NO324472B1 - TNF-a-produksjonsinhibitore, farmasøytisk preparat og terapeutisk middel for inhibering av TNF-a-produksjon - Google Patents

TNF-a-produksjonsinhibitore, farmasøytisk preparat og terapeutisk middel for inhibering av TNF-a-produksjon Download PDF

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NO324472B1
NO324472B1 NO20025718A NO20025718A NO324472B1 NO 324472 B1 NO324472 B1 NO 324472B1 NO 20025718 A NO20025718 A NO 20025718A NO 20025718 A NO20025718 A NO 20025718A NO 324472 B1 NO324472 B1 NO 324472B1
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production
compound
therapeutic agent
salt
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Hiroshi Suhara
Hiroyuki Inoue
Masakazu Ban
Masato Horiuchi
Noriyoshi Yamamoto
Hiroshi Enomoto
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Santen Pharmaceutical Co Ltd
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Description

Foreliggende oppfinnelsen angår TNF-a-produksjonsinhibitorer som er anvendelige som terapeutisk middel for autoimmune sykdommer slik som reumatoid artritt.
TNF-a (tumornekrosefaktor-a) er et cytokin som ofte deltar i biofylakseimmune mekanismer ved inflammasjon. Det er kjent at forlenget og overdrevet produksjon av TNF-a er en faktor som forårsaker vevsskade og forskjellige sykdommer. Eksempler på patologi hvori TNF-a deltar er mange patologier slike som artroreumatisme, systemisk lupus erytematosus (SLE), kakeksi, akutt infeksjonssykdom, allergi, pyreksi, anemi og diabetes (Yamazaki, Clinical Immunology, 27,1270,1995). Det er også rapportert at TNF-a spiller en viktig rolle i patogenesen av reumatoid artritt og Crohn's sykdom, som er autoimmune sykdommer (Andreas Eigler et al., Immunology Today, 18,487, 1997).
Fra disse rapportene forventes forbindelser som inhiberer eller undertrykker TNF-a-produksjon å være effektive for behandling av de ovenfor nevnte sykdommene, og forskjellige studier har blitt gjort (de ovenfor nevnte litteraturstedene: Yamazaki, Clinical Immunology, 27,1270,1995, Andreas Eigler et al., Immunology Today, 18, 487, 1997). Nylig har det blitt rapportert at metalloprotease, som er et proteolyttisk enzym, deltar i sekresjon av TNF-a og metalloproteaseinhibitorer har viktige effekter på inhiberingen av TNF-a-produksjon og lignende (publisert japansk oversettelse av PCT nr. 508115/1997). Japansk "Laid-open" patentpublikasjonsnr. 44533/2000 og 119249/2000 beskriver forbindelser som har inhiberende effekt på TNF-a-produksjon. Alle disse forbindelsene er ureaderivater som har et svovelatom i sidekjedene.
Det er viktig å lete etter forbindelser som har inhiberingsaktiviteter på TNF-a-produksjon og er anvendelige som terapeutiske midler for de autoimmune sykdommene slike som reumatoid artritt, allergi og diabetes.
I forbindelse med foreliggende oppfinnerene ble det fremstilt forbindelser som har forskjellige kjemiske strukturer og det ble utført farmakologiske tester. Som et resultat fant man at en ny forbindelse, nærmere bestemt forbindelsen l-[2-(l-adamantyl)etyl]-l-penyl-3-[3-(4-pyirdyl)propyl]urea eller et salt derav har svært gode inhiberingsaktiviteter på TNF-a-produksjon for å oppnå foreliggende oppfinnelse.
Ifølge et første trekk er oppfinnelsen rettet mot denne oppfinnelsen.
Foreliggende forbindelse er egnet til å utgjøre farmasøytiske sammensetninger og er aktive ingredienser for TNF-a-produksjonsinhibitorer som er anvendelige som terapeutiske midler for autoimmune sykdommer slike som reumatoid artritt, allergi og diabetes.
Salter i foreliggende oppfinnelse refererer til hvilke som helst farmasøytisk akseptable salter og er eksemplifisert ved salter med en uorganisk syre slike som saltsyre, salpetersyre, svovelsyre eller fosforsyre, og salter med en organisk syre, slike som eddiksyre, fumarsyre, maleinsyre, ravsyre eller vinsyre, salter med et alkalimetall eller et jordalkalimetall slike som natrium, kalium eller kalsium, og lignende. Kvaternære ammoniumsalter av foreliggende forbindelse er også inkludert i saltene ifølge oppfinnelsen. Videre når det er geometriske eller optiske isomerer i foreliggende forbindelse er disse isomerene også inkludert innenfor omfanget av oppfinnelsen. Foreliggende forbindelse kan foreligge i form av hydrater og solvater.
Forbindelsene ifølge foreliggende forbindelse er følgende forbindelse og salter derav:
l-[2-(l-adamantyl)etyl]-l-pentyl-3-[3-(4-pyridyl)propyl]urea
Detaljerte syntesefremgangsmåter for forbindelsen ifølge oppfinnelsen og salter derav vil bli beskrevet i senere eksempler.
Forbindelsene oppnådd ifølge oppfinnelsen kan omdannes til de ovenfor nevnte saltene ved vanlige fremgangsmåter.
Inhiberingseffektene av TNF-a-produksjonen ble undersøkt for å studere anvendelsen av foreliggende forbindelser. Detaljer vil bli beskrevet i avsnittet "Farmakologiske test" nedenfor. Ved å studere in vivo inhiberingseffektene på frigivelse av TNF-a forårsaket av stimulering av lipopolysakkarid (LPS), fremviste foreliggende forbindelse svært gode inhiberingsaktiviteter av TNF-a-produksjon.
TNF-a-produksjon er kjent å være nært beslektet med patogenese av autoimmune sykdommer, slike som reumatoid artritt, Crohn's sykdom og systemisk lupus erytematosus, kakeksi, akutt infeksjonssykdom, allergi, pyreksi, anemi, diabetes og lignende. Forbindelser som inhiberer TNF-a-produksjon, som foreliggende forbindelser, forventes å være anvendelige for behandling av disse forskjellige sykdommene.
Foreliggende oppfinnelse omfatter videre et farmasøytisk preparat, kjennetegnet ved at det omfatter forbindelsen eller et salt derav ifølge krav 1, som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
Oppfinnelsen omfatter videre et terapeutisk middel for inhibering av TNF-a-produksjon, kjennetegnet ved at det omfatter en effektiv mengde av forbindelsen eller et salt derav ifølge krav 1 som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
Oppfinnelsen omfatter videre et terapeutisk middel for autoimmune sykdommer, kjennetegnet ved at det omfatter forbindelsen eller et salt derav ifølge krav 1 som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
Endelig omfatter oppfinnelsen et antireumatisk middel, kjennetegnet ved at det omfatter en effektiv mengde av forbindelsen eller et salt derav i henhold til krav 1 som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
Forbindelsen ifølge foreliggende forbindelse kan administreres oralt eller parenteralt. Eksempler på doseringsformer er tabletter, kapsler, granuler, pulvere, injeksjoner og lignende. Foreliggende forbindelse kan formuleres til preparater ved vanlige fremgangsmåter. For eksempel, kan orale preparater slike som tabletter, kapsler, granuler og pulvere produseres ved å tilsette et eventuelt fortynningsmiddel slik som laktose, krystallisk cellulose, stivelse eller vegetabilsk olje; et smøremiddel slik som magnesiumstearat eller talkum; et bindemiddel slik som hydroksypropylcellulose eller polyvinylpyrrolidin; en disintegrator slik som kalsiumkarboksymetylcellulose eller lavsubstituert hydroksypropylmetylcellulose; et belegningsmiddel slik som hydroksypropylmetylcellulose, makrogol eller silikonharpiks; eller et fllmdannende middel slik som gelatinfilm.
Doseringen av forbindelsen ifølge foreliggende forbindelser kan velges ut fra symptomet, alder, doseringsform og lignende. I tilfelle oralt preparat, kan foreliggende forbindelse administreres en til flere ganger daglig med en daglig dose på 0,1 til 5000 mg, foretrukket 1 til 1000 mg.
Eksempler på fremstilling av preparater, eksempler på fremstillinger og formuleringer av foreliggende forbindelser og resultater av farmakologiske tester er vist nedenfor. Disse eksemplene er ment for å gjøre oppfinnelsen mer klart forståelig.
[A] Fremstilling av intermediater
Fremstillingseksempel 1
• 2-(l-adamantyl)-N-pentyletylamin hydroklorid (Intermediat nr. 1-1)
Pentylamin (2,69 ml, 23,2 mmol), kaliumkarbonat (2,14 g, 15,5 mmol) og natriumjodid (2,30 g, 15,3 mmol) ble tilsatt til en løsning av 2-(l-adamantyl)etyl metansulfonat (2,07 g, 8,01 mmol) i etanol (45,8 ml) og blandingen ble refluksert i 17 timer. Reaksjonsblandingen ble konsentrert under redusert trykk og konsentratet ble fortynnet med kloroform (100 ml). Dette ble vasket med IN vandig natriumhydroksidløsning (100 ml) og en mettet vandig natriumkloirdløsning (100 ml) suksessivt, og det organiske sjiktet ble tørket over magnesiumsulfat. Løsemidlet ble fordampet under redusert trykk og resten ble renset med silikagelkolonnekromatografi. En 4N løsning av hydrogenklorid i etylacetat (3,1 ml) ble tilsatt til en løsning av den resulterende frie formen (1,52 g, 6,10 mmol) av tittelforbindelsen i etylacetat (0,50 ml). Det presipiterte faste stoffet ble vasket med etylacetat og filtrert fra som ga 1,33 g (60%) av tittelforbindelsen.
IR (KBr): 2924, 2850,2519,1456 cm<1>.
Smeltepunkt: 263,0-264,5°C.
Fremstillingseksempel 2
• 4-(3-aminopropyl)pyridin (Intermediat nr. 2-1)
N-[3-(4-pyridyl)propyl]ftalimid (67,1 g, 252 mmol) ble blandet med metanol (504 ml) og hydrazinmonohydrat (18,3 ml, 378 mmol) og blandingen ble refluksert i 3 timer. Reaksjonsblandingen ble stående og deretter ble uløselig stoff filtrert fra og filtratet ble konsentrert under redusert trykk. Kloroform (1 1) og 4N vandig natriumhydroksidløsning (500 ml) ble tilsatt til resten, sjiktene ble separert og det organiske sjiktet ble tørket over natriumsulfat. Det organiske sjiktet ble konsentrert under redusert trykk og deretter destillert under redusert trykk hvilket ga 20,5 g (60%) av tittelforbindelsen som et farveløst oljeaktig stoff.
IR (ren): 3362,2933,1603 cm<1>.
Kp.: 76,0-79,0°C/40 Pa
[B] Fremstilling av foreliggende forbindelse
Eksempel 1
• l-[2-(l-adamantyl)etyl]-l-pentyl-3-[3-(4-pyridyl)propyl]urea
(Forbindelse nr. 1-1)
l,r-karbonyldiimidazol (427 mg, 2,63 mmol) ble tilsatt til en løsning av 4-(3-aminopropyl)pyridin (Intermediat nr. 2-1) (285 mg, 2,09 mmol) i tetrahydrofuran (10 ml) og blandingen ble rørt ved romtemperatur i 20 minutter. 2-(l-adamantyl)-N-pentyletylaminhydroklorid (Intermediat nr. 1-1) (571 mg, 2,00 mmol) ble tilsatt til blandingen og hele blandingen ble refluksert i 1 time. Reaksjonsblandingen ble fortynnet med etylacetat (50 ml), hele blandingen ble vasket med en mettet vandig natriurnhydrogenkarbonatløsning (50 ml) og en mettet vandig natriumkloridløsning (50 ml) suksessivt, og det organiske sjiktet ble tørket over magnesiumsulfat. Løsemidlet ble fordampet under redusert trykk og det presipiterte faste stoffet ble vasket med diisopropyleter og filtrert fra som ga 606 mg (73%) av tittelforbindelsen.
IR (KBr): 2900,2845,1618,1534 cm-<1>.
Smp.: 124,0-124,7°C.
[Cl Formulering
Generelle formuleringseksempler av orale preparater og injeksjoner ved anvendelse av foreliggende forbindelse er vist nedenfor.
1) Tablett
Formulering 1 (i 100 mg)
Tablettene ifølge formuleringen som vist ovenfor blir belagt med 2 mg/tablett av et bdegningsmiddel (dette er et vanlig belegningsmiddel slik som hydroksypropylmetylcellulose, makrogol eller silikonharpiks) for å oppnå ønskede belagte tabletter. (Samme gjelder for tabletter nevnt nedenfor.) Ønskede tabletter kan oppnås ved å forandre mengder av den foreliggende forbindelsen og passende additiver.
2) Kapsel
Formulering 1 (i 150 mg)
Ønskede kapsler kan oppnås ved å forandre blandingsforholdet mellom foreliggende forbindelse og laktose på en hensiktsmessig måte. 3) Injeksjon Formulering 1 (i 10 ml)
Ønskede injeksjoner kan oppnås ved å forandre blandingsforholdet mellom foreliggende forbindelse og additiver på en hensiktsmessig måte.
[D] Farmakologisk test
Inhiberingseffekter på TNF-a-produksjon indusert ved lipopolysakkarid (LPS) stimulering ble studert i in vivo tester ifølge fremgangsmåten til Tsuji et al. (Inflamm. res. 46 (1997) 193-198).
Hunnrotter (fem pr. gruppe), kroppsvekt på ca. 200 g, ca. 8 uker gamle, ble anvendt som testdyr. LPS fra Salmonella ble løst i fysiologisk saltvann for å fremstille en LPS-løsning (1 mg/ml). Hver testsubstans ble løst eller enhetlig suspendert i en 1% metylcelluloseløsning som ga testsubstans-preparatvæskene.
Den ovenfor nevnte LPS-løsningen (0,5 ml/kg) ble administrert til fotbladet til rotten. Umiddelbart etter LPS-administrasjonen ble testsubstanspreparatvæsken (som inneholdt 10 mg/kg eller 3 mg/kg testsubstans) administrert oralt. 2 timer eller LPS-administrasjonen, ble blod samlet opp fra abdominal aorta og sentrifugert ved 4°C og 3000 opm i 10 minutter. TNF-a-nivåene i det oppnådde plasma ble målt med et rotte TNF-a-spesifikt ELISA-kit. TNF-a ble ikke observert i plasma med hensyn til en LPS ikke-administrert gruppe (kontroll).
Inhiberingsgraden på TNF-a-produksjon av testsubstansen ble stemt ved følgende ligning.
Inhiberingsgrad (%) = [(A-B)/A]xl00
A: TNF-oc-nivå i plasma av testsubstansnkke-administert gruppe.
B: TNF-a-nivå i plasma av testsubstans»administrert gruppe
(Resultater).
Ved beregning av TNF-a-produksjonsinhiberingsgrader (%) ved administrasjon av testsubstansene (10 mg/kg eller 3 mg/kg) oralt til rottene, fremviste mange av foreliggende forbindelse høy inhiberingsgrad på produksjon. Tabell 1 viser testresultatet ved oral administrasjon av 1 mg/kg, tabell 2 viser testresultatet ved oral administrasjon av 3 mg/kg.
Industriell anvendbarhet
Resultatene av de farmakologiske testene viser klart at siden foreliggende oppfinnelse har svært gode TNF-a-produksjonsinhiberingseffekter, kan foreliggende forbindelse ha stor anvendelse som terapeutisk middel for sykdommer hvori TNF-a deltar, f.eks. autoimmune sykdommer, slike som reumatoid artritt, Crohn's sykdom og systemisk lupus erytematosus, kakeksi, akutt infeksjonssykdom, allergi, pyreksi, anemi, diabetes og lignende.

Claims (6)

1. l-[2-(l-adamantyl)etyl]-l-pentyl-3-[3-(4-pyridyl)propyl]urea eller et salt derav.
2. Farmasøytisk preparat, karakterisert ved at det omfatter forbindelsen eller et salt derav ifølge krav 1 som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
3. Terapeutisk middel for inhibering av TNF-a-produksjon, karakterisert ved at det omfatter en effektiv mengde av forbindelsen eller et salt derav ifølge krav 1 som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
4. Terapeutisk middel for autoimmine sykdommer, karakterisert v e d at det omfatter forbindelsen eller et salt derav ifølge krav 1, som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
5. Antireumatisk middel, karakterisert ved at det omfatter en effektiv mengde av en forbindelsen eller et salt derav ifølge krav 1, som en aktiv bestanddel og et farmakologisk akseptabelt additiv.
6. Terapeutisk middel ifølge krav 4, karakterisert ved at autoimmunsykdommen er reumatoid artritt, allergi eller diabetes.
NO20025718A 2000-05-31 2002-11-28 TNF-a-produksjonsinhibitore, farmasøytisk preparat og terapeutisk middel for inhibering av TNF-a-produksjon NO324472B1 (no)

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