Insulin derivatives having an extremely delayed time-action profile

• US 9,644,017 B2
• Filed: 06/22/2010
• Issued: 05/09/2017
• Est. Priority Date: 01/09/2008
• Status: Expired due to Fees

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Habermann, Paul, Seipke, Gerhard, Kurrle, Roland, Muller, Gunter, Sommerfeld, Mark, Tennagels, Norbert, Tschank, Georg, Werner, Ulrich
• Primary Examiner(s): LIEB, JEANETTE M
• Application Number:
  US12/820,722
• Publication Number:
  US 20110077197A1
• Time in Patent Office: 2,513 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention relates to novel insulin analogs having a basal time-action profile, which are characterized by the following features: a) the B chain end consists of an amidated basic amino acid residue such as lysine or arginine amide; b) the N-terminal amino acid residue of the insulin A chain is a lysine or arginine radical; c) the amino acid position A8 is occupied by a histidine radical; d) the amino acid position A21 is occupied by a glycine radical; and e) one or more substitutions and/or additions of negatively charged amino acid residues are carried out in the positions A5, A15, A18, B-1, B0, B1, B2, B3 and B4.

Claims

1. An insulin analogue of the formula:

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

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

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

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

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

7. The insulin analogue as claimed in claim 1, wherein B1 corresponds to Asp.

8. The insulin analogue as claimed in claim 1, wherein B2 corresponds to Val.

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

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

11. The insulin analogue as claimed in claim 1, wherein B29 corresponds to Lys.

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

13. The insulin analogue as claimed in claim 1, wherein B31 corresponds to Arg or Lys.

14. The insulin analogue as claimed in claim 1, selected from the group consisting of:

Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B1), Arg (B31), Arg (B32)—

NH₂ human insulin;

Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B1), Arg (B31), Lys (B32)—

NH₂ human insulin;

,

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B1), Arg (B31), Arg (B32)—

NH₂ human insulin;

Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B1), Arg (B31), Lys (B32)—

NH₂ human insulin;

Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B1), Arg (B31), Arg (B32)—

NH₂ human insulin;

Arg (A0), His (A8), Gly (A21), Glu (B1), Asp (B1), Arg (B31), Arg (B32)—

NH₂ human insulin; and

Arg (A0), His (A8), Gly (A21), Glu (B1), Asp (B1), Arg (B31), Lys (B32)—

NH₂ human insulin.

15. A process for preparing an insulin analogue as claimed in claim 1, comprising the steps of:

(a) recombinantly preparing a precursor of the insulin analogue;

(b) enzymatically processing the precursor to two-chain insulin;

(c) coupling the two-chain insulin to argininamide in the presence of an enzyme having trypsin activity to produce the insulin analogue; and

(d) isolating the insulin analogue.

16. A method of making a medicament for treating diabetes mellitus, the method comprising combining the insulin analogue of claim 1 with one or more pharmaceutically acceptable ingredients.

17. The method of making of claim 16, wherein the medicament is for the treatment of diabetes mellitus of type I or type II or for therapeutically assisting beta cell regeneration.

18. A pharmaceutical composition comprising the insulin analogue of claim 1 or a physiologically acceptable salt thereof.

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

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

21. The formulation of claim 20, wherein the insulin analogue is present in crystalline or amorphous form.

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

23. A formulation of the insulin analogue of claim 1, wherein the formulation further comprises a chemical chaperone.

24. The formulation of claim 19, further comprises a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, exendin-3 or an analogue or derivative thereof, or exendin-4 or an analogue or derivative therof.

26. The formulation of claim 21, further comprises a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, exendin-3 or an analogue or derivative thereof, or exendin-4 or an analogue or derivative thereof.

27. The formulation of claim 22, further comprises a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, exendin-3 or an analogue or derivative thereof, or exendin-4 or an analogue or derivative thereof.

28. The formulation of claim 23, further comprises a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, exendin-3 or analogue or derivative thereof, or exendin-4 or an analogue or derivative thereof.

29. The formulation of claim 24, wherein the formulation comprises exendin-4 or an analogue or derivative thereof.

30. The formulation of claim 29, wherein the exendin-4 analogue is selected from a group comprising of:

H-desPro³⁶-exendin-4-Lys₆—

NH₂,

H-des(Pro^36,37)-exendin-4-Lys₄—

NH₂ , and

H-des(Pro^36,37)-exendin-4-Lys₅—

NH₂,

or a pharmacologically tolerable salt thereof.

31. The formulation of claim 29, wherein the exendin-4 analogue is selected from a group comprising of:

desPro³⁶ [Asp²⁸]exendin-4 (1-39),

desPro³⁶ [IsoAsp²⁸]exendin-4 (1-39),

desPro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4 (1-39),

desPro³⁶ [Met(O)¹⁴, IsoAsp²⁸]exendin-4 (1-39),

desPro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-4 (1-39),

desPro³⁶ [Trp(O₂)²⁵, IsoAsp²⁸]exendin-4 (1-39),

desPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, Asp²⁸]exendin-4 (1-39) and

desPro³⁶ [Met(O)¹⁴Trp(O₂)²⁵, IsoAsp²⁸]exendin-4 (1-39),

or a pharmacologically tolerable salt thereof.

32. The formulation of claim 31, where the peptide -Lys₆—

NH₂ is attached to the C terminus of the exendin-4 analogue.

33. The formulation of claim 24, wherein the exendin-4 analogue is selected from the group comprising of:

H-(Lys)₆-des Pro³⁶ [Asp²⁸]exendin-4(1-39)-Lys₆-NH₂;

des Asp²⁸Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)—

NH₂;

H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)—

NH₂;

des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆—

NH₂;

H-des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵]exendin-4(1-39)—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [TrP(O₂)²⁵, Asp²⁸]exendin-4(1-39)—

NH₂;

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)—

NH₂;

des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [TrP(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-Lys₆—

NH₂;

des Met(O)¹⁴ Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ exendin-4(1-39)—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)—

NH₂;

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)—

NH₂;

des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸]exendin-4(1-39)-Lys₆—

NH₂;

H-Asn-(Glu)₅ des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-Lys₆—

NH₂;

des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵]exendin-4(1-39)—

NH₂;

H-(Lys)₆-des Pro³⁶′

Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)—

NH₂;

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Asp²⁸] exendin-4(1-39)—

NH₂;

des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂;

H-(Lys)₆-des Pro³⁶′

Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸]exendin-4(1-39)-(Lys)₆—

NH₂; and

H-Asn-(Glu)₅-des Pro³⁶, Pro³⁷, Pro³⁸ [Met(O)¹⁴, Trp(O₂)²⁵, Asp²⁸] exendin-4(1-39) -(Lys)₆—

NH₂;

or a pharmacologically tolerable salt thereof.

34. The formulation of claim 24, further comprising Arg³⁴, Lys²⁶ (N^ε

(γ

-glutamyl(N^α

-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof.

35. An aqueous formulation comprising the insulin analogue of claim 1, which comprises less than 15 μ

g/ml of zinc.

36. An aqueous formulation comprising the insulin analogue of claim 1, which comprises less than 2 mg/ml of zinc.

37. The aqueous formulation of claim 36, which comprises 200 μ

g/ml of zinc.

25. The formulation of 20, further comprises a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, exendin-3 or an analogue or derivative thereof, or exendin-4 or an analogue or derivative thereof.