AU665787B2 - 1,8-benzonaphthyridine derivatives and antimicrobial 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

k OPI DATE 03/05/93 APPLN. ID 27860/92 AJDP DATE 08/07/93 PCT NUMBER PCT/FR92/00901 IIIIII IIIII 111111111 III11111 III11111 liii1111 AU9227860 DEMANDE INTERNATIONALE PUBLIFE EN VERTU DU TRAITE DE COOPERATION EN MATIERE DE BREVETS (PCT) (51) Classification internationale des brevets 5 (11) Num~ro de publication internationale: WO 93/07144 C07D 471/04, A61 K31/435 Al (4)Dtdepbiainitrainl: 1 vl193150.) II(CO7D 471/04, 221 :00, 221:00)(4)Dtdepbiainitnaoae: 1avi193(50.) (21) Num~ro de la demande internationale: PCT/FR92/00901 (74) Mandataire: LOBJO IS, Franqoise; Rh~ne-Poulenc Rorer Direction Brevets, 20, ave. Raymond-Aron, F- (22) Date de d~p6t international: 29 septembre 1992 (29.09.92) 92165 Antony C~dex (FR).

Doinn~es relatives A~ la priorit6: (81) Etats disign~s: AU, CA, CS, Fl, HU, JP, KR, NO, PL, 91/12058 1ler octobre 1991 (01.10.9 1) FR RU, US, brevet europ~en (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE).

(71) DWposant (pour tolls les Etats d~sign~s saul US): LABORA- TOIRE ROGER BELLON [FR/FR]; 159, ave. Achille- Publi~e Peretti, F-92201 Neuilly-sur-Seine Avec rapport de rechierche internationale.

(72) Inventeurs; etR FRI; 19, rue Colas, F-91390 Morsang-sur-Orge (FR).

BARREAU, Michel [FR/FR]; 24 bis, avenue du Clos-6 1, de-S~nart, F-9 1230 Montgeron DESCONCLOIS, 8 Jean-Franqois [FR/FR]; 12, rue Beccarria, F-75012 Paris GIRARD, Philippe [FR/FR]; 7, rue du Bois-Gaudron, Ollainville, F-91290 Arpajon KRYVENKO, Michel [FR/FR]; 5, rue Franklin, F-75116 Paris (FR).

LAVERGNE, Marc, Pierre [FR/FR]; 8, sente de l'Esp&rance, F-94520 Mand res- les- Roses PARIS, Jean- Marc [FR/FR]; 8, rue des Acacias, F-77360 Vaires-sur- Marne PICAUT, Guy [FR/FR]; 152, rue de Chevilly, F-94800 Villejuif (FR).

(54) Title: 1,8-BENZONAPHTHYRIDINE DERIVATIVES AND ANTIMICROBIAL COMPOSITIONS (54) Titre: DERIVES DE BENZONAPHTYRIDINE-I,8 ET COMPOSITIONS ANTIMICROBIENNES

COOH-

R

4 (57) Abstract A novel I,8-benzo[bjnaphthyridine derivative of general formula wherein R is H or a amino or alkylamino radical optionally substituted by amino or hydroxy, or R is dialkylamino of which the alkyl portions may form, with the nitrogen atom, a 5- or 6-membered heterocyclic ring which optionally contains a further heteroatom chosen from nitrogen, oxygen or sulphur, or R is C 3 6 cycloalkylamino or an alkanylamino, N-alkyl N-a~kanylamino or aminoalkylphenylamino radical; R, and

R

2 which are the same or different, are in positions 2 and 3 and represent H, alkyl, C 2 4 alkenyl, phenyl, or substituted phenyl, or R, and R 2 are in position 2 and represent alkyl; R 3 is H or alkyl, fluoroalkyl, carboxyalkyl, C 3 6 cycloalkyl, fluorophenyl, difluorophenyl, alkyloxy or alkylamino; and R 4 is H or F, wherein tho C 1 4 alkanyl and alkyl radg..s are linear or branched; stereoisomeric forms thereof or mixtures of these; and salts and hydrated forms thereof. These novel derivatives are useful as antimicrobials.

(57) Abr~g6 Nouveau d~riv6 de la benzo[b]naphtyridine-l,8 de formule g~n~rale dans laquelle, R est H ou un radical hydroxy, amino, alcoylamino 6ventuellement substitu6 par amino ou hydroxy ou R est dialcoylamino dont les parties alcoyle peuvent former avec I'atome d'azote, un h~t~rocycle A~ 5 ou 6 chainons contenant 6ventuellement un autre h~t~roatome choisi parmi l'azote, l'oxygene ou le soufir, ou R est cycloalcoylamino (3 A 6C), ou un radical alcanoylamino, N-alcoyl N-alcanoyl amino ou aminoalcoylph~nylamino, R, et R 2 identiques ou diff~rents sont en position 2 et 3 et repr~sentent H, alcoyle, alc~nyle (2 A 4C), ph~nyle, ph~nyle substitu6, ou bien R, et R 2 sont en position 2 et repr~sentent alcoyle, R 3 est H ou alcoyle, fluoroalcoyle, cwiboxyalcoyle, cycloalcoyle contenant 3 A 6 atomes de carbore, fluoroph~nyle, difluoroph~nyle, alcoyloxy 00 alcoylamino, et R 4 est H ou F, les radicaux alcoyle et alcanoyle (I d 4C) 6tant droits ou ramifi~s, sous ses formes st~r~oisom~res ou leurs m~langes ainsi que ses sels et ses formes hydrat~es. Ces nouveaux d~riv~s sont utiles comme antimicrobiens.

r 'C4" WO 93/07144 PCT/FR92/00901 BENZO[1,81NAPHTHYRIDINE DERIVATIVES, AND ANTIMICROBIAL COMPOSITIONS The present invention relates to new benzo[b][1,8]naphthyridine derivatives of general formula: 0 F CO OH OO (I) compositions containing them.

benzonaphthyridine derivatives of structure: 0 F N N N RN R 4

R

R

3 in which R, is H, hydroxy or alkyl, R, is H, alkyl, fluoroalkyl, cycloclalkyl, alkyloxy or alkylamino, R 3 is phenyl or phenylalkyl, optionally substituted, and R 4 is H or a fluorine atom, have been described. These products are useful as antimicrobial agents.

products are useful as antimicrobial agents.

REPLACEMENT SHEET 2 It has been found that the products of general formula in which: R represents a hydrogen atom or a hydroxyl or amino radical or an alkylamino radical in which the alkyl portion is optionally substituted with an amino or hydroxyl radical, or represents a dialkylamino radical in which the alkyl portions, with the nitrogen atom to which they are attached, can optionally form a or 6-membered heterocycle optionally containing another hetero atom chosen from nitrogen, oxygen and sulphur, or represents a to 6-membered cycloalkyl)amino radical, or an alkanoylamino, N-alkyl-N-alkanoylamino or aminoalkylphenylamino radical, RI and which may be identical or different, are located, respectively, at positions 2 and 3 and represent hydrogen atoms, alkyl radicals, alkenyl radicals containing 2 to 4 carbon atoms, phenyl radicals or phenyl radicals substituted with a halogen atom or with an alkyl, alkyloxy, hydroxyl, nitro, amino, alkylamino, dialkylamino or haloalkyl radical, or alternatively R, and R 2 are located at position 2 and represent alkyl radicals,

R

3 represents a hydrogen atom or an alkyl, fluoroalkyl or carboxyalkyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms or a fluorophenyl, difluorophenyl, alkyloxy or alkylamino radical, and

R

4 represents a hydrogen atom or a fluorine atom, a the alkyl and alkanoyl radicals mentioned above being f T 0D~Z REPLACEMENT SHEET

F'

3 unbranched or branched and containing 1 to 4 carbon atoms, as well as their salts and, where appropriate, their stereoisomers, manifest especially advantageous antibacterial activity.

When R represents a dialkylamino radical in which the alkyl portions, with the nitrogen atom, form a heterocycle. the latter can be, in particular, pyrrolidinyl or piperidyl.

The products of general formula can exist in the state of a hydrated form; it is understood that these hydrates also fall within the scope of the present invention.

According to the invention, the products of general formula may be obtained by substitution of an azetidine of general formula: NH (II) in which R, R, and R 2 are defined as above, with a bonzo[b][1,8]naphthyridine of general formula:

COOH

Hal N

N

(II)

in which R 3 is defined as above, Hal is a fluorine,

J

r 1 4 chlorine or bromine atom if R 4 is hydrogen, or alternatively Hal and R 4 are simultaneously fluorine atoms.

The action of the azetidine derivative of general formula (II) is generally performed in the presence of an excess of this derivative as acidacceptor in suitable organic solvents. It is possible to work with or without a solvent, at a temperature of between 20 and 150 0 C. When the working conditions include the presence of a solvent, the reaction is advantageously performed in solvents such as pyridine, Sdimethylformamide, dimethyl sulphoxide or acetonitrile.

It is also possible to work in an aqueous medium.

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

It is understood that, in the case where the symbol R 3 of the product of general formula (III) is a hydrogen atom, or when R is an amino, optionally substituted alkylamino, cycloalkylamino or aminoalkylphenylamino radical, it is preferable to protect the starting material beforehand. The protection and removal of the protective radical after the reaction are performed according to the customary methods.

The protection may be carried out with any compatible group whose use and removal has no adverse effect on the remainder of the molecule. In particular, the 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).

As an example, the protective groups may be chosen from trimethylsilyl, benzhydryl, tetrahydropyranyl, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, ethoxycarbonyl, t-butoxycarbonyl and trichloroethoxycarbonyl radicals.

According to the invention, the benzo[b][l,8]naphthyridine derivatives of general formula may also be obtained from the corresponding ester of general formula: OO

(IV)

R

|o i protected alkylamino radical and Alk represents an unbranched- or branched-chain alkyl radical containing A 4 1 to 4 carbon atoms, by any known method for obtaining r~

F-F

6 an acid from an ester without affecting the remainder of the molecule.

The preparation of the acid from the ester is 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 0

C.

In the case where an ester of general formula (IV) for which R is an alkanoylamino or N-alkyl- N-alkanoylamino radical or for which R is a protected amino radical is hydrolysed, it is understood that, depending on the conditions employed, the product obtained is either the acid for which R is an alkanonylamino or N-alkyl-N-alkanoylamino radical or for which R is a protected amino radical, or the acid for which hydrolysis of the amide has been performed simultaneously, i.e. for which R is an amino radical.

The working conditions are chosen in accordance with the expected final product. When R is a protected amino radical, it is naturally advantageous to remove the protective radical simultaneously.

When R 3 represents a protected alkylamino radical, the protective radical can be any aminoprotective 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 r la 7 general formula (III) may be obtained from the corresponding ester of general formula: N N R3 in which R 3

R

4 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 general formula may be prepared by the action of 3 -amino-l,2,4-triazine (to obtain a product for which R 3 is a hydrogen atom), or by the action of a product of general formula:

R

3

-NH

2 (VI) in which R 3 is alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl, fluorophenyl, difluorophenyl, alkyloxy or alkylamino, optionally protected, on a quinoline derivative of general formula: o COO Alk Hal N Cl N (CH3) 2 R4

(VII)

in which Hal and Alk are defined as above, followed by cyclisation by the action of an acid-acceptor agent.

In general, the reaction of 3-amino-1,2,4triazine or of the product of general formula (VI) is RA4, -v

\ATO'<<

8 carried out in an organic solvent such as an alcohol ethanol, methanol) or a chlorinated solvent (e.g.

trichloromethane), at a temperature of between 10 and 0

C.

The cyclisation is performed in an unbranched- or branched-chain alcohol containing 1 to 4 carbon atoms, at a temperature between 20 0 C and the refluxing temperature of the reaction mixture.

The acid-acceptor agent can be, in particular, chosen from nitrogenous bases (e.g.

triethylamine), 1,8-diazabicyclo[5.4.0]undec-7-ene and an excess of the amine employed.

The benzo[b]naphthyridine derivatives of general formula (III) and for which R 3 is a carboxyalkyl, fluorophenyl or difluorophenyl radical are new products. It is 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 general formula (VII) may be obtained as described in Patent US 4,990,515.

The aminoazetidine derivatives of general formula (II) may be prepared according to the processes described by: T. Okutani et al. Chem. Pharm. Bull., 22 1490 (1974); S. Chatterjee et al, Chem. Comm., 93 (1968); D. Nisato et al. J. Heterocyclic. Chem., 22, 961 (1985); Akira Morimoto et al., Chem. Pharm. Bull., 21 228 (1973); A.G. Anderson et al., J. Org.

I, cI -AI f "'eep 9 Chem., 37, 3953 (1972); V.R. Gaertner., J. Org. Chem., 2972 (1967), J.N. Wells et al., J. Org. Chem., 34, 1477 (1969), J. Antibiotics, 39 1243 (1986) and J. Pharm. Soc., 60 156 (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, (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 general formula (IV) may be obtained from the benzo[b]naphthyridine of general formula by substitution of an azetidine derivative of general formula (II).

It is advantageous to work under the conditions described above for obtaining a product of general formula from an azetidine of general formula (II) and a benzo[b][1,8]naphthyridine of general formula (III). It is understood that, in the option or the reaction is performed in an aqueous .ledium, the product of general formula may be obtained directly without isolating the intermediate derivative of general formula (IV).

T According to the invention, where appropriate, when it is desired to obtain the stereoisomers of the benzonaphthyridine derivatives of general formula the separation of the stereoisomeric forms of the azetidines of general formula (II) is performed by any known method which is compatible with the molecule. As an example, the separation is performed by acylation by means of a chiral acid or 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 1275 (1976). It is also possible to perform the separation of the stereoisomers by chiralphase high performance liquid chromatography.

The new products according to the present invention, as well as their synthesis intermediates, can be optionally purified by physical methods such as crystallisation or chromatography.

The products according to the present invention, as well as their intermediates of general formula (III) and, where appropriate, their intermedates of general formula may be converted to metal salts or to addition salts with nitrogenous bases according to methods known per se. These salts may be obtained by the action of a metal-containing base (containing, an alkali metal or alkaline earth metal), ammonia or an amine on a product RA.k according to the invention in a suitable solvent such r as an 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 also be converted to addition salts with acids. The products of general formula 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 pharmaceutically acceptable salts, there may be mentioned the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), the ammonium salt, the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, 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 orgaLnic acids (succinates, fumarates, maleates, methanesulphonates, p-toluenesulphonates, isethionates).

The new benzo[b)[1,8]naphthyridine derivatives of general formula according to the tn'

R

O

r /P f^: J' ^Y VL r 7. 1

-I

12 present invention and their pharmaceutically acceptable salts exhibit especially 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 new benzo[b][1,8]naphthyridine derivatives of general formula manifest especially advantageous antibacterial activity against Gramnegative microorganisms.

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

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

Moreover, some of the products according to the invention proved especially advantageous against mycoplasma. Their minimal inhibitory concentration is between 0.03 and 8 pg/ml.

Lastly, the products 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, given without pp. I If 13 Simplied limitation, illustrate the present invention.

EXAMPLE 1 8-(3-Amino-l-azetidinyl)-7-fluoro-l-methyl-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: A suspension of 1.16 g of 7,8-difluoro-lmethyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3carboxylic acid and 1.38 g of 3-aminoazetidine in 15 cm 3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95 0 C for 6 hours. After I 10 cooling to approximately 20 0 C, 100 cm 3 of water are added to the reaction mixture. The insoluble matter is drained, washed with 3 times 20 cm 3 of water, taken up with 100 cm 3 of water and treated with 4 cm 3 of N methanesulphonic acid. After removal of some slight insoluble matter by filtration through diatomaceous silica and addition of 4 cm 3 of N aqueous sodium hydroxide, the suspension obtained is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60 0 C to a volume of approximately 80 cm 3 The insoluble matter is drained, washed with 100 cm 3 of water and 100 cm 3 of ethanol and recrystallised in 150 cm 3 of dimethylformamide. 0.7 g of 8-(3-amino-1azetidinyl)-7-fluoro-l-methyl-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 358 0

C.

7,8-Difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid is 14 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-1-azetidinyl)-7-fluoro-1-methyl-4oxo-1,4-dihydrobenzo[b]l[l,8]naphthyridine-3-carboxylic acid: A suspension of 1.9 g of 8-(3-dimethylamino- 1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine in 20 cm 3 of ethanol and 19 cm 3 of 0.5 N aqueous potassium hydroxide is heated with stirring to a temperature in the region of 80'C for 3 hours. After cooling to approximately 5 0 C, the reaction mixture is treated with 9.5 cm 3 of N aqueous methane sulphonic acid solution. The insoluble matter is drained, washed with twice 10 cm' of water and 3 times 25 cm 3 of ethanol and recrystallised in 125 cm' of dimethylformamide. 1.4 g of 8-(3dimethylamino-1-azetidinyl)-7-fluoro-1-methyl-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 312 0

C.

8-(3-Dimethylamino-1-azetidinylj-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared in the following manner: A suspension of 2 g of 3-ethoxycarbonyl-7,8- I/VT O'j/

CFJTO~

difluoro-1-methyl-4-oxo-1,4-dihydrobenzo~b] naphthyridine, 1.2 g of 3-(dimethylamino)azetidine dihydrochioride and 1.5 g of sodium carbonate in 30 cm' of dimethyl suiphoxide is heated with stirring to a temperature in the region of 95*C for 5 hours. After cooling to approximately 20*C, the reaction mixture is treated with 60 cm 3 of water. The insoluble matter is drained and washed with 3 times 20cm of water. 2 g of 8- (3-dimethylamino-1-azetidinyl) -3-ethoxycarbonyl-7fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 224*C, which is used without further purification for the subsequent steps.

3-Ethoxycarbonyl-7 ,8-difluoro-1-methyl-4-oxo- 1,4-dihydrobenzotb][1,8]naphthyridine may be prepared as descibed in Patent US 4,970,213.

EXAMPLE 3 8-(3-Amino-l-azetidinyl)--ethyl-7-fluoro-4-oxo-1,4dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 0.72 g of 8-( 3 -amino-1-azetidinyl)-3-ethoxycarbonyl-1ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8].

naphthyridine. Without recrystallisation, 0.6 g of 8 3 -amino--azetidinyl)--ethyl-7-fluoro4oxo1,4dihydrobenzo naphthyridine-3-carboxylic acid monohydrate is obtained in the form of a yellow solid, which decomposes at 306*C.

16 8- (3-Amino-1-azetidinyl) -3-ethoxycarbonyl-lethyl-7-f luoro-4-oxo-1,4-dihydrobenzo[b] 1, 8]naphthyridine was prepared under the conditions described in Example 2, but starting with 1.7 g of 3-ethoxy-carbonyl-1-ethyl-7, 8-difluoro-4-oxo-1,4dihydrobenzo-[b] 8]naphthyridine and 1.62 g of 3-aminoazetidine dimethanesulphonate. The crude product is taken up with 100 cm' of dimethylformamide 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 60*C. The residue is recrystallised in cm' of ethanol. 0.72 g of 8-(3-amino--azetidinyl)-3ethoxycarbonyl-l1-ethyl- 7 -fluoro-4-oxo,- 1,4 dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid, melting point 255-256*C.

3 -Ethoxyc arbonyl-l1-ethyl- 7, 8 -dif luoro-4 -oxo- 1 ,4-dihydrobenzo[b] [1,8]naphthyridine was prepared as described in Patent US 4,970,213.

EXAMPLE 4 8- (3-Dimethylamino-l-azetidinyl) -1-ethyl-7-fluoro-4oxo-1,4-dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in 2xample 2, but sta~rting with 2 g of 8-(3--dimethylaxnino--azetidinyl)-3ethoxycarbonyl- 1-ethyl- 7-f luoro-4 -oxo- 1, 4 4RA4,,

N)

TO

17 dihydrobenzo[bJ[1,8]naphthyridine. 1.68 g of 8-(3-dimethylamino-1-azetidinyl)-1-ethyl-7-fluoro-4oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 278 0

C.

8-(3-Dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 1.7 g of 3-ethoxy-carbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4dihydrobenzo[b][1,8]-naphthyridine, and 1.3 g of 3-(dimethyl- amino)azetidine dihydrochloride. After reaction, the reaction mixture, cooled to approximately 200W, is poured into 50 cm 3 of water and extracted with 3 times 100 cm 3 of dichloromethane. The combined organic extracts are washed with 3 times 150 cm 3 of water and dried over magnesium sulphate, After concentration to dryness under reduced pressure (20 kPa) at approximately 40 0 C, the residue is taken up with 50 cm 3 of ethyl ether, filtered off and washed with twice cm 3 of the same solvent. 2 g of 8-(3-dimethylamino-1azetidinyl)-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 2320W, which is used without further purification for the subsequent steps.

F-

1)18 1-3An--azetidinyl) -1 -cyclopropyl-7-fluoro-4-oxo- 1dihydrobenzo[b jnaphthyridine-3-carboxylic i heihdrTe iseobtin in teform onde atyelwsld whchdeiomsesie at Exapl 2-bt tatigCit 1 gof8- (3-amino--azetidinyl) cyclopropyl-3 ethoxycarbonyl-7-fluoro-4-oxo-1, 4-dihydrobenzo- [b][1,8]naphthyridine. was6 prpae unde the i ondtin 3-aetoycrnyl-7 8-di -fluoro-4-oxo-1,4-ro benzdobeob][1,8]naphthyridine -3and 1.88 g ofi 3-minoaeiinbtiehansuephoate ftaelo 1 oid j~ ~hc recrysta esation2in 50 3 'oCthnl,105go 8--(3-amino-1-azetidinyl) -cyclopropyl-3 ethoxycarbonyl-7-fluoro-4-oxo-1 ,4-iyrbno ihdnz[b][1,8]naphthyridine are obtained in the iin Eormpl f a byllo sldmting point7 o ~1ylprpl3-ethoxycarbonyl-7,8-difluoro-4o-1-dhr- 4-noo 1,ihdonb][,8]naphthyridine may be8 o dipreproe as decribed nPtedn are 4,970,213. th F- 19 EXAMPLE 6 1-Cyclopropyl-8- (3-dimethylamino-l-azetidinyl) -7fluoro-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid: The reaction is performed under the conditions described in Example 4, but starting with 1.27 g of 1-cyclopropyl-B-(3-dimethylamino-1azetidinyl) -3-ethoxycarbonyl-7-fluor:o-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine. 0.8 g of 1-cyclopropyl-8-( 3-dimethylainino-1-azetidinyl) 7-fluoro-4-oxo-1,4-dihydrobenzo[b] [1,8 ]naphthyridine-3carboxylic acid is obtained in the form of yellow solid, melting pcint 264*C.

1-Cyclopropyl-8- 3-dixneth ,ylamino-1azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1,4dihydrobenzo 11,8] naphthyridine was prepared under the conditions described in Example 4, but starting with 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl- 7, 8-difluoro-4-oxo- 1,4-dihydrobenzo~b][,l,8]naphthyridine and 1.04 g of 3- (dimethylamino) azetiuiine dihydrochloride. After concentration of the combined organic extracts to dryness, the solid obtained is recrystallised in 40 cm' of ethanol. 1.2 g of 1-cyclopropyl-8-(3-dimethylamino- 1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-4-oxo-1,4dihydrobenzo[b][1L,8]naphthyridine are obtained in the form of a yellow solid, melting point 225*C.

F"

r-71~- EXAMPLE 7 8- (3-Amino-1-azetidinyl) -1-cyclopropyl- 7 9-dif luoro-4oxo-1,4-dihydrobenzo~b] [1,8 ]naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 0.8 g of 8 -amino- 1-azetidinyl) 1-cycloPropyl- 3-ethoxycarbonyl-7 ,9-difluoro-4-oxo-1, 4-dihydrobenzo~b] 8]naphthyridine. Without recrystallisation, 1 10 0.6 g of 8- (3 -amino- 1-azetidinyl) -1-cyclopropyl-7, 9 difluoro-4-oxo-l, 4-dihydrobenzo[b][r1,8]naphthyridine-3carboxylic acid monohydrate is obtained in the form of a yellow solid, which decomposes at 308-312*C.

8- (3-Amino-1-azetidinyl) -l-cyclopropyl-3ethoxycarbonyl-7 ,9-difluoro-4-oxo-1, 4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.3 g of 1-cyclopropyl-3-ethoxycarbonyl-7, 8, 9-trifluoro-4-oxo- 1,4-dihydrobenzo[b][1,8lnaphthyridine and 1.32 g of 3-aminoazetidine dimethanesulphonate. Aitter recrystallisation. in 50 cm 3 of ethanol, 0.8 g of 8- (3 3-amino- 1-azetidinyl) -1-cyclopropyl-3ethoxycarbonyl-7, 9-difluoro-4-oxo-1, 4'dihydrobenzo 1, 8] naphthyridine is obtained in the form of a yellow solid, melting point 236-238'C.

I-Cyclopropyl-3-athoxycarbonyl-7 9-tnif luoro-4-oxo-1, 4-di hydrob 1,8] naphthyridine was prepared as described in Patent US 4,970,213.

21 EXAMPLE 8 3-Diethylamino-1-azetidinyl) -7-f luoro-4oxo-1-methyl-1, 4-dihydrobenzo[b] [1,8 Jnaphthyridine-3carboxylic acid was prepared under the conditions of Example 2, but starting with 1.75 g of 8- (3-diethylamino-1-azetidinyl) -3-ethoxycarbonyl-7fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b] 11,8)naphthyridine. 1.4 g of 8-(3-diethylamino-1azetidinyl) -7-f luoro-4-oxo-1-methyl-1,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 297'C.

8- (3-Diethylainino-1-azetidinyl) -3-ethoxycarbonyl-7-fluoro-1-methyl-4-uxo-1, 4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 2 g of 3-ethoxy-carbonyl-7 ,8-difluoro- 1-methyl-4-oxo- 1,4-dihydro-benzo[b][1,B]naphthyridine and 1.4 g of 3-(diethylamino)-azetidine dihydrochioride. After recrystallisation of the crude product in 500 cm' of methanol, 2.07 g of 8-(3-diethylamino-1-azetidinyl)- 3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1, 4-dihydrobenzo~b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 260*C.

3-(Diethylamino)azetidine was prepared in the form of dihydrochloride, melting point 175 0 C, according to the method described in Japanese Patent Application 74/109, 369.

7~R4 22 EXAMPLE 9 8- (3 -Ethyl amino- 1-a zetidinyl) -7-f luoro-1-methyl-4-oxo- 1, 4-dihydrobenzo[b] 8 naphthyridine-3-carboxylic acid: The reaction is performed under the conditions described in Example 2, but starting with 0.51 g of 3-ethoxycarbonyl-8-(3-ethylamino- 1-azetidinyl) -7-f luoro-1-methyl-4-oxo-.

1,4-dihydrobenzo[b][1,8]naphthyridine. 0.4 g of 8 3 -ethylamino-l-azetidinyl) -7-f luoro--methyj.-4-oxo- 1,4-dihydrobenzo~b] 8]naphthyridine-3-carboxylic acid ionohydrate is obtained in the form of a yellow solid, which decomposes at 270*C.

3-Ethoxycarbonyl-8- (3-ethylamino-1azetidinyl) -7-f luoro-1-methyl-4-oxo-1, 4-dihydrobenzo 8 jnaphthyridine was prepared under the conditions of Example 2, but starting with 2 g of 7, 8 -dif luoro-3-ethoxycarbonyl-l-methyl-4-oxol,4-dihydrobenzo~b][1,8]naphthyridine and 1.3 g of 3 -(ethyl-ainino)azetidine dihydrochioride. After the addition of 300 cm' of water to the reaction mixtere, the suspension obtained is extracted with 3 times 100 cm' of dichloromethane. 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 dichioromethane J 23 containing 1 of methanol. The desired product is eluted with 500 cm 3 of dichloromethane containing 5 of methanol. 0.51 g of 3-ethoxycarbonyl-8-(3-ethyl-amino- 1-azetidinyl)-7-fluoro-l-methyl-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid, which decomposes at 215 0 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): 4 g of 1-benzhydryl-3-(ethylamino)azetidine dihydrochloride in 50 cm 3 of methanol are hydrogenated at atmospheric pressure and at a temperature in the region of 20°C for 1 hour in the presence of 800 mg of palladium hydroxide on carbon. After removal of the catalyst by filtration and concentration to dryness under reduced pressure (20 kPa) at approximately 40 0

C,

the residue is taken up with 30 cm 3 of ethyl ether, drained and washed with 3 times 20 cm 3 of the same solvent. 2.05 g of 3-(ethylamino)azetidine dihydrochloride are obtained in the form of a colourless solid, melting point 200 0 C, which is used without further purification for the subsequent steps.

l-Benzhydryl-3-(ethylamino) azetidine dihydrochloride is prepared in the following manner: A mixture of 55 g of l-benzhydryl-3-(methanesulphonyloxy)azetidine and 70 g of ethylamine in 400 cm 3 24 of methanol is heated to approximately 60°C for 16 hours. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at approximately 40°C and the residue is taken up with 200 cm 3 of ethyl ether. The organic phase, washed with cm 3 of 2N aqueous sodium hydroxide and 3 times 30 cm 3 of water, is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 40 0 C, 22.6 cm 3 of 12N hydrochloric acid are added to the dry extract obtained, and the mixture is again concentrated to dryness under the above conditions but at approximately 70 0 C. The residue is taken up with 100 cm 3 of ethyl acetate and 200 cm 3 of acetone and drained. 41.4 g of 1-benzhydryl- 3-(ethylamino)azetidine dihydrochloride are obtained in the form of a colourless solid, melting point 180 0

C,

which is used without further purification for the subsequent steps.

l-Benzhydryl-3-(methanesulphonyloxy)azetidine was prepared according to the method described by A. G. Anderson et al., J. Org. Chem., 37, 3953 (1972).

EXAMPLE 8-(3-Amino-l-azetidinyl)-7-fluoro-l-methylamino-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: A suspension of 1.8 g of 8-(3-acetylaminolazetidinyl)-3-ethoxycarbonyl-7-fluoro-l-(N-formyl-Nmethylamino)-4-oxoi 1 t i 1,4-dihydrobenzo[b][1,8]-naphthyridine in 40 cm 3 of N aqueous potassium hydroxide is heated with stirring to a temperature in the region of 100°C for 24 hours.

After cooling to approximately 70 0 C, some slight insoluble matter is removed by filtration. At the same temperature, 40 cm 3 of N methanesulphonic acid are added to the filtrate, and the precipitate formed is drained and washed with 3 times 20 cm 3 of water at approximately 0 C. After recrystallisation in 100 cm 3 of dimethylformamide, 1.05 g of 8-(3-amino-l-azetidinyl)- 7-fluoro-l-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 315-318 0

C.

8-(3-Acetylamino-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-l-(N-formyl-N-methylamino)-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine was prepared in the following manner: 1.8 g of 7,8-difluoro-3-ethoxycarbonyl-l-(Nformyl-N-methylamino)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are added to a mixture at approximately of 1.13 g of 3-(acetylamino)azetidine hydrochloride and 0.85 g of sodium carbonate in 40 cm 3 of dimethyl sulphoxide, and the mixture is heated to approximately 80°C for 2 hours. After cooling to approximately 20°C, the reaction mixture is poured into 100 cm 3 of water at approximately 5°C. The precipitate is drained and washed with 3 times 50 cm 3 of water.

2.05 g of 8-(3-acetyl-amino-l-azetidinyl)- T5 A ;t/ro r 26 3-ethoxycarbonyl-7-fluoro-l-(N-formyl-N-methylamino)- 4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, which decomposes at 305*C.

7,8-Difluoro-3-ethoxycarbonyl-1-(N-formyl-Nmethylamino)-4-oxo-1,4-dihydrobenzo[b][1, 8 naphthyridine was prepared in the following manner: A solution of 1.63 g of N-formyl-Nmethylhydrazine in 30 cm 3 of dichloromethane is added in the course of 10 minutes at approximately 20 0 C to a stirred solution of 7.4 g of ethyl 2-(2-chloro- 6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate in 30 cm 3 of dichloromethane. After 16 hours at a temperature in the region of 20 0 C, the reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 40 0 C. The dry extract is taken up with 100 cm 3 of ethanol and 3 cm 3 of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and heated to approximately 75 0 C for minutes. After cooling to approximately 20 0 C, the product is drained and washed with twice 50 cm 3 of ethanol and twice 30 cm 3 of ethyl ether. 3.9 g of 7,8-difluoro-3-ethoxy-carbonyl-1-(N-formyl-Nmethylamino)-4-oxo-l,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 259-260 0 C, which is used without further purification for the subsequent steps.

Ethyl 2-(2-chloro-6,7-difluoro-3ae quinolinecarbonyl) -3-(dimethylamino) acrylate was 7 27 prepared as described in Patent US 4,970,213.

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-1-azetidinyl)-7-fluoro-1methyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid: A solution of 18 g of trans-3-amino- 2-methylazetidine dimethanesulphonate and 12.7 g of triethylamine in 150 cm 3 of dimethyl sulphoxide is heated with stirring to approximately 70 0 C for minutes. At the same temperature, 14.5 g of 7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b r1,8]naphthyridine-3-carboxylic acid are added in small portions in the course of 10 minutes, and the mixture is heated to approximately 90 0 C for 2 hours. After cooling to approximately 20 0 C, the reaction mixture is poured into 400 cm 3 of water at the same temperature.

The insoluble matter is drained, washed with twice 100 cm 3 of water and twice 100 cm 3 of ethanol and recrystallised in 300 cm 3 of dimethylformamide. 13.9 g of 8-(trans-3-amino-2-methyl-1-azetidinyl)-7-fluoro-1methyl-4-oxo-1,4-dihydrobenzolb]l 8]naphthyridine-3carboxylic acid are obtained in the form of a yellow solid, which decomposes at 265-267 0

C.

trans- 3 -Amino-2-methylazetidine was prepared in the form of the dimethanesulophonate, 28 m.p. 170-175*C, according to the synthesis described in Patent Application EP 406,112.

EXAMPLE 12 8- (cis-3-Am)jino-2-methyl-1-azetidinyl) -7-fluoro-1methyl-4-oxo-1,4-dihydrobenzo[b] 11,8 ]naphthyridine-3carboxylic acid: The reaction is performed under the conditions of Example 11, but starting with 1.45 g of 7 ,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b] [1,81naphthyridine-3-carboxylic acid and 2.1 g of cis-3amino-2-methylazetidine dimethanesulphonate. 1.32 g of 8- (cis-3-amino-2-methyl-1-azetidinyl) -7-f luoro-1methyl-4-oxo-1,4-dihydrobenzo[b] [1,81-acid are obtained in the form of yellow solid, which decomposes at 312-315 0

C.

cis-3-Amino-2-methylazetidine was prepared in the form of the dimethanesulphonate, melting point 160- 170*C, according to the synthesis described in Patent Application EP 406,112.

EXAMPLE 13 8- (trans-3-Amino-2-methyl-1-azetidinyl) -1-cyclopropyl- 7-fluoro-4-oxo-1,4-dihydrobenzo~b] [1,8]naphthyridine-3- K carboxylic acid: A suspension of 1.4 g of 8-(trans-3-amino- 2-methyl-1-azetidinyl) -1-cyclopropyl-3-ethoxycarbonyl- 7-fluoro-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine in cm' of water and 6.8 cm 3 of N aqueous potassium hydroxide is heated to approximately,95 0 C for 3 hours.

1 29 After cooling to approximately 600C, some very slight insoluble matter is removed by filtration; at the same temperature, 6.8 cm 3 of N methanesulphonic acid are added to the filtrate. The insoluble matter formed is drained at approximately 200C and washed with 3 times cm 3 of water and twice 25 cm 3 of ethanol. After recrystallisation in 30 cm 3 of dimethylformamide, one obtains 1.03 g of 8-(trans-3-amino-2-methyl- 1-azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3-carboxylic acid in the form of a yellow solid, which decomposes at 268-270°C.

8-(trans-3-Amino-2-methyl-l-azetidinyl)-1cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine was prepared in the following manner: 1.7 g of l-cyclopropyl-3-ethoxycarbonyl- 7,8-difluoro-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine are added in small portions in the course of 10 minutes to a solution of trans-3-amino-2methylazetidine dimethanesulphonate in 20 cm 3 of dimethyl suphoxide and 1.52 g of triethylamine at approximately 60 0 C. The reaction mixture is heated to a i' temperature in the region of 80°C and kept stirring at the same temperature for approximately 4 hours. After cooling to approximately 20°C, the reaction mixture is poured into 100 cm 3 of water and extracted with twice 100 cm 3 of dichloromethane. The combined organic extracts are washed with twice 50 cm 3 of water, dried pr

::I

over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately The dry extract is chromatographed on 125 g of silica gel (0.04-0.063 mm) suspended in a dichloromethane mixture containing 20 of ethanol. The desired product is eluted with 300 cm 3 of the same mixture. 1.6 g of 8-(trans-3-amino-2-methyl-l-azetidinyl) -1-cyclopropyl- 3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo- [b][l,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, melting point 170 0

C.

EXAMPLE 14 8- (3-Amino-l-azetidinyl) -7-fluoro-4-oxo-1-tert-butyl- 1,4-dihydrobenzo[b] [1,8]naphthyridine-3-carboxylic acid* A suspension of 2.2 g of 8-(3-trifluoroacetamido-l-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4oxo-1-tert-butyl-1,4-dihydrobenzo naphthyridine in 17 cm 3 of N aqueous potassium hydroxide is heated to approximately 95°C for 7 hours. At the same temperature, 17 cm 3 of N methanesulphonic acid are added and the product is drained at approximately 90 0

C,

washed with twice 30 cm 3 of water and twice 30 cm 3 of ethanol and recrystallised in 50 cm 3 of dimethylformamide. 1.4 g of 8-(3-amino-l-azetidinyl)- 7 -fluoro-4-oxo-l-tert-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 333-335°C.

RA4, 3-Ethoxycarbonyl-7-fluoro-8-(3-trifluoro- 'N O\

U

31 acetamido-1-azetidinyl) -4-oxo-1-tert--butyl-1, 4-dihydrobenzo~b]ll,8jjnaphthyridine was prepared under the conditions described in Example 2, but starting with with 1.8 g of 3-ethoxycarbonyl-7,8-difluoro-4-oxo-1tert-butyl-1 ,4-dihydrobenzo[bJ [1,8]naphthyridine, 1.5 g of 3- (trifluoroacetamido) azetidine hydrochloride and 0.79 g of sodium carbonate. 2.25 g of 3-(ethoxycarbonyl-7-fluoro-8-(3-trifluoroacetamido- 1-azetidinyl) -4-oxo-1-tert--butyl-1,4-dihydrobenzo- [b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 328-330 0

C.

3-Ethoxycarbonyl-7, 8-difluoro--4-oxo-l-tertbutyl-1, 4-dihydrobenzo[b] 8]naphthyridine was prepared under the conditions described in Example but starting with 4 g of ethyl 2-(2-chloro- 6, 7-difluoro-3-quinolylcarbonyl) -3 (dimethylamino)- A acrylate and 0.87 g of tert-butylamine. 2.7 g of 3-ethoxycarbonyl-7, 8-difluoro-4-oxo-1-tert-butyl-1, 4dihydrobenzo[b][l,8]naphthyridine are obtained in the form of a yellow solid, melting point 206WC, which is used without further purification for the subsequent steps.

3- (Trifluoroacetamido) azetidine hydrochloride was prepared as described in Patent Application EP 406,112.

EXAMPLE 8- (3-Amino-3-propyl-1-azetidinyl) -7-f luoro-1-methyl-4oxo-1 ,4-dihydrobenzo naphthyridine-3-carboxylic 32 acid: 2.3 g of 3-amiio-3-propylazetidine dimethanesulphonate are added to a solution of 1.22 g of sodium ethylate in 18 cm' of ethanol. After the addition of 30 cm 3 of dimethyl sulphoxide, the solution is stirred for 10 minutes at approximately 20 0 C. At the same temperature, 1.45 g of 7,8-difluoro-l-methyl- 4-oxc.- 1,4-dihydrobenzo[b 1,8 naphthyridine-3-acid are added and the mixture is heated with stirring to approximately 90*C for 5 hours. After cooling to approximately 20 0 C, the product is drained and washed with 4 times 20 cm 3 of water and twice 10 cm 3 of ethanol. After recrystallisation in 30 cm 3 of dimethylformamide, 1.52 g of 8-(3-amino-3-propyl- 1-azetidinyl) -7-fluoro-l-methyl-4-oxo-1,4-dihydrobenzo- [1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 304-305 0

C.

3-Amino-3-propylazetidine in the form of the dimethanesulphonate was prepared under conditions similar to those described by D. Nisato et al., J. Heterocyclic, 22, 961 (1985).

By hydrogenation of 7.3 g of 3-amino- 1-benzhydryl-3-propylazetidine at a pressure of 1 atmosphere in the presence of 5 g of methanesulphonic acid in 75 cm 3 of methanol and 1.5 g of 20 palladium hydroxide on carbon, 6.5 g of 3-amino-3-propylazetidine dimethanesulphonate are obtained. The product is taken 33 up in ethanol and isolated in the form of a colourless solid, melting point 2000C.

3-Amino-l-benzhydryl-3-propylazetidine was prepared in the following manner: 7.5 g of l-benzhydryl-3-methanesulphonyloxy- 3-propyl-azetidine are added to a solution at approximately 5°C of 100 cm 3 of a solution of ammonia in ethanol (prepared from 15 g of ammonia in 100 cm 3 of ethanol at 5 0 C [lacuna], 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 kPa) at approximately 40°C, the residue is taken up with 25 cm 3 of water and 2.22 g of methanesulphonic acid. The aqueous phase is washed with twice 25 cm 3 of ethyl ether, treated with 10 cm 3 of 40 aqueous sodium hydroxide and extracted with 3 times 50 cm 3 of dichloromethane; the combined organic extracts are washed with 10 cm 3 of water saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness under the above conditions.

5.2 g of 3 -amino-l-benzhydryl-3-propylazetidine are obtained in the form of an oily product, which is used without further purification for the subsequent steps.

l-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine was prepared under the conditions described for l-benzhydryl-3-methanesulphonyloxy-3methylazetidine in Patent Application EP 406,112, but 34 starting with 2.4 g of l-benzhydryl-3-hydroxy- 3-propylazetidine. 2.4 g of 1-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine are obtained in the form of a colourless solid, melting point 700C.

1-Benzhydryl-3-hydroxy-3-propylazetidine was prepared under the following conditions: A solution of 7.5 g of 1-benzhydryl- 3-oxoazetidine dissolved in 50 cm 3 of ethyl ether is added in the course of 20 minutes at between 0 and to a solution of propylmagnesium iodide in ethyl ether, prepared under the usual conditions from 10.75 g of iodopropane and 1.55 g of magnesium in 75 cm 3 of ethyl ether. 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 approximately 0 C, 50 cm 3 of water and 50 cm 3 of 10 aqueous ammonium chloride solution are added Ssuccessively while the latter temperature is maintained. The aqueous phase is extracted with 3 times 50 cm 3 of ethyl ether. The combined organic extracts are dried over magnesium sulphate and concentrated to idryness under reduced pressure (20 kPa) at Sapproximately 30°C. The dry extract is chromatographed on 100 g of silica gel (0.04-0.063 mm) suspended in a cyclohexane mixture containing 20 of ethyl acetate.

The desired product is eluted with 130 cm 3 of the same solvent mixture. 8 g of l-benzhydryl-3-hydroxy- 3-propyl-azetidine are obtained in the form of a pale L L f yellow oil, which is used 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. 21 228-231 (1973).

EXAMPLE 16 8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl-4oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid: 2.09 g of 3-amino-3-methylazetidine dimethanesulphonate are added to a solution of 1.02 g of sodium ethylate in 30 cm 3 of ethanol at approximately 0 C. The temperature is allowed to rise to approximately 20°C and the mixture is stirred for 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 0 C. The residue is dissolved in cm 3 of dimethyl sulphoxide is treated at a temperature in the region of 20 0 C with 1.45 g of 7,8-difluoro-l-ethyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid. The suspension obtained is stirred for 16 hours at the same temperature and then heated to approximately 60 0 C for 1 hour. After cooling to approximately 20°C, the insoluble matter is drained and washed with 30 cm 3 of ethanol. The product isolated is recrystallised in cm 3 of dimethylformamide, drained and washed with L

.I

i ~I .rcm 36 cm 3 of ethanol at approximately 75 0 C. 1.2 g of 8-(3-amino-3-methyl-l-azetidinyl)-7-fluoro-l-methyl- 4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine- 3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 345°C.

3-Amino-3-methylazetidine in the form of the dimethanesulphonate, melting point 204-206 0 C, is prepared under the conditions described in Patent Application EP 406,112.

EXAMPLE 17 8-(3-Amino-3-methyl-l-azetidinyl)-l-ethyl-7fluoro-4-oxo-1,4-dihydrobenzo[b][l,8]naphthyridine-3carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.52 g of 7,8-difluoro-l-ethyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.22 g of 3-amino- 3-methylazetidine dimethanesulphonate, for 72 hours at approximately 20°C and then 1 and a half hours at a temperature in the region of 90°C. The ;.-soluble matter in the reaction mixture is drained at approximately 0 C, washed with twice 20 cm 3 of water, recrystallised in 70 cm 3 of dimethylformamide and washed with 40 cm 3 of ethanol at approximately 75 0 C. 1.45 g of 8-(3-Amino-3methyl-l-azetidinyl)-l-ethyl-7-fluoro-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 334°C.

37 EXAPIJE 18 8- (3-Amino-3-methyl-1-azetidinyl) -1cyclopropy- luoro-4 -oxo- 1, 4-dinyarenzuL .Jb,1J8 naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 16, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4dihydrobenzo naphthyridine-3-carboxylic acid and 2.22 g of 3 -amino- 3-methyl a zetidine d.rnethanesulphonate. 1.7 g of 8-(3-axnino-3-methyl- 1-azetidinyl) -1-cyclopropyl-7-f luoro-4-oxo- 1, 4-dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid are obtained in the f orm of a yellow solid, which decomposes at 298*C.

1-Cyclopropyl-7 ,8-difluoro-4-oxo-1 14dihydrobenzo[b] [1 ,8jnaphthyridine-3-carboxylic acid was pr~epared under the following -onditions; A suspension of 8.05 g of 1-cyclopropyl- 3-ethoxy-carbonyl-7, 8-difluoro-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine in a mixture of 80 cm' of 17.5 aqueous hydrochloric acid solution and 80 cm 3 of acetic acid is heated with stirring to a temperature in the region of 1000C for 2 hours. After cooling to approximately 20 0 C, the product is drained and washed with 3 times 100 cm' of water. 6.25 g of 1-cyclopropyl- 7,3-difluoro-4-.oxo-1,4-dihydrobenzo[b][1,83naphthyridine-3-carboxylic acid are obtained in the form of a pale yellow solid, which decomposes at 238 0

C

and which is used without further purification for the

IL

38 subsequent steps.

EXAMPLE 19 (RS) (3-Amino-2, 2-dimethyl-1-azetidinyl) -7fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo- [b][1,83naphthyridine-3-carboxylic acid and 2.33 g of 3 -amino- 2, 2 -dimethyla zetidine dimethanesuiphonate. The reaction mixture is heated with stirring to approximately 100*C for 5 hours. 0.6 g of amino-2,2-dimethyl-1-azetidinyl) -7-fluoro-l-methyl-4oxo-1,4-dihydrobenzo~b] [1,8 ]naphthyridine-3-carboxylic acid is obtained in the f orm of a yellow solid, which decomposes at 2851C.

3 -Amino-2, ,2-dimethyl a zetidine dimethanesulphonate was prepared in the form of a white solid, melting point 125-130'C, from 3-amino-2,2,dimethylazetidine, by adaptation of the method described by Akira Morimoto Chem. Pharm. Bull., 21 228 (1973) EXAMPLE 7-Fluoro-1-methyl-8- (3-methyl-3-methylamino- 1-azetidinyl)-4--oxo-1,4-dihydrobenzo~b][1,8]nal.hthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.45 g of 7, 8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b]- [1,8]naphthyridine-3-carboxylic acid and 2.34 g of 39 3-methyl-3- (methylanino) azetidine dimethanesuiphonate.

The reaction mixture is heated for 1 and a half hours to approximately 90*C. 1.12 g of 7-f luoro-1-methyl- 8- (3-methyl-3-methylamino-1-azetidinyl) -1-methyl-4-oxo- 1,4-dihydrobenzo[b] 8naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at approximately 336WC.

3-Methyl-3- (methylamino) azetidine in the form of the dimethanesulphonate (melting point 1350) was prepared under the conditions described in Patent Application EP 406,112.

EXAMPLE 21 1-Cyclopropyl-7-fluoro-8-( 3-methyl-3methylamino-1-azetidinyl) -4-oxo-1, 4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxyl&c, cid was prepared under the conditions of Example 15, but starting with 1.58 g of 7,8-difluoro-1-cyclopropyl-4-oxo- 1,4-dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylaxnino)azetidine dimethanesulphonate. 1.57 g of 1-cyclopropyl-7-fluoro- 8- (3-methyl-3-methylamino-1-azetidinyl) -4-oxo- 1,4-dihydrobenzo[b] [1,8 Jnaphthyridine-3-carboxylic acid V are obtained in the form of a yellow solid, which decomposes at 330'C.

EXAMPLE 22 1-Ethyl--7-fluoro-8- (3-methyl-3-xnethylamino- 1-azetidinyl)-4-oxo-1,4-dihydrobenzc( naphthyridine-3-carboxylic acid was prepared under the pr conditions of Example 15, but starting with 1.52 g of 7, 8-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo~b]- [1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3- (methylamino) azetidine dimethanesuiphonate.

1.18 g of 1-ethyl-7-fluoro-8-(3-methyl-3-methylamino-1azetidinyl) -4-oxo-1,4-dihydrobenzo~b3 naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 338 0

C.

EXAMPLE 23 8- (3 -Amino- 3-methyl- 1-azetidinyl) -7-f luoro-1methoxy-4-oxo-1, 4-dihydrobenzo[b] 1, 8 ]naphthyridine-3carboxylic acid was prepared under the conditions of Example 15, but starting with 1.53 g of 7,8-difluoro-1methoxy-4-oxo-1,4-dihydrobenzo~b] 11, 8]naphthyridine-3carboxylic acid and 2.22 g of 3 -amino- 3-methyla zetidine dimethane-sulphonate. 1.27 g of 8-(3-amino-3-methyl- 1-azetidinyl) -7-f luoro-1-methoxy-4-oxo- 1, 4-dihydrobenzo~b] 8]naphthyridine-3-carboxylic acid are obtained in the f orm of a yellow solid, which decomposes at 346 0

C.

7, 8-Dif luoro-1-methoxy-4-oxo- 1, 4 -dihydrobenzo~b] [1,8 ]naphthyridine-3-carboxylic acid is prepared under the conditions described in Patent US 4,970,213.

EXAMPLE 24 1-Cyclopropyl-7-filuoro-8- 3-methyl-3dimethyl amino- 1-a zetidinyl) -4-oxo-1, 4-dihydrobenzo~b] [1,8 ]naphthyridine-3-carboxylic acid was 41 prepared under the conditions of Example 15, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro- Vt 4-oxo-1 ,4-dihydrobenzo[b] 8]naphthyridine- V 3-carboxylic acid and 2.45 g of 3-methyl- 3-(dimethylamino)azetidine dimethanesuiphonate. 1.55 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-3-dimethylamino- 1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 268*C.

410 3-Methyl-3-(dimethylamino)azetidine in the form of the dimethanesulphonate, melting point 148*C, is prepared under the conditions described in Patent Application EP 406,112.

EXAMPLE 7-Fluoro-1-methyl-8- (3-methyl-3dimethylainino-1-azetidinyl) -4-oxo-1,4-dihydrobenzo- [b][l,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo- 1, 4-dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate. 1.56 g of 7-f luoro-1-methyl- 8- (3-methyl-3-dimethylamino-1-azetidinyl) -4-oxo- 1, 4-dihydrobenzo~b] 8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 274*C.

EXAMPLE 26 8- (3-Amino-3-methyl-1-azetidinyl) -7,9- 42 difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b] 1,8naphthyridine-3-carboxylic acid was prepared under the following conditions: 1.33 g of 3-amino-3-methylazetidine dimethanesulphonate are added to a solution of 0.68 g of sodium ethylate in 7 cm 3 of ethanol. After the addition of 20 cm 3 of dimethyl sulphoxide, the solution is stirred for 10 minutes at approximately 20 0 C. At the same temperature, 0.75 g of 7,8,9-trifluoro-1-methyl- 4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine- 3-carboxylic acid is added, and the mixture is stirred for 72 hours at approximately 20 0

C,

The insoluble matter is drained and washed with twice 20 cm 3 of water and twice 20 cm 3 of ethanol.

After recrystallisation in 70 cm 3 of dimethylformamide, 0.45 g of 8-(3-amino-3-methyl-1-azetidinyl)- 7,9-difluoro-1-methyl-4-oxo-1,4-dihydrobenzolb][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 359 0

C.

7,8,9-Trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared in the following manner: A suspension of 0.88 g of 3-ethoxycarbonyl- 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine in a mixture of 10 cm 3 of 17.5 aqueous hydrochloric acid solution and 10 cm 3 of acetic acid is heated with stirring to a temperature in the region of 100 0 C for 3 hours. After cooling to 43 approximately 20 0 C, the product is drained and washed with 3 times 10 cm' of water. 0.75 g of 7,8,9-trifluoro- 1-methyl-4-oxo-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid 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-1-methyl-4oxo-1,4-dihydrobenzo[b] 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-1-methyl-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.45 g of 7, 8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo- [b]ll,8]naphthyridine-3-carboxylic acid and 2.5 g of 3-cyclopropylamino-3-methylazetidine dimethanesulphonate. 1.73 g of 8-(3-cyclopropylamino-3-methyl- 1-azetidinyl) -7-f luoro-1-methyl-4-oxo-1 ,4-dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid, solvated with 0.7 of water is obtained in the form of a yellow solid, which decomposes at 300*C.

3 -Cyclopropylamino- 3-methylazetidine dimethanesuiphonate was prepared in the following manner: 14.5 g of 1-benzhydryl-3-cyclopropylamino- RZ 3 -methyl-azetidine in 150 cm' of methanol are

~TO~

h. I 44 hydrogenated at atmospheric pressure and at a temperature in the region of 20 0 C for 1 hour in the presence of 5.6 g of 20 palladium hydroxide on carbon. The reaction mixture is treated with 10 g of methanesulphonic acid. After removal of the catalyst by filtration and concentration to dryness under reduced pressure (20 kPa) at approximately 40 0 C, the residue is washed with 3 times 150 cm 3 of ethyl ether. The final residue is taken up with 100 cm 3 of 2-propanol, drained and washed with twice 50 cm 3 of acetone. 9.1 g of 3-cyclopropylamino-3-methylazetidine dimethanesulphonate are obtained in the form of a colourless solid, melting point 136 0

C.

1-Benzhydryl-3-cyclopropylamino-3-methylazetidine was prepared in the following manner: A suspension of 16.6 g of 1-benzhydryl- 3 -methane-sulphonyloxy-3-methylazetidine and 28.84 g of of cyclopropylamine in 250 cm 3 of ethanol is stirred for 96 hours at approximately 20°C. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 30 0 C. The dry extract is taken up with cm 3 of water and 8.8 g of methanesulphonic acid. The I aqueous phase is washed with 3 times 25 cm 3 of dichloromethane, treated with 12 cm 3 of 35 aqueous sodium hydroxide and extracted with 3 times 50 cm 3 of ethyl acetate. The combined organic phases are washed with twice 50 cm 3 of water, dried over magnesium a sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 25 0 C. 14.6 g of l-benzhydryl-3-cyclopropylamino-3-methylazetidine are obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.

l-Benzhydryl-3-methanesulphonyloxy-3-methylazetidine was prepared according to the conditions described in Patent Application EP 406,112.

EXAMPLE 28 8-(3-Ethylamino-3-methyl-l-azetidinyl)-7fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.45 g of 7,8-difluoro-l-methyl-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid and 2.24 g of 3-ethylamino-3-methylazetidine dimethanesulphonate.

1.66 g of 8-(3-Ethylamino-3-methyl-l-azetidinyl)-7fluoro-l-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 3120C.

I 20 3-Ethylamino-3-methylazetidine dimethanesulphonate was prepared under the conditions described in Example 27, but starting with 14 g of 1-benzhydryl- 3-ethyl-amino-3-methylazetidine. 9.7 g of 3-ethylamino- 3-methyl-azetidine dimethanesulphonate are obtained in the form of a colourless solid, melting point 140 0

C.

l-Benzhydryl-3-ethylamino-3-methylazetidine was prepared under the conditions described in Example 27, but starting with 16.6 g of 1-benzhydryl- 46 3-methanesulphonyl-oxy-3-methylazetidine and 45 g of ethylamine. 14 g of 1-benzhydryl-3-ethylamino- 3-methylazetidine are obtained in the form of a yellow oil, which is used without further purification for the EXAMPLE 29 subsequent steps.

7-Fluoro-8-(3-methylamino-1-azetidinyl)-1methoxy-4-oxo-1,4-dihydrobenzob] [1,8]naphthyridine-3carboxylic acid was prepared under the conditions of Example 2, but starting with 2.6 g of 3-ethoxycarbonyl- 7-fluoro-1-methoxy-8-(3-methylamino-1-azetidinyl)-4oxo-1,4-dihydrobenzo[b][1,8]naphthyridine. 1.7 g of 7-fluoro-8-(3-methylamino-1-azetidinyl)-1-methoxy- 4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine- 3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 255-260 0

C.

3-Ethoxycarbonyl-7-fluoro-1-methoxy-8-(3methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the following conditions: 2.8 g of 3-(methylamino)azetidine dihydrochloride are added to a solution of 2.36 g of sodium ethylate in 20 cm 3 of ethanol. After 15 minutes' stirring at a temperature in the region of 20 0 C and removal of the inorganic salts by filtration, the filtrate is concentrated to dryness under reduced pressure (20 kPa) at approximately 30 0 C. The residue is dissolved in 40 cm 3 of dimethylsulphoxide and the

,L

47i solution treated with 2.7 g of 3-ethoxycarbonyl- 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b] naphthyridine. The reaction mixture is heated to approximately 60*C for 1 and a half hours. 2.7 g of 3ethoxycarbonyl-7-fluoro-8- (3-methylamino-1-azetidinyl) 1-methoxy-4-oxo-1 ,4-dihydrobenzo naphthyridine are obtained in the form of a yellow solid, melting point 234*C.

3- (Methylamino) azetidine dihydrochloride was prepared under the conditions described in Example 9, but starting with 32.2 [lacuna] of 1-benzhydryl- 3-(methylamino)azetidine. 19.1 g of 3-(methylamino) azetidine dihydrochloride are obtained in the form of a colourless solid, melting point 138-1401C.

1-Benzhydryl-3-(methylamino)azetidine was prepared under the conditions of Example 9, but starting with 50 g of 1-benzhydryl- 3-(methanesulphonyloxy)-azetidine and 48.9 g of methylamine in 250 cm' of methanol. 27 g of 1-benzhydryl-3-(methylainino)azetidine are obtained in the form of a colourless solid, melting point EXAMPLE 1-Cyclopropyl-7-fluoro-8-( 3-methylamino-1azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11, but starting with 1.5 g of l-cyclopropyl-7 ,8-dif luoro-4-oxo-1 ,4 -dihydrobenzo~b][1,8]naphthyridine-3-carboxylic acid and 1.13 g 48 of 3-(methylamino)azetidine dihydrochioride. The reaction mixture is stirred for 1 hour at 40 0 C. 1 g of 1-cyclopropyl-7-fluoro-8- (3-methylamino-1--azetidinyl) 4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine- 3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 262WC.

EXAMPLE 31 7, 9-Difluoro-1-methyl-8- (3-methylaminoazetidinyl)-4-oxo--1,4-dihydrobenzo[b] [1,81naphthyridine-3-carboxylic acid was prepared under the conditions of Example 30, but starting with 1.5 g of 7,8, 9-trifluoro--mxethyl-4-oxo-1, 4-dihydrobenzo- [b][l,8]naphthyridine-3-carboxylic acid and 1.2 g of 3-(methylamino)azetidine dihydrochloride. 1.54 g of 7,9-difluoro-1-methyl-8-(3-methylamino-1-azetidinyl) 4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine- 3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 3021C.

EXAMPLE 32 8-(3-Amino-3-ethyl-1-azetidinyl)-7-fluoro-1xethyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid was prepared under the conditions of V Example 15, but sta~cting with 1.66 g of 7,8-difluoro- 1-methyl-4-oxo-1,4-dihydrobenzo[b] 8jnaphthyridine-3carboxylic acid and 3.1 g of 3-amino-3-ethylazetidin-Le dimethane-sulphonate. 1.46 g of 8-(3-ainino-3-ethyl- 1-azetidinyl) -7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid are obtained in 49 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 15 for 3-amino-3-propylazetidine dimethanesulphonate: 5.7 g of 3-amino-3-ethylazetidine dimethanesulphonate were obtained in the form of a colourless solid, melting point 184 0 C, by hydrogenation of 6 g of 3-amino-l-benzhydryl-3-ethylazetidine.

13.6 g of 3-amino-l-benzhydryl- 3-ethylazetidine were obtained in the form of a yellow oil from 24.6 g of l-benzhydryl-3-ethyl- 3-(methanesulphonyloxy)azetidine dissolved in 174 cm 3 of solution of ammonia in ethanol. The product isolated was used without further purification for the subsequent steps.

24.6 g of l-benzhydryl-3-ethyl- 3-(methanesulphonyloxy)-azetidine were obtained in the form of a yellow solid, melting point 68 0 C, from 35.5 g of l-benzhydryl-3-hydroxy-3-ethyl-azetidine.

35.5 g of 1-benzhydryl-3-hydroxy- 3-ethylazetidine were obtained in the form of a yellow Ioil from 44 g of l-benzhydryl-3-oxoazetidine and 80 cm 3 of ethylmagnesium bromide at a concentration of 399 g per litre in ether.

EXAMPLE 33 8-(3-Amino-3-ethyl-l-azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid methanesulphonate was

I

r fi i- l- I prepared under the conditions of Example 15, but starting with 1.8 g of 7,8-difluoro-l-cyclopropyl- 4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine- 3-carboxylic acid and 2.94 g of 3-amino- 3-ethylazetidine dimethanesulphonate. After recrystallisation in dimethylformamide, the product obtained, suspended in 20 cm 3 of ethanol, is treated with 3.4 cm 3 of a solution at a concentration of 9.6 g of methanesulphonic acid in ethanol. The suspension is stirred for 5 minutes at approximately 80°C, cooled to a temperature in the region of 20°C, drained and washed with 3 times 10 cm 3 of ethanol. 0.55 g of 8-(3-amino- 3-ethyl-l-azetidinyl)-l-cyclopropyl-7-fluoro-4-oxo- 1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid methanesulphonate is obtained in the form of a yellow solid, which decomposes at 2480C.

EXAMPLE 34 7-Fluoro-l-methyl-8-[3-(l-pyrrolidinyl)-lazetidinyl]-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but starting with 1.2 g of 3-ethoxy-carbonyl-7-fluoro-l-methyl-8-[3-(1pyrrolidinyl)-l-azetidinyl]-4-oxo-l,4-dihydrobenzo- [b][l,8]naphthyridine. 0.7 g of 7-fluoro-1-methyl-8-[3- (l-pyrrolidinyl)-l-azetidinyl]-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 302 0

C.

3-Ethoxycarbonyl-7-fluoro-l-methyl-8-[3-(1- L .plc j i- 7 51 pyrrolidinyl) -1-azetidinyl] -4-oxo-1, 4-dihydrobenzo- [b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.6 g of 3-ethoxycarbonyl-7, 8-difluoro-1-methyl-4-oxo- 1,4-dihydrobenzo[bJ[1,8]naphthyri6'.ne and 1.5 g of 3- -pyrrolidinyl) azetidine dihydrochloride. The reaction mixture is stirred for 24 hours at approximately 95*C. 1.3 g of 3-ethoxy-carbonyl- 7-f luoro-1-methyl-8-[L3- -pyrrolidinyl) -1-azetidinyl] 4-oxo-1,4-dihydrcbenzo~b] [1,8]naphthyridine are obtained in the form of a yellow solid, melting point 246*C.

3,*(1-Pyrrolidinyl) azetidine was prepared in the form of the dihydrochloride, melting point 195*C, under the conditions described in Japanese Patent Application 74 109 369.

EXAMPLE 8- 3 -Cyclopropylalnino-l-azetidinyl) -7-f luoro- 1-methyl-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.3 g of 8-(3-cyclopropylamino- 1-azetidinyl) 3 -ethoxycarbonyl-7-fluoro--methyl-4-oxol,4-dihyrdro-benzo(b] [1,8]naphthyridine. 0.8 g of 8- 3 -cyclopropyl-amino-1-azetidinyl) -7-f luoro-1-methyl- 4-1, 4-di1bydrobenzo~b] 8]naphthyridine is obtained in the form of a yellow solid, which decomposes at 272*C.

8- 3 -Cyclopropylamino-1-azetidinyl) -3etoyabnl--loolmehl4oo14-dihydro- TO~z'A 52 benzo[b][1,B]naphthyridine was prepared under the conditions of Example 15, but starting with 1.45 g of 3-ethoxycarbonyl-7,8-i oro-1-methyl-4-oxo- 1,4-dihydrobenzo[b]l thyridine and 1.7 g of 3-(cyclopropylamino)azet-.iine dihydrochioride. 1.35 g of 8- (3-cyclopropylamino-1-azetidinyl) 3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo- 1, 4-dihydrobenzo naphthyridine are obtained in the form of a yellow solid, melting point 221*C and then 245*C.

3- (Cyclopropylamino) azetidine dihydrochioride was prepared under the conditions described in Example 9 for 3-(ethylamino)azetidine dihydrochioride, but starting with 5.4 g of 1-benzhydryl- 3-(cyclopropylamino)azetidine dihydrochioride. 2.25 g of 3- (cyclopropylanino) azetidine dihydrochloride are obtained in the form of a colourless solid, melting point 140*C.

1-Benzhydryl-3- (cyclopropyamino) azetidine dihydrochloride was prepared under the conditions described in Example 9 for 1-benzhydryl-3-(ethylamino)azetiine dihydrochloride, but starting with 15 g of 1-benzhydryl-'3-(methanesulphonyloxy)azetidine and 8.2 g of cyclopropylamine. 5.4 g of 1-benzhydryl- 3- (cyclopropyl-amino) azetidine dihydrochioride are obtained in the form of a colourless solid, melting point 182*C.

53 E XAMPZ E 3 6 Using the procedure described in the above examples, the following products are prepared: 7-Fluoro-l-methyl-8- (3-methylainino-1-azetidinyl) 4-oxo-1,4-dihydrobenzo~b] 8]naphthyridine-3carboxylic acid; (2-Aminoethyl)amino-1-azetidinyl]-7-fluoro-lmethyl-4-oxo-l,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 7-Fluoro-8-[3- (2-hydroxyethyl) amino-l-azetidinyl]- 1-methyl-4-oxo-1, 4-dihydrobenzo[b] i, 8]naSl lthyridine-3carboxylic acid; -7-Fluoro-l-inethyl-4-oxo-8-[3-(l-piperazinyl)-1azetidinyl]-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; -8-{3-[4-(2-Aminoethyl)phenyl]axnino-1-azetidinyl}- 7-f luoro-l-methyl-4-oxo-1.,4-dihydrobenzolbl- 11, 8]naphthyridine-3-carboxylic acid; 8- (3-Amino-3-phenyl- 1-azetidinyl) -7-f luoro- 1mthy-4-ox-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; (3-Amino-2-dimethylainino-l-azetidinyl) -7-flo- 1-methyl-4-oxo-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; l-Ethyl-7-fluoro-8-(3-methylamino-l-azetidinyl)-4-.

oxo-1, 4-dihydrobenzo[b) 8]naphthyridine-3-carboxylic acid; 54 8-(3-Ethylamino-1-azetidinyl)-1-ethyl-7-fluoro-4oxo-1, 4-dihydrobenzo [1,81 naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-1-azetidinyl)-l-ethyl-7fluoro-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; -Ethyl-7-fluoro-8-[3-(2-hydroxyethyl) amino-iazetidinyl]-4-oxo-1,4-dihydrobenizo[b] naphthyridiz.ie-3-carboxylic acid; 8-(3-Cyclopropylamino-2-azetidinyl)-1-ethyl-7fluoro-4-oxo-1,4-dihydrobenzo~b] [1,8 ]naphthyridine-3carboxylic acid; -Ethyl-7-fluoro-4-oxo-8-[3-(1-piperazinyl)-1azetidinyl]-1,4-dihydrobenzo[b] Slnaphthyridine-3carboxylic acid; -8-{3-[4-(2-Aminoethyl)phenyljamino-l-azetidinyl}- 1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 8- (3-Azino-3-phenyl-1-azetidinyl) -1-ethyl-7fluoro-4-oxo-1,4--dihydrobenzo[b] 11, 8]naphthyridine-3carboxylic acid; 8- (3-2Amino-2-dimethylaniino-1-azetidinyl) -1-ethyl- 7-f luoro-4-oxo-1,4-dihydrobenzo~b] [1,8]naphthyridine-3carboxylic acid; 1-Cyclopropyl-8-(3-ethylamino-3.-azetidinyl)-7fluoro-4,-ox)-1 ,4-dihydrobenzo[b] [1,8 ]naphthyridine-3carboxylin, acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-1-cyclopropyl-7-fluoro-4-t..xo-l,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 1-Cyclopropyl-7-fluoro-8-[3-(2-hydroxyethyl) amino-1-azetidinyl]-4-oxo-1,4-dihydrobenzo~b][1,8]naphthyridine-3-carboxylic acid; 1-Cyclopropyl-8- (3-cyclopropylamino-1-azetidinyl) 7-f luoro-4-oxo-1 ,4-dihydrobenzo[b] [1 ,8]naphthyridine-3carboxylic acid; 1-Cyclopropyl-7-fluoro-4-oxo-B-[3-(l-piperazinyl)- 1-azetidinyl]-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]axnino-1-azetidinyl}- 1-cyclopropyl-7-fluoro-4-oxo-1, 4dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid; 8-(3-Axnino-3-phenyl-1-azetidinyl) -1-cyclopropyl-7fluoro-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 8- (3-Axino-2-dimethylamino-1-azetidinyl) -1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo~b] 1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-1--methylamino-8- (3-methylamino-1azetidinyl)-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8-(3-Ethylainino-l-azetidinyl) -7-fluoro-1-methylaiino-4-oxo-1,4-dihydrobenzo[b] 8Jnaphthyridine-3carboxylic acid; RA4y <&i~w /~Vr> L 56 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7-fluoro-1methylamino-4-oxo-1,4-dihydrobenzolb] naphthyridine-3-carboxylic acid; 7-Fluoro-8-[3-(2-hydroxyethyl) amino-1-azetidinyl] 1-methylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8- (3-Cyclopropylamino-1-azetidinyl) -7-f luoro-1methylamirio-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 7-Fluoro-1-methylamino-4-oxo-8-[3- -piperazinyl) 1-azetidinyl]-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; -8-{3-[4-(2-Aminoethyl)phenyl]amino-1-azetidinyl}- 7-f luoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b] [1,81naphthyridine-3-carboxylic acid; -8-(3-Amino-3-phenyl-1-azetidinyl)-7-fluoro-1methylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; -8-(3-Amino-3-methyl-l-azetidinyl)-7-fluoro-lmethylainino-4-oxo-1,4dihydrobenzo[b] 8]naphthyridine-3-carboxylic acid; 8- (3-Amino-2-dimethylanino-1-azetidinyl) -7-f luoro- 1-methylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 7-Fluoro-1-(2-:Cl'uoroethyl)-8-(3-methylamino-lazetidinyl)-4-oxo-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 8-(3-Ethylamino-1-azetidinyl)-7-fluoro-1-(2fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-l-azetidinyl]-7-fluoro-l- (2-fluoroethyl)-4-oxo-1,4-dihydrobenzo~b][1,8]naphthyridine-3-carboxylic acid; 7-Fluoro-1-(2-fluoroethyl)-8-[3-(2-hydroxyethyl)amino-1-azetidinyl]-4-oxo-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 8-(3-Cyclopropylanino-1--azetidinyl)-7-fluoro-1-(2fluoroethyl) -4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 7-Fluoro--1-(2-fluoroethyl)-4-oxo-8-[3-(1piperazinyl) -1-azetidinyl] 4-dihydrobenzo[b] 1, 8naphthyridine- 3-carboxylic acid; 8-13-[4-(2-Amninoethyl)phenylJamnino-l-azetidinyl}- 7 -f luoro- 1- (2 -f luoroethyl) -4 -oxo- 1, 4 dihydrobenzo~b] [1,8 ]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7-fluoro-l-(2fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-methyl-1-azetidinyl)-7-fluoro-1-(2fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxy.ic acid; 8- (3-Amino-2-dimethylamino-1-azetidinyl) -7-f luoro- 1-(2-fluoroethyl)-4-oxo-1,4-dihydrobenzo~b][1,8]naphthyridine-3-carboxylic acid; 58 7-Fluoro-8- (3-methylamino-1-azetidinyl) -4-oxo-1-tbutyl-1,4-dihydrobenzo[b] [1,8 )naphthyridine-3carboxylic acid; 8- (3-Ethylamino-l-azetidinyl)-7-fluoro-4-oxo-l-tbutyl-1, 4-dihydrobenzo[b) 8]naphthyridine-3carboxylic acid; (2-Aminoethyl) amino- 1-azetidinyl] -7-f luoro-4oxo-1-t-butyl-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 7-Fluoro-8-(3- (2-hydroxyethyl) amino-1-azetidinyl]- 4-oxo-l-t-butyl-1,4-dihydrobenzo[b] 8]naphthyridine- 3-carboxylic acid; (3-Cyclopropylamino-l-azetidinyl) -7-f luoro-4oxo-1-t-butyl-1,4-dihydrobenzo~b] Bjnaphthyridine-3carboxylic acid; -7-Fluoro-4-oxo-8-[3-(l-piperazinyl)-l-azetidinyl]- 1-t-butyl-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; (2-Aminoethyl)phenyl]amino-1-azetidinyl}- 7-f luoro-4-oxo-l-t-butyl-1, 4-dihydrobenzo- 8)naphthyridine-3-carboxylic acid; 8- (3-Amino-3-phenyl-l-azetidinyl) -7-f luoro-4-oxo- 1-t-butyl-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 8- (3-PAmino-3-methyl-l-azetidinyl) -7-f luoro-4-oxo- 1-t-butyl-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; Li AIV y 59 8- (3-Amino-2-dixnethyJlamino-1-azetidinyl) -7-f luoroii 4-oxo-1-t-butyl-1, 4-dihydrobenzo[b] 8]naphthyridine- 3-carboxylic acid; 7,9-Difluoro-8-(3-ethylamino-1-azetidinyl)-lmethyl-4-oxo-1,4-dihydrobenzo~b] 8]naphthyridine-3- F carboxylic acid; 8-[3-(2-Aiinoethyl)amino-l-azetidinyl]-7,9difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 7,9-Difluoro-B-[3-(2-hydroxyethyl)amino-1azetidinyl]-1-methyl-4-oxo-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 8- (3-Cyclopropylamino-l-azetidinyl) 9-difluoro- 1-methyl-4-oxo-1,4-dihydrobenzo~b] [1,8]naphthyridine-3carboxylic acid; -7,9-Difluoro-l-methyl-4-oxo-8-[3-(l-piperazinyl)- 1-azetidinyl]-1,4-dihydrobenzo[b] [1,8Jnaphthyridine-3carboxylic acid; -8-{3-[4-(2-Aminoethyl)phenyl]amino-1-azetidinyl}- 7,9-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8-(3-Azino-3-phenyl-1-azetidinyl)-7,9-difluoro-1methyl-4-oxo-1,4-dihydrobenzo~b] [1,8]naphthyridine-3carboxylic acid; 8-(3-AInino-2-dimethylaxnino-l-azetidinyl) -7,9-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[bJ naphthyridine-3-carboxylic acid; 7, 9-Difluoro-1-ethyl-8- (3-methylainino-lazetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Ethylaiino-l-azetidinyl) -7 ,9-difluoro-1ethyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; 8-[3-(2-Aminoethyl)-l-azetidinyl]-7,9-difluoro-lethyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; 7,9-Difluoro-l-ethyl-8-[3-(2-hydroxyethyl)-1azetidinyl]-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8- (3-Cyclopropylamino-l-azetidinyl) 9-difluoro- 1-ethyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; 7,9-Difluoro-l-ethyl--4-oxo-8-[3-(1-piperazinyl)-lazetidinyl]-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; (2-Aminoethyl)phenyl]amino-l-azetidinyl}- 7,9-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; 8-(3-Axnino-3-phenvi-1-az etidinyl) 9-difluoro-1ethyl-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; 8-(3-Amino-3-xnethyl-l-azetidinyl)-7,9-difluoro-1ethyl-4-oxo-1,4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 61 8- (3-Amino-2-dimethylamino-1-azetidinyl) -7,9difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b] naphthyridirle-3-carboxylic acid; 1-Cyclopropyl-7 ,9-difluoro-8- (3-methylamino-1azetidinyl)-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 1-Cyclopropyl-8- (3-ethylamino-1-azetidinyl) -7,9difluoro-4-oxo-1,4-dihydrobenzo[b] [1,8]naphthyridine-3carboxylic acid; 8-[3-(2-Aminoethyl)amino-1-azetidinyl]-1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; -1-Cyclhpropyl-7, 9-difluoro-8- (2-hydroxyethyl) amino-l-azetidinyl]-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 1-Cyclopropyl-8-( 3-cyclopropylamino-1-azetidinyl) 7,8-difluoro-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylicacd 1-Cyclopropyl-7 ,9-difluoro-4-oxo-8-[3-( 1piperazinyl)-1-azetidinyl]-1,4-dihydrobenzo[b] naphthyridine- 3-carboxylic acid; 8-{3-[4-(2-Aminoethyl)phenyl]amnino-l-azetidinyl}- 1-cyclopropyl-7, 9-difluoro-4-oxo-1,4-dihydrobenzo- 8]naphthyridine-3-carboxylic acid; 8- (3-Amino-3-phenyl-1-azetidinyl) -1-cyclopropyl- 7,9-difluoro-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; pr Lf 62 8- (3-Amino-3-methyl-1-azetidinyl) -l-cyclopropyl- 7,9-difluoro-4-oxo-1,4-dihydrobenzo~b] naphthyridine- 3-carboxylic acid; 8- (3-A]nino-2-dimethylamino-1-azetidinyl) -1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobeizo[bJ naphthyridine-3-carboxylic acid; 7, 9-Difluoro-1-methylamino-8- (3-methylamino-lazetidinyl)-4-oxo-1,4-dihydrobenzo[b] naphthyridine- 3-carboxylic acid; 8-(3-Ethylamino-l-azetidinyl)-7,9-difluoro-1methylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8-[3-(2-Aminoethyl)amino-1-azetiiinyl]-7,9difluoro-1-methylamino-4-oxo-1, 4-dihydrobenzo- 8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-[3-(2-hydroxyethyl)amino-lazetidinyl] -1-methylamino-4-oxo-1, 4-dihydrobenzo- 8]naphthyridine-3-carboxylic acid; 8- (3-Cyclopropylamino-1-azetidinyl) 9-difluoro- 1-methylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 7, 9-Difluoro-1-methylamino-4-oxo-8- (1piperazinyl) -1-azetidinyl]-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8-{f3- (2 -Aminoethyl) phenyl ]amino- '-azetidinyll 7, 9-difluoro-1--methylamino-4-oxo-1, 4- ll~ycrbenzo- [1,8 ]naphthyridine-3-carboxylic acid; m 63 (3 -Amino- 3-phenyl- 1- az etidinyl) -7,9-dif luoro-lmethylamino-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; 8 8-(3 -Amino- 3-methyl- 1-azetidinyl) 9-dif luoro- 1methylamino-4-oxo-1, 4-dihydrobenzo[b] [1183naphthyridine-3-carboxylic acid; 8- (3 -Amino- 2-dimethyl amino- 1-a zetidinyl) -7,9difluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b] 1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-(2-fluoroethyl)-8-(3-methylamino-lazetidinyl)-4-oxo-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 7,9-Difluoro-8-(3-ethylamino)-1-azetidinyl)-1-(2fluoroethyl)-4-oxo-1,4-dihydrobenzo[b] naphthyridine-3-carboxylic acid; (2-Aminoe-thyl) amino- I-azetidinyl -7,9difluoro-1- (2-iluoroethyl) -4-oxo-1 ,4-dihydrobenzo- [bJ 8]naphthyridine-3-carboxylic acid; 7 ,9-Difluoro-1-(2-fluoroethyl)-8-[3-(2-hydroxyethyl) amino-1-azetidinyl]-4-oxo-1,4-dihydrobenzo- 8]naphthyridine-3-carboxylic acid; (3-Cyclopropylamino- 1-azetidinyl) -7 ,9-dif luoro- 1-(2-fluoroethyl)-p-oxo-1,4-dihydrobenzo~b][1,8]naphthyridine-3-carboxylic acid; 7,9-Difluoro-l-(2-fluoroethyl)-4-oxo-8-[3-(lpiperazinyl) -1-azetidinyl]-1,4-dihydrobenzo~b] 8]naphthyridine-3-'carboxylic acid; 64 8 3 -[4-(2-Arninoethyl)phenyl]amino-l-azetidinyl}- 7, 9-difluoro-l- (2-f luoroethyl) -4-oxo-1, 4-dihydrobenzo- [1,8 ]naphthyridine-3-carboxylic acid; 8- (3 -Amino- 3-phenyl- 1-azetidinyl) -7,9-dif luoro-1- (2-f luoroethyl) -4-oxo-1, 4-.dihydrobenzo[b] 8] naphthyridine-3-carboxylic acid; 8- (3 -Amino- 3-methyl- 1-azetidiny.) -7,9-df luoro-1- (2-f luoroethyl) -4-oxo-1,4-dihydrobenzo[b][(1, 8] naphthyridine-3-carboxylic acid; 8- 3 -?Amino-2-dimethylamino--azetidinyl) -7,9difluoro-1- (2-f luoroethyl) -4-oxo-1,4-dihydrobenzo- [1,8 ]naphthyridine-3-carboxylic acid; 7 -Fluoro-8- (3-methylainino- 1-azetidinyl) -4 -oxo- 1-t~butyl-1 ,4-di'hydrobenzo~b] [1,8 ]naphthyridine-3carboxylic acid; 8- (3-Ethylaxino-1-azetidinyl) -7-f luoro-4-oxo-1-tbutyl-1, 4-dihydrobenzo[b] 8]naphthyridine-3carboxylic acid; 8 3 -(2-Aninoethyl)amino-1-azetidinyl]-7,9.

difluoro-4-oxo-1-t-butyl-1,4-dihydrobenzob] naphthyridine-3-carboxylic acid; 9-Dif luoro-8- (2-hydroxyethyl) amino-i1azetidinyl]-4-oxo-1-t-butyl-1,4-dihydrobenzo~b] naphthyridine-3-carboxylic acid; 8- 3 -CyclopropyamL no--azetidiny) 7...dif uoro- 4-oxo-1-t-butyl-1,4-dihydrobenzo~bJ [1,8 ]naphthyridine- 3-carboxylic acid; 7,9-Difluoro-4-oxo-8-3-(l-piprazinyl)azetidinyl]--t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid; S 8-3-[4-(2-Aminethyl)phenyl]amino-1-azetidinyl 7,8-difluoro-4-oxo-1-t-butyl-1,4-dihydrobenzob][1,8]naphthyridine-3-carboxylic acid; 8-(3-Amino-3-phenyl-l-azetidinyl)-7,9-difluoro-4oxo--t-butyl-1,4-dihydrobenzob][1,8)naphthyridine-3carboxylic acid; 8-(3-Amino-3-methyl--azetidinyl)-7,9-difluoro-4oxo--t-butyl-1,4-dihydrobenzo[b[1,8]naphthyridine-3carboxylic acid; 8-(3-Amino-2-dimethylamino-1-azetidinyl)-7,9difluoro-4-oxo-1-t-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid.

The present invention also relates to pharmaceutical compositions which can be used in human or veterinary medicine, containing as active product at least one product of general formula 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 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 j 66 mixed with one or more inert diluents or adjuvants such as sucrose, lactose or 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, 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 can be suspensions, emulsions or sterile, aqueous or non-aqueous 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 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 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, pr 67 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 in the treatment of infections of bacterial origin.

Generally speaking, the doctor will determine the 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.

The example which follows, given without implied limitation, illustrates a composition according to the invention: Example Tablets containing 250 mg of active product and having the following composition are prepared according to the customary techniques: 8-(3-Amino-l-azetidinyl)-l-cyclopropyl-7fluoro-l-methyl-4-oxo-1,4-dihydrobenzo- [b][1,8]naphthyridine-3-carboxylic acid 250 mg Starch 50 mg Lactose 35 mg 15 mg The products of general formula are als advantageous in the agrochemical field, for 0 cCr 3 pr 7 r 68 antibacterial treatment of plants and crops. It is understood that the compositions for agrochemical use contain a product of general formula also falling within the scope of the present invention.

Moreover, the products of general 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 or water treatment. It is also understood that the compositions containing a product of general formula 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.

'I

(j

Claims (8)

1. A new benzo[b][1,8]naphthyridine derivative, characterised in that it corresponds to the general formula: 0 COOH R 4 R3 in which R represents a hydrogen atom or a hydroxyl or amino radical or an alkylamino radical in which the alkyl portion is optionally substituted with an amino Sor hydroxyl radical, or represents a dialkylamino radical in which the alkyl portions, with the nitrogen Satom to which they are attached, can optionally form a or 6-membered heterocycle optionally containing another hetero atom chosen from nitrogen, oxygen and sulphur, or represents a to 6-membered cycloalkyl)- amino radical, or an alkanoylamino, N-alkyl-N-alkanoyl- amino or aminoalkylphenylamino radical, RI and R 2 which may be identical or different, are located, respectively, at positions 2 and 3 and represent hydrogen atoms, alkyl radicals, alkenyl radicals containing 2 to 4 carbon atoms, phenyl radicals or phenyl radicals substituted with a halogen r f r 1 atom or with an alkyl, alkyloxy, hydroxyl, nitro, amino, alkylamino, dialkylamino or haloalkyl radical, or alternatively R I and R 2 are located at position 2 and represent alkyl radicals, R 3 represents a hydrogen atom or an alkyl, fluoro- alkyl or carboxyalkyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms or a fluorophenyl, difluorophenyl, alkyloxy or alkylamino radical, and R 4 represents a hydrogen atom or a fluorine atom, the alkyl and alkanoyl radicals mentioned above being unbranched or branched and containing 1 to 4 carbon atoms, in its stereoisomeric forms or mixtures thereof, as well as its metal salts, its addition salts with nitrogenous bases, its addition salts with acids and its hydrated forms.

2. Process for preparing a benzo[b][l,8]naphthyridine derivative according to claim 1, characterised in that an azetidine derivative of general formula: R< NH R in which R, R, and R 2 are defined as in claim 1, is Sreacted with a benzo[b][1,8]naphthyridine of general o formula: F JI COOH F^ ,Av ,71 CooH I 71 in which R 3 and R 4 are defined as in claim 1 and Hal is a fluorine, chlorine or bromine atom if R 4 is a hydrogen atom, or Hal and R 4 are simultaneously fluorine atoms, and the product obtained is then optionally converted to a salt.

3. Process for preparing a benzo[b][1,8]naphthyridine derivative according to claim 1, characterised in that the ester of general formula: F, COOAlk -N N N R R4 R 3 R in which Ri, R 2 and R 4 are defined as in claim 1, R is defined as in claim 1 or represents a protected amino radical, R 3 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, is converted by any known method for obtaining an acid from an ester without affecting the remainder of the molecule, and then, where appropriate, the group protecting the alkylamino radical is removed and/or the salt of the benzo[b]naphthyridine derivative obtained is optionally prepared.

4. A benzo[b]naphthyridine derivative corresponding to the general formula: R A r 1 i 72 0 COOH Hal N 1 R4 R 3 or corresponding to the general formula: 0 F //2lCOO Ak Hal Y N N R 4 R3 O in which R 4 and Hal are defined as in claim 2, Alk is defined as in claim 3 and R 3 represents a carboxyalkyl, fluorophenyl or difluorophenyl radical, as well as, where they exist, its metal salts or its addition salts with a nitrogenous base. A pharmaceutical composition which contains at least one derivative according to claim 1, in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. Dated this 14th day of November, 1995 Laboratoire Roger Bellon By its Patent Attorneys Davies Collison Cave INTERNATIONAL SEARCH REPORT Interntional application No. PCT/FR92/00901 A. CIASSMFCATION OF SUTJBECT MA77ER Int.Cl.: 5 C07D471-/04; A61K31/435; //(C07D471/04,221:00,221 :00) According to International patent Classification (1PC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int.Cl.: 5 CO7D; A61K< Documentation searched other than minimum documentatioa to, the extent that such documents are joel uded in the fields searched Electronic data base consulted during ther international search (name of data base and, wher practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A EP,A,O 388 298 (ESTEVE) 19 September 1990 see claims 1,5,6 ElFurther documents are listed in the continuation of Box C. j See patent family annex. Special categories of cited documeats: later documnent published after Mr. nternational rhiingdaeorprorty document defining the general stale of the art wich is sot cosdee titl and not in ouflct with the application bat cited to understan to be of particular relevanice the princile or theory nderlylog the invati~ eadlierdocument but published on orafter thilmastonal filiagdate document of particular relevance; the claimed invention cannot he hc doumn whc awho obso rciycamnsidetcd novel or cannot be considered to involve an inventive docmet hih aythowdobt o pioit(cas) or whc is sepwe the documet is takcen alone cdtr4d to establishi the publicaltin date of another citation or othe are~ial reason (as specified) document of particular relevance; the claimed invention cannot be d cutnent referring to an oral disclosure, wn, abhlbition or other considered to involve an inventive step when the docameat Is r iests cormbined with oneormore otbersuch docummeessucht combihation 6Dcument published prior to the iznteralonul filing date but later thtan being obvious to a person Aklled is the art fic priority date clainmed document member of the same patent family Date fl the actual completion of the international search Date of mailing of the international search, report December 1992 (18.12.92) 15 January 1993 (15..01.93) Name a,,td mailinio a ress of the ISA/ Authorized officer EUROPEAN PATENT OFFICE Facsimile No. Teiephone No. I Form PCIYISA21O (second sheet) (July 1992). ANNEX TO THE INTERNATIONAL SEARCH REPOR ON INTERNATIONAL PATENT i.PPLICATION NO. FR9200901 SA 65341 Mhie &ax lists the patentfamfly mmnIa relating to the patent doannenats cited in dh oy ebndmnfo =rda irore. The nyeit amae its conrihd in the European Patent Oflcc EDP fie on The European Patent Oficen is in no way liable for theen partkunhw whieb am merely gien for the purpose of information. 18/12/92 PAtent doenzW Plumeaion Patent fumily Publication cfted LIn esarh reponrt dat member(s) date EP-A-0388298 19-09-90 FR-A- 2644455 21-09-90 FR-A- 2649106 04-01-91 FR-A- 2654728 24-05-9 1 AU-A- 5137590 20-09-90 CA-A- 2012223 16-09-90 JP-A- 2279683 15-11-90 w "For moret &bUISoa tbs am= me M Jourtul of the Eaupas Patt Office, No. 12192 RAPPORT DE RECHERCHE INTERNATIONALE PCT/FR 92/00901 1. a.SSEEN-r DE LINVENTION (sl pluiewos symboiBs do dassffiensica sciat appfLmhla, les indlqwe too,) I Scion is clslfi-d-m Lutdraalmcil dos bftMt (CI) ma11 oll salon A& dwauiicatia mat1n*a at As CII CIB 5 C07D471/04; A61K31/435; //(C07D471/04,222:00,221: 00) G. DOWANES SUR LESQUELS LA RECHERCHJE A FORTE Doaunw lonminmal.s aanzutio' Systimne do clawiflcatin syinbaka de cft sfiettion CIB 5 C07D A61K Docuomtation connsite antis quo is doeumontation nimaal. donw Is meow,. o0~ do togs dnaaomest: foot pas dos donminos sur lesquols I& rocherche a poutoF 11L DOCUMENTS CONSIDERES COMAE PEAT9NENTS"o Jikli dentificati des docmsoass 6s avoc; indfcatDon, AI oicomarv No. dos njoyctonos A EP,A,D 388 298 (EST 19 Septembre 1990 voir revendications 1,5,6 C41dlories spkdaiu do docmunts dt&- inwma uliitur publA poakiouroment A I& data do dkpW e' document dflisint rdt o ksa. dela technique, no n -e l o o A Ia dato do priositk at onappartanmusn pas conrdhionimo szlcuflnmot pstiootA 1.6tat do IR technique posilont, ials dtb pows cinpoodr cosdocue mntimow pacli pubfll pertinen t loj 5 prndpo omItilori ba o stituaat Is bose do flonadoa IV ocnt noaturh m ite dat. i A am:i ~thaon- 1Idmmat partiatullhemt pertinnt; flnimtinan nvmedS- tion.I as prds one dte so pout Atto comwasd o comng owou 1 on uComm W document poomt loto an dooto sn, tone rodlcation do anpuquont o nmctt AIventve prioriti no chii pour diterminar It dato do poblicatlo. Weunt I docozmmi particllinom. porthuet; rinmmtio rowec.- intro citation on poor o* mison spidalo (tellsqulndiquio) diquuo no Pout Air cosdins com=o impaqvut Una docuoat -o ridrnnt A uno divula WWIl, Aion usqo, i actvfti Inientive lorsque Is documenta ssodi A an oc Una aposIas as tous aniros wou pllduus um. documents do mie m zso, calo combS 'P document publli auant Ia dato do ddpdt litteninoaal, gmais mllen iat bridoao pomr we pasoaoe do in~du. Postiirlouoient A la daba do puioriti nwovmdoo WI jocamot quA halt pauio do Ia taboo famlflo do koustt ,V CRIFCATION Date I laqunilo I& rechrch Antanomale a dii ofoctilwmmt savhoio 18 DECEMBRE 1992 Date i'ompition dii prisct rapport do recherchenamatnalo

15. 01. %W3 Madnismnution clags o ael ahclso Atnalao In s du foodlounnarO auwuws IFICC EROPEEN DES BRETM ALFARO FAUS .1. fomlmr PCTIIAIG (imam buoe a~i mi ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMIANDE INTERNATIONALE NO. FR 9200901 SA 65341 La ristmc nuondwu its membz de [n famii dc brews rihtmm ardow bmeym dtis dama c rapport do tcbace kwtnw wisi d-e i~ttmuebm nt cou u fiebicr inkraque de rofi serpien des brevW2 i In dati dui Lec zofkmtrfumls vdonis i dicindcafst ofn'gaent pas I ta uwaWWit de I'Oftice murpi dgw betz. 18/ 12/9 2 Doauneurhrevati Deba do Membre() do ka Date d au rapor d r tct Iulcfo famm e khnwt*) piidkcatii EP-A-0388298 19-09-90 FR-A- 2644455 21-09-90 FR-A- 2649106 04-01-91 FR-A- 2654728 24-05-91 AU-A- 5137590 20-09-90 CA-A- 2012223 16-09-90 JP-A- 2279683 15-11-90 Pwtt rouhivamuxt coemam~ cui mecu voi JWIrm Offd de YOffm fupis des bmw' N0.1222 INTERNATIONAL SEARCH REPORT International application No. PCT/FR92/00901 i -r A. CLASSIFICATION OF SUBJECT MATTER Int.Cl.: 5 C07D471/04; A61K31/435; //(C07D471/04,221:00,221:00) According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int.Cl.: 5 C07D; A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A EP,A,O 388 298 (ESTEVE) 19 September 1990 see claims 1,5,6 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: laterdocumentpublishedaftcrtheinternational filingdateorpriority document defining the general state of the artwhich is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier document but published on or after the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with one or more othersuch documents, such combination being obvious to a person skilled in the art document pu'.sned prior to the international filing date but later than bg o s to a se n te a the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 18 December 1992 (18.12.92) 15 January 1993 (15.01.93) Name and mailing address of the ISA/ Authorized officer EUROPEAN PATENT OFFICE Facsiimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. FR 9200901 SA 65341 7Tis annex lists the patent family memubers relating to the patent documents cited in the xbove-mentioned international search rtport. Ile members arm as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which ame mrely een for the purpose of ,-orrnation. 18/ 12/92 Patent document Publication Patent familyPulcto cited in search report date member(s) dt EP-A-0388298 19-09-90 FR-A- FR-A- FR-A- AU-A- CA-A- ~JP-A- 2644455 2649106 2654728 5137590 2012223 2279683

21-09-90 04-01-91

24-05-9 1 20-09-90 16-09-90 15-11-90 h.C I C For more details about this annex see Official Journal of the European Patent Office, No. 12182 RAPPORT DE RECHERCHE INTERNATIONALE Demands Internationals No PCT/FR 92/00901 11- CLASSEMENT DE L'INvENTioN (si piusieurs symiboies do classification soot applicahios, les indiquar totia) 7 Sdlon la cb~ssification internationae des brevets (CB) oti A la fois solon I& classification nationals et la CIB CIB 5 ^L070471/04; A61K31/435; //(C07D471/04,221:00,221:00) HI. DOMAINES SU'R LESQUEIS LA RECHERCHIE A PORTE Documentation minimale consufte 1 Sysl~ne do classification Syssboies do classification CIB 5 C07D ;A61K Documentation consuit6e autre quo ha documentation minimal. dans Ia inosure oil do teis documents font partie des domaines sur lesquels la recherche a portof

111. DOCUMENTS CONSIDERES COMME PERTINENTS' 0 Catilpri a Identification des documents clti1, avec indication, si nkcossalreP No. des revendications des pasos prtinents L 3 ____vlskos 14 A EP,A,0 388 298 (ESTEVE) 19 Septembre 1990 voir revendications 1,5,6 oCatkgw'ies spiciales do documents clt&r. 1 T' 0 document ultirleur publ.16 postirleurement A la data de dkpot international ou i la date de prioriti et n'appartenenaint ps document d~finissant fltat gkn&ral do I3L technique, c00 A i'Atat do Is technique pertinent, mals dti powt comprendro considWr comma particuidrment pertinent [a principe oti I& hborlo constituant is bass do lovmntion Er document antkrleur, mals publi Al& date do dkpOt Interim- 'r document pati ullhment pertinent; rlanaition revendi- tjonal ou apris cotta date qulie no pout Wet consid~ris comma nouwfl ou comma 'V document pouvant later un doute sur tine rovendicatlon do ipllqu&at tine activiti Inventive prioit6 oti cltt pour ddterminer ia date do publication d'une 'V document partlcullkrmatit pertinent; rinventinx roveni- autro citation ou pour tin. raison spiclals (tols qu'indiquis) diquko no ptst etro considiria comma impLiquant tine documient so rdfhtrant i tine divuigation orals, A tin tiso, Al activiti Inveative lorsque Is document est assocAi A un oti une exposition oti tonsi autres moyens piusiturs autres documents do W~at nature, calts combi. P document publik avant I& date do dbpdt International, mali nalson tnt Wvdento pour tine persoons o nmi.. postkrieurement A la data do prioritt rovendiquu. W. document qul fait partlo do Is Mmo faMlllo brevets WV. CERTIFICATION Date A laquelle I& rcchercito Internationzla a *t6 effectivment achey~o 18 DECEMBRE 1992 01. 93 AdmInastration charg"a de I& recherche intornational* Signature du fonmlionnalro ajatoris OFFICE EUROPEEN DES BREVETS ALFARO FAUS I. Fwatarv PCT(ISA/21 (mei 6"1i IUSI ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE R-ELATIF A LA DEMANDE INTERNATIONALE NO. FR SA 9200901 65341 La prismne &iwez indque les membres d~e In famille de breets relatifs aux douments brevets citis dans le rapport de rechierche rVtionmle vise ci-&uus. L-Sdits mam-m sont contemn mu fileier informatique de l'Office europiaa des brevets i la date du LI et-ivncowvtx fournis sont donnis i titre inicmff et n'engn~t pas In responsahi de l'Office europien des brevet&. 18/ 12/92 Docuumt b.revet citi Date de Menibre(s) de In Date de mu rapport de recherche publication famife de brevet(s) T publication EP-A-0388298 19-09-90 FR-A- 2644455 2 1-09-90 FR-A- 2649106 04-01-91 FR-A- 2654728 24-05-91 AU-A- 5137590 20-09-90 CA-A- 2012223 16-09-90 JP-A- 2279683 15-11-90 Pour tout rcaweamt coaccrizant ctte ammie voir Jourali Offid de I'M= ieuropeca des breveti 1 No.1ZIHZ pp II i _I------rmr4pW INTERNATIONAL SEARCH REPORT International application No. PCT/FR92/00901 A. CLASSIFICATION OF SUBJECT MATTER Int.Cl.: 5 C07D471/04; A61K31/435; //(C07D471/04,221:00,221:00) According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int.Cl.: 5 C07D; A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A EP,A,O 388 298 (ESTEVE) 19 September 1990 see claims 1,5,6 S Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: later document publishedafterthe international filing dateor priority document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier document but published on or after the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is sieewh d noe o cannot e one involv a inveive cited to establish the publication date of another citation or other step when the document is taken alone special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined withoneormore othersuch documents, such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 18 December 1992 (18.12.92) 15 January 1993 (15.01.93) Name and mailing address of the ISA/ Authorized officer EUROPEAN PATENT OFFICE Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 9200901 SA 65341 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. 18/12/92 Patent document Publication Patent family Publication cited in search report date member(s) date EP-A-0388298 19-09-90 FR-A- 2644455 21-09-90 FR-A- 2649106 04-01-91 FR-A- 2654728 24-05-91 AU-A- 5137590 20-09-90 CA-A- 2012223 16-09-90 JP-A- 2279683 15-11-90 *'1 For more details about this annex: see Official Journal of the European Patent Office, No. 12/82 RAPPORT DE RECHERCHE INTERNATIONALE Demtande Intemnationale No PCT/FR 92/00901 L. CLSSEMENT DE L'INVENTJON (si plusleurs symboles do classification sont appllcables, les indlqoor tous) 7 Sain 11 classification intarnationule des breyets (CsB) on A la fols solon I& classification natlonalo et I& Cifi CIB 5 C070471/04; A61K31/435; //(C07D471/04,221:00,221: 00) 01. DOMAINES SU'R LESQUELS LA RtECHERCHE A PORTE Ill. DOCUMENTS CONSIDERES COMMAE PERTINENTS 10 Catigorie Identification des documents citks, avec indication, sA n~cessar0, 2 No. des revendicatlons des passages perd nents L 3 A EP,A,0 388 298 (ESTEVE) 19 Septembre 1990 voir revendications 1,5,6 Catlgorles spkdiales do documents dtir.1 t document ultideur publib postddotirement A Ia. dato do dwpt difiissnt Iita g~tralde s tchniuenoninternational ou Al% date do prioriti at n'appautanenant ps document A~iisn 'a ~kald &tcnqe o I'ktat do I& technique pertinent, toils; olt pour conaprendre conidirk comma particullirement pertinent le prlncipe ou Ia thdorlo constituent la base do IL'nV~ntonl 'El document antkrleur, mals pubIl6i Ala date de dipdt Intama- 1XI document particulllroment pertinent; rinvetion revoodli- tional oti apris cotte date qua no pouw fir. conidbie comma nou"Malo i comas 'Vi document pouvant leter un douto stir one revendicaLtion do Itpliquant one activith Inventive priorit6 ou cit pour diterminer I& date do pblication d'uno document pauticulltrament pertinent; rinveeion rewon- autro citation 00 pour on. mlson spidiale (toll. qu'lndlqudo) diquic no pout itre considirie comma impliqoant tine document so rifnt Ai une divulgation oraje, A un usage, ii actvt Inventive larsque I@ document est assocl A un 00 tine exposition 00 tons autres moyeas plusleurs autres documents do mime nature, cette comabi- 'P document publik avant la date do dipdt International, mais nikson itant Wvdente pour une persona. du male. postirieurement A la date de priorit6 revendlquke W document qul fit parte d. la meme famile do brevets IV. CERTIFICATION Date A laquelle la recherdhe Internationale a 60i effectivement atbevie 18 DECEMBRE 1992 Adinistration chargie de I& echerchie Internatdozal. OFFICE EUROPEEN DES BREVETS Date d'expition do priseni rapport do rechache interfltonsle 15. 01.93 Fwxzsuir PCTIISA1210 (MO 611"e) fJmv.r ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR SA 9200901 65341 La presente annexe indque les mewbes de In hilei de brvt relatifs aux documat brevets cites dams le rapport de recherche intenationale visieidsoms Leadits membres sont Conteaws au ficbier infornatque de I'Office europeaa des brevets i Ia date du Les renseigneents fournis *out donnis i titre iniatif et n'engagent psl In pomsbilit6 de I'Office europien des brevets 18/ 12/92 Docnnent brevet citi Date de Membre(s) de In Date de au rapport de recherche publication famiflc de brevet(s) pubiato EP-A-0388298 19-09-90 FR-A- FR-A- FR-A- AU-A- CA-A- JP-A- 2644455 2649106 2654728 5137590 2012223 2279683 21-09-90 04-01-91 24-05-91 20-09-90 16-09-90 15-11-90 pour tout rermiganmzt coneermnm cette aueze :voir Journa Offie do rOffice atopeen des brevets, No.12/82