Compounds and compositions for treating tissue ischemia

Abstract

There is disclosed a genus of compounds and pharmaceutical compositions that are protective for mitigating damage associated with tissue ischemia, particularly stroke (CNS ischemia), and ischemia of the myocardium. The present invention further provides a method for treating tissue damage caused by ischemia. Lastly, the present invention provides a method for treating tissue damage caused by providing a compound that inhibits the cytotoxic activity of 3-aminopropanal.

We claim:  
     
         1 . An ischemia-damage mitigating compound having a formula I:  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C 1-6  alkyl, straight or branched C 2-6  alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F), wherein both R and R 1  cannot be hydrogen, wherein R 2  and R 3  are independently hydrogen, sulfamnide, carboxyamide, cyano, straight or branched C 1-6  alkyl, straight or branched C 2-6  alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F).  
     
     
         2 . The ischemia-damage mitigating compound of  claim 1  wherein R and R 1  are meta to each other and to the heteroatom.  
     
     
         3 . The ischemia-damage mitigating compound of  claim 1  wherein R is COOH.  
     
     
         4 . The ischemia-damage mitigating compound of  claim 1  wherein R 1  is COOH.  
     
     
         5 . The ischemia-damage mitigating compound of  claim 1  wherein R 2  and R 3  are both hydrogen.  
     
     
         6 . The ischemia-damage mitigating compound of  claim 1  wherein R and R 1  are each COOH, and R 2  and R 3  are both hydrogen.  
     
     
         7 . The ischemia-damage mitigating compound of  claim 1  wherein the compound is selected from the group consisting of 1-phenacyl-2,3-dicarboxypyrdiniun bromide; 1-phenacyl-2,4-dicarboxypyrdinium bromide; 1-phenacyl-2,5-dicarboxypyrdinium bromide (AP5); 1-phenacyl-2,6-dicarboxypyrdinium bromide; 1-phenacyl-2,3-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,4-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,5-dicarboxyirnidepyrdinium bromide; and 1-phenacyl-2,6-dicarboxyimidepyrdinium bromide.  
     
     
         8 . A pharmaceutical composition comprising a compound from formula I in a pharmaceutically acceptable carrier, wherein formula I comprises:  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C 1-6  alkyl, straight or branched C 2-6  alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F), wherein both R and R 1  cannot be hydrogen, wherein R 2  and R 3  are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C 1-6  alkyl, straight or branched C 2-6  alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F).  
     
     
         9 . The pharmaceutical composition of  claim 8  wherein R and R 1  are meta to each other and to the heteroatom.  
     
     
         10 . The pharmaceutical composition of  claim 8  wherein R is COOH.  
     
     
         11 . The pharmaceutical composition of  claim 8  wherein R 1  is COOH.  
     
     
         12 . The pharmaceutical composition of  claim 8  wherein R 2  and R 3  are both hydrogen.  
     
     
         13 . The pharmaceutical composition of  claim 8  wherein R and R 1  are each COOH, and R 2  and R 3  are both hydrogen.  
     
     
         14 . The pharmaceutical composition of  claim 8  wherein the compound is selected from the group consisting of 1-phenacyl-2,3-dicarboxypyrdinium bromide; 1-phenacyl-2,4-dicarboxypyrdinium bromide; 1-phenacyl-2,5-dicarboxypyrdinium bromide (AP5); 1 -phenacyl-2,6-dicarboxypyrdinium bromide; 1-phenacyl-2,3dicarboxyimidepyrdinium bromide; 1-phenacyl-2,4-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,5-dicarboxyimidepyrdiniun bromide; and 1-phenacyl-2,6-dicarboxyimidepyrdinium bromide.  
     
     
         15 . A method for inhibiting tissue damage caused by ischemia, comprising administering an effective amount of a compound of formula I, wherein formula I comprises:  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C 1-6 alkyl, straight or branched C 2-6 . alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Dr, Cl, I, F), wherein both R and R 1  cannot be hydrogen, wherein R 2  and R 3  are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C 1-6  alkyl, straight or branched C 2-6  alkenyl, straight or branched C 1-6  alkoxy, a straight chain C 1-6  alkyl or a straight chain C 2-6  alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F).  
     
     
         16 . The method of  claim 15  wherein R and R 1  are meta to each other and to the heteroatom.  
     
     
         17 . The method of  claim 15  wherein R is COOH.  
     
     
         18 . The method of  claim 15  wherein R 1  is COOH.  
     
     
         19 . The method of  claim 15  wherein R 2  and R 3  are both hydrogen.  
     
     
         20 . The method of  claim 15  wherein R and R 1  are each COOH, and R 2  and R 3  are both hydrogen.  
     
     
         21 . The method of  claim 15  wherein the compound is selected from the group consisting of 1-phenacyl-2,3-dicarboxypyrdinium bromide; 1-phenacyl-2,4-dicarboxypyrdinium bromide; 1-phenacyl-2,5-dicarboxypyrdinium bromide (AP5); 1-phenacyl-2,6-dicarboxypyrdinium bromide; 1-phenacyl-2,3-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,4-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,5-dicarboxyimidepyrdinium bromide; and 1-phenacyl-2,6-dicarboxyimidepyrdinium bromide.  
     
     
         22 . A method for inhibiting tissue damage caused by ischemia, comprising administering an effective amount of a compound of formula II, wherein formula II comprises:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy C 1-6  alkyl, C 1-6  alkoxy C 1-6  alkyl, and R 1  and R 2  together with their ring carbons may be an aromatic fused ring; wherein Z is hydrogen or an amino group; wherein Y is hydrogen or a group of the formula —CH 2 COR; wherein R is C 1-6  alkyl, C 1-6  alkoxy, hydroxy, amino, aryl, or —CH 2 R 3  wherein R 3  is H, C 1-6  alkyl, C 2-6  alkenyl, or C 4-6  aryl.  
     
     
         23 . The method of  claim 22  wherein the compound of formula II is a halide (Cl. Br, F or I), tosylate, methanesulfonate or mesitylene sulfonate salt.  
     
     
         24 . A method for treating tissue damage caused by ischemia, comprising administering an effective amount of a compound that detoxifies 3-aminopropanal.  
     
     
         25 . The method of  claim 24  wherein the tissue damage resulting from ischemia are manifest as myocardial infarction or stroke.  
     
     
         26 . An in vivo screening assay comprising administering a polyamine compound or 3-aminopropanal into the brain parenchyma of a test animal by microinjection, administering a test compound or control agent locally or systemically, and measuring cytotoxicity in stained brain sections from the test animals.  
     
     
         27 . An in vitro screening assay comprising exposing cultured glial cells or neuronal cells related cell lines to 3-aminopropanal at a concentration of from about 50 to about 1000 μM, adding various concentrations of test compound or control media to the cell cultures, incubated under cell culture conditions for a period of from about 5 minutes to about 20 hours, and determining the percentage of cell viability.