Insulin derivatives having an extremely delayed time-action profile

Patent metadata

Field	Value
Publication number	US-9644017-B2
Application number	US-82072210-A
Country	US
Kind code	B2
Filing date	Jun 22, 2010
Priority date	Jan 9, 2008
Publication date	May 9, 2017
Grant date	May 9, 2017

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.

First claim

What is claimed is:

1. An insulin analogue of the formula:

wherein
A0 corresponds to Lys or Arg;
A5 corresponds to Asp, Gln or Glu;
A15 corresponds to Asp, Glu or Gln;
A18 corresponds to Asp, Glu or Asn;
B-1 corresponds to Asp, Glu;
B0 corresponds to Asp, Glu or a chemical bond;
B1 corresponds to Asp, Glu or Phe;
B2 corresponds to Asp, Glu or Val;
B3 corresponds to Asp, Glu or Asn;
B4 corresponds to Asp, Glu or Gln;
B29 corresponds to Lys 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 two amino acid residues 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 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)—NH 2 human insulin;
Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B1), Arg (B31), Lys (B32)—NH 2 human insulin;,
Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B1), Arg (B31), Arg (B32)—NH 2 human insulin;
Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B1), Arg (B31), Lys (B32)—NH 2 human insulin;
Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B1), Arg (B31), Arg (B32)—NH 2 human insulin;
Arg (A0), His (A8), Gly (A21), Glu (B1), Asp (B1), Arg (B31), Arg (B32)—NH 2 human insulin; and
Arg (A0), His (A8), Gly (A21), Glu (B1), Asp (B1), Arg (B31), Lys (B32)—NH 2 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.

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.

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-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.

31. The formulation of claim 29 , wherein the exendin-4 analogue is selected from a group comprising of:
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-4 (1-39),
desPro 36 [Trp(O 2 ) 25 , IsoAsp 28 ]exendin-4 (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.

32. The formulation of claim 31 , where the peptide -Lys 6 —NH 2 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 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 2

Assignees

• Habermann Paul
• Seipke Gerhard
• Kurrle Roland
• Mueller Guenter
• Sommerfeld Mark
• Tennagels Norbert
• Tschank Georg
• Werner Ulrich
• Sanofi Aventis Deutschland

Inventors

• Habermann Paul
• Seipke Gerhard
• Kurrle Roland
• Muller Gunter
• Sommerfeld Mark
• Tennagels Norbert
• Tschank Georg
• Werner Ulrich

Classifications

• A61P3/08

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07K14/62 Primary

  Insulins · CPC title

• C12N15/102

  Mutagenizing nucleic acids · CPC title

• A61K38/00

  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 title