Pyrimidine nucleoside compounds and oligonucleoside compounds containing same
First Claim
Patent Images
1. A compound of the structure:
- ##STR5## wherein;
R5 is H or CH3 ;
one of R2 and R4 is ═
O, ═
NH, or ═
NH2+ ; and
the other of R2 and R4 is Q, ═
C(RA)--Q, C(RA)(RB)--C(RC)(RD)--Q, C(RA)═
C(RC)--Q or C.tbd.C--Q;
RA, RB, RC and RD independently are H, SH, OH, NH2, or C1 -C20 alkyl, or one of (RA)(RB) or (RC)(RD) is ═
O;
Q is hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, NH2, C2 -C20 alkenyl, C2 -C20 alkynyl, hydroxyl, thiol, keto, carboxyl, a nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, or a polyether;
T3 and T5 independently are H, phosphate, an activated phosphate, a hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages;
X1 and X2 independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, a polyamine, a polyamide, or a polyether;
orT3 and one of X1 or X2, together, form a hydroxyl protecting group; and
provided that when T5 is a hydroxyl protecting group or together T3 and one of X1 or X2 is a hydroxyl protecting group, then R2 is not CH3 ; and
that when T3 and T5 are H or benzoyl, then R2 is not CH2 OC6 H5 ; and
that when R4 is Q, then Q is not hydroxyl, thiol, amino or hydrogen.
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Accused Products
Abstract
Novel 2- and 4-substituted pyrimidine nucleosides and oligonucleosides are provided, as are methods and intermediates useful in preparing same. In preferred embodiments, one of the 2- and 4-substituents is ═O, ═NH, or ═NH2+ and the other is Q, ═C (RA)--Q, C(RA)(RB)--C(RC)(RD)--Q, C (RA)═C(RC)--Q or C.tbd.C--Q, where RA, RB, RC and RD independently are H, SH, OH, NH2, or C1 -C20 alkyl, or one of (RA)(RB) or (RC)(RD) is ═O, and Q is halogen, hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, imidazole, bis-imidazole, amine, N-phthalimide, C2 -C20 alkenyl, C2 -C20 alkynyl, hydroxyl, thiol, keto, carboxyl, nitrates, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, an intercalator, a reporter molecule, a conjugate, a polyamine, a polyamide, a polyethylene glycol, a polyether, or a depurination enhancing group.
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Citations
44 Claims
-
1. A compound of the structure:
- ##STR5## wherein;
R5 is H or CH3 ;one of R2 and R4 is ═
O, ═
NH, or ═
NH2+ ; and
the other of R2 and R4 is Q, ═
C(RA)--Q, C(RA)(RB)--C(RC)(RD)--Q, C(RA)═
C(RC)--Q or C.tbd.C--Q;RA, RB, RC and RD independently are H, SH, OH, NH2, or C1 -C20 alkyl, or one of (RA)(RB) or (RC)(RD) is ═
O;Q is hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, NH2, C2 -C20 alkenyl, C2 -C20 alkynyl, hydroxyl, thiol, keto, carboxyl, a nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, or a polyether; T3 and T5 independently are H, phosphate, an activated phosphate, a hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages; X1 and X2 independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, a polyamine, a polyamide, or a polyether;
orT3 and one of X1 or X2, together, form a hydroxyl protecting group; and provided that when T5 is a hydroxyl protecting group or together T3 and one of X1 or X2 is a hydroxyl protecting group, then R2 is not CH3 ; and
that when T3 and T5 are H or benzoyl, then R2 is not CH2 OC6 H5 ; and
that when R4 is Q, then Q is not hydroxyl, thiol, amino or hydrogen. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 36, 37, 38, 39, 40, 41)
- ##STR5## wherein;
-
19. A compound of the structure:
- ##STR6## wherein;
R5 is H or CH3 ;one of R2 and R4 is ═
O, ═
NH, or ═
NH2+ ; and
the other of R2 and R4 is ═
C(RA)--Q, C(RA)(RB)--C(RC)(RD)--Q or C(RA)═
C(RC)--Q;RA, RB, RC and RD independently are H, SH, OH or NH2, or one of (RA)(RB) or (RC)(RD) is ═
O;Q is halogen, hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, or NH2 ; T3 and T5 independently are H, phosphate, an activated phosphate, hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages; X1 and X2 independently are hydrogen, hydroxyl or O-(hydroxyl protecting group);
orT3 and one of X1 or X2, together, form a hydroxyl protecting group; and provided that when T5 is a hydroxyl protecting group or together T3 and one of X1 or X2 is a hydroxyl protecting group, then R2 is not CH3 ; and
that when T3 and T5 are H or benzoyl, then R2 is not CH2 OC6 H5 and the when R4 is Q, Q is not hydrogen, hydroxyl, thiol, amino or hydrogen. - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 42)
- ##STR6## wherein;
-
33. An oligonucleoside comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages, at least one of said nucleosides having the structure:
- ##STR7## wherein;
R5 is H or CH3 ;one of R2 and R4 is ═
O, ═
NH, or ═
NH2+ ; and
the other of R2 and R4 is Q, C(RA)(RB)--C(RC)(RD)--Q, C(RA)═
C(RC)--Q or C.tbd.C--Q;RA, RB, RC and RD independently are H, SH, OH, NH2 or C1 -C20 alkyl, or one of (RA)(RB) or (RC)(RD) is ═
O;Q is hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, C2 -C20 alkenyl, C2 -C20 alkynyl, hydroxyl, thiol, keto, carboxyl, a nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, or a polyether; X1 and X2 independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, a polyamine, a polyamide, or a polyether; and T3 and T5 independently are H, a nucleoside or an oligonucleoside, provided that T3 and T5 are not both H. - View Dependent Claims (43, 44)
- ##STR7## wherein;
-
34. An oligonucleoside containing at least one nucleoside of the structure:
- ##STR8## wherein;
R5 is H or CH3 ;one of R2 and R4 is ═
O, ═
NH, or ═
NH2+ ; and
the other of R2 and R4 is C(RA)(RB)--C(RC)(RD)--Q or C (RA)═
C(RC)--Q;RA, RB, RC and RD independently are H, SH, OH or NH2, or one (RA)(RB) or (RC)(RD) is ═
O;Q is halogen, hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, imidazole, bis-imidazole, amine or N-phthalimide; X1 and X2 independently are hydrogen, hydroxyl or O-(hydroxyl protecting group); and T3 and T5 independently are H, a nucleoside, or an oligonucleoside that is joined to said structure.
- ##STR8## wherein;
-
35. A compound of the structure:
- ##STR9## wherein;
J is N or CH;R4 is --OH, --NH2, or --NH3+ ; R2 is Q, ═
C(RA)--Q, C(RA)(RB)--C(RC)(RD)--Q, C(RA)═
C(RC)--Q or C.tbd.C--Q;RA, RB, RC and RD independently are H, SH, OH, NH2 or C1 -C20 alkyl, or one of (RA)(RB) or (RC)(RD) is ═
O;Q is hydrogen, C1 -C20 alkyl, C1 -C20 alkylamine, C1 -C20 alkyl-N-phthalimide, C1 -C20 alkylimidazole, C1 -C20 alkylbis-imidazole, NH2 C2 -C20 alkenyl, C2 -C20 alkynyl, hydroxyl, thiol, keto, carboxyl, a nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, or a polyether; T3 and T5 independently are H, phosphate, an activated phosphate, hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3'"'"'-5'"'"' internucleoside linkages; and X1 and X2 independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, a polyamine, a polyamide, or a polyether.
- ##STR9## wherein;
Specification
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Current AssigneeISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
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Original AssigneeISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
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InventorsDunkel, Martin G., Cook, Phillip Dan, Acevedo, Oscar L.
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Primary Examiner(s)Wilson, James O.
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Application NumberUS08/212,006Time in Patent Office2,251 DaysField of Search536/22.1, 536/23.1, 536/25.3, 536/25.32, 536/26.8, 536/28.1-28.55, 536/22.3, 514/43, 514/885, 514/49, 514/50US Class Current536/23.1CPC Class CodesA61K 48/00 Medicinal preparations cont...C07H 19/04 Heterocyclic radicals conta...C07H 19/06 Pyrimidine radicalsC07H 19/10 with the saccharide radical...C07H 19/16 Purine radicalsC07H 19/20 with the saccharide radical...C07H 21/00 Compounds containing two or...C07H 23/00 Compounds containing boron,...C07J 43/003 not condensedC07K 14/005 from virusesC12N 15/113 Non-coding nucleic acids mo...C12N 15/1137 against enzymes viral enzym...C12N 2310/3125 MethylphosphonatesC12N 2310/315 PhosphorothioatesC12N 2310/32 of the sugarC12N 2310/321 2'-O-R ModificationC12N 2310/322 2'-R ModificationC12N 2310/33 of the baseC12N 2310/333 Modified AC12N 2310/336 Modified GView All
