Double-acylated GLP-1 derivatives

Patent metadata

Field	Value
Publication number	US-10000542-B2
Application number	US-201314399087-A
Country	US
Kind code	B2
Filing date	May 2, 2013
Priority date	May 8, 2012
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue and a second K residue, at positions corresponding to position 26, and 37, respectively, of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1: HOOC—(CH 2 ) x —CO—*, and Chem. 2: HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*, in which x is an integer in the range of 8-16, and y is an integer in the range of 6-13; and the linker comprises Chem. 3: *—NH—(CH 2 ) q —CH[(CH 2 ) w —NR 1 R 2 ]—CO—*, which is connected at its CO—* end to the epsilon amino group of the first or the second K residue of the GLP-1 analogue, and wherein q is an integer in the range of 0-5, R 1 and R 2 independently represent *—H or *—CH 3 , and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.

First claim

The invention claimed is:

1. A derivative of a GLP-1 analogue, wherein the analogue is a peptide of Formula I:
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala -Xaa 25 -Xaa 26 -Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 (SEQ ID NO:11), wherein
Xaa 7 is L-histidine, imidazopropionyl, α-hydroxy-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, N α -formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;
Xaa 8 is Ala, Gly, Val, Leu, Ile, Thr, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;
Xaa 12 is Phe or Leu;
Xaa 16 is Val or Leu;
Xaa 18 is Ser, Val, or Leu;
Xaa 19 is Tyr or Gln;
Xaa 20 is Leu or Met;
Xaa 22 is Gly, Glu, or Aib;
Xaa 23 is Gln, Glu, or Arg;
Xaa 25 is Ala or Val;
Xaa 26 is Lys
Xaa 27 is Glu or Leu;
Xaa 30 is Ala, Glu, or Arg;
Xaa 31 is Trp or His;
Xaa 33 is Val;
Xaa 34 is Glu, Asn, Gly, Gln, Arg, or His;
Xaa 35 is Gly or Aib;
Xaa 36 is Arg or Gly; and
Xaa 37 is Lys
Xaa 38 is Ser, Gly, Ala, Glu, Pro, Arg, or absent,
wherein Xaa 26 is a first K residue and Xaa 37 is a second K residue and the analogue comprises a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1),
wherein the derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein
each protracting moiety is independently selected from Chem. 2 and Chem. 1:

Chem. 2: HOOC—CH 6 H 4 —O—(CH 2 ) y —CO—*
Chem. 1: HOOC—(CH 2 ) x —CO—*,
in which xis an integer in the range of 8-14, and y is an integer in the range of 6-13; and
the linker comprises

Chem. 3: *—NH—(CH 2 ) q —CH[(CH 2 ) w —NH 2 ]—CO—*,
which is connected at its CO—* end to the epsilon amino group of the first or the second K residue of the GLP-1 analogue, and wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5;
or a pharmaceutically acceptable salt, amide, or ester thereof.

2. The derivative of claim 1 , wherein w is 0.

3. The derivative of claim 2 , wherein Chem. 3 is represented by
Chem. 4: *—NH—(CH 2 ) q —CH(NH 2 )—CO—*,
wherein q is an integer in the range of 3-5.

4. The derivative of claim 3 , wherein q is 4.

5. The derivative of claim 1 , wherein the protracting moiety is Chem. 1, and x is 12 or 14.

6. The derivative of claim 1 , wherein the protracting moiety is Chem. 2, and y is 9, 10, or 11.

7. The derivative of claim 1 , wherein the analogue has a maximum of six amino acid changes.

8. The derivative of claim 1 , wherein the analogue is a peptide of Formula I:
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala -Xaa 25 -Lys-Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Lys-Xaa 38 (SEQ ID NO: 11), wherein
Xaa 7 is L-histidine, or desamino -histidine;
Xaa 8 is Aib;
Xaa 12 is Phe;
Xaa 16 is Val;
Xaa 18 is Ser;
Xaa 19 is Tyr;
Xaa 20 is Leu;
Xaa 22 is Gly, or Glu;
Xaa 23 is Gln;
Xaa 25 is Ala;
Xaa 27 is Glu;
Xaa 30 is Ala, or Glu;
Xaa 31 is Trp or His;
Xaa 33 is Val;
Xaa 34 is Gln, Arg, or His;
Xaa 35 is Gly;
Xaa 36 is Arg; and
Xaa 38 is Glu, or absent.

9. The derivative of claim 8 , wherein Xaa 8 is Aib.

10. The derivative of claim 9 , wherein Xaa 34 is Arg.

11. The derivative of claim 9 , wherein Xaa 34 is Gln.

12. The derivative of claim 8 , wherein Xaa 7 is His; Xaa 8 is Aib; Xaa 12 is Phe; Xaa 16 is Val; Xaa 18 is Ser; Xaa 19 is Tyr; Xaa 20 is Leu; Xaa 22 is Gly or Glu; Xaa 23 is Gln; Xaa 25 is Ala; Xaa 27 is Glu; Xaa 30 is Ala; Xaa 31 is Trp or His; Xaa 33 is Val; Xaa 34 is Gln, Arg, or His; Xaa 35 is Gly; Xaa 36 is Arg; and Xaa 38 is absent.

13. The derivative of claim 1 , wherein the linker comprises a second linker element, Chem. 12:

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5.

14. The derivative of claim 1 , wherein the analogue has a maximum of three amino acid changes.

15. A pharmaceutical composition comprising a derivative according to claim 1 and a pharmaceutically acceptable excipient.

16. A method for treating diabetes in a subject in need of such treatment, said method comprising administering to said subject a pharmaceutically active amount of a derivative according to claim 1 .

17. A compound selected from the group consisting of:

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 4,

where the amino acid sequence is that of SEQ ID NO: 5,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 6,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

where the amino acid sequence is that of SEQ ID NO: 3,

Assignees

• Novo Nordisk As

Inventors

• Kofoed Jacob
• Garibay Patrick W
• Lau Jesper

Classifications

• 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title