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Last Updated: March 28, 2024

Details for Patent: 6,268,343


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Title: Derivatives of GLP-1 analogs
Abstract:The present invention relates to GLP-1 derivatives having a lipophilic substituent, pharmaceutical compositions comprising same, and methods of making an using same. The GLP-1 derivatives of the present invention have a protracted profile of action.
Inventor(s): Knudsen; Liselotte Bjerre (Valby, DK), Huusfeldt; Per Olaf (K.o slashed.benhavn K, DK), Nielsen; Per Franklin (V.ae butted.rl.o slashed.se, DK), Kaarsholm; Niels C. (Vanl.o slashed.se, DK), Olsen; Helle Birk (Aller.o slashed.d, DK), Bj.o slashed.rn; S.o slashed.ren Erik (Lyngby, DK), Pedersen; Freddy Zimmerdahl (V.ae butted.rl.o slashed.se, DK), Madsen; Kjeld (V.ae butted.rl.o slashed.se, DK)
Assignee: Novo Nordisk A/S (Bagsvaerd, DK)
Filing Date:Feb 26, 1999
Application Number:09/258,750
Claims:1. A GLP-1 derivative of formula I (SEQ ID NO:2):

wherein

Xaa at position 8 is Ala,

Xaa at position 9 is Glu,

Xaa at position 11 is Thr,

Xaa at position 14 is Ser,

Xaa at position 16 is Val,

Xaa at position 17 is Ser,

Xaa at position 18 is Ser,

Xaa at position 19 is Tyr,

Xaa at position 20 is Leu,

Xaa at position 21 is Glu,

Xaa at position 22 is Gly,

Xaa at position 23 is Gln,

Xaa at position 24 is Ala,

Xaa at position 25 is Ala,

Xaa at position 26 is Lys,

Xaa at position 27 is Glu,

Xaa at position 30 is Ala,

Xaa at position 31 is Trp,

Xaa at position 32 is Leu,

Xaa at position 33 is Val,

Xaa at position 34 is Arg,

Xaa at position 35 is Gly,

Xaa at position 36 is Arg, and

Xaa at position 37 is Gly,

wherein

(a) the .epsilon.-amino group of Lys at position 26 is substituted with a lipophilic substituent, optionally via a spacer,

(b) the lipophilic substituent is (i) CH.sub.3 (CH.sub.2).sub.n CO-- wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22, (ii) HOOC(CH.sub.2).sub.m CO-- wherein m is 10, 12, 14, 16, 18, 20 or 22, or (iii) lithochoyl, and

(c) the spacer is (i) an unbranched alkane .alpha.,.omega.-dicarboxylic acid group having from 1 to 7 methylene groups, (ii) an amino acid residue except Cys, or (iii) .gamma.-aminobutanoyl.

2. The GLP-1 derivative of claim 1, wherein the lipophilic substituent is linked to the .epsilon.-amino group of Lys via a spacer.

3. The GLP-1 derivative of claim 2, wherein the spacer is .gamma.-glutamyl.

4. The GLP-1 derivative of claim 2, wherein the spacer is .beta.-asparagyl.

5. The GLP-1 derivative of claim 2, wherein the spacer is glycyl.

6. The GLP-1 derivative of claim 2, wherein the .gamma.-aminobutanoyl.

7. The GLP-1 derivative of claim 2, wherein the .beta.-alanyl.

8. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -tetradecanoyl), Arg.sup.34 -GLP-1(7-37).

9. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.omega.-carboxynonadecanoyl)), Arg.sup.34 -GLP-1(7-37).

10. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.omega.-carboxyheptadecanoyl)), Arg.sup.34 -GLP-1(7-37).

11. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.omega.-carboxyundecanoyl)), Arg.sup.34 -GLP-1(7-37).

12. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.omega.-carboxypentadecanoyl)), Arg.sup.34 -GLP-1(7-37).

13. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -lithochoyl),Arg.sup.34 -GLP-1(7-37).

14. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.-glutamyl(N.sup..alpha. -hexadecanoyl))), Arg.sup.34 -GLP-1(7-37).

15. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.glutamyl(N.sup..alpha. tetradecanoyl))), Arg.sup.34 -GLP-1(7-37).

16. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.glutamyl(N.sup..alpha. lithochoyl))), Arg.sup.34 -GLP-1(7-37).

17. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.glutamyl(N.sup..alpha. octadecanoyl))), Arg.sup.34 -GLP-1(7-37).

18. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -decanoyl), Arg.sup.34 -GLP-1(7-37).

19. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -hexadecanoyl), Arg.sup.34 -GLP-1(7-37).

20. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -octanoyl), Arg.sup.34 -GLP-1(7-37).

21. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -dodecanoyl), Arg.sup.34 -GLP-1(7-37).

22. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. (N.sup.68 (.gamma.aminobutyroyl-(N.sup..gamma. -hexadecanoyl))), Arg.sup.34 -GLP-1(7-37).

23. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.-D-glutamyl(N.sup..alpha. hexadecanoyl))), Arg.sup.34 -GLP-1(7-37).

24. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.glutamyl(N.sup..alpha. -dodecanoyl))), Arg.sup.34 -GLP-1(7-37).

25. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.beta.alanyl(N.sup..alpha. -hexadecanoyl))), Arg.sup.34 -GLP-1(7-37).

26. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.alpha.-glutamyl(N.sup..alpha. -hexadecanoyl))), Arg.sup.34 -GLP-1(7-37).

27. The GLP-1 derivative of claim 1, which is Lys.sup.26 (N.sup..epsilon. -(.gamma.-glutamyl(N.sup..alpha. -decanoyl))), Arg.sup.34 -GLP-1(7-37).

28. A pharmaceutical composition comprising a GLP-1 derivative of claim 1 and a pharmaceutically acceptable vehicle or carrier.

29. A pharmaceutical composition of claim 28, further comprising an isotonic agent, a preservative and a buffer.

30. A pharmaceutical composition of claim 29, wherein the isotonic agent is sodium chloride, mannitol and glycerol.

31. A pharmaceutical composition of claim 29, wherein the preservative is phenol, m-cresol, methyl p-hydroxybenzoate or benzyl alcohol.

32. A pharmaceutical composition of claim 29, wherein the buffer is sodium acetate or sodium phosphate.

33. A pharmaceutical composition of claim 28, further comprising a surfactant.

34. A pharmaceutical composition of claim 28, further comprising zinc.

35. A pharmaceutical composition of claim 28, further comprising another antidiabetic agent.

36. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is human insulin.

37. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is a hypoglycemic agent.

38. A pharmaceutical composition of claim 28, further comprising another antiobesity agent.

39. A method of treating diabetes, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.

40. A method of treating obesity, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.

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