DK173401B1 - Anvendelse af en quinolon- eller naphthyridinforbindelse til fremstilling af et lægemiddel til topisk behandling af øjeninf - Google Patents
Anvendelse af en quinolon- eller naphthyridinforbindelse til fremstilling af et lægemiddel til topisk behandling af øjeninf Download PDFInfo
- Publication number
- DK173401B1 DK173401B1 DK198700524A DK52487A DK173401B1 DK 173401 B1 DK173401 B1 DK 173401B1 DK 198700524 A DK198700524 A DK 198700524A DK 52487 A DK52487 A DK 52487A DK 173401 B1 DK173401 B1 DK 173401B1
- Authority
- DK
- Denmark
- Prior art keywords
- oxo
- dihydro
- pyrrolidinyl
- cyclopropyl
- ethyl
- Prior art date
Links
- 208000001860 Eye Infections Diseases 0.000 title claims abstract description 7
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 5
- -1 naphthyridine compound Chemical class 0.000 title claims description 15
- 239000003814 drug Substances 0.000 title claims description 12
- 208000011323 eye infectious disease Diseases 0.000 title claims description 6
- 230000000699 topical effect Effects 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- WDBGUJBLPRXPIX-UHFFFAOYSA-N 1-cyclopropyl-7-[3-(ethylaminomethyl)pyrrolidin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(CNCC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F WDBGUJBLPRXPIX-UHFFFAOYSA-N 0.000 claims description 2
- AZURXMGITRDFMD-UHFFFAOYSA-N 7-[3-(aminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(CN)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F AZURXMGITRDFMD-UHFFFAOYSA-N 0.000 claims description 2
- KFBDAMQESLTGCT-UHFFFAOYSA-N 7-[3-(aminomethyl)pyrrolidin-1-yl]-1-ethyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCC(CN)C1 KFBDAMQESLTGCT-UHFFFAOYSA-N 0.000 claims description 2
- VHLLMPCLAADZQM-UHFFFAOYSA-N 7-[3-(aminomethyl)pyrrolidin-1-yl]-1-ethyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCC(CN)C1 VHLLMPCLAADZQM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
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- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Ophthalmology & Optometry (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 173401 B1 i
Qinolon- og naphthyridinforbindelser med nedenstående formel I er kendte antibakterielle midler, som er aktive mod et bredt spektrum af gram-positive og gram-negative organismer, som beskrevet i EP-patent-5 skrift nr. 106.469.
Hovedparten af bakterielle øjeninfektioner forårsages af gram-positive bakterier. Idet de ovennævnte quinolon- og naphthyridinforbindelser har bemærkelsesværdig virkning mod sådanne bakterier, blev de udvalgt 10 som fortrinlige kandidater til behandling af sådanne infektioner.
Den foreliggende opfindelse har relation til den opdagelse, at disse bredspektrede antibiotika er forligelige med øjenvæv, og at terapeutiske koncentrationer 15 påvises i forskellige øjenvæv og -væsker efter topisk administrering, hvorfor de er nyttige til behandling af mange forskellige bakterielle øjeninfektioner ved topisk administrering.
Desuden har midler indeholdende disse antibakte-20 rielle midler veterinær anvendelse, f.eks. til behandling af rødøje hos kvæg og andre dyr.
Endvidere er midler indeholdende de omhandlede forbindelser nyttige til anvendelse som desinfektionsmidler, f.eks. som aktive komponenter i præparater til 25 rensning og/eller desinficering af kontaktlinser.
Følgelig angår den foreliggende opfindelse anvendelse af en quinolon- eller naphthyridinforbindelse med formlen i _______ 0 30 f^VV°2Ri • · 1 R2
35 ^ I
hvori Z er 2 DK 173401 B1 O(ch . eller ,CVnNaR3 ~\Sr^ 5 hvori n er 0 eller 1, og R3 er hydrogen, methyl, ethyl, 1- eller 2-propyl, X er CH, CF eller N, R1 er hydrogen eller alkyl med 1-6 carbonatomer, og 10 R2 er alkyl med 1-4 carbonatomer, vinyl, halogenalkyl eller hydroxyalkyl med fra 2-4 carbonatomer eller cycloalkyl med 3-6 carbonatomer, eller et ophthalmologisk acceptabelt syreadditionssalt eller basesalt deraf til fremstilling af et lægemiddel 15 til topisk behandling af øjeninfektioner.
De forbindelser med formlen I, hvori Rj er hydrogen, eller ophthalmologisk acceptable basesalte deraf, såsom metal- eller aminsalte, f.eks. natrium- eller kaliumsalte, er foretrukne forbindelser til anvendelsen 20 ifølge den foreliggende opfindelse.
Andre foretrukne forbindelser til den omhandlede anvendelse er forbindelserne med formlen I, hvori Rj er hydrogen, R2 er ethyl eller cyclopropyl, og X er CF eller N, eller ophthalmologisk acceptable syreadditions-25 salte eller basesalte deraf.
Foretrukne ophthalmologisk acceptable syreadditionssalte er saltene af mineralsyrer eller organiske syrer, f.eks saltsyre, maleinsyre, pamoesyre eller lignende .
30 Særlig foretrukne forbindelser til den omhandlede anvendelse er følgende: 7-[3-aminomethyl)-1-pyrrolidinyl]-l-ethyl-6-fluor-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre, 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-ethyl-6,8-difluor-35 1,4-dihydro-4-oxo-3-quinolincarboxylsyre, l-ethyl-7-[3-[(ethylamino)methyl]-l-pyrrolidinyl]-6- 3 DK 173401 B1 fluor-1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxyl-syre, l-ethyl-7-[3-[(ethylamino)methyl]-l-pyrrolidinyl]-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre, 5 l-ethyl-6-fluor-l,4-dihydro-7-[3-[[(l-methylethyl)-amino]methyl]-l-pyrrolidinyl]-4-oxo-l,8-naphthyridin- 3-carboxylsyre, l-ethyl-7-[3[[(1-methylethyl·) amino]methy1]-1-pyrrol1-dinyl]-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxyl-10 syre, l-ethyl-6-fluor-l,4-dihydro-7-(7-methyl-2, 7-diazaspiro-[4.4]non-2-yl)4-oxo-l,8-naphthyridin-3-carboxylsyre, l-ethyl-6,8-difluor-l,4-dihydro-7-(7-ethyl-2,7-di-azaspiro[4.4]non-2-yl)-4-oxo-3-quinolincarboxylsyre, 15 l-ethyl-6,8-difluor-l,4-dihydro-7-(7-methyl-2,7-diazaspiro-[4.4]non-2-yl)-4-oxo-3-quinolincarboxyl-syre, 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre, 20 7-[3-(aminomethyl)-l-pyrrolidinyl]-l-cyclopropyl-6,8-d ifluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre, l-cyclopropyl-7-[3—[(ethylamino)methyl]-l-pyrrolidinyl]- 6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre, 7-[3-amino-l-pyrrolidinyl]-l-cyclopropyl-6,8-difluor-25 1,4-dihydro-4-oxo-qulnolincarboxylsyre, l-cyclopropyl-7-[3-[(methylamino)methyl]-l-pyrrolidi-nyl]-6,8-dihydro-4-dihydro-4-oxo-3-qinolincarboxylsyre, l-cyclopropyl-7-[3-(ethylamino)-1-pyrrolodinyl]-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre, 30 l-cyclopropyl-6,8-difluor-l,4-dihydro-7-[3-[[(l-methylethyl ) amino jmethyl]-1-pyrrolidinyl]-4-oxo-3-qulnolincarboxylsy re , ““ 7-[3-aminomethyl)-l-pyrrolidinyl]-l-cyclopropyl-l,4-dihydro-6-fluor-4-oxo_-l, 8-naphthyridin-3-carboxyl-35 syre, 1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrrolid inyl]- 4 DK 173401 B1 1,4-dihydro-6-fluor-4-oxo-l,8-naphthyridin-3-carboxyl-syre, 7-[3-amino-i-pyrrolidinyl]-1-cyclopropyl-l,4-dihydro-6-fluor-4-oxo-l,8-naphthyridin-3-carboxylsyre, eller 5 ophthalmologisk acceptable syreadditionssalte eller basesalte deraf.
Fra EP offentliggørelsesskrift nr. 142.426 er det kendt at anvende med forbindelserne med ovenstående formel I beslægtede forbindelser til topisk behandling af 10 øjeninfektioner, nemlig forbindelserne betegnet norfloxacin, ofloxacin, pefloxacin, AT-2266 og Bayer 09867, eller hydrater eller ophthalmologisk acceptable salte heraf, idet norfloxacin (l-ethyl-6-fluor-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolincarboxylsyre) angives at 15 være den foretrukne forbindelse. Forbindelserne med ovenstående formel I adskiller sig derfra ved at_ have en substitueret amino-pyrrolidinyl- eller spiro-biocyclisk substituent i 7-stillingen i de pågældende quiholoh- eller naphthyridinringe, medens norfloxacin og de oven-20 nævnte, dermed strukturelt beslægtede forbindelser har en piperazinylsubstituent. Desuden viser sammenlignende forsøgsdata, at de ifølge den foreliggende opfindelse anvendte forbindelser med formlen I uventet har betydelig kraftigere virkning mod bakterier, der vides at være 25 involveret i øjeninfektioner, end norfloxacin.
De ifølge opfindelsen anvendte forbindelser med formlen I kan fremstilles ved fremgangsmåderne beskrevet i EP-patentskrift nr. 106.489 eller i den samtidig verserende US-ansøgning med serienummeret 692.820.
30 Præparater af disse forbindelser kan indeholde fra ca. 0,003 til 3%, især 0,15 til 0,6% medikament, skønt højere eller lavere doser kan anvendes. Som en enhedsdosisform anvendes i almindelighed mellem 0,015 og 1,5 mg, fortrinsvis 0,05-1,0 mg, især 0,1-0,3 mg, af 35 forbindelsen til det humane øje, og en enhedsdosis kan administrers så hyppigt som nødvendigt.
5 DK 173401 B1
Disse i det foregående beskrevne dosismængder formodes at være nøjagtige for mennesker og er baseret på forbindelsernes kendte og på indeværende tidspunkt forståede farmakologi og virkningen af andre lignende "5 éntiteter i det humane øje. De afspejler den bedste, kendte fremgangsmåde. Som ved alle 'medikamenter, varierer de krævede doser, og doserne må bestemmes individuelt på basis af sygdommen og patientens reaktion.
Ved fremstilling af lægemidler blandes den virk-10 somme forbindelse hensigtsmæssigt med en ikke-toxisk, farmaceutisk, organisk eller uorganisk bærer. Typiske farmaceutisk acceptable bærere er f.eks. vand, blandinger af vand og vandblandbare opløsningsmidler, såsom lavere alkanoler eller aralkanoler, vegetabile olier, 15 polyalkylenglycoler^ vaseline, ethylcellulose, ethylole- at, carboxymethylcellulose, polyvinylpyrrolidon, isopro-pylmyristat og andre sædvanligt anvendte acceptable bærere. Det opthalmologiske præparat kan også indeholde ikke-toxiske hjælpestoffer såsom emulgerings-, 20 konserverings-, befugtnings-, konsistensmidler o.l-, f.eks. polyethylenglycol 200, 300, 400 og 600, carbowax 1.000, 1,500, 4.000,6,000 og 10.000, andre anti- bakterielle komponenter, såsom kvaternære ammonium-forbindelser, phenylkviksølvsalte, der er kendte for at 5 5 have koldsteriliserende egenskaber, og som ikke er skadelige ved anvendelse, thimerosgl, methyl- og propylparaben, benzylalkohol, phenylethanol, puffere, såsom natriumchlorid, natriumborat, natriumacetat, gluconat-puffere og andre sædvanlige komponenter, såsom sorbitan-monolaurat, triethanolamin, oleat, polyoxyethylen-sorbitan-momopalmitylat, dioctylnatriumsulfosuccinat, monothioglycerol, thiosorbitol, ethylendiamintetraeddike-syre o.l.. Desuden “kan passende ophthalmiske bærere, herunder sædvanlige phosphatpufferbæresystemer, isoto-35 niske borsyrebærer^, "Tsotoniske natriumchloridbærere, isotoniske natriumboratbærere o.l., anvendes som bæremedium. Det farmaceutiske præparat kan også foreligge i form af en fast indsats.
6 DK 173401 B1
Skønt mange patienter finder behandling med flydende medikamenter helt tilfredsstillende, kan andre foretrække et fast medikament, der påføres øjet topisk, f.eks._en fast dosisform, der er egnet til indsættelse i 5 cul-de-sac’en. Til dette formål kan antibiotikummet være inkorporeret i en ikke-bionedbrydelig indsats, dvs. en indsats som efter afgivelse af medikamentet forbliver i det væsentlige intakt, eller en bionedbrydelig indsats, dvs. en indsats som enten er opløselig i lacrimalvæsker 10 eller nedbrydes på anden måde. Skønt det ikke er afgørende hvilken indsats, der anvendes, og de, der er beskrevet i US patentskrifterne nr* 3.630.200 Higuchi, 3.811.444, Heller et al; 4.177.256 Michaels et al; 3.868.445, Ryde et al; 3.845.201 Haddad; 3.981.303 Higu-15 chi; og 3.867.519 Michaels, er tilfredsstillende, foretrækkes indsatserne beskrevet nedenfor imidlertid i almindelighed . _ F.eks. kan man anvende en fast vandopløselig polymer som bærer for medikamentet. Polymeren, der anven-20 £es til fremstilling af indsatsen, kan være en vilkårlig vandopløselig, ikke-toxisk polymer, f.eks. cellulosederivater, såsom methylcellulose, natriumcarboxymethyl-cellulose eller en hydroxy-lavere alkyl cellulose, såsom hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-25 propylmethylcellulose o.l., aerylater, såsom poly-acrylsyresalte, ethylacrylater og .polyacrylamider, naturprodukter, såsom gelatine, —alginater, pectiner, tragacanth, karaya, chondrus, agar og acacia, stivelsesderivater, såsom stivelsesacetat, hydroxyethylstivelses-ethere og hydroxypropylstivelse, og andre syntetiske derivater, såsom polyvinylalkohol, polyvinylpyrrolidon, polyvinylraethylether, polyethylenoxid, neutraliseret carbopol og xanthangummi, samt blandinger af disse polymere.
55 Det opthalmiske præparat kan også foreligge i form af en klar, fysiologisk acceptabel væske, der danner en halvfast "gel" ved menneskets legemstemperatur. Tetrasubstituerede derivater af ethylendiamin 7 DK 173401 B1 (poloxamin; W=2 i formel I), propylendiamin (w=3), buty-lendiamin (w=4), pentylendiamin (w=5) eller hexylendia-min (w=6), polymere med sådanne egenskaber. Substituen-terne _ er blok copolymere af poly(oxypropylen) og 5 poly(oxyethylen) med forskellige kædelængder og forhold mellem x og y i den almene formel for polymeren vist nedenfor
H«X2H4)y(OC3H6) /(C3860)x(C2H40)yH
. ,U ----- N-(CH2)n-N
H(CC2H4)y(CC3H6)/ X (C3H50)x(C2H40lyH
15 hvori w er et helt tal fra og med 2 til og med 6.
En typisk polymerblanding ville indeholde en polymer indeholdende ca. 40-80% poly(oxypropylen).
Den anvendte polymers samlede molekylvægt er mindst ca.
7.000/ og den kan være så høj som 50.000, men den ligger 20 fortrinsvis i «nrådet fra 7.000 til 30.000, og x og y er vilkårlige hele tal indenfor de ovennævnte grænser. Foretrukne polymere er ·polymere med en ovennævnte formel, hvori w=2, nemlig poloxaminpolymeren.
Den vandige medikamentafgivelsesbærer vil inde-25 holde fra 10-50 vægt% polymer, som beskrevet ovenfor, af hele bæreren, ben vandige medikamentafgivelsesbærer kan desuden indeholde medikamentet bestående af terapeutisk forbindelse og forskellige additiver, såsom syrer eller baser tij. Indstilling af midlets pH-værdi, 30 puffere til bibeholdelse af pH-værdien, konserveringsmidler til modvirkning af bakteriel kontaminering og andre additiver, der bibringer medikamentet opløselighed og stabilitet, formuleringsevne, idet renset vand udgør resten af medikamentafgivelsesbæreren.
35 Det opthalmiske præparat kan også foreligge i form af stabile multilamellare vesikler, der omfatter den antibiotisk aktive komponent indkapslet med liposo-mer, som beskrevet i US-patentskrift nr. 4.552.803.
8 DK 173401 B1
Til dokumentation for den omhandlede uventede, nyttige terapeutiske virkning er der i nedenstående tabel I anført sammenlignende forsøgsdata for anti-bakteriel virkning, udtrykt ved minimal hæmningskon-5 centration, for norfloxacin og et repræsentativt udvalg af de ifølge opfindelsen anvendte forbindelser, nærmere angivet syv af de i krav 3 anførte forbindelser, nemlig de efterfølgende forbindelser nr. 1, 2, 7-10 og 12: TO 1. 7- [3-(aminomethyl) - 1-pyrrolidinyl]-l-ethyl-6- f luor-1,4 -dihydro- 4-oxo-1, 8 -naphthyridin- 3 - carboxylsyre, 2. 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-ethyl-6,8- difluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre, T5 7. 7-[3-(aminomethyl)-1-pyrrolidinyl]-1-cyclopropyl- 6,8-difluor-l,4-dihydro-4-oxo-3-quino1incarboxy1-syre, _ 8. l-cyclopropyl-7-[3-[(ethylamino)-methyl]-1-pyrrolidinyl] - 6,8-difluor-1,4-dihydro-4-oxo-3-quino- 20 lincarboxylsyre, 9. 7- [3-amino-l-pyrrolidinyl]-l-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre, 10. 7-[3-(aminomethyl)-1-pyrrolidinyl]-1-cyclopropyl- 1,4 - dihydro-6-f luor-4 - oxo-1,8-naphthyridin-3 - 25 carboxylsyre, 12 . 7- [3 - amino-l-pyrrolidinyl] -1-cyclopropyl-1,4- dihydro - 6 - fluor - 4 - oxo -1, e^apht hyr idin - 3 - carb -oxylsyre.
30 35 9_ DK 173401 B1 B i
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o o w o 10 DK 173401 B1
De i tabel I anførte forsøgsdata viser, at et repræsentativt udvalg af de ifølge opfindelsen avendte forbindelser har betydelig kraftigere virkning mod bakterier, der vides at være involveret i øjeninfektio-_ 5 . ner, end norfloxacin, der er den foretrukne forbindelse ved den kendte anvendelse.
Anvendelsen ifølge opfindelsen belyses nærmere ved hjælp af de efterfølgende præparateksempler.
.10
Fremstilling af 0,3% opløsning ____________Kom£onent_ ______mg/mJL__
Eksempel 1 15 i-Ethyl-7-[3-(ethylamino)methyl ]-l- 3,0 pyrrolidinyl]-6,8-difluor-1,4-dihydro 4-oxo-3-quinolincarboxylsyre
Natriumacetat 3H20 2,27
Benzalkoniumchlorid 0,11 20 Ethylendiamintetraeddieksyre, 0,10 natriumsalt
Natriumchlorid 7,42
Saltsyre til pH 5,2
Vand q.s.
25
Eksempel 2 1-cyclopropyl-7-[3-(ethylamino)methyl ]- 3,0 1-pyrrolidinyl ]-6,8-dif luor-1,4-dihydro- 4-oxo-3-quinolincarboxylsyre-hydro-30 chlorid
Vaseline q.s. ad. 1,0 g
Eksempel 3 7-[3-Amino-l-pyrrolidinyl ]-l-cyclopropyl- 1,0 3^ 6,8-difluor-1,4-dihydro-4-oxo-3-quino- lincarboxylsyre-hydrochlorid
Hydroxypropylcellulose q.s__12,0_ 11 DK 173401 B1
Opthalimiske indsatser fremstilles ud fra presse-støbtefilm, som fremstilles på en Carver Press ved at udsætte den pulveriserede blanding af de ovennævnte komponenter for en pressekraft på 12.000 pund (standard) 5 (5.400 kg) ved 149°C i 1-4 min.. Filmen afkøles under tryk ved hjælp af et kredsløb med koldt vand i pressefladen. De ophthalmiske indsatser skæres dernæst enkeltvis ud fra filmen ved hjælp af et stavformet stempel.
Hver indsats placeres i et hætteglas/ som dernæst an-bringes i et be fugtningskammer (8SS R.H. ved 30°C) i 2-4 dage. Efter fjernelse fra befugtningskammeret autoklaveres hætteglasset indeholdende den hydratiserede indsats dernæst ved 121°C i 0,5 timer.
Claims (3)
1. Anvendelse af en quinolon- eller naphthyridin-forbindelse med formlen 5 "docV002*1 R2 10 hvori Z er -O ^TV3 X^(CH2)nNHR3 β11βΓ 15 hvori n er 0 eller 1, og R3 er hydrogen, methyl, ethyl, 1- eller 2-propyl, X er CH, CP eller N, R1 er hydrogen eller alkyl med 1-6 carbonatomer, og 20 R2 er alkyl med 1-4 carbonatomer, vinyl, halogen-alkyl, hydroxyalkyl med fra 2-4 carbonatomer eller cycloalkyl med 3-6 carbonatomer, eller et ophthalmologisk acceptabelt syreadditionssalt eller basesalt deraf til fremstilling af et lægemiddel 25 til topisk behandling af øjeninfektioner.
2. Anvendelse ifølge krav l, kendetegnet ved,at den anvendte forbindelse er en forbindelse med formlen I, hvori X er CP eller N, Rj^ er hydrogen, R2 er ethyl eller cyclopropyl, eller et ophthalmologisk 30 acceptabelt syreadditionssalt eller basesalt deraf.
3. Anvendelse ifølge krav 2, kendetegnet ved, at forbindelsen med formlen I er 7-[3-(aminomethyl)-l-pyrrolidinyl]-l-ethyl-6-fluor-1,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxyl- i DK 173401 B1 13 syre, 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-ethyl-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxylsyre, 1-ethyl-7-[3-[(ethylamino)methyl]-l-pyrrolidinyl]-5 6-fluor-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylsyre, 1-ethyl-7-[3-(ethylamino)methyl]-1-pyrrolid iny 1- 6.8- difluor-l,4-dihydro-4-oxo-3-quinolincarboxyl-syre, 10 l-ethyl-6-fluor-l , 4-clihydro-7- (7-methyl-2,7- diazaspiro[4.4]non-2-yl)-4-oxo-l,8-naphthyridin- 3-carboxylsyre, l-ethyl-6,8-difluor-l,4-dihydro-7-(7-methyl-2,7- diazaspiro[4.4]non-2-y-4-oxo-3-quinolincarboxylsyre, 15 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-cyclopropyl- 6.8- difluor-l,4-dihydro-4-oxo-3-quinolin-carboxylsyre, l-cyclopropyl-7-[3-[(ethylamino)-methyl]-l-pyrrolidi-nyl]-6,8-difluor-l,4-dihydro-4-oxo-3-quinolincarboxyl-syre, 20 7-[3-amino-l-py r rolid iny1]-1-cyclopropy1-6,8-d i fluor- 1.4- dihydro-4-oxo-3-quinolincarboxylsyre, 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-cyclopropyl- 1.4- dihydro-6-fluor-4-oxo-l,8-naphthyridin-3-carboxyl-syre, 25 l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]- 1.4- dihydro-6-fluor-4-oxo-l,8-naphthyridin-3-carboxyl-syre, 7-[3-amino-l-pyrrolidinyl]-l-cyclopropyl-l,4-dihydro-6-fluor-4-oxo-l,8-naphthyridin-3-carboxylsyre, 30 i-cyclopropyl-7-[3-[(methylamino)methyl]-l-pyrrolidi-nyl]-6,8-difluor-l/4-dihydro-4-oxo-3-quinolincarboxyl-syre, l-cyclopropyl-7-[3-ethylamino)-1-pyrrolidinyl]-6,8-difluor-1,4-dihydro-4-oxo-3-quinolincarboxylsyre.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82500786 | 1986-02-03 | ||
| US06/825,007 US4692454A (en) | 1986-02-03 | 1986-02-03 | Opthalmic use of quinolone antibiotics |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK52487D0 DK52487D0 (da) | 1987-02-02 |
| DK52487A DK52487A (da) | 1987-08-04 |
| DK173401B1 true DK173401B1 (da) | 2000-09-25 |
Family
ID=25242879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198700524A DK173401B1 (da) | 1986-02-03 | 1987-02-02 | Anvendelse af en quinolon- eller naphthyridinforbindelse til fremstilling af et lægemiddel til topisk behandling af øjeninf |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US4692454A (da) |
| EP (1) | EP0235589B1 (da) |
| JP (1) | JPS62185085A (da) |
| AT (1) | ATE81776T1 (da) |
| AU (1) | AU588958B2 (da) |
| CA (1) | CA1281653C (da) |
| DE (1) | DE3782346T2 (da) |
| DK (1) | DK173401B1 (da) |
| ES (1) | ES2044843T3 (da) |
| GR (1) | GR3006180T3 (da) |
| IE (1) | IE61017B1 (da) |
| NZ (1) | NZ219138A (da) |
| PH (2) | PH23722A (da) |
| ZA (1) | ZA87164B (da) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826985A (en) * | 1986-04-25 | 1989-05-02 | Abbott Laboratories | Intermediates for preparation of racemate and optically active ofloxacin and related derivatives |
| US5229128A (en) * | 1986-06-11 | 1993-07-20 | Haddad Heskel M | Drug delivery ophthalmic insert and method of preparing same |
| KR920700691A (ko) * | 1989-04-04 | 1992-08-10 | 존.에프.맥인티리 | 상처부위, 절개부위, 찰과상 부위에 치료제의 투여에 대한 리포좀(liposomes)의 용도 |
| WO1991009616A1 (en) * | 1989-12-22 | 1991-07-11 | Yale University | Quinolone antibiotics encapsulated in lipid vesicles |
| US4992449A (en) * | 1990-02-01 | 1991-02-12 | American Cyanamid Company | 7-(substituted)cycloalkylamino-1-(substituted)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| US5185390A (en) * | 1990-03-07 | 1993-02-09 | Ppg Industries, Inc. | Water strippable photochromic resin composition |
| US5130353A (en) * | 1990-03-07 | 1992-07-14 | Ppg Industries, Inc. | Method for preparing photochromic plastic article |
| JPH0725747B2 (ja) * | 1990-03-16 | 1995-03-22 | エスエス製薬株式会社 | キノロンカルボン酸誘導体 |
| US5252318A (en) * | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
| CA2174803C (en) * | 1996-04-23 | 2000-07-11 | Jonathan P. Wong | Use of liposome encapsulated ciprofloxacin as an immunotherapeutic drug |
| US6861411B1 (en) | 1997-12-02 | 2005-03-01 | Pfizer, Inc. | Method of treating eye infections with azithromycin |
| US7056893B2 (en) * | 1999-03-31 | 2006-06-06 | Insite Vision, Inc. | Topical treatment for prevention of ocular infections |
| US6685958B2 (en) | 2001-04-25 | 2004-02-03 | Insite Vision Incorporated | Quinolone carboxylic acid compositions and related methods of treatment |
| US6239113B1 (en) * | 1999-03-31 | 2001-05-29 | Insite Vision, Incorporated | Topical treatment or prevention of ocular infections |
| US6699492B2 (en) | 1999-03-31 | 2004-03-02 | Insite Vision Incorporated | Quinolone carboxylic acid compositions and related methods of treatment |
| JP4756674B2 (ja) * | 2000-09-05 | 2011-08-24 | 株式会社サクラクレパス | 塗布具 |
| US20060046970A1 (en) * | 2004-08-31 | 2006-03-02 | Insite Vision Incorporated | Topical otic compositions and methods of topical treatment of prevention of otic infections |
| JP2011520963A (ja) * | 2008-05-19 | 2011-07-21 | アルコン リサーチ， リミテッド | カルボキシビニルポリマーおよびポビドンポリマーを有する医薬組成物 |
| TW202400160A (zh) * | 2022-04-22 | 2024-01-01 | 美商米突倍基公司 | 轉錄因子eb活化子及其用途 |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3963736A (en) * | 1970-01-28 | 1976-06-15 | Sumitomo Chemical Company, Limited | Preparation of 1-(lower alkyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acids |
| US3753993A (en) * | 1971-05-17 | 1973-08-21 | Sterling Drug Inc | 1,4-dihydro-4-oxo-7-pyridyl-3-quinoline-carboxylic acid derivatives |
| US3907808A (en) * | 1971-05-17 | 1975-09-23 | Sterling Drug Inc | 1,4-Dihydro-4-oxo-7-pyridyl-3-quinolinecarboxylic acid derivatives |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| DE2808070A1 (de) * | 1978-02-24 | 1979-08-30 | Bayer Ag | Verfahren zur herstellung von 4-pyridon-3-carbonsaeuren und/oder deren derivaten |
| JPS5845426B2 (ja) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | 置換キノリンカルボン酸誘導体 |
| JPS5649382A (en) * | 1979-09-28 | 1981-05-02 | Dainippon Pharmaceut Co Ltd | 6-fluoro-7-cyclic amino-1,8-naphthylidine derivative and its salt |
| JPS5746986A (en) * | 1980-09-02 | 1982-03-17 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| DE3033157A1 (de) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| SE440354B (sv) * | 1981-02-19 | 1985-07-29 | Kyorin Seiyaku Kk | Kinolinkarboxylsyraderivat |
| US4382937A (en) * | 1981-02-27 | 1983-05-10 | Dainippon Pharmaceutical Co., Ltd. | Naphthyridine derivatives and their use as anti-bacterials |
| JPS57145862A (en) * | 1981-03-06 | 1982-09-09 | Kyorin Pharmaceut Co Ltd | Quinolinecarboxylic acid derivative |
| 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 |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
| 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 |
| FR2559484B2 (fr) * | 1983-07-06 | 1986-09-26 | Provesan Sa | Nouveau derive 7-(pyrrol-1-yl) de l'acide 1-ethyl-1,4-dihydro-4-oxo-(1,8-naphtyridin)-3-carboxylique, sa preparation et son application en tant que medicament |
| CS274601B2 (en) * | 1983-07-27 | 1991-09-15 | Dainippon Pharmaceutical Co | Method of 1,8-naphthyridine derivative production |
| US4551456A (en) * | 1983-11-14 | 1985-11-05 | Merck & Co., Inc. | Ophthalmic use of norfloxacin and related antibiotics |
| US4604401A (en) * | 1984-07-20 | 1986-08-05 | Warner-Lambert Company | Antibacterial agents III |
| IN162769B (da) * | 1984-11-13 | 1988-07-09 | Kyorin Seiyaku Kk | |
| JPH0670032B2 (ja) * | 1984-11-22 | 1994-09-07 | 大日本製薬株式会社 | アミノピロリジン誘導体、そのエステルおよびその塩 |
| AU578793B2 (en) * | 1985-02-15 | 1988-11-03 | Dainippon Pharmaceutical Co. Ltd. | Novel 1,8-naphthyridine derivatives and processes for preparation thereof |
| JPH0635457B2 (ja) * | 1985-06-28 | 1994-05-11 | 杏林製薬株式会社 | ピリドンカルボン酸誘導体およびその製造方法 |
| JP2874664B2 (ja) * | 1996-09-18 | 1999-03-24 | 日本電気株式会社 | ページプリンタ |
-
1986
- 1986-02-03 US US06/825,007 patent/US4692454A/en not_active Expired - Lifetime
-
1987
- 1987-01-05 CA CA000526640A patent/CA1281653C/en not_active Expired - Fee Related
- 1987-01-09 ZA ZA870164A patent/ZA87164B/xx unknown
- 1987-01-12 AU AU67505/87A patent/AU588958B2/en not_active Ceased
- 1987-01-29 IE IE23787A patent/IE61017B1/en not_active IP Right Cessation
- 1987-01-30 PH PH34791A patent/PH23722A/en unknown
- 1987-02-02 EP EP87101354A patent/EP0235589B1/en not_active Expired - Lifetime
- 1987-02-02 DE DE8787101354T patent/DE3782346T2/de not_active Expired - Fee Related
- 1987-02-02 NZ NZ219138A patent/NZ219138A/xx unknown
- 1987-02-02 ES ES87101354T patent/ES2044843T3/es not_active Expired - Lifetime
- 1987-02-02 DK DK198700524A patent/DK173401B1/da not_active IP Right Cessation
- 1987-02-02 AT AT87101354T patent/ATE81776T1/de not_active IP Right Cessation
- 1987-02-02 JP JP62020634A patent/JPS62185085A/ja active Pending
- 1987-06-17 US US07/062,999 patent/US4851415A/en not_active Expired - Lifetime
-
1988
- 1988-08-17 PH PH37421A patent/PH25096A/en unknown
-
1992
- 1992-11-05 GR GR920402501T patent/GR3006180T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3782346T2 (de) | 1993-03-11 |
| AU6750587A (en) | 1987-08-06 |
| IE61017B1 (en) | 1994-09-07 |
| NZ219138A (en) | 1990-03-27 |
| DE3782346D1 (de) | 1992-12-03 |
| EP0235589A2 (en) | 1987-09-09 |
| ZA87164B (en) | 1988-07-11 |
| IE870237L (en) | 1987-08-03 |
| PH23722A (en) | 1989-11-03 |
| EP0235589B1 (en) | 1992-10-28 |
| US4851415A (en) | 1989-07-25 |
| PH25096A (en) | 1991-02-19 |
| DK52487A (da) | 1987-08-04 |
| JPS62185085A (ja) | 1987-08-13 |
| CA1281653C (en) | 1991-03-19 |
| ATE81776T1 (de) | 1992-11-15 |
| US4692454A (en) | 1987-09-08 |
| EP0235589A3 (en) | 1989-12-13 |
| AU588958B2 (en) | 1989-09-28 |
| GR3006180T3 (da) | 1993-06-21 |
| DK52487D0 (da) | 1987-02-02 |
| ES2044843T3 (es) | 1994-01-16 |
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| Date | Code | Title | Description |
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| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |
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