IP Library › Granted Patent US 6,964,860

Granted Patent B2

US 6,964,860 · App. 10/131,847 · Granted Nov 15, 2005

Glycopeptide antibiotics

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Quick Facts

Patent No.: US 6,964,860
App. No.: 10/131,847
Granted: Nov 15, 2005
Kind: B2

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Abstract

The invention provides compounds of formula Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c , R 6d , R 6e and R 7 are defined in the specification. These compounds are useful as antibiotic agents.

Claims (451)

1. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4744, LL4773, LL4779, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

2. A process according to claim 1 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

3. A process according to claim 1 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

4. A process according to claim 1 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 ); and

R 3 and R 4 are OH.

5. A process according to claim 4 in which the glycopeptide antibiotic produced has the structure selected from the group

6. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

7. The process according to claim 6 wherein R 1 is

8. The process according to claim 6 wherein R 1 is

9. The process according to claim 6 wherein R 1 is

10. The process according to claim 6 wherein R 1 is

11. The process according to claim 6 wherein R 1 is

12. A process according to claim 6 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

13. A process according to claim 6 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

14. A process according to claim 6 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

15. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4744, LL4773, LL4779, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium and in the presence of a substrate ZCO 2 H until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

16. A process according to claim 15 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

17. A process according to claim 15 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

18. A process according to claim 15 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

19. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

20. A process according to claim 19 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

21. A process according to claim 19 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

22. A process according to claim 19 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

23. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4773, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium in the presence of substrates

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

24. The process according to claim 23 wherein R 1 is

25. The process according to claim 23 wherein R 1 is

26. The process according to claim 23 wherein R 1 is

27. The process according to claim 23 wherein R 1 is

28. The process according to claim 23 wherein R 1 is

29. A process according to claim 23 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

30. A process according to claim 23 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

31. A process according to claim 23 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

32. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

33. The process according to claim 32 wherein R 1 is

34. The process according to claim 32 wherein R 1 is

35. The process according to claim 32 wherein R 1 is

36. The process according to claim 32 wherein R 1 is

37. The process according to claim 32 wherein R 1 is

38. A process according to claim 32 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

39. A process according to claim 32 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

40. A process according to claim 32 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

41. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

42. The process according to claim 41 wherein R 1 is

43. The process according to claim 41 wherein R 1 is

44. The process according to claim 41 wherein R 1 is

45. The process according to claim 41 wherein R 1 is

46. The process according to claim 41 wherein R 1 is

47. A process according to claim 41 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

48. A process according to claim 41 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

49. A process according to claim 41 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

50. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H, F or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

51. The process according to claim 50 wherein R 1 is

52. The process according to claim 50 wherein R 1 is

53. A process according to claim 50 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

54. A process according to claim 50 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

55. A process according to claim 50 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

56. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4773, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium in the presence of substrates

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

57. The process according to claim 56 wherein R 1 is

58. The process according to claim 56 wherein R 1 is

59. The process according to claim 56 wherein R 1 is

60. The process according to claim 56 wherein R 1 is

61. The process according to claim 56 wherein R 1 is

62. A process according to claim 56 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

63. A process according to claim 56 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

64. A process according to claim 56 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

65. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

66. The process according to claim 65 wherein R 1 is

67. The process according to claim 65 wherein R 1 is

68. The process according to claim 65 wherein R 1 is

69. The process according to claim 65 wherein R 1 is

70. The process according to claim 65 wherein R 1 is

71. A process according to claim 65 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

72. A process according to claim 65 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

73. A process according to claim 65 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

74. A process for producing a compound of the formula:

wherein:

R 1 is selected from

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4744, LL4773, LL4779, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium in the presence of a substrate

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic from said medium.

75. A process according to claim 74 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H; and

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ).

76. A process according to claim 74 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are H.

77. A process according to claim 74 in which R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

Z is straight or branched alkyl(C 1 -C 9 ) or straight or branched alkenyl(C 2 -C 10 ); and

R 3 and R 4 are OH.

78. A process according to claim 74 in which R 1 is

79. A process for producing of a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is H;

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H;

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 is H;

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4742, LL4744, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

80. A process for producing of a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus selected from the group LL4742, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in the presence of mannose in a suitable culture medium until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

81. A process for producing a compound of the formula:

wherein:

R 1 is selected from:

R 1a is H;

R 2 is a moiety

R 2a is selected from

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

which process comprises:

82. The process of claim 81 wherein the hydrolyzing step is accomplished with sodium hydroxide.

83. The process of claim 81 wherein the hydrolyzing step is accomplished with (3-[cyclohexylamino]-1-propanesulfonic acid).

84. The process of claim 81 wherein the pH is adjusted from about 8.0 to about 12.5 with acetic acid or propanoic acid to about 4.0 to about 5.0.

85. The process of claim 81 wherein the pH is adjusted from about 8.0 to about 12.5 with hydrochloric acid to about 1.8 to about 5.0.

86. The process of claim 81 wherein the pH is adjusted with (3-[N-morpholino]propanesulfonic acid) to about 6.0 to about 6.5.

87. A process for producing a compound of the formula

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is selected from H,

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently H, or —C(O)—Y-Z;

Y is a single bond;

Z is straight or branched alkyl(C 1 -C 20 ) or straight or branched alkenyl(C 2 -C 20 );

which process comprises:

cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus LL4780, or a mutant thereof under aerobic conditions, in a suitable culture medium in the presence of a substrate:

wherein:

R 1 is selected from:

R 1a is H or halogen;

R 2 is a moiety

R 2a is H and

R 2b is H, F, or NH 2 ;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

88. A process for the production of a compound of the formula:

wherein:

R 1 is

R 2 is a moiety

R 2a is

R 2b is H;

R 2c is H;

R 3 and R 4 are independently H or OH;

R 5 is H or

R 6a , R 6b , R 6c , R 6d , or R 6e are H;

R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are H;

the process comprising cultivating a glycopeptide antibiotic producing strain of Streptomyces hygroscopicus which is selected from the group LL4600, LL4614, LL4666, LL4690, LL4728, LL4741, LL4742, LL4744, LL4773, LL4779, LL4783, LL4902, BD2, BD20 and BD70 or a mutant thereof under aerobic conditions, in a suitable culture medium in the presence of alpha-aminocyclohexane-propionic acid until a recoverable amount of said antibiotic is formed in said medium and recovering said antibiotic therefrom.

89. A process for producing glycopeptides of the formula

wherein:

R 1 is a moiety selected from:

R 1a is H or halogen;

R 2 is a moiety selected from:

provided when R 2 is selected from the moieties:

that R 1 is selected from the moieties:

R 2a is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), the group —C(O)—Y-Z, and a moiety selected from:

Y is selected from a single bond, —O— and —NR 8a —;

Z is selected from alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl;

and when Y is a single bond then Z is also selected from H, alkenyl(C 2 -C 20 ) and alkynyl (C 2 -C 20 );

R 2b and R 2c are independently selected from H, halogen, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 2 -C 20 ), alkynyl(C 2 -C 20 ), aryl, heteroaryl, —NH 2 , —NR 2f R 2g , and —NO 2 , provided when R 2b is —NO 2 , that R 2c must be H;

R 2d is selected from alkyl (C 1 -C 20 ), alkenyl(C 2 -C 20 ), alkynyl(C 2 -C 20 ), aryl, heteroaryl, and when R 2 is

R 2d may also be the group L-M, wherein;

L is selected from —NH—, —S—, —SCH 2 C(O)—, and a group of the formula:

M is selected from alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ) and alkynyl(C 3 -C 20 );

and when:

a) L is not —S—, M may also be aryl or heteroaryl;

b) L is —SCH 2 C(O)—, M may also be H, alkenyl(C 2 -C 20 ) or alkynyl(C 2 -C 20 ); or

c) L is —NH— or a group of the formula:

M may also be a moiety of the formula:

z is an integer of 1 or 2;

R 2i , R 2j and R 2k are independently selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), acyl, —Si(alkyl(C 1 -C 20 )) 3 , —Si(alkyl(C 1 -C 20 )) 2 (aryl), —Si(alkyl(C 1 -C 20 ))(aryl) 2 , —Si(aryl) 3 , and aroyl;

R 2e is S or O;

R 2f is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl;

R 2g is H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl, and the group D-E-G, wherein;

D is selected from —C(O)—, —C(S)— and —S(O) 2 —;

E is selected from a single bond, and, when D is —C(O)— or —C(S)—, E is also selected from —O— and —NR 2h —;

G is selected from alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl;

and when:

a) E is a single bond, then G may also be alkenyl(C 2 -C 20 ) or alkynyl(C 2 -C 20 ); or

b) D is —C(O)— or —C(S)— and E is a single bond, then G may also be H;

R 2f and R 2g may optionally when taken together with the nitrogen atom to which each is attached form a monocyclic ring having three to seven atoms independently selected from the elements C, N, O and S where said monocyclic ring optionally contains up to three nitrogen atoms, up to two oxygen atoms and up to two sulfur atoms provided said monocyclic ring does not contain —O—O—, —S—S— or —S—O— bonds;

R 2h is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl;

R 2h and G may optionally when taken together with the nitrogen atom to which each is attached form a monocyclic ring having three to seven atoms independently selected from the elements C, N, O and S where said monocyclic ring optionally contains up to three nitrogen atoms, up to two oxygen atoms and up to two sulfur atoms provided said monocyclic ring does not contain —O—O—, —S—S— or —S—O— bonds;

R 3 and R 4 are independently H, OH, —Si(alkyl(C 1 -C 20 )) 3 , —Si(alkyl(C 1 -C 20 )) 2 (aryl), —Si(alkyl(C 1 -C 20 ))(aryl) 2 , —Si(aryl) 3 or the group —C(O)—Y-Z;

R 5 is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), the group —C(O)—Y-Z and moieties of the formulae;

R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), the group —C(O)—Y-Z and moieties of the formulae;

R 6f is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl, heteroaryl, halogen, hydroxy, alkoxy(C 1 -C 20 ), aryloxy, amino, monoalkyl(C 1 -C 20 )amino, dialkyl(C 1 -C 20 )amino, carboxy, carboxyalkyl(C 1 -C 20 ), carboxyaryl and carboxyamido;

R 7 is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), —Si(alkyl(c 1 -C 20 )) 3 , —Si(alkyl(C 1 -C 20 )) 2 (aryl), —Si(alkyl(C 1 -C 20 ))(aryl) 2 , —Si(aryl) 3 and the group —C(O)—Y-Z;

R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), —Si(alkyl(C 1 -C 20 )) 3 , —Si(alkyl(C 1 -C 20 )) 2 (aryl), —Si(alkyl(C 1 -C 20 ))(aryl) 2 , —Si(aryl) 3 and the group —C(O)—Y-Z or, optionally,

R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , R 13 and R 14 , R 15 and R 16 , R 16 and R 17 , R 17 and R 18 , R 19 and R 20 , R 20 and R 21 or R 21 and R 22 may independently be taken together forming moieties of the formulae:

provided when;

a) R 8 and R 9 are so joined, R 9 and R 10 may not be so joined;

b) R 9 and R 10 are so joined, R 8 and R 9 and R 10 and R 11 may not be so joined;

c) R 15 and R 16 are so joined, R 16 and R 17 may not be so joined;

d) R 18 and R 17 are so joined, R 15 and R 16 , R 17 and R 18 may not be so joined;

e) R 19 and R 20 are so joined, R 20 and R 21 may not be so joined;

f) R 20 and R 21 are so joined, R 19 and R 20 , and R 21 and R 22 may not be so joined;

R 8a is selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 3 -C 20 ), alkynyl(C 3 -C 20 ), aryl and heteroaryl;

R 8a and Z may optionally when taken together with the nitrogen atom to which each is attached form a monocyclic ring having three to seven atoms independently selected from the elements C, N, O and S where said monocyclic ring optionally contains up to three nitrogen atoms, up to two oxygen atoms and up to two sulfur atoms provided said monocyclic ring does not contain —O—O—, —S—S— or —S—O— bonds;

R 23 and R 24 are independently selected from H, alkyl(C 1 -C 20 ), cycloalkyl(C 3 -C 20 ), alkenyl(C 2 -C 20 ), alkynyl(C 2 -C 20 ), aryl, and heteroaryl;

R 23 and R 24 may optionally when taken together with the carbon atom to which each is attached form carbocyclic, monocyclic, fused, bridged, spirocyclic or polycyclic rings from three to twenty ring atoms optionally selected from the elements C, N, O and S where said monocyclic ring optionally contains up to three nitrogen atoms, up to two oxygen atoms and up to two sulfur atoms provided said monocyclic ring does not contain —O—O—, —S—S— or —S—O— bonds;

which process comprises:

treating a compound of the formula:

wherein:

R 2 is selected from

R 2a is selected from

with an α-mannosidase in an aqueous buffer at about pH 3.5 to about 6.5 and isolating said glycopeptide therefrom.

Assignments (6)

ASSIGNEE CHANGE OF ADDRESS Recorded May 1, 2017

From: ZOETIS SERVICES LLC

To: ZOETIS SERVICES LLC

Reel/Frame 042375/0667 →

MERGER Recorded May 13, 2015

From: ZOETIS WHC 2 LLC

To: ZOETIS SERVICES LLC

Reel/Frame 035623/0959 →

CHANGE OF NAME Recorded Mar 27, 2013

From: PAH WHC 2 LLC

To: ZOETIS WHC 2 LLC

Reel/Frame 030120/0783 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 21, 2013

From: WYETH HOLDINGS CORPORATION

To: PAH WHC 2 LLC

Reel/Frame 030062/0025 →

CHANGE OF NAME Recorded May 14, 2003

From: AMERICAN CYANAMID COMPANY

To: WYETH HOLDINGS CORPORATION

Reel/Frame 014038/0964 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 14, 2002

From: ABBANAT, DARREN ROBERT; BAILEY, ARTHUR EMERY; BERNAN, VALERIE SUE; GREENSTEIN, MICHAEL; LOTVIN, JASON ARNOLD; RUPPEN, MARK EDWARD; SUTHERLAND, ALAN GORDON; HE, HAIYIN

To: AMERICAN CYANAMID COMPANY

Reel/Frame 012993/0258 →