of concentrated hydrochloric acid is added 0.5 g of 1-(3-fluoro-4-pyridyl)- 6-fluoro-7-(3-acetamido-1-pyrrolidin)- 1,4-dihydro-4-oxoindole - 3-carboxylic acid. The reaction mixture is boiled for 18 hours, cooled and contentresult until complete solvent removal.

The residue is recrystallized from a mixture of ethanol and water, get 0,22 g of the desired compound. So pl. 274-276o

Example 6.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)- 3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 225-227oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 2,38-of 2.72 (m, 2H), 3,60-3,98 (m, 2H), 4,18-4,60 (m, 3H), of 6.26 (d, 1H, J = 4,80 Hz), of 8.28 (d, 1H, J = 12,82 Hz), 8,58-8,84 (m, 1H), 9,12-9,52 (m, 3H).

Example 7.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1 - piperazinil)-1,4-dihydro-3-oxo-1,8-naphthiridine-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 273-275oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,42-of 3.60 (m, 8H), 8,32 (d, 1H, J = 12,02 Hz), 8,60-8,86 (m, 1H), 9,10-9,58 (m, 3H).

Example 8.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4 - methyl-1-piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 275oC.

Range1H-NMR (CF3COOD, M. D.): 3,10 (m, 3H), 3,14-4,10 (m, 6H), 4.26 deaths to 4.92 (m, 2H), 8,30 (d, 1H, J = 12,00 Hz), 8,60-8,88 (m, 1H), 9,20-9,50 (m, 3H).

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 277-279oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 1,32 by 1.68 (m, 3H), 3,32-4,08 (m, 5H), 4,34-4,84 (m, 2H), 8,32 (d, 1H, J = 12,02 Hz), 8,60-of 8.90 (m, 1H), 9,20-9,50 (m, 3H).

Example 10.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)- 6-fluoro-7-(3,5-dimethyl-1-piperazinil)- 1,4-dihydro-4-oxo-1,8-naphthiridine - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 270oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 1,30-1,60 (m, 6H), 3,32-to 3.92 (m, 4H), of 4.44 to 4.92 (m, 2H), at 8.36 (d, 1H, J = 12,02 Hz), 8,62-of 8.90 (m, 1H), 9,16-9,52 (m, 3H).

Example 11.

Obtain hydrochloride of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)- 3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 269oC.

Range1H-NMR (CF3COOD, M. D.): 2,14-2,84 (m, 2H), 3,56-to 3.64 (m, 5H), 8,23 (d, 1H, J = 12,04 Hz), 8,62-8,96 (m, 1H), 9,10-9,52 (m, 3H).

Example 12.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1 - piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

To 10 ml of water and 10 ml koncentrirane-naphthiridine-3-carboxylic acid. The mixture is heated under reflux for 24 hours, cooled to room temperature and concentrate under reduced pressure. To the concentrate is added 20 ml of ethanol and stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized from a mixture of water and methanol, to obtain 0.39 g of the desired compound. So pl. > 300oC.

Range1H-NMR (CF3COOD, M. D.): 3,60-of 3.80 (m, 4H), 4,14-to 4.46 (m, 4H), 7,92-of 8.50 (m, 3H), 8,70 (ush.S., 1H), 9,40 (s, 1H).

Example 13.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1 - piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 275-277oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,10 (s, 3H), 3,60-5,00 (m, 8H), 7,84-of 8.50 (m, 3H), 8,68 (ush.S., 1H), 9,38 (s, 1H).

Example 14.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1 - piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 268oC.

Range1H-NMR (CF3COOD, M. D.): 1,40-1,60 (m, 3H), 3,50-3,90 (m, 5H), 4,56-4,80 (m, 2H), 8,12-8,46 (m, 3H), Il-1-piperazinil)- 1,4-dihydro-4-oxo-1,8-naphthiridine - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 289oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 1,30-of 1.64 (m, 6H), 3,28-4,00 (m, 4H), to 4.52 to 4.92 (m, 2H), of 7.96-8,48 (m, 3H), 8,78 (ush.S., 1H), 9,40 (s, 1H).

Example 16.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1 - pyrrolidin)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid.

To 10 ml of water and 10 ml of concentrated hydrochloric acid is added 0.5 g of ethyl ester of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(acetamido-1 - pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid. The mixture is heated under reflux for 24 hours, cooled to room temperature and concentrate under reduced pressure. To the concentrate is added 20 ml of ethanol and completely dissolved. Then add 70 ml of ethyl ether to precipitate the product, stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized from a mixture of water and methanol, to obtain 0.35 g of the desired compound. So pl. > 208-210oC.

Range1H-NMR (CF3COOD, M. D.): 2,30 is 2.80 (m, 2H), 3,78-and 4.68 (m, 5H), of 7.96-8,32 (m, 3H), 8,70 (ush.S., 1H), to 9.32 (m, 1H).

Example 17.

Obtain hydrochloride of 1-(5-fluoro-2-piluca way basically similar to the method of example 12. So pl. 300oC (decomp.).

Range1H-NMR (CFCOOD, M. D.): 3,51-of 4.05 (m, 8H), to 6.80 (d, 1H, J = 7,60 Hz), 7,84-8,21 (m, 2H), 8,32 (d, 1H, J = 12,04 Hz), 8,70 (ush.s, 1H), of 9.30 (s, 1H).

Example 18.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1 - piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. > 300oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,12 (s, 3H), 3,28-the 4.29 (m, 8H), for 6.81 (d, 1H, J = 7,60 Hz), 7,84-of 8.15 (m, 2H), with 8.33 (d, 1H, J = 12,20 Hz), 8,71 (ush.s, 1H), 9,29 (s, 1H).

Example 19.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1 - piperazinil)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 295oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,12 (s, 3H), ethyl-1-piperazinil, 3,28-the 4.29 (m, 8H), 6,8 (d, 1H, J=7,60 Hz), 7,84-of 8.15 (m, 2H), with 8.33 (d, 1H, J= 12,20 Hz), 8,71 (ush.s, 1H), 9,29 (s, 1H).

Example 19a.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinil)-1,4-dihydro - 4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of the doctor): 1,51 (d, 3H, J=4,40 Hz), 3,23-4,11 (m, 7H), to 6.80 (d, 1H, J=6,20 Hz), of 7.96-8,16 (m, 2H), 8,30 (d, 1H, J=14,00 Hz), 8,69 (s, 1H), of 9.30 (s, 1H).

Example 20.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)- 6-fluoro-7-(3,5-dimethyl-1-piperazinil)- 1,4-dihydro-4-oxoindole - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 297oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 1,30-of 1.65 (m, 6H), 3,10-of 4.57 (m, 6H), 6.89 in (d, J=6,20 Hz), 7,93-to 8.20 (m, 2H), to 8.70 (d, 1H, J=12,82 Hz), 8,48 (s, 1H), to 9.32 (s, 1H).

Example 21.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro - 4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 16. So pl. 275oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 2.40-2.73 (m, 2H), 3,60-4,56 (m, 5H), 6,33 (d, 1H, J=6,20 Hz), 7,98-of 8.37 (m, 3H), up 8.75 (s, 1H), 9,24 (s, 1H).

Example 22.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3S)-3-amino-1-pyrrolidinyl-1,4-dihydro - 4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 1. So pl. 268-272oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 2,40-by 2.73 (m, 2H), 3,60-4,56 (m, 5H),pyridyl)-6,8-debtor-7-(1-piperazinil)-1,4-dihydro-4 - oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 300oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,76-was 4.02 (m, 8H), 8,00-8,48 (m, 3H), 8,68 (ush.s, 1H), to 9.32 (s, 1H).

Example 24.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6,8 - debtor-7-(4-methyl-1-piperazinil)- 1,4-dihydro-4-oxoindole - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 300oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 3,10 (s, 3H), 3,20-4,00 (m, 8H), 7,98 is 8.38 (m, 3H), 8,58 (ush.s, 1H), of 9.30 (s, 1H).

Example 25.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7-(3-methyl-1-piperazinil)- 1,4-dihydro-4-oxoindole - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 295oC (decomp.)

Range1H-NMR (CF3COOD, M. D.): 1,45-to 1.60 (d, 3H, J=3,20 Hz), 3,38-was 4.02 (m, 7H), 7,92-of 8.50 (m, 3H), 8,70 (ush.s, 1H), of 9.30 (s, 1H).

Example 26.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (3,5-dimethyl-1-piperazinil)-1,4-dihydro-4-exogenesis-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 297the, 1H).

Example 27.

Obtain hydrochloride of 1-(5-fluoro-2-pyridyl)-6,8-debtor-7- (3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 16. So pl. 275oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 2,40-2,60 (m, 2H), 3,98-4,24 (m, 5H), 8,08 is 8.38 (m, 3H), 8,64 (s, 1H), 9,24 (c, 1H).

Example 28.

Getting hydrochloride 5-methyl-7- (4-methyl-1-piperazinil)-1- (5-fluoro-2-pyridyl)- 6-fluoro-1,4-dihydro-4-oxoindole - 3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 262oC (decomp.).

Range1H-NMR (CF3COOD, M. D.): 2,99 (m, 3H), 3,10 (m, 3H), 3,15-4,20 (m, 8H), 6,60 (d, 1H, J=7,20 Hz), 8,02 (m, 2H), to 8.70 (s, 1H), 9,24 (s, 1H).

Example 29.

Getting hydrochloride 5-methyl-7-(3-methyl-1-piperazinil)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4 - dihydro-4-oxoindole-3-carboxylic acid.

The named compound is obtained by way of, basically similar to the method of example 12. So pl. 267oC (decomp.).

Range1H-NMR (CFCOOD, M. D.): 1,60 (d, 3H, J=6,00 Hz), of 2.97 (s, 3H), 3,15-is 4.21 (m, 7H), 6,60 (d, 1H, J=8,00 Hz), 8,40 (m, 2H), 8,65 (s, 1H), 9,25 (s, 1H).

Antibiotic activity in vitro with the hate. Bacteria inoculant at a concentration of approximately 105colony forming units/ml after growing overnight at 37oC in cardio-cerebral broth. The new compounds of the present invention is converted into chlorhydrate and diluted with sterile distilled water to obtain an aqueous solution with a concentration of 10 mg/ml. After receiving the mother liquor, in which the concentration is reduced in 2 times, 0.1 ml of the diluted solution is transferred into a cell and inoculant with 0.1 ml of the culture fluid to a concentration of (105-106)/2 colony forming units/ml

After cultivation at 37oC measure the minimum inhibitory concentration (MIC) and the obtained values are recorded in table 1-5.

In tables 1-5 presents the minimum inhibiting concentration.

The full name of the strains listed in tables 1-5:

Acinetobacter calcoaceticus ATCC 19606

Citrobacter freundii ATCC 8090

Enterobacter aerogenes ATCC 13048

Enterobacter cloacae ATCC 23355

Escherichia coli ATCC 25922

Haemophilus influeza ATCC 35056

Klebsiella pneumoniae ATCC 13883

Proteus vulgaris ATCC 13315

Pseudomonas aeruginosa ATCC 27853

Salmonella typhimurium ATCC 14028

Shigella flexneri ATCC 12022

Shigella sonnei ATCC 25931

Serratia marcescens ATCC 8100

Streptococcus faecalis ATCC TV studied by oral administration and subcutaneous injection of the test compounds and control compounds 1CR mice weighing 22 g of 10%. Blood samples are taken through 10, 20, 30, 45, 60, 90, 120, 150, 180 and 240 minutes and analyzed by miocence (method agar cells).

Mean values of four experiments for each compound are presented in table.6.

The pharmacokinetic properties of the compound of example 13 in table 6 show that when administered orally to mice, the half-life time of 8.07 h, Cmax- 11,46 µg/ml, POK 41,05 μg h/ml, bioavailability -73,95%.

On the other hand, for ciprofloxacin half life is 0.92 h, Cmax- 1,71 µg/ml, POK of 2.27 µg h/ml, bioavailability of 14.6%. Therefore, the connection of the present invention has a significantly higher activity due to their wonderful pharmacokinetic characteristics.

Average values U50(mg/kg) compound of example 13 and ciprofloxacin, respectively 25 and >50 against systemic infection of mice caused by microogranisms S. aureus giorgio. Minimum inhibitory concentration (MIC, μg/ml) in vitro for the above compounds are respectively to 0.78 and 0.39.

ED50the compound of example 13 is 1000 g/kg and the compound of example 18 - >3000 g/kg (oral, mouse).

1. Production the nitrogen atom;

Y is a hydrogen atom or a methyl group;

R1is a hydrogen atom or alkyl;

R2group of the formula

< / BR>
where A and B - fluorocarbon group or a nitrogen atom, provided that when A=CF, B=N, and when A=N, B=CF;

R3group of the formula

< / BR>
where substituent R4the amino groups with the formation of the racemate or /S/ -enantiomer or a group of the formula,

< / BR>
where the substituents R5, R6and R7is a hydrogen atom or a C1-C3is an alkyl group,

or their pharmaceutically acceptable salts.

2. Connection on p. 1 having the following formula (IA), where the substituent R3is a derivative of piperazine

< / BR>
where the substituents X, Y, R1, R2, R6and R7take the values defined in paragraph 1.

3. Connection on p. 1 having the following formula (IB), where the substituent R3is a derivative of pyrrolidine

< / BR>
where the substituents X, Y, R1, R2and R4take the values defined in paragraph 1.

4. Connection on p. 2, which is 1-(5-fluoro-2-pyridyl)-6 - fluoro-7-(4-methyl-1-piperazinil)-1,4-dihydro-4-oxo-1,8-naphthiridine - 3-carboxylic acid.

5. Connection on p. 2, which is 1-(5-fluoro-2-pyridyl)-6 - fluoro-7-(3-methyl-1-piperazinil) is DIL)-6 - fluoro-7-(4-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3 - carboxylic acid.

7. Connection on p. 2, which is 1-(5-fluoro-2-pyridyl)-6 - fluoro-7-(3-methyl-1-piperazinil)-1,4-dihydro-4-oxoindole-3 - carboxylic acid.

8. Connection on p. 2, which is 5-methyl-7-(4-methyl-1 - piperazinil)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxylic acid.

9. Connection on p. 2, which is 5-methyl-7-(3-methyl-1 - piperazinil)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4 - oxoindole-3-carboxylic acid.

10. Connection on p. 3, which is 1-(3-fluoro-4-pyridyl)-6 - fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoindole - 3-carboxylic acid.

11. Connection on p. 3, which is 1-(5-fluoro-2-pyridyl)-6 - fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoindole - 3-carboxylic acid.

 

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< / BR>
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in which

X represents the number of carbon atoms equal to 0-5 in aminoalkyl group, located at the nitrogen atom in the 6 position of the canonical formulas indrosophila, to their salts with inorganic and organic acids and method of production thereof
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