Double-acylated GLP-1 derivatives

Patent metadata

Field	Value
Publication number	US-11034746-B2
Application number	US-201815968950-A
Country	US
Kind code	B2
Filing date	May 2, 2018
Priority date	Apr 12, 2011
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

The invention relates to 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 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 ) 2 —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 analogues. 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 24 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 K 27 , and the second K residue is designated K 24 ; wherein the analogue comprises no K residues other than the first and the second K residue;
which derivative comprises two protracting moieties attached to K 27 and K 24 , 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 )—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 Chem. 5 is included m times, wherein m is an integer in the range of 1-10:

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.

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 protracting moiety is Chem. 1.

4. The derivative of claim 3 , wherein k is 1.

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

6. The derivative of claim 5 , wherein m is an integer in the range of 1-2.

7. The derivative of claim 6 , wherein x is an integer in the range of 12-16.

8. The derivative of claim 7 , wherein the linker further comprises a Glu di-radical that is Chem. 6.

9. The derivative of claim 1 , wherein the derivative is a derivative of a GLP-1 analogue of Formula I (SEQ ID NO:3):
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Xaa 24 -Xaa 25 -Xaa 26 -Lys-Phe-Ile-Xaa 30 -Xaa 31 -Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 ,  Formula I:

(1) wherein
Xaa 7 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;
Xaa 8 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;
Xaa 12 is Phe;
Xaa 16 is selected from the group consisting of Val and Leu;
Xaa 18 is selected from the group consisting of Ser, Arg, Asn, Gln, and Glu;
Xaa 19 is selected from the group consisting of Tyr and Gln;
Xaa 20 is selected from the group consisting of Leu and Met;
Xaa 22 is selected from the group consisting of Gly, Glu and Aib;
Xaa 23 is selected from the group consisting of Gln, Glu, and Arg;
Xaa 24 is Lys;
Xaa 25 is selected from the group consisting of Ala and Val;
Xaa 26 is selected from the group consisting of Val, His, and Arg;
Xaa 30 is selected from the group consisting of Ala, Glu, and Arg;
Xaa 31 is selected from the group consisting of Trp and His;
Xaa 34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa 35 is selected from the group consisting of Gly, Aib, and absent;
Xaa 36 is selected from the group consisting of Arg, Gly and absent;
Xaa 37 is selected from the group consisting of Gly, Ala, Glu, Pro and absent;
Xaa 38 is selected from the group consisting of Ser, Gly, Ala, Glu, Gln, Pro, Arg, and absent; and
Xaa 39 is selected from the group consisting of Gly and absent.

10. The derivative of claim 9 , wherein the linker further comprises a Glu di-radical selected from the group consisting of

11. The derivative of claim 9 , wherein
Xaa 7 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;
Xaa 8 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;
Xaa 12 is Phe;
Xaa 16 is Val;
Xaa 18 is Ser;
Xaa 19 is Tyr;
Xaa 20 is Leu;
Xaa 22 is selected from the group consisting of Gly, Glu and Aib;
Xaa 23 is Gln;
Xaa 24 is Lys;
Xaa 25 is selected from the group consisting of Ala and Val;
Xaa 26 is selected from the group consisting of Val, His, and Arg;
Xaa 3 o is selected from the group consisting of Ala, Glu, and Arg;
Xaa 31 is selected from the group consisting of Trp and His;
Xaa 34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa 35 is selected from the group consisting of Gly and absent;
Xaa 36 is selected from the group consisting of Arg and absent;
Xaa 37 is selected from the group consisting of Gly and absent;
Xaa 3 s is selected from the group consisting of Ser and absent; and
Xaa 39 is selected from the group consisting of Gly and absent.

12. The derivative of claim 11 , wherein Xaa 38 and Xaa 39 are absent.

13. The derivative of claim 12 , wherein Xaa 26 is Arg.

14. The derivative of claim 13 , wherein Xaa 34 is selected from the group consisting of Gly, Gln, and Arg.

15. The derivative of claim 14 , wherein Xaa 34 is selected from the group consisting of Gly and Gln.

16. The derivative of claim 15 , wherein Xaa 30 is Glu.

17. The derivative of claim 16 , wherein Xaa 25 is Val.

18. The derivative of claim 15 , wherein Xaa 31 is His.

19. The derivative of claim 18 , wherein Xaa 35 , Xaa 36 and Xaa 37 are absent.

20. The derivative of claim 13 , wherein Xaa 34 is Arg.

21. The derivative of claim 20 , wherein Xaa 31 is His.

22. The derivative of claim 21 , wherein Xaa 25 is Val.

23. The derivative of claim 22 , wherein Xaa 36 and Xaa 37 are absent.

24. The derivative of claim 14 , wherein the protracting moiety is Chem. 1.

25. The derivative of claim 24 , further comprising a Glu di-radical that is Chem. 6:

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

26. The derivative of claim 25 , wherein n is 1 and k is 1.

27. The derivative of claim 26 , wherein m is an integer in the range of 1-3.

28. The derivative

Assignees

• Novo Nordisk As

Inventors

• Wieczorek Birgit
• Spetzler Jane
• Kruse Thomas
• Linderoth Lars
• Kofoed Jacob

Classifications

• A61K38/26

  Glucagons · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• A61P3/00

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

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61P43/00

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