Fatty acid acylated salicylates and their uses

1. A synergistically active molecular conjugate comprising a salicylate and a fatty acid

wherein the salicylate is selected from the group consisting of substituted or unsubstituted salicylic acid, aminosalicylic acid, diflunisal, and triflusal, and

wherein the fatty acid is selected from the group consisting of all-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid, or tetracosahexaenoic acid;

with the proviso that when the molecular conjugate comprises a fatty acid containing seven contiguous unsubstituted methylene units, the methylene units must be preceded by an adjacent carbonyl moiety,

wherein the synergistic activity is derived from in vivo delivery of the salicylate and of the fatty acid to a target tissue or a target cell together.

2. A compound of Formula I,

or a pharmaceutically acceptable salt, 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, difluorophenyl, and trifluoromethyl;

W 1 and W 2 are each independently null or NH, or when W 1 and W 2 are both NH, then both W 1 and W 2 can be taken together to form a piperidine moiety;

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 and c is independently H, CH 3 , —OCH 3 , —OCH 2 CH 3 , C(O)OH, C(O)OR or benzyl;

each b is independently H, CH 3 , C(O)OH, O—Z, C(O)OR or benzyl;

each d is independently H, C(O)OH, C(O)OR or benzyl;

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;

m is 1, 2, or 3;

each R 7 is independently H or C 1 -C 6 alkyl, or both R 7 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;

each R 8 is independently e, H or straight or branched C 1 -C 10 which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine;

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, NR 2 , or halogen;

each Z is independently H or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

w is 0 or 1;

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

each e is independently H or any one of the side chains of the naturally occurring amino acids;

W 3 is null or —N(R)—; and

T is H, C(O)CH 3 , or Z;

provided that when w is 0, then W 1 is NH.

3. A compound of claim 2 , wherein W 1 and W 2 are each NH.

4. A compound of claim 3 , wherein r is 2, s is 6, w is 1, Z is

and t is 1.

5. A compound of claim 3 , wherein the compound is selected from the group consisting of:

6. A compound of claim 4 , wherein the compound is

7. A compound of claim 4 , wherein the compound is

8. A compound of claim 2 , wherein Q is Z.

9. A compound of claim 2 , wherein Q is

10. A compound of claim 2 , wherein m is 1 and L is —S—S— or —O—.

11. A compound of Formula III:

or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,

wherein

R 1 , 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, difluorophenyl, and trifluoromethyl;

each W 1 , W 1′ , W 2 and W 2′ is independently null, O, or NH, or when W 1 and W 2 or W 1′ and W 2′ are both NH, then both W 1 and W 2 or W 1′ and W 2′ can be taken together to form a piperidine moiety;

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, a′, c, and c′ is independently H, CH 3 , —OCH 3 , —OCH 2 CH 3 , C(O)OH, C(O)OR or benzyl;

each b and b′ is independently H, CH 3 , C(O)OH, O—Z, C(O)OR or benzyl;

each d and d′ is independently H, C(O)OH, C(O)OR or benzyl;

each n, n′, o, o′, p, p′, q, and q′ is independently 0 or 1;

each L and 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 and m′ is independently 0, 1, 2, or 3;

each R 7 is independently H or C 1 -C 6 alkyl, or both R 7 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;

each R 8 is independently e, H or straight or branched C 1 -C 10 which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine;

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, NR 2 , or halogen;

each Z and 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;

w is 0 or 1;

u is 0 or 1;

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

each e is independently H or any one of the side chains of the naturally occurring amino acids;

each W 3 is independently null, O, or —N(R)—; and

each T is independently H, C(O)CH 3 , or Z;

provided that

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

then t must be 0;

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

then t must be 0;

when w is 0, then W 1 is NH; and

when w is 1, Z is

and r is 7, then t is 1.

12. A compound of claim 11 , wherein Q is H.

13. A compound of Formula IIIa,

or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,

wherein

R 1 , 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, difluorophenyl, and trifluoromethyl;

each W 1 and W 2 is independently null, O, or NH, or when W 1 and W 2 are both NH, then both W 1 and W 2 can be taken together to form a piperidine moiety;

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 and c is independently H, CH 3 , —OCH 3 , —OCH 2 CH 3 , C(O)OH, C(O)OR or benzyl;

each b is independently H, CH 3 , C(O)OH, O—Z, C(O)OR or benzyl;

each d is independently H, C(O)OH, C(O)OR or benzyl;

each n, o, p, and q is independently 0 or 1;

each L is independently —O—, —S—, —S(O)—, —S(O) 2-5 —S—S—,

each g is independently 2, 3 or 4;

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

m is 0, 1, 2, or 3;

each R 7 is independently H or C 1 -C 6 alkyl, or both R 7 groups, when taken together with the nitrogen to which they are attached, can form a heterocycle;

each R 8 is independently e, H or straight or branched C 1 -C 10 which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine;

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, NR 2 , or halogen;

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;

with the proviso that when r is 7, s is 3;

each t is independently 0 or 1;

w is 0 or 1;

each Q is independently null, H, C(O)CH 3 , Z,

each e is independently H or any one of the side chains of the naturally occurring amino acids;

each W 3 is independently null, O, or —N(R)—; and

each T is independently H, C(O)CH 3 , or Z;

provided that

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

then t must be 0;

when w is 0, then W 1 is NH; and

when w is 1, Z is

and r is 7, then t is 1.

14. A compound of claim 13 , wherein at least one t is 1, and at least one Q is H.

15. A method of treating inflammation that is associated with a metabolic disorder selected from the group consisting of Type II diabetes, insulin resistance, atherosclerosis, dyslipidemia, retinopathy associated with diabetic complications, nephropathy associated with diabetic complications, neuropathy associated with diabetic complications, and macular edema associated with diabetic complications, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 2 .

16. The method of claim 15 , wherein Q is H.

17. A method of treating inflammation that is associated with an inflammatory bowel disease selected from the group consisting of ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 2 .

18. A method of treating inflammation that is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, amylotrophic lateral sclerosis, and multiple sclerosis, comprising administering to a patient in need thereof an effective amount of a compound of claim 2 .

19. A method of treating inflammation that is associated with Duchenne's muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of claim 2 .

20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

21. A method of treating inflammation that is associated with a metabolic disorder selected from the group consisting of Type II diabetes, insulin resistance, atherosclerosis, dyslipidemia, retinopathy associated with diabetic complications, nephropathy associated with diabetic complications, neuropathy associated with diabetic complications, and macular edema associated with diabetic complications, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 11 .

22. The method of claim 21 , wherein Q is H.

23. A method of treating inflammation associated with an inflammatory bowel disease selected from the group consisting of ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 11 .

24. A method of treating inflammation associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease and multiple sclerosis, comprising administering to a patient in need thereof an effective amount of a compound of claim 11 .

25. A method of treating inflammation associated with Duchenne's muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of claim 11 .

26. The method of claim 23 , wherein Q is H.

27. The method of claim 24 , wherein Q is H.

28. The method of claim 25 , wherein Q is H.

29. A method of treating inflammation that is associated with a metabolic disorder selected from the group consisting of Type II diabetes, insulin resistance, atherosclerosis, dyslipidemia, retinopathy associated with diabetic complications, nephropathy associated with diabetic complications, neuropathy associated with diabetic complications, and macular edema associated with diabetic complications, the method comprising administering to a patient in need thereof an effective amount of a compound of claim 13 .

30. The method of claim 29 , wherein at least one t is 1, and at least one Q is H.

31. A method of treating inflammation of treating inflammation that is associated with an inflammatory bowel disease selected from the group consisting of ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease, comprising administering to a patient in need thereof an effective amount of a compound of claim 13 .

32. The method of claim 31 , wherein at least one t is 1, and at least one Q is H.

33. A method of treating inflammation that is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease and multiple sclerosis, comprising administering to a patient in need thereof an effective amount of a compound of claim 13 .

34. The method of claim 33 , wherein at least one t is 1, and at least one Q is H.

35. A method of treating inflammation that is associated with Duchenne's muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of claim 13 .

36. The method of claim 35 , wherein at least one t is 1, and at least one Q is H.

37. A method of treating inflammation that is associated with a metabolic disorder selected from the group consisting of Type II diabetes, insulin resistance, atherosclerosis, dyslipidemia, retinopathy associated with diabetic complications, nephropathy associated with diabetic complications, neuropathy associated with diabetic complications, and macular edema associated with diabetic complications, the method comprising administering to a patient in need thereof an effective amount of the conjugate of claim 1 .

38. The method of claim 37 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).

39. The method of claim 38 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA).

40. A method of treating inflammation of treating inflammation that is associated with an inflammatory bowel disease selected from the group consisting of ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease, comprising administering to a patient in need thereof an effective amount of the conjugate of claim 1 .

41. The method of claim 40 , wherein the salicylate is aminosalicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).

42. The method of claim 41 , wherein the salicylate is aminosalicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA).

43. A method of treating inflammation that is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, amylotrophic lateral sclerosis, and multiple sclerosis, comprising administering to a patient in need thereof an effective amount of the conjugate of claim 1 .

44. The method of claim 43 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).

45. The method of claim 44 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA).

46. A method of treating inflammation that is associated with Duchenne's muscular dystrophy comprising administering to a patient in need thereof an effective amount of the conjugate of claim 1 .

47. The method of claim 46 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).

48. The method of claim 47 , wherein the salicylate is unsubstituted salicylic acid, and wherein the fatty acid is eicosapentaenoic acid (EPA).

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

50. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.

52. The compound

or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising the compound claim 52 or the pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

54. A method of treating inflammation that is associated with Duchenne's muscular dystrophy comprising administering to a patient in need thereof an effective amount of the compound of claim 52 or the pharmaceutically acceptable salt thereof.