GLP-1 derivatives

1. A derivative of a GLP-1 peptide, wherein the GLP-1 peptide has a sequence according to Formula I:

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala-Xaa 25 -Xaa 26 -Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 , wherein

Xaa 7 is L-histidine, imidazopropionyl, α-hydroxy-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, N α -formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;

Xaa 8 is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;

Xaa 16 is Val or Leu;

Xaa 18 is Ser or Lys;

Xaa 19 is Tyr or Gln;

Xaa 20 is Leu or Met;

Xaa 22 is Gly, Glu, Lys, or Aib;

Xaa 23 is Gln, Glu, or Arg;

Xaa 25 is Ala or Val;

Xaa 26 is Val, His, Lys, or Arg;

Xaa 27 is Glu, Leu, or Lys;

Xaa 30 is Ala, Glu, Lys, or Arg;

Xaa 31 is Trp, Lys, or His;

Xaa 33 is Val or Lys;

Xaa 34 is Lys, Glu, Asn, Gly, Gln, His, Arg, or absent;

Xaa 35 is Gly, Aib, or absent;

Xaa 36 is Arg, Gly, Lys, or absent;

Xaa 37 is Gly, Ala, Glu, Pro, Lys, Arg, or absent; and

Xaa 38 is Ser, Gly, Ala, Glu, Pro, Lys, Arg, or absent;

which peptide has only two Lys residues designated a first and a second Lys residue, and a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3),

which derivative comprises two protracting moieties where one protracting group is attached to the epsilon amino group of said first Lys residue, respectively, via a linker, and the other protracting group is attached to the epsilon amino group of said second Lys residue, respectively, via a linker, wherein

the protracting moiety is selected from Chem. 15, and Chem. 16:

HOOC—(CH 2 ) x —CO—*  Chem. 15:

HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*,  Chem. 16:

in which x is an integer in the range of 10-16, and y is an integer in the range of 8-12; and

the linker comprises gGlu-Ser, wherein gGlu has the structure of Chem. 5:

and Ser has the structure of Chem. 1:

wherein the gamma carboxy group of gGlu is connected to the N-terminus of Ser in the first linker element;

or a pharmaceutically acceptable salt, amide, or ester of said derivative.

2. The derivative of claim 1 , wherein the linker further comprises Chem. 2:

or Chem. 7:

3. The derivative of claim 2 , wherein the linker comprises Chem. 3:

4. The derivative of claim 2 , wherein the linker comprises a Chem. 4:

5. The derivative of claim 1 , wherein the linker comprises Chem. 6:

6. The derivative of claim 5 , wherein the linker further comprises Chem. 12:

*—NH—(CH 2 ) 4 —CH(NH 2 )—CO—*.

7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

8. A method for treating diabetes, obesity, binge eating, bulimia nervosa, cardiovascular diseases, gastrointestinal diseases, diabetic complications, critical illness poly-nephropathy (CIPNP), systemic inflammatory response syndrome (SIRS), bacteraemia, septicaemia, septic shock and/or polycystic ovary syndrome; and/or for improving lipid parameters, improving β-cell function, and/or for delaying or preventing diabetic disease progression in a subject in need of such treatment, said method comprising administering to said subject a pharmaceutically active amount of a compound according to claim 7 .

9. The derivative according to claim 1 , wherein in the sequence of Formula I, Xaa 18 and Xaa 26 are each Lys.

10. The derivative according to claim 9 , wherein the GLP-1 peptide of Formula I has a maximum of four amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3).

11. The derivative according to claim 10 , wherein in the sequence of Formula I, Xaa 34 is selected from Gln or Arg.

12. The derivative according to claim 11 , wherein in the sequence of Formula I, Xaa 8 is Aib.

13. The derivative according to claim 1 , wherein in the sequence of Formula I, Xaa 26 and Xaa 37 are each Lys.

14. The derivative according to claim 13 , wherein the GLP-1 peptide of Formula I has a maximum of four amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3).

15. The derivative according to claim 14 , wherein in the sequence of Formula I, Xaa 34 is selected from Gln or Arg.

16. The derivative according to claim 15 , wherein in the sequence of Formula I, Xaa 8 is Aib.