Fatty acid niacin conjugates and their uses

1. A method for treating a metabolic disease selected from dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, atherosclerosis, Type 2 diabetes, diabetic nephropathy, metabolic syndrome, and cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes, the method comprising administering to a patient in need thereof an effective amount of 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 independently null, O, S, NH, NR, or W 1 and W 2 can be taken together can form an imidazolidine or piperazine group, with the proviso that W 1 and W 2 can not be O simultaneously;

each a, b, c, and d is independently —H, -D, —CH 3 , —OCH 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 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 Z is independently —H, or

with the proviso that there is at least one

in the compound;

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 —C 1 -C 3 alkyl;

provided that

when m, n, o, p, and q are each 0, W 1 and W 2 are each null, and Z is

then t must be 0; and

when each of m, n, o, p, and q is 0, and W 1 and W 2 are each null, then Z must not be

2. The method of claim 1 , wherein the metabolic disease is hypertriglyceridemia.

3. The method of claim 1 , wherein the metabolic disease is hypercholesterolemia.

4. The method of claim 1 , wherein the metabolic disease is fatty liver disease.

5. The method of claim 4 , wherein the fatty liver disease is nonalcoholic fatty liver disease (NAFLD).

6. The method of claim 1 , wherein W 1 and W 2 are each NR.

7. The method of claim 1 , wherein Z is

r is 3;

s is 5; and

t is 1.

8. The method of claim 1 , wherein Z is

r is 2;

s is 6; and

t is 1.

9. The method of claim 1 , wherein the compound of Formula I is

N-(2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)disulfanyl)ethyl)nicotinamide.

10. The method of claim 1 , wherein the compound of Formula I is

N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)nicotinamide.

11. The method of claim 1 , wherein the compound of Formula I is:

N-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethyl)nicotinamide.

12. The method of claim 1 , wherein the compound of Formula I is

(S)-6-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-2-(nicotinamido)hexanoic acid.

13. The method of claim 1 , wherein the compound of Formula I is

(S)-2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoic acid.

14. A method for treating a metabolic disease selected from dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, atherosclerosis, Type 2 diabetes, diabetic nephropathy, metabolic syndrome, and cardiovascular disease associated with dyslipidemia, hypertriglyceridemia, hypercholesterolemia, or Type 2 diabetes, the method comprising administering to a patient in need thereof an effective amount of a molecular conjugate comprising a niacin and a fatty acid selected from α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid, and wherein the conjugate comprises at least two amides.

15. The method of claim 14 , wherein the metabolic disease is hypertriglyceridemia.

16. The method of claim 14 , wherein the metabolic disease is hypercholesterolemia.

17. The method of claim 14 , wherein the metabolic disease is fatty liver disease.

18. The method of claim 14 , wherein the metabolic disease is nonalcoholic fatty liver disease (NAFLD).