FR2664595A1 - New 1,8-benzonaphthyridine derivatives, their preparation and the compositions which contain them - Google Patents

Abstract

New benzo[b][1,8]naphthyridine derivatives of general formula (I) in which R1 is a hydrogen atom or a hydroxyl or alkyl radical, R2 is a hydrogen atom or an alkyl, fluoroalkyl, cycloalkyl (3 to 6 C), alkyloxy or alkylamino radical, R3 is a phenyl radical or a phenylalkyl radical substituted by one or a number of halogen atoms or alkyl, cycloalkyl (3 to 6 C), alkyloxy, cyano, amino, alkylamino, dialkylamino, alkyloxyalkyl, hydroxyalkyl, hydroxyalkyloxy, methylenedioxy, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radicals, or R3 is a heterocyclyl radical, and R4 is a hydrogen atom or a fluorine atom [it being understood that when R1 represents a hydrogen atom or an alkyl radical, R3 cannot simultaneously represent a phenyl radical or a phenylalkyl radical which is unsubstituted or substituted on the phenyl ring by one or a number of halogen atoms or alkyl, cycloalkyl (3 to 6 C), alkyloxy, cyano, amino, alkylamino or dialkylamino radicals], the alkyl (1 to 4 C) radicals being straight or branched, their salts, their preparation and the compositions which contain them. These new products are useful as antimicrobial agents.

Description

leurs sels, leur préparation et les compositions qui les contiennent.The present invention relates to new derivatives of benzotb) naphthyridine-I, 8 of general formula

their salts, their preparation and the compositions containing them.

dans laquelle X peut être l'oxygène et deux des radicaux R1 à R5 adjacents peuvent former un cycle benzénique.In US Patents 4,229,456 and 4,133,885, structural naphthyridine derivatives have been described

in which X can be oxygen and two of the adjacent radicals R1 to R5 can form a benzene ring.

 These products are useful as inhibitors of acidic gastric secretions.

dans laquelle les radicaux X, Y et Z peuvent être O ou un radical
NR4 ou CRs=CRs dans lequel les R5 peuvent former un cycle benzénique. Patent application DE 3 302 126 describes hypotensors of general formula

in which the radicals X, Y and Z can be O or a radical
NR4 or CRs = CRs in which the R5 can form a benzene ring.

It has been found that the products of general formula (I) in which - R1 represents a hydrogen atom or a hydroxy or alkyl radical, - R2 represents a hydrogen atom or an alkyl, fluoroalkyl, cycloalkyl radical containing 3 to 6 carbon atoms, alkyloxy or alkyllamino, - R3 represents a phenyl or phenylalkyl radical substituted by one or more halogen atoms or alkyl, cycloalkyl radicals containing 3 to 6 carbon atoms, alkyloxy, cyano, amino, alkyllamino, dialkoylamino, alkyloxyalkyl, hydroxyalkyl, hydroxyalkyloxy, methylenedioxy, aminoalkyl, alkylaminoalkyl or dialkoylaminoalkyl, the alkyl parts of which may form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle or represents a 5-membered heterocyclyl radical containing 1 or 2 heteroatoms nitrogen, oxygen or sulfur, and - R4 represents a hydrogen atom or a fluorine atom,
It being understood that when R1 represents a hydrogen atom or an alkyl radical, R3 cannot simultaneously represent a phenyl or phenylalkyl radical which is unsubstituted or substituted on the phenyl nucleus by one or more halogen atoms or alkyl or cycloalkyl radicals containing 3 with 6 carbon atoms, alkyloxy, cyano, amino, alkylamino or dialkoylamino], and in which the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms, as well as their salts, and their isomers, show a particularly interesting antibacterial activity .

 The products of general formula (I) can exist in the hydrated form, it is understood that these hydrates also come within the scope of the present invention.

 In the general formula (I), when R3 represents a heterocyclyl radical, the latter can be advantageously chosen from furyl, thienyl, pyrrolyl, N-alkyl pyrrolyl, imidazolyl, pyrazolyl or thiazolyl.

dans laquelle R1 et R3 sont définis comme précédemment, sur une benzo[b]naphtyridine-1,8 de formule générale

dans laquelle R2 est défini comme précédemment, Hal est un atome de fluor, de chlore ou de brome si R4 est hydrogène, ou bien Hal et R4 sont simultanément des atomes de fluor, suivie éventuellement, si R1 est un atome d'hydrogène et si l'on veut obtenir un dérivé de benzo(b]naphtyridine-I,8 dans laquelle R1 est méthyle, de la transformation du produit obtenu en une (méthyl-4 pipérazinyl-l) -8 benzo[b]naphtyridine.According to the invention, the products of general formula (I) can be obtained by substitution of a piperazine of general formula:

in which R1 and R3 are defined as above, on a benzo [b] naphthyridin-1,8 of general formula

in which R2 is defined as above, Hal is a fluorine, chlorine or bromine atom if R4 is hydrogen, or Hal and R4 are simultaneously fluorine atoms, optionally followed, if R1 is a hydrogen atom and if we want to obtain a benzo (b] naphthyridine-I derivative, 8 in which R1 is methyl, from the transformation of the product obtained into a benzo [b] naphthyridine (4-methylpiperazinyl-1) -8.

 The action of the piperazine derivative of general formula (II) is generally carried out in the presence of an excess of this derivative as an acid acceptor in suitable organic solvents. It is possible to operate with or without solvent, at a temperature between 30 and 1200C. When operating in the presence of a solvent, the reaction is advantageously carried out in solvents such as pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

 it can also be advantageous to operate in the presence of an acid acceptor such as for example an organic nitrogenous base (triethylamine in particular), an alkali carbonate (sodium carbonate for example) or an alkali or alkaline earth metal hydroxide.

 it is understood that, in the case where the symbol R2 of the product of general formula (III) is a hydrogen atom, or when R3 contains an amino, alkylamino, aminoalkyl or alkylaminoalkyl substituent, it is preferable to protect the product beforehand departure. The protection and removal of the protective radical after the reaction is carried out according to the usual methods.

 The protection can be carried out by any compatible group and the implementation and elimination of which does not alter the rest of the molecule. In particular, one operates according to the methods described by T.W. GREENE, Protective Groups in Organic Synthesis, A.

Wiley-Intersc, ience Publication (1981), or by Mc OMIE, Protective
Groups in Organic Chemistry, Plenum Press (1973).

 By way of example, the protective groups can be chosen from the trimethylsilyl, benzhydryl, tetrahydropyrannyl, formyl, acetyl, chloracetyl, trichloracetyl, trifluoroacetyl, ethoxycarbonyl, t.butoxycarbonyl, trichlorethoxycarbonyl radicals.

 Where appropriate, the subsequent methylation operation of the piperazinyl radical is advantageously carried out by the action of formalin in the presence of formic acid. It is generally carried out in an aqueous medium, at a temperature between 90 and 1000 C.

dans laquelle Ri, R3 et R4 sont définis comme précédemment, R2 est défini comme précédemment ou représente un radical alcoylamino protégé et Alk représente un radical alcoyle contenant 1 à 4 atomes de carbone en chaîne droite ou ramifiée, par toute méthode connue pour obtenir un acide à partir d'un ester sans toucher au reste de la molécule, suivie le cas échéant de l'élimination du groupement protecteur du radical alcoylamino, et/ou si l'on a obtenu un produit de formule générale (I) dans lequel R1 est un atome d'hydrogène et si l'on veut obtenir le produit correspondant pour lequel R1 est méthyle, suivie de la transformation du produit obtenu en une (méthyl-4 pipérazinyl-1 ) -8 benzo[b]naphtyridine. According to the invention, the benzo derivatives (b] naphthyridin-I, 8 of general formula (I) can also be obtained from the corresponding ester of general formula

in which Ri, R3 and R4 are defined as above, R2 is defined as above or represents a protected alkylamino radical and Alk represents an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain, by any known method for obtaining an acid from an ester without touching the rest of the molecule, followed where appropriate by the elimination of the protecting group for the alkylamino radical, and / or if a product of general formula (I) in which R1 is obtained a hydrogen atom and if one wants to obtain the corresponding product for which R1 is methyl, followed by the transformation of the product obtained into a (methyl-4 piperazinyl-1) -8 benzo [b] naphthyridine.

 The preparation of the acid from the ester is generally carried out by acid hydrolysis. It is advantageously carried out in a mixture of acetic acid - hydrochloric acid, in sulfuric acid or in methanesulfonic acid at a temperature between 20 and 1000C. It is also possible to operate by saponification in the presence of potash or soda, in a hydro-alcoholic medium, at a temperature between 20 and 800C.

 If necessary, the methylation of the piperazinyl radical takes place, as described above.

 When R2 represents a protected alkylamino radical, the protective radical can be any amino protecting group compatible with the molecule. It is particularly advantageous to choose a protective radical which can be eliminated simultaneously with the hydrolysis of the ester.

dans laquelle R4, Hal et Alk sont définis comme précédemment, et R2 est défini comme précédemment ou représente un radical alcoylamino protégé, par toute méthode connue pour obtenir un acide à partir d'un ester, sans toucher au reste de la molécule, suivie éventuellement de l'élimination du groupement protecteur du radical alcoylamino.The benzo [b] naphthyridine-1,8 derivative of general formula (III) can be obtained from the corresponding ester of general formula

in which R4, Hal and Alk are defined as above, and R2 is defined as above or represents a protected alkylamino radical, by any known method for obtaining an acid from an ester, without touching the rest of the molecule, optionally followed elimination of the protective group of the alkylamino radical.

 One operates in particular under the conditions described above to obtain a product of general formula (I) from an ester of general formula (II).

dans laquelle R4, Hal et Alk sont définis comme précédemment, suivie de la cyclisation par action d'un agent accepteur d'acide.The benzo [b] naphthyridin-1,8 ester of general formula (V) can be prepared by the action of the 3-amino trian-5,2,4,4,4 to obtain a product for which R2 is an atom of hydrogen or by the action of a product of general formula
R2 - NH2 (VI) in which R2 is alkyl, fluoroalkyl, cycloalkyl, alkyloxy or alkylamino optionally protected on a quinoline derivative of general formula

wherein R4, Hal and Alk are defined as above, followed by cyclization by the action of an acid acceptor.

 Generally, the reaction of 3-amino-1,2,4-triazine or of the product of general formula (VI) is carried out in an organic solvent such as an alcohol (ethanol, methanol for example) or a chlorinated solvent (trichloromethane for example), at a temperature between 10 and 250C.

 The cyclization is carried out in a straight or branched chain alcohol containing 1 to 4 carbon atoms, at a temperature between 200C and the reflux temperature of the reaction mixture.

 The acid-accepting agent can in particular be chosen from nitrogen bases (triethylamine for example) or diaza-1,8-bicy clo [5.4.0] undecene-7.

dans laquelle R4, Hal et Alk sont définis comme précédemment, par action d'un NN-diméthylformamide acétal de formule générale
(CH3)2N - CH(OAlk1)2 (IX) dans laquelle Alk1 est un radical alcoyle contenant 1 à 4 atomes de carbone en chaîne droite ou ramifiée.The quinoline derivative of general formula (VII) can be obtained from the ketoester of general formula

in which R4, Hal and Alk are defined as above, by the action of an acetal NN-dimethylformamide of general formula
(CH3) 2N - CH (OAlk1) 2 (IX) in which Alk1 is an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain.

 The reaction is generally carried out in an organic solvent such as an ester (ethyl acetate for example) at a temperature between 60 and 750C.

 The ketoester of general formula (VIII) for which R4 is a hydrogen atom and Hal is defined as above can be obtained from 2,7-dichloro-6 fluoro-6 quinoline carboxylic-3 acid or chloro acid -2 difluoro-6,7 quinoline carboxylic-3 as described below in Example 1 or from bromo-7 chloro-2 fluoro-6 quinoline carboxylic-3 by analogy with this method. In this case, the bromo-3 fluoro-4 aniline used as starting material, can be prepared according to the method described by W.B. Austin et al., J. Org. Chem., 46 (11), 2280 (1981).

The ketoester of general formula (VIII) for which R4 and
Hal are simultaneously fluorine atoms, can be obtained from chloro-2-trifluoro-6,7,8 carboxylic-3 as described below, in Example 3.

 The benzo [b] naphthyridine-1,8 derivative of general formula (IV) can be obtained from the benzobnaphthyridine of general formula (V), by substitution of a piperazine derivative of general formula (II).

 The operation is advantageously carried out under the conditions described above to obtain a product of general formula (I) from a piperazine of general formula (II) and a benzo [b] - naphthyridine-1,8 of general formula (III) .

The piperazine of general formula (II) can be obtained by applying the methods described by
- E. Jucker et al., Helv. Chim. Acta, 45 (7), 2383 (1962)
- European patent application 230 053
- patent application FR 2 351 108
- Japanese patent application 01 117 869
- Toschio Uno et al., J. Het. Chem., 26,393 (1988)
- WR Roderick et al., J. Med. Chem., 9, 181 (1966);
- JD Behan and Coll, J. Org. Chem, 26, 3379 (1961);
- JWH Watthey et al., J. Med. Chem., 26, 1116 (1983)
- LJ Kitchen et al., J. Am. Chem. Soc., 69, 854 (1947)
and J. Org. Chem., 8, 342 (1943);
- JD Behun et al., J. Org. Chem., 26, 3379 (1961)
- Or by application or by analogy with the methods described below in the examples.

The piperazines of general formula (II) for which R1 is a hydroxy radical and R3 is other than the hydrogen atom, can be prepared by oxidation of the corresponding piperazine in which the nitrogen atom in position -4 has been previously protected, according to the method described by AJ Biloski et al.,
Synthesis, 537 (1983).

When R3 represents a phenyl radical substituted by a dialkoylaminomethyl radical, the piperazine of general formula (II) can be obtained from a (hydroxyphenyl) -2 piperazine whose nitrogen atoms have been previously protected by any compatible group, by application of the method described by
M. Tromontini, Synthesis, 703-775 (1973).

 According to the invention, when it is desired to obtain the isomers of the benzonaphthyridine derivatives of general formula (I), the isomeric forms of the piperazines of general formula (II) are separated by any known method compatible with the molecule. For example, the separation is carried out by acylation using an acid or a reactive derivative of a chiral acid, separation of the isomers by high performance liquid chromatography, then deacylation by acid hydrolysis.

 In the examples which follow, the isomer (-) is called the isomer of the benzonaphthyridine derivative of general formula (I) whose rotary power in solution in acetic acid is negative, obtained from the piperazine derivative whose rotational power in ethanol is positive; the isomer (+) is the isomer of the benzonaphthyridine derivative of general formula (I) whose rotary power in solution in acetic acid is positive, obtained from the piperazine derivative whose rotary power, in solution in ethanol is negative.

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

 The products according to the present invention can be transformed into metallic salts or into addition salts with nitrogenous bases according to the methods known per se. These salts can be obtained by the action of a metal base (for example alkaline or alkaline-earth), ammonia or an amine on a product according to the invention in a suitable solvent such as an alcohol, an ether or water or by exchange reaction with a salt of an organic acid. The salt formed precipitates after optional concentration of its solution, it is separated by filtration, decantation or lyophilization.

 The new products according to the invention can also be transformed into addition salts with acids. The products of general formula (I) obtained in the form of these salts can be released and transformed into salts of other acids according to the usual 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, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-B-phenethylamine, NN '-dibenzylethylene-diamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, arginine ), as well as the addition salts with mineral acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or organic acids (succinates, fumarates, maleates, methanesulfonates, p.toluenesulfonates).

 The new benzo [b] naphthyridine-1,8 derivatives of general formula (I) according to the present invention and their pharmaceutically acceptable salts have particularly advantageous antibacterial properties. They show remarkable activity in vitro and in vivo on gram-positive germs and in general on the germs responsible for most infections of the upper and lower airways.

 In vitro, the products of general formula (I) have been shown to be active at a concentration of between 0.12 and 4 pg / cm3 on staphylococcus aureus IP 8203.

 In vivo, the products of general formula (I) have been shown to be active on experimental infections of the mouse with staphylococcus aureus IP 8203 at doses between 2 and 150 mg / kg subcutaneously or at doses between 4 and 100 mg / kg orally.

 Another advantage of the products according to the invention is their low toxicity. Their LD50 is generally greater than 500 mg / kg subcutaneously in mice.

 The following examples, given without limitation, illustrate the present invention.

EXAMPLE 1
A suspension of 1.3 g of ethoxycarbonyl-3 fluoro-7 L (furyl-2) -3 piperazinyl-1] -8 methyl-1 oxo-4 1,4-dihydro-1,4 benzo [b] naphthyridin-1, 8- (RS) in 12 cm3 of 0.5N aqueous potassium hydroxide and 12 cm3 of ethanol is heated for 1 hour to a temperature in the region of 800C, then added to this same temperature of 6 cm3 of an aqueous solution of N methanesulfonic acid. After cooling to around 200C, the insoluble material is drained, washed with 3 times 10 cm3 of water, 3 times with 10 cm3 of ethanol, 3 times 10 cm3 of ethyl ether and recrystallized from a mixture of 13 cm3 of ethanol and 27 cm3 of dimethylformamide. 0.570 g of fluoro-7 ((furyl-2) -3 piperazinyl-1 1-8 methyl-1 oxo-4, 1,4 dihydro-1,4 benzotb] naphthyridin-1,8 carboxylic acid is obtained. -3- (RS) in the form of a yellow solid melting at 258 2600C
3-ethoxycarbonyl fluoro-7 ((furyl-2) -3 piperazinyl-1 -8 methyl-1 oxo-4 1,4-dihydro-benzo (b) naphthyridine-1,8- (RS) was prepared from as follows:
A suspension of 0.96 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-benzo (1,8-benaphthyridine, of 0,6 g of (2-furyl) -2 piperazine - (RS) and 0.38 g of sodium carbonate in 20 cm3 of dimethylsulfoxide is heated to approximately 950C for 5 and a half hours. After cooling to approximately 200C, the mixture is poured into 50 cm3 of water at a similar temperature of 50C and extracted with 3 times 100 cm3 of dichloromethane The combined organic extracts are washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa), at approximately 400C The residue obtained is taken up in 20 cm3 of ethanol, drained, washed with twice 20 cm3 of ethanol and 3 times 30 cm3 of ethyl ether. 1.3 g of 3-fluoro-7-ethoxycarbonyl are obtained [( furyl-2) -3 piperazinyl-1 1-8 methyl-1 oxo-4 dihydro-1,4 benzo [b] naphthyridine-1,8- (RS) in the form of a yellow solid melting at 198-2000C which is used without further purification for es subsequent steps.
3-ethoxycarbonyl-difluoro-7,8 methyl-1 oxo-4 dihydro-1,4 benzo ib] - naphthyridine-1,8 is prepared in the following manner
In a suspension with stirring of 22.3 g of (2-chloro-difluoro-6,7 quinolinecarbonyl-3) -2 dimethylamino-3 ethyl acrylate in 480 cm3 of ethanol, maintained at a temperature close to OOC, is added in 10 minutes between 0 and 50C, a solution of 11.3 g with about OOC of methylamine in 50 cm3 of ethanol, stirred for 1 hour between 0 and 50C, allowed the temperature to rise to around 250C and stirred for another 16 hours at the same temperature. The insoluble material is drained, washed with 3 times 100 cm3 of ethanol and 2 times 100 cm3 of ethyl ether. After 1 recrystallization from 250 cm3 of dimethylformamide, 16 g of 3-ethoxycarbonyl-7.8 difluoro-1,8-methyl-4-oxo-1,4-dihydro-benzo [b] naphthyridin-1,8 are obtained in the form of a yellow solid melting at 323-3240C.

(2-Chloro-difluoro-6,7 quinolinecarbonyl-3) -2 dimethylamino-3 acrylate is prepared in the following manner
A suspension of 6.17 g of (2-chloro-difluoro-6,7 quinolyl-3) -oxo-3 ethyl propionate in 7.15 g of N, N-dimethylformamidedimethyl acetal and 60 cm3 of acetate ethyl is heated to a temperature in the region of 750C for 1 hour 15 minutes. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at approximately 500C.

The residue is taken up in 50 cm3 of isopropyl ether, drained, washed with 3 times 25 cm3 of the same solvent. 6.65 g of (2-chloro-difluoro-6,7 quinolinecarbonyl-3) -2 dimethylamino-3 acrylate are obtained in the form of an orange solid melting at 1400C.

Ethyl (2-chloro-difluoro-6,7 quinolyl-3) -3-oxo-3-propionate is prepared in the following manner
A suspension of 14.13 g of 2-chloro-difluoro-6,7 quinoline carboxylic-3 in 29 cm3 of thionyl chloride and 220 cm3 of trichloromethane is heated to a temperature in the region of 600C for 4 hours. The solution obtained is concentrated to dryness under reduced pressure (20 kPa) at around 600C. The residue obtained is taken up in 75 cm3 of n-hexane, drained, washed with 2 times 60 cm3 of the same solvent. The 14.4 g of yellow solid obtained is dissolved in 115 cm3 of tetrahydrofuran. This solution is introduced, drop by drop, with stirring, in 35 minutes, between 5 and 100C, in 70 cm3 of a solution of magnesium chelate of ethyl monomalonate in tetrahydrofuran prepared under the conditions described below. let the temperature rise to around 200C, and stir for another 2 hours under these conditions. The solution obtained is introduced, drop by drop, with stirring, in 30 minutes, at a temperature close to 50C, in 560 cm3 of 0.5N sulfuric acid. The temperature of the suspension obtained is allowed to rise to 200C and stirred again 1 hour and a half at this temperature. Extraction is carried out with 3 times 250 cm 3 of ethyl acetate. The combined organic extracts are washed with 2 times 250 cm3 of water, dried over magnesium sulphate, filtered, and concentrated to dryness under reduced pressure (20 kPa) at 500C. The residue obtained is taken up in 50 cm3 of n-hexane containing 20% isopropyl ether, drained, washed with 10 cm3 of the same mixture and recrystallized from 60 cm3 of isopropanol containing 30% n-hexane. 11.84 g of (2-chloro-difluoro-6,7 quinolyl-3) -3 ethyl oxo-propionate are obtained in the form of a cream solid melting at 1070C.

Preparation of magnesium chelate of ethyl monomalonate
To 2.78 g of magnesium in turn, 2 cm 3 of absolute ethanol, 0.1 cm 3 of tetrachloromethane and 1 g of ethyl monomalonate are gradually added. After heating, a solution of 9 g of ethyl monomalonate in 180 cm 3 of ethanol is added over 15 minutes. The mixture is heated for 20 hours to a temperature in the region of 750C, concentrated under reduced pressure (20 kPa) to 500C. The residue is taken up in 2 times 100 cm3 of toluene and concentrated under reduced pressure under the same conditions as above. The gray powder obtained is dissolved by adding anhydrous tetrahydrofuran so as to obtain a total volume of 70 cm3.

The chloro-2-difluoro-6,7 quinoline carboxylic-3 acid was prepared as follows
To a suspension, with stirring, cooled to 100C, of 70.18 g of 2-chloro-difluoro-6,7 3-formyl-1,4-dihydro-quinoline in 970 cm 3 of aqueous potassium hydroxide N, the following is added over 1 hour. keeping the temperature between 10 and 140C, a solution of 115 g of potassium permanganate in 1.215 liters of water. The temperature is allowed to rise to around 200C and stirred for another 30 minutes at this temperature. 38.5 g of sodium dithionite are added, the mixture is stirred for 10 minutes at a temperature in the region of 200C, filter on diatomaceous silica, washed with 3 times 200 cm3 of water. The filtrate and the aqueous washing phases are combined and added with 140 cm 3 of hydrochloric acid in 35% aqueous solution. The precipitate formed is extracted with 4 times 800 cm3 of ethyl acetate. The combined organic extracts are washed with 2 times 500 cm3 of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at 500C. . The residue is taken up in 400 cm3 of ethyl ether, drained, washed with 2 times 200 cm3 of the same solvent. 49.2 g of chloro-2-difluoro-6,7 quinoline carboxylic-3 are obtained in the form of a beige solid melting at 2320C which is used, without further purification, for the subsequent steps.

2-chloro-6,7-difluoro-3-formyl-1,4-dihydro-quinoline was prepared in the following manner
To a mixture of 800 cm3 of trichloromethane and 74.35 cm3 of dimethylformamide, 76.9 cm3 of phosphoryl chloride is added over 30 minutes, with stirring, and stirred for 1 hour at a temperature in the region of 200C. To the solution obtained, 65.8 g of difluoro-6,7 dihydro-3,4 carbostyrile are added over 10 minutes at approximately 200 ° C., with vigorous stirring. The suspension obtained is heated to a temperature in the region of 600C and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 500C until a pasty mixture is obtained. With vigorous stirring, a mixture of 500 g of ice and 500 cm3 of water is added. The solid obtained is drained at around 50C and washed with 3 times 300 cm3 of water at 50C. The wet product obtained and 60 g of sodium acetate are added simultaneously, over 1 hour, to 1.5 liters of water at 900C, so as to maintain the pH at around 6. Agitation is continued for 30 minutes at 900C, the temperature drops to about 500C, wrung at this temperature and washed with 3 times 300 cm3 of water at about 200C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydro-1,4-quinoline are obtained in the form of a yellow solid melting at 2600C which is used as it is for the subsequent stages.

The difluoro-6,7 dihydro-3,4 carbostyril is obtained in the following manner
To 67 g of difluoro-3 ', 4' N-chloro-3-propionanilide, 134 g of aluminum chloride are added with vigorous stirring, then after approximately 2 minutes, again, in small portions, in 15 minutes, 135.9 g of 3 'difluoro, 4' N-chloro propionanilide and 272 g of aluminum chloride. The temperature itself increases to around 600C and the reaction mixture becomes liquid. It is then heated to 1100C in 20 minutes and maintained between 110 and 1200C for 2 hours. The reaction mixture (at around 1100C) is poured, over 10 minutes, with vigorous stirring, into a mixture of 840 cm3 of 35% hydrochloric acid and 1 kg of crushed ice. The temperature is allowed to rise to around 200C, wring out, washed with 600 cm3 of water twice, 300 cm3 of ethanol at 50C and 2 times 400 cm3 of ethyl ether at about 200C.

131.58 g of difluoro-6,7 dihydro-1,4 carbostyril are obtained in the form of a beige solid melting at 2160C which is used as it is for the subsequent steps.

Difluoro-3 ', 4' N-chloro-3 propionanilide is prepared as follows
To a solution of 125 g of 3.4 difluoroaniline in 80 cm 3 of pyridine and 1.5 liters of acetone heated to a temperature close to 550 ° C., 139.16 g of chloride are added with stirring over 1 hour and a half. 3-chloro propionic acid and maintains this temperature for 1 hour and a half. After cooling to around 200C, the solution is poured, with stirring, into a mixture of 1 liter of water and 500 g of crushed ice. The temperature is allowed to rise to around 200C and extracted with 3 times 500 cm3 of dichloromethane. The combined organic extracts are washed with 500 cm3 of N hydrochloric acid, 5 times 500 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at approximately 500 C. The solid obtained is taken up in 500 cm3 of n-hexane, drained, washed with 2 times 100 cm3 of the same solvent. 202.9 g of difluoro-3 ', 4' N-chloro-3 propionanilide are obtained in the form of a beige solid melting at 760C which is used without further purification for the subsequent steps.

(Furyl-2) -2 piperazine- (RS) was prepared by the method described in patent application EP 230 053.

EXAMPLE 2
By operating under the conditions of Example 1, but starting with 1.25 g of cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 ((furyl-2) -3 pipérazi nyl-1) -8 oxo-4 dihydro-1 , 4 benzoLb] naphthyridine-1, 8- (RS), 0.95 g of cyclopropyl-1 fluoro-7 [(furyl-2) -3 piperazinyl-1] -8 oxo-4 dihydro-1 is obtained, 4 benzo [b] naphthyridine-1,8 carboxylic-3- (RS) in the form of a yellow solid melting at 240-2410C.

Cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 [(furyl-2) -3 piperazinyl-1] -8 oxo-4 1,4-dihydro-1,4 benzo [b] naphthyridine-1,8- (RS) was prepared in conditions of Example 1, but from 1.05 g of cyclopropyl-1 difluoro-7,8 ethoxycarbonyl-3 oxo-4 dihydro-1,4 benzoLb] naphthyridine-1,8 and 0.6 g of ( furyl-2) -2 piperazine- (RS).

1.3 g of cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 [(furyl-2) -3 piperazinyl-1] -8 oxo-4 dihydro-1,4, benzo [b] naphthyridin-1,8- are obtained. (RS) in the form of a yellow solid melting at 1820C.

Cyclopropyl-1 ethoxycarbonyl-3 difluoro-7,8 oxo-4 dihydro-1,4 benzo [b] naphthyridine-1,8 was prepared as follows
A solution of 20 g of (2-chloro-difluoro -6.7 quinolinecarbonyl-3) -2 ethyl dimethylamino-acrylate and 9.25 g of cyclopropylamine in 80 cm3 of trichloromethane is stirred at a temperature in the region of 200C for 5 hours. The solution is concentrated under reduced pressure (20kPa) at around 400C. The residue is taken up in 300 cm3 of ethanol, added with 8.2 g of DBU and heated, with stirring, to about 750C for 30 minutes. After cooling to around 200C, the insoluble material is drained, washed with 2 times 30 cm3 of ethanol. 11.1 g of cyclopropyl-1-ethoxycarbonyl-3 difluoro-7,8 oxo-4 dihydro-1,4 benzo are obtained [ b] naphthyridine-1,8 in the form of a yellow solid melting at 2300C
EXAMPLE 3
By operating under the conditions of Example 1, but from 1.58 g of 3-ethoxycarbonyl-7.9 L (2-furyl) -3 piperazinyl-1] -8-methyl-4-oxo-4 dihydro -1.4 benzo [b] naphthyridine-1,8- (RS). 1.07 g of difluoro-7.9 [(furyl-2) -3 piperazinyl-1-8 methyl-1 oxo-4, dihydro-1,4, benzo [b] naphthyridin-1, 8 carboxylic-3 is obtained. - (RS) in the form of a yellow solid melting at 295-296 C.

Ethoxycarbonyl-3 difluoro-7,9 ((furyl-2) -3 piperazinyl-1l-8 methyl-1 oxo-4 1,4-dihydro-benzo [b] naphthyridine-1,8- (RS) was prepared under the conditions of Example 1, but from 1.85 g of 3-ethoxycarbonyl-7,8,9,9 methyl 4-oxo-1,4-dihydro-1,4 benzo [b] naphthyridin-1,8 and I g of (furyl-2) -2 piperazine- (RS).

After concentration under reduced pressure of the combined organic extracts (20kPa, about 400C) the residual solid is recrystallized from 100 cm3 of ethanol. 1.72 g of ethoxycarbonyl-3 difluoro-7.9 L (furyl-2) -3 piperazinyl-1) -8 methyl-1 oxo-4-1,4-dihydro-1,4-benzoLb3naphthyridin-1,8- (RS) are obtained. in the form of a yellow solid melting at 208-2100C.

Ethoxycarbonyl-3, trifluoro-7,8,9 methyl-1 oxo-4 dihydro-1,4, benzoLb] naphthyridin-I, 8 is prepared as follows
In a suspension with stirring of 19.3 g of (chloro-2 tri fluoro-6, 7.8 quinolinecarbonyl-3) -2 dimethylamino-3 acrylate in 150 cm3 of ethanol maintained at a temperature close to 50C, is added in 10 minutes between 5 and 100C, a solution at about 50C of 10 g of methylamine in 50 cm3 of ethanol, stirred for 1 hour between 5 and 100C and the temperature rises to about 200C. 7.6 g of DBU are added to the solution obtained and heated to around 300C for 1 hour. After cooling to a temperature in the region of 200C, the product is drained, washed with 2 times 100 cm3 of ethanol and 2 times 100 cm3 of isopropyl ether. 13.4 g of 3-trifluoro-7.8-ethoxycarbonyl are obtained, 9 methyl-1 oxo-4 dihydro-1,4 benzo [b] naphthyridin-1,8 in the form of a yellow solid melting at 3200C which is used without further purification for the subsequent steps.

(2-Chloro-trifluoro-6,7,8 quinolinecarbonyl-3) -2 dimethylamino-3 acrylate can be prepared as follows
A suspension of 26.7 g of (2-chloro-6,7fluoro-6,7,8 quinolyl-3) -3 ethyl oxo-propionate in 270 cm3 of ethyl acetate and 32 cm3 of N, N dimethylformamidedimethylacetal is heated to a temperature close to 750C, with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20kPa) at around 500C. The dry extract is taken up in 175 cm3 of isopropyl ether, drained, washed with 2 times 85 cm3 of the same solvent. 19.32 g of (2-chloro-6,7,8-chloro-3-quinoline-3-carbonyl) -2 ethyl dimethylamino-acrylate are obtained in the form of an orange solid melting at 1180C which is used without further purification for the stages later.

Ethyl (2-chloro-trifluoro-6,7,8 quinolyl-3) -3-oxo-propionate is prepared in the following manner
A suspension of 46.3 g of 2-chloro-trifluoro-6,7,8 quinoline carboxylic-3 in 640 cm3 of trichloromethane and 84 cm3 of thionyl chloride is heated, with stirring, to a temperature in the region of 600C for 6 hours. The solution obtained is concentrated to dryness under reduced pressure (20kPa) at around 500C.

The dry extract obtained is taken up in 140 cm3 of petroleum ether (40-60), drained, washed with 2 times 60 cm3 of the same solvent. The 47.61 g of the yellow solid obtained are dissolved in 400 cm3 of tetrahydrofuran. This solution is introduced, drop by drop, with stirring, in 1 hour and a half, between 50C and 100C, in 250 cm3 of a solution of magnesium chelate of ethyl monomalonate in tetrahydrofuran prepared under the conditions of the example. 11. The temperature is allowed to rise to around 200C and stirred for another 2 hours under these conditions. The solution obtained is introduced dropwise, with vigorous stirring, in 1 hour, at a temperature close to 50C in 1750 cm3 of 0.5N sulfuric acid. The mixture is stirred for another 2 hours at this temperature, extracted at around 50C with 3 times 600 cm3 of ethyl ether. The combined organic phases are washed with 3 times 500 cm3 of water, dried over magnesium sulfate, and concentrated under reduced pressure (20kPa) at a temperature in the region of 300C. The dry extract is taken up in a mixture of 135 cm3 of isopropyl ether and 15 cm3 of n-hexane, drained at around 50C, washed twice with 115 cm3 of the same mixture at the same temperature.

Obtained 47.4 g of (2-chloro-trifluoro-6,7,8 quinolyl-3) -3 ethyl oxo-propionate in the form of a beige solid melting at 78-800C which is used without further purification for the next steps.

The chloro-2-trifluoro-6,7,8 quinoline carboxylic-3 acid is prepared as follows
To a suspension, with stirring, cooled to about 100C, of 45.7 g of 2-chloro-6,7-trifluoro-3,7-formyl-1,4-dihydro-1,4-quinoline in 585 cm3 of N potassium hydroxide, is added over 1 hour in keeping the temperature between 10 and 140C, a solution of 69.65 g of potassium permanganate in 730 cm3 of water. The mixture is left to stir for 30 minutes at approximately 100C. 12 g of sodium dithionite are added, the mixture is stirred for 10 minutes at a temperature in the region of IOOC, filtered on diatomaceous silica and washed with 3 times 400 cm3 of water. The filtrate and the washes are combined and added with 70 cm 3 of hydrochloric acid in aqueous solution at 35 t. The precipitate formed is extracted with 3 times 500 cm3 of ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure (20kPa) at 500C. The residue is taken up in a mixture of 100 cm3 of ethyl ether and 100 cm3 of isopropyl ether, drained, washed with 100 cm3 of the same mixture. 46.43 g of 2-chloro-trifluoro-6,7,8 quinoline carboxylic-3 is obtained in the form of a colorless solid decomposing at 225-2300C which is used without further purification for the subsequent steps.

2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydro-quinoline is prepared in the following manner
To a mixture of 525 cm3 of trichloromethane and 49 cm3 of dimethylformamide, 50 cm3 of phosphoryl chloride is added over 40 minutes, with stirring, between 5 and 100 ° C., stirred for 15 minutes at this temperature and the temperature rises to approximately 200 ° C. . To the solution obtained, 46.8 g of trifluoro-6,7,8 dihydro-3,4 carbostyril are gradually added over 20 minutes at approximately 200C, with vigorous stirring. The mixture is left to stir for 30 minutes at a temperature in the region of 200C, heated to approximately 600C and maintained at this same temperature for 2.5 hours. The reaction mixture is concentrated under reduced pressure (20kPa) to around 500C. The oily residue is poured with vigorous stirring into 500 g of ice. 100 g of sodium acetate are added in small portions over 30 minutes. The suspension obtained is poured in 15 minutes, with vigorous stirring in 1 liter of water previously heated to about 900C and stirred for another 15 minutes at this same temperature. The insoluble material is drained at around 900C and washed with 3 times 250 cm3 of water. 47.7 g of 2-chloro-trifluoro-6,7,8 3-formyl-1,4-dihydro-1,4-quinoline are obtained in the form of a colorless solid decomposing at 2200C.

The trifluoro 6,7,8 3,4-dihydro-carbostyril is prepared in the following manner 24.35 g of trifluoro-6,7,8 carbostyril suspended in a mixture of 450 cm3 of ethanol and 150 cm3 of dimethylformamide are hydrogenated , with stirring, at around 500C, in the presence of 5 g of Raney nickel under a pressure of 1 atmosphere, until the end of hydrogen absorption. The Raney nickel used in W-2 quality is washed beforehand with 50 cm3 of a 2% aqueous acetic acid solution, with 2 times 50 cm3 of water and with 3 times 50 cm3 of ethanol. 250 cm3 of dimethylformamide are added to the reaction mixture, filtered at around 500 ° C. over diatomaceous silica. The filtrate is concentrated under reduced pressure (20kPa) at around 700C. The dry extract is taken up in 150 cm3 of water, drained and washed with 2 times 50 cm3 of water. 23.6 g of trifluoro 6,7.8 3,4-dihydro-carbostyril are obtained in the form of a solid. light beige melting at 2170C which is used without further purification for the subsequent steps.

The trifluoro-6,7,8 carbostyril is prepared in the following way: 60.83 g of chloro-4 trifluoro-6,7,8 carbostyril suspended in 520 m3 of acetic acid and 38.15 cm3 of triethylamine are hydrogenated under a pressure of 1 atmosphere, in the presence of 5.25 g of 10% palladium on carbon until the end of absorption of hydrogen, at a temperature in the region of 250C. The reaction mixture is then heated to about 400C, filtered at this same temperature, on diatomaceous silica for filtration. The filtrate is concentrated under reduced pressure (20kPa) at a temperature close to 500C. The dry extract is taken up in 400 cm3 of water; the insoluble material is drained, washed with 4 times 170 cm 3 of water, 2 times 110 cm 3 of ethanol and 2 times with 100 cm 3 of isopropyl ether. 48.35 g of trifluoro-6,7.8 carbostyril are obtained, in the form of a colorless solid sublimating at 2880C, which is used without further purification for the subsequent steps.

Chloro-4, trifluoro-6,7,8 carbostyril is prepared as follows
A suspension of 70.4 g of 4-chloro-2-ethoxy-6,7-trifluoro-quinoline in 170 cm3 of an aqueous solution of 35% hydrochloric acid, 420 cm3 of acetic acid and 250 cm3 of water is heated with stirring to a temperature close to 1000C for 2.5 hours. After cooling to around 200C, the reaction mixture is poured into 1100 cm3 of water at around 50C, stirred for 15 minutes at this same temperature, then the insoluble material is drained and washed with 3 times 220 cm3 of water. 61 g of chloro-4,7-trifluoro-6,7,8 carbostyril are obtained, in the form of a cream solid melting at 2130C which is used without further purification for the subsequent steps.

4-chloro-2-ethoxy-6,7-trifluoroquinoline is prepared in the following manner
A suspension of 69.5 g of 2-ethoxy-6,7,8-hydroxy-4-quinoline in 430 cm 3 of phosphoryl chloride is heated, with stirring, at a temperature in the region of 100 C for 30 minutes. The solution obtained is concentrated, under reduced pressure (20kPa) at around 600C, to a volume of 100 cm3. The residue is taken up in 750 cm3 of ethyl acetate; the solution obtained is poured with stirring, over 10 minutes, into a mixture of 400 cm3 of water and 200 g of ice and left to stir under these conditions for 30 minutes. After separation of the organic extract, the aqueous phase is again extracted with 2 times 250 cm3 of ethyl acetate. The combined organic extracts are washed with 3 times 250 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20kPa) at around 400C. The oily residue obtained is taken up in 370 cm3 of petroleum ether ((40-60). After filtration through diatomaceous silica, the filtrate is concentrated to dryness, under reduced pressure (20kPa) at approximately 300C. 70.7 g are obtained. of 4-chloro-2-ethoxy-6,7,8-quinoline, in the form of a beige solid melting at 450C which is used without further purification for the subsequent steps.

2-ethoxy-6,7,8-4-hydroxy-quinoline ethoxy can be prepared as follows
A solution of 122 g of trifluoro-2,3,4 N - [(ethoxy-1 'ethoxycarbonyl-2') ethylidene] -aniline in 120 cm3 of phenyl oxide is introduced dropwise over 25 minutes under stirring, in 600 cm3 of phenyl oxide at a temperature in the region of 2500C while eliminating the ethanol formed by distillation. After stirring for 15 minutes at this same temperature, the solution is cooled to about 200C and added with 750 cm3 of n-hexane. The precipitate formed is drained and washed 3 times with 200 cm 3 of n-hexane. 69.5 g of 2-ethoxy-6,7.8-hydroxy-4-quinoline are obtained in the form of a beige solid melting at 1710C which is used without further purification for the subsequent steps.

2,3,4,4-Nt trifluoro (1-ethoxy-2 'ethoxycarbonyl-2') ethylidene] aniline can be prepared as follows
To a solution of 90 g of (2-ethoxycarbonyl-1-ethoxy-1) ethylideneamine hydrochloride in 820 cm 3 of ethanol, 58.8 g of 2,3,4-trifluoroaniline are added all at once, with stirring. After 48 hours of stirring at a temperature close to 200C, the suspension obtained is filtered; the filtrate is concentrated under reduced pressure (20kPa) at a temperature in the region of 50 Oc. The oily residue is taken up in 250 cm3 of water. The mixture obtained is extracted with 3 times 200 cm 3 of ethyl ether. The combined organic extracts are washed with 4 times 150 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20kPa) at approximately 30 "C. 122 g of 2,3,4 N-trifluoro are obtained - [( 1-ethoxy-2 'ethoxycarbonyl) ethylidene] -aniline in the form of a yellow oil which is used without further purification for the subsequent steps.

(2-ethoxycarbonyl-1-ethoxy-1) ethylideneamine hydrochloride was prepared according to the method described by A. Pinner, et al., Ber.

Dtsch. Chem. Ges., 28, 478 (1895).

EXAMPLE 4
By operating under the conditions of Example 1, but starting with 2 g of 3-ethoxycarbonyl-7-fluoro-methyl-1 oxo-4 [(2-thienyl) -3 piperazinyl-1 1-8 dihydro-1,4 benzo [b] naphthyridine-1,8- (RS), 1.8 g of fluoro-7 methyl acid oxo-4 [(2-thienyl) -3 piperazinyl-1 d-8 dihydro-1 are obtained without recrystallization, 4 pure benzo [b] naphthyridine-1,8 carboxylic-3- (RS) in the form of a yellow solid melting at 268-2700C
Ethoxycarbonyl-3 fluoro-7 methyl-1 oxo-4 t (2-thienyl) -3 piperazinyl-1] -8 1,4-dihydro-benzoEb) naphthyridin-1, 8- (RS) was prepared under the conditions from Example 1, but from 1.59 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-benzo [b] 1,8-naphthyridin and from 1.02 g of (2-thienyl) -2 piperazine- (RS). 2.25 g of ethoxycarbonyl-3 fluoro-7 methyl-1 oxo-4 E (2-thienyl) -3 piperazinyl-1- 1-8 dihydro-1,4 benzoEb] naphthyridin-1,8- (RS) are obtained. in the form of a yellow solid melting at 2280C.

(2-Thienyl) -2 piperazine- (RS) was prepared according to the conditions described by Jeffrey W.H. Watthey et al., J. Med. Chem., 26, 1116 (1983).

EXAMPLE 5
By operating under the conditions of example 1, but starting from 2 g of cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 oxo-4 E (thienyl-2) -3 pipérazinyl-1 1-8 dihydro-1, 4 benzo [b] naphthyridine-1,8- (RS), 1.75 g of cyclopropyl-1 fluoro-7 oxo-4 L (2-thienyl) -3 piperazinyl-1 1-8 dihydro-1,4 are obtained. benzo [b] naphthyridine-1,8 carboxylic-3- (RS) in the form of a yellow solid melting at 2450C.

Cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 oxo-4 [(2-thienyl) -3 piperazinyl-1 1-8 1,4-dihydro-benzo [b] naphthyridine-1,8- (RS) was prepared in conditions of Example 1, but starting from 1.7 g of cyclopropyl-1 difluoro-7,8 ethoxycarbonyl-3 oxo-4 dihydro-1,4 benzoEb] naphthyridine-1,8 and 1 g of (thienyl- 2) -2 piperazine- (RS).
2.2 g of cyclopropyl-1 ethoxycarbonyl-3 fluoro-7 oxo-4 E (2-thienyl) -3 piperazinyl-1] -8 dihydro-1,4 banzoEb] naphthyridin-1,8- (RS) are obtained. form of a yellow solid melting at 210-2120C.

EXAMPLE 6
By operating under the conditions of Example 1, but starting with 1.6 g of 3-ethoxycarbonyl-7.9 difluoro-1,9 methyl-oxo-4 [(2-thienyl) -3 piperazinyl-1] -8 dihydro -1.4 benzo [b] naphthyridine-1,8- (RS), 0.75 g of difluoro-7.9 methyl-1 oxo-4 [[(2-thienyl) -3 piperazinyl-1]] is obtained -8 dihydro-1,4 benzo [b] naphthyridine-1,8 carbaxy-3- (RS) in the form of a yellow solid melting at 292-2940C.

Ethoxycarbonyl-3 difluoro-7,9 methyl-1 oxo-4 E (2-thienyl) -3 piperazinyl-1] -8 1,4-dihydro-benzo [b] naphthyridin-1,8- (RS) was prepared under the conditions of Example 1, but from 1.68 g of 3-ethoxycarbonyl-7,8,9,9-1-methyl-1,4-oxo-1,4-dihydro-benzo [b] -naphthyridin-1,8 and 1.01 g of (2-thienyl) -2 piperazine- (RS). 1.68 g of ethoxycarbonyl-3 difluoro-7.9 methyl-1 oxo-4 [(2-thienyl) -3 piperazinyl-1] -8 dihydro-1,4 benzoEb] naphthyridin-1,8- are thus obtained. (RS) in the form of a yellow solid melting at 2200C.

EXAMPLE 7
By operating under the conditions of example 1, but starting from 3.2 g of 3-ethoxycarbonyl-fluoro-7 (4-hydroxy-piperazinyl-1) -8 methyl-1 oxo-4 dihydro-1,4 benzo [ b] 1,8-naphthyridine, 2.86 g of fluoro-7 (4-hydroxy-piperazinyl-1) -8 methyl-1 oxo-4 dihydro-1,4-benzotb] naphthyridin-1,8 is obtained 3 in the form of a yellow solid melting at 2900C.

Ethoxycarbonyl-3 fluoro-7 (4-hydroxy-piperazinyl-1) -8 methyl 4-oxo-1,4-dihydro-benzoEbjnaphtyridine-1,8 was prepared under the conditions of Example 1, but starting from 3 g 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dizo-benzo [b] 1,8-naphthyridine, 1.97 g of 1-hydroxy piperazine dihydrochloride and 1.99 g sodium carbonate. 3.25 g of ethoxycarbonyl-3 fluoro-7 (4-hydroxy-piperazinyl-1) -8 methyl-1 oxo-4 dihydro-1,4, benzoEb] naphthyridin-1,8 are obtained in the form of a melting yellow solid at 258-260 C.

1-Hydroxy piperazine dihydrochloride was prepared according to the method described by Toschio Uno et al., J. Het. Chem., 26, 393 (1988).

EXAMPLE 8
By operating under the conditions of example 1, but starting with 1.4 g of 3-ethoxycarbonyl-7,9-difluoro (4-hydroxy-1-piperazinyl) -8 methyl-1 oxo-4 dihydro-1,4 benzo [bl naphthtyridine-1,8, 0.5 g of difluoro-7.9 (4-hydroxy-piperazinyl-1) -8 methyl 4-oxo-1,4-dihydro-1,4-benzo [blnaphthyridin-1,8 carboxylic- 3 in the form of a yellow solid melting at 285-288 C.

Ethoxycarbonyl-3 difluoro-7,9 (4-hydroxy-piperazinyl-1) -8 methyl-1 oxo-4 1,4-dihydro-1,4 benzo Lb] napthtyridine-1,8 was prepared under the conditions of Example 1 , but from 1.9 g of 3-ethoxycarbonyl-7,8,9,9-methyl-4-oxo-1,4-dihydro-benzo [b] naphthyridin-1,8, of 1 g of hydroxy dihydrochloride -1 piperazine and 1.6 g of potassium carbonate. 1.4 g of ethoxycarbonyl-3 difluoro-7.9 (4-hydroxy-piperazinyl-1) -8 methyl-1 oxo-4-1,4-dihydro-1,4-benzo (b] naphthyridin-1,8 are obtained in the form of a yellow solid melting at 255-2580C.

EXAMPLE 9 (RP 70529)
A suspension of 1.015 g of 7.8-difluoro-1 methyl-4-oxo-1,4-dihydro-benzo [b] naphthyridine-1,8 carboxylic-3 acid and of 1.7 g of [(hydroxy-2 ethoxy) ) -4 phenyl] -2 piperazine- (RS) in 15 cm3 of dimethylsulfoxide is heated, with stirring, to a temperature in the region of 1000C for 2.5 hours. After cooling to about 200C, the suspension is added with 30 cm3 of water, drained, washed with 3 times 10 cm3 of water. After recrystallization from 15 cm3 of dimethylformamide, 1.2 g of 7-fluoro-fE (2-hydroxyethoxy) -4 phenyl] -3 piperazinyl-1) -8 methyl-1-oxo-4-dihydro-1 is obtained, 4 benzoEbinaphtyridine-1,8 carboxylic-3 - (RS) in the form of a yellow solid melting at 2760C.

(2-hydroxyethoxy) -4 phenyl] -2 piperazine- (RS) can be prepared according to the method described in patent application FR 2 351 108, from 18.5 g of [(2-hydroxy-2 ethoxy) -4 phenyl] -2 glyoxal and 6.86 g of ethylenediamine. 4 g of (2-hydroxyethoxy) -4 phenyl] -2 piperazine- (RS) are obtained in the form of a beige solid melting at 1410 C. The [(2-hydroxyethoxy) -4 phenyl] -2 glyoxal can be prepared according to the method described by Nathan kornblum et al., J. Am. Chem. Soc., 79, 6562 (1957). From 30.5 g of (2-hydroxy-ethoxy) -4 '2-bromo-acetophenone, 18.5 g of L (2-hydroxyethoxy) -4 phenyl] -2 glyoxal are obtained in the form of a yellow oil which is used without further purification for the subsequent steps.

(2-hydroxy-ethoxy) -4 '2-bromo acetophenone can be prepared according to the method described by NG.PH. Buu-Hoï et al., J. Chem.Soc., 255 (1951). From 27 g of (2-hydroxyethoxy) -4 acetophenone, 28.85 g of (2-hydroxyethoxy) -4 '2-bromo-acetophenone are obtained in the form of a beige solid melting at 780C.

(2-hydroxyethoxy) -4 acetophenone was prepared according to C. Rufer and
Coll., J. Med. Chem., 18 (3), 253, (1975).

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

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

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

 The compositions for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, it is possible to use propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, and injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which will be dissolved in when to use in sterile water or any other sterile injectable medium.

 The compositions for rectal administration are suppositories or rectal capsules which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

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

 In general, the doctor will determine the dosage he considers most appropriate based on age, weight, degree of infection and other factors specific to the subject to be treated. Generally, the doses are between 0.2 and 1 g of active product twice a day, orally or parenterally for an adult.

The following example, given without limitation, illustrates a composition according to the invention
Example
Tablets containing 250 mg of active product, having the following composition, are prepared according to the usual techniques.

- fluoro-7 acid [(furyl-2) -3 piperazinyl-1] -8 methyl-1 oxo-4
dihydro-1,4 benzo [b] naphthyridine-1,8 carboxylic-3 (RS) 250 mg - starch .......................... ........ 50 mg - lactose ................................ 35 mg - talc .. .......................... 15 mg
The products of general formula (I) are also of interest in the field of agrochemistry for the antibacterial treatments of plants and plants. It is understood that the compositions for agrochemical use containing a product of general formula (I) also fall within the scope of the present invention.

 Furthermore, the products of general formula (I) can also be used as preservatives or disinfectants for organic or mineral materials. Particularly in the colorants, fats, paper, wood, polymers industry or in the textile industry, the food industry or water treatment. It is also understood that the compositions containing a product of general formula (I) in the pure state or in the form of a combination with compatible diluents or adjuvants also fall within the scope of the present invention.

Claims (4)

 1 - A new derivative of benzoEb] naphthyridine-1,8 characterized in that it corresponds to the general formula

 in which, - R1 represents a hydrogen atom or a hydroxy or alkyl radical, - R2 represents a hydrogen atom or an alkyl, fluoroalkyl, cycloalkyl radical containing 3 to 6 carbon atoms, alkyloxy or alkyllamino, - R3 represents a phenyl or phenylalkyl radical substituted by one or more halogen atoms or alkyl or cycloalkyl radicals containing 3 to 6 carbon atoms, alkyloxy, cyano, amino, alkyllamino, dialkoylamino, alkyloxyalkyl, hydroxyalkyloyloxy, methylalkylalkylalkylalkylalkyl, alkylenedoyloyalkyloyloyloyloyloyloyloyloyloyloyloyloyl the alkyl parts can form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle, or represents a 5-membered heterocyclyl radical containing 1 or 2 heteroatoms chosen from nitrogen, oxygen or sulfur , and - R4 represents a hydrogen atom or a fluorine atom, It being understood that when R1 represents a hydrogen atom or an alkyl radical, R3 cannot simultaneously represent a phenyl or phenylalkyl radical which is unsubstituted or substituted on the phenyl nucleus by one or more halogen atoms or alkyl or cycloalkyl radicals containing 3 with 6 carbon atoms, alkyloxy, cyano, amino, alkyllamino or dialkoylamino], and of which the alkyl radicals are straight or branched and contain 1 to 4 carbon atoms, in its isomeric forms or their mixtures as well as its metal salts, its salts addition with nitrogenous bases, its addition salts with acids and its hydrated forms.  2 - Process for the preparation of a benzoEb] naphthyridine-1,8 derivative according to claim 1, characterized in that a piperazine derivative of the general formula is made to act

 in which R1 and R3 are defined as in claim 1, on a benzo [b] naphthyridine-1,8 of general formula

 wherein R2 and R4 are defined as in claim 1 and Hal is a fluorine, chlorine or bromine atom, if R4 is a hydrogen atom, or Hal and R4 are simultaneously fluorine atoms, then, if necessary, when it is desired to obtain a product according to claim 1 for which R1 is methyl and when the corresponding product has been obtained for which Ri is a hydrogen atom, transforms the product obtained into a derivative of (methyl-4 piperazinyl-1) -8 benzoEbinaphtyridine, then optionally transforms the product obtained in a salt.  3 - Process for the preparation of a benzo [b] naphthyridine-1,8 derivative according to claim 1, characterized in that the ester of general formula is transformed

 in which R1, R2, R3 and R4 are defined as in claim 1, or R2 represents a protected alkylamino radical and Alk is a straight or branched alkyl radical containing 1 to 4 carbon atoms, by any known method for obtaining an acid with starting from an ester, without touching the rest of the molecule, then, if necessary, eliminating the protective group from the alkyllamino radical, and / or when it is desired to prepare a product according to claim 1, for which R1 is methyl and when the corresponding product has been obtained for which R1 is a hydrogen atom, transforms the product obtained into a derivative of (methyl-4 piperazinyl-1) -8 benzo [b] na phtyridine then, optionally, prepares the salt of the benzo [b] naphthyridine derivative obtained.  4 - Composition characterized in that it contains at least one derivative according to claim 1, in the pure state or in combination with one or more compatible diluents or adjuvants.