SMALL MOLECULE INHIBITORS OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE (mtPTP)

Abstract

The present technology relates to compounds of any one of Formula I, II, IIa, III, IV, and/or V as described herein and their tautomers and/or pharmaceutically acceptable salts, compositions, and methods of uses thereof.

1 . A compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Y 1  and W 1  are each independently 0, N, NH, NR 6 , S, CH, or CR 7 , or Y 1  and W 1  are each independently CR 8  or NR 8  where R 8  joins Y 1  and W 1  to form an aryl, heteroaryl, or heterocylyl ring; 
 Z 1 , Z 2 , and Z 3  are each independently CH, C—R 9 , or N; 
 m is 1 or 2; 
 G 1  is C═O, C═S, SO, or SO 2 ; 
 R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 9  are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 9  together form an aryl, heteroaryl, or heterocyclyl ring; and 
 R 3  is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl. 
 
       
     
     
         2 . The compound of  claim 1 , wherein the compound of Formula I is a compound of Formula II or III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Y 1  is O, NH, NR 6 , or S; 
 W 1  is N, CH, or CR 7 ; 
 G 2  is C═O, C═S, SO, or SO 2 ; 
 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  together form an aryl, heteroaryl, or heterocyclyl ring; and 
 R 20  is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl. 
 
       
     
     
         3 . The compound of  claim 1 , wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 9  are independently at each occurrence hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkenyl, C 2 -C 8  alkynyl, aryl, cyano, carboxyl, carboxyl ester, acyl, formyl, C 3 -C 7  heteroaryl, or C 3 -C 7  heterocyclyl, or two adjacent R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 9  together form an aryl, heteroaryl, or heterocyclyl ring. 
     
     
         4 . The compound of  claim 2 , wherein the compound of Formula II is a compound of Formula IIa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 21  is H, F, Cl, or alkoxy. 
       
     
     
         5 . The compound of  claim 4 , wherein R 21  is H, F, Cl, or methoxy. 
     
     
         6 . The compound of  claim 2 , wherein Y 1  is O and W 1  is N or Y 1  is NH and W 1  is N. 
     
     
         7 . The compound of  claim 2 , wherein Z 1  is CH. 
     
     
         8 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         9 . The composition of  claim 8 , wherein the compound of Formula I is a compound of Formula II or III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Y 1  is O, NH, NR 6 , or S; 
 W 1  is N, CH, or CR 7 ; 
 G 2  is C═O, C═S, SO, or SO 2 ; 
 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  together form an aryl, heteroaryl, or heterocyclyl ring; and 
 R 20  is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl. 
 
       
     
     
         10 . The composition of  claim 9 , wherein the compound of Formula II is a compound of Formula IIa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 21  is H, F, Cl, or alkoxy. 
       
     
     
         11 .- 12 . (canceled) 
     
     
         13 . A method for treating a disease in a subject, wherein the method comprises administering an effective amount of a compound of  claim 1 , to the subject, wherein the disease is multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis (type A, and/or B, and/or C), type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, and/or stroke. 
     
     
         14 . The method of  claim 13 , wherein the compound of Formula I is a compound of Formula II or III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Y 1  is O, NH, NR 6 , or S; 
 W 1  is N, CH, or CR 7 ; 
 G 2  is C═O, C═S, SO, or SO 2 ; 
 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two adjacent R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  together form an aryl, heteroaryl, or heterocyclyl ring; and 
 R 20  is hydrogen, alkyl, cycloalkyl, alkenyl, or alkynyl. 
 
       
     
     
         15 . The method of  claim 14 , wherein the compound of Formula II is a compound of Formula IIa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 21  is H, F, Cl, or alkoxy. 
       
     
     
         16 . A method for inhibiting the mitochondrial permeability transition pore, wherein the method comprises contacting a cell with an effective amount of a compound of  claim 1 . 
     
     
         17 . A method for treating a condition in a subject, wherein the method comprises administering to a patient an effective amount of a compound of  claim 1 ; and the condition in the subject is mediated at least in part by [Ca 2+ ] dysregulation and/or a reactive oxygen species. 
     
     
         18 . A method for treating multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis, type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, and/or stroke, wherein the method comprises administering to a patient a composition of  claim 8 . 
     
     
         19 . A compound according to Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Y 2  is O, NH, NR 25 , or S; 
 W 2  is N, CH, or CR 26 ; where when Y 2  is NR 25  and W 2  is CR 26  then R 25  and R 26  may optionally join Y 2  and W 2  to form an aryl, heteroaryl, or heterocylyl ring; 
 Z 4 , Z 5 , and Z 6  are each independently CH, C—R 27 , or N; and 
 R 22 , R 23 , R 24 , R 25 , R 26 , and R 27  are independently at each occurrence hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkoxy, alkynyl, amino, aminosulfinyl, aminosulfonyl, sulfinyl, sulfonyl, sulfonyloxy, aminosulfonyloxy, aminosulfinyloxy, aminosulfonylamino, acylamino, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl, acyloxy, aryl, heteroaryl, cyano, nitro, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, acyl, or formyl; or two R 22 , R 23 , R 24 , R 25 , R 26 , and R 27  together form an aryl, heteroaryl, or heterocyclyl ring. 
 
       
     
     
         20 . A composition comprising a compound of  claim 19  and a pharmaceutically acceptable excipient. 
     
     
         21 . (canceled) 
     
     
         22 . The composition of  claim 20 , wherein the compound is present in an amount effective for the treatment of multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis, type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, and/or stroke. 
     
     
         23 . A method for treating a disease in a subject, wherein the method comprises administering an effective amount of a compound of  claim 19 , to the subject, wherein the disease is multiple sclerosis, amyotropic lateral sclerosis, ischemic reperfusion injury, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-induced hypoglycemia, cerebral ischemia, brain damage from epilepsy or experimental trauma, Bethlem myopathy, pancreatitis, hepatitis, type II diabetes, diabetic retinopathy, muscular dystrophy, traumatic brain injury, heart infarction, and/or stroke.