Use of chemotherapeutic agents

Abstract

The use of chemotherapeutic agents for the preparation of a medicament for the topical and/or local treatment of diseases caused by bacteria and/or for prophylaxis in humans or animals.

1 . A method for the topical and/or local treatment of wounds caused by infections comprising administering a therapeutically effective amount of at least one compound of formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 A is CH, CCl, CBr, C—CH 3 , C—CN, C—OCH 3 , C—OCHF 2  or N, 
 R1 is C 1-5  alkyl, C 1-5  alkenyl, 2-fluoroethyl, cycloalkyl, bicycloalkyl, 2-fluorocyclopropyl, 1-oxetan-3-yl, methylamino, optionally substituted phenyl or pyridyl, or 
 A and R1 together form the group —C—O—CH 2 —CH(CH 3 )—, 
 R2 is hydrogen or C 1-3  alkyl optionally substituted by hydroxyl, halogen or amino, 
 R3 is hydrogen, halogen, methyl, amino or NH—NH 2 , 
 R4 is hydrogen, halogen or amino, and 
 R5 is an optionally monosubstituted or polysubstituted mono-, bi- or tricyclic alicycle which is saturated or has at least one double bond and which optionally has at least one heteroatom in the ring system, or an aromatic mono-, bi- or tricycle optionally having at least one heteroatom, 
 
       and/or 
       at least one compound of formula (II) 
       
         
           
           
               
               
           
         
       
       in which:
 R1 is hydrogen or C 1-3  alkyl, and 
 R2 is an optionally monosubstituted or polysubstituted mono-, bi- or tricyclic alicycle which is saturated or has at least one double bond and which optionally has at least one heteroatom in the ring system, or an aromatic mono-, bi- or tricycle optionally having at least one heteroatom, 
 and/or their corresponding hydrate and/or their corresponding physiologically compatible acid addition salt and/or optionally their corresponding physiologically compatible salt of the carboxylic acid of the compounds of formula (I) in which R2 is H and/or the compounds of formula (II) in which R1 is H, and/or corresponding enantiomers and/or corresponding diastereomers and/or corresponding racemates and/or a corresponding mixture of at least two of the above-mentioned compounds, and optionally other physiologically compatible auxiliary substances, 
 
       to a subject in need thereof. 
     
     
         2 . The method of  claim 1  where the wound is caused by a postoperative or posttraumatic infection. 
     
     
         3 . The method of  claim 2  where the wound is caused by a posttraumatic infection resulting from a cut, a sting, a bruise, a bite or gunshot wound, an infected burn, a hand infection, panaritium cutaneum, panaritium subcutaneum, panaritium ossale, panaritium articulare or tendovaginitis purulenta, postoperative sepsis, an infected ulcer, gangrene, a mucosal ulceration, an acute bacterial skin infection, pyrodermia, erysipelas, a furuncle, a carbuncle, phlegmon, an abscess, ulcus cruris, a decubital ulcer, a blood blister, erythrasma, and/or chronic bacterial skin infection, lupus vulgaris, swimming-pool granuloma, Buruli ulcer, or actinomycosis, secondarily infected dermatoses, acne or rosacea. 
     
     
         4 . The method of  claim 1  where in formula (I):
 A is CH, CCl, CBr, C—CH 3 , C—CN, C—OCH 3 , C—OCHF 2  or N, 
 R1 is ethyl, 1,1-dimethyl-ethyl, 1-ethenyl, 1,1-dimethyl-prop-2-ynyl, 2-fluoroethyl, cyclopropyl, bicycle[1.1.1]pent-1-yl, 2-fluorocyclopropyl, 1-oxetan-3-yl, methylamino, 4-fluorophenyl, 2,4-difluorophenyl, 5-amino-2,4-difluoro-phenyl, 5-fluoro-pyridin-2/1 or 6-amino-3,5-difluoro-pyridin-2-yl, or 
 A and R1 together form the group —C—O—CH 2 —CH(CH 3 )—, where the —CH(CH 3 )— part of this group is bonded to the nitrogen atom of the heterocycle, 
 R2 is hydrogen, methyl or ethyl, 
 R3 is hydrogen, F, Cl, Br, methyl, amino or NH—NH 2 , 
 R4 is hydrogen, F or amino, 
 R5 is optionally monosubstituted or polysubstituted cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyridyl or imidazolyl, where at least two substituents are optionally coupled together, 
 
       and/or in formula (II),
 R1 is hydrogen, and 
 R2 is optionally monosubstituted or polysubstituted cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, where at least two substituents are optionally coupled together. 
 
     
     
         5 . The method of  claim 1  where in formula (I):
 A is CH, CCl, C—CN, C—OCH 3  or N, 
 R1 is cyclopropyl, 2-fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl, or 
 A and R1 together form the group C—O—CH 2 —CH(CH 3 )—, where the —CH(CH 3 )-part of this group is bonded to the nitrogen atom of the heterocycle, 
 R2 is hydrogen, 
 R3 is hydrogen or amino, 
 R4 is hydrogen or F, 
 R5 is optionally monosubstituted or polysubstituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, where at least two substituents are optionally coupled together. 
 
     
     
         6 . The method of  claim 1  where in formula (I):
 A is CH, CCl, C—OCH 3  or N, 
 R1 is cyclopropyl or 2,4-difluorophenyl, or 
 A and R1 together form the group C—O—CH 2 —CH(CH 3 )—, where the —CH(CH 3 )-part of this group is bonded to the nitrogen atom of the heterocycle, 
 R2 is hydrogen, 
 R3 is hydrogen or amino, 
 R4 is hydrogen or F, and 
 R5 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 3-aza-bicyclo[3.1.0]hexyl optionally substituted by amino, methyl, aminomethyl and/or methoxyimino, or piperidino-pyrrolidinyl. 
 
     
     
         7 . The method of  claim 1  where in formula (II):
 R1 is hydrogen, and 
 R2 is optionally monosubstituted or polysubstituted cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, where at least two substituents are optionally coupled together. 
 
     
     
         8 . The method of  claim 1  where the compound is selected from at least one of
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-743-(methylamino)-1-piperidinyl]-4-oxo-3-quinolinecarboxylic acid (balofloxacin), 
 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid monohydrochloride (BAY Y3118), 
 1-cyclopropyl-6-fluoro-8-difluoromethoxy-1,4-dihydro-7-((3S)-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride (caderofloxacin), 
 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (ciprofloxacin), 
 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (clinafloxacin), 
 (1a,5a,6b)-(+)-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (ecenofloxacin), 
 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (enoxacin), 
 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (enrofloxacin), 
 6-fluoro-1-(5-fluoro-2-pyridinyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (fandofloxacin), 
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (gatifloxacin), 
 7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (gemifloxacin), 
 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin), 
 (3S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (levofloxacin), 
 1-cyclopropyl-8-fluoro-1,4-dihydro-8-methoxy-74(40S,70S)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl 1-4-oxo-3-quinolinecarboxylic acid (moxifloxacin), 
 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (nadifloxacin), 
 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (norfloxacin), 
 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin), 
 5-amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (olamufloxacin), 
 (3S)-10-(1-aminocyclopropyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid (pazufloxacin), 
 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (pefloxacin), 
 6-fluoro-1-methyl-744-[(5-methyl-2-oxo-1,3-dioxot-4-yOmethyl]-1-piperazinyll-4-oxo-1H,4H41,3]thiazeto[3,2-a]guinoline-3-carboxylic acid (prulifloxacin), 
 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid (rosoxacin), 
 7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (sitafloxacin), 
 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (tosufloxacin), and 
 7-(1a,5a,60-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (trovafloxacin). 
 
     
     
         9 . The method of  claim 8  where the compound is selected from at least one of
 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (clinafloxacin), 
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinylY4-oxo-3-quinolinecarboxylic acid (gatifloxacin), 
 7-[(4Z)-3-(aminomethyl)-4-(methoxylmino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (gemifloxacin), 
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid (moxifloxacin), 
 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (tosufloxacin), and 
 7-(1a,5a,6a-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (trovafloxacin). 
 
     
     
         10 . The method according to  claim 8  where the compound is selected from at least one of
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (gatifloxacin), 
 7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (gemifloxacin) and 
 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolop, 4-bipyridin-6-y11-4-oxo-3-quinolinecarboxylic acid (moxifloxacin). 
 
     
     
         11 . The method of  claim 1  where the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate and tolylsulfonate. 
     
     
         12 . The method of  claim 1  where the physiologically compatible salts of the carboxylic acid are selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts, silver salts and guanidinium salts. 
     
     
         13 . The method of  claim 1  wherein the wound infection is present in a human or an animal. 
     
     
         14 . A gelatinous formulation containing at least one compound of formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 A is CH, CCl, CBr, C—CH 3 , C—CN, C—OCH 3 , C—OCHF 2  or N, 
 R1 is C 1-5  alkyl, C 1-5  alkenyl, 2-fluoroethyl, cycloalkyl, bicycloalkyl, 2-fluorocyclopropyl, 1-oxetan-3-yl, methylamino, optionally substituted phenyl or pyridyl, or 
 A and R1 together form the group —C—O—CH 2 —CH(CH 3 )—, 
 R2 is hydrogen or C 1-3  alkyl optionally substituted by hydroxyl, halogen or amino, 
 R3 is hydrogen, halogen, methyl, amino or NH—NH 2 , 
 R4 is hydrogen, halogen or amino, and 
 R5 is an optionally monosubstituted or polysubstituted mono-, bi- or tricyclic alicycle which is saturated or has at least one double bond and which optionally has at least one heteroatom in the ring system, or an aromatic mono-, bi- or tricycle optionally having at least one heteroatom, 
 
       and/or 
       at least one compound of formula (II) 
       
         
           
           
               
               
           
         
       
       in which:
 R1 is hydrogen or C 1-3  alkyl, and 
 R2 is an optionally monosubstituted or polysubstituted mono-, bi- or tricyclic alicycle which is saturated or has at least one double bond and which optionally has at least one heteroatom in the ring system, or an aromatic mono-, bi- or tricycle optionally having at least one heteroatom, 
 and/or their corresponding hydrate and/or their corresponding physiologically compatible acid addition salt and/or optionally their corresponding physiologically compatible salt of the carboxylic acid of the compounds of formula (I) in which R2 is H and/or the compounds of formula (II) in which R1 is H, and/or corresponding enantiomers and/or corresponding diastereomers and/or corresponding racemates and/or a corresponding mixture of at least two of the above-mentioned compounds, and optionally other physiologically compatible auxiliary substances 
 wherein the compounds of formula (I) and/or of formula (II) are present in concentrations of from 0.005 mg/ml to 200 mg/ml. 
 
     
     
         15 . The gelatinous formulation of  claim 14  which contains as physiologically compatible auxiliary substances, solvents, gelling agents, surface-active compounds, thickeners or mixtures of at least two of these auxiliary substances. 
     
     
         16 . The gelatinous formulation of  claim 15  which contains modified celluloses, polyalkylene glycols and water and optionally at least one polysorbate. 
     
     
         17 . The gelatinous formulation of  claim 16  which contains, as the polysorbate, at least one mono-, di- or triester of oleic acid, lauric acid, palmitic acid or stearic acid and sorbitol and/or its anhydride with up to 20 mol of ethylene oxide units per mol of sorbitol or anhydride. 
     
     
         18 . The gelatinous formulation of  claim 14  which has been applied to an inert carrier or an inert carrier material or has been incorporated therein. 
     
     
         19 . The gelatinous formulation of  claim 18  where the inert carriers are strip inserts, thread inserts, chips, trays, collagen sponges, tampons, cotton wool plugs or foam pellets. 
     
     
         20 . The gelatinous formulation according to  claim 14  where the compounds of formula (I) and/or of formula (II) are employed in concentrations of from 0.5 mg/ml to 200 mg/ml. 
     
     
         21 . The gelatinous formulation according to  claim 20  where the compounds of formula (I) and/or of formula (II) are employed in concentrations of from 10 mg/ml to 150 mg/ml. 
     
     
         22 . The method of  claim 1  where the compounds of formula (I) and/or of formula (II) are administered in the form of a solution, a suspension, an emulsion, in form of liposomes or in form of micelles and have optionally been applied to or incorporated in a carrier material or an inert carrier. 
     
     
         23 . The method of  claim 22  where the compounds of formula (I) and/or of formula (II) are administered in the form of an aqueous solution. 
     
     
         24 . The method according to  claim 1  where the compounds of formula (I) and/or of formula (II) are administered in the form of a medicament which contains, as other physiologically compatible auxiliary substances, solvents, solubilizers, thickeners, preservatives, emulsifiers, mucins, osmolality regulators, antioxidants, chelating agents, disinfectants, dispersants, emulsion stabilizers, hydrocolloids, wetting agents or a mixture of at least two of the above-mentioned auxiliary substances.