INHIBITORS OF CELLULAR NECROSIS AND RELATED METHODS

• US 20160168128A1
• Filed: 12/11/2015
• Published: 06/16/2016
• Est. Priority Date: 12/11/2014
• Status: Active Grant

• Current Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Inventors: ZHOU, Yijun, QIAN, Shan, MA, Dawei, YUAN, Junying
• Granted Patent: US 9,944,628 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/78 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A compound having the following structure (I):

or a pharmaceutically acceptable salt, prodrug, stereoisomer or tautomer thereof, is provided. Related compounds, methods for preparation of the same and uses of the compounds for treatment of various indications, including treatment of necrotic cell diseases and/or inflammation, are also provided.

Claims

1. A compound having the following structure (I):

2. The compound of claim 1, having the following structure (Ia):

3. The compound of claim 1, having the following structure (Ib):

13. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, prodrug or tautomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

14. A method for treating a necrotic cell disease, the method comprising administering an effective amount of the composition of claim 13 to a subject in need thereof.

15. The method of claim 14, wherein the necrotic cell disease is trauma, ischemia, stroke, cardiac infarction, infection, Gaucher'"'"'s disease, Krabbe disease, sepsis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, Huntington'"'"'s disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

16. A method for treating an inflammatory disorder, the method comprising administering an effective amount of the composition of claim 13 to a subject in need thereof.

17. The method of claim 16, wherein the inflammatory disorder is inflammatory bowel disease.

18. The method of claim 16, wherein the inflammatory disorder is Crohn'"'"'s disease or ulcerative colitis.

4. A compound having the following structure (II):

5. The compound of claim 4, wherein R¹⁰ is H.

6. The compound of claim 4, wherein R¹⁰ is F.

7. The compound of claim 4, wherein R⁷ is F.

8. The compound of claim 4, wherein R⁸ is F.

9. The compound of claim 4, wherein R⁹ is F.

10. The compound of claim 4, wherein R⁷ and R⁸ are F.

11. The compound of claim 4, wherein R⁸ and R⁹ are F.

12. The compound of claim 4, wherein the compound has one of the following structures:

55. A pharmaceutical composition comprising the compound of claim 4, or a pharmaceutically acceptable salt, prodrug or tautomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

56. A method for treating a necrotic cell disease, the method comprising administering an effective amount of the composition of claim 55 to a subject in need thereof.

57. A method for treating an inflammatory disorder, the method comprising administering an effective amount of the composition of claim 55 to a subject in need thereof.

19. A method for preparing a compound having the following structure (III):

20. The method of claim 19, wherein aldehyde (5) has one of the following structures (5′

) or (5″

);

21. The method of claim 19, wherein compound (7) has one of the following structures (7′

) or (7″

);

22. The method of claim 19, wherein R⁶ is C₁-C₆ alkyl, C₁-C₆ alkenyl, aralkyl, cycloalkylalkyl or heterocyclylalkyl, and the method further comprises reacting compound (7), or a salt, stereoisomer or tautomer thereof, with an alkylating agent (8) to yield (1), or a salt, stereoisomer or tautomer thereof, as follows:

23. The method of claim 22, wherein compound (1) has one of the following structures (1′

) or (1″

);

24. The method of claim 22, wherein the leaving group is halogen.

25. The method of claim 24, wherein halogen is bromine or iodine.

26. The method of claim 22, wherein R⁶ is C₁-C₆ alkyl.

27. The method of claim 26, wherein R⁶ is methyl.

28. The method of claim 27, wherein the alkylating agent is methyl iodide.

29. The method of claim 22, wherein R⁶ is aralkyl.

30. The method of claim 29, wherein R⁶ is benzyl.

31. The method of claim 30, wherein R⁶ has one of the following structures:

32. The method of claim 22, wherein R⁶ is heterocyclyalkyl.

33. The method of claim 32, wherein R⁶ is heteroarylalkyl.

34. The method of claim 33, wherein R⁶ has the following structure:

35. The method of claim 22, wherein R⁶ is aliphatic heterocyclylalkyl.

36. The method of claim 35, wherein R⁶ has one of the following structures:

37. The method of claim 22, wherein R⁶ is cycloyalkylalkyl.

38. The method of claim 37, wherein R⁶ has one of the following structures:

39. The method of claim 22, wherein R⁶ is C₁-C₆ alkenyl.

40. The method of claim 39, wherein R⁶ has the following structure:

41. The method of claim 22, further comprising treating compound (1) with a halogenating reagent to form a compound of structure (III), wherein R⁵ is halogen.

42. The method of claim 41, wherein the halogenating reagent is N-bromosuccinimide or N-chlorosuccinimide.

43. The method of claim 19, wherein aldehyde compound (5) has been prepared by reducing compound (4):

44. The method of claim 43, wherein compound (4) has one of the following structures (4′

) or (4″

);

45. The method of claim 43, wherein reducing comprises treating compound (4) under conditions for hydrogenation.

46. The method of claim 45, wherein the conditions for hydrogenation comprise contacting compound (4) with palladium and triethylsilane.

47. The method of claim 43, wherein compound (4) has been prepared from the corresponding acid (3) as follows:

48. The method of claim 47, wherein compound (3) has one of the following structures (3′

) or (3″

);

49. The method of claim 47, wherein the activating agent is DCC.

50. The method of claim 47, wherein compound (3) has been prepared from an amino acid having the following structure (2):

51. The method of claim 50, wherein compound (2) has one of the following structures (2′

) or (2″

);

52. The method of claim 19, wherein the method comprises one or more of the following transformations (A), (B), (C), (D), (E) or (F):

53. The method of claim 52, further comprising the following transformation:

54. A compound having one of the following structures (4′

), (4″

), (5′

) or (5″

);