Phenothiazine analogues as mitochondrial therapeutic agents

Abstract

The present disclosure provides phenothiazine derivative compounds and salts thereof, compositions comprising these compounds, and methods of using these compounds in a variety of applications, such as treatment or suppression of diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation.

1 - 107 . (canceled) 
     
     
         108 . A method of treating or suppressing diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation, comprising administering to a subject in need of such treatment an effective amount a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         109 . The method of  claim 108 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         110 . The method of  claim 108 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         111 . The method of  claim 108 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         112 . The method of  claim 108 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         113 . The method of  claim 108 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         114 . A method of treating or suppressing diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation, comprising administering to a subject in need of such treatment an effective amount a compound of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Y is N + R 4 R 5 X or O; 
         X −  is an inorganic or organic counterion selected from the group consisting of halide, hydroxide, nitrate, oxide, phosphate, sulfate, acetate, monofluoroacetate, difluoroacetate, trifluoroacetate, trimethylacetate, benzoate, 3-(4-hydroxybenzoyl)benzoate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate cinnamate, citrate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, hexanoate, lactate, malate, maleate, malonate, mandelate, muconate, hydroxynaphthoate, oxalate, palmitate, propionate, 3-phenylpropionate, pyruvate, salicylate, stearate, succinate, lauryl sulfate, alkyl sulfonate, aryl sulfonate, and tartrate; 
       
       (i) R 1  is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, N(R 7 ) 2 , OR 7 , or SR 7 , wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C(O)N(R 8 ) 2 , C(O)OR 8 , N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; and
 R 3  is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, or OR 7  wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C(O)N(R 8 ) 2 , C(O)OR 8 , N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; or 
 
       (ii) R 1  is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, N(R 7 ) 2 , OR 7 , or SR 7 , wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C(O)N(R 8 ) 2 , C(O)OR 8 , N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; and
 R 3  is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, or OR 7 , wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1,2,3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C(O)N(R 8 ) 2 , C(O)OR 8 , N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; 
 R 2  is N(R 12 ) 2 ; 
 R 4  and R 5  together with the nitrogen atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or more independently selected R 9  substituents; 
 R 6  is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, N(R 11 ) 2 , OR 10 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, Ct-Ce haloalkyl, CON(R 8 ) 2 , C(O)ORs, N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein each C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; 
 each R 7  is independently hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 each R 8  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heteroaryl(C 1 -C 6  alkyl), C 3 -C 8  cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents; 
 each R 9  is independently halogen, CN, N 3 , NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, NH 2 , NHC 1 -C 6  alkyl, N(C 1 -C 6  alkyl) 2 , or OC 1 -C 6  alkyl; 
 R 10  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heteroaryl(C 1 -C 6  alkyl), C 3 -C 8  cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 or more independently selected R 9  substituents; 
 each R 11  is independently hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl; and 
 both R 12 , together with the nitrogen atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or more independently selected R 9  substituents. 
 
     
     
         115 . The method of  claim 114 , wherein R 1  is C 1 -C 20  alkyl, wherein the C 1 -C 20  alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, and aryl, wherein each cycloalkyl, cycloalkenyl, and aryl is optionally and independently substituted with 1 or more independently selected R 9  substituents. 
     
     
         116 . The method of  claim 114 , wherein:
 R 1  is OR 7 ; and   R 7  is C 1 -C 6  alkyl.   
     
     
         117 . The method of  claim 114 , wherein R 2  is pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, morpholin-4-yl, or diazepan-1-yl, each optionally substituted with 1 or more independently selected R 9  substituents. 
     
     
         118 . The method of  claim 114 , wherein R 3  is C 1 -C 20  alkyl, C 1 -C 20  alkenyl, C 1 -C 20  alkynyl, or OR 7 , wherein the C 1 -C 20  alkyl, C 2 -C 20  alkenyl, and C 2 -C 20  alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C(O)N(R 8 ) 2 , C(O)OR 8 , N(R 8 ) 2 , OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 5  cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with 1 or more independently selected R 9  substituents. 
     
     
         119 . The method of  claim 114 , wherein R 3  is C 5 -C 20  alkyl, wherein the C 5 -C 20  alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, and aryl, wherein each cycloalkyl, cycloalkenyl, and aryl is optionally and independently substituted with 1 or more independently selected R 9  substituents. 
     
     
         120 . The method of  claim 114 , wherein R 3  is C 1 -C 20  alkyl, wherein the C 1 -C 20  alkyl is optionally-substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, and aryl, wherein each cycloalkyl, cycloalkenyl, and aryl is optionally and independently substituted with 1 or more independently selected R 9  substituents. 
     
     
         121 . The method of  claim 114 , wherein R 3  is C 10 -C 20  alkyl, wherein the C 10 -C 20  alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, and aryl, wherein each cycloalkyl, cycloalkenyl, and aryl is optionally and independently substituted with 1 or more independently selected R 9  substituents. 
     
     
         122 . The method of  claim 114 , wherein R 3  is heptadecyl. 
     
     
         123 . The method of  claim 114 , wherein R 6  is hydrogen. 
     
     
         124 . The method of  claim 114 , wherein R 6  is N(R 11 ) 2 . 
     
     
         125 . The method of  claim 114 , wherein the compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         126 . A method of treating or suppressing diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation, comprising administering to a subject in need of such treatment an effective amount a compound of formula: 
       
         
           
           
               
               
           
         
         wherein 
         X −  is a counterion; 
         R 1  is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, —OR 7 , —SR 7 , —NHR 7 , or —N(R 7 ) 2 , each optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), —OR 8 , —NR 8   2 , —CO 2 R 8 , —CONR 8   2 , C 3 -C 8  cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle are optionally substituted with one or more R 9 ;
 where each R 7  independently is hydrogen, C 1 -C 6  alkyl, or halo(C 1 -C 6  alkyl); 
 where each R 8  independently is hydrogen, C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 3 -C 8  cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6  alkyl), C 3 -C 8 cycloalkyl(C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heteroaryl(C 1 -C 6  alkyl), or heterocycle(C 1 -C 6  alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocycle are optionally substituted with one or more R 9 ; 
 where each R 9  independently is halogen, —CN, —NO 2 , —N 3 , C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, amino, C 1 -C 6 alkylamino, or diC 1 -C 6 alkylamino; 
 
         R 2  and R 6  are independently —N(R 11 ) 2 ;
 where each R 11  independently is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl; 
 
         R 3  is hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, or —OR 7 , each optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), —OR 8 , —NR 8   2 , —CO 2 R 8 , —CONR 8   2 , C 3 -C 8  cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle are optionally substituted with R 9 ; 
         R 4  and R 5  are independently C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl, each optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), —OR 8 , —NR 8   2 , —CO 2 R 8 , —CONR 8   2 , C 3 -C 8  cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle are optionally substituted with R 9 ;
 where R 10  is C 1 -C 6  alkyl, halo(C 1 -C 6  alkyl), C 3 -C 8  cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6  alkyl), C 3 -C 8 cycloalkyl(C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heteroaryl(C 1 -C 6  alkyl), or heterocycle(C 1 -C 6  alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocycle are optionally substituted with R 9 ; and 
 
         R 7  is hydrogen or —N(R 11 ) 2 . 
       
     
     
         127 . The method of  claim 126 , wherein R 1  is hydrogen, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl, optionally substituted C 2 -C 20  alkynyl, or —OR 7 . 
     
     
         128 . The method of  claim 126 , wherein R 2  is —N(R 11 ) 2 , where each R 11  independently is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl. 
     
     
         129 . The method of  claim 126 , wherein R 2  is —N(CH 3 ) 2 . 
     
     
         130 . The method of  claim 126 , wherein R 3  is hydrogen, optionally substituted C 1 -C 20  alkyl, or —OR 7 . 
     
     
         131 . The method of  claim 126 , wherein R 3  is C 5 -C 20  alkyl optionally substituted with —OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 . 
     
     
         132 . The method of  claim 126 , wherein R 3  is C 7 -C 20  alkyl optionally substituted with —OR 8 , C 3 -C 8  cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 . 
     
     
         133 . The method of  claim 126 , wherein R 3  is heptadecyl. 
     
     
         134 . The method of  claim 126 , wherein R 7  is hydrogen. 
     
     
         135 . The method of  claim 126 , wherein R 7  is —N(CH 3 ) 2 . 
     
     
         136 . The method of  claim 126 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         137 . The method of  claim 108 , wherein the disease is selected from the group consisting of Friedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-Sayre Syndrome, Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes, Leigh syndrome, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease and Parkinson's disease. 
     
     
         138 . The method of  claim 114 , wherein the disease is selected from the group consisting of Friedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-Sayre Syndrome, Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes, Leigh syndrome, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease and Parkinson's disease. 
     
     
         139 . The method of  claim 126 , wherein the disease is selected from the group consisting of Friedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-Sayre Syndrome, Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes, Leigh syndrome, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease and Parkinson's disease. 
     
     
         140 . A method for treating or protecting mitochondria with respiratory chain lesions, comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to  claim 108 . 
     
     
         141 . A method for treating or protecting mitochondria with respiratory chain lesions, comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to  claim 114 . 
     
     
         142 . A method for treating or protecting mitochondria with respiratory chain lesions, comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to  claim 126 .