Method for minimizing and containing ischemic and reperfusion injury

• US 5,455,229 A
• Filed: 12/23/1992
• Issued: 10/03/1995
• Est. Priority Date: 12/23/1992
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: MacDonald, Brian R., Hahn, Richard A., Smith, Gerald F., Shuman, Robert T.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Lukton, David
• Application Number:
  US07/996,347
• Time in Patent Office: 1,014 Days
• Field of Search: 514/18, 514/19, 530/331, 562/560, 562/445, 548/535
• US Class Current: 514/16.4
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

The present invention is a method for minimizing and containing injury caused when tissue is subject to ischemia and reperfusion. The method comprises administering certain derivatized tripeptide arginal compounds concurent with, or immediately after, reestablishing blood flow to the ischemic tissue. The method is particularly useful for minimizing and containing damage to the heart during evolving myocardial infarction.

Claims

1. A method of treatment for minimizing and containing reperfusion injury in mammals which comprises administering to a mammal in need of such treatment an effective non-toxic amount of a compound of the general formula:

space="preserve" listing-type="equation">A-Pro-Arg-H

wherein substituent A has an α

-carbon, the stereochemical configuration of which is either D or L, preferably D, and wherein Pro and Arg are both of the L configuration;

##STR8## Z is C₁ -C₄ alkyl, or H;

X is NH₂, NHZ, t-butyloxycarbonyl-NH, acetyl-NH, or trifluoroacetyl-NH;

R is H, OH, halogen, alkoxy, CF₃, C₁ -C₄ alkyl, NO₂, or NH₂ ; and

,

q is CH₂, or CO.

2. The method of claim 1 wherein the administering is done by intravenous infusion.

3. The method of claim 2 wherein the mammal in need of treatment is a mammal experiencing evolving myocardial infarction.

4. The method of claim 3 wherein the mammal is a human being.

5. The method of claim 1 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

6. The method of claim 2 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

7. The method of claim 3 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

8. The method of claim 4 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

17. The method of claim 1 wherein the administered compound is D-3-Piq-L-Prolyl-L-Arginal.

18. The method of claim 1 wherein the administered compound is D-7-hydroxyl-1,2,3,4-Tiq-3-carbonyloxy-L-Prolyl-L-Arginal.

19. The method of claim 1 wherein the administered compound is D-3-Tiq-L-Prolyl-L-Arginal.

20. The method of claim 1 wherein the administered compound is D-1,2,3,4-Tiq-1-carbonyl-L-Prolyl-L-Arginal.

21. The method of claim 1 wherein the administered compound is N-Methyl-D-Phenytalanyl-L-Prolyl-L-Arginal.

22. The method of claim 1 wherein the administered compound is N.sup.α

-t-butyloxycarbonyl-D-Phenylanyl-L-Prolyl-L-Arginal.

9. A method for minimizing and containing reperfusion injury in mammals which comprises administering to a mammal in need of such treatment an effective non-toxic amount of a compound selected from the group consisting of D-3-Piq-L-Prolyl-L-Arginal, D-7-hydroxyl-1,2,3,4-Tiq-3-carbonyloxy-L-Prolyl-L-Arginal, D-3-Tiq-L-Prolyl-L-Arginal, D-1,2,3,4-Tiq-1-carbonyl-L-Prolyl-L-Arginal, N-Methyl-D-Phenylalanyl-L-Prolyl-L-Arginal, and N.sup.α

-t-butyloxycarbonyl-D-Phenylanyl-L-Prolyl-L-Arginal.

10. The method of claim 9 wherein the administering is done by intravenous infusion.

11. The method of claim 10 wherein the mammal in need of treatment is a mammal experiencing evolving myocardial infarction.

12. The method of claim 11 wherein the mammal is a human being.

13. The method of claim 9 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

14. The method of claim 10 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

15. The method of claim 11 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.

16. The method of claim 12 wherein the compound is co-administered with an effective, non-toxic amount of aspirin.