Insulin analogs modified at position 29 of the B chain

• US 5,514,646 A
• Filed: 05/05/1993
• Issued: 05/07/1996
• Est. Priority Date: 02/09/1989
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: DiMarchi, Richard D., Frank, Bruce H., Shields, James E., Chance, Ronald E.
• Primary Examiner(s): SCHAIN, HOWARD
• Application Number:
  US08/057,201
• Time in Patent Office: 1,098 Days
• Field of Search: 514/3, 514/4, 405/68.1, 405/69.4, 530/303
• US Class Current: 514/6.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/622 at least 1 amino acid in D-form

Abstract

Analogs of human insulin modified at position 29 of the B chain thereof and, optionally, at other positions, have modified physico-chemical and pharmacokinetic properties and are useful in the treatment of hyperglycemia.

Claims

1. An insulin analog of the formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein A₂₁ is Asn, or Ala;

B₁ is Phe, or is absent;

B₂ is Val, or is absent;

B₁₀ is His, or Asp;

B₂₈ is any amino acid;

B₂₉ is L-Pro, D-Pro, L-hydroxyproline, D-hydroxyproline;

and,

B₃₀ is Thr, Ala, or is absent.

2. The insulin analog of claim 1 wherein B₂₈ is Asp, Val, Leu, Ile, Pro, Arg, His, Lys, Phe, Ala, Gly, norisoleucine, citrulline, or ornithine.

3. The insulin analog of claim 1 wherein B₂₈ is Lys.

4. The insulin analog of claim 1 wherein A₂₁ is Ala.

5. The insulin analog of claim 1 wherein B₁ is absent.

6. The insulin analog of claim 5 wherein B₁₀ is Asp.

7. The insulin analog of claim 5 wherein B₂ is absent.

8. The insulin analog of claim 6 wherein B₂ is absent.

9. The insulin analog of claim 1 wherein B₃₀ is absent.

10. The insulin analog of claim 1 wherein B₃₀ is Ala.

12. The insulin analog of claim 1 wherein A₂₁ is Ala, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is Thr.

13. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is Val, B₁₀ is His, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is Thr.

14. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is Val, B₁₀ is Asp, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is Thr.

15. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is absent, B₁₀ is His, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is Thr.

16. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is absent, B₁₀ is Asp, B₂₈ is Lys, B29 is Pro, and B₃₀ is Thr.

17. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is absent.

18. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Lys, B₂₉ is Pro, and B₃₀ is Ala.

19. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

20. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), and D-lysine.

21. The insulin analog of claim 1 wherein A₂₁ is Ala, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

22. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

23. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is Val, B₁₀ is Asp, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

24. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is absent, B₁₀ is His, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

25. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is absent, B₂ is absent, B₁₀ is Asp, B₂₈ is Pro, B₃₀ is Thr, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

26. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is absent, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

27. The insulin analog of claim 1 wherein A₂₁ is Asn, B₁ is Phe, B₂ is Val, B₁₀ is His, B₂₈ is Pro, B₃₀ is Ala, and B₂₉ is selected from the group consisting of L-(N-methyllysine), D-lysine, L-(N-methylarginine), and D-arginine.

28. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 1.

29. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 2.

30. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 3.

31. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 4.

32. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 5.

33. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 6.

34. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 7.

35. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 8.

36. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 9.

37. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 10.

39. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 12.

40. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 13.

41. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 14.

42. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 15.

43. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 16.

44. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 17.

45. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 18.

46. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 19.

47. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 20.

48. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 21.

49. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 22.

50. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 23.

51. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 24.

52. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 25.

53. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an, insulin analog according to claim 26.

54. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog according to claim 27.

55. A pharmaceutical composition which comprises an insulin analog according to claim 1 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

56. A pharmaceutical composition which comprises an insulin analog according to claim 2 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

57. A pharmaceutical composition which comprises an insulin analog according to claim 3 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

58. A pharmaceutical composition which comprises an insulin analog according to claim 4 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

59. A pharmaceutical composition which comprises an insulin analog according to claim 5 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

60. A pharmaceutical composition which comprises an insulin analog according to claim 6 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

61. A pharmaceutical composition which comprises an insulin analog according to claim 7 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

62. A pharmaceutical composition which comprises an insulin analog according to claim 8 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

63. A pharmaceutical composition which comprises an insulin analog according to claim 9 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

64. A pharmaceutical composition which comprises an insulin analog according to claim 10 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

66. A pharmaceutical composition which comprises an insulin analog according to claim 12 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

67. A pharmaceutical composition which comprises an insulin analog according to claim 13 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

68. A pharmaceutical composition which comprises an insulin analog according to claim 14 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

69. A pharmaceutical composition which comprises an insulin analog according to claim 15 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

70. A pharmaceutical composition which comprises an insulin analog according to claim 16 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

71. A pharmaceutical composition which comprises an insulin analog according to claim 17 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

72. A pharmaceutical composition which comprises an insulin analog according to claim 18 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

73. A pharmaceutical composition which comprises an insulin analog according to claim 19 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

74. A pharmaceutical composition which comprises an insulin analog according to claim 20 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

75. A pharmaceutical composition which comprises an insulin analog according to claim 21 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

76. A pharmaceutical composition which comprises an insulin analog according to claim 22 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

77. A pharmaceutical composition which comprises an insulin analog according to claim 23 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

78. A pharmaceutical composition which comprises an insulin analog according to claim 24 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

79. A pharmaceutical composition which comprises an insulin analog according to claim 25 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

80. A pharmaceutical composition which comprises an insulin analog according to claim 26 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

81. A pharmaceutical composition which comprises an insulin analog according to claim 27 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

11. An insulin analog of the formula ##STR12##

38. A method of treating hyperglycemia which comprises administering, to a patient in need thereof, an effective amount of an insulin analog of the formula ##STR13##

65. A pharmaceutical composition which comprises an insulin analog of the formula ##STR14## in combination with a pharmaceutically acceptable carrier, diluent, or excipient.