NO333992B1 - Anvendelse av fumarsyreanhydrider og legemiddel omfattende et fumarsyreanhydrid - Google Patents
Anvendelse av fumarsyreanhydrider og legemiddel omfattende et fumarsyreanhydrid Download PDFInfo
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- NO333992B1 NO333992B1 NO20031748A NO20031748A NO333992B1 NO 333992 B1 NO333992 B1 NO 333992B1 NO 20031748 A NO20031748 A NO 20031748A NO 20031748 A NO20031748 A NO 20031748A NO 333992 B1 NO333992 B1 NO 333992B1
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- radical
- fumaric acid
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Abstract
Foreliggende oppfinnelse vedrører anvendelse av fumarsyreamider med den generelle formelen (I) hvori R1 representerer OR3 eller et D- eller L- aminosyre radikal -NH-CHR4-COOH bundet via en aminbinding, hvori R3 er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert C1-24 alkylradikal, et fenylradikal eller C6-10 aralkylradikal og R4 er en sidekjede av en naturlig eller syntetisk aminosyre og R2 representerer et D- eller L- aminosyreradikal - NH-CHR5-COOH bundet via en amidbinding eller et peptidradikal omfattende 2 til 100 aminosyrer bundet via en aminbinding, hvori R5 er en sidekjede av en naturlig eller syntetisk aminosyre, for å fremstille et legemiddel for terapi av en autoimmun sykdom, for anvendelse i transplantasjonsmedisin, for terapi av mitokondriale sykdommer, samt for terapi av NF-kappaB medierte sykdommer.
Description
Foreliggende oppfinnelse vedrører anvendelse av fumarsyreanhydrider, vedrørende visse fumarsyre-mono- og diamider, eller monoamidofumarsyre-monoestere, hen-holdsvis, samt et legemiddel omfattende nevnte forbindelser.
I lang tid har fumarsyredialkylestere samt fumarsyremonoalkylestere og salter derav blitt vellykket anvendt for å behandle psoriasis. Anvendelsen er beskrevet i et antall patenter, for eksempel EP-A-0 188 749, DE-25 30 327, DE 26 21 214 eller EP-B-0 312 697.
Anvendelsen av fumarsyre mono- eller diestere er også beskrevet for behandlingen av autoimmune sykdommer slik som polyartritt, multippel sklerose (jf. DE 197 21 099.6 og DE 198 53 487.6), men også for anvendelse i transplantasjonsmedisin (jf. DE 198 53 487.6 og DE 198 39 566.3). Anvendelsen av fumarsyre mono- og diestere for behandlingen av NF-kappaB medierte sykdommer og behandlingen av mitokondriale sykdommer er også kjent fra de upubliserte tyske søknadene DE 101 01 307.8 og DE 100 00 577.2. Derimot beskriver alle de siterte dokumentene kun fumarsyre-mono- og diestere, valgfritt i formen av visse salter, dvs. forbindelser hvori en eller begge syrefunksjoner av fumarsyre er esterifisert med en alkohol.
På grunn av deres flyktighet og sublimabilitet derimot, har de ovennevnte fumarsyreestere ulempen av å være vanskelige å håndtere ved fremstilling av farmasøytis-ke produkter, spesielt de i fast form for oral administrasjon. Spesielt krever fremstillingen av slike produkter beskyttende tiltak slik som anvendelsen av pustemas-ker, hansker, beskyttende klær.
I tillegg absorberes fumarsyreesterne i det gastrointestinale system etter oral administrasjon og tas opp uspesifikt fra blodstrømmen av alle kroppscellene. Derfor er det nødvendig å administrere høye doser for å tilveiebringe et terapeutisk effektivt nivå av den aktive ingrediens på eller i målcellene.
Slike høye doser i sin tur fører til de kjent bieffektene av en fumarsyreterapi som rødmesymptomer (bli rød) eller gastrointestinal irritasjon (kvalme, diaré, luft). Selv om slike bieffekter kan reduseres betraktelig ved å administrere den aktive ingrediens i formen av mi krota bl ette r som beskrevet i den ovennevnte tidligere teknikk, kan de ikke unngås fullstendig.
Samtidig hydrolyseres fumarsyreesterne raskt i blodet og produktene av hydroly-sen, alkohol og fumarsyre eller fumarsyremonoester metaboliseres. For å beholde de terapeutiske effektive nivåer er gjentatt og hyppig administrasjon derfor nød-vendig. Selv om en viss tilpasning er observert når det gjelder bieffekter, ville en ytterligere reduksjon av bieffektene være ønskelig.
Derfor er det et formål med foreliggende oppfinnelse å tilveiebringe fumarsyrederi-vater som kan administreres strategisk, og er mer motstandsdyktige mot hydrolyse og lettere å håndtere, og anvendelsen av slike derivater.
Foreliggende formål oppnås ved anvendelse av fumarsyreanhydrider, vedrørende visse fumarsyre mono- og diamider eller monoamido fumarsyre-monoestere, hen-holdsvis, og et legemiddel for terapien av visse sykdommer og legemidler omfattende det samme.
Fumarsyre diamider og monoamider har også blitt beskrevet i US-A-5,242,905 og US-A-5,214,196 til Blank for behandlingen av psoriasis. Derimot beskriver disse siterte publikasjoner kun fremstillingen av enkle fumarsyre mono- eller diamider, men ikke fremstillingen av farmasøytiske produkter og anvendelsen av amidene på mennesker. En teoretisk fordel av fumaramidene over fumarsyreestere sitert av de ovennevnte publikasjoner er forbeholdet av visse aminosyrer fra fumaramidene i keratinocyter for å komplementere metabolske mangler i psoriasis.
Overraskende har oppfinnerne nå funnet at fumarsyre mono- og diamider eller monoamido fumarsyre-monoestere kan anvendes fordelaktig for terapien av en varia-sjon av sykdommer.
Spesielt vedrører det første aspektet av foreliggende oppfinnelse derfor anvendelsen av fumarsyreamider med den generelle formelen (I)
hvor
Ri representerer -OR3eller et D- eller L-aminosyreradikal -NH-CHR4-COOH bundet via en amidbinding, hvor R3er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert Ci^alkylradikal, et fenylradikal eller C6.i0aralkylradikal, og
R2representerer et D- eller L-aminosyreradikal -NH-CHR5-COOH bundet via en amidbinding, hvor hver av R4og R5er uavhengig valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly,
for å fremstille et legemiddel
(1) for terapi av en autoimmun sykdom valgt fra gruppen bestående av polyartritt, multippel sklerose, transplantat-mot-vert reaksjoner, barneinntrådt diabetes, Hashimotos thyroiditis, Graves sykdom, systemisk Lupus erythematodes, Sjøgrens syndrom, pernisiøs anemi og kronisk aktiv (= lupoid) hepatitt; (2) for terapi eller anvendelse i transplantasjonsmedisin; (3) for terapi av mitokondriale sykdommer fra gruppen bestående av Parkinson syndrom, Alzheimers sykdom, Chorea Huntington sykdom, retinopathia pigmentosa eller former av mitokondrial encefalomyopati; eller (4) for terapi av en NF-kappaB mediert sykdom valgt fra gruppen bestående av progressiv systemisk skleroderma, osteokondritis syphilitica (Wegeners sykdom), cutis marmorata (livedo reticularis), Behcet sykdom, panarteritis,
colitis ulcerosa, vasculitis, osteoarthritis, urinsyregikt, arteriosklerose, Reiters sykdom, pulmonar granulomatosis, typer av encephalitis, endotoksisk sjokk (septisk-toksisk sjokk), sepsis, pneumoni, encephalomyelitis, anorexia nevrosa, hepatitt, Rennert T-lymphomatosis, mesanginal nephritis, post-angioplastisk restenosis, re-perfusions-syndrom, cytomegaloviral retinopati, adenovirale sykdommer, AIDS, Guillain-Barré syndrom, post-herpetisk eller post-zoster neuralgia, inflammatorisk demyeliniserende polyneuropati, mononeuropathia multiplex, mucoviscidosis, Bech-terews sykdom, Barett oesophagus, EBV (Epstein-Barr virus) infeksjon, hjertere-modelering, interstitial cystitis, diabetes mellitus type II, menneskelig tumor radio-sensitisasjon, multi-resistens av ondartede celler for kjemoterapeutiske midler, granuloma annulare og kreft.
Foretrukne anvendelser av nevnte fumarsyreamider er angitt i uselvstendige krav 2-16.
Fumarsyreamider med formelen (I)refereres til:
hvori Ri representerer OR3eller et D- eller L-aminosyre radikal -NH-CHR4-COOH bundet via en aminbinding, hvori R3er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert Ci-24alkylradikal, fortrinnsvis et Ci-6alkylradikal, et fenylradikal eller C6.i0aralkylradikal og R4er en sidekjede av en naturlig eller syntetisk aminosyre og
R2representerer et D- eller L-aminosyreradikal -NH-CHR5-COOH bundet via en amidbinding eller et peptidradikal omfattende 2 til 100 aminosyrer, fortrinnsvis 2 til 30 aminosyrer bundet via en amidbinding, hvori R5er en sidekjede av en naturlig eller syntetisk aminosyre,
med forbeholdet at
Når R3= H, er R2et peptidradikal valgt fra gruppen bestående av peptidhormoner, vekstfaktorer, cytosiner, neurotransmittere, nuropeptider, antistoff fragmenter, koaguleringsfaktorer og cyklosporiner samt derivater og fragmenter derav; og
Når Ri = -NH-CHR4-COOH, er R2et peptidradikal valgt fra gruppen bestående av peptidhormoner, vekstfaktorer, cutokiner, neurotransmittere, neuropeptider, antistoff- fragmenter, cyklosporiner og koaguleringsfaktorer samt derivater og fragmenter derav, eller representerer -NH-CHR5-COOH hvori R5er valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly.
Betegnelsen "sidekjede av en naturlig eller syntetisk aminosyre" betyr radikalene av hver naturlige eller syntetiske aminosyre posisjonert på a-karbonatomet. Amino-syreradikalene Ri og R2kan være tilstede i D- og L-konfigurasjon, den naturlige L-konfigurasjoner er foretrukket. Under er de vanlige forkortelser og betegnelser i 3-bokstavkoden anvendt for å karakterisere aminosyrene.
Ifølge en utførelse representerer Ri -NH-CHR4-COOH og R2representerer -NH-CHR5-COOH hvori R4 og R5er uavhengig valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly.
Ifølge en annen utførelse representerer Ri -OR3og R2representerer et L-aminosyre radikal -NH-CHR5-COOH hvori R5er valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly.
Spesielt fordelaktig er R5en polar aminosyre i begge utførelser, enda mer foretrukket en ladningsbærende aminosyre valgt fra gruppen bestående av aspargin, glutamin, lysin, arginin og histidin.
Når radikalet Ri representerer -OR3, dvs. når forbindelsen av formelen (I) som skal anvendes er en monoamido fumarsyre monoester eller monoamid, er R3fortrinnsvis valgt fra gruppen bestående av et lineært, forgrenet, cyklisk, mettet eller umet-tet Ci-24alkylradikal, fortrinnsvis et C1-6alkylradikal, et fenylradikal eller en Ci-6aralkylradikal og dette radikalet er valgfritt substituert med halogen (F, Cl, Br, I), hydroksy, Ci-4alkoksy, nitro eller cyano. Fortrinnsvis er R3metyl, etyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyklopentyl, 2-etylheksyl, heksyl, cykloheksyl, heptyl, cykloheptyl, oktyl, vinyl, a Hyl, 2-hydroksyetyl, 2- eller 3-hydroksypropyl, 2,3-dihydroksypropyl, 2-metoksyetyl, metoksymetyl eller 2- eller 3- metoksypropyl. Mest foretrukket er R3metyl eller etyl.
Ifølge en annen utførelse representerer Ri -OR3, fortrinnsvis med R3= metyl eller etyl, og R2representerer et peptidradikal med 2 til 100, fortrinnsvis 2 til 30 amino og mest foretrukket 5 til 25 aminosyrer bundet via en aminbinding. Peptid radi ka le-ne kan være naturlige, rekombinante eller syntetiske peptid radi ka ler.
Mer foretrukket er peptid rad i ka let R2valgt fra gruppen bestående av peptidhormoner, vekstfaktorer, cytokiner, neurotransmittere, neuropeptider, antistoff fragmenter, koaguleringsfaktorer og cyklosporiner samt derivater og fragmenter derav. Nevnte peptider kan renses fra naturlige kilder, gjenvinnes ved rekombinante me-toder eller syntetiseres i henhold til kjente prosesser. Anvendelsen av syntetiske peptider er foretrukket.
Å koble fumarsyrelegemet til et slikt funksjonelt peptid har fordelen av at peptidet tilveiebringer en transmisjon av den aktive ingrediens "fumarsyrelegeme" til mål-celler med hvilket peptiddelen av amidene samvirker. Samtidig kan peptiddelen ha dens egen effekt på sykdommen som skal behandles slik at en kombinasjonsterapi utføres i dette tilfellet. Derimot tillater en kombinasjonsterapi og/eller strategisk administrasjon reduksjon av dosen som skal administreres i en ønskelig, og kanskje også synergistisk måte.
Ifølge en foretrukket utførelse kan peptidradikalet være et cyklosporinradikal hvis syklus har blitt kløvet ved hver peptidbinding for å gå inn i fumarsyreamidbindingen. Generelt kan alle cyklosporiner bindes til fumarsyreamidbindingen ved en amidbinding. Fordi cyklosporiner er cykliske peptider er peptidringen vanligvis kløvet ved enhver posisjon (ved enhver amidbinding) for å oppnå en lineærisert cyklosporin i stand til å gå inn i en amidbinding. Fortrinnsvis anvendes cyklosporin A lineærisert før posisjon 1.
Betegnelsen "peptidhormoner" som anvendt her betyr fysiologisk høyt aktive peptider med omtrent opp til 100 aminosyrer som utvikler en hormoneffekt eller hormonlignende effekt. Eksempler er de glandulære peptidhormonene av hypofysen slik som kortikotropin, follitropin, lutropin, melanotropin, prolaktin, somatotropin, thyrotropin, oksytocin og vasopressin, de frigivende hormoner og inhiberende fak-torene av hypothalamus, peptidhormonene fra pancreas, mage eller innvoll slik som glucagon, insulin, somatostatin, sekretin, gastrin og kolecystokinin, peptidhormoner av thyroid slik som kalcitonin, parathyrin og lignende.
Betegnelsen "vekstfaktor" betyr hormonlignende peptider og proteiner som støtter celledivisjon og celledifferensiering, promoterer vekst og organutvikling og er nød-vendig for skadeleging. Eksempler er kolonistimulerende faktorer, den epidermale vekstfaktor (EGF), erythropoietin, fibroblast vekstfaktorer, haematopoietiske vekstfaktorer, hepatocytt vekstfaktorer, insulin og insulinlignende vekstfaktorer, platelet avledet vekstfaktor (PDGF), trombopoietin, tranformerende vekstfaktorer, virale vekstfaktorer, men også interleukiner.
Betegnelsen "cytokiner" som anvendt her refererer til polypeptider som sekreres ved cellene og, etter binding med spesifikke reseptorer, kan påvirke funksjonen av andre, vanligvis tilstøtende celler. Cytokiner regulerer primært den komplekse in-teraksjon av cellene av immunsystemet. Eksempler på slike cytokiner er interferon-er, interleukiner, kjemokiner eller kolonistimulerende faktorer.
Betegnelsen "neurotransmitter" betyr messenger-substanser som forårsaker det kjemiske signal eller informasjonsoverføring på synapsene av nervesystemet. Av-hengig av deres kjemiske karakteristikker er neurotransmittere delt i aminosyrer slik som glutaminsyre, aminosyrederivater slik som acetylkolin, monoaminer som katakolaminer, slik som L-noradrenalin, L-adrenalin og dopamin, serotonin og peptider. Følgelig er "neuropeptidene" som bradykinin, men også enkephaliner, endor-fin etc. en undergruppe av neurotransmitterene.
Betegnelsen "koaguleringsfaktorer" som anvendt her betyr proteiner av koagula-sjonskaskade. Likeledes kan peptidet kobles til fumarsyren via en amidbinding være et antistoff-fragment, fragmentet omfatter fortrinnsvis også en gjen-kjenningsfrekvens og/eller bindingssekvens.
Fragmenter og/eller derivater av alle peptidene spesifisert over er egnet og kan også anvendes. Betegnelsen "fragment" betyr en del av de ovennevnte peptider som er i stand til amidbinding. Fortrinnsvis omfatter fragmentet gjenkjennings-sekvenser for å arrangere binding til en cellereseptor og/eller et aktivt senter for å overføre en aktiv funksjon.
Betegnelsen "derivat" betyr et peptid som kan avledes fra de ovennevnte peptider og/eller fragmenter ved homolog substitusjon, fjerning eller innsetting av en eller flere aminosyrer inn i eller fra peptidkjedene.
Fumarsyreamidene kan fremstilles i henhold til de ovennevnte US patenter til Blank.
I et andre aspekt vedrører den foreliggende oppfinnelsen et legemiddel omfattende et fumarsyreamid med den generelle formelen (I)
hvor
Ri representerer -OR3eller et D- eller L-aminosyreradikal -NH-CHR4-COOH
bundet via en amidbinding, hvor R3
er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert Ci^alkylradikal, et fenylradikal eller C6-i0-aralkylradikal, og
R2representerer et D- eller L-aminosyreradikal -NH-CHR5-COOH bundet via en amidbinding,
hvor hver av R4og R5er uavhengig valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly,
legemidlet er en fast oral doseringsform og har et enterisk belegg.
Legemidlet er nærmere angitt i uselvstendige krav 18-26.
Legemidlene oppnådd gjennom anvendelsen ifølge oppfinnelsen kan være til stede i former egnet for oral, nasal, parenteral, rektal, pulmonar, oftal eller transdermal administrasjon.
Fortrinnsvis er legemidlet ment for oral administrasjon. Den faste orale doseringsformen har et enterisk belegg (belegg resistent mot gastrisk syre) og kan være
valgt fra tabletter, belagte tabletter, o-kapsler, mikrokapsler, mikrotabletter, pelleter eller pulvere samt granulat, mikrotabletter, pelleter og pulverfylte kapsler, mikrotabletter fylt i kapsler og pulvere fylt i kapsler. Fortrinnsvis er den faste orale doseringsformen valgt fra tabletter, belagte tabletter, mikrotabletter, pelleter eller kapsler.
Prinsippmessig kan legemidlet av oppfinnelsen inneholde egnede farmasøytiske bærere, eksipienter, additiver etc. Disse er kjent for fagpersoner og er ikke nærmere forklart.
Anvendelsen av mikrotabletter eller pelleter er mest foretrukket. Fortrinnsvis har disse en gjennomsnittlig diameter på 300 til 5000 pm, mer foretrukket 300 til 2000 pm, når ubelagt.
Når administrert parenteralt ved injeksjon, er sammensetningen til stede i en form egnet for dette formål. Alle vanlige flytende bærere egnet for injeksjon kan anvendes.
I ethvert tilfelle er det foretrukket at legemidlet inneholder en mengde av fumarsyreamidet med formel (I) per enkel dose som tilsvarer 1 til 500 mg fumarsyre, fortrinnsvis 10 til 300 mg fumarsyre.
Claims (26)
1. Anvendelse av fumarsyreamider med den generelle formelen (I)
hvor
Ri representerer -OR3eller et D- eller L-aminosyreradikal -NH-CHR4-COOH bundet via en amidbinding, hvor R3
er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert Ci.24alkylradikal, et fenylradikal eller C6-ioaralkylradikal, og
R2representerer et D- eller L-aminosyreradikal -NH-CHR5-COOH bundet via en amidbinding, hvor hver av R4og R5er uavhengig valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly,
for å fremstille et legemiddel (1) for terapi av en autoimmun sykdom valgt fra gruppen bestående av polyartritt, multippel sklerose, transplantat-mot-vert reaksjoner, barneinntrådt diabetes, Hashimotos thyroiditis, Graves sykdom, systemisk Lupus erythematodes, Sjøgrens syndrom, pernisiøs anemi og kronisk aktiv (= lupoid) hepatitt; (2) for terapi eller anvendelse i transplantasjonsmedisin; (3) for terapi av mitokondriale sykdommer fra gruppen bestående av Parkinson syndrom, Alzheimers sykdom, Chorea Huntington sykdom, retinopathia pigmentosa eller former av mitokondrial encefalomyopati; eller (4) for terapi av en NF-kappaB mediert sykdom valgt fra gruppen bestående av progressiv systemisk skleroderma, osteokondritis syphilitica (Wegeners sykdom), cutis marmorata (livedo reticularis), Behcet sykdom, panarteritis,
colitis ulcerosa, vasculitis, osteoarthritis, urinsyregikt, arteriosklerose, Reiters sykdom, pulmonar granulomatosis, typer av encephalitis, endotoksisk sjokk (septisk-toksisk sjokk), sepsis, pneumoni, encephalomyelitis, anorexia nevrosa, hepatitt, Rennert T-lymphomatosis, mesanginal nephritis, post-angioplastisk restenosis, re-perfusions-syndrom, cytomegaloviral retinopati, adenovirale sykdommer, AIDS, Guillain-Barré syndrom, post-herpetisk eller post-zoster neuralgia, inflammatorisk demyeliniserende polyneuropati, mononeuropathia multiplex, mucoviscidosis, Bech-terews sykdom, Barett oesophagus, EBV (Epstein-Barr virus) infeksjon, hjertere-modelering, interstitial cystitis, diabetes mellitus type II, menneskelig tumor radio-sensitisasjon, multi-resistens av ondartede celler for kjemoterapeutiske midler, granuloma annulare og kreft.
2. Anvendelse ifølge krav 1, hvor Ri representerer -OR3og R2representerer et L-aminosyreradikal -NH-CHR5-COOH, hvor R5er valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly.
3. Anvendelse ifølge krav 1, hvor Ri representerer -NH-CHR4-COOH og R2representerer -NH-CHR5-COOH, hvor R4og R5kan være samme eller forskjellig og er som definert i krav 1.
4. Anvendelse ifølge krav 1 eller 2, hvor R3er metyl eller etyl.
5. Anvendelse ifølge krav 1, 2 eller 3, hvor R5er valgt fra gruppen bestående av Gin, Asn, Lys, Arg og His.
6. Anvendelse ifølge ethvert av kravene 1-5, hvor legemidlet er i en form egnet for oral, nasal, parenteral, rektal, pulmonar, oftal eller transdermal administrasjon.
7. Anvendelse ifølge ethvert av kravene 1-5, hvor legemidlet er i en form egnet for oral administrasjon og er i formen av tabletter, belagte tabletter, kapsler, granulater, løsninger for å drikke, liposomer, nano-kapsler, mikrokapsler, mikrotabletter, pelleter eller pulvere; eller i formen av granulater, mikrotabletter, pelleter eller pulverfylte kapsler.
8. Anvendelse ifølge krav 7, hvor legemidlet er en fast oral doseringsform og har et enterisk belegg.
9. Anvendelse ifølge krav 7, hvor mi krota blettene eller pelletene uten belegg har en gjennomsnittlig diameter på 300 til 5000 pm.
10. Anvendelse ifølge krav 9, hvor den gjennomsnittlige diameter er 300 til 2000 pm.
11. Anvendelse ifølge ethvert av kravene 1-9, hvor legemidlet inneholder en mengde av fumarsyreamidet med formel (I) per enkel dose som tilsvarer 1 til 500 mg av fumarsyre.
12. Anvendelse ifølge krav 11, hvor legemidlet inneholder en mengde av fumarsyreamidet per enkel dose som tilsvarer 10 til 300 mg av fumarsyre.
13. Anvendelse ifølge ethvert av kravene 1-12, hvor hepatitt er valgt fra akutt hepatitt, kronisk hepatitt, toksisk hepatitt, alkohol-indusert hepatitt, viral hepatitt, gulsott, og lever insuffiens og cytomegalviral hepatitt.
14. Anvendelse ifølge ethvert av kravene 1-12, hvor adenoviral sykdom er valgt fra adenovirale forkjølelser, adenoviral pharyngoconjunctival feber og adenoviral ophthalmia.
15. Anvendelse ifølge ethvert av kravene 1-12, hvor kreft er valgt fra brystkreft, tarmkreft, melanoma, primær levercelle carcinoma, adenocarcinoma, Kaposis sar-coma, prostata carcinoma, leukemi, multippel myeloma (plasmocytoma), Burkitt lymphoma og Castleman tumor.
16. Anvendelse ifølge krav 15, hvor leukemi er akutt myeloid leukemi.
17. Legemiddel omfattende et fumarsyreamid med den generelle formelen (I)
hvor
Ri representerer -OR3eller et D- eller L-aminosyreradikal -NH-CHR4-COOH bundet via en amidbinding, hvor R3
er hydrogen, et rettkjedet eller forgrenet, valgfritt substituert Ci^alkylradikal, et fenylradikal eller C6-i0-aralkylradikal, og
R2representerer et D- eller L-aminosyreradikal -NH-CHR5-COOH bundet via en amidbinding,
hvor hver av R4og R5er uavhengig valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly,
legemidlet er en fast oral doseringsform og har et enterisk belegg.
18. Legemiddel ifølge krav 17, hvor Ri representerer -OR3og R2representerer et L-aminosyreradikal -NH-CHR5-COOH, hvor R5er valgt fra gruppen bestående av sidekjedene av Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar og Me-Gly.
19. Legemiddel ifølge krav 17 eller 18, hvor R3er metyl eller etyl.
20. Legemiddel ifølge krav 17, hvor Ri representerer -NH-CHR4-COOH og R2representerer -NH-CHR5-COOH, hvor R4og R5kan være samme eller forskjellig og er som definert i krav 17.
21. Legemiddel ifølge krav 17, 18 eller 20, hvor R5er valgt fra gruppen bestående av Gin, Asn, Lys, Arg og His.
22. Legemiddel ifølge krav 17, hvor den faste orale doseringsformen er valgt fra tabletter, belagte tabletter, mikrotabletter, pelleter eller kapsler.
23. Legemiddel ifølge krav 22, hvor mikrotablettene eller pelletene uten belegg har en gjennomsnittlig diameter på 300 til 5000 pm.
24. Legemiddel ifølge krav 23, hvor den gjennomsnittlige diameter er 300 til 2000 pm.
25. Legemiddel ifølge ethvert av kravene 17-24, hvor legemidlet inneholder en mengde av fumarsyreamidet med formel (I) per enkel dose som tilsvarer 1 til 500 mg av fumarsyre.
26. Legemiddel ifølge krav 17-25, hvor legemidlet inneholder en mengde av fumarsyreamidet per enkel dose som tilsvarer 10 til 300 mg av fumarsyre.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10101307A DE10101307A1 (de) | 2001-01-12 | 2001-01-12 | Fumarsäurederivate als NF-kappaB-Inhibitor |
| DE10133004 | 2001-07-06 | ||
| PCT/EP2002/000107 WO2002055063A2 (de) | 2001-01-12 | 2002-01-08 | Fumarsäureamide |
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| NO20031748D0 NO20031748D0 (no) | 2003-04-15 |
| NO20031748L NO20031748L (no) | 2003-09-12 |
| NO333992B1 true NO333992B1 (no) | 2013-11-11 |
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| NO20031748A NO333992B1 (no) | 2001-01-12 | 2003-04-15 | Anvendelse av fumarsyreanhydrider og legemiddel omfattende et fumarsyreanhydrid |
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-
2002
- 2002-01-08 WO PCT/EP2002/000107 patent/WO2002055063A2/de active IP Right Grant
- 2002-01-08 DE DE50213989T patent/DE50213989D1/de not_active Expired - Lifetime
- 2002-01-08 HU HU0302656A patent/HU230252B1/hu not_active IP Right Cessation
- 2002-01-08 EP EP02729423A patent/EP1372634B1/de not_active Expired - Lifetime
- 2002-01-08 JP JP2002555797A patent/JP2004523511A/ja active Pending
- 2002-01-08 EE EEP200300280A patent/EE05472B1/xx not_active IP Right Cessation
- 2002-01-08 SK SK827-2003A patent/SK288238B6/sk not_active IP Right Cessation
- 2002-01-08 CZ CZ2003-1919A patent/CZ304198B6/cs not_active IP Right Cessation
- 2002-01-08 CA CA2425599A patent/CA2425599C/en not_active Expired - Fee Related
- 2002-01-08 CA CA2776023A patent/CA2776023A1/en not_active Abandoned
- 2002-01-08 RS YU56003A patent/RS52083B/sr unknown
- 2002-01-08 PL PL392748A patent/PL392748A1/pl not_active Application Discontinuation
- 2002-01-08 PL PL02364222A patent/PL364222A1/xx not_active IP Right Cessation
- 2002-01-08 RU RU2003124752/15A patent/RU2290946C2/ru not_active IP Right Cessation
- 2002-01-08 AU AU2002219236A patent/AU2002219236B2/en not_active Ceased
- 2002-01-08 PL PL392750A patent/PL392750A1/pl not_active Application Discontinuation
- 2002-01-08 AT AT02729423T patent/ATE447945T1/de not_active IP Right Cessation
- 2002-01-08 ME MEP-2008-206A patent/ME00135B/me unknown
- 2002-01-08 US US10/433,295 patent/US7157423B2/en not_active Expired - Lifetime
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2003
- 2003-04-15 NO NO20031748A patent/NO333992B1/no not_active IP Right Cessation
- 2003-05-09 BG BG107795A patent/BG66256B1/bg unknown
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