DK163992B - 1-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre - Google Patents

1-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre Download PDF

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DK163992B
DK163992B DK154591A DK154591A DK163992B DK 163992 B DK163992 B DK 163992B DK 154591 A DK154591 A DK 154591A DK 154591 A DK154591 A DK 154591A DK 163992 B DK163992 B DK 163992B
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cyclopropyl
dihydro
oxo
trifluoro
acid
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DK154591A
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DK154591A (da
DK154591D0 (da
DK163992C (da
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Klaus Grohe
Uwe Petersen
Hans-Joachim Zeiler
Karl Georg Metzger
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Bayer Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Fodder In General (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Hydrogenated Pyridines (AREA)

Description

i
DK 163992B
Den foreliggende opfindelse angår den hidtil ukendte forbindelse l-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo- 3-quinolincarboxylsyre med formlen 0 5 ' R^AxCOOH (II)
Den her omhandlede forbindelse finder anvendelse som 10 udgangsmateriale ved fremstilling af de ligeledes hidtil ukendte 7-amino-l-cyclopropyl-6,8-dif luor-1,4-dihydro-4-oxo-3-quinolin-carboxylsyrederivater med formlen (I) 0 15 rL XX/ (i)
N I A
r2/ f Δ i hvilken R1 og R2 er ens eller forskellige og betyder en eventuelt 20 med en hydroxy-, amino-, methylamino- eller dimethylamino-gruppe substitueret C1-C4-alkylgruppe, eller R1 og R2 kan sammen med det nitrogenatom, hvortil de er bundet, danne en 5- eller 6-leddet heterocyclisk ring, der som ringled yderligere kan indeholde atomerne eller grupperne 25 -0-, -S-, -SO-, -S02- eller ^N-R3, og som eventuelt kan være substitueret en til tre gange på carbonatomerne med Ci-C4-alkyl, hydroxy, alkoxy med 1-3 carbonatomer, amino, methylamino eller ethylamino, idet hvert carbonatom kun kan bære én substituent, hvor 30 R3 betyder hydrogen, en forgrenet eller uforgrenet alkyl-, alkenyl- eller alkynylgruppe med 1 til 6 carbonatomer, der eventuelt kan være substitueret med en hydroxy-, trifluor-methylthio, alkoxy-, alkylthio-, alkylamino- eller dial-kylaminogruppe med 1 til 3 carbonatomer i en alkylgruppe, 35 en cyangruppe eller en alkoxycarbonylgruppe med 1 til 4 carbonatomer i alkoholdelen, eller R3 betyder en eventuelt
DK 163992 B
2 i phenyldelen med nitro eller amino monosubstitueret phenyl-alkylgruppe med op til 4 carbonatomer i alkyIdelen, en eventuelt med hydroxy, methoxy, chlor eller fluor én eller to gange substitueret phenylgruppe, en eventuelt med hydroxy, 5 methoxy, chlor og fluor én eller to gange substitueret phen-acylgruppe, en oxoalkylgruppe med op til 6 carbonatomer, en cycloalkyl-alkylgruppe med op til 6 carbonatomer i den cy-cliske del og op til 3 carbonatomer i den acycliske del eller en COR4-, CN- eller S02R5-gruppe, hvor 10 R4 betyder hydrogen, eventuelt 1 eller 2 gange med amino, alkoxycarbonyl med 1 til 3 carbonatomer i alkyldelen, car-boxy, alkoxy med 1 til 3 carbonatomer eller trifluormethyl-thio substitueret, ligekædet eller forgrenet alkyl med 1 til 4 C-atomer, eventuelt med chlor, hydroxy, amino eller 15 carboxy monosubstitueret phenyl, alkoxy med 1 til 4 C-atomer, alkylthio med 1 til 2 C-atomer, benzyloxy, amino, eventuelt med alkoxycarbonyl med 1 til 3 C-atomer i alkyldelen eller carboxy monosubstitueret alkylamino med 1 til 5 C-atomer, og R5 betyder ligekædet eller forgrenet alkyl med 1 til 3 c-20 atomer, phenyl eller methylphenyl.
Forbindelserne med formlen (I) eller farmaceutiske acceptable syreadditionssalte deraf er egnede som antibak-terielle midler i human- og veterinærmedicin, idet forebyggelse hos og behandling af fisk henregnes til veterinær-25 medicinen.
Fra DE offentliggørelsesskrift nr. 3.106.013, EP patentskrift nr. 0.078.362 og DK fremlæggelsesskrift nr. 151.624 kendes quinoloncarboxylsyrer med en struktur, som ligner den i forbindelserne med formel (I), idet der dog i 30 1-stilling ikke kan sidde en cyclopropylgruppe i de fra DE offentliggørelsesskriftet og DK patentskriftet kendte forbindelser, medens de fra EP patentskriftet kendte forbindelser er 6-monofluorforbindelser. Disse kendte forbindelser er ligeledes antibakterielt virksomme, men forbindelserne 35 med formel (I) udviser sammenlignet med de kendte en mikroorganismespecifikt forbedret, antibakteriel virkning.
DK 163992 B
3
Forbindelserne med formlen (I) er genstand for krav i stamansøgningen, DK patentansøgning nr. 2470/84, hvori også deres biologiske aktivitet er belyst.
Omdannelsen af den her omhandlede l-cyclopropyl-6,7,8-5 -trifluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre til de antibakterielt aktive 7-amino-l-cyclopropyl-6,8-difluor- l,4-dihydro-4-oxo-3-quinolin-carboxylsyrederivater med formlen (I) sker ved, at trifluorquinolincarboxylsyren med formlen (II) 10 0 (II) rÅ 15 omsættes med en amin med formlen (III) R1 \ NH (III) 20 / R2 i hvilken R1 og R2 har de ovenfor angivne betydninger, eventuelt i nærværelse af syrebindere.
Omsættes l-cyclopropyl-6,7,8-trifluor-4-oxo-l,4-dihy- 25 dro-3-quinolincarboxylsyre (II) med f.eks. 2-methylpiperazin, kan reaktionsforløbet gengives ved følgende reaktionsskema
? tt S COOH
„ 9··:ψ
Denne omsætning er beskrevet mere detaljeret i stamansøgningen, DK patentansøgning nr. 2470/84.
35 Den her omhandlede, hidtil ukendte 1-cyclopropyl- 6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre med ovenstående formel (II) kan fremstilles efter følgende reaktionsskema:
DK 163992 B
4 F^^. COC1 yCOOC 2 H5 YV + CH Mg (OEt) 2 \2 - F I F x COOC2H5
5 F
Π) (2) i? ^ cooc h5 ° F > fv^v^:-ch2cooc2h[- _v T i ^cooc2h, ^ TT 25 —^ F^rS ρΛΛρ 10 F p (3) (4) ? C-C-COCC2H5 F__^ «X CH _. YV^ ^C-COOC2H5 F I F Ac H -»
15 ' °C2H5 F I F HlT
F Δ (5) (6)
O O
F /^X/COOC-H,- F ^ I, COOH
„ ,w - FÅ FÅ (7) (II) 25 Ifølge reaktionsskemaet acyleres malonsyrediethylester (2) i nærværelse af magnesiumethylat med 2,3,4,5-tetrafluor-benzoylchlorid (1) til aroylmalonesteren (3) (Organicum, 3. oplag, 1964, s. 438).
I stedet for (1) kan 2,3,4,5-tetrafluorbenzoesyrefluo-3 0 rid anvendes.
Ved partiel forsæbning og decarboxylering af (3) i vandigt medium med en katalytisk mængde svovlsyre eller p-toluensulfonsyre fås aroyleddikesyreethylesteren (4) i godt udbytte. Denne går med o-myresyre-triethylester/eddikesyre-35 anhydrid over i 2-(2,3,4,5-tetrafluorbenzoyl)-3-ethoxy-acryl-syreethylesteren (5). Omsætning af (5) med cyclopropylamin
DK 163992B
5 i et opløsningsmiddel, f.eks. methylenchlorid, alkohol, chloroform, cyclohexan eller toluen, fører ved en svagt exoterm reaktion til det ønskede mellemprodukt (6).
Cycliseringsreaktionen (6) -* (7) gennemføres i et 5 temperaturområde fra 60 til 300"C, fortrinsvis fra 80 til 180eC.
Som fortyndingsmidler kan dioxan, dimethylsulfoxid, N-methylpyrrolidon, sulfolan, hexamethylphosphorsyretriamid og foretrukket Ν,Ν-dimethylforaamid anvendes.
10 På tale som syrebindere til dette reaktionstrin kommer kalium-tert. butanol at, butyl-lithium, lithium-phenyl, phenyl-magnesiumbromid, natriummethylat, natriumhydrid, natriumeller kaliumcarbonat, og særligt foretrukkent kalium- eller natriumfluorid. Det kan være fordelagtigt at anvende et 15 overskud på 10 molprocent af basen.
Den i det sidste trin udførte esterhydrolyse af (7) under basiske eller sure betingelser fører til l-cyclopropyl--6,7,8-trifluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre med formlen (II).
20 Det som udgangsmateriale til denne syntesevej anvendte 2,3,4,5-tetrafluorbenzoylchlorid (1) fås ud fra den fra litteraturen kendte 2,3,4,5-tetrafluor-benzoesyre (G.G. Yakobson, V.N. Odinokov og N.N. Vorozhtsov Jr., Zh. Obsh.
Khim. 36, 139 (1966)) ved hjælp af thionylchlorid på gængs 25 måde. Det har et kogepunkt på 75 til 80eC/1700 Pa. 2,3,4,5--Tetrafluorbenzoylfluorid har et kogepunkt på 46 til 47*C/200 Pa (n^0: 1,4375).
Nedenstående eksempel illustrerer fremstillingen af den her omhandlede l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-30 4-oxo-3-quinolincarboxylsyre og dens omdannelse til en biologisk aktiv forbindelse med formel (I).
DK 163992B
6
Eksempel , 'Δ 24,3 g magnesiumspåner suspenderes i 50 ml vandfrit ethanol. Der tilsættes 5 ml carbontetrachlorid, og når reaktionen er kommet i gang, tildryppes der en blanding af 160 g malonsyrediethylester, 100 ml absolut ethanol og 400 ml 10 vandfrit toluen ved 50-60°C. Der opvarmes i endnu 1 time til 50-60°C, der afkøles med en blanding af tøris og acetone til -5°C til -10°C, og ved denne temperatur tildryppes langsomt en opløsning af 212,5 g 2,3,4,5-tetrafluorbenzoylchlorid (1) i 80 ml absolut toluen. Der omrøres i 1 time ved 0 til 15 -5°C, blandingen får lov at komme op på stuetemperatur i løbet af natten, og under isafkøling lader man en blanding af 400 ml isvand og 25 ml koncentreret svovlsyre løbe til. Faserne adskilles, og der efterekstraheres to gange med toluen. De forenede toluenopløsninger vaskes med mættet 20 NaCl-opløsning, der tørres med NaS04, og opløsningsmidlet fjernes i vakuum. Der fås 335 g 2,3,4,5-tetrafluorbenzoylma-lonsyrediethylester (3) som råprodukt.
Til en emulsion af 284,8 g rå 2,3,4,5-tetrafluorben-zoylmalonsyrediethylester (3) i 300 ml vand sættes 0,3 g p-25 toluensulfonsyre. Der opvarmes til kogepunktet under god omrøring i 5 timer, den afkølede emulsion ekstraheres flere gange med methylenchlorid, de forenede CH2Cl2-opløsninger vaskes én gang med mættet NaCl-opløsning, der tørres med Na2S04, og opløsningsmidlet afdestilleres i vakuum. Frak-30 tionering af remanensen i finvakuum giver 160,2 g 2,3,4,5-tetrafluorbenzoyleddikesyreethylester (4) med kogepunktet 100-110'C/9-10 Pa. Smeltepunkt 47-49°C.
En blanding af 110,7 g 2,3,4,5-tetrafluorbenzoyleddi-kesyreethylester (4), 93,5 g o-myresyretriethylester og 107 35 g eddikesyrehydrid opvarmes i 2 timer til 150°c. Derpå afdestilleres de flygtige bestanddele i vandstrålevakuum og til
DK 163992B
7 sidst i finvakuum ved en badtemperatur på ca. 120°C. Tilbage bliver 123,9 g rå 2-(2,3,4,5-tetrafluorbenzoyl)-3-ethoxy-acrylsyreethylester (5) . Den er tilstrækkeligt ren til de videre omsætninger.
5 Til en opløsning af 123,9 g 2-(2,3,4,5-tetrafluorben- zoyl) -3-ethoxyacrylsyreethylester (5) i 250 ml ethanol sættes under isafkøling og omrøring dråbevist 23,2 g cyclopropy1a-min. Når den eksoterme reaktion er døet hen, omrøres der i endnu 1 time ved stuetemperatur, opløsningsmidlet fjernes i 10 vakuum, og remanensen omkrystalliseres fra en blanding af cyclohexan og petroleumsether. Der fås 115 g 2-(2,3,4,5-tetraf luorbenzoyl) -3-cyclopropylaminoacrylsyreethylester (6) med smeltepunkt 63-65“C.
Til en opløsning af 107,8 g 2-(2,3,4,5-tetrafluorben-15 zoyl)-3-cyclopropylaminoacrylsyreethylester (6) i 400 ml vandfrit dimethylformamid sættes 21,2 g natriumfluorid. Der omrøres i 2 timer under tilbagesvaling, og reaktionsblandingen hældes varm ud på is. Bundfaldet skilles fra ved sugning, vaskes godt med vand og tørres i vakuum over calciumchlorid 20 ved 100°C. Der fås 91,2 g l-cyclopropyl-6,7,8-trifluor-l,4--dihydro-4-oxo-3-quinolin-carboxylsyreethylester (7) med smeltepunktet 167-168'C.
En blanding af 94 g l-cyclopropyl-6,7,8-trifluor- l,4-dihydro-4-oxo-2-guinolincarboxylsyreethylester (7), 600 25 ml iseddike, 450 ml vand og 70 ml koncentreret svovlsyre opvarmes i 1,5 timer til tilbagesvaling. Den varme suspension hældes i ud i is, bundfaldet skilles fra ved sugning, der vaskes godt med vand og tørres i vakuum ved 100* C. På denne måde fås 88,9 g rent l-cyclopropyl-6,7,8-trifluor-l,4-dihy-30 dro-4-oxo-3-quinolincarboxylsyre med formlen '(II) og smeltepunktet 228-230eC (sønderdeling).
DK 163992 B
8
Omdannelse til en forbindelse med formel m.
Γγ/τΗ 5 HtfYTf * HC1
En blanding af 2,83 g (0,01 mol) l-cyclopropyl-6,7,8--trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre (II), 4,4 10 g (0,051 mol) vandfrit piperazin og 30 ml tørt pyridin opvarmes i 6 timer under tilbagesvaling. Opløsningsmidlet fjernes i vakuum, remanensen optages i 25 ml vand, og under isafkøling indstilles der på pH 1 med koncentreret saltsyre, bundfaldet skilles fra koldt, og der vaskes med kold 10%'s salt-15 syre og ethanol. Efter tørring i vakuum ved 100°C fås 3,05 g 1-cyclopropyl, 6,8-dif luor-7- (1-piperazinyl) -1,4-dihydro- 4-oxo-3-quinolincarboxylsyre-hydrochlorid med sønderdelingspunkt 354-355*C.
•S».

Claims (1)

  1. DK 163992B Patentkrav. l-Cyclopropyl-6,7,8-trif luor-l , 4-dihydro-4-oxo-3-guinolincarboxylsyre, kendetegnet ved, at den har formlen 5 0 Fn^nA^COOH 10 Λ
DK154591A 1983-05-18 1991-09-03 1-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre DK163992C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19833318145 DE3318145A1 (de) 1983-05-18 1983-05-18 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
DE3318145 1983-05-18

Publications (4)

Publication Number Publication Date
DK154591A DK154591A (da) 1991-09-03
DK154591D0 DK154591D0 (da) 1991-09-03
DK163992B true DK163992B (da) 1992-04-27
DK163992C DK163992C (da) 1992-09-21

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ID=6199330

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DK247084A DK164902C (da) 1983-05-18 1984-05-17 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyrederivater eller farmaceutisk acceptable syreadditionssalte deraf samt laegemiddel indeholdende disse forbindelser og fremgangsmaade til midlets fremstilling
DK154591A DK163992C (da) 1983-05-18 1991-09-03 1-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre

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DK247084A DK164902C (da) 1983-05-18 1984-05-17 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyrederivater eller farmaceutisk acceptable syreadditionssalte deraf samt laegemiddel indeholdende disse forbindelser og fremgangsmaade til midlets fremstilling

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US (2) US4556658A (da)
EP (1) EP0126355B1 (da)
JP (3) JPH0643402B2 (da)
KR (1) KR870000921B1 (da)
AU (1) AU573765B2 (da)
CA (1) CA1304738C (da)
CY (1) CY1487A (da)
DE (2) DE3318145A1 (da)
DK (2) DK164902C (da)
ES (4) ES8507535A1 (da)
GR (1) GR79952B (da)
HK (1) HK27088A (da)
PT (1) PT78588B (da)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5281612A (en) * 1982-09-09 1994-01-25 Warner-Lambert Company Naphthyridine antibacterial agents
US4665079A (en) * 1984-02-17 1987-05-12 Warner-Lambert Company Antibacterial agents
DE3577089D1 (de) * 1984-01-26 1990-05-17 Abbott Lab Antibakterielle chinolinderivate.
CA1285279C (en) * 1984-02-17 1991-06-25 Joseph P. Sanchez 7-amine derivatives of 1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acids and 1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine- 3-carboxylic acidsas antibacterial agents
DE3409922A1 (de) * 1984-03-17 1985-09-26 Bayer Ag, 5090 Leverkusen 1,7-diamino-1,4-dihydro-4-oxo-3-(aza)chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie ihre verwendung bei der bekaempfung bakterieller erkrankungen
DE3420116A1 (de) * 1984-05-30 1985-12-05 Bayer Ag, 5090 Leverkusen Immunstimulierende mittel
US5200548A (en) * 1984-06-04 1993-04-06 Bayer Aktiengesellschaft 2,4,5-Trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivatives
US5468861A (en) * 1984-06-04 1995-11-21 Bayer Aktiengesellschaft 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and alkyl esters thereof
US5530158A (en) * 1984-06-04 1996-06-25 Bayer Aktiengesellschaft 2,4,5-trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivatives
DE3420743A1 (de) * 1984-06-04 1985-12-05 Bayer Ag, 5090 Leverkusen 7-amino-1-cyclopropyl-6,8-dihalogen-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
DE3420798A1 (de) * 1984-06-04 1985-12-05 Bayer Ag, 5090 Leverkusen 7-(3-aryl-l-piperazinyl)- sowie 7-(3-cyclohexyl-l-piperazinyl)-3-chinoloncarbonsaeuren
JPS6191183A (ja) * 1984-10-11 1986-05-09 Kyorin Pharmaceut Co Ltd キノロンカルボン酸誘導体
IN162769B (da) * 1984-11-13 1988-07-09 Kyorin Seiyaku Kk
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ES540891A0 (es) 1985-12-01
DK164902C (da) 1993-01-18
ES8602753A1 (es) 1985-12-01
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DE3465989D1 (en) 1987-10-15
JPH0826001B2 (ja) 1996-03-13
JPH0559007A (ja) 1993-03-09
JPH0764731B2 (ja) 1995-07-12
ES540890A0 (es) 1985-12-01
US4952695A (en) 1990-08-28
US4556658A (en) 1985-12-03
CA1304738C (en) 1992-07-07
KR860004048A (ko) 1986-06-16
ES8602754A1 (es) 1985-12-01
DK154591A (da) 1991-09-03
DK164902B (da) 1992-09-07
ES8602755A1 (es) 1985-12-01
DE3318145A1 (de) 1984-11-22
EP0126355B1 (de) 1987-09-09
PT78588B (en) 1986-06-26
ES532380A0 (es) 1985-09-01
ES540892A0 (es) 1985-12-01
DK247084D0 (da) 1984-05-17
DK247084A (da) 1984-11-19
HK27088A (en) 1988-04-22
PT78588A (en) 1984-06-01
AU573765B2 (en) 1988-06-23
AU3530084A (en) 1986-05-15
GR79952B (da) 1984-10-31
DK8402470A (da) 1984-11-19
CY1487A (en) 1989-12-08
DK154591D0 (da) 1991-09-03
ES8507535A1 (es) 1985-09-01
EP0126355A1 (de) 1984-11-28
DK163992C (da) 1992-09-21
US4556658B1 (da) 1987-09-15
KR870000921B1 (ko) 1987-05-07
JPS59212474A (ja) 1984-12-01
JPH0592922A (ja) 1993-04-16

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