IP Library › Granted Patent US 8,633,156
Granted Patent B2
US 8,633,156 · App. 12/820,727 · Granted Jan 21, 2014

Insulin derivatives having an extremely delayed time-action profile

Inventors: Paul Habermann (Frankfurt am Main, DE); Gerhard Seipke (Frankfurt am Main, DE); Roland Kurrle (Frankfurt am Main, DE); Gunter Muller (Frankfurt am Main, DE); Mark Sommerfeld (Frankfurt am Main, DE); Norbert Tennagels (Frankfurt am Main, DE); Georg Tschank (Frankfurt am Main, DE); Ulrich Werner (Frankfurt am Main, DE)
Assignee: Sanofi-Aventis Deutschland GmbH
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Quick Facts
Patent No.
US 8,633,156
App. No.
12/820,727
Granted
Jan 21, 2014
Kind
B2
Abstract

The invention relates to novel insulin analogs having a basal time-action profile, which are characterized by the addition and/or substitution of negatively and positively charged amino acid residues and by an amidation of the C-terminal carboxy group of the B chain and histidine in position 8 of the insulin A chain. The invention also relates to the production and use thereof.

Claims (88)

1. An insulin analogue of the formula I:

wherein

A-1 corresponds to Lys, Arg or an amino group;

A0 corresponds to Lys, Arg or a chemical bond;

A1 corresponds to Arg or Gly;

A5 corresponds to Asp, Glu or Gln;

A15 corresponds to Asp, Glu or Gin;

A18 corresponds to Asp, Glu or Asn;

A21 corresponds to Ala, Ser, Thr or Gly;

B-1 corresponds to Asp, Glu or an amino group;

B0 corresponds to Asp, Glu or a chemical bond;

B1 corresponds to Asp, Glu, Phe or a chemical bond;

B3 corresponds to Asp, Glu or Asn;

B4 corresponds to Asp, Glu or Gln;

B29 corresponds to Arg, Lys or an amino acid selected from the group comprising the amino acids Phe, Ala, Thr, Ser, Val, Leu, Glu or Asp, or a chemical bond;

B30 corresponds to Thr or a chemical bond;

B31 corresponds to Arg, Lys or a chemical bond;

B32 corresponds to Arg-amide or Lys-amide; and

wherein no more than one amino acid residue of the group comprising A5, A15, A18, B-1, B0, B1, B2, B3 and B4 correspond simultaneously and independently of one another to Asp or Glu.

2. The insulin analogue as claimed in claim 1 , wherein A-1 corresponds to Arg.

3. The insulin analogue as claimed in claim 1 , wherein A0 corresponds to Arg.

4. The insulin analogue as claimed in claim 1 , wherein A5 corresponds to Glu.

5. The insulin analogue as claimed in claim 1 , wherein A15 corresponds to Glu.

6. The insulin analogue as claimed in claim 1 , wherein A18 corresponds to Asp.

7. The insulin analogue as claimed in claim 1 , wherein A8 corresponds to His.

8. The insulin analogue as claimed in claim 1 , wherein A21 corresponds to Gly.

9. The insulin analogue as claimed in claim 1 , wherein B0 corresponds to Glu.

10. The insulin analogue as claimed in claim 1 , wherein B3 corresponds to Asp.

11. The insulin analogue as claimed in claim 1 , wherein B4 corresponds to Glu.

12. The insulin analogue as claimed in claim 1 , wherein B30 corresponds to Arg.

13. The insulin analogue as claimed in claim 1 , wherein B30 corresponds to Lys.

14. The insulin analogue as claimed in claim 1 , which is

Arg (A0), His (A8), Gly (A21), Arg (B31), Arg (B32) NH 2 human insulin.

15. A pharmaceutical composition comprising an insulin analogue as claimed in claim 1 or a physiologically acceptable salt thereof.

16. A formulation of the insulin analogue as claimed in claim 1 , wherein the formulation is in aqueous form comprising the dissolved insulin analogue.

17. The formulation as claimed in claim 16 , which additionally comprises a glucagon-like peptide-1 (GLP 1) or an analogue thereof, or exendin-3 or -4 or an analogue thereof.

18. The formulation as claimed in claim 17 , which additionally comprises exendin-4.

19. The formulation as claimed in claim 18 , wherein an analogue of exendin-4 is selected from a group comprising

H-desPro 36 -exendin-4-Lys 6 -NH 2 ,

H-des(Pro 36,37 )-exendin-4-Lys 4 -NH 2 and

H-des(Pro 36,37 )-exendin-4-Lys 5 -NH 2 ,

or a pharmacologically tolerable salt thereof.

20. The formulation as claimed in claim 18 , wherein an analogue of exendin-4 is selected from a group comprising

desPro 36 [Asp 28 ]exendin-4 (1-39),

desPro 36 [IsoAsp 28 ]exendin-4 (1-39),

desPro 36 [Met(O) 14 , Asp 28 ]exendin-4 (1-39),

desPro 36 [Met(O) 14 , IsoAsp 28 ]exendin-4 (1-39),

desPro 36 [Trp(O 2 ) 25 , Asp 28 ]exendin-2 (1-39),

desPro 36 [Trp(O 2 ) 25 , IsoAsp 28 ]exendin-2 (1-39),

desPro 36 [Met(O) 14 Trp(O 2 ) 25 , Asp 28 ]exendin-4 (1-39) and

desPro 36 [Met(O) 14 Trp(O 2 ) 25 , IsoAsp 28 ]exendin-4 (1-39),

or a pharmacologically tolerable salt thereof.

21. The formulation as claimed in claim 18 , wherein the peptide -Lys 6 -NH 2 is attached to the C termini of the analogues of exendin-4.

22. The formulation as claimed in claim 18 , wherein an analogue of exendin-4 is selected from a group consisting of:

H-(Lys) 6 -des Pro 36 [Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2

des Asp 28 Pro 36 , Pro 37 , Pro 38 exendin-4(1-39)-NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Asp 28 ]exendin-4(1-39)-NH 2 ,

H-Asn-(Glu) 5 des Pro 36 , Pro 37 , Pro 38 [Asp 28 ]exendin-4(1-39)-NH 2 ,

des Pro 36 , Pro 37 , Pro 38 [Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2 ,

H-des Asp 28 Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 ]exendin-4(1-39)-NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-NH 2 ,

des Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 [Met(O) 14 , Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2 ,

des Met(O) 14 Asp 28 Pro 36 , Pro 37 , Pro 38 exendin-4(1-39)-NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Asp 28 ]exendin-4(1-39)-NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Asp 28 ] exendin-4(1-39)-NH 2 ,

des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2 ,

H-Asn-(Glu) 5 des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Asp 28 ] exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 [Met(O) 14 , Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2 ,

des Asp 28 Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Trp(O 2 ) 25 ]exendin-4(1-39)-NH 2 ,

H-(Lys) 6 -des Pro 36 ′ Pro 37 , Pro 38 [Met(O) 14 , Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Met(0) 14 , Asp 28 ] exendin-4(1-39)-NH 2 ,

des Pro 36 , Pro 37 , Pro 38 [Met(0) 14 , Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-(Lys) 6 -des Pro 36 ′ Pro 37 , Pro 38 [Met(O) 14 , Trp(O 2 ) 25 , Asp 28 ]exendin-4(1-39)-(Lys) 6 -NH 2 ,

H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Trp(O 2 ) 25 , Asp 28 ] exendin-4(1-39)-(Lys) 6 -NH 2 ,

or a pharmacologically tolerable salt thereof.

23. The formulation as claimed in claim 18 , which additionally comprises Arg 34 , Lys 26 (N ε (γ-glutamyl(N α -hexadecanoyl))) GLP-1 (7-37) [liraglutide].

24. A formulation of the insulin analogue as claimed in claim 1 , wherein the formulation is in the form of a powder.

25. The formulation as claimed in claim 24 , wherein the insulin analogue as claimed in claim 1 is present in crystalline or amorphous form.

26. A formulation of the insulin analogue as claimed in claim 1 , wherein the formulation is in the form of a suspension.

27. A formulation of the insulin analogue as claimed in claim 1 , wherein the formulation additionally comprises a chemical chaperone.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 5, 2010
From: HABERMANN, PAUL; SEIPKE, GERHARD; KURRLE, ROLAND; MULLER, GUNTER; SOMMERFELD, MARK; TENNAGELS, NORBERT; TSCHANK, GEORG; WERNER, ULRICH
To: SANOFI-AVENTIS DEUTSCHLAND GMBH
Reel/Frame 025319/0799 →
Priority Claims (2)
DE 10 2008 003 566 · Jan 9, 2008 · national
DE 10 2008 025 007 · May 24, 2008 · national
Continuity (3)
Continuation PCTEP2009000018 · Jan 6, 2009
Provisional Application 61044662 · Apr 14, 2008
Related Publication 20110173722A1 · Jul 14, 2011