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

,.:The present invention relates to certain new 1-cyclo Propyl-6-fluoro-l,4-dihydro-4־oxo-7-piperazino-quinoline-

3-carboxylic acids, to a process for their production and to their use in feed additives and as antibacterial agents.

It has already been disclosed that l-ethyl-6fluoro-l,^dihydro-4-oxo-7־pipera_Zino-quinoline-3-carbo_Xylic acids possess antibacterial properties [J. Med. Chem 23 1358(1980)]. ’ —’

According ^{t0 the} Present invention we now provide, as new compounds, l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo7-p1perazino-quinoline3־-carboxylic acids of the general formula

<img file="IL66243A_D0001.tif" />

or salts or hydrates thereof, in which

R denotes a hydrogen atom or a methyl or ethyl . group.

The compounds of the present invention have an antibacterial action superior to that of the known quinolonecarboxylic acids and azaquinolone-carboxylic acids. The compounds according to the invention exhibit their superior antibacterial activity against both gram positive and gram negative bacteria, including Pseudomonas aeruginosa.

According to the present invention we further 25 provide a process for the production of a compound of the invention in which (a) 7-־hloro-l-cyclopropyl-6-f1uoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid of the formula

<img file="IL66243A_D0002.tif" />

Le A 21 353 ,- .

Λ. . י י . י י ־ . , ^v in which denotes a hydrogen atom, is reacted with piperazine or a piperazine derivative of the general formula (III) in which

R has the meaning given above, or (b) a compound of the formula (II), as given in reaction variant (a) in which R¹ denotes an alkyl group, is reacted with a compound of formula (III) as defined in reaction variant (a), if appropriate in the presence of an acid-binding agent (such as triethylamine, l,4-diaza-bicyclo[2,2,’2]octane or l,8-diaza־bicyclo(5,4,0]undec-7-ene) and the 7piperazino-quinolone-3-carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (1), and the compound of formula (I) obtained by reaction variant (a) or (b) is converted, if desired, into a salt or hydrate thereof.

²⁰ The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethylformamide, hexamethyl-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between . 20 and 200°C, preferably between 80 and 180°C.

²5 ' ' The reaction variants can be carried out under normal pressure, but also under elevated pressure, in particular in the' case of a low-boiling solvent. In general, the reaction is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

In carrying out reaction variants 1 to 5 mol of alkyl-piperazine (in the case of piperazine 1 to 15 mol), preferably 2 to 3 mol of alkylpiperazine (in the case of piperazine 5 to 10 mol), are employed per mol of carboxylic acid, or carboxylic acid: ester of formula (II).

Le A 21 353 ־ 3 Among the new; l-cyclopropyl-6-fluoro-l,4-dihydro-

4-oxo-7־piperazo-quinoline3־-carboxylic acid salts and hydrates of the invention those salts or hydrate that are pharmaceutically acceptable are particular^ important and are preferred.

The new free;l-cyclopropyl-6-fluoro-l,4-dihydro-

4-oxo-7-piperazino-quinoline-3-carboxylic acids of the general formula (I) and their salts and hydrates can be interconverted in any suitable manner; methods for such interconversion are known in the art.

Thus the 7־piperazino-quinolone-3־carboxylic acids of formula (I) obtained can, if required, be converted into a salt using an organic or inorganic acid. Examples of acids which are suitable for salt formation are hydrohalic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.

If 7־chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4oxo-quinoline-J-carboxylic acid and methylpiperazine are used as starting materials in reaction variant (a), the course of the reaction is illustrated by the following equation:

<img file="IL66243A_D0003.tif" />

The following may be mentioned individually as active compounds according to the present invention: 7-piperazino-, 7־4)־methylpiperazino)-, 7־4)־ethylpiperazino)-, l-cyclopropyl-6-fluoro-1,4-

Le A 21 353 dihydro-4-oxo-quinoline3־“cart1oxylic acid and pharmaceutically tolerated acid addition salts or alkali metal salts of these compounds.

The starting compounds of formula (II) can be prepared via a malonic ester synthesis, according to the following equation:

<img file="IL66243A_D0004.tif" />

C00C₂H₅ ch₂ .

^xcooc₂h₅

MgOEt _v----7

<img file="IL66243A_D0005.tif" />

C00C₂H5

C00C₂

IV _V1J

<img file="IL66243A_D0006.tif" />

<img file="IL66243A_D0007.tif" />

<img file="IL66243A_D0008.tif" />

• Le A 21 353

־ 5 ־

According to this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (IV) in the presence of magnesium, alcoholate to give the acylmalonate of formula (VIII) (Organicum, 3rd edition .1964, page 438).

...The ethyl aroylacetate of formula (IX) is obtained in good yield by partial hydrolysis and decarboxylation of the compound of formula (VIII) in an aqueous medium containing a catalytic amount of p-toluenesulphonic acid, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,1!-dichloro-5־fluoro־benzoyl)-3־ethoxyacrylate of formula (X). The reaction of the compound of formula (X) with cyclopropylamine in a solvent (such as methylene chloride, alcohol, chloroform, cyclohexane or toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction.

The cyclisation reaction VI —* II (R־'־ = alkyl) is carried out in a temperature range from 60° to 280°C, preferably 80° to 180°C.

Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphoric acid triamide and preferably Ν,Ν-dimethylformamide can be used as diluents.

Potassium t-butanolate, butyl-lithium, lithiumphenyl, phenyl magnesium bromide, sodium ethylate and particularly preferably sodium hydride or potassium car.donate are suitable acid-binding agents for this reaction stage. It can be advantageous to employ an excess of 10 mol$ of base.

The 2,4-dichloro־5־fluoro-benzoyl chloride of formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic acid, and the 3-fluoro4,6-dichlorotoluene of formula (XI) required for the preparation of formula (IV) were not yet known in the literature.

The equation below shows the preparation of these

Le A 21 353 precursors or intermediate products, .starting from 2,4dichloro-5־־methyl-anilir.e of formula (XII).

9 ^C1xA

Ίι ו * ^NaN02׳ ^h3° π ר γ׳ΝΗ HN(CH₃)₂^&lt;χγ^^Λ'Ν=Ν-Ν (CH₃) ₂

Cl ² Cl xila XII HF w

<img file="IL66243A_D0009.tif" />

<img file="IL66243A_D0010.tif" />

Le A 21 353

-ך According to this equation, 2,4-dichloro־5־ methyl-aniline of formula (XII) is diazotised by means of

NaN0₂j and the resulting diazonium salt is converted into the triazene of formula (Xlla), using dimethyl amine.

The triazene of formula (Xlla) is dissolved in excess anhydrous HF. In this step, the .triazene is cleaved to give 2,4-dichloro5־-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is.cleaved thermally at 1J0 to 140° to give 5־ fluoro-4,6'-dichlorotoluene XI, N₂ being split off (Yield: 77-77־ of theory).

The 3-fluoro-4,6-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to 160°C, under UV irradiation, to give 2,4-dichloro-5־fluoro-115 trichloro-methylbenzene of formula (XIII).

The hydrolysis of the compound of formula (XIII) . with 95 per cent, sulphuric acid leads to 2,4-dichloro5־. fluoro-benzoic acid of. formula (XV), which is converted . .'. with thionyl chloride into the carboxylic. acid-chloride . 20 of formula (IV).

The compounds according to the invention are distinguished by a particularly good antibacterial action against gram positive and gram negative bacteria, in particular in comparison with the compounds of German 25 Patent Application P 30 35 157-8 of 5.9.1980 and DE-OS (German Published Specification) 2,804,097, as can be seen from the table below.

Le Ά 21 355

<img file="IL66243A_D0011.tif" />

<td></td><td> Example 2 of German Patent Application P 30 33 157.8 of 3.9.80 ....</td><td> (disclosed in DE-OS (German Published Specification) 2,804,097).....</td><td> (compound according to the invention, of the formula I (R = H)</td>

<td> Staphylococcus . aureus 133...</td><td> 8</td><td> 1</td><td> ' 0.5 ־ 0.25</td>

<td colspan="4"></td>

<td> E. coli A .2.6.1 .</td><td> . . ...1.....</td><td> .....0..1.25....</td><td> ...0..06. .</td>

<td> E״ c.oli. N.e.um. .</td><td> .....1......</td><td> ..... 0,25</td><td></td>

<td></td><td></td><td></td><td> v t uu</td>

<td> Klebsiella .80.8.5.</td><td> ....1.....</td><td> ....0.25.</td><td> Ο Πίί</td>

<td></td><td></td><td></td><td> v ,uu</td>

<td> Proteus 1017 ..</td><td> .....0.5....</td><td> .0.06</td><td> ח ox</td>

<td></td><td></td><td></td><td> . . .V.UJ</td>

<td> Pseudomonas aeruginasa W ..</td><td></td><td> 1</td><td> 0.5</td>

Agar dilution test

DST (dexhase sensitivity test) medium; 12־ x 10^ germs/plate

As stated above, the invention also relates to the use in human and veterinary medicine as antibacterial agents of the compounds of the invention.

The present invention provides a pharmaceutical composition containing as active ingredient a compound . of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or physiologically isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprising a compound of the invention.

The inventionalso provides a.medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.

Medicament as used in this Specification means physically discrete coherent portions suitable for medical' administration. Medicament in dosage unit form as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association 'with a carrier and/or enclosed within an envelope.

Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose willdepend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.

. . The pharmaceutical composition according to the

Le A 21 353׳ invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates, or powders.

'The. diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to .be formed into tablets, dragees, capsules and pills include the following:

(a) fillers and extenders, e.g. starch, sugars, mannitol, 10 and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate;

(e) agents for retarding dissolution e.g. paraffin;

(f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h)׳adsorptive carriers, e.g.

kaolin and bentonite; (i) lubricants, e.g. talc, calcium 20 and magnesium' stearate and solid polyethyl glycols.

The tablets, dragees, capsules and pills formed from the pharmaceutical׳compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can' be 25 so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, pos.sibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.

. The ingredient can also be made up in microencapsulated form together with one or several of the abovementioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into. suppositories can, for example, 35 be the usual water-soluble diluents, such as polyethylene

L'e A ^,?I 35 3 glycols and fats (e.g. cocoa oil and high esters (e.g.

C^-alcohol with C-^-fatty acid)) or mixtures of these diluents.

The pharmaceutical compositions which are ointments, 5 pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these, substances. 10 The pharmaceutical compositions which are powders and sprays can, for example,, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, 15 contain the usual propellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and׳ emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion . of solvents having a molecular weight below 200 except 20 in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,5-butylene 25 glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures . thereof. ׳

For parenteral administration, solutions and emulsions 30 should be sterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are. suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol,.propylene glycol, surfaceactive agents (e.g. ethoxylated isostearyl alcohols, 35 polyoxyethylene sorbite and sorbitane esters), microLe' A 21 353 crystalline cellulose,, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can also contain colouring agents 5 and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).

In addition to a compound of the invention, the pharmaceutical compositions and medicaments according ¹⁰ to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.

Any diluent in the' medicaments of the present invention may be any. of those mentioned above in relation 1.5־ to the pharmaceutical compositions of the present invention. . Such .medicaments may include solvents of molecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according to the invention will generally 20 be adapted by virtue of their shape or packaging for , medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up 25 for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of. the medicament physically discrete ' .and coherent.

The production of the abovermentioned pharmaceutical 50 compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a׳ pharmaceutical composition (e.g. a granulate) and then forming the composition into, the medicament (e.g. tablets.). 35 This invention further provides' a method of combating ' Le A 21 353 ' 66243/2 (including prevention, relief and cure of) the abovementioned diseases in non-human animals, י which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or.in the form of a medicament according to; the invention.

The present invention further provides a feed additive comprising an active compound of the present invention in admixture with a feed additive-carrier.

The Examples which follow illustrate the inven10 tion further.

Example 1

<img file="IL66243A_D0012.tif" />

A mixture of 20 g of 7־chloro-l-cyclppropyl-6fluor01,4־-dihydro-4-oxo-quincline-3-carboxylie acid, 28.ל g of N-methylpiperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to 140°C for 1.5 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of H₂0. The suspension was filtered under suction, and the residue was rinsed with H₂0, dried in a vacuum drying cabinet at 80°C over CaCl₂, and recrystallised from glycol monomethyl ether. 14.5 g. of l-cyclopropyl-6-fluoro-1,4-dihydro7 (4 methyIpiperazino)-4-oxo-quinoline-3־carboxylic acid which decomposes at 248 to 25O°C were obtained.

י,'^,

י ’

<img file="IL66243A_D0013.tif" />

A mixture of 19-7 g of 7-chloro-l-cyclopropyl-6fluoro-l,4-dihydro-4-oxo-quinoline-3־carboxylic acid, , 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide was heated at 135 to 140°C for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in ¾0, filtered off under suction and washed with water. For further purification, the moist crude product was boiled with 100 ml of water, filtered off under suction at room temperature, washed with ^H2° and dried over CaCl₂ in a vacuum drying cabinet at 100 C until its weight remained constant. 19.6 g of ¹־cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylie acid which decomposed at 255 to 257 C were obtained.

The compound prepared according to Example 3 was dissolved in 50 ml of hot 10 per cent hydrochloric acid. 150 ml of ethanol were added to the filtered solution, the

Le A 21 353 mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100 C. 18.5 g of l-cyclopropyl-6-fluoro-l,4dihydro-4-oxo-7-piperazino-quinoline3־-carbo.xylic acid hydrochloride were obtained as colourless crystals which ' decomposed at 308 to 310°C.

Example ,3 .

a) A mixture of 1.2 g of l-cyclopropyl-6-fluoro-l,4dihydro-4-oxo-7-piperazipo־quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of Ν,Ν-dimethylformamide was heated at 70 to 80°C for 2.5 hours. The solvent was distilled off in vacuo, and’the residue was suspended in water. The product was filtered off under suction, rinsed with HgO and pressed on clay. 1.15 g of 1-cyclopropy1-6-fluoro-7-(ethylpiperazino)l,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydroiodide which decomposes at 306°C were obtained.

b) The 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-

4-oxo-quinoline-3-carboxylic acid used as the starting material was prepared as follows:

24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was added(topwise, a vigorous reflux being observed. After the reaction had ceased, the mixture was heated at the boil for a further 2 hours and was cooled with dry ice/acetone at -5°C to -10°C and a solution of 227.5 g of 2,4-dichloro5־-

Le A 21 353 fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mixture was stirred for 1 hour at 0°C to -5°C and was allowed’ to reach room temperature overnight, and a mixture of 400 5 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while cooling with ice. The phases were separated and were extracted twice with ether. The combined ether solutions were washed with saturated NaCl solution, and dried with Na₂S0_1|, and the solvent was 10 stripped off in vacuo. 549.5 g of diethyl 2,4-di-.

chloro-5-fluoro-benzoyl-malonate were obtained as the crude product.

0.15 g of p-toluenesulphonic acid was added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro־5־fluoro15 benzoyl-malonate in 50 ml of water. The emulsion was heated at the boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride, the combined CE^Cl^ solutions were washed once . . with saturated NaCl solution and dried with Na₂S0₁p and 20 the solvent was distilled off in vacuo. Fractionation of the residue under a fine vacuum gave 21.8 g of ethyl 2,4-dichloro־5־fluoro-benzoyl acetate IX of boiling point 127 to 142°C/Q.O9 mbar.

A mixture of 21.1 g of ethyl 2,4-dichloro־5־ 25 fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150°C for 2 ' hours. The volatile constituents were then distilled off under a waterjet vacuum and finally under a fine . vacuum, at a. bath temperature of 120°C. 25.2 g of crude ethyl 2-(2,4-dichloro־5־fluoro-benzoyl)־3־ethoxy-acrylate remained. It was sufficiently pure for the further׳ reactions.

4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro־5־fluoro35' benzoyl)-3-ethoxy-acrylate in'80’ml of ethanol while

Le A 21 353 cooling with ice and stirring. When the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/ petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro5־fluoro-benzoyl)-3־cyclopropylamino-acrylate (R־*־ = ) of melting point 89 to 90°C were obtained.

3-44 g.of80־ per cent sodium hydride were added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro5־fluoro-benzoyl)-3־cyclopropylamino-acrylate (R־'־ = C^H^) in 100ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room • temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H₂0. The filtrate was then acidified to pH = 1 to 2 with semiconcentrated hydrochloric acid, while cooling, with ice, and the precipitate wa.5 filtered off under suction, washed with water and dried in vacuo at 100°C. 27•7 g of 7־chloro-l-cyclopropyl. 6-fluoro-1,4-dihydro-4-oxo-quinoline־3־carboxylic acid (R = H) of melting point .234 to 237°C were obtained in this manner.

The present invention also comprises pharmaceutically acceptable bioprecursors of the active compounds of ׳' the present invention.

For the purposes of this specification the term 30 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the' ' 35 active compound.