Double-acylated GLP-1 derivatives

Patent metadata

Field	Value
Publication number	US-9708383-B2
Application number	US-201113882947-A
Country	US
Kind code	B2
Filing date	Nov 9, 2011
Priority date	Nov 9, 2010
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve 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, Chem. 2, and Chem. 3:

HOOC—(CH 2 ) x —CO—*  Chem. 1:

HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*  Chem. 2:

R 2 —C 6 H 4 —(CH 2 ) z —CO—*,  Chem. 3:
in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, and R 2 is a group having a molar mass not higher than 150 Da; and the linker comprises

*—NH—(CH 2 ) 2 —(O—(CH 2 ) 2 ) k —O—(CH 2 ) n —CO—*.  Chem. 4:

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; 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 peptides and side chain intermediates. The derivatives are suitable for oral administration.

First claim

The invention claimed is:

1. A derivative of a GLP-1 analogue,
which analogue comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 22, 26, 27, 30, 31, 34, or 37 of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of twelve 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. 2, Chem. 1, and Chem. 3:
HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*  Chem. 2:

HOOC—(CH 2 ) x —CO—*  Chem. 1:

R 2 —C 6 H 4 —(CH 2 ) z —CO—*,  Chem. 3:

in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, and R 2 is a group having a molar mass not higher than 150 Da; and
the linker comprises

wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5;
or a pharmaceutically acceptable salt, amide, or ester thereof.

2. The derivative of claim 1 , wherein the protracting moiety is selected from Chem. 1 and Chem. 2.

3. The derivative of claim 1 , wherein the second K residue is at positions 22, 27, 30, 31, or 37.

4. The derivative of claim 1 , wherein the analogue comprises a GLP-1 analogue of Formula I:
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Lys-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 , wherein  Formula I:

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, β-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 19 is Tyr or Gln;
Xaa 20 is Leu or Met;
Xaa 22 is Gly, Glu, Lys, or Aib;
Xaa 23 is Gln, Glu, or Arg;
Xaa 25 is Ala or Val;
Xaa 26 is Val, His, Lys, or Arg;
Xaa 27 is Glu, His, Leu, or Lys;
Xaa 30 is Ala, Glu, Lys, or Arg;
Xaa 31 is Trp, Lys, or His
Xaa 33 is Val or Lys;
Xaa 34 is Lys, Glu, Asn, Gly, Gln, Arg, His, or absent;
Xaa 35 is Gly, Aib, or absent;
Xaa 36 is Arg, Gly, or absent;
Xaa 37 is Gly, Ala, Glu, Pro, Lys, Arg, or absent; and
Xaa 38 is Ser, Gly, Ala, Glu, Pro, Arg, or absent.

5. The derivative of claim 1 , wherein x is 10, 12, 14, or 16.

6. The derivative of claim 1 , wherein y is 7, 8 or 9.

7. The derivative of claim 1 , wherein the analogue is modified so as to comprise a C-terminal amide.

8. The derivative of claim 1 , wherein the analogue has a C-terminal carboxylic acid.

9. A compound selected from the following:

where the amino acid sequence is that of SEQ ID NO: 13,

where the amino acid sequence is that of SEQ ID NO: 7,

where the amino acid sequence is that of SEQ ID NO: 8,

where the amino acid sequence is that of SEQ ID NO: 14,

where the amino acid sequence is that of SEQ ID NO: 9,

where the amino acid sequence is that of SEQ ID NO: 15,

where the amino acid sequence is that of SEQ ID NO: 16,

where the amino acid sequence is that of SEQ ID NO: 9,

where the amino acid sequence is that of SEQ ID NO: 17,

where the amino acid sequence is that of SEQ ID NO: 18,

where the amino acid sequence is that of SEQ ID NO: 18,

where the amino acid sequence is that of SEQ ID NO: 19,

where the amino acid sequence is that of SEQ ID NO: 19,

where the amino acid sequence is that of SEQ ID NO: 20,

where the amino acid sequence is that of SEQ ID NO: 21,

where the amino acid sequence is that of SEQ ID NO: 22,

where the amino acid sequence is that of SEQ ID NO: 23,

where the amino acid sequence is that of SEQ ID NO: 24,

where the amino acid sequence is that of SEQ ID NO: 9,

where the amino acid sequence is that of SEQ ID NO: 9,

where the amino acid sequence is that of SEQ ID NO: 25,

where the amino acid sequence is that of SEQ ID NO: 25,

where the amino acid sequence is that of SEQ ID NO: 7,

where the amino acid sequence is that of SEQ ID NO: 26,

where the amino acid sequence is that of SEQ ID NO: 20,

where the amino acid sequence is that of SEQ ID NO: 26,

where the amino acid sequence is that of the SEQ ID NO: 16,

Assignees

• Madsen Alice Ravn
• Wieczorek Birgit
• Kofoed Jacob
• Lau Jesper
• Spetzler Jane
• Kodra Janos Tibor
• Linderoth Lars
• Garibay Patrick William
• Sauerberg Per
• Kruse Thomas
• Novo Nordisk As

Inventors

• Madsen Alice Ravn
• Wieczorek Birgit
• Kofoed Jacob
• Lau Jesper
• Spetzler Jane
• Kodra Janos Tibor
• Linderoth Lars
• Garibay Patrick William
• Sauerberg Per
• Kruse Thomas

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P43/00

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

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title