HRP20170707T1 - Spojevi i sastavi kao modulatori tlr-aktiviteta - Google Patents

Spojevi i sastavi kao modulatori tlr-aktiviteta Download PDF

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HRP20170707T1
HRP20170707T1 HRP20170707TT HRP20170707T HRP20170707T1 HR P20170707 T1 HRP20170707 T1 HR P20170707T1 HR P20170707T T HRP20170707T T HR P20170707TT HR P20170707 T HRP20170707 T HR P20170707T HR P20170707 T1 HRP20170707 T1 HR P20170707T1
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naphthyridin
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ethyl
methylbenzo
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Alex Cortez
Yongkai Li
Manmohan Singh
David Skibinski
Tom Yao-Hsiang Wu
Kathy Yue
Xiaoyue Zhang
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Claims (23)

1. Spoj, naznačen time, da ima sljedeću formulu (I), ili njegova farmaceutski prihvatljiva sol: [image] formula (I) u kojoj: R1 je C1-C4alkil, -L1R5, -L1R6, -L2R5 ili -L2R6; L1 je -C(O)- ili -O-; L2je C1-C6alkilen ili C2-C6alkenilen, gdje su C1-C6alkilen i C2-C6alkenilen od L2, opcijski supstituirani s jednom do četiri fluoro-skupina; svaki L3 je neovisno odabran od sljedećih: C1-C6alkilen i -((CR4R4)pO)q(CH2)p-, pri čemu je C1-C6alkilen od L3, opcijski supstituiran s jednom do četiri fluoro-skupina; L4 je arilen; R2 je C1-C4alkil; R3 je odabran od sljedećih: -OL3R7, -OL3L4L3R7, -OR8 i -OL3L4R5; svaki R4 je neovisno odabran od H i fluoro; R5 je -P(O)(OH)2, R6je -C(O)OH ili -CF2P(O)(OH)2; R7je -CF2P(O)(OH)2; R8je H ili C1-C4alkil; svaki p je neovisno odabran from 1, 2, 3, 4, 5 i 6, te q je 1, 2, 3 ili 4, uz uvjet da, kada R3 je -OR8, tada R1 je -L1R5, -L1R6, -L2R5 ili -L2R6, dok R6je -CF2P(O)(OH)2 i R7je -CF2P(O)(OH)2.
2. Spoj prema zahtjevu 1, naznačen time, da: R1 je C1-C4alkil; R2 je C1-C4alkil; R3 je -OL3R7; R7je -CF2P(O)(OH)2, i L3 je C1-C6alkilen.
3. Spoj prema zahtjevu 1, naznačen time, da: R1 je C1-C4alkil; R2 je C1-C4alkil; R3 je -OL3R7; R7je -CF2P(O)(OH)2; L3 je -((CR4R4)pO)q(CH2)p-; R4 je H; q je 1 ili 2, i p je 2.
4. Spoj prema zahtjevu 1, naznačen time, da: R1 je -L2R6; R2 je C1-C4alkil; R3 je -OL3R7; R6je -C(O)OH; R7je -CF2P(O)(OH)2; L2 je C1-C6alkilen, i L3 je C1-C6alkilen.
5. Spoj prema zahtjevu 1, naznačen time, da: R1 je -L2R6; R2 je C1-C4alkil; R3 je -OL3R7; R6je-C(O)OH; R7je-CF2P(O)(OH)2; L2 je C1-C6alkilen; L3 je -((CR4R4)pO)q(CH2)p-; R4 je H; q je 1 ili 2, i p je 2.
6. Spoj prema zahtjevu 1, naznačen time, da: R1 je -C(R5)2OH, -L1R5, -L2R5 ili -L1R6; R2 je C1-C4alkil; R3 je -OR8; R8 je C1-C4alkil; R6je -CF2P(O)(OH)2; L1 je -C(O)-, i L2 je C1-C6alkilen ili C2-C6alkenilen, od kojih je svaki opcijski supstituiran s jednom do četiri fluoro-skupine.
7. Spoj prema zahtjevu 1, naznačen time, da: R1 je C1-C4alkil; R2 je C1-C4alkil; R3 je -OL3L4R5, -OL3L4L3R5 ili -OL3L4L3R7; R5 je -P(O)(OH)2; R7je -CF2P(O)(OH)2; svaki L3 je neovisno C1-C6alkilen, i L4 je fenilen.
8. Spoj prema zahtjevu 1 ili zahtjevu 6, naznačen time, da R8 je metil.
9. Spoj prema bilo kojem od zahtjeva 1 do 3 ili 7 do 8, naznačen time, da R1 je metil.
10. Spoj prema bilo kojem od zahtjeva 1 do 9, naznačen time, da R2 je metil.
11. Spoj prema zahtjevu 1, naznačen time, da je spoj odabran od sljedećih: 4-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)-1,1-difluorobutil-fosfonska kiselina; 3-(5-amino-2-(4-(4,4-difluoro-4-fosfonobutoksi)-2-metilfenetil)benzo[f][1,7] naftiridin-8-il)-propanska kiselina; 3-(5-amino-2-(4-(2-(3,3-difluoro-3-fosfonopropoksi)etoksi)-2-metilfenetil) benzo[f][1,7]naftiridin-8-il)-propanska kiselina; 5-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)-1,1-difluoropentil-fosfonska kiselina; 3-(2-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)etoksi)-1,1-difluoropropil-fosfonska kiselina; 2-(4-((4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi) metil)fenil)-1,1-difluoroetil-fosfonska kiselina; 2-(5-amino-2-(4-metoksi-2-metilfenetil)benzo[f][1,7]naftiridin-8-il)-1,1-difluoro-2-oksoetil-fosfonska kiselina; 3-((4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi) metil)fenil-fosfonska kiselina; 5-amino-2-(4-metoksi-2-metilfenetil)benzo[f][1,7]naftiridin-8-karbonil-fosfonska kiselina; 3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-fosfonopropoksi)etoksi)etoksi)-2-metilfenetil)benzo[f][1,7]naftiridin-8-il)propanska kiselina; 6-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)- 1,1-difluoroheksil-fosfonska kiselina; i 3-(2-(2-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi) etoksi)etoksi)-1,1-difluoropropil-fosfonska kiselina.
12. Spoj, naznačen time, da je odabran od sljedećih: 3-(5-amino-2-(2-metil-4-(2-(2-(2-fosfonoetoksi)etoksi)etoksi)fenetil)benzo [f][1,7]naftiridin-8-il)propanska kiselina; 3-(5-amino-2-(2-metil-4-(2-(2-(2-(2-fosfonoetoksi)etoksi)etoksi)etoksi) fenetil)benzo[f][1,7]naftiridin-8-il)propanska kiselina; 4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenil-dihidrogen-fosfat; (4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)metil-fosfonska kiselina; (E)-2-(5-amino-2-(4-metoksi-2-metilfenetil)benzo[f][1,7]naftiridin-8-il)vinil-fosfonska kiselina; 2-(5-amino-2-(4-metoksi-2-metilfenetil)benzo[f][1,7]naftiridin-8-il)etil- fosfonska kiselina; (E)-2-(5-amino-2-(4-metoksi-2-metilfenetil)benzo[f][1,7]naftiridin-8-il)-1-fluorovinil-fosfonska kiselina; 3-(5-amino-2-(2-metil-4-(3-fosfonopropoksi)fenetil)benzo[f][1,7]naftiridin-8-il) propanska kiselina; 3-(5-amino-2-(2-metil-4-(2-(2-fosfonoetoksi)etoksi)fenetil)benzo[f][1,7]naftiridin-8-il)propanska kiselina; 2-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)etil-fosfonska kiselina; 6-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)heksil-fosfonska kiselina; 2-(2-(2-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi) etoksi)etoksi)etil-fosfonska kiselina; 5-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)pentil-fosfonska kiselina; 4-((4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)metil) benzil-fosfonska kiselina; i 4-(4-(2-(5-amino-8-metilbenzo[f][1,7]naftiridin-2-il)etil)-3-metilfenoksi)butil-fosfonska kiselina;
13. Farmaceutski sastav, naznačen time, da obuhvaća terapeutski učinkovitu količinu spoja prema bilo kojem od zahtjeva 1 do 12, i farmaceutski prihvatljiv nosač.
14. Farmaceutski sastav prema zahtjevu 13, naznačen time, da je spoj formule (I) vezan na pomoćno sredstvo koje sadrži aluminij.
15. Farmaceutski sastav prema zahtjevu 14, naznačen time, da je pomoćno sredstvo koje sadrži aluminij, odabrano između aluminijevog hidroksida, aluminijevog oksihidroksida i aluminijevog hidroksifosfata.
16. Spoj prema bilo kojem od zahtjeva 1 do 12, naznačen time, da se upotrebljava u liječenju.
17. Spoj prema bilo kojem od zahtjeva 1 do 12, naznačen time, da se upotrebljava u liječenju pacijenta koji ima bolest ili poremećaj povezanu/povezan s TLR7-aktivitetom, pri čemu je spoj formule (I) agonist TLR7-receptora.
18. Spoj za uporabu u postupku liječenja prema zahtjevu 17, naznačen time, da se kod bolesti ili poremećaja radi o sljedećem stanju: infektivna bolest, upalna bolest, respiratorna bolest, dermatološka bolest ili autoimuna bolest.
19. Spoj za uporabu u postupku liječenja prema zahtjevu 17, naznačen time, da su bolest ili stanje sljedeći: astma, kronična opstrukcijska plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih (ARDS), ulcerativni kolitis, Crohnova bolest, bronhitis, dermatitis, aktinijska keratoza, karcinom bazalnih stanica, alergijski rinitis, psorijaza, skleroderma, urtikarija, reumatoidni artritis, multipla skleroza, rak, rak dojke, HIV ili lupus.
20. Uporaba spoja prema bilo kojem od zahtjeva 1 do 12, naznačena time, da je za proizvodnju lijeka za liječenje bolesti ili poremećaja kod pacijenta gdje se implicira modulacija TLR7-receptora.
21. Uporaba prema zahtjevu 20, naznačena time, da se kod bolesti ili poremećaja radi o sljedećem stanju: infektivna bolest, upalna bolest, respiratorna bolest, dermatološka bolest ili autoimuna bolest.
22. Uporaba prema zahtjevu 20, naznačena time, da su bolest ili stanje sljedeći: astma, kronična opstrukcijska plućna bolest (COPD), sindrom respiratornog poremećaja kod odraslih (ARDS), ulcerativni kolitis, Crohnova bolest, bronhitis, dermatitis, aktinijska keratoza, karcinom bazalnih stanica, alergijski rinitis, psorijaza, skleroderma, urtikarija, reumatoidni artritis, multipla skleroza, rak, rak dojke, HIV ili lupus.
23. Postupak in vitro za aktiviranje TLR7-receptora, naznačen time, da postupak obuhvaća primjenu terapeutski učinkovite količine spoja prema bilo kojem od zahtjeva 1 do 12, na sustav ili na pojedinca.
HRP20170707TT 2009-09-02 2017-05-11 Spojevi i sastavi kao modulatori tlr-aktiviteta HRP20170707T1 (hr)

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ES2623794T3 (es) 2008-12-09 2017-07-12 Gilead Sciences, Inc. Intermedios para la preparación de moduladores de receptores tipo toll
CA2772916C (en) 2009-09-02 2019-01-15 Novartis Ag Immunogenic compositions including tlr activity modulators
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