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 desazadesferrithiocin analog of the 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.
2. An analog of claim 1 wherein R 1 is H or —CH 3 .
3. An analog of claim 1 wherein R 2 is H or —OCH 3 .
4. An analog of claim 1 wherein —OR 3 is —O—[(CH 2 ) 2 —O] 3 —CH 3 .
5. A pharmaceutical composition comprising at least one analog of claim 1 , or a salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier therefor.
6. A pharmaceutical composition of claim 5 , wherein R 1 is H or —CH 3 .
7. A pharmaceutical composition of claim 5 , wherein R 2 is H or —OCH 3 .
8. A pharmaceutical composition of claim 5 , wherein —O—R 3 is —O—[(CH 2 ) 2 —O] 3 —CH 3 .
9. The analog of claim 1 , wherein R 4 and R 5 are each H.
10. (R)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof.
11. A mixture of (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof, and (R)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxyl)phenyl]-4-methyl-4-thiazolecarboxylic acid, or a salt, hydrate, or solvate thereof.
12. The mixture of claim 11 , wherein said mixture is racemic.
13. A pharmaceutical composition comprising the compound of claim 10 , or a salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising the mixture of claim 11 , and optionally a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , wherein said mixture is racemic.
16. An analog of claim 1 , wherein R 1 is —CH 3 .
17. An analog of claim 1 , wherein R 2 is H.
18. An analog of claim 1 , wherein each instance of n is 2.
19. A pharmaceutical composition of claim 5 , wherein R 1 is —CH 3 .
20. A pharmaceutical composition of claim 5 , wherein R 2 is H.
21. A pharmaceutical composition of claim 5 , wherein each of R 4 and R 5 is H.
22. A pharmaceutical composition of claim 5 , wherein each instance of n is 2.
23. An analog of claim 1 , wherein the salt is an alkali or alkaline earth metal salt.
24. An analog of claim 1 , wherein the salt is a sodium salt, potassium salt, magnesium salt, or calcium salt.