Insulin derivatives

• US 8,828,923 B2
• Filed: 09/16/2009
• Issued: 09/09/2014
• Est. Priority Date: 08/05/2003
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Jonassen, Ib, Hoeg-Jensen, Thomas, Havelund, Svend, Ribel-Madsen, Ulla, Tagmose, Tina Mller, Madsen, Peter
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): TELLER, ROY R
• Application Number:
  US12/560,833
• Publication Number:
  US 20100009899A1
• Time in Patent Office: 1,819 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The present invention relates to insulin derivatives which are naturally occurring insulins or analogues thereof which have a side chain attached either to the α-amino group of the N-terminal amino acid residue of the B chain or to the ε-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula:
—W—X—Y—Z
wherein W, X, Y and Z are as defined in the disclosure.

Claims

1. An insulin derivative which is a naturally occurring insulin or an analogue thereof which has a side chain attached to the α

-amino group of the N-terminal amino acid residue of the B chain or to the ε

-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula;

—

W—

X—

Y—

Z

wherein

W is two amino acid residues linked together via amide bonds, which chain—

via an amide bond—

is linked to the α

-amino group of the N-terminal amino acid residue of the B chain or to the ε

-amino group of a Lys residue present in the B chain of the parent insulin, the amino acid residues of W being selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain so that W has at least one amino acid residue which has a carboxylic acid group in the side chain;

X is —

CO—

;

Y is —

(CH₂)_m—

where m is an integer in the range of 6 to 32; and

Z is —

COOH;

and any Zn²⁺complexes thereof.

2. An insulin derivative according to claim 1, wherein side chain —

W—

X—

Y—

Z is attached to the ε

-amino group of a Lys residue present in the B chain of the parent insulin.

3. An insulin derivative according to claim 1, wherein W is a chain composed of two α

-amino acid residues of which one has from 4 to 10 carbon atoms and a free carboxylic acid group while the other has from 2 to 11 carbon atoms but no free carboxylic acid group.

4. An insulin derivative according to claim 3 wherein W is selected from the group consisting of α

-Asp-Gly;

Gly-α

-Asp;

β

-Asp-Gly;

Gly-β

-Asp;

α

-Glu-Gly;

Gly-α

-Glu;

γ

-Glu-Gly;

Gly-γ

-Glu;

α

-hGlu-Gly;

Gly-α

-hGlu;

δ

-hGlu-Gly; and

Gly-δ

-hGlu.

5. An insulin derivative according to claim 1, wherein W is a chain composed of two α

-amino acid residues, independently having from 4 to 10 carbon atoms, and both having a free carboxylic acid group.

6. An insulin derivative according to claim 5, wherein W is selected from the group consisting of α

-Asp-α

-Asp;

α

-Asp-α

-Glu;

α

-Asp-α

-hGlu;

α

-Asp-β

-Asp;

α

-Aspγ

-Glu;

α

-Asp-δ

-hGlu;

β

-Asp-α

-Asp;

β

-Asp-α

-Glu;

β

-Asp-α

-hGlu;

β

-Asp-β

-Asp;

β

-Asp-γ

-Glu;

β

-Asp-δ

-hGlu;

α

-Glu-α

-Asp;

α

-Glu-α

-Glu;

α

-Glu-α

-hGlu;

α

-Glu-β

-Asp;

α

-Glu-γ

-Glu;

α

-Glu-δ

-hGlu;

γ

-Glu-α

-Asp;

γ

-Glu-α

-Glu;

γ

-Glu-α

-hGlu;

γ

-Glu-β

-Asp;

γ

-Glu-γ

-Glu;

γ

-Glu-δ

-hGlu;

α

-hGlu-α

-Asp;

α

-hGlu-α

-Glu;

α

-hGlu-α

-hGlu;

α

-hGlu-β

-Asp;

α

-hGlu-γ

-Glu;

α

-hGlu-δ

-hGlu;

δ

-hGlu-α

-Asp;

δ

-hGlu-α

-Glu;

δ

-hGlu-α

-hGlu;

δ

-hGlu-β

-Asp;

δ

-hGlu-γ

-Glu; and

δ

-hGlu-δ

-hGlu.

7. An insulin derivative according to claim 1, wherein Y is —

(CH₂)_m—

where m is an integer in the range of from 12-16.

8. An insulin derivative according to claim 1, wherein the parent insulin is des(B30) human insulin.

9. An insulin derivative according to claim 1, wherein the insulin derivative is selected from the group consisting of N^ε

B29—

(N-HOOC(CH₂)₁₆CO-γ

-Glu-N-(γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N-HOOC(CH₂)₁₆CO-α

-Glu)-N-(β

-Asp) des(B30) human insulin; and

N<sup>ε

B29</sup>—

(N-HOOC(CH₂)₁₆CO-α

-Glu)-N-(AspAsp) des(B30) human insulin.

10. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds two zinc ions.

11. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds three zinc ions.

12. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds four zinc ions.

13. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, said composition comprising a therapeutically effective amount of an insulin derivative according to claim 1 together with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, said composition comprising a therapeutically effective amount of an insulin derivative according to claim 1 in mixture with an insulin or an insulin analogue which has a rapid onset of action, together with a pharmaceutically acceptable carrier.

15. A method of treating diabetes, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of an insulin derivative according to claim 1 together with a pharmaceutically acceptable carrier.

16. A method of treating diabetes, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of an insulin derivative according to claim 1 in mixture with an insulin or an insulin analogue which has a rapid onset of action, together with a pharmaceutically acceptable carrier.