Insulin derivatives and the medical uses hereof

1. An insulin derivative, which insulin derivative is an acylated analogue of human insulin, which analogue is

[A22K, desB27, B29R, desB30] relative to human insulin;

and which insulin analogue is derivatized by acylation of the epsilon amino group of the lysine residue at the A22 position with a group of Formula II:

[Acyl]-[Linker]-

wherein the Linker group is an amino acid chain composed of from 1 to 10 amino acid residues selected from -gGlu- and -OEG-; wherein

gGlu represents a gamma glutamic acid residue;

OEG represents the residue of 8-amino-3,6-dioxaoctanoic acid (i.e. a group of the formula —NH—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —CO—);

which amino acid residues may be present in any order; and

which amino acid chain comprises at least one gGlu residue; and

wherein the Acyl group is a residue of an α,ω-di-carboxylic acid selected from

1,14-tetradecanedioic acid;

1,15-pentadecanedioic acid; and

1,16-hexadecanedioic acid;

which acylated analogue, may only comprise additional substitution of A14E, and/or B3E or B3Q.

2. The insulin derivative according to claim 1 , which analogue is [A14E, A22K, B3E, desB27, B29R, desB30], [A14E, A22K, desB27, B29R, desB30], [A22K, B3E, desB27, B29R, desB30], [A22K, B3Q, desB27, B29R, desB30], or [A22K, desB27, B29R, desB30] relative to human insulin, and which insulin analogue is acylated at the epsilon amino group of the lysine residue at the A22 position.

3. The insulin derivative according to claim 1 , wherein the Linker group is selected from -gGlu-; -2×gGlu-; -3×gGlu-; -4×gGlu-; -gGlu-2×OEG-; -gGlu-3×(OEG-gGlu)-; -4×gGlu-2×OEG-; -2×OEG-; and -2×OEG-gGlu-.

4. The insulin derivative according to claim 3 , wherein the Linker group is selected from -gGlu-; -2×gGlu-; -4×gGlu-; -gGlu-2×OEG-; -gGlu-3×(OEG-gGlu)-; -2×OEG-; and -2×OEG-gGlu-.

5. The insulin derivative according to claim 4 , wherein the Linker group is -4×gGlu-.

6. The insulin derivative according to claim 1 , wherein the Acyl group is a di-acid group derived from 1,14-tetradecanedioic acid; 1,15-pentadecanedioic acid; or 1,16-hexadecanedioic acid.

7. The insulin derivative according to claim 6 , wherein the Acyl group is a 1,14-tetradecanedioic acid.

8. The insulin derivative according to claim 1 , wherein the group of Formula II (i.e. [Acyl]-[Linker]-) is tetradecanedioyl-gGlu-; tetradecanedioyl-2×gGlu-; tetradecanedioyl-3×gGlu-; tetradecanedioyl-4×gGlu-; tetradecanedioyl-gGlu-2×OEG-; tetradecanedioyl-4×gGlu-2×OEG-; tetradecanedioyl-2×OEG-; pentadecanedioyl-4×gGlu; hexadecanedioyl-4×gGlu-; hexadecanedioyl-gGlu-2×OEG-; or hexadecanedioyl-3×(gGlu-OEG)-gGlu-.

9. The insulin derivative according to claim 8 , wherein the group of Formula II (i.e. [Acyl]-[Linker]-) is tetradecanedioyl-4×gGlu-.

10. A pharmaceutical composition comprising an insulin derivative according to claim 1 , and one or more pharmaceutically acceptable carriers or diluents.

11. The pharmaceutical composition according to claim 10 , formulated as a low-zinc composition, with no added zinc ions.

12. The pharmaceutical composition according to claim 11 , formulated as a low-zinc composition, comprising less than 0.2 Zn 2+ ions per 6 insulin molecules.

13. The low-zinc pharmaceutical composition according to claim 11 , wherein no surfactant has been added.

14. The low-zinc pharmaceutical composition according to claim 11 , comprising a nicotinic compound, and in particular nicotinamide.

15. The pharmaceutical composition according to claim 10 , formulated as a low-zinc composition, with no added zinc ions, and comprising an acylated analogue of human insulin selected from:

A22K(N(eps)-tetradecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-3×(gGlu-OEG)-gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-pentadecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-4×gGlu), B3Q, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-gGlu-2×OEG), B3Q, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-3×(gGlu-OEG)-gGlu), B3Q, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3Q, desB27, B29R, desB30 human insulin;

A22K(N(eps)-hexadecanedioyl-4×gGlu), B3Q, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-4×gGlu-2×OEG), desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-4×gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin;

A14E, A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin;

A14E, A22K(N(eps)-tetradecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-2×gGlu), B3E, desB27, B29R, desB30 human insulin;

A22K(N(eps)-tetradecanedioyl-gGlu), B3E, desB27, B29R, desB30 human insulin; and

A22K(N(eps)-tetradecanedioyl-3×gGlu), B3E, desB27, B29R, desB30 human insulin.

16. A method for the treatment or alleviation of a disease, disorder or condition relating to diabetes, Type 1 diabetes, Type 2 diabetes, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, metabolic syndrome (metabolic syndrome X, insulin resistance syndrome), hypertension, cognitive disorders, atherosclerosis, myocardial infarction, stroke, cardiovascular disorders, coronary heart disease, inflammatory bowel syndrome, dyspepsia, or gastric ulcers, which method comprises administration to a subject in need thereof a therapeutically effective amount of the insulin derivative according to claim 1 .

17. The insulin derivative according to claim 1 , which acylated analogue additionally comprises the A14E substitution.

18. The insulin derivative according to claim 1 , which acylated analogue additionally comprises the A14E and B3E substitutions.

19. The insulin derivative according to claim 1 , which acylated analogue additionally comprises the B3E substitution.

20. The insulin derivative according to claim 1 , which acylated analogue additionally comprises the B3Q substitution.

21. The insulin derivative according to claim 1 , which analogue is [A14E, A22K, desB27, B29R, desB30], [A22K, B3E, desB27, B29R, desB30], [A22K, B3Q, desB27, B29R, desB30], or [A22K, desB27, B29R, desB30] relative to human insulin, and which insulin analogue is acylated at the epsilon amino group of the lysine residue at the A22 position.

22. The insulin derivative according to claim 21 , which analogue is [A22K, B3E, desB27, B29R, desB30] relative to human insulin, and which insulin analogue is acylated at the epsilon amino group of the lysine residue at the A22 position.

23. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-4×gGlu), desB27, B29R, desB30 human insulin.

24. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin.

25. The insulin derivative according to claim 1 , which is A14E, A22K(N(eps)-tetradecanedioyl-4×gGlu), desB27, B29R, desB30 human insulin.

26. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin.

27. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin.

28. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-3×(gGlu-OEG)-gGlu), B3E, desB27, B29R, desB30 human insulin.

29. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-4×gGlu), B3Q, desB27, B29R, desB30 human insulin.

30. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-gGlu-2×OEG), B3Q, desB27, B29R, desB30 human insulin.

31. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-3×(gGlu-OEG)-gGlu), B3Q, desB27, B29R, desB30 human insulin.

32. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-2×gGlu), desB27, B29R, desB30 human insulin.

33. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-4×gGlu), desB27, B29R, desB30 human insulin.

34. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-gGlu-2×OEG), desB27, B29R, desB30 human insulin.

35. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-3×(gGlu-OEG)-gGlu), desB27, B29R, desB30 human insulin.

36. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-gGlu), desB27, B29R, desB30 human insulin.

37. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin.

38. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3Q, desB27, B29R, desB30 human insulin.

39. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-2×OEG), desB27, B29R, desB30 human insulin.

40. The insulin derivative according to claim 1 , which is A22K(N(eps)-hexadecanedioyl-4×gGlu), B3Q, desB27, B29R, desB30 human insulin.

41. The insulin derivative according to claim 1 , which is A22K(N(eps)-pentadecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin.

42. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-4×gGlu-2×OEG), desB27, B29R, desB30 human insulin.

43. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-4×gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin.

44. The insulin derivative according to claim 1 , which is A14E, A22K(N(eps)-tetradecanedioyl-gGlu-2×OEG), B3E, desB27, B29R, desB30 human insulin.

45. The insulin derivative according to claim 1 , which is A14E, A22K(N(eps)-tetradecanedioyl-4×gGlu), B3E, desB27, B29R, desB30 human insulin.

46. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-2×gGlu), B3E, desB27, B29R, desB30 human insulin.

47. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-gGlu), B3E, desB27, B29R, desB30 human insulin.

48. The insulin derivative according to claim 1 , which is A22K(N(eps)-tetradecanedioyl-3×gGlu), B3E, desB27, B29R, desB30 human insulin.