Derivatives of 1,8-benzo/b/naphthiridine in the form of stereoisomers or racemic mixtures and their salts with metals, nitrogen-containing organic bases or acids, and their hydrates, methods for their preparation, pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of 1,8-benzonitriles, method of production thereof, to compositions based on them and to intermediate compounds for the synthesis of new derivatives. The new compounds exhibit high antibacterial activity and can find application in pharmacology and agriculture for antibacterial treatment plants. 3 S. and 1 C.p. f-crystals, 1 table.

The present invention relates to new derivatives of 1,8-benzo-/b/naphthiridine and their salts, to a process of receiving and containing compositions.

In European patent application N431991 describes derivatives of benzonitriles structure (a):

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in which R1denotes hydrogen, hydroxyl or alkyl; R2denotes hydrogen, alkyl, foralkyl, cycloalkyl, alkyloxy or alkylamino, R3denotes phenyl or phenylalkyl, in some cases substituted; and R4denotes a hydrogen or fluorine atom. These products valuable for its antimicrobial activity.

The applicant has developed new connections benzonitriles series that exhibit particularly high antibacterial activity in the absence of toxicity.

With the hydroxyl; amino radical; alkylamino-radical, the alkyl part of which in certain cases is substituted by an amino or hydroxyl radical, or denotes dialkylamino-radical, the alkyl part of which in certain cases together with the nitrogen atom to which they are linked can form a 5 - or 6-membered heterocycle, containing in some cases another heteroatom selected among nitrogen, oxygen or sulphur; or represents a 3 - to 6-membered, cyclooctylamino radical; or alkanoyl-amino-, N-alkyl-N-alkanoyl-amino - or aminoalcohol-amino radical;

R1and R2the same or different, respectively, are in position 2 and 3 and denote hydrogen atoms; alkyl radical, alkanniny radical with 2 to 4 C-atoms; a phenyl radical; a phenyl radical substituted by a halogen atom or alkyl, alkyloxy-, hydroxyl -, nitro-, amino-, alkylamino, dialkylamino or halogenosilanes radical; or R1and R2are in position 2 and denote alkyl radicals;

R3denotes a hydrogen atom or alkyl, alkyl fluoride, carboxialkilnuyu, C3-C6-cycloalkenyl, forfinally, differenly, alkyloxy or alkylamino radical; and

R4denotes a hydrogen atom or a the mi and contain 1 - 4 C-atoms;

also their salts and stereoisomers.

When R denotes dialkylamino-radical, the alkyl part of which together with the nitrogen atom form a heterocycle, the latter can be a particularly pyrrolidinyl or piperidinyl.

The products of General formula (I) may exist in the form of hydrates, keeping in mind that these hydrates are also included in the scope of the present invention.

According to the invention, the products of General formula (I) can be obtained by interaction of azetidine General formula (II):

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in which R, R1and R2have the above significance, with a 1.8-benzo/b/naphthiridine General formula (III):

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in which R3has the above meaning; Hal represents fluorine atom, chlorine or bromine, if R4denotes hydrogen; or Hal and R4at the same time are fluorine atoms.

Interaction with derivatives of azetidine General formula (II) is carried out usually in the presence of excess derived as the acid acceptor in a suitable organic solvent. You can work with a solvent or without, at a temperature of 20 - 150oC. When working in the presence of a solvent, the reaction is preferably carried out in such a solution.

Also, it is preferable to operate in the presence of an acid acceptor, such as nitrogen-containing organic bases (especially triethylamine), carbonate of an alkali metal (e.g. sodium carbonate or hydroxide of an alkaline or alkaline-earth metal.

Have in mind that, if the symbol R3the product of General formula (III) represents a hydrogen atom when R represents amino radical; alkylamino-radical, in some cases substituted; cyclooctylamino or aminoethylethanolamine radical, preferably pre-to protect the original product. Protection and removal of the protective radical after the reaction carried out by conventional methods.

Protection can be implemented using any acceptable group, the introduction and the removal of which does not affect the rest of the molecule. Especially operate according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or Mc OMIE, Protective Groups in Organic Chemistry, Plenum Press (1973).

As an example, the protective group can be selected among trimethylsilyl, benzhydryl, tetrahydropyranyl, formyl, acetyl, chloroceryle, trichloroethylene, trifluoracetyl, ethoxycarbonyl, tert.-butoxy-carbonyl the Dean of General formula (I) can also be obtained from the corresponding esters of the General formula (IV):

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in which R1, R2and R4have the above significance, and R has the above meaning, or represents a protected amino radical; R3has the above meaning, or represents protected alkylamino-moiety; and Alk denotes an alkyl radical with 1 to 4 C-atoms in linear or branched chain, in any way, famous for producing acid from ether complex without affecting the rest of the molecule.

Getting acid complex ester is usually carried out by saponification in the presence of potassium hydroxide or sodium, in an aqueous or aqueous-alcoholic medium, at a temperature of 20 - 100oC.

When hydrolyzing an ester of the General formula (IV) in which R denotes alkanolamine - or N-alkyl-N-alkanolamine-radical or in which R is a protected amino radical, meaning that, depending on the conditions, get or acid, in which R denotes alkanolamine - or N-alkyl-N-alkanolamine-radical or in which R is a protected amino radical, or an acid, in which a simultaneous hydrolysis of amide, i.e., in which R denotes an amino radical. The operating conditions are chosen depending on the expected target product is="ptx2">

When R3indicates protected alkylamino-radical, the protective radical can be any protective for amino group, compatible with the molecule. Especially, it is preferable to choose a protective radical, which may be removed simultaneously with the hydrolysis of ester.

Derivative of 1,8-benzo/b/naphthiridine General formula (III) can be obtained from the corresponding complex ester of General formula (V):

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in which R3, R4Hal and Alk have the above significance, in the application of the method described in U.S. patent N4990515, or by analogy with the described method.

Ester derivative of 1,8-benzo/b/naphthiridine General formula (V) can be obtained by exposure to 3-amino-1,2,4-triazine (to obtain a product in which R3denotes a hydrogen atom) or by exposure of the product of General formula (VI): R3-NH2(VI) in which R3denotes alkyl, foralkyl, carboxyethyl, cycloalkyl, forfinal, differenl, alkyloxy or alkylamino, in some cases substituted on the quinoline derivative of General formula (VII):

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in which R4Hal and Alk have the above significance, with subsequent cyclization due to the impact of the acceptor to the com solvent, such as alcohol (e.g. ethanol, methanol) or a chlorinated solvent (for example, trichlormethane), at a temperature of 10 - 25oC.

The cyclization is carried out in an alcohol with a linear or branched chain with 1 to 4 C-atoms, at a temperature of 20oC to the boiling temperature under reflux the reaction mixture.

The acid acceptor is chosen, in particular, of the nitrogenous bases (such as triethylamine), 1,8-diaza-bicyclo[5.4.0]undec-7-ene or an excess of amine used.

Derivatives of benzo/b/naphthiridine General formulas (III) and (V) in which R3means carboxialkilnuyu, forfinally or differenly radical, are new products.

Derivatives of quinoline General formula (VII) can be obtained as described in U.S. patent N4990515.

Derivatives aminoacridine General formula (II) can be obtained according to the methods described in: T. Okutani al., Chem. Pharm. Bull., 22(7), 1490 (1974); S. Chatterjee al., Chem. Comm., 93 (1968); D. Nisato al., J. Heterocyclic. Chemistry, 22, 961 (1985); Akira Morimoto al., Chem. Pharm. Bull. , 21 (1), 228 (1973); A. G. Anderson and al., J. Org. Chem., 37, 3953 (1972); R. V. Gaertner., J. Org. Chem., 2972 (1967); J. N. Wells al., J. Org. Chem., 34, 1477 (1969), J. Antibiotics, 39, (9), 1243 (1986) and J. Pharm. Soc., 60 (1), 156 (1971); European patents: NN406112, 314362, 106489, 324298; azetidin can be obtained by reinstatement of azetidin-2-it, according to the method described in J. Pharm. Sci., 60, 5 (1971). 3-Amino-3-phenyl-azetidin-2-he will receive, by analogy with the method described in J. Am. Chem. Soc., 111, 1073 (1989), followed by removal of the protective for amino radical.

Derivative of 1,8-benzo/b/naphthiridine General formula (IV) can be obtained from benzo/b/naphthiridine General formula (V) by substitution derivative of azetidine General formula (II).

Preferably working under conditions described above to obtain a product of General formula (I) of azetidine General formula (II) and 1,8-benzo/b/naphthiridine General formula (III). Meaning, if you work in an aquatic environment, it is possible directly to obtain the product of General formula (I) without intermediate highlight derivative of General formula (IV).

According to the invention, if want to get stereoisomers derived benzonitriles General formula (I), carry out the separation of stereoisomeric forms azetidinol General formula (II) any known and compatible with the molecules of the way. As an example, the separation is carried out by acylation with a chiral acid or reactive derivative chiral acid, separation of the isomers by high-performance liquid chromatography (HPLC), C is better separation of stereoisomers by HPLC on a chiral phase.

New products according to the present invention, as well as their intermediate products of synthesis, in certain cases can be purified by physical methods such as crystallization or chromatography.

The products according to the present invention as well as their intermediate products of General formula (III) and, where appropriate, their intermediate products of General formula (V) can be converted into metal salts or salts of joining the nitrogenous bases in a known manner. These salts can be obtained by exposing metal base (e.g. alkali or alkaline-earth metal, ammonia or amine in the product according to the invention in an appropriate solvent, such as alcohol, simple ester or water, or by an exchange reaction with a salt of an organic acid. The formed salt is precipitated possible after concentration of its solution, then her evolve by filtering, decanting or lyophilization.

New products according to the invention can also be turned into salt accession acids. The products of General formula (I) are obtained in the form of these salts can be isolated and converted into the salts of other acids according to conventional methods.

As examples Vermaelen-earth metals (such as magnesium, calcium), ammonium salts, salts of nitrogen-containing bases such as ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, Propylamine, Diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-phenethylamine, N,N'-dibenziletilendiaminom, diferentiation, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamino), as well as salt accession inorganic acids (chlorhydrate, bromhidrosis, sulfates, nitrates, phosphates) or salt accession of organic acids (succinate, fumarate, maleate, methanesulfonate, p-toluensulfonate, isetionate).

New derivatives of 1,8-benzo/b/naphthiridine General formula (I) according to the present invention and their pharmaceutically acceptable salts possess particularly interesting antibacterial properties. They have remarkable activity in vivo and in vitro against gram-positive microbes and generally in respect of the microbes responsible for most infections, airborne paths. In addition, new derivatives of 1,8-benzo/b/naphthiridine General formula (I) are particularly interesting antibacterial activity against gram-negative microbes.

In vitro, the products of General formula (I) occh/cm3against Escherichia coli, strain NIHJ JC2.

In vivo, the products of General formula (I) are active against experimental infections of mice with Staphylococcus aureus IP 8203 in doses of 2 to 200 mg/kg orally.

In addition, some products according to the invention are particularly interesting in relation to the impact on Mycoplasma. Minimum inhibitory concentration is 0.03 - 8 g/ml.

Finally, the products according to the invention does not have toxicity when used doses. They are usually non-toxic in the amount of 500 mg/kg orally in the case of the mouse.

The following examples, data as not limiting the scope of protection of the invention, illustrate the present invention.

Example 1.

8-(3-Amino-1-azetidine)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A suspension of 1.16 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo /b/naphthiridine-3-carboxylic acid and 1.38 g of 3-amino-azetidine 15 cm3dimethyl sulfoxide is heated with stirring at a temperature of about 95oC for 6 h, After cooling to a temperature of about 20oC to the reaction mixture was added 100 cm3water. The insoluble part is sucked off, sulfoxylate. After removal of a small amount of insoluble portion by filtration through kieselguhr and add 4 cm3aqueous 1 n sodium hydroxide solution, the resulting suspension is concentrated under reduced pressure (20 kPa) at a temperature of about 60oC to a volume of about 80 cm3. The insoluble part is sucked off, washed with 100 cm3water, 100 cm3ethanol and recrystallized from 150 cm3of dimethylformamide. Obtain 0.7 g of 8-(3-Amino-1-azetidine)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 358oC.

7,8-Debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo /b/naphthiridine-3-carboxylic acid is obtained as described in U.S. patent N4990515.

3-Amino-azetidin receive according to the method described Dino Nisato al., J. Het. Chem., 22, 961 (1985).

Example 2.

8-(3-Dimethylamino-1-azetidine)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A suspension of 1.9 g of 8-(3-dimethylamino-1-azetidine)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine 20 cm3ethanol and 19 cm3aqueous 0.5 n solution of potassium hydroxide is heated under stirring, is added 9.5 cm3aqueous 1 n solution methansulfonate. The insoluble part is sucked off, washed with 2 times 10 cm3water, 3 times by 25 cm3ethanol and recrystallized from 125 cm3of dimethylformamide. Obtain 1.4 g of 8-(3-dimethylamino-1-azetidine)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid as a yellow solid, decomposing at 312oC.

8-(3-Dimethylamino-1-azetidine)-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine obtained as follows.

A suspension of 2 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine, 1.2 g of 3-dimethylamino-azetidin-dichlorhydrate and 1.5 g of sodium carbonate in 30 cm3dimethyl sulfoxide is heated with stirring at a temperature of about 95oC for 5 hours After cooling to a temperature of about 20oC in the reaction mixture was added 60 cm3water. The insoluble product is sucked off and washed 3 times with 20 cm3water. Receive 2 g of 8-(3-dimethylamino-1-azetidine)-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/- naphthiridine in a solid yellow color with so pl. 224oC, which is used without other purification in the subsequent stages.

The USA N4970213.

Example 3.

8-/3-Amino-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

Working under the conditions described in example 2, but from 0,72 g 8-/3-amino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Receive, without recrystallization, 0.6 g of 8-/3-amino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 306oC.

8-/3-Amino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions described in example 2, but from 1.7 g of 3-etoxycarbonyl-1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and of 1.62 g of 3-amino-azetidin-dimethanesulfonate. The crude product is treated with 100 cm3of dimethylformamide and stirred for 10 min at a temperature of approximately 150oC. After cooling to a temperature of about 20oC to remove insoluble product by filtration. The filtrate is concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 60oC. the Balance is recrystallized from 50 cm3of ethanol. Get 0,72 g 8-/3-amino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-f the d 255 - 256oC.

3-Etoxycarbonyl-1-ethyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine receive, as described in U.S. patent N4970213.

Example 4.

8-/3-Dimethylamino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo /b/naphthiridine-3-carboxylic acid.

Working under the conditions described in example 2, but from 2 g of 8-/3-dimethylamino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 1.68 g of 8-/3-dimethylamino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 278oC.

8-/3-Dimethylamino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions described in example 2, but from 1.7 g of 3-etoxycarbonyl-1-ethyl - 7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.3 g of 3-dimethyl-amino-azetidin-dichlorhydrate. After the reaction, the reaction mixture is cooled to a temperature of about 20oC, poured into 50 cm3water and extracted with 3 times 100 cm3dichloromethane. The combined organic extracts are washed with 3 times 150 cm3with water and dried over magnesium sulfate. After concentration to dryness, etilovogo ether, filtered off and washed with 2 times 50 cm3the same solvent. Receive 2 g of 8-/3-dimethylamino-1-azetidine/-3-etoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 232oC, which is used without purification in the subsequent stages.

Example 5.

8-/3-Amino-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro - 1,8-benzo/b/naphthiridine-3-carboxylic acid.

Working under the conditions described in example 2, but from 1 g of 8-/3-amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 0.56 g of 8-/3-amino-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 298 - 303oC.

8-/3-Amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions of example 2, but from 1.7 g of 1-cyclopropyl-3-etoxycarbonyl - 7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.88 g of 3-amino-azetidin-dimethanesulfonate. After one recrystallization from 50 cm3ethanol gain of 1.05 g of 8-/3-amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-sapropel-3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine can be obtained, as described in U.S. patent N4970213.

Example 6.

1-Cyclopropyl-8-/3-dimethylamino-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro - 1,8-benzo/b/naphthiridine-3-carboxylic acid.

Working under the conditions described in example 4, but on the basis of 1.27 g of 1-cyclopropyl-8-/3-dimethylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 0.8 g of 1-cyclopropyl-8-/3-dimethylamino-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color with so square 264oC.

1-Cyclopropyl-8-/3-dimethylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions described in example 4, but on the basis of 1.4 g of 1-cyclopropyl-3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.04 g of 3-dimethylamino-azetidin-dichlorhydrate. After concentration to dryness the combined organic extracts obtained solid substance is recrystallized from 40 cm3of ethanol. Obtain 1.2 g of 1-cyclopropyl-8-/3-dimethylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 225oC.

Example 7.

8-/3-Amino-1-azetidine/-1-cichlids, described in example 2, but on the basis of 0.8 g of 8-/3-amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Get without recrystallization 0.6 g of monohydrate 8-/3-amino-1-azetidine/-1-cyclopropyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 308 - 312oC.

8-/3-Amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions of example 2, but from 1.3 g of 1-cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor-4-oxo-1,4-dihydro-1,8-benzo/b/ naphthiridine and of 1.32 g of 3-amino-azetidin-dimethanesulfonate. After recrystallization from 50 cm3of ethanol and 0.8 g of 8-/3-amino-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7,9 - debtor-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 236 - 238oC.

1-Cyclopropyl-3-etoxycarbonyl-7,8,9-Cryptor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive, as described in U.S. patent N4970213.

Example 8.

8-/3-Diethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

Get in the conditions of example 2, but from 1,75 g 8-/3-di is ethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color, decomposing at 297oC.

8-/3-Diethylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions of example 2, but from 2 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.4 g of 3-diethylamino-azetidin - dichlorhydrate. After recrystallization of the crude product from 500 cm3methanol receive 2,07 g 8-/3-diethylamino-1-azetidine/-3 - etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 260oC.

3 Diethylamino-azetidin receive in the form of dichlorhydrate with so pl. 175oC according to the method described in Japan patent N7419369.

Example 9.

8-/3-Ethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4 - dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

Working under the conditions described in example 2, but from 0.51 g of 3-etoxycarbonyl-8-/3-ethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 0.4 g of monohydrate 8-/3-ethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 270oC.

3-Etoxycarbonyl-8-/on of 2 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.3 g of 3-ethylamino-azetidine-dichlorhydrate. After adding 300 cm3water to the reaction mixture, the resulting suspension is extracted with 3 times 100 cm3dichloromethane. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (20 kPa) at a temperature of approximately 40oC. the resulting product was then purified by chromatography on silica gel with a particle size 0,063 - 0,200 mm, in the form of a suspension in dichloromethane with 1% methanol. Target product elute with 500 cm3dichloromethane and 5% methanol. Obtain 0.51 g of 3-etoxycarbonyl-8-/3-ethylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine in a solid yellow color decomposing at 215oC, which is used without other purification in the subsequent stages.

3 Ethylamino-azetidine-dichlorhydrate receive by analogy with the method described Dino Nisato al. J. Het. Chem., 22, 961 /1985/.

4 g of 1-Benzhydryl-3-ethylamino-azetidine-dichlorhydrate 50 cm3methanol hydronaut at atmospheric pressure, at a temperature of about 20oC for 1 h in the presence of 800 mg of 20% palladium hydroxide-on-charcoal grill. After removal of catalyst by filtration, concentration to dryness under reduced pressure (20 kPa) at about 40ooC, which is used without other purification in the subsequent stages.

1-Benzhydryl-3-ethylamino-azetidine-dichlorhydrate obtained as follows.

A mixture of 55 g of 1-benzhydryl-3-methanesulfonate-azetidine and 70 g of ethylamine 400 cm3methanol for 16 h, heated at 60oC. the Reaction mixture was then concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 40oC and the residue is treated with 200 cm3diethyl ether. Washed with 90 cm32 n sodium hydroxide solution and 3 times with 30 cm3water the organic phase is dried over sodium sulfate and concentrated to dryness under reduced pressure (20 kPa) at a temperature of approximately 40oC. To the resulting dry extract add 22.6 cm312 n hydrochloric acid, again concentrated to dryness, the previous conditions, but at a temperature of approximately 70oC. the Residue is treated with 100 cm3ethyl acetate and 200 cm3acetone and sucked off. Get to 41.4 g of 1-benzhydryl-3-ethylamino-azetidine-dichlorhydrate in the form of a colorless solid substance with so pl. 180oC used without the method, described by A. G. Anderson and al., J. Org. Chem., 37, 3953 (1972).

Example 10.

8-/3-Amino-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A suspension of 1.8 g of 8-/3-acetylamino-1-azetidine/-3-ethoxy-carbonyl-7-fluoro-N-formyl-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine 40 cm31 n aqueous solution of potassium hydroxide is heated under stirring at a temperature of about 100oC, within 24 hours After cooling to a temperature of about 70oC is removed by filtering a small amount of insoluble part. At the same temperature to the filtrate add 40 cm31 h methansulfonate, the formed precipitate is sucked off and washed 3 times with 20 cm3water with a temperature of about 70oC. After recrystallization from 100 cm3of dimethylformamide get 1,05 g 8-/3-amino-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 315 - 318oC.

8-/3-Acetylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-N-formyl-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine obtained as follows.

At a temperature of about 30oC to a mixture of 1.13 g debtor-3-ethoxy-carbonyl-N-formyl-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine and heated at about 80oC for 2 h, After cooling to a temperature of about 20oC, the reaction mixture was poured into 100 cm3water with a temperature of about 5oC. the Precipitate is sucked off and washed with 3 times 50 cm3water. Get 2,05 g 8-/3-acetylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-N-formyl-1-N-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color decomposing at 305oC.

7,8-Debtor-3-etoxycarbonyl-N-formyl-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine obtained as follows.

To a solution of 7.4 g of ethyl-2-/2-chloro-6,7-debtor-3-quinoline-carbonyl/-3-dimethylamino-acrylate in 30 cm3dichloromethane, with stirring, for 10 minutes and at a temperature of about 20oC add a solution of 1.63 g of N-formyl-N-methylhydrazine 30 cm3dichloromethane. After incubation for 16 h at a temperature of about 20oC, the reaction mixture was concentrated under reduced pressure (20 kPa) at a temperature of approximately 40oC. the Dry extract is treated with 100 cm3ethanol, 3 cm31,8-diaza-bicyclo/5.4.0/-undec-7-ene (DBU) and heated for 30 minutes at about 75oC. After cooling to a temperature of about 20oC the product is sucked off, washed with 2 times the mil-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color, with so pl. 259 -260oC, which is used without any other purification in the subsequent stages.

Ethyl-2-/2-chloro-6,7-debtor-3-hinolincarbonova/-3-dimethylamino-acrylate receive as described in U.S. patent N4970213.

3-Acetylamino-azetidin-hydrochloride receive according to the method described Dino Nisato al. J. Heterocyc. Chem., 22, 961 /1985/.

Example 11.

8-TRANS-3-amino-2-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A solution of 18 g of TRANS-3-amino-2-methyl-azetidin-dimethanesulfonate and 12.7 g of triethylamine in 150 cm3dimethyl sulfoxide is heated for 20 minutes under stirring at a temperature of approximately 70oC. At the same temperature is added in small portions over 10 min 14.5 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/ naphthiridine-3-carboxylic acid for 2 h, heated at about 90oC. After cooling to about 20oC, the reaction mixture was poured into 400 cm3water at the same temperature. The insoluble product is sucked off, washed with 2 times 100 cm3water, 2 times 100 cm3ethanol and recrystallized from 300 cm3of dimethylformamide. Get a 13.9 g of 8-/TRANS-3-amino-2-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-is ri 265 - 267oC.

TRANS-3-amino-2-methyl-azetidin get dimethanesulfonate with so pl. 170 - 175oC according to the synthesis in the European patent N406112.

Example 12.

8-/CIS-3-amino-2-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

Work in the conditions of example 11, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid 2.1 g of CIS-3-amino-2-methyl-azetidin-dimethanesulfonate. Get 1,32 g 8-/CIS-3-amino-2-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/-naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 312 - 315oC.

CIS-3-amino-2-methyl-azetidin get dimethanesulfonate with so pl. 160 - 170oC according to the synthesis in European patent application N406112.

Example 13.

8-/TRANS-3-amino-2-methyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo - 1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A suspension of 1.4 g of 8-/TRANS-3-amino-2-methyl-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine 15 cm3water and 6.8 cm3aqueous 1 n solution of potassium hydroxide is heated at a temperature of OK is dilaut by filtration; at the same temperature to the filtrate add 6.8 cm31 h methansulfonate. The formed precipitate is sucked off at about the 20oC, washed 3 times in 50 cm3water and 2 times with 25 cm3the ethanol. After recrystallization from 30 cm3of dimethylformamide gain of 1.03 g of 8-/TRANS-3-amino-2-methyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 268 - 270oC.

8-/TRANS-3-amino-2-methyl-1-azetidine/-1-cyclopropyl-3 - etoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine obtained as follows.

To a solution of TRANS-3-amino-2-methyl-azetidin-dimethanesulfonate 20 cm3dimethyl sulfoxide and 1.52 g of triethylamine, approximately at 60oC for 10 min and small portions add 1.7 g of 1-cyclopropyl-3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo - 1,4-dihydro-1,8-benzo/b/naphthiridine. The reaction mixture is heated to a temperature of about 80oC with stirring and kept at this temperature for approximately 4 h After cooling to about 20oC, the reaction mixture was poured into 100 cm3water, extracted with 2 times 100 cm3dichloromethane. The combined organization is eigendom pressure (20 kPa) at about 40oC. the Dry extract chromatographic on 125 g of silica gel /0,04 - 0,063 mm/, suspending in a mixture of dichloromethane with 20% ethanol. Target product elute with 300 cm3the same mixture. Obtain 1.6 g of 8-/TRANS-3-amino-2-methyl-1-azetidine/-1-cyclopropyl-3-etoxycarbonyl-7-fluoro-4-oxo-1,4 - dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 170oC.

Example 14.

8-/3-Amino-1-azetidine/-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

A suspension of 2.2 g of 8-/3-triptoreline-1-azetidine/-3 - etoxycarbonyl-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo /b/naphthiridine 17 cm31 n aqueous solution of potassium hydroxide is heated at a temperature of approximately 95oC for 7 hours At the same temperature type 17 cm31 h methansulfonate, sucked off at a temperature of approximately 90oC, washed 2 times with 30 cm3water, 2 times with 30 cm3ethanol and recrystallized from 50 cm3of dimethylformamide. Obtain 1.4 g of 8-/3-amino-1-azetidine/-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/ naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 333 - 335oC.

3-Etoxycarbonyl-7-ft is the iMER 2, but on the basis of 1.8 g of 3-etoxycarbonyl-7,8-debtor-4-oxo-1-tert.- butyl-1,4-dihydro-1,8-benzo/b/naphthiridine, 1.5 g of 3-triptoreline-azetidin-hydrochloride and 0.79 g of sodium carbonate. Obtain 2.25 g of 3-etoxycarbonyl-7-fluoro-8-/3-triptoreline-1-azetidine/-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 328 - 330oC.

3-Etoxycarbonyl-7,8-debtor-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions described in example 10, but on the basis of 4 g of ethyl-2-/2-chloro-6,7-debtor-3-hinolincarbonova/-3-dimethylamino-acrylate and 0.87 g of tert. -butylamine. Obtain 2.7 g of 3-etoxycarbonyl-7,8-debtor-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/-naphthiridine in a solid yellow color with so pl. 206oC, which is used without any other purification in the subsequent stages.

3 Trifurcated-azetidin-hydrochloride receive, as described in European patent application N406112.

Example 15.

8-/3-Amino-3-propyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

To a solution of 1.22 g of ateleta sodium in 18 cm3ethanol added 2.3 g of 3-amino-3-propyl-azetidin-dimethanesulfonate. After adding 30 cm3deer added 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and heated with stirring at about 90oC for 5 hours After cooling to a temperature of about 20oC the product is sucked off, washed 4 times with 20 cm3water and 2 x 10 cm3the ethanol. After recrystallization from 30 cm3of dimethylformamide obtain 1.52 g of 8-/3-amino-3-propyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 304 - 305oC.

3-Amino-3-propyl-azetidin in the form dimethanesulfonate get in conditions similar to those described by D. Nisato al., J. Heterocyclic Chem., 22, 961 /1985/.

By hydrogenation of 7.3 g of 3-amino-1-benzhydryl-3-propyl-azetidine under the pressure of 1 ATM., in the presence of 5 g of methansulfonate 75 cm3methanol and 1.5 g of 20% palladium hydroxide-on-coal obtain 6.5 g of 3-amino-3-propyl-azetidin-dimethanesulfonate. The product is treated with ethanol and isolated in the form of a colourless solid with so pl. 200oC.

3-Amino-1-benzhydryl-3-propyl-azetidin obtained as follows. To the cooled approximately to 5oC 100 cm3solution of ammonia in ethanol /obtained from 15 g of ammonia in 100 cm3ethanol in 5oC/ add 7.5 g 1-benzhydryl-3-methanesulfonate-3-propyl-azetidine, leave temperature to dryness under reduced pressure (20 kPa) at about 40oC residue is treated with 15 cm3water and 2,22 g methansulfonate. The aqueous phase is washed with 2 times 25 cm3diethyl ether, to which was added 10 cm340% aqueous sodium hydroxide solution, extracted with 3 times 50 cm3dichloromethane; the combined organic extracts are washed with 10 cm3saturated sodium chloride water, dried over magnesium sulfate and concentrated to dryness on the previous conditions. Gain of 5.2 g of 3-amino-1-benzhydryl-3-propyl-1-azetidine in the form of an oily product that is used without any other purification in the subsequent stages.

1-Benzhydryl-3-methanesulfonate-3-propyl-azetidin receive under the conditions described for 1-benzhydryl-3-methanesulfonyl-hydroxy-3-methyl-azetidine in European patent application N406112, but on the basis of 2.8 g of 1-benzhydryl-3-hydroxy-3-propyl-azetidine. Obtain 2.4 g of 1-benzhydryl-3-methanesulfonate-3-propyl-azetidine in the form of a solid substance with so pl. 70oC.

1-Benzhydryl-3-hydroxy-3-propyl-azetidin receive the following conditions.

To a solution of PROPYLENEIMINE in diethyl ether, obtained under normal conditions of 10.75 g iodopropane and 1.55 g of magnesium in 75 cm3diethyl ether during the first broadcast. Leave the temperature to rise to about 20oC and at this temperature, stirred for 2 hours, After cooling to about 0oC, maintaining this temperature, add successively 50 cm3water and 50 cm310% aqueous solution of ammonium chloride. The aqueous phase is extracted with 3 times 50 cm3diethyl ether. The combined organic extracts are dried over magnesium sulfate, concentrated to dryness under reduced pressure (20 kPa) at about 30oC. the Dry extract chromatographic on 100 g of silica gel (0.04 to 0,063 mm), suspending in a mixture of cyclohexane with 20% ethyl acetate. Target product elute with 130 cm3the same mixture of solvents. Get 8 g of 1-benzhydryl-3-hydroxy-3-propyl - azetidine in the form of a pale yellow oil which is used without any other purification in the subsequent stages.

1-Benzhydryl-3-oxo-azetidin receive under the conditions described A. Morimoto al., Chem. Pharm. Bull., 21 (1), 228 - 231 (1973).

Example 16.

8-/3-Amino-3-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

To a solution of 1.02 g of ethylate of sodium in 30 cm3ethanol, at a temperature of about 5oC add 2.9 g of 3-amino-3-methyl-s 15 min at the same temperature. After removal by filtration of inorganic salts, the filtrate is concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 30oC. the Residue is dissolved in 20 cm3dimethyl sulfoxide, at a temperature of about 20oC added 1.45 g of 7,8-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid. The resulting suspension is stirred for 16 h at the same temperature, then heated for 1 h at about 60oC. After cooling to a temperature of about 20oC insoluble part is sucked off and washed with 30 cm3of ethanol. The selected product is crystallized from 90 cm3of dimethylformamide, is sucked off and washed with 20 cm3ethanol at about the 75oC. Obtain 1.2 g of 8-/3-amino-3-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 345oC.

3-Amino-3-methyl-azetidin as dimethanesulfonate with so pl. 204 - 206oC get the conditions described in European patent application N406112.

Example 17.

8-/3-Amino-3-methyl-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

oC, then for 1.5 h at a temperature of approximately 90oC. the Insoluble portion of the reaction mixture is sucked off at about the 20oC, washed 2 times with 20 cm3water, recrystallized from 70 cm3of dimethylformamide, washed with 40 cm3ethanol at about the 75oC. Obtain 1.45 g of 8-/3-amino-3-methyl-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 334oC.

Example 18.

8-/3-Amino-3-methyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid.

Get in the conditions of example 16, but based on 1,58 g 1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2,22 g 3-amino-3-methyl-azetidin-dimethanesulfonate. Obtain 1.7 g of 8-/3-amino-3-methyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo - 1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 298oC.

1-Cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the following conditions.

Suspension with 8.05 g of 1-cyclopropyl-3-ethoxycarbonyl who you and 80 cm3acetic acid is heated under stirring at a temperature of about 100oC for 2 h, After cooling to about 20oC the product is sucked off and washed with 3 times 100 cm3water. Obtain 6.25 g of 1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in the form of a solid pale yellow color decomposing at 283oC, which is used without any further purification for the subsequent steps.

Example 19.

[R, S] -8-/3-Amino-2,2-dimethyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4 - dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions described in example 15, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and of 2.33 g of 3-amino-2,2-dimethyl-azetidin-dimethanesulfonate. The reaction mixture is heated under stirring for 5 h at about 100oC. Obtain 0.6 g of [R,S]-8-/3-amino-2,2-dimethyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 285oC.

3-Amino-2,2-dimethyl-1-azetidine-dimethanesulfonate get in a solid white color with so pl. 125 - 130oC from 3-amino-2,2-dimethyl-azetidin Teal-8-/3-methyl-3-methylamino-1-azetidine/-4-oxo-1,4 - dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in terms described in example 15, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and of 2.34 g of 3-methyl-3-methylamino-azetidin-dimethanesulfonate. The reaction mixture is heated for 1.5 h at about 90oC. Obtain 1.12 g of 7-fluoro-1-methyl-8-/3-methyl-3-methylamino-1-azetidine/-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color, decomposing at about 336oC.

3-Methyl-3-methylamino-azetidin as dimethanesulfonate /so pl. 135oC/ receive under the conditions described in European patent application N406112.

Example 21.

1-Cyclopropyl-7-fluoro-8-/3-methyl-3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but based on 1,58 g of 7,8-debtor-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and of 2.34 g of 3-methyl-3-methylamino-azetidin-dimethanesulfonate. Gain of 1.57 g of 1-cyclopropyl-7-fluoro-8-/3-methyl-3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 330oC.

Example 22.

1-Ethyl-7-fluoro-8-/3-methyl-3-methylamino-1-azetidine/-4-ACOR-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and of 2.34 g of 3-methyl-3-methylamino-azetidin-dimethanesulfonate. Obtain 1.18 g of 1-ethyl-7-fluoro-8-/3-methyl-3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 338oC.

Example 23.

8-/3-Amino-3-methyl-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but based on 1,53 g of 7,8-debtor-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2,22 g 3-amino-3-methyl-azetidin-dimethanesulfonate. Obtain 1.27 g of 8-/3-amino-3-methyl-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro - 1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 346oC.

7,8-Debtor-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions described in U.S. patent N4970213.

Example 24.

1-Cyclopropyl-7-fluoro-8-/3-methyl-3-dimethylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but based on 1,58 g 1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2.45 g of 3-methyl-3-dimethylamino-azetidin-dimethanesulfonate. Obtain 1.55 g of 1-cyclopropyl-7-fluoro-8-/3-methyl-3-dimethylamino-1-Astragalus at 268oC.

3-Methyl-3-dimethylamino-azetidin as dimethanesulfonate with so pl. 148oC get the conditions described in European patent application N406112.

Example 25.

7-Fluoro-1-methyl-8-/3-methyl-3-dimethylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2.45 g of 3-methyl-3-dimethylamino-azetidin-dimethanesulfonate. Obtain 1.56 g of 7-fluoro-1-methyl-8-/3-methyl-3-dimethylamino - 1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 274oC.

Example 26.

8-/3-Amino-3-methyl-1-azetidine/-7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the following conditions.

To a solution of 0.68 g of ateleta sodium 7 cm3ethanol added to 1.33 g of 3-amino-3-methyl-azetidin-dimethanesulfonate. After adding 20 cm3the dimethyl sulfoxide solution is stirred for about 10 min at 20oC. At the same temperature, add 0.75 g 7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and AC is t 2 times in 20 cm3water and 2 times with 20 cm3the ethanol. After recrystallization from 70 cm3of dimethylformamide obtain 0.45 g of 8-/3-amino-3-methyl-1-azetidine/-7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 359oC.

7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained as follows.

A suspension of 0.88 g of 3-etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine in a mixture of 10 cm3of 17.5% hydrochloric acid and 10 cm3acetic acid is heated under stirring at a temperature of about 100oC for 3 hours After cooling to about 20oC the product is sucked off and washed 3 times in 10 cm3water. Obtain 0.75 g 7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in the form of a solid pale yellow color decomposing at 152oC, which is used without any other purification in the subsequent stages.

3-Etoxycarbonyl-7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions described in U.S. patent N4970213.

Example 27.

8-/3-Cyclopropylamino-3-methyl-1-RA 15, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2.5 g of 3-cyclopropylamino-3-methyl-azetidin-dimethanesulfonate. Obtain 1.73 g of 8-/3-cyclopropylamino-3-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid solvated with 0.7% of water, in the form of a solid yellow color decomposing at 300oC.

3 Cyclopropylamino-3-methyl-azetidin-dimethanesulfonate obtained as follows.

14.5 g of 1-Benzhydryl-3-cyclopropylamino-3-methyl-azetidine 150 cm3methanol hydronaut at atmospheric pressure, at a temperature of about 20oC for 1 h in the presence of 5.6 g of 20% palladium hydroxide-on-charcoal grill. To the reaction mixture are added 10 g of methansulfonate. After removal of the catalyst by filtration, concentration to dryness under reduced pressure (20 kPa) and about 40oC the residue is washed 3 times with 150 cm3diethyl ether. The final residue is treated with 100 cm3propane-2-ol, sucked off, washed 7 times 50 cm3the acetone. Gain of 9.1 g of 3-cyclopropyl-amino-3-methyl-azetidin - dimethanesulfonate in the form of a colorless solid substance with so pl. 136oC.

1 Benzylethanolamine-3-methyl-azetidine and 28,84 g cyclopropylamine 250 cm3ethanol is stirred for 96 h at about 20oC. the Reaction mixture was concentrated under reduced pressure (20 kPa) at a temperature of about 30oC. the Dry extract is treated with 50 cm3water and 8.8 g of methansulfonate; the aqueous phase is washed with 3 times 25 cm3dichloromethane, to which was added 12 cm3aqueous 5% sodium hydroxide solution, and extracted with 3 times 50 cm3the ethyl acetate. The combined organic phases are washed with 2 times 50 cm3water, dried over magnesium sulfate, concentrated to dryness under reduced pressure (20 kPa) at a temperature of approximately 25oC. Obtain 14.6 g of 1-benzhydryl-3-cyclopropylamino-3-methyl-azetidine in the form of a yellow oil, which was used without any further purification for the subsequent steps.

1-Benzhydryl-3-methanesulfonate-3-methyl-azetidin receive according to the conditions described in European patent application N406112.

Example 28.

8-/3-Ethylamino-3-methyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but on the basis of 1.45 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2.24 g of 3-ethylamino-3-methyl-azetidin-diedin-3-carboxylic acid in a solid yellow color, decomposing at 312oC.

3 Ethylamino-3-methyl-azetidin-dimethanesulfonate receive under the conditions described in example 27, but on the basis of 14 g of 1-benzhydryl-3-ethylamino-3-methyl-azetidine. Obtain 9.7 g of 3-ethylamino-3-methyl-azetidin-dimethanesulfonate in the form of a colourless solid with so pl. 140oC.

1-Benzhydryl-3-ethylamino-3-methyl-azetidin receive under the conditions described in example 27, but on the basis of 16.6 g of 1-benzhydryl-3-methanesulfonate-3-methyl-azetidine and 45 g of ethylamine. Get 14 g of 1-benzhydryl-3-ethylamino-3-methyl-azetidine in the form of a yellow oil, which was used without any further purification in the subsequent stages.

Example 29.

7-Fluoro-8-/3-methylamino-1-azetidine/-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 2, but from 2.6 g of 3-etoxycarbonyl-7-fluoro-1-methoxy-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8 - benzo/b/naphthiridine. Obtain 1.7 g of 7-fluoro-8-/3-methylamino-1-azetidine/-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 255 - 260oC.

3-Etoxycarbonyl-7-fluoro-1-methoxy-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/billaut 2.8 g of 3-methylamino-azetidin-dichlorhydrate. After stirring for 15 min at a temperature of about 20oC and removal of inorganic salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 30oC. the Residue is dissolved in 40 cm3dimethyl sulfoxide and the solution was added 2.7 g of 3-etoxycarbonyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. The reaction mixture is heated for 1.5 h at about 60oC. Obtain 2.7 g of 3-etoxycarbonyl-7-fluoro-8-/3-methylamino-1-azetidine/-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine in the form of a yellow solid with so pl. 234oC.

3-Methylamino-azetidin-dichlorhydrate receive under the conditions described in example 9, but according to 32.2 g of 1-benzhydryl-3-methylamino-azetidine. Get to 19.1 g of 3-methylamino-azetidin-dichlorhydrate in the form of a colourless solid with so square 138 - 140oC.

Benzhydryl-3-methylamino-azetidin receive under the conditions of example 9, but based on 50 g of 1-benzhydryl-3-methanesulfonate-azetidine and for 48.9 g of methylamine in 250 cm3of methanol. Obtain 27 g of 1-banggitin-3-methylamino-azetidine in the form of a colourless solid with so pl. 75oC.

Example 30.

1-Cyclopropyl-7-fluoro-8-/3-methylamino-1-azet 1.5 g 1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 1.13 g of 3-methylamino-azetidin-dichlorhydrate. The reaction mixture was stirred for 1 h at 40oC. Receive 1 g of 1-cyclopropyl-7-fluoro-8-/3-methylamino-1-azetidine/-4-oxo-1,4 - dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in the form of solid yellow, decaying at 262oC.

Example 31.

7,9-Debtor-1-methyl-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 30, but on the basis of 1.5 g 7,8,9-Cryptor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 1.2 g of 3-methylamino-azetidin-dichlorhydrate. Obtain 1.54 g of 7,9-debtor-1-methyl-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in the form of hard yellow substance, decomposing at 302oC.

Example 32.

8-/3-Amino-3-ethyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 15, but on the basis of 1.66 g of 7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 3.1 g of 3-amino-3-utilisation-dimethanesulfonate. Get 1,46 g 8-/3-amino-3-ethyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color, decomposing p the least 15 to obtain 3-amino-3-propyl-azetidin-dimethanesulfonate: 5.7 g of 3-amino-3-ethyl-azetidin-dimethanesulfonate obtained as colorless solids with so pl. 184oC by hydrogenation of 6 g of 3-amino-1-benzhydryl-3-ethyl-azetidine.

of 13.6 g of 3-Amino-1-benzhydryl-3-ethyl-azetidine receive in the form of a yellow oil, according to 24.6 g of 1-benzhydryl-3-ethyl-3-methanesulfonate-azetidine in the form of a solution in 174 cm3a 15% solution of ammonia in ethanol. The selected product is used without any other purification in the subsequent stages.

of 24.6 g of 1-Benzhydryl-3-ethyl-methanesulfonate-azetidine get in a solid yellow color with so pl. 68oC, on the basis of 35.5 g of 1-benzhydryl-3-hydroxy-3-ethyl-azetidine.

35.5 g of 1-Benzhydryl-3-hydroxy-3-ethyl-azetidine receive in the form of a yellow oil, on the basis of 44 g of 1-benzhydryl-3-oxo-azetidine and 80 cm3ethylacetamide concentration 399 grams per liter in the air.

Example 33.

Methanesulfonate 8-/3-amino-3-ethyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo - 1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid get in the conditions of example 15, but on the basis of 1.8 g of 7,8-debtor-1-cyclopropyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid and 2.94 g of 3-amino-3-ethyl-azetidin - dimethanesulfonate. After recrystallization from dimethylformamide to the obtained product, suspended in 20 cm3ethanol, add 3.4 with theoC, cooled to a temperature of about 20oC, sucked off and washed precipitate 3 times in 10 cm3the ethanol. Obtain 0.55 g of methansulfonate 8-/3-amino-3-ethyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo - 1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid in a solid yellow color decomposing at 248oC.

Example 34.

7-Fluoro-1-methyl-8-[3-/1-pyrrolidinyl/-1-azetidine] -4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 2, but from 1.2 g of 3-etoxycarbonyl-7-fluoro-1-methyl-8-[3-/1-pyrrolidinyl/-1-azetidine] -4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 0.7 g of 7-fluoro-1-methyl-8-[3-/1-pyrrolidinyl/-1-azetidine] -4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid as yellow solid with so pl. 302oC.

3-Etoxycarbonyl-7-fluoro-1-methyl-8-[3-/1-pyrrolidinyl/-1-azetidine] -4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions of example 2, but from 1.6 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.5 g 3-/1-pyrrolidinyl/-azetidin-dichlorhydrate. The reaction mixture was stirred for 24 h at a temperature of approximately 95oC. Obtain 1.3 g of 3-etoxycarbonyl-7-fluoro-1-methyl-8-[3-/1-pyrrolidinyl/-1-azetidine] -4 is leinil/-azetidin receive in the form of dichlorhydrate with so pl. 195oC under the conditions described in the patent application of Japan N74109369.

Example 35.

8-/3-Cyclopropylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid is obtained in the conditions of example 2, but from 1.3 g of 8-/3-cyclopropylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine. Obtain 0.8 g of 8-/3-cyclopropylamino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/ naphthiridine-3-carboxylic acid as a yellow solid, decomposing at 272oC.

8-/3-Cyclopropylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine receive under the conditions of example 15, but on the basis of 1.45 g of 3-etoxycarbonyl-7,8-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine and 1.7 g of 3-cyclopropylamino-azetidin-dichlorhydrate. Obtain 1.35 g of 8-/3-cyclopropylamino-1-azetidine/-3-etoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine in the form of a yellow solid with so pl. 221oC, then 245oC.

3 Cyclopropylamino-azetidin-dichlorhydrate receive under the conditions described in example 9, to obtain 3-ethylamino-azetidine-dichlorhydrate, but on the basis of the 5.4 g of 1-benzhydryl-3-cyclopropylamino-the substance with so pl. 140oC.

1-Benzhydryl-3-cyclopropylamino-azetidin-dichlorhydrate receive under the conditions described in example 9, to obtain 1-benzhydryl-3-ethylamino-azetidine-dichlorhydrate, but on the basis of 15 g of 1-benzhydryl-3-methanesulfonate-azetidine and 8.2 g of cyclopropylamine. Gain of 5.4 g of 1-benzhydryl-3-cyclopropylamino-azetidin-dichlorhydrate in the form of a colorless solid substance, so pl. 182oC.

Example 36.

Working as described in the previous examples, you receive the following products:

- 7-fluoro-1-methyl-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-/2-amino-ethyl/amino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-8-/3-/2-hydroxy-ethyl/amino-1-azetidine/-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-methyl-4-oxo-8-/3-/1-piperazinil/-1-azetidine/-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-/4-/2-amino-ethyl/phenyl/-amino-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-DL-7-fluoro-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-/2-amino-ethyl/-amino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-ethyl-7-fluoro-8-/3-/2-hydroxy-ethyl/-amino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-ethyl-7-fluoro-4-oxo-8-/3-/1-piperazinil/-1-azetidine/-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/-phenyl} -amino-1-azetidine]-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-8-/3-ethylamino-1-azetidine/-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine]-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-7-fluoro-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine]-4-oxo-1,4 PRS-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-7-fluoro-4-oxo-8-/3-/1-piperazinil/-1-azetidine/-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/phenyl} -amino-1-azetidine] -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-methylamino-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/amino-1-azetidine] -7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-methylamino-4-oxo-8-[3-/1-piperazinil/-1-azetidine]-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{4-/2-amino-e is
- 8-/3-amino-3-phenyl-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-methyl-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-/2-foradil/-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-/2-fluoro-ethyl/-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine]-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-1-/2-fluoro-ethyl/-4-oxo-8-[3-/1-piperazinil/-1-azetidine] -1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{4-/2-amino-ethyl/-phenyl}-amino-1-azetidine]-7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-AZE-1-azetidine/-7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7-fluoro-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-8-/3-methylamino-1-azetidine/-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7-fluoro-4-oxo-1-tert.butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7-fluoro-4-oxo-1-tert.butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -4-oxo-1-tert. butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-4-oxo-8-[3-/1-piperazinil/-1-azetidine]-1-tert.-butyl - 1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/-phenyl} -amino-1-azetidine]-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-methyl-1-azetidine/-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-timeteller-8-/3-ethylamino-1-azetidine/-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-methyl-4-oxo-8-[3-/1-piperazinil/-1-azetidine]-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/-phenyl} -amino-1-azetidine] -7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7,9-debtor-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-ethyl-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-ethyl-8-[3-/2-hydroxy-ethyl/-amidine/-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-ethyl--4-oxo-8-[3-/1-piperazinil/-1-azetidine]-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{4-/2-amino-ethyl/-phenyl}-amino-1-azetidine]-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-methyl-1-azetidine/-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7,9-debtor-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-7,9-debtor-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-8-/3-ethylamino-1-azetidine/-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-7,9-debtor-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine]-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-8-/3-cyclopropylamino-1-azetidine/-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 1-cyclopropyl-7,-/2-amino-ethyl/-phenyl}-amino-1-azetidine]-1-cyclopropyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-1-cyclopropyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/amino-3-methyl-1-azetidine/-1-cyclopropyl-7,9-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-1-cyclopropyl-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-methylamino-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7,9-debtor-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7,9-debtor-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7,9-debtor-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-methylamino-4-oxo-8-[3-/1-piperazinil/-1-azetidine] -1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/-phenyl} -amino-1-azetidine] -7,9-debtor-1-methyl-amino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-Churbanova acid;

- 8-/3-amino-3-methyl-1-azetidine/-7,9-debtor-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7,9-debtor-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-/2-fluoro-ethyl/-8-/3-methylamino-1-azetidine/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-8-/3-ethylamino-1-azetidine/-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine] -7,9-debtor-1-/2-fluoro-ethyl/- 4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-/2-fluoro-ethyl/-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine/-7,9-debtor-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-1-/2-fluoro-ethyl/-4-oxo-8-[3-/1-piperazinil/-1-azetidine] -1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4-/2-amino-ethyl/-phenyl} -amino-1-azetidine]-7,9-debtor-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/1-amino-3-phenyl-1-azetidine/-7,9-debtor-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carbon is carboxylic acid;

- 8-/3-amino-2-dimethylamino-1-azetidine/-7,9-debtor-1-/2-fluoro-ethyl/-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7-fluoro-8-/3-methylamino-1-azetidine/-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3 - carboxylic acid;

- 8-/3-ethylamino-1-azetidine/-7-fluoro-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-/2-amino-ethyl/-amino-1-azetidine]-7,9-debtor-4-oxo-1-tert.-butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-8-[3-/2-hydroxy-ethyl/-amino-1-azetidine] -4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-cyclopropylamino-1-azetidine]-7,9-debtor-4-oxo-1-tert.-butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 7,9-debtor-4-oxo-8-[3-/1-piperazinil/-1-azetidine]- 1-tert.-butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-[3-{ 4/2-amino-ethyl/-phenyl}-amino-1-azetidine]-7,8-debtor-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-phenyl-1-azetidine/-7,9-debtor-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-amino-3-methyl-1-azetidine/-7,9-debtor-4-oxo-1-tert. -butyl-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid;

- 8-/3-lot.

The present invention also relates to pharmaceutical compositions used in human medicine or veterinary medicine, which contain as the active product, at least one product of General formula (I) in a pure state (in free form or in salt form) or in Association with one or more compatible and pharmaceutically acceptable diluents or auxiliary means. These compositions can be administered orally, parenterally or rectally.

As solid compositions for administration orally, you can use a tablet, gelatin capsule (medicine), pills, powders or granules. In these compositions, the active product according to the invention can be mixed with one or more inert diluents or auxiliary means, such as sucrose, lactose or starch. These compositions can also include other than the diluents, substance, for example a lubricant such as magnesium stearate.

As liquid compositions for administration orally can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents, such as water or paraffin oil. These communityradio substances.

Compositions for parenteral administration can be a sterile, aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or excipient you can use propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and a complex organic esters for injection, for example etiloleat. These compositions can also contain auxiliary funds, in particular wetting, emulsifying agents, dispersing agents or isotonic means. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating in the composition of sterilizing agents, by irradiation or heating. The composition can also be prepared in the form of sterile solid compositions which dissolve at the time of use in sterile water or any other sterile environment for injection.

Compositions for rectal (intestinal) introduction are candles or rectal capsules, which can contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

In the treatment of human or veterinary compositions according to the invention is particularly suitable for the treatment of infections tank is testwuide way depending on age, weight, extent of injury infection and other factors inherent to the object, which should be treated. Usually doses include 0.2 to 1 g of active start to receive twice daily, orally or parenterally to an adult.

The following example is given as a non limiting the scope of protection of the invention, illustrates a composition according to the invention.

Example.

According to the usual methods of work to prepare tablets with 250 mg of active beginning, which have the following composition:

- 8-/3-amino-1-azetidine/-1-cyclopropyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo/b/naphthiridine-3-carboxylic acid 250 mg

- starch 50 mg

- lactose - 35 mg

- talc - 15 mg

The products of General formula (I) are also of interest in the field of chemistry for antibacterial treatment plants. There is a view that composition for agrochemical use, including the product of General formula (I), are also included in the scope of the present invention.

In addition, the products of General formula (I) can also be used as a preservative or disinfectant organic and inorganic materials agents, especially in industry for the production of dyes, fats; in the paper, AI; in the food industry or water treatment. Also it should be clear that the composition comprising the product of General formula (I) in the pure state or in Association with an acceptable diluents or auxiliary means are also included in the scope of the present invention.

The bacteriostatic activity in vitro

The bacteriostatic activity of compounds is determined according to the standard of the USA (the Study of antimicrobial susceptibility: methods of test antimicrobial susceptibility by dilution for aerobic bacteria. 1992. The state Committee for clinical laboratory standards (1992 National commitee for clinical Laboratory Standards, M7-A2, Villanova, PA).

After two dilutions checked antibacterial solution with a concentration of 1280 mg/l is added to the molten agar Mueller-Hinton (Mueller-Hinton), optionally containing 25 mg/l of Mg++and 50 mg/l of Ca++(1 part antibacterial solution to 9 parts of liquid agar), then pour mixture into cups. To be applied on the agar spots about 104colony forming units (CFU) of each tested strain using multipoint dry inoculant. After inoculation Cup incubated for 18 h at 37

Antibacterial activity in vivo model of staphylococcus aureus sepsis in mice

Mice vaccinated intraperitoneally with 0.5 ml of bacterial strains cultured with shaking in the injector for the brain and heart (Brain Heart Infusion) at 37oC and diluted to 7.5% pig mucin thus, in order to obtain approximately 106CFU/ml Under these conditions, infected control animals die within 24 - 48 hours

Check connections injected orally twice a day of infection, the first dose given within one hour after infection, and the second dose after 2 h after infection. The filler is an aqueous solution or suspension in sterile distilled water to which was added 0.1% Polysorbate 80. Injected volume is 1 ml per mouse for each injection. Apply 4 to 6 doses up to 150 mg/kg

50% effective dose (ED50), calculated after 7 days after infection, defined as the dose which protects 50% of infected and treated mice, when all infected or treated control animals die. The invention is illustrated by table.

1. Derivatives of 1,8-benzo/b/naphthiridine3WITH6- cycloalkylcarbonyl;

R1and R2identical or different, are respectively in position 2 and 3 represent a hydrogen atom or an alkyl radical;

R3alkyl radical, WITH3WITH6-cycloalkenyl radical, alkoxy - or acylaminoalkyl;

R4a hydrogen atom or a fluorine atom,

moreover, these alkyl radicals are linear or branched and contain 1 to 4 carbon atoms, in the form of stereoisomers or racemic mixtures and their salts with metals, nitrogen-containing organic bases or acids, and their hydrates.

2. A method of obtaining a connection on p. 1, characterized in that the derivative of azetidine General formula II

< / BR>
in which R, R1and R2are specified in paragraph 1 values, enter into interaction with a derivative of 1,8-benzo/b/naphthiridine General formula III

< / BR>
in which R3and R4are specified in paragraph 1 of meanings and Hal is fluorine atom, chlorine or bromine, provided that R4a hydrogen atom or Hal and R4at the same time means a fluorine atom, and optionally the obtained target product is converted into its salts with metals, nitrogen-containing organic bases or acids.

3. A method of obtaining a connection is specified in paragraph 1 values;

R is specified in paragraph 1 value or means secured aminoacyl;

R3has specified in paragraph (1 value or means secured acylaminoalkyl;

Alk is linear or branched C1WITH4is an alkyl radical,

converted into the corresponding acid without affecting the rest of the molecule, and, if necessary, removing the protective group of acylaminoalkyl and/or obtained target product was transferred to its salts with metals, nitrogen-containing organic bases or acids.

4. Pharmaceutical composition having antibacterial activity and containing the active principle on the basis of the derived azetidine and the target inert additives, characterized in that the active agent composition contains at least one compound of General formula I, as described in paragraph 1, in the form of stereoisomers or racemic mixture or pharmaceutically acceptable salt, or hydrate in an effective dose.

 

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3 ex

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