DK3143038T3 - Peptidnukleinsyre-monomerer og -oligomerer - Google Patents

Peptidnukleinsyre-monomerer og -oligomerer Download PDF

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DK3143038T3
DK3143038T3 DK15724512.7T DK15724512T DK3143038T3 DK 3143038 T3 DK3143038 T3 DK 3143038T3 DK 15724512 T DK15724512 T DK 15724512T DK 3143038 T3 DK3143038 T3 DK 3143038T3
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flupac
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guaninyl
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Thomas Lindhorst
Birgit Werner
Holger Bock
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Ugisense Ag
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Claims (11)

1. Forbindelse med den generelle formel I:
(i) hvor K repræsenterer en carboxylsyre-aktivester-gruppe eller -O-Rm; hvor Rm repræsenterer et H-atom, en methyl-, ethyl-, allyl-, benzyl-, phenyl-, tert.-butyl- eller en trimethyl-silyl-gruppe; Pr repræsenterer et H-atom eller en aminobeskyttelsesgruppe; # betegner et asymmetrisk C-atom; E repræsenterer en adeninyl-, cytosinyl-, pseudoisocytosinyl-, guaninyl-, thyminyl-, uracilyl- eller phenyl-gruppe, eventuelt substitueret med en nukleobasebeskyttelses-gruppe; R1 er en gruppe repræsenteret ved den generelle formel II:
(II) hvor R2 er en phosphonsyreestergruppe eller en phosphonsyregruppe; R3 er et H-atom eller en aminobeskyttelsesgruppe; m er 1,2, 3 eller 4; og h er 0, 1,2 eller 3; med den forudsætning, at summen af m og h i den generelle formel II er 2 < x < 5.
2. Forbindelse ifølge krav 1, hvor E repræsenterer en thyminyl-, uracilyl-, phenyl-, N2- acetyl-guaninyl-, N2-isobutyryl-guaninyl-, N2-benzyloxycarbonyl-guaninyl-, N2-(4-
methoxyphenyl)-diphenylmethyl-guaninyl-, N2-benzhydryloxycarbonyl-guaninyl-, N2-di-benzhydryloxycarbonyl-guaninyl-, N2-tert-butyloxycarbonyl-guaninyl-, N2-di-tert-butyloxycarbonyl-guaninyl-, N6-benzyloxycarbonyl-adeninyl-, N6-(4-methoxyphenyl)-diphenylmethyl-adeninyl-, N6-anisoyl-adeninyl-, N6-benzhydryloxycarbonyl-adeninyl-, N6-di-benzhydryloxycarbonyl-adeninyl-, N6-tert-butyloxycarbonyl-adeninyl-, N6-di-tert-butyloxycarbonyl-adeninyl-, 06-benzylguaninyl-, N2-acetyl-O6-diphenylcarbamoyl-guaninyl-, N2-isobutyryl-06-diphenyl-carbamoyl-guaninyl-, N2-benzyloxycarbonyl-O6-diphenylcarbamoyl-guaninyl-, N2-(4-methoxyphenyl)-diphenylmethyl-O6-diphenyl-carbamoyl-guaninyl-, N2-benzhydryloxycarbonyl-O6-diphenyl-carbamoyl-guaninyl-, N4-benzyloxycarbonyl-cytosinyl-, N4-(4-methoxyphenyl)-diphenyl-methyl-cytosinyl-, N4-4-tert.-butyl-benzoyl-cytosinyl-, N4-benz-hydryloxycarbonyl-cytosinyl-, N4-di-benzhydryloxycarbonyl-cytosinyl-, N4-tert-butyloxycarbonyl-cytosinyl-, N4-di-tert-butyloxycarbonyl-cytosinyl-, N2-benzyloxycarbonyl-pseudo-isocytosinyl-, N2-(4-methoxyphenyl)-diphenylmethyl-pseudoisocytosinyl-, N2-4-tert-butylbenzoyl-pseudo-isocytosinyl-, N2-benz-hydryloxycarbonyl-pseudo-isocytosinyl-, N2-di-benzhydryloxy-carbonyl-pseudo-isocytosinyl-, N2-tert-butyloxycarbonyl-pseudoisocytosinyl- eller en N2-di-tert-butyloxycarbonyl-pseudoisocytosinyl-gruppe.
3. Forbindelse ifølge krav 2, hvor E repræsenterer en thyminyl-, uracilyl-, phenyl-, N2-benzyloxycarbonyl-guaninyl-, N2-benzhydryloxycarbonyl-guaninyl-, N2-tert-butyloxy-carbonyl-guaninyl-, N2-benzyloxycarbonyl-O6-diphenylcarbamoyl-guaninyl-, N2-benzhydryloxycarbonyl-O6-diphenylcarbamoyl-guaninyl-, N6-benzyloxycarbonyl-adeninyl-, N6-benzhydryloxycarbonyl-adeninyl-, N6-tert-butyloxycarbonyl-adeninyl-, N6-di-tert-butyloxycarbonyl-adeninyl-, N4-benzyloxycarbonyl-cytosinyl-, N4-benz-hydryloxycarbonyl-cytosinyl-, N4-di-tert-butyloxycarbonyl-cytosinyl-, N2-benzyl-oxycarbonyl-pseudo-isocytosinyl-, N2-benz-hydryloxycarbonyl-pseudo-isocytosinyl-eller en N2-tert-butyloxycarbonyl-pseudo-isocytosinyl-gruppe.
4. Forbindelse ifølge ethvert af kravene 1 til 3, hvor R2 repræsenterer en phosphonsyreestergruppe med formlen -P(=O)(OV)2 eller -P(=O)(OV)(OH); og hvert V uafhængigt repræsenterer en methyl-, ethyl-, cyclohexyl- eller benzyl-gruppe.
5. Forbindelse ifølge ethvert af kravene 1 til 4, hvor R3 er et H-atom.
6. Forbindelse ifølge ethvert af kravene 1 til 4, hvor R3 repræsenterer en oxocarba-mat-, thiocarbamat- eller en Mmt-beskyttelses-gruppe.
7. Forbindelse repræsenteret ved den generelle formel VI:
(vi) hvor hvert Y, i hvert enkelt tilfælde uafhængigt repræsenterer en gruppe med den generelle formel IV:
(IV) ; hvort Z, i hvert enkelt tilfælde, uafhængigt repræsenterer en gruppe med den generelle formel V:
(V) hvor hvert E i hvert enkelt tilfælde uafhængigt repræsenterer en adeninyl-, cytosinyl-, pseudoisocytosinyl-, guaninyl-, thyminyl-, uracilyl- eller phenyl-gruppe; # betegner et asymmetrisk C-atom;
hvert R41 i hvert enkelt tilfælde repræsenterer en H-atom; hvert R11 repræsentereren gruppe -(CH2)m-NH-(CH2)h-CH2-R12; hvor R12 i hvert enkelt tilfælde uafhængigt repræsenterer en phosphonsyreestergruppe med formlen -P(=O)(OV)2 eller -P(=O)(OV)(OH); og hvert V i hvert enkelt tilfælde uafhængigt repræsenterer en methyl-, ethyl-, cyclohexyl- eller benzyl-gruppe; m i hvert enkelt tilfælde uafhængigt er 1,2, 3 eller 4 og h i hvert enkelt tilfælde uafhængigt er 0, 1,2 eller 3; med den forudsætning, at summen af m og h er: 2 < x < 5; d i hvert enkelt tilfælde uafhængigt er 0, 1,2,3 eller 4; f i hvert enkelt tilfælde uafhængigt er 0, 1,2,3 eller 4; g i hvert enkelt tilfælde uafhængigt er 0, 1,2,3 eller 4; j i hvert enkelt tilfælde uafhængigt er 0, 1,2, 3 eller 4; n = 0, 1,2, 3, 4, 5, 6, 7 eller 8; med den forudsætning, at summen af alle gentagelsesenheder Yd, Zf, Yg og Zj i den generelle formel VI er 7 < x < 30; og i det mindste én af de variable f eller j repræsenterer et heltal fra 1 til 5; med den forudsætning, at forholdet (summen af gentagelsesenheder Zf og Zj): (summen af alle gentagelsesenheder Yd, Zf, Yg og Zj) i den generelle formel VI er 0,1 <x< 0,5; R31 repræsenterer et H-atom; en sidekæde af aminosyren alanin, arginin, asparagin, asparaginsyre, cystein, glutamin, glutaminsyre, histidin, isoleucin, leucin, lysin, methionin, ornithin, phenylalanin, prolin, histidin, serin, threonin, tryptophan, tyrosin eller valin; eller en gruppe -(CH2)m-NH-(CH2)h-CH2-R12; hvor R12 er en phosphonsyreestergruppe eller en phosphonsyregruppe; m repræsenterer et heltal fra 1 til 5; og h repræsenterer et heltal fra 0 til 4; med den forudsætning af summen af m og h er: 2 < x ^5; R47 i hvert enkelt tilfælde uafhængigt er et H-atom, eller en sidekæde af aminosyren lysin, ornithin eller arginin; t = 0, 1,2, 3, 4, 5, 6, 7 eller 8; L repræsenterer OH, OEt, NH2 eller -NHNH2; U repræsenterer en gruppe med den generelle formel VII:
hvor B repræsenterer et H-atom, en phenylgruppe eller en substitueret phenylgruppe, substitueret med 1 til 3 substituenter, valgt fra gruppen bestående af OH, F, Cl, Br, I og NO2; R48 er et H-atom; og (i) hvert R46 repræsenterer i hvert enkelt tilfælde uafhængigt af hinanden et H-atom eller en sidekæde af aminosyren alanin, arginin, asparagin, asparaginsyre, cystein, glutamin, glutaminsyre, histidin, isoleucin, leucin, lysin, methionin, ornithin, phenyl-alanin, prolin, histidin, serin, threonin, tryptophan, tyrosin eller valin; og s er 0, 1,2, 3, 4, 5, 6, 7 eller 8; eller (ii) hvert R46 repræsenterer i hvert enkelt tilfælde uafhængigt af hinanden et H-atom eller en gruppe med formlen IXb:
(IXb); en gruppe med formlen IXc:
en gruppe med formlen IXd:
eller en gruppe med formlen IXe:
p i formlerne IXb, IXc, IXd og IXe repræsenterer tallet 3 eller 4; og S = 1,2, 3 eller 4.
8. Forbindelse ifølge krav 7, hvor hvert R9 * 11 i hvert enkelt tilfælde repræsenterer en gruppe med formlen: -CH2-CH2-CH2-CH2-NH-CH2-CH2-P=O(OEt)2, eller en gruppe med formlen: -CH2-CH2-CH2-NH-CH2-CH2-P=O(OEt)2.
9. Forbindelse ifølge krav 7 eller 8, hvor hvert R31 repræsenterer et H-atom, en sidekæde af aminosyren lysin, ornithin, arginin, histidin, tryptophan, tyrosin, threonin eller serin, en gruppe med formlen: -CH2-CH2-CH2-CH2-NH-CH2-CH2-P=O(OEt)2, eller en gruppe med formlen: -CH2-CH2-CH2-NH-CH2-CH2-P=O(OEt)2.
10. Forbindelse ifølge ethvert af kravene 7 til 9 til anvendelse som et medikament.
11. Farmaceutisk sammensætning indeholdende i det mindste én forbindelse ifølge ethvert af kravene 7 til 9, og eventuelt i det mindste et bærestof og/eller i det mindste ét adjuvans.
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