Cyclohexenyl nucleic acids analogs

Patent metadata

Field	Value
Publication number	US-9409934-B2
Application number	US-201314069773-A
Country	US
Kind code	B2
Filing date	Nov 1, 2013
Priority date	Sep 24, 2008
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present disclosure describes cyclohexenyl nucleic acid analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, cyclohexenyl nucleic acid analogs are provided, having one or more chiral substituents, that are expected to be useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

First claim

What is claimed is:

1. A cyclohexenyl nucleic acid analog having Formula I:

wherein:
Bx is a heterocyclic base moiety selected from uracil, thymine, cytosine, 5-methyl-cytosine, adenine and guanine wherein exocyclic amino groups are optionally protected;
X is fluoro;
one of T 1 and T 2 is H or a hydroxyl protecting group and the other of T 1 and T 2 is H, a hydroxyl protecting group or a reactive phosphorus group;
q 1 , q 2 , q 3 and q 4 are each, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl or substituted C 2 -C 6 alkynyl;
j 1 , j 2 , j 3 and j 4 are each, independently, H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl or substituted C 2 -C 6 alkynyl; and
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , OC(═O)J 1 and CN, wherein each J 1 and J 2 is, independently, H or C 1 -C 6 alkyl.

2. The cyclohexenyl nucleic acid analog of claim 1 wherein q 1 , q 2 , q 3 and q 4 are each H.

3. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is substituted C 1 -C 6 alkyl.

4. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is substituted C 1 -C 6 alkyl comprising at least one substituent group selected from fluoro or OCH 3 .

5. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is C 1 -C 6 alkyl.

6. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is methyl.

7. The cyclohexenyl nucleic acid analog of claim 1 wherein j 1 , j 2 , j 3 and j 4 are each H.

8. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is substituted C 1 -C 6 alkyl.

9. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is substituted C 1 -C 6 alkyl comprising at least one substituent group selected from fluoro or OCH 3 .

10. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is C 1 -C 6 alkyl.

11. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is methyl or fluoro.

12. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is fluoro.

13. The cyclohexenyl nucleic acid analog of claim 1 wherein q 1 , q 2 , q 3 , q 4 , j 1 , j 2 , j 3 and j 4 are each H.

14. The cyclohexenyl nucleic acid analog of claim 13 wherein X and J 2 are each fluoro.

15. The cyclohexenyl nucleic acid analog of claim 13 having Formula II:

wherein:
Bx is a heterocyclic base moiety; and
one of T 1 and T 2 is H or a hydroxyl protecting group and the other of T 1 and T 2 is H, a hydroxyl protecting group or a reactive phosphorus group.

16. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.

17. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is 4,4′-dimethoxytrityl.

18. The cyclohexenyl nucleic acid analog of claim 1 wherein T 2 is a reactive phosphorus group.

19. The cyclohexenyl nucleic acid analog of claim 1 wherein T 2 is a reactive phosphorus group selected from diisopropylcyanoethoxy phosphoramidite and H-phosphonate.

20. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Swayze Eric E

Classifications

• C07F9/6512

  having the nitrogen atoms in positions 1 and 3 · 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

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title