DK3013843T3 - Substituerede nukleosider, nukleotider og analoger dertil - Google Patents
Substituerede nukleosider, nukleotider og analoger dertil Download PDFInfo
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- DK3013843T3 DK3013843T3 DK14817999.7T DK14817999T DK3013843T3 DK 3013843 T3 DK3013843 T3 DK 3013843T3 DK 14817999 T DK14817999 T DK 14817999T DK 3013843 T3 DK3013843 T3 DK 3013843T3
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- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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Claims (31)
1. Forbindelse med formel (I) eller et farmaceutisk acceptabelt salt deraf,
hvor: B1A er en eventuelt substitueret heterocyklisk base eller en eventuelt substitueret heterocyklisk base med en beskyttet aminogruppe; RA er hydrogen eller deuterium; R1A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret acyl, en eventuelt substitueret O-koblet aminosyre,
Ral og Ra2 uafhængigt er hydrogen eller deuterium; R2A er en Ci-6azidoalkyl eller en Ci-6aminoalkyl; R3A er valgt fra gruppen, der består af OH, -OC(=O)R"A og en eventuelt substitueret O-koblet aminosyre; R4A er halogen; R5A er hydrogen eller halogen; R8A, r7a og R8A er valgt uafhængigt fra gruppen, der består af fraværende, hydrogen, en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C3-24alkenyl, en eventuelt substitueret C3-24alkynyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret C3-6cycloalkenyl, en eventuelt substitueret aryl, en eventuelt substitueret heteroaryl, en eventuelt substitueret aryl(Ci-6alkyl), en eventuelt substitueret *-(CR15AR16A) p-O-Ci-24alkyl, en eventuelt substitueret *- (CR17AR18A) q-O-Ci-24alkenyl,
eller R6A er og R7A er fraværende eller hydrogen; eller R6A og R7A sammen danner en del valgt fra gruppen, der består af en eventuelt substitueret
og en eventuelt substitueret
hvor oxygenatomerne, der er bundet til R6A og R7A, phosphoratomet og delen danner et 6-leddet til 10-leddet ringsystem; R9A er valgt fra gruppen, der består af en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C2-24alkenyl, en eventuelt substitueret C2-24alkynyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret C3-6cycloalkenyl, NR30AR31A, en eventuelt substitueret N-koblet aminosyre og et eventuelt substitueret N-koblet aminosyreesterderivat ; R10A og R11A uafhængigt er en eventuelt substitueret N-koblet aminosyre eller et eventuelt substitueret N-koblet aminosyreesterderivat; R12A, R13A og R14A uafhængigt er fraværende eller hydrogen; hver R15A, hver R16A, hver R17A og hver R18A uafhængigt er hydrogen, en eventuelt substitueret Ci-24alkyl eller alkoxy; R19A, R20A, R22A og R23A er valgt uafhængigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl og en eventuelt substitueret aryl; R21A og R24A er valgt uafhængigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret aryl, en eventuelt substitueret -O-Ci-24alkyl, en
eventuelt substitueret -O-aryl, en eventuelt substitueret -0-heteroaryl og en eventuelt substitueret -O-monocyklisk heterocyclyl; R25A og R29A er valgt uafhængigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl og en eventuelt substitueret aryl; R26A og R27A uafhængigt er -C^N eller en eventuelt substitueret substituent valgt fra gruppen, der består af C2-8organylcarbonyl, C2-salkoxycarbonyl og C2-8organylaminocarbonyl ; r28a er vaigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C2-24alkenyl, en eventuelt substitueret C2-24alkynyl, en eventuelt substitueret C3-6cycloalkyl og en eventuelt substitueret C3-6cycloalkenyl ; R30A og R31A er valgt uafhængigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C2-24alkenyl, en eventuelt substitueret C2-24alkynyl, en eventuelt substitueret C3-6cycloalkyl og en eventuelt substitueret C3-6cycloalkenyl ; R"A er en eventuelt substitueret Ci-24alkyl; m og t uafhængigt er 0 eller 1; p og q er valgt uafhængigt fra gruppen, der består af 1, 2 og 3; r er 1 eller 2; s er 0, 1, 2 eller 3; og Z1A, Z2A, Z3A og Z4A uafhængigt er 0 eller S; og forbindelsen med formel (I) eller et farmaceutisk acceptabelt salt ikke kan være
2. Forbindelse ifølge krav 1, hvor R2A er azidomethyl.
3. Forbindelse ifølge krav 1, hvor R2A er aminomethyl.
4. Forbindelseifølge et hvilket som helst af kravene 1-3, hvor R1A er
hvor R1A er
eller hvor R1A er
5. Forbindelse ifølge krav 4, hvor R1A er
og R6A og R7A begge er hvdroaen eller fraværende; eller hvor R1A er
R6A er
og R7A er hydrogen eller fraværende; fortrinsvis m er 0; og R7A, R12A og R13A uafhængigt er fraværende eller hydrogen; eller fortrinsvis m er 1; og R7A, R12A, R13A og R14A uafhængigt er fraværende eller hydrogen.
6. Forbindelse ifølge krav 4, hvor både R6A og R7A er valgt uafhængigt fra gruppen, der består af en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C3-24alkenyl, en eventuelt substitueret C3-24alkynyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret C3-6cycloalkenyl, en eventuelt substitueret aryl, en eventuelt substitueret heteroaryl og en eventuelt substitueret aryl(Ci-6alkyl) ; fortrinsvis R6A og R7A begge er en eventuelt substitueret Ci-24alkyl; eller fortrinsvis R6A og R7A begge er en eventuelt substitueret C3-24alkenyl; eller fortrinsvis R6A og R7A begge er *-(CR15AR16A) p-O-Ci-24alkyl; eller fortrinsvis R6A og R7A begge er *-(CR17AR18A) q-O-C2-24alkenyl; eller fortrinsvis R6A og R7A begge er en eventuelt substitueret aryl; eller fortrinsvis R6A og R7A begge er en eventuelt substitueret aryl (Ci-6alkyl) .
7. Forbindelse ifølge krav 4, hvor R6A og R7A begge er
eller
eller R6A og R7A sammen danner en del valat fra gruppen, der består af en eventuelt substitueret
og en eventuelt substitueret
hvor oxygenatomerne, der er bundet til R6A og R7A, phosphoratomet og delen danner et 6-leddet til 10-leddet ringsystem.
8. Forbindelse ifølge krav 4, hvor R8A er hydrogen; og R9A er NR30AR31A, hvor R30A og R31A er valgt uafhængigt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-24alkyl, en eventuelt substitueret C2-24alkenyl, en eventuelt substitueret C2-24alkynyl, en eventuelt substitueret C3-6cycloalkyl og en eventuelt substitueret C3-6cycloalkenyl; eller hvor R8A er en eventuelt substitueret aryl; og R9A er en eventuelt substitueret N-koblet aminosyre eller et eventuelt substitueret N-koblet aminosyreesterderivat; eller hvor R8A er en eventuelt substitueret aryl; og R9A har strukturen
hvor R33A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret aryl, en eventuelt substitueret aryl(Ci-6alkyl) og en eventuelt substitueret halogenalkyl; R34A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret Ci-6halogenalkyl, en eventuelt
substitueret C3-6cycloalkyl, en eventuelt substitueret Cgaryl, en eventuelt substitueret Cioaryl og en eventuelt substitueret aryl (Ci-6alkyl) ; og R35A er hydrogen eller en eventuelt substitueret Ci-4alkyl; eller R34A og R35A sammen danner en eventuelt substitueret C3-6cycloalkyl.
9. Forbindelse ifølge krav 4, hvor R10A og R11A begge er en eventuelt substitueret N-koblet aminosyre eller et eventuelt substitueret N-koblet aminosyreesterderivat; eller hvor R10A og R11A uafhængigt har strukturen
hvor R36A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret aryl, en eventuelt substitueret aryl(Ci-6alkyl) og en eventuelt substitueret halogenalkyl; R37A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret Ci-6halogenalkyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret Csaryl, en eventuelt substitueret Cioaryl og en eventuelt substitueret aryl (Ci-6alkyl) ; og R38A er hydrogen eller en eventuelt substitueret Ci-4alkyl; eller R37A og R38A sammen danner en eventuelt substitueret C3-6cycloalkyl.
10. Forbindelse ifølge krav 1, hvor R1A er H.
11. Forbindelse ifølge krav 1, hvor R1A er en eventuelt substitueret acyl; eller hvor R1A er en eventuelt substitueret O-koblet aminosyre; eller hvor R1A er
hvor R40A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret Ci-6halogenalkyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret Csaryl, en eventuelt substitueret Cioaryl og en eventuelt substitueret aryl (Ci-6alkyl) ; og R41A er hydrogen eller en eventuelt substitueret Ci-4alkyl; eller R40A og R41A sammen danner en eventuelt substitueret C3-6cycloalkyl.
12. Forbindelse ifølge et hvilket som helst af kravene 1-11, hvor B1A er valgt fra gruppen, der består af:
hvor: RA2 er valgt fra gruppen, der består af hydrogen, halogen og NHRJ2, hvor RJ2 er valgt fra gruppen, der består af hydrogen, -C(=O)RK2 og - C(=O)ORL2; RB2 er halogen eller NHRW2, hvor Rw2 er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C2-6alkenyl, en eventuelt substitueret C3-8cycloalkyl, -C(=O)RM2 og -C(=O)ORN2; Rc2 er hydrogen eller NHR02, hvor R02 er valgt fra gruppen, der består af hydrogen, -C(=O)RP2 og -C(=O)ORQ2; RD2 er valgt fra gruppen, der består af hydrogen, deuterium, halogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C2-6alkenyl og en eventuelt substitueret C2-6alkynyl; RE2 er valgt fra gruppen, der består af hydrogen, hydroxy, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C3-8cycloalkyl, -C(=O)RR2 og - C(=O)ORS2; RF2 er valgt fra gruppen, der består af hydrogen, halogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C2-6alkenyl og en eventuelt substitueret C2-6alkynyl; Y2 og Y3 uafhængigt er N eller CR12, hvor R12 er valgt fra gruppen, der består af hydrogen, halogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret C2-6alkenyl og en eventuelt substitueret C2-6alkynyl; RG2 er en eventuelt substitueret Ci-6alkyl; RH2 er hydrogen eller NHRT2, hvor RT2 er valgt uafhængigt fra
gruppen, der består af hydrogen, -C(=O)RU2 og -C(=O)ORV2; og RK2, RL2, RM2, RN2, Rp2, RQ2 RR2, Rs2, Ru2 og Rv2 er valgt uafhængigt fra gruppen, der består af Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-ioaryl, heteroaryl, heterocyclyl, aryl (Ci-6alkyl) , heteroaryl (Ci-6alkyl) og heterocyclyl (Ci-6alkyl) .
13. Forbindelse ifølcre krav 12, hvor B1A er
14. Forbindelse ifølge et hvilket som helst af kravene 1-13, hvor R3A er OH.
15. Forbindelse ifølge et hvilket som helst af kravene 1-13, hvor R3A er -OC(=O)R"A; eller hvor R3A er en eventuelt substitueret O-koblet aminosyre; eller hvor R3A er
hvor R42A er valgt fra gruppen, der består af hydrogen, en eventuelt substitueret Ci-6alkyl, en eventuelt substitueret Ci-6halogenalkyl, en eventuelt substitueret C3-6cycloalkyl, en eventuelt substitueret Csaryl, en eventuelt substitueret Cioaryl og en eventuelt substitueret aryl (Ci-6alkyl) ; og R43A er hydrogen eller en eventuelt substitueret Ci-4alkyl; eller R42A og R43A sammen danner en eventuelt substitueret C3-6cycloalkyl.
16. Forbindelse ifølge et hvilket som helst af kravene 1-15, hvor R5A er hydrogen; eller R5A er halogen; fortrinsvis R5A er fluor eller chlor.
17. Forbindelse ifølge et hvilket som helst af kravene 1-16,
hvor R4A er fluor eller chlor.
18. Forbindelse ifølge et hvilket som helst af kravene 1-17, hvor Ral og Ra2 begge er hydrogen; eller hvor Ral og Ra2 begge er deuterium.
19. Forbindelse ifølge et hvilket som helst af kravene 1-18, hvor RA er hydrogen.
20. Forbindelse ifølge et hvilket som helst af kravene 1-19, hvor en forbindelse med formel (I) eller et farmaceutisk acceptabelt salt ikke kan være
21. Forbindelse ifølge krav 1, hvor forbindelsen med formel (I) er:
eller et farmaceutisk acceptabelt salt deraf.
22. Forbindelse ifølge krav 1, hvor forbindelsen med formel (I) er:
eller et farmaceutisk acceptabelt salt deraf.
23. Forbindelse ifølge krav 1, hvor forbindelsen med formel (I) er valgt fra gruppen, der består af:
eller et farmaceutisk acceptabelt salt af en hvilken som helst af ovennævnte.
24. Forbindelse ifølge krav 1, hvor forbindelsen med formel (I) er valgt fra gruppen, der består af:
eller et farmaceutisk acceptabelt salt af en hvilken som helst af ovennævnte.
25. Farmaceutisk sammensætning, der omfatter en effektiv mængde af en forbindelse ifølge et hvilket som helst af kravene 1-24 eller et farmaceutisk acceptabelt salt deraf og et farmaceutisk acceptabelt bæremiddel, fortyndingsmiddel, excipiens eller en kombination deraf.
26. Forbindelse ifølge et hvilket som helst af kravene 1-24 eller et farmaceutisk acceptabelt salt deraf til anvendelse til bedring eller behandling af en paramyxovirus-infektion.
27. Forbindelse ifølge et hvilket som helst af kravene 1-24 eller et farmaceutisk acceptabelt salt deraf til anvendelse til hæmning af replikation af en paramyxovirus.
28. Forbindelse til anvendelse ifølge krav 26 eller krav 27, hvor forbindelsen anvendes i kombination med et eller flere midler valgt fra gruppen, der består af ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771, RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300, YM-53403 og en RSV-F-partikelvaccine, hvor fortrinsvis paramyxovirussen er en human respiratorisk syncytialvirus.
29. Forbindelse til anvendelse ifølge krav 26 eller krav 27, hvor paramyxovirussen er en human respiratorisk syncytialvirus.
30. Forbindelse til anvendelse ifølge krav 26 eller krav 27, hvor paramyxovirussen er en human parainfluenzavirus, fortrinsvis en human parainfluenzavirus 3.
31. Forbindelse til anvendelse ifølge krav 27 eller krav 28, hvor paramyxovirussen er en human metapneumovirus.
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