Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists

Patent metadata

Field	Value
Publication number	US-9982029-B2
Application number	US-201615205689-A
Country	US
Kind code	B2
Filing date	Jul 8, 2016
Priority date	Jul 10, 2015
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention relates to dual GLP-1/glucagon receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

First claim

The invention claimed is:

1. A peptidic compound having the formula (I):

(I)

H 2 N-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-

Lys-Gln-X14-Asp-Glu-Gln-Arg-Ala-Lys-Leu-Phe-Ile-

Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Pro-Ser-Aib-Lys-

Pro-Pro-Pro-Lys-R 1

wherein X14 is an amino acid residue with a functionalized —NH 2 side chain group, selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is functionalized by —Z—C(O)—R 5 , wherein
Z is a linker comprising 1-5 amino acid linker groups selected from the group consisting of gamma glutamate (gGlu), AEEAc (amino ethoxy ethoxy acetyl), and combinations thereof in all stereoisomeric forms and
R 5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O;
X28 is an amino acid residue selected from Ala, Lys and Ser;
X29 is an amino acid residue selected from D-Ala and Gly; and
R 1 is NH 2 or OH;
or a salt or solvate thereof.

2. The compound of claim 1 , wherein R 1 is NH 2 ; or a salt or solvate thereof.

3. The compound of claim 1 , wherein the peptidic compound or the salt or solvate thereof has a relative activity of at least 0.09% compared to that of natural glucagon at the glucagon receptor.

4. The compound of claim 1 , wherein the peptidic compound or the salt or solvate thereof exhibits a relative activity of at least 0.1% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor.

5. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized with a group —Z—C(O)R 5 , wherein Z is a group selected from gGlu, gGlu-gGlu, AEEAc-AEEAc-gGlu, and AEEAc-AEEAc-AEEAc; and
R 5 is a group selected from pentadecanyl or heptadecanyl;
or a salt or solvate thereof.

6. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-;
X28 is Ala;
X29 is an amino acid residue selected from D-Ala and Gly; and
R 1 is NH 2 ;
or a salt or solvate thereof.

7. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is Ser;
X29 is an amino acid residue selected from D-Ala and Gly; and
R 1 is NH 2 ;
or a salt or solvate thereof.

8. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X28 is Lys;
X29 is an amino acid residue selected from D-Ala and Gly; and
R 1 is NH 2 ;
or a salt or solvate thereof.

9. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is an amino acid residue selected from Ala, Lys and Ser;
X29 is D-Ala;
R 1 is NH 2 ; and
or a salt or solvate thereof.

10. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-;
X28 is an amino acid residue selected from Ala, Lys and Ser;
X29 is Gly; and
R 1 is NH 2 ;
or a salt or solvate thereof.

11. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is Ala;
X29 is an amino acid residue selected from Gly and D-Ala;
R 1 is NH 2 ; and
or a salt or solvate thereof.

12. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is an amino acid residue selected from Ala, Ser and Lys;
X29 is an amino acid residue selected from Gly and D-Ala; and
R 1 is NH 2 ;
or a salt or solvate thereof.

13. The compound of claim 1 , selected from the compounds of SEQ ID NOs: 6-17, or salts or solvates thereof.

14. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 6, or a salt or solvate thereof.

15. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 7, or a salt or solvate thereof.

16. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 8, or a salt or solvate thereof.

17. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 9, or a salt or solvate thereof.

18. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 10, or a salt or solvate thereof.

19. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO:11, or a salt or solvate thereof.

20. The compound of claim 1 , wherein the compound is the compound of SEQ ID NO: 15, or a salt or solvate thereof.

21. A medicament comprising the compound of claim 1 , or a salt or solvate thereof.

22. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, which is present as an active agent together with at least one pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 , further comprising at least one additional therapeutically active agent.

24. The pharmaceutical composition of claim 23 , wherein the at least one additional therapeutically active agent is selected from the group consisting of:
insulin and insulin derivatives selected from the group consisting of: insulin glargine, insulin glusiline, insulin detemir, insulin lispro, insulin degludec, insulin aspart, basal insulin and analogues thereof, pegylated insulin, recombinant human insulin, polysialated insulins, long-acting insulin, NN1045, insulin in combination with pramlintide, PE0139, fast-acting and short-acting insulins, insulin hydrogel, oral insulin, inhalable insulin, transdermal insulin and sublingual insu

Assignees

• Sanofi Sa

Inventors

• Bossart Martin
• Evers Andreas
• Haack Torsten
• Lorenz Katrin
• Kadereit Dieter
• Wagner Michael
• Henkel Bernd

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title