5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
The invention provides 5-deuterium-enriched 2,4-thiazolidinediones (e.g., 5-[4-[2-(5-ethyl-2-pyridyl)-2-oxoethoxy]benzyl]-5-deutero-thiazolidine-2,4-dione), deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same.
1. A method of treating a disorder selected from the group consisting of adrenoleukodystrophy (ALD), nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), the method comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of formula IIa or IIb or a pharmaceutically acceptable salt form thereof:
wherein:
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are H;
R 1 is H or D, provided that the abundance of deuterium in R 1 is at least 90%;
Z is H or D, provided that the abundance of deuterium in Z is at least 30%;
R 10 is H and R 11 is OH or OD; or
R 10 and R 11 are taken together with the carbon to which they are attached to form a carbonyl;
R A is ethyl;
wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 5%.
2. The method of claim 1 , wherein R 10 is H and R 11 is OH.
3. The method of claim 1 , wherein R 10 and R 11 are taken together with the carbon to which they are attached to form a carbonyl.
4. The method of claim 3 , wherein the abundance of deuterium in Z is at least 50%.
5. The method of claim 3 , wherein the abundance of deuterium in Z is at least 80%.
6. The method of claim 3 , wherein the abundance of deuterium in Z is at least 90%.
7. The method of claim 3 , wherein the abundance of deuterium in Z is at least 95%.
8. The method of claim 3 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 80%, and Z is H or D, provided that the abundance of deuterium in Z is at least 50%.
9. The method of claim 8 , wherein the abundance of deuterium in Z is at least 80%.
10. The method of claim 8 , wherein the abundance of deuterium in Z is at least 90%.
11. The method of claim 8 , wherein the abundance of deuterium in Z is at least 95%.
12. The method of claim 1 , wherein the compound is of formula IIa,
R 10 and R 11 are taken together with the carbon to which they are attached to form a carbonyl, the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 80%, and that the abundance of deuterium in Z is at least 50%.
13. The method of claim 12 , wherein the abundance of deuterium in Z is at least 80%.
14. The method of claim 12 , wherein the abundance of deuterium in Z is at least 90%.
15. The method of claim 12 , wherein the abundance of deuterium in Z is at least 95%.
16. The method of claim 14 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 90%.
17. The method of claim 14 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 95%.
18. The method of claim 1 , wherein the compound is of formula IIb,
R 10 and R 11 are taken together with the carbon to which they are attached to form a carbonyl, the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 80%, and that the abundance of deuterium in Z is at least 50%.
19. The method of claim 18 , wherein the abundance of deuterium in Z is at least 80%.
20. The method of claim 18 , wherein the abundance of deuterium in Z is at least 90%.
21. The method of claim 18 , wherein the abundance of deuterium in Z is at least 95%.
22. The method of claim 20 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 90%.
23. The method of claim 20 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 95%.
24. The method of claim 1 , wherein the abundance of deuterium in Z is at least 80%.
25. The method of claim 1 , wherein the compound is in a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.
26. The method of claim 3 , wherein the compound is in a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.
27. The method of claim 12 , wherein the compound is in a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.
28. The method of claim 18 , wherein the compound is in a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.