Compounds as peptidic trigonal GLP1/glucagon/GIP receptor agonists

Patent metadata

Field	Value
Publication number	US-10538567-B2
Application number	US-201715829680-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Dec 2, 2016
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present invention relates to trigonal GLP-1/glucagon/GIP 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 compound of the formula I:
H 2 N-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-X14-Glu-Glu-Gln-Arg-Gln-X20-Glu-Phe-Ile-Glu-Trp-Leu-Lys-Ala-X29-Gly-X31-Pro-Ser-Aib-Lys-Pro-Pro-Pro-Lys-R 1   I

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 in all stereoisomeric forms and
R 5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,

X20 is an amino acid residue selected from Aib and Lys,
X29 is an amino acid residue selected from D-Ala and Gly,
X31 is an amino acid residue selected from His and Pro,
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 , or the salt or solvate thereof, which has a relative activity of at least 5% compared to that of natural glucagon at the glucagon receptor.

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

5. The compound of claim 1 , or the salt or solvate thereof, which exhibits a relative activity of at least 4% compared to that of GIP at the GIP receptor.

6. The compound of claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized with the group —Z—C(O)R 5 , wherein:
Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc; and
R 5 is a group selected from pentadecanyl and heptadecanyl;
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 with a group —Z—C(O)R 5 , wherein:
Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA- and gGlu-gGlu-AEEAc; and
R 5 is a group selected from pentadecanyl and heptadecanyl:
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-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4 S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4 S)-4-Carboxy-4-octadecanoyl amino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-; 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 a group selected from (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, and (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl; and
R 1 is NH 2 ;
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-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X20 is selected from Lys and Aib;
X29 is an amino acid residue selected from D-Ala and Gly;
X31 is an amino acid residue selected from His and Pro; 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 a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X20 is Lys;
X29 is an amino acid residue selected from D-Ala and Gly;
X31 is an amino acid residue selected from His and Pro; and
R 1 is NH 2 ;
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 a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X20 is Lys;
X29 is an amino acid residue selected from D-Ala and Gly;
X31 is His; and
R 1 is NH 2 ;
or a salt or solvate thereof.

13. The compound of claim 1 , wherein:
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X20 is Lys;
X29 is Gly;
X31 is an amino acid residue selected from His and Pro; and
R 1 is NH 2 ;
or a salt or solvate thereof.

14. The compound of claim 1 , wherein:
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X20 is Aib;
X29 is an amino acid residue selected from D-Ala and Gly;
X31 is an amino acid residue selected from His and Pro; and
R 1 is NH 2 ;
or a salt or solvate thereof.

15. The compound of claim 1 , wherein:
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X20 is Aib;
X29 is an amino acid residue selected from D-Ala and Gly;
X31 is Pro; and
R 1 is NH 2 ;
or a salt or solvate thereof.

16. 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-;
X20 is Aib;
X29 is D-Ala;
X31 is an amino acid residue selected from His and Pro; and
R 1 is NH 2 ;
or a salt or solvate thereof.

17. The compound of claim 1 , selected from the compounds of SEQ ID NOs: 6-27, or salts or solvates thereof.

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

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

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

21. A pharmaceutical composition 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 21 , 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; GLP-1, GLP-1 analogues and GLP-1 receptor agonists;
DPP-4 inhibitors; SGLT2 inhibitors; dual SGLT2/SGLT1 inhibitors;
biguanides, thiazolidinediones, dual PPAR agonists, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, amylin and amy

Assignees

• Sanofi Sa

Inventors

• Bossart Martin
• Evers Andreas
• Haack Torsten
• Kadereit Dieter
• Lorenz Katrin
• Wagner Michael
• Pfeiffer-Marek Stefania
• Lorenz Martin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · 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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title