DD257428A5 - PROCESS FOR PREPARING 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTHYDRIDINE-3-CARBON ACIDES - Google Patents

Abstract

The invention relates to a process for the preparation of 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids. According to the invention, compounds of the formula (I) are prepared in which, for example: or chlorine or fluorine, R 1 is hydrogen, branched or unbranched alkyl group having 1 to 4 carbon atoms, an optionally substituted phenylacyl radical and the like. a, R2 is hydrogen, methyl or optionally substituted by chlorine, fluorine, methyl, hydroxy or methoxy phenyl or thienyl, R3 is hydrogen or methyl and their pharmaceutically acceptable hydrates, Saede addition salts, alkali, alkaline earth, silver and guanidinium salts and their esters and other common prodrug forms. Formula (I)

Description

Field of application of the invention

The invention relates to processes for the preparation of novel 6,7-disubstituted i-cyclopropyl-i ^ -dihydro- ^ oxo-i ^ -naphthyridin-S-carboxylic acids and their intermediates and these compounds containing anti-bacterial agents and feed additives.

Characteristic of the known technical solutions

The most obvious state of the art is in

- Organic, 3rd ed. 1964, p.438

- HeIv. Chim. Acta 59, 222 (1976)

- HeIv. Chim. Acta 59, 190 (1976)

- J. Amer. Chem. Soc. 101, 4223 (1979)

J. Org. Chem. 46, 846 (1981)

- US-PS 4166180

- J. Med. Chem. 26, 1116 (1983).

Object of the invention

The invention provides processes for the preparation of 6,7-disubstituted i-cyclopropyl-1-dihydro-1-oxo-1-naphthyridine-3-carboxylic acids and their intermediates.

These compounds have a high anti-bacterial effect in the usual Proding forms. They are therefore suitable as active ingredients for human and veterinary medicine.

Explanation of the essence of the invention

The object of the invention is to provide processes for the preparation of novel compounds which have a high antibacterial activity.

It has been found that the new 6,7-disubstituted i-cyclopropyl-1-dihydro-1-oxo-1-naphthyridine-S-carboxylic acids of the formula (I)

cook

in which

X for halogen or nitro and

\ _A 4

A for R ·· NN - or,. ^^^ or halogen, in particular chlorine or fluorine, in which

R ^{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, which may optionally be substituted by a hydroxy or methoxy group, a phenacyl radical optionally substituted by hydroxy, methoxy, chloro or fluoro, an oxoalkyl radical having 2 to 4 carbon atoms, 4 -Aminobenzyl, formyl or acetyl,

CH, C-O

or for the rest «.pti -p I

² \ I

0-C = O

R ^{2 is} hydrogen, methyl or optionally substituted by chlorine, fluorine, methyl, hydroxy or methoxy-substituted phenyl or

Thienyl, R ^{3 is} hydrogen or methyl and

R ^{4 is} hydrogen, hydroxy, amino, alkyl or dialkylamino having 1 or 2 carbon atoms in the alkyl group,

Hydroxymethyl, aminomethyl, alkyl or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl group, and their pharmaceutically acceptable hydrates, acid addition salts, alkali, alkaline earth, silver and guanidinium salts, and in the form of their esters and in other conventional prodrug forms a have high antibacterial activity. They are therefore suitable as active ingredients for human and veterinary medicine, veterinary medicine also includes the treatment of fish for the treatment or prevention of bacterial infections. Preference is given to those compounds of the formula (I) in which X is chlorine or fluorine and

A is R - JI il- or I N- or halogen, in particular chlorine or fluorine, wherein

R ^{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 3 carbon atoms, which may optionally be substituted by a hydroxy group, a phenacyl radical optionally substituted by chlorine or fluorine, an oxoalkyl radical having 3 or 4 carbon atoms, 4-aminobenzyl, formyl or acetyl,

R ^{2 is} hydrogen, methyl or optionally substituted by chlorine or fluorine-substituted phenyl, R ^{3 is} hydrogen or methyl and

R ^{4 is} hydrogen, hydroxy, amino, aminomethyl, methylaminomethyl, ethylaminomethyl or diethylaminomethyl.

Particularly preferred are those compounds of formula (I) in which X represents chlorine or fluorine and

R * R *

A is R · ηW · or [TiTi · or halogen, in particular chlorine or fluorine, in which

R ^{1 is} hydrogen, methyl, ethyl, 2-hydroxyethyl, phenacyl, 2-oxopropyl, 3-oxobutyl or formyl, R ^{2 is} hydrogen, methyl or phenyl,

R ^{3 is} hydrogen or methyl and

R ^{4 is} hydrogen, amino, aminomethyl, ethylaminomethyl or diethylaminomethyl.

Otherwise, the compounds of the formula (I) are preferably in the form of their methyl, ethyl, pivaloyloxymethyl, pivaloyloxyethyl or (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) esters.

Furthermore, it was found that the compounds of formula (I) wherein A is

or

obtained when the 1-cyclopropyl-7-halogeno-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids of the formula (II)

COOH

in which

X has the meaning given above and

Y is halogen, preferably chlorine or fluorine, with amines of the formula (III)

A-H. (III)

in which

A has the meaning given above,

if appropriate in the presence of acid binders (Method A).

Compounds of the formula (I) according to the invention wherein A represents:

stands,

R ₁ -N

can also be obtained by reacting i-cyclopropyl-i-dihydro-oxo-T-d-piperazinyl-J 1 -naphthyridine-S-carboxylic acids of the formula (IV)

_R 2 ^X. _A I COCH

(IV)

in which

X, R ² and R ^{3 have} the abovementioned meaning, with compounds of the formula (V),

R ¹ -Z (V)

in which

R ^{1 has} the abovementioned meaning, but can not be hydrogen, and Z is halogen, in particular chlorine, bromine or iodine, acyloxy, ethoxy or hydroxyl,

if appropriate in the presence of acid binders (Method B). Compounds of the formula (I) according to the invention are obtained.

(R ^ CH ₃ -CO-CH ₂ CH ₂ -) also, if a compound of formula I + V) with methyl vinyl ketone of the formula (Vl)

CH ₃ -CO-CH = CH ₂ (VI)

implemented (method C).

If, in the reaction according to method A, 2-methylpiperazine and T-chloro-1-cyclopropyl-e-fluoro-1-dihydro-1-oxo-1-naphthyridine-3-carboxylic acid are used as starting materials, the course of the reaction can be described below Formula scheme are reproduced: _w

COOH

If, for example, in the reaction according to Method B, chloroacetone and e-chloro-i-cyclopropyl-i, -d (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid are used as starting materials, the reaction sequence can be represented by the following equation become:

+ hnn

ch ₃ -c> ch ₂ h (_) i

If, for example, by method C methyl vinyl ketone and i-cyciopropyl-e-fluoM ^ dihydro ^ -oxo-y-Clpiperazinyl) -1,8-naphthyridine-3-carboxylic acid as starting compounds, the reaction sequence can be represented by the following equation:

CH ₃ -CO-CH = CH ₂ + HN N

The i-cyclopropyl-T-halo-i ^ -dihydro ^ -oxo-1-naphthyridine-S-carboxylic acids of the formula (II) used as starting materials according to method A can be prepared according to the following reaction scheme:

^{X C0} " ^X COOC ₂ H ₅ Mg (OC ₂ H ₅ ) ₂

+ CH ₂ "^

(1), X ¹ _f X ² = Cl, Br or F

(2)

(C ₂ H ₅ O) ₃ CH

(3)

(4)

(5)

CO-C COCCJJ,

CO-C-COCC_H _c ²⁵

(6)

base

COOH

Thereafter, diethyl malonate (2) is acylated in the presence of magnesium ethylate with the corresponding nicotinic acid halide (1) to the acylmalonic ester (3) (Organicum, 3rd edition 1964, p.438).

By partial saponification and decarboxylation of (3) in an aqueous medium with catalytic amounts of sulfuric acid or 4-toluenesulfonic acid, the acylacetic acid ethyl ester (4) is obtained in good yield, which is treated with orthoformic acid triethyl ester / acetic anhydride in the 2- (nicotinoyl) -3-ethoxy- acrylic acid ethyl ester (5) passes. The reaction of (5) with cyclopolyamine in

a solvent, such as. As methylene chloride, an alcohol, chloroform, cyclohexane or toluene leads in a slightly exothermic reaction to the desired intermediate (6).

The cyclization reaction (6) -> (7) is carried out in a temperature range of about 60 to 300 ⁰ C, preferably 80 to 18O ⁰ C.

Dioxane, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, hexamethylphosphoric acid trisamide and preferably Ν, Ν-dimethylformamide can be used as diluents.

Suitable acid binders for this reaction stage are potassium tert-butoxide, butyl lithium, lithium phenyl, phenylmagnesium bromide, sodium methoxide, sodium hydrate, sodium or potassium carbonate. Particularly preferred are potassium or sodium fluoride, when hydrogen fluoride must be removed. It may be advantageous to use an excess of 10 mol% of base.

The ester hydrolysis of (7) under basic or acidic conditions in the last step leads to the 1-cyclopropyl-halo-1-dihydro-1-oxo-1-naphthyridine-S-carboxylic acids (II).

The 2,5,6-trichloropyridine-3-carboxylic acid chloride (HeIv, Chim. Acta 59, 222 [1976]) used as starting material for this synthesis route is already known. 2,6-Dichloro-5-fluoro-pyridine-3-carboxylic acid chloride can be obtained in the following way: 5-Amino-2,6-dichloro-3-methylpyridine (HeIv. Chim Acta 59, 190 [1976]) becomes over 2.6 Dichloro-3-methyl-5- (3,3-dimethyl-1-triazeno) -pyridine or by a Baltz-Schiemann reaction to 2,6-dichloro-5-fluoro-3-methyl-pyridine. This is chlorinated to 2,6-dichloro-5-fluoro-3-trichloromethyl-pyridine. Subsequent hydrolysis with sulfuric acid gives the carboxylic acid, which is converted by conventional means into 2,6-dichloro-5-fluoro-pyridine-3-carboxylic acid chloride. Alternatively, 5-fluoro-2,6-dihydroxypyridine-3-carboxamide (J.Amer.Chem.Soc.101.4423 [1979]; J. Org. Chem. 46, 846 [1981]) can also be used with phosphorus oxychloride Convert 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile and this also after saponification to carboxylic acid to acid chloride. By oxidation of 2,6-dichloro-3-chloromethyl-5-nitro-pyridine (HeIv. Chim. Acta 59, 190 [1976]), the corresponding nicotinic acid is obtained, which with thionyl chloride is 2,6-dichloro-5-nitro-pyridine 3-carboxylic acid chloride. The amines of the formula (III) used as starting materials are known (US Pat. No. 4,161,880, J. Med. Chem. 26, 1116 [1983]). Examples which may be mentioned are: piperazine, N-methylpiperazine, N-ethylpiperazine, N- (2-hydroxyethyl) piperazine, N- (2-methoxyethyl) piperazine, N-propylpiperazine, N-isopropylpiperazine, N-butylpiperazine, N- ( sec-butyl) piperazine, N-formylpiperazine, 2-methylpiperazine, cis- and trans-2,6-dimethylpiperazine, 2-phenylpiperazine, 2- (4-fluorophenyl) piperazine, 2- (4-chlorophenyl) piperazine , 2- (4-Methylphenyl) piperazine, 2- (4-IVethoxyphenyl) piperazine, 2- (4-hydroxyphenyl) piperazine, 2- (2-thienyl) piperazine, pyrrolidine, 3-amino-pyrrolidine, 3 Aminomethylpyrrolidine, 3-methylaminomethylpyrrolidine, 3-dimethylaminomethylpyrrolidine, 3-ethylaminomethylpyrrolidine, 3-hydroxypyrrolidine.

The compounds of the formula (V) used as starting materials are known. Examples are: methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, 2-hydroxyethyl chloride, 3-hydroxypropyl chloride, n-propyl bromide, isopropyl iodide, n-butyl bromide, sec-butyl iodide, isobutyl bromide, formic acid anhydride, ethyl formate, formic acid, acetic anhydride, acetyl chloride.

The reaction of (II) with (III) according to method A is preferably carried out in a diluent such as dimethylsulfoxide, Ν, Ν-dimethylformamide, hexamethylphosphoric trisamide, sulfolane, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or Pyridine made. Likewise, mixtures of these diluents may be used.

As acid binder, it is possible to use all customary inorganic and organic acid binding agents. These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specific examples are: triethylamine, 1,4-diazabicyclo [2,2,2] octane (DABCO),!, S-diazabicyclo-OA-undecene (DBU) or excess amine (III).

The reaction temperatures can be varied within a substantial range. In general, one works between about 20 and 200 ° C, preferably between 80 and 180 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 to 15 mol, preferably 1 to 6 mol, of the amine (III) are employed per mole of the carboxylic acid (11).

Free amino groups can be protected during the reaction by a suitable amino-protecting group, for example the tert-butoxycarbonyl, ethoxycarbonyl or acetyl group, and released again after the reaction has ended. An aromatic amino group is introduced via the reduction of a nitro group.

The reaction of (IV) with (V) is preferably carried out in a diluent such as dimethylsulfoxide, dioxane, Ν, Ν-dimethylformamide, hexamethylphosphoric acid trisamide, sulfolane, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Likewise, mixtures of these diluents may be used.

As acid binder, it is possible to use all customary inorganic and organic acid binding agents. These preferably include the alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Specific examples which may be mentioned are: triethylamine, 1,4-diazabicyclo [2,2,2] octane (DABCO) or!, S-diazabicyclo-1-amino-undecene (DBU). The reaction temperatures can be varied within a substantial range. In general, one works between about 20 and about 180 ⁰ C, preferably between 40 and 110 ⁰ C.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally, at pressures between about 1 and about 100 bars, preferably between 1 and 10 bars are used.

When carrying out the process according to method B according to the invention, 1 to 4 moles, preferably 1 to 1.5 moles, of the compound (V) are employed per mole of the compound (IV).

The reaction of (IV) with (VI) (Method C) is preferably carried out in a diluent such as dioxane, dimethyl sulfoxide, Ν, Ν-dimethylformamide, methanol, ethanol, isopropanol, n-propanol, glycol monomethyl ether or else in mixtures of these diluents.

The reaction temperatures can be varied within a substantial range. In general, one works between about 2O ⁰ C and about 150 ⁰ C, preferably between 5O ⁰ C and 100X.

The reaction can be carried out at normal pressure, but also at elevated pressure. In general, at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to method C according to the invention, 1 to 5 mol, preferably 1 to 2 mol, of compound (VI) are employed per mole of compound (IV).

The preparation of the acid addition salts of the compounds according to the invention is usually carried out, for example, by dissolving the betaine in excess aqueous acid and precipitating the salt with a water-miscible organic solvent (methanol, ethanol, acetone, acetonitrile). It is also possible to heat equivalent amounts of betaine and acid in water until dissolved and then evaporate to dryness. Examples of suitable pharmaceutically acceptable salts are the salts of hydrochloric, sulfuric, acetic, glycolic, lactic, succinic, citric, tartaric, methanesulfonic, galacturonic, gluconic, glutamic or aspartic acid.

The alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the betaine in a submerged alkali or alkaline earth liquor, filtering undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are sodium, potassium or calcium salts. By reaction of an alkali or alkaline earth metal salt with a suitable silver salt, such as silver nitrate, the corresponding silver salts of the 1-dihydro-1-oxo-1-naphthyridine-S-carboxylic acids are obtained.

Apart from the compounds listed in the examples, new active substances may be mentioned in detail:

i-Cyclopropyl-e-fluoro-i-dihydro-i-S-S-dimethyl-i-piperazinyl M-oxo-1-naphthyridine-S-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7 - (4-isopropyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, 7- (4-butyl-1-piperazinyl) -6-chloro-1-cyclopropyl-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-phenacyl-1-piperazinyl) -1,8-naphthyridine 3-carboxylic acid, 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3,4-dimethyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, 1 -Cyclopropyl-6-fluoro-1,4-dihydro-7- [3-methyl-4- (2-oxopropyl) -1-piperazinyl] -4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro 1-cyclopropyl-1,4-dihydro-4-oxo-7- [4- (3-oxobutyl) -1-piperazinyl] -1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7 - (4-Formyl-1-piperazinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7- (4-acetyl-1-piperazinyl) -1-cyclopropyl-6-fluoro 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-1,4-dihydro-7- (1-piperazinyl) -4-oxo 1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-7 (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-7 [4- (3-oxo-propyl) -1-piperazinyl] -1,8-naphthyridine-3-carboxylic acid hydrochloride, 1-cyclopropyl-6-fluoro-7- [3- (4-fluorophenyl) -1-piperazinyl ] -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-7- (3-phenyl-1-piperazinyl ) -1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7- (i-piperazinyl) -1,8-naphthyridine-3-carboxylic acid, 1- Cyclopropyl-1,4-dihydro-7- (4-methyl-1-piperazinyl) -6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 6-fluoro-7- [4- (4- Aminobenzyl) -1-piperazinyl] -1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, e-fluoro-tS-amino-i-pyrrolidinyO-i-cyc lopropyl-i ^ -dihydro ^ -oxo-i ^ -naphthyridine-S-carboxylic acid, i-cyclopropyl-e-fluoro-IS-ethylaminomethyl-i-pyrrolidinyl J-i ^ -dihydro ^ -oxo-IS-naphthyridine-S- carboxylic acid.

Another object of the invention are compounds of formula (VII)

.CO-R

(VII)

in the

X is halogen or nitro,

X 'and X "are identical or different and are halogen, in particular chlorine or fluorine, and R is OH, halogen, in particular chlorine, or alkoxycarbonylmethyl with methyl or ethyl in the alkoxy part.

The following examples illustrate the invention:

embodiments

Preparation of starting compounds

Example A

2,6-dichloro-3-methyl-5- (3,3-dimethyl-1-triazeno) -pyridine

43 g (0.24 mol) of 5-amino-2,6-dichloro-3-methylpyridine (HeIv Chim Acta 59.190 [1976]) are slowly mixed with 285ml of semi-concentrated hydrochloric acid, cooled to 0 ⁰ C, then a solution of 17.2 g (0.25 mol) of sodium nitrite in 70 ml of water was added dropwise and stirred at 0 ⁰ C for some time. This diazonium salt solution is added dropwise at 0-3 ° C within 90 minutes to a solution of 150g sodium carbonate in 430 ml of water and 70ml of 40-50% aqueous dimethylamine solution and stirred at 0 ⁰ C. Man the precipitate is suctioned off, washed well with water and dried in high vacuum at 40 ⁰ C. Yield: 49,3g (88% of theory), Melting point: 91-95 ° C.

Example B

2,6-dichloro-5-fluoro-3-methyl-pyridine

43.9 g (0.19 mol) of 2,6-dichloro-3-methyl-5- (3,3-dimethyl-1-triazeno) -pyridine are decomposed in 80 ml of hydrofluoric acid at 125-135 ⁰ C in an autoclave. After distillation, a product is obtained with a specific gas chromatographic purity of 87%, which also contains 12% chlorine-fluorine exchange product. Yield: 19g, boiling point: 81-95 ° C / 18mbar. Melting point: 39-41 ° C. Example C

2,6-dichloro-5-fluoro-3-trichloromethylpyridine F CCl,

49.4 g (0.27 mol) of 2,6-dichloro-5-fluoro-3-methyl-pyridine are chlorinated at 12O ⁰ C for a total of about 20 hours until no more aliphatic proton is detectable by NMR spectroscopy. The reaction mixture is distilled in a Kugelrohr distillation apparatus.

Yield: 61,7g (80.6%), Boiling point: 130-150 ⁰ C (oven temperature) / 0,4mbar.

Mass spectrum: "Ve 281 (M ⁺ ), 246 (100%, M ⁺ -Cl), 211 (246-CI), 176 (211-CI).

Example D

2,6-dichloro-5-fluoro-pyridine-3-carboxylic acid

57 g (0.2 mol) of 2,6-dichloro-5-fluoro-3-trichloromethyl-pyridine are dissolved in 53 ml of 92% sulfuric acid and for 25 minutes at 25 ° C, then for 3 hours at 100 ⁰ C until the decay of Hydrogen chloride evolution stirred. It is mixed with 24 g of 50% sulfuric acid and heated for a further 6 hours at 100 ⁰ C then cooled, the reaction mixture poured onto ice, the precipitate sucked off, washed with water and dried.

Crude yield: 42 g (~ 100% of theory), m.p .: 137-149 ° C; after recrystallization from water: melting point: 154-161 ° C.

Mass spectrum: "Ve 209 (M ⁺ ), 192 (M ⁺ -OH), 164 (192-CO), 129 (164-CI), 94 (129-CI).

Example E

2,6-dichloro-5-fluoro-pyridine-3-carbonyl chloride

tx

CO-Cl

Cl IT Cl

42 g (0.2 mol) of 2,6-dichloro-5-fluoro-pyridine-3-carboxylic acid are refluxed in a mixture of 43 g of thionyl chloride, 15 ml of dimethylformamide and 640 ml of toluene for 6 hours. The mixture is concentrated and the residue is distilled.

Yield: 33.8 g (74% of theory), boiling point 94-98 ° C / 1.3 mbar.

Mass spectrum: "Ve 277 (M ⁺ ), 192 (100%, M ⁺ -Cl), 164 (40%, M ⁺ -COCl).

Example F

(2,6-dichloro-5-fluoro-pyridine-3-carbonyl) acetate

3.7 g (0.15 mol) of magnesium turnings are mixed with 0.8 g of tetrachloromethane in 9.3 ml of ethanol and, after hydrogen evolution has begun, a mixture of 23.9 g (0.15 mol) of diethyl malonate, 18.5 ml of ethanol and 58 ml of toluene at 50-60 ⁰ C added dropwise. The mixture is stirred for 1 hour at this temperature, cooled to -5 to -10 ⁰ C and slowly added dropwise a solution of 31 g (0.14 mol) of 2,6-dichloro-5-fluoro-pyridine-3-carbonyl chloride in 14.5ml Toluene too. After that

is stirred for 1 hour at 0 ° C, brought to room temperature overnight and heated to 40-50 ° C for 2 hours. The reaction mixture is added with ice cooling with a mixture of 60 ml of water and 9 ml of concentrated sulfuric acid and the organic phase separated. The aqueous phase is extracted with toluene and the combined organic extract washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent removed. This gives 50.1 g (2,6-dichloro-5-fluoro-pyridine-3-carbonyl) -malonsäurediethylester as a crude product. This is heated after addition of 50 ml of water and 0.1 g of 4-toluenesulfonic acid for 10 hours under reflux, the mixture extracted with dichloromethane, the extract dried with sodium sulfate, concentrated, the residue stirred with a little ether and the crystals were isolated. Yield: 14.3 g (34% of theory), Melting point: 69-72 ⁰ C.

Mass spectrum: "Va 279 (M ⁺ ), 244 (60%, M ⁺ -Cl), 216 (74%, 244-28), 192 (100%, C ₆ HCI ₂ FNO), 164.29 Spectrum (CDCI ₃ ), the compound is almost completely present as enol.

Example G

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo "1,8-naphthyridine-3-carboxylic acid

14g (50 mmol) (2,6-dichloro-5-fluoro-pyridine-3-carbonyl) -acetic acid ethyl ester are heated with 11.1 g Orthoameisensäuretriethylesterin (75mmol) 13g acetic anhydride for 2 hours at 150-160 ⁰ C. The mixture is concentrated in vacuo to give 15.6 g of ethyl 2- (2,6-dichloro-5-fluoro-pyridine-3-carbonyl) -3-ethoxyacrylate as an oily residue.

15.5 g (46 mmol) of this intermediate are added dropwise in 35 ml of ethanol with ice cooling with 3 g of cyclopropylamine and stirred at 20 ° C for 1 hour. The precipitated product is filtered off with suction, washed with methanol and dried. This gives 13.3 g of 2- (2,6-dichloro-5-fluoro-pyridine-3-carbonyl) -3-cyclopropylaminoacrylsäureethylester of melting point 130-133 ⁰ C (from ethanol).

12.5 g (36 mmol) of 2- (2,6-dichloro-5-fluoro-pyridine-3-carbonyl) -3-cyclopropylamino-acrylic acid ethyl ester are heated for 1 hour at 100 ⁰ C in 75 mL of dimethylformamide with 6.5 g of potassium carbonate. The reaction mixture is poured into ice-water and the precipitated product is filtered off with suction, washed with water and methanol and dried. There are obtained 10.5 g (94% of theory) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester of melting point 176-18O ⁰ C.

10,5g (34mmol) of this ester are heated in a mixture of 100 ml of acetic acid, 70 ml of water and 10 ml concentrated sulfuric acid for 2 hours at 150 ⁰ C. The suspension is poured into 300 ml of ice-water, the precipitate is filtered off with suction, washed with water and methanol and dried in vacuo.

Yield: 7.85 g (82% of theory) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid of melting point 230-233 ° C.

Example H

ej-dichloro-i-cyclopropyl-IAdihydro ^ -oxo-I.E-naphthyridine-S-carboxylic acid

Cl. ^ ^ V ^ COOH Cl

Starting from 2,5,6-trichloropyridine-3-carboxylic acid chloride [HeIv. Chim. Acta 59, 222 (1976)] is analogous to Example F (2,5,6-trichloropyridine-S-carbonyD-acetic acid ethyl ester (melting point: 69-71 ⁰ C, according to the ¹ H-NMR spectrum in deuterochloroform to 50% as This is then analogously to Example G übererej-dichloro-i-cyclopropyli ^ -dihydro ^ -oxo-i ^ -naphthyridin-S-carboxylic acid ethyl ester (mp 176-178 ° C) zur6,7-dichloro- Reacted 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, which melts after decomposition from dimethylformamide at 243-245 ⁰ C with decomposition.

example 1

i-cyclopropyl-e-fluoro-i ^ -dihydro ^ -oxo ^ -O-piperazinyO-i ^ naphthyridine-S-carboxylic acid

COOH

1.3 g (4 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are dissolved in 8 ml of dimethyl sulfoxide with 860 mg (10 mmol) of anhydrous piperazine for 15 minutes 110 ⁰ C heated. The solvent is evaporated in vacuo, the residue boiled with 5 ml of water (pH 7), the precipitate is filtered off, washed with water and boiled with methanol.

Yield: 1.0 g (75% of theory), Melting point: 278-282 ⁰ C (with decomposition).

Example 2

i-cyclopropyl-e-fluoro-i ^ -dihydro ^ -O-methyl-i-piperazinyO ^ -oxo-i ^ naphthyridine-S-carboxylic acid

COOH

The procedure is analogous to Example 1, wherein reacted with 2-methylpiperazine 15 minutes at 100 ⁰ C and the reaction product is recrystallized from glycol monomethyl ether.

Yield: 0.9 g (65% of theory), Melting point: 243-247 ⁰ C (with decomposition).

Example 3

1-Cyclopropyi-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

H ₃ CN N

COOH

/ "Λ

, HCl

The procedure is analogous to Example 1, wherein reacted with N-methylpiperazine 15 minutes at 100 ⁰ C and the reaction product is recrystallized from glycol monomethyl ether. The obtained 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid (1.2 g of the melting point 241- 244 ⁰ C with decomposition) is boiled in a mixture of 20 ml ethanol and 5 ml of 2N hydrochloric acid, the hydrochloride formed drained, washed with ethanol and dried. Yield: 1.1 g (72%), melting point: 305-310 ⁰ C (with decomposition).

Example 4

1-Cyclopropyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

, HCl

Analogously to Example 3 is reacted with N-ethyl-piperazine for 30 minutes at 100 ⁰ C and then converted the reaction product into the hydrochloride.

Yield: 1.05 g (66% of theory), m.p .:> 300 ° C (with decomposition).

Example 5

1-cyclopropyl-6-fluoro-1,4-dihydro 7- [4- (2-hydroxyethyl) -1 -piperazinyl] -4-oxo-1,8-naphthyridine-3-carboxylic acid

HO-CH ₀ CH ₀ -N 2 i

Analogously to Example 1 is reacted with N- (2-hydroxyethyl) piperazine for 30 minutes at 100 ° C and the reaction product recrystallized from glycol monomethyl ether.

Yield: 0.9 g (60% of theory), mp: 241-245 ° C (with decomposition).

Example 6

i-cyclopropyl-e-fluoro-IAdihydro- ^ oxo-T-iS-phenyl-i-piperazinyD-i ^ naphthyridine-S-carboxylic acid

COOH

Analogously to Example 1, 810 mg (5 mmol) of 2-phenylpiperazine are reacted in the presence of 1.8 g (8 mmol) of 1,4-diazabicyclo [2,2,2] octane (DABCO) for 30 minutes at 100X.

Yield: 0.85 g (42% of theory), mp: 280-283 ° C (with decomposition).

Example 7

i-cyclopropyl-e-fluoro-i ^ -dihydro ^ -oxo ^ -II-pyrrolidinyll-i ^ naphthyridine-S-carboxylic acid

COOH

Analogously to Example 1, pyrrolidine is reacted at 10O ⁰ C for 30 minutes and the reaction product recrystallized from dimethylformamide.

Yield: 70% of theory, m.p .: 314-316X (with decomposition).

Example 8

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [4- (2-oxo-propyl) -1-piperazinyl] -1,8-naphthyridine-3-carboxylic acid hydrochloride

COOH N ^ "N" ^ V

CH ₃ -CO-CH ₂ -N

, HCl

1.65 g (5 mmol) of i-cyclopropyl-e-fluoro-i-dihydro ^ -oxo ^ -fiperiperazinyl-1-naphthyridine-S-carboxylic acid are dissolved in 25 ml of dimethylformamide with 0.7 g (7.6 mmol) of chloroacetone and 1.05 g of triethylamine and heated to 80 ⁰ C for 3 hours. The suspension is concentrated in vacuo, the residue is stirred with 10 ml of water, filtered off with suction and dried. The product is heated in 15 ml of dilute hydrochloric acid (1: 1), precipitated with ethanol, filtered off with suction and dried. Yield: 1.5 g (71% of theory), melting point:> 300 ° C (with decomposition).

Example 9

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [4- (3-oxobutyl) -1-piperazinyl] -1,8-naphthyridine-3-carboxylic acid hydrochloride

CQOH

CH, -CO-CH ₀ -CH ₀ -NN. HCl

1.66 g (5 mmol) of the compound from Example 1 and 1.95 g (28 mmol) of methyl vinyl ketone are refluxed in 25 ml of ethanol for 7 hours, the precipitate obtained is dissolved with dilute hydrochloric acid (1: 1) and precipitated with ethanol. Yield: 1.1 g (55% of theory), Melting point:> 300 ⁰ C (with decomposition).

Example 10

6-chloro-1-cyclopropyl-1,4-dihydro-7- {4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

^C00h

* HC1

The procedure is analogous to Example 3, starting from SJ-dichloro-i-cyclopropyl-IAdihydro ^ -oxo-i ^ -naphthyridin-S-carboxylic acid and starting N-methyl-piperazine as starting compounds

Yield: 66%, Melting point: 304-308 ⁰ C (with decomposition).

Example of a tablet according to the invention

Each tablet contains:

Compound of Example 1 583.0 mg

Microcrystalline cellulose 55.0 mg

Corn starch 72.0 mg

Poly (1-vinyl-2-pyrrolidone) insoluble 30.0 mg

Highly dispersed silica '' 5.0 mg

Magnesium stearate 5.0 mg

750.0 mg

The paint cover contains:

Poly (0-hydroxypropyl-0-methyl) -cellulose 15cp 6.0 mg

Macrogol4000rec. INN (polyethylene glycol DAB) 2.0 mg

Titanium (IV) oxide 2.0 mg

10.0 mg

The compounds of the present invention exhibit, at low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative bacteria, particularly against enterobacteriaceae; especially against those that are resistant to various antibiotics, such. Penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties enable their use as chemotherapeutic agents in medicine as well as substances for the preservation of inorganic and organic materials, especially organic materials of all kinds,

z. As polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds of the invention are effective against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled and the diseases caused by these pathogens prevented, ameliorated and / or cured.

The compounds of the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

For example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

Gram-positive cocci, e.g. Staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept.

faecalis, Strept. pneumoniae, Strept. pyogenes); gram-negative cocci (Neisseria gonorrhoeae) as well as Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.friendii, Citrob. Divernis), Salmonella and Shigella; Klebsiella (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) and strictly anaerobic bacteria such. B. Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium, also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and mycobacteria, eg. B.

Mycobacterium tuberculosis.

The above enumeration of pathogens is merely exemplary and by no means limiting. As diseases which can be prevented, ameliorated and / or cured by the compounds according to the invention, mention may be made, for example:

otitis; pharyngitis; Pneumonia; peritonitis; pyelonephritis; cystitis; endocarditis; Systemic infections; Bronchitis; Arthritis; local infections; septic diseases.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active substances according to the invention and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparation in the form of individual parts, for. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active substance content corresponding to a fraction or a multiple of a single dose. The dosage units can z. B. 1.2, 3 or 4 single doses or V2, V3 or ¹ Ai contain a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

By non-toxic, inert pharmaceutically acceptable excipients are meant solid, semi-solid or liquid diluents, fillers and formulation aids of any kind.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients, such as (a) fillers and extenders, e.g. Starches, lactose, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. Glycerine, (d) disintegrants, e.g. Agar agar, calcium carbonate and sodium carbonate, (e) solution delay, e.g. Paraffin and (f) resorption accelerators, e.g. B. quaternary ammonium compounds, (g) wetting agents, for. Cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. Kaolin and bentonite and (i) lubricants, e.g. As talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules may be provided with the usual, optionally opacifying, containing coatings and shells and also be composed so that they deliver the active substance or only optionally delayed in a certain part of the intestinal tract, where as embedding masses z. As polymer substances and waxes can be used.

The active substance (s) may optionally also be present in microencapsulated form with one or more of the excipients specified above.

Suppositories may contain the usual water-soluble or water-insoluble excipients in addition to the active substance or substances, for. As polyethylene glycols, fats, z. As cocoa fat and higher esters (eg., Cu-alcohol with Ci ₆ fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels, in addition to the active ingredient or the usual excipients may contain, for. As animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays may contain the usual excipients in addition to the active ingredient or substances, for. As lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain the usual propellants, eg. For example, chlorofluorocarbons.

Solutions and emulsions, in addition to the active substance or the usual carriers such as solvents, solubilizers and emulsifiers, eg. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylene formamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions may also be present in sterile and blood isotonic form. Suspensions may in addition to the active ingredient or the usual carriers such as liquid diluents, for. For example, water, ethyl alcohol, propylene glycol, suspending agent, z. Example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances. The formulation forms mentioned can also colorants, preservatives and odor and taste-improved additives, eg. Peppermint oil and eucalyptus oil and sweeteners, e.g. For example, saccharin. The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of from about 0.1 to 99.5, preferably from about 0.5 to 95,% by weight of the total mixture. The pharmaceutical preparations listed above may contain, in addition to the compounds according to the invention, other active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in a customary manner by known methods, e.g. by mixing the active substance (s) with the excipient (s).

The active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.

In general, it has proven to be advantageous both in human and in veterinary medicine, the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24 hours, optionally in the form several single doses to give the desired results. One single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to about 250, in particular 3 to 60 mg / kg of body weight. However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the type and serious illness, the type of preparation and the application of the drug and the period or interval, within which the administration takes place.

Thus, in some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. The determination of the respectively required optimal dosage and mode of administration of the active ingredients can be done easily by any specialist due to his expertise.

The new compounds can be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. Thereby, infection by Gram-negative or Gram-positive bacteria can be prevented, ameliorated and / or cured, thereby achieving promotion of growth and improvement of utilization of the feed.

The table below gives the MIC values of some of the compounds of the invention. As a comparison, the corresponding MIC values of those disclosed in European Patent Application 9425, Japanese Patent Application 81/45473 [C. A. 95, 15597 (1981)], 81/46811 [C. A. 95, 121142 (1981)], J. Med. Chem. 27,292 (1984) or from J. Heterocycl. Chem. 21,673 (1984) discloses 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid (AT 2266, enoxacin), which shows that the compounds of the invention are superior to the known compound.

Table 1: MIC values (mcg / ml)

tribe

example 1 Example 2 Example 3

enoxacin

E.COÜ4418 E.coli Neum

 E. CoIi 455/7 Kiebsiella63 Klebsiella6179 Proteus me. 8175 Proteus vulg. 1017 Proteus morg. 11006 Providencia 12012 Serratia 16040 Staphyloc. 1756 Staphyloc. 133 PseudomonasW.

0.03 <0.015 4

0.03 0.125 0.125 0.06 0.06 0.03 8

0.5 0.5 0.125

12:03

<0.015 8

<0.015 0.125 0.25 0.125 0.03 0.125 8

0.5 0.5 1

0.06 <0.015

<0.015 0.03 0.25 0.125 0.06 0.06 8

0.5 0.5 1

0.25 0.06

16 0.5 2

0.25 0.125 0.125 0.25

32 1 1 2

Agar dilution test / lsosensitestmedium

Claims (1)

Formula (l) _/ A process for the preparation of i-cyclopropyl-i ^ -dihydro- ^ oxo-i ^ -naphthyridin-S-carboxylic acids of / COOH in which X for halogen or nitro and ι / - \ ^R N ^ \ A is R-N N- or I N- or chlorine or fluorine, IN R ^{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, which may optionally be substituted by a hydroxy or methoxy group, a phenacyl radical optionally substituted by hydroxy, methoxy, chlorine or fluorine, an oxoalkyl radical having 2 to 4 carbon atoms, 4 -Aminobenzyl, formyl or acetyl, '? ^H 3 orthe radical -CrU-C | stands, ^ 0-C = R ^{2 is} hydrogen, methyl or optionally by chlorine, fluorine, methyl, hydroxy or methoxy substituted phenyl or thienyl, R ^{3 is} hydrogen or methyl and their pharmaceutically usable hydrates, acid addition salts, alkali, alkaline earth, silver and guanidinium salts and their esters and other conventional prodrug forms, characterized in that i-cyclopropyl-IAdihydro ^ -oxo-yd-piperazinyl-1-naphthyridine-3-carboxylic acids of the formula (IV), in which X, R ² and R ^{3 have} the abovementioned meaning, with compounds of the formula (V), R ¹ -Z (V) in which R ^{1 has} the abovementioned meaning, but can not be hydrogen and Z is halogen, in particular chlorine, bromine or iodine, acyloxy, ethoxy or hydroxy, optionally in the opposite of acid binders and optionally converted into the salts, esters and other prodrug forms ,