GLP-1 compounds

Patent metadata

Field	Value
Publication number	US-9920106-B2
Application number	US-201213473154-A
Country	US
Kind code	B2
Filing date	May 16, 2012
Priority date	Dec 18, 2003
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

Novel GLP-1 compounds and their therapeutic use.

First claim

The invention claimed is:

1. A compound having a structure of formula (I)
Insulinotropic agent(-Y—C*) f -Q  (I)

wherein
Insulinotropic agent is a radical comprising an insulinotropic peptide wherein said peptide comprises the amino acid sequence of formula (III):
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa 18 -Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -Glu-Phe-Ile-Xaa 30 -Trp-Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38    Formula (III)(SEQ ID NO: 4)

wherein
Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;
Xaa 8 is Ala, D-Ala, Gly, Val, Leu, Ile, Lys, 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 18 is Ser, Lys or Arg;
Xaa 22 is Gly, Glu or Aib;
Xaa 23 is Gln, Glu, Lys or Arg;
Xaa 26 is Lys, Glu or Arg;
Xaa 30 is Ala, Glu or Arg;
Xaa 34 is Lys, Glu or Arg;
Xaa 35 is Gly or Aib;
Xaa 36 is Arg or Lys;
Xaa 37 is Gly, Ala, Glu or Lys;
Xaa 38 is Lys, NH 2 or is absent,
wherein said insulinotropic agent contains one or more Aib residues and
wherein
Y is a bivalent connecting chemical group connecting C* with the Insulinotropic agent, and
C* is a bivalent polar separating chemical group where 20-50% of the heavy atoms are either O or N, and
f is 0 or 1 and
Q is selected from

wherein
A is mPEGyl or A is mPEGyl-C(═O)—(CH 2 ) r —, wherein r is an integer in the range from 1-10, and
W is a bivalent chemical group whereby A is connected, and
X is a bivalent connecting chemical group whereby B is connected, and
B is a connecting or branching chemical group.

2. The compound according to claim 1 , wherein A is monodisperse.

3. The compound according to claim 1 , wherein A is polydisperse.

4. The compound according to claim 1 , wherein the branching chemical group B is selected from

wherein a, b, c, d, e, f, g, h, i are integers independently selected from the range from 0 to 24.

5. The compound according to claim 1 , wherein the branching group B is

wherein a, b, c are integers independently selected from the range from 0 to 24.

6. The compound according to claim 4 , wherein the branching chemical group B is selected from

wherein a, b, c, d, e, f, g, h, i are integers independently selected from the range from 0 to 24.

7. The compound according to claim 4 , wherein a+b is less than 6 or a+b+c is less than 14 or a+b+c+d+e+f+g+h+l is less than 16.

8. The compound according to claim 4 , wherein a is 0 or 1 and b, c, d, e, f, h and i are all in the range from 0 to 5.

9. The compound according to claim 4 , wherein a, c, d, e, g and i are all 0 and b, f and h are all in the range from 1 to 4.

10. The compound according to claim 1 , wherein a, c, d, e, g and l are all 0 and b, f and h are all in the range from 1 to 4.

11. The compound according to any claim 1 , wherein W and X are independently selected from the bivalent connecting chemical groups comprising
amides: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl,
amine: —NR—, where R is hydrogen or C 1-6 -alkyl,
thioethers: —S—, —S—(CH 2 ) 2 —SO 2 — or

ethers: —O—,
urethanes: —N(R 1 )—CO—N(R 2 )—, where R 1 and R 2 independently is hydrogen or C 1-6 -alkyl,
carbamates: —O—CO—N(R)—, where R is hydrogen or C 1-6 -alkyl,
hydrazines:

where R is hydrogen or C 1-6 -alkyl,
oximes: —O—N═C(—R)—, where R is hydrogen or C 1-6 -alkyl,
oxazolidines or thiazolidines:

and

12. The compound according to claim 1 , wherein W is: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl.

13. The compound according to claim 12 , wherein the insulinotropic agent is attached to W via the left hand terminal (the carbon) of W.

14. The compound according to claim 12 , wherein the insulinotropic agent is attached to W via the right hand terminal (the nitrogen) of W.

15. The compound according to claim 1 , wherein f is 0.

16. The compound according to claim 1 , wherein C* is —(CH 2 ) n1 O[(CH 2 ) n2 O] n3 (CH 2 ) n4 —, where n1, n2 and n4 independently is an integer in the range from 1 to 10, n3 is an integer in the range from 1 to 5000, and where n3 multiplied by n2+1 is less than 10000.

17. The compound according to claim 16 , wherein n2 is 2 or 3.

18. The compound according to claim 16 , wherein n3 is in the range from 1-20.

19. The compound according to claim 1 , wherein C* is —(CH 2 ) n5 —, where n5 is an integer in the range from 1 to 10.

20. The compound according to claim 1 , wherein Y is selected from the bi-valent connecting chemical groups comprising
amides: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl,
amine: —NR—, where R is hydrogen or C 1-6 -alkyl,
thioethers: —S—, —S—(CH 2 ) 2 —SO 2 — or

ethers: —O—,
urethanes: —N(R 1 )—CO—N(R 2 )—, where R 1 and R 2 independently is hydrogen or C 1-6 -alkyl,
carbamates: —O—CO—N(R)—, where R is hydrogen or C 1-6 -alkyl,
hydrazines:

where R is hydrogen or C 1-6 -alkyl,
oximes: —O—N═C(—R)—, where R is hydrogen or C 1-6 -alkyl,
oxazolidines or thiazolidines:

and

21. The compound according to claim 1 , wherein said insulinotropic agent comprises no more than 4 amino acid residues which are not encoded by the genetic code.

22. The compound according to claim 1 , wherein said insulinotropic agent comprises an Aib residue as the second amino acid residue from the N-terminal.

23. The compound according to claim 1 , wherein Xaa 7 in SEQ ID NO: 4 of said insulinotropic agent is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine and 4-pyridylalanine.

24. The compound according to claim 1 , wherein said insulinotropic agent is selected from the group consisting of [Aib 8,22,35 ]GLP-1(7-37), [Aib 8,35 ]GL

Assignees

• Johansen Nils Langeland
• Lau Jesper
• Madsen Kjeld
• Hansen Thomas Kruse
• Sturis Jeppe
• Novo Nordisk As

Inventors

• Johansen Nils Langeland
• Lau Jesper
• Madsen Kjeld
• Hansen Thomas Kruse
• Sturis Jeppe

Classifications

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• 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

• A61P3/06

  Antihyperlipidemics · CPC title