1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4beta-hydroxyethyl piperazino)-quinoline-3-carboxylic acid,its preparation and antibacterial agents containing it

:. i

The present invention relates to a new| l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-4B,.I hydroxyethyl-piperazino)-quinoline-3-carboxylic acid, to a process for its production and to its use as feed additive and as antibacterial agent.

It has already been disclosed that l-ethyl-6fluoro-1,4-dihydpo-4-oxo-7-piperazino-quinoline-3carboxylic acids possess antibacterial properties [J. Med. Chem. 23, 1358 (1980)].

The compound of the present invention has an antibacterial action superior to that of the known quinolone-carboxylic acids and azaquinolone-carboxylic acids. The compound according to the invention exhibits its superior antibacterial activity against both gram positive and gram negative bacteria, including Pseudomonas aeruginosa.

According to the present invention we further provide a process for the production of the compound of the invention in which (a) 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4oxo-quinoline-3-carboxylic acid of the formula

<img file="IL80514A_D0001.tif" />

COOR¹ (ID in which

R1 denotes a hydrogen atom, is reacted with a piperazine derivative of the formula

HOCH₂CH₂־N NH (III) (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,ⁱ1,0]undec-7־־ene) and the 7־ piperazino-quinolone5־־“carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (I), and the compound of formula (I) obtained by reaction variant (a) or (b) is converted, if desired, into a salt or hydrate thereof.

The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, Ν,Ν-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.

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 the above reaction variants, 1 to 5 mol of alkyl-piperazine (in the case of piperazine 1 to 15 mol), preferably 2 to 5 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).

~ Among the new acid salts and hydrates of the invention those salts or hydrate that are pharmaceutically acceptable are particularly important and are preferred, and the new salts and hydrates can be interconverted in any suitable manner; methods for such interconversion are known in the art.

Thus the free acid 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, hydro-־ iodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.

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

F״COC1 C00C₂H₅ r ״ -^COOC₂^H

C-CH

COOC₂ HCOOC₂H₅

VIII

C-C-i

CH

C-C-C00C₂H5

11 c-ch₂cooc₂h₅

<img file="IL80514A_D0002.tif" />

ΌΗ

C-COOR¹ .CO OR¹

־ 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 196 , 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 0-formate/acetic anhydride into the ethyl 2-(2,4-dichloro-5־fluoro-benzoyl)-J-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 (R¹ = 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 carbonate 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-fluoro-

4,6-aichlorotoluene 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

4.

precursors or intermediate products, dichloro-5־methyl-aniline of formula starting from 2,4 (XII).

<img file="IL80514A_D0003.tif" />

1. NaNO₂, H₃O ® hn(ch₃)₂

CH₃

<img file="IL80514A_D0004.tif" />

Cl

XI la

HF

V

<img file="IL80514A_D0005.tif" />

XI cc!₃

<img file="IL80514A_D0006.tif" />

COOH Cl

XIII w

<img file="IL80514A_D0007.tif" />

Cl

XV

COCI (IV) ^c

<img file="IL80514A_D0008.tif" />

Cl i According to this equation, 2,4-dichior0-5־ methyl-aniline of formula (XII) is diazotised by means of NaNOg, 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-dichloro-5־methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is cleaved thermally at 130 to 140° to give 3־ fluoro-4,6-dichIorotoluene XI, being split off (Yield: 77.7% of theory).

The 3־fluoro4,6־-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to 160°C, underiUV irradiation, to give 2,4-dichloro־5־fluoro-1trichloro-methylbenzene of formula (XIII).

The hydrolysis of the compound of formula (XIII) with 95 Ρθι. cent sulphuric acid leads to 2,4-dichloro־5־ fluoro-benzoic acid of. formula (XV), which is converted with thionyl chloride into the carboxylic acid-chloride of formula (IV).

The compound ,.according to the invention is distinguished by a particularly good antibacterial action against gram positive and gram negative bacteria, in particular in comparison with the compounds of German Patent Application P 30 33 157.8 of 3-9.1980 and DE-OS (German Published Specification) 2,804,097.

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

The present invention provides a pharmaceutical composition containing as active ingredient the׳ 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 the 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 .the compound of the invention.

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

’¹Medicament 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 will depend 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 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, 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 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 so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly 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, he the usual water-soluble diluents, such as polyethylene .0 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, 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.

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, 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 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, 1,3-butylene 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 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, polyoxyethylene sorbite and sorbitane esters), micro- 11 _ 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 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 the compound ־of the. invention, the pharmaceutical compositions and medicaments according 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 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 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 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 above-mentioned pharmaceutical 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).

This invention further provides a method of combating.

(including prevention, relief and cure of) the abovementioned diseases in non-human animals, 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 Example which follows illustrates the invention further.

Example 1

<img file="IL80514A_D0009.tif" />

a) A suspension of 2.81 of 7־chloro-l-cyclopropyl6־flu0r0-l,4-dihydr0-4-0x0“quin01ine-3^carbcxylic acid and 5.2 g of N-B-hydroxyethy!piperazine in 25 ml of dimethylsulphoxide was' heated at 135 to 14C°C for 2 hours. The solvent was distilled off under a fine vacuum, the residue was toiled for a short time with 2C ml of HgO and left to stand overnight at room temperature, and the precipitate was filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaCl₂ at 80°C. 2.1 g of l-cyclcpropyl-o-fluoro-

1,4-dihy dro-4-oxo-74-3 )־-hydroxyethy lpiperazi.no )-quinoline-3־carboxylic acid which decomposed at 237 to 239°C were obtained.

b) The 7-chloro-l-cyclopropyl-6-fluoro־l,4־dihydro4-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 aide ב cropwise, a vigorous reflux being observed. After the reaction had ceased, the mixture was heated at the toil fcr a further 2 hours and was cooled with dry ice/acetcr.e at -5°C to -10°C and a solution of 227.5 g of 2,4-dichlcrc-5־

- .13 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 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 Na^SO^, and the solvent was stripped off in vacuo. 349-5 g of diethyl 2,4-dichloro־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־fluorobenzoyl-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 CH^CL^ solutions were washed once with saturated NaCl solution and dried with Na₂S0_i|, and 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/O.O9 mbar.

A mixture of 21.1 g of ethyl 2,4-dichloro־5־ 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-henzoyl.)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־fluorobenzoyl)־3־ethoxy-acrylate in‘80‘ml of ethanol while 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 S ethyl 2-(2,4-dichloro-5־ fluoro-benzoyl)-3-cyclopropylamino-acrylate (R¹ = C₂H^) of melting point 89 to 90°C were obtained.

3.44 g of .80 per cent sodium hydride were added in portions to a solution of 319י g of ethyl 2-(2,4-dichloro5־fluoro-benzoyl)־3־cyclopropylamino-acrylate (R¹ = C₂H^) in 100 ml 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 was 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 ’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 active compound.