1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, process for their preparation and antibacterial agents containing them

(74) Attorney Mag.scient. Knud-Henry Lund, Bryns Patentkontor A / S, Oslo.

(30) Priority requested 29.10.81, DE, No. P 31 42 85ft.

(54) DESCRIPTION OF THE INVENTION ANALOGY PROGRESS HATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-CYCLEPROPYL-6-FLUDR-1,4-DIHYDR0-4-0KS07-PIPERAZINO-QUINOLINE-J-CARBOXYL ACID.

(57) Summary

1-Cyclopropyl-6-fluoro-1,4 They are prepared using 7-chloro dihydro-4-oxo-7-piperazinoquino-cyclopropyl-6-fluoro-1,4-diline-3-carboxylic acid of formula I

<img file="NO158018B_D0001.tif" />

hydro-4-oxo-quinoline-3-carboxylic acid of formula (R R = H)

<img file="NO158018B_D0002.tif" />

R is hydrogen, methyl, ethyl or β-hydroxyethyl, and their pharmaceutically usable acid addition salts and hydrates have an antibacterial effect which exceeds that of the known ohinolone and azachinolone carboxylic acids.

react with piperazine piperazine derivatives or formula n

RN HH \ _ / wherein R has the above meaning.

(56) Published publications None.

This invention relates to the preparation of novel 1-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids.

It is already known that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids have antibacterial properties [J. With. Chem. 23, 1358 (1980)].

It has now been found that the novel 1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-7-piperazino-quinoline-3-carboxylic acid of formula I

COOH

RN wherein R is hydrogen, methyl, ethyl or e-hydroxyethyl, and their pharmaceutically acceptable acid addition salts and hydrates have an antibacterial effect, which is superior to known clnolone and azakinolone carboxylic acids. The compound of the invention shows their superior antibacterial activity against both Gram-positive as well as Gram-negative bacteria including Pseudonomas aeruginosa.

Further, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid of formula (I) is prepared by adding 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4 4-oxo-chloro-3-carboxylic acid of formula II (R 1 - H)

<img file="NO158018B_D0003.tif" />

react with plperazine or piperazine derivatives of formula III

<img file="NO158018B_D0004.tif" />

(III) wherein R is as defined above.

Furthermore, the compounds of formula II (R 4 = alkyl) may be reacted with III optionally in the presence of an acid blender such as e.g. triethylamine, 1,4-diaza-bicyclo- (2,2,2) octane or 1,8-diazabicyclo (5.4,0) undec-7-ene, and then the resulting 7-piperazino-quinolone-3-carboxylic acid esters are saponified alkaline to I.

The reaction of II (R | - E) with III is preferably carried out in a diluent such as dimethylsulfoxide, Ν, Ν-dimethylformamide, hexamethylphosphoric trisamide, sulfolane, water, an alcohol or pyridine at temperatures of 20-200 ° C, preferably 80180 ° C. . The reaction can be carried out at normal pressure, but also at elevated pressure, especially with low boiling diluents. Typically, one works at pressures between approx. 1 to 100 bar, preferably between 1 and 10 bar.

In carrying out the process, 1 mole of carboxylic acids II is used with 1-5 moles of alkylplperazine (with plperazine 1-15 moles), preferably 2-3 moles of alkylplperazine (with plperazine 5-10 moles).

The piperazinoquinolone-3-carboxylic acid I formed can optionally be transferred with an organic or inorganic acid to a salt. Acids suitable for salt formation are e.g. halohydrogen acids, such as hydrochloric acid, bromohydrogenic acid, iodohydrogenic acid, sulfuric acid, acetic acid, sltronic acid and benzenesulfonic acid.

If the reaction of II with III is used, for example, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3 carboxylic acids and methylplperazine as reaction participants, the reaction process can be represented by the following formula:

<img file="NO158018B_D0005.tif" />

As new antibacterial active substances, 1 detail should be mentioned:

7-piperazino-, 7- (4-methylpiperazino) -, 7- (4-ethylpiperazino) -, 7- (4-iso-hydroxyethylpiperazino) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline -3-carboxylic acid and pharmaceutically acceptable acid addition salts or alkali salts of these compounds.

The starting compounds II can be prepared by a malone ester synthesis according to the following reaction scheme:

<img file="NO158018B_D0006.tif" />

<img file="NO158018B_D0007.tif" />

COOCgH VII

<img file="NO158018B_D0008.tif" />

C00C₂H₅

COOC₂H₅

<img file="NO158018B_D0009.tif" />

IX

<img file="NO158018B_D0010.tif" />

<img file="NO158018B_D0011.tif" />

The malonic acid ethyl ester (VII) is acylated with IV in the presence of magnesium alcoholate to acyl malon ester (VIII) (Organicium 3, Edition 1964, page 438).

Partial saponification of decarboxylation of VIII in aqueous medium with catalytic amounts of p-toluenesulfonic acid yields in good yield the aroylacetic acid ethyl ester IX which, with o-formic acid triethyl ester / acetanhydride, yields 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxy -acrylsyreetylester. The reaction of X with cyclopropylamine in a solvent e.g. methylene chloride, alcohol, chloroform, cyclohexane or toluene in weak exothermic reaction results in the desired intermediate VI.

The cyclization reaction VI-II (R 2 = alkyl) is carried out in a temperature range of about 60 to 280 ° C, preferably 80 to 180 ° C.

Diloxane, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, hexamethylphosphoric acid ether amide and preferably N, N-dimethylformamide may be used as diluents.

As the acid binders, for this reaction step, potassium t-butanolate, butyl-lithlum, lithlum-phenyl, phenylmagnesium bromide, sodium ethylate and especially preferred sodium hydride or potassium carbonate are considered. It may be advantageous to use an excess of 10 moles of base.

The starting material used for this method of 2,4dichloro-5-fluoro-benzoyl chloride IV and the corresponding carboxylic acid, as well as the 3-fluoro-4,6-dichlorotoluene XI required for the production of IV, were not yet discussed in the literature.

The following formula shows the preparation of these precursor intermediates as starting from 2,4-dichloro-5-methyl-aniline XII.

<img file="NO158018B_D0012.tif" />

IV

Then, 2,4-dichloro-5-methylaniline (XII) is diazotized by NaNOg and the dlazonium salt thus formed is transferred with dimethylamine to the triazene (XIIa).

The triazene (XIIa) is dissolved in excess anhydrous HF. Thereby the triazene is cleaved into 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate solubility, this solution is thermally cleaved at 130 DEG-140 DEG C. under N2 decomposition to 3-fluoro-4,6-dichlorotoluene XI yield 77.76 DEG of theory.

3-Fluoro-4,6-dichlorotoluene XI is chlorinated in a temperature range from 110 to 160 ° C under UV irradiation to 2,4-dichloro-5-fluoro-1-trichloromethylbenzene XIII.

₁₅ The saturations of XIII with 95 µl of sulfuric acid result in 2,4dichloro-5-fluoro-benzoic acid XV which, with thionyl chloride, is converted into carboxylic acid chloride IV.

The compounds of the invention are characterized by a particularly good antibacterial effect against Gram-positive and Gram-negative bacteria, especially on the compounds according to German applications Nos. P 30 33 157.8 and DEOS 28 04 097 as shown in the following table.

æ ο ο ο

<img file="NO158018B_D0013.tif" />

<img file="NO158018B_D0014.tif" />

<img file="NO158018B_D0015.tif" />

sO Q

Ο sO Ο ο * | β ο

<img file="NO158018B_D0016.tif" />

<td>Ο</td><td>ιη</td><td>ο</td>

<td>Η</td><td>Η</td><td>Ν</td>

ιη Ν

The invention will be explained by the following examples.

EXAMPLE 1

<img file="NO158018B_D0017.tif" />

COOH

A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethylsulfoxide is heated 1.5 hours at 135140. 'C. The solvent is distilled off in a fine vacuum and the residue is suspended for approx. 50 ml of HgO, dry in a vacuum drying cabinet at 80 ° C over CaCl 2 and recrystallize from glycol monomethyl ether. 14.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-piperazino) -4-oxo-quinoline-3-carboxylic acid are obtained from cleavage point 248-250 ° C.

EXAMPLE 2

<img file="NO158018B_D0018.tif" />

A suspension of 2.81 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid and 5.2 g of Ν-β-hydroxyethylplperazine in 25 ml of dimethyl sulfoxide is heated for 2 hours. at 135-140 ° C. The solvent is distilled off in fine vacuum,

5801 The remainder is briefly boiled with 20 ml of HgO, allowed to stand overnight at room temperature, the precipitate is suctioned off under ice-cooling, washed with water and dried in vacuo over CaCl 2 at 80 ° C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- (4-βhydroxyethylpiperazino) -quinoline-3-carboxylic acid are obtained from cleavage point 237-39 ° C.

EXAMPLE 3

<img file="NO158018B_D0019.tif" />

COOH

A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl sulfoxide is heated at 135-140 for 2 hours. 'C. The solvent is distilled off in fine vacuum, the residue is suspended in HgO, suctioned off and washed with water. For further purification, the moist crude product is boiled in 100 ml of water, suctioned at room temperature, washed with H 2 O and dried in a vacuum drying cabinet over CaCl 2 at 100 ° C to weight constant. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained from cleavage point 255-257 ° C.

The compound of Example 3 is dissolved in 50 ml of 10 µg hydrochloric acid. To the filtered solution is added 150 ml of ethanol, cooled with ice, extracted and washed with alcohol and dried in vacuo at 100 ° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride are obtained as colorless crystals of 308-310 ° C.

EXAMPLE 4

<img file="NO158018B_D0020.tif" />

X HI

A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4oxo-7-piperazinoquinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of Ν, Ν -dimethylformamide is heated for 2.5 hours at 70-80 ° C. The solvent is distilled off in vacuo and the residue is suspended in water. They are extracted, washed with HgO and applied to clay. 1.15 g of 1-cyclopropyl-6fluoro-7- ( ethylpipe razino) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride are obtained from cleavage point 306 ° C.

The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-chloro-3-carboxylic acid II used as starting material is prepared as follows:

24.3 g of magnesium chips are suspended in 50 ml of anhydrous ethanol. Mix with 5 ml of carbon tetrachloride and drop when a reaction is started with a mixture of 160 g of malonic acid diethyl ester VII, 100 ml of abs. ethanol and 400 ml of anhydrous ether, in which a vigorous reflux is observed. After the reaction is complete, it is heated for two more hours to boiling, cooled with dry ice / acetone to -5 to -10 ° C, and at this temperature a solution of 227.5 g of 2,4-dichloro-5-fluoro-benzoyl chloride IV is slowly added dropwise. 100 ml abs. ether. It is stirred for 1 hour at 0 ° C to -5 ', allowed to come to room temperature overnight, and allowed to cool to 400 ml of ice-water and 25 ml of conc. sulfuric acid. The phases are separated and re-extracted twice with ether. The combined ether solutions are washed with saturated NaCl solution, dried with Na 2 SO 4 and the solvent removed in vacuo. You get

349.5 g of 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ether VIII as crude product.

An emulsion of 34.9 g of crude 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ester VIII in 50 ml of water is mixed with 0.15 g of ptoluenesulfonic acid. The mixture is heated under good stirring for 3 hours, the cooled emulsion is extracted several times with methylene chloride, the combined CHgCl 2 solutions are washed once with saturated NaCl solution, dried with NaaSC4, and the solvent is distilled off in vacuo. Fractionation of the residue in fine vacuum gives 21.8 g of 2,4-dichloro-5-fluoro-benzoylacetic acid ethyl ester IX of boiling point 127-142 ° C / 0.09 mbar.

A mixture of 21.1 g of 2,4-dichloro-5-fluoro-benzoyl-acetic acid ethyl ester IX, 16.65 g of o-formic acid ethyl ether and 18.55 g of acetanic anhydride is heated at 150 ° C for 2 hours. Then, in water jet vacuum and last in fine vacuum, a bath temperature of 120 ° C to volatiles is distilled off. There remains 25.2 g of crude 2- (2,4-dichloro-5-benzoyl) -3-ethoxy-acrylic acid ethyl ester X. It is sufficiently pure for the further reaction.

A solution of 24.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester X in 80 ml of ethanol is mixed under ice-cooling and stirred dropwise with 4.3 g of cyclopropylamine.

When this exothermic reaction is completed, stir for another hour at room temperature and the solvent is removed in vacuo and the residue recrystallized from cyclohexane / petroleum ether. 22.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI (R¹ = Melting point 8990 ° C.

A solution of 31.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI (R¹ - C2H5) 100 ml of anhydrous dioxane is mixed under ice cooling and stirred portionwise with 3.44 g of 80 µl sodium hydride. Then, stir for 30 minutes at room temperature and 2 hours under reflux and remove the deoxane in vacuo. The residue (40.3 g) is suspended i

150 ml of water, mix with 6.65 g of ether and reflux reflux for 1 hour. The hot solution is then filtered and washed with HgO. Then, acidify with semi-concentrated hydrochloric acid under ice-cooling to pH = 1-2, the precipitate from 5 is sucked, washed with water, dried in vacuo at 100 ° C. There is thus obtained 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II (r = H) of m.p. 234-237 ° C.