Fatty acid niacin conjugates and their uses
The invention relates to fatty acid niacin conjugates; compositions comprising an effective amount of a fatty acid niacin conjugate; and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate.
1. A compound of Formula I:
or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof;
wherein
R 1 , R 2 , and R 3 are each independently selected from the group consisting of —H, -D, —Cl, —F, —CN, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , —NH(C(O)C 1 -C 3 alkyl), —N(C(O)C 1 -C 3 alkyl) 2 , —C(O)H, —C(O)C 1 -C 3 alkyl, —C(O)OC 1 -C 3 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, —S(O)C 1 -C 3 alkyl, and —S(O) 2 C 1 -C 3 alkyl;
W 1 and W 2 are each NR;
each a, b, c, and d is independently —H, -D, Halogen, —CH 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , or —C(O)OR, —O—Z, or benzyl, or two of a, b, c, and d can be taken together along with the single carbon to which they are bound to form a cycloalkyl or heterocycle;
each n, o, p, and q is independently 0 or 1;
each L is independently —O—, —S—, —S(O)—, —S(O) 2 —, —S—S—,
each g is independently 2, 3 or 4;
each h is independently 1, 2, 3 or 4;
each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different;
each m1 is independently 0, 1, 2, or 3;
k is 0, 1, 2, or 3;
each R 6 is independently H or C 1 -C 6 alkyl, or both R 6 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;
each R 7 is independently e, H or straight or branched C 1 -C 10 alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine;
each e is independently H or any one of the side chains of the naturally occurring amino acids;
each R 9 is independently —H, -D, C 1 -C 4 alkyl, halogen, cyano, oxo, thiooxo, —OH, C(O)C 1 -C 4 alkyl, O-aryl, O-benzyl, OC(O)C 1 -C 4 alkyl, C 1 -C 3 alkene, C 1 -C 3 alkyne, C(O)C 1 -C 4 alkyl, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , NH(C(O)C 1 -C 3 alkyl), N(C(O)C 1 -C 3 alkyl) 2 , SH, S(C 1 -C 3 alkyl), S(O)C 1 -C 3 alkyl, S(O) 2 C 1 -C 3 alkyl;
each Z is independently —H,
with the proviso that there is at least one
each r is independently 2, 3, or 7;
each s is independently 3, 5, or 6;
each t is independently 0 or 1;
each v is independently 1, 2, or 6;
R 4 and R 5 are each independently hydrogen, deuterium, —C 1 -C 4 alkyl, -halogen, —OH, —C(O)C 1 -C 4 alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4 alkyl, —C 1 -C 3 alkene, —C 1 -C 3 alkyne, —C(O)C 1 -C 4 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , —NH(C(O)C 1 -C 3 alkyl), —N(C(O)C 1 -C 3 alkyl) 2 , —SH, —S(C 1 -C 3 alkyl), —S(O)C 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl; and
each R is independently —H, or straight or branched C 1 -C 4 alkyl optionally substituted with OR, NR 2 , or halogen.
2. The compound of claim 1 , wherein Z is
3. The compound of claim 2 , wherein t is 1.
4. The compound of claim 3 , wherein r is 2 and s is 6.
5. The compound of claim 3 , wherein r is 3 and s is 5.
6. The compound of claim 3 , wherein r is 7 and s is 3.
7. The compound of claim 4 , wherein L is —S—S—.
8. The compound of claim 4 , wherein L is —O—.
9. The compound of claim 4 , wherein L is
10. The compound of claim 4 , wherein L is
11. The compound of claim 4 , wherein L is
12. The compound of claim 4 , wherein L is
13. The compound of claim 4 , wherein one of n, o, p, and q are each 1.
14. The compound of claim 4 , wherein two of n, o, p, and q are each 1.
15. The compound of claim 4 , wherein m is 1, n, o, p, and q are each 1, and L is O.
16. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 1, and L is —S—S—.
17. The compound of claim 4 , wherein m, n, and o are each 0, and p and q are each 1.
18. The compound of claim 4 , wherein m is 1, n, o, p, and q are each 0, and L is
19. The compound of claim 4 , wherein m is 1, n and o are each 1, p and q are each 0, and L is
20. The compound of claim 4 , wherein m is 1, n, o, p, and q are each 1, and L is
21. The compound of claim 4 , wherein m is 1, n, o, p, and q are each 1, and L is NR 6 .
22. The compound of claim 4 , wherein m is 1, n and o are each 1, p and q are each 0, and L is
23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
24. The compound of claim 5 , wherein L is —S—S—.
25. The compound of claim 5 , wherein L is —O—.
26. The compound of claim 5 , wherein L is
27. The compound of claim 5 , wherein L is
28. The compound of claim 5 , wherein L is
29. The compound of claim 5 , wherein L is
30. The compound of claim 5 , wherein one of n, o, p, and q is 1.
31. The compound of claim 5 , wherein two of n, o, p, and q are each 1.
32. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 1, and L is O.
33. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 1, and L is —S—S—.
34. The compound of claim 5 , wherein m, n, and o are each 0, and p and q are each 1.
35. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 0, and L is
36. The compound of claim 5 , wherein m is 1, n and o are each 1, p and q are each 0, and L is
37. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 1, and L is
38. The compound of claim 5 , wherein m is 1, n, o, p, and q are each 1, and L is NR 6 .
39. The compound of claim 5 , wherein m is 1, n and o are each 1, p and q are each 0, and L is
40. The compound of claim 5 , wherein m is 0, n, o, are each 1, p and q are each 0, and a and b are each —H.