Acyclovir-peptide analogs

• US 7,825,086 B2
• Filed: 08/19/2008
• Issued: 11/02/2010
• Est. Priority Date: 12/04/2001
• Status: Expired due to Fees

• Current Assignee: Curators of the University of Missouri (University of Missouri)
• Original Assignee: Curators of the University of Missouri (University of Missouri)
• Inventors: Mitra, Ashim K.
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US12/194,248
• Publication Number:
  US 20090082566A1
• Time in Patent Office: 805 Days
• Field of Search: None
• US Class Current: 514/4.2
• 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: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06052 Val-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Dipeptide and tripeptide ester derivatives of acyclovir and its analogs are disclosed which are useful to treat herpes virus infections. Also disclosed is a method for preparing a therapeutic agent for targeted delivery to ocular tissue comprising linking the therapeutic agent to one or more groups of the formula —X—Y-Z_(n)-R; wherein each X, Y and Z is independently Met, Val, Thr, Tyr, Trp, Ser, Ala or Gly; each R is independently H or an amino-protecting group; and each n is independently 0 or 1.

Claims

1. A compound of formula (1):

2. The compound of claim 1 wherein each Q is O.

3. The compound of claims 1 wherein at least one of R, R¹, R², and R³ is H.

4. The compound of claim 3 wherein each Y and X is individually Gly or Val.

5. The compound of claim 4 wherein each R is H, acetyl, or t-butoxycarbonyl.

6. The compound of claim 5 wherein each R is H.

7. The compound of claim 1 wherein each n is 0.

8. The compound of claim 1, of formula (IV):

9. The compound of claim 8 wherein Y—

X—

is Val-Val- or Gly-Gly-.

10. The compound of claim 1 wherein R² is CH₂OH and R⁴ is R^a.

11. The compound of claim 1 wherein R² is CH₂R^a and R⁴ is R^a.

12. The compound of claim 1 wherein R² is CH₂R^a and R⁴ is OH.

13. The compound of claim 1 wherein each Y—

X—

is independently Val-Val-, Gly-Gly-, Val-Gly-, or Gly-Val-.

14. A therapeutic composition comprising an effective anti-viral amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

15. The composition of claim 14 wherein the carrier is a liquid.

16. The composition of claim 14 wherein the carrier is an ointment.

17. A method of treating herpes simplex virus comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

18. The method of claim 17 wherein the mammal is a human.

19. The method of claim 17 wherein the herpes virus is HSV-1.

20. The method of claim 17 wherein the herpes virus is HSV-2.

21. The method of claim 17 wherein the herpes virus is human cytomegalovirus and the compound is a compound of claim 1.

22. The method of claim 17 wherein the compound is administered to the eye in eyedrops.

23. The method of claim 17 wherein the effective amount is up to about 20 mg/ml of the compound.

24. The method of claim 17 wherein the infection is an infection of the eye.

25. The method of claim 24 wherein the infection is an infection of the retina.

26. The method of claim 17 wherein the compound is administered systemically.

27. The method of claim 17 wherein the compound is administered orally.