Deuterium-substituted xanthine derivatives and methods of use

• US 8,987,442 B2
• Filed: 04/17/2012
• Issued: 03/24/2015
• Est. Priority Date: 02/27/2009
• Status: Active Grant

• Current Assignee: Sun Pharmaceutical Industries, Inc. (Sun Pharmaceutical Industries Limited)
• Original Assignee: Concert Pharmaceuticals Inc.
• Inventors: Tung, Roger D., Liu, Julie F., Harbeson, Scott L.
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): MAURO, JOHN MATTHEW
• Application Number:
  US13/448,930
• Publication Number:
  US 20120202830A1
• Time in Patent Office: 1,071 Days
• Field of Search: 544/267, 514/263.36
• US Class Current: 544/267
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 473/06 with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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:

2. The method of claim 1, wherein the disease or condition is diabetic nephropathy.

3. The method of claim 2, wherein R¹ is —

CH₃.

4. The method of claim 2, wherein R¹ is —

CD₃.

5. The method of claim 2 wherein R² is —

CH₃.

6. The method of claim 2 wherein R² is —

CD₃.

7. The method of claim 2, wherein R¹ is —

CH₃ and R² is —

CH₃.

8. The method of claim 2, wherein Y¹ is deuterium.

9. The method of claim 2, wherein Y¹ is hydrogen.

10. The method of claim 2, wherein the compound is selected from the group consisting of the following compounds:

21. The method of claim 1, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

25. The method of claim 10, 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.

30. The method of claim 1, 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.

36. The method of claim 1, wherein the compound comprises less than 5% of the other stereoisomer.

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:

12. The method of claim 11, wherein the disease or condition is diabetic nephropathy.

13. The method of claim 12, wherein R¹ is —

CH₃.

14. The method of claim 12, wherein R¹ is —

CD₃.

15. The method of claim 12, wherein R² is —

CH₃.

16. The method of claim 12, wherein R² is —

CD₃.

17. The method of claim 12, wherein R¹ is —

CH₃ and R² is —

CH₃.

18. The method of claim 12, wherein Y¹ is deuterium.

19. The method of claim 12, wherein Y¹ is hydrogen.

20. The method of claim 12, wherein the compound is selected from the group consisting of the following compounds:

22. The method of claim 11, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

28. The compound of claim 11, wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.

31. The method of claim 11, wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.

34. The method of claim 11, wherein the compound comprises less than 10% of the other stereoisomer.

37. The method of claim 11, wherein the compound comprises less than 5% of the other stereoisomer.

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:

24. The method of claim 23, wherein the disease or condition is diabetic nephropathy.

26. The method of claim 23, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

29. The method of claim 23, wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.

32. The method of claim 23, wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.

35. The method of claim 23, wherein the compound comprises less than 10% of the other stereoisomer.

38. The method of claim 23, wherein the compound comprises less than 5% of the other stereoisomer.