RU2088581C1 - Azethidine derivatives or their pharmaceutically acceptable salts, method of their synthesis and composition based on thereof showing antimicrobial effect - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: pyridone carboxylic acid derivatives. Invention proposes new azethidine derivatives of pyridone carboxylic acid showing high antimicrobial effect, method of their synthesis, pharmaceutical composition based on thereof and using. EFFECT: improved method of synthesis, enhanced effectiveness. 4 cl, 11 tbl

Description

 The invention relates to new azetidine derivatives of pyridone carboxylic acids, such as 1,4-dihydro-4-oxo-3-quinoline-carboxylic, 4-oxo-1,8-naphthyridine-3-carboxylic and 2,3-dihydro-7-oxo- 7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acids, therapeutically suitable salts of these compounds, methods for their preparation, as well as their use as medical products.

 The compounds of the invention can be used in the pharmaceutical industry as intermediates, as well as for the manufacture of medicaments.

 The present invention is a continuation of the invention described in European Patent (EP) N 324,298, which encompasses azetidine derivatives of quinolones and pyridobenzoxazines, as well as a continuation of the invention described in EP N 388 298, which encompasses various azetidine derivatives of naphthyridines, quinolones and pyridobenzoxazines, each of these derivatives is a compound having very high antimicrobial activity.

 New azetidine derivatives of 1,4-dihydro-4-oxo-3-quinolinecarboxylic, 4-oxo-1,8-naphthyridine-3-carboxylic and 2,3-dihydro-7-oxo-7H-pyrido [1,2,3 -de] [1,4] -benzoxazine-6-carboxylic acids, which are the subject of this invention, have a very high antimicrobial effect. The compounds constituting the object of the invention meet the general form (I).

в которой A представляет собой атом азота или при желании атом углерода со связанным с ним атомом водорода (C-H), или при желании атом углерода со связанным с ним атомом галогена (C-X), и в этом случае X представляет собой атом хлора, фтора;
R₁ группу низшего алкила или циклоалкила, фенил, дизамещенный фтором,
R₂ атом водорода, группу низшего алкила;
R₃ аминогруппу или NH (низший алкил);
R₄ и R₅ (могут быть одинаковыми или различными) атом водорода или группу низшего алкила;
R₆ атом водорода или аминогруппу.

in which A represents a nitrogen atom or, if desired, a carbon atom with an attached hydrogen atom (CH), or optionally a carbon atom with an associated halogen atom (CX), in which case X represents a chlorine atom, fluorine atom;
R ₁ a lower alkyl or cycloalkyl group, phenyl disubstituted by fluorine,
R _{2 is} a hydrogen atom, a lower alkyl group;
R _{3 is an} amino group or NH (lower alkyl);
R ₄ and R ₅ (may be the same or different) a hydrogen atom or a lower alkyl group;
R _{6 is} a hydrogen atom or an amino group.

Depending on the number, type, and relative position, azetidine substituents may include up to three chiral centers, each with an “R” or “S” configuration;
The invention also encompasses physiologically suitable salts of these compounds formed with inorganic acids, such as hydrochloric acid, or with organic acids, such as toluenesulfonates or methylsulfonates.

 The stereochemistry of these products constituting the subject of the invention is determined by the stereochemistry of the starting materials. By selecting the stereoisomerism of each source material, all possible stereoisomers can be obtained. In the case where the reaction product is a mixture of stereoisomers, these compounds can be separated, and their configuration can be established by well-known methods.

 New derivatives of the general formula (I) can be prepared according to the invention as follows.

в которой A, R₁, R₆ имеют указанные выше значения, и Z представляет собой атом галогена, предпочтительно атом хлора или фтора, с азетидином общей формулы

в которой R₂, R₃, R₄ и R₅ имеют указанные выше значения. Гетероциклические соединения общей формулы (II), которые могут использоваться в качестве исходных продуктов для получения соединений, отвечающих изобретению, представляют собой соединения, описанные, например, в работе H. Koga, A. Itoh, S. Murayama, S. Suzue and T.Irikura J.Med. Chem. 1980, 23 1358 или в работе H. Egawa, T. Miyamoto, A. Minamida, Y. Nishimura, H. Gkada, H. Uno, J. Matsumoto, J. Med. Chem. 1984, 27 1543, или в работе Д.Т. W. Chu, P. B. Fernandes, A. K.Claiborne, L. Shen u A. G. Pernet, Drugs, Exptl. Chim. Res. 1988, 14, 379.By reaction of a compound of general formula (II)

in which A, R ₁ , R ₆ have the above meanings, and Z represents a halogen atom, preferably a chlorine or fluorine atom, with azetidine of the general formula

in which R ₂ , R ₃ , R ₄ and R ₅ have the above meanings. Heterocyclic compounds of the general formula (II), which can be used as starting materials for the preparation of the compounds of the invention, are compounds described, for example, by H. Koga, A. Itoh, S. Murayama, S. Suzue and T. Irikura J. Med. Chem. 1980, 23, 1358, or H. Egawa, T. Miyamoto, A. Minamida, Y. Nishimura, H. Gkada, H. Uno, J. Matsumoto, J. Med. Chem. 1984, 27 1543, or in the work of D.T. W. Chu, PB Fernandes, AK Claiborne, L. Shen u AG Pernet, Drugs, Exptl. Chim. Res. 1988, 14, 379.

 In addition, compounds of general formula (III), which are other starting materials for the preparation of compounds of the invention having general formula (I), are already known or synthesized as described, for example, by AG Anderson u R. Zok, J .Org. Chem. 1972, 37. 3953 in R. H. Higgins u N. H. Cromwell, J. Heterocycl. Chem. 1971, 8, 1059, and also by N. H. Cromwell and B. Phillips, Chem. Revs. 1979, 79, 331, and J. Frigola-Constansa, A. Colombo-Pinol, J. Pares-Colominas, Heb. Patent Application (EP) N 406112.

 The azetidines of general formula (III), depending on the number, type and relative position of the substituents, can include up to three chiral centers and various stereoisomers can be obtained either by asymmetric synthesis or by various types of separations according to known methods of organic chemistry.

 The reaction is carried out in the presence of a suitable solvent, for example dimethyl sulfoxide, dimethylformamide, pyridine, trialkylamines, such as triethylamine, methylene chloride or chlorofl, or in the presence of ethers such as tetrahydrofuran or dioxane, or in the presence of mixtures of these solvents.

 The most suitable temperatures range from room temperature to reverse reflux the solvent and the reaction time is from 1 to 24 hours. The following examples describe the preparation of new derivatives of the invention.

 These examples are given merely as illustrations, but not as limitations on the scope of the invention.

 Example 1. Obtaining 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6 fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid.

Mixture of 8.0 (23.7 mmol) of 1- (2,4-difluorophenyl) -6,7-difluoro, 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5.7 g (35.8 mmol) ) (2S, 3R) -3-amino-2-methylazetidine dichlorohydrate and 25 ml (245 mmol) of triethylene in 80 ml of pyridine are heated to 110 ^° C. in a closed container for 2 hours. The mixture is cooled and the product is washed with water, ethanol and simple ether. The result is 7.7 (19.1 mmol) - 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl-1- (2,4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, with a melting point of 227,230 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = 40.8 (c = 1.08NaOH0.5n.)
Spectrum ¹ H NMR (300 MHz) Dimethyl sulfoxide (DMSO-d ₆ trifluoroacetic K-ta (TFA) 1.25 and 1.31 (2 x D, 6.50 Hz, 3H) 3.62 3.92 (m. 2H); 4.20 4.42 (m 2H); 5.76 (d. J 6.84 Hz, 1H); 7.41 (m. 1H); 7.67 (m. 1H); 7.84 7.98 (m 2H (δ 7.94), J 12.7 Hz); 8.23 (br 3H); 877 and 8.80 (2x 1H). IR Spectrum (KBr) 1630, 1611 , 1509.

 Compounds identified in accordance with Examples 2, 3, 4, 5, 6, 10, 11, 12, 17, 20, 23, 26, 27, 28, 29, and 30 are obtained in the same manner. The data for their identification are presented in table. 1 and 2.

 Example 2. Obtaining a par-toluenesulfonate salt of 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl-1- (2,4-difluoromethyl) -6-fluoro-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid.

 A solution of p-toluenesulfonic acid and in ethanol is introduced into a suspension of 0.2 (0.50 mmol) 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] 1- (2,4-difluoromethyl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 3 ml of ethanol at boiling point until the pH becomes slightly acidic (6).

After cooling, the precipitated solid was filtered and washed with cold ethanol to give 0.23 g (0.40 mmol) of the para-toluenesulfonate salt of -7 - [(2S, 3R) amino-2-methyl -1-azetidinyl] - 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with a melting point of 214 216 ^o C
[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -36.5 (c = 1.0 DMSO)
Spectrum ¹ H NMR (300 MHz) DMSO-d ₆ ) 1.26 and 1.32 (2 x d, J 6.1 Hz, 3H); 2.28 (s. 3H); 3.64 3.92 (m, 2H); 4.16 4.42 (m, 2H); 5.76 (d. J, 7.3 Hz, IH); 7.11, 7.46 (system AB J 7.98 Hz, 4H); 7.72 7.84 (m, 4H) δ 7.98, d. J 12.68 Hz); 8.16 (br. 3H); 8.81 and 8.85 (2 x s. HH). IR Spectrum (KBr) 1729, 1630, 1507, 1460.

 Example 24. Preparation of 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo hydrochloride -3-quinoline carboxylic acid.

A solution of hydrochloric acid in ethanol is added to a suspension of 1.0 g (2.48 mmol) -7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] 1- (2,4-difluorophenyl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 20 ml of ethanol at the boiling point until the pH becomes slightly acidic (6). After cooling, the precipitated solid product is filtered off and washed with cold ethanol to give 0.86 g (1.95 mmol) of the hydrochloride salt of -7 - [(2S, 3R) -3-amino-2-methyl-1-azithidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, with a melting point of 211 214 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -54.8 (c = 1.0 in dimethylformamide (DMF)
¹ H NMR Spectrum (300 MHz) (DMSO-d ₆ ); 1.29 and 1.33 (2 x d) J 6.0 Hz, 3H); 3.70 (m, 1H); 3.89 (m, 1P); 4.35 (m, 2H); 5.77 (d) J 6.9 Hz, 1H); 7.47 (m, 1H); 7.57 (m, 1H); 7.89 8.00 (a.s. 2H δ 5.77, d. J 6.9 Hz); 8.30 8.70 (broad, 2H); 8.79 and 8.82 (2 x s. 1H)
IR Spectrum (KBr) 3700-2300 (br.) 1721, 1630, 1507, 1466, 1335 cm ^-1 .

 Example 25. Preparation of 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1-2,4-difluorophenyl-6-fluoro -1,4-dihydro-4-oxo-3 methanol sulfonate -quinoline acetocarboxylic acid.

 A solution of methanesulfonic acid in ethanol is introduced into a suspension of 2.0 g (4.96 mmol) -7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] 1- (2,4-difluorophenyl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 40 ml of ethanol at boiling point until the pH is slightly acidic.

After cooling, the precipitated solid product is filtered off and washed with cold ethanol to give 1.50 g (3.00 mmol of methanesulfonate salt 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2, 4-difluorophenyl) -6-fluoro-1,4-dihydro-45-oxo-3-quinolinecarboxylic acid with a melting point of 190-194 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -45.6 (c = 1.0 in dimethylformamide).
^-1 H NMR (300 MHz) (DMSO-d ₆ ) δ 1.28 and 1.32 (2 x d J 6.0 Hz 3H); 2.31 (s. 3H); 3.29 (broad 2H); 3.71 M. 1H); 3.84 (m, 1H); 4.20-4.43 (m, 2H); 5.77 (d. J, 7.2 Hz, 1H); 7.45 (m, 1H); 7.55 (m 1H) 7.88 8.0 (a.s. 2H) (d 7.96, d. J 12.6 Hz); 8.79 and 8.82 (2 x s. 1H)
IR Spectrum (KBr) 3700-2300 (broad) 1720, 1631, 1505, 1465, 1331 cm ^-1
Compounds identified in accordance with examples 7, 8, 9, 13, 14, 15, 16, 18, 19 and 22 are obtained in this way, and the data for their identification are presented in table. 1 and 2.

Biological effect: the antimicrobial pharmacological effect of these compounds was studied according to the methods described in the following publications:
Pharmacological antimicrobial action (Actvite 'pharmacologique antimicrobienne) (GL Daquet and JA Chabbect. Techniques adopted in bacteriology (Techniques en bacteriologie), vol. 3, Flammarion medicine-Sciences, Paris, 1972 and WB Hago and AD Rusell.

 Pharmaceutical Microbiology. Blackwell Scientific Publications. London, 1977.

Nutrient medium and solvent:
Antibiotic agar N 1 (Oxoid CM 327)
Tryptone soybean nutrient broth (Oxide SM 129)
Tinger physiological saline 1/4 (Oxide BP 52)
Dextrose Agar (BBL 11165)
Microorganisms:
"Bacillus subtilis" ATCC 6638
"Citrobacter freundii" ATCC 112606
"Enterobacter aerogenes" ATCC 15038
"Enterobacter cloacae" ATCC 23355
"Bacillus cereus" ATCC 1178
"Escherichia coli" ATCC 10799
"Escherichia coli" ATS 23559
"Klebsiella pneumoniae" ATS 10031
"Proteus vulgaris" ATS 8427
"Morg. Morganii" ATCC 8019
"Pseudomonas aeruginosa" ATCC 9721
"Pseudomonas aeruginosa" ATCC 10145
"Salmonella tiphymurium" ATCC 14028
"Salmonella tiphymurium" ATCC 6539
"Serratia marcescens" ATS 13880
"Shigella flexnerii" ATCC 12022
"Staphylococcus epidermis" ATCC 155-1
"Staphylococcus aureus" ATCC 25178
"Streptococcus faecalis" ATCC 10541
Inoculum preparation.

Each of the microorganisms is seeded by dashed in tubes with antibiotic agar No. 1, and incubated for 20 hours at 37 ^° C. The grown culture loop is then removed; sowing is carried out in tryptone nutrient broth; the culture is incubated for 20 hours at 37 ^° C. The resulting culture is diluted four times with Ringer's physiological saline so that a standard suspension of 10 ⁷ -10 ⁹ cfu / ml per organism is obtained.

 Preparation of a medium containing compounds of the general formula (I).

Using a solution of 100 μg / ml of this compound in 0.1-normal sodium hydroxide, each product is diluted in dextrose agar (previously melted and maintained at 50 ^o C) by successive dilutions so that the following concentrations are obtained: 64, 32, 16, 8 , 4, 2, 1, 0, 5, 0.25 and 0.125 μg of this compound per ml of medium.

 Each product of each concentration is distributed in Petri dishes with a diameter of 20 cm at the rate of 20 ml of medium per cup. The same number of cups as microorganisms are tested.

When the medium is cooled in the cups, inoculum is sown at the rate of 0.4 ml per cup. They are distributed by the Driglasky loop and the surface layer is removed. The culture inoculated plates are incubated at 37 ^° C. for 20 hours.

 The results are presented in table.3. The activity of these compounds in vitro is compared with the activity of norfloxadine. Concentrations are given in μg / ml.

 In the treatment of people, the administered dose of the drug depends on the sensitivity of the infectious strain, the type of compound administered and the route of administration. Typically, the dose is from about 0.200 to 300 mg per kg of body weight per day. For example, the compounds of this invention may be administered in the form of tablets, solution or suspension, or, as another possible option, in the form of gelatin capsules.

 The following are examples of dosage forms of the compounds of the present invention.

Example tablet formulation (per tablet)
The compound of example 1 250 mg
Microcrystalline Cellulose 69 mg
Povidone 15 mg
Wheat Starch 36 mg
Colloidal Silica (Silica Gel) 2 mg
Magnesium Stearate 3 mg
Tablet Weight 375 mg
Gelatin capsule formulation example
The compound of example 250 mg
Polyoxyethylene glyceride 85 mg
Glyceryl Behenate 15 mg
Excipient: Soft gelatin, up to a total weight of 450 mg

Claims (4)

1. Derivatives of azetidine of General Form I

where A is a nitrogen atom or a group —CH—, —CCl— or —CF—;
R ¹ lower alkyl or cycloalkyl, phenyl disubstituted by fluorine;
R ^{2 is} a hydrogen atom; lower alkyl;
R ^{3 is an} amino group or NH (lower alkyl);
R ⁴ and R ^{5 are the} same or different, hydrogen or lower alkyl;
R ^{6 is} hydrogen or an amino group,
or their pharmaceutically acceptable salts.  2. The compounds of general formula I according to claim 1, selected from the following: 7 - [(2S, 3R) 3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro -1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -8-chloro-1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6,8-difluoro -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7 - [(2S, 3R) - 3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, 7 - [(2S, 2R) -3-amino-2-methyl-1-azetidinyl] -8-chloro-1- (2,4-difluorophenyl) - 6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, paratoluene sulfonate 7- (3-amino-3-methyl-1-azetidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, paratoluene sulfonate 7 - [(2RS, 3SR) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-ethyl-1,4- dihydro-4-oxo-3-quinoline carboxylic acid, paratoluene sulfonate 7 - [(2RS, 3SR) -3-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro 4-oxo-3-quinoline carboxylic acid, 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo -3- quinoline carboxylic acid, 7 - [(2R, 3S) -3-amino2-methyl-1-azetidinyl] -1- (2,4-dif orphenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4 -difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, paratoluene sulfonate 7 - [(2RS, 3SR) -3-amino-2-methyl-1-azetidinyl ] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, paratoluene sulfonate 7 - [(2S, 3R) -3-amino-2-methyl-1 -azetidinyl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7- (3-amino-3-methyl-1-azetidinyl) paratoluenesulfonate - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid s, 1-cyclopropyl-6-fluoro-7- (3-methyl-3-methylamino-1-azetidinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid paratoluenesulfonate, 7- [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2, 4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid, methanesulfonate 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid, hydrochloride 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6, 8-difluoro-1- (2,4-difluorophenyl) -1,4 dihydride ro-4-oxo-3-quinoline carboxylic acid, paratoluene sulfonate 7 - [(2C, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, methanesulfonate 7 - [(2S, 2R) - 3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro 4-oxo-3-quinolecarboxylic acid, 5-amino-7- (3-amino-1-azetidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, hydrochloride 7 - [(2S, 3R) - 3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids, methanesulfonate 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-dif torphenyl) -6- fluoro-1,4-dihydro-4-oxo-3-quinol carboxylic acid, 7- (3-amino-1-azetidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3-quinoline carboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-7- (3-methylamino-1-azetidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7- (3-amino-1-azetidinyl) - 8-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-hydro-4-oxo-3-quinolinecarboxylic acid, 8-chloro-1 - (2,4-difluorophenyl) -6-fluoro-7- (3-methylamino-1-azetidinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7 - [(2R, 3S) -3 -amino-2-methyl-1-azetidinyl] -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-7- (3-amino-3-methyl-1-azetidinyl) -6,8-difluoro-1- (2,4-difluorophenyl) -1, 4-dihydro-4-oxo-3- quinoline carboxylic acid, 5-amino-7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro- (2,4-difluorophenyl) -1, 4-dihydro-4 -oxo-3-quinolcarboxylic acid, 5-amino-7 (3-amino-1-azetidinyl) -6,8-difluoro-1- (2,4-difluorophenyl) -1, 4-dihydro-4-oxo-3 -quinoline carboxylic acid, 5-amino-7- (3-amino-3-methyl-1-azetidinyl) -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 5 amino-7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-ethyl-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5-amino-7- (3-amino-1- azetidinyl) -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 3. A method of producing azetidine derivatives of formula I according to claim 1 or 2, characterized in that the compounds of general formula II are reacted

where A is a nitrogen atom or a group —CH—, —CCl—, —CF—;
R ¹ lower alkyl or cycloalkyl, phenyl disubstituted by fluorine;
R ^{6 is} hydrogen or an amino group;
Z is a halogen atom, preferably a chlorine or fluorine atom,
with azetidine of general formula III

where R ^{2 is} a hydrogen atom, lower alkyl;
R ^{3 is an} imino group or NH (lower alkyl);
R ⁴ and R ^{5 are the} same or different, hydrogen or lower alkyl.  4. An antimicrobial composition containing azetidine derivatives as an active substance and a pharmaceutically acceptable carrier, characterized in that as compounds of azetidine are used the compounds of formula I according to claim 1 or pharmaceutically acceptable salts thereof in an effective amount.

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