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US 10,377,789 B2Granted
Oligonucleotide and artificial nucleoside having guanidine bridge
AssigneeOsaka University
InventorsSatoshi Obika, Yutaro Kotobuki, Reiko Waki
Life of this patent
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Abstract
A compound represented by formula I or II below or a salt thereof: wherein B1 represents a purin-9-yl group or a 2-oxo-1,2-dihydropyrimidin-1-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom.
Claims7
A compound represented by formula I or II below or a salt thereof:
- wherein B1 represents:
- a purin-9-yl group;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group;
- a purin-9-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- R1, R12, and R13 each independently represent a hydrogen atom, a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring, a protecting group for an amino group, or
- and
- R2 and R3 each independently represent
- a hydrogen atom,
- a protecting group for a hydroxyl group in nucleic acid synthesis,
- a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C2 to C7 alkenyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C6 to C12 aryl group,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an acyl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a silyl group that has three substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, and an amino group protected by a protecting group in nucleic acid synthesis,
- a phosphate group,
- a phosphate group that has any one or more substituents selected from the group consisting of a C1 to C6 linear alkyl group, and a C1 to C6 linear alkoxy group,
- a phosphate group protected by a protecting group in nucleic acid synthesis, or
- —P(R4)R5, wherein R4 and R5 each independently represent a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C5 alkoxy group, a C1 to C6 cyanoalkoxy group, or a dialkylamino group substituted with a two C1 to C6 alkyl groups,
- wherein the protecting group in nucleic acid synthesis is a C1 to C6 alkyl group;
- a C1 to C6 alkenyl group;
- an acyl group;
- a tetrahydropyranyl group or a tetrahydrothiopyranyl group;
- a tetrahydrofuranyl group or a tetrahydrothiofuranyl group;
- a methyl group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a halogen atom;
- an ethyl group substituted with a C1 to C6 alkoxy group;
- an ethyl group substituted with a halogen atom;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, and a cyano group;
- a carbonyl group substituted with a C1 to C6 alkoxy group;
- an aryl group substituted with at least one substituents selected from the group consisting of a halogen atom, a C1 to C6 alkoxy group, and a nitro group;
- a carbonyl group substituted with a C1 to C6 alkoxy group substituted with at least one substituent selected from the group consisting of a halogen atom and a silyl group substituted with three C1 to C6 alkyl groups;
- an alkenyloxycarbonyl group;
- or an aralkyloxycarbonyl group substituted with an aryl group substituted with at least one substituent selected from the group consisting of a C1 to C6 alkoxy group and a nitro group;
- wherein the protecting group for a hydroxyl group in nucleic acid synthesis is an aliphatic acyl group;
- an aromatic acyl group;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, a cyano group and a trialkyl substituted silyl group;
- and
- wherein the protecting group for an amino group is an acyl group, a benzoyl group, a tert-butoxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl group;
- and with the proviso that substituents specified in all chemical structures by each of the terms —OH (hydroxyl group), mercapto group (—SH), a C1 to C6 linear alkylamino group, a phosphate group, and an amino group (—NH2) or substituted amino group in compounds intended to be phosphoramidites, must be modified before phosphoramidite group introduction with all necessary protecting groups.
46 more elements
An oligonucleotide synthesized by a phosphoramidite protocol according to Caruthers' method with the substitution of a step of reacting a compound represented by formula I or II below or a salt thereof with a nucleic acid, followed by a step of oxidation to form a phosphate diester linkage therebetween, or a pharmacologically acceptable salt thereof,
- wherein the compound represented by formula I or II is:
- wherein
- (i) B1 represents:
- a purin-9-yl group;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group;
- a purin-9-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- R1, R12, and R13 each independently represent a hydrogen atom, a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring, a protecting group for an amino group, or
- and
- (ii) one substituent of R2 and R3 represents —P(R4)R5, wherein R4 represents a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C5 alkoxy group, or a C1 to C6cyanoalkoxy group, and R5 represents a dialkylamino group substituted with two C1 to C6 alkyl groups, and
- (iii) the other substituent of R2 and R3 represents
- a hydrogen atom,
- a protecting group for a hydroxyl group in nucleic acid synthesis,
- a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C2 to C7 alkenyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C6 to C12 aryl group,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an acyl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a silyl group that has three substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, and an amino group protected by a protecting group in nucleic acid synthesis,
- a phosphate group,
- a phosphate group that has any one or more substituents selected from the group consisting of a C1 to C6 linear alkyl group, and a C1 to C6 linear alkoxy group, or
- a phosphate group protected by a protecting group in nucleic acid synthesis, and
- wherein the protecting group in nucleic acid synthesis is a C1 to C6 alkyl group;
- a C1 to C6 alkenyl group;
- an acyl group;
- a tetrahydropyranyl group or a tetrahydrothiopyranyl group;
- a tetrahydrofuranyl group or a tetrahydrothiofuranyl group;
- a silyl group;
- a methyl group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a halogen atom;
- an ethyl group substituted with a C1 to C6 alkoxy group;
- an ethyl group substituted with a halogen atom;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, and a cyano group;
- a carbonyl group substituted with a C1 to C6 alkoxy group;
- an aryl group substituted with at least one substituents selected from the group consisting of a halogen atom, a C1 to C6 alkoxy group, and a nitro group;
- a carbonyl group substituted with a C1 to C6 alkoxy group substituted with at least one substituent selected from the group consisting of a halogen atom and a silyl group substituted with three C1 to C6 alkyl groups;
- an alkenyloxycarbonyl group;
- or an aralkyloxycarbonyl group substituted with an aryl group substituted with at least one substituent selected from the group consisting of a C1 to C6 alkoxy group and a nitro group;
- wherein the protecting group for a hydroxyl group in nucleic acid synthesis is an aliphatic acyl group;
- an aromatic acyl group;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, and a cyano group and a trialkylsubstituted silyl group;
- and
- wherein the protecting group for an amino group is an acyl group, a benzoyl group, a tert-butoxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl group;
- and with the proviso that substituents specified in all chemical structures by each of the terms —OH (hydroxyl group), mercapto group (—SH), a C1 to C6 linear alkylamino group, a phosphate group, and an amino group (—NH2) or substituted amino group in compounds intended to be phosphoramidites, must be modified before phosphoramidite group introduction with all necessary protecting groups.
49 more elements
An oligonucleotide synthesized according to Caruthers' method with the substitution of a step of reacting of a compound represented by formula I or II below or a salt thereof and a nucleic acid followed by a step of treating with a sulfurizing agent to form a phosphorothioate linkage therebetween, or a pharmacologically acceptable salt thereof,
- wherein the compound represented by formula I or II is:
- wherein
- (i) B1 represents:
- a purin-9-yl group;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group;
- a purin-9-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- a 2-oxo-1,2-dihydropyrimidin-1-yl group that has any one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom;
- R1, R12, and R13 each independently represent a hydrogen atom, a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring, a protecting group for an amino group, or
- and
- (ii) one substituent of R2 and R3 represents —P(R4)R5, wherein R4 represents a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C5 alkoxy group, or a C1 to C6 cyanoalkoxy group, and R5 represents a dialkylamino group substituted with two C1 to C6 alkyl groups, and
- (iii) the other substituent of R2 and R3 represents
- a hydrogen atom,
- a protecting group for a hydroxyl group in nucleic acid synthesis,
- a C1 to C7 alkyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C2 to C7 alkenyl group that is a straight chain, a branched chain or up to a C7 ring,
- a C6 to C12 aryl group,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a C6 to C12 aryl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an aralkyl group having a C6 to C12 aryl moiety,
- an aralkyl group having a C6 to C12 aryl moiety that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a mercapto group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- an acyl group that has any one or more substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, a C1 to C6 linear alkylthio group, a C1 to C6 linear alkylamino group, an amino group protected by a protecting group in nucleic acid synthesis, and a halogen atom,
- a silyl group that has three substituents selected from the group consisting of a hydroxyl group protected by a protecting group in nucleic acid synthesis, a C1 to C6 linear alkyl group, a C1 to C6 linear alkoxy group, and an amino group protected by a protecting group in nucleic acid synthesis,
- a phosphate group,
- a phosphate group that has any one or more substituents selected from the group consisting of a C1 to C6 linear alkyl group, and a C1 to C6 linear alkoxy group, or
- a phosphate group protected by a protecting group in nucleic acid synthesis, and
- wherein the protecting group in nucleic acid synthesis is a C1 to C6 alkyl group;
- a C1 to C6 alkenyl group;
- an acyl group;
- a tetrahydropyranyl group or a tetrahydrothiopyranyl group;
- a tetrahydrofuranyl group or a tetrahydrothiofuranyl group;
- a silyl group;
- a methyl group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a C1 to C6 alkoxy group;
- a methyl group substituted with a C1 to C6 alkoxy group substituted with a halogen atom;
- an ethyl group substituted with a C1 to C6 alkoxy group;
- an ethyl group substituted with a halogen atom;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, and a cyano group;
- a carbonyl group substituted with a C1 to C6 alkoxy group;
- an aryl group substituted with at least one substituents selected from the group consisting of a halogen atom, a C1 to C6 alkoxy group, and a nitro group;
- a carbonyl group substituted with a C1 to C6 alkoxy group substituted with at least one substituent selected from the group consisting of a halogen atom and a silyl group substituted with three C1 to C6 alkyl groups;
- an alkenyloxycarbonyl group;
- or an aralkyloxycarbonyl group substituted with an aryl group substituted with at least one substituent selected from the group consisting of a C1 to C6 alkoxy group and a nitro group;
- wherein the protecting group for a hydroxyl group in nucleic acid synthesis is an aliphatic acyl group;
- an aromatic acyl group;
- a methyl group substituted with one to three aryl groups;
- a methyl group substituted with one to three aryl groups substituted with at least one substituent selected from the group consisting of a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, and a cyano group and a trialkylsubstituted silyl group;
- and
- wherein the protecting group for an amino group is an acyl group, a benzoyl group, a tert-butoxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl group;
- and with the proviso that substituents specified in all chemical structures by each of the terms —OH (hydroxyl group), mercapto group (—SH), a C1 to C6 linear alkylamino group, a phosphate group, and an amino group (—NH2) or substituted amino group in compounds intended to be phosphoramidites, must be modified before phosphoramidite group introduction with all necessary protecting groups.
49 more elements
Dependencies are inferred from the claim text.