Double-acylated GLP-1 derivatives

Patent metadata

Field	Value
Publication number	US-9527900-B2
Application number	US-201514961064-A
Country	US
Kind code	B2
Filing date	Dec 7, 2015
Priority date	Apr 12, 2011
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position T of GLP-1(7-37), where T is an integer in the range of 7-37 except 18 and 27; and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K 27 , and the second K residue is designated K T ; which derivative comprises two albumin binding moieties attached to K 27 and K T , respectively, via a linker, wherein the albumin binding moiety comprises a protracting moiety selected from HOOC—(CH 2 ) x —CO— and HOOC—C 6 H 4 —O—(CH 2 ) y —CO—; in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; wherein the linker comprises an element of the formula —NH—(CH 2 ) 2 —(O—(CH 2 ) 2 ) k —O—(CH 2 ) n —CO—, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel GLP-1 analogs. The derivatives are suitable for oral administration.

First claim

The invention claimed is:

1. A derivative of a GLP-1 analogue,
which analogue comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position 37 of GLP-1(7-37), and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K27, and the second K residue is designated K37;
which derivative comprises two protracting moieties attached to K27 and K37, respectively, via a linker, wherein
the protracting moiety is selected from the group consisting of Chem. 2 and Chem. 1:
HOOC—C 6 H 4 —O—(CH 2 ) y -CO—*  Chem. 2

HOOC(CH 2 ) x -CO—*,  Chem. 1

in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; and
the linker comprises Chem. 5:

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5 and wherein Chem. 5 is included m times, wherein m is an integer in the range of 1-10;
or a pharmaceutically acceptable salt, amide, or ester thereof.

2. The derivative of claim 1 , wherein the linker further comprises a Glu di-radical selected from the group consisting of

wherein the Glu di-radical is included p times, wherein p is an integer in the range of 1-2.

3. The derivative of claim 2 , wherein the analogue comprises no K residues other than the first and the second K residue.

4. The derivative of claim 3 , wherein the protracting moiety is Chem. 1.

5. The derivative of claim 4 , wherein k is 1.

6. The derivative of claim 5 , wherein n is 1.

7. The derivative of claim 6 , wherein m is an integer in the range of 1-2.

8. The derivative of claim 7 , wherein x is an integer in the range of 12-16.

9. The derivative of claim 8 , wherein the linker further comprises a Glu di-radical that is Chem. 6.

10. The derivative of claim 3 , wherein the protracting moiety is Chem. 2.

11. The derivative of claim 9 , wherein k is 1.

12. The derivative of claim 11 , wherein n is 1.

13. The derivative of claim 12 , wherein m is an integer in the range of 1-2.

14. The derivative of claim 13 , wherein y is an integer in the range of 9-11.

15. The derivative of claim 14 , wherein the linker further comprises a Glu di-radical that is Chem. 6.

16. The derivative of claim 15 , wherein m is 2.

17. The derivative of claim 16 , wherein y is 9.

18. The derivative of claim 17 , wherein p is 1.

19. The derivative of claim 1 , wherein the derivative is a derivative of a GLP-1 analogue of Formula I (SEQ. ID NO: 3):
Xaa7-Xaa8-Glu-Gly-Thr-Xaa12-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26-Lys-Phe-Ile-Xaa30-Xaa31-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39,
wherein
Xaa7 is selected from the group consisting of 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, and 4-pyridylalanine;
Xaa8 is selected from the group consisting of 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, and (1-aminocyclooctyl) carboxylic acid;
Xaa12 is selected from the group consisting of Lys and Phe;
Xaa16 is selected from the group consisting of Val and Leu;
Xaa28 is selected from the group consisting of Ser, Arg, Asn, Gln, and Glu;
Xaa19 is selected from the group consisting of Tyr and Gln;
Xaa20 is selected from the group consisting of Leu, Lys, and Met;
Xaa22 is selected from the group consisting of Gly, Glu, Lys, and Aib;
Xaa23 is selected from the group consisting of Gln, Glu, and Arg;
Xaa24 is selected from the group consisting of Ala and Lys;
Xaa25 is selected from the group consisting of Ala and Val;
Xaa26 is selected from the group consisting of Val, His, and Arg;
Xaa30 is selected from the group consisting of Ala, Glu, and Arg;
Xaa31 is selected from the group consisting of Trp and His;
Xaa34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa35 is selected from the group consisting of Gly, Aib and absent;
Xaa36 is selected from the group consisting of Arg, Gly, Lys and absent;
Xaa37 is Lys;
Xaa38 is selected from the group consisting of Ser, Gly, Ala, Glu, Gln, Pro, Arg, and absent; and
Xaa39 is selected from the group consisting of Gly and absent.

20. The derivative of claim 19 , wherein the linker further comprises a Glu di-radical selected from the group consisting of

wherein the Glu di-radical is included p times, wherein p is an integer in the range of 1-2.

21. The derivative of claim 20 , wherein the analogue comprises no K residues other than the first and the second K residue.

22. The derivative of claim 21 , wherein
Xaa7 is L-histidine;
Xaa8 is selected from the group consisting of Ala, Gly, Val, Leu, Ile, Thr, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, and (1-aminocyclooctyl) carboxylic acid;
Xaa12 is Phe;
Xaa16 is Val;
Xaa18 is Ser;
Xaa19 is Tyr;
Xaa20 is Leu;
Xaa22 is selected from the group consisting of Gly, Glu, and Aib;
Xaa23 is selected from the group consisting of Gln, Glu, and Arg;
Xaa24 is Ala;
Xaa25 is selected from the group consisting of Ala and Val;
Xaa26 is selected from the group consisting of Val, His, and Arg;
Xaa30 is Ala;
Xaa31 is selected from the group consisting of Trp and His;
Xaa34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa35 is Gly; and
Xaa36 is selected from the group consisting of Arg, Gly, and absent.

23. The derivative of claim 22 , wherein
Xaa26 is Arg; and
Xaa34 is selected from the group consisting of Gln, and Arg.

24. The derivative of claim 23 , wherein Xaa22 is Glu.

25. The derivative of claim 24 , wherein
Xaa34 is Arg.

26. The derivative of claim 25 , wherein the protracting moiety is Chem. 2.

27. The derivative of claim 26 , wherein the Glu di-radical is Chem. 6.

28. The derivative of claim 27 , wherein n is 1 and k is 1.

29. The derivative of claim 28 , wherein m is an integer in the range of 1-3.

30. The derivative of claim 29 , wherein y is an integer in the range of 9-11.

31. The derivative of claim 30 , wherein p is 1.

32. The derivative of claim 23 , wherein the protracting moiety is Chem. 1.

33. The derivative of claim 32 , wherein the Glu di-radical is Chem. 6.

34. The derivative of claim 33 , wherein n is 1 and k is 1.

35. The derivative of claim 34 , wherein m is an integer in the range of 1-3.

36. The derivative of claim 32 , wherein x is an

Assignees

• Novo Nordisk As

Inventors

• Linderoth Lars
• Kofoed Jacob

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title