Derivatives of GLP-1 analogs

• US 6,268,343 B1
• Filed: 02/26/1999
• Issued: 07/31/2001
• Est. Priority Date: 08/30/1996
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Olsen, Helle Birk, Madsen, Kjeld, Pedersen, Freddy Zimmerdahl, Bjørn, Søren Erik, Kaarsholm, Niels C., Knudsen, Liselotte Bjerre, Nielsen, Per Franklin, Huusfeldt, Per Olaf
• Primary Examiner(s): Borin, Michael
• Application Number:
  US09/258,750
• Time in Patent Office: 886 Days
• Field of Search: 530/324, 514/12
• US Class Current: 514/4.8
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/2264 Obesity-gene products, e.g. leptin
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C11D 3/0063 Photo- activating compounds
• CPC Class Codes: C11D 3/168 Organometallic compounds or orgometallic complexes

Abstract

The present invention relates to GLP-1 derivatives having a lipophilic substituent, pharmaceutical compositions comprising same, and methods of making an using same. The GLP-1 derivatives of the present invention have a protracted profile of action.

Claims

1. A GLP-1 derivative of formula I (SEQ ID NO:

2);

2. The GLP-1 derivative of claim 1, wherein the lipophilic substituent is linked to the ε

-amino group of Lys via a spacer.

3. The GLP-1 derivative of claim 2, wherein the spacer is γ

-glutamyl.

4. The GLP-1 derivative of claim 2, wherein the spacer is β

-asparagyl.

5. The GLP-1 derivative of claim 2, wherein the spacer is glycyl.

6. The GLP-1 derivative of claim 2, wherein the γ

-aminobutanoyl.

7. The GLP-1 derivative of claim 2, wherein the β

-alanyl.

8. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-tetradecanoyl), Arg³⁴-GLP-1(7-37).

9. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(ω

-carboxynonadecanoyl)), Arg³⁴-GLP-1(7-37).

10. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(ω

-carboxyheptadecanoyl)), Arg³⁴-GLP-1(7-37).

11. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(ω

-carboxyundecanoyl)), Arg³⁴-GLP-1(7-37).

12. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(ω

-carboxypentadecanoyl)), Arg³⁴-GLP-1(7-37).

13. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-lithochoyl),Arg³⁴-GLP-1(7-37).

14. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

-glutamyl(N^α

-hexadecanoyl))), Arg³⁴-GLP-1(7-37).

15. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

glutamyl(N^α

tetradecanoyl))), Arg³⁴-GLP-1(7-37).

16. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

glutamyl(N^α

lithochoyl))), Arg³⁴-GLP-1(7-37).

17. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

glutamyl(N^α

octadecanoyl))), Arg³⁴-GLP-1(7-37).

18. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-decanoyl), Arg³⁴-GLP-1(7-37).

19. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-hexadecanoyl), Arg³⁴-GLP-1(7-37).

20. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-octanoyl), Arg³⁴-GLP-1(7-37).

21. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-dodecanoyl), Arg³⁴-GLP-1(7-37).

22. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

(N⁶⁸ (γ

aminobutyroyl-(N^γ

-hexadecanoyl))), Arg³⁴-GLP-1(7-37).

23. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

-D-glutamyl(N^α

hexadecanoyl))), Arg³⁴-GLP-1(7-37).

24. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

glutamyl(N^α

-dodecanoyl))), Arg³⁴-GLP-1(7-37).

25. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(β

alanyl(N^α

-hexadecanoyl))), Arg³⁴-GLP-1(7-37).

26. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(α

-glutamyl(N^α

-hexadecanoyl))), Arg³⁴-GLP-1(7-37).

27. The GLP-1 derivative of claim 1, which is Lys²⁶(N^ε

-(γ

-glutamyl(N^α

-decanoyl))), Arg³⁴-GLP-1(7-37).

28. A pharmaceutical composition comprising a GLP-1 derivative of claim 1 and a pharmaceutically acceptable vehicle or carrier.

29. A pharmaceutical composition of claim 28, further comprising an isotonic agent, a preservative and a buffer.

30. A pharmaceutical composition of claim 29, wherein the isotonic agent is sodium chloride, mannitol and glycerol.

31. A pharmaceutical composition of claim 29, wherein the preservative is phenol, m-cresol, methyl p-hydroxybenzoate or benzyl alcohol.

32. A pharmaceutical composition of claim 29, wherein the buffer is sodium acetate or sodium phosphate.

33. A pharmaceutical composition of claim 28, further comprising a surfactant.

34. A pharmaceutical composition of claim 28, further comprising zinc.

35. A pharmaceutical composition of claim 28, further comprising another antidiabetic agent.

36. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is human insulin.

37. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is a hypoglycemic agent.

38. A pharmaceutical composition of claim 28, further comprising another antiobesity agent.

39. A method of treating diabetes, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.

40. A method of treating obesity, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.