Lipoic acid acylated salicylate derivatives and their uses

1. A molecular conjugate comprising a lipoic acid and an ortho salicylate wherein the lipoic acid and the ortho salicylate are conjugated through at least two amides.

2. A compound of Formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, or stereoisomer thereof;

wherein

R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, 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 S, NR, or W 1 and W 2 can be taken together can form an imidazolidine or piperazine group;

each symbol ----- represents an optional bond, which when present between the phenolic oxygen and the methylene containing substituent a, requires that Q is null, or when present between substituent a and the carbon of the methylene containing substituent a, requires that Q not be null;

each a, b, c, and d is independently —H, -D, —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, —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, 1, or 2;

each L is independently —O—, —S—, —S(O)—, —S(O) 2 —, —S—S—,-(C 1 -C 6 alkyl)-

wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1 side of the compound of Formula I;

each g is independently 2, 3 or 4;

each h is independently 1, 2, 3 or 4;

m is 0, 1, 2, or 3; if m is more than 1, then L can be the same or different;

each R 5 is independently H or C 1 -C 6 alkyl, or both R 5 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;

each R 6 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 t is independently 0 or 1;

Q is null, C(O)CH 3 , Z,

W 3 is null, —O—, or —N(R)—;

each R is independently H, —C(O)—C 1 -C 3 alkyl, or straight or branched C 1 -C 4 alkyl optionally substituted with or halogen; and

T is H, C(O)CH3, or Z.

3. The compound of claim 2 selected from a group consisting of

(S)—N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)-2-hydroxybenzamide (I-1);

(S)—N-(2-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)disulfanyl)ethyl)-2-hydroxybenzamide (I-2);

(S)—N-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethoxy)ethyl)-2-hydroxybenzamide (I-3);

(S)—N-(2-((2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)(methyl)amino)ethyl)-2-hydroxybenzamide (I-4);

6-(5-(1,2-dithiolan-3-yl)pentanamido)-2-(2-hydroxybenzamido)hexanoic acid (I-8);

3-hydroxy-2-(hydroxymethyl)propyl 6-(5-(1,2-dithiolan-3-yl)pentanamido)-2-(2-hydroxybenzamido)hexanoate (I-9);

2-(5-(1,2-dithiolan-3-yl)pentanamido)-6-(2-hydroxybenzamido)hexanoic acid (I-11);

3-hydroxy-2-(hydroxymethyl)propyl 2-(5-(1,2-dithiolan-3-yl)pentanamido)-6-(2-hydroxybenzamido)hexanoate (I-12); and

N-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethylamino)ethyl)-2-hydroxybenzamide (I-24).

4. A pharmaceutical composition comprising a molecular conjugate comprising a lipoic acid and an ortho salicylate wherein the lipoic acid and the ortho salicylate are conjugated through at least two amides and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

6. The compound of claim 2 , wherein W 1 and W 2 are each independently NR, wherein R is hydrogen.

7. The compound of claim 2 , wherein m is 0.

8. The compound of claim 2 , wherein m is 1.

9. The compound of claim 2 , wherein L is —S—S—.

10. The compound of claim 2 , wherein L is —O—.

11. The compound of claim 2 , wherein L is

12. The compound of claim 2 , wherein L is

13. The compound of claim 2 , wherein n, o, p and q are each 1.

14. The compound of claim 2 , wherein two of n, o, p and q are each 1.

15. The compound of claim 2 , wherein Z is

16. The compound of claim 2 , wherein Z is

17. The compound of claim 2 , wherein Z is

18. The compound of claim 2 , wherein W 1 and W 2 are each NR, n, o, p and q are each 1, t is 1, L is —S—S—, and each R is hydrogen.

19. The compound of claim 2 , wherein W 1 and W 2 are each NR, n, o, p and q are each 1, t is 1, L is —O—, and each R is hydrogen.

20. The compound of claim 2 , wherein, W 1 and W 2 are each NR, n, o, p and q are each 1, t is 1, each R is hydrogen and L is

wherein R5 is C 1 -C 3 alkyl.