SK37394A3 - 1,8-benzonaphthyridine derivatives, method of their preparation and compositions containing these derivatives - Google Patents

Abstract

New 1,8-benzo[b]naphthyridine derivative of general formula: <IMAGE> in which R is H or a hydroxyl, amino or alkylamino radical, the alkylamino radical optionally being substituted with amino or hydroxyl, or R is dialkylamino in which the alkyl parts may form, with the nitrogen atom, a 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen or sulphur, or R is cycloalkylamino (3 to 6C), or an alkanoylamino, N-alkyl-N-alkanoylamino or aminoalkylphenylamino radical, R1 and R2, which are identical or different, are in position 2 and 3 and represent H, alkyl, alkenyl (2 to 4C), phenyl or substituted phenyl, or else R1 and R2 are in position 2 and represent alkyl, R3 is H or alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl containing 3 to 6 carbon atoms, fluorophenyl, difluorophenyl, alkyloxy or alkylamino, and R4 is H or F, the alkyl and alkanoyl (1 to 4C) radicals being straight or branched, in its stereoisomeric forms or their mixtures as well as its salts and its hydrated forms. These new derivatives are useful as antimicrobial agents.

Description

It has now been found that compounds of formula T

Ii

Ktorom in which

R represents a hydrogen atom or a hydroxy group, an amino group, an alkylamine group whose alkyl radical is optionally substituted by an amino group or a hydroxy group, or represents a dialkylamino group whose alkyl radicals may optionally form a heterocyclic group with the nitrogen atom to which they are attached 5 or 6 members optionally containing another heteroatom selected from the group consisting of nitrogen, oxygen or sulfur, or a 3 to 6 membered cycloalkylamino group, alkanoylamino, N-alkyl-N-alkanoylamino or aminoalkylphenylamino,

Rx and R-, which are the same or different, are located at positions 2 and 2, respectively. 3 and represent a hydrogen atom, an alkyl or C 2 -C 4 alkenyl group, a phenyl group substituted with a halogen or an alkyl group, an alkyloxy group, a hydroxy group, a nitro group, an amino group, an alkylamino group, a dialkylamino group or a haloalkyl group , or R _x and R ₂ are in the 2-position and represent alkyl,

R ₃ represents a hydrogen atom, an alkyl group, a fluoroalkyl group, a carboxyalkyl group, a C 3 -C 6 cycloalkyl group, a fluorophenyl group, a difluorophenyl group, an alkyloxy group or an alkylamino group; the groups have a straight or branched carbon chain and contain 1 to 4 carbon atoms, as well as their salts and optionally their stereoisomers.

have particularly interesting antibacterial activity.

When R is a dialkylamino group, the alkyl radicals of which together with the nitrogen atom to which they are attached form a heterocyclic group, the heterocyclic group may in particular be pyrrolidinyl or piperidinyl.

The compounds of formula I may exist in hydrated form and, of course, these hydrates are within the scope of the invention.

According to the invention, the compounds of the formula I can be obtained by substituting the azetidine of the formula II

ΜΗ (II) wherein R, R ± and R; are as defined above, to 1,8-benzo (b) naphthyridine of formula III

(III) wherein R ₃ is as defined above, Hal represents a fluorine atom, a chlorine atom or a bromine atom when R ₄ represents a hydrogen atom, or also Hal and R ₄ simultaneously represent fluorine atoms.

The reaction of the azetidine derivative (II) is generally carried out in the presence of an excess of the acid acceptor derivative in conventional suitable organic solvents. The reaction may be carried out in the presence or absence of a solvent at a temperature between 20 and 150 ° C. If the reaction is carried out in the presence of a solvent, the reaction is preferably carried out in solvents such as pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile. This reaction can also be carried out in a suitable environment.

Said reaction may conveniently be carried out in the presence of an acid acceptor, such as a nitrogenous organic base (especially triethylamine), an alkali metal carbonate (e.g. sodium carbonate) or an alkali metal or alkaline earth metal hydroxide.

Of course, when R @ 1 is hydrogen or R @ 2 is amine, alkylamino optionally substituted, cycloalkylamino or aminoalkylphenylamino, it is preferred to pre-protect the starting materials with protecting groups. . The introduction of these protecting groups before the reaction and their cleavage after the reaction is carried out by known methods.

Said protection may be accomplished by using any compatible protecting group whose introduction and cleavage does not adversely affect the rest of the molecule of the protected compound. In particular, the methods described by T.W. Greene in Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981) or Mc Omie in Protective Groups in Organic Chemistry, Plenum Press (1973).

Examples of protecting groups include trimethylsilyl, benzhydryl, tetrahydropyranyl, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, and three chloroethoxy.

The 1,8-benzo [b] naphthyridine derivatives of the formula I can also be obtained according to the invention from the corresponding ester of the formula IV

C00 Alk

D in which R 1, R 2 and R 4 are as defined above, R is as defined above or is a protected amino group, R ₃ is as defined above or is a protected alkylamino group and Alk is a C 1 -C 4 alkyl group or a branched carbon chain, by any suitable method to recover the acid from the ester without disturbing the rest of the molecule.

Said preparation of the acid from the ester is usually carried out by saponification in the presence of sodium hydroxide in an aqueous or aqueous-alkaline medium and at a temperature between 20 and 100 ° C.

When the ester of formula (IV) in which R is an alkanoylamino group or an N-alkyl-N-alkanoylamino group or in which R is a protected amine group is hydrolyzed, it will be understood that depending on the reaction conditions used, wherein R represents an alkanoylamino group or an N-alkyl-N-alkanoylamino group or wherein R represents a protected amine group, or an acid, wherein amide hydrolysis has taken place simultaneously, i. an acid wherein R is an amino group. The reaction conditions are therefore selected according to the desired end product. If R is a protected amine group, it is of course advantageous to simultaneously remove the protecting group.

Where R ₃ is a protected alkylamino group, the protecting group may be any protecting group of the amine function compatible with the molecule of the protected compound. It is of course advantageous to select a protecting group which can be simultaneously cleaved during ester hydrolysis.

The 1,8-benzo (b) naphthyridine derivative of formula III can be obtained from the corresponding ester of formula V

wherein R 5, R ₄ , Hal and Alk are as defined above, using the method described in U.S. Patent 4,990,515 or a method analogous thereto.

The 1,8-benzo (b) naphthyridine ester derivative of formula V can be prepared by treatment with 3-amino-1,2,4-triazine (to give a product in which R 5 is hydrogen) or by treatment with a compound of formula VI

R5-NHa (VI) wherein R5 is alkyl, fluoroalkyl, carboxyacyl, cycloalkyl, fluorophenyl, difluorophenyl, alkyloxy or alkylamino, optionally protected, to a quinoline derivative of formula VII

P in which R 1, Hal 1 and Alk have the meanings given above, and subsequent cyclization with an acid binding agent.

Typically, the reaction of 3-amino-1,2,4-triazine or the product of formula VI with the product of formula VII is carried out in an organic solvent such as an alcohol (ethanol, methanol) or a chlorinated solvent (e.g. trichloromethane) at a temperature between 10 and 25. C.

Said cyclization is carried out in a straight-chain or branched C 1 -C 4 -alcohol at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

As the acid binding agent, a nitrogen base (e.g. triethylamine), 1,8-diazabicyclo [5.4.0] -7-undecene, or an excess of the amine used may be used.

The benzo (b) naphthyridine derivatives of the general formula III and the general formula V in which R ₃ represents a carboxyalkyl group, a fluorophenyl group or a difluorophenyl group are novel compounds. It goes without saying that these products as well as their salts, if any, are also within the scope of the invention.

The quinoline derivative of general formula (VII) may be obtained by the procedure described in U.S. Pat. No. 4,990,515.

Aminoazetidine derivatives of formula (II) prepared according to the procedures described by T. Okutani et al., 22 (7) 1490 (1974), S (1968), D. Nisato et al.

Pharm.Bul1 Comn., 93

Chatterjee et al. in J. Heterocyclic may be in Chem.

in Chem.

. Chem.

22, 961 (1985); Akira Morimoto et al., In Chem. 21 (1), 228 (1973); Anderson et al., J. Org. 37, 3753 (1972), V.R. Gaertner in J. Org. 2972 (1967), J.N. Wells et al. in J. Org. Chem., 34, 1477 (1969), J. Antibiotics, 39 (9), 1243

Q (1986) and J.Pharm. , 60 (1), 156 (1971) or described in patents EP 406 112, EP 314 362, EP 106 489, EP 324 298, JP 74 109 369 (CA83-9760 (1975)) and US 4,834,846 or methods which are analogous to these procedures.

3-Amino-3-phenylazetidine can be obtained by reduction of the corresponding 2-azetidinone according to the method described in J. Pharm. Sci., 60.5 (1971). 3-Amino-3-phenyl-2-azetidinone was prepared by a procedure analogous to that described in J. Am. Chem. Soc., 111, 1073 (1989) and then release of the amine function.

The 1,8-3-benzo (b) naphthyridine derivative of formula (IV) may be obtained from the benzo (b) naphthyridine of formula (V) by substituting the azetidine derivative of formula (II).

Preferably, the reaction is carried out under the conditions previously described for obtaining the product of formula II from azetidine of formula II and 1,8-benzo [b] naphthyridine of formula III. It goes without saying that, in an alternative aqueous method, a product of formula (I) can be obtained directly without isolating the derivative of formula (IV) in an intermediate step.

If it is desired to obtain, within the scope of the invention, stereoisomers of the benzonaphthyridine derivatives of formula (I), then the stereoisomeric forms of the azetidines of formula (II) are separated by any known method compatible with the molecule of the compound whose diastereoisomeric forms are separated. Examples of such separation include separation by acylation using a chiral acid or a reactive derivative of a chiral acid, separation of isomers by high pressure liquid chromatography, followed by deacylation according to the procedure described by P.G. Gaseman et al. in J.Am.Chem.Soc. 98 (5), 1275 (1976). Said separation of stereoisomers can also be carried out by high-pressure liquid chromatography on a chiral phase.

The novel products of the invention, as well as intermediates thereof, can optionally be purified by conventional physical methods such as crystallization or chromatography.

The products of the invention, their intermediates of formula III and optionally their intermediates of formula V can be converted into metal salts or addition salts with nitrogenous bases by known methods. These salts can be obtained by treating a compound of the invention in a suitable solvent such as an alcohol, an ether or water, or by exchanging it with an organic acid salt, by treating a compound of the invention with bases derived from metals (e.g. alkali or alkaline earth metals), ammonia or amine. The salt formed, which, upon possible concentration of its solution, precipitates, is separated by filtration, decantation or lyophilization.

The novel compounds of the invention can be converted into acid addition salts. The products of formula (I) obtained in the form of these salts can be released and converted into salts of other acids by conventional methods.

Examples of pharmaceutically acceptable salts include alkali metal salts (sodium, potassium, lithium) or alkaline earth metal salts (magnesium, calcium), ammonium salt, nitrogen base salts (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine , diisopropylamine, N, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, Ν, Ν'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, nibenzylamine, dibenzylamine hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or with organic acids (succinates, fumarates, maleates, methanesulfonates, p-toluenesulfonates and isethionates).

XI

The novel 1,8-benzo (b) naphthyridine derivatives of the formula I according to the invention and their pharmaceutically acceptable salts have particularly interesting antibacterial properties. They have remarkable in vitro and in vivo efficacy on gram-positive germs and, overall, on germs responsible for most upper and lower respiratory tract infections. In addition, the novel 1,8-benzo (b) naphthyridine derivatives of the formula I have particularly interesting antibacterial activity on gram-negative germs.

The products of formula (I) have been shown to be effective in vitro against Staphylococcus aureus IP 8203 at a concentration between 0.06 and 4 μς / cm ³ and against the NIHJ JC2 strain Escherichia coli at a concentration between 0.25 and 20 pg / cm ³ .

In vitro, the products of formula I have been shown to be effective against experimental infections of mice with Staphylococcus aureus IP 8203 at oral doses between 2 and 200 mg / kg.

In addition, it has been shown that some of the products of the invention are of particular interest at the level of mycoplasma. Their minimum inhibitory concentration is 0.03 to 8 pg / ml.

Finally, it has been found that the products of the invention have no toxicity at pharmacologically usable doses. They are usually atoxic at an oral dose in mice of 500 mg / kg.

In the following, the invention will be further elucidated by means of exemplary embodiments, which, however, are illustrative only and are not intended to limit the scope of the invention, which is clearly defined by the terms of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

8- (3-Amino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

A suspension of 1,16 g of 7,3-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 1.38 g of 3-aminoazetidine in 15 cm ³ of dimethyl sulfoxide was heated to 96 ° C with stirring for δ hours. After cooling to about 20 DEG C., 100 cm @ ^{3 of} water are added to the reaction mixture. The insoluble matter is centrifuged, washed three times with 20 cm @ ³ and taken up with 100 cm @ ^{3 of} water, then 4 cm @ ³ of methanesulfonic acid are added to the mixture obtained. After separating the light insoluble matter by filtration through diatomaceous earth and adding 4 cm @ ^{3 of a} 1N aqueous sodium hydroxide solution, the suspension obtained is concentrated under reduced pressure (20 kPa) at a temperature close to 60 DEG C. to a volume of about 80 cm @ ³ . The insoluble matter is centrifuged, washed with 100 cm @ ^{3 of} water, 100 cm @ ^{3 of} ethanol and recrystallized from 150 cm @ ^{3 of} dimethylformamide. 0.7 g of 3- (3-amino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained. j in the form of a yellow solid which decomposes at 358 ° C,

7,8-Difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared according to the procedure described in U.S. Patent 4,990,515.

3-Aminoazetidine was prepared as described by Dino Nasato et al. in J.Het.Chem. 22,961 (1985).

Example 2

8- (3-Dimethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

Suspension 1.9 g of 3- (3-dimethylamino-1-azetidinyl) -3-ethoxy-13-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo (b) Naphthyridine in 20 cm @ ^{3 of} ethanol and 19 cm @ ^{3 of a} 0.5N aqueous potassium hydroxide solution are stirred and heated to a temperature in the region of 80 DEG C. for 5 hours. After cooling to about 5 ° C, 9.5 cm ^{3 of a} 1N aqueous methanesulfonic acid solution are added to the reaction mixture. The insoluble matter is centrifuged, washed twice with 10 cm @ ^{3 of} water, washed three times with 25 cm @ ^{3 of} ethanol and recrystallized from 125 cm @ ^{3 of} dimethylformamide. 1.4 g of 8- (3-dimethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3- are obtained. of carboxylic acid as a yellow solid which decomposes at 312 ° C.

8- (3-Dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared by the following: way.

A suspension of 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine, 1.2 g of 3-dimethylaminoazetidine dihydrochloride and 1.5 g of carbonate of sodium sulfide in 30 cm @ ^{3 of} dimethylsulfoxide is heated with stirring to a temperature in the region of 95 DEG C. for 5 hours. After cooling to about 20 ° C, 60 cm ^{3 of} water are added to the reaction mixture. The insoluble matter is centrifuged and washed 3 times with 20 cm @ ^{3 of} water. 2 g of 8- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. as a yellow solid, m.p. 224 DEG C., which was used without further purification in the next reaction steps.

3-Sthoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as described in U.S. Patent 4,970,213.

Example 3

8- (3-Amino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-di-14-hydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

The reaction conditions are as described in Example 2, but starting from 0.72 g of 3- (3-amino-1-azetidinyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4 dihydro-1,8-benzo [b] naphthyridine. Without recrystallization, 0.6 g of 8- (3-amino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridio] - was obtained without recrystallization. 3-carboxylic acid is in the form of the monohydrate as a yellow solid which decomposes at 306 ° C.

8- (3-Amino-1-azetidinyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the conditions described in of Example 2, but starting from 1.7 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.62 g of 3- aminoazetidíndimetánsulfonátu. The crude product is taken up in 100 cm ^{3 of} dimethylformamide and stirred at about 150 ° C for 10 minutes. After cooling to about 20 ° C, the insoluble material was collected by filtration. The filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 60 C. ^The residue was recrystallized chews of 50 cm ³ of ethanol. 0.72 g of 8- (3-amino-1-azetidinyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. m.p. 255-156 ° C.

3-Ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as described in U.S. Patent 4,970,213.

Example 4

8- (3-Dimethylamino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

The reaction conditions are as described in Example 2, but starting from 2 g of 8- (3-dimethylamino-1-azet 15-ynyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo 1,4-dihydro-1,8-benzo [b] naphthyridine. 1.68 g of 8- (3-dimethylamino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3 are obtained. -carboxylic acid in the form of a solid sewn product which decomposes at 278 ° C.

- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the reaction conditions described in Example 2, starting from 1.7 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.3 g of 3-dimethylaminoazetidine dihydrochioride . After the reaction, the reaction mixture is cooled to about 20 DEG C. and then poured into 50 cm @ ^{3 of} water, then extracted 3 times with 100 cm @ ^{3 of} dichloromethane. The combined organic extracts are washed three times with 150 cm @ ^{3 of} water and dried over magnesium sulphate. After concentration to dryness under reduced pressure (20 kPa) at a temperature of about 40 ° C, the residue is taken up in 50 cm ^{3 of} diethyl ether, filtered and washed twice with 50 cm ^{3 of} the same solvent. 2 g of 8- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in this manner. as a yellow solid, m.p. 232 DEG C., which is used as is in the following stages.

Example 5

8- (3-Amino-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

Using the reaction conditions described in Example 2, starting from 1 g of 8- (3-amino-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4 -dihydro-1,8-benzo [b] naphthyridine. 0.56 g of S- (3-amino-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,3-benzo [b] was obtained. naphthyl di-3-carboxylic acid in the form of a semihydrate such as

A solid product, which decomposes at 298 to 303 ° C.

8- (3-Amino-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the reaction conditions described in Example 2, starting from 1.7 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.88 g of 3- aminoazetidine dimethanesulfonate. Single recrystallization from 50 cm ^{3 of} ethanol yields 8- (3-amino-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo]. b) naphthyridine as a sewn solid, m.p. 178-180 ° C.

1-Cyclopropyl-3-ethoxycarbonyl-7, 5-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as described in U.S. Pat. No. 4,970,213.

Example 6

1-Cyclopropyl-8- (3-dimethylamino-1-azetidinyl) -7-fluoro acid

4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-carboxylic acid

Using the reaction conditions described in Example 4, starting from 1.27 g of 1-cyclopropyl-8 (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1,

4-dihydro-l, 8-benzo / b / naphthyridine. 0.8 g of 1-cyclopropyl-8- (3-dimethylamino-1-azetidinyl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained in the form of a stitched solid. m.p.

1-Cyclopropyl-8- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine n is prepared under the reaction conditions described in Example 4, but starting from 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl.

7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.04 g of 3-dimethylaminoazetidine dihydrochloride. After concentrating the combined organic extracts to dryness, the solid residue obtained is recrystallized from 40 cm @ ^{3 of} ethanol. 1.2 g of 1-cyclopropyl-8- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a yellow solid. mp 225 ° C.

Example 7

8- (3-Amino-1-azetidinyl) -1-cyclopropyl-7,9-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

Using the reaction conditions described in Example 2, starting with 33 g of 8- (3-amino-1-azetinyl) -1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4 oxo-l, 4-dihydro-1,8-benzo / b / naphthyridine. Without recrystallization, 0.6 g of 3- (3-amino-1-azetidinyl) -1-cyclopropyl-7,9-difluoro-4-oxo-1,4-dihydro-1,8-benzo / b is obtained. The naphthyridine-3-carboxylic acid monohydrate is a yellow solid which decomposes at 308-312 ° C.

8- (3-Amino-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under conditions as described in Example 2, but starting from 1.3 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.32 g of 3-aminoazetidine dimethanesulfonate. After recrystallization from 50 cm @ ^{3 of} ethanol, 0.8 g of 8- (3-amino-1-azetinyl) -1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1 is obtained. 4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid, m.p. 236-238 ° C.

1-Cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as described in U.S. Patent 4,970,213.

Example 8

8- (3-Diethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benso [b] naphthyridine-3-carboxylic acid was prepared under the reaction conditions described in the example. 2, but starting from 1.75 g of 8- (3-diethylamino-1-azetidinyl) 3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo]; b-naphthyridine. 1.4 g of 8- (3-diethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3- are obtained. carbonyloxy in the form of a yellow solid which decomposes at 297 ° C.

8r (3-Diethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,3-benzo [b] naphthyridine was prepared under the reaction conditions described in Example 2, but starting from 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.4 g of 3-di ethylaminazetidine dihydrochloride. After recrystallization of the crude product from 500 cm @ ^{3 of} methanol, 2.07 g of 8- (3-diethylamino-1-azetidinyl) -3-ethoxycarbones of 1-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1 are obtained. 8-benzo (b) naphthyridine as a yellow solid, m.p.

2-Diethylaminoazetidine is prepared in the form of the dihydrochloride, m.p. 175 DEG C. according to the procedure described in Japanese patent 74 109 369.

Example 9

8- (3-ethylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

Using the reaction conditions described in Example 2, starting with 0.51 g of 3-ethoxycarbonyl-8- (3-ethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1, 4-dihydro-1,8-benzo / b / naphthyridine. 0.4 g of 8- (3-ethylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained. in the form of the monohydrate as a solid sewn product which decomposes at 270 ° C.

3-Ethoxycarbonyl-8- (3-ethylamino-1-azetinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared in reaction starting from 2 g 2-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.3 g 3 Lamyazetidine dihydrochloride. After adding 300 cm ^{3 of} water to the reaction mixture, the suspension obtained is extracted three times with 100 cm ^{3 of} dichloromethane. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at a temperature close to 40 ° C. The product obtained is purified by chromatography on silica gel (0.063-0.200 mm) in a dichloromethane slurry containing 1% methanol. The desired product is eluted with 500 cm @ ^{3 of} dichloromethane with 5% methanol content. 0.51 g of 3-ethoxycarbonyl-8- (3-ethyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is obtained in as a yellow solid, which decomposes at 215 ° C and is used without further purification in the following reaction steps.

3-Ethylaminoazetidine dihydrochloride can be prepared by a procedure analogous to that described by Dino Nisato et al. in J.Het.Chem. 22,961 (1985)

g of 1-benzhydryl-3-ethylaminoazetidine is hydrogenated in 50 cm @ ^{3 of} methanol at atmospheric pressure and at a temperature close to 20 DEG C. for one hour in the presence of 800 mg of 20% palladium hydroxide on carbon. After removal of the hydrogenation catalyst by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) and at about 40 ° C the residue is taken up in 30 cm ^{3 of} diethyl ether, centrifuged, washed three times with 20 cm ^{3 of} the same solvent. 2.05 g of 3-ethylaminoazetidine dihydrochloride are obtained in the form of a colorless solid, m.p. 200 DEG C., which is used as is in the following stages without purification.

1-Benzhydryl-3-ethylaminoazetidine was prepared as follows.

A mixture of 55 g of 1-benzhydryl-3-methanesulfonyloxyazetidine and 70 g of ethylamine in 400 cm @ ^{3 of} methanol is heated at a temperature of about 60 DEG C. for 16 hours. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 40 ° C and the residue is taken up in 200 cm ^{3 of} diethyl ether. The organic phase is washed with 90 cm @ ^{3 of} 2N aqueous sodium hydroxide solution and three times with 30 cm @ ^{3 of} water, dried over sodium sulphate and concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 40 ° C.

22.6 cm @ ^{3 of} 12N hydrochloric acid and the mixture are again concentrated to dryness under the preceding conditions, but at a temperature of about 70 ° C. The residue is taken up in 100 cm @ ^{3 of} ethyl acetate and 200 cm @ ^{3 of} acetone and centrifuged. 41.4 g of 1-benzhydryl-3-ethylaminoazetidine hydrochloride are obtained in the form of a colorless solid, m.p. 180 DEG C., which is used as is in the following stages.

1-Benzhydryl-3-methanesulfonyloxyazetidine was prepared as described by A. G. Anderson et al. in J.Org.Chem. 37, 3953 (1972).

Example 10

8- (3-Amino-1-azetidin-1-yl) -7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

A suspension of 1.8 g of 8- (3-acetylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-N-formyl-N-methylamino-4-oxo-1,4-dihydro-1,8benzo] b) naphthyridine in 40 cm ^{3 of} an aqueous solution of potassium hydroxide is heated under stirring to a temperature close to 100 ° C for 24 hours. After cooling to about 70 ° C, the light insoluble matter was removed by filtration. At this temperature, 40 cm @ ³ of methanesulfonic acid are added to the filtrate, the precipitate formed is filtered off by suction and washed three times with 20 cm @ ^{3 of} water at about 70 ° C. After recrystallization from 100 cm @ ^{3 of} dimethylformamide, 1.05 g of 8- (3-amino-1-azetidinyl) -7-fluoro-1-methylamino-1,4-dihydro-1,8-benzoic acid is obtained. of naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 315 to 318 ° C.

8- (3-Acetylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-N-formyl-1-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was obtained as follows.

To a mixture (about 30 ° C) of 1.13 g of 3-acetylazetidine-dihydrochloride and 0.85 g of sodium carbonate in 40 cm ^{3 of} dimethylsulfoxide is added 1.8 g of 7,8-difluoro-3-ethoxycarbonyl-N. -formyl-1H-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine, and the mixture is heated at about 80 ° C for 2 hours. After cooling to about 20 ° C, the reaction mixture is poured into 100 cm ^{3 of} water at about 5 ° C. The precipitate is centrifuged and washed three times with 50 cm @ ^{3 of} water. 2.05 g of 8- (3-acetylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-N-form of 1-1-N-methylamino-4-oxo-1,4-dihydro-1 are obtained. 8-benzo (b) naphthyridine as a yellow solid which decomposes at 305 ° C.

7,8-Difluoro-3-N-etoxykarbony1 formy1-1-N-methylamino-4-oxo-

1,4-Dihydro-1,8-benzo [b] naphthyridine was prepared as follows.

To a solution of 7.4 g of ethyl 2- (2-chloro-δ, 7-difluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate in 30 cm ^{3 of} dichloromethane is added under stirring over 10 minutes at a temperature of about 20 ° C solution of 1.53 g of N-formyl-N-methylhydrazine in 30 cm ^{3 of} dichloromethane. After 15 hours at a temperature in the region of 20 ° C, the reaction mixture is concentrated under reduced pressure (20 kPa) and at a temperature of about 40 ° C. The dried extract is taken up in 100 cm ^{3 of} ethanol and 3 cm ^{3 of} 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the mixture is heated at a temperature of about 75 ° C for 30 minutes. After cooling to about 20 DEG C., the product is centrifuged, washed twice with 50 cm @ ^{3 of} ethanol and then twice more with 30 cm @ ^{3 of} diethyl ether. 3.9 g of 7,8-difluoro-3-ethoxycarbonyl-N-formyl-N-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a yellow solid. m.p. 259 DEG-260 DEG C., which was used in subsequent stages without further purification.

Ethyl 2- (2-chloro-6,7-difluoro-3-quinolinyl) -3-dimethylaminoacrylate was prepared as described in U.S. Patent 4,970,213.

3-Acetylaminoazetidine hydrochloride was prepared as described by Dino Nisato et al. in J. Heterocycin Chem. 22, 96 (1985).

Example 11

8- (3-Trans-amino-2-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

A solution of 18 g of 3-trans-amino-2-methyl-azetidine-dimethanesulfonate and 12.7 g of triethylamine in 150 cm ^{3 of} dimethylsulfoxide is heated to about 70 ° C with stirring for 20 minutes. At this temperature, it is added in small portions and over 10 minutes

14.5 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridene-3-carboxylic acid are heated to about 2 hours for about 2 hours. 90 ° C. After cooling to about 20 ° C, the reaction mixture is poured into 400 cm ^{3 of} water (at this temperature). The insoluble matter is drained, washed twice with 100 cm @ ^{3 of} water and then twice with 100 cm @ ^{3 of} ethanol, then recrystallized from 300 cm @ ^{3 of} dimethylformamide. 13.9 g of 8- (3-transamino-2-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylic acid as a yellow solid which decomposes at 265-267 ° C.

3-Trans-amino-2-methylazetidine is prepared in the form of dimethanesulfonate, m.p. 170-175 ° C by the synthesis described in European patent application 406 112.

Example 12

8- (3-cis-amino-2-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

The reaction conditions were as described in Example 11, but starting from 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. n-3-carboxylic acid and 2.1 g of 3-cis-amino-2-methyl-azetidine-dimethanesulfonate. 1.32 g of 8- (3-cis-amino-2-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8- are obtained. benzo (b) naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 312-315 ° C.

3-cis-Amino-2-methiazolidine is prepared in the form of dimethanesulfonate with a melting point of 160-170 ° C by the synthesis described in European patent application EP 406 112.

Example 13

8- (3-Trans-amino-2-methyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

Suspension 1.4 g of 8- (3-trans-amino-2-methyl-1-azetidinyl) 1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8benzo (b) naphthyridine in 1 ^cm3 of water and 6.8 cm ³ N aqueous potassium hydroxide solution was heated for 3 hours at about 95 ° C. After cooling to about 60 ° C, the light insoluble matter was removed by filtration at the same temperature. 6.8 cm @ ³ of methanesulfonic acid are then added to the filtrate. The precipitate obtained is centrifuged at 20 ° C and washed three times with 50 cm ^{3 of} water and twice with 25 cm ^{3 of} ethanol. After recrystallization from 30 cm ^{3 of} dimethylformamide, 1.03 g of 8- (3-trans-amino-2-methyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-acid is obtained. dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is a yellow solid which decomposes at 268-270 ° C.

- (3-Trans-amino-2-methyl-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as follows.

To a solution of 3-trans-amino-2-methyl-azetidine dimethanesulfonate in 20 cm @ ^{3 of} dimethyl sulfoxide and 1.52 g of triethylamine, 1.7 g of i-cyclopropyl- ^1-3 is added at about 60 over about 10 minutes and in small portions. -ethoxycarbonyl-7,8-difluoro-4-fluoro-1,4-dihydro-1,3-benzo [b] naphthyridine. The reaction mixture is heated to a temperature in the region of 80 DEG C. and then maintained at this temperature under stirring for about 4 hours. After cooling to about 20 ° C, the reaction mixture is poured into 100 cm ^{3 of} water and extracted twice with 100 cm ^{3 of} dichloromethane. The combined organic extracts are washed twice with 50 cm @ ^{3 of} water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at a temperature of about 40 ° C. The dry extract is then chromatographed on 125 g of silica gel (0.04-0.063 mm) suspended in a mixture of dichloromethane containing 20% ethanol. The desired product is eluted with 300 cm ^{3 of the} same mixture. 1.6 g of 8- (3-trans-amino-2-methyl-1-azetidinyl) -1-cyclopropyl-3-ethoxy-7-fluoro-4-oxo-1,4-dihydro-1,8- are obtained. benzo (b) naphthyridine as a yellow solid, m.p. 170 ° C.

Example 14

S- (3-Amino-1-azetidinyl) -7-fluoro-4-οχο-1-tert-butyl25

1,4-benzo (b) naphthyridio-3-carboxylic acid

Suspension 2.2 g of 8- (3-trifluoroacetate-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8 -benzo (b) naphthyridine in 17 cm @ ^{3 of} an aqueous potassium hydroxide solution is heated at about 95 DEG C. for 7 hours. 17 cm @ ³ of methanesulfonic acid are added at the same temperature and the solid is centrifuged at about 90 DEG C., washed twice with 30 cm @ ^{3 of} water and twice with 30 cm @ ^{3 of} ethanol, then recrystallized from 50 cm @ ^{3 of} dimethylformamide. 1.4 g of 8- (3-amino-1-azetinyl) -7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] are obtained. naphthyridine-3-carboxylic acid in the form of a solid, rye product which decomposes at a temperature of 333 to 335 ° C.

3-Ethoxycarbonyl-7-fluoro-3- (3-trifluoroacetate-1-azetinyl) -4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine prepared under the conditions described in Example 2, but starting from 1,8 3-ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine and 1.5 g of 3-fluoroacetamidoazetidine hydrochloride and 0.79 g of sodium carbonate. 2.25 g of 3-ethoxycarbonyl-7-fluoro-8- (trifluoroacetamido-1-azetidinyl) -4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. yellow solid, m.p. 328 DEG-330 DEG.

3-Ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the conditions described in Example 10, but starting from from 4 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate and 0.87 g of tert-butylamine. 2.7 g of 3-ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a yellow solid, m.p. 206 ° C, which was used in the next reaction steps without further purification.

3-Trifluoroacetamidoazetine din hydrochloride is prepared according to the procedure described in European patent application E? 406 112.

Example 15

8- (3-Amino-3-propyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

To a solution of 1.22 g of sodium ethoxide in 18 cm @ ^{3 of} ethanol is added 2.3 g of 3-amino-3-propyl-azetidine-dimethanesulfonate. After addition of 30 cm ^{3 of} dimethylsulfoxide, the solution is stirred for 10 minutes at a temperature of about 20 ° C. At this temperature, 1.45 g of 7,8difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is added, followed by the resulting mixture is heated to about 90 ° C with stirring for 5 hours. After cooling to about 20 ° C, the product is centrifuged, washed 4 times with 20 cm ^{3 of} water and twice with 10 cm ^{3 of} ethanol. After recrystallization from 30 cm @ ^{3 of} dimethylformamide, 1.52 g of 8- (3-amino-3-propyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,3 acid are obtained. -benzo [b] naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 304-305 ° C.

3-Amino-3-propylazetidine was prepared as the dimethanesulfonate using reaction conditions analogous to those described by D. Nisato et al. in J. Heterocyclic, 22, 961 (1985).

Hydrogenation of 7.3 g of 3-amino-1-benzhydryl-3-propylazetidine at 0.1 pPa pressure in the presence of 5 g of 1-phonic acid methane in 75 cm ^{3 of} methanol and 1.5 g of 20% palladium hydroxide on carbon affords 6 g. 5 g of 3-amino-3-propyl azetidine-dimethanesulfonate. The product was taken up in ethanol and isolated as a solid colorless product, m.p. at 200 ° C.

3-Amino-1-benzhydryl-3-propylazetidine was prepared as follows.

To a solution of 100 cm ³ of a 0 ° C solution of ammonia in ethanol (prepared from 15 g of ammonia and 100 cm ^{3 of} 5 ° C ethanol) is added 7.5 g of 1-benzhydryl-3-methanesulfonyloxy-3-propvlazetidine, then the temperature is allowed to rise to about 20 ° C and the mixture is then stirred at this temperature for 16 hours. After concentration to dryness under reduced pressure (20 kPa) and at a temperature of about 40 ° C, the residue is taken up in 25 cm ^{3 of} water and 2.22 g of methanesultonic acid. The aqueous phase is washed twice with diethyl ether, then treated with 10 cm @ ^{3 of a} 40% aqueous sodium hydroxide solution and extracted three times with 50 cm @ ^{3 of} dichloromethane. The combined organic extracts are washed with 10 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under the previous conditions. 5.2 g of 3-amino-1-benzhydryl-3-propylazetidine are obtained in the form of an oily product which is used as is in the next stages.

1-Benzhydryl-3-methanesulfonyloxy-3-propylazetidine was prepared using the reaction conditions described for 1-benzhydryl-3-methanesulfonyloxy-3-methylazetidine in European Patent Application EP 406 112, starting from 2.8 g of 1-benzhydryl-3 hydroxy-3-propylazetidínu. 2.4 g of 1-benzhydryl-3-methanesulfonyloxy-3-propylazetine are obtained in the form of a colorless solid, m.p.

1-Benzhydryl-3-hydroxy-3-propylazetidine was prepared using the following reaction conditions.

To a solution of propylmagnesium iodide in diethyl ether, prepared under conventional conditions from 10.75 g of iodopropane and 1.55 g of magnesium in 75 cm ^{3 of} diethyl ether, a solution of 7.5 g of l- benzhydryl-3-oxaazetidine in a solution of 50 cm ^{3 of} diethyl ether. The temperature is then allowed to rise to about 20 ° C and the mixture is stirred at this temperature for 2 hours. After cooling to about 0 ° C, 50 cm ^{3 of} water and 50 cm ^{3 of a} 10% aqueous ammonium chloride solution are added successively while maintaining this temperature. The aqueous phase is extracted three times with 50 cm ^{3 of} diethyl ether. The combined organic extracts are dried over magnesium sulphate, concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 30 ° C. The dry extract is then chromatographed on 100 g of silica gel (0.04-0.063 mm) in suspension in a mixture of cyclohexane containing 20% ethyl acetate. The desired product is eluted with 130 cm ^{3 of the} same solvent mixture. 8 g of 1-benzhydryl-3-hydroxy-3-propylasetidine are obtained in the form of a pale yellow oil, which is used as is in the subsequent stages without further purification.

1-Benzhydryl-3-oxoazetidine was prepared under the conditions described by A. Morimoto et al. in Chem.Pharra.Bul1.21 (1) 2 2S231 (1973).

Example 15.

8- (3-Amino-3-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

To a solution of 1.02 g of sodium ethoxide in 30 cm @ ^{3 of} ethanol at a temperature of about 5 DEG C. is added 2.09 g of 3-amino-3-methylazetidine-dimethanesulfonate. The temperature is then allowed to rise to about 20 ° C and the mixture is stirred at this temperature for 15 minutes. After separation of the mineral salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 30 ° C. The residue is dissolved in 20 cm @ ^{3 of} dimethylsulfoxide and 1.45 g of 7,8-difluoro-letyl-4-oxo-1,4-dihydro-1,8-benzoic acid is added at a temperature in the region of 20 DEG C. b) naphthyridine-3-carboxylate; The resulting suspension was stirred at about 60 ° C for 16 hours. After cooling to about 20 DEG C., the insoluble matter is centrifuged and washed with 30 cm @ ^{3 of} ethanol. The isolated product is recrystallized in 90 cm ^{3 of} dimethylformamide, centrifuged and washed with 20 cm ^{3 of} ethanol at a temperature of about 75 ° C. 1.2 g of S- (3-amino-3-methylazetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained. j as a yellow solid.

which decomposes at 345 ° C.

3-Amino-3-methylazetidine is prepared in the form of dimethanesulfonate, m.p. 204-206 ° C using the reaction conditions described in European patent application EF 406 112.

Example 17

8- (3-Amino-3-methyl-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under conditions as described in Example 15, but starting from 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid. and 2.22 g of 3-amino-3-methylazetidine dimethanesulfonate, which was heated at a temperature in the region of 90 ° C for 72 hours. The insoluble portion of the reaction mixture is centrifuged at about 20 ° C, washed twice with 20 cm ^{3 of} water, recrystallized from 70 cm ^{3 of} dimethylformamide, washed with 40 cm ^{3 of} ethanol at a temperature of about 75 ° C. 1.45 g of 8- (3-amino-3-methyl-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3 are obtained. -carboxyl. as a yellow solid which decomposes at 334 ° C.

Example 18

8- (3-Amino-3-methyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared in reaction using the conditions described in Example 16, but starting from 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1 acid. 4-dihydro-1,8-benzo [b] naphthyridin-3-carboxylic acid and 2.22 g of 3-amino-3-methyl-azetidine-dimethylsulfonate. 1.7 g of 8- (3-amino-3-methyl-1-azetidinyl) -1'-clopropyl-7-fluoro-4-chloro-1,4-dihydro-1,8-benzoic acid are obtained. (b) naphthyridine-3-carboxylic acid as a yellow solid, which was set at 298 ° C.

1-Cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8benzo [b] naphthyridine-3-carboxylic acid was prepared using the following reaction conditions.

A suspension of 8.05 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in a mixture of 2 N hydrochloric acid (aq. 5 solution) and 80 at 20 ° C for two hours. 6 cm ³ of acetic acid are heated with stirring to a temperature close to 100 ° C. After cooling to duct, it is centrifuged and washed three times with 100 cm @ ^{3 of} water.

g of 1-cyclopropyl-7, S-difluoro-4-oxo-1,4-dihydro-1,8benzo [b] naphthyridine carboxylic acid as a pale yellow product, which decomposes at 2S3 ° C and which is free from further purification is used in the next reaction steps.

Example 19

(RS) -8- (3-Amino-2,2-dimethyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3 The carboxylic acid was prepared under the reaction conditions described in Example 15, but starting from 1.45 c of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. n-3-carboxylic acid and 2.33 g of 3-amino-2,2-dimethylazetidine dimethanesulfonate. The reaction mixture was heated to about 100 ° C with stirring for 5 hours. 0.6 g of (RS) -8- (3-amino-2,2-dimethyl-1-azetinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1 is obtained. 8-benzo [b] naphthylidene-3-carboxylic acid is a yellow solid which decomposes at 285 ° C.

3-Amino-2,2, dimethylazetidine dimethanesulfonate was prepared as a white solid, m.p. 125-130 ° C, from 3-amino-2,2-dimethylazetidine using a modified form of the method described by Akira Morimoto in Chem.

Pharm. Bu11., 21 (1), 228 (1973).

Example 20

7-Fluoro-1-methyl-8- (3-methyl-3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared. under the conditions described in Example 15, but starting from 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid; 34 g of 3-methyl-3-methylaminoazetidine dimethanesulfonate. The reaction mixture is heated at about 90 ° C for one hour and 30 minutes. 1.12 g of 7-fluoro-1-methyl-8- (3-methyl-3-methylamino-lazetidinyl) -1-methyl-4-oxo-1,4-dihydro-1,8-benzo / b is obtained. of naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 335 ° C. 3-Methyl-3-methylaminoazetidine is prepared in the form of dimethanesulfonate (melting point: 135 ° C) under the conditions described in European patent application EP 406 112.

Example 21

1-Cyclopropyl-7-fluoro-8- (3-methyl-3-methylamino-lazetinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid prepared under the conditions described in Example 15, but starting from 1.58 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyric acid. 3-methyl-3-methylamino-azetin-dimethanesulfonate is added. 1.57 g of 1-cyclopropyl-7-fluoro-8- (3-methyl-3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylate as a yellow solid which decomposes at 330 ° C.

Example 22

1-Ethyl-7-fluoro-8- (3-methyl-3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid prepared under the conditions described in Example 15, but starting from 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. 3-carboxylic acid and 2.34 g of 3-methyl-3-methylaminoazetidine dimethanesulfonate. 1.18 g of i-ethyl-7-fluoro-8- (3-methyl-3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylic acid as a yellow solid which decomposes at 338 ° C.

Example 23

8- (3-Amino-3-methyl-1-azetidinyl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15 but starting from 1.53 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.22 g of 3 -Amino-3-methyl-azetidin-dimethanesulfonate. 8- (3-Amino-3-methyl-1-azetidinyl) -7-fluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained in the form of of a yellow solid which decomposes at 346 ° C.

7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions described in U.S. Patent 4,970,213.

Example 24

1-Cyclopropyl-7-fluoro-8- (3-methyl-3-dimethylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3-carboxylic acid Prepared under the conditions described in Example 15, starting from 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid. and 2.45 g of 3-methyl-3-dimethylaminoazetidine dimethanesulfonate. 1.55 g of 1-cyclopropyl-7-fluoro-8- (3-methyl-3-dimethylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3 are obtained. -carboxylic acid as a yellow solid which decomposes at 268 ° C.

3-Methyl-3-dimethylaminoazetidine is obtained in the form of dimethanesulfonate with a melting point at 148 ° C under the conditions described in European patent application EP 406 112.

Example 25

7-Fluoro-1-methyl-8- (3-methyl-3-dimethylamino-4-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-dimethylaminoazetidine dimethanesulfonate. 1.56 g of 7-fluoro-1-methyl-8- (3-methyl-3-dimethylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylic acid as a yellow solid which decomposes at 274 ° C.

Example 26

8- (3-Amino-3-methyl-1-azetidinyl) -7,9-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3 acid The carboxylic acid is prepared under the following conditions.

To a solution of 0.68 g of sodium ethoxide in 7 cm ^{3 of} ethanol is added 1.33 g of 3-amino-3-methylazetidine dimethanesulfonate. After addition of 20 cm ^{3 of} dimethylsulfoxide, the solution is stirred at a temperature of about 20 ° C for 10 minutes. At this temperature, 0.75 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is added and the mixture The mixture was stirred at about 20 ° C for 72 hours. The insoluble matter is centrifuged, washed twice with 20 cm @ ^{3 of} water and twice with 20 cm @ ^{3 of} ethanol. After recrystallization from 70 cm @ ^{3 of} dimethylformamide, 0.45 g of 8- (3-amino-3-methyl-2-azetidinyl) -7,9-difluoro-1-methyl-4-oxo-1,4-dihydro acid is obtained. -1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 359 ° C.

7,8,9-Trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared as follows.

A suspension of 0.83 g of 3-ethoxycarbonyl-7,3,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 10 cm @ ^{3 of a} 17.5% aqueous acid solution of hydrochloric acid and 10 cm @ ³ of acetic acid are heated with stirring to a temperature in the region of 100 DEG C. for 3 hours. After cooling to about 20 ° C, the product is centrifuged and washed three times with 10 cm ^{3 of} water. 0.75 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained in the form of a pale yellow product which decomposes at temperature 352 ° C and used in the next reaction steps without further purification.

3-Ethoxycarbonyl-7,8,9-trifluoromethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared under the conditions described in U.S. Patent 4,970,213.

Example 27

3- (3-Cyclopropyl-amino-3-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared under the reaction conditions described in Example 15, but starting from 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine- 3-carboxylic acid and 2.5 g of 3-cyclopropylamino-3-methylazetidine dimethanesulfonate. 1.73 g of 8- (3-cyclopropylamino-3-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. 3-carboxylic acid solvated 0.7% water as a solid, lysed product decomposing at 300 ° C.

3-Cyclopropylamino-3-methylazetidine dimethanesulfonate was prepared as follows.

14.5 g of 1-benzhydryl-3-cyclopropylamino-3-methylazetidine in 150 cm @ ^{3 of} methanol are hydrogenated at atmospheric pressure and at a temperature close to '20 for one hour' in the presence of 5.6 g of 20% palladium hydroxide on carbon. To the reaction mixture was added 10 g of methanesulfonic acid. After removal of the hydrogenation catalyst by filtration and concentration of the filtrate to dryness under reduced pressure (20 kPa) at a temperature of about 40 ° C, the residue is washed three times with 150 cm ^{3 of} diethyl ether. The residue is taken up in 100 cm ³

2-propanol, the solid is centrifuged and washed twice with 50 cm ^{3 of} acetone. 9.1 g of 3-cyclopropylamino-3-methylazetidine dimethanesulfonate are obtained in the form of a solid colorless product, melting at 136 ° C.

1-5-Benzhydryl-3-cyclopropylamino-3-methylazetidine was prepared as follows.

Tylazethiain suspension a

16.6 g of 1-benzhydryl-3-methanesulfonyloxy-3-me28.84 g of cyclopropylamine in 250 cm ^{3 of} ethanol are stirred for 96 hours at a temperature of about 20 ° C. The reaction mixture is concentrated under reduced pressure (20 kPa) and at a temperature of about 30 ° C. The dry extract is taken up in 50 cm @ ^{3 of} water and 8.8 g of methanesulfonic acid. The aqueous phase is washed three times with 25 cm @ ^{3 of} dichloromethane, then 12 cm @ ^{3 of} 35% aqueous sodium hydroxide solution are added and the mixture is washed twice with 50 cm @ ^{3 of} water, dried over magnesium sulphate, concentrated to dryness under reduced pressure (20 kPa); at about 25 ° C. 14.6 g of 1-benzhydryl-3-cyclopropylamino-3-methyiazetidine are obtained in the form of a yellow oil which is used as is in the following stages without further purification.

1-Benzhydryl-3-methanesulfonyloxy-3-methylazetidine is prepared under the conditions described in patent application EP 406 112.

Example 28

8- (3-ethylamino-3-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions described in Example 15, but starting from 1.45 of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.24 g of 3ethylamino-3-methyl-azetidine dimethanesulfonate. 1.66 g of 8- (3-ethylamino-3-methyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylic acid as a yellow solid which decomposes at 312 ° C.

3-Ethylamino-3-methyl-azetidine-dimethanesulfonate was prepared under the conditions described in Example 27, starting from 14 g of 1-benzhydryl-3-ethylamino-3-methylazetidine. 9.7 g of 3-ethylamino-3-methyl-azetidin-dimethanesulfonate as a colorless solid, melting point at ^about 140 C.

1-Benzhydryl-3-ethylamino-3-methylazetidine was prepared under the conditions described in Example 27, but starting from 16.6 g of 1-benzhydryl-3-methanesulfonyloxy-3-methylazetidine and 45 g of ethylamine. 14 g of 1-benzhydryl-3-ethylamino-3-methylazetidine are obtained in the form of a sewn oil which is used as is in the following stages without further purification.

Example 29

7-Fluoro-8- (3-methylamino-1-azetidinyl) -1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 2 but using 2.6 g of 3-ethoxycarbonyl-7-fluoro-1-methoxy-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine. 1.7 g of 7-fluoro-8- (3-methylamino-1-azetidinyl) 1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3 are obtained. -carboxylic acid in the form of a solid, rye product which decomposes at 255 to 260 ° C.

3-Ethoxycarbonyl-7-fluoro-1-methoxy-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as follows: .

To a solution of 2.35 g of sodium ethoxide in 20 cm ^{3 of} ethanol is added 2.8 g of 3-methylaminoazetidine dihydrochloride. After stirring for 15 minutes at a temperature in the region of 20 DEG C. and removal of the mineral salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 30 DEG C. The residue is dissolved in 40 cm @ ^{3 of} dimethylsulfoxide. g 3-ethoxy. arbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. The reaction mixture is heated at about 60 ° C for one hour and 30 minutes. 2.7 g of 3-ethoxycarbonyl-7-fluoro- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a solid, sewed product having a temperature. mp 234 ° C.

3-Methylaminoazetidine dihydrochloride was prepared under the conditions described in Example 9, but starting from 32.2 g of 1-benzhydryl-3-methylaminoazetidine. 19.1 g of 3-methylaminoazetidine dihydrochloride are obtained in the form of a solid colorless product, m.p. 138-140 ° C.

1-Benzhydryl-3-methylaminoazetidine is prepared using the reaction conditions described in Example 9, but starting from 50 g of 1-benzhydryl-3-methanesulfonyloxyazetidine and 48.9 g of methylamine in 250 cm ^{3 of} methanol. 27 g of 1-benzhydryl-3-methylaminoazetidine are obtained in the form of a solid colorless product, melting at 75 ° C.

Example 30

1-Cyclopropyl-7-fluoro-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared according to the conditions described in of Example 11, but starting from 1.5 g of 1-cyclopropyl-7, 5-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 1.13 g of 3 -methylaminoazetine dihydrochloride. The reaction mixture was stirred at 40 ° C for 1 hour. 1 g of 1-cyclopropyl-7-fluoro-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,3-benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid. , which decomposes at 262 ° C.

Example 31

7,9-Difluoro-1-methyl-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the reaction conditions. starting from 1.5 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3 acid. carboxylic acid and 1.2 g of 3-methylaminoazetidine dihydrochloride. 1.54 g of 7,9-difluoro-1-methyl-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3- acid is obtained. carboxylic acid as a yellow solid which decomposes at 302 ° C.

Example 32

8- (3-Amino-3-ethyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the reaction conditions. starting from 1.66 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 1 g of 3-amino-3-ethylazetidine dimethanesulfonate. 1.46 g of 8- (3-amino-3-ethyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3 are obtained. -carboxylic acid as a yellow solid which decomposes at 294 ° C.

3-Amino-3-ethylazetidine-n-dimethanesulfonate was prepared according to the reaction conditions described in Example 15 for 3-amino-3-propyl azetinine. Hydrogenation of 6 g of 3-amino-1-benzhydryl-3-ethylazetidine afforded 5.7 g of 3-amino-3-ethylazetidine-dimethylsulphonate as a colorless solid, m.p. 184 ° C.

From 24.6 g of 1-benzhydryl-3-ethyl-3-methanesulfonyloxyazetidine in a solution in 174 cm @ ^{3 of a} 15% solution of ammonia in ethanol is obtained

13.6 g of 3-amino-1-benzhydryl-3-ethylazetine. The isolated product was used in the next reaction steps without further purification.

From 35.5 g of 1-benzhydryl-3-hydroxy-3-ethylazetidine was obtained

24.6 g of 1-benzhydryl-3-ethyl-3-methanesulfonyloxyazetidine as a sewn solid, m.p.

From 44 g of 1-benzhydryl-3-oxoazetidine and 80 cm @ ^{3 of a} solution of ethyl magnesium bromide in diethyl ether at a concentration of 399 g / l, 35.5 g of 1-benzhydryl-3-hydroxy-3-ethylazetidine are obtained in the form of a yellow oil.

Example 33

8- (3-Amino-3-ethyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine methanesulfonate n40

The 3-carboxylic acid is prepared according to the reaction conditions given in Example 15, but starting from 1.8 g of 7,8di fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] 3-Amino-3-ethylazetidine-dimethanesulfonate (2.94 g) was obtained. After recrystallization from dimethylformamide, the product obtained is suspended in 20 cm @ ^{3 of} ethanol, then 3.4 cm @ ^{3 of a} 9.6% solution of methanesulfonic acid in ethanol are added. The suspension is stirred for 5 minutes at about 80 ° C, cooled to a temperature in the region of 20 ° C, centrifuged and washed three times with 10 cm ^{3 of} ethanol. 0.55 g of 8- (3-amino-3-ethyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,3-benzo [b] naphthyridin acid methanesulfonate is obtained. -3-carboxylic acid is a yellow solid which decomposes at 243 ° C.

Example 34

7-Fluoro-1-methyl-8- [3- (1-pyrrolidinyl-1-azetidinyl-1H-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3-acid) The carboxylic acid was prepared according to the conditions described in Example 2, but starting from 1.2 g of 3-ethoxycarbonyl-7-fluoro-1-methyl-8- [3- (pyrrolidinyl-1-azetidinyl) -4-oxo. -1,4-dihydro-1,8-benzo [b] naphthyridine to give 0.7 g of 7-fluoro-1-methyl-8- [3- (1-pyrrolidinyl) -1-azetidinyl] -4 -oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 302 ° C.

3-Ethoxycarbonyl-7-fluoro-1-methyl-8- [3- (1-pyrrolidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared according to the conditions described in Example 2 starting from 1,6 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 1,5 g of 3 - (1-pyrrolidinyl) azetine dihydrochloride. The reaction mixture was stirred at 95 ° C for 24 hours. 1.3 g of 3-ethoxycarbonyl-7-fluoro-1-methyl-3- [3- (1-pyrrolidinyl) -1-azetinyl] -4-oxo-1,4-dihydro-1,8-benzo are obtained. (b) naphthyridine as a yellow solid, m.p. 246 ° C.

3- (1-Pyrrolidinyl) azetinine was prepared in the form of the dihydrochloride, m.p. 195 ° C, according to the reaction conditions described in Japanese Patent Application 74 109 369. Example 35

8- (3-Cyclopropylamino-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the conditions described in Example 2 starting from 1.3 g of 8- (3-cyclopropylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo] b / naphthyridine. 0.8 g of 8- (3-cyclopropylamino-1-azetinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is obtained. The 3-carboxylic acid is a yellow solid which decomposes at 272 ° C.

8- (3-Cyclopropylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine Prepared according to the conditions described in Example 15, starting from 1.45 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo / b and naphthyridine and 1.7 g of 3-cyclopropylazetidine. 1.35 g of 8- (3-cyclopropylamino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a solid. m.p. 245 ° C.

3-Cyclopropylaminoazetidine dihydrochloride was prepared according to the conditions described in Example 9 for 3-ethylaminoazetidine dihydrochloride, starting from 5.4 g of 1-benzhydryl-13-cyclopropylaminoazetidine dihydrochloride. 2.25 g of 3-cyclopropylaminoazetidine dihydrochloride are obtained in the form of a colorless solid, m.p.

1-Benzhydryl-3-cyclopropylaminoazetidine n-dihydrochloride is prepared according to the conditions described in Example 9 for 1-benzhydryl-3-ethylaminoazetidine dihydrochloride starting from 15 g of 1-benzhydryl-3-methanesulfonyloxyazetidine and 8.2 g of cyclopropylamine. 5.4 g of 1-benzhydryl-3-cyclopropylamino-azididine-dihydrochloride are obtained in the form of a colorless solid, m.p. 132 ° C.

Example 36

Using the procedures described in the previous examples, the following products are prepared:

7-Fluoro-1-methyl-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3- (2-Aminoethyl) amino-1-azetidinyl) 7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin-3- 7-Fluoro-3- [3- (2-hydroxyethyl) amino-1-azethioinyl] -1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] carboxylic acid naphthyridine-3-carboxylic acid, 7-fluoro-1-methyl-4-oxo-8- [3- (i-piperazinyl) -1-azetidinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine -3-carboxylic acid 8- [3- [4- (2-aminoethyl) phenyl] amino-1-azetidinyl] -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8- Benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetidinyl} -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo) b) naphthyridine-3-carboxylic acid 1-ethyl-7-fluoro-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo b) naphthyridine-3-carboxylic acid , 8- (3-ethyl Lamino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- (2-amine) 1-ethyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-ethyl- 7-fluoro-8- [3- (2-hydroxyethyl) amino-1-azetinyl] -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 8- (3-cyclopropylamino-1-azetidinyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-ethyl-7-fluoro) -4-οχο-8- / 3- (1-piperazinyl-1-azetidinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- / 4 - (2-aminoethyl) phenyl (amino-1-azetinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-Amino-3-phenyl-1-azetidinyl) -1-ethyl-1- 7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetidinyl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine- 3-carboxylic acid 1-Cyclopropyl-8- (3-ethylamino-1-azetinyl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 8- / 3- (2-Aminoethyl) amino-1-azetidinyl] -1-cyclopropyl-17-fluoro-4-oxo-1,4-dihydro-1,3-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl-7- fluoro-8 / 3- (2-hydroxyety1) amino-l-azetidinyl / 4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-carboxylic acid.

1-Cyclopropyl-8- (3-cyclopropylamino-1-azetidinyl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl- 7-Fluoro-4-oxo-S- [3- (1-piperazinyl-1-a44 zetidinyl) -1,4-dihydro-1,8-benzo] b] naphthyridine-3-carboxylic acid 8- / 3- [4- (2-Aminoethyl) phenyl] amino-1-azetidinyl] -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine- 3-Carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid , 8- (3-amino-2-dimethylamino-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 7-fluoro-1-methylamino-8- (3-methylamino-1-azetidinyl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3) -ethylamino-1-azetidinyl / -7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- (2-aminoethyl) ) amino-1-azetidin-7-fluoro-1-methyl-amino-4-oxo-1,4-dihydro-1,8-benzo b) naphthyridine-3-carboxylic acid, 7-fluoro-8- (3- (2-hydroxyethyl) amino-1-azetidinyl) -1-methylamino-4-oxo-1,4-dihydro-1,8-benzo) b) naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) -7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyric acid 7-fluoro-1-methylamino-4-oxo-8- (3- (1-piperazinyl) -1-azetidinyl) -1,4-dihydro-1,8-benzoic acid, 7-fluoro-3-carboxylic acid b) naphthyridine-3-carboxylic acid 8- [3- [4- (2-aminoethyl) phenyl] amino-1-azetidinyl] -7-fluoro-1-methylamino-4-oxo-1,4- dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -7-fluoro-1-methylamino-4-ω-1,4 dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3-methyl-1-azetidinyl) -7-fluoro-1-methylamino-4-oxo-1, 4-Dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetinyl) -7-fluoro-1-methylamino-4 7-Fluoro-1- (2-fluoroethyl) -3-methyl-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 4- (3-ethylamino-1-azetidinyl) -7-fluoro-1-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid - (2-fluoroethyl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3- (2-aminoethyl) amino-1-azetidinyl) - 7-Fluoro-1- (2-fluoroethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7-fluoro-1- (2-fluoroethyl) -8 - [3- (2-hydroxyethyl) amino-lazetidinyl] -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) 7-Fluoro-1- (2) -7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid -fluoroethyl) -4-oxo-8- [3- (1-piperazinyl) -1-azetidinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- / 4 - (2-aminoethyl) phenyl / amino-1-azetidinyl / -7-fluoro-1- (2-fluoroethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 8) - (3-amino-3-phenyl-1-azetidinyl) -7-fluoro-1- (2-fluoro-4-ethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3- carboxylic acid 8- (3-Amino-3-methyl-1-azetidinyl) -7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyrene idine-3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetidinyl) -7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid, 7-fluoro-3- (3-methylamino-1-azetidinyl) -4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo] b (naphthyridine-3-carboxylic acid, 8- (3-ethylamino-1-azetidinyl) -7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo) b) naphthyridine- 3-carboxylic acid 8- [3- (2-aminoethyl) amino-1-azetidin-1 H -7-fluoro-4-mono-tert-butyl-1,4-dihydro -1,8-benzo [b] naphthyridine-3-carboxylic acid 7-fluoro-8- [3- (2-hydroxyethyl) amino-1-azetidinyl] -4-oxo-1-tert-butyl-1 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) -7-fluoro-4-oxo-tert-butyl-1,4 dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7-fluoro-4-oxo-8- [3- (1-piperazinyl) -1-azetidinyl] -1-tert-butylamine .huty1-1,4-di hydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- [3- [4- (2-aminoethyl) phenyl] amino-1-azetidinyl] -7-fluoro-4-oxy-1-tert butyl-1,4-dihydro-1,5S-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -7-fluoro-4- oxo-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 3- (3-amino-3-methyl-1-azethynyl) acid] -7-fluoro-4-oxo-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-2-dimethylamino-1- azetidinyl) -7-fluoro-4-fluoro-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-8- (3- ethylamino-1-azetidinyl) -1-methyl-4oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid 8- (3- (2-aminoethyl) amino-1-azetidinyl) -7 _/ 9-Difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-8- / 3- (2-hydroxyethyl) Amino-1-azetinyl / 1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) -7 9- Difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 7-Sdifluoro-1-methyl-4-oxo-8- / 3 - (1-piperazinyl) -1-azetidinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3- / 4- (2-aminoethyl) phenyl) amino -1-azetidinyl] -7,9-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridene-3-carboxylic acid 8- (3-amine) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, amino-3-phenyl-1-azetidinyl] -7,9-difluoro-1-methyl-8- ( 3-Amino-2-dimethylamino-1-azetinyl / -7,9-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-Difluoro-1-ethyl-8- (3-methylamino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 8 - (3-ethylamino-1-azetidinyl) -7,9-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3 - (2-aminoethyl) amino-l-azetidinyl) -7,9-difluór48

1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-1-ethyl-8- / 3- (2-hydroxyethyl) amino-1-azetidinyl / -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) -7,9 -difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-1-ethyl-4-oxo-8 - [3- (1-piperazinyl) -1-azetidinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- / 4- (2-aminoethyl) Phenyl (amino-1-azetidinyl) -7,9-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3) -phenyl-1-azetidinyl) -7,9-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3- methyl-1-azetidinyl) -7,9-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-2-dimethylamino) (1-azetidinyl) -7,9-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl-7,9-difluoro acid 8- (3-methyl- mino-1-azetidinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl-8 - (3-ethylamino-1-azetidinyl) -7 9-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3- (2-aminoethyl) amino-1-azetidinyl) 1-cyclopropyl-17,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl-7,9,8- / 3 - (2-hydroxyethyl) amino-1-azetidin-4-oxo-1,4-dihydro-1,3-benzo [b] naphthyridine-3-carboxylic acid, 1-cyclopropyl-8- (3-cyclopropylamino-1-azetidinyl) -7,5-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] n-phthyridine-3-carboxylic acid, 1- cyclopropyl-7,9-difluoro-4-oxo-8- [3- (1-piperasinyl) -1-azetidine] -1,4-dihydro-1,8-benzo [b] naphthyridin-3- carboxyl ..

8- (3- [4- (2-Aminoethyl) phenyl) amino-1-azetidinyl] -1-cyclopropyl-7,9-difluoro-4-oxo-1,4-dihydro-1,8-benzo] b) naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -1-cyclopropyl-7,9-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 3-carboxylic acid 3- (3-amino-3-methyl-1-azetidinyl) -1-cyclopropyl-7,9-difluoro-4-pho-1,4-dihydro-1,8-benzo / b / naphthyridium η-3-carboxyV ä.

8- (3-Amino-2-dimethylamino-1-azetidinyl) -1-cyclopropyl-17,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine- 3-carboxylic acid, 7,9-difluoro-1-methylamino-8- (3-methylamino-1-azetidinyl)

4-Oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 3- (3-ethylamino-1-azetinyl) -7,9-difluoro-1-methylamino -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- [3- (2-aminoethyl) amino-1-azetidinyl] -7,9-difluoro-1-methylamino 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-8- / 3- (2-hydroxyethyl) amino -1-azetidinyl-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-cyclopropylamino-1-azetidinyl) - 7,9-Difluoro-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-1-methylamino-4- oxo-8- / 3- (piperazinyl-11-azetidinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- / 3- / 4- (2-aminoethyl) Phenyl (amino-1-azetidinyl) -7,9-difluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 3-carboxylic acid 8- (3-amino-3) -phenyl-1-azetidinyl) -7,9-difluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbo xylic acid 8- (3-amino-3-methyl-1-azetidin) -7,9-difluoro-1-methylamino-4-oxo-1,4-dihydro-1 8-benzo [b] naphthyridin-3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetinyl) -7,9-difluoro-1-methylamino- 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-1- (2-fluoroethyl) -8- (3-methylamino-1-azet) idinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 7,9-difluoro-8- (3-ethylamino-1-azetidinyl) -1- (2 (fluoro) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 8- [3- (2-aminoethyl) amino-1-azetidinyl] - 7,9-Difluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-5-carboxylic acid, 7,9-difluoro-1- (2-Fluoroethyl) -8- [3- (2-hydroxyethyl) amino-1-azetidinyl] -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3 -cyclopropylamino-1-azetidinyl) -7,9-difluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7.9 difluoro-l- (2-fluoro ethyl) -4-oxo-S- [3- (piperazinyl) -1-azetidinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- [3- / 4- ( 2-Aminoethyl) phenyl] -1-azetidinyl / -7,9-difluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] (Naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -7,9-difluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo) b) naphthyridine-3-carboxylic acid 8- (3-amino-3-methyl-1-azetidinyl) -7,9-difluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro- 1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-2-dimethylamino-1-azetidinyl) -7,9-difluoro- (2-fluoroethyl) -4-oxo 1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 7-fluoro-8- (3-methylamino-1-azetidinyl) -4-oxo-1-tert-butyl- 1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-ethylamino-1-azetidinyl) -7-fluoro-4-oxo-1-tert-butyl -1,4-dihydroc-1,8-benzo [b] naphthyridine-2-carboxylic acid 8- [3- (2-aminoethyl) amino] -1-azetidinyl] -7,9-di fluoro-4-oxo-1,4-dihydro-l, 8-benzo / b / naphthyridin n-3-carboxylic acid, 7,9-difluoro-8- / 3- (2-hydroxyethyl) amino-1-azetidinyl) 4-oxo-1-tert-butyl-1,4-dihydro-1,8- Benzo [b] naphthyridine-3-carboxylic acid, 8- (3-cyclopropylamino-1-azethynyl) -7,9-difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1 8-benzo [b] naphthyridine-3-carboxylic acid, 7,9-difluoro-4-oxo-8- [3- (1-piperazinyl) -1-azetidinyl] -1-tert-butyl-1,4- dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3- (4- (aminoethyl) phenyl) amino-1-azetidinyl) -7,8-difluoro-4-oxo-1- tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 8- (3-amino-3-phenyl-1-azetidinyl) -7,9-difluoro-4-oxoterbutyl -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 3- (3-amino, -3-methyl-1-azetidinyl) -7,9-. Difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 3- (3-amino-2-dimethylamino-1-azetidinyl) - 7,9-Difluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid,

The invention also relates to pharmaceutical compositions for use in human or veterinary medicine, characterized in that they comprise an active ingredient consisting of at least one compound of the formula I in pure form (in free form or in salt form) or in combination with one or more several compatible and pharmaceutically acceptable diluents or in combination with one or more compatible and pharmaceutically acceptable excipients. These compositions may be administered orally, parenterally or rectally.

As solid compositions for oral administration, tablets, gelatin capsules, pills, powders or granules may be used. In these compositions, the active ingredient of the invention may be admixed with one or more inert diluents or one or more inert ingredients such as sucrose 53, lactose or starch. These compositions may also contain substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as paraffin oil may be used. These compositions may also contain substances other than diluents, for example wetting, sweetening or flavoring agents.

The compositions for parenteral use may be aqueous or non-aqueous sterile solutions, suspensions, or emulsions. Propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate, may be used as a solvent or vehicle. These compositions may also contain additives, especially wetting agents, emulsifying agents, dispersing agents or isotonizing agents. Sterilization can be accomplished in a variety of ways, for example by using bacteriological filters, adding sterilizing agents to the composition, irradiating or heating. These compositions may also be prepared in the form of sterile solid compositions which are dissolved in sterile water or any other sterile injectable medium at the time of intended use.

Compositions for rectal administration are in the form of suppositories or rectal capsules, which may contain, in addition to the active ingredient, excipients such as cocoa butter or lace wax.

In human or veterinary medicine, the compositions of the invention are particularly useful for the treatment of infections of bacterial origin.

Usually it will be the attending physician who determines the most appropriate dosage of the active ingredient according to the invention, depending on the age, body weight, infection rate and other characteristics of the patient being treated. Usually, these doses are 0.2 to 1 g of active ingredient administered to an adult patient parenterally or orally twice daily.

The following example composition of the invention.

it maintains without limitation

Example

Tablets containing 250 mg of the active ingredient are prepared by conventional techniques and have the following composition:

8- (3-Amino-1-azetidinyl) -1-cyclopropyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] -

naphthyridine-3-carboxylic acid 2 5 0 m g starch 5 0 mg lactose 3 5 mg talc 15 mg

The compounds of formula I are also of interest in the field of agrochemistry for the antibacterial treatment of crops or plants. It goes without saying that these compositions for agrochemical applications comprising a compound of formula I are also within the scope of the invention.

Alternatively, the compounds of formula (I) may also be used as preservatives or disinfectants for organic or mineral substances, in particular in the field of dyes, fats, talc, wood and polymers, or else in the textile, food or water treatment industries. . It goes without saying that such compositions containing the compound of formula I in pure form or in combination with compatible diluents or additives are within the scope of the invention.

Claims (5)

A novel 1,8-benzo (b) naphthyridine derivative of the general formula I in which R represents a hydrogen atom or a hydroxy group, an amino group, an alkylamino group whose alkyl radical is optionally substituted by an amino or hydroxy group, or represents a dialkylamino group whose alkyl radicals may optionally form a heterocyclic group with the nitrogen atom to which they are attached Or a member optionally containing another heteroatom selected from the group consisting of nitrogen, oxygen or sulfur, or is a 3 to 8 membered cycloalkylamino group, an alkanoylamino group, an N-alkyl-N-alkanoylamino group or an aminoalkylphenylamino group, R 1 and R ', which are the same or different, are in position 2 and 2, respectively. 3 and represent a hydrogen atom, an alkyl or C 2 -C 4 alkenyl group, a phenyl group, a phenyl group substituted by a halogen or an alkyl group, an alkyloxy group, a hydroxy group, a nitro group, an amino group, an alkylamino group, dialkylarain or haloalkyl, or R _xa . R ₂ are in the 2-position and are alkyl groups, Ra represents a hydrogen atom, an alkyl group, a fluoroalkyl group, a carboxyalkyl group, a C 3-6 cycloalkyl group, a fluorophenyl group, a difluorophenyl group, a fluorophenyl group, an alkyloxy group or an alkylamino group R 1 represents a hydrogen atom or a fluorine atom, the above-mentioned alkyl and alkanoyl groups having a straight or branched carbon chain and containing 1 to 4 carbon atoms, in the form of their stereoisomers or mixtures thereof, as well as their salts, their addition salts with nitrogenous bases, its acid addition salts and its hydrates. Process for the preparation of a 1,8-benzo (b) naphthyridine derivative according to claim 1, characterized in that the azetidine derivative of the general formula wherein R, R 1 and R 2 are as defined in claim 1, is reacted with 1,8-benzo. (b) a naphthyridine of formula (III) Where R 3 and R * have the meanings given in claim 1 and Hal represents a fluorine atom, a chlorine atom or a bromine atom in case R m represents a hydrogen atom, or Hal and R 7 represent simultaneously fluorine atoms, then optionally converting the product into salt. 3. A process for the preparation of a 1,8-benzo [b] naphthyridine derivative according to claim 1, wherein the ester is in general C00 Alk have the meanings defined in claim 1, R has the protected amine claim of claim 1 or k represents direct or 4 carbon atoms, converting the acid from the ester to disturb the residue, the alkylaprotecting protecting group obtained in which R1, R; and R is as defined in claim 1 or from a group, R 3 is as defined in a protected alkylamino group and an Al branched alkyl group with 1 to any known method to obtain the corresponding acid without molecules then optionally removing the mine group and / or optionally a benzo (b) naphthyridine derivative. The benzo (b) naphthyridine derivative of the general formula Cl QO wherein R ₄ and Hal are as defined in Claim 2, Alk is as defined in claim 3 and R represents a carboxyalkyl group, fluorophenyl or difluorophenyl and the salts or addition salts with nitrogenous bases where these salts is . * A composition comprising at least one derivative according to claim 1 in pure form or in combination with one or more compatible diluents or one or more compatible additives.