Ligand-conjugated monomers
View Patent ↗This invention relates composition and methods for making and using chemically modified oligonucleotides agents for inhibiting gene expression.
1. A compound having the formula:
wherein:
y ranges from 4-11;
DMTr is a dimethoxytrityl group;
R is H or —CH 3 ; and
R′ is —CH 3 or a lipophilic moiety selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesterol residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine,
or R and R′, together with the nitrogen to which they are bound, form a
group.
2. The compound of claim 1 , wherein y is 5; R is H; and R′ is a lipophilic moiety selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesterol residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine,
3. The compound of claim 2 , wherein the lipophilic moiety is selected from the group consisting of:
4. A compound of claim 1 , wherein the compound is compound (7):
5. The compound of claim 1 , wherein the compound is compound (13):
6. The compound of claim 1 , wherein the compound is compound (20):
7. The compound of claim 1 , wherein the compound is compound (26):
8. The compound of claim 1 , wherein the compound is compound (45a):
9. The compound of claim 1 , wherein the compound is compound (229a):
10. The compound of claim 1 , wherein the compound is compound (229b):
11. The compound of claim 1 , wherein the compound is compound (212a):
12. The compound of claim 1 , wherein the compound is compound (100a):
13. The compound of claim 1 , wherein the compound is compound (212b):
14. The compound of claim 1 , wherein the compound is compound (95):
15. The compound of claim 1 , wherein the compound is compound (45b):
16. The compound of claim 1 , wherein the compound is compound (85):
17. The compound of claim 1 , wherein the compound is compound (91):
18. The compound of claim 1 , wherein the compound is compound (106):
19. The compound of claim 1 , wherein the compound is compound (112):
20. A compound having the formula:
wherein:
y ranges from 4-11;
DMTr is a dimethoxytrityl group;
is any solid support;
R is H or —CH 3 ; and
R′ is —CH 3 or a lipophilic moiety selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesterol residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine,
; or R and R′, together with the nitrogen to which they are bound, form a
group.
21. The compound of claim 20 , wherein y is 5; R is H; and R′ is a lipophilic moiety selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesterol residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, phenoxazine,
22. The compound of claim 21 , wherein the lipophilic moiety is selected from the group consisting of:
23. The compound of claim 20 , wherein the compound is compound (9):
24. The compound of claim 20 , wherein the compound is compound (15):
25. The compound of claim 20 , wherein the compound is compound (22):
26. The compound of claim 20 , wherein the compound is compound (28):
27. The compound of claim 20 , wherein the compound is compound (46a):
28. The compound of claim 20 , wherein the compound is compound (230a):
29. The compound of claim 20 , wherein the compound is compound (230b):
30. The compound of claim 20 , wherein the compound is compound (211a):
31. The compound of claim 20 , wherein the compound is compound (102):
32. The compound of claim 20 , wherein the compound is compound (211b):
33. The compound of claim 20 , wherein the compound is compound (97):
34. The compound of claim 20 , wherein the compound is compound (46b):
35. The compound of claim 20 , wherein the compound is compound (87):
36. The compound of claim 20 , wherein the compound is compound (93):
37. The compound of claim 20 , wherein the compound is compound (106):
38. The compound of claim 20 , wherein the compound is compound (114):
39. The compound of claim 1 , wherein the lipophilic moiety is selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesteryl residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, and phenoxazine.
40. The compound of claim 20 , wherein the lipophilic moiety is selected from the group consisting of a lipid, cholesterol, oleyl, retinyl, cholesteryl residues, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, and phenoxazine.