Granted Patent B2

US 7,314,880 · App. 10/749,437 · Granted Jan 1, 2008

Abstract

Claims (43)

1. A method of reducing ischemic damage in cardiac tissue in a subject comprising:

administering to the subject in need thereof an effective amount of a composition comprising a non-analgesic diarylmethylpiperazine compound of the general formula:

wherein:

Z is selected from the group consisting of:

hydrogen;

halogen;

C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;

C 1 -C 6 haloalkyl;

C 1 -C 6 alkoxy;

C 3 -C 6 cycloalkoxy;

sulfides of the formula SR 8 where R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, arylalkyl having a C 5 -C 10 aryl moiety and an C 1 -C 6 alkyl moiety, or C 5 -C 10 aryl;

sulfoxides of the formula SOR 8 where R 8 is the same as above;

sulfones of the formula SO 2 R 8 where R 8 is the same as above;

nitrile;

C 1 -C 6 acyl;

alkoxycarbonylamino (carbamoyl) of the formula NHCO 2 R 8 where R 8 is the same as above;

carboxylic acid, or an ester, amide, or salt thereof;

aminomethyl of the formula CH 2 NR 9 R 10 where R 9 and R 10 may be the same or different, and may be hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 hydroxyalkyl, C 2 -C 6 methoxyalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 10 aryl, or R 9 and R 10 together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;

carboxamides of the formula CONR 9 R 10 where R 9 and R 10 are the same as above, or C 2 -C 30 peptide conjugates thereof; and

sulfonamides of the formula SO 2 NR 9 R 10 where R 9 and R 10 are the same as above; and

X is selected from the group consisting of hydrogen, hydroxyl, halogen and alkoxy,

or a pharmaceutically acceptable ester or salt thereof.

2. A method of reducing ischemic damage in cardiac tissue in a subject comprising: administering to the subject in need thereof an effective amount of a therapeutic composition comprising a non-analgesic diarylmethylpiperazine compound of the formula:

or a pharmaceutically acceptable salt or ester thereof.

3. A method of reducing ischemic damage in cardiac tissue in a mammal, the method comprising: administering to the mammal in need thereof an effective amount of a non-analgesic diarylmethylpiperazine compound of the formula:

or a pharmaceutically acceptable salt or ester thereof.

4. The method according to claim 3 , wherein the diarylmethylpiperazine compound is administered multiple times concurrently with the onset of an ischemic event.

5. The method according to claim 3 , wherein the diarylmethylpiperazine compound is administered to the mammal to reduce cardiac tissue damage in an individual in a symptomatic phase of ischemic heart disease.

6. The method according to claim 3 , wherein the diarylmethylpiperazine compound is administered after the onset of an ischemic event.

7. The method according to claim 3 , further comprising administering a second compound that effectuates a corrective cardiac response.

8. The method according to claim 7 , wherein the second compound is selected from the group consisting of nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa antagonists and aspirin.

9. The method according to claim 7 , wherein the second compound is administered contemporaneously with the diarylmethylpiperazine compound.

10. The method according to claim 3 , wherein the diarylmethylpiperazine compound is administered by a mode of administration selected from the group consisting of parenteral, non-parenteral, oral, rectal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, sublingual, oral mucosal, bronchial, lymphatic, and intra-uterine administration.

11. The method according to claim 3 , wherein the mammal is a human.

12. A method of treating ischemia and reperfusion injury in cardiac tissue in a mammal comprising administering to the mammal in need thereof an effective amount of a non-analgesic delta opioid receptor agonist of the formula:

or pharmaceutically acceptable esters and salts thereof in combination with a second compound that effectuates an anti-ischemic effect.

13. The method of claim 12 , wherein the second compound is arginine hydrochloride.

14. A method of effectuating ischemic preconditioning of cardiac tissue in a subject in need thereof, the method comprising: administering to the subject an effective amount of a non-analgesic diarylmethylpiperazine compound of the formula:

or pharmaceutically acceptable esters and salts thereof.

15. The method of claim 14 , wherein the compound is administered by a mode of administration selected from the group consisting of parenteral, non-parenteral, oral, rectal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, sublingual, oral mucosal, bronchial, lymphatic, and intra-uterine administration.

16. The method according to claim 14 , further comprising administering a second compound that effectuates a corrective cardiac response.

17. The method according to claim 16 , wherein the second compound is selected from the group consisting of nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa antagonists and aspirin.

18. The method according to claim 16 , wherein the second compound is administered contemporaneously with the diarylmethylpiperazine compound.

Assignments (11)