Enantiomerically pure opioid diarylmethylpiperazine as a cardioprotection agent
View Patent ↗(−)3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol and pharmaceutically acceptable esters or salts thereof, in essentially enantiomerically pure form have utility as a cardioprotection agent.
1. A method of reducing ischemic damage in a subject comprising:
administering an effective amount of a therapeutic composition comprising a compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the animal is a human.
3. The method of claim 1 , 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.
4. The method according to claim 1 , wherein the compound is administered concurrently with the onset of an ischemic event; prior to onset of ischemia pre-surgery; or after the onset of an ischemic event.
5. The method according to claim 1 , further comprising administering a second compound that effectuates a protective or corrective cardiac response.
6. The method according to claim 5 , wherein the second compound is selected from the group consisting of arginine hydrochloride, nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa antagonists and aspirin.
7. The method according to claim 5 , wherein the second compound is administered contemporaneously with the compound of formula (I).
8. A method of reducing ischemic damage in cardiac tissue, comprising:
administering to the animal a pharmaceutical composition comprising an effective amount of an enantiomeric diarylmethylpiperazine compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable salt thereof.
9. The method according to claim 8 , wherein the enantiomeric diarylmethylpiperazine compound is administered multiple times concurrently with the onset of an ischemic event.
10. The method according to claim 8 , wherein the enantiomeric diarylmethylpiperazine compound is administered to a subject as a preventive regime to prevent disease progression in an individual in the symptomatic phase of ischemic heart disease.
11. The method according to claim 8 , wherein the enantiomeric diarylmethylpiperazine compound is administered after the onset of an ischemic event.
12. The method according to claim 8 , further comprising administering a second compound that effectuates a protective or corrective cardiac response.
13. The method according to claim 8 , wherein the enantiomeric 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.
14. A pharmaceutical composition comprising:
(a) an effective amount of a bioactive agent for treatment of a cardiac condition; and
(b) an effective amount of a compound comprising the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable salt thereof.
15. The composition according to claim, wherein the second compound is selected from the group consisting of arginine hydrochloride, nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa antagonists and aspirin.
16. The composition according to claim 14 , wherein the composition further comprises a pharmaceutically acceptable carrier.
17. A method of protecting against ischemia and reperfusion injury in a mammal comprising administering to the mammal an effective amount of an enantiomeric diarylmethylpiperazine compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or pharmaceutically acceptable salts thereof; and a second compound that effectuates an anti-ischemic effect.
18. A method of reducing ischemic damage in a subject comprising:
administering an effective amount of a therapeutic composition comprising a compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or pharmaceutically acceptable ester of formula I wherein the ester is selected from the group consisting of:
a) carboxylic acid esters of the hydroxyl group of the compound of formula (I) wherein a non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl, arylalkyl, aryloxyalky, aryl;
b) amino acid esters;
c) dicarboxylic acid esters; and
d) carbonate esters; carbamate esters; and inorganic esters.
19. A method of reducing ischemic damage in cardiac tissue, comprising:
administering to the animal a pharmaceutical composition comprising an effective amount of an enantiomeric diarylmethylpiperazine compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable ester of formula I wherein the ester is selected from the group consisting of:
a) carboxylic acid esters of the hydroxyl group of the compound of formula (I) wherein a non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl, arylalkyl, aryloxyalky, aryl;
b) amino acid esters;
c) dicarboxylic acid esters; and
d) carbonate esters; carbamate esters; and inorganic esters.
20. A method of protecting against ischemia and reperfusion injury in a mammal comprising administering to the mammal an effective amount of an enantiomeric diarylmethylpiperazine compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or pharmaceutically acceptable salts thereof; and a second compound that effectuates an anti-ischemic effect.
a pharmaceutically acceptable ester of formula I wherein the ester is selected from the group consisting of:
a) carboxylic acid esters of the hydroxyl group of the compound of formula (I) wherein a non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl, arylalkyl, aryloxyalky, aryl;
b) amino acid esters;
c) dicarboxylic acid esters; and
d) carbonate esters; carbamate esters; and inorganic esters; and and a second compound that effectuates an anti-ischemic effect.
21. A method of protecting against ischemia and reperfusion injury in a mammal comprising administering to the mammal an effective amount of an enantiomeric diarylmethylpiperazine compound of the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable ester of formula I wherein the ester is selected from the group consisting of:
a) carboxylic acid esters of the hydroxyl group of the compound of formula (I) wherein a non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl, arylalkyl, aryloxyalky, aryl;
b) ammo acid esters;
c) dicarboxylic acid esters; and
d) carbonate esters; carbamate esters; and inorganic esters.
22. A pharmaceutical composition comprising:
(a) an effective amount of a bioactive agent for treatment of a cardiac condition; and
(b) an effective amount of a compound comprising the formula:
(−)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol or a pharmaceutically acceptable ester of formula I wherein the ester is selected from the group consisting of:
a) carboxylic acid esters of the hydroxyl group of the compound of formula (I) wherein a non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl, arylalkyl, aryloxyalky, aryl;
b) amino acid esters;
c) dicarboxylic acid esters; and
d) carbonate esters; carbamate esters; and inorganic esters.
23. The composition according to claim 22 , wherein the a bioactive agent is selected from the group consisting of arginine hydrochloride, nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotensin II antagonists, IIb/IIIa antagonists and aspirin.