Novel Insulin Derivatives

• US 20100009899A1
• Filed: 09/16/2009
• Published: 01/14/2010
• Est. Priority Date: 08/05/2003
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Madsen, Peter, Havelund, Svend, Tagmose, Tina Møller, Hoeg-Jensen, Thomas, Ribel-Madsen, Ulla, Jonassen, Ib
• Granted Patent: US 8,828,923 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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;

an α

-amino acid residue having a carboxylic acid group in the side chain which residue forms, with one of its carboxylic acid groups, an amide group together with the α

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

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

a chain composed of two, three or four α

-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;

or

a covalent bond from X 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;

X is;

—

CO—

;

—

CH(COOH)CO—

;

—

N(CH₂COOH)CH₂CO—

;

—

N(CH₂COOH)CH₂CON(CH₂COOH)CH₂CO—

;

—

N(CH₂CH₂COOH)CH₂CH₂CO—

;

—

N(CH₂CH₂COOH)CH₂CH₂CON(CH₂CH₂COOH)CH₂CH₂CO—

;

—

NHCH(COOH)(CH₂)₄NHCO—

;

—

N(CH₂CH₂COOH)CH₂CO—

;

or

—

N(CH₂COOH)CH₂CH₂CO—

.

that

a) when W is an amino acid residue or a chain of amino acid residues, via a bond from the underscored carbonyl carbon forms an amide bond with an amino group in W, or

b) when W is a covalent bond, via a bond from the underscored carbonyl carbon forms an amide bond with the N-terminal α

-amino group in the B chain or with the ε

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

Y is;

—

(CH₂)_m—

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

a divalent hydrocarbon chain comprising 1, 2 or 3 —

CH═

CH—

groups and a number of —

CH₂—

groups sufficient to give a total number of carbon atoms in the chain in the range of 10 to 32;

a divalent hydrocarbon chain of the formula —

(CH₂)_vC₆H₄(CH₂)_w—

wherein v and w are integers or one of them is zero so that the sum of v and w is in the range of 6 to 30; and

Z is;

—

COOH;

—

CO—

Asp;

—

CO—

Glu;

—

CO—

Gly;

—

CO—

Sar;

—

CH(COOH)₂;

—

N(CH₂COOH)₂;

—

SO₃H;

or

—

PO₃H;

and any Zn²⁺ complexes thereof, provided that when W is a covalent bond and X is —

CO—

, then Z is different from —

COOH.

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

W—

X—

Y—

Z is attached to the ε

-amino group of the N-terminal amino acid residue of the B chain of the parent insulin.

3. 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.

4. An insulin derivative according to claim 1, wherein W is a covalent bond.

5. An insulin derivative according to claim 1, wherein W is an α

-amino acid residue having from 4 to 10 carbon atoms.

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

-Asp, β

-Asp, α

-Glu, γ

-Glu, α

-hGlu and δ

-hGlu.

7. 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.

8. An insulin derivative according to claim 7 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.

9. 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.

10. An insulin derivative according to claim 9, 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

-Asp-γ

-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.

11. An insulin derivative according to claim 1, wherein X is —

CO—

or —

CH(COOH)CO—

.

12. An insulin derivative according to claim 1, wherein X is

—

N(CH₂COOH)CH₂CO—

;

—

N(CH₂COOH)CH₂CON(CH₂COOH)CH₂CO—

;

—

N(CH₂CH₂COOH)CH₂CH₂CO—

;

—

N(CH₂CH₂COOH)CH₂CH₂CON(CH₂CH₂COOH)CH₂CH₂CO—

—

N(CH₂CH₂COOH)CH₂CO—

;

or

—

N(CH₂COOH)CH₂CH₂CO—

.

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

(CH₂)_m—

where m is an integer in the range of from 6 to 32, from 8 to 20, from 12 to 20 or from 12-16.

14. An insulin derivative according to claim 1, wherein Z is —

COOH.

15. An insulin derivative according to claim 1, wherein Z is —

CH(COOH)₂.

16. An insulin derivative according to claim 1, wherein Z is —

N(CH₂COOH)₂.

17. An insulin derivative according to claim 1, wherein Z is —

SO₃H.

18. An insulin derivative according to claim 1, wherein Z is —

PO₃H.

19. An insulin derivative according to claim 1, wherein the parent insulin has Asn or Gly at position A21.

20. An insulin derivative according to claim 1, wherein the parent insulin is a des(B1) analogue.

21. An insulin derivative according to claim 1, wherein the parent insulin is a des(B30) analogue.

22. An insulin derivative according to claim 1, wherein position B29 in the parent insulin can be any codable amino acid except Cys, Met, Arg and Lys and the amino acid in position B30 is Lys.

23. An insulin derivative according to claim 1, wherein the parent insulin has Thr at position B29 and Lys at position B30.

24. An insulin derivative according to claim 1, wherein the parent insulin is selected from the group consisting of human insulin;

des(B1) human insulin;

des(B30) human insulin;

Gly^A21 human insulin;

Gly^A21 des(B30)human insulin;

Asp^B28 human insulin;

porcine insulin;

Lys^B28Pro^B29 human insulin;

Gly^A21Arg^B31Arg^B32 human insulin; and

Lys^B3Gly^B29 human insulin.

25. An insulin derivative according to claim 1 selected from the group consisting of N^ε

B29—

(N^α

-(HOOC(CH₂)₁₄CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₅CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₆CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₇CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₈CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-γ

-Glu—

N—

(γ

-Glu)) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(Asp-OC(CH</sup>₂)₁₆CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(Glu—

OC(CH</sup>₂)₁₄CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(Glu—

OC(CH</sup>₂)₁₄CO—

) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(Asp—

OC(CH</sup>₂)₁₆CO—

) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-α

-Glu—

N-(β

-Asp)) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Gly—

OC(CH₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(Sar—

OC(CH</sup>₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(HOOC(CH</sup>₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

(N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₃CO)-β

-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₃CO)-α

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₆CO)-γ

-D-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N<sup>α

-(HOOC(CH</sup>₂)₁₄CO)-β

-D—

Asp) des(B30) human insulin N<sup>ε

B29</sup>—

(N^α

-(HOOC(CH₂)₁₄CO)-β

-D-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N—

HOOC(CH₂)₁₆CO-β

-D-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N—

HOOC(CH₂)₁₄CO—

IDA) des(B30) human insulin;

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₆CO)—

N-(carboxyethyl)-Gly] des(B30) human insulin;

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₄CO)—

N-(carboxyethyl)-Gly] des(B30) human insulin; and

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₄CO)—

N-(carboxymethyl)-β

-Ala] des(B30) human insulin.

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

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

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

29. 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.

30. 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.

31. 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.

32. 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.