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 deuterium-enriched compound, wherein the compound is a compound of formula III or a stereoisomer or pharmaceutically acceptable salt form thereof:
wherein:
R 10 is H or D;
Z is H or D, provided that the abundance of deuterium in Z is at least 30%;
R A is C 1-2 alkyl; and
R 11 is selected from OH and OD.
2. The deuterium-enriched compound of claim 1 , wherein the compound is a compound of formula IIIa or IIIb or a pharmaceutically acceptable salt form thereof:
wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 5%.
3. The deuterium-enriched compound of claim 1 , wherein the compound is a compound of formula IIIc, IIId, IIIe, or IIIf or a pharmaceutically acceptable salt form thereof:
wherein:
R 10 is D;
Z is H or D, provided that the abundance of deuterium in Z is at least 30%;
R A is C 1-2 alkyl;
R 11 is selected from OH and OD; wherein the compound has a stereomeric purity of at least 5%.
4. The deuterium-enriched compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R A is ethyl; and Z is H or D, provided that the abundance of deuterium in Z is at least 50%.
5. The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in Z is at least 80%.
6. The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in Z is at least 95%.
7. The deuterium-enriched compound of claim 2 , or a pharmaceutically acceptable salt form thereof, wherein R A is ethyl; and 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%.
8. The deuterium-enriched compound of claim 7 , wherein the abundance of deuterium in Z is at least 80%.
9. The deuterium-enriched compound of claim 7 , wherein the abundance of deuterium in Z is at least 95%.
10. The deuterium-enriched compound of claim 7 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 90%.
11. The deuterium-enriched compound of claim 7 , wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 95%.
12. The deuterium-enriched compound of claim 3 , wherein the compound has an enantiomeric excess, with respect to the C(R 10 R 11 ) carbon, of at least 80%.
13. The deuterium-enriched compound of claim 3 , wherein the compound has an enantiomeric excess, with respect to the C(R 10 R 11 ) carbon, of at least 90%.
14. The deuterium-enriched compound of claim 3 , wherein the compound has an enantiomeric excess, with respect to the C(R 10 R 11 ) carbon, of at least 95%.
15. The deuterium-enriched compound of claim 2 wherein the abundance of deuterium in Z is selected from: (a) at least 40%, (b) at least 50%, (c) at least 60%, (d) at least 70%, (e) at least 80%, (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%.
16. The deuterium-enriched compound of claim 2 , wherein the enantiomeric excess, with respect to the C—Z carbon, or stereomeric purity is selected from: (a) at least 10%, (b) at least 20%, (c) at least 30%, (d) at least 40%, (e) at least 50%, (f) at least 60%, (g) at least 70%, (h) at least 80%, (i) at least 90%, (j) at least 95%, (k) at least 97%, (1) at least 98%, and (m) at least 99%.
17. The deuterium-enriched compound of claim 3 , wherein the enantiomeric excess, with respect to the C(R 10 R 11 ) carbon, or stereomeric purity is selected from: (a) at least 10%, (b) at least 20%, (c) at least 30%, (d) at least 40%, (e) at least 50%, (f) at least 60%, (g) at least 70%, (h) at least 80%, (i) at least 90%, (j) at least 95%, (k) at least 97%, (1) at least 98%, and (m) at least 99%.
18. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 2 .
19. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 7 .
20. A method of treating a metabolic inflammation mediated disease selected from the group consisting of Type I diabetes, Type II diabetes, insulin resistance, and inadequate glucose tolerance, comprising administering to a patient in need thereof a therapeutically effective amount a compound of claim 2 to treat the disease.
21. The method of claim 20 , wherein the disease is Type II diabetes.