Treatment of mitochondrial diseases

Abstract

The invention relates the method of treatment or amelioration of mitochondrial disorders such as Alzheimer's disease, Parkinson's disease, Friedreich's ataxia (FRDA), cerebellar ataxias, Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERFF), amyotrophic lateral sclerosis (ALS), motor neuron diseases, Huntington's disease, macular degeneration, and epilepsy, with chroman derivatives of Formula I or Formula II as described herein.

What is claimed is: 
     
         1 . A method of treating or ameliorating a subject suffering from a mitochondrial disorder comprising administering to said subject a therapeutically effective amount of a compound of Formula I or Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         -A-B— is —CH 2 —CH 2 —; —CH═CH— or —CH 2 —O—; 
         n is 0; 
         R 1  is C 1-4  alkyl; 
         R 2  is C 1-20  alkyl or C 2-20  alkenyl, halogen, cyano, or R 2  and A together with the atoms to which they are attached form a ring; 
         R 3  is
 hydrogen; 
 halogen; 
 aralkyl, optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —SO 2 NR 2  or —C(O)OR; 
 heteroaralkyl optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —SO 2 NR 2  or —C(O)OR; 
 C 1-6  alkyl; 
 C 2-20  alkenyl; 
 —(CR 2 ) 1-3 S(O) 0-2 (CR 2 ) 1-3 C(O)OR; 
 —(CR 2 ) 1-3 OR a ; 
 —(CR 2 ) 1-3 NR b R c    
 —C(O)R a ; or 
 nitro; 
 
         R 4  is hydrogen; optionally substituted C 1-6  alkyl; C 2-12  alkenyl; hydroxyalkyl; acyl; glucoside; phosphoryl; phosphoryloxyalkyl; carboxyalkylcarbonyl; or aminoalkylcarbonyl; 
         R 5  and R 6  are independently of each other hydrogen, halogen, haloalkyl, nitro, acyl, C 1-6  alkyl or C 2-12  alkenyl; or R 5  and R 6  taken together with the carbon to which they are attached form a 5-6 membered aliphatic, unsaturated or aromatic ring, optionally substituted with C 1-6  alkyl, C 1-6  alkoxy, hydroxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, or hydroxyalkyl; 
         R is hydrogen or C 1-6  alkyl; 
         R a  is hydrogen; optionally substituted C 1-6  alkyl; optionally substituted C 2-12  alkenyl; optionally substituted aryl; optionally substituted cycloalkyl; or optionally substituted saturated, partially unsaturated or unsaturated heterocyclyl; 
         R b  and R c  are independently of each other hydrogen; C 1-6  alkyl; hydroxyalkyl; aminoalkyl; optionally substituted aryl; optionally substituted benzyl; or optionally substituted heterocyclyl; or R b  and R c  taken together with the atom to which they are attached form a 5 to 8 membered aromatic, saturated or unsaturated ring, optionally incorporating one additional atom chosen from N, O, or S and optionally substituted with a substituent selected from the group consisting of lower alkyl, halo, cyano, alkylthio, lower alkoxy, oxo, phenyl, benzyl and carboxy; 
         with the proviso that the compound is not alpha-tocopherol; or 
       
       
         
           
           
               
               
           
         
         wherein: 
         G is —O—, —S—, —SO—, —SO 2 —, a secondary or tertiary amine group, a phosphate group, a phosphoester group, or an unsubstituted or substituted methylene group, 
         R 7  and R 8  independently are hydrogen, hydroxy, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6-member aliphatic or aromatic ring, 
         R 9  and R 10  independently are hydrogen, hydroxy, alkyl, aryl, alkenyl, alkynyl, aromatic, ether, ester, unsubstituted or substituted amine, amide, halogen or unsubstituted or substituted sulfonyl, or jointly complete a 5- or 6-member aliphatic, aromatic or heterocyclic ring, 
         R 11  is hydrogen, hydroxy, alkyl, aryl, alkenyl, alkynyl, aromatic, ester or unsubstituted or substituted amine, 
         R 12  is —COOH, —COOR 13 , —CONH 2 , —CONHR 13 , —CONR 13 R 14 , —NH 2 , —NHR 13 , —NR 13 R 14 , or a carboxylate salt, 
         R 13  and R 14  independently are unsubstituted or substituted alkyl, aryl, alkaryl, aralkyl, alkenyl or alkynyl, 
         p is 0 to 3, and 
         m is 0 to 5; or 
         single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1 , comprising administering to said subject a therapeutically effective amount of a compound of Formula I. 
     
     
         3 . The method of  claim 2 , comprising administering the compound of Formula I wherein R 3  is hydrogen, C 1-6  alkyl, or C 2-20  alkenyl. 
     
     
         4 . The method of  claim 2 , comprising administering the compound of Formula I wherein R 5  and R 6  are independently of each other C 1-4  alkyl or halogen. 
     
     
         5 . The method of  claim 4 , comprising administering the compound of Formula I wherein R 1  is C 1-6  alkyl and R 2  is C 1-6  alkyl. 
     
     
         6 . The method of  claim 2 , comprising administering the compound of Formula I wherein R 1  is C 1-6  alkyl, and R 2  is C 16  alkyl or C 16  alkenyl. 
     
     
         7 . The method of  claim 2 , comprising administering the compound of Formula I wherein R 5  and R 6  taken together with the carbon to which they are attached form a 5-6 membered carbocyclic ring, optionally substituted with C 1-6  alkyl, C 1-6  alkoxy, hydroxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, or hydroxyalkyl. 
     
     
         8 . The method of  claim 1 , comprising administering to said subject a therapeutically effective amount of a compound of Formula II. 
     
     
         9 . The method of  claim 8 , comprising administering the compound of Formula II, wherein R 12  is —COOH, or —COOR 13  and R 13  is C 1-6  alkyl. 
     
     
         10 . The method of  claim 1 , comprising administering a compound selected from:
 8-Chloro-2-(3-chloro-propyl)-2,5-dimethyl-chroman-6-ol;   5-Chloro-2-(3-chloro-propyl)-2,8-dimethyl-chroman-6-ol;   7-tert-Butyl-2-(3-chloro-propyl)-2-methyl-chroman-6-ol;   Acetic acid 2,2,5-trimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl ester;   2,2,5,7-Tetramethyl-8-trifluoromethyl-chroman-6-ol;   5-Methoxy-2,2,7,8-tetramethyl-chroman-6-ol;   8-Fluoro-2,2,5,7-tetramethyl-chroman-6-ol;   2,2,5,7-Tetramethyl-8-(3-methyl-butyl-chroman-6-ol;   6-Hydroxy-2,2,5,7-tetramethyl-chroman-8-carbaldehyde;   2,2,5,7-Tetramethyl-8-nitro-chroman-6-ol;   5-(1-Hydroxy-ethyl)-2,2,7,8-tetramethyl-chroman-6-ol;   5-Hydroxymethyl-2,2,7,8-tetramethyl-chroman-6-ol;   5-(2-Hydroxy-ethyl)-2,2,7,8-tetramethyl-chroman-6-ol;   10-Methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-ol;   2-Ethynyl-2,5,7,8-tetramethyl-chroman-6-ol;   2-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-N-(3-trifluoromethyl-phenyl)-acetamide;   (6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-piperazin-1-yl-methanone;   6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxamidine;   N-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethyl)-N-methyl-acetamide;   2,2,5,7,8-Pentamethyl-2H-chromen-6-ol;   2-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethyl)-propane-1,3-diol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   2,2,5,8-Tetramethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   2-(3-Chloro-propyl)-2,7,8-trimethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-chroman-6-ol;   (6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylsulfanyl)-acetic acid methyl ester;   5,6,9-Trimethyl-8-oxa-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-trien-4-ol;   2,2,7,8-Tetramethyl-5-(3-methyl-butyl)-chroman-6-ol;   2,2,7,8-Tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   3-(6-Hydroxy-2,8-dimethyl-chroman-2-yl)-propionic acid;   2,2,7,8-Tetramethyl-chroman-6-ol;   3-[6-Hydroxy-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-2-yl]-propionic acid;   3-(5-Bromo-6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,7,8-trimethyl-5-nitro-chroman-2-yl)-propionic acid;   3-(2,5,7,8-Tetramethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2-methyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2-methyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid;   2-Hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol;   5-[3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propyl]-thiazolidine-2,4-dione;   2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-ylmethylsulfanyl]-ethylcarbamoyl}-butyric acid;   5-(4-Benzyl-piperazin-1-ylmethyl)-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol;   3-(5-Bromo-6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2-methyl-3,4-dihydro-2H-benzo[h]chroman-2-yl)-propionic acid;   4-[1-(Carboxymethyl-carbamoyl)-2-mercapto-ethylcarbamoyl]-2-[3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionylamino]-butyric acid);   2,2,7,8-Tetramethyl-chroman-6-ol;   Delta tocopherol;   Delta tocotrienol;   Gamma-tocopherol;   Gamma-tocotrienol; and   Alpha tocotrienol; or   
       single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof. 
     
     
         11 . The method of  claim 1 , comprising administering a therapeutically effective amount of a compound of Formula I or of Formula II to a subject suffering from a disease involving mitochondrial dysfunctions selected from Alzheimer's disease, Parkinson's disease, Friedreich's ataxia (FRDA), cerebellar ataxias, Leber's hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERFF), amyotrophic lateral sclerosis (ALS), motor neuron diseases, Huntington's disease, macular degeneration, and epilepsy. 
     
     
         12 . The method of  claim 1 , comprising administering a therapeutically effective amount of a compound of Formula I or of Formula II to a subject suffering from Friedreich's ataxia (FRDA), MELAS, or MERFF. 
     
     
         13 . The method of  claim 12 , comprising administering a therapeutically effective amount of a compound selected from:
 8-Chloro-2-(3-chloro-propyl)-2,5-dimethyl-chroman-6-ol;   5-Chloro-2-(3-chloro-propyl)-2,8-dimethyl-chroman-6-ol;   7-tert-Butyl-2-(3-chloro-propyl)-2-methyl-chroman-6-ol;   Acetic acid 2,2,5-trimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl ester;   2,2,5,7-Tetramethyl-8-trifluoromethyl-chroman-6-ol;   5-Methoxy-2,2,7,8-tetramethyl-chroman-6-ol;   8-Fluoro-2,2,5,7-tetramethyl-chroman-6-ol;   2,2,5,7-Tetramethyl-8-(3-methyl-butyl-chroman-6-ol;   6-Hydroxy-2,2,5,7-tetramethyl-chroman-8-carbaldehyde;   2,2,5,7-Tetramethyl-8-nitro-chroman-6-ol;   5-(1-Hydroxy-ethyl)-2,2,7,8-tetramethyl-chroman-6-ol;   5-Hydroxymethyl-2,2,7,8-tetramethyl-chroman-6-ol;   5-(2-Hydroxy-ethyl)-2,2,7,8-tetramethyl-chroman-6-ol;   10-Methoxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-ol;   2-Ethynyl-2,5,7,8-tetramethyl-chroman-6-ol;   2-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-N-(3-trifluoromethyl-phenyl)-acetamide;   (6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-piperazin-1-yl-methanone;   6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxamidine;   N-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethyl)-N-methyl-acetamide;   2,2,5,7,8-Pentamethyl-2H-chromen-6-ol;   2-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethyl)-propane-1,3-diol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   2,2,5,8-Tetramethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   2-(3-Chloro-propyl)-2,7,8-trimethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-chroman-6-ol;   2-(2-Chloro-ethyl)-2,7,8-trimethyl-chroman-6-ol;   (6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-ylmethylsulfanyl)-acetic acid methyl ester;   5,6,9-Trimethyl-8-oxa-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-trien-4-ol;   2,2,7,8-Tetramethyl-5-(3-methyl-butyl)-chroman-6-ol;   2,2,7,8-Tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol;   3-(6-Hydroxy-2,8-dimethyl-chroman-2-yl)-propionic acid;   2,2,7,8-Tetramethyl-chroman-6-ol;   3-[6-Hydroxy-2,7,8-trimethyl-5-(3-methyl-but-2-enyl)-chroman-2-yl]-propionic acid;   3-(5-Bromo-6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,7,8-trimethyl-5-nitro-chroman-2-yl)-propionic acid;   3-(2,5,7,8-Tetramethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2-methyl-chroman-2-yl)-propionic acid;   3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2-methyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid;   2-Hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-ol;   5-[3-(6-Hydroxy-2,7,8-trimethyl-chroman-2-yl)-propyl]-thiazolidine-2,4-dione;   2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-5-ylmethylsulfanyl]-ethylcarbamoyl}-butyric acid;   5-(4-Benzyl-piperazin-1-ylmethyl)-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol;   3-(5-Bromo-6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid methyl ester;   3-(6-Hydroxy-2-methyl-3,4-dihydro-2H-benzo[h]chroman-2-yl)-propionic acid;   4-[1-(Carboxymethyl-carbamoyl)-2-mercapto-ethylcarbamoyl]-2-[3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionylamino]-butyric acid);   2,2,7,8-Tetramethyl-chroman-6-ol;   Delta tocopherol;   Delta tocotrienol;   Gamma-tocopherol;   Gamma-tocotrienol; and   Alpha tocotrienol; or   
       single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof. 
     
     
         14 . The method of  claim 12 , comprising treating or ameliorating a subject in need of protection of Friedreich's ataxia comprising administering a therapeutically effective amount of a tocopherol selected from beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, and gamma-tocotrienol.