Exendin analogues, processes for their preparation and medicaments containing them

• US 6,767,887 B1
• Filed: 06/04/1999
• Issued: 07/27/2004
• Est. Priority Date: 06/05/1996
• Status: Expired due to Fees

• Current Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Original Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Inventors: Hoffmann, Eike, Göke, Burkhard-Johannes, Göke, Rüdiger
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US09/147,345
• Time in Patent Office: 1,880 Days
• Field of Search: 514/2, 514/866, 530/324
• US Class Current: 514/5.9
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

The invention concerns exendin analogues which can be used in the treatment of diabetes mellitus. The invention also concerns processes for preparing these substances and medicaments containing them. The exendin analogues are derived from SEQ ID:1(I) or SEQ ID:2(II).

Claims

1. A peptide consisting essentially of SEQ ID NO:

1 or SEQ ID NO;

2

2. A peptide as claimed in claim 1, wherein the Xaa amino acid at position 30 in SEQ ID NO:

1 or SEQ ID NO;

2 is Arg, D-Arg, Tyr or D-Tyr.

3. A peptide as claimed in claim 2, wherein the Xaa amino acid at position 30 in SEQ ID NO:

1 or SEQ ID NO;

2 is Arg or Tyr.

4. A peptide as claimed in claim 1, in which Xaa specifies one of the non-proteinogenic amino acids amino acids Dab, Dap, Om, β

-Ala, Aib, Cit, Cha, Oak, Mab, Pab, Amb, Ahx, Ahp, Aoc, Ade, Atd, Nal, Nle, Sar, Tic.

6. A pharmaceutical preparation for stimulating the release of insulin comprising at least one peptide as claimed in claim 1, in addition to physiologically acceptable carriers and auxiliary substances.

7. A pharmaceutical composition comprising peptides as claimed in claim 1 for the treatment of diabetes.

8. A method of stimulating the release of insulin in a mammal comprising administering to the mammal a peptide according to claim 1 in an amount sufficient to release insulin.

9. The method of claim 8, wherein the mammal is a human.

5. A peptide consisting essentially of SEQ ID NO:

1 or SEQ ID NO;

2 wherein the peptide has one of the sequences identified by sequence ID NOS. 5, 68, 69, 71, 78-82 or 84-91, and wherein the N-terminus is represented by NR₁R₂ in which

R₁ denotes hydrogen, acetyl, trifluoroacetyl, adamantyl, Fmoc, benzyloxycarbonyl, Boc, Alloc, C₁-C₆ alkyl, C₂-C₈ alkenyl or C₇-C₉ aralkyl,

R₂ denotes hydrogen, acetyl, trifluoroacetyl, adamantyl, Fmoc, benzyloxycarbonyl, Boc, Alloc, C₁-C₆ alkyl, C₂-C₈ alkenyl or C₇-C₉ aralkyl,

and the C-terminus is represented by COR₃ in which R₃ equals OR₄ or NR₄R₅

in which R₄ equals hydrogen or C₁-C₆ alkyl

in which R₅ equals hydrogen or C₁-C₆ alkyl

as well as physiologically tolerated salts and esters thereof.

10. A peptide consisting essentially of SEQ ID NO:

1 or SEQ ID NO;

2

11. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 1 is Ala, Gly or Lys.

12. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 2 is Thr, Ala, Val, Ile or Leu.

13. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 3 is Ala.

14. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 4 is Ala.

15. A peptide as claimed in claim 10 wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 6 is Ala, Ile, Val, Leu or Tyr.

16. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 7 is Ala, Tyr or Ser.

17. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 9 is Ala or Glu.

18. A peptide as claimed in claim 10 wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in positions 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 24, 28, 29 is a proteinogenic L-amino acid.

19. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 13 is a neutral proteinogenic L-amino acid.

20. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 14 is Nle, D-Nle, Ala, D-Ala, Ile, D-Ile, Val or D-Val.

21. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 14 is Ile, Val or Ala.

22. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 22 is Tyr, Leu or Val.

23. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 23 is Leu, Val, Tyr or Phe.

24. A peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in positions 25, 26 or 27 is a proteinogenic L-amino acid.

25. Peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 2.

26. Peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 14.

27. Peptide as claimed in claim 10, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 3.

28. A peptide of 25-30 amino acids in length having at least 25 contiguous amino acids of SEQ ID NO:

1 or SEQ ID NO;

2

29. A peptide as claimed in claim 28, wherein the α

amino acid at position 30 in SEQ ID NO;

1 or SEQ ID NO;

2 is Arg, D-Arg, Tyr or D-Tyr.

30. A peptide as claimed in claim 28, in which Xaa specifies one of the non-proteinogenic amino acids amino acids Dab, Dap, Om, β

-Ala, Aib, Cit, Cha, Oak, Mab, Pab, Amb, Ahx, Ahp, Aoc, Ade, Atd, Nal, Nle, Sar, Tic.

31. Pharmaceutical preparation for stimulating the release of insulin comprising at least one peptide as claimed in claim 28, in addition to physiologically acceptable carriers and auxiliary substances.

32. A pharmaceutical composition comprising peptides as claimed in claim 28 for the treatment of diabetes.

53. A method of stimulating the release of insulin in a mammal comprising administering to the mammal a peptide according to claim 28 in an amount sufficient to release insulin.

54. The method of claim 53, wherein the mammal is a human.

33. A peptide of 25-30 amino acids in length wherein the peptide has one of the sequences identified by SEQ ID NO:

'"'"'S 5, 68, 69, 71, 78-82 or 84-91, and wherein the N-terminus is represented by NR₁R₂ in which

R₁ denotes hydrogen, acetyl, trifluoroacetyl, adamantyl, Fmoc, benzyloxycarbonyl, Boc, Alloc, C₁-C₆ alkyl, C₂-C₈ alkenyl or C₇-C₉ aralkyl,

R₂ denotes hydrogen, acetyl, trifluoroacetyl, adamantyl, Fmoc, benzyloxycarbonyl, Boc, Alloc, C₁-C₆ alkyl, C₂-C₈ alkenyl or C₇-C₉ aralkyl,

and the C-terminus is represented by COR₃ in which R₃ equals OR₄ or NR₄R₅

in which R₄ equals hydrogen or C₁-C₆ alkyl

in which R₅ equals hydrogen or C₁-C₆ alkyl

as well as physiologically tolerated salts and esters thereof.

34. A peptide of 25-30 amino acids in length and having at least 25 contiguous amino acids derived from SEQ ID NO:

1 or SEQ ID NO;

2

35. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 2.

36. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 14.

37. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 an amino acid has been substituted at position 3.

38. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 1 is Ala, Gly or Lys.

39. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 2 is Thr, Ala, Val, Ile or Leu.

40. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 3 is Ala.

41. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or NO.2 the α

-amino acid in position 4 is Ala.

42. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 6 is Ala, Ile, Val, Leu or Tyr.

43. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 7 is Ala, Tyr or Ser.

44. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 9 is Ala or Glu.

45. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in positions 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 24, 28, 29 is a proteinogenic L-amino acid.

46. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 13 is a neutral proteinogenic L-amino acid.

47. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 14 is Nle, D-Nle, Ala, D-Ala, Ile, D-Ile, Val or D-Val.

48. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 14 is Ile, Val or Ala.

49. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 22 is Tyr, Leu or Val.

50. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in position 23 is Leu, Val, Tyr or Phe.

51. A peptide as claimed in claim 34, wherein in SEQ ID NO:

1 or SEQ ID NO;

2 the α

-amino acid in positions 25, 26 or 27 is a proteinogenic L-amino acid.

52. A peptide as claimed in claim 34 wherein the α

-amino acid in position 30 is Arg or Tyr.