Dinucleotides

Patent metadata

Field	Value
Publication number	US-11110114-B2
Application number	US-201816037157-A
Country	US
Kind code	B2
Filing date	Jul 17, 2018
Priority date	Jul 17, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The present disclosure relates to novel dinucleotides comprising at least two locked nucleosides, one of which is directly attached to the 3′ end of the triazole linker moiety and the other of which is directly linked to the 5′ end of the triazole linker moiety and that are useful for the preparation of oligonucleotides. The disclosed dinucleotides may be used in gene therapy.

First claim

The invention claimed is:

1. A dinucleotide of Formula (I) or Formula (II), or a salt thereof, as shown below:

wherein:
C 3 and C 4 are the carbon atoms at the 3′ and 4′ positions of their respective 5-membered rings;
Q 1 and Q 2 are independently selected from CR p R q , O, S or NR s , wherein R p and R q are each independently selected from H, (1-4C)alkyl or halo and R 5 is selected from hydrogen or (1-4C)alkyl;
B and B′ are each independently:
a) a nucleobase;

R P1 is a protecting group;
one of X 1 and X 2 is (CR a R b ) x , wherein x is selected from 1 or 2 and the other is CR a R b , O, NR c or S, wherein R a and R b are independently selected from hydrogen, (1-2C)alkyl, hydroxy, amino, halo or mercapto, and R c is selected from hydrogen or a (1-6C)alkyl;
or one of X 1 and X 2 is O and the other is NR c ;
bond a is either absent or a single bond;
one of X 3 and X 4 is (CR d R c ) y , wherein y is selected from 1 or 2 and the other is CR d R e , O, NR f or S, wherein R d and R e are independently selected from hydrogen, (1-2C)alkyl, hydroxy, amino, halo or mercapto, and R f is selected from hydrogen or a (1-6C)alkyl; or
one of X 3 and X 4 is O and the other is NR f ; or
one of X 3 and X 4 is H and the other is selected from H, OH, NH 2 , OCH 3 or F;
R z is a solid support or group of formula A 1 or A 2 shown below:

with the proviso that A 1 or A 2 is not present when X 3 is CR d R e , and R d and R e is amino, hydroxyl, or mercapto,
wherein:

 denotes the point of attachment;
W 1 is selected from O, S or (1-4C)alkyl;
 R P2 is a protecting group;
Z + is a positively charged counter ion;
R 1 and R 2 are independently selected from hydrogen or (1-6C)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano or (1-2C)haloalkyl, with the proviso that the halo substituent is not present on the alpha carbon atom; or
R 1 and R 2 are linked, such that, together with the nitrogen to which they attached they form a pyrrolidin-1-yl ring which is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, or nitro; and
L is a triazole phosphodiester mimic, optionally of Formula A or Formula B:

wherein:

denotes the point of attachment to C 3 ;

denotes the point of attachment to C 4 ;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen or (1-4C)alkyl, wherein each (1-4C)alkyl is optionally substituted with one or more NH 2 , OH or SH;
V and Y are independently selected from O, S or NR x , wherein R x is selected from hydrogen or (1-4C)alkyl;
m, n, r and s are integers independently selected from 0 to 2; and
p and q are integers independently selected from 0 to 1;
with the proviso that:
i) the sum of integers m, n, p, q, r and s is either 0, 1, 2, 3, 4, 5 or 6; and
ii) when W 1 is a (1-4C)alkyl, R P2 is absent;
iii) bond a is only absent when one of X 3 and X 4 is H and the other is selected from H, OH, NH 2 , OCH 3 or F.

2. A dinucleotide according to claim 1 , wherein the dinucleotide is of Formula I.

3. A dinucleotide according to claim 1 , wherein the dinucleotide is of Formula II.

4. A dinucleotide according to claim 2 , wherein the R z is a group of formula A 1 :

wherein bond a, C 3 , C 4 , Q 1 , Q 2 , B, B′, R P1 , R P2 , W 1 , R 1 , R 2 , X 1 , X 2 , X 3 , X 4 and L are each as defined in claim 1 .

5. A dinucleotide according to claim 4 , wherein W 1 is O.

6. A dinucleotide according to claim 1 , wherein Q 1 and Q 2 are independently selected from O or S.

7. A dinucleotide according to claim 1 , wherein Q 1 and Q 2 are both oxygen.

8. A dinucleotide according to claim 1 , wherein R P1 and R P2 are protecting groups independently selected from the group consisting of an alkanoyl group, an aroyl group an arylmethyl group, an ether, a silyl ether, an alkylthiol, an alkylcyano, an alkyl thiobenzoyl, trityl-based compound, or a cyclic saturated heterocyclic ring.

9. A dinucleotide according to claim 1 , wherein R P1 is a trityl-based protecting group.

10. A dinucleotide according to claim 1 , wherein R P2 is an alkylcyano protecting group.

11. A dinucleotide according to claim 1 , wherein one of X 1 and X 2 is selected from O, NR c or S and the other of X 1 and X 2 is CH 2 , wherein R c is selected from hydrogen or a (1-6C)alkyl.

12. A dinucleotide according to claim 1 , wherein one of X 1 and X 2 is O, and the other of X 1 and X 2 is CH 2 .

13. A dinucleotide according to claim 1 , wherein X 1 is CH 2 and X 2 is O.

14. A dinucleotide according to claim 1 , wherein bond a is absent and one of X 3 and X 4 is H and the other is selected from H or OH.

15. A dinucleotide according to claim 1 , wherein bond a is a single bond and one of X 3 and X 4 is selected from O, NR f or S and the other of X 1 and X 2 is CH 2 , wherein R f is selected from hydrogen or a (1-6C)alkyl.

16. A dinucleotide according to claim 1 , wherein bond a is a single bond and one of X 3 and X 4 is O, and the other of X 3 and X 4 is CH 2 .

17. A dinucleotide according to claim 1 , wherein bond a is a single bond and X 3 is CH 2 and X 4 is O.

18. A dinucleotide according to claim 1 , wherein R 1 and R 2 are independently selected from hydrogen or (1-6C)alkyl; or R 1 and R 2 are linked, such that, together with the nitrogen to which they are attached they form a pyrrolidin-1-yl ring.

19. A dinucleotide according to claim 1 , wherein R 1 and R 2 are independently selected from hydrogen or (1-6C)alkyl.

20. A dinucleotide according to claim 1 , wherein R 1 and R 2 are both a (1-4C)alkyl.

21. A dinucleotide according to claim 2 , wherein the dinucleotide has the structural Formula (Id) shown below:

wherein:
C 3 and C 4 are as defined in claim 1 ;
B and B′ are each independently either a nucleobase;
one of X 1 and X 2 is selected from O, NR c or S and the other of X 1 and X 2 is CH 2 , wherein R c is selected from hydrogen or a (1-6C)alkyl;
bond a is absent or a single bond;
one of X 3 and X 4 is selected from O, NR f or S and the other of X 1 and X 2 is CH 2 , wherein R f is selected from hydrogen or a (1-6C)alkyl; or
one of X 3 and X 4 is H and the other is selected from H o

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Brown Tom
• El-Sagheer Afaf Helmy
• Kumar Pawan

Classifications

• A61P31/00 Primary

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07H19/00

  Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides ; Anhydro-derivatives thereof · CPC title

• C07D201/00

  Preparation, separation, purification or stabilisation of unsubstituted lactams · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title