Non nucleoside reverse transcriptase inhibitors

• US 7,462,608 B2
• Filed: 04/25/2003
• Issued: 12/09/2008
• Est. Priority Date: 04/26/2002
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Xu, Lianhong, Kim, Choung U., Lee, Christopher P., Chen, Xiaowu, Chen, James M., Lee, William A., Nelson, Peter H., Tario, James D.
• Primary Examiner(s): McKane; Joseph
• Assistant Examiner(s): Coppins; Janet L
• Application Number:
  US10/424,130
• Publication Number:
  US 20050197320A1
• Time in Patent Office: 2,055 Days
• Field of Search: 544/90, 514/230.5, 514/75
• US Class Current: 514/75
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 233/42 Sulfur atoms
• CPC Class Codes: C07D 239/49 with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 243/04 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07D 265/18 with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/645 : having two nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 9/6506 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/650905 : having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/650947 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6512 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65128 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65335 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Q 1/18 : Testing for antimicrobial activity of a material
• CPC Class Codes: C12Q 1/37 : involving peptidase or proteinase
• CPC Class Codes: C12Q 1/44 : involving esterase
• CPC Class Codes: C40B 40/04 : Libraries containing only organic compounds
• CPC Class Codes: G01N 2333/16 : HIV-1, HIV-2
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/5038 : involving detection of metabolites per se

Abstract

Phosphorus-substituted imidazole compounds with anti-HIV properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit reverse transcriptase activity and are useful therapeutically for the inhibition of such enzymes, as well as in assays for the detection of such enzymes.

Claims

1. A phosphonate anolog of Efavirenz or a pharmaceutically acceptable salt, thereof.

2. A compound according to claim 1 of the Formula:

3. A compound of claim 2 having the formulas:

4. The compound of claim 2 wherein A¹ is of the formula:

5. The compound of claim 4 wherein A¹ is of the formula:

6. The compound of claim 5 wherein A¹ is of the formula:

7. The compound of claim 6 wherein A¹ is of the formula:

8. The compound of claim 7 wherein M12a is 1.

9. The compound of claim 7 wherein A¹ is selected from the formulas:

10. The compound of claim 2 wherein A³ is of the formula:

11. The compound of claim 10 wherein A³ is of the formula:

12. The compound of claim 11 wherein A³ is of the formula:

13. The compound of claim 12 wherein A³ is of the formula:

14. The compound of claim 13 wherein A³ is of the formula:

15. The compound of claim 14 wherein A³ is of the formula:

16. The compound of claim 15 wherein M12d is 1.

17. The compound of claim 2 wherein A³ is of the formula:

18. The compound of claim 17 wherein A³ is of the formula:

19. The compound of claim 18 wherein W⁵ is a carbocycle.

20. The compound of claim 19 wherein A³ is of the formula:

21. The compound of claim 20 wherein W⁵ is phenyl.

22. The compound of claim 17 wherein M12b is 1.

23. The compound of claim 22 wherein A³ is of the formula:

24. The compound of claim 23 wherein A³ is of the formula:

25. The compound of claim 24 wherein A³ is of the formula:

26. The compound of claim 25 wherein R¹ is H.

27. The compound of claim 25 wherein M12d is 1.

28. The compound of claim 25 wherein A³ is of the formula:

29. The compound of claim 28 wherein Y^2b is N(R^x).

30. The compound of claim 29 wherein A³ is of the formula:

31. The compound of claim 28 wherein A³ is of the formula:

32. A compound of claim 2 wherein R^x is of the formula:

33. A compound of claim 32 wherein R^x is of the formula:

34. A compound of claim 32 wherein R^x is of the formula:

35. A compound of claim 34 wherein R^x is of the formula:

36. A compound of claim 35 wherein R^x is of the formula:

37. The compound of claim 2 wherein R^x is of the formula:

38. The compound of claim 37 wherein A³ is of the formula:

39. The compound of claim 2 wherein A³ is of the formula:

40. The compound of claim 39 wherein A³ is of the formula:

41. The compound of claim 40 wherein A³ is of the formula:

42. The compound of claim 41 wherein A³ is of the formula:

43. The compound of claim 42 wherein A³ is of the formula:

44. The compound of claim 43 wherein A³ is of the formula:

45. The compound of claim 44 wherein A³ is of the formula:

46. The compound of claim 2 wherein A³ is of the formula:

47. The compound of claim 46 wherein A³ is of the formula:

48. The compound of claim 47 wherein A³ is of the formula:

49. The compound of claim 48 wherein A³ is of the formula:

50. The compound of claim 49 wherein R¹ is H;

and Y^1a and Y^2d are O.

51. The compound of claim 50 wherein M12d is 1.

52. The compound of claim 2 wherein A¹ is of the formula:

53. The compound of claim 52 wherein A¹ is of the formula:

54. The compound of claim 53 wherein A¹ is of the formula:

55. The compound of claim 54 wherein A¹ is of the formula:

56. The compound of claim 55 wherein A¹ is of the formula:

57. The compound of claim 56 wherein A¹ is of the formula:

58. The compound of claim 2 wherein A¹ is of the formula:

59. The compound of claim 58 wherein A¹ is of the formula:

60. The compound of claim 59 wherein A¹ is of the formula:

61. The compound of claim 60 wherein A¹ is of the formula:

62. The compound of claim 61 wherein A³ is of the formula:

63. The compound of claim 59 wherein A¹ is of the formula:

64. The compound of claim 63 wherein A¹ is of the formula:

65. The compound of claim 2 wherein A² is of the formula:

66. The compound of claim 65 wherein A² is of the formula:

67. The compound of claim 66 wherein M12b is 1.

68. The compound of claim 66 where M12b is 0, Y² is a bond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally and independently substituted with 1, 2, or 3 R² groups.

69. The compound of claim 66 wherein A² is of the formula:

70. The compound of claim 69 wherein M12a is 1.

71. The compound of claim 70 wherein A² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

72. The compound of claim 2 wherein A² is of the formula:

73. The compound of claim 72 wherein A² is of the formula:

74. The compound of claim 73 wherein M12b is 1.

75. The compound of claim 1 wherein the half-life is improved by at least about 100%.