Cardioprotective delta opioid receptor agonists and methods of using same

Abstract

The present invention relates to compositions and methods of treatment for cardioprotection through the use of non-peptidic delta opioid receptor agonist compound(s) that mediate cardioprotective effects of ischemic preconditioning. The compounds are used to reduce injury associated with ischemia and reperfusion of cardiac tissue. Further, the compounds may be used in solutions preserving the viability of an isolated organ.

1 . A therapeutic composition for combating ischemic damage, the composition comprising an effective amount of a 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 . The composition according to  claim 1 , wherein the composition further comprises an effective amount of a second compound used for treatment of a cardiac disorder. 
     
     
         3 . The composition according to  claim 2 , 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. 
     
     
         4 . The composition according to  claim 2 , wherein the second compound is administered contemporaneously with the diarylmethylpiperazine compound. 
     
     
         5 . The composition according to  claim 1 , wherein the diarylmethylpiperazine compound is a non-analgesic compound. 
     
     
         6 . The composition according to  claim 5 , wherein the diarylmethylpiperazine compound acts predominately on peripheral delta opioid receptors. 
     
     
         7 . The composition according to  claim 1 , wherein the diarylmethylpiperazine 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. 
     
     
         8 . A composition comprising an effective amount of a non-analgesic diarylmethylpiperazine compound of the formula:
 or a pharmaceutically acceptable ester or salt thereof.   
       
         
           
           
               
               
           
         
       
     
     
         9 . The composition according to  claim 8 , wherein the composition further comprises a second compound used to mediate a protective or corrective cardiac response or activity. 
     
     
         10 . The composition according to  claim 9 , 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. 
     
     
         11 . The composition according to  claim 10 , wherein the second compound is administered contemporaneously with the diarylmethylpiperazine compound. 
     
     
         12 . The composition according to  claim 9 , wherein the non-analgesic diarylmethylpiperazine 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. 
     
     
         13 . A therapeutic composition, the composition comprising an effective amount of a non-analgesic diarylmethylpiperazine compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable ester or salt thereof. 
       
     
     
         14 . The composition according to  claim 13 , wherein the composition further comprises a second compound used to mediate a protective or corrective cardiac response or activity. 
     
     
         15 . The composition according to  claim 14 , 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. 
     
     
         16 . The composition according to  claim 13 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         17 . A preserving solution for an isolated organ comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         18 . The solution of  claim 17 , wherein the isolated organ is selected from the group consisting of heart, liver, kidney, cornea, lung and combination thereof.