GIP and GLP-1 co-agonist compounds

Patent metadata

Field	Value
Publication number	US-9474780-B2
Application number	US-201614987791-A
Country	US
Kind code	B2
Filing date	Jan 5, 2016
Priority date	Jan 9, 2015
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention relates to dual incretin peptide mimetic compounds that agonize receptors for both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and may be useful for treating type 2 diabetes mellitus (T2D).

First claim

We claim:

1. A compound of Formula:

YX 1 EGTFTSDYSIX 2 LDKIAQKAX 3 VQWLIAGGPSSGAPPPS;

wherein
X 1 is Aib;
X 2 is Aib;
K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) a -CO—(CH 2 ) b —CO 2 H wherein a is 1 to 2 and b is 10 to 20;
X 3 is Phe or 1-Nal;
and the C-terminal amino acid is optionally amidated as a C-terminal primary amide (SEQ ID NO: 11),

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X 3 is Phe.

3. The compound of claim 1 , wherein X 3 is 1-Nal.

4. The compound of claim 2 , wherein b is 14 to 18.

5. The compound of claim 4 , wherein b is 16 to 18.

6. The compound of claim 5 , wherein b is 18.

7. The compound of claim 4 , wherein a is 1.

8. The compound of claim 4 , wherein a is 2.

9. The compound of claim 4 , wherein the C-terminal amino acid is amidated as a C-terminal primary amide.

10. The compound of claim 1 , wherein
X 1 is Aib
X 2 is Aib;
K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO—(CH 2 ) 18 —CO 2 H;
X 3 is Phe;
and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 3),

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein
X 1 is Aib
X 2 is Aib;
K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 2 -CO—(CH 2 ) 18 —CO 2 H;
X 3 is 1-Nal;
and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 4),

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 10 with a pharmaceutically acceptable carrier, diluent, or excipient.

13. A method of treating type 2 diabetes mellitus, comprising administering to a patient in need thereof, an effective amount of the compound of claim 10 .

14. The method of claim 13 , further comprising administering simultaneously, separately, or sequentially in combination with an effective amount of one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, and sodium glucose co-transporters.

15. The compound of claim 1 , wherein the Formula is

16. A pharmaceutical composition comprising the compound of claim 15 with a pharmaceutically acceptable carrier, diluent, or excipient.

17. A method of treating type 2 diabetes mellitus, comprising administering to a patient in need thereof, an effective amount of the compound of claim 15 .

18. The method of claim 17 , further comprising administering simultaneously, separately, or sequentially in combination with an effective amount of one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, and sodium glucose co-transporters.

Assignees

• Lilly Co Eli

Inventors

• Bokvist Bengt Krister
• Coskun Tamer
• Cummins Robert Chadwick
• Alsina-Fernandez Jorge

Classifications

• C07K14/575 Primary

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · CPC title

• A61K38/00

  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 title

• A61K38/26 Primary

  Glucagons · CPC title

• C07K14/605

  Glucagons · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title