DD291556A5 - METHOD FOR PRODUCING NEW 1,8-BENZONAPHTYRIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of novel 1,8-benzo / b / naphthyridine derivatives of the general formula (I) (see formula sheet) in which R is a hydrogen atom or an alkyl, fluoroalkyl, cycloalkyl (3 to 6 * alkyloxy) or alkylamino radical and R3 is alkyl, R4 and R5 are different and are hydrogen or alkyl, or R3 is hydrogen, alkyl or cycloalkyl and R4 and R5 are hydrogen, R6 is hydrogen or fluorine and n is 1 or 2 and their salts These new products are applicable as antimicrobial agents {1,8-benzonaphthyridine derivative production; antimicrobial effective}

Description

For this 2 pages formulas

Field of application of the invention

The present invention relates to processes for the preparation of novel 1,8-benzo [b] naphthyridine derivatives of the general formula (I) (see formula sheet) and their salts, which are used as active ingredients in pharmaceuticals.

Furthermore, they are used as active ingredients in compositions for antibacterial treatment in plants and plant substances.

Another use is the use as an active ingredient in preservatives and disinfectants for organic or mineral materials.

Characteristic of the known state of the art

Naphthyridine derivatives of the structure (A) (see formula sheet) in which X may be oxygen and two of the pendant radicals R ₁ to R _{6 may form} a benzene ring have been described in US-4229456 and US-4133885. These products are useful as inhibitors of gastric acid secretion.

The patent application DE-3302126 describes hypertensive agents of the general formula (B) (see formula sheet) in which the radicals X, Y and Z can be zero or can also denote an NR.sup.10 radical or a CRs.dbd.CRs radical, wherein the R.sup ₅ -TeUe can form a benzene ring.

Object of the invention

By the method according to the invention antibacterial effective new 1,8-benzonaphthyridine derivatives are provided.

Explanation of the essence of the invention

The present invention has for its object to provide processes for the preparation of antibacterial compounds.

It has been found that the products of the general formula (I) (see formula sheet), in which:

R) represents a hydrogen atom, an aikyl radical or a hydroxyalkyl radical,

R 2 represents a hydrogen atom, an aicyclic radical, a fluoroalkyl radical, a cycloalkyl radical, an alkyloxy radical or an alkylamino radical,

- R _{3 is} an Aikyl radical and

R ₄ and R _{5 are} different and represent a hydrogen atom or an aikyl radical, or

R _{3 represents} a hydrogen atom, an aicyclic radical or a cycloalkyl radical, and

R ₄ and R _{6 are} hydrogen atoms,

Rg represents a hydrogen or a fluorine atom, and

- η is 1 or 2,

wherein the alkyl radicals contain 1 to 4 carbon atoms in a straight or branched chain and the cycloalkyl radicals contain 3 to 6 carbon atoms, and their salts and optionally their isomers show a particularly interesting antibacterial activity.

The products of general formula (I) may exist in hydrated form and it is to be understood that these hydrates are also within the scope of the present invention.

According to the invention, these prodrugs of the general formula (I) can be obtained by substitution of a piperazine of the general formula (II) embedded image in which Ri, R ₃ , R ₄ , Re and η are as defined above, with a 1,8-benzo (b) naphthyridine of general formula (III) wherein R _{2 is} as defined above and Hai represents a fluorine, chlorine or bromine atom when R _{8 is} hydrogen or Hai and R _{0 are} simultaneously fluorine atoms, optionally followed when H _{1 is} one Is hydrogen atom and if one wants to obtain a 1,8-benzo [b] naphthyridine derivative in which R, is methyl, from the conversion of the product obtained into an 8- (4-methyl-1-piperazinyl) benzo [b ] naphthyridine.

The action of the piperazine derivative of the general formula (II) is generally carried out in the presence of an excess of this derivative as an acid acceptor or in the presence of an organic or mineral acid acceptor in suitable organic solvents. It is possible to work with or without solvent, at a temperature between 30 ° C and 120 ° C. When operating in the presence of a solvent, the reaction is advantageously carried out in solvents such as pyridine, dimethylformamide, dimethyl sulfoxide or acetonitrile.

It is understood that in the case where the symbol R _{2 of} the product of formula (III) is a hydrogen atom, it is preferable to protect this product in advance. The protection and removal of the protecting group after the reaction are carried out by conventional methods.

The protection can be carried out with any suitable groups whose use and removal does not affect the remainder of the molecule. In particular, the procedure according to T.W. GREENE, Protective Groups in Organic Synthesis, A.Wileyl Science Publication (1981), or methods described by McMIE, Protective Groups in Organic Chemistry, Plenum Press, (1973). For example, the protecting groups can be selected from the following radicals: trimethylsilyl, methoxymethyl, ethoxymethyl, benzhydryl, trityl, tetrahydropyranyl, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, trichloroethoxycarbonyl.

Optionally, the subsequent operation of methylating the piperazinyl radical is advantageously by reaction of the formol in the presence of formic acid. It is generally carried out in an aqueous medium at a temperature between 90 ° C and 100 ⁰ C.

According to the invention, the 1,8-benzo [blnaphthyridine derivatives of the general formula (I) can also be obtained starting from the ester of the general formula (IV) (see formula sheet) in which Rt, R ₂ , R ₃ , R ₄ , R 5 , Rg and η are as defined above, or R _{2 is} a protected alkylamino radical and alkenyn is a straight or branched alkyl radical of 1 to 4 carbon atoms, according to a known method for producing an acid from an ester without attacking the remainder of the molecule and subsequently optionally removing the protecting group of the alkylamino radical and / or, when a product of general formula (I) has been obtained, in which Ri is a hydrogen atom and it is desired to prepare the corresponding product in which Ri is methyl which converts the product obtained into an 8- (4-methyl-1-piperazinyl) benzo [b] naphthyridine.

The production of the acid from the ester is generally carried out by acid hydrolysis. It works advantageously in an acetic acid-hydrochloric acid mixture, in sulfuric acid or in methanesulfonic acid at a temperature between 2O ⁰ C and 100 ° C. It is also possible to work with the aid of the saponification, in the presence of potassium hydroxide or sodium hydroxide, in an aqueous-alcoholic medium and at a temperature between 20 ° C and 8O ⁰ C.

Optionally, methylation of the piperazinyl radical is as described above.

When R _{2 is} a protected alkylamino radical, the protecting group may be any corresponding amino protecting group that is compatible with the molecule. It is particularly advantageous to select a protective radical which can be removed simultaneously with the hydrolysis of the ester (for example the formyl radical).

The 1,8-benzo [b] naphthyridine derivative of general formula (III) can be obtained starting from the corresponding ester of general formula (V) (see formula sheet) in which Hal, R ₆ and Alk are as defined above and R _{2 is} also as defined above or is a protected alkylamino radical to attack the rest of the molecule by any known method for preparing an acid from an ester without λ , followed by removal of the protecting group from the alkylamino radical. It works in particular under the conditions described above for the preparation of a product of general formula t'l) from an ester of general formula (IV).

The ester derivative of 1,8-benzo [b] naphthyridine of the general formula (V) can be prepared by the action of 3-amino-i, 2,4-triazine, to give a product in which R _{2 is} a hydrogen atom or by the action of a product of the general formula (VI) (see formula sheet) in which R _{2 is} alkyl, fluoroalkyl, cycloalkyl, alkyloxy or alkylamino, optionally protected, to a quinoline derivative of the general formula (VII) in which R ₆ , Hal and Alk are as defined above, followed by cyclization by the action of an acid acceptor.

In general, the reaction of the 3-amino-1,2,4-triazine or the product of the general formula (VI) is carried out in an organic solvent such as an alcohol (for example ethanol or methanol) or in a chlorinated solvent (for example trichloromethane). at a temperature between 1O ⁰ C and 25 ° C, the cyclization takes place in an alcohol with straight or branched chain and 1 to 4 carbon atoms, at a temperature between 2O ⁰ C and the reflux temperature of the reaction mixture.

The acid acceptor may in particular be chosen from nitrogen bases (for example triethylamine or an excess of the amine used) or the diene-diazo-ol-bicyclo -undecene.

The quinoline derivative of the general formula (VII) can be obtained starting from the ketoester of the general formula (VIII) in which Re, Hal and Alk are as defined above, by the action of an acetal-N, N-dimethylformamide of the general formula (IX) in which Alk _{1 represents} an alkyl radical having 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 (for example ethyl acetate) at a temperature between 60 ^° C. and 75 ^° C.,

The keto ester of the general formula (VII ¹ ) in which R _{6 is} a hydrogen atom can be prepared starting from 2,7-dichloro-6-fluoroquinoline-3-carboxylic acid or 2-chloro-6,7-dinucor-quinoline-3 carboxylic acid, as described in Examples 1 and 23 below, or starting from 7-bromo-2-chloro-6-fluoro-quinoline-3-carboxylic acid analogously to this method. In this case, the starting 3-bromo-4-fluoroaniline can be prepared according to the method described by WB AUSTIN et al., J. Org. Chem., 46 (11), 2280 (1981).

The ketoester of the general formula (VIII) wherein R _{8 is} a fluorine atom may be obtained starting from the 2-chloro-6,7,8-trifluoro-quinoline-3-carboxylic acid as described in Example 25 below.

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

The reaction is generally carried out under the conditions described above for the preparation of a product of the general formula (I) starting from a piperazine of the general formula (II) and a 1,8-benzo [b] naphthyridine of the general formula (III).

Lie piperazine derivatives of the general formula (II) can be obtained according to or in analogy to ei2η methods described by the following authors:

- S. HARRY et al., J. Am. Chem. Soc., 75, 499 (1963),

G.CIGNARELLA, J.Med.Chem., 7,241 (1964) or J.Het.Chem., 11,985 (1974),

J.PIPER, J. Org. Chem., 28, 981 (1963),

- ISCHIGURO, MATSUMARA, J. Pharm. Soc. Japan, 79, 153 and 302 (1959).

When R3 and R4 are different, the benzo [b] naphthyridine derivatives of the general formula (I) are present in isomeric forms according to the invention. It is understood that these isomers and their mixtures are within the scope of the present invention.

If one wishes to obtain the isomers of the benzonaphthyridine derivatives of the general formula (I), the separation of the isomeric forms of the piperazines of the general formula (II) is carried out by means of any known method compatible with the molecule. For example, the separation is carried out by acylation with a chiral acid, separation of the isomers by high performance liquid chromatography and subsequent deacylation mg by acid hydrolysis. The novel novel products and their synthesis intermediates may optionally be purified by physical methods such as crystallizates or chromatography.

The products according to the invention can be converted into metal salts or in addition salts with nitrogen bases by methods known per se. These salts may be prepared by the action of a metal base (for example an alkali metal or alkaline earth metal), 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 the salt of an organic Acid are obtained. The precipitate optionally formed after concentration of its solution is separated by filtration, decantation or lyophilization.

The new products according to the invention can also be converted into addition salts with acids. The products of the general formula (I) obtained in the form of these salts can be liberated by customary methods or converted into salts of other acids.

As examples of pharmaceutically acceptable salts, the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), the ammonium salt, the salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, Ν , Ν-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-β-phenethylamine, Ν, Ν'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibonzylamine) and the addition salts with mineral acids (hydrochlorides, hydrobromides, Sulfates, nitrates, phosphates) or with organic acids, succinates, fumarates, maleates, para-toluenesulfonates.

The novel 1,8-benzo [b] naphthyridine derivatives of the general formula (I) according to the invention and their pharmaceutically acceptable salts have particularly interesting antibacterial properties. They have remarkable activity in vitro and in vivo in gram-positive bacteria and have a general effect on germs responsible for a variety of high and low airway infections.

In vitro, the products of general formula (I) show active at a concentration between 0.12 and 50pg / cm ³ on staphylococcus aureus IP8203.

In vivo, the products of general formula (I) are active in experimental mouse infections of staphylococcus aureus IP8203 at doses between 2 and 150 mg / kg by the oral or subcutaneous route.

Another significance of the products according to the invention lies in their low toxicity. Their DL50 is generally higher than 500 mg / kg by subcutaneous route in the mouse.

Of particular interest are the products of general formula (I) in which

R _{1 represents} a hydrogen atom or alkyl radical having 1 or 2 carbon atoms, optionally substituted by a hydroxy radical,

R _{2 represents} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms in a straight or branched chain, optionally substituted by a fluorine atom,

- R3 is a methyl radical and

- R ₄ and R _{9 are} different and represents a hydrogen atom or a methyl radical), or also

R _{3 represents} a hydrogen atom or a methyl radical and R ₄ and R _{6 are} hydrogen atoms,

- R _{8 is} a hydrogen or a fluorine atom, urd

- η is 1 or 2.

Among these products are particularly interesting:

- 7-Fluoro-1-methyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

i-ethyl-fluoro-e-piperazinylM-oxo-i-dihydro-d-benzo-1-naphthyridine-S-carboxylic acid

i-Cyclopropyl-fluoro-e-d-piperazinyl M-oxo-1-dihydro-d-benzol-naphthyridine-S-carboxylic acid

- 7,9-Difluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid

e-fS-dimethyl-i-piperazinyl-i-ethyl-y-fluoroM-oxo-i-dihydro-d-benzol-naphthyridine-S-carboxylic acid. The following non-limiting examples illustrate the present invention.

Ausführungsbeisplale

example 1

A suspension of 3.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 4.6 g of 2-methylpiperazine in 40 cm * Pyridine is heated with stirring to a temperature of 115 ° C for 13 hours. The reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of 6O ⁰ C to dryness. The residue is taken up twice in 30 cm ^{3 of} ethanol and concentrated under reduced pressure under the abovementioned conditions. The solid obtained is taken up in 60 cm ^{3 of} water and 10 cm ^{3 of} 30% potassium hydroxide solution. The aqueous phase is washed twice with 100 cm ³ Trichlormothan, then you are zugegebsn 10,28g methane and washed again twice with 100 cm ³ of trichloromethane. Then add 10cm ^{3 of} 30% potassium hydroxide solution. The precipitate formed is centrifuged and washed three times with 10 cm ^{3 of} water and twice with 10 cm ^{3 of} ethanol. This gives 2.7 g of 7-fluoro-1-methyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form a yellow solid of melting point 360-363 ⁰ C.

The e-chloro-fluoro-i-methyl-oxo-i-dihydro-dibenzo-4-naphthyridinyl-S-carboxylic acid can be prepared in the following manner:

A suspension of 15 g of e-chloro-S-ethoxycarbonyl ^ -fluoro-i-methyM-oxo-i ^ -dihydro-ie-benzoIblnaphthyridin in 150cm ³ of acetic acid and 150 cm ³ of 17.5% igerSalzsäurowird4 hours with stirring to a temperature of close to 100 ⁰ C heated. After cooling to a temperature of near 20 ° C, the product is centrifuged and washed twice with 150cm ^{3 of} ethanol and twice with 100cm ^{3 of} ethyl ether. 12.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a beige solid which is dissolved at 400.degree. Sublimed at 405 ° C and used without further purification in the later stages.

The e-chloro-S-ethoxycarbonyl-fluoro-i-methyl-oxo-i-dihydro-diterbenzene-benzenaphthyridine is prepared in the following manner:

Into a suspension of 19.3 g of 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 250cm ^{3 held} at a temperature between 10 ° C and 15 ⁰ C ethanol is passed with stirring methylamine until the absorption of 16g of gas. The temperature is allowed to rise to about 20 ⁰ C, 0.8 g of 1,8-diaza [5.4.0] bicyclo-7-undecene (DBU) is added and heated for 2 hours to a temperature of near 75 ⁰ C. After cooling to about 20 ° C, the product is centrifuged, washed twice with 150cm ^{3 of} ethanol and washed twice with 100cm ^{3 of} ethyl ether, to give 15g e-chloro-S-ethoxycarbonyl ^ -fluoM-methyl-4-oxo-1,4-dihydro-1 , 8-benzo [b] naphthyridine in the form of a yellow solid of melting point 360-362 ⁰ C, which is used without further purification in the later stages.

The ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate is prepared in the following manner:

A suspension of 16.5 g of 3- (2,7-dichloro-6-fluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester in 160 cm ³ of ethyl acetate and 19 cm ³ N, N-dimethylformamide dimethylacetal is heated under stirring for 2 hours to a temperature of near 75 ° C heated. Then the reaction mixture under reduced pressure (20 kPa) at a temperature of 5O ⁰ C to dryness. The dry extract is taken up in 50 cm ³ of isopropyl ether, centrifuged and washed twice with 10 cm ³ of isopropyl ether.

This gives 16.57g 2- (2,7-dichloro-6-fluoro-3-quinolincarbonyl) -3-dimethylamino-acrylic acid ethyl ester in the form of an orange solid of melting point 122 ⁰ C. This product is without further purification in the later Stages used.

The 3- (2,7-dichloro-6-fluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester is prepared in the following manner:

A suspension of 38.75 g of 2,7-dichloro-6-fluoro-quinoline-3-carboxylic acid in 410 cm ^{3 of} trichloromethane and 24 cm ^{3 of} thionyl chloride is heated with stirring for 6 hours to a temperature of near 60 ⁰ C. The resulting solution is concentrated under reduced pressure (2OkPa) at a temperature of 50 ° C. The dry extract is taken up twice with a total of 200 cm ³ of toluene and concentrated again under reduced pressure and the same conditions as before. The resulting yellow solid of melting point 124 ⁰ C is dissolved in 230cm ^{3 of} anhydrous tetrahydrofuran. Dio solution is added dropwise with stirring and within 30 minutes at a temperature between 5 ° C and 10 ° C in 200cm ^{3 of} a solution of magnesium chelate in tetrahydrofuran, the preparation of which is described below.

The temperature is allowed to rise again to 20 ° C and stirred for 90 minutes at this temperature. Then, the resulting solution is added dropwise with vigorous stirring and at a temperature of near 5 ⁰ C in 1 liter of O, 5N sulfuric acid.

The temperature of the resulting suspension is allowed to rise ^. on to 2O ⁰ C and stirring for 2 hours at this temperature.

It is then extracted with 1 liter of ethyl acetate, the organic and aqueous phases are filtered through diatomaceous earth for filtration, allowing the removal of a slight insoluble fraction, and the aqueous phase is extracted twice more with 500 cm ^{3 of} ethyl acetate. The combined organic extracts are washed twice with 500 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a temperature of 40 ⁰ C. The residue is taken up in 100 cm ³ of isopropyl ether at 2O ⁰ C, centrifuged and washed twice with 30 cm ³ of isopropyl ether. 40,55g is obtained 3 - ( '7-dichloro-6-fluoro-3-chinoryl) -3-oxo-propionic acid ethyl ester in the form of a beige solid of melting point 112-114 ⁰ C. This product is used without further purification in used in the later stages Preparation of magnesium chelate from monomalonic acid ethyl ester:

To 6.9 g of magnesium shavings are added sequentially 5cm ³ of absolute ethanol, 0.2 cm ³ of carbon tetrachloride and 2g Monomalonsäure ethyl ester. After heating, a solution of 23.8 g monomalonic acid ethyl ester in 450 cm ^{3 of} ethanol is added within 15 minutes. The mixture is heated for 20 hours to a temperature of close to 78 ⁰ C and concentrated under reduced pressure (2OkPa) at a temperature of 5O ⁰ C. The residue is taken up twice in 100 cm ³ of toluene and concentrated as before under reduced pressure at the same conditions. The gray powder obtained is dissolved by adding anhydrous tetrahydrofuran so as to obtain a total volume of 200 cm. ³ The monomalonic acid ethyl ester was prepared according to the method described by DS BRESLOW, E. BAUMGARTEN, CRHAUSER., J. Am. Chem. Soc., 66, 1287 (1944) and distilled under reduced pressure (bp = 132 ° C / 2.7 kPa ). The 2,7-dichloro-6-fluoro-quinoline-3-carboxylic acid is prepared in the following manner:

To a suspension of 69.5 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydro-quinoline in 282 cm ^{3 of} 2N potassium hydroxide solution and 282 cm ^{3 of} water, cooled to a temperature of 10 ° C, are added Within one hour, a solution of 89.3 g of potassium permanganate in 1.4 liters of water, the temperature between 1O ⁰ C and 14 ⁰ C is maintained. The temperature is allowed again anrtdigen to about 2O ⁰ C and is stirred for 30 minutes at this temperature. Then add 26 g of sodium dithionite, stirred for 10 minutes at a temperature of near 20 ° C, filtered through diatomaceous earth for filtration and washed twice with 250cm ^{3 of} water. The filtrate and the aqueous washings are combined and added 90cm ³ 35% hydrochloric acid. The precipitate formed is extracted four times with 500 cm ^{3 of} ethyl acetate. The combined organic extracts are washed three times with 500 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) is concentrated at a temperature of 5O ⁰ C. The residue is taken up in 350 cm ^{3 of} ethyl ether, centrifuged and washed twice with 200 cm ^{3 of} ethyl ether. This gives 45g of 2,7-dichloro-6-fluoro-quinoline-3-carboxylic acid in the form of a beige solid of melting point 230 ⁰ C, which is used without further purification in the later stages. ! 2.7-Dich or-6-fluoro-3-formyl-1,4-dihydro-quinoline was prepared in the following manner: To a mixture of 250 cm ³ of trichloromethane and 54 cm ³ of dimethylformamide are added over 30 minutes under stirring at a temperature between 1O ⁰ C and 15 ⁰ C 55,6cm ³ of phosphoryl chloride and stirred for one hour at a temperature of close to 2O ⁰ C. to the resulting solution are added over 10 minutes at about 20 ° C successively with vigorous stirring 52g 7-chloro-6-fluoro-3,4-dihydro-carbostyril. The suspension obtained is heated to a temperature of near 60 ⁰ C and kept at this temperature for a further 2 hours with stirring. Then, the reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of 5O ⁰ C until a pasty mixture is present. Then, with vigorous stirring, a mixture of 250 cm ^{3 of} water and 250 g of crushed ice is added. The solid obtained is centrifuged at about 5 ⁰ C and four times with 125 cm ³ of water of 5 ° Cgewaschon. The wet product obtained and sodium acetate been 58g of 1 hour to 500 cm ³ of water at 9O ⁰ C innerhalh added simultaneously in such a way that the pH is maintained at about the 6th The mixture is stirred for 15 minutes at 9O ⁰ C, the temperature is allowed to drop to about 50 ⁰ C, centrifuged at this temperature and washed three times with 250cm ^{3 of} water of about 2O ⁰ C. to give 54.3g 2,7-dichloro-6 -fluoro-3-formyl-1,4-dihydro-quinoline in the form of a yellow solid of melting point 260 ⁰ C, which is used as it is in the later stages. The 7-chloro-6-fluoro-3,4-dihydro-carbostyri! is prepared in the following manner: To 174.4 g of S'-ChloM'-fluoro-SN-chloro-propionanilide are added with vigorous stirring within 5 Minu'en 350g of aluminum chloride. The solid mixture is heated to about 60 ^° C. within 30 minutes. Then c increases ie temperature of 8O ⁰ C seihst an'etwa and the reaction mixture liquefies. It is then heated for 15 minutes at 110 ⁰ C and the temperature is then maintained for 3 hours between 11O ⁰ C and 120 ⁰ C. Then the reaction mixture (bti about 11O ⁰ C) within 10 minutes and with vigorous stirring in a mixture of 550cm ³ 35% hydrochloric acid and 500g crushed ice poured. The temperature is allowed to rise to 2O ⁰ C, centrifuged and washed six times with 500cm ^{3 of} water. The moist product is recrystallized in 1.2 liters of ethanol. This gives 108 g of 7-chloro-6-fluoro-3,4-dihydro-carbostyril in the form of a beige solid of melting point 215 ⁰ C.

The S'-ChioM'-fluoro-S-N-chloro-propionanilide was prepared in the following manner:

To a solution of 291 g of 3-chloro-4-fluoroaniline in 500 cm ^{3 of} acetone is added at a temperature of near 55 ⁰ C with stirring over 35 minutes, a solution of 127 g of 3-chloro-propionic acid chloride in 200cm ^{3 of} acetone and keeps this temperature for 2 hours upright. After cooling to about 20 ° C, the insoluble fraction is removed by filtration and washed twice with 200cm ^{3 of} acetone. The filtrate and the combined washings are poured with stirring into 2 liters of water and 1 kg of ice. The temperature is allowed to rise to 20 ° C and extracted four times with 500 ° C dichloromethane. The combined organic extracts are washed three times with 500 cm ^{3 of} water, dried over magnesium sulfate, stirred for 15 minutes with 6 g Norit-charcoal, filtered through diatomaceous earth for filtration and under reduced pressure (2.7 kPa) at a temperature of 50 ⁰ C. concentrated. The solid obtained is recrystallized in a mixture of 133 cm ^{3 of} cyclohexane and 67 cm ^{3 of} isopropyl ether. This gives 176 g of S'-ChloM'-fluoro-SN-chloro-propionanilide in the form of a beige solid of melting point 94 ⁰ C, which is used as it is in the later stages.

Example 2

The 7-fluoro-1-methyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1, but starting from 10g e-chloro - ^ - fluoro-i-methyM-oxo-i ^ -dihydro-ie-benzoIblnaphthyridin-S-carboxylic acid and 28 g of piperazine in 100 cm ³ of pyridine. This gives 5.5 g of 7-fluoro-1-methyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid hemihydrate in the form of a yellow Solid of melting point 370-375 ⁰ C.

Example 3

The 7-fluoro-1-methyl-4-oxo-8- (4-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphlhyridine-3-carboxylic acid is added under analogous conditions as in example 1, but starting from 5 g of e-chloro ^ -fluoro-i-mäthyM-oxo-i / l-dihydro-i.ebenzo (b] naphthyridine-3-carboxylic acid and 16 g 1-methyl-piperazine in 50 cm ³ of pyridine. after concentrating the reaction mixture under reduced pressure, the residue was dissolved in 100cm ³ of water is suspended and 25cm ³ of acetic acid. one removes a very small unit, considerable share by filtration through diatomaceous earth for the filtration. Then, to the filtrate 200cm ³ 3 N-Kaliiauge To and removed again a very small insoluble portion by filtration over diatomaceous earth for the filtration.Then the 5cm ³ acetic acid are added to the filtrate.The formed precipitate is centrifuged and washed three times with 50cm ³ water After two recrystallizations in 17 cm ³ each Dimethylformamide is obtained 3.2 g of 7-fluoro-1-methyl-4-oxo-8- (4-methyl -1-piperazinyl) -1,4-dihydro-1,8-Banzo [bl-naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 356 ⁰ C.

Example 4

The 7-fluoro-1-methyl-4-oxo-8- (4-ethyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the following in Example 5, but starting from 1.85 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2 , 75g of 1-ethyl-piperazine in 20cm ^{3 of} pyridine. This gives 1.3 g of 7-fluoro-1-methyl-4-oxo-8- (4-ethyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 285-286 ⁰ C.

Example 5

The 7-fluoro-1-methyl-4-oxo-8- (4- (2-hydroxyethyl) -1-piperazinyl] - *, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1, but starting from 1.6 g of e-chloro-fluoro-i-methyl-oxo-i-dihydro-IS-benzo [b] naphthyridine-3-carboxylic acid and 6.8 g. (2-hydroxyethyl) piperazine in 16 cm ^{3 of} pyridine After concentration of the reaction mixture under reduced pressure to dryness, the residue is taken up in 50 cm ^{3 of} water The reaction mixture is brought to a pH of 6 by addition of 0.4 cm ^{3 of} acetic acid, The resulting precipitate is centrifuged, washed twice with 10 cm ^{3 of} water and recrystallized twice in 10 cm ^{3 of} dimethylformamide to give 1,1g7-fluoro-1-methyl-4-oxo-8- [2-hydroxy-ethyl) -1 piperazinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid inform a yellow solid of melting point 275-276 ⁰ C.

Example 6

The 7-fluoro-1-methyl-4-oxo-8- (3,5-dimethyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is added under the conditions from Example 3, but starting from 1.7 g of e-chloro-fluoro-i-methyl-oxo-1-dihydro-bisbenzene-bjnaphthyridine-S-carboxylic acid and 2.5 g of 2,6-dimethyl-piperazine in 20 cm ^{3 of} pyridine. 1.1 g of 7-fluoro-1-methyl-4-o'-O-OS-dimethyl-1-piperazinyl-1-dihydro-1-benzolblonaphthyridine-S-carboxylic acid hemihydrate are obtained in the form of a yellow solid of melting point 294- 295 ° C.

Example 7

The 7-fluoro-1-ethyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5, but starting from 1.6 g of 8-chloro-7-fluoro-1-ethyl-4-oxo-i, 4-dihydro-1,8-benzo [blnaphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 cm ^{3 of} pyridine. After 3 recrystallizations in a total of 300 cm ^{3 of} dimethylformamide is obtained 0.94 g of 7-fluoro-1-ethyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzolb] naphthyridine-3-carboxylic acid Trihydrate in the form of a yellow solid of melting point 320-322 ° C.

The 8-chloro-7-fluoro-1-ethyl-4-oxo-i ^ -dihydro-ie-benzonaphthyridine-S-carboxylic acid is prepared under the conditions of Example 1, but starting from 10.5 g of S-chloro-fluoro -i-othyl S ethoxycarbonyM-oxo-i ^ -dihydro-ie-benzoIblnaphthyridin.

This gives 9.3 g of e-chloro-7-fluoro-i-ethyl-4-oxo-1,4-dihydro-1, e-benzonaphthyridine-S-carboxylic acid in the form of a beige solid of melting point 38O ⁰ C, which without further Cleaning is used in the later stages.

The e-chloro-fluoro-i-ethyl-S-ethoxycarbonyM-oxo-i ^ -dihydro-d-benzoibnaphthyridine is prepared in the following manner:

In a suspension of 13.5 g of 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 135 cm ^{3 of} ethanol are added within 5 minutes at a temperature between 10 and 15 ° C 16g ethylamine, the temperature is allowed to rise again to about 20 ° C, 0.5g DBU added and heated for 2 hours with stirring to a temperature of near 75 ° C.

After cooling to a temperature of near 20 ° C, the precipitate is centrifuged, washed twice with 100cm ^{3 of} ethanol and twice with 100cm ^{3 of} ethyl ether. 10.4 g of 8-chloro-7-fluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine are obtained in the form of a yellow solid of melting point 300-301 ° C, which is used without further purification in the later stages.

Example 8

The 7-fluoro-1-ethyl-4-oxo-8 · (4-methyl · 1-pipthrazinyl) -1,4-dihydro · 1,8-benzo [b] naphthyrdin-3-carboxylic acid is prepared under the conditions of Example 5, but starting from 1.6 g of e-chloro-fluoroM-ethyl ^ -oxo-M-dihydro-i.ebanzo [b] naphthyridine-3-carboxylic acid and 4.5 g of 1-methyl-piperazine in 16 cm ^{3 of} pyridine. After 4 recrystallizations in a total of 120 cm ^{3 of} dimethylformamide are obtained 1.2 g of 7-fluoro-1-ethyl-4-oxo-8- (4-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzoIbjnaphthyridin-S -carboxylic acid in the form of a yellow solid of melting point 285-286 ⁰ C, which is solvated with 1% water.

Example 9

The y-fluoro-i-methyl-oxo-eO-methyl-1-piperazinyl-1-dihydro-1-benzo-1-naphthyridine-S-carboxylic acid is prepared under the conditions of Example 1 but starting from 2.1 g of 8-chloro -7-fluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in 20 cm ^{3 of} pyridine and 2.4 g of 2-methylpiperazine. After uptake in ethanol and concentration under reduced pressure (2OkPa at 50 ⁰ C) to dryness, the solid residue is taken up in 20 cm ^{3 of} water and 10 cm ³ 2 N-potassium hydroxide. The resulting aqueous solution is washed twice with 20cm ³ trichloromethane, 10cm ³ acetic acid

added and washed twice with 40cm ³ trichloromethane. Are then 23cm ³ 4.5N potassium hydroxide solution added and heated the resulting suspension to a temperature of close to 9O ⁰ C. After cooling to a temperature close to 2O ⁰ C and the precipitate is centrifuged, washed three times with 10 cm ³ of water and twice with 10 cm ³ Washed ethanol. After two recrystallizations in each case 120 cm ³ of dimethylformamide to obtain 1.7 g of 7-fluoro-1-ethyl-4-oxo-8- (3-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b ] naphthyridine-3-carboxylic acid in the form of a yellow dye of melting point 310-312 ⁰ C.

Example 10

The 7-fluoro-1-ethyl-4-oxo-8- (4-ethyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-α-i, arbonsäure is under the conditions prepared from Example 5, but starting from 1.6 g of e-chloro-fluoro-i-ethyl ^ -oxo-i ^ -dihydro-i.ebonzoIb] naphthyridine-3-carboxylic acid in 16 cm ^{3 of} pyridine and 2.3 g of 1-ethyl piperazine. Is ', Ag 7-fluoro-1-ethyl-4-oxo-8- (4-ethyl-i-piperazinyO-i ^ dihydro-ie-benzolblnaphthyridin-S-carboxylic acid in the form of a yellow ι solid of melting point 287th -288 ⁰ C solvated with 1.6% water.

Example 11

The 7-fluoro-1-ethyl-4-oxo-8- [4- (2-hydroxyethyl} -1-piperazinyl] -1,4-dihydro-1,8-benzo (b) naphthyridine-3-one carboxylic acid was prepared under the conditions of Example 5, but starting from 1.6 g of 8-chloro-7-fluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. 3-carboxylic acid in 16 cm ^{3 of} pyridine and 2.6 g of 1- (2-hydroxyethyl) piperazine, giving 1.3 g of 7-fluoro-1-ethyl-4-oxo-8- [4- (2-hydroxybenzoyl) ethyl) -1-piperazinyl] -1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 264-265 ⁰ C.

Example 12

The 7-fluoro-1-methylamino-4-oxo-8- (1-piperaziphenyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5, each Starting with 2.25 g of e-chloro-fluoro-i-methyl-amino-o-oxo-i / 1-dihydro-bisbenzo [b] naphthyridine-3-carboxylic acid in γ, ω ³ -pyridine and 2.4 g piperazine. After three recrystallizations in a total of 400 cm ^{3 of} dimethylformamide is obtained 0.82 g of 7, - 'luor-i-methylamino ^ -oxo-e-li-piperazinyO-i ^ dihydro-he-benzolblnaphthyridin-S-carboxylic acid in the form of a dark' Jen Solid of melting point 322-324 ° C.

The e-chloro-fluoro-i-methylamino ^ -oxo-i ^ -dihydro-diterbenzene-bjnaphthyridine-S-carboxylic acid can be prepared under the following conditions:

A suspension of 16.4 g of e-chloro-fluoro-S-ethoxycarbonyl-i-IN-formyl-N-methyl-amino-M-oxo-i-dihydro-IS-benzo [b] naphthyridine in 164 cm ^{3 of} acetic acid and 164 cm ³ 17.5% hydrochloric acid is heated with stirring for 4 hours to a temperature of near 100 ° C. After cooling to a temperature of near 10 ⁰ C is added between 10 and 2O ⁰ C 165cm ³ 30% sodium hydroxide solution. The product is centrifuged, washed three times with 150 cm ^{3 of} water, three times with 150 cm ^{3 of} ethanol and three times with 150 cm ^{3 of} ethyl ether. This gives 13.64 g of e-chloro-fluoro-i-methylamino ^ -oxo-M-dihydro-bisbenzene bolnaphthyridine-S-carboxylic acid in the form of a yellow solid of melting point 354-356 ° C, which without further purification in the late Stages is used.

The e-chloro-fluoro-S-ethoxycarbonyl-i-IN-formyl-N-methyl-aminole-oxo-i-dihydro-ie-benzo-1-naphthyridine was prepared under the conditions of Example 1, but starting from 19 , 25g of 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester, 4.05g of N-formyl-N-methyl-hydrazine and 1.6g of DBU in 200cm ^{3 of} ethanol. This gives 16.4 g of e-chloro-fluoro-S-ethoxycarbonyl-i-tN-formyl-N-methyl-arninoM-oxo-i ^ dihydro-'le-benzolbJnaphthyridin in the form of a colorless solid of melting point 296-298 ⁰ C. , which is used without further purification in the later stages.

The N-formyl-N-methyl hydrazine can be prepared according to the method described by Carl Th. Pederers Acta Chem. Scand., 18 (9), 2199 (1964).

Example 13

The 7-fluoro-1-methylamino-4-oxo-8- (4-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under analogous conditions as in Example 1, but starting from 1.93 g of e-chloro-fluoro-methylamino ^ -oxo-i ^ - dihydro-benzo [b] naphthyridine-3-carboxylic acid in 20 cm ^{3 of} pyridine and 2.4 g of 1-methyl-piperazine. After two recrystallizations in 15 cm ^{3 of} dimethylformamide is obtained 0.9 g of 7-fluoro-1-methylamino-4-oxo-8- {4-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b ] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 263-264 ° C.

Example 14

The 7-fluoro-1-methylamino-4-oxo-8- (3-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5, but starting from 3.2 g of 8-chloro-7-fluoro-1-methylaminoM-oxo-M-dihydro-i, 8-benzoIb) naphthyridine-3-carboxylic acid and 4 g of 2-methyl-piperazine in 40 cm ^{3 of} pyridine. The crude product obtained is taken up ³ of water and 7 cm ³ of 2N potassium hydroxide solution in 30 cm. A very small insoluble fraction is removed by filtration over diatomaceous earth. The filtrate is washed twice with 20 cm ³ of ethyl ether, and then is precipitated by addition of 3.5 cm ³ of 4N methanesulfonic acid. The resulting precipitate is centrifuged, washed three times with 20 cm ^{3 of} water and three times with 20 cm ^{3 of} ethanol. This gives 2.2 g of 7-fluoro-1-methylamino-4-oxo-8- (3-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo (b] 3-carboxylic acid in the form of a dark yellow Solid of melting point 343-345 ° C, which is solvated with 3.7% water.

Example 15

The 7-fluoro-1-cyclopropyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzo [b] niphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1 g of 8-chloro-7-fluoro-1-cyclopropyl-4-oo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.6 g of piperazine in 10 cm ^{3 of} pyridine. .vian receives 0.6 g of 7-fluoro-1-cyclopropyl-m-oxo-e-tipiperazinyl-di-dihydro-he-benzol-naphthyridine-S-carboxylic acid dihydrate as a yellow solid of melting point

The 8-chloro-7-fluoro-1-cyclopropyl-oxy-1,4-dihydro-1, e-benzene-1-naphthyridine-S-carboxylic acid is prepared under the conditions of Example 1, but starting from e.ige-chloro-fluoro i-cyclopropyl-S-ethoxycarbonyl ^ -oxo-M-dihydro-ie-benzo-

lblnaphthyridin. This gives 4.85 g of 8-chloro-7-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 33O ⁰ C. , which is used without further purification in the later stages. The e-chloro-T-fluoro-i-cyclopropyl-S-ethoxycarbonyl ^ -oxo-i ^ -dihydro-he-benzolblnaphthyridine is prepared under the following conditions:

A solution of 20.8 g of 2- {2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester and 6 g of cyclopropylamine in 100 cm ³ of trichloromethane is stirred at a temperature of 20 ° C for 24 hours , The reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of 50 ⁰ C. The residue is taken up in 180 cm ³ of ethanol and 10 g of DBU and the resulting solution heated for 4 hours to a temperature of close to 78 ⁰ C. After cooling to a temperature of near 20 ° C, the precipitate obtained is centrifuged and washed twice with 60cm ^{3 of} ethanol. 13,65g is obtained 8-chloro-7-fluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a pale yellow solid of melting point 256 ⁰ C , which is used without further purification in the later stages.

Example 16

The 7-fluoro-1-cyclopropyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5, but starting from 1 g of S-chloro-fluoro-i-cyclopropyl ^ -oxo-i, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 3 g of 1-methyl-piperazine in 10 cm ³ Pyrid.n. Recrystallization in 10 cm ^{3 of} dimethylformamide gives 0.63 g of 7-fluoro-1-cyclopropyl-8 (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. 3-carboxylic acid in the form of a ge'ban solid of melting point 25O ⁰ C.

Example 17

The 7-fluoro-1-cyclopropyl-4-oxo-8- (3-methyl-1-piperazinyl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1, but starting from 1 g of e-chloro-fluoro-i-cyclopropyl ^ -oxo-i ^ -dihydro-IS-benzo [b] naphthyridine-3-carboxylic acid and 3g of 2-methyl-piperazine in 10 cm ^{3 of} pyridine. Dar crude product is obtained after additional purification by recrystallization in 200cm ³ of dimethylformamide. 0.5 g of 7-fluoro-1-cyclopropyl-4-oxo-8- (3-methyl-1-piperazinyl-1H-dihydro-1-benzo-1-naphthyridine-S-carboxylic acid hemihydrate in the form of a yellow solid of melting point 343 is obtained ° C.

Example 18

The 7-fluoro-1-cyclopropyl-4-oxo-8- (4-ethyl-1-piperazinyl) -1,4-dihydro-1,8-benzeneb naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 2 g of 8-chloro-7-fluoro-1-cyclopropyl-m-oxo-i-dihydro-i, 8-benzo / b / naphthyridine-3-carboxylic acid and 2.74 g of 1-ethylpiperazine in 20 cm ³ Pyi idin. The pure product is isolated after a first recrystallization in 105cm ^{3 of} ethanol containing 25% dimethylformamide followed by a second recrystallization in 75cm ^{3 of} ethanol containing 50% dimethylformamide. This gives 0.67 g of 7-fluoro-1-cyclopropyl-4-oxo-8- (4-ethyl-1-piperazinyl) -1,4-dihydro-ie-benzolblnaphthyridin-S-carboxylic acid in the form of a yellow-green solid of melting point 254th ⁰ C.

Example 19

The 7-fluoro-1-cyclopropyl-4-oxo-8- [4- (2-hydroxy-ethyl) -1-piperazinyl-1,4-dihydro-1,8-benzeneb naphthyridine-3-carboxylic acid is added under the conditions prepared from Example 5, but starting from 4g e-chloro-fluoro-i-cyclopropyl ^ -oxo-i ^ - dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 6,2g1- (2-hydroxy-ethyl ) -piperazine in 40cm ^{3 of} pyridine. The reaction mixture is heated for 22 hours to a temperature of 115 ° C. The pure product is isolated after three recrystallizations in three times 200 cm ^{3 of} ethanol, each containing 10% of dimethylformamide, giving 0.94 g of 7-fluoro-1-cyclopropyl 4-oxo-8- [4- (2-hydroxy-ethyl) -1-piperazinyl] -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of mp 255 ⁰ C.

Example 20

The 7-fluoro-1-tert-butyl-4-oxo-8- (1-piperazinyl! -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.7 g of e-chloro-fluoro-i-tert.-buty-W-oxo-i-dihydro-IS-benzolblnaphthyridine-S-carboxylic acid and 4.3 g of piperazine in 20 cm ^{3 of} pyridine single recrystallization in 20 cm ^{3 of} dimethylformamide, isolating 1.25 g of 7-fluoro-tert-butyl-4-oxo-8- (1-piperazinyl) -1,4-dihydro-1,8-benzo (b) naphthyridine-3 Carboxylic acid in the form of a yellow solid of melting point 29O ⁰ C, which solvated with 4.5% water.

The 8-chloro-7-fluoro-tert-butyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid can be prepared in the following manner:

A suspension of 1.88 g of e-chloro ^ -fluoro-i-tert-butyl-S-ethoxy-carbonyM-oxo-i ^ -dihydro-ie-benzolblnaphthyridin is in 10cm ³ of ethanol, 5 cm ³ of water and 15 cm ³ of 2N potassium hydroxide solution with stirring for one hour to a temperature of near 75 ⁰ C heated. To the resulting solution is then added 2 cm ^{3 of} acetic acid. The precipitate formed is centrifuged, washed three times with 10 cm ^{3 of} water and three times with 10 cm ^{3 of} ethanol. After recrystallization in 50 cm ^{3 of} dimethylformamide, 1.7 g of e-chloro-fluoroM-tert-butyl-oxo-i-dihydro-ie-benzenebnaphthyridine-S-carboxylic acid are obtained in the form of a yellow solid of melting point 398.degree.

The e-chloro-fluoro-i-tert-butyl-S-ethoxycarbonyl-i-dihydro-ie-benzolblonaphthyridine is prepared under the conditions of Example 17, except starting from 8.86 g of 2- (2,7-dichloro) 6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester and 4,03g of t-butylamine in 45 cm ³ of trichloromethane and then in 4,53g DBU and 45cm ³ of ethanol. This gives 5 g of e-chloro-fluoro-i-tert-butyl-S-ethoxycarbonyM / l-dihydro-he-benzolblnaphthyridin in the form of a yellow solid of melting point 239 ⁰ C.

Example 21

A suspension of 2 g of e-chloro-fluoro-i-methyl-oxo-i-dihydro-ie-benzolblonaphthyridine-S-carboxylic acid in 7.44 g of 2,2-dimethylpiperazine and 20 cm ^{3 of} pyridine is heated to a temperature of 44.degree heated to near 115 ° C. The reaction mixture is concentrated to dryness under reduced pressure (2OkPa) at a temperature of about 60'C. The residue is in

50cm ^{3 of} ethanol and concentrated again under reduced pressure and the above conditions. The solid obtained is taken up in 50 cm ³ Ethyfester, centrifuged, washed twice with 30 cm ³ of the same solvent and added to ³ of water and 2g Methansulfonsa'ure in 120cm. A very small insoluble portion is removed by filtration over diatomaceous earth. Then the resulting solution 2 -: m ³ 50% potassium hydroxide solution is added. The precipitate formed is filtered, washed three times with 25 cm ³ of water and once with 50 cm ³ of ethanol of about 50 ⁰ C. This gives 1.6 g of 7-fluoro-1-methyl-8- (3 _l 3-dimethyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 362-365 ° C, which colvated with 4.9% water.

Example 22

A suspension of 1.2 g of 8-chloro-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in 3, 52 g of 1-methyl-piperazine and 12 cm ^{3 of} pyridine is heated with stirring to a temperature of near 11O ⁰ C for 6 hours. The reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of about 6O ⁰ C. Then the residue is taken up in 15 cm ^{3 of} water and ² cm ^{3 of} acetic acid. A small amount of insoluble matter is removed by filtration over diatomaceous earth. Then 6 cm ^{3 of} 20% potassium hydroxide solution are added to the filtrate, and again a very small insoluble fraction is removed by filtration through diatomaceous earth. Subsequently, the filtrate 0.6 cm ^{3 of} acetic acid

added. The resulting precipitate is centrifuged, washed twice with 5 cm ^{3 of} water and twice with 5 cm ^{3 of} ethanol and recrystallized twice in 10 cm ^{3 of} dimethylformamide. 6 g of 7-fluoro-1- (2-fluoroethyl) -8- (4-methyl-1-piperazinyl) -4-oxo-1, .Vihydro-1,8-benzo | naphthyridine are obtained. 3-carboxylic acid in the form of a yellow solid of melting point

The 8-chloro-7-fluoro-1- (2-fluoro-etiiyl) -4-oxo-1,4-dihydro-1,8-benzo [naphthyridine-3-carboxylic acid was prepared under the conditions of Example 26, but starting from 2.2 g of 8-chloro-7-fluoro-3-ethoxycarbonyl-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. After two recrystallizations in 10 cm ^{3 of} dimethylformamide each gives 1.4 g of 8-chloro-7-fluoro-1 (2-fluoro-ethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridin 3-carboxylic acid in the form of a yellow solid of melting point

The chloro-7-fluoro-3-ethoxycarbonyl-1- (2-fluoro-ethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] -naphthyridine is prepared in the following manner :

To a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm ^{3 of} trichloromethane is added 2.7 cm ^{3 of} triethylamine.

To the resulting solution is added 3.5 g of 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester at about 2O ⁰ C. After 16 hours of stirring at this temperature the solution under reduced pressure (2OkPa) at about 5O ⁰ C is concentrated to dryness. The residue is taken up in 20 cm ^{3 of} ethanol and ³ cm ^{3 of} triethylamine and heated with stirring to about 75 ° C for 2 hours. After cooling to about 2O ⁰ C, the insoluble fraction is centrifuged, washed twice with 10 cm ³ of ethanol and twice with 10 cm ³ of isopropyl ether. This gives 1.9 g of 8-chloro-7-fluoro-3-ethoxycarbonyl-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a yellow solid of melting point 268 ° C, which is used without further purification in the later stages.

Example 23

A suspension of 2 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in 2.8 g of piperazine and 40 cm ³ of dimethyl sulphoxide is 15 minutes stirred at a temperature of near 4O ⁰ C. After cooling to about 20 ° C, the reaction mixture is poured into 150cm ^{3 of} water and it 27.75 cm ³ 2 N-methanesulfonic acid are added. A very small insoluble portion is removed by filtration over diatomaceous earth. Then, to the resulting solution, 15 cm ³ of 2N potassium hydroxide solution are added. The precipitate formed is filtered, washed three times with 15 cm ³ of water was added to 100cm ³ of dimethylformamide and heated with stirring for 10 minutes at a temperature of close to 150 ⁰ C. The suspension is cooled to about 100 ° C, the insoluble fraction is centrifuged, taken up in 100 cm ^{3 of} ethanol and heated again to a temperature of 75 ° C for one hour. The insoluble fraction is centrifuged at 5O ⁰ C and washed with 40 cm ³ of the same solvent at the same temperature as before. This gives 1.8 g of 7-fluoro-1-methoxy-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a brown solid from Melting point 298-300 ° C, which solvated with 2.4% water.

The 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzeneb naphthyridine-3-carboxylic acid is prepared under the following conditions:

A suspension of 2.78 g of 7,8-difluoro-1-methoxy-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine in 30 cm ^{3 of} 17.5% hydrochloric acid and 30 cm ³ Acetic acid is heated for one hour to a temperature of close to 100 ° C. After cooling to about 20 ° C., the reaction mixture is poured into 100 cm ^{3 of} water The precipitate formed is centrifuged, washed three times with 30 cm ^{3 of} water and twice with 5 cm ^{3 of} ethanol After recrystallization in 100 cm ^{3 of} dimethylformamide containing 20% of ethanol, 2.03 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. 3-carboxylic acid in the form of a yellow solid of melting point 325-327 ⁰ C,

The 7,8-difluoro-1-methoxy-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared under the following conditions:

To a suspension of 1.7 g of methoxylamine hydrochloride in 40 cm ^{3 of} trichloromethane is added 2.13 g of triethylamine. After stirring for 15 minutes at a temperature of close to 2O ⁰ C was added 2- (2-chloro-6,7-difluoro-3-chinolincarbonyD-S-methylamino-acrylic acid ethyl ester 3,69g to the resulting solution and a further 4 '/ Stirring hours at about 2O ⁰ C. The reaction mixture is concentrated to dryness under reduced pressure (2OkPa) at a temperature of near 50 ° C.

The residue is taken up in 70 cm ^{3 of} ethanol and 3.6 g of triethylamine and heated to a temperature of near 75 ° C. for 30 minutes. After cooling to about 2O ⁰ C, the residue obtained is centrifuged and washed three times with 30cm ^{3 of} ethanol. This gives 2.67 g of 7,8-difluoro-1-methoxy-S-ethoxycarbonyM-oxo-i ^ dihydro-i, 8-benzo (b) naphthyridine in the form of a pale yellow solid of melting point 766-268 ⁰ C.

The 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester is prepared in the following manner:

A suspension of 6,17g 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester in 7,15g Ν, Ν-dimethylformamide dimethyl acetal and 60 cm ³ of ethyl acetate is 1 hour 15 minutes heated to a temperature of near 75 ⁰ C. The

Reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of about 5O ⁰ C to dryness.

The residue is taken up in 50 cm ^{3 of} isopropyl ether, centrifuged and washed three times with 25 cm ^{3 of} the same solvent. This gives 6.65 g of 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in the form of an orange solid of melting point 140 ° C.

The 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester is prepared in the following manner:

A suspension of 14.13 g of 2-chloro-6,7-difluoro-quinulin-3-carboxylic acid in 29 cm ^{3 of} thionyl chloride and 220 cm ^{3 of} trichloromethane is heated for 4 hours to a temperature of close to 60 ° C. The solution obtained is then concentrated under reduced pressure print

(2OkPa) at a temperature of about 60 ° C to dryness. The residue obtained is taken up in 75 cm ^{3 of} n-hexane, centrifuged and washed twice with 60 cm ^{3 of} the same solvent. The resulting 14.4 g of yellow solid are suspended in 115 cm ^{3 of} tetrahydrofuran. This solution is added dropwise with stirring and within 35 minutes at a temperature between 5 and 1O ⁰ C in 70 cm ³ of a solution of ethyl-magnesium chelate Monomalonsäure in tetrahydrofuran, prepared under the conditions described below. The temperature is allowed to rise again to about 20 ° C and stirred for 2 hours under these conditions. The resulting solution is then added dropwise with stirring and within 30 minutes at a temperature of near 5 ° C in 560cm ³ 0.5 N sulfuric acid. Allowing the temperature of the suspension obtained at 2O ⁰ C and stirred for a further increase 1 '/ 2 hours at this temperature. Then it is extracted three times with 250 cm ^{3 of} ethyl acetate. The combined organic extracts are washed twice with 250 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a

Temperature of 50 ° C concentrated to dryness. The residue obtained is taken up in 50 cm ³ η-hexane containing 20% isopropyl ether, centrifuged, washed with 10 cm ³ of the same mixture and in 60 cm ³ of isopropanol containing 30% n-hexane recrystallized. This gives 11.84 g of 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester in the form of a cream-colored solid of melting point 107 ° C.

Preparation of monomalonic acid ethylester magnesium chelate:

To 2.78 g of magnesium turnings are added successively ² cm ^{3 of} absolute ethanol, 0.1 cm ^{3 of} tetrachloromethane and 1 g of monomalonic acid ethyl ester. After heating, a solution of 9 g Monomalonsäureethyiester in 180cm ^{3 of} ethanol is added within 15 minutes. The mixture is heated for 20 hours at a temperature of close to 75 ° C and under reduced pressure (2OkPa) concentrated at a temperature of 5O ⁰ C. The residue is taken up twice in 100 cm ³ of toluene and concentrated under reduced pressure and the same conditions as before. The resulting gray powder is brought into solution by adding anhydrous tetrahydrofuran to give a total volume of 70 cm ³ .

The 2-chloro-6,7-difluoro-quinoline-3-carboxylic acid was prepared in the following manner:

To a suspension of 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydro-quinoline in 970 cm ³ N-potassium hydroxide, cooled to a temperature of 10 ⁰ C, are added within one hour While stirring, a solution of 115g of potassium permanganate in 1.215 liters of water is maintained, maintaining the temperature between 10 and 14 ° C. Then the temperature is allowed to rise to 20 ⁰ C and stirred for 30 minutes at this temperature. Add 38.5 g of sodium dithionite, stirred for 10 minutes at a temperature of near 20 ⁰ C, filtered through diatomaceous earth and washed three times with 200cm ^{3 of} water. The filtrate and aqueous washings are combined and 140 cm ^{3 of} 35% hydrochloric acid added. Then, the precipitate formed is extracted four times with 800cm ^{3 of} ethyl acetate. The combined organic extracts are washed twice with 500 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a temperature of 5O ⁰ C. The residue is taken up in 400 cm ^{3 of} ethyl ether, centrifuged and washed twice with 200 cm ^{3 of} the same solvent. This gives 49.2 g of 2-chloro-6,7-difluoro-quinoline-3-carboxylic acid in the form of a beige solid of melting point 232 ° C, which is used without further purification in the later stages.

The 2-chloro-6,7-difluoro-3-formyl-1,4-dihydro-quinoline was prepared in the following manner:

To a mixture of 800cm ³ trichloromethane and 74.35cm ³ dimethylformamide is added within 30 minutes with stirring and at a temperature between 10 and 15 ° C 76.9cm ³ phosphoryl chloride and stirred for one hour at a temperature of near 20 ° C. , 65.8 g of 6,7-difluoro-3,4-dihydro-carbostyril are added to the resulting solution over 10 minutes at about 20 ° C. with vigorous stirring. The resulting suspension is heated to a temperature near 6O ⁰ C and kept at this temperature for 2 hours. Then, the reaction mixture is concentrated under reduced pressure (2OkPa) at a temperature of 50 ⁰ C until a pasty mixture is present. With vigorous stirring, a mixture of 500g of ice and 500cm ^{3 of} water is added. The solid obtained is centrifuged at a temperature of about 5 ⁰ C and washed three times with 300 cm ³ Wassor of 5 ° C. The resulting moist product and 60 g of sodium acetate are added simultaneously over one hour to 1.5 liters of water at 90 ° C in such a way that the pH is maintained at about 6. The mixture is stirred for 30 minutes at 90 ° C, the temperature is allowed to drop to near 50 ⁰ C, centrifuged at this temperature and washed three times with 300cm ^{3 of} water of about 2O ⁰ C. This gives 70.18g 2-chloro-6.7 -difluoro-3-formyl-1,4-dihydro-quinoline in the form of a yellow solid of melting point 260 ⁰ C, which is as it is used in the later stages.

The 6,7-difluoro-3,4-dihydro-carbostyril is obtained in the following manner:

To 67 g of 3 ', 4'-difluoro-3-N-chloro-propionanilide is added with vigorous stirring 134g of aluminum chloride and then, after about two minutes, of ne.'om in small fractions within 15 minutes 135.9 g 3' , 4'-Difluoro-3-N-chloro-propionanilide and 272g of aluminum chloride. The temperature rises by itself to about GO ⁰ C and the reaction mixture liquefies. The mixture is then heated for a further 20 minutes at 110 ° C. and the temperature is maintained between 110 and 12O ⁰ C for a period of hours. Thereafter, the reaction mixture is stirred at about 110 ° C. within 10 minutes with vigorous stirring into a mixture of 840 cm ³ 35%. iger hydrochloric acid and 1 kg of crushed ice poured. The temperature is allowed to rise to about 20 ⁰ C, centrifuged, washed with 600cm ^{3 of} water, twice with 300cm ^{3 of} ethanol of 5 ⁰ C and twice with 400cm ³ ethyl ether of about 2O ⁰ C. This gives 131.58g 6,7-difluoro -3,4-dihydro-carbostyril in the form of a beige solid of melting point 216 ⁰ C, which is used as it is in the later stages.

The 3 ', 4'-difluoro-3-N-chloro-propionanilide is prepared in the following manner:

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 of 55 ° C, are added with vigorous stirring within 90 minutes 139.16g S-chloro-propionic acid chloride and keeps this temperature up for another 90 minutes. After cooling to about 20 ⁰ C, the solution is thrust in a mixture of 1 liter of water and 500g *. Poured ice. The temperature is allowed to rise to about 20 ° C and extracted three times with 500cm ³

Dichloromethane. The combined organic extracts were washed with 500 cm ³ N hydrochloric acid and five times with 500 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a temperature of about 50 ° C. The solid obtained is taken up in 500 cm ^{3 of} η-hexane, centrifuged and washed twice with 100 cm ^{3 of} the same solvent. This gives 202.9 g of 3 ', 4'-difluoro-3-N-chloro-propii.iianilid in the form of a beige solid of melting point 76 ⁰ C, which is used without further purification in the later stages.

Example 24

A suspension of 0.93 g7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [blnaphthyridin-3-carboxylic acid in 0.6 g of 1-methylpiperazine and 20 cm ³ of dimethyl sulphoxide is Heated to a temperature of near 8O ⁰ C for 5 minutes. After cooling to about 20 ^° C., the reaction mixture is poured into 30 cm ^{3 of} water, 1.5 cm ^{3 of} 2N-methanesulfonic acid are added, centrifuged and washed three times with 5 cm ^{3 of} water. After recrystallization in 30 cm ^{3 of} dimethylformamide containing 30% of ethanol, 0.55 g of 7-fluoro-1-methoxy-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydric acid are obtained. 1.8-benzo | b) naphthyridine-3-carboxylic acid in the form of a brown solid of melting point 27O ⁰ C.

Example 25

A suspension of 0.47 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 7 cm ³ Dimethylsufoxide is heated for 15 minutes to a temperature of close to 80 ° C. Then, the reaction mixture is poured into 25 cm ^{3 of} water and added 9 cm ³ N hydrochloric acid. The resulting solid is centrifuged and washed three times with 5 cm ^{3 of} water. Recrystallization in a mixture of 4.5 cm ^{3 of} ethanol and 4.5 cm ^{3 of} dimethylformamide gives 0.29 g of 7-fluoro-1-cyclopropyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4 -dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 25O ⁰ C.

The 7,8-difluoro-1-cyclopropylM-oxo-i-dihydro-i, 8-benzo [b] naphthyridine-3-carboxylic acid can be prepared in the following manner:

A suspension of 1.95 g of 7,8-difluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 20 cm ^{3 of} 17.5% hydrochloric acid and 20 cm ³ acetic acid is heated for 90 minutes to a temperature of near 100 ⁰ C. After cooling to about 2O ⁰ C, the reaction mixture in 100cm ³ of water gegosse n. The precipitate is centrifuged and washed three times with 20 cm ³ of water. After recrystallization in a mixture of 30 cm ^{3 of} dimethylformamide and 30 cm ^{3 of} ethanol, 1.31 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. 3-carboxylic acid in the form of a yellow solid of melting point 284-285 ° C.

The 7,8-difluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared in the following manner and

Way made:

A suspension of 5.27 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-cyclopropylaminoacrylate in 2.22 g of 1,8-diazabicyclo / 5.4.0 / -7-undocene ( DBU) and 120 cm ³ of ethanol is heated with stirring to a temperature of close 7UE ° C for 35 minutes. After cooling to about 20 ⁰ C, the reaction mixture is taken up in 100cm ^{3 of} water and extracted once with 100cm ³ and twice with 50cm ³ trichloromethane. The combined organic extracts are washed three times with 50 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a temperature of close to 20 ⁰ C and concentrated. The resulting dry extract is taken up in 30 cm ^{3 of} isopropyl ether, centrifuged and recrystallized in a mixture of 75 cm ^{3 of} ethanol and 75 cm ^{3 of} dimethylformamide. This gives 3.57 g of 7,8-difluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a yellow solid of melting point 229 to

The 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-cyclopropylamino-acrylic acid ethyl ester is prepared in the following manner:

A solution of 6,25g 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 2.91 g of cyclopropylamine and 25cm ³ trichloromethane is for 3 hours at a temperature of 2O ⁰ C stirred. Then the reaction mixture under reduced pressure (2OkPa) is concentrated at a temperature of close to 50 ⁰ C. The dry extract is taken up in 50 cm ^{3 of} isopropyl ether, centrifuged and then washed with 20 cm ^{3 of} the same solvent.

This gives 5.27 g of 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-cyclopropylamino-acrylic acid ethyl ester in the form of an orange solid of melting point 116-117 ° C. This product is used in the later stages without further purification.

Example 26

A suspension of 4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid in 60 cm ^{3 of} dimethyl sulfoxide and ³ g of 1-methylpiperazine is heated to a temperature of 8O ⁰ C for 90 minutes. After cooling to about 20 ⁰ C are employed 150cm ³ water is added. Then, to the solution obtained, 18 cm ³ of 10% strength acetic acid are added. the precipitate formed is filtered, washed three times with 50 cm Washed ³ water and recrystallized in 50cm ^{3 of} dimethylformamide.

This gives 4 g of 7,9-difluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow dye of melting point 316 ^° C.

The 7,8,9-trifluoro-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared in the following manner:

A suspension of 4 g of 7,8,9-trifluoro-1-methyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine in 30 cm ^{3 of} acetic acid and 30 cm ^{3 of} 50% hydrochloric acid is heated to a temperature of close to 100 ⁰ C for 2 hours. After cooling to about 20 ° C are added 100 cm ³ of water is added. The precipitate formed is filtered, washed three times with 50 cm ³ of water and recrystallized in 80 cm ³ of dimethylformamide. This gives 3 , 4g 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzolb] naphthyridine-3-carboxylic acid in form of a colorless solid of melting point 350-352 ⁰ C.

The 7,8,9-trifluoro-1-methyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared in the following manner in r " 3.

In sine suspension of 19.3g 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 150cm ^{3 of} ethanol, kept at a temperature of 5 ⁰ C, one carries within 10 minutes and stirring at a temperature between 5 and 10 ° C, a cooled to 5 ⁰ C solution of 10g methylamine in 50cm ^{3 of} ethanol, stirred for one hour at a

Temperature between 5 and 10 ⁰ C and then let the temperature rise again to about 2O ⁰ C. Are added 7.6 g of the obtained solution DBU and heated to about 3O ⁰ C for one hour. After cooling to a temperature close to 20 ⁰ C, the product is centrifuged, washed twice with 100 cm ³ of ethanol and twice with 100 cm ³ isopropyl ether. This gives 13.4 g of 7,8,9-trifluoro-methyl-S-ethoxycarbonyM-oxo-M-dihydro-i, 8-benzo [b] naphthyridine in the form of a yellow solid of melting point 320 ⁰ C, which without further purification in the later stages is used.

The 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester can be prepared in the following manner:

A suspension of 26.7 g of 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) - 'l-oxo-propionic acid ethyl ester in 270 cm ^{3 of} ethyl acetate and 32 cm ³ Ν, Ν-dimethylformamide dimethyl acetal is added Stirred to a temperature of near 75 ° C for 2 hours. Then the reaction mixture under reduced pressure (2OkPa) at a temperature of about 5O ⁰ C is concentrated to dryness. The dry extract is taken up in 175 cm ^{3 of} isopropyl ether, centrifuged and washed twice with 85 cm ^{3 of} the same solvent. This gives 19.32g 2- (2-chloro-6,?, 8-trifluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in the form of an orange solid of melting point 118 ⁰ C, which without further purification in the later Stages is used.

The 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) -3-oxo-propionic acid ethyl ester is prepared in the following manner: A suspension of 46.3 g of 2-chloro-6,7 , 8-i: rifluor-quinoline-3-carboxylic acid in 640cm ³ trichloromethane and 84cm ³ of thionyl chloride is heated under stirring for 6 hours to a temperature of close to 60 ° C. Then, the resulting solution is concentrated under reduced pressure (2OkPa) at a temperature of about 5O ⁰ C to dryness. The resulting dry extract is taken up in 140 cm ³ petroleum ether (40-60), centrifuged and washed twice with 60 cm ^{3 of the} same solvent. The resulting 47.61 g of yellow solid are dissolved in 400 cm ^{3 of} tetrahydrofuran. This solution is added dropwise with stirring within 90 minutes and be! a temperature between 5 and 10 ° C in 250cm ^{3 of} a solution of monomalonic acid ethyl ester magnesium chelate in tetrahydrofuran, which was prepared under the conditions of Example 23. The temperature is allowed to rise to about 20 ° C and stirred for 2 hours under these conditions. Subsequently, the solution obtained is added dropwise with vigorous stirring, within one hour and at a temperature of near 5 ° C, in 1750cm ³ O, 5N sulfuric acid. The mixture is stirred for a further 7 hours at this temperature and extracted at about 5 ° C three times with 600cm ^{3 of} ethyl ether. The combined organic phases are washed three times with 500 cm ^{3 of} water, dried over magnesium sulfate and concentrated under reduced pressure (2OkPa) at a temperature of near 30 ° C. The dry extract is taken up in a mixture of isopropyl ether and 135 cm ³ 15 cm ³ η-hexane, centrifuged at approximately 5 ⁰ C and washed twice with 115 cm ³ of the same mixture at the same temperature. This gives 47.4 g of 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) -3-o: (0-propionic acid ethyl ester in the form of a beige solid of melting point 78-8O ⁰ C, without Further purification is used in the later stages The 2-chloro-6,7,8-trifluoro-c'ainoline-3-carboxylic acid is prepared in the following manner:

To a suspension of 45 ⁷ g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydro-quinoline in 585cm ³ N potassium hydroxide solution, cooled to a temperature of about 10 ° C, is added under stirring within one hour at 10 to 14 "C, a solution of potassium permanganate 69,65g in 730cm ³ of water. Then the mixture is stirred for 30 minutes at about 10 ⁰ C. it 12g adds sodium dithionite, stirred for 10 minutes at a temperature of close to 10 ⁰ C, filtered through diatomaceous earth and washed three times with 400 cm ³ of water. the Ritrat and washings are combined and added to 70 cm ³ of 35% hydrochloric acid. the precipitate formed is extracted three times with 500 cm ³ of ethyl acetate. the combined organic extracts are dried, filtered and concentrated under reduced pressure (2OkPa) at a temperature of 5O ⁰ C over magnesium sulfate and concentrated. the residue is dissolved in a mixture of 100 cm ³ of ethyl ether and isopropyl ether was added to 100cm ^3, centrifuged and washed with 100 cm ³ of the same mixture g . ewaschen obtained 46,43g 2-chloro-6,7,8-trifluoro-quinoline-3-carboxylic acid in form of a colorless solid which decomposes at 225-23O ⁰ C and which is used without further purification in the later stages , The 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydro-quinoline is prepared in the following manner: To a mixture of trichloromethane and 525cm ³ 49cm ³ of dimethylformamide is added over 40 minutes with stirring and at a temperature between 5 and 1O ⁰ C 50cm ³ of phosphoryl chloride is stirred for 15 minutes at this temperature and the temperature is allowed to rise to about 2O ⁰ C. To the resulting solution is added over 20 minutes at about 20 ° C in succession, with vigorous stirring 46.8g ej.e-trifluoro-SAdihydro-carbostyril. The mixture is stirred for 30 minutes at a temperature of near 2O ⁰ C and keeps the mixture after heating to 60 ⁰ C for 2'Λ hours at this temperature. Then the reaction mixture under reduced pressure (2OkPa) is concentrated at a temperature of about 5O ⁰ C. The oily residue is then poured into 500 g F.is with vigorous stirring. Thereafter, 100 g of sodium acetate are added in small fractions within 30 minutes. The suspension obtained is then poured over 15 minutes with vigorous stirring in 1 liter of water, which was previously heated to about 9O ⁰ C and stirring is continued for another 15 minutes at this temperature. The insoluble fraction is centrifuged at about 90 ⁰ C and washed three times with 250 cm ^{3 of} water. This gives 47.7 g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydro-quinoline in the form of a colorless solid which decomposes at 22O ⁰ C. The 6,7,8-trifluoro-3,4-dihydro-carbostyril is prepared in the following manner:

24.35g 6,7,8-trifluoro-carbostyril in suspension of a mixture of 450cm ^{3 of} ethanol and 150cm ^{3 of} dimethylformamide are stirred at about 50 ⁰ C in the presence of 5g Raney nickel at a pressure of 1 atmosphere until the completion of the hydrogen -Absorption hydrogenated. The used Raney nickel of quality W-2 is washed in advance with 50cm ³ 2% acetic acid, twice with 50cm ^{3 of} water and three times with 50cm ^{3 of} ethanol. Then the reaction mixture 250 cm ³ of dimethylformamide is added and the mixture is filtered at about 5O ⁰ C over diatomaceous earth. The filtrate is concentrated under reduced pressure (2OkPa) at a temperature of about 70 ⁰ C. The dry extract is taken up in 150 cm ^{3 of} water, centrifuged and washed twice with 50 cm ^{3 of} water. This gives 23.6 g ej.e-trifluoro-S ^ dihydro-carbostyril in the form of a pale beige solid of melting point 217 ⁰ C, which is used without further purification in the later stages. The 6,7,8-trifluoro-carbostyril is prepared in the following manner:

60.83 g of 4-chloro-6,7,8-trifluoro-carbostyrii in a suspension of 520 cm ^{3 of} acetic acid and 38.15 cm ^{3 of} triethylamine under a pressure of 1 atmosphere in the presence of 5.25 g of 10% palladium carbon until the end of the Hydrogen absorption at a temperature of near 25 ⁰ C hydrogenated. The crude mixture is then heated to 4OX and filtered through diatomaceous earth for filtration at the same temperature. The filtrate is concentrated under reduced pressure (2OkPa) at a temperature close to 5O ⁰ C. The dry extract is taken up in 400 cm ^{3 of} water; the insoluble fraction is centrifuged,

washed four times with 170 cm ^{3 of} water, twice with 110 cm ^{3 of} ethanol and twice with 100 cm ^{3 of} isopropyl ether. This gives 48.35g 6,7,8-trifluoro-carbostyril in the form of a colorless solid which is sublimed at 288 ⁰ C and used without further purification in the later stages.

The 4-chloro-6,7,8-trifluoro-carbostyril is prepared in the following manner:

A suspension of 70.4 g of 4-chloro-6,7,8-trifluoro-2-ethoxy-quinoline in 170 cm ^{3 of} 35% hydrochloric acid, 420 cm ^{3 of} acetic acid and 250 cm ^{3 of} water with stirring for 2 '/ 2 hours to a temperature heated from near 100 ° C. After cooling to about 2O ⁰ C, the reaction mixture is poured into 1100 cm ^{3 of} water at 5 ⁰ C, stirred for 15 minutes at this temperature, and then centrifuged the insoluble portion and washed three times with 220cm ^{3 of} water. This gives 61 g of 4-chloro-6,7,8-trifluoro-carbostyril in the form of a cream-colored solid of melting point 213 ⁰ C, which is used without further purification in the later stages.

The 4-chloro-6,7,8-trifluoro-2-ethoxy-quinoline is prepared in the following manner:

A suspension of 69.5 g ej.e-trifluoro-i-ethoxy ^ -hydroxy-quinoline in 430 cm ^{3 of} phosphoryl chloride is heated with stirring to a temperature of 100 ⁰ C for 30 minutes. The resulting solution is under reduced pressure (2OkPa) konzentriort at a temperature of about 60 ⁰ C to a volume of 100 ⁰ C. Thereafter, the residue is taken up in 750 cm ^{3 of} ethyl acetate and the resulting solution is poured into a mixture of 400 cm ^{3 of} water and 200 g of ice with stirring over 10 minutes, after which stirring is continued for 30 minutes under these conditions. After separation of the organic extract, the aqueous phase is re-extracted twice with 250 cm ^{3 of} ethyl acetate. The combined organic extracts are washed three times with 250 cm ³ of water, dried over magnesium sulfate and concentrated under reduced pressure (20 kPa) at a temperature of about 4O ⁰ C and concentrated. The oily oily residue is taken up in 370 cm ³ Potrolether (40-60).

After filtration through diatomaceous earth, the filtrate is concentrated under reduced pressure (2OkPa) at a temperature of about 3O ⁰ C to dryness. One obtains 70,7g 4-chloro-6,7,8-trifluoro-2-ethoxychinolin in the form of a beige fatty substance having a melting point of 45 ⁰ C, which is used without further purification in the later stages.

The 6,7,8-trifluoro-2-ethoxy-4-hydroxy-quinoline can be prepared in the following manner:

A solution of 122 g of 2,3,4-trifluoro-N- [ethylidene- (1 '-ethoxy-2-ethoxycarbonyDl-aniline in 120 cm ^{3 of} phenoxide is added dropwise with stirring over 25 minutes at a temperature of near 25O ⁰ C in 600cm entered ³ Phonyloxid, the ethanol formed is removed by distillation. After 15 minutes of stirring at the same temperature, the solution is cooled to about 20 ⁰ C and 750cm ³ of n-Hsxan added. the precipitate formed is filtered and washed three times with 200 cm ³ η- hexane. This gives 69,5g ej.e-trifluoro ^ -ethoxy ^ -hydroxy-quinoline as a beige solid from Melted point 171 ⁰ C, which is used without further purification in the later stages.

The 2,3,4-trifluoro-N- [ethylidene- (1'-ethoxy-2-ethoxycarbonyl] -aniline can be prepared in the following manner: To a solution of 90g (2-ethor; arbonyl-1) ethoxy) -ethylenediamine hydrochloride in 820cm ³ of ethanol is added all at once with stirring 58,8g of 2,3,4-trifluoro-aniline. After 48 hours of stirring at a temperature of close to 20 ° C the obtained suspension is filtered and the filtrate concentrated under reduced pressure (2OkPa) at a temperature of close to 50 ° C. Then, the oily residue is taken up in 250 cm of water. the resulting mixture is extracted three times with 200 cm ³ of ethyl ether. the combined organic extracts are washed four times with 150 cm ³ of water, about Dried magnesium sulfate and concentrated under reduced pressure (2OkPa) at a temperature of near 30 ⁰ C. 122 g of 2,3,4-trifluoro-N- [ethylidene {1 'ethoxy-2-ethoxycarbonyl) l-aniline in the form a yellow oil, which is used without further purification in the later stages.

The (2-ethoxycarbonyl-1-ethoxy) ethylenediamine hydrochloride was prepared according to the procedure described by A. PINNER et al., Ber. Dtsch. Chem. Ges., 28,478 (1895).

Example 27

A suspension of 2g ej.e-trifluoro-i-mathoxy ^ -oxo-i ^ -dihydro-ie-benzolblnaphthyridin-S-carboxylic acid and 2.8 g of piperazine in 40 cm ³ of dimethyl sulfoxide under stirring for 45 minutes at a temperature of about 50 ° C heated. After cooling to a temperature close to 2O ⁰ C, the suspension is poured into 100 cm ³ of water, and one adds 9,22g methanesulfonic acid. A small insoluble portion is removed by filtration over diatomaceous earth. Then 32 cm ^{3 of} 2N potassium hydroxide solution are added to the filtrate. The resulting precipitate is centrifuged, washed three times with 50 cm ^{3 of} water and recrystallized in 80 cm ^{3 of} dimethylformamide. This gives 1.4 g of 7,9-difluoro-1-methoxy-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow Solid of melting point 305-308 ⁰ C.

The ej.s-trifluoro-1-methoxy-1-oxo-i-dihydro-hexybenzolblhaphthyidine-S-carboxylic acid was prepared under the conditions of Example 25, but starting from 9g ej.e-trifluoro-i-methoxy-S -ethoxycarbonyl ^ -oxo-i / l-dihydro-IS-benzofblnaphthyridin. This gives 7.7 g e ^ .e-trifluoro-i-methoxy ^ -oxo-IAdihydro-diterbenzene-benzolblnaphthyridin-S-carboxylic acid in the form of a beige solid of melting point 322 ° C.

The ej.e-trifluoro-i-methoxy-S-ethoxycarbonyl ^ -oxo-IAdihydro-dentrbenzene-bjnaphthyridine is prepared under the following conditions:

To a suspension of 5.1 g of methylhydroxylamine hydrochloride in 120 cm ^{3 of} trichloromethane 8.7 cm ^{3 of} triethylamine are added. To the resulting solution is added 7.8 g of 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-chinolincarbonyll-S-dimethylamino-acrylic acid ethyl ester at about 2O ⁰ C. After stirring for 2 hours at this temperature, the solution is concentrated to dryness under reduced pressure (2OkPa) at about 5 ° C. The residue obtained is taken up in 150 cm ³ of ethanol and 10 cm ³ of triethylamine and heated under stirring for 30 minutes. After cooling to about 20 ⁰ C, the insoluble fraction is centrifuged, washed three times with 50cm ^{3 of} ethanol and twice with 50cm ³ isopropyl ether. After recrystallization in 120 cm ^{3 of} dimethylformamide, 9 g of ej.e-trifluoro-i-methoxy-S-ethoxycarbonyM-oxo-i ^ -dihydro-bisbenzo [b] naphthyridine are obtained in the form of a yellow solid of melting point 298-39O ⁰ C.

Step Example! 28

A solution of 1.15 g of 7-fluoro-1-methyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [naphthyridine-3-carboxylic acid in 1, 35 cm ³ 98% formic acid and 3.25 cm ³ 30% aqueous formaldehyde solution is heated for 2 hours to a temperature of near 100 ° C. Then, the reaction mixture under reduced pressure (2OkPa) at a temperature

of 5O ⁰ C concentrated, added 5 cm ^{3 of} water, the resulting solution by the addition of 0.5 cm ³ 2 N-potassium hydroxide solution adjusted to pH 7 and heated to a temperature of near 100 ⁰ C for 2 minutes. The crystallized product is centrifuged at 2O ⁰ C and washed twice with 10 cm ³ of water. The crude product obtained is crystallized twice in 10 cm ^{3 of} dimethylformamide. 0.55 g of 7-fluoro-1-methyl-8- (3,4-dimethyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid of melting point 306-308 ⁰ C.

Example 29

The reaction is carried out under the conditions of Example 28, but starting from 2.3 g of 7-fluoro-1-ethyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, 2.26 cm ³ 98% formic acid and 5.6 cm ³ 30% aqueous formaldehyde solution and receives 1.75 g of 7-fluoro-1-ethyl-8- (3,4-dimethyl -1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzoIb] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 293-294 ⁰ C.

Example 30

The reaction is carried out under the conditions of Example 28, but starting from 1.9 g of 7-fluoro-1-cyclopropyl-8- (3-methyl-1-piperazinylM-oxo-IAdihydro-ie-benzo-1-naphthyridine-S-carboxylic acid, 1.38 cm ³ Formic acid and 3.30 cm ^{3 of} 30% strength aqueous formaldehyde solution After recrystallization of the crude product in 50 cm ^{3 of} ethanol, 1.3 g of 7-fluoro-1-cyclopropyl-S-O-dimethyl-1-piperazinyl-D-oxo-i are obtained ^ -dihydro-he-benzolblnaphthyridin-S-carboxylic acid in the form of a yellow solid of melting point 219 ° C.

Example 31

A suspension of 0.85 g of 7-fluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 12cm ^{3 of} ethanol 5cm ^{3 of} 2 N potassium hydroxide and 7cm ^{3 of} water is heated for one hour to a temperature near 80 ° C. After addition of 5.8 cm ^{3 of} 10% acetic acid, the resulting precipitate is centrifuged and washed three times with 5 cm ^{3 of} water. After two recrystallizations in a mixture of 7.5 cm ^{3 of} ethanol and 7.5 cm ^{3 of} dimethylformamide is obtained 0.4 g of 7-fluoro-1-cyclapropyl-8- (4-methyl-1-piperazinyl) -4-oxo-1, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid of melting point 250 ⁰ C.

The 7-fluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared in the following manner and Way made:

A suspension of 1.2 g of 7,8-difluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 1.4 g of 1-methylpiperazine and 20 cm ³ of dimethyl sulfoxide is heated to a temperature of 95 ° C for 45 minutes. After cooling to a temperature of near 20 ° C, the reaction mixture is diluted with 100cm ^{3 of} water and extracted three times with 30cm ^{3 of} trichloromethane. The combined organic extracts are washed three times with 30 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) at a temperature of near 50 ⁰ C. The solid obtained is taken up in 20 cm ³ Isopropylethor, centrifuged, washed with 10 cm ³ of the same solvent and recrystallized in 150cm ³ Ethylucetat. 1.1 g of 7-fluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine are obtained Form of a yellow solid of melting point 223 ° C.

Example 32

A suspension of 0.98 g of 7-fluoro-1-methoxy-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 15cm ³ of ethanol, 9 cm ³ of water and 6 cm ³ of 2N potassium hydroxide solution is stirred at a temperature of 20 ° C for nr.he eino hour. To the resulting solution are added 6cm ³ 2 N-methanesulfonic acid, and the mixture is extracted three times with 10 cm ³ of trichloromethane. The combined organic extracts are washed three times with 5 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) concentrated at a temperature of close to 5O ⁰ C. The obtained dry extract is taken up in 5 cm ^{3 of} isopropyl ether, centrifuged and washed twice with ² cm ^{3 of} the same solvent. After recrystallization in 30 cm ^{3 of} dimethylformamide containing 30% of ethanol, 0.3 g of 7-fluoro-1-methoxy-8- {4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1 is obtained , 8-benzo (b) naphthyridine-3-carboxylic acid in the form of a brown solid of melting point 27O ⁰ C.

The 7-fluoro-1-methoxy-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine is prepared under the following conditions :

A suspension of 1.17 g of 7,8-difluoro-1-methoxy-S-oxo-ethoxycarbonyM-i, 4-dihydro-1,8-benzo / b / naphthyridin and 0.7 g of 1-methyl-piperazine in 15 cm ³ of dimethyl sulfoxide is heated to a temperature of near 95 ^° C. for 30 minutes. After cooling to a temperature of near 20 ° C, the reaction mixture is poured into 60cm ^{3 of} water and extracted three times with 25cm ^{3 of} trichloromethane. The combined organic extracts are washed three times with 25 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) concentrated at a temperature of close to 5O ⁰ C. The solid obtained is taken up in 10 cm ^{3 of} isopropyl ether, centrifuged and washed with 5 cm ^{3 of} the same solvent. Recrystallization in 90 cm ^{3 of} ethanol gives 1.18 g of 7-fluoro-1-methoxy-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo / b / naphthyridine in the form of a yellow solid of melting point 23O ⁰ C.

Example 33

Using the conditions of Example 35 below, but starting from 2 g of 7,9-difluoro-1-methyl-3-ethoxycarbonyl-e-IM-perhydrodiazepin-i-ylM-oxo-i ^ -dihydro-IS-benzolblnaphthyridin and obtains 1.5 g of 7,9-difluoro-1-methyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3 carboxylic acid in the form of a yellow solid of melting point 340-342 ⁰ C.

The 7,9-difluoro-1-methyl-3-ethoxycarbonyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was obtained under prepared from the conditions of Example 3, but starting from 2 g of 7,8,9-trifluoro-1-methyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 2g 1 , 4-hexahydrodiazepine. This gives 2 g of 7,9-difluoro-1-methyl-3-ethoxycarbonyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a yellow solid of melting point

Example 34

A suspension of 0.8 g of γS-difluoro-1-methyl-α-ethoxycarbonyl-ed-piperazinylD-i-oxo-1H-dihydro-ie-benzo-Ib) naphthyridine in 20 cm ^{3 of} ethanol and 20 cm ^{3 of} N-potassium hydroxide solution is allowed to stand for 90 minutes heated to a temperature of near 75 ⁰ C. Then 12 g of 10% acetic acid are added to the resulting solution at this temperature. The resulting insoluble fraction is centrifuged at about 75 ⁰ C and washed three times with 30cm ^{3 of} water of about 2O ⁰ C. After recrystallization in 90 cm ^{3 of} dimethylformamide, 0.5 g of 7,9-difluoro-1-methyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [blnaphthyridine-3 -carboxylic acid in the form of a yellow solid of melting point 345-347 ⁰ C.

The 7,9-difluoro-1-methyl-3-ethoxycarbonyl-8- {1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared in the following manner :

A suspension of 2 g of 7,8,9-trifluoro-1-methyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 30 cm ³ of dimethylsulfoxide and 5 g of piperazine is 2 hours heated with stirring to a temperature of near 100 ° C. Then the resulting solution is poured with stirring at about 100 ° C in a mixture of 150cm ^{3 of} water and 50g of ice. The resulting solution is extracted three times with 40 cm ^{3 of} trichloromethane. Subsequently, the combined organic phases are extracted twice with 50 cm ^{3 of} 0.1 N-methanesulfonic acid. 10g of potassium carbonate are added to the combined aqueous layers and the mixture is extracted three times with 40cm ^{3 of} trichloromethane. The combined organic extracts are washed twice with 50 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) concentrated at a temperature of close to 5O ⁰ C to dryness. Thereafter, the residue obtained is recrystallized in 25 cm ^{3 of} ethanol. 0.8 g of 7,9-difluoro-1-methyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [naphthyridine in the form of a yellow solid from Melting point 221 ⁰ C.

Example 35

A suspension of 1.5 g of (RS) -7,9-difluoro-1-methyl-3-othoxycarbonyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8- benzo [b] naphthyridine in 20 cm ³ of ethanol and 20 cm ³ N potassium hydroxide solution is heated for 90 minutes on eineTempsratur from near 75 ⁰ C. The resulting solution is added at this temperature, 12 g of a 10% acetic acid. The resulting insoluble fraction is centrifuged at about 75 ⁰ C and washed three times with 30cm ^{3 of} water of about 2O ⁰ C. Recrystallization in 100 cm ^{3 of} dimethylformamide gives 0.9 g of (RS) -7,9-difluoro-1-methyl-8- (3-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1 , 8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 380-382 ⁰ C.

The (RSl) .g-difluoro-i-methyl-S-ethoxycarbonyl-e-f S -methyl-i-piperazinyl D ^ -oxo-i ^ -dihydro-diterbenzene-naphthyridine was prepared in the following manner:

A suspension of 2 g of 7,8,9-trifluoro-1-methyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 30 cm ^{3 of} dimethyl sulfoxide and 5 g of 2-methylpiperazine is heated with stirring for 2 hours to a temperature of near 100 ⁰ C. At this temperature, the solution obtained is poured with stirring into a mixture of 150 cm ^{3 of} water and 50 g of ice. Is added at about 2O ⁰ C 5 g of potassium carbonate added and extracted three times with 50 cm ³ of trichloromethane. The combined organic extracts are washed twice with 50 cm ³ of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2OkPa) concentrated at a temperature of close to 5O ⁰ C to dryness. The residue obtained is recrystallized in 30 cm ^{3 of} ethanol. This gives 1.6 g of (RSJ-T ^ -Difluor-i-methyl-S-ethoxycarbonyl-eO-methyl-i-piperazinyl) -D ^ -oxo-i ^ -dihydro-in-benzo [b] naphthyridine in the form of a yellow solid from Melting point 24O ⁰ C.

Example 36

The reaction is carried out under the conditions of Example 35, but starting from 1 g of 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8- benzo [b] naphthyridine and obtains 0.7 g of 7,9-fluoro-1-ethyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3- carboxylic acid in the form of a yellow solid of melting point 340-342 ⁰ C.

The 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-i, 8-benzo [b] naphthyridine was prepared under the conditions of Example 35 but starting from 1.75 g of 7,8,9-trifluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 4.3 g of piperazine, and man receives 1.1 g of 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a yellow Solid of melting point 229 ⁰ C.

Example 37

The reaction is carried out under the conditions of Example 35, but starting from 1.1 g of 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4- dihydro-1,8-benzo [b] naphthyridine, to give 0.75 g of 7,9-difluoro-1-ethyl-8- (4-methyl-1-piperazinyl) M-oxo-1-dihydro-1-benzene-bjnap'i. thyridine-d-carboxylic acid in the form of a yellow solid of melting point

The 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (4-diethyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [B] naphthyridine was prepared under the conditions of Example 3, but starting from 1.4 g of 7,8,9-trifluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 4 g of 1-methyl piperazine. This gives 1.1 g of 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid of melting point 206 ⁰ C.

The 7,8,9-trifluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [naphthyridine was prepared in the following manner:

In a suspension of 7.1 g of 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 100 cm ^{3 of} ethanol, kept at a temperature of near S ⁰ C, are added with stirring within 10 minutes between 5 and 10 ° C 4.5g ethylamine, stirred for one hour between 5 and 10 ° C and then allowed to rise to about 2C ⁰ C temperature. The resulting solution is 4g 1,8-Dia2a-bicyclo [5.4.ü] -7-undecene (DBU) was added and the mixture heated to a temperature close to 75 ⁰ C for 90 minutes. After cooling to a temperature close to 2O ⁰ C, the product is centrifuged, washed twice with 30 cm ³ of ethanol and twice with 50 cm ³ of isopropyl ether. This gives 4 g of 7,8,9-trifluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (blnaphthyridine in the form of a cream-colored solid of melting point 284 "C, which without further Cleaning is used in the later stages.

Example 38

Working under the conditions of example 35, but starting from 1.7 g of 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (1,4-perhydrodiazepl: v1-yl) -4-oxo-1, 4-dihydro-1,8-benzo (.b) naphthyridine and obtains 1.1 g of 7,9-difluoro-1-ethyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a galben solid of melting point 274 ⁰ C.

The 7,9-difluoro-1-ethyl-3-ethoxycarbonyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was obtained under prepared from the conditions of Example 35, but starting from 3 g of 7,8,9-trifluoro-1-ethyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 2g 1, 4-hexahydrodiazepine. This gives 1.7 g of 7,9-difluoro-1-ethyl-3-ethoxyctrbonyl-8- (1,4-perhydrodiazepin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [Blnaphthyridin in the form of a yellow solid of melting point 19O ⁰ C.

Example 39

The reaction is carried out under the conditions of Example 35, but starting from 2 g of 7,9-difluoro-1-tert-butyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1, 8-benzo [b] naphthyridine. Recrystallization in 35 cm ^{3 of} dimethylformamide and 35 cm ^{3 of} ethanol gives 1 g of 7,9-difluoro-1-tert-butyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 318 ° C.

The 7,9-difluoro-1-tert-butyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the conditions of Example 3Ei prepared, but starting from 1.9 g of 7,8,9-trifluoro-1-tert-butyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (b) pf) phthyridin and 4 , 3g Pipeiozine. After recrystallization in 50 cm ³ of isopropyl ether and 10 cm ³ of 2-propanol to obtain 2 g of 7,9-difluoro-1-tert-butyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro- 1,8-benzotb] naphthyridine as a yellow solid of melting point 186 ⁰ C.

The 7,8,9-trifluoro-1-tert-butyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzene] idhtyl: idine was prepared under the following conditions:

In a solution of 11.7 g of 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylic acid ethyl ester in 150 cm ^{3 of} trichloromethane is carried with stirring at a temperature of about 2O ⁰ C within 5 minutes 9.5 g of tert-butylamine.

After 4 hours of stirring at about 2O ⁰ C, the solution is concentrated under reduced pressure (2OkPa) at a temperature of about 5O ⁰ C to dryness. Thereafter, the residue obtained is taken up in 100 cm ^{3 of} ethanol. To the resulting solution was added 5 g of DBU and heated for 3 hours to a temperature of close to 75 ⁰ C. After cooling to about 20 ⁰ C the obtained Ni ³ of isopropyl ether is centrifuged jderschlag, washed twice with 50 cm ³ of ethanol and twice with 50 cm washed , This gives 9.5 g of 7,8,9-trifluoro-1-tert-butyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine in the form of a colorless solid of melting point 229th ⁰ C, which is used without further purification in the later stages.

Example 40

The reaction is carried out under the conditions of Example 35, but starting from 1 g of 7,9-difluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (1-piperazinyl) M-oxo-1-dihydro-1-benzo-1-naphthyridyl, the result is 0, 70 g of 7,9-difluoro-1-cyclopropyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid in the form of a yellow solid of melting point 305 -307 ⁰ C.

The 7,9-difluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared under the conditions of Example 35 but starting from 1.5 g of 7,8,9-trifluoro-1-cyclopropyl-3-ethoxycarbonyl-1,4-dihydro-1,8-benzo [b] naphthyridine and 2.7 g of piperazine. After recrystallization in 40 cm ^{3 of} 2-propanol, 1 g of 7,9-difluoro-1-cyclopropyl-S-ethoxycarbonyl-ed-piperazinyl-1-oxo-1-dihydro-1-benzolblonaphthyridine are suspended in the form of a yellow solid of melting point 256 ⁰ C.

Example 41

The reaction is carried out under the conditions of Example 35, but starting from 1.7 g of 7,9-difluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1, 4-dihydro-1,8-benzo [b] naphthyridine. Recrystallization in 60 cm ^{3 of} ethanol gives 1.3 g of 7,9-difluoro-1-cyclopropyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b ] naphthyridine-3-carboxylic acid in the form of an orange colored solid of melting point 248 ⁰ C.

The 7,9-difluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] n & thethrin was prepared under the conditions of Example However, starting from 1.5 g, 7,8,9-trifluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo (blnaphthyridine and 3 g of 1-methyl-piperazine. This gives 1.5 g of 7,9-difluoro-1-cyclopropyl-3-ethoxycarbonyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in the form of a yellow solid of melting point 23O ⁰ C.

Example 42

The reaction is carried out under the conditions of Example 35, but starting from 1.9 g of (RS 1 -) - difluoro-i-cyclopropyl-S-ethoxycarbonyl-e-O-methyl-1-piperazinyl-D 1 -oxo-1-dihydro-1-benzol-bjnaphthyridine. After recrystallization in a mixture of 20 cm ^{3 of} dimethylformamide and 20 cm ^{3 of} ethanol, 1.1 g of (RS) -7,9-difluoro-1-cyclopropyl-eO-methyl-piperazinylM-oxo-1-dihydro-he-benzolblonaphthyridine are obtained. S-carboxylic acid in the form of a yellow solid of melting point 309 ⁰ C.

The (RSl, .g-difluoro-i-cyclopropyl-S-ethoxycarbonyl-eO-methyl-i-piperazinyl) -D ^ -oxo-1Adihydro-ie-benzeneb naphthyridine was prepared under the conditions of Example 35 but starting from 1.8g 7,8,9-Trifluoro-1-cyclopropyl-3-ethoxycarbonyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 2g (RS) -2-propanol-piperazine Following a recrystallization in 15 cm ^{3 of} 2-propanol and 15 cm ^{3 of} isopropyl ether to give 1.9 g (RSl ^^ - difluoro-i-cyclopropyl-S-ethoxycarbonyl-e-ß-methyl-piperazinyl) -4-oxo-1,4-dihydro-1 , 8-benzo [b] naphthyridine in the form of a yellow solid of melting point 19O ⁰ C. The present invention also relates to the applicable in human or veterinary medicine pharmaceutical compositions containing as active ingredient at least one product of general formula (I) in pure state (in free form or in the form of a salt) or in the form of a composition with one or more pharmaceutically compatible diluents or additives Mixtures can be administered orally, parenterally or rectally.

As solid compositions for oral administration, tablets, pills, powders or granules may be used.

In these compositions, the active ingredient of the invention is mixed with one or more inert diluents or additives such as sucrose, lactose or starch.

These compositions may also contain other substances than the said diluent! contain, for example, a lubricant such as magnesium stearate.

As liquid compositions for oral administration, one may use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or the like; Paraffin oil, included. These compositions may also comprise substances other than the diluents mentioned, for example wetting agents, sweeteners or flavoring agents,

The compositions for parenteral administration may preferably be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or as a filler, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, for example, ethyl oleate, may be used.

These compositions may also contain additives, in particular wetting agents, emulsifiers or dispersants. The sterilization can be carried out in several ways, for example by means of a bacteriological filter, incorporation of sterilizing agents in the composition, by irradiation or heating. They may also be prepared in the form of solid sterile compositions, which are then dissolved at the moment of use in sterile water or other injectable sterile medium.

The compositions for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, also contain fillers such as cocoa butter or suppo wax.

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

In general, the physician will determine the dosage which he considers most appropriate depending on the age, weight, degree of infection and other factors of the person being treated. The poses are generally between 0.2 and 1 g of active ingredient twice a day, orally or parenterally in adults.

The following non-limiting example illustrates a composition of the invention:

example

It is produced by conventional techniques tablets with 250mg active ingredient of the following composition.

- 7-Fluoro-1-cyclopropyl-8-d-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine-3-carboxylic acid 250mg

- Strength 50mg

- Lactose 35 mg

- Talc 15mg

The products of the general formula (I) are also of interest in the field of agrochemistry for the antibacterial treatment of plants and plant substances. It will be understood that the agrochemical compositions comprising a product of general formula (I) are within the scope of the present invention. In addition, the products of general formula (I) can be used as agents for the preservation or disinfection of organic or mineral materials, in particular in the dye industry, the fat industry, the paper industry, the wood industry, the polymer industry. Industry or even in the textile industry, the food industry or wastewater treatment. It is also to be understood that the compositions comprising a product of general formula (I) in the pure state or in association with suitable diluents or additives also come within the scope of the present invention.

formula sheet

Gooh

R6

R ₂

N 'N (A)

Z. . (CH ₂ Jm - _s \ / VCOOH

V-U

χ ι N - COCHR ₂ - (CH ₂ J _n -

R ₁ -

\ __ (CH2) n R

R3 R4I «)

COOH (S)

COOAlk

[K)

- 43 '

COOAlk

R ₂

(V)

R ₂ - NH ₂

(VI) '

COOAlk

(VII)

COOAlk

(VIII)

Cl

(IX)

Claims (1)

Process for the preparation of a novel 1,8-benzo [b] naphthyridine derivative of the general formula (I) (see formula sheet), in which Ri represents a hydrogen atom, an alkyl radical or a hydroxyalkyl radical, R _{2 represents} a hydrogen atom, an alkyl radical, a fluoroalkyl radical, a cycloalkyl radical having 3 to 6 carbon atoms, an alkyloxy radical or an alkylamino radical, R _{3 is} an alkyl radical and R ₄ and R _{5 are} different and represent a hydrogen atom or an alkyl radical, or R _{3 represents} a hydrogen atom, an alkyl radical or a cycloalkyl radical, R ₄ and R _{5 are} hydrogen atoms, - Re represents a hydrogen or a fluorine atom, and - η is 1 or 2, wherein the alkyl radicals contain 1 to 4 carbon atoms in straight or branched chain, its metal salts, its addition salts with nitrogen bases and its addition salts with acids, and its hydrated forms and optionally its isomers and mixtures thereof, characterized in that a piperazine derivative of the general formula (II) (see formula sheet), wherein Rn R3. R 4 and R ₅ are as defined below, with a 1,8-benzo [b] naphthyridine of general formula (III) (see formula sheet) is reacted in which R ₂ is as defined above and Hal is a fluorine, chlorine or Bromine atom, when R _{6 is} a hydrogen atom, or Hai and R _{6 are} simultaneously fluorine atoms, or that the ester of the general formula (IV) (see formula sheet), wherein R ₁ , R ₂ , Ra, R4 »Re. R ₆ and η are as defined above or R _{2 is} a protected alkylamino radical and Alk is a straight or branched alkyl radical of 1 to 4 carbon atoms, converted from an ester by a known method for producing an acid, without the remainder of the Attacking molecule, and then optionally removing the protective group of the alkylamino radical, and / or, if one wants to produce a product in which R _{1 is} methyl and when the corresponding product has been obtained, in which R _{1 is} a Wasserstoffatorr. is, converts this product into an 8- (4-methyl-1-piperazinyl) benzo [b] naphthyridine and optionally subsequently produces the salt of the resulting benzo [b] naphthyridine derivative.