Oligomeric compounds having at least one neutrally linked terminal bicyclic nucleoside

Patent metadata

Field	Value
Publication number	US-9290534-B2
Application number	US-93449809-A
Country	US
Kind code	B2
Filing date	Apr 3, 2009
Priority date	Apr 4, 2008
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

The present disclosure describes oligomeric compounds having at least one bicyclic nucleoside attached to the 3′ or 5′ termini by a neutral internucleoside linkage and methods of using the oligomeric compounds. 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 gapped oligomeric compound comprising a contiguous sequence of linked monomeric subunits having two external regions and an internal region including one neutral internucleoside linkage covalently attaching a 3′ or 5′-terminal bicyclic nucleoside to the gapped oligomeric compound wherein the gapped oligomeric compound comprises from 12 to 16 linked monomeric subunits and is complementary to at least a portion of a target RNA wherein said neutral internucleoside linkage is a phosphotriester, methylphosphonate, MMI (3′-CH 2 —N(CH 3 )—O-5′), amide-3 (3′-CH 2 —C(═O)—N(H)-5′), formacetal (3′-O—CH 2 —O-5′) or a thioformacetal (3′-S—CH 2 —O-5′).

2. The gapped oligomeric compound of claim 1 wherein said neutral internucleoside linkage covalently attaches the bicyclic nucleoside to the 3′-terminus.

3. The gapped oligomeric compound of claim 2 wherein the penultimate nucleoside on the 3′-end of the oligomeric compound is also a bicyclic nucleoside.

4. The gapped oligomeric compound of claim 1 wherein said neutral internucleoside linkage covalently attaches the bicyclic nucleoside to the 5′-terminus.

5. The gapped oligomeric compound of claim 4 wherein the penultimate nucleoside on the 5′-end of the oligomeric compound is also a bicyclic nucleoside.

6. The gapped oligomeric compound of claim 1 wherein said neutral internucleoside linkage is MMI (3′-CH 2 —N(CH 3 )—O-5′), amide-3 (3′-CH 2 —C(═O)—N(H)-5′), formacetal (3′-O—CH 2 —O-5′) or thioformacetal (3′-S—CH 2 —O-5′).

7. The gapped oligomeric compound of claim 1 wherein each of said bicyclic nucleoside has formula 1a:

wherein:
Bx is a heterocyclic base moiety;
T 1a and T 2a are each independently, hydroxyl, a protected hydroxyl, a linked conjugate group, a terminal group, an internucleoside linking group or a neutral internucleoside linking group;
q 1 and q 2 are each independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
Q is a bivalent bridging group comprising from 1 to 8 linked biradical groups independently selected from —O—, —S—, —N(R 1 )—, —C(R 1 )(R 2 )—, —C(R 1 )═C(R 1 )—, —C(R 1 )═N—, —C(═NR 1 )—, —Si(R 1 ) 2 —, —SO 2 —, —SO—, —C(═O)— and —C(═S)—;
each R 1 and R 2 is, independently, H, hydroxyl, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, OJ 1 NJ 1 J 2 , SJ 1 , N 3 , COOJ 1 , acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O) 2 -J 1 ) or sulfoxyl (S(═O)-J 1 ); and
wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , NJ 1 J 2 , ═NJ 1 , SJ 1 , N 3 , CN, OC(=L)J 1 , OC(=L)NJ 1 J 2 and NJ 3 C(=L)NJ 1 J 2 , wherein each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl and L is O, S or NJ 1 .

8. The gapped oligomeric compound of claim 7 wherein Q is 4′-[CH(R 1 )] n —O-2′ wherein R j is H, alkyl or substituted alkyl and n is from 1 to 3.

9. The gapped oligomeric compound of claim 8 wherein R 1 is H or methyl.

10. The gapped oligomeric compound of claim 9 wherein n is 1.

11. The gapped oligomeric compound of claim 7 wherein said oligomeric compound further comprises at least one 3′ or 5′-linked terminal group.

12. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group that is not a neutral internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.

13. The gapped oligomeric compound of claim 1 wherein each Bx is, independently, uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

14. The gapped oligomeric compound of claim 7 comprising at least one region of from 1 to about 5 contiguous bicyclic nucleosides of formula Ia.

15. The gapped oligomeric compound of claim 7 wherein each linked monomeric subunit that is not a bicyclic nucleoside having formula Ia is, independently, a β-D-2′-deoxyribonucleoside or a modified nucleoside.

16. The gapped oligomeric compound of claim 15 wherein each of the modified nucleosides is, independently, a 2′-modified nucleoside, a 4′-thio modified nucleoside or a 4′-thio-2′-modified nucleoside.

17. The gapped oligomeric compound of claim 14 wherein each linked monomeric subunit that is not a bicyclic nucleoside of formula Ia is a β-D-2′-deoxyribonucleoside.

18. The gapped oligomeric compound of claim 7 wherein each external region independently comprises from 1 to 5 contiguous bicyclic nucleosides of formula Ia.

19. The gapped oligomeric compound of claim 18 wherein each monomeric subunit in the internal region is, independently, a β-D-2′-deoxyribonucleoside or a modified nucleoside.

20. The gapped oligomeric compound of claim 19 wherein essentially each monomeric subunit in the internal region is a β-D-2′-deoxyribonucleoside.

21. The gapped oligomeric compound of claim 18 wherein each external region independently comprises from 1 to 3 bicyclic nucleosides of formula Ia.

22. The gapped oligomeric compound of claim 18 wherein each internucleoside linking group that is not a neutral internucleoside linkage is, independently, a phosphodiester or a phosphorothioate.

23. A method comprising contacting a cell with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA.

24. The method of claim 23 wherein said cell is in a human.

25. The method of claim 23 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA.

26. The method of claim 23 further comprising evaluating the antisense activity of said oligomeric compound on said cell wherein said evaluating comprises detecting the levels of target RNA and or a protein.

Assignees

• Seth Punit P
• Swayze Eric E
• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Swayze Eric E

Classifications

• C07H21/00 Primary

  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