DK2608796T3 - Inhibering af proteinfucosylering in vivo under anvendelse af fucoseanaloger - Google Patents

Inhibering af proteinfucosylering in vivo under anvendelse af fucoseanaloger Download PDF

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DK2608796T3
DK2608796T3 DK11815404.6T DK11815404T DK2608796T3 DK 2608796 T3 DK2608796 T3 DK 2608796T3 DK 11815404 T DK11815404 T DK 11815404T DK 2608796 T3 DK2608796 T3 DK 2608796T3
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fucose
cancer
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fucose analogue
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Peter Senter
Stephen Alley
Dennis Benjamin
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Seattle Genetics Inc
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Claims (23)

1. Fucoseanalog valgt fra gruppen bestående af én af følgende formler (V) eller (VI):
eller et biologisk acceptabelt salt eller solvat deraf, hvor hver af formel (V) eller (VI) kan være alfa- eller beta-anomeren eller den tilsvarende aldoseform; hvor hver af R1, R3 og R4 uafhængigt er valgt fra gruppen bestående af -OH, -OC(O)H, -OC(0)Ci-Cio alkyl, -OC(0)C2-Cio alkenyl, -OC(0)C2-Cio alkynyl, -OC(O)aryl, -OC(O)heterocykel, -OC(O)Ci-Cw alkylen(aryl), -OC(O)-C2.Cio alkenylen(aryl), -OC(O)C2-Cw alkynylen(aryl), -OC(O)Ci-Cw alkylen-(heterocykel), -OC(O)C2-Cw alkenylen(heterocykel), -OC(O)C2-Cw alkyny-len(heterocykel), -OCH2OC(O) alkyl, -OCH2OC(O)O alkyl, -OCH2OC(O) aryl, -OCH2OC(O)O aryl, -OC(O)CH2O(CH2CH2O)nCH3, -OC(O)CH2CH2O-(CH2CH2O)nCH3, -O-tri-Ci-C3 alkylsilyl, -OC1-C10 alkyl, hvor hvert n er et helt tal, som uafhængigt er valgt blandt 0-5; R2 er F, R2a og R3a hver er H, og R5 er -CH3; til anvendelse til behandling eller profylakse af cancer.
2. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 1, hvor fucoseanalogen er valgt fra gruppen bestående af én af de følgende formler (III) eller (IV):
eller et biologisk acceptabelt salt eller solvat deraf, hvor hver af formel (III) eller (IV) kan være alfa- eller beta-anomeren eller den tilsvarende aldoseform; hvor
hver af R1, R3 og R4 uafhængigt er valgt fra gruppen bestående af OH og -OC(0)Ci-Cio alkyl; R2 er F, R2a og R3a hver er H, og R5 er -CH3.
3. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 1, hvor R1, R3 og R4 hver uafhængigt er valgt blandt -OH og -OAc.
4. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 1, hvor fucoseanalogen er 2-deoxy-2-fluorfucose.
5. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 1, hvor fucoseanalogen er 2-deoxy-2-fluorfucoseperacetat.
6. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, som er formuleret til oral administration til et pattedyr.
7. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, som er formuleret til oral administration til et menneske.
8. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 1, hvor behandling eller profylakse af cancer omfatter administration til individet af en effektiv mængde af fucoseanalogen og et kemoterapeutisk middel.
9. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 8, hvor det kemoterapeutiske middel er valgt fra gruppen bestående af alkyleringsmidler, nitrogensenneper (cyclophosphamid, ifosfamid, trofosfamid, chlorambucil), nitrosourea-stoffer (carmustin (BCNU), lomustin (CCNU)), alkylsulfonater (busulfan, treosulfan), triazener (dacarbazin), platinholdige forbindelser (cisplatin, oxaliplatin, carboplatin), plantealkaloider (vincaalkaloider - vineristin, vinblastin, vindesin, vinorelbin), taxoider (paclitaxel, docetaxol), DNA-topoisomeraseinhibitorer, epipodophylliner (etoposid, teni-posid, topotecan, 9-aminocamptothecin, camptothecin), crisnatol, mitomyciner (mitomycin C); anti-metabolitter såsom anti-folater: DHFR-inhibitorer: methotrexat, tri-metrexat; IMP-dehydrogenaseinhibitorer: mycophenolsyre, tiazofurin, ribavirin, EICAR; ribonukleotidreduktaseinhibitorer: hydroxyurea, deferoxamin; pyrimidinanaloger: uracil-analoger: 5-fluoruracil, floxuridin, doxifluridin, ratitrexed; cytosinanaloger: cytarabin (ara C), cytosinarabinosid, fludarabin; purinanaloger: mercaptopurin, thioguanin; hormonale terapier: receptorantagonister: anti-østrogen: tamoxifen, raloxifen, megestrol; LHRH-agonister: goserelin, leuprolidacetat; anti-androgener: flutamid, bicalutamid; retinoi-der/deltoider: vitamin D3-analoger: EB 1089, CB 1093, KH 1060; fotodynamiske terapier: vertoporfin (BPD-MA), phthalocyanin, fotosensibilisator Pc4, demethoxy-hypocrellin A (2BA-2-DMHA); cytokiner: interferon-alfa, interferon-gamma; tumornekro-sefaktor: andre: isoprenyleringsinhibitorer: lovastatin; dopaminerge neurotoksiner: 1-methyl-4-phenylpyridiniumion; cellecyklusinhibitorer: staurosporin; actinomyciner: actinomycin D, dactinomycin; bleomyciner: bleomycin A2, bleomycin B2, peplomycin; anthracycliner: daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubi-cin, zorubicin, mitoxantron; MDR-inhibitorer: verapamil; og Ca2+ATPase-inhibitorer: thapsigargin; taxol, L-asparaginase, procarbizin, cytoxan, irinotecan, plicamycin.
10. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge krav 8, hvor det kemoterapeutiske middel er et taxoid.
11. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor canceren erfibrosarkom, myxosarkom, lipo-sarkom, chondrosarkom, osteogent sarkom, chordom, angiosarkom, endotheliosar-kom, lymphangiosarkom, lymphangioendotheliosarkom, synoviom, mesotheliom, Ewings tumor, leiomyosarkom, rhabdomyosarkom, koloncancer, kolorektal cancer, nyrecancer, cancer i bugspytkirtlen, knoglecancer, brystcancer, ovariecancer, prostata-cancer, cancer i spiserøret, mavecancer, oral cancer, nasal cancer, halscancer, plade-cellecarcinom, basalcellecarcinom, adenocarcinom, svedkirtelcarcinom, talgkirtelcarci-nom, papillært carcinom, papillære adenocarcinomer, cystadenocarcinom, medullært carcinom, bronkogent carcinom, nyrecellecarcinom, hepatom-galdegangscarcinom, choriocarcinom, seminom, embryonalt carcinom, Wilms tumor, cervikal cancer, livmodercancer, testikelcancer, småcellet lungecarcinom, blærecarcinom, lungecancer, epi-telcarcinom, gliom, glioblastom, multiformt astrocytom, medulloblastom, craniopharyn-giom, ependymom, pinealom, hemangioblastom, akustisk neurom, oligodendrogliom, meningiom, hudcancer, melanom, neuroblastom, retinoblastom, akut lymfoblastisk leukæmi "ALL", akut lymfoblastisk B-celleleukæmi, akut lymfoblastisk T-celleleukæmi, akut myeloblastisk leukæmi "AML", akut promyelocytisk leukæmi "APL", akut monobla-stisk leukæmi, akut erythroleukæmisk leukæmi, akut megakaryoblastisk leukæmi, akut myelomonocytisk leukæmi, akut ikke-lymfocytisk leukæmi, akut udifferentieret leukæ mi, kronisk myelocytisk leukæmi "CML", kronisk lymfocytisk leukæmi "CLL", hårcelle-leukæmi, multipelt myelom, akutte og kroniske leukæmier (fx lymfoblastiske myelogene og lymfocytiske myelocytiske leukæmier), Hodgkins sygdom, non-Hodgkins lymfom, multipelt myelom, Waldenstroms makroglobulinæmi, tung kæde-sygdom eller polycythemia vera.
12. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor canceren er brystcancer, lungecancer eller nyrecellecarcinom.
13. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af fucosy-lering af hvide blodlegemer i pattedyrets serum med mindst ca. 20%.
14. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af fucosy-lering af hvide blodlegemer i pattedyrets serum med mindst ca. 50%.
15. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af fucosy-lering af hvide blodlegemer i pattedyrets serum med mindst ca. 60%.
16. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med mindst 10% for celleoverfladeproteiner i pattedyret.
17. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med ca. 20% for celleoverfladeproteiner i pattedyret.
18. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med ca. 30% for celleoverfladeproteiner i pattedyret.
19. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med ca. 40% for celleoverfladeproteiner i pattedyret.
20. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med ca. 50% for celleoverfladeproteiner i pattedyret.
21. Fucoseanalog til anvendelse til behandling eller profylakse af cancer ifølge et hvilket som helst af de foregående krav, hvor fucoseanalogen virker til reduktion af protein-fucosylering med ca. 60% for celleoverfladeproteiner i pattedyret.
22. Farmaceutisk præparat til anvendelse til behandling eller profylakse af cancer, hvi-ket præparat omfatter en terapeutisk eller profylaktisk effektiv mængde af en fucoseanalog ifølge et hvilket som helst af kravene 1 til 21 og én eller flere farmaceutisk kompatible ingredienser.
23. Farmaceutisk præparat til anvendelse til behandling eller profylakse af cancer ifølge krav 22, hvilket præparat er formuleret til oral administration til et menneske.
DK11815404.6T 2010-08-05 2011-08-05 Inhibering af proteinfucosylering in vivo under anvendelse af fucoseanaloger DK2608796T3 (da)

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