Compounds and method for the prevention and treatment of diabetic retinopathy

• US 20040082501A1
• Filed: 04/11/2003
• Published: 04/29/2004
• Est. Priority Date: 09/10/1997
• Status: Active Grant

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Grant, Maria, Bodor, Nicholas Stephen
• Granted Patent: US 7,115,566 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• 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: A61K 47/559 Redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: C07K 14/655 Somatostatins

Abstract

The invention provides peptide derivatives designed to deliver peptides having growth factor inhibitory activity, especially somatostatin analogs, to the retina by sequential metabolism. The peptide derivatives, which comprise a dihydropyridine⇄pyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptide spacer, are used in the prevention and treatment of diabetic retinopathy.

Claims

1. A compound of the formula

2. A compound according to claim 1, wherein the depicted ring system is a 1,4-dihydroquinoline, 1,2-dihydroquinoline or 1,2-dihydroisoquinoline.

3. A compound according to claim 1, wherein R₅ is t-butyl.

4. A compound according to claim 1, wherein the peptide is lanreotide.

5. A compound according to claim 1, wherein the peptide is octreotide and wherein the octreotide'"'"'s C-terminal —

CH₂OH group has been replaced with a —

CH₂OCOR₄ group and wherein the free amino group —

NH₂ of the Lys unit of octreotide has been replaced with a —

NHCOOR₅ group.

6. A compound according to claim 4, wherein lanreotide'"'"'s C-terminal —

CONH₂ group has been replaced with a —

CO-Gly-OR₄ group and wherein the free amino group —

NH₂ of the Lys unit of lanreotide has been replaced with a —

NHCOOR₅ group.

7. A compound according to claim 4, wherein lanreotide has its C-terminal —

CONH₂ group unchanged and wherein the free amino group —

NH₂ of the Lys unit of lanreotide has been replaced with a —

NHCOOR₄ group.

8. A compound according to claim 1, wherein R₄ is a radical of the formula

9. A compound according to claim 8, wherein R₆ is methyl.

10. A compound according to claim 1, wherein R₄ is —

C_pH_2p-adamantyl.

11. A compound according to claim 10, wherein R₄ is

12. A compound of the formula

13. A compound according to claim 12, wherein the depicted ring system is a 1,4-dihydroquinoline, 1,2-dihydroquinoline or 1,2-dihydroisoquinoline.

14. A compound according to claim 12, wherein R₅ is t-butyl.

15. A compound according to claim 12, wherein the peptide is lanreotide.

16. A compound according to claim 12, wherein the peptide is octreotide and wherein the octreotide'"'"'s C-terminal —

CH₂OH group has been replaced with a —

CH₂OCOR₄ group and wherein the free amino group —

NH₂ of the Lys unit of octreotide has been replaced with a —

NHCOOR₅ group.

17. A compound according to claim 15, wherein lanreotide'"'"'s C-terminal —

CONH₂ group has been replaced with a —

CO-Gly-OR₄ group and wherein the free amino group —

NH₂ of the Lys unit of lanreotide has been replaced with a —

NHCOOR₅ group.

18. A compound according to claim 15, wherein lanreotide has its C-terminal —

CONH₂ group unchanged and wherein the free amino group —

NH₂ of the Lys unit of lanreotide had been replaced with a —

NHCOOR₄ group.

19. A compound according to claim 12, wherein R₄ is —

C_pH_2p-steryl wherein p is 0.

20. A compound according to claim 19, wherein R₄ is a radical of the formula

21. A compound according to claim 20, wherein R₆ is methyl.

22. A compound according to claim 12, wherein R₄ is —

C_pH_2p-adamantyl.

23. A compound according to claim 22, wherein R₄ is

24. A compound according to claim 15, wherein R₄ is —

C_pH_2p-steryl or —

C_pH_2p-adamantyl.

25. A compound according to claim 16, wherein R₄ is —

C_pH_2p-steryl or —

C_pH_2p-adamantyl.

26. A compound according to claim 21, wherein the peptide is octreotide and wherein R₄ is —

C_pH_2p-steryl or —

C_pH_2p-adamantyl.

27. A compound according to claim 17, wherein R₄ is —

C_pH_2p-steryl or —

C_pH_2p-adamantyl.

28. A compound according to claim 18, wherein R₄ is —

C_pH_2p-steryl or —

C_pH_2p-adamantyl.

29. The compound according to claim 16, having the formula

30. The compound according to claim 17, having the formula

31. The compound according to claim 18, having the formula