HRP20200943T1 - Kombinirani tretman s agonistom tlr7 i inhibitorom hbv kapside - Google Patents

Kombinirani tretman s agonistom tlr7 i inhibitorom hbv kapside Download PDF

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HRP20200943T1
HRP20200943T1 HRP20200943TT HRP20200943T HRP20200943T1 HR P20200943 T1 HRP20200943 T1 HR P20200943T1 HR P20200943T T HRP20200943T T HR P20200943TT HR P20200943 T HRP20200943 T HR P20200943T HR P20200943 T1 HRP20200943 T1 HR P20200943T1
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oxo
methyl
image
thiazolo
pyrazin
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HRP20200943TT
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Lue DAI
Lu Gao
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F. Hoffmann - La Roche Ag
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Claims (20)

1. Farmaceutski pripravak koji sadrži agonist TLR7 i inhibitor HBV kapside u farmaceutski prihvatljivom nosaču, naznačen time, što je agonist TLR7 odabran između [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] i 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-diona koji ima strukturu [image] te time, što je inhibitor HBV kapside odabran između 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera.
2. Farmaceutski pripravak prema patentnom zahtjevu 1, naznačen time, što se pripravak sastoji od [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] u farmaceutski prihvatljivom nosaču.
3. Farmaceutski pripravak prema patentnom zahtjevu 1, naznačen time, što se pripravak sastoji od [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] u farmaceutski prihvatljivom nosaču.
4. Farmaceutski pripravak prema patentnom zahtjevu 1, naznačen time, što se pripravak sastoji od 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-diona koji ima strukturu [image] i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] u farmaceutski prihvatljivom nosaču.
5. Farmaceutski pripravak prema patentnom zahtjevu 1, naznačen time, što se pripravak sastoji od 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-diona koji ima strukturu [image] i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] u farmaceutski prihvatljivom nosaču.
6. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, što pripravak dodatno sadrži jedno ili više ostalih antivirusnih agensa.
7. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, što su navedeni ostali antivirusni agensi odabrani između lamivudina, adefovira, tenofovira, telbivudina i entekavira.
8. Komplet, naznačen time, što sadrži spremnik u kojem je sadržan agonist TLR7 i inhibitor HBV kapside, pri čemu je agonist TLR7 odabran između [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] ili 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-diona koji ima strukturu [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera; i pritom je inhibitor HBV kapside odabran između 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] ili 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera.
9. Komplet prema patentnom zahtjevu 8, naznačen time, što su agonist TLR7 i inhibitor HBV kapside koji se koriste u spremniku, sljedeći: [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5−d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetat i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5−d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetat i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; ili 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5−d]pirimidin-2,7-dion i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; u farmaceutski prihvatljivom nosaču.
10. Komplet prema patentnom zahtjevu 9, naznačen time, što nadalje sadrži sterilni razrjeđivač.
11. Komplet prema bilo kojem od patentnih zahtjeva 8 do 10, naznačen time, što nadalje sadrži informativni umetak za korisnika s tiskanim uputama za uporabu kombiniranog tretmana agonistom TLR7 i inhibitorom HBV kapside kao postupka za liječenje ili profilaksu infekcije virusom hepatitisa B.
12. Kombinacije [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5−d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetat i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5−d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetat i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion i 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; ili 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil]tetrahidrofuran-2-il]-6H-tiazolo[4,5−d]pirimidin-2,7-dion i 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoična kiselina; ili njihova farmaceutski prihvatljiva sol, njihov enantiomer ili dijastereomer, naznačene time, što se upotrebljavaju u liječenju ili profilaksi infekcije virusom hepatitisa B.
13. Kombinacija [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] te 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera, naznačena time, što se upotrebljava u liječenju ili profilaksi infekcije virusom hepatitisa B.
14. Kombinacija [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]acetata koji ima strukturu [image] te 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline; [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera, naznačena time, što se upotrebljava u liječenju ili profilaksi infekcije virusom hepatitisa B.
15. Kombinacija 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil] tetrahidrofuran-2-il]-6H-tiazolo[4,5-d] pirimidin-2,7-diona koji ima strukturu [image] te 3-[(8aS)-7-[[(4R)-4-(2-kloro-3-fluoro-fenil)-5-etoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline: [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera, naznačena time, što se upotrebljava u liječenju ili profilaksi infekcije virusom hepatitisa B.
16. Kombinacija 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[(1S)-1-hidroksipropil] tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-diona koji ima strukturu [image] te 3-[(8aS)-7-[[(4S)-5-etoksikarbonil-4-(3-fluoro-2-metil-fenil)-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1H-imidazo[1,5-a]pirazin-2-il]-2,2-dimetil-propanoične kiseline koja ima strukturu [image] ili njihove farmaceutski prihvatljive soli, njihovog enantiomera ili dijastereomera, naznačena time, što se upotrebljava u liječenju ili profilaksi infekcije virusom hepatitisa B.
17. Kombinacija za uporabu prema bilo kojem od patentnih zahtjeva 13 do 16, naznačena time, što se agonist TLR7 i inhibitor HBV kapside zajedno uvode u tijelo u istoj ili u različitoj formulaciji.
18. Kombinacija za uporabu prema bilo kojem od patentnih zahtjeva 13 do 17, naznačena time, što su agonist TLR7 i inhibitor HBV kapside namijenjeni uvođenju u tijelo istim ili različitim putem.
19. Kombinacija za uporabu prema bilo kojem od patentnih zahtjeva 13 do 18, naznačena time, što su agonist TLR7 i inhibitor HBV kapside namijenjeni uvođenju u tijelo parenteralnim ili oralnim putem.
20. Kombinacija za uporabu prema bilo kojem od patentnih zahtjeva 13 do 19, naznačena time, što je uvođenje u tijelo istodobno ili uzastopno.
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