Compositions and methods for treating mitochondrial diseases

Abstract

The invention described herein relates to methods for treating mitochondrial diseases. In particular, the invention relates to methods for treating mitochondrial diseases by administering therapeutically effective amounts of one or more tetracyclic pyrazinoindoles, and/or pharmaceutically acceptable salts thereof.

1 . A method for treating a mitochondrial disease in a patient, the method comprising the step of administering a therapeutically effective amount of one or more tetracyclic pyrazinoindoles, pharmaceutically acceptable salts thereof, or a combination thereof to the patient. 
     
     
         2 . The method of  claim 1  wherein the mitochondrial disease is selected from the group consisting of FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, and MELAS. 
     
     
         3 . The method of  claim 1  wherein the mitochondrial disease is FRDA. 
     
     
         4 . The method of  claim 1  wherein the mitochondrial disease is LHON. 
     
     
         5 . The method of  claim 1  wherein at least one of the tetracyclic pyrazinoindoles is a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R a  is hydrogen, or R a  represents 1 to 4 substituents, each independently selected from halo and hydroxy, and alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; 
 R c  is hydrogen, or R c  represents 1 or 2 substituents, each independently selected from alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; 
 R d  is hydrogen, or R d  represents 1 or 2 substituents, each independently selected from alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; and 
 R N  is hydrogen or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or R N  and the attached nitrogen form an amide, carbamate, or urea, or thiono derivative thereof; or R N  and the attached nitrogen form an amine prodrug. 
 
     
     
         6 . The method of  claim 1  wherein at least one of the tetracyclic pyrazinoindoles is a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R a  is hydrogen, halo, or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; 
 R c  is hydrogen, or alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and 
 R N  is hydrogen or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or R N  and the attached nitrogen form an amide, carbamate, or urea, or thiono derivative thereof; or R N  and the attached nitrogen form an amine prodrug. 
 
     
     
         7 . The method of  claim 1  wherein at least one of the tetracyclic pyrazinoindoles is a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R a  is hydrogen, halo, or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and 
 R N  is hydrogen or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or R N  and the attached nitrogen form an amide, carbamate, or urea, or thiono derivative thereof; or R N  and the attached nitrogen form an amine prodrug. 
 
     
     
         8 . The method of  claim 1  wherein at least one of the tetracyclic pyrazinoindoles is a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R c  is hydrogen, or alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and 
 R N  is hydrogen or hydroxy, or alkoxy, acyloxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or R N  and the attached nitrogen form an amide, carbamate, or urea, or thiono derivative thereof; or R N  and the attached nitrogen form an amine prodrug. 
 
     
     
         9 . The method of  claim 5  wherein R a  is alkyl. 
     
     
         10 . The method of  claim 5  wherein R a  is methyl. 
     
     
         11 . The method of  claim 5  wherein R a  is cycloalkyl. 
     
     
         12 . The method of  claim 5  wherein R a  is cyclohexyl. 
     
     
         13 . The method of  claim 5  wherein R a  is alkoxy. 
     
     
         14 . The method of  claim 5  wherein R a  is methoxy. 
     
     
         15 . The method of  claim 5  wherein R c  is 
     
     
         16 . The method of  claim 5  wherein R d  is hydrogen. 
     
     
         17 . The method of  claim 5  wherein R N  is hydrogen. 
     
     
         18 . The method of  claim 5  wherein R N  is alkyl. 
     
     
         19 . The method of  claim 5  wherein R N  is methyl. 
     
     
         20 . The method of  claim 5  wherein R N  is cycloalkyl. 
     
     
         21 - 26 . (canceled)