Glucagon-like insulinotropic peptide analogs, compositions, and methods of use

• US 5,512,549 A
• Filed: 10/18/1994
• Issued: 04/30/1996
• Est. Priority Date: 10/18/1994
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: DiMarchi, Richard D., Stucky, Russell D., Kriauciunas, Aidas V., Smiley, David L., Chen, Victor J.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/324,960
• Time in Patent Office: 560 Days
• Field of Search: 530/308, 530/324, 514/12
• US Class Current: 514/5.9
• 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 14/605 Glucagons
• CPC Class Codes: Y10S 977/712 formed from plural layers of nanosized material, e.g. stacked structures
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/868 with optical means
• CPC Class Codes: Y10S 977/897 Polymerization
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/907 Liposome
• CPC Class Codes: Y10S 977/911 Cancer cell destruction
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

Glucagon-like insulinotropic peptide (GLP-1(7-37)) analogs and derivatives are disclosed. The analogs include amino acid substitutions, amino and carboxyl terminal modifications, and C₆ -C₁₀ acylations. The claimed compounds stimulate the secretion or biosynthesis of insulin in poorly functioning beta cells and are therefore useful in treating Type II diabetics

Claims

1. A compound of the formula:

##STR5## wherein R¹ is selected from the group consisting of 4-imidazopropionyl, 4-imidazoacetyl, or 4-imidazo-α

,α

dimethylacetyl;

R² is selected from the group consisting of C₆ -C₁₀ unbranched acyl, or is absent;

R³ is selected from the group consisting of Gly-OH or NH₂ ; and

,

Xaa is Lys or Arg.

2. The compound of claim 1 wherein R¹ is 4-imidazopropionyl, R² is C₈ unbranched acyl, R₃ is Gly-OH, and Xaa is Arg.

3. The compound of claim 2 wherein R² is absent.

4. The compound of claim 1 wherein R¹ is 4-imidazoacetyl and R² is C₈ unbranched acyl.

5. The compound of claim 4 wherein R² is absent.

6. The compound of claim 1 wherein R¹ is 4-imidazo-α

,α

dimethyl-acetyl and R² is C₈ unbranched acyl.

7. The compound of claim 6 wherein R² is absent.

8. A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

9. A pharmaceutical composition comprising the compound of claim 2 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

10. A pharmaceutical composition comprising the compound of claim 3 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

11. A pharmaceutical composition comprising the compound of claim 4 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

12. A pharmaceutical composition comprising the compound of claim 5 in combination with a pharmaceutically acceptable carrier, diluent, or exciplent.

13. A pharmaceutical composition comprising the compound of claim 6 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

14. A pharmaceutical composition comprising the compound of claim 7 in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

15. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 1 to said mammal.

16. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 2 to said mammal.

17. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 3 to said mammal.

18. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 4 to said mammal.

19. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 5 to said mammal.

20. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 6 to said mammal.

21. A method for treating non-insulin dependent diabetes mellitus in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 7 to said mammal.

22. The method of claim 15 wherein the mammal is a human and the compound is administered sub-cutaneously.

23. The method of claim 16 wherein the mammal ms a human and the compound is administered sub-cutaneously.

24. The method of claim 17 wherein the mammal ms a human and the compound is administered sub-cutaneously.

25. The method of claim 18 wherein the mammal ms a human and the compound is administered sub-cutaneously.

26. The method of claim 19 wherein the mammal ms a human and the compound is administered sub-cutaneously.

27. The method of claim 20 wherein the mammal is a human and the compound is administered sub-cutaneously.

28. The method of claim 21 wherein the mammal ms a human and the compound is administered sub-cutaneously.