AU602024B2 - Optically active gyrase inhibitors, their preparation and use as antibiotics - Google Patents

Description

COMMONWEALTH OF AUSTRALI6 O 1 4 PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: rrr t r r

P

I

Complete Specification Lodged: Accepted: Published: P-iority This document contains the amendments made under Section 49 and is correct for prining.

SRelated Art: Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main 80, Federal Republic of Germany WALTER DURCKHEIMER and KARL LEUBE EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: OPTICALLY ACTIVE GYRASE INHIBITORS, THEIR PREPARATION AND USE AS ANTIBIOTICS The following statement is a full description of this invention, including the best method of performing it known to US

I.

I -d

.:I

HOECHST AKTIENGESELLSCHAFT HOE 86/F 283 Dr.KA/rh Description OpticaLLy active gyrase inhibitors, their preparation and use as antibiotics Gyrase inhibitors of the nalidixic acid and norfloxacin, ciprofloxacin, enoxacin, pefloxacin and ofLoxacin type are SquinoLonecarboxylic acids and have great importance as agents for treating bacterial infections. Moreover, ring systems related to the quinolones, as reviewed in Drugs of the Future, volume 11, No. 5, 1986, pages 366 369, have, when suitably substituted, antibiotic activity comparable to that of the abovementioned prototypes.

Among the highly active gyrase inhibitors there are structures which have a center of asymmetry, i.e. there is a dextrorotatory and a Levorotatory form. However, to date they have been used only in racemic form. A major reason is that these active compounds have the characteristics of betaines, are sparingly soluble, and to date separation into the antipodes via diastereomeric salts has not been possible.

For example, it has been possible to obtain the and i forms of ofloxacin to date only by a difficult multistage synthesis in which it was necessary to fractionate a j 3,5-dinitrobenzoyl intermediate of ofloxacin by highpressure liquid chromatography (HPLC) and to reduce the alcohol functionality, which had been introduced for this purpose, to the methyl group in several synthetic steps (Antimicrobial Ag. Chemother. 29, (1986), page 163).

This way of preparing optically active ofloxacin cannot be carried out industrially. Thus there was a need to develop a practicable way to prepare optically active gyrase inhibitors, in particular ofloxacin.

i1

I

-2- The present invention is now based on the idea of resolving betaine-like gyrase inhibitors of the quinolone type which are in the form of racemates into their antipodes via hydroazinium intermediates using optically active acids, and subsequently liberating therefrom the active compounds in optically active form.

Thus the invention relates to a process for the preparation of the topically active antipodes of gyrase inhibitors of the general formula 0

(II)

R

iA denotes -0- R denotes C-C-alkyl which is substituted b dimethylamino or diethylamino, or denotes a pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl or pyridyl group which can be further substituted by C 1

-C

4 -alkyl, hydroxy-C -C 4 -alkyl or C -C-dialkylamino, and i 4 a R R and R, which can be identical or different, denote 3 hydrogen or C 1

-C

4 -alkyL which can be substituted by C 1

-C

4 -alkoxy, hydroxyL, fluorine or C1-C4dialkylamino, which comprises reaction of a compound of the formula II, in the form of its racemate, with an aminating reagent to give an intermediate in which the tertiary amino group present in at Least one of the radicals R R 2

R

and R is converted into a hydrazinium group of the formula III

NH

2

(III)

in which the bonds indicated by Lines go to carbon atoms which can also be part of a4\ring system, conversion of the hydrazinium intermediate into its betaine form, and conversion of the Latter into diastereomeric salts by addition of an optically active organic acid, separation of the enantiomers by crystaLLization of these salts, removal of the optically active acid again, and finally conversion, by reductive cleavage, of the resulting optically active hydrazinium intermediates into the optically active enantiomers of a compound of the formula II.

The following diagram illustrates the essential steps:

C-

0E~ 4 )N G CO 2

H

a) eLectrophilic amination b) conversion into the betaine form NH I r G CO2 8 I NH2 1 '2 SremovaL of the opticaLLy active acid, reduction >N G CO 2

H

Enantiomer addition of optically active acid and fractional crystallization N G- CO 2 removaL of the optically active acid, reduction G CO 2

H

Enantiomer S G

G

molecular skeleton of the racemic gyrase inhibitor molecular skeleton of the dextrorotatory gyrase inhibitor G molecular skeleton of the Levorotatory gyrase inhibitor The present invention particularly relates to the preparation of optically active compounds in which the substituents in the formula II have the following meanings: X or preferably -CH=, Y hydrogen or halogen, preferably halogen, in particular fluorine, 1.r1 P-C n 6 i- -'i I_ l III~( II ~--L~_)IYIILYL1 iU-Ir-IL\_U P P 5 P A :frb: L R C 1

-C

4 -aLkyL which is substituted by dimethylamino or diethyLamino, it being possible for the substituted alkyl radical preferably to represent methyL, ethyL, propyl or isopropyl, a saturated 5- or 6-membered ring with 1 or 2 nitrogen atoms, such as, in particuLar, pyrroLidinyL, piperidinyL or piperazinyl, or zn unsaturated or 6-membered ring with 1 or 2 nitrogen atoms, such as, in particular, pyrrolyl, imidazoLyL or pyridyL, it also being possible for the abovementioned ring systems, in particular the saturated 5- or 6-membered systems, to be substituted by C 1

-C

4 -aLkyL, preferably methyl, by hydroxy-

C

1

-C

4 -akyL, preferably hydroxymethyl, or by C1-C 4 -dialkyamino, preferably dimethylamino, particularly interesting examples of substituted rings being N-methyLpiperazinyL, 2-methylpiperazinyl, 3-methylpyrrolidiny or 2-hydroxymethylpyrrolidinyL, -C 1 -r-aky' prfraby methyl, ethyL, prp-' or isopropyl, in particular ethyl

C

2

-C

3 -aLkenyl, in partj'au4z- vinyL, cyclopropyL, ar referably phenyl, amino and it also being possible for the abovementioned radicats R (with the exception of amino and dimethylamino) to be substituted by chlorine or fluorine, fluorine being preferred, hydroxyL, methoxy, ethoxy or diethylamino, particularly interesting substituted radicals being fluoroethyl, preferably 2-fluoroethyl, hydroxyethyL, preferably 2-hydroxyethyL, difluoroethyl, trifLuoroethyl, methoxyethyl, fluorocyclopropy, difluorocycLopropyl, 2- and 4fluorophenyl and 2,4-difluoropheny, and pgLI, V3 and R 4 which can be identical or different, can 2 yl 1LII 6 represent hydrogen, C 1

-C

4 -aLkyL, preferably methyl, which can also be further substituted by

C

1

-C

4 -aLkoxy; preferably methoxy, by hydroxyl, by fluorine or by C 1

-C

4 -dialkylamino, preferably dimethyLamino.

Particularly interesting according to the invention is the preparation of the therapeuticaLLy very important Levorotatory ofloxacin (II) with Y fluorine, R -N N-CH 3 R hydrogen, A oxygen, X -CH= and R 3 methyl.

Examples of suitable aminating reagents are chloramine T and, in particular, hydroxylamine-0-sulfonic acid, as well as its derivatives such as, for example, 0-mesitylenesulfonylhydroxylamine or 0-(diphenylphosphinyl)hydroxyLamine.

The optically active organic acids known from the Literature for separation into the antipodes are suitable for this purpose, for example the optically active forms of tartaric acid, malic acid, camphor-10-sulfonic acid, 3bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, dibenzoyltartaric acid, di(4-toluyl)tartaric acid, phenylethylsuccinamic acid, and preferably the optically active forms of mandelic acid.

The racemic compounds of the formulae I and II are known from the literature or can be prepared by processes known from the literature.

The electrophilic amination according to the invention of the tertiary amino group of the gyrase inhibitors can advantageously make use of the commercially available hydroxylamine-0-sulfonic acid. It is also possible just as well to make use of other aminating reagents such as, for example, chloramine T or, for example, the abovementioned 0-substituted hydroxylamines.

7- It is normally sufficient to use equimolar amounts or a slight excess, for example of up to 20%, of aminating reagent.

Water is, especially when hydroxyLamine-0-suLfonic acid is used, a suitable solvent for this reaction step. Addition of organic solvents such as, for example, methanol, ethanol, isopropanol or dimethylformamide is possible if the solubility of the starting materials in water is low.

As a rule, the reaction is carried out at room temperature and takes a few hours.

The racemic hydrazinium stage is converted, from the salts resulting from the amination and the precipitation which advantageously follows it (for example as hydrochloride), by treatment with a basic component, for example with a conventional basic ion exchanger such as, for example, Serdolit, or with an inorganic base, such as, for example, sodium hydroxide solution, into the betaine form, which can also be further purified by further precipitation as salt (for example the hydrochloride) and renewed Liberation of the betaine.

Various optically active acids, for example the abovementioned, can be used for the separation into the antipodes via diastereomeric salts. (+)-Mandelic acid and (-)-mandelic acid have proven particularly favorable, and these can also be used alternately for more rapid enrichment of the enantiomers, i.e. (+)-mandelic acid is used .i first to enrich the form of the hydrazinium intermediates, and then the form of mandelic acid is added to the mother liquor which contains the form of the hydrazinium intermediate in excess. The separation into the antipodes is carried out in a manner known per se and is checked by following the optical rotation. The amounts of solvent should be adjusted app'opriately, depending on the solubility of the optically active acids used for the IC_ 8 separation.

Suitable for the reductive cleavage of the optically active hydrazinium intermediates into the optically active compounds of the formula II are the customary reduction processes such as, for example, with zinc dust, by electrolytic reduction, but preferably with catalytically activated hydrogen. In general, the cleavage takes place under atmospheric pressure, but it can also be carried out under elevated pressure if further speeding up of the hydrogenation is desired. Suitable catalysts are all hydrogenation catalysts which do not form adducts or undergo reactions with the substrates. The noble metal catalysts palladium and platinum are regarded as preferred catalysts. It suffices to use only the very small amounts of catalyst which are described in the literature for hydrogenations of this type and which can be used several times.

The process according to the invention can be particularly advantageously carried out in such a way that, initially, for the eLectrophilic amination a racemic compound of the formula e II, for example (+)-ofloxacin, is suspended in water and induced to dissolve at room temperature or slightly elevated temperature by addition of alkali, such as, for example, solid sodium bicarbonate or sodium carbonate, and/or an aqueous solution thereof, and an aqueous solution of the aminating reagent, preferably of hydroxylamine-0-sulfonic acid, which has been neutralized with, for example, sodium bicarbonate, is added in equimolar amount or, preferably, an approximately 10% excess. After the mixture has stood at room temperature for a considerable time (for example about 20 hours) it is acidified, for example with 4N hydrochloric acid, to a pH of about 3, whereupon the racemic aminated product precipitates out as hydrochloride.

The separation of enantiomers can then be carried out r 9 particuLarly advantageously in such a way that the hydrochloride of the racemic amination product is dissolved in water at slightly elevated temperature, a commercially available basic ion exchanger such as, for example, SerdoLit

(R)

Blue is added, the mixture is Left for a certain time, for example half an hour, advantageously being stirred, the exchanger is removed by, for example, filtration or centrifugation, and the filtrate is cautiously evaporated, preferably in vacuo at room temperature or slightly elevated temperature. The residue (betaine) is then dissolved in water, and an aqueous solution of the equimolar amount of an optically active organic acid, for example mandelic acid, is added. After concentration in vacuo at room temperature or slightly elevated temperature, and subsequent standing for many hours (for example about hours) in an ice bath, one of the two enantiomers of the aminated intermediate separates out in the form of a diastereoisomeric salt. In general, it is then necessary to purify the salt by recrystallization several times (for example 5 to 7 times), for example from water, until the optical rotation is constant.

The removal and recovery of the optically active acid is carried out, for example, in such a way that the resulting diastereomeric salt, for example with (S)-(+)-mandelic acid, is dissolved in water and stirred with a basic ion exchanger such as, for example, Serdolit for a few minutes (for example 15 minutes). The other enantiomer of the aminated intermediate can be isolated from the mother Liquor in the same way, merely with the difference that, S l 30 for example, the (R)-(-)-mandelic acid is added to separate out the enantiomer.

Residues, which may still be present, of unfractionated racemic mixture of the aminated intermediate can be recovered by adjusting the pH of the combined mother liquors from all the operations, for example with hydrochloric acid, to about 3 and thus precipitating their rr La 10 hydrochlorides.

In order to obtain the optically active compounds of the formula 4-Ie II, for example ofloxacin, it is now necessary to eliminate the amino group (cf. formula III). This can be carried out by reductive deamination, for example by acidification of the solution of the levorotatory or dextrorotatory aminated intermediate, for example with glacial acetic acid, and, after addition of a hydrogenation catalyst, for example palladium, carrying out hydrogenation under atmospheric pressure in a manner known per se, which takes about 2 to 4 hours as a rule. After the catalyst has been removed by filtration with suction, the solution can be dried, for example, by freeze-drying, the residue taken up in a suitable solvent, such as, for example, in ethanol, induced to crystallize out by cooling, and, where appropriate, further recrystallized.

The process according to the invention is distinguished by being carried out almost exclusively in water without using costly apparatus and chemicals.

Since no processes which can be used to resolve gyrase inhibitors into their optical antipodes have yet been described, it could not have been expected that the component produced by conversion to the hydrazinium intermediate would, by reason of its physicochemical properties, be amenable to resolution into its antipodes particularly readily, and to subsequent conversion into the optically active gyrase inhibitor.

The invention relates not only to the new resolution process described above but olso to the pharmaceutically effective, optically active antipodes of the compound ad II which are obtained therewith and which, with the exception of ofloxacin, it has not hitherto been possible to prepare.

I 1 11 The invention also relates to the new racemic and opticaLLy active hydrazinium intermediate compounds of the gyrase inhibitors of the formula II, in which the tertiary amino group(s) is in the form of the hydrazinium group of the formula III

NH

2 I (III) They represent the crucial intermediates for the resolution I into the optical antipodes according to the invention.

The pharmaceutically effective, optically active antipodes of the compounds of the formula -nd II are valuable antibiotics and can in the pure form be used with the customary pharmaceutical auxiliaries or in combination with other antibiotics orally and parenterally in human and veterinary medicine. Medicaments can be prepared in such a way that a pharmaceutically effective, optically active antipode of the compounds of the formula 4-e II is mixed with one or more pharmacologically tolerated vehicles or diluents, such as, for example, fillers, emulsifiers, lubricants, masking flavors or buffer substances, and converted into a suitable pharmaceutical presentation such as, for example, tablets, coated tablets, capsules, or a suspension or solution suitable for parenteral adminis- Stration.

Examples of vehicles or diluents which may be mentioned are tragacanth, lactose, talc, agar-agar, polyglycols, ethanol and water. Suitable and preferred for parenteral administration are suspensions or solutions in water. It is also possible to auiminister the active compounds as such, without vehicle or diluent, in a suitable form, for example in capsules. Suitable doses of the active compounds are about 0.05 to 1 g/day, preferably about 0.05 to g/day.

It is possible to administer single or, in general, multiple L i 12 doses, it being possible for the single dose to contain the abovementioned amount of the active compound.

i To illustrate the invention, as a typical example the pre- 1 paration of the key hydrazinium compound, which is necessary for the enantiomer separation, of oxacin, its resolution into the antipodes, and their reduction to give the optically active enantiomers, are described.

Example: Separation of the optically active enantiomers of (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-oiperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-(1,4)-benzoxazine-6carboxylic acid A. Amination with hydroxylamine-0-sulfonic acid 216.8 g (0.6 mole) of (+)-9-fluoro-2,3-dihydro-3-methyl- 10-(4-methyL-1-piperazinyl)-7-oxo-7H-pyrido i ,2,3-de]- (1,4)-benzoxazine-6-carboxylic acid are suspended in 3 L of water and, while stirring at room temperature, 101 g of solid sodium bicarbonate and 1.2 L of 2N sodium carbonate solution are added. A clear solution is rapidly produced, to which is added a neutralized solution of hydroxylamine-0-sulfonic acid, prepared from g (0.66 mole) of hydroxylamine-0-sulfonic acid, the equivalent amount of sodium bicarbonate and 600 ml of water, with stirring. After the reaction solution has stood at room temperature for 20 h, it is cooled in ice and the pH is adjusted to about 3 with 4N hydrochloric acid (about 900 ml). he aminated product immediately separates out as the crystalline hydrochloride which is filtered off on a suction funnel and washed four times with 100 ml of ice-water each time.

Analysis C 18

H

2 1

FN

4 0 4 x HCL, H 2 0 content 3% C calculated 50.8% found 50.8% H calculated 5.5% found 5.4% N calculated 13.2% found 13.0% ir -it j 13 113 i B. Separation of the enantiomers using optically active mandelic acid The separation of the enantiomers can be carried out i on the stiLL moist precipitate. For this purpose, the i 5 precipitate is dissolved in 8 L of water at 45 0

C,

700 g of a strongly basic exchanger [Serdolit BlueR (Serva), particle size 0.3-0.9 nm] are added, and the mixture is stirred for about half an hour. The exchanger is then removed by filtration with suction or cen- 10 trifugation, and is washed twice with 500 ml of water.

The washings are combined with the filtrate, and the entire amount of liquid is removed by distillation in vacuo (about 20 mm) at a bath temperature of 20-40 0

C.

i; The crystalline residue, which still contains small amounts of water, is dissolved in 1.1 L of water at 400C, and a solution of 91.3 g (0.6 mole) of (S)-(+)-mandelic acid in 400 ml of water, prepared at 400, is added.

The clear solution is concentrated to a total volume of 1 L under waterpump vacuum and a bath temperature of 20 400, and the solution is cooled in an ice bath for about 20 hours. Only the enantiomer of the aminated intermediate separates out as salt of mandelic acid and is filtered off with suction and washed twice with 50 ml of ice-water each time and dried. The process for purification of this crude product is as follows: The crude product is recrystallized five to seven times from 150 ml of water each time, by heating to about 750C and then cooling in an ice bath. The optical rotation shows no further increase. After drying over phosphorus pentoxide in vacuo, 126 g are obtained, of decomposition point 239 241o.

i i i 14 i Analysis C 18

H

2 1

FN

4 0 4 x C 8

H

8 0 3 (528.6),

H

2 0 content: 2 C calculated 57.9% found 58.0% H calculated 5.6% found 5.4% N calculated 10.4% found 10.4% To determine the optical purity, 0.2 g is dissolved in mL of water, stirred with 2 g of Serdolit exchanger at room temperature for 15 min, and the exchanger is removed by filtration with suction, and the filtrate is evaporated in a rotary evaporator. The optical rotation of the crystals which had been dried over P 2 0 5 and then rehydrated in air was determined to be [a 26 -61 (C 1.0 in H 2 The second enantiomer of the aminated intermediate is present in the mother Liquor and is isolated as follows: 350 g of Serdolit are added to this mother liquor, the mixture is stirred at room temperature for 30 minutes, and the exchanger is filtered off with suction and washed three times with 200 mL of water each time 64 g (0.42 mole) of (R)-(-)-mandelic acid are added to the combined filtrates, which are concentrated to 800 mL and cooled in an ice bath for about 20 hours. The enantiomer of the aminated intermediate crystaLLizes out as saLt of (R)-(-)-mandeLic acid and is filtered off with suction and washed twice with 50 mL of icewater each time. The purification and determination of purity are carried out in anaLogy to the procedure de- J scribed above for the enantiomer. 99.2 g of decomposition point 239 2410 are obtained. [a] 6 +60 (C 1.0 in H 2 0) Analysis C 18

H

2 1

FN

4 0 4 x C 8

H

8 0 3 (528.6), content: 3'% C caLculated 57.3% found 57.0% H calculated 5.7% found 5.3% N calculated 10.28% found 10.1% The collected mother Liquors from all the operations are adjusted to pH 3 with hydrochloric acid, whereupon the racemic mixture of aminated intermediates which has not bee.n fractionated is recovered as hydrochLoride (59 g 22.3%).

5 C. Reductive deamination 42.6 g of thb aminated intermediate of decomposition point 239 2410 and Ca 6 -610 are dissolved in 1.2 L of water at 40°, 112 g of Serdolit exchanger are added, the mixture is stirred for 15 min, and the exchanger is filtered off with suction and washed twice with 100 mL of water each time. The filtrate is acidified with 4.6 mL of glacial acetic acid and, after addition of catalytic amounts of palladium, is hydrogenated under atmospheric pressure, with shaking. The calculated amount of hydrogen is taken up within 2 to 4 hours.

The hydrogenation time depends on the amount of catalyst.

The catalyst is removed by filtration with suction, washed with a little water (about 50 ml) and the solution is freeze-dried. The residue is stirred in 400 ml of ethanol in an ice bath for one hour, the crystals are filtered off with suction, washed twice with 40 ml of cold ethanol, and the still moist product is recrystallized from 320 ml of ethanol. After washing twice with 25 ml of ethanol each time, 22.3 g of 25 fluoro-2,3-dihydro-3-methyl-10-(4-methyL-1-piperazinyl)- 7-oxo-7H-pyrido[1,2,3-del-(1,4)-benzoxazine-6-carboxy- Lic acid are obtained, of decomposition point 218 2190 and 2 -76.4 10 (C 0.385 in 0.05 N NaOH).

.0 Analysis C 18

H

20

FN

3 0 4 (361.38), H 2 0 content 1% C calculated 59.2% found 59.2% H calculated 5.6% found 5.6% N calculated 11.5% found 11.5% The enantiomer is obtained in an analogous manner starting from the dextrorotatory intermediate of 16 decomposition point 239 2410 and Eel] 26 +60 which has been described.

The yie~d of (+)-9-fLuoro-2,3-di hydro-3-methyL-10-(4methyL-1-piperazinyL)-7-oxo-7H-pyrido1,2,3-de-(1,4)benzoxazine-6-carboxyLic acid is 23.45 g, decomposition point 218 2190, 23 =+76.6 10 (C 0.385 in 0.05 N NaOH).

AnaLysis C 18

H

2 0

FN

3 0 4 (361.33), H 2 0 content 2% C caLcuLated 58.6% found 58.5% H caLcuLated 5.7% found 5.7% N caLcuLated 11.4% found 11.5%

I

Claims (6)

1. A process for the preparation of the optically active antipodes of gyrase inhibitors of the formulae II 0 Iy 2 H (II) R 1 N A R 3 i 4 in which X denotes -CH=, Y denotes halogen, i A denotes i R denotes C -C -alkyl which is substituted by dimethylamino or diethylamino, or denotes a pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl or pyridyl group which can be further substituted by C -C 4 -alkyl, 1 hydroxy-C -C -alkyl or C -C 4 -dialkylamino, and K R 3 and R which can be identical or different, denote hydrogen or C -C 4 alkyl which can be substituted by fI C -C -alkoxy, hydroxyl, fluorine, or C -C -dialkylamino, I which comprises reaction of a compound of the i formulae II, in the form of its racemate, with an aminating V reagent to give an intermediate in which the tertiary amino I group present in at least one of the radicals R 1 R 3 and R 4 is converted into a hydrazinium group of the formula III NH (III) in which the bonds indicated by lines go to carbon atoms which can also be part of the tertiary amine ring system, conversion of the hydrazinium intermediate into its betaine form, and conversion of the latter into diastereomeric salts by addition of an optically active organic acid, separation rli L- _^I~U~UF~l~~rPn9-U'rurx-.- -18- of the enantiomers by crystallization of these salts, removal of the optically active acid again, and finally conversion, by reductive cleavage, of the resulting optically active hydrazinium intermediates into the optically active enantiomers of a compound of the formula II.

2. The process as claimed in claim 1, wherein hydroxylamine-0-sulfonic acid is used as aminating reagent.

3. The process as claimed in claims 1 and 2, wherein dextrorotatory or levorotatory mandelic acid is used as o oO optically active acid. 0 0 oa 4. The process as claimed in claims 1-3, wherein the "o o reaction is made with a racemate of the compound II in which o ooe X represents A represents oxygen, Y represents 0 fluorine, R 1 represents -N _N-CH R 3 represerts methyl, 00 and R 4 represents hydrogen (ofloxacin). The pharmaceutically effective, optically active So,, antipodes of the compounds of the formula II mentioned in 4 'claim 1, an exception being made of a compound of the S' formula II in which X represents A represents oxygen, Y represents fluorine, R 1 represents N-CH R 3 i represents methyl, and R 4 represents hydrogen (ofloxacin). i 6. Racemates and optically active antipodes of the I hydrozinium compounds of the general formula II as defined in claim 1 in which a contained tertiary amino group represented by at least one of the radical R 1 R 3 and R 4 is converted into a hydroazinium group of the formula III NH in which the bonds indicated by lines go to carbon atoms which can also be part of a ring system. L 0 <P -19-

7. Compounds as claimed in claim 6, which are based on a compound of the formula II in which X represents A represents oxygen, Y represents fluorine, R 1 represents -N N-CH R 3 represents methyl, and R 4 represents hydrogen.

8. A pharmaceutical product active against bacterial infections, which contains a pharmaceutically effective, optically active antipode of the compounds of the formula II as defined in claim 1, an exception being made of a compound of the formula II in which X represents A represents 3 oxygen, Y represents fluorine, R 1 represents R represents methyl, and R 4 represents hydrogen (ofloxacin) in adjunct with a pharmaceutically acceptable carrier or excipient.

9. A process for the preparation of pharmaceutical i products active against bacterial infections, which comprises converting a pharmaceutically effective, optically active antipode of the compounds of the formula II as defined in claim 1 into a pharmaceutically suitable customary vehicles. A method of controlling bacterial infections comprising administering to a patient suffering therefrom a i pharmaceutically effective amount of an optically active antipode of the general formula II as defined in claim 1. i DATED this 27th day of June, 1990. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADE MARK ATTORNEYS 'THE ATRIUM', 2ND FLOOR 290 BURWOOD ROAD HAWTHORN VIC. 3122 L