HRP20210454T1 - 3-supstituirani 5-amino-6h-tiazolo[4,5-d]pirimidin-2,7-dion spojevi za liječenje i profilaksu virusne infekcije - Google Patents

3-supstituirani 5-amino-6h-tiazolo[4,5-d]pirimidin-2,7-dion spojevi za liječenje i profilaksu virusne infekcije Download PDF

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HRP20210454T1
HRP20210454T1 HRP20210454TT HRP20210454T HRP20210454T1 HR P20210454 T1 HRP20210454 T1 HR P20210454T1 HR P20210454T T HRP20210454T T HR P20210454TT HR P20210454 T HRP20210454 T HR P20210454T HR P20210454 T1 HRP20210454 T1 HR P20210454T1
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amino
thiazolo
tetrahydrofuran
pyrimidine
hydroxy
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Dongdong Chen
Song Feng
Lu Gao
Li CHAO
Baoxia Wang
Lisha Wang
Hongying Yun
Xiufang ZHENG
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F. Hoffmann - La Roche Ag
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

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Claims (18)

1. Spoj formule (I), [image] naznačen time, da R1 je hidroksi, C1-6 alkil, C1-6 alkilkarbonil-O-, C1-6 alkil-S-, azido ili C2-6 alkenil; R2 je C1-6 alkil, C1-6 alkoksi C1-6 alkil, C3-7 cikloalkil, C2-6 alkinil, C2-6 alkenil, benzil i tiofenil; R3 je vodik ili C1-6 alkoksikarbonil; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da R1 je hidroksi, C1-6 alkil, C1-6 alkil-S-, azido ili C2-6 alkenil.
3. Spoj prema bilo kojem od patentnih zahtjeva 1 do 2, naznačen time, da R2 je C1-6 alkil, C3-7 cikloalkil, C2-6 alkinil ili C2-6 alkenil.
4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, da R3 je vodik ili C1-6 alkilkarbonil.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da R1 je halogen C1-6 alkil, C1-6 alkil-S-, cijano, C2-6 alkenil, C1-6 alkilsulfonil-NH-, (C1-6 alkil)2N-, C1-6 alkilkarbonil-NH- ili heterociklički amino; R2 je vodik; R3 je vodik; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
6. Spoj prema patentnom zahtjevu 5, naznačen time, da je R1 C1-6 alkil-S- ili heterociklični amino.
7. Spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da je odabran iz skupine koju čine: 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksipropil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; [(2R,3R,5S)-2-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-5-(1-hidroksipropil)tetrahidrofuran-3-il] acetat; [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil] acetat; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksietil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksibut-3-enil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksipentil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksibutil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[ciklopentil(hidroksi)metil]-3-hidroksi-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksi-2-fenil-etil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksi-3-metil-butil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[ciklopropil(hidroksi)metil]-3-hidroksi-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; [[(2S,4R,5R)-5-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]-ciklopropil-metil] acetat; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksiprop-2-inil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksibut-2-inil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-[hidroksi(2-tienil)metil]tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksi-2-metoksi-etil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(1-hidroksipropil)-3-metilsulfanil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-azido-5-(1-hidroksipropil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksialil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-((2R,3R,5S)-3-azido-5-((S)-1-hidroksietil)tetrahidrofuran-2-il)tiazolo[4,5-d]pirimidin-2,7(3H,6H)-dion; 3-[(2R,3R,5S)-3-alil-5-(1-hidroksipropil)tetrahidrofuran-2-il]-5-amino-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksipropil]-3-propil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1R)-1-hidroksipropil]-3-propil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksipropil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksibut-2-inil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(S)-ciklopropil(hidroksi)metil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksietil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-pirolidin-1-il-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; N-[(2R,3R,5S)-2-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-5-(hidroksimetil)tetrahidrofuran-3-il]metansulfonamid; N-[(2R,3R,5S)-2-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-5-(hidroksimetil)tetrahidrofuran-3-il]acetamid; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-morfolino-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-(1-piperidil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-(dimetilamino)-5-(hidroksimetil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; (2R,3R,5S)-2-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-5-(hidroksimetil)tetrahidrofuran-3-karbonitril; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-metilsulfanil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-(1-fluoro-1-metil-etil)-5-(hidroksimetil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-(2-metilalil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion i [(1S)-1-[(2S,4R,5S)-5-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil]2-metilpropanoat; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
8. Spoj prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, da je odabran iz skupine koju čine: 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksipropil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksibutil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[ciklopropil(hidroksi)metil]-3-hidroksi-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksiprop-2-inil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksibut-2-inil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(1-hidroksipropil)-3-metilsulfanil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-azido-5-(1-hidroksipropil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksialil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 3-[(2R,3R,5S)-3-alil-5-(1-hidroksipropil)tetrahidrofuran-2-il]-5-amino-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksipropil]-3-propil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1R)-1-hidroksipropil]-3-propil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksipropil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksibut-2-inil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(S)-ciklopropil(hidroksi)metil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-[(1S)-1-hidroksietil]-3-metil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-pirolidin-1-il-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; 5-amino-3-[(2R,3R,5S)-5-(hidroksimetil)-3-metilsulfanil-tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion; i [(1S)-1-[(2S,3R,5R)-5-(5-amino-2,7-diokso-6H-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil] 2-metilpropanoat; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
9. Spoj prema bilo kojem od patentnih zahtjeva 1 do 8, naznačen time, da je taj spoj 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksipropil)tetrahidrofuran-2-il]-6H-tiazolo[4,5-d]pirimidin-2,7-dion.
10. Spoj formule (II), [image] naznačen time, da R4 je hidroksi, C1-6 alkil, C1-6 alkil-S-, azido ili C2-6 alkenil; R5 je C1-6 alkil, C3-7 cikloalkil, C2-6 alkinil ili C2-6 alkenil; R6 je vodik ili C1-6 alkoksikarbonil; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
11. Spoj prema patentnom zahtjevu 10, naznačen time, da R4 je hidroksi ili C1-6 alkoksikarbonil-O-; R5 je C1-6 alkil ili C3-7 cikloalkil; R6 je vodik ili C1-6 alkoksikarbonil; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
12. Spoj prema bilo kojem od patentnih zahtjeva 10 do 11, naznačen time, da je odabran iz skupine koju čine: 5-amino-3-[(2R,3R,5S)-3-hidroksi-5-(1-hidroksipropil)tetrahidrofuran-2-il] tiazolo[4,5-d]pirimidin-2-on; [(2R,3R,5S)-2-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-5-(1-hidroksipropil)tetrahidrofuran-3-il] acetat; 1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propilacetat; [(S)-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]-ciklopropil-metil] acetat; i 5-amino-3-[(2R,3R,5S)-5-[ciklopropil(hidroksi)metil]-3-hidroksi-tetrahidrofuran-2-il]tiazolo[4,5-d]pirimidin-2-on; ili njihove farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri.
13. Spoj prema bilo kojem od patentnih zahtjeva 10 do 12, naznačen time, da je taj spoj 5-amino-3-[(2R, 3R, 5S)-3-hidroksi-5-(1-hidroksipropil)tetrahidrofuran-2-il]tiazolo[4,5-d]pirimidin-2-on.
14. Spoj prema bilo kojem od patentnih zahtjeva 10 do 12, naznačen time, da je spoj 1-[(2S,4R,5R)-5-(5-amino-2-okso-tiazolo[4,5-d]pirimidin-3-il)-4-hidroksi-tetrahidrofuran-2-il]propil acetat
15. Postupak za pripremu spoja prema bilo kojem od patentnih zahtjeva 1 do 14, naznačen time, da obuhvaća sljedeće korake: (a) reakcija spoja formule (X), [image] s bazom ili fluoridnim reagensom, gdje Ra predstavlja R2 ili R5; Rb je acil, benzoil, terc-butil(dimetil)silil ili terc-butil(difenil)silil; Rc je vodik ili hidroksi; (b) reakcija spoja formule (P1), [image] s kiselim anhidridom ili kiselim kloridom, gdje Ra predstavlja R2 ili R5; Rc je vodik ili hidroksi; (c) reakcija spoja formule (XIV), [image] s bazom ili fluoridnim reagensom, gdje Ra predstavlja R2 ili R5; Rb je acil, benzoil ili terc-butil(difenil)silil; Rc je vodik ili hidroksi; Re je R1 ili R4; (d) reakcija spoja formule (XXIII), [image] s bazom, gdje Ra predstavlja R2 ili R5; Rc je vodik ili hidroksi; Re je R1 ili R4; (e) reakcija spoja formule (XXVI), [image] s bazom, gdje Rc predstavlja vodik ili hidroksi; Re je R1 ili R4; (f) reakcija spoja formule (XXXI), [image] s bazom, gdje Ra predstavlja R2 ili R5; Rc je vodik ili hidroksi; Re je R1 ili R4; ili pri čemu su Ra, Rb, Rd, Re, R1, R2, R3, R4, R5 i R6 definirani kao u bilo kojem od patentnih zahtjeva 1 do 6, 10 i 11.
16. Spoj ili farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri prema bilo kojem od patentnih zahtjeva 1 do 14, naznačeni time, da se upotrebljavaju kao terapijski djelatna tvar.
17. Farmaceutski pripravak, naznačen time, da sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 14 i terapijski inertni nosač.
18. Spoj ili farmaceutski prihvatljive soli, enantiomeri ili dijastereomeri prema bilo kojem od patentnih zahtjeva 1 do 14, naznačeni time, da se upotrebljavaju u liječenju ili profilaksi infekcije virusom hepatitisa B.
HRP20210454TT 2014-12-08 2021-03-17 3-supstituirani 5-amino-6h-tiazolo[4,5-d]pirimidin-2,7-dion spojevi za liječenje i profilaksu virusne infekcije HRP20210454T1 (hr)

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