Fatty acid modified urocortin-2 analogs for the treatment of diabetes and chronic kidney disease

Patent metadata

Field	Value
Publication number	US-10894817-B2
Application number	US-201715648542-A
Country	US
Kind code	B2
Filing date	Jul 13, 2017
Priority date	Jul 15, 2016
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

The present invention provides a compound or a pharmaceutically acceptable salt of the Formula:

X 1 IVX 2 SLDVPIGLLQILX 3 EQEKQEKEKQQAK*TNAX 4 ILAQV-NH 2
wherein the X 1 denotes that the I residue is modified by either acetylation or methylation at the N-terminus; wherein X 2 is L or T; wherein X 3 is L or I; wherein X 4 is Q or E; and wherein a modified K residue (“K*”) at position 29 is modified through conjugation to the epsilon-amino group of the K-side chain with a group of the formula —X 5 —X 6 , wherein X 5 is selected from the group consisting of one to four amino acids; one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties; and combinations of one to four amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties; and X 6 is a C 14 -C 24 fatty acid. In some embodiments, the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) x —CO 2 H where x is 16 or 18.

First claim

We claim:

1. A compound of the Formula:
X 1 IVX 2 SLDVPIGLLQILX 3 EQEKQEKEKQQAK*TNAX 4 ILAQV-NH 2   (Formula II),

wherein X 1 denotes that the I residue is modified by either acetylation or methylation at the N-terminus,
wherein X 2 is L or T,
wherein X 3 is L or I,
wherein X 4 is Q or E,
wherein a modified K residue (“K*”) at position 29 is modified through conjugation to the epsilon-amino group of the K-side chain with a group of the formula —X 5 —X 6 ,
wherein X 5 is selected from the group consisting of:
one to four more amino acids,
one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, and
combinations of one to four amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, and

wherein X 6 is a C 14 -C 24 fatty acid (SEQ ID NO:16);
or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein X5 is selected from the group consisting of: one to four E or γE amino acids, one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, and combinations of one to four E or γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.

3. The compound or salt of claim 2 , wherein X 5 is a combination of one to four E or γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.

4. The compound or salt of claim 3 , wherein X 5 is a combination of two to four γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.

5. The compound or salt of claim 3 , wherein X5 is a combination of two γE amino acids and two ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.

6. The compound or salt of claim 1 , wherein X 6 is a straight chain fatty acid of the formula CO—(CH 2 ) x —CO 2 H, and wherein x is 16, 18, or 20.

7. The compound or salt of claim 1 , wherein the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) x —CO 2 H, and wherein x is 16 or 18.

8. The compound or salt according to claim 1 wherein:
X 1 denotes that the I residue is modified by acetylation at the N-terminus;
X 2 is L;
X 3 is L;
X 4 is Q; and
the group of the formula —X 5 —X6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) x —CO 2 H where x is 16 or 18.

9. The compound or salt according to claim 8 wherein x is 18.

10. The compound or salt according to claim 8 wherein x is 16.

11. The compound or salt according to claim 1 , wherein: X 1 denotes that the I residue is modified by methylation at the N-terminus, X 2 is L, X 3 is L, X 4 is Q, and the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) 18 —CO 2 H.

12. The compound or salt according to claim 1 wherein:
X 1 denotes that the I residue is modified by methylation at the N-terminus;
X 2 is L;
X 3 is L;
X 4 is Q; and
the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) 16 —CO 2 H.

13. The compound or salt according to claim 1 wherein:
X 1 denotes that the I residue is modified by methylation at the N-terminus;
X 2 is T;
X 3 is L;
X 4 is E; and
the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) 18 —CO 2 H.

14. The compound or salt according to claim 1 wherein:
X 1 denotes that the I residue is modified by methylation at the N-terminus;
X 2 is L;
X 3 is L;
X 4 is E; and
the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) 18 —CO 2 H.

15. The compound or salt according to claim 1 wherein:
X 1 denotes that the I residue is modified by methylation at the N-terminus;
X 2 is T;
X 3 is
X 4 is E; and
the group of the formula —X 5 —X 6 is ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) 2 -(γE) 2 -CO—(CH 2 ) 18 —CO 2 H.

16. A compound or salt according to claim 1 for use in therapy.

17. A compound or salt according to claim 1 for use in the treatment of type II diabetes.

18. A compound or salt according to claim 1 for use in the treatment of chronic kidney disease.

19. A pharmaceutical composition comprising a compound or salt according to claim 1 and one or more pharmaceutically acceptable carriers, diluents, and excipients.

20. A method for treating type II diabetes in a patient comprising administering to a patient in need of such treatment an effective amount of a compound or salt according to claim 1 .

21. A method for treating chronic kidney disease in a patient comprising administering to a patient in need of such treatment an effective amount of a compound or salt according to claim 1 .

22. The method according to claim 21 wherein the chronic kidney disease is caused by diabetic nephropathy.

23. The method according to claim 21 wherein the chronic kidney disease is caused by hypertensive nephropathy.

24. The method according to claim 21 , wherein the administration of the compound or salt to the patient in need of such treatment is subcutaneous.

Assignees

• Lilly Co Eli

Inventors

• Alsina-Fernandez Jorge
• Guo Lili
• Lee John

Classifications

• C07K14/575 Primary

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

• C07K14/4705

  stimulating, promoting or activating activity · CPC title

• A61K38/2228

  Corticotropin releasing factor [CRF] (Urotensin) · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title