Benzofurazan anti-amyloid compounds and methods

Abstract

In general, among other things, compounds of Formula I are provided: in which R 11 is selected from the group consisting of benzylamino, N-methylbenzylamino, morpholino, thiomorpholino, pyrrolidino, etc.; R 13 is selected from the group consisting of 3-(1-ethanol-2-yl)phenyl, 3-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, 2-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, etc.; and R 12 and R 14 are each independently hydrogen or alkyl. Methods of treatment are also provided.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in which
 R11 is selected from the group consisting of benzylamino, N-methylbenzylamino, N-methyl(4-fluorobenzyl)amino, N-methyl(4-methoxybenzyl)amino, N-methyl(3,5-dimethoxybenzyl)amino, N-methyl(pyridin-2-yl)amino, N-methyl(pyridin-3-yl)amino, piperidino, 4-methylpiperzin-1-yl, morpholino, thiomorpholino, pyrrolidino, 3-methylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, pyrrolidin-3-ol-1-yl, 2-(2-methanol-1-yl)pyrrolid-1-yl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, 2-(2-propanol-2-yl)pyrrolidin-1-yl, isoindolin-2-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, N,N-diethylamino, N-methyl-N-ethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-ethynylamino, N-(2-methoxyethyl)-N-methylamino, N-(thiazol-2-ylmethyl)-N-methylamino, azetidin-1-yl, 3-methyl-3-ol-azetidin-1-yl, 3-(ethanol-2-yl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, 3-ethoxyazetidin-1-yl, 3-isopropoxyazetidin-1-yl, 3-(2-propanol-2-yl)azetidin-1-yl, 3-(morpholinomethyl)azetidin-1-yl, 3-morpholinoazetidin-1-yl, 3-(pyyrolidin-1-yl)azetidin-1-yl, 3-(pyrrolidin-1-ylmethyl)azetidin-1-yl, 3-(1-methoxyethyl)azetidin-1-yl, N-(3-(N,N-dimethylamino)propyl)-N-methylamino, and 4-(N,N-dimethylamino)piperidin-1-yl; 
 R13 is selected from the group consisting of 3-(1-ethanol-2-yl)phenyl, 3-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, 2-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, 4-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, 3-(3-ol-oxetan-3-yl)phenyl, 3-methanonylphenyl, 3-((piperazin-1-yl)methanon-2-yl)phenyl, 3-((morpholin-1-yl)methanon-2-yl)phenyl, 3-((pyrrolidin-1-yl)methanon-2-yl)phenyl, 3-((N-cyclopropyl)amid-2-yl)phenyl, methanonyl, trifluoromethanonyl, 1-ol-2,2,2-trifluoroethan-2-yl, 3-ol-oxetan-3-yl, (1-ol-2,2,2-trifluoroethan-2-yl)thiophen-2-yl, 1-ol-prop-2-en-3-yl, 2-ol-but-3-en-4-yl, and 2-ol-2-trifluoromethyl-(1,1,1-trifluoro)but-3-en-4-yl; 
 and R12 and R14 are each independently hydrogen or alkyl. 
 
     
     
         2 . The compound Formula I of  claim 1 , in which R 11  is selected from the group consisting of benzylamino, N-methylbenzylamino, N-methyl(4-fluorobenzyl)amino, pyrrolidino, isoindolin-2-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, 3-methyl-3-ol-azetidin-1-yl, 3-(ethanol-2-yl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, and 3-ethoxyazetidin-1-yl; and R 13  is selected from the group consisting of 3-(1-ethanol-2-yl)phenyl and 3-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl. 
     
     
         3 . The compound Formula I of  claim 1 , in which R 11  is selected from the group consisting of benzylamino, N-methylbenzylamino, N-methyl(4-fluorobenzyl)amino, pyrrolidino, isoindolin-2-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, 3-methyl-3-ol-azetidin-1-yl, 3-(ethanol-2-yl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, and 3-ethoxyazetidin-1-yl. 
     
     
         4 . The compounds of  claim 1 , which have a percent inhibition of Aβ 40 (20 μm) of 65% or more. 
     
     
         5 . A method of treatment of an amyloid disease in a subject comprising administering a therapeutically effective amount of a compound of  claim 1  to the subject. 
     
     
         6 . The method of  claim 5  in which the amyloid disease is Alzheimer's disease. 
     
     
         7 . The method of  claim 5  in which the amyloid disease is progressive supranuclear palsy. 
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A method for treating a condition which is a member selected from loss of memory, loss of cognition and a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         10 . The method according to  claim 9 , wherein said condition is associated with Alzheimer's disease. 
     
     
         11 . The method according to  claim 9 , wherein a total daily dose of from about 0.0003 to about 50 mg/kg of body weight is administered. 
     
     
         12 . A method of treatment of an amyloid disease in a subject comprising administering a therapeutically effective amount of a compound of  claim 2  to the subject. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method for treating a condition which is a member selected from loss of memory, loss of cognition and a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 2 . 
     
     
         16 . A method for treating a condition which is a member selected from loss of memory, loss of cognition and a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 3 .