Crosslinked nucleoside and nucleotide

Patent metadata

Field	Value
Publication number	US-9611479-B2
Application number	US-201515118546-A
Country	US
Kind code	B2
Filing date	Feb 17, 2015
Priority date	Feb 18, 2014
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

Disclosed are bridged nucleosides and nucleotides. The nucleosides of the present invention have a 2′,4′-bridged structure and are represented by formula I below:

An oligonucleotide containing a 2′,4′-bridged artificial nucleotide of the present invention has a binding affinity for single-stranded RNA comparable to that of known 2′,4′-BNA/LNA and higher nuclease resistance than LNA. In particular, since the oligonucleotide has a much higher binding affinity for single-stranded RNA than S-oligo, it is expected that the oligonucleotide is applicable to nucleic acid drugs.

First claim

The invention claimed is:

1. A compound represented by formula I below or a salt thereof:

wherein Base represents a purine-9-yl group or a 2-oxo-1,2-dihydropyrimidine-1-yl group that may have any one or more substituents selected from group α, where the group α consists of a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkyl group, a C 1 to C 6 linear alkoxy group, a mercapto group, a mercapto group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkylthio group, an amino group, a C 1 to C 6 linear alkylamino group, an amino group protected by a protective group for nucleic acid synthesis, and a halogen atom;
R 2 and R 3 each independently represent a hydrogen atom, a protective group for a hydroxyl group on nucleic acid synthesis, a C 1 to C 7 alkyl group that may be branched or form a ring, a C 2 to C 7 alkenyl group that may be branched or form a ring, a C 3 to C 10 aryl group that may have any one or more substituents selected from the group α and that may contain a hetero atom, an aralkyl group having a C 3 to C 12 aryl moiety that may have any one or more substituents selected from the group α and that may contain a hetero atom, an acyl group that may have any one or more substituents selected from the group α, a silyl group that may have any one or more substituents selected from the group α, a phosphate group that may have any one or more substituents selected from the group α, a phosphate group protected by a protective group for nucleic acid synthesis, or —P(R 4 )R 5 , where R 4 and R 5 each independently represent a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protective group for nucleic acid synthesis, an amino group, a C 1 to C 5 alkoxy group, a C 1 to C 5 alkylthio group, a C 1 to C 6 cyanoalkoxy group, or an amino group substituted with a C 1 to C 6 alkyl group; and
R 6 and R 7 each independently represent a hydrogen atom; a C 1 to C 7 alkyl group that may be substituted with a C 3 to C 12 aryl group that may contain a hetero atom, and that may be branched or form a ring; or an aralkyl group having a C 3 to C 12 aryl moiety that may contain a hetero atom; or
R 6 and R 7 are taken together to represent —(CH 2 ) n —, where n is an integer from 2 to 5.

2. The compound or salt thereof according to claim 1 , wherein the Base in the formula I is a 6-aminopurine-9-yl group, a 2,6-diaminopurine-9-yl group, a 2-amino-6-chloropurine-9-yl group, a 2-amino-6-fluoropurine-9-yl group, a 2-amino-6-bromopurine-9-yl group, a 2-amino-6-hydroxypurine-9-yl group, a 6-amino-2-methoxypurine-9-yl group, a 6-amino-2-chloropurine-9-yl group, a 6-amino-2-fluoropurine-9-yl group, a 2,6-dimethoxypurine-9-yl group, a 2,6-dichloropurine-9-yl group, a 6 mercaptopurine-9-yl group, a 2-oxo-4-amino-1,2-dihydropyrimidine-1-yl group, a 4-amino-2-oxo-5-fluoro-1,2-dihydropyrimidine-1-yl group, a 4-amino-2-oxo-5-chloro-1,2-dihydropyrimidine-1-yl group, a 2-oxo-4-methoxy-1,2-dihydropyrimidine-1-yl group, a 2-oxo-4 mercapto-1,2-dihydropyrimidine-1-yl group, a 2-oxo-4-hydroxy-1,2-dihydropyrimidine-1-yl group, a 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidine-1-yl group, or a 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidine-1-yl group.

3. The compound or salt thereof according to claim 2 , wherein the Base in the formula I is a 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidine-1-yl group.

4. The compound or salt thereof according to claim 3 , wherein R 6 and R 7 in the formula I are both hydrogen atoms.

5. The compound or salt thereof according to claim 2 , wherein R 6 and R 7 in the formula I are both hydrogen atoms.

6. The compound or salt thereof according to claim 1 , wherein the Base in the formula I is a 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidine-1-yl group.

7. The compound or salt thereof according to claim 6 , wherein R 6 and R 7 in the formula I are both hydrogen atoms.

8. The compound or salt thereof according to claim 1 , wherein R 6 and R 7 in the formula I are both hydrogen atoms.

9. An oligonucleotide containing at least one nucleoside structure represented by formula II below or a pharmacologically acceptable salt thereof:

wherein Base represents a purine-9-yl group or a 2-oxo-1,2-dihydropyrimidine-1-yl group that may have any one or more substituents selected from group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkyl group, a C 1 to C 6 linear alkoxy group, a mercapto group, a mercapto group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkylthio groups, an amino group, a C 1 to C 6 linear alkylamino group, an amino group protected by a protective group for nucleic acid synthesis, and a halogen atom; and
R 6 and R 7 each independently represent a hydrogen atom; a C 1 to C 7 alkyl group that may be substituted with a C 3 to C 12 aryl group that may contain a hetero atom, and that may be branched or form a ring; or an aralkyl group having a C 3 to C 12 aryl moiety that may contain a hetero atom; or
R 6 and R 7 are taken together to represent —(CH 2 ) n —, where n is an integer from 2 to 5.

10. The oligonucleotide or pharmacologically acceptable salt thereof according to claim 9 , wherein R 6 and R 7 in the formula II are both hydrogen atoms.

11. A method for producing the oligonucleotide or pharmacologically acceptable salt thereof according to claim 9 , comprising:
synthesizing an oligonucleotide using a compound represented by formula I below or a pharmacologically acceptable salt thereof:

wherein Base represents a purine-9-yl group or a 2-oxo-1,2-dihydropyrimidine-1-yl group that may have any one or more substituents selected from group α, wherein group α consists of a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkyl group, a C 1 to C 6 linear alkoxy group, a mercapto group, a mercapto group protected by a protective group for nucleic acid synthesis, a C 1 to C 6 linear alkylthio group, an amino group, a C 1 to C 6 linear alkylamino group, an amino group protected by a protective group for nucleic acid synthesis, and a halogen atom;
R 2 and R 3 each independently represent a hydrogen atom, a protective group for a hydroxyl group on nucleic acid synthesis, a C 1 to C 7 alkyl group that may be branched or form a ring, a C 2 to C 7 alkenyl group that may be branched or form a ring, a C 3 to C 10 aryl group that may have any one or more substituents selected from the group α and that may contain a hetero atom, an aralkyl group having a C 3 to C 12 aryl moiety that may have any one or more substituents selected from the group α and that may contain a hetero atom, an acyl group that may have any one or more substituents selected from the group α, a silyl group that may have any one or more substituents selected from the group α, a phosphate group that may have any one or more substituents selected from the group α, a phosphate group protected by a protective group for nucleic acid synthesis, or —P(R 4 )R 5 , where R 4 and R 5 each independently represent a hydroxyl group, a

Assignees

• Univ Osaka

Inventors

• Obika Satoshi
• Yamaguchi Takao
• Horiba Masahiko
• Waki Reiko

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/31

  of the backbone · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title