Deuterium-substituted xanthine derivatives and methods of use
This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial.
1. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —CH 3 and —CD 3 ; R 2 is selected from —CH 3 and —CD 3 ; Y 1 is deuterium or hydrogen, wherein the isotopic enrichment factor for each designated deuterium atom is at least 5000, wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy and intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
2. The method of claim 1 , wherein the disease or condition is diabetic nephropathy.
3. The method of claim 2 , wherein R 1 is —CH 3 .
4. The method of claim 2 , wherein R 1 is —CD 3 .
5. The method of claim 2 wherein R 2 is —CH 3 .
6. The method of claim 2 wherein R 2 is —CD 3 .
7. The method of claim 2 , wherein R 1 is —CH 3 and R 2 is —CH 3 .
8. The method of claim 2 , wherein Y 1 is deuterium.
9. The method of claim 2 , wherein Y 1 is hydrogen.
10. The method of claim 2 , wherein the compound is selected from the group consisting of the following compounds:
or a pharmaceutically acceptable salt thereof.
11. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —CH 3 and —CD 3 ; R 2 is selected from —CH 3 and —CD 3 ; Y 1 is deuterium or hydrogen;
with the proviso that
(i) if Y 1 is deuterium, then R 2 is CD 3 ; and
(ii) if Y 1 is hydrogen, then R 1 is CH 3 , wherein the isotopic enrichment factor for each designated deuterium atom is at least 5000, wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy and intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
12. The method of claim 11 , wherein the disease or condition is diabetic nephropathy.
13. The method of claim 12 , wherein R 1 is —CH 3 .
14. The method of claim 12 , wherein R 1 is —CD 3 .
15. The method of claim 12 , wherein R 2 is —CH 3 .
16. The method of claim 12 , wherein R 2 is —CD 3 .
17. The method of claim 12 , wherein R 1 is —CH 3 and R 2 is —CH 3 .
18. The method of claim 12 , wherein Y 1 is deuterium.
19. The method of claim 12 , wherein Y 1 is hydrogen.
20. The method of claim 12 , wherein the compound is selected from the group consisting of the following compounds:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
22. The method of claim 11 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
23. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein the isotopic enrichment factor for each designated deuterium atom is at least 5000, wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy or intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
24. The method of claim 23 , wherein the disease or condition is diabetic nephropathy.
25. The method of claim 10 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
26. The method of claim 23 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
27. The method of claim 1 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.
28. The compound of claim 11 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.
29. The method of claim 23 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.
30. The method of claim 1 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.
31. The method of claim 11 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.
32. The method of claim 23 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.
33. The method of claim 1 , wherein the compound comprises less than 10% of the other stereoisomer.
34. The method of claim 11 , wherein the compound comprises less than 10% of the other stereoisomer.
35. The method of claim 23 , wherein the compound comprises less than 10% of the other stereoisomer.
36. The method of claim 1 , wherein the compound comprises less than 5% of the other stereoisomer.
37. The method of claim 11 , wherein the compound comprises less than 5% of the other stereoisomer.
38. The method of claim 23 , wherein the compound comprises less than 5% of the other stereoisomer.