DK169334B1 - 7-(1-Pyrrolidinyl)-3-quinoloncarboxylsyrederivater, fremgangsmåder til deres fremstilling og deres anvendelse i lægemidler og dyrefodertilsætninger - Google Patents
7-(1-Pyrrolidinyl)-3-quinoloncarboxylsyrederivater, fremgangsmåder til deres fremstilling og deres anvendelse i lægemidler og dyrefodertilsætninger Download PDFInfo
- Publication number
- DK169334B1 DK169334B1 DK103687A DK103687A DK169334B1 DK 169334 B1 DK169334 B1 DK 169334B1 DK 103687 A DK103687 A DK 103687A DK 103687 A DK103687 A DK 103687A DK 169334 B1 DK169334 B1 DK 169334B1
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- DK
- Denmark
- Prior art keywords
- pyrrolidinyl
- carboxylic acid
- oxo
- acid derivatives
- cyclopropyl
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Classifications
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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
-
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Description
DK 169334 B1
Opfindelsen angår hidtil ukendte 7-(l-pyrrolidinyl)- 3-quinoloncarboxylsyrederivater, fremgangsmåder til deres fremstilling samt lægemidler, især til dyr, og dyrefodertilsætninger indeholdende disse forbindelser.
5 Det er allerede kendt, at l-cyclopropyl-6-fluor-l,4- dihydro-4-oxo-7-(1-piperazinyl)-3-quinolincarboxylsyre (ciprofloxacin, DE-A nr. 3.142.854) og 8-chlor-l-cyclopropyl- 6-fluor-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinoloncar-boxylsyre (DE-A nr. 3.420.734) er højvirksomme antibakteriel- 10 le midler.
Endvidere er der i EP-A nr. 0153.828, 0.160.578 og 0.047.005 samt i US-patentskrift nr. 4.571.396 beskrevet quinolon- hhv. naphthyridoncarboxylsyrer med antibakteriel virkning.
15 Fra US patentskrift nr. 4.563.459 kendes forbindelsen l-cyclopropyl-6-fluor-l,4-dihydro-4-oxo-7-(4-hydroxy-l-pipe-ridinyl)-3-quinolincarboxylsyre med antibakteriel virkning. Forbindelserne ifølge opfindelsen har overlegen antibakteriel virkning i forhold til denne forbindelse.
20 Den foreliggende opfindelse angår hidtil ukendte 7-
(1-pyrrolidinyl)-3-quinoloncarboxylsyrederivater, som er ejendommelige ved, at de har den almene formel I
« 25 n
JXCJ
Λ
30 J
hvori A betyder CH, CC1 eller CF, R1 betyder hydroxy eller hydroxymethyl, og R2 betyder hydrogen, methyl eller ethyl, 35 med det forbehold at A ikke kan betyde CF, når R·*- betyder hydroxy, 2 DK 169334 B1 og deres farmaceutisk anvendelige hydrater og alkalimetal-, jordalkalimetal-, sølv- og guanidiniumsaltene af de tilgrundliggende carboxylsyrer.
De her omhandlede forbindelser udviser en stærk anti-5 bakteriel virkning i det grampositive og det gramnegative område.
De er derfor egnede som aktive stoffer i human- og veterinærmedicinen, idet også behandling af fisk med henblik på behandling eller forebyggelse af bakterieinfektioner 10 regnes til veterinærmedicinen.
En fremgangsmåde ifølge opfindelsen til fremstilling af forbindelserne med formlen I er ejendommelig ved, at en forbindelse med formlen II
15 0
Fvn^vv^v/c0°R2 XQCX <n)* ’ Λ 20 hvori A og R2 har de ovenfor angivne betydninger, og Y betyder halogen, især fluor eller chlor, omsættes med en pyrrolidin med formlen III 25 i—r^1 ζΓ
H
30 hvori R1 har den ovenfor angivne betydning, eventuelt i nærværelse af syrebindende midler (fremgangsmåde A).
En anden fremgangsmåde ifølge opfindelsen til frem-35 stilling af forbindelserne med den almene formel I
3 DK 169334 B1
O
5 fYyVcoor2 ΝΛαΛν^ -Kj
10 hvori A, R1 og R2 har de ovenfor angivne betydninger, idet dog R2 ikke kan betyde hydrogen, er ejendommelig ved, at en forbindelse med formlen IV
0
15 F\^'N^As^C00H
^crx <iv)·
20 hvori R1 og A har de ovenfor angivne betydninger, omsættes med en forbindelse med formlen V
R2 - Z (V) hvori 2 R har den ovenfor angivne betydning, men dog ikke kan betyde 25 hydrogen, og Z betyder hydroxy eller halogen, især chlor, brom eller iod, eventuelt i nærværelse af syrebindende midler eller under vandfraspaltende betingelser (fremgangsmåde B).
30 Anvendes ved reaktionen efter fremgangsmåde A 1-cy- clopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-quinolincarboxyl-syre og 3-hydroxypyrrolidin som udgangsforbindelser, kan reaktionsforløbet gengives ved følgende reaktionsskema:
O
4 DK 169334 B1
0 S
li + base 5 Η ΛΛ^ -HF /-
A A
Anvendes ved reaktionen efter fremgangsmåde B 1--cyclopropyl-6-fluor-1,4-dihydro-7-(3-hydroxy-l-pyrrolidi-10 nyl) -4-oxo-quinolincarboxylsyre og ethylalkohol som udgangsforbindelser, kan reaktionsforløbet gengives ved følgende reaktionsskema: 0 j} 15 >VYVC00CiH5
T 11 O [H ] JL JL JJ
/ n\An/ + c2h5oh -» /— »o-o t -¾° h^vj 2^, 20 De som udgangsstoffer anvendte forbindelser med formlen II er kendte. Som eksempler skal nævnes: 7- Chlor-l-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-3-quino~ linearboxy1syre (tysk patentansøgning nr. 3.142.854), 25 l-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-quinolin- carboxylsyre (europæisk patentansøgning nr. 113.091), 8- chlor-l-cyclopropy1-6,7-difluor-1,4-dihydro-4-oxo-3--quinolincarboxylsyre (tysk patentansøgning nr. 3.420.743), 30 l-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quinolin-carboxylsyre (tysk patentansøgning nr. 3.318.145), 35 5 DK 169334 B1 7-chlor-l-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-3-qui.no-lincarboxylsyreethylester (tysk patentansøgning nr.
3.142.854), 5 l-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-quinolin--carboxylsyreethylester (europæisk patentansøgning nr.
113.091), 10 8-chlor-l-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3--quinolincarboxylsyreethylester (tysk patentansøgning nr. 3.420.743) og l-cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-quino-15 lincarboxylsyreethylester (tysk patentansøgning nr.
3.318.145).
De som udgangsforbindelser anvendte pyrrolidi-ner med formlen III er kendte. Forbindelserne kan an-20 vendes både som racemater og som rene enantiomere, der kan fås ved gængse metoder. Følgende forbindelser anvendes: (+)-3-Hydroxy-pyrrolidin, (+)-3-hydroxy-pyrrolidin, (-)-3-hydroxy-pyrrolidin, (+)-3-hydroxymethyl-pyrrolidin, 25 (+)-3-hydroxymethyl-pyrrolidin og (-)-3-hydroxymethyl-pyrro lidin.
De som udgangsforbindelser ved fremgangsmåde B anvendte forbindelser med formlen IV er hidtil ukendte og fremstilles ved fremgangsmåde A ifølge opfindelsen.
30 De som udgangsstoffer anvendte forbindelser med form len V er kendte. Som eksempel skal nævnes: methanol, ethanol, methyliodid og ethylbromid.
6 DK 169334 B1
Omsætningen af II med III ifølge fremgangsmåde Af foretages fortrinsvis i et fortyndingsmiddel som dimethylsul-foxid, N, N-dimethy1 formamid, hexamethylphosphorsyretriamid, sulfolan, acetonitril, vand, en alkohol, f.eks. methanol, 5 ethanol, n-propanol eller isopropanol, glycolmonomethylether eller pyridin. Ligeledes kan blandinger af disse fortyndingsmidler anvendes.
Som syrebindende midler kan alle gængse uorganiske og organiske syrebindende midler anvendes. Hertil 10 hører fortrinsvis alkalimetalhydroxider, alkalimetalcar-bonater, organiske aminer og amidiner. Som særlig egnede skal i detaljer nævnes: triethylamin, 1,4-diaza-bicyclo--[2,2,2]-octan (DABCO), 1,8-diazabicyclo[5,4,0]undec-7--en (DBU) eller pyrrolidin III i overskud.
15 Reaktionstemperaturerne kan varieres inden for et større område. Sædvanligvis arbejdes mellem ca. 20 og 200°C, fortrinsvis mellem 80 og 180°C.
Reaktionen kan udføres ved normalt tryk, men også ved forhøjet tryk. Sædvanligvis arbejdes ved tryk mel-20 lem 1 og 100 bar, fortrinsvis mellem 1 og 10 bar.
Ved udførelsen af fremgangsmåde A ifølge opfindelsen anvendes normalt 1 til 15 mol, fortrinsvis 1 til 6 mol af forbindelsen III pr. mol carboxylsyre II.
Frie hydroxygrupper kan beskyttes under reaktio-25 nen med en passende hydroxybeskyttelsesgruppe, f.eks. tetrahydropyranylgruppen, og efter afslutning af reaktionen atter frigøres.
Til fremstilling af estrene ifølge opfindelsen ved fremgangsmåde B omsættes den til grund liggende car-30 boxylsyre med formlen IV fortrinsvis i overskud af alkohol i nærværelse af stærke syrer, f.eks. svovlsyre, vandfrit hydrogenchlorid, methansulfonsyre, p-toluensulfon-syre eller sure ionbyttere, ved temperaturer fra ca. 20 til 200°C, fortrinsvis ca. 60 til 120°C. Det dannede reak-35
O
7 DK 169334 B1 tionsvand kan fjernes ved azeotrop destillation med chloroform, carbontetrachlorid, benzen eller toluen.
Alkylestrene kan ligeledes fås ved omsætning af et alkalimetal- eller aminsalt af den til grund liggende 5 carboxylsyre med formlen IV med et alkylhalogenid fortrinsvis i et fortyndingsmiddel som dimethylsulfoxid, dimethyl-forraamid, pyridin, sulfolan eller tetramethylurinstof ved temperaturer fra ca. 0 til ca. 150°C, fortrinsvis ved 10 til 100°C.
10 Alkalimetal- eller jordalkalimetalsaltene af car- boxylsyrerne ifølge opfindelsen fås f.eks. ved opløsning af syren i underskud af alkalimetal- eller jordalkalime-talhydroxid, filtrering og inddampning af filtratet til tørhed. Farmaceutisk egnede er natrium-, kalium- og cal-15 ciumsalte. Ved omsætning af et alkalimetal- eller jord- alkalimetalsalt med et passende sølvsalt såsom sølvnitrat fås de tilsvarende sølvsalte.
De aktive stoffer ifølge opfindelsen kan foreligge både som racemater og som rene enantiomere forbindel-20 ser.
Foruden de i eksemplerne anførte forbindelser skal følgende hidtil ukendte aktive stoffer specielt nævnes: l-Cyclopropyl-6-fluor-l,4-dihydro-7-[3-(S)-hydroxy-1-25 pyrrolidinyl]-4-oxo-3-quinolincarboxylsyre, l-cyclopropyl-6-fluor-l,4-dihydro-7-[3-(R)-hydroxy-1-pyrrolidinyl]-4-oxo-3-quinolincarboxylsyre, 8-chlor-l-cyclopropyl-6-fluor-l,4-dihydro-7-[3-(S)-hydroxy-l-pyrrolidinyl]-4-oxo-3-quinolincarboxylsyre, 30 8-chlor-l-cyclopropyl-6-fluor-l,4-dihydro-7-[3-(R)- hydroxy-l-pyrrolidinyl]-4-oxo-3-quinolincarboxylsyre, natrium-l-cyclopropyl-6-fluor-l,4-dihydro-7-[3-(S) -hydroxy-l-pyrrolidinyl]-4-oxo-3-quinolincarboxylat, kalium-l-cyclopropyl-6-fluor-l,4-dihydro-7-[3-(R)-hy-35 droxy-l-pyrrolidinyl]-4-oxo-3-quinolincarboxylat, natrium-8-chlor-l-cyclopropyl-6-fluor-1,4-dihydro-7--[3-(S)-hydroxy-l-pyrrolidinyl]-4-oxo-3-quinolincarb-oxylat, o DK 169334 Bl 8 sølv-8-chlor-l-cyclopropyl-6-fluor-1,4-dihydro-7-[3-(R) -hydroxy-1-pyrrolidinyl] -4-oxo-3-quinolincarboxylat, l-cyclopropyl-6-fluor-l,4-dihydro-7- [3- (S) -hydroxy-1-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre-methylester, 5 l-cyclopropyl-6-fluor-l,4-dihydro-7-[3- (R) -hydroxy-1-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre-ethy lester, 8-chlor-l-cyclopropyl-6-fluor-l,4-dihydro-7- [3- (S) -hydroxy-l-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre-ethylester, 10 l-cyclopropyl-6-f luor-1,4-dihydro-7- [3- (S) -hydroxyme- thyl-l-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre/ l-cyclopropyl-6-fluor-1,4-dihydro-7- [3- (R) -hydroxyme-thyl-l-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre, 8-chlor-l-cyclopropyl-6-fluor-1,4-dihydro-7-[3-(S)-hy- 15 droxymethyl-l-pyrrolidinyl]-4-oxo-3-quinolincarboxylsyre, 8-chlor-l-cyclopropy 1-6-f luor-1,4-dihydro-7- [3- (R) -hydroxymethyl-1-pyrrolidinyl] -4-oxo-3-quinolincarboxylsyre, 1-cyclopropy 1-6,8-dif luor-1,4-dihydro-7- (3-hydroxymethyl--1-pyrrolidinyl) -4-oxo-3-quinolincarboxylsyreethylestere 20
Eksempel på en tablet ifølge opfindelsen.
25 Hver tablet indeholder:
Forbindelse ifølge eksempel 1 583,0 mg
Mikrokrystallinsk cellulose 55,0 mg
Majsstivelse 72,0 mg 30 Poly-(l-vinyl-2-pyrrolidon) uopløseligt 30,0 mg Højdisperst siliciumdioxid 5,0 mg
Magnesiumstearat 5,0 mg 750,0 mg 35 DK 169334 B1
O
'9
Lakovertrækket indeholder:
Poly-(O-hydroxypropyl-O-methyl)- 6,0 mg cellulose 15 cp 5 Macrogol 4000 rec. INN 2,0 mg polyethylenglycoler (DAB)
Titan-(IV)-oxid 2,0 mg 10,0 mg
Forbindelserne ifølge opfindelsen udviser ved ringe toksicitet et bredt antibakterielt spektrum mod grampositive og gramnegative kim, især mod enterobak- teriaceae, især også mod sådanne, der er resistente mod forskellige antibiotika, f.eks. penicilliner, cephalospo- riner, aminoglycosider, sulfonamider og tetracycliner.
15
Disse værdifulde egenskaber muliggør deres anvendelse som aktive kemoterapeutiske forbindelser i medicinen og som konserveringsstoffer til uorganiske og organiske materialer, især til organiske materialer af 20 enhver art, f.eks. polymere, smøremidler, farver, fibre, læder, papir og træ, af levnedsmidler og af vand.
De aktive forbindelser ifølge opfindelsen er virksomme mod et meget bredt spektrum af mikroorganismer. Ved hjælp af dem kan gramnegative og grampositive bakterier 25 og bakterielignende mikroorganismer bekæmpes, og de af disse sygdomsvækkere fremkaldte sygdomme hindres, Undres og/eller helbredes.
Særlig virksomme er forbindelserne ifølge opfindelsen mod bakterier og bakterielignende mikroorganis-3Q mer. De er derfor særlig velegnede til profylakse og kemoterapi af lokale og systemiske infektioner i human- og veterinærmedicinen, der frembringes af disse sygdomsvækkere.
F.eks. kan lokale og/eller systemiske sygdomme 3g behandles og/eller forhindres, der forårsages af følgende sygdomsvækkere eller blandinger af følgende sygdoms- 10 DK 169334 B1 o vækkere:
Gram-positive kokker, f.eks. Staphylokokker (Staph, aureus og Staph, epidermidis) og Streptokokker (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae og 5 Strept. pyogenes), gram-negative kokker (Neisseria gonorrhoeae) og gram-negative stavbakterier som Entero-bakteriaceae, f.eks. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii og Citrob. di-vernis), Salmonella og Shigella, endvidere Klebsiellae 10 (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. Agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia og slægten Acineto-bacter. Derudover omfatter det antibakterielle spektrum 15 slægten Pseudomonas (Ps. aeruginosa, Ps. maltophilia) og strengt anaerobe bakterier som f.eks. Bacteroides fragilis, repræsentanter for slægten Peptococcus, Peptostrepto-coccus og slægten Clostridium, endvidere mykoplasmaer (M. pneumoniae, M. hominis, M. urealyticum) og mykobak-20 terier, f.eks. Mycobacterium tuberculosis.
Som sygdomme, der forårsages af de nævnte sygdomsvækkere eller blandingsinfektioner og hindres, lindres eller helbredes af forbindelserne ifølge opfindelsen, skal f.eks.
25 nævnes: infektionssygdomme hos mennesker som f.eks. Otitis, pharyngitis, pneumoni, peritonitis, pyelonephritis, cystitis, endocarditis, systeminfektioner, bronchitis (akut og kronisk), septiske infektioner, sygdomme i de 30 øvre luftveje, diffus panbronchiolitis, pulmonært emphy- sem, dysenteri, enteritis, leverabscesser, urethritis, prostatitis, epididymitis, gastrointestinale infektioner, knogle- og ledinfektioner, cystisk fibrose, hudinfektioner, postoperative sårinfektioner, abscesser, 35 phlegmoner, sårinfektioner, inficerede forbrændinger, 11 DK 169334 B1 o brandsår, infektioner i mundområdet, infektioner efter tandoperationer, osteomyelitis, septisk arthritis, cholecystitis, peritonitis med appendicitis, cholangitis, intraabdominale abscesser, pankreatitis, sinusitis, ma-5 stoiditis, mastitis, tonsillitis, typhus, meningitis og infektioner i nervesystemet, salpingitis, endometritis, genital-infektioner, pelveoperitonitis og øjeninfektioner.
Foruden hos mennesker kan også bakterieinfektioner hos andre arter behandles. Som eksempler skal nævnes: 10 Svin: coli-diarrhoe, enterotoxæmi, sepsis, dysenteri, salmonellose, mastitis-metritis-agalakti-syndrom og mastitis, drøvtyggere (okse, får og ged): diarrhoe, sepsis, bron-chopneumoni, salmonellose, pasteurellose, mykoplasmose 15 og genitalinfektioner,
Hest: bronchopneumonier, føllammelse, puerperale og post-puerperale infektioner, salmonellose.
Hund og Kat: bronchopneumoni, diarrhoe, dermatitis, otitis, urinvejsinfektioner og prostatitis, og 20 Fjerkræ (høne, kalkun, vagtel, due, prydfugle og andre): mycoplasmose, E. coli-infektioner, kroniske luftvejssygdomme, salmonellose, pasteurellose og psittakose.
Ligeledes kan bakterielle sygdomme behandles, som optræder, når nytte- og prydfisk opdrættes og holdes, i-25 det det antibakterielle spektrum strækker sig ud over de ovenfor nævnte sygdomsfremkaldere til andre sygdomsfremkaldere som f.eks. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebakterier, Borrelia, Treponema, Nocardia, Rikettsien og Yersinia.
30
Opfindelsen angår tillige de her omhandlede forbindelsers anvendelse til fremstilling af lægemidler, samt lægemidler især til dyr, der er ejendommelige ved, at de indeholder disse forbindelser og eventuelt ikke-toksiske, indif-35 ferente, farmaceutisk egnede bærestoffer.
Opfindelsen angår endelig en dyrefodertilsætning, der er ejendommelig ved, at den indeholder de her omhandlede forbindelser.
O
12 DK 169334 B1 Lægemidler omfatter også farmaceutiske præparater i doseringsenheder. Dette betyder, at præparaterne foreligger i form af enkelte dele, f.eks. tabletter, drageer, kapsler, piller, suppositorier og ampuller, hvis indhold 5 af aktivt stof svarer til en brøkdel eller et mulitiplum af en enkelt dosis. Doseringsenhederne kan f.eks. indeholde 1,2,3 eller 4 enkeltdoser eller 1/2, 1/3 eller en 1/4 enkeltdosis. En enkeltdosis indeholder fortrinsvis den mængde aktivt stof, der indgives på en gang, og som sæd-10 vanligvis svarer til 1/1, 1/2, 1/3 eller 1/4 af en dagsdosis.
Ved ikke toksiske, indifferente, farmaceutisk egnede bærestoffer skal forstås faste, halvfaste eller flydende fortyndingsmidler, fyldstoffer og formuleringshjælpe-15 midler af enhver art.
Som foretrukne farmaceutiske præparater skal nævnes tabletter, drageer, kapsler, piller, granulater, suppositorier, opløsninger, suspensioner og emulsioner, pastaer, salver, geler, cremer, lotioner, puddere og spray's.
20
Tabletter, drageer, kapsler, piller og granulater kan indeholde det eller de aktive stoffer sammen med sædvanlige bærestoffer, såsom a) fyld- og strækkemidler, f.eks. stivelse, mælkesukker, rørsukker, glucose, mannitol og kiselsyre, b) bindemidler, f.eks. carboxymethylcellulose, 25 algmater, gelatine og polyvinylpyrrolidon, c) fugtigheds-bevarende midler, f.eks. glycerin, d) sprængemidler, f.eks. agar-agar, calciumcarbonat og natriumcarbonat, e) opløsningsforhalende midler, f.eks. paraffin, f) resorptions- fremskyndende midler, f.eks. kvaternære ammoniumforbinde1-30 ser, g) befugtningsmidler, f.eks. cetylalkohol og glycerinmonos tearat, h) adsorptionsmidler, f.eks. kaolin og bentonit, og i) glidemidler, f.eks. talkum, calcium- og magnesiumstearat og faste polyethylenglycoler, eller blandinger af de under a) til i) anførte stoffer.
Tabletterne, drageerne, kapslerne, pillerne og granulaterne kan forsynes med de sædvanlige overtræk og hylstre, der eventuelt indeholder opakiseringsmidler, og 35
O
13 DK 169334 B1 kan også være sammensat således, at det eller de aktive stoffer kun eller fortrinsvis afgives forsinket i en bestemt del af intestinalområdet, idet der som indlejringsmasser f.eks. kan anvendes polymersubstanser og voksarter.
5 Det eller de aktive stoffer kan også foreligge i form af mikrokapsler, eventuelt sammen med et eller flere af de ovennævnte bærestoffer.
Suppositorier kan foruden det eller de aktive stoffer indeholde gængse vandopløselige eller vanduopløselige 10 bærestoffer, f.eks. polyethylenglycoler, fedtstoffer, f.eks. kakaofedt og højere estere, f.eks. C^-alkohol roed C^g-fedtsyre, eller blandinger af disse stoffer.
Salver, pastaer, cremer og geler kan foruden det eller de aktive stoffer indeholde gængse bærestoffer, 15 f.eks. animalske eller vegetabilske fedtstoffer, voksarter, paraffiner, stivelse, tragant, cellulosederivater, polyethylenglycoler, silicone, bentonit, kiselsyre, talkum og zinkoxid eller blandinger af disse stoffer.
Puddere og spray's kan foruden det eller de aktive 20 stoffer indeholde de sædvanlige bærestoffer, f.eks. mælkesukker, talkum, kiselsyre, aluminiumhydroxid, calciumsili-cat og polyamidpulver eller blandinger af disse stoffer. Spray's kan desuden indeholde gængse drivmidler, f.eks. chlorfluorcarbonhydrider.
25 Opløsninger og emulsioner kan foruden det eller de aktive stoffer indeholde gængse bærestoffer såsom opløsningsmidler, opløselighedsfremmende midler og emulgatorer, f.eks. vand, ethylalkohol, isopropylalkohol, ethylcarbo-nat, ethylacetat, benzylalkohol, benzylbenzoat, propylen-30 glycol, 1,3-butylenglycol, dimethylformamid, olier, især bomuldsfrøolie, jordnøddeolie, majskimolie, olivenolie, ricinusolie og sesamolie, glycerin, glycerinformal, tetra-hydrofurfyrylalkohol, polyethylenglycoler og fedtsyreestere af sorbitan eller blandinger af disse stoffer.
35 Til parenteral indgivelse kan opløsningerne og emulsionerne også foreligge i steril og blodisotonisk form.
O
14 DK 169334 B1
Suspensioner kan foruden det eller de aktive stoffer indeholde sædvanlige bærestoffer såsom flydende fortynding smidler, f.eks. vand, ethylalkohol og propylengly-col, suspenderingsmidler, f.eks. ethoxylerede isostearyl-5 alkoholer, polyoxyethylensorbitol- og sorbitan-estere, mikrokrystallinsk cellulose, aluminiummetahydroxid, bentonit, agar-agar og tragant eller blandinger af disse stoffer.
De nævnte præparatformer kan også indeholde farvestoffer, konserveringsstoffer og lugt- og smagsforbed-10 rende tilsætninger, f.eks. pebermynteolie og eukalyptusolie og sødemidler, f.eks. saccharin.
De terapeutisk virksomme forbindelser bør i de o-venfor anførte farmaceutiske præparater fortrinsvis være til stede i en koncentration fra ca. 0,1 til 99,5, for-15 trinsvis fra ca. 0,5 til 95 vægtprocent af præparatet.
De ovenfor anførte farmaceutiske præparater kan foruden forbindelserne ifølge opfindelsen også indeholde andre farmaceutisk aktive stoffer.
Fremstillingen af de ovenfor nævnte farmaceutiske 20 præparater sker på gængs måde ved kendte fremgangsmåder, f.eks. ved blanding af den eller de aktive forbindelser med bærestoffet eller -stofferne.
De nævnte præparater kan anvendes til mennesker og dyr enten oralt, rektalt, parenteralt (intravenøst, 25 intramuskulært, subcutant), intracisternalt, intravagi- nalt, intraperitonealt, lokalt (pudder, salve, dråber) og til behandling af infektioner i hulrum og legemshulheder.
Som egnede præparater kan injektionsopløsninger, opløsninger og suspensioner til oral terapi, geler, påhæld-30 ningspræparater, emulsioner, salver eller dråber anvendes. Til lokal behandling kan der anvendes ophthalmologiske og dermatologiske formuleringer, sølv- og andre salte, øredråber, øjensalver, puddere eller opløsninger.
Hos dyr kan optagelsen også ske gennem foderet eller drik- kevandet i passende præparater. Endvidere kan der til mennesker og dyr anvendes geler, pulvere, puddere, tabletter, Retard-tabletter, premixer, koncentrater, granulater, 35
O
15 DK 169334 B1 piller, boli, kapsler, aerosoler, spray's og inhalerings-midler. Endvidere kan forbindelserne ifølge opfindelsen indarbejdes i andre bærematerialer som f.eks. kunststoffer (kunststofkæder til lokal behandling), kollagen eller 5 knoglecement.
Det har generelt vist sig fordelagtigt både i human- og i veterinærmedicinen at indgive det eller de aktive stoffer ifølge opfindelsen i totalmængder fra ca.
0,5 til ca. 500, fortrinsvis 5 til 100 mg pr. kg legems-10 vægt pr. 24 timer, eventuelt i form af flere enkelte indgivelser, for at opnå de ønskede resultater. En enkelt indgivelse indeholder fortrinsvis det eller de aktive stoffer ifølge opfindelsen i mængder fra ca. 1 til ca.
80, især 3 til 30 mg pr. kg legemsvægt. Det kan dog også 15 være nødvendigt at afvige fra de nævnte doseringer, nemlig afhængigt af det behandlede objekts art og legemsvægt, sygdommens art og grad, lægemidlets præparatform og ind-givelsesmåde og det tidsrum, inden for hvilket indgivelsen sker.
20 Det kan således i nogle tilfælde være tilstrækkeligt at anvende mindre end den ovenfor nævnte mængde aktivt stof, medens den ovenfor nævnte mængde aktiv stof i andre tilfælde må overskrides. Fastlæggelsen af den i hvert tilfælde nødvendige optimale dosering og indgivelsesmåde af 25 de aktive stoffer kan let foretages af enhver fagmand på grundlag af hans faglige viden.
De hidtil ukendte forbindelser kan i de gængse koncentrationer og præparater indgives sammen med foderet, med foderpræparater eller med drikkevandet. Derved kan en on infektion med gramnegative eller grampositive bakterier forhindres, lindres og/eller helbredes, og derved kan væksten fremmes og udnyttelsen af foderet forbedres.
I den efterfølgende tabel er MHK-værdier for nogle forbindelser ifølge opfindelsen anført i sammenligning med 35
Ciprofloxacin.
5 16 DK 169334 B1 MHK-værdier (mcr/1)* v. Eksempel 1 3 Ciprofloxacin
Kim _ E.coli 4418 <0,015 <0,015 <0,015
Neumann <0,015 <0,015 <0,015 T7 <0,015 <0,015 <0,015 10 455/7 32 0,25 1 A261 <0,015 <0,015 <0,015
Klebsiella pneum.
63 <0,015 x< 0,015 0,03 8085 <0,015 <0,015 <0,015 6179 0,125 <0,015 0,125 57USA 0,125 <0,015 <0,015 15 6318 0,06 <0,015 0,06
Proteus mir«8223 2 0,06 4 8175 0,06 <0,015 0,06 vulg.1017 <0,015 <0,015 <0,015 morg.932 <0,015 <0,015 <0,015 11006 <0,015 <0,015 <0,015
Providencia stuartei 20 12012 <0,015 <0,015 <0,015 12052 32 1 16
Serratia mare.
16040 32 1 8
Staph, aureus FK422 <0,015 <0,015 0,5 1756 <0,015 <0,015 0,25 25 133 <0,015 <0,015 0,25
Strepto. faecal i s 27101 0,125 <0,015 0,25 9790 0,125 <0,015 0,5
Psdm, aeruginosa
Walter 1 0,25 0,5
Ellsworth 0,125 <0,015_0,06_ 30 *) Agarfortyndingsforsøg (Multipoint-inokulator)
Isosens i testmedium pH 7,2 35 DK 169334 B1
O
17
O
Eksempel 1
Fn^V^V-^OOH
5 /- h°<j
Til 7,95 g (30 mmol) l-cyclopropyl-6,7-difluor--1,4-dihydro-4-oxo-3-quinolincarboxylsyre i en blanding 10 af 60 ml acetonitril og 30 ml dimethylformamid sættes 3,9 g (31 mmol) 3-hydroxypyrrolidinhydrochlorid (race-misk) og 9,9 g (88 mmol) l,4-diazabicyclo[2,2,2]octan, og der opvarmes i 3 timer under tilbagesvaling. Suspensionen inddampes, remanensen udrøres i ca. 100 ml vand, 15 og pH indstilles til 6-7 med 2 N saltsyre. Det uopløste reaktionsprodukt filtreres fra ved sugning, vaskes med vand og tørres.
Udbytte: 9,3 g (93,3% af det teoretiske) 1-cyclo-propyl-6-fluor-1,4-dihydro-7-(3-hydroxy-l-pyrrolidinyl)-20 -4-oxo-3-quinolincarboxylsyre med smeltepunkt 325-328°C (dekomp.).
Eksempel 2 2,65 g (10 mmol) l-cyclopropyl-6,7-difluor-l,4-25 -dihydro-4-oxo-3-quinolincarboxylsyre opvarmes i 3 timer til 130°C i 6 ml dimethylsulfoxid med 1 g (11 mmol) 3--hydroxypyrrolidin (racemisk) og 2,2 g (20 mmol) 1,4-di-azabicyclo[2,2,2]octan. Efter afkøling udrøres suspensionen i 30 ml vand, pH-værdien indstilles til 6-7 med 2 N 30 saltsyre, og bundfaldet filtreres fra ved sugning, vaskes med vand og koges op i 30 ml glycolmonomethylether.
Der fås 2,7 g (81% af det teoretiske) l-cyclopropyl-6--fluor-1,4-dihydro-7-(3-hydroxy-l-pyrrolidinyl)-4-oxo-3--quinolincarboxylsyre med smeltepunkt 332-336°C (dekomp.).
35 Forbindelsen er tyndtlagschromatografisk identisk med forbindelsen fra eksempel 1.
O
13 DK 169334 B1
Eksempel 3
5 *K_i LA
Til 1,5 g (5 mmol) 8-chlor-l-cyclopropyl-6,7-di-fluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre i 10 ml acetonitril og 5 ml dimethylformamid sættes 1,1 g (10 mmol) 1,4-diazabicyclo[2,2,2]octan og 650 mg (5,3 mmol) 3-hydroxypyrrolidinhydrochlorid, og der opvarmes i 3 timer under tilbagesvaling. Suspensionen inddampes, remanensen udrøres i vand, pH-værdien indstilles på 6-7 med 2 N saltsyre, og bundfaldet filtreres fra ved sugning, 15 tørres og omkrystalliseres fra glycolmonomethylether.
Udbytte: l,2g(65% af det teoretiske) 8-chlor-l-cyclopropyl-6-fluor-l,4-dihydro-7-(3-hydroxy-l-pyrrolidi-nyl)-4-oxo-3-quinolincarboxylsyre med smeltepunkt 221-223°C (dekomp.).
20
Eksempel 4 0 25 /- ho-ch2—{ |
Analogt med eksempel 1 omsættes der med 3-hydroxy- methyl-pyrrolidin, og der fås l-cyclcprcoyl-6-fluor-l,4-30 -dihydro-7-(3-hydroxymethyl-l-pyrrolidinyl)-4-oxo-3-qui-nolincarboxylsyre med smeltepunkt 278-2iil°C (dekomp.). Analogt fås: 8-Chlor-l-cyclopropyl-6-fluor-l,4-dihydro-7-(3-hydroxy- methyl-l-pyrrolidinyl)-4-oxo-3-quinolincarboxylsyre med 55 q smeltepunkt 160-162 (dekomp) og
O
19 DK 169334 B1 l-cyclopropyl-6,8-difluor-l,4-dihydro-7-(3-hydroxymethyl--1-pyrrolidinyl)-4-oxo-3-guinolincarboxylsyre med smeltepunkt 236-240°C (dekomp.)· 5 10 15 20 25 30 i 35
Claims (6)
- 2. Fremgangsmåde til fremstilling af 7-(l-pyrro- lidinyl)-3-quinoloncarboxylsyrederivater ifølge krav 1, kendetegnet ved, at en forbindelse med formlen II O ud, 30 hvori 2 A og R har de x krav 1 angivne betydninger, og Y betyder halogen, især fluor eller chlor, omsættes med en pyrrolidin med den almene formel III 35 o DK 169334 B1 i—r"*1 ζΧ H 5 hvori R^ har den i krav 1 angivne betydning, eventuelt i nærværelse af syrebindende midler.
- 3. Fremgangsmåde til fremstilling af forbindelser med den almene formel I ifølge krav 1, idet R2 dog ikke kan betyde hydrogen, 10 kendetegnet ved, at en forbindelse med formlen IV 0 15 j / (iv), R"VJ hvori R·*· og A har de i krav 1 angivne betydninger, omsæt-20 tes med en forbindelse med formlen V R2 - Z (V), 2 hvori R har den i krav 1 angivne betydning, men dog ikke kan betyde hydrogen, og 25. betyder hydroxy eller halogen, især chlor, brom eller iod, eventuelt i nærværelse af syrebindende midler eller under vandfraspaltende betingelser.
- 4. Lægemiddel, kendetegnet ved, at det 30 indeholder 7-(1-pyrrolidinyl) -3-quinoloncarboxylsyrederi- vater ifølge krav 1.
- 5. Anvendelse af 7-(1-pyrrolidinylj-3-quinolon- carboxylsyrederivater ifølge krav 1 til fremstilling af lægemidler. 35
- 6. Lægemiddel til dyr, kendetegnet ved, DK 169334 B1 O at det indeholder 7-(1-pyrrolidinyl)-3-quinoloncarboxyl-syrederivater ifølge krav 1.
- 7. Dyrefodertilsætning, kendetegnet ved, at den indeholder 7-(1-pyrrolidinyl)-3-quinoloncarb-5 oxylsyrederivater ifølge krav 1. 10 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863606698 DE3606698A1 (de) | 1986-03-01 | 1986-03-01 | 7-(1-pyrrolidinyl)-chinoloncarbonsaeure -derivate |
| DE3606698 | 1986-03-01 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK103687D0 DK103687D0 (da) | 1987-02-27 |
| DK103687A DK103687A (da) | 1987-09-02 |
| DK169334B1 true DK169334B1 (da) | 1994-10-10 |
Family
ID=6295255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK103687A DK169334B1 (da) | 1986-03-01 | 1987-02-27 | 7-(1-Pyrrolidinyl)-3-quinoloncarboxylsyrederivater, fremgangsmåder til deres fremstilling og deres anvendelse i lægemidler og dyrefodertilsætninger |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4820716A (da) |
| EP (1) | EP0235676B1 (da) |
| JP (1) | JPH0784458B2 (da) |
| KR (1) | KR950007590B1 (da) |
| AT (1) | ATE53582T1 (da) |
| CA (1) | CA1337564C (da) |
| DE (2) | DE3606698A1 (da) |
| DK (1) | DK169334B1 (da) |
| ES (1) | ES2017651B3 (da) |
| GR (1) | GR3000560T3 (da) |
| HU (1) | HU208129B (da) |
| IL (1) | IL81702A (da) |
| ZA (1) | ZA871431B (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5153204A (en) * | 1986-03-01 | 1992-10-06 | Bayer Aktiengesellschaft | 7-(1-Pyrrolidinyl)-quinolonecarboxylic acid derivatives |
| JPH0262875A (ja) * | 1988-05-23 | 1990-03-02 | Wakunaga Pharmaceut Co Ltd | 新規イソインドリン誘導体 |
| KR910003630B1 (ko) * | 1988-06-17 | 1991-06-07 | 한국과학기술원 | 벤조일 아세틱 에스테르 유도체 및 그 제조방법 |
| CA2001203C (en) * | 1988-10-24 | 2001-02-13 | Thomas P. Demuth, Jr. | Novel antimicrobial dithiocarbamoyl quinolones |
| EP0366189A3 (en) * | 1988-10-24 | 1992-01-02 | Norwich Eaton Pharmaceuticals, Inc. | Novel antimicrobial lactam-quinolones |
| FR2673426B1 (fr) * | 1991-03-01 | 1993-07-16 | Bouchara Sa | Nouvelles quinolones, leur procede de preparation et les compositions en refermant. |
| FR2674247B1 (fr) * | 1991-03-19 | 1993-07-16 | Bouchara Sa | Nouvelles quinolones fluorees, leur procede de preparation et les compositions pharmaceutiques en renfermant. |
| US5330992A (en) * | 1992-10-23 | 1994-07-19 | Sterling Winthrop Inc. | 1-cyclopropyl-4-pyridyl-quinolinones |
| CN111087409B (zh) * | 2018-10-24 | 2021-06-08 | 江阴安博生物医药有限公司 | 一种喹诺酮类化合物及其制备方法和应用 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5746986A (en) * | 1980-09-02 | 1982-03-17 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| US4620007A (en) * | 1980-09-03 | 1986-10-28 | Bayer Aktiengesellschaft | 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid |
| US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
| US4499091A (en) * | 1982-03-31 | 1985-02-12 | Sterling Drug Inc. | 1-Amino (or substituted amino)-1,4-dihydro-4-oxo-6-fluoro-7-heterylquinoline-3-carboxylic acids and their use as antibacterial agents |
| DE3248507A1 (de) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | Mikrobizide mittel auf chinoloncarbonsaeure basis |
| DE3318145A1 (de) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| NZ208470A (en) * | 1983-07-18 | 1988-06-30 | Abbott Lab | 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives and antibacterial compositions containing such |
| NZ210847A (en) * | 1984-01-26 | 1988-02-29 | Abbott Lab | Naphthyridine and pyridopyrimidine derivatives and pharmaceutical compositions |
| IL74244A (en) * | 1984-02-17 | 1988-06-30 | Warner Lambert Co | Quinoline derivatives,their preparation and pharmaceutical compositions containing them |
| DE3574380D1 (en) * | 1984-02-17 | 1989-12-28 | Daiichi Seiyaku Co | 1,8-naphthyridine derivatives |
| US4571396A (en) * | 1984-04-16 | 1986-02-18 | Warner-Lambert Company | Antibacterial agents |
| 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 |
| US4623650A (en) * | 1984-12-06 | 1986-11-18 | Pfizer Inc. | Antibiotic derivatives of 7-phenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| FR2574404B1 (fr) * | 1984-12-12 | 1987-04-24 | Provesan Sa | Derives 1-substitues de l'acide 6-fluoro-7-(pyrrol-1-yl)-1,4-dihydro-4-oxoquinoleine-3-carboxylique, leur preparation et leur application en tant que medicaments |
| DE3517535A1 (de) * | 1985-05-15 | 1986-11-20 | Bayer Ag, 5090 Leverkusen | 1-aryl-4-chinolon-3-carbonsaeuren |
-
1986
- 1986-03-01 DE DE19863606698 patent/DE3606698A1/de not_active Withdrawn
-
1987
- 1987-02-12 US US07/013,744 patent/US4820716A/en not_active Expired - Fee Related
- 1987-02-18 DE DE8787102290T patent/DE3763192D1/de not_active Expired - Lifetime
- 1987-02-18 ES ES87102290T patent/ES2017651B3/es not_active Expired - Lifetime
- 1987-02-18 EP EP87102290A patent/EP0235676B1/de not_active Expired - Lifetime
- 1987-02-18 AT AT87102290T patent/ATE53582T1/de active
- 1987-02-27 DK DK103687A patent/DK169334B1/da not_active IP Right Cessation
- 1987-02-27 CA CA000530762A patent/CA1337564C/en not_active Expired - Fee Related
- 1987-02-27 HU HU87818A patent/HU208129B/hu not_active IP Right Cessation
- 1987-02-27 IL IL81702A patent/IL81702A/xx not_active IP Right Cessation
- 1987-02-27 ZA ZA871431A patent/ZA871431B/xx unknown
- 1987-02-28 JP JP62044163A patent/JPH0784458B2/ja not_active Expired - Lifetime
- 1987-02-28 KR KR1019870001788A patent/KR950007590B1/ko not_active IP Right Cessation
-
1990
- 1990-06-14 GR GR90400330T patent/GR3000560T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3606698A1 (de) | 1987-09-03 |
| IL81702A (en) | 1991-05-12 |
| HUT43581A (en) | 1987-11-30 |
| GR3000560T3 (en) | 1991-07-31 |
| DE3763192D1 (de) | 1990-07-19 |
| DK103687A (da) | 1987-09-02 |
| ATE53582T1 (de) | 1990-06-15 |
| EP0235676B1 (de) | 1990-06-13 |
| KR870008867A (ko) | 1987-10-21 |
| DK103687D0 (da) | 1987-02-27 |
| JPH0784458B2 (ja) | 1995-09-13 |
| IL81702A0 (en) | 1987-09-16 |
| KR950007590B1 (ko) | 1995-07-12 |
| HU208129B (en) | 1993-08-30 |
| EP0235676A2 (de) | 1987-09-09 |
| EP0235676A3 (en) | 1987-11-25 |
| CA1337564C (en) | 1995-11-14 |
| ZA871431B (en) | 1987-08-20 |
| US4820716A (en) | 1989-04-11 |
| ES2017651B3 (es) | 1991-03-01 |
| JPS62207269A (ja) | 1987-09-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |