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 pharmaceutical composition comprising a pharmaceutically acceptable carrier and a deuterium-enriched compound of Formula II or VII or a stereoisomer or pharmaceutically acceptable salt form of any of the foregoing, wherein Formula II is represented by:
wherein:
R 1 is selected from H and D;
Z is H or D, provided that the abundance of deuterium in Z is at least 30%;
R A is C 1-6 alkyl; and
R 11 is selected from OH and OD; and
Formula VII is represented by:
wherein:
R 1 is selected from H and D;
Z is H or D, provided that the abundance of deuterium in Z is at least 30%;
R B is selected from CH 3 C(O)—, CH 3 CH(OR)—, and —CH 2 CO 2 H; and
R is selected from H and D.
2. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is a deuterium-enriched compound of Formula II or a stereoisomer or pharmaceutically acceptable salt form thereof.
3. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a stereoisomer thereof or pharmaceutically acceptable salt form thereof; wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
4. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof;
wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
5. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof;
wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
6. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
7. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
8. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is a deuterium-enriched compound of Formula VII or a stereoisomer or pharmaceutically acceptable salt form thereof.
9. The pharmaceutical composition of claim 8 , wherein R B is CH 3 C(O)—.
10. The pharmaceutical composition of claim 8 , wherein R B is CH 3 CH(OR)—.
11. The pharmaceutical composition of claim 8 , wherein R B is —CH 2 CO 2 H.
12. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a stereoisomer or pharmaceutically acceptable salt form thereof; wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
13. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
14. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
15. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a stereoisomer or pharmaceutically acceptable salt form thereof; wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
16. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
17. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
18. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a stereoisomer or pharmaceutically acceptable salt form thereof; wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
19. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
20. The pharmaceutical composition of claim 1 , wherein the deuterium-enriched compound is
or a pharmaceutically acceptable salt form thereof; wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 90%, and Z is H or D, provided that the abundance of deuterium in Z is at least 30%.
21. The pharmaceutical composition of claim 2 , wherein the abundance of deuterium in Z is at least 90%.
22. The pharmaceutical composition of claim 9 , wherein the abundance of deuterium in Z is at least 90%.
23. The pharmaceutical composition of claim 10 , wherein the abundance of deuterium in Z is at least 90%.
24. The pharmaceutical composition of claim 11 , wherein the abundance of deuterium in Z is at least 90%.
25. The pharmaceutical composition of claim 12 , wherein the abundance of deuterium in Z is at least 90%.
26. The pharmaceutical composition of claim 14 , wherein the abundance of deuterium in Z is at least 90%.
27. The pharmaceutical composition of claim 14 , wherein the abundance of deuterium in Z is at least 95%.
28. The pharmaceutical composition of claim 15 , wherein the abundance of deuterium in Z is at least 90%.
29. The pharmaceutical composition of claim 17 , wherein the abundance of deuterium in Z is at least 90%.
30. The pharmaceutical composition of claim 17 , wherein the abundance of deuterium in Z is at least 95%.
31. The pharmaceutical composition of claim 18 , wherein the abundance of deuterium in Z is at least 90%.
32. The pharmaceutical composition of claim 19 , wherein the abundance of deuterium in Z is at least 90%.
33. The pharmaceutical composition of claim 26 , wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 95%.
34. The pharmaceutical composition of claim 27 , wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 95%.
35. The pharmaceutical composition of claim 29 , wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 95%.
36. The pharmaceutical composition of claim 30 , wherein the compound has an enantiomeric excess, with respect to the C-Z carbon, of at least 95%.
37. A dosage form selected from the group consisting of a tablet, caplet, and capsule, wherein the dosage form comprises a pharmaceutical composition of claim 2 .
38. A dosage form selected from the group consisting of a tablet, caplet, and capsule, wherein the dosage form comprises a pharmaceutical composition of claim 8 .
39. A dosage form selected from the group consisting of a tablet, caplet, and capsule, wherein the dosage form comprises a pharmaceutical composition of claim 26 .
40. A dosage form selected from the group consisting of a tablet, caplet, and capsule, wherein the dosage form comprises a pharmaceutical composition of claim 29 .
41. A method of treating a disease selected from the group consisting of Type I diabetes, Type II diabetes, insulin resistance, and inadequate tolerance, comprising administering to a patient in need thereof a therapeutically effective amount a pharmaceutical composition of claim 1 to treat the disease.
42. The method of claim 41 , wherein the disease is Type II diabetes.