Bicyclic cyclohexitol nucleic acid analogs
View Patent ↗The present disclosure provides bicyclic cyclohexitol nucleoside analogs of formula I and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are expected to be useful for enhancing properties of oligomeric compounds including for example nuclease resistance.
1. A bicyclic nucleoside analog having formula I:
wherein:
Bx is a heterocyclic base moiety;
Z is O or S;
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 and q 2 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;
Q consists of from 1 to 4 linked biradical groups independently selected from —O—, —S—, —N(R 1 )—, —C(R 1 )(R 2 )—, —C(R 1 )═C(R 2 )—, —C(R 1 )═N—, —C(═NR 1 )—, Si(R 1 )(R 2 )—, —SO 2 —, —SO—, —C(═O)— and —C(═S)—;
each R 1 and R 2 is, 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, substituted C 2 -C 6 alkynyl, halogen, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 or CN, wherein each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, Substituted C 1 -C 6 alkyl or a protecting group; and
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, OE 1 , NE 1 E 2 , SE 1 , N 3 , OC(═O)E 1 and CN, wherein each E 1 and E 2 is, independently, H, C 1 -C 6 alkyl or a protecting group.
2. The bicyclic nucleoside analog of claim 1 , wherein Z is O.
3. The bicyclic nucleoside analog of claim 1 , wherein q 1 and q 2 are each H.
4. The bicyclic nucleoside analog of claim 1 , wherein at least one of q 1 and q 2 is other than H.
5. The bicyclic nucleoside analog of claim 1 , wherein at least one of q 1 and q 2 is methyl.
6. The bicyclic nucleoside analog of claim 1 wherein Bx is uracil, 5 thiazolo-uracil, 2-thio-uracil, 5-propynyl-uracil, thymine, 2′-thio-thymine, cytosine, 5-methylcytosine, 5-thiazolo-cytosine, 5-propynyl-cytosine, adenine, guanine, 2,6-diamino purine, 1H-pyrimido[5,4-][1,4benzoxazin-2(3H)-one), 1H-pyrimido [5,4-b][1,4]benzothiazin-2(3H)-one, 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H) -one, 2H-pyrimido[4,5-b]indol-2-one or H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one.
7. The bicyclic nucleoside analog of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, 2,6-diaminopurine, adenine or guanine.
8. The bicyclic nucleoside analog of claim 1 wherein T 1 is acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4′-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substituted pixyl.
9. The bicyclic nucleoside analog of claim 1 , wherein T 1 is acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or dimethoxytrityl.
10. The bicyclic nucleoside analog of claim 1 , wherein T 1 is 4,4′-dimethoxytrityl.
11. The bicyclic nucleoside analog of claim 1 , wherein T 2 is diisopropylcyanoethoxy phosphoramidite or H-phosphonate.
12. The bicyclic nucleoside analog of claim 1 , wherein T 2 is diiso-propylcyanoethoxy phosphoramidite.
13. The bicyclic nucleoside analog of claim 1 , wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.
14. The bicyclic nucleoside analog of claim 1 , wherein Q consists of from 2 to 4 of said linked biradical groups.
15. The bicyclic nucleoside analog of claim 1 , wherein Q consists of 2 or 3 of said linked biradical groups.
16. The bicyclic nucleoside analog of claim 1 , wherein Q comprises 1 of said biradical groups.
17. The bicyclic nucleoside analog of claim 1 , having the configuration:
18. The bicyclic nucleoside analog of claim 1 , wherein Q is —O—[C(R 1 )(R 2 )] n — wherein n is 1 or 2.
19. The bicyclic nucleoside analog of claim 1 , having formula II:
wherein:
n is 1 or 2.
20. The bicyclic nucleoside analog of claim 19 , wherein Z is O.
21. The bicyclic nucleoside analog of claim 20 , wherein q 1 and q 2 are each H.
22. The bicyclic nucleoside analog of claim 21 , wherein R 1 and R 2 are each H.
23. The bicyclic nucleoside analog of claim 22 , wherein n is 1.
24. The bicyclic nucleoside analog of claim 22 , wherein n is 2.
25. An oligomeric compound comprising at least one bicyclic nucleoside analog having formula III:
wherein independently for each of said at least one bicyclic nucleoside analog having formula III:
Bx is a heterocyclic base moiety;
Z is O or S;
T 3 and T 4 are each, independently, an internucleoside linking group linking the bicyclic nucleoside analog to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the bicyclic nucleoside analog to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a linked conjugate group or a 5′ or 3′-terminal group;
q 1 and q 2 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 C2-C 6 alkynyl;
Q comprises from 1 to 4 linked biradical groups independently selected from —O—, —S—, —N(R 1 )—, —C(R 1 )(R 2 )—, —C(R 1 )═C(R 2 )—, —C(R 1 )═N—, —C(═NR 1 )—, —Si(R 1 )(R 2 )—, —SO 2 —, —SO—, —C(═O)— and —C(═S)—;
each R 1 and R 2 is, 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, substituted C 2 -C 6 alkynyl, halogen, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 or CN, wherein each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl or a protecting group; and
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, OE 1 , NE 1 E 2 , SE 1 , N 3 , OC(═O)E 1 and CN, wherein each E 1 and E 2 is, independently, H, C 1 -C 6 alkyl or a protecting group.
26. The oligomeric compound of claim 25 , wherein each Z is O.
27. The oligomeric compound of claim 25 , wherein each q 1 and q 2 is H.
28. The oligomeric compound of claim 25 , wherein at least one of q 1 or q 2 is other than H for each of said bicyclic nucleoside analogs having formula III.
29. The oligomeric compound of claim 25 , wherein at least one of q 1 or q 2 is methyl for each of said bicyclic nucleoside analogs having formula III.
30. The oligomeric compound of claim 25 , wherein Q comprises from 2 to 4 of said linked biradical groups for each of said bicyclic nucleoside analogs having formula III.
31. The oligomeric compound of claim 25 , wherein Q comprises from 2 or 3 of said linked biradical groups for each of said bicyclic nucleoside analogs having formula III.
32. The oligomeric compound of claim 25 , wherein Q comprises 1 of said biradical groups for each of said bicyclic nucleoside analogs having formula III.
33. The oligomeric compound of claim 25 , wherein each of said bicyclic nucleoside analogs has the configuration:
34. The oligomeric compound of claim 25 , wherein Q is —O—[C(R 1 )(R 2 )] n — and n is 1 or 2, for each of said bicyclic nucleoside analogs having formula III.
35. The oligomeric compound of claim 25 , wherein each bicyclic nucleoside analog has formula IV:
wherein:
n is 1 or 2.
36. The oligomeric compound of claim 35 , wherein each Z is O.
37. The oligomeric compound of claim 35 , wherein each q 1 and q 2 is H.
38. The oligomeric compound of claim 35 , wherein each R 1 and R 2 is H.
39. The oligomeric compound of claim 35 , wherein each n is 1.
40. The oligomeric compound of claim 35 , wherein each n is 2.
41. The bicyclic nucleoside analog of claim 1 having the formula:
wherein m is 1 or 2.
42. The oligomeric compound of claim 35 , having the formula:
wherein m is 1 or 2.