Antiparasitic Agents Based On mTOR Inhibitors

• US 20130296316A1
• Filed: 07/11/2011
• Published: 11/07/2013
• Est. Priority Date: 07/09/2010
• Status: Abandoned Application

• Current Assignee: Ana Rodriguez, Michael P. Pollastri, Miguel Navarro, Stephen Beverley
• Original Assignee: Ana Rodriguez, Michael P. Pollastri, Miguel Navarro, Stephen Beverley
• Inventors: Pollastri, Michael P., Navarro, Miguel, Beverley, Stephen, Rodriguez, Ana
• Application Number:
  US13/808,892
• Publication Number:
  US 20130296316A1
• Time in Patent Office: Days
• US Class Current: 514/232.5
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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

Disclosed is the use of mammalian target of rapamycin (mTOR) and/or phosphoinositide-3-kinase (PI3K) inhibitors as antiparasitic drugs, particularly in those parasitic infections caused by trypanosomatid parasites {Trypanosoma sp. and Leishmania sp.). These inhibitors are useful as trypanocides.

Claims

1. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (I),

2. The method of claim 1, wherein R₃₁ is CN.

3. The method of claim 1, wherein R₃₂ and R₃₃ are each H.

4. The method of claim 1, wherein R₃₀ is Me.

5. The method of claim 1, wherein R₂₇ is OMe, OH, or OAc.

6. The method of claim 1, wherein R₂₉ and R₃₄ are each H.

7. The method of claim 1, wherein the compound is

60. The method of any one of claims 1, 8, 15, 22, 35, 41, and 56, wherein the disease is selected from the group consisting of Human African Trypanosomiasis, leishmaniasis, and Chagas Disease.

61. The method of claim 60, wherein the Human African Trypanosomiasis is caused by Trypanosoma brucei.

62. The method of claim 60, wherein the leishmaniasis is caused by Leishmania sp.

63. The method of claim 60, wherein leishmaniasis is visceral or cutaneous leishmaniasis.

64. The method of claim 60, wherein the Chagas Disease is caused by Trypanosoma cruzi.

8. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (VI),

9. The method of claim 8, wherein X₁ and X₂ are each independently O.

10. The method of claim 8, wherein R₄ is attached to the C1 position of Formula (VI).

11. The method of claim 8, wherein R₄ is OMe.

12. The method of claim 8, wherein R₆ is Me.

13. The method of claim 8, wherein R₁ is OH.

14. The method of claim 8, wherein the compound is:

15. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (II),

16. The method of claim 15, wherein R₇ and R₈ are H.

17. The method of claim 15, wherein R₁₃ is H.

18. The method of claim 15, wherein R₉ is methyl, ethyl, or isopropyl.

19. The method of claim 15, wherein R₁₀ is H.

20. The method of claim 15, wherein R₁₁ is OH.

21. The method of claim 15, wherein the compound is:

22. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (III),

23. The method of claim 22, wherein X₄ is N-benzyl.

24. The method of claim 22, wherein X₄ is N-(pyridin-3-ylmethyl).

25. The method of claim 22, wherein X₄ is NC(O)OMe.

26. The method of claim 22, wherein X₄ is NH.

27. The method of claim 22, wherein R₁₄ is

28. The method of claim 22, wherein R₁₇ is NH₂, OH, NHC(O)OMe, or NHC(O)OC(CH₃)₃.

29. The method of claim 22, wherein R₁₅ is H.

30. The method of claim 22, wherein R₁₅ is NHCH₂CH₂OCH₂CH₃.

31. The method of claim 22, wherein R₁₄ is CH₂CH₂NHC(O)OCH₃.

32. The method of claim 22, wherein X₃ is CH₂.

33. The method of claim 22, wherein X₃ is O.

34. The method of claim 22, wherein the compound is selected from the group consisting of:

35. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (IV),

36. The method of claim 35, wherein X₅ is O.

37. The method of claim 35, wherein X₆ is O.

38. The method of claim 35, wherein X₆ is NH.

39. The method of claim 35, wherein R₂₀ is H.

40. The method of claim 35, wherein the compound is selected from the group consisting of:

41. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (V),

42. The method of claim 41, wherein R₂₄ is H.

43. The method of claim 41, wherein R₂₄ is NHCH₂CH₂OCH₂CH₃.

44. The method of claim 41, wherein R₂₄ is

45. The method of claim 41, wherein R₂₄ is

46. The method of claim 41, wherein R₂₄ is

47. The method of claim 41, wherein R₂₃ is H.

48. The method of claim 41, wherein R₂₃ is ortho-OEt.

49. The method of claim 41, wherein R₂₃ is meta-OMe, meta-OH, or meta-OAc.

50. The method of claim 41, wherein R₂₃ is para-OMe.

51. The method of claim 41, wherein R₂₃ is meta-CH₂CH₂OH.

52. The method of claim 41, wherein X₇ is S or O.

53. The method of claim 41, wherein Y is N.

54. The method of claim 41, wherein Y is C.

55. The method of claim 41, wherein the compound is selected from the consisting of:

56. A method of treating a disease caused by a trypanosomatid parasite, comprising administering a therapeutically effective amount of an mTOR and/or PI3K inhibitor compound to a subject in need of treatment, wherein the compound has the structure of Formula (VII),

57. The method of claim 56, wherein R₃₅ is H or OMe.

58. The method of claim 56, wherein X₉ is O.

59. The method of claim 56, wherein the compound is

65-66. -66. (canceled)