Nucleoside derivative and use thereof

Patent metadata

Field	Value
Publication number	US-11780874-B2
Application number	US-201816760781-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	Oct 31, 2017
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

A nucleoside that is more practical for RNA pharmaceuticals and other applications and use thereof is represented by formula (1) or (2) below, or a salt thereof:(In formula (1), R1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group in which a hydrogen atom is substituted by an alkyl group or alkenyl group, or a protected group, and in formula (2), X represents a halogen atom. In formula (1) and formula (2), R2 and R3 may be the same or different, and each represents a hydrogen atom etc., R4 represents NHR7 (in which R7 represents a hydrogen atom etc., and B represent represents any of a purine-9-yl group, 2-oxo-pyrimidin-1-yl group, substituted purine-9-yl group or substituted 2-oxo-pyrimidin-1-yl group).

First claim

The invention claimed is:

1. An oligonucleotide comprising a nucleoside derivative represented by formula (1) or (2) below, or a salt thereof:

wherein:
R 1 represents
a hydroxyl group,
a hydroxyl group in which a hydrogen atom is substituted by an alkyl group or
alkenyl group, or
a protected group,

X represents a halogen atom;
R 2 and R 3 may be the same or different, and each represents
a hydrogen atom,
a hydroxyl protecting group,
a phosphate group,
a protected phosphate group, or
—P(=O) n R 5 R 6 (in which n is 0 or 1, and R 5 and R 6 may be the same or different, with each representing a hydrogen atom, hydroxyl group, protected hydroxyl group, mercapto group, protected mercapto group, lower alkoxy group, cyano lower alkoxy group, amino group or substituted amino group, but when n is 1, R 5 and R 6 are not both hydrogen atoms),

R 4 represents NHR 7 (in which R 7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protecting group for an amino group), an azide group, an amidino group or a guanidino group, each having a linking group that is an alkylene group having two to eight carbon atoms, and
B represents a nucleobase.

2. The oligonucleotide according to claim 1 , wherein either R 7 represents a hydrogen atom or R 4 represents the guanidino group having a linking group.

3. The oligonucleotide according to claim 1 , wherein the linking group of R 4 in formulae (1) and (2) above is an alkylene group having two or three carbon atoms.

4. The oligonucleotide according to claim 1 , wherein said oligonucleotide comprises cell membrane permeability properties.

5. A ribonuclease resistance imparting agent comprising the oligonucleotide according to claim 1 .

6. The oligonucleotide according to claim 1 , wherein said oligonucleotide comprises at least two of said nucleoside derivative.

7. The oligonucleotide according to claim 1 , wherein said oligonucleotide comprises a least three of said nucleoside derivative.

8. The oligonucleotide according to claim 1 , wherein said oligonucleotide comprises 3 to 8 of said nucleoside derivative.

9. The oligonucleotide according to claim 1 , comprising at least 3 of said nucleoside derivative positioned roughly equally at the 5′ end, the center and the 3′ end of the oligonucleotide.

10. The oligonucleotide according to claim 1 , wherein said oligonucleotide consists of a siRNA.

11. The oligonucleotide according to claim 1 , wherein said oligonucleotide is selected from the group consisting of a DNA molecule, a RNA molecule, and a duplex comprising a DNA and/or a RNA molecule.

12. The oligonucleotide according to claim 1 , wherein said oligonucleotide consists of a RNA molecule.

13. The oligonucleotide according to claim 1 , wherein said nucleoside derivative consists of one of the following structures:

14. A RNA molecule comprising an oligoribonucleotide derivative represented by represented by formula (1) or (2) below, or a salt thereof:

wherein:
R 1 represents
a hydroxyl group,
a hydroxyl group in which a hydrogen atom is substituted by an alkyl group or
alkenyl group, or
a protected group,

X represents a halogen atom,
R 2 and R 3 may be the same or different, and each represents
a hydrogen atom,
a hydroxyl protecting group,
a phosphate group,
a protected phosphate group, or
—P(=O) n R 5 R 6 (in which n is 0 or 1, and R 5 and R 6 may be the same or different,
with each representing a hydrogen atom, hydroxyl group, protected hydroxyl
group, mercapto group, protected mercapto group, lower alkoxy group, cyano lower alkoxy group, amino group or substituted amino group, but when n is 1, R 5 and R 6 are not both hydrogen atoms),

R 4 represents NHR 7 (in which R 7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protecting group for an amino group), an azide group, an amidino group or a guanidino group, each having a linking group that is an alkylene group having two to eight carbon atoms, and
B represents a purine-9-yl group, 2-oxo-pyrimidin-l-yl group, substituted purine-9-yl group or substituted 2-oxo-pyrimidin-l-yl group.

15. The RNA molecule according to claim 14 , wherein R 2 and R 3 each represents a hydrogen atom.

16. The RNA molecule according to claim 14 , wherein R 7 represents a hydrogen atom.

17. The RNA molecule according to claim 14 , wherein said RNA molecule comprises a least three of said nucleoside derivative.

18. The RNA molecule according to claim 14 , wherein said RNA molecule comprises 3 to 8 of said nucleoside derivative.

19. The RNA molecule according to claim 14 , comprising at least 3 of said nucleoside derivative positioned roughly equally at the 5′ end, the center and the 3′ end of the RNA molecule.

20. The RNA molecule according to claim 14 , wherein said RNA molecule consists of a siRNA.

Assignees

• Yamasa Corp
• National Univ Corporation Tokai National Higher Education And Research System

Inventors

• Ueno Yoshihito
• Maeda Yusuke
• KAJINO Ryohei

Classifications

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C12N15/113

  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

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• A61K31/712 Primary

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title