MOENOMYCIN ANALOGS, METHODS OF SYNTHESIS, AND USES THEREOF

• US 20110136759A1
• Filed: 10/03/2008
• Published: 06/09/2011
• Est. Priority Date: 10/04/2007
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Zhang, Yi, Walker, Suzanne Kahne, Lin, Xiaonan, Adachi, Masaatsu, Fuse, Shinichiro, Ostash, Bohdan, Tsukamoto, Hirokazu, Kahne, Daniel, Doud, Emma
• Granted Patent: US 8,604,004 B2
• Time in Patent Office: Days
• US Class Current: 514/61
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07H 11/04 Phosphates; Phosphites; Polyphosphates
• CPC Class Codes: C07H 15/10 containing unsaturated carbon-to-carbon bonds

Abstract

The present invention provides novel moenomycin analogs as well as pharmaceutical compositions thereof, methods of synthesis, and methods of use in treating an infection by administering an inventive compound to a subject in need thereof. The moenomycin analogs may be prepared synthetically, biosynthetically, or semi-synthetically. The analogs are particularly useful in treating or preventing infections caused by Gram-positive organisms. Certain inventive compounds may have a broader spectrum of coverage, which includes Gram-negative organisms.

Claims

1. A compound of formula (I):

5. The compound according to claim 1, wherein R^1a and R^1b are, independently, H or the group:

6. The compound according to claim 1, wherein R² is —

CH₃ or —

CH₂OH.

7. The compound according to claim 1, wherein R³ is —

OH or —

OR^w.

8. The compound according to claim 1, wherein R³ is OR^w, wherein R^w is a carbohydrate moiety.

12. The compound according to claim 1, wherein R⁴ and R⁵ are, independently, H, —

CH₃, —

N(R^z)₂, or —

OR^z.

19. The compound according to claim 1, wherein each instance of R⁶ is, independently, H or —

C(═

O)CH₃.

22. The compound according to claim 1, wherein R⁷ is H, —

C(═

O)CH₃, or —

C(═

O)NH₂.

25. The compound according to claim 1, wherein R⁸ is H or —

C(═

O)CH₃.

27. The compound according to claim 1, wherein R^C is —

C(═

O)H, —

C(═

O)OH, or —

C(═

O)NH₂.

28. The compound according to claim 1, wherein Rⁱ is H or a hydroxyl protecting group.

29. The compound according to claim 1, wherein R⁹ is an optionally substituted, optionally unsaturated, C_10-20 hydrocarbon chain, wherein 0 to 8 methylene units are optionally replaced with —

O—

,—

NR^x, —

S—

, —

C(═

O)—

, —

C(═

NR^x)—

, —

S(═

O)—

, —

S(═

O)₂—

, —

N═

N—

, —

C═

N—

, —

C(R^y)═

C(R^y)—

, —

N—

O—

, an optionally substituted arylene or an optionally substituted heteroarylene moiety.

31. The compound of claim 1, wherein R⁹ is an optionally substituted, optionally unsaturated, C₁₀-C₁₆ aliphatic moiety.

34. The compound of claim 1 wherein R⁹ is of one of the formulae:

37. The compound of claim 1, wherein R⁹ is a fluorinated, C₈-C₁₆ alkyl moiety.

39. The compound of claim 1, wherein R⁹ is of one of the formulae:

40. The compound of claim 1 any one of claims 1, wherein R⁹ is of one of the formulae:

44. The compound of claim 1, wherein R⁹ is of the formula:

50. The compound of claim 1, wherein [Linker] is of formula:

67. The compound of claim 1, wherein R¹⁰ is —

C(═

O)NHR⁸.

70. The compound of claim 1, wherein R¹⁰ is —

C(═

O)NH₂.

73. The compound of claim 1, wherein R¹¹ is —

OR⁶.

75. The compound of claim 1, wherein R¹¹ is —

OH.

80. The compound of claim 1, wherein R¹² is —

OR⁶.

82. The compound of claim 1, wherein R¹² is —

OH.

97. A pharmaceutical composition comprising a compound of claim 1.

98. A method of treating a bacterial infection comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

100. A method of synthesizing a compound of claim 1 partially biosynthetically comprising isolating a first intermediate from a cell culture and synthetically modifying the first intermediate to provide a second intermediate.

2. (canceled)

3. A compound of formula (III) or formula (IV):

4. (canceled)

9-11. -11. (canceled)

13-18. -18. (canceled)

20-21. -21. (canceled)

23-24. -24. (canceled)

26. (canceled)

30. (canceled)

32-33. -33. (canceled)

35-36. -36. (canceled)

38. (canceled)

41-43. -43. (canceled)

45-49. -49. (canceled)

51-66. -66. (canceled)

68-69. -69. (canceled)

71-72. -72. (canceled)

74. (canceled)

76-79. -79. (canceled)

81. (canceled)

83-96. -96. (canceled)

99. (canceled)

101-113. -113. (canceled)