Compositions and methods for neuroprotectin

Abstract

Disclosed herein are neuroprotective compounds. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of neurodegenerative conditions are provided.

1 . A pharmaceutical composition, comprising at least one compound having the structure of Formula I:  
       
         
           
           
               
               
           
         
         wherein each compound of Formula I is in a substantially purified form; and  
         Y 1  is O and Y 2  is OH or O-alkyl; or Y 1  and Y 2  together form a furan group;  
         R 1  and R 2  together form a substituted cycloalkyl or cycloalkenyl group; and   is selected from  , or  
         
           
             
             
                 
                 
             
           
         
         wherein X 4  and R 2  together form a substituted heteroalicyclic group provided that R 1  is H; or  
         pharmaceutically acceptable salts, prodrugs, or metabolites thereof;  
         or ester derivatives, saccharide derivatives, or —(CH 2 CH 2 O) n CH 3  derivatives thereof, where n is 1 to 100;  
         and a pharmaceutically acceptable excipient.  
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the at least one compound of Formula I has a structure selected from:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 4  and R 5  together form a substituted cycloalkyl or cycloalkenyl group.  
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 6  and R 7  together form a substituted cycloalkyl or cycloalkenyl group; and 
 X 1  is selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl.  
 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the at least one compound of Formula I has a structure selected from:  
       
         
           
           
               
               
           
         
       
       wherein R 8  and R 9  are independently H or alkyl; 
 X 2  and X 3  are independently selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl; and   is selected from   or  
                     
 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 4  and R 5  together form a substituted cycloalkyl or cycloalkenyl group.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 6  and R 7  together form a substituted cycloalkyl or cycloalkenyl group; and 
 X 1  is selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl.  
 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the at least one compound of Formula I has a structure selected from:  
       
         
           
           
               
               
           
         
       
       wherein R 8  and R 9  are independently H or alkyl; 
 X 2  and X 3  are independently selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl; and   is selected from   or  
                     
 
     
     
         9 . The pharmaceutical composition of  claim 2 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
         X 4  and R 10  together form a substituted heteroalicyclic group.  
       
     
     
         10 . The pharmaceutical composition of  claim 2 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 12  together form a substituted cycloalkyl or cycloalkenyl group.  
     
     
         11 . The pharmaceutical composition of  claim 2 , wherein the at least one compound of Formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 13  and R 14  are independently H or alkyl; 
 X 5  is selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl; and  
 R 15  is alkyl-C(O)O-alkyl.  
 
     
     
         12 . A method for treating or reducing the risk of a neurodegenerative condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 1 .  
     
     
         13 . The method of  claim 12 , wherein, at a concentration of 10 μM, the compound provides at least about 20% protection against 3 mM 3-nitropropionic acid to rat mixed hippocampal cultures.  
     
     
         14 . The method of  claim 12 , wherein the subject in need thereof is diagnosed as suffering from the neurodegenerative condition prior to the administration.  
     
     
         15 . The method of  claim 12 , wherein the administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.  
     
     
         16 . The method of  claim 12 , wherein the neurodegenerative condition is a chronic neurodegenerative condition.  
     
     
         17 . The method of  claim 16 , wherein the chronic neurodegenerative condition is selected from Alzheimer's Disease, multiple sclerosis, Huntington's Disease, or Parkinson's Disease.  
     
     
         18 . The method of  claim 16 , wherein the chronic neurodegenerative condition is AIDS related dementia.  
     
     
         19 . The method of  claim 16 , wherein the chronic neurodegenerative condition is Amyotrophic Lateral Sclerosis.  
     
     
         20 . The method of  claim 16 , wherein the chronic neurodegenerative condition is a retinal disease.  
     
     
         21 . The method of  claim 16 , wherein the chronic neurodegenerative condition is epilepsy.  
     
     
         22 . The method of  claim 12 , wherein the neurodegenerative condition is an acute neurodegenerative condition.  
     
     
         23 . The method of  claim 22 , wherein the acute neurodegenerative condition is stroke.  
     
     
         24 . The method of  claim 23 , wherein the stroke is selected from an acute thromboembolic stroke, a focal ischemia, a global ischemia, or a transient ischemic attack.  
     
     
         25 . The method of  claim 22 , wherein the acute neurodegenerative condition is an ischemia resulting from a surgical technique involving prolonged halt of blood flow to the brain.  
     
     
         26 . The method of  claim 22 , wherein the acute neurodegenerative condition is selected from head trauma, spinal trauma, optic nerve stroke, anterior ischemic optic neuropathy, or traumatic optic neuropathy.  
     
     
         27 . The method of  claim 16 , wherein the chronic neurodegenerative condition is glaucoma, optic neuritis, compressive optic neuropathy, or a hereditary neuropathy.  
     
     
         28 . The method of  claim 16 , wherein the chronic neurodegenerative condition is schizophrenia.  
     
     
         29 . A method for treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of  claim 1 .  
     
     
         30 . A method for treating AIDS-related dementia in a subject in need thereof, comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of  claim 1.