Exendin-4 derivatives as selective glucagon receptor agonists

• US 9,932,381 B2
• Filed: 06/12/2015
• Issued: 04/03/2018
• Est. Priority Date: 06/18/2014
• Status: Active Grant

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Haack, Torsten, Stengelin, Siegfried, Evers, Andreas, Wagner, Michael, Henkel, Bernd
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US14/738,261
• Publication Number:
  US 20150368311A1
• Time in Patent Office: 1,026 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The present invention relates to glucagon receptor agonists and their medical use, for example in the treatment of severe hypoglycemia.

Claims

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

Tza-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Lys-Gln-X14-Glu-Ser-Arg-Arg-Ala-Gln-X21-Phe-Ile-Glu-Trp-Leu-Leu-Ala-X29-Gly-Pro-Glu-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R¹ 

 

(I)

wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phe, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine, Cyclohexylglycine and tert-Leucine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents an amino acid residue selected from Gly and Thr; and

R¹ represents OH or NH₂;

or a salt or solvate thereof.

2. The peptidic compound of claim 1, wherein R¹ represents OH.

3. The peptidic compound of claim 1, wherein,

X10 represents Leu;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents an amino acid residue selected from Gly and Thr; and

R¹ represents OH;

or a salt or solvate thereof.

4. The peptidic compound of claim 1, wherein,

X10 represents Tyr;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents Glu;

X29 represents an amino acid residue selected from Gly and Thr; and

R¹ represents OH;

or a salt or solvate thereof.

5. The peptidic compound of claim 1, wherein,

X10 represents 1-Naphthylalanine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents Thr; and

R¹ represents OH;

or a salt or solvate thereof.

6. The peptidic compound of claim 1, wherein,

X10 represents Cyclohexylglycine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents Thr; and

R¹ represents OH;

or a salt or solvate thereof.

7. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine and Cyclohexylglycine;

X14 represents Leu;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents an amino acid residue selected from Gly and Thr; and

R¹ represents OH;

or a salt or solvate thereof.

8. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Ile, Phe, 1-Naphthylalanine, Cyclohexylglycine and tert-Leucine;

X14 represents Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents Thr; and

R¹ represents OH;

or a salt or solvate thereof.

9. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Leu, Phe, 1-Naphthylalanine, 2-Fluorophenylalanine and Cyclohexylglycine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents Asp;

X29 represents Thr; and

R¹ represents OH;

or a salt or solvate thereof.

10. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phenylglycine, 1-Naphthylalanine, Cyclohexylglycine and tert-Leucine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents Glu;

X29 represents an amino acid residue selected from Gly and Thr; and

R¹ represents OH;

or a salt or solvate thereof.

11. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phe, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine, Cyclohexylglycine and tert-Leucine;

X14 represents an amino acid residue selected from Leu and Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents Thr; and

R¹ represents OH;

or a salt or solvate thereof.

12. The peptidic compound of claim 1, wherein,

X10 represents an amino acid residue selected from Tyr, Leu and Val;

X14 represents Leu;

X21 represents Glu;

X29 represents Gly; and

R¹ represents OH;

or a salt or solvate thereof.

13. The peptidic compound of claim 1, wherein the peptidic compound is selected from the compounds of SEQ ID NO:

3-25 or a salt or solvate thereof.

14. The peptidic compound of claim 1, wherein the peptidic compound is selected from the compounds of SEQ ID NO:

3, 5, 6, 9, 15, 20, 23, 24 and 25 or a salt or solvate thereof.

15. A pharmaceutical composition comprising the peptidic compound of claim 1 and at least one pharmaceutically acceptable carrier.

16. A method for treating hypoglycemia or type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1.

17. A pharmaceutical composition comprising at least one peptidic compound of claim 1 or a physiologically acceptable salt or solvent thereof.

18. A method for treating hypoglycemia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1.

19. The method of claim 18, wherein the at least one peptidic compound and the at least one other compound are administered simultaneously, separately, or sequentially.

20. The method of claim 18, wherein the at least one peptidic compound is administered parenterally.

21. A method for treating hypoglycemia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1 and a therapeutically effective amount of at least one other compound useful for treating hypoglycemia.