HU206501B - Process for producing new 1,8-benzonaphtiridine derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

1,8-Benzo (b) naphthyridine derivs. of formula (I), and their salts with metals and nitrogen bases, are new. R = H, alkyl, fluoroalkyl, 3-6C cycloalkyl, alkoxy, alkylamino, or it is a protecting gp., Hal = F, Cl, or Br and R' = H, or Hal = R' = F, 'alkyl' gps. may be opt. branched and contain 1-4C atoms.

Description

The present invention relates to novel 1,8-benzo [b] naphthyridine derivatives of the general formula (I), their salts and to processes for the preparation thereof.

U.S. Patent Nos. 4,229,456 and 4,333,885 disclose a naphthyridine derivative of formula (A) wherein X is oxygen and two of R _b R ₂ , R ₃ , R ₄ and R ₅ are taken together to form a benzene ring. form.

These compounds inhibit the secretion of the weed juice.

German Patent No. 3,302,126 discloses a compound of formula (B) which has antihypertensive activity, wherein X, Y and Z are 0 or a group -NR ₄ or -CR ₅ = * CR ₃ -, wherein the R ₅ substituents may form a benzene ring.

In the compound of formula I, R is hydrogen, alkyl, fluoroalkyl, C3-6cycloalkyl, alkyloxy, alkylamino or alkoxyalkyl, and

Hal is fluorine, chlorine or bromine when R 'is hydrogen, or

Hal and R 'are simultaneously 1 to 1 fluorine.

Alkyl groups are straight or branched C 1 -C 4 groups.

In the process of the present invention, the 1,8-benzo [b] naphthyridine derivatives of formula (I) may be prepared from the corresponding ester of formula (II):

R is hydrogen, alkyl, fluoroalkyl, cycloalkyl, alkyloxy, alkoxyalkyl, alkylamino or protected alkylamino,

Hal and R'are as defined above and

Alk is a straight or branched C 1 -C 4 alkyl group by any known method of making an ester from an acid without altering the rest of the molecule and optionally deprotecting the alkylamino group.

When R is a protected alkylamino group, the protecting group may be any known amino protecting group which is compatible with the molecule and the conditions of the process. Preferably, a protecting group which can be removed simultaneously with the hydrolysis of the ester, such as formyl, is used. {[Greene, T. W .: Protective Groups in Organic Synthesis [(A Wiley-Interscience Publication (1981)], McOmie: Protective Groups in Organic Chemistry, Plenum Press, 1973)}).

The ester starting acid is generally prepared by acid hydrolysis. Preferably, it is carried out in a mixture of acetic acid and hydrochloric acid, sulfuric acid or methanesulfonic acid, at a temperature between 60 and 100 ° C. The reaction may also be carried out by saponification in the presence of potassium hydroxide or sodium hydroxide in an aqueous alcoholic medium at a temperature between 20 ° C and 80 ° C.

The introduction of the protecting groups at the 1-position can be carried out according to the methods described in the above literature.

The 1,8-benzo [b] naphthyridine ester derivatives of formula (II) may be prepared by reacting a 3-amino-1,2,4-triazine compound of formula (II) wherein R is hydrogen or to prepare compounds of formula (Π) wherein:

R is an alkyl group, a fluoroalkyl group, a cycloalkyl group, an alkyloxy group, an alkoxyalkyl group, an alkylamino group or a protected alkylamino group, a compound of formula (III) wherein R is as defined above in an (IV) ) with a quinoline derivative of the formula:

R ', Hal and Alk are as defined above and subsequently reacted with an acid acceptor.

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

The cyclization is generally carried out in excess of 1,8-diazabicyclo [5.4.0] undec-7-ene or a nitrogen-containing base such as triethylamine or the amine used in straight or branched C 1 -C 4 alcohol between 20 ° C and the boiling point of the reaction mixture. temperature.

The quinoline derivative of formula (IV) may be prepared by reacting a ketoester of formula (V) wherein R ', Hal and Alk are as described above with Ν, Ν-dimethylformamide-acetane of formula (VI), wherein Alk is a straight or branched C 1 -C 4 alkyl group.

The reaction is usually carried out in an organic solvent such as an ester (e.g. ethyl acetate) at a temperature between 60 and 75 ° C.

The ketoester of formula (V) wherein R 'is hydrogen and Hal is as defined above

2.7-dichloro-6-fluoro-quinoline-3-carboxylic acid or 2-chloro-6,7-difluoro-quinoline-3-carboxylic acid may be prepared according to the procedure of Examples 1 and 6, or

Starting from 7-bromo-2-chloro-6-fluoroquinoline-3-carboxylic acid, the reaction is carried out analogously to the above procedure. In the case where 3-bromo-4-fluoroaniline is used as a starting material, the method described by Austin, W.B., et al., J. Org. Chem., 46 [11], 2280 [1981].

The ketoester of formula (V) wherein R 'and Hal are both fluoro may be prepared starting from 2-chloro-6,7,8-trifluoroquinoline-3-carboxylic acid according to the procedure of Example 9.

Important intermediates of the compounds of formula (I) obtained by the process of the present invention are the 1,8-benzo [b] naphthyridine derivatives of formula (VII), salts, hydrates and optionally isomers thereof, wherein

HU 206 501 Β

R) is hydrogen, alkyl, or hydroxyalkyl,

R ₂ is hydrogen, alkyl, fluoroalkyl, C 3 -C 6 cycloalkyl, alkyloxy, or alkylamino,

R ₃ is hydrogen or alkyl,

R ₄ and R ₅ are identical or different, are hydrogen or alkyl, or

R ₃ is hydrogen, alkyl or cycloalkyl and

R ₄ and R ₅ are hydrogen and

R 'is hydrogen or fluorine.

Compounds of formula (VII) may be prepared by substitution with a piperazine of formula (VIII) wherein R _b, R ₃ , R ₄ and R ₅ are as defined above, replacing a 1,8-benzo [b] of formula (I). ] naphthyridine and, if desired, for the preparation of 1,8-benzo [b] naphthyridine derivatives wherein R [is methyl], a compound is obtained wherein R 1 is methyl. is hydrogen, is converted to 8- (4-methylpiperazin-1-yl) -benzo [b] naphthyridine, and optionally deprotected.

The piperazine derivatives of formula (VIII) are generally reacted in excess of the compound as an acid acceptor or in the presence of an organic or mineral acid acceptor in a suitable organic solvent. The reaction may be carried out in a solvent or in the absence of a solvent at a temperature between 30 ° C and 120 ° C. When reacting the reactants in a solvent, the following solvents may be used: pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

For the preparation of compounds wherein R ₂ is hydrogen, it is preferable to use a benzonaphthyridine derivative where R is a protecting group. The introduction of the protecting group and removal of the protecting group after the reaction can be carried out by conventional means.

The methylation of the piperazinyl group is carried out after the reaction, preferably with formol in the presence of formic acid. Generally, reagents are reacted in aqueous media at temperatures between 90 ° C and 100 ° C.

The novel compounds of the present invention and the compounds of formula VII may optionally be purified by physical methods such as crystallization and chromatography.

The compounds of formula (I) and the compounds of formula (VII) obtained by the process of the present invention can be converted into metal salts or addition salts with nitrogenous bases by known methods. These salts may be prepared by reacting a metal base (alkali metal or alkaline earth metal) with ammonium hydroxide or an amine of the compounds of this invention in a suitable solvent such as alcohol, ether or water. The resulting salt precipitates and can be isolated by concentration or filtration, pouring or lyophilization.

The 1,8-benzo [b] naphthyridine derivatives of formula (VII) and their pharmaceutically acceptable salts have antibacterial activity. Both in vitro and in vivo effective a

Gram positive bacteria that are responsible for most of the lower respiratory tract and upper respiratory tract infections.

Compounds of formula (VII) are active in vitro against Staphylococcus aureus IP 8203 at concentrations of 0.12 and 50 µg / ml.

Compounds of formula (VII) are also active in vivo in mice with experimentally induced infections of Staphylococcus aureaus IP 8203 administered orally or subcutaneously at doses of 2-150 mg / kg.

In addition, the compounds are only slightly toxic, with LD ₅₀ values generally administered subcutaneously to mice above 500 mg / kg.

Novel benzo [b] naphthyridine derivatives of formula (I) wherein R is other than a protecting group and their salts also have valuable antibacterial activity in vitro and consequently are particularly useful for topical application against dermal Staphylococcus infections.

The 1,8-benzo [b] naphthyridine derivatives prepared by the process of the present invention are active in vitro at concentrations of 0.2-500 µg / ml Staphylococcus aureus IP 8203 blunt.

The LD50 value is greater than 500 mg / kg subcutaneously in mice.

Examples of pharmaceutically acceptable salts include salts with alkali metals (sodium, potassium, lithium) or alkaline earth metals (magnesium, calcium), ammonium hydroxide, nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, trimethylamine, methylamine, propylamine, diisopropylamine, Ν, Ν-dimethylethanamine, benzylamine, dicyclohexylamine, N-benzyl-beta-phenethylamine, NN'-dibenzylethylenediamine, diphenylenediamine , benzhydrylamine, quinine, choline, arginine, lysine, leuc n, dibenzylamine).

Particularly valuable are compounds of formula I wherein R is hydrogen, C1-C4 alkyl, fluoroethyl, cyclopropyl, methoxy, or methylamino and Hal is fluoro or chloro and R 'is hydrogen, or Hal is and R 'is simultaneously 1-1 fluorine.

Of these compounds, the following are particularly valuable:

7.8-Difluoro-1-methyl-4-one-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid;

8-chloro-7-fluoro-1-methyl-4-chloro-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid;

l-methyl-4-oxo-7,8,9-trifluoro-l, 4-dihydro-l, 8-benzo [b] naphthyridine-3-carboxylic acid;

7.8-Difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid;

l-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid.

The following examples illustrate the process of the present invention, but are not intended to be limiting.

Example 1 8-Chloro-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxole, 4-dihydro-1,8-benzo [b] naphthyridine in 150 ml acetic acid

A suspension of 501 1 and 150 ml of a 17% aqueous hydrochloric acid solution was heated at 100 ° C for 4 hours with stirring. After cooling to a temperature in the region of 20 ° C, the product is filtered off with suction and washed twice with 150 ml of ethanol and twice with 100 ml 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. ° C sublimation.

8-Chloro-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

To a suspension of 19.3 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 250 ml of ethanol, kept at 10 and 15 ° C with stirring, as soon as it is flushed until it takes up 16 g of gas. At this time, the temperature was allowed to rise to 20 ° C, 0.8 g of 1,8-diazabicyclo [5.4.0] undec-7-ene was added and heated at 75 ° C for 2 hours. After cooling to 20 [deg.] C., the product is filtered off with suction and washed twice with 150-150 ml of ethanol and twice with 100-100 ml of ethyl ether. There was thus obtained 15 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-methyl-4-o-o-1,4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid, m.p. 360-362 ° C. It melts at C and can be used without further purification.

Ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate can be prepared as follows:

16.5 g of a suspension of ethyl 3- (2,7-dichloro-6-fluoro-3-quinolyl) -3-oxopropionate in 160 ml of ethyl acetate and 19 ml of N, N-dimethylformamide dimethyl acetate Heat at about 75 ° C for 2 hours with stirring. The reaction mixture was then concentrated to dryness under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in 50 ml of diisopropyl ether, filtered off with suction and washed twice with 10 ml of diisopropyl ether. so

16.57 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate are obtained as an orange solid, m.p. 122 ° C. The product can be used without further purification.

Ethyl 3- (2,7-dichloro-6-fluoro-3-quinolyl) -3-oxopropionate can be prepared as follows:

A suspension of 38.75 g of 2,7-dichloro-6-fluoroquinoline-3-carboxylic acid in 410 ml of trichloromethane and 24 ml of thionyl chloride is heated at about 60 ° C for 6 hours. The resulting solution was concentrated to dryness under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up twice in a total of 200 ml of toluene and concentrated again under reduced pressure under the same conditions. The resulting yellow solid melts at 124 ° C and is dissolved in 230 ml of anhydrous tetrahydrofuran. The resulting solution was added dropwise, with stirring, to a solution of magnesium tetrahydrofuran (200 mL) at 5 to 10 ° C over 30 minutes, as described below. The temperature was then allowed to rise to 20 ° C and stirred at this temperature for 1.5 hours. The resulting solution was added dropwise, with vigorous stirring, at 5 ° C, to 1 liter of 0.5 N sulfuric acid. The reaction temperature was allowed to rise to 0 ° C and stirred at this temperature for 2 hours. It is then extracted with 1 liter of ethyl acetate, the organic phase and the aqueous phase are filtered through diatomaceous earth to remove insoluble matters, and the aqueous phase is extracted twice more with 500 ml of ethyl acetate. The organic extracts were combined, washed with water (2 x 500 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (20 kPa) at 40 ° C. The residue obtained is taken up in 100 ml of diisopropyl ether at 20 ° C, filtered off with suction and washed twice with 30 ml of diisopropyl ether. This gave 40.55 g of ethyl 3- (2,7-dichloro-6-fluoro-3-quinolyl) -3-oxopropionate as a beige solid, m.p. 112-114 ° C. The product obtained can be used without further purification.

The magnesium chelate of malonic acid monoethyl ester can be prepared as follows:

To 6.9 g of magnesium filings, 5 ml of anhydrous ethanol, 0.2 ml of tetrachloromethane and 2 g of malonic acid monoethyl ester are added in small amounts. After heating for 15 minutes

A solution of 23.8 g of malonic acid monoethyl ester in 450 ml of ethanol is added. The mixture was heated at about 78 ° C for 20 hours and then concentrated under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in toluene (2 x 100 ml) and concentrated under reduced pressure under the same conditions. The resulting gray powder was dissolved in anhydrous tetrahydrofuran and enough tetrahydrofuran was added to make a total volume of 200 mL.

The malonic acid monoethyl ester may be prepared by the method described by Breslow, DS, Baumgarten, E. and Hauser, CR, J. Am. Chem. Soc., 66, 1287 (1944) and distilled under reduced pressure (boiling point - 132 ° C / 2.7 kPa).

2,7-Dichloro-6-fluoroquinoline-3-carboxylic acid can be prepared as follows:

A suspension of 69.5 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline in 282 ml of aqueous 2N potassium hydroxide solution and 282 ml of water at 10 ° C is stirred. while maintaining the temperature between 10 and 14 ° C, a solution of 89.3 g of potassium permanganate in 1.4 L of water is added. The temperature of the mixture was allowed to rise to 20 ° C and stirred at this temperature for a further 30 minutes. Sodium dithionite (26 g) was added and the mixture was stirred for 10 minutes at 20 ° C, filtered through diatomaceous earth and washed with water (2 x 250 ml). The filtrate and the washings were combined and 90 ml of a 35% aqueous hydrochloric acid solution were added. The resulting precipitate was extracted with ethyl acetate (4 x 500 mL). The organic extracts were combined and washed with water (3 x 500 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in 350 ml of ethyl ether, filtered off with suction and washed twice with 200 ml of ethyl ether each time. 45 g of 2,7-dichloro-6-fluoroquinoline-3-carboxylic acid are obtained in the form of a beige solid, m.p. 230 DEG C., which can be used without further purification.

HU 206501 Β

2,7-Dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline can be prepared as follows:

To a mixture of trichloromethane (250 mL) and dimethylformamide (54 mL) was added phosphorus oxychloride (55.6 mL) with stirring at 10 to 15 ° C over 30 minutes and stirred at about 20 ° C for 1 hour. To the resulting solution was added 52.0 g of 7-chloro-6-fluoro-3,4-dihydro-carbostyril (carbostyril = alpha-hydroxyquinoline lactime) over 10 minutes at 20 ° C with vigorous stirring. The resulting suspension is heated to about 60 ° C and maintained at this temperature for 2 hours with stirring. The reaction mixture is then concentrated under reduced pressure (20 kPa) at 50 ° C until the mixture becomes a paste. Under vigorous stirring, 250 ml of water and 250 g of crushed ice are added. The resulting solid was filtered off with suction at 5 ° C and washed four times with 125-125 ml of 5 ° C water. The resulting wet product and 58 g of sodium acetate are added simultaneously to 500 ml of 90 ° C water for 1 hour and the pH is maintained at about 6. After stirring for 15 minutes at 90 ° C, the temperature was allowed to drop to 50 ° C, the product was filtered off with suction and washed three times with 250-250 ml of water at 20 ° C. This gives 54.3 g of 2,7-dichloro-6-fluoro-3-formyl-1,4-dihydroquinoline as a yellow solid, m.p. 260 ° C, which can be used without further purification.

7-Chloro-6-fluoro-3,4-dihydrocarbostyril can be prepared as follows:

To 174.4 g of 3'-chloro-4'-fluoro-3-i'-chloropropionic anilide is added 350 g of aluminum chloride with vigorous stirring for 5 minutes. The solid mixture was heated at 60 ° C for 30 minutes. The temperature automatically rises to 80'C and the reaction mixture becomes liquid. It is then heated at 110 ° C for 15 minutes and maintained at 110 ° C to 120 ° C for 3 hours. The reaction mixture (about 110 ° C) was poured into a mixture of 550 ml of 35% hydrochloric acid solution and 500 g of ice with vigorous stirring for 10 minutes. The temperature was allowed to rise to 20 ° C, filtered off with suction and washed with water (500 ml-500 ml).

The wet product was recrystallized from 1.2 L of ethanol. 108 g of 7-chloro-6-fluoro-3,4-dihydrocarbostyril are obtained in the form of a beige solid, m.p.

3'-Chloro-4'-fluoro-3-N-chloropropionic anilide can be prepared as follows:

To a solution of 291 g of 3-chloro-4-fluoroaniline in 500 ml of acetone at 55 ° C was added 127 g of 3-chloropropionic acid chloride in 200 ml of acetone with stirring for 35 minutes and maintained at this temperature for 2 hours. It is then cooled to a temperature in the region of 20 ° C, the insolubles are separated by filtration and washed twice with 200 ml of acetone each time. The filtrate and wash were poured into a mixture of water (2 L) and ice (1 kg) with stirring. The temperature was allowed to rise to 20 ° C and extracted with dichloromethane (4 x 500500 mL). The organic extracts were combined, washed with water (3.times.500 ml), dried over magnesium sulfate, stirred for 6 minutes with carbon (6 g) (Norit type), filtered through diatomaceous earth and then under reduced pressure (20 kPa) at 50 ° C. concentrated. The resulting solid residue was recrystallized from a mixture of cyclohexane (130 mL) and diisopropyl ether (67 mL). This gives 176 g of 3'-chloro-4'-fluoro-3-N-chloropropionic anilide as a beige solid, m.p. 94 ° C, which can be used without further purification.

Example 2

However, the procedure of Example 1 was followed

Starting with 10.5 g of 8-chloro-7-fluoro-3-ethoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. so

9.3 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained as a beige solid, m.p. are.

8-Chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

To a suspension of 13.5 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 135 ml of ethanol at 10 to 15 ° C for 5 minutes, 16 g. ethyl amine was added with stirring, and the temperature was allowed to rise to 20 ° C, at which time 0.5 g of 8-diazabicyclo [5.4.0] undec-7-ene was added and the mixture was heated at 75 'for 2 hours with stirring. At about C. The reaction mixture was cooled to 20 ° C and the precipitate was suctioned off, washed twice with 100 ml of ethanol and twice with 100 ml of ethyl ether. so

10.4 g of 8-chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a yellow solid, m.p. and can be used without further purification.

Example 3

16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1- (n-formylN-methylamino) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 164 g. A suspension of 1 ml of acetic acid and 164 ml of an aqueous solution of 17.5% hydrochloric acid was heated at 100 ° C with stirring for 4 hours. It is then cooled to about 10 ° C and 165 ml of 30% sodium carbonate solution are added at 10 to 20 ° C. The resulting product was filtered off with suction, washed with water (3 x 150 mL), ethanol (3 x 150 mL) and ethyl ether (3 x 150 mL). 13.64 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained as a yellow solid, m.p. They are C's.

8-Chloro-3-ethoxycarbonyl-7-fluoro-1- (N-formyl-N-methylamino) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine However, 19.25 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate, 4.05 g of N-formylN-methylhydrazine and Starting from 6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene and 200 ml of ethanol

HU off. Thus, 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1- (N-formyl-N-methylamino) -4-oxo-1,4-dihydro-1,8-benzo [b Naphthyridine is obtained as a colorless solid, m.p. 296-298 ° C, which can be used without further purification.

N-formyl-N-methylhydrazine can be prepared according to the procedure described by Pedersen, C. Th., Acta Chem. Scand. (18 (9), 2199 (1964)).

Example 4

However, the procedure of Example 1 was followed

Starting from 6.1 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. There was thus obtained 8.85 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid. are good.

8-Chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

A solution of 20.6 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate and 6 g of cyclopropylamine in 100 ml of trichloromethane is stirred for 20 hours. At about ° C. Subsequently, the reaction mixture is concentrated under reduced pressure (20 kPa) to 50 'Con. The resulting residue was taken up in 180 ml of ethanol and 10 g of 1,8-diazabicyclo [5.4.0] undec-7-ene and the resulting solution was heated at about 78 ° C for 4 hours. After cooling to about 20 'C, the resulting precipitate was filtered off with suction and washed twice with 60 ml of ethanol (60 ml each). 13.65 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a pale yellow solid, m.p. on and can be used without further purification in the following operations.

Example 5

1.88 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine in 10 ml of ethanol, 5 ml of water and A suspension of 2 ml of aqueous 2N potassium hydroxide was heated at about 75 ° C with stirring for 1 hour. The resulting solution was added to 2 ml of acetic acid. The resulting precipitate was filtered off with suction, washed with water (3 x 10 ml), ethanol (3 x 10 ml), recrystallized from dimethylformamide (50 ml) to give 1.7 g of 8-chloro-7-fluoro-4-oxo-1-tert-butyl-1,4- dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 398 ° C.

8-Chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine may be prepared according to the procedure of Example 4, but Starting from 8.86 g of ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate, 4.03 g of tert-butylamine in 45 ml of trichloromethane. 53 g of 8-diazabicyclo [5.4.0] undec-7-ene and 45 ml of ethanol are added. This gave 5 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid, m.p. Con are.

501 B 2

Example 6

1.95 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 20 ml of a 17.5% solution of hydrogen chloride and a suspension of 20 ml of acetic acid is heated at about 100 ° C for 1.5 hours. The reaction mixture was cooled to about 20 ° C and the reaction mixture was poured into water (100 mL). The precipitate formed is filtered off with suction and washed three times with 20 ml of water each time. Recrystallization from a mixture of 30 ml of dimethylformamide and 30 ml of ethanol afforded 1.31 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid. as a solid, m.p. 284-285 ° C.

1-Cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

5.27 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) 3-cyclopropylamino-acrylate 2.22 g of 1,8-diazabicyclo [5.4.0] A suspension of undec-7-ene and 120 ml of ethanol was heated at about 75 ° C for 35 minutes. The reaction mixture was cooled to about 20 ° C and the reaction mixture was taken up in 100 ml of water, extracted once with 100 ml and twice with 50 ml of trichloromethane. The organic extracts were combined and washed with water (3 x 50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at a temperature in the region of 20 ° C. The resulting solid was taken up in diisopropyl ether (30 mL), filtered off and recrystallized from ethanol (75 mL) and dimethylformamide (75 mL). so

3.57 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a yellow solid, m.p. 229-230 ° C. melted.

Ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-cyclopropylaminoacrylate is prepared as follows:

A solution of 6.25 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 2.91 g of cyclopropylamine in 25 ml of trichloromethane is stirred for 3 hours. At a temperature of about 20'C. The reaction mixture is then concentrated under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken up in 50 ml of diisopropyl ether, filtered off and washed with 20 ml of diisopropyl ether.

5.27 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolylcarbonyl) -3-cyclopropylaminoacrylate are obtained as an orange solid, m.p. 116-117 ° C. The product obtained can be used without further purification.

Ethyl 2- (2-chloro-6,7-difluoro-3-quinolylcarbonyl) -3-dimethylaminoacrylate is prepared as follows:

A suspension of 6.17 g of ethyl 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxopropionate in 7.15 g of N, N-dimethylformamide dimethylacetal and 60 ml of ethyl acetate Heat at about 75 ° C for 1 hour 15 minutes. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The residue is taken up in 50 ml of diisopropyl ether, suctioned off and washed three times with 25 ml of diisopropyl ether. There was thus obtained 6.65 g of ethyl 2- (2-chloro)

HU 206501 Β

6,7-Difluoro-3-quinolylcarbonyl) -3-dimethylaminoacrylate is obtained as an orange solid, m.p. 140 ° C.

Ethyl 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxopropionate can be prepared as follows:

A suspension of 14.13 g of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid in 29 ml of thionyl chloride and 220 ml of trichloromethane was heated at 60 ° C for 4 hours. The resulting solution was then concentrated under reduced pressure (20 kPa) at a temperature in the region of 60 ° C. The residue obtained is taken up in 75 ml of n-hexane, filtered off with suction and washed twice with 60 ml of n-hexane. 14.4 g of a yellow solid are obtained, which is dissolved in 115 ml of tetrahydrofuran. This solution was added dropwise, with stirring, over a period of 35 minutes at 5 to 10 ° C to a solution of 70 ml of malonic acid monoethyl ester magnesium chelate in tetrahydrofuran, prepared as described below. The temperature was then allowed to rise to 20 ° C and stirred at this temperature for a further 2 hours. The resulting solution was added dropwise with stirring over 30 minutes at 5 ° C to 560 ml of 0.5N sulfuric acid. The temperature was then allowed to rise to 20 ° C and

Stir at this temperature for 1.5 hours. Extract three times with 250 mL each of ethyl acetate. The organic extracts were combined, washed with water (2 x 250 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in 50 ml of 20% isopropyl ether in n-hexane, washed with 10 ml of the same solvent and recrystallized in 60 ml of 30% n-hexane in isopropanol. 11.84 g of ethyl 3- (2-chloro-6,7-difluoro-3-quinolyl) -3-oxopropionate are obtained as a cream solid, m.p. 107 ° C.

Preparation of magnesium chelate of malonic acid monoethyl ester:

To 2.78 g of magnesium filings are added portionwise 2 ml of anhydrous ethanol, 0.1 ml of tetrachloromethane and 1 g of malonic acid monoethyl ester. After heating, a solution of 9 g of malonic acid monoethyl ester in 180 ml of ethanol is added over 15 minutes. The mixture is heated at a temperature in the region of 75 ° C for 20 hours, then concentrated under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in toluene (2 x 100 ml) and concentrated under reduced pressure under the same conditions. The resulting gray powder was dissolved in anhydrous tetrahydrofuran to a total volume of 70 ml.

2-Chloro-6,7-difluoroquinoline-3-carboxylic acid can be prepared as follows:

To a suspension of 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline in 970 ml of 1N potassium hydroxide solution cooled to 10 ° C with stirring for 1 hour and while maintaining the temperature between 10 and 14 ° C, a solution of 115 g of potassium permanganate in 1.215 liters of water is added. The temperature was allowed to rise to 20 ° C and stirred at this temperature for another 30 minutes. At this time, 38.5 g of sodium dithionite were added, stirred for 10 minutes at about 20 ° C, filtered through diatomaceous earth and washed three times with 200-200 ml of water. The filtrate and the washings were combined and 140 ml of 35% aqueous hydrochloric acid were added. The resulting precipitate was extracted with ethyl acetate (4 x 800 mL). The organic extracts were combined and washed with water (2 x 500 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at 50 ° C. The residue obtained is taken up in 400 ml of ethyl ether, filtered off with suction and washed twice with 200 ml of ethyl ether each time. 49.2 g of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid are obtained in the form of a beige solid, m.p. 232 DEG C., which can be used without further purification.

2-Chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline can be prepared as follows:

To a mixture of trichloromethane (800 ml) and dimethylformamide (74.35 ml) was added phosphorus trichloride oxide (76.9 ml) with stirring at 10 to 15 ° C over 30 minutes and stir at about 20 ° C for 1 hour. Approximately 10 minutes was added to the resulting solution. At 20 'C, 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril is added with vigorous stirring. The resulting suspension is heated at a temperature in the region of 60 ° C for 2 hours. The reaction mixture is then concentrated under reduced pressure (20 kPa) at 50 ° C until the mixture becomes a paste. With vigorous stirring, a mixture of 500 g of ice and 500 ml of water is added. The resulting solid was filtered off with suction at 5 ° C and washed three times with 300-300 ml of water at 5 ° C. The resulting wet product and 60 g of sodium acetate are added simultaneously to 1.5 liters of 90 ° C water over 1 hour while maintaining the pH at about 6. After stirring for 30 minutes at 90 ° C, allow to cool to 50 ° C, drain at this temperature and wash three times with 300300 ml of water at about 20 ° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid, m.p. 260 DEG C., which can be used without further purification.

6,7-Difluoro-3,4-dihydrocarbostyril can be prepared as follows:

To 3 g of 4 ', 4'-difluoro-3-N-chloropropionic anilide is added 134 g of aluminum chloride with vigorous stirring, and after about 2 minutes, 135.9 g of 3', 4'-difluor is added in small portions over 15 minutes. -3-N-chloropropionic anilide and 272 g of aluminum chloride were added. The temperature automatically rises to 60 ° C and the reaction mixture becomes liquid. It is then heated at 110 ° C for 20 minutes and maintained at 110-120 ° C for 2 hours. The reaction mixture (about 110 ° C) was poured into a mixture of 840 ml of 35% hydrochloric acid and 1 kg of crushed ice with vigorous stirring for 10 minutes. The temperature is allowed to rise to 20 ° C, suction filtered, twice with 600-600 ml water, 300 ml 5 ° C ethanol and twice 400-400 ml ca. Wash with ethyl ether at 20 ° C. This gives 131.58 g of 6,7-difluoro-3,4-dihydrocarbostyril as a beige solid.

EN 206 50Í Β

Mp 216 ° C and can be used without further purification.

The 3 ', 4'-difluoro-3-N-chloropropionic anilide can be prepared as follows:

To a solution of 125 g of 3,4-difluoroaniline in 80 ml of pyridine and 1.5 liters of acetone and heated to 55 ° C was added 139.16 g of 3-chloropropionic acid chloride with stirring over 13 hours. hours. After cooling to about 20 ° C, the solution was poured into 1 liter of water and 500 g of ice with stirring. The temperature was allowed to rise to 20 ° C and extracted with dichloromethane (3 x 500 mL). The organic extracts were combined, washed with 500 mL of hydrochloric acid, five times with 500 mL of 500 mL of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at about 50 ° C. The resulting solid is taken up in 500 ml of n-hexane, filtered off with suction and washed twice with 100 ml of n-hexane each time. so

202.9 g of 3 ', 4'-difluoro-3-N-chloropropionic anilide are obtained as a beige solid, m.p. 76 ° C, which can be used without further purification.

Example 7

2.78 g of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxol, 4-dihydro-1,8-benzo [b] naphthyridine in 30 ml of 17.5% hydrochloric acid and A suspension of 1 ml of acetic acid was heated at 100 ° C for 1 hour. The reaction mixture was cooled to about 20 ° C and poured into water (100 mL). The resulting precipitate was filtered off with suction and washed three times with 3030 ml of water and twice with 5 ml of ethanol. Recrystallization from 100 ml of 20% ethanol in dimethylformamide gave 2.03 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid. as a solid, m.p. 325-327 ° C.

3-Ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

A suspension of 1.7 g of methoxylamine hydrochloride in 40 ml of trichloromethane was added to 2.13 g of trimethylamine. After stirring for 15 minutes at a temperature in the region of 20 ° C, the resulting solution was added to ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate (3.69 g) and stirred for 43 hours. stirring at a temperature of about 20 ° C. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken up in 70 ml of ethanol and 3.6 g of triethylamine are added and the mixture is heated for 30 minutes at a temperature in the region of 75 ° C. It was cooled to about 20 ° C and the resulting precipitate was filtered off with suction and washed three times with 30 ml of ethanol. This gives 2.67 g of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine as a pale yellow solid, m.p. 266-268 ° C. are good.

Example 8 3-Ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 80 ml aqueous 17.5% hydrochloride and 80 ml of acetic acid were heated at 100 ° C with stirring for 1.5 hours. After cooling to a temperature in the region of 20 ° C, the resulting solid is filtered off with suction and washed six times with 100 ml of water. Recrystallization from 160 ml of dimethylformamide gives 6.44 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid. , which decomposes at 360 ° C.

3-Ethoxycarbonyl-7,8-difluoro-1-methyl-4-o-o-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

To a suspension of 22.3 g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 480 ml of ethanol at 0 ° C for 10 minutes at 0 to 5 ° C A solution of methylamine (11.3 g, 0 ° C) in ethanol (50 ml) was added and stirred at 0-5 ° C for 1 hour, then allowed to rise to 25 ° C and stirred at this temperature for 16 hours. The insolubles were filtered off with suction, washed three times with 100 ml of ethanol and twice with 100 ml of ethyl ether. Recrystallized from 250 ml of dimethylformamide to give 16 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl- 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is obtained as a yellow solid, m.p. 323-324 ° C.

Example 9 3-Ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine with 30 ml acetic acid and 30 ml 50% hydrogen chloride solution is heated at about 100 ° C for 1 hour. The reaction mixture was cooled to 20 ° C and water (100 ml) was added. The resulting precipitate was filtered off with suction, washed with water (3 x 50 ml) and recrystallized from dimethylformamide (80 ml). 3.4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a colorless solid, m.p. are good.

3-Ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-one-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as follows:

To a suspension of 19.3 g of ethyl 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 150 ml of ethanol at a temperature in the region of 5 ° C for 10 minutes is 5 and 10 ° C. A solution of 10 g of methylamine in 50 ml of ethanol at a temperature of about 5 ° C was added at a temperature of 5 ° C, stirred at 5 ° C to 10 ° C for 1 hour and then allowed to rise to 20 ° C. The resulting solution was added to 1,8-diazabicyclo [5.4.0] undec-7-ene (7.6 g) and heated at a temperature in the region of 30 ° C for 1 hour. After cooling to about 20 ° C, the product is filtered off with suction and washed twice with 100 ml of ethanol and twice with 100 ml of diisopropyl ether. 13.4 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyrldine are obtained in the form of a yellow solid, m.p. 320 ° C. and can be used without further purification for further operations.

Ethyl 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate can be prepared as follows:

HU 206 501 Β

A suspension of 26.7 g of ethyl 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) -3-oxopropionate in 270 ml of ethyl acetate and 32 ml of Ν, Ν-dimethylformamide dimethylacetal is added at about 75 ° C. while stirring for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The resulting dry residue is taken up in 175 ml of diisopropyl ether, filtered off and washed twice with 85 ml of diisopropyl ether (85 ml each). 19.32 g of ethyl 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate are obtained in the form of an orange solid, m.p. which can be used without further purification.

Ethyl 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) -3-oxopropionate is prepared as follows:

A suspension of 46.3 g of 2-chloro-6,7,8-trifluoroquinoline-3-carboxylic acid in 640 ml of trichloromethane and 84 ml of thionyl chloride is heated with stirring at about 60 ° C for 6 hours. The resulting solution was concentrated to dryness under reduced pressure (20 kPa) at about 50 ° C. The resulting solid was taken up in 140 ml of light petroleum (40-60) and filtered off with suction and washed twice with 60-60 ml of light petroleum. 47.61 g of a yellow solid are obtained, which is dissolved in 400 ml of tetrahydrofuran. The solution was added dropwise, with stirring, over a period of 1.5 hours to a solution of 250 ml of malonic acid monoethyl ester magnesium chelate in tetrahydrofuran at 5 to 10 ° C, prepared as in Example 6. The temperature was then allowed to rise to 20 ° C and stirred for 2 hours at this temperature. The resulting solution was added dropwise to 1750 mL of 0.5 N sulfuric acid solution with vigorous stirring over 1 hour at about 5 ° C. After stirring for another 2 hours at 5 'C, it is extracted three times with 600-600 ml of ethyl ether at about 5' C. The organic layers were combined and washed with water (3 x 500 mL), dried over magnesium sulfate and concentrated under reduced pressure (20 kPa) at about 30 ° C. The resulting solid was taken up in a mixture of diisopropyl (135 mL) and n-hexane (15 mL), filtered off with suction, washed twice with 115 mL of the same mixture at about 5 C. There was thus obtained 47.4 g of ethyl 3- (2-chloro-6,7,8-trifluoro-3-quinolyl) -3-oxopropionate as a beige solid, m.p. 78-80 ° C. can be used without further action.

2-Chloro-6,7,8-trifluoro-quinoline-3-carboxylic acid can be prepared as follows:

To a suspension of 45.7 g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline in 585 ml of potassium hydroxide solution cooled to about 10 ° C with stirring for 1 hour and a solution of potassium permanganate (69.65 g) in water (730 ml) was added. It is then stirred for another 30 minutes at about 10 ° C. At this time, 12 g of sodium dithionite were added and the mixture was stirred for 10 minutes at about 10 ° C, filtered through diatomaceous earth and washed three times with 400-400 ml of water. The filtrate and the washings were combined and 70 ml of 35% aqueous hydrochloric acid was added. The resulting precipitate was extracted with ethyl acetate (3 x 500500 mL). The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 kPa) at 50 ° C. The residue was taken up in 100 ml of ethyl ether and 100 ml of diisopropyl ether, filtered off and washed with 100 ml of ethyl ether and diisopropyl ether to give 46.43 g of 2-chloro-6,7,8-trifluoroquinoline-3. Carboxylic acid is obtained as a colorless solid which decomposes at 225230 ° C and can be used without further purification.

2-Chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline can be prepared as follows:

525 ml of dichloromethane and 49 ml of dimethylformamide was added over 40 minutes with stirring in 50 ml of phosphorus oxychloride was added dropwise at 5 to 10 ° C and stirred for 15 minutes at this temperature, then allowed to warm to a temperature close to ^those of C 20 . To the resulting solution 46.8 g in portions under vigorous stirring over 20 minutes at about 20 ° C

6,7,8-Trifluoro-3,4-dihydro-carboxylic acid is added. Stir for 30 minutes at about 20 'C, then warm to 60' C and hold at this temperature for 2.5 hours. The reaction mixture is then concentrated under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The oily residue is poured onto 500 g of ice with vigorous stirring. Sodium acetate (100 g) was added in small portions over 30 minutes. The resulting slurry was poured into 1 L of water with vigorous stirring for 15 minutes, which was preheated to 90 ° C and stirred for 15 minutes at 90 ° C. The insoluble material is filtered off with suction at 90 ° C and washed three times with 250-250 ml of water. so

47.7 g of 2-chloro-6,7,8-trifluoro-3-formyl-1,4-dihydroquinoline are obtained as a colorless solid which decomposes at 220 '.

6,7,8-Trifluoro-3,4-dihydrocarbostyril can be prepared as follows:

A mixture of 24.35 g of 6,7,8-trifluorocarbostyril in 450 ml of ethanol and 150 ml of dimethylformamide was hydrogenated with stirring at about 50 ° C in the presence of 5 g of Raney nickel at atmospheric pressure until hydrogen uptake ceased. The quality of the Raney nickel used was washed with W-2, previously with 50 ml of 2% aqueous acetic acid, twice with 50 ml of water and three times with 50 ml of ethanol. The reaction mixture is then added to 250 ml of dimethylformamide and filtered through diatomaceous earth at a temperature in the region of 50 ° C. The filtrate was concentrated under reduced pressure (20 kPa) at about 70 ° C. The dry residue is taken up in 150 ml of water, filtered off with suction and washed twice with 5050 ml of water. 23.6 g of 6,7,8-trifluoro-3,4-dihydrocarbostyril are obtained in the form of a light beige solid, m.p. 217C, which can be used without further purification.

6,7,8-trifluorocarbostyril can be prepared as follows:

60.83 g of 4-chloro-6,7,8-trifluorocarbostyril in 520 ml of acetic acid and 38.15 ml of triethylamine

The suspension is hydrogenated at 1 atmospheric pressure in the presence of 5.25 g of 10% palladium on carbon at about 25 ° C until hydrogen uptake ceases. Subsequently, the reaction mixture is heated to 40 ° C, filtered through diatomaceous earth at this temperature, and the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken up in 400 ml of water, the insoluble matters are filtered off with suction, washed four times with 170-170 ml of water, twice with 110-110 ml of ethanol and twice with 100-100 ml of diisopropyl ether. 48.35 g of 6,7,8-trifluorocarbostyril are obtained in the form of a colorless solid which sublimates at 288C and can be used without further purification.

4-Chloro-6,7,8-trifluorocarbostyril can be prepared as follows:

A suspension of 70.4 g of 4-chloro-2-ethoxy-6,7,8-trifluoroquinoline in 170 ml of aqueous 35% hydrochloric acid and 420 ml of acetic acid and 250 ml of water is stirred at a temperature of about 100 ° C. heated in

2.5 hours. It is then cooled to about 20 ° C and the reaction mixture is poured into 1100 ml of water at about 5 ° C and stirred for 15 minutes at this temperature. The insoluble material is then suctioned off and washed three times with 220-220 ml of water. This gives 61 g of 4-chloro-6,7,8-trifluorocarbostyril as a cream colored solid, m.p. 213 ° C, which can be used without further purification.

4-Chloro-2-ethoxy-6,7,8-trifluoro-quinoline can be prepared as follows:

A suspension of 69.5 g of 2-ethoxy-6,7,8-trifluoro-4-hydroxyquinoline in 430 ml of phosphorus trichloride is heated at 100 ° C for 30 minutes with stirring. The resulting solution was concentrated under reduced pressure (20 kPa) at a temperature in the region of 60 ° C to a volume of 100 ml. The residue is taken up in 750 ml of ethyl acetate and the resulting solution is poured into a mixture of 400 ml of water and 200 g of ice with stirring for 10 minutes and then stirred under the same conditions for 30 minutes. The organic extract was separated and the aqueous phase was extracted with ethyl acetate (2 x 250 mL). The organic extracts were washed with water (3.times.250 ml), dried over magnesium sulfate and concentrated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The resulting oily residue was taken up in 370 ml of light petroleum (40-60). It is filtered through diatomaceous earth and the filtrate is concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 30 ° C. 70.7 g of 4-chloro-2-ethoxy-6,7,8-trifluoroquinoline are obtained in the form of a beige solid, m.p. 45 ° C, which can be used without further purification.

2-Ethoxy-6,7,8-trifluoro-4-hydroxyquinoline can be prepared as follows:

A solution of 122 g of 2,3,4-trifluoro-N - [(1'-ethoxy-2'-ethoxycarbonyl) ethylidene] aniline in 120 ml of diphenyl ether was added dropwise with stirring over a period of 25 minutes to 600 ml at about 250 ° C. temperature, and the resulting ethanol is removed by distillation. After stirring for 15 minutes at 250 ° C, the solution is cooled to 20 ° C and 750 ml of n-hexane are added. The resulting precipitate was filtered off with suction and washed three times with 200 ml of n-hexane. so

69.5 g of 2-ethoxy-6,7,8-trifluoro-4-hydroxyquinoline are obtained in the form of a beige solid, m.p. 171 ', which can be used without further purification.

A2,3,4-Trifluoro-N - [(1'-ethoxy-2'-ethoxycarbonyl) ethylidene] aniline can be prepared as follows:

To a solution of (2-ethoxycarbonyl-1-ethoxy) ethylideneaminine hydrochloride (8 g) in ethanol (820 mL) was added 2,3,4-trifluoroaniline (58.8 g). After stirring for 48 hours at a temperature in the region of 20 ° C, the resulting suspension is filtered, and the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. An oily residue is obtained which is taken up in 250 ml of water. The resulting mixture was extracted with ethyl ether (3 x 200 mL). The organic extracts were combined and washed with water (4 x 150 mL), dried over magnesium sulfate and concentrated under reduced pressure (20 kPa) at about 30 ° C. 122 g of 2,3,4-trifluoro (N - [(1 '-ethoxy-2'-ethoxycarbonyl) ethylidene] aniline are obtained as a yellow oil which can be used without further purification.

(2-Ethoxycarbonyl-1-ethoxy) -ethylenediamine hydrochloride was prepared by Pinner, A. et al. Dtsch. Chem. Ges., 28, 478 (1895). j

Example 10

6,7,8-Trifluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid can be prepared according to the procedure of Example 9, but 9 g of 3-ethoxy starting from carbonyl-6,7,8-trifluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. 7.7 g of 6,7,8-trifluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a beige solid, m.p. .

3-Ethoxycarbonyl-6,7,8-trifluoro-1-methoxy-4-oxol, 4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

A suspension of 5.1 g of methyl hydroxylamine HCL in 120 ml of trichloromethane is added to 8.7 ml of triethylamine. The resulting solution was heated to about 20 ° C

Ethyl 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate (7.8 g) was added. After stirring for two hours at about 20 ° C, the solution was concentrated to dryness under reduced pressure (20 kPa) at about 50 ° C. The resulting residue was taken up in 150 ml of ethanol and heated with 10 ml of triethylamine with stirring for 30 minutes. After cooling to a temperature in the region of 20 'C, the insolubles were filtered off with suction, washed three times with 50 ml of ethanol and twice with 50 ml of diisopropyl ether. Recrystallization from 120 ml of dimethylformamide gives 9 g of 3-ethoxycarbonyl-6,7,8-trifluoro-1-methoxy-4-οχο-1,4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid. 298-300'C.

HU 206 501 Β

Π. example

The procedure of Example 9, however, was followed

Starting from 1.8 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo (b) naphthyridine, 1.1 g of 1-cyclopropyl are obtained. -7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 304 ° C.

1-Cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

of ethyl 2- (2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate in 100 ml of trichloromethane at a temperature in the region of 20 DEG C. for 5 min. g of cyclopropylamine was added and stirring was continued for 4 hours at this temperature. The reaction mixture was then concentrated under reduced pressure (20 kPa) at a temperature in the region of 50 ° C. The resulting oily residue is taken up in 100 ml of ethanol and 3 g of 1,8-diazabicyclo [5.4.0] undec-7-ene are added. The mixture was heated to 80 ° C and stirred at this temperature for 1.5 hours. Cool for approx. At 20 'C, the insoluble matters are filtered off with suction, washed twice with 30-30 ml of ethanol and twice with 30-30 ml of diisopropyl ether. 4.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a colorless solid. The C's are.

Example 12 8-Chloro-3-ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 120 ml water, 120 ml ethanol and 47 g. A suspension of 5 ml of aqueous 2N potassium hydroxide was heated at 75 ° C with stirring for 2.5 hours. The insoluble material is filtered off at a temperature of about 75 ° C. Cool to about 20 ° C and add 6 ml of acetic acid to the filtrate. The precipitate formed is filtered off with suction. washed three times with 20 ml of water and then recrystallized in 60 ml of dimethylformamide. There was thus obtained 4 g of 8-chloro-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a yellow solid which decomposes at 285 ° C. .

8-Chloro-3-ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

of a suspension of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine and 5.16 g of potassium carbonate in 120 ml of dimethylformamide. It is heated to 'C and maintained at this temperature for 1 hour. After cooling to 15 'C, 5.44 ml of chloromethyl ether was added and stirred for 5 hours at a temperature between 15 and 20 ° C. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at 60 ° C. The residue was taken up three times with 150150 ml of trichloromethane. The organic extracts were combined and the insolubles removed by filtration. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure (20 kPa) at a temperature in the region of 40 ° C. The resulting residue was recrystallized from 55 ml of dimethylformamide. 5.6 g of 8-chloro-3-ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a beige solid. They are C's.

8-Chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

Ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) 3-dimethylaminoacrylate (11.3 g) and 3-amino-1,2,4-triazine (5.65 g) in 60 ml trichloromethane was stirred for 16 hours at a temperature in the region of 20 ° C. The reaction mixture is then concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 30 ° C. The residue obtained is taken up in 60 ml of ethanol and 5.6 g

1.8-Diazabicyclo [5.4.0] undec-7-ene is added and heated at about 75 ° C for 20 hours. The reaction mixture was cooled to 20 ° C, the insoluble material was suctioned off and washed twice with 40 ml of ethanol. 6.1 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained in the form of a brown solid, m.p. decomposes and can be used without further purification.

Example 13

A suspension of 5.75 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 60 ml of 17.5% hydrochloric acid was added. while stirring, at a temperature of about 100 ° C for 30 minutes. It is cooled to about 20 ° C and the insoluble matters are filtered off with suction, washed three times with 20 ml of ethanol and three times with 20 ml of ethyl ether. This gives 3.05 g of 8-chloro-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a beige solid which decomposes at 416 ° C. .

Example 14 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 80 ml of 17.5% hydrochloric acid and a suspension of 80 ml of acetic acid was heated at about 100 ° C with stirring for 1.5 hours. It is then cooled to about 20 ° C, the insolubles are suctioned off, washed three times with 20 ml of water and recrystallized in 50 ml of dimethylformamide. 6.3 g of 1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, m.p.

3-Ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is prepared as follows:

g of ethyl 2- (2-chloro-6,7-difluoro-3-quinolinecarbonyl) -3-dimethylaminoacrylate in 200 ml of ethanol at about 2 ° C for 10 minutes at 2 and 5 ° C with stirring. 6 g ethylamine in 200 ml ethanol and ca. A solution of 2 'C was added and the mixture was stirred for 40 minutes at 2-5' C and then allowed to rise to about 20 'over 2 hours. The reaction mixture was allowed to stand at 20 ° C for 24 hours, and the insolubles were filtered off with suction, washed twice with 3030 ml of ethanol and twice with 50 ml of diisopropyl ether.

HU 206 501 Β Wash. 16.35 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained as a beige solid, m.p. They are C's.

Example 15

8-Chloro-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydrol, 8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the procedure of Example 9, but 2.2 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. Recrystallization from 2 x 10 mL dimethylformamide gave 1.4 g of 8-chloro-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine -3-Carboxylic acid is obtained as a yellow solid, m.p. 310 ° C.

8-Chloro-3-ethoxycarbonyl-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine can be prepared as follows:

A suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 ml of trichloromethane was added to 2.7 ml of triethylamine. The resulting solution was heated to about 20 ° C

Ethyl 2- (2,7-dichloro-6-fluoro-3-quinolinecarbonyl) -3-dimethylamino-acrylate (3.5 g) was added. After stirring for 16 hours at about 20 ° C, the resulting solution is concentrated to dryness under reduced pressure (20 kPa) at about 50 ° C. The resulting residue was taken up in ethanol (20 ml) and triethylamine (3 ml) was added and heated at about 75 ° C for 2 hours with stirring. After cooling to about 20 ° C, the insoluble material is suctioned off, washed twice with 10 ml of ethanol and twice with 10 ml of diisopropyl ether. This gives 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine as a yellow solid m.p. 268 DEG C. which can be used without further purification.

The compounds of the present invention may be used in the following exemplary processes:

/. reference example

3.5 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 ml of pyridine of the slurry was heated at about 115 ° C with stirring for 13 hours. The reaction mixture was then concentrated to dryness under reduced pressure (20 kPa) at 60 ° C. The residue obtained is taken up in twice 30-30 ml of ethanol and concentrated again under reduced pressure under the above conditions. The resulting solid was taken up in 60 mL water and 10 mL 30% aqueous potassium hydroxide solution. The aqueous phase was washed with trichloromethane (2 x 100 mL), methanesulfonic acid (10.28 g) was added and washed again with trichloromethane (2 x 100 mL). At this time, 10 ml of a 30% aqueous solution of potassium hydroxide was added. The resulting precipitate was filtered off with suction, washed three times with 10 ml of water and twice with 10 ml of ethanol. 2.7 g of 7-fluoro-1-methyl-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are thus obtained in the form of a yellow solid. as a solid, m.p. 360-363 ° C.

Reference Example 2

7-Fluoro-1-methyl-4-oxo-8- (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared according to the procedure of Reference Example 1. , however, 10 g

Starting from a mixture of 8-chloro-7-fluoro-1-methyl-4-χχο-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 28 g of piperazine in 100 ml of pyridine. 5.5 g 7-fluoro-l-methyl-4-oxo-8- (piperazin-l-yl) -l, 4-dihydro-8benzo [b] naphthyridine-3-karbonsavxl / 2 H ₂ O as a yellow as a solid, m.p. 370-375 ° C.

Reference Example 3

7-Fluoro-1-methyl-8- (4-methylpiperazin-1-yl) -4-oxole, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared as described in Reference Example 1. but with 5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 16 g of 1-methylpiperazine Start from a mixture of 50 ml of pyridine. The reaction mixture was concentrated under reduced pressure and the resulting residue was suspended in 100 ml of water and 25 ml of acetic acid were added. Insolubles were removed by filtration through diatomaceous earth. To the filtrate was added 200 ml of aqueous 3N potassium hydroxide solution and the insolubles were again removed by filtration through diatomaceous earth, and 5 ml of acetic acid was added to the filtrate. The precipitate formed is filtered off with suction and washed three times with 50 ml of water. It was recrystallized from dimethylformamide (2 x 17 mL) to give 3.2 g of 7-fluoro-1-methyl-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,4- Benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 356 ° C.

Reference Example 4

8- (4-Ethyl-piperazin-1-yl) -7-fluoro-1-methyl-4-oxol, 4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared as described in Reference Example 5. However, 1.85 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.75 g

Start from a mixture of 1-ethylpiperazine with 20 ml of pyridine. This gives 1.3 g of 8- (4-ethylpiperazin-1-yl) -7-fluoro-1-methyl-4-chloro-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, as a yellow solid, m.p. 285286 ° C.

Reference Example 5

7-Fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -1-methyl4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid prepared according to the procedure of Reference Example 1, but 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrol, 8-benzo [b] naphthyridine-3-carboxylic acid and Starting from 8 g of 1- (2-hydroxyethyl) -piperazine in 16 ml of pyridine. The reaction mixture was concentrated under reduced pressure and the residue was taken up in 50 ml of water. The pH of the mixture was adjusted to 6.9 by the addition of 0.4 ml of acetic acid. The resulting precipitate was filtered off with suction, washed with water (2 x 0 ml) and recrystallized (2 x 10 ml) from dimethylformamide. Thus 1.1 g of 7-fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -1-methyl-4-o-o-1,4-dihydro-1,8-benzo [b] naphthyridine -3-carboxylic acid was obtained as a yellow solid, m.p. 275-276 ° C.

HU 206501 Β Int Cl ⁵ : C 07 D 471/04

Reference Example 6

8- (3,5-Dimethyl-piperazin-1-yl) -7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid except for 1.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid Start with a mixture of 2,6-dimethylpiperazine in 20 ml of pyridine. Thus 1.1 g of 8- (3,5-dimethylpiperazin-1-yl) -7-fluoro-1-methyl-4-o-o-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained. 2 H ₂ O is obtained as a yellow solid, m.p. 294-295 ° C.

Reference Example 7

1-Ethyl-7-fluoro-8- (piperazin-1-yl) -4-oxo-1,4-dihydrol, 8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the procedure of Reference Example 5, but Starting from a mixture of 1.6 g of 8-chloro-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 ml of pyridine. Recrystallization three times in a total of 300 ml of dimethylformamide gives 0.94 g of 1-ethyl-7-fluoro-8- (piperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine. 3-Carboxylic acid 3 H ₂ O is obtained as a yellow solid, m.p. 320-322 ° C.

Reference Example 8

1-Ethyl-7-fluoro-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid according to Reference Example 5. however,

1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 4.5 g of 4-methylpiperazine of pyridine. Recrystallize four times in a total of 120 ml of dimethylformamide to give 1.2 g of 1-ethyl-7-fluoro-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8- Benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 285-286 ° C and solvated with 1% water.

Reference Example 9

1-Ethyl-7-fluoro-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to Reference Example 1. however,

2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.4 g of 2-methylpiperazine. of pyridine.

It is taken up in ethanol and concentrated to dryness under reduced pressure (20 kPa) at 50 ° C. The resulting solid residue was taken up in water (20 mL) and 2N potassium hydroxide solution (10 mL). The resulting aqueous solution was washed with trichloromethane (2 x 20 mL) and acetic acid (10 mL) was added, followed by washing with trichloromethane (2 x 40 mL). Subsequently, 23 ml of 4.5 N potassium hydroxide solution were added and the resulting suspension was heated to about 90 ° C. After cooling to about 20 'C, the resulting precipitate was filtered off with suction, washed three times with 10 ml of water and twice with 10 ml of ethanol. Recrystallization twice from 120-120 ml of dimethylformamide gives 1.7 g of 1-ethyl-7-fluoro-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8- Benzo [b] n aphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 310-312 ° C.

Reference Example 10

1-Ethyl-8- (4-ethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid according to Reference Example 5. however,

1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 2.3 g of 1-ethylpiperazine in 16 ml starting from a mixture of pyridine. so

1.4 g of 1-ethyl-8- (4-ethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid. m.p. 287-288 ° C and solvated with 1.6% water.

Reference Example 11 1-Ethyl-7-fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine 3-Carboxylic acid was prepared according to the procedure of Reference Example 5, but 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrol, 8-benzo [b] naphthyridine-3 Starting from a mixture of carboxylic acid and 2.6 g of 1- (2-hydroxyethyl) piperazine in 16 ml of pyridine. Thus 1.3 g of 1-ethyl-7-fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxylic acid is obtained as a yellow solid, m.p. 264-265 ° C.

Reference Example 12

7-Fluoro-1-methylamino-4-oxo-8- (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the procedure of Reference Example 5. , However

8-Chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid (2.25 g) and piperazine (2.4 g) in pyridine (30 ml) we start with. Recrystallization three times in a total of 400 mL of dimethylformamide gives 0.82 g of 7-fluoro-1-methylamino-4-oxo-8- (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine. 3-Carboxylic acid is obtained as a dark yellow solid, m.p. 322-324 ° C, solvated with 13.6% dimethylformamide.

Reference Example 13

7-Fluoro-1-methylamino-8- (4-methylpiperazin-1-yl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is illustrated in Example 1. Prepared according to the procedure of Reference Example 1, but 1.93 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2 Start with a mixture of 4 g of 1-methylpiperazine in 20 ml of pyridine. Recrystallize twice from 15 ml of dimethylformamide to give 0.9 g of 7-fluoro-1-methylamino-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] Naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 263-264 ° C.

Reference Example 14

7-Fluoro-1-methylamino-8- (3-methylpiperazin-1-yl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is described in Example 5. Prepared according to the procedure of Reference Example 3, however, 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 4 g of Start with a mixture of 2-methylpiperazine in 40 ml of pyridine. The crude product obtained is taken up in 30 ml of water and 7 ml of aqueous 2N potassium hydroxide solution. The no

HU 206 501 Β

Int. Cl. ⁵ : C 07 D 471/04 soluble parts are removed by filtration through diatomaceous earth. The filtrate was washed with ethyl ether (2 x 20 mL) and a precipitate was formed by addition of 4 mL of 4N methanesulfonic acid solution. The resulting precipitate was filtered off with suction, washed with water (3 x 20-20 mL) and ethanol (3 x 20-20 mL) to give 2.2 g of 7-fluoro-1-methylamino-8- (3-methylpiperazin-1-yl) -4- Oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a dark yellow solid, m.p. 343-345 ° C, solvated with 3.7% water.

/ 5, Reference Example

1-Cyclopropyl-7-fluoro-4-oxo-8- (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the procedure of Reference Example 5. however, starting from 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.6 g of piperazine in 10 ml of pyridine . There was thus obtained 0.6 g of 1-cyclopropyl-7-fluoro-4-oxo-8- (piperazin-1-yl) 1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid ₂ , as a solid, m.p. 342-343 ° C.

Reference Example 16

1-Cyclopropyl-7-fluoro-8- (4-methylpiperazin-1-yl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared according to Reference Example 5. However, 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 3 g of 1-methyl- of piperazine in 10 ml of pyridine. After recrystallization from 10 ml of dimethylformamide, 0.63 g of 1-cyclopropyl-7-fluoro-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [. b] Naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 250 ° C.

Reference Example 17

1-Cyclopropyl-7-fluoro-8- (3-methylpiperazin-1-yl) 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is prepared from Reference Example 1. However, 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 3 g of 2-methyl- of piperazine in 10 ml of pyridine. The pure product obtained is purified once more by recrystallization from 200 ml of dimethylformamide. 0.5 g of 1-cyclopropyl-7-fluoro-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained. H ₂ O is obtained as a yellow solid, m.p. 343 ° C.

/ Reference Example 8

1-Cyclopropyl-8- (4-ethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid according to Reference Example 5. However, 2 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.74 g of 1-ethylpiperazine Start from a mixture of 20 ml of pyridine. The pure product obtained is isolated by recrystallization first in 105 ml of 25% dimethylformamide ethanol and second in 75 ml of 50% dimethylformamide ethanol. Thus 0.67 g of 1-cyclopropyl-8- (4-ethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained. m.p. 254 DEG C. as a yellow-green solid.

Reference Example 19

1-Cyclopropyl-7-fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -4-O-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid Prepared according to the procedure of Reference Example 5, but 4 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and

Start from 6.2 g of 1- (2-hydroxyethyl) piperazine in 40 ml of pyridine. The reaction mixture was heated at about 115 ° C for 22 hours. The product is isolated and recrystallized three times from 200-200 ml of 10% dimethylformamide in ethanol. Thus 0.94 g of 1-cyclopropyl-7-fluoro-8- [4- (2-hydroxyethyl) piperazin-1-yl] -4-oxo-1,4-dihydro-1,8-benzo [b] are obtained. Naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 255 ° C.

Reference Example 20

7-Fluoro-4-oxo-8- (piperazin-1-yl) -1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared according to the procedure of Reference Example 5. however,

A mixture of 1.7 g of 8-chloro-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 ml of pyridine let's start. The pure product obtained was recrystallized from dimethylformamide (20 ml). There was thus obtained 1.25 g of 7-fluoro-4-oxo-8- (piperazin-1-yl) -1-tert-butyl-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid, as a solid, m.p. 290 ° C, solvated with 1.5% water.

Reference Example 21

1.15 g 7-Fluoro-1-methyl-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 1.35 g A solution of formic acid solution and 3.25 ml of 98% aqueous ml, 30% aqueous formaldehyde solution is heated at about 100 C for 2 hours ^e. The reaction mixture was then concentrated under reduced pressure (20 kPa) at 50 ° C, water (5 ml) was added, and the resulting solution was adjusted to pH 7 with 0.5 ml of aqueous 2N potassium hydroxide solution (100 ml). Heat at a temperature in the region of 2 ° C for 2 minutes. The product crystallized, filtered off with suction at 20 ° C and washed twice with 10 ml of water. The crude product obtained was recrystallized from dimethylformamide (2 x 10 ml). 0.55 g of 8- (3,4-dimethyl-piperazin-1-yl) -7-fluoro-1-methyl-4-o-o-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid M.p. 306-308 ° C.

Reference Example 22

8- (3,4-Dimethyl-piperazin-1-yl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid except that 2.3 g of 1-ethyl-7-fluoro-8- (3-methylpiperazin-1-yl) 4-oxo-1,4-dihydro-1,8-benzo [b] were obtained. naphthyridine-3-carboxylic acid,

2.26 ml of 98% formic acid solution and 5.6 ml of water,

HU 206 501 Β

Int Cl ⁵ : C 07 D 471/04

Start from a mixture of 30% formaldehyde. There was thus obtained 1.75 g of 8- (3,4-dimethylpiperazin-1-yl) -1-ethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a solid, m.p. 293-294 ° C.

Reference Example 23

1-Cyclopropyl-8- (3,4-dimethyl-piperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid Prepared according to Reference Example II, but 1.9 g of 1-cyclopropyl-7-fluoro-8- (3-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo Starting from a mixture of [b] naphthyridine-3-carboxylic acid in 1.38 ml of formic acid and 3.30 ml of 30% aqueous formaldehyde solution. The crude product was recrystallized from ethanol (50 mL) to give 1.3 g of 1-cyclopropyl-8- (3,4-dimethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1 8benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 219 ° C.

Reference Example 24

0.47 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrol, 8-benzo [b] naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine with 7 ml of dimethyl sulfoxide of the suspension is heated at a temperature in the region of 80 ° C for 15 minutes. The reaction mixture was poured into water (25 mL) and 1N hydrochloric acid (9 mL) was added. The resulting solid is filtered off with suction and washed three times with 5 ml of water. Recrystallization from a mixture of 4.5 ml of ethanol and 4.5 ml of dimethylformamide gives 0.29 g of 1-cyclopropyl-7-fluoro-8- (4-methylpiperazin-1-yl) -4-oxo-1,4 dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 250 ° C.

Reference Example 25 A suspension 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 in 40 ml of dimethylsulfoxide. Stir for 15 minutes at 40 ° C. After cooling to about 20 ° C, the reaction mixture was poured into 150 ml of water and 27.75 ml of 2N methanesulfonic acid solution was added. Insolubles were removed by filtration through diatomaceous earth. To the resulting solution was added 15 ml of aqueous 2N potassium hydroxide solution. The resulting precipitate is filtered off with suction, washed three times with 15 ml of water and taken up in 100 ml of dimethylformamide. It is heated for 10 minutes at about 150 ° C with stirring. The suspension is cooled to about 100 ° C, the insolubles are suctioned off, taken up in 100 ml of ethanol and heated at about 75 ° C for 1 hour. The insoluble material is suctioned off at about 50 ° C and washed with 40 ml of 50 ° C ethanol. This gave 1.8 g of 7-fluoro-1-methoxy-4-oxo-8 (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid as a brown solid, m.p. M.p. -300 ° C, solvated with 2.4% water.

Reference Example 26

0.93 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1.8;

A suspension of benzo (b) naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 20 ml of dimethyl sulfoxide was heated at about 80 ° C for 5 minutes, cooled to about 20 ° C and poured into water (30 ml). 1.5 ml of 2N methanesulfonic acid solution are added, filtered off with suction and washed three times with 5 ml of water each, recrystallized in 30 ml of 30% ethanol dimethylformamide to give 0.55 g of 7-fluoro- 1-methoxy-8- (4). methyl methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a brown solid, m.p. 270 ° C.

Reference Example 27 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 7.44 g of 2,2-dimethylpiperazine in 20 ml of piperazine was heated at 115 ° C for 44 hours. Reference is made to the procedure of Reference Example 1 and so on

1.6 g of 8- (3,3-dimethylpiperazin-1-yl) -7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained as a yellow solid, m.p. mp 362-365 ° C and solvated with 4.9% water.

Reference Example 28 7,8,9-Trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 3 g 1-methylpiperazine in 60 ml A suspension of dimethyl sulfoxide was heated at 80 ° C for 1.5 hours. The reaction mixture was cooled to 20 ° C and water (150 ml) was added. To the resulting solution was added 18 ml of a 10% acetic acid solution. The resulting precipitate was filtered off with suction, washed three times with 5050 ml of water and recrystallized from 50 ml of dimethylformamide. Thus 4 g of 7,9-difluoro-1-methyl-8- (4-methylpiperazin-1-yl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained. of the title compound as a yellow solid, m.p. 316 ° C.

Reference Example 29 6,7,8-Trifluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 2.8 g piperazine in 40 ml dimethylsulfoxide the suspension is heated with stirring at a temperature in the region of 50 ° C for 45 minutes. After cooling to a temperature in the region of 20 'C, the suspension is poured into 100 ml of water and then 9.22 g of methanesulfonic acid are added. Insolubles were removed by filtration through diatomaceous earth. The filtrate was added to 32 ml of aqueous 2N potassium hydroxide solution. The resulting precipitate was filtered off with suction, washed with water (3 x 50 ml) and recrystallized from dimethylformamide (80 ml). 1.4 g of 7,9-difluoro-1-methoxy-4-oxo-8 (piperazin-1-yl) -1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, m.p. mp 305-308 ° C.

Reference Example 30

1.2 g of 8-chloro-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid and 3.52 g A suspension of 1-methylpiperazine in 12 ml of pyridine was heated with stirring at about 110 ° C for 6 hours. Referred to in Reference Example 3

HU 206 501 Β

Int. Cl. ⁵ : C 07 D 471/04 gave 0.6 g of 7-fluoro-1- (2-fluoroethyl) -8- (4-methylpiperazin-1-yl) -4-. Oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid is obtained as a yellow solid, m.p. 306-308 ° C.

The invention also relates to a process for the preparation of human and veterinary topical formulations containing as active ingredient at least one compound of formula I wherein R is other than a protecting group, alone (in free form or in the form of a salt) or pharmaceutically acceptable carrier (s). with excipients.

Solid topical formulations include powders, creams, ointments and gels. These formulations contain the active ingredient of the formula I in admixture with one or more excipients or inactive excipients such as lactose, cellulose derivatives or talc. The formulations may also contain other excipients, such as fatty acids or derivatives thereof, or animal, vegetable or synthetic fats.

Liquid topical formulations are pharmaceutically acceptable emulsions, solutions and suspensions containing inert diluents such as water, oils (paraffin oil, olive oil), their organic esters. The formulations may also contain other excipients such as wetting agents, emulsifying, dispersing or stabilizing agents.

The formulations may also be prepared as solid formulations and reconstituted immediately prior to use.

Formulations containing the compounds of formula (I) are useful in the treatment of dermal staphylococcal infections.

The formulations generally have a concentration of 0.1% to 1%.

The following example illustrates a composition comprising a compound of formula (I).

Example

-cyclopropyl 1 -7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid 1 g zinc oxide supplemented with 1.5 g talc to 100 g the mass.

The compounds of formula (I) may also be used for the preservation and disinfection of organic or inorganic materials and in the following industries: dyes, fats, paper, wood, polymers, textiles, food or water. The present invention relates to all compositions containing the compound of formula (I) alone or in combination with compatible diluents or excipients and for use in disinfection or preservation.

Claims (6)

A process for the preparation of 1,8-benzo [b] naphthyridine derivatives of formula I wherein R is hydrogen, alkyl, fluoroalkyl, C3-6cycloalkyl, alkyloxy, alkylamino or alkoxyalkyl. . Hal is fluorine, chlorine or bromine when R 'is hydrogen Hal and R 'are 1 to 1 fluorine atoms, and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms, to form their metal salts and addition salts with nitrogenous bases, wherein ester - in the formula Hal and R'a have the meanings above, and R is hydrogen, alkyl, fluoroalkyl, C3-C6 cycloalkyl, alkyloxy, alkoxyalkyl or optionally protected alkylamino, Alk is alkyl, and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms, the optional protecting group of the alkylamino group is removed, optionally with the metal salt of the compound of formula I or with a nitrogenous base. to its addition salt. (Priority: 15.1.1990) 2. A process for the preparation of 1,8-benzo [b] naphthyridine derivatives of the formula I: R is hydrogen, alkyl, C3-6 cycloalkyl or alkylamino, Fish means chlorine or bromine, and R 'is hydrogen and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms, to form their metal salts and addition salts with nitrogenous bases, wherein an ester of formula II wherein Hal is and R'a have the meanings given above, and R is hydrogen, alkyl, C3-6 cycloalkyl, alkylamino or N-formyl-N-methylamino, Alk is alkyl, and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms known to be converted into the acid in a known manner, optionally removing the formyl from the N-formyl-N-methyl group to the metal salt thereof. with a nitrogen-containing base. (Priority: January 16, 1989) 3. A process for the preparation of 1,8-benzo [b] naphthyridine derivatives of formula (I) R is hydrogen, alkyl, C3-6 cycloalkyl, alkyloxy or alkylamino, Hal is fluorine, R 'is hydrogen, and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms with their metals and nitrogenous bases. HU 206 501 Β Int. Cl. ⁵ : C 07 D 471/04 for the addition of an ester of formula (II) Fish and R 'have the meaning fend, and R is hydrogen, alkyl, C3-C6 cycloalkyl, alkyloxy, alkoxyalkyl or optionally protected alkylamino, Alk is alkyl and the above alkyl groups and moieties are linear or branched and have 1 to 4 carbon atoms known to be acidified in a known manner, optionally deprotecting the alkylamino group, optionally to give the compound of formula I as its metal salt or with a nitrogen-containing base. (Priority: July 28, 1989) A process for the preparation of a pharmaceutical composition comprising a 1,8-benzonaphthyridine derivative of the Formula I wherein R, Hal and R 'are as defined in claim 1, except alkoxyalkyl, or a metal salt or a nitrogen-containing addition salt thereof. The active ingredient of the method of claim 1 is processed together with the usual excipients into a pharmaceutical composition. (Priority: January 15, 1990) 5. A process for the preparation of a pharmaceutical composition comprising, as active ingredient, a 1,8-benzonaphthyridine derivative of the Formula I, wherein R, Hal and R 'are as defined in claim 2, or a metal salt or a nitrogen addition salt thereof. The active ingredient of the process of claim 2, together with the usual excipients, is processed into a pharmaceutical composition. (Priority: Jan 16, 1989) 6. A process for the preparation of a pharmaceutical composition comprising, as active ingredient, a 1,8-benzonaphthyridine derivative of formula (I) wherein R, Hal and R 'are as defined in claim 3, or a metal salt or a nitrogen addition salt thereof. The active ingredient of the process of claim 3, together with the usual excipients, is processed into a pharmaceutical composition. (Priority: July 28, 1989)