IP Library › Granted Patent US 9,023,986
Granted Patent B2
US 9,023,986 · App. 13/274,372 · Granted May 5, 2015

Glucose-dependent insulinotropic peptide analogs

Inventors: Waleed Danho (Del Mar, CA); George Ehrlich (Bronx, NY); Wajiha Khan (East Hanover, NJ); Joseph Swistok (Nutley, NJ); Jefferson Wright Tilley (North Caldwell, NJ)
Assignee: Hoffmann-La Roche Inc.
C07K14/605A61K38/00A61K38/22
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Quick Facts
Patent No.
US 9,023,986
App. No.
13/274,372
Granted
May 5, 2015
Kind
B2
Abstract

The present invention provides compounds which are analogs of glucose-dependent insulinotropic polypeptide (GIP) and pharmaceutically acceptable salts of such compounds. These compounds have activity as agonists of GIP receptor.

Claims (81)

1. A compound having the formula (I):

(Y) n —R 1 -Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-R 2 -Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-R 3 —NH 2   (I)

wherein:

R 1 is selected from the group consisting of: (D)Tyr; DesNH 2 -Tyr; (D)Phe; DesNH 2 -Phe; (D)Trp; (D)3Pya; 2-Cl(D)Phe; 3-Cl(D)Phe; 4-Cl(D)Phe; 2-F(D)Phe; 3-F(D)Phe; 3,5 DiF(D)Phe; and 3,4,5TriF(D)Phe;

R 2 is Lys or Ala;

R 3 is Lys or PEGylated Lys;

Y is acyl;

n is 1 when R 1 is (D)Tyr; (D)Phe; (D)Trp; (D)3Pya; 2-Cl-(D)Phe; 3-Cl-(D)Phe; 4-Cl-(D)Phe; 2-F-(D)Phe; 3-F-(D)Phe; 3,5-DiF(D)Phe; or 3,4,5-TriF(D)Phe; and

n is 0 when R 1 is DesNH 2 -Tyr; (D)Phe or DesNH 2 -Phe;

or a pharmaceutically-acceptable salt thereof.

2. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr.

3. A compound of claim 1 wherein R 1 is (D)Tyr.

4. A compound of claim 1 wherein R 1 is selected from the group consisting of: (D)Phe; DesNH 2 -Phe; 2-Cl-(D)Phe; 3-Cl-(D)Phe; 4-Cl-(D)Phe; 2-F-(D)Phe; 3-F-(D)Phe; 3,5-DiF-(D)Phe; and 3,4,5-TriF-(D)Phe.

5. A compound of claim 1 wherein R 1 is (D)Trp.

6. A compound of claim 1 wherein R 1 is (D)3Pya.

7. A compound of claim 1 wherein R 2 is Lys.

8. A compound of claim 1 wherein R 2 is Ala.

9. A compound of claim 1 wherein R 3 is Lys.

10. A compound of claim 1 wherein R 3 is PEGylated Lys.

11. A compound of claim 1 wherein R 3 is Lys-PEG.

12. A compound of claim 1 wherein R 3 is Lys-PEG m .

13. A compound of claim 1 wherein R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of from about 5,000 to about 40,000 Daltons.

14. A compound of claim 1 wherein R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of from about 10,000 to about 30,000 Daltons.

15. A compound of claim 1 wherein R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of from about 15,000 to about 25,000 Daltons.

16. A compound of claim 1 wherein R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of about 20,000 Daltons.

17. A compound of claim 1 wherein R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 5,000 to about 40,000 Daltons.

18. A compound of claim 1 wherein R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 10,000 to about 30,000 Daltons.

19. A compound of claim 1 wherein R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 15,000 to about 25,000 Daltons.

20. A compound of claim 1 wherein R 3 is Lys-PEG m wherein the PEG m has a molecular weight of about 20,000 Daltons.

21. A compound of claim 1 wherein R 3 is Lys (epsilon-SSA-PEG m ).

22. A compound of claim 1 wherein R 3 is selected from the group consisting of: Lys(epsilon-SSA-PEG m (12,000)), Lys(epsilon-SSA-PEG m (20,000)), and Lys(epsilon-SSA-PEG m (30,000)).

23. A compound of claim 1 wherein R 3 is Lys(epsilon-SSA-PEG m (20,000)).

24. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr and R 2 is Ala.

25. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is PEGylated Lys.

26. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is PEGylated Lys wherein the PEG moiety a molecular weight of from about 5,000 to about 40,000 Daltons.

27. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of from about 10,000 to about 30,000 Daltons.

28. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of from about 15,000 to about 25,000 Daltons.

29. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is PEGylated Lys wherein the PEG moiety has a molecular weight of about 20,000 Daltons.

30. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 5,000 to about 40,000 Daltons.

31. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 10,000 to about 30,000 Daltons.

32. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is Lys-PEG m wherein the PEG m has a molecular weight of from about 15,000 to about 25,000 Daltons.

33. A compound of claim 1 wherein R 1 is (D)Tyr or DesNH 2 -Tyr, R 2 is Ala, and R 3 is Lys-PEG m wherein the PEG m has a molecular weight of about 20,000 Daltons.

34. A compound of claim 1 wherein R 1 is (D)Tyr, R 2 is Ala, and R 3 is Lys-PEG m wherein the PEG m has a molecular weight of about 20,000 Daltons.

35. A compound of claim 1 wherein selected from the group consisting of:

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 3);

DesNH 2 -Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 4);

Ac-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 5);

DesNH 2 -Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 6);

Ac-(D)Trp-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 7);

Ac-(D)3Pya-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 8);

Ac-2-Cl-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 9);

Ac-3-Cl-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 10);

Ac-4-Cl-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 11);

Ac-2-F-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 12);

Ac-3-F-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 13);

Ac-3,5-DiF-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 14);

Ac-3,4,5-TriF-(D)Phe-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 15);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 16);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (12,000))—NH 2 (SEQ ID NO: 17);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (20,000))—NH 2 (SEQ ID NO: 18);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (30,000))—NH 2 (SEQ ID NO: 19); and

pharmaceutically acceptable salts thereof.

36. A compound of claim 1 wherein selected from the group consisting of:

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 16);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (12,000))—NH 2 (SEQ ID NO: 17);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (20,000))—NH 2 (SEQ ID NO: 18);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (30,000))—NH 2 (SEQ ID NO: 19);

and pharmaceutically-acceptable salts thereof.

37. A compound of claim 1 wherein said compound is:

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-NH 2 (SEQ ID NO: 16) or a pharmaceutically-acceptable salt thereof.

38. A compound of claim 1 wherein the compound is selected from the group consisting of:

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (12,000))—NH 2 (SEQ ID NO: 17);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (20,000))—NH 2 (SEQ ID NO: 18); and

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (30,000))—NH 2 (SEQ ID NO: 19);

and pharmaceutically-acceptable salts thereof.

39. A compound of claim 1 wherein the compound is selected from the group consisting of:

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (20,000))—NH 2 (SEQ ID NO: 18);

Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (30,000))—NH 2 (SEQ ID NO: 19);

and pharmaceutically-acceptable salts thereof.

40. A compound of claim 1 wherein the compound is Ac-(D)Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Ala-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys(epsilon-SSA-PEG m (20,000))—NH 2 (SEQ ID NO: 18) or a pharmaceutically-acceptable salt thereof.

41. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2015
From: DANHO, WALEED; EHRLICH, GEORGE; KHAN, WAJIHA; SWISTOK, JOSEPH; TILLEY, JEFFERSON WRIGHT
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 035308/0329 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2015
From: HOFFMANN-LA ROCHE INC.
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 035308/0652 →
Continuity (2)
Provisional Application 61406186 · Oct 25, 2010
Related Publication 20120101037A1 · Apr 26, 2012