Cross-linked nucleoside and nucleotide using same

Patent metadata

Field	Value
Publication number	US-12473299-B2
Application number	US-202117800339-A
Country	US
Kind code	B2
Filing date	Feb 17, 2021
Priority date	Feb 18, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

A cross-linked nucleoside of the present invention is a compound represented by the formula (I) below. The cross-linked nucleoside of the present invention is usable as a substitute for a phosphorothioate-modified nucleic acid, which has a risk of, for example, accumulation in a specific organ. The cross-linked nucleoside also has excellent industrial productivity.

First claim

The invention claimed is:

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

where Base represents a purin-9-yl group that may have any one or more substituents selected from an a group, or a 2-oxo-1,2-dihydropyrimidin-1-yl group that may have any one or more substituents selected from the α group, the α group consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, linear alkyl groups having 1 to 6 carbon atoms, linear alkoxy groups having 1 to 6 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, linear alkylthio groups having 1 to 6 carbon atoms, an amino group, linear alkylamino groups having 1 to 6 carbon atoms, an amino group protected by a protecting group for nucleic acid synthesis, and halogen atoms;
R 2 and R 3 each independently represent a hydrogen atom, a hydroxy group protecting group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms that may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms that may form a branch or a ring, an aryl group having 3 to 10 carbon atoms that may have any one or more substituents selected from the α group and may have a heteroatom, an aralkyl group with an aryl moiety having 3 to 12 carbon atoms that may have any one or more substituents selected from the α group and may have a heteroatom, an acyl group that may have any one or more substituents selected from the α group, a silyl group that may have any one or more substituents selected from the α group, a phosphate group that may have any one or more substituents selected from the α group, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 4 )R 5 , where R 4 and R 5 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or a dialkylamino group that has an alkyl group having 1 to 6 carbon atoms;
X 1 is an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, or —Y 1 —(CH 2 ) n —, —(CH 2 ) n —Y 1 — or —(CH 2 ) l —Y 1 —(CH 2 ) m —, where Y 1 is a sulfonyl group, a sulfonamide group, an amide group, an ester group, or a carbonyl group, n is an integer of 1 to 5, 1 and m are positive integers, and the sum of l and m is 2 to 5; and
X 2 is an oxygen atom, a sulfur atom, —NH—, or a methylene group.

2 . The compound or salt thereof according to claim 1 , wherein the formula (I) is represented by any one of formulae (I-1) to (I-3) below:

3 . The compound or salt thereof according to claim 2 , wherein the Base is a 6-aminopurin-9-yl group, a 2,6-diaminopurin-9-yl group, a 2-amino- 6 -chloropurin-9-yl group, a 2-amino-6-fluoropurin-9-yl group, a 2-amino-6-bromopurin-9-yl group, a 2-amino-6-hydroxypurin-9-yl group, a 6-amino-2-methoxypurin-9-yl group, a 6-amino-2-chloropurin-9-yl group, a 6-amino-2-fluoropurin-9-yl group, a 2,6-dimethoxypurin-9-yl group, a 2,6-dichloropurin-9-yl group, a 6-mercaptopurin-9-yl group, a 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl group, a 4-amino-2-oxo-5-fluoro-1,2-dihydropyrimidin-1-yl group, a 4-amino-2-oxo-5-chloro-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-methoxy-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-mercapto-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl group, or a 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl group.

4 . The compound or salt thereof according to claim 2 , wherein the Base is a group represented by a formula below:

5 . The compound or salt thereof according to claim 1 , wherein the Base is a 6-aminopurin-9-yl group, a 2,6-diaminopurin-9-yl group, a 2-amino-6-chloropurin-9-yl group, a 2-amino-6-fluoropurin-9-yl group, a 2-amino-6-bromopurin-9-yl group, a 2-amino-6-hydroxypurin-9-yl group, a 6-amino-2-methoxypurin-9-yl group, a 6-amino-2-chloropurin-9-yl group, a 6-amino-2-fluoropurin-9-yl group, a 2,6-dimethoxypurin-9-yl group, a 2,6-dichloropurin-9-yl group, a 6 -mercaptopurin-9-yl group, a 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl group, a 4-amino-2-oxo-5-fluoro-1,2-dihydropyrimidin-1-yl group, a 4-amino-2-oxo-5-chloro-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-methoxy-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-mercapto-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl group, a 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl group, or a 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl group.

6 . The compound or salt thereof according to claim 1 , wherein the Base is a group represented by a formula below:

7 . The compound or salt thereof according to claim 1 , wherein, in the formula (I), X 1 is an alkylene group having 1 to 4 carbon atoms, and X 2 is an oxygen atom, a sulfur atom, —NH—, or a methylene group.

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

where Base represents a purin-9-yl group that may have any one or more substituents selected from an a group, or a 2-oxo-1,2-dihydropyrimidin-1-yl group that may have any one or more substituents selected from the α group, the α group consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, linear alkyl groups having 1 to 6 carbon atoms, linear alkoxy groups having 1 to 6 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, linear alkylthio groups having 1 to 6 carbon atoms, an amino group, linear alkylamino groups having 1 to 6 carbon atoms, an amino group protected by a protecting group for nucleic acid synthesis, and halogen atoms;
X 1 is an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, or —Y 1 —(CH 2 ) n —, —(CH 2 ) n —Y 1 — or —(CH 2 ) l -—Y 1 —(CH 2 ) m —, where Y 1 is a sulfonyl group, a sulfonamide group, an amide group, an ester group, or a carbonyl group, n is an integer of 1 to 5, 1 and m are positive integers, and the sum of l and m is 2 to 5; and
X 2 is an oxygen atom, a sulfur atom, —NH—, or a methylene group.

9 . The oligonucleotide or pharmacologically acceptable salt thereof according to claim 8 , wherein the formula (II) is represented by any one of formulae (II-1) to (II-3) below:

10 . The oligonucleotide or pharmacologically acceptable salt thereof according to claim 8 , wherein the Base is a 6-aminopurin-9-yl group, a 2,6-diaminopurin-9-yl group, a 2-amino-6-chloropurin-9-yl group, a 2-amino-6-fluoropurin-9-yl group, a 2-amino-6-bromopurin-9-yl group, a 2-amino-6-hydroxypurin-9-yl group, a 6-amino-2-methoxypurin-9-yl group, a 6-amino-2-chloropurin-9-yl group, a 6-amino-2-fluoropurin-9-yl group, a 2,6-dimethoxypurin

Assignees

• Univ Osaka
• Japan As Represented By Director General Of Nat Institute Of Health Sciences

Inventors

• Obika Satoshi
• Yamaguchi Takao
• Sakurai Yota
• Yamamoto Chika
• Sugita Kei
• Inoue Takao
• Yoshida Tokuyuki

Classifications

• C07H21/04

  with deoxyribosyl as saccharide radical · CPC title

• C07D239/10

  Oxygen or sulfur atoms · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/113

  targeting other non-coding nucleic acids, e.g. antagomirs · CPC title

• C12N2310/315

  Phosphorothioates · CPC title