NZ244518A - Benzo[b][1,8] naphthyridine derivatives and pharmaceutical compositions - 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

New Zealand Paient Spedficaiion for Paient Number £44518 24 4 5 1 Complete rpcciucsticn Filed: Class; f °1 CWnW,. OM ...

Publication Date: . .2 7. .APR. 199$! P.O. Jo'.'rnd, No: ....vCffi. 28 s:v ;r; NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NEW BENZO ri.81NAPHTHYRIDINE DERIVATIVES. THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM We, LABORATOIRE ROGER BELLON, a French body corporate, of 159 Avenue Achille Peretti, 92201 Neuilly-Sur-Seine, France, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page - la -) The present invention relates to benzo[b][l,8]naphthyridine derivatives, their preparation and compositions containing them.

In European Patent Application EP 431,991, benzonaphthyridine derivatives of formula: o in which Rj is H, hydroxy or alkyl, R2 is H, alkyl, fluoroalkyl, cycloclalkyl, alkyloxy or alkylamino, R3 is phenyl or phenylalkyl, optionally substituted, and ^ is H or a fluorine atom, have been described. These compounds are useful as antimicrobial agents.

It has now been found that the benzo[b][1,8]naphthyridine derivatives of formula: COOH '• 8 in which: R represents a hydrogen atom, a hydroxy1 radical, an amino radical, an alkylamino radical in which the alkyl portion is optionally substituted by an amino or hydroxyl 5 radical, a dialkylamino radical in which the alkyl portions, with the nitrogen atom to which they are attached, can optionally form a 5- or 6-membered heterocyclic ring optionally containing another hetero atom chosen from nitrogen, oxygen and sulphur, a (3- to 10 6-membered cycloalkyl)-amino radical, an alkanoylamino radical, an N-alkyl-N-alkanoyl-amino radical or an aminoalkylphenylamino radical,' R! and R2, which may be identical or different, are located, respectively, at positions 2 and 3 and each 15 represents a-hydrogen atom, an alkyl radical, an alkenyl radical containing 2 to 4 carbon atoms, a phenyl radical or a phenyl radical substituted by a halogen atom or by an alkyl, alkyloxy, hydroxyl, nitro, amino, alkylamino, dialkylamino or haloalkyl radical, or alternatively R, and 20 R2 are both located at position 2 and represent alkyl radicals; Rj represents a hydrogen atom, an alkyl radical, a fluoroalkyl radical, a carboxyalkyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms, a fluorophenyl 25 radical, a difluorophenyl radical, an alkyloxy radical, or an alkylamino radical; and R4 represents a hydrogen atom or a fluorine atom, 24 4 5 1 3 the aforesaid alkyl and alkanoyl radicals being unbranched or branched and containing 1 to 4 carbon atoms each, and their salts and, where appropriate, their stereoisomers, show especially advantageous anti-bacterial 5 activity. hydrated form, and these hydrates also fall within the scope of the present invention. compounds of formula (I) may be obtained by reaction of an 15 azetidine of formula: When R represents a dialkylamino radical in which the alkyl portions, with the nitrogen atom, form a heterocyclic ring, the latter can be, for examaple, pyrrolidinyl or piperidyl.

The products of formula (I) can exist in the According to a feature of the invention, the (II) in which R, R, and R2 are defined as above, with a benzo[b][l,8]naphthyridine of formula: o Hal F COOH (III) 2 0 in which R3 is defined as above, Hal is a fluorine, j f'i ,J>7 ^ S I C H- ^ o s chlorine or bromine atom if R4 is hydrogen, or alternatively Hal and R4 are simultaneously fluorine atoms.

The reaction of the azetidine derivative of formula (II) is generally performed in the presence of an 5 excess of this derivative as acid-acceptor in a suitable organic solvent. It is possible to work with or without a solvent, at a temperature of between 20 and 150°C. When the working conditions include the presence of a solvent, the reaction is advantageously performed in a solvent such as 10 pyridine, dimethylformamide, dimethyl sulphoxide or acetonitrile. It is also possible to operate in aqueous medium.

It can also be advantageous to work in the presence of an acid-acceptor such as, e.g., a nitrogenous 15 organic base (especially triethylamine) an alkali metal carbonate (e.g. sodium carbonate) or an alkali metal or alkaline earth metal hydroxide.

It is understood that, in the case where the symbol R3 of the product of formula (III) is a hydrogen 20 atom, or when R is an amino, optionally substituted alkylamino, cycloalkylamino or aminoalkyl-phenylamino radical, it is preferable to protect the starting material beforehand. The protection and the removal of the protective radical after the reaction may be performed by 25 the customary methods.

The protection may be carried out with any compatible group whose use and removal have no adverse effect on the remainder of the molecule. In particular, the ) A /.. & 1 methods employed are those described by T. W. GREENE, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication (1981), or by McOMIE, Protective Groups in Organic Chemistry, Plenum Press (1973) . For 5 example, the protective group may be a trimethylsilyl, benzhydryl, tetrahydro-pyranyl, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, ethoxycarbony1, t-butoxycarbonyl or trichloroethoxycarbonyl radical.

According to a further feature of the invention, the benzo[b][l,8]naphthyridine derivatives of formula (I) are also obtained froir. the corresponding esters of formula: in which Rlf R2 and R, are defined as above, R is defined as 15 above or represents a protected amino radical, R3 is defined as above or represents a protected alkylamino radical and Alk represents an unbranched- or branched-chain alkyl radical containing 1 to 4 carbon atoms, by any known method for obtaining an acid from an ester without 20 affecting the remainder of the molecule. o R R COO Alk (IV) The preparation of the acid from the ester is II t'l J % generally performed by saponification in the presence of potassium hydroxide or sodium hydroxide, in an aqueous or aqueous-alcoholic medium, at a temperature of between 20 and 100°C.

In the case where an ester of formula (IV) in which R is an alkanoylamino or N-alkyl-N-alkanoylamino radical or in which R is a protected amino radical, is hydrolysed, it is to be understood that, depending on the conditions employed, the product obtained is either the 10 acid in which R is an alkanoylamino or N-alkyl-N- alkanoylamino radical or in which R is a protected amino radical, or the acid in which hydrolysis of the amide has been performed simultaneously, i.e. in which R is an amino radical. The working conditions are chosen in accordance 15 with the expected final product. When R is a protected amino radical, it is naturally advantageous to remove the protective radical simultaneously.

When R3 represents a protected alkylamino radical, the protective radical can be any amino-protective 20 group compatible with the molecule. It is especially advantageous to choose a protective radical which can be removed simultaneously with the hydrolysis of the ester.

The benzo[b][1,8]naphthyridine derivative of formula (III) may be obtained from the corresponding ester of formula: Hal COO Alk (V) in which R3, R4, Hal and Alk are defined as above, by application of the method described in Patent US 4,990,515 or by a technique analogous to that described.

The ester derived from benzo[b][1,8]naphthyridine of formula (V) may be prepared by the action of 3-amino-10 1,2,4-triazine (to obtain a product in which R3 is a hydrogen atom), or by the action of a compound of formula: R3-NH2 (VI) in which R3 is alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl, fluorophenyl, difluorophenyl, alkyloxy or 15 alkylamino, optionally protected, on a quinoline derivative of formula: Hal COO Alk n(ch3)2 (VII) in which R4, Hal and Alk are defined as above, followed by cyclisation by the action of an acid-acceptor agent. 20 In general, the reaction of 3-amino-l,2,4- Of- /, R / i.:-, 1 triazine or of the product of formula (VI) is carried out in an organic solvent such as an alcohol (e.g. ethanol, methanol) or a chlorinated solvent (e.g. trichloromethane), at a temperature of between 10 and 25°C.

The cyclisation is performed in an unbranched- or branched-chain alcohol containing 1 to 4 carbon atoms, at a temperature between 20°C and the refluxing temperature of the reaction mixture.

The acid-acceptor agent can be, in particular, a 10 nitrogenous base (e.g. triethylamine), 1,8-diazabicyclo-[5.4.0]undec-7-ene, or an excess of the amine employed.

The benzo[b]naphthyridine derivatives of formulae (III) and (V) in which R3 is a carboxyalkyl, fluorophenyl or difluorophenyl radical are new products. It is 15 understood that these products as well as their salts, where they exist, also fall within the scope of the present invention.

The quinoline derivative of formula (VII) may be obtained as described in Patent US 4,990,515. 20 The aminoazetidine derivatives of formula (II) may be prepared according to the processes described by: T. Okutani et al. Chem. Pharm. Bull., 22 (7) 1490 (1974); S. Chatterjee et al. Chem. Comm., 93 (1968); D. Nisato et al. J. Heterocyclic. Chem., 22, 961 (1985); Akira Morimoto et 25 al., Chem. Pharm. Bull., 21 (1), 228 (1973); A.G. Anderson et al., J. Org. Chem., 37., 3953 (1972); V.R. Gaertner., J. Org. Chem., 2972 (1967), J.N. Wells et al., J. Org. Chem., a 34, 1477 (1969), J. Antibiotics, 39 (9), 1243 (1986) and J. Pharm. Soc., 60 (1), 156 (1971); EP 406,112; EP 314,362; EP 106,489; EP 324,298; JP 74/109,369 [C.A.83-9760 (1975)]; US 4,834,846 or by methods analogous to these. 3-Amino-3-phenylazetidine may 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 is prepared by a method analogous to that described in J. Am. Chem. Soc., 111. 1073 (1989) followed by liberation of the radical protecting the amine.

The benzo[b][1,8]naphthyridine derivative of formula (IV) may be obtained from the benzofb]-naphthyridine of formula (V) by substitution of an azetidine derivative of formula (II).

It is advantageous to work under the conditions described above for obtaining a product of formula (I) from an azetidine of formula (II) and a benzo[b][1,8]-naphthyridine of formula (III). When the reaction is carried out in aqueous medium, it is possible to obtain the product of formula (I) directly without intermediate isolation of the compound of formula (IV).

According to the invention, where appropriate, when it is desired to obtain the stereo-isomers of the benzonaphthyridine derivatives of formula (I), the separation of the stereo-isomeric forms of the azetidines of formula (II) is performed by any known method which is compatible with the molecule. As an example, the separation may be performed by acylation with a chiral acid or a reactive derivative of a chiral acid, separation of the & isomers by high performance liquid chromatography and then deacylation according to the method described by P. G. Gaseman et al., J. Am. Chem. Soc., 98 (5), 1275 (1976). It is also possible to perform the separation of the 5 stereoisomers by chiral-phase high performance liquid chromatography.

The compounds of formula (I) according to the present invention, and their synthesis intermediates, can be optionally purified by physical methods such as 10 crystallisation or chromatography.

The compounds of formula (I) according to the present invention, and their intermediates of formula (III) and, where appropriate, their intermediates of formula (V), may be converted into metal salts or into addition salts 15 with nitrogenous bases according to methods known per se. These salts may be obtained by the action of a metal-containing base (containing, e.g., an alkali metal or alkaline earth metal), ammonia or an amine on a compound according to the invention in a suitable solvent such as an 20 alcohol, an ether or water, or by an exchange reaction with a salt of an organic acid. The salt formed precipitates after concentration, where appropriate, of its solution; it is separated by filtration, decantation or lyophilisation.

The new products according to the invention may 25 also be converted to addition salts with acids. The products of formula (I) obtained in the form of these salts may be liberated and converted to salts of other acids according to the customary methods.

As examples of pharmaceutical^ acceptable salts, there may be mentioned the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals 5 (magnesium, calcium), the ammonium salt, the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, 10 N,N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine), as well as the addition salts with inorganic acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or organic acids (succinates, 15 fumarates, maleates, methanesulphonates, p-toluenesulphonates, isethionates).

The benzo[b][l,8]naphthyridine derivatives of formula (I) according to the present invention and their pharmaceutically acceptable salts exhibit especially 2 0 advantageous antibacterial properties. They manifest exceptional activity in vitro and in vivo against Gram-positive microorganisms and, generally, against the microorganisms responsible for most infections of the upper and lower airways. Furthermore, the benzo[b][1,8]-25 naphthyridine derivatives of formula (I) manifest especially advantageous antibacterial activity against Gram-negative microorganisms.

Preferred compounds in accordance with the invention include: 30 8-(3-amino-3-propyl-1-azetidinyl)-7-fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 8-(3-amino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; /' A r;:.

I.. "V s-' 8-(3-amino-3-methyl-l-azetidinyl) -7, 9-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b] [ 1,8]naphthyridine-3-carboxylic acid; and 8 - (3 -amino-3-ethy1-1-azetidiny1) -7 -f luoro-l-methy 1-4 -oxo-5 1,4-dihydrobenzo[b] [ 1, 8] naphthyridine-3-carboxylic acid and their salts.

In vitro, the products of formula (I) were shown to be active at a concentration of between 0.06 and 4 jug/cc against Staphylococcus aureus IP 8203, and at a 10 concentration of between 0.25 and 20 txq/cc against Escherichia Coli strain NIHJ JC2.

In vivo, the products of formula (I) were shown to be active against experimental Staphylococcus aureus IP 8203 infections of mice at oral doses of between 2 and 15 200 mg/kg.

Moreover, the preferred compounds of the invention have proved active against mycoplasma. Their minimal inhibitory concentration is between 0.03 and 8 /ig/ml.

The compounds according to the invention exhibit no toxicity at the doses used. They are generally non-toxic at oral doses of 500 mg/kg in mice.

The Examples which follow illustrate the present invention.

EXAMPLE 1 8- (3-Amino-l-azetidinyl) -7-fluoro-l-methyl-4-oxo-l, 4-dihydrobenzo[b] [1, 8] naphthyridine-3-carboxylic acid: A suspension of 7,8-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b] [ 1,8]naphthyridine-3-carboxylic acid 30 (1.16 g) and 3-aminoazetidine (1.38 g) in dimethyl sulphoxide (15 cc) is heated with stirring to a temperature in the region of 95°C for 6 hours. After cooling to approximately 20°C, water (100 cc) is added to the reaction mixture. The insoluble matter is drained, washed with water ? (. /', z 1 ^ ' ••I (3 x 20 cc), taken up with water (100 cc) and treated with N methanesulphonic acid (4 cc). After removal of some slight insoluble matter by filtration through diatomaceous silica and addition of N aqueous sodium hydroxide (4 cc), 5 the suspension obtained is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60°C to a volume of approximately 80 cc. The insoluble matter is drained, washed with water (100 cc) and ethanol (100 cc) and recrystallised in dimethylformamide (150 cc). 10 8-(3-Amino-i-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4- dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (0.7 g) is obtained in the form of a yellow solid, which decomposes at 358°C. 7,8-Difluoro-l-methy1-4-oxo-l,4-dihydro-15 benzo[b][l,8]naphthyridine-3-carboxylic acid is prepared as described in Patent US 4,990,515. 3-Aminoazetidine was prepared according to the method described by Dino Nisato et al., J. Het. Chem., 22, 961, (1985).

EXAMPLE 2 8-(3-Dimethylamino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: A suspension of 8-(3-dimethylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-l-methyl-4-oxo-l,4-25 dihydrobenzo[b][l,8]naphthyridine (1.9 g) in ethanol (20 cc) and 0.5 N aqueous potassium hydroxide (19 cc) is heated with stirring to a temperature in the region of 80°C i-%. for 5 hours. After cooling to approximately 5°C, the reaction mixture is treated with N aqueous methane sulphonic acid solution (9.5 cc). The insoluble matter is drained, washed with water (2 x io cc) and ethanol (3 x 5 25 cc) and recrystallised in dimethylformamide (125 cc). 8-(3-Dimethylamino-l-azetidinyl)-7-fluoro-l-methy1-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.4 g) is obtained in the form of a yellow solid, which decomposes at 312°c. 10 8-(3-Dimethylamino-l-azetidinyl)-3-ethoxy- carbonyl-7-fluoro-l-methyl-4-oxo-l,4-dihydro-benzo[b][1,8]naphthyridine was prepared in the following manner: A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-15 methyl-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine (2 g), 3-(dimethylamino)azetidine dihydrochloride (1.2 g) and sodium carbonate (1.5 g) in dimethyl sulphoxide (30 cc) is heated with stirring to a temperature in the region of 95°C for 5 hours. After cooling to approximately 20°C, the 20 reaction mixture is treated with water (60 cc). The insoluble matter is drained and washed with water (3 x 20 cc). 8-(3-Dimethylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (2 g) is obtained in the 25 form of a yellow solid, m.p. 224°C, which is used without further purification for the subsequent steps. 3-Ethoxycarbonyl-7,8-difluoro-l-methyl-4-oxo-l,4- i li K. < q dihydrobenzo[b] [1,8]naphthyridine may be prepared as descibed in Patent US 4,970,213.

EXAMPLE 3 8- (3-Amino-l-azetidinyl) -l-ethyl-7-fluoro-4-oxo-l, 4-5 dihydrobenzo[b] [l,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 8-(3-amino-l-azetidinyl) -3-ethoxycarbonyl-l-ethyl-7-f luoro-4-oxo-l, 4-dihydrobenzo[b][l,8]naphthyridine (0.72 g). Without 10 recrystallisation, 8-(3-amino-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-l, 4-dihydrobenzo[b] [1,8]naphthyridine-3-carboxylic acid monoh^drate (0.6 g) is obtained in the form of a yellow solid, which decomposes at 306°C. 8-(3-Amino-l-azetidinyl)-3-ethoxycarbonyl-l-15 ethyl-7-fluoro-4-oxo-l, 4-dihydrobenzo[b] [1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 3-ethoxy-carbonyl-l-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo-[b] [1,8]naphthyridine (1.7 g) and 3-aminoazetidine dimethanesulphonate (1.62 g) . The crude 20 product is taken up with dimethylformamide (100 cc) and stirred for 10 minutes at approximately 150°C. After cooling to approximately 20°C, some insoluble matter is removed by filtration. The filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 25 60°C. The residue is recrystallised in ethanol (50 cc) . 8- (3-Amino-l-azetidinyl) -3-ethoxycarbonyl-l-ethyl-7-fluoro- 4-oxo-l,4-dihydrobenzo[b] [1,8]naphthyridine (0.72 g) is obtained in the form of a yellow solid, m.p. 255-256°C. 3-Ethoxycarbonyl-l-ethyl-7,8-difluoro-4-oxo-l,4-^dihydrobenzo[b][1,8]naphthyridine was prepared as described in Patent US 4,970,213.

EXAMPLE 4 8- (3-Dimethylamino-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 8-(3-10 dimethylamino-l-azetidinyl)-3-ethoxycarbonyl-l-ethyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (2 g). 8-(3-Dimethylamino-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.68 g) is obtained in the form of a yellow solid, which 15 decomposes at 278°C. 8-(3-Dimethylamino-l-azetidinyl)-3-ethoxy-carbonyl-l-ethyl-7-fluoro-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 3-ethoxy-2 0 carbonyl-l-ethyl-7,8-difluoro-4-oxo-l,4-dihydrobenzo [b] [1,8] -naphthyridine (1.7 g), and 3-(dimethyl-amino)azetidine dihydrochloride (1.3 g). After reaction, the reaction mixture, cooled to approximately 20°C, is poured into water (50 cc) and extracted with 25 dichloromethane (3 x 100 cc). The combined organic extracts are washed with water (3 x 150 cc) and dried over magnesium sulphate. After concentration to dryness under reduced pressure (20 kPa) at approximately 40°C, the residue is taken up with ethyl ether (50 cc), filtered off and washed with the same solvent (2 x 50 cc). 8-(3-Dimethylamino-l-azetidinyl) -3-ethoxycarbonyl-l-ethyl-7-fluoro-4-oxo-l,4-5 dihydrobenzo[b][1,8]naphthyridine (2 g) is obtained in the form of a yellow solid, m.p. 232°C, which is used without further purification for the subsequent steps.

EXAMPLE 5 8-(3-Amino-l-azetidinyl)-l-cyclopropy1-7-fluoro-4-oxo-l,4-10 dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 8-(3-amino-l-azetidinyl)-l-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1 g). 8-(3-Amino-l-15 azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid hemihydrate (0.56 g) is obtained in the form of a yellow solid, which decomposes at 298-303°C. ^ 8-(3-Amino-l-azetidinyl)-l-cyclopropyl-3-20 ethoxycarbonyl-7-fluoro-4-oxo-l,4-dihydrobenzo- [b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with l-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-l,4-dihydrobenzo [b] [1,8] naphthyridine (1.7 g) and 3-aminoazetidine 25 dimethanesulphonate (1.88 g). After 1 recrystallisation in ethanol (50 cc), 8-(3-amino-l-azetidinyl)-l-cyclopropyl-3-ethoxycarbony1-7-fluoro-4-oxo-1,4- C*''< dihydrobenzo[b][1,8]naphthyridine (1.05 g) is obtained in the form of a yellow solid, m.p. 178-180°C. l-Cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine may be prepared 5 as described in Patent US 4,970,213.

EXAMPLE 6 l-Cyclopropyl-8-(3-dimethylamino-l-azetidinyl)-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 4, but starting with l-cyclopropyl-8-(3-dimethylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.27 g). l-Cyclopropyl-8-(3-dimethylamino-l-azetidinyl)-7-fluoro-4-15 oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.8 g) is obtained in the form of yellow solid, m.p. 264°C. l-Cyclopropyl-8-(3-dimethylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-l, 4-20 dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 4, but starting with 1-cyclopropy1-3-ethoxycarbony1-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.4 g) and 3-(dimethylamino)azetidine dihydrochloride (1.04 g). After 25 concentration of the combined organic extracts to dryness, the solid obtained is recrystallised in ethanol (40 cc). l-Cyclopropyl-8-(3-dimethylamino-l-azetidinyl)-3- ethoxycarbonyl-7-fluoro-4-oxo-l, 4- dihydrobenzo[b][1,8]naphthyridine (1.2 g) is obtained in the form of a yellow solid, m.p. 225°C.

EXAMPLE 7 8-(3-Amino-l-azetidinyl)-l-cyclopropyl-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 8-(3-amino-l-azetidinyl)-l-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-10 oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.8 g). Without recrystallisation, 8-(3-amino-l-azetidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid monohydrate (0.6 g) is obtained in the form of a yellow solid, which decomposes at 308-312°C. 15 8-(3-Amino-l-azetidinyl)-l-cyclopropyl-3- ethoxycarbony1-7,9-difluoro-4-oxo-l,4-dihydro-benzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with l-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-l,4-20 dihydrobenzo[b][1,8]naphthyridine (1.3 g) and 3-aminoazetidine dimethanesulphonate (1.32 g). After recrystallisation in ethanol (50 cc), 8-(3-amino-l-azetidinyl) -l-cyclopropyl-3-ethoxycarbonyl-7 ,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.8 g) is obtained in the form of a yellow solid, m.p. 236-238°C. l-Cyclopropyl-3-ethoxycarbonyl-7,8,9-tri-fluoro- 4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine was prepared as r: o ■•j (.) described in Patent US 4,970,213.

EXAMPLE 8 8-(3-Diethylamino-l-azetidinyl)-7-fluoro-4-oxo-1-methyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic 5 acid was prepared under the conditions of Example 2, but starting with 8-(3-diethylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (1.75 g) . 8-(3-Diethylamino-l-azetidinyl)-7-fluoro-4-oxo-l-methyl-10 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.4 g) is obtained in the form of a yellow solid, which decomposes at 297°C. 8-(3-Diethylamino-l-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-l-methyl-4-oxo-l,4-dihydro-15 benzofb][l,8]naphthyridine was prepared under the conditions of Example 2, but starting with 3-ethoxy-carbonyl-7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (2 g) and 3-(diethylamino)-azetidine dihydrochloride (1.4 g). After recrystallisation 20 of the crude product in methanol (500 cc) , 8—(3 — diethylamino-l-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (2.07 g) is obtained in the form of a yellow solid, m.p. 260°C. 3-(Diethylamino)azetidine was prepared in the 25 form of dihydrochloride, m.p. 175°C, according to the method described in Japanese Patent Application 74/109,369. EXAMPLE 9 'i n 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 3-ethoxycarbonyl-5 8-(3-ethylamino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzofb][1,8]naphthyridine (0.51 g). 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid monohydrate (0.4 g) is obtained in the form of a yellow 10 solid, which decomposes at 270°C. 3-Ethoxycarbonyl-8-(3-ethylamino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo [b] [1,8] naphthyridine was prepared under the conditions of Example 2, but starting with 7,8-difluoro-3-15 ethoxycarbonyl-l-methyl-4-oxo-l,4- dihydrobenzofb][1,8]naphthyridine (2 g) and 3-(ethyl-amino)azetidine dihydrochloride (1.3 g). After the addition of water (300 cc) to the reaction mixture, the suspension obtained is extracted with dichloromethane (3 x 100 cc). 20 The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 40°C. The product obtained is purified by chromatography on 0.063-0.200 mm silica gel suspended in dichloromethane containing 25 ethanol (1 %). The desired product is eluted with dichloromethane (500 cc) containing methanol (5 %). 3-Ethoxycarbonyl-8-(3-ethyl-amino-l-azetidinyl)-7-fluoro-1- methyl-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine (0.51 g) is obtained in the form of a yellow solid, which decomposes at 215°C and which is used without further purification for the subsequent steps. 3-(Ethylamino)azetidine dihydrochloride may be prepared by a method analogous to that described by Dino Nisato et al., J. Het. Chem., 22., 961 (1985): l-Benzhydryl-3-(ethylamino)azetidine dihydrochloride (4 g) in methanol (50 cc) is hydrogenated 10 at atmospheric pressure and at a temperature in the region of 20°C for 1 hour in the presence of 20 % palladium hydroxide on carbon (800 mg). After removal of the catalyst by filtration and concentration to dryness under reduced pressure (20 kPa) at approximately 40°C, the residue is 15 taken up with ethyl ether (30 cc), drained and washed with the same solvent (3 x 20 cc). 3-(Ethylamino)azetidine dihydrochloride (2.05 g) is obtained in the form of a colourless solid, m.p. 200°C, which is used without further purification for the subsequent steps. 20 l-Benzhydryl-3-(ethylamino) azetidine dihydrochloride is prepared in the following manner: A mixture of l-benzhydryl-3-(methane-sulphonyloxy)azetidine (55 g) and ethylamine (70 g) in methanol (400 cc) is heated to approximately 60°C for 16 25 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2 0 kPa) at approximately 40°C and the residue is taken up with ethyl ether (200 cc). The organic phase, washed with 2N aqueous sodium hydroxide (90 cc) and water (3 x 30 cc), is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 40°C, 12N hydrochloric acid 5 (22.6 cc) is added to the dry extract obtained, and the mixture is again concentrated to dryness under the above conditions but at approximately 70°C. The residue is taken up with ethyl acetate (100 cc) and acetone (200 cc) and drained. l-Benzhydryl-3-(ethylamino)azetidine 10 dihdyrochloride (41.4 g) is obtained in the form of a colourless solid, m.p. 180°C, which is used without further purification for the subsequent steps. l-Benzhydryl-3-(methanesulphonyloxy)azetidine was prepared according to the method described by 15 A. G. Anderson et al., J. Org. Chem., 37, 3953 (1972). EXAMPLE 10 8-(3-Amino-l-azetidinyl)-7-fluoro-l-methylamino-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: A suspension of 8-(3-acetylamino-l-azetidinyl)-3-2 0 ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) in N aqueous potassium hydroxide (4 0 cc) is heated with stirring to a temperature in the region of 100°C for 24 hours. After cooling to approximately 70°C, some slight insoluble matter 25 is removed by filtration. At the same temperature, N methanesulphonic acid (40 cc) is added to the filtrate, and the precipitate formed is drained and washed with water (3 x 20 cc) at approximately 70°C. After recrystallisation in dimethylformamide (100 cc) , 8-(3-amino-l-azetidinyl)-7-fluoro-l-methylamino-4-oxo-l,4- dihydrobenzo[b][i,8]naphthyridine-3-carboxylic acid 5 (1.05 g) is obtained in the form of a yellow solid, which decomposes at 315-318°C. 8-(3-Acetylamino-l-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-i-(N-formyl-N-methylamino)-4-oxo-l, 4-dihydrobenzo[b][1,8]naphthyridine was prepared in the 10 following manner: 7,8-Difluoro-3-ethoxycarbonyl-l-(N-formyl-N-methylamino) -4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) is added to a mixture at approximately 30°C of 3-(acetylamino)azetidine hydrochloride (1.13 g) and sodium 15 carbonate (0.85 g) in dimethyl sulphoxide (40 cc), and the mixture is heated to approximately 80°C for 2 hours. After cooling to approximately 20°C, the reaction mixture is poured into water (100 cc) at approximately 5°C. The precipitate is drained and washed with water (3 x 50 cc). 20 8-(3-Acetyl-amino-i-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-l,4-dihydro-benzo[b][1,8]naphthyridine (2.05 g) is obtained in the form of a yellow solid, which decomposes at 305°C. 7, 8-Difluoro-3-ethoxycarbonyl-l-(N-formyl-N-25 methylamino)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine was prepared in the following manner: A solution of N-formyl-N-methylhydrazine (1.63 g) in dichloromethane (3 0 cc) is added in the course of 10 minutes at approximately 20°C to a stirred solution of ethyl 2-(2-chloro-6,7-difluoro-3-quinolyl-carbonyl)-3-(dimethylamino)acrylate (7.4 g) in dichloromethane (30 cc). 5 After 16 hours at a temperature in the region of 20°C, the reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 40°C. The dry extract is taken up with ethanol (100 cc) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3 cc) and heated to approximately 75°C for 3 0 10 minutes. After cooling to approximately 20°C, the product is drained and washed with ethanol (2 x 50 cc) and ethyl ether (2 x 30 cc). 7,8-Difluoro-3-ethoxy-carbonyl-l-(N-formyl-N-methylamino)-4-oxo-l,4-dihydro- benzo[b][1,8]naphthyridine (3.9 g) is obtained in the form 15 of a yellow solid, m.p. 259-260°C, which is used without further purification for the subsequent steps.

Ethyl 2-(2-chloro-6,7-difluoro-3-quinolyl-carbonyl)-3-(dimethylamino)acrylate was prepared as described in Patent US 4,970,213. 20 3-(Acetylamino)azetidine hydrochloride was prepared according to the method described by Dino Nisato et al., J. Heterocyclic Chem. 22., 961 (1985).

EXAMPLE 11 8-(trans-3-Amino-2-methyl-l-azetidinyl)-7-fluoro-l-methyl-25 4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: A solution of trans-3-amino-2-methylazetidine dimethanesulphonate (18 g) and triethylamine (12.7 g) in dimethyl sulphoxide (150 cc) is heated with stirring to approximately 70°C for 20 minutes. At the same temperature, 7,8-difluoro-l-methyl-4-oxo-l,4-dihydro-5 benzo[b][l,8]naphthyridine-3-carboxylic acid (14.5 g) is added in small portions in the course of 10 minutes, and the mixture is heated to approximately 90°C for 2 hours. After cooling to approximately 20°C, the reaction mixture is poured into water (4 00 cc) at the same temperature. The 10 insoluble matter is drained, washed with water (2 x 100 cc) and ethanol (2 x 100 cc) and recrystallised in dimethylformamide (30C cc). 8-(trans-3-Amino-2-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid 15 (13.9 g) is obtained in the form of a yellow solid, which decomposes at 265-267°C. trans-3-Amino-2-methylazetidine was prepared in the form of the dimethanesulophonate, m.p. 170-175°C, according to the synthesis described in Patent Application 20 EP 406,112.

EXAMPLE 12 8-(cis-3-Amino-2-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions of Example 11, but starting with 7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.45 g) and cis-3-amino-2-methylazetidine dimethanesulphonate (2.1 g). 8-(cis-3-Amino-2-methyl-l-azetidinyl)-7-fluoro-l-methy1-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid 5 (1.32 g) is obtained in the form of yellow solid, which decomposes at 312-315°C. cis-3-Amino-2-methylazetidine was prepared in the form of the dimethanesulphonate, m.p. 160-170°C, according to the synthesis described in Patent Application EP 10 406,112.

EXAMPLE 13 8-(trans-3-Amino-2-methyl-l-azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: A suspension of 8-(trans-3-amino-2-methyl-l- azetidinyl)-l-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.4 g) in water (15 cc) and N aqueous potassium hydroxide (6.8 cc) is heated to approximately 95 °C for 3 hours. After cooling to 20 approximately 60°C, some very slight insoluble matter is removed by filtration; at the same temperature, N methanesulphonic acid (6.8 cc) is added to the filtrate. The insoluble matter formed is drained at approximately 20°C and washed with water (3 x 50 cc) and ethanol 25 (2 x 25 cc). After recrystallisation in dimethylformamide (30 cc), 8-(trans-3-amino-2-methyl-l-azetidinyl)-1-cyclopropy1-7-fluoro-4-oxo-1,4-dihydro- r..s ■ 5 benzo[b][l,8]naphthyridine-3-carboxylic acid (1.03 g) is obtained in the form of a yellow solid, which decomposes at 268-270 °C. 8-(trans-3-Amino-2-methyl-l-azetidinyl)-1-5 cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine was prepared in the following manner: l-Cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.7 g) is added 10 in small portions in the course of 10 minutes to a solution of trans-3-amino-2-methylazetidine dimethanesulphonate in dimethyl sulphoxide (20 cc) and triethylamine (1.52 g) at approximately 60°C. The reaction mixture is heated to a temperature in the region of 80°C and kept stirring at the 15 same temperature for approximately 4 hours. After cooling to approximately 2 0°c, the reaction mixture is poured into water (100 cc) and extracted with dichloromethane (2 x 100 cc) . The combined organic extracts are washed with water (2 x 50 cc), dried over magnesium sulphate and 20 concentrated to dryness under reduced pressure (20 kPa) at approximately 40°C. The dry extract is chromatographed on silica gel (0.04-0.063 mm) (125 g) suspended in a dichloromethane mixture containing ethanol (20 %). The desired product is eluted with the same mixture (300 cc). 25 8-(trans-3—Amino-2-methyl-l-azetidinyl)-l-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-l,4- dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.6 g) ■o is obtained in the form of a yellow solid, m.p. 170°C. EXAMPLE 14 8-(3-Amino-l-azetidinyl)-7-fluoro-4-oxo-l-tert-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: 5 A suspension of 8-(3-trifluoroacetamido-l- azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-l-tert-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine (2.2 g) in N aqueous potassium hydroxide (17 cc) is heated to approximately 95°C for 7 hours. At the same temperature, N methanesulphonic 10 acid (17 cc) is added and the product is drained at approximately 90°C, washed with water (2 x 30 cc) and ethanol (2 x 30 cc) and recrystallised in dimethylformamide (50 cc). 8-(3-Amino-l-azetidinyl)-7-fluoro-4-oxo-l-tert-butyl-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic 15 acid (1.4 g) is obtained in the form of a yellow solid, which decomposes at 333-335°C. 3-Ethoxycarbonyl-7-fluoro-8-(3-trifluoro-acetamido-l-azetidinyl)-4-oxo-l-tert-butyl-l,4-dihydro-benzo[b][l,8]naphthyridine was prepared under the 20 conditions described in Example 2, but starting with 3-ethoxycarbonyl-7,8-difluoro-4-oxo-l-tert-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g), 3-(trifluoroacetamido)azetidine hydrochloride (1.5 g) and sodium carbonate (0.79 g). 3-(Ethoxycarbonyl-7-fluoro-8-(3-25 trifluoroacetamido-l-azetidinyl)-4-oxo-l-tert-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine (2.25 g) is obtained in the form of a yellow solid, m.p. 328-330°C. ■" o 3-Ethoxycarbonyl-7,8-difluoro-4-oxo-l-tert-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 10, but starting with ethyl 2-(2-chloro-6,7-difluoro-3-quinolylcarbonyl)-3-5 (dimethylamino)acrylate (4 g) and tert-butylamine (0.87 g) . 3-Ethoxycarbonyl-7,8-difluoro-4-oxo-l-tert-buty1-1,4-dihydrobenzo[b][1,8]naphthyridine (2.7 g) is obtained in the form of a yellow solid, m.p. 206°C, which is used without further purification for the subsequent steps. 10 3-(Trifluoroacetamido)azetidine hydrochloride was prepared as described in Patent Application EP 406,112. EXAMPLE 15 8-(3-Amino-3-propyl-l-azetidinyl)-7-fluoro-l-methy1-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: 15 3-Amino-3-propylazetidine dimethanesulphonate (2.3 g) is added to a solution of sodium ethylate (1.22 g) in ethanol (18 cc). After the addition of dimethyl sulphoxide (30 cc), the solution is stirred for 10 minutes at approximately 20°C. At the same temperature, 7,8-20 difluoro-l-methyl-4-oxo-l,4-dihydro- benzo[b][l,8]naphthyridine-3-carboxylic acid (1.45 g) is added and the mixture is heated with stirring to approximately 90°C for 5 hours. After coooling to approximately 20°C, the product is drained and washed with 25 water (4 x 20 cc) and ethanol (2 x 10 cc). After recrystallisation in dimethylformamide (30 cc), 8-(3-amino-3-propyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.52 g) is obtained in the form of a yellow solid, which decomposes at 304-305°C. 3-Amino-3-propylazetidine in the form of the 5 dimethanesulphonate was prepared under conditions similar to those described by D. Nisato et al., J. Heterocyclic, 22, 961 (1985) .

By hydrogenation of 3-amino-l-benzhydryl-3-propylazetidine (7.3 g) at a pressure of 1 atmosphere in 10 the presence of methanesulphonic acid (5 g) in methanol (75 cc) and 20 % palladium hydroxide on carbon (1.5 g), 3-amino-3-propylazetidine dimethanesulphonate (6.5 g) is obtained. The product is taken up in ethanol and isolated in the form of a colourless solid, m.p. 200°C. 15 3-Amino-l-benzhydryl-3-propylazetidine was prepared in the following manner: l-Benzhydryl-3-methanesulphonyloxy-3-propyl-azetidine (7.5 g) is added to a solution (100 cc) of ammonia in ethanol (prepared from 15 g of ammonia in 20 100 cm3 of ethanol at 5°C) at approximately 5°C, the temperature is allowed to rise to approximately 20°C and the mixture is stirred for 16 hours at the same temperature. After concentration to dryness under reduced pressure (20 kPa) at approximately 40°C, the 25 residue is taken up with water (25 cc) and methanesulphonic acid (2.22 g). The aqueous phase is washed with ethyl ether (2 x 25 cc), treated with 40 % aqueous sodium hydroxide (10 cc) and extracted with dichloromethane (3 x 50 cc); the combined organic extracts r) are washed with water (10 cc) saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness under the above conditions. 3-Amino-l-benzhydryl-3-propylazetidine (5.2 g) is obtained in the form of a oily 5 product, which is used without further purification for the subsequent steps. l-Benzhydryl-3-methanesulphonyloxy-3-propyl-azetidine was prepared under the conditions described for l-benzhydryl-3-methanesulphonyloxy-3-methylazetidine in 10 Patent Application EP 406,112, but starting with l-benzhydryl-3-hydroxy-3-propylazetidine (2.8 g). l-Benzhydryl-3-methanesul-phonyloxy-3-propylazetidine (2.4 g) is obtained in the form of a colourless solid, m.p. 70°C. l-Benzhydryl-3-hydroxy-3-propylazetidine was prepared under the following conditions: A solution of l-benzhydryl-3-oxoazetidine (7.5 g) dissolved in ethyl ether (50 cc) is added in the course of 20 minutes at between 0 and 5°c to a solution of 20 propylmagnesium iodide in ethyl ether, prepared under the usual conditions from iodopropane (10.75 g) and magnesium (1.55 g) in ethyl ether (75 cc). The temperature is allowed to rise to approximately 20°C and the mixture is stirred at the same temperature for 2 hours. After cooling to 25 approximately 0°C, water (50 cc) and 10 % aqueous ammonium chloride solution (50 cc) are added successively while the latter temperature is maintained. The aqueous phase is J ) extracted with ethyl ether (3 x 50 cc). The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 30°C. The dry extract is chromatographed on 5 silica gel (0.04-0.063 mm) (100 g) suspended in a cyclohexane mixture containing ethyl acetate (20 %). The desired product is eluted with the same solvent mixture (130 cc). l-Benzhydryl-3-hydroxy-3-propyl-azetidine (8 g) is obtained in the form of a pale yellow oil, which is used 10 without further purification for the subsequent steps. l-Benzhydryl-3-oxo-azetidine was prepared under the conditions described by A. Morimoto et al. Chem. Pharm. Bull. 21 (1) 228-231 (1973).

EXAMPLE 16 8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid: 3-Amino-3-methylazetidine dimethanesulphonate (2.09 g) is added to a solution of sodium ethylate (1.02 g) in ethanol (30 cc) at approximately 5°C. The temperature is 20 allowed to rise to approximately 20°C and the mixture is stirred for 15 minutes at the same temperature. After removal of inorganic salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 30°c. The residue is dissolved in dimethyl 25 sulphoxide (20 cc) and treated at a temperature in the region of 20°C with 7,8-difluoro-l-ethyl-4-oxo-l,4-dihydro-benzo[b][l,8]naphthyridine-3-carboxylic acid (1.45 g). The suspension obtained is stirred for 16 hours at the same temperature and then heated to approximately 60°C for 1 hour. After cooling to approximately 20 °C, the insoluble matter is drained and washed with ethanol (30 cc). The 5 product isolated is recrystallised in dimethylformamide (90 cc), drained and washed with ethanol (20 cc) at approximately 75°C. 8-(3-Amino-3-methyl-l-azetidinyl) -7-fluoro-l-methyl-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.2 g) 10 is obtained in the form of a yellow solid, which decomposes at 345°C. 3-Amino-3-methylazetidine in the form of the dimethanesulphonate, m.p. 204-206°c, is prepared under the conditions described in Patent Application EP 406,112. 15 EXAMPLE 17 8-(3-Amino-3-methyl-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 7,8-difluoro-l-ethyl-4-20 oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.52 g) and 3-amino-3-methylazetidine dimethanesulphonate (2.22 g), for 72 hours at approximately 20°C and then 1 and a half hours at a temperature in the region of 90°C. The insoluble matter in the reaction mixture is drained at 25 approximately 20°C, washed with water (2 x 20 cc), recrystallised in dimethylformamide (70 cc) and washed with ethanol (40 cc) at approximately 75°C. 8-(3-Amino-3-methyl- v / A ^ 1 sL.. ' i ' u i"1' t - 35 - 1-azetidinyl)-l-ethyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.45 g) is obtained in the form of a yellow solid, which decomposes at 334°C.

EXAMPLE 18 8-(3-Amino-3-methyl—1-azetidinyl)-1-cyclopropyl-7-fluoro—4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 16, but starting with l-cyclopropyl-7,8-10 difluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.58 g) and 3-amino-3-methylazetidine dimethanesulphonate (2.22 g). 8-(3-Amino-3-methyl-l-azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.7 g) 15 is obtained in the form of a yellow solid, which decomposes at 2980c. l-Cyclopropyl-7,8-difluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid was prepared under the following conditions: 20 A suspension of l-cyclopropyl-3-ethoxy-carbonyl-' 7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (8.05 g) in a mixture of 17.5 % aqueous hydrochloric acid solution (80 cc) and acetic acid (80 cc) is heated with stirring to a temperature in the region of 100°C for 2 25 hours. After cooling to approximately 20°C, the product is drained and washed with water (3 x 100 cc). 1-Cyclopropyl-7,8-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3- carboxylic acid (6.25 g) is obtained in the form of a pale yellow solid, which decomposes at 238°C and which is used without further purification for the subsequent steps. EXAMPLE 19 (RS)-8-(3-Amino-2,2-dimethyl-l-azetidinyl)-7- fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]— naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 7,8-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b]-10 [l,8]naphthyridine-3-carboxylic acid (1.45 g) and 3-amino-2,2-dimethylazetidine dimethanesulphonate (2.33 g). The reaction mixture is heated with stirring to approximately 100°C for 5 hours. (RS)-8-(3-Amino-2,2-dimethyl-l-azetidinyl) -7-fluoro-i-methyl-4-oxo-l,4-15 dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.6 g) is obtained in the form of a yellow solid, which decomposes at 285°C. 3-Amino-2,2-dimethylazetidine dimethanesulphonate was prepared in the form of a white solid, m.p. 20 125-130°C, from 3-amino-2,2,-dimethylazetidine, by adaptation of the method described by Akira Morimoto Chem. Pharm. Bull., 21 (1), 228 (1973).

EXAMPLE 20 7-Fluoro-l-methyl-8-(3-methyl-3-methylamino-l-25 azetidinyl)-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-methyl-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.45 g) and 3-methyl-3-(methylamino)azetidine dimethanesulphonate (2.34 g). The reaction mixture is heated for 1 and a half hours to approximately 90°C. 7-Fluoro-l-methyl-8- (3-methyl-3-methylamino-l-azetidinyl) -1-methy1-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.12 g) is obtained in the form of a yellow solid, which decomposes at approximately 336°C. 3-Methyl-3-(methylamino)azetidine in the form of 10 the dimethanesulphonate (m.p. 135°) was prepared under the conditions described in Patent Application EP 406,112. EXAMPLE 21 l-Cyclopropyl-7-fluoro-8-(3-methy1-3-methylamino-1-azetidiny1)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-15 3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-cyclopropyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.58 g) and 3-methyl-3-(methylamino) azetidine dimethanesulphonate (2.34 g). l-Cyclopropyl-7-fluoro-8-(3-20 methyl-3-methylamino-l-azetidinyl)-4-oxo-l,4-dihydrobenzo-[b][l,8]naphthyridine-3-carboxylic acid (1.57 g) is obtained in the form of a yellow solid, which decomposes at 330°C.

EXAMPLE 22 l-Ethyl-7-fluoro-8-(3-methyl-3-methylamino-l- azetidinyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-ethyl-4-oxo-1,4-dihydrobenzo[b] [1,8 Jnaphthyridine-3-carboxylic acid (1.52 g) and 3-methyl-3-(methylamino)azetidine dimethanesulphonate (2.34 g). l-Ethyl-7-fluoro-8-(3-methyl-5 3-methylamino-l-azetidinyl)-4-oxo-l, 4-dihydrobenzo[b] [1,8]-naphthyridine-3-carboxylic acid (1.18 g) is obtained n the form of a yellow solid, which decomposes at 338°C.

EXAMPLE 23 8- (3-Amino-3-methyl-l-azetidinyl) -7-f luoro-1-10 methoxy-4-oxo-l, 4-dihydrobenzo[b] [1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-methoxy-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3-carboxylic acid (1.53 g) and 3-amino-3-methylazetidine dimethane-sulphonate 15 (2.22 g). 8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-1-methoxy-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.27 g) is obtained in the form of a yellow solid, which decomposes at 346°C. 7,8-Difluoro-l-methoxy-4-oxo-l,4-dihydrobenzo-20 [b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions described in Patent US 4,970,213.

EXAMPLE 24 l-Cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-l-azetidinyl)-4-oxo-l,4-dihydro-25 benzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1-cyclopropyl-7,8-difluoro-4-oxo-l,4- dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.58 g) and 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate (2.45 g). l-Cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino-l-azetidinyl)-4-oxo-l,4-5 dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.55 g) is obtained in the form of a yellow solid, which decomposes at 268°C. 3-Methyl-3-(dimethylamino)azetidine in the form of the dimethanesulphonate, m.p. 148°C, is prepared under 10 the conditions described in Patent Application EP 406,112. EXAMPLE 25 7-Fluoro-l-methyl-8-(3-methyl-3-dimethylamino-l-azetidinyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 7,8-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.45 g) and 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate (2.45 g). 7-Fluoro-l-methyl-8-(3-methyl-3-dimethylamino-l-azetidinyl)-4-oxo-l,4-20 dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.56 g) is obtained in the form of a yellow solid, which decomposes at 274°C.

EXAMPLE 26 8-(3-Amino-3-methyl-1-azetidinyl)-7,9-difluoro-l-25 methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3- carboxylic acid was prepared under the following conditions: 3-Amino-3-methylazetidine dimethanesulphonate (1.33 g) is added to a solution of sodium ethylate (0.68 g) in ethanol (7 cc). After the addition of dimethyl sulphoxide (20 cc), the solution is stirred for 10 minutes 5 at approximately 20°C. At the same temperature, 7,8,9-Trifluoro-l-methyl-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.75 g) is added, and the mixture is stirred for 72 hours at approximately 2 0°C.

The insoluble matter is drained and washed with water (2 x 20 cc) and ethanol (2 x 20 cc). After recrystallisation in dimethylformamide (70 cc) , 8-(3-amino-3-methyl-l-azetidinyl)-7,9-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid 15 (0.45 g) is obtained in the form of a yellow solid, which decomposes at 359°C. 7,8,9-Trifluoro-l-methyl-4-oxo-l,4-dihydrobenzo [b] [1, 8] naphthyridine-3-carboxylic acid was prepared in the following manner: A suspension of 3-ethoxycarbonyl-7,8,9-trifluoro- l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.88 g) in a mixture of 17.5 % aqueous hydrochloric acid solution (10 cc) and acetic acid (10 cc) is heated with stirring to a temperature in the region of 100°C for 3 25 hours. After cooling to approximately 20°C, the product is drained and washed with water (3 x io cc). 7,8,9-Trifluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3- (, i carboxylic acid (0.75 g) is obtained in the form of a pale yellow solid, which decomposes at 352°C and which is used without further purification for the subsequent steps. 3-Ethoxycarbonyl-7,8,9-trifluoro-l-methyl-4-oxo-5 l,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Patent US 4,970,213.

EXAMPLE 27 8-(3-Cyclopropylamino-3-methyl-l-azetidinyl)-7-fluoro-l-methy1-4-oxo-l,4-dihydrobenzo[b][1,8]-10 naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-1-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.45 g) and 3-cyclopropylamino-3-methylazetidine dimethanesul-phonate (2.5 g). 8—(3— 15 Cyclopropylamino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.73 g), solvated with water (0.7 %) is obtained in the form of a yellow solid, which decomposes at 300°C. 3-Cyclopropylamino-3-methylazetidine 20 dimethanesulphonate was prepared in the following manner: l-Benzhydryl-3-cyclopropylamino-3-methyl-azetidine (14.5 g) in methanol (150 cc) are hydrogenated at atmospheric pressure and at a temperature in the region of 20°C for 1 hour in the presence of 20 % palladium hydroxide 25 on carbon (5.6 g). The reaction mixture is treated with methanesulphonic acid (10 g). After removal of the catalyst by filtration and concentration to dryness under reduced 11 b pressure (20 kPa) at approximately 40°C, the residue is washed with ethyl ether (3 x 150 cc). The final residue is taken up with 2-propanol (100 cc), drained and washed with acetone (2 x 50 cc). 3-Cyclopropylamino-3-methylazetidine 5 dimethanesulphonate (9.1 g) is obtained in the form of a colourless solid, m.p. 136°C. l-Benzhydryl-3-cyclopropylamino-3-methyl-azetidine was prepared in the following manner: A suspension of l-benzhydryl-3-methane-10 sulphonyloxy-3-methylazetidine and cyclopropylamine (28.84 g) in ethanol (250 cc) is stirred for 96 hours at approximately 20°C. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 30°C. The dry extract is taken up with water (50 cc) and 15 methanesulphonic acid (8.8 g). The aqueous phase is washed with dichloromethane (3 x 25 cc), treated with 35 % aqueous sodium hydroxide (12 cc) and extracted with ethyl acetate (3 x 50 cc). The combined organic phases are washed with water (2 x 50 cc), dried over magnesium sulphate and 20 concentrated to dryness under reduced pressure (20 kPa) at approximately 25°C. l-Benzhydryl-3-cyclopropylamino-3-methylazetidine (14.6 g) is obtained in the form of a yellow oil, which is used without further purification for the subsequent steps. 25 l-Benzhydryl-3-methanesulphonyloxy-3-methyl- azetidine was prepared according to the conditions described in Patent Application EP 406,112.

EXAMPLE 28 8- (3-Ethylamino-3-methyl-l-azetidinyl) -7-f luoro-l-methy 1—4-oxo-l ,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.45 g) and 3-ethylamino-3-methylazetidine dimethanesulphonate (2.24 g). 8-(3-Ethylamino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.66 g) is obtained in the form of a yellow solid, which decomposes at 312°C. 3-Ethylamino-3-methylazetidine dimethanesulphonate was prepared under the conditions described in Example 27, but starting with l-benzhydryl-3-ethyl-amino-3-methylazetidine (14 g). 3-Ethylamino-3-methyl-azetidine dimethanesulphonate (9.7 g) is obtained in the form of a colourless solid, m.p. 140°C. l-Benzhydryl-3-ethylamino-3-methylazetidine was prepared under the conditions described in Example 27, but starting with l-benzhydryl-3-methanesulphonyl-oxy-3-methylazetidine (16.6 g) and ethylamine (45 g). l-Benzhydryl-3-ethylamino-3-methylazetidine (14 g) is obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.

EXAMPLE 29 7-Fluoro-8-(3-methylamino-l-azetidinyl)-1- methoxy-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but starting with 3-ethoxycarbonyl-7-fluoro-1-methoxy-8-(3-methylamino-l-azetidinyl)-4-oxo-l,4-5 dihydrobenzo[b][1,8]naphthyridine (2.6 g). 7-Fluoro-8-(3-methylamino-l-azetidinyl)-l-methoxy-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.7 g) is obtained in the form of a yellow solid, which decomposes at 255-260°C. 3-Ethoxycarbonyl-7-fluoro-l-methoxy-8-(3- methylamino-l-azetidinyl)-4-oxo-l,4-dihydrobenzo [b][1,8]naphthyridine was prepared under the following conditions: 3-(Methylamino)azetidine dihydrochloride (2.8 g) 15 is added to a solution of sodium ethylate (2.36 g) in ethanol (20 cc). After 15 minutes' stirring at a temperature in the region of 2 0°C and removal of the inorganic salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 20 30°C. The residue is dissolved in dimethylsulphoxide (40 cc) and the solution treated with 3-ethoxycarbonyl-7,8-difluoro-l-methoxy-4-oxo-1,4- dihydrobenzo[b][1,8]naphthyridine (2.7 g). The reaction mixture is heated to approximately 60°C for l and a half 25 hours. 3-Ethoxycarbonyl-7-fluoro-8-(3-methylamino-l-azetidinyl) -l-methoxy-4 -oxo-1, 4-dihydrobenzo [b] -[1,8]naphthyridine (2.7 g) is obtained in the form of a yellow solid, m.p. 234°C. 3-(Methylamino)azetidine dihydrochloride was prepared under the conditions described in Example 9, but starting with l-benzhydryl-3-(methylamino)azetidine 5 (32.2 g). 3-(Methylamino)azetidine dihydrochloride (19.1 g) is obtained in the form of a colourless solid, m.p. 138-140°C. l-Benzhydryl-3-(methylamino)azetidine was prepared under the conditions of Example 9, but starting 10 with l-benzhydryl-3-(methanesulphonyloxy)-azetidine (50 g) and methylamine (48.9 g) in methanol (250 cc). 1-Benzhydryl-3-(methylamino)azetidine (27 g) is obtained in the form of a colourless solid, m.p. 75°c. ) f.. >: 0 EXAMPLE 3 0 l-Cyclopropyl-7-fluoro-8-(3-methylamino-l-azetidinyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of 5 Example 11, but starting with l-cyclopropyl-7,8-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8Jnaphthyridine-3-carboxylic acid (1.5 g) and 3-(methylamino)azetidine dihydrochloride (1.13 g). The reaction mixture is stirred for 1 hour at 40°c. l-Cyclopropyl-7-fluoro-8-(3-methylamino-l-10 azetidinyl)-4-oxo-l,4-dihydrobenzo[b][l#8]naphthyridine-3-carboxylic acid (1 g) is obtained in the form of a yellow solid, which decomposes at 262°C.

EXAMPLE 31 7,9-Difluoro-l-methy1-8-(3-methylamino-l-15 azetidinyl)-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 30, but starting with 7,8,9-trifluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.5 g) and 3-(methylamino)azetidine dihydrochloride 20 (1.2 g). 7,9-Difluoro-l-methyl-8-(3-methylamino-l- azetidinyl)-4-oxo-l,4-dihydrobenzo[b][l, 8]naphthyridine-3-carboxylic acid (1.54 g) is obtained in the form of a yellow solid, which decomposes at 302°C.

EXAMPLE 32 8-(3-Amino-3-ethyl-l-azetidinyl)-7-fluoro-1- methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of $ n 9 /• mo Example 15, but starting with 7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (1.66 g) and 3-amino-3-ethylazetidine dimethane-sulphonate (3.1 g). 8-(3-Amino-3-ethyl-l-azetidinyl)-7-fluoro-l-5 methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.46 g) is obtained in the form of a yellow solid, which decomposes at 294°C. 3-Amino-3-ethylazetidine dimethanesulphonate was prepared according to the conditions described in Example 10 15 for 3-amino-3-propylazetidine dimethane-sulphonate: 3-amino-3-ethylazetidine dimethanesulphonate (5.7 g) were obtained in the form of a colourless solid, m.p. 184°C, by hydrogenation of 3-amino~l-benzhydryl-3-ethylazetidine (6 g). 3-Amino-l-benzhydryl-3-ethylazetidine (13.6 g) were obtained in the form of a yellow oil from 1-benzhydryl-3-ethyl-3-(methanesulphonyloxy)azetidine (24.6 g) dissolved in a 15 % solution (174 cc) of ammonia in ethanol. The product isolated was used without further 20 purification for the subsequent steps. l-Benzhydryl-3-ethyl-3-(methanesulphonyloxy)-azetidine (24.6 g) is obtained in the form of a yellow solid, m.p. 68°C, from l-benzhydryl-3-hydroxy-3-ethyl-azetidine (35.5 g). 25 l-Benzhydryl-3-hydroxy-3-ethylazetidine (35.5 g) were obtained in the form of a yellow oil from 1-benzhydryl-3-oxoazetidine (44 g) and ethylmagnesium bromide (80 cc) at a concentration of 399 g per litre in ether. EXAMPLE 33 8-(3-Amino-3-ethyl-l-azetidinyl)-l-cyclo-propyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-5 carboxylic acid methanesulphonate was prepared under the conditions of Example 15, but starting with 7,8-difluoro-l-cyclopropyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.8 g) and 3-amino-3-ethylazetidine dimethanesulphonate (2.94 g). After recrystallisation in 10 dimethylformamide, the product obtained, suspended in ethanol (20 cc), is treated with a solution (3.4 cc) at a concentration of 9.6 g % of methanesulphonic acid in ethanol. The suspension is stirred for 5 minutes at approximately 80°C and cooled to a temperature in the 15 region of 20°C and the product is drained and washed with ethanol (3 x io cc). 8-(3-Amino-3-ethyl-l-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid methanesulphonate (0.55 g) is obtained in the form of a 20 yellow solid, which decomposes at 248°C.

EXAMPLE 34 7-Fluoro-l-methyl-8-[3-(1-pyrrolidinyl)-1-azetidinyl]-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of 25 Example 2, but starting with 3-ethoxy-carbonyl-7-fluoro-1-methyl-8-[3-(1-pyrrolidinyl)-1-azetidinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.2 g). 7-Fluoro-l- methyl-8-[3-(1-pyrrolidinyl)-1-azetidinyl]-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid (0.7 g) is obtained in the form of a yellow solid, which decomposes at 302°C. 3-Ethoxycarbonyl-7-fluoro-l-methyl-8-[3-(1- pyrrolidinyl)-1-azetidinyl]-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 3-ethoxycarbonyl-7,8-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (1.6 10 g) and 3-(1-pyrrolidinyl)azetidine dihydrochloride (1.5 g). The reaction mixture is stirred for 24 hours at approximately 95°C. 3-Ethoxy-carbonyl-7-fluoro-l-methyl-8-[3-(1-pyrrolidinyl)-1-azetidinyl]-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine (1.3 g) is obtained in 15 the form of a yellow solid, m.p. 246°C. 3-(1-Pyrrolidinyl)azetidine was prepared in the form of the dihydrochloride, m.p. 195°C, under the conditions described in Japanese Patent Application 74 109 369.

EXAMPLE 35 8-(3-Cyclopropylamino-l-azetidinyl)-7-fluoro-1-methyl-4-oxo-i,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 8-(3-cyclopropylamino-l-azetidinyl)-3-ethoxycarbonyl-25 7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo [b] [1,8] naphthyridine (1.3 g). 8-(3-Cyclopropyl-amino-l-azetidinyl) -7-f luoro-l-methy 1-4-1,4-dihydro- benzo[b][1,8]naphthyridine (0.8 g) is obtained in the form of a yellow solid, which decomposes at 272°C. 8-(3-Cyclopropylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-l-methy1-4-oxo-1,4-dihydro-5 benzo[b][1,8]naphthyridine was prepared under the conditions of Example 15, but starting with 3-ethoxycarbonyl-7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine (1.45 g) and 3-(cyclopropylamino)azetidine dihydrochloride (1.7 g). 10 8-(3-Cyclopropylamino-l-azetidinyl)-3-ethoxycarbonyl-7- fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine (1.35 g) is obtained in the form of a yellow solid, m.p. 221°C and then 245°C. 3-(Cyclopropylamino)azetidine dihydrochloride was 15 prepared under the conditions described in Example 9 for 3-(ethylamino)azetidine dihydrochloride, but starting with 1-benzhydryl-3-(cyclopropylamino)azetidine dihydrochloride (5.4 g). 3-(Cyclopropyl-amino)azetidine dihydrochloride (2.25 g) is obtained in the form of a colourless solid, 20 m.p. 140°C. l-Benzhydryl-3-(cyclopropylamino)azetidine dihydrochloride was prepared under the conditions described in Example 9 for l-benzhydryl-3-(ethylamino)-azetidine dihydrochloride, but starting with l-benzhydryl-3-25 (methanesulphonyloxy)azetidine (15 g) and cyclopropylamine (8.2 g). l-Benzhydryl-3-(cyclopropyl-amino)azetidine dihydrochloride (5.4 g) is obtained in the form of a colourless solid, m.p. 182°C.

EXAMPLE 36 Using the procedure described in the above examples, the following products are prepared: 5 - 7-Fluoro-l-methyl-8-(3-methylamino-l-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8—[3—(2—Aminoethyl)amino-l-azetidinyl]-7-fluoro-l-methy 1-4 -oxo-l ,4-dihydrobenzo[b][1,8]naphthyridine-3-10 carboxylic acid; 7-Fluoro-8-[3-(2-hydroxyethyl)amino-l-azetidinyl]-1 methy1-4-oxo-l,4-dihyarobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-l-methyl-4-oxo-8-[3-(1-piperaEinyl)-1-15 azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3- carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b]- [1,8]naphthyridine-3-carboxylic acid; 20 - 8-(3-Amino-3-phenyl-l-azetidinyl)-7-fluoro-l-methy 1 oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7-fluoro-1 methy1-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-25 carboxylic acid; n l-Ethyl-7-fluoro-8-(3-methylamino-i-azetidinyl) -4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; - 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Ethyl-7-fluoro-8-[3-(2-hydroxyethyl)amino-l-azetidinyl ]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-10 carboxylic acid; 8-(3-Cyclopropylamino-2-azetidinyl)-l-ethyl-7-fluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; l-Ethyl-7-fluoro-4-oxo-8-[3-(l-piperazinyl)-1-15 azetidinyl]-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 8—{3—[4—(2-Aminoethyl)phenyl]amino-l-azetidinyl}-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 20 - 8-(3-Amino-3-phenyl-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-25 carboxylic acid; l-Cyclopropyl-8-(3-ethylamino-l-azetidinyl)-7-fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-l-cyclo-propyl 5 7-fluoro—4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Cyclopropyl-7-fluoro-8-[3-(2-hydroxyethyl)-amino-l-azetidinyl] -4-oxo-l, 4-dihydrobenzo [b] [1,8]naphthyridine-3-carboxylic acid; 10 - l-Cyclopropyl-8-(3-cyclopropylamino-l-azetidinyl)-7-fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Cyclopropyl-7-fluoro-4-oxo-8-[3-(1-piperazinyl)-1-azetidinyl]-l,4-dihydrobenzo[b][1,8]naphthyridine-3-15 carboxylic acid; 8 — {3 — [4—(2 —Aminoethy1)phenyl]amino-l-azetidinyl}-l-cyclopropyl-7-fluoro-4-oxo-l,4- dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-1-azetidinyl)-l-cyclopropyl-7-20 fluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylie acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-1-cyclo-propyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 25 - 7-Fluoro-l-methylamino-8-(3-methylamino-l-azetidinyl) 4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-l-methy1-amino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7-fluoro-1-5 methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-8-[3-(2-hydroxyethy1)amino-l-azetidinyl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; - 8-(3-Cyclopropylamino-l-azetidinyl)-7-fluoro-l- methylamino-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 7-Fluoro-l-methylamino-4-oxo-8-[3-(l-piperazinyl)-1-azetidiny1]-1,4-dihydrobenzo[b][1,8]naphthyridine-3- carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-1-azetidinyl}-7-fluoro-l-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7-fluoro-1- methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-l-methy lamino-4 -oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; - 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7-fluoro-l-methylamino-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-l-(2-fluoroethyl)-8-(3-methylamino-l-azetidinyl) -4-oxo-l, 4-dihydrobenzo[b] [1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-1-(2- fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7-fluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; 10 - 7-Fluoro-l-(2-fluoroethyl)-8-[3-(2-hydroxyethyl)-amino-l-azetidinyl]-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 8-(3-Cyclopropylamino-1-azetidinyl)-7-fluoro-l-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 15 carboxylic acid; 7-Fluoro-l-(2-fluoroethyl)-4-oxo-8-[3-(1-piperazinyl) 1-azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7-20 fluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]- naphthyridine-3-carboxylic acid; 8-(3—Amino-3-phenyl-l-azetidinyl)-7-fluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; 25 - 8-(3-Amino-3-methyl-1-azetidinyl)-7-fluoro-1-(2- f luoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; - 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7-fluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 7-Fluoro-8-(3-methylamino-l-azetidinyl)-4-oxo-l-t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-4-oxo-1-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7-fluoro-4-oxo 1-t-butyl-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 7-Fluoro-8-[3-(2-hydroxyethyl) amino-l-azetidinyl]-4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Cyclopropylamino-1-azetidinyl)-7-fluoro-4-oxo-l-t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-4-oxo-8-[3-(1-piperazinyl)-1-azetidinyl]-1-t butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7-fluoro-4-oxo-l-t-butyl-l,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-1-azetidinyl)-7-fluoro-4-oxo-1-t-butyl-l ,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8- (3—Amino-2-dimethylamino-l-azetidinyl) -7-fluoro-4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-(3-ethylamino-l-azetidinyl)-l-methyl-4 oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7,9-difluoro-1 methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-[3-(2-hydroxyethyl)amino-l-azetidinyl] l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Cyclopropylamino-1-azetidinyl)-7,9-difluoro-1-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-methyl-4-oxo-8-[3-(1-piperazinyl)-1-azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7,9-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7,9-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino—2-dimethylamino-1-azetidiny 1) -7,9-di-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo[b] [1,8]-naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-ethyl—8-(3-methylamino-l-azetidinyl)-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7,9-difluoro-l-ethyl-4 oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)-l-azetidinyl]-7,9-difluoro-l-ethyl-4 -oxo-1 , 4-dihydrobenzo [b] [1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-ethyl-8-[3-(2-hydroxyethyl)-1-azetidinyl]-4-oxo-l, 4-dihydrobenzo[b] [1,8]naphthyridine-3 carboxylic acid; 8-(3-Cyclopropylamino-l-azetidinyl)-7,9-difluoro-l-ethyl-4 -oxo-1 , 4-dihydrobenzo [b] [1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-ethyl-4-oxo-8-[3-(l-piperazinyl)-1-azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-{3-[4—(2-Aminoethyl)phenyl]amino-l-azetidinyl>-7,9 difluoro-l-ethyl-4-oxo-l,4-dihydrobenzo[b] [ 1,8] -naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7,9-difluoro-l-ethyl-4 -oxo-1 ,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; o >\ * " / K' - am « - 8-(3-Amino-3-methyl-1-azetidinyl)-7,9-difluoro-1-ethyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-2-dimethylamino-1-azetidinyl)-7,9-difluoro l-ethyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Cyclopropyl-7,9-difluoro-8-(3-methylamino-l-azetidinyl )-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Cyclopropyl-8-(3-ethylamino-l-azetidinyl)-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-1-cyclo-propyl 7,8-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; l-Cyclopropyl-7,9-difluoro-8-[3-(2-hydroxyethyl)-amino-l-azetidinyl]-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; l-Cyclopropyl-8-(3-cyclopropylamino-l-azetidinyl)-7,8 difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; l-Cyclopropyl-7,9-difluoro-4-oxo-8-[3-(1-piperazinyl) 1-azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8 — {3 — [4—(2-Aminoethyl)phenyl]amino-l-azetidinyl}-1-cyclopropyl-7,9-difluoro-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid; l"\ 'H 8-(3-Amino-3-phenyl-l-azetidinyl)-l-cyclopropyl-7,9-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-methyl-l-azetidinyl)-l-cyclopropyl-7,9-5 difluoro-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-1-cyclo-propyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 10 - 7,9-Difluoro-l-methylamino-8-(3-methylamino-l- azetidinyl) -4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7,9-difluoro-l-methy lamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-15 carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7,9-difluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-[3-(2-hydroxyethyl)amino-l-azetidinyl]-20 l-methylamino-4-oxo-l,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid; 8-(3-Cyclopropylamino-l-azetidinyl)-7,9-difluoro-1-methylamino-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; - 7,9-Difluoro-l-methylamino-4-oxo-8-[3-(l-piperazinyl)-1-azetidinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; ( 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7,9-difluoro-l-methylamino-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-1-azetidinyl)-7,9-difluoro-1-5 methy lamino-4-oxo-1,4-dihydrobenzo [b] [ 1,8] naphthyr idine-3-carboxylic acid; 8-(3-Amino-3-methyl-l-azetidinyl)-7,9-difluoro-l-methy lamino-4 -oxo-1 ,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 10 - 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7,9-difluoro-l-methylamino-4-oxo-i,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-1-(2-fluoroethyl)-8-(3-methylamino-l-azetidinyl) -4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-15 carboxylic acid; - 7,9-Difluoro-8-(3-ethylamino)-l-azetidinyl)-1-(2-f luoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7,9-difluoro-1-20 (2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 7,9-Difluoro-1-(2-fluoroethyl)-8-[3-(2-hydroxy-ethyl)amino-l-azetidinyl]-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid; 25 - 8-(3-Cyclopropylamino-l-azetidinyl)-7,9-difluoro-l-(2-f luoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-1-(2-fluoroethyl)-4-oxo-8-[3-(1-piperazinyl)-1-azetidinyl]-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl}-7,9-difluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo-[b][l,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7,9-difluoro-1-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; 8-(3-Amino-3-methyl-l-azetidinyl)-7,9-dfluoro-l-(2-fluoroethyl)-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3 carboxylic acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7,9-difluoro 1-(2-fluoroethyl)-4-oxo-l, 4-dihydrobenzo-[b][l,8]naphthyridine-3-carboxylic acid; 7-Fluoro-8-(3-methylamino-l-azetidinyl)-4-oxo-l-t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7-fluoro-4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7,9-difluoro-4 oxo-l-t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-[3-(2-hydroxyethyl)amino-l-azetidinyl] 4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; '"*1 8-(3-Cyclopropylamino-l-azetidinyl)-7,9-difluoro-4-oxo-l-t-butyl-1,4-dihydrobenzo[b][1;8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-4-oxo-8-[3-(1-piperazinyl)-1-azetidinyl]-5 1-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amino-l-azetidinyl>-7,8-difluoro-4-oxo-l-t-butyl-l,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid; 10 - 8-(3-Amino-3-phenyl-l-azetidinyl)-7,9-difluoro-4-oxo-1-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-methyl-i-azetidinyl)-7,9-difluoro-4-oxo-1-t-butyl-l,4-dihydrobenzo[b][1,8]naphthyridine-3-15 carboxylic acid; 8-(3-Amino-2-dimethylamino-l-azetidinyl)-7,9-difluoro-4-oxo-l-t-buty1-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid.

The present invention also provides 20 pharmaceutical compositions which can be used in human or veterinary medicine, containing as an active ingredient at least one compound of formula (I) in the pure state (in free form or in salt form) or in the form of a combination with one or more compatible and pharmaceutically acceptable 25 diluents or adjuvants. These compositions may be used orally, parenterally or rectally.

As solid compositions for oral administration, tablets, hard gelatin capsules, pills, powders or granules may be used. In these compositions, the active product according to the invention may be mixed with one or more inert diluents or adjuvants such as sucrose, lactose or 5 starch. These compositions can also comprise substances other than diluents, e.g. a lubricant such as magnesium stearate.

As liquid compositions for oral administration, it is possible to use solutions, suspensions, syrups, 10 elixirs and pharmaceutically acceptable emulsions, containing inert diluents such as water or liquid paraffin. These compositions can also comprise substances other than diluents, e.g. wetting, sweetening or flavouring products.

The compositions for parenteral administration 15 can be suspensions, emulsions or sterile, aqueous or nonaqueous solutions. As a solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can also 20 contain adjuvants, especially wetting, emulsifying, dispersing or tonicity agents. The sterilisation may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilising agents in the composition, by irradiation or by heating. They may also be 25 prepared in the form of sterile solid compositions which will be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which can contain, apart from the active product, excipients such as cocoa butter or Suppocire.

In human or veterinary therapy, the compositions according to the invention are especially useful as antibacterial agents in the treatment of infections of bacterial origin.

Generally speaking, the doctor will determine the 10 dosage he considers most suitable in accordance with the age, weight, degree of infection and other factors specific for the subject to be treated. Generally, the doses are between 0.2 and 1 g of active product twice a day, administered orally or parenterally, for an adult. 15 The example which follows illustrates a composition according to the invention: Example Tablets containing active product (250 mg) and having the following composition are prepared according to 20 the customary techniques: 8-(3-Amino-l-azetidinyl)-l-cyclopropyl-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylie acid 250 mg Starch 50 mg - Lactose 35 mg Talc 15 mg The compounds of formula (I) are also advantageous in the agrochemical field, for antibacterial treatment of plants and crops. Compositions for agrochemical use containing a compound of formula (I) also fall within the scope of the present invention.

Moreover, the compounds of formula (I) may also be used as agents for the preservation or disinfection of organic or inorganic substances; in particular, in the dyestuffs, fat, paper, wood or polymer industry or alternatively in the textiles industry, the food industry 10 or water treatment. Compositions for these purposes containing a compound of formula (I), in the pure state or in the form of a combination with compatible diluents or adjuvants, also fall within the scope of the present invention. t")

Claims (10)

WHAT WE CLAIM IS:

1. A benzo[b][1,8]naphthyridine derivative of the formula: COOH in which 5 R represents a hydrogen atom, a hydroxyl radical, an amino radical, an alkylamino radical in which the alkyl portion is optionally substituted by an amino or hydroxyl radical, a dialkylamino radical in which the alkyl portions, with the nitrogen atom to which they are 10 attached, can optionally form a 5- or 6-membered heterocyclic ring optionally containing another hetero atom chosen from nitrogen, oxygen and sulphur, a (3- to 6-membered cycloalkyl)-amino radical, an alkanoylamino radical, an N-alkyl-N-alkanoylamino radical or an 15 aminoalkylphenylamino radical; R, and R2, which may be identical or different, are located, respectively, at positions 2 and 3 and each represents a hydrogen atom, an alkyl radical, an alkenyl radical containing 2 to 4 carbon atoms, a phenyl radical or 20 a phenyl radical substituted by a halogen atom or by an V 2 . - 68 - alkyl, alkyloxy, hydroxyl, nitro, amino, alkylamino, dialkylamino or haloalkyl radical, or alternatively R, and R2 are both located at position 2 and represent alkyl radicals; 5 R3 represents a hydrogen atom, an alkyl radical, a fluoroalkyl radical, a carboxyalkyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms, a fluorophenyl radical, a difluorophenyl radical, an alkyloxy radical or an alkylamino radical; and 10 - R4 represents a hydrogen atom or a fluorine atom, the aforesaid alkyl and alkanoyl radicals being unbranched or branched and containing 1 to 4 carbon atoms each, in its stereoisomeric forms or mixtures thereof, and its metal salts, its addition salts with nitrogenous bases, its 15 addition salts with acids and its hydrated forms.

2. A benzo[b][l,8]naphthyridine derivative according to claim l which is 8-(3-amino-3-propyl-l-azetidinyl) -7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid in its 20 stereoisomeric forms or mixtures thereof, and its metal salts, its addition salts with nitrogenous bases, its addition salts with acids and its hydrated forms.

3. A benzo[b][1,8]naphthyridine derivative according to claim 1 which is 8-(3-amino-3-methyl-l- 25 azetidinyl) -7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo-[b][l,8]naphthyridine-3-carboxylic acid in its stereoisomeric forms or mixtures thereof, and its metal - 69 - salts, its addition salts with nitrogenous bases, its addition salts with acids and its hydrated forms.

4. A benzo[b][1,8]naphthyridine derivative according to claim 1 which is 8-(3-amino-3-methyl-l-5 azetidinyl)-7,9-difluoro-l-methyl-4-oxo-l,4-dihydrobenzo-[b][l,8]naphthyridine-3-carboxylic acid in its stereoisomeric forms or mixtures thereof, and its metal salts, its addition salts with nitrogenous bases, its addition salts with acids and its hydrated forms. 10

5. A benzo[b][1,8]naphthyridine derivative according to claim 1 which is 8-(3-amino-3-ethyl-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-l,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid in its stereoisomeric forms or mixtures thereof, and its metal 15 salts, its addition salts with nitrogenous bases, its addition salts with acids and its hydrated forms.

6. A process for preparing a benzofb][1,8]-naphthyridine derivative according to claim 1, which comprises reacting an azetidine derivative of formula: R </ NH 20 in which R, R, and R2 are defined as in claim 1, with a benzo[b][1,8]naphthyridine of formula: - 70 - Hal COOH in which R3 and R4 are defined as in claim 1 and Hal is a fluorine, chlorine or bromine atom if R4 is a hydrogen atom, or Hal and R4 are both simultaneously fluorine atoms, and optionally converting the product obtained into a salt.

7. A process for preparing a benzo[b][1,8]- naphthyridine derivative according to claim 1, which comprises converting an ester of formula: coo Alk in which R,, R2 and R4 are defined as in claim 1, R is defined as in claim 1 or represents a protected amino 10 radical, R3 is defined as in claim 1 or represents a protected alkylamino radical and Alk is an unbranched or branched alkyl radical containing 1 to 4 carbon atoms, by any known method for obtaining an. acid from an ester without affecting the remainder of the molecule, and then, 15 where appropriate, removing the group protecting the alkylamino radical and/or optionally preparing the salt of - 71 - 2 4 4 5 1 8' the benzo[b]naphthyridine derivative obtained.

8. A pharmaceutical composition which contains at least one benzo[b][1,8]naphthyridine derivative according to claim 1, in combination with one or more compatible diluents or adjuvants.

9. A benzo[b][l,8]naphthyridine derivative as defined in claim 1 substantially as herein described with reference to any example thereof.

10. A process for preparing a benzo[b][l,8]-naphthyridine derivative as defined in claim 1 substantially as herein described with reference to any example thereof. .LabnrnHTre flrrW 134-^ By tho authorised agents C7