Desferrithiocin polyether analogues
View Patent ↗A relatively non-toxic desazadesferrithiocin analog having the formula: wherein: R 1 , R 2 , R 4 and R 5 may be the same or different and may be H, straight or branched chain alkyl having up to 14 carbon atoms, e.g., methyl, ethyl, propyl and butyl, or arylalkyl wherein the aryl portion is hydrocarbyl and the alkyl portion is straight or branched chain, the arylalkyl group having up to 14 carbon atoms, R 2 optionally being alkoxy having up to 14 carbon atoms; R 3 is [(CH 2 ) n —O] x —[(CH 2 ) n —O] y -alkyl; n is, independently, an integer from 1 to 8; x is an integer from 1 to 8; y is an integer from 0 to 8, and R 3 O may occupy any position on the phenyl ring except the 4-position, or a salt, hydrate or solvate thereof; and methods and compositions for treating the effects of trivalent metal, i.e., iron, overload.
1. A method of treating a pathological condition in a subject comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula:
wherein:
R 1 , R 4 , and R 5 are the same or different and are H, straight or branched chain alkyl having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 2 is H, straight or branched chain alkyl having up to 14 carbon atoms, alkoxy having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 3 is —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y -alkyl;
n is, independently, an integer from 1 to 8;
x is 3;
y is 0; and
—OR 3 occupies the 3-position on the phenyl ring; or a salt, hydrate, or solvate thereof;
wherein the pathological condition is metal overload, diabetes, liver disease, Friedreich ataxia (FRDA), heart disease, or radiation injury.
2. The method of claim 1 , wherein R 1 is H or —CH 3 .
3. The method of claim 1 wherein R 2 is H or —OCH 3 .
4. The method of claim 1 , wherein —OR 3 is —O—[(CH 2 ) 2 —O] 3 —CH 3 .
5. The method of claim 1 , wherein R 4 and R 5 are each H.
6. The method of claim 1 , wherein R 1 is —CH 3 .
7. The method of claim 1 , wherein R 2 is H.
8. The method of claim 1 , wherein each instance of n is 2.
9. The method of claim 1 , wherein the salt is an alkali or alkaline earth metal salt.
10. The method of claim 1 , wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.
11. The method of claim 1 , wherein the metal is trivalent.
12. The method of claim 1 , wherein the pathological condition is metal overload.
13. The method of claim 12 , wherein the metal overload is iron overload.
14. The method of claim 13 , wherein the iron overload is primary hemochromatosis.
15. The method of claim 13 , wherein the iron overload is secondary hemochromatosis.
16. The method of claim 13 , wherein the iron overload is focal iron overload.
17. The method of claim 13 , wherein the iron overload is thalassemia.
18. The method of claim 1 , wherein the pathological condition is diabetes.
19. The method of claim 1 , wherein the pathological condition is liver disease.
20. The method of claim 1 , wherein the pathological condition is Friedreich ataxia (FRDA).
21. The method of claim 1 , wherein the pathological condition is heart disease.
22. The method of claim 1 , wherein the pathological condition is radiation injury.
23. A method of treating iron overload due to blood transfusions in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula:
wherein:
R 1 , R 4 , and R 5 are the same or different and are H, straight or branched chain alkyl having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 2 is H, straight or branched chain alkyl having up to 14 carbon atoms, alkoxy having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 3 is —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y -alkyl;
n is, independently, an integer from 1 to 8;
x is 3;
y is 0; and
—OR 3 occupies the 3-position on the phenyl ring; or a salt, hydrate, or solvate thereof.
24. The method of claim 23 , wherein the desazadesferrithiocin analog is of the formula:
or a salt, hydrate, or solvate thereof.
25. The method of reducing oxidative stress in a subject comprising administering to the subject a therapeutically effective amount of a desazadesferrithiocin analog of formula:
wherein:
R 1 , R 4 , and R 5 are the same or different and are H, straight or branched chain alkyl having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 2 is H, straight or branched chain alkyl having up to 14 carbon atoms, alkoxy having up to 14 carbon atoms, or arylalkyl wherein the aryl portion is hydrocarbyl, the alkyl portion is straight or branched chain, and the arylalkyl group has up to 14 carbon atoms;
R 3 is —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y -alkyl;
n is, independently, an integer from 1 to 8;
x is 3;
y is 0; and
—OR 3 occupies the 3-position on the phenyl ring; or a salt, hydrate, or solvate thereof.
26. The method of claim 12 , wherein the metal overload is aluminum overload.
27. The method of claim 26 , wherein the desazadesferrithiocin analog is of the formula:
or a salt, hydrate, or solvate thereof.
28. The method of claim 20 , wherein the desazadesferrithiocin analog is of the formula:
or a salt, hydrate, or solvate thereof.
29. The method of claim 23 , wherein R 1 is H or —CH 3 .
30. The method of claim 23 wherein R 2 is H or —OCH 3 .
31. The method of claim 23 , wherein —OR 3 is —O—[(CH 2 ) 2 —O] 3 —CH 3 .
32. The method of claim 23 , wherein R 4 and R 5 are each H.
33. The method of claim 23 , wherein R 1 is —CH 3 .
34. The method of claim 23 , wherein R 2 is H.
35. The method of claim 23 , wherein each instance of n is 2.
36. The method of claim 23 , wherein the salt is an alkali or alkaline earth metal salt.
37. The method of claim 23 , wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.
38. The method of claim 25 , wherein R 1 is H or —CH 3 .
39. The method of claim 25 wherein R 2 is H or —OCH 3 .
40. The method of claim 25 , wherein —OR 3 is —O—[(CH 2 ) 2 —O] 3 —CH 3 .
41. The method of claim 25 , wherein R 4 and R 5 are each H.
42. The method of claim 25 , wherein R 1 is —CH 3 .
43. The method of claim 25 , wherein R 2 is H.
44. The method of claim 25 , wherein each instance of n is 2.
45. The method of claim 25 , wherein the salt is an alkali or alkaline earth metal salt.
46. The method of claim 25 , wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.
47. The method of claim 25 , wherein the desazadesferrithiocin analog is of the formula:
or a salt, hydrate, or solvate thereof.